Clinical trial NCT03976648
Conditions: Systemic Sclerosis
Sponsor: Galapagos NV
Start date: 2019-07-18; Completion date: 2021-04-13
Enrollment: 31 participants; Allocation: NA; Intervention model: PARALLEL

Brief summary:
This study was the extension of the double-blind study GLPG1690-CL-204 (NCT03798366). The main purpose of the study was to see how GLPG1690 was tolerated in participants with systemic sclerosis and whether there were any side effects in a long-term treatment period.

Detailed description:

Arms: arm 1: Participants who received GLPG1690 600 milligrams (mg) in the GLPG1690-CL-204 (NCT03798366) study received GLPG1690 600 mg orally once daily up to 91 weeks. arm 2: Participants who received placebo matched to GLPG1690 in the GLPG1690-CL-204 (NCT03798366) study received GLPG1690 600 mg orally once daily up to 91 weeks.
Interventions: intervention 1: GLPG1690
Intervention descriptions: intervention 1: film-coated tablets of GLPG1690 to be administered orally

Protocol documents:
Prot_000.pdf: 
-1 - 
 
 
C o nfi de nti alit y St ate me nt  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is pri vile ge d a n d c o nfi de ntial. It is t he pr o pert y of Gala pa g os N V a n d 
ma y n ot be use d, discl ose d, re pr o d uce d or ot her wise disse mi nate d wit hi n y o ur or ga nizati o n or c o m m u nicate d t o a n y 
t hir d parties wit h o ut t he e x press writte n a ut h orizati o n of Gal a pa g os N V. 
 
 
C LI NI C A L S T U D Y P R O T O C O L  
Pr oj e ct N u m b er:   
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St u d y N u m b er :  
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A m e n d m e nt:   
1  
 
 
St u d y Titl e   
A m ulti c e nt er , o p e n -l a b el e xt e n si o n st u d y t o e v al u at e t h e l o n g-t er m s af et y, 
t ol er a bilit y a n d effi c a c y of or all y a d mi ni st er e d G L P G 1 6 9 0 i n s u bj e ct s wit h 
s y st e mi c s cl er o si s  
St at u s  
Fi n al  
D e v el o p m e nt 
P h a s e:  
2  
 
 
E u dr a C T N o:   
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C T. g o v N o:   
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I N D N o 
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S p o n s or:  
G al a p a g o s N V, G e n er a al D e Witt el a a n L 1 1 A 3, 2 8 0 0 M e c h el e n, B el gi u m  
M e di c al L e a d er : 
, M D 
G e n er al Pr ot o c ol  
 


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E M E R G E N C Y C O N T A C T I N F O R M A TI O N  
I n case of a seri o us a d verse e ve nt ( S A E), a special sit uati o n (see S ecti o n 8. 1. 6 ) or i n cas e of 
pre g n a nc y  d uri n g t he cli nical st u d y t he i n vesti gat or m ust re p ort t his i m me diatel y, a n d u n der n o 
circ u msta nces later t ha n 2 4 h o urs f oll o wi n g t he k n o wle d ge of t he S A E or pre g na nc y, as f oll o ws:   
  
Fa x 
 
or  
E -mail: 
 
 
I n case of me dical q u esti o ns d uri n g t he c o urse of t he st u d y, t he i n vesti gat or m ust c o ntact t he 
c o ntract r esearc h or ga nizati o n ( C R O)  m e dical m o nit or . F or ur ge nt me dical safet y q uesti o ns, t he 
i n vesti gat or ca n c o nt act t he safet y h otli ne:  
 
C o ntact Safet y H otli ne:  
E M E A: 
 
N ort h A merica: 
 
 
 
S p o ns or co ntact  n u m ber : 
  
 
 
 


 
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T A B L E O F C O N T E N T S  
E M E R G E N C Y C O N T A C T I N F O R M A TI O N  ........................................................................... 2  
T A B L E O F C O N T E N T S  ........................................................................................................ 3  
C LI NI C A L S T U D Y P R O T O C O L HI S T O R Y  ............................................................................ 7  
S U M M A R Y O F C H A N G E S  ................................................................................................... 8  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S ..................................................1 2  
P R O T O C O L S Y N O P SI S  ......................................................................................................1 6  
1.  
I N T R O D U C TI O N ...........................................................................................................1 9  
1. 1.   
B a c k gr o u n d - N o n cli ni c al St u di e s  .......................................................................2 0  
1. 1. 1.   
P h y si c al, C h e mi c al, P h ar m a c e uti c al Pr o p erti e s, a n d F or m ul ati o n  .......2 0  
1. 1. 2.   
P h ar m a c ol o g y  .....................................................................................2 0  
1. 1. 2. 1.   
Pri m ar y a n d S e c o n d ar y P h ar m a c ol o g y  ..............................2 0  
1. 1. 2. 2.   
S af et y P h ar m a c ol o g y  .........................................................2 1  
1. 1. 3.   
N o n cli ni c al P h ar m a c o ki n eti c s a n d Pr o d u ct M et a b oli s m  ......................2 1  
1. 1. 4.   
T o xi c ol o g y  ..........................................................................................2 2  
1. 1. 4. 1.   
G e n er al T o xi c ol o g y  ............................................................2 2  
1. 2.   
B a c k gr o u n d - Cli ni c al St u di e s  ............................................................................2 3  
1. 2. 1.   
Cli ni c al S af et y  .....................................................................................2 3  
1. 2. 2.   
Cli ni c al Effi c a c y  ...................................................................................2 4  
1. 2. 3.   
C li ni c al P h ar m a c o ki n eti c s ...................................................................2 4  
1. 2. 4.   
Cli ni c al P h ar m a c o d y n a mi c s  ................................................................2 5  
2.  
C LI NI C A L S T U D Y O B J E C TI V E S  ..................................................................................2 5  
2. 1.   
Pri m ar y O bj e cti v e ...............................................................................................2 5  
2. 2.   
Ot h er  O bj e cti v e s  ................................................................................................2 5  
3.  
I N V E S TI G A TI O N A L P L A N ............................................................................................2 6  
3. 1.   
Cli ni c al St u d y D e si g n  .........................................................................................2 6  
3. 2.   
E n d of St u d y D efi niti o n  ......................................................................................2 7  
3. 3.   
Cli ni c al St u d y R ati o n al e  .....................................................................................2 7  
3. 3. 1.   
D o s e R ati o n al e  ...................................................................................2 7  
3. 3. 2.   
Cli ni c al St u d y D e si g n R ati o n al e  ..........................................................2 7  
3. 4.   
E n d p oi nt s  ...........................................................................................................2 7  
3. 4. 1.   
Pri m ar y E n d p oi nt  ................................................................................2 8  
3. 4. 2.   
Ot h er E n d p oi nt s  ..................................................................................2 8  
3. 5.   
P ot e nti al Ri s k s a n d B e n efit s  ..............................................................................2 8  
3. 6.   
Cli ni c al St u d y P o p ul ati o n  ...................................................................................2 9  
3. 6. 1.   
I n cl u si o n Crit eri a .................................................................................2 9  
3. 6. 2.   
E x cl u si o n Crit eri a  ................................................................................3 0  
3. 6. 3.   
P r o hi biti o n a n d R e stri cti o n s ................................................................3 0  
3. 6. 3. 1.   
Pr e c a uti o n s f or S e x u al I nt er c o ur s e  ....................................3 0  
3. 6. 3. 1. 1.   
F e m al e s u bj e ct s .............................................3 0  






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9. 2. 3.   
Ar c hi vi n g  .............................................................................................5 9  
9. 2. 4.   
P arti ci p ati o n C ar d s  ..............................................................................6 0  
9. 3.   
C o nfi d e nti alit y  ....................................................................................................6 0  
9. 4.   
Et hi c al  C o n si d er ati o n s  .......................................................................................6 1  
9. 4. 1.   
I n d e p e n d e nt Et hi c s C o m mitt e e / I n stit uti o n al R e vi e w B o ar d ...............6 1  
9. 4. 2.   
I nf or m e d C o n s e nt ...............................................................................6 1  
9. 5.   
D at a Q u alit y C o ntr ol/ A s s ur a n c e  .........................................................................6 2  
9. 5. 1.   
M o nit ori n g  ...........................................................................................6 2  
9. 5. 2.   
A u dit a n d I n s p e cti o n  ...........................................................................6 2  
1 0.  R E F E R E N C E S  ..............................................................................................................6 3  
1 1.  A P P E N DI C E S  ...............................................................................................................6 4  
SI G N A T U R E P A G E –  S P O N S O R  ........................................................................................6 9  
SI G N A T U R E P A G E –  I N V E S TI G A T OR  ...............................................................................7 0  
 
 






G al a p a g o s  
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E ve nts meeti n g t he f oll o wi n g defi ne d criteria m ust be re p orte d as a seri o us a d verse e ve nt ( S A E) a n d 
In vesti gati o nal Me dici nal Pr o d uct (I M P)  m ust be disc o nti n ue d:  
  A S T or A L T ≥8 x U L N  
  A S T or A L T ≥3 x U L N wit h si g ns of se vere li ver da ma ge (i.e. wit h t he a p peara nce of fati g ue, na usea, 
v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h a n d/ or e osi n o p hilia [ > 5 %], a n d/ or t otal 
bilir u bi n ≥1. 5 x U L N or inter nati o nal n or malize d rati o [I N R] > 1. 5)  
T he i n vesti gati o ns a n d ste ps t o be ta ke n b y t he i n vesti gat or ha ve bee n descri be d i n Secti o n 3 .6 . 4. 
A p plic a ble Secti o ns:  
Secti o n 3 .6 . 4 Treat me nt Disc o nti n uati o n ( T e m p oraril y a n d Per ma ne ntl y), S u bj ect Wit h dra wal a n d St u d y 
T er mi nati o n  
Secti o n 8. 1. 5. Cli nical La b orat or y A b n or malities a n d O ther A b n or mal Assess me nts as A d verse E ve nts or 
Seri o us A d verse E ve nts  
H y dr o x yc hl or o q ui ne has bee n a d de d t o t he list of me dicati o n k n o w n t o pr ol o n g Q T i nter val (t o be use d wit h 
ca uti o n)  i n A p pe n di x 5, a n d felo di pi ne was re m o ve d fr o m t he list of pr o hi bite d me dicati o n ( Errat u m 2, 
2 7 -A u g -2 0 1 9 ). 
S u b o x o ne was re m o ve d fr o m t he list of k n o w n str o n g c yt oc hr o me P 4 5 0 ( C Y P) C Y P 3 A 4 i n hi bit ors beca use 
its c o nstit ue nts, nal o x o ne a n d b u pe n o p hi ne are n ot k n o w n t o be str o n g i n hi bit ors. 
T he pr o hi biti o n of B -cell de pleti n g a ge nts has bee n br oa de ne d t o “ ot her m o n ocl o nal a nti b o dies”.  
Restricti o ns o n t he c o ns u m pti o n of d o u ble -stre n gt h gra pefr uit j uice ha ve bee n a d de d i n Se cti o n 3. 6. 3. 3.  
A p plic a ble Secti o ns :  
Secti o n 3. 6 . 3. 2 Pri or a n d C o nc o mita nt Me dicati o ns  
Secti o n 3. 6. 3. 3 F o o d a n d Be vera ge Restricti o ns  
A p pe n di x 2 K n o w n Str o n g C Y P 3 A 4 I n d ucers a n d P ote nt P -g p I n d ucers  
A p pe n di x 3  K n o w n Str o n g C Y P 3 A 4 I n hi bit ors  
A p pe n di x 5 Me dicati o n K n o w n t o Pr ol o n g Q T i nter val  
T he E C G para meter Q T c B  will n ot be deri ve d.  
A p plic a ble Secti o n:   
Secti o n 5 . 6. 5 1 2-lea d Electr ocar di o gra m 
T he pr ot oc ol was u p date d wit h g ui da nce f or male s u bj ects t o wit h dra w if t he y i nte n d t o fat her a c hil d.  
A p plic a ble Secti o ns:  
Secti o n 3. 5  P ote ntial Ris ks a n d Be nefits  
Secti o n  3. 6. 3. 1. 2 Preca uti o ns f or Se x ual I nterc o urse: Male s u bj ects  


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T he pr ot oc ol was u p date d t o c orrect t he Safet y h otli ne n u m b er a n d e -mail  a d dress ( Errat u m 1 , 2 3-J ul-2 0 1 9 ). 
A p plic a ble Secti o ns :  
E mer ge nc y C o ntact I nf or mati o n  
Mi n or e dits a n d a d mi nistrati ve u p dates t hr o u g h o ut t he pr ot oc ol.   
A p plic a ble Secti o ns :  
List of A b bre viati o ns a n d Defi niti o n of T er ms  
Secti o n 3. 3  Cli nical St u d y Rati o nale  
Secti o n 3. 6. 3. 3 F o o d a n d Be vera ge Restricti o ns  
Secti o n 3. 6. 4 Treat me nt Disc o nti n uati o n  ( T e m p oraril y a n d Per ma ne ntl y), S u bj ect Wit h dra wal a n d St u d y 
T er mi nati o n  
Secti o n 4. 4 St ora ge  
Secti o n 5. 6. 2 Cli nical La b orat or y E val uati o ns  
Secti o n 6. 3. 2 I nteri m A nal ysis  
A p pe n di x 2  
A p pe n di x 5  
 
 
 


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U p date t o Versi o n 1. 0 0  (0 9 -A pr -2 0 1 9 ) 
T he o ver all re as o n f or t his u p d ate : 
A d diti o n of E u dra C T n u m ber  a n d pr ot oc ol clarificati o ns. 
T he c h a n ges ma de t o C S P G L P G 1 6 9 0 -C L -2 0 6 Versi o n  1. 0 0 date d 3 0 -Ja n-2 0 1 9, are liste d  bel o w, reflecti n g a 
brief rati o nale of eac h c ha n ge a n d t he a p plica ble secti o ns.  
T he pr ot oc ol  E u dra C T n u m ber  a d de d 
A p plic a ble Se cti o ns: 
Title pa ge  
T he pr ot oc ol was u p date d t o clarif y t hat d osi n g of I n vesti gati o nal Me dici nal Pr o d uct (I M P) i n t his st u d y starts 
o n t he da y after t he R oll o ver visit  
A p plic a ble Secti o ns :  
S y n o psis  
Secti o n 3. 1 Cli nical St u d y desi g n  
Secti o n 5. 8 Sc he d ule of  Acti vities  
T he list of safet y la b orat or y para meters was u p date d t o ali g n wit h t he pri or G L P G 1 6 9 0-C L -2 0 4 st u d y  
A p plic a ble Secti o ns :  
Secti o n 5. 6. 2 Cli nical La b orat or y E val uati o ns  
Clarificati o ns ha ve bee n ma de t hr o u g h o ut t he pr ot oc ol.  
 
 
 
 


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LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N O F T E R M S  
A b bre vi ati o ns  
A D L   
acti vities of dail y li vi n g  
A E  
a d verse e ve nt  
A L T   
ala ni ne a mi n otra nsferas e  
A S T   
as partate a mi n otra nsferas e  
 
 
A T X   
a ut ota xi n 
 
  
B C R P   
breast c a ncer resista nce pr otei n  
B W  
b o d y wei g ht  
C R F   
case re p ort f or m  
 
 
C R O   
c o ntract r esearc h or ga nizati o n  
C S P   
cli nical st u d y pr ot o c ol  
C T C A E   
C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts  
C Y P   
c yt o c hr o me P 4 5 0  
E C G   
electr ocar di o gra m  
E D  
earl y disc o nti n uati o n  
E N P P   
ect o n ucle oti de p yr o p h os p hatase/ p h os p h o diesterase  
E o T  
e n d of treat me nt  
E U  
E ur o pea n U ni o n  
F A S   
f ull a nal ysis set 
 
 


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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(s)  
G G T   
ga m ma gl uta m yl tra nsferase  
GI  
gastr oi ntesti nal  
G L P   
G o o d La b orat or y Practice  
I B 
i n vesti gat or’s br oc h ure 
I C5 0 
5 0 % i n hi bit or y c o n ce ntrati o n  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o nisati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u m a n Use  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I L-6   
i nterle u ki n 6  
I M P  
i n vesti gati o nal me dici nal pr o d uct 
I N R 
i nter nati o nal n or malize d rati o 
I P F 
i di o pat hic p ul m o nar y fi br osis 
I R B 
I nstit uti o nal Re vie w B oar d 
L F T   
li ver f u ncti o n test 
L P A   
l ys o p h os p hati dic aci d 
L P C   
lys o p h os p hati d yl c h oli ne  
L P D   
l ys o p h os p h oli pase D  
M A T E   
m ulti dr u g a n d t o xi n e xtr usi o n  tra ns p orter 
M CI D   
Mi ni mal Cli nicall y I m p orta nt Differe nce  
M M F   
m yc o p h e n olate m ofetil  




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Defi niti o n of Ter ms  
Q Tc F   
Q T i nter val c orrecte d f or heart rate  usi n g Fri derici a’s f or m ula:  
Q Tc F = Q T/ R R 1/ 3 


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P R O T O C O L S Y N O P SI S  
T itle of St u d y 
A m ultice nter, o pe n -l a bel e xte nsi o n st u d y t o e val u ate t he l o n g-ter m safet y, t olera bilit y a n d 
efficac y of orall y a d mi nistere d G L P G 1 6 9 0 i n s u bjects wit h s yste mic s cler osis. 
P h ase of De vel o p me nt : 2  
Pl a n ne d N u m ber o f S u bjects  
U p t o 3 0  s u bjects ma y  roll o ver fr o m St u d y G L P G 1 6 9 0-C L -2 0 4 i nt o t his o p e n -la bel 
e xte nsi o n  ( O L E) st u d y. 
St u d y D ur ati o n  
Eac h s u bject will be i n t h e st u d y f or u p t o 1 1 6 wee ks ( 1 0 4 wee ks of treat me nt a n d 1 2 wee ks 
of f oll o w -u p).   
St u d y Desi g n  
A n o pe n -la bel, m ultice nt er, si n gl e-ar m, 1 0 4 -wee k e xte nsi o n st u d y f or s u bjects wit h 
s yste mic scler osis w h o c o m plete d t he 2 4-wee k  d o u ble -bli n d treat me nt peri o d of St u d y 
G L P G 1 6 9 0 -C L -2 0 4.  
O bjecti ves a n d E n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ary  
 
T o e val uate t he l o n g-ter m safet y a n d t olera bilit y of 
G L P G 1 6 9 0 i n s u bj ects wit h s yste mic scler osis . 
I nci de nce of treat me nt-e mer ge nt a d verse e ve nts 
( T E A Es), seri o us a d verse e ve nts ( S A Es), A Es o ver 
ti me. 
Key Sec o n d ary  
 
N ot a p plica ble  
 
 
M ai n Criteri a f or I ncl usi o n a n d E xcl usi o n  
Ke y I ncl usi o n Criteria  
 
Male or fe m ale s u bjects w h o c o m plete d t he 2 4 -wee k treat me nt peri o d of St u d y 
G L P G 1 6 9 0 -C L -2 0 4 a n d w h o acc or di n g t o t he i n vesti gat or’s j u d g m e nt ma y be nefit 
fr o m l o n g-ter m treat me nt wit h G L P G 1 6 9 0. 
Ke y E x cl usi o n Criteria  
 
A n y c o n diti o n or circ u msta nces t hat, i n t he o pi ni o n of t he i n vesti gat or, ma y ma ke a 
s u bject u nli kel y or u na bl e t o c o m plete t he st u d y or c o m pl y wit h st u d y pr oce d ures a n d 
re q uire me nts. 






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1.   
I N T R O D U C TI O N 
S yste mic S cler osis  
S yste mic scler osis (scler o der ma) is a rare a ut oi m m u ne disease of t he c o n n ecti ve tiss ue wit h t he 
hi g hest m ortalit y rate of all r he u matic diseas es. T he disease h as a fe male pre d o mi na nce ( 3: 1) a n d 
a pea k o nset i n t he f o urt h deca d e of life. S yste mic scler osis has 3  maj or pat h o ge ni c c o m p o ne nts: 
(i) fi br osis wit h t hic ke ni n g of t he s ki n a n d i n ner or ga ns, (ii) i nfla m mati o n, a n d (iii) vasc ul o pat h y. 
Maj or or ga ns affecte d are t he s ki n, t he l u n g ( p ul m o nar y fi br osis a n d p ul m o nar y arterial 
h y perte nsi o n), t he ki d ne ys, t he  gastr oi ntesti nal ( GI) tract, t he m usc ul os kel etal s yste m, t he 
retr o perit o neal s pace, a n d t he heart. C urre nt treat me nt o pti o ns f or s yste mi c scler osis are li mite d 
a n d i ncl u de t o pical s ki n treat me nts, n o nster oi dal a nti -i nfla m mat or y dr u gs, ster oi ds, a n d ot her 
i m m u n os u p pressa nts ( met hotre x ate, m yc o p he n ol ate m ofetil  [ M M F], azat hi o pri ne, 
c ycl o p h os p ha mi de).  
At prese nt, t here are n o a p pr o ve d dr u gs f or t he treat me nt of s yste mic s cler osis, i n dicati n g a hi g h 
u n met me dical nee d.  
M o de of Acti o n  
G L P G 1 6 9 0 is a n o v el, p ote nt,  a n d selecti ve s mall -m olec ule i n hi bit or of a ut ota xi n ( A T X ), 
tar geti n g dis ease rele va nt si g nal tra ns d u cti o n pat h wa ys, c urre ntl y i n de vel o p me nt f or t he 
treat me nt of s yste mic scl er osis. 
A T X, als o k n o w n as ect o n ucle oti de p yr o p h os p hat ase/ p h os p h o diesteras e ( E N P P) 2 or 
l ys o p h os p h oli pase D ( L P D), is a ~ 1 2 0 -k Da pr otei n t hat bel o n gs t o t he E N P P e nz y me fa mil y. 
A T X is t he o nl y E N P P e nz y m e wit h L P D acti vit y a n d is res p o nsi ble f or t he h y dr ol ysis of 
l ys o p h os p hati d yl c h oli ne ( L P C) t o pr o d u ce t he bi o acti ve li pi d l ys o ph os p hati dic aci d ( L P A). T he 
ter m L P A c o vers s e veral c he mical s pe cies a ble t o acti vate L P A rece pt ors d e pe n di n g o n t he nat ure 
of t he fatt y aci d si de c hai n o n t he gl ycer ol bac k b o ne. T he m ost a b u n da nt L P A s pecies i n h u ma n 
plas ma is L P A C 1 8: 2 wit h a fatt y aci d si de c hai n of 1 8 car b o n at o ms i ncl u di n g t w o  u nsat urate d 
b o n ds  ( Ba n d o h, et al. 2 0 0 0). Literat ur e data ha ve i de ntifie d t he A T X/ L P C a xis as t he mai n s o urce 
of L P A i n bl o o d ( Ta na ka, et al. 2 0 0 6, Ts u da, et al. 2 0 0 6).  
L P A acts t hr o u g h 6  differe nt G -pr otei n c o u ple d rece pt ors ( L P A 1 -6) w here b y mai nl y L P A 1 -3 
ha ve bee n ass ociat e d wit h t he pat h o ge nic ( pr o -i nfla m mat or y a n d pr o-fi br otic) effects of L P A. 
Tar geti n g t he A T X p at h wa y b y a nta g o nizi n g L P A 1 i n a p re vi o us P hase 2 a st u d y ( S A R 1 0 0 8 4 2) i n 
s yste mic scler osis was w ell t olerate d a n d res ulte d i n cli nical i m pr o ve me nts of s ki n pat h ol o gies 
( m o difie d R o d na n S ki n S c ore [ m R S S]) a n d s ki n bi o mar kers, s u g gesti n g t hat tar geti n g t he A T X 
pat h wa y is pr o misi n g i n m o d ulat i n g s ki n pat h ol o gies i n s yste mic scler osis ( Alla n ore, et al. 2 0 1 8). 
A vaila ble literat ur e a n d n o ncli nical p har mac ol o g y data ge nerate d b y Gala pa g os s u g gest t hat 
i nter ve nti o ns tar geti n g t he A T X/ L P A pat h wa y c o ul d lea d t o a ne w class of t hera p y f or dis ease 
m o dificati o n i n s yste mic scler osis . 
F or m ore d etails, refer t o t he latest versi o n of t he i n vesti gat or’s br oc h ure (I B) a n d rele va nt 
u p dates/a d de n da.  




G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-2 1 - 
 
T he ef fi cac y of G L P G 1 6 9 0 was assesse d i n a m uri ne m o del of c hr o nic graft-vers us -h ost disease 
rese m bli n g k e y c o m p o ne nts of der mal a n d p ul m o nar y s yste mic scler osis disease ma nifest ati o ns 
b y e v al uati n g cli nical sc ori n g, der mal t hic ke ni n g, h y dr o x y pr oli ne c o nte nt, a n d m y ofi br o blast 
c o u nts. I n t his m o del , G L P G 1 6 9 0 s h o we d effi cac y f or s ki n a n d l u n g rea d-o ut para meters si milar 
t o t hat of ni nte da ni b. 
1. 1. 2. 2.   
S af et y P h ar m a c ol o g y  
T he safet y p h ar mac ol o g y pac ka ge c o n d uct e d t o i n vesti gate t h e p ote ntial effect of G L P G 1 6 9 0 o n 
car di o vas cular, res pirat or y, a n d ce ntr al ner v o us s yste ms di d n ot s h o w a n y bi ol o gicall y rel e va nt 
effects.  
1. 1. 3.   
N o n cli ni c al P h ar m a c o ki n eti c s a n d Pr o d u ct M et a b oli s m  
T he a bs ol ute oral bi oa v aila bilit y was m o derate i n r o de nts ( 2 5 % t o 3 6 %), l o w i n m o n ke ys ( 1 4 %), 
a n d hi g h i n d o gs ( 1 0 2 %).  
G L P G 1 6 9 0 was hi g hl y b o u n d t o plas ma pr otei ns: 9 9. 1 % i n h u ma n a n d 9 7. 9 -9 9. 6 % i n rat, d o g, 
m o use, ra b bit, a n d m o n k e y.  
O verall, G L P G 1 6 9 0 di d n ot e xte nsi vel y distri b ute i nt o tiss ues as s h o w n b y t he l o w v ol u me of 
distri b uti o n at stea d y stat e ra n gi n g  fr o m 0. 3 5 L/ k g i n t he m o use t o 0. 5 5 L/ k g i n t he m o n ke y. I n 
rat, [1 4C] -G L P G 1 6 9 0 was wi del y distri b ute d t hr o u g h o ut t he b o d y. Hi g hest c o nce ntrati o ns of 
ra di oacti vit y were o bser ve d i n c onte nts of t he GI  tract, gla n d ular tiss ues, li ver, a n d u veal tract. 
G L P G 1 6 9 0 a n d/ or meta b olites  s h o we d s o me affi nit y f or mel a ni n-c o ntai ni n g tiss ues, li ke u veal 
tract a n d me ni n ges. 
After oral a d mi nistrati o n, dr u g -relat e d material is e x crete d mai nl y i n feces i n rat (a b o ut 9 0 % or 
greater). I n bile d u ct -ca n n ulate d rats, a b o ut 5 0 % of  orall y a d mi nistere d ra di oacti vit y was 
rec o vere d i n bile. 
U p o n re peate d o nce dail y ( q. d.) oral d osi n g of G L P G 1 6 9 0, n o si g nifica nt acc u m ulati o n was 
o bser ve d i n plas ma, e x ce pt i n male rats ( 2 0  m g/ k g/ da y) a n d d o gs ( 5 0/ 6 5  m g/ k g/ da y at Wee k  3 9). 
Se x  differe nces  i n P K pr ofiles were o bs er ve d i n rats b ut n ot i n d o gs. 
T he t otal plas ma cleara n ce of G L P G 1 6 9 0 was l o w i n mice, rats, m o n ke ys, a n d d o gs, ra n gi n g 
bet wee n 3 % a n d 2 3 % of t he he patic bl o o d fl o w. T heref ore, G L P G 1 6 9 0 is e x pecte d t o u n der g o a 
l o w first pass effect after oral d osi n g.  
T he pri mar y c yt o c hr o me P 4 5 0 ( C Y P) e nz y m e i n v ol ve d i n G L P G 1 6 9 0 met a b olis m was C Y P 3 A 4. 
I n vitr o met a b olis m st u dies i n he pat oc ytes re veale d 2 6 p ote ntial meta b olites. Meta b olites f or me d 
i n h u ma n he pat oc ytes were all pres e nt t o a si milar or hi g her e xte nt i n rat a n d/ or d o g h e pat oc ytes, 
t he a ni mal s pecies sel ect e d f or t o xicit y st u dies.  
A n i n vitr o st u d y wit h G L P G 1 6 9 0 i n h u ma n he p at oc ytes s h o we d n o cli nicall y rele va nt i n d ucti o n 
of h u ma n C Y P 2 B 6 a n d C Y P 2 C e nz y mes. Wea k i n d ucti o n of  C Y P 1 A 2 a n d C Y P 3 A 4 ca n n ot be 
e x cl u de d at a G L P G 1 6 9 0 d ose of 6 0 0 m g i n h u ma n, wit h a ma xi mal decrease of ar o u n d 3 0 % i n 
t he e x p os ure of a se nsiti ve pr o be s u bstrat e f or b ot h C Y P e nz y m es. 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-2 2 - 
 
A n i n vitr o st u d y wit h G L P G 1 6 9 0 i n h u ma n li ver micr os o mes i n dicate d n o cli nicall y rele va nt 
i n hi biti o n of t he maj orit y of C Y P e nz y m es. W ea k c o m petiti ve re versi ble i n hi biti o n  of C Y P 2 C 8 
a n d C Y P 3 A 4/ 5  ca n n ot b e e x cl u de d at a G L P G 1 6 9 0 d ose of 6 0 0 m g i n h u ma n, wit h a ma xi mal 
i ncreas e of a p pr o xi matel y 1. 7 - a n d 1. 5 -f ol d, res pecti vel y, i n t he e x p os ure of a se nsiti ve pr o be 
s u bstrate. 
G L P G 1 6 9 0 de m o nstrate d a str o n g ti me -d e pe n d e nt, irre versi ble i n hi biti o n p ote ntial a gai nst 
C Y P 2 C 8 -me diate d meta b olis m. T his c o ul d li kel y lea d t o a pr o n o u nce d i nteracti o n wit h a 
se nsiti ve C Y P 2 C 8 pr o be s u bstrate (i ncrease d e x pos ure) if c o -a d mi nistere d wit h a G L P G 1 6 9 0 
d ose of 6 0 0 m g i n h u ma n.  
N o i nteracti o n of G L P G 1 6 9 0 is e x pecte d wit h re nal u pta ke tra ns p orters, or ga nic cati o n 
tra ns p orter ( O C T) 2, or ga nic a ni o n tra ns p orter ( O A T) 1 a n d O A T 3 a n d he p atic effl u x tra ns p orters 
P -gl yc o pr ot ei n ( P -g p) a n d breast c a ncer resista nce pr otei n ( B C R P). F or t he he patic u pta ke 
tra ns p orters O A T P 1 B 1, O A T P 1 B 3, a n d O C T 1, a n d t he m ulti dr u g a n d t o xi n e xtr usi o n ( M A T E) 
effl u x tra ns p orters M A T E 1 ( he patic/r e nal) a n d M A T E 2 K (re nal), a cli nical i nteracti o n wit h 
G L P G 1 6 9 0 ca n n ot be r ul e d o ut, h o we ver s u bsta ntial i nteracti o ns are n ot a ntici pate d. F or t he 
i ntesti nal effl u x P-g p a n d B C R P tra ns p orters a n d t he he patic effl u x bile salt e x p ort p u m p 
tra ns p orters a n i nteracti o n ca n n ot be r ule d o ut. 
1. 1. 4.   
T o xi c ol o g y  
1. 1. 4. 1.   
G e n er al T o xi c ol o g y  
A c o m pre he nsi v e t o xic ol o g y pr o gra m has bee n c o n d ucte d wit h G L P G 1 6 9 0. T his pr o gra m 
i ncl u des G o o d La b orat or y Practice ( G L P) oral re p eat d ose t o xicit y st u dies of u p t o 2 6 wee ks i n 
rats a n d 3 9 wee ks i n d o gs, e m br y ofetal de v el o p me nt st u dies i n rats an d ra b bits,  fertilit y st u dies i n 
male a n d fe m ale rats, n o n -T gras H 2 mice preli mi nar y st u dies, preli mi nar y carci n o ge nicit y st u dies,  
a n d i n vi v o a n d i n vitr o ge n ot o xicit y st u dies. A d diti o nal t o xic ol o g y st u dies c o n d ucte d i ncl u de  
p h ot ot o xicit y st u dies a n d d ose -ra n ge fi n di n g st u dies i n rats a n d d o gs. 
I n rats, n o G L P G 1 6 9 0-relate d m ortalit y was o bser ve d. T he d ose-li miti n g a d verse effects 
c o nsiste d of re d u ce d f o o d c o ns u m pti o n a n d mar k e dl y d ecrease d b o d y wei g ht ( B W) gai n at 
1 0 0 0  m g/ k g/ da y i n t he 4 -wee k t o xicit y st u d y , hist o pat h ol o gical c ha n ges i n t he testes wit h 
re d uce d s p er m para meters at ≥1 3 0 m g/ k g/ da y i n t he 1 3- a n d 2 6-wee k G L P st u dies, a n d t he 
prese nce of vac u olate d al ve olar macr o p ha ges, wit h al ve olar a m or p h o us material a n d peri vasc ular 
i nfla m mat or y cell i nfiltrati o n i n t he l u n gs of fe mal es i n t he 2 6-wee k G L P st u d y. T he n o o bser ve d 
a d verse effects le vel ( N O A E L) val ues i n rats were set at 4 0 a n d 1 3 0 m g/ k g/ da y i n mal es a n d 
fe males, res pecti vel y, i n t he 2 6-wee k G L P st u d y.  
I n re peat oral d ose t o xicit y st u dies i n d o gs, t he d ose-li miti n g effects c orres p o n de d t o decrease d 
w hite bl o o d cell c o u nt a n d f o o d c o ns u m pti o n, e mesis a n d B W l oss, ass ociate d wit h p o or cli nical 
c o n diti o ns at d oses ≥1 0 0 m g/ k g/ da y i n t he 1 3 - a n d 3 9-wee k G L P st u dies, res pecti vel y. Q T 
pr ol o n gati o n (i n 4 -, 1 3 -, a n d 3 9-wee k st u dies), w hic h was c o nsi dere d n o n -a d verse, were als o 
o bser ve d i n re peat or al d ose t o xicit y st u dies i n d o gs. A d diti o nal fi n di n gs i n d o gs c o nsiste d of 
a d verse altere d s p er m para meters a n d i nfla m mat or y cell i nfiltrates i n t he li ver a n d mi ni mal bile 
d uct h y p er plasia at 1 5 0/ 1 0 0 m g/ k g/ da y (i n t he 1 3 -wee k G L P t o xicit y st u d y) a n d Q T pr ol o n gati o n 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-2 3 - 
 
(i n 4-, 1 3- a n d 3 9-wee k st u dies). T he N O A E L val ue i n d o gs was set at 5 0/ 6 5  m g/ k g/ da y i n t he 
3 9 -wee k G L P st u d y.  
Male a n d fe male fertilit y st u dies i n rats  s h o we d t hat t here were n o effects of G L P G 1 6 9 0 o n 
mati n g perf or ma nce, fertilit y, or re pr o d ucti o n i n eit her male or fe male rats at t he differe nt d ose 
le vels teste d. As t he effects o n s per m a n d testis pr o ve d re versi ble a n d ha d n o f u ncti o nal i m pact 
o n a ni mal fertilit y para m eters, t he ris k of a n i m pact o n male fertilit y i n a d ult s u bjects is 
c o nsi dere d l o w. I n males, t he n o o bser ve d effect l e vel ( N O E L) f or m ati n g perf or ma n ce a n d 
fertilit y was set at 4 0 0 m g/ k g/ da y a n d t h e N O A E L f or s per m c ha n ges was deter mi ne d at  
4 0  m g/ k g/ da y; t he latter is i n li ne wit h pre vi o us st u dies (i.e.  1 3 -wee k rat st u d y). I n fe mal es, t he 
N O E L f or mati n g perf or ma nce a n d fertilit y was c o nsi dere d t o be 1 2 0  m g/ k g/ da y.   
I n re pr o d ucti ve e m br y ofetal de vel o p me nt st u dies wit h G L P G 1 6 9 0 i n rats a n d rab bits, maj or 
e xter nal, visceral, a n d s k eletal a b n or malities were see n i n fet uses of b ot h s pecies as well as 
i ncreas e d i nci de nces of p osti m pla ntati o n l osses. I n rats, t he mater nal a n d de vel o p me ntal 
N O A E Ls were det er mi ne d at 6 0 m g/ k g/ da y a n d 1 0 m g/ k g/ da y, re s p ecti vel y. I n ra b bits, t he 
mater nal a n d de vel o p me ntal N O A E Ls were det er mi ne d at 1 5 m g/ k g/ da y a n d 5 m g/ k g/ da y, 
res pecti vel y. 
G L P G 1 6 9 0 s h o we d n o ge n ot o xic effects i n vitr o or i n vi v o.  
G L P G 1 6 9 0 s h o we d a p h ot ot o xic p ote ntial i n vitr o. H o we ver, t his p ote ntial has n ot bee n 
c o nfir me d i n a n i n vi v o  st u d y i n fe mal e pi g m e nte d L o n g-E va ns rats, i n vesti gati n g t he p h ot ot o xic 
effects o n t he e yes a n d t h e s ki n. N o e vi de nce of c uta ne o us or oc ular p h ot ot o xicit y was n ote d at 
d oses of 1 0 0 a n d 3 0 0 m g/ k g.  
1. 2.   
B a c k gr o u n d - Cli ni c al S t u di e s 
1. 2. 1.   
Cli ni c al S af et y  
I n cli nical p har mac ol o g y st u dies, G L P G 1 6 9 0 has bee n a d mi nistere d t o 8 5 healt h y s u bjects as 
si n gle d oses ( d os e ra n ge: 2 0 t o 1 5 0 0 m g) a n d t o 9 6 healt h y s u bjects i n re peate d d oses ( d ose 
ra n ge: 1 0 0 t o 1 0 0 0 m g f or eit her 7 or 1 4 d a ys).  
A d mi nistrati o n of G L P G 1 6 9 0  i n t hese P hase 1 st u dies was c o nsi dere d safe a n d well t olerate d. N o 
deat hs, ot her seri o us treat me nt -e mer ge nt a d verse e ve nts ( T E A Es), T E A Es lea di n g t o I M P 
disc o nti n uati o n, or cli nicall y si g nifica nt a b n or malities relate d t o la b orat o r y para meters, 
electr ocar di o gra m ( E C G), vital si g ns, or p h ysical e x a mi nati o ns were re p orte d d uri n g a n y of t hese 
P hase  1 st u dies. A ll T E A Es were at m ost m o derat e i n se verit y.  
A d mi nistrati o n of oral d oses of G L P G 1 6 9 0 6 0 0 m g q. d. as a ca ps ul e f or 1 2 wee ks i n 1 7 s u bjects 
wit h I P F was well t olerate d ( P hase 2a S t u d y G L P G 1 6 9 0-C L -2 0 2). N o deat hs were re p orte d. 
Seri o us T E A Es were e x perie nce d b y o ne s u bject i n t he G L P G 1 6 9 0 6 0 0 m g q. d. g r o u p 
(c h ola n gi ocarci n o ma le d t o per ma ne nt disc o nti n uati o n) a n d b y 2  s u bjects i n t he place b o gr o u p 
(atri o ve ntric ular bl oc k sec o n d de gree i n o ne s u bject, le d t o per ma ne nt disc o nti n uati o n; a n d l o wer 
res pirat or y tr act i nfecti o n, uri nar y tract i nfecti o n, a n d acute ki d ne y i nj ur y i n t he ot her s u bject , 
w h o re mai ne d o n tr eat me nt i n t he st u d y ). 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-2 4 - 
 
N o ne of t hese s eri o us T E A Es were c o nsi dere d rel ate d t o I M P acc or di n g t o t he i n vesti gat or. N o 
n ota ble differe nces were o bser ve d i n t he i nci de n ces of treat me nt -e mer ge nt a b n or mal ities bet wee n 
s u bjects wit h I P F treat e d wit h G L P G 1 6 9 0 6 0 0 m g q. d. or place b o. T he maj orit y of T E A Es were 
mil d t o m o derate i n se verit y. N o cli nicall y si g nifica nt a b n or malities relat e d t o la b orat or y 
para meters, electr ocar di o gra m ( E C G), vital si g ns or p h ysica l e xa mi nati o ns were re p orte d. 
1. 2. 2.   
Cli ni c al Effi c a c y  
D uri n g 1 2 wee ks of treat me nt of  s u bjects wit h I P F i n S t u d y G L P G 1 6 9 0-C L -2 0 2, f orce d vital 
ca pacit y ( F V C) val ues re mai ne d sta ble i n t he maj orit y of s u bjects ta ki n g G L P G 1 6 9 0 6 0 0 m g q. d. , 
a n d decli ne d i n s u bject s t a ki n g place b o. 
1. 2. 3.   
Cli ni c al P h ar m a c o ki n eti c s  
G L P G 1 6 9 0 f or m ulate d as a li q ui d s us pe nsi o n was ra pi dl y a bs or be d wit h a me dia n ti me t o 
ma xi m u m o bser ve d plas ma c o nce ntr ati o n (t
ma x ) of 0. 5 t o 2 h o urs. Stea d y -state e x p os ure of 
G L P G 1 6 9 0 i ncreas e d a p pr o xi matel y (sli g ht o ver pr o p orti o nalit y) i n pr o p orti o n wit h t he d ose 
bet wee n 3 0 0  t o 10 0 0  m g t otal dail y d ose. E xcreti o n of u nc ha n ge d G L P G 1 6 9 0 i n h u ma n uri ne 
was l o w ( < 1. 8 % i n 2 4  h o urs) a n d ra pi d. T here was n o i m pact o n t he uri nar y 6 -β -O H -
c ortis ol/c ortis ol ra ti o after re peate d d osi n g s u g gesti n g a lac k of C Y P 3 A 4 i n d ucti o n b y 
G L P G 1 6 9 0.  
Gi ve n as ta blet, f o o d d ecrease d t h e rate of a bs or pti o n of G L P G 1 6 9 0 b ut t here was n o cli nicall y 
rele va nt differe nce i n t he bi oa vaila bilit y of G L P G 1 6 9 0. A hi g her bet w ee n-s u bject varia bilit y was 
o bser ve d i n fast e d state, wit h f o ur  s u bjects o ut of 1 2 ha vi n g 5- t o 1 0-f ol d l o wer e x p os ure t ha n t he 
ot her s u bjects. T he rate of eli mi nati o n was n ot i m pacte d b y f o o d. T he o verall mea n ter mi nal 
eli mi nati o n half -life (t1/ 2) after a si n gle d ose as tablets was  a p pr o xi matel y 1 1  h . 
G L P G 1 6 9 0 e x p os ure is re d uce d u p t o 9 0 % b y t he str o n g C Y P 3 A 4/ p ote nt P -g p i n d ucer rifa m pi n  
( b y 6. 0- a n d 9. 3-f ol d f or Cma x  a n d area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o 
2 4 h  [ A U C0 -2 4 h], res pecti vel y). E x p os ure of G L P G 1 6 9 0, as meas ure d b y t he area u n der t he 
plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me zer o e xtra p olate d t o i nfi nit y ( A U C0 -∞), was 3- a n d 
4 -f ol d great er w h e n a d mi nistere d i n c o m bi nati o n wit h itrac o naz ole (a str o n g C Y P 3 A 4 a n d p ote nt 
P -g p i n hi bit or) a n d v ori c o naz ole (a str o n g C Y P 3 A 4 i n hi bit or), res pecti vel y, t ha n w h e n as 
a d mi nistere d al o ne. Ma xi m u m e x p os ure ( C ma x ) of G L P G 1 6 9 0 i ncreas e d sli g htl y f oll o wi n g 
a d mi nistrati o n of G L P G 1 6 9 0 i n c o m bi nati o n wit h itrac o naz ole or v oric o n az ole c o m pare d wit h 
a d mi nistrati o n of  G L P G 1 6 9 0 o nl y ( C ma x  val ues were 1. 4 -f ol d greater f oll o wi n g a d mi nistrati o n i n 
c o m bi nati o n wit h itrac o naz ole or v oric o naz ole). T his i ncrease is u nli kel y t o be cli nicall y 
si g nifica nt. G L P G 1 6 9 0 ca n t heref ore b e classifie d as a m o deratel y se nsiti ve s u bstrate o f C Y P 3 A 4 
as it de m o nstrate d a n i ncrease i n A U C of ≥2 t o < 5 -f ol d wit h str o n g i n de x i n hi bit ors. 
T he P K of G L G 1 6 9 0 was si milar bet wee n Ca ucasia n a n d J a pa nese healt h y male s u bjects. T he 
P K of G L P G 1 6 9 0 i n s u bj ects wit h I P F was n ot mar ke dl y differe nt fr o m t h ose o bser ve d i n h ealt h y 
s u bjects at t he sa me d ose le vel. 




G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-2 6 - 
 
3.   
I N V E S TI G A TI O N A L P L A N 
3. 1.   
Cli ni c al S t u d y D e si g n 
T his is a n o pe n -la bel, m ultice nter, si n gl e-ar m, 1 0 4 -wee k  e xte nsi o n st u d y f or s u bjects wit h 
s yste mic scler osis w h o c o m plete d t he 2 4-wee k d o u ble -bli n d treat me nt peri o d of 
St u d y  G L P G 1 6 9 0 -C L -2 0 4 . U p t o 3 0 s u bjects ma y r oll o ver fr o m St u d y G L P G 1 6 9 0 -C L -2 0 4 i nt o 
t his O L E  st u d y. 
A sc he matic dia gr a m of t he cli nical st u d y d esi g n is pr o vi de d i nFi g ure  1 Fi g ure  1 : Sc he matic 
St u d y O ver vi e w . 
 
Fi g ure  1 : 
Sc he m atic St u d y O ver vie w  
D = Da y, E o T =e n d of  st u d y, F U = F oll o w -u p, V = Visit, W = W ee k.  
 
F or t he i n - a n d e x cl usi o n criteria please refer t o Secti o n 3. 6. 1 , “I ncl usi o n Criteria” a n d 
Secti o n  3. 6. 2 , “E x cl usi o n Criteria ”.  
S u bjects will e nter t h is O L E  st u d y at t he R oll o ver v isit o n Da y 1, w hic h will occ ur o n t he sa m e 
da y as t he Wee k 2 4 visit (t he last visit of t he treat me nt peri o d) of  t he prece di n g G L P G 1 6 9 0-C L -
2 0 4 st u d y. S u bjects w h o r oll o ver t o t his O L E st u d y will partici pat e i n t he p ost treat me nt foll o w -
u p peri o d of t he O L E st u d y i nstea d of F oll o w -u p i n St u d y G L P G 1 6 9 0 -C L -2 0 4.  
After t he R oll o ver v isit, the s u bse q ue nt visits  d uri n g t he o pe n -la bel treat me nt peri o d will ta ke 
place at Wee ks 2, 4, 8 , 1 6, 2 8, 4 0 , 5 2, 6 4, 7 6, 8 8, a n d at Wee k 1 0 4 ( E n d of Treat me nt [E o T ]). I n 
case of wit h dra wal, a n E arl y Disc o nti n uati o n ( E D) visit will be sc he d ule d. After  t he 1 0 4 -wee k 
o pe n -la bel treat me nt peri o d (or earl y dis c o nti n uati o n of treat me nt) , 2  f oll o w-u p visit s will be 
pla n ne d 4  wee ks a n d 1 2 wee ks after t he last a d mi nistrati o n of I M P . A d diti o nal u nsc he d ule d visits 
are all o we d f or a n y safet y ass ess me nts if cli nicall y i n dicat e d . 
S u bjects will recei ve 6 0 0  m g  G L P G 1 6 9 0,  oral l y q. d. , starti n g t he da y after t he R ollo ver visit.  F or 
detaile d i nf or mati o n re gar di n g d osa ge f or m, p ac ka gi n g a n d la bel i n g of t he I M P please refer t o 
Secti o n 4. 2 , “D osa ge a n d A d mi nistrati o n ” a n d Secti o n  4. 3 , “Pac ka gi n g, La b eli n g a n d 
Distri b uti o n ”. 
Eac h s u bject will  be i n t h e st u d y f or u p t o 1 1 6 wee ks ( 1 0 4 wee ks of treat me nt a n d 1 2 wee ks of 
f oll o w-u p).  






G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-2 9 - 
 
at t his sta ge of de vel o p m e nt , G L P G 1 6 9 0 s h o ul d n ot be gi ve n t o pre g na nt or lactati n g w o me n. I n 
a d diti o n, hi g hl y effecti ve c o ntrace pti ve meas ures/ pre ve nti ve e x p o s ure meas ures s h o ul d be ta ke n 
b y w o me n of c hil d beari n g p ote ntial ( W O C B P)  a n d b y me n  t o pre ve nt pre g na nc y a n d t o a v oi d t he 
ris k of e x p os ure of t he e m br y o or fet us. Det a ile d i nf or mati o n o n c o ntrace pti ve meas ures is gi ve n 
i n Secti on 3. 6. 3. 1 . 
Q T I nter v al Pr ol o n g ati o n  
T he p ote ntial effect of G L P G 1 6 9 0 o n Q T i nter val pr ol o n gati o n is u n der i n vesti gati o n . 
C o nse q ue ntl y, s u bjects meeti n g t he st o p pi n g r ules f or Q T/ Q Tc -c ha n ges  will be e x cl u de d. T he 
c hr o nic use or i nitiati o n of me dicati o n k n o w n t o pr ol o n g t he Q T i nter val n ee ds t o be e v al uate d o n 
a case -b y -case b asis. Peri o dic E C G rec or di n g a n d m o nit ori n g wit h ce ntral rea di n g will be 
i m ple me nte d f or t he d urati o n of t he st u d y. A list i nte n de d as g ui da nce f or t he i n vesti gat or is 
pr o vi de d i n A p pe n di x  5 . 
Dr u g -dr u g I nter acti o n  
F or p ote ntial c o n c o mita nt me dicati o n i nteracti o ns, s pecific m o nit ori n g a n d g ui da nce will be 
i m ple me nte d d uri n g t he st u d y (refer t o Secti o n 3. 6. 3. 2 ).  
S peci al P o p ul ati o ns  
As t here is li mite d cli nical e x perie nce wit h G L P G 1 6 9 0 s o far, t he I M P s h o ul d n ot be 
a d mi nistere d t o s u bjects wit h m o derate t o se vere re nal i m pair me nt or h e p atic i m pair me nt.  
Refer t o t he latest I B f or G L P G 1 6 9 0 a n d rele va nt u p dates/a d de n da f or a d diti o nal i nf or mati o n o n 
t he safet y of t he I M P. 
3. 6.   
Cli ni c al St u d y P o p ul ati o n  
3. 6. 1.   
I n cl u si o n Crit eri a 
S u bjects m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or p artici pati o n i n t his 
st u d y: 
1.  Male or fe m ale s u bjects w h o c o m plete d t he 2 4 -wee k treat me nt peri o d of St u d y G L P G 1 6 9 0 -
C L -2 0 4 a n d w h o  acc or di n g t o t he i n vesti gat or’s j u d g me nt  ma y b e ne fit fr o m l o n g-ter m 
treat me nt wit h G L P G 1 6 9 0. 
2.  A ble a n d willi n g t o c o m pl y wit h t he pr ot oc ol re q uire me nts a n d t o si g n t h e i nf or me d c o ns e nt 
f or m (I C F) as a p pr o ve d b y t he I n d e pe n d e nt Et hics C o m mittee (I E C) / I nstit uti o nal Re vie w 
B oar d ( I R B), pri or t o t he eli gi bilit y e v al uati o n.  
3.  S u bject m ust be a ble a n d willi n g t o c o m pl y wit h restricti o ns o n c o nc o mita nt me dicati o n as  
descri be d i n Secti o n 3. 6. 3. 2 . 
4.  Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a ne gati ve  uri ne pre g n a nc y test . 
5.  Fe male s u bjects of c hil d beari n g p ote ntial or male s u bjects wit h fe male  part ners of 
c hil dbeari n g p ote ntial are willi n g t o c o m pl y wit h t he c o ntrace pti ve met h o ds descri be d i n  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 0 - 
 
Secti o n  3. 6. 3. 1  d uri n g t h e cli nical st u d y  a n d f or at least 9 0 da ys after t he last d ose of t he I M P 
f or male s u bjects a n d at l east 3 0  da ys after t he last d ose of t he I M P f or fe m ale s u bjects. 
 
3. 6. 2.   
E x cl u si o n Crit eri a  
S u bjects meeti n g o ne or m ore of t he f oll o wi n g criteria ca n n ot b e e nr olle d i n t his cli nical st u d y:  
1.  I n v esti gat or or ot her st u d y staff or relati ve t here of w h o is directl y i n v ol ve d i n t he c o n d uct of 
t he st u d y. 
2.  A n y c o n diti o n or circ u msta nces t hat , i n t he o pi ni o n of t he i n vesti gat or, ma y ma ke a s u bject 
u nli kel y or u na bl e t o c o m plete t he st u d y or c o m pl y wit h st u d y pr oce d ures a n d re q uire me nts.  
3.  Persiste nt a b n or mal la b orat or y v al ues (i ncl u di n g a n d n ot li mi te d t o he mat ol o g y, li ver a n d 
re nal f u n cti o n val ues), acc or di n g t o t he i n v esti gat or’s cli nical j u d g me nt (c o nsi deri n g 
s yste mic scler osis diseas e- a n d me dicati o n -rel ate d c ha n ges). 
4.  Fe male s u bject i nte n di n g t o bec o me pre g n a nt or breastfee d.  
5.  A hist or y of bei n g a d mitte d t o a n i nstit uti o n u n der a n a d mi nistrati ve or c o urt or der, if 
a p plica ble b y l ocal le gisl ati o n.  
 
3. 6. 3.   
Pr o hi biti o n a n d R e stri cti o n s  
3. 6. 3. 1.   
Pr e c a uti o n s f or S e x u al Int er c o ur s e  
Hi g hl y effecti ve c o ntrace pti ve meas ures f or b ot h fe males of c hil d beari n g p ote ntial a n d males 
m ust be d oc u me nte d i n t he s o urce d o c u me nts.  
3. 6. 3. 1. 1.  F e m al e S u bj e ct s  
I n li ne wit h the Hea ds of Me dici nes A ge n cies’  Cli nical Trial Facilitati o n Gr o u p rec o m me n d ati o n, 
fe male s u bjects are c o nsi dere d of n o n-c hil d beari n g p ote ntial if t he y meet o ne of t he f oll o wi n g 
criteria:  
 
N o me nses f or 1 2 or m ore m o nt hs wit h o ut a n alter nati ve me dical ca use. A hi g h f ollicle 
sti m ulati n g h or m o ne ( F S H) le vel i n t he p ostme n o pa usal  ra n ge ma 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 mo nal re place me nt 
t hera p y. 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 m e nt is 
i ns ufficie nt. 
 
Per ma ne ntl y s ur gicall y st erile ( bilateral o o p h orect o m y, i.e. s ur gical re m o val of o varies, 
bilateral sal pi n gect o m y or h ysterect o m y, i.e. s ur gi cal re m o val of uter us). 
All ot her fe male s u bjects are c o nsi d ere d t o be of c hil d beari n g p ot e ntial ( W O C B P) a n d m ust use 
o ne of t he f oll o wi n g hi g hl y effecti ve met h o ds of birt h c o ntr ol d uri n g t he cli nical st u d y a n d f or at 
least 3 0 da ys  after t he last d os e of I M P:  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 1 - 
 
 
C o m bi ne d (estr o ge n a n d pr o gester o ne c o ntai ni n g) ( oral, i ntra va gi n al, tra ns d er mal) 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 pl us a barrier met h o d 1 
 
Pr o gester o ne -o nl y h or m o nal ( oral, i njecta bl e, i m pla nta ble) c o ntrace pti o n ass oc iate d wit h 
i n hi biti o n of o v ulati o n pl us a barrier met h o d1 
 
I ntr a uteri ne de vice 
 
I ntr a uteri ne h or m o ne-rel easi n g s yst e m 
 
Bilateral t u bal occl usi o n  
 
Se x u al a bsti ne nce defi ne d as refrai ni n g fr o m het er ose x ual i nterc o urse is c o nsi dere d a hi g hl y 
effecti ve c o ntr ace pti ve m eas ure o nl y if it is t he preferre d a n d us ual lifest yle of t he s u bject. T he 
relia bilit y of se x ual a bsti ne nce n ee ds t o be e v al uat e d i n relati o n t o t he d urati o n of t he cli nical 
st u d y.  
Peri o dic a bsti ne nce ( e. g. cale n dar, s y m pt ot her mal, p ost o v ulati o n  met h o ds), declarati o n of 
a bsti ne nce f or t he d urati o n of a cli nical st u d y, wit h dra wal, s per mici des o nl y , a n d lactati o nal 
a me n orr hea met h o d are n ot acce p t a ble as met h o ds of c o ntrace pti o n. 
I n case a W O C B P has a vasect o mize d part ner, pr o vi de d t hat part ner is t he s ole se x ual part ner of 
t he W O C B P cli nical st u d y partici pa nt a n d t hat t he vasect o mize d part ner has recei v e d me dical 
assess me nt of t he s ur gical s ucces s, t he n s he is n ot re q uire d t o use a n a d diti o nal f or m of 
c o ntrace pti o n.  
Wit hi n t hese li mits, t he s pecific f or ms of c o ntrace pti o n e m pl o ye d are left t o t he discreti o n of t he 
s u bject, t he i n vesti gat or, a n d/ or t he s u bject’s p h ysicia n. 
W O C B P will be re q ueste d t o d o a m o nt hl y uri ne pre g na nc y t est d uri n g t h e treat me nt peri o d. I n 
m o nt hs wit h n o st u d y visit, t he m o nt hl y pre g na n c y test  will be perf or me d at h o me b y t h e s u bject 
usi n g h o me testi n g kits. T he site will i nstr uct t he s u bjects o n h o w t o use a n d rea d t he pre g na n c y 
tests. T he o utc o me m ust be d oc u me nte d o n t he s u bject diar y car d a n d t h e site will o btai n t he 
res ults a n d rec or d i n t he case re p ort f or m ( C R F). I n case of a p ositi ve uri ne pre g na nc y t est at 
h o me, t he s u bjec t s h o ul d i m me diatel y c o ntact t he cli nical st u d y ce nter a n d t he i n vesti gat or m ust 
re p ort t his i m me diatel y, a n d u n der n o circ u msta n ces later t ha n 2 4 h o urs after bei n g ma de a ware . 
T he safet y of G L P G 1 6 9 0  d uri n g breastf ee di n g is u n k n o w n. N ursi n g w o me n  are n ot all o we d t o 
ta ke part i n t his cli nical st u d y. 
3. 6. 3. 1. 2.  M al e S u bj e ct s  
Me n s h o ul d be a d vise d n ot t o fat her a c hil d w hile recei vi n g treat me nt a n d m ust use effecti ve 
c o ntrace pti o n d uri n g a n d u p t o 9 0 da ys after treat me nt.  
                                                 
1 As t here is n o c urre nt data a vaila ble re gar di n g p ote ntial i nteracti o ns bet wee n I M P a n d h or m o nal c o ntrace pti ves, 
fe male s u bj ects w h o use h or m o nal c o ntrace pti o n s h o ul d s u p ple me nt t his wit h a barrier met h o d ( prefera bl y male 
c o n d o m).  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 2 - 
 
N o n -vasect o mize d male s u bjects wit h fe male part n ers of c hil d beari n g p ote ntial m ust be willi n g 
t o use a c o n d o m fr o m t he ti me of t he first d ose of I M P, d uri n g t he cli nical st u d y a n d f or at least 
9 0 da ys  after t h e last d ose of I M P, i n a d diti o n t o ha vi n g t heir fe male part ner use o ne  of t he 
f oll o wi n g f or ms of c o ntr ace pti o n: 
 
C o m bi ne d (estr o ge n a n d pr o gester o ne c o ntai ni n g) ( oral, i ntra va gi n al, tra ns d er mal) 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  
 
Pr o gester o ne -o nl y h or m o nal ( oral, i njecta bl e, i m pla nta ble) c o ntrace pti o n ass ociate d wit h 
i n hi biti o n of o v ulati o n 
 
I ntr a uteri ne de vice 
 
I ntr a uteri ne h or m o ne-rel easi n g s yst e m 
Se x ual a bsti ne nce defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse is c o nsi dere d a hi g hl y 
effecti ve c o ntrace pti ve meas ure o nl y if it is t he preferre d a n d us ual lifest yl e o f t he s u bject. T he 
relia bilit y of se x ual a bsti ne nce nee ds t o b e e v al uat e d i n relati o n t o t h e d urati o n of t he cli nical st u d y.  
Peri o dic a bsti ne nce ( e. g. cale n dar, s y m pt ot her mal a n d p ost o v ulati o n  met h o ds), declarati o n of 
a bsti ne nce f or t he d urati o n of a cli n ical st u d y, wit h dra wal, s per mici des o nl y a n d lactati o nal 
a me n orr hea met h o d are n ot acce pt a ble met h o ds of c o ntrace pti o n.  
I n a cas e w here t he fe mal e part ner of a mal e s u bject has u n der g o n e d oc u me nte d s ur gi cal 
sterilizati o n t hat was perf or me d m ore t ha n o n e  ye ar bef ore scree ni n g, t he n t he s u bject is n ot 
re q uire d t o use a n a d diti o nal f or m of c o ntrace pti o n. 
Vasect o mize d male s u bjects wit h fe male part ners of c hil d beari n g p ote ntial are n ot re q uire d t o use 
a n a d diti o nal f or m of c o ntrace pti o n pr o vi di n g t hat s ur gical sterilizati o n has bee n s uccessf ul 
( d oc u me nte d az o os per mi a b y s e me n a n al ysis). 
Male s u bjects w h o wis h t o fat her a c hil d s h o ul d st o p treat me nt wit h I M P a n d wait f or at least 
9 0  da ys b ef ore st o p pi n g t he c o ntrace pti ve meas ures detaile d i n t his secti o n.  
N o s per m d o nati o n is all o we d fr o m t he first d ose of I M P d uri n g t he cli nical st u d y u ntil at least 
9 0  da ys  after t h e last d ose  of I M P . 
3. 6. 3. 2.   
Pri or a n d C o n c o mit a nt M e di c ati o n s  
C o nc o mit a nt Me dic ati o n  
S h o ul d a n y treat me nt ot her t ha n t he I M P be us e d d uri n g t he c o urse of t he st u d y, t he na m e of t he 
me dicati o n, t he d osa ge, t he r o ute, t he reas o n f or me dicati o n, a n d t he start a n d st o p dates of 
a d mi nistrati o n m ust be rec or de d i n t he C R F u ntil foll o w -u p v isit 2.  
C o nc o mita nt me dicati o ns ta ke n f or t he l o n g -t er m treat me nt of pre-e xisti n g c o n diti o ns ca n 
c o nti n ue d uri n g t h e S t u d y G L P G 1 6 9 0 -C L -2 0 6 . It is re q uire d t hat t hese m e dicati o ns co nti n ue 
wit h o ut variati o n of d ose or re gi me n d uri n g t he st u d y.  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 3 - 
 
I n case a d diti o nal c o nc o mita nt me dicati o n nee ds t o be a d mi nistere d or d os e a dj ust me nts f or 
pre -e xisti n g c o n diti o ns nee d t o be perf or me d d uri n g t he st u d y, t he be n efit -ris k t o t he s u bject 
s h o ul d be caref ull y assesse d a n d c o nsi derati o n gi v e n t o t he ti mi n g of a n y n ecessar y i ntr o d uc ti o n 
of ne w me dicati o ns.  
T he f oll o wi n g m e dicati o ns are pr o hi bite d d uri n g t he treat me nt peri o d:  
 
warfari n, a ntifi br otic a ge nts (i ncl u di n g c olc hi ci ne, mi n oc ycli ne, t yr osi n e ki nase i n hi bit ors 
[ nil oti ni b, i mati ni b, dasati ni b, ni nte da ni b], pirfe ni d o ne), or T y p e 1 oral c oll a ge n  
 
stea d y d os e of pre d nis o n e or its e q ui vale nt > 1 0 m g/ da y, met h otre x ate > 2 0 m g/ wee k, 
azat hi o pri ne > 1 5 0  m g/ d a y, M M F  > 3 g/ da y, m yc o p he n olic aci d > 2. 1 6 g/ d a y, lefl u n a mi de 
> 2 0  m g/ da y  
 
cycl o p h os p ha mi de  a n d t h e f oll o wi n g bi ol o gics: t o ciliz u ma b or ot her dr u gs tar geti n g I L -6/I L -
6 rece pt or, a bat ac e pt, a nti -t u m or necr osis fact or dr u gs, rit u xi ma b, beli m u ma b, or ot her 
m o n ocl o nal a nti b o dies   
 
b ose nta n  
 
If d uri n g t he st u d y, t he s u bject’s c o n diti o n necessitates t he use of o ne of t he a b o ve-m e nti o ne d 
me dicati o ns (e x cl u di n g pre d nis o ne or its e q ui vale nt > 1 0 m g/ da y), t he use of I M P s h o ul d be 
i nterr u pte d u ntil res ol uti o n or sta bilizati o n of t his c o n diti o n, prefera bl y after c o ns ultati o n wit h t he 
c o ntract r esearc h or ga nizati o n ( C R O ) me dical m o nit or (as per st u d y c o n tact list) or s p o ns or’s 
st u d y p h ysicia n (if t h e f or mer is n ot a vaila ble).  
Prec a uti o ns W it h C o nc o mit a nt M e dic ati o n K n o w n t o P r ol o n g t he Q T Inter v al  
T he use of me dicati o n k n o w n t o pr ol o n g Q T i nter val d uri n g t he st u d y n ee ds t o be base d o n a 
be nefit -ris k e v al uati o n b y t he i n vesti gat or, e. g. i n t he case of atrial fi brillati o n. I n certai n ot her 
sit uati o ns (e. g. t he i nitiati o n of macr oli des or fl u or o q ui n ol o nes i n case of a l o wer res pirat or y tract 
i nfecti o n), w he n t h e be nefit-ris k e val uati o n necessitates t he ad mi nistrati o n of me dicati o n k n o w n 
t o or p ote ntiall y pr ol o n gi n g Q T, I M P ca n be i nterr u pte d as e val uat e d b y t he i n vesti gat or after 
cli nical assess me nt of t he s u bject’s pr ofile, i ncl u di n g t he baseli ne Q Tc F a n d h o w t his has 
c ha n ge d o v er ti me f or t his s pecific s u bject. If t he i n vesti gat or elects t o c o nti n ue I M P, a d diti o nal 
m o nit ori n g will be perf or me d as per i n vesti gat or’s j u d g me nt. A n o n -e x ha usti ve list of me dicati o n 
k n o w n t o pr ol o n g Q T i nt er val is pr o vi de d i n A p pe n di x 5 . N ote: I n case Q T i nter val pr ol o n gati o n 
is re p orte d i n a s u bject w hile recei vi n g o ne of t hes e me dicati o ns, t he i n vesti gat or s h o ul d f oll o w 
t he la bels a n d Ris k E val u ati o n a n d Miti gati o n Strate gies g ui da nce.  
Prec a uti o ns W it h O t her C o nc o mit a nt M e dic ati o ns 
At d ose l e vels of 6 0 0 m g q. d., G L P G 1 6 9 0 has t he p ote ntial t o s u bsta ntiall y i nfl ue nce t he 
meta b olis m of C Y P 2 C 8 s u bstrates a n d t o p ote ntiall y be i nfl ue n ce d b y k n o w n str o n g 
C Y P 3 A 4/ p ote nt P -g p i n d ucers/i n hi bit ors.  
 
G L P G 1 6 9 0 de m o nstrate d a str o n g ti me -d e pe n d e nt i n hi biti o n p ote ntial a gai nst C Y P 2 C 8 
me diate d meta b olis m. C o nse q ue ntl y, G L P G 1 6 9 0 s h o ul d n ot be use d c o nc o mita ntl y wit h 
me dicati o ns pri maril y or s olel y meta b olize d via C Y P 2 C 8 (see A p pe n di x 1 ). F or ot her 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 4 - 
 
me dicati o ns i n v ol vi n g part of t heir meta b olis m pat h wa y via C Y P 2 C 8, ca uti o n s h o ul d be 
a p plie d o n a case -b y -cas e basis ta ki n g i nt o c o nsi d erati o n t he be n efit -ris k rati o. Stati ns s uc h 
as fl u vastati n a n d pita vastati n are meta b olize d t o s o me de gree b y C Y P 2 C 8, a n d nee d t o be 
use d wit h ca uti o n. Ot her st ati ns s uc h as si m vastati n, l o vastati n, a n d at or vastati n are 
t he oreticall y less meta b olize d b y C Y P 2 C 8. M o nit ori n g of li ver f u ncti o n tests (L F Ts ) a n d 
creati ne ki n ase is i m ple me nte d d uri n g t he st u d y, a n d g ui da nce t o t he s u bject ali g ne d wit h 
g ui da nce f or stati ns i n cli nical practice is t heref ore str o n gl y rec o m me n de d. L o pera mi de is 
als o a s u bstrate of C Y P 2 C 8, a n d s pecial ca uti o n s h o ul d be a p plie d i n ali g n me nt wit h cli nical 
practice.  
 
G L P G 1 6 9 0 is a s u bstrate of C Y P 3 A 4 a n d P -g p, a n d c o ul d t heref ore be i nfl ue nce d b y  t heir 
res pecti ve i n hi bit ors a n d i n d ucers. G L P G 1 6 9 0 e x p os ure is re d uce d u p t o 9 0 % b y t he str o n g 
C Y P 3 A 4/ p ote nt P -g p i n d ucer rif a m pi n. As a c o ns e q ue nce, str o n g i n d ucers of C Y P 3 A 4 
a n d/ or P -g p s h o ul d b e a v oi de d d uri n g t he st u d y t o e ns ure pr o per e x p os ure t o G L P G 1 6 9 0 (s ee 
A p pe n di x 2 ). G L P G 1 6 9 0 e x p os ure i ncreas e d b y 3 t o 4 f ol d w he n c oa d mi nistere d  wit h str o n g 
C Y P 3 A 4 i n hi bit ors a n d d ual str o n g 3 A 4 a n d p ote nt P -g p i n hi bit ors c o m pare d t o G L P G 1 6 9 0 
a d mi nistere d al o ne. T h eref ore  us e of k n o w n str o n g C Y P 3 A 4 i n hi bit ors a n d p ote nt P -g p 
i n hi bit ors is pr o hi bite d d uri n g t he st u d y (see A p pe n di x 3  a n d A p pe n di x 4 ). A nti bi otics fr o m 
t he macr oli de t hera pe utic class are e x cl u de d, u nless t he y are use d f or t he s h ort-ter m 
treat me nt of a l o w er res pirat or y tract i nfecti o n wit h i nterr u pti o n of I M P, w hic h is restarte d as 
s o o n as p ossi ble after t he c o m pleti o n of t he treat m e nt wit h macr oli des. 
 
It is hi g hl y rec o m me n d e d t hat t he C R O me dical m o nit or (as per st u d y c o ntact list) or s p o ns or’s 
st u d y p h ysicia n (if t h e f or mer is n ot a vaila ble) are c o ns ulte d bef ore t he i nitiati o n of ne w c o -
me dicati o n, i n partic ular me dicati o n k n o w n t o pr ol o n g Q T i nter val, t o be a C Y P 2 C 8 s u bstrate, or 
t o i n hi bit or i n d uce P-g p/ C Y P 3 A 4.  
I n cert ai n sit uati o ns, w he n t he be nefit-ris k e val uati o n necessitates t he a d mi nistrati o n of 
me dicati o n e x cl u de d fr o m use d uri n g t he st u d y, t he use of I M P s h o ul d be i nterr u pte d u ntil 
res ol uti o n or sta bilizati o n of t his c o n diti o n, prefera bl y after c o ns ultati o n wit h t he C R O me dical 
m o nit or (as per st u d y c o ntact list) or s p o ns or’s st u d y p h ysicia n (if t he f or mer is n ot a vaila ble) a n d 
restarte d as s o o n as p ossi ble.  
As a r ule, i ncl usi o n of s u bjects wit h sta ble c hr o nic ill ness o n sta ble me dicati o ns t hat are 
meta b olize d/tra ns p orte d b y t he a b o ve -me nti o ne d C Y P/tra ns p orter e nz y mes s h o ul d be deci de d o n 
a case -b y -case b asis if n ot e xcl u de d or pr o hi bite d, ta ki n g i nt o acc o u nt t he me dical hist or y, 
c o nc o mita nt me dicati o n of t he s u bject, t he t hera p e utic i n de x of t he me dicati o n, a n d safet y pr ofile.  
As i n dicate d i n t he st u d y c o ntact list, t he C R O me dical m o nit or s h o ul d be c o ntacte d, or t he 
s p o ns or’s st u d y p h ysicia n i n case t he f or mer is n ot a vaila ble ( w he n dee m e d necessar y b y t he 
i n vesti gat or), s p ecificall y f or me dicati o n wit h a narr o w t hera pe utic i n de x a n d/ or a ris k of 
( u n) pre dict a ble A Es.  
Resc ue M e dic ati o n  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 5 - 
 
If t he s u bject s h o ws a w orse ni n g of his/ her s yste mic scler osis disease c o n diti o n (e. g. ac ute 
e x acer bati o n), all treat me nt o pti o ns are all o we d at t he i n vesti gat or’s discreti o n. T he dec isi o n t o 
c o nti n ue t he I M P s h o ul d be ta ke n o n a case -b y -cas e basis.  
3. 6. 3. 3.   
F o o d a n d B e v er a g e R e stri cti o n s  
T he use of St. J o h n’s W ort is pr o hi bite d d uri n g t he st u d y.  
D o u ble -stre n gt h gra pefr uit j uice is p ote ntiall y a p ote nt C Y P 3 A 4 i n hi bit or a n d t heref ore s h o ul d be 
av oi de d d uri n g t he st u d y.  
3. 6. 3. 4.   
Ot h er Pr o hi biti o n s a n d R e stri cti o n s  
N ot a p plica ble.  
3. 6. 4.   
Tr e at m e nt Di s c o nti n u ati o n ( T e m p or aril y a n d P er m a n e ntl y), S u bj e ct 
Wit h dr a w al a n d St u d y T er mi n ati o n  
A s u bject ma y be wit h dr a w n fr o m t he cli nical st u d y at a n y ti me wit h o ut t he s u bject’s c o ns e nt if 
t he i n vesti gat or or s p o ns or deter mi nes t hat it is n ot i n t he best i nterest of t he s u bject t o c o nti n ue 
partici pati o n. I n s uc h cas e, t he reas o n f or wit h dra wal wil l be d oc u me nte d i n t he s o urce 
d oc u me nts, a n d t he s u bject will c o m plete t he E D  v isit a n d, or foll o w -u p v isit(s) f or safet y 
assess me nts.  
Treat me nt wit h I M P s h o ul d be disc o nti n ue d b y t h e i n vesti gat or ( prefera bl y after disc ussi o n wit h 
t he C R O me dical m o nit or, w h o ma y c o ns ult a n d m ust i nf or m t he s p o ns or’s st u d y p h ysicia n) f or 
a n y of t he f oll o wi n g c o n diti o ns:  
 
Lif e -t hreate ni n g A E  or a n  S A E  t hat places t he s u bject at i m me diate ris k. 
 
Seri o us i nfecti o ns dee me d relate d t o st u d y treat me nt b y t he i n vesti gat or, a n d re q ui ri n g 
pare nteral a nti micr o bial t hera p y a n d/ or h os pitalizati o n . 
 
C o nfir me d pre g na n c y . If a s u bject bec o m es pre g n a nt d uri n g t he st u d y (t o be c o nfir me d b y 
l ocal ser u m pre g n a nc y test; ce ntral meas ure me nt will als o be perf or me d), t he I M P has t o be 
st o p pe d i m me diatel y a n d t he s u bject has t o be f oll o we d u p u ntil birt h or ot her wise 
ter mi nati o n of pre g na n c y. T he s u bject ma y  be u n bli n de d t o t he treat me nt recei ve d d uri n g 
G L P G 1 6 9 0 -C L -2 0 4 if a p pr o priate. R e peat c o u nseli n g o n birt h defect ris k m ust be offere d . 
 
Arr h yt h mia or c o n d u cti o n a b n or malit y, i ncl u di n g b ut n ot li mite d t o pr ol o n ge d Q T i nter val 
c orrecte d f or t he heart rat e usi n g Fri dericia’s f or m ula ( Q Tc F), w h ere t h e se verit y is 
cate g orize d as C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) Gra d e 3 or 
hi g her ( Q Tc > 5 0 0 ms o n at least 2  se parate E C Gs). 
 
A n i ncreas e f or Q Tc F wit h > 6 0 ms c ha n ge  fr o m t he G L P G 1 6 9 0 -C L -2 0 4 b aseli ne or 
Q Tc F  > 5 0 0 ms at a n y E C G rec or di n g  n ee ds t o be c o nfir me d b y a n E C G rec or di n g as s o o n as 
p ossi ble after t he ori gi nal a b n or mal rec or di n g at t h e sa me visit. If t he a b n or mal rec or di n g is 
disc o vere d after t h e visit, t he rec o r di n g s h o ul d be c o nfir me d as s o o n as p ossi ble. I n case of 
a n a b n or mal E C G o n b ot h of t hese 2  rec or di n gs is c o nfir me d, t he i n vesti gat or nee ds t o se n d 
a n i m me diate alert t o t he C R O me dical m o nit or (as per st u d y c o ntact list) or s p o ns or’s st u d y 
p h ysicia n (if t he f or m er is n ot a vaila ble). If t he E C G a b n or malit y is bef ore I M P i nta ke, I M P 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 6 - 
 
a d mi nistrati o n will be wit h hel d u ntil t he ce ntral rea der has re vie we d t he E C G re gistrati o n. I n 
case of c o nfir mati o n of t he E C G a b n or malit y, I M P will be te m p orarily dis c o nti n ue d f or t his 
s u bject.  
 
I n crease i n L F Ts : 
 
As partate a mi n otra nsferase ( A S T) a n d/ or ala ni ne a mi n otra nsferase ( A L T) ele vati o ns 
> 8 x u p per li mit of n or mal ( U L N).  
 
A S T a n d/ or A L T ele vati o ns > 3 x U L N  wit h si g ns of se vere li ver da m a ge (i.e. wit h t he 
a p peara nce of fati g u e , na usea, v o miti n g, ri g ht u p p er q ua dra nt pai n or te n der ness, fe v er, 
ras h a n d/ or e osi n o p hilia [ > 5 %], a n d/ or t otal bilir u bi n ≥1. 5 x U L N or i nter nati o nal 
n or malize d rati o [I N R] > 1. 5).  
 
A S T or A L T ≥3 x U L N f or m ore t ha n 2 wee ks . 
 
Cli nical la b orat or y test s u g gesti ve of c h olestasis wit h t otal ser u m bile aci d le vels 
> 3 x  U L N o n a s a m ple ta ke n i n faste d state (at least 8  h o urs faste d). If t he r o uti ne 
ra n d o m or p ost pra n dial t otal ser u m bile aci d sa m ple is > 3 x U L N, t he n t he s u bject s h o ul d 
ha ve a faste d sa m ple ta k e n wit hi n 1 t o 5 da ys. T he res ults of t his test will deter mi ne 
w het her t he s u bject s h o ul d disc o nti n ue I M P or n ot.  
 
F or a s u bject ha vi n g:  
 
A S T or A L T ≥8 x U L N  
 
A S T or A L T ≥3 x U L N wit h si g ns of se vere li ver da ma ge (i.e. wit h t he a p peara nce of 
fati g u e, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe v er, ras h a n d/ or 
e osi n o p hilia [ > 5 %], a n d/ or t otal bilir u bi n ≥1. 5 x U L N or I N R > 1. 5)  
 
t he f oll o wi n g ste ps will n ee d t o be perf or me d b y t he i n vesti gat or:  
 
T he site s h o ul d i m me diatel y c o ntact t he s u bject a n d re q uire t he s u bject t o disc o nti n ue I M P 
i m me diatel y. T he s u bject s h o ul d be as ke d t o ret ur n t o t he site wit hi n a 4 8-h o ur wi n d o w fr o m 
a ware ness of t he res ult.   
 
A n assess me nt of ot her c o nc o mita nt me dicati o ns s h o ul d be ma de. T he i n vesti gat or s h o ul d 
c o nsi der w het h e r is i n t he best i nterest of t he s u bj ect t o i nterr u pt c o nc o mita nt me dicati o ns.  
 
A detaile d hist or y i ncl u di n g rele va nt i nf or m ati o n o n alc o h ol use, recreati o nal dr u g use, 
s u p ple me nt c o ns u m pti o n, a n y h er bal re me dies, fa mil y hist or y, se x ual hist or y, tra vel his t or y, 
hist or y of c o ntact wit h a ja u n dice d s u bject, s ur ger y, occ u pati o nal hist or y, bl o o d tra nsf usi o n, 
hist or y of li ver or aller gi c disease, a n d a n y ot her p ote ntial ca uses of a li ver i ns ult s h o ul d be 
c ollecte d.  
 
A detaile d assess me nt of t he s u bject’s cli nica l c o n diti o n a n d re peat la b orat or y tests f or L F T, 
i ncl u di n g al b u mi n, creati ne ki nase, t otal bilir u bi n ( direct a n d i n direct), ga m ma gl uta m yl 
tra nsferase, I N R a n d al kali ne p h os p hatase s h o ul d be d o ne.  
 
F urt her t esti n g f or h e patitis A, B, a n d C, a n d f or a ut oi m m u ne he patitis s h o ul d be d o ne. Ot her 
ca uses of viral he patitis ( C yt o m e gal o vir us  or E pst ei n -Barr vir us  etc) s h o ul d be e x cl u de d.  
Li ver i ma gi n g s h o ul d be c o nsi dere d.  
 
Referral t o a he p at ol o gist or gastr oe nter ol o gist s h o ul d be c o nsi dere d.  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 7 - 
 
 
All t hese cases s h o ul d be re p orte d as S A Es.  
 
E ver y eff ort s h o ul d be m a de t o kee p s u bjects i n t he st u d y a n d o n treat me nt. H o we ver, t he 
i n vesti gat or ca n c o nsi der st o p pi n g t he treat me nt wit h I M P, prefera bl y after c o ns ultati o n wit h t he 
s p o ns or’s st u d y p h ysicia n, i n case of c o ncer ns a b o ut t he s u bject’s safet y, maj or pr ot oc ol 
n o nc o m plia nce, seri o us or se vere A Es or w orse ni n g of t he dis ease c o n diti o n, w hic h i n t he 
i n vesti gat or’s o pi ni o n nee ds a n alter nati ve treat me nt a p pr oac h n ot bei n g c o vere d i n t he cli nical 
st u d y (e. g. resc u e me dicati o n) . 
W he n st u d y treat me nt is disc o nti n ue d, t he s u bject will be re q ueste d t o ret ur n f or t he E D v isit a n d 
t he F oll o w -u p visits.  
S u bjects will be i nf or me d pri or t o cli nical st u d y e ntr y t hat t he y are all o we d t o wit h dra w fr o m t he 
cli nical st u d y. At a n y ti m e a n d f or a n y reas o n, a s u bject’s partici pati o n i n t h e cli nical st u d y m a y 
ter mi nate at his/ her re q uest wit h o ut prej u dice t o his/ her f ut ure me di cal care. T he s u bject will be 
e nc o ura ge d t o s hare t he reas o n(s) f or wit h dra wal s o t his ca n be d oc u me nte d i n t he s o urce 
d oc u me nts, a n d t o c o m plete  t he E D v isit an d F oll o w -u p v isits f or safet y assess me nts, b ut will n ot 
be o bli ge d t o d o s o.  
S u bjects w h o wit h dra w fr o m t he cli nical st u d y wit h o ut c o ntact wit h t he site (l ost -t o-f oll o w-u p) 
s h o ul d be c o ntacte d b y t h e site s o t hat t heir healt h stat us ca n be ass esse d a n d d oc u me nte d i n t he 
s o urce d oc u m e nts. T he site s h o ul d ma ke e ver y eff ort t o u n dersta n d w het her t he s u bject is ali ve, 
i ncl u din g c h ec ki n g t he m e dical rec or ds  a n d c o ntacti n g ge neral practiti o ner or relati ves, if 
n ecessar y. All atte m pts m ust be d oc u me nte d i n t he s o urce d o c u me nts. S u bjects w h o disc o nti n ue 
I M P or t he st u d y will n ot be re place d. 
T he s p o ns or has t he ri g ht t o ter mi nate t he cli nical st u d y at a n y ti me i n case of safet y c o n cer ns or 
if s pecial cir c u msta nces c o ncer ni n g t he I M P or t he c o m pa n y itself occ ur, ma ki n g f urt her 
treat me nt of s u bjects i m p ossi ble. I n t his e ve nt, t he i n vesti gat or(s) a n d rele va nt a ut h orities will be 
i nf or me d of t he reas o n f or cli nical st u d y t er mi nati o n. 
3. 7.   
M e a s ur e s t o Mi ni mi z e Bi a s  
3. 7. 1.   
R a n d o mi z at i o n 
T his is a n o pe n -la bel st u d y wit h o ne d ose le vel of I M P; n o ra n d o mizati o n will be perf or me d. 
At  t he R oll o ver v isit (v isit 1), s u bjects c o nfir me d t o be eli gi ble f or t h is O L E st u d y will be 
e nr olle d. S u bjects will retai n t he s u bject i de ntificati o n n u m ber a ssi g ne d i n G L P G 1 6 9 0-C L -2 0 4 . 
3. 7. 2.   
Bli n di n g a n d U n bli n di n g  
T his is a n o pe n -la bel cli nical st u d y a n d treat me nt i n t his e xte nsi o n st u d y will n ot be bli n de d . 
Bef ore t he u n bli n di n g of t he G L P G 1 6 9 0 -C L -2 0 4 st u d y, t he bli n d of treat me nt recei ve d i n St u d y 
G L P G 1 6 9 0 -C L -2 0 4 ca n be br o ke n o nl y if t he i n v esti gat or dee ms it necessar y f or t he safet y of a 
s u bject. T he i n vesti gat or is e nc o ura ge d t o disc uss c o nsi derati o ns t o brea k t he bli n d wit h t he C R O 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 8 - 
 
me dical m o nit or w he ne v er p ossi ble  a n d w here t he sit uati o n all o ws. H o we ver, t he res p o nsi bilit y 
t o brea k t he treat me nt c o de i n e mer ge n c y sit uati o ns resi des s olel y wit h t he i n vesti gat or. T he 
i n vesti gat or is n ot re q uir e d t o disc uss u n bli n di n g bef ore h a n d if he or s he feels ra pi d e m er ge n c y 
u n bl i n di n g is necessar y, b ut is re q uire d t o i nf or m t he s p o ns or i n a ti mel y fas hi o n after u n bli n di n g 
has occ urre d.  
T he bli n d of treat me nt r ecei ve d i n St u d y G L P G 1 6 9 0 -C L -2 0 4 ca n b e br o ke n b y t he i n vesti gat or 
via i nteracti ve we b res p o nse s yste m. 
4.   
I N V E S TI G A TI O N A L M EDI CI N A L P R O D U C T S  
4. 1.   
I d e ntit y of t h e I nv e sti g ati o n al M e di ci n al Pr o d u ct( s ) 
T he I M P ( G L P G 1 6 9 0) will be s u p plie d t o t he cli nical st u d y ce nter, b y a n d u n der t he 
res p o nsi bilit y of t he s p o ns or, w h o will als o pr o vi de t he i n vesti gat or wit h E ur o pea n U ni o n ( E U) 
Q ualifie d Pers o n release d oc u me nts.  
G L P G 1 6 9 0 will be pr o vi de d as fil m -c oat e d ta blets f or oral use, c o ntai ni n g 2 0 0 m g G 4 5 1 9 9 0 eac h 
( G 4 5 1 9 9 0 is t he c o m p o u n d c o de f or G L P G 1 6 9 0).  
A f ull list of e x ci pie nts use d i n t he fil m -c oate d ta blet f or m ulati o n is a vaila ble i n t he  latest versi o n 
of t he  I B f or G L P G 1 6 9 0 a n d rele va nt u p dates/a d de n da. 
4. 2.   
D o s a g e a n d A d mi ni str ati o n  
T he d ose will be 6 0 0 m g G L P G 1 6 9 0 q. d. (as 3  G L P G 1 6 9 0 fil m -c oate d ta bl ets of 2 0 0  m g).  
T he I M P is t o be ta ke n ar o u n d t he sa me ti me e ver y da y wit h f o o d (e. g. brea kfast, s mall meal, or a 
s nac k) or after f o o d i nta k e, wit h a ma xi m u m of 2 h o urs bet wee n t h e f o o d i nta ke a n d I M P i nta ke. 
S u bjects will be i nstr ucte d t o s wall o w t he ta blets as a w h ole wit h a glass of water a n d t o n ot c h e w 
t he I M P pri or t o s w all o wi n g. 
If a s u bject misses a d os e (e. g. beca use h e/s he f or g ot t o ta ke t he me dicati o n), he/s he s h o ul d ta ke 
t he misse d d ose wit hi n 1 2 h o urs after t he pla n ne d i nta ke ti me a n d wit hi n 2 h o urs of f o o d i nta ke. 
If t he I M P is n ot ta ke n wit hi n 1 2 h o urs after t he pl a n ne d ti me, t he misse d d ose s h o ul d be s ki p pe d. 
4. 3.   
P a c k a gi n g, L a b eli n g a n d Di stri b uti o n  
T he fil m -c oate d t a blet f or oral use will be pac ka ge d i n blisters. A m ulti ple of kits will be 
pr o vi de d t o t he s u bject at eac h cli nical st u d y ce nter visit, pr o vi di n g t he s u bject wit h s uf ficie nt 
ta blets t o c o ver t he p eri o d u ntil t he ne xt sc he d ule d cli nical st u d y ce nter visit. I M P pac k a ges will 
be la bele d wit h cli nical st u d y -s p ecific d etails. 
All ma n ufact uri n g, pac ka gi n g  a n d la beli n g o p erati o ns will be perf or me d acc or di n g t o G o o d 
Ma n ufact ur i n g Practice f or Me dici nal Pr o d ucts a n d t he rele va nt re g ulat or y re q uire me nts. 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-3 9 - 
 
T he distri b uti o n will o nl y occ ur after t he re q uire d l ocal d oc u me ntati o n is o btai ne d , i ncl u di n g 
cli nical st u d y a p pr o val b y C o m pete nt A ut h orities a n d t he I E Cs/I R Bs, d oc u me ntati o n o n w hic h 
t he assess me nt of t he i n v esti gat or’s q ualificati o ns was base d (e. g. c urric ul u m vitae), a n d t he 
si g ne d a n d date d st u d y a gree me nt a n d fi na ncial a gree me nt.  
4. 4.   
St or a g e  
Sites are t o st ore I M P s u p plies i n a sec ure area bel o w 3 0° C , pr otecte d fr o m li g ht, u ntil dis pe nse d. 
Sites will be re q uire d t o m o nit or t he st ora ge te m p erat ure b y usi n g at least a mi n -ma x 
te m perat ur e-rec or di n g de vice a n d t o kee p a mi ni m u m t o ma xi m u m te m perat ure l o g, w hic h m ust 
be c o m plete d eac h w or ki n g da y i n or der t o esta blis h a rec or d o f c o m plia nce wit h t hese st ora ge 
c o n diti o ns. T he i n vesti gat or will i nstr uct s u bjects o n h o w t he I M P s h o ul d be st ore d at h o me. 
4. 5.   
Tr e at m e nt C o m pli a n c e  a n d Dr u g A c c o u nt a bilit y  
T he p har macist or desi g n ate d cli nical st u d y pers o n nel will mai ntai n a l o g of t he t otal  a m o u nt of 
I M P recei ve d at site, a m o u nt dis pe nse d t o t he s u bject, a n d t he a m o u nt of I M P ret ur ne d b y t he 
s u bject t o t he site. I M P s u p plies f or eac h s u bject will be i n ve nt orie d a n d acc o u nte d f or 
t hr o u g h o ut t he cli nical st u d y. At t he e n d of t he treat me nt perio d , t hese rec or ds will be c hec k e d 
a gai nst t he i n ve nt or y b y t he st u d y m o nit or. All cli nical s u p plies will be st ore d i n l oc ke d facilities.  
F or eac h d ose t a ke n at h o me, t he date a n d n u m b er of ta blets ta ke n s h o ul d be rec or de d o n t he 
s u bject diar y car d ( Secti o n 5. 4 ). A n y i nterr u pti o n or c ha n ge i n treat me nt (t o get h er wit h t he reas o n 
f or c ha n ge) s h o ul d be d o c u me nte d o n t he s u bject diar y car d. S u bjects will r et ur n a n y u n us e d I M P 
a n d e m pt y I M P pac ka ges at eac h v isit. At eac h cli nical st u d y ce nter visit, cli nical st u d y ce nt er 
staff will re vie w tr eat me nt c o m plia nce b y assessi n g t he n u m ber of ret ur ne d I M P. Misse d d oses 
s h o ul d be disc usse d t o tr y t o ascertai n t he reas o n(s). E ver y eff ort s h o ul d be ma de t o e ns ure t h e 
pr o per s u bject d os e. S u bjects wit h p o or c o m plia nce will be retrai ne d b y t he cli nical st u d y site. 
U p o n s p o ns or a p pr o val , all u n use d I M P a n d e m pt y I M P pac ka ges s h o ul d b e ret ur ne d t o t he dr u g 
s u p plier/ dr u g d e p ot or will be destr o ye d at t he site. I n case of destr ucti o n b y t he site  or t he 
s u p plier/ dr u g d e p ot, a n acce pta bl e destr ucti o n pr o cess s h o ul d be i n place a n d a destr ucti o n 
certificate s h o ul d be pr o vi de d t o t he  s p o ns or. 
5.   
C LI NI C A L S T U D Y A S S E S S M E N T S  
E ver y eff ort s h o ul d be m a de t o e ns ure t hat cli nical st u d y p r ot oc ol (C S P )-re q uire d tests a n d 
pr oce d ures are c o m plete d as descri be d i n t he Sc he d ule of Acti vities (see Secti o n  5. 9 ).  
5. 1.   
Ti mi n g of A s s e s s m e nt s  
T he st u d y assess me nts will be u n derta ke n at ti me p oi nts as s pecifie d i n t he Sc he d ule of Acti vities 
i n Secti o n 5. 9 . A wi n d o w of ±2  da ys is all o we d f or Visit s 2  a n d 3, a wi n d o w of ± 4 da ys is 
all o we d f or V isit 4, a n d a wi n d o w of ± 7  da ys is all o we d f or  V isits 5, 6, 7, 8, 9, 1 0, 1 1,  t he E o T  
Wee k 1 0 4  v isit ( or E D visit ), a n d f or t he 2  f oll o w-u p visits.  
T he I C F n ee ds t o be si g n e d bef ore a n y st u d y pr oce d ure f or t his e xte nsi o n st u d y is carrie d o ut. 








G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-4 3 - 
 
 
He m at ol o g y :  
he mat ocrit, mea n c or p usc ular v ol u me, mea n c or p usc ular  he m o gl o bi n , mea n c or p usc ular 
he m o gl o bi n c o n ce ntrati o n , he m o gl o bi n, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt, w hite 
bl o o d cell differe ntial c o u nt (a bs ol ute a n d rel ati ve), a n d platelets.  
 
C o a g ul ati o n:  
I N R, acti vate d partial t hr o m b o plasti n ti me , a n d pr ot hr o m bi n ti me.  
 
Ser u m/ Pl as m a  c he mistr y:  
ra n d o m gl u c ose, urea, creati ni ne, uric aci d, s o di u m, p otassi u m, calci u m, c hl ori de, 
p h os p h or us, A S T, A L T, G G T, t otal bilir u bi n, al kali ne p h os p hatase, lact ate de h y dr o ge nas e, 
t otal ser u m bile aci d, al b u mi n, t otal pr o tei ns, tri gl yceri des, c h olester ol, hi g h de nsit y 
li p o pr otei n, l o w de nsit y li p o pr otei n, creati ne ki nase , a n d C-reacti ve pr otei n. 
 
Uri n al ysis:  
 
Di pstic k: p H, gl uc ose, pr otei ns, bl o o d, le uc oc yt es, ket o nes.  
 
Micr osc o pic e x a mi nati o n of t he se di me nt (c yli n ders, er y t hr oc yt es, le uc oc yt es) if 
i n dicate d. 
 
Pre g n a nc y test f or fe m ales:  
u ri ne di pstic k o n a m o nt hl y basis u ntil t he F U 1 foll o w -u p v isit ( o nl y f or W O C B P). 
U nsc he d ule d F S H la b testi n g ma y be p erf or me d if a fe male s u bj ect re p orts a n a me n orr hea 
≥1 2 m o nt hs d uri n g t he  st u d y. 
 
T he cli nical la b orat or y e val uati o ns will be perf or me d at  visits s pecifie d i n t he Sc he d ule of 
A cti vities i n Secti o n  5. 9  (see als o Secti o n 5. 1 , “Ti mi n g of Assess me nts ”). Refere n ce ra n ges will 
be s u p plie d b y t he ce ntr al la b orat or y. Cli nical la b orat or y val ues o utsi de t h e n or mal ra n ge will be 
fla g ge d a n d cli nical rele va nce will be assesse d b y t he i n vesti gat or. O nl y l a b orat or y test 
a b n or malities j u d ge d as cli nicall y si g nifica nt b y t h e pri nci pal i n vesti gat or s h o ul d be rec or de d as 
A Es . 
T he details of bl o o d a n d uri ne sa m ple ha n dli n g a n d s hi p me nt i nstr ucti o ns will be pr o vi de d i n a 
se parat e la b orat or y ma n ual. 
5. 6. 3.   
P h y si c al E x a mi n ati o n  
P h ysical e xa mi nati o ns will be perf or me d as a p pr o priate f or a n y s y m pt o ms re p orte d b y t he 
s u bject. T he y will be c o n d ucte d b y a p h ysicia n, trai ne d p h ysicia n’s assista nt, or n urse practiti o ner 
as acce pta ble acc or di n g t o l ocal re g ulati o n at v isits s pecifie d i n t he Sc he d ul e of Acti vities i n 
Secti o n 5. 9 . T he pers o n c o n d ucti n g t he p h ysical e x a mi nati o n will d oc u me nt t his i n t he s u bject’s 
me dical rec or ds. Cli nicall y si g nifica nt a b n or mal fi n di n gs s h o ul d be rec or de d as A Es.  
5. 6. 4.   
Vit al Si g n s  
Vital si g n s (s yst olic a n d diast olic bl o o d press ure, heart rate, res pir at or y rate, a n d b o d y 
te m perat ur e) will be rec or de d i n a sta n dar dize d ma n ner (i. e. after t he s u bject has reste d i n a 
s u pi ne p ositi o n f or 5 mi n utes) at visits s pecifie d i n t he S c he d ule of A cti vities i n Secti o n 5. 9 . 
Cli nicall y si g nifica nt a b n or mal val ues s h o ul d be rec or de d as A Es.  




G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-4 5 - 
 
 
5. 9.   
S c h e d ul e of A cti viti e s  
F or detaile d i nstr ucti o ns o n t he cli nical st u d y pr oce d ures, please see referre d secti o ns a n d Secti o n 5. 1 , “Ti mi n g of Ass ess me nts ”. 
E V E N T  
T R E A T M E N T P E RI O D  
F O L L O W -
U P  
St u d y Visit  
R oll -o ver 
Visit  1  
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1  
E o T   
/ E D  
F U 1   
F U 2  
St u d y Wee k ( W) or D a y ( D) ± 
d a ys ( d)  
D 1  
W 2  
± 2 d  
W 4  
± 2 d  
W 8  
± 4 d  
W 1 6  
± 7 d  
W 2 8  
± 7 d  
W 4 0  
± 7 d  
W 5 2  
± 7 d  
W 6 4  
± 7 d  
W 7 6  
± 7 d  
W 8 8  
± 7 d  
W 1 0 4  
± 7 d  
W 1 0 8  
± 7 d  
W 1 1 6  
± 7 d  
I nf or me d c o nse nt 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
I ncl usi o n/e xcl usi o n criteria 
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Pre g na nc y test  
()1  
 
  
  
  
  
  
  
  
  
  
  
 
 
S y m pt o m -directe d p h ysical 
e xa mi nati o n  
()1  
  
  
  
  
  
  
  
  
  
  
  
  
 
Vital si g ns  
()1 
  
  
  
  
  
  
  
  
  
  
  
 
 
1 2 -Lea d E C G  
()1  
  
  
  
  
  
  
  
  
  
  
  
  
 
Cli nical la b orat or y tests  
()1  
  
  
  
  
  
  
  
  
  
  
  
  
 




G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-4 7 - 
 
 
6.   
S T A TI S TI C A L M E T H O D S  
All statistical met h o d s will be detaile d i n a statistical a nal ysis pla n t hat will be pre pare d pri or t o 
data base l oc k . All rele va nt data c ollecte d i n t his cli nical st u d y will be d oc u me nte d usi n g 
s u m mar y ta bl es, fi g ures, a n d s u bject data listi n gs. 
A n y d e viati o ns fr o m t he pr ot oc ol  are t o b e j ustifie d i n t he statistical a nal ysis pla n. 
6. 1.   
D et er mi n ati o n  of S a m pl e Si z e  
T hirt y  s u bjects ( 2 0 o n 6 0 0 m g oral q. d.  G L P G 1 6 9 0 a n d 1 0 o n place b o) are pla n ne d t o be 
ra n d o mize d i n t he p recedi n g G L P G 1 6 9 0 -C L -2 0 4 st u d y. All s u bjects w h o c o m plete d t he 2 4 -wee k 
d o u ble -bli n d treat me nt i n t his prece di n g st u d y, si g ne d t he I C F of t he O L E  st u d y, a n d are eli gi ble 
f or t he O L E  will be i ncl u de d . T h us , u p t o 3 0 s u bjects ma y r oll o ver a n d b e e nr olle d  i n t his O L E 
st u d y. No f or mal sa m ple siz e calc ulati o n was  perf or me d.  
6. 2.   
P o p ul ati o n f or A n al y s e s  
6. 2. 1.   
All E nr oll e d S u bj e ct s  
All s u bjects w h o were f o u n d eli gi ble t o partici p ate i n t he cli nical st u d y.  
6. 2. 2.   
F ull A n al y si s S et  
T he O L E f ull a n al ysis set ( F A S) is defi n e d as all s u bjects w ho ha d  at least o ne i nta ke of I M P  i n 
t he O L E  st u d y. 
6. 3.   
St ati sti c al A n al y s e s  
6. 3. 1.   
G e n er al St ati sti c al C o n si d er ati o n s  
S u m mar y ta b ulati o ns will be prese nte d a n d will dis pla y t he n u m ber of o bser vati o ns, mea n, 
sta n dar d deviati o ns a n d/ or sta n dar d err or ( as a p pr o priate ), me dia n, mi ni m u m a n d ma xi m u m (f or 
c o nti n u o us varia bl es), a n d t he n u m ber a n d perce nta ge per cate g or y (f or cat e g orical data). I n 
a d diti o n t o ta b ulate d descri pti ve statistics, gra p hical data dis pla ys ma y b e use d t o s u m marize t he 
data. Data will be p o ole d acr oss ce nters a n d c o u ntries.  
Ta bles will be pres e nte d b y ra n d o mizati o n gr o u p of t he prece di n g G L P G 1 6 9 0 -C L -2 0 4 st u d y.  
Baseli ne will be defi ne d as t he last meas ure me nt bef ore t h e first d ose of I M P i n t he prece di n g 
G L P G 1 6 9 0 -C L -2 0 4 st u d y ,   
 f or   
 s afet y. 




G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-4 9 - 
 
6. 3. 5.   
A n al y s e s of S af et y D at a  
All safet y a nal yses will be perf or me d usi n g t he F A S ( Secti o n 6. 2. 2 ). S u bjects will be a nal yze d 
acc or di n g t o t he pri or treat me nt gr o u p i n t he prece di n g G L P G 1 6 9 0 -C L -2 0 4 st u d y . All safet y d ata 
c ollecte d o n or after t h e first d ose of I M P a d mi nistrati o n i n t he pr ece di n g G L P G 1 6 9 0 -C L -2 0 4  
st u d y u p t o t he last c o ntact after t h e last d ose of I M P, u nless s pecifie d ot her wise, will be 
s u m marize d b y treat me nt gr o u p acc or di n g t o t he I M P recei ve d i n St u d y G L P 1 6 9 0-C L -2 0 4, a n d 
o verall . I n a d diti o n, si milar s u m maries of s afet y d ata c ollecte d o nl y after t he first i nta ke of I M P 
d uri n g t his O L E st u d y will be pr o vi de d.   
Cli nical safet y will be a d dresse d b y ass essi n g A E s, la b orat or y ass ess me nts, p h ysical 
e x a mi nati o ns, vital si g ns,  a n d 1 2 -lea d E C Gs. 
6. 3. 5. 1.   
E xt e nt of E x p o s ur e  
A s u bject’s e xte nt of e x p os ure t o t he I M P will be ge n erat e d fr o m t he I M P a d mi nistrati o n pa ge of 
t he C R F. E x p os ure data will be s u m marize d b y treat me nt gr o u p of t he prece di n g G L P G 1 6 9 0 -C L -
2 0 4 st u d y . D urati o n of e x p os ure t o t he I M P will be e x presse d as t he n um b er of  wee ks  bet w ee n 
t he first (i n C L-2 0 4)  a n d last d ose of I M P, i ncl usi ve, re gar dless of te m p orar y i nterr u pti o ns i n 
I M P a d mi nistrati o n a n d s u m marize d b y treat me nt gr o u p, d efi ne d i n C L-2 0 4 . A si milar s u m mar y 
f or t he d urati o n of e x p os ure fr o m t he first d ose of I M P i n t he O L E u p t o t he last d ose will als o be 
pr o vi de d.  
6. 3. 5. 2.   
A d v er s e E v e nt s  
Cli nical a n d la b orat or y A Es will be c o de d usi n g t h e latest versi o n of t he M e dical Dicti o nar y f or 
Re g ulat or y Acti vities. S yste m Or ga n Class ( S O C), Hi g h -Le vel Gr o u p Ter m, Hi g h -Le ve l Ter m, 
Preferre d Ter m, a n d L o wer -Le v el Ter m will be attac he d t o t he cli nical data base.  
T he f oll o wi n g A Es will be c o nsi dere d as T E A Es : 
A n y A E ( or a n y w orse ni n g of a n A E) wit h a n o nset date o n or after t he I M P start date i n t he 
prece di n g G L P G 1 6 9 0 -C L -2 0 4 st u d y a n d n o later t ha n 3 0 da ys after last d ose of I M P  i n 
G L P G 1 6 9 0 -C L -2 0 6  
S u m maries ( n u m ber a n d perce nt a ge of s u bjects) of T E A Es per s u bj ect b y S O C a n d Preferre d 
Ter m will be pr o vi de d b y treat me nt gr o u p. T E A Es will als o be s u m marize d b y ca usal 
relati o ns hi p to t he I M P a n d se verit y. I n a d diti o n, T E A Es lea di n g t o pre mat ure disc o nti n uati o n of 
t he I M P will be s u m mari ze d a n d liste d. Als o, all S A Es, i ncl u di n g t he n o n-treat me nt-e mer ge nt 
S A Es, will be liste d.  
I n a d diti o n, s u m maries a n d/ or listi n gs will be pr o vi de d f or t he s us pecte d s y m pt o ms/ A Es of   
 
wit h a n o nset date o n or after t he I M P start date u ntil t he e n d of foll o w -u p (i ncl u di n g i nf or m ati o n 
fr o m foll o w -u p v isit 2).  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-5 0 - 
 
6. 3. 5. 3.   
Cli ni c al L a b or at or y E v al u ati o n s  
La b orat or y assess me nts will be a nal yze d d escri pti vel y. C ha n ges  fr o m baseli ne ( Da y 1 pred ose ) i n 
t he G L P G 1 6 9 0 -C L -2 0 4 st u d y a n d s hifts acc or di n g t o n or mal ra n ges will be prese nte d as well. 
A nal ys es will be d o ne per pri or treat me nt gr o u p i n G L P G 1 6 9 0 -C L -2 0 4 . Si milar a nal yses of 
safet y data c ollecte d o nl y d uri n g t his O L E st u d y will be pr o vi de d. 
6. 3. 5. 4.   
P h y si c al E x a mi n ati o n s  
O nl y a b n or mal p ost baseli ne  p h ysic al e xa mi nati o n res ults will be liste d.  
6. 3. 5. 5.   
Vit al S i g n s 
Vital si g ns will be a nal yz e d descri pti vel y. C ha n ges fr o m baseli ne ( Da y 1 pre d ose ) i n G L P G 1 6 9 0 -
C L -2 0 4 a n d s hifts acc or di n g t o n or mal ra n ges will be prese nt e d as well. A nal yses will be d o ne 
per pri or tr eat me nt gr o u p as defi ne d i n G L P G 1 6 9 0 -C L -2 0 4 . Si milar a n al ys es of safet y dat a 
c ollecte d o nl y d uri n g t his O L E st u d y will be pr o vi de d.  
6. 3. 5. 6.   
1 2 -L e a d El e ctr o c ar di o gr a m  
A descri pti ve a n al ysis will be d o ne f or t he 1 2-l ea d E C G. C ha n ges fr o m baseli ne ( Da y 1 pred ose ) 
i n G L P G 1 6 9 0 -C L -2 0 4 a n d s hifts acc or di n g t o n or mal ra n ges will be prese nte d as well. A nal yses 
will be d o ne per pri or treat me nt gr o u p i n G L P G 1 6 9 0 -C L -2 0 4 . Si milar a n al ys es of safet y d ata 
collecte d o nl y d uri n g t his O L E st u d y will be pr o vi de d.  
6. 3. 6.   
A n al y si s of Ot h er A s s e s s m e nt s  
E x pl orat or y efficac y  a n d safet y a n al ys es ma y be a d de d w he n dee me d usef ul t o better u n dersta n d 
t he c ollecte d dat a. I n di vi d ual a n d/ or mea n ± sta n d ar d err or efficac y a n d s afety ma y b e pl otte d 
a gai nst o ne a n ot her.   
6. 3. 7.   
A d diti o n al St ati sti c al C o n si d er ati o n s  
N ot a p plica ble.  
7.   
D A T A M O NI T O RI N G  
A n i n de pe n de nt me dical safet y re vi e w will be i m ple me nte d f or G L P G 1 6 9 0 -C L -2 0 4 as well as f or 
t his G L P G 1 6 9 0-C L -2 0 6 cli nical st u d y. T he re vie w will be c o n d ucte d b y a n i n de pe n de nt cli nicia n 
e x perie nce d i n t he fiel d of s yste mic s cler osis. T he i n de pe n de nt e x pert will re vie w safet y data a n d 
assess a n y p ote ntial safet y iss ues arisi n g d uri n g t h e c o n d u ct of t he cli nical st u d y. T his pr ocess 
will be descri be d i n a s e p arate ‘I n de p e n de nt Me di cal Safet y Re vie w C harter’ . 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-5 1 - 
 
8.   
S A F E T Y R E P O R TI N G  
8. 1.   
D efi niti o n s of A d v er s e E v e nt s,  S eri o u s A d v er s e E v e nt s  a n d 
S p e ci al S it u ati o n s 
8. 1. 1.   
A d v er s e E v e nt s  
A n A E is a n y u nt o war d me dical o cc urre n ce, ne w or w orse ni n g of a n y pre -e xisti n g c o n diti o n, i n a 
cli nical st u d y s u bject a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y h a ve t o 
ha ve a ca usal r elati o ns hi p wit h t his treat me nt.  
A n A E ca n t h eref ore b e a n y u nfa v ora bl e a n d u ni nt e n de d si g n ( e. 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 dis ease te m p orall y ass ociate d wit h t he use of a me dici nal pr o d uct, w het her 
or n ot c o nsi dere d relate d. A Es  ma y als o i ncl u de pre - or p ost treat me nt c o m plicati o ns t hat occ ur as 
a res ult of C S P -s pecifie d pr oce d ures, w ors e ni n g of t he tar gete d disease, o ver d ose, dr u g 
a b use/ mis use re p orts, or occ u pati o nal e x p os ure. Pre -e xisti n g c o n diti o ns t hat i ncrease i n se verit y 
or c ha n ge i n n at ure d uri n g or as a c o ns e q ue n ce of partici pati o n i n t he cli nical st u d y will a ls o be 
c o nsi dere d A Es.  
8. 1. 2.   
S eri o u s A d v er s e E v e nt s  
A n S A E is defi ne d as a n A E t hat:  
 
Res ults i n deat h;  
 
Is life-t hreate ni n g ( N ote: T he ter m ‘life-t hreat e ni n g’ i n t he d efi 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 ve 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  d eat h if it were m ore s e vere.);  
 
Re q uires i n -patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;  
 
Res ults i n persiste nt or si g nifica nt disa bilit y/i n ca p acit y;  
 
Is a c o n ge nital a n o mal y / birt h defect;  
 
Is me di call y si g nifi ca nt ( me dical a n d scie ntific j u d g me nt s h o ul d be e x ercise d i n deci di n g 
w het her ot her sit uati o ns s h o ul d be c o nsi dere d s eri o us s uc h as i m p orta nt me dical e ve nts t hat 
mi g ht n ot be i m me diatel y life -t hreat e ni n g or res ult i n deat h or h os pitalizati o n b ut mi g ht 
je o par dize t he s u bject or mi g ht re q uire i nter ve nti o n t o pre ve nt o ne of t h e ot her o utc o mes 
liste d i n t he defi niti o n a b o ve). 
8. 1. 3.   
U nli st e d ( U n e x p e ct e d) A d v er s e E v e nt s / R ef er e n c e S af et y I nf or m ati o n  
A n A E is c o nsi dere d u nliste d if t he nat ure or i nte nsit y is n ot c o nsiste nt wit h t he a p plica ble 
pr o d uct refere nce s afet y i nf or mati o n. F or a n I M P, t he e x pecte d ness of a n A E will be deter mi ne d 
b y w het her or n ot it is liste d i n t he refere n ce safet y i nf or m ati o n part of t he I B.  
8. 1. 4.   
A d v er s e E v e nt s of S p e ci al Int er e st  
N ot a p plica ble.  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-5 2 - 
 
8. 1. 5.   
Cli ni c al L a b or at or y A b n or m aliti e s a n d Ot h er A b n or m al A s s e s s m e nt s a s 
A d v er s e E v e nt s  or S eri o u s A d v er s e E v e nt s  
La b orat or y a b n or malities wit h o ut cli nical si g nifica nce base d o n t h e i n vesti gat or’s j u d g me nt  are 
n ot c o nsi dere d A Es or S A Es. H o we ver, la b orat or y a b n or malities (e. g. cli nical c he mistr y, 
he mat ol o g y , a n d uri nal ysis) or ot her a b n or mal (cli nical st u d y -s p ecific) assess me nts (e. g. E C G, 
ra di o gra p h y, vital si g ns) t hat re q uire me dical or s ur gical i nter venti o n, are ass ociate d wit h si g ns 
a n d/ or s y m pt o ms, a n d/ or lea d t o I M P i nterr u pti o n, m o dificati o n or disc o nti n uati o n m ust be 
rec or de d as a n A E or S A E if t he y m eet t he defi niti o n as descri be d i n Secti o ns 8. 1. 1  a n d 8. 1. 2 , 
res pecti vel y. If t he la b orat or y a b n or malit y is part of a s y n dr o me, t he s y n dr o me or dia g n osis is t o 
be re p ort e d (e. g. a ne mia i nstea d of decrease d he m o gl o bi n).  
T he f oll o wi n g li ver e nz y me ele vati o ns s h o ul d be re p orte d as S A Es:  
 
A S T or A L T ≥8 x U L N  
 
A S T or A L T ≥3 x U L N wit h si g ns of se vere li ver da ma ge (i.e. wit h t he a p peara nce of fati g u e, 
na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, ras h a n d/ or e osi n o p hilia 
[ > 5 %], a n d/ or t otal bilir u bi n ≥1. 5 x U L N or I N R > 1. 5) 
 
8. 1. 6.   
S p e ci al Sit u ati o n s  
S pecial sit uati o ns are sit uati o ns t hat ha ve a p ossi ble i m pact o n t he safe use of t he I M P. T hese 
sit uati o ns mi g ht be or mi g ht n ot be ass o ciate d wit h AEs . 
 
Pre g n a nc y  
 
A b use or mis use of I M P 
 
A b use of I M P is defi ne d as t he persiste nt or s p ora dic, i nte nti o nal e x cessi ve use of t he 
I M P, w hic h is a cc o m pa ni e d b y h ar mf ul p h ysical or ps yc h ol o gi cal effects. 
 
Mis use of I M P is defi n e d as a sit uati o n w here t h e I M P is i nte nti o nall y a n d 
i na p pr o priatel y use d n ot i n acc or da nce wit h t he pr o d uct i nf or mati o n. 
 
Dr u g i nteracti o n or f o o d i nteracti o n wit h I M P 
 
A dr u g i nteracti o n wit h I M P is defi ne d as a sit uati o n i n w hich t here is e vi d e nce or a 
s us pici o n t hat t he I M P i nteracts wit h a n ot her dr u g w he n b ot h are a d mi nistere d t o get her. 
 
A f o o d i nteracti o n wit h I M P is defi ne d as a sit uati o n i n w hic h t here is e vi d e nce or a 
s us pici o n t hat t he I M P i nteracts wit h a f o o d w he n ta ke n to get her.  
 
 Me dicati o n err or wit h I M P 
 
A me dicati o n err or wit h I M P is defi ne d as a n u ni nte n de d fail ure i n t he dr u g treat me nt 
pr ocess t hat lea ds t o, or h as t he p ote ntial t o lea d t o, har m t o t he s u bject. 
 
Occ u pati o nal e x p os ure t o I M P 
 
Occ u pati o nal e x p os ure t o I M P is defi ne d as a n e x p os ure t o t he I M P as a res ult of o ne’s 
pr ofessi o nal or n o n pr ofessi o nal  occ u pati o n.  
 
O ver d ose wit h I M P 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-5 3 - 
 
A n o ver d ose of I M P is defi ne d as t he a d mi nistrati o n of a q ua ntit y of t he I M P gi ve n per 
a d mi nistrati o n or c u m ulati vel y, w hic h is t he i nta ke of m ore t ha n 3  t a blets/ da y. 
 
 Pr o d uct c o m plai nt or q ualit y defect of I M P 
 
Pr o d uct c o m plai nt or q ualit y d efect of I M P is defi ne d as c o m plai nts or defects of t he 
I M P arisi n g fr o m p ote ntial de viati o n s i n t he ma n ufact ure, pac k a gi n g or distri b uti o n of 
t he I M P. 
8. 2.   
A s s e s s m e nt of A d v er s e E v e nt s  a n d S eri o u s A d v er s e E v e nt s  
T he i n vesti gat or is res p o nsi ble f or assessi n g A Es a n d S A Es f or ca usalit y a n d se verit y. T his is t he 
basis f or t he s p o ns or’s fi nal re vie w a n d c o nfir m ati o n of acc urac y a n d c o m plete ness of e v e nt 
i nf or mati o n a n d ca us alit y assess me nts. 
8. 2. 1.   
A s s e s s m e nt of C a u s alit y  
T he i n vesti gat or is res p o nsi ble f or assessi n g t he ca usal relati o ns hi p t o I M P(s) a d mi nistrati o n or 
st u d y pr oce d ures (e. g. i n vasi ve pr oce d ures s u c h as ve ni p u nct ure) base d o n her/ his cli nical 
j u d g me nt. T he f oll o wi n g decisi o n c h oice will be use d b y t h e i n vestigat or t o descri be t he ca usalit y 
assess me nt bet wee n t he re p orte d e v e nt or la b orat or y test a b n or malit y a n d t he I M P . 
 
U nrel ate d:  
Ti me relati o ns hi p t o I M P i nta ke is i m pr o ba ble. Relate d t o ot her eti ol o gi es s uc h as 
c o nc o mita nt me dicati o ns or s u bject's cli nical st ate. 
 
U nli kel y:  
Ti me relati o ns hi p t o I M P i nta ke is i m pr o ba ble ( b ut n ot i m p ossi ble). C o nc o mita nt disease or 
ot her dr u gs pr o vi de pla usi ble e x pla nati o ns.  
 
P ossi ble:  
Ti me relati o ns hi p t o I M P i nta ke is reas o na bl e. E ve nt or la b orat or y test a b n or malit y c o ul d 
als o be e x plai ne d b y dise ase or ot her dr u gs. I nf or mati o n o n I M P wit h dra wal ma y b e lac ki n g 
or u nclear.  
 
Pr o b a ble:  
Ti me relati o ns hi p t o I M P i nta ke is reas o na bl e. U nli kel y t o be attri b ute d t o c o nc urre nt disease 
or ot her dr u gs. Res p o nse t o wit h dra wal is cli nicall y re as o na bl e a n d rec halle n ge n ot re q uire d.  
 
Cert ai n:  
Ti me relati o ns hi p t o I M P i nta ke is pla usi ble. Ca n n ot be e x plai ne d b y c o n c o mita nt disease or 
ot her dr u gs. Res p o nse t o wit h dra wal is pla usi ble ( p har mac ol o gicall y, p at h ol o gicall y). E v e nt 
defi niti ve p har mac ol o gic all y or p he n o me n ol o gicall y ( i.e. a n o bjecti ve a n d s pecific me dical 
dis or der or a rec o g nize d p har mac ol o gical p he n o m e n o n). Rec h alle n ge satisfact or y, if et hical 
a n d necessar y. 
 
It s h o ul d be e m p hasize d t hat i neffecti ve treat me nt ( w orse ni n g of t he dis ease) s h o ul d n ot be 
c o nsi dere d as ca us all y relate d i n t he c o nte xt of A E re p orti n g.  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-5 4 - 
 
8. 2. 2.   
A s s e s s m e nt of S e v erit y  
T he se verit y of A Es s h o ul d be gra de d usi n g t he C T C A E  versi o n 5. 0. If a C T C A E criteri o n d oes 
n ot e xist, t he i n vesti gat or s h o ul d use t he gra de or a djecti ves: Gra d e  1 ( mil d), Gra de 2 ( m o derat e), 
Gra de 3 (se vere), Gra d e 4 (life -t hreate ni n g) or Gra de 5 (fatal) t o des cri be t he ma xi m u m i nte nsit y 
of t he A E. F or p ur p oses of c o nsiste nc y wit h t he C T C A E, t hese i nte nsit y gra des are defi ne d i n t he 
ta ble bel o w. 
T a ble 1   
Gr a di n g of A E  Se verit y  
Gr a de   
A djecti ve   
Descri pti o n  
Gra de 1   
Mil d  
As y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n n ot i n dicate d  
Gra de 2   
M o derate  
L ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -a p pr o priate 
i nstr u me ntal A D L *  
Gra de 3   
Se vere   
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pitalizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; 
li miti n g self-care A D L * *  
Gra de 4   
Life -t hreate ni n g  Ur ge nt i nter ve nti o n i n dicate d  
Gra de 5   
Deat h  
Deat h -relate d A E  
*   
I nstr u me ntal A cti vities of Dail y Li vi n g ( A D L) r ef er t o pre pari n g meals, s h o p pi n g f or gr oceries or cl ot hes, usi n g t he 
  
tele p h o ne, ma na gi n g m o ne y, etc. 
* *   
Self -care A D L r ef er t o bat hi n g, dressi n g a n d u n dressi n g, fee di n g self, usi n g t he t oilet, ta ki n g me dicati o ns, a n d n ot 
  
be dri d de n.  
 
F or A Es ass ociate d wit h la b orat or y a b n or malities, t he e ve nt s h o ul d be gra d e d o n t he basis of t he 
cli nical se verit y i n t he c o nte xt of t he u n derl yi n g c o n diti o ns; t his ma y or ma y n ot be i n a gree m e nt 
wit h t he gra di n g of t he la b orat or y a b n or malit y. T his is u p o n t he i n vesti gat or’s assess me nt.  
If t here is a c ha n ge i n i nte nsit y ( w orse ni n g or i m pr o ve me nt) of a n A E, it m ust be rec or de d. 
8. 2. 3.   
O ut c o m e  
Eac h A E m ust be rate d b y c h o osi n g a m o n g:  
 
Rec o vere d/res ol ve d;  
 
Rec o vere d/re s ol ve d wit h se q uelae; 
 
Rec o veri n g/res ol vi n g;  
 
N ot rec o vere d/ n ot res ol v e d;  
 
Fatal;  
 
U n k n o w n.  


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-5 5 - 
 
8. 3.   
I n v e sti g at or R e q uir e m e nt s a n d I n str u cti o n s f or R e p orti n g Ad v er s e 
E v e nt s , S eri o u s A d v er s e E v e nt s , Pr e g n a n ci e s, a n d O t h er S p e ci al 
S it u ati o n s t o t h e S p o n s or 
8. 3. 1.   
A d v er s e E v e nt s  
T he A E re p orti n g p eri o d f or safet y s ur veilla nce be gi ns w he n t h e s u bject si g ns t he I C F a n d e n ds at 
t he s u bject’s last f oll o w-u p visit (t he last f oll o w -u p visit after t he last d ose of I M P). I n t his 
peri o d, all ne w A Es, re gar dless of ca us e or relati o ns hi p, d eri ve d b y s p o nta ne o us, u ns olicite d 
re p orts of s u bjects, b y o bser vati o n a n d b y r o uti ne o pe n q uesti o ni n g (s uc h as “ H o w d o y o u feel? ”) 
nee d t o be rec or de d i n t he s o urce a n d i n t he C R F.  
I n case a n A E is o n g oi n g at t he ti me of t he last f oll o w-u p visit, t he i n ve sti gat or nee ds t o f oll o w-
u p  o n t he s u bject u ntil A E res ol uti o n or reas o n a bl e sta bilizati o n a n d t o d oc u me nt i n t he s u bject’s 
s o urce d oc u m e ntati o n. N o relate d u p dat es or a d diti o nal data o n t he A E s h o ul d be re p orte d i n t he 
C R F.  
If a s u bject is d oc u m e nte d as lost -t o-f oll o w-u p, o n g oi n g/ u n k n o w n o utc o me A Es will n ot be 
f oll o we d u p.  
If t he A E meets t he criteria f or seri o us n ess, t he S A E f or m m ust be c o m plete d a n d se nt t o t he 
s p o ns or wit hi n 2 4 h o urs (see Secti o n 8. 3. 2 ). 
8. 3. 2.   
S eri o u s A d v er s e E v e nt s  
S u bjects e x perie nci n g a n S A E or a n e mer ge nc y sit uati o n will be e x a mi ne d b y a p h ysi cia n as s o o n 
as p ossi ble. T he s u bject will re mai n u n der o bser vati o n as l o n g as m e dicall y i n dicat e d. 
A p pr o priate la b orat or y tests will be perf or me d u ntil all para meters ret ur n t o n or mal or are 
ot her wise e x plai ne d or st a ble.  
All S A Es, w het her or n ot dee me d I M P -relate d, m ust be rec or de d i n t he C R F a n d o n t he S A E 
f or m. T he i n vesti gat or must re p ort eac h S A E i m me diatel y, a n d u n der n o circ u msta nces s h o ul d 
t his e x cee d 2 4 h o urs f oll o wi n g t he k n o wl e d ge of t he S A E, as is i n dicate d o n p a ge 2  u n der 
“ E mer ge n c y C o ntact I nf or mati o n”.  
T he S A E f or m s h o ul d at least c o ntai n i de ntifiers of t he s u bject a n d  t he re p orter, S A E ter m a n d 
state me nt of relat e d ness t o t he I M P, a n d at a later sta ge if n ot yet a vaila ble wit hi n 2 4 h o urs, t he 
f or m nee ds t o be c o m plete d wit h a clearl y writte n narrati ve d escri bi n g si g ns, s y m pt o ms, a n d 
treat me nt of t he e ve nt, dia g n ostic pr oce d ures, as well as a n y rele va nt la b orat or y data a n d a n y 
se q uelae. 
F oll o w -u p a n d o utc o mes s h o ul d be re p orte d a n d d oc u me nte d i n t he s o urce d oc u me nts f or all 
s u bjects t hat e x perie nce a n S A E. It is i m p orta nt t hat t he i nf or mati o n pr o vi de d o n t he S A E f or m 
mat c hes t he i nf or mati o n rec or de d o n t he C R F f or t he sa me e ve nt.  
C o pies of a d diti o nal la b orat or y tests, c o ns ultati o n re p orts, p ost m orte m  re p orts, h os pital case 
re p orts, a ut o ps y re p orts, a n d ot her d oc u me nts s h o ul d be se nt w he n re q uest e d a n d a v aila ble. O nl y 


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s u bject i de ntifiers (s u bject n u m ber) s h o ul d a p pear o n t he c o pies, a n d all na mes a n d i nitials s h o ul d 
be blac ke n e d a n d re n dere d ille gi ble. F oll o w -u p re p orts relati ve t o t he s u bject’s s u bse q ue nt c o urse 
m ust be s u b mitte d u ntil t he e ve nt has s u bsi de d or, i n case of  p er ma ne nt i m pair me nt, u ntil t he 
c o n diti o n sta bilizes. 
A n y S A Es t hat occ ur after t he p ost treat me nt f oll o w-u p visit b ut wit hi n 3 0 da ys of t he last d ose of 
I M P(s), re gar dless of ca usalit y, s h o ul d als o be re p orte d ( E mer ge nc y C o ntact I nf or mati o n o n 
pa ge  2 ). I nv esti gat ors are n ot o bli gate d t o acti vel y see k S A Es after t he C S P -defi ne d f oll o w -u p 
peri o d. H o we v er, if t he i n vesti gat or is i nf or m e d a b o ut a n S A E t hat occ urs at a n y ti me after t he 
s u bjects’ p osttreat me nt f oll o w-u p visit a n d t he e ve nt is dee me d rele va nt t o t he use of I M P(s), 
he/s he s h o ul d pr o m ptl y d oc u me nt a n d re p ort t he e ve nt t o t he s p o ns or b y usi n g t he S A E f or m.  
8. 3. 3.   
Pr e g n a n c y  
All i nitial re p orts of pre g na nc y i n fe mal e s u bjects a n d pre g na n cies i n part ners of male s u bjects 
i ncl u de d i n t he cli nical st u d y m ust be rec or de d a n d d oc u me nte d i n t he s o urce d oc u me nts a n d o n 
t he pre g na n c y f or m. T h e i n vesti gat or m ust re p ort eac h pre g na n c y i m me diatel y, a n d u n d er n o 
circ u msta nces s h o ul d t his e x cee d 2 4 h o urs f oll o wi n g t he k n o wle d ge of t he pre g na nc y, as is 
i n dicate d o n p a ge 2  u n d er “ E mer ge nc y C o ntact I nf or mati o n”.  
All  pre g n a ncies s h o ul d b e f oll o we d  u p u ntil deli ver y or pre g na nc y i nterr u pti o n. T he i n vesti gat or 
will c o ntact t he s u bject or part ner of t he s u bject after gi vi n g c o ns e nt, at t he e x pecte d ti me of 
deli ver y f or f oll o w -u p a n d f or i nf or mati o n re gar di n g t he o utc o m e of t he ne w b or n. A b n or mal 
pre g na nc y a n d/ or a b n or mal ne w b or n o utc o mes are c o nsi dere d S A Es a n d m ust be re p orte d usi n g 
t he S A E f or m. 
8. 3. 4.   
R e p orti n g of S p e ci al Sit u ati o n s ( O t h er T h a n Pr e g n a n c y) a n d A s s o ci at e d 
A d v er s e E v e nt s  
I n case a s peci al sit uati o n is n ot ass ociate d wit h a n A E, t he s pecial sit uati o n s h o ul d be re p orte d 
wit hi n 2 4 h o urs b y usi n g t he S pecial Sit uati o ns f or m as i s i n dicate d o n pa ge 2  u n der “ E mer ge nc y 
C o ntact I nf or mati o n” . 
I n case a s peci al sit uati o n is ass ociate d wit h a n A E, t he s pecial sit uati o n s h o ul d be re p orte d 
wit hi n 2 4 h o urs b y usi n g t he S pecial Sit uati o ns f or m a n d t he ass ociate d A E s h o ul d be re p orte d as 
s pecifie d i n Secti o n  8. 3. 1 . 
I n case a s peci al sit uati o n is ass ociate d wit h a n S A E, t he s pecial sit uati o n s h o ul d be re p orte d 
wit hi n 2 4 h o urs b y usi n g t he S A E f or m (a n d n ot t h e S pecial Sit uati o ns f or m) a n d t he ass o ciate d 
S A E s h o ul d be re p orte d as s peci fie d i n S ecti o n 8. 3. 2 . 
8. 4.   
S p o n s or R e p orti n g R e q uir e m e nt s  
De pe n di n g o n rele va nt l o cal le gislati o n or re g ulati o ns, i ncl u di n g t he a p plica ble U nite d State s 
Fe deral Dr u g A d mi nistrati o n C o de of Fe deral Re g ulati o ns, t he E U  Cli nical Trials Directi ve 
( 2 0 0 1/ 2 0/ E C) a n d rele va nt u p dates, a n d ot her c o u ntr y-s p ecific l e gislati o n or re g ulati o ns, t he 
s p o ns or ma y b e re q uire d t o e x pe dite t o w orl d wi de re g ulat or y a ge ncies re p orts of S A Es, seri o us 


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a d verse dr u g reacti o ns  or s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs). T he 
s p o ns or or a s pecifie d desi g nee will n otif y w orl d wi de re g ulat or y a ge n cies a n d t he rele va nt 
I E C/I R B i n c o ncer ne d M e m ber States of a p plica bl e S U S A Rs as o utli ne d i n c urre nt re g ulati o ns. 
Assess me nt of e x pecte d ness f or S A Es will be deter mi ne d usi n g t he refere n ce safet y i nf or mati o n 
secti o n i n t he I B or rele va nt l ocal la bel as a p plica ble. 
All c o ncer ne d i n vesti gat ors will recei ve a safet y letter n otif yi n g t h e m of rele va nt S U S A R re p orts 
ass ociate d wit h a n y I M P(s). T he i n vesti gat or s h o ul d n otif y t he I E C/I R B of S U S A R re p orts as 
s o o n as is practical, w h ere t his is re q uire d b y l ocal re g ulat or y a ge ncies, a n d i n acc or da nce wit h 
t he l ocal i nstit uti o nal p olic y. 
9.   
S P O N S O R’ S A N D I N V E S TI G A T O R’ S R E S P O N SI BI LI TI E S  
T his cli nical st u d y is c o n d ucte d i n acc or da n ce wit h t he c urre nt a p plica ble re g ul ati o ns, I C H -G C P 
G ui deli ne E 6 a n d its u p dates, a n d l ocal et hical a n d le gal re q uire me nts.  
G o o d Cli nical Practice is a n i nter nati o nal et h ical a n d scie ntific q ualit y sta n dar d f or desi g ni n g, 
c o n d ucti n g, rec or di n g a n d re p orti n g st u dies t hat i n v ol ve t he partici pati o n of h u ma n s u bjects. 
C o m plia nce wit h t his sta n dar d pr o vi des p u blic ass ura nce t h at t he ri g hts, safet y a n d well -bei n g of 
cli nical st u d y s u bjects are pr otecte d, c o nsiste nt wit h t he pri nci ples t hat ha v e t heir ori gi n i n t he 
Declarati o n of Helsi n ki, a n d t hat t he cli nical st u d y dat a are cre di ble.  
T he na me a n d a d dress of eac h t hir d  part y ve n d or (e. g. C R O) us e d i n t his st u d y a n d t h e s p o ns or’s 
st u d y tea m me m bers will be mai ntai ne d i n t he i n vesti gat or’s a n d s p o ns or’s files as a p pr o priate.  
9. 1.   
S p o n s or’ s R e s p o n si biliti e s  
9. 1. 1.   
R e g ul at or y A p pr o v al / N otifi c ati o n  
Pri or t o cli nical st u d y start, t his C S P t o get her wit h all rele va nt d oc u m e ntati o n will be s u b mitte d 
t o t he l ocal re g ulat or y aut h orities f or re vie w a n d a p pr o val a n d/ or n otificati o n i n c o m plia nce wit h 
l ocal re q uir e me nts. 
9. 1. 2.   
Cli ni c al St u d y Cl o s ur e C o n si d er ati o n s  
T he s p o ns or res er ves t he ri g ht t o cl ose t he i n v esti gati o nal site or e n d t he cli nical st u d y at a n y 
ti me f or a n y reas o n. I n case of a n earl y ter mi nati o n of t he cli nical st u d y or te m p orar y halt b y t he 
s p o ns or, t he I E C/I R B s h o ul d be n otifie d wit hi n 1 5 cale n dar da ys , u nless ot her wise s pecifie d b y 
t he I E C/I R B, i ncl u di n g a detaile d writte n e x pla nati o n of t he reas o ns f or t he ter mi nati o n/ halt. 
T he e n d of cli nical st u d y declarati o n will be s u b mitte d t o t he re g ulat or y a ut h orities a n d I E C/I R B 
after t he c o m plete cli nica l st u d y has e n d e d i n all partici pati n g ce nters, i n all c o u ntries. T his 
n otificati o n will als o be s u b mitte d wit hi n 9 0 da ys of t he e n d of t he cli nical st u d y i n a gi ve n 
c o u ntr y/ me m b er state or wit hi n t he ti meli nes re q uire d b y t h e l ocal re g ulati o ns.  
Reas o ns f o r t he cl os ure of a n i n vesti gati o nal site ma y i ncl u d e, b ut are n ot li mite d t o:  


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 
S uccessf ul c o m pleti o n of t he cli nical st u d y at t he ce nter.  
 
T he o verall re q uire d n u m ber of s u bjects f or t he cli nical st u d y has b ee n recr uite d.  
 
Fail ure of t he i n vesti gat or t o c o m pl y wit h t he C S P, I C H -G C P g ui deli nes or l ocal 
re q uire me nts. 
 
I n a de q uat e recr uit me nt of s u bjects b y t he i n vesti gat or. 
 
Reas o ns f or earl y ter mi n ati o n of a cli nical st u d y b y t he s p o ns or m a y i ncl u de , b ut are n ot li mite d 
t o: 
 
Safet y c o ncer ns.  
 
S ufficie nt data s u g ges ti n g lac k of efficac y. 
9. 1. 3.   
I n d e m nifi c ati o n 
U n der t he c o n diti o ns of a c o ntract c o ncl u de d bet w ee n i n vesti gat or, site a n d s p o ns or or desi g nee, 
w hic h s hall pre vail, t he s p o ns or s hall, e x ce pt i n case of gr oss ne gli ge n ce or willf ul misc o n d uct, 
i n de m nif y a n d h ol d h armless t he i n vesti gat or a n d his/ her me dical staff fr o m a n y clai m arisi n g 
fr o m t he cli nical st u d y acti vities carrie d o ut i n c o m plia nce wit h t he C S P, s p o ns or’s i nstr ucti o ns 
a n d a p plica ble l ocal re g ulati o ns.  
T he i n vesti gat or m ust n otif y t he s p o ns or i m me diatel y  u p o n n otice of a n y cl ai ms or la ws uits.  
9. 1. 4.   
I n s ur a n c e 
T he s p o ns or s hall mai ntai n i ns ura nce c o v era ge t hat is s ufficie nt t o c o ver its o bli gati o ns a n d t hat 
is c o nsiste nt wit h h u ma n cli nical st u d y l ocal re g ul ati o ns. Pr o vi de d t hat t he s u bject has bee n 
treate d acc ordi n g t o t he C S P a n d s p o ns or’s i nstr ucti o ns, a n y i nj ur y ca use d t o a s u bject w hic h is 
t he direct r es ult of his/ her partici pati o n t o t he cli nical st u d y s h all be c o vere d b y t he s p o ns or’s 
i ns ura nce, e x ce pt i n case of gr oss ne gli ge nce or willf ul misc o n d uct b y t he i n vesti gat or . 
9. 1. 5.   
R e p orti n g  
W here re q uire d b y I E C/I R B per l ocal re q uire me nts, at least o nce a year t he i n vesti gat or will 
pr o vi de t he I E C/I R B wit h a pr o gress re p ort t o all o w re vie w of t he cli nical st u d y (see 
Secti o n  9. 4. 1 ). At t he e n d of t he cli nical st u d y, t he res ults of t he cli nical st u d y will be re p orte d i n 
a cli nical st u d y re p ort. A s u m mar y or f ull re p ort, de pe n di n g o n t he re q uire me nts, will be pr o vi de d 
t o t he i n vesti gat ors, t o t h e a p plica ble re g ulat or y a ut h orities, a n d I E Cs/I R Bs  (if re q uire d b y t he 
a p plica ble re g ulat or y re q uire me nts ) wit hi n o ne year, or 6 m o nt hs f or p e diatric st u dies, after t he 
e n d of t he cli nical st u d y.  
9. 1. 6.   
P u bli c ati o n  
It is u n derst o o d b y t he i n vesti gat or t h at t he s p o ns or s hall be free t o use t he c o m p o u n d -relat e d 
i nf or mati o n, w hic h is ge nerate d d uri n g t h e cli nical st u d y a n d ma y discl ose it t o ot her cli nical 
i n vesti gat ors a n d t o re g ul at or y a ge n cies. As a c o ns e q ue nce, t he i n vesti gat or a grees t o pr o vi d e all 
cli nical st u d y res ults a n d data ge nerate d d uri n g t his cli nical st u d y t o t he s p o ns or.  


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T he i n vesti gat or s hall n ot be a ut h orize d t o s u b mit t he res ults of t his cli nical st u d y a n d a n y data 
f or p u blic discl os ure (e. g. p u blicati o n or prese ntati on) wit h o ut t he pri or writte n a p pr o val of t h e 
s p o ns or, w hic h s hall n ot be u nreas o n a bl y wit h hel d.  
H o we ver, it is u n derst o o d a n d a gree d b y t he i n vesti gat ors t hat t heir res ults a n d/ or fi n di n gs s h all 
n ot be a ut h orize d f or p u blicati o n pri or t o s p o ns or’s p u blicat i o n of t he o verall cli nical st u d y 
res ults. T he i n vesti gat or a grees t h at pri or t o t he p u blicati o n of a n y res ults, he/s he s hall pr o vi de 
t he s p o ns or wit h a draft c o py of t h e i nte n de d p u blicati o n. T he s p o ns or s hall ha ve t he ri g ht t o 
re vie w it a n d t o ma ke a n y co m me nts. I n acc or da n ce wit h ge nerall y acce pte d scie ntific 
c olla b orati o n pri nci ples, c o -a ut h ors hi p wit h a n y st aff me m ber s p o ns or i n v ol ve d i n t he cli nical 
st u d y, will be disc usse d a n d m ut uall y a gree d u p o n bef ore s u b missi o n of a n y ma n uscri pt t o a 
p u blis her.  
9. 2.   
In v e sti g at or’ s R e s p o n si biliti e s  
9. 2. 1.   
Fi n a n ci al Di s cl o s ur e  
T he discl ose d fi na ncial i nterest of t he i n vesti gat ors m ust be c ollecte d bef ore scree ni n g of t he first 
s u bject, f oll o wi n g cli nical st u d y c o m pleti o n at t he i n vesti gat or site, a n d 1 year f oll o wi n g o verall 
cli nical st u d y c o m pleti o n. T he i n vesti gat ors s h o ul d pr o m ptl y u p date t his i nf or mati o n if a n y 
rele va nt c ha n ges o cc ur d uri n g t his peri o d. Discl os a ble fi na nci al i nterests will be rec or de d o n t he 
I n v esti gat or Fi na ncial Discl os ure F or m. 
A n y i n vesti gat or(s) a d d e d  as i n vesti gati o nal staff m ust c o m plete t he I n vesti gat or Fi na nci al 
Discl os ure F or m at t he b e gi n ni n g of t heir partici p ati o n i n t he cli nical st u d y. F or a n y 
i n vesti gat or(s) lea vi n g t h e site pri or t o cli nical st u d y c o m pleti o n, a n I n vesti gat or Fi na ncial 
Discl os ure F or m s h o ul d be o btai ne d at t he e n d of t heir c o ntri b uti o n t o t he cli nical st u d y.  
9. 2. 2.   
S o ur c e D at a a n d D at a C a pt ur e  
T he nat ure a n d l ocati o n of all s o urce d o c u me nts nee d t o be i de ntifie d a n d d o c u me nte d t o e ns ure 
t hat all s o urces of ori gi nal data re q uir e d t o c om plete t he C R F are k n o w n a n d are accessi ble f or 
verificati o n b y t he m o nit or.  
S o urce data ma y b e directl y ca pt ur e d fr o m d e vices tra nsferre d fr o m t hir d part ners ( e. g. l a b orat or y 
data) or e ntere d m a n uall y i nt o t he C R F. T he C R F c o m pleti o n g ui deli nes will be pr o vi de d t o eac h 
i n vesti gati o nal site. 
It is rec o m me n de d t hat t h e a ut h or of a n e ntr y i n t h e s o urce d o c u me nts s h o ul d be i de ntifia ble. 
F oll o wi n g I C H -G C P g ui deli nes, dir ect access t o s p o ns or’s re prese ntati ves t o s o urce d oc u m e nts 
m ust be gra nte d f or t h e p ur p ose of verif yi n g t hat t he data rec or de d o n t he C R F are c o nsiste nt 
wit h t he ori gi nal s o urce d ata.  
9. 2. 3.   
Ar c hi vi n g  
T he i n vesti gat or s hall mai ntai n t he cli nical st u d y -s pecific doc u m e nts as s pecifie d i n Secti o n 8  
“ Esse ntial D oc u me nts f or t he C o n d uct of a Cli nical St u d y” of t he I C H -G C P g ui deli nes a n d as 


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re q uire d b y t he a p plica bl e re g ulat or y re q uire me nt(s). T he i n vesti gat or s h o ul d ta ke meas ures t o 
pre ve nt acci de ntal or pre mat ure des tr ucti o n of t h ese d oc u me nts. 
Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 2 years after t he l ast a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g 
a p plicati o ns i n a n I C H re gi o n or at leas t 2 years ha ve ela pse d si nce t he f or mal disc o nti n uati o n of 
cli nical de vel o p me nt of t he I M P. T hese d oc u m e nts s h o ul d be retai ne d f or a l o n ger peri o d (if 
re q uire d b y t he a p plica bl e re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he s p o ns or). 
U n der n o cir c u ms ta nce s hall t he i n vesti gat or rel ocate or dis p ose a n y cli nical st u d y d oc u me nts 
bef ore h a vi n g o btai ne d a writte n a p pr o val of t h e s p o ns or.  
If it bec o mes necessar y f or t he s p o ns or or t he a p pr o priate re g ulat or y a ut h orit y t o re vi e w a n y 
d oc u me ntati o n relati n g t o t his cli nical st u d y, t he i n vesti gat or m ust per mit access t o s uc h re p orts. 
T he s u bject is gra nti n g access t o his/ her s o urce data b y si g ni n g t he I C F.  
A n y diffic ult y i n st ori n g ori gi nal d oc u m e nts m ust be disc usse d wit h t he m o nit or pri or t o t he 
i nitiati o n of the cli nical st u d y.  
9. 2. 4.   
P arti ci p ati o n C ar d s  
If t he s u bjects are n ot u n der 2 4-h o ur s u p er visi o n of t he i n vesti gat or or site staff, t he y m ust be 
pr o vi de d wit h a s u bject p artici pati o n car d i n dicati n g t he na me of t he I M P, t he cli nical st u d y 
n u m ber, t he i n vesti gat or' s na me, a n d a 2 4 -h o ur e mer ge nc y c o ntact n u m ber. T he s u bject s h o ul d be 
a d vise d t o kee p t he partici pati o n car d i n his/ her wallet at all ti mes.  
9. 3.   
C o nfi d e nti alit y  
T he s u bject will recei ve all i nf or mati o n as re q uire d b y t he E U Ge n eral D ata Pr otecti o n 
Re g ulati o n, na mel y t he i de ntit y a n d c o ntact details of t he c o ntr oller, t he c o ntact details of t he data 
pr otecti o n officer, t he cli nical researc h p ur p oses, t he le gal basis f or t h e pr ocessi n g, t h e reci pie nts 
of t he pers o nal d ata, t he tra nsfer of t he pers o nal data t o t hi r d c o u ntries a n d res pecti ve safe g uar ds, 
t he rete nti o n peri o ds, t he fair pr ocessi n g of his dat a, a n d all his/ her dat a s u bject’s ri g hts. All 
details are liste d i n t he I C F.  
All i nf or mati o n c o ncer ni n g t he pr o d uct a n d t he s p o ns or’s o perati o ns (s uc h as pate nt a p plicati o ns, 
f or m ulas, ma n ufact uri n g pr ocesses, b asic scie ntifi c data, or f or m ulati o n i nf or mati o n s u p plie d t o 
t he i n vesti gat or b y t h e s p o ns or a n d n ot pre vi o usl y p u blis he d) is c o nsi dere d c o nfi de ntial a n d 
s h o ul d n ot be discl ose d b y t he i n vesti gat or t o a n y t hir d part y wit h o ut t he s p o ns or’s pri or writte n 
a p pr o val. T he i n v esti gat or a grees t o use t his i nf or mati o n o nl y i n acc o m plis hi n g t he cli nical st u d y 
a n d will n ot use it f or ot her p ur p oses.  
I n or der t o per mit eas y i d e ntificati o n of t he i n di vi d ual s u bject d uri n g a n d after t he cli nical st u d y, 
t he i n vesti gat or is r es p o nsi ble f or kee pi n g a n u p d ate d S u bject I d e ntificati o n C o de List. T he 
m o nit or will re vie w t his d oc u me nt f or c o m plet e ness. H o we ver, t he i n vesti gat or m ust g uara ntee 
t he s u bject’s a n o n y mit y will be mai ntai ne d. T heref ore, i n or der t o e ns ure s u bject c o nfi de ntialit y, 
t he S u bject I d e ntificati o n C o de List m ust re mai n at t he ce nter a n d n o c o p y will be ma de. 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 1 - 
 
9. 4.   
Et hi c al C o n si d er ati o n s  
9. 4. 1.   
I n d e p e n d e nt Et hi c s C o m mitt e e / I n stit uti o n al R e vi e w B o ar d  
T his cli nical st u d y ca n o n l y be u n d erta ke n after f ull a p pr o val of t he C S P, I C F, a n y ot her writte n 
i nf or mati o n gi ve n t o s u bj ects a n d s u bject recr uit me nt materials has bee n o btai ne d fr o m t he 
I E C/I R B. T his a p pr o val d oc u me nt m ust be date d a n d clearl y i d e ntif y t he cli nical st u d y a n d t he 
relate d cli nical st u d y d oc u me nts bei n g a p pr o ve d, i ncl u di n g t he s u bject c o m pe nsati o n pr o gra ms, if 
a p plica ble.  
D uri n g t h e c o urse of t he cli nical st u d y, at least t he f oll o wi n g d oc u me nts will be s u b mitte d t o t he 
I E C/I R B, per l ocal re q uir e me nts:  
 
C ha n ges t o t he  I B 
 
Re p orts of A Es t hat are s eri o us, u nliste d , a n d ass o ciate d wit h t he I M P (i n c o m plia nce wit h 
I E C/I R B, per l ocal re q uir e me nts) 
 
C S P a me n d me nts  
 
I C F a me n d me nts 
 
C S P a me n d me nts a n d a p plica ble I C F a me n d me nts m ust pr o m ptl y be s u b mitte d t o t he I E C/I R B 
f or re vie w a n d a p pr o val pri or t o i m ple me ntati o n of t he c ha n ge(s), e x ce pt w he n necessar y t o 
eli mi nate a n i m me diate hazar d t o t he cli nical st u d y s u bjects, or acc or di n g t o l ocal re q uire me nts.  
T he I E C/I R B is res p o nsi ble f or c o nti n u o us re vi e w of t he cli nical st u d y. W here  re q uire d b y 
I E C/I R B, per l ocal re q uir e me nts, at least o nce a year t he i n vesti gat or will pr o vi de t he I E C/I R B 
wit h a pr o gress r e p ort t o all o w re vie w of t he cli nical st u d y. A d diti o nal pr o gress re p orts s h o ul d be 
pr o vi de d acc or di n g t o l ocal le gal r e q uire me nts.  T hese re q u ests a n d (re -)a p pr o vals, if a p plica ble, 
s h o ul d be d oc u me nte d i n writi n g. 
9. 4. 2.   
I nf or m e d C o n s e nt 
T he i n vesti gat or or desi g nate d pers o n nel m ust e x plai n t he cli nical st u d y a n d t he i m plicati o ns of 
partici pati o n ( e. g. o bjecti ves, met h o ds, a ntici pate d be nef its, p ossi ble ris ks) t o p ote ntial s u bjects 
acc or di n g t o a p plica ble re g ul ati o ns pri or t o a n y cli nical st u d y -relate d acti vit y. S u bjects will be 
i nf or me d t hat t heir partici pati o n is v ol u ntar y a n d t hat t he y m a y wit h dra w fr o m t he cli nical st u d y 
at a n y ti me. T he y will be i nf or me d t hat c h o osi n g n ot t o partici pate or t o wit h dra w fr o m t he 
cli nical st u d y will n ot ha ve a n i m pact o n t he care t he s u bject will recei ve f or t he treat me nt of 
his/ her disease.  
T he s u bject will be gi ve n s ufficie nt ti me t o rea d t h e I C F a n d t o a s k a d diti o nal q uesti o ns. After 
t his e x pla nati o n a n d bef ore e ntr y i n t he cli nical st u d y, t he s u bject’s c o nse nt s h o ul d be 
a p pr o priatel y rec or de d b y mea ns of t he s u bject's pers o nall y date d si g nat ure a n d b y t he 
i n vesti gat or’s d ate d si g nat ure. I n case t he s u bject is u na ble t o rea d a n d/ or write, oral c o nse nt i n 
t he prese n ce of at least o ne i m partial wit ness, w h o was als o i ncl u de d w h e n t he affecte d pers o n 
was bei n g i nf or me d, ma y be gi v e n. T he wit ness m a y n ot b e a n y o ne w or ki n g at t he st u d y site n or 
a me m ber of t h e i n vesti gati n g tea m. T he orall y gi ve n c o nse nt s hall be d o c u me nte d i n writi n g, 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 2 - 
 
date d a n d si g ne d b y t he wit ness.  After ha vi n g o bt ai ne d t he c o nse nt, a c o p y of t he si g n e d a n d 
date d I C F m ust be gi ve n t o t he s u bject.  
If ne w i nf or mati o n bec o mes a vaila ble rele va nt t o t he s u bject’s willi n g ness t o partici pate i n t he 
cli nical st u d y, t he s u bject will be i nf or me d i n a ti mel y ma n ner b y mea ns of a n a me n de d I C F. T his 
a me n de d I C F will be si g ne d a n d date d b y t h e s u bject ( or, if a p plica ble, b y a n i n de pe n de nt 
wit ness) a n d t he i n vesti gat or t o d oc u me nt t he willi n g ness of t h e s u bject t o c o nti n ue wit h t he 
cli nical st u d y.  
T his si g ne d a n d d ate d a m e n de d versi o n will be file d t o get her wit h t he i nitial si g ne d a n d date d 
I C F. 
A pre g na nt part ner , w h o a grees t h at i nf or mati o n will be gat h ere d  a b o ut her pre g na n c y will si g n a 
s pecific I C F t o partici pat e i n t he data c ollecti o n. Data a b o ut t he h ealt h of t he ba b y will be 
c ollecte d if t he pare nts a gree wit h t he dat a c ollecti o n a n d si g n a s p ecific I C F.  
9. 5.   
D at a Q u alit y C o ntr ol/ A s s ur a n c e  
9. 5. 1.   
M o nit ori n g  
T his c li nical st u d y will be m o nit ore d b y s p o ns or re prese nt ati ves acc or di n g t o t heir c urre nt 
Sta n dar d O perati n g Pr oce d ures f or t he m o nit ori n g of cli nical st u dies as des cri be d i n t he 
m o nit ori n g pla n.  
T o g uara ntee a d e q uate pr otecti o n of t he s u bjects a n d t o g uara nte e t h e q ualit y of t he d ata, t he 
s p o ns or will e ns ure o versi g ht of a n y cli nical st u d y-relate d d uties a n d f u ncti o ns carrie d o ut o n its 
be half, i ncl u di n g cli nical st u d y -relate d d uties a n d f u ncti o ns t hat are s u bc o ntracte d t o a n ot h er 
part y b y t h e s p o ns or’s c o ntra cte d C R O(s).  
9. 5. 2.   
A u dit a n d I n s p e cti o n  
T o e ns ure c o m plia nce wit h rele va nt r e g ulati o ns, a n i n de pe n de nt q ualit y ass ura nce re prese ntati ve, 
re g ulat or y a ut h orities a n d/ or I E Cs/I R Bs ma y re vi e w t his cli nical st u d y. T his i m plies t hat 
a u dit ors/i ns pect ors will ha ve t he r i g ht t o i ns pect t h e cli nical st u d y ce nter(s) at a n y ti me d uri n g 
a n d/ or after c o m pleti o n of t he cli nical st u d y a n d will ha ve access t o t he data ge n erat e d d uri n g t he 
cli nical st u d y, s o urce d oc u me nts, a n d s u bject's files. B y partici pati n g i n t his cli nical st u d y, 
i n vesti gat ors a gree t o t his re q uire me nt. 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 3 - 
 
1 0.   
R E F E R E N C E S  
Alla n ore, Y, O Distler, A J a gersc h mi dt, S Illia n o, L Le dei n, E B oitiere, I A g ue us o p, C P 
De nt o n, a n d D K ha n na. 2 0 1 8. " L ys o p h os p hati dic Aci d Rece pt or 1 A nta g o nist 
S A R 1 0 0 8 4 2 f or Patie nts Wit h Diff use C uta ne o us S yste mic Scler osis: A D o u ble -Bli n d, 
Ra n d o mize d, Ei g ht -Wee k Place b o -C o ntr olle d St u d y F oll o we d b y a Si xtee n -Wee k 
O pe n -La b el E xte nsi o n St u d y." Art hritis R he u m at ol.  7 0( 1 0): 1 6 3 4 -1 6 4 3.  
Ba n d o h, K, J A o ki, M Taira, M Ts uji m ot o, H A rai, a n d K I n o ue. 2 0 0 0. " L ys o p h os p hati dic aci d 
( L P A) rece pt ors of t h e E D G fa mil y are differe ntiall y acti vate d b y L P A s pecies. 
Str uct ure -acti vit y relati o ns hi p of cl o ne d L P A rece pt ors." F E B S Letters  4 7 8: 5 9 -6 5.  
 
 
 
 
 
 
 
 
 
 
 
 
 
Ta na ka, M, S O k u daira, Y Kis hi, R O h ka wa, a n d S Ise ki. 2 0 0 6. " A ut ota xi n sta bilizes bl o o d 
vessels a n d is re q uir e d f or e m br y o nic vas c ulat ure b y pr o d u ci n g l ys o p h os p h ati dic aci d." 
J o ur n al of Bi ol o gic al C he mistry  2 8 1: 2 5 8 2 2 -3 0.  
Ts u da, S, S O k u daira, K M ori ya -It o, M Ta na ka, a n d J A o ki. 2 0 0 6. " C yclic p h os p hati dic aci d is 
pr o d uce d b y a ut ota xi n i n bl o o d." J o ur n al of Bi ol o gic al C he mistry  2 8 1: 2 6 0 8 1 -8.  
W o osle y R L, Heise C W, R o mer o K A. 2 0 1 8. " Q T Dr u gs Lists." Cre di ble Me ds.  J ul y 2 4. 
w w w. Cre di ble Me ds. or g.  
 
 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 4 - 
 
1 1.   
A P P E N DI C E S  
A p pe n di x 1:  K n o w n C Y P 2 C 8 S u bstr ates  
E xcl u de d me dic ati o n:  
A mi o dar o ne  
B u pre n or p hi ne  
A mi o da q ui ne; C hl or o q ui ne  
Re pa gli ni de  
R osi glitaz o ne,  pi o glitaz o ne  
Vera pa mil  
Z o picl o ne  
 
T his n o n -e x ha usti ve  list is i nte n de d as a g ui da nce f or t he i n vesti gat or. 
 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 5 - 
 
A p pe n di x 2:  K n o w n Str o n g C Y P 3 A 4 I n d ucers a n d P ote nt P -g p I n d ucers  
E xcl u de d me dic ati o n:  
Bar bit urates  
Car ba maze pi ne  
Gl uc oc ortic oi ds , if stea d y d os e of pre d nis o ne or e q ui vale nt > 1 0 m g/ da y  
M o dafi nil  
O xcar baze pi ne  
P he n o bar bital  
P he n yt oi n  
Pi o glitaz o ne  
Rifa b uti n  
Rifa m pi n  
St. J o h n’s w ort  
 
T his n o n -e x ha usti ve  list is i nte n de d as a g ui da nce f or t he i n vesti gat or. 
 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 6 - 
 
 
A p pe n di x 3:  K n o w n Str o n g C Y P 3 A 4 I n hi bit ors 
E xcl u de d me dic ati o n:  
Clarit hr o m yci n  
Itrac o naz ole 
Ket oc o naz ole  
Nefaz o d o ne  
T elit hr o m yci n  
 
T his n o n -e x ha usti ve  list is i nte n de d as a g ui da nce f or t he i n vesti gat or. 
 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 7 - 
 
 
A p pe n di x 4:  K n o w n P ote nt P -g p  I n hi bit ors 
E xcl u de d me dic ati o n:  
A mi o dar o ne  
Azelasti ne  
Azit hr o m yci n –  Clarit hr o m yci n –  Er yt hr o m yci n –  R o xit hr o m yci n –  T elit hr o m yci n  
( u nless use d u n der t he c o n diti o n descri be d i n Secti o n 3. 6. 3. 2 ) 
C ycl os p ori ne  
Itrac o naz ole - Ket oc o naz ole  
T a m o xife n  
Vera pa mil  
 
T his n o n -e x ha usti ve list is i nte n de d as a g ui da nce f or t he i n vesti gat or. 
 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 8 - 
 
 
A p pe n di x 5:  Me dic ati o n K n o w n t o Pr ol o n g Q T I nte r v al 
Me dicati o ns k n o w n t o pr ol o n g Q T i nter val are t o be use d wit h ca uti o n d uri n g t he st u d y. T he 
f oll o wi n g, bas e d o n t he Cre di ble Me ds list of me dicati o n k n o w n t o pr ol o n g Q T i nter val/ca us e 
T orsa de de P oi ntes ( W o osle y R L 2 0 1 8), is a n o n -e x ha usti ve list of t hese me dicati o ns:  
Dis o p yra mi de  
D ofetili de  
Flecai ni de  
H y dr o x yc hl or o q ui ne  
I b utili de 
Q ui ni di ne  
S otal ol  
 
T his list is i nte n de d as a g ui da nce f or t he i n vesti gat or.  
 
 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-6 9 - 
 
SI G N A T U R E P A G E –  S P O N S O R  
St u d y Title:   
A m ulti ce nter, o pe n-l a bel e xte nsi o n st u d y t o e val u ate t he l o n g -ter m safet y, 
t olera bilit y a n d efficac y of orall y a d mi nistere d G L P G 1 6 9 0 i n s u bjects wit h 
s yste mic scler osis. 
C S P Versi o n:  
2 . 0 0 
Date:   
0 8  J a n uar y 2 0 2 0  
 
 
 
 
A n electr o nic si g n at ure f or t he s p o ns or is pr o vide d at t he e n d of t he d oc u me nt.  
 
T his cli nical st u d y pr ot oc ol  has bee n re vie we d a n d a p pr o ve d b y t he s p o ns or t o e ns ure c o m plia nce 
wit h I nter nati o nal C o u ncil f or Har m o ni sati o n of Tec h nical Re q uire me nts f or P har mace uticals f or 
H u ma n Use (I C H) g ui deli nes f or G o o d Cli nical Practices ( G C P) a n d a p plica ble re g ulat or y 
re q uire me nts. 
 
 
, M D  
  
  
Me dical Lea der  
 Si g nat ure  
 Date  
 
 
 


G al a p a g o s  
C O N FI D E N TI A L  
D o c i d  4 0 2 9 9 5 
G L P G 1 6 9 0 -C L -2 0 6  
-7 0 - 
 
SI G N A T U R E P A G E –  I N VE S TI G A T O R  
St u d y Title:   
A m ulti ce nter, o pe n-l a bel e xte nsi o n st u d y t o e val u ate t he l o n g-ter m safet y, 
t olera bilit y a n d efficac y of orall y a d mi nistere d G L P G 1 6 9 0 i n s u bjects wit h 
s yste mic scler osis. 
C S P Versi o n:  
2 . 0 0 
Date:   
0 8  J a n uar y 2 0 2 0  
 
 
 
 
 
I, t he u n dersi g ne d, h a ve rea d t his cli nical st u d y pr ot oc ol a n d will c o n d uct t he st u d y as descri be d 
i n c o m plia nce wit h t he cli nical st u d y pr ot oc ol, i n acc or da n ce wit h I nt er nati o nal C o u ncil f or 
Har m o ni sati o n of Tec h nical Re q uire me nts f or P har mace uticals f or H u ma n Use (I C H) g ui d eli nes 
f or G o o d Cli nical Practices ( G C P) a n d a p plica ble re g ulat or y re q uire me nts.  
 
 
  
  
I n v esti gat or Na me 
 Si g nat ure  
 Date  
 


Si g nat ure Pa ge f or gl p g 1 6 9 0-cl- 2 0 6- pr ot oc ol 1 1 1 5 6
Si g nat ure Pa ge f or gl p g 1 6 9 0-cl- 2 0 6- pr ot oc ol 1 1 1 5 6
A p pr o val
al Direct or P hase I
Tra nslati o nal Me dici ne
1 0-Ja n- 2 0 2 0 0 7: 1 4: 1 4 G M T + 0 0 0 0

SAP_001.pdf: 
 
 
CONFIDENTIALITY STATEMENT 
The information contained in this document is privileged and confidential. It is the property of Galapagos 
NV or Galapagos SASU and may not be used, disclosed, reproduced or otherwise disseminated within your 
organization or communicated to any third parties without the express written authorization of Galapagos 
NV or Galapagos SASU. 
 
 
STATISTICAL ANALYSIS PLAN 
 
Project Number: 
GLPG1690 
 
Study Number: 
GLPG1690-CL-206 
Study Title: 
A multicenter, open-label extension study to evaluate the long-
term safety, tolerability and efficacy of orally administered 
GLPG1690 in subjects with systemic sclerosis 
 
Development Phase: 
II 
Status: 
Final 
Version: 
1.00 
Date: 13-Apr-2021 
EudraCT: 
2019-001279-34 
IND: 
140691 
Sponsor: 
Galapagos NV, Generaal De 
Wittelaan 
L11 
A3, 
2800 
Mechelen, Belgium 
 
 Biostatistician: 
 
GLPG Biostatistician: 
 
Medical Lead: 
 
  


 
Galapagos 
CONFIDENTIAL   
43952_19643_47970 
Statistical Analysis Plan GLPG1690-CL-206 
Page 2/47 
 
 
 
 
 
 
TABLE OF CONTENTS  
Statistical Analysis Plan ........................................................................................................... 1 
Table of contents ....................................................................................................................... 2 
Version History ......................................................................................................................... 5 
List of Abbreviations ................................................................................................................ 6 
1. Introduction ........................................................................................................................ 8 
2. Study Design and Objectives ............................................................................................. 8 
2.1. 
Study Objectives ........................................................................................................ 8 
2.2. 
Study Endpoints ......................................................................................................... 9 
2.3. 
Study Design .............................................................................................................. 9 
2.4. 
CSP and CSP Amendments ..................................................................................... 10 
2.5. 
Flow Chart ................................................................................................................ 10 
2.6. 
Sample Size Justification ......................................................................................... 10 
2.7. 
Randomization and Blinding .................................................................................... 11 
3. General Methodology ....................................................................................................... 11 
3.1. 
Analysis Sets ............................................................................................................ 11 
3.1.1. 
Full Analysis Set ......................................................................................... 11 
3.1.2. 
OLE All Enrolled Subjects ......................................................................... 11 
3.1.3. 
OLE Full Analysis Set ................................................................................ 11 
3.2. 
Randomized versus Actual Treatment Group .......................................................... 11 
3.3. 
Analysis Periods and Analysis Time Points ............................................................. 11 
3.3.1. 
Relative Day ................................................................................................ 11 
3.3.2. 
Duration ...................................................................................................... 12 
3.3.3. 
Analysis Periods .......................................................................................... 12 
3.3.4. 
Analysis Windows ...................................................................................... 13 
3.4. 
Handling of Data ...................................................................................................... 16 
3.4.1. 
Handling of Missing Data ........................................................................... 16 
3.4.1.1. 
Handling of Missing Date Time Data ...................................... 16 
3.4.1.2. 
Handling of Missing Result Data ............................................. 16 
3.4.2. 
Handling of Values Below or Above a Threshold ...................................... 16 
3.4.3. 
Handling of Outliers.................................................................................... 16 
3.5. 
Presentation of Results ............................................................................................. 17 
3.5.1. 
Presentation of Treatment groups ............................................................... 17 
3.5.2. 
Calculation of Descriptive Statistics ........................................................... 17 
3.5.3. 
Calculation of Percentages .......................................................................... 17 
3.5.4. 
Additional Considerations........................................................................... 17 
4. Interim Analyses and Data Monitoring Committee review .......................................... 17 
5. Statistical Analyses ........................................................................................................... 18 
5.1. 
Changes to the Planned Analyses, Not Covered by Protocol Amendments ............ 18 
5.2. 
Subject Information .................................................................................................. 18 
5.2.1. 
Demographic and Baseline Disease Characteristics ................................... 18 
5.2.2. 
Disposition Information .............................................................................. 19 
5.2.3. 
Protocol Deviations and Eligibility ............................................................. 20 
5.2.4. 
Inclusion and Exclusion Criteria ................................................................. 20 
5.2.5. 
Medical History and Concomitant Diseases ............................................... 20 




 
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5.4.4.3. 
Abnormalities ........................................................................... 40 
5.4.4.4. 
Worst-Case Abnormality ......................................................... 40 
5.4.4.5. 
Treatment Emergent Abnormalities ......................................... 41 
5.4.4.6. 
Presentation of Results ............................................................. 41 
5.4.5. 
Vital Signs ................................................................................................... 41 
5.4.5.1. 
Available Data .......................................................................... 41 
5.4.5.2. 
Abnormalities ........................................................................... 42 
5.4.5.3. 
Treatment Emergent Principle ................................................. 42 
5.4.5.4. 
Worst-Case Abnormality ......................................................... 42 
5.4.5.5. 
Presentation of Results ............................................................. 42 
5.4.6. 
Physical Examinations ................................................................................ 43 
5.4.7. 
Hospitalization ............................................................................................ 43 
6. References .......................................................................................................................... 44 
Appendix 1 .............................................................................................................................. 45 
Appendix 2 ............................................................................................................................... 47 
 
 
 


 
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VERSION HISTORY 
SAP Amendment # 
Date 
Description of changes 
 
 
 
 
 
 
 




 
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SE 
standard error 
 
 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
treatment-emergent adverse event 
TLF 
tables, listings and figures 
ULN 
upper limit of the normal range 
VAS 
visual analogue scale 
WBC 
white blood cell 
WHO-DD 
World Health Organization Drug Dictionary 
 
 
 
 


 
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1. 
INTRODUCTION 
This statistical analysis plan (SAP) defines the statistical analysis methods and data preparations 
to be used in the analysis and presentation of data for Galapagos protocol number 
GLPG1690-CL-206 entitled ‘A multicenter, open-label extension study to evaluate the long-
term safety, tolerability and efficacy of orally administered GLPG1690 in subjects with 
systemic sclerosis’. 
A decision was taken to halt the GLPG1690-CL-206 clinical study with the investigational 
autotaxin inhibitor ziritaxestat (sponsor product code GLPG1690) in subjects with systemic 
sclerosis. The decision is based on the recommendations of the Independent Data Monitoring 
Committee of the ISABELA Phase 3 clinical studies (study numbers GLPG1690-CL-303 and 
GLPG1690-CL-304) which, following a regular review of unblinded data on February 9, 
concluded that ziritaxestat’s benefit-risk profile no longer supported continuing these studies. 
In view of the above, no market authorisation application will be submitted for ziritaxtestat for 
the treatment of systemic sclerosis. Therefore, it was decided to limit the analyses to the primary 
safety endpoints and any analyses important to better understand the reason for the results seen, 
or for scientific knowledge for future compounds. 
The results will be presented in an abbreviated clinical study report (CSR). 
All descriptions as documented in the SAP were kept for reference, but endpoints and analyses 
deemed not applicable for the abbreviated CSR are in Italic font and will not be included for 
the final analysis. A list of analyses that will not be performed can be found in section Error! R
eference source not found.. 
The statistical analysis will process and present the results following the International Council 
for Harmonization (ICH) standards, particularly the ICH-E3, ICH-E6 and ICH-E9 guidelines, 
and 
 Global Biostatistics and Programming & Galapagos Standard Operating Procedures 
(SOPs). This SAP is created based on the latest Clinical Study Protocol (CSP) as referred in 
section 2.4. Technical details on derivations and mock Tables, Listings and Figures (TLFs) will 
be presented in a separate document. 
Data from both the GLPG1690-CL-204 (CL-204) and GLPG1690-CL-206 (CL-206) protocols 
will be stored in CL-206 SDTM and ADaM datasets, the CSR prepared for CL-206 study will 
report cumulative data across both protocols. 
2. 
STUDY DESIGN AND OBJECTIVES 
2.1. 
STUDY OBJECTIVES 
Primary Objective 
- 
To evaluate the long-term safety and tolerability of ziritaxestat in subjects with systemic 
sclerosis. 




 
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Subjects will receive 600 mg ziritaxestat, orally once daily (q.d.), starting the day after the 
Rollover visit.   
A schematic diagram of the clinical study design, procedures, and stages is provided in Figure 
1 (section 2.5). 
Each subject will be in the study for up to 116 weeks (104 weeks of treatment and 12 weeks 
of follow-up). 
2.4. 
CSP AND CSP AMENDMENTS 
Protocol Versions 
Date (ddMMMyyyy) 
Version 1 
30JAN2019 
Version 1 updated 
09APR2019 
Amendment 1: Version 2 
08JAN2020 
This SAP was based on the latest version of the protocol that was available at the time of its 
finalization. 
2.5. 
FLOW CHART 
A schematic diagram of the clinical study design, procedures, and stages is provided in Figure 
1. 
Figure 1: Schematic Study Overview 
 
D=Day, EoT=End of Treatment, FU=Follow-up, V=Visit, W=Week. 
2.6. 
SAMPLE SIZE JUSTIFICATION 
Thirty subjects (20 on 600 mg oral q.d. ziritaxestat and 10 on placebo) are planned to be 
randomized in the preceding CL-204 study. All subjects who completed the 24-week double-
blind treatment in this preceding study, signed the informed consent form (ICF) of the OLE 
study, and are eligible for the OLE will be included. Thus, up to 30 subjects may roll over and 
be enrolled in this OLE study. No formal sample size calculation was performed. 


 
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2.7. 
RANDOMIZATION AND BLINDING 
Randomization 
This is an open-label study with one dose level of IP; no randomization will be performed.  
At the Rollover visit (visit 1), subjects confirmed to be eligible for this OLE study will be 
enrolled. Subjects will retain the subject identification number assigned in CL-204. 
Blinding and Unblinding 
This is an open-label clinical study and treatment in this extension study will not be blinded. 
3. 
GENERAL METHODOLOGY 
Subjects will be analyzed as per their CL-204 study treatment assignment; therefore, this will 
be meant by the ‘treatment group’ reference. 
3.1. 
ANALYSIS SETS 
The analysis sets used in the statistical analyses are detailed in the following subsections. The 
analysis set will always be indicated in a subtitle in the TLF. 
3.1.1. Full Analysis Set 
The full analysis set (FAS) is defined as all randomized subjects who had received at least 1 
intake of IP in the preceding CL-204 study.   
3.1.2. OLE All Enrolled Subjects 
All subjects who were found eligible to participate in the OLE clinical study. 
3.1.3. OLE Full Analysis Set 
The OLE full analysis set (OLE FAS) is defined as all subjects who had at least one intake of 
IP in the OLE study. 
3.2. 
RANDOMIZED VERSUS ACTUAL TREATMENT GROUP 
This is an open-label study with one dose level of IP; no randomization will be performed. 
Subjects will be analyzed according to the treatment arm to which they were randomized in the 
preceding CL-204 study. 
3.3. 
ANALYSIS PERIODS AND ANALYSIS TIME POINTS 
3.3.1. Relative Day 
The timing of an assessment or an event relative to a reference date will be calculated as follows: 
Relative day ሺDYሻ 


 
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ൌconcerned date െreference date ൅1 day,  when concerned date  ൒ reference date  
ൌconcerned date െreference date, when the concerned date ൏ reference date  
- 
The reference date is the date of the first CL-204 IP intake, unless specified otherwise. 
The first OLE IP intake can also be used as reference date, if specifically stated. 
- 
The concerned date could be the measurement date of the assessment, or the start or end 
date of the event. 
- 
Date implies a complete date. If the date is (partially) missing, the relative day will be 
missing.  
Exception: if the end date of an event is fully missing at database lock (in case of an interim 
analysis) or at the subject’s study termination, the event will be considered as ongoing. The end 
date will be imputed by the database cutoff date or the date of last visit for cases where subject 
terminated study. 
3.3.2. Duration 
The duration of an assessment or an event will be calculated as follows: 
Duration ሺdaysሻൌend date െstart date ൅1 day 
Date implies a complete date. If the date is (partially) missing, the duration will be missing.  
Exception: If the end date of an event is fully missing at database lock (in case of an interim 
analysis) or at the subject’s study termination, the event will be considered as ongoing. The end 
date will be imputed by the database cutoff date or the date of last visit for cases where subject 
terminated study. In listing, the duration will be printed as “> X days”. 
3.3.3. Analysis Periods  
All event-type data (e.g., AEs) and assessments will be allocated to analysis periods according 
to Table 1. Analysis periods will be defined based on cumulative data collected during both 
CL-204 and CL-206 studies. 
Table 1: Analysis Periods 
Analysis Period 
Sub-period 
within Analysis 
Period 
Start Analysis Period 
End Analysis Period 
Screening 
NA 
Date of signing the 
ICF. 
Date of first CL-204 IP intake - 1 
day 
Treatment 
Double-blind 
(CL-204 study) 
Date of first CL-204 
IP administration. 
Date of last intake of CL-204 IP + 
30 days or date of first OLE IP 
administration 
(excluded), 
whichever comes first. 
OLE (CL-206 
study) 
Date of first OLE IP 
administration. 
Date of last intake of OLE IP + 30 
days 
Post-Treatment 
NA 
End 
date 
of 
the 
treatment period + 1 
day. 
Date of last contact in CL-206 
study. 


 
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3.3.4. Analysis Windows 
All CL-204 study assessments prior to the first OLE IP dose day including data collected on 
unscheduled visits, will be allocated to analysis visits (time windows) based on the relative day 
of the assessment using the first CL-204 IP dose date as reference date (see section 3.3.1) and 
according to the algorithm in Table 2. All CL-206 study assessments from the day of the first 
OLE IP dose onwards including data collected on unscheduled visits will be allocated to 
analysis visits where the reference date will be regarded as the first OLE IP dose date. All non-
follow-up post-baseline visits will fall within the treatment period as defined in Table 1. TLFs 
will present the analysis visits when analysis is derived.  
Table 2: Analysis Windows  
Analysis  
Visit label 
Target Day 
Interval Lower Bound 
Interval Upper Bound 
Vital signs, Clinical Laboratory tests 
Baseline* 
1 
-INF 
1 
Week 2 
15 
2 
22 
Week 4 
29 
23 
43 
Week 8 
57 
44 
85 
Week 16 
113 
86 
141 
Week 24 
169 
142 
197 
Week 28 
198 
198 
+INF (CL-204) 
OLE visits** 
OLE Week 2 
15 
2 
22 
OLE Week 4 
29 
23 
43 
OLE Week 8 
57 
44 
85 
OLE Week 16 
113 
86 
155 
OLE Week 28 
197 
156 
239 
OLE Week 40 
281 
240 
323 
OLE Week 52 
365 
324 
407 
OLE Week 64 
449 
408 
491 
OLE Week 76 
533 
492 
575 
OLE Week 88 
617 
576 
673 
OLE Week 104 
729 
674 
743 
OLE Follow-up 
Date of last intake of OLE 
IP + 31 days  
Date of last intake of OLE 
IP + 31 days  
+ INF (CL-206) 
12-Lead ECG 
Baseline* 
1 
-INF 
1 
Day 1*** 
1 
1 
2 
Week 2 
15 
3 
64 
Week 16 
113 
65 
141 
Week 24 
169 
142 
197 
Week 28  
198 
198 
+INF (CL-204) 
OLE visits** 
OLE Week 2 
15 
2 
22 
OLE Week 4 
29 
23 
43 
OLE Week 8 
57 
44 
85 
OLE Week 16 
113 
86 
155 
OLE Week 28 
197 
156 
239 
OLE Week 40 
281 
240 
323 
OLE Week 52 
365 
324 
407 
OLE Week 64 
449 
408 
491 
OLE Week 76 
533 
492 
575 
OLE Week 88 
617 
576 
673 






 
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multiple values on the same day and no time indicating which one is last, the average of the 
values will be calculated. 
3.4. 
HANDLING OF DATA 
3.4.1. Handling of Missing Data 
3.4.1.1. 
Handling of Missing Date Time Data 
Generally, no imputations will be done in case of missing date (time) fields, nor for the missing 
parts of partially known date (time) fields apart from partially missing initial diagnosis dates. 
When the date of initial diagnosis is partially missing, the following rules will be used in order 
to determine the duration of disease: 
• 
If the day of initial diagnosis is missing, then 01 will be assigned to the missing 
fields. 
• 
If the month of initial diagnosis is missing, then January will be assigned to the 
missing fields. 
• 
If date of initial diagnosis is completely missing, no imputation will be done. 
Assessments with completely missing date (time) will be omitted from the analysis.  
Event-type data (e.g. adverse events, concomitant medications) with missing date (time) will 
be allocated to analysis periods using a worst-case approach as explained in the respective 
sections. If the end date of an event is fully missing at database lock (in case of an interim 
analysis) or at the subject’s study termination, the event will be considered as ongoing. 
3.4.1.2. 
 Handling of Missing Result Data 
No imputation will be done of missing results unless specified otherwise in corresponding 
sections (i.e. observed cases (OC) analysis). 
3.4.2. Handling of Values Below or Above a Threshold 
Values below (above) the quantification limit will be imputed by the value one unit smaller 
(larger) than the quantification limit itself. In listings, the original value will be presented. 
Example: if the database contains the value “<0.04”, then for the descriptive statistics the value 
“0.03” will be used. The value “>1000” will be imputed by “1001”. 
3.4.3. Handling of Outliers 
There will be no outlier detection, all measured values will be included in the analyses. 


 
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3.5. 
PRESENTATION OF RESULTS 
3.5.1. Presentation of Treatment groups 
A grand total “Total” will be added to summarize all subjects over all CL-204 treatment groups 
in all tables and figures. 
3.5.2. Calculation of Descriptive Statistics 
For continuous parameters, descriptive statistics will be presented when n≥2. When n=1, only 
the summary statistics for n and mean will be displayed, other summary statistics will be left 
blank.  
Descriptive statistics will include:  
- 
the number of non-missing data points (n)  
- 
the arithmetic mean 
- 
the standard error (SE) and standard deviation (SD) 
- 
the median, minimum and maximum 
- 
95% confidence interval (CI) of the mean (if indicated in the relevant section). 
3.5.3. Calculation of Percentages 
Frequencies and percentages will be generated for categorical parameters. 
For event-type data (e.g. Adverse Events), the denominator will be all subjects in the analysis 
set and analysis visit/period. For other data (e.g. worst-case analysis of assessments), the 
denominator will be all subjects with post-baseline data for the parameter, in the analysis set 
and analysis visit/period. 
3.5.4. Additional Considerations 
All data collected except for assessment that were not done will be listed in data listings. 
4. 
INTERIM 
ANALYSES 
AND 
DATA 
MONITORING 
COMMITTEE REVIEW 
Interim Analysis 
Interim analyses may be performed during this clinical study, after unblinding of the CL-204 
study, to allow sponsor planning of future clinical studies. 
Data Monitoring 
An independent medical safety review will be implemented for CL-204 as well as for this CL-
206 clinical study. The review will be conducted by an independent clinician experienced in 






 
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completed Follow-up phase and subjects who discontinued the CL-206 study and the 
reasons for discontinuation. 
5.2.3.  Protocol Deviations and Eligibility 
Major protocol deviations are determined and recorded while the study is ongoing, and the list 
is finalized prior to database lock. For more details, please refer to the Study Deviations Rules 
document. 
The number (percent) of subjects with major protocol deviations will be tabulated, overall and 
per class of deviation, by treatment group and overall.  
All available information concerning major protocol deviations, deviations on eligibility criteria 
and subjects not treated will be listed. Major and minor protocol deviations related to the 
COVID-19 pandemic will be displayed separately. 
5.2.4. Inclusion and Exclusion Criteria 
All CL-206 study inclusion and exclusion criteria that subjects did not fulfil will be listed in 
detail for the FAS. 
5.2.5. Medical History and Concomitant Diseases 
Medical history will be coded using the version of the medical dictionary for regulatory 
activities (MedDRA) used in the preceding CL-204 study as per the data validation manual 
(DVM). The number and percentage of subjects with any medical history will be summarized 
overall and for each predefined system organ class (SOC) and preferred term (PT). Frequency 
tabulations per SOC and PT will be provided for the medical history findings: (i.e., any event 
with a stop date prior to first CL-204 IP intake) as well as for the concomitant diseases (i.e., 
ongoing conditions or conditions with a stop date on or after first CL-204 IP intake). 
5.2.6. Prior and Concomitant Medications 
A prior medication is defined as any medication that is taken prior to the first dose of CL-204 
IP. A concomitant medication is defined as any medication that has a stop date that is on or 
after the date of first dose of CL-204 IP or is ongoing. Medications that started prior to the 
first dose of CL-204 IP and have stop date on or after the first dose of CL-204 IP or is 
ongoing are defined as both prior and concomitant medications. 
5.2.6.1. 
Coding of Reported Terms 
All prior and concomitant therapy terms will be coded in the database using the version of 
World Health Organization Drug Dictionary (WHO-DD) used in the preceding CL-204 study. 
5.2.6.2. 
Classification of Medications 
All prior and concomitant medication records will be categorized as follows, considering their 
date and flags indicating the relative timing versus study (IP) start or end (before, after, 
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- 
Prior only: when the record ended before first CL-204 IP administration date. 
- 
Concomitant only: when the record started on or after the first CL-204 IP administration 
date. 
- 
Prior and concomitant: when the record started before the date of first CL-204 IP 
administration, and ended on or after this point, or continued, or if end date is missing. 
When the start or end date of the prior and concomitant medication records are incomplete (and 
no flags indicating relative timing are available), the date of first CL-204 IMP administration 
will be considered to the same level of information provided by these incomplete dates to 
categorize the timing of these records. This means that a record only having month and year 
will be categorized comparing only to the month and year of the date of first CL-204 IP 
administration. Worst case scenario will be used to categorize concomitant medications: if the 
same level of information provided by incomplete concomitant medication start date is identical 
to first CL-204 IP administration, then the medication will be considered as both prior and 
concomitant, given end date is not prior to first CL-204 IP administration. If the same level of 
information provided by incomplete concomitant medication end date is identical to first CL-
204 IP administration, then the medication will be considered as both prior and concomitant, 
given start date is not after to first CL-204 IP administration. 
5.2.6.3. 
Calculation of Relative Days 
For both the start and the end dates of the concomitant medication records, their day relative to 
the day of first CL-204 IP administration will be calculated as described in section 3.3.1. In 
addition, start and end dates relative to the day of first OLE IP administration will be presented. 
5.2.6.4. 
Presentation of Results 
A frequency tabulation of the anatomical therapeutic chemical (ATC) classes Level 4 by 
therapeutic subgroup (ATC Level 2) and anatomical main group (ATC Level 1) of the prior 
medications (defined as ‘prior only’ and ‘prior and concomitant’) will be provided as well as 
of the concomitant medications (defined as ‘concomitant only’ and ‘prior and concomitant’). A 
separate table will be produced for concomitant medications taken during the CL-206 study. 
All medications will be listed in detail. 
5.2.7. Prior and Concomitant Non-Drug Therapies 
5.2.7.1. 
Coding of Reported Terms 
All non-drug therapies used within 12 weeks prior to and during the screening period will be 
collected on the electronic case report form (eCRF). All non-drug therapies will be coded 
according to the version of MedDRA Dictionary used in the preceding CL-204 study. 
A prior non-drug therapy is defined as any non-drug therapy that is taken prior to the first dose 
of CL-204 IP. A concomitant non-drug therapy is defined as any non-drug therapy that has a 
stop date that is on or after the date of first dose of CL-204 IP or is ongoing.  


 
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5.2.7.2. 
Classification of Non-Drug Therapies 
All prior and concomitant non-drug therapy records will be categorized as specified in section 
5.2.6.2. 
5.2.7.3. 
Calculation of Relative Days 
For both the start and the end dates of the concomitant non-drug therapy records, their day 
relative to the day of first CL-204 IP administration will be calculated as described in section 
3.3.1. 
5.2.7.4. 
Presentation of Results 
A frequency tabulation of the SOC and PT term of non-drug therapies of the prior therapies 
(defined as ‘prior only’ and ‘prior and concomitant’) will be provided. Similarly, a separate 
table will be provided for concomitant therapies (defined as ‘concomitant only’ and ‘prior and 
concomitant’). 
All non-drug therapies will be listed in detail. 
 


 
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5.2.8. Exposure to IP and Compliance 
5.2.8.1. 
Derivation Rules 
Derived Parameters: Extent of Exposure to IP 
- 
Total treatment duration (weeks) =  
୪ୟୱ୲ ୓୐୉ ୍୔ ୟୢ୫୧୬୧ୱ୲୰ୟ୲୧୭୬ ୢୟ୲ୣ – ୤୧୰ୱ୲ େ୐ିଶ଴ସ ୍୔ ୟୢ୫୧୬୧ୱ୲୰ୟ୲୧୭୬ ୢୟ୲ୣ ାଵ ୢୟ୷ 
଻
 . 
- 
Total treatment duration, excluding weeks off study IP: Number of weeks with any IP 
administration based on both CL-204 and CL-206 study data.  
- 
Total treatment duration, fully compliant (weeks): Number of weeks with IP 
administration, as planned per CSP based on both CL-204 and CL-206 study data.  
Additionally, extent of exposure parameters will be derived separately for CL-206 study data: 
- 
 Total OLE treatment duration (weeks) =  
୪ୟୱ୲ ୓୐୉ ୍୔ ୟୢ୫୧୬୧ୱ୲୰ୟ୲୧୭୬ ୢୟ୲ୣ – ୤୧୰ୱ୲ ୓୐୉ ୍୔ ୟୢ୫୧୬୧ୱ୲୰ୟ୲୧୭୬ ୢୟ୲ୣ ାଵ ୢୟ୷ 
଻
 . 
- 
Total OLE treatment duration, excluding weeks off study IP: Number of weeks with 
any OLE IP administration.  
- 
Total OLE treatment duration, fully compliant (weeks): Number of weeks with OLE IP 
administration, as planned per CSP. 
Derived Parameters: Compliance 
- 
Overall compliance (%) =  
100 x ቀ
୬୳୫ୠୣ୰ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୟୡ୲୳ୟ୪୪୷ ୳ୱୣୢ during both CLെ204 and CLെ206 studies
୬୳୫ୠୣ୰ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୲୦ୟ୲ ୱ୦୭୳୪ୢ ୦ୟ୴ୣ ୠୣୣ୬ ୳ୱୣୢ during both CLെ204 and CLെ206 studiesቁ 
Number of tablets that should have been used will be calculated as: 
Total treatment duration * 3 
- 
Percentage weeks with any intake (%) =  
100 x ቀ
୲୭୲ୟ୪ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬,ୣ୶ୡ୪୳ୢ୧୬୥ ୵ୣୣ୩ୱ ୭୤୤ ୍୔
୲୭୲ୟ୪ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬
ቁ. 
- 
Percentage weeks fully compliant (%) = 100 x ቀ
୲୭୲ୟ୪ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬,୤୳୪୪୷ ୡ୭୫୮୪୧ୟ୬୲
୲୭୲ୟ୪ ୲୰ୣୟ୲୫ୣ୬୲ ୢ୳୰ୟ୲୧୭୬
ቁ 
Additionally, compliance parameters will be derived separately for CL-206 study data: 
- 
Overall OLE compliance (%) =  
100 x ቀ
୬୳୫ୠୣ୰ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୟୡ୲୳ୟ୪୪୷ ୳ୱୣୢ during CLെ206 study
୬୳୫ୠୣ୰ ୭୤ ୲ୟୠ୪ୣ୲ୱ ୲୦ୟ୲ ୱ୦୭୳୪ୢ ୦ୟ୴ୣ ୠୣୣ୬ ୳ୱୣୢ during CLെ206 studyቁ 
















 
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Coding information (SOC, PT, high level group term, high level term, low level term and 
verbatim) based on all the collected AE data will be presented in a listing.   
5.4.1.3. 
Allocation of Adverse Events to Analysis Periods 
All AEs records will be placed into analysis periods considering their start date, aiming to report 
the incidence of these events only in the analysis period during which they started. 
The general rule for allocation of AEs to analysis periods follows: 
Analysis period start date ≤ AE start date ≤ analysis period end date  
If the start date of an AE is missing or incomplete to a level preventing a clear allocation of the 
AE to one single analysis period and no flag indicating timing relative to study medication is 
available, a worst-case consideration (see below) will be done aiming to allocate the AE to one 
single analysis period, if possible. When a worst-case consideration is needed, the end date of 
the AE, if and as available, should also be considered; if such AEs clearly end on a given point, 
this will exclude the possibility to allocate the AE to an analysis period after that point. 
- 
An AE which according to the available information of its start date could belong to the 
screening as well as to the treatment period will only be placed in the treatment period. 
- 
An AE which according to the available information of its start date could belong to 
treatment period as well as to follow-up period will only be placed in the treatment 
period. 
- 
An AE with a missing start date will be allocated to treatment period. 
- 
If an AE can be allocated to both double-blind (i.e. CL-204 study) and open-label (i.e. 
CL-206 study) treatment sub-periods, then the event will be reported for CL-204 
double-blind treatment sub-period during CL-206 study analyses.  
5.4.1.4. 
Treatment Relatedness 
Following ICH-E3 (ICH), the originally reported relatedness to IP of an AE will be 
dichotomized as follows: 
- 
Not IP related: all non-missing weaker levels of relatedness than ‘possibly IP related’ 
(unrelated, unlikely).  
- 
IP related: ‘possibly IP related’ and all stronger levels of relatedness (probable, certain) 
- this class also includes any missing IP relatedness, as a worst-case consideration. 
Only this dichotomized relatedness will be used in tables. Relatedness as originally reported 
will only be listed.  
5.4.1.5. 
Presentation of Adverse Events and of Event Episodes 
All AEs tables will only show TEAEs and will show counts of the number of subjects with 
TEAEs. The number of event episodes will be shown only in tables where explicitly mentioned. 


 
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Tables will be produced for cumulative data collected during both CL-204 and CL-206 studies. 
Separate tables will be produced for CL-206 study data. 
AEs starting before first CL-204 IP administration or later than 30 days after the last OLE dose 
of IP will only be listed.  
AEs leading to death will be presented in a separate listing.  
5.4.1.6. 
Worst-Case Selections 
When cross-tabulating AE preferred terms versus an AE attribute (like severity), only the worst-
case within each same preferred term, same subject and same analysis period will be considered, 
i.e., when a same subject has more than once the same AE preferred term reported in the same 
treatment group, the subject will be counted only once and will be shown under the worst 
outcome (like the worst severity for that AE in the concerned treatment period). 
Worst-case will be defined based on cumulative data collected during both CL-204 and CL-206 
studies. Additionally, worst-case will be defined based on CL-206 study data. 
5.4.1.7. 
Calculation of Relative Days and Duration 
For each AE record, its start day in study (the day of the AE start date relative to the date of 
first IP administration), its start day in the analysis period, and its duration (in days) will be 
calculated and shown only in listings.  
See sections 3.3.1 and 3.3.2 for the calculation of relative days and duration respectively. 
5.4.1.8. 
Presentation of Results 
A summary table will be provided, showing then number (percentage) of subjects with: 
- 
at least one TEAE, 
- 
at least one IP-related TEAE,  
- 
at least one serious TEAE,  
- 
at least one TEAE leading to death,  
- 
any TEAEs by worst severity (mild, moderate, severe, life threatening, and death),  
- 
at least one TEAE leading to IP discontinuation, 
- 
at least one TEAE leading to IP interruption. 
Frequency tabulations, by SOC and PT, of the number (percent) of subjects with a TEAE will 
be presented by prior treatment group as assigned in the preceding study. Similar tables will be 
provided for the following groups: 
- 
Severity (‘Grade 1 - Mild’, ‘Grade 2 - Moderate’, ‘Grade 3 - Severe’, ‘Grade 4 - Life 
Threatening’, and ‘Grade 5 - Death’) 






 
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Table 3: Laboratory Toxicity Grades 
Parameter 
Direction of 
abnormality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Alanine amino 
transferase 
high 
>ULN-3 x ULN 
>3 x ULN -5 x 
ULN 
>5 x ULN - 8 x 
ULN 
>8 x ULN  
Albumin (g/L) 
low 
<LLN-30 
<30-20 
<20 
- 
Alkaline 
phosphatase 
high 
>ULN-2.5 x 
ULN 
>2.5 x ULN -5 x 
ULN 
>5 x ULN -20 x 
ULN 
>20 x ULN  
Aspartate 
amino 
transferase 
high 
>ULN-3 x ULN 
>3 x ULN -5 x 
ULN 
>5 x ULN -8 x 
ULN 
>8 x ULN  
Bilirubin 
[total] 
high 
>ULN-1.5 x 
ULN 
>1.5 x ULN -3 x 
ULN 
>3 x ULN -10 x 
ULN 
>10 x ULN  
Calcium, 
below 
(mmol/L) 
low 
<LLN-2.0 
<2.0-1.75 
<1.75-1.5 
<1.5 
Calcium, 
above 
(mmol/L) 
high 
>ULN-2.9 
>2.9-3.1 
>3.1-3.4 
>3.4 
Cholesterol 
(mmol/L) 
high 
>ULN-7.75 
>7.75-10.34 
>10.34-12.92 
>12.92 
Creatine 
kinase 
high 
>ULN-2.5 x ULN 
>2.5 x ULN -5 x 
ULN 
>5 x ULN -10 x 
ULN 
>10 x ULN 
Creatinine 
high 
>ULN-1.5 x ULN 
>1.5 x ULN -3 x 
ULN or 
>1.5 x baseline -3 
x baseline 
>3 x ULN -6 x 
ULN or >3 x 
baseline 
>6 x ULN 
eGFR/  
Creatinine 
clearance 
(mL/min/1.73 
m2) 
low 
<LLN-60 
<60-30 
<30-15 
<15 
Eosinophils 
absolute count 
high 
>ULN 
- 
- 
- 
Eosinophils 
relative count 
(%) 
high 
>7 
- 
- 
- 
Gamma-
glutamyl 
transferase 
high 
>ULN-2.5 x 
ULN 
>2.5 x ULN -5 x 
ULN 
>5 x ULN -20 x 
ULN 
>20 x ULN 
Glucose 
[fasting], 
below 
(mmol/L)  
low 
<LLN-3.0 
<3.0-2.2 
<2.2-1.7 
<1.7 
Hemoglobin, 
below (g/L) 
low 
<LLN-100 
<100-80 
<80 
- 
Hemoglobin, 
above (g/L) 
high 
Increase >0-20 
Increase >20-40 
Increase >40 
- 
Lymphocytes, 
below 
(10^9/L) 
low 
<LLN-0.8 
<0.8-0.5 
<0.5-0.2 
<0.2 
Lymphocytes, 
above 
(10^9/L) 
high 
- 
>4.0-20.0 
>20.0 
- 
Neutrophils, 
below 
(10^9/L) 
low 
<LLN-1.5 
<1.5-1.0 
<1.0-0.5 
<0.5 


 
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Parameter 
Direction of 
abnormality 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Potassium, 
below 
(mmol/L) 
low 
<LLN-3.0 
- 
<3.0-2.5 
<2.5 
Potassium, 
above 
(mmol/L) 
high 
>ULN-5.5 
>5.5-6.0 
>6.0-7.0 
>7.0 
Sodium, below 
(mmol/L) 
low 
<LLN-130 
<130-125 
<125-120 
<120 
Sodium, above 
(mmol/L) 
high 
>ULN-150 
>150-155 
>155-160 
>160 
Triglycerides 
fasting 
and 
non-fasting 
(mmol/L)  
high 
>1.71-3.42 
>3.42-5.7 
>5.7-11.4 
>11.4 
Partial 
thromboplastin 
time [activated 
or not 
specified]  
high 
>ULN-1.5 x ULN 
>1.5 x ULN -2.5 
x ULN 
>2.5 x ULN 
- 
International 
normalized 
ratio 
high 
>1.2 x ULN -1.5 x 
ULN 
>1.5 x ULN -2.5 
x ULN 
>2.5 x ULN 
- 
Platelets 
(10^9/L) 
low 
<LLN-75 
<75-50 
<50-25 
<25 
White blood 
cells, below 
(10^9/L) 
low 
<LLN-3 
<3-2 
<2-1 
<1 
White blood 
cells, above 
(10^9/L) 
high 
- 
- 
>100 
- 
Legend: 
[Specifications].  
(Specific unit into which the defined grades apply). 
Baseline value is defined as abnormal if the value is not within the normal range. For directional toxicity of high an abnormal baseline 
will be a baseline value which is higher than the upper limit of the reference range. For directional toxicity of low, an abnormal baseline 
will be a baseline value which is lower than the lower limit of the reference range. 
x LLN / x ULN = times the lower / times the upper limit of the normal range. 
Below / above = differentiate grade definitions in the low / high sense for a same parameter.  
 
The following parameters will be analyzed and categorized based on pre-defined criterion 
without using the above defined grading system: 
- Prothrombin time: >ULN-1.5 x ULN; >1.5 x ULN - 2.5 x ULN; >2.5 x ULN 
- Glucose [fasting] (mmol/L): >7.2 
- High density lipoprotein (mmol/L): <1.554 
- Low density lipoprotein (mmol/L): >4.144 
The analysis of these parameters will be performed in the same way as the analysis of the 
parameters with standard toxicity grade. 


 
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5.4.3.4. 
Definition of Non-Graded Abnormalities 
Non-graded abnormalities will be determined only for the parameters having no definitions of 
toxicity grades (see section 5.4.3.3). 
For laboratory tests provided by the laboratory, the position of the actual analysis values versus 
their normal ranges will be determined directly by using the position indicator provided in the 
database as reported, expressing the classes for these analysis values as low (L), normal (N) or 
high (H). L, N and H are further referred to as non-graded abnormalities. 
5.4.3.5. 
Urinalysis Tests with Categorical Results  
Results of urinalysis with qualitative results will be tabulated by time point. No toxicity grading 
or non-graded abnormalities will be derived.  
5.4.3.6. 
Treatment Emergent Principle  
Toxicity Grades 
A post-baseline toxicity grade 1, 2, 3 or 4 is defined as treatment-emergent when higher than 
the toxicity grade of the baseline result. If the baseline result is missing, a post-baseline toxicity 
grade 1, 2, 3 or 4 will always be considered as treatment-emergent. 
For prothrombin time parameter a post-baseline value meeting the defined abnormality criteria 
is regarded as treatment-emergent if the post-baseline criteria meet a higher degree of 
abnormality than the baseline value (e.g. post-baseline value meeting >1.5-2.5 x ULN category 
while baseline meeting >ULN-1.5 x ULN category) or the baseline value is missing or does not 
meet any abnormality criteria. For glucose [fasting], high density lipoprotein and low-density 
lipoprotein a post-baseline abnormal category will be regarded as treatment emergent, if the 
baseline value is missing or does not meet the defined abnormality criteria. 
Non-graded Abnormalities 
A post-baseline non-graded abnormality class L or H is defined as treatment-emergent when it 
differs from the abnormality class of the baseline result. If the baseline result is missing, a post-
baseline abnormality L or H will always be considered as treatment-emergent. 
5.4.3.7. 
Worst-Case 
Toxicity Grading 
The worst-case post-baseline toxicity grade 0, 1, 2, 3 or 4 will be determined per subject, per 
parameter (and sense, if below and above) during the on-treatment analysis period, using all 
non-missing post-baseline records within that period (including unscheduled and follow-up 
visits). 
The worst-case toxicity grade is the highest toxicity grade scored for the parameter (in each 
sense, if below and above).  
Worst-case will be defined based on cumulative data collected during both CL-204 and CL-206 
studies. Additionally, worst-case will be defined based on CL-206 study data. 




 
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Continuous parameters will be summarized by means of descriptive statistics (including 95% 
CI of the mean change from t-test) by parameter, treatment group and analysis visit. Actual 
values and changes from baseline will be tabulated separately.  
Figures of the mean (± SE) actual values over time and of the mean (± SE) change from baseline 
will be prepared for all parameters.  
All laboratory abnormalities on or after the first dose of IP administration in the preceding CL-
204 study up to the last contact after the last dose of OLE IP will be included. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality/toxicity grade. The table will be created per parameter and 
treatment group for the on-treatment analysis period. The results of non-graded abnormalities 
and toxicities grades will be shown separately. 
A frequency table of the number (percentage) of subjects with treatment-emergent worst-case 
abnormalities per parameter and treatment group for the on-treatment analysis period will be 
presented. The results of non-graded abnormalities and toxicities grades will be shown 
separately. 
Urinalysis tests for which no normal range is available will be tabulated separately as 
categorical data. 
Clinical laboratory values will also be listed including normal ranges and indicating if value is 
out of range. A separate listing will also be created to include all abnormal laboratory values. 
Analyses will be performed for cumulative data collected during both CL-204 and CL-206 
studies. Additionally, analyses will be performed for CL-206 study data. 
5.4.4. Electrocardiogram 
5.4.4.1. 
Available Data 
All subjects will have a standard 12-lead electrocardiogram (ECG) performed at the time points 
specified in the Schedule of Activities (see Appendix 1). The following ECG parameters will 
be analyzed: heart rate (bpm), PR interval, QRS interval, uncorrected QT interval (ms), 
morphology, QT interval corrected for the heart rate using Fridericia’s formula (QTcF) (ms). 
5.4.4.2. 
Derivation Rules 
Derived Parameters 
The ECG parameters will be provided in the clinical database, no imputation will be done. 
Handling of ECGs Measured in Triplicate 
If ECG is collected in triplicates (or duplicates), the following approach will be taken.  
 
 


 
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The mean of the triplicate (or duplicate) ECG values will be calculated for each individual 
ECG parameter, without rounding the result. These calculated means will constitute the 
analysis values; any derivation (e.g. change from baseline, assignment of abnormalities) and 
statistic will be based on the mean value of the triplicates (or duplicates). 
When a single ECG is performed, the actual results of the single ECG will be summarized. 
The values of the individual triplicate (or duplicate) assessments will be listed, i.e. will not be 
summarized or graphically presented. 
5.4.4.3. 
Abnormalities 
The actual analysis values and changes from baseline of the QT and QTcF parameters will be 
categorized into the abnormality classes as defined in ICH E14: 
Table 5: Abnormalities on ECG Parameters 
Parameter 
Abnormality 
Limits 
Abnormalities on actual values 
QT and QTcF (ms) 
QT* ≤ 450 
450 < QT* ≤ 480 
480 < QT* ≤ 500 
QT* > 500 
≤ 450 
450 < value ≤ 480 
480 < value ≤ 500 
> 500 
Abnormalities on change from Baseline 
QT and QTcF (ms) 
QT* change ≤ 30 
≤ 30 
 
30 < QT* change ≤ 60 
30 < value ≤ 60 
 
QT* change > 60 
> 60 
* Indicate which QT(c) parameter is analyzed in the label 
For electrocardiogram (ECG), where triplicates (or duplicates) results are measured, the 
baseline is defined as the mean of the last recorded triplicates (or duplicates) results before 
first IP administration. If no triplicate (or duplicate) results are available before the first dose, 
the last value before first study drug administration will be used. 
5.4.4.4. 
Worst-Case Abnormality 
For the overall interpretation the worst-case post-baseline will be determined per subject, per 
parameter, and for on-treatment analysis period, using all non-missing post-baseline records 
(including unscheduled and follow-up visits) as follow: 
- 
Normal: if all the post-baseline results are normal 
- 
Abnormal: if at least one post-baseline result is abnormal. 
Worst-case will be defined based on cumulative data collected during both CL-204 and CL-206 
studies. Additionally, worst-case will be defined based on CL-206 study data. 
 
 


 
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5.4.4.5. 
Treatment Emergent Abnormalities 
Actual value: An abnormal post-baseline abnormality is defined as treatment-emergent when 
the abnormality is worse compared to the abnormality at baseline. If the baseline result is 
missing, a post-baseline result outside of the normal range will always be considered as 
treatment-emergent. 
An abnormal category for change from baseline is always treatment-emergent. 
Additional analyses will be performed for CL-206 study data, where baseline will be regarded 
the last non-missing value before first OLE IP administration. 
5.4.4.6. 
Presentation of Results 
No formal inferential statistics (p-values) will be presented. 
Continuous parameters will be summarized by means of descriptive statistics (including 95% 
CI of the mean change from t-test) by parameter, treatment group and analysis visit. Actual 
values and changes from baseline will be tabulated separately and tables will be produced 
including all time points in the preceding CL-204 and CL-206 studies. Separate tables will be 
produced for CL-206 study data. 
All ECG abnormalities on or after the first dose of IP administration in the preceding CL-204 
study up to the last contact after the last dose of OLE IP will be listed. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter and treatment group 
for the on-treatment analysis period. Tables will be produced for cumulative data collected 
during both CL-204 and CL-206 studies. Separate tables will be produced for CL-206 study 
data. 
A frequency table of the number (percentage) of subjects with treatment-emergent worst-case 
abnormalities per parameter and treatment group for the on-treatment analysis period will be 
presented. Overall interpretation as assessed by the investigator will also be summarized and 
listed. 
5.4.5. Vital Signs 
5.4.5.1. 
Available Data 
The following vital signs parameters will be analyzed: Systolic Blood Pressure (SBP) (mmHg), 
Diastolic Blood Pressure (DBP) (mmHg), heart rate (bpm), respiratory rate (breaths/minute), 
and body temperature (ᵒC). If blood pressure is collected supine, semi-recumbent, sitting, or 
standing, then results are presented by assessment position. If there are more values available 
for a subject taken by different positions for a visit, then selection rules for the analyses will be 
applied as described in Section 3.3.4. No adjustment to the temperature will be made to account 
for the possible different method of collection. 


 
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5.4.5.2. 
Abnormalities 
The relevant vital sign values at each visit will be classified based on the reference ranges found 
in Table 6 below.  
Table 6: Normal Ranges for Vital Signs 
Normal ranges applicable in supine position: 
Systolic blood 
pressure 
(mmHg) 
Diastolic blood 
pressure 
(mmHg) 
Heart rate 
(bpm) 
Tympanic 
temperature (°C) 
Respiratory rate 
(breaths per 
min) 
90≤ SBP ≤140 
45≤ DBP ≤90 
50≤ HR ≤100 
35.5≤ t° ≤37.5 
12≤ RR ≤20 
5.4.5.3. 
Treatment Emergent Principle 
A post-baseline abnormality class L or H is defined as treatment-emergent when it differs from 
the abnormality class at baseline. If the baseline result is missing, a post-baseline abnormality 
L or H will always be considered as treatment-emergent. 
Baseline is defined as the last non-missing value before first IP administration in the preceding 
CL-204 study. Additional analyses will be performed for CL-206 study data, where baseline 
will be regarded the last non-missing value before first OLE IP administration.  
5.4.5.4. 
Worst-Case Abnormality 
The following worst-case post-baseline abnormalities low, below the lower limit of the normal 
range (L), normal, with the limits of the normal range (N) or high, above the upper limit of the 
normal range (H) will be determined per subject, per parameter and for the on-treatment 
analysis period, using all non-missing post-baseline records (including unscheduled and follow-
up visits):   
- 
L = low: at least one post-baseline result is classified as L. 
- 
N = normal: all post-baseline results are classified as N.  
- 
H = high: at least one post-baseline result is classified as H. 
If, for a subject, both L and H are reported, the subject will be counted twice in the table: once 
with a worst-case L and once with a worst-case H. 
Worst-case will be defined based on cumulative data collected during both CL-204 and CL-206 
studies. Additionally, worst-case will be defined based on CL-206 study data. 
5.4.5.5. 
Presentation of Results 
No formal inferential statistics (p-values) will be derived. 


 
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Continuous parameters will be summarized by means of descriptive statistics (including 95% 
CI of the mean change from a t-test) for all vital sign parameters and analysis visits, by treatment 
group and overall. Actual values and changes from baseline will be tabulated separately and 
tables will be produced including all time points in the preceding CL-204 and CL-206 studies. 
Separate tables will be produced for CL-206 study data.  
All abnormalities on or after the first dose of IP administration in the preceding CL-204 study 
up to the last contact after the last dose of OLE IP will be included. 
Abnormalities of the actual values will be presented as shift tables of the worst-case abnormality 
versus the baseline abnormality. The table will be created per parameter (and position if 
applicable), and treatment group for the on-treatment analysis period. Tables will be produced 
for cumulative data collected during both CL-204 and CL-206 studies. Separate tables will be 
produced for CL-206 study data. 
Frequency table of the number (percentage) of subjects with treatment-emergent worst-case 
abnormalities per parameter and treatment group for the on-treatment analysis period will be 
presented. Tables will be produced for cumulative data collected during both CL-204 and CL-
206 studies. Separate tables will be produced for CL-206 study data. 
Mean (± SE) plots over time for both treatment groups, with heart rate, respiratory rate, body 
temperature, and blood pressure by position on a new page, will be displayed. Separate plots 
will be produced for mean actual values and changes from baseline. 
5.4.6. Physical Examinations 
Abnormal physical examination results (including gynaecological exam results for female 
subjects) will be presented in a listing.  
5.4.7. Hospitalization 
All information recorded in the eCRF page “Hospitalization Details” will be listed. 
 
 


 
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6. 
REFERENCES  
Bazett, H. (1920 (7)). An analysis of the time-relations of electrocardiograms. Heart, 353–370. 
Fridericia, L. (1920). Die systolendauer im elektrokardiogramm bei normalen menschen und bei 
herzkranken. 53:469-486. 
ICH-E3. (December 1995). Structure and content of clinical study reports. Step 4 Guideline.  
ICH-E6. (17 July 1996). Guideline for good clinical practice. Step 5 Guideline.  
ICH-E9. (5 February 1998). Statistical principles for clincal trials. Step 4 guideline.  
ICH-E14. (12 May 2005). The clinical evaluation of QT/QTc interval prolongation and proarrhythmic 
potential for non-antiarrhythmic drugs. 
 
 
 
 


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APPENDIX 1 
EVENT 
TREATMENT PERIOD 
FOLLOW-UP 
Study Visit 
Roll-over 
Visit 1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
EoT/ 
ED 
FU1 
FU2 
Study Week (W) or Day (D) ± 
days (d) 
D1 
W2 
±2d 
W4 
±2d 
W8 
±4d 
W16 
±7d 
W28 
±7d 
W40 
±7d 
W52 
±7d 
W64 
±7d 
W76 
±7d 
W88 
±7d 
W104 
±7d 
W108 
±7d 
W116 
±7d 
Informed consent 
9 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
9 
9 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
ሺ9ሻଵ 
 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
 
Symptom-directed physical 
examination 
ሺ9ሻଵ 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
 
Vital signs 
ሺ9ሻଵ 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
 
12-Lead ECG 
ሺ9ሻଵ 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
 
Clinical laboratory tests 
ሺ9ሻଵ 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
 
Dispense subject diary 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
9 
 






Signature Page for glpg1690-cl-206-sap 17838
Signature Page for glpg1690-cl-206-sap43952_19643_47970
Approval
nager
Biometrics
23-Apr-2021 09:54:22 GMT+0000
Approval
al Director Phase I
Translational Medicine
23-Apr-2021 12:43:32 GMT+0000