The ASCEND Study: A Phase III, Multicenter, Double Blinded Vehicle Controlled Study of TMB-001 - With a Parallel Optional Maximal Use Arm - in the Treatment of RXLI (X-linked) or ARCI Ichthyosis in Subjects Aged ≥6 Years
Phase: PHASE3
Conditions: Ichthyosis
Sponsor: Timber Pharmaceuticals Inc.

 
 
 
 
 
 
 
 
 
C o ver Pa ge 
 
 
St u d y  title: T he A S C E N D St u d y: A P hase III, M ultice nter, D o u ble Bli n de d Ve hicle C o ntr olle d St u d y of 
T M B - 0 0 1 - wit h a Parall el O pti o nal Ma xi mal Use Ar m - i n t he Treat me nt of R X LI ( Xli n ke d) or A R CI 
Ic ht h y osis i n S u bjects A ge d ≥6 Years 
L E O P h ar m a n u m ber:  T M B 0 1 - 3 0 1 
N C T  n u m ber:  N C T 0 5 2 9 5 7 3 2 
D ate: 2 5-J ul- 2 0 2 2  
 

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TI T L E P A G E  
 
 
Pr ot oc ol Title: T h e A S C E N D St u d y: A P h ase III, M ultice nter, 
D o u ble Bli n de d Ve hicle C o ntr olle d St u d y of T M B -0 0 1 - wit h a  
P ar allel  O pti o n al M a xi m al Use Ar m - i n t he Tre at m e nt of R X LI ( X-
li n ke d) or A R CI I c ht h y osis i n S u bjects A ge d ≥6 Ye ars  
 
 
Pr ot oc ol N u m ber: T M B 0 1 -3 0 1  
St u d y Pr o d uct: T M B -0 0 1 ( pre vi o usl y P A T -0 0 1) (Is otreti n oi n) Oi nt me nt ( 0. 0 5 %)  
 
S h ort Title:  T he A S C E N D St u d y: E v al u ati n g T M B -0 0 1 i n t he tre at m e nt of R X LI or A R CI - 
Ic ht h y osis 
St u d y P h ase: 3  
 
S p o ns or N a me: Ti m ber P h ar m ace utic als, L L C  
Le g al Re gistere d A d dress: 1 1 0 Alle n R o a d, S uite 4 0 1, B as ki n g Ri d ge, N J 0 7 9 2 0  
 
I n vesti g ati o n al Ne w Dr u g (I N D) n u m ber: 1 2 2, 0 5 8  
E u dr a C T n u m ber 2 0 2 2 -0 0 0 4 5 9 -3 5  
 
D ate of Pr ot oc ol: 2 5 J ul y 2 0 2 2  
Versi o n: 2. 0  
Pr ot oc ol A me n d me nt 1  
 
 

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A P P R O V A L SI G N A T U R E P A G E  
S p o ns or Si g n at or y:  
 
 
I h a ve re a d t his pr ot oc ol i n its e ntiret y a n d a p pr o ve  its c o nte nts: 
 
 
 
 
 
 
 
 
 
C hief Me dic al Officer  
 
D ate  
 
 
 
 
 
 
 
 
T he Me dic al M o nit or’s n a me a n d c o nt act i nf or m ati o n c a n be f o u n d i n  A p pe n di x  1 . 
T he I n vesti g at or’s A gree me nt P a ge is pr o vi de d i n  A p pe n di x  6  
 
 

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T A B L E O F C O N T E N T S  
TI T L E P A G E  ................................................................................................................................ 1  
A P P R O V A L SI G N A T U R E P A G E  ............................................................................................. 2  
T A B L E O F C O N T E N T S  ............................................................................................................. 3  
T A B L E O F T A B L E S  .................................................................................................................... 7  
T A B L E O F FI G U R E S  .................................................................................................................. 7  
1. 1  
S y n o psis  .......................................................................................................................... 8  
1. 2  
Sc he d ule of Assess m e nts ( S o A)  .................................................................................. 1 6  
2  
I N T R O D U C TI O N............................................................................................................... 1 9  
2. 1  
St u d y R ati o n ale  ........................................................................................................... 2 0  
2. 2  
B ac k gr o u n d  ................................................................................................................. 2 0  
2. 3  
Be nefit/ Ris k Assess m e nt  ............................................................................................. 2 1  
2. 3. 1  Ris k/ b ur de n i n mi n ors  .............................................................................................. 2 2  
3  
O B J E C TI V E S A N D E N D P OI N T S  ................................................................................... 2 3  
4  
S T U D Y D E SI G N  ................................................................................................................. 2 6  
4. 1  
O ver all Desi g n  ............................................................................................................. 2 6  
4. 2  
Disc ussi o n of St u d y Desi g n  ......................................................................................... 2 7  
4. 3  
J ustific ati o n f or D ose  .................................................................................................. 2 8  
4. 4  
E n d of St u d y Defi niti o n  .............................................................................................. 2 8  
5  
S T U D Y P O P U L A TI O N  ..................................................................................................... 2 9  
5. 1  
I ncl usi o n Criteri a ........................................................................................................ 2 9  
5. 2  
E xcl usi o n Criteri a  ....................................................................................................... 3 0  
5. 3  
Scree n F ail ures  ............................................................................................................ 3 1  
6  
S T U D Y T R E A T M E N T  ...................................................................................................... 3 3  
6. 1  
St u d y Tre at me nt(s) A d mi nistere d  ............................................................................. 3 3  
6. 1. 1  Treat me nt Area  ......................................................................................................... 3 3  
6. 1. 2  Treat me nt A d mi nistrati o n  ......................................................................................... 3 3  
6. 1. 2. 1  
Ma xi m u m Dail y D ose  ....................................................................................... 3 3  
6. 2  
Pre p ar ati o n/ H a n dli n g/ St or a ge/ Acc o u nt a bilit y  ........................................................ 3 5  
6. 3  
R a n d o miz ati o n  ............................................................................................................ 3 5  
6. 3. 1  Bli n di n g a n d U n bli n di n g ........................................................................................... 3 6  
6. 4  
St u d y Tre at me nt C o m pli a nce  .................................................................................... 3 6  

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6. 5  
C o nc o mit a nt T her a p y  ................................................................................................. 3 6  
7  
DI S C O N TI N U A TI O N O F S T U D Y T R E A T M E N T A N D S U B J E C T 
DI S C O N TI N U A TI O N/ WI T H D R A W A L  ........................................................................ 3 8  
7. 1  
Te m p or ar y Disc o nti n u ati o n ( Dr u g I nterr u pti o n/ Re d ucti o n)  ................................. 3 8  
7. 2  
S u bject Disc o nti n u ati o n/ Wit h dr a w al fr o m t he St u d y  ............................................. 3 9  
7. 3  
L ost t o F oll o w -U p  ........................................................................................................ 3 9  
7. 4  
Pre g n a nc y  .................................................................................................................... 4 0  
8  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ............................................................. 4 1  
8. 1  
Ge ner al St u d y Assess me nts  ........................................................................................ 4 1  
8. 1. 1  I nf or me d C o nse nt/ Asse nt.......................................................................................... 4 1  
8. 1. 2  Ge netic Testi n g  ......................................................................................................... 4 1  
8. 1. 3  De m o gra p hics/ Me dical Hist or y  ................................................................................ 4 2  
8. 2  
Effic ac y Assess m e nts  .................................................................................................. 4 2  
8. 2. 1  I n v esti gat or’s Gl o bal Ass ess me nt (I G A) .................................................................. 4 2  
8. 2. 2  Vis ual I n d e x f or Ic ht h y osis Se verit y ( VII S) –  Scali n g  ............................................. 4 3  
8. 2. 3  Defi ni n g Treat me nt Area a n d Perce nt B o d y S urfac e ............................................... 4 4  
8. 2. 4  Itc h-N u meri c Rati n g Scale (I -N R S) .......................................................................... 4 5  
8. 2. 5  Der mat ol o g y Life Q u alit y I n d e x ( D L QI) ................................................................. 4 5  
8. 2. 6  Ic ht h y osis Q ualit y of Life (I Q o L-3 2)  ....................................................................... 4 6  
8. 2. 7  P h ot o gra p h y  .............................................................................................................. 4 6  
8. 3  
S afet y Assess me nts  ...................................................................................................... 4 7  
8. 3. 1  P h ysical E xa mi nati o n ................................................................................................ 4 7  
8. 3. 2  Vital Si g ns  ................................................................................................................. 4 7  
8. 3. 3  L ocal S ki n Reacti o ns a n d E val uati o n of Aller gic C o ntact Der matitis  ..................... 4 7  
8. 3. 4  Cli nical Safet y La b orat or y Assess me nts  .................................................................. 4 7  
8. 3. 5  Pre g na nc y T esti n g  ..................................................................................................... 4 8  
8. 4  
A d verse E ve nts  ............................................................................................................ 4 8  
8. 4. 1  Ti me Peri o d a n d Fre q ue n c y f or C ollecti n g A d verse E ve nt a n d Seri o us A d v erse 
E ve nt I nf or mati o n  ................................................................................................................. 4 8  
8. 4. 2  Re g ulat or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts  ............................ 4 9  
8. 4. 3  Pre g na nc y  .................................................................................................................. 4 9  
8. 5  
Tre at me nt of O ver d ose  ............................................................................................... 4 9  
9  
O P TI O N A L M A XI M A L U S E A R M  ................................................................................ 5 1  
9. 1  
St u d y Desi g n  ................................................................................................................ 5 1  
9. 1. 1  Disc ussi o n of St u d y Desi g n  ...................................................................................... 5 1  
9. 1. 2  E n d of St u d y Defi niti o n  ............................................................................................ 5 2  
9. 2  
St u d y Tre at me nt  ......................................................................................................... 5 6  

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9. 3  
S pecific Assess m e nts a n d Pr oce d ures  ....................................................................... 5 6  
9. 3. 1  Efficac y assess me nts  ................................................................................................. 5 6  
9. 3. 2  P har mac o ki netic Assess me nts  .................................................................................. 5 6  
9. 4  
St atistic al C o nsi der ati o ns  ........................................................................................... 5 7  
9. 5  
P h ar m ac o ki netic A n al ysis  .......................................................................................... 5 7  
1 0  S T A TI S TI C A L C O N SI D E R A TI O N S  .............................................................................. 5 9  
1 0. 1  
S a m ple Size Deter mi n ati o n  ........................................................................................ 5 9  
1 0. 2  
P o p ul ati o ns f or A n al yses  ............................................................................................ 5 9  
1 0. 3  
St atistic al A n al yses ...................................................................................................... 5 9  
1 0. 3. 1. 1  
Efficac y A nal yses  ......................................................................................... 6 0  
1 0. 3. 1. 1. 1  Pri mar y Efficac y E n d p oi nt  ........................................................................ 6 0  
1 0. 3. 1. 1. 2  Ke y Sec o n dar y Effi cac y E n d p oi nts ........................................................... 6 0  
1 0. 3. 1. 1. 3  Ot her Effi cac y E n d p oi nts  .......................................................................... 6 1  
1 0. 3. 1. 2  
Safet y A nal yses  ............................................................................................. 6 2  
1 0. 3. 1. 3  
Ot her A nal yses  .............................................................................................. 6 2  
1 0. 3. 1. 3. 1  Vital Si g ns  ................................................................................................. 6 2  
1 0. 3. 1. 3. 2  P h ysical E xa mi nati o ns  .............................................................................. 6 2  
1 0. 3. 1. 3. 3  Cli nical La b orat or y Tests  .......................................................................... 6 2  
1 0. 3. 1. 3. 4  L ocal S ki n Reacti o ns  ................................................................................. 6 3  
1 0. 3. 1. 4  
Missi n g Data  ................................................................................................. 6 3  
1 0. 3. 1. 5  
E xte nt of E x p os ure  ........................................................................................ 6 3  
1 0. 3. 1. 6  
D osi n g C o m plia nce  ....................................................................................... 6 3  
1 1  R E F E R E N C E S  .................................................................................................................... 6 4  
1 2  A P P E N DI C E S  ..................................................................................................................... 6 6  
A p pe n di x  1: Re g ul at or y, Et hic al a n d St u d y O versi g ht C o nsi der ati o ns  ............................ 6 6  
Re g ulat or y a n d Et hical C o nsi derati o ns  ................................................................................. 6 6  
Fi na ncial Discl os ur e .............................................................................................................. 6 6  
I ns ura nce ............................................................................................................................... 6 7  
I nf or me d C o nse nt Pr ocess .................................................................................................... 6 7  
Data Pr otecti o n ...................................................................................................................... 6 7  
A d mi nistrati ve Str uct ure  ....................................................................................................... 6 8  
St u d y Site I nit iati o n .............................................................................................................. 6 8  
Disse mi nati o n of Cli nical St u d y Data ................................................................................... 6 8  
Data Q ualit y Ass ur a nce  ........................................................................................................ 6 8  
A u dits a n d I ns p ecti o ns  .......................................................................................................... 6 9  
S o urce D oc u m e nts  ................................................................................................................ 6 9  
St u d y a n d St u d y Ce nter Cl os ure  ........................................................................................... 7 0  
St u d y C o n d uct D uri n g t he C O VI D -1 9 Pa n d e mic  ................................................................. 7 0  
C O VI D -1 9 I nfecti o n i n St u d y S u bjects  ................................................................................ 7 0  

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P u blicati o n P olic y  ................................................................................................................. 7 0  
A p pe n di x  2: Cli nic al L a b or at or y Tests ................................................................................. 7 2  
A p pe n di x  3: A d verse E ve nts:  Defi niti o ns a n d Pr oce d ures f or Rec or di n g, E v al u ati n g, 
F oll o w -u p, Re p orti n g  .............................................................................................................. 7 5  
A p pe n di x  4: C o ntr ace pti ve G ui d a nce a n d C ollecti o n of Pre g n a nc y I nf or m ati o n  ............ 7 9  
Defi niti o ns:  ........................................................................................................................... 7 9  
C o ntrace pti o n G ui da nce ........................................................................................................ 7 9  
Pre g na nc y T esti n g: ................................................................................................................ 8 0  
C ollecti o n of Pre g na nc y I nf or mati o n .................................................................................... 8 1  
A p pe n di x  5: Ge netics  .............................................................................................................. 8 2  
A p pe n di x  6: Si g n at ure of I n vesti g at or  .................................................................................. 8 3  
A p pe n di x  7: Itc h -N u m eric R ati n g Sc ale  ............................................................................... 8 4  
A p pe n di x  8: Der m at ol o g y Life Q u alit y I n de x  ...................................................................... 8 5  
A p pe n di x  9: C hil dre n’s Der m at ol o g y Life Q u alit y I n de x  .................................................. 8 6  
A p pe n di x  1 0: Ic ht h y osis Q u alit y of Life (I Q o L -3 2)  ............................................................. 8 7  
A p pe n di x  1 1: P atc h Testi n g  ................................................................................................... 8 8  
A p pe n di x  1 2: A b bre vi ati o ns  .................................................................................................. 8 9  
 
 

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T A B L E O F T A B L E S  
Ta ble 1  Sc he d ule of Assess me nts  .............................................................................................. 1 6  
Ta ble 2  O bjecti ves a n d E n d p oi nts  ............................................................................................. 2 3  
Ta ble 3  O bjecti ves a n d E n d p oi nts –  O pti o nal Ma xi mal Use Ar m  ............................................ 2 5  
Ta ble 4 Ma xi m u m Dail y D ose  ...................................................................................................... 3 3  
Ta ble 5  Treat me nt A d mi nistrati o n  ............................................................................................. 3 4  
Ta ble 6  St u d y Treat me nts  .......................................................................................................... 3 4  
Ta ble 7  Pr o hi bite d Me dicati o n a n d Treat me nts I n cl u di n g Ti me P oi nt of Disc o nti n uati o n  ....... 3 7  
Ta ble 8  Rec o m me n de d Acti o ns t a ke n at A E/ L S R Occ urre nce  ................................................. 3 8  
Ta ble 9  I n v esti gat or’s Gl o bal Ass ess me nt Sc ore ( 5-P oi nt Scale)  .............................................. 4 2  
Ta ble 1 0  
Vis ual I n d e x f or Ic ht h y osis Se verit y Sc ore ( 5 -P oi nt -Scale)  ..................................... 4 4  
Ta ble 1 1  
Der mat ol o g y Life Q u alit y I n d e x Scale ..................................................................... 4 5  
Ta ble 1 2  
C hil dre n’s Der mat ol o g y Life Q ualit y I n de x Scale  ................................................... 4 6  
Ta ble 1 3  
Sc he d ule of Assess me nts O pti o nal Ma xi mal Use Ar m  ............................................ 5 3  
Ta ble 1 4  
Bl o o d Sa m pli n g Sc he d ule f or S u bjects 1 2 years t o a d ult  ......................................... 5 6  
Ta ble 1 5  
Bl o o d Sa m pli n g Sc he d ule f or S u bjects 6 t o 1 1 years  ............................................... 5 7  
Ta ble 1 6  
A nal ysis Sets  ............................................................................................................. 5 9  
Ta ble 1 7  
Pr ot oc ol -Re q uire d Safet y La b orat or y Ass ess me nts  .................................................. 7 4  
Ta ble 1 8  
Hi g hl y Effecti ve C o ntrace pti ve Met h o ds  ................................................................. 8 0  
 
 
T A B L E O F FI G U R E S  
Fi g ure 1  
O verall St u d y Sc he ma ............................................................................................... 2 6  
Fi g ure 2  
O pti o nal Ma xi mal Use Ar m Sc he ma  ........................................................................ 5 1  
 

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P R O T O C O L S U M M A R Y  
1. 1  S y n o psis  
Pr ot oc ol Title  
T he A S C E N D St u d y: A P hase III, M ultice nter, D o u ble Bli n de d Ve hicle C o ntr olle d 
St u d y of T M B -0 0 1 - wit h a P arallel  O pti o nal Ma xi mal Use Ar m - i n t he Treat me nt of 
R X LI ( X -li n ke d) or A R CI Ic ht h y osis i n S u bjects A ge d ≥6 Years 
St u d y Pr o d uct  
T M B -0 0 1 ( pre vi o usl y P A T -0 0 1) (Is otreti n oi n) Oi nt me nt ( 0. 0 5 %)  
I N D N u m ber 
1 2 2 0 5 8  
Pr ot oc ol N u m ber  
T M B 0 1 -3 0 1  
P h ase of De v el o p m e nt  
III 
St u d y Desi g n  
T his ra n d o mize d, d o u ble -bli n d, ve hicle -c o ntr olle d P hase III st u d y is desi g ne d t o 
e v al uate t he efficac y a n d safet y of t o pical T M B -0 0 1 0. 0 5 % oi nt me nt f or t he treat me nt 
of recessi ve X -li n ke d ic ht h y osis ( R X LI) a n d a ut os o mal recessi ve c o n ge nital ic ht h y osis 
( A R CI). I n a d diti o n, a s u bset of preselecte d ce nters will recr uit s u bjects i n parallel f or 
e nr oll me nt i nt o a n O pti o nal Ma xi mal Use ar m f or e val uati o n of t he s yste mic e x p os ure 
a n d safet y of t o pical T M B -0 0 1 0. 0 5 % oi nt me nt f or t he treat me nt R X LI or A R CI.  
T he st u d y has  t hree peri o d s: 
•  
Peri o d 1 –  I n d ucti o n ( 3 wee ks):   
At t he be gi n ni n g of t he 3 -wee k i n d ucti o n peri o d, eli gi ble s u bjects will b e 
ra n d o mize d (2: 1 rati o ) t o eit her T M B -0 0 1 0. 0 5 % o nce -a-da y ( Q D) or Ve hicle 
Q D treat me nt, wit h use of ma n dat or y sta n dar dize d bla n d e m ollie nt  ( Ceta p hil™) 
pr o vi de d b y t he S p o ns or .  
•  
Peri o d 2 –  Tre at m e nt ( 9 wee ks):   
T he d osi n g fre q ue nc y i n t he 9 -wee k treat me nt peri o d will be i ncrease d i n eac h 
treat me nt gr o u p t o T M B-0 0 1 0. 0 5 % or Ve hicle t wice a da y ( BI D). Ma n dat or y 
bla n d  e m ollie nt will be disc o nti n ue d.  
•  
Peri o d 3 –  M ai nte n a nce ( 1 2 wee ks):   
At Wee k 1 2, eli gi ble s u bjects i n t he T M B -0 0 1 treat me nt gr o u p  will be 
ra n d o mize d (1: 1 rati o ) t o o pe n -la bel treat me nt wit h T M B -0 0 1 0. 0 5 % BI D or Q D. 
T o be eli gi ble , s u bjects m ust ha ve ac hie v e d a ≥1-p oi nt re d ucti o n i n I n vesti gat or 
Gl o bal Assess me nt ( I G A) sc ore fr o m Baseli ne. S u bjects wit h < 1 -p oi nt re d ucti o n 
i n I G A sc ore fr o m Baseli ne will be disc o nti n ue d fr o m t he st u d y.  
Ve hicle -treate d s u bjects w h o ac hie ve d < 1 -p oi nt re d ucti o n i n I G A sc ore fr o m 
Baseli ne are eli gi ble t o cr oss o ver t o t he T M B -0 0 1 0. 0 5 % BI D treat me nt gr o u p. 
S u bjects wit h a ≥1 -p oi nt re d ucti o n i n I G A sc ore fr o m Baseli ne will be 
disc o nti n ue d fr o m t he st u d y.  
O pti o n al M a xi m al Use Ar m  
A d ult a n d pe diatr ic s u bjects, at a s u bset of preselecte d ce nters, will be e nr olle d i n a n 
o pe n -la bel O pti o nal Ma xi mal Use ar m t o e val uate t he s yste mic e x p os ure a n d safet y of 
t o pical T M B-0 0 1 0. 0 5 % oi nt me nt f or t he treat me nt of CI u n der ma xi mal use 
c o n diti o ns. 
I nitiall y, ad ult CI s u bjects (≥1 7  y ears; n = 1 6) a n d pe diatric s u bjects ( 1 2-1 6  y ears; n = 7-
9 ) will be d ose d f or 1 4 da ys wit h T M B-0 0 1 0. 0 5 % BI D. F oll o wi n g a n i nteri m 
p har mac o ki netic ( P K) a nal ysis a n d base d o n t he e x p os ure data f or s u bjects a ge d ≥1 2  
y ears, pe diatric s u bjects a ge d  6 t o 1 1  y ears ( n = 7-9) will be gi n  d os i n g wit h T M B -0 0 1  
0. 0 5 % BI D f or 1 4 da ys. F oll o wi n g t he 1 4 -da y  P K assess me nt peri o d , s u bjects will 

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recei ve T M B -0 0 1 0. 0 5 % BI D treat me nt f or 1 0 wee ks t o pr o vi de a d diti o nal safet y a n d 
li mite d efficac y data.  
S a m ple Size  
A p pr o xi matel y 1 1 0 s u bjects  
O pti o n al M a xi m al Use Ar m : a p pr o xi matel y 3 2 s u bjects  
St u d y D ur ati o n  
U p t o 9 0 -da y scree ni n g + 2 4 wee ks treat me nt  
O pti o n al  M a xi m al Use A r m : U p t o 9 0 -da y scree ni n g , 1 4 -da y treat me nt  peri o d f or 
i nte nsi ve P K sa m pli n g f oll o we d b y 1 0 wee ks of o pe n -la bel treat me nt 
St u d y Eli gi bilit y 
Criteri a  
S u bjects m ust f ulfill all of t he f oll o wi n g i ncl usi o n criteri a t o be eli gi ble f or 
partici pati o n:  
1.  S u bject is male or fe male, 6 years of a ge a n d ol der a t Visit 2 ( Baseli ne). 
2.  S u bject has pr o vi de d writte n i nf or me d c o nse nt/asse nt. A s u bject u n der 1 8 years of 
a g e m ust pr o vi de writte n i nf or me d asse nt a n d be acc o m pa nie d b y t he pare nt or 
le gal g uar dia n at t he ti me of c o nse nt/asse nt si g ni n g. T he pare nt or le gal g uar dia n 
m ust pr o vi de i nf or me d c o nse nt f or t he s u bject. If a s u bject bec o mes 1 8 years of 
a g e d uri n g t he st u d y, t he s u bject m ust pr o vi de writte n i nf or me d c o nse nt at t hat 
ti me t o c o nti n ue st u d y partici pati o n. 
3.  Fe males m ust be p ost me n o pa usal ( defi ne d as a me n orr hea greater t ha n 1 2 
c o nsec uti ve m o nt hs i n w o me n 5 0 years of a ge a n d ol der), s ur gicall y sterile 
( h ysterect o m y, bilateral sal pi n gect o m y, or bilateral o o p h orect o m y), or use 2 
acce pta ble f or ms of birt h c o ntr ol. W o me n of c hil d beari n g p ote ntial ( W O C B P) 
m u st h a v e a ne gati ve ser u m pre g na nc y test at scree ni n g a n d ne gati ve uri ne 
pre g na nc y test ( U P T) at Visit  2 ( Baseli ne) ( U P Ts m ust ha ve a mi ni m u m 
se nsiti vit y t o detect 2 5 mI U beta -h u ma n c h ori o nic g o na d otr o pi n [ β -h C G]/ m L). 
Met h o ds of acce pta ble c o ntrace pti o n are  f urt her defi ne d i n A p pe n di x  4 . Fe male 
s u bjects w h o bec o me se x uall y acti ve or be gi n t o ha ve relati o ns wit h a part ner 
d uri n g t he st u d y m ust a gree t o use 2 f or ms of birt h c o ntr ol f or 3 0  da ys pri or t o 
ha vi n g relati o ns a n d t o c o nt i n ue s uc h f or ms of birt h c o ntr ol f or t he d urati o n of t he 
st u d y. 
4.  S u bject has cli nical dia g n osis of CI base d u p o n p he n ot y pe a n d has a ge netic 
c o nfir mati o n of eit her A R CI ( i ncl u di n g b ut n ot e xcl usi vel y tra ns gl uta mi nase 1-
deficie nt , A L O X-1 2 B ) or R X LI (e. g., deleti o n of ster oi d s ulfatase ge ne) s u bt y pes 
of CI. Ot her ge neticall y c o nfir me d A R CI m utati o ns ca n p ote ntiall y be e nr olle d as 
l o n g as t he p he n ot y pe is c o nsiste nt wit h A R CI a n d t he ot her i ncl usi o n criteria are 
met, as deter mi ne d b y t he I n vesti gat or  (A p pe n di x  5 ).  
5.  T he a m o u nt of CI affecte d s ki n i n t he Treat me nt Area at Baseli ne will be bet wee n 
a mi ni m u m of 1 0 % a n d ma xi m u m of 9 0 % of t he t otal b o d y s urface area (B S A ; 
1 % B S A is a p pr o xi matel y e q ual t o t he s urface area of t he s u bject’s pal m a n d 
fi n gers, wit h t he fi n gers e xte n de d yet gr o u pe d t o get her, creati n g a flat o val-li ke 
s urface area). 
•  
F or t he O pti o n al M a xi m al Use ar m : T he a m o u nt of CI affecte d s ki n i n t he 
Treat me nt Area at Baseli ne will be bet wee n a mi ni m u m of 7 5 % a n d 
ma xi m u m of 9 0 % of t he t otal B S A . 
6.  D oc u me nte d  hist or y of m o derate t o se vere disease at S cree ni n g . S u bject’s 
desi g nate d Vis ual I n de x f or Ic ht h y osis Se verit y ( VII S ) A ssess me nt A reas at 
Baseli ne  (n ot a p plic a ble f or O pti o n al  M a xi m al Use ar m ) M U S T:  
•  
I ncl u de a n y of t he 4 VII S A ssess me nt A reas t hat ha ve s o me CI disease 
i n v ol vi n g: ( a) t he u p per bac k fr o m t he p osteri or a xillar y f ol d t o t he ot her 
e n c o m passi n g t he T 1 -T 1 0,  ( b) t he u p per ar m (e xcl u di n g el b o ws), left or ri g ht, 

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(c) t he s hi n/l o wer le g (t he p orti o n bel o w t he pr o xi mal as pect of t he k neeca p), 
left or ri g ht, a n d ( d) d orsal f o ot (left or ri g ht); A N D  
•  
At least 2 of t he 4 VII S A ssess me nt A reas M U S T ha ve a scali n g sc ore of 3 or 
m ore.  
7.  S u bject’s I G A sc ore i n t he Treat me nt Area at Baseli ne m ust be 3  or m ore . 
8.  S u bject a n d pare nt/ g uar dia n (if a p plica ble) are willi n g a n d a ble t o a p pl y t he st u d y 
treat me nt(s) as directe d, c o m pl y wit h st u d y i nstr ucti o ns, a n d c o m mit t o all f oll o w-
u p visits f or t he d urati o n of t he st u d y.  
9.  S u bject, i n t he I n vesti gat or’s o pi ni o n, is i n g o o d ge neral healt h a n d free of a n y 
disease state or p h ysical c o n diti o n t hat mi g ht i m pair e val uati o n of t he Treat me nt 
Areas or e x p oses t he s u bject t o a n u nacce pta ble ris k b y st u d y partici pati o n.  
A s u bject is i neli gi ble t o e nter t he st u d y if he/s he meets 1 or m ore of t he f oll o wi n g 
e x cl usi o n criteri a : 
1.  S u bject is pre g na nt, lactati n g, or is pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y.  
2.  S u bject has i nfla m mat or y s ki n diseases t hat c o nf o u n d t he i nter pret ati o n of res ults 
(e. g., at o pic der matitis) u nrelate d t o ic ht h y osis. 
3.  S u bject has p he n ot y pic cli nical prese ntati o n a n d/ or ge netic a b n or malit y c o nsiste nt 
wit h n o n -la mellar t y pe or s y n dr o mic ic ht h y oses (i ncl u di n g b ut n ot e xcl usi vel y 
K R T 1, K R T 1 0, K R T 2, GJ B 3, GJ B 4, C D S N).  
4.  S u bject, i n t he Treat me nt Areas, has use d: ( a ) a n y t o pical prescri pti o n or o ver-t he-
c o u nter t hera pies (e xce pt e m ollie nts, kerat ol ytics, a n d t o pical ster oi ds - see 
bel o w), t hat are i nte n de d f or, or t hat i n t he o pi ni o n of t he I n vesti gat or, ma y 
i m pr o ve CI wit hi n 2 wee ks of Visit 2 ( Baseli ne), or (b ) kerat ol ytics or t o pical 
c ortic oster oi ds wit hi n 5 da ys pri or t o Visit 2 ( Baseli ne).   
5.  S u bject, i n t he Treat me nt  A reas, has use d T M B -0 0 1  i n t he past or oral is otreti n oi n 
i n t he past 1 2 m o nt hs ( n ot a p plic a ble f or O pti o n al  M a xi m al Use ar m ) 
6.  S u bject has use d a n y t o pical pr o d ucts i n t he Treat me nt  Areas, i ncl u di n g bla n d 
e m ollie nts, o n Visit 2 ( Baseli ne) .  
7.  S u bject has use d ultra vi olet treat me nt wit hi n 4 wee ks pri or t o Visit  2 ( Baseli ne).  
8.  S u bjec t h as u n der g o ne s yste mic t hera pies usi n g vita mi n A s u p ple me nts or St. 
J o h n’s W ort wit hi n 4 wee ks pri or t o Visit 2 ( Baseli ne). N ote: Use of a 
m ultivit a mi n i ncl u di n g vit a mi n A is n ot excl usi o n ary pr ovi de d it is t ake n as 
directe d o n t he p ack a gi n g.  
9.  S u bject is i m m u n os u p presse d (e. g., h u ma n i m m u n o deficie nc y vir us, s yste mic 
mali g na n c y, graft h ost disease) or recei ves s yste mic i m m u n ot hera p y.  
1 0.  S u bject is c urre ntl y ta ki n g c o nc o mita nt i m m u n os u p pressi ve dr u gs, i ncl u di n g 
s yste mic c ortic oster oi ds, wit hi n 2 wee ks of Visit 2 ( Baseli ne).  
1 1.  S u bject has u ntreate d sec o n dar y i nfecti o ns; h o we v er, s u bject ma y bec o me eli gi ble 
after s uccessf ul treat me nt of his/ her i nfecti o n(s) at t he I n vesti gat or’s discreti o n.  
1 2.  S u bject is c urre ntl y e nr olle d i n a n i n vesti gati o nal dr u g or de vice st u d y or has use d 
a n i n vesti gati o nal dr u g or i n vesti gati o nal de vice treat me nt wit hi n 3 0 da ys or fi ve 
half -li ves pri or t o Visit 2 ( Baseli ne).  
1 3.  S u bject has lesi o ns s us pici o us f or s ki n ca ncer ( if s ki n ca ncer is n ot r ule d o ut b y 
bi o ps y) , a k n o w n pers o nal or i m me diate fa mil y hist or y of s q ua m o us cell 
carci n o ma of t he s ki n or mela n o ma  or u ntreate d s ki n ca ncers wit hi n t he Treat me nt  
A reas. 

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1 4.  S u bject has a p h ysical c o n diti o n or ot her der mat ol o gic dis or der t hat, i n t he 
I n vesti gat or’s o pi ni o n, mi g ht i m pair e val uati o n of CI, or t hat e x p oses t he s u bject 
t o u nacce pta ble ris k b y st u d y partici pati o n. 
1 5.  S u bjects wit h A L T or A S T > 2  x  U p per Li mit of N or mal ( U L N) a n d/ or creati ni ne 
> 1. 5  x  U L N.  
1 6.  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 g e pr o ble ms, i m paire d cere bral f u ncti o n, or p h ysical li mitati o ns.  
1 7.  S u bject has a hist or y of dr u g or alc o h ol a b use wit hi n t he past 6  m o nt hs, or if 
s us pecte d t o be n o nc o m plia nt or is u nli kel y t o c o m pl y wit h t he re q uire me nts of 
t he st u d y pr ot oc ol (e. g., d ue t o alc o h olis m, dr u g de pe n de nc y, me ntal i nca pacit y) i n 
t he o pi ni o n of t he I n vesti gat or. 
1 8.  S u bject has a hist or y of se nsiti vit y t o a n y of t he i n gre die nts i n t he st u d y 
treat me nts. 
St u d y O bjecti ves   
•  Pri m ar y O bjecti ve  
T o ascertai n t he efficac y of T M B -0 0 1 0. 0 5 % t o pical oi nt me nt as a treat me nt f or CI 
c o m pare d wit h V e hicle d uri n g a 1 2 -wee k treat me nt.   
•  Ke y Sec o n d ar y  Effic ac y  O bjecti ve s 
1 . T o ascertai n t he efficac y of T M B -0 0 1 0. 0 5 % t o pical oi nt me nt at Wee k 1 2 usi n g t he 
VII S -5 0 scali n g sc ore. 
2 . T o ascertai n t he efficac y of T M B -0 0 1 0. 0 5 % t o pical oi nt me nt at Wee k 1 2 usi n g t he 
I G A-scali n g a n d fiss uri n g sc ores. 
3. T o e val uate t he effect of T M B -0 0 1 0. 0 5 % t o pical oi nt me nt o n s u bject  W orst  Itc h-
Q o L sc ores at Wee k 1 2 i n s u bjects wit h b aseli ne Itc h-N u meric Rati n g Scale ( I-
N R S ) of ≥7  
 
Ot her Sec o n d ar y Effic ac y O bjecti ve s  
4. T o ascertai n t he efficac y of T M B -0 0 1 0. 0 5 % t o pical oi nt me nt at Wee k 1 2 usi n g 
differe nt le vels of VII S -scali n g a n d I G A -scali n g a n d fiss uri n g sc ores. 
5 . T o deter mi ne o pti mal mai nte na nce t hera p y wit h T M B -0 0 1 0. 0 5 % t o pical oi nt me nt 
usi n g t he I G A -scali n g a n d fiss uri n g sc ores. 
6 . T o deter mi ne o pti mal mai nte na nce t hera p y wit h T M B -0 0 1 0. 0 5 % t o pical oi nt me nt 
usi n g VII S -scali n g sc ores. 
•  P atie nt -re p orte d O utc o m e Me as ures  
7 . T o e val uate t he effect of T M B -0 0 1 0. 0 5 % t o pical oi nt me nt o n s u bject Q ualit y of 
Life ( Q o L ) d uri n g t he 1 2 -wee k treat me nt peri o d a n d s u bse q ue nt 1 2 -wee k 
mai nte na n ce peri o d.  
•  S afet y  O bjecti ve  
8 . T o i n vesti gate t he safet y of t o picall y a p plie d T M B-0 0 1 0. 0 5 % oi nt me nt.  
9.  T o e val uate i nci de nce of s us pecte d aller gic c o ntact der matitis s u p ple me nte d b y 
s u bse q ue nt c o nfir mat or y cli nical testi n g. 
 
O pti o n al M a xi m al Use Ar m  

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•  Pri m ar y O bjecti ve  
T o deter mi ne s yste mic e x p os ure of is otreti n oi n a n d meta b olites after si n gle or m ulti ple 
a p plicati o ns of T M B -0 0 1 0. 0 5 % oi nt me nt i n s u bjects wit h R X LI or A R CI . 
•  Sec o n d ar y  O bjecti ve  
T o c o m pare s yste mic e x p os ure of is otreti n oi n a n d meta b olites after si n gle or m ulti ple 
a p plicati o ns of T M B -0 0 1 0. 0 5 % oi nt me nt cr oss -trial f or P K para meters o btai ne d f or 
oral is otreti n oi n (si n gle d ose 8 0 m g) i n healt h y v ol u nteers . 
•  S afet y  O bjecti ve  
T o assess l ocal safet y a n d t olera bilit y of T M B -0 0 1 0. 0 5 % oi nt me nt i n a d ult a n d 
pe diatric  s u bjects f or u p t o 1 2 wee ks. 
St u d y E n d p oi nts  
•  Pri m ar y E n d p oi nt  
C o m paris o n of pr o p orti o ns of s u bjects wit h ≥2 -p oi nt c ha n ges fr o m Baseli ne i n I G A -
scali n g a n d fiss uri n g sc ores i n t he Treat me nt Area at Wee k 1 2 bet wee n T M B -0 0 1 
0. 0 5 % a n d ve hicle -treate d s u bjects. 
•  Ke y Sec o n d ar y  Effic ac y  E n d p oi nts  
1 . C o m paris o n of pr o p orti o n of s u bjects w h o ac hie ve 5 0 % re d ucti o n fr o m Baseli ne i n 
VII S -scali n g sc ores at Wee k 1 2 i n all areas wit h B aseli ne VII S sc ore ≥3  bet wee n 
T M B -0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects. 
2 a.  C o m paris o n of pr o p orti o n of s u bjects wit h I G A -scali n g a n d fiss uri n g sc ores of 
clear or al m ost clear  at Wee k 1 2 bet wee n T M B -0 0 1 0. 0 5 % a n d ve hicle -treate d 
s u bjects. 
2 b .C o m paris o n of pr o p orti o ns of s u bjects w h o ac hie ve I G A-scali n g se verit y s u b-sc ore 
i m pr o ve me nt >  2 -p oi nts  fr o m Baseli ne t o Wee k 1 2 bet wee n T M B-0 0 1  0. 0 5 % a n d 
ve hicle -treate d s u bjects. 
3.  C o m paris o n of pr o p orti o n of s u bjects wit h  > 4 -p oi nt i m pr o ve me nt fr o m b aseli ne i n 
W orst Itc h-Q o L sc ores at Wee k 1 2 i n s u bjects wit h b aseli ne Itc h-N u meric Rati n g 
Scale ( I-N R S ) of ≥7 bet wee n T M B -0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects. 
 
•   Ot her Sec o n d ar y Effic ac y E n d p oi nts  
4 a. C o m paris o n of pr o p orti o n of s u bjects w h o ac hie ve 2 5 % re d ucti o n fr o m Baseli ne i n 
VII S -scali n g sc ores at Wee k 1 2 i n all areas wit h Baseli ne VII S sc ore ≥3 bet wee n 
T M B -0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects. 
4 b. C o m paris o n of pr o p orti o n of s u bjects  ac hie vi n g > 2 p oi nt i m pr o ve me nt i n I G A-
fiss uri n g se v erit y s u b-sc ores fr o m Baseli ne t o Wee k 1 2 bet wee n T M B-0 0 1 0. 0 5 %  
a n d ve hicle -treate d s u bjects. 
5.  C o m paris o n of pr o p orti o ns of s u bjects ac hie vi n g >  2 -p oi nt i m pr o ve me nt fr o m 
Baseli ne i n I G A -scali n g a n d fiss uri n g sc ores at Wee k 2 4 bet wee n s u bjects 
ra n d o mize d t o T M B-0 0 1 0. 0 5 % BI D a n d Q D mai nte na nce d osi n g . 
6.  C o m paris o n of pr o p orti o n of s u bjects w h o ac hie ve 5 0 % re d ucti o n fr o m Baseli ne i n           
VII S -scali n g sc ores at Wee k 2 4 i n all areas wit h Baseli ne VII S sc ore ≥3  bet wee n 
s u bjects ra n d o mize d t o T M B -0 0 1 0. 0 5 % BI D a n d Q D mai nte na nce d osi n g . 
P atie nt -re p orte d O utc o m e E n d p o ints  
7 a . C o m paris o n of pr o p orti o ns of s u bjects wit h >  1 1 -p oi nt c ha n ges fr o m Baseli ne i n 
I Q O L-3 2  sc ores at Wee k 1 2 bet wee n T M B-0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects. 

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7 b . C o m paris o n of pr o p orti o n of s u bjects wit h re d ucti o n fr o m Baseli ne i n D L QI or 
C D L QI ≥4 p oi nts at Wee k 1 2 bet wee n T M B -0 0 1 0. 0 5 % a n d ve hicle -treate d 
s u bjects i n a d ult s u bjects wit h B aseli ne sc ores ≥1 1 a n d pe diatric s u bjects wit h 
Baseli ne sc ores of > 1 3.  
7 c. C o m paris o n of pr o p orti o ns of s u bjects wit h I -N R S a n d WI -N R S i m pr o ve me nt > 4 
p oi nts  fr o m Baseli ne i n Itc h-Q o L  sc ores (i n s u bjects wit h B aseli ne I -N R S ≥7) at 
Wee k 2 4 bet wee n s u bjects ra n d o mize d t o T M B -0 0 1 0. 0 5 % BI D a n d Q D 
mai nte na n ce d osi n g . 
7 d . C o m paris o n of c ha n ges fr o m Baseli ne i n D L QI or C D L QI at Wee k 2 4 bet wee n 
s u bjects ra n d o mize d t o T M B-0 0 1 0. 0 5 % BI D a n d Q D mai nte na nce d osi n g i n a d ult 
s u bjects wit h B aseli ne sc ores ≥1 1 a n d pe diatric s u bjects wit h B aseli ne sc ores of 
> 1 3.  
7 e. Pr o p orti o ns of s u b jects wit h >  1 1  p oi nt c ha n ge  fr o m Baseli ne i n I Q o L-3 2  at Wee k 
2 4 bet wee n s u bjects ra n d o mize d t o T M B -0 0 1 0. 0 5 % BI D a n d Q D mai nte na nce 
d osi n g i n a d ult s u bjects. 
•  S afet y  E n d p oi nts  
8 a.  C o m paris o n of pr o p orti o n of s u bjects e x perie nci n g l ocal s ki n reacti o ns ( L S R s) 
t hr o u g h Wee k 1 2 bet wee n T M B-0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects. 
8 b . C o m paris o n of pr o p orti o n of s u bjects e x perie nci n g treat me nt-e mer ge nt a d verse 
e v e nts ( T E A Es)  t hr o u g h Wee k 1 2 bet wee n T M B-0 0 1 0. 0 5 % a n d ve hicle -treate d 
s u bjects. 
8 c. C o m paris o n of pr o p orti o n of s u bjects e x perie nci n g L S Rs t hr o u g h Wee k 2 4 
bet wee n s u bjects ra n d o mize d t o T M B -0 0 1 0. 0 5 % BI D a n d Q D mai nte na nce 
d osi n g . 
8 d . C o m paris o n of pr o p orti o n of s u bjects e x perie nci n g T E A Es t hr o u g h Wee k 2 4. 
9.  C o m paris o n of pr o p orti o n of s u bjects de m o nstrati n g cli nicall y c o nfir me d aller gic 
c o ntact der matitis b y patc h testi n g  t hr o u g h Wee k 1 2 bet wee n T M B-0 0 1 0. 0 5 % a n d 
ve hicle -treate d s u bjects. 
O pti o n al M a xi m al Use Ar m  
•  Pri m ar y E n d p oi nt  
Assess me nt of i n di vi d ual c o nce ntrati o ns of is otreti n oi n, treti n oi n, 4 -o x o -treti ni o n a n d 
4 -o x o -is otreti n oi n a n d c ha n ge fr o m Baseli ne . 
 
•  Sec o n d ar y  E n d p oi nt  
Assess me nt of i n di vi d ual c o nce ntrati o ns of meta b olites ( is otreti n oi n, treti n oi n a n d 4-
o x o -is otreti n oi n, 4-o x o -treti nio n)  a n d c ha n ge fr o m B aseli ne  i n c o nte m p ora ne o usl y 
treate d s u bjects wit h oral a n d t o pical is otreti n oi n . 
•  S afet y  E n d p oi nt  
L ocal safet y a n d t olera bilit y base d o n der mal irritati o n scale, p h ysical e xa m a n d 
m o nit ori n g of a d verse e ve nts . 
St atistic al Met h o ds  
Deta ils of all statistical a nal ys es will b e descri be d i n a se parate S tatistical A nal ysis 
P la n. 
•  S a m ple Size Deter mi n ati o n  
Sa m ple size calc ulati o ns are base d o n t he res ults of t he P hase II b st u d y “ A 
Ra n d o mize d, Parallel, D o u ble -Bli n d, Ve hicle -C o ntr olle d St u d y t o E val uate t he Safet y 

C o nfi de ntial  
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a n d Efficac y of T w o C o nce ntrati o ns of T o pical T M B -0 0 1 f or t he Treat me nt of 
C o n ge nital Ic ht h y osis ”. Res p o nse rate ass u m pti o ns f or t he pri mar y e n d p oi nt 
(pr o p orti o n of s u bjects wit h I G A > 2 -p oi nt i m pr o ve me nt fr o m Baseli ne) are 5 0 % i n t he 
T M B -0 0 1 gr o u p a n d 1 0 % i n t he ve hicle gr o u p. A t otal sa m ple size of 1 1 0 s u bjects 
ra n d o mize d i n a 2: 1 rati o bet wee n T M B-0 0 1 0. 0 5 % a n d V e hicle will ha ve 
ap pr o xi matel y 9 0 % p o wer t o detect a differe nce of 4 0 % bet wee n t he treat me nt gr o u ps 
at t he 1 % si g nifica n ce le vel ( 2 -si de d). T he sa m ple size als o c o vers t he pr o p orti o n of 
a p pr o xi matel y 1 5 % of dr o p o uts a n d n o n -e val ua ble s u bject s.  
•  Pri m ar y Effic ac y A n al ysis  
T he differe nce i n pr o p orti o n of s u bjects ac hie vi n g I G A treat me nt s uccess at Wee k 1 2 
( Visit 6) bet wee n t he T M B-0 0 1 0. 0 5 % a n d ve hicle gr o u ps will be t he pri mar y efficac y 
e n d p oi nt. F or t his e n d p oi nt, t he I G A sc ore will be dic h ot o mize d t o “treat me nt s uccess” 
or “treat me nt fail ure”, w here “treat me nt s uccess” is defi ne d as at least a 2 -gra de 
i m pr o ve me nt ( decrease) i n se verit y sc ore as c o m pare d t o Baseli ne. I nfere nce will be 
ma d e b y c o m pari n g t he pr o p orti o ns of treat me nt s uccesses i n t he T M B-0 0 1 0. 0 5 % 
gr o u p vs t he ve hicle gr o u p at Wee k 1 2 usi n g t he C oc hra n -Ma ntel -Hae nszel ( C M H) 
test stratifie d b y a ge ( > 1 7, 1 2-1 6 a n d 6 -1 1 years ol d) , a n d ge netic s u bt y pe ; a t w o-si de d 
al p ha of 0. 0 1 will be use d f or si g nifica n ce testi n g.   
•  Ke y Sec o n d ar y Ef fic ac y A n al ysis 
T he f oll o wi n g ke y  sec o n dar y efficac y e n d p oi nts will be a nal yze d i n a si milar fas hi o n 
as t he pri mar y efficac y e n d p oi nt base d o n t he i nitial 1 2 wee ks of treat me nt ( Peri o ds 1 
& 2):  
•  t he differe nce i n pr o p orti o ns of s u bjects w h o ac hie ve 5 0 % re d ucti o n fr o m Baseli ne 
i n VII S-scali n g sc ores i n all areas wit h Baseli ne VII S sc ore ≥3 bet wee n T M B -0 0 1 
0. 0 5 % a n d ve hicle -treate d s u bjects,  
•  t he differe nce i n pr o p orti o n of s u bjects wit h I G A-scali n g a n d  fiss uri n g sc ores of 
clear or al m ost clear bet wee n T M B -0 0 1  0. 0 5 % a n d ve hicle -treate d s u bjects, 
•  t he differe nce i n pr o p orti o n of s u bjects wit h > 2 -p oi nt i m pr o ve me nt  fr o m baseli ne 
i n I G A-scali n g se verit y s u b-sc ores bet wee n T M B-0 0 1 0. 0 5 % a n d ve hicle -treate d 
s u bjects, a n d 
•  t he differe nces i n pr o p orti o ns of s u bjects wit h > 4 -p oi nt i m pr o ve me nt  fr o m b aseli ne 
i n W orst Itc h-Q o L sc ores at Wee k 1 2 i n s u bjects wit h b aseli ne Itc h -N u meric Rati n g 
Scale (I -N R S) of ≥7 bet wee n T M B -0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects.  
It is i m p orta nt t o e ns ure t hat reas o na ble certai nt y is ac hie ve d i n t he c o ncl usi o ns 
reac h e d f or ke y sec o n dar y e n d p oi nts. T heref ore, ke y sec o n dar y e n d p oi nts will be 
a dj uste d f or m ulti ple statistical testi n g t hr o u g h a gate kee pi n g hierarc hical 
met h o d ol o g y, as f oll o ws: statistic al si g nifica n ce f or t he first ke y sec o n dar y e n d p oi nt 
o utli ne d a b o ve will be declare d o nl y if t he pri mar y e n d p oi nt has pre vi o usl y reac he d 
statistical si g nifica n ce. S u bse q ue nt e n d p oi nt a nal yses i n t he or der prese nte d a b o ve will 
be declare d si g nifica nt o nl y i f t he pre vi o us e n d p oi nt i n or der has reac he d statistical 
si g nifica n ce. All a nal yses of ke y sec o n dar y e n d p oi nts will be perf or me d  at t he t w o -
si de d al p ha-le vel of 0. 0 1. Missi n g data f or ke y sec o n dar y e n d p oi nts will be ha n dle d i n 
a si milar ma n ner as t he pri ma r y e n d p oi nt. 
T he c h a n ges i n c o nti n u o us e n d p oi nts will be a nal yze d usi n g a nal ysis of c o varia nce 
(A N C O V A ) m o dels wit h d osi n g fre q ue nc y, Baseli ne sc ores, a ge, ge netic s u bt y pes, 
a n d disease se v erit y as c o variates.  
•  S afet y A n al ysis  
All A Es re p orte d d uri n g t he st u d y will be liste d, d oc u me nti n g o nset, w het her t hera p y 
was re q uire d, a n y c ha n ge i n st u d y treat me nt d osi n g, se verit y, p ossi ble relati o ns hi p t o 

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st u d y treat me nt, a n d o utc o me. Ver bati m ter ms o n t he electr o nic case re p ort f or ms 
(e CR Fs ) will be li n ke d t o preferre d ter ms ( P Ts) a n d s yste m or ga n class ( S O C) 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) ma p pi n g s yste m. All 
re p orte d T E A Es a n d i nci de nce rates will be s u m marize d b y t he n u m ber of s u bjects 
re p orti n g A Es, S O C, P T, se verit y, a n d relati o ns hi p t o st u d y treat me nt b y treat me nt 
gr o u p.  T E A Es a n d rele v a nt patie nt years of e x p os ure will be prese nte d, as a p pr o priate.  
All la b orat or y test res ults, vital si g ns meas ure me nts, a n d wei g ht will be s u m marize d 
f or eac h treat me nt gr o up usi n g descri pti ve statistics f or ra w n u m bers a n d c ha n ge fr o m 
Baseli ne. T he i nci de nce of treat me nt -e mer ge nt cli nica ll y si g nifica nt la b orat or y a n d 
vital si g ns val ues will als o be s u m marize d usi n g descri pti ve statistics.  
O pti o n al M a xi m al Use Ar m  
T he sa m ple size f or t he O pti o nal Ma xi mal Use ar m was re q ueste d b y t he F D A a n d n o 
f or mal p o wer calc ulati o ns were perf or me d. All a nal yses will be perf or me d o n t he 
Ma xi mal Use P o p ulati o n, c o nsisti n g of all s u bjects i n t his st u d y ar m t hat recei ve d at 
least 1 d ose of st u dy me dicati o n . N o statistical a nal yses are pla n ne d, a n d all data 
c ollecte d will be pr o vi de d i n b y -s u bject listi n gs. If warra nte d, s u m mar y ta b ulati o ns 
usi n g descri pti ve statistics f or eac h visit ma y be pr o vi de d.  
 

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f. 
E xa mi nati o n will i ncl u de hea d a n d nec k, der mat ol o gic, car di o vasc ular, res pirat or y, gastr oi ntesti nal (a b d o me n), a n d gr oss  m ot or a n d gait assess me nts. 
A d diti o nal e xa mi nati o ns will be c o n d ucte d at Visit 2 ( Baseli ne) t o i de ntif y a n y c ha n ges si nce  Scree ni n g , at Visit 6 a n d Visit 9 ( E O S) t o assess c h a n ges 
t hr o u g h o ut t he st u d y. A b n or malities at Visit 1 ( Scree ni n g) a n d Visit  2 ( Bas eli ne) will be rec or de d as me dical hist or y. A n y ne w or w orse ni n g a b n or malit y at 
all s u bse q ue nt visits will be rec or de d as A Es.  
g.  If t here are less t ha n t w o wee ks bet wee n Visit 1 ( Scree ni n g) a n d Visit 2 ( Baseli ne), t he p h ysical e xa mi nati o n at t he Visit 2 ( Baseli ne) i ncl u des o nl y a 
der mat ol o gical assess me nt .  
h.  S u bjects w h o meet all i ncl usi o n criteria a n d n o ne of t he e xcl usi o n criteria will be ra n d o mize d at Baseli ne ( 2: 1 rati o) t o eit her t he T M B -0 0 1 0. 0 5 % or t he 
v e hicle treat me nt gr o u p, stratifie d b y a ge a n d CI s u bt y pe.  
i. 
At Wee k 1 2, eli gi ble s u bjects i n t he T M B -0 0 1 0. 0 5 % treat me nt gr o u p will be ra n d o mize d ( 1: 1 rati o) t o eit her T M B -0 0 1 0. 0 5 % Q D or BI D mai nte na n ce 
treat me nt. 
j. 
Cli nical la b orat or y tests ( he mat ol o g y, cli nical c he mistr y, r o uti ne uri nal ysis) are pr o vi de d i n Err or! Refere nce s o urce n ot f o u n d. . S u bjects m ust b e fasti n g 
(at least 8 h o urs) f or Visit 1 ( Scree ni n g) a n d, if p ossi ble, f or Visit 6 a n d Visit 9 ( E O S). H o we v er, if a s u bject arri ves at t he cli nic f or Visit 6 ( Wee k 1 2) or 
Visit  9  ( E O S) wit h o ut fasti n g f or at least 8 h o urs, la b orat or y s peci me ns ma y be c ollecte d as n o n -fasti n g, at t he discreti o n of t he I n vesti gat or a n d 
d oc u me nte d as s uc h o n t he la b ora t or y re q uisiti o n f or m.  
k.  Assess me nts will be ma d e after t he s u bject has reste d i n a seate d p ositi o n f or at least 5 mi n utes. Hei g ht a n d wei g ht will als o be meas ure d at Visit 1 
( Scree ni n g). 
l. 
T he ter m W O C B P is defi ne d i n A p pe n di x  4 . 
m.  Uri ne pre g na n c y testi n g will be perf or me d  d uri n g i n -cli nic visits a n d pr o vi de d t o st u d y partici pa nts t o c o n d uct at h o me d uri n g re m ote visits . All uri ne 
pre g na nc y tests m ust h a v e a mi ni m u m se nsiti vit y of 2 5 mI U β -h C G/ m L.  
n.  I G A will be assesse d as Scali n g a n d Fiss uri n g C o m bi ne d Sc ores a n d  se parate Scali n g a n d Fiss uri n g S u b -sc ores.  
o.  S u bjects ≥1 6 years will be assesse d usi n g t he Der mat ol o g y Life Q ualit y I n de x ( D L Q L) w hile s u bjects < 1 6 years will be assesse d usi n g t he C hil dre n’s 
Der mat ol o g y Life Q ualit y I n de x ( C D L QI).  
p.  Ic ht h y osis Q ualit y of Life Q uesti o n naire  (I Q o L-3 2) will be use d f or s u bjects > 1 5  years.  
q.  P h ot o gra p hs will be ta ke n  at selecte d sites ( per P h ot o gra p hic G ui de pr o vi de d b y S p o ns or).  
r. 
F or visits perf or me d re m otel y, l ocal s ki n reacti o ns will be assesse d via t he S u bject e Diar y . S us pecte d cases of aller gic c o ntact der matitis are t o be f oll o we d 
as per A p pe n di x  1 1 . 
s. 
I nstr ucti o n f or st u d y treat me nt a d mi nistrati o n will be pr o vi de d i n pa per f or m a n d will be  i ncl u ded i n t he S u bject e Diar y. 
t. 
D uri n g a n y was h o ut a n d scree ni n g peri o ds, a n y c ha n ges i n t he healt h of s u bjects s h o ul d be rec or de d as c ha n ges i n me dical hist or y u nless a n e v e nt o cc urre d 
as a res ult of a st u d y -relate d pr oce d ure a n d was u na ntici pate d. I n s uc h cases, t he e ve nt s h o ul d be rec or de d as a n A E a n d re p orte d t o t he I nstit uti o n al Re vie w 
B oar d/I n de p e n de nt Et hics C o m mittee as a n “ u na ntici pate d pr o ble m” i n acc or da nce wit h l ocal pr oce d ures.  
u.  
A n y treat me nt-relate d A Es t hat are o n g oi n g at Visit 9 ( E O S) m ust be f oll o we d u ntil res ol uti o n or sta bilizati o n.   
v.  
I-N R S sc ores will b e c ollecte d o n a dail y basis f or first 1 2 wee ks  
 

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2  I N T R O D U C TI O N 
T he classificati o n of c o n ge nital ic ht h y osis ( CI) is c o m ple x beca use t he dis or der prese nts i n a 
m ultit u de of f or ms a n d p he n ot y pes. T he mai n feat ures, h o we v er , are scali n g a n d ofte n t hic ke ni n g 
of t he s ki n (Va hl q uist 2 0 0 8 ). T he pres e ntati o n a n d se verit y of s y m pt o ms ca n differ greatl y b y 
patie nt a n d b y t he f or m of ic ht h y osis, b ut ge nerall y i ncl u de s ki n i nfla m mati o n a n d fra gilit y, 
pr urit us, fiss uri n g a n d crac ki n g of t hic ke n e d s ki n, a n hi dr osis, a n d i n s o me se vere cases, a n 
i ncreas e d s usce pti bilit y t o i nfecti o n. Recessi ve X-li n ke d ic ht h y osis ( R X LI), w hic h occ urs at a 
fre q ue n c y of a b o ut o n e i n 2 5 0 0 (i n males), is cli nicall y c haracterize d b y wi des prea d, d ar k br o w n, 
p ol y g o nal scales, a n d g e neralize d dr y ness  (T a kei c hi 2 0 1 6 ). T he dia g n osis ca n be c o nfir me d 
usi n g ge netic testi n g t o i de ntif y a c o m plete deleti o n of t he ge ne e nc o di n g ster oi d s ulfatase ( S T S) 
t hat is l ocate d at t he ter mi n us of t he X c hr o m os o m e (N o m ura 1 9 9 5 ). A ut os o mal recessi ve 
c o n ge nital  ic ht h y osis ( A R CI), w hic h occ urs at a fre q ue nc y of a b o ut o ne i n 1 0 0, 0 0 0 t o 3 0 0, 0 0 0, is 
a me m ber of t h e n o n -s y n dr o mic a ut os o mal recessi ve CI gr o u p w hic h ma nifests itself cli nicall y 
as h y per kerat osis a n d dr y, scali n g s ki n acr oss t he e ntire b o d y  (Va hl q uist 2 0 1 4 ); pat h o ge nesis is 
relate d t o a s e verel y dist ur be d barrier f u n cti o n d ue eit her a b n or m al c or ne o c ytes or t o a defecti ve 
de p ositi o n of strat u m c or ne u m li pi ds a n d ca n be ca use d b y tr u ncati o n or misse nse m utati o ns i n 
t he ge ne e n c o di n g kerati n oc yte tra ns gl uta mi nase t y pe 1 ( T G M 1) (Va hl q uist 2 0 0 8 , 
Va hl q uist  2 0 1 4 ). 
Is otr eti n oi n is a “ nat ural ” reti n oi d ( 1 3-cis is o mer of nat urall y occ urri n g treti n oi n 
[all-tra ns-reti n oic aci d  { R A }] ) t hat was i nitiall y de vel o pe d as a s y nt hetic reti n oi d, b ut it is als o 
prese nt i n cells as a nat ur all y occ urri n g met a b olite  (Di gi o va n na 2 0 1 3 ). Is otreti n oi n is str uct urall y 
a n d p har mac ol o gicall y relate d t o vita mi n A, w hic h re g ulates e pit helial cell gr o wt h a n d 
differe ntiati o n (Gla x o S mit h Kli ne  A ustralia  Pt y  Lt d 2 0 1 3 ). Is otreti n oi n has se veral 
p har mac ol o gical mec ha nis ms of acti o n t hat res ult i n t he s u p pressi o n of se b ace o us gla n d acti vit y, 
re d ucti o n of se b u m pr o d ucti o n, re d ucti o n of c o m e d o ge nesis b y decreasi n g h y per kerati nizati o n, 
s u p pressi o n of Pr o pi o ni b acteri u m ac nes  (P.  ac nes ), a n d re d u cti o n of i nfla m mati o n 
(La yt o n  2 0 0 9 ). Is otr eti n oi n has at least 5 bi ol o gicall y i m p orta nt meta b olites: 1 3-cis -4 -o x o -R A 
( 4-o x o -is otreti n oi n), all-tra ns-R A (tr eti n oi n), all -tr a ns-4 -o x o -R A ( 4 -o x o -tr eti n oi n), 9-cis-R A 
(alitreti n oi n), a n d 9-cis-4 -o x o -R A; a n d ca n be c o nsi dere d a pr o -dr u g, i n w hic h is otreti n oi n ca n 
be meta b olize d i nt o t he n at urall y occ urri n g treti n oi n ( or o ne of t he ot her meta b olites) as t he 
acti ve i ntracell ular m oiet y  (La yt o n 2 0 0 9 ). I n a d diti o n, w hile s o me of is otreti n oi n’s acti vit y ma y 
be me diate d b y treti n oi n, t he is o merizati o n of is otreti n oi n ( 1 3 -cis-R A) i nt o treti n o i n (all-tra ns-
R A) d oes n ot acc o u nt f or all of t he p har mac ol o gical effects o bser ve d u p o n use of t his reti n oi d 
(Bla ner 2 0 0 1 ). T h us, is otreti n oi n’s br oa der ra n g e of acti vit y c o m pare d t o ot her reti n oi ds ma kes it 
a d va nta ge o us f or cli nical de vel o p me nt.  
Oral is otreti n oi n ( Acc uta ne ®) ca ps ul es w ere first a p pr o ve d b y t he U nite d States ( U S) F o o d a n d 
Dr u g A d mi nistrati o n ( F D A) as treat me nt f or se v ere recalcitra nt n o d ular ac n e i n 1 9 8 2  
(R oc he  La b orat ories  I n c 1 9 8 2). Terat o g e nicit y is re gar de d as o ne of t h e m ost seri o us p ote ntial 
a d verse effects of oral reti n oi ds, w hile c o m m o n m uc oc uta ne o us si de effects are d ose -de pe n d e nt 
a n d ca n b e ma na g e d b y m o dificati o n of t he d ose ( e.g ., re d u cti o ns a n d/ or dr u g h oli da ys) a n d 
a d diti o nal s y m pt o matic t hera p y (e .g ., m oist urizers). T o pical f or m ulati o n of is otreti n oi n, Is otre x ® 

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gel a n d crea m, 0. 0 5 %, h as si nce bee n a p pr o ve d i n vari o us c o u ntries o utsi de of t he U S f or t he 
treat me nt of mil d t o m o derate ac ne v ul g aris, c haracterize d b y c o me d o nes, p a p ules, a n d p ust ules 
(Gla x o S mit h Kli ne  A ustralia  Pt y  Lt d 2 0 1 3 , Gla x o S mit h Kli ne  U K  Li mite d 2 0 1 4 ). A n ot her t o pical 
f or m ulati o n, is otreti n oi n crea m, 0. 1 %, has als o be e n st u die d i n vari o us i n dicati o ns i ncl u di n g 
ic ht h y osis a n d ot her dis or ders of k erati nizati o n (B ur ge 1 9 9 5 , Steijle n 1 9 9 3 ) a n d ac n e v ul garis 
(C hal ker 1 9 8 7 , D o mi n g u ez 1 9 9 8 , H u g hes 1 9 9 2 , I oa n ni des 2 0 0 2, Je nse n 1 9 9 1). 
2. 1  St u d y R ati o n ale  
S yste mic reti n oi ds, i ncl u di n g is otreti n oi n, ha ve bee n use d f or t h e i n vesti gati o nal treat me nt of CI 
a n d ha ve d e m o nstrate d re mar ka ble effi cac y i n r e d uci n g t he cli nical si g ns of t he disease w hile 
d osi n g of t he dr u g is mai ntai ne d. Alt h o u g h n ot F D A a p pr o ve d, t o pical f or m ulati o ns of 
is otreti n oi n (e. g., 0. 0 5 % gel a n d 0. 1 % crea m) h a v e de m o nstrate d s o me effi cac y i n r e d uci n g t he 
cli nical si g ns ass ociate d wit h ic ht h y osis a n d ot her dis or ders of kerati nizati o n.  
Ti m ber P har mace uticals, L L C is de vel o pi n g a t o pical oi nt me nt ( 0. 0 5 % ) f or m ulati o n of 
is otreti n oi n calle d T M B-0 0 1 ( pre vi o usl y P A T -0 0 1) (is otreti n oi n) oi nt me nt f or t he treat me nt of 
CI, i ncl u di n g R X LI a n d A R CI s u bt y pes . A n i nitial P hase IIa st u d y i n s u bjects  a ge d ≥1 2 years has 
s h o w n fa v ora ble efficac y after treat me nt wit h T M B -0 0 1 0. 1 % oi nt me nt. A s u bse q ue nt P hase II b 
st u d y wit h T M B-0 0 1 0. 0 5 % a n d 0. 1 % oi nt me nt d e m o nstrate d  re d u ced  cli nical si g ns of CI i n 
s u bjects a ge d ≥9 years, wit h si g nifica nt i m pr o ve me nt of Vis ual I n de x f or Ic ht h y osis Se verit y 
( VII S)-s cali n g a n d t he I n vesti gat or Gl o bal Assess me nt (I G A) scali n g/fiss uri n g se verit y sc ore.  
T he p ur p ose of t his P has e III st u d y is t o i n vesti gate t he efficac y a n d safet y of to picall y a p plie d 
T M B -0 0 1 0. 0 5 % i n s u bjects a ge d ≥6  years wit h R X LI or A R CI w hile t he O pti o nal Ma xi mal Use 
ar m will e val uate s yste mic  e x p os ure a n d safet y. 
2. 2  B ac k gr o u n d  
CI  is a lar ge, het er o ge n e o us fa mil y of i n herite d s ki n dis or ders of c or nificati o n res ulti n g fr o m a n 
a b n or malit y of s ki n kerati nizati o n  (Va hl q uist 2 0 0 8 ).  
T he ma na ge m e nt of CI  is a life-l o n g e n dea v or, w hic h re mai ns lar gel y s y m pt o matic (i.e., 
e m ollie nts wit h or wit h o ut kerat ol ytics) a n d c o m m o nl y f oc use d o n re d u ci n g scali n g a n d/ or s ki n 
l u bricati o n wit h b ot h s yste mic a n d t o pical treat me nts (Va hl q uist 2 0 0 8 ). A first-li ne t hera p y 
i ncl u des h y drati o n a n d l u bricati o n acc o m plis he d b y crea ms a n d oi nt me nts c o ntai ni n g l o w 
c o nce ntr ati o ns of salt, urea, or gl yc er ol, w hic h i ncreases t he water -bi n di n g ca pacit y o f t he h or n y 
la yer. A d diti o n of kerat ol ytics is use d t o decrease c or ne oc yt e c o hesi v e ness, t o pr o m ote 
des q ua mati o n, a n d t o diss ol ve kerati ns a n d li pi ds (e .g ., α-h y dr o x y aci ds, salic ylic aci d, hi g h -d ose 
urea, pr o p yl e ne gl yc ol, N -acet ylc yst ei ne, a n d reti n oi ds) . S yste mic reti n oi d treat me nt is res er ve d 
f or t h ose patie nts w h o are refract or y t o t o pical a ge nts beca us e of l o n g-ter m a d verse effects a n d 
terat o ge nicit y (Di gi o va n na 2 0 1 3 ); h o we v er, t he i n vesti gati o nal use of oral is otreti n oi n has 
de m o nstrate d re m ar ka bl e effic ac y w h e n use d f or t he treat me nt of ic ht h y oses a n d is belie ve d t o 
be attri b uta ble t o is otreti n oi n’s a bilit y t o decreas e h y per kerati nizati o n (Va hl q uist 2 0 0 8 , 
Di gi o va n na 2 0 1 3 ). F or t h e treat me nt of CI, it w o ul d be desira ble t o h a ve a t o pical f or m ulati o n of 
is otreti n oi n, s uc h as T M B -0 0 1, Ti m ber’s  p r o priet ar y is otreti n oi n o i nt me nt, as it w o ul d aff or d 

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tar gete d deli ver y of t he dr u g  at t he disease tiss ue site, w hile p ote ntiall y mi ni mizi n g s yste mic 
e x p os ure c o m p are d t o t h at of s yste mic reti n oi d treat me nt , a n d a d diti o nall y pr o vi di n g h y drati o n 
a n d l u bricati o n t o t he disease d s ki n.  
A n i nitial P hase IIa, m ultice nter st u d y i n s u bjects  a ge d ≥1 2 years s h o we d t o picall y a p plie d 
T M B -0 0 1 oi nt me nt ( 0. 1 %) t o be safe, t olera bl e, a n d s u p p orti n g a fa v ora ble effi cac y si g nal wit h 
i m pr o ve me nt i n o verall I G A f or CI tr eat me nt.  
I n a s u bse q ue nt p arallel, d o u ble-bli n d, ve hicle -c o ntr olle d P hase II b st u d y i n s u bjects a ge d ≥9 
years wit h c o nfir me d CI, 1 0 % – 9 0 % of t otal b o d y s urface area ( B S A) affect e d, s u bjects were 
ra n d o mize d ( 1: 1: 1 r ati o) t o T M B-0 0 1 0. 0 5 % ( n = 1 1), T M B -0 0 1 0. 1 % ( n = 1 0) or V e hicl e ( n = 1 2) 
t wice dail y ( BI D) f or 1 2 wee ks. K e y efficacy e n d p oi nts at 1 2 wee ks were t he pr o p orti o n of 
s u bjects wit h a ≥5 0 % re d ucti o n c o m pare d wit h Baseli ne i n VII S-scali n g ( VII S-5 0); a n d t he 
pr o p orti o n of s u bjects wit h ≥2 -gra de re d ucti o n i n I G A -scali n g a n d fiss uri n g se verit y sc ore vs 
Baseli ne. A d vers e e ve nts ( A Es) a n d l ocal s ki n reacti o ns ( L S Rs) were als o assesse d.  T he m ea n 
a ge of t he s u bjects was 3 4. 5 years; 5 5 % a n d 4 5 % of t he e nr olle d s u bjects ha d la mella r ic ht h y osis 
( LI) a n d R X LI s u bt y pes of CI, res pecti vel y. O verall, 6 4 % a n d 4 0 % of I nte nti o n-t o-treat (I T T) 
s u bjects treate d wit h T M B-0 0 1 0. 0 5 % a n d 0. 1 %, res pecti vel y ac hie ve d VII S -5 0 c o m pare d wit h 
3 3 % treate d wit h ve hicle ( n o mi nal P = 0. 1 7  f or T M B-0 0 1 0. 0 5 % vs  ve hicle). Me dia n ti me (I T T) 
t o VII S-5 0 ac hi e ve me nt was 2 8. 0 da ys f or T M B -0 0 1 0. 0 5 % a n d 5 4. 0 da ys f or T M B -0 0 1 0. 1 % 
c o m pare d wit h 6 3. 5 da ys f or V e hicl e (P = 0. 0 2 f or 0. 0 5 %). I m pr o ve m e nt of ≥2 -gra de I G A sc ore 
was o bser v e d i n 5 5 % of T M B -0 0 1 0. 0 5 % a n d 4 0 % of T M B -0 0 1 0. 1 % c o m pare d wit h 8 % f or 
V e hicle ( n o mi nal P = 0. 0 2 f or 0. 0 5 %). M ost L S Rs were mil d or m o derate i n se verit y a n d occ urre d 
at Wee ks 2 a n d 4. B y  Wee k 1 2, b ur ni n g/sti n gi n g a n d er yt he ma were re p ort e d i n 1 8 % a n d 3 6 % of 
s u bjects recei vi n g T M B-0 0 1 0. 0 5 % a n d T M B -0 0 1 0. 1 %, res pecti vel y. N o s u bjects re p orte d 
e de ma a n d 1 8 % a n d 3 0 % of s u bjects re p orte d mil d s ki n er osi o ns f or T M B -0 0 1 0. 0 5 % a n d 0. 1 %, 
res pecti vel y. N o h os pitalizati o ns, seri o us a d verse e ve nts ( S A Es) or d eat hs were o bs er ve d. 
2. 3  Be nefit/ Ris k Assess me nt  
W hile n o t o pical is otreti n oi n f or m ulati o n is a p pr o ve d f or use i n treat me nt of CI ( or a n y 
i n dicati o n i n t he U S), t o pical f or m ulati o ns of is otreti n oi n (e.g ., 0. 0 5 % gel a n d 0. 1 % crea m) ha v e 
de m o nstrate d s o me effic ac y i n re d u ci n g t he cli nical si g ns ass ociate d wit h i c ht h y osis a n d ot her 
dis or ders of kerati nizati o n. I n o n e st u d y, t o pical 1 3 -cis-R A (is otreti n oi n) crea m 0. 1 % 
de m o nstrate d a mar ke d re d ucti o n i n scali n g a n d a n i m pr o ve me nt i n s ki n s m o ot h ness after 
4  wee ks of treat me nt i n 4 0 % of s u bjects ( 2/ 7 s u bjects wit h n o n -er yt hr o der mic LI, 2/ 2 s u bjects 
wit h Darier’s dis ease, a n d 0/ 1  s u bjects wit h a ut os o mal d o mi na nt ic ht h y osis v ul garis). H o we v er, 
t his cli nical i m pr o ve me nt was acc o m pa nie d b y l ocal s ki n irritati o n (e.g ., itc h y er yt he ma) i n 
res p o n ders, a n d d ose m o dificati o ns were ofte n prescri be d t o miti gate s uc h effects  
(Steijle n  1 9 9 3 ). Si milarl y, t o pical is otreti n oi n gel, 0. 0 5 % (Is otre x ®) de m o nstrate d partial 
res ol uti o n or cleara nce of h y per kerat osis a n d pa p ules i n t he treat me nt area ( 1 0 c m 2 area) after 3 
m o nt hs of treat me nt ( u p t o BI D  as t olerate d) i n 5 0 % ( 6/ 1 2) of s u bjects wit h Darier’s disease.  I n 
a d diti o n, s yste mic reti n oi ds, i ncl u di n g is otreti n oi n, ha ve bee n use d f or t he i n vesti gati o nal 
treat me nt of CI a n d h a ve de m o nstrate d re m ar ka bl e efficac y i n re d u ci n g t he cli nical si g ns of t he 
disease w hile d osi n g of t he dr u g is mai ntai ne d  (Va hl q uist 2 0 0 8 , Di gi o va n na 2 0 1 3 ). 

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T he m ost n ota ble a d vers e reacti o ns wit h oral is otreti n oi n are: terat o g e nicit y, dr y li p, dr y s ki n, 
bac k pai n, dr y e ye, art hral gia, e pista xis, hea dac he, nas o p har y n gitis, c ha p pe d li ps, der matitis, 
re nal or h e pat ot o xicit y, m usc ul os keletal disc o mf ort, a n d vis ual ac uit y re d uce d. 
T he f oll o wi n g are c o ncer ns f or w o me n  of c hil d beari n g p ote ntial ( W O C B P):  
•  Se vere birt h defects ca n occ ur d uri n g pre g na n c y w hile ta ki n g oral is otreti n oi n, wit h a n y 
a m o u nt a n d e ve n if ta k e n f or s h ort peri o ds of ti me;  
•  Pre g na nc y m ust be a v oi d e d 1  m o nt h bef ore, d uri n g, a n d f or 1  m o nt h after treat me nt.  
As wit h a n y reti n oi d, t he si de effects of T M B -0 0 1 ma y i ncl u de t he f oll o wi n g L S Rs: b ur ni n g, 
dr y ness, e de m a, er yt he m a, h y per pi g me ntati o n, h y p o pi g me ntati o n, p h ot ose nsiti vit y, pr urit us, 
scali n g/ peeli n g, sti n gi n g, a n d te n der ness. 
S yste mic e x p os ure is e x p ect e d t o be l o w gi ve n t h e r o ute of t o pical a d mi nistrati o n. I n mi ni pi gs 
recei vi n g o nce dail y der mal a p plicati o ns of T M B-0 0 1 oi nt me nt f or 9 0 da ys at c o nce ntr ati o ns of 
0. 0 2 5 %, 0. 1 %, a n d 0. 2 %, t here was little t o n o s yste mic a bs or pti o n of is otreti n oi n wit h m ost 
v al ues bei n g near or bel o w t he li mit of q ua ntitati o n ( 0. 3 7 4  n g/ m L).  
I n a d diti o n, i n a P hase IIa cli nical st u d y of s u bjects wit h CI  i n v ol vi n g 1 2 % B S A, w here T M B -
0 0 1 0. 1 % a n d 0. 2 % oi nt me nt c o nce ntr ati o ns were teste d , t he ser u m c o nce ntrati o ns of is otreti n oi n 
a n d treti n oi n were meas ure d  f or 1 2 wee ks ( n = 5). Plas ma c o nce ntrati o ns of is otreti n oi n a n d 
treti n oi n i n dicate d t hat s yste mic e x p os ure was mi ni mal wit hi n t he 4 h o urs f oll o wi n g i nitial 
a p plicati o n. Tr o u g h c o n ce ntrati o ns meas ure d o n Da ys  8, 2 9, 5 7 a n d 8 4 a p pr o xi matel y 1 2  h o urs 
f oll o wi n g t he prece di n g d ose i n dicate d t hat s yste mic c o nce ntr ati o ns of is otreti n oi n a n d treti n oi n 
were wit hi n ra n ge of t he e n d o ge n o us le vels meas ure d at Baseli ne pri or t o t he first a p plicati o n.  
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits a n d ris ks a n d reas o n a bl y 
e x pecte d A Es of T M B -0 0 1 o i nt me nt ma y be f o u n d i n t he I n v esti gat or’s Br oc h ure. 
2. 3. 1  Ris k/ b ur de n i n mi n ors  
T he e x pecte d ris k/ b ur de n i n mi n ors is e x pecte d t o be si milar t o s u bjects o ver t he a ge of 1 8 years. 
T he c urre nt st u d y pr o p os es si milar a m o u nts of i n vesti gati o nal pr o d uct a p plie d/ m 2  , re gar dless of 
a ge. T he s afet y pr ofile ac hie ve d i n mi n or s u bjects i n t he P hase 2 A a n d P has e 2 B pr o gra ms was 
si milar t o t hat of ol der s u bjects. L ocal t o xi cit y a n d s ki n reacti o ns will be c o nsiste ntl y e val uate d 
t hr o u g h o ut t he trial i n t hese mi n or s u bjects. Ris k t o c hil dre n i n t his pr o gra m s h o ul d be c o m pare d 
wit h lac k of o n -la b el alter nati ve pr o d ucts f or treat me nt of c o n ge nital ic ht h y osis i n c hil dre n a n d 
a d olesce nts; f or e xa m ple, acitreti n is n ot a p pr o ve d f or use i n c hil dre n wit h c o n ge nital ic ht h y osis 
i n t he E ur o pea n U ni o n. 

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4  S T U D Y D E SI G N  
4. 1  O ver all Desi g n  
T his is a ra n d o mize d, d o u ble -bli n d  a n d ve hicle -c o ntr olle d P hase III st u d y t o e val uate t he s afet y 
a n d effi cac y of t o pical T M B -0 0 1  0. 0 5 % oi nt me nt f or t he treat me nt of CI i n s u bjects wit h eit her 
t he R X LI or A R CI s u bt y pes.  
I n a d diti o n, a s u bset of pre selecte d ce nters will recr uit s u bjects i n parallel wit h eit her t he R X LI 
or A R CI s u bt y pes  f or e nr oll me nt i nt o a n O pti o nal Ma xi mal Use ar m f or e v al uati o n of t he 
s yste mic e x p os ure a n d s afet y of t o pical T M B -0 0 1  0. 0 5 % oi nt me nt f or t he treat me nt of CI.  
Pr ot oc ol S ecti o ns 1 t hr o u g h 8 are a p plic a ble f or b ot h t he P h ase III st u d y a n d t he O pti o n al 
M a xi m al Use a r m , u nless ot her wise st ate d. As pects t h at are s pecifi c t o t he O pti o n al 
M a xi m al Use a r m are  descri be d i n Secti o n 9 .  
T he o verall st u d y desi g n is prese nte d i n Fi g ur e 1 . 
 
A b bre viati o ns: A R CI = A ut os o mal R ecessi v e C o n ge nital Ic ht h y osis; BI D = T wice D ail y; I G A = I n vesti g at or’s Gl o bal 
Assess me nt; P K = P har mac o ki netic; Q D = O nce a D a y; R X LI = Recessi v e X -li n ke d Ic ht h y osis 
 
 
Fi g ure 1  
O ver all  St u d y Sc he m a  
 
 
 

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T he  P hase  III St u d y  is desi g ne d i n t hree peri o ds  (Fi g ure 1 ): 
•  Peri o d 1  –  In d ucti o n  ( 3 wee ks): 
At t he be gi n ni n g of t he 3 -wee k In d ucti o n P eri o d, eli gi ble s u bjects will be ra n d o mize d 
( 2: 1 rati o) t o eit her T M B-0 0 1 0. 0 5 % o nce -a-d a y ( Q D) or Ve hicle Q D treat me nt, wit h use 
of ma n dat or y sta n dar dize d bla n d e m ollie nt ( Ceta p hil ™) pr o vi de d b y t he S p o ns or.  
•  Peri o d  2 –  T re at me nt  ( 9 wee ks):  
T he  d osi n g fre q u e nc y i n t he  9 -wee k treat me nt p eri o d will be i ncrease d i n eac h treat me nt 
gr o u p  t o T M B-0 0 1 0. 0 5 % BI D or Ve hi cle  BI D . Ma n dat or y bla n d e m ollie nt  will be 
disc o nti n ue d . 
•  Peri o d 3 –  M ai nte n a nce  ( 1 2 wee ks):  
At Wee k 1 2, eli gi ble s u bjects i n t he T M B -0 0 1 treat me nt gr o u p will be  ra n d o mize d ( 1: 1 
rati o) t o a n o pe n-l a bel treat me nt wit h T M B-0 0 1 0. 0 5 % BI D or T M B -0 0 1 0. 0 5 % Q D. T o 
be eli gi ble, s u bjects m ust ha ve ac hie ve d a ≥1 -p oi nt re d ucti o n i n I G A sc ore fr o m 
Baseli ne. S u bjects wit h less t ha n a 1 -p oi nt re d u cti o n i n I G A sc ore fr o m Baseli ne will be 
disc o nti n ue d fr o m t he st u d y.  
Ve hicle -tr eate d s u bjects w h o ac hie ve d <1 -p oi nt re d ucti o n i n I G A sc ore fr o m Baseli ne are 
eli gi ble t o cr oss o ver t o t he T M B -0 0 1 0. 0 5 % BI D treat me nt gr o u p. S u bjects wit h a ≥1 -
p oi nt re d ucti o n i n I G A sc ore fr o m Baseli ne will be disc o nti n ue d fr o m t he st u d y.  
S u bjects at t he e n d of t he st u d y or s u bjects disc o nti n ue d fr o m t he st u d y at a n y ti me will be 
f oll o we d-u p f or a d diti o nal 2 wee ks  f or A Es.  
Eac h s u bject will partici p ate i n t he st u d y f or a p pr o xi matel y  3 6  wee ks (i ncl u di n g u p t o a 9 0-da y 
scree ni n g p eri o d). 
T he st u d y  will be c o n d ucte d i n a p pr o xi matel y  3 0 -4 0  st u d y ce nters fr o m U nite d States of 
A merica , Ca n a da a n d se v eral E ur o p ea n c o u ntries.   
4. 2  Disc ussi o n of St u d y Desi g n  
T his is a m ultice nter, ra n d o mize d, d o u ble -bli n d , ve hicle -c o ntr olle d  P hase III st u d y t o e val uate 
t he effic ac y a n d safet y of T M B-0 0 1 0. 0 5 % t o pical oi nt me nt i n t he treat me nt of CI. S u bjects will 
be selecte d acc or di n g t o pre defi n e d e ntr y criteria. T he st u d y treat me nt d ur ati o n is 2 4 wee ks a n d 
e x pecte d t o b e s ufficie nt t o s h o w a treat me nt effect. 
Is otr eti n oi n is a n a p pr o ve d acti ve p har m ac ol o gical i n gre die nt wit h a l o n g hist or y of safe us e i n 
h u ma ns. H o we ver,  is otreti n oi n is a k n o w n terat o ge n wit h a n e xtre m el y hi g h ris k  f or se vere birt h 
defects if pre g na n c y oc c ur w hile ta ki n g oral is otr eti n oi n i n a n y a m o u nt, e ve n f or a s h ort peri o d 
of ti me . T heref ore oral, s yste mic  is otreti n oi n re q uires a n i P L E D G E pr o gra m (i P L E D G E 2 0 1 2), 
w hic h is a ris k ma na ge m e nt distri b uti o n pr o gra m ma n date d b y t he F D A . T o mi ni mize pre g na nc y 
ris ks, W O C B P will o nl y be e nr olle d if t he y a gree t o use hi g hl y effecti ve m et h o d s of 
c o ntrace pti o n c o nsiste ntl y a n d c orrectl y as des cri b e d i n Ta ble 1 8  a n d u n d er g o  re g ular pre g na n c y 
testi n g (Secti o n 8. 3. 5 ). 

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T o mi ni mize bias, s u bjects will be bli n de d a n d ra n d o ml y assi g ne d t o treat me nt wit h T M B -0 0 1 
0. 0 5 %  or  Ve hicl e  (Fi g ure 1 ), a d diti o nall y s u bjects w h o  ha d pre vi o usl y bee n treate d wit h 
T M B -0 0 1 will be e xcl u d e d fr o m t his st u d y  b ut ca n be e nr olle d i n t he o pti o nal Ma xi mal Use ar m 
(i n a s u bset of preselect e d ce nters). T he u se of a v e hicle c o ntr ol gr o u p is c o nsiste nt wit h F D A ’s 
sta n dar d f or ge nerati n g vali d scie ntific e vi de nce t o defi niti vel y s u p p ort safet y a n d  efficac y. T he 
ve hicle gr o u p  acc o u nts f or t he effects of tr eat me nt t hat d o n ot de pe n d o n t he  test treat me nt. T he 
st u d y is desi g ne d t o miti gate safet y ris ks b y usi n g a n i ni tial 2: 1 ra n d o mizati o n (acti ve  treat me nt 
t o ve hicle), al o n g wit h fre q ue nt cli nic visits  o ver t he 1 2 -wee k treat me nt peri o d. T he s u bse q ue nt 
1: 1 ra n d o mizati o n of eli gi ble T M B -0 0 1 0. 0 5 % treate d s u bjects t o t w o d osi n g re gi me n ( Q D or 
BI D) all o ws f or assessme nt o f t he o pti mal T M B -0 0 1 0. 0 5 % mai nte na nce t hera p y  as well as 
pr o vi des a d diti o nal safet y data f or 1 2 w ee ks. T h e cr oss -o ver of eli gi ble s u bjects fr o m t he ve hicl e 
c o ntr ol gr o u p will als o pr o vi de a d diti o nal safet y  d ata.    
O verall, t he st u d y desi g n is c o nsi dere d t o be sci e ntificall y r o b ust a n d cli nicall y rele va nt f or 
e val uati n g T M B -0 0 1 0. 0 5 % treat me nt f or t he safe a n d effecti ve tr eat me nt of CI.  
T he desi g n of t he O pti o n al Ma xi mal Use ar m is disc usse d i n Secti o n 9. 1. 1  
4. 3  J ustific ati o n f or D ose  
T he c o nce ntrati o n of T M B -0 0 1 0. 0 5 % o i nt me nt c h ose n f or t his st u d y is base d o n t he f or m ulati o n 
i nte grit y, t he safet y a n d efficac y data fr o m t he pri or P hase IIa a n d P hase IIb  cli nical st u d ies, 
s pecific la b orat or y a ni mal t o xic ol o g y st u dies perf or me d b y t he S p o ns or, a n d a re vie w of t he 
p u blis he d safet y data f or is otreti n oi n. T he d ose t o be a p plie d, T M B -0 0 1 0. 0 5 %, is base d o n t he 
p ote ntial f or t hera p e utic be nefit bala n ce d wit h  t he safet y ris k fr o m t he P has e IIb st u d y  
(Secti o n  2. 1 ). 
4. 4  E n d of St u d y Defi niti o n  
A s u bject is c o nsi dere d t o ha ve c o m plete d t h e st u d y if he/s he has c o m plete d t he last sc he d ule d 
visit ( Visit 6 f or s u bjects w h o  d o n ot q ualif y f or m ai nte na nce thera p y, Visit 9  f or s u bjects w h o 
q ualif y f or m ai nte na n ce thera p y ) p er t he S o A  (Ta ble  1 ). T he e n d of t he st u d y is defi ne d as t he 
date of t he last visit of t he last s u bject i n  t he st u d y. 
T he e n d of st u d y defi niti o n of t he O pti o nal Ma xi mal Use ar m is descri be d i n Secti o n 9. 1. 2 . 

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5  S T U D Y P O P U L A TI O N   
T he f oll o wi n g i ncl usi o n/e xcl usi o n criteria will be use d at V isit 1 (S cree ni n g ) a n d Visit  2 
(Baseli ne ) t o deter mi ne eli gi bilit y f or e ntr y i nt o t he P hase III st u d y a n d t he O pti o nal Ma xi mal 
Use ar m (Secti o n s 5. 1  a n d 5. 2 ).  
5. 1  I ncl usi o n Criteri a 
S u bjects m ust f ulfill all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or partici pati o n:  
1.  S u bject is male or fe male, 6 years of a ge a n d ol der at Visit 2 ( Baseli ne). 
2.  S u bject has pr o vi de d writte n i nf or me d c o nse nt/ass e nt. A s u bject u n der 1 8 y ears of a ge 
m ust pr o vi de writte n i nf or me d asse nt a n d b e acc o m pa nie d b y t he pare nt or le gal g uar dia n 
at t he ti me of c o nse nt/ass e nt si g ni n g. T he pare nt or le gal g uar di a n m ust pr o vi de i nf or me d 
c o nse nt f or t he s u bject. If a s u bject bec o m es 1 8 years of a g e d uri n g t he st u d y, t he s u bject 
m ust pr o vi de writte n i nf or me d c o nse nt at t hat ti me t o c o nti n ue st u d y partici pati o n.  
3.  Fe males m ust be p ost me n o pa usal ( defi n e d as a m e n orr hea great er t ha n 1 2 c o nsec uti ve 
m o nt hs i n w o me n 5 0 years of a ge a n d ol der), s ur gicall y sterile ( h ysterect o m y, bilateral 
sal pi n gect o m y, or bilateral o o p h orect o m y), or us e 2 acce pta ble f or ms of birt h c o ntr ol. 
W O C B P m ust ha ve  a ne gati ve ser u m pre g n a nc y t est at scree ni n g a n d ne g ati ve uri ne 
pre g na nc y t est ( U P T) at Visit  2 ( Baseli ne) ( U P Ts m ust ha ve a mi ni m u m se nsiti vit y t o 
detect 2 5  mI U bet a -h u ma n c h ori o nic g o na d otr o pi n [ β -h C G]/ m L). Met h o ds of acce pta ble 
c o ntrace pti o n are f urt he r defi ne d i n A p pe n di x  4 . Fe male s u bjects w h o  b ec o me se x uall y 
acti ve or be gi n t o ha v e relati o ns wit h a part ner d uri n g t he st u d y m ust a gree t o use 2 f or ms 
of birt h c o ntr ol f or 3 0  da ys pri or t o ha vi n g relati o ns a n d t o c o nti n ue s uc h f or ms of birt h 
c o ntr ol f or t he d urati o n of t he st u d y. 
4.  S u bject has cli nical dia g n osis of CI bas e d u p o n p he n ot y pe a n d has a ge netic c o nfir mati o n 
of eit her A R CI ( i ncl u di n g b ut n ot e xcl usi vel y  tra ns gl uta mi nase 1-defici e nt , A L O X-1 2 B ) 
or R X LI (e .g ., d eleti o n of ster oi d s ulfatase g e ne) s u bt y pes of CI. Ot her ge n eticall y 
c o nfir me d A R CI m utati o ns ca n p ote ntiall y be e nr olle d as l o n g as t he p he n ot y pe is 
c o nsiste nt wit h A R CI a n d t he ot he r i ncl usi o n criteria are met, as deter mi ne d b y t he 
I n v esti gat or (see A p pe n di x  5 ).  
5.  T he a m o u nt of CI affecte d s ki n i n t he Treat me nt Area at Baseli ne will be bet wee n a 
mi ni m u m of 1 0 % a n d ma xi m u m of 9 0 % of t he t otal B S A ( 1 % B S A is a p pr o xi matel y 
e q ual t o t he s urface area of t he s u bject’s pal m a n d fi n gers, wit h t he fi n gers e xte n de d yet 
gr o u pe d t o get her, creati n g a flat o val -li ke s urface area). 
•  
F or t he O pti o n al M a xi m al Use ar m:  T he a m o u nt of CI affecte d s ki n i n t he 
Treat me nt Area at Baseli ne will be bet wee n a mi ni m u m of 7 5 % a n d ma x i m u m of 
9 0 % of t he t otal B S A . 
6.  D oc u me nte d hist or y of m o derate t o se v ere dise ase at S cree ni n g. S u bject’s desi g nate d  
VII S A ssess me nt A reas at Baseli ne (n ot a p plic a ble f or O pti o n al M a xi m al Use ar m ) 
M U S T:  

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•  
I n cl u de a n y of t he 4 VII S A ssess me nt A reas t hat ha ve s o me CI diseas e i n v ol vi n g: 
(a ) t he u p per bac k fr o m t he p osteri or a xillar y f ol d t o t he ot her e nc o m passi n g t he 
T 1 -T 1 0, ( b ) t he u p p er ar m (e xcl u di n g el b o ws), left or ri g ht, (c) t he s hi n/l o wer le g 
(t he p orti o n bel o w t he pr o xi mal as pect of t he k n eeca p), left or ri g ht, a n d (d ) d orsal 
f o ot (left or ri g ht); A N D 
•  
At least 2 of t he 4 VII S A ssess me nt A reas M U S T ha ve a s cali n g sc ore of 3 or 
m ore.  
7.  S u bject’s I G A sc ore i n t h e Treat me nt Area at B aseli ne m ust be 3  or m ore . 
8.  S u bject a n d pare nt/ g uar dia n (if a p plica ble) are wil li n g a n d a ble t o a p pl y t he st u d y 
treat me nt(s) as directe d, c o m pl y wit h st u d y i nstr ucti o ns, a n d c o m mit t o all f oll o w-u p 
visits f or t he d urati o n of t he st u d y.  
9.  S u bject, i n t he I n v esti gat or’s o pi ni o n, is i n g o o d ge neral h ealt h a n d free of a n y disease 
state or p h ysical c o n diti o n t hat mi g ht i m pair e val uati o n of t he Treat me nt Areas or 
e x p oses t he s u bject t o a n u nacce pta ble ris k b y st u d y partici pati o n.  
5. 2  E xcl usi o n Criteri a  
A s u bject is i neli gi ble t o e nter t he st u d y if he/s he meets 1 or m ore of t h e f oll o wi n g e xcl usi o n  
criteria: 
1.  S u bject is pre g na nt, lactati n g, or is pla n ni n g t o bec o me pre g na nt d uri n g t he st u d y.  
2.  S u bject has i nfla m mat or y s ki n diseases t hat c o nf o u n d t he i nter pretati o n of res ults (e .g ., 
at o pic der matitis) u nrelat e d t o ic ht h y osis.  
3.  S u bject has  p he n ot y pic cli nical prese ntati o n a n d/ or  ge netic a b n or malit y c o nsiste nt wit h 
n o n -la mellar t y pe or s y n dr o mic ic ht h y oses (i ncl u di n g b ut n ot e xcl usi vel y K R T 1, K R T 1 0, 
K R T 2, GJ B 3, GJ B 4, C D S N ) 
4.  S u bject, i n t he Treat me nt Areas, h as use d: ( a ) a n y t o pical prescri pti o n or o v er -t he-c o u nter 
( O T C) t hera pi es (e x ce pt e m ollie nts, kerat ol ytics, a n d t o pical ster oi ds –  see bel o w), t hat 
are i nte n de d f or, or t h at i n t he o pi ni o n of t he I n vesti gat or, ma y i m pr o ve CI wit hi n 2 
wee ks of Visit 2 ( Baseli n e), or ( b ) kerat ol ytics or t o pical c ortic oster oi ds wit hi n 5 da ys 
pri or t o Visit 2 ( Baseli ne).  
5.  S u bject, i n t he Treat me nt  Areas, h as use d T M B -0 0 1 i n t he past or oral is otreti n oi n i n t he 
past 1 2 m o nt hs ( n ot a p plic a ble f or O pti o n al M a xi m al Use ar m ). 
6.  S u bject has use d a n y t o pi cal pr o d ucts i n t he Treat me nt Areas, i ncl u di n g bl a n d e m ollie nts, 
o n Visit 2 ( Baseli ne).  
7.  S u bject has use d ultra vi olet ( U V) treat me nt wit hi n 4 wee ks pri or t o Visit  2 ( Baseli ne).  
8.  S u bject has u n der g o ne s yste mic t hera pies usi n g vita mi n A s u p ple me nts or St. J o h n’s 
W or t wit hi n 4 wee ks pri or t o Visit 2 ( Baseli ne). N ote: Use of a m ultivit a mi n i ncl u di n g 
vit a mi n A is n ot excl usi o n ary pr ovi de d it is t ake n as directe d o n t he p ack a gi n g. 

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9.  S u bject is i m m u n os u p presse d (e. g., h u ma n i m m u n o deficie nc y vir us, s yste mic 
mali g na nc y, graft  h ost disease) or recei ves s yste mic i m m u n ot hera p y.  
1 0.  S u bject is c urre ntl y ta ki n g c o nc o mita nt i m m u n os u p pressi ve dr u gs, i ncl u di n g s yste mic 
c ortic oster oi ds, wit hi n 2 wee ks of Visit 2 ( Baseli n e).  
1 1.  S u bject has u ntreate d s ec o n dar y i nfecti o ns; h o we ver, s u bject ma y b ec o me eli gi ble after 
s uccessf ul treat me nt of his/ her i nfecti o n(s) at t he I n vesti gat or’s discreti o n.  
1 2.  S u bject is c urre ntl y e nr olle d i n a n i n vesti gati o nal dr u g or de vice st u d y or has use d a n 
i n vesti gati o nal dr u g or i n vesti gati o nal de vice treat me nt wit hi n 3 0 da ys or fi ve half -li ves 
pri or t o Visit  2 ( Baseli ne).  
1 3.  S u bject has lesi o ns s us pici o us f or s ki n ca n cer ( if s ki n ca ncer is n ot r ule d o ut b y bi o ps y) , a 
k n o w n pers o nal or i m me diate fa mil y hist or y of s q ua m o us cell carci n o ma of t he s ki n or 
mela n o ma  or u ntreate d s ki n ca ncers wit hi n t he Treat me n t Areas. 
1 4.  S u bject has a p h ysical c o n diti o n or ot her der mat ol o gic dis or der t hat, i n t he I n v esti gat or’s 
o pi ni o n, mi g ht i m pair e val uati o n of CI, or t hat e x p oses t he s u bject t o u nacce pta ble ris k 
b y st u d y partici pati o n.  
1 5.  S u bjects wit h  A L T or A S T > 2  x  U p per  Li mit of N or mal ( U L N) a n d / or creati ni ne 
> 1. 5  x  U L N.  
1 6.  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 v esti gat or d ue t o la n g ua ge 
pr o ble ms, i m paire d cere bral f u ncti o n, or p h ysical li mitati o ns.  
1 7.  S u bject has a hist or y of dr u g or alc o h ol a b us e wit hi n t he past 6  m o nt hs, or if s us pecte d t o 
be n o nc o m plia nt or is u nli kel y t o c o m pl y wit h t he re q uire me nts of t h e st u d y pr ot oc ol 
(e. g., d ue t o alc o h olis m, dr u g de pe n de nc y, me ntal i nca pacit y) i n t he o pi ni o n of t he 
I n v esti gat or. 
1 8.  S u bject has a hist or y of s e nsiti vit y t o a n y of t he i n gre die nts i n t he st u d y treat me nts.  
5. 3  Scree n F ail ures  
Scree n fail ures are defi ne d as s u bjects  w h o  c o nse nt t o partici pate i n eit her t he P hase III st u d y or 
t he O pti o nal Ma xi mal Use ar m b ut d o  n ot  meet t he eli gi bilit y crite ria. A mi ni mal set of scree n 
fail ure i nf or m ati o n is re q uire d t o e ns ure tr a ns pare nt re p orti n g of scree n fail ure s u bjects t o meet 
t he C o ns oli date d Sta n dar ds of Re p orti n g Trials ( C O N S O R T) p u blis hi n g re q uire me nts a n d t o 
res p o n d t o q ueries fr o m r e g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, 
eli gi bilit y criteria, a n d a n y S A E will be c ollecte d a n d rec or de d i n t he electr o nic data ca pt ure 
s yste m. 
I n di vi d uals w h o d o n ot meet t he criteri a f or p arti ci pati o n i n t he st u dies (scree n fail ure) m a y be 
rescree ne d f or t he f oll o wi n g circ u msta nces: 
•  S u bjects w h o fail t o c o m plete t heir was h o ut i n ti me f or t heir s c he d ule d Visit 2 ( Baseli ne) 
ca n be all o we d t o c o nti n ue t he was h o ut a n d V isit 2 ma y be res c he d ule d.  

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•  S u bject s w h o  ha ve a cli nicall y n o n -si g nifica nt o ut-of -ra n g e la b orat or y res ult ma y be 
rescree ne d o n e  ti me. 
A n y s u bject w h o is rescree ne d is r e q uire d t o ha ve a ne w i nf or m e d c o nse nt f or m (I C F)/asse nt. 

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6  S T U D Y T R E A T M E N T  
6. 1  St u d y Tre at me nt(s) A d mi nistere d  
6. 1. 1  Tre at me nt Are a  
T he  Treat me nt Area  f or eac h s u bject is defi n e d as t he area of t he e ntire b o d y wit h acti ve CI 
w here t he st u d y me di cati o n will be a p plie d (t he e ntire b o d y [e xce pt f or t he ha n ds, face, nec k, 
scal p, i n ner t hi g hs near ge nitalia a n d ge nitalia] are p ossi ble treat me nt areas) .  
6. 1. 2  Tre a t me nt A d mi nistr ati o n 
Treat me nts a d mi nistere d d uri n g t he P hase III st u d y, i ncl u di n g fre q ue n cies a n d d urati o ns are 
prese nte d  b el o w  i n Ta ble 5 . St u d y me dicati o n  will be a p plie d t o u p t o 9 0 % of t he B S A.  Pri or t o 
ra n d o mizati o n, t he l ocati o n of t he CI t o be treate d a n d t he perce nt B S A wit h CI i n t he Treat me nt 
Area (see Secti o n 8. 2. 3 ) will be rec or de d.  
6. 1. 2. 1  M a xi m u m D ail y D ose  
T he a p pr o xi mate m a xi m u m dail y d oses e x pecte d are o utli ne d bel o w i n T a ble 4. As st u d y 
me dicati o n ca n be a p plie d t o u p t o 9 0 % B S A t wice dail y, t hese para meters were calc ulat e d t o 
esti mate t he ma xi mu m dail y d oses i n pe d iatric a n d a d ult  s u bjects. 
T a ble 4  M a xi m u m D ail y D ose  
  
H ei g ht  
W ei g ht  
B S A i n m 2  
9 0 % B S A  
A m o u nt of 
Is otr eti n oi n 
a p pli e d d aily 
( T M B-0 0 1 
0. 0 5 % at BI D 
d osi n g)  
A m o u nt of 
dr u g/ m 2 
a p pli e d d aily 
wit h BI D 
d osi n g  
A v er a g e 6 
y e ar ol d 
1 1 0c m  
2 0. 3k g  
0. 7 7 9 9 m 2 
0. 7 0 1 9 m 2 
0. 0 1 3 g a d ay  
0. 0 1 9 g/ m 2 
A v er a g e 
a d ult m al e  
1 7 9c m  
7 1. 9k g  
1. 9 0 0 2 m 2 
1. 7 1 0 1 m 2 
0. 0 3 4 g a d ay  
0. 0 2 0 g/ m 2 
 
 
 
 
 
 
 
Treat me nt a d mi nistrati o n s pecific t o t he O pti o nal Ma xi mal Use ar m is descri be d i n Secti o n 9. 2 . 

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gr o u p, stratifie d b y a g e, a n d CI s u b -t y pe. At  Wee k 1 2, eli gi ble s u bjects i n t he T M B -0 0 1 0. 0 5 %  
treat me nt gr o u p will be ra n d o mize d (1: 1 r ati o ) t o eit her T M B-0 0 1 0. 0 5 % Q D or BI D 
mai nte na nce tr eat me nt (Fi g ure 1 ).  
All s u bjects will be ce ntr all y assi g ne d t o ra n d o mize d st u d y treat me nt usi n g a n I nteracti ve We b 
Res p o nse S yste m (I W R S). Bef ore t h e st u d y is i nitiate d, t he l o g i n i nf or mati o n a n d directi o ns f or 
t he I W R S will be pr o vi de d t o eac h st u d y ce nter.  
T he O pti o nal Ma xi mal Use ar m is o pe n -la bel a n d d oes n ot re q uire ra n d o mi zati o n. 
6. 3. 1  Bli n di n g  a n d U n bli n di n g  
I n t he d o u ble -bli n d I n d ucti o n a n d Treat me nt Peri o d ( St u d y Peri o ds 1 a n d 2) of t he st u d y, all 
pers o n ne l i n v ol ve d, i.e., p h ysicia ns, site staff, partici pa nts a n d S p o ns or will re mai n bli n de d at all 
ti mes, e xce pt i n a n e mer ge nc y, w here k n o wl e d ge of t he ra n d o mizati o n c o d e is re q uire d t o 
pr o vi de a p pr o priate treat me nt. I n case of a n e m er ge nc y, t he I n v esti gat or h as t he s ole 
res p o nsi bilit y f or deter mi ni n g if u n bli n di n g of a s u bject’s treat me nt assi g n me nt is warra nt e d. 
S u bject safet y m ust al wa ys be t he first c o nsi derati o n i n ma ki n g s uc h a deter mi nati o n.  
If t he I n vesti gat or d eci des t hat u n bli n di n g is warra nte d, e very eff ort s h o ul d be ma de t o c o ntact 
t he S p o ns or a n d Me dical M o nit or pri or t o u n bli n di n g a s u bject’s treat me nt assi g n me nt u nless 
t his c o ul d dela y e mer g e n c y treat me nt of t h e s u bject. If a s u bject’s treat me nt assi g n me nt is 
u n bli n de d, t he S p o ns or m ust be n otifi e d wit hi n 2 4 h o urs after brea ki n g t he bli n d. T he date a n d 
reas o n t hat t he bli n d was br o ke n m ust be rec or de d i n t he s o urce d oc u m e ntati o n a n d electr o nic 
Case Re p ort F or m (e C R F), as a p plica ble.  
6. 4  St u d y Tre at me nt C o m pli a nce  
T he prescri be d d osa g e, ti mi n g, a n d m o d e of a d mi nistrati o n ma y n ot be c ha n ge d, e xce pt as 
defi ne d i n Secti o n 7. 1 . A n y de part ures fr o m t he i nte n de d re gi me n m ust be rec or de d i n t he e C R F. 
D uri n g t he c o u rs e of t he st u d y, c o m plia nce t o st u d y dr u g a p plicati o n will be e val uat e d via 
S u bject e Diaries a n d acc o u nta bilit y b y t he site. S u bjects e x hi biti n g p o or c o m plia nce s h o ul d be 
c o u nsele d o n t he i m p orta nce of g o o d c o m plia nce t o t he st u d y d osi n g re gi me n.  
6. 5  C o nc o mi t a nt T her a p y 
Pr o hi bite d me dicati o n a n d treat me nts i ncl u di n g t he was h o ut peri o ds are s u m marize d i n Ta ble 7 . 
•  N o n -petr olat u m  bla n d e m ollie nts a a n d O T C l o w p ote nc y h y dr oc ortis o ne (e. g., 1 % crea m) 
ma y o nl y be use d i n t he e ve nt of se vere disc o mf ort (e. g., b ur ni n g/er yt he m a/itc h) (aft er 
Wee k 3  i n t he P hase III st u d y a n d d uri n g t he e ntire ti me i n t he O pti o nal Ma xi mal Use 
ar m) a n d if it is t he o pi ni o n of t he I n vesti gat or t hat a dr u g i nterr u pti o n ( per Secti o n 7. 1 ) 
 
a S u bjects e nr olle d i n t he st u d y will use ma n dat or y bla n d e m ollie nts d uri n g t he I n d ucti o n Peri o d ( 1 -3 wee ks). After 
t he I n d ucti o n Peri o d, bla n d e m ollie nts will be pr o hi bite d f or t hese s u bjects u ntil t he E O S visit. S u bjects e nr olle d i nt o 
t he O pti o nal Ma xi mal Use ar m s h o ul d disc o nti n ue t he use of bla n d e m ollie nts at Visit 2 ( Baseli ne).  

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visit sc he d ule a n d ascertai n w het her t he s u bject wis hes t o a n d/ or s h o ul d c o nti n ue i n t he 
st u d y. 
•  Bef ore a s u bj ect is dee m e d l ost t o f oll o w-u p, t he I n vesti gat or or desi g ne e m ust ma ke 
e ver y eff ort t o r e gai n c o ntact wit h t he s u bject ( w h ere p ossi ble, 3 tele p h o ne calls a n d, if 
necessar y, a certifie d lett er t o t he s u bject’s last k n o w n maili n g a d dress or l ocal e q ui vale nt 
met h o ds). T hese c o nt a ct atte m pts s h o ul d be d oc u me nte d i n t he s u bject’s me dical rec or d.  
•  If t he s u bject c o nti n ues t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y a n d l ost t o f oll o w-u p.  
7. 4  Pre g n a nc y  
A n y fe male s u bject w h o bec o mes pre g na nt d uri n g t he st u d y m ust disc o nti n ue treat me nt. If a 
pre g na nc y is r e p orte d, t h e I n vesti gat or s h o ul d i nf or m t he S p o ns or wit hi n 2 4 h o urs of lear ni n g of 
t he pre g na n c y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n Secti o n 8. 4. 3  a n d A p pe n di x  4 . 
 
 

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8  S T U D Y  A S S E S S M E N T S  A N D P R O C E D U R E S  
St u d y pr oce d ures a n d t heir ti mi n g f or b ot h t he st u d y a n d t he O pti o nal Ma xi m al Use ar m are 
s u m marize d i n t he S o A  (Ta ble  1  a n d T a b le 1 3 ). A d here nce t o t he st u d y desi g n re q uire me nts, 
i ncl u di n g t h ose s pecifie d i n t he S o A , is esse ntial a n d re q uire d f or st u d y c o n d uct.  
All scree ni n g e v al uati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial s u bjects 
meet all eli gi bilit y criteria. T he I n v esti gat or will mai ntai n  a scree ni n g l o g t o rec or d t he d etails of  
all s u bjects scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or scree ni n g fail ure, as 
a p plica ble.  
Pr ot oc ol wai vers will n ot be c o nsi dere d f or t his st u d y a n d assess me nts/ pr oce d ures n ot c o m plete d 
as per pr ot oc ol will be rec or de d as d e viati o ns.  Ac ute  safet y c o ncer ns s h o ul d be disc usse d wit h 
t he S p o ns or i m me diatel y u p o n occ urre nce or a ware ness t o deter mi ne if t h e s u bject s h o ul d 
c o nti n ue or disc o nti n ue st u d y treat me nt.  
8. 1  Ge ner al St u d y Assess me nts  
8. 1. 1  I nf or me d C o nse nt/ Asse nt  
A c o m plete descri pti o n of t he st u d y will  be prese nte d t o t he  s u bject or pare nt/le gal g uar dia n of 
eac h p ote ntial s u bject (f or s u bjects a ge d < 1 8 years)  a n d si g ne d a n d d ate d. I nf or me d c o ns e nt will  
be o btai ne d bef ore a n y st u d y -s pecific pr oce d ures are perf or m e d. T he det aile d i nf or me d c o ns e nt 
pr ocess is descri be d i n A p pe n di x  1 .  
8. 1. 2  Ge netic Testi n g  
T o be eli gi ble f or t he st u d y, s u bjects m ust ha ve m o derate t o se v ere CI t h at has bee n ge n eticall y 
c o nfir me d t o be of eit her t he A R CI or R X LI s u bt y pe. F or A R CI s u bjects, e nr oll me nt is n ot 
li mite d t o tra ns gl uta mi nase 1 m utati o ns. Ot her ge neticall y c o nfir me d A R CI- m utati o ns wit h a 
la mellar p he n ot y pe ca n p ote ntiall y be e nr olle d (A p pe n di x  5 ) as l o n g as t he p he n ot y pe is 
c o nsiste nt wit h A R CI a n d t he ot her i ncl usi o n criteria are met, as deter mi ne d b y t he I n vesti gat or .  
Ge netic testi n g/c o nfir mati o n will be perf or me d at t he ti me p oi nts desi g nate d i n t he S o A (Ta ble  1  
a n d Ta b le 1 3 ).  
S u bjects  w h o alrea d y h a ve ha d a g e netic test d oc u me nti n g A R CI or R X LI t y pes of CI will n ot be 
re q uire d t o pr o vi de s a m ples f or ge netic t esti n g. H o we ver, t he s u bj ect m ust pr o vi de t he 
I n v esti gat or wit h a c o p y of t he ge netic re p ort f or t he s o urce d o c u me ntati o n file. 
S u bjects re q uiri n g ge neti c test c o nfir mati o n will ha ve t he testi n g perf or me d b y a n i n de pe n de nt 
la b orat or y after t he I n vesti gat or or desi g nee h as deter mi ne d t he y are li kel y t o be ot her wise 
eli gi ble f or e nr oll me nt . G e netic testi n g will c o nsist of a b uccal s wa b t hat is se nt t o o ne of t w o 
ce ntral la b orat ories de pe n di n g o n t he s u bject’s ge o gra p hic l ocati o n ( N ort h A merica  vs E ur o pe ). 
T he s wa b ca n eit her be o btai ne d at t he cli nical s ite or b y t he s u bject at h o m e. I nstr ucti o ns o n h o w 
t o c o m plete t he s wa b are i ncl u de d i n t he kit. T he test will o nl y re p ort o n ge nes ass ociate d wit h 
CI a n d res ults will be se nt directl y t o t he I n vesti gat or.  

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8. 3  S afet y Assess me nts  
8. 3. 1  P h ysic al E x a mi n ati o n  
A  p h ysical e xa mi nati o n will be perf or me d at t he ti me p oi nts desi g nate d i n t he S o A  (Ta ble  1  a n d 
Ta b le 1 3 ), i ncl u di n g hea d a n d nec k, d er mat ol o gical, car di o vas c ular, res pir at or y, gastr oi ntesti nal 
(a b d o me n), a n d gr oss m ot or a n d gait b o d y assess me nts.  
A b n or malities at Visit  1 ( Scree ni n g) a n d Visit  2 ( Baseli ne) pri or t o treat me nt will be rec or de d as 
me dical hist or y. A n y ne w or w orse ni n g a b n or malities at Visit 6 a n d/ or Visit 9 ( E O S) i n t he st u d y 
or at Visit 8  ( E O S) i n t he O pti o nal Ma xi mal Use ar m will be rec or de d as A Es.  
If t here are less t ha n t w o weeks bet w ee n Visit 1 ( S cree ni n g) a n d Visit 2 ( Baseli ne), t he p h ysical 
e xa mi nati o n at t he Visit 2 ( Baseli ne) i ncl u des o nl y a der mat ol o gical assess me nt.   
8. 3. 2  Vit al Si g ns  
Vital si g ns i ncl u di n g te m perat ur e, s yst olic a n d diast olic bl o o d press ure, heart rate, a n d 
res pirati o n rat e will be meas ure d at t he ti me p oi nts desi g nate d i n t he S o A  (Ta ble  1  a n d T a b le 1 3 ). 
Assess me nts will be ma de after t he s u bject has reste d i n a seate d p ositi o n f or at least 5  mi n utes i n 
a q uiet setti n g wit h o ut distracti o ns (e .g ., tele visi o n, cell p h o nes). Hei g ht a n d wei g ht will o nl y be 
mea s ure d at Visit 1  (Scree ni n g ). 
8. 3. 3  L oc al S ki n Re acti o ns  a n d E v al u ati o n of Aller gic C o nt act Der m atitis  
At t he ti me p oi nts desi g nate d i n t he S o A  (Ta ble  1  a n d Ta b le 1 3 , t he I n vesti gat or or desi g ne e will 
e val uate L S Rs k n o w n t o be ass ociate d wit h reti n oi ds ( b ur ni n g/sti n gi n g, er yt he ma, er osi o ns, a n d 
e de ma) or ot her ca uses r e gar dless of bli n de d ca usalit y assess me nt wit hi n t he areas treate d wit h 
st u d y me dicati o n usi n g a 4-p oi nt or di nal scale w h ere 0  =  n o n e, 1  =  mil d, 2  =  m o derate, a n d 
3  =  se vere.  
N ote: At Visit 2 ( B aseli ne), t he L S R assess me nt m ust be perf or me d pri or t o t he a p plic ati o n of t he 
st u dy me dic ati o n.  
F or dr u g i nterr u pti o n d ue t o L S Rs, refer t o str uct ur e d dr u g i nterr u pti o n sc h e me ( dr u g re d u cti o n) 
descri be d i n Secti o n 7. 1 . 
Aller gic c o nta ct der matitis is defi ne d as  a der matitis t hat lasts at least 2 wee ks, d oes n ot be gi n 
i m me diatel y after dr u g a p plicati o n  (f or e x a m ple, reacti o n be gi ns after first  2 4 h o urs of dr u g  
a p plicati o n ) a n d bec o mes  ecze mat o u s o ver ti me. 
If at a n y p oi nt d uri n g treat me nt t he I n vesti gat or b elie ves t hat t he s u bject is e x perie n ci n g a n 
aller gic c o nta ct der matitis, t he s u bject s h o ul d u n der g o i n vesti gat or directe d patc h testi n g. as 
defi ne d i n A p pe n di x  1 1 . 
8. 3. 4  Cli nic al S afet y L a b or at or y Assess m e nts  
Uri ne a n d bl o o d sa m ples will be c ollecte d fr o m eac h s u bject f or s afet y la b orat or y a n al yses at t he 
ti me p oi nts desi g nate d i n t he S o A  (Ta ble  1  a n d T a b le 1 3 ).  

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S u bjects m ust be fasti n g (at least 8 h o urs) f or Visit 1 ( Scree ni n g) a n d, if p ossi ble, f or Visit 6 a n d 
t he E O S visit; h o we ver, if a s u bject arri ves at t he cli nic f or t he E O S visit wit h o ut fasti n g f or at 
least 8 h o urs, la b orat or y s peci me ns ma y be c ollecte d as n o n -fasti n g, at t he discreti o n of t he 
I n v esti gat or, a n d wit h t he a p pr o priate fasti n g stat us d oc u me nte d o n t he la b orat or y re q uisiti o n 
f or m.  
See A p pe n di x  2  f or t h e list of cli nical la b orat or y t ests t o be perf or me d. 
8. 3. 5  Pre g n a nc y Testi n g  
Ser u m h C G pre g na n c y test s a n d U P T will be perf or me d at t he ti me p oi nts desi g nated i n t he S o A  
(Ta ble  1  a n d T a b le 1 3 ) f or W O C B P. W o me n w h o are pre g na nt or breastf ee di n g ma y n ot be 
a d mi nistere d T M B -0 0 1 o i nt me nt. 
Detaile d i nf or mati o n o n pre g na nc y re p orti n g is prese nte d i n A p pe n di x  4 .  
8. 4  A d verse E ve nts  
All A Es will be rec or de d. At eac h p ost -b aseli ne v isit, s u bjects will als o be q uesti o ne d 
s pecificall y a b o ut t he stat us of a n y o n g oi n g A Es. 
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n  A p pe n di x  3 . 
A E s will be re p orte d b y t he s u bject ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or t h e 
s u bject’s le gall y a ut h orize d re prese ntati ve). 
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es. O pe n -e n d e d a n d 
n o n -lea di n g ver b al q uesti o ni n g of t he s u bject is t he preferre d met h o d t o i n q uire a b o ut 
A E  occ urre nces.  
T he I n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g 
e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g u p A Es 
t hat are seri o us, c o nsi dere d relate d t o t he st u d y m e dicati o n or st u d y pr oce d ures, or t hat ca use d 
t he s u bject t o disc o nti n ue t he st u d y. T he trial bli n d ma y be br o ke n f or a n i n di vi d ual o nl y if 
k n o wle d ge of t he i n vesti gati o nal me dici nal pr o d u ct is esse ntial f or cli nical ma na ge me nt of t he 
s u bject.  
8. 4. 1  Ti m e Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt a n d Seri o us A d verse 
E ve nt I nf or m ati o n  
All A Es a n d S A Es will be c ollecte d fr o m si g ni n g t he I C F u ntil t he E O S v isit at t he ti me p oi nts 
s pecifie d i n t he S o A (T a ble  1  a n d Ta b le 1 3 ). 
All S A Es will be rec or de d a n d re p ort e d t o t he S p o ns or  or desi g nee wit hi n 2 4 h o urs, as i n dicate d 
i n A p pe n di x  3 . T he I n vesti gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or wit hi n 
2 4  h o urs of it bei n g a vail a ble.   
After t he i nitial A E/ S A E re p ort , t he I n v esti gat or is re q uire d t o pr o acti vel y f oll o w eac h s u bject at 
s u bse q ue nt visits/c o ntacts. All S A Es will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt is 

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ot her wise e x plai n e d, or t he s u bject is l ost t o f oll o w -u p (as d efi ne d i n Secti o n  7. 3 ). F urt her 
i nf or mati o n o n f oll o w-u p pr oce d ures is gi ve n i n  A p pe n di x  3 . 
I n v esti gat ors are n ot o bli gate d t o acti vel y se e k A E or S A E i nf or mati o n after t he c o ncl usi o n of 
st u d y partici pati o n. H o w e ver, if t he I n vesti gat or l ear ns of a n y S A E, i ncl u di n g a deat h, at a n y 
ti me after a s u bject has b ee n disc har ge d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be 
reas o na bl y r elate d t o t he st u d y me dicati o n or st u d y partici pati o n, t he I n vesti gat or m ust pr o m ptl y 
n otif y t he S p o ns or. 
T he met h o ds of rec or di n g, e val uati n g, a n d ass ess i n g t he ca usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n  A p pe n di x  3 . 
8. 4. 2  Re g ul at or y Re p orti n g Re q uire me nts f o r Seri o us A d verse E ve nts  
Pr o m pt n otificati o n b y t he I n vesti gat or t o t he S p o ns or of a n S A E is esse nti al s o t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of s u bjects a n d t he safet y of a st u d y 
treat me nt u n der cli nical i n vesti gati o n are met.  
T he S p o ns or has a  le g al r es p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a g e ncies a b o ut t he safet y of a st u d y tr eat me nt u n der cli nical i n v esti gati o n. T he 
S p o ns or will c o m pl y wit h c o u ntr y -s pecific re g ul at or y re q uire me nts relati n g t o safet y re p orti n g t o 
t he re g ulat or y a ut h orit y, I nstit uti o nal Re vie w B oar ds (I R Bs)/I n de pe n d e nt Et hics C o m mittees 
(I E Cs), a n d I n v esti gat ors. 
I n v esti gat or safet y re p orts m ust be pre pare d f or s us pecte d u ne x p ecte d s eri o us a d verse reacti o ns 
( S U S A Rs) acc or di n g t o l ocal reg ulat or y re q uir e m e nts a n d t he S p o ns or’s p olic y a n d f or war de d t o 
t he I n v esti gat ors as necessar y. 
A n I n vesti gat or w h o recei ves a n I n vesti gat or safet y re p ort descri bi n g a n S A E or ot her s pecific 
safet y i nf or mati o n ( e.g ., s u m mar y or listi n g of S A Es) fr o m t he S po ns or will re vie w a n d t he n file 
it al o n g wit h t he I n vesti g at or’s Br oc h ure a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o 
l ocal re q uir e me nts. 
8. 4. 3  Pre g n a nc y  
A n  U P T will be perf or m e d at t he ti me p oi nts desi g nate d i n t he S o A  (Ta ble  1  a n d Ta b le 1 3 ) f or 
W O C B P. W o me n w h o are pre g na nt or breastfee di n g ma y n ot be a d mi nistere d T M B -0 0 1 
o i nt me nt. 
If a pre g na nc y is r e p orte d, t he I n v esti gat or s h o ul d i nf or m t he S p o ns or wit hi n 2 4 h o urs of 
lear ni n g of t he pre g na n c y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x  4 . 
A b n or mal pre g n a nc y o ut c o mes (e .g ., s p o nta n e o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g n a nc y) are c o nsi de re d S A Es. 
8. 5  Tre at me nt of O ver d ose  
O ver d ose i n t his st u d y ca n be defi ne d as eit her oral i n gesti o n of a t u be of T M B -0 0 1 or a p pl yi n g 
t he T M B-0 0 1 oi nt me nt m ore ofte n t ha n t he pr ot oc ol s pecifie d re gi me n of t wice dail y. 

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Oral i n gesti o n of a n 8 0 -gra m  t u be of T M B-0 0 1  o i nt me nt 0.0 5 % is calc ulat e d t o res ult i n less 
e x p os ure t ha n ac hie v e d wit h t he rec o m me n de d d osa ge of oral is otreti n oi n  ( 8 0 m g/ da y). 
C o nse q ue ntl y, t he t he oretical occ urre nce of s y m pt o ms of o ver d osa ge (e .g ., h y per vita mi n osis A) 
is hi g hl y u nli kel y. 
If a s u bject d o es recei ve a n o ver d ose of T M B-0 0 1 o i nt me nt, t he s u bject s h o ul d be c o u nsele d 
a b o ut t he terat o ge ni cit y of is otreti n oi n a n d c o u nsel e d o n t he pre v e nti o n of pre g na nc y. A n y 
W O C B P m ust be e val uate d f or pre g na nc y a n d m ust be war ne d t o a v oi d pre g na nc y per t h e 
c o ntrace pti ve meas ur es o utli ne d i n A p pe n di x  4  f or at least 1 m o nt h after o ver d ose. Me n s h o ul d 
use a c o n d o m or a v oi d re pr o d ucti ve se x ual  acti vit y wit h a fe male w h o is or mi g ht bec o me 
pre g na nt f or at least 1  m o nt h after a n o v er d ose. S u bjects  w h o  pres e nt wit h a n o ver d ose s h o ul d 
n ot d o nate bl o o d f or at least 1  m o nt h.  
I n t he e ve nt of a n o ver d ose, t he I n vesti gat or s h o ul d: 
1.  C o ntact t he Me dical M o nit or i m me diatel y.  
2.  Cl osel y m o nit or t he s u bject f or a n y A Es, S A Es, a n d la b orat or y a b n or malities f or 1  m o nt h 
after t he o v er d ose.  
3.  O btai n a plas ma sa m ple f or P K  a nal ysis if re q u este d b y t he Me dical M o nit or ( deter mi ne d 
o n a case -b y -case b asis).  
4.  D oc u me nt t he q ua ntit y of t he e xcess d ose as w ell as t he d urati o n of t he o ver d ose i n t he 
e C R F. 
Decisi o ns re g ar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he I n vesti gat or i n 
c o ns ultati o n wit h t he Me dical M o nit or base d o n t he cli nical e val u ati o n of t h e s u bject.  
 
 

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9  O P TI O N A L M A XI M A L  U S E A R M  
9. 1  St u d y Desi g n  
T he ai m of t he o pe n -la bel O pti o nal Ma xi m al Use ar m is t o e val uate t he s yste mic e x p os ure a n d 
safet y of t o pical T M B-0 0 1 0. 0 5 % oi nt me nt f or t he treat me nt of R X LI or A R CI  u n der c o n diti o ns 
of ma xi mal use i n a d ult a n d pe diatric s u bjects.  
T his st u d y ar m will use a sta g gere d e ntr y ( Fi g ure 2 ):  
1.  A d ult CI s u bjects (≥1 7  y ear s; n = 1 6) a n d pe diatric CI s u bject s (a ge d 1 2 -1 6 years; n = 7 -9)  
recei v e T M B -0 0 1 0. 0 5 %  BI D  f or 1 4 da ys. 
2.  Interi m a nal ysis of P K para meters f or s u bjects a g e d 1 2 years t o a d ult  are o btai ne d o ver 
t he 1 5-da y peri o d.   
3.  Base d o n t he e x p os ur e data of s u bjects  a ge d 1 2 y ears t o a d ult, pe diatric s u bjects (a ge d 6 -
1 1 years; n = 7 -9) will be e nr olle d a n d recei ve T M B -0 0 1 0. 0 5 % BI D f or 1 4 da ys.  
4.  F oll o wi n g t he c o m pleti o n of t he 1 4 -da y P K peri o d , s u bjects will recei ve a n a d diti o nal 
1 0  wee ks of o p e n -la b el T M B-0 0 1 0. 0 5 % BI D.  
A b bre viati o ns: A R CI = A ut os o mal R ecessi ve C o n ge nital Ic ht h y osis; BI D = T wice D ail y; B S A = B o d y S urface 
Area; CI = C o n ge nital Ic ht h y osis; P K = P har mac o ki netic; R X LI = Recessi ve X -li n ke d Ic ht h y osis 
S u bjects at t he e n d of t he st u d y or s u bjects disc o nti n ue d fr o m t he st u d y at a n y ti me will be 
f oll o we d-u p f or a d diti o nal 2 wee ks f or A Es.   
9. 1. 1  Disc ussi o n of St u d y Desi g n   
S u bjects will be e nr olle d acc or di n g t o st u d y eli gi bilit y criteria (Secti o ns 5. 1  a n d 5. 2 ). T he st u d y 
treat me nt d urati o n f or P K sa m pli n g is 1 4 da ys  w hic h is e x pecte d t o be s ufficie nt f or dr u g 
acc u m ulati o n t o occ ur.  S u bjects will t he n be pr o vi de d o pe n -la bel T M B-0 0 1 0. 0 5 % oi nt me nt BI D 
u p t o Wee k 1 2. O n e a d diti o nal P K sa m ple will be ac q uire d at c o m pleti o n of t he st u d y t o c hec k 
f or mainte na n ce of stea d y state p har mac o ki netics.  
Fi g ure 2  
O pti o n al M a xi m al Use Ar m Sc he m a  

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T he O pti o nal Ma xi mal Use ar m will e nr oll s u bjects wit h CI (i nstea d of healt h y v ol u nteers) as 
t here are p h ysi ol o gical differe nces b et wee n diseas e d a n d healt h y s ki n. H o we ver, t he P K d ata 
fr o m t his st u d y will be c o m pare d wit h  oral is otreti n oi n (si n gle d ose of 8 0 m g) e x p os ure d ata i n 
healt h y s u bjects fr o m  ot h er st u dies .  
A p plicati o n of t he T M B -0 0 1 0. 0 5 % oi nt me nt t o 7 5 % -9 0 % of t he B S A all o ws f or a lar ge a m o u nt 
of st u d y treat me nt t o be a p plie d a n d is m ore i n li ne wit h h o w T M B -0 0 1 0. 0 5 % oi nt me nt ma y be 
use d i n cli nical practice.  
T he st u d y is desi g ne d t o miti gate safet y ris ks  f or p e diatric s u bjects b y c o n d ucti n g a n i nteri m P K 
a nal ysis after treat me nt of s u bjects a ge d 1 2 y ears t o a d ult wit h BI D T M B -0 0 1 0. 0 5 % oi nt me nt 
f or 1 4 da ys. S u bse q ue nt e nr oll me nt of pe diatric s u bjects (a ge d 6 -1 1 years) will be base d o n 
e x p os ure dat a of s u bjects a ge d 1 2 years t o a d ult.   
9. 1. 2  E n d of St u d y Defi niti o n  
A s u bject is c o nsi dere d t o ha ve c o m plete d t h e st u d y if he/s he has c o m plete d t he last sc he d ule d 
visit ( Visit  8 , Ta b le 1 3 ). T he e n d of t he st u d y is d efi ne d as t he d ate of t he l ast visit of t he last 
s u bject i n t his st u d y. 

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j. 
T he ter m W O C B P is defi ne d i n A p pe n di x  4 . 
k.  All uri ne pre g na n c y tests m ust h a v e a mi ni m u m se nsiti vit y of 2 5 mI U β -h C G/ m L.  
l. 
S u bjects ≥1 6 years will be assesse d usi n g t he Der mat ol o g y Life Q ualit y I n de x ( D L Q L) w hile s u bjects < 1 6 years will be assesse d usi n g t he C hil dre n’s 
Der mat ol o g y Life Q ualit y I n de x ( C D L QI).  
m.  Ic ht h y osis Q ualit y of Life-3 2 (I Q o L -3 2) will be use d f or s u bjects > 1 5  years.  
n.  F or visits perf or me d re m otel y, l ocal s ki n reacti o ns will be assesse d via t he S u bject e Diar y .  
o.  I nstr ucti o n f or st u d y treat me nt a d mi nistrati o n will be pr o vi de d i n pa per f or m a n d will be i ncl u de d i n t he S u bject e Diar y. 
p.  Pre -d ose sa m ple ( wit hi n 1 h o ur bef ore d osi n g) a n d e xte nsi ve p ost -d ose sa m pli n g ( 1, 2, 4 , 6 a n d 1 2 h o urs p ost -d ose a n d wit hi n 1 h o ur bef ore sec o n d d ose)  
q.  Si n gle m or ni n g sa m ple ( pre -d ose wit hi n 1 h o ur bef ore m or ni n g d ose)  
r. 
Pre -d ose sa m ple ( wit hi n 1 h o ur bef ore m or ni n g d ose) a n d e xte nsi ve p ost -d ose sa m pli n g ( 1, 2, 4, 6 a n d 1 2 h o urs p ost -d ose)  
s. 
Si n gle m or ni n g sa m ple ( ~ 2 4 h o urs after d ose o n Da y 1 4)  
t. 
Si n gle sa m ple ( wit hi n ± 7 da ys of Da y 8 4)  
u.  D uri n g a n y was h o ut a n d scree ni n g peri o ds, a n y c h a n ges i n t he healt h of s u bjects s h o ul d be rec or de d as c ha n ges i n me dical hist or y u nless a n e v e nt 
occ urre d as a res ult of a st u d y -relate d pr oce d ure a n d was u na ntici pate d. I n s uc h cases, t he e ve nt s h o ul d be rec or de d as a n A E a n d re p orte d t o t he 
I nstit uti o nal Re vie w B oar d/I n de p e n de nt Et hics C o m mittee as a n “ u na ntici pate d pr o ble m” i n acc or da nce wit h l ocal pr oce d ure.  
v.  
A n y treat me nt -relate d A Es t hat are o n g oi n g at Visit 8  ( E O S) m ust be f oll o we d u ntil res ol uti o n or sta bilizati o n. 
 

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meta b olites is m ost li kel y  i n pe diatric patie nts (a g e d 6 t o 1 1 years) . T he first ti me p oi nt wi n d o w 
will c orres p o n d t o t he T ma x f or is otreti n oi n. T he sec o n d ti me p oi nt will be use d f or t he T ma x of 
is otreti n oi n meta b olite(s) if differe nt fr o m is otreti n oi n T ma x or t o esti mate t he eli mi nati o n after 
T ma x f or t he meta b ol ite wit h hi g hest c o nce ntrati o n a b o ve e n d o g e n o us le vels.  
T he res ults of t he i nteri m P K a nal ysis will be pres e nte d i n a n i nteri m re p ort wit h P K pr ofiles of 
a nal ytes as me as ure d a n d as c ha n ge fr o m Baseli ne , a n d deri ve d P K para met ers C ma x, T ma x, 
A U Ct f or meas ur e d a n d c ha n ge fr o m Baseli ne c o nce ntrati o ns. T he i nteri m P K re p ort will be 
re vie we d b y t h e S p o ns or a n d will be i ncl u ded as a s u p p orti n g d oc u me nt f or t he decisi o ns o n  P K 
sa m pli n g wi n d o ws f or a g e gr o u p 6 t o 1 1 years ol d. T he me m o a n d s u p p orti n g i nteri m P K re p ort 
will be a vaila ble t o I R Bs u p o n re q u est. 

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a n d sa m ple size, m ea n, me dia n, S D, mi ni m u m, a n d ma xi m u m will be re p orte d f or t he c o nti n u o us 
varia bles.  
I n di vi d ual s u bject data will be prese nte d i n listi n gs. 
1 0. 3. 1. 1  Effic ac y A n al yses   
All efficac y a n al yses will be perf or me d o n b ot h t he I T T a n d P P p o p ulati o ns wit h t he I T T 
p o p ulati o n c o nsi dere d pri mar y. Ot her p ost h oc a nal ysis ma y be c o n d ucte d usi n g a m o difie d I T T 
p o p ulati o n. A n y s uc h a nal yses will be f ull y descri be d i n t he S A P pri or t o data base l oc k.  
1 0. 3. 1. 1. 1  Pri m ary Effic acy E n d p oi nt  
T he differe nce i n pr o p orti o n of s u bjects ac hie vi n g I G A tr eat me nt s uccess at Wee k 1 2 ( Visit 6) 
bet wee n t he T M B -0 0 1 0. 0 5 % a n d ve hicle gr o u ps  will be t he pri mar y efficac y e n d p oi nt. F or t his 
e n d p oi nt, t he I G A sc ore will be dic h ot o mize d t o “treat me nt s uccess” or “tr eat me nt fail ure”, 
w here “treat me nt s uccess ” is defi n e d as at least a 2 -gra de i m pr o ve me nt ( decrease) i n se verit y 
sc ore as c o m pare d t o B aseli ne. I nfere nce will be ma de b y c o m pari n g t he pr o p orti o ns of 
treat me nt s uccesses i n t he T M B-0 0 1 0. 0 5 % gr o u p v s t he ve hicle gr o u p  at Wee k 1 2 usi n g t he 
C oc hra n -Ma nt el -Hae nsz el ( C M H) test stratifie d b y a ge  (> 1 7, 1 2 -1 6 a n d 6 -1 1)  a n d ge netic 
s u bt y pe, a t w o-si de d al p h a of 0. 0 1 will be use d f or si g nifica nce testi n g.  
T he pri mar y a n al ysis will i ncl u de a m ulti ple i m p utati o n ( MI) m o del t hat will be use d t o i m p ute 
t he meas ure m e nts f or s u bjects wit h missi n g data u p t o t he Wee k 1 2 visit. T he pr o p orti o ns will be 
calc ulate d f or 5 0 i m p ute d datasets,  a n d will be c o m bi ne d usi n g R u bi n’s R ule t o pr o vi de a n 
o verall esti mate of t he differe nce i n pr o p orti o ns wit h c orres p o n di n g c o nfi d e nce i nter vals  a n d 
p -val ue  (Little 2 0 1 9 ). 
Vari o us se nsiti vit y a nal yses will be perf or me d , i ncl u di n g ( b ut n ot li mite d t o) a ti p pi n g p oi nt 
a nal ysis a n d a c o m plet er a nal ysis ; details will be pr o vi de d i n t he S A P.  
1 0. 3. 1. 1. 2  Key Sec o n d ary Effic a cy E n d p oi nts  
T he f oll o wi n g ke y  sec o n dar y efficac y e n d p oi nts will be a nal yze d si milar t o t he pri mar y efficac y 
e n d p oi nt at Wee k 1 2 ( Peri o ds 1 & 2):  
•  t he differe nce i n pr o p orti o ns of s u bjects w h o ac hi e ve 5 0 % re d ucti o n fr o m B aseli ne i n 
VII S -scali n g sc ores i n all areas wit h B aseli ne VII S sc ore ≥3 bet w ee n T M B -0 0 1 0. 0 5 % 
a n d ve hicle-treate d s u bj ects,  
•  t he differe nce i n pr o p orti o n of s u bjects wit h I G A-scali n g a n d fiss uri n g sc ores of clear or  
al m ost clear bet w ee n T M B -0 0 1  0. 0 5 %  a n d ve hicle-treate d s u bjects, 
•  t he differe nce i n pr o p orti o n of s u bjects wit h > 2 -p oi nt c ha n ge  fr o m Bas eli ne i n I G A-
scali n g se verit y s u b-sc ores bet wee n T M B-0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects, a n d 
•  t he differe nce i n pr o p orti o ns of s u bjects w h o ac hi e ve a > 4 -p oi nt  i m pr o ve m e nt fr o m 
baseli ne i n W orst Itc h-Q o L sc ores at Wee k 1 2 i n s u bjects wit h baseli ne Itc h -N u meric 
Rati n g Scale (I -N R S) of ≥7 .  

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It is i m p orta nt t o e ns ure t hat reas o n a ble certai nt y is ac hie ve d i n t he c o ncl usi o ns reac h e d f or k e y 
sec o n dar y e n d p oi nts. T heref ore, ke y s ec o n d ar y e n d p oi nts will be a dj uste d f or m ulti ple statistical 
testi n g t hr o u g h a gate kee pi n g hierarc hi cal met h o d ol o g y, as f oll o ws: statistical si g nifica nce f or 
t he first ke y sec o n d ar y e n d p oi nt o utli ne d a b o ve will be declare d o nl y if t he pri mar y e n d p oi nt has 
pre vi o usl y reac he d statistical si g nifica nce. S u bse q ue nt e n d p oi nt a nal yses i n t he or der prese nte d 
a b o ve will be declare d si g nifica nt o nl y if t he pre vi o us e n d p oi nt i n or der has reac h e d statistical 
si g nifica nce. All a n al yses of ke y sec o n d ar y e n d p oi nts will be c o n d ucte d at t he t w o -si de d al p ha-
le vel of 0. 0 1. Missi n g data f or ke y s ec o n dar y e n d p oi nts will be ha n dle d i n a si milar ma n ner as 
t he pri mar y e n d p oi nt. 
1 0. 3. 1. 1. 3  Ot her  Effic acy E n d p oi nts  
T he a b o ve p ara m eters will als o be a nal yze d f or Peri o d 3, i n vesti gati n g t he differe n ce b et wee n 
s u bjects ra n d o mize d t o T M B-0 0 1 0. 0 5 % BI D a n d Q D mai nte n a nce d osi n g at Wee k 2 4. 9 5 % 
c o nfi de nce i nter vals will be pr o vi de d.  
T he differe nce i n pr o p orti o n of s u bjects wit h > 2 -p oi nt c ha n ges fr o m Baseli ne i n I G A -fiss uri n g 
s u b-sc ores at Wee k 1 2 ( b et wee n T M B-0 0 1 0. 0 5 % a n d ve hicle -treate d s u bj ects) a n d at Wee k 2 4 
(f or b ot h scali n g a n d fiss uri n g sc ores, bet w ee n s u bjects ra n d o mize d t o T M B -0 0 1 0. 0 5 % BI D a n d 
Q D mai nte na nce d osi n g) will be pr o vi de d, al o n g wit h 9 5 % c o nfi de nce i nter vals . C I n a d diti o n, 
t he co m paris o n of pr o p orti o ns of s u bjects wit h re d ucti o n fr o m Baseli ne i n D L QI or C D L QI ≥4 
p oi nts at Wee k 1 2 bet w ee n T M B -0 0 1 0. 0 5 % a n d ve hicle -tr eate d s u bjects will be pr o vi de d, al o n g 
wit h a 9 5 % c o nfi de n ce i nter val. T his a nal ysis will o nl y i ncl u de a d ult s u bjects wit h Baseli ne 
sc ores of ≥1 1 a n d pe diatric s u bjects wit h Baseli ne scores of ≥1 3.  
A d diti o nall y, t he differe n ces i n pr o p orti o ns of s u bj ects wit h > 4 -p oi nt c ha n g es fr o m Baseli ne i n 
W orst Itc h-Q o L sc ores at Wee k 1 2 i n s u bjects wit h Baseli ne I -N R S of ≥7 a n d D L QI/ C D L QI 
( wit h Baseli ne sc ores of ≥1 1 a n d ≥1 3 f or a d ult a n d pe diatric s u bjects, r es p ecti vel y) bet w ee n 
T M B -0 0 1 0. 0 5 % a n d ve hicle -treate d s u bjects will be pr o vi de d, al o n g wit h 9 5 % c o nfi de n ce 
i nter vals.  
T he a b o ve a nal yses will be re peate d f or t he mai nt e na nce p hase ( Peri o d 3), c o m pari n g s u bjects 
ra n d o mize d t o T M B-0 0 1 0. 0 5 % BI D a n d Q D at Wee k 2 4.  

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1 0. 3. 1. 2  S afet y A n al yses  
All A Es re p orte d d uri n g t he st u d y will be liste d, d oc u me nti n g o nset, w het h er t hera p y was 
re q uire d, a n y c ha n g e i n st u d y treat me nt d osi n g, se verit y, p ossi ble relati o ns hi p t o st u d y treat me nt, 
a n d o utc o me. Ver bati m ter ms o n t he e C R Fs will b e li n ke d t o preferre d ter ms ( P Ts) a n d s yste m 
or ga n class ( S O C) 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) ma p pi n g 
s yste m. 
T E A Es are d efi ne d as A Es t hat first occ ur or w orse n i n se verit y aft er t he first a d mi nistrati o n of  
st u d y treat me nt a n d pri or t o 3 0 da ys after t he l ast a d mi nistrati o n of st u d y treat me nt. All re p ort e d 
T E A Es a n d i nci de n ce rates will be s u m marize d b y t he n u m ber of s u bjects r e p orti n g A Es, S O C, 
P T, se verit y, a n d rel ati o ns hi p t o st u d y treat me nt b y treat me nt g r o u p. 
T E A Es b y ma xi m u m se verit y, T E A Es b y rel ati o ns hi p t o st u d y treat me nt, S A Es, T E A Es lea di n g 
t o deat h, a n d T E A Es le a di n g t o disc o nti n uati o n of st u d y treat me nt will be ta b ulate d f or eac h 
treat me nt gr o u p. C o m m o nl y occ urri n g T E A Es, i.e., t h ose t hat occ ur i n 5 % or m ore of t he 
s u bjects i n eit her treat me nt gr o u p, will be s u m marize d usi n g descri pti ve statistics.  T E A Es a n d 
rele va nt patie nt y ears of e x p os ure will be prese nte d, as a p pr o pri ate. 
All la b orat or y test res ults, vital si g ns meas ure me nts, a n d wei g ht will b e s u m marize d f or eac h 
treat me nt gr o u p usi n g descri pti ve statistics f or ra w n u m bers a n d c h a n ge fr o m Baseli ne. T he 
i nci de nce of treat me nt-e mer ge nt cli nicall y si g nifica nt  la b orat or y a n d vital si g ns val ues will als o 
be s u m marize d usi n g des cri pti ve statistics.  
1 0. 3. 1. 3  Ot her A n al yses  
1 0. 3. 1. 3. 1  Vit al Si g ns  
Descri pti ve statistics of vital si g ns (te m perat ure, s yst olic a n d diast olic bl o o d press ure, h eart rate, 
a n d res pirati o n rate) t hr o u g h Visit 9 (E O S ), a n d c ha n ge fr o m B as eli ne, will be pr o vi de d b y 
treat me nt gr o u p  
1 0. 3. 1. 3. 2  P hysic al E x a mi n ati o ns  
Fi n di n gs fr o m p h ysical e xa mi nati o ns ( hea d a n d n ec k, car di o vasc ul ar, der mat ol o gical, 
res pirat or y, g astr oi ntesti nal [a b d o me n], a n d gr oss m ot or a n d gait assess me nts) will be pr o vi de d  
at Visit  1 (Scree ni n g ), Visit 6  (Wee k 1 2 ), a n d Visit 9 (E O S ). S hift ta bles ma y be pr o vi de d b y 
treat me nt gr o u p . 
1 0. 3. 1. 3. 3  Cli nic al  L a b or at ory Tests  
Cli nical la b orat or y tests will be e val uate d f or a n y material c ha n g es d uri n g t he st u d y. All 
la b orat or y dat a ( he mat ol o g y, c he mistr y, a n d uri na lysis ) will be liste d i n t he u nits recei ve d b y t he 
la b orat or y a n d re p ort e d usi n g i nter nati o nal u nits . S u m mar y ta bles b y a nal yt e, at Visit  1 
(Scree ni n g ), Visit 6  (Wee k 1 2 ), a n d Visit 9 (E O S ), a n d c ha n g e fr o m B aseli ne, will be prese nt e d . 
S hift ta bles ma y be pr o vi de d b y treat me nt gr o u p . 

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1 0. 3. 1. 3. 4  L oc al S ki n Re acti o ns  
T he L S Rs ( b ur ni n g/sti n gi n g, e r yt he ma, er osi o ns, a n d e de ma) a n d ot hers will be s u m marize d b y 
fre q ue n c y of eac h i n di vi d ual L S R f or eac h tr eat m e nt gr o u p . C ha n ge fr o m Baseli ne i n L S Rs will 
be cate g orize d i nt o “ w orse ne d” a n d “sa me or i m pr o ve d” a n d will be ta b ulate d  t hr o u g h Visit 9 
(E O S ).  
1 0. 3. 1. 4  Missi n g D at a  
Missi n g data f or t he pri m ar y a n d sec o n dar y effi cac y e n d p oi nts will be ha n dle d b y a m ulti ple 
i m p utati o n m o del c o ntai ni n g, at a mi ni m u m, B aseli ne val ues, p ost -bas eli ne val ues, treat me nt, 
a n d ra n d o mizati o n stratificati o n fact ors. I m p ut ati o n of missi n g data wi ll be c o n d ucte d u n der a 
w or ki n g ass u m pti o n of missi n g at ra n d o m ( M A R), mea ni n g t hat t he pr o pe nsit y f or a data p oi nt 
t o be missi n g is n ot relate d t o t he missi n g data, b ut it is relate d t o s o me of t he o bser ve d d ata.  
T he i m p utati o ns will be perf or me d f or p os t-b aseli ne visits. T he Mar k o v C hai n M o nte Carl o 
( M C M C) met h o d will be use d u n der t he m ulti vari ate n or malit y ass u m pti o n t o i m p ute t he 
missi n g pri mar y a n d sec o n dar y efficac y e n d p oi nts b y treat me nt gr o u p.  T h e M C M C met h o d will 
i m p ute 5 0 datasets i n or der t o esti mate t he treat me nt effect, a n d will be c o m bi ne d usi n g R u bi n’s 
R ule t o pr o vi de a n o verall esti mate of t he differe n ce i n pr o p orti o ns wit h c orres p o n di n g 
c o nfi de nce inter vals a n d p -val ue ( Little 2 0 1 9). F or descri pti ve s u m mar y statistics,  t he me dia n 
val ue ac r oss t he i m p ute d datasets will be use d f or s u bjects wit h missi n g e n d p oi nts.  
Ot her met h o ds f or h a n dli n g missi n g data ma y be e x pl ore d f or r o b ust n ess. F ull details will be 
pr o vi de d i n t he S A P.  
1 0. 3. 1. 5  E xte nt of E x p os ure  
T he t otal a m o u nt of st u d y me dicati o n use d will  be s u m marize d usi n g s u bject -re p orte d dat a 
c ollecte d via t he e Diar y . Descri pti ve statistics ( mea n, me dia n, S D, mi ni m u m, a n d ma xi m u m) will 
be deter mi ne d f or t he t ot al a m o u nt of st u d y me dicati o n use d b y eac h s u bj ect b y treat me nt gr o u p . 
1 0. 3. 1. 6  D osi n g C o m pli a nce  
Desc ri pti ve statistics will be use d t o s u m marize st u d y treat me nt c o m plia nce f or t he I T T a n d P P 
p o p ulati o n s. A s u bject will be c o nsi dere d c o m plia nt wit h t he d osi n g re gi me n if t he s u bject a p plies 
at least 5 0 % of t he e x pecte d n u m ber of a p plicati o ns or d ose.  
Meas u res of o verall st u d y treat me nt c o m plia nce will i ncl u de t he d urati o n of treat me nt ( n u m ber of 
da ys d ose d), t he t otal n u m ber of a p plicati o ns ( det er mi ne d fr o m t he act ual n u m ber of a p plicati o ns 
re p orte d b y t he s u bject), q ua ntit y of d ose, a n d t he perce nt of e x pe cte d d oses a p plie d . 
 
 

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Pr ot oc ol T M B 0 1 -3 0 1  V 2. 0  
 
Pa ge 6 4  of 9 0  
 
1 1  R E F E R E N C E S  
Bla ner, W. S. ( 2 0 0 1) Cell ular meta b olis m a n d acti o ns of 1 3 -cis-reti n oic aci d. J A m Ac a d 
Der m at ol,  4 5 , S 1 2 9 -3 5.  
B ur ge, S. M. & P. K. B u xt o n ( 1 9 9 5) T o pical is otr eti n oi n i n Darier's diseas e. Br J Der m at ol,  1 3 3 , 
9 2 4 -8.  
C hal ker, D. K., J. L. L es her, Jr., J. G. S mit h, Jr., H. C. Kla u da, P. E. P oc hi, W. S. Jac o b y, D. M. 
Y o n k os k y, J. J. V o or hees, C. N. Ellis, S. Mats u da -J oh n & et al. ( 1 9 8 7) Effi cac y of t o pical 
is otreti n oi n 0. 0 5 % gel i n ac ne v ul garis: res ults of a m ultice nter, d o u ble-bli n d 
i n vesti gati o n. J A m Ac a d Der m at ol,  1 7 , 2 5 1 -4.  
Di gi o va n na, J. J., T. Ma ur o, L. M. Milst o ne, M. Sc h m ut h & J. R. T or o ( 2 0 1 3) S yste mic reti n o i ds 
i n t he ma na ge me nt of ic ht h y oses a n d relate d s ki n t y pes. Der m at ol T her,  2 6 , 2 6 -3 8.  
D o mi n g uez, J., M. T. H oj y o, J. L. Cela y o, L. D o mi n g uez -S ot o & F. Tei xeira ( 1 9 9 8) T o pical 
is otreti n oi n vs. t o pical reti n oic aci d i n t he treat me nt of ac ne v ul garis. I nt J Der m at ol, 3 7 , 
5 4 -5.  
Gla x o S mit h Kli ne  A ustralia  Pt y  Lt d ( 2 0 1 3) Is otr e x ® (is otreti n oi n) Gel, 0. 0 5 % 
( A ustralia n Re gister  of  T hera pe utic  G o o ds  Pr o d uct  I nf or mati o n). A b b otsf or d Vict oria, 
A ustralia: Gla x o S mit h Kli ne A ustralia Pt y Lt d.  
Gla x o S mit h Kli ne  U K  Li mite d ( 2 0 1 4) Is otre x ® (is otreti n oi n) Crea m, 0. 0 5 % ( U K Pac k a ge 
Leaflet). U x bri d ge, Mi d dlese x, U K: Gla x o S mit h Kli ne U K Li mite d.  
H u g hes, B. R., J. F. N orris & W. J. C u nliffe ( 1 9 9 2) A d o u ble -bli n d e val u ati o n of t o pical 
is otreti n oi n 0. 0 5 %, be nz o yl per o xi de gel 5 % a n d place b o i n patie nts wit h ac ne. Cli n Ex p 
Der m at ol,  1 7 , 1 6 5 -8.  
I o a n ni des, D., D. Ri g o p o ul os & A. Katsa m bas ( 2 0 0 2) T o pical a da pale ne gel 0. 1 % vs. 
is otreti n oi n gel 0. 0 5 % i n t he treat me nt of ac ne v ul garis: a ra n d o mize d o pe n-la bel cli nical 
trial. Br J Der m at ol,  1 4 7 , 5 2 3 -7.  
i P L E D G E ( 2 0 1 2) Ris k e val uati o n a n d miti gati o n strate g y ( R E M S): T he i P L E D G E Pr o gra m –  
si n gle s hare d s yste m f or is otreti n oi n ( 3 1 3 6 4 5 6). 
htt ps:// w w w.f d a. g ov/ me di a/ 8 0 0 2 3/ d o w nl o a d , Accesse d 1 5 A u g 2 0 1 9. . 
Je nse n, B. K., L. A. Mc G a n n, V. Kac he vs k y & T. J. Fra n z ( 1 9 9 1) T h e ne gli gi ble s yste mic 
a vaila bilit y of reti n oi ds wit h m ulti ple a n d e xcessi ve t o pical a p plicati o n of is otreti n oi n 
0. 0 5 % gel (Is otr e x) i n patie nts wit h ac ne v ul garis. J A m Ac a d Der m at ol,  2 4 , 4 2 5 -8.  
La yt o n, A. ( 2 0 0 9) T h e us e of is otreti n oi n i n ac ne. Der m at oe n d ocri n ol,  1 , 1 6 2 -9.  
Little, R. J. & D. B. R u bi n ( 2 0 1 9) Statistical A nal ysis wit h Missi n g Data, 3r d E diti o n ( V ol. 7 9 3). 
J o h n Wiley & S o n d, I n c . 
N o m ura, K., H. N a ka n o, K. U me ki, K. Hara da, A. K o n, K. Ta mai, D. Sa wa m ura & I. Has hi m ot o 
( 1 9 9 5) A st u d y of t he ster oi d s ulfatase ge n e i n fa milies wit h X-li n ke d ic ht h y osis usi n g 
p ol y merase c h ai n reacti o n. Act a Der m Ve nere ol,  7 5 , 3 4 0 -2.  
R oc he  La b orat ories  I nc ( 1 9 8 2) Acc uta ne ® (is otreti n oi n) ca ps ules, 1 0 -m g, 2 0 -m g, 4 0 -m g ( U S 
Pac ka ge I ns ert). N utle y, NJ: R oc he La b orat ories I nc.  
Steijle n, P. M., D. O. Reife nsc h w eiler, F. C. Ra mae kers, G. N. va n M uije n, R. Ha p ple, M. Li n k, 
D. J. R uiter & P. C. va n de Ker k h of ( 1 9 9 3) T o pi cal treat me nt of ic ht h y oses a n d Darier's 
disease wit h 1 3 -cis -reti n oic aci d. A cli nical a n d i m m u n o hist oc he mical st u d y. Arc h 
Der m at ol Res,  2 8 5 , 2 2 1 -6.  
Ta keic hi, T. & M. A ki ya ma ( 2 0 1 6) I n h erite d ic ht h y osis: N o n -s y n dr o mic f or ms. J Der m at ol,  4 3 , 
2 4 2 -5 1.  

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Pr ot oc ol T M B 0 1 -3 0 1  V 2. 0  
 
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Va hl q uist, A., S. Bl oc k h u ys, P. Steijle n, K. va n R osse m, B. Di d o na, D. Bla nc o & H. Tra u p e 
( 2 0 1 4) Oral liar oz ole i n t he treat me nt of p atie nts wit h m o derate/se vere la mellar 
ic ht h y osis: res ults of a ra n d o mize d, d o u ble-bli n d, m ulti nati o nal, place b o -c o ntr olle d p hase 
II/III tri al. Br J Der m at ol,  1 7 0 , 1 7 3 -8 1.  
Va hl q uist, A., A. Ga ne m o & M. Virta ne n ( 2 0 0 8) C o n ge nital ic ht h y osis: a n o ver vie w of c urre nt 
a n d e mer gi n g t hera pies. Act a Der m Ve nere ol,  8 8 , 4 -1 4.  
 
 

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1 2  A P P E N DI C E S  
A p pe n di x  1 : Re g ul at or y, Et hic al a n d St u d y O versi g ht C o nsi der ati o ns  
Re g ul at or y a n d Et hic al C o nsi der ati o ns  
•  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 pr ot oc ol a n d wit h t he f oll o wi n g:  
o  C o nse ns us et hical pri nci ples deri ve d fr o m i nter nati o nal g ui deli nes i ncl u di n g t he 
Declarati o n of Helsi n ki a n d C o u ncil f or I nter nati o nal Or ga nizati o ns of Me dical 
Scie nces ( CI O M S) I nter nati o nal Et hical G ui deli nes.  
o  A p plica ble I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) G o o d Cli nical Practice 
( G C P) G ui deli nes. 
o  A p plica ble la ws a n d re g u lati o ns. 
•  T he pr ot oc ol, pr ot oc ol a me n d me nts, I C F, I n vesti gat or Br oc h ure, a n d ot her rele va nt 
d oc u me nts (e .g ., a d v ertis e me nts) m ust be s u b mitte d t o a n I R B/I E C b y t he I n v esti gat or 
a n d re vie we d a n d a p pr o ve d b y t he I R B/I E C b ef ore t he st u d y is i nitiate d.  
•  A n y a me n d me nts t o t he pr ot oc ol will re q uire I R B/I E C a n d re g ulat or y a ut h orit y a p pr o val, 
w he n a p plica bl e, bef ore i m ple me ntati o n of c ha n ges ma de t o t he st u d y desi g n, e xce pt f or 
c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o s u bjects.  
•  T he I n vesti gat or will be  res p o nsi ble f or t he f oll o wi n g: 
o  Pr o vi di n g writte n s u m maries of t he stat us of t he st u d y t o t he I R B/I E C a n n uall y or 
m ore fre q u e ntl y i n acc or da nce wit h t he re q uire m e nts, p olicies, a n d pr oce d ures 
esta blis he d b y t he I R B/I E C.  
o  N otif yi n g t he I R B/I E C of S A Es or ot h er si g nifica nt safet y fi n di n gs as re q uire d b y 
I R B/I E C pr oce d ures. 
o  Pr o vi di n g o versi g ht of t he c o n d uct of t he st u d y at t he st u d y ce nter a n d a d here nce 
t o re q uire me nts of 2 1 C F R, I C H g ui deli nes, t he I R B/I E C, E ur o pea n re g ul ati o n 
5 3 6/ 2 0 1 4 f or cli nical st u dies (if a p plica ble), a n d all ot her a p plica ble l ocal 
re g ulati o ns. 
After rea di n g t he pr ot o c ol, eac h I n v esti gat or will si g n t he pr ot oc ol si g nat ure pa ge a n d se n d a 
c o p y of t he si g ne d pa g e t o t he S p o ns or or re prese ntati ve  (A p pe n di x  6 ). T h e st u d y will n ot start at 
a n y st u d y ce nter at w hic h t he I n v esti gat or has n ot si g ne d t he pr ot oc ol.  
Fi n a nci al Discl os ure  
I n v esti gat ors a n d s u b-I n vesti gat ors will pr ovi de t he S p o ns or wit h e n o u g h, acc urat e fi na n cial 
i nf or mati o n as re q u este d t o all o w t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a ut h orities. I n v esti gat ors are 
res p o nsi ble f or pr ovi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he st u d y a n d f or 1 year after 
c o m pleti o n of t he st u d y.  

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I ns ur a nce 
T he S p o ns or has o btai ne d lia bilit y i ns ura nce, w hic h c o vers t his st u d y as re q uire d b y l ocal la w 
a n d/ or nati o nal re g ul ati o ns a n d/ or I C H g ui deli nes, w hic he ver is a p plica ble. T he ter ms of t he 
i ns ura nce will be k e pt i n t he st u d y files. 
I nf or me d C o nse nt Pr ocess 
•  T he I n vesti gat or or his/ h er re prese nt ati ve will e x plai n t he nat ure of t h e st u d y t o t he 
s u bject or his/ her le gall y a ut h orize d re pres e ntati ve an d a ns wer all q uesti o ns re gar di n g t he 
st u d y.  
•  S u bjects m ust be i nf or me d t hat t heir partici pati o n is v ol u ntar y. S u bjects or t heir le gall y 
a ut h orize d re pres e ntati ve  will be re q uire d t o si g n a state me nt of i nf or me d c o nse nt t hat 
meets t he re q uir e me nts of 2 1 C F R 5 0, l ocal re g ul ati o ns, I C H g ui deli nes, Healt h 
I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act ( HI P A A) re q uire me nts, w here a p plica ble, 
a n d t he I R B/I E C or st u d y ce nte r.  
•  T he me dical r ec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o ns e nt was o btai ne d 
bef ore t h e s u bject was e ntere d i n t he st u d y a n d t he date t he writte n c o ns e nt was o btai ne d. 
T he a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.  
•  S u bjects m ust be re -c o ns e nte d t o t he m ost c urre nt versi o n of t he I C F(s) d uri n g t heir 
partici pati o n i n t he st u d y.  
•  A c o p y of t he I C F(s) m ust be pr o vi de d t o t he s u bject or t he s u bject’s le gall y a ut h orize d 
re pres e ntati ve.  
W here p er mitte d, t he use of e C o ns e nt will be accesse d  t hr o u g h Datac u be d’s we b -bas e d 
a p plicati o n . T he e C o nse nt will i ncl u de t he I C F i n its e ntiret y. C o nse nti n g partici pa nts’ si g nat ures 
are f ull y F D A 2 1 C F R part 1 1 c o m plia nt. T his m o d ule all o ws t he deli ver y of pre defi ne d I C Fs, 
t he ca pt ure of si g nat ures, a n d t he deli ver y of c o m pre he nsi o n q uesti o n nair es. U p o n c o m pleti o n of 
t he m o d ule, a P D F c o p y of t he c o m plete d e C o nse nt f or m is se nt t o t he partici pa nt a n d is 
a vaila ble f or d o w nl oa d fr o m t he site p ortal.  
D at a Pr otecti o n  
•  S u bjects will be assi g n e d a u ni q ue i de ntifier b y t h e S p o ns or. A n y s u bject r ec or ds or 
datasets t hat are tra nsf erre d t o t he S p o ns or will c o ntai n t he i de ntifier o nl y; s u bject na mes 
or a n y i nf or mati o n w hic h w o ul d ma ke t he s u bject i de ntifia ble will n ot be tra nsferre d.  
•  T he s u bject m u st be i nf or me d t hat his/ her pers o nal st u d y-relate d dat a will be use d b y t he 
S p o ns or i n acc or da nce wit h l ocal data pr otecti o n l a w. T he le vel of discl os ure a n d t he 
ulti mate tra nsfer of ps e u d o n y mize d data t o t he U S  m ust als o be e x plai ne d t o t he s u bject. 
T he s u bject m ust be i nf or me d t hat his/ her me dical rec or ds ma y b e e x a mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he S p o ns or, b y 
a p pr o priate I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities.  

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•  Data c ollecti o n a n d tra nsfer usi n g t he S u bject eDi ar y/e P R O a p p will be c o n d ucte d i n  
acc or da nce wit h l ocal dat a pr otecti o n la w.  
•  T he I C F will i nc or p orate ( or, i n s o me cas es, be acc o m pa nie d b y a se parate d oc u me nt 
i nc or p orati n g) w or di n g t hat c o m plies wit h rele va nt data pr otecti o n a n d pri vac y 
le gislati o n. 
•  T he S p o ns or or its re prese ntati ve will n ot pr o vi de i n di vi d ual ge n ot y pe res ults t o s u bjects, 
a n y i ns ura nce c o m pa n y, a n y e m pl o yer, t heir fa mil y me m bers, ge neral p h ysicia n, or a n y 
ot her t hir d part y, u nless re q uire d t o d o s o b y  la w. 
•  E xtra preca uti o ns are ta k e n t o preser ve c o nfi de ntialit y a n d pre ve nt ge netic data bei n g 
li n ke d t o t he i de ntit y of t he s u bject. I n e x ce pti o nal circ u msta nces, h o we ver, certai n 
i n di vi d uals mi g ht see b ot h t he ge netic data a n d t he pers o nal i de ntifiers of a s u bject. F or 
e xa m ple, i n t he cas e of a me dical e mer ge nc y, t he S p o ns or or re prese ntati ve p h ysicia n or 
a n I n vesti gat or mi g ht k n o w a s u bject’s i de ntit y a n d ha ve access t o his or her ge netic dat a. 
Als o, re g ulat or y a ut h oriti es ma y re q uir e access t o t he rele va n t files. 
A d mi nistr ati ve Str uct u re  
T he S p o ns or of t his st u d y is Ti m ber P har mace uti cals, L L C ( A d dress: 1 1 0 Alle n R oa d, S uite 4 0 1, 
Bas ki n g Ri d ge, NJ 0 7 9 2 0 ). St u d y a d mi nistrati ve str uct ure i ncl u di n g e mer ge nc y c o ntacts, 
Cli nical Researc h Or ga ni zati o n ( C R O), La b orat or y, a n d a ncillar y s er vices ca n be f o u n d i n t he 
I n v esti gat or St u d y Bi n der. 
Me dic al M o nit or:   
St u d y  Site I niti ati o n  
T he I n vesti gat or m ust n ot scree n a n y s u bject pri or t o c o m pleti o n of t he st u d y i nitiati o n visit, 
c o n d ucte d b y t he C R O. T his i nitiati o n visit will i ncl u de a det aile d re vie w of t he pr ot oc ol a n d 
st u d y pr oce d ures. 
Disse mi n ati o n of Cli nic al St u d y D at a  
T he res ults of t he st u d y s h o ul d be re p orte d wit hi n 1 year fr o m t he e n d of t h e c li nical st u d y. 
Irres p ecti ve of t he o ut c o me, t he S p o ns or will s u b mit t o t he Cli nical Trials. g o v data base a 
s u m mar y of t he res ults of t he cli nical st u d y wit hi n 1 year fr o m t he e n d of t h e cli nical st u d y. It 
s hall be acc o m p a nie d b y a s u m mar y writte n i n a ma n ner t hat is u n dersta n da ble t o la y pers o ns. 
D at a Q u alit y Ass ur a nce  
•  All s u bject data rel ati n g t o t he st u d y will be rec or de d o n pri nte d or eC R Fs u nless 
tra ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e.g ., la b orat or y d ata). T he 

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I n v esti gat or is res p o nsi ble f or verif yi n g t hat data e ntries are acc urate a n d c orrect b y 
p h ysicall y or electr o ni call y si g ni n g t he e C R F.  
•  T he I n vesti gat or m ust mai ntai n acc urate d oc u me ntati o n (s o urce dat a) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e e C R F.  
•  T he I n vesti gat or m ust per mit st u d y -relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d 
re g ulat or y a g e nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce data d oc u me nts.  
•  T he S p o ns or or desi g ne e is res p o nsi ble f or t he dat a ma na ge m e nt of t his st u d y i ncl u di n g 
q ua lit y c hec ki n g of t he d ata.  
•  St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d 
i nt o t he e C R F b y a ut h orize d st u d y ce nter pers o n nel are acc urate, c o m plete, a n d verifia bl e 
fr o m s o urce d o c u me nts; t hat t he safet y a n d ri g hts of s u bjects are bei n g pr ot ecte d; a n d t hat 
t he st u d y is bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot oc ol a n d a n y 
ot her st u d y a gree me nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts.  
•  Rec or ds a n d d o c u me nts, i ncl u di n g si g ne d I C Fs, p ertai ni n g t o t he c o n d uct of t his st u d y 
m ust be retai ne d b y t he I n vesti gat or f or 1 5 years after st u d y c o m pleti o n u nless l ocal 
re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n g er ret e nti o n peri o d. N o rec or ds ma y be 
destr o ye d d uri n g t he rete nti o n peri o d w it h o ut t he writte n a p pr o val of t h e S p o ns or. N o 
rec or ds ma y b e tra nsferre d t o a n ot her l ocati o n or p art y wit h o ut writte n n otificati o n t o t he 
S p o ns or.  
A u dits a n d I ns pecti o ns  
A ut h orize d re pres e ntati ves of t he S p o ns or, a re g ul at or y a ut h orit y, a n I R B or I E C ma y  visit t he 
site t o perf or m a u dits or i ns pecti o ns, i ncl u di n g s o urce dat a verifi cati o n. T he p ur p ose of a 
S p o ns or a u dit or i ns pecti o n is t o s yste maticall y a n d i n de pe n de ntl y e xa mi ne all st u d y -relate d 
acti vities a n d d oc u me nts t o deter mi ne w het her t hese acti viti es were c o n d ucte d, a n d data were 
rec or de d, a n al yze d, a n d acc urat el y re p ort e d acc or di n g t o t he pr ot oc ol, I C H-G C P g ui deli nes, a n d 
a n y a p plica ble re g ulat or y re q uire me nts. T h e I n vesti gat or s h o ul d c o ntact t he S p o ns or 
i m me diatel y if c o ntacte d b y a re g ulat or y a gen c y a b o ut a n i ns pecti o n . 
S o urce D oc u me nts  
T he I n vesti gat or/i nstit uti o n s h o ul d mai ntai n a de q uate a n d acc urate s o urce d oc u me nts a n d st u d y 
rec or ds t hat i ncl u d e all p erti ne nt o bser vati o ns o n eac h of t h e st u d y ce nter’s s u bjects. S o urce data 
s h o ul d be attri b uta ble, le gi ble, c o nte m p ora ne o us, ori gi nal, acc urate, a n d c o m plete. C ha n ges t o 
s o urce dat a s h o ul d be tracea ble, s h o ul d n ot o bsc ure t he ori gi nal e ntr y, a n d s h o ul d be e x plai ne d if 
necessar y (e .g ., vi a a n a u dit trail). 
•  S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e x iste n ce of t he s u bject a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o urce d o c u me nts are file d at t he I n vesti gat or’s st u d y 
ce nter.  

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•  Data e ntere d i n t he e C R F t hat are tr a nscri be d fr o m s o urce d oc u m e nts m ust be c o nsiste nt 
wit h t he s o urce d oc u m e nts or t he discre pa n cies m ust be e x plai ne d. T he I n vesti gat or ma y 
nee d t o re q u est pre vi o us me dical rec or ds or tr a nsfer rec or ds, de p e n di n g o n t he st u d y. 
Als o, c urre nt me dic al rec or ds m ust be a vaila ble.  
•  Defi niti o n of w hat c o nstit utes s o urce data ca n b e f o u n d i n I n v e sti gat or St u d y Bi n der. 
St u d y a n d St u d y Ce nter Cl os ure  
T he S p o ns or desi g nee reser ves t he ri g ht t o cl ose t he st u d y ce nter or ter mi n ate t he st u d y at a n y 
ti me f or a n y reas o n at t he s ole discreti o n of t he S p o ns or. St u d y ce nters will be cl ose d u p o n st u d y 
c o m plet i o n. A st u d y ce nter is c o nsi dere d cl ose d w he n all re q uir e d d oc u me nts a n d st u d y s u p plies 
ha ve bee n c ollecte d a n d a st u d y ce nter cl os ure visit has bee n perf or me d.  
T he I n vesti gat or ma y i nitiate st u d y ce nter cl os ure at a n y ti me, pr o vi de d t here is reas o n a ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n.  
Reas o ns f or t he earl y cl os ure of a st u d y ce nter b y t he S p o ns or or I n vesti gat or ma y i ncl u de b ut 
are n ot li mite d t o:  
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uir e me nts of t he I R B/I E C 
or l ocal healt h a ut h orities, t he S p o ns or’s pr oce d ures, or G C P g ui deli nes.  
•  I n a de q uat e recr uit me nt of s u bjects b y t he I n vesti g at or. 
•  Disc o nti n uati o n of f urt her st u d y treat me nt de vel o p me nt.  
St u d y C o n d uct D uri n g t he C O VI D -1 9 P a n de mic  
T he w orl d wi de C O VI D -1 9 pa n de mic ma y i m pact t he c o n d uct of cli nical st u dies d ue t o t he 
c halle n ges fr o m q uara nti nes, site cl os ures, tra v el li mitati o ns, a n d ot her c o nsi derati o ns if site 
pers o n nel or st u d y partici pa nts bec o me p ote ntiall y e x p ose d t o or i nfecte d wit h C O VI D -1 9. I n 
s uc h cases, t h e S p o ns or will ass ure t he safet y of st u d y partici pa nts, mai ntai n c o m plia nce wit h 
G C P, a n d mi ni mize ris ks t o st u d y i nte grit y . 
C O VI D -1 9 I nfecti o n i n St u d y S u bjects  
T here are c urre ntl y n o a v aila ble data s u g gesti n g t h at patie n ts treate d wit h T M B -0 0 1  s h o ul d ha ve 
treat me nt i nterr u pte d d uri n g t he C O VI D-1 9 pa n d e mic. If a s u bject d e vel o ps s y m pt o ms 
ass ociate d wit h c or o na vir us i nfecti o n, it is rec o m me n de d t o c o nfir m t he di a g n osis usi n g l ocall y 
a p pr o ve d la b orat or y kits a n d re p ort it t o  t he l ocal healt h a ut h orities, as re q uire d. S u bject s wit h 
p ositi ve test res ults f or S A R S -C o V -2 s h o ul d ha ve t his rec or de d as a n A E, a n d if h os pitalize d, 
t his s h o ul d be re p orte d as an  S A E . 
P u blic ati o n P olic y  
•  T he res ults of t his st u d y i n a g gre gat e ma y be p u bl is he d or pres e nte d at scie ntific 
meeti n gs. If t his is f oresee n, t he I n vesti gat or a grees t o s u b mit all ma n uscri pts or a bstracts 
t o t he S p o ns or bef ore s u b missi o n. T his all o ws t he S p o ns or t o pr otect pr o pri etar y 

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i nf or mati o n a n d t o pr o vi de c o m me nts. N o i n di vi d u al site relate d st u d y res ults will be 
all o we d t o be pres e nte d.  
•  T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. I n 
acc or da nce wit h sta n dar d e dit orial a n d et hical pr actice, t he S p o ns or will ge nerall y 
s u p p ort p u blicati o n of m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual 
st u d y ce nter dat a. I n t his case, a C o or di n ati n g I n vesti gat or will be desi g nate d b y m ut ual 
a gree m e nt.  
•  A ut h ors hi p will be deter mi ne d b y m ut ual a gree m e nt a n d i n li ne wit h I nt er nati o nal 
C o m mittee of  Me dical J o ur nal E dit ors a ut h ors hi p re q uire me nts.  
 
 

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A p pe n di x  2: Cli nic al L a b or at or y Tests  
T he tests detaile d i n Ta bl e 1 7  will be perf or me d b y t he ce ntral la b orat or y.  
L ocal la b orat or y res ults are o nl y re q uir e d if t he ce ntral la b orat or y res ults are n ot a vaila ble i n 
ti me f or eit her st u d y treat me nt a d mi nistrati o n a n d/ or res p o nse e val uati o n. If a l ocal sa m ple is 
re q uire d, it is i m p orta nt t hat t he sa m ple f or ce ntr al a nal ysis is o btai ne d at t he sa me ti me. 
A d diti o nall y, if t he l ocal la b orat or y res ults are use d t o ma ke eit her a st u d y treat me nt decisi o n or 
res p o nse e v al uati o n, t he res ults m ust be e ntere d i nt o t he e C R F.  
Pr ot oc ol -s pecific re q uire me nts f or i ncl usi o n or e x cl usi o n of s u bjects are d etaile d i n Secti o n  5 . 
A d diti o nal tests ma y be perf or me d at a n y ti me d uri n g t he st u d y as deter mi ne d necessar y b y t he 
I n v esti gat or or re q uire d b y l ocal re g ulati o ns. 
T he I n vesti gat or m ust re vie w t he la b orat or y re p ort, d oc u me nt t his re vie w, a n d rec or d a n y 
cli nicall y rele va nt c ha n g es occ urri n g d uri n g t he st u d y i n t he A E secti o n of t he e C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d o c u me nts. Cli nicall y si g nifica nt a b n or m al 
la b orat or y fi n di n gs are t h ose t hat are n ot ass ociate d wit h t he u n derl yi n g disease u nless j u d ge d b y 
t he I n vesti gat or t o be o ut of ra n ge t o a greater d e gree t h an e x pect e d f or t he s u bject’s c o n diti o n.  
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y a b n or mal d uri n g partici pati o n 
i n t he st u d y or wit hi n 3 0 da ys after t h e last d ose of st u d y me dicati o n s h o ul d be re peate d u ntil t he 
val ues, sta bilize, ret ur n t o n or mal or Baseli ne, or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt 
b y t he I n vesti gat or or Me dical M o nit or.  
If s uc h val ues d o n ot ret ur n t o n or mal/ Baseli ne wit hi n a peri o d j u d ge d reas o na ble b y t he 
I n v esti gat or, t he eti ol o g y s h o ul d be i de ntifie d, a n d t he S p o ns or s h o ul d be n otifie d. 
If la b orat or y val ues fr o m n o n-pr ot oc ol -s pecifie d l a b orat or y assess me nts perf or me d at t he 
i nstit uti o n’s l ocal la b orat or y re q uire a c h a n ge i n s u bject ma na ge me nt or are c o nsi dere d cli nicall y 
si g nifica nt b y t he I n vesti gat or (e.g ., S A E, A E, d os e i nterr u pti o n), t he n t he res ults m ust be 
rec or de d i n t he e C R F.  
A n y ne w or w orse ni n g of cli nicall y si g nifica nt a b n or malities at t he E O S visit will be rec or de d as 
A Es.  
 
 
 
 
 
 
 

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A p pe n di x  3: A d verse E ve nts: Defi niti o ns a n d Pr oce d ures f or Rec or di n g, 
E v al u ati n g, F oll o w -u p, Re p orti n g  
Defi niti o n of A E  
A E Defi niti o n  
•  
A n A E is a n y u nt o war d me dical occ urre nce i n a patie nt or s u bject, te m p orall y ass ociate d wit h t he use 
of st u d y treat me nt, w het her or n ot c o nsi dere d relate d t o t he st u d y treat me nt.  
•  
N O T E: A n A E ca n t heref ore be a n y u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal 
la b orat or y fi n di n g), s y m pt o m, or disease ( ne w or e xacer bate d) te m p orall y ass ociate d wit h t he use of 
st u d y treat me nt. 
 
E ve nts Meeti n g  t he A E Defi niti o n  
•  
A n y a b n or mal la b orat or y test res ults ( he mat ol o g y, cli nical c he mistr y, or uri nal ysis) or ot her safet y 
assess me nts (e .g ., E C G, ra di ol o gical sca ns, vital si g ns meas ure me nts), i ncl u di n g t h ose t hat w orse n 
fr o m Baseli ne, c o nsi dere d cli nicall y si g nifica nt i n t he me dical a n d scie ntific j u d g me nt of t he 
I n vesti gat or (i.e., n ot relate d t o pr o gressi o n of u n derl yi n g disease). 
•  
E xacer bati o n of a c hr o nic or i nter mitte nt pre -e xisti n g c o n diti o n i ncl u di n g eit her a n i ncrease i n 
fre q ue nc y a n d/ or i nte nsit y of t he c o n diti o n, i ncl u di n g l ocal s ki n reacti o ns. 
•  
Ne w c o n diti o ns detecte d or dia g n ose d after st u d y treat me nt a d mi nistrati o n  e ve n t h o u g h it ma y ha ve 
bee n prese nt bef ore t he start of t he st u d y.  
•  
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d dr u g -dr u g i nteracti o n.  
•  
Si g ns, s y m pt o ms, or t he cli nical se q uelae of a s us pecte d o ver d ose of eit her st u d y treat me nt or a 
c o nc o mita n t me dicati o n. O ver d ose per se will n ot be re p orte d as a n A E/ S A E u nless it is a n i nte nti o nal 
o ver d ose ta ke n wit h p ossi ble s uici dal/self -har mi n g i nte nt. S uc h o ver d oses s h o ul d be re p orte d 
re g ar dless of se q uelae. 
•  
" Lac k of efficac y" or "fail ure of e x pecte d p har mac ol o gical acti o n" per se will n ot be re p orte d as a n A E 
or S A E. S uc h i nsta nces will be ca pt ure d i n t he efficac y assess me nts. H o we v er, t he si g ns, s y m pt o ms, 
a n d/ or cli nical se q uelae res ulti n g fr o m lac k of efficac y will be re p orte d as A E or S A E if t he y f ulfi l t he 
defi niti o n of a n A E or S A E.  
 
E ve nts N O T  Meeti n g t he A E Defi niti o n  
•  
A n y cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs or ot her a b n or mal safet y assess me nts t hat are 
ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he I n vesti gat or t o be m ore se vere t ha n 
e x pecte d f or t he s u bject’s c o n diti o n.  
•  
T he disease/ dis or der bei n g st u die d or e x pecte d pr o gressi o n, si g ns, or s y m pt o ms of t he disease/ dis or der 
bei n g st u die d, u nless m ore se vere t ha n e x pecte d f or t he s u bject’s c o n diti o n.  
•  
Me dical or s ur gical pr oce d ure (e .g ., e n d osc o p y, a p pe n dect o m y): t he c o n diti o n t hat lea ds t o t he 
pr oce d ure is t he A E.  
•  
Sit uati o ns i n w hic h a n u nt o war d me dical occ urre nce di d n ot occ ur (s ocial a n d/ or c o n ve nie nce 
a d missi o n t o a h os pital).  
•  
A ntici pate d da y -t o-da y f l uct uati o ns of pre-e xisti n g disease(s) or c o n diti o n(s) prese nt or detecte d at t he 
start of t he st u d y t hat d o n ot w orse n. 
•  
 
 

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Defi niti o n of S A E  
If a n e v e nt is n ot a n A E per defi niti o n a b o ve, t h e n it ca n n ot be a n S A E e v e n if seri o us c o n diti o ns 
are met ( e. g., h os pitalizati o n f or si g ns/s y m pt o ms of t he disease u n d er st u d y, deat h d ue t o 
pr o gressi o n of diseas e).  
 
 
A n S A E is defi ne d as a n y u nt o w ar d m e dic al occ urre nce t h at, at a n y d ose:  
a)  Res ults i n de at h  
b)  Is life-t hre ate 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 ve nt i n w hic h t he s u bject was at ris k 
of deat h at t he ti me of t he e v e nt. It d oes n ot refer t o a n e ve nt t hat h y p ot heticall y mi g ht ha ve ca use d deat h if 
it were m ore se v ere. 
c) Re q uires i n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n  
I n ge n eral, h os pitalizati o n si g nifies t hat t he s u bject has bee n detai ne d ( us uall y i n v ol vi n g at least a n 
o ver ni g ht sta y) at t he h os pital or e mer ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat w o ul d  n ot ha ve 
bee n a p pr o priate i n t he p h ysicia n’s office or o ut patie nt setti n g. C o m plicati o ns t hat occ ur d uri n g 
h os pitalizati o n are A Es. If a c o m plicati o n pr ol o n gs h os pitalizati o n or f ulfills a n y ot her seri o us criteria, t he 
e v e nt is seri o us. W he n i n d o u bt as t o w het her “ h os pitalizati o n” occ urre d or was necessar y, t he A E s h o ul d 
be c o nsi dere d seri o us.  
H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n fr o m Baseli ne is n ot 
c o nsi dere d a n A E.  
d)  Res ults i n persiste nt dis a bilit y/i nc a p acit y  
•  
T he ter m disa bilit y mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
•  
T his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical si g nifica nce s uc h as 
u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, a n d acci de ntal tra u ma (e .g ., s prai ne d 
a n kle) w hic h ma y i nterfere wit h or pre v e nt e ver y da y life f u ncti o ns b ut d o n ot c o nstit ute a s u bsta ntial 
disr u pti o n.  
e) Is a c o n ge nit al a n o m al y/ birt h defect 
f) 
Ot her sit u ati o ns:  
•  
Me dical or scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her S A E re p orti n g is a p pr o priate 
i n ot her sit uati o ns s uc h as i m p orta nt me dical e ve nts t hat ma y n ot b e 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 dize t he s u bject or ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt 1 of t he ot her o utc o mes liste d i n t he a b o ve defi niti o n. T hese e ve nts s h o ul d 
us uall y be c o nsi dere d seri o us.  
E xa m ples of s uc h e v e nts i ncl u de i n vasi ve or mali g na nt ca ncers, 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 f or aller gic br o nc h os pas m, bl o o d d yscrasias, or c o n v ulsi o ns t hat d o n ot res ult i n 
h os pitalizati o n, or de v el o p me nt of dr u g de pe n de nc y or dr u g a b use.  

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Rec or di n g a n d F oll o w -U p of A E a n d/ or S A E  
A E a n d S A E Rec or di n g  
•  
W he n a n A E/ S A E occ urs, it is t he res p o nsi bilit y of t he I n vesti gat or t o re vie w all  d oc u me ntati o n (e .g ., 
h os pital pr o gress n otes, la b orat or y re p orts, a n d dia g n ostics re p orts) relate d t o t he e ve nt.  
•  
T he I n vesti gat or will t he n rec or d all rele v a nt A E/ S A E i nf or mati o n i n t he C R F. Eac h e ve nt m ust be 
rec or de d se p aratel y.  
•  
It is n ot  acce pta ble f or t he I n vesti gat or t o se n d p h ot oc o pies of t he s u bject’s me dical rec or ds t o 
A d va n ce d Cli nical - Gl o bal Safet y Ser vices i n lie u of c o m pleti o n of t he A E/ S A E C R F pa ge. 
•  
T here ma y be i nsta n ces w he n c o pies of me dical rec or ds f or certai n cases are re q ueste d b y  A d va nce d 
Cli nical - Gl o bal Safet y Ser vices . I n t his case, all s u bject i de ntifiers, wit h t he e xce pti o n of t he s u bject 
n u m ber, will be re d acte d o n t he c o pies of t he me dical rec or ds bef ore s u b missi o n t o A d va nce d Cli nical 
- Gl o bal Safet y Ser vices . 
•  
T he I n vesti gat or will atte m pt t o esta blis h a dia g n osis of t he e ve nt base d o n si g ns, s y m pt o ms, a n d/ or 
ot her cli nical i nf or mati o n. W he n e v er p ossi ble, t he dia g n osis ( n ot t he i n di vi d ual si g ns/s y m pt o ms) will 
be d oc u me nte d as t he A E/ S A E.  
Assess m e nt of I nte nsit y  
T he I n vesti gat or will ma k e a n assess me nt of i nte nsit y f or eac h A E a n d S A E re p orte d d uri n g t he st u d y a n d 
assi g n it t o 1 of t he f oll o wi n g cate g ories:  
•  
Mil d : A n e ve nt t hat is easil y t olerate d b y t he s u bject, ca usi n g mi ni mal disc o mf ort a n d n ot i nterferi n g 
wit h e v er y da y acti vities.  
•  
M o der ate : A n e v e nt t hat ca uses s ufficie nt disc o mf ort a n d i nterferes wit h n or mal e ver y da y acti vities. 
•  
Se vere : A n e v e nt t hat pre v e nts n or mal e ver y da y acti vities. A n A E t hat is assesse d as se vere s h o ul d n ot 
be c o nf use d wit h a S A E. Se vere is a cate g or y utilize d f or rati n g t he i nte nsit y of a n e ve nt; a n d b ot h A Es 
a n d S A Es ca n be assesse d as s e v ere.  
A n e v e nt is defi ne d as ‘seri o us’ w he n it meets at least 1 of t he pre defi ne d o utc o mes as descri be d i n t he 
defi niti o n of a n S A E, N O T w he n it is rate d as se vere.  
 
Assess m e nt of C a us alit y  
•  
T he I n vesti gat or is o bli gate d t o assess t he relati o ns hi p bet wee n st u d y treat me nt a n d eac h occ urre nce of 
eac h A E/ S A E. T he A E m ust be c h aracterize d as u nrelate d, u nli kel y t o be relate d, p ossi bl y relate d, 
pr o ba bl y relate d, or u n k n o w n ( u na ble t o j u d ge).  
o  
“ Pr o b a bl y rel ate d ”  c o n ve ys t hat t here are facts, e vi de nce, a n d/ or ar g u me nts t o s u g gest a 
ca usal relati o ns hi p, rat her t ha n a relati o ns hi p c a n n ot be r ule d o ut.  
o  
“ P ossi bl y rel ate d ”  s u g gests t hat t he ass ociati o n of t he A E wit h t he st u d y treat me nt is 
u n k n o w n; h o we ver, t he A E is n ot reas o na bl y s u p p orte d b y ot her c o n diti o ns.  
o  
“ U nli k el y t o be rel ate d ”  s u g gests t hat o nl y a re m ote c o n necti o n e xists bet wee n t he st u d y 
treat me nt a n d t he A E. Ot her c o n diti o ns, i ncl u di n g c hr o nic ill ness, pr o gressi o n or e x pressi o n 
of t he disease state or reacti o n t o c o nc o mita nt t hera p y, a p pear t o e x plai n t he re p orte d A E.  
o  
“ U nrel ate d ”  is use d if t here is n ot a reas o na ble p ossi bilit y t hat t he st u d y treat me nt ca use d t he 
A E.  
o  
All eff orts s h o ul d be ma d e t o classif y t he A E acc or di n g t o t he a b o ve cate g ories. T he cate g or y 
“ u n k n o w n” ( u na ble t o j u d ge) ma y be use d o nl y if t he ca usalit y is n ot assessa ble, e .g ., beca use 
of i ns ufficie nt e vi de n ce, c o nflicti n g e vi de nce, c o nflicti n g data, or p o or d oc u me ntati o n.  
•  
T he I n vesti gat or will use cli nical j u d g me nt t o deter mi ne t he relati o ns hi p.  

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•  
Alter nati ve ca uses, s uc h as u n derl yi n g disease(s), c o nc o mita nt t hera p y, a n d ot her ris k fact ors, as well 
as t he te m p oral relati o ns hi p of t he e v e nt t o st u d y treat me nt a d mi nistrati o n will be c o nsi dere d a n d 
i n vesti gate d. 
•  
T he I n vesti gat or will als o c o ns ult t he I n vesti gat or’s Br oc h ure a n d/ or Pr o d uct I nf or mati o n, f or 
mar kete d pr o d ucts, i n his/ her assess me nt.  
•  
F or eac h A E/ S A E,  t he I n vesti gat or m ust d oc u me nt i n t he me dical n otes t hat he/s he has re vie we d t he 
A E/ S A E a n d has pr o vi de d a n assess me nt of ca usalit y.  
•  
T here ma y be sit uati o ns i n w hic h a n S A E has occ urre d, a n d t he I n vesti gat or has mi ni mal i nf or mati o n 
t o i ncl u de i n t he i nitial re p ort t o  A d va n ce d Cli nical - Gl o bal Safet y Ser vices . H o we v er, it is ver y 
i m p orta nt t hat t he I n vesti gat or al wa ys ma ke a n assess me nt of ca usalit y f or e ver y e ve nt bef ore t he 
i nitial tra ns missi o n of t he S A E data t o A d va nce d Cli nical - Gl o bal Safet y Ser vice s. 
•  
T he I n vesti gat or ma y c ha n ge his/ her o pi ni o n of ca usalit y i n li g ht of f oll o w -u p i nf or mati o n a n d se n d a n 
S A E f oll o w -u p re p ort wit h t he u p date d ca usalit y assess me nt.  
•  
T he ca usalit y assess me nt is o ne of t he criteria use d w he n deter mi ni n g re g ulat or y re p orti n g  
re q uire me nts. 
 
F oll o w -U p of A Es a n d S A Es  
•  
T he I n vesti gat or is o bli gate d t o perf or m or arra n ge f or t he c o n d uct of s u p ple me ntal meas ure me nts 
a n d/ or e val uati o ns as me dicall y i n dicate d or as re q ueste d b y  A d va nce d Cli nical - Gl o bal Safet y 
Ser vices  t o el uci date t he nat ure a n d/ or ca usalit y of t he A E or S A E as f ull y as p ossi ble. T his ma y 
i ncl u de a d diti o nal la b orat or y tests or i n vesti gati o ns, hist o pat h ol o gical e xa mi nati o ns, or c o ns ultati o n 
wit h ot her healt h ca re pr ofessi o nals. 
•  
If a s u bject dies d uri n g partici pati o n i n t he st u d y or d uri n g a rec o g nize d f oll o w-u p peri o d, t he 
I n vesti gat or will pr o vi de A d va n ce d Cli nical - Gl o bal Safet y Ser vices  wit h a c o p y of a n y p ost m orte m 
fi n di n gs i ncl u di n g hist o pat h ol o g y. 
•  
Ne w or u p date d i nf or mati o n will be rec or de d i n t he ori gi nall y c o m plete d e C R F.  
•  
T he I n vesti gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or/ A d va nce d Cli nical - Gl o bal Safet y 
Ser vices wit hi n 2 4 h o urs of recei pt of t he i nf or mati o n.  
 
Re p orti n g of S A Es  
S A E Re p orti n g  vi a P a per C R F  
•  
E -mail tra ns missi o n of t he S A E pa p er C R F is t he preferre d met h o d t o tra ns mit t his i nf or mati o n t o  
A d va n ce d Cli nical - Gl o bal Safet y Ser vices  wit h Facsi mile tra ns missi o n as bac k -u p met h o d.  
•  
I n rare circ u msta nces a n d i n t he a bse n ce of e-mail/facsi mile e q ui p me nt, n otificati o n b y tele p h o ne is 
acce pta ble wit h a c o p y of t he S A E data c ollecti o n t o ol se nt b y o ver ni g ht mail or c o urier ser vice.  
•  
I nitial n otificati o n via tele p h o ne d oes n ot re place t he nee d f or t he I n vesti gat or t o c o m plete a n d si g n t he 
S A E e C R F pa g es wit hi n t he desi g nate d re p orti n g ti me fra mes.  
•  
C o ntacts f or S A E re p orti n g ca n be f o u n d i n  t he I n vesti gat or St u d y Bi n der. All S A Es m ust als o be 
re p orte d t o A d va nce d Cli nical - Gl o bal Safet y Ser vices wit hi n 2 4  h o urs of first a ware ness of t he e ve nt. 
A pa p er S A E Re p ort F or m s h o ul d be c o m plete d a n d s u b mitte d via e -mail t o 
dr u gsafet y p v @a d va n ce dcli nical.c o m  or fa xe d t o  1. 8 8 8. 4 9 3. 0 9 1 0 . 
 
 

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A p pe n di x  4 : C o ntr ace pti ve G ui d a nce a n d C ollecti o n of Pre g n a nc y 
I nf or m ati o n 
Defi niti o ns:  
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)  
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc h e a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile (see bel o w).  
W o me n i n t he f oll o wi n g c ate g ories are n ot c o nsi dere d W O C B P:  
1.  Pre me narc hal  
2.  Pre me n o pa usal f e male wit h 1 of t he f oll o wi n g:  
a)  D oc u me nte d h ysterect o m y.  
b)  D oc u me nte d bilateral sal pi n gect o m y.  
c)  D oc u me nte d bilateral o o p h orect o m y.  
N ote: D oc u me nt ati o n c a n c o me fr o m t he st u dy ce nter pers o n n el’s: revie w of t he 
s u bject’s me dic al rec or ds, me dic al ex a mi n ati o n, or me dic al hist ory i ntervie w.  
3.  P ost me n o pa usal fe male:  
a)  A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca us e. A hi g h f ollicle sti m ulati n g h or m o ne ( F S H) l e vel i n t he 
p ost me n o pa usal ra n ge m a y be use d t o c o nfir m a p ost me n o pa usal state i n w o me n n ot 
usi n g h or m o nal c o ntrace pti o n or h or m o nal re place me nt t hera p y ( H R T). H o we ver, i n 
t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt.  
b)  Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use 1 of 
t he n o n-estr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y wis h t o 
c o nti n ue t heir H R T d uri n g t he st u d y. Ot her wise, t he y m ust disc o nti n ue H R T t o all o w 
c onfir mati o n of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.  
C o ntr ace pti o n G ui d a nce  
Fe male s u bjects of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o us e a hi g hl y 
effecti ve met h o d of c o ntrace pti o n c o nsiste ntl y a n d c orrectl y as descri be d i n Ta ble 1 8  bel o w.  

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Hi g hl y Effecti ve C o ntr a ce pti ve Met h o ds  
Hi g hl y Effecti ve C o ntr ace pti ve Met h o ds T h at Are User De pe n de nt
a  
F ail ure r ate of <  1 % per ye ar w he n use d c o nsiste ntly a n d c orrectly.  
C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n b  
•  
Oral.  
•  
I ntra v a gi nal.  
•  
Tra ns der mal.  
Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  
Oral.  
•  
I njecta ble.  
C o n d o ms  
Hi g hl y Effecti ve Met h o ds T h at Are User I n de pe n de nt
a 
I m pla nta ble pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n b 
•  
I ntra uteri ne de vice (I U D). 
•  
I ntra uteri ne h or m o ne-releasi n g s yste m (I U S). 
•  
Bilateral t u bal occl usi o n.  
V asect o mize d p art ner  
A v asect o mize d p art ner is a hi g hly effective birt h c o ntr ol met h o d pr ovi de d t h at t he p art ner is t he s ole m ale sex u al 
p art ner of t he W O C B P a n d t he a bse n ce o f s per m h as bee n c o nfir me d. If n ot, a n a d diti o n al hi g hly effective met h o d 
of c o ntr ace pti o n s h o ul d be use d.  
Se x u al a bsti ne nce  
Sex u al a bsti ne nce is c o nsi dere d a hi g hly effective met h o d o nly if defi ne d as refr ai ni n g fr o m heter osex u al 
i nterc o urse d uri n g t he e ntire peri o d of risk ass oci ate d wit h t he st u dy tre at me nt. T he reli a bility of sex u al a bsti ne n ce 
nee ds t o be ev al u ate d i n rel ati o n t o t he d ur ati o n of t he st u dy a n d t he preferre d a n d us u al lifestyle of t he s u bject.   
a. T y pical use fail ure rates ma y differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y. Use s h o ul d be c o nsiste nt wit h l ocal 
re g ulati o ns re gar di n g t h e use of c o ntrace pti ve met h o ds f or s u bjects partici p ati n g i n cli nical st u dies.  
b.  H or m o nal c o ntrace pti o n ma y be s usce pti ble t o i nteracti o n wit h t h e st u d y treat me nt, w hic h ma y re d uce t h e efficac y of t he 
c o ntrace pti ve met h o d. I n t his case, 2 hi g hl y effecti ve met h o ds of c o ntrace pti o n s h o ul d be utilize d d uri n g t h e treat me nt 
peri o d a n d f or at least 3 0  da ys after t h e last  d ose of st u d y treat me nt  or o ne f ull me nstr ual c ycle ; w hic he ver is l o n ger.  
Pre g n a nc y Testi n g : 
•  W O C B P are o nl y eli gi ble t o be i ncl u de d i n t he st u d y after a c o nfir m e d ne gati ve ser u m 
h C G  pre g na nc y t est at Visit  1  (Scree ni n g ).  
•  W O C B P will o nl y be i ncl u de d i n t he st u d y after a c o nfir me d ne g ati ve U P T  at Visit 2 
( Baseli ne). T he U P T m ust ha ve a mi ni m u m se nsiti vit y of 2 5 mI U β -h C G . 
•  A d diti o nal pre g na nc y testi n g will occ ur at ti mes s pecifie d i n t he S o A  Ta bl e  1 , Ta b le 
1 3 a n d as re q uire d l ocall y.  
 
 

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C ollecti o n of Pre g n a nc y I nf or m ati o n  
Fe m ale s u bjects w h o  bec o me pre g n a nt  
•  T he I n vesti gat or will c oll ect pre g n a nc y i nf or m ati o n o n a n y fe male s u bj ect w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y. I nf or mati o n will be rec or de d o n t he a p pr o pri ate 
f or m a n d s u b mitte d t o t he S p o ns or wit hi n 2 4 h o urs of lear ni ng of a s u bject’s pre g na nc y. 
T he s u bject will be f oll o we d t o deter mi ne t he o ut c o me of t he pre g na n c y. T he I n vesti gat or 
will c ollect f oll o w -u p i nf or mati o n o n t he s u bject a n d t he ne o nate, a n d t he i nf or mati o n 
will be f or war de d t o t he S p o ns or. Ge nerall y, f oll o w -u p will n ot be re q uire d f or l o n ger 
t ha n 6 t o 8 wee ks be y o n d t he esti mate d deli ver y date. A n y ter mi nati o n of pre g na nc y will 
be re p ort e d, re g ar dless of fetal stat us ( pres e nce or a bse nce of a n o malies) or i n dicati o n f or 
t he pr oce d ure. 
•  W hile pre g na n c y itself is  n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y 
c o m plicati o n or electi ve t er mi nati o n of a pre g na nc y will be re p orte d as a n A E or S A E. A 
s p o nta ne o us a b orti o n is al wa ys c o nsi dere d t o be a n S A E a n d will be re p ort e d as s uc h.  
•  A n y p ost -st u d y pre g na nc y relate d S A E c o nsi dere d reas o na bl y r elate d t o t he st u d y 
treat me nt b y t he I n v esti gat or will be re p ort e d t o t he S p o ns or as descri be d i n 
Secti o n  8. 4. 3 . W hile t he I n v esti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n 
f or mer s u bjects, he or s h e ma y lear n of a n S A E t hr o u g h s p o nta ne o us re p orti n g.  
•  A n y fe male s u bject w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y will be 
wit h dra w n fr o m t he st u d y.  
 
 

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A p pe n di x  5 : Ge netics  
Use/ A n al ysis of De o x yri b o n ucleic Aci d ( D N A)  
•  Ge netic variati o n ma y i m pact a s u bject’s res p o nse t o st u d y treat me nt, s usce pti bilit y t o, 
a n d se verit y a n d pr o gressi o n of disease. Varia ble res p o nse t o st u d y treat me nt ma y be d ue 
t o ge netic deter mi na nts t hat i m pact dr u g a bs or pti o n, distri b uti o n, meta b olis m, a n d 
e xcreti o n; mec h a nis m of acti o n of t he dr u g; diseas e eti ol o g y; a n d/ or m olec ular s u bt y pe of 
t he disease bei n g treate d. T heref ore, w here l o cal r e g ulati o ns a n d I R B/I E C all o w, a 
bl o o d/sali va / b uccal sa m ple will be c ollecte d f or D N A a nal ysis fr o m c o ns e nti n g s u bjects.  
•  D N A sa m ples will be use d f or res earc h rel ate d t o t o pical is otreti n oi n f or treat me nt of CI  
a n d relate d dis eases. G e n etic researc h m a y c o nsist of t he a nal ysis of 1 or m ore ca n di d ate 
ge nes or t he a nal ysis of g e netic mar k ers t hr o u g h o ut t he ge n o me (as a p pr o pri ate).  
•  I n t he s a m ples recei ve d fr o m s u bjects i n t he U S a n d Ca na da, D N A sa m ples will be 
a nal yze d usi n g C o n ge nit al Ic ht h y osis X o me D x Slice t o dia g n ose b ot h R X LI a n d A R CI.  
•  If t he sa m ples are recei ve d fr o m s u bjects i n E ur o p e , D N A sa m ples will be a nal yze d usi n g 
si n gle ge ne testi n g f or t h e detecti o n of a s pecifi c pa nel of ge n es, t o dia g n ose b ot h R X LI 
a n d A R CI.   
•  T he sa m ples ma y be a nal yze d as part of a m ulti-st u d y assess me nt of ge n etic fact ors 
i n v ol ve d i n t he res p o nse t o st u d y treat me nt or st u d y treat me nts of t his class t o u n dersta n d 
st u d y disease or relate d c o n diti o ns. 
•  T he res ults of ge n etic a n al yses ma y be re p or te d i n t he Cli nical St u d y Re p ort or i n a 
se parat e st u d y s u m mar y. 
•  T he D N A sa m ples will be ha n dle d b y a n i n d e pe n d e nt la b orat or y a n d will be destr o ye d 
u p o n t he c o m pleti o n of st u d y. T he y will be i n a sec ure st ora g e s pace wit h a de q uate 
meas ures t o pr otect c o nfi de ntialit y. T he tests are c o nsi dere d la b orat or y-de v el o pe d tests  
a n d are t h us re g ulate d p er U S re g ulati o ns 4 2 C F R 4 9 3 a n d t he la b orat or y is accre dite d b y 
t he C olle ge of A meric a n Pat h ol o gists. 
•  Ca usati ve Ge nes li n ke d t o A R CI : 
A B C A 1 2  
A L O X E 3  
A L O X 1 2 B  
C E R S 3  
C Y P 4 F 2 2  
NI P A L 4  
P N P L A 1  
S D R 9 C 7  
T G M -1  
If t he ge n etic res ults i ncl u de a n y of t he a b o ve m ut ati o ns a n d t he s u bject cli nicall y 
prese nts wit h La mellar Ic ht h y osis, t he y ma y be i ncl u de d i n t he st u d y.  
 
 

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A p pe n di x  6 : Si g n at ure of I n vesti g at or  
P R O T O C O L TI T L E:   T he A S C E N D St u d y: A P hase III, M ultice nter, D o u ble Bli n de d Ve hicle 
C o ntr olle d St u d y of T M B -0 0 1 - wit h a  P arallel O pti o nal Ma xi mal Use Ar m - i n t he Treat me nt of 
R X LI ( X -li n ke d) or A R CI Ic ht h y osis i n S u bjects A ge d ≥6 Years 
P R O T O C O L N O:  
T M B 0 1 -3 0 1  
V E R SI O N:  
 
2. 0 2 5 J ul y 2 0 2 2; Pr ot oc ol A me n d me nt 1  
T his pr ot oc ol is a c o nfi de ntial c o m m u nicati o n of Ti m ber P har mace uticals, L L C. I c o nfir m t hat I 
ha ve rea d t his pr ot oc ol, I u n dersta n d it, a n d I will w or k acc or di n g t o t his pr ot oc ol. I will als o 
w or k c o nsiste ntl y wit h t he et hical pri nci ples t hat h a ve t heir ori gi n i n t he Declarati o n of Helsi n ki 
a n d t hat are c o nsiste nt wit h G o o d Cli nical Practices a n d t he a p plica ble l a ws a n d re g ulati o ns. 
Acce pt a nce of t his d oc u me nt c o nstit utes m y a gree me nt t hat n o u n p u blis he d i nf or mati o n 
c o ntai ne d herei n will be p u blis he d or discl ose d wit h o ut pri or writte n a p pr o val fr o m t he S p o ns or.  
I nstr ucti o ns t o t he I n vesti g at or:  Please SI G N a n d D A T E t his si g nat ure pa ge. P RI N T y o ur na me, title, a n d t he na me of t h e st u d y 
ce nter i n w hic h t he st u d y will be c o n d ucte d. Ret ur n t h e si g ne d c o p y t o C R O.  
 
I h a ve rea d t his pr ot oc ol i n its e ntiret y a n d a gree t o c o n d uct t he st u d y acc or di n gl y: 
 
Si g nat ure of I n vesti gat or:      _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _            Date:  _ _ _ _ _ _ _ _  
Pri nte d Na me:                                _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
I n v esti gat or Title:                           _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
Na me/ A d dress of Ce nter:               
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
 
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 
 
 
 
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A p pe n di x  8: Der m at ol o g y Life Q u alit y I n de x  

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A p pe n di x  9: C hil dre n’s Der m at ol o g y Life Q u alit y I n de x  

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Pa ge 8 8  of 9 0  
 
A p pe n di x  1 1 : P atc h Testi n g  
C o ntact der matitis re prese nts t w o f or ms of e x o ge n o us ecze mat o us der matitis; irrita nt a n d aller gic c o ntact 
der matitis.  Irrita nt der matitis re prese nts a direct t o xic effect of c he micals o n e pi der mal cells res ulti n g i n 
destr ucti o n of s ki n cells  a n d i m pair me nt of barrier f u ncti o n.  Aller gic c o ntact der matitis is dela ye d t y pe 
h y perse nsiti vit y (aller g y) t o s mall m olec ular wei g ht m olec ules a n d re q uires i nitial se nsitizati o n a n d t he n 
s u bse q ue nt elicitati o n.  Aller gic c o ntact der matitis m ost ofte n occurs wit hi n da ys t o wee ks after re peate d 
e x p os ure t o pr o v ocati ve c he micals.  Aller gic c o ntact der matitis t o acti ve i n gre die nts a n d e xci pie nts of 
t o pical pr o d ucts is well descri be d i n t he literat ure.   
 
Patie nts s us pecte d of ha vi n g a n a d verse e ve nt of h y pers e nsiti vit y/aller gic c o ntact der matitis t o t he 
t o picall y a p plie d i n vesti gati o nal pr o d uct will be e val uate d b y t he i n vesti gat or b y patc h testi n g.  If 
te m p orar y wit h dra wal of t he i n vesti gati o nal me dicati o n d oes n ot res ult i n a meli orati o n of s y m pt o ms, 
t o pical c ortic oster oi ds ma y be e m pl o ye d a n d t he patie nt ca n disc o nti n ue t he trial.  T he pres u m pti o n of 
p ossi ble aller gic c o ntact der matitis will be base d o n t he i n vesti gat or’s e val uati o n of a n ecze mat o us 
a p peari n g er u pti o n (er yt he mat o us, scal y, vesic ular, or er o de d patc h or pla q ue) occ urri n g at a pre vi o usl y 
clear site t hat is t he rece nt or c urre nt reci pie nt of t he i n vesti gati o nal pr o d uct.  
 
Patc h test a p plicati o n sites s h o ul d i deall y be cli nicall y i nacti ve wit h o ut a n y ecze mat o us der matitis, a n d as 
i nacti ve a n area of ic ht h y osis as is cli nicall y practica ble.  T he site of t he patc h test s h o ul d n ot be a djace nt 
t o t he c urre ntl y s us pecte d ecze mat o us area.  Patie nts utilizi n g t o pical c ortic oster oi ds f or ot her l ocal s ki n 
reacti o ns s h o ul d was h o ut f or 1 wee k pri or t o t he i nitiati o n of patc h testi n g.  Flat areas s uc h as t he u p per 
bac k are preferre d, b ut alter nati ve sites s uc h as t he ve ntral f orear m or t hi g h ca n be use d if t he bac k is n ot 
clear.   Hair beari n g areas s h o ul d be pre p pe d wit h a safet y raz or t o e ns ure a d hesi o n of t h e test material. 
 
Patc h test c o nse nts a n d dis p ositi o n of si g ns a n d s y m pt o ms will be rec or de d i n t he s o urce d oc u me nt a n d 
e C R F. T he i n vesti gat or will a p pl y a n a p pr o xi matel y 5 m m ri b b o n of i n vesti gati o nal t o pical me dicati o n 
fr o m t he patie nt’s e xisti n g me dicati o n s u p pl y t o t he i nteri or p orti o n of a n I Q ultra patc h test c ha m ber 
( C he m otec h ni q ue, S we de n) a n d sec ure d wit h a d diti o nal pa per ta pe.  T w o a d diti o nal tests will c o nsist of a 
ve hicle c o ntr ol a n d w hite petr olat u m t hat will be s u p plie d b y t he s p o ns or u p o n re q uest.  T he c ha m bers 
will re mai n i n place f or a p pr o xi matel y 4 8 h o urs ( 2 da ys).  Patie nts will prese nt t o t he cli nical site f or 
re m o val of t he patc h test a n d i nitial i nter pretati o n b y t he i n vesti gat or.  ( See i nter pretati o n g ui deli ne bel o w 
fr o m t he I nter nati onal C o ntact Der matitis Researc h Gr o u p).  Patie nts will ret ur n 1 -4 da ys after re m o val 
f or a n a d diti o nal a n d fi nal i nter pretati o n of t he patc h test.  Patc h test res ults will be rec or de d i n t he s o urce 
d oc u me nt a n d e C R F.  
 
 
Patc h test i nter pretati o n acc or di n g t o t he I nter nati o nal C o ntact Der matitis Researc h Gr o u p (I C D R G)  
? +  
D o u btf ul  
+  
Mil d reacti o n, p ossi ble er yt he ma, i nfiltrati o n a n d pa p ules  
+ +  
Str o n g reacti o n, er yt he ma, i nfiltrati o n, pa p ules a n d vesicles  
+ + +  Ver y str o n g reacti o n, i nte nse er yt he ma, i nfiltrati o n a n d c oalesci n g vesicles  
I R 
Irrita nt reacti o n, of vari o us t y pes 
 
 
 
 

C o nfi de ntial  
Ti m ber P har mace uticals, L L C  
 
Pr ot oc ol T M B 0 1 -3 0 1  V 2. 0  
 
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A p pe n di x  1 2 : A b bre vi ati o ns  
A E  
A d verse e ve nt  
A N C O V A  
A nal ysis of c o vari a nce  
A R CI  
A ut os o mal recessi ve c o n ge nital ic ht h y osis  
β -h C G  
B eta-h u ma n c h ori o nic g o na d otr o pi n  
BI D  
T wice dail y  
B S A  
B o d y s urface area  
C D L QI  
C hil dre n Der mat ol o g y Life Q ualit y I n de x  
C F R  
C o de of Fe d eral Re g ulati o ns  
CI  
C o n ge nital ic ht h y osis  
CI O M S  
C o u ncil f or I nter nati o nal Or ga nizati o ns of M e dical Scie nces  
C M H  
C oc hra n -Ma nt el -Hae nszel  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O VI D -1 9  
C or o na vir us Disease 2 0 1 9  
C R O  
Cli nical researc h o r ga ni zati o n 
D L QI  
Der mat ol o g y Life Q ualit y I n d e x  
D N A  
De o x yri b o n ucleic Aci d  
e C R F 
E lectr o nic c ase re p ort for m  
e Diar y  
Electr o nic diar y  
E O S  
E n d of st u d y 
e P R O 
Electr o nic p atie nt-re p ort e d o utc o me  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
F ollicle sti m ulati n g h or m o ne  
G C P  
G o o d Cli nical Practice  
G M P  
G o o d Ma n ufact uri n g Practice  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y A ct  
H R T  
H or m o nal re pla ce me nt t h era p y  
I C F 
I nf or me d c o ns e nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I G A 
I n v esti gat or Gl o bal Assess me nt  
I-N R S  
Itc h-N u meri c Rati n g Scale  
I Q o L-3 2  
Ic ht h y osis Q ualit y of Life -3 2  
I R B 
I nstit uti o nal Re vie w B oar d 

C o nfi de ntial  
Ti m ber P har mace uticals, L L C  
 
Pr ot oc ol T M B 0 1 -3 0 1  V 2. 0  
 
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I T T 
Inte nt -t o-treat 
I W R S 
I nteracti ve We b Res p o ns e S yste m 
LI  
La mellar ic ht h y osis  
L S R  
L ocal s ki n reacti o ns  
M A R  
Missi n g at ra n d o m  
M C M C  
Mar k o v C hai n M o nte Carl o  
Me d D R A  
Me dical Dicti o nar y f or R e g ulat or y Acti vities  
MI  
M ulti ple i m p utati o n  
mI T T  
M o difie d i nte nt -t o-treat 
O T C  
O ver -t he-c o u nter  
P P  
P er-pr ot oc ol  
P T  
Preferre d ter m  
Q D  
O nce a d a y  
Q o L  
Q ualit y of Life  
R A  
Reti n oic aci d  
R O A T  
R e peat o pe n a p plicati o n test  
R X LI  
Recessi ve X -li n ke d i c ht h y osis 
S A E  
S eri o us a d verse e ve nt  
S A P  
Statistical anal ysis p la n 
S D  
Sta n dar d de viati o n  
S o A  
Sc he d ule of Assess me nts  
S O C  
S yste m or ga n class  
S T S  
S ter oi d s ulfatase 
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o ns  
T E A E  
Treat me nt -e mer ge nt a d v erse e v e nt  
T G M 1  
T ra ns gl uta mi nase t y pe 1  
U L N  
U p per li mit of n or mal  
U P T  
U ri ne pre g n a nc y test 
U S  
U nite d States  
U V  
U ltra vi olet  
VII S  
Vis ual I n d e x f or Ic ht h y osis Se verit y  
VII S -5 0  
Vis ual I n d e x f or Ic ht h y osis Se verit y –  Scale “treat me nt s uccess”  
W O C B P  
W o me n of c hil d beari n g p ote ntial