Clinical trial NCT02812771
Conditions: Onychomycosis
Sponsor: Bausch Health Americas, Inc.
Start date: 2016-08-04; Completion date: 2019-01-14
Enrollment: 62 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Safety and Pharmacokinetics (PK) of a once daily topical application of efinaconazole in the treatment of pediatric subjects with mild to severe onychomycosis of the toenails.

Detailed description:
This is an open label, single-arm study designed to evaluate the safety and PK of a once daily topical application of efinaconazole in the treatment of pediatric subjects with mild to severe onychomycosis of the toenails.

Arms: arm 1: Efinaconazole
Interventions: intervention 1: Efinaconazole
Intervention descriptions: intervention 1: Solution

Protocol documents:
Prot_SAP_000.pdf: 
NCT02812771 
Clinical Study Protocol 
Efinaconazole 1 Oo/o Topical Solution 
Protocol VOl-lOSA-401
A Multicenter, Open Label, Single-arm Study Evaluating the 
Safety and Phrumacokinetics of Efinaconazole 10% Topical 
Solution in Subjects with Mild to Severe Onychomycosis of the 
Toenails 
Development phase of study: 
Study design: 
Date: 
Sponsor: 
4 
Multi center, open label , single-arm, safety 
and pharmacokinetics study 
May 10, 2016 
Dow Pharmaceutical Sciences, a wholly 
owned subsidiary of Valeant 
Pharmaceuticals International 
1330 Redwood Way, Suite C 
Petaluma, CA 94954 
CO FIDENTIAL 
Notbingherein is to be disclosed without prior approval of the 
sponsor. 
VA LEANT 
Research 
& 
Development 


Pr ot oc o l V 0 1 -1 0 8 A -4 0 1,  Efi n ac o naz ole  Pe diatric  Safet y a n d P K  St u d y  
V nlca nt Researc h &  De v el o p me nt  
 
 
Pr ot oc ol R e vi e w a n d A p pr o v als  
 
A M ulti ce ntcr, O p e n L a b el, Si n gl e -ar m St u d y E v al u ati n g t h e S af et y a n d 
P h ar m a c o ki n eti cs of Efi n ac o n az ol e 1 0 % T o pi cal S ol uti o n i n S u bje cts wit h Mil d t o 
S e v er e O n y c h o m y c osis of t h e T o e n ails  
 
 
R e vi e w e d a n d a p p r o v e d:  
 
 
 
 
 
 
 
 
 
 
 
 
 
2 0/ k'  
 
 
 
 
 
D t; - I \ • 2 0{ 6  
D at e  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical  St u d y  Pr ot o c ol,  I O Ma y  20 1 6  
C O N FI D E N TI A L  
 
2  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
3  
 
 
 
Pers o n nel Res p o nsi ble f or C o n d ucti n g t he St u d y  
 
A M ultice nter, O pe n L a bel, Si n gle - ar m St u d y E v al u ati n g t he S afet y a n d 
P h ar m ac o ki netics of Efi n ac o n az ole 1 0 % T o pic al S ol uti o n i n S u bjects wit h Mil d t o 
Se vere O n yc h o m yc osis of t he T oe n ails  
S p o ns or  
D o w P har mace uticals Scie nces, a w h oll y o w n e d s u bsi diar y of 
Valea nt P har mace uticals I nter nati o nal  
1 3 3 0 Re d w o o d Wa y, S uite C 
Petal u ma, C A 9 4 9 5 4  
 
 
 
St u d y M a n a ger 
 
4 0 0 S o merset C or p orate B o ule var d 
Bri d ge water, NJ  0 8 8 0 7  
Tele p h o ne: 
 
 
Gl o b al S afet y a n d Vi gil a nce  
C o nt act f or Re p orti n g Seri o us A d verse E ve nts  
 
 
4 0 0 S o merset C or p orate B o ule var d 
Bri d ge water, NJ 0 8 8 0 7  
Tele p h o ne: 
 
 
Fa x: 
 
S A E I n b o x: 
 
 
Ret ur n of Use d a n d U n use d St u d y Dr u g  
Cli nical Trial Materials 
S u p pl y C hai n, Area 5 6 
1 4 0 0 N ort h G o o d ma n Street 
R oc hest er, N Y 1 4 6 0 9 
 
C o ntract Resear c h Or g a nizati o n/ Me dical M o nit or  
 
Me d Tri als, I nc.  
 
 
 
 
2 6 2 6 C ole A ve.  
S uite 4 0 0  
Dallas, T X 7 5 2 0 4  
 
Tele p h o ne:  
 
M o bile:  
 
E mail:  
 
 
 
 
T ele p h o ne: 
 
 
Fa x:  
 
E mail:  
 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4  
 
 
 
Pri nci p al I n vesti g at or Pr ot oc ol A gree me nt P a ge  
I a gree: 
•  T o ass u me res p o nsi bilit y f or t he pr o per c o n d u ct of t his cli nical st u d y at t his site a n d t o 
c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, a n y f ut ure a me n d me nts, a n d wit h 
a n y ot her st u d y c o n d uct pr oce d ures pr o vi de d b y t he  s p o ns or. 
•  T hat I a m a w are of, a n d will c o m pl y wit h, t he i nter nati o nall y rec o g nize d c o de of G o o d 
Cli nical Practices ( G C P) a n d all ot her a p plica ble re g ulat or y re q uire me nts t o o btai n 
writte n a n d date d a p pr o v al fr o m t he I nstit uti o nal or Ce ntral Re vie w B oar d (I R B) or 
I n d e pe n de nt Et hics C o m mittee (I E C) f or t he st u d y pr ot oc ol, writte n i nf or me d c o nse nt, 
c o nse nt f or m u p dates, s u bject -recr uit me nt pr oce d ures (e g, a d vertise me nts), a n d a n y 
ot her writte n i nf or mati o n t o be pr o vi de d t o t he s u bjects, bef ore i nitiati n g t his cli nical 
st u d y. 
•  N ot t o i m ple me nt a n y c ha n ges t o, or de viati o ns fr o m t he pr ot oc ol wit h o ut pri or 
a gree m e nt fr o m t he s p o ns or a n d re vie w a n d d o c u me nte d a p pr o val fr o m t he  I R B/I E C, 
e xce pt t o eli mi nate a n i m me diate hazar d t o t he st u d y s u bjects, or w he n c ha n ge(s) 
i n v ol ves o nl y l o gistical or a d mi nistrati ve as pects of t he cli nical  st u d y. 
•  T o per mit direct m o nit ori n g a n d a u diti n g b y t he s p o ns or or s p o ns or’s re pres e ntati ves 
a n d i ns pecti o n b y t he a p pr o priate re g ulat or y  a ut h orit y(ies).  
•  T hat I a m t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he i n vesti gati o nal 
pr o d ucts(s), as d escri be d i n t his pr ot oc ol, a n d a n y ot her i nf or mati o n pr o vi d e d b y t he 
s p o ns or or desi g nee, i n cl u di n g, b ut n ot li mite d t o, t he c urre nt I n vesti gat or Br oc h ure or 
e q ui vale nt d oc u me nt a n d a p pr o ve d pr o d u ct la bel (if  a p plica ble).  
•  T o pr o vi de s ufficie nt ti m e a n d a d e q uate n u m bers of q ualifie d staff a n d facilities f or  t he 
f oresee n d urati o n of t he cli nical st u d y t o c o n d uct t he st u d y pr o perl y, et hicall y, a n d 
safel y. 
•  T o e ns ure t hat all pers o ns assisti n g i n t his st u d y are a de q u atel y i nf or me d a b o ut t he 
pr ot oc ol, i n vesti gati o nal pr o d uct(s), a n d t h eir cli nical st u d y -relat e d d uties a n d 
f u ncti o ns. 
 
 
Pri nci pal I n v esti gat or ( pri nt na me)  
 
 
Pri nci pal  I n vesti gat or (si g nat ure) 
Date  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5  
 
 
 
2  S y n o psis  
 
N a m e of S p o ns or/ C o m p a n y:  
D o w P h ar m ace utic als Scie nces, a w h oll y o w ne d s u bsi di ar y of V ale a nt 
P h ar m ace utic als I nter n ati o n al  
N a m e of i n vesti g ati o n al pr o d uct:  
Efi nac o naz ole 1 0 % T o pical S ol uti o n  
N a m e of acti ve i n gre die nt:  
Efi nac o naz ole  
Title of st u d y:  
A M ultice nter, O pe n La bel, Si n gle -ar m St u d y E val uati n g t he Safet y a n d P har mac o ki netics of Efi nac o naz ole 
1 0 % T o pical S ol uti o n i n S u bjects wit h Mil d t o Se vere O n yc h o m yc osis of t he T oe nails  
N u m ber of cli nic al ce nters:  
A p pr o xi matel y 1 0 -1 5 i n vesti gati o nal ce nters i n t he U nite d States, a n d t he Cari b bea n  
O bjecti ves:  
T he pri mar y o bjecti ves of t his st u d y are t o e val uate: 1) safet y of o nce dail y t o picall y a d mi nistere d 
efi nac o naz ole 1 0 % f or 4 8 wee ks i n pe diatric s u bjects ( 6 -1 6 years of a ge) wit h at least mil d o n yc h o m yc osis of 
t he t oe nails, a n d 2) p har mac o ki netics P K ( 4 wee ks) of o nce dail y t o picall y a d mi nistere d efi nac o naz ole 1 0 % 
i n pe diatric s u bjects ( 1 2-1 6 years of a ge) wit h m o derate t o se vere o n yc h o m yc osis of t he t oe nails.  
Met h o d ol o g y:  
T his is a n o pe n la bel, si n gle -ar m st u d y d esi g ne d t o e val uate t he safet y a n d P K of a o nce dail y t o pical 
a p plicati o n of efi nac o naz ole i n t he treat me nt of pe diatric s u bjects wit h mil d t o se vere o n yc h o m yc osis of t he 
t oe nails. T he st u d y will i ncl u de s u bjects 6 t o 1 6 years of a ge, i ncl usi ve, b ut P K assess me nts will o nl y be 
perf or me d o n s u bjects 1 2 t o 1 6 years of a ge, i ncl usi ve (referre d t o t hr o u g h o ut t he pr ot oc ol as t he P K s u bset). 
All s u bjects m ust ha ve o n yc h o m yc osis of at least 1 great t oe nail; s u bjects i n t he P K s u bset m ust ha ve 
o n yc h o m yc osis of b ot h  great t oe nails a n d at least 4 ot her t oe nails. Eff orts will be ma de t o e nr oll s u bjects i nt o 
t he P K s u bset s uc h t hat t he s u bjects are e ve nl y distri b ute d acr oss t he re q uire d a ge ra n ge. 
F or s u bjects n ot partici pati n g i n t he P K s u bset, t he st u d y will c o nsist o f 1 4 sc he d ule d visits, i ncl u di n g 
Scree ni n g ( u p t o Da y -4 2), Baseli ne ( Da y 1), 1 2 treat me nt visits ( Wee ks 4, 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 
4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( We e k 5 2). S u bjects i ncl u de d i n t he P K s u bset will 
atte n d t he sc he d ule d visits u p t o Wee k 4 a n d a n a d diti o nal st u d y visit at Da y 2 9 f or c ollecti o n of t he fi nal P K 
bl o o d sa m ple. T he P K assess me nts will be perf or me d u n der ma xi mal use c o n diti o ns. O nce P K assess me nts 
are c o m plete at Da y 2 9, t he P K s u bset of s u bject s will c o nti n ue treat me nt t hr o u g h wee k 4 8 wit h a d diti o nal 
visits at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit  
( Wee k 5 2). 
At t he Scree ni n g Visit, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will si g n a n i nf or me d c o nse nt/asse nt 
f or m a n d a p h ot o gra p h y c o nse nt/asse nt f or m, pr o vi de t heir me dical hist ories, re p ort t heir pre vi o us a n d 
c o nc o mita nt me dicati o ns, a n d be e val uate d a gai nst t he i ncl usi o n/e xcl usi o n criteria. Fe males of c hil d beari n g 
p ote ntial ( F O C B P) will ha ve uri ne pre g na nc y tests perf or me d. D uri n g t his visit, s u bjects will u n der g o a n 
e xa mi nati o n of t heir feet t o vis uall y ascertai n t he prese nce of o n yc h o m yc osis i n at least 1 great t oe nail f or 
s u bjects n ot i ncl u de d i n t he P K assess me nts, a n d o n b ot h great t oe nails a n d at least 4 ot her t oe nails f or 
s u bjects i ncl u de d i n t he P K assess me nts. A d diti o nall y, t he perce nt i n v ol ve me nt of t he affecte d great 
t oe nail(s) will be rec or de d. A direct micr osc o pic e xa mi nati o n f or t he h y p hae ass ociate d wit h der mat o p h ytes 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6  
 
 
 
 
will be perf or me d at t he i n vesti gati o nal ce nter usi n g p otassi u m h y dr o xi de ( K O H) o n t oe nail scra pi n gs 
c ollecte d fr o m t he affecte d great t oe nail(s) (ie, at least 1 great t oe nail f or all s u bjects a n d b ot h great t oe nails 
f or s u bjects i n t he P K s u bset). S u bjects wit h K O H-p ositi ve t oe nail sa m ples will pr o vi de a d diti o nal sa m ples 
fr o m t he affecte d great t oe nail(s) f or K O H e xa mi nati o n a n d m yc ol o gical c ult ure (c o n d ucte d at a ce ntral 
m yc ol o g y la b orat or y). Bl o o d a n d uri ne s peci me ns will be c ollecte d f or ser u m c he mistr y , he mat ol o g y, a n d 
uri nal ysis e val uati o ns. At rele va nt p ost -Scree ni n g Visits, t he tar get great t oe nail will be tri m me d bac k t o t he 
distal gr o o ve bef ore t he cli nical e val uati o ns are perf or me d a n d bef ore p h ot o gra p hs are ta ke n.  
At t he Baseli ne Visit ( w hic h s h oul d be sc he d ule d after K O H a n d f u n gal c ult ure res ults ha ve bee n o btai ne d 
fr o m t he m yc ol o g y la b), s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will u p date t heir me dical hist ories a n d 
c o nc o mita nt me dicati o n uses, a n d t he i ncl usi o n/e xcl usi o n criteria will be  c o nfir me d. S u bjects will u n der g o 
a b bre viate d p h ysical e xa mi nati o ns, cli nical la b orat or y e val uati o ns, assess me nts of vital si g ns (sitti n g bl o o d 
press ure, res pirati o n, p ulse, a n d te m perat ure), a n d meas ure me nts of hei g ht a n d wei g ht. All F O C B P will ha ve 
uri ne  pre g na nc y tests perf or me d. F or t he p ur p oses of efficac y assess me nts, 1 tar get great t oe nail will be 
selecte d fr o m t he st u d y-eli gi ble great t oe nail(s), i ncl u di n g s u bjects i n t he P K s u bset f or w h o m b ot h great 
t oe nails m ust be i n v ol ve d. W here b ot h great t oe n ails are st u d y -eli gi ble, t he t oe nail wit h t he greater perce nt of 
affecte d area will be selecte d f or m yc ol o gic data a n d f or i ncl usi o n i n t he efficac y a nal ysis. I n t he i nsta nce 
w here t he perce nt of affecte d area is t he sa me f or b ot h st u d y-eli gi ble great t oe n ails, t he i n vesti gat or ma y 
select eit her great t oe nail as t he tar get t oe nail. T he tar get great t oe nail will be i de ntifie d a n d rec or de d f or eac h 
s u bject, p h ot o gra p hs of t he tar get great t oe nail will be o btai ne d, a n d a tra ns verse n otc h will be i nscri be d i n 
the tar get great t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d (as a mar ker f or meas uri n g t oe nail gr o wt h at 
s u bse q ue nt visits). Assess me nts of all ot her n o ntar get t oe nails, i ncl u di n g t he ot her i n v ol ve d t oe nails of 
s u bjects i n t he P K s u bset, will als o be c o n d ucte d t o assess t he prese nce or a bse nce of o n yc h o m yc osis o n eac h 
t oe nail. T his assess me nt will c o nti n ue t hr o u g h o ut t he st u d y visits t hr o u g h wee k  5 2.  
After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit, s u bjects will be e nr olle d i n t he treat me nt peri o d. S u bjects or 
t heir pare nts/le gal g uar dia ns will a p pl y t he first d ose of st u d y dr u g t o t he q ualifie d t oe nails at t he 
i n vesti gati o nal ce nter u n der t he s u per visi o n of desi g nate d st u d y pers o n nel. A n y l ocal s ki n reacti o ns t hat  
occ ur at t he st u d y dr u g a p plicati o n site, al o n g wit h a n y a d verse e ve nts ( A Es), will be rec or de d. S u bjects or 
t heir pare nts/le gal g uar dia ns will recei ve wei g he d st u d y dr u g b ottles a n d gi ven ver bal a n d writte n 
i nstr ucti o ns f or treat me nt a p plicati o n. S pecificall y, s u bjects w h o are n ot i ncl u de d i n t he P K s u bset will be 
i nstr ucte d t o a p pl y t he st u d y dr u g t o t he affecte d t oe nails o nce dail y at be dti me f or 4 8 wee ks. S u bjects w h o 
are i ncl u de d i n t he P K s u bset will be i nstr ucte d t o a p pl y t he st u d y dr u g t o all 1 0 t oe nails o nce dail y at 
be dti me f or 4 wee ks. F oll o wi n g t he P K bl o o d c ollecti o ns o n Da ys 2 8 a n d 2 9, t hese s u bjects will be i nstr ucte d 
t o c o nti n ue treat me nt wit h st u d y dr u g t o o nl y t he affecte d t oe nails a n d ret ur n t o t he i n vesti gati o nal ce nter at 
Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 5 2). 
All s u bjects or t heir pare nts/le gal g uar dia ns will als o recei ve diaries, wit h i nstr ucti o ns t o c o m plete a rec or d of 
all a p plicati o ns a n d t o n ote a n y misse d a p plicati o ns of t he st u d y dr u g.  
S u bjects i n t he P K s u bset will n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( Da y 2 8) visit. F oll o wi n g 
t he Da y 2 8 st u d y pr oce d ures, s u bjects i n t he P K s u bset will u n der g o ti me d bl o o d c ollecti o ns t o assess plas ma 
c o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4). Assess me nts will re q uire c ollecti o n of 
a p pr o xi matel y 4 m L of w h ole bl o o d at eac h ti me p oi nt (a p pr o xi matel y 2 0 m L t otal). Wit hi n 1 h o ur after  t he 
pre d ose bl o o d sa m ple is dra w n, t he s u bjects/ pare nts/le gal g uar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails at 
t he i n vesti gati o nal ce nter. S u bse q ue nt bl o o d c ollecti o ns will occ ur 2, 4, a n d 1 2 h o urs p ost d ose o n Da y 2 8. 
T he s u bjects will g o h o me after Da y 2 8, b ut will n ot a p pl y st u d y dr u g o n t he ni g ht of t he Da y 2 8 visit. P K 
s u bjects will ret ur n t o t he i n vesti gati o nal ce nter t he f oll o wi n g da y ( Da y 2 9) f or c ollecti o n of a 2 4 -h o ur 
p ost d ose bl o o d sa m ple. P K s u bjects will c o nti n ue treat me nt wit h st u d y dr u g t o o nl y t he tar get great t oe nail 
a n d t he ot her affecte d t oe nails a n d ret ur n t o t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6,  
4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 5 2).  
Safet y will be assesse d b y re vie wi n g t he occ urre nce of A Es a n d l ocal s ki n reacti o ns, assessi n g vital si g n 
meas ure me nts a n d a b bre viate d p h ysical e xa mi nati o n fi n di n gs, a n d n oti n g a n y a d diti o ns or c ha n ges i n 
c o nc o mita nt me dicati o n uses. Bl o o d sa m ples will be c ollecte d at Scree ni n g a n d Wee k 4 8 f or r o uti ne safet y 
la b orat or y e val uati o ns (ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis); uri ne pre g na nc y tests will be o btai ne d 
f or all F O C B P at eac h st u d y visit. Efficac y assess me nts will be perf or me d t hr o u g h o ut t he st u dy. T he efficac y 
a nal yses will be base d o n micr osc o pic e xa mi nati o n a n d m yc ol o gical c ult ure res ults f or t he tar get great  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
7  
 
 
 
 
t oe nail, t he perce nt i n v ol ve me nt of t he tar get great t oe nail, t he le n gt h of t he u naffecte d part of t he tar get great 
t oe nail, t he gr o wt h of t he tar get great t oe nail, a n d t he n u m ber of affecte d n o ntar get t oe nails. 
N ote t hat gr o wt h of t he tar get great t oe nail will be meas ure d b y i nscri bi n g a tra ns verse n otc h, at t he ce nter of 
t he t oe nail, i n t he t oe nail a djace nt t o t he pr oxi mal t oe nail f ol d at Baseli ne a n d meas uri n g t oe nail gr o wt h fr o m 
t hat p oi nt f or war d. At e ver y s u bse q ue nt visit, t he dista nce bet wee n t he pr o xi mal t oe nail f ol d a n d t he n otc h 
will be meas ure d a n d rec or de d. A ne w n otc h will be i nscri be d i n t he t oe nail a djace n t t o t he pr o xi mal t oe nail 
f ol d if t he i nitiall y a p plie d n otc h gr o ws o ut d uri n g t he c o urse of t he st u d y. 
A p ost -treat me nt f oll o w-u p visit will occ ur 4 wee ks after t he last treat me nt visit f or eac h s u bject (ie, at Wee k 
5 2). S u bjects w h o disc o nti n ue fr o m t he st u d y pri or t o Wee k 4 8 will c o m plete t he Wee k 4 8 st u d y pr oce d ures. 
N u m ber of s u bjects pl a n ne d: 
A p pr o xi matel y 6 0 s u bjects t otal 
A p pr o xi matel y 2 0 s u bjects i n t he P K s u bset  
Di a g n osis a n d criteri a f or i ncl usi o n:  
1.  Male or fe male s u bjects of a n y race, 6 t o 1 6 years of a ge (i ncl usi ve).  
•  
P K S u bset: Male or fe male s u bjects of a n y race, 1 2 t o 1 6 years of a ge (i ncl usi ve). 
2.  Ver bal a n d writte n i nf or me d c o nse nt/asse nt o btai ne d fr o m t he s u bject a n d/ or t heir pare nt or le gal 
g uar dia n.  
3.  G o o d ge neral healt h, as assess e d b y t he i n vesti gat or, base d o n t he s u bject’s me dical hist or y, 
p h ysical e xa mi nati o n, a n d safet y la b orat or y  tests. 
4.  At least 1 great t oe nail (t he “tar get great t oe nail”) wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at least 2 0 % of t he affecte d great t oe nail at t he Scree ni n g a n d Baseli ne 
Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut der mat o p h yt o mas or l u n ula ( matri x) 
i n v ol ve me nt. U p t o 6 t oe nails ma y ha ve o n yc h o m yc osis.  
•  
P K S u bset: B ot h great t oe nails wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at least 5 0 % of t he affecte d great t oe nail at t he Scree ni n g a n d 
Baseli ne Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut der mat o p h yt o mas or l u n ula 
( matri x) i n v ol ve me nt. S u bjects m ust als o ha ve at least 4 t oe nails ot her t ha n t he great 
t oe nails wit h  o n yc h o m yc osis.  
5.  Tar get great t oe nail f or all s u bjects, a n d b ot h great t oe nails f or s u bjects i n t he P K s u bset, m ust ha ve 
e v i de nce of t oe nail gr o wt h, per s u bject’s re p ort t hat m o nt hl y cli p pi n g is nee de d.  
6.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( Da y 1) Visit, ha ve a p ositi ve K O H e xa mi nati o n (at t he 
i n vesti gati o nal ce nter a n d c o nfir me d b y t he m yc ol o g y la b) of t he tar get great t oe nai l f or all s u bjects, 
7.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( Da y 1) Visit, ha ve a p ositi ve der mat o p h yte c ult ure f or 
Tric h o p hyt o n r u br u m or Tric h o p hyt o n me nt a gr o p hytes (at t he ce ntral m yc ol o g y la b orat or y) fr o m 
t he tar get great t oe nail i n all s u bjects 
•  
P K S u bset : Pri or t o t he Baseli ne Visit, t he great t oe nail desi g nate d f or efficac y 
assess me nts as t he tar get great t oe nail m ust ha ve b ot h a p ositi ve K O H e xa mi nati o n 
(c o nfir me d b y t he m yc ol o g y la b) a n d a p ositi ve f u n gal c ult ure.  
8.  All F O C B P m ust ha ve a ne gati ve uri ne pre g na nc y test at t he Scree ni n g a n d Baseli ne Visits a n d m ust 
a gree t o use a n effecti ve met h o d of c o ntrace pti o n t hr o u g h o ut t he st u d y. Effecti ve c o ntrace pti o n is 
defi ne d as use of a n i ntra uteri ne de vice, c o n d o m wit h s per mici de, dia p hra g m wit h s per mici de, 
a bsti ne nce (s u bject is n ot se x uall y acti ve), or sta ble use of a h or m o nal c o ntrace pti ve ( oral, i m pla nt, 
i njecti o n, or tra ns der mal patc h) f or at least 3 m o nt hs pri or t o t he Baseli ne  Visit.  
9.  S u bjects a n d t heir pare nts/le gal g uar dia ns are willi n g t o c o m pl y wit h st u d y i nstr ucti o ns a n d ret ur n t o 
t he i n vesti gati o nal ce nter f or all re q uire d visits (a visit sc he d ule wit h t he le n gt h of eac h visit will be 
pr o vi de d t o e ns ure t hat t he s u bject ca n meet the re q uire me nts a n d ha ve a de q uate  tra ns p ortati o n). 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
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1 0. S u bject a n d t heir pare nts/le gal g uar dia ns a gree t hat t he s u bject will a v oi d t he use of t oe nail p olis h, 
c os metic t oe nail pr o d ucts, a n d pe dic ures d uri n g t he st u d y peri o d.  
E xcl usi o n criteri a:  
1.  Fe males w h o are pre g na nt, n ursi n g a n i nfa nt, or pla n ni n g a pre g na nc y d uri n g t he st u d y  peri o d.  
2.  Hist or y of i m m u n os u p pressi o n a n d/ or cli nical si g ns i n dicati ve of p ossi ble i m m u n os u p pressi o n, as 
deter mi ne d b y t he i n vesti gat or, or k n o w n h u ma n  i m m u n o deficie nc y vir us i nfecti o n. 
3.  Hist or y of dia betes t hat is u nc o ntr olle d as deter mi ne d b y t he i n vesti gat or ( dia betes t hat is c o ntr olle d 
b y diet or me dicati o n d oes n ot e xcl u de a  s u bject). 
4.  Prese nce of a n y t oe nail i nfecti o n ot her t ha n or i n a d diti o n t o dermat o p h ytes, s uc h as Scyt ali di u m as 
deter mi ne d b y t he i n vesti gat or (ca n di dal o n yc h o m yc osis i nfecti o n, c o nc urre nt wit h a p ositi ve 
der mat o p h yte c ult ure, is  acce pta ble).  
5.  Prese nce of a n y of t he f oll o wi n g: der mat o p h yt o ma, f u n gal “s pi kes” wit hi n 3 m m of t he pr o ximal 
t oe nail f ol d o n t he tar get great t oe nail, i nfecti o n e xte n di n g t o t he matri x, or o nl y lateral t oe nail 
disease i n t he tar get great  t oe nail. 
6.  Prese nce of se vere m occasi n ti nea pe dis at t he Scree ni n g or Baseli ne Visits, as deter mi ne d b y t he 
i n vesti gat or (if i nter di gital ti nea pe dis re q uires treat me nt d uri n g t he st u d y, t he s u bject m ust a gree t o 
use o nl y a n i n vesti gat or -a p pr o ve d t o pical a ntif u n gal t hera p y). 
7.  Prese nce of a n y disease/c o n diti o n t hat mi g ht ca use t oe nail a b n or malities or ma y i nterfere wit h t he 
e val uati o n of t he st u d y dr u g as deter mi ne d b y t he i n vesti gat or (e g, o pe n s ores or ulcerati o n o n t he 
t oes of affecte d t oe nails, ps oriasis, i m m u ne d ysf u ncti o n, c olla ge n-va sc ular diseases, lic he n pla n us, 
peri p heral vasc ular disease, or tra u matic o n yc h o d ystr o p h y d ue t o c hr o nic p h ysical sti m uli). 
8.  A n y pre vi o us s ur ger y o n t he tar get great t oe nail. 
9.  Prese nce of o n yc h o m yc osis of t he  fi n ger nail. 
1 0.  Hist or y of i m m u n o deficie nc y as deter m i ne d b y t he i n vesti gat or. 
1 1.  Prese nce of 1 -ha n d, 2 -f o ot s y n dr o me, or fi n ger nail der mat o p h yt osis.  
1 2.  Tar get great t oe nail (i ncl u di n g t oe nail plate a n d a n y s u b u n g ual de bris) t hic ker t ha n 3 m m at t he 
Scree ni n g a n d Baseli ne  Visits.  
1 3.  Prese nce of o n yc h o d ystr o p h y t hat c o ul d i nterfere wit h cli nical assess me nts as deter mi ne d b y t he 
i n vesti gat or. 
1 4.  Hist or y of h y perse nsiti vit y or aller gic reacti o ns t o az ole deri vati ves or a n y of t he st u d y dr u g 
c o nstit ue nts.  
1 5.  Prese nce of a n y u n derl yi n g disease t hat, i n t he o pi ni o n of t he i n vesti gat or, c o ul d prese nt a safet y 
c o ncer n f or t he s u bject b y partici pati n g i n t he  st u d y. 
1 6.  S u bject has recei ve d treat me nt f or a n y t y pe of ca ncer i n t he pre vi o us 6 m o nt hs, e xce pt f or 
n o n mela n o ma s ki n ca nce r (e g, basal cell carci n o ma or n o n metastatic s q ua m o us cell carci n o ma) t hat 
was treate d  s uccessf ull y. 
1 7.  Prese nce of a n y der mat ol o gical c o n diti o n o n t he feet t hat c o ul d i nterfere wit h cli nical e val uati o ns as 
deter mi ne d b y t he i n vesti gat or. 
1 8.  Prese nce of a n y u n derl yi n g disease or der mat ol o gical c o n diti o n ot her t ha n o n yc h o m yc osis t hat 
re q uires t he use of i nterferi n g t o pical or s yste mic t hera p y a n d w o ul d ma ke e val uati o ns i nc o ncl usi ve 
as deter mi ne d b y t he i n vesti gat or, or s u bject re q uires treat me nt wit h a t o pical pr o d uct o n t he t oe nails 
ot her t ha n t he st u d y dr u g d uri n g t he  st u d y. 
1 9.  S u bjects usi n g t he f oll o wi n g t o pical pre parati o ns wit hi n t he i n dicate d ti me pri or t o t he Baseli ne 
Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g t o pical pre parati o ns d uri n g t he st u d y: 
•  
T oe nail p olis h, c os metic t oe nail pr o d ucts, or t o pical prescri pti o n or o ver -t he-c o u nter 
a ntif u n gal t hera p y f or ti nea pe dis: 1 da y  
•  
Ot her t o pical prescri pti o n or o ver -t he-c o u nter me dicati o ns t o t he feet or t oe nails ( wit h t he 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
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Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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e xce pti o n of bla n d e m ollie nts): 2 wee ks  
•  
T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t oe nails, i ncl u di n g 
de vices t o treat o n yc h o m yc osis: 4  wee ks  
•  
T o pical c ortic oster oi ds f or t he feet: 2  wee ks  
2 0.  S u bjects usi n g t he f oll o wi n g s yste mic me dicati o ns wit hi n t he i n dicate d ti me pri or t o t he Baseli ne 
Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g s yste mic me dicati o ns d uri n g t he st u d y: 
•  
S yste mic a ntif u n gal t hera p y: 4  wee ks  
•  
M ore t ha n t w o, 2 -wee k c o urses of oral c ortic oster oi d t hera p y or 1 i ntra m usc ular, 
i ntra ve n o us, or i ntra-artic ular i njecti o n of c ortic oster oi ds ( nasal ster oi d s pra ys a n d ster oi d 
i n halers are per mitte d if use is sta ble a n d n ot e x pecte d t o c ha n ge d uri n g t he st u d y): 3 
m o nt hs  
•  
S yste mic i m m u n os u p pressi ve a ge nts: 6 m o nt hs  
2 1.  S u bject has pre vi o usl y bee n n o nres p o nsi ve t o s yste mic a ntif u n gal t hera p y f or  o n yc h o m yc osis.  
2 2.  S u bject is u na ble t o c o m m u nicate or c o o perate wit h t he i n vesti gat or d ue t o la n g ua ge pr o ble ms, p o or 
me ntal de vel o p me nt, or i m paired cere bral  f u ncti o n. 
2 3.  Use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 half -li ves ( w hic he ver is l o n ger) pri or 
t o t he Scree ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal 
dr u g or  de vice.  
I n vesti g ati o n al pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n: 
I n vesti g ati o n al Dr u g: Efi nac o naz ole 1 0 % S ol uti o n (efi nac o naz ole)  
D osi n g f or S u bjects N O T I n cl u de d i n t he P K S u bset: S u bjects a n d t heir pare nts/le gal g uar dia ns will be 
i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject’s tar get great t oe nail a n d all ot her affecte d t oe nail(s) 
(if a n y) o nce dail y at be dti me. S u bjects a n d t heir pare nts/le g al g uar dia ns will be i nstr ucte d t o c o nti n ue 
a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire treat me nt peri o d, e ve n if t he disease clears  
a n d n o affecte d area is o bser ve d o n t he tar get great t oe nail. If ot her affecte d t oe nails treate d since baseli ne 
clear d uri n g t he c o urse of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o 
c o nti n ue treat me nt o n t h ose t oe nails f or  t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me  
i nfecte d d uri n g t he st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). 
All s u bjects a n d t heir pare nts/le gal g uar dia ns will be gi ve n i nstr ucti o ns re gar di n g h o w t o a p pl y t he st u d y 
dr u g, ie, b y c o m pletel y c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he st u d y dr u g will be a p plie d t o eac h of t he ot her 
i nfecte d t oe nails i n a si milar ma n ner. 
D osi n g f or S u bjects I ncl u de d i n t he P K S u bset:  
D a ys 1 t o 2 8 –  S u bjects a n d  t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y st u d y dr u g t o all 
1 0 t oe nails, o nce dail y at be dti me f or 4 wee ks. D uri n g t his peri o d, all P K s u bjects will be i nstr ucte d t o a p pl y 
t he st u d y dr u g b y c o m pletel y c o veri n g eac h t oe nail a n d 0. 5 c m of a djace nt s ki n, i ncl u di n g t he t oe nail f ol ds, 
t oe nail be d, h y p o n yc hi u m, u n ders urface of t he t oe nail plate. T he s u bjects will n ot a p pl y st u d y dr u g t he ni g ht 
pri or t o t he Wee k 4 ( Da y 2 8) visit, n or will t he y a p pl y st u d y dr u g o n t he ni g ht of t he Wee k 4/ Da y 2 8 V isit. 
Wit hi n 1 h o ur after t he pre d ose bl o o d sa m ple is dra w n o n Da y 2 8, s u bjects a n d/ or t heir pare nts/le gal 
g uar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails i n t he ma n ner descri be d a b o ve at t he i n vesti gati o nal ce nter.  
 
D a ys 2 9 t o Wee k 4 8:  
After c o m pleti o n of t he P K p orti o n of t he st u d y, s u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d 
t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject’s tar get great t oe nail a n d all ot her affecte d t oe nail(s) o nce 
dail y at be dti me. S u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o c o nti n ue a p pl yi n g t he st u d y 
dr u g t o t he tar get great t oe nail f or t he e ntire treat me nt peri o d, e ve n if t he disease clears a n d n o affecte d area 
is o bser ve d o n t he tar get great t oe nail. If ot her affecte d t oe nails treate d si nce baseli ne clear d uri n g t he c o urse 
of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt o n t h ose  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me i nfecte d d uri n g t he st u d y, t he 
s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). All s u bjects a n d t heir 
pare nts/le gal g uar dia ns will be gi ve n i nstr ucti o ns re gar di n g h o w t o a p pl y t he st u d y  dr u g, ie, b y c o m pletel y 
c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f ol ds, t oe nail be d, h y p o n yc hi u m, a n d t he u n ders urface 
of t he t oe nail plate (if o n yc h o m yc osis is prese nt). T he st u d y dr u g will be a p plie d t o eac h of t he ot her i nfecte d 
t oe nails i n a si milar ma n ner.  
 
M o de of A d mi nistr ati o n:  
T o pical a p plicati o n: t he s u bjects will a p pl y t he st u d y dr u g t o t heir t oe nail(s), t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he s u bjects a n d t heir pare nts/le gal g u ar dia ns will be 
i nstr ucte d t o wait f or t he t oe nails t o air-dr y t h or o u g hl y bef ore t o uc hi n g wit h cl ot hi n g.  
D ur ati o n of tre at m e nt:  
4 8 wee ks  
Refere nce t her a p y, d os a ge a n d m o de of a d mi nistr ati o n:  
N ot a p plica ble  
Criteri a f or e v al u ati o n:  
Safet y : 
A d verse e ve nts will be c ollecte d as s p o nta ne o us re p orts b y t he s u bjects a n d as o bser vati o ns b y t he 
i n vesti gat ors. T he c ollecti o n of A Es s h o ul d be gi n f oll o wi n g t he s u bject's c o m pleti o n of t he c o nse nt/asse nt 
pr ocess t o partici pate i n t he st u d y.  
L ocal s ki n reacti o ns (re d ness, s welli n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) will be re vie we d wit h t he s u bject 
starti n g at t he Baseli ne Visit ( after st u d y dr u g a p plicati o n at t he i n vesti gati o nal ce nter) a n d c o nti n ui n g 
t hr o u g h t he last st u d y visit. T he prese nce or a bse nce of b ur ni n g, itc hi n g, a n d vesic ulati o n will be re p orte d 
si m pl y as “ yes” or “ n o”. T he w orst i nsta nces of re d ness a n d s welli n g o bser ve d si nce t he pre vi o us st u d y visit 
will be re p orte d usi n g a 4 -p oi nt scale ( w here 0 = N o ne, 1 = Mil d, 2 = M o derate, a n d 3 = Se vere).  
Bl o o d a n d uri ne sa m ples will be c ollecte d f or r o uti ne cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, 
a n d uri nal ysis) at Scree ni n g a n d Wee k 4 8. A n y cli nicall y si g nifica nt a b n or malities i n safet y la b orat or y test 
res ults t hat are prese nt at t he last treat me nt visit ( Wee k 4 8/ Earl y Ter mi nati o n) will be f oll o we d t o res ol uti o n 
(ie, ret ur n t o n or mal val ues or t o t he baseli ne state) or u ntil cli nicall y sta ble as deter mi ne d b y t he i n vesti gat or. 
Vital si g n meas ure me nts (sitti n g bl o o d press ure, res pirati o n, p ulse, a n d te m perat ure) will be o btai ne d at 
Baseli ne a n d Wee ks 1 2, 2 4, 3 6, a n d 4 8. A n a b bre viate d p h ysical e xa mi nati o n will be perf or me d at Baseli ne 
a n d Wee k 4 8; as part of t he e xa mi nati o n, hei g ht a n d wei g ht will be meas ure d at Baseli ne a n d We e k 4 8. 
Uri ne pre g na nc y tests will be perf or me d f or all F O C B P at t h e Scree ni n g Visit a n d at eac h s u bse q ue nt st u d y 
visit. If a s u bject bec o mes pre g na nt d uri n g t he treat me nt peri o d, t he st u d y dr u g will be disc o nti n ue d 
i m me diatel y, t he s u bject will be disc o ntin ue d fr o m t he st u d y, a n d t he i n vesti gat or will n otif y t he s p o ns or. 
T he pre g na nc y will be f oll o we d t o ter m wit h t he o utc o me re p orte d t o t he s p o ns or.  
Efficac y will be assesse d t o e v al uate c o m plia nce wit h treat me nt as part of t he safet y assess me nt. T he efficac y 
varia bles e val uate d i n t his st u d y i ncl u de micr osc o pic K O H e xa mi nati o n a n d m yc ol o gical c ult ure o utc o mes of 
t he tar get great t oe nail, perce nt i n v ol ve me nt of t he tar get great t oe nail, gr o wt h of t he tar get great t oe nail, a n d 
assess me nts of t he n o ntar g et t oe nails.  
P har mac o ki netics : C o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4), al o n g wit h ot her rele va nt 
P K para meters, will be assess e d base d o n bl o o d sa m ples c ollecte d at Da ys 2 8 a n d 2 9. T he s pecific c ollecti o n 
ti me p oi nts are pre d ose o n Da y 2 8 a n d 2, 4, 1 2, a n d 2 4 h o urs p ost d ose.  
 
P h ot o gra p h y : 
Cl ose -u p p h ot o gra p hs of t he s u bject’s tar get great t oe nail will be use d f or d oc u me ntati o n p ur p oses o nl y a n d 
will n ot be use d f or deter mi nati o ns of eli gi bilit y or a n y st u d y -relate d acti vities. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
1 1  
 
 
 
 
St atistic al Met h o ds:  
Safet y : 
All s u bjects w h o recei ve at least 1 c o nfir me d d ose of st u d y dr u g will be i ncl u de d i n t he safet y a nal ysis set. 
N o i m p utati o ns will be ma de f or missi n g safet y data. T he pri mar y safet y o bjecti ve will be c o nsi dere d  met 
w he n a p pr o xi matel y 4 0 e val ua ble s u bjects ha ve bee n treate d f or 4 8 wee ks.  
All A Es occ urri n g d uri n g t he st u d y will be rec or de d a n d classifie d usi n g t he Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A). Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are t h ose A Es wit h a n o nset 
o n or after t he date of first st u d y dr u g a p plicati o n. All T E A Es will be s u m marize d b y t he n u m ber of s u bjects 
re p orti n g eac h T E A E, t he ass ociate d s yste m or ga n class a n d preferre d ter m, t he se verit y, a n d t he relati o ns hi p 
t o st u d y dr u g f or t he Safet y, P K a n d N o n-P K p o p ulati o ns. Eac h s u bject will be c o u nte d o nl y o nce wit hi n a 
s yste m or ga n class or a preferre d ter m usi n g t he e ve nt wit h t he greatest se verit y or ca usalit y, res pecti vel y, 
wit hi n eac h cate g or y.  
Seri o us a d verse e ve nts ( S A Es) wi ll be s u m marize d b y t he n u m ber of s u bjects re p orti n g eac h S A E, t he 
ass ociate d s yste m or ga n class a n d preferre d ter m, t he se verit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he 
Safet y, P K a n d N o n -P K p o p ulati o ns.  
L ocal s ki n reacti o n sc ores (re d ness, s welli n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) at eac h st u d y visit will be 
s u m marize d usi n g fre q ue nc y ta bles f or t he Safet y, P K a n d N o n-P K p o p ulati o ns. A d diti o nall y, re d ness a n d 
s welli n g se verit y sc ores will be s u m marize d usi n g descri pti ve statistics ( mea n, sta n dar d de viati o n [ S D], 
me dia n, a n d mi ni m u m a n d ma xi m u m). S u bjects wit h a se verit y sc ore w orse t ha n baseli ne will als o be 
s u m marize d at eac h p ost baseli ne st u d y visit. T he w orst sc ore a n d t he last sc ore d uri n g t he p ost -baseli ne 
peri o d will als o be s u m mari ze d. 
Res ults of safet y la b orat or y para meters a n d vital si g n meas ure me nts will be s u m marize d at eac h st u d y visit 
usi n g descri pti ve statistics or fre q ue ncies a n d perce nta ges, as a p pr o priate, f or t he Safet y, P K a n d N o n -P K 
p o p ulati o ns. C ha n ges fr o m baseli ne i n  safet y la b orat or y val ues will be s u m marize d b y treat me nt gr o u p at 
Wee k 4 8 usi n g descri pti ve statistics. I n a d diti o n, c ha n ges fr o m baseli ne i n safet y la b orat or y val ues will be 
s u m marize d usi n g s hift ta bles acc or di n g t o n or mal ra n ges. 
T his st u d y’s pri mar y o bject is t o assess t he safet y of t he st u d y dr u g. Descri pti ve efficac y statistics f or t he 
e n d p oi nts will assist i n e val uati n g c o m plia nce wit h treat me nt f or t he p ur p oses of safet y assess me nt.  
T he efficac y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  
C o m plete C ure, defi n e d as 0 % cli nical i n v ol ve me nt of t he tar get t oe nail a n d ne gati ve K O H 
a n d f u n gal c ult ure at Wee k 5 2  
•  
C o m plete or Al m ost C o m plete C ure at Wee k 5 2, defi ne d as : S 5 % t oe nail  i n v ol ve me nt 
•  
Cli nical Efficac y rate at Wee k 5 2, defi ne d as a n affecte d tar get great t oe n ail area of <  1 0 %  
•  
M yc ol o gic C ure rate at Wee k 5 2, defi ne d as a ne gati ve K O H e xa mi nati o n a n d a ne gati ve 
f u n gal c ult ure of t he tar get great t oe nail sa m ple 
T he C o m plete C ure rate, t he C o m plete or Al m ost C o m plete C ure rate, t he Cli nical Efficac y rate, a n d t he 
M yc ol o gic C ure rate will be prese nte d usi n g descri pti ve statistics (sa m ple size n, fre q ue nc y c o u nts a n d 
perce nta ges) f or t he Safet y, P K a n d N o n -P K p o p ulati o ns. I n a d diti o n, t he gr o wt h of t he tar get great t oe nail at 
eac h st u d y visit a n d t he c ha n ge fr o m baseli ne i n t he n u m ber of affecte d n o ntar get t oe nails will be 
descri pti vel y s u m marize d.  
A last o bser vati o n carrie d f or war d ( L O C F) i m p utati o n will be use d t o i m p ute missi n g val ues f or t he efficac y 
varia bles at Wee k 5 2. N o se nsiti vit y a nal yses will be c o n d uc te d. 
A n y s u bjects re mai ni n g (i.e., ha ve n ot bee n treate d f or 4 8 wee ks) will be f oll o we d u ntil c o m pleti o n. T he 
fi nal re p ort will be a me n de d wit h data o n t hese s u bjects. 
 
P har mac o ki netics : 
All s u bjects i n t he P K s u bset w h o recei ve at least 1 c o nfir me d d ose o f st u d y dr u g a n d ha ve a n y P K data o n 
Da ys 2 8 a n d 2 9 will be i ncl u de d i n t he P K a nal ysis set. Bl o o d sa m ples will be teste d f or plas ma 
c o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4). N o i m p utati o ns will be ma de f or missi n g data.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
1 2  
 
 
 
 
Plas ma c o nce ntrati o ns t hat are re p orte d as bel o w t he li mit of q ua ntitati o n ( B L Q) i n t he data tra nsfer file will 
be set t o zer o f or t he s u m maries of c o nce ntrati o ns as well as calc ulati o n of P K para meters. Missi n g val ues 
will be treate d as if t he y were ne ver dra w n. Plas ma c o nce ntrati o ns of efi nac o naz ole a n d meta b olite ( H 3 a n d 
H 4) a n d P K para meters will be s u m marize d usi n g descri pti ve statistics ( n, mea n, S D, sta n dar d err or of t he 
mea n [ S E M], c oefficie nt of variati o n [ C V], me dia n, mi ni m u m, a n d ma xi m u m). Ge o m etric mea ns will als o be 
use d t o s u m marize C ma x , C mi n , A U C ( 0-t) a n d  A U C ( 0-2 4 h). 
T he mea n plas ma c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will be 
prese nte d gra p hicall y f or Da ys 2 8 a n d 2 9 i n b ot h li near a n d l o garit h mic scales. I n di vi d ual s u bject plas ma 
c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will als o be create d.  
Plas ma P K para meters f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will be calc ulate d usi n g 
n o nc o m part me ntal a nal y sis. T he P K para meters will be calc ulate d f or eac h s u bject usi n g act ual sa m pli n g 
ti mes. T he ma xi m u m plas ma c o nce ntrati o n ( Cma x ) a n d ti me t o Cma x  ( Tma x ) will be ta ke n directl y fr o m t he 
data.  
T he f oll o wi n g P K para meters will be calc ulate d fr o m t he i n di vi d ual  plas ma c o nce ntrati o ns o n Da ys 2 8 a n d 
2 9 w he n p ossi ble:  
•  
C ma x  ( o bser ve d pea k dr u g [efi nac o naz ole a n d meta b olites] c o nce ntrati o n) 
•  
T m a x  (ti me at w hic h Cma x  occ urs)  
•  
C mi n  ( o bser ve d mi ni m u m dr u g c o nce ntrati o n) 
•  
A U C 0 -t (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 u p t o t he sa m pli n g ti me 
c orres p o n di n g t o t he last q ua ntifia ble  c o nce ntrati o n) 
•  
A U C 0 -2 4 h (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
[c orres p o n di n g t o t he d osi n g i nter val]) 
A d diti o nal P K para meters ma y be calc ulate d as a p pr o priate.  
 
T he P K o bjecti ves will be c o nsi dere d met w he n a p pr o xi matel y 1 6 e val ua ble s u bjects are  treate d u n der 
ma xi mal use c o n diti o ns t hr o u g h da y 2 8 of t he P K e val uati o n.  
S a m ple size c alc ul ati o ns:  
A p pr o xi matel y 6 0 s u bjects will be e nr olle d a n d recei ve treat me nt wit h st u d y dr u g. A p pr o xi matel y 2 0 of t he 
s u bjects will be e nr olle d i n t he P K s u bset. T hese sa m ple sizes were base d o n P K a n d cli nical c o nsi derati o ns; 
n o f or mal sa m ple size calc ulati o n was perf or me d. T he n u m bers of pla n ne d s u bjects are c o nsi dere d a de q uate 
f or deter mi ni n g t he safet y pr ofile a n d t he P K para meters of efi nac o naz ole i n a pe diatric p o p ulati o n of 
s u bjects a ge d 6 t o 1 6 years wit h mil d t o se vere o n yc h o m yc osis of t he t oe nails. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
1 3  
 
 
 
 
 
3  T a ble of  C o nte nts  
1  
TI T L E  P A G E  ...........................................................................................................1  
2  
S Y N O P SI S  ...............................................................................................................5  
3  
T A B L E  O F  C O N T E N T S  .......................................................................................1 3  
4  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S  O F  T E R M S  ........................1 7  
5  
I N T R O D U C TI O N .................................................................................................1 8  
6  
S T U D Y O BJ E C TI V E S  A N D  P U R P O S E  ..............................................................1 9  
7  
I N V E S TI G A TI O N A L P L A N  ................................................................................1 9  
8  
S E L E C TI O N A N D WI T H D R A W A L  O F  S U BJ E C T S  .........................................2 8  
8. 1  
S u bject  I ncl usi o n Criteria  ..........................................................................2 8  
8. 2  
S u bject  E xcl usi o n  Criteria  .........................................................................2 9  
8. 3  
S u bject  Wit h dra wal  Criteria  ......................................................................3 1  
9  
T R E A T M E N T S  P L A N N E D  ................................................................................ 3 2  
9. 1  
Met h o ds of Assi g ni n g S u bjects t o  Treat me nt  Gr o u ps  ...............................3 2  
9. 2  
Ra n d o mizati o n  a n d Bli n di n g  .....................................................................3 2  
9. 3  
Treat me nt  C o m plia nce  ...............................................................................3 2  
9. 4  
Treat me nt  A d mi nistrati o n  ..........................................................................3 2  
9. 5  
C o nc o mita nt  Me dicati o ns  ..........................................................................3 4  
9. 5. 1  
All o we d  Me dicati o ns/ T hera pies  ....................................................3 4  
9. 5. 2  
Pr o hi bite d  Me dicati o ns/ T hera pies  .................................................3 4  
9. 6  
Pr ot oc ol De viati o ns  a n d Vi olati o ns  ...........................................................3 5  
1 0  
S T U D Y D R U G M A T E RI A L S  A N D  M A N A G E M E N T  ......................................3 6  
1 0. 1  
St u d y  Dr u g  .................................................................................................3 6  
1 0. 1. 1  Pac ka gi n g  a n d L a beli n g  .................................................................3 7  
1 0. 1. 2  St ora ge, Ha n dli n g, a n d Dis p osal of  St u d y  Dr u g  ............................3 7  
1 0. 1. 3  St u d y  Dr u g  Pre parati o n  ..................................................................3 8  
1 0. 2  
St u d y  Dr u g  Acc o u nta bilit y  ........................................................................3 8  
1 1  
S T U D Y P R O C E D U R E S  A N D  E V A L U A TI O N S  ................................................3 8  
1 1. 1  
Sc he d ule of E val u ati o ns  a n d Pr oce d ures  ...................................................3 8  
1 1. 1. 1  Scree ni n g Visit ( Visit 1, U p t o  Da y  -4 2)  .......................................3 8  
1 1. 1. 2  Baseli ne Visit ( Visit 2,  Da y  1)  .......................................................4 1  
1 1. 1. 3  Visit 3 ( Wee k 4, Da y 2 8 [ ± 5 da ys]), Visit 4 ( Wee k 8 [ ± 5 
da ys]), Visit 6 ( Wee k 1 6 [ ± 5 da ys]), Visit 7 ( Wee k  2 0  
[ ± 5 da ys]), Visit 9 ( Wee k 2 8 [ ± 5 da ys]), Visit 1 0 ( Wee k 3 2 [ ±  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
1 4  
 
 
5 da ys]), Visit 1 2 ( Wee k 4 0 [ ± 5 da ys]), Visit 1 3 ( Wee k 4 4  
[ ± 5  da ys])  ......................................................................................4 3  
1 1. 1. 4  Visit 3 A ( Wee k 4, Da y 2 9) –  A d diti o nal Visit f or S u bjects  i n 
t he P K  S u bset  .................................................................................4 4  
1 1. 1. 5  Visit 5 ( Wee k 1 2 [ ± 5 da ys]), Visit 8 ( Wee k 2 4 [ ± 5  da ys]),  
Visit 1 1 ( Wee k 3 6 [ ±  5  d a ys])  ....................................................... 4 4  
1 1. 1. 6  Visit 1 4 ( Wee k 4 8 [ ± 5 d a ys]) / Earl y  T er mi nati o n  Visit  ............... 4 5  
1 1. 1. 7  Visit 1 5 ( Wee k 5 2 [ ± 5 d a ys]) P ost -Treat me nt F oll o w -u p  Visit  
/ St u d y E xit  .....................................................................................4 6  
1 1. 1. 8  U nsc he d ule d  Visits  ........................................................................4 7  
1 1. 1. 9  Misse d  Visits  ..................................................................................4 7  
1 1. 1. 1 0  S u bject C o m pleti o n  .......................................................................4 8  
1 1. 2  
St u d y  E val uati o ns.  .....................................................................................4 8  
1 1. 2. 1  L ocal  S ki n  Reacti o ns ......................................................................4 8  
1 1. 2. 2  Cli nical  La b orat or y  T ests  .............................................................. 4 8  
1 1. 2. 3  Vital  Si g n  Meas ure me nts  ...............................................................4 9  
1 1. 2. 4  P h ysical  E xa mi nati o ns  ...................................................................4 9  
1 1. 2. 5  Efficac y f or Ass essi n g Treat me nt C o m plia nce  a n d Safet y  ............4 9  
1 1. 2. 5. 1  
K O H E xa mi nati o n a n d  F u n gal  C ult uri n g  ......................5 0  
1 1. 2. 5. 2  
Tar get Great  T oe n ail  Assess me nts  ............................... 5 0  
1 1. 2. 5. 3  
N o ntar get  T o e nail  Assess me nt  ......................................5 1  
1 1. 2. 6  E val uati o n  of  P har mac o ki netics  .....................................................5 1  
1 1. 2. 7  P h ot o gra p h y  .................................................................................. 5 1  
1 1. 3  
Defi niti o n of  A d verse  E v e nts  .....................................................................5 2  
1 1. 3. 1. 1  
Defi niti o n of Seri o us  A d verse  E v e nts  ...........................5 2  
1 1. 3. 1. 2  
Assess me nt  of  Se verit y  .................................................5 3  
1 1. 3. 1. 3  
Assess me nt  of  Ca usalit y  ...............................................5 4  
1 1. 3. 1. 4  
Pr oce d ures f or Re p orti n g A d verse E v e nts  a n d 
Seri o us  A d verse  E ve nts  .................................................5 4  
1 1. 3. 1. 5  
S u b mitti n g a n E x pe dite d Safet y Re p ort t o t he I R B 
( Ce ntral or  L ocal)  ..........................................................5 6  
1 1. 3. 2  Pre g na nc y  .......................................................................................5 7  
1 2  
S T A TI S TI C S  ........................................................................................................ 5 7  
1 2. 1  
Assess me nt  of  Safet y  .................................................................................5 7  
1 2. 1. 1  A d verse  E ve nts  ..............................................................................5 7  
1 2. 1. 2  L ocal  S ki n  Reacti o ns ......................................................................5 8  
1 2. 1. 3  Cli nical  La b orat or y  T ests  .............................................................. 5 8  
1 2. 1. 4  Vital  Si g ns  ......................................................................................5 8  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
1 5  
 
 
1 2. 1. 5  C o nc o mita nt  Me dicati o ns  ..............................................................5 8  
1 2. 1. 6  Efficac y f or Ass essi n g  Treat me nt  C o m plia nce  .............................5 9  
1 2. 2  
Assess me nt  of  P har mac o ki netics  ...............................................................5 9  
T H E P K O BJ E C TI V E S WI L L B E C O N SI D E R E D M E T W H E N 
A P P R O XI M A T E L Y 1 6 E V A L U A B L E S U BJ E C T S A R E T R E A T E D 
U N D E R M A XI M A L U S E C O N DI TI O N S T H R O U G H D A Y 2 8 O F T H E P K  
E V A L U A TI O N ..................................................................................................... 5 9  
1 2. 3  
S u bject  Dis p ositi o n  ....................................................................................6 0  
1 2. 4  
De m o gra p hics a n d Baseli ne  C haracteristics  ..............................................6 0  
1 2. 5  
Pr ot oc ol  De viati o ns  ....................................................................................6 0  
1 2. 6  
C o m plia nce  ................................................................................................6 1  
1 2. 7  
I nteri m A nal yses  ........................................................................................6 1  
1 2. 8  
A d diti o nal  Statistical  C o nsi derati o ns  .........................................................6 1  
1 2. 8. 1  A nal ysis  P o p ulati o ns  ......................................................................6 1  
1 2. 8. 2  Sa m ple Size  Dete r mi nati o n............................................................6 1  
1 2. 8. 3  Ha n dli n g of  Missi n g  Data  ..............................................................6 2  
1 2. 8. 4  M ultice nter  Iss ues ......................................................................... 6 2  
1 2. 8. 5  M ulti plicit y  Iss ues ..........................................................................6 2  
1 2. 8. 6  Wi n d o wi n g  R ules ...........................................................................6 2  
1 3  
Q U A LI T Y C O N T R O L A N D  Q U A LI T Y  A S S U R A N C E  .....................................6 2  
1 3. 1  
St u d y  M o nit ori n g  ...................................................................................... 6 2  
1 3. 2  
A u dits  a n d I ns pecti o ns .............................................................................. 6 3  
1 3. 3  
Data Q ualit y  Ass ura n ce  ............................................................................ 6 3  
1 4  
E T HI C S A N D  A D MI NI S T R A TI V E  I S S U E S ..................................................... 6 4  
1 4. 1  
Et hical C o n d uct of  t he St u d y  .....................................................................6 4  
1 4. 2  
Et hics  Re vie w  ............................................................................................6 4  
1 4. 3  
Writte n  I nf or me d C o nse nt  .........................................................................6 4  
1 4. 4  
S u bject  Data  Pr otecti o n  .............................................................................6 5  
1 4. 5  
Data M o nit ori n g  C o m mittee  ......................................................................6 5  
1 4. 6  
Fi na ncial  Discl os ur e  .................................................................................. 6 6  
1 4. 7  
Esse ntial  D oc u me nts  ..................................................................................6 6  
1 4. 8  
I n v esti gat or O bli gati o ns  ............................................................................ 6 6  
1 4. 9  
C ha n ges t o t he Pr ot oc ol  .............................................................................6 7  
1 4. 1 0  C o nfi de ntialit y/ P u blicati o n of  t he St u d y  ....................................................6 7  
1 4. 1 1  St u d y  Ter mi nati o n  ..................................................................................... 6 7  
1 5  
D A T A H A N D LI N G A N D  R E C O R D  K E E PI N G  ................................................ 6 8  
1 5. 1  
I ns p ecti o n of  Rec or ds  .................................................................................6 8  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
1 6  
 
 
1 5. 2  
Case Re p ort  F or ms  .....................................................................................6 8  
1 5. 3  
Rete nti o n  of  Rec or ds  ................................................................................. 6 9  
1 6  
R E F E R E N C E S  ......................................................................................................7 0  
 
LI S T O F T A B L E S  
Ta ble  1:  
St u d y Desi g n a n d Sc he d ule  of  Assess me nts  ...................................................2 4  
Ta ble  2.  
St u d y  Dr u g  I de ntificati o n .............................................................................. 3 6  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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4  List of A b bre vi ati o ns a n d Defi niti o ns of  Ter ms  
 
A b bre vi ati o n or  S peci alist  T er m  
Defi niti o n or  E x pl a n ati o n  
A E  
A d verse  e ve nt 
A U C 0 -2 4 h 
Area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
(c orres p o n di n g t o t he d osi n g i nter val) 
A U C 0 -t 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 u p t o t he 
sa m pli n g ti me c orres p o n di n g t o t he last q ua ntifia ble c o nce ntrati o n  
C ma x  
O bser ve d pea k dr u g  c o n ce ntrati o n  
C mi n  
O bser ve d mi ni m u m dr u g  c o nce ntrati o n 
e C R F  
Electr o nic case re p ort  f or m 
Efi nac o naz ole  
Efi nac o naz ole 1 0 %  S ol uti o n  
F O C B P  
Fe males of c hil d beari n g  p ote ntial  
G C P  
G o o d Cli nical Practice  
I C H 
I nter nati o nal C o nfere nce o n  Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mittee  
I R B 
I nstit uti o nal Re vie w B oar d  
K O H  
P otassi u m  h y dr o xi de  
L O Q  
Li mit of  q ua ntitati o n  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y  Acti vities  
P K  
P har mac o ki netic  
S A E  
Seri o us a d verse  e ve nt 
T E A E  
Treat me nt -e mer ge nt a d verse  e ve nt 
T m a x  
Ti me a t w hic h t he o bser ve d pea k dr u g c o nce ntrati o n occ urs  
U S  
U nite d  States  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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5  I ntr o d ucti o n 
O n yc h o m yc osis is a c hr o nic a n d rec urri n g f u n g al i nfecti o n of t he fi n g er nails or t oe nails t hat 
acc o u nts f or a b o ut half of all nail dis or ders. O n yc h o m yc osis is us uall y ca use d b y 
der mat o p h ytes, eit her Tri c h o p hyt o n r u br u m ( 7 1 %) or Tric h o p hyt o n me nt a gr o p hytes (2 0 %). 
T he pre v ale nce of o n yc h o m yc osis i n t he U nite d States ( U S) ma y be as lar g e as 1 3 %, wit h t he 
i nfecti o n o bser ve d pre d o mi na ntl y i n el derl y patie nts ( 6 0 %) [ 1, 2]. O n y c h o m yc osis of t he 
t oe nail ca n r es ult i n per ma ne nt t oe nail def or mit y a n d has a si g nifica nt i m pact o n q ualit y of 
life d ue t o c o ncer ns wit h t he a p peara nce of t he t oe nails a n d i nterfere nce wit h weari n g s h oes, 
wal ki n g, a n d partici pati n g i n vari o us s p orts acti vities [ 3, 4]. 
C ure rates f or t o pical treat me nts ha ve bee n si g nifica ntl y l o wer t ha n c urre nt l y a vaila ble 
s yste mic me dicati o ns [5 ], pres u ma bl y beca use t he y bi n d str o n gl y t o kerati n a n d d o n ot 
a de q uatel y p e netrat e t he nail u nit. H o we ver, w hile effecti ve, oral t hera p y is li mite d b y safet y 
c o ncer ns d u e t o s yste mic e x p os ure. F or e x a m ple, b ot h oral itr ac o naz ole a n d oral ter bi nafi n e 
ha ve t he p ote ntial t o ca us e dr u g -dr u g i nteracti o ns a n d he pat ot o xicit y. Efi nac o naz ole 1 0 % 
S ol uti o n (efi nac o naz ol e) has a l o w affi nit y f or kerati n bi n di n g a n d has a hi g her bi n di n g 
re versi bilit y t ha n t hat of ot her ref ere nce dr u gs. T h eref ore, efi nac o n az ole a p pears t o be a 
pr o misi n g a ntif u n gal c o m p o u n d f or t he t o pical treat me nt of o n yc h o m yc osis.  
Efi nac o naz ole is a n o vel triaz ole a ntif u n gal a ge nt t hat is acti ve i n vitr o a gai nst a wi de ra n g e 
of pat h o ge nic f u n gi a n d is e x pecte d t o be effecti ve i n t he treat me nt of mil d t o m o derate 
o n yc h o m yc osis.  
Efi nac o naz ole has b ee n s h o w n t o be effi caci o us i n vitr o a gai nst a pa nel of f u n gal s pecies t hat 
i n va de h u ma n s ki n, hair, a n d nails i ncl u di n g der m at o p h ytes Tric h o p h yt o n, Micr os p or u m, 
E pi der m o p h yt o n, a n d t he yeast, Malassezia s peci es, res p o nsi ble f or ti nea u n g ui u m 
( o n yc h o m yc osis), ti nea c or p oris, ti nea pe dis, ti nea ca pitis, a n d pit yriasis versic ol or. 
Efi nac o naz ole has b ee n s h o w n t o be f u n gici dal a g ai nst C a n di d a al bic a ns a n d ot her Ca n d i da 
s pecies res p o nsi ble f or t h e maj or yeast ( n o n d er mat o p h yte) f or m of o n y c h o m yc osis a n d 
c uta ne o us ca n di diasis. I n vitr o st u dies a gai nst der mat o p h ytes s h o we d t hat efi nac o n az ole w as 
m ore p ote nt t ha n cl otri maz ole, b ut less p ote nt t ha n b ute nafi ne.  
Efi nac o naz ol e has s u ccessf ull y treate d e x p eri me nt all y i n d uce d der mal ca n di diasis, ti nea 
c or p oris, ti nea pe dis, a n d ti nea u n g ui u m i n vi v o i n g ui nea pi g m o dels. It has ge nerall y o ut 
perf or me d ref er e nce dr u gs i n t hese m o dels, a n d i n partic ular o ut perf or me d t he mar kete d 
dr u gs f or ti nea u n g ui u m: cicl o pir o x ola mi ne (a p pr o ve d f or t he t o pical treat me nt of 
o n yc h o m yc osis i n t he U S), a m or olfi ne (a v aila ble o utsi de t he U S as a t o pical nail lac q uer), 
a n d ter bi nafi n e (a v aila ble i n t he U S i n oral f or m).  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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T he safet y a n d  efficac y of o nce dail y use of efi n ac o naz ole f or t he treat me nt of 
o n yc h o m yc osis of t he t oe nail wer e assesse d i n t w o 5 2 -wee k pr os pecti ve, m ultice nter, 
ra n d o mize d, d o u ble-bli n d cli nical st u dies. T hese st u dies were c o n d ucte d i n s u bjects 1 8 t o 
7 0 years of a ge wit h 2 0 % t o 5 0 % cli nical i n v ol ve me nt of t he tar get great t oe nail, wit h o ut  
der mat o p h yt o mas or l u n ula ( matri x) i n v ol ve me nt ( n = 8 7 0 i n St u d y 1 a n d n = 7 8 1 i n St u d y 2) 
[6 ]. T hese st u dies e val uat e d 4 8-wee ks of treat me nt wit h efi nac o naz ole relati ve t o ve hicle 
sol uti o n. At Wee k 5 2 ( 4 -wee ks after c o m pleti o n of t hera p y), efi nac o naz ole was s u peri or t o 
ve hicle s ol uti o n i n b ot h st u dies a n d t h us de m o nstrate d efficac y i n t he treat me nt of 
o n yc h o m yc osis. T he m ost c o m m o n a d verse reacti o ns (ie, reacti o ns wit h i nci de nces > 1 %) 
re p orte d i n t he st u dies w ere i n gr o w n t o e nails, a p plicati o n site der matitis, a p plicati o n site 
vesicles, a n d a p plicati o n site pai n.  
Efi nac o naz ole w as a p pr o ve d b y t he U S F o o d a n d Dr u g A d mi nistrati o n i n J u ne 2 0 1 4 f or t he 
t o pical treat me nt of o n yc h o m yc osis of t he t oe nail(s) d ue t o T r u br u m a n d T me nt a gr o p hytes 
(J u blia®  [efi nac o n az ole] t o pical s ol uti o n, 1 0 % [6 ]). T he a p pr o v e d dr u g is i nte n de d f or t o pical 
a p plicati o n t o affecte d t o e nails o nce dail y f or 4 8 wee ks. D uri n g a p plicati o n, t he t oe nail, 
t oe nail f ol ds, toe nail be d, h y p o n yc hi u m, a n d u n ders urface of t he t oe n ail plate are t o b e 
c o m pletel y c o ver e d.  
T he c urr e nt cli nical st u d y is desi g ne d t o e val uate t he safet y a n d p h ar mac o ki netics ( P K) of 
o nce dail y t o pical a p plicati o n of efi nac o naz ole i n t he treat me nt of p e diatric s u bjects wit h 
mil d t o se vere o n yc h o m y c osis of t he t oe nails. A p plicati o n a n d use of t he st u d y dr u g is 
c o nsiste nt wit h t he a p pr o ve d pac k a ge i nsert. T h e e val uati o ns i ncl u de d i n t he c urre nt st u d y are 
c o nsiste nt wit h t he e val u ati o ns c o n d ucte d i n t he de vel o p me nt of t he a p pr o ve d dr u g.  
 
6  St u d y O bjecti ves a n d  P ur p ose  
T he pri mar y o bjecti ves of t his st u d y are t o e val uat e: 1) safet y of o nce d ail y t o picall y 
a d mi nistere d efi nac o naz ole 1 0 % f or 4 8 w ee ks i n pe diatric s u bjects ( 6 -1 6 y ears of a ge) wit h 
at least mil d o n yc h o m yc osis of t he t oe nails, a n d 2) p har mac o ki netics P K ( 4 wee ks) of o nce 
dail y t o picall y a d mi nistere d efi nac o naz ol e 1 0 % i n pe diatric s u bjects ( 1 2 -1 6 years of a g e) 
wit h m o derate t o se vere o n yc h o m yc osis of t he t oe nails.  
 
7  I n vesti g ati o n al Pl a n 
7. 1  I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct ure  
A p pr o xi matel y 1 0 t o 1 5 i n vesti gati o nal ce nters are pla n ne d t o partici pate i n t his st u d y. Eac h 
cli nical i n vesti gat or will be re q uir e d t o pr o vi de a c o p y of his/ her c urric ul u m vitae a n d 
me dical lice nse, c o m plete a fi na n cial discl os ure st ate me nt, a n d ge n erat e a list of st u d y 
pers o n nel w h o will be i n v ol ve d i n t he st u d y, wit h a s u m mar y of t heir r oles a n d q ualificati o ns.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
2 0  
 
 
 
 
T he S p o ns or has desi g nate d a C o ntract Researc h Or ga nizati o n t o ass u me res p o nsi bilit y f or 
acti vities relate d t o t he c o n d uct of t he st u d y. T he S p o ns or als o has desi g nate d ce ntral 
la b orat ories t o a n al yze bi ol o gical sa m ples relate d t o cli nical safet y, p h ar mac oki netics, a n d 
m yc ol o g y. A listi n g of t he or ga nizati o ns i n v ol ve d i n t he c o n d uct of t he st u d y is pr o vi de d 
u n der Pers o n nel Secti o n i n t he fr o nt of t he pr ot oc ol. A c o m plete descri pti o n of t he S p o ns or’s 
a n d dele gat es’ st u d y -rel ate d r oles/res p o nsi bilities, i ncl udi n g ke y pers o n nel, is c o ntai ne d 
wit hi n t he S p o ns or’s st u d y pr oject pla n.  
7. 2  S u m m ar y of St u d y  Desi g n  
T his is a n o pe n la bel, si n gle-ar m st u d y desi g ne d t o e val uate t he s afet y a n d P K of a o nce dail y 
t o pical a p plicati o n of efi nac o naz ole i n t he treat me nt of pe diatric s u bjects wit h mil d t o se vere 
o n yc h o m yc osis of t he t oe nails. T he st u d y will i ncl u de a t otal of 6 0 s u bjects, 4 0 of w h o m will 
be 6 t o 1 6 years of a g e, i ncl usi ve, a n d P K assess me nts will be perf or me d o n a p pr o xi matel y 
2 0 s u bjects 1 2 t o 1 6 years of a ge, i ncl usi ve (referre d t o t hr o u g h o ut t he pr ot oc ol as t he P K 
s u bset). All s u bjects m ust ha ve o n yc h o m yc osis of at least 1 great t oe nail; s u bjects i n t he P K 
s u bset m ust ha ve o n yc h o m yc osis of b ot h great t oe nails a n d at least 4 ot her t oe nails. E ff orts 
will be ma de t o e nr oll s u bjects i nt o t he P K s u bset s uc h t hat t he s u bjects are e ve nl y distri b ute d 
acr oss t he r e q uire d a ge  r a n ge. 
F or s u bjects n ot partici pati n g i n t he P K s u bset, t he st u d y will c o nsist of 1 4 sc he d ule d visits, 
i ncl u di n g Scree ni n g ( u p to Da y -4 2), Bas eli ne ( D a y 1), 1 2 treat me nt visits ( Wee ks 4, 8, 1 2,  
1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 
5 2). S u bjects i ncl u de d i n t he P K s u bset will atte n d t he sc he d ule d visits u p t o Wee k 4 ( Da y  
2 8)  a n d a n a d diti o nal st u d y visit at Da y 2 9 f or c ollecti o n of t he fi nal P K bl o o d sa m ple. T he 
P K assess me nts will be perf or me d u n d er ma xi mal use c o n diti o ns. O nce P K assess me nts are 
c o m plete at Da y  2 9,  t he P K  s u bset of  s u bjects will  c o nti n ue treat me nt t hr o u g h wee k  4 8  wit h 
visits at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt 
f oll o w-u p visit ( Wee k 5 2).  
At t he Scree ni n g Visit, s u bjects a n d t heir pare nts/le gal g uar dia ns will si g n a n i nf or me d 
c o nse nt/asse nt f or m a n d a p h ot o gra p h y c o ns e nt/asse nt f or m, pr o vi de t heir me dical hist ories, 
re p ort t heir pr e vi o us a n d c o nc o mita nt me dicati o ns, a n d be e val uate d a gai nst t he 
i ncl usi o n/e xcl usi o n criteria. Fe mal es of c hil d beari n g p ote ntial ( F O C B P) will ha ve uri ne 
pre g na nc y t ests perf or m e d. D uri n g t his visit, s u bjects will u n der g o a n e x a mi nati o n of t heir 
feet t o vis uall y ascertai n t he prese n ce of o n y c h o m yc osis i n at least 1 great t oe nail f or s u bjects 
n ot i ncl u de d i n t he P K assess me nts, a n d o n b ot h great t oe nails a n d at least 4 ot her t oe na ils f or 
s u bjects i ncl u de d i n t he P K assess me nts. A d diti o nall y, t he perce nt i n v ol ve me nt of t he 
affecte d gr eat t oe nail(s) will be rec or d e d. A direct micr osc o pic e xa mi nati o n f or t he h y p hae 
ass ociate d wit h der m at o p h ytes will be perf or m e d at t he i n vesti gati o nal  ce nter usi n g  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
2 1  
 
 
 
 
p otassi u m h y dr o xi de ( K O H) o n t oe nail scra pi n gs c ollecte d fr o m t he affect e d great t oe n ail(s) 
(ie, at least 1 gr eat t oe nail f or all s u bjects a n d b ot h great t oe nails f or s u bjects i n t he P K 
s u bset). S u bjects wit h K O H -p ositi ve t oe nail sa m ples will pr o vi de a n a d diti o nal sa m ple fr o m 
t he aff ecte d gr eat t oe n ail(s) f or K O H e x a mi nati o n a n d m yc ol o gical c ult ure (c o n d ucte d at a 
ce ntral m yc ol o g y la b orat or y). Bl o o d a n d uri ne s peci me ns will be c ollecte d f or ser u m 
c he mistr y, he m at ol o g y, a n d uri nal ysis e val uati o ns. At rele va nt p ost -Scree ni n g Visits, t he 
tar get great t oe nail will be tri m me d bac k t o t he distal gr o o ve bef ore t he cli nical e val uati o ns 
are perf or m e d a n d bef ore p h ot o gra p hs are ta ke n.  
If a s u bject fails scree ni n g, eit her at t he Scree ni n g or Baseli ne visit ( pri or t o e nr oll me nt t o 
treat me nt), t he s u bject ma y be res cree ne d at a later date. S u bjects w h o are rescree ne d, will be 
assi g ne d a ne w s cree ni n g n u m ber, m ust be re -c o ns e nte d, a n d u n der g o all scree ni n g 
pr oce d ur es per pr ot o c ol.  
At t he Baseli ne Visit ( w hic h s h o ul d be sc he d ule d after K O H a n d f u n gal c ult ure res ults ha ve 
bee n o btai ne d fr o m t he m yc ol o g y la b), s u bjects a n d/ or t heir pare nts/le g al g uar dia ns will 
u p date t heir me dical hist ories a n d c o n c o mita nt me dicati o n uses, a n d t he  i n cl usi o n/e xcl usi o n 
criteria will be c o nfir me d. S u bjects will u n der g o a b bre viate d p h ysical e xa mi nati o ns, cli nical 
la b orat or y e v al uati o ns, assess me nts of vital si g ns (sitti n g bl o o d press ure, res pirati o n, p ulse, 
a n d te m perat ure), a n d meas ure me nts of h ei g ht a n d wei g ht. All F O C B P will ha ve uri ne 
pre g na nc y t ests perf or me d. F or t he p ur p os es of efficac y ass ess me nts, 1 tar g et great t oe n ail 
will be selecte d fr o m t he st u d y -eli gi ble great t oe nail(s), i ncl u di n g s u bjects i n t he P K s u bset 
f or w h o m b ot h great t oe nails m ust be i n v ol ve d. W here b ot h great t oe nails are st u d y-eli gi ble, 
t he t oe nail wit h t he great er per ce nt of affecte d area will be selecte d f or m y c ol o gic data a n d 
f or i ncl usi o n i n t he efficac y a nal ysis. I n t he i nsta n ce w here t he p erce nt of affect e d area is t he 
same f or b ot h st u d y -eli gi ble great t oe n ails, t he i n vesti gat or ma y select eit her great t oe n ail as 
t he tar get t oe nail. T he t ar get great t oe n ail will be i de ntifie d a n d rec or d e d f or eac h s u bj ect, 
p h ot o gra p hs of t he tar g et great t oe nail will be o btai ne d, a n d a tr a ns v erse n ot c h will be 
i nscri be d i n t he tar get great t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d (as a mar ker f or 
meas uri n g t oe nail gr o wt h at s u bse q ue nt visits). Assess me nts of all ot her n o ntar get t oe nails, 
i ncl u di n g t he ot her i n v ol ve d t oe nails of s u bjects i n t he P K s u bset, will als o be c o n d ucte d t o 
assess t he pres e nce or a bse nce of o n y c h o m yc osis o n eac h t oe n ail. T his assess me nt will 
c o nti n ue t hr o u g h o ut t he st u d y visits t hr o u g h wee k 5 2.  
 
After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit ( Da y 1), s u bjects  will be e nr olle d i n t he  
treat me nt peri o d. S u bjects or t heir pare nts/le gal g uar dia ns will a p pl y t he first d ose of st u d y 
dr u g t o t he q ualifie d t oe n ails at t he i n vesti gati o nal ce nter u n d er t he s u per visi o n of desi g nate d 
st u d y pers o n nel. A n y l ocal s ki n reacti ons t hat occ ur at t he st u d y dr u g a p pli cati o n site, al o n g  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
2 2  
 
 
 
 
wit h a n y a d vers e e ve nts ( A Es), will be rec or d e d. S u bjects a n d t heir pare nts/le gal g uar dia ns 
will recei ve w ei g he d st u d y dr u g b ottles a n d gi ve n ver bal a n d writte n i nstr ucti o ns f or 
treat me nt a p plicati o n. S p ecificall y, s u bjects w h o are n ot i ncl u de d i n t he P K s u bset will be 
i nstr ucte d t o a p pl y t he st u d y dr u g t o t he affecte d t oe nails o nce dail y at b e dti me f or 4 8 w ee ks. 
S u bjects w h o are i ncl u d e d i n t he P K s u bset will be i nstr ucte d t o a p pl y t he st u d y dr u g t o all 
1 0 t oe nails o nce dail y at be dti me f or 4 wee ks. F oll o wi n g t he P K bl o o d c ollecti o ns o n Da ys 
2 8  a n d 2 9, t hese s u bjects will be i nstr ucte d t o c o nti n ue treat me nt wit h st u d y dr u g t o o nl y t he 
affecte d t oe n ails a n d ret ur n t o t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8,  3 2,  
3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( We e k 5 2). All s u bjects or 
t heir pare nts/le gal g u ar di a ns will als o recei v e diari es, wit h i nstr ucti o ns t o c o m plete a rec or d 
of all a p plicati o ns a n d t o n ote a n y misse d a p plicati o ns of t he st u d y dr u g.  
 
 
S u bjects i n t he P K s u bset will n ot a p pl y st u d y dr u g t he ni ght pri or t o t he Wee k 4 ( D a y 2 8) 
visit. F oll o wi n g t he Da y 2 8 st u d y pr oce d ures, s u bjects i n t he P K s u bset will u n der g o ti me d 
bl o o d c ollecti o ns t o assess plas ma c o nce ntrati o ns of efi nac o naz ol e a n d met a b olites ( H 3 a n d 
H 4). Assess me nts will re q uire c ollecti o n o f a p pr o xi matel y 4 m L of w h ole bl o o d at eac h ti me 
p oi nt (a p pr o xi matel y 2 0 m L t otal). Wit hi n 1 h o ur after t he pre d ose bl o o d sa m ple is dra w n, 
t he s u bjects/ pare nts/le gal g uar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails at t he 
i n vesti gati o nal ce nter. S u bse q uent bl o o d c ollecti o ns will occ ur 2, 4, a n d 1 2 h o urs p ost d ose o n 
Da y 2 8. T he s u bjects will g o h o me after Da y 2 8, b ut will n ot a p pl y st u d y dr u g o n t he ni g ht of 
t he Da y 2 8 visit. P K s u bjects will ret ur n t o t he i n v esti gati o nal ce nter t he f oll o wi n g da y ( D a y 
2 9)  f or c ollecti o n of a 2 4-h o ur p ost d ose bl o o d s a m ple. P K s u bjects will  c o nti n ue treat me nt 
wit h st u d y dr u g t o o nl y t he tar g et great t oe n ail a n d t he ot her affecte d t oe n ails a n d ret ur n t o 
t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4,  a n d 4 8), a n d  a 
4 -wee k p ost -tr eat me nt f oll o w-u p visit ( Wee k 5 2).  
Safet y will be assesse d b y re vie wi n g t he occ urre n ce of A Es a n d l ocal s ki n reacti o ns, 
assessi n g vital si g n meas ure me nts a n d a b bre viate d p h ysical e xa mi nati o n fi n di n gs, a n d n oti n g 
a n y a d diti o ns or c ha n g es i n c o nc o mita nt me dicati o n uses. Bl o o d sa m ples will be c ollecte d at 
Scree ni n g a n d Wee k 4 8 f or r o uti ne safet y la b orat or y e val uati o ns (ser u m c h e mistr y, 
he mat ol o g y, a n d uri nal ysis); uri ne pre g na n c y tests will be o btai ne d f or all F O C B P at eac h 
st u d y visit. Efficac y assess me nts will be perf or me d t hr o u g h o ut t he st u d y. Efficac y a nal yses 
will be base d o n micr osc o pic e xa mi nati o n a n d m y c ol o gical c ult ure res ults f or t he tar get great 
t oe nail, t he perce nt i n v ol ve me nt of t he tar g et great t oe nail, t he le n gt h of t he u naffecte d p art 
of t he tar get gr eat t oe n ail, t he gr o wt h of t he tar g et great t oe nail, a n d t h e n u m ber of affecte d 
n o ntar get t oe nails.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
2 3  
 
 
 
 
A p ost -treat me nt f oll o w-u p visit will occ ur 4 wee ks after t h e last treat me nt visit f or eac h 
s u bject (ie, at Wee k 5 2). S u bjects w h o disc o nti n u e fr o m t he st u d y pri or t o Wee k 4 8 will 
c o m plete t he Wee k 4 8 st u d y pr oce d ures.  
T he st u d y desi g n a n d sc h e d ule of assess m e nts is prese nte d i n Ta bl e 1.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 4  
 
 
 
T a ble  1:  
St u d y Desi g n a n d Sc he d ule of  Assess me nts  
 
 
 
Tre at m e nt Peri o d  
P ost - 
Tre at m e nt  
Visit  
1 - 
S C R  
2 - 
B L  
3  
3 A a 
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4 b 
1 5  
Wee k  
 
P R O C E D U R E S  
U p t o 
Da y  
-4 2  
Da y 
1  
4  
( Da y 
2 8)  
4  
( Da y 
2 9)  
8  
1 2  
1 6  
2 0  
2 4  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 2  
O btai n I nf or me d C o nse nt/ Asse nt a n d 
P h ot o gra p h y C o nse nt/ Asse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w Me dical Hist or y  
X  
X c  
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w Pre vi o us T hera pies  
X  
X c  
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w I ncl usi o n/ E xcl usi o n Criteria  
X  
X c  
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n d uct Uri ne Pre g na nc y Test (all 
fe males of c hil d beari n g p ote ntial) d 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Cli p T oe nails e 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
N otc h Tar get Great T oe nail f 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meas ure Tar get Great T oe nail Gr o wt h 
(fr o m t he P N F t o t he n otc h) f 
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o n d uct Tar get Great T oe nail 
Assess me nts g 
X  
X  
 
 
 
X   
 
X   
 
X   
 
X  
X  
C o n d uct N o ntar get T oe nail 
Assess me nts h 
X  
X  
 
 
 
X   
 
X   
 
X   
 
X  
X  
O btai n P h ot o gra p h y  
 
X  
 
 
 
 
 
 
X   
 
 
 
 
X  
X  
Perf or m K O H E xa mi nati o n i 
X  
 
 
 
 
X   
 
X   
 
X   
 
X  
X  
Sa m ple f or F u n gal C ult ure i 
X  
 
 
 
 
X   
 
X   
 
X   
 
X  
X  
C o n d uct A b bre viate d P h ysical E xa m j  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X   
O btai n Vital Si g ns k 
 
X  
 
 
 
X   
 
X   
 
X   
 
X   
 
 
 
Cli nical St u d y Pr ot oc ol, 1 0  Ma y  2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 5  
 
 
 
 
 
Tre at m e nt Peri o d  
P ost - 
Tre at m e nt  
Visit  
1 - 
S C R  
2 - 
B L  
3  
3 A a 
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4 b 
1 5  
Wee k  
 
P R O C E D U R E S  
U p t o 
Da y  
-4 2  
Da y 
1  
4  
( Da y 
2 8)  
4  
( Da y 
2 9)  
8  
1 2  
1 6  
2 0  
2 4  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 2  
C ollect Bl o o d a n d Uri ne Sa m ples f or 
C B C/ Diff, C he mistr y, a n d 
Uri nal ysis  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X l 
 
E nr oll Q ualifie d S u bjects  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w D osi n g I nstr ucti o ns  
 
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
A p pl y First D ose i n Cli nic  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g h/ Dis pe nse St u d y Dr u g  
 
X  
X n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
A p pl y St u d y Dr u g  
 
 
 
  
C ollect/ Wei g h St u d y Dr u g  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
Re vie w C o m plia nce  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
Dis pe nse Diar y  
 
X  
X o  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
 
C ollect/ Re vie w Diar y  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X   
P K Bl o o d Sa m ple C ollecti o n m  
 
 
X m  
X m   
 
 
 
 
 
 
 
 
 
 
 
Re vie w L ocal S ki n Reacti o ns  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Re vie w C o nc o mita nt Me dicati o ns  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Re vie w A d verse E ve nts  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E xit St u d y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
A b bre viati o ns: B L = Baseli ne Visit; C B C/ Diff = c o m plete bl o o d c o u nt/ differe ntial; K O H = p otassi u m h y dr o xi de; P K = p har mac o ki n etic; P N F = pr o xi mal t oe nail 
f ol d; S C R = Scree ni n g Visit 
N ote: P ost -baseli ne visits are t o be sc he d ule d i n refere nce t o Visit 2 ( Baseli ne Visit) a n d wit hi n a wi n d o w of ± 5 da ys.  
a Visit 3 A ( Da y 2 9) is o nl y t o be c o n d ucte d f or s u bjects i n t he P K s u bset.  
b All Wee k 4 8 pr oce d ures are t o be c o m plete d f or s u bjects w h o disc o nti n ue fr o m t he st u d y d uri n g t he treat me nt peri o d (ie, E arl y Ter mi nati o n). 
c C o nfir mati o n of e val uati o ns c o n d ucte d at t he Scree ni n g Visit.  
d Uri ne pre g na nc y tests are re q uire d t o ha ve a mi ni m u m se nsiti vit y of 2 5 mI U of h u ma n c h ori o nic g o na d otr o pi n per m L of uri ne.  
 
Cli nical St u d y Pr ot oc ol, 1 0  Ma y  2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 6  
 
 
e T oe nails are cli p pe d pri or t o c o n d ucti n g t he assess me nts.  
f T he tra ns verse n otc h i nscri be d at t he Baseli ne Visit is e n ha nce d, as nee de d, at s u bse q ue nt visits t o all o w c o nti n ue d meas ure m e nt of t oe nail gr o wt h o ver t he 
c o urse of t he st u d y. I n cases w here t he i nitial n otc h gr o ws o ut or is cli p pe d a wa y, a ne w n otc h is i nscri be d i n t he t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d 
a n d meas ure me nts of t oe nail gr o wt h (ie, pr o xi mal t oe nail f ol d t o n otc h) will c o nti n ue usi n g t he ne w  n otc h.  
g Assess me nts i ncl u de calc ulati o n of t he perce nt i n v ol ve me nt of t he t oe nail affecte d b y o n yc h o m yc osis a n d meas ure me nt of t he di sta nce fr o m t he pr o xi mal 
t oe nail f ol d t o t he pr o xi mal o n yc h o m yc otic b or der. 
h Assess me nt of n o ntar get nails f or prese nce or a bse nce of o n yc h o m yc osis.  
i At t he Scree ni n g visit, K O H e xa mi nati o n will be perf or me d at t he site. If p ositi ve, a d diti o nal s peci me ns f or K O H a n d f u n gal c ult ures are o btai ne d fr o m st u d y - 
eli gi ble great t oe nails at t he Scree ni n g Visit. At all s u bse q ue ntl y  i n dicate d st u d y visits, s peci me ns f or K O H e xa mi nati o ns a n d f u n gal c ult ures are o btai ne d 
fr o m t he tar get great t oe nail. 
j T he a b bre viate d p h ysical e xa mi nati o n at t he Baseli ne Visit a n d Wee k 4 8 i ncl u des hei g ht a n d wei g ht,  
k Vital si g n meas ure me nts at eac h v isit i ncl u de te m perat ure, p ulse, res pirati o ns, a n d sitti n g bl o o d press ure. 
l A n y cli nicall y si g nifica nt la b orat or y a b n or malit y prese nt at Wee k 4 8 ( or Earl y Ter mi nati o n) is t o be f oll o we d t o res ol uti o n o r u ntil cli nicall y sta ble as 
deter mi ne d b y t he i n vesti gat or.  
m A s u bset of e nr olle d s u bjects will be assi g ne d t o P K e val uati o ns. At t he Wee k 4/ Da y 2 8 Visit, s u bjects i n t he P K s u bset will u n der g o ti me d bl o o d sa m pli n g o n 
Da ys 2 8 t o 2 9 as f oll o ws:  
n St u d y dr u g s h o ul d be wei g he d a n d dis pe nse at Visit 3 A f or P K s u bjects 
o Diar y s h o ul d be dis pe nse d wit h st u d y dr u g at Visit 3 A f or P K  s u bjects. 
 
Visit  
3  
3 A  
D a y 
( Wee k) 
2 8  
( 4) 
2 9  
( 4) 
P R O C E D U R E S  
 
Pre d ose  
~ 1 h 
F oll o wi n g 
Pre -d ose 
Sa m ple  
 
2 h  
( ± 5 mi n) 
4 h  
( ± 5 mi n) 
 
1 2 h  
( ± 1 5 mi n) 
 
2 4 h  
( ± 3 0 mi n) 
P K S u bset - C ollect Bl o o d f or Plas ma 
C o nce ntrati o ns  
X p  
 
X  
X  
X  
X  
P K S u bset - St u d y Dr u g A p plicati o n   
X q  
 
 
 
 
p T he pre d ose bl o o d sa m ple is t o be c ollecte d after all Da y 2 8/ Wee k 4 st u d y pr oce d ures are c o m plete d.  
q St u d y dr u g a p plicati o n o n Da y 2 8/ Wee k 4 will occ ur at t he i n vesti gati o nal ce nter wit hi n 1 h o ur after c ollecti n g t he pre d ose bl o o d sa m ple.  
T his will be t he last a p plicati o n of st u d y dr u g t o all 1 0 t oe nails f or s u bjects i n t he P K s u bset. P ost Da y 2 8, s u bjects a n d t heir pare nts/le gal g uar dia ns will be 
instr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject’s tar get great t oe nail a n d all ot her affecte d t oe nail(s). S u bjects a n d t heir pare nts/le gal g uar dia ns will 
be i nstr ucte d t o c o nti n ue a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire  treat me nt peri o d, e ve n if t he disease clears a n d n o affecte d area is 
o bser ve d o n t he tar get great t oe nail. If ot her affecte d t oe nails treate d si nce baseli ne clear d uri n g t he c o urse of t he st u d y,  s u bjects a n d/ or t heir pare nts/le gal 
 
Cli nical St u d y Pr ot oc ol, 1 0  Ma y  2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 7  
 
 
 
g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe na ils bec o me i nfecte d d uri n g t he 
st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical St u d y Pr ot oc ol, 1 0  Ma y  2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
2 8  
 
 
 
8  Selecti o n a n d Wit h dr a w al of  S u bjects  
8. 1  S u bject I ncl usi o n  Criteri a  
S u bjects meeti n g all of t he f oll o wi n g criteria will be eli gi ble f or st u d y e ntr y: 
1.  Male or fe m ale s u bjects of a n y race, 6 t o 1 6 years of a ge  (i n cl usi ve). 
•  P K S u bset : Male or fe male s u bjects of a n y race, 1 2 t o 1 6 years of a ge  (i ncl usi ve). 
2.  Ver bal a n d writte n i nf or me d c o nse nt/asse nt o btai ne d fr o m t he s u bject a n d/ or  t heir 
pare nt or le g al  g uar di a n.  
3.  G o o d ge ner al healt h, as assesse d b y t he i n vesti gat or, base d o n t he s u bject’s me dical 
hist or y, p h ysical e xa mi nati o n, a n d safet y la b orat or y  tests. 
4.  At least 1 great t oe nail (t he “tar g et great t oe nail”) wit h cli nicall y dia g n ose d distal 
lateral s u b u n g ual o n yc h o m yc osis i n v ol vi n g at least 2 0 % of t he affecte d great t oe nail 
at t he Scree ni n g a n d Bas eli ne Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut 
der mat o p h yt o mas or l u n ula ( matri x) i n v ol ve me nt. U p t o 6 t oe nails ma y ha ve 
o n yc h o m yc osis i n s u bjects n ot partici pati n g i n t he P K s u bset. 
•  P K S u bset : B ot h great t oe nails wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at least 5 0 % of t he affecte d great t oe nail at t he 
Scree ni n g a n d Bas eli ne Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut 
der mat o p h yt o mas or l u n ula ( matri x) i n v ol ve me nt. S u bjects m ust als o ha ve at least 
4 t oe nails ot her t ha n t he great t oe nails wit h o n y c h o m yc osis.  
5.  Tar get gr eat t oe nail f or all s u bjects, a n d b ot h great t oe nails f or s u bjects i n t he P K 
s u bset, m ust h a ve e vi d e n ce of t oe n ail gr o wt h, per s u bject’s re p ort t hat m o nt hl y 
cli p pi n g is nee de d.  
6.  Wit hi n 4 2 d a ys pri or t o t he Baseli ne ( D a y 1) Visit, ha ve a p ositi ve K O H 
e xa mi nati o n (at t he i n vesti gati o nal ce nter a n d c o nfir me d b y t he m yc ol o g y la b) of  t he 
tar get great t oe nail f or all s u bjects 
7.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( D a y 1) Visit, ha ve a p ositi ve der m at o p h yte 
c ult ure f or T r u br u m or T me nt a gr o p hytes (at t he ce ntral m yc ol o g y la b orat or y) fr o m 
t he tar get gr eat t oe nail i n all s u bjects 
•  P K S u bset : Pri or t o t he Baseli ne Visit, t he great t oe nail desi g nate d f or 
efficac y ass ess me nts as t he tar get great t oe nail m ust ha ve b ot h a p ositi ve 
K O H e xa mi nati o n (c o nfir me d b y t he m yc ol o g y la b) a n d a p ositi ve f u n gal 
c ult ure.  
8.  All F O C B P m ust ha ve a ne gati ve uri ne p re g na n c y test at t he Scree ni n g a n d Baseli ne 
Visits a n d m ust a gree t o use a n effecti ve m et h o d of c o ntrace pti o n t hr o u g h o ut t he 
st u d y. Effecti ve c o ntrace pti o n is defi ne d as use of a n i ntra uteri ne d e vice, c o n d o m 
wit h s per mici de, dia p hra g m wit h s per mici de, a bst i ne nce (s u bject is n ot  se x uall y 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
2 9  
 
 
 
acti ve), or sta bl e use of a h or m o nal c o ntrace pti ve ( oral, i m pla nt, i njecti o n, or 
tra ns der mal pat c h) f or at least 3 m o nt hs pri or t o t he Baseli ne Visit. 
9.  S u bjects a n d t heir par e nts/le gal g uar dia ns are willi n g t o c o m pl y wit h st u d y 
i nstr ucti o ns a n d ret ur n t o t he i n vesti gati o nal ce nter f or all re q uire d visits (a visit 
sc he d ule wit h t he le n gt h of eac h visit will be pr o vi de d t o e ns ure t hat t he s u bject ca n 
meet t he re q uir e me nts a n d ha ve a d e q uate  tra ns p ortati o n). 
1 0.  S u bjects a n d pare nts/le gal g uar dia ns a gree t hat t he s u bject will a v oi d t he use of 
t oe nail p olis h, c os metic t oe nail pr o d ucts, a n d p e dic ures d uri n g t he st u d y peri o d.  
 
8. 2  S u bject E xcl usi o n  Criteri a  
S u bjects meeti n g a n y o ne of t he f oll o wi n g criteria will be e xcl u de d fr o m t he st u d y:  
1.  Fe males w h o ar e pre g n a nt, n ursi n g a n i nfa nt, o r pla n ni n g a pre g na n c y d uri n g t he 
st u d y peri o d.  
2.  Hist or y of i m m u n os u p pressi o n a n d/ or cli nical si g ns i n dicati ve of  p ossi ble 
i m m u n os u p pressi o n, as deter mi ne d b y t he i n vesti g at or, or k n o w n h u ma n 
i m m u n o deficie nc y vir us i nfecti o n. 
3.  Hist or y of dia betes t hat is u nc o ntr olle d as deter mi ne d b y t he i n vesti gat or ( dia betes 
t hat is c o ntr olle d b y diet or me dicati o n d oes n ot e xcl u de a s u bject). 
4.  Prese nce of a n y t oe n ail i nfecti o n ot her t ha n or i n a d diti o n t o der mat o p h ytes, s uc h as 
Scyt ali di u m as deter mi ne d b y t he i n vesti gat or (ca n di dal o n yc h o m yc osis i nfecti o n, 
c o nc urr e nt wit h a p ositi ve der mat o p h yte c ult ure, is acce pta bl e).  
5.  Prese nce  of  a n y  of  t he f oll o wi n g: der mat o p h yt o ma, f u n gal  “s pi kes” wit hi n  3  m m  of 
t he pr o xi mal t oe nail f ol d o n t he tar get great t oe nail, i nfecti o n e xte n di n g t o t he 
matri x, or o nl y lateral t oe nail disease i n t he tar get great t oe n ail. 
6.  Prese nce of se vere m occasi n ti nea pe dis at t he Scree ni n g or Baseli ne Visits, as 
deter mi ne d b y t he i n vesti gat or (if i nter di gital ti nea pe dis re q uires treat me nt d uri n g 
t he st u d y, t he s u bject m ust a gree t o use o nl y a n i n vesti gat or -a p pr o v e d t o pical 
a ntif u n gal  t hera p y). 
7.  Prese nce of a n y disease/c o n diti o n t hat mi g ht ca use t oe nail a b n or malities or ma y 
i nterfere wit h t he e val u ati o n of t he st u d y dr u g as d eter mi ne d b y t he i n vesti g at or 
(e g, o pe n s or es or ulcerati o n o n t he t oes of affecte d t oe nails, ps oriasis, i m m u ne 
d ysf u ncti o n, c olla ge n -v asc ular diseas es, lic he n pl a n us, peri p heral vasc ul ar  disease, 
or tra u matic o n yc h o d ystr o p h y d ue t o c hr o nic p h ysical  sti m uli). 
8.  A n y pre vi o us s ur ger y o n t he tar get great  t oe nail. 
9.  Prese nce of o n yc h o m yc osis of t he  fi n ger nail. 
1 0.  Hist or y of i m m u n o deficie nc y as det er mi ne d b y t h e  i n vesti gat or. 
1 1.  Prese nce of 1 -ha n d, 2 -f o ot s y n dr o me, or fi n ger n ail der mat o p h yt osis.  


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C O N FI D E N TI A L  
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1 2.  Tar get gr eat t oe nail (i ncl u di n g t oe nail plate a n d a n y s u b u n g ual de bris) t hic ker  t ha n 
3 m m at t he Scree ni n g a n d Baseli ne  Visits.  
1 3.  Prese nce of o n yc h o d ystr o p h y t hat c o ul d i nterfere wit h cli nical assess me nts  as 
deter mi ne d b y t he  i n vesti gat or. 
1 4.  Hist or y  of  h y perse nsiti vit y  or  aller gic reacti o ns t o az ole deri vati ves  or  a n y of  t he 
st u d y dr u g c o nstit ue nts.  
1 5.  Prese nce of a n y u n d erl yi n g disease t hat, i n t he o pi ni o n of t he i n vesti gat or, c o ul d 
prese nt a safet y c o n cer n f or t he s u bject b y partici p ati n g i n t he st u d y. 
1 6.  S u bject has recei ve d treat me nt f or a n y t y p e of ca n cer i n t he pre vi o us 6 m o nt hs, 
e xce pt f or n o n mela n o ma s ki n ca ncer (e g, basal cell carci n o ma or  n o n metastatic 
s q ua m o us cell car ci n o ma) that was treate d  s uccessf ull y. 
1 7.  Prese nce of a n y d er mat ol o gical c o n diti o n o n t he feet t hat c o ul d i nterfere wit h 
cli nical e val uati o ns as deter mi ne d b y t he i n vesti gat or.  
1 8.  Prese nce of a n y u n d erl yi n g disease or d er mat ol o gical c o n diti o n ot her t ha n 
o n yc h o m yc osis t ha t re q uires t he use of i nterferi n g t o pical or s yste mic t hera p y a n d 
w o ul d ma ke e val u ati o ns i nc o ncl usi ve as deter mi ne d b y t he i n vesti gat or, or s u bject 
re q uires tr eat me nt wit h a t o pical pr o d uct o n t he t oe nails ot her t ha n t he st u d y dr u g 
d uri n g t he  st u d y. 
1 9.  S u bjec ts usi n g t he f oll o wi n g t o pical pre parati o ns wit hi n t he i n dicate d ti me pri or t o 
t he Baseli ne Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g t o pical 
pre par ati o ns d uri n g t he  st u d y: 
•  T oe nail p olis h, c os metic t oe nail pr o d ucts, or t o pical prescri pti o n  or o ver -t he- 
c o u nter a ntif u n g al t hera p y f or ti nea pe dis: 1  da y  
•  Ot her t o pical pr escri pti o n or o ver -t he-c o u nter me dicati o ns t o t he feet or t oe nails 
( wit h t he e xce pti o n of bl a n d e m ollie nts): 2 wee ks  
•  T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t oe n ails, 
i ncl u di n g de vices t o treat o n yc h o m yc osis: 4 wee ks  
•  T o pical c ortic oster oi ds f or t he feet: 2  wee ks  
2 0.  S u bjects usi n g t he f oll o wi n g s yste mic me dicati o ns wit hi n t he i n dicate d ti me pri or  t o 
t he Baseli ne Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g s yste mic 
me dicati o ns d uri n g t he  st u d y: 
•  S yste mic a ntif u n gal t hera p y: 4  wee ks  
•  M ore t ha n t w o, 2 -w ee k c o urses of oral c ortic oster oi d t hera p y or 1 i ntra m us c ular, 
i ntra ve n o us, or i ntra-artic ular i njecti o n of c ortic ost er oi ds ( nasal ster oi d s pra ys a n d 
ster oi d i n halers ar e per mitte d if use is sta ble a n d n ot e x pecte d t o c ha n ge d uri n g 
t he st u d y): 3 m o nt hs  


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C O N FI D E N TI A L  
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•  S yste mic i m m u n os u p pressi ve a ge nts: 6  m o nt hs  
2 1.  S u bject has pre vi o usl y bee n n o nres p o nsi v e t o s yste mic a ntif u n gal t hera p y f or 
o n yc h o m yc osis.  
2 2.  S u bject is u na ble t o c o m m u nicate or c o o p erate wit h t he i n vesti gat or d ue t o la n g ua ge 
pr o ble ms, p o or me ntal de vel o p me nt, or i m paire d cere bral  f u ncti o n. 
2 3.  Use of a n y i n v esti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 half -li ves ( w hic he ver 
is l o n ger) pri or t o t he Scree ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her cli nical 
st u d y wit h a n i n vesti gati o nal dr u g or de vice.  
 
8. 3  S u bject Wit h dr a w al  Criteri a  
W he n p ossi ble, s u bjects w h o disc o nti n ue fr o m t he st u d y pri or t o c o m pleti n g t he 4 8 -wee k 
treat me nt peri o d s h o ul d r et ur n t o t he i n vesti gati o nal ce nter t o p erf or m t he assess me nts 
sc he d ule d f or Wee k 4 8. If a p pr o priat e, disc o nti n ue d s u bjects ma y be place d o n ot her 
c on ve nti o nal t hera p y u p o n re q uest or w h e ne v er cli nicall y necess ar y, as d eter mi ne d b y t he  
p h ysicia n. T he E n d of St u d y s o urce d oc u m e nts a n d all rele va nt dat a s h o ul d be e ntere d i nt o 
t he electr o nic cas e re p ort f or m (e C R F) s yste m at t he ti me t he s u bject disc o nti nues fr o m t he 
st u d y. 
Reas o ns f or s u bject wit h dra wal ma y i ncl u d e, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  O n yc h o m yc osis pr o gressi o n, as deter mi ne d b y t he i n vesti gat or, w hic h  re q uires 
treat me nt wit h a pr o hi bite d t hera p y 
•  Eit her at t he i n vesti gat or's discreti o n f or safet y reas o ns (e g, se vere a d v erse reacti o ns 
or u na ut h orize d c o nc o mita nt t hera p y), or at t he s u bject’s re q u est f or pers o n al reas o ns 
•  W he n t he r e q uire me nts of t he pr ot oc ol are n ot  f oll o we d 
•  W he n a c o nc o mita nt t her a p y li kel y t o i nterfere wit h t he res ults of t he st u d y is 
re p orte d or re q uir e d b y t he s u bject (t he i n vesti gat or will re p ort all s uc h i nf or mati o n 
o n t he s o urce d o c u me nts/e C R Fs a n d deci de, i n acc or da nce wit h t he S p o ns or, w het her 
t he s u bject is t o be  wit h dra w n)  
•  W he n a s u bject is l ost t o f oll o w-u p; t he i n vesti gat or ( or desi g nee) will tr y t wice t o 
reac h t h e s u bject b y tele p h o ne, a n d will se n d a f oll o w-u p letter b y certifie d mail 
bef ore c o nsi deri n g t he s u bject as l ost t o f oll o w-u p; t hese act i o ns will be d oc u me nte d 
i n t he s o urce d oc u me nts a n d rec or de d o n t he E n d of St u d y e C R F, wit h a c o p y of t he 
f oll o w-u p letter mai ntai n e d i n t he i n vesti gat or's file 
•  If a s u bject b ec o mes pr e g na nt d uri n g t he treat me nt peri o d, t he st u d y dr u g will be 
disc o nti n ue d i m me diatel y, t he s u bject will be disc o nti n ue d fr o m t he st u d y, a n d t he 
i n vesti gat or will n otif y t he s p o ns or. T he pre g na n c y will be f oll o we d t o ter m wit h t he 
o utc o me re p ort e d t o t he  s p o ns or. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
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Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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9  Tre at me nts  Pl a n ne d  
9. 1  Met h o ds of Assi g ni n g S u bjects t o Tre at me nt  Gr o u ps  
T his is a si n gle -ar m, o pe n la bel st u d y. After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit, 
s u bjects will be e nr olle d i n t he treat me nt peri o d a n d will recei ve efi nac o naz ole i n acc or da n ce 
wit h t he pr ot oc ol ( Secti o n 1 0).  
 
9. 2  R a n d o mi z ati o n a n d  Bli n di n g  
Ra n d o mizati o n a n d bli n di n g d o n ot a p pl y.  
P K assess me nts will be perf or me d o n a s u bset of t he st u d y p o p ulati o n. Eff orts will be ma de 
t o e nr oll s u bjects i nt o t he P K s u bset s uc h t hat t he y are e ve nl y distri b ute d acr oss t he re q uire d 
a ge ra n g e.  
 
9. 3  Tre at m e nt  C o m pli a nce  
S u bjects a n d t heir par e nts/le gal g uar dia ns will be dis pe nse d a n i nitial b ottle of st u d y dr u g at 
Baseli ne ( Da y 1). S u bjects a n d t heir pare nts/le g al g uar dia ns will be i nstr uct e d o n t he 
i m p orta nce of r et ur ni n g t he s u bject’s st u d y dr u g b ottle(s) at t he ne xt st u d y visit. If a s u bject 
d oes n ot ret ur n his/ her st u d y dr u g b ottle, he/s he will be i nstr ucte d t o ret ur n it at his/ her ne xt 
st u d y visit. A ne w st u d y dr u g b ottle will be dis pe nse d t o t he s u bjects at eac h p ost baseli ne 
st u d y visit t hr ou g h Wee k 4 4. S u bjects i n t he P K s u bset will be dis pe nse d 2 b ottles of st u d y 
dr u g at Baseli ne ( D a y 1), a n d will be dis pe nse d o n e b ottle of st u d y dr u g at eac h s u bse q ue nt 
st u d y visit t hr o u g h Wee k 4 4. All use d a n d u n use d st u d y dr u g b ottles will be c ollecte d at 
Wee k 4 8.  
T he i n vesti gati o nal ce nter staff will wei g h a n d rec or d eac h b ottle of st u d y dr u g bef ore 
dis pe nsi n g t o t he s u bject a n d t heir pare nt/le gal g uar dia n a n d f oll o wi n g ret ur n b y t he s u bject. 
B ottle wei g hts will be rec or de d i n t he i n di vi d ual st u d y dr u g l o g a n d i n t he a p pr o priate e C R F.  
At eac h p ost bas eli ne st u d y visit, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be as ke d 
t o re p ort a n y misse d d oses of st u d y dr u g, a n d pr o vi de t he date a n d a n e x pla nati o n f or eac h 
misse d d ose. A s u bject w h o has de viate d fr o m t he o nce dail y d osi n g re gi me n will be 
c o u nsele d i n t he pr ese nce of t heir pare nt/le gal g u ar dia n. T he d ates of a n y misse d d oses of 
st u d y dr u g will be rec or d e d i n t he s u bject’s s o urce d oc u me nt a n d a p pr o priate e C R F.  
 
9. 4  Tre at m e nt  A d mi nistr ati o n  
S u bj ects a n d t heir par e nts/le gal g uar dia ns will recei ve b ot h ver bal a n d writte n i nstr ucti o ns o n 
t he a p plicati o n of t he st u d y dr u g. T he s u bject a n d/ or t heir pare nt/le gal g uar dia n will a p pl y t he 
first d ose of st u d y dr u g at t he i n vesti gati o nal ce nter d uri n g t he Baseli ne Visit. All of t he 
re mai ni n g st u d y dr u g d oses will be a p plie d b y t he s u bject at h o me. T he s u bjects a n d t heir 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
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Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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pare nts/le gal g uar dia ns will be i nstr ucte d t o wait f or t he t oe nails t o air -dr y t h or o u g hl y bef ore 
t o uc hi n g wit h cl ot hi n g. 
D osi n g f or S u bjects N O T I ncl u de d i n t he P K S u bset: S u bjects a n d t heir pare nts/le gal 
g uar dia ns will be i nstr uct e d t o a p pl y t heir assi g ne d st u d y dr u g t o t he tar get great t oe nail a n d 
all ot her aff ecte d t o e nail(s) (if a n y) o n ce dail y at b e dti me. S u bjects a n d t heir  pare nts/le gal 
g uar dia ns will be i nstr uct e d t o c o nti n ue a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or 
t he e ntire treat me nt peri o d, e ve n if t he disease clears a n d n o affect e d area is o bser ve d o n t he 
tar get great t oe nail. If ot h er affect e d t oe nails treate d si nce baseli ne clear d uri n g t he c o urse of 
t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g u ar dia ns will be e nc o ura ge d t o c o nti n ue 
treat me nt o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me 
i nfecte d d uri n g t he stu d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y 
affecte d t oe n ail(s). All s u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y 
t he st u d y dr u g b y c o m pletel y c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f olds, 
t oe nail be d, h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he st u d y dr u g will be 
a p plie d t o eac h of t he ot h er i nfecte d t oe nails i n a si milar ma n ner.  
D osi n g f or S u bjects I ncl u de d i n t he P K S u bset:  
D a ys 1 t o 2 8 –  S u bjects a n d t heir pare nts/le g al g u ar dia ns will be i nstr ucte d t o a p pl y st u d y 
dr u g t o all 1 0 t oe nails, o nce dail y at be dti me. D uri n g t his peri o d, all P K s u bjects will be 
i nstr ucte d t o a p pl y t he st u d y dr u g b y c o m pletel y c o veri n g eac h t oe nail a n d 0. 5 c m of a djace nt 
s ki n, i ncl u di n g t he t oenail f ol ds, t oe nail be d, h y p o n yc hi u m, u n ders urface of t he t oe nail plate. 
T he s u bjects will n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( Da y 2 8) visit, n or will 
t he y a p pl y st u d y dr u g o n t he ni g ht of t he Wee k 4/ Da y 2 8 Visit. Wit hi n 1 h o ur after t h e 
pr e d ose bl o o d sa m ple is dra w n o n D a y 2 8, s u bjects will a p pl y st u d y dr u g t o all 1 0 t oe nails i n 
t he ma n ner des cri be d a b o ve at t he i n vesti gati o nal ce nter. 
D a ys 2 9 t o Wee k 4 8:  
After c o m pleti o n of t he P K p orti o n of t he st u d y, s u bjects a n d t heir pare nts/le gal g uar dia ns 
will be i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject’s tar get great t oe nail a n d all 
ot her aff ecte d t o e nail(s) o nce dail y at be dti me. S u bjects a n d t heir pare nts/le gal g uar dia ns  will 
be i nstr ucte d t o c o nti n ue a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire 
treat me nt peri o d, e ve n if t he disease cl ears a n d n o affecte d area is o bser v e d o n t he tar get 
great t oe nail. If ot h er aff ecte d t oe n ails treate d si n ce baseli ne clear d uri n g t he c o urse of t he 
st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt 
o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me i nfecte d 
d uri n g t he st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affect e d 
t oenail(s). All s u bjects a n d t heir pare nts/le gal g u ar dia ns will be gi ve n i nstr ucti o ns re gar di n g 
h o w  t o a p pl y t he st u d y dr u g,  ie, b y c o m plet el y c o v eri n g t he tar g et great  t oe n ail, i ncl u di n g t he 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
3 4  
 
 
 
t oe nail f ol ds, t oe nail be d, h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate (if 
o n yc h o m yc osis is prese nt). T he st u d y dr u g will be a p plie d t o eac h of t he ot her i nfecte d 
t oe nails i n a si milar ma n ner. 
 
9. 5  C o nc o mit a nt  Me dic ati o ns  
C o nc o mita nt me dicati o ns/t hera pies refer t o all me dicati o ns/t hera pies use d b y t he s u bject 
d uri n g t he st u d y. D uri n g t he c o urse of t h e st u d y, if a p pr o priate, e ver y atte m pt s h o ul d be  
ma de  t o kee p  t h e d osi n g  a n d re gi me n of  c o n c o mita nt  me dicati o ns/t hera pies  c o nsta nt, a n d  a n y 
c ha n ge t o a m e dicati o n/t hera p y d uri n g t he st u d y m ust be rec or de d. I nf or m ati o n o n 
c o nc o mita nt me dicati o ns/t hera pies (i ncl u di n g i n dicati o n, d osi n g, a n d start a n d st o p dates) 
will be rec or de d i n t he s o urce d oc u m e nt a n d o n t h e a p pr o pri ate e C R F. All c o nc o mita nt 
me dicati o ns/t hera pies (i n cl u di n g f o ot care pr o d ucts) use d d uri n g t he st u d y will be rec or d e d 
u n der C o nc o mita nt  Me di cati o ns.  
All pri or me dicati o ns (t h ose use d wit hi n 3 0 da ys pri or t o t he Scree ni n g Visit) a n d pre vi o us 
a ntif u n gal me dicati o ns use d b y t he s u bject, i ncl u di n g a n y rece nt o ver -t h e-c o u nter t o pical 
treat me nts (t h ose use d wit hi n 6 0 da ys pri or t o t he Scree ni n g Visit) will be rec or de d u n d er 
Pri or T hera pies i n t he e C R F (e g, as piri n, acet a mi n o p he n, birt h c o ntr ol pills, vita mi ns, her bal 
pr o d ucts, h o me o pat hic pr e parati o ns).  
D uri n g t he st u d y, all f o ot care pr o d ucts us e d b y t h e s u bject will be rec or de d u n der 
C o nc o mita nt T hera pies.  
9. 5. 1  
All o we d  Me dic ati o ns/ T her a pies  
C o nc o mita nt me dicati o ns ( prescri pti o n or o ver -t h e-c o u nter) t hat are c o nsi d ere d necessar y f or 
t he s u bject’s welf are a n d d o n ot i nterfere wit h st u d y assess me nts a n d e v al uati o ns will be 
all o we d d uri n g t he st u d y at t he i n vesti gat or’s discreti o n.  
If, d uri n g t he st u d y, a s u bject re q uires t o pical a ntif u n gal t hera p y f or ti nea p e dis, t he 
i n vesti gat or is t o d oc u me nt t he pr o ble m a n d t he i n vesti gat or-a p pr o v e d treat me nt o n t he A E 
a n d c o nc o mita nt t her a p y e C R Fs, res pecti vel y, a n d t o e ns ure t hat t he s u bject a v oi ds 
a p plicati o n of t he c o n c o mita nt t hera p y t o t he t oe nails or a djace nt s urr o u n di n g s ki n s urface.  
9. 5. 2  
Pr o hi bite d  Me dic ati o ns/ T her a pies  
N o t o pical treat me nts/ pr o d ucts will be all o we d o n t he t oes or feet ot her t ha n t he st u d y dr u g 
d uri n g t he st u d y, e xce pt f or i n vesti gat or -a p pr o v e d treat me nts.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
3 5  
 
 
 
Use of t he f oll o wi n g t o pical treat me nts is pr o hi bite d wit hi n t he i n dicate d ti me pri or t o t he 
Baseli ne Visit:  
 
T oe nail p olis h, c os metic t oe nail pr o d ucts, or t o pical prescri pti o n or o v er -t h e- 
c o u nter a ntif u n g al t hera p y f or ti nea pe dis  
1 da y  
Ot her t o pical pr escri pti o n or o ver -t he-c o u nter me dicati o ns t o t he feet or 
t oe nails ( wit h t he e xce pti o n of blan d e m ollie nts)  
2 wee ks  
T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t o e nails, 
i ncl u di n g de vices use d t o treat o n yc h o m yc osis 
4 wee ks  
T o pical c ortic oster oi ds f or t he feet  
2 wee ks  
 
Use of t he f oll o wi n g s yst e mic me dicati o ns is pr o hi bite d wit hi n t he i n dicate d ti me pri or t o t he 
Baseli ne Visit a n d f or t he d urati o n of t he st u d y:  
S yste mic a ntif u n gal t hera p y  
4 wee ks  
M ore t ha n t w o, 2 -w ee k c o urses of oral c ortic oster oi d t hera p y or  
1 i ntra m usc ular, i ntra v e n o us, or i ntra-artic ular i njecti o n of c ortic oster oi ds a 
3 m o nt hs  
S yste mic i m m u n os u p pressi ve a ge nts  
6 m o nt hs  
a Nasal ster oi d s pra ys a n d ster oi d i n halers are per mitte d if use is sta ble a n d n ot e x pecte d t o c ha n ge 
d uri n g t he st u d y.  
I n a d diti o n, use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 h alf-li ves 
( w hic he ver is l o n ger) pri or t o t he Scree ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her 
cli nical st u d y wit h a n i n vesti gati o nal dr u g or de vice d uri n g t he st u d y peri o d i s n ot all o we d. 
If a s pecific me dicati o n/t hera p y has t h e p ote ntial t o i nterfere wit h t he treat me nt effect of t he 
st u d y dr u g or i nter pretati o n of t he st u d y res ults, t he i n vesti gat or s h o ul d c o ntact t he me dical 
m o nit or pri or t o use (if p ossi ble).  
A n y s u bject u si n g a pr o hi bite d t hera p y d uri n g t he c o urse of t he st u d y t hat c o ul d i nterfere 
wit h t he treat me nt effect of t he st u d y dr u g or i nter pretati o n of t he st u d y res ults (i ncl u di n g, 
b ut n ot li mite d t o, t h ose liste d a b o ve) ma y b e wit h dra w n fr o m t he st u d y at t he disc reti o n of 
t he i n vesti gat or a n d/ or s p o ns or. H o we ver, t he i n vesti gat or s h o ul d n ot wit h dra w a s u bject 
wit h o ut first c o nfir mi n g it wit h t he s p o ns or.  
 
9. 6  Pr ot oc ol D e vi ati o ns a n d  Vi ol ati o ns  
A de viati o n fr o m t he pr ot oc ol is a n u ni nte n de d a n d/ or u na ntici pate d de p art ure fr o m t he 
pr oce d ur es a n d/ or pr ocesses a p pr o ve d b y t h e s p o ns or a n d t he i nstit uti o nal re vie w b oar d 
(I R B) or i n de pe n d e nt et hics c o m mittee (I E C) a n d a gree d t o b y t he i n v esti gat or. De viati o ns 
us uall y ha ve a n i m pact o n i n di vi d ual s u bjects or a s mall gr o u p of s u bjects a n d d o n ot i n v ol ve 
i ncl usi o n/e xcl usi o n or pri mar y e n d p oi nt criteri a. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
3 6  
 
 
 
A pr ot oc ol vi olati o n occ urs w he n t here is n o na d h ere nce t o t he pr ot oc ol t hat res ults i n a  
si g nifica nt, a d diti o nal ris k t o t he s u bject, w he n t he s u bject or i n vesti gat or has faile d t o a d h ere 
t o si g nifica nt pr ot oc ol re q uire me nts (i ncl usi o n/e x cl usi o n criteria) a n d t he s u bject was 
e nr olle d wit h o ut pri or s p o ns or a p pr o val, or w he n t here is n o na d here n ce t o U S F o o d a n d Dr u g 
A d mi nistrati o n re g ulati o ns a n d/ o r I nter n ati o nal C o nfere n ce o n H ar m o nisati o n (I C H) G o o d 
Cli nical Practice ( G C P)  g ui deli ne.  
T he i n vesti gat or or desi g nee m ust rec or d a n d e x pl ai n i n t he s u bjects’ s o urce d oc u me ntati o n 
a n y de viati o n fr o m t he a p pr o ve d pr ot oc ol. T he i n vesti gat or ma y i m ple me nt a de viati o n fr o m, 
or a c ha n ge of, t he pr ot oc ol t o eli mi nate a n i m me diate hazar d t o st u d y s u bjects wit h o ut pri or 
I R B/I E C a p pr o v al. As s o o n as p ossi ble after s u c h a n occ urre n ce, t he i m ple me nte d de viati o n 
or c ha n ge, t h e reas o ns f or it, a n d a n y pr o p ose d pr ot oc ol  a me n d me nt(s) s h o ul d be s u b mitte d 
t o t he s p o ns or f or a gr ee m e nt, t o t he I R B/I E C f or re vie w a n d a p pr o v al, a n d t o t he re g ulat or y 
a ut h orities, if re q uire d. 
 
1 0  St u d y Dr u g M ateri als a n d  M a n a ge me nt  
T he st u d y dr u g will be pr o vi de d t o t he i n vesti gati o nal ce nters b y t h e s p o ns or a n d will be 
dis pe nse d t o t he s u bject a n d t heir pare nt/le g al g uar dia n b y t he p har mac y or a n a p pr o pri atel y 
q ualifie d me m ber of t h e st u d y staff assi g ne d b y t h e i n vesti gat or.  
All la b orat or y kits c o ntai ni n g materials n ecess ar y t o c ollect bl o o d a n d ur i n e f or r o uti ne 
cli nical la b orat or y tests, uri ne pre g n a nc y tests, f u n gal c ult ures, a n d P K a n al yses will be 
s u p plie d t o t he i n vesti gati o nal ce nters b y t he d esi g nate d ce ntral la b orat ories. 
 
1 0. 1  St u d y  Dr u g  
A descri pti o n of t he st u d y dr u g is i ncl u de d i n Ta ble 2.  
T a ble 2. St u d y Dr u g I de ntific ati o n  
 
 
I n vesti g ati o n al Pr o d uct 
Dr u g Na me  
Efi nac o naz ole 1 0 % s ol uti o n f or t o pical a d mi nistrati o n  
Na me of Acti ve I n gre die nt  
Efi nac o naz ole  
Ma n ufact urer  
Valea nt P har mace uticals  
C he mical Na me  
( 2 R, 3 R)-2 -( 2, 4-difl u or o p he n yl) -3 -( 4-met h yle ne pi peri di n -1 - 
yl) -1 -( 1 H-1, 2, 4 -triaz ol-1 -yl) b uta n -2 -ol  
C he mical F or m ula/ M olec ular Wei g ht  
C 1 8H 2 2F 2N 4O / 3 4 8. 3 9 a m u  
T hera pe utic Cate g or y  
A ntif u n gal  
A p peara nce  
Clear t o yell o w s ol uti o n 
I nacti ve I n gre die nts 
Alc o h ol, a n h y dr o us citric aci d, b ut ylate d h y dr o x yt ol ue ne, 
C 1 2 -1 5 al k yl lactate, c ycl o met hic o ne, diis o pr o p yl a di pate, 
dis o di u m e detate, a n d p urifie d water.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
3 7  
 
 
 
1 0. 1. 1  P ac k a gi n g a n d  L a beli n g  
Efi nac o naz ole will be pr o vi de d t o t he i n vesti gati o nal ce nters i n 1 0 m L b ottles c o ntai ni n g 
8 m L of st u d y dr u g per b ottle. I n di vi d ual b ottles will be s u p plie d t o t he i n vesti gati o nal 
ce nter. T h e s u bjects a n d t heir par e nts/le gal g uar dia ns will be dis pe nse d 1 b ottle at t he  
Baseli ne Visit a n d 1 b ottle at eac h s u bse q ue nt st u d y visit t hr o u g h Wee k 4 4. S u bjects i n t he 
P K s u bset will be dis pe nse d 2 b ottles of st u d y dr u g at t he Baseli ne Visit, a n d will be 
dis pe nse d o ne b ottle of st u d y dr u g at eac h s u bse q u e nt st u d y visit t hr o u g h Wee k 4 4.  
T he  la bel o n eac h b ottle of st u d y dr u g will i de ntif y t he pr o d uct as “ Efi nac o naz ole”. T h e la bel 
o n t he st u d y dr u g b ottles will c o ntai n t he f oll o wi n g i nf or mati o n:  
•  Pr ot oc ol  n u m ber  
•  Kit  n u m ber  
•  Pr o d uct i de ntificati o n ( Efi nac o naz ole 1 0 %  S ol uti o n)  
•  S u bject  n u m ber   
 
•  S u bject  i nitials  
 
•  Date  dis pe nse d    
 
•  A state me nt i n dicati n g t he v ol u me of t he c o nte nts as 8  m L  
•  I nstr u cti o ns t o kee p b ottle ti g htl y cl ose d a n d st ore i n a n u pri g ht p ositi o n at r o o m 
te m perat ur e ( 2 0° C t o 2 5° C [ 6 8º F t o 7 7º F]), wit h e xc ursi o ns per mitte d bet w ee n 
1 5º C a n d 3 0º C ( 5 9º F a n d 8 6º F)  
•  L ot n u m ber/e x pirati o n  date  
•  S p o ns or na me a n d  a d dress  
•  A state me nt i n dicati n g, “ Ca uti o n: Ne w Dr u g - Li mite d b y Fe deral L a w t o 
I n v esti gati o nal Use”  
•  A state me nt i n dicati n g t hat t he dr u g s h o ul d be ke pt o ut of reac h of c hil dre n 
A d diti o nal i nf or mati o n ma y be i ncl u de d o n t he b ottle la bel as  necess ar y.  
1 0. 1. 2  St or a ge, H a n dli n g, a n d Dis p os al of St u d y  Dr u g  
St u d y dr u g s h o ul d be st ore d i n a sec ure area at t he i n vesti gati o nal ce nter acc or di n g t o l ocal 
re g ulati o ns, i n a n u pri g ht p ositi o n at c o ntr olle d r o o m te m perat ure ( 2 0° C t o 2 5° C [ 6 8º F t o 
7 7º F]), wit h e x c ursi o ns p er mitte d bet wee n 1 5° C a n d 3 0º C ( 5 9º F a n d 8 6º F).  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
3 8  
 
 
 
S u bjects a n d t heir par e nts/le gal g ua r dia ns will be i nstr ucte d t o kee p t heir st u d y dr u g b ottle at 
r o o m te m perat ur e, o ut of t he reac h of c hil dre n, n ot t o s hare t he st u d y dr u g wit h a n y o ne else, 
a n d t o use it o nl y o n t he affecte d t oe n ails as direct e d b y t he i n vesti gat or. S u bjects a n d t heir 
pare n ts/le gal g uar dia ns will be as ke d t o n otif y t he i n vesti gati o nal ce nter i m me diatel y if a 
st u d y dr u g b ottle is da ma ge d or l ost. 
All use d a n d u n use d st u d y dr u g s u p plies will be ret ur ne d t o t he s p o ns or f or destr ucti o n.  
 
1 0. 1. 3  St u d y Dr u g  Pre p ar ati o n  
N ot a p plica ble; s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will a p pl y t he st u d y dr u g 
directl y fr o m t he st u d y dr u g b ottles.  
 
1 0. 2  St u d y Dr u g  Acc o u nt a bilit y  
T he I n vesti gat or or d esi g nee will be res p o nsi ble f or kee pi n g c urre nt a n d acc urate rec or ds of 
t he a m o u nt of st u d y dr u g recei v e d a n d dis pe nse d, a n d its dis p ositi o n. T he st u d y dr u g m ust be 
st ore d u n der t he a p pr o pri ate c o n diti o ns i n a sec ure area a n d is t o be dis pe ns e d o nl y t o 
s u bjects e nr olle d i n t he st u d y, i n acc or d a nce wit h t he c o n diti o ns s pecifie d i n t his pr ot oc ol. 
D uri n g t h e c o urs e of t he st u d y, t he I n v esti gat or or desi g nee m ust mai ntai n a n i n ve nt or y of all 
st u d y dr u g dis pe nse d t o or ret ur ne d b y t h e s u bject, i ncl u di n g s u bject i de ntifiers.  
A st u d y dr u g acc o u nt a bilit y l o g will be c o m plete d b y t he i n vesti gat or or desi g nee t o 
d oc u me nt t he recei pt, dis pe nsati o n, a n d ret ur n of st u d y dr u g b ottles.  
All s u p plies se nt t o t he I n vesti gat ors will be acc o u nte d f or a n d, i n n o case, use d i n a n y 
u na ut h orize d sit uati o n. B ottles will be wei g he d ( wit h t he ca p o n) bef ore dis pe nsi n g t o a n d 
u p o n ret ur n b y t he s u bjects, a n d wei g hts will be rec or de d o n t he p h ar mac y l o g a n d 
a p pr o priate C R F. All use d a n d u n use d s u p plies will be ret ur ne d t o s p o ns or/ desi g nee f or 
destr ucti o n at t he c o n cl usi o n of t he st u d y.  
 
1 1  St u d y Pr oce d ures a n d  E v al u ati o ns  
1 1. 1  Sc he d ule of E v al u ati o ns a n d  Pr oce d ures  
All s u bject i nf or mati o n a n d data o btai ne d d uri n g t he st u d y visit pr oce d ures m ust be rec or d e d 
i n t he s o urce d oc u m e nts, a p plica ble st u d y l o gs, a n d e C R Fs. 
1 1. 1. 1  Scree ni n g Visit ( Visit 1, U p t o D a y -4 2)  
After si g ni n g t he i nf or m e d c o nse nt/asse nt, s u bjects will u n der g o t he scree ni n g pr oce d ures t o 
c o nfir m eli gi bilit y t o partici pate i n t he st u d y.  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
3 9  
 
 
 
1.  Re vie w a n d e x plai n t he n at ure of t he st u d y. Pr o vi d e a visit sc he dule wit h t he le n gt h 
of eac h visit t o e ns ure t hat t he s u bject ca n meet t he re q uire me nts a n d h as a d e q uate 
tra ns p ortati o n. 
2.  O btai n ver bal a n d writte n i nf or me d c o nse nt/asse nt fr o m t he s u bject a n d t he  s u bject’s 
pare nt(s) or le gal g uar dia n(s) pri or t o perf or mi n g a n y st u d y -relate d pr o ce d ures. 
Pr o vi de si g ne d c o pies of t he c o nse nt a n d ass e nt f or ms t o t he s u bject/ pare nt(s) or 
le gal g uar dia n(s).  
3.  O btai n p h ot o gra p h y c o ns e nt/asse nt fr o m s u bject a n d/ or t he s u bjec t’s pare nt(s) or 
le gal g uar dia n(s).  
4.  Assi g n a 6 -di git st u d y n u m ber, w hic h i ncl u des t he 3 -di git i n vesti gati o nal  ce nter 
n u m ber pl us a u ni q ue 3 -di git s u bject n u m ber be gi n ni n g wit h 0 0 1 (e g, 0 0 1 -0 0 1, 
0 0 1 -0 0 2, 0 0 1 -0 0 3). N u m bers m ust be assi g ne d i n c hr o n ol o gical  o r d er. 
5.  Rec or d s u bject’s de m o gr a p hic i nf or mati o n (se x, date of birt h, a ge, et h nicit y,  a n d 
race). 
6.  Rec or d s u bject’s me di cal hist or y i ncl u di n g dia betes  hist or y.  
7.  C olle ct a detaile d hist or y of o n yc h o m yc osis, i ncl u di n g a n esti mate d start date of 
i nfecti o n, d urati o n of c urre nt i nfecti o n i n t he p ote ntial tar get great t oe n ail, a n d all 
pre vi o us t hera pies us e d f or o n yc h o m yc osis  treat me nt. 
8.  Re vie w all pri or me dicati o ns (t h ose us e d wit hi n 3 0 da ys pri or t o t he Scree ni n g Visit) 
a n d pre vi o us a ntif u n gal me dicati o ns use d b y t he s u bject, i ncl u di n g a n y  rece nt 
o ver -t he-c o u nter t o pical treat me nts (t h ose use d wit hi n 6 0 da ys pri or t o t he Scree ni n g 
Visit).  
9.  
Re vie w i ncl usi o n/e xcl usi o n  criteria.  
1 0.  E xa mi nati o n of t oe nails f or cli nical pres e nce of o n yc h o m yc osis i n at least 1 great 
t oe nail, wit hi n t he defi niti o n of eli gi bilit y criteria. F or s u bjects i n t he P K p o p ulati o n, 
b ot h great t oe nails a n d 4 ot her t oe nails m ust meet eli gi bilit y criteria. 
1 1.  E xa mi nati o n of  all ot her t oe nails f or prese nce or a bse nce of o n y c h o m yc osis o n eac h 
t oe nail. 
1 2.  E xa mi nati o n of b ot h feet f or pres e nce of s y m pt o matic ti nea pe dis; res c he d ule 
c o m pleti o n of Scree ni n g after a p pr o priat e treat me nt a n d was h o ut, as  a p plica ble.  
1 3.  Cli p t he t oe nails ( bef ore perf or mi n g nail meas ure me nts). Re mi n d s u bject a n d t heir 
pare nt/le gal g uar dia n n ot t o cli p t oe nails at h o me i n bet wee n  visits.  
1 4.  Perf or m t he i n vesti gat or’s assess me nt of t he great t oe nail(s) wit h a calc ulati o n of  t he 
perce nt a ge of t o e nail aff ecte d wit h disease, after cli p pi n g t he u n healt h y t oe nail. If 
t he great t oe n ail has bee n cli p pe d pr o xi mal t o t he distal gr o o ve, t he e ntire area t o t he 
distal  gr o o ve s h o ul d be i ncl u de d. T he i n vesti gat or/e val uat or will use a fi ne ti p pe d 
mar ker t o o utli ne t he area affecte d o n t h e tar get great  t o e nail. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 0  
 
 
•  S u bjects n ot i ncl u de d i n t he P K s u bset m ust ha v e at least 1 great  t oe nail 
wit h � 2 0 % i n v ol ve me nt  
•  S u bjects i ncl u de d i n t he P K s u bset m ust ha ve b ot h great t oe nails  i n v ol ve d 
wit h � 5 0 % i n v ol ve me nt i n eac h great t oe nail.  
 
1 5.  O btai n s peci me ns fr o m t he great t oe n ail(s) f or f u n gal c ult ure a n d K O H e x a mi nati o n. 
B ot h great t oe nails ma y be sa m ple d if b ot h are s us pecte d of ma nifesti n g 
o n yc h o m yc osis (at least 2 0 %  i n v ol ve me nt). 
1 6.  Perf or m t he K O H e xa mi nati o n o n site. If n e gati ve, scree n -fail t he s u bject a n d st o p 
t he Scree ni n g Visit. If p ositi ve, o btai n a d diti o nal sa m ples fr o m t he sa me area of t he 
t oe nail t o se n d t o t he ce ntral m yc ol o g y la b orat or y f or c o nfir m ati o n of t he K O H 
e xa mi nati o n a n d f u n gal c ult ure per i nstr ucti o ns pr o vi de d i n t he la b ma n ual.  
1 7.  Perf or m a uri n e pre g n a nc y test 1 f or all F O C B P.2 E xcl u de t he s u bject if t he 
pre g na nc y t est res ult is p ositi ve.  
Uri ne pre g n a ncy testi n g is m a n d at ory f or all F O C B P at t he Scree ni n g Visit, 
B aseli ne Visit, a n d at all s u bse q ue nt st u dy visits. T he decisi o n m ay be m a de by 
t he i nvesti g at or t o d o a d diti o n al uri ne pre g n a ncy tests d uri n g t he c o urse of t he 
st u dy. 
1 8.  C ollect bl o o d a n d uri ne sa m ples f or r o uti ne safet y la b orat or y  a nal ysis ( he m at ol o g y, 
ser um c he mistr y, a n d uri nal ysis). Pr ocess a n d s hi p t he sa m ples t o t he ce ntral safet y 
la b orat or y per i nstr ucti o ns pr o vi de d i n t he la b orat or y ma n ual.  
1 9.  Sc he d ule s u bject t o ret ur n f or t he Baseli ne Visit ( Visit 2, Da y  1).  
If a s u bject f ails scree ni n g, eit her at t he Scree ni n g or B aseli ne visit ( pri or t o 
e nr oll me nt t o tre at me nt), t he s u bject m ay be rescree ne d at a l ater d ate. S u bjects 
w h o are rescree ne d will be assi g ne d a ne w scree ni n g n u m ber, m ust be re - 
c o nse nte d, a n d u n der g o all scree ni n g pr oce d ures per pr ot oc ol . 
 
 
 
 
 
 
1 Uri ne pre g na nc y tests m ust ha ve a mi ni m u m se nsiti vit y of 2 5 mI U of h u ma n c h ori o nic g o na d otr o pi n per m L 
of uri ne. Uri ne pre g na nc y test kits will be pr o vi de d b y t he s p o ns or.  
 
2 F O C B P i ncl u de a n y fe male s u bjects w h o ha ve e x perie nce d me narc he a n d w h o ha ve n ot u n der g o ne s uccessf ul 
s ur gical sterilizati o n ( h ysterect o m y, bilateral t u bal li gati o n, or bilateral o o p h orect o m y) or are n ot 
p ost me n o pa usal ( defi ne d as a me n orr hea f or > 1 2 c o nse c uti ve m o nt hs or w o me n o n h or m o ne re place me nt 
t hera p y wit h d oc u me nte d plas ma f ollicle-sti m ulati n g h or m o ne le vels > 3 5 m L U/ m L). E ve n a fe male s u bject 
w h o is usi n g a n oral, i m pla nte d, i njecta ble, or tra ns der mal c o ntrace pti ve h or m o ne, a n i ntra uteri ne de vice, a 
c o n d o m wit h s per mici de, or a dia p hra g m wit h s per mici de t o pre ve nt pre g na nc y, or is practici n g a bsti ne nce, 
s h o ul d be c o nsi dere d of c hil d beari n g p ote ntial. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 1  
 
 
 
1 1. 1. 2  B aseli ne Visit ( Visit 2, D a y  1)  
If t he Baseli ne Visit is m ore t ha n 4 2 da ys after t h e Scree ni n g Visit, t he s u bject m ust be 
re p orte d as a scr ee n fail ure a n d t he n ma y b e rescree ne d ( wit h a ne w s u bject n u m ber) at t he 
i n vesti gat or’s discreti o n. 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bjects a n d t hei r pare nts/le gal g uar dia ns, “ Are t h ere a n y 
c ha n ges i n y o ur healt h si nce t he last visit?”).  
2.  C o nfir m p ositi ve K O H a n d c ult ure res ults fr o m t h e ce ntral m yc ol o g y  la b orat or y. 
•  All s u bjects (i ncl u di n g t h ose i n P K s u bset) m ust h a ve at least 1 great t oe n ail 
wit h p os iti ve K O H (c o nfir me d b y ce ntral m yc ol o g y la b) a n d p ositi ve 
der mat o p h yte c ult ure f or T r u br u m or T  me nt a gr o p hytes.  
3.  Re vie w t he saf et y la b orat or y test  res ults. 
If a ny s afety l a b or at ory test res ults o bt ai ne d at t he Scree ni n g Visit, w hic h will be 
receive d by t he i nvesti g at or pri or t o c o n d ucti n g t he B aseli ne Visit, are a b n or m al 
a n d cli nic ally si g nific a nt as deter mi ne d by t he i n vesti g at or, t he i nvesti g at or 
s h o ul d disc uss wit h t he me dic al m o nit or w het her it is i n t he s u bject’s best i nterest 
t o p articip ate i n t he st u dy.  
4.  C o nfir m t he s u bject’s me dical hist or y a n d pri or m e dicati o n  uses.  
5.  Re vie w all c o nc o mita nt me dicati o ns a n d ne w me dicati o ns starte d si nce t h e last st u d y 
visit.  
6.  O btai n vital si g n meas ure me nts. Vital si g ns will be meas ure d after t he s u bj ect is 
seate d f or at least 5 mi n utes, a n d will i ncl u de s yst olic a n d diast olic bl o o d press ure, 
p ulse rate, r es pirat or y r at e, a n d oral b o d y  te m perat ure. 
7.  Meas ure h ei g ht a n d  w ei g ht.  
8.  C o n d uct a n a b bre vi ate d p h ysical e xa mi nati o n (e x cl u di n g  ur o ge nital/re pr o d ucti ve 
s yste ms). 
9.  Perf or m a uri n e pre g n a nc y test f or all F O C B P. E xcl u de t he s u bject if t he pre g na nc y 
test res ult is p ositi ve.  
1 0.  Cli p  t he t oe nails t o t he distal  gr o o ve  ( bef ore p erf or mi n g  t oe nail meas ure me nts  a n d 
cl ose-u p  p h ot o gr a p h y).  
1 1.  C o n d uct t he i n vesti gat or’s assess me nt of t he great t oe nail (s), wit h a deter mi nati o n 
of t he per ce nta g e of t oe n ail affecte d wit h diseas e. Meas ure t he dista n ce fr o m t he 
pr o xi mal nail f ol d t o t he pr o xi mal  o n yc h o m yc otic  b or der.  
•  S u bjects n ot i ncl u de d i n t he P K s u bset m ust ha v e at least 1 great  t oe nail 
wit h � 2 0 % i n v ol ve me nt  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 2  
 
 
•  S u bjects i ncl u de d i n t he P K s u bset m ust ha ve b ot h great t oe nails  i n v ol ve d 
wit h � 5 0 % i n v ol ve me nt i n eac h great t oe nail. 
1 2.  Select tar get gr eat t oe nail i n eac h eli gi ble s u bject f or efficac y assess me nts. W here 
b ot h great t oe nails ar e st u d y -eli gi ble (i ncl u di n g perce nt i n v ol ve me nt,  K O H -p ositi ve, 
a n d c ult ure-p ositi ve r es ults), t he t oe na il wit h t he greater perce nt affecte d area at t he 
Baseli ne Visit will be selecte d as t he t ar get great t oe nail pri or t o e nr oll me nt i n t he 
treat me nt peri o d. I n t h e i nsta nce w here t he p erce nt affecte d area is t he sa m e f or b ot h 
st u d y-eli gi ble great t oe nails at t he Baseli ne Visit, t he i n vesti gat or ma y c h o ose eit her 
great t oe nail t o be t he tar get great t oe nail. 
1 3.  I ns cri be a tra ns verse n otc h i n t he great t oe nail at t he pr o xi mal nail f ol d wit h a file or 
scal pel. T his will be use d as a mar k er at s u bse q u e nt visits f or deter mi ni n g ne w 
t oe nail gr o wt h.  
1 4.  Perf or m t he i n vesti gat or’s assess me nt of t he n o ntar get t oe nails f or t he pres e nce or 
a bse nce of o n yc h o m yc osis. S u bjects i n t he P K s u bset m ust ha ve at least 4 t oe nails 
ot her t ha n t he gr eat t oe nails wit h  o n yc h o m yc osis.  
1 5.  Ta ke cl os e -u p p h ot o gra p hs of t he tar get great t oe n ail. T he first p h ot o gra p h will be 
ta ke n after t oe nail cli p pi n g. After t hat p h ot o gra p h is ta ke n, t he i n vesti gat or/e val uat or 
will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n t he tar get great t oe nail. 
W he n  t he mar k er i n k h as drie d, a sec o n d cl ose -u p p h ot o gra p h will be  ta ke n. 
1 6.  Re vie w i ncl usi o n/e xcl usi o n criteria. If t he s u bject c o nti n ues t o meet all i ncl usi o n 
criteria a n d n o ne of t he e xcl usi o n criteria, e nr oll t he s u bject i n t he treat me nt peri o d.  
1 7.  O btai n 1 b ottle of st u d y dr u g a n d wei g h t he b ottle. Rec or d t he assi g ne d b ottle 
n u m ber f or t he st u d y dr u g i n t he s u bject’s s o urce d oc u me nt a n d o n t he a p pr o priate 
e C R F. Dis pe nse t he b ottl e t o t he s u bject a n d t heir pare nt/le gal g uar dia n (c o m plete 
t he la bel a nd r e q uire d r ec or ds). F or s u bj ects i n t he P K s u bset, 2 b ottles of st u d y dr u g 
s h o ul d be o btai ne d. T he b ottles s h o ul d be wei g he d se parat el y a n d rec or d e d as 
se parat e e ntries, as descri be d a b o ve.  
1 8.  I nstr u ct t he s u bject a n d t heir pare nt/le gal g uar dia n o n diar y c o mpleti o n a n d  dis pe nse 
diar y.  
1 9.  T he s u bject or t heir p are nt/le gal g uar dia n will a p pl y t he first d ose of st u d y dr u g i n 
t he i n vesti gati o nal ce nter. I nstr u ct t he s u bject a n d t heir pare nt/le gal g u ar dia n i n t he 
pr o per a p plicati o n tec h ni q ue f or t he st u d y dr u g a n d pr o vi de t he a p pr o priate S u bject 
I nstr u cti o n S heet wit h d osi n g i nstr ucti o ns (ie, f or n o n-P K or P K s u bjects),  de pe n di n g 
o n w het her t he s u bject is e nr olle d i n t he P K s u bset. Rec or d a n y A Es f oll o wi n g t he 
i nitial treat me nt a p plicati o n. 
2 0.  Rec or d l ocal s ki n r eacti o ns . I nstr u ct t he s u bject a n d t heir pare nt/le gal g u ar dia n t o 
re p ort l ocal s ki n r eacti o ns (if a n y) at eac h st u d y visit.  
2 1.  Sc he d ule t he ne xt st u d y visit ( Visit 3 [ Wee k 4, Da y 2 8]) i n 2 8 da ys ( ± 5 da ys). 
I nstr u ct t he s u bject a n d t heir pare nt/le gal g uar dia n t o ret ur n f or eac h st u d y visit at t he 
sa me ti me of da y as t he Baseli ne Visit.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 3  
 
 
 
N ote: ( ± 5 d ays) o nly a p plies t o N o n -P K s u bjects, P K s u bset o nly h as a ( ± 1 d ay) 
visit wi n d o w 
•  F or s u bjects i n t he P K s u bset, Visit 3 ( Wee k 4, D a y 2 8) t o Visit 3 A ( Wee k 
4, Da y 2 9) r e mi n d s u bjects n ot t o a p pl y st u d y dr u g t he ni g ht pri or t o t heir 
Visit 3 ( Wee k 4, Da y 2 8)  visit.  
1 1. 1. 3  Visit 3 ( Wee k 4, D a y 2 8 [ ± 5 d a ys]), Visit 4 ( Wee k 8 [ ± 5 d a ys]), Visit 6 ( Wee k 1 6 
[ ± 5 d a ys]), Visit 7 ( Wee k 2 0 [ ± 5 d a ys]), Visit 9 ( Wee k 2 8 [ ± 5 d a ys]), Visit 1 0 
( Wee k 3 2 [ ± 5 d a ys]), Visit 1 2 ( Wee k 4 0 [ ± 5 d a ys]), Visit 1 3 ( Wee k 4 4 [ ± 5 d a ys])  
Visits are t o be sc he d ul e d i n refer e nce t o Visit 2 ( Baseli ne). 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bjects a n d t heir pare nts/le gal g uar dia ns, “ Are t h ere a n y 
c ha n ges i n y o ur healt h si nce t he last visit?”).  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he  t oe nails. 
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse n otc h). If t he m ost rece ntl y a p plie d n otc h h as gr o w n 
o ut or has bee n cli p pe d off, i nscri be a ne w n otc h a djace nt t o t he pr o xi mal n ail  f ol d. 
6.  C oll ect t he diar y a n d st u d y dr u g b ottle fr o m t he s u bject a n d/ or t heir pare nt/le gal 
g uar dia n. Wei g h t h e use d b ottle of t h e st u d y dr u g. Rec or d t he n u m ber of misse d 
d oses fr o m t he s u bject di ar y a n d re vie w c o m plia nce wit h t he  s u bject. 
7.  C o n d uct a uri ne pre g na nc y tes t o n F O C B P s u bjects ( disc o nti n ue a n y s u bject fr o m 
t he st u d y w h o has a p ositi ve test res ult) 
8.  O btai n 1 b ottle of st u d y dr u g a n d wei g h t he b ottle, c o m plete t he la bel a n d dr u g l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d t heir p are nt/le gal g uar dia n. Re vie w t he 
d osi n g i nstr ucti o ns wit h t he s u bject. ( S u bjects i n t he P K s u bset will n ot be dis pe nse d 
st u d y dr u g t his da y).  
9.  Dis pe nse diar y. ( S u bjects i n t he P K s u bset will n ot be dis pe nse d a diar y t his  da y.)  
1 0.  Sc he d ule t he ne xt st u d y visit. I nstr uct t he s u bject a n d t heir pare nt/le gal g uar dia n t o 
ret ur n f or eac h st u d y visit at t he sa me ti me of da y as t he Baseli ne  Visit.  
F or s u bjects i n t he P K s u bset at Visit 3 o nl y: 
•  C ollect a pre d ose bl o o d sa m ple after all ot her st u d y pr oce d ures are  c o m plet e d. 
•  A p pl y t he st u d y dr u g t o all 1 0 t oe nails at t he i n vesti gati o nal ce nter wit hi n 1 h o ur 
after c ollecti n g t he pre d ose bl o o d  sa m ple. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 4  
 
 
•  C ollect p ost d ose bl o o d sa m ples at a p pr o xi matel y 2 h o urs ( ± 5 mi n), 4 h o urs 
( ± 5 mi n), a n d 1 2 h o urs ( ± 1 5 mi n) after st u d y dr u g  a p plicatio n.  
•  I nstr u ct t he s u bject t o ret ur n t he f oll o wi n g m or ni n g f or t heir 2 4-h o ur bl o o d 
sa m ple ( Visit 3 A ( Da y 2 9). S u bject will n ot d ose o n t he e ve ni n g of D a y  2 8.  
1 1. 1. 4  Visit 3 A ( Wee k 4, D a y 2 9) –  A d diti o n al Visit f or S u bjects i n t he P K  S u bset  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject “ Are t here a n y c ha n ges i n y o ur  healt h?”).  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he  s u bject. 
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  C ollect a bl o o d sa m ple 2 4 h o urs ( ± 3 0 mi n) after st u d y dr u g a p plicati o n at Visit  3.  
5.  O btai n 1 b ottle of st u d y dr u g a n d wei g h t he b ottle, c o m plete t he la bel a n d dr u g l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d t heir p are nt/le gal g uar dia n. Re vie w t he 
ne w d osi n g i nstr ucti o ns wit h t he s u bject (a p pli cati o n t o o nl y t he tar get great t oe nail 
a n d t o a n y ot her affect e d t oe nails) a n d pr o vi de a c o p y of ne w d osi n g i nstr ucti o ns  t o 
t he s u bject. 
6.  Dis pe nse a ne w diar y t hat i ncl u des t he ne w d osi n g  i nstr ucti o ns. 
7.  Sc he d ule t he P K s u bset s u bject f or t he n e xt st u d y visi t. I nstr uct t he s u bject a n d t heir 
pare nt/le gal g uar dia n t o ret ur n f or eac h st u d y visit at t he sa me ti me of da y as t he 
Baseli ne Visit.  
1 1. 1. 5  Visit 5 ( Wee k 1 2 [ ± 5 d a ys]), Visit 8 ( Wee k 2 4 [ ± 5 d a ys]), Visit 1 1 ( Wee k  3 6 
[ ± 5 d a ys])  
Visits are t o be sc he d ul e d i n re fere nce t o Visit 2 ( Baseli ne). 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t hese visits:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n “ Are t h ere  a n y 
c ha n ges i n y o ur healt h si nce t he last visit?”).  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  C o n d uct a uri ne pre g na nc y test o n F O C B P s u bjects ( disc o nti n ue a n y s u bject fr o m 
t he st u d y w h o has a p ositi ve test res ult). 
5.  Cli p t he  t oe nails. 
6.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse n otc h). If t he m ost rece ntl y a p plie d n otc h h as gr o w n 
o ut or has bee n cli p pe d off, i nscri be a ne w n otc h a djace nt t o t he pr o xi mal n ail  f ol d. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 5  
 
 
 
7.  C o n d uct t he i n vesti gat or’s assess me nt of t he tar g et great t oe nail, wit h a 
deter mi nati o n of t he perce nta ge of t oe n ail affecte d wit h disease. Meas ure  t h e 
dista nce fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
8.  Perf or m t he i n vesti gat or’s assess me nt of t he n o ntar get t oe nails f or t he prese nce or 
a bse nce of o n y c h o m yc osis.  
9.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b per i nstr ucti o ns pr o vi de d i n t he 
la b orat or y ma n u al.  
1 0.  O btai n vital si g n meas ure me nts. Vital si g ns will be meas ure d after t he s u bj ect is 
seate d f or at least 5 mi n utes a n d will i ncl u de s yst olic a n d diast olic bl o o d press ure, 
p ulse rate, r es pirat or y r at e, a n d oral b o d y  te m perat ure. 
1 1.  At Visit 8/ W ee k 2 4 o nl y : Ta ke cl ose-u p p h ot o gra p hs of t he tar get great t oe nail. T he 
first p h ot o gra p h will be ta ke n aft er t oe n ail cli p pi n g. After t hat p h ot o gra p h is ta ke n, 
t he i n vesti gat or/e val uat or will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n 
t he tar get gr eat t oe nail. W he n t he mar k er i n k h as drie d, a sec o n d cl ose -u p 
p h ot o gra p h will be  ta ke n. 
1 2.  C ollect t he diar y a n d st u d y dr u g b ottle fr o m t he s u bject a n d/ or t heir p are nt/le gal 
g uar dia n. Wei g h t he use d b ottle of t he st u d y dr u g. Rec or d t he n u m ber of misse d 
d oses fr o m t he s u bject di ar y a n d re vie w c o m plia nce wit h t he s u bject a n d p are nt/le gal 
g uar dia n.  
1 3.  O btai n 1 b ottle of st u d y dr u g a n d wei g h t he b ottle, c o m plete t he la bel a n d dr u g l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d pare nt/le gal  g uar dia n.  
1 4.  Re vie w t he d osi n g i nstr ucti o ns wit h t he  s u bject. 
1 5.  Dis pe nse diar y.  
1 6.  Sc he d ule t he s u bject f or t he Visit 6 ( W ee k 1 6 [ ± 5 da ys]) st u d y visit, a n d i nstr uct t he 
s u bject t o ret ur n at t he sa me ti me of da y as t he Baseli ne Visit. T he Visit 7 ( Wee k 2 0 
[ ± 5 da ys]) a n d Visit 8 ( Wee k 2 4 [ ± 5 da ys]) st u d y visits will f oll o w Visit 6. I nstr u ct 
t he s u bject a n d t heir p are nt/le gal g uar dia n t o ret ur n f or eac h st u d y visit at t he sa me 
ti me of da y as t he Baseli ne Visit . 
1 1. 1. 6  Visit 1 4 ( Wee k 4 8 [ ± 5 d a ys]) / E arl y Ter mi n ati o n  Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n “ Are t h ere  a n y 
c ha n ges i n y o ur healt h si nce t he last visit?”).  
2.  Rec or d l ocal s k i n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he  t oe nails. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 6  
 
 
 
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse n otc h). If t he m ost rece ntl y a p plie d n otc h h as gr o w n 
o ut or has bee n cli p pe d off, i nscri be a ne w n otc h a djace nt t o t he pr o xi mal n ail  f ol d. 
6.  C o n d uct t he i n vesti gat or’s assess me nt of t he tar g et great t oe nail, wit h a 
deter mi nati o n of t he perce nta ge of t oe n ail affecte d wit h disease. Meas ure  t h e 
dista nce fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
7.  Perf or m t he i n vesti gat or’s as sess me nt of t he n o ntar get t oe nails f or t he prese nce or 
a bse nce of o n y c h o m yc osis.  
8.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b per i nstr ucti o ns pr o vi de d i n t he 
la b orat or y ma n u al.  
9.  Ta ke cl ose -u p p h ot o gra p hs of t he tar get great t oe n ail. T he first p h ot o gra p h will be 
ta ke n after t oe nail cli p pi n g. After t hat p h ot o gra p h is ta ke n, t he i n vesti gat or/e val uat or 
will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n t he tar get great t oe nail. 
W he n t he mar k er i n k h as drie d, a sec o n d cl ose -u p p h ot o gra p h will be  ta ke n. 
1 0.  C o n d uct a n a b bre vi ate d p h ysical e xa mi nati o n (e x cl u di n g  ur o ge nital/re pr o d ucti ve 
s yste ms). 
1 1.  Meas ure h ei g ht a n d  w ei g ht  
1 2.  O btai n vital si g n meas ure me nts. Vital si g ns will be meas ure d after t he s u bj ect is 
seate d f or at least 5 mi n utes, a n d i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse 
rate, r es pirat or y r ate, a n d oral b o d y te m perat ure. 
1 3.  C ollect  t he diar y  a n d st u d y dr u g  b ottle  fr o m t he s u bject a n d/ or pare nt/le gal  g uar dia n. 
Wei g h t he use d b ottle of t he st u d y dr u g. Rec or d t h e n u m ber of misse d d oses fr o m 
t he s u bject diar y a n d re vi e w c o m plia nce wit h t he s u bject a n d pare nt/le gal g u ar dia n.  
1 4.  C o n d uct a uri ne pre g na nc y test o n F O C B P s u bjects (if p ositi ve test res ult, t he s u bject 
s h o ul d ret ur n f or Visit 1 5 [ Wee k  5 2]  
1 5.  C ollect bl o o d a n d uri ne sa m ples f or r o uti ne safet y la b orat or y  a nal ysis ( he m at ol o g y, 
ser u m c he mistr y, a n d uri nal ysis). Pr ocess a n d s hi p t he sa m ples to t he ce ntral safet y 
la b orat or y per i nstr ucti o ns pr o vi de d i n t he la b orat or y ma n ual.  
1 6.  If t his is t he Earl y Ter mi nati o n Visit, rec or d t he reas o n f or s u bject disc o nti n uati o n 
fr o m t he st u d y a n d c o m plete t he E xit St u d y e C R F. All ot her s u bjects s h o ul d be 
sc he d ule d t o ret ur n f or t h e Visit 1 5 ( Wee k 5 2) st u d y visit. I nstr uct t he s u bject t o 
ret ur n at t he sa m e ti me of da y as t he Bas eli ne Visit.  
1 1. 1. 7  Visit 1 5 ( Wee k 5 2 [ ± 5 d a ys]) P ost -Tre at me nt F oll o w -u p Visit / St u d y E xit  
F or all s u bjects, t his visit s h o ul d occ ur 4 wee ks aft er t he last treat me nt visit f or eac h s u bject, 
w het her t he 4 8 -wee k treat me nt peri o d is c o m plete d per pr ot oc ol at Wee k 4 8 or t he s u bject  
disc o nti n ues st u d y treat me nt earl y f or a n y reas o n.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 7  
 
 
 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n, “ Are t h ere a n y 
c ha n ges i n y o ur healt h si nce t he last visit?”).  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he  t oe nails. 
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse  n otc h).  
6.  C o n d uct t he i n vesti gat or’s assess me nt of t he tar g et great t oe nail, wit h a 
deter mi nati o n of t he perce nta ge of t oe n ail affecte d wit h disease. Meas ure  t h e 
dista nce fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
7.  Perf or m t he i n vesti gat or’s assess me nt of t he n o ntar get t oe nails f or t he prese nce or 
a bse nce of o n y c h o m yc osis.  
8.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b p er i nstr ucti o ns pr o vi de d i n t he 
la b orat or y ma n u al.  
9.  Ta ke cl ose -u p p h ot o gra p hs of t he tar get great t oe n ail. T he first p h ot o gra p h will be 
ta ke n after t oe nail cli p pi n g. After t hat p h ot o gra p h is ta ke n, t he i n vesti gat or/e val uat or 
will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n t he tar get great t oe nail. 
W he n t he mar k er i n k h as drie d, a sec o n d cl ose -u p p h ot o gra p h will be  ta ke n. 
1 0.  C o n d uct a uri ne pre g na nc y test o n F O C B P  s u bjects. 
1 1.  E xit t he s u bject fr o m t he  st u d y. 
1 1. 1. 8  U nsc he d ule d  Visits  
A d diti o nal visits ma y be sc he d ule d, as n ecess ar y, t o e ns ure t he safet y a n d well -bei n g of 
s u bjects. All a d diti o nal e xa ms s h o ul d be f ull y d oc u me nte d i n t he s o urce d o c u me nts a n d o n 
U nsc he d ule d Visit e C R Fs, as a p pr o priat e. Visits i nte n de d t o f ulfill sc he d ul e d visit 
re q uire me nts t hat f all o utsi de t he desi g nate d sc h e d ule d visit ra n ge, are n ot u nsc he d ule d visits. 
I n t hes e cases, t he visit data will be c ollecte d a n d tra nscri be d t o t he a p pr o priate sc he d ule d 
visit  e C R F. 
1 1. 1. 9  Misse d  Visits  
If a s u bject misses a n y s c he d ule d visit a n d ca n n ot be see n pri or t o t he st art of t he all o we d 
visit ra n ge f or t he n e xt sc he d ule d f oll o w -u p visit, t he visit is c o nsi dere d misse d.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 8  
 
 
 
1 1. 1. 1 0  S u bject  C o m pleti o n  
A s u bject has c o m plete d t he st u d y w he n Visit 1 5 ( Wee k 5 2) has bee n c o m plete d a n d t he 
s u bject has bee n e xite d fr o m t he st u d y. S u bjects w h o re q uire f urt her f oll o w -u p f or a n  A E 
f oll o wi n g c o m pleti o n of t he st u d y will be f oll o we d acc or di n g t o Secti o n 1 2. 0.  
 
1 1. 2  St u d y  E v al u ati o ns  
1 1. 2. 1  L oc al S ki n  Re acti o ns  
T olera bilit y will be e val u ate d t hr o u g h assess me nt of l ocal re d n ess, s welli n g, b ur ni n g, itc hi n g, 
a n d vesic ulati o n i n t he selecte d treat me nt areas o n t he t oes. Eac h si g n or s y m pt o m is t o be 
re vie we d wit h t he s u bjects a n d t heir pare nts/le g al g uar dia ns aft er t he first a p plicati o n of t he 
st u d y dr u g at t he Baseli ne Visit a n d at eac h f oll o w -u p visit t hr o u g h Wee k 5 2. T he s u bjects 
a n d t heir par e nts/le gal g u ar dia ns s h o ul d assess eac h reacti o n bas e d o n t he w orst reacti o n 
e x perie n ce d si nce t he pri or visit usi n g t he f oll o wi n g scales:  
 
Re acti o n  
Sc ore  
Re d ness, S welli n g  
0 = N o ne  
1 = Mil d  
2 = M o derate  
3 = Se vere  
B ur ni n g, Itc hi n g, a n d Vesic ulati o n  
Yes or N o  
 
Occ urre nce of vesic ulati o n will al wa ys be re p orte d as a n A E. A n y ot her si g n or s y m pt o m 
will be re p ort e d as a n A E o nl y if it re q uires c o nc o mita nt t hera p y or res ults i n a te m p orar y 
i nterr u pti o n or per ma n e nt disc o nti n uati o n of t he st u d y dr u g d ue t o disc o mf ort. 
1 1. 2. 2  Cli nic al L a b or at or y  Tests  
Bl o o d a n d uri ne sa m ples will be c ollecte d f or r o uti ne safet y la b orat or y tests ( he mat ol o g y, 
ser u m c he mistr y, a n d uri nal ysis) at t he Scree ni n g a n d Wee k 4 8/ Earl y Ter mi nati o n visit. A n y 
s u bject wit h a scree ni n g la b orat or y a b n or malit y t hat is deter mi ne d b y t he i n vesti gat or t o be 
cli nicall y si g nifica nt m ust be a p pr o ve d f or i ncl usi o n i n t he st u d y b y t he me dical m o nit or. All 
results will be re p orte d, i ncl u di n g a b n or mal res ults. Cli nicall y si g nifica nt c ha n ges i n la b 
res ults fr o m Scree ni n g, i n t he o pi ni o n of t he i n vesti gat or, s h o ul d be re p orte d as A Es. 
Cli nicall y si g nifica nt c ha n ges prese nt at Wee k 4 8/ Earl y Ter mi nati o n are t o be f o ll o we d t o 
res ol uti o n or u ntil cli nicall y sta ble as deter mi ne d b y t he i n vesti gat or. If a n A E s h o ul d re q uire 
la b orat or y testi n g, t he r es ults of t he test m ust be o btai ne d b y t he i n vesti gati o nal ce nter a n d 
file d i n t he s u bject’s d oc u me ntati o n. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
4 9  
 
 
 
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nt ers b y t he s p o ns or 
or ce ntr al la b orat or y. I nstr ucti o ns f or pr o cessi n g a n d s hi p pi n g sa m ples t o t he ce ntral 
la b orat or y are c o nt ai ne d i n t he st u d y la b orat or y ma n ual. 
F or all F O C B P, ur i ne pre g na nc y testi n g will be perf or me d at t he Scree ni n g a n d Baseli ne 
Visits, as well as at eac h s u bse q ue nt st u d y visit. F O C B P is defi ne d as a n y fe male s u bject w h o 
has e x peri e nce d m e nar c h e. T he r es ults at t he Scree ni n g a n d Baseli ne Visits m ust be ne gati ve 
f or a s u bject t o e nt er t he st u d y. Materials f or pre g na nc y testi n g will be pr o vi de d t o t he 
i n vesti gati o nal ce nters b y t he s p o ns or or ce ntral la b orat or y. 
1 1. 2. 3  Vit al Si g n  Me as ure m e nts  
Meas ure me nt of vital si g ns will be perf or me d at t he Baseli ne Visit, as well as a t Wee ks 1 2, 
2 4, 3 6, a n d 4 8/ Earl y Ter mi nati o n. After t he s u bjects ha ve bee n sitti n g f or at least 5 mi n utes, 
s yst olic a n d diast olic bl o o d press ures, p ulse rates, res pirati o n rat es, a n d oral te m perat ures 
will be rec or d e d.  
1 1. 2. 4  P h ysic al  E x a mi n ati o ns  
A n a b bre viat e d p h ysical e xa mi nati o n will be perf or me d at t he Baseli ne Visit a n d at  
Wee k 4 8/ Earl y Ter mi nati o n. Hei g ht a n d wei g ht will be meas ure d at t he Bas eli ne Visit a n d at 
t he Wee k 4 8/ E arl y Ter mi nati o n Visit. 
1 1. 2. 5  Effic ac y f o r Assessi n g Tre at me nt C o m pli a nce a n d  S afet y  
Effic ac y assess me nts will be perf or m e d t hr o u g h o ut t he st u d y. T he efficac y a nal yses will be 
base d o n micr osc o pic e x a mi nati o n a n d m yc ol o gical c ult ure res ults f or t he t ar get great 
t oe nail, t he perce nt i n v ol ve me nt of t he tar g et great t oe nail, t he le n gt h of t he u naffecte d p art 
of t he tar get gr eat t oe n ail, t he gr o wt h of t he tar g et great t oe nail, a n d t h e n u m ber of affecte d 
n o ntar get t oe nails.  
I n v esti gat ors/e val uat ors will be trai ne d b y t he s p o ns or t o e ns ure c o nsiste n c y acr oss 
i n vesti gati o nal ce nters r e gar di n g t oe nail cli p pi n g, e val uati o ns a n d meas ure me nts, as well as 
c ollecti o n of s uffici e nt material f or K O H e xa mi nati o ns a n d f u n gal c ult ures. E val uat ors m ust 
be pre -a p pr o ve d b y t he s p o ns or a n d m ust ha ve a p pr o priate d oc u m e nte d e x perie nce a n d 
trai ni n g, or ha ve a wai ver o btai ne d fr o m t he s p o ns or base d o n e x p erie n ce ( or t hr o u g h 
a d diti o nal trai ni n g or ga nize d b y t he s p o ns or).  
E ver y eff ort s h o ul d be m a de t o ha ve t he sa me s p o ns or -a p pr o v e d e val u at or perf or m t he t ar get 
great t oe n ail assess me nts a n d meas ure me nts f or a partic ular s u bj ect at t he Baseli ne Visit a n d 
eac h f oll o w -u p visit.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5 0  
 
 
 
1 1. 2. 5. 1  K O H E x a mi n ati o n a n d F u n g al C ult uri n g  
T he K O H e xa mi nati o n a n d f u n gal c ult uri n g of t oe nail scra pi n g a n d s u b u n g ual de bris will be 
perf or me d f or st u d y -eli gi ble great t oe n ail(s) at t he Scree ni n g Visit a n d f or t he tar get great 
t oe nail o nl y (as deter mi n e d at t he Baseli ne Visit) at Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y Ter mi nati o n, 
a n d 5 2 (t he 4 -w ee k p ost -treat me nt f oll o w-u p) st u d y visits. At t he Scree ni n g visit, K O H 
e xa mi nati o n will be perf or me d at t he i n vesti gati ve site. If p ositi ve, a d diti o nal s peci me ns f or 
K O H a n d f u n g al c ult ures are o btai ne d fr o m st u d y -eli gi ble great t oe nails at t his visit a n d se nt 
t o t he ce ntral m yc ol o g y l a b orat or y. 
F u n gal c ult uri n g will be perf or me d b y t h e ce ntral m yc ol o g y la b orat or y. T o e nail s peci me ns 
will be ta ke n b y cli p pi n g t he t oe nail t o t he p oi nt of attac h me nt (re m o vi n g u n healt h y nai l) a n d 
o btai ni n g a n y cr u m bli n g s u b u n g ual de bris fr o m u n der t he distal e d ge of t he tar get great 
t oe nail usi n g a dis p osa ble c urette. All tar get great t oe nail plate cli p pi n gs a n d “ distal” 
s u b u n g ual de bris s h o ul d be discar d e d. O nl y t he s oft nail be d kerati n beneat h t he cli p pe d e d ge 
of t he nail s h o ul d be c oll ecte d a n d us e d as a s p eci me n f or b ot h t he K O H e xa mi nati o n a n d t he 
f u n gal c ult ure. Caref ul s p eci me n c ollecti o n i n t his ma n ner will mi ni mize t oe nail s peci me n 
c o nta mi na nts a n d ma xi mize der mat o p h ytic p at h o ge n is olati o n.  
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nt ers b y t he s p o ns or 
or ce ntr al m yc ol o g y la b orat or y. I nstr ucti o ns f or pr ocessi n g a n d s hi p pi n g sa m ples t o t he 
ce ntral la b orat or y are c o ntai ne d i n t he st u d y la b orat or y ma n ual.  
1 1. 2. 5. 2  T ar get Gre at T oe n ail  Assess me nts  
T he per ce nt of t he aff ect e d t oe nail area a n d h ealt h y ( u naffecte d) t oe nail meas ure me nts f or 
t he tar get gr eat t oe nail(s) will be e val uate d b y t he i n vesti gat or/e val uat or at t he Scree ni n g a n d 
Baseli ne Visits, a n d at Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y Ter mi nati o n, a n d 5 2 (t he 4 -wee k p ost - 
treat me nt f oll o w-u p) st u d y visits.  
Perce nt of Affecte d Tar g et Great T o e nail Area  
T he aff ecte d ar ea of t he t oe nail will be esti mate d as t he perce nt of t oe nail area ( nail a n d n ail 
be d) i n v ol ve d (t he dist al mar gi n f or deter mi ni n g area will be t he distal gr o o ve after t he 
t oe nail has bee n cli p pe d). 
Healt h y ( U naffecte d) T ar get Great T o e nail Meas ure me nt a n d Gr o wt h  
T he healt h y ( u n aff ecte d) t oe nail meas ure m e nt will be defi ne d as t he dista nce (i n m m) 
bet wee n t he pr o xi mal nail f ol d a n d a tra ns verse li n e o n t he healt h y part of t he t oe nail 
i m me diatel y pr o xi mal t o t he nail i nfecti o n. At eac h e val uati o n, t his dista nce will be meas ure d 
fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic b or der. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5 1  
 
 
 
T oe nail gr o wt h will be m eas ure d b y i ns cri bi n g a tra ns verse n otc h i n t he nail of t he tar get 
great t oe nail(s) a djace nt t o t he pr o xi mal nail f ol d at t he ce nter of t he nail at t he Baseli ne 
Visit, a n d meas uri n g nail gr o wt h fr o m t hat p oi nt f or war d. At e ver y s u bs e q ue nt visit, t he 
dista nce (i n m m) bet wee n t he pr o xi mal nail f ol d a n d t he n otc h will be meas ure d a n d 
rec or d e d. T he n otc h s h o ul d be e n ha nce d as nee de d at s u bse q ue nt visits t o all o w c o nti n ue d 
meas ure me nt of t o e nail gr o wt h o ver t he c o urse of t he st u d y. If t he  i nitiall y a p plie d n otc h 
i nscri be d at t he Baseli ne Visit has gr o w n o ut or is cli p pe d a wa y, i nscri be a ne w n otc h i n t he 
t oe nail a djace nt t o t he pr o xi mal nail f ol d, a n d c o nti n ue wit h meas ure me nts usi n g t he ne w 
n otc h.  
1 1. 2. 5. 3  N o nt ar get T oe n ail  Assess me nt  
A n assess me n t of b ot h feet will be ma de f or assessi n g t he prese nce or a bs e nce of 
o n yc h o m yc osis of n o ntar get t oe nails at t he Scree ni n g, Baseli ne, Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y 
Ter mi nati o n, a n d 5 2 (t he 4 -wee k p ost -treat me nt f oll o w-u p) st u d y visits. All n o ntar get 
t oe nails will be assesse d f or t he pres e nce or a bs e n ce of o n yc h o m y c osis. S u bjects i n t he P K 
s u bset m ust prese nt wit h o n yc h o m yc osis o n at least 4 t oe nails besi des t he great t oe nails.  
1 1. 2. 6  E v al u ati o n of P h ar m ac o ki netics  
T he P K assess me nts will be perf or me d o n a s u bs et of t h e st u d y p o p ulati o n w h o will recei ve 
treat me nt u n der m a xi mal use c o n diti o ns f or 2 8 da ys. Plas ma sa m ples f or d eter mi nati o n of 
efi nac o n az ole a n d meta b olite le vels will be c ollecte d at t he f oll o wi n g ti me p oi nts:  
•  Visit 3 ( Da y 2 8): Pre d ose (after all Da y 2 8 pr o c e d ures are c o m plete d). St u d y dr u g 
m ust be a p plie d wit hi n 1 h o ur after t h e pre d os e sa m ple is c ollecte d. Sa m ples are 
t he n c ollecte d at 2 ( ± 5 mi n), a n d at 4 ( ± 5 mi n), a n d at 1 2 ( ± 1 5 mi n) h o urs 
p ost d ose.  
•  Visit 3 A ( Da y 2 9): 2 4 ( ± 3 0 mi n) h o urs after Da y 2 8 s t u d y dr u g a p plicati o n. 
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nt ers b y t he s p o ns or 
or ce ntr al la b orat or y. I nstr ucti o ns f or pr o cessi n g a n d s hi p pi n g sa m ples t o t he bi oa nal ytical 
la b orat or y are c o nt ai ne d i n t he st u d y la b orator y ma n ual.  
1 1. 2. 7  P h ot o gr a p h y  
At all i n vesti gati o nal ce nters, cl ose -u p p h ot o gra p hs of t he tar get great t oe n ail(s) will be ta ke n 
at t he Baseli ne, Wee ks 2 4, 4 8/ Earl y Ter mi nati o n, a n d 5 2 (t he 4 -w ee k p ost -treat me nt 
f oll o w-u p) st u d y visits. O ne p h ot o gra p h will be t a ke n aft er t oe n ail cli p pi n g. After t he first 
p h ot o gra p h has bee n ta ke n, t he i n vesti gat or/e val uat or will use a fi ne ti p pe d mar ker t o o utli ne 
t he area affect e d o n t he t ar get gr eat t oe nail. Aft er t he i n k has drie d, a sec o n d p h ot o gra p h will 
be ta ke n. T he c oll ecte d p h ot o gra p hs will be use d f or d oc u me ntati o n p ur p os es o nl y a n d will  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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n ot be use d f or d eter mi nati o ns of eli gi bilit y, efficac y, or a n y st u d y -relate d acti vities. Bef ore 
p h ot o gra p hs ar e ta ke n, t h e st u d y s u bject a n d t heir pare nt(s)/le g al g uar dia n(s) m ust 
c o nse nt/asse nt t o p h ot o gr a p h y. If t he p h ot o gra p h y c o nse nt/asse nt is decli ne d, t he s u bject 
ma y still partici pate i n t he st u d y.  
 
1 1. 3  Defi niti o n of A d verse  E ve nts  
A n A E is a n y u nt o war d me dical occ urre n ce i n a s u bject or cli nical i n vesti g ati o n s u bject 
a d mi nistere d a me dici nal pr o d uct a n d w hic h d o es n ot necessaril y ha v e a ca usal relati o ns hi p 
wit h t he st u d y dr u g. T h us, A Es i ncl u de a n y u nfa v ora ble a n d u ni nte n d e d ill ness, si g n, 
s y m pt o m, cli nicall y si g nifica nt la b orat or y test a b n or malit y, or disease te m p orall y ass ociate d 
wit h t he use of a me dici n al pr o d uct t hat has a p p eare d or w orse ne d d uri n g t he c o urse of t he 
cli nical st u d y, re gar dl ess of ca usal relati o ns hi p t o t he st u d y dr u g(s) u n der st u d y. T he 
c ollecti o n of n o nseri o us A Es a n d seri o us a d v erse e ve nts ( S A Es) s h o ul d be gi n f oll o wi n g t he 
s u bject's c o m pleti o n of t he c o nse nt/asse nt pr o cess t o partici pate i n t he st u d y. 
1 1. 3. 1. 1  Defi niti o n of Seri o us A d verse  E ve nts  
All A Es will be assesse d as eit her seri o us or n o nseri o us. A n S A E or seri o us a d verse reacti o n 
is defi ne d as a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose: 
•  Res ults i n deat h.  
•  Is i m me diatel y life t hreat e ni n g, (t he ter m “life t hreate ni n g” i n t he defi niti o n of 
“seri o us” r efers t o a n e ve nt i n w hic h t he s u bject is at ris k of deat h at t he ti m e of 
t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve ca us e d 
deat h if it were m ore  s e v ere). 
•  Re q uires i n s u bject h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
( h os pitalizati o n f or electi ve s ur ger y f or a b aseli ne c o n diti o n is n ot  c o nsi dere d a n 
A E).  
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y ( per m a ne nt or s u bst a 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). 
•  Is a c o n ge nital a n o mal y/ birt h defect.  
•  Is a me dicall y i m p orta nt e ve nt t hat ma y n ot be i m me diatel y life t hreate ni n g or 
res ult i n deat h or h os pitalizati o n, b ut ma y je o par di ze t he s u bject a n d ma y re q uire 
me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he a b o ve liste d  o utc o mes.  
I m p ort a nt me dical e v e nts t hat ma y n ot ha ve res ult e d i n deat h, be life-t hreate ni n g, or 
re q uire h os pitalizati o n m a y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate 
me dical j u d g me nt, t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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s ur gical i nter venti o n t o pre ve nt o ne of t he o utc o m es liste d i n t his defi niti o n. 
E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve 
treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o 
n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n d e nc y or dr u g 
a b use.  
H os pitalizati o n is a criteri o n f or assess me nt of seri o us ness. T o q ualif y as seri o us u n der t he 
criteria of “ h os pitalizati o n,” a h os pital a d missi o n of at least a 2 4 -h o ur peri o d is re q uire d. I f a 
s u bject is retai ne d t he e mer ge nc y r o o m greater t ha n 2 4 h o urs, b ut n ot a d mitte d f or me dical 
care, t h ese cases s h o ul d be e val uat e d i n di vi d uall y, as criteria s u c h as “ m e dicall y si g nifica nt” 
ma y als o a p pl y.  
H os pitalizati o n wit h o ut a me dical A E s h o ul d n ot b e c o nsi dere d eit her s eri o us or a n A E. 
E xa m ples i ncl u de:  
•  A d missi o n  f or  treat me nt  of  a  pre -e xisti n g  c o n diti o n  n ot  ass ociate d  wit h  t he  
de vel o p me nt of a ne w A E or wit h w orse ni n g of t he pre-e xisti n g c o n diti o n (e g, f or 
w or k -u p of p ersiste nt pre -treat me nt la b a b nor malit y).  
•  H os pitalizati o n f or a p ur p ose u nrelate d t o t he st u d y (e g, “ pla n n e d” or electi ve s ur ger y 
sc he d ule d  pri or  t o  st u d y  partici pati o n)  w o ul d  n ot  or di naril y  nee d  t o be re p orte d, 
u nless  a  c o m plicati o n  occ urre d  w hic h  ot her wise  ca use d  pr ol o n gati o n  of  t his  
h os pitalizati o n.  
•  Pr ot oc ol -s pecifie d a d missi o n or pr o ce d ure (e g, cataract s ur ger y re q uire d b y a st u d y 
pr ot oc ol; or o ver ni g ht sta y f or m o nit ori n g d ue t o pr ot oc ol re q uire d s ur ger y, wit h n o 
ass oci ate d S A E or c o m plic ati o n necessit ati n g pr ol o n ge d  st ay) 
•  S ocial a d missi o n (e g, s ocial h os pitalizati o n f or p ur p oses of res pite care)  
N ote: A s p o nta ne o us a b orti o n will be c o nsi dere d a n S A E, a n d m ust be re p orte d t o t he 
s p o ns or wit hi n 2 4 h o urs of y o ur a w are n ess of t he e ve nt. 
1 1. 3. 1. 2  Assess m e nt of  Se verit y  
T he se verit y assi g ne d t o a n A E s h o ul d be  deter mi ne d b y t he ma xi m u m se verit y of t he A E. 
T he cate g ories des cri be d bel o w s h o ul d be use d t o esti mate t he se verit y of A Es:  
•  Mil d: Tra nsie nt or mil d disc o mf ort; n o li mitati o n i n acti vit y; n o me dical 
i nter ve nti o n/t hera p y r e q uire d. 
•  M o derate: Mil d t o m o derat e li mitati o n i n acti vit y; s o me assista nce ma y be 
nee de d; n o or mi ni mal me dical i nter ve nti o n/t hera p y  re q uire d. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5 4  
 
 
•  Se vere: Mar k e d li mitati o n i n acti vit y; s o me assista nce us uall y re q uire d; m e dical 
i nter ve nti o n/t hera p y r e q uire d; h os pitalizati o n or pr ol o n gati o n of c urre nt 
h os pitalizati o n p ossi ble; ma y be i nca pacitati n g or life t hreate ni n g. 
1 1. 3. 1. 3  Assess m e nt of  C a us alit y  
T he i n vesti gat or s h o ul d assess t he relati o ns hi p of t he A E, if a n y, t o t he st u d y dr u g as eit her 
“ Relate d” or “ N ot Relate d”.  
•  Rel ate d: T h er e is at least a reas o na ble p ossi bilit y t hat t he A E/ S A E is relate d t o t h e 
st u d y dr u g. Reas o na ble p ossi bilit y mea ns t hat t here is e vi de nce t o s u g gest a ca usal 
relati o ns hi p bet wee n t h e dr u g a n d t he A E.  
•  N ot Rel ate d: T here is little or n o reas o na ble p ossi bilit y t hat t he A E/ S A E is relate d t o 
t he st u d y dr u g. T his ass ess me nt i m plies t hat t he A E/ S A E has little or n o te m p oral 
relati o ns hi p t o t he st u d y dr u g a n d/ or  a m ore li kel y or certai n alter nati ve eti ol o g y 
e xists. 
T he f oll o wi n g s h o ul d be ta ke n i nt o acc o u nt w h e n assessi n g A E/ S A E ca usalit y:  
•  P ositi ve te m p oral relati o ns hi p t o st u d y dr u g, s uc h as if t he st u d y dr u g was 
wit h dra w n a n d t he S A E res ol ve d or t he e v e nt rec urre d after re  i ntr o d u cti o n. 
•  If t here is a r eas o na ble p ossi bilit y t hat t he A E is ass ociate d wit h a n u n derl yi n g or 
c o nc o mita nt  ill ness. 
•  P ossi ble ass ociati o n wit h pre vi o us or c o n c o mita nt  t hera p y. 
•  N o te m p oral rel ati o ns hi p t o t he st u d y dr u g a n d/ or a m ore li kel y  alter n ati ve 
eti ol o g y e xists. 
•  If t he A E is directl y relate d t o st u d y pr oce d ures or t here is a lac k of  efficac y. 
1 1. 3. 1. 4  Pr oce d ures f or R e p orti n g A d verse E ve nts a n d Seri o us A d verse  E ve nts  
T hr o u g h o ut t he c o urse of t he st u d y, eff orts will be ma de b y t he I n vesti gat or t o re mai n alert t o 
p ossi ble A Es t hat are eit h er s yste mic or oc ul ar i n n at ure. T he p eri o d of o bser vati o n f or 
c ollecti o n of A Es e xte n ds fr o m t he ti me t he s u bject a n d pare nt/le gal g uar di a n gi ves i nf or me d 
c o nse nt/asse nt u ntil t he last st u d y visit or disc o nti n uati o n fr o m t he st u d y. T he first c o ncer n 
will be t he safet y of t he s u bj ect, a n d a p pr o priate m e dical i nter ve nti o n will b e ma de.  
T he I n vesti gat or or d esi g nee will elicit re p orts (ie, via direct q uesti o ni n g, o bser vati o n, 
cli nical e val uati o n) of A Es fr o m t he s u bject at eac h st u d y visit a n d rec or d all A Es. T he 
I n v esti gat or will  d o c u me nt  t he dates  of  o ns et,  pr o gress, o utc o me,  a n d res ol uti o n of  s uc h A Es. 
T he I n vesti gat or will als o pr o vi de a n ass ess me nt of all A Es as t o t he se verit y, ca usal 
relati o ns hi p t o st u d y dr u g, a n d ca usal relati o ns hi p t o st u d y pr ot oc ol.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5 5  
 
 
 
It is t he i n vesti gat or’s res p o nsi bilit y t o d oc u me nt all A Es t hat occ ur d uri n g t he st u d y. T he 
A Es s h o ul d be d oc u me nt e d as a si n gle me dical dia g n osis. W he n t his is n ot p ossi ble, t he A E 
s h o ul d be d oc u me nte d i n ter ms of si g ns a n d/ or s y m pt o ms o bser ve d b y t he i n vesti gat or or 
re p orte d b y t he s u bject a n d/ or t heir pare nt/le g al g uar dia n at eac h st u d y visit. 
All A Es occ urri n g after t he s u bject a n d t heir p are nt/le gal g uar dia n si g ns t he asse nt/i nf or me d 
c o nse nt t hr o u g h t he last st u d y visit m ust be re p orte d, re gar dl ess of w het h er or n ot t he A Es 
are c o nsi d ere d dr u g -r elat e d. All A Es, w het her i n res p o nse t o a q uer y, o bser ve d b y t he st u d y 
site pers o n nel, or r e p orte d s p o nta ne o usl y b y t he s u bject a n d/ or t heir p are nt/le gal g uar dia n, 
will be rec or d e d.  
At eac h visit d uri n g t he st u d y, t he s u bject will be assesse d f or t h e occ urre n ce of ne w a n d 
o n g oi n g A Es. C uta ne o us t olera bilit y si g ns a n d s y m pt o ms t hat res ult i n t he s u bject’s re q uiri n g 
a c o nc o mita nt t her a p y or disc o nti n uati o n fr o m t he st u d y will be re p orte d as a n A E. T he 
f oll o wi n g data will be c ollecte d o n all A Es a n d rec or de d o n t he a p pr o priat e e C R F: 
•  E ve nt na me ( dia g n osis preferre d, if u n k n o w n, rec or d t he si g ns/s y m pt o ms).  
•  O nset date a n d e n d  date.  
•  Ma xi m u m i nte nsit y  (se verit y). 
•  Seri o us ness.  
•  Acti o n ta ke n re g ar di n g st u d y dr u g.  
•  C orrecti ve tr eat me nt, if gi ve n. 
•  O utc o me.  
I n a d diti o n, t he i n vesti gat or’s assess me nt of ca usalit y will be rec or de d.  
A n y S A E m ust be re p orte d t o t he S p o ns or, i n de pe n de nt of t he circ u msta nce or s us pecte d 
ca use, wit hi n 2 4 h o urs fr o m t he ti me t he e ve nt was re p orte d t o t he I n v esti gat or. All S A Es 
e x perie n ce d fr o m t he dat e of c o nse nt t hr o u g h at least 3 0 da ys after t he last d ose of st u d y dr u g 
m ust be re p orte d t o t he S p o ns or re gar dless of t he relati o ns hi p t o t he st u d y dr u g or t he 
pr ot oc ol. F or e ve nts occ urri n g be y o n d t he mi ni m u m 3 0- da y peri o d after t he last d ose of 
st u d y dr u g, or f or a n y ti mefra me after war d d ee m e d me dicall y si g nifica nt, o nl y S A Es 
c o nsi dere d r elate d t o t he st u d y dr u g s h o ul d be re p orte d pr o m ptl y t o t he S p o ns or. 
Wit hi n 2 4 h o urs of n otificati o n t he I n vesti gat or will fa x or e mail a c o m plete d Seri o us 
A d verse E v e nt Re p ort t o t he S p o ns or:  
Fa x: 
 
S A E I n b o x: 
 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
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Att n: Valea nt Gl o bal Saf et y a n d Vi gila nce  
I n v esti gat ors s h o ul d n ot wait t o recei ve a d diti o nal i nf or mati o n t o d oc u me nt t he e ve nt bef ore 
n otif yi n g t he s p o ns or of a n S A E. If o nl y li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w-u p 
re p orts ar e re q uire d. If t he I n vesti gat or bec o mes a ware of a n y ne w i nf or mati o n re gar di n g a 
S A E (ie , res ol uti o n, c ha n ge i n c o n diti o n, or ne w treat me nt), a n e w S A E F or m m ust be 
c o m plete d a n d f a xe d/e m aile d t o t he S p o ns or wit hi n 2 4 h o urs. T he ori gi nal S A E f or m is n ot 
t o be altere d. T he r e p ort s h o ul d be mar ke d as a “f oll o w -u p re p ort ” a n d des cri be w het her t h e 
e ve nt has r es ol ve d or c o nti n ues a n d h o w t he e ve nt was treat e d. A d diti o nal rele va nt 
i nf or mati o n s uc h as h os pital rec or ds a n d a ut o ps y re p orts s h o ul d be pr o vi de d t o t he s p o ns or as 
s o o n as t he y ar e a v aila ble. 
S h o ul d t he i n vesti gat or bec o me a ware of a n S A E (r e gar dless of its relati o ns hi p t o 
i n vesti gati o nal pr o d uct) t hat occ urs wit hi n 3 0 da ys after st o p pi n g t he st u d y dr u g, t he S A E 
m ust be re p orte d i n acc or da nce wit h pr o ce d ures s p ecifie d i n t his pr ot oc ol.  
T he i n vesti gat or s h o ul d ta ke all a p pr o priate meas ures t o e ns ure t h e safet y of t he s u bjects, 
n ota bl y he/s he s h o ul d f oll o w a s u bject wit h a n S A E u ntil t he e ve nt has res ol ve d or t he 
c o n diti o n has sta bilize d. T his ma y i m pl y t hat f oll o w -u p will c o nti n ue after t he s u bject has 
left t he st u d y, a n d t hat a d diti o nal i n vesti gati o ns ma y be re q u este d b y t he s p o ns or. 
1 1. 3. 1. 5  S u b mitti n g a n E x pe dite d S afet y Re p ort t o t he I R B ( Ce ntr al or  L oc al)  
A n y s us pecte d u ne x p ecte d seri o us a d vers e reacti o n ( S U S A R) warra nts e x p e dite d re p orti n g. 
I n a d diti o n, a n y u ne x pecte d S A E relate d t o a s u bject’s partici pati o n i n t he st u d y ( or c o n d uct 
of st u d y), re gar dless if t h e st u d y dr u g was a d mi nistere d, will be e v al uate d b y Gl o bal Safet y 
a n d Vi gila nce t o det er mi ne if e x pe dite d re p orti n g is re q uire d. F or e x a m ple, a n u ne x pecte d, 
seri o us a n d se vere r eacti o n w hic h c o ul d be ass o ciate d t o t he st u d y pr oce d ures, a n d w hic h 
c o ul d m o dif y t he st u d y c o n d uct re q uires e x pe dite d re p orti n g.  
Eac h e x p e dite d saf et y re p ort will r o uti nel y i ncl u de a brief c o ver me m ora n d u m, t he 
c o m plete d Me d Watc h F or m F D A 3 5 0 0 A or C o u ncil f o r I nter n ati o nal Or ga nizati o ns of 
Me dical Scie nces I F or m, a cli nical a nal ysis of t he e ve nt wit h a n y si milar e ve nts t hat ha ve 
occ urr e d wit h t he pr o d uct, a n d a n y a d diti o nal perti ne nt i nf or mati o n rec o m me n de d b y t he 
st u d y Me dical M o nit or. O nce t he r e p ort is c om pile d b y Ba usc h + L o m b Gl o bal Safet y a n d 
Vi gila nce, t he site I n v esti gat or m ust s u b mit t he e x pe dite d safet y re p ort t o t he l ocal I R B/ E C 
wit hi n t he re q uire d r e p orti n g ti mefra me. F oll o w -u p re p orts s h o ul d be s u b mitte d w he n 
re q ueste d or w he n p erti ne nt i nf or matio n bec o mes a vaila ble. T he site pri nci pal I n v esti gat or 
m ust retai n a c o m plete c o p y of eac h e x pe dite d s afet y re p ort as it was s u b mitte d t o t he I R B. It 
is i m p orta nt t hat t he pri nci pal I n vesti gat or re vie w t hese e x pe dite d re p orts, as t he y c o ntai n 
safet y i nf or mati o n t hat ma y be rele va nt t o eac h of t he partici pati n g  s u bjects. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5 7  
 
 
 
1 1. 3. 2  Pre g n a nc y  
All fe male s u bjects of c hil d beari n g p ote ntial m ust use a n effecti ve m et h o d of birt h c o ntr ol 
d uri n g t he c o urse of t he st u d y, i n a ma n ner s uc h t h at ris k of c o ntr ace pti ve fail ure is 
mi ni mize d. A bsti ne nce is all o we d as a birt h c o ntr ol met h o d.  
Bef ore e nr olli n g a fe mal e s u bject of c hil d beari n g p ote ntial i n t his cli nical st u d y, t he 
i n vesti gat or m ust re vie w t he f oll o wi n g i nf or mati o n a b o ut st u d y partici pati o n: 
•  I nf or me d co ns e nt/asse nt  re q uire me nts. 
•  C o ntrace pti ves i n c urre nt  use.  
F oll o wi n g re vie w of t his i nf or mati o n a n d a p pr o priate c o u nseli n g f or t h e s u bject a n d t heir 
pare nt/le gal g uar dia n, t he i n vesti gat or or desi g nee a n d t he s u bject a n d p are nt/le gal g uar dia n 
m ust si g n t he  asse nt/i nf or me d c o nse nt bef ore st u d y e nr oll me nt.  
D uri n g t he st u d y, all fe m ale s u bjects of c hil d beari n g p ote ntial s h o ul d be i nstr ucte d t o c o ntact 
t he i n vesti gat or i m me diatel y if t he y s us pect t he y mi g ht be pre g na nt (e g, misse d or late 
me nstr ual peri o d).  
If a s u bject or i n vesti gat or s us pects t hat t he s u bject ma y be pre g n a nt pri or t o st u d y 
e nr oll me nt, t he st u d y dr u g m ust be wit h hel d u ntil t he res ults of la b orat or y pre g na nc y t esti n g 
are a v aila ble. If pre g n a nc y is c o nfir me d, t he s u bject m ust n ot recei ve st u d y dr u g a n d m ust 
n ot be e nr olle d i n t he st u d y. If pre g n a nc y is s us pecte d w hile t he s u bject is recei vi n g st u d y  
treat me nt, t he st u d y dr u g m ust i m me diatel y be wit h hel d u ntil t he res ult of pre g na nc y t esti n g 
is k n o w n. If pr e g na nc y is c o nfir me d, t he st u d y dr u g will be per ma ne ntl y disc o nti n ue d a n d t he 
s u bject will be f oll o we d u ntil t he pre g na nc y c o m es t o ter m. A Pre g na nc y R e p ort f or m will be 
s u b mitte d t o t he s p o ns or, i nitiall y a n d at t he e n d of t he pre g n a nc y, w hic h i n cl u des t he 
o utc o me o f t he pr e g na nc y a n d a n y c o m plicati o ns occ urri n g d uri n g t he pre g na nc y or t he 
deli ver y.  
 
1 2  St atistics  
1 2. 1  Assess m e nt of  S afet y  
1 2. 1. 1  A d verse E ve nts  
All A Es t hat occ ur d uri n g t he st u d y will be rec or d e d a n d classifie d usi n g t h e Me dical 
Dicti o nar y f or Re g ul at or y Acti vities  ( Me d D R A). Treat me nt-e mer ge nt a d v erse e v e nts 
( T E A Es) are t h ose A Es wit h a n o nset o n or after t he date of first st u d y dr u g a p plicati o n. All 
T E A Es will be s u m marize d b y t he n u m ber of s u bj ects re p orti n g eac h T E A E, t he ass ociate d 
s yste m or ga n class a n d preferre d t er m, t he se v erit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he 
safet y, P K, a n d n o n-P K p o p ulati o ns. Eac h s u bject will be c o u nte d o nl y o nce wit hi n a s yste m  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5 8  
 
 
 
or ga n class or a pr eferre d ter m usi n g t he e ve nt wit h t he greatest se v erit y or ca usalit y, 
res pecti vel y, wit hi n eac h cate g or y. 
All S A Es will be s u m marize d b y t he n u m ber of s u bjects re p orti n g eac h S A E, t he ass ociate d 
s yste m or ga n class a n d preferre d t er m, t he se v erit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he 
safet y, P K, a n d n o n-P K p o p ulati o ns.  
All i nf or mati o n pertai ni n g t o A Es n ote d d uri n g t he st u d y will be liste d b y s u bject a n d will 
i ncl u de t he ver b ati m ter m gi ve n b y t he i n vesti gat or, t he ass ociate d s yste m or ga n class a n d 
preferre d t er m, t he start a n d st o p (if st o p pe d) dates, t he se ri o us ness, a n d t he se verit y of t he 
e ve nt. A d diti o nall y, a n y acti o n ta ke n wit h t he st u d y dr u g, a n y c orrecti ve treat me nt 
a d mi nistere d, t he o utc o m e, a n d t he relati o ns hi p t o st u d y dr u g as well as a list of s u bjects w h o 
pre mat urel y disc o nti n ue fr o m t he st u d y d u e t o a n A E will be pr o vi de d.  
1 2. 1. 2  L oc al S ki n  Re acti o ns  
L ocal s ki n reacti o n sc ores (re d ness, s w elli n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) at eac h visit 
will be s u m marize d usi n g fre q ue n c y ta bles f or t he safet y, P K, a n d n o n -P K p o p ulati o ns.  
A d diti o nall y, re d ness a n d s welli n g se verit y sc ores will be s u m marize d usi n g descri pti ve 
statistics ( mea n, sta n dar d de viati o n [ S D], me dia n, a n d mi ni m u m, a n d ma xi m u m). S u bjects 
wit h a se verit y sc or e w orse t ha n baseli ne will als o be s u m marize d at eac h p ost -ba seli ne visit. 
T he w orst sc or e a n d t he l ast sc ore d uri n g t he p ost -baseli ne peri o d will als o be s u m marize d.  
1 2. 1. 3  Cli nic al L a b or at or y  Tests  
Res ults of safet y la b orat or y para m eters will be s u m marize d at eac h st u d y visit usi n g 
descri pti ve statistics or fr e q ue ncies a n d perce nta g es, as a p pr o priat e, f or t he safet y, P K, a n d 
n o n -P K p o p ulati o ns. C ha n ges fr o m baseli ne i n safet y la b orat or y v al ues will be s u m marize d 
b y treat me nt gr o u p at Wee k 4 8 usi n g descri pti ve st atistics. I n a d diti o n, c h a n ges fr o m baseli ne 
i n safet y la b orat or y val ues will be s u m marize d usi n g s hift ta bles acc or di n g t o n or mal ra n ges. 
1 2. 1. 4  Vit al  Si g ns  
Res ults of vital si g n meas ure me nts will be s u m marize d at Wee ks 1 2, 2 4, 3 6, a n d 4 8 usi n g 
descri pti ve statistics or fr e q ue ncies a n d perce nta g es, as a p pr o priat e, f or t he  safet y, P K, a n d 
n o n -P K p o p ulati o ns. C ha n ges fr o m baseli ne i n vit al si g n meas ure me nts will be s u m marize d 
at t hese visits.  
1 2. 1. 5  C o nc o mit a nt  Me dic ati o ns  
All pre vi o us t hera pies a n d c o nc o mita nt me dicati o ns will be classifie d base d o n ter mi n ol o g y 
fr o m t he W orl d H ealt h Or ga nizati o n Dr u g Dicti o nar y. Pre vi o us t hera pies a n d c o nc o mita nt 
me dicati o ns data will be prese nte d i n dat a listi n gs.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
5 9  
 
 
 
1 2. 1. 6  Effic ac y f o r Assessi n g Tre at me nt  C o m pli a nce  
T his pri mar y o bjecti ve of t his st u d y is t o assess t he safet y of t he st u d y dr u g. Descri pti ve 
efficac y statistics f or t he e n d p oi nts will assist i n e val uati n g c o m plia nce wit h treat me nt f or t he 
p ur p oses of saf et y assess me nt. T he effi cac y v aria bles e val uate d i n t his st u d y i ncl u de 
micr osc o pic K O H e xa mi nati o n a n d m yc ol o gical c ult ure o utc o mes of t he tar get great t oe nail, 
perce nt i n v ol ve me nt of t he tar get great t oe nail, gr o wt h of t he tar get great t oe nail, a n d 
assess me nts of t he n o ntar get t oe nails. T he efficac y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  C o m plete C ure, defi ne d as 0 % cli nical i n v ol ve me n t of t he tar get t oe n ail a n d 
ne gati ve K O H a n d f u n g al c ult ure at Wee k  5 2  
•  C o m plete or Al m ost C o m plete C ure at Wee k 5 2, defi ne d as : S 5 %  t oe n ail 
i n v ol ve me nt 
•  T he Cli nical Efficac y rat e at Wee k 5 2, defi ne d as a n affecte d t ar get great t o e nail 
area of <  1 0 %  
•  T he M yc ol o gic C ure r ate at Wee k 5 2, defi ne d as a ne gati ve K O H e xa mi nati o n 
a n d a ne g ati ve f u n gal c ult ure of t he tar g et great t oe nail  sa m ple 
T he C o m plete C ure rat e, t he C o m plete or Al m ost C o m plete C ure rate, t he Cli nical Efficac y 
rate, a n d t he M y c ol o gic C ure rate will be prese nt e d usi n g descri pti ve statistics (sa m ple size n, 
fre q ue n c y c o u nts, a n d p erce nta g es) f or t h e safet y, P K, a n d n o n-P K p o p ulati o ns. I n a d diti o n, 
t he gr o wt h of t he tar g et great t oe nail at eac h st u d y visit a n d t he c ha n ge fr o m baseli ne i n t he 
n u m ber of affecte d n o ntar get t oe nails will be s u m marize d des cri pti vel y.  
A last o bser vati o n carrie d f or war d ( L O C F) i m p utati o n will be use d t o i m p ute missi n g val ues 
f or t he efficac y vari a bles at Wee k 5 2. N o se nsiti vit y a nal yses will be c o n d u cte d. 
 
1 2. 2  Assess m e nt  of  P h ar m ac o ki netics  
 
T he P K o bjecti ves will be c o nsi der e d met w he n a p pr o xi matel y 1 6 e val ua bl e s u bjects are 
treate d u n der ma xi mal us e c o n diti o ns t hr o u g h da y 2 8 of t he P K e val uati o n. 
N o i m p utati o ns will be ma de f or missi n g data. Plas ma c o nce ntrati o ns t hat a re re p ort e d as 
bel o w t he li mit of q ua ntitati o n ( B L Q) i n t he data tra nsfer file a n d will be set t o zer o f or t h e 
s u m maries of  c o nce ntrati o ns  as well  as calc ulati o n  of  P K  para meters.  Missi n g  val ues  will  be 
treate d as if t he y were n e ver dra w n. Plas ma c o nce ntrati o ns a n d P K para met ers will be 
s u m marize d f or t h e P K a nal ysis set usi n g descri pti ve statistics ( n, mea n, S D, sta n dar d err or 
of t he mea n [ S E M], c oefficie nt of vari ati o n [ C V], me dia n, mi ni m u m, a n d ma xi m u m).  
Ge o metric mea ns will als o be use d t o s u m marize C m a x , C mi n , A U C ( 0-t) a n d A U C ( 0-2 4 h). 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 0  
 
 
 
Plas ma c o nce ntr ati o ns of efi nac o n az ole a n d meta b olite ( H 3 a n d H 4) at eac h sc he d ule d 
sa m pli n g ti me p oi nt will be s u m marize d usi n g des cri pti ve statistics. T he i n di vi d ual plas ma 
c o nce ntr ati o ns will be liste d f or eac h s u bject. C o n ce ntrati o ns B L Q will be dis pla ye d as B L Q 
i n t he listi n gs. 
T he mea n plas ma c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d met a b olites ( H 3 a n d H 4) 
will be prese nte d gr a p hicall y f or Da ys 2 8 a n d 2 9 i n b ot h li near a n d l o garit h mic scales.  
I n di vi d ual s u bject plas ma c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 
a n d H 4) will als o be create d.  
Plas ma P K para meters f or efi nac o naz ol e a n d meta b olites ( H 3 a n d H 4) will be calc ul ate d 
usi n g n o nc o m part me ntal a nal ysis. T he P K para meters will be calc ul ate d f or eac h s u bject 
usi n g act ua l sa m pli n g ti mes. T he ma xi m u m plas ma c o nce ntrati o n ( Cma x ) a n d ti me t o Cma x  
( Tma x ) will be ta ke n directl y fr o m t he data. 
T he f oll o wi n g P K para m eters will be calc ulate d fr o m t he i n di vi d ual plas ma c o nce ntrati o ns 
o n Da ys 2 8 a n d 2 9 w h e n p ossi ble:  
•  C m a x  ( o bser ve d pea k dr u g [efi nac o naz ol e a n d met a b olites]  c o nce ntrati o n)  
•  T ma x  (ti me at w hic h C m a x  occ urs)  
•  C mi n  ( o bser ve d mi ni m u m dr u g c o nce ntrati o n)  
•  A U C 0 -t (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 u p t o t he sa m pli n g 
ti me c orres p o n di n g t o t he last q ua ntifia bl e  c o n ce ntrati o n)  
•  A U C 0 -2 4 h (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
[c orr es p o n di n g t o t he d osi n g  i nter val]) 
A d diti o nal P K para meters ma y be calc ul ate d as a p pr o priate.  
 
1 2. 3  S u bject  Dis p ositi o n  
S u bject dis p ositi o n will be s u m marize d f or eac h a nal ysis p o p ulati o n.  
 
1 2. 4  De m o gr a p hics a n d B aseli ne  C h ar acteristics  
S u bject de m o gra p hic a n d baseli ne c haracteristics will be s u m marize d usi n g descri pti ve 
statistics f or eac h a nal ysis p o p ulati o n. 
 
1 2. 5  Pr ot oc ol  De vi ati o ns  
All pr ot oc ol de viati o ns will be re p orte d t o t he s p o ns or a n d r ec or de d t hr o u g h o ut t he st u d y. 
A ta b ulati o n of pr ot oc ol de viati o ns will be i ncl u de d i n t he fi nal st u d y re p ort.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 1  
 
 
 
1 2. 6  C o m pli a nce  
Efficac y e val u ati o ns are bei n g c o n d ucte d t o ass ess treat me nt c o m plia nce. I nf or mati o n 
re gar di n g t he e val uati o ns a n d t heir a nal ys es are prese nte d i n Secti o n 1 2. 1. 6.  
St u d y dr u g c o m plia nce will be calc ulate d f or eac h s u bject b y ta ki n g i nt o acc o u nt w het her a 
s ubject t o o k all d oses of st u d y dr u g as i nstr ucte d. Calc ulati o n of st u d y dr u g c o m plia nce will 
be d oc u me nte d i n t he a nal ysis pla n.  
 
1 2. 7  I nteri m A n al yses  
N o i nteri m a nal yses are pla n ne d.  
 
1 2. 8  A d diti o n al St atistic al  C o nsi der ati o ns  
W he n a p pr o xi mat el y 4 0 e val ua ble s u bjec ts ha ve b ee n treate d f or 4 8 wee ks meeti n g t he 
pri mar y saf et y o bjecti ve (re gar dless if s u bjects i n t he P K s u bset are c o nti n ui n g), a data c ut 
will be d o ne a n d t he st u d y re p ort will be writte n. O nce all s u bjects i n t he P K s u bset 
c o m pletes t he st u d y, data base l oc k will be perf or m e d a n d t he st u d y re p ort a me n d me nt will be 
writte n.  
All statistical pr ocessi n g will be perf or me d usi n g S A S ®  versi o n 9. 3 or hi g her u nless 
ot her wise state d. N o h y p ot hesis testi n g will be c o n d ucte d i n t his st u d y. A statistical a nal ysis 
pla n , descri bi n g all statistical a nal yses, will be pr o vi de d as a se p arate d o c u me nt pri or t o data 
a nal ysis is perf or me d.  
1 2. 8. 1  A n al ysis  P o p ul ati o ns  
All s u bjects w h o recei ve at least 1 c o nfir me d d os e of st u d y dr u g will be i ncl u de d i n t he 
safet y p o p ulati o n. 
All s u bject s i n t he P K s u bset w h o recei ve at least 1 c o nfir me d d ose of st u d y dr u g a n d ha v e 
a n y P K data o n Da ys 2 8 a n d 2 9 will be i ncl u de d i n t he P K p o p ulati o n.  
All safet y p o p ulati o n s u bjects w h o are n ot i n t he P K s u bset will be i ncl u de d i n t he N o n -P K 
p o p ulati o n.  
1 2. 8. 2  S a m ple Size  Det er mi n ati o n  
A p pr o xi matel y 6 0 s u bjects will be e nr olle d a n d recei ve treat me nt wit h st u d y dr u g. 
A p pr o xi matel y 2 0 of t he 6 0 s u bjects will be e nr olle d i n t he P K s u bset. T hes e sa m ple sizes 
were b ase d o n P K a n d cli nical c o nsi derati o ns; n o f or mal sa m ple size calc ul ati o n was 
perf or me d. T he n u m bers of pla n ne d s u bjects are c o nsi dere d a d e q uate f or d eter mi ni n g t he 
safet y pr ofile a n d t he P K para meters of efi nac o n az ole i n a pe diatri c p o p ulati o n of s u bjects 
a ge d 6 t o 1 6 years 1 1 m o nt hs wit h mil d t o se vere o n yc h o m yc osis of t he t oe nails. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 2  
 
 
 
1 2. 8. 3  H a n dli n g of Missi n g  D at a  
N o i m p utati o ns will be ma de f or missi n g safet y or P K data. As i n dicate d pre vi o usl y, t he 
efficac y e n d p oi nts, w hic h are use d t o assess treat me nt c o m plia nce, will ha ve missi n g data 
i m p ute d wit h L O C F f or n o n-P K p o p ulati o n a nal yses. Missi n g efficac y dat a will n ot be 
i m p ute d f or safet y a n d P K p o p ulati o n a nal yses. 
1 2. 8. 4  M ultice nter  Iss ues 
T he st u d y will be c o n d ucte d at m ulti ple i n vesti gati o nal ce nters i n t he U S, Ce ntral A meri ca, 
an d t he Cari b bea n wit h t he i nte nti o n of p o oli n g t he res ults f or a nal ysis.  
1 2. 8. 5  M ulti plicit y  Iss ues 
N ot a p plica ble.  
 
1 2. 8. 6  Wi n d o wi n g  R ules  
T he ti mi n g of all st u d y visits is relati ve t o t he Baseli ne ( Da y 1) visit. Visit 3 ( Wee k 4) s h o ul d 
occ ur wit hi n 5 da ys of D a y 2 8 a n d Visit 3 A ( Wee k 4) s h o ul d occ ur 1 d a y after Visit 3. T he 
Wee k 8 a n d all s u bse q ue nt visits s h o ul d occ ur wit hi n 5 da ys of t he tar get e d ti mes.  
 
1 3  Q u alit y C o ntr ol a n d Q u alit y  Ass ur a nce  
T his st u d y will be c o n d ucte d u n der t he s p o ns ors hi p of Valea nt, i n c o nf or m a ti o n wit h all 
a p pr o priate l o cal a n d f e d eral r e g ulati o ns as well as I C H g ui deli nes.  
T he s p o ns or is res p o nsi ble f or i m ple me nti n g a n d mai ntai ni n g q ualit y ass ura nce a n d q ualit y 
c o ntr ol s yste ms t o e ns ure t hat st u dies are c o n d u cte d a n d data are ge n erate d, d oc u me nte d, a n d 
re p orte d i n c o m plia n ce wit h t he pr ot oc ol, G C P g ui deli nes, a n d a p plica bl e re g ulat or y 
re q uire me nts. I n a d diti o n, t he s p o ns or will be res p o nsi ble f or sec uri n g a gree me nt fr o m all 
i n v ol ve d parties t o e ns ur e direct access t o all st u d y-relate d sites, s ource d ata/ d oc u me nts, 
e C R Fs, a n d re p orts f or t h e p ur p ose of m o nit ori n g a n d a u diti n g b y t he s p o ns or, a n d i ns pecti o n 
b y d o mestic a n d f orei g n re g ulat or y a ut h orities.  
Ce ntral la b orat or y s er vices will be perf or me d b y a q ualifie d, lice nse d facilit y t hat will be 
liste d o n t he U S F o o d a n d Dr u g A d mi nistrati o n F or m 1 5 7 2. C o pies of all n or mal val ues 
(as a p plica bl e), la b or at or y certificati o ns, a n d t he direct or’s c urric ul u m vitae will be pr o vi de d 
t o eac h i n vesti gati o nal ce nter a n d t o t he s p o ns or. 
 
1 3. 1  St u d y  M o nit ori n g  
T he c o n d uct of t h e st u d y will be cl osel y m o nit ore d. S p o ns or re pres e ntati ves m ust be 
per mitte d t o visit all st u d y site l ocati o ns t o assess t he data, q ualit y of st u d y perf or ma n ce, a n d  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 3  
 
 
 
st u d y i nte grit y i n a ma n ner c o nsiste nt wit h a p plica ble healt h a ut h orit y re g ul ati o ns a n d t he 
pr oce d ur es descri be d i n t his pr ot oc ol.  
Pri or t o t he start of t he st u d y, t he S p o ns or or its desi g nee(s) will re vie w t he pr ot oc ol, e C R Fs, 
re g ulat or y o bli gati o ns, a n d ot her material or e q ui p me nt rele va nt t o t he c o n d uct of t he st u d y 
wit h t he I n v esti gat or/ S u b/ C o I n vesti gat or a n d rele va nt st u d y site pers o n nel.  
M o nit ori n g visits a n d tele p h o ne c o ns ultati o ns will occ ur as n ecessar y, or p er t he st u d y 
m o nit ori n g pla n, d uri n g t he c o urse of t he i n vesti gati o n t o verif y t he f oll o wi n g:  
•  T he ri g hts a n d well -b ei n g of s u bjects are  pr otecte d  
•  T he c o n d uct of t h e i n vesti gati o n is i n c o m plia nce wit h t he c urre ntl y a p pr o v e d 
pr ot oc ol/a me n d me nt, I C H G C Ps, a n d I R B/ E C  re q uire me nts 
•  T he i nte grit y of t he data is mai ntai ne d, i ncl u di n g a de q uate st u d y  d oc u m e ntati o n  
•  T he facilities re mai n  acce pta ble  
•  T he I n vesti gat or a n d site pers o n nel re m ai n q ualifie d a n d a ble t o c o n d uct t he st u d y 
•  St u d y dr u g acc o u nta bilit y is d oc u me nte d  pr o perl y  
D uri n g t he c o urs e of t he st u d y, if t he S p o ns or deter mi nes t hat a n I n vesti gat o r is n o n- 
c o m plia nt wit h t he st u d y pla n a n d/ or a p plica bl e re g ulat or y re q uire m e nts, t he S p o ns or will 
ta ke acti o n t o sec ure or r ei nstate c o m plia nce. I n a d diti o n, t he S p o ns or ma y ter mi nate t he 
I n v esti gat or’s partici pati o n i n t he st u d y if a p pr o priate, or if t he I n v esti gat or re mai ns n o n - 
c o m plia nt des pite t he re me dial acti o ns of t he S p o ns or..  
 
1 3. 2  A u dits a n d  I ns pecti o ns 
I nteri m a n d e n d of st u d y a u dits of ra w d ata, st u d y files, a n d t he fi nal re p ort ma y be 
c o n d ucte d b y t he s p o ns or’s q ualit y ass ura nce de part me nt or its desi g nee. A certificate 
attesti n g t o t he a u dit(s) will be iss ue d as a p plica ble. I n a d diti o n, i ns pecti o ns or o n -site a u dits 
ma y be carrie d o ut b y l ocal a ut h orities. T he i n vesti gat ors will all o w t he s p o ns or's 
re pres e ntati ves a n d a n y r e g ulator y a ge n c y t o e xa mi ne all st u d y rec or ds a n d l o gs, e C R Fs, 
c orres p o n di n g s u bject me dical rec or ds, st u d y dr u g dis pe nsi n g rec or ds, st u d y dr u g st ora ge 
area, a n d a n y ot her d oc u me nts c o nsi dere d s o urce d oc u me ntati o n. T he i n vesti gat ors a gree t o 
assist t he re pres e nt ati ve, if re q uire d.  
 
1 3. 3  D at a Q u alit y  Ass ur a nce  
All assess me nts perf or m e d will be acc uratel y d o c u me nte d i n t he s u bject’s s o urce d oc u m e nts 
a n d e C R Fs. T he i n vesti g at or or desi g nee will e nter t he i nf or mati o n re q uire d b y t he pr ot oc ol  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 4  
 
 
 
i nt o t he s o urce d oc u me nts a n d e C R Fs pr o vi de d b y t he s p o ns or or desi g nee. S u bjects will be 
i de ntifie d i n t he e C R Fs b y t heir assi g ne d s u bject n u m ber a n d i nitials o nl y. 
T he i n vesti gat ors m ust rea d t he pr ot oc ol t h or o u g hl y a n d m ust f oll o w t he i nstr ucti o ns e xactl y. 
A n y de viati o ns s h o ul d be a gree d t o b y pri or disc ussi o n bet wee n t he s p o ns or a n d t he 
i n vesti gat or, wit h a p pr o priate writte n pr ot oc ol a me n d me nts ma de pri or t o effecti n g t he 
a gree d u p o n c ha n g es. A n y a me n d me nt c o ntai ni n g maj or m o dificati o ns ( partic ularl y if it ma y 
i n v ol ve a n i ncrease d ris k t o t he s u bjects) will be a p pr o ve d b y t he I R B/I E C bef ore it ma y be 
i m ple me nte d. N o c ha n ge i n t he c o n d uct of t he st u d y ca n be i nstit ute d wit h o ut writte n 
a p pr o val fr o m t he s p o ns or.  
 
1 4  Et hics a n d A d mi nistr ati ve  Iss ues 
1 4. 1  Et hic al C o n d uct of t he  St u d y  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he et hical pri nci ples ori gi nati n g fr o m t he 
Declar ati o n of Helsi n ki, I C H g ui deli nes, G C P g ui deli nes, a n d i n c o m plia nce wit h l ocal a n d 
fe der al re g ulat or y re q uir e me nts. T he i n vesti gat or a grees, w h e n si g ni n g t he pr ot oc ol, t o 
a d here t o t he i nstr u cti o ns a n d pr oce d ures d escri be d i n it a n d t here b y t o a d h ere t o t he 
pri nci ples of G C P.  
 
1 4. 2  Et hics  Re vie w  
T his pr ot oc ol, pr o p ose d i nf or me d c o ns e nt/asse nt f or m a n d ot her i nf or m ati o n t o t he s u bjects, 
a n d all a p pr o pri ate a me n d me nts, will be pr o perl y re vie we d, a n d a p pr o ve d b y a n I R B/I E C.  
A si g ne d a n d date d n otifi cati o n of t he I R B/I E C a p pr o val will be pr o vi de d t o t he s p o ns or a n d 
i n vesti gat or pri or t o st u d y i nitiati o n. T he na me a n d occ u pati o n of t he c hair a n d me m bers of 
t he I R B/I E C will be s u p plie d t o t he s p o ns or. T he i n vesti gat or will pr o vi de re q uire d pr o gress 
re p orts a n d r e p ort all S A Es t o t he I R B/I E C as re q uire d. 
 
1 4. 3  Writte n I nf or m e d  C o nse nt  
Writte n i nf or me d c o ns e nt/asse nt, i n acc or da nce wit h l ocal cli nical i n vesti gati o n re g ulati o ns, 
m ust be o btai ne d pri or t o partici pati o n i n t he st u d y. T he i n vesti gat or or desi g nee will disc uss 
t he p ur p ose of t he st u d y wit h eac h s u bject a n d t heir pare nt(s)/le g al g uar di a n(s) a n d will 
pr o vi de a des cri pti o n of t he st u d y dr u g (i ncl u di n g  a n y p ote ntial a n d p ossi ble si de effects) a n d 
t he st u d y pr oce d ur es. I nf or mati o n m ust be gi ve n b ot h i n oral a n d writte n f or m. T he s u bject 
i nf or mati o n pr o vi de d will be i n a la n g ua ge u n dersta n da ble t o t he s u bject a n d t heir 
pare nt(s)/le g al g uar dia n(s) a n d ma y n ot i ncl u de a n y la n g ua ge t hat a p p ears t o wai ve a n y of  t he 
s u bject’s le gal ri g hts or a p pears t o rel ease t h e i n vesti gat or, t he s p o ns or, or t he i nstit uti o n 
fr o m lia bilit y or ne gli ge nce.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 5  
 
 
 
T he i n vesti gat or or desi g nee will pr o vi de t he pr os pecti ve s u bject a n d t h e s u bject’s pare nt(s) 
or le gal g uar di a n(s) s ufficie nt ti me t o c o nsi der w h et her t o partici pat e, mi ni mizi n g t he 
p ossi bilit y of c oerci o n or u n d ue i nfl ue nce a n d will disc uss a n y q uesti o ns t he s u bject a n d/ or 
t heir pare nt(s)/le gal g uar dia n(s) ma y ha v e. T he i n vesti gat or or desi g nee will e x plai n t o t he 
s u bject a n d t heir pare nt(s)/le gal g uar dia n(s) t hat p artici pati o n i n t he st u d y is v ol u ntar y a n d 
t hat wit h dra wal fr o m t he st u d y is p ossi ble at a n y ti me wit h o ut detri me nt t o care. T he c o ns e nt 
m ust i ncl u de ac k n o wle d g me nt t hat me dical rec or ds a n d me dical data d eri ve d fr o m t he st u d y 
ma y be f or w ar de d t o t he s p o ns or or t o t he res p o nsi ble a ut h orities or fe d eral a ut h orities.  
N o s u bject ca n e nter t he st u d y or ha ve a n y st u d y-relate d pr oce d ures perf or me d bef ore his/ her 
writte n i nf or me d c o ns e nt/asse nt has bee n o btai n e d. S u bjects u n der t he a g e of c o nse nt m ust 
si g n a n asse nt f or m a n d t heir par e nts/le gal g uar dia ns m ust si g n t he i nf or me d c o nse nt f or m.  
S u bject s o ver t he a g e of c o nse nt m ust si g n t he i nf or me d c o nse nt f or m. S u bjects a n d t heir 
pare nts/le gal g uar dia ns will als o pr o vi de writte n c o nse nt/asse nt t o o btai n p h ot o gra p hs of t he 
tar get great t oe nail. T he ori gi nal si g ne d a n d date d i nf or me d c o nse nt a n d asse nt f or ms will be 
retai ne d wit h t he st u d y rec or ds, a n d a c o p y of t he si g ne d f or ms will be gi ve n t o t he s u bject 
a n d t heir par e nt or le gal g uar dia n as a p plica ble.  
A n i nf or me d c o ns e nt/asse nt te m plate will be s u p plie d b y t he s p o ns or t o t he i n vesti gat or. 
A n y c ha n ge s t o t he i nf or me d c o nse nt/asse nt f or m m ust be a gree d t o b y t he s p o ns or pri or t o 
s u b missi o n t o t he I R B/I E C, a n d a c o p y of t he a p pr o ve d versi o n m ust be pr o vi de d t o t he 
s p o ns or after I R B/I E C a p pr o val. 
 
1 4. 4  S u bject D at a  Pr otecti o n  
S u bject data will be pr otecte d b y  e ns uri n g t hat n o ca pt ure d d ata c o ntai n s u bject na mes, 
a d dresses, tel e p h o ne n u m bers, e mail a d dresses, or ot her direct pers o nall y i de ntif yi n g 
i nf or mati o n. It is ac k n o wle d ge d t hat s u bject i nitials, de m o gra p hics (i ncl u di n g birt h dates), 
me dical hist ories, a n d pri or c o nc o mita nt me dicati o n uses, al o n g wit h t he na me a n d a d dress of 
t he e nr olli n g i n vesti gat or ma y all o w f or pers o nal i de ntificati o n of st u d y partici pa nts. Ot her 
t ha n w here n ecessar y t o meet re g ulat or y re q uire me nts, all data c ollect e d i n t his st u d y will be 
prese nte d i n ta b ulat e d (ie, a g gre gat e) f or m a n d listi n gs c o ntai ni n g i nf or mati o n t hat c o ul d be 
use d t o i de ntif y a n i n di vi d ual s u bject will n ot be i ncl u de d i n a n y p u blic discl os ures of t he 
st u d y data or t he st u d y res ults. 
 
1 4. 5  D at a M o nit ori n g  C o m mittee  
N ot a p plica ble.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 6  
 
 
 
1 4. 6  Fi n a nci al  Discl os ure  
Fi na ncial discl os ur es will be o btai ne d fr o m all i n vesti gat ors i n or der t o d oc u me nt a n y 
p ote ntial c o nflicts of i nterest.  
 
1 4. 7  Esse nti al  D oc u m e nts  
I n v esti gat or m ust mai ntai n esse ntial d oc u me nts d uri n g t he c o n d uct of t he st u d y a n d retai n 
t hese d oc u me nts aft er t he c o m pleti o n of t he st u d y i n acc or d a nce wit h t he S p o ns or’s rec or d 
rete nti o n i nstr ucti o ns. T he I n vesti gat or a grees t o a d here t o t he d oc u m e nt ret e nti o n pr oce d ures 
w he n si g ni n g t he pr ot oc ol I n vesti gat or State m e nt of A p pr o val.  
Esse ntial d oc u me nts i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  I R B a p pr o v als f or t he st u d y pr ot oc ol, all a me n d me nts, I C F(s), a n d a d v ertise me nts  
•  I R B a n n u al st u d y re vie w 
•  I R B c orres p o n de n ce a n d re p orts (e g, S A E re p orts, pr ot oc ol de viati o ns, a n d safet y 
u p dates)  
•  Re g ulat or y d oc u me nts (e g, fi na ncial discl os ure a n d dele gati o n of a ut h orit y  f or ms) 
•  All s o urce  d oc u m e nts  
•  C R Fs  
•  S u bject’s si g ne d I C F  
•  F D A F or m  1 5 7 2  
•  Acc o u nta bilit y rec or ds f or t he st u d y  dr u g  
•  C orres p o n de nce fr o m a n d t o s p o ns or 
•  A n y ot her d oc u me nts r ele va nt t o t he c o n d uct of t h e  st u d y 
I n t he e ve nt t hat t he I n vesti gat or wit h dra ws fr o m t he st u d y (e g, retire me nt or rel ocati o n), 
st u d y rec or ds will be tra nsferr e d t o a m ut uall y a gree d u p o n desi g nee (e g, a n ot her I n vesti gat or 
or site I R B/ E C). T he I n v esti gat or will pr o vi de n otice of s uc h tra nsfer i n writi n g t o t he 
s p o ns or 
 
1 4. 8  I n vesti g at or O bli g ati o ns  
T he i n vesti gat ors m ust rea d t he pr ot oc ol t h or o u g hl y, c o m plete a n d si g n t he pr ot oc ol 
si g nat ure pa ge, a n d m ust foll o w t he i nstr ucti o ns e xactl y. W he n e ver p ossi ble, a n y pla n ne d 
de viati o ns s h o ul d be a gree d t o b y pri or disc ussi o n bet wee n t he s p o ns or a n d t he i n vesti gat or, 
wit h a p pr o priate d o c u me ntati o n of s p o ns or a p pr o val pri or t o effecti n g t he a gree d u p o n  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 7  
 
 
 
c ha n ges. A n y d e viati o ns s h o ul d be re p orte d t o t he s p o ns or a n d re p orte d t o t he I R B/I E C 
acc or di n g t o t he re q uire me nts of t he I R B/I E C.  
 
1 4. 9  C h a n ges t o t he  Pr ot o c ol  
A n y a me n d me nt c o ntai ni n g maj or m o dificati o ns ( partic ularl y if it ma y i n v ol ve a n i ncrease d 
ris k t o t he s u bjects) will be a p pr o ve d b y t he I R B bef ore it ma y b e i m ple me nte d. N o c h a n ge i n 
t he c o n d uct of t he st u d y ca n be i nstit ute d wit h o ut pri or writte n a p pr o v al fr o m t he s p o ns or. 
 
1 4. 1 0  C o nfi de nti alit y/ P u blic ati o n of t he  St u d y  
All t he data f ur nis he d t o t he i n vesti gat or a n d his/ her staff a n d all data o bt ai ne d t hr o u g h t his 
pr ot oc ol will be re gar de d as c o nfi de ntial a n d pr o prietar y i n nat ure a n d will n ot be discl ose d 
t o a n y t hir d part y, e xce pt f or t he U S F o o d a n d Dr u g A d mi nistrati o n or ot her re g ulat or y  b o d y, 
wit h o ut writte n c o nse nt fr o m t he  s p o ns or. 
T he res ults of t he st u d y ma y be p u blis he d or pres e nte d b y t he I n vesti gat or(s) after t he re vie w 
b y, a n d i n c o ns ultati o n a n d a gree m e nt wit h t he S p o ns or, a n d s uc h t hat c o nfi de ntial or 
pr o pri etar y i nf or mati o n is n ot discl ose d. Pri or t o s u b missi o n f or p u blicati o n or prese ntati o n, a 
c o p y of t he fi nal te xt s h o ul d be f or war de d b y t h e I n vesti gat or(s) t o t he S p o ns or or its 
desi g nee f or re vie w a n d c o m me nt. S uc h c o m me nts s hall ai m t o e ns ure t he scie nt ific i nte grit y 
of t he pr o p ose d p u blicati o ns a n d/ or prese nt ati o ns a n d e ns ure t h at t he data a n d material 
referri n g t o t he S p o ns or pr o d ucts a n d acti vities recei ve fair, acc urate, a n d reas o na ble 
prese ntati o n.  
 
1 4. 1 1  St u d y  Ter mi n ati o n  
T he s p o ns or res er ves t he ri g ht t o disc o nti n ue t he st u d y o verall or at a partic ular st u d y site at 
a n y ti me f or reas o ns i ncl u di n g b ut n ot li mite d t o:  
•  E mer ge nce of effects t hat d o n ot j ustif y t he be nefit/ris k relati o ns hi p t o t he st u d y 
p o p ulati o n as a  w h ole.  
•  Fail ure t o c o m pl y wit h t h e pr ot oc ol, G C P, or a n y ot her vi olati o n dist ur bi n g  t he 
a p pr o priate c o n d uct of t h e  st u d y. 
•  Fail ure t o meet e nr oll me nt g oals o verall or at a partic ular st u d y  site. 
If a st u d y is ter mi nate d, t he S p o ns or will pr o m ptl y n otif y t he I n v esti gat or. After n otificati o n, 
t he I n v esti gat or m ust c o ntact all partici pati n g s u bjects a n d t heir p are nts/le g al g uar dia ns 
wit hi n a reas o na bl e ti mefra me a gree d u p o n b y t h e S p o ns or. All st u d y materials m ust be 
c ollecte d a n d all e C R Fs c o m plete d t o t he greatest e xte nt p ossi ble  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 8  
 
 
 
1 5  D at a H a n dli n g a n d Rec or d  Kee pi n g  
1 5. 1  I ns pecti o n of Rec o r ds  
I n v esti gat ors m ust mai nt ai n detaile d rec or ds o n all st u d y s u bjects w h o are e nr olle d i n t he 
st u d y or w h o u n der g o scr ee ni n g. Data will be rec or de d i n t he s u bject’s s o urce d oc u me nts a n d 
i n a p plica ble st u d y l o gs pr o vi de d b y t he s p o ns or. S o urce d oc u m e nts i ncl u de s u bject’s 
me dical rec or ds, h os pital c harts, cli nic c h arts, a n d t he i n vesti gat or’s s u bject st u d y files, as 
well as t he res ults of dia g n ostic tests (e g, la b orat or y tests). All me dical i nf or mati o n o btai ne d 
at eac h st u d y visit m ust be rec or d e d i n t he s u bject’s s o urce d oc u m e ntati o n i n real ti me as it is 
c ollecte d a n d t he n e nter e d o nt o t he e C R F b y site  p ers o n nel.  
S u bject -c o m plete d f or ms s uc h as diaries a n d q uesti o n naires are als o c o nsi d ere d s o urce dat a. 
O nl y s u bjects are t o r ec or d i nf or mati o n i n s u bject diaries a n d q uesti o n naires. I n n o i nsta nce, 
s h o ul d a n I n v esti gat or or st u d y site pers o n nel rec or d a n y data or ma ke c ha n ges t o s u bject 
c o m plete d for ms. T he I n vesti gat or or desi g nee s h o ul d re vie w s u bject -c o m plete d f or ms 
d uri n g st u d y visits. If a n e ntr y is f o u n d t o be ille gi ble or a mista ke is f o u n d (e g, a n i nc orrect 
year w as rec or de d), t he s u bject s h o ul d be i nstr ucte d t o e dit t he e ntr y b y dra wi n g a si n gle li ne 
t hr o u g h t he ori gi nal e ntr y, e nteri n g t he ne w i nf or mati o n, dati n g, a n d writi n g s u bject’s year of 
birt h t o  ac k n o wle d ge.  
U p o n st u d y c o m pleti o n or at a n y ot her ti me s pecifie d b y t he s p o ns or or desi g nee, t he 
a p pr o priate st u d y d oc u m e nts m ust be s u b mit te d t o t he s p o ns or. 
Tele p h o ne c o n versati o ns a n d electr o nic mail wit h t he s u bject, t he s p o ns or, or t he s p o ns or’s 
desi g nee c o n cer ni n g t he st u d y m ust be rec or de d or ke pt o n file. All s o urce d oc u me nts m ust 
be ma de a vaila ble t o t he s p o ns or a n d t he s p o ns or’s des i g nate d m o nit or u p o n re q uest. 
 
1 5. 2  C ase Re p ort  F o r ms  
S u bject data re q uir e d b y t his pr ot oc ol are t o be rec or de d o n e C R Fs. S u bject data rec or de d o n 
e C R Fs d uri n g t he st u d y will be d oc u me nte d i n a c o de d fas hi o n. T h e s u bject will o nl y be 
i de ntifie d b y t he s u bject nu m ber a n d b y t heir y ear of birt h if als o re q uire d. C o nfi de ntialit y of 
s u bject rec or ds m ust be mai ntai ne d t o e ns ure a d h ere nce t o a p plica bl e l ocal pri vac y 
re g ulati o ns. 
T he I n vesti gat or a n d st u d y site pers o n nel will be res p o nsi ble f or c o m pleti n g t he e C R Fs. T h e 
I n v esti gat or is re q uir e d t o verif y t hat all of t he re q ueste d i nf or mati o n is acc uratel y rec or de d 
o n t he e C R Fs. All i nf or m ati o n re q ueste d o n t he e C R Fs nee ds t o be s u p plie d, i ncl u di n g 
s u bject i de ntificati o n, dat e(s), ass ess me nt val ues, etc., a n d a n y o missi on or discre pa n c y will 
re q uire e x pla nati o n. All i nf or mati o n o n e C R Fs m ust be tracea ble t o s o urce d oc u me nts. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
6 9  
 
 
 
T he st u d y m o nit or will be res p o nsi ble f or re vie wi n g a n d verif yi n g t he d ata rec or d e d o n t he 
e C R Fs, utilizi n g t he ori gi nal s o urce d o c u me ntati o n a n d will q uer y discre p a nt fi n di n gs. T he 
I n v esti gat or a n d st u d y site pers o n nel will be res p o nsi ble f or a ns weri n g all q ueries. T he 
e C R Fs will be s u b mitte d t o Ba usc h + L o m b or its desi g nee(s) f or q ualit y ass ura nce re vie w, 
a n d statistical a nal ysi s. 
A c o p y of t he e C R Fs will be retai ne d b y t he I n vesti gat or at t he c o ncl usi o n of t he st u d y, w h o 
m ust e ns ure t hat it is st ore d i n a sec ure place  
 
1 5. 3  Rete nti o n of  Rec o r ds  
T he i n vesti gat or s h o ul d pr o perl y st ore a n d mai ntai n all st u d y rec or ds i n acc or da nce wit h 
s p o ns or directi ves. All rec or ds relati n g t o t he c o n d uct of t his st u d y are t o be retai ne d b y t he 
i n vesti gat or u ntil n otifie d b y t he s p o ns or i n writi n g t hat t he rec or ds ma y be destr o ye d. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, 1 0 Ma y 2 0 1 6  
C O N FI D E N TI A L  
7 0  
 
 
 
1 6  Refere nces  
1.  Ele ws ki B E. O n yc h o m yc osis: pa t h o ge nesis, dia g n osis, a n d ma na ge me nt. Cli n 
Micr o bi ol Re v.  1 9 9 8; 1 1( 3): 4 1 5 -2 9.  
2.  Le v y L. E pi de mi ol o g y of o n yc h o m yc osis i n s pecial-ris k p o p ulati o ns. J A m P o diatr 
Me d Ass oc.  1 9 9 7; 8 7( 1 2): 5 4 6 -5 0.  
3.  Zaias N, T osti A, Re bell G, M orelli R, Bar dazzi F, Biele y H, et al. A ut os o mal 
d o mi na nt patter n of distal s u b u n g ual o n yc h o m yc osis ca use d b y Tric h o p h yt o n 
r u br u m. J A m Aca d Der mat ol. 1 9 9 6; 3 4( 2 Pt 1): 3 0 2 -4.  
4.  Tre pa nier E F, A ms de n G W. C urre nt iss ues i n o n yc h o m yc osis. A n n P har m ac ot her. 
1 9 9 8; 3 2( 2): 2 0 4 -1 4.  
5.  G u pta A K, T u L Q. T her a pies f or o n yc h o m yc osis: a re vie w. Der m at ol Cli n. 
2 0 0 6; 2 4( 3): 3 7 5  9.  
6.  J u blia (efi n ac o naz ole) t o pical s ol uti o n, 1 0 %.  [ U S Prescri bi n g  I nf or m ati o n]. Valea nt 
P har mace uticals N ort h A merica, L L C;  2 0 1 4.  


 
Cli nic al St u d y Pr ot oc ol 
Efi n ac o n az ole 1 0 % T o pic al S ol uti o n 
Pr ot oc ol V 0 1 -1 0 8 A -4 0 1  
A M ultice nter, O pe n L a bel, Si n gle -ar m St u d y E v al u ati n g t he 
S afet y a n d P h ar m ac o ki netics of Efi n ac o n az ole 1 0 % T o p ic al 
S ol uti o n i n S u bjects wit h Mil d t o S e vere O n yc h o m yc osis of  t he 
T oe n ails  
 
De vel o p me nt p hase  of  st u d y: 
4  
St u d y  desi g n:  
M ultice nter, o pe n la bel, si n gle -ar m, safet y 
a n d p har mac o ki netics  st u d y 
Date:  
A me n d me nt 1 Date:  
Ma y 1 0, 2 0 1 6  
Dece m ber 0 5, 2 0 1 6  
S p o ns or:  
D o w P har mace utical Scie nces, a w h oll y 
o w ne d s u bsi diar y of Valea nt P har mace uticals 
I nter nati o nal 
1 3 3 0 Re d w o o d Wa y, S uite C 
Petal u ma, C A 9 4 9 5 4  
 
C O N FI D E N TI A L  
N ot hi n g herei n is t o be discl ose d wit h o ut pri or a p p r o v al of t he s p o ns or.  
 
 
 
 
 
 
 
 
 


 
Pr ot oc ol  V OI - I O & A-4 0  l, Efi n ac o n az ole  Pe diatric  Safet y  a n d P K  St u d y  
Valea nt Researc h &  De v e l op me nt  
 
Pr ot oc ol R e vi e w a n d A p pr o v als  
 
A M ultic e nt er, O p e n L a b el, Si n gl e -a r m St u d y E v al u ati n g t he S af et y a n d 
P b a r m a c o ki n eti cs of Efi n a c o n az ol e 1 0 % T o pic al S ol uti o n i n S u bj e cts wit h Mil d t o 
S e ve r e O n y c b o m y c osis of t he T o e n ails  
 
 
R e vi e w e d a n d a p p r o v e d:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli ni c al St u d y Pr ot oc o l, A m e n d m e nt 1 d at e d D e c e m b er 0 5, 2 0 1 6  
 
2  
 
C O N FI D E N TI A L  
l 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
3  
 
 
 
Pers o n nel Res p o nsi ble f or C o n d ucti n g t he St u d y  
 
A M ultice nter, O pe n L a bel, Si n gle - ar m St u d y E v al u ati n g t he S afet y a n d 
P h ar m ac o ki netics of Efi n ac o n az ole 1 0 % T o pic al S ol uti o n i n S u bjects wit h Mil d t o 
Se vere O n yc h o m yc osis of t he T oe n ails  
S p o ns or  
D o w P har mace uticals Scie nces, a w h oll y o w n e d s u bsi diar y of 
Valea nt P har mace uticals I nter nati o nal  
1 3 3 0 Re d w o o d Wa y, S uite C 
Petal u ma, C A 9 4 9 5 4  
 
 
 
 
C o nt act f or Re p orti n g Seri o us A d verse E ve nts  
Me d Trials Safet y 
Fa x: 
 
E mail : 
 
 
 
Ret ur n of Use d a n d U n use d St u d y Dr u g  
Cli nical Trial Materials 
S u p pl y C hai n, Area 5 6 
1 4 0 0 N ort h G o o d ma n Street 
R oc hester, N Y 1 4 6 0 9  
 
C o ntr act Rese arc h Or g a niz ati o n/ Me dic al M o nit or  
Me d Trials, I nc. C R O  
 
 
Tele p h o ne: 
 
Fa x:  
 
E mail:  
 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
4  
 
 
Pri nci p al I n vesti g at or Pr ot oc ol A gree me nt P a ge  
I a gree: 
•  T o ass u me res p o nsi bilit y f or t he pr o per c o n d u ct of t his cli nical st u d y at t his site a n d  t o 
c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, a n y f ut ure a me n d me nts, a n d wit h 
a n y ot her st u d y c o n d uct pr oce d ures pr o vi de d b y t he  s p o ns or. 
•  T hat I a m a w are of, a n d will c o m pl y wit h, t he i nter nati o nall y rec o g nize d c o de of G o o d 
Cli nical Practices ( G C P) a n d all ot her a p plica ble re g ulat or y re q uire me nts t o o btai n 
writte n a n d date d  a p pr o v al fr o m t he I nstit uti o nal or Ce ntral Re vie w B oar d (I R B) or 
I n d e pe n de nt Et hics C o m mittee (I E C) f or t he st u d y pr ot oc ol, writte n i nf or me d c o nse nt, 
c o nse nt f or m u p dates, s u bject -recr uit me nt pr oce d ures (e g, a d vertise me nts), a n d a n y 
ot her writte n i nf or mat i o n t o be pr o vi de d t o t he s u bjects, bef ore i nitiati n g t his cli nical 
st u d y. 
•  N ot t o i m ple me nt a n y c ha n ges t o, or de viati o ns fr o m t he pr ot oc ol wit h o ut pri or 
a gree m e nt  fr o m t he s p o ns or a n d re vie w a n d d oc u me nte d  a p pr o val  fr o m t h e I R B/I E C, 
e xce pt t o eli mi nate a n i m me diate hazar d t o t he st u d y s u bjects, or w he n c ha n ge(s) 
i n v ol ves o nl y l o gistical or a d mi nistrati ve as pects of t he cli nical st u d y. 
•  T o per mit direct m o nit ori n g a n d a u diti n g b y t he s p o ns or or s p o ns or's  re pres e ntati ves 
a n d i ns pecti o n b y t he a p pr o priate re g ulat or y a ut h orit y(ies).  
•  T hat I a m t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he i n vesti gati o nal 
pr o d ucts(s), as d escri be d i n t his pr ot oc ol, a n d a n y ot her i nf or mati o n pr o vi d e d b y t he 
s p o ns or or desi g nee, i n cl u di n g, b ut n ot li mite d t o, t he c urre nt I n vesti gat or Br oc h ure or 
e q ui vale nt d oc u me nt a n d a p pr o ve d pr o d u ct la bel (if  a p plica ble).  
•  T o pr o vi de s ufficie nt ti m e a n d a d e q uate n u m bers of q ualifie d staff a n d facilities f or t he 
f oresee n d urati o n of t he cli nical st u d y t o c o n d uct t he st u d y pr o perl y, et hicall y, a n d 
safel y. 
•  T o e ns ure t hat all pers o ns assisti n g i n t his st u d y are a de q u atel y i nf or me d a b o ut t he 
pr ot oc ol, i n vesti gati o nal pr o d uct(s), a n d t h eir cli nical st u d y -relat e d d uties a n d 
f u ncti o ns. 
 
 
Pri nci pal I n v esti gat or ( pri nt na me)  
 
 
Pri nci pal  I n v esti gat or (si g nat ure) 
Date  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
5  
 
 
 
2  S y n o psis  
 
N a m e of S p o ns or/ C o m p a n y:  
D o w P h ar m ace utic als Scie nces, a w h oll y o w ne d s u bsi di ar y of V ale a nt 
P h ar m ace utic als I nter n ati o n al  
N a m e of i n vesti g ati o n al pr o d uct:  
Efi nac o naz ole 1 0 % T o pical S ol uti o n  
N a m e of acti ve i n gre die nt:  
Efi nac o naz ole  
Title of st u d y:  
A M ultice nter, O pe n La bel, Si n gle -ar m St u d y E val uati n g t he Safet y a n d P har mac o ki netics of Efi nac o naz ole 
1 0 % T o pical S ol uti o n i n S u bjects wit h Mil d t o Se vere O n yc h o m yc osis of t he T oe nails  
N u m ber of cli nic al ce nters:  
A p pr o xi matel y 2 0 -2 5 i n vesti gati o nal ce nters i n t he U nite d States, a n d t he Cari b bea n  
O bjecti ves:  
T he pri mar y o bjecti ves of t his st u d y are t o e val uate: 1) safet y of o nce dail y t o picall y a d mi nistere d 
efi nac o naz ole 1 0 % f or 4 8 wee ks i n pe diatric s u bjects ( 6 -1 6 years 1 1 m o nt hs of a ge) wit h at least mil d 
o n yc h o m yc osis of t he t oe nails, a n d 2) p har mac o ki netics P K ( 4 wee ks) of o nce dail y t o picall y a d mi nistere d 
efi nac o naz ole 1 0 % i n pe diatric s u bjects ( 1 2 -1 6 y ears 1 1 m o nt hs of a ge) wit h m o derate t o se vere 
o n yc h o m yc osis of t he t oe nails.  
Met h o d ol o g y:  
T his is a n o pe n la bel, si n gle -ar m st u d y desi g ne d t o e val uate t he safet y a n d P K of a o nce dail y t o pical 
a p plicati o n of efi nac o naz ole i n t he treat me nt of pe diatric s u bjects wit h mil d t o se vere o n yc h o m yc osis of t he 
t oe nails. T he st u d y will i ncl u de s u bjects 6 t o 1 6 years of a ge, i ncl usi ve, b ut P K assess me nts will o nl y be 
perf or me d o n s u bjects 1 2 t o 1 6 years of a ge, i ncl usi ve (referre d t o t hr o u g h o ut t he pr ot oc ol as t he P K  s u bset). 
All s u bjects m ust ha ve o n yc h o m yc osis of at least 1 great t oe nail; s u bjects i n t he P K s u bset m ust ha ve 
o n yc h o m yc osis of b ot h great t oe nails a n d at least 4 ot her t oe nails. Eff orts will be ma de t o e nr oll s u bjects i nt o 
t he P K s u bset s uc h t hat t he s u bjects are e ve nl y distri b ute d acr oss t he re q uire d a ge ra n ge. 
F or s u bjects n ot partici pati n g i n t he P K s u bset, t he st u d y will c o nsist of 1 4 sc he d ule d visits, i ncl u di n g 
Scree ni n g ( u p t o Da y -4 2), Baseli ne ( Da y 1), 1 2 treat me nt visits ( Wee ks 4, 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 
4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( We e k 5 2). S u bjects i ncl u de d i n t he P K s u bset will 
atte n d t he sc he d ule d visits u p t o Wee k 4 a n d a n a d diti o nal st u d y visit at Da y 2 9 f or c ollecti o n of t he fi nal P K 
bl o o d sa m ple . T he P K assess me nts will be perf or me d u n der ma xi mal use c o n diti o ns. O nce P K assess me nts 
are c o m plete at Da y 2 9, t he P K s u bset of s u bjects will c o nti n ue treat me nt t hr o u g h wee k 4 8 wit h a d diti o nal 
visits at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8 ), a n d a 4-wee k p ost -treat me nt f oll o w-u p visit  
( Wee k 5 2). 
At t he Scree ni n g Visit, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will si g n a n i nf or me d c o nse nt/asse nt 
f or m a n d a p h ot o gra p h y c o nse nt/asse nt f or m, pr o vi de t heir me dical hist ories, re p ort t heir pre vi o us a n d 
c o nc o mita nt me dicati o ns, a n d be e val uate d a gai nst t he i ncl usi o n/e xcl usi o n criteria. Fe males of c hil d beari n g 
p ote ntial ( F O C B P) will ha ve uri ne pre g na nc y tests perf or me d. D uri n g t his visit, s u bjects will u n der g o a n 
e xa mi nati o n of t heir feet t o vis uall y ascertai n t he prese nce of o n yc h o m yc osis i n at least 1 great t oe nail f or 
s u bjects n ot i ncl u de d i n t he P K assess me nts, a n d o n b ot h great t oe nails a n d at least 4 ot her t oe nails f or 
s u bjects i ncl u de d i n t he P K assess me nts. A d diti o nall y, t he perce nt i n v ol ve me nt of t he affecte d great 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
6  
 
 
 
t oe nail(s) will be rec or de d. S peci me n will be o btai ne d fr o m t he great t oe nail(s) t o s hi p t o t he m yc ol o g y la b. 
B ot h t oe nails ma y be sa m ple d if b ot h are s us pecte d of ma nifesti n g o n yc h o m yc osis (at least 2 0 % 
i n v ol ve me nt). Bl o o d a n d uri ne s peci me ns will be c ollecte d f or ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis 
e val uati o ns. At rele va nt p ost -Scree ni n g Visits, t he tar get great t oe nail will be tri m me d bac k t o t he distal 
gr o o ve bef ore t he cli nical e val uati o ns are perf o r me d a n d bef ore p h ot o gra p hs are ta ke n. 
At t he Baseli ne Visit ( w hic h s h o ul d be sc he d ule d after K O H a n d f u n gal c ult ure res ults ha ve bee n o btai ne d 
fr o m t he m yc ol o g y la b), s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will u p date t heir me dical hist ories a n d 
c o nc o mita nt me dicati o n uses, a n d t he i ncl usi o n/e xcl usi o n criteria will be c o nfir me d. S u bjects will u n der g o 
a b bre viate d p h ysical e xa mi nati o ns, cli nical la b orat or y e val uati o ns, assess me nts of vital si g ns (sitti n g bl o o d 
press ure, res pirati o n, p u lse, a n d te m perat ure), a n d meas ure me nts of hei g ht a n d wei g ht. All F O C B P will ha ve 
uri ne pre g na nc y tests perf or me d. F or t he p ur p oses of efficac y assess me nts, 1 tar get great t oe nail will be 
selecte d fr o m t he st u d y-eli gi ble great t oe nail(s), i ncl u di n g s u bject s i n t he P K s u bset f or w h o m b ot h great 
t oe nails m ust be i n v ol ve d. W here b ot h great t oe nails are st u d y-eli gi ble, t he t oe nail wit h t he greater perce nt of 
affecte d area will be selecte d f or m yc ol o gic data a n d f or i ncl usi o n i n t he efficac y a nal ysis. I n t he i ns ta nce 
w here t he perce nt of affecte d area is t he sa me f or b ot h st u d y -eli gi ble great t oe nails, t he i n vesti gat or ma y 
select eit her  great  t oe nail as t he tar get t oe nail. T he  tar get great  t oe nail will be  i de ntifie d a n d  rec or de d f or eac h 
s u bject, p h ot o gra p hs of t he tar get great t oe nail will be o btai ne d, a n d a tra ns verse n otc h will be i nscri be d i n 
t he tar get great t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d (as a mar ker f or meas uri n g t oe nail gr o wt h at 
s u bse q ue nt visits). Assess me nts of all ot her n o ntar get t oe nails, i ncl u di n g t he ot her i n v ol ve d t oe nails of 
s u bjects i n t he P K s u bset, will als o be c o n d ucte d t o assess t h e prese nce or a bse nce of o n yc h o m yc osis o n eac h 
t oe nail. T his assess me nt will c o nti n ue t hr o u g h o ut t he st u d y visits t hr o u gh wee k  5 2.  
After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit, s u bjects will be e nr olle d i n t he treat me nt peri o d. S u bjects or 
t heir pare nts/le gal g uar dia ns will a p pl y t he first d ose of st u d y dr u g t o t he q ualifie d t oe nails at t he 
i n vesti gati o nal ce nter u n der t he s u per visi o n of desi g nate d st u d y pers o n nel. A n y l ocal s ki n reacti o ns t hat 
occ ur at t he st u d y dr u g a p plicati o n site, al o n g wit h a n y a d verse e ve nts ( A Es), will be rec or de d. S u bjects or 
t heir pare nts/le gal g uar dia ns will recei ve wei g he d st u d y dr u g b ottles a n d gi ve n ver bal a n d writte n 
i nstr ucti o ns f or treat me nt a p plicati o n. S pecificall y, s u bjects w h o are n ot i ncl u de d i n t he P K s u bset will be 
i nstr ucte d t o a p pl y t he st u d y dr u g t o t he affecte d t oe nails o nce dail y at be dti me f or 4 8 wee ks. S u bjects w h o 
are i nc l u de d i n t he P K s u bset will be i nstr ucte d t o a p pl y t he st u d y dr u g t o all 1 0 t oe nails o nce dail y at 
be dti me f or 4 wee ks. F oll o wi n g t he P K bl o o d c ollecti o ns o n Da ys 2 8 a n d 2 9, t hese s u bjects will be i nstr ucte d 
t o c o nti n ue treat me nt wit h st u d y dr u g t o o nl y t he affecte d t oe nails a n d ret ur n t o t he i n vesti gati o nal ce nter at 
Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 5 2). 
All s u bjects or t heir pare nts/le gal g uar dia ns will als o recei ve diaries, wit h  i nstructi o ns t o c o m plete a rec or d of 
all a p plicati o ns a n d t o n ote a n y misse d a p plicati o ns of t he st u d y  dr u g.  
S u bjects i n t he P K s u bset will n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( Da y 2 8) visit. F oll o wi n g 
t he Da y 2 8 st u d y pr oce d ures, s u bjects i n t he P K s u bset will u n der g o ti me d bl o o d c ollecti o ns t o assess plas ma 
c o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4). Assess me nts will re q uire c ollecti o n of 
a p pr o xi matel y 4 m L of w h ole bl o o d at eac h ti me p oi nt (a p pr o xi matel y 2 0 m L t otal). Wit hi n 1 h o ur after t he 
pre d ose bl o o d sa m ple is dra w n, t he s u bjects/ pare nts/le gal g uar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails at 
t he i n vesti gati o nal ce nter. S u bse q ue nt bl o o d c ollecti o ns will occ ur 2, 4, a n d 1 2 h o urs p ost d ose o n Da y 2 8. 
T he s u bjects will g o h o me after Da y 2 8, b ut will n ot a p pl y st u d y dr u g o n t he ni g ht of t he Da y 2 8 visit. P K 
s u bjects will ret ur n t o t he i n vesti gati o nal ce nter t he f oll o wi n g da y ( Da y 2 9) f or c ollecti o n of a 2 4 -h o ur 
p ost d ose bl o o d sa m ple. P K s u bjects will c o nti n ue treat me nt wit h s t u d y dr u g t o o nl y t he tar get great t oe nail 
a n d t he ot her affecte d t oe nails a n d ret ur n t o t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6,  
4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 5 2).  
Safet y will be assesse d b y r e vie wi n g t he occ urre nce of A Es a n d l ocal s ki n reacti o ns, assessi n g vital si g n 
meas ure me nts a n d a b bre viate d p h ysical e xa mi nati o n fi n di n gs, a n d n oti n g a n y a d diti o ns or c ha n ges i n 
c o nc o mita nt me dicati o n uses. Bl o o d sa m ples will be c ollecte d at Scree ni n g a n d W ee k 4 8 f or r o uti ne safet y 
la b orat or y e val uati o ns (ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis); uri ne pre g na nc y tests will be o btai ne d 
f or all F O C B P at eac h st u d y visit. Efficac y assess me nts will be perf or me d t hr o u g h o ut t he st u d y. T he efficac y 
a nal yses wil l be base d o n micr osc o pic e xa mi nati o n a n d m yc ol o gical c ult ure res ults f or t he tar get great 
t oe nail, t he perce nt i n v ol ve me nt of t he tar get great t oe nail, t he le n gt h of t he u naffecte d part of t he tar get great 
t oe nail, t he gr o wt h of t he tar get great t oe nail, a n d t he n u m ber of affecte d n o ntar get t oe nails.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
7  
 
 
 
N ote t hat gr o wt h of t he tar get great t oe nail will be meas ure d b y i nscri bi n g a tra ns verse n otc h, at t he ce nter of 
t he t oe nail, i n t he t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d at Baseli ne a n d meas uri n g t oe nail gr o wt h fr o m 
t hat p oi nt f or war d. At e ver y s u bse q ue nt visit, t he dista nce bet wee n t he pr o xi mal t oe nail f ol d a n d t he n otc h 
will be meas ure d a n d rec or de d. A ne w n otc h will be i nscri be d i n t he t oe nail a djace nt t o t he pr o xi mal t oe n ail 
f ol d if t he i nitiall y a p plie d n otc h gr o ws o ut d uri n g t he c o urse of t he st u d y. 
A p ost -treat me nt f oll o w-u p visit will occ ur 4 wee ks after t he last treat me nt visit f or eac h s u bject (ie, at Wee k 
5 2). S u bjects w h o disc o nti n ue fr o m t he st u d y pri or t o Wee k 4 8  will c o m plete t he Wee k 4 8 st u d y pr oce d ures.  
N u m ber of s u bjects pl a n ne d: 
A p pr o xi matel y 6 0 s u bjects t otal 
A p pr o xi matel y 2 0 s u bjects i n t he P K s u bset  
Di a g n osis a n d criteri a f or i ncl usi o n:  
1.  Male or fe male s u bjects of a n y race, 6 t o 1 6 years of a ge (i ncl usi ve) at Scree ni n g.  
•  
P K S u bset: Male or fe male s u bjects of a n y race, 1 2 t o 1 6  years of a ge (i ncl usi ve) at 
Scree ni n g.  
2.  Ver bal a n d writte n i nf or me d c o nse nt/asse nt o btai ne d fr o m t he s u bject a n d/ or t heir pare nt or le gal 
g uar dia n.  
3.  G o o d ge neral healt h, as as sess e d b y t he i n vesti gat or, base d o n t he s u bject's me dical hist or y,  
p h ysical e xa mi nati o n, a n d safet y la b orat or y tests.  
4.  At least 1 great t oe nail (t he "tar get great t oe nail") wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at least 2 0 % of t he affecte d great t oe nail at t he Scree ni n g a n d Baseli ne 
Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut de r mat o p h yt o mas or l u n ula ( matri x) 
i n v ol ve me nt. T here is n o s pecific u p per li mit f or perce nt i n v ol ve me nt. U p t o 6 t oe nails ma y ha ve 
o n yc h o m yc osis.  
•  
P K S u bset: B ot h great t oe nails wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at le ast 5 0 % of t he affecte d great t oe nail at t he Scree ni n g a n d 
Baseli ne Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut der mat o p h yt o mas or l u n ula 
( matri x) i n v ol ve me nt. T here is n o s pecific u p per li mit f or perce nt i n v ol ve me nt. S u bjects 
m ust als o ha ve at lea st 4 t oe nails ot her t ha n t he great t oe nails wit h o n yc h o m yc osis.  
5.  Tar get great t oe nail f or all s u bjects, a n d b ot h great t oe nails f or s u bjects i n t he P K s u bset, m ust  ha ve  
e vi de nce of t oe nail gr o wt h, per s u bject's re p ort t hat m o nt hl y cli p pi n g is nee de d.  
6.  Wit hi n  4 2 da ys pri or t o t he Baseli ne ( Da y 1) Visit, ha ve a p ositi ve K O H e xa mi nati o n (res ults  will 
be pr o vi de d b y t he ce ntral m yc ol o g y la b) of t he tar get great t oe nail f or all  s u bjects, 
7.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( Da y 1) Visit, ha ve a p ositi ve der mat o p h yte c ult ure f or 
Tric h o p hyt o n r u br u m or Tric h o p hyt o n me nt a gr o p hytes (at t he ce ntral m yc ol o g y la b orat or y) fr o m 
t he tar get great t oe nail i n all s u bjects 
•  
P K S u bset: Pri or t o t he Baseli ne Visit, t he great t oe nail desi g nate d f or efficac y 
assess me nts as t he tar get great t oe nail m ust ha ve b ot h a p ositi ve K O H e xa mi nati o n (res ults 
will be pr o vi de d b y t he ce ntral m yc ol o g y la b) a n d a p ositi ve f u n gal  c ult ure. 
8.  All F O C B P m ust ha ve a ne gati ve uri ne pre g na nc y test at t he Scree ni n g a n d Baseli ne Visits a n d m ust 
a gree t o use a n effecti ve met h o d of c o ntrace pti o n t hr o u g h o ut t he st u d y. Effecti ve c o ntrace pti o n is 
defi ne d as use of a n i ntra uteri ne de vice, c o n d o m wit h s per mici de, dia p hra g m wit h s per mici de, 
a bsti ne nce (s u bject is n ot se x uall y acti ve), or sta ble use of a h or m o nal c o ntrace pti ve ( oral, i m pla nt, 
i njecti o n, or tra ns der mal patc h) f or at least 3 m o nt hs pri or t o t he Baseli ne Visit.  
9.  S u bjects a n d t heir pare nts/le gal g uar dia ns are willi n g t o c o m pl y wit h st u d y i nstr ucti o ns a n d ret ur n t o 
t he i n vesti gati o nal ce nter f or all re q uire d visits (a visit sc he d ule wit h t he le n gt h of eac h visit will be 
pr o vi de d t o e ns ure t hat t he s u bject ca n meet t he re q uire me nts a n d ha ve a de q uate  tra ns p ortati o n). 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
8  
 
 
 
1 0. S u bject a n d t heir pare nts/le gal g uar dia ns a gree t hat t he s u bje ct will a v oi d t he use of t oe nail p olis h, 
c os metic t oe nail pr o d ucts, a n d pe dic ures d uri n g t he st u d y peri o d.  
E xcl usi o n criteri a:  
1.  Fe males w h o are pre g na nt, n ursi n g a n i nfa nt, or pla n ni n g a pre g na nc y d uri n g t he st u d y  peri o d.  
2.  Hist or y  of  i m m u n os u p pressi o n a n d/ or cli nical si g ns i n dicati ve of  p ossi ble  i m m u n os u p pressi o n, as 
deter mi ne d b y t he i n vesti gat or, or k n o w n h u ma n i m m u n o deficie nc y vir us  i nfecti o n. 
3.  Hist or y of dia betes t hat is u nc o ntr olle d as deter mi ne d b y t he i n vesti gat or ( dia betes t hat is c o ntr olle d 
b y diet or me dicati o n d oes n ot e xcl u de a  s u bject). 
4.  Prese nce of a n y t oe nail i nfecti o n ot her t ha n or i n a d diti o n t o der mat o p h ytes, s uc h as Scyt ali di u m as 
deter mi ne d b y t he i n vesti gat or (ca n di dal o n yc h o m yc osis i nfecti o n, c o nc urre nt wit h a p ositi ve 
der mat o p h yte c ult ure, is  acce pta ble).  
5.  Prese nce of a n y of t he f oll o wi n g: der mat o p h yt o ma, f u n gal "s pi kes" wit hi n 3 m m of t he pr o xi mal 
t oe nail f ol d o n t he tar get great t oe nail, i nfecti o n e xte n di n g t o t he matri x, or o nl y lateral t oe nail 
disease i n t he tar get great t oe nail. 
6.  Prese nce of se vere m occasi n ti nea pe dis at t he Scree ni n g or Baseli ne Visits, as deter mi ne d b y  t he 
i n vesti gat or. (If t he s u bject has i nter di gital ti nea pe dis t hat re q uires treat me nt, t he s u bject m ust 
a gree t o use o nl y a n i n vesti gat or -ap pr o ve d t o pical a ntif u n gal  t hera p y). 
7.  Prese nce of a n y disease/c o n diti o n t hat mi g ht ca use t oe nail a b n or malities or ma y i nterfere wit h t he 
e val uati o n of t he st u d y dr u g as deter mi ne d b y t he i n vesti gat or (e g, o pe n s ores or ulcerati o n o n t he 
t oes of affecte d t oenails, ps oriasis, i m m u ne d ysf u ncti o n, c olla ge n -vasc ular diseases, lic he n pla n us, 
peri p heral vasc ular disease, or tra u matic o n yc h o d ystr o p h y d ue t o c hr o nic p h ysical  sti m uli). 
8.  A n y pre vi o us s ur ger y o n t he tar get great  t oe nail. 
9.  Prese nce of o n yc h o m yc osis of t he  fi n ger nail. 
1 0.  Hist or y of i m m u n o deficie nc y as deter mi ne d b y t he  i n vesti gat or. 
1 1.  Prese nce of 1 -ha n d, 2 -f o ot s y n dr o me, or fi n ger nail der mat o p h yt osis.  
1 2.  Tar get great t oe nail (i ncl u di n g t oe nail plate a n d a n y s u b u n g ual de bris) t hic ker t ha n 3 m m  at t he 
Scree ni n g a n d Baseli ne  Visits.  
1 3.  Prese nce  of  o n yc h o d ystr o p h y  t hat c o ul d  i nterfere wit h  cli nical assess me nts as deter mi ne d  b y  t he 
i n vesti gat or. 
1 4.  Hist or y  of  h y perse nsiti vit y  or  aller gic reacti o ns t o az ole deri vati ves  or  a n y  of  t he st u d y dr u g 
c o nstit ue nts.  
1 5.  Prese nce  of  a n y u n derl yi n g  disease  t hat, i n t he o pi ni o n  of  t he i n vesti gat or, c o ul d  prese nt  a safet y 
c o ncer n f or t he s u bject b y partici pati n g i n t he  st u d y. 
1 6.  S u bject has recei ve d treat me nt f or a n y t y pe of ca ncer i n t he pre vi o us 6 m o nt hs, e xce pt f or 
n o n mela n o ma  s ki n ca ncer (e g, basal  cell carci n o ma  or  n o n metastatic  s q ua m o us cell carci n o ma)  t hat 
was treate d s uccessf ull y.  
1 7.  Prese nce of a n y der mat ol o gical c o n diti o n o n t he feet t hat c o ul d i nterfere wit h cli nical e val uati o ns  as 
deter mi ne d b y t he  in vesti gat or.  
1 8.  Prese nce of a n y u n derl yi n g disease or der mat ol o gical c o n diti o n ot her t ha n o n yc h o m yc osis t hat 
re q uires t he use of i nterferi n g t o pical or s yste mic t hera p y a n d w o ul d ma ke e val uati o ns i nc o ncl usi ve 
as deter mi ne d  b y  t he i n vesti gat or, or  s u bject re q uires treat me nt wit h  a t o pical pr o d uct  o n  t he t oe nails 
ot her t ha n t he st u d y dr u g d uri n g t he  st u d y. 
1 9.  S u bjects usi n g t he f oll o wi n g t o pical pre parati o ns wit hi n t he i n dicate d ti me pri or t o t he  Baseli ne 
Visit,  or  re q uires c o nc urre nt  use  of  a n y  of  t he f oll o wi n g t o pical pre parati o ns  d uri n g  t he st u d y: 
•  
T oe nail p olis h or c os metic t oe nail pr o d ucts: 1  da y  
•  
Ot her t o pical prescri pti o n or o ver -t he-c o u nter me dicati o ns t o t he t oe nails ( wit h  t he 
e xce pti o n of bla n d e m ollie nts): 2  wee ks  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
9  
 
 
 
•  
T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t oe nails,  i ncl u di n g 
de vices t o treat o n yc h o m yc osis: 4  wee ks  
2 0.  S u bjects  usi n g  t he f oll o wi n g s yste mic me dicati o ns  wit hi n  t he i n dicate d ti me pri or  t o t he Baseli ne 
Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g s yste mic me dicati o ns d uri n g t he st u d y: 
•  
S yste mic a ntif u n gal t hera p y: 4  wee ks  
•  
S yste mic i m m u n os u p pressi ve a ge nts: 6  m o nt hs  
2 1.  S u bject has pre vi o usl y bee n n o nres p o nsi ve t o s yste mic a ntif u n gal t hera p y f or  o n yc h o m yc osis.  
2 2.  S u bject  is u na ble  t o c o m m u nicate  or  c o o perate  wit h  t he i n vesti gat or d ue  t o la n g ua ge pr o ble ms,  p o or 
me ntal de vel o p me nt, or i m paire d cere bral  f u ncti o n. 
2 3.  Use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 half -li ves ( w hic he ver is l o n ger) pri or 
t o t he Scree ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal 
dr u g or  de vice.  
I n vesti g ati o n al pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n: 
I n vesti g ati o n al Dr u g: Efi nac o naz ole 1 0 % S ol uti o n (efi nac o naz ole)  
D osi n g f or S u bjects N O T I n cl u de d i n t he P K S u bset: S u bjects a n d t heir pare nts/le gal g uar dia ns will be 
i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject's tar get great t oe nail a n d all ot her affecte d t oe nail(s) 
(if a n y) o nce dail y at be dti me. S u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o c o nti n ue 
a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire treat me nt peri o d, e ve n if t he disease clears 
a n d n o affecte d area is o bser ve d o n t he tar get great t oe nail. If ot her affec te d t oe nails treate d si nce baseli ne 
clear d uri n g t he c o urse of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o 
c o nti n ue treat me nt o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me 
i nfecte d duri n g t he st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d  t oe nail(s). 
All s u bjects a n d t heir pare nts/le gal g uar dia ns will be gi ve n i nstr ucti o ns re gar di n g h o w t o a p pl y t he st u d y 
dr u g, ie, b y c o m pletel y c o veri n g t he tar get g reat t oe nail, i ncl u di n g t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he st u d y dr u g will be a p plie d t o eac h of t he ot her 
i nfecte d t oe nails i n a si milar ma n ner. 
D osi n g f or S u bjects I ncl u de d i n t he P K S u bset:  
D a ys 1 t o 2 8 - S u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y st u d y dr u g t o all  
1 0 t oe nails, o nce dail y at be dti me f or 4 wee ks. D uri n g t his peri o d, all P K s u bjects will be i nstr ucte d t o a p pl y 
t he st u d y dr u g b y c o m pletel y c o veri n g eac h t oe nail a n d 0. 5 c m of a djace nt s ki n, i ncl u di n g t he t oe nail f ol ds, 
t oe nail be d, h y p o n yc hi u m, u n ders urface of t he t oe nail plate. T he s u bjects will n ot a p pl y st u d y dr u g t he ni g ht 
pri or t o t he Wee k 4 ( Da y 2 8) visit, n or will t he y a p pl y st u d y dr u g o n t he ni g ht of t he Wee k 4/ Da y 2 8 Visit. 
Wit hi n 1 h o ur after t he pre d ose bl o o d sa m ple is dra w n o n Da y 2 8, s u bjects a n d/ or t heir pare nts/le gal 
g uar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails i n t he ma n ner descri be d a b o ve at t he i n vesti gati o nal ce nter.  
 
D a ys 2 9 t o Wee k 4 8:  
After c o m pleti o n of t he P K p orti o n of t he st u d y, s u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d 
t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject's tar get great t oe nail a n d all ot her affecte d t oe nail(s) o nce 
dail y at be dti me. S u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o c o nti n ue a p pl yi n g t he st u d y 
dr u g t o t he tar get great t oe nail f or t he e ntire treat me nt peri o d, e ve n if t he disease clears a n d n o affecte d area 
is o bser ve d o n t he tar get great t oe nail. If ot her affecte d toe nails treate d si nce baseli ne clear d uri n g t he c o urse 
of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt o n t h ose 
t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me i nfecte d d uri n g t he st u d y, t he 
s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). All s u bjects a n d t heir 
pare nts/le gal g uar dia ns will be gi ve n i nstr ucti o ns re gar di n g h o w t o a p pl y t he st u d y dr u g, ie, b y c o m pletel y 
c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f ol ds, t oe nail be d, h y p o n yc hi u m, a n d t he u n ders urface 
of  t he t oe nail plate  (if o n yc h o m yc osis  is prese nt).  T he  st u d y dr u g will  be  a p plie d  t o eac h  of  t he ot her  i nfecte d 
t oe nails i n a si milar ma n ner. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 0  
 
 
 
 
M o de of A d m i nistr ati o n: 
T o pical a p plicati o n: t he s u bjects will a p pl y t he st u d y dr u g t o t heir t oe nail(s), t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he s u bjects a n d t heir pare nts/le gal g uar dia ns will be 
i nstr ucte d t o wait f or t he t oe nails t o air-dr y t h or o u g hl y bef ore t o uc hi n g wit h cl ot hi n g.  
D ur ati o n of tre at m e nt:  
4 8 wee ks  
Refere nce t her a p y, d os a ge a n d m o de of a d mi nistr ati o n:  
N ot a p plica ble  
Criteri a f or e v al u ati o n:  
Safet y : 
A d verse e ve nts will be c ollecte d as s p o nta ne o us re p orts b y t he s u bjects a n d as o bser vati o ns b y t he 
i n vesti gat ors. T he c ollecti o n of A Es s h o ul d be gi n f oll o wi n g t he s u bject's c o m pleti o n of t he c o nse nt/asse nt 
pr ocess t o partici pate i n t he st u d y.  
L ocal s ki n reacti o ns (re d ness, s well i n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) will be re vie we d wit h t he s u bject 
starti n g at t he Baseli ne Visit ( after st u d y dr u g a p plicati o n at t he i n vesti gati o nal ce nter) a n d c o nti n ui n g 
t hr o u g h t he last st u d y visit. T he prese nce or a bse nce of b ur ni n g, itc hi n g, a n d vesic ulati o n will be re p orte d 
si m pl y as " yes" or " n o". T he w orst i nsta nces of re d ness a n d s welli n g o bser ve d si nce t he pre vi o us st u d y visit 
will be re p orte d usi n g a 4 -p oi nt scale ( w here 0 = N o ne, 1 = Mil d, 2 = M o derate, a n d 3 = Se vere).  
Bl o o d a n d uri ne  sa m ples will be c ollecte d f or r o uti ne cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, 
a n d uri nal ysis) wit hi n t he 4 2 da y Scree ni n g visit wi n d o w a n d at Wee k 4 8. A n y cli nicall y si g nifica nt 
a b n or malities i n safet y la b orat or y test res ults t hat are pres e nt at t he last treat me nt visit ( Wee k 4 8/ Earl y 
Ter mi nati o n) will be f oll o we d t o res ol uti o n (ie, ret ur n t o n or mal val ues or t o t he baseli ne state) or u ntil 
cli nicall y sta ble as deter mi ne d b y t he i n vesti gat or.  
Vital si g n meas ure me nts (sitti n g bl o o d press ure, res pirati o n, p ulse, a n d te m perat ure) will be o btai ne d at 
Baseli ne a n d Wee ks 1 2, 2 4, 3 6, a n d 4 8. A n a b bre viate d p h ysical e xa mi nati o n will be perf or me d at Baseli ne 
a n d Wee k 4 8; as part of t he e xa mi nati o n, hei g ht a n d wei g ht will be meas ure d at Basel i ne a n d Wee k 4 8. 
Uri ne pre g na nc y tests will be perf or me d f or all F O C B P at t h e Scree ni n g Visit a n d at eac h s u bse q ue nt st u d y 
visit. If a s u bject bec o mes pre g na nt d uri n g t he treat me nt peri o d, t he st u d y dr u g will be disc o nti n ue d 
i m me diatel y, t he s u bject will be disc o nti n ue d fr o m t he st u d y, a n d t he i n vesti gat or will n otif y t he s p o ns or. 
T he pre g na nc y will be f oll o we d t o ter m wit h t he o utc o me re p orte d t o t he s p o ns or.  
Efficac y will be assesse d t o e val uate c o m plia nce wit h treat me nt as part of t he safet y assess me nt. T he efficac y 
varia bles e val uate d i n t his st u d y i ncl u de micr osc o pic K O H e xa mi nati o n a n d m yc ol o gical c ult ure o utc o mes of 
t he tar get great t oe nail, perce nt i n v ol ve me nt of t he tar get great t oe nail, gr o wt h of t he tar get great t oe nail, a n d 
assess me nts of t he n o n tar get t oe nails. 
P har mac o ki netics : C o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4), al o n g wit h ot her rele va nt 
P K para meters, will be assess e d base d o n bl o o d sa m ples c ollecte d at Da ys 2 8 a n d 2 9. T he s pecific c ollecti o n 
ti me p oi nts are pre d ose o n Da y 2 8 a n d 2, 4, 1 2, a n d 2 4 h o urs p ost d ose.  
 
P h ot o gra p h y : 
Cl ose -u p p h ot o gra p hs of t he s u bject's tar get great t oe nail will be use d f or d oc u me ntati o n p ur p oses o nl y a n d  
will n ot be use d f or deter mi nati o ns of eli gi bilit y or a n y st u d y -relate d acti vities. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 1  
 
 
 
St atistic al Met h o ds:  
Safet y : 
All s u bjects w h o recei ve at least 1 c o nfir me d d ose of st u d y dr u g will be i ncl u de d i n t he safet y a nal ysis set. 
N o i m p utati o ns will be ma de f or missi n g safet y data. T he pri mar y safet y o bjecti ve will be c o nsi dere d met 
w he n a p pr o xi matel y 4 0 e val ua ble s u bjects ha ve bee n treate d f or 4 8 wee ks.  
All A Es occ urri n g d uri n g t he st u d y will be rec or de d a n d classifie d usi n g t he Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A). Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are t h ose A Es wit h a n o nset 
o n or after t he date of first st u d y dr u g a p plicati o n. All T E A Es will be s u m marize d b y t he n u m ber of s u bjects 
re p orti n g eac h T E A E, t he ass ociate d s yste m or ga n class a n d preferre d ter m, t he se verit y, a n d t he relati o ns hi p 
t o st u d y dr u g f or t he Safet y, P K a n d N o n-P K p o p ulati o ns. Eac h s u bject will be c o u nte d o nl y o nce wit hi n a 
s yste m or ga n class or a preferre d ter m usi n g t he e ve nt wit h t he greatest se verit y or ca usalit y, res pecti vel y, 
wit hi n eac h cate g or y.  
Seri o us a d verse e ve nts ( S A Es) wil l be s u m marize d b y t he n u m ber of s u bjects re p orti n g eac h S A E, t he 
ass ociate d s yste m or ga n class a n d preferre d ter m, t he se verit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he 
Safet y, P K a n d N o n -P K p o p ulati o ns.  
L ocal s ki n reacti o n sc ores (re d ness, s welli n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) at eac h st u d y visit will be 
s u m marize d usi n g fre q ue nc y ta bles f or t he Safet y, P K a n d N o n-P K p o p ulati o ns. A d diti o nall y, re d ness a n d 
s welli n g se verit y sc ores will be s u m marize d usi n g descri pti ve statistics ( mea n, sta n dar d de viati o n [ S D], 
me dia n, a n d mi ni m u m a n d ma xi m u m). S u bjects wit h a se verit y sc ore w orse t ha n baseli ne will als o be 
s u m marize d at eac h p ost baseli ne st u d y visit. T he w orst sc ore a n d t he last sc ore d uri n g t he p ost -baseli ne 
peri o d will als o be s u m mari ze d. 
Res ults of safet y la b orat or y para meters a n d vital si g n meas ure me nts will be s u m marize d at eac h st u d y visit 
usi n g descri pti ve statistics or fre q ue ncies a n d perce nta ges, as a p pr o priate, f or t he Safet y, P K a n d N o n -P K 
p o p ulati o ns. C ha n ges fr o m baseli ne i n  safet y la b orat or y val ues will be s u m marize d b y treat me nt gr o u p at 
Wee k 4 8 usi n g descri pti ve statistics. I n a d diti o n, c ha n ges fr o m baseli ne i n safet y la b orat or y val ues will be 
s u m marize d usi n g s hift ta bles acc or di n g t o n or mal ra n ges. 
T his st u d y's pri mar y o bject is t o assess t he safet y of t he st u d y dr u g. Descri pti ve efficac y statistics f or t he 
e n d p oi nts will assist i n e val uati n g c o m plia nce wit h treat me nt f or t he p ur p oses of safet y assess me nt.  
T he efficac y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  
C o m plete C ure, defi n e d as 0 % cli nical i n v ol ve me nt of t he tar get t oe nail a n d ne gati ve  K O H 
a n d f u n gal c ult ure at Wee k  5 2  
•  
C o m plete or Al m ost C o m plete C ure at Wee k 5 2, defi ne d as :: 5 % t oe nail  i n v ol ve me nt 
•  
Cli nical Efficac y rate at Wee k 5 2, defi ne d as a n affecte d tar get great t oe nail area of < 1 0 %  
•  
M yc ol o gic C ure rate at Wee k 5 2, defi ne d as a ne gati ve K O H e xa mi nati o n a n d a  ne gati ve 
f u n gal c ult ure of t he tar get great t oe nail sa m ple 
T he C o m plete C ure rate, t he C o m plete or Al m ost C o m plete C ure rate, t he Cli nical Efficac y rate, a n d t he 
M yc ol o gic C ure rate will be prese nte d usi n g descri pti ve statistics (sa m ple size n, fre q ue nc y c o u nts a n d 
perce nta ges) f or t he Safet y, P K a n d N o n -P K p o p ulati o ns. I n a d diti o n, t he gr o wt h of t he tar get great t oe nail at 
eac h st u d y visit a n d t he c ha n ge f r o m baseli ne i n t he n u m ber of affecte d n o ntar get t oe nails will be 
descri pti vel y s u m marize d.  
A last o bser vati o n carrie d f or war d ( L O C F) i m p utati o n will be use d t o i m p ute missi n g val ues f or t he efficac y 
varia bles at Wee k 5 2. N o se nsiti vit y a nal yses will be c o n d ucte d.  
A n y s u bjects re mai ni n g (i.e., ha ve n ot bee n treate d f or 4 8 wee ks) will be f oll o we d u ntil c o m pleti o n. T he 
fi nal re p ort will be a me n de d wit h data o n t hese s u bjects. 
 
P har mac o ki netics : 
All s u bjects i n t he P K s u bset w h o recei ve at least 1 c o nfir me d d o se of st u d y dr u g a n d ha ve a n y P K data o n 
Da ys 2 8 a n d 2 9 will be i ncl u de d i n t he P K a nal ysis set. Bl o o d sa m ples will be teste d f or plas ma 
c o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4). N o i m p utati o ns will be ma de f or missi n g data.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 2  
 
 
 
Plas ma c o nce ntrati o ns t hat are re p orte d as bel o w t he li mit of q ua ntitati o n ( B L Q) i n t he data tra nsfer file will 
be set t o zer o f or t he s u m maries of c o nce ntrati o ns as well as calc ulati o n of P K para meters. Missi n g val ues 
will be treate d as if t he y were ne ver dra w n. Plas ma c o nce ntrati o ns of efi nac o naz ole a n d meta b olite ( H 3 a n d 
H 4) a n d P K para meters will be s u m marize d usi n g descri pti ve statistics ( n, mea n, S D, sta n dar d err or of t he 
mea n [ S E M], c oefficie nt of variati o n [ C V], me dia n, mi ni m u m, a n d ma xi m u m). Ge o metric mea ns will als o be 
use d t o s u m marize C ma x , Cmi n , A U C( 0-t) a n d A U C ( 0-2 4 h). 
T he mea n plas ma c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will be 
prese nte d gra p hicall y f or Da ys 2 8 a n d 2 9 i n b ot h li near a n d l o garit h mic scales. I n di vi d ual s u bject plas ma 
c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will als o be create d.  
Plas ma P K para meters f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will be calc ulate d usi n g 
n o nc o m part me n tal a nal ysis. T he P K para meters will be calc ulate d f or eac h s u bject usi n g act ual sa m pli n g 
ti mes. T he ma xi m u m plas ma c o nce ntrati o n ( Cma x ) a n d ti me t o Cma x  ( Tma x ) will be ta ke n directl y fr o m t he 
data.  
T he f oll o wi n g P K para meters will be calc ulate d fr o m t he i n di vi d ual plas ma c o nce ntrati o ns o n Da ys 2 8 a n d 
2 9 w he n p ossi ble:  
•  
C ma x  ( o bser ve d pea k dr u g [efi nac o naz ole a n d meta b olites] c o nce ntrati o n) 
•  
T ma x  (ti me at w hic h Cma x  occ urs)  
•  
C mi n  ( o bser ve d mi ni m u m dr u g c o nce ntrati o n) 
•  
A U C 0 -t (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 u p t o t he sa m pli n g ti me 
c orres p o n di n g t o t he last q ua ntifia ble  c o nce ntrati o n) 
•  
A U C 0 -2 4 h (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
[c orres p o n di n g t o t he d osi n g i nter val]) 
A d dit i o nal P K para meters ma y be calc ulate d as a p pr o priate. 
 
T he P K o bjecti ves will be c o nsi dere d met w he n a p pr o xi matel y 1 6 e val ua ble s u bjects are treate d u n der 
ma xi mal use c o n diti o ns t hr o u g h da y 2 8 of t he P K e val uati o n.  
S a m ple size c alc ul ati o ns:  
A p pr o xi matel y 6 0 s u bjects will be e nr olle d a n d recei ve treat me nt wit h st u d y dr u g. A p pr o xi matel y 2 0 of t he 
s u bjects will be e nr olle d i n t he P K s u bset. T hese sa m ple sizes were base d o n P K a n d cli nical c o nsi derati o ns; 
n o f or mal sa m ple size calc ulati o n was per f or me d. T he n u m bers of pla n ne d s u bjects are c o nsi dere d a de q uate 
f or deter mi ni n g t he safet y pr ofile a n d t he P K para meters of efi nac o naz ole i n a pe diatric p o p ulati o n of 
s u bjects a ge d 6 t o 1 6 years 1 1 m o nt hs wit h mil d t o se vere o n yc h o m yc osis of t he t oe nails. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 3  
 
 
 
3  T a ble of  C o nte nts  
1  
TI T L E  P A G E  ...........................................................................................................1  
2  
S Y N O P SI S  ...............................................................................................................5  
3  
T A B L E  O F  C O N T E N T S  .......................................................................................1 3  
4  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S  O F  T E R M S  ........................1 7  
5  
I N T R O D U C TI O N .................................................................................................1 8  
6  
S T U D Y O BJ E C TI V E S  A N D P U R P O S E  .............................................................1 9  
7  
I N V E S TI G A TI O N A L P L A N  ................................................................................1 9  
8  
S E L E C TI O N A N D WI T H D R A W A L  O F  S U BJ E C T S  .........................................2 7  
8. 1  
S u bject  I ncl usi o n Criteri a .......................................................................... 2 7  
8. 2  
S u bject  E xcl usi o n Criteria  ......................................................................... 2 8  
8. 3  
S u bject  Wit h dra wal Criteria  ......................................................................3 0  
9  
T R E A T M E N T S  P L A N N E D  ................................................................................. 3 1  
9. 1  
Met h o ds of Assi g ni n g S u bjects t o  Treat me nt Gr o u ps  ............................... 3 1  
9. 2  
Ra n d o mizati o n  a n d Bli n di n g  ..................................................................... 3 1  
9. 3  
Treat me nt  C o m plia nce  ............................................................................... 3 1  
9. 4  
Treat me nt  A d mi nistrati o n  ..........................................................................3 1  
9. 5  
C o nc o mita nt Me dicati o ns  ..........................................................................3 3  
9. 5. 1  All o we d  Me dicati o ns/ T hera pies  ....................................................3 3  
9. 5. 2  Pr o hi bite d  Me dicati o ns/ T hera pies  .................................................3 3  
9. 6  
Pr ot oc ol De viati o ns a n d  Vi olati o ns  ........................................................... 3 4  
1 0  
S T U D Y D R U G M A T E RI A L S  A N D  M A N A G E M E N T  ......................................3 5  
1 0. 1  
St u d y  Dr u g  .................................................................................................3 5  
1 0. 1. 1  Pac ka gi n g  a n d L a beli n g  .................................................................3 5  
1 0. 1. 2  St ora ge, Ha n dli n g, a n d Dis p osal of  St u d y  Dr u g  ............................ 3 6  
1 0. 1. 3  St u d y  Dr u g  Pre parati o n  .................................................................. 3 7  
1 0. 2  
St u d y  Dr u g  Acc o u nta bilit y  ........................................................................ 3 7  
1 1  
S T U D Y P R O C E D U R E S  A N D E V A L U A TI O N S  ................................................3 7  
1 1. 1  
Sc he d ule of E val u ati o ns  a n d Pr oce d ures  ................................................... 3 7  
1 1. 1. 1  Scree ni n g Visit ( Visit 1, U p t o  Da y  -4 2)  ....................................... 3 7  
1 1. 1. 2  Baseli ne Visit ( Visit 2,  Da y  1)  .......................................................3 9  
1 1. 1. 3  Visit 3 ( Wee k 4, D a y 2 8 [ ± 5 da ys]), Visit 4 ( Wee k 8 [ ± 5 
da ys]), Visit 6 ( Wee k 1 6 [ ± 5 da ys]), Visit 7 ( Wee k  2 0  
[ ± 5 da ys]), Visit 9 ( Wee k 2 8 [ ± 5 da ys]), Visit 1 0 ( Wee k 3 2 [ ± 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 4  
 
 
5 da ys]), Visit 1 2 ( Wee k 4 0 [ ± 5 da ys]), Visit 1 3 ( Wee k 4 4  
[ ± 5 da ys])  ......................................................................................4 2  
1 1. 1. 4  Visit  3 A  ( We e k 4,  D a y  2 9)  - A d diti o nal  Visit  f or S u bj ects  i n 
t he P K S u bset  .................................................................................4 3  
1 1. 1. 5  Visit 5 ( Wee k 1 2 [ ± 5 d a ys]), Visit 8 ( Wee k 2 4 [ ± 5  da ys]),  
Visit 1 1 ( Wee k 3 6 [ ±  5  d a ys])  ........................................................4 3  
1 1. 1. 6  Visit 1 4 ( Wee k 4 8 [ ± 5 d a ys]) / Earl y  Ter mi nati o n  Visit  .............. 4 4  
1 1. 1. 7  Visit 1 5 ( Wee k 5 2 [ ± 5 d a ys]) P ost-Treat me nt F oll o w -u p  Visit  
/ St u d y E xit .....................................................................................4 5  
1 1. 1. 8  U nsc he d ule d  Visits  ........................................................................ 4 6  
1 1. 1. 9  Misse d  Visits  ..................................................................................4 6  
1 1. 1. 1 0  S u bject  C o m pleti o n  ....................................................................... 4 6  
1 1. 2  
St u d y  E val uati o ns  ......................................................................................4 7  
1 1. 2. 1  L ocal  S ki n  Reacti o ns  .....................................................................4 7  
1 1. 2. 2  Cli nical  La b orat or y  T ests  ...............................................................4 7  
1 1. 2. 3  Vital  Si g n Meas ure me nts  ............................................................... 4 8  
1 1. 2. 4  P h ysical  E xa mi nati o ns  ................................................................... 4 8  
1 1. 2. 5  Efficac y f or Ass essi n g Treat me nt C o m plia nce  a n d  Safet y  ............4 8  
1 1. 2. 5. 1  K O H E xa mi nati o n a n d  F u n gal C ult uri n g  ..................... 4 8  
1 1. 2. 5. 2  Tar get Great  T o e nail  Ass ess me nts  ................................ 4 9  
1 1. 2. 5. 3  N o ntar get  T oe n ail  Assess me nt  ......................................5 0  
1 1. 2. 6  E val uati o n of P har mac o ki netics  .................................................... 5 0  
1 1. 2. 7  P h ot o gra p h y  ................................................................................... 5 0  
1 1. 3  
Defi niti o n of  A d verse  E v e nts  ..................................................................... 5 0  
1 1. 3. 1. 1  Defi niti o n of Seri o us  A d verse  E ve nts  ...........................5 1  
1 1. 3. 1. 2  Assess me nt  of  Se v erit y  .................................................5 2  
1 1. 3. 1. 3  Assess me nt of Ca usalit y  ...............................................5 2  
1 1. 3. 1. 4  Pr oce d ures f or Re p orti n g A d verse E v e nts  a n d  
Seri o us  A d verse  E ve nts  ................................................. 5 3  
1 1. 3. 1. 5  S u b mitti n g a n E x pe dite d Safet y Re p ort t o t he I R B 
( Ce ntral or L ocal)  .......................................................... 5 5  
1 1. 3. 2  Pre g na nc y  .......................................................................................5 5  
1 2  
S T A TI S TI C S  .........................................................................................................5 6  
1 2. 1  
Assess me nt of  Saf et y  ................................................................................. 5 6  
1 2. 1. 1  A d verse  E ve nts  ..............................................................................5 6  
1 2. 1. 2  L ocal  S ki n  Reacti o ns  .....................................................................5 7  
1 2. 1. 3  Cli nical  La b orat or y  Tests  ...............................................................5 7  
1 2. 1. 4  Vital  Si g ns  ......................................................................................5 7  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 5  
 
 
1 2. 1. 5  C o nc o mita nt Me dicati o ns  ..............................................................5 7  
1 2. 1. 6  Efficac y f or Ass essi n g  Treat me nt  C o m plia nce  ..............................5 7  
1 2. 2  
Assess me nt  of  P har mac o ki netics  ...............................................................5 8  
T H E P K O BJ E C TI V E S WI L L B E C O N SI D E R E D M E T W H E N 
A P P R O XI M A T E L Y 1 6 E V A L U A B L E S U BJ E C T S A R E T R E A T E D 
U N D E R M A XI M A L U S E C O N DI TI O N S T H R O U G H D A Y 2 8 O F T H E P K  
E V A L U A TI O N ...................................................................................................... 5 8  
1 2. 3  
S u bject  Dis p ositi o n  ....................................................................................5 9  
1 2. 4  
De m o gra p hics a n d  Baseli ne  C haracteristics  ..............................................5 9  
1 2. 5  
Pr ot oc ol De viati o ns  ....................................................................................5 9  
1 2. 6  
C o m plia nce  ................................................................................................ 5 9  
1 2. 7  
I nteri m A nal yses  ........................................................................................6 0  
1 2. 8  
A d diti o nal  Statistical C o nsi derati o ns  ......................................................... 6 0  
1 2. 8. 1  A nal ysis  P o p ulati o ns  ......................................................................6 0  
1 2. 8. 2  Sa m ple  Size  Deter mi nati o n  ............................................................6 0  
1 2. 8. 3  Ha n dli n g of  Missi n g  Data  ..............................................................6 0  
1 2. 8. 4  M ultice nter  Iss ues .......................................................................... 6 1  
1 2. 8. 5  M ulti plicit y  Iss ues ..........................................................................6 1  
1 2. 8. 6  Wi n d o wi n g  R ules.  ..........................................................................6 1  
1 3  
Q U A LI T Y C O N T R O L A N D  Q U A LI T Y  A S S U R A N C E  ..................................... 6 1  
1 3. 1  
St u d y  M o nit ori n g  .......................................................................................6 1  
1 3. 2  
A u dits  a n d I ns p ecti o ns ...............................................................................6 2  
1 3. 3  
Data Q ualit y  Ass ura n ce  ............................................................................. 6 2  
1 4  
E T HI C S A N D  A D MI NI S T R A TI V E  I S S U E S ......................................................6 3  
1 4. 1  
Et hical C o n d uct of  t he St u d y .....................................................................6 3  
1 4. 2  
Et hics Re vie w  ............................................................................................6 3  
1 4. 3  
Writte n I nf or m e d C o nse nt  .........................................................................6 3  
1 4. 4  
S u bject  Data Pr otecti o n  .............................................................................. 6 4  
1 4. 5  
Data  M o nit o ri n g C o m mittee  ......................................................................6 4  
1 4. 6  
Fi na ncial  Discl os ure  ...................................................................................6 4  
1 4. 7  
Esse ntial D oc u me nts  .................................................................................. 6 5  
1 4. 8  
I n v esti gat or O bli gati o ns  .............................................................................6 5  
1 4. 9  
C ha n ges t o  t he Pr ot oc ol .............................................................................6 6  
1 4. 1 0  C o nfi de ntialit y/ P u blicati o n of  t he St u d y ................................................... 6 6  
1 4. 1 1  St u d y  Ter mi nati o n ...................................................................................... 6 6  
1 5  
D A T A H A N D LI N G A N D  R E C O R D K E E PI N G  ................................................. 6 7  
1 5. 1  
I ns p ecti o n of  Rec or ds  ................................................................................6 7  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 6  
 
 
1 5. 2  
Case Re p ort F or ms  ..................................................................................... 6 7  
1 5. 3  
Rete nti o n  of Rec or ds  ..................................................................................6 8  
1 6  
R E F E R E N C E S  ...................................................................................................... 6 9  
 
LI S T O F T A B L E S  
Ta ble  1:  
St u d y Desi g n a n d Sc he d ule  of  Assess me nts  ................................................... 2 3  
Ta ble  2.  
St u d y  Dr u g  I d e ntificati o n ...............................................................................3 5  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 7  
 
 
 
4  List of A b bre vi ati o ns a n d Defi niti o ns of  Ter ms  
 
A b bre vi ati o n or  S peci alist  T er m  
Defi niti o n or E x pl a n ati o n  
 
A E  
A d verse  e ve nt 
A U C 0 -2 4 h 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
(c orres p o n di n g t o t he d osi n g i nter val) 
A U C 0 -t 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 u p t o t he 
sa m pli n g ti me c orres p o n di n g t o t he last q ua ntifia ble c o nce ntrati o n  
C ma x  
O bser ve d pea k dr u g  c o nce ntrati o n  
C mi n  
O bser ve d mi ni m u m dr u g c o nce ntrati o n  
e C R F  
Electr o nic case re p ort f or m  
Efi nac o naz ole  
Efi nac o naz ole 1 0 %  S ol uti o n  
F O C B P  
Fe males of c hil d beari n g  p ote ntial  
G C P  
G o o d Cli nical  Practice  
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mittee  
I R B 
I nstit uti o nal Re vie w B oar d  
K O H  
P otassi u m  h y dr o xi de  
L O Q  
Li mit of  q ua ntitati o n  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y  Acti vities  
P K  
P har mac o ki netic  
S A E  
Seri o us a d verse  e ve nt 
T E A E  
Treat me nt -e mer ge nt a d verse  e ve nt 
T ma x  
Ti me at w hic h t he o bser ve d pea k dr u g c o nce ntrati o n  occ urs  
U S  
U nite d  States  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 8  
 
 
 
5  Intr o d ucti o n  
O n yc h o m yc osis is a c hr o nic a n d rec urri n g f u n g al i nfecti o n of t he fi n g er nails or t oe nails t hat 
acc o u nts f or a b o ut half of all nail dis or ders. O n yc h o m yc osis is us uall y ca use d b y 
der mat o p h ytes, eit her Tri c h o p hyt o n r u br u m ( 7 1 %) or Tric h o p hyt o n me nt a gr o p hytes ( 2 0 %). 
T he pre v ale nce of o n yc h o m yc osis i n t he U nite d States ( U S) ma y be as lar g e as 1 3 %, wit h t he 
i nfecti o n o bser ve d pre d o mi na ntl y i n el derl y patie nts ( 6 0 %) [ 1, 2]. O n y c h o m yc osis of t he 
t oe nail ca n r es ult i n per ma ne nt t oe nail def or mit y a n d has a si g nifica nt i m pact o n q ualit y of 
life d ue t o c o ncer ns wit h t he a p peara nce of t he t oe nails a n d i nterfere nce wit h weari n g s h oes, 
wal ki n g, a n d partici pati n g i n vari o us s p orts acti vities [ 3, 4]. 
C ure rates f or t o pical treat me nts ha ve bee n si g nifica ntl y l o wer t ha n c urre ntl y a vaila ble 
s yste mic me dicati o ns [5 ], pres u ma bl y beca use t he y bi n d str o n gl y t o kerati n a n d d o n ot 
a de q uatel y p e netrat e t he nail u nit. H o we ver, w hile effecti ve, oral t hera p y is li mite d b y safet y 
c o ncer ns d u e t o s yste mic e x p o s ure. F or e x a m ple, b ot h oral itrac o naz ole a n d oral ter bi nafi n e 
ha ve t he p ote ntial t o ca us e dr u g -dr u g i nteracti o ns a n d he pat ot o xicit y. Efi nac o naz ole 1 0 % 
S ol uti o n (efi nac o naz ol e) has a l o w affi nit y f or kerati n bi n di n g a n d has a hi g her bi n di n g 
re versi bilit y tha n t hat of ot her ref ere nce dr u gs. T h eref ore, efi nac o n az ole a p pears t o be a 
pr o misi n g a ntif u n gal c o m p o u n d f or t he t o pical treat me nt of o n yc h o m yc osis.  
Efi nac o naz ole is a n o vel triaz ole a ntif u n gal a ge nt t hat is acti ve i n vitr o a gai nst a wi de ra n g e 
of pat h o ge nic f u n gi a n d is e x pecte d t o be effecti ve i n t he treat me nt of mil d t o m o derate 
o n yc h o m yc osis.  
Efi nac o naz ole has b ee n s h o w n t o be effi caci o us i n vitr o a gai nst a pa nel of f u n gal s pecies t hat 
i n va de h u ma n s ki n, hair, a n d nails i ncl u di n g der m at o p h ytes Tric h o p hyt o n, Micr os p or u m, 
E pi der m o p h yt o n, a n d t he yeast, Malassezia s peci es, res p o nsi ble f or ti nea u n g ui u m 
( o n yc h o m yc osis), ti nea c or p oris, ti nea pe dis, ti nea ca pitis, a n d pit yriasis versic ol or. 
Efi nac o naz ole has b ee n s h o w n t o be f u n gici dal a g ai nst C a n di d a al bic a ns a n d ot her Ca n di da 
s pecies res p o nsi ble f or t h e maj or yeast ( n o n d er mat o p h yte) f or m of o n y c h o m yc osis a n d 
c uta ne o us ca n di diasis. I n vitr o st u dies a gai nst der mat o p h ytes s h o we d t hat efi nac o n az ole w as 
m ore p ote nt t ha n cl otri maz ole, b ut less p ote nt t ha n b ute nafi ne.  
Efi nac o naz ole has s u ccessf ull y treate d e x p eri me nt all y i n d uce d der mal ca n di diasis, ti nea 
c or p oris, ti nea pe dis, a n d ti nea u n g ui u m i n vi v o i n g ui nea pi g m o dels. It has ge nerall y o ut 
perf or me d ref er e nce dr u gs i n t hese m o dels, a n d i n partic ular o ut perf or me d t he mar kete d 
dr u gs f or ti nea u n g ui u m: cicl o pir o x ola mi ne (a p pr o ve d f or t he t o pical treat me nt of 
o n yc h o m yc osis i n t he U S), a m or olfi ne (a v aila ble o utsi de t he U S as a t o pical nail lac q uer), 
a n d ter bi nafi n e (a v ai la ble i n t he U S i n oral f or m). 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
1 9  
 
 
 
T he safet y a n d efficac y of o nce dail y use of efi n ac o naz ole f or t he treat me nt of 
o n yc h o m yc osis of t he t oe nail wer e assesse d i n t w o 5 2 -wee k pr os pecti ve, m ultice nter, 
ra n d o mize d, d o u ble-bli n d cli nical st u dies. T he se st u dies were c o n d ucte d i n s u bjects 1 8 t o 
7 0 years of a ge wit h 2 0 % t o 5 0 % cli nical i n v ol ve me nt of t he tar get great t oe nail, wit h o ut  
der mat o p h yt o mas or l u n ula ( matri x) i n v ol ve me nt ( n = 8 7 0 i n St u d y 1 a n d n = 7 8 1 i n St u d y 2) 
[6 ]. T hese st u dies e val uat e d 4 8-wee ks of treat me nt wit h efi nac o naz ole relati ve t o ve hicle 
s ol uti o n. At Wee k 5 2 ( 4-wee ks after c o m pleti o n of t hera p y), efi nac o naz ole was s u peri or t o 
ve hicle s ol uti o n i n b ot h st u dies a n d t h us de m o nstrate d efficac y i n t he treat me nt of 
o n yc h o m yc osis. T he m ost  c o m m o n a d verse reacti o ns (ie, reacti o ns wit h i nci de nces > 1 %) 
re p orte d i n t he st u dies w ere i n gr o w n t o e nails, a p plicati o n site der matitis, a p plicati o n site 
vesicles, a n d a p plicati o n site pai n.  
Efi nac o naz ole w as a p pr o ve d b y t he U S F o o d a n d Dr u g A d mi nistrati o n i n J u ne 2 0 1 4 f or t he 
t o pical treat me nt of o n yc h o m yc osis of t he t oe nail(s) d ue t o T r u br u m a n d T me nt a gr o p hytes 
(J u blia®  [efi nac o n az ole] t o pical s ol uti o n, 1 0 % [6 ]). T he a p pr o v e d dr u g is i nte n de d f or t o pical 
a p plicati o n t o affecte d t o e nails o nce dail y f or  4 8 wee ks. D uri n g a p plicati o n, t he t oe nail, 
t oe nail f ol ds, t oe nail be d, h y p o n yc hi u m, a n d u n ders urface of t he t oe n ail plate are t o b e 
c o m pletel y c o ver e d.  
T he c urr e nt cli nical st u d y is desi g ne d t o e val uate t he safet y a n d p h ar mac o ki netics ( P K) of 
o nce dail y t o pical a p plicati o n of efi nac o naz ole i n t he treat me nt of p e diatric s u bjects wit h 
mil d t o se vere o n yc h o m y c osis of t he t oe nails. A p plicati o n a n d use of t he st u d y dr u g is 
c o nsiste nt wit h t he a p pr o ve d pac k a ge i nsert. T h e e val uati o ns i ncl u de d i n t he c urre nt st u d y are 
c o nsiste nt wit h t he e val u ati o ns c o n d ucte d i n t he d e vel o p me nt of t he a p pr o ve d  dr u g.  
 
6  St u d y O bjecti ves a n d  P ur p ose  
T he pri mar y o bjecti ves of t his st u d y are t o e val uat e: 1) safet y of o nce d ail y t o picall y 
a d mi nistere d efi nac o naz ole 1 0 % f or 4 8 w ee ks i n pe diatric s u bjects ( 6 -1 6 y ears, 1 1 m o nt hs of 
a ge) wit h at least mil d o n yc h o m yc osis of t he t oe nails, a n d 2) p har mac o ki n etics P K ( 4 
wee ks) of o nce d ail y t o picall y a d mi nistere d efi nac o naz ole 1 0 % i n pe di atric s u bjects ( 1 2 -1 6 
years, 1 1 m o nt hs of a g e) wit h m o de rate t o se vere o n yc h o m yc osis of t he t oe nails. 
 
7  I n vesti g ati o n al Pl a n  
7. 1  I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct u re  
A p pr o xi matel y 2 0 -2 5 i n v esti gati o nal ce nters are pl a n ne d t o partici pat e i n t his st u d y. Eac h 
cli nical i n vesti gat or will be re q uir e d t o pr o vi d e a c o p y of his/ her c urric ul u m vitae a n d 
me dical lice nse, c o m plete a fi na n cial discl os ure st ate me nt, a n d ge n erat e a list of st u d y 
pers o n nel  w h o  will  be  i n v ol ve d i n t he st u d y, wit h  a s u m mar y of  t heir r oles a n d q ualificati o ns.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
2 0  
 
 
 
T he S p o ns or has desi g nate d a C o ntract Researc h Or ga nizati o n t o ass u me res p o nsi bilit y f or 
acti vities relate d t o t he c o n d uct of t he st u d y. T he S p o ns or als o has desi g nate d ce ntral 
la b orat ories t o a n al yze bi ol o gical sa m ples relate d t o cli nical safet y, p h ar mac o ki netics, a n d 
m yc ol o g y. A listi n g of t he or ga nizati o ns i n v ol ve d i n t he c o n d uct of t he st u d y is pr o vi de d 
u n der Pers o n nel Secti o n i n t he fr o nt of t he pr ot oc ol. A c o m plete descri pti o n of t he S p o ns or's 
a n d dele gat es' st u d y -relat e d r oles/res p o nsi bilities, i ncl u di n g ke y pers o n nel, is c o ntai ne d 
wit hi n t he S p o ns or's st u d y pr oject pla n.  
7. 2  S u m m ar y of St u d y Desi g n  
T his is a n o pe n la bel, si n gle -ar m st u d y desi g ne d t o e val uate t he s afet y a n d P K of a o nce d ail y 
t o pical a p plicati o n of efi nac o naz ole i n t he treat me nt of pe diatric s u bjects wit h mil d t o se vere 
o n yc h o m yc osis of t he t oe nails. T he st u d y will i ncl u de a t otal of 6 0 s u bjects, 4 0 of w h o m will 
be 6 t o 1 6 years of a ge, i ncl usi ve, a n d P K assess me nts will be perf or me d o n a p pr o xi matel y 
2 0 s u bjects 1 2 t o 1 6 years of a ge, i ncl usi v e (referre d t o t hr o u g h o ut t he pr ot oc ol as t he P K 
s u bset). All s u bjects m ust ha ve o n yc h o m yc osis of at least 1 great t oe nail; s u bjects i n t he P K 
s u bset m ust ha ve o n yc h o m yc osis of b ot h great t oe nails a n d at least 4 ot her t oe nails. Eff orts 
will be ma de t o e nr o ll s u bjects i nt o t he P K s u bset s uc h t hat t he s u bjects are e ve nl y distri b ute d 
acr oss t he r e q uire d a ge  r a n ge. 
F or s u bjects n ot partici pati n g i n t he P K s u bset, t he st u d y will c o nsist of 1 4 sc he d ule d visits, 
i ncl u di n g Scree ni n g ( u p t o Da y -4 2), Bas eli ne ( D a y 1 ), 1 2 treat me nt visits ( Wee ks 4, 8, 1 2, 
1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 
5 2). S u bjects i ncl u de d i n t he P K s u bset will atte n d t he sc he d ule d visits u p t o Wee k 4 ( Da y  
2 8)  a n d a n a d diti o nal st u d y visit at Da y 2 9 f or c ollecti o n of t he fi nal P K bl o o d sa m ple. T he 
P K assess me nts will be perf or me d u n d er ma xi mal use c o n diti o ns. O nce P K assess me nts are 
c o m plete at Da y 2 9, t h e P K s u bset of s u bjects will c o nti n ue treat me nt t hr o u g h wee k 4 8 wit h 
visits at Wee ks 8, 1 2,  1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8, a n d a 4 -wee k p ost -treat me nt 
f oll o w-u p visit ( Wee k  5 2).  
At t he Scree ni n g Visit, s u bjects a n d t heir pare nts/le gal g uar dia ns will si g n a n i nf or me d 
c o nse nt/asse nt f or m a n d a p h ot o gra p h y c o ns e nt/asse nt f or m, pr o vi de t hei r me dical hist ories, 
re p ort t heir pr e vi o us a n d c o nc o mita nt me dicati o ns, a n d be e v al uate d a g ai nst t he 
i ncl usi o n/e xcl usi o n criteria. Fe mal es of c hil d beari n g p ote ntial ( F O C B P) will ha ve uri ne 
pre g na nc y t ests perf or me d. D uri n g t his visit, s u bjects will u n der g o  a n e x a mi nati o n of t heir 
feet t o vis uall y ascertai n t he prese n ce of o n y c h o m yc osis i n at least 1 great t oe nail f or s u bjects 
n ot i ncl u de d i n t he P K assess me nts, a n d o n b ot h great t oe nails a n d at least 4 ot her t oe nails f or 
s u bjects i ncl u de d i n t he P K assess ments. A d diti o nall y, t he perce nt i n v ol ve me nt of t he 
affecte d gr eat t oe nail(s) will be rec or d e d.  S peci me n will be o btai ne d fr o m t he great 
t oe nail(s) t o s hi p t o t he m yc ol o g y la b. B ot h t oe nails ma y be sa m ple d if b ot h are s us pect e d of  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
2 1  
 
 
 
ma nifesti n g  o n yc h o m yc osis (at least 2 0 % i n v ol ve me nt). Bl o o d a n d uri ne s peci me ns will be 
c ollecte d f or ser u m c h e mistr y, he mat ol o g y, a n d uri nal ysis e val uati o ns. At rele va nt p ost - 
Scree ni n g Visits, t he tar g et great t oe n ail will be tri m me d bac k t o t he distal gr o o ve bef or e t he 
cli nical e val uati o ns ar e p erf or me d a n d bef ore p h ot o gra p hs are ta ke n.  
If a s u bject fails scree ni n g, eit her at t he Scree ni n g or Baseli ne visit ( pri or t o e nr oll me nt t o 
treat me nt), t he s u bject ma y be res cree ne d at a later date. S u bjects w h o are rescree ned, will be 
assi g ne d a ne w s cree ni n g n u m ber, m ust be re -c o ns e nte d, a n d u n der g o all scree ni n g 
pr oce d ur es per pr ot oc ol.  
At t he Baseli ne Visit ( w hic h s h o ul d be sc he d ule d after K O H a n d f u n gal c ult ure res ults ha ve 
bee n o btai ne d fr o m t he m yc ol o g y la b), s u bjects a n d/ or t heir pare nts/le g al g uar dia ns will 
u p date t heir me dical hist ories a n d c o n c o mita nt me dicati o n uses, a n d t he i n cl usi o n/e xcl usi o n 
criteria will be c o nfir me d. S u bjects will u n der g o a b bre viate d p h ysical e xa mi nati o ns, cli nical 
la b orat or y e v al uati o ns, assess me nts of vital si g ns (sitti n g bl o o d press ure, res pirati o n, p ulse, 
a n d te m perat ure), a n d meas ure me nts of h ei g ht a n d wei g ht. All F O C B P will ha ve uri ne 
pre g na nc y t ests perf or me d. F or t he p ur p os es of efficac y ass ess me nts, 1 tar g et great t oe n ail 
will be select e d fr o m t he st u d y -eli gi ble great t oe nail(s), i ncl u di n g s u bjects i n t he P K s u bset 
f or w h o m b ot h great t oe nails m ust be i n v ol ve d. W here b ot h great t oe nails are st u d y-eli gi ble, 
t he t oe nail wit h t he great er per ce nt of affecte d area will be selecte d f or m y c ol o gic data a n d 
f or i ncl usi o n i n t he efficac y a nal ysis. I n t he i nsta n ce w here t he p erce nt of affect e d area is t he 
sa me f or b ot h st u d y-eli gi ble great t oe n ails, t he i n vesti gat or ma y select eit her great t oe n ail as 
t he tar get t oe nail. T he t ar get great t oe n ail will be i de ntifie d a n d rec or d e d f or eac h s u bj ect, 
p h ot o gra p hs of t he tar g et great t oe nail will be o btai ne d, a n d a tra ns v erse n ot c h will be 
i nscri be d i n t he tar get great t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d (as a mar ker f or 
meas uri n g t oe nail gr o wt h at s u bse q ue nt visits). Assess me nts of all ot her n o ntar get t oe nails, 
i ncl u di n g t he ot her i n v ol ve d t oe nails of s u bjects i n t he P K s u bset, will als o be c o n d ucte d t o 
assess t he pres e nce or a bse nce of o n y c h o m yc osis o n eac h t oe n ail. T his assess me nt will 
c o nti n ue t h r o u g h o ut t he st u d y visits t hr o u g h wee k 5 2. 
 
After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit ( Da y 1), s u bjects will be e nr olle d i n t he 
treat me nt peri o d. S u bjects or t heir pare nts/le gal g uar dia ns will a p pl y t he first d ose of st u d y 
dr u g t o t he q ualifie d t o e n ails at t he i n vesti gati o nal ce nter u n d er t he s u per visi o n of desi g nate d 
st u d y pers o n nel. A n y l ocal s ki n reacti o ns t hat occ ur at t he st u d y dr u g a p pli cati o n site, al o n g 
wit h a n y a d vers e e ve nts ( A Es), will be rec or de d. S u bjects a n d t heir pare nts/le gal g uar di a ns 
will recei ve w ei g he d st u d y dr u g b ottles a n d gi ve n ver bal a n d writte n i nstr ucti o ns f or 
treat me nt a p plicati o n. S p ecificall y, s u bjects w h o are n ot i ncl u de d i n t he P K s u bset will be 
i nstr ucte d t o a p pl y t he st u d y dr u g t o t he affecte d t oe nails o nce dail y at b e dti me f or 4 8 wee ks.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  
2 2  
 
 
 
S u bjects w h o are i ncl u d e d i n t he P K s u bset will be i nstr ucte d t o a p pl y t he st u d y dr u g t o all 
1 0 t oe nails o nce dail y at be dti me f or 4 wee ks. F oll o wi n g t he P K bl o o d c ollecti o ns o n Da ys 
2 8 a n d 2 9, t hese s u bjects will be i n str ucte d t o c o nti n ue treat me nt wit h st u d y dr u g t o o nl y t he 
affecte d t oe n ails a n d ret ur n t o t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2,  
3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 5 2). All s u bjects or 
t heir parents/le gal g u ar di a ns will als o recei v e diari es, wit h i nstr ucti o ns t o c o m plete a rec or d 
of all a p plicati o ns a n d t o n ote a n y misse d a p plicati o ns of t he st u d y dr u g.  
 
 
S u bjects i n t he P K s u bset will n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( D a y 2 8) 
visit. F oll o wi n g t he Da y 2 8 st u d y pr oce d ures, s u bjects i n t he P K s u bset will u n der g o ti me d 
bl o o d c ollecti o ns t o assess plas ma c o nce ntrati o ns of efi nac o naz ol e a n d met a b olites ( H 3 a n d 
H 4). Assess me nts will re q uire c ollecti o n of a p pr o xi matel y 4 m L of w h ole bl o o d at eac h ti me 
p oi nt (a p pr o xi matel y 2 0 m L t otal). Wit hi n 1 h o ur after t he pre d ose bl o o d s a m ple is dra w n, 
t he s u bjects/ pare nts/le gal g uar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails at t he 
i n vesti gati o nal ce nter. S u bse q ue nt bl o o d c ollecti o ns will occ ur 2, 4, a n d 1 2 h o urs p ost d ose o n 
Da y 2 8. T he s u bjects will g o h o me after D a y 2 8, b ut will n ot a p pl y st u d y dr u g o n t he ni g ht of 
t he Da y 2 8 visit. P K s u bjects will ret ur n t o t he i n v esti gati o nal ce nter t he f oll o wi n g da y ( Da y 
2 9)  f or c ollecti o n of a 2 4-h o ur p ost d ose bl o o d sa m ple. P K s u bjects will c o nti n ue treat me nt 
wit h st u d y dr u g t o o nl y t he tar g et great t oe n ail a n d t he ot her affecte d t o e nails a n d ret ur n t o 
t he i n vesti gati o nal ce nter  at Wee ks  8,  1 2,  1 6,  2 0,  2 4,  2 8,  3 2,  3 6,  4 0,  4 4,  a n d 4 8),  a n d a 
4 -wee k p ost -tr eat me nt f oll o w-u p visit ( Wee k 5 2).  
Safet y will be assesse d b y re vie wi n g t he occ urre n ce of A Es a n d l ocal s ki n reacti o ns, 
assessi n g vital si g n meas ure me nts a n d a b bre viate d p h ysical e xa mi nati o n fi n di n gs, a n d n oti n g 
a n y a d diti o ns or c ha n g es i n c o nc o mita nt me dicati o n uses. Bl o o d sa m ples will be c ollecte d at 
Scree ni n g a n d Wee k 4 8 f or r o uti ne safet y la b orat or y e val uati o ns (ser u m c h e mistr y, 
he mat ol o g y, a n d uri nal ysis); uri ne pre g na n c y tests will be o btai ne d f or all F O C B P at eac h 
st u d y visit. Efficac y assess me nts will be perf or me d t hr o u g h o ut t he st u d y. Efficac y a nal yses 
will be base d o n micr osc o pic e xa mi nati o n a n d m y c ol o gical c ult ure res ults f or t he tar get great 
t oe nail, t he perce nt i n v ol ve me nt of t he tar g et great t oe nail, t he le n gt h of t he u naffecte d p art 
of t he t ar get gr eat t oe n ail, t he gr o wt h of t he tar g et great t oe nail, a n d t h e n u m ber of affecte d 
n o ntar get t oe nails.  
A p ost -treat me nt f oll o w-u p visit will occ ur 4 wee ks after t he last treat me nt visit f or eac h 
s u bject w h o c o nti n ues t hr o u g h Wee k 4 8 (ie, at Wee k 5 2). S u bjects w h o disc o nti n ue fr o m t he 
st u d y pri or t o Wee k 4 8 will ret ur n t o c o m plete t he Wee k 4 8 st u d y pr o ce d ures. 
T he st u d y desi g n a n d sc h e d ule of assess m e nts is prese nte d i n Ta bl e 1.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 3  
 
 
 
T a ble  1:  
St u d y Desi g n a n d Sc he d ule of  Assess me nts  
 
 
 
Tre at m e nt Peri o d  
P ost - 
Tre at me nt  
Visit  
1 - 
S C R  
2 - 
B L  
3  
3 A a 
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4 b 
1 5  
Wee k  
 
P R O C E D U R E S  
U p t o 
Da y  
-4 2  
Da y 
1  
4  
( Da y 
2 8)  
4  
( Da y 
2 9)  
8  
1 2  
1 6  
2 0  
2 4  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 2  
O btai n I nf or me d C o nse nt/ Asse nt a n d 
P h ot o gra p h y C o nse nt/ Asse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w Me dical Hist or y  
X  
X c  
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w Pre vi o us T hera pies  
X  
X c  
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w I ncl usi o n/ E xcl usi o n Criteria  
X  
X c  
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n d uct Uri ne Pre g na nc y Test (all 
fe males of c hil d beari n g p ote ntial) d 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Cli p T oe nails e 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
N otc h Tar get Great T oe nail f 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meas ure Tar get Great T oe nail Gr o wt h 
(fr o m t he P N F t o t he n otc h) f 
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o n d uct Tar get Great T oe nail 
Assess me nts g 
X  
X  
 
 
 
X   
 
X   
 
X   
 
X  
X  
C o n d uct N o ntar get T oe nail 
Assess me nts h 
X  
X  
 
 
 
X   
 
X   
 
X   
 
X  
X  
O btai n P h ot o gra p h y  
 
X  
 
 
 
 
 
 
X   
 
 
 
 
X  
X  
Perf or m K O H E xa mi nati o n i 
X  
 
 
 
 
X   
 
X   
 
X   
 
X  
X  
Sa m ple f or F u n gal C ult ure i 
X  
 
 
 
 
X   
 
X   
 
X   
 
X  
X  
C o n d uct A b bre viate d P h ysical E xa m j  
X  
 
 
 
 
 
 
 
 
 
 
 
 
X   
O btai n Vital Si g ns k 
 
X  
 
 
 
X   
 
X   
 
X   
 
X   
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5,  2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 4  
 
 
 
 
 
Tre at m e nt Peri o d  
P ost - 
Tre at me nt  
Visit  
1 - 
S C R  
2 - 
B L  
3  
3 A a 
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4 b 
1 5  
Wee k  
 
P R O C E D U R E S  
U p t o 
Da y  
-4 2  
Da y 
1  
4  
( Da y 
2 8)  
4  
( Da y 
2 9)  
8  
1 2  
1 6  
2 0  
2 4  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 2  
C ollect Bl o o d a n d Uri ne Sa m ples f or 
C B C/ Diff, C he mistr y, a n d 
Uri nal ysis  
 
X p  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X l 
 
E nr oll Q ualifie d S u bjects  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w D osi n g I nstr ucti o ns  
 
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A p pl y First D ose i n Cli nic  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g h/ Dis pe nse St u d y Dr u g  
 
X  
X n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A p pl y St u d y Dr u g  
 
X q  
 
  
C ollect/ Wei g h St u d y Dr u g  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Re vie w C o m plia nce  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Dis pe nse Diar y  
 
X  
X o  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
C ollect/ Re vie w Diar y  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
P K Bl o o d Sa m ple C ollecti o n m  
 
 
X m  
X m   
 
 
 
 
 
 
 
 
 
 
 
Re vie w L ocal S ki n Reacti o ns  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Re vie w C o nc o mita nt Me dicati o ns  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Re vie w A d verse E ve nts  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E xit St u d y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X  
A b bre viati o ns: B L = Baseli ne Visit; C B C/ Diff = c o m plete bl o o d c o u nt/ differe ntial; K O H = p otassi u m h y dr o xi de; P K = p har mac o ki n etic; P N F = pr o xi mal t oe nail 
f ol d; S C R = Scree ni n g Visit 
N ote: P ost -baseli ne visits are t o be sc he d ule d i n refere nce t o Visit 2 ( Baseli ne Visit) a n d wit hi n a wi n d o w of ± 5 da ys.  
a Visit 3 A ( Da y 2 9) is o nl y t o be c o n d ucte d f or s u bjects i n t he P K s u bset.  
b All Wee k 4 8 pr oce d ures are t o be c o m plete d f or s u bjects w h o disc o nti n ue fr o m t he st u d y d uri n g t he treat me nt peri o d (ie, Earl y Ter mi nati o n). 
c C o nfir mati o n of e val uati o ns c o n d ucte d at t he Scree ni n g Visit.  
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5,  2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 5  
 
 
d Uri ne pre g na nc y tests are re q uire d t o ha ve a mi ni m u m se nsiti vit y of 2 5 mI U of h u ma n c h ori o nic g o na d otr o pi n per m L of uri ne. 
e T oe nails are cli p pe d pri or t o c o n d ucti n g t he assess me nts.  
f T he tra ns verse n otc h i nscri be d at t he Baseli ne Visit is e n ha nce d, as nee de d, at s u bse q ue nt visits t o all o w c o nti n ue d meas ur e me nt of t oe nail gr o wt h o ver t he 
c o urse of t he st u d y. I n cases w here t he i nitial n otc h gr o ws o ut or is cli p pe d a wa y, a ne w n otc h is i nscri be d i n t he t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d  
a n d meas ure me nts of t oe nail gr o wt h (ie, pr o xi mal t oe nail f ol d  t o n otc h) will c o nti n ue usi n g t he ne w n otc h. 
g Assess me nts i ncl u de calc ulati o n of t he perce nt i n v ol ve me nt of t he t oe nail affecte d b y o n yc h o m yc osis a n d meas ure me nt of t he di sta nce fr o m t he pr o xi mal 
t oe nail f ol d t o t he pr o xi mal o n yc h o m yc otic b or der. 
h Asses s me nt of n o ntar get nails f or prese nce or a bse nce of o n yc h o m yc osis. 
i At t he Scree ni n g visit, K O H s peci me ns f or K O H a n d f u n gal c ult ures will be s hi p pe d t o t he m yc ol o g y la b. At all s u bse q ue ntl y i n dicate d st u d y visits, 
s peci me ns f or K O H e xa mi nati o ns a n d f u n gal c ult ures are o btai ne d fr o m t he tar get great t oe nail. 
j T he a b bre viate d p h ysical e xa mi nati o n at t he Baseli ne Visit a n d Wee k 4 8 i ncl u des hei g ht a n d wei g ht,  
k Vital si g n meas ure me nts at eac h visit i ncl u de te m perat ure, p ulse, res pirati o ns, a n d sitti n g bl o o d press ure.  
l A n y cli nicall y si g nifica nt la b orat or y a b n or malit y prese nt at Wee k 4 8 ( or Earl y Ter mi nati o n) is t o be f oll o we d t o res ol uti o n o r u ntil cli nicall y sta ble as 
deter mi ne d b y t he i n vesti gat or.  
m A s u bset of e nr olle d s u bjects will be assi g ne d t o P K e val uati o ns. At t he Wee k 4/ Da y 2 8 Visit, s u bjects i n t he P K s u bset will u n der g o ti me d bl o o d sa m pli n g o n 
Da ys 2 8 t o 2 9 as f oll o ws:  
n St u d y dr u g s h o ul d be wei g he d a n d dis pe nse at Visit 3 A f or P K s u bjects 
o Diar y s h o ul d be dis pe nse d wit h st u d y dr u g at Visi t 3 A f or P K s u bjects. 
p C ollecti o n of Scree ni n g safet y la bs ma y be p ost p o ne d u ntil after p ositi ve Scree ni n g m yc ol o g y res ults are recei ve d, o nl y if  t he s u bject/ pare nt are willi n g t o 
ret ur n t o t he researc h site f or safet y la b c ollecti o n pri or t o t he e n d of the 4 2 -da y scree ni n g wi n d o w. Scree ni n g safet y la b res ults m ust be recei ve d wit hi n t he 
4 2 -da y scree ni n g visit wi n d o w.  
q T he s u bject or t heir pare nt/le gal g uar dia n will a p pl y t he first d ose of st u d y dr u g i n t he i n vesti gati o nal ce nter, wit h g ui da n ce fr o m st u d y  staff. 
 
 
 
Visit  
3  
3 A  
D a y 
( Wee k) 
2 8  
( 4) 
2 9  
( 4) 
P R O C E D U R E S  
 
Pre d ose  
~ 1 h 
F oll o wi n g 
Pre -d ose 
Sa m ple  
 
2 h  
( ± 5 mi n) 
4 h  
( ± 5 mi n) 
 
1 2 h  
( ± 1 5 mi n) 
 
2 4 h  
( ± 3 0 mi n) 
P K S u bset - C ollect Bl o o d f or Plas ma 
C o nce ntrati o ns  
X p  
 
X  
X  
X  
X  
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5,  2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
2 6  
 
 
 
Visit  
3  
3 A  
D a y 
( Wee k) 
2 8  
( 4) 
2 9  
( 4) 
P K S u bset - St u d y Dr u g A p plicati o n  
 
X q  
 
 
 
 
p T he pre d ose bl o o d sa m ple is t o be c ollecte d after all Da y 2 8/ Wee k 4 st u d y pr oce d ures are c o m plete d.  
q St u d y dr u g a p plicati o n o n Da y 2 8/ Wee k 4 will occ ur at t he i n vesti gati o nal ce nter wit hi n 1 h o ur after c ollecti n g t he pre d ose b l o o d sa m ple. 
T his will be t he last a p plicati o n of st u d y dr u g t o all 1 0 t oe nails f or s u bjects i n t he P K s u bset. P ost Da y 2 8, s u bjects a n d t heir pare nts/le gal g uar dia ns will be 
i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject's tar get great t oe nail a n d all ot her affecte d t oe nail(s). S u bjects a n d t heir pare nts/le gal g uar dia ns will 
be i nstr ucte d t o  c o nti n ue a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire treat me nt peri o d, e ve n if t he disease clears a n d n o affecte d area is 
o bser ve d o n t he tar get great t oe nail. If ot her affecte d t oe nails treate d si nce baseli ne clear d uri n g t he c o urs e of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal 
g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe na ils bec o me i nfecte d d uri n g t he 
st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8  Selecti o n a n d Wit h dr a w al of  S u bjects  
8. 1  S u bject I ncl usi o n  Criteri a  
S u bjects meeti n g all of t he f oll o wi n g criteria will be eli gi ble f or st u d y e ntr y: 
1.  Male or fe m ale s u bjects of a n y race, 6 t o 1 6 years of a ge (i n cl usi ve) at  Scree ni n g.  
•  P K S u bset : Male or fe male s u bjects of a n y race, 1 2 t o 1 6 years of a ge (i ncl usi ve) 
at Scree ni n g.  
2.  Ver bal a n d writte n i nf or me d c o nse nt/asse nt o btai ne d fr o m t he s u bject a n d/ or t heir 
pare nt or le g al  g uar dia n.  
3.  G o o d ge ner al healt h, as assesse d b y t he i n vesti gat or, base d o n t he  s u bject's 
me dical hist or y, p h ysical e xa mi nati o n, a n d safet y la b orat or y tests.  
4.  At least 1 great t oe n ail (t he "tar get great t oe nail") wit h cli nicall y dia g n ose d distal 
lateral s u b u n g ual o n yc h o m yc osis i n v ol vi n g at least 2 0 % of t he affect e d great 
t oe nail at t he Scree ni n g a n d Baseli ne Visits (as det er mi ne d b y t he i n vesti gat or), 
wit h o ut de r mat o p h yt o mas or l u n ula ( matri x) i n v ol ve me nt. T here is n o s pecific 
u p per li mit f or perce nt i n v ol ve me nt. U p t o 6 t oe nails ma y ha ve o n yc h o m yc osis i n 
s u bjects n ot partici pati n g i n t he P K s u bset. 
•  P K S u bset : B ot h great t oe nails wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at least 5 0 % of t he affecte d great t oe nail at t he 
Scree ni n g a n d Bas eli ne Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut 
der mat o p h yt o mas or l u n ula ( matri x) i n v ol ve me nt. T here is n o s pecific u p p er li mit 
f or per ce nt i n v ol ve me nt. S u bjects m ust als o ha ve at least 4 t oe nails ot her t ha n t he 
great t oe nails wit h  o n yc h o m yc osis.  
5.  Tar get gr eat t oe nail f or all s u bjects, a n d b ot h great t oe nails f or s u bjects i n t he P K 
s u bset, m ust ha ve e vi de n ce of t oe n ail gr o wt h, per s u bject's re p ort t hat m o nt hl y 
cli p pi n g is  nee de d.  
6.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( D a y 1) Visit, ha ve a p ositi ve K O H 
e xa mi nati o n (res ults will be pr o vi de d b y t he ce ntral t he m yc ol o g y la b) of t h e  tar get 
great t oe nail f or all  s u bjects 
7.  Wit hi n  4 2  da ys  pri or  t o t he Baseli ne  ( Da y 1)  Visit,  ha ve  a p ositi ve  d er mat o p h yte 
c ult ure f or T r u br u m or T me nt a gr o p hytes (at t he ce ntral m yc ol o g y la b orat or y) 
fr o m t he tar get great t oe n ail i n all s u bjects 
•  P K S u bset : Pri or t o t he Baseli ne Visit, t he great t oe nail desi g nate d f or 
efficac y ass ess me nts as t he tar get great t oe nail m ust ha ve b ot h a p ositi ve 
K O H e xa mi nati o n (res ults will be pr o vi de d b y t he ce ntral m yc ol o g y la b) 
a n d a p ositi ve f u n gal  c ult ure.  
 
 
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Valea nt Researc h & De vel o p me nt  
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8.  All F O C B P m ust ha ve a ne gati ve uri ne pre g na n c y test at t he Scree ni n g a n d 
Baseli ne Visits a n d m ust a gree t o us e a n effecti ve met h o d of c o ntrace pti o n 
t hr o u g h o ut t he st u d y. Effecti ve c o ntrace pti o n is defi ne d as use of a n i ntra ut eri ne 
de vice, c o n d o m wit h s per mici de, dia p hra g m wit h s per mici de, a bsti ne nce  (s u bject 
is n ot se x uall y acti ve), or sta ble use of a h or m o nal c o ntrace pti ve ( oral, i m pla nt, 
i njecti o n, or tra ns der m al patc h) f or at least 3 m o nt hs pri or t o t he Baseli ne Visit.  
9.  S u bjects a n d t heir par e nts/le gal g uar dia ns are willi n g t o c o m pl y wit h st u d y 
i nstr ucti o ns a n d ret ur n t o t he i n vesti gati o nal ce nter f or all re q uire d visits (a visit 
sc he d ule wit h t he le n gt h of eac h visit will be pr o vi de d t o e ns ure t hat t he s u bject 
ca n meet t he re q uire m e nts a n d ha ve a d e q uate  tra ns p ortati o n). 
1 0.  S u bjects a n d pare nts/le gal g uar dia ns a gree t hat t he s u bj ect will a v oi d t he use of 
t oe nail p olis h, c os metic t oe nail pr o d ucts, a n d p e dic ures d uri n g t he st u d y peri o d.  
 
8. 2  S u bject E xcl usi o n  Criteri a  
S u bjects meeti n g a n y o ne of t he f oll o wi n g criteria will be e xcl u de d fr o m t he st u d y:  
1.  Fe males w h o ar e pre g n a nt, n ursi n g a n  i nfa nt, or pla n ni n g a pre g na n c y d uri n g t he 
st u d y peri o d.  
2.  Hist or y of i m m u n os u p pressi o n a n d/ or cli nical si g ns i n dicati ve of p ossi ble 
i m m u n os u p pressi o n, as deter mi ne d b y t he i n vesti g at or, or k n o w n h u ma n 
i m m u n o deficie nc y vir us i nfecti o n. 
3.  Hist or y of dia betes t hat is u nc o ntr olle d as deter mi ne d b y t he i n vesti gat or ( dia betes 
t hat is c o ntr olle d b y diet or me dicati o n d oes n ot e xcl u de a s u bject). 
4.  Prese nce  of  a n y t oe n ail i nfecti o n ot her  t h a n or  i n a d diti o n t o der mat o p h ytes,  s uc h 
as Scyt ali di u m as deter mi ne d b y t he i n vesti gat or (ca n di dal o n yc h o m yc osis 
i nfecti o n, c o nc urre nt wit h a p ositi ve der mat o p h yt e c ult ure, is acce pta ble).  
5.  Prese nce of a n y of t he f oll o wi n g: der mat o p h yt o ma, f u n gal "s pi kes" wit hi n 3 m m 
of t he pr o xi mal t oe nail f ol d o n t he tar get grea t t o e nail, i nfecti o n e xte n di n g t o t he 
matri x, or o nl y lateral t oe nail disease i n t he tar g et great  t oe n ail. 
6.  Prese nce of se vere m occasi n ti nea pe dis at t he Scree ni n g or Baseli ne Visits, as 
deter mi ne d b y t he i n vesti gat or. If t he s u bject has i nter di gital ti nea  pe dis t hat 
re q uires tr eat me nt, t he s u bject m ust a gree t o use o nl y a n i n vesti gat or-a p pr o ve d 
t o pical a ntif u n gal t hera p y. 
7.  Prese nce of a n y disease/c o n diti o n t hat mi g ht ca use t oe nail a b n or malities or ma y 
i nterfer e wit h t he e val u ati o n of t he st u d y dr u g as d etermi ne d b y t he i n vesti g at or 
(e g, o pe n s or es or ulcerati o n o n t he t oes of affecte d t oe nails, ps oriasis, i m m u ne 
d ysf u ncti o n, c olla ge n -v asc ular diseas es, lic he n pl a n us, peri p heral vasc ul ar disease, 
or tra u matic o n yc h o d ystr o p h y d ue t o c hr o nic p h ysical  sti m uli). 
8.  A n y pre vi o us s ur ger y o n t he tar get great  t oe n ail. 
 
 
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9.  Prese nce of o n yc h o m yc osis of t he  fi n ger n ail. 
1 0.  Hist or y of i m m u n o deficie nc y as det er mi ne d b y t h e  i n vesti gat or. 
1 1.  Prese nce of 1 -ha n d, 2 -f o ot s y n dr o me, or fi n ger n ail der mat o p h yt osis.  
1 2.  Tar get gr eat t oe nail (i ncl u di n g t oe nail plate a n d a n y s u b u n g ual de bris) t hic ker t ha n 
3 m m at t he Scree ni n g a n d Baseli ne  Visits.  
1 3.  Prese nce  of  o n y c h o d ystr o p h y  t hat c o ul d i nterfere wit h  cli nical ass ess me nts  as 
deter mi ne d b y t he  i n vesti gat or. 
1 4.  Hist or y of h y perse nsiti vit y or aller gic reacti o ns t o az ole deri vati ves or a n y of  t he 
st u d y dr u g c o nstit ue nts.  
1 5.  Prese nce  of  a n y u n derl yi n g  disease  t hat, i n t he o pi ni o n  of  t he i n vesti gat or, c o ul d 
prese nt a safet y c o n cer n f or t he s u bject b y partici p ati n g i n t he  st u d y. 
1 6.  S u bject has recei ve d tr eat me nt f or a n y t y pe of ca n cer i n t he pre vi o us 6 m o nt hs, 
e xce pt  f or n o n mela n o m a  s ki n ca ncer (e g, basal  cell carci n o ma or  n o n metast atic 
s q ua m ous cell car ci n o ma) t hat was treate d  s uccessf ull y. 
1 7.  Prese nce of a n y d er mat ol o gical c o n diti o n o n t he feet t hat c o ul d i nterfere wit h 
cli nical e val uati o ns as deter mi ne d b y t he  i n vesti gat or. 
1 8.  Prese nce of a n y u n d erl yi n g disease or d er mat ol o gical c o n diti o n ot her t ha n 
o n yc h o m yc osis t hat re q uires t he use of i nterferi n g t o pical or s yste mic t hera p y a n d 
w o ul d  ma ke  e val uati o ns  i nc o ncl usi ve as deter mi ne d  b y  t he i n vesti gat or, or  s u bject 
re q uires tr eat me nt wit h a t o pical pr o d uct o n t he t oe nails ot her t ha n t he st u d y dr u g 
d uri n g t he  st u d y. 
1 9.  S u bjects  usi n g  t he f oll o wi n g t o pical pre parati o ns  wit hi n  t he i n dicate d ti me pri or  t o 
t he Baseli ne Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g t o pical 
pre par ati o ns d uri n g t he  st u d y: 
•  T oe nail p olis h or c os metic t oe na il pr o d ucts: 1 da y 
•  Ot her t o pical pr escri pti o n or o ver -t he-c o u nter me dicati o ns t o t he t oe nails ( wit h 
t he e xce pti o n of bla n d e m ollie nts): 2 wee ks  
•  T o pical  pres cri pti o n  or  o ver -t he-c o u nter  a ntif u n gal  t hera p y f or t he t o e nails, 
i ncl u di n g de vices t o treat o n yc h o m yc osis: 4  wee ks  
2 0.  S u bjects usi n g t he f oll o wi n g s yste mic me dicati o ns wit hi n t he i n dicate d ti me  pri or 
t o t he Baseli ne Visit, or re q uires c o n c urre nt use of a n y of t he f oll o wi n g s yste mic 
me dicati o ns d uri n g t he  st u d y: 
•  S yste mic a ntif u n gal t hera p y: 4  wee ks  
•  S yste mic i m m u n os u p pressi ve a ge nts: 6  m o nt hs  
 
 
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2 1.  S u bject  has  pre vi o usl y  bee n  n o nres p o nsi ve  t o s yste mic a ntif u n gal  t hera p y f or 
o n yc h o m yc osis.  
2 2.  S u bject is u na ble t o c o m m u nicate or c o o p erate wit h t he i n vesti gat or d ue t o 
la n g ua ge pr o bl e ms,  p o or  me ntal  de vel o p me nt,  or  i m paire d cere bral  f u ncti o n. 
2 3.  Use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5  half -li ves ( w hic he ver 
is l o n ger) pri or t o t he Scree ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her 
cli nical st u d y wit h a n i n vesti gati o nal dr u g or  de vice.  
 
8. 3  S u bject Wit h dr a w al  Criteri a  
W he n p ossi ble, s u bjects w h o disc o nti n ue fr o m t he st u d y pri or t o c o m pleti n g t he 4 8 -wee k 
treat me nt peri o d s h o ul d r et ur n t o t he i n vesti gati o nal ce nter t o p erf or m t he assess me nts 
sc he d ule d f or Wee k 4 8. If a p pr o priat e, disc o nti n ue d s u bjects ma y be place d o n ot her 
c o n ve nti o nal t hera p y u p o n re q uest or w h e ne v er cli nicall y necess ar y, as d eter mi ne d b y t he 
I n v esti gat or. T he E n d of St u d y s o urce d oc u me nts a n d all rele v a nt data s h o ul d be e ntere d i nt o 
t he electr o nic case re p ort f or m (e C R F) s yste m at t he ti me t he s u bject disc o nti n ues fr o m t he 
st u d y. 
Reas o ns f or s u bject wit h dra wal ma y i ncl u d e, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  O n yc h o m yc osis  pr o gr essi o n,  as det er mi ne d  b y  t he i n vesti gat or, w hic h  re q uires 
treat me nt wit h a pr o hi bite d t hera p y 
•  Eit her at t he i n vesti gat or's discreti o n f or safet y reas o ns (e g, se vere a d v erse  reacti o ns 
or u na ut h orize d c o nc o mita nt t hera p y), or at t he s u bject's re q uest f or pers o n al reas o ns  
•  W he n t he r e q uire me nts of t he pr ot oc ol are n ot  f oll o we d 
•  W he n a c o nc o mita nt t her a p y li kel y t o i nterfere wit h t he res ults of t he st u d y is 
re p orte d or re q uir e d b y t he s u bject (t he i n vesti gat or will re p ort all s uc h i nf or mati o n 
o n  t he s o urce d oc u me nts/ e C R Fs  a n d deci d e,  i n acc or da nce  wit h  t he S p o ns or,  w het her 
t he s u bject is t o be wit h dra w n)  
•  W he n a s u bject is l ost t o f oll o w -u p; t he i n vesti gat or ( or desi g nee) will tr y t wice t o 
reac h t h e s u bject b y tele p h o ne, a n d will se n d a f oll o w-u p letter b y certi fie d mail 
bef ore c o nsi deri n g t he s u bject as l ost t o f oll o w -u p; t hese acti o ns will be d oc u me nte d 
i n t he s o urce d oc u m e nts a n d rec or de d o n t he E n d of St u d y e C R F, wit h a c o p y of t he 
f oll o w-u p letter mai ntai n e d i n t he i n vesti gat or's  fil e 
•  If a s u bject b ec o mes pr e g na nt d uri n g t he treat me nt peri o d, t he st u d y dr u g will be 
disc o nti n ue d i m me diatel y, t he s u bject will be disc o nti n ue d fr o m t he st u d y, a n d t he 
i n vesti gat or will n otif y t he s p o ns or. T he pre g na n c y will be f oll o we d t o ter m wit h t he 
o utc o me re p ort e d t o t he  s p o ns or. 
 
 
 
 
 
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Valea nt Researc h & De vel o p me nt  
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9  Tre at me nts  Pl a n ne d  
9. 1  Met h o ds of Assi g ni n g S u bjects t o Tre at me nt  Gr o u ps  
T his is a si n gle -ar m, o pe n la bel st u d y. After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit, 
s u bjects will be e nr olle d i n t he treat me nt peri o d a n d will recei ve efi nac o naz ole i n acc or da n ce 
wit h t he pr ot oc ol ( Secti o n 1 0).  
 
9. 2  R a n d o miz ati o n a n d  Bli n di n g  
Ra n d o mizati o n a n d bli n di n g d o n ot a p pl y.  
P K assess me nts  will be perf or me d o n a s u bset of t he st u d y p o p ulati o n. Eff orts will be ma de 
t o e nr oll s u bjects i nt o t he P K s u bset s uc h t hat t he y are e ve nl y distri b ute d acr oss t he re q uire d 
a ge ra n g e.  
 
9. 3  Tre at m e nt C o m pli a nce  
S u bjects a n d t heir par e nts/le gal g uar dia ns will be  dis pe nse d a n i nitial b ottle of st u d y dr u g at 
Baseli ne ( Da y 1). S u bjects a n d t heir pare nts/le g al g uar dia ns will be i nstr uct e d o n t he 
i m p orta nce of r et ur ni n g t he s u bject's st u d y dr u g b ottle(s) at t he ne xt st u d y visit. If a s u bject 
d oes n ot ret ur n his/ her st u d y dr u g b ottle, he/s he will be i nstr ucte d t o ret ur n it at his/ her ne xt 
st u d y visit. A ne w st u d y dr u g b ottle will be dis pe nse d t o t he s u bjects at eac h p ost baseli ne 
st u d y visit t hr o u g h Wee k 4 4. S u bjects i n t he P K s u bset will be dis pe nse d 2 b ottles of st u d y 
dr u g at Baseli ne ( D a y 1), a n d will be dis pe nse d o n e b ottle of st u d y dr u g at eac h s u bse q ue nt 
st u d y visit t hr o u g h Wee k 4 4. All use d a n d u n use d st u d y dr u g b ottles will be c ollecte d at 
Wee k 4 8.  
T he i n vesti gati o nal ce nter staff will wei g h a n d rec or d eac h b ottl e of st u d y dr u g bef ore 
dis pe nsi n g t o t he s u bject a n d t heir pare nt/le gal g uar dia n a n d f oll o wi n g ret ur n b y t he s u bject. 
B ottle wei g hts will be rec or de d i n t he i n di vi d ual st u d y dr u g l o g a n d i n t he a p pr o priate e C R F.  
At eac h p ost bas eli ne st u d y visit, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be as ke d 
t o re p ort a n y misse d d oses of st u d y dr u g, a n d pr o vi de t he date a n d a n e x pla nati o n f or eac h 
misse d d ose. A s u bject w h o has de viate d fr o m t he o nce dail y d osi n g re gi me n will be 
c o u nsele d i n t he pr ese nce of t h eir pare nt/le gal g u ar dia n. T he d ates of a n y misse d d oses of 
st u d y dr u g will be rec or d e d i n t he s u bject's s o urce d oc u me nt a n d a p pr o priat e e C R F.  
 
9. 4  Tre at m e nt A d mi nistr ati o n  
S u bjects a n d t heir p are nts/le gal g uar dia ns will recei ve b ot h ver bal a n d writte n i nstr ucti o ns o n 
t he a p plicati o n of t he st u d y dr u g. T he s u bject a n d/ or t heir pare nt/le gal g uar dia n will a p pl y t he 
first d ose of st u d y dr u g at t he i n vesti gati o nal ce nter d uri n g t he Baseli ne Visit. All of t he 
 
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re mai ni n g st u d y dr u g d oses will be a p plie d b y t he s u bject at h o me. T he s u bjects a n d t heir 
pare nts/le gal g uar dia ns will be i nstr ucte d t o  wait f or t he t oe nails t o air -dr y t h or o u g hl y bef ore 
t o uc hi n g wit h cl ot hi n g. 
D osi n g f or S u bjects N O T I ncl u de d i n t he P K S u bset: S u bjects a n d t heir pare nts/le gal 
g uar dia ns will be i nstr uct e d t o a p pl y t heir assi g ne d st u d y dr u g t o t he tar get great t oe nail a n d 
all ot her aff ecte d t o e nail(s) (if a n y) o n ce dail y at b e dti me. S u bjects a n d t heir pare nts/le gal 
g uar dia ns will be i nstr uct e d t o c o nti n ue a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or 
t he e ntire treat me nt peri o d, e ve n if t he disease clears a n d n o affect e d area is o bser ve d o n t he 
tar get great t oe nail. If ot h er affect e d t oe nails treate d si nce baseli ne clear d uri n g t he c o urse of 
t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g u ar dia ns will be e nc o ura ge d t o c o nti n ue 
treat me nt o n t h ose t oe nails f or t he durati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me 
i nfecte d d uri n g t he st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y 
affecte d t oe n ail(s). All s u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y 
t he st u d y dr u g b y c o m pletel y c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f ol ds, 
t oe nail be d, h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he st u d y dr u g will be 
a p plie d t o eac h of t he ot h er i nfecte d t oe nails i n a si milar ma n ner.  
D osi n g f or S u bjects I ncl u de d i n t he P K S u bset:  
D a ys 1 t o 2 8 - S u bjects a n d t heir pare nts/le gal g u ar dia ns will be i nstr ucte d t o a p pl y st u d y 
dr u g t o all 1 0 t oe nails, o nce dail y at be dti me. D uri n g t his peri o d, all P K s u bjects will be 
i nstr ucte d t o a p pl y t he st u d y dr u g b y c o m pletel y c o veri n g eac h t oe nail a n d 0. 5 c m of a djace nt 
s ki n, i ncl u di n g t he t oe nail f ol ds, t oe nail be d, h y p o n yc hi u m, u n ders urface of t he t oe nail plate. 
T he s u bjects will n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( Da y 2 8) visit, n or will 
t he y a p ply st u d y dr u g o n t he ni g ht of t he Wee k 4/ Da y 2 8 Visit. Wit hi n 1 h o ur after t h e 
pre d ose bl o o d sa m ple is dra w n o n D a y 2 8, s u bjects will a p pl y st u d y dr u g t o all 1 0 t oe nails i n 
t he ma n ner des cri be d a b o ve at t he i n vesti gati o nal ce nter. 
D a ys 2 9 t o Wee k 4 8:  
After c o m pleti o n of t he P K p orti o n of t he st u d y, s u bjects a n d t heir pare nts/le gal g uar dia ns 
will be i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject's tar get great t oe nail a n d all 
ot her aff ecte d t o e nail(s) o nce dail y at be dti me. S u bjects a n d t hei r pare nts/le gal g uar dia ns will 
be i nstr ucte d t o c o nti n ue a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire 
treat me nt peri o d, e ve n if t he disease cl ears a n d n o affecte d area is o bser ve d o n t he tar get 
great t oe nail. If ot her aff ecte d t oe n ail s treate d si n ce baseli ne clear d uri n g t he c o urse of t he 
st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura g e d t o c o nti n ue treat me nt 
o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me i nfecte d 
d uri n g t he s t u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affect e d 
t oe nail(s). All s u bjects a n d t heir pare nts/le gal g u ar dia ns will be gi ve n i nstr ucti o ns re gar di n g 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
3 3  
 
 
 
 
h o w t o a p pl y t he st u d y dr u g, ie, b y c o m pletel y c o v eri n g t he tar g et great t oe nail, i ncl u di n g t he 
t oe nail f ol ds, t oe nail be d, h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate (if 
o n yc h o m yc osis is prese nt). T he st u d y dr u g will be a p plie d t o eac h of t he ot her i nfecte d 
t oe nails i n a si milar ma n ner. 
 
9. 5  C o nc o mit a nt  Me dic ati o ns  
C o nc o mita nt me dicati o ns/t hera pies refer t o all me dicati o ns/t hera pies use d b y t he s u bject 
d uri n g t he st u d y. D uri n g t he c o urse of t h e st u d y, if a p pr o priate, e ver y atte m pt s h o ul d be 
ma de t o kee p t he d osi n g a n d re gi me n of c o nc o mit a nt me dicati o ns/t hera pies c o nsta nt, a n d a n y 
c ha n ge t o a m e dicati o n/t hera p y d uri n g t he st u d y m ust be rec or d e d. I nf or mati o n o n 
c o nc o mita nt me dicati o ns/t hera pies (i ncl u di n g i n dicati o n, d osi n g, a n d start  a n d st o p dates) 
will be rec or d e d i n t he s o urce d oc u m e nt a n d o n t h e a p pr o pri ate e C R F. All c o nc o mita nt 
me dicati o ns/t hera pies (i n cl u di n g f o ot care pr o d ucts) use d d uri n g t he st u d y will be rec or d e d 
u n der C o nc o mita nt Me dicati o ns.  
All pri or me dicati o ns (t h ose us e d wit hi n 3 0 da ys pri or t o t he Scree ni n g Visit) a n d pre vi o us 
a ntif u n gal me dicati o ns use d b y t he s u bject, i ncl u di n g a n y rece nt o ver -t h e-c o u nter t o pical 
treat me nts (t h ose use d wit hi n 6 0 da ys pri or t o t he Scree ni n g Visit) will be rec or de d u n d er 
Pri or a n d C o nc o mita nt Me dicati o ns i n t he e C R F (e g, as piri n, aceta mi n o p he n, birt h c o ntr ol 
pills, vita mi ns, her bal pr o d ucts, h o me o pat hic pre parati o ns).  
D uri n g t he st u d y, all f o ot care pr o d ucts use d b y t h e s u bject will be rec or de d u n der Pri or a n d 
C o nc o mita nt Me dicati o ns.  
9. 5. 1  A ll o we d Me dic ati o ns/ T her a pies  
C o nc o mita nt me dicati o ns ( prescri pti o n or o ver -t h e-c o u nter) t hat are c o nsi d ere d necessar y f or 
t he s u bject's welfare a n d d o n ot i nterfere wit h st u d y assess me nts a n d e v al uati o ns will be 
all o we d d uri n g t he st u d y at t he i n vesti gat or's discreti o n. 
If, d uri n g t he st u d y, a s u bject re q uires t o pical a ntif u n gal t hera p y f or ti nea p e dis, t he 
i n vesti gat or is t o d oc u me nt t he pr o ble m a n d t he i n vesti gat or-a p pr o v e d treat me nt o n t he A E 
a n d c o nc o mita nt t her a p y e C R Fs, res pecti vel y, a n d t o e ns ure t hat t he s u bject a v oi ds 
a p plicati o n of t he c o n c o mita nt t hera p y t o t he t oe nails or a djace nt s urr o u n di n g s ki n s urface.  
9. 5. 2  Pr o hi bite d  Me dic ati o ns/ T her a pies  
N o t o pical treat me nts/ pr o d ucts will be all o we d o n t he t oes or feet ot her t ha n t he st u d y dr u g 
d uri n g t he st u d y, e xce pt f or i n vesti gat or -a p pr o v e d treat me nts. T he s u bject ma y use a n y 
t o pical a ntif u n gal t hera p y t he I n v esti gat or a p pr o v es f or use. Us e of t he f oll o wi n g t o pical 
treat me nts is pr o hi bite d wit hi n t he i n dicate d ti me pri or t o t he Baseli ne Visit: 
 
C li nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber 0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
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T oe nail p olis h or c os metic t oe nail pr o d ucts  
1 da y  
Ot her t o pical pr escri pti o n or o ver -t he-c o u nter me dicati o ns t o t he t oe nails 
( wit h t he e xce pti o n of bl a n d e m ollie nts) 
2 wee ks  
T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t o e nails, 
i ncl u di n g de vices use d t o treat o n yc h o m yc osis 
4 wee ks  
 
Use of t he f oll o wi n g s yst e mic me dicati o ns is pr o hi bite d wit hi n t he i n dicate d ti me pri or t o t he 
Baseli ne Visit a n d f or t he d urati o n of t he st u d y:  
S yste mic a ntif u n gal t hera p y  
4 wee ks  
S yste mic i m m u n os u p pressi ve a ge nts  
6 m o nt hs  
 
I n a d diti o n, use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 h alf-li ves 
( w hic he ver is l o n ger) pri or t o t he Scree ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her 
cli nical st u d y wit h a n i n vesti gati o nal dr u g or de vice d uri n g t he st u d y peri o d is n ot all o we d.  
If a s pecific me dicati o n/t hera p y has t h e p ote ntial t o i nterfere wit h t he treat me nt effect of t he 
st u d y dr ug or i nter pretati o n of t he st u d y res ults, t he i n vesti gat or s h o ul d c o ntact t he me dical 
m o nit or pri or t o use (if p ossi ble).  
A n y s u bject usi n g a pr o hi bite d t hera p y d uri n g t he c o urse of t he st u d y t hat c o ul d i nterfere 
wit h t he treat me nt effect of t he st u d y dr u g  or i nter pretati o n of t he st u d y res ults (i ncl u di n g, 
b ut n ot li mite d t o, t h ose liste d a b o ve) ma y b e wit h dra w n fr o m t he st u d y at t he discreti o n of 
t he i n vesti gat or a n d/ or s p o ns or. H o we ver, t he i n vesti gat or s h o ul d n ot wit h dra w a s u bject 
wit h o ut first c o nfir mi n g it wit h t he s p o ns or.  
 
9. 6  Pr ot oc ol D e vi ati o ns a n d  Vi ol ati o ns  
A de viati o n fr o m t he pr ot oc ol is a n u ni nte n de d a n d/ or u na ntici pate d de p art ure fr o m t he 
pr oce d ur es a n d/ or pr ocesses a p pr o ve d b y t h e s p o ns or a n d t he i nstit uti o nal re vie w b oar d 
(I R B) or i n de pe n d e nt et hics c o m mittee (I E C) a n d a gree d t o b y t he i n v esti gat or. De viati o ns 
us uall y ha ve a n i m pact o n i n di vi d ual s u bjects or a s mall gr o u p of s u bjects a n d d o n ot i n v ol ve 
i ncl usi o n/e xcl usi o n or pri mar y e n d p oi nt criteri a. 
A pr ot oc ol vi olati o n occ urs w he n t here is n o na d h ere nce t o t he pr ot oc ol t hat res ults i n a 
si g nifica nt, a d diti o nal ris k t o t he s u bject, w he n t he s u bject or i n vesti gat or h as faile d t o a d h ere 
t o si g nifica nt pr ot oc ol re q uire me nts (i ncl usi o n/e x cl usi o n criteria) a n d t he s u bject was 
e nr olle d wi t h o ut pri or s p o ns or a p pr o val, or w he n t here is n o na d here nce t o U S F o o d a n d Dr u g 
A d mi nistrati o n re g ulati o ns a n d/ or I nter n ati o nal C o nfere n ce o n H ar m o nisati o n (I C H) G o o d 
Cli nical Practice ( G C P)  g ui deli ne.  
 
 
 
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C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
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T he i n vesti gat or or desi g nee m ust rec or d a n d e x pl ai n i n t he s u bjects' s o urce d oc u me ntati o n 
a n y de viati o n fr o m t he a p pr o ve d pr ot oc ol. T he i n vesti gat or ma y i m ple me nt a de viati o n fr o m, 
or a c ha n g e of, t he pr ot oc ol t o eli mi nate a n i m me diate hazar d t o st u d y s u bjects wit h o ut pri or 
I R B/I E C a p pr o v al. As s o o n as p ossi ble after s u c h a n occ urre n ce, t he i m ple me nte d de viati o n 
or c ha n ge, t h e reas o ns f or it, a n d a n y pr o p ose d pr ot oc ol a me n d me nt(s) s h o ul d be s u b mitte d 
t o t he s p o ns or f or a gr ee m e nt, t o t he I R B/I E C f or re vie w a n d a p pr o val, a n d t o t he re g ulat or y 
a ut h orities, if re q uire d.  
 
1 0  St u d y Dr u g M ateri als a n d  M a n a ge me nt  
T he st u d y dr u g will be pr o vi de d t o t he i n vesti gati o nal ce nters b y t h e s p o ns or a n d will be 
dis pe nse d t o t he s u bject a n d t heir pare nt/le g al g uar dia n b y t he p har mac y or a n a p pr o pri atel y 
q ualifie d me m ber of t h e st u d y staff assi g ne d b y t h e i n vesti gat or.  
All la b orat or y kits c o ntai ni n g materials necess ar y t o c ollect bl o o d a n d uri ne f or r o uti ne 
cli nical la b orat or y test s, uri ne pre g n a nc y t ests, f u n gal c ult ures, a n d P K a n al yses will be 
s u p plie d t o t he i n vesti gati o nal ce nters b y t he d esi g nate d ce ntral la b orat ories. 
 
1 0. 1  St u d y  Dr u g  
A descri pti o n of t he st u d y dr u g is i ncl u de d i n Ta ble 2.  
T a ble  2.  
St u d y Dr u g I de ntific ati o n 
 
 
I n vesti g ati o n al Pr o d uct 
Dr u g Na me  
Efi nac o naz ole 1 0 % s ol uti o n f or t o pical a d mi nistrati o n  
Na me of Acti ve I n gre die nt  
Efi nac o naz ole  
Ma n ufact urer  
Valea nt P har mace uticals  
C he mical Na me  
( 2 R, 3 R)-2 -( 2, 4-difl u or o p he n yl) -3 -( 4-met h yle ne pi peri di n -1 - 
yl) -1 -( 1 H-1, 2, 4 -triaz ol-1 -yl) b uta n -2 -ol  
C he mical F or m ula/ M olec ular Wei g ht  
C 1 8H 2 2F 2N 4O / 3 4 8. 3 9 a m u  
T hera pe utic Cate g or y  
A ntif u n gal  
A p peara nce  
Clear t o yell o w s ol uti o n  
I nacti ve I n gre die nts 
Alc o h ol, a n h y dr o us citric aci d, b ut ylate d h y dr o x yt ol ue ne, 
C 1 2 -1 5 al k yl lactate, c ycl o met hic o ne, diis o pr o p yl a di pate, 
dis o di u m e detate, a n d p urifie d water.  
 
1 0. 1. 1  P ac k a gi n g a n d  L a beli n g  
Efi nac o naz ole will be pr o vi de d t o t he i n vesti gati o nal ce nters i n 1 0 m L b ottles c o ntai ni n g 
8 m L of st u d y dr u g per b ottle. I n di vi d ual b ottles will be s u p plie d t o t he i n vesti gati o nal 
ce nter. T h e s u bjects a n d t heir par e nts/le gal g uar dia ns will be dis pe nse d 1 b ottle at t he  
Baseli ne Visit a n d 1 b ott le at eac h s u bse q ue nt st u d y visit t hr o u g h Wee k 4 4. S u bjects i n t he 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
3 6  
 
 
 
 
P K s u bset will be dis pe nse d 2 b ottles of st u d y dr u g at t he Baseli ne Visit, a n d will be 
dis pe nse d o ne b ottle of st u d y dr u g at eac h s u bse q u e nt st u d y visit t hr o u g h Wee k 4 4.  
T he la bel o n eac h b ottle of st u d y dr u g will i de ntif y t he pr o d uct as " Efi nac o naz ole". T he la b el 
o n t he st u d y dr u g b ottles will c o ntai n t he f oll o wi n g i nf or mati o n:  
•  Pr ot oc ol n u m ber  
•  Kit  n u m ber  
•  Pr o d uct i de ntificati o n ( Efi nac o naz ole 1 0 %  S ol uti o n)  
•  S u bject  n u m ber   
 
•  S u bject  i nitials  
 
•  Date  dis pe nse d    
 
•  A state me nt i n dicati n g t he v ol u me of t he c o nte nts as 8  m L  
•  I nstr u cti o ns t o kee p b ottle ti g htl y cl ose d a n d st ore i n a n u pri g ht p ositi o n at r o o m 
te m perat ur e ( 2 0° C t o 2 5° C [ 6 8º F t o 7 7º F]), wit h e xc ursi o ns per mitte d bet w ee n 
1 5º C a n d 3 0º C ( 5 9º F a n d  8 6º F)  
•  L ot n u m ber/e x pirati o n  date  
•  S p o ns or na me a n d  a d dress  
•  A state me nt i n dicati n g, " Ca uti o n: Ne w Dr u g - Li mite d b y Fe deral La w  t o 
I n v esti gati o nal Use" 
•  A  state me nt i n dicati n g t hat t he dr u g  s h o ul d b e  ke pt  o ut  of  reac h of  c hil dre n 
A d diti o nal i nf or mati o n ma y be i ncl u de d o n t he b ottle la bel as  necessar y.  
1 0. 1. 2  St or a ge, H a n dli n g, a n d Dis p os al of St u d y  Dr u g  
St u d y dr u g s h o ul d be st ore d i n a sec ure area at t he i n vesti gati o nal ce nter acc or di n g t o l ocal 
re g ulati o ns, i n a n u pri g ht p ositi o n at c o ntr olle d r o o m te m perat ure ( 2 0° C t o 2 5° C [ 6 8º F t o 
7 7º F]), wit h e x c ursi o ns p er mitte d bet wee n 1 5° C a n d 3 0º C ( 5 9º F a n d 8 6º F).  
S u bjects a n d t heir par e nts/le gal  g uar dia ns will be i nstr ucte d t o kee p t heir st u d y dr u g b ottle at 
r o o m te m perat ur e, o ut of t he reac h of c hil dre n, n ot t o s hare t he st u d y dr u g wit h a n y o ne else, 
a n d t o use it o nl y o n t he affecte d t oe n ails as direct e d b y t he i n vesti gat or. S u bjects a n d t heir 
p are nts/le gal g uar dia ns will be as ke d t o n otif y t he i n vesti gati o nal ce nter i m me diatel y if a 
st u d y dr u g b ottle is da ma ge d or l ost. 
All use d a n d u n use d st u d y dr u g s u p plies will be ret ur ne d t o t he s p o ns or f or destr ucti o n.  
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
3 7  
 
 
 
 
1 0. 1. 3  St u d y Dr u g  Pre p ar ati o n  
N ot a p plica ble; s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will a p pl y t he st u d y dr u g 
directl y fr o m t he st u d y dr u g b ottles.  
 
1 0. 2  St u d y Dr u g  Acc o u nt a bilit y  
T he I n vesti gat or or d esi g nee will be res p o nsi ble f or kee pi n g c urre nt a n d acc urate rec or ds of 
t he a m o u nt of st u d y dr u g recei v e d a n d dis pe nse d, a n d its dis p ositi o n. T he st u d y dr u g m ust be 
st ore d u n der t he a p pr o pri ate c o n diti o ns i n a sec ure area a n d is t o be dis pe ns e d o nl y t o 
s u bjects e nr olle d i n t he st u d y, i n acc or d a nce wit h t he c o n diti o ns s pecifie d i n t his pr ot oc ol. 
D uri n g t he c o urs e of t he st u d y, t he I n v esti gat or or desi g nee m ust mai ntai n a n i n ve nt or y of all 
st u d y dr u g dis pe nse d t o or ret ur ne d b y t h e s u bject, incl u di n g s u bject i de ntifiers.  
A st u d y dr u g acc o u nt a bilit y l o g will be c o m plete d b y t he i n vesti gat or or desi g nee t o 
d oc u me nt t he recei pt, dis pe nsati o n, a n d ret ur n of st u d y dr u g b ottles.  
All s u p plies se nt t o t he I n vesti gat ors will be acc o u nte d f or a n d, i n n o  case, use d i n a n y 
u na ut h orize d sit uati o n. B ottles will be wei g he d ( wit h t he ca p o n) bef ore dis pe nsi n g t o a n d 
u p o n ret ur n b y t he s u bjects, a n d wei g hts will be rec or de d o n t he p h ar mac y l o g a n d 
a p pr o priate C R F. All use d a n d u n use d s u p plies will be ret ur ne d t o s p o ns or/ desi g nee f or 
destr ucti o n at t he c o n cl usi o n of t he st u d y.  
 
1 1  St u d y Pr oce d ures a n d  E v al u ati o ns  
1 1. 1  Sc he d ule of E v al u ati o ns a n d  Pr oce d ures  
All s u bject i nf or mati o n a n d data o btai ne d d uri n g t he st u d y visit pr oce d ures m ust be rec or d e d 
i n t he s o urce d oc u m e nts, a p plica ble st u d y l o gs, a n d e C R Fs.  
1 1. 1. 1  Scree ni n g Visit ( Visit 1, U p t o D a y  -4 2)  
After si g ni n g t he i nf or me d c o nse nt/asse nt, s u bjects will u n der g o t he scree ni n g pr oce d ures t o 
c o nfir m eli gi bilit y t o partici pate i n t he st u d y.  
T he f oll o wi n g pr oce d ures wil l be c o n d ucte d at t his visit: 
1.  Re vie w a n d e x plai n t he n at ure of t he st u d y. Pr o vi d e a visit sc he d ule wit h t h e 
le n gt h of eac h visit t o e ns ure t hat t he s u bject ca n meet t he re q uire me nts a n d has 
a de q uate  tra ns p ortati o n. 
2.  O btai n ver bal a n d writte n i nf or me d c o nse n t/asse nt fr o m t he s u bject a n d t he 
s u bject's pare nt(s) or le gal g uar dia n(s) pri or t o perf or mi n g a n y st u d y-relate d 
pr oce d ur es. Pr o vi de si g n e d c o pies of t he c o nse nt a n d asse nt f or ms t o t he 
s u bject/ pare nt(s) or le gal g uar dia n(s).  
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
3 8  
 
 
 
 
3.  O btai n p h ot o gra p h y c o ns e nt/asse nt fr o m s u bject a n d/ or t he s u bject's pare nt(s) or 
le gal g uar dia n(s).  
4.  Assi g n a 6 -di git st u d y n u m ber, w hic h i ncl u d es t he 3 -di git i n vesti gati o nal ce nter 
n u m ber pl us a u ni q ue 3 -di git s u bject n u m ber be gi n ni n g wit h 0 0 1 (e g, 0 0 1 -0 0 1, 
0 0 1 -0 0 2, 0 0 1 -0 0 3). N u m bers m ust be assi g ne d i n c hr o n ol o gical  or der.  
5.  Rec or d s u bject's de m o gr a p hic i nf or mati o n (se x, d ate of birt h, a g e, et h nicit y,  a n d 
race). 
6.  Rec or d s u bject's me dical hist or y i ncl u di n g dia betes  hist or y.  
7.  C ollect a detaile d hist or y of o n yc h o m yc osis, i ncl u di n g a n esti mate d start date of 
i nfecti o n, d urati o n  of  c urre nt  i nfecti o n i n t he p ote ntial  tar get great  t oe n ail, a n d all 
pre vi o us t hera pies us e d f or o n yc h o m yc osis  treat m e nt. 
8.  Re vie w all pri or me dicati o ns (t h ose use d wit hi n 3 0 da ys pri or t o t he Scree ni n g 
Visit) a n d pre vi o us a ntif u n gal me dicati o ns use d b y t he s u bject, i ncl u di n g a n y 
rece nt o v er-t he-c o u nter t o pical treat me nts (t h ose use d wit hi n 6 0 da ys pri or t o t he 
Scree ni n g  Visit).  
9.  Re vie w i ncl usi o n/e xcl usi o n  criteria.  
1 0.  E xa mi nati o n  of  t oe nails f or cli nical prese n ce  of  o n yc h o m yc osis  i n at least 1  great 
t oe nail, wit hi n t he defi niti o n of eli gi bilit y criteria. F or s u bjects i n t he P K 
p o p ulati o n, b ot h great t oe nails a n d 4 ot her t oe n ails m ust meet eli gi bilit y  criteria  
1 1.  E xa mi nati o n of all ot her t oe nails f or pres e nce or a bse nce of o n y c h o m yc osis o n 
eac h t o e nail. 
1 2.  E xa mi nati o n of b ot h feet f or pres e nce of s y m pt o matic ti nea pe dis; treat as 
a p pr o priate usi n g i n vesti gat or a p pr o v e d t o pical a ntif u n gal  t hera p y 
1 3.  Cli p t he t oe nails ( bef ore perf or mi n g nail meas ure me nts). Re mi n d s u bject a n d t heir 
pare nt/le gal g uar dia n n ot t o cli p t oe nails at h o me i n bet wee n  visits.  
1 4.  Perf or m t he i n vesti gat or's assess me nt of t he great t oe nail(s) wit h a  calc ulati o n of 
t he perce nta ge of t oe nail affecte d wit h diseas e, aft er cli p pi n g t he u n healt h y t oe nail. 
If t he great t oe nail has b ee n cli p pe d pr o xi mal t o t he distal gr o o ve, t he e ntire area t o 
t he distal gr o o ve s h o ul d be i ncl u de d. T he i n vesti g at or/e val uat or will use a fi ne 
ti p pe d mar ker t o o utli ne t he area affecte d o n t he tar get great t oe nail (t his is 
o pti o nal at t his visit si nce p h ot o gra p h y is n ot d o ne at t his visit; o utli ni n g s h o ul d be 
d o ne if be neficial t o perf or mi n g  assess me nts).  
•  S u bjects n ot i ncl u de d i n t he P K s u bset m ust ha ve at least 1 great t oe nail 
wit h 2 2 0 % i n v ol ve me nt  
•  S u bjects i ncl u de d i n t he P K s u bset m ust ha ve b ot h great t oe nails  i n v ol ve d 
wit h 2 5 0 % i n v ol ve me nt i n eac h great t oe nail.  
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
3 9  
 
 
 
 
1 5.  O btai n s peci me n fr o m t h e great t oe n ail(s) t o s hi p t o t he m yc ol o g y la b. B ot h great 
t oe nails ma y be sa m ple d if b ot h are s us pecte d of ma nifesti n g o n yc h o m yc osis (at 
least 2 0 % i n v ol ve me nt). 
1 6.  Perf or m a uri n e pre g n a nc y test 1 f or all F O C B P.2 E xcl u de t he s u bject if t he 
pre g na nc y t est res ult is  p ositi ve.  
Uri ne pre g n a ncy testi n g is m a n d at ory f or all F O C B P at t he Scree ni n g Visit, 
B aseli ne Visit, a n d at all s u bse q ue nt st u dy visits. T he decisi o n m ay be m a de by 
t he i nvesti g at or t o d o a d diti o n al uri ne pre g n a ncy tests d uri n g t he c o urse of t he 
st u dy. 
1 7.  C ollect bl o o d a n d uri ne sa m ples f or r o uti ne safet y la b orat or y a n al ysis 
( he mat ol o g y, ser u m c h e mistr y, a n d uri nal ysis). Pr ocess a n d s hi p t he s a m ples t o t he 
ce ntral safet y la b or at or y per i nstr u cti o ns pr o vi de d i n t he la b orat or y  m a n ual.  
N ote: C ollecti o n of Scree ni n g s afety l a bs m ay be p ost p o ne d u ntil after p ositive 
Scree ni n g myc ol o gy res ults are receive d, o nly if  t he s u bject/ p are nt are willi n g t o 
ret ur n t o t he rese arc h site f or s afety l a b c ollectio n pri or t o t he e n d of t he 4 2 -d ay 
scree ni n g wi n d o w. Scree ni n g s afety l a b res ults m ust be receive d wit hi n t he 4 2- 
d ay scree ni n g visit wi n d o w.  
1 8.  Sc he d ule s u bject t o ret ur n f or t he Baseli ne Visit ( Visit 2, Da y  1).  
If a s u bject f ails scree ni n g, eit her at t he Scree ni n g or B aseli ne visit ( pri or t o 
e nr oll me nt t o tre at me nt), t he s u bject m ay be rescree ne d at a l ater d ate. S u bjects 
w h o are rescree ne d will be assi g ne d a ne w scree ni n g n u m ber, m ust be re - 
c o nse nte d, a n d u n der g o all scree ni n g pr oce d ures per pr ot oc ol . 
1 1. 1. 2  B asel i ne Visit ( Visit 2, D a y 1) 
If t he Baseli ne Visit is m ore t ha n 4 2 da ys after t h e Scree ni n g Visit, t he s u bject m ust be 
re p orte d as a scr ee n fail ure a n d t he n ma y b e rescree ne d ( wit h a ne w s u bject n u m ber) at t he 
i n vesti gat or's discreti o n. 
 
 
 
 
 
1 Uri ne pre g na nc y tests m ust ha ve a mi ni m u m se nsiti vit y of 2 5 mI U of h u ma n c h ori o nic g o na d otr o pi n per m L 
of uri ne. Uri ne pre g na nc y test kits will be pr o vi de d b y t he s p o ns or.  
 
2 F O C B P i ncl u de a n y fe male s u bjects w h o ha ve e x perie nce d me narc he a n d w h o ha ve n ot u n der g o ne s uccessf ul 
s ur gical sterilizati o n ( h ysterect o m y, bilateral t u bal li gati o n, or bilateral o o p h orect o m y) or are n ot 
p ost me n o pa usal ( defi ne d as a me n orr hea f or > 1 2 c o nsec uti ve m o nt hs or w o me n o n h or m o ne re place me nt 
t hera p y wit h d oc u me nte d plas ma f ollicle-sti m ulati n g h or m o ne le vels > 3 5 m L U/ m L). E ve n a fe male s u bject 
w h o is usi n g a n oral, i m pla nte d, i njecta ble, or tra ns der mal c o ntrace pti ve h or m o ne, a n i ntra uteri ne de vice, a 
c o n d o m wit h s per mici de, or a dia p hra g m wit h s per mici de t o pre ve nt pre g na nc y, or is pr actici n g a bsti ne nce, 
s h o ul d be c o nsi dere d of c hil d beari n g p ote ntial. 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 0  
 
 
 
 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bjects a n d t he ir pare nts/le gal g uar dia ns, " Are t here a n y 
c ha n ges i n y o ur h ealt h si nce t he last  visit?").  
2.  C o nfir m p ositi ve K O H a n d c ult ure res ults fr o m t h e ce ntral m yc ol o g y  la b orat or y. 
•  All s u bjects (i ncl u di n g t h ose i n P K s u bset) m ust ha ve at least 1 great t oe n ail 
wit h p o siti ve K O H ( perf or me d at ce ntral m yc ol o g y la b) a n d p ositi ve 
der mat o p h yte c ult ure f or T r u br u m or T  me nt a gr o p hytes.  
3.  Re vie w t he saf et y la b orat or y test  res ults. 
If a ny s afety l a b or at ory test res ults o bt ai ne d at t he Scree ni n g Visit, are a b n or m al 
a n d cli nic ally si g nific a nt as deter mi ne d by t he i n vesti g at or, t he i nvesti g at or 
s h o ul d disc uss wit h t he me dic al m o nit or w het her it is i n t he s u bject's best i nterest 
t o p artici p ate i n t he st u dy. 
4.  C o nfir m t he s u bject's me dical hist or y a n d pri or m e dicati o n  uses.  
5.  Re vie w  all c o nc o mita nt  me dicati o ns  a n d  ne w  me dicati o ns  starte d si nce t he last 
st u d y visit.  
6.  O btai n vital si g n meas ure me nts. Vital si g ns will be meas ure d after t he s u bj ect is 
seate d f or at least 5  mi n utes,  a n d will  i ncl u de s yst olic a n d diast olic  bl o o d  press ure, 
p ulse rate, r es pirat or y r at e, a n d oral b o d y  te m perat ure. 
7.  Meas ure h ei g ht a n d  wei g ht.  
8.  C o n d uct  a n a b bre vi ate d  p h ysical  e xa mi nati o n  (e xcl u di n g ur o ge nital/re pr o d u cti ve 
s yste ms). 
9.  Perf or m  a uri ne  pr e g na n c y  test f or all F O C B P.  E xcl u de  t he s u bject if t he 
pre g na nc y t est res ult is  p ositi ve.  
1 0.  Cli p  t he t oe nails t o t he distal  gr o o ve  ( b ef ore perf or mi n g  t oe nail meas ure me nts  a n d 
cl ose-u p  p h ot o gra p h y).  
1 1.  C o n d uct t he i n vesti gat or's assess me nt of t he great t oe nail (s), wit h a deter mi nati o n 
of t he per ce nta g e of t oe n a il affecte d wit h diseas e. Meas ure t he dista n ce fr o m t he 
pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
•  S u bjects n ot i ncl u de d i n t he P K s u bset m ust ha ve at least 1 great  t oe nail 
wit h 2 2 0 % i n v ol ve me nt  
•  S u bjects i ncl u de d i n t he P K s u bset m ust ha ve b ot h great t oe nails  i n v ol ve d 
wit h 2 5 0 % i n v ol ve me nt i n eac h great t oe nail.  
1 2.  Select tar get gr eat t oe nail i n eac h eli gi ble s u bject f or efficac y assess me nts. W here 
b ot h great t oe nails ar e st u d y -eli gi ble (i ncl u di n g perce nt i n v ol ve me nt, K O H - 
p ositi ve, a n d c ult ure -p ositi ve res ults), t he t oe nail wit h t he greater perce nt affect e d 
area at t he Baseli ne Visit will be selecte d as t h e tar get great t oe nail pri or  t o 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 1  
 
 
 
 
e nr oll me nt i n t he treat me nt peri o d. I n t he i nsta nce w here t he p erce nt affecte d area 
is t he sa me f or b ot h st u d y-eli gi ble great t oe n ails at t he Baseli ne Visit, t he 
i n vesti gat or ma y c h o ose eit her great t oe nail t o be t he tar get great t oe nail. 
1 3.  I ns cri be a tr a ns vers e n otc h  i n t he great  t oe nail at t he pr o xi mal  nail  f ol d wit h  a file 
or scal pel. T his will be use d as a mar ker at s u bse q ue nt visits f or deter mi ni n g ne w 
t oe nail gr o wt h.  
1 4.  Perf or m t he i n vesti gat or's assess me nt of t he n o ntar get t oe nails f or t h e pres e nce or 
a bse nce of o n y c h o m yc osis. S u bjects i n t he P K s u bset m ust ha ve at l east 4 t oe nails 
ot her t ha n t he gr eat t oe nails wit h  o n yc h o m yc osis.  
1 5.  Ta ke  cl ose -u p  p h ot o gra p hs  of  t he tar get great  t oe n ail. T he  first p h ot o gra p h  will  be 
ta ke n after t oe nail cli p pi n g. After t hat p h ot o gra p h is ta ke n, t he 
i n vesti gat or/e val uat or will use a fi ne ti p pe d mar k er t o o utli ne t he area affecte d o n 
t he tar get gr eat t oe nail. W he n t he mar k er i n k has drie d, a sec o n d cl ose-u p 
p h ot o gra p h will be  ta ke n. 
1 6.  Re vie w i ncl usi o n/e xcl usi o n criteria. If t he s u bject c o nti n ues t o meet all i ncl usi o n 
criteria a n d n o ne of t he e xcl usi o n criteria, e nr oll t he s u bject i n t he treat me nt 
peri o d.  
1 7.  O btai n 1 b ottle of st u d y dr u g a n d wei g h t he b ottle. Rec or d t he assi g ne d b ottle 
n u m ber f or t he st u d y dr u g i n  t he s u bject's s o urce d oc u me nt a n d o n t he a p pr o priate 
e C R F. Dis pe nse t he b ottl e t o t he s u bject a n d t heir pare nt/le gal g uar dia n (c o m plete 
t he la bel a n d r e q uire d r ec or ds). F or s u bj ects i n t he P K s u bset, 2 b ottles of st u d y 
dr u g s h o ul d be o btai ne d. T he b ottles  s h o ul d be wei g he d se paratel y a n d rec or de d 
as se par ate e ntri es, as des cri be d  a b o v e.  
1 8.  I nstr u ct t he s u bject a n d t heir pare nt/le gal g uar dia n o n diar y c o m pleti o n a n d 
dis pe nse  diar y.  
1 9.  T he s u bject or t heir p are nt/le gal g uar dia n will a p pl y t he first d ose of st u d y d r u g i n 
t he i n vesti gati o nal ce nter. I nstr u ct t he s u bject a n d t heir pare nt/le gal g u ar dia n i n t he 
pr o per a p plicati o n tec h ni q ue f or t he st u d y dr u g a n d pr o vi de t he a p pr o priate S u bject 
I nstr u cti o n S heet wit h d osi n g i nstr ucti o ns (ie, f or n o n-P K or P K s u bjects), 
d e pe n di n g o n w het her t he s u bject is e nr olle d i n t h e P K s u bset. Rec or d a n y A Es 
f oll o wi n g t he i nitial treat me nt a p plicati o n. 
2 0.  Rec or d l ocal s ki n r eacti o ns. I nstr u ct t he s u bject a n d t heir pare nt/le gal g u ar dia n t o 
re p ort l ocal s ki n r eacti o ns (if a n y) at eac h st u dy  visit.  
2 1.  Sc he d ule t he ne xt st u d y visit ( Visit 3 [ Wee k 4, D a y 2 8]) i n 2 8 da ys ( ± 5  da ys).  
N ote: ( ± 5 d ays) o nly a p plies t o N o n -P K s u bjects, P K s u bset o nly h as a ( ± 1 d ay) 
visit wi n d o w 
•  F or s u bjects i n t he P K s u bset, Visit 3 ( Wee k 4, D a y 2 8) t o Visit 3 A ( Wee k 
4, Da y 2 9) r e mi n d s u bjects n ot t o a p pl y st u d y dr u g t he ni g ht pri or t o t heir 
Visit 3 ( Wee k 4, D a y 2 8)  visit.  
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 2  
 
 
 
 
1 1. 1. 3  Visit 3 ( Wee k 4, D a y 2 8 [ ± 5 d a ys]), Visit 4 ( Wee k 8 [ ± 5 d a ys]), Visit 6 ( Wee k 1 6 
[ ± 5 d a ys]), Visit 7 ( Wee k 2 0 [ ± 5 d a ys]), Visit 9 ( Wee k 2 8 [ ± 5 d a ys]), Visit 1 0 
( Wee k 3 2 [ ± 5 d a ys]), Visit 1 2 ( Wee k 4 0 [ ± 5 d a ys]), Visit 1 3 ( Wee k 4 4 [ ± 5 d a ys])  
Visits are t o be sc he d ul e d i n refer e nce t o Visit 2 ( Baseli n e). 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bjects a n d t heir pare nts/le gal g uar dia ns, " Are t here a n y 
c ha n ges i n y o ur h ealt h si nce t he last  visit?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d par e nt/le gal g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he t oe nails.  
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse n otc h). If t he m ost rece ntl y a p plie d n ot c h h as 
gr o w n o ut or has bee n cli p pe d off, i nscri b e a ne w n otc h a djace nt t o t he pr o xi mal 
nail f ol d.  
6.  C ollect t he diar y a n d st u d y dr u g b ottle fr o m t he s u bject a n d/ or t heir pare nt/le gal 
g uar dia n. Wei g h t he use d b ottle of t he st u d y dr u g. Rec or d t he n u m ber of misse d 
d oses fr o m t he s u bject di ar y a n d re vie w c o m plia nce wit h t he s u bject. 
7.  C o n d uct  a uri ne  pre g na n c y  test o n  F O C B P  s u bjects ( disc o nti n ue a n y s u bject fr o m 
t he st u d y w h o has a p ositi ve test res ult) 
8.  O btai n  1  b ottle  of  st u d y dr u g  a n d w ei g h  t he b ottle,  c o m plete t he l a bel a n d dr u g  l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d t heir p are nt/le gal g uar dia n. Re vie w t he 
d osi n g i nstr ucti o ns wit h t he s u bject. ( S u bjects i n t he P K s u bset will n ot be 
dis pe nse d st u d y dr u g t his  da y).  
9.  Dis pe nse diar y. ( S u bjects i n t he P K s u bset will n ot be  dis pe nse d a diar y t his  da y.)  
1 0.  Sc he d ule t he ne xt st u d y  visit.  
F or s u bjects i n t he P K s u bset at Visit 3 o nl y: 
•  C ollect a pre d ose bl o o d s a m ple after all ot her st u d y pr oce d ures are  c o m plete d. 
•  A p pl y t he st u d y dr u g t o all 1 0 t oe nails at t he i n vesti gati o nal ce nter wit hi n 1 h o ur 
after c ollecti n g t he pre d ose bl o o d  sa m ple. 
•  C ollect p ost d ose bl o o d sa m ples at a p pr o xi matel y 2 h o urs ( ± 5 mi n), 4 h o urs 
( ± 5 mi n), a n d 1 2 h o urs ( ± 1 5 mi n) after st u d y dr u g a p plicati o n. 
•  I nstr u ct t he s u bject t o ret ur n t he f oll o wi n g m or ni n g f or t heir 2 4-h o ur bl o o d 
sa m ple ( Visit 3 A ( Da y 2 9). S u bject will n ot d ose o n t he e ve ni n g of D a y 2 8.  
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 3  
 
 
 
 
1 1. 1. 4  Visit  3 A  ( W ee k 4,  D a y  2 9)  - A d diti o n al  Visit  f or S u bjects  i n t h e P K  S u bset  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject " Are t here a n y c ha n ges i n y o ur  healt h?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he  s u bject. 
3.  Re vie w c o nc o mita nt  m e dicati o ns. 
4.  C ollect a bl o o d sa m ple 2 4 h o urs ( ± 3 0 mi n) after st u d y dr u g a p plicati o n at Visit  3.  
5.  O btai n  1  b ottle  of  st u d y dr u g  a n d wei g h  t he b ottle,  c o m plete t he l a bel a n d dr u g  l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d t heir p are nt/le gal g uar dia n. Re vie w t he 
ne w d osi n g i nstr ucti o ns wit h t he s u bject (a p plicati o n t o o nl y t he tar get great 
t oe nail a n d t o a n y ot her affect e d t oe nails) a n d pr o vi de a c o p y of n e w d osi n g 
i nstr ucti o ns t o t he s u bject. 
6.  Dis pe nse a ne w diar y t hat i ncl u des t he ne w d osi n g  i nstr ucti o ns. 
1 1. 1. 5  Sc he d ule t he P K s u bset s u bject f or t he ne xt st u d y visit. Visit 5 ( Wee k 1 2 [ ± 5 
d a ys]), Visit 8 ( Wee k 2 4 [ ± 5 d a ys]), Visit 1 1 ( W ee k 3 6 [ ± 5  d a ys])  
Visits are t o be sc he d ul e d i n refere nce t o Visit 2 ( Baseli ne).  
T he f oll o wi n g pr oce d ures will be  c o n d ucte d at t hese visits:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n " Are t here a n y 
c ha n ges i n y o ur h ealt h si nce t he last  visit?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  C o n d uct a uri ne pre g n a n c y test o n F O C B P s u bjects ( disc o nti n ue a n y s u bject fr o m 
t he st u d y w h o has a p ositi ve test res ult). 
5.  Cli p t he t oe nails.  
6.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse n otc h). If t he m ost rece ntl y a p plie d n ot c h h as 
gr o w n o ut or has bee n cli p pe d off, i nscri b e a ne w n otc h a djace nt t o t he pr o xi mal 
nail f ol d.  
7.  C o n d uct t he i n vesti gat or's assess me nt of t he tar g et great t oe nail, wit h a 
deter mi nat i o n of  t he p erce nta ge  of  t oe nail affecte d  wit h  disease.  Meas ure  t he 
dista nce fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
8.  Perf or m t he i n vesti gat or's assess me nt of t he n o ntar get t oe nails f or t he prese nce  or  
a bse nce of o n yc h o m yc osis.  
 
 
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 4  
 
 
 
 
9.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b per i nstr ucti o ns pr o vi de d i n t he 
la b orat or y m a n ual.  
1 0.  O btai n vital si g n meas ure me nts. Vital si g ns will be meas ure d after t he s u bj ect is 
seate d f or at least 5  mi n ut es  a n d will  i ncl u de s yst olic a n d diast olic  bl o o d  press ure, 
p ulse rate, r es pirat or y r at e, a n d oral b o d y  te m perat ure. 
1 1.  At Visit 8/ Wee k 2 4 o nl y : Ta ke cl ose-u p p h ot o gra p hs of t he tar get great t oe n ail. 
T he first p h ot o gra p h will be ta ke n after t oe n ail cli p pi n g. After t hat p h ot o gra p h is 
ta ke n, t he i n vesti gat or/e v al uat or will use a fi ne ti p pe d mar ker t o o utli ne t he area 
affecte d o n  t he tar get great t oe nail. W he n t he mar ker i n k has drie d, a sec o n d cl ose- 
u p p h ot o gra p h will be  ta ke n. 
1 2.  C ollect t he diar y a n d st u d y dr u g b ottle fr o m t he s u bject a n d/ or t heir p are nt/le gal 
g uar dia n.  Wei g h  t he us e d  b ottle  of  t he st u d y dr u g.  Rec or d  t he n u m ber  of  misse d 
d oses fr o m t he s u bject di ar y a n d re vie w c o m plia nce wit h t he s u bject a n d 
pare nt/le gal  g u ar dia n.  
1 3.  O btai n  1  b ottle  of  st u d y dr u g  a n d wei g h  t he b ottle,  c o m plete t he l a bel a n d dr u g  l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d pare nt/le gal  g uar dia n.  
1 4.  Re vie w t he d osi n g i nstr ucti o ns wit h t he  s u bject. 
1 5.  Dis pe nse  diar y.  
1 6.  Sc he d ule t he s u bject f or t he Visit 6 ( Wee k 1 6 [ ± 5 da ys]) st u d y visit, a n d  i nstr uct 
t he s u bject t o ret ur n at t h e sa me ti me of da y as t he Baseli ne Visit. T he Visit 7 
( Wee k 2 0 [ ± 5 da ys]) a n d Visit 8 ( Wee k 2 4 [ ± 5 da ys]) st u d y visits will f oll o w 
Visit 6.  
1 1. 1. 6  Visit 1 4 ( Wee k 4 8 [ ± 5 d a ys]) / E arl y Ter mi n ati o n  Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n " Are t here a n y 
c ha n ges i n y o ur h ealt h si nce t he last  visit?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he t oe nails.  
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse n otc h). If t he m ost rece ntl y a p plie d n ot c h h as 
gr o w n o ut or has bee n cli p pe d off, i nscri b e a ne w n otc h a djace nt t o t he pr o xi mal 
nail f ol d.  
 
 
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 5  
 
 
 
 
6.  C o n d uct t he i n vesti gat or's assess me nt of t he tar g et great t oe nail, wit h a 
deter mi nati o n  of  t he p erce nta ge  of  t oe nail affecte d  wit h  disease.  Meas ure  t he 
dista nce fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
7.  Perf or m t he i n vesti gat or's assess me nt of t he n o ntar get t oe nails f or t he prese nce or 
a bse nce of o n yc h o m y c osis.  
8.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b per i nstr ucti o ns pr o vi de d i n t he 
la b orat or y m a n ual.  
9.  Ta ke  cl ose -u p  p h ot o gra p hs  of  t he tar get great  t oe n ail. T he  first p h ot o gra p h  will  be 
ta ke n after t oe nail cli p pi n g. After t hat p h ot o gra p h is ta ke n, t he 
i n vesti gat or/e val uat or will use a fi ne ti p pe d mar k er t o o utli ne t he area affecte d o n 
t he tar get gr eat t oe nail. W he n t he mar k er i n k has drie d, a sec o n d cl ose-u p 
p h ot o gra p h will be  ta ke n. 
1 0.  C o n d uct  a n a b bre vi ate d  p h ysical  e xa mi nati o n  (e xcl u di n g ur o ge nital/re pr o d u cti ve 
s yste ms). 
1 1.  Meas ure h ei g ht a n d  wei g ht  
1 2.  O btai n vital si g n meas ure me nts. Vital si g ns will be meas ure d after t he s u bj ect is 
seate d f or at least 5 mi n utes, a n d i ncl u de s yst olic a n d diast olic bl o o d press ure, 
p ulse rate, r es pirat or y r at e, a n d oral b o d y  te m perat ure. 
1 3.  C ollect t he diar y a n d st u d y dr u g b ot tle fr o m t he s u bject a n d/ or pare nt/le gal 
g uar dia n.  Wei g h  t he use d  b ottle  of  t he st u d y dr u g.  Rec or d  t he n u m ber  of  misse d 
d oses fr o m t he s u bject di ar y a n d re vie w c o m plia nce wit h t he s u bject a n d 
pare nt/le gal  g u ar dia n.  
1 4.  C o n d uct a uri ne pre g n a n c y test o n F O C B P s u bjects (if p ositi ve test res ult, t he 
s u bject s h o ul d ret ur n f or Visit 1 5 [ Wee k 5 2]  
1 5.  C ollect bl o o d a n d uri ne sa m ples f or r o uti ne safet y la b orat or y a n al ysis 
( he mat ol o g y, ser u m c h e mistr y, a n d uri nal ysis). Pr ocess a n d s hi p t he s a m ples t o t he 
ce ntral safet y la b or at or y per i nstr ucti o ns pr o vi de d i n t he la b orat or y  ma n u al.  
1 6.  If t his is t he Earl y Ter mi nati o n Visit, rec or d t he reas o n f or s u bject disc o nti n uati o n 
fr o m t he st u d y a n d c o m plete t he Wee k 4 8 e C R F. All ot her s u bjects s h o uld be 
sc he d ule d t o ret ur n f or t h e Visit 1 5 ( Wee k 5 2) st u d y visit.  
1 1. 1. 7  Visit 1 5 ( Wee k 5 2 [ ± 5 d a ys]) P ost -Tre at me nt F oll o w -u p Visit / St u d y  E xit  
F or all s u bjects w h o c o nti n ue t hr o u g h t he Wee k 4 8 visit, t his visit s h o ul d occ ur 4 w ee ks after 
t he last treat me nt visit. 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n, " Are t here a n y 
c ha n ges i n y o ur h ealt h si nce t he last  visit?").  
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5 , 2 0 1 6 
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 6  
 
 
 
 
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he t oe nails.  
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse  n otc h).  
6.  C o n d uct t he i n vesti gat or's assess me nt of t he tar g et great t oe nail, wit h a 
deter mi nati o n  of  t he p erce nta ge  of  t oe nail affecte d  wit h  disease.  Meas ure  t he 
dista nce fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or d er.  
7.  Perf or m t he i n vesti gat or's assess me nt of t he n o ntar get t oe nails f or t he prese nce  or  
a bse nce of o n yc h o m yc osis.  
8.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b p er i nstr ucti o ns pr o vi de d i n t he 
la b orat or y m a n ual.  
9.  Ta ke  cl ose -u p  p h ot o gra p hs  of  t he tar get great  t oe n ail. T he  first p h ot o gra p h  will  be 
ta ke n after t oe nail cli p pi n g. After t hat p h ot o gra p h is ta ke n, t he 
i n vesti gat or/e val uat or will use a fi ne ti p pe d mar k er t o o utli ne t he area affecte d o n 
t he tar get gr eat t oe nail. W he n t he mar k er i n k has drie d, a sec o n d cl ose-u p 
p h ot o gra p h will be  ta ke n. 
1 0.  C o n d uct a uri ne pre g n a n c y test o n F O C B P  s u bjects. 
1 1.  E xit t he s u bject fr o m t he  st u d y. 
1 1. 1. 8  U nsc he d ule d Visits  
A d diti o nal visits ma y be sc he d ule d, as n ecess ar y, t o e ns ure t he safet y a n d well -bei n g of 
s u bjects. All a d diti o nal e xa ms s h o ul d be f ull y d oc u me nte d i n t he s o urce d o c u me nts a n d o n 
U nsc he d ule d Visit e C R Fs, as a p pr o priat e. Visits i nte n de d t o f ulfill sc he d ul e d visit 
re q uire me nts t hat f all o utsi de t he desi g nate d sc h e d ule d visit ra n ge, are n ot u nsc he d ule d visits. 
I n t hes e cases, t he visit data will be c ollecte d a n d tra nscri be d t o t he a p pr o priate sc he d ul e d 
visit e C R F.  
1 1. 1. 9  Misse d Visits  
If a s u bject misses a n y s c he d ule d visit a n d ca n n ot be see n pri or t o t he st art of t he all o we d 
visit ra n ge f or t he n e xt sc he d ule d f oll o w -u p visit, t he visit is c o nsi dere d misse d.  
1 1. 1. 1 0  S u bject  C o m pleti o n  
A s u bject has c o m plete d t he st u d y w he n Visit 1 5 ( Wee k 5 2) h as bee n c o m plete d a n d t he 
s u bject has bee n e xite d fr o m t he st u d y. S u bjects w h o re q uire f urt her f oll o w-u p f or a n A E 
f oll o wi n g c o m pleti o n of t he st u d y will be f oll o we d acc or di n g t o Secti o n 1 2. 0. 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 7  
 
 
 
 
1 1. 2  St u d y E v al u ati o n s 
1 1. 2. 1  L oc al S ki n  Re acti o ns  
T olera bilit y will be e val u ate d t hr o u g h assess me nt of l ocal re d n ess, s welli n g, b ur ni n g, itc hi n g, 
a n d vesic ulati o n i n t he selecte d treat me nt areas o n t he t oes. Eac h si g n or s y m pt o m is t o be 
re vie we d wit h t he s u bjects a n d t heir pare nts/le g al g uar dia ns aft er t he first a p plicati o n of t he 
st u d y dr u g at t he Baseli ne Visit a n d at eac h f oll o w-u p visit t hr o u g h Wee k 5 2. T he s u bjects 
a n d t heir par e nts/le gal g u ar dia ns s h o ul d assess eac h reacti o n bas e d o n t he w orst reacti o n 
e x perie n ce d si nce t he pr i or visit usi n g t he f oll o wi n g scales: 
 
Re acti o n  
Sc ore  
Re d ness, S welli n g  
0 = N o ne  
1 = Mil d  
2 = M o derate  
3 = Se vere  
B ur ni n g, Itc hi n g, a n d Vesic ulati o n  
Yes or N o  
 
Occ urre nce of vesic ulati o n will al wa ys be re p orte d as a n A E. A n y ot her si g n or s y m pt o m 
will be re p orte d as a n A E o nl y if it re q uires c o n c o mita nt t hera p y or res ults i n a te m p orar y 
i nterr u pti o n or per ma n e nt disc o nti n uati o n of t he st u d y dr u g d ue t o disc o mf ort. 
1 1. 2. 2  Cli nic al L a b or at or y Tests  
Bl o o d a n d uri ne sa m ples will be c ollecte d f or r o uti ne safet y la b orat or y tests ( he mat ol o g y, 
ser u m c he mistr y, a n d uri nal ysis) at t he Scree ni n g a n d Wee k 4 8/ Earl y Ter mi nati o n visit. A n y 
s u bject wit h a scree ni n g la b orat or y a b n or malit y t hat is deter mi ne d b y t he i n vesti gat or t o be 
cli nicall y si g nifica nt m ust be a p pr o ve d f or i ncl usi o n i n t he st u d y b y t he me dical m o nit or. All 
res ults will be re p orte d, i ncl u di n g a b n or mal res ults. Cli nicall y si g nifica nt c ha n ges i n la b 
res ults fr o m Scree ni n g, i n t he o pi ni o n of t he i n vesti gat or, s h o ul d be re p orte d as A Es. 
Cli nicall y si g nifica nt  c ha n ges prese nt at Wee k 4 8/ Earl y Ter mi nati o n are t o be f oll o we d t o 
res ol uti o n or u ntil cli nicall y sta ble as deter mi ne d b y t he i n vesti gat or. If a n A E s h o ul d re q uire 
la b orat or y testi n g, t he r es ults of t he test m ust be o btai ne d b y t he i n vesti gati o nal ce nter a n d 
file d i n t he s u bject's d oc u me ntati o n. 
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nt ers b y t he s p o ns or 
or ce ntr al la b orat or y. I nstr ucti o ns f or pr o cessi n g a n d s hi p pi n g sa m ples t o t he ce ntral 
la b orat or y are c o nt ai ne d i n t he st u d y la b orat or y ma n ual. 
F or all F O C B P, uri ne pre g na nc y testi n g will be perf or me d at t he Scree ni n g a n d Baseli ne 
Visits, as well as at eac h s u bse q ue nt st u d y visit. F O C B P is defi ne d as a n y fe male s u bject w h o 
has e x peri e nce d m e nar c h e. T he r es ults at t he Scree ni n g a n d Baseli ne Visits m ust be ne gati ve  
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
4 8  
 
 
 
 
f or a s u bject t o e nt er t he st u d y. Materials f or pre g na nc y testi n g will be pr o vi de d t o t he 
i n vesti gati o nal ce nters b y t he s p o ns or or ce ntral la b orator y.  
1 1. 2. 3  Vit al Si g n  Me as ure m e nts  
Meas ure me nt of vital si g ns will be perf or me d at t he Baseli ne Visit, as well as at Wee ks 1 2, 
2 4, 3 6, a n d 4 8/ Earl y Ter mi nati o n. After t he s u bjects ha ve bee n sitti n g f or at least 5 mi n utes, 
s yst olic a n d diast olic bl o o d press ures, p ulse rates, res pirati o n rat es, a n d oral te m perat ures 
will be rec or d e d.  
1 1. 2. 4  P h ysic al  E x a mi n ati o ns  
A n a b bre viat e d p h ysical e xa mi nati o n will be perf or me d at t he Baseli ne Visit a n d at  
Wee k 4 8/ Earl y Ter mi nati o n. Hei g ht a n d wei g ht will be meas ure d at t he Bas eli ne V isit a n d at 
t he Wee k 4 8/ E arl y Ter mi nati o n Visit. 
1 1. 2. 5  Effic ac y f o r Assessi n g Tre at me nt C o m pli a nce a n d  S afet y  
Efficac y assess me nts will be perf or m e d t hr o u g h o ut t he st u d y. T he efficac y a nal yses will be 
base d o n micr osc o pic e x a mi nati o n a n d m yc ol o gical c ult ure res u lts f or t he t ar get great 
t oe nail, t he perce nt i n v ol ve me nt of t he tar g et great t oe nail, t he le n gt h of t he u naffecte d p art 
of t he tar get gr eat t oe n ail, t he gr o wt h of t he tar g et great t oe nail, a n d t h e n u m ber of affecte d 
n o ntar get t oe nails.  
I n v esti gat ors/e val uat ors will be trai ne d b y t he s p o ns or t o e ns ure c o nsiste n c y acr oss 
i n vesti gati o nal ce nters r e gar di n g t oe nail cli p pi n g, e val uati o ns a n d meas ure me nts, as well as 
c ollecti o n of s uffici e nt material f or K O H e xa mi nati o ns a n d f u n gal c ult ures. E v al uat ors m ust 
be pre -a p pr o ve d b y t he s p o ns or a n d m ust ha ve a p pr o priate d oc u m e nte d e x perie nce a n d 
trai ni n g, or ha ve a wai ver o btai ne d fr o m t he s p o ns or base d o n e x p erie n ce ( or t hr o u g h 
a d diti o nal trai ni n g or ga nize d b y t he s p o ns or).  
E ver y eff ort s h o ul d be ma de  t o ha v e t he sa m e s p o ns or-a p pr o v e d e v al uat or perf or m t he tar get 
great t oe n ail assess me nts a n d meas ure m e nts f or a partic ular s u bject at t he Baseli ne Visit a n d 
eac h f oll o w -u p visit.  
1 1. 2. 5. 1  K O H E x a mi n ati o n a n d F u n g al  C ult uri n g  
T he K O H e xa mi nati o n a n d f u n gal c ult uri n g of t oe nail scra pi n g a n d s u b u n g ual de bris will be 
perf or me d f or st u d y -eli gi ble great t oe n ail(s) at t he Scree ni n g Visit a n d f or t he tar get great 
t oe nail o nl y (as deter mi n e d at t he Baseli ne Visit) at Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y Ter mi nati o n, 
a n d 5 2 (t he 4 -w ee k p ost -treat me nt f oll o w-u p) st u d y visits. At t he Scree ni n g visit, s peci me ns 
f or K O H a n d f u n gal c ult ures ar e o btai ne d fr o m st u d y-eli gi ble great t oe n ails at t his visit a n d 
se nt t o t he ce ntral m yc ol o g y la b orat or y f or testi n g. 
 
 
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T oe nail s peci me ns will b e ta ke n b y cli p pi n g t he t o e nail t o t he p oi nt of attac h me nt (re m o vi n g 
u n healt h y nail) a n d o btai ni n g a n y cr u m bli n g s u b u n g ual de bris fr o m u n der t he distal e d ge of 
t he tar get gr eat t oe nail usi n g a dis p osa ble c urette. All tar get great t oe nail plate cli p pi n gs a n d 
" distal" s u b u n g ual de bris s h o ul d be discar de d. O nl y t he s oft nail be d kerati n be neat h t he 
cli p pe d e d ge of t h e nail s h o ul d be c ollecte d a n d use d as a s peci m e n f or b ot h t he K O H 
e xa mi nati o n a n d t he f u n g al c ult ure. Caref ul s peci me n c ollecti o n i n t his ma n ner will mi ni mize 
t oe nail s peci me n c o nta mi na nts a n d ma xi mize der mat o p h ytic pat h o ge n is olati o n. 
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gat i o nal ce nt ers b y t he s p o ns or 
or ce ntr al m yc ol o g y la b orat or y. I nstr ucti o ns f or pr ocessi n g a n d s hi p pi n g sa m ples t o t he 
ce ntral la b orat or y are c o ntai ne d i n t he st u d y la b orat or y ma n ual.  
1 1. 2. 5. 2  T ar get Gre at T oe n ail  Assess me nts  
T he per ce nt of t he aff ect e d t oe nail area a n d h ealt h y ( u naffecte d) t oe nail meas ure me nts f or 
t he tar get gr eat t oe nail will be e val uate d b y t he i n v esti gat or/e val uat or at t he Scree ni n g a n d 
Baseli ne Visits, a n d at Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y Ter mi nati o n, a n d 5 2 (t he 4-wee k p ost - 
treat me nt f oll o w-u p) st u d y visits.  
Perce nt of Affecte d Tar g et Great T o e nail Area  
T he aff ecte d ar ea of t he t oe nail will be esti mate d as t he perce nt of t oe nail area ( nail a n d n ail 
be d) i n v ol ve d (t he distal mar gi n f or deter mi ni n g area will b e t he distal gr o o ve after t he 
t oe nail has bee n cli p pe d). 
Healt h y ( U naffecte d) T ar get Great T o e nail Meas ure me nt a n d Gr o wt h  
T he healt h y ( u n aff ecte d) t oe nail meas ure m e nt will be defi ne d as t he dista nce (i n m m) 
bet wee n t he pr o xi mal nail f ol d a n d a tra ns verse l i n e o n t he healt h y part of t he t oe nail 
i m me diatel y pr o xi mal t o t he nail i nfecti o n. At eac h e val uati o n, t his dista nce will be meas ure d 
fr o m t he pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic b or der. 
T oe nail gr o wt h will be m eas ure d b y i ns cri bi n g a tra ns ver se n otc h i n t he nail of t he tar get 
great t oe nail a dj ace nt t o t he pr o xi mal nail f ol d at t he ce nter of t he n ail at t he Baseli ne Visit, 
a n d meas uri n g nail gr o wt h fr o m t hat p oi nt f or war d. At e ver y s u bse q u e nt visit, t he dista nce 
(i n m m) bet wee n t he pr o xi mal nail f ol d a n d t he n otc h will be meas ure d a n d rec or d e d. T he 
n otc h s h o ul d be e n ha nce d as nee de d at s u bse q ue nt visits t o all o w c o nti n ue d meas ure me nt of 
t oe nail gr o wt h o ver t he c o urse of t he st u d y. If t h e i nitiall y a p plie d n otc h i nscri be d at t he 
Baseli ne Visit ha s gr o w n o ut or is cli p pe d a wa y, i nscri be a n e w n otc h i n t h e t oe nail a djace nt 
t o t he pr o xi mal nail f ol d, a n d c o nti n ue wit h meas ure me nts usi n g t he ne w n otc h. 
 
 
 
 
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1 1. 2. 5. 3  N o nt ar get T oe n ail  Assess me nt  
A n assess me nt of b ot h feet will be ma de f or assessi n g t he prese nce or a bs e nce of 
o n yc h o m yc osis of n o ntar get t oe nails at t he Scree ni n g, Baseli ne, Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y 
Ter mi nati o n, a n d 5 2 (t he 4 -wee k p ost -treat me nt f oll o w-u p) st u d y visits. All n o ntar get 
t oe nails will be assesse d f or t he pres e nce or a bs e n ce of o n yc h o m y c osis. S u bjects i n t he P K 
s u bset m ust prese nt wit h o n yc h o m yc osis o n at least 4 t oe nails besi des t he great t oe nails.  
1 1. 2. 6  E v al u ati o n of P h ar m ac o ki netics  
T he P K assess me nts will be perf or me d o n a s u bs et of t he st u d y p o p ulati o n w h o will recei ve 
treat me nt u n der m a xi mal use c o n diti o ns f or 2 8 da ys. Plas ma sa m ples f or d eter mi nati o n of 
efi nac o n az ole a n d meta b olite le vels will be c ollecte d at t he f oll o wi n g ti me p oi nts:  
•  Visit 3 ( Da y 2 8): Pre d ose (after all Da y 2 8 pr o ce d ures are c o m plete d). St u d y dr u g 
m ust be a p plie d wit hi n 1 h o ur after t h e pre d os e sa m ple is c ollecte d. Sa m ples are 
t he n c ollecte d at 2 ( ± 5 mi n), a n d at 4 ( ± 5 mi n), a n d at 1 2 ( ± 1 5 mi n) h o urs 
p ost d ose.  
•  Visi t 3 A ( Da y 2 9): 2 4 ( ± 3 0 mi n) h o urs after Da y 2 8 st u d y dr u g a p plicati o n. 
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nt ers b y t he s p o ns or 
or ce ntr al la b orat or y. I nstr ucti o ns f or pr o cessi n g a n d s hi p pi n g sa m ples t o t he bi oa nal yti cal 
la b orat or y are c o nt ai ne d i n t he st u d y la b orat or y ma n ual. 
1 1. 2. 7  P h ot o gr a p h y  
At all i n vesti gati o nal ce nters, cl ose -u p p h ot o gra p hs of t he tar get great t oe n ail will be ta ke n at 
t he Baseli ne, Wee ks 2 4, 4 8/ Earl y Ter mi nati o n, a n d 5 2 (t he 4-wee k p ost -treat me nt f oll ow -u p) 
st u d y visits. O ne p h ot o gra p h will be ta ke n after t o e nail cli p pi n g. After t he first p h ot o gra p h 
has bee n ta k e n, t he i n vesti gat or/e val uat or will use a fi ne ti p pe d mar k er t o o utli ne t he area 
affecte d o n t he tar get great t oe nail. After t h e i n k has drie d, a sec o n d p h ot o gra p h will be 
ta ke n. T he c ollecte d p h ot o gra p hs will be use d f or d oc u me ntati o n p ur p oses o nl y a n d will n ot 
be use d f or d eter mi nati o ns of eli gi bilit y, efficac y, or a n y st u d y -rel ate d acti vities. Bef ore 
p h ot o gra p hs ar e ta ke n, t h e st u d y s u bject a n d  t heir pare nt(s)/le g al g uar dia n(s) m ust 
c o nse nt/asse nt t o p h ot o gr a p h y. If t he p h ot o gra p h y c o nse nt/asse nt is decli ne d, t he s u bject 
ma y still partici pate i n t he  st u d y. 
 
1 1. 3  Defi niti o n of A d verse E ve nts  
A n A E is a n y u nt o war d me dical occ urre n ce i n a s u bject or cli nical i n vesti g ati o n s u bject 
a d mi nistere d a me dici nal pr o d uct a n d w hic h d o es n ot necessaril y ha v e a ca usal relati o ns hi p 
wit h t he st u d y dr u g. T h us, A Es i ncl u de a n y u nfa v ora ble a n d u ni nte n d e d ill ness, si g n,  
 
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s y m pt o m, cli nicall y si g nifica nt la b orat or y test a b n or malit y, or disease te m p orall y ass ociate d 
wit h t he use of a me dici n al pr o d uct t hat has a p p eare d or w orse ne d d uri n g t he c o urse of t he 
cli nical st u d y, re gar dl e ss of ca usal relati o ns hi p t o t he st u d y dr u g(s) u n der st u d y. T he 
c ollecti o n of n o nseri o us A Es a n d seri o us a d v erse e ve nts ( S A Es) s h o ul d be gi n f oll o wi n g t he 
s u bject's c o m pleti o n of t he c o nse nt/asse nt pr o cess t o partici pate i n t he st u d y. 
1 1. 3. 1. 1  Defi niti o n of Seri o us A d verse  E ve nts  
All A Es will be assesse d as eit her seri o us or n o nseri o us. A n S A E or seri o us a d verse reacti o n 
is defi ne d as a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose: 
•  Res ults i n  deat h.  
•  Is i m me diatel y life t hr eat e ni n g, (t he ter m "life t hreate ni n g" i n the defi niti o n of 
"seri o us" refers t o a n e v e nt i n w hic h t he s u bject is at ris k of deat h at t he ti m e of 
t he e ve nt; it d oes n ot refer t o a n e ve nt w hic h h y p ot heticall y mi g ht ha ve ca us e d 
deat h if it wer e m ore  se v ere). 
•  Re q uires i n s u bject h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
( h os pitalizati o n f or electi ve s ur ger y f or a bas eli ne  c o n diti o n is n ot  c o nsi dere d  a n 
A E).  
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y ( per m a ne nt or  s u bst a 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).  
•  Is a c o n ge nital a n o mal y/ birt h defect. 
•  Is a me dicall y i m p orta nt e ve nt t hat ma y n ot be i m me diatel y life t hreat e ni n g or 
res ult i n deat h or h os pitalizati o n, b ut ma y je o par di ze t he s u bject a n d ma y re q uire 
me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he a b o ve liste d o utc o mes.  
I m p ort a nt me dical e v e nts t hat ma y n ot ha ve res ult e d i n deat h, be life-t hreate ni n g, or 
re q uire h os pitalizati o n m a y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate 
me dical j u d g me nt, t he y ma y je o par dize t he s u bject a n d ma y re q uire me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o m es liste d i n t his defi niti o n. 
E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m re q uiri n g i nte nsi ve 
treat me nt i n a n e mer ge nc y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o 
n ot res ult i n i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n d e nc y or dr u g 
a b use.  
H os pitalizati o n is a criteri o n f or assess me nt of seri o us ness. T o q ualif y as seri o us u n der t he 
criteria of " h os pitalizati o n," a h os pital a d missi o n of at least a 2 4 -h o ur peri o d is re q uire d. If a 
s u bject is retai ne d t he e mer ge nc y r o o m greater t ha n 2 4 h o urs, b ut n ot a d mitte d f or me dical  
 
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care, t h ese cases s h o ul d be e val uat e d i n di vi d uall y, as criteria s u c h as " me dicall y si g nifica nt" 
ma y als o a p pl y.  
H os pitalizati o n  wit h o ut  a me dical  A E  s h o ul d n ot  b e  c o nsi dere d  eit her seri o us or  a n A E. 
E xa m ples i ncl u de:  
•  A d missi o n  f or  treat me nt  of  a  pre -e xisti n g  c o n diti o n  n ot  ass ociate d  wit h  t he  
de vel o p me nt of a ne w A E or wit h w ors e ni n g of t he pre -e xisti n g c o n diti o n (e g, f or 
w or k -u p of p ersiste nt pre -treat me nt la b a b n or m alit y).  
•  H os pitalizati o n f or a p ur p ose u nrel ate d t o t h e st u d y (e g, " pla n ne d" or ele cti ve s ur ger y 
sc he d ule d  pri or  t o  st u d y  partici pati o n)  w o ul d  n ot  or di naril y  nee d  t o  be  re p orte d,  
u nless  a  c o m plicati o n  occ urre d  w hi c h  ot her wise  ca us e d  pr ol o n gati o n  of  t his  
h os pitalizati o n.  
•  Pr ot oc ol -s pecifie d a d missi o n or pr oce d ure (e g, cataract s ur ger y re q uire d b y a st u d y 
pr ot oc ol; or o ver ni g ht sta y f or m o nit ori n g d ue t o pr ot oc ol re q uire d s ur ger y, wit h n o 
ass oci ate d S A E or c o m plic ati o n necessit ati n g pr ol o n ge d st ay ) 
•  S ocial a d missi o n (e g, s ocial h os pitalizati o n f or p ur p oses of res pite  care)  
N ote: A s p o nta ne o us  a b orti o n will be c o nsi dere d a n S A E, a n d m ust be re p orte d t o t he 
s p o ns or wit hi n 2 4 h o urs of y o ur a w are n ess of t he e ve nt. 
1 1. 3. 1. 2  Assess m e nt of  Se verit y  
T he se verit y assi g ne d t o a n A E s h o ul d be deter mi ne d b y t he ma xi m u m se verit y of t he A E. 
T he cate g ories des cri be d bel o w s h o ul d be use d t o esti mate t he se verit y of A Es:  
•  Mil d: Tra nsie nt or mil d disc o mf ort; n o li mitati o n i n acti vit y; n o  me dical 
i nter ve nti o n/t hera p y re q uire d. 
•  M o derate: Mil d t o m o derate li mitati o n i n acti vit y; s o me assista nce ma y  be 
nee de d; n o or mi ni mal me dical i nter ve nti o n/t hera p y  re q uire d. 
•  Se vere: Mar k e d li mitati o n i n acti vit y; s o me assista nce us uall y re q uire d; m e dical 
i nter ve nti o n/t hera p y r e q uire d; h os pitalizati o n or pr ol o n gati o n of c urre nt 
h os pitalizati o n p ossi ble; ma y be i nca p acitati n g or life t hreate ni n g. 
1 1. 3. 1. 3  Assess m e nt of  C a us alit y  
T he i n vesti gat or s h o ul d assess t he relati o ns hi p of t he A E, if a n y, t o t he st u d y dr u g as eit her  
" Relate d" or " N ot Relate d". 
•  Rel ate d: T here is at least a reas o na ble p ossi bilit y t hat t he A E/ S A E is re late d t o t he 
st u d y dr u g. Reas o n a ble p ossi bilit y mea ns t hat t here is e vi de n ce t o s u g gest a ca usal 
relati o ns hi p bet wee n t h e dr u g a n d t he A E.  
 
 
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•  N ot R el ate d: T her e is lit tle or n o reas o na ble p ossi bilit y t hat t he A E/ S A E is relate d t o 
t he st u d y dr u g. T his ass ess me nt i m plies t hat t he A E/ S A E has little or n o te m p oral 
relati o ns hi p t o t he st u d y dr u g a n d/ or a m ore li kel y or certai n alter n ati ve eti ol o g y 
e xists. 
T he f oll o wi n g s h o ul d be ta ke n i nt o acc o u nt w h e n assessi n g A E/ S A E ca usalit y:  
•  P ositi ve te m p oral relati o ns hi p t o st u d y dr u g, s uc h as if t he st u d y dr u g was 
wit h dra w n  a n d t he S A E  res ol ve d or  t he e ve nt rec urre d after re i ntr o d ucti o n. 
•  If t here is a  reas o na ble p ossi bilit y  t hat t he A E  is ass ociate d  wit h  a n u n derl yi n g  or 
c o nc o mita nt ill ness.  
•  P ossi ble ass ociati o n wit h pre vi o us or c o n c o mita nt  t hera p y. 
•  N o  te m p oral r elati o ns hi p t o t he st u d y dr u g  a n d/ or a m ore  li kel y alter nati ve 
eti ol o g y e xists. 
•  If t he A E is directl y relat e d t o st u d y pr oce d ures or t here is a lac k of efficac y. 
1 1. 3. 1. 4  Pr oce d ures f or R e p orti n g A d verse E ve nts a n d Seri o us A d verse  E ve nts  
T he peri o d of o bs er vati o n f or c ollecti o n of A Es e xte n ds fr o m t he ti me t he s u bject a n d 
pare nt/le gal g uar dia n gi v es i nf or me d c o ns e nt/asse nt u n til t he last st u d y visit or 
disc o nti n uati o n fr o m t he st u d y. T he first c o ncer n will be t he safet y of t he s u bject, a n d 
a p pr o priate m e dical i nter ve nti o n will be ma de.  
T he I n vesti gat or or d esi g nee will elicit re p orts (ie, via direct q uesti o ni n g, o bser vati o n, 
cli nical e val uati o n) of A Es fr o m t he s u bject at eac h st u d y visit a n d rec or d all A Es. T he 
I n v esti gat or will d oc u me nt t he dates of o nset, pr o gress, o utc o me, a n d res ol uti o n of s uc h A Es. 
T he I n vesti gat or will als o pr o vi de a n ass ess me nt of all A Es as t o t he se ve rit y, ca usal 
relati o ns hi p t o st u d y dr u g, a n d ca usal relati o ns hi p t o st u d y pr ot oc ol.  
It is t he i n vesti gat or's r es p o nsi bilit y t o d oc u me nt all A Es t hat occ ur d uri n g t he st u d y. T he 
A Es s h o ul d be d oc u me nt e d as a si n gle me dical dia g n osis. W he n t his is n ot p ossi b le, t he A E 
s h o ul d be d oc u me nte d i n ter ms of si g ns a n d/ or s y m pt o ms o bser ve d b y t he i n vesti gat or or 
re p orte d b y t he s u bject a n d/ or t heir pare nt/le g al g uar dia n at eac h st u d y visit. 
All A Es occ urri n g after t he s u bject a n d t heir p are nt/le gal g uar dia n si g ns t he asse nt/i nf or me d 
c o nse nt t hr o u g h t he last st u d y visit m ust be re p orte d, re gar dl ess of w het h er or n ot t he A Es 
are c o nsi d ere d dr u g -r elat e d. All A Es, w het her i n res p o nse t o a q uer y, o bser ve d b y t he st u d y 
site pers o n nel, or r e p orte d s p o nta ne o usl y b y t he s u bject a n d/ or t heir p are nt/le gal g uar dia n, 
will be rec or d e d.  
 
 
 
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At eac h visit d uri n g t he st u d y, t he s u bject will be assesse d f or t h e occ urre n ce of ne w a n d 
o n g oi n g A Es. C uta ne o us t olera bilit y si g ns a n d s y m pt o ms t hat res ult i n t he s u bject's re q uiri n g 
a c o nc o mita nt t her a p y or disc o nti n uati o n fr o m t he st u d y will be re p orte d as a n A E. T he 
f oll o wi n g data will be c ollecte d o n all A Es a n d rec or de d o n t he a p pr o priat e e C R F: 
•  E ve nt na me ( dia g n osis preferre d, if u n k n o w n, rec or d t he si g ns/s y m pt o ms).  
•  O nset date a n d e n d  date.  
•  Ma xi m u m i nte nsit y  (se verit y). 
•  Seri o us ness.  
•  Acti o n ta ke n re g ar di n g st u d y dr u g.  
•  C orrecti ve tr eat me nt, if  gi ve n. 
•  O utc o me.  
I n a d diti o n, t he i n vesti gat or's assess me nt of ca usalit y will be rec or d e d.  
A n y S A E m ust be re p ort e d t o t he S p o ns or, i n de pe n de nt of t he circ u msta nce or s us pecte d 
ca use, wit hi n 2 4 h o urs fr o m t he ti me t he e ve nt was re p orte d t o t he I n v esti gat or. All S A Es 
e x perie n ce d fr o m t he dat e of c o nse nt t hr o u g h at least 3 0 da ys after t he last d ose of st u d y dr u g 
m ust be re p orte d t o t he S p o ns or re gar dless of t he relati o ns hi p t o t he st u d y dr u g or t he 
pr ot oc ol. F or e ve nts occ urri n g be y o n d t he mi ni m u m 3 0- da y peri o d after t he last d ose of 
st u d y dr u g, or f or a n y ti mefra me after war d d ee m e d me dicall y si g nifica nt, o nl y S A Es 
c o nsi dere d r elate d t o t he st u d y dr u g s h o ul d be re p orte d pr o m ptl y t o t he S p o ns or.  
Wit hi n 2 4 h o urs of n otificati o n t he I n vesti gat or will fa x or e mail a c o m plete d Seri o us 
A d verse E v e nt Re p ort t o t he S p o ns or:  
M e d Trials Safet y: 
Fa x: 
 
* * Please f oll o w u p wit h a n e mail n otificati o n t o 
 t o c o nfir m t he fa xe d s u b missi o n. 
 
I n v esti gat ors s h o ul d n ot wait t o recei v e a d diti o nal i nf or mati o n t o d oc u me nt t he e ve nt bef ore 
n otif yi n g t he s p o ns or of a n S A E. If o nl y li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w- u p 
re p orts ar e re q uire d. If t he I n vesti gat or bec o mes a ware of a n y ne w i nf or mati o n re gar di n g a 
S A E (ie, res ol uti o n, c ha n ge i n c o n diti o n, or ne w treat me nt), a n e w S A E F or m m ust be 
c o m plete d a n d f a xe d/e m aile d t o t he S p o ns or wit hi n 2 4 h o urs. T he ori gi nal S A E f or m is n ot 
t o be altere d. T h e re p ort s h o ul d be mar ke d as a "f oll o w- u p re p ort" a n d d escri be w het h er t he 
e ve nt has r es ol ve d or c o nti n ues a n d h o w t he e ve nt was treat e d. A d diti o nal rele va nt  
 
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i nf or mati o n s uc h as h os pital rec or ds a n d a ut o ps y re p orts s h o ul d be pr o vi de d t o t he s p o ns or as 
s o o n as t he y ar e a vaila bl e. 
S h o ul d t he i n vesti gat or bec o me a ware of a n S A E (re gar dless of its relati o ns hi p t o 
i n vesti gati o nal pr o d uct) t hat occ urs wit hi n 3 0 da ys after st o p pi n g t he st u d y dr u g, t he S A E 
m ust be re p orte d i n acc or da nce wit h pr o ce d ures s p ecifie d i n t hi s pr ot oc ol. 
T he i n vesti gat or s h o ul d ta ke all a p pr o priate meas ures t o e ns ure t h e safet y of t he s u bjects, 
n ota bl y he/s he s h o ul d f oll o w a s u bject wit h a n S A E u ntil t he e ve nt has res ol ve d or t he 
c o n diti o n has sta bilize d. T his ma y i m pl y t hat f oll o w -u p will c o nti n ue after t he s u bject has 
left t he st u d y, a n d t hat a d diti o nal i n vesti gati o ns ma y be re q u este d b y t he s p o ns or. 
1 1. 3. 1. 5  S u b mitti n g a n E x pe dite d S afet y Re p ort t o t he I R B ( Ce ntr al or  L oc al)  
A n y s us pecte d u ne x p ecte d seri o us a d vers e reacti o n ( S U S A R) warra nts e x p e di te d re p orti n g. 
I n a d diti o n, a n y u ne x pecte d S A E relate d t o a s u bject's partici pati o n i n t he st u d y ( or c o n d uct 
of st u d y), re gar dless if t h e st u d y dr u g was a d mi nistere d, will be e v al uate d b y Gl o bal 
P har mac o vi gila nce a n d Ris k Ma na ge me nt ( G P R M) t o deter mi ne if e x p e dite d re p orti n g is 
re q uire d. F or e xa m ple, a n u ne x pecte d, s eri o us a n d se vere reacti o n w hic h c o ul d be ass ociate d 
t o t he st u d y pr oce d ures, a n d w hic h c o ul d m o dif y t he st u d y c o n d uct re q uires e x pe dite d 
re p orti n g. Eac h e x pe dite d safet y re p ort will r o uti nel y incl u de a brief c o v er me m ora n d u m, t he 
c o m plete d Me d Watc h F or m F D A 3 5 0 0 A or C o u ncil f or I nter n ati o nal Or ga nizati o ns of 
Me dical Scie nces I F or m, a cli nical a nal ysis of t he e ve nt wit h a n y si milar e ve nts t hat ha ve 
occ urr e d wit h t he pr o d uct, a n d a n y a d diti o nal p erti ne nt i nf or mati o n rec o m me n de d b y t he 
st u d y Me dical M o nit or. O nce t he r e p ort is c o m pile d b y G P R M, t he site I n v esti gat or m ust 
s u b mit t he e x pe dite d safet y re p ort t o t he l ocal I R B/ E C wit hi n t he re q uire d re p orti n g 
ti mefra me. F oll o w-u p re p orts s h o ul d be s u b mi tte d w he n re q u este d or w h e n perti ne nt 
i nf or mati o n bec o mes a v aila ble. T he site pri nci pal I n v esti gat or m ust retai n a c o m plete c o p y of 
eac h e x pe dite d safet y re p ort as it was s u b mitte d t o t he I R B. It is i m p orta nt t hat t he pri nci pal 
I n v esti gat or re vi e w t hese e xpe dite d re p orts, as t he y c o ntai n safet y i nf or mati o n t hat ma y be 
rele va nt t o eac h of t he partici pati n g s u bjects. 
1 1. 3. 2  Pre g n a nc y  
All fe male s u bjects of c hil d beari n g p ote ntial m ust use a n effecti ve m et h o d of birt h c o ntr ol 
d uri n g t he c o urse of t he st u d y, i n a ma n ne r s uc h t h at ris k of c o ntrace pti ve fail ure is 
mi ni mize d. A bsti ne nce is all o we d as a birt h c o ntr ol met h o d.  
Bef ore e nr olli n g a fe mal e s u bject of c hil d beari n g p ote ntial i n t his cli nical st u d y, t he 
i n vesti gat or m ust re vie w t he f oll o wi n g i nf or mati o n a b o ut st u d y partici pati o n:  
•  I nf or me d c o ns e nt/asse nt re q uire me nts. 
 
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•  C o ntrace pti ves i n c urre nt use.  
F oll o wi n g re vie w of t his i nf or mati o n a n d a p pr o priate c o u nseli n g f or t h e s u bject a n d t heir 
pare nt/le gal g uar dia n, t he i n vesti gat or or desi g nee a n d t he s u bject a n d p are nt/le gal g uar dia n 
m ust si g n t he asse nt/i nf or me d c o nse nt bef ore st u d y e nr oll me nt.  
D uri n g t he st u d y, all fe m ale s u bjects of c hil d beari n g p ote ntial s h o ul d be i nstr uc te d t o c o ntact 
t he i n vesti gat or i m me diatel y if t he y s us pect t he y mi g ht be pre g na nt (e g, misse d or late 
me nstr ual peri o d).  
If a s u bject or i n vesti gat or s us pects t hat t he s u bject ma y be pre g n a nt pri or t o st u d y 
e nr oll me nt, t he st u d y dr u g m ust be wit h hel d u nti l t he res ults of la b orat or y pre g na nc y t esti n g 
are a v aila ble. If pre g n a nc y is c o nfir me d, t he s u bject m ust n ot recei ve st u d y dr u g a n d m ust 
n ot be e nr olle d i n t he st u d y. If pre g n a nc y is s us pecte d w hile t he s u bject is recei vi n g st u d y 
treat me nt, t he st u d y dr u g m ust i m me diatel y be wit h hel d u ntil t he res ult of pre g na nc y t esti n g 
is k n o w n. If pre g n a nc y is c o nfir me d, t he st u d y dr u g will be per ma ne ntl y dis c o nti n ue d a n d t he 
s u bject will be f oll o we d u ntil t he pre g na nc y c o m es t o ter m. A Pre g na nc y R e p ort f or m will be 
s u b mitte d t o t he s p o ns or, i nitiall y a n d at t he e n d of t he pre g n a nc y, w hic h i n cl u des t he 
o utc o me of t he pr e g na nc y a n d a n y c o m plicati o ns occ urri n g d uri n g t he pre g na nc y or t he 
deli ver y.  
 
1 2  St atistics  
1 2. 1  Assess m e nt of  S afet y  
1 2. 1. 1  A d verse  E ve nts  
All A Es t hat occ ur d uri n g t he st u d y will be rec or d e d a n d classifie d usi n g t h e Me dical 
Dicti o nar y f or Re g ul at or y Acti vities ( Me d D R A). Treat me nt -e mer ge nt a d v erse e v e nts 
( T E A Es) are t h ose A Es wit h a n o nset o n or after t he date of first st u d y dr u g a p plicati o n. All 
T E A Es will be s u m marize d b y t he n u m ber of s u bj ects re p orti n g eac h T E A E, t he ass ociate d 
s yste m or ga n class a n d preferre d t er m, t he se v erit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he 
safet y, P K, a n d n o n-P K p o p ulati o ns. Eac h s u bject will be c o u nte d o nl y o nce wit hi n a s yste m 
or ga n class or a pr eferre d ter m usi n g t he e ve nt wit h t he greatest se v erit y or ca usalit y, 
res pecti vel y, wit hi n eac h cate g or y. 
All S A Es will be s u m marize d b y t he n u m ber of s u bjects re p orti n g eac h S A E, t he ass ociate d 
s yste m or ga n class a n d preferre d t er m, t he se v erit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he 
safet y, P K, a n d n o n-P K p o p ulati o ns.  
All i nf or mati o n pertai ni n g t o A Es n ote d d uri n g t he st u d y will be liste d b y s u bject a n d will 
i ncl u de t he ver b ati m ter m gi ve n b y t he i n vesti gat or, t he ass ociate d s yste m or ga n class a n d 
 
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preferre d t er m, t he start a n d st o p (if st o p pe d) dates, t he seri o us ness, a n d t he se verit y of t he 
e ve nt. A d diti o nal l y, a n y acti o n ta ke n wit h t he st u d y dr u g, a n y c orrecti ve treat me nt 
a d mi nistere d, t he o utc o m e, a n d t he relati o ns hi p t o st u d y dr u g as well as a list of s u bjects w h o 
pre mat urel y disc o nti n ue fr o m t he st u d y d ue t o a n A E will be pr o vi de d.  
1 2. 1. 2  L oc al S ki n  Re acti o ns  
L o cal s ki n reacti o n sc ores (re d ness, s w elli n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) at eac h visit 
will be s u m marize d usi n g fre q ue n c y ta bles f or t he safet y, P K, a n d n o n -P K p o p ulati o ns.  
A d diti o nall y, re d ness a n d s welli n g se verit y sc ores will be s u m marize d usi n g  descri pti ve 
statistics ( mea n, sta n dar d de viati o n [ S D], me dia n, a n d mi ni m u m, a n d ma xi m u m). S u bjects 
wit h a se verit y sc or e w orse t ha n baseli ne will als o be s u m marize d at eac h p ost -baseli ne visit. 
T he w orst sc or e a n d t he l ast sc ore d uri n g t he p ost -baseli ne p eri o d will als o be s u m marize d.  
1 2. 1. 3  Cli nic al L a b or at or y Tests  
Res ults of safet y la b orat or y para m eters will be s u m marize d at eac h st u d y visit usi n g 
descri pti ve statistics or fr e q ue ncies a n d perce nta g es, as a p pr o priat e, f or t he safet y, P K, a n d 
n o n -P K p o p ulati o ns.  C ha n ges fr o m baseli ne i n safet y la b orat or y v al ues will be s u m marize d 
b y treat me nt gr o u p at Wee k 4 8 usi n g descri pti ve st atistics. I n a d diti o n, c h a n ges fr o m baseli ne 
i n safet y la b orat or y val ues will be s u m marize d usi n g s hift ta bles acc or di n g t o n or mal ra n ges. 
1 2. 1. 4  Vit al Si g ns  
Res ults of vital si g n meas ure me nts will be s u m marize d at Wee ks 1 2, 2 4, 3 6, a n d 4 8 usi n g 
descri pti ve statistics or fr e q ue ncies a n d perce nta g es, as a p pr o priat e, f or t he safet y, P K, a n d 
n o n -P K p o p ulati o ns. C ha n ges fr o m baseli ne i n vit al si g n meas ure me nts will be s u m marize d 
at t hese visits.  
1 2. 1. 5  C o nc o mit a nt  Me dic ati o ns  
All pre vi o us t hera pies a n d c o nc o mita nt me dicati o ns will be classifie d base d o n ter mi n ol o g y 
fr o m t he W orl d H ealt h Or ga nizati o n Dr u g Dicti o nar y. Pre vi o us t hera pies a n d c o nc o mita nt 
me dicati o ns data will be prese nte d i n dat a listi n gs.  
1 2. 1. 6  Effic ac y f o r Assessi n g Tre at me nt  C o m pli a nce  
T his pri mar y o bjecti ve of t his st u d y is t o assess t he safet y of t he st u d y dr u g. Descri pti ve 
efficac y statistics f or t he e n d p oi nts will assist i n e val uati n g c o m plia nce wit h treat me nt f or t he 
p ur p oses of saf et y assess me nt. T he effi cac y v aria bles e val uate d i n t his st u d y i ncl u de 
micr osc o pic K O H e xa mi nati o n a n d m yc ol o gical c ult ure o utc o mes of t he tar get great t oe nail, 
perce nt i n v ol ve me nt of t he tar get great t oe nail, gr o wt h of t he tar get great t oe nail, a n d 
assess me nts of t he n o ntar get t oe nails. T he efficac y e n d p oi nts i ncl u de t he f oll o wi n g:  
 
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•  C o m plete C ure, defi ne d as 0 % cli nical i n v ol ve me nt of t he tar get t oe n ail a n d 
ne gati ve K O H a n d f u n g al c ult ure at Wee k  5 2  
•  C o m plete or Al m ost C o m plete C ure at Wee k 5 2, defi ne d as :: 5 %  t oe n ail 
i n v ol ve me nt 
•  T he Cli nical Efficac y rat e at Wee k 5 2, defi n e d as a n affecte d t ar get great t o e nail 
area of <  1 0 %  
•  T he M yc ol o gic C ure r ate at Wee k 5 2, d efi ne d as a ne gati ve K O H e xa mi nati o n 
a n d a ne g ati ve f u n gal c ult ure of t he tar g et great t oe nail  sa m ple 
T he C o m plete C ure rat e, t he C o m plete or Al m ost C o m plete C ure rate, t he Cli nical Efficac y 
rate, a n d t he M y c ol o gic C ure rate will be prese nt e d usi n g descri pti ve statistics (sa m ple size n, 
fre q ue n c y c o u nts, a n d p erce nta g es) f or t h e safet y, P K, a n d n o n-P K p o p ulati o ns. I n a d diti o n, 
t he gr o wt h of t he tar g et great t oe nail at eac h st u d y visit a n d t he c ha n ge fr o m baseli ne i n t he 
n u m ber of affecte d n o ntar get t oe nails will be s u m marize d des cri pti vel y.  
A last o bser vati o n carrie d f or war d ( L O C F) i m p utati o n will be use d t o i m p ute missi n g val ues 
f or t he efficac y vari a bles at Wee k 5 2. N o se nsiti vit y a nal yses will be c o n d u cte d.  
 
1 2. 2  Assess m e nt of  P h ar m ac o ki netics  
 
T he P K o bjecti ves will be c o nsi der e d met w he n a p pr o xi matel y 1 6 e val ua bl e s u bjects are 
treate d u n der ma xi mal us e c o n diti o ns t hr o u g h da y 2 8 of t he P K e val uati o n. 
N o i m p utati o ns will be ma de f or missi n g data. Plas ma  c o nce ntrati o ns t hat are re p orte d as 
bel o w t he li mit of q ua ntitati o n ( B L Q) i n t he data tra nsfer file a n d will be set t o zer o f or t h e 
s u m maries of c o nce ntrati o ns as well as calc ulati o n of P K para met ers. Missi n g val ues will be 
treate d as if t h e y were ne ver dra w n. Plas ma c o nce ntrati o ns a n d P K para met ers will be 
s u m marize d f or t h e P K a nal ysis set usi n g descri pti ve statistics ( n, mea n, S D, sta n dar d err or 
of t he mea n [ S E M], c oefficie nt of vari ati o n [ C V], me dia n, mi ni m u m, a n d ma xi m u m).  
Ge o metric mea ns will als o be  use d t o s u m marize C ma x , Cmi n , A U C( 0-t) a n d A U C ( 0-2 4 h). 
Plas ma c o nce ntr ati o ns of efi nac o n az ole a n d meta b olite ( H 3 a n d H 4) at eac h sc he d ule d 
sa m pli n g ti me p oi nt will be s u m marize d usi n g des cri pti ve statistics. T he i n di vi d ual plas ma 
c o nce ntr ati o ns will be liste d f or eac h s u bject. C o n ce ntrati o ns B L Q will be dis pla ye d as B L Q 
i n t he listi n gs. 
T he mea n plas ma c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d met a b olites ( H 3 a n d H 4) 
will be prese nte d gr a p hicall y f or Da ys 2 8 a n d 2 9 i n b ot h li near a n d l o garit h mic scales.  
 
 
 
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I n di vi d ual s u bject plas ma c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 
a n d H 4) will als o be create d.  
Plas m a P K para meters f or efi nac o naz ol e a n d meta b olites ( H 3 a n d H 4) will be calc ul ate d 
usi n g n o nc o m part me ntal a nal ysis. T he P K para meters will be calc ul ate d f or eac h s u bject 
usi n g act ual sa m pli n g ti mes. T he ma xi m u m plas ma c o nce ntrati o n ( C ma x ) a n d ti me t o Cma x  
( Tma x ) will be ta ke n directl y fr o m t he data. 
T he f oll o wi n g P K para m eters will be calc ulate d fr o m t he i n di vi d ual plas ma c o nce ntrati o ns 
o n Da ys 2 8 a n d 2 9 w h e n p ossi ble:  
•  C ma x  ( o bser ve d pea k dr u g [efi nac o naz ol e a n d meta b olites] c o nce ntrati o n)  
•  T ma x  (ti me at w hic h C ma x  occ urs)  
•  C mi n  ( o bser ve d mi ni m u m dr u g c o nce ntrati o n)  
•  A U C 0 -t (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 u p t o t he sa m pli n g 
ti me c orres p o n di n g t o t he last q ua ntifia ble c o nce ntrati o n)  
•  A U C 0 -2 4 h (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
[c orr es p o n di n g t o t he d osi n g i nter val]) 
A d diti o nal P K para meters ma y be calc ul ate d as a p pr o priate.  
 
1 2. 3  S u bject  Dis p ositi o n  
S u bject dis p ositi o n will be s u m marize d f or eac h a nal ysis p o p ulati o n.  
 
1 2. 4  De m o gr a p hics a n d B aseli ne  C h ar acteristics  
S u bject de m o gra p hic a n d baseli ne c haracteristics will be s u m marize d usi n g descri pti ve 
statistics f or eac h a nal ysis p o p ulati o n. 
 
1 2. 5  Pr ot oc ol  De vi ati o ns  
All pr ot oc ol de viati o ns will be re p orte d t o t he s p o ns or a n d r ec or de d t hr o u g h o ut t he st u d y. 
A ta b ulati o n of pr ot oc ol de viati o ns will be i ncl u de d i n t he fi nal st u d y re p ort.  
 
1 2. 6  C o m pli a nce  
Efficac y e val u ati o ns are bei n g c o n d ucte d t o ass ess treat me nt c o m plia nce. I nf or mati o n 
re gar di n g t he e val uati o ns a n d t heir a nal ys es are prese nte d i n Secti o n 1 2. 1. 6.  
 
 
 
 
 
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St u d y dr u g c o m plia nce will be calc ulate d f or eac h s u bject b y ta ki n g i nt o acc o u nt w het her a 
s u bject t o o k all d oses of st u d y dr u g as i nstr ucte d. Calc ulati o n of st u d y dr u g c o m plia nce will 
be d oc u me nte d i n t he a nal ysis pla n.  
 
1 2. 7  I nteri m A n al yses  
N o i nteri m a nal yses are pla n ne d. 
 
1 2. 8  A d diti o n al St atistic al  C o nsi der ati o ns  
W he n a p pr o xi mat el y 4 0 e val ua ble s u bjects ha ve b ee n treate d f or 4 8 wee ks meeti n g t he 
pri mar y saf et y o bjecti ve (re gar dless if s u bjects i n t he P K s u bset are c o nti n ui n g), a data c ut 
will be d o ne a n d t he st u d y re p ort will be writte n. O nce all s u bjects i n t he P K s u bset 
c o m pletes t he st u d y, data base l oc k will be perf or m e d a n d t he st u d y re p ort a me n d me nt will be 
writte n.  
All statistical pr ocessi n g will be perf or me d usi n g S A S ®  versi o n 9. 3 or hi g her  u nless 
ot her wise state d. N o h y p ot hesis testi n g will be c o n d ucte d i n t his st u d y. A statistical a nal ysis 
pla n, descri bi n g all statistical a nal yses, will be pr o vi de d as a se p arate d o c u me nt pri or t o data 
a nal ysis is perf or me d.  
1 2. 8. 1  A n al ysis  P o p ul ati o ns  
All s u bject s w h o recei ve at least 1 c o nfir me d d os e of st u d y dr u g will be i ncl u de d i n t he 
safet y p o p ulati o n. 
All s u bjects i n t he P K s u bset w h o recei ve at least 1 c o nfir me d d ose of st u d y dr u g a n d ha v e 
a n y P K data o n Da ys 2 8 a n d 2 9 will be i ncl u de d i n t he P K p o p ulati o n.  
All safet y p o p ulati o n s u bjects w h o are n ot i n t he P K s u bset will be i ncl u de d i n t he N o n -P K 
p o p ulati o n.  
1 2. 8. 2  S a m ple Size  Deter mi n ati o n  
A p pr o xi matel y 6 0 s u bjects will be e nr olle d a n d recei ve treat me nt wit h st u d y dr u g. 
A p pr o xi matel y 2 0 of t he 6 0 s u bjects will be e nr olle d i n t he P K s u bset. T hes e sa m ple sizes 
were b ase d o n P K a n d cli nical c o nsi derati o ns; n o f or mal sa m ple size calc ul ati o n was 
perf or me d. T he n u m bers of pla n ne d s u bjects are c o nsi dere d a d e q uate f or d eter mi ni n g t he 
safet y pr ofile a n d t he P K para meters of efi nac o n az ole i n a pe diatri c p o p ulati o n of s u bjects 
a ge d 6 t o 1 6 years 1 1 m o nt hs wit h mil d t o se vere o n yc h o m yc osis of t he t oe nails.  
1 2. 8. 3  H a n dli n g of Missi n g D at a  
N o i m p utati o ns will be ma de f or missi n g safet y or P K data. As i n dicate d pre vi o usl y, t he 
efficac y en d p oi nts, w hic h are use d t o assess treat me nt c o m plia nce, will ha ve missi n g data  
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i m p ute d wit h L O C F f or n o n-P K p o p ulati o n a nal yses. Missi n g efficac y dat a will n ot be 
i m p ute d f or safet y a n d P K p o p ulati o n a nal yses. 
1 2. 8. 4  M ultice nter  Iss ues 
T he st u d y will be c o n d ucte d at m ulti ple i n vesti gati o nal ce nters i n t he U S a n d t he Cari b bea n 
wit h t he i nte nti o n of p o oli n g t he res ults f or a nal ysis.  
1 2. 8. 5  M ulti plicit y Iss ues  
N ot a p plica ble.  
 
1 2. 8. 6  Wi n d o wi n g  R ules  
T he ti mi n g of all st u d y visits is relati ve t o t he Baseli ne ( Da y 1) visit. Visit 3 ( Wee k 4) s h o ul d 
occ ur wit hi n 5 da ys of D a y 2 8, (e xce pt f or t he P K -s u bset; Visit 3 s h o ul d occ ur wit hi n 1 da y 
of Da y 2 8) a n d Visit 3 A ( Wee k 4) s h o ul d occ ur 1 da y after Visit 3. T he Wee k 8 a n d all 
s u bse q ue nt visits s h o ul d occ ur wit hi n 5 da ys of t h e tar gete d ti mes. 
 
1 3  Q u alit y C o ntr ol a n d Q u alit y  Ass ur a nce  
T his st u d y will be c o n d ucte d u n der  t he s p o ns ors hi p of Valea nt, i n c o nf or m ati o n wit h all 
a p pr o priate l o cal a n d f e d eral r e g ulati o ns as well as I C H g ui deli nes.  
T he s p o ns or is res p o nsi ble f or i m ple me nti n g a n d mai ntai ni n g q ualit y ass ura nce a n d q ualit y 
c o ntr ol s yste ms t o e ns ure t hat st u dies are c o n d u cte d a n d data are ge n erate d, d oc u me nte d, a n d 
re p orte d i n c o m plia n ce wit h t he pr ot oc ol, G C P g ui deli nes, a n d a p plica bl e re g ulat or y 
re q uire me nts. I n a d diti o n, t he s p o ns or will be res p o nsi ble f or sec uri n g a gree me nt fr o m all 
i n v ol ve d parties t o e ns ur e direct access t o all st u d y-relate d sites, s o urce d ata/ d oc u me nts, 
e C R Fs, a n d re p orts f or t h e p ur p ose of m o nit ori n g a n d a u diti n g b y t he s p o ns or, a n d i ns pecti o n 
b y d o mestic a n d f orei g n re g ulat or y a ut h orities.  
Ce ntral la b orat or y s er vices will be perf or me d b y a q ualifie d, lice nse d facilit y t hat will be 
liste d o n t he U S F o o d a n d Dr u g A d mi nistrati o n F or m 1 5 7 2. C o pies of all n or mal val ues 
(as a p plica bl e), la b or at or y certificati o ns, a n d t he direct or's c urric ul u m vitae will be pr o vi de d 
t o eac h i n vesti gati o nal ce nter a n d t o t he s p o ns or. 
 
1 3. 1  St u d y  M o nit ori n g  
T he c o n d uct of t h e st u d y will be cl osel y m o nit ore d. S p o ns or re pres e ntati ves m ust be 
per mi tte d t o visit all st u d y site l ocati o ns t o assess t he data, q ualit y of st u d y perf or ma n ce, a n d 
st u d y i nte grit y i n a ma n ner c o nsiste nt wit h a p plica ble healt h a ut h orit y re g ul ati o ns a n d t he 
pr oce d ur es descri be d i n t his pr ot oc ol.  
 
 
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Pri or t o t he start of t he st u d y, t he S p o ns or or its desi g nee(s) will re vie w t he pr ot oc ol, e C R Fs, 
re g ulat or y o bli gati o ns, a n d ot her material or e q ui p me nt rele va nt t o t he c o n d uct of t he st u d y 
wit h t he I n v esti gat or/ S u b/ C o I n vesti gat or a n d rele va nt st u d y site pers o n nel.  
M o nit ori n g visits a n d tele p h o ne c o ns ultati o ns will occ ur as n ecessar y, or p er t he st u d y 
m o nit ori n g pla n, d uri n g t he c o urse of t he i n vesti gati o n t o verif y t he f oll o wi n g:  
•  T he ri g hts a n d well -b ei n g of s u bjects are  pr otecte d  
•  T he  c o n d uct  of  t he i n vesti gati o n is i n c o m plia nce wit h  t he c urre ntl y a p pr o v e d 
pr ot oc ol/a me n d me nt, I C H G C Ps, a n d I R B/ E C  re q uire me nts 
•  T he i nte grit y of t he data is mai ntai ne d, i ncl u di n g a de q uate st u d y  d oc u m e ntati o n  
•  T he facilities re mai n  acce pta ble  
•  T he I n vesti gat or a n d site pers o n nel re m ai n q ualifie d a n d a ble t o c o n d u ct t he  st u d y 
•  St u d y dr u g acc o u nta bilit y is d oc u me nte d  pr o perl y  
D uri n g t he c o urs e of t he st u d y, if t he S p o ns or deter mi nes t hat a n I n vesti gat o r is n o n- 
c o m plia nt wit h t he st u d y pla n a n d/ or a p plica bl e re g ulat or y re q uire m e nts, t he S p o ns or will 
ta ke acti o n t o sec ure or r ei nstate c o m plia nce. I n a d diti o n, t he S p o ns or ma y ter mi nate t he 
I n v esti gat or's partici pati o n i n t he st u d y if a p pr o pri ate, or if t he I n v esti gat or re mai ns n o n - 
c o m plia nt des pite t he re me dial acti o ns of t he S p o ns or..  
 
1 3. 2  A u dits a n d  I ns pecti o ns 
I nteri m a n d e n d of st u d y a u dits of ra w d ata, st u d y files, a n d t he fi nal re p ort ma y be 
c o n d ucte d b y t he s p o ns or's q ualit y ass ura nce d e part me nt or its  desi g nee. A certificate 
attesti n g t o t he a u dit(s) will be iss ue d as a p plica ble. I n a d diti o n, i ns pecti o ns or o n -site a u dits 
ma y be carrie d o ut b y l ocal a ut h orities. T he i n vesti gat ors will all o w t he s p o ns or's 
re pres e ntati ves a n d a n y r e g ulat or y a ge n c y t o e xami ne all st u d y rec or ds a n d l o gs, e C R Fs, 
c orres p o n di n g s u bject me dical rec or ds, st u d y dr u g dis pe nsi n g rec or ds, st u d y dr u g st ora ge 
area, a n d a n y ot her d oc u me nts c o nsi dere d s o urce d oc u me ntati o n. T he i n vesti gat ors a gree t o 
assist t he re pres e ntati ve, if re q uire d.  
 
1 3. 3  D at a Q u alit y  Ass ur a nce  
All assess me nts perf or m e d will be acc uratel y d o c u me nte d i n t he s u bject's s o urce d oc u m e nts 
a n d e C R Fs. T he i n vesti g at or or desi g nee will e nter t he i nf or mati o n re q uire d b y t he pr ot oc ol 
i nt o t he s o urce d oc u me nts a n d e C R Fs pr o vi de d b y t he s p o ns or or desi g nee. S u bjects will be 
i de ntifie d i n t he e C R Fs b y t heir assi g ne d s u bject n u m ber a n d i nitials o nl y. 
 
 
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T he i n vesti gat ors m ust rea d t he pr ot oc ol t h or o u g hl y a n d m ust f oll o w t he i nstr ucti o ns e xactl y. 
A n y de viati o ns s h o ul d be a gree d t o b y pri or disc ussi o n bet wee n t he s p o ns or a n d t he 
i n vesti gat or, wit h a p pr o priate writte n pr ot oc ol a me n d me nts ma de pri or t o effecti n g t he 
a gree d u p o n c ha n g es. A n y a me n d me nt c o ntai ni n g maj or m o dificati o ns ( partic ularl y if it ma y 
i n v ol ve a n i ncrease d ris k t o t he s u bjects) will be a p pr o ve d b y t he I R B/I E C bef ore it ma y b e 
i m ple me nte d. N o c ha n g e i n t he c o n d uct of t he st u d y ca n be i nstit ute d wit h o ut writte n 
a p pr o val fr o m t he s p o ns or.  
 
1 4  Et hics a n d A d mi nistr ati ve  Iss ues 
1 4. 1  Et hic al C o n d uct of t he  St u d y  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he et hical pri nci ples ori gi nati n g fr o m t he 
Declar ati o n of Helsi n ki, I C H g ui deli nes, G C P g ui deli nes, a n d i n c o m plia nce wit h l ocal a n d  
fe der al re g ulat or y re q uir e me nts. T he i n vesti gat or a grees, w h e n si g ni n g t he pr ot oc ol, t o 
a d here t o t he i nstr u cti o ns a n d pr oce d ures d escri be d i n it a n d t here b y t o a d h ere t o t he 
pri nci ples of G C P.  
 
1 4. 2  Et hics  Re vie w  
T his pr ot oc ol, pr o p ose d i nf or me d c o ns e nt/asse nt f or m a n d ot her i nf or m ati o n t o t he s u bjects, 
a n d all a p pr o pri ate a me n d me nts, will be pr o perl y re vie we d, a n d a p pr o ve d b y a n I R B/I E C.  
A si g ne d a n d date d n otifi cati o n of t he I R B/I E C a p pr o val will be pr o vi de d t o t he s p o ns or a n d 
i n vesti gat or pri or t o st u d y i nitiati o n. T he na me a n d occ u pati o n of t he c hair a n d me m bers of 
t he I R B/I E C will be s u p plie d t o t he s p o ns or. T he i n vesti gat or will pr o vi de re q uire d pr o gress 
re p orts a n d r e p ort all S A Es t o t he I R B/I E C as re q uire d. 
 
1 4. 3  Writte n I nf or m e d  C o nse nt  
Writte n  i nf or me d c o ns e nt/asse nt, i n acc or d a nce wit h l ocal cli nical i n vesti gati o n re g ulati o ns, 
m ust be o btai ne d pri or t o partici pati o n i n t he st u d y. T he i n vesti gat or or desi g nee will disc uss 
t he p ur p ose of t he st u d y wit h eac h s u bject a n d t heir pare nt(s)/le g al g uardi a n(s) a n d will 
pr o vi de a des cri pti o n of t he st u d y dr u g (i ncl u di n g a n y p ote ntial a n d p ossi ble si de effects) a n d 
t he st u d y pr oce d ur es. I nf or mati o n m ust be gi ve n b ot h i n oral a n d writte n f or m. T he s u bject 
i nf or mati o n pr o vi de d will be i n a la n g ua ge u n d ersta nda ble t o t he s u bject a n d t heir 
pare nt(s)/le g al  g uar dia n(s)  a n d ma y  n ot  i ncl u de a n y la n g ua ge t hat a p pears  t o wai ve  a n y of  t he 
s u bject's le gal ri g hts or a p pears t o rel ease t h e i n vesti gat or, t he s p o ns or, or t he i nstit uti o n  
fr o m lia bilit y or ne gli ge nce.  
T he i n vesti gat or or desi g nee will pr o vi de t he pr os pecti ve s u bject a n d t h e s u bject's pare nt(s) 
or le gal g uar di a n(s) s ufficie nt ti me t o c o nsi der w h et her t o partici pat e, mi ni mizi n g t he  
 
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p ossi bilit y of c oerci o n or u n d ue i nfl ue nce a n d will disc uss a n y q uesti o ns t he s u bject a n d/ or 
t heir pare nt(s)/le gal g uar dia n(s) ma y ha v e. T he i n vesti gat or or desi g nee will e x plai n t o t he 
s u bject a n d t heir pare nt(s)/le gal g uar dia n(s) t hat p artici pati o n i n t he st u d y is v ol u ntar y a n d 
t hat wit h dra wal fr o m t he st u d y is p ossi ble at a n y ti me wit h o ut detri me nt t o care. T he c o ns e nt 
m ust i ncl u de ac k n o wle d g me nt t hat me dical rec or ds a n d me dical data d eri ve d fr o m t he st u d y 
ma y be f or w ar de d t o t he s p o ns or or t o t he res p o nsi ble a ut h orities or fe d eral a ut h orities.  
N o s u bject ca n e nter t he st u d y or ha ve a n y st u d y -relate d pr oce d ures perf or me d bef ore his/ her 
writte n i nf or me d c o ns e nt/asse nt has bee n o btai n e d. S u bjects u n der t he  a g e of c o nse nt m ust 
si g n a n asse nt f or m a n d t heir par e nts/le gal g uar dia ns m ust si g n t he i nf or me d c o nse nt f or m.  
S u bjects o ver t he a g e of c o nse nt m ust si g n t he i nf or me d c o nse nt f or m. S u bjects a n d t heir 
pare nts/le gal g uar dia ns will als o pr o vi de writte n c o nse nt/asse nt t o o btai n p h ot o gra p hs of t he 
tar get great t oe nail. T he ori gi nal si g ne d a n d date d i nf or me d c o nse nt a n d asse nt f or ms will be 
retai ne d wit h t he st u d y rec or ds, a n d a c o p y of t he si g ne d f or ms will be gi ve n t o t he s u bject 
a n d t heir par e nt or le gal g uar dia n as a p plica ble.  
A n i nf or me d c o ns e nt/asse nt te m plate will be s u p plie d b y t he s p o ns or t o t he i n vesti gat or. 
A n y c ha n ges t o t he i nf or me d c o nse nt/asse nt f or m m ust be a gree d t o b y t he s p o ns or pri or t o 
s u b missi o n t o t he I R B/I E C, a n d a c o p y of t he a p pr o ve d versi o n m ust be pr o vi de d t o t he 
s p o ns or after I R B/I E C a p pr o val. 
 
1 4. 4  S u bject D at a  P r otecti o n  
S u bject data will be pr otecte d b y e ns uri n g t hat n o ca pt ure d d ata c o ntai n s u bject na mes, 
a d dresses, tel e p h o ne n u m bers, e mail a d dresses, or ot her direct pers o nall y i de ntif y i n g 
i nf or mati o n. It is ac k n o wle d ge d t hat s u bject i nitials, de m o gra p hics (i ncl u di n g birt h dates), 
me dical hist ories, a n d pri or c o nc o mita nt me dicati o n uses, al o n g wit h t he na me a n d a d dress of 
t he e nr olli n g i n vesti gat or ma y all o w f or pers o nal i de ntificati o n of st u d y partici pa nts. Ot her 
t ha n w here n ecessar y t o meet re g ulat or y re q uire me nts, all data c ollect e d i n t his st u d y will be 
prese nte d i n ta b ulat e d (ie, a g gre gat e) f or m a n d listi n gs c o ntai ni n g i nf or mati o n t hat c o ul d be 
use d t o i de ntif y a n i n di vi d ual s u bject w ill n ot be i ncl u de d i n a n y p u blic discl os ures of t he 
st u d y data or t he st u d y res ults. 
 
1 4. 5  D at a M o nit ori n g  C o m mittee  
N ot a p plica ble.  
 
1 4. 6  Fi n a nci al  Discl os ure  
Fi na ncial discl os ur es will be o btai ne d fr o m all i n vesti gat ors i n or der t o d oc u me nt a n y 
p ote ntial c o nflicts of i nterest.  
 
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1 4. 7  Esse nti al  D oc u m e nts  
I n v esti gat or m ust mai ntai n esse ntial d oc u me nts d uri n g t he c o n d uct of t he st u d y a n d retai n 
t hese d oc u me nts aft er t he c o m pleti o n of t he st u d y i n acc or d a nce wit h t he S p o ns or's rec or d 
rete nti o n i nstr ucti o ns. T he I n vesti gat or a grees t o a d here t o t he d oc u m e nt ret e nti o n pr oce d ures 
w he n si g ni n g t he pr ot oc ol I n vesti gat or State m e nt of A p pr o val.  
Esse ntial d oc u me nts i ncl u de, b ut ar e n ot li mite d t o, t he f oll o wi n g:  
•  I R B a p pr o v als f or t he st u d y pr ot oc ol, all a me n d me nts, I C F(s), a n d a d vertise me nts  
•  I R B a n n u al st u d y re vie w 
•  I R B c orres p o n de n ce a n d re p orts (e g, S A E re p orts, pr ot oc ol de viati o ns, a n d safet y 
u p dates)  
•  Re g ulat or y d oc u me nts (e g, fi na ncial discl os ure a n d dele gati o n of a ut h orit y  f or ms) 
•  All s o urce  d oc u me nts  
•  C R Fs  
•  S u bje ct's si g n e d  I C F 
•  F D A F or m  1 5 7 2  
•  Acc o u nta bilit y rec or ds f or t he st u d y  dr u g  
•  C orres p o n de nce fr o m a n d t o  s p o ns or 
•  A n y ot her d oc u me nts r ele va nt t o t he c o n d uct of t h e  st u d y 
I n t he e ve nt t hat t he I n vesti gat or wit h dra ws fr o m t he st u d y (e g, retire me nt or rel ocati o n), 
st u d y rec or ds will  be  tra nsferr e d t o a m ut uall y  a gree d u p o n  desi g nee  (e g, a n ot her I n vesti gat or 
or site I R B/ E C). T he I n v esti gat or will pr o vi de n otice of s uc h tra nsfer i n writi n g t o t he 
s p o ns or 
 
1 4. 8  I n vesti g at or O bli g ati o ns  
T he i n vesti gat ors m ust rea d t he pr ot oc ol t h or o u g hl y, c o m plete a n d si g n t he pr ot oc ol 
si g nat ure pa ge, a n d m ust f oll o w t he i nstr ucti o ns e xactl y. W he n e ver p ossi ble, a n y pla n ne d 
de viati o ns s h o ul d be a gree d t o b y pri or disc ussi o n bet wee n t he s p o ns or a n d t he i n vesti gat or, 
wit h a p pr o priate d o c u me ntati o n of s p o ns or a p pr o val pri or t o effecti n g t he a gree d u p o n 
c ha n ges. A n y d e viati o ns s h o ul d be re p orte d t o t he s p o ns or a n d re p orte d t o t he I R B/I E C 
acc or di n g t o  t he re q uire me nts of t he I R B/I E C. 
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
6 6  
 
 
 
 
1 4. 9  C h a n ges t o t he  Pr ot oc ol  
A n y a me n d me nt c o ntai ni n g maj or m o dificati o ns ( partic ularl y if it ma y i n v ol ve a n i ncrease d 
ris k t o t he s u bjects) will be a p pr o ve d b y t he I R B bef ore it ma y b e i m ple me nte d. N o c h a n ge i n 
t he c o n d uct of t he st u d y ca n be i nstit ute d wit h o ut pri or writte n a p pr o v al fr o m t he s p o ns or. 
 
1 4. 1 0  C o nfi de nti alit y/ P u blic ati o n of t he St u d y  
All t he data f ur nis he d t o t he i n vesti gat o r a n d his/ her staff a n d all data o bt ai ne d t hr o u g h t his 
pr ot oc ol will be re gar de d as c o nfi de ntial a n d pr o prietar y i n nat ure a n d will n ot be discl ose d 
t o a n y t hir d part y, e xce pt f or t he U S F o o d a n d Dr u g A d mi nistrati o n or ot her re g ulat or y b o d y, 
wit h o ut writte n c o nse nt fr o m t he s p o ns or.  
T he res ults of t he st u d y ma y be p u blis he d or pres e nte d b y t he I n vesti gat or(s) after t he re vie w 
b y, a n d i n c o ns ultati o n a n d a gree m e nt wit h t he S p o ns or, a n d s uc h t hat c o nfi de ntial or 
pr o prietar y i nf or mati o n is n ot discl ose d. Pri or  t o s u b missi o n f or p u blicati o n or prese ntati o n, a 
c o p y of t he fi nal te xt s h o ul d be f or war de d b y t he I n vesti gat or(s) t o t he S p o ns or or its 
desi g nee f or re vie w a n d c o m me nt. S uc h c o m me nts s hall ai m t o e ns ure t he scie ntific i nte grit y 
of t he pr o p ose d p u blicati o ns a n d/ or prese nt ati o ns a n d e ns ure t h at t he data a n d material 
referri n g t o t he S p o ns or pr o d ucts a n d acti vities recei ve fair, acc urate, a n d reas o na ble 
prese ntati o n.  
 
1 4. 1 1  St u d y  Ter mi n ati o n  
T he s p o ns or res er ves t he ri g ht t o disc o nti n ue t he st u d y o verall or at a p artic ular st u d y site at 
a n y ti me f or reas o ns i ncl u di n g b ut n ot li mite d t o:  
•  E mer ge nce of effects t hat d o n ot j ustif y t he be nefit/ris k relati o ns hi p t o t he st u d y 
p o p ulati o n as a  w h ole.  
•  Fail ure  t o c o m pl y wit h  t he pr ot oc ol,  G C P,  or  a n y ot her  vi olati o n  dist ur bi n g  t he 
a p pr o priate c o n d uct of t h e  st u d y. 
•  Fail ure t o meet e nr oll me nt g oals o verall or at a p artic ular st u d y  site. 
If a st u d y is ter mi nate d, t he S p o ns or will pr o m ptl y n otif y t he I n v esti gat or. After n otificati o n, 
t he I n v esti gat or m ust c o ntact all partici pati n g s u bjects a n d t heir p are nts/le g al g uar dia ns 
wit hi n a reas o na bl e ti mefra me a gree d u p o n b y t h e S p o ns or. All st u d y materials m ust be 
c ollecte d a n d all e C R Fs c o m plete d t o t he greatest e xte nt p ossi ble  
 
 
 
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
6 7  
 
 
 
1 5  D at a H a n dli n g a n d Rec or d  Kee pi n g  
1 5. 1  I ns pecti o n of Rec or ds  
I n v esti gat ors m ust mai ntai n detaile d rec or ds o n all st u d y s u bjects w h o are e nr olle d i n t he 
st u d y or w h o u n der g o scr ee ni n g. Data will be rec or de d i n t he su bject's s o urce d oc u me nts a n d 
i n a p plica ble st u d y l o gs pr o vi de d b y t he s p o ns or. S o urce d oc u m e nts i ncl u de s u bject's 
me dical rec or ds, h os pital c harts, cli nic c h arts, a n d t he i n vesti gat or's s u bject st u d y files, as 
well as t he res ults of dia g n ostic tests (e g, la b orat or y tests). All me dical i nf or mati o n o btai ne d 
at eac h st u d y visit m ust be rec or de d i n t he s u bject's s o urce d oc u m e ntati o n i n real ti me as it is 
c ollecte d a n d t he n e nter e d o nt o t he e C R F b y site  pers o n nel.  
S u bject -c o m plete d f or ms s uc h as diaries a n d q uesti o n naires are als o c o nsi d ere d s o urce dat a. 
O nl y s u bjects are t o r ec or d i nf or mati o n i n s u bject diaries a n d q uesti o n naires. I n n o i nsta n ce, 
s h o ul d a n I n v esti gat or or st u d y site pers o n nel rec or d a n y data or ma ke c ha n ges t o s u bject 
c o m plete d f or ms. T he I n vesti gat or or desi g nee s h o ul d re vie w s u bject -c o m plete d f or ms 
d uri n g st u d y visits. If a n e ntr y is f o u n d t o be ille gi ble or a mista ke is f o u n d (e g, a n i nc orrect 
year w as rec or de d), t he s u bject s h o ul d be i nstr ucte d t o e dit t he e ntr y b y dra wi n g a si n gle li ne 
thr o u g h t he ori gi nal e ntr y, e nteri n g t he ne w i nf or mati o n, dati n g, a n d writi n g s u bject's year of 
birt h t o ac k n o wle d ge.  
U p o n st u d y c o m pleti o n or at a n y ot her ti me s pecifie d b y t he s p o ns or or desi g nee, t he 
a p pr o priate st u d y d oc u m e nts m ust be s u b mitte d t o t he s p o ns or. 
Tele p h o ne c o n v ersati o ns a n d electr o ni c mail wit h t he s u bject, t he s p o ns or, or t he s p o ns or's 
desi g nee c o n cer ni n g t he st u d y m ust be rec or d e d or ke pt o n file. All s o urce d oc u me nts m ust 
be ma de a v aila ble t o t he s p o ns or a n d t he s p o ns or's desi g nate d  m o nit or u p o n re q uest.  
 
1 5. 2  C ase Re p ort F or ms  
S u bject data re q uir e d b y t his pr ot oc ol are t o be rec or de d o n e C R Fs. S u bject data rec or de d o n 
e C R Fs d uri n g t he st u d y will be d oc u me nte d i n a c o de d fas hi o n. T h e s u bject will o nl y be 
i de ntifie d b y t he s u bject n u m ber an d b y t heir y ear of birt h if als o re q uire d. C o nfi de ntialit y of 
s u bject rec or ds m ust be mai ntai ne d t o e ns ure a d h ere nce t o a p plica bl e l ocal pri vac y 
re g ulati o ns. 
T he I n vesti gat or a n d st u d y site pers o n nel will be res p o nsi ble f or c o m pleti n g t he e C R Fs. T he 
I n v esti gat or is re q uir e d t o verif y t hat all of t he re q ueste d i nf or mati o n is acc uratel y rec or de d 
o n t he e C R Fs. All i nf or m ati o n re q ueste d o n t he e C R Fs nee ds t o be s u p plie d, i ncl u di n g 
s u bject i de ntificati o n, dat e(s), ass ess me nt val ues, etc., a n d a n y o missi o n or discre pa n c y will 
re q uire e x pla nati o n. All i nf or mati o n o n e C R Fs m ust be tracea ble t o s o urce d oc u me nts. 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
6 8  
 
 
 
 
T he st u d y m o nit or will be res p o nsi ble f or re vie wi n g a n d verif yi n g t he d ata rec or d e d o n t he 
e C R Fs, utilizi n g t he ori gi nal s o urce d o c u me ntati o n a n d will q uer y discre p a nt fi n di n gs. T he 
I n v esti gat or a n d st u d y site pers o n nel will be res p o nsi ble f or a ns weri n g all q ueries. T he 
e C R Fs will be s u b mitte d t o Valea nt or its desi g ne e(s) f or q u alit y ass ura nce re vie w, a n d 
statistical a nal ysis. 
A c o p y of t he e C R Fs will be retai ne d b y t he I n vesti gat or at t he c o ncl usi o n of t he st u d y, w h o 
m ust e ns ure t hat it is st ore d i n a sec ure place  
 
1 5. 3  Rete nti o n of R ec or ds  
T he i n vesti gat or s h o ul d pr o perl y st ore a n d mai ntai n all st u d y rec or ds i n acc or da nce wit h 
s p o ns or directi ves. All rec or ds relati n g t o t he c o n d uct of t his st u d y are t o be retai ne d b y t he 
i n vesti gat or u ntil n otifie d b y t he s p o ns or i n writi n g t hat t he rec or ds ma y be destr o ye d.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
6 9  
 
 
 
 
1 6  Refere nces  
1.  Ele ws ki B E. O n yc h o m yc osis: pat h o ge nesis, dia g n osis, a n d ma na ge me nt. Cli n 
Micr o bi ol Re v.  1 9 9 8; 1 1( 3): 4 1 5 -2 9.  
2.  Le v y L. E pi de mi ol o g y of o n yc h o m yc osis i n s pecial -ris k p o p ulati o ns. J A m P o diatr 
Me d Ass oc.  1 9 9 7; 8 7( 1 2): 5 4 6 -5 0.  
3.  Zaias N, T osti A, Re b ell G, M orelli R, Bar dazzi F, Biele y H, et al. A ut os o mal 
d o mi na nt patter n of distal s u b u n g ual o n yc h o m yc osis ca use d b y Tric h o p h yt o n 
r u br u m. J A m Aca d Der mat ol. 1 9 9 6; 3 4( 2 Pt 1): 3 0 2 -4.  
4.  Tre pa nier E F, A ms de n G W. C urre nt iss ues i n o n y c h o m yc osis. A n n P har m ac ot her. 
1 9 9 8; 3 2( 2): 2 0 4 -1 4.  
5.  G u pta A K, T u L Q. T h era pies f or o n yc h o m yc osis: a re vie w. Der m at ol Cli n. 
2 0 0 6; 2 4( 3): 3 7 5 9.  
6.  J u blia (efi nac o n az ole) t o pical s ol uti o n, 1 0 %. [ U S Prescri bi n g I nf or m ati o n]. 
Valea nt P har mace uticals N ort h A merica, L L C;  2 0 1 4.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical St u d y Pr ot oc ol, A me n d me nt 1 date d Dece m ber  0 5, 2 0 1 6  
C O N FI D E N TI A L  


 
Cli nic al St u d y Pr ot oc ol 
Efi n ac o n az ole 1 0 % T o pic al S ol uti o n 
Pr ot oc ol V 0 1 -1 0 S A -4 0 1  
A M ultice nter, O pe n L a bel, Si n gle -ar m St u d y E v al u ati n g t he S afet y 
a n d P h ar m ac o ki n etics of Efi n ac o n az ole 1 0 % T o pic al S ol uti o n i n 
S u bjects wit h Mil d t o Se vere O n yc h o m yc osis of t he T oe n ails  
 
De vel o p me nt p hase  of  st u d y: 
4  
St u d y  desi g n:  
M ultice nter, o pe n la bel, si n gle -ar m, safet y 
a n d p har mac o ki netics  st u d y 
Date:  
A me n d me nt 1  Date:  
A me n d me nt 2  Date:  
Ma y 1 0, 2 0 1 6  
Dece m ber 0 5, 2 0 1 6  
A u g ust 1 8, 2 0 1 7  
S p o ns or:  
D o w P har mace utical Scie nces, a w h oll y 
o w ne d s u bsi diar y of Valea nt P har mace uticals 
I nter nati o nal 
1 3 3 0 Re d w o o d Wa y, S uite C 
Petal u ma, C A 9 4 9 5 4  
 
C O N FI D E N TI A L  
N ot hi n g herei n is t o be discl ose d wit h o ut pri or a p pr o v al of t he s p o ns or.  
 
 
 
 
 
 
 
 
 


 
Pr ot oc ol V 0l -l 0 S A-4 0 1, Eti n nc o naz olc Pe diatric Safet y a n d  P K  St u d y  
Va]ea nt Researc h & De vel o p me nt  
 
 
Pr ot o c ol Re vie w a n d A p pr o v als  
 
A M ultic c nt er, O p e n L a b el, Si n gl e -a r m St u d y E v al u ati n g t he S af et y a n d P h a r m a c o ki n eti cs 
of Efi n ac o n a z ol c 1 0 % T o pic al S ol uti o n i n S u bj e cts wit h Mil d t o Se v e r e O n y c h o m y c osis of 
t he T o e n ails 
 
 
R e vi e w e d a n d a p p r o v e d:  
 
 
 
                  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cli nical  S 1 u d y  Pr ot oc ol,  A me n d me nt  2 d ate d  A u g ust  1 8,  2 0 1 7  
C O N FI D E N TI A L  
 
2  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3  
 
 
 
Pers o n nel Res p o nsi ble f or C o n d ucti n g t he St u d y  
 
A M ultice nter, O pe n L a bel, Si n gle - ar m St u d y E v al u ati n g t he S afet y a n d P h ar m ac o ki netics 
of Efi n ac o n az ole 1 0 % T o pic al S ol uti o n i n S u bjects wit h Mil d t o Se vere O n yc h o m yc osis of 
t he T oe n ails 
S p o ns or  
D o w P har mace u ticals Scie nces, a w h oll y o w n e d s u bsi diar y of 
Valea nt P har mace uticals I nter nati o nal  
1 3 3 0 Re d w o o d Wa y, S uite C 
Petal u ma, C A 9 4 9 5 4  
 
 
 
 
C o nt act f or Re p orti n g Seri o us A d verse E ve nts  
Me d Trials Safet y 
Fa x: 
 
E mail : 
 
 
 
Ret ur n of Use d a n d U n use d St u d y Dr u g  
Cli nical Trial Materials 
S u p pl y C hai n, Area 5 6 
1 4 0 0 N ort h G o o d ma n Street 
R oc hester, N Y 1 4 6 0 9  
 
C o ntr act Rese arc h Or g a niz ati o n/ Me dic al M o nit or  
Me d Trials,  I nc. C R O 
 
 
Tele p h o ne: 
 
Fa x:  
 
E mail:  
 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4  
 
 
 
Pri nci p al I n vesti g at or Pr ot oc ol A gree me nt P a ge  
I a gree: 
•  T o ass u me res p o nsi bilit y f or t he pr o per c o n d u ct of t his cli nical st u d y at t his site a n d t o 
c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, a n y f ut ure a me n d me nts, a n d wit h a n y 
ot her st u d y c o n d uct pr oce d ures pr o vi d e d b y t he  s p o ns or. 
•  T hat I a m a w are of, a n d will c o m pl y wit h, t he i nter nati o nall y rec o g nize d c o de of G o o d 
Cli nical Practices ( G C P) a n d all ot her a p plica ble re g ulat or y re q uire me nts t o o btai n writte n 
a n d date d a p pr o val fr o m t he I nstit uti o nal or Ce ntral Re vie w B oar d (I R B) or I n de pe n d e nt 
Et hics C o m mittee (I E C) f or t he st u d y pr ot oc ol, writte n i nf or me d c o nse nt, c o nse nt f or m 
u p dates, s u bject -r ecr uit m e nt pr oce d ures (e g, a d vertise me nts), a n d a n y ot her writte n 
i nf or mati o n t o be pr o vi de d t o t he s u bjects, bef ore i nitiati n g t his cli nical st u d y. 
•  N ot  t o i m ple me nt a n y c ha n ges  t o, or  de viati o ns  fr o m t he pr ot oc ol  wit h o ut  pri or  a gree me nt 
fr o m t he s p o ns or a n d r e vie w a n d d oc u me nt e d a p pr o val fr o m t he I R B/I E C, e xce pt t o 
eli mi nate a n i m me diate h azar d t o t he st u d y s u bjects, or w he n c h a n ge(s) i n v ol ves o nl y 
l o gistical or a d mi nistrati ve as pects of t h e cli nical st u d y. 
•  T o per mit direct m o nit ori n g a n d a u diti n g b y t he s p o ns or or s p o ns or's re pres e ntati ves a n d 
i ns pecti o n b y t he a p pr o priate re g ulat or y a ut h orit y(ies).  
•  T hat  I a m t h or o u g hl y fa miliar wit h  t he a p pr o priat e use  of  t h e i n vesti gati o nal pr o d ucts(s), 
as descri be d i n t his pr ot o c ol, a n d a n y ot her i nf or m ati o n pr o vi de d b y t he s p o ns or or 
desi g nee, i ncl u di n g, b ut n ot li mite d t o, t he c urre nt I n v esti gat or Br oc h ure or e q ui vale nt 
d oc u me nt a n d a p pr o v e d pr o d uct la bel (if  a p plica ble).  
•  T o pr o vi de s ufficie nt ti m e a n d a d e q uate n u m bers of q ualifie d staff a n d facilities f or t he 
f oresee n d ur ati o n  of  t he cli nical st u d y t o c o n d uct  t he st u d y pr o perl y,  et hicall y, a n d safel y. 
•  T o e ns ure t hat all pers o ns assisti n g i n t his st u d y are a de q u atel y i nf or me d a b o ut t he 
pr ot oc ol,  i n vesti gati o nal pr o d uct(s),  a n d t h eir cli nical st u d y-relate d d uties  a n d f u ncti o ns. 
 
 
Pri nci pal I n v esti gat or ( pri nt na me)  
 
 
Pri nci pal  I n vesti gat or (si g nat ure) 
Date  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5  
 
 
 
2  S y n o psis  
 
N a m e of S p o ns or/ C o m p a n y:  
D o w P h ar m ace utic als Scie nces, a w h oll y o w ne d s u bsi di ar y of V ale a nt P h ar m ace utic als 
I nter n ati o n al 
N a m e of i n vesti g ati o n al pr o d uct:  
Efi nac o naz ole 1 0 % T o pical S ol uti o n  
N a m e of acti ve i n gre die nt:  
Efi nac o naz ole  
Title of st u d y:  
A M ultice nter, O pe n La bel, Si n gle -ar m St u d y E val uati n g t he Safet y a n d P har mac o ki netics of Efi nac o naz ole 
1 0 % T o pical S ol uti o n i n S u bjects wit h Mil d t o Se vere O n yc h o m yc osis of t he T oe nails  
N u m ber of cli nic al ce nters:  
A p pr o xi matel y 2 0 -2 5 i n vesti gati o nal ce nters i n t he U nite d States, a n d t he Cari b bea n  
O bjecti ves:  
T he pri mar y o bjecti ves of t his st u d y are t o e val uate: 1) safet y of o nce dail y t o picall y a d mi nistere d 
efi nac o naz ole 1 0 % f or 4 8 wee ks i n pe diatric s u bjects ( 6 -1 6 years 1 1 m o nt hs of a ge) wit h at least mil d 
o n yc h o m yc osis of t he t oe nails,  a n d 2) p har mac o ki netics P K ( 4 wee ks) of o nce dail y t o picall y a d mi nistere d 
efi nac o naz ole 1 0 % i n pe diatric s u bjects ( 1 2 -1 6 years 1 1 m o nt hs of a ge) wit h m o derate t o se vere 
o n yc h o m yc osis of t he t oe nails.  
Met h o d ol o g y:  
T his is a n o pe n la bel, si n gle -ar m st u d y desi g ne d t o e val uate t he safet y a n d P K of a o nce dail y t o pical 
a p plicati o n of efi nac o naz ole i n t he treat me nt of pe diatric s u bjects wit h mil d t o se vere o n yc h o m yc osis of t he 
t oe nails. T he st u d y will i ncl u de s u bjects 6 t o 1 6 years of a ge, i ncl usi ve, b ut P K assess me nts will o nl y be 
perf or me d o n s u bjects 1 2 t o 1 6 years of a ge, i ncl usi ve (referre d t o t hr o u g h o ut t he pr ot oc ol as t he P K s u bset). 
All s u bjects m ust ha ve o n yc h o m yc osis of at least 1 great t oe nail; s u bjects i n t he P K s u bset m ust ha ve 
o n yc h o m yc osis of b ot h great t oe nails a n d at least 4 ot her t oe nails. Eff orts will be ma de t o e nr oll s u bjects i nt o 
t he P K s u bset s uc h t hat t he s u bjects are e ve nl y distri b ute d acr oss t he re q uire d a ge ra n ge. 
F or s u bjects n ot partici pati n g i n t he P K s u bset, t he st u d y will c o nsist of 1 4 sc he d ule d visits, i ncl u di n g 
Scree ni n g ( u p t o Da y -4 2), Baseli ne ( Da y 1), 1 2 treat me nt visits ( Wee ks 4, 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 
4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( We e k 5 2).  
S u bj ects i ncl u de d i n t he P K s u bset M U S T deci de at ti me of c o nse nt w het her t o partici pate i n t he 4 -Wee k 
trial, atte n d t he sc he d ule d visits u p t o Wee k 4 ( Da y 2 9) f or c ollecti o n of t he fi nal P K a n d e xit t he st u d y O R 
partici pate i n t he 5 2 -Wee k trial, wit h t he sa me  sc he d ule d visits as i n t he 4-Wee k trial f oll o we d b y c o nti n ue d 
treat me nt t hr o u g h wee k 4 8 wit h a d diti o nal visits at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 
4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 5 2). T he P K assess me nts will be perf o r me d u n der ma xi mal use 
c o n diti o ns . 
At t he Scree ni n g Visit, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will si g n a n i nf or me d c o nse nt/asse nt 
f or m a n d a p h ot o gra p h y c o nse nt/asse nt f or m, pr o vi de t heir me dical hist ories, re p ort t heir pre vi o us a n d 
c o nc o mita n t me dicati o ns, a n d be e val uate d a gai nst t he i ncl usi o n/e xcl usi o n criteria. Fe males of c hil d beari n g 
p ote ntial ( F O C B P) will ha ve uri ne pre g na nc y tests perf or me d. D uri n g t his visit, s u bjects will u n der g o a n 
e xa mi nati o n of t heir feet t o vis uall y ascertai n t he p rese nce of o n yc h o m yc osis i n at least 1 great t oe nail f or 
s u bjects n ot i ncl u de d i n t he P K assess me nts, a n d o n b ot h great t oe nails a n d at least 4 ot her t oe nails f or 
s u bjects i ncl u de d i n t he P K assess me nts. A d diti o nall y, t he perce nt i n v ol ve me nt of t he affecte d great  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6  
 
 
 
 
t oe nail(s) will be rec or de d. S peci me n will be o btai ne d fr o m t he great t oe nail(s) t o s hi p t o t he m yc ol o g y la b. 
B ot h t oe nails ma y be sa m ple d if b ot h are s us pecte d of ma nifesti n g o n yc h o m yc osis (at least 2 0 % 
i n v ol ve me nt). Bl o o d a n d uri ne s peci me ns will be c ollecte d f or ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis 
e val uati o ns. At rele va nt p ost -Scree ni n g Visits, t he tar get great t oe nail will be tri m me d bac k t o t he distal 
gr o o ve bef ore t he cli nical e val uati o ns are perf or me d a n d bef ore p h ot o gra p hs are ta ke n.  
At t he Baseli ne Visit ( w hic h s h o ul d be sc he d ule d after K O H a n d f u n gal c ult ure res ults ha ve bee n o btai ne d 
fr o m t he m yc ol o g y la b), s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will u p date t heir me dical hist ories a n d 
c o nc o mita nt me dicati o n uses, a n d t he i ncl usi o n/e xcl usi o n criteria will be c o nfir me d. S u bjects will u n der g o 
a b bre viate d p h ysical e xa mi nati o ns, cli nical la b orat or y e val uati o ns, assess me nts of vital si g ns (sitti n g bl o o d 
press ure, res pirati o n, p ulse, a n d te m pe rat ure), a n d meas ure me nts of hei g ht a n d wei g ht. All F O C B P will ha ve 
uri ne pre g na nc y tests perf or me d. F or t he p ur p oses of efficac y assess me nts, 1 tar get great t oe nail will be 
selecte d fr o m t he st u d y-eli gi ble great t oe nail(s), i ncl u di n g s u bjects i n t he P K s u bset f or w h o m b ot h great 
t oe nails m ust be i n v ol ve d. W here b ot h great t oe nails are st u d y-eli gi ble, t he t oe nail wit h t he greater perce nt of 
affecte d area will be selecte d f or m yc ol o gic data a n d f or i ncl usi o n i n t he efficac y a nal ysis. I n t he i nsta nce 
w here t h e perce nt of affecte d area is t he sa me f or b ot h st u d y -eli gi ble great t oe nails, t he i n vesti gat or ma y 
select eit her  great  t oe nail as t he tar get t oe nail. T he  tar get great  t oe nail will be  i de ntifie d a n d  rec or de d f or eac h 
s u bject, p h ot o gra p hs of t he tar get great t oe nail will be o btai ne d, a n d a tra ns verse n otc h will be i nscri be d i n 
t he tar get great t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d (as a mar ker f or meas uri n g t oe nail gr o wt h at 
s u bse q ue nt visits). Assess me nts of all ot her n o ntar get t oe nails, i ncl u di n g the ot her i n v ol ve d t oe nails of 
s u bjects i n t he P K s u bset, will als o be c o n d ucte d t o assess t h e prese nce or a bse nce of o n yc h o m yc osis o n eac h 
t oe nail. T his assess me nt w o ul d c o nti n ue t hr o u g h o ut t he st u d y visits t hr o u g h wee k 5 2.  
After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit, s u bjects will be e nr olle d i n t he treat me nt peri o d. S u bjects or 
t heir pare nts/le gal g uar dia ns will a p pl y t he first d ose of st u d y dr u g t o t he q ualifie d t oe nails at t he 
i n vesti gati o nal ce nter u n der t he s u per visi o n of desi g nate d st u d y pers on nel. A n y l ocal s ki n reacti o ns t hat 
occ ur at t he st u d y dr u g a p plicati o n site, al o n g wit h a n y a d verse e ve nts ( A Es), will be rec or de d. S u bjects or 
t heir pare nts/le gal g uar dia ns will recei ve wei g he d st u d y dr u g b ottles a n d gi ve n ver bal a n d writte n 
i nstr ucti o ns f or treat me nt a p plicati o n. S pecificall y, s u bjects w h o are n ot i ncl u de d i n t he P K s u bset will be 
i nstr ucte d t o a p pl y t he st u d y dr u g t o t he affecte d t oe nails o nce dail y at be dti me f or 4 8 wee ks.  
S u bjects w h o are i ncl u de d i n t he P K s u bset will be i nstr ucte d t o a p pl y t he st u d y dr u g t o all 1 0 t oe nails o nce 
dail y at be dti me f or 4 wee ks. F oll o wi n g t he P K s u bjects partici pati n g i n t he 5 2 -Wee k trial, ff F oll o wi n g t he 
P K bl o o d c ollecti o ns o n Da ys 2 8 a n d 2 9, P K s u bjects t hat c o nse nte d t o t he 5 2 -Wee k trial will c o nti n ue  
treat me nt wit h st u d y dr u g t o o nl y t he affecte d t oe nails . 
All s u bjects or t heir pare nts/le gal g uar dia ns will als o recei ve diaries, wit h i nstr ucti o ns t o c o m plete a rec or d of 
all a p plicati o ns a n d t o n ote a n y misse d a p plicati o ns of t he st u d y dr u g.  
S u bjects i n t he P K s u bset will n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( Da y 2 8) visit. F oll o wi n g 
t he Da y 2 8 st u d y pr oce d ures, s u bjects i n t he P K s u bset will u n der g o ti me d bl o o d c ollecti o ns t o assess plas ma 
c o nce ntrati o ns of efi nac o naz ole a n d met a b olites ( H 3 a n d H 4). Assess me nts will re q uire c ollecti o n of 
a p pr o xi matel y 4 m L of w h ole bl o o d at eac h ti me p oi nt (a p pr o xi matel y 2 0 m L t otal). Wit hi n 1 h o ur after t he 
pre d ose bl o o d sa m ple is dra w n, t he s u bjects/ pare nts/le gal g uar dia ns will a p pl y st u d y dr u g  t o all 1 0 t oe nails at 
t he i n vesti gati o nal ce nter. S u bse q ue nt bl o o d c ollecti o ns will occ ur 2, 4, a n d 1 2 h o urs p ost d ose o n Da y 2 8. 
T he s u bjects will g o h o me after Da y 2 8, b ut will n ot a p pl y st u d y dr u g o n t he ni g ht of t he Da y 2 8 visit. All 
P K s u bjects i n t he 4 -Wee k trial will ret ur n t o t he i n vesti gati o nal ce nter t he f oll o wi n g da y ( Da y 2 9) f or 
c ollecti o n of a 2 4 -h o ur p ost d ose bl o o d sa m ple a n d e xit t he st u d y. P K s u bjects t hat c o nse nte d t o t he 5 2 -Wee k 
trial will c o nti n ue treat me nt wit h st u d y dr u g t o o nl y t he tar get great t oe nail a n d t he ot her affecte d t oe nails 
a n d ret ur n t o t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k 
p ost -treat me nt f oll o w-u p visit ( Wee k  5 2).  
Safet y will be assesse d b y re vie wi n g t he occ urre nce of A Es a n d l ocal s ki n reacti o ns, assessi n g vital si g n 
meas ure me nts a n d a b bre viate d p h ysical e xa mi nati o n fi n di n gs, a n d n oti n g a n y a d diti o ns or c ha n ges i n 
c o nc o mita nt me dicati o n uses. Bl o o d sa m ples will be c ollecte d at Scree ni n g, Wee k 4( Da y 2 8) a n d Wee k 4 8 
f or r o uti ne safet y la b orat or y e val uati o ns (ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis); uri ne pre g na nc y 
tests will be o btai ne d f or all F O C B P at eac h st u d y visit. Efficac y assess me nts will be perf or me d t hro u g h o ut  
t he st u d y. T he efficac y a nal yses will be base d o n micr osc o pic e xa mi nati o n a n d m yc ol o gical c ult ure res ults 
f or t he tar get great t oe nail, t he perce nt i n v ol ve me nt of t he tar get great t oe nail, t he le n gt h of t he u naffecte d 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
7  
 
 
 
 
part of t he tar get great t oe nail, t he gr o wt h of t he tar get great t oe nail, a n d t he n u m ber of affecte d n o ntar get 
t oe nails. 
N ote t hat gr o wt h of t he tar get great t oe nail will be meas ure d b y i nscri bi n g a tra ns verse n otc h, at t he ce nter of 
t he t oe nail, i n t he t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d at Baseli ne a n d meas uri n g t oe nail gr o wt h fr o m 
t hat p oi nt f or war d. At e ver y s u bse q ue nt visit, t he dista nce bet wee n t he pr o xi mal t oe nail f ol d a n d t he n otc h 
will be meas ure d a n d rec or de d. A ne w n otc h will be i nscri be d i n t h e t oe nail a djace nt t o t he pr o xi mal t oe nail 
f ol d if t he i nitiall y a p plie d n otc h gr o ws o ut d uri n g t he c o urse of t he st u d y. 
A p ost -treat me nt f oll o w-u p visit will occ ur 4 wee ks after t he last treat me nt visit f or eac h s u bject (ie, at Wee k 
5 2). S u bjects w h o disc o nti n ue fr o m t he st u d y pri or t o Wee k 4 8 will c o m plete t he Wee k 4 8 st u d y pr oce d ures.  
N u m ber of s u bjects pl a n ne d: 
A p pr o xi matel y 6 0 s u bjects t otal 
A p pr o xi matel y 2 0 s u bjects i n t he P K s u bset  
Di a g n osis a n d criteri a f or i ncl usi o n:  
1.  Male or fe male s u bjects of a n y race, 6 t o 1 6 years of a ge (i ncl usi ve) at Scree ni n g.  
•  
P K S u bset: Male or fe male s u bjects of a n y race, 1 2 t o 1 6  years of a ge (i ncl usi ve) at 
Scree ni n g.  
2.  Ver bal a n d writte n i nf or me d c o nse nt/asse nt o btai ne d fr o m t he s u bject a n d/ or t heir pare nt or  le gal 
g uar dia n.  
3.  G o o d ge neral healt h, as assess e d b y t he i n vesti gat or, base d o n t he s u bject's me dical hist or y, 
p h ysical e xa mi nati o n, a n d safet y la b orat or y  tests. 
4.  At least 1 great t oe nail (t he "tar get great t oe nail") wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at least 2 0 % of t he affecte d great t oe nail at t he Scree ni n g a n d Baseli ne 
Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut de r mat o p h yt o mas or l u n ula ( matri x) 
i n v ol ve me nt. T here is n o s pecific u p per li mit f or perce nt i n v ol ve me nt. U p t o 6 t oe nails ma y ha ve 
o n yc h o m yc osis.  
•  
P K S u bset: B ot h great t oe nails wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at le ast 5 0 % of t he affecte d great t oe nail at t he Scree ni n g a n d 
Baseli ne Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut der mat o p h yt o mas or l u n ula 
( matri x) i n v ol ve me nt. T here is n o s pecific u p per li mit f or perce nt i n v ol ve me nt. S u bjects 
m ust als o ha ve at lea st 4 t oe nails ot her t ha n t he great t oe nails wit h o n yc h o m yc osis.  
5.  Tar get great t oe nail f or all s u bjects, a n d b ot h great t oe nails f or s u bjects i n t he P K s u bset, m ust  ha ve 
e vi de nce of t oe nail gr o wt h, per s u bject's re p ort t hat m o nt hl y cli p pi n g is  nee de d.  
6.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( Da y 1) Visit, ha ve a p ositi ve K O H e xa mi nati o n (res ults  will 
be pr o vi de d b y t he ce ntral m yc ol o g y la b) of t he tar get great t oe nail f or all  s u bjects, 
7.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( Da y 1) Visit, ha ve a p ositi ve der mat o p h yte c ult ure f or 
Tric h o p hyt o n r u br u m or Tric h o p hyt o n me nt a gr o p hytes (at t he ce ntral m yc ol o g y la b orat or y) fr o m 
t he tar get great t oe nail i n all s u bjects 
•  
P K S u bset: Pri or t o t he Baseli ne Visit, t he great t oe nail desi g nate d f or efficac y 
assess me nts as t he  tar get great t oe nail m ust ha ve b ot h a p ositi ve K O H e xa mi nati o n (res ults 
will be pr o vi de d b y t he ce ntral m yc ol o g y la b) a n d a p ositi ve f u n gal  c ult ure. 
8.  All F O C B P m ust ha ve a ne gati ve uri ne pre g na nc y test at t he Scree ni n g a n d Baseli ne Visits a n d m ust 
a gree t o  use a n effecti ve met h o d of c o ntrace pti o n t hr o u g h o ut t he st u d y. Effecti ve c o ntrace pti o n is 
defi ne d as use of a n i ntra uteri ne de vice, c o n d o m wit h s per mici de, dia p hra g m wit h s per mici de, 
a bsti ne nce (s u bject is n ot se x uall y acti ve), or sta ble use of a h or m o nal  c o ntrace pti ve ( oral, i m pla nt, 
i njecti o n, or tra ns der mal patc h) f or at least 3 m o nt hs pri or t o t he Baseli ne Visit.  
9.  S u bjects a n d t heir pare nts/le gal g uar dia ns are willi n g t o c o m pl y wit h st u d y i nstr ucti o ns a n d ret ur n t o 
t he i n vesti gati o nal ce nter f or all re q uire d visits (a visit sc he d ule wit h t he le n gt h of eac h visit will be  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
8  
 
 
 
 
pr o vi de d t o e ns ure t hat t he s u bject ca n meet t he re q uire me nts a n d ha ve a de q uate tra ns p ortati o n).  
1 0. S u bject a n d t heir pare nts/le gal g uar dia ns a gree t hat t he s u bject will a v oi d t he use of t oe nail p olis h, 
c os metic t oe nail pr o d ucts, a n d pe dic ures d uri n g t he st u d y peri o d.  
E xcl usi o n criteri a:  
1.  Fe males w h o are pre g na nt, n ursi n g a n i nfa nt, or pla n ni n g a pre g na nc y d uri n g t he st u d y  peri o d.  
2.  Hist or y  of  i m m u n os u p pressi o n a n d/ or  cli nical si g ns i n dicati ve of  p ossi ble  i m m u n os u p pressi o n, as 
deter mi ne d b y t he i n vesti gat or, or k n o w n h u ma n i m m u n o deficie nc y vir us  i nfecti o n. 
3.  Hist or y of dia betes t hat is u nc o ntr olle d as deter mi ne d b y t he i n vesti gat or ( dia betes t hat is c o ntr olle d 
b y diet or me dicati o n d oes n ot e xcl u de a  s u bject). 
4.  Prese nce of a n y t oe nail i nfecti o n ot her t ha n or i n a d diti o n t o der mat o p h ytes, s uc h as Scyt ali di u m as 
deter mi ne d b y t he i n vesti gat or (ca n di dal o n yc h o m yc osis i nfecti o n, c o nc urre nt wit h a p ositi ve 
der mat o p h yte c ult ure, is  acce pta ble).  
5.  Prese nce of a n y of t he f oll o wi n g: der mat o p h yt o ma, f u n gal "s pi kes" wit hi n 3 m m of t he pr o xi mal 
t oe nail f ol d o n t he tar get great t oe nail, i nfecti o n e xte n di n g t o t he matri x, or o nl y lateral t oe nail 
disease i n t he tar get great t oe nail. 
6.  Prese nce of se vere m occasi n ti nea pe dis at t he Scree ni n g or Baseli ne Visits, as deter mi ne d b y  t he 
i n vesti gat or. (If t he s u bject has i nter di gital ti nea pe dis t hat re q uires treat me nt, t he s u bject m ust 
a gree t o use o nl y a n i n vesti gat or -ap pr o ve d t o pical a ntif u n gal  t hera p y). 
7.  Prese nce of a n y disease/c o n diti o n t hat mi g ht ca use t oe nail a b n or malities or ma y i nterfere wit h t he 
e val uati o n of t he st u d y dr u g as deter mi ne d b y t he i n vesti gat or (e g, o pe n s ores or ulcerati o n o n t he 
t oes of affecte d t oenails, ps oriasis, i m m u ne d ysf u ncti o n, c olla ge n -vasc ular diseases, lic he n pla n us, 
peri p heral vasc ular disease, or tra u matic o n yc h o d ystr o p h y d ue t o c hr o nic p h ysical  sti m uli). 
8.  A n y pre vi o us s ur ger y o n t he tar get great  t oe nail. 
9.  Prese nce of o n yc h o m yc osis of t he  fi n ger nail. 
1 0.  Hist or y of i m m u n o deficie nc y as deter mi ne d b y t he  i n vesti gat or. 
1 1.  Prese nce of 1 -ha n d, 2 -f o ot s y n dr o me, or fi n ger nail der mat o p h yt osis.  
1 2.  Tar get great t oe nail (i ncl u di n g t oe nail plate a n d a n y s u b u n g ual de bris) t hic ker t ha n 3 m m at  t he 
Scree ni n g a n d Baseli ne  Visits.  
1 3.  Prese nce  of  o n yc h o d ystr o p h y  t hat c o ul d  i nterfere wit h cli nical assess me nts as deter mi ne d b y  t he 
i n vesti gat or. 
1 4.  Hist or y of h y perse nsiti vit y or aller gic reacti o ns t o az ole deri vati ves or a n y of t he st u d y dr u g 
c o nstit ue nts.  
1 5.  Prese nce  of  a n y u n derl yi n g  disease  t hat, i n t he o pi ni o n  of  t he i n vesti gat or, c o ul d  prese nt  a safet y 
c o ncer n f or t he s u bject b y partici pati n g i n t he  st u d y. 
1 6.  S u bject has recei ve d treat me nt f or a n y t y pe of ca ncer i n t he pre vi o us 6 m o nt hs, e xce pt f or 
n o n mela n o ma  s ki n ca ncer (e g, basal  cell carci n o ma  or  n o n metastatic  s q ua m o us cell carci n o ma)  t hat 
was treate d  s uccessf ull y. 
1 7.  Prese nce  of  a n y  der mat ol o gical  c o n diti o n  o n  t he feet t hat c o ul d  i nterfere wit h  cli nical e val uati o ns as 
deter mi ne d b y t he  i n vesti gat or. 
1 8.  Prese nce of a n y u n derl yi n g disease or der mat ol o gical c o n diti o n ot her t ha n o n yc h o m yc osis t hat 
re q uires t he use of i nterferi n g t o pical or s yste mic t hera p y a n d w o ul d ma ke e val uati o ns i nc o ncl usi ve 
as deter mi ne d b y t he i n vesti gat or, or s u bject re q uires treat me nt wit h a t o pical pr o d uct o n t he t oe nails 
ot her t ha n t he st u d y dr u g d uri n g t he  st u d y. 
1 9.  S u bjects  usi n g  t he f oll o wi n g t o pical pre parati o ns  wit hi n  t he i n dicate d ti me pri or  t o t he Baseli ne 
Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g t o pical pre parati o ns d uri n g t he st u d y: 
•  
T oe nail p olis h or c os metic t oe nail pr o d ucts: 1  da y  
•  
Ot her t o pical prescri pti o n or o ver -t he-c o u nter me dicati o ns t o t he t oe nails ( wit h  t he 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
9  
 
 
 
 
e xce pti o n of bla n d e m ollie nts): 2 wee ks  
•  
T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t oe nails,  i ncl u di n g 
de vices t o treat o n yc h o m yc osis: 4  wee ks  
2 0.  S u bjects  usi n g  t he f oll o wi n g s yste mic me dicati o ns wit hi n  t he i n dicate d ti me pri or  t o t he Baseli ne 
Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g s yste mic me dicati o ns d uri n g t he  st u d y: 
•  
S yste mic a ntif u n gal t hera p y: 4  wee ks  
•  
S yste mic i m m u n os u p pressi ve a ge nts: 6  m o nt hs  
2 1.  S u bject has pre vi o usl y bee n n o nres p o nsi ve t o s yste mic a ntif u n gal t her a p y f or  o n yc h o m yc osis.  
2 2.  S u bject  is u na ble  t o c o m m u nicate  or  c o o perate  wit h  t he i n vesti gat or d ue  t o la n g ua ge pr o ble ms,  p o or 
me ntal de vel o p me nt, or i m paire d cere bral  f u ncti o n. 
2 3.  Use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 half -li ves ( w hic he ver is l o n ger) pri or 
t o t he Scree ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal 
dr u g or  de vice.  
I n vesti g ati o n al pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n: 
I n vesti g ati o n al Dr u g: Efi nac o naz ole 1 0 % S ol uti o n (efi nac o naz ole)  
D osi n g f or S u bjects N O T I n cl u de d i n t he P K S u bset: S u bjects a n d t heir pare nts/le gal g uar dia ns will be 
i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject's tar get great t oe nail a n d all ot her affecte d t oe nail(s) 
(if a n y) o nce dail y at be dti me. S u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o c o nti n ue 
a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire treat me nt peri o d, e ve n if t he disease clears 
a n d n o affecte d area is o bser ve d o n t he tar get grea t t oe nail. If ot her affecte d t oe nails treate d si nce baseli ne 
clear d uri n g t he c o urse of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o 
c o nti n ue treat me nt o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me 
i nfecte d d uri n g t he st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). 
All s u bjects a n d t heir pare nts/le gal g uar dia ns will be gi ve n i nstr ucti o ns re gar di n g h o w t o a p pl y t he st u d y 
dr u g, ie, b y c o m plet el y c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he st u d y dr u g will be a p plie d t o eac h of t he ot her 
i nfecte d t oe nails i n a si milar ma n ner. 
D osi n g f or S u bjects I ncl u de d  i n t he P K S u bset: 
D a ys 1 t o 2 S - S u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y st u d y dr u g t o all  
1 0 t oe nails, o nce dail y at be dti me f or 4 wee ks. D uri n g t his peri o d, all P K s u bjects will be i nstr ucte d t o a p pl y 
t he st u d y dr u g b y c o m pletel y c o veri n g eac h t oe nail a n d 0. 5 c m of a djace nt s ki n, i ncl u di n g t he t oe nail f ol ds, 
t oe nail be d, h y p o n yc hi u m, u n ders urface of t he t oe nail plate. T he s u bjects will n ot a p pl y st u d y dr u g t he ni g ht 
pri or t o t he Wee k 4 ( Da y 2 8) visit, n or will t he y a p pl y  st u d y dr u g o n t he ni g ht of t he Wee k 4/ Da y 2 8 Visit. 
Wit hi n 1 h o ur after t he pre d ose bl o o d sa m ple is dra w n o n Da y 2 8, s u bjects a n d/ or t heir pare nts/le gal 
g uar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails i n t he ma n ner descri be d a b o ve at t he i n vesti gati o na l ce nter. 
 
D a ys 2 9 t o Wee k 4 S ( o nl y P K s u bjects c o nse nte d t o t he 5 2 -Wee k Tri al):  
After c o m pleti o n of t he P K p orti o n of t he st u d y, if t he s u bject c o nse nte d t o t he 5 2 -Wee k trial, s u bjects a n d 
t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y t he assig ne d st u d y dr u g t o t he s u bject's tar get great 
t oe nail a n d all ot her affecte d t oe nail(s) o nce dail y at be dti me f or t he e ntire treat me nt peri o d, e ve n if t he 
disease clears a n d n o affecte d area is o bser ve d o n t he tar get great t oe nail. If ot her affecte d t oe nai ls treate d 
si nce baseli ne clear d uri n g t he c o urse of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be 
e nc o ura ge d t o c o nti n ue treat me nt o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d diti o n, if ne w t oe nails 
bec o me i nfecte d d uri n g t he st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d 
t oe nail(s). All s u bjects a n d t heir pare nts/le gal g uar dia ns will be gi ve n i nstr ucti o ns re gar di n g h o w t o a p pl y t he 
st u d y dr u g, ie, b y c o m pletel y c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate (if o n yc h o m yc osis is prese nt). T he st u d y dr u g will be 
a p plie d t o eac h of t he ot her i nfecte d t oe nails i n a si milar ma n ner.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 0  
 
 
 
 
M o de of A d mi nist r ati o n:  
T o pical a p plicati o n: t he s u bjects will a p pl y t he st u d y dr u g t o t heir t oe nail(s), t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m, a n d t he u n ders urface of t he t oe nail plate. T he s u bjects a n d t heir pare nts/le gal g uar dia ns will be 
i nstr ucte d t o wait f or t he t oe nails t o air-dr y t h or o u g hl y bef ore t o uc hi n g wit h cl ot hi n g.  
D ur ati o n of tre at m e nt:  
4 8 wee ks  
Refere nce t her a p y, d os a ge a n d m o de of a d mi nistr ati o n:  
N ot a p plica ble  
Criteri a f or e v al u ati o n:  
Safet y : 
A d verse e ve nts will be c ollecte d as s p o nta ne o us re p orts b y t he s u bjects a n d as o bser vati o ns b y t he 
i n vesti gat ors. T he c ollecti o n of A Es s h o ul d be gi n f oll o wi n g t he s u bject's c o m pleti o n of t he c o nse nt/asse nt 
pr ocess t o partici pate i n t he st u d y.  
L ocal s ki n reacti o ns (re d ness, s welli n g, b ur ni n g,  itc hi n g, a n d vesic ulati o n) will be re vie we d wit h t he s u bject 
starti n g at t he Baseli ne Visit ( after st u d y dr u g a p plicati o n at t he i n vesti gati o nal ce nter) a n d c o nti n ui n g 
t hr o u g h t he last st u d y visit. T he prese nce or a bse nce of b ur ni n g, itc hi n g, a n d vesic ulati o n will be re p orte d 
si m pl y as " yes" or " n o". T he w orst i nsta nces of re d ness a n d s welli n g o bser ve d si nce t he pre vi o us st u d y visit 
will be re p orte d usi n g a 4 -p oi nt scale ( w here 0 = N o ne, 1 = Mil d, 2 = M o derate, a n d 3 = Se vere).  
Bl o o d a n d uri ne sa m ples will  be c ollecte d f or r o uti ne cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, 
a n d uri nal ysis) wit hi n t he 4 2 da y Scree ni n g visit wi n d o w. T hese sa m ples will be c ollecte d a gai n at Wee k 4 8, 
or at Da y 2 8 f or P K s u bjects w h o c o nse nte d t o o nl y t he 4 -Wee k tria l. A n y cli nicall y si g nifica nt a b n or malities 
i n safet y la b orat or y test res ults t hat are prese nt at t he last treat me nt visit ( Da y 2 8/ Wee k 4 8/ Earl y 
Ter mi nati o n) will be f oll o we d t o res ol uti o n (ie, ret ur n t o n or mal val ues or t o t he baseli ne state) or u ntil 
clinicall y sta ble as deter mi ne d b y t he i n vesti gat or.  
Vital si g n meas ure me nts (sitti n g bl o o d press ure, res pirati o n, p ulse, a n d te m perat ure) will be o btai ne d at 
Baseli ne a n d wee ks 1 2, 2 4, 3 6, a n d 4 8 or at Da y 2 8 f or P K s u bjects w h o c o nse nte d t o o nl y t he 4 -Wee k trial. 
A n a b bre viate d p h ysical e xa mi nati o n will be perf or me d at Baseli ne a n d Wee k 4 8, a n d at Da y 2 8 f or P K 
s u bjects w h o c o nse nte d t o o nl y t he 4-Wee k trial; as part of t he e xa mi nati o n, hei g ht a n d wei g ht will be 
meas ure d at Baseli ne a n d Wee k 4 8.  
Uri ne  pre g na nc y tests will be perf or me d f or all F O C B P at t h e Scree ni n g Visit a n d at eac h s u bse q ue nt st u d y 
visit. If a s u bject bec o mes pre g na nt d uri n g t he treat me nt peri o d, t he st u d y dr u g will be disc o nti n ue d 
i m me diatel y, t he s u bject will be disc o nti n ue d fr o m t he st u d y, a n d t he i n vesti gat or will n otif y t he s p o ns or. 
T he pre g na nc y will be f oll o we d t o ter m wit h t he o utc o me re p orte d t o t he s p o ns or.  
Efficac y will be assesse d t o e val uate c o m plia nce wit h treat me nt as part of t he safet y assess me nt. T he efficac y 
varia bles  e val uate d i n t his st u d y i ncl u de micr osc o pic K O H e xa mi nati o n a n d m yc ol o gical c ult ure o utc o mes of 
t he tar get great t oe nail, perce nt i n v ol ve me nt of t he tar get great t oe nail, gr o wt h of t he tar get great t oe nail, a n d 
assess me nts of t he n o ntar get t oe nails.  
P har m ac o ki netics: C o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4), al o n g wit h ot her rele va nt 
P K para meters, will be assess e d base d o n bl o o d sa m ples c ollecte d at Da ys 2 8 a n d 2 9. T he s pecific c ollecti o n 
ti me p oi nts are pre d ose o n Da y 2 8 a n d 2, 4, 1 2, a n d 2 4 h o urs p ost d ose.  
 
P h ot o gra p h y : 
Cl ose -u p p h ot o gra p hs of t he s u bject's tar get great t oe nail will be use d f or d oc u me ntati o n p ur p oses o nl y a n d 
will n ot be use d f or deter mi nati o ns of eli gi bilit y or a n y st u d y -relate d acti vities. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 1  
 
 
 
 
St atistic al Met h o ds:  
Safet y : 
All s u bjects w h o recei ve at least 1 c o nfir me d d ose of st u d y dr u g will be i ncl u de d i n t he safet y a nal ysis set. 
N o i m p utati o ns will be ma de f or missi n g safet y data. T he pri mar y safet y o bjecti ve will be c o nsi dere d met 
w he n a p pr o xi matel y 4 0 e val ua ble s u bjects ha ve bee n treate d f or 4 8 wee ks.  
All A Es occ urri n g d uri n g t he st u d y will be rec or de d a n d classifie d usi n g t he Me dical Dicti o nar y f or 
Re g ulat or y Acti vities ( Me d D R A). Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are t h ose A Es wit h a n  o nset 
o n or after t he date of first st u d y dr u g a p plicati o n. All T E A Es will be s u m marize d b y t he n u m ber of s u bjects 
re p orti n g eac h T E A E, t he ass ociate d s yste m or ga n class a n d preferre d ter m, t he se verit y, a n d t he relati o ns hi p 
t o st u d y dr u g f or t he Safet y, P K a n d N o n -P K p o p ulati o ns. Eac h s u bject will be c o u nte d o nl y o nce wit hi n a 
s yste m or ga n class or a preferre d ter m usi n g t he e ve nt wit h t he greatest se verit y or ca usalit y, res pecti vel y, 
wit hi n eac h cate g or y.  
Seri o us a d verse e ve nts ( S A Es) will be s u m marize d b y t he n u m ber of s u bjects re p orti n g eac h S A E, t he 
ass ociate d s yste m or ga n class a n d preferre d ter m, t he se verit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he 
Safet y, P K a n d N o n -P K p o p ulati o ns.  
L ocal s ki n reacti o n sc ores (re d ness, s welli n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) at eac h st u d y visit will be 
s u m marize d usi n g fre q ue nc y ta bles f or t he Safet y, P K a n d N o n-P K p o p ulati o ns. A d diti o nall y, re d ness a n d 
s welli n g se verit y sc ores will be s u m marize d usi n g descri pti ve statistics ( mea n, sta n dar d de viati o n  [ S D], 
me dia n, a n d mi ni m u m a n d ma xi m u m). S u bjects wit h a se verit y sc ore w orse t ha n baseli ne will als o be 
s u m marize d at eac h p ost baseli ne st u d y visit. T he w orst sc ore a n d t he last sc ore d uri n g t he p ost -baseli ne 
peri o d will als o be s u m marize d.  
Res ults of saf et y la b orat or y para meters a n d vital si g n meas ure me nts will be s u m marize d at eac h st u d y visit 
usi n g descri pti ve statistics or fre q ue ncies a n d perce nta ges, as a p pr o priate, f or t he Safet y, P K a n d N o n -P K 
p o p ulati o ns. C ha n ges fr o m baseli ne i n safet y la b orat or y val ues will be s u m marize d b y treat me nt gr o u p at 
Wee k 4 8 usi n g descri pti ve statistics. I n a d diti o n, c ha n ges fr o m baseli ne i n safet y la b orat or y val ues will be 
s u m marize d usi n g s hift ta bles acc or di n g t o n or mal ra n ges. 
T his st u d y's pri mar y o bject is t o assess t he safet y of t he st u d y dr u g. Descri pti ve efficac y statistics f or t he 
e n d p oi nts will assist i n e val uati n g c o m plia nce wit h treat me nt f or t he p ur p oses of safet y assess me nt.  
T he efficac y e n d p oi nts i ncl u de t he f oll o wi n g:  
•  
C o m plete C ure, defi ne d as 0 % cli nical i n v ol ve me nt of t he tar get t oe nail a n d ne gati ve  K O H 
a n d f u n gal c ult ure at Wee k  5 2  
•  
C o m plete or Al m ost C o m plete C ure at Wee k 5 2, defi ne d as :: 5 % t oe nail  i n v ol ve me nt 
•  
Cli nical Efficac y rate at Wee k 5 2, defi ne d as a n affecte d tar get great t oe nail area of <  1 0 %  
•  
M yc ol o gic  C ure  rate at Wee k  5 2,  defi ne d  as a ne gati ve  K O H  e xa mi nati o n  a n d  a ne gati ve 
f u n gal c ult ure of t he tar get great t oe nail sa m ple 
T he C o m plete C ure rate, t he C o m plete or Al m ost C o m plete C ure rate, t he Cli nical Efficac y rate, a n d t he 
M yc ol o gic C ure rate will be prese nte d usi n g descri pti ve statistics (sa m ple size n, fre q ue nc y c o u nts a n d 
perce nta ges) f or t he Safet y, P K a n d N o n -P K p o p ulati o ns. I n a d diti o n, t he gr o wt h of t he tar get great t oe nail at 
eac h st u d y visit a n d t he c ha n ge fr o m baseli ne i n t he n u m ber of affecte d n o ntar get t oe nails will be 
descri pti vel y s u m marize d.  
A last o bser vati o n carrie d f or war d ( L O C F) i m p utati o n will be use d t o i m p ute missi n g val ues f or t he efficac y 
varia bles at Wee k 5 2. N o se nsiti vit y a nal yses will be c o n d ucte d.  
A n y s u bjects r e mai ni n g (i.e., ha ve n ot bee n treate d f or 4 8 wee ks) will be f oll o we d u ntil c o m pleti o n. T he 
fi nal re p ort will be a me n de d wit h data o n t hese s u bjects. 
 
P har mac o ki netics : 
All s u bjects i n t he P K s u bset w h o recei ve at least 1 c o nfir me d d ose of st u d y dr u g a n d ha ve a n y P K data o n 
Da ys 2 8 a n d 2 9 will be i ncl u de d i n t he P K a nal ysis set. Bl o o d sa m ples will be teste d f or plas ma 
c o nce ntrati o ns of efi nac o naz ole a n d meta b olites ( H 3 a n d H 4). N o i m p utati o ns will be ma de f or missi n g data. 
Plas ma c o nce ntrati o ns t hat are re p o rte d as bel o w t he li mit of q ua ntitati o n ( B L Q) i n t he data tra nsfer file will 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 2  
 
 
 
 
be set t o zer o f or t he s u m maries of c o nce ntrati o ns as well as calc ulati o n of P K para meters. Missi n g val ues 
will be treate d as if t he y were ne ver dra w n. Plas ma c o nce ntrati o ns of efi nac o naz ole a n d meta b olite ( H 3 a n d 
H 4) a n d P K para meters will be s u m marize d usi n g descri pti ve statistics ( n, mea n, S D, sta n dar d err or of t he 
mea n [ S E M], c oefficie nt of variati o n [ C V], me dia n, mi ni m u m, a n d ma xi m u m). Ge o metric mea n s will als o be 
use d t o s u m marize C ma x , Cmi n , A U C( 0-t) a n d A U C ( 0-2 4 h). 
T he mea n plas ma c o nce ntrati o n ti me  pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will be 
prese nte d gra p hicall y f or Da ys 2 8 a n d 2 9 i n b ot h li near a n d l o garit h mic scales. I n di vi d ual s u bject plas ma 
c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will als o be  create d.  
Plas ma P K para meters f or efi nac o naz ole a n d meta b olites ( H 3 a n d H 4) will be calc ulate d usi n g 
n o nc o m part me ntal a nal ysis. T he P K para meters will be calc ulate d f or eac h s u bject usi n g act ual sa m pli n g 
ti mes. T he ma xi m u m plas ma c o nce ntrati o n ( Cma x ) a n d ti me t o Cma x  ( Tma x ) will be ta ke n directl y fr o m t he 
data.  
T he f oll o wi n g P K para meters will be calc ulate d fr o m t he i n di vi d ual plas ma c o nce ntrati o ns o n Da ys 2 8 a n d 
2 9 w he n p ossi ble:  
•  
C ma x  ( o bser ve d pea k dr u g [efi nac o naz ole a n d meta b olites] c o nce ntrati o n) 
•  
T ma x  (ti me at w hic h Cma x  occ urs)  
•  
C mi n  ( o bser ve d mi ni m u m dr u g c o nce ntrati o n) 
•  
A U C 0 -t (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 u p t o t he sa m pli n g ti me 
c orres p o n di n g t o t he last q ua ntifia ble  c o nce ntrati o n) 
•  
A U C 0 -2 4 h (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
[c orres p o n di n g t o t he d osi n g i nter val]) 
A d diti o nal P K para meters ma y be calc ulate d as a p pr o priate.  
 
T he P K o bjecti ves will be c o nsi dere d met w he n a p pr o xi matel y 1 6 e val ua ble s u bjects are treate d u n der 
ma xi mal use c o n diti o ns t hr o u g h da y 2 8 of t he P K e val uati o n.  
S a m ple size c alc ul ati o ns:  
A p pr o xi matel y 6 0 s u bjects will be e nr olle d a n d recei ve treat me nt wit h st u d y dr u g. A p pr o xi matel y 2 0 of t he 
s u bjects will be e nr olle d i n t he P K s u bset. T hese sa m ple sizes were base d o n P K a n d cli nical c o nsi derati o ns; 
n o f or mal sa m ple size calc ulati o n was perf or me d. T he n u m bers of pla n ne d s u bjects are c o nsi dere d a de q uate 
f or deter mi ni n g t he safet y pr ofile a n d t he P K para meters of efi nac o naz ole in a pe diatric p o p ulati o n of 
s u bjects a ge d 6 t o 1 6 years 1 1 m o nt hs wit h mil d t o se vere o n yc h o m yc osis of t he t oe nails. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 3  
 
 
 
 
 
3  T a ble of  C o nte nts  
1  
TI T L E  P A G E  ........................................................................................................... 1  
2  
S Y N O P SI S  ............................................................................................................... 5  
3  
T A B L E  O F  C O N T E N T S  .......................................................................................1 3  
4  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S  O F  T E R M S  ........................1 7  
5  
I N T R O D U C TI O N ................................................................................................. 1 8  
6  
S T U D Y O BJ E C TI V E S  A N D  P U R P O S E  .............................................................. 1 9  
7  
I N V E S TI G A TI O N A L P L A N  ................................................................................1 9  
8  
S E L E C TI O N A N D WI T H D R A W A L  O F  S U BJ E C T S  .........................................2 7  
8. 1  
S u bject  I ncl usi o n Criteri a  ..........................................................................2 7  
8. 2  
S u bject  E xcl usi o n  Criteria  .........................................................................2 8  
8. 3  
S u bject  Wit h dra wal  Criteria .......................................................................3 0  
9  
T R E A T M E N T S  P L A N N E D  .................................................................................3 0  
9. 1  
Met h o ds of Assi g ni n g S u bjects t o  Treat me nt  Gr o u ps  ...............................3 0  
9. 2  
Ra n d o mizati o n  a n d Bli n di n g  ..................................................................... 3 1  
9. 3  
Treat me nt  C o m plia nce  ...............................................................................3 1  
9. 4  
Treat me nt  A d mi nistrati o n  ..........................................................................3 1  
9. 5  
C o nc o mita nt  Me dicati o ns  ..........................................................................3 2  
9. 5. 1  All o we d  Me dicati o ns/ T hera pies  ....................................................3 3  
9. 5. 2  Pr o hi bite d  Me dicati o ns/ T hera pies  .................................................3 3  
9. 6  
Pr ot oc ol De viati o ns  a n d Vi olati o ns  ...........................................................3 4  
1 0  
S T U D Y D R U G M A T E RI A L S  A N D  M A N A G E M E N T  .......................................3 4  
1 0. 1  
St u d y  Dr u g  ................................................................................................. 3 5  
1 0. 1. 1  Pac ka gi n g  a n d L a beli n g  ................................................................. 3 5  
1 0. 1. 2  St ora ge, Ha n dli n g, a n d Dis p osal of  St u d y  Dr u g  ............................3 6  
1 0. 1. 3  St u d y  Dr u g  Pre parati o n  .................................................................. 3 6  
1 0. 2  
St u d y  Dr u g  Acc o u nta bilit y  ........................................................................3 6  
1 1  
S T U D Y P R O C E D U R E S  A N D  E V A L U A TI O N S .................................................3 7  
1 1. 1  
Sc he d ule of E val u ati o ns  a n d Pr oce d ures  ...................................................3 7  
1 1. 1. 1  Scree ni n g Visit ( Visit 1, U p t o  Da y  -4 2)  ........................................3 7  
1 1. 1. 2  Baseli ne Visit ( Visit 2,  Da y  1)  .......................................................3 9  
1 1. 1. 3  Visit 3 ( Wee k 4, D a y 2 8 [ ± 5 da ys]), Visit 4 ( Wee k 8 [ ± 5 da ys]), 
Visit 6 ( Wee k 1 6 [ ± 5 d a ys]), Visit 7 ( Wee k 2 0 [ ± 5 da ys]), Visit 9 
( Wee k 2 8 [ ± 5 da ys]), Visit 1 0 ( Wee k 3 2 [ ± 5 d a ys]), Visit 1 2 
( Wee k 4 0 [ ± 5 da ys]), Visit 1 3 ( Wee k 4 4 [ ± 5  d a ys])  ....................4 1  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 4  
 
 
1 1. 1. 4  Visit  3 A  ( We e k 4,  Da y  2 9)  - A d diti o n al  Visit  f or S u bje cts  i n t he 
P K  S u bset  .................................................................................. 4 2  
1 1. 1. 5  Visit 5 ( Wee k 1 2 [ ± 5 d a ys]), Visit 8 ( Wee k 2 4 [ ± 5 da ys]), Visit 
1 1 ( Wee k 3 6 [ ±  5  da ys]) .................................................................4 3  
1 1. 1. 6  Visit 1 4 ( Wee k 4 8 [ ± 5 d a ys]) / Earl y  Ter mi nati o n  Visit  ..............4 4  
1 1. 1. 7  Visit 1 5 ( Wee k 5 2 [ ± 5 d a ys]) P ost -Treat me nt F oll o w -u p Visit / 
St u d y  E xit.  ......................................................................................4 5  
1 1. 1. 8  U nsc he d ule d  Visits  ........................................................................ 4 5  
1 1. 1. 9  Misse d  Visits  ..................................................................................4 6  
1 1. 1. 1 0  S u bject  C o m pleti o n  ....................................................................... 4 6  
1 1. 2  
St u d y  E val uati o ns  ......................................................................................4 6  
1 1. 2. 1  L ocal  S ki n  Reacti o ns  ..................................................................... 4 6  
1 1. 2. 2  Cli nical  La b orat or y  Tests  ...............................................................4 6  
1 1. 2. 3  Vital  Si g n  Meas ure m e nts  ............................................................... 4 7  
1 1. 2. 4  P h ysical  E xa mi nati o ns  ................................................................... 4 7  
1 1. 2. 5  Efficac y f or Ass essi n g Treat me nt C o m plia nce  a n d  Safet y  ............4 7  
1 1. 2. 5. 1  K O H E xa mi nati o n a n d  F u n gal  C ult uri n g  .....................4 7  
1 1. 2. 5. 2  Tar get Grea t T o e nail  Ass ess me nts  ................................4 8  
1 1. 2. 5. 3  N o ntar get  T oe n ail  Assess me nt  ......................................4 9  
1 1. 2. 6  E val uati o n  of  P har mac o ki netics .....................................................4 9  
1 1. 2. 7  P h ot o gra p h y  ...................................................................................4 9  
1 1. 3  
Defi niti o n of  A d verse  E v e nts  .....................................................................4 9  
1 1. 3. 1. 1  Defi niti o n of Seri o us  A d verse  E v e nts  ...........................5 0  
1 1. 3. 1. 2  Assess me nt  of  Se v erit y  .................................................5 1  
1 1. 3. 1. 3  Assess me nt  of  Ca usalit y  ...............................................5 1  
1 1. 3. 1. 4  Pr oce d ures f or Re p orti n g A d verse E v e nts a n d Seri o us 
A d verse  E ve nts.  .............................................................5 2  
1 1. 3. 1. 5  S u b mitti n g a n E x pe dite d Safet y Re p ort t o t he I R B 
( Ce ntral or  L ocal)  ..........................................................5 4  
1 1. 3. 2  Pre g na nc y  .......................................................................................5 4  
1 2  
S T A TI S TI C S  ......................................................................................................... 5 5  
1 2. 1  
Assess me nt  of  Safet y  .................................................................................5 5  
1 2. 1. 1  A d verse  E ve nts  .............................................................................. 5 5  
1 2. 1. 2  L ocal  S ki n  Reacti o ns  ..................................................................... 5 5  
1 2. 1. 3  Cli nical  La b orat or y  Tests  ...............................................................5 6  
1 2. 1. 4  Vital  Si g ns  ......................................................................................5 6  
1 2. 1. 5  C o nc o mita nt  Me dicati o ns  ..............................................................5 6  
1 2. 1. 6  Efficac y f or Ass essi n g  Treat me nt  C o m plia nce  ..............................5 6  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 5  
 
 
1 2. 2  
Assess me nt  of  P har mac o ki netics  ...............................................................5 7  
T H E P K O BJ E C TI V E S WI L L B E C O N SI D E R E D M E T W H E N A P P R O XI M A T E L Y 
1 6 E V A L U A B L E S U BJ E C T S A R E T R E A T E D U N D E R M A XI M A L U S E 
C O N DI TI O N S T H R O U G H D A Y 2 8 O F T H E  P K  E V A L U A TI O N.  ...................5 7  
1 2. 3  
S u bject  Dis p ositi o n  ....................................................................................5 8  
1 2. 4  
De m o gra p hics a n d  Baseli ne  C haracteristics  .............................................. 5 8  
1 2. 5  
Pr ot oc ol  De viati o ns  ....................................................................................5 8  
1 2. 6  
C o m plia nce  ................................................................................................5 8  
1 2. 7  
I nteri m A nal yses  ........................................................................................5 8  
1 2. 8  
A d diti o nal  Statistical  C o nsi derati o ns  .........................................................5 8  
1 2. 8. 1  A nal ysis  P o p ulati o ns  ...................................................................... 5 8  
1 2. 8. 2  Sa m ple  Size  Deter mi nati o n  ............................................................5 9  
1 2. 8. 3  Ha n dli n g of  Missi n g  Data  ..............................................................5 9  
1 2. 8. 4  M ultice nter  Iss ues .......................................................................... 5 9  
1 2. 8. 5  M ulti plicit y  Iss ues .......................................................................... 5 9  
1 2. 8. 6  Wi n d o wi n g  R ules.  .......................................................................... 5 9  
1 3  
Q U A LI T Y C O N T R O L A N D  Q U A LI T Y  A S S U R A N C E  .....................................5 9  
1 3. 1  
St u d y  M o nit ori n g  .......................................................................................6 0  
1 3. 2  
A u dits  a n d I ns p ecti o ns ...............................................................................6 0  
1 3. 3  
Data  Q ualit y  Ass ura nce  .............................................................................6 1  
1 4  
E T HI C S A N D  A D MI NI S T R A TI V E  I S S U E S ......................................................6 1  
1 4. 1  
Et hical C o n d uct of  t he St u d y .....................................................................6 1  
1 4. 2  
Et hics Re vie w  ............................................................................................6 1  
1 4. 3  
Writte n  I nf or me d C o nse nt .........................................................................6 1  
1 4. 4  
S u bject  Data  Pr otecti o n  ..............................................................................6 2  
1 4. 5  
Data  M o nit ori n g  C o m mittee  ...................................................................... 6 2  
1 4. 6  
Fi na ncial  Discl os ure  ...................................................................................6 2  
1 4. 7  
Esse ntial  D oc u me nts  ..................................................................................6 3  
1 4. 8  
I n v esti gat or O bli gati o ns  .............................................................................6 3  
1 4. 9  
C ha n ges t o  t he Pr ot oc ol .............................................................................6 4  
1 4. 1 0  C o nfi de ntialit y/ P u blicati o n of  t he St u d y ...................................................6 4  
1 4. 1 1  St u d y  Ter mi nati o n ......................................................................................6 4  
1 5  
D A T A H A N D LI N G A N D  R E C O R D  K E E PI N G  .................................................6 4  
1 5. 1  
I ns p ecti o n of  Rec or ds  ................................................................................6 4  
1 5. 2  
Case Re p ort F or ms  .....................................................................................6 5  
1 5. 3  
Rete nti o n  of  Rec or ds  ..................................................................................6 6  
1 6  
R E F E R E N C E S  ...................................................................................................... 6 7  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 6  
 
 
 
 
LI S T O F T A B L E S  
Ta ble  1:  
St u d y Desi g n a n d Sc he d ule  of  Assess me nts  ...................................................2 3  
Ta ble  2.  
St u d y  Dr u g  I de ntificati o n ............................................................................... 3 5  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 7  
 
 
 
 
4  List of A b bre vi ati o ns a n d Defi niti o ns of  Ter ms  
 
A b bre vi ati o n or  S peci alist  T er m  
Defi niti o n or E x pl a n ati o n  
 
A E  
A d verse  e ve nt 
A U C 0 -2 4 h 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
(c orres p o n di n g t o t he d osi n g i nter val) 
A U C 0 -t 
Area u n der t he c o nce ntrati o n -ti me c ur ve fr o m ti me 0 u p t o t he sa m pli n g 
ti me c orres p o n di n g t o t he last q ua ntifia ble  c o nce ntrati o n 
C ma x  
O bser ve d pea k dr u g  c o nce ntrati o n  
C mi n  
O bser ve d mi ni m u m dr u g c o nce ntrati o n  
e C R F  
Electr o nic case re p ort f or m  
Efi nac o naz ole  
Efi nac o naz ole 1 0 %  S ol uti o n  
F O C B P  
Fe males of c hil d beari n g  p ote ntial  
G C P  
G o o d Cli nical  Practice  
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n  
I E C 
I n de pe n de nt Et hics C o m mittee  
I R B 
I nstit uti o nal Re vie w B oar d  
K O H  
P otassi u m  h y dr o xi de  
L O Q  
Li mit of  q ua ntitati o n  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y  Acti vities  
P K  
P har mac o ki netic  
S A E  
Seri o us a d verse  e ve nt 
T E A E  
Treat me nt -e mer ge nt a d verse  e ve nt 
T ma x  
Ti me at w hic h t he o bser ve d pea k dr u g c o nce ntrati o n  occ urs  
U S  
U nite d  States  
 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 8  
 
 
 
 
5  I ntr o d ucti o n 
O n yc h o m yc osis is a c hr o nic a n d rec urri n g f u n g al i nfecti o n of t he fi n g er nails or t oe nails t hat 
acc o u nts f or a b o ut half of all nail dis or ders. O n yc h o m yc osis is us uall y ca use d b y der mat o p h ytes, 
eit her Tric h o p hyt o n r u br u m ( 7 1 %) or Tric h o p h yt o n me nt a gr o p hytes (2 0 %). T he pre v ale nce of 
o n yc h o m yc osis i n t he U nite d States ( U S) ma y be as lar ge as 1 3 %, wit h t he i nfecti o n o bser v e d 
pre d o mi na ntl y i n el derl y patie nts ( 6 0 %) [ 1, 2]. O n yc h o m yc osis of t he t oe nail ca n res ult i n 
per ma ne nt t oe n ail def or mit y a n d has a si g nifica nt  i m pact o n q ualit y of life d ue t o c o ncer ns wit h 
t he a p peara nce of t he t oe nails a n d i nterfere nce wit h weari n g s h oes, wal ki n g, a n d partici pati n g i n 
vari o us s p orts acti vities [ 3, 4]. 
C ure rates f or t o pical treat me nts ha ve bee n si g nifica ntl y l o wer t ha n c urre nt l y a vaila ble s yste mic 
me dicati o ns [ 5 ], pr es u ma bl y beca use t he y bi n d str o n gl y t o kerati n a n d d o n ot a de q uatel y 
pe netrate t h e nail u nit. H o we ver, w hile effecti ve, oral t hera p y is li mite d b y safet y c o n cer ns d u e 
t o s yste mic e x p os ure. F or e xa m ple, b ot h oral itrac o naz ole a n d oral ter bi n afi ne ha ve t he p ote ntial 
t o ca use dr u g-dr u g i nteracti o ns a n d he pat ot o xicit y. Efi nac o naz ole 1 0 % S ol uti o n (efi nac o n az ole) 
has a l o w affi nit y f or ker ati n bi n di n g a n d has a hi g her bi n di n g re versi bilit y t ha n t hat of ot her 
refere nce dr u g s. T h er ef or e,  efi nac o naz ol e a p p ears  t o be  a pr o misi n g  a ntif u n gal  c o m p o u n d  f or t he 
t o pical treat me nt of o n y c h o m yc osis.  
Efi nac o naz ole is a n o vel triaz ole a ntif u n gal a ge nt t hat is acti ve i n vitr o a gai nst a wi de ra n g e of 
pat h o ge nic f u n gi a n d is e x pecte d t o be effecti ve i n t he treat me nt of mil d t o m o derate 
o n yc h o m yc osis.  
Efi nac o naz ole has b ee n s h o w n t o be effi caci o us i n vitr o a gai nst a pa nel of f u n gal s pecies t hat 
i n va de h u ma n s ki n, hair, a n d nails i ncl u di n g der m at o p h ytes Tric h o p h yt o n, Micr os p or u m, 
E pi der m o p h yt o n, a n d t he yeast, Malassezia s peci es, res p o nsi ble f or ti nea u n g ui u m 
( o n yc h o m yc osis), ti nea c or p oris, ti nea pe dis, ti nea ca pitis, a n d pit yriasis versic ol or. 
Efi nac o naz ole has b ee n s h o w n t o be f u n gici dal a g ai nst C a n di d a al bic a ns a n d ot her Ca n di d a 
s pecies res p o nsi ble f or t h e maj or yeast ( n o n d er mat o p h yte) f or m of o n y c h o m yc osis a n d 
c uta ne o us ca n di diasis. I n vitr o st u dies a gai nst der mat o p h ytes s h o we d t hat efi nac o n az ole w as 
m ore p ote nt t ha n cl otri maz ole, b ut less p ote nt t ha n b ute nafi ne.  
Efi nac o naz ole has s u ccessf ull y treate d e x p eri me nt all y i n d uce d der mal ca n di diasis, ti nea 
c or p oris, ti nea pe dis, a n d ti nea u n g ui u m i n vi v o i n g ui nea pi g m o dels. It has ge nerall y o ut 
perf or me d ref er e nce dr u gs i n t hese m o dels, a n d i n partic ular o ut perf or me d t he mar kete d dr u gs 
f or ti nea u n g ui u m: cicl o pir o x ola mi ne (a p pr o v e d f or t he t o pical treat me nt of o n yc h o m yc osis i n 
t he U S), a m or olfi ne ( a vaila ble o utsi de t he U S as a t o pical nail lac q uer), a n d ter bi nafi ne 
(a vaila ble i n t he U S i n or al f or m). 
T he safet y a n d efficac y of o nce dail y use of efi n ac o naz ole f or t he treat me nt of o n yc h o m yc osis of 
t he t oe nail wer e assesse d i n t w o 5 2-wee k pr os p ecti ve, m ultice nter, ra n d o mi ze d, d o u ble -bli n d  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
1 9  
 
 
 
 
cli nical st u dies. T hese st u dies were c o n d ucte d i n s u bjects 1 8 t o 7 0 years of a ge wit h 2 0 % t o 5 0 % 
cli nical i n v ol ve me nt of t he tar get gr eat t oe nail, wit h o ut der mat o p h yt o mas or l u n ula ( matri x) 
i n v ol ve me nt ( n = 8 7 0 i n St u d y 1 a n d n = 7 8 1 i n St u d y 2) [6 ]. T hes e st u dies e val uate d 4 8-wee ks 
of treat me nt wit h efi n ac o naz ole r elati ve t o ve hicle s ol uti o n. At Wee k 5 2 ( 4 -wee ks after 
c o m pleti o n of t hera p y), efi nac o naz ole was s u p eri or t o ve hicle s ol uti o n i n b ot h st u dies a n d t h us 
de m o nstrate d efficac y i n t he treat me nt of o n y c h o m yc osis. T he m ost c o m m o n a d verse reacti o ns 
(ie, reacti o ns wit h i nci de nces > 1%) re p orte d i n t he st u dies were i n gr o w n t oe nails, a p plicati o n 
site der matitis, a p plicati o n site vesicles, a n d a p plicati o n site pai n. 
Efi nac o naz ole w as a p pr o ve d b y t he U S F o o d a n d Dr u g A d mi nistrati o n i n J u ne 2 0 1 4 f or t he 
t o pical treat me nt of o n yc h o m yc osis of t he t oe nail(s) d ue t o T r u br u m a n d T me nt a gr o p hytes 
(J u blia®  [efi nac o n az ole] t o pical s ol uti o n, 1 0 % [6 ]). T he a p pr o v e d dr u g is i nte n de d f or t o pical 
a p plicati o n t o affecte d t o e nails o nce dail y f or 4 8 wee ks. D uri n g a p plicati o n, t he t oe nail, t oe nail 
f ol ds, toe nail be d, h y p o n yc hi u m, a n d u n ders urface of t he t oe nail plate are t o be c o m pletel y 
c o vere d.  
T he c urr e nt cli nical st u d y is desi g ne d t o e val uate t he safet y a n d p h ar mac o ki netics ( P K) of o nce 
dail y t o pical a p plicati o n of efi nac o naz ol e i n t he treat me nt of pe di atri c s u bjects wit h mil d t o 
se vere o n y c h o m yc osis of t he t oe nails. A p plicati o n a n d use of t he st u d y dr u g is c o nsiste nt wit h 
t he a p pr o v e d  pac ka g e  i nsert. T he  e val u ati o ns  i ncl u de d i n t he c urre nt  st u d y are c o nsiste nt  wit h  t he 
e val uati o ns c o n d ucte d i n t he de vel o p me nt of t he a p pr o ve d  dr u g.  
 
6  St u d y O bjecti ves a n d  P ur p ose  
T he pri mar y o bjecti ves of t his st u d y are t o e val uat e: 1) safet y of o nce d ail y t o picall y 
a d mi nistere d efi nac o naz ole 1 0 % f or 4 8 w ee ks i n pe diatric s u bjects ( 6 -1 6 y ears, 1 1 m o nt hs of 
a ge) wit h at least mil d o n yc h o m yc osis of t he t oe nails, a n d 2) p har mac o ki n etics P K ( 4 wee ks) of 
o nce dail y t o picall y a d mi nistere d efi nac o naz ole 1 0 % i n pe diatric s u bjects ( 1 2 -1 6 years, 1 1 
m o nt hs of a ge) wit h m o derate t o se v ere o n y c h o m yc osis of t he t oe nails.  
 
7  I n vesti g atio n al Pl a n  
7. 1  I n vesti g at ors a n d St u d y A d mi nistr ati ve Str uct u re  
A p pr o xi matel y 2 0 -2 5 i n v esti gati o nal ce nters are pl a n ne d t o partici pat e i n t his st u d y. Eac h 
cli nical i n vesti gat or will be re q uir e d t o pr o vi de a c o p y of his/ her c urric ul u m vitae a n d me dical 
lice nse, c o m plete a fi na n cial discl os ure state me nt, a n d ge nerate a list of st u d y pers o n nel w h o will 
be i n v ol ve d i n t he st u d y, wit h a s u m mar y of t heir r oles a n d  q ualificati o ns.  
T he S p o ns or has desi g nate d a C o ntract Researc h Or ga nizati o n t o ass u me res p o nsi bilit y f or 
acti vities relate d t o t he c o n d uct of t he st u d y. T he S p o ns or als o has desi g nate d ce ntral la b orat ories 
t o a nal yze bi ol o gical sa m ples relate d t o cli nical s afet y, p har mac o ki n etics, a n d m yc ol o g y. A 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 0  
 
 
 
 
listi n g of t he or ga nizati o ns i n v ol ve d i n t he c o n d uct of t he st u d y is pr o vi de d u n der Pers o n nel 
Secti o n i n t he fr o nt of t he pr ot oc ol. A c o m plete d escri pti o n of t he S p o ns or's a n d dele gates' 
st u d y-relate d r ol es/res p o nsi bilities, i ncl u di n g ke y pers o n nel, is c o ntai ne d wit hi n t he S p o ns or's 
st u d y pr oject plan.  
7. 2  S u m m ar y of St u d y Desi g n  
T his is a n o pe n la bel, si n gle -ar m st u d y desi g ne d t o e val uate t he s afet y a n d P K of a o nce d ail y 
t o pical a p plicati o n of efi nac o naz ole i n t he treat me nt of pe diatric s u bjects wit h mil d t o se vere 
o n yc h o m yc osis of t he t oe nails. T he st u d y will i ncl u de a t otal of 6 0 s u bjects, 4 0 of w h o m will be 
6 t o 1 6 years of a ge, i ncl usi ve, a n d P K assess me nts will be perf or me d o n a p pr o xi matel y 2 0 
s u bjects 1 2 t o 1 6 years of a ge, i ncl usi ve (referre d t o t hr o u g h o ut t he pr ot oc ol as t he P K s u bset). 
All s u bje cts m ust ha ve o n yc h o m yc osis of at least 1 great t oe nail; s u bjects i n t he P K s u bset m ust 
ha ve o n yc h o m yc osis of b ot h great t oe nails a n d at least 4 ot her t oe n ails. Eff orts will be ma de t o 
e nr oll s u bjects i nt o t he P K s u bset s uc h t hat t he s u bjects are e ve nl y di stri b ute d acr oss t he re q uire d 
a ge ra n g e.  
F or s u bjects n ot partici pati n g i n t he P K s u bset, t he st u d y will c o nsist of 1 4 sc he d ule d visits, 
i ncl u di n g Scree ni n g ( u p t o Da y -4 2), Bas eli ne ( D a y 1), 1 2 treat me nt visits ( Wee ks 4, 8, 1 2, 1 6,  
2 0, 2 4, 2 8, 3 2, 3 6, 4 0,  4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p visit ( Wee k 5 2). 
S u bjects i ncl u de d i n t he P K s u bset M U S T deci de at ti me of c o nse nt w het h er t o partici pate i n t he 
4 -Wee k trial, atte n d t he s c he d ule d visits u p t o Wee k 4 ( Da y 2 9) f or c ollecti o n of t he fi nal  P K 
sa m ple a n d e xit t he st u d y O R partici pate i n t he 5 2 -Wee k trial treat me nt t hr o u g h wee k 4 8 wit h 
a d diti o nal visits at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost - 
treat me nt f oll o w-u p visit ( Wee k 5 2). T he P K assess me nts will be p erf or me d u n der ma xi mal use 
c o n diti o ns.  
At t he Scree ni n g Visit, s u bjects a n d t heir pare nts/le gal g uar dia ns will si g n a n i nf or me d 
c o nse nt/asse nt f or m a n d a p h ot o gra p h y c o ns e nt/asse nt f or m, pr o vi de t heir me dical hist ories, 
re p ort t heir pr e vi o us a n d c o nc o mita nt me dicati o ns, a n d be e v al uate d a g ai nst t he 
i ncl usi o n/e xcl usi o n criteria. Fe mal es of c hil d beari n g p ote ntial ( F O C B P) will ha ve uri ne 
pre g na nc y t ests perf or me d. D uri n g t his visit, s u bjects will u n der g o a n e x a mi nati o n of t heir feet t o 
vis uall y ascertai n t he p rese nce of o n y c h o m yc osis i n at least 1 great t oe n ail f or s u bjects n ot 
i ncl u de d i n t he P K assess me nts, a n d o n b ot h great t oe nails a n d at least 4 ot h er t oe nails f or 
s u bjects i ncl u de d i n t he P K assess me nts. A d diti o nall y, t he perce nt i n v ol ve me nt of t he affected 
great t oe nail(s) will be rec or de d. S peci me n will be o btai ne d fr o m t he great t oe nail(s) t o s hi p t o 
t he m yc ol o g y la b. B ot h t oe nails ma y be sa m ple d if b ot h are s us pecte d of m a nifesti n g 
o n yc h o m yc osis (at least 2 0 % i n v ol ve me nt). Bl o o d a n d uri ne s peci me ns will  be c ollecte d f or 
ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis e val uati o ns. At rele va nt p ost-Scree ni n g Visits, t he 
tar get great t oe nail will be tri m me d bac k t o t he distal gr o o ve bef ore t he cli nical e val uati o ns are 
perf or me d a n d bef ore p h ot o gra p hs are t a ke n.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 1  
 
 
 
 
If a s u bject fails scree ni n g, eit her at t he Scree ni n g or Baseli ne visit ( pri or t o e nr oll me nt t o 
treat me nt), t he s u bject ma y be res cree ne d at a later date. S u bjects w h o are rescree ne d, will be 
assi g ne d a ne w s cree ni n g n u m ber, m ust be re -c o ns e nte d, a n d u n der g o all scree ni n g pr o ce d ures 
per pr ot oc ol.  
At t he Baseli ne Visit ( w hic h s h o ul d be sc he d ule d after K O H a n d f u n gal c ult ure res ults ha ve b ee n 
o btai ne d fr o m t he m yc ol o g y la b), s u bjects a n d/ or t heir pare nts/le gal g u ar di a ns will u p date t heir 
me di cal hist ories a n d c o n c o mita nt me dicati o n uses, a n d t he i ncl usi o n/e xcl usi o n criteria will be 
c o nfir me d. S u bjects will u n der g o a b br e viate d p h ysical e xa mi nati o ns, cli nical la b orat or y 
e val uati o ns, assess me nts of vital si g ns (sitti n g bl o o d press ure, res pirati o n , p ulse, a n d 
te m perat ur e), a n d meas ur e me nts of hei g ht a n d w ei g ht. All F O C B P will ha ve uri ne pre g na nc y 
tests perf or me d. F or t he p ur p oses of efficac y assess me nts, 1 tar get great t o e nail will be selecte d 
fr o m t he st u d y-eli gi ble great t oe nail(s), i ncl u di n g s u b jects i n t he P K s u bset f or w h o m b ot h great 
t oe nails m ust be i n v ol ve d. W here b ot h great t oe n ails are st u d y-eli gi ble, t h e t oe nail wit h t he 
greater per ce nt of aff ecte d area will be selecte d f or m yc ol o gic data a n d f or i ncl usi o n i n t he 
efficac y a n al ysis. I n t h e  i nsta nce w here t he p erce nt of affecte d area is t he sa me f or b ot h st u d y- 
eli gi ble great t oe nails, t h e i n vesti gat or ma y select eit her great t oe nail as t he tar get t oe nail. T he 
tar get great t oe nail will be i de ntifie d a n d rec or d e d f or eac h s u bject, p h ot o gra p hs of t he tar g et 
great t oe nail will be o btai ne d, a n d a tr a ns vers e n otc h will be i nscri be d i n t h e tar get great t oe nail 
a djace nt t o t he pr o xi mal t oe nail f ol d (as a m ar ker f or meas uri n g t oe nail gr o wt h at s u bse q ue nt 
visits). Assess me nts of all ot her n o ntar get t o e n ails, i ncl u di n g t he ot her i n v ol ve d t oe nails of 
s u bjects i n t he P K s u bset, will als o be c o n d ucte d t o assess t he pres e nce or a bse nce of 
o n yc h o m yc osis o n eac h t oe nail. T his assess me nt will c o nti n ue t hr o u g h o ut t he st u d y visits 
t hr o u g h wee k 5 2. 
 
After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit ( Da y 1), s u bjects will be e nr olle d i n t he 
treat me nt peri o d. S u bjects or t heir par e nts/le gal g uar dia ns will a p pl y t he first d ose of st u d y dr u g 
t o t he q ualifie d t oe nails at t he i n vesti gati o nal ce nter u n der t h e s u per visi o n of desi g nate d st u d y 
pers o n nel. A n y l ocal s ki n reacti o ns t hat occ ur at t h e st u d y dr u g a p plicati o n site, al o n g wit h a n y 
a d verse e ve nts ( A Es), will be rec or d e d. S u bjects a n d t heir pare nts/le gal g u ar dia ns will recei v e 
wei g he d st u d y dr u g b ottles a n d gi ve n ver bal a n d writte n i nstr ucti o ns f or treat me nt a p plicati o n. 
S pecificall y, s u bjects w h o are n ot i ncl u de d i n t he P K s u bset will be i nstr ucte d t o a p pl y t he st u d y 
dr u g t o t he aff ecte d t oe n ails o nce dail y at be dti me f or 4 8 wee ks. S u bjects w h o are i ncl u de d i n  t he 
P K s u bset will be i nstr ucte d t o a p pl y t he st u d y dr u g t o all 1 0 t oe nails o nce dail y at be dti me f or 4 
wee ks. F oll o wi n g t he P K bl o o d c ollecti o ns o n Da ys 2 8 a n d 2 9, P K s u bjects t hat c o nse nte d t o t he 
5 2 -Wee k trial will c o nti n ue treat me nt wit h st u d y dr u g t o  o nl y t he affect e d t oe nails. a n d ret ur n t o 
t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4-wee k 
p ost -treat me nt f oll o w-u p visit ( Wee k 5 2). All s u bj ects or t heir pare nts/le gal g uar dia ns will als o  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 2  
 
 
 
 
recei v e diaries, wit h i nstr ucti o ns t o c o m plete a rec or d of all a p plicati o ns a n d t o n ote a n y misse d 
a p plicati o ns of t he st u d y dr u g.  
S u bjects i n t he P K s u bset will n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( D a y 2 8) visit. 
F oll o wi n g t he Da y 2 8 st u d y pr oce d ur es, s u bjects i n t he P K s u bset will u n der g o ti me d bl o o d 
c ollecti o ns t o assess plas ma c o nce ntr ati o ns of efi n ac o naz ole a n d meta b olites ( H 3 a n d  H 4).  
Assess me nts will re q uire c ollecti o n of a p pr o xi mat el y 4 m L of w h ole bl o o d at eac h ti me p oi nt 
(a p pr o xi mately 2 0 m L t otal). Wit hi n 1 h o ur after t he pre d ose bl o o d s a m ple is dra w n, t he 
s u bjects/ pare nts/le gal g u ar dia ns will a p pl y st u d y dr u g t o all 1 0 t oe nails at t he i n vesti gati o nal 
ce nter. S u bse q u e nt bl o o d c ollecti o ns will occ ur 2, 4, a n d 1 2 h o urs p ost d ose o n Da y 2 8. T he 
s u bjects will g o h o me after Da y 2 8, b ut will n ot a p pl y st u d y dr u g o n t he ni g ht of t he Da y 2 8 
visit. All P K s u bjects i n t he 4 -Wee k trial will ret ur n t o t he i n vesti gati o nal ce nter t he f oll o wi n g 
da y ( Da y 2 9) f or c ollecti o n of a 2 4 -h o ur p ost d ose bl o o d s a m ple, a n d e xit t he st u d y. P K s u bjects 
t hat c o nse nte d 5 2-w ee k trial will c o nti n ue treat me nt wit h st u d y dr u g t o o nl y t he tar get great 
t oe nail a n d t he ot her aff ecte d t oe nails a n d ret ur n t o t he i n vesti gati o nal ce nt er at Wee ks 8, 1 2, 1 6, 
2 0, 2 4, 2 8, 3 2, 3 6, 4 0 , 4 4, a n d 4 8), a n d a 4-wee k p ost -treat me nt f oll o w-u p visit ( Wee k  5 2)  
Safet y will be assesse d b y re vie wi n g t he occ urre n ce of A Es a n d l ocal s ki n reacti o ns, ass essi n g 
vital  si g n meas ure me nts  a n d a b br e viate d  p h ysical  e xa mi nati o n  fi n di n gs, a n d n oti n g  a n y a d diti o ns 
or c ha n ges i n c o nc o mita nt me dicati o n uses. Bl o o d sa m ples will be c ollect e d at Scree ni n g, at 
Wee k 4 ( Da y 2 8) o nl y f or P K s u bjects w h o ha ve c o nse nte d t o o nl y 4 wee ks of treat me nt, a n d at 
Wee k 4 8 f or r o uti ne safet y la b orat or y e v al uati o ns (ser u m c he m istr y, he m at ol o g y, a n d 
uri nal ysis); uri ne pre g n a nc y tests will be o btai ne d f or all F O C B P at eac h st u d y visit. Efficac y 
assess me nts will be perf or me d t hr o u g h o ut t he st u d y. Efficac y a nal ys es will be base d o n 
micr osc o pic e x a mi nati o n a n d m yc ol o gical c ult ure re s ults f or t he tar g et great t oe nail, t he perce nt 
i n v ol ve me nt of t he tar get great t oe nail, t he le n gt h of t he u naffecte d p art of t he tar get great 
t oe nail, t he gr o wt h of t he tar get great t oe nail, a n d t he n u m ber of affecte d n o ntar get t oe n ails. 
A p ost -treat me nt f oll o w-u p visit will occ ur 4 wee ks after t he last treat me nt visit f or eac h s u bject 
w h o c o nti n ues t hr o u g h Wee k 4 8 (ie, at Wee k 5 2). S u bjects w h o disc o nti n ue fr o m t he st u d y pri or 
t o Wee k 4 8 will ret ur n t o c o m plete t he Wee k 4 8 st u d y pr oce d ures. 
T he st u d y desi g n a n d sc h e d ule of assess m e nts is prese nte d i n Ta bl e 1  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 3  
 
 
 
 
Ta ble  1:  
St u d y Desi g n a n d Sc he d ule of  Assess me nts  
 
 
Tre at m e nt Peri o d  
P ost - 
Tre at me nt  
Visit  
1 - 
S C R  
2 -B L  
3  
3 A a 
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4 b 
1 5  
Wee k  
 
P R O C E D U R E S  
U p t o 
Da y  
-4 2  
Da y 
1  
4  
( Da y 
2 8)  
4  
( Da y 
2 9)  
8  
1 2  
1 6  
2 0  
2 4  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 2  
O btai n I nf or me d C o nse nt/ Asse nt a n d 
P h ot o gra p h y C o nse nt/ Asse nt  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w Me dical Hist or y  
X  
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w Pre vi o us T hera pies  
X  
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w I ncl usi o n/ E xcl usi o n Criteria 
X  
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n d uct Uri ne Pre g na nc y Test (all 
fe males of c hil d beari n g p ote ntial) d 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Cli p T oe nails e 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
N otc h Tar get Great T oe nail f 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Meas ure Tar get Great T oe nail Gr o wt h 
(fr o m t he P N F t o t he n otc h) f 
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o n d uct Tar get Great T oe nail 
Assess me nts g 
X  
X  
 
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
C o n d uct N o ntar get T oe nail 
Assess me nts h 
X  
X  
 
 
 
X  
 
 
X  
 
 
X  
 
 
X  
X  
O btai n P h ot o gra p h y  
 
X  
 
 
 
 
 
 
X   
 
 
 
 
X  
X  
Perf or m K O H E xa mi nati o n i 
X  
 
 
 
 
X   
 
X   
 
X  
 
 
X  
X  
Sa m ple f or F u n gal C ult ure i 
X  
 
 
 
 
X   
 
X   
 
X  
 
 
X  
X  
C o n d uct A b bre viate d P h ysical E xa m j  
X  
X t 
 
 
 
 
 
 
 
 
 
 
 
X  
 
O btai n Vital Si g ns k 
 
X  
X t 
 
 
X   
 
X   
 
X  
 
 
X  
 
C ollect Bl o o d a n d Uri ne Sa m ples f or 
C B C/ Diff, C he mistr y, a n d 
Uri nal ysis  
 
X p  
 
 
X t 
 
 
 
 
 
 
 
 
 
 
 
 
X l 
 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 4  
 
 
 
 
 
 
 
Tre at m e nt Peri o d  
P ost - 
Tre at me nt  
Visit  
1 - 
S C R  
2 -B L  
3  
3 A a 
4  
5  
6  
7  
8  
9  
1 0  
1 1  
1 2  
1 3  
1 4 b 
1 5  
Wee k  
 
P R O C E D U R E S  
U p t o 
Da y  
-4 2  
Da y 
1  
4  
( Da y 
2 8)  
4  
( Da y 
2 9)  
8  
1 2  
1 6  
2 0  
2 4  
2 8  
3 2  
3 6  
4 0  
4 4  
4 8  
5 2  
E nr oll Q ualifie d S u bjects  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re vie w D osi n g I nstr ucti o ns  
 
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A p pl y First D ose i n Cli nic  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wei g h/ Dis pe nse St u d y Dr u g  
 
X  
X n u   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A p pl y St u d y Dr u g  
 
X q  
 
  
C ollect/ Wei g h St u d y Dr u g  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Re vie w C o m plia nce  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Dis pe nse Diar y  
 
X  
X o u   
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
C ollect/ Re vie w Diar y  
 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
P K Bl o o d Sa m ple C ollecti o n m  
 
 
X m  
X m   
 
 
 
 
 
 
 
 
 
 
 
Re vie w L ocal S ki n Reacti o ns  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Re vie w C o nc o mita nt Me dicati o ns  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Re vie w A d verse E ve nts  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E xit St u d y  
 
 
 
X t 
 
 
 
 
 
 
 
 
 
 
 
X  
A b bre viati o ns: B L = Baseli ne Visit; C B C/ Diff = c o m plete bl o o d c o u nt/ differe ntial; K O H = p otassi u m h y dr o xi de; P K = p har mac o ki n etic; P N F = pr o xi mal t oe nail 
f ol d; S C R = Scree ni n g Visit 
N ote: P ost -baseli ne visits are t o be sc he d ule d i n refere nce t o Visit 2 ( Baseli ne Visit) a n d wit hi n a wi n d o w of ± 5 da ys. 
a Visit 3 A ( Da y 2 9) is o nl y t o be c o n d ucte d f or s u bjects i n t he P K s u bset.  
b F or all N o n -P K s u bjects a n d P K s u bjects i n 5 2 wee k trial, all Wee k 4 8 pr oce d ures are t o be c o m plete d f or s u bjects w h o disc o nti n ue fr o m t he st u d y d uri n g t he 
treat me nt peri o d (ie, Earl y Ter mi nati o n). 
c C o nfir mati o n of e val uati o ns c o n d ucte d at t he Scree ni n g Visit.  
d Uri ne pre g na nc y tests are re q uire d t o ha ve a mi ni m u m se nsiti vit y of 2 5 mI U of h u ma n  c h ori o nic g o na d otr o pi n per m L of uri ne.  
e T oe nails are cli p pe d pri or t o c o n d ucti n g t he assess me nts.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 5  
 
 
 
 
f T he tra ns verse n otc h i nscri be d at t he Baseli ne Visit is e n ha nce d, as nee de d, at s u bse q ue nt visits t o all o w c o nti n ue d meas ure m e nt of  t oe nail gr o wt h o ver t he 
c o urse of t he st u d y. I n cases w here t he i nitial n otc h gr o ws o ut or is cli p pe d a wa y, a ne w n otc h is i nscri be d i n t he t oe nail a djace nt t o t he pr o xi mal t oe nail f ol d 
a n d meas ure me nts of t oe nail gr o wt h (ie, pr o xi mal t oe nail f ol d t o n otc h) will c o nti n ue usi n g t he ne w n otc h.  
g Assess me nts i ncl u de calc ulati o n of t he perce nt i n v ol ve me nt of t he t oe nail affecte d b y o n yc h o m yc osis a n d meas ure me nt of t he di sta nce fr o m t he pr o xi mal 
t oe nail f ol d t o t he pr o xi mal o n yc h o m yc otic b or der. 
h Assess me nt of  n o ntar get nails f or prese nce or a bse nce of o n yc h o m yc osis.  
i At t he Scree ni n g visit, K O H s peci me ns f or K O H a n d f u n gal c ult ures will be s hi p pe d t o t he m yc ol o g y la b. At all s u bse q ue ntl y i n dicate d st u d y visits, 
s peci me ns f or K O H e xa mi nati o ns a n d f u n gal c ult ures are o btai ne d fr o m t he tar get great t oe nail.  
j T he a b bre viate d p h ysical e xa mi nati o n at t he Baseli ne Visit a n d Wee k 4 8 i ncl u des hei g ht a n d wei g ht,  
k Vital si g n meas ure me nts at eac h visit i ncl u de te m perat ure, p ulse, res pirati o ns, a n d sitti n g bl o o d press ure . 
l A n y cli nicall y si g nifica nt la b orat or y a b n or malit y prese nt at Wee k 4 8 ( or Earl y Ter mi nati o n) is t o be f oll o we d t o res ol uti o n o r u ntil cli nicall y sta ble as 
deter mi ne d b y t he i n vesti gat or.  
m A s u bset of e nr olle d s u bjects will be assi g ne d t o P K e val uati o ns. At t he Wee k 4/ Da y 2 8 Visit, s u bjects i n t he P K s u bset will u n der g o ti me d bl o o d sa m pli n g o n 
Da ys 2 8 t o 2 9  
n St u d y dr u g s h o ul d be wei g he d a n d dis pe nse at Visit 3 A f or P K s u bjects 
o Diar y s h o ul d be dis pe nse d wit h st u d y dr u g at Visit 3 A f or P K s u b jects. 
p C ollecti o n of Scree ni n g safet y la bs ma y be p ost p o ne d u ntil after p ositi ve Scree ni n g m yc ol o g y res ults are recei ve d, o nl y if  t he s u bject/ pare nt are willi n g t o 
ret ur n t o t he researc h site f or safet y la b c ollecti o n pri or t o t he e n d of t he 4 2-da y scree ni n g wi n d o w. Scree ni n g safet y la b res ults m ust be recei ve d wit hi n t he 
4 2 -da y scree ni n g visit wi n d o w.  
q T he s u bject or t heir pare nt/le gal g uar dia n will a p pl y t he first d ose of st u d y dr u g i n t he i n vesti gati o nal ce nter, wit h g ui da n ce fr o m st u d y staff. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 6  
 
 
 
 
Visit  
3  
3 A u 
D a y 
( Wee k) 
2 8  
( 4) 
2 9  
( 4) 
P R O C E D U R E S  
 
Pre d ose  
 
-1 h F oll o wi n g 
Pre -d ose Sa m ple  
 
2 h  
( ± 5 mi n) 
4 h  
( ± 5 mi n) 
 
1 2 h  
( ± 1 5 mi n) 
 
2 4 h  
( ± 3 0 mi n) 
P K S u bset - C ollect Bl o o d f or Plas ma 
C o nce ntrati o ns  
X r 
 
X  
X  
X  
X  
P K S u bset - St u d y Dr u g A p plicati o n  
 
X s 
 
 
 
 
r T he pre d ose bl o o d sa m ple is t o be c ollecte d after all Da y 2 8/ Wee k 4 st u d y pr oce d ures are c o m plete d.  
s St u d y dr u g a p plicati o n o n Da y 2 8/ Wee k 4 will occ ur at t he i n vesti gati o nal ce nter wit hi n 1 h o ur after c ollecti n g t he pre d ose bl o o d sa m ple. T his will be t he last 
a p plicati o n of st u d y dr u g t o all 1 0 t oe nails f or s u bjects i n t he P K s u bset. F or P K s u bjects t hat ha ve c o nse nte d t o c o nti n ui n g  treat me nt t hr o u g h wee k 4 8: After Da y 
2 8, s u bjects a n d t heir pare nts/le g al g uar dia ns will be i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he s u bject's tar get great t oe nail a n d all ot her affecte d  
t oe nail(s) o nce dail y at be dti me f or t he e ntire treat me nt peri o d, e ve n if t he disease clears a n d n o affecte d area is o bser ve d o n t he tar get great t oe nail. If ot her 
affecte d t oe nails treate d si nce baseli ne clear d uri n g t he c o urse of t he st u d y, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt 
o n t h ose t oe nails f or t he d urati o n of t he st u d y. I n a d di ti o n, if ne w t oe nails bec o me i nfecte d d uri n g t he st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he 
a d diti o nall y affecte d t oe nail(s).  
t A p plies o nl y t o P K s u bjects i n w h o c o nse nte d t o 4 wee k trial  
u N ot a p plica ble f or P K s u bjects w h o c o nse nt t o o nl y t he 4 wee k trial.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 7  
 
 
 
 
8  Selecti o n a n d Wit h dr a w al of  S u bjects  
S. 1  S u bject I ncl usi o n  Criteri a  
S u bjects meeti n g all of t he f oll o wi n g criteria will be eli gi ble f or st u d y e ntr y:  
1.  Male or fe m ale s u bjects of a n y race, 6 t o 1 6 years of a ge (i n cl usi ve) at  Scree ni n g.  
•  P K S u bset : Male or fe male s u bjects of a n y race, 1 2 t o 1 6 years of a ge (i ncl usi ve) at 
Scree ni n g.  
2.  Ver bal a n d writte n i nf or me d c o nse nt/asse nt o btai ne d fr o m t he s u bject a n d/ or t heir 
pare nt or le g al  g uar dia n.  
3.  G o o d ge ner al healt h, as assesse d b y t he i n vesti gat or, base d o n t he s u bject's me dical 
hist or y, p h ysical e xa mi nati o n, a n d safet y la b orat or y  tests. 
4.  At least 1 great t oe n ail (t he "tar get great t oe nail") wit h cli nicall y dia g n ose d distal 
lateral s u b u n g ual o n yc h o m yc osis i n v ol vi n g at least 2 0 % of t he affect e d great t oe nail  at 
t he Scree ni n g a n d B aseli ne Visits (as deter mi ne d b y t he i n vesti gat or), wit h o ut 
der mat o p h yt o mas or l u n ula ( matri x) i n v ol ve me nt. T here is n o s pecific u p p er li mit f or 
perce nt i n v ol ve me nt. U p t o 6 t oe nails ma y ha ve o n yc h o m yc osis i n s u bjects n ot 
partici pati n g i n t he P K  s u bset. 
•  P K S u bset : B ot h great t oe nails wit h cli nicall y dia g n ose d distal lateral s u b u n g ual 
o n yc h o m yc osis i n v ol vi n g at least 5 0 % of t he affecte d great t oe nail at t he S cree ni n g 
a n d Baseli ne Visits (as d eter mi ne d b y t he i n vesti g at or), wit h o ut der mat o p h yt o mas or 
l u n ula ( matri x) i n v ol ve me nt. T here is n o s pecific u p per li mit f or perce nt i n v ol ve me nt. 
S u bjects m ust als o ha ve at least 4 t oe nails ot her t ha n t he great t oe nails wit h 
o n yc h o m yc osis.  
5.  Tar get  gr eat  t oe nail f or all s u bjects, a n d b ot h  great  t oe nails f or s u bjects i n t h e P K 
s u bset, m ust ha ve e vi de n ce of t oe n ail gr o wt h, per s u bject's re p ort t hat m o nt hl y 
cli p pi n g is  nee de d.  
6.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( D a y 1) Visit, ha ve a p ositi ve K O H e x a mi nati o n 
(res ults will be pr o vi de d b y t he ce ntral t he m y c ol o g y la b) of t he tar g et great t oe nail f or 
all s u bjects 
7.  Wit hi n 4 2 da ys pri or t o t he Baseli ne ( D a y 1) Visit, ha ve a p ositi ve der mat o p h yte 
c ult ure f or T  r u br u m or  T  me nt a gr o p hytes  (at the  ce ntral m yc ol o g y  la b orat or y) fr o m 
t he tar get gr eat t oe nail i n all s u bjects 
•  P K S u bset : Pri or t o t he Baseli ne Visit, t he great t oe nail desi g nate d f or efficac y 
assess me nts as t he tar g et great t oe nail m ust ha ve b ot h a p ositi ve K O H 
e xa mi nati o n (res ults will be pr o vi de d b y t he ce ntral m yc ol o g y la b) a n d a 
p ositi ve f u n gal c ult ure.  
8.  All  F O C B P  m ust  ha ve  a ne gati ve  uri ne  pre g na n c y  test at t he Scree ni n g  a n d Baseli ne 
Visits a n d m ust a gree t o use a n effecti ve m et h o d of c o ntrace pti o n t hr o u g h o ut  t he 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 8  
 
 
 
st u d y. Effecti ve c o ntrace pti o n is defi ne d as use of a n i ntra uteri ne d e vice, c o n d o m wit h 
s per mici de, dia p hr a g m wit h s per mici de, a bsti ne nce (s u bject is n ot se x uall y acti ve), or 
sta ble use of a h or m o nal c o ntrace pti ve ( oral, i m pla nt, i njecti o n, or tra ns der mal patc h) 
f or at least 3 m o nt hs pri or t o t he Baseli ne Visit. 
9.  S u bjects a n d t heir par e nts/le gal g uar dia ns are willi n g t o c o m pl y wit h st u d y i nstr ucti o ns 
a n d ret ur n t o t he i n vesti g ati o nal ce nter f or all re q uire d visits (a visit sc he d ule wit h t he 
le n gt h of eac h visit will be pr o vi de d t o e ns ure t hat t he s u bject ca n meet t he 
re q uire me nts a n d h a ve a de q uate tra ns p ort ati o n). 
1 0.  S u bjects a n d pare nts/le gal g uar dia ns a gree t hat t he s u bject will a v oi d t he use of  t oe n ail 
p olis h, c os metic t oe nail pr o d ucts, a n d pe dic ures d uri n g t he st u d y  peri o d.  
 
S. 2  S u bject E xcl usi o n  Criteri a  
S u bjects meeti n g a n y o ne of t he f oll o wi n g criteria will be e xcl u de d fr o m t he st u d y:  
1.  Fe males w h o ar e pre g n a nt, n ursi n g a n i nfa nt, or pla n ni n g a pre g na n c y d uri n g t he st u d y 
peri o d.  
2.  Hist or y of i m m u n os u p pressi o n a n d/ or cli nical si g ns i n dicati ve of p ossi ble 
i m m u n os u p pressi o n, as deter mi ne d b y t he i n vesti g at or, or k n o w n h u ma n 
i m m u n o deficie nc y vir us i nfecti o n. 
3.  Hist or y  of  dia betes  t h at is u nc o ntr olle d  as deter mi n e d  b y  t he i n vesti gat or ( di a betes t hat 
is c o ntr olle d b y diet or me dicati o n d oes n ot e xcl u d e a s u bject). 
4.  Prese nce of a n y t oe n ail i nfecti o n ot her t ha n or i n a d diti o n t o der mat o p h ytes, s uc h  as 
Scyt ali di u m as deter mi ne d b y t he i n vesti gat or (ca n di dal o n yc h o m yc osis i nfecti o n, 
c o nc urr e n t wit h a p ositi ve der mat o p h yte c ult ure, is acce pt a ble).  
5.  Prese nce of a n y of t h e f oll o wi n g: der mat o p h yt o ma, f u n gal "s pi kes" wit hi n 3 m m of 
t he pr o xi mal  t oe nail f ol d o n  t he tar g et great  t oe nail, i nfecti o n e xte n di n g t o t he matri x, 
or o nl y lateral t oe n ail disease i n t he tar get great t oe nail. 
6.  Prese nce of se vere m occasi n ti nea pe dis at t he Scree ni n g or Baseli ne Visits, as 
deter mi ne d b y t he i n vesti gat or. If t he s u bject has i nter di gital ti nea pe dis t hat re q uires 
treat me nt, t he s u bject m ust a gree t o use o nl y a n i n vesti gat or -a p pr o v e d t o pical 
a ntif u n gal  t hera p y. 
7.  Prese nce of a n y dis ease/c o n diti o n t hat mi g ht ca use t oe nail a b n or malities or ma y 
i nterfer e wit h t h e e v al uati o n of t he st u d y dr u g as deter mi ne d b y t he i n vesti gat or 
(e g, o pe n s or es or ulcerati o n o n t he t oes of affecte d t oe nails, ps oriasis, i m m u ne 
d ysf u ncti o n, c olla ge n -v asc ular diseas es, lic he n pl a n us, peri p heral vas c ular disease, or 
tra u matic o n yc h o d ystr o p h y d ue t o c hr o nic p h ysical sti m uli). 
8.  A n y pre vi o us s ur ger y o n t he tar get great  t oe n ail. 
9.  Prese nce of o n yc h o m yc osis of t he  fi n ger nail. 
1 0.  Hist or y of i m m u n o deficie nc y as det er mi ne d b y t h e  i n vesti gat or. 
1 1.  Prese nce of 1 -ha n d, 2 -f o ot s y n dr o me, or fi n ger n ail der mat o p h yt osis.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
2 9  
 
 
 
1 2.  Tar get  great  t oe nail (i ncl u di n g t oe nail plate  a n d a n y s u b u n g ual de bris)  t hic ker t ha n 
3 m m at t he Scree ni n g a n d Baseli ne  Visits.  
1 3.  Prese nce of o n yc h o d ystr o p h y t hat c o ul d i nterfere wit h cli nical assess me nts  as 
deter mi ne d b y t he  i n vesti gat or. 
1 4.  Hist or y of h y perse nsiti vit y or aller gic reacti o ns t o az ole deri vati ves o r a n y of t he st u d y 
dr u g  c o nstit ue nts.  
1 5.  Prese nce of a n y u n d erl yi n g disease t hat, i n t he o pi ni o n of t he  i n vesti gat or, c o ul d 
prese nt a safet y c o n cer n f or t he s u bject b y partici p ati n g i n t he  st u d y. 
1 6.  S u bject has recei ve d treat me nt f or a n y t y pe of ca n cer i n t he pre vi o us 6 m o nt hs, e xce pt 
f or n o n mela n o ma s ki n ca ncer (e g, basal cell carci n o ma or n o n metastatic s q ua m o us 
cell car ci n o ma) t hat w as treate d  s u ccessf ull y. 
1 7.  Prese nce of a n y d er mat ol o gical c o n diti o n o n t he feet t hat c o ul d i nterfere wit h cli nical 
e val uati o ns as deter mi ne d b y t he  i n vesti gat or. 
1 8.  Prese nce of a n y u n d erl yi n g disease or d er mat ol o gical c o n diti o n ot her t ha n 
o n yc h o m yc osis t hat re q uires t he use of i nterferi n g t o pical or s yste mic t hera p y a n d 
w o ul d  ma ke  e val u ati o ns  i nc o ncl usi ve as det er mi ne d  b y  t he i n vesti gat or, or  s u bject 
re q uires tr eat me nt wit h a t o pical pr o d uct o n t he t oe nails ot her t ha n t he st u d y dr u g 
d uri n g t he  st u d y. 
1 9.  S u bjects usi n g t he f oll o wi n g t o pical pre parati o ns wit hi n t he i n dicate d ti me pri or t o t he 
Baseli ne Visit, or re q uires c o nc urr e nt use of a n y of t he f oll o wi n g t o pical pre parati o ns 
d uri n g t he  st u d y: 
•  T oe nail p olis h or c os metic t oe nail pr o d ucts: 1  da y  
•  Ot her t o pical pr escri pti o n or o ver -t he-c o u nter me dicati o ns t o t he t oe nails ( wit h t he 
e xce pti o n of bla n d e m ollie nts): 2  wee ks  
•  T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t o e nails, i ncl u di n g 
de vices t o treat o n yc h o m yc osis: 4  wee ks  
2 0.  S u bjects usi n g t he f oll o wi n g s yste mic me dicati o ns  wit hi n t he i n dicate d ti me pri or  t o 
t he Baseli ne Visit, or re q uires c o nc urre nt use of a n y of t he f oll o wi n g s yste mic 
me dicati o ns d uri n g t he  st u d y: 
•  S yste mic a ntif u n gal t hera p y: 4  wee ks  
•  S yste mic i m m u n os u p pressi ve a ge nts: 6  m o nt hs  
2 1.  S u bject has pre vi o usl y bee n n o nres p o nsi v e t o s yste mic a ntif u n gal t hera p y f or 
o n yc h o m yc osis.  
2 2.  S u bject is u na ble t o c o m m u nicate or c o o p erate wit h t he i n vesti gat or d ue t o  la n g ua ge 
pr o ble ms, p o or me ntal de vel o p me nt, or i m paire d cere bral  f u n cti o n. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 0  
 
 
 
2 3.  Use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 half-li ves ( w hic he ver is 
l o n ger) pri or t o t he Scr ee ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her cli nical 
st u d y wit h a n i n vesti gati o nal dr u g or de vice.  
 
S. 3  S u bject Wit h dr a w al  Criteri a  
W he n p ossi ble, s u bj ects w h o disc o nti n ue fr o m t he st u d y pri or t o c o m pleti n g t he 4 8 -wee k 
treat me nt peri o d s h o ul d r et ur n t o t he i n vesti gati o nal ce nter t o p erf or m t he assess me nts sc he d ule d 
f or Wee k 4 8. If a p pr o pri ate, disc o nti n ue d s u bjects ma y be place d o n ot h er c o n ve nti o nal t hera p y 
u p o n re q uest or w h e ne v er cli nicall y necessar y, as deter mi ne d b y t he I n v esti gat or. T he E n d of 
St u d y s o urce d oc u me nts a n d all rele v a nt data s h o ul d be e ntere d i nt o t he electr o nic cas e re p ort 
f or m (e C R F) s yste m at t he ti me t he s u bject disc o nti n ues fr o m t he st u d y. 
Reas o ns f or s u bject wit h dra wal ma y i ncl u d e, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  O n yc h o m yc osis  pr o gressi o n,  as deter mi ne d  b y  t he i n vesti gat or, w hic h  re q uires treat me nt 
wit h a pr o hi bite d  t hera p y 
•  Eit her at t he i n vesti gat or's discreti o n f or safet y reas o ns (e g, se vere a d v erse reacti o ns or 
u na ut h orize d c o n c o mita nt t hera p y), or at t he s u bject's re q uest f or pers o n al  reas o ns 
•  W he n t he r e q uire me nts of t he pr ot oc ol are n ot  f oll o we d 
•  W he n  a c o nc o mita nt  t her a p y li kel y t o i nterfere wit h  t he res ults of  t h e st u d y is re p orte d or 
re q uire d b y t he s u bject (t he i n vesti gat or will re p ort all s uc h i nf or mati o n o n t he s o urce 
d oc u me nts/e C R Fs a n d deci de, i n acc or da n ce wit h t he S p o ns or, w het her t he s u bject is t o 
be  wit h dra w n)  
•  W he n a s u bject is l ost t o f oll o w -u p; t he i n vesti gat or ( or desi g nee) will tr y t wice t o reac h 
t he s u bject b y tele p h o ne, a n d will se n d a f oll o w-u p letter b y certifie d mail bef ore 
c o nsi deri n g t he s u bject as l ost t o f oll o w -u p; t hese acti o ns will be d oc u me nt e d i n t he 
s o urce d oc u m e nts a n d rec or de d o n t he E n d of St u d y e C R F, wit h a c o p y of t he f oll o w-u p 
letter mai ntai ne d i n t he i n vesti gat or's file 
•  If a s u bject b ec o mes pr e g na nt d uri n g t he treat me nt peri o d, t he st u d y dr u g will be 
disc o nti n ue d i m me diatel y, t he s u bject will be disc o nti n ue d fr o m t he s t u d y, a n d t he 
i n vesti gat or will n otif y t he s p o ns or. T he pre g na n c y will be f oll o we d t o ter m wit h t he 
o utc o me re p ort e d t o t he  s p o ns or. 
 
 
9  Tre at me nts Pl a n ne d  
9. 1  Met h o ds of Assi g ni n g S u bjects t o Tre at me nt  Gr o u ps  
T his is a si n gle -ar m, o pe n la bel st u d y. After c o nfir mi n g eli gi bilit y at t he Baseli ne Visit, s u bjects 
will be e nr olle d i n t he treat me nt peri o d a n d will recei ve efi nac o n az ole i n acc or da nce wit h t he 
pr ot oc ol ( Secti o n 1 0).  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 1  
 
 
 
9. 2  R a n d o miz ati o n a n d  Bli n di n g  
Ra n d o mizati o n a n d bli n di n g d o n ot a p pl y.  
P K assess me nts will be p erf or me d o n a s u bset of t he st u d y p o p ulati o n. Eff orts will be ma de t o 
e nr oll s u bjects i nt o t he P K s u bset s uc h t hat t he y are e v e nl y distri b ute d acr oss t he re q uire d a g e 
ra n ge. 
 
9. 3  Tre at m e nt C o m pli a nce  
S u bjects a n d t heir par e nts/le gal g uar dia ns will be dis pe nse d a n i nitial b ottle of st u d y dr u g at 
Baseli ne ( Da y 1). S u bjects a n d t heir pare nts/le g al g uar dia ns will be i nstr uct e d o n t he i m p orta nce 
of ret ur ni n g t he s u bject's st u d y dr u g b ottle(s) at t he ne xt st u d y visit. If a s u b ject d oes n ot ret ur n 
his/ her st u d y dr u g b ottle, he/s he will be i nstr ucte d t o ret ur n it at his/ her ne xt st u d y visit. A ne w 
st u d y dr u g b ottle will be dis pe nse d t o t he s u bjects at eac h p ost bas eli ne st u d y visit t hr o u g h Wee k  
4 4. S u bjects i n t he P K s u bset will be dis pe nse d 2 b ottles of st u d y dr u g at Baseli ne ( D a y 1),  a n d 
will be dis pe nse d o ne b ottle of st u d y dr u g at eac h s u bse q ue nt st u d y visit t hr o u g h Wee k 4 4. All 
use d a n d u n use d st u d y dr u g b ottles will be c ollecte d at Wee k  4 8.  
T he i n vesti gati o nal ce nter staff w ill wei g h a n d rec or d eac h b ottle of st u d y dr u g bef ore dis pe nsi n g 
t o t he s u bject a n d t heir p are nt/le gal g uar dia n a n d f oll o wi n g ret ur n b y t he s u bject. B ottle wei g hts 
will be rec or d e d i n t he i n di vi d ual st u d y dr u g l o g a n d i n t he a p pr o priate e C R F.  
At eac h p ost bas eli ne st u d y visit, s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be as ke d t o 
re p ort a n y misse d d oses of st u d y dr u g, a n d pr o vi d e t he date a n d a n e x pla nati o n f or eac h misse d 
d ose. A s u bject w h o has de viate d fr o m t he o n ce d ail y d osi n g re gi me n will be c o u nsele d i n t he 
prese nce of t heir p are nt/l e gal g uar dia n. T he dat es of a n y misse d d oses of st u d y dr u g will be 
rec or d e d i n t he s u bject's s o urce d oc u m e nt a n d a p pr o priate e C R F. 
 
9. 4  Tre at m e nt A d mi nistr ati o n  
S u bjects a n d t heir par e nts/le gal g uar dia ns will recei ve b ot h ver bal a n d writte n i nstr ucti o ns o n t he 
a p plicati o n of t he st u d y dr u g. T he s u bject a n d/ or t heir pare nt/le gal g uar dia n will a p pl y t he first 
d ose of st u d y dr u g at t he i n vesti gati o nal ce nter d uri n g t he Baseli ne Visit. All of t he re mai ni n g 
st u d y dr u g d oses will be a p plie d b y t he s u bject at h o me. T he s u bjects a n d t heir pare nts/le gal 
g uar dia ns will be i nstr uct e d t o wait f or t he t oe n ails t o air -dr y t h or o u g hl y bef ore t o uc hi n g wit h 
cl ot hi n g. 
D osi n g f or S u bjects N O T I ncl u de d i n t he P K S u bset: S u bjects a n d t heir pare nts/le gal 
g uar dia ns will be i nstr uct e d t o a p pl y t heir assi g ne d st u d y dr u g t o t he tar get great t oe nail a n d all 
ot her aff ecte d t o e nail(s) (if a n y) o nce dail y at be dti me. S u bjects a n d t heir p are nts/le gal g uar dia ns 
will be i nstr ucte d t o c o nti n ue a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or t he e ntire 
treat me nt peri o d, e ve n if t he disease cl ears a n d n o affecte d area is o bser ve d o n t he tar get great 
t oe nail. If ot her aff ecte d t oe nails treate d si nce bas eli ne clear d uri n g t he c o urse of t he st u d y,  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 2  
 
 
 
s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt o n t h ose 
t oe nails f or t he d ur ati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me i nfecte d d uri n g t he 
st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). All 
s u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y t he st u d y dr u g b y 
c o m pletel y c o veri n g t he t ar get gr eat t oe nail, i ncl u d i n g t he t oe nail f ol ds, t oe nail be d, 
h y p o n yc hi u m,  a n d t he u n ders urf ace  of  t he t oe n ail plate. T he  st u d y dr u g  will  be  a p plie d t o eac h of 
t he ot her i nfecte d t oe nails i n a si milar ma n ner.  
D osi n g f or S u bjects I ncl u de d i n t he P K S u bset:  
D a ys 1 t o 2 S - S u bjects a n d t heir par e nts/le gal g u ar dia ns will be i nstr ucte d t o a p pl y st u d y dr u g 
t o all 1 0 t oe nails, o nce dail y at be dti me. D uri n g t his peri o d, all P K s u bjects will be i nstr ucte d t o 
a p pl y t he st u d y dr u g b y c o m pletel y c o veri n g eac h t oe nail a n d 0. 5 c m of a d j ace nt s ki n, i ncl u di n g 
t he t oe nail f ol ds, t oe nail be d, h y p o n yc hi u m, u n ders urface of t he t oe n ail plate. T he s u bjects will 
n ot a p pl y st u d y dr u g t he ni g ht pri or t o t he Wee k 4 ( Da y 2 8) visit, n or will t he y a p pl y st u d y dr u g 
o n t he ni g ht of t he Wee k 4/ Da y 2 8 Vis it. Wit hi n 1 h o ur after t h e pre d os e bl o o d sa m ple is dra w n 
o n Da y 2 8, s u bjects will a p pl y st u d y dr u g t o all 1 0 t oe nails i n t he ma n ner descri be d a b o ve at t he 
i n vesti gati o nal ce nter. 
D a ys 2 9 t o Wee k 4 S ( o nl y P K s u bjects c o nse nti n g i n t he 5 2 -Wee k Tri al):):  
Aft er c o m pleti o n of t he P K p orti o n of t he st u d y, if t he s u bject c o nse nte d t o t he 5 2 -Wee k trial, , 
s u bjects a n d t heir pare nts/le gal g uar dia ns will be i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o 
t he s u bject's tar get gr eat t oe nail a n d all ot her affect e d t oe nail(s) o nce dail y at be dti me f or t he 
e ntire treat me nt peri o d, e ve n if t he disease clears a n d n o affecte d area is o bs er ve d o n t he tar get 
great t oe nail. If ot her aff ecte d t oe n ails treate d si n ce baseli ne clear d uri n g t he c o urse of t he st u d y, 
s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will be e nc o ura ge d t o c o nti n ue treat me nt o n t h ose 
t oe nails f or t he d ur ati o n of t he st u d y. I n a d diti o n, if ne w t oe nails bec o me i nfecte d d uri n g t he 
st u d y, t he s u bject will be i nstr ucte d t o start treati n g t he a d diti o nall y affecte d t oe nail(s). All 
s u bjects a n d t heir pare nts/le gal g uar dia ns will be gi ve n i nstr ucti o ns re gar di n g h o w t o a p pl y t he 
st u d y dr u g, ie, b y c o m pletel y c o veri n g t he tar get great t oe nail, i ncl u di n g t he t oe nail f ol ds, t oe nail 
be d, h y p o n yc hi u m, a n d t he u n ders urface of  t he t o e nail plate (if o n y c h o m yc osis is prese nt). T he 
st u d y dr u g will be a p plie d t o eac h of t he ot h er i nfecte d t oe n ails i n a si milar ma n ner. 
 
9. 5  C o nc o mit a nt  Me dic ati o ns  
C o nc o mita nt me dicati o ns/t hera pies refer t o all me dicati o ns/t hera pies use d b y t he s u bject d uri n g 
t he st u d y. D uri n g t he c o urse of t he st u d y, if a p pr o priate, e ver y atte m pt s h o ul d be ma de t o kee p 
t he d osi n g a n d re gi me n of c o nc o mita nt me dicati o ns/t hera pies c o nsta nt, a n d a n y c ha n g e t o a 
me dicati o n/t hera p y d uri n g t he st u d y m ust be rec or de d. I nf or mati o n o n c o n c o mita nt 
me dicati o ns/t hera pies (i n cl u di n g i n dicati o n, d osi n g, a n d start a n d st o p dates) will be rec or de d i n 
t he s o urce d o c u me nt a n d o n t he a p pr o priat e e C R F. All c o nc o mita nt me dicati o ns/t hera pies 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 3  
 
 
 
(i ncl u di n g f o ot car e pr o d ucts) use d d uri n g t he st u d y will be rec or d e d u n der C o nc o mita nt 
Me dicati o ns.  
All pri or me dicati o ns (t h ose use d wit hi n 3 0 da ys pri or t o t he Scree ni n g Visit) a n d pre vi o us 
a ntif u n gal me dicati o ns use d b y t he s u bject, i ncl u di n g a n y rece nt o ver -t h e-c o u nter t opical 
treat me nts (t h ose use d wit hi n 6 0 da ys pri or t o t he Scree ni n g Visit) will be rec or de d u n d er Pri or 
a n d C o nc o mita nt Me dicati o ns i n t he e C R F (e g, as piri n, aceta mi n o p he n, birt h c o ntr ol pills, 
vita mi ns, her bal pr o d ucts, h o me o pat hic pre p arati o ns).  
D uri n g t h e st u d y, all f o ot care pr o d ucts use d b y t h e s u bject will be rec or de d u n der Pri or a n d 
C o nc o mita nt Me dicati o ns.  
9. 5. 1  All o we d  Me dic ati o ns/ T her a pies  
C o nc o mita nt me dicati o ns ( prescri pti o n or o ver -t h e-c o u nter) t hat are c o nsi d ere d necessar y f or t h e 
s u bject's welfare an d d o n ot i nterfere wit h st u d y assess me nts a n d e val uati o ns will be all o we d 
d uri n g t he st u d y at t he i n vesti gat or's discreti o n.  
If, d uri n g t he st u d y, a s u bject re q uir es t o pical a ntif u n gal t hera p y f or ti nea p e dis, t he i n vesti gat or 
is t o d oc u me nt t he pr o ble m an d t he i n vesti gat or -a p pr o ve d treat me nt o n t he A E a n d c o nc o mita nt 
t hera p y e C R Fs, res pecti vel y, a n d t o e ns ure t h at t he s u bject a v oi ds a p plicati o n of t he c o nc o mita nt 
t hera p y t o t he t oe nails or a djace nt s urr o u n di n g s ki n s urface. 
9. 5. 2  Pr o hi bite d  Me dic ati o ns/ T her a pie s 
N o t o pical treat me nts/ pr o d ucts will be all o we d o n t he t oes or feet ot her t ha n t he st u d y dr u g 
d uri n g t he st u d y, e xce pt f or i n vesti gat or -a p pr o v e d treat me nts. T he s u bject ma y use a n y t o pical 
a ntif u n gal t hera p y t h e I n vesti gat or a p pr o ves f or use. Use of t he f oll o wi n g t o pical treat me nts is 
pr o hi bite d wit hi n t he i n dicate d ti me pri or t o t he Baseli ne Visit:  
 
T oe nail p olis h or c os metic t oe nail pr o d ucts  
1 da y  
Ot her t o pical pr escri pti o n or o ver -t he-c o u nter me dicati o ns t o t he t oe nails ( wit h 
t he e xce pti o n of bla n d e m ollie nts)  
2 wee ks  
T o pical prescri pti o n or o ver -t he-c o u nter a ntif u n gal t hera p y f or t he t o e nails, 
i ncl u di n g de vices use d t o treat o n yc h o m yc osis 
4 wee ks  
 
Use of t he f oll o wi n g s yst e mic me dicati o ns is pr o hi bite d wit hi n t he i n dicate d ti me pri or t o t he 
Baseli ne Visit a n d f or t he d urati o n of t he st u d y:  
S yste mic a ntif u n gal t hera p y  
4 wee ks  
S yste mic i m m u n os u p pressi ve a ge nts  
6 m o nt hs  
 
I n a d diti o n, use of a n y i n vesti gati o nal dr u g or de vice wit hi n 3 0 da ys or 5 h alf-li ves ( w hic h e ver is 
l o n ger) pri or t o t he Scr ee ni n g Visit, or c o nc urre nt partici pati o n i n a n ot her cli nical st u d y wit h a n 
i n vesti gati o nal dr u g or de vice d uri n g t he st u d y peri o d is n ot all o we d. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 4  
 
 
 
If a s pecific me dicati o n/t hera p y has t h e p ote ntial t o i nterfere wit h t he treat me nt effect of t he 
st u d y dr u g or i nter pretati o n of t he st u d y res ults, t he i n vesti gat or s h o ul d c o ntact t he me dical 
m o nit or pri or t o use (if p ossi ble).  
A n y s u bject usi n g a pr o hi bite d t hera p y d uri n g t he c o urse of t he st u d y t hat c o ul d i nterfere wit h 
t he treat me nt effect of t he st u d y dr u g or i nter pretati o n of t he st u d y res ults (i ncl u di n g, b ut n ot 
li mite d t o, t h ose liste d a b o ve) ma y be wit h dra w n fr o m t he st u d y at t he discreti o n of t he 
i n vesti gat or a n d/ or s p o ns or. H o we v er, t he i n vesti g at or s h o ul d n ot wit h dra w a s u bject with o ut 
first c o nfir mi n g it wit h t he s p o ns or. 
 
9. 6  Pr ot oc ol D e vi ati o ns a n d  Vi ol ati o ns  
A de viati o n fr o m t he pr ot oc ol is a n u ni nte n de d a n d/ or u na ntici pate d de p art ure fr o m t he 
pr oce d ur es a n d/ or pr ocesses a p pr o ve d b y t h e s p o ns or a n d t he i nstit uti o nal re vie w b oar d (I R B) or 
i n de pe n de nt et hics c o m mittee (I E C) a n d a gree d t o b y t he i n vesti gat or. De vi ati o ns us uall y ha ve 
a n i m pact o n i n di vi d ual s u bjects or a s mall gr o u p of s u bjects a n d d o n ot i n v ol ve 
i ncl usi o n/e xcl usi o n or pri mar y e n d p oi nt criteri a. 
A pr ot oc ol vi olati o n occ urs w he n t her e is n o na d h ere nce t o t he pr ot oc ol t hat res ults i n a 
si g nifica nt, a d diti o nal ris k t o t he s u bject, w he n t he s u bject or i n vesti gat or h as faile d t o a d h ere t o 
si g nifica nt pr ot oc ol re q uire me nts (i ncl usi o n/e xcl usi o n criteria) a n d t he s u bject was e nr olle d 
wit h o ut pri or s p o ns or a p pr o val, or w he n t h ere is n o na d here n ce t o U S F o o d a n d Dr u g 
A d mi nistrati o n re g ulati o ns a n d/ or I nter n ati o nal C o nfere n ce o n H ar m o nisati o n (I C H) G o o d 
Cli nical Practice ( G C P) g ui deli ne.  
T he i n vesti gat or or des i g nee m ust rec or d a n d e x pl ai n i n t he s u bjects' s o urce d oc u me ntati o n a n y 
de viati o n fr o m t he a p pr o ve d pr ot oc ol. T he i n vesti gat or ma y i m ple me nt a d e viati o n fr o m, or a 
c ha n ge of, t h e pr ot oc ol t o eli mi nate a n i m me diate hazar d t o st u d y s u bjects wit h o ut pri or 
I R B/I E C a p pr o v al. As s o o n as p ossi ble after s u c h a n occ urre n ce, t he i m ple me nte d de viati o n or 
c ha n ge, t he reas o ns f or it, a n d a n y pr o p ose d pr ot o c ol a me n d me nt(s) s h o ul d be s u b mitte d t o t he 
s p o ns or f or a gr ee me nt, t o t he I R B/I E C f or re vie w a n d a p pr o val, a n d t o t he re g ulat or y a ut h orities, 
if re q uire d. 
 
1 0  St u d y Dr u g M ateri als a n d  M a n a ge me nt  
T he st u d y dr u g will be pr o vi de d t o t he i n vesti gati o nal ce nters b y t h e s p o ns or a n d will be 
dis pe nse d t o t he s u bject a n d t heir pare nt/le g al g uar dia n b y t he p har mac y or a n a p pr o pri ate l y 
q ualifie d me m ber of t h e st u d y staff assi g ne d b y t h e i n vesti gat or.  
All la b orat or y kits c o ntai ni n g materials necessar y t o c ollect bl o o d a n d uri n e f or r o uti ne cli nical 
la b orat or y tests, uri ne pr e g na nc y t ests, f u n gal c ult ures, a n d P K a n al yses will be s u p plie d t o t he 
i n vesti gati o nal ce nters b y t he desi g nate d ce ntral la b orat ories. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 5  
 
 
 
1 0. 1  St u d y  Dr u g  
A descri pti o n of t he st u d y dr u g is i ncl u de d i n Ta ble 2.  
T a ble 2.  
St u d y Dr u g  I de ntific ati o n 
 
 
I n vesti g ati o n al Pr o d uct 
Dr u g Na me  
Efi nac o naz ole 1 0 % s ol uti o n f or t o pical a d mi nistrati o n 
Na me of Acti ve I n gre die nt  
Efi nac o naz ole  
Ma n ufact urer  
Valea nt P har mace uticals  
C he mical Na me  
( 2 R, 3 R)-2 -( 2, 4-difl u or o p he n yl) -3 -( 4-met h yle ne pi peri di n -1 -yl) - 
1 -( 1 H-1, 2, 4 -triaz ol-1 -yl) b uta n -2 -ol  
C he mical F or m ula/ M olec ular Wei g ht  
C 1 8H 2 2F 2N 4O / 3 4 8. 3 9 a m u  
T hera pe utic Cate g or y  
A ntif u n gal  
A p peara nce  
Clear t o yell o w s ol uti o n  
I nacti ve I n gre die nts 
Alc o h ol, a n h y dr o us citric aci d, b ut ylate d h y dr o x yt ol ue ne, C 1 2 - 
1 5 al k yl lactate, c ycl o met hic o ne, diis o pr o p yl a di pate, dis o di u m 
e detate, a n d p urifie d water. 
 
1 0. 1. 1  P ac k a gi n g a n d  L a beli n g  
Efi nac o naz ole will be pr o vi de d t o t he i n vesti gati o nal ce nters i n 1 0 m L b ottles c o ntai ni n g 8 m L 
of st u d y dr u g per b ottle. I n di vi d ual b ottles will be s u p plie d t o t he i n vesti gati o nal ce nter. T h e 
s u bjects a n d t heir pare nts/le gal g uar dia ns will be dis pe nse d 1 b ottle at t he Baseli ne Visit a n d 1 
b ottle at eac h s u bse q u e nt st u d y visit t hr o u g h Wee k 4 4. S u bjects i n t he P K s u bse t will be 
dis pe nse d 2 b ottles of st u d y dr u g at t he Baseli ne Visit, a n d will be dis pe nse d o ne b ottle of st u d y 
dr u g at eac h s u bse q ue nt st u d y visit t hr o u g h Wee k 4 4.  
T he la bel o n eac h b ottle of st u d y dr u g will i de ntif y t he pr o d uct as " Efi nac o naz ole". T he la b el  o n 
t he st u d y dr u g b ottles will c o ntai n t he f oll o wi n g i nf or mati o n: 
•  Pr ot oc ol  n u m ber  
•  Kit  n u m ber  
•  Pr o d uct i de ntificati o n ( Efi nac o naz ole 1 0 %  S ol uti o n)  
•  S u bject  n u m ber   
 
•  S u bject  i nitials  
 
•  Date  dis pe nse d    
 
•  A state me nt i n dicati n g t he v ol u me of t he c o nte nts as 8  m L  
•  I nstr u cti o ns t o kee p b ottle ti g htl y cl ose d a n d st ore i n a n u pri g ht p ositi o n at r o o m 
te m perat ur e ( 2 0° C t o 2 5° C  [ 6 8° F t o 7 7° F]),  wit h  e xc ursi o ns  per mitte d  bet w ee n  1 5° C 
a n d 3 0° C ( 5 9° F a n d  8 6° F)  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 6  
 
 
 
•  L ot n u m ber/e x pirati o n  date  
•  S p o ns or na me a n d  a d dress  
•  A state me nt i n dicati n g, " Ca uti o n: Ne w Dr u g - Li mite d b y Fe deral La w t o 
I n v esti gati o nal Use"  
•  A state me nt i n dicati n g t hat t he dr u g s h o ul d be ke pt o ut of reac h of  c hil dre n 
A d diti o nal i nf or mati o n ma y be i ncl u de d o n t he b ottle la bel as necessar y.  
1 0. 1. 2  St or a ge, H a n dli n g, a n d Dis p os al of St u d y  Dr u g  
St u d y dr u g s h o ul d be st ore d i n a sec ure area at t he i n vesti gati o nal ce nter acc or di n g t o l ocal 
re g ulati o ns, i n a n u pri g ht p ositi o n at c o ntr olle d r o o m te m perat ure ( 2 0° C t o 2 5° C [ 6 8° F t o 7 7° F]), 
wit h e xc ursi o ns per mitte d bet wee n 1 5° C a n d 3 0° C ( 5 9° F a n d 8 6° F).  
S u bjects a n d t heir par e nts/le gal g uar dia ns will be i nstr ucte d t o kee p t heir st u d y dr u g b ottle at 
r o o m te m perat ur e, o ut of t he reac h of c hil dre n, n ot t o s hare t he st u dy dr u g wit h a n y o ne else, a n d 
t o use it o nl y o n t he affecte d t oe nails as direct e d b y t he i n vesti gat or. S u bjects a n d t heir 
pare nts/le gal g uar dia ns will be as ke d t o n otif y t he i n vesti gati o nal ce nter i m me diatel y if a st u d y 
dr u g b ottle is da ma ge d or l ost.  
All u se d a n d u n use d st u d y dr u g s u p plies will be ret ur ne d t o t he s p o ns or f or destr ucti o n. 
 
1 0. 1. 3  St u d y Dr u g  Pre p ar ati o n  
N ot a p plica ble; s u bjects a n d/ or t heir pare nts/le gal g uar dia ns will a p pl y t he st u d y dr u g directl y 
fr o m t he st u d y dr u g b ottles. 
 
1 0. 2  St u d y Dr u g  Acc o u nt a bilit y  
T he I n vesti gat or or d esi g nee will be res p o nsi ble f or kee pi n g c urre nt a n d acc urate rec or ds of t he 
a m o u nt of st u d y dr u g recei ve d a n d dis pe nse d, a n d its dis p ositi o n. T he st u d y dr u g m ust be st ore d 
u n der t he a p pr o priate c o n diti o ns i n a sec ure are a a n d is t o be dis pe nse d o nl y t o s u bjects e nr olle d 
i n t he st u d y, i n acc or da n ce wit h t he c o n diti o ns s pecifie d i n t his pr ot oc ol. D uri n g t he c o urs e of t he 
st u d y, t he I n v esti gat or or desi g nee m ust mai ntai n a n i n ve nt or y of all st u d y dr u g dis pe nse d t o or 
ret ur ned b y t he s u bject, i ncl u di n g s u bject i de ntifiers.  
A st u d y dr u g acc o u nt a bilit y l o g will be c o m plete d b y t he i n vesti gat or or desi g nee t o d oc u me nt 
t he recei pt, dis pe nsati o n, a n d ret ur n of st u d y dr u g b ottles. 
All s u p plies se nt t o t he I n vesti gat ors will be acc o u nte d f or a n d, i n n o case, use d i n a n y 
u na ut h orize d sit uati o n. B ottles will be wei g he d ( wit h t he ca p o n) bef ore dis pe nsi n g t o a n d u p o n 
ret ur n b y t he s u bjects, a n d wei g hts will be rec or d e d o n t he p har mac y l o g a n d a p pr o priate C R F. 
All use d a n d u n use d s u p plies will be ret ur ne d t o s p o ns or/ desi g nee f or destr ucti o n at t he 
c o ncl usi o n of t he st u d y.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 7  
 
 
 
1 1  St u d y Pr oce d ures a n d  E v al u ati o ns  
1 1. 1  Sc he d ule of E v al u ati o ns a n d  Pr oce d ures  
All s u bject i nf or mati o n a n d data o btai ne d d uri n g t he st u d y visit pr oce d ures m u st be rec or d e d i n 
t he s o urce d o c u me nts, a p plica ble st u d y l o gs, a n d e C R Fs. 
1 1. 1. 1  Scree ni n g Visit ( Visit 1, U p t o D a y  -4 2)  
After si g ni n g t he i nf or me d c o nse nt/asse nt, s u bjects will u n der g o t he scree ni n g pr oce d ures t o 
c o nfir m eli gi bilit y t o partici pate i n t he st u d y.  
Ne wl y scr ee ne d P K s u bj ects will deci de at t he ti me of si g ni n g c o nse nt w het her t he y will c o nse nt 
t o t he 4-Wee k trial or partici pate i n t he 5 2 -Wee k trial.  
N ote: S u bjects t h at c o nse nt t o 4 -Week tri al will n ot be all o we d t o exte n d t heir st u dy c o nse nt t o 
5 2 w eeks. S u bse q u e ntly, P K s u bjects w h o c o nse nt t o t he 5 2 -Week tri al will be c o nsi dere d 
disc o nti n ue d/ E arly Ter mi n ate d if he/s he disc o nti n ues pri or t o t he Week 5 2 visit.  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Re vie w  a n d e x pl ai n t he n at ure  of  t he st u d y. Pr o vi de  a visit  sc he d ule wit h  t he le n gt h of 
eac h visit t o e ns ure t hat t he s u bject ca n m eet t he re q uire me nts a n d h as a de q uate 
tra ns p ortati o n. 
2.  O btai n ver bal  a n d writte n i nf or me d c o nse nt/asse nt fr o m t he s u bject a n d t he s u bject's 
pare nt(s) or le gal g uar dia n(s) pri or t o perf or mi n g a n y st u d y -relate d pr o ce d ures. 
Pr o vi de si g ne d c o pies of t he c o nse nt a n d ass e nt f or ms t o t he s u bject/ pare nt(s) or le gal 
g uar dia n(s).  
3.  O b tai n p h ot o gra p h y c o ns e nt/asse nt fr o m s u bject a n d/ or t he s u bject's pare nt(s) or le gal 
g uar dia n(s).  
4.  Assi g n a 6 -di git st u d y n u m ber, w hic h i ncl u d es t he 3 -di git i n vesti gati o nal ce nter 
n u m ber pl us a u ni q ue 3 -di git s u bject n u m ber be gi n ni n g wit h 0 0 1 (e g, 0 0 1 -0 0 1, 
0 0 1 -0 0 2, 0 0 1 -0 0 3). N u m bers m ust be assi g ne d i n c hr o n ol o gical  or der.  
5.  Rec or d s u bject's de m o gr a p hic i nf or mati o n (se x, d ate of birt h, a g e, et h nicit y, a n d  race). 
6.  Rec or d s u bject's me dical hist or y i ncl u di n g dia betes  hist or y.  
7.  C ollect a detaile d hist or y of o n yc h o m y c osis, i ncl u di n g a n esti mate d start date of 
i nfecti o n, d urati o n  of  c urre nt  i nfecti o n i n t he p ote ntial  tar get great  t oe nail, a n d all 
pre vi o us t hera pies us e d f or o n yc h o m yc osis  treat m e nt. 
8.  Re vie w  all pri or  m e dicati o ns  (t h ose use d  wit hi n  3 0  da ys  pri or  t o t he Scree ni n g  Visit) 
a n d pre vi o us a ntif u n gal me dicati o ns use d b y t he s u bject, i ncl u di n g a n y  rece nt 
o ver -t he-c o u nter t o pical treat me nts (t h ose use d wit hi n 6 0 da ys pri or t o t he Scree ni n g 
Visit).  
9.  Re vie w i ncl usi o n/e xcl usi o n  criteria.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 8  
 
 
 
1 0.  E xa mi nati o n of t oe nails f or cli nical pres e nce of o n yc h o m yc osis i n at least 1 great 
t oe nail, wit hi n t he defi niti o n of eli gi bilit y criteria. F or s u bjects i n t he P K p o p ulati o n, 
b ot h great t oe nails a n d 4 ot her t oe nails m ust meet eli gi bilit y  criteria 
1 1.  E xa mi nati o n of all ot her t oe nails f or pres e nce or a bse nce of o n y c h o m yc osis o n  eac h 
t oe nail. 
1 2.  E xa mi nati o n of b ot h feet f or pres e nce of s y m pt o matic ti nea pe dis; treat as a p pr o priate 
usi n g i n vesti gat or a p pr o v e d t o pical a ntif u n gal  t hera p y 
1 3.  Cli p t he t oe nails ( bef ore perf or mi n g nail meas ure me nts). Re mi n d s u bject a n d t heir 
pare nt/le gal g uar dia n n ot t o cli p t oe nails at h o me i n bet wee n  visits.  
1 4.  Perf or m t he i n vesti gat or's assess me nt of t he great t oe nail(s) wit h a calc ulati o n of t he 
perce nt a ge of t o e nail aff ecte d wit h diseas e, after cli p pi n g t he u n healt h y t oe nail. If t he 
great  t oe n ail has  b ee n  cli p pe d pr o xi mal  t o t he distal  gr o o ve,  t he e ntire area t o t he distal 
gr o o ve s h o ul d be i ncl u de d. T he i n vesti gat or/e val u at or will use a fi ne ti p pe d mar ker t o 
o utli ne t he area aff ecte d o n t he tar get great t oe nail (t his is o pti o nal at t his visit si nce 
p h ot o gra p h y is n ot d o ne at t his visit; o utli ni n g s h o ul d be d o ne if be neficial t o 
perf or mi n g  assess me nts).  
•  S u bjects n ot i ncl u de d i n t he P K s u bset m ust ha ve at least 1 great t oe nail wit h 
2 2 0 % i n v ol ve me nt  
•  S u bjects i ncl u de d i n t he P K s u bset m ust ha ve b ot h great t oe nails i n v ol ve d wit h 
2 5 0 % i n v ol ve me nt i n eac h great  t oe nail. 
1 5.  O btai n s peci me n fr o m t h e great t oe n ail(s) t o s hi p t o t he m yc ol o g y la b. B ot h great 
t oe nails ma y be sa m ple d if b ot h are s us pecte d of ma nifesti n g o n yc h o m yc osis (at least 
2 0 %  i n v ol ve me nt). 
1 6.  Perf or m a uri n e pre g n a nc y test 1 f or all F O C B P.2 E xcl u de t he s u bject if t he pre g na nc y 
test res ult is p ositi ve.  
Uri ne pre g n a ncy testi n g is m a n d at ory f or all F O C B P at t he Scree ni n g Visit, 
B aseli ne Visit, a n d at all s u bse q ue nt st u dy visits. T he decisi o n m ay be m a de by t he 
i nvesti g at or t o d o a d diti o n al uri ne pre g n a ncy tests d uri n g t he c o urse of t he st u dy. 
 
 
 
 
1 Uri ne pre g na nc y tests m ust ha ve a mi ni m u m se nsiti vit y of 2 5 mI U of h u ma n c h ori o nic g o na d otr o pi n per m L of 
uri ne. Uri ne pre g na nc y test kits will be pr o vi de d b y t he s p o ns or.  
 
2 F O C B P i ncl u de a n y fe male s u bjects w h o ha ve e x perie nce d me narc he a n d w h o ha ve n ot u n der g o ne s uccessf ul 
s ur gical sterilizati o n ( h ysterect o m y, bilateral t u bal li gati o n, or bilateral o o p h orect o m y) or are n ot p ost me n o pa usal 
( defi ne d as a me n orr hea f or > 1 2 c o nsec uti ve m o nt hs or w o me n o n h or m o ne re place me nt t hera p y wit h d oc u me nte d 
plas ma f ollicle -sti m ulati n g h or m o ne le vels > 3 5 m L U/ m L). E ve n a fe male s u bject w h o is usi n g a n oral, i m pla nte d, 
i njecta ble, or tra ns der mal c o ntrace pti ve h or m o ne, a n i ntra uteri ne de vice, a c o n d o m wit h s per mici de, or a dia p hra g m 
wit h s per mici de t o pre ve nt pre g na nc y, or is pr actici n g a bsti ne nce, s h o ul d be c o nsi dere d of c hil d beari n g p ote ntial.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
3 9  
 
 
 
1 7.  C ollect bl o o d a n d uri ne sa m ples f or r o uti ne safet y la b orat or y a nal ysis  ( he m at ol o g y, 
ser u m c he mistr y, a n d uri nal ysis). Pr ocess a n d s hi p t he sa m ples t o t he ce ntral safet y 
la borat or y per i nstr ucti o ns pr o vi de d i n t he la b orat or y  ma n ual.  
N ote: C ollecti o n of Scree ni n g s afety l a bs m ay be p ost p o ne d u ntil after p ositive 
Scree ni n g myc ol o gy res ults are receive d, o nly if  t he s u bjectl p are nt are willi n g t o 
ret ur n t o t he rese arc h site f or s afety l a b c ollecti o n pri or t o t he e n d of t he 4 2-d ay 
scree ni n g wi n d o w. Scree ni n g s afety l a b res ults m ust be receive d wit hi n t he 4 2-d ay 
scree ni n g visit wi n d o w. 
1 8.  Sc he d ule s u bject t o ret ur n f or  t he Baseli ne Visit ( Visit 2, Da y 1).  
If a s u bject f ails scree ni n g, eit her at t he Scree ni n g or B aseli ne visit ( pri or t o 
e nr oll me nt t o tre at me nt), t he s u bject m ay be rescree ne d at a l ater d ate. S u bjects w h o 
are rescree ne d will be assi g ne d a ne w scree ni n g n u m ber, m ust be re-c o nse nte d, a n d 
u n der g o all scree ni n g pr oce d ures per pr ot oc ol . 
1 1. 1. 2  B aseli ne Visit ( Visit 2, D a y 1)  
If t he Bas eli ne Visit is m ore t ha n 4 2 da ys after t he Scree ni n g Visit, t he s u bject m ust be re p orte d 
as a scr ee n f ail ure a n d t h e n ma y b e res cree ne d ( wit h a ne w s u bject n u m ber) at t he i n vesti gat or's 
discreti o n.  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bjects a n d t heir pare nts/le gal g uar dia ns, " Are t here a n y 
c ha n ges i n y o ur h ealt h si nce t he last  visi t?"). 
2.  C o nfir m p ositi ve K O H a n d c ult ure res ults fr o m t h e ce ntral m yc ol o g y  la b orat or y. 
•  All s u bjects (i ncl u di n g t h ose i n P K s u bset) m ust ha ve at least 1 great t oe n ail 
wit h p ositi ve K O H ( perf or me d at ce ntral m yc ol o g y la b) a n d p ositi ve 
der mat o p h yte c ult ur e f or T r u br u m or T  me nt a gr o p hytes.  
3.  Re vie w t he saf et y la b orat or y test  res ults. 
lf a ny s afety l a b or at ory test res ults o bt ai ne d at t he Scree ni n g Visit, are a b n or m al a n d 
cli nic ally si g nific a nt as deter mi ne d by t he i n vesti g at or, t he i nvesti g at or s h o ul d 
disc uss wit h t he me dic al m o nit or w het her it is i n t he s u bject's best i nterest t o 
p artici p ate i n t he st u dy.  
4.  C o nfir m t he s u bject's me dical hist or y a n d pri or m e dicati o n  uses.  
5.  Re vie w all c o nc o mita nt me dicati o ns a n d ne w me dicati o ns starte d si nce t h e last st u d y 
visit.  
6.  O btai n  vital  si g n meas ure me nts.  Vital  si g ns will  be  meas ure d  after t he s u bj ect is seate d 
f or at least 5 mi n utes, a n d will i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, 
res pirat or y r ate, a n d oral b o d y te m perat ure. 
7.  Meas ure h ei g ht a n d  wei g ht.  
8.  C o n d uct  a n a b bre viate d  p h ysical  e xa mi nati o n  (e x cl u di n g ur o ge nital/re pr o d ucti ve 
s yste ms). 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4 0  
 
 
 
9.  Perf or m a uri n e pre g n a nc y test f or all F O C B P. E xcl u de t he s u bject if t he pre g na nc y 
test res ult is p ositi ve.  
1 0.  Cli p t he t oe nails t o t he distal gr o o ve ( bef ore p erf or mi n g t oe nail meas ure me nts  a n d 
cl ose-u p  p h ot o gra p h y).  
1 1.  C o n d uct t he i n vesti gat or's assess me nt of t he great t oe nail (s), wit h a deter mi nati o n of 
t he perce nta ge of t oe nail affecte d wit h diseas e. Meas ure t he dista nce fr o m t he 
pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
•  S u bjects n ot i ncl u de d i n t he P K s u bset m ust ha ve at least 1 great t oe nail wit h 
2 2 0 % i n v ol ve me nt  
•  S u bjects i ncl u de d i n t he P K s u bset m ust ha ve b ot h great t oe nails i n v ol ve d wit h 
2 5 0 % i n v ol ve me nt i n ea c h great  t oe nail. 
1 2.  Select tar get gr eat t oe nail i n eac h eli gi ble s u bject f or efficac y assess me nts. W here b ot h 
great t oe nails are st u d y -eli gi ble (i ncl u di n g perce nt i n v ol ve me nt, K O H -p ositi ve, a n d 
c ult ure-p ositi ve res ults), t he t oe nail wit h t he great er perce nt affecte d area at t he 
Baseli ne Visit will be selecte d as t he t ar get great t oe nail pri or t o e nr oll me nt i n t he 
treat me nt peri o d. I n t h e i nsta nce w here t he p erce nt affecte d area is t he sa m e f or b ot h 
st u d y-eli gi ble great t oe nails at t he Baseli ne Visit, t he i n ve sti gat or ma y c h o ose eit her 
great t oe nail t o be t he t ar get great  t oe n ail. 
1 3.  I ns cri be a tra ns verse n otc h i n t he great t oe nail at t h e pr o xi mal nail f ol d wit h a file or 
scal pel. T his will be use d as a mar k er at s u bse q u e nt visits f or deter mi ni n g ne w t oe nail 
gr o wt h.  
1 4.  Perf or m t he i n v esti gat or's assess me nt of t he n o ntar get t oe nails f or t he pres e nce or 
a bse nce of o n yc h o m y c osis. S u bjects i n t he P K s u bset m ust ha ve at least 4 t oe nails 
ot her t ha n t he gr eat t oe nails wit h  o n yc h o m yc osis.  
1 5.  Ta ke cl ose -u p p h ot o gra p hs of t he tar g et great t oe n ail. T he first p h ot o gra p h will be 
ta ke n after t oe n ail cli p pi n g. After  t hat p h ot o gra p h  is ta ke n, t he i n vesti gat or/e val uat or 
will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n t he tar get great t oe nail. 
W he n t he mar k er i n k has drie d, a  sec o n d cl ose-u p p h ot o gra p h will be  ta ke n. 
1 6.  Re vie w i ncl usi o n/e xcl usi o n criteria. If t he s u bject c o nti n ues t o meet all i ncl usi o n 
criteria a n d  n o ne  of  t he e xcl usi o n criteria,  e nr oll t he s u bject i n t he treat me nt peri o d.  
1 7.  O btai n 1 b ottle of st u d y dr u g a n d wei g h t he b ottle. Rec or d t he assi g ne d b ottle n u m ber 
f or t he st u d y dr u g i n t he s u bject's s o urce d o c u me nt a n d o n t he a p pr o pri ate e C R F. 
Dis pe nse t he b ottle t o t he s u bject a n d t heir pare nt/le gal g uar dia n (c o m plete t he la bel 
a n d re q uir e d rec or ds).  F or s u bjects i n t he P K s u bset, 2 b ottles of st u d y dr u g s h o ul d be 
o btai ne d. T he b ottles s h o ul d be wei g he d se p arat el y a n d rec or de d as se parat e e ntries, 
as descri be d  a b o v e.  
1 8.  I nstr u ct t he s u bject a n d t heir pare nt/le gal g uar dia n o n diar y c o m pleti o n a n d dis pe nse 
diar y.  
1 9.  T he s u bject or t heir p are nt/le gal g uar dia n will a p pl y t he first d ose of st u d y dr u g i n t he 
i n vesti gati o nal ce nter. I nstr uct t he s u bject a n d t heir pare nt/le g al g uar dia n i n t he pr o per  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4 1  
 
 
 
a p plicati o n tec h ni q ue f or t he st u d y dr u g a n d pr o vi de t he a p pr o pr iate S u bject 
I nstr u cti o n S heet wit h d osi n g i nstr ucti o ns (ie, f or n o n-P K or P K s u bjects), de pe n di n g 
o n w het her t he s u bject is e nr olle d i n t he P K s u bset. Rec or d a n y A Es f oll o wi n g t he 
i nitial treat me nt a p plicati o n. 
2 0.  Rec or d l ocal s ki n r eacti o ns. I nstr u ct t he s u bject a n d t heir pare nt/le gal g u ar dia n t o 
re p ort l ocal s ki n r eacti o ns (if a n y) at eac h st u d y visit.  
2 1.  Sc he d ule t he ne xt st u d y visit ( Visit 3 [ Wee k 4, D a y 2 8]) i n 2 8 da ys ( ± 5  da ys).  
N ote: ( ± 5 d ays) o nly a p plies t o N o n -P K s u bjects, P K s u bset o nly h as a ( ± J d ay) visit 
wi n d o w  
•  F or s u bjects i n t he P K s u bset, Visit 3 ( Wee k 4, D a y 2 8) t o Visit 3 A ( Wee k 4, 
Da y 2 9) r e mi n d s u bjects n ot t o a p pl y st u d y dr u g t he ni g ht pri or t o t heir Visit  3 
( Week 4, Da y 2 8)  visit.  
1 1. 1. 3  Visit  3  ( Wee k 4,  D a y  2 S  [ ± 5  d a ys]),  Visit  4  ( Wee k S  [ ± 5  d a ys]),  Visit  6  ( Wee k 1 6  [ ± 5 
d a ys]), Visit 7 ( Wee k 2 0 [ ± 5 d a ys]), Visit 9 ( Wee k 2 S [ ± 5 d a ys]), Visit 1 0 ( Wee k 3 2 
[ ± 5 d a ys]), Visit 1 2 ( W ee k 4 0 [ ± 5 d a ys]), Visit 1 3 ( Wee k 4 4 [ ± 5 d a ys])  
Visits are t o be sc he d ul e d i n refer e nce t o Visit 2 ( Baseli ne). 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bjects a n d t heir pare nts/le gal g uar dia ns, " Are t here a n y 
c ha n ges i n y o ur h ealt h si nce t he last  visit?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he t oe nails.  
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal  nail  f ol d t o tra ns verse n otc h).  If t he m ost  rece ntl y a p plie d n otc h  h as  gr o w n 
o ut or has bee n cli p pe d off, i nscri be a ne w n otc h a djace nt t o t he pr o xi mal n ail  f ol d. 
6.  C ollect t he diar y a n d st u d y dr u g b ottle fr o m t he s u bject a n d/ or t heir p are nt/le gal 
g uar dia n.  Wei g h  t he use d  b ottle  of  t he st u d y dr u g.  Rec or d  t he n u m ber  of  misse d  d oses 
fr o m t he s u bject diar y a n d re vie w c o m plia n ce wit h t he s u bject. 
7.  C o n d uct  a uri ne  pr e g na n c y  test o n  F O C B P  s u bjects ( disc o nti n ue a n y s u bject fr o m t he 
st u d y w h o has a p ositi ve test res ult) 
8.  O btai n 1 b ot tle of st u d y dr u g a n d wei g h t he b ottle, c o m plete t he la bel a n d dr u g l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d t heir p are nt/le gal g uar dia n. Re vie w t he 
d osi n g i nstr ucti o ns wit h t he s u bject. ( S u bjects i n t he P K s u bset will n ot be dis pe nse d 
st u d y dr u g t his da y).  
9.  Dis pe nse diar y. ( S u bjects i n t he P K s u bset will n ot be dis pe nse d a diar y t his  da y.)  
1 0.  Sc he d ule t he ne xt st u d y  visit.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4 2  
 
 
 
N ote : P K s u bjects e xiti n g t he st u d y o n Da y 2 9 (c o nse nte d t o o nl y t he 4-Wee k trial), t he 
f oll o wi n g pr oce d ur es will be c o n d ucte d i n a d diti o n t o t he pr oce d ures liste d a b o ve.  
1 1.  C ollect  bl o o d  a n d uri n e  s a m ples f or r o uti ne safet y la b orat or y a nal ysis ( he m at ol o g y, 
ser u m c he mistr y, a n d uri nal ysis). Pr ocess a n d s hi p t he sa m ples t o t he ce ntral safet y 
la b orat or y per i nstr ucti o ns pr o vi de d i n t he la b orat or y ma n ual.  
1 2.  Meas ure h ei g ht a n d  wei g ht.  
1 3.  C o n d uct  a n a b bre viate d  p h ysical  e xa mi nati o n  (e x cl u di n g ur o ge nital/re pr o d ucti ve 
s yste ms). 
 
F or s u bjects i n t he P K s u bset at Visit 3 o nl y: 
•  C ollect a pre d ose bl o o d s a m ple after all ot her st u d y pr oce d ures are  c o m plet e d. 
•  A p pl y t he st u d y dr u g t o all 1 0 t oe nails at t he i n vesti gati o nal ce nter wit hi n 1 h o ur  after 
c ollecti n g t he pre d os e bl o o d  sa m ple. 
•  C ollect p ost d ose bl o o d sa m ples at a p pr o xi matel y 2 h o urs ( ± 5 mi n), 4 h o urs 
( ± 5 mi n), a n d 12 h o urs ( ± 1 5 mi n) after st u d y dr u g  a p plicati o n.  
•  I nstr u ct t he s u bject t o ret ur n t he f oll o wi n g m or ni n g f or t heir 2 4-h o ur bl o o d sa m ple 
( Visit 3 A ( Da y 2 9). S u bj ect will n ot d ose o n t he e ve ni n g of Da y 2 8.  
1 1. 1. 4  Visit  3 A  ( We e k 4,  D a y  2 9)  - A d diti o n al  Visit  f or S u bjects  i n t h e P K  S u bset  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject " Are t here a n y c ha n ges i n y o ur  healt h?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he  s u bject. 
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  C ollect a  bl o o d sa m ple 2 4 h o urs ( ± 3 0 mi n) after st u d y dr u g a p plicati o n at Visit  3.  
5.  O btai n 1 b ottle of st u d y dr u g a n d wei g h t he b ottle, c o m plete t he la bel a n d dr u g l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d t heir p are nt/le gal g uar dia n. Re vie w t he ne w 
d osi n g i nstr ucti o ns wit h t he s u bject (a p plicati o n t o o nl y t he tar get great t oe nail a n d t o 
a n y ot her affecte d t oe nails) a n d pr o vi de a c o p y of ne w d osi n g i nstr ucti o ns t o t he 
s u bject. 
6.  Dis pe nse a ne w diar y t hat i ncl u des t he ne w d osi n g  i nstr ucti o ns. 
N ote : P K s ubjects w h o c o nse nte d t o o nl y t he 4 Wee k trial will e xit t he st u d y o n Da y  
2 9. Dr u g a n d s u bject diar y will n ot be dis pe nse d a n d uri ne pre g n a nc y test will 
n ot be c ollecte d at t his visit. .  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4 3  
 
 
 
1 1. 1. 5  Sc he d ule t he P K s u bset s u bject (if c o nse nte d t o t he 5 2 -Wee k tri al) f or t he ne xt st u d y 
visit. Visit 5 ( Wee k 1 2 [ ± 5 d a ys]), Visit S ( Wee k 2 4 [ ± 5 d a ys]), Visit 1 1 ( Wee k  3 6  
[ ± 5 d a ys]) 
Visits are t o be sc he d ul e d i n refere nce t o Visit 2 ( Baseli ne).  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t hese  visits:  
1.  Re c or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n " Are t here a n y c ha n ges 
i n y o ur healt h si nce t he l ast visit?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  C o n d uct a uri ne pre g n a n c y test o n F O C B P s u bjects ( disc o nti n ue a n y s u bject fr o m t he 
st u d y w h o has a p ositi ve test res ult). 
5.  Cli p t he t oe nails.  
6.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal  nail  f ol d t o tra ns verse n otc h).  If t he m ost  rece ntl y a p plie d n otc h  h as  gr o w n 
o ut or has bee n cli p pe d off, i nscri be a ne w n otc h a djace nt t o t he pr o xi mal n ail  f ol d. 
7.  C o n d uct t he i n vesti gat or's assess me nt of t he tar g et great t oe nail, wit h a d eter mi nati o n 
of t he per ce nta g e of t oe n ail affecte d wit h d iseas e. Meas ure t he dista n ce fr o m t he 
pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
8.  Perf or m t he i n vesti gat or's assess me nt of t he n o ntar get t oe nails f or t he prese nce or 
a bse nce of o n yc h o m yc osis.  
9.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b per i nstr ucti o ns pr o vi de d i n t he 
la b orat or y m a n ual.  
1 0.  O btai n  vital  si g n meas ure me nts.  Vital  si g ns will  be  meas ure d  after  t he s u bject is seate d 
f or at least 5 mi n utes a n d will i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, 
res pirat or y r ate, a n d oral b o d y te m perat ure. 
1 1.  At Visit 8/ Wee k 2 4 o nl y : Ta ke cl ose-u p p h ot o gra p hs of t he tar get great t oe n ail. T he 
first p h ot o gra p h  will  be  t a ke n after  t oe nail cli p pi n g. After  t hat p h ot o gra p h  is ta ke n, t he 
i n vesti gat or/e val uat or will use a fi ne ti p pe d mar k er t o o utli ne t he area affecte d o n t he 
tar get great t oe nail. W he n t he mar ker i n k h as drie d, a sec o n d cl os e-u p p h ot o gra p h will 
be  ta ke n. 
1 2.  C ollect t he diar y a n d st u d y dr u g b ottle fr o m t h e s u bject a n d/ or t heir p are nt/le gal 
g uar dia n.  Wei g h  t he use d  b ottle  of  t he st u d y dr u g.  Rec or d  t he n u m ber  of  misse d  d oses 
fr o m t he s u bject diar y a n d re vie w c o m plia n ce wit h t he s u bject a n d pare nt/le gal 
g uar dia n.  
1 3.  O btai n  1  b ottle  of  st u d y dr u g  a n d wei g h  t he b ottle,  c o m plete t he la bel a n d dr u g  l o g, 
a n d dis pe nse t he b ottle t o t he s u bject a n d pare nt/le gal  g uar dia n.  
1 4.  Re vie w t he d osi n g i nstr ucti o ns wit h t he  s u bject. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4 4  
 
 
 
1 5.  Dis pe nse  diar y.  
1 6.  Sc he d ule t he s u bject f or t he Visit 6 ( Wee k 1 6 [ ± 5 da ys]) st u d y visit, a n d i nstr uct t he 
s u bject t o ret ur n at t he s a me ti me of da y as t he Baseli ne Visit. T he Visit 7 ( Wee k 2 0 [ ± 
5 da ys]) a n d Visit 8 ( Wee k 2 4 [ ± 5 da ys]) st u d y visits will f oll o w Visit  6.  
1 1. 1. 6  Visit 1 4 ( Wee k 4 S [ ± 5 d a ys]) / E arl y Ter mi n ati o n  Visit  
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n " Are t here a n y c ha n ges 
i n y o ur healt h si nce t he l ast visit?").  
2.  Rec or d l ocal s ki n r eacti o n sc ores re p orte d b y t he s u bject a n d pare nt/le gal  g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he t oe nails.  
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal  nail  f ol d t o tra ns verse n otc h).  If t he m ost  rece ntl y a p plie d n otc h  h as  gr o w n 
o ut or has bee n cli p pe d off, i nscri be a ne w n otc h a djace nt t o t he pr o xi mal n ail f ol d. 
6.  C o n d uct t he i n vesti gat or's assess me nt of t he tar g et great t oe nail, wit h a d eter mi nati o n 
of t he per ce nta g e of t oe n ail affecte d wit h diseas e. Meas ure t he dista n ce fr o m t he 
pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
7.  Perf or m t he i n vesti gat or's assess me nt of t he n o ntar get t oe nails f or t he prese nce or 
a bse nce of o n yc h o m yc osis.  
8.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b per i nstr ucti o ns pr o vi de d i n t he 
la b orat or y m a n ual.  
9.  Ta ke cl ose -u p p h ot o gra p hs of t he tar get great t oe n ail. T he first p h ot o gra p h will be 
ta ke n after t oe n ail cli p pi n g. After  t hat p h ot o gra p h  is ta ke n, t he i n vesti gat or/e val uat or 
will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n t he tar get great t oe nail. 
W he n t he mar k er i n k has drie d, a sec o n d cl ose -u p p h ot o gra p h will be  ta ke n. 
1 0.  C o n d uct  a n a b bre viat e d  p h ysical  e xa mi nati o n  (e x cl u di n g ur o ge nital/re pr o d u cti ve 
s yste ms). 
1 1.  Meas ure h ei g ht a n d  wei g ht  
1 2.  O btai n  vital  si g n meas ure me nts.  Vital  si g ns will  be  meas ure d  after  t he s u bject is seate d 
f or at least 5 mi n utes, a n d i ncl u de s yst olic a n d diast olic bl o o d press ure, p ulse rate, 
res pirat or y r ate, a n d oral b o d y te m perat ure. 
1 3.  C ollect t he diar y a n d st u d y dr u g b ottle fr o m t he s u bject a n d/ or pare nt/le gal g uar dia n. 
Wei g h  t he us e d  b ottle  of t he  st u d y dr u g.  Rec or d  t he n u m ber  of  misse d  d oses  fr o m t he 
s u bject diar y a n d r e vie w c o m plia nce wit h t he s u bj ect a n d pare nt/le gal g uar dia n.  
1 4.  C o n d uct a uri ne pre g n a n c y test o n F O C B P s u bjects (if p ositi ve test res ult, t he s u bject 
s h o ul d ret ur n f or Visit 1 5 [ Wee k 5 2]  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4 5  
 
 
 
1 5.  C ollect  bl o o d  a n d uri n e  s a m ples f or r o uti ne safet y la b orat or y a nal ysis ( he m at ol o g y, 
ser u m c he mistr y, a n d uri nal ysis). Pr ocess a n d s hi p t he sa m ples t o t he ce ntral safet y 
la b orat or y per i nstr ucti o ns pr o vi de d i n t he la b orat or y ma n ual.  
1 6.  If t his is t he Earl y Ter mi nati o n Visit, rec or d t he reas o n f or s u bject disc o nti n uati o n 
fr o m t he st u d y a n d c o m plete t he Wee k 4 8 e C R F. If t his is n ot a n Earl y Ter mi nati o n 
Visit,  t he s u bject s h o ul d be  sc he d ul e d t o ret ur n f or t he Visit  1 5  ( Wee k 5 2)  st u d y visit.  
1 1. 1. 7  Visit 1 5 ( Wee k 5 2 [ ± 5 d a ys]) P ost -Tre at me nt F oll o w -u p Visit / St u d y  E xit  
F or all s u bjects w h o c o nti n ue t hr o u g h t he Wee k 4 8 visit, t his visit s h o ul d occ ur 4 w ee ks after t he 
last treat me nt visit. 
T he f oll o wi n g pr oce d ures will be c o n d ucte d at t his visit:  
1.  Rec or d a n y A Es ( q uer y s u bject a n d t heir pare nt/le gal g uar dia n, " Are t here a n y c ha n g es 
i n y o ur healt h si nce t he l ast visit?").  
2.  Rec or d l ocal s ki n r eacti o n  sc ores re p orte d b y t he s u bject a n d pare nt/le gal g uar dia n.  
3.  Re vie w c o nc o mita nt  me dicati o ns.  
4.  Cli p t he t oe nails.  
5.  Meas ure t he t ar get gr eat t oe nail gr o wt h si nce t he B aseli ne Visit ( dista nce fr o m 
pr o xi mal nail f ol d t o tra ns verse  n otc h).  
6.  C o n d uct t he i n vesti gat or's assess me nt of t he tar g et great t oe nail, wit h a d eter mi nati o n 
of t he per ce nta g e of t oe n ail affecte d wit h diseas e. Meas ure t he dista n ce fr o m t he 
pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic  b or der.  
7.  Perf or m t he i n vesti gat or's assess me nt of t he n o ntar get t oe nails f or t he prese nce or 
a bse nce of o n yc h o m yc osis.  
8.  O btai n s peci me ns fr o m t he tar get great t oe nail f or f u n gal c ult ure a n d K O H 
e xa mi nati o n a n d se n d t o t he m yc ol o g y ce ntral la b per i nstr ucti o ns pr o vi de d i n t he 
la b orat or y m a n ual.  
9.  Ta ke cl ose -u p p h ot o gra p hs of t he tar get great t oe n ail. T he first p h ot o gra p h will be 
ta ke n after t oe n ail cli p pi n g. After  t hat p h ot o gra p h  is ta ke n, t he i n vesti gat or/e val uat or 
will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n t he tar get great t oe nail. 
W he n t h e mar k er i n k has drie d, a sec o n d cl ose -u p p h ot o gra p h will be  ta ke n. 
1 0.  C o n d uct a uri ne pre g n a n c y test o n F O C B P  s u bjects. 
1 1.  E xit t he s u bject fr o m t he  st u d y. 
1 1. 1. S U nsc he d ule d Visits  
A d diti o nal visits ma y be sc he d ule d, as n ecess ar y, t o e ns ure t he safet y a n d well -bei n g of s u bjects. 
All a d diti o nal e xa ms s h o ul d be f ull y d oc u me nte d i n t he s o urce d oc u m e nts a n d o n U nsc he d ul e d 
Visit e C R Fs, as a p pr o pri ate. Visits i nte n de d t o f ulfill sc he d ule d visit re q uire me nts t hat fall 
o utsi de t he desi g nate d sc he d ule d visit ra n ge, are n ot u nsc he d ule d visits. I n t hese cas es, t he visit 
data will be c ollecte d a n d tra nscri be d t o t he a p pr o priate sc he d ul e d visit e C R F.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
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1 1. 1. 9  Misse d  Visits  
If a s u bject misses a n y s c he d ule d visit a n d ca n n ot be see n pri or t o t he st art of t he all o we d visit 
ra n ge f or t he ne xt sc h e d ule d f oll o w-u p visit, t he visit is c o nsi dere d misse d.  
1 1. 1. 1 0  S u bject  C o m pleti o n  
A s u bject has c o m plete d t he st u d y w he n Visit 1 5 ( Wee k 5 2) h as bee n c o m plete d a n d t he s u bject 
has bee n e xite d fr o m t he st u d y. S u bjects w h o re q uire  f urt her f oll o w-u p f or a n A E f oll o wi n g 
c o m pleti o n of t he st u d y will be f oll o we d acc or di n g t o Secti o n 1 2. 0.  
 
1 1. 2  St u d y E v al u ati o ns  
1 1. 2. 1  L oc al S ki n  Re acti o ns  
T olera bilit y will be e val u ate d t hr o u g h assess me nt of l ocal re d n ess, s welli n g, b ur ni n g, itc hi n g, 
a n d vesic ulat i o n i n t he selecte d treat me nt areas o n t he t oes. Eac h si g n or s y m pt o m is t o be 
re vie we d wit h t he s u bjects a n d t heir pare nts/le g al g uar dia ns aft er t he first a p plicati o n of t he st u d y 
dr u g at t he Baseli ne Visit a n d at eac h f oll o w -u p visit t hr o u g h Wee k 5 2. T he  s u bjects a n d t heir 
pare nts/le gal g uar dia ns s h o ul d assess eac h reacti o n base d o n t he w orst reacti o n e x perie nce d si nce 
t he pri or visit usi n g t he f oll o wi n g scales: 
 
Re acti o n  
Sc ore  
Re d ness, S welli n g  
0 = N o ne  
1 = Mil d  
2 = M o derate  
3 = Se vere  
B ur ni n g, Itc hi n g, a n d Vesic ulati o n 
Yes or N o  
 
Occ urre nce of vesic ul ati o n will al wa ys be re p orte d as a n A E. A n y ot her si g n or s y m pt o m will be 
re p orte d as a n A E o nl y if it re q uires c o nc o mita nt t hera p y or res ults i n a te m p orar y i nterr u pti o n or 
per ma ne nt disc o nti n uati o n of t he st u d y dr u g d ue t o disc o mf ort.  
1 1. 2. 2  Cli nic al L a b or at or y  Tests  
Bl o o d a n d uri ne sa m ples will be c ollecte d f or r o uti ne safet y la b orat or y tests ( he mat ol o g y, ser u m 
c he mistr y, a n d uri nal ysis) at t he Scree ni n g a n d Wee k 4 8/ Earl y T er mi nati o n visit. A n y s u bject 
wit h a scree ni n g la b orat or y a b n or malit y t hat is deter mi ne d b y t he i n vesti gat or t o be cli nicall y 
si g nifica nt m ust be a p pr o ve d f or i ncl usi o n i n t he st u d y b y t he me dical m o nit or. All res ults will 
be re p ort e d, i ncl u di n g a b n or mal res ults. Cli nicall y si g nifica nt c ha n ges i n la b res ults fr o m 
Scree ni n g, i n t he o pi ni o n of t he i n vesti gat or, s h o ul d be re p ort e d as A Es. Cli nicall y si g nifica nt 
c ha n ges pr ese nt at Wee k 4 8/ Earl y Ter mi nati o n are t o be f oll o we d t o res ol uti o n or u ntil cli nicall y 
sta ble as deter mi ne d b y t he i n vesti gat or. If a n A E s h o ul d re q uire la b orat or y testi n g, t he res ults of 
t he test m ust be o btai ne d b y t he i n vesti gati o nal ce nter a n d file d i n t he s u bject's d oc u me ntati o n. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
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Materials f or sa m ple c ollecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nters b y t he s p o ns or or 
ce ntral la b orat or y. I nstr u cti o ns f or pr ocessi n g a n d s hi p pi n g sa m ples t o t he ce ntral la b orat or y are 
c o ntai ne d i n t he st u d y la b orat or y ma n ual.  
F or all F O C B P, uri ne pre g na nc y testi n g will be perf or me d at t he Scree ni n g a n d Baseli ne Visits, 
as well as at eac h s u bse q ue nt st u d y visit. F O C B P is defi ne d as a n y fe male s u bject w h o has 
e x perie n ce d me n arc h e. T he res ults at t he Scree ni n g a n d Baseli ne Visits m ust be ne gati ve f or a 
s u bject t o e nter t he st u d y. Materials f or pre g na n c y testi n g will be pr o vi de d t o t he i n vesti gati o nal 
ce nters b y t he s p o ns or or ce ntral la b orat or y.  
1 1. 2. 3  Vit al Si g n  Me as ure m e nts  
Meas ure me nt of vital si g ns will be perf or me d at t he Baseli ne Vi sit, as well as at Wee ks 1 2, 2 4, 
3 6, a n d 4 8/ Earl y Ter mi nati o n. After t he s u bjects ha ve bee n sitti n g f or at least 5 mi n utes, s yst olic 
a n d diast olic bl o o d press ures, p ulse rat es, res pirati o n rates, a n d oral te m perat ures will be 
rec or d e d. 
1 1. 2. 4  P h ysic al  E x a mi n ati o n s 
A n a b bre viat e d p h ysical e xa mi nati o n will be perf or me d at t he Baseli ne Visit a n d at  
Wee k 4 8/ Earl y Ter mi nati o n. Hei g ht a n d wei g ht will be meas ure d at t he Bas eli ne Visit a n d at t he 
Wee k 4 8/ Earl y Ter mi nati o n Visit.  
1 1. 2. 5  Effic ac y f o r Assessi n g Tre at me nt C o m pli a nce  a n d  S afet y  
Efficac y assess me nts will be perf or m e d t hr o u g h o ut t he st u d y. T he efficac y a nal yses will be 
base d o n micr osc o pic e x a mi nati o n a n d m yc ol o gical c ult ure res ults f or t he t ar get great t oe nail, t he 
perce nt i n v ol ve me nt of t he tar get gr eat t oe nail, t h e l e n gt h of t he u naffecte d part of t he tar g et 
great  t oe nail, t he gr o wt h  of  t he tar get great  t oe n ail, a n d t he n u m b er  of  affecte d n o ntar get  t oe nails. 
I n v esti gat ors/e val uat ors will be trai ne d b y t he s p o ns or t o e ns ure c o nsiste n c y acr oss 
i n vesti gati o nal ce nters r egar di n g t oe nail cli p pi n g, e val uati o ns a n d meas ure me nts, as well as 
c ollecti o n of s uffici e nt material f or K O H e xa mi nati o ns a n d f u n gal c ult ures. E val uat ors m ust be 
pre -a p pr o ve d b y t he s p o ns or a n d m ust ha ve a p pr o priate d oc u me nte d e x perie nce a n d trai ni n g, or 
h a ve a w ai ver o btai n e d fr o m t he s p o ns or base d o n e x perie n ce ( or t hr o u g h a d diti o nal trai ni n g 
or ga nize d b y t he s p o ns or).  
E ver y eff ort s h o ul d be m a de t o ha v e t he sa me s p o ns or -a p pr o v e d e v al uat or perf or m t he tar get 
great t oe n ail assess me nts a n d meas ure m e nts f or a partic ular s u bject at t he Baseli ne Visit a n d 
eac h f oll o w -u p visit.  
1 1. 2. 5. 1  K O H E x a mi n ati o n a n d F u n g al  C ult uri n g  
T he K O H e xa mi nati o n a n d f u n gal c ult uri n g of t oe nail scra pi n g a n d s u b u n g ual de bris will be 
perf or me d f or st u d y -eli gi ble great t oe n ail(s) at t he Scree ni n g Visit a n d f or t he tar get great t oe nail 
o nl y (as deter mi ne d at t he Baseli ne Visit) at Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y Ter mi nati o n, a n d 5 2 (t he  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
4 8  
 
 
 
4 -wee k p ost -tr eat me nt f oll o w-u p) st u d y visits. At t he Scree ni n g visit, s peci me ns f or K O H a n d 
f u n gal c ult ures are o btai n e d fr o m st u d y-eli gi ble great t oe nails at t his visit a n d se nt t o t he ce ntral 
m yc ol o g y la b orat or y f or testi n g.  
T oe nail s peci me ns will b e ta ke n b y cli p pi n g t he t o e nail t o t he p oi nt of attac h me nt (re m o vi n g 
u n healt h y nail) a n d o btai ni n g a n y cr u m bli n g s u b u n g ual de bris fr o m u n der t he distal e d ge of t he 
tar get great t oe nail usi n g a dis p osa ble c urette. All tar get great t oe nail plate cli p pi n gs a n d " distal" 
s u b u n g ual de bris s h o ul d be discar d e d. O nl y t he s oft nail be d kerati n be neat h t he cli p pe d e d ge of 
t he nail s h o ul d be c ollect e d a n d use d as a s peci me n f or b ot h t he K O H e xa mi nati o n a n d t he 
f un gal c ult ure. Caref ul s p eci me n c ollecti o n i n t his ma n ner will mi ni mize t oe nail s peci me n 
c o nta mi na nts a n d ma xi mize der mat o p h ytic p at h o ge n is olati o n.  
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nt ers b y t he s p o ns or or 
ce ntral m y c ol o g y la b orat or y. I nstr ucti o ns f or pr o cessi n g a n d s hi p pi n g sa m ples t o t he ce ntral 
la b orat or y are c o nt ai ne d i n t he st u d y la b orat or y ma n ual. 
1 1. 2. 5. 2  T ar get Gre at T oe n ail  Assess me nts  
T he per ce nt of t he aff ect e d t oe nail ar ea a n d h ealt h y ( u naffecte d) t oe nail meas ure me nts f or t he 
tar get great t oe nail will be e val uat e d b y t he i n vesti gat or/e val uat or at t he Scree ni n g a n d Baseli ne 
Visits, a n d at Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y Ter mi nati o n, a n d 5 2 (t he 4 -wee k p ost -treat me nt 
f oll o w-u p) st u d y visits.  
Perce nt of Affecte d Tar g et Grea t T o e nail Area 
T he aff ecte d ar ea of t he t oe nail will be esti mate d as t he perce nt of t oe nail area ( nail a n d n ail be d) 
i n v ol ve d (t he distal mar gi n f or deter mi ni n g area will be t he distal gr o o ve after t he t oe nail has 
bee n cli p pe d).  
Healt h y ( U naffecte d) T ar get  Great T o e nail Meas ure me nt a n d Gr o wt h  
T he healt h y ( u n aff ecte d) t oe nail meas ure m e nt will be defi ne d as t he dista nce (i n m m) bet wee n 
t he pr o xi mal nail f ol d a n d a tra ns vers e li ne o n t he healt h y part of t he t o e nail i m me diatel y 
pr o xi mal t o t he nail i nfecti o n. A t eac h e v al uati o n, t his dista nce will be meas ure d fr o m t he 
pr o xi mal nail f ol d t o t he pr o xi mal o n yc h o m yc otic b or der.  
T oe nail gr o wt h will be m eas ure d b y i ns cri bi n g a tra ns verse n otc h i n t he nail of t he tar get great 
t oe nail a djace nt t o t he pr o xi mal nail f ol d at t he ce nter of t he nail at t he Bas eli ne Visit, a n d 
meas uri n g nail gr o wt h fr o m t hat p oi nt f or war d. At e ver y s u bse q u e nt visit, t he dista nce (i n m m) 
bet wee n t he pr o xi mal nail f ol d a n d t he n otc h will be meas ure d a n d rec or d e d. T he n otc h s h o ul d 
be e n ha n ce d as n ee de d at s u bse q ue nt visits t o all o w c o nti n ue d meas ure me nt of t oe nail gr o wt h 
o ver t he c o urse of t he st u d y. If t he i nitiall y a p plie d n otc h i nscri be d at t he Baseli ne Visit has 
gr o w n o ut or is cli p pe d a wa y, i nscri be a ne w n otc h i n t he t oe nail a djace nt t o  t he pr o xi mal nail 
f ol d, a n d c o nti n ue wit h meas ure me nts usi n g t he ne w n otc h. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
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1 1. 2. 5. 3  N o nt ar get T oe n ail  Assess m e nt  
A n assess me nt of b ot h feet will be ma de f or assessi n g t he prese nce or a bs e nce of o n yc h o m y c osis 
of n o ntar get t oe n ails at t he Scree ni n g, Bas eli ne, Wee ks 1 2, 2 4, 3 6, 4 8/ Earl y Ter mi nati o n, a n d 5 2 
(t he 4-wee k p ost -treat me nt f oll o w-u p) st u d y visits. All n o ntar get t oe nails will be assesse d f or t he 
prese nce or a bs e nce of o n yc h o m yc osis. S u bjects i n t he P K s u bset m ust prese nt wit h 
o n yc h o m yc osis o n at least 4 t oe nails besi des t he great t oe nails.  
1 1. 2. 6  E v al u ati o n of P h ar m ac o ki netics  
T he P K assess me nts will be perf or me d o n a s u bs et of t he st u d y p o p ulati o n w h o will recei ve 
treat me nt u n der m a xi mal use c o n diti o ns f or 2 8 da ys. Plas ma sa m ples f or d eter mi nati o n of 
efi nac o n az ole a n d meta b olite le vels will be c ollecte d at t he f oll o wi n g ti me p oi nts:  
•  Visit 3 ( Da y 2 8): Pre d ose (after all Da y 2 8 pr o ce d ures are c o m plete d). St u d y dr u g 
m ust be a p plie d wit hi n 1 h o ur after t h e pre d os e sa m ple is c ollecte d. Sa m ples are t h e n 
c ollecte d at 2 ( ± 5 mi n), a n d at 4 ( ± 5 mi n), a n d at 1 2 ( ± 1 5 mi n) h o urs p ost d ose.  
•  Visit 3 A ( Da y 2 9): 2 4 ( ± 3 0 mi n) h o urs after Da y 2 8 st u d y dr u g  a p plicati o n. 
Materials f or s a m ple c oll ecti o n will be pr o vi de d t o t he i n vesti gati o nal ce nt ers b y t he s p o ns or or 
central la b orat or y. I nstr u cti o ns f or pr ocessi n g a n d s hi p pi n g sa m ples t o t he bi oa nal ytical 
la b orat or y are c o nt ai ne d i n t he st u d y la b orat or y ma n ual. 
1 1. 2. 7  P h ot o gr a p h y  
At all i n vesti gati o nal ce nters, cl ose -u p p h ot o gra p hs of t he tar get great t oe n ail will be ta ke n at t he 
Baseli ne, Wee ks 2 4, 4 8/ Earl y Ter mi nati o n, a n d 5 2 (t he 4 -wee k p ost -treat me nt f oll o w-u p) st u d y 
visits. O ne p h ot o gra p h will be ta ke n after t o e nail cli p pi n g. After t he first p h ot o gra p h has bee n 
ta ke n, t he i n vesti gat or/e v al uat or will use a fi ne ti p pe d mar ker t o o utli ne t he area affecte d o n t h e 
tar get great t oe nail. After t he i n k has drie d, a sec o n d p h ot o gra p h will be ta ke n. T he c ollecte d 
p h ot o gra p hs will be use d  f or d oc u me ntati o n p ur p oses o nl y a n d will n ot be use d f or 
deter mi nati o ns of eli gi bilit y, efficac y, or a n y st u d y -relate d acti vities. Bef ore p h ot o gra p hs ar e 
ta ke n, t he st u d y s u bject a n d t heir pare nt(s)/le gal g uar dia n(s) m ust c o ns e nt/asse nt t o p h ot o gra p h y. 
If t he p h ot o gra p h y c o nse nt/asse nt is decli ne d, t he s u bject ma y still partici pate i n t he st u d y. 
 
1 1. 3  Defi niti o n of A d verse E ve nts  
A n A E is a n y u nt o war d me dical occ urre n ce i n a s u bject or cli nical i n vesti g ati o n s u bject 
a d mi nistere d a me dici nal pr o d uct a n d w hic h d o es n ot necessaril y ha v e a ca usal relati o ns hi p wit h 
t he st u d y dr u g. T h us, A Es i ncl u de a n y u nfa v ora bl e a n d u ni nte n de d ill ness, si g n, s y m pt o m, 
cli nicall y si g nifica nt la b orat or y test a b n or m alit y, or disease te m p orall y ass o ciate d wit h t he use of 
a me dici nal pr o d uct t hat has a p peare d or w orse n e d d uri n g t he c o urse of t he cli nical st u d y, 
re gar dl ess of ca us al relati o ns hi p t o t he st u d y dr u g(s) u n der st u d y. T he c ollecti o n of n o nseri o us 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
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A Es a n d seri o us a d v erse e ve nts ( S A Es) s h o ul d be gi n f oll o wi n g t he s u b ject's c o m pleti o n of t he 
c o nse nt/asse nt pr ocess t o partici pate i n t he st u d y.  
1 1. 3. 1. 1  Defi niti o n of Seri o us A d verse  E ve nts  
All A Es will be assesse d as eit her seri o us or n o nseri o us. A n S A E or seri o us a d verse reacti o n is 
defi ne d as a n y u nt o war d me dical occ urre n ce t hat at a n y d ose:  
•  Res ults i n deat h.  
•  Is i m me diatel y life t hr eat e ni n g, (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 v e nt i n w hic h t he s u bject is at ris k of deat h at t he ti m e of t he 
e ve nt; it d oes  n ot  ref er t o a n e v e nt w hic h  h y p ot heti call y  mi g ht  ha ve  ca use d deat h  if it 
were m or e  se vere). 
•  Re q uires i n s u bject h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
( h os pitalizati o n f or electi ve s ur ger y f or a bas eli ne  c o n diti o n is n ot  c o nsi dere d  a n A E).  
•  Res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y ( per m a ne nt or  s u bst a 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). 
•  Is a c o n ge nital a n o mal y/ birt h defect. 
•  Is a me dicall y i m p orta nt e ve nt t hat ma y n ot be i m me diatel y life t hreat e ni n g or res ult 
i n deat h or h os pitalizati o n, b ut ma y je o par dize t h e s u bject a n d ma y re q uire me dical or 
s ur gical i nter ve nti o n t o pre ve nt o ne of t he a b o v e liste d o utc o mes.  
I m p ort a nt me dical e v e nts t hat ma y n ot ha ve res ult e d i n deat h, be life-t hreate ni n g, or 
re q uire h os pitalizati o n m a y be c o nsi dere d a n S A E w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he s u bj ect a n d ma y re q uire me di cal or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n. E xa m ples of s uc h 
me dical e v e nts i ncl u de aller gic br o nc h os p as m re q uiri n g i nte nsi ve treat me nt i n a n 
e mer ge n c y r o o m or at h o me, bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n 
i n patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g de pe n de n c y or dr u g a b use. 
H os pitalizati o n is a cri teri o n f or assess me nt of seri o us ness. T o q ualif y as seri o us u n der t he 
criteria of " h os pitalizati o n," a h os pital a d missi o n of at least a 2 4 -h o ur peri o d is re q uire d. If a 
s u bject is retai ne d t he e mer ge nc y r o o m greater t ha n 2 4 h o urs, b ut n ot a d mitte d f or me dical care, 
t hese cas es s h o ul d be e val uate d i n di vi d uall y, as criteria s uc h as " me dicall y si g nifica nt" ma y als o 
a p pl y. 
H os pitalizati o n wit h o ut a me dical A E s h o ul d n ot be c o nsi dere d eit her s eri o us or a n A E. 
E xa m ples i ncl u de:  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 1  
 
 
 
•  A d missi o n f or treat m e nt of a pre-e xisti n g c o n diti o n n ot ass ociate d wit h t he de vel o p me nt 
of  a  ne w  A E  or  wit h  w orse ni n g  of  t he  pre -e xisti n g  c o n diti o n  (e g,  f or  w or k -u p  of  
persiste nt pre -tr eat me nt l a b a b n or malit y).  
•  H os pitalizati o n f or a p ur p ose u nrelate d t o t he st u d y (e g, " pla n ne d" or el ecti ve s ur ger y 
sc he d ule d pri or t o st u d y partici pati o n) w o ul d n ot or di naril y nee d t o be re p orte d, u nless a 
c o m plicati o n occ urre d w hic h ot her wise ca use d pr ol o n gati o n of t his  h os pitalizati o n.  
•  Pr ot oc ol -s pecifie d  a d missi o n  or  pr oce d ure  (e g,  cataract  s ur ger y  re q uire d  b y  a  st u d y  
pr ot oc ol;  or  o ver ni g ht  sta y  f or  m o nit ori n g  d ue  t o  pr ot oc ol  re q uire d  s ur ger y,  wit h  n o  
ass oci ate d S A E or c o m plic ati o n necessit ati n g pr ol o n ge d  st ay) 
•  S ocial a d missi o n (e g, s ocial h os pitalizati o n f or p ur p oses of res pite  care)  
N ote:  A  s p o nta ne o us a b orti o n will  be  c o nsi dere d  a n S A E,  a n d m ust  be  re p orte d t o t he s p o ns or 
wit hi n 2 4 h o urs of y o ur a ware n ess of t he  e v e nt.  
1 1. 3. 1. 2  Assess m e nt of  Se verit y  
T he se verit y assi g ne d t o a n A E s h o ul d be deter mi ne d b y t he ma xi m u m se verit y of t he A E. T h e 
cate g ories d escri b e d bel o w s h o ul d be use d t o esti mate t he se verit y of A Es:  
•  Mil d: Tra nsie nt or mil d disc o mf ort; n o li mitati o n i n acti vit y; n o  me dical 
i nter ve nti o n/t hera p y re q uire d. 
•  M o derate: Mil d t o m o der ate li mitati o n i n acti vit y; s o me assista nce ma y b e nee de d; 
n o or mi ni mal me dical i nter ve nti o n/t hera p y  re q uire d. 
•  Se vere: Mar k e d li mitati o n i n acti vit y; s o me assista nce us uall y re q uire d; m e dical 
i nter ve nti o n/t hera p y r e q uire d; h os pitalizati o n or pr ol o n gati o n of c urre nt 
h os pitalizati o n p ossi ble; ma y be i nca p acitati n g or life t hreate ni n g. 
1 1. 3. 1. 3  Assess m e nt of  C a us alit y  
T he  i n vesti gat or s h o ul d assess  t he relati o ns hi p of  t he A E,  if a n y,  t o t he st u d y dr u g  as eit her 
" Relate d" or " N ot Relate d".  
•  Rel ate d: T here is at least a reas o na bl e p ossi bilit y t hat t he A E/ S A E is relate d t o t he st u d y 
dr u g. Reas o na ble p ossi bilit y mea ns t hat t here is e vi de nce t o s u g gest a ca usal relati o ns hi p 
bet wee n t he dr u g a n d t he  A E.  
•  N ot R el ate d: T her e is little or n o reas o na ble p ossi bilit y t hat t he A E/ S A E is relate d t o t he 
st u d y  dr u g.  T his  assessme nt  i m plies  t hat  t he  A E/ S A E  has  little  or  n o  te m p oral  
relati o ns hi p t o t he st u d y dr u g a n d/ or a m ore li kel y or cert ai n alter nati ve eti ol o g y e xists. 
T he f oll o wi n g s h o ul d be ta ke n i nt o acc o u nt w h e n assessi n g A E/ S A E ca usalit y:  
•  P ositi ve te m p oral relati o ns hi p t o st u d y dr u g, s uc h as if t he st u d y dr u g was wit h dra w n 
a n d t he S A E res ol ve d or t he e ve nt rec urre d after re  i ntr o d ucti o n. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 2  
 
 
 
•  If t her e is a reas o n a ble p ossi bilit y  t hat t he A E  is ass ociate d  wit h  a n u n d erl yi n g  or 
c o nc o mita nt ill ness.  
•  P ossi ble ass ociati o n wit h pre vi o us or c o n c o mita nt  t hera p y. 
•  N o te m p oral rel ati o ns hi p t o t he st u d y dr u g a n d/ or a m ore li kel y alter n ati ve eti ol o g y 
e xists. 
•  If t he A E is directl y relat e d t o st u d y pr oce d ures or t here is a lac k of effi cac y. 
1 1. 3. 1. 4  Pr oce d ures f or R e p orti n g A d verse E ve nts a n d Seri o us A d verse  E ve nts  
T he peri o d of o bs er vati o n f or c ollecti o n of A Es e xte n ds fr o m t he ti me t he s u bject a n d 
pare nt/le gal g uar dia n gi v es i nf or me d c o ns e nt/asse nt u ntil t he last st u d y visit or disc o nti n uati o n 
fr o m t he st u d y. T he first c o ncer n will be t he safet y of t he s u bject, a n d a p pr o priate me dical 
i nter ve nti o n will be ma de. 
T he I n vesti gat or or d esi g nee will elicit re p orts (ie, via direct q uesti o ni n g, o bser vati o n, cli nical 
e val uati o n) of A Es fr o m t he s u bject at eac h st u d y visit a n d rec or d all A Es. T he I n vesti gat or will 
d oc u me nt t he dates of o nset, pr o gress, o utc o me, a n d res ol uti o n of s uc h A Es. T he I n vesti gat or 
will als o pr o vi de a n assess me nt of all A Es as t o t he se verit y, ca usal relati o ns hi p t o st u d y dr u g, 
a n d ca usal relati o ns hi p  t o st u d y pr ot oc ol. 
It is t he i n vesti gat or's r es p o nsi bilit y t o d oc u me nt all A Es t hat occ ur d uri n g t he st u d y. T he A Es 
s h o ul d be d oc u me nte d as a si n gle me dical dia g n osis. W he n t his is n ot p ossi ble, t he A E s h o ul d be 
d oc u me nte d i n ter ms of si g ns a n d/ or s y m pt o m s o bser ve d b y t he i n vesti gat or or re p orte d b y t he 
s u bject a n d/ or t heir pare nt/le gal g uar dia n at eac h st u d y visit. 
All A Es occ urri n g after t he s u bject a n d t heir p are nt/le gal g uar dia n si g ns t he asse nt/i nf or me d 
c o nse nt t hr o u g h t he last st u d y visit m ust be re p orte d, re gar dl ess of w het h er or n ot t he A Es are 
c o nsi dere d dr u g -r elate d. All A Es, w het her i n res p o nse t o a q uer y, o bs er ve d b y t he st u d y site 
pers o n nel, or r e p orte d s p o nta ne o usl y b y t he s u bject a n d/ or t heir pare nt/le g al g uar dia n, will be 
rec or d e d. 
At eac h v isit d uri n g t he st u d y, t he s u bject will be assesse d f or t h e occ urre n ce of ne w a n d o n g oi n g 
A Es. C uta ne o us t olera bilit y si g ns a n d s y m pt o ms t hat res ult i n t he s u bject's re q uiri n g a 
c o nc o mita nt t hera p y or disc o nti n uati o n fr o m t he st u d y will be re p orte d as a n A E. T he f oll o wi n g 
data will be c ollecte d o n all A Es a n d rec or de d o n t he a p pr o pri ate e C R F:  
•  E ve nt na me ( dia g n osis pr eferre d, if u n k n o w n, rec or d t he  si g ns/s y m pt o ms). 
•  O nset date a n d e n d  date.  
•  Ma xi m u m i nte nsit y  (se verit y). 
•  Seri o us ness.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 3  
 
 
 
•  Acti o n ta ke n re g ar di n g st u d y dr u g.  
•  C orrecti ve tr eat me nt, if  gi ve n. 
•  O utc o me.  
I n a d diti o n, t he i n vesti gat or's assess me nt of ca usalit y will be rec or d e d. 
A n y S A E m ust be re p ort e d t o t he S p o ns or, i n de pe n de nt of t he circ u msta nce or s us pecte d ca us e, 
wit hi n 2 4 h o urs fr o m t he ti me t he e ve nt was re p ort e d t o t he I n vesti gat or. All S A Es e x perie nce d 
fr o m t he date of c o nse nt t hr o u g h at least 3 0 da ys after t he last d ose of st u d y dr u g m ust be 
re p orte d t o t he S p o ns or r e gar dless of t h e relati o ns hi p t o t he st u d y dr u g or t he pr ot oc ol. F or 
e ve nts occ urri n g be y o n d t he mi ni m u m 3 0- da y peri o d after t he l ast d ose of st u d y dr u g, or f or a n y 
ti mefra me after w ar d dee me d me dicall y si g nifica nt, o nl y S A Es c o nsi dere d relate d t o t he st u d y 
dr u g s h o ul d be re p ort e d pr o m ptl y t o t he S p o ns or.  
Wit hi n 2 4 h o urs of n otificati o n t he I n vesti gat or will fa x or e mail a c o m plete d Seri o us A d vers e 
E ve nt Re p ort t o t he S p o ns or:  
Me d Trials Safet y:  
Fa x: 
 
* * Please f oll o w u p wit h a n e mail n otificati o n t o 
 t o c o nfir m t he fa xe d s u b missi o n. 
 
I n v esti gat ors s h o ul d n ot wait t o recei v e a d diti o nal i nf or mati o n t o d oc u me nt t he e ve nt bef ore 
n otif yi n g t he s p o ns or of a n S A E. If o nl y li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w- u p 
re p orts ar e re q uire d. If t he I n vesti gat or bec o mes a ware of a n y ne w i nf or mati o n re gar di n g a S A E 
(ie, res ol uti o n, c ha n g e i n c o n diti o n, or ne w treat me nt), a ne w S A E F or m m ust be c o m plete d a n d 
fa xe d/e maile d t o t he S p o ns or wit hi n 2 4 h o urs. T he ori gi nal S A E f or m is n ot t o be altere d. T h e 
re p ort s h o ul d be mar k e d as a "f oll o w- u p re p ort" a n d descri be w h et her t he e ve nt has res ol ve d or 
c o nti n ues a n d h o w t he e v e nt was treate d. A d diti o nal rele va nt i nf or mati o n s uc h as h os pital 
rec or ds a n d a ut o ps y r e p orts s h o ul d be pr o vi de d t o t he s po ns or as s o o n as t h e y are a vaila ble.  
S h o ul d t he i n vesti gat or bec o me a war e of a n S A E (re gar dless of its relati o ns hi p t o i n vesti gati o nal 
pr o d uct) t hat occ urs wit hi n 3 0 da ys after st o p pi n g t he st u d y dr u g, t he S A E m ust be re p orte d i n 
acc or d a nce wit h pr oce d ures  s pecifi e d i n t his pr ot oc ol. 
T he i n vesti gat or s h o ul d ta ke all a p pr o priate meas ures t o e ns ure t h e safet y of t he s u bjects, n ota bl y 
he/s he s h o ul d f oll o w a s u bject wit h a n S A E u ntil t he e ve nt has res ol ve d or t he c o n diti o n has 
sta bilize d. T his ma y i m pl y t hat f oll o w- u p will c o nti n ue after t h e s u bject has left t he st u d y, a n d 
t hat a d diti o nal i n vesti gati o ns ma y be re q u este d b y t he s p o ns or. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 4  
 
 
 
1 1. 3. 1. 5  S u b mitti n g a n E x pe dite d S afet y Re p ort t o t he I R B ( Ce ntr al or  L oc al)  
A n y s us pecte d u ne x p ecte d seri o us a d vers e reac ti o n ( S U S A R) warra nts e x p e dite d re p orti n g. I n 
a d diti o n, a n y u ne x pect e d S A E relate d t o a s u bject's partici pati o n i n t he st u d y ( or c o n d uct of 
st u d y), re gar dl ess if t he st u d y dr u g was a d mi nistere d, will be e val uat e d b y Gl o bal 
P har mac o vi gila nce a n d Ris k Ma na ge me nt ( G P R M) t o deter mi ne if e x p e dite d re p orti n g is 
re q uire d. F or e xa m ple, a n u ne x pecte d, s eri o us a n d se vere reacti o n w hic h c o ul d be ass ociate d t o 
t he st u d y pr oce d ur es, a n d w hic h c o ul d m o dif y t he st u d y c o n d uct re q uires e x pe dite d re p orti n g. 
Eac h e x p e dite d sa f et y re p ort will r o uti nel y i ncl u de a brief c o ver me m ora n d u m, t he c o m plete d 
Me d Watc h F or m F D A 3 5 0 0 A or C o u ncil f or I nter nati o nal Or ga ni zati o ns of Me dical Scie n ces I 
F or m, a cli nical a nal ysis of t he e ve nt wit h a n y si milar e ve nts t hat ha v e occ urre d wit h t he p r o d u ct, 
a n d a n y a d diti o nal perti n e nt i nf or mati o n rec o m me n de d b y t he st u d y Me dical M o nit or. O nce t he 
re p ort is c o m pile d b y G P R M, t he site I n vesti gat or m ust s u b mit t he e x pe dite d safet y re p ort t o t he 
l ocal I R B/ E C wit hi n t he re q uire d r e p orti n g ti mefra me. F oll ow -u p re p orts s h o ul d be s u b mitte d 
w he n re q u este d or w h e n perti ne nt i nf or mati o n bec o mes a vaila ble. T h e site pri nci pal I n vesti gat or 
m ust retai n a c o m plete c o p y of eac h e x pe dite d s afet y re p ort as it was s u b mitte d t o t he I R B. It is 
i m p orta nt t hat t he pri nci pal I n v esti gat or re vie w t hese e x pe dite d re p orts, as t he y c o ntai n safet y 
i nf or mati o n t hat ma y be r ele va nt t o eac h of t he p artici pati n g s u bjects. 
1 1. 3. 2  Pre g n a nc y  
All fe male s u bjects of c hil d beari n g p ote ntial m ust use a n effecti ve m et h o d of birt h c o ntr ol d uri n g 
t he c o urse of t h e st u d y, i n a ma n ner s u c h t hat ris k of c o ntrace pti ve fail ure is mi ni mize d. 
A bsti ne nce is all o we d as a birt h c o ntr ol met h o d.  
Bef ore e nr olli n g a fe mal e s u bject of c hil d beari n g p ote ntial i n t his cli nical st u d y, t he i n vesti gat or 
m ust re vie w t he f oll o w i n g i nf or mati o n a b o ut st u d y partici pati o n: 
•  I nf or me d c o ns e nt/asse nt re q uire me nts. 
•  C o ntrace pti ves i n c urre nt use.  
F oll o wi n g re vie w of t his i nf or mati o n a n d a p pr o priate c o u nseli n g f or t h e s u bject a n d t heir 
pare nt/le gal g uar dia n, t he i n vesti gat or or desi g nee a n d t he s u bject a n d p are nt/le gal g uar dia n m ust 
si g n t he asse nt/i nf or me d c o nse nt bef or e st u d y e nr oll me nt. 
D uri n g t he st u d y, all fe m ale s u bjects of c hil d beari n g p ote ntial s h o ul d be i nstr ucte d t o c o ntact t he 
i n vesti gat or i m me diatel y if t he y s us pect the y mi g ht be pre g na nt (e g, misse d or late me nstr ual 
peri o d).  
If a s u bject or i n vesti gat or s us pects t hat t he s u bject ma y be pre g n a nt pri or t o st u d y e nr oll me nt, 
t he st u d y dr u g m ust be wit h hel d u ntil t he res ults of la b orat or y pre g na n c y testi n g are a vaila ble. If 
pre g na nc y is c o nfir me d, t he s u bject m ust n ot recei ve st u d y dr u g a n d m ust n ot be e nr olle d i n t he 
st u d y. If pre g na n c y is s us pecte d w hile t he s u bject is recei vi n g st u d y treat me nt, t he st u d y dr u g 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 5  
 
 
 
m ust i m me diatel y be wit h hel d u ntil t he res ult of pre g na nc y t esti n g is k n o w n. If pre g n a nc y is 
c o nfir me d, t he st u d y dr u g will be per ma ne ntl y dis c o nti n ue d a n d t he s u bject will be f oll o we d 
u ntil t he pre g na nc y c o m es t o ter m. A Pre g na nc y R e p ort f or m will be s u b mitte d t o t he s p o ns or, 
i nitiall y a n d at t he e n d of t he pre g na n c y, w hic h i n cl u des t he o utc o me of t h e pre g na n c y a n d a n y 
c o m plicati o ns occ urri n g d uri n g t he pre g na n c y or t he deli ver y.  
 
1 2  St atistics  
1 2. 1  Assess m e nt of  S afet y  
1 2. 1. 1  A d verse  E ve nts  
All A Es t hat occ ur d uri n g t he st u d y will be rec or d e d a n d classifie d usi n g t h e Me dical Dicti o nar y 
f or Re g ulat or y A cti vities ( Me d D R A). Treat me nt-e mer ge nt a d v erse e ve nts ( T E A Es) are t h ose 
A Es t hat occ ur or w orse n o n or after t h e date of first st u d y dr u g a p plicati o n. All T E A Es will be 
s u m marize d b y t he n u m b er of s u bjects re p orti n g eac h T E A E, t he ass ociate d s yste m or ga n class 
a n d pref err e d ter m, t he s e verit y, a n d t he relati o ns hi p t o st u d y dr u g f or t he safet y, P K, a n d n o n - 
P K p o p ulati o ns. Eac h s u bject will be c o u nte d o nl y o nce wit hi n a s yste m or ga n class or a 
preferre d  t er m usi n g t he e ve nt wit h t he greatest se verit y or ca us alit y, res pecti vel y, wit hi n eac h 
cate g or y.  
All S A Es will be s u m marize d b y t he n u m ber of s u bjects re p orti n g eac h S A E, t he ass ociate d 
s yste m or ga n class a n d preferre d t er m, t he se v erit y, a n d t he relati ons hi p t o st u d y dr u g f or t he 
safet y, P K, a n d n o n-P K p o p ulati o ns.  
All i nf or mati o n pertai ni n g t o A Es n ote d d uri n g t he st u d y will be liste d b y s u bject a n d will 
i ncl u de t he ver b ati m ter m gi ve n b y t he i n vesti gat or, t he ass ociate d s yste m or ga n class a n d 
preferre d  t er m, t he start a n d st o p (if st o p pe d) dates, t he seri o us ness, a n d t he se verit y of t he e v e nt. 
A d diti o nall y, a n y acti o n ta ke n wit h t he st u d y dr u g, a n y c orrecti ve treat me nt a d mi nistere d, t he 
o utc o me, a n d t he r elati o ns hi p t o st u d y dr u g as well as a list of s u bjects w h o pre mat urel y 
disc o nti n ue fr o m t he st u d y d ue t o a n A E will be pr o vi de d.  
1 2. 1. 2  L oc al S ki n  Re acti o ns  
L ocal s ki n reacti o n sc ores (re d ness, s w elli n g, b ur ni n g, itc hi n g, a n d vesic ulati o n) at eac h visit will 
be s u m marize d usi n g fr e q ue nc y ta bles f or t he safet y, P K, a n d n o n -P K p o p ulati o ns. A d diti o nall y, 
re d ness a n d s w elli n g se v erit y sc ores will be s u m marize d usin g descri pti ve statistics ( mea n, 
sta n dar d de viati o n [ S D], me dia n, a n d mi ni m u m, a n d ma xi m u m). S u bjects wit h a se verit y sc ore 
w orse t ha n bas eli ne will als o be s u m marize d at eac h p ost -baseli ne visit. T he w orst sc ore a n d t he 
last sc ore d uri n g t he p ost-baseli ne  peri o d will als o be s u m marize d.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 6  
 
 
 
1 2. 1. 3  Cli nic al L a b or at or y  Tests  
Res ults of safet y la b orat or y para m eters will be s u m marize d at eac h st u d y visit usi n g descri pti ve 
statistics or fre q ue n cies a n d perce nt a ges, as a p pr o priate, f or t he s afet y, P K, a n d n on -P K 
p o p ulati o ns. C ha n ges fr o m baseli ne i n safet y la b orat or y val ues will be s u m marize d b y treat me nt 
gr o u p at Wee k 4 8 usi n g descri pti ve statistics. I n a d diti o n, c ha n ges fr o m baseli ne i n safet y 
la b orat or y val u es will be s u m marize d usi n g s hift ta bles acc or di ng t o n or mal ra n ges.  
1 2. 1. 4  Vit al Si g ns  
Res ults of vital si g n meas ure me nts will be s u m marize d at Wee ks 1 2, 2 4, 3 6, a n d 4 8 usi n g 
descri pti ve statistics or fr e q ue ncies a n d perce nta g es, as a p pr o priat e, f or t he safet y, P K, a n d n o n - 
P K p o p ulati o ns. C ha n ges fr o m baseli n e i n vital si g n meas ure me nts will be s u m marize d at t hes e 
visits.  
1 2. 1. 5  C o nc o mit a nt  Me dic ati o ns  
All  pre vi o us  t her a pies a n d c o nc o mita nt  me dicati o ns  will  be  classifie d b ase d  o n  ter mi n ol o g y fr o m 
t he W orl d Healt h Or ga ni zati o n Dr u g Dicti o nar y. Pre vi o us t hera pies a n d c o nc o mita nt 
me dicati o ns data will be prese nte d i n dat a  listi n gs. 
1 2. 1. 6  Effic ac y f o r Assessi n g Tre at me nt  C o m pli a nce  
T his pri mar y o bjecti ve of t his st u d y is t o assess t he safet y of t he st u d y dr u g. Descri pti ve efficac y 
statistics f or t he e n d p oi nts will assist i n e val uati n g c o m plia nce wit h treat me nt f or t he p ur p oses of 
safet y assess me nt. T h e efficac y v aria bles e val uate d i n t his st u d y i ncl u de micr osc o pic K O H 
e xa mi nati o n a n d m yc ol o gical c ult ure o utc o mes of t he tar get great t oe nail, p erce nt i n v ol ve me nt 
of t he tar get gr eat t oe n ail, gr o wt h of t he tar g et great t oe nail, a n d assess me nts of t he n o ntar get 
t oe nails. T he efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  C o m plete  C ure,  defi ne d  as 0 %  cli nical  i n v ol ve me nt of  t he tar get t oe n ail a n d ne gati ve 
K O H a n d f u n g al c ult ure at Wee k  5 2  
•  C o m plete or Al m ost C o m plete C ure at Wee k 5 2, defi ne d as :: 5 % t oe n ail  i n v ol ve me nt 
•  T he Cli nical Efficac y rat e at Wee k 5 2, defi n e d as a n affecte d t ar get great t o e nail area 
of <  1 0 %  
•  T he M yc ol o gic C ure r ate at Wee k 5 2, d efi ne d as a ne gati ve K O H e xa mi nati o n a n d  a 
ne gati ve f u n gal c ult ure of t he tar get great t oe n ail  sa m ple 
T he C o m plete C ure rat e, t he C o m plete or Al m ost C o m plete C ure rate, t he Cli nical Efficac y rate, 
a n d t he M yc ol o gic C ure rate will be prese nte d usi n g descri pti ve statistics (sa m p le size n, 
fre q ue n c y c o u nts, a n d p erce nta g es) f or t h e safet y, P K, a n d n o n-P K p o p ulati o ns. I n a d diti o n, t he 
gr o wt h of t he tar g et great t oe nail at eac h st u d y visit a n d t he c ha n g e fr o m baseli ne i n t he n u m ber 
of aff ecte d n o ntar get t oe nails will be s u m marize d d escri pti vel y.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 7  
 
 
 
A last o bser vati o n carrie d f or war d ( L O C F) i m p utati o n will be use d t o i m p ute missi n g val ues f or 
t he efficac y v aria bles at Wee k 5 2 f or t he n o n-P K p o p ulati o n a nal yses. N o se nsiti vit y a nal yses 
will be c o n d ucte d.  
 
1 2. 2  Assess m e nt of  P h ar m ac o ki netics  
 
T he P K o bjecti ves will b e c o nsi der e d met w h e n a p pr o xi matel y 1 6 e val ua bl e s u bjects are treate d 
u n der ma xi mal use c o n diti o ns t hr o u g h da y 2 8 a n d P K sa m ples c ollecte d at pre d ose a n d 2, 4, 1 2 
hrs p ost d ose o n Da y 2 8 a n d 2 4 hrs p ost d ose o n Da y 2 9. .  
N o i m p utati o ns will be ma de f or missi n g data. Plas ma c o nce ntrati o ns t hat are re p orte d as b el o w 
t he li mit of q ua ntitati o n ( B L Q) i n t he data tra nsfer file a n d will be set t o zer o f or t he s u m maries 
of c o nce ntrati o ns as well as calc ulati o n of P K p ara meters. Missi n g val ues will be treate d as if 
t he y were n e ver dra w n. Plas ma c o nce ntrati o ns a n d P K para meters will be s u m marize d f or t h e 
P K a nal ysis set usi n g descri pti ve statistics ( n, mea n, S D, sta n dar d err or of t he mea n [ S E M], 
c oeffi cie nt of v ariati o n [ C V], me dia n, mi ni m u m, a n d ma xi m u m). Ge o metric mea ns will als o be 
use d t o s u m marize C ma x , Cmi n , A U C( 0-t) a n d A U C ( 0-2 4 h). 
Plas ma c o nce ntr ati o ns of efi nac o n az ole a n d meta b olite ( H 3 a n d H 4) at eac h sc he d ule d sa m pli n g 
ti me p oi nt will be s u m marize d usin g descri pti ve statistics. T he i n di vi d ual plas ma c o nce ntrati o ns 
will be liste d f or eac h s u bject. C o nce ntrati o ns B L Q will be dis pla ye d as B L Q i n t he listi n gs.  
T he mea n plas ma c o nce ntrati o n ti me pr ofiles f or efi nac o naz ole a n d met a b olites ( H 3 a n d H 4) will 
be prese nt e d gra p hicall y f or Da ys 2 8 a n d 2 9 i n b ot h li near a n d l o garit h mic scales. I n di vi d ual 
s u bject plas ma c o nce ntrati o n ti me pr ofiles f or efi n ac o naz ole a n d meta b olites ( H 3 a n d H 4) will 
als o be cr eate d.  
Plas ma P K para meters f or efi nac o naz ol e a n d meta b olites  ( H 3 a n d H 4) will be calc ul ate d usi n g 
n o nc o m part me ntal a n al ysis. T he P K para meters will be calc ulate d f or eac h s u bject usi n g act ual 
sa m pli n g ti mes. T he ma xi m u m plas ma c o nce ntrati o n ( C ma x ) a n d ti me t o Cma x  ( Tma x ) will be ta ke n 
directl y fr o m t he dat a.  
T he f o ll o wi n g P K para m eters will be calc ulate d fr o m t he i n di vi d ual plas ma c o nce ntrati o ns o n 
Da ys 2 8 a n d 2 9 w h e n p ossi ble:  
•  C ma x  ( o bser ve d pea k dr u g [efi nac o naz ol e a n d meta b olites] c o nce ntrati o n)  
•  T ma x  (ti me at w hic h Cma x  occ urs)  
•  C mi n  ( o bser ve d mi ni m u m dr u g c o nce ntrati o n)  
•  A U C 0 -t (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 u p t o t he sa m pli n g ti me 
c orres p o n di n g t o t he last q ua ntifia ble  c o nce ntrati o n)  
•  A U C 0 -2 4 h (area u n der t he c o nce ntrati o n-ti me c ur ve fr o m ti me 0 t hr o u g h 2 4 h o urs 
[c orr es p o n di n g t o t he d osi n g i nter val]) 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 8  
 
 
 
A d diti o nal P K para meters ma y be calc ul ate d as a p pr o priate.  
 
1 2. 3  S u bject  Dis p ositi o n  
S u bject dis p ositi o n will be s u m marize d f or eac h a n al ysis p o p ulati o n.  
 
1 2. 4  De m o gr a p hics a n d B aseli ne  C h ar acteristics  
S u bject de m o gra p hic a n d baseli ne c haracteristics will be s u m marize d usi n g descri pti ve statistics 
f or eac h a n al ysis p o p ulati o n. 
 
1 2. 5  Pr ot oc ol  D e vi ati o ns  
All pr ot oc ol de viati o ns will be re p orte d t o t he s p o ns or a n d rec or de d t hr o u g h o ut t he st u d y. 
A ta b ulati o n of pr ot oc ol de viati o ns will be i ncl u de d i n t he fi nal st u d y re p ort.  
 
1 2. 6  C o m pli a nce  
Efficac y e val u ati o ns are bei n g c o n d ucte d t o ass ess treat me nt c o m plia nce. I nf or mati o n re gar di n g 
t he e val uati o ns a n d t heir a nal yses ar e prese nte d i n Secti o n 1 2. 1. 6.  
St u d y dr u g c o m plia nce will be calc ulate d f or eac h s u bject b y ta ki n g i nt o acc o u nt w het her a 
s u bject t o o k all d oses of st u d y dr u g as i nstr ucte d. Calc ulati o n of st u d y dr u g c o m plia nce will be 
d oc u me nte d  i n t he a n al ysis pla n. 
 
1 2. 7  I nteri m A n al yses  
A n i nteri m a n al ysis will be perf or me d t o s u m mari ze a vaila ble s afet y data at a pre defi n e d date t o 
be deter mi ne d b y t he s p o ns or. It will be perf or me d f or all a vaila ble data o n t he P K a n d n o n -P K 
p orti o n of t he st u d y. T his i nteri m a nal ysis will c o ntai n all ta bles a n d all listi n gs j ust li ke t he fi nal 
a nal ysis, usi n g t he l oc ke d data f or t he i nteri m a nal ysis.  
 
1 2. S A d diti o n al St atistic al C o nsi der ati o ns  
All statistical pr ocessi n g will be perf or me d usi n g S A S ®  versi o n 9. 3 or h i g her u nless ot her wis e 
state d. N o h y p ot hesis testi n g will be c o n d ucte d i n t his st u d y. A statistical a nal ysis pla n, 
descri bi n g all statistical a nal yses, will be pr o vi de d as a se parate d o c u me nt pri or t o data a n al ysis.  
1 2. S. 1  A n al ysis P o p ul ati o ns  
All s u bjects w h o recei ve at least 1 c o nfir me d d os e of st u d y dr u g will be i ncl u de d i n t he safet y 
p o p ulati o n.  
All s u bjects i n t he P K s u bset w h o recei ve at least 1 c o nfir me d d ose of st u d y dr u g a n d ha v e a n y 
P K data o n Da ys 2 8 a n d 2 9 will be i ncl u de d i n t he P K p o p u lati o n. 
All safet y p o p ulati o n s u bjects w h o ar e n ot i n t he P K s u bset will be i ncl u de d i n t he N o n -P K 
p o p ulati o n.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
5 9  
 
 
 
1 2. S. 2  S a m ple Size  Deter mi n ati o n  
A p pr o xi matel y 6 0 s u bjects will be e nr olle d a n d recei ve treat me nt wit h st u d y dr u g. 
A p pr o xi matel y 2 0 of t h e 6 0 s u bjects will be e nr olle d i n t he P K s u bset. T hes e sa m ple sizes w ere 
base d o n P K a n d cli nical c o nsi derati o ns; n o f or mal sa m ple size calc ulati o n was perf or me d. T h e 
n u m bers of pla n ne d s u bj ects ar e c o nsi dere d a d e q uate f or d eter mi ni n g t he safet y pr ofile a n d t he 
P K para meters of efi nac o naz ole i n a p e diatric p o p ulati o n of s u bjects a ge d 6 t o 1 6 years 1 1 
m o nt hs wit h mil d t o se vere o n yc h o m yc osis of t he t oe nails.  
1 2. S. 3  H a n dli n g of Missi n g D at a  
N o i m p utati o ns will be ma de f or a nal yses of safet y or P K e n d p oi nts. T he effi cac y e n d p oi nts at 
Wee k 5 2, w hi c h ar e use d t o assess treat me nt c o m plia nce will ha ve missi n g data i m p ute d wit h t he 
last o bser vati o n carrie d f or war d ( L O C F) f or n o n-P K p o p ulati o n a nal yses.  
1 2. S. 4  M ultice nter  Iss ues 
T he st u d y will be c o n d ucte d at m ulti ple i n vesti gati o nal ce nters i n t he U S a n d t he Cari b bea n wit h 
t he i nte nti o n of p o oli n g t he res ults f or a nal ysis. 
1 2. S. 5  M ulti plicit y  Iss ues 
N ot a p plica ble.  
 
1 2. S. 6  Wi n d o wi n g  R ules  
T he ti mi n g of all st u d y visits is relati ve t o t he Baseli ne ( Da y 1) visit. Visit 3 ( Wee k 4) s h o ul d 
occ ur wit hi n 5 da ys of D a y 2 8, (e xce pt f or t he P K -s u bset; Visit 3 s h o ul d occ ur wit hi n 1 da y of 
Da y 2 8) a n d Visit 3 A ( Wee k 4) s h o ul d occ ur 1 da y after Visit 3. T he Wee k 8 a n d all s u bse q ue nt 
visits s h o ul d occ ur wit hi n 5 da ys of t he tar g ete d ti mes.  
 
1 3  Q u alit y C o ntr ol a n d Q u alit y  Ass ur a nce  
T his st u d y will be c o n d ucte d u n der t he s p o ns ors hi p of Valea nt, i n c o nf or m ati o n wit h all 
a p pr o priate l o cal a n d f e d eral r e g ulati o ns as well as I C H g ui deli nes.  
T he s p o ns or is res p o nsi ble f or i m ple me nti n g a n d mai ntai ni n g q ualit y as s ura nce a n d q ualit y 
c o ntr ol s yste ms t o e ns ure t hat st u dies are c o n d u cte d a n d data are ge n erate d, d oc u me nte d, a n d 
re p orte d i n c o m plia n ce wit h t he pr ot oc ol, G C P g ui deli nes, a n d a p plica bl e re g ulat or y 
re q uire me nts. I n a d diti o n, t he s p o ns or will be res p o nsi ble f or sec uri n g a gree me nt fr o m all 
i n v ol ve d parties t o e ns ur e direct access t o all st u d y-relate d sites, s o urce d ata/ d oc u me nts, e C R Fs, 
a n d re p orts f or t he p ur p ose of m o nit ori n g a n d a u diti n g b y t he s p o ns or, a n d i ns pecti o n b y 
d o mestic a n d f orei g n re g ulat or y a ut h orities.  
Ce ntral la b orat or y s er vices will be perf or me d b y a q ualifie d, lice nse d facilit y t hat will be liste d 
o n t he U S F o o d a n d Dr u g A d mi nistrati o n F or m 1 5 7 2. C o pies of all n or mal val ues  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 0  
 
 
 
(as a p plica bl e), la b or at or y certificati o ns, a n d t he direct or's c urric ul u m vitae will be pr o vi de d t o 
eac h i n vesti gati o nal ce nt er a n d t o t he s p o ns or.  
 
1 3. 1  St u d y M o nit ori n g  
T he  c o n d u ct  of  t he st u d y will  be  cl osel y m o nit ore d.  S p o ns or  re pres e ntati ves m ust  be  per mitte d  t o 
visit all st u d y site l ocati o ns t o assess t he data, q ualit y of st u d y perf or ma nce, a n d st u d y i nte grit y 
i n a ma n ner c o nsiste nt wit h a p plica ble healt h a ut h orit y re g ulati o ns a n d t he pr oce d ures descri be d 
i n t his pr ot oc ol. 
Pri or t o t he start of t he st u d y, t he S p o ns or or its desi g nee(s) will re vie w t he pr ot o c ol, e C R Fs, 
re g ulat or y o bli gati o ns, a n d ot her material or e q ui p me nt rele va nt t o t he c o n d uct of t he st u d y wit h 
t he I n v esti gat or/ S u b/ C o I n vesti gat or a n d rel e va nt st u d y site pers o n nel. 
M o nit ori n g visits a n d tele p h o ne c o ns ultati o ns will occ ur as n ecessar y, or p er t he st u d y 
m o nit ori n g pla n, d uri n g t he c o urse of t he i n vesti gati o n t o verif y t he f oll o wi n g:  
•  T he ri g hts a n d well -b ei n g of s u bjects are  pr otecte d  
•  T he  c o n d uct  of  t he i n vesti gati o n is i n c o m plia nce wit h  t he c urre ntl y a p pr o v e d 
pr ot oc ol/a me n d me nt, I C H G C Ps, a n d I R B/ E C  re q uire me nts 
•  T he i nte grit y of t he data is mai ntai ne d, i ncl u di n g a de q uate st u d y  d oc u me nt ati o n  
•  T he facilities re mai n  acce pta ble  
•  T he I n vesti gat or a n d site pers o n nel re m ai n q ualifie d a n d a ble t o c o n d u ct t he  st u d y 
•  St u d y dr u g acc o u nta bilit y is d oc u me nte d  pr o perl y  
D uri n g t he c o urs e of t he st u d y, if t he S p o ns or deter mi nes t hat a n I n vesti gat or is n o n -c o m plia nt 
wit h t he st u d y pla n a n d/ or a p plica ble re g ulat or y re q uire me nts, t he S p o ns or will ta ke acti o n t o 
sec ure or rei nstate c om plia nce. I n a d diti o n, t he S p o ns or ma y ter mi nate t he I n v esti gat or's 
partici pati o n i n t he st u d y if a p pr o priate, or if t he I n vesti gat or re mai ns n o n -c o m plia nt des pite t he 
re me dial acti o ns of t he S p o ns or. 
 
1 3. 2  A u dits a n d  I ns pecti o ns 
I nteri m a n d e n d of st u d y a u dits of ra w d ata, st u d y files, a n d t he fi nal re p ort ma y be c o n d uct e d b y 
t he s p o ns or's q ualit y ass ura nce d e part me nt or its desi g nee. A certificate attesti n g t o t he a u dit(s) 
will be iss ue d as a p plica ble. I n a d diti o n, i ns pecti o ns or o n -site a u dits ma y be carrie d o ut b y l ocal 
a ut h orities. T he i n vesti gat ors will all o w t he s p o ns or's re prese ntati ves a n d a n y re g ulat or y a g e nc y 
t o e xa mi ne all st u d y rec or ds a n d l o gs, e C R Fs, c orres p o n di n g s u bject me dical rec or ds, st u d y dr u g 
dis pe nsi n g rec or ds, st u d y dr u g st ora ge area , a n d a n y ot her d oc u me nts c o nsi dere d s o urce 
d oc u me ntati o n. T he i n vesti gat ors a gree t o assist t he re prese ntati ve, if re q uire d.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 1  
 
 
 
1 3. 3  D at a Q u alit y  Ass ur a nce  
All assess me nts perf or m e d will be acc uratel y d o c u me nte d i n t he s u bject's s o urce d oc u m e nts a n d 
e C R Fs. T he i n vesti gat or or desi g nee will e nter t he i nf or mati o n re q uire d b y t he pr ot oc ol i nt o t he 
s o urce d oc u m e nts a n d e C R Fs pr o vi de d b y t he s p o ns or or desi g nee. S u bjects will be i de ntifie d i n 
t he e C R Fs b y t heir assi g ne d s u bject n u m ber a n d i nitials o nl y. 
T he i n vesti gat ors m ust rea d t he pr ot oc ol t h or o u g hl y a n d m ust f oll o w t he i nstr ucti o ns e xactl y. 
A n y de viati o ns s h o ul d be a gree d t o b y pri or disc ussi o n bet wee n t he s p o ns or a n d t he i n vesti gat or, 
wit h a p pr o priate writte n pr ot oc ol a me n d me nts ma de pri or t o effect i n g t he a gree d u p o n c h a n ges. 
A n y a me n d me nt c o ntai ni n g maj or m o dificati o ns ( partic ularl y if it ma y i n v ol ve a n i ncrease d ris k 
t o t he s u bjects) will be a p pr o ve d b y t he I R B/I E C bef ore it ma y b e i m ple me nte d. N o c h a n ge i n 
t he c o n d uct of t he st u d y ca n be i nstit ute d wit h o ut writte n a p pr o val fr o m t he s p o ns or.  
 
1 4  Et hics a n d A d mi nistr ati ve  Iss ues 
1 4. 1  Et hic al C o n d uct of t he  St u d y  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he et hical pri nci ples ori gi nati n g fr o m t he 
Declar ati o n of Helsi n ki, I C H g ui deli nes, G C P g ui deli nes, a n d i n c o m plia nce wit h l ocal a n d 
fe der al re g ulat or y re q uir e me nts. T he i n vesti gat or a grees, w h e n si g ni n g t he pr ot oc ol, t o a d here t o 
t he i nstr ucti o ns a n d pr oce d ures des cri be d i n it a n d t here b y t o a d here t o t he pri nci ples of G C P. 
 
1 4. 2  Et hics  Re vie w  
T his pr ot oc ol, pr o p ose d i nf or me d c o ns e nt/asse nt f or m a n d ot her i nf or m ati o n t o t he s u bjects, a n d 
all a p pr o priate a me n d me nts, will be pr o perl y re vi e we d, a n d a p pr o v e d b y a n I R B/I E C. A si g ne d 
a n d date d n otificati o n of t he I R B/I E C a p pr o v al will be pr o vi d e d t o t he s p o ns or a n d i n vesti gat or 
pri or t o st u d y i nitiati o n. T he na me a n d o cc u p ati o n of t he c hair a n d me m bers of t he I R B/I E C will 
be s u p plie d t o t he s p o ns or. T he i n vesti gat or will pr o vi de re q uire d pr o gress re p orts a n d re p ort all 
S A Es t o t he I R B/I E C as re q uire d.  
 
1 4. 3  Writte n I nf or m e d  C o nse nt  
Writte n i nf or me d c o ns e nt/asse nt, i n acc or d a nce wit h l ocal cli nical i n vesti gati o n re g ulati o ns, m ust 
be o btai ne d pri or t o partici pati o n i n t he st u d y. T he i n vesti gat or or desi g nee will disc uss t he 
p ur p ose of t he st u d y wit h eac h s u bject a n d t heir p are nt(s)/le gal g u ar dia n(s) a n d will pr o vi de a 
descri pti o n of t he st u d y dr u g (i ncl u di n g a n y p ote ntial a n d p ossi ble si de effects) a n d t he st u d y 
pr oce d ur es. I nf or mati o n m ust be gi ve n b ot h i n oral a n d writte n f or m. T he s u bject i nf or mati o n 
pr o vi de d will be i n a la n g ua ge u n derst a n da ble t o t he s u bject a n d t heir p are nt(s)/le gal g uar dia n(s) 
a n d ma y n ot i ncl u de a n y la n g ua ge t hat a p p ears t o wai ve a n y of t h e s u bject's le gal ri g hts or 
a p pears t o r eleas e t he i n v esti gat or, t he s p o ns or, or t he i nstit ut i o n fr o m lia bilit y or ne gli ge nce. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 2  
 
 
 
T he i n vesti gat or or desi g nee will pr o vi de t he pr os pecti ve s u bject a n d t h e s u bject's pare nt(s) or 
le gal g uar dia n(s) s uffici e nt ti me t o c o nsi der w het h er t o partici pate, mi ni mizi n g t he p ossi bilit y of 
c oerci o n o r u n d ue i nfl ue nce a n d will disc uss a n y q uesti o ns t he s u bject a n d/ or t heir 
pare nt(s)/le g al g uar dia n(s) ma y ha ve. T h e i n vesti gat or or desi g nee will e x plai n t o t he s u bject a n d 
t heir pare nt(s)/le gal g uar dia n(s) t hat partici p ati o n i n t he st u d y is v ol u ntar y a n d t hat wit h dra wal 
fr o m t he st u d y is p ossi ble at a n y ti me wit h o ut detri me nt t o care. T h e c o ns e nt m ust i ncl u de 
ac k n o wle d g me nt t hat me dical rec or ds a n d me dical data deri ve d fr o m t he st u d y ma y be 
f or war de d t o t he s p o ns or or t o t he res p o nsi ble a ut h orities or fe deral a ut h oriti es. 
N o s u bject ca n e nter t he st u d y or ha ve a n y st u d y -relate d pr oce d ures perf or me d bef ore his/ her 
writte n i nf or me d c o ns e nt/asse nt has bee n o btai n e d. S u bjects u n der t he a g e of c o nse nt m ust si g n 
a n asse nt f or m a n d t heir pare nts/le gal g uar dia ns m u st si g n t he i nf or me d c o nse nt f or m. S u bjects 
o ver t he a g e of c o ns e nt m ust si g n t he i nf or me d c o nse nt f or m. S u bjects a n d t heir pare nts/le gal 
g uar dia ns will als o pr o vi de writte n c o nse nt/ass e nt t o o btai n p h ot o gra p hs of t he tar get great 
t oe nail. T he ori gi nal si gne d a n d date d i nf or me d c o nse nt a n d asse nt f or ms will be retai ne d wit h 
t he st u d y rec or ds, a n d a c o p y of t he si g ne d f or ms will be gi ve n t o t he s u bject a n d t heir pare nt or 
le gal g uar dia n as a p plica ble. 
A n i nf or me d c o ns e nt/asse nt te m plate will be s u p plie d b y t he s p o ns or t o t he i n vesti gat or.  
A n y c ha n ges t o t he i nf or me d c o nse nt/asse nt f or m m ust be a gree d t o b y t he s p o ns or pri or t o 
s u b missi o n t o t he I R B/I E C, a n d a c o p y of t he a p pr o ve d versi o n m ust be pr o vi de d t o t he s p o ns or 
after I R B/I E C a p pr o v al.  
 
1 4. 4  S u bject D at a  P r otecti o n  
S u bject data will be pr otecte d b y e ns uri n g t hat n o ca pt ure d d ata c o ntai n s u bject na mes, 
a d dresses, tel e p h o ne n u m bers, e mail a d dresses, or ot her direct pers o nall y i de ntif yi n g 
i nf or mati o n. It is ac k n o wle d ge d t hat s u bject i nitials, de m o gra p hics (i nclu di n g birt h dates), 
me dical  hist ories,  a n d pri or  c o nc o mita nt  me dicati o n  uses,  al o n g wit h  t he na me  a n d a d dress  of  t he 
e nr olli n g i n vesti gat or ma y all o w f or pers o nal i de ntificati o n of st u d y partici pa nts. Ot her t ha n 
w here n ecess ar y t o meet re g ulat or y r e q uire me n ts, all data c ollecte d i n t his st u d y will be 
prese nte d i n ta b ulat e d (ie, a g gre gat e) f or m a n d listi n gs c o ntai ni n g i nf or mati o n t hat c o ul d be use d 
t o i de ntif y a n i n di vi d ual s u bject will n ot be i ncl u de d i n a n y p u blic discl os ures of t he st u d y data 
or t he st u d y  res ults. 
 
1 4. 5  D at a M o nit ori n g  C o m mittee  
N ot a p plica ble.  
 
1 4. 6  Fi n a nci al  Discl os ure  
Fi na ncial discl os ur es will be o btai ne d fr o m all i n vesti gat ors i n or der t o d oc u me nt a n y p ote ntial 
c o nflicts of i nterest.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 3  
 
 
 
1 4. 7  Esse nti al  D oc u m e nts  
I n v esti gat or m ust mai ntai n esse ntial d oc u me nts d uri n g t he c o n d uct of t he st u d y a n d retai n t hes e 
d oc u me nts after t h e c o m pleti o n of t he st u d y i n acc or da nce wit h t he S p o ns or's rec or d ret e nti o n 
i nstr ucti o ns. T he I n v esti gat or a gr ees t o a d here t o t he d oc u me nt ret e nti o n pr oce d ures w he n 
si g ni n g t he pr ot oc ol I n v esti gat or State me nt of A p pr o val. 
Esse ntial d oc u me nts i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  I R B a p pr o v als f or t he st u d y pr ot oc ol, all a me n d me nts, I C F(s), a n d a d v ertise me nts  
•  I R B a n n u al st u d y re vie w 
•  I R B c orres p o n de n ce a n d re p orts (e g, S A E re p orts, pr ot oc ol de viati o ns, a n d safet y 
u p dates)  
•  Re g ulat or y d oc u me nts (e g, fi na ncial discl os ure a n d dele gati o n of a ut h orit y  f or ms) 
•  All s o urce  d oc u me nts  
•  C R Fs  
•  S u bje ct's si g n e d  I C F 
•  F D A F or m  1 5 7 2  
•  Acc o u nta bilit y rec or ds f or t he st u d y  dr u g  
•  C orres p o n de nce fr o m a n d t o  s p o ns or 
•  A n y ot her d oc u me nts r ele va nt t o t he c o n d uct of t h e  st u d y 
I n t he e v e nt t hat t he I n vesti gat or wit h dra ws fr o m t he st u d y (e g, retire m e nt or rel ocati o n), st u d y 
rec or ds will be tra nsferre d t o a m ut uall y a gree d u p o n desi g nee (e g, a n ot her I n v esti gat or or site 
I R B/ E C). T he I n v esti gat or will pr o vi de n otice of s uc h tra nsfer i n writi n g t o t he s p o ns or 
 
1 4. S I n vesti g at or O bli g ati o ns  
T he i n vesti gat ors m ust rea d t he pr ot oc ol t h or o u g hl y, c o m plete a n d si g n t he pr ot oc ol si g nat ure 
pa ge, a n d m ust f oll o w t h e i nstr ucti o ns e xactl y. W he ne ver p ossi ble, a n y pla n ne d de viati o ns 
s h o ul d be a gree d t o b y pri or disc ussi o n bet wee n t h e s p o ns or a n d t he i n vesti gat or, wit h 
a p pr o priate d o c u me ntati o n of s p o ns or a p pr o v al pr i or t o effecti n g t he a gree d u p o n c ha n ges. A n y 
de viati o ns s h o ul d be re p orte d t o t he s p o ns or a n d re p orte d t o t he I R B/I E C acc or di n g t o t he 
re q uire me nts of t h e I R B/I E C. 


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 4  
 
 
 
14.9 C h a n ges t o t he  Pr ot oc ol  
A n y a me n d me nt c o ntai ni n g maj or m o dificati o ns ( partic ularl y if it ma y i n v ol ve a n i ncrease d ris k 
t o t he s u bjects) will be a p pr o ve d b y t he I R B bef ore it ma y be i m ple me nte d. N o c ha n ge i n t he 
c o n d uct of t he st u d y ca n be i nstit ute d wit h o ut pri or writte n a p pr o v al fr o m t he s p o ns or.  
 
14.10 C o nfi de nti a lit y/ P u blic ati o n of t he St u d y 
All t he data f ur nis he d t o t he i n vesti gat or a n d his/ her staff a n d all data o bt ai ne d t hr o u g h t his 
pr ot oc ol will be re gar de d as c o nfi de ntial a n d pr o prietar y i n nat ure a n d will n ot be discl ose d t o 
a n y t hir d part y, e x ce pt f or t he U S F o o d a n d Dr u g A d mi nistrati o n or ot her re g ulat or y b o d y, 
wit h o ut writte n c o nse nt fr o m t he s p o ns or.  
T he res ults of t he st u d y ma y be p u blis he d or pres e nte d b y t he I n vesti gat or(s) after t he re vie w b y, 
a n d i n c o ns ultati o n a n d a gree me nt wit h t he S p o ns or, a n d s u c h t hat c o nfi de ntial or pr o prietar y 
i nf or mati o n is n ot discl ose d. Pri or t o s u b missi o n f or p u blicati o n or pres e ntati o n, a c o p y of t he 
fi nal te xt s h o ul d be f or w ar de d b y t he I n vesti gat or(s) t o t he S p o ns or or its desi g nee f or re vie w a n d 
c o m me nt. S uc h c o m me nts s hall ai m t o e ns ure t he scie ntific i nte grit y of t he pr o p ose d p u blicati o ns 
a n d/ or prese nt ati o ns a n d e ns ure t hat t he d ata a n d material referri n g t o t he S p o ns or pr o d ucts a n d 
acti vities recei v e fair, acc urate, a n d reas o n a ble prese ntati o n.  
 
14.11 St u d y  Ter mi n ati o n  
T h e s p o ns or res er ves t he ri g ht t o disc o nti n ue t he st u d y o verall or at a partic ular st u d y site at a n y 
ti me f or reas o ns i ncl u di n g b ut n ot li mite d t o: 
•  E mer ge nce of effects t hat d o n ot j ustif y t he be nefit/ris k relati o ns hi p t o t he st u d y 
p o p ulati o n as a  w h ole.  
•  Fail ure t o c o m pl y wit h t h e pr ot oc ol, G C P, or a n y ot her vi olati o n dist ur bi n g t he 
a p pr o priate c o n d uct of t h e  st u d y. 
•  Fail ure t o meet e nr oll me nt g oals o verall or at a p artic ular st u d y  site. 
If a st u d y is ter mi nate d, t he S p o ns or will pr o m ptl y n otif y t he I n v estigat or. After n otificati o n, t he 
I n v esti gat or m ust c o ntact all partici pati n g s u bjects a n d t heir pare nts/le gal g uar dia ns wit hi n a 
reas o na bl e ti mefra me a gr ee d u p o n b y t he S p o ns or. All st u d y materials m ust be c ollecte d a n d all 
e C R Fs c o m plete d t o t he greatest e x t e nt p ossi ble 
 
1 5  D at a H a n dli n g a n d Rec or d  Kee pi n g  
1 5. 1  I ns pecti o n of Rec or ds 
I n v esti gat ors m ust mai ntai n detaile d rec or ds o n all st u d y s u bjects w h o are e nr olle d i n t he st u d y 
or w h o u n der g o s cree ni n g. Data will be rec or d e d i n t he s u bject's s o urce d o c u me nts a n d i n 
a p plica ble st u d y l o gs pr o vi de d b y t he s p o ns or. S o urce d oc u m e nts i ncl u de s u bject's me dical  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 5  
 
 
 
rec or ds, h os pital c h arts, cli nic c harts, a n d t he i n vesti gat or's s u bject st u d y files, as well as t he 
res ults of dia g n ostic tests (e g, la b or at or y tests). All me dical i nf or mati o n o btai ne d at eac h st u d y 
visit m ust be rec or de d i n t he s u bject's s o urce d o c u me ntati o n i n real ti me as it is c ollecte d a n d 
t he n e ntere d o nt o t he e C R F b y site pers o n nel. 
S u bject -c o m plete d f or ms s uc h as diaries a n d q uesti o n naires are al s o c o nsi d ere d s o urce dat a. 
O nl y s u bjects are t o r ec or d i nf or mati o n i n s u bject diaries a n d q uesti o n naires. I n n o i nsta n ce, 
s h o ul d a n I n v esti gat or or st u d y site pers o n nel rec or d a n y data or ma ke c ha n ges t o s u bject 
c o m plete d f or ms. T he I n vesti gat or or desi g ne e s h o ul d re vie w s u bject -c o m plete d f or ms d uri n g 
st u d y visits. If a n e ntr y is f o u n d t o be ille gi ble or a mista ke is f o u n d (e g, a n i nc orrect year was 
rec or d e d), t he s u bject s h o ul d be i nstr ucte d t o e dit t he e ntr y b y dra wi n g a si n gle li ne t hr o u g h t he 
ori gi nal e ntr y, e nteri n g t h e ne w i nf or m ati o n, dati n g, a n d writi n g s u bject's y ear of birt h t o 
ac k n o wle d g e.  
U p o n st u d y c o m pleti o n or at a n y ot her ti me s pecifie d b y t he s p o ns or or desi g nee, t he a p pr o priate 
st u d y d oc u me nts m ust be s u b mitte d t o t he s p o ns or. 
Tele p h o ne c o n v ersati o ns a n d electr o ni c mail wit h t he s u bject, t he s p o ns or, or t he s p o ns or's 
desi g nee c o n cer ni n g t he st u d y m ust be rec or de d or ke pt o n file. All s o urce d oc u me nts m ust be 
ma de a vaila ble t o t he s p o ns or a n d t he s p o ns or's desi g nate d m o nit or u p o n  re q uest. 
 
1 5. 2  C ase Re p ort  F o r ms  
S u bject data re q uir e d b y t his pr ot oc ol are t o be rec or de d o n e C R Fs. S u bject data rec or de d o n 
e C R Fs d uri n g t he st u d y will be d oc u me nte d i n a c o de d fas hi o n. T h e s u bject will o nl y be 
i de ntifie d b y t he s u bject n u m ber a n d b y t heir year of birt h if als o re q uire d. C o nfi de ntialit y of 
s u bject rec or ds m ust be mai ntai ne d t o e ns ure a d h ere nce t o a p plica bl e l ocal pri vac y re g ulati o ns.  
T he I n vesti gat or a n d st u d y site pers o n nel will be res p o nsi ble f or c o m pleti n g t he e C R Fs. T he 
I n v esti gat or is req uir e d t o verif y t hat all of t he re q ueste d i nf or mati o n is acc uratel y rec or de d o n 
t he e C R Fs. All i nf or mati o n re q ueste d o n t he e C R Fs nee ds t o be s u p plie d, i ncl u di n g s u bject 
i de ntificati o n, date(s), assess me nt val ues, etc., a n d a n y o missi o n or discre pa nc y will re q uire 
e x pla nati o n. All i nf or mati o n o n e C R Fs m ust be tracea ble t o s o urce d o c u me nts.  
T he st u d y m o nit or will be res p o nsi ble f or re vie wi n g a n d verif yi n g t he d ata rec or d e d o n t he 
e C R Fs, utilizi n g t he ori gi nal s o urce d o c u me ntati o n a n d will q uer y discre p a nt f i n di n gs. T he 
I n v esti gat or a n d st u d y site pers o n nel will be res p o nsi ble f or a ns weri n g all q ueries. T he e C R Fs 
will be s u b mitte d t o Valea nt or its desi g nee(s) f or q ualit y ass ura nce re vie w, a n d statistical 
a nal ysis. 
A c o p y of t he e C R Fs will be retai ne d b y t he I n vesti gat or at t he c o ncl usi o n of t he st u d y, w h o 
m ust e ns ure t hat it is st ore d i n a sec ure place  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 6  
 
 
 
1 5. 3  Rete nti o n of R ec or ds  
T he i n vesti gat or s h o ul d pr o perl y st ore a n d mai ntai n all st u d y rec or ds i n acc or da nce wit h s p o ns or 
directi ves. All rec or ds r e lati n g t o t he c o n d uct of t his st u d y are t o be ret ai ne d b y t he i n vesti gat or 
u ntil n otifie d b y t he s p o ns or i n writi n g t hat t he rec or ds ma y be destr o y e d.  


Pr ot oc ol V 0 1 -1 0 8 A -4 0 1, Efi nac o naz ole Pe diatric Safet y a n d P K St u d y  
Valea nt Researc h & De vel o p me nt  
Cli nical St u d y Pr ot oc ol, A me n d me nt 2 date d A u g ust 1 8, 2 0 1 7  
C O N FI D E N TI A L  
6 7  
 
 
 
1 6  Refere nces  
1.  Ele ws ki B E. O n yc h o m yc osis: pat h o ge nesis, dia g n osis, a n d ma na ge me nt. Cli n 
Micr o bi ol Re v.  1 9 9 8; 1 1( 3): 4 1 5 -2 9.  
2.  Le v y L. E pi de mi ol o g y of o n yc h o m yc osis i n s pecial -ris k p o p ulati o ns. J A m P o diatr 
Me d Ass oc.  1 9 9 7; 8 7( 1 2): 5 4 6 -5 0.  
3.  Zaias N, T osti A, Re bell G, M orelli R, Bar dazzi F, Biele y H, et al. A ut os o mal 
d o mi na nt  patter n  of  distal  s u b u n g ual o n yc h o m yc osis  ca use d b y  Tric h o p h yt o n  r u br u m. 
J A m Aca d D er mat ol. 1 9 9 6; 3 4( 2 Pt 1): 3 0 2 -4.  
4.  Tre pa nier  E F,  A ms de n  G W.  C urre nt  iss ues i n o n yc h o m yc osis.  A n n  P har mac ot her. 
1 9 9 8; 3 2( 2): 2 0 4 -1 4.  
5.  G u pta A K, T u L Q. T h era pies f or o n yc h o m yc osis: a re vie w. Der m at o l Cli n. 
2 0 0 6; 2 4( 3): 3 7 5 9.  
6.  J u blia (efi n ac o naz ole) t o pical s ol uti o n, 1 0 %.  [ U S Prescri bi n g  I nf or m ati o n]. Valea nt 
P har mace uticals N ort h A merica, L L C;  2 0 1 4.  


P R O T O C O L V 0 1 -1 0 8 A -4 0 1  
Pa ge 1  of 5  
 
 
 
 
S U M M A R Y O F C H A N G E S  
A me n d me nt 2, 1 8 A u g ust 2 0 1 7  
 
 
Secti o n  
P a ge  
Descri pti o n of C h a n ge or Cl arific ati o n  
R ati o n ale  
 
 
Si g n at ure 
p a ge  
 
 
2  
Re pl ace d: 
 
 
 wit h  
 
 
 
Ne w safet y pers o n nel  
 
 
1 -Re vise d Fr o m: " S u bjects i ncl u de d i n t he P K s u bset 
will atte n d t he sc he d ule d visits u p t o Wee k 4 a n d a n 
a d diti o nal st u d y visit at Da y 2 9 f or c ollecti o n of t he 
fi nal P K bl o o d sa m ple. T he P K assess me nts will be 
perf or me d u n der ma xi mal use c o n diti o ns. O nce P K 
assess me nts are c o m plete at Da y 2 9, t he P K s u bset of 
s u bjects will c o nti n ue treat me nt t hr o u g h wee k 4 8 wit h 
a d diti o nal visits at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6,  
4 0, 4 4, a n d 4 8), a n d a 4 -wee k p ost -treat me nt f oll o w-u p  
visit ( Wee k 5 2)."  
 
 
 
S y n o psis 
7. 2  
 
 
5- 1 0  
2 0 - 2 2  
T O  
" S u bjects i ncl u de d i n t he P K s u bset M U S T deci de at 
ti me of c o nse nt w het her t o partici pate i n t he 4-Wee k 
trial, atte n d t he sc he d ule d visits u p t o Wee k 4 ( Da y 2 9) 
f or c ollecti o n of t he fi nal P K a n d e xit t he st u d y O R 
partici pate i n t he 5 2 -Wee k trial, wit h t he  sa me 
sc he d ule d visits as i n t he 4-Wee k trial f oll o we d b y 
c o nti n ue d treat me nt t hr o u g h wee k 4 8 wit h a d diti o nal 
visits at Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4,  
a n d 4 8), a n d a 4-wee k p ost -treat me nt f oll o w-u p visit 
( Wee k 5 2). T he P K assess me nts will be perf or me d 
u n der ma xi mal use c o n diti o ns"  
T o meet t he st u d y ti meli ne, 
e nr oll me nt re q uire me nt was 
re defi ne d t o all o w P K s u bset t o 
partici pate i n t he 5 2 -Wee k trial or 
e xit t he st u d y at wee k 4 o nce P K 
sa m ples are c ollecte d. 
 
 
2- Re vise d Fr o m: " S u bjects w h o are i ncl u de d i n t he 
P K s u bset will be i nstr ucte d t o a p pl y t he st u d y dr u g t o 
all 1 0 t oe nails o nce dail y at be dti me f or 4 wee ks.  
 
 
Pr ot oc ol St u d y V 0 1 -1 0 S A -4 0 1  
A M ultice nter, O pe n L a bel, Si n gle - ar m St u d y E v al u ati n g t he S afet y a n d P h ar m ac o ki netics 
of Efi n ac o n az ole 1 0 % T o pic al S ol uti o n i n S u bjects wit h Mil d t o Se vere O n yc h o m yc osis of 
t he T oe n ails 
 
S p o ns or:  
D o w P har mace utical Scie nces, a w h oll y o w ne d s u bsi diar y of Valea nt P har mace uticals I nter nati o nal 
1 3 3 0 Re d w o o d Wa y, S uite C  
Petal u ma, C A 9 4 9 5 4  


P R O T O C O L V 0 1 -1 0 8 A -4 0 1  
Pa ge 2  of 5  
 
 
 
 
 
F oll o wi n g t he P K bl o o d c ollecti o ns o n Da ys 2 8 a n d 
2 9, t hese s u bjects will be i nstr ucte d t o c o nti n ue 
treat me nt wit h st u d y dr u g t o o nl y t he affecte d t oe nails 
a n d ret ur n t o t he i n vesti gati o nal ce nter at Wee ks 8, 1 2, 
1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8), a n d a 4 -wee k  
p ost -treat me nt f oll o w-u p visit ( Wee k 5 2).  
T O  
" S u bjects w h o are i ncl u de d i n t he P K s u bset will be 
i nstr ucte d t o a p pl y t he st u d y dr u g t o all 1 0 t oe nails 
o nce dail y at be dti me f or 4 wee ks. F oll o wi n g t he P K 
bl o o d c ollecti o ns o n Da ys 2 8 a n d 2 9, P K s u bjects t hat 
c o nse nte d t o t he 5 2-Wee k trial wil l c o nti n ue treat me nt 
wit h st u d y dr u g t o o nl y t he affecte d t oe nails. 
 
3 - Re vise d Fr o m: " P K s u bjects will ret ur n t o t he 
i n vesti gati o nal ce nter t he f oll o wi n g da y ( Da y 2 9) f or 
c ollecti o n of a 2 4 -h o ur p ost d ose bl o o d sa m ple. P K 
s u bjects will c o nti n ue treat me nt wit h st u d y dr u g t o 
o nl y t he tar get great t oe nail a n d t he ot her affecte d 
t oe nails a n d ret ur n t o t he i n vesti gati o nal ce nter at 
Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d  4 8),  
a n d a 4-Wee k p ost -treat me nt f oll o w-u p visit ( Wee k 
5 2).  
T O  
All P K s u bjects i n t he 4 -Wee k trial will ret ur n t o t he 
i n vesti gati o nal ce nter t he f oll o wi n g da y ( Da y 2 9) f or 
c ollecti o n of a 2 4 -h o ur p ost d ose bl o o d sa m ple a n d 
e xit t he st u d y. P K s u bjects t hat c o nse nte d t o t he 5 2 - 
Wee k trial will c o nti n ue treat me nt wit h st u d y dr u g t o 
o nl y t he ta r get great t oe nail a n d t he ot her affecte d 
t oe nails a n d ret ur n t o t he i n vesti gati o nal ce nter at 
Wee ks 8, 1 2, 1 6, 2 0, 2 4, 2 8, 3 2, 3 6, 4 0, 4 4, a n d 4 8),  
a n d a 4-wee k p ost -treat me nt f oll o w-u p visit ( Wee k 
5 2).  
 
4 - Re vise d Fr o m: After c o m pleti o n of t he P K p orti o n 
of t he st u d y, s u bjects a n d t heir pare nts/le gal g uar dia ns 
will be i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o 
t he s u bject's tar get great t oe nail a n d all ot her affecte d 
t oe nail(s) o nce dail y at be dti me. S u bjects a n d t heir 
pare nts/le gal g uar dia ns w ill be i nstr ucte d t o c o nti n ue 
a p pl yi n g t he st u d y dr u g t o t he tar get great t oe nail f or 
t he e ntire treat me nt peri o d  
T O  
After c o m pleti o n of t he P K p orti o n of t he st u d y, if t he 
s u bject c o nse nte d t o partici pate i n t he 5 2-Wee k trial, 
s u bjects a n d t heir pare nts/le gal g uar dia ns will be 
i nstr ucte d t o a p pl y t he assi g ne d st u d y dr u g t o t he 
s u bject's tar get great t oe nail a n d all ot her affecte d 
t oe nail(s) o nce dail y at be dti me f or t he e ntire treat me nt 
peri o d  
 
5 -Re vise d Fr o m: " Bl o o d a n d uri ne sa m ples will be 
c ollecte d f or r o uti ne cli nical la b orat or y tests 
( he mat ol o g y, ser u m c he mistr y, a n d uri nal ysis) wit hi n 
 


P R O T O C O L V 0 1 -1 0 8 A -4 0 1  
Pa ge 3  of 5  
 
 
 
 
 
t he 4 2 da y Scree ni n g visit wi n d o w a n d at Wee k 4 8." 
T O  
Bl o o d a n d uri ne sa m ples will be c ollecte d f or r o uti ne 
cli nical la b orat or y tests ( he mat ol o g y, ser u m c he mistr y, 
a n d uri nal ysis) wit hi n t he 4 2 da y Scree ni n g visit 
wi n d o w. T hese sa m ples will be c ollecte d a gai n at 
Wee k 4 8, or at Da y 2 8 f or P K s u bjects w h o c o nse nte d 
t o o nl y 4 wee ks of treat me nt. 
 
6 - Re vise d Fr o m: Vital si g n meas ure me nts (sitti n g 
bl o o d press ure, res pirati o n, p ulse, a n d te m perat ure) 
will be o btai ne d at Baseli ne a n d Wee ks 1 2, 2 4, 3 6, a n d  
4 8. A n a b bre viate d p h ysical e xa mi nati o n will be 
perf or me d at Baseli ne a n d Wee k 4 8; as part of t he 
e xa mi nati o n, hei g ht a n d wei g ht will be meas ure d at 
Baseli ne a n d Wee k 4 8.  
T O  
Vital si g n meas ure me nts (sitti n g bl o o d press ure, 
res pirati o n, p ulse, a n d te m perat ure) will be o btai ne d at 
Baseli ne a n d wee ks 1 2, 2 4, 3 6, a n d 4 8; f or P K s u bjects 
w h o c o nse nte d t o o nl y 4 wee ks of treat me nt, t he se 
pr oce d ures will be d o ne at Da y 2 8. A n a b bre viate d 
p h ysical e xa mi nati o n will be perf or me d at Baseli ne 
a n d Wee k 4 8, a n d at Da y 2 8 f or P K s u bjects w h o 
c o nse nte d t o o nl y 4 wee ks of treat me nt; as part of t he 
e xa mi nati o n, hei g ht a n d wei g ht will be meas ure d at  
Baseli ne a n d Wee k 4 8.  
 
 
 
U p date d f o ot n otes p t o r 
U p date d f o ot n ote r t o s  
 
D u plicate f o ot n otes  
 
 
A d de d f o ot n otes  
 
Ta ble 1  
2 6  
 
 
 
 
t " A p plies o nl y t o P K s u bjects w h o c o nse nte d t o 4 
wee k trial"  
u " N ot a p plica ble f or P K s u bjects w h o c o nse nt t o o nl y 
t he 4 wee k trial."  
Clarificati o n t o st u d y pr oce d ures  
 
Secti o n  9. 4  
( Da ys 2 9 t o 
Wee k 4 8)  
 
 
3 2  
A d de d : After c o m pleti o n of t he P K p orti o n of t he 
st u d y, if t he s u bject c o nse nte d t o t he 5 2-Wee k trial,  
 
Delete d: S u bjects a n d t heir pare nts/le gal g uar dia ns 
will be i nstr ucte d t o c o nti n ue a p pl yi n g t he st u d y dr u g 
t o t he tar get great t oe nail 
 
 
Clarificati o n  
 
 
 
 
1 1. 1. 1  
 
 
 
 
3 7  
A d de d: Ne wl y scree ne d P K s u bjects will deci de at 
t he ti me of si g ni n g c o nse nt w het her t he y will c o nse nt 
t he 4-Wee k trial or t he 5 2 -Wee k  trial. 
 
N ote: S u bjects t h at c o nse nt t o 4 -Week tri al will n ot 
be all o we d t o exte n d t heir st u dy c o nse nt t o 5 2 weeks. 
S u bse q ue ntly,  P K  s u bjects  w h o  c o nse nt  t o  t he  5 2 - 
week tri al will be c o nsi dere d  disc o nti n ue d/ E arly  
Ter mi n ate d if he/s he disc o nti n ues pri or t o t he Week 
5 2  visit. 
 
 
 
T o f urt her defi ne e nr oll me nt 
re q uire me nts 
 
1 1. 1. 3  
 
4 2  
A d de d:  
N ote: P K s u bjects e xiti n g t he st u d y o n Da y 2 9 
(c o nse nte d t o o nl y 4-Wee k trial), t he f oll o wi n g  
 
T o f urt her defi ne st u d y pr oce d ures  


P R O T O C O L V 0 1 -1 0 8 A -4 0 1  
Pa ge 4  of 5  
 
 
 
 
 
pr oce d ures will be c o n d ucte d i n a d diti o n t o t he 
pr oce d ures liste d a b o ve.  
 
1 1.  C ollect bl o o d a n d uri ne sa m ples f or r o uti ne safet y 
la b orat or y  a nal ysis  ( he mat ol o g y,  ser u m  c he mistr y,  
a n d uri nal ysis). Pr ocess a n d s hi p t he sa m ples t o t he 
ce ntral safet y la b orat or y per i nstr ucti o ns pr o vi de d i n 
t he la b orat or y ma n ual.  
1 2.  Meas ure hei g ht a n d  wei g ht.  
1 3.  C o n d uct  a n  a b bre viate d  p h ysical  e xa mi nati o n  
(e xcl u di n g ur o ge nital/re pr o d ucti ve s yste ms). 
 
 
1 1. 1. 4  
 
4 2  
A d de d: N ote: P K s u bjects w h o c o nse nte d t o o nl y 4 
Wee k trial will e xit t he st u d y o n Da y 2 9. Dr u g a n d 
s u bject diar y will n ot be dis pe nse d a n d uri ne 
pre g na nc y test will n ot be c ollecte d at t his visit.  
 
T o f urt her defi ne st u d y pr oce d ures  
 
 
 
 
1 1. 1. 6  
 
 
 
 
4 5  
Re vise d Fr o m: If t his is t he Earl y Ter mi nati o n Visit, 
rec or d t he reas o n f or s u bject disc o nti n uati o n fr o m t he 
st u d y a n d c o m plete t he Wee k 4 8 e C R F. All ot her 
s u bjects s h o ul d be sc he d ule d t o ret ur n f or t he Visit 1 5 
( Wee k 5 2) st u d y visit 
T O  
If t his is t he Earl y Ter mi nati o n Visit, rec or d t he 
reas o n f or s u bject disc o nti n uati o n fr o m t he st u d y a n d 
c o m plete t he Wee k 4 8 e C R F. If t his is n ot a n Earl y  
Ter mi nati o n Visit, t he s u bject s h o ul d be sc he d ule d t o 
ret ur n f or t he Visit 1 5 ( Wee k 5 2) st u d y visit. 
 
 
 
 
T o f urt her defi ne st u d y pr oce d ures  
 
 
1 2. 1. 1  
 
 
5 5  
Re vise d Fr o m: Treat me nt -e mer ge nt a d verse e ve nts 
( T E A Es) are t h ose A Es wit h a n o nset o n or after t he 
date of first st u d y dr u g  a p plicati o n  
T O  
Treat me nt -e mer ge nt a d verse e ve nts ( T E A Es) are  
t h ose A Es t hat occ ur or w orse n o n or after t he date of 
first st u d y dr u g a p plicati o n. 
 
 
T o matc h t he la n g ua ge i n t he S A P  
1 2. 1. 6  
5 7 (last  
para,)  
A d de d: "f or t he n o n-P K p o p ulati o n a nal yses"  
Clarificati o n  
 
 
 
 
1 2. 2  
 
 
 
 
5 7  
Re vise d Fr o m: T he P K o bjecti ves will be c o nsi dere d 
met w he n a p pr o xi matel y 1 6 e val ua ble s u bjects are 
treate d u n der ma xi mal use c o n diti o ns t hr o u g h da y 2 8 
of t he P K e val uati o n  
T O  
T he P K o bjecti ves will be c o nsi dere d met w he n 
a p pr o xi matel y 1 6 e val ua ble s u bjects are treate d u n der 
ma xi mal use c o n diti o ns t hr o u g h da y 2 8 a n d P K 
sa m ples c ollecte d at pre d ose a n d 2, 4, 1 2 hrs 
p ost d ose o n Da y 2 8 a n d 2 4 hrs p ost d ose o n Da y 2 8 
a n d 2 4 h o urs p ost d ose Da y 2 9.  
 
 
 
 
Clarif y ma xi mal use  


P R O T O C O L V 0 1 -1 0 8 A -4 0 1  
Pa ge 5  of 5  
 
 
 
 
 
 
 
 
1 2. 7  
 
 
 
 
 
5 8  
 
Delete d:  
N o i nteri m a nal yses are pla n ne d  
A d de d:  
A n i nteri m a nal ysis will be perf or me d t o s u m marize 
a vaila ble safet y data at a pre defi ne d date t o be 
deter mi ne d b y t he s p o ns or. It will be perf or me d f or 
all a vaila ble data o n t he P K a n d n o n -P K p orti o n of 
t he st u d y. T his i nteri m a nal ysis will c o ntai n all ta bles 
a n d all listi n gs j ust li ke t he fi nal a nal ysis, usi n g t he 
l oc ke d data f or t he i nteri m a nal ysis. 
 
 
 
 
 
T o meet F D A re q uire me nts  
 
 
 
 
1 2. 8  
 
 
 
 
5 8  
Delete d: W he n a p pr o xi matel y 4 0 e val ua ble s u bjects 
ha ve bee n treate d f or 4 8 wee ks meeti n g t he pri mar y 
safet y o bjecti ve (re gar dless if s u bjects i n t he P K s u bset 
are c o nti n ui n g), a data c ut will be d o ne a n d t he st u d y 
re p ort will be writte n. O nce all s u bjects i n t he P K 
s u bset c o m pletes t he st u d y, data base l oc k will be 
perf or me d a n d t he st u d y re p ort a me n d me nt will be 
writte n.  
 
 
 
T he pla n f or t his a nal ysis h as bee n 
re vise d. It is n o w descri be d i n 
Secti o n 1 2. 7 (I nteri m A nal yses).  
 
 
 
 
 
 
 
1 2. 8. 3  
 
 
 
 
 
 
 
5 9  
Re vise d Fr o m: N o i m p utati o ns will be ma de f or 
missi n g safet y or P K data. As i n dicate d pre vi o usl y, t he 
efficac y e n d p oi nts, w hic h are use d t o assess treat me nt 
c o m plia nce, will ha ve missi n g data i m p ute d wit h 
L O C F f or n o n -P K p o p ulati o n a nal yses. Missi n g 
efficac y data will n ot be i m p ute d f or safet y a n d P K 
p o p ulati o n a nal yses.  
T O:  
N o i m p utati o ns will be ma de f or a nal yses of safet y or 
P K e n d p oi nts. T he effi cac y e n d p oi nts at Wee k 5 2, 
w hic h are use d t o assess treat me nt c o m plia nce will 
ha ve missi n g data i m p ute d wit h t he last o bser vati o n 
carrie d f or war d ( L O C F) f or n o n -P K p o p ulati o n 
a nal yses.  
 
 
 
 
 
 
 
T o be c o nsiste nt wit h t he S A P