A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of AKST4290 in Subjects With Parkinson's Disease on Stable Dopaminergic Treatment
Phase: PHASE2
Conditions: Parkinson Disease
Sponsor: Alkahest, Inc.

 
 
 
 
 
 
 
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o  
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects wit h  
Par ki ns o n’s Disease o n Sta ble D o pa mi ner gic Treat me nt   
 
 
 
 
 
 
Pr ot oc ol N u m ber:  
A K S T 4 2 9 0 -2 1 1  
E u dr a C T N u m ber:  
2 0 1 9 -0 0 1 6 5 7 -4 2  
I N D N u m ber: 
1 4 2 5 9 7  
Cli nic al P h ase:  
2  
S p o ns or:  
Al ka hest, I nc.   
1 2 5  S h ore wa y R oa d, S uite D  
Sa n Carl os, C A 9 4 0 7 0  
St u d y  A ge nt : 
A K S T 4 2 9 0  
I n dic ati o ns: 
Par ki ns o n’s Disease  
A ut h orize d Re pres e nt ati ve:  
 
 
 
 
 
 
Versi o n N u m ber:  
V 4 .0  
Versi o n D ate  
2 2 M A Y 2 0 2 0  
Re pl aces Versi o n:  
V 3. 1, 0 6 JA N 2 0 2 0  
 
 
 
 
 
 
C O N FI D E N TI A L S T A T E M E N T  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt a n d all i nf or mati o n pr o vi de d as relate d t o t his cli nical st u d y are t he 
c o nfi de ntial a n d pr o prietar y i nf or mati o n of t he S p o ns or a n d e xce pt as ma y be re q uire d b y fe deral, state, or l ocal la ws or 
re g ulati o ns ma y n ot be discl ose d t o ot hers wit h o ut pri or writte n per missi o n of t he S p o ns or. T he Pri nci pal I n vesti gat or 
ma y, h o we v er, discl ose s uc h i nf or mati o n t o s u per vise d i n di vi d uals w or ki n g o n t he cli nical st u d y, pr o vi de d s uc h 
i n di vi d uals a gree t o mai ntai n t he c o nfi de ntialit y of s uc h i nf or mati o n. 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 3  of 9 9
 
 
 
5. 3  
S T R A T E GI E S F O R R E C R UI T M E N T A N D R E T E N TI O N  ............................................. 2 1  
5. 4  
S U B J E C T WI T H D R A W A L O R T E R MI N A TI O N  ............................................................ 2 1  
5. 4. 1  
R E A S O N S F O R WI T H D R A W A L O R T E R MI N A TI O N  ........................................................ 2 1  
5. 4. 2  
H A N D LI N G O F P A R TI CI P A N T WI T H D R A W A L S O R T E R MI N A TI O N  ........................... 2 2  
5. 5  
P R E M A T U R E T E R MI N A TI O N O R S U S P E N SI O N O F S T U D Y  .................................... 2 2  
6  
S T U D Y A G E N T  ..................................................................................................................... 2 2  
6. 1  
S T U D Y A G E N T A N D C O N T R O L D E S C RI P TI O N  .......................................................... 2 2  
6. 1. 1  
A C Q UI SI TI O N  ......................................................................................................................... 2 2  
6. 1. 2  
F O R M U L A TI O N, A P P E A R A N C E, P A C K A GI N G, A N D L A B E LI N G  ................................. 2 2  
6. 1. 3  
P R O D U C T S T O R A G E A N D S T A BI LI T Y .............................................................................. 2 3  
6. 1. 4  
D O SI N G A N D A D MI NI S T R A TI O N  ...................................................................................... 2 3  
6. 1. 5  
R O U T E O F A D MI NI S T R A TI O N  ............................................................................................ 2 3  
6. 2  
S T U D Y A G E N T A C C O U N T A BI LI T Y ................................................................................ 2 3  
7  
S T U D Y P R O C E D U R E S A N D S C H E D U L E  ....................................................................... 2 4  
7. 1  
S T U D Y P R O C E D U R E S/ E V A L U A TI O N S  .......................................................................... 2 4  
7. 1. 1  
S T U D Y S P E CI FI C P R O C E D U R E S  ........................................................................................ 2 4  
7. 2  
L A B O R A T O R Y P R O C E D U R E S/ E V A L U A TI O N S  ........................................................... 2 9  
7. 2. 1  
C LI NI C A L L A B O R A T O R Y E V A L U A TI O N S  ....................................................................... 2 9  
7. 2. 2  
O T H E R T E S T S O R P R O C E D U R E S  ....................................................................................... 2 9  
7. 3  
S T U D Y S C H E D U L E  .............................................................................................................. 3 0  
7. 3. 1  
S C R E E NI N G  ............................................................................................................................ 3 0  
7. 3. 2  
B A S E LI N E  ............................................................................................................................... 3 1  
7. 3. 3  
T R E A T M E N T  .......................................................................................................................... 3 2  
7. 3. 4  
F O L L O W -U P ............................................................................................................................ 3 3  
7. 3. 5  
E A R L Y T E R MI N A TI O N  ......................................................................................................... 3 4  
7. 3. 6  
S C H E D U L E O F E V E N T S T A B L E  .......................................................................................... 3 4  
7. 3. 7  
E N D O F T RI A L/ E N D O F S T U D Y  .......................................................................................... 3 4  
7. 4  
C O N C O MI T A N T M E DI C A TI O N S  ..................................................................................... 3 4  
7. 5  
P R O HI BI T E D M E DI C A TI O N S, T R E A T M E N T S, A N D P R O C E D U R E S  ...................... 3 4  
8  
A S S E S S M E N T O F S A F E T Y  ................................................................................................ 3 5  
8. 1  
S P E CI FI C A TI O N O F S A F E T Y P A R A M E T E R S  .............................................................. 3 5  
8. 1. 1  
D E FI NI TI O N O F A D V E R S E E V E N T S ( A E)  ......................................................................... 3 5  
8. 1. 2  
D E FI NI TI O N O F S E RI O U S A D V E R S E E V E N T S  ................................................................. 3 6  
8. 2  
C L A S SI FI C A TI O N O F A N A D V E R S E E V E N T  ................................................................ 3 7  
8. 2. 1  
S E V E RI T Y O F E V E N T  ........................................................................................................... 3 7  
8. 2. 2  
R E L A TI O N S HI P T O S T U D Y A G E N T  ................................................................................... 3 7  
8. 2. 3  
E X P E C T E D N E S S  .................................................................................................................... 3 7  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 4  of 9 9
 
 
 
8. 3  
TI M E P E RI O D/ F R E Q U E N C Y F O R E V E N T A S S E S S M E N T/ F O L L O W -U P  ................ 3 8  
8. 3. 1  
P O S T -S T U D Y A E A N D S A E  .................................................................................................. 3 8  
8. 4  
R E P O R TI N G P R O C E D U R E S  .............................................................................................. 3 8  
8. 4. 1  
A D V E R S E E V E N T R E P O R TI N G  ........................................................................................... 3 8  
8. 4. 2  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  ......................................................................... 3 9  
8. 4. 3  
 
8. 4. 4  
R E P O R TI N G O F P R E G N A N C Y  ............................................................................................. 4 1  
8. 5  
S T U D Y H A L TI N G R U L E S  ................................................................................................... 4 1  
8. 6  
S A F E T Y O V E R SI G H T  ......................................................................................................... 4 1  
9  
C LI NI C A L M O NI T O RI N G  ................................................................................................. 4 2  
1 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  .................................................................................. 4 2  
1 0. 1  
S T A TI S TI C A L D E SI G N M O D E L A N D A N A L Y TI C A L P L A N S  .................................... 4 2  
1 0. 2  
S T A TI S TI C A L H Y P O T H E S E S  ........................................................................................... 4 2  
1 0. 3  
A N A L Y SI S D A T A S E T S  ........................................................................................................ 4 2  
1 0. 4  
D E S C RI P TI O N O F S T A TI S TI C A L M E T H O D S  ............................................................... 4 3  
1 0. 4. 1  G E N E R A L A P P R O A C H  .......................................................................................................... 4 3  
1 0. 4. 2  A N A L Y SI S O F T H E P RI M A R Y E N D P OI N T  ........................................................................ 4 3  
1 0. 4. 3  A N A L Y SI S O F T H E S E C O N D A R Y E N D P OI N T S  ................................................................ 4 3  
1 0. 4. 4  P L A N N E D I N T E RI M A N A L Y S E S  ......................................................................................... 4 4  
1 0. 4. 5  M U L TI P L E C O M P A RI S O N/ M U L TI P LI CI T Y  ....................................................................... 4 4  
1 0. 4. 6  E X P L O R A T O R Y A N A L Y S E S  ............................................................................................... 4 4  
1 0. 5  
S A M P L E SI Z E ........................................................................................................................ 4 4  
1 0. 6  
M E A S U R E S T O MI NI MI Z E BI A S  ...................................................................................... 4 4  
1 0 . 6. 1 E N R O L L M E N T/ R A N D O MI Z A TI O N/ M A S KI N G P R O C E D U R E S  ...................................... 4 4  
1 0. 6. 2  E V A L U A TI O N O F S U C C E S S O F B LI N DI N G  ...................................................................... 4 4  
1 0. 6. 3  B R E A KI N G T H E S T U D Y B LI N D/ S U BJ E C T C O D E  ............................................................ 4 5  
1 1  
S O U R C E D O C U M E N T S A N D A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  ............ 4 5  
1 2  
E T HI C S/ P R O T E C TI O N O F H U M A N S U B J E C T S ........................................................... 4 5  
1 2. 1  
E T HI C A L S T A N D A R D  ......................................................................................................... 4 5  
1 2. 2  
I N S TI T U TI O N A L R E VI E W B O A R D ................................................................................. 4 5  
1 2. 3  
I N F O R M E D C O N S E N T P R O C E S S .................................................................................... 4 6  
1 2. 3 . 1 C O N S E N T F O R M S  .................................................................................................................. 4 6  
1 2. 3. 2  C O N S E N T P R O C E D U R E S A N D D O C U M E N T A TI O N  ........................................................ 4 6  
1 2. 4  
P A R TI CI P A N T A N D D A T A C O N FI D E N TI A LI T Y .......................................................... 4 6  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 5  of 9 9
 
 
 
1 2. 5  
F U T U R E U S E O F S T O R E D S P E CI M E N S  ......................................................................... 4 7  
1 3  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ................................................................ 4 7  
1 3. 1  
D A T A C O L L E C TI O N A N D M A N A G E M E N T R E S P O N SI BI LI TI E S  ............................ 4 7  
1 3. 1. 1  I N V E S TI G A T O R R E S P O N SI BI LI TI E S ................................................................................. 4 8  
1 3. 1. 2  S T U D Y FI L E S  .......................................................................................................................... 4 8  
1 3. 2  
S T U D Y R E C O R D S R E T E N TI O N  ....................................................................................... 4 8  
1 3. 3  
P R O T O C O L D E VI A TI O N S  ................................................................................................. 4 8  
1 3. 4  
P U B LI C A TI O N A N D D A T A S H A RI N G P O LI C Y  ............................................................ 4 9  
1 4  
FI N A N CI A L DI S C L O S U R E A N D C O N F LI C T O F I N T E R E S T P O LI C Y  .................... 5 0  
1 5  
S C H E D U L E O F E V E N T S  .................................................................................................... 5 1  
1 6  
R E F E R E N C E S  ....................................................................................................................... 5 3  
1 6. 1  
P U B LI S H E D R E F E R E N C E S  ............................................................................................... 5 3  
1 6. 2  
U N P U B LI S H E D R E F E R E N C E S  .......................................................................................... 5 6  
1 7  
A P P E N DI C E S  ........................................................................................................................ 5 7  
1 7. 1  
M O V E M E N T DI S O R D E R S O CI E T Y’ S U NI FI E D P A R KI N S O N’ S DI S E A S E R A TI N G 
S C A L E  .................................................................................................................................................. 5 8  
1 7. 2  
M O N T R E A L C O G NI TI V E A S S E S S M E N T  ....................................................................... 6 4  
1 7. 3  
S C H W A B A N D E N G L A N D A C TI VI TI E S O F D AI L Y LI VI N G  ..................................... 6 5  
1 7. 4  
C LI NI C A L I M P R E S SI O N O F S E V E RI T Y I N D E X –  P A R KI N S O N’ S DI S E A S E  ......... 6 6  
1 7. 5  
P A R KI N S O N’ S DI S E A S E Q U A LI T Y O F LI F E Q U E S TI O N N AI R E -3 9  ........................ 6 7  
1 7. 6  
S H E E H A N S UI CI D A LI T Y T R A C KI N G S C A L E  .............................................................. 7 2  
1 7. 7  
M O V E M E N T DI S O R D E R S O CI E T Y’ S P A R KI N S O N’ S DI S E A S E C RI T E RI A  .......... 7 4  
1 7. 8  
H A U S E R 3 -D A Y P A TI E N T DI A R Y  .................................................................................... 7 5  
1 7. 9  
M O DI FI C A TI O N O F DI E T I N R E N A L DI S E A S E F O R M U L A  ...................................... 7 6  
1 7. 1 0  
 
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 6  of 9 9
 
 
 
1 7. 1 1  C LI NI C A L E V A L U A TI O N O F LI V E R I N J U R Y  .............................................................. 7 8  
1 7. 1 1. 1  I N T R O D U C TI O N .................................................................................................................. 7 8  
1 7. 1 1. 2  P R O C E D U R E S  ....................................................................................................................... 7 9  
1 7. 1 2  P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C, A N D F A C S 
S A M P LI N G  .......................................................................................................................................... 8 1  
1 7. 1 2. 1  T A B L E O F P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C, A N D F A C S 
S A M P LI N G  ............................................................................................................................................ 8 1  
1 7. 1 3  P H A R M A C O KI N E TI C M E A S U R E S A N D E V A L U A TI O N  ............................................ 8 1  
1 7. 1 3. 1  TI MI N G O F P H A R M A C O KI N E TI C B L O O D S A M P LI N G  ................................................. 8 1  
1 7. 1 3. 2  P H A R M A C O KI N E TI C S A M P L E H A N D LI N G A N D S HI P M E N T  ..................................... 8 2  
1 7. 1 3. 3  P H A R M A C O KI N E TI C D A T A E V A L U A TI O N  ................................................................... 8 2  
1 7. 1 3. 4  H A N D LI N G O F MI S SI N G BI O A N A L Y TI C A L D A T A  ....................................................... 8 2  
1 8  
R E VI SI O N HI S T O R Y  ........................................................................................................... 8 3  
1 8. 1  
S U M M A R Y O F C H A N G E S  .................................................................................................. 8 3  
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 7  of 9 9
 
 
 
L I ST O F A B B R E VI A TI O N S  
A D  
Al z h ei m er’s dis eas e  
A E  
A d v ers e e v e nt  
A E SI  
A d v ers e e v e nt of s p eci al i nt erest  
A L T  
Al a ni n e a mi n otr a nsf er as e  
A P  
Al k ali ne p h os p h at as e  
a P T T  
A cti vat e d p arti al t hr o m b o pl asti n  ti m e 
A S T  
As p art at e a mi n otr a nsf er as e  
A U C  
Are a u n d er t h e c ur v e  
B C R P  
Br e ast ca n c er r esist a n ce pr ot ei n  
b.i. d.  
T wi ce per d a y  
B L Q  
B el o w t h e li mit of q u a ntifi cati o n  
B P  
Bl o o d press ur e  
C B C  
C o m pl et e bl o o d c o u nt  
 
 
 
 
 
 
C F R  
C o d e of Fe d eral R e g ul ati o ns  
CI SI -P D  
Cli nic al I m pr essi o n of Se v erit y I n d e x –  Par ki ns o n’s Dise ase  
C K  
Cr e ati ni n e ki n as e  
C K -M B  
Cr e ati ni n e ki n as e -M B  
C LI A  
Cli nic al L a b or at or y I m pr o v e me nt A m e n d m e nts 
C ma x  
M a xi m u m pl as m a c o nc e ntrati o n  
C M P  
Cli nic al M o nit ori n g Pl a n  
C N S  
C e ntral n er v o us s yst e m  
C O VI D -1 9  
C or o n a vir us dis e as e 2 0 1 9  
C P K  
Cr e ati n e p h os p h o ki n as e  
C R A  
Cli nic al R es earc h A ss o ci at e 
C R F  
C as e R e p ort F or m  
C R O  
C o ntr a ct Rese ar c h Or g a nizati o n  
C R P  
C -r e acti v e pr otei n 
C S F  
C er e br os pi n al fl ui d  
 
 
DI LI  
Dr u g -i n d u ce d li v er i nj ur y 
D N A  
D e o x yri b o n u cl ei c a ci d  
E C G  
El e ctr o car di o gr a m  
E D T A  
Et h yle n e di a mi n et etr a ac eti c a ci d  
e G F R  
Esti mat e d g l o mer ular filtrati o n rat e  
E M A  
E ur o p e a n M e di ci n es A g e n c y  
E N T  
Ears, n os e , t hr oat 
 
 
E u dr a C T  
E ur o p e a n U ni o n Dr u g R e g ul ati n g A ut h oriti es Cli ni cal Tri als D at a b as e  
F A C S  
Fl o w c yt o metr y /fl u or es ce n c e-a cti vat e d cell s orti n g   

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 8  of 9 9
 
 
 
F D A  
F o o d a n d Dr u g A d mi nistr ati o n  
G C P  
G o o d Cli nic al Pr a cti ce  
G F R  
Gl o m er ul ar filtrati o n r at e  
H B V  
H e p atitis B v ir us 
H C V  
H e p atitis C vir us  
H E V  
H e p atitis E vir us  
HI P A A  
H e alt h I ns ur a n c e P ort a bilit y a n d A c c o u nt a bilit y A ct  
HI V  
H u m a n i m m u n o d efi ci e n c y vir us  
H P L C -M S/ M S  
Hi g h p erf or ma n c e li q ui d c hr o m at o gr a p h y, ta n de m m ass sp e ctr o m etr y  
I C H 
I nt er nati o n al C o nf er e nc e o n H ar m o ni z ati o n 
I C H E 6 R 2 
I nter nati o nal C ou ncil f or  Har m o nizati o n of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use G ui da nce f or I n d ustr y, G o o d Cli nical Practice: 
C o ns oli date d G ui da nce, Re visi o n 2  
I E C  
I n d e p e n d e nt Et hi cs C o m mitt ee 
I g G 
I m m u n o gl o b uli n G 
I g M 
I m m u n o gl o b uli n M 
I N D 
I n v esti g ati o n N e w Dr u g A p pli c ati o n  
I N R 
I nt er nati o n al n or m ali ze d r ati o 
I R B 
I nstit uti o n al R e vi e w B o ar d  
I S F 
I n v esti g at or Sit e Fil e 
I T T 
I nt e nt-t o-tr e at 
L D H  
La ct at e d e h y dr o g e n ase  
 
 
M D S -P D  
M o v e m e nt Dis or d er S o ci et y’s Cli ni cal Di a g n osti c Crit eri a f or Par ki ns o n’s 
Dise ase  
M D S -U P D R S  
M o v e m e nt Dis or d er S o ci et y’s U nifi e d Par ki ns o n’s Dise ase R ati n g Sc al e  
M e d D R A  
M e di c al Dicti o n ar y f or R e g ul at or y A cti viti es  
mI T T  
M o difi e d i nte nt -t o-tr eat 
M o C A  
M o ntre al C o g niti ve Ass ess m e nt  
M P T P  
1 -m et h yl -4 -p h e n yl -1, 2, 3, 6 -t etr a h y dr o p yri di n 
N O A  
N ot a n al y ze d  
N O P  
N o p ea k d et ect a ble  
N O R  
N o v ali d r es ults  
N O S  
N o s a m ple a v ail a bl e  
 
 
 
 
P D  
Par ki ns o n’s dis ease  
P D D  
Par ki ns o n’s dis ease de m e nti a  
P D Q -3 9  
Par ki ns o n’s Dis e as e Q u alit y of Life Q u esti o n n aire -3 9  
 
 
P G X  
P h ar m a c o g e n o mi c  
p H  
P ot e nti al of h y dr o g e n  
P K  
P h ar m a c o ki neti c (s) 
P P  
P ol y pr o p yle n e  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 9  of 9 9
 
 
 
P T  
Pref err e d T er m  
Q R S  
Q R S i nt er val o n E C G  
Q T  
Q T i nt er v al o n E C G 
R B C  
R e d bl o o d c ell c o u nt  
R N A  
Ri b o n u cl ei c aci d  
S A E  
Seri o us a d vers e e v e nt  
S A P  
St atisti c al a n al yti c al p l a n 
S E -A D L  
Sc h w a b a n d E n gla n d A cti viti es of D ail y Li vi n g  
S O C  
S yst e m Or g a n Cl ass  
S -S T S  
S h e e h a n -S ui ci d alit y Tr ac ki n g Sc al e  
S U S A R  
S us p e ct e d u n e x p e ct e d s eri o us a d v ers e re a cti o n  
U L N  
U p p er li mit of n or m al  
U S  
U nit e d St at es  
w A M D  
W et a g e -r el at e d ma c ul ar d e g e ner ati o n 
W B C  
W hit e bl o o d c ell c o u nt  
W O C B P  
W o m e n of c hil d b e ari n g p ot e nti al  
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 1 0  of 9 9
 
 
 
P R O T O C O L A P P R O V A L P A G E  
 
 
 
St u d y Title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o 
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects wit h 
P ar ki ns o n’s Disease o n  Sta ble  D o pa mi ner gic Treat me nt  
Pr ot oc ol N u m ber:  
A K S T 4 2 9 0 -2 1 1  
Versi o n/ Date:  
V 4 .0 _ 2 2 M A Y 2 0 2 0  
S p o ns or Na me a n d 
A d dress:  
 
Al ka hest, I nc.  
1 2 5  S h ore wa y R oa d , S uite D 
Sa n Carl os, C A 9 4 0 7 0  
 
 
 
I, t he u n d ersi g ne d, h a ve rea d a n d a p pr o ve t his pr ot oc ol a n d a gree o n its c o nte nt. It is c o nfir me d t hat 
t he i nf or mati o n a n d g ui d a nce gi ve n i n t his pr ot oc ol c o m plies wit h scie ntific pri nci ples, t he g ui deli n es 
of G o o d Cli nical Practice, t he Declarati o n of Helsi n ki i n t he latest rele va nt versi o n, a n d a p plica ble 
le gal a n d re g ul at or y re q uire me nts. 
 
 
 
 
A p pr o ve d b y:  
 
 
  
 
 
 
 
 Ma y 2 2 , 2 0 2 0 
S p o ns or Re prese ntati ve ( pri nt)  
 Si g nat ure  
 Date  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1  
 
 
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                   Pa ge 1 1  of 9 9
 
 
 
S T A T E M E N T  O F C O M P LI A N C E  
 
Pr ot oc ol Title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o 
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects 
wit h P ar ki ns o n’s Disease o n Sta ble D o pa mi ner gic 
Treat me nt  
Pr ot oc ol N u m ber:  
A K S T 4 2 9 0 -2 1 1  
 
Versi o n/ Date : 
V 4 .0 _ 2 2 M A Y 2 0 2 0  
 
 
B y m y si g nat ure, I:  
• 
C o nfir m t hat m y staff a n d I ha ve caref ull y rea d a n d u n dersta n d t his pr ot oc ol or pr ot oc ol a me n d me nt , 
ha ve recei ve d t he I n vesti gat or Br oc h ure , a n d are t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he 
i n vesti gati o nal a ge nt  descri be d herei n.  
• 
A gree t o c o m pl y wit h t he c o n d uct a n d ter ms of t he st u d y s pecifie d h erei n a n d wit h a n y ot her st u d y 
c o n d uct pr oce d ures pr o vi de d b y t he S p o ns or, Al ka hest, I nc., or t heir desi g nee . 
• 
A gree t o ass u me res p o nsi bilit y f or t he pr o per c o n d uct of t he st u d y at t his site, i ncl u di n g c o m pl yi n g 
wit h c urre nt rele va nt versi o ns of t he F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns, E ur o pea n 
Me dici nes A ge nc y ( E M A)  re g ulati o ns, l ocal dr u g la ws, t he I nter nati o nal C ou n cil f or Har m o nizati 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 C P g ui deli nes, t he Declarati o n of 
Helsi n ki , a n d all a p plica ble r ules, re g ulati o ns, a n d fe deral, state, a n d l ocal la ws relati n g t o t he c o n d uct 
of cli nical st u dies a n d t he pr otecti o n of h u ma n s u bjects.  
• 
A gree n ot t o i m ple me nt de viati o ns fr o m or c ha n ges t o t he pr ot oc ol or pr ot oc ol a me n d me nts wit h o ut 
a gree me nt fr o m t he S p o ns or a n d pri or s u b missi o n t o a n d writte n a p pr o val ( w here re q uire d) fr o m t he 
I nstit uti o nal Re vie w B oar d (I R B) or I n de pe n de nt Et hics C o m mittee (I E C), e xce pt w he n necessar y t o 
eli mi nate a n i m me diate hazar d t o t he s u bjects, or f or a d mi nistrati ve as pects of t he st u d y ( w here 
per mitte d b y all a p plica ble re g ulat or y re q uire me nts).  
• 
A gree t o o nsite m o nit ori n g of all s o urce d oc u me nts b y Al ka hest, I nc.  or desi g nee a n d t o o nsite 
i ns pecti o n of s o urce d oc u me nts b y a p pr o priate re g ulat or y a ut h orities, i ncl u di n g b ut n ot li mite d t o t he 
F D A, E M A , l ocal g o ver ni n g re g ulat or y b o dies, a n d I R B/I E C i ns pect ors. 
 
 
 
 
 
 
I n v esti gat or's Si g nat ure 
 
Date  
 
 
 
Pri nt Na me  
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 2  of 9 9   
 
P R O T O C O L S U M M A R Y  
 
 
Title:  
A Ra n d o mize d, D o u ble -Bli n d, Place b o -C o ntr olle d St u d y t o 
E val uate t he Efficac y a n d Safet y of A K S T 4 2 9 0 i n S u bjects wit h 
Par ki ns o n’s Disease o n Sta ble D o pa mi ner gic Treat me nt  
 
Précis:  
T his is a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o 
assess t he efficac y a n d safet y of  A K S T 4 2 9 0 i n s u bjects wit h  
Par ki ns o n’s d isease ( P D). 
 
T he st u d y  will e nr oll  a p pr o xi matel y 1 2 0  s u bjects w h o  will be 
ra n d o mize d i n a 1 : 1 rati o t o acti ve treat me n t i n Ar m 1 
(a p pr o xi matel y 6 0  s u bjects) or place b o i n Ar m 2 (a p pr o xi matel y 6 0  
s u bjects). S u bjects will ta ke 4 0 0 m g of A K S T 4 2 9 0 or place b o ta ke n 
orall y, t wice per da y (b.i. d. ) f or a t otal dail y d ose of 8 0 0 m g. T he 
st u d y d urati o n f or t he s u bjects will be a p pr o xi matel y  1 8  wee ks 
i ncl u di n g scree ni n g, 1 2 wee ks of treat me nt, a n d 4  wee ks of f oll o w -
u p.  
 
O bjecti ves:  
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effects of 
A K S T 4 2 9 0 o n m ot or f u ncti o n i n t he practicall y defi ne d off -
me dicati o n state , defi ne d as ≥1 2 ho urs  off le v o d o pa,  i n s u bjects 
wit h P D. T he sec o n dar y o bjecti ves i ncl u de t he assess me nt of t he 
safet y of A K S T 4 2 9 0 i n s u bjects wit h P D as well as t he p ote ntial 
effects o n cli nical f u ncti o n a n d acti vities of dail y li vi n g. T he 
e x pl orat or y o bjecti ve s i ncl u de a nal ysis of p har mac o ki netic  ( P K) 
para meters f oll o wi n g t wice dail y d osi n g wit h A K S T 4 2 9 0. 
A d diti o nall y, fl o w c yt o metr y, p har mac o ge n o mic , a n d bi o mar ker 
e val uati o ns will be c o n d ucte d o n bl o o d a n d plas ma sa m ples . 
B ra d y ki nesia, tre m or, ge neral acti vit y, a n d slee p  ma y be assesse d 
wit h  a weara ble de vice.  I n c o nse nti n g s u bjects, fecal sa m ples will 
be o btai ne d at scree ni n g a n d f oll o wi n g treat me nt t o assess p ote ntial 
micr o bi o me c ha n ges .  
 
E n d p oi nts:  
Pri mar y E n d p oi nt s:  
• 
C ha n ge fr o m Baseli ne  ( Da y 1) i n m ot or f u ncti o n d uri n g t he 
practicall y defi ne d off -me dicati o n state , defi ne d as ≥1 2 
h o u rs off le v o d o pa,  at Wee k 1 2 ( Da y 8 4) as meas ure d b y 
M o ve me nt Dis or der S ociet y's U nifie d Par ki ns o n's Disease 
Rati n g Scale ( M D S -U P D R S), Part 3.  
 
Sec o n dar y E n d p oi nt s:  
• I nci de nce of treat me nt-e mer ge nt a d verse e ve nts ( A Es) a n d 
seri o us a d verse e ve nts ( S A Es) i de ntifie d b y t he Me dical 
Dicti o nar y f or Re g ulat or y Acti vities  ( Me d D R A) preferre d 
ter m ( P T) a n d gr o u pe d b y Me d D R A S yste m Or ga n Class 
( S O C). 
• 
I nci de nce of a b n or malities or cli nicall y -si g nifica nt c ha n ges 
fr o m Baseli ne  i n la b orat or y test data, vital si g n 
meas ure me nts, a n d electr ocar di o gra ms ( E C Gs) . 
• C ha n ge fr o m Baseli ne  ( Da y 1) i n cli nical f u ncti o n, m ot or 
f u ncti o n, a n d acti vities of dail y li vi n g at Wee k 1 2 ( Da y 8 4) 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 3  of 9 9   
 
d uri n g t he o n -me dicati o n state as assesse d b y:  
o  M D S -U P D R S Parts 1 -4  
o  M o ntreal C o g niti ve Assess me nt ( M o C A)  
o  S c h wa b a n d E n gla n d Acti vities of Dail y Li vi n g 
( S E-A D L) Scale  
o  Cli nical I m pressi o n of Se verit y I n de x –  P D ( CI SI -
P D)  
o  P D Q ualit y of Life Q uesti o n naire -3 9 ( P D Q -3 9)  
o  S he e ha n-S uici dalit y Trac ki n g Scale ( S-S T S)  
o  1 0 -meter ti me d wal k  ( will als o be assesse d i n t he 
off -me dicati o n state ) 
o  Ha user 3 -Da y Patie nt Diar y  
 
E x pl orat or y  E n d p oi nt s: 
• 
C ha n ges i n c o nce ntrati o n of A K S T 4 2 9 0 or its maj or 
meta b olites i n plas ma at vari o us ti me p oi nts.  
• 
Fl o w c yt o metric a nal yses a n d e val uati o n of 
p har mac o ge n o mic c haracteristics  a n d bi o mar kers i n bl o o d 
a n d plas ma sa m ples . 
• 
C ha n ges i n bra d y ki nesia , tre m or, ge neral acti vit y, a n d slee p  
as meas ure d b y a n F D A -clear e d weara ble se ns or de vice . 
• 
I n c o nse nti n g s u bjects ( o pti o nal): c haracterizati o n of  t he 
c o m p ositi o n a n d f u ncti o n of t he fecal g ut micr o bi o me.  
 
P o p ulati o n:  
A p pr o xi matel y 1 2 0  s u bjects bet wee n 5 0 a n d 8 0  years of a ge wit h a 
dia g n osis of P D  o n d o pa mi ner gic treat me nt . Ass u mi n g a dr o p -o ut 
rate of 1 0 %, e nr oll me nt at t his le vel will yiel d a p pr o xi matel y 1 0 8  
e val ua ble s u bjects . 
 
P hase:  
2  
 
N u m ber of Sites:  
A p pr o xi matel y 3 0 sites are pla n ne d gl o ball y  
Descri pti o n  of  St u d y A ge nt:  
A K S T 4 2 9 0 : 
 
 
St u d y D urati o n:  
A p pr o xi matel y 1 5  m o nt hs  
 
S u bject  Partici pati o n : 
 
A p pr o xi matel y 1 8  wee ks   
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 5  of 9 9   
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 8  of 9 9   
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
3  
O B J E C TI V E S A N D P U R P O S E  
 
T he pri mar y o bjecti ve of t he st u d y is t o assess t he effects of A K S T 4 2 9 0 o n m ot or f u ncti o n i n t he practicall y 
defi ne d off -me dicati o n state i n s u bjects wit h P D. T he sec o n dar y o bjecti ves i ncl u de t he assess me nt of t he safet y of 
A K S T 4 2 9 0 i n s u bjects wit h P D as well as t he p ote ntial effects o n cli nical f u ncti o n , c o g niti o n, a n d acti vities of 
dail y li vi n g. T h e e x pl orat or y o bjecti ve s i ncl u de a nal ysis of P K  para meters f oll o wi n g t wice dail y d osi n g wit h 
A K S T 4 2 9 0. A d diti o nall y, fl o w c yt o metr y/fl u oresce nce-acti vate d cell s orti n g ( F A C S), p har mac o ge n o mic , a n d 
bi o mar ker e val uati o ns will be c o n d ucte d o n bl o o d a n d plas ma  sa m ples. Bra d y ki nesia, tre m or, ge neral acti vit y, a n d 
slee p ma y be assesse d wit h a weara ble se ns or de vice.  I n c o nse nti n g s u bjects, fecal sa m ples will be o btai ne d at 
scree ni n g a n d f oll o wi n g treat me nt t o assess p ote ntial micr o bi o me c ha n ges .  
 
4  
S T U D Y D E SI G N A N D E N D P OI N T S  
4. 1  
D E S C RI P TI O N O F T H E S T U D Y D E SI G N  
 
T his is a ra n d o mize d, d o u ble-bli n d, place b o -c o ntr olle d st u d y c o n d ucte d at a p pr o xi matel y 3 0 sites gl o ball y . 
D uri n g t he scree ni n g p eri o d ( Da y -1 4 t hr o u g h Da y -7 ), s u bjects will u n der g o  all scree ni n g a ssess me nts t o assess 
eli gi bilit y.  I n c o nse nti n g s u bjects, fecal sa m ples will als o be c ollecte d at scree ni n g f or micr o bi o me assess me nt. 
D uri n g t he B aseli ne Vi sit ( Da y 1 ), s u bjects will be ra n d o mize d i n a 1: 1 rati o t o A K S T 4 2 9 0 ( Ar m 1) or place b o 
( Ar m 2). Su b jects will t he n c o m plete  m ot or assess me nt i n b ot h o n-me dicati o n a n d off -me dicati o n states , as well 
as testi n g f or n o n-m ot or s y m pt o ms of P D,  acti vities of dail y li vi n g  a n d q ualit y of life .  
 
Safet y a n d t olera bilit y assess me nts will occ ur at e ver y visit . M ot or f u ncti o n a n d sec o n dar y e n d p oi nts will be 
c o n d ucte d  at Baseli ne a n d at peri o dic i nteri m visits f oll o wi n g d osi n g. I n t he e ve nt of earl y ter mi nati o n, a s u bject 
w h o has  recei ve d at least 1  d ose ( 4 0 0  m g) of A K S T 4 2 9 0  or place b o , will  u n der g o t he e n d of treat me nt pr oce d ures 
u nless t he s u bject has wit h dra w n c o nse nt . A c o m pre he nsi ve efficac y a n d safet y assess me nt of all data i n t ot o will 
be c o n d ucte d at t he e n d of t he st u d y.  
 
T he o verall d urati o n of t he st u d y /recr uit me nt peri o d is a p pr o xi matel y 1 0  m o nt hs fr o m st u d y i nitiati o n 
(i.e., foll o wi n g c o nse nt of f irst s u bject) t o st u d y c o m pleti o n (i.e., last s u bject, last visit). T he s u bject partici pati o n 
peri o d is a p pr o xi matel y 1 8  wee ks  fr o m S cree ni n g t hr o u g h E n d of S t u d y, u nless pre mat urel y disc o nti n ue d.  
 
4. 2  
S T U D Y E N D P OI N T S  
 
4. 2. 1  
P RI M A R Y E N D P OI N T  
 
Pri mar y E n d p oi nt:  
• 
C ha n ge fr o m Baseli ne ( Da y 1) i n m ot or f u ncti o n d uri n g t he practicall y defi ne d off -me dicati o n  state, 
defi ne d as ≥1 2 h o u rs off le v o d o pa,  at Wee k 1 2 ( Da y 8 4) as meas ure d b y t he M D S -U P D R S  Part 3.   

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 1 9  of 9 9   
 
 
4. 2. 2  
S E C O N D A R Y E N D P OI N T S  
 
Sec o n dar y E n d p oi nt s:  
• 
I nci de nce of treat me nt-e mer ge nt A Es a n d S A Es i de ntifie d b y Me d D R A P T a n d gr o u pe d b y Me d D R A 
S O C.   
• 
I nci de nce of a b n or malities or cli nicall y-si g nifica nt c ha n ges fr o m Baseli ne i n la b orat or y test data, vital 
si g n meas ure me nts, a n d E C Gs. 
• 
Baseli ne ( Da y 1) a n d l o n git u di nal c ha n ge i n cli nical f u ncti o n, m ot or f u ncti o n, a n d acti vities of dail y 
li vi n g at Wee k 1 2 ( Da y 8 4) d uri n g t he o n-me dicati o n state as assesse d b y  t he f oll o wi n g:  
o  M D S -U P D R S  Parts 1 -4  (Fa h n 1 9 8 7 , G oetz 2 0 0 8 )(Secti o n 1 7 . 1) 
o  M o C A ( Nasre d di ne 2 0 0 5 )(Secti o n 1 7. 2 ) 
o  S E -A D L Scale  (Sc h wa b 1 9 6 8 )(Secti o n 1 7. 3 ) 
o  CI SI -P D ( Marti nez -Marti n 2 0 0 6 )(Secti o n 1 7. 4 )  
o  P D Q -3 9  (Pet o 1 9 9 8 )(Secti o n 1 7. 5 ) 
o  S -S T S ( S hee ha n 2 0 1 4 )(Secti o n 1 7. 6 ) 
o  1 0 -meter ti me d wal k  (La n g 2 0 1 6 )(als o assesse d i n t he off-me dicati o n state)  
o  Ha user 3 -Da y Patie nt Diar y ( Ha user 2 0 0 0 , Ha user 2 0 0 4 )(Secti o n 1 7. 8 ) 
 
4. 2. 3  
E X P L O R A T O R Y E N D P OI N T S  
 
E x pl orat or y E n d p oi nts:  
• 
C ha n ges i n c o nce ntrati o ns of A K S T 4 2 9 0 or its maj or meta b olites i n plas ma at vari o us ti me p oi nts. 
• 
Fl o w c yt o metric a nal yses ( F A C S) a n d e val uati o n of p har mac o ge n o mic c haract eristics  a n d bi o mar kers i n 
bl o o d a n d plas ma sa m ples . 
• 
C ha n ges i n bra d y ki nesia , tre m or, a n d slee p  acti vit y as meas ure d b y a weara ble se ns or de vice . 
• 
I n c o nse nti n g s u bjects ( o pti o nal): c haracterizati o n of  t he c o m p ositi o n a n d f u ncti o n of t he fecal g ut 
micr o bi o me  (Sc h wiertz 2 0 1 8 , Si n g h 2 0 1 9 ). 
 
5  
S T U D Y E N R O L L M E N T A N D WI T H D R A W A L  
5. 1  
I N C L U SI O N C RI T E RI A 
 
I n or der t o be eli gi ble f or i ncl usi o n, all s u bjects m ust meet t he f oll o wi n g criteri a: 
1.  A ge d 5 0 -8 0  years at ti me of e nr oll me nt, i ncl usi ve.  
2.  Dia g n osis of cli nicall y esta blis he d or cli nicall y pr o ba ble P D acc or di n g t o M D S -P D  criteria  
(P ost u ma  2 0 1 5 ) (Secti o n 1 7. 7 ) wit h at least 1 y ear of P D s y m pt o ms.  
3.  M o difie d H oe h n a n d Ya hr ≤2. 5 . 
4.  Ha ve n ota ble m ot or w orse ni n g d uri n g off -me dicati o n state.  
5.  Clear -c ut i m pr o ve me nt of m ot or res p o nse t o le v o d o pa me dicati o ns, as assesse d b y t he i n vesti gat or . 
6.  M ust be o n sta ble  d o pa mi ner gic t hera p y ( e. g., le v o d o pa, d o pa mi ne a g o nists, m o n oa mi ne o xi dase 
i n hi bit ors, catec h ol-O -met h yl tra nsferase i n hi bit ors, a ma nta di ne),  f or at least 8  wee ks pri or t o 
e nr oll me nt a n d re mai n o n sta ble d ose  d uri n g t he 1 2 -wee k treat me nt peri o d.  
7.  If o n me dicati o ns f or c o g niti o n (e. g., ri vasti g mi ne, gala nta mi ne, d o ne pezil, me ma nti ne), m ust be o n 
sta ble d osa ge f or at least 8 wee ks pri or t o baseli ne. 
8.  If o n a nti de pressa nt or ne ur ole ptic me dicati o ns, m ust be o n sta b le d osa ge f or at least 8 wee ks pri or t o 
e nr oll me nt. 
9.  A bilit y t o tra vel t o cli nic i n t he practicall y defi ne d off -me dicati o n state, defi ne d b y wit h dra wal of 
le v o d o pa pri or t o t he cli nic visit f or at least 1 2 h o urs, or a bilit y t o sta y o ver ni g ht i n a n i n patie nt  
me dical setti n g o ne ni g ht pri or t o off -me dicati o n assess me nt.  
1 0.  Fe male  s u bjects m ust n ot be pre g na nt or breastfee di n g. W o me n of c hil d beari n g p ote ntial  ( W O C B P) 
m ust ha ve a ne gati ve pre g na nc y test at Scree ni n g . W O C B P  m ust a gree t o use hi g hl y effecti ve 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 0  of 9 9   
 
c o ntrace pti o n  w hic h i ncl u des c o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n ( oral, i ntra va gi nal, tra ns der mal), pr o gest o ge n -
o nl y h or m o nal c o ntrace pti o n ass oci ate d wit h i n hi biti o n of o v ulati o n ( oral, i njecta ble, i m pla nta ble), 
i ntra uteri ne de vice, i ntra uteri ne h or m o ne-releasi n g s yste m, bilateral t u bal occl usi o n, or vasect o mize d 
part ner  (Cli nical Trial Facilitati o n Gr o u p 2 0 1 4 ) pri or t o st u d y e ntr y. A w o ma n is c o nsi dere d of 
c hil d beari n g p ote ntial f oll o wi n g me narc he a n d u nt il bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d a w o ma n bec o me pre g na nt or s us pect s he is 
pre g na nt w hi le s he or her part ner is partici pati n g i n t he st u d y, s he s h o ul d i nf or m her treati n g 
p h ysicia n i m me diatel y . Male s u bjects m ust be willi n g t o use a barrier met h o d c o ntrace pti o n.  
1 1.  T he s u bject m ust be a ble t o f oll o w t he st u d y pr oce d ures , recei ve t he treat me nt in t he esta blis he d 
ti mefra me, a n d c o nti n ue d uri n g t he f oll o w-u p i nter val .  
1 2.  T he s u bject m ust be a ble t o u n dersta n d t he pr oce d ures a n d a gree t o c o m plete t he re q uire d 
assess me nts. 
1 3.  Pr o vi de a si g ne d a n d date d i nf or me d c o nse nt f or m i n acc or da nce wit h l ocal re g ula ti o ns a n d/ or 
I R B/I E C g ui deli nes.  
 
5. 2  
E X C L U SI O N C RI T E RI A  
 
A n i n di vi d u al  will n ot be eli gi ble f or i ncl usi o n if a n y of t he f oll o wi n g criteri a a p pl y : 
1.  Sec o n dar y or at y pical par ki ns o nia n s y n dr o mes, f or e xa m ple, patie nts wit h par ki ns o nis m fr o m 
e nce p halitis, meta b olic dis or ders, vasc ular par ki ns o nis m, dr u g -i n d uce d par ki ns o nis m, m ulti ple 
syste m atr o p h y, cortic o basal g a n glia d e ge nerati o n, p r o gressi ve su pra n uclear p als y, Le w y b o d y 
d e me ntia.   
2.  Me dical hist or y or c o n dit i o n:  
•  
U nc o ntr olle d dia betes mellit us, wit h he m o gl o bi n A 1c ( H b A 1c) > 8 % .  
•  
M y ocar dial i nfarcti o n or str o ke wit hi n 1 2 m o nt hs of scree ni n g . 
•  
Si g nifica nt car diac arr h yt h mia .  
•  
Acti ve blee di n g dis or der . 
•  
Maj or s ur ger y wit hi n 1 m o nt h of scree ni n g or pla n ne d wit hi n t he st u d y peri o d . 
•  
C urre nt, acti ve li ver disease: > 3 -f ol d ele vati o n of li ver e nz y mes (ala ni ne a mi n otra nsferase 
[ A L T] a n d as partate a mi n otra nsferase [ A S T] o ver u p per li mit of n or mal). 
•  
U nc o ntr olle d hi g h bl o o d press ure (s yst olic bl o o d press ure of 1 6 0 m m H g or hi g her a n d/ or 
diast olic bl o o d press ure of 1 0 0 m m H g or hi g her) des pite a de q uate treat me nt d uri n g t he 3 
m o nt hs pri or t o d osi n g . 
•  
P ositi ve scree ni n g  test res ult f or he patitis B vir us ( H B V) , he patitis C vir us ( H C V) , or h u ma n 
i m m u n o deficie nc y vir us ( HI V).  
3.  
 
  
4.  
 
 
5.  
 
6.  Re nal f u ncti o n as defi ne d b y esti mate d gl o mer ular filtrati o n rate (e G F R) < 4 5 m L/ mi n/ 1. 7 3 m 2 
usi n g t he M o dificati o n of Diet i n Re nal Disease ( M D R D) st u d y e q uati o n  (Secti o n 1 7. 9 ).  
7.  
 
 
8.  
 
9.  Hist or y of a n y brai n s ur ger y f or P D ( e. g., palli d ot o m y, dee p brai n sti m ulati o n, or fetal tiss ue 
tra ns pla nt). 
1 0.  
 
 
 
1 1.  Cli nicall y rele va nt a b n or mal la b orat or y  val ue at scree ni n g, i ncl u di n g he mat ol o g y, bl o o d c he mistr y, 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 1  of 9 9   
 
or uri nal ysis (la b orat or y testi n g ma y be re peate d o nce d uri n g t he scree ni n g p hase).  
1 2.  C o n diti o ns affecti n g t he peri p heral or ce ntral ner v o us s yste m, u nless relate d t o P D , t hat w o ul d 
affect t he a bilit y t o a de q uatel y perf or m t he M D S -U P D R S a n d m ot or assess me nts: i.e., se vere 
se ns or y ne ur o pat h y affecti n g ar m or le g f u ncti o n, or str o ke affecti n g m ot or or gait f u ncti o n.  
1 3.  Si g nifica nt alc o h ol or dr u g a b use wit hi n past 2 years.  
1 4.  Ba se d o n E C G rea di n g, s u bjects wit h a ris k of Q T pr ol o n gati o n i ncl u di n g: 
•  
A baseli ne pr ol o n gati o n of Q Tc ( usi n g Fri dericia’s f or m ula: ≥ 4 5 0 ms i n me n a n d ≥ 4 7 0 ms 
i n w o me n) wit h c o nfir mati o n o n a re peat E C G.  
•  
A hist or y of a d diti o nal ris k fact ors f or T orsa des de p oi ntes arr h yt h mia ( e. g., heart fail ure, 
h y p o kale mia, fa mil y hist or y of L o n g Q T S y n dr o me, etc.) . 
•  
T he use of c o nc o mita nt me dicati o ns k n o w n t o pr ol o n g t he Q T/ Q Tc i nter val . 
1 5.  Si g nifica nt me dical c o n diti o ns (as deter mi ne d b y me dical hist or y, e xa mi nati o n, a n d cli nical 
i n vesti gati o ns at scree ni n g) t hat ma y, i n t he o pi ni o n of t he i n vesti gat or, res ult i n t he a n y of t he 
f oll o wi n g:  
•  
P ut t he patie nt at ris k beca use of partici pati o n i n t he st u d y .  
•  
I nfl ue nce t he res ults of t he st u d y.  
•  
Ca use c o ncer n re gar di n g t he patie nt’s a bilit y t o partici pate i n t he st u d y . 
•  
I ncl usi o n of v ul nera ble pers o ns b y l ocal re g ulati o n (e. g., i m pris o ne d or i nstit uti o nalize d).  
1 6.  Mali g na nc y f or w hic h t he patie nt has u n der g o ne resecti o n, ra diati o n or c he m ot hera p y wit hi n past 
5  years (treate d ba sal cell carci n o ma or f ull y c ure d s q ua m o us cell carci n o ma are all o we d). 
1 7.  C o nc urre nt partici pati o n i n a n ot her i nter ve nti o nal cli nical trial ; pri or cli nical trial s u bjects m ust 
ha ve bee n off st u d y a ge nts f or at least 3 0 da ys f or s mall m olec ules, 4 m o nt hs f or disease m o dif yi n g 
t hera pies, a n d 1 year f or vacci ne or i m m u n ot hera p y trials pri or t o scree ni n g. 
 
5. 3  
S T R A T E GI E S F O R R E C R UI T M E N T A N D R E T E N TI O N  
 
T he S p o ns or d oes n ot a ntici pate a n y s pecific c halle n ges i n meeti n g recr uit me nt g oals of e nr olli n g a n d retai ni n g  a 
t otal of 1 2 0  s u bjects i n t his st u d y. S u bjects will be recr uite d c o nti n u o usl y u ntil t he pla n ne d  sa m ple size is 
ac hie ve d . S u bjects w h o wit h dra w or are wit h dra w n d uri n g S cree ni n g, as well as s u bjects w h o disc o nti n ue, ma y be 
re place d (see Secti o n 5. 4. 2 Ha n dli n g of Partici pa nt Wit h dra wals or Ter mi nati o n ).  
 
T he e x pecte d le n gt h of partici pati o n i n t he st u d y  of a p pr o xi matel y 1 8  wee ks  is n ot e x pecte d t o be c halle n gi n g t o  
s u bjects. F i na ncial s u p p ort f or meal an d miscella ne o us e x pe nses will be a vaila ble  d uri n g t he st u d y , as a p pr o priate  
a n d base d o n l ocal re g ulati o ns  a n d g ui deli nes . U se of visit tra ns p ort ser vices ma y als o be i nc or p orate d i nt o t he 
trial t o s u p p ort t he s u bject i n mai ntai ni n g st u d y visit c o m plia nce. A descri pti o n of t he st u d y will be i ncl u de d i n 
l ocal cli ni cal trial  data b ases, as re q uire d.  
 
5. 4  
S U B J E C T  WI T H D R A W A L O R T E R MI N A TI O N  
 
5. 4 . 1 
R E A S O N S F O R WI T H D R A W A L O R T E R MI N A TI O N  
 
 
 
 
A s u bject ma y  be  wit h dra w n fr o m  st u d y treat me nt f or t he f oll o wi n g me dical or a d mi nistrati ve reas o ns: 
• 
Occ urre nce of a n A E  t hat re prese nts a n u nacce pta ble ris k t o t he s u bject a n d w he n c o nti n ue d 
partici pati o n i n t he i n vesti gati o nal st u d y is n ot warra nte d, i n  t he j u d g me nt of t he i n vesti gat or, 
S p o ns or , or me dical m o nit or . T he i n vesti gat or m ust f oll o w t he s u bject u ntil t he A E res ol ves or is 
sta ble u nless t he s u bject is l ost t o f oll o w u p . 
• 
Treat me nt wit h a pr o hi bite d c o nc o mita nt me dicati o n ot her t ha n t he use of a p pr o priate me dicati o ns 
f or t he treat me nt of A Es u n der directi o n of t he i n vesti gat or. 
• 
S u bject n o nc o m plia nce, defi ne d as ref usal or i na bilit y t o a d h ere t o t he trial sc he d ule or pr oce d ures . 
• 
At t he re q uest of t he s u bject (e. g., s u bject wit h dra ws c o nse nt), i n vesti gat or, S p o ns or , or re g ulat or y 
a ut h orit y . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 2  of 9 9   
 
• 
Pre g na nc y . 
 
5. 4 . 2 
H A N D LI N G O F P A R TI C IP A N T WI T H D R A W A L S O R T E R MI N A TI O N   
 
 
S u bjects will be e nc o ura ge d t o c o m plete t he st u d y a n d all assess me nts . S u bjects ma y v ol u ntaril y wit h dra w at 
a n y ti me, a n d t he i n vesti gat or ma y disc o nti n ue i n di vi d ual s u bjects fr o m t he st u d y at a n y ti me.  
 
A p pr o xi matel y 1 2 0  s u bjects (A K S T 4 2 9 0 : 6 0 ; place b o : 6 0 ) will be e nr olle d i n t he st u d y wit h t he i nte nt of 
o btai ni n g ~ 1 0 8  e val ua ble s u bjects . S u bjects w h o disc o nti n ue or are u n bli n de d pri or t o Visit 6 ma y be 
re place d. S u bjects w h o wit h dra w or are wit h dra w n d uri n g scree ni n g will be re place d . S u bjects w h o are 
wit h dra w n d ue t o a d verse dr u g e ve nts or a d verse reacti o ns base d o n st u d y pr oce d ures will n ot be re place d.  
 
S u bjects w h o ha ve recei ve d at least 1  d ose ( 4 0 0  m g)  b ut  are wit h dra w n  or wit h dra w  fr o m t he st u d y will be 
e nc o ura ge d t o c o m plete t he e n d of treat me nt pr oce d ures . T he pri mar y reas o n f or st u d y disc o nti n uati o n will be 
d oc u me nte d o n t he case re p ort f or m ( C R F).  
 
5. 5  
P R E M A T U R E T E R MI N A TI O N O R S U S P E N SI O N O F S T U D Y  
 
T he S p o ns or  reser ves t he ri g ht t o ter mi nate t he st u d y at a n y ti me. S h o ul d t his be necessar y, t he S p o ns or a n d/or 
t heir re prese ntati ves will arra n ge disc o nti n uati o n pr o ce d ures a n d n otif y t he a p pr o priate re g ulat or y a ut h orit y(ies), 
I R Bs, a n d I E Cs . I n ter mi nati n g t he st u d y, t he S p o ns or  a n d t he i n vesti gat or will c o nti n ue t o pr otect t he s u bjects’ 
pri vac y a n d i de ntit y as re q uire d b y rele va nt stat ues a n d re g ulati o ns.  
 
Al ka hest, I nc. has t he ri g ht t o ter mi nate a st u d y site fr o m partici pati n g i n t he st u d y at a n y ti me . Reas o ns f or st u d y 
or sit e ter mi nati o n ma y i ncl u de, b ut are n ot li mite d t o:  
• 
(I m me diate) ris k t o s u bject safet y. 
• 
U nsatisfact or y s u bject e nr oll me nt . 
• 
U nacce pta ble pr ot oc ol de viati o ns / vi olati o ns as assesse d b y t he me dical mo nit or . 
• 
I nacc urate or i nc o m plete data e ntr y a n d rec or di n g/fa bricate d data. 
• 
I n vesti gati o nal site n o n-c o m plia nce wit h I C H/ G C P . 
• 
U nacce pta ble e mer ge nt safet y pr ofile . 
 
6  
S T U D Y A G E N T  
6. 1  
S T U D Y A G E N T  A N D C O N T R O L  D E S C RI P TI O N  
 
 
6. 1. 1  
A C Q UI SI TI O N  
 
T he st u d y a ge nt will be ma n ufact ure d, la bele d, pac ka ge d, a n d distri b ute d b y Al ka hest, I nc.  
 
6. 1. 2  
F O R M U L A TI O N, A P P E A R A N C E, P A C K A GI N G, A N D L A B E LI N G  
 
A K S T 4 2 9 0  is a fil m-c oate d pi n k, o bl o n g ta blet ma n ufact ure d b y Al ka hest, I nc., wit h a u nit stre n gt h of 
2 0 0  m g . T he st u d y a ge nt  ( A K S T 4 2 9 0/ place b o) will be deli vere d t o t he site a n d la bele d f or i n vesti gati o nal use 
o nl y acc or di n g t o t he rele va nt re g ulat or y re q uire me nt s f or cli nical st u dies.  
 
F or f urt her details a n d i nf or mati o n o n A K S T 4 2 9 0, i ncl u di n g pac ka gi n g a n d la beli n g, see t he I n vesti gat or’s 
Br oc h ure .  
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 3  of 9 9   
 
6. 1. 3  
P R O D U C T S T O R A G E A N D S T A BI LI T Y  
 
T he st u d y a ge nt will be ke pt i n its ori gi nal pac ka gi n g i n a sec ure li mite d access st ora ge area at 1 5° C - 3 0° C . 
A te m perat ure l o g m ust be mai ntai ne d t o ma ke certai n t he st u d y a ge nt is st ore d at t he c orrect te m perat ure. If 
t he st ora ge c o n diti o ns are f o u n d t o be o utsi de t he s pecifie d ra n ge, t he site m ust i m me diatel y n otif y t he 
s p o ns or or desi g nee. 
 
6. 1. 4  
D O SI N G A N D A D MI NI S T R A TI O N  
 
T he st u d y a ge nt will be self -a d mi nistere d orall y b.i. d.  ( 2 x 2 0 0 m g per d ose), a p pr o xi matel y 1 2 h o urs a part, 
f or a t otal dail y d ose of 8 0 0 m g. A K S T 4 2 9 0 s h o ul d be ta ke n 1 h o ur bef ore meals or 2 h o urs f oll o wi n g a meal. 
Trai ni n g o n st u d y a ge nt  a d mi nistrati o n will be c o n d ucte d pri or t o i nitial  d ose . D uri n g t he treat me nt peri o d  
( Visits 2-6) , s u bjects will  be i nstr ucte d t o wait t o a d mi nister t heir first dail y d ose u ntil t hey are as ke d  t o d o s o 
b y st u d y pers o n nel f or d oc u me ntati o n of precise a d mi nistrati o n ti mes (f oll o wi n g P K  testi n g).  
 
6. 1. 5  
R O U T E O F A D MI NI S T R A TI O N  
 
T he st u d y a ge nt will be a d mi nistere d orall y . 
  
6. 2  
S T U D Y A G E N T A C C O U N T A BI LI T Y  
 
T he i n vesti gat or a n d/ or p har macist will recei ve t he st u d y a ge nt a n d place b o deli vere d b y t he s p o ns or w he n t he 
f oll o wi n g re q uire me nts are f ulfille d: 
•  
A p pr o val of t he st u d y pr ot oc ol a n d inf or me d co nse nt (s) b y t he I R B or I E C . 
•  
A vaila bilit y of a si g ne d a n d date d cli nical trial c o ntract bet wee n t he s p o ns or a n d t he i n vesti gati o nal 
site. 
•  
A p pr o val/ n otificati o n of t he a p pr o priate re g ulat or y a ut h orit y (ies). 
•  
A vaila bilit y of t he c urric ul u m vitae of t he pri nci pal i n vesti gat or . 
•  
A vaila bilit y of a si g ne d a n d date d cli nical trial pr ot oc ol or i m me diatel y i m mi ne nt si g ni n g of t he cli nical 
trial pr ot oc ol. 
T he i n vesti gat or a n d/ or p har macist m ust mai ntai n rec or ds of t he st u d y a ge nt’s a n d place b o’s deli ver y t o t he trial 
site, t he i n ve nt or y at t he site, t he use b y eac h s u bject, a n d t he ret ur n t o t he s p o ns or or alter nati ve dis p ositi o n of 
u n use d st u d y a ge nt .  
T hese rec or ds will i ncl u de dates, q ua ntities, batc h/serial n u m bers, e x pir y (‘ use b y’) dates, a n d t he u ni q ue c o de 
n u m bers assi g ne d t o t he st u d y a ge nt , place b o , a n d trial s u bjects . T he i n vesti gat or/ p har macist will mai ntai n 
rec or ds t hat d oc u me nt a de q uatel y t hat t he s u bjects were pr o vi de d t he d oses s pecifie d b y t he pr ot oc ol a n d 
rec o ncile all st u d y a ge nt a n d place b o recei ve d fr o m t he s p o ns or. At t he ti me of fi nal st u d y a ge nt a n d place b o 
rec o nciliati o n, t he i n vesti gat or/ p har macist m ust verif y t hat all u n use d or partiall y use d p orti o n of st u d y a ge nt 
a n d place b o  ha ve bee n ret ur ne d b y t he cli nical trial s u bject a n d t hat n o re mai ni n g st u d y a ge nt a n d place b o is 
retai ne d b y t he i n vesti gat or.  
Acc o u nta bilit y rec or ds m ust be mai ntai ne d a n d rea dil y a vaila ble f or m o nit ori n g  a n d a u diti n g p ur p oses  b y 
re prese ntati ves of Al ka hest, I nc. or t heir desi g nee a n d are o pe n t o i ns pecti o n b y re g ulat or y a ut h orities at a n y 
ti me. T he acc o u nts of a n y st u d y a ge nt a n d place b o acci de ntall y waste d or i nte nti o nall y dis p ose d of m ust be 
mai ntai ne d.  
T he dis p osal of use d, partiall y use d, or waste d st u d y a ge nt a n d place b o m ust be c o n d ucte d  i n acc or da nce wit h 
t he i nstit uti o n’s dr u g dis p osal p olic y. At st u d y i nitiati o n, t he cli nical st u d y m o nit or will e val uate t he site’s 
sta n dar d o perati n g pr oce d ure f or st u d y a ge nt dis p osal/ destr ucti o n t o e ns ure it c o m plies wit h st u d y re q uire me nts . 
At t he e n d of t he st u d y, f oll o wi n g fi nal st u d y a ge nt a n d place b o rec o nciliati o n b y t he m o nit or, t he st u d y site will 
be i nstr ucte d b y t he s p o ns or t o ret ur n or destr o y all u n use d st u d y a ge nt  a n d place b o . A c o p y of t he i nstit uti o n’s 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 4  of 9 9   
 
dr u g dis p osal p olic y s h o ul d be mai ntai ne d or refere nce d i n t he I n vesti gat or Site File (I S F) if ap plica ble . 
 
7  
S T U D Y P R O C E D U R E S A N D S C H E D U L E  
7. 1  
S T U D Y P R O C E D U R E S/ E V A L U A TI O N S  
 
7. 1. 1  
S T U D Y S P E CI FI C P R O C E D U R E S  
 
7. 1. 1. 1 Scree ni n g Pr oce d ures  
D uri n g scree ni n g, t he f oll o wi n g will be c o n d ucte d: 
•  
Assess me nt of P D , i ncl u di n g m o difie d H oe h n a n d Ya hr . 
•  
Me dical hist or y . 
•  
De m o gra p hics . 
•  
Re vie w of me dicati o ns . 
•  
Vital si g ns . 
•  
P h ysical e xa mi nati o n . 
•  
1 2 -Lea d E C G . 
•  
Bl o o d a n d uri ne c ollecti o n f or la b orat or y e val uati o ns . 
 
Detaile d descri pti o ns of eac h of t hese pr oce d ures are pr o vi de d i n t he secti o ns i m me diatel y f oll o wi n g. 
I nf or mati o n pertai ni n g t o all st u d y acti vities c o n d ucte d d uri n g scree ni n g, a n d t he se q ue nce of e ve nts, is 
pr o vi de d i n  Secti o n 7. 3. 1 Scree ni n g . 
 
7. 1. 1. 1. 1  Assess me nt of P ar ki ns o n’s Disease  a n d C o g niti ve I m pair me nt 
T he dia g n osis of P D  will be verifie d usi n g  M D S -P D criteria (P ost u ma 2 0 1 5 ) (Secti o n 1 7. 7 ). T he prere q uisite 
t o a p pl y t he M D S-P D criteria is t he  prese nce  of t he car di nal s y m pt o ms of Par ki ns o n’s Disease, defi ne d as 
bra d y ki nesia, i n c o m bi nati o n wit h eit her rest i n g tre m or, ri gi dit y, or b ot h. T hese feat ures m ust be clearl y 
de m o nstra ble a n d n ot attri b uta ble t o c o nf o u n di n g fact ors ( P ost u ma 2 0 1 5 ). T he sta ge of t he disease will be 
classifie d usi n g t he m o difie d H oe h n a n d Ya hr scale .  
 
7. 1. 1. 1. 2  Me dical Hist or y  
T he i n vesti gat or or desi g nee will o btai n a detaile d me dical hist or y t hr o u g h i nter vie w wit h t he s u bject d uri n g 
scree ni n g. T he me dical hist or y s h o ul d f oc us o n rece nt hist or y, wit h a n e m p hasis o n t he hist or y of m ot or 
s y m pt o ms relate d t o P D . A d diti o nall y, t he me dical hist or y s h o ul d i ncl u de:  
•  
C urre nt/ past ill nesses a n d c o n diti o ns . 
•  
C urre nt s y m pt o ms  of a n y acti ve me dical c o n diti o n . 
•  
S ur geries a n d pr oce d ures . 
•  
Aller gies . 
•  
Fa mil y hist or y  i n bi ol o gical pare nts, si bli n gs, a n d offs pri n g of P D, A D , or ot her de me ntias or 
ne ur ol o gical dis or ders . 
•  
S ocial hist or y ( e. g., e xercise, s m o ki n g, alc o h ol, ille gal s u bsta nces) a n d c urre nt li vi n g sit uati o n  
•  
Ca use of pare ntal deat h (if n ot li vi n g) . 
•  
Pri or i ma gi n g, C S F assess me nts, or  ot her rele va nt dia g n ostic test  res ults, i ncl u di n g ge netics. 
 
7. 1. 1. 1. 3  De m o gra p hics  
De m o gra p hic i nf or m ati o n s uc h as t he s u bject’s e d ucati o n  le vel, et h nicit y, a n d race will be c ollecte d b y 
i nter vie w wit h t he s u bject at scree ni n g. 
 
7. 1. 1. 1. 4  Re vie w of Me dicati o ns  
T he i n vesti gat or or desi g nee s h o ul d o btai n a c o m plete list of t he s u bject’s c urre nt me dicati o ns, i ncl u di n g 
o ver -t he-c o u nter dr u gs, her bal s u p ple me nts a n d/ or vita mi ns, as well as t h ose ta ke n b y t he s u bject i n t he past 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 5  of 9 9   
 
1 2 m o nt hs  a n d a n y d ose c ha n ges of me dicati o ns f or P D  i n t he last 3 m o nt hs. Assess me nt of eli gi bilit y s h o ul d 
i ncl u de a re view of per mitte d a n d pr o hi bite d  me dicati o ns . A n y a d diti o ns,  disc o nti n uati o n , or d osa ge c ha n ges 
i n me dicati o n d uri n g t he c o urse of t he st u d y will be rec or de d. 
 
7. 1. 1. 1. 5  Vital Si g ns  
Vital si g ns will i ncl u de seate d s yst olic a n d diast olic bl o o d press ure ( m m  H g) , heart rate ( beats per mi n ute 
[ b p m]), res pirati o n rate ( breat hs per mi n ute), a n d b o d y  te m perat ure. Vital si g ns will be meas ure d after t he 
s u bject has bee n seate d f or 5 mi n utes.  
 
7. 1. 1. 1. 6  F ull P h ysical E xa mi nati o n  
A f ull p h ysical e xa mi nati o n will be perf or me d  a n d d oc u me nte d t o assess t he f oll o wi n g or ga n s yste ms: s ki n, 
E N T (ears, n ose, a n d t hr oat), hea d, e yes, l u n gs/c hest, heart, a b d o me n, m usc ul os keletal, e xtre mities, 
ne ur ol o gic a n d l y m p hatic s yste ms . T he c o m plete ne ur ol o gical e xa m i nati o n will i ncl u de , b ut n ot be li mite d t o 
me ntal stat us, cra nial ner ves ( vis ual fiel ds, f u n d osc o pic e xa m, p u pillar y li g ht refle x, e xtra oc ular m uscles, 
facial se nsati o n a n d s y m metr y, palate a n d t o n g ue, a n d hea d t ur ni n g a n d s h o ul der s hr u g); m uscle stre n gt h, 
t o ne, b ul k, a n d a b n or mal m o ve me nts; refle xes ( bice ps, trice ps, k nees, a n kles, a n d pla ntar); c o or di nati o n 
(fi n ger-t o-n ose, heel -k nee -s hi n); se ns or y f u ncti o n (li g ht t o uc h, pi n pric k , a n d vi brati o n ); a n d gait. Hei g ht will 
be meas ure d at scree n i n g a n d wei g ht will be m o nit ore d d uri n g t he trial.  
 
7. 1. 1. 1. 7  1 2 -Lea d E C G  
T wel ve -lea d E C Gs (I, II, III, a V R, a V L, a V F, V 1 - V 6) will be rec or de d usi n g a c o m p uterize d 
electr ocar di o gra p h. A 1 2 -lea d E C G will be perf or me d  after t he s u bject has reste d q uietl y f or at least 5 mi n utes 
i n a s u pi ne p ositi o n. I n s o me cases, it ma y be a p pr o priate t o re peat a b n or mal E C Gs t o r ule o ut tec h nical 
fact ors c o ntri b uti n g t o E C G artifacts or a b n or malit y. It is i m p orta nt t hat lea ds are placed i n t he sa me p ositi o ns 
eac h ti me f or c o nsiste nc y . T he o verall c o ncl usi o n wit h t he i nter pretati o n of t he E C Gs will be rec or de d o n t he 
a p pr o priate C R F . T he i nter pretati o n of t he E C Gs will be rec or de d as n or mal, a b n or mal b ut n ot cli nicall y 
si g nifica nt, or a bn or mal a n d cli nicall y si g nifica nt . C orrecte d Q Tc i nter vals will be calc ulate d usi n g 
Fri dericia’s c orrecti o n f or m ula  a n d e ntere d i nt o t he C R F .  
 
7. 1. 1. 1. 8  Scree ni n g Bi ol o gical S peci me n C ollecti o n  
F or scree ni n g e val uati o n, b l o o d will be dra w n b y a q ualifie d me dical pr o vi der, a n d uri ne s peci me ns will als o 
be c ollecte d  (see Secti o n 7. 1. 1. 2. 7 ).  
 
7. 1. 1. 1. 9  A d mi nistrati o n of D o pa mi ner gic Me dicati o n   
S u bjects will be i nstr ucte d b y site pers o n nel t o ta ke t heir prescri be d d o pa mi ner gic me dicati o n f oll o wi n g 
c o m pleti o n of t he off -me dicati o n assess me nts o n Visit 2 ( Da y 1), Visit 4 ( Da y 2 8), Visit 6 ( Da y 8 4), a n d Visit 
7 ( Da y 9 8).      
 
7. 1. 1. 2 Pr oce d ures t o Assess S afet y  
S u bjects e nr olle d i n t he trial will be m o nit ore d cl osel y t o assess safet y a n d t olera bilit y of t he st u d y a ge nt a n d 
i nter ve nti o n. St u d y -s pecific pr oce d ures t hat will be use d f or t his p ur p ose are s u m marize d bel o w . I nf or mati o n 
re gardi n g t he ti mi n g a n d fre q ue nc y of t hese pr oce d ures is pr o vi de d i n  Secti o n 7. 3 St u d y Sc he d ule .  
• 
Re vie w of A Es . 
• 
Re vie w of me dicati o ns . 
• 
Vital si g ns . 
• 
S -S T S . 
• 
1 2 -Lea d E C Gs . 
• 
Tar gete d p h ysical e xa m i nati o ns a n d wei g ht.  
• 
E n d o f St u d y ( or Earl y Ter mi nati o n) p h ysical exa m i nati o n. 
• 
Bl o o d d ra w a n d u ri ne collecti o n f or la b orat or y eval uati o ns . 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 6  of 9 9   
 
7. 1. 1. 2. 1 Re vie w of A d verse E ve nts  
A Es will be re vie we d, d oc u me nte d, a n d re p orte d as re q uire d at eac h visit, be gi n ni n g at S cree ni n g . F or 
defi niti o ns, g ui da nce, a n d a d diti o nal i nf or mati o n re gar di n g A Es, refer t o  Secti o n 8 .  
 
7. 1. 1. 2. 2 Re vie w of Me dicati o ns  
T he i n vesti gat or or desi g nee s h o ul d re vie w t he s u bject’s c urre nt me dicati o ns, i ncl u di n g o ver -t he-c o u nter 
dr u gs, her bal s u p ple me nts a n d/ or vita mi ns, as well as t h ose ta ke n b y t he s u bject si nce t he last visit . C ha n ges 
t o t he s u bject’s list of me dicati o ns s ho ul d be re vie we d a n d rec or de d . Re vie w of me dicati o ns s h o ul d occ ur at 
e ver y visit. 
 
7. 1. 1. 2. 3 Vital Si g ns  
Refer t o Secti o n 7. 1. 1. 1. 5  f or a descri pti o n of v ital si g ns. Vital si g ns will be c ollecte d at e ver y visit (see t he 
Sc he d ule of E ve nts ).  
 
7. 1. 1. 2. 4 S hee ha n -S uici dalit y Trac ki n g Scale  
Refer t o Secti o n 7. 1. 1. 3 .6  f or a descri pti o n of t he S -S T S .  
 
7. 1. 1. 2. 5 1 2 -Lea d E C G  
Refer t o  Secti o n 7. 1. 1. 1. 7  f or i nf or mati o n pertai ni n g t o 1 2-Lea d E C Gs.  
 
7. 1. 1 . 2.6  Tar gete d P h ysical E xa m i nati o n 
D uri n g t he st u d y peri o d, a tar gete d p h ysical e xa m i nati o n, i ncl u di n g a usc ultati o n of t he heart a n d meas ure me nt 
of wei g ht, will be perf or me d  per t he Sc he d ule of E ve nts .  
 
7. 1. 1. 2. 7  Bl o o d a n d Uri ne C ollecti o n f or La b orat or y E val uati o ns  
Bl o o d sa m ples a n d uri ne will be c ollecte d ac c or di n g t o t he Sc he d ule of E ve nts . L a b orat or y tests will 
i ncl u de he mat ol o g y, c he mistr y, c oa g ulati o n, q ualitati ve uri nal ysis , a n d pre g na nc y testi n g i n W O C B P.  
•  
He mat ol o g y: he m o gl o bi n, he mat ocrit,  re d bl o o d cell ( R B C) c o u nt, w hite bl o o d cell ( W B C) 
c o u nt wit h differe ntial, platelets  
•  
C he mistr y: gl uc ose, s o di u m, p otassi u m, calci u m, i n or ga nic p h os p hate, c hl ori de, 
bicar b o nate, ma g nesi u m, creati ni ne, as partate a mi n otra nsferase ( A S T), ala ni ne 
a mi n otra nsferase ( A L T), al kali ne p h os p hatase ( AL P), lactate de h y dr o ge nase  ( L D H), t otal 
bilir u bi n, bl o o d urea  nitr o ge n , t otal pr otei n, al b u mi n, creati ne p h os p h o ki nase  ( C P K), 
c h olester ol (t otal), C -reacti ve pr otei n ( C R P) 
•  
Ser ol o g y  (c o n d ucte d  at Scree ni n g o nl y) : H B V, H C V, a n d HI V  
•  
C oa g ulati o n: acti vate d partial t hr o m b o plasti n  ti me (a P T T), pr ot hr o m bi n ti me/i nter nati o nal 
n or malize d rati o (I N R)  
•  
Uri n al ysis: p H, gl uc ose, er yt hr oc ytes, le u k oc ytes, pr otei n, nitrite 
 
A d diti o nal la b orat or y  para meters  ma y be  re p orte d as detaile d  i n t he la b orat or y ma n ual. Gl o mer ular 
filtrati o n rate ( G F R) will be esti mate d b y t he M D R D  F or m ula utilizi n g ser u m creati ni ne (see  Secti o n 
1 7. 9 ). All safet y la b orat or y meas ure me nts will be c o n d ucte d b y a C LI A -certifie d  la b orat or y. 
I n vesti gat ors will get g ui da nce a n d i nstr ucti o ns o n la b orat or y sa m pli n g a n d pr ocessi n g t hr o u g h a se parate 
La b orat or y  Ma n ual pr o vi de d b y t he ce ntral la b orat or y.  
 
Ser ol o g y will o nl y be c o n d ucte d at scree ni n g. P ote ntial s u bjects wit h p ositi ve scree ni n g test res ult f or H B V, 
H C V, or HI V will n ot be eli gi ble f or st u d y partici pati o n.  
 
T he i n vesti gat or is res p o nsi ble f or deter mi ni n g a n d d oc u me nti n g if o ut -of -ra n ge la b orat or y val ues are 
cli nicall y si g nifica nt . All cli nicall y si g nifica nt v al ues will be rec or de d as A Es i n t he C R F a n d f oll o we d 
u ntil res ol uti o n . O nce res ol ve d, t he a p pr o priate C R F pa ge(s) will be u p date d.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 7  of 9 9   
 
 
S a m ples ma y be use d f or re -testi n g, f urt her e val uati o n of a n A E a n d/ or assess me nt, a n d f oll o w-u p of ot her 
e x pl orat or y e n d p oi nts . Sa m ples t hat  re mai n after st u d y testi n g is c o m plete will be st ore d i n t he e ve nt 
a d diti o nal testi n g ( e. g., f urt her e val uati o n of a n A E or assess me nt of effect) is re q uire d. Sa m ples will be 
st ore d i n a dei de ntifie d c o de d f or m. S u bjects ca n o pt o ut of st ora ge of sa m ples f or f ut ure a nal ysis.  
 
7. 1. 1. 3 Pr oce d ures t o Assess Effic ac y  
Pr oce d ures t o assess efficac y i ncl u de m ot or a n d c o g niti ve  f u ncti o n testi n g, assess me nt of acti vities of dail y 
li vi n g, a n d, i n c o nse nti n g s u bjects, micr o bi o me assess me nt . I nf or mati o n re gar di n g t he ti mi n g a n d fre q ue nc y 
of t hese pr oce d ures is pr o vi de d i n  Secti o n 7. 3  a n d Secti o n 1 5 Sc he d ule of E ve nts . 
 
All  testi n g will be  c o n d ucte d  b y q ualifie d e val uat ors w h o ha ve u n der g o ne sta n dar dize d rater trai ni n g  a n d 
certifi cati o n, as a p pr o priate. T he sa me e val uat or s h o ul d be use d f or t he d urati o n of eac h s u bject’s 
partici pati o n u nless a c ha n ge i n rater is u na v oi da ble . T he M D S -U P D R S  Part 3 a n d 1 0 -meter ti me d wal k will 
be perf or me d  i n t he off -me dicati o n a n d o n -me dicati o n state s. A ll ot her assess me nts s h o ul d be c o n d ucte d  i n 
t he o n -me dicati o n state  as liste d i n Secti o n 7. 3 :  
 
• 
M D S -U P D R S  Parts 1 -4  
• 
M o C A   
• 
S E -A D L  
• 
CI SI -P D  
• 
P D Q -3 9  
• 
S -S T S  
• 
1 0 -meter ti me d wal k  
• 
Weara ble se ns or de vice  (as a p plica ble) 
• 
Fecal mar kers of i ntesti nal i nfla m mati o n a n d per mea bilit y ( o pti o nal)  
• 
Ha user 3 -Da y Patie nt Diar y  
 
Descri pti o ns of eac h assess me nt are pr o vi de d bel o w.  
 
7. 1. 1. 3. 1 M o ve me nt Dis or der S ociet y’s U nifie d Par ki ns o n’s Disease Rati n g Scale  
T he M D S -U P D R S ( Fa h n 1 9 8 7 , G oetz 2 0 0 8 ) (Secti o n 1 7. 1 ) was de vel o pe d t o i nc or p orate ele me nts fr o m 
e xisti n g scales t o pr o vi de a c o m pre he nsi ve b ut efficie nt a n d fle xi ble mea ns t o m o nit or P D -relate d disa bilit y 
a n d i m pair me nt. T he M D S -U P D R S has f o ur c o m p o ne nts ( Part 1 , Me ntati o n, Be ha vi or, a n d M o o d; Part 2 , 
Acti vities of Dail y Li vi n g; Part 3 , M ot or; Part 4 , C o m plicati o ns). O ne of t he c ore a d va nta ges of t he U P D R S is 
t hat it was de vel o pe d as a c o m p o u n d scale t o ca pt ure m ulti ple as pects of P D. T he rati n g f or eac h ite m is fr o m 
0 ( n or mal) t o 4 (se vere). T he t otal sc ore f or eac h Part is o btai ne d fr o m t he s u m of t he c orres p o n di n g ite m 
sc ores.  
 
7. 1. 1. 3. 2  M o ntreal C o g niti ve Assess me nt   
T he M o C A ( Nasre d di ne 2 0 0 5 ) (Secti o n 1 7. 2 ) is a scree ni n g test easil y a d mi nistere d b y n o n-s pecialist staff. It 
assesses atte nti o n a n d c o nce ntrati o n, e xec uti ve f u ncti o n, me m or y, la n g ua ge, vis u oc o nstr ucti o nal s kills, 
c o nce pt ual t hi n ki n g, calc ula ti o ns, a n d orie ntati o n. T he t otal p ossi ble sc ore is 3 0 p oi nts wit h a sc ore of 2 6 or 
m ore c o nsi dere d n or mal .  
 
7. 1. 1. 3. 3  Sc h wa b a n d E n gla n d Acti vities of Dail y Li vi n g Scale  
T he S E -A D L e val uates patie nts’ perce pti o n s of gl o bal f u ncti o nal ca pacit y a n d de pe n de nce ( Sc h wa b 1 9 6 8 ) 
(Secti o n 1 7. 3 ). Sc ori n g is e x presse d i n ter ms of perce nta ge, i n 1 0 ste ps fr o m 1 0 0 t o 0 ( 1 0 0 %, n or mal stat us; 
0 %, be dri d de n wit h i m paire d ve getati ve f u ncti o n s), s o t hat t he l o wer t he sc ore, t he w orse t he f u ncti o nal 
stat us. T he rati n g is ma de b y a  trai ne d cli nicia n. 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 8  of 9 9   
 
7. 1. 1. 3. 4  Cli nical I m pressi o n of Se verit y I n de x –  Par ki ns o n’s Disease  
T he CI SI -P D is a se verit y i n de x f or me d b y f o ur ite ms ( m ot or si g ns, disa bilit y, m ot or c o m plicati o ns, a n d 
c o g niti ve stat us), rate d 0 ( n ot at all) t o 6 ( ver y se vere or c o m pletel y disa ble d) ( Marti nez -Marti n 2 0 0 6 ) 
(Secti o n 1 7. 4 ). A t otal sc ore is calc ulated b y s u m mi n g t he ite m sc ores. T he scale is c o m plete d b y a cli nicia n . 
It o nl y ta kes a fe w mi n utes t o c o m plete o nce t he state of t he s u bject is k n o w n. 
 
7. 1. 1. 3. 5  Par ki ns o n’s Disease Q ualit y of Life Q uesti o n naire -3 9  
T he P D Q -3 9 is a self -a d mi nistere d q uesti o n n aire of 3 9 q uesti o ns relati n g t o 8 ke y areas of healt h a n d dail y 
acti vities, i ncl u di n g b ot h m ot or a n d n o n -m ot or s y m pt o ms ( Pet o 1 9 9 8 )(Secti o n 1 7. 5 ). T he ei g ht di me nsi o ns 
i ncl u de: m o bilit y, acti vities of dail y li vi n g, e m oti o nal well-bei n g, sti g ma, s ocial s u p p ort, c o g niti o n , 
c o m m u nicati o n, a n d b o dil y disc o mf ort . It is sc ore d o n a scale of 0-1 0 0 wit h l o wer sc ores i n dicati n g better 
healt h a n d hi g h sc ores i n dicati n g m ore se vere s y m pt o ms .  
 
7. 1. 1. 3 .6  S hee ha n -S uici dalit y Trac ki n g Scale  
T he S -S T S was de vel o pe d t o pr o vi de a brief b ut efficie nt i nstr u me nt f or use i n assessi n g c ha n ge i n s uici dal 
i deati o n a n d be ha vi or w hile pr o vi di n g a c o m pre he nsi ve descri pti o n of s uici dal i deati o n a n d be ha vi or. T he 
pri mar y g oals i n t he desi g n of t he S -S T S were f or t he scale t o be: 1) sh ort a n d i ne x pe nsi ve; 2) si m ple, clear, 
a n d eas y t o a d mi nister or self -rate; 3) h i g hl y se nsiti ve (i.e., a ble t o detect a hi g h pr o p orti o n of patie nts w h o 
are s uici dal); 4) specific ( i.e., a ble t o scree n o ut t h ose w h o are n ot s uici dal); 5) se nsiti ve t o c ha n ge i n s uici dal 
i deati o n a n d be ha vi or; 6) co m pati ble wit h t he re g ulat or y cate g ories of assess me nt f or s uici dal i deati o n a n d 
be ha vi or; 7) u sef ul i n cli nical as well as researc h setti n gs; 8) u sef ul i n detecti n g a n efficac y si g nal f or a nti-
s uici dal me dicati o ns; a n d 9) ca pa ble of use i n pe diatric a n d geriatric setti n gs ( S hee ha n 2 0 1 4 ). T he sta n dar d 
versi o n of t he S -S T S ( Secti o n 1 7. 6 ) is a 1 6-ite m scale t hat assesses t he seri o us ness of s uici dalit y p he n o me na 
o n a Li kert -t y pe scale ( 0-4) ra n gi n g fr o m “n ot at all” ( 0) t o “e xtre mel y” ( 4) . It als o assesses t he fre q ue nc y of 
ke y p he n o me na a n d t he o verall ti me s pe nt i n s uici dalit y .  
 
7. 1. 1. 3 .7  1 0 -Meter Ti me d Wal k  
T he 1 0 -meter wal k test is a c o m m o nl y use d t o ol f or assessi n g gait s pee d i n i n di vi d uals wit h gait li mitati o ns  
(La n g 2 0 1 6 ). Gait s pee d is p ositi vel y c orrelate d wit h t he a m o u nt of  c o m m u nit y a m b ulati o n a n d q ualit y of life, 
a n d t heref ore  it is a n i m p orta nt meas ure of m o bilit y i n i n di vi d uals wit h P D.  T his test has bee n vali date d i n 
vari o us p o p ulati o ns  a n d is a rec o m me n de d o utc o me  meas ure f or use i n patie nts wit h P D  (La n g 2 0 1 6 ).  
 
7. 1. 1. 3. 8   Weara ble Se ns or De vice  
Weara ble se ns or de vices ha ve a d va nce d i n rece nt years t o e na ble c o nti n u o us meas ure me nt of  healt h -relate d 
s y m pt o ms, w hic h i n Par ki ns o n’s i ncl u de t he m ot or a n d n o n m ot or feat ures of bra d y ki nesia, tre m or, acti vit y , 
a n d slee p . As a p plica ble, s u bjects  will be s u p plie d t he weara ble se ns or de vices. F ull i nf or mati o n as t o t he 
o perati o n a n d data ca pt ure fr o m t he de vices will be i ncl u de d i n t he I n vesti gat or Site File (I S F). 
 
7. 1. 1. 3. 9   Fecal Mar kers of I ntesti nal I nfla m mati o n a n d Per mea bilit y  
I ntesti nal i nfla m mati o n a n d i ncrease i ntesti nal per mea bilit y ( b ot h p ossi bl y f uele d b y d ys bi osis) ha ve bee n 
i m plicate d i n t he m ultifact orial pat h o ge nesis of P D ( Sc h wiertz 2 0 1 8 ). I n c o nse nti n g s u bjects, fecal sa m ples 
will be c ollecte d at scree ni n g a n d at e n d of treat me nt a n d sa m ples will be flas h fr oze n f or assess me nt. F ull 
inf or mati o n as t o pr oce d ure f or c ollecti o n a n d pr ocessi n g of sa m ples will be i ncl u de d i n t he I S F.  
 
7. 1. 1. 3. 1 0  Ha user 3 -Da y Patie nt Diar y  
T he Ha user Patie nt Diar y was de vel o pe d t o assess f u ncti o nal stat us o ver a peri o d of ti me i n patie nts wit h 
m ot or fl uct uati o ns a n d d ys ki nesia (Ha user 2 0 0 0 )(Secti o n 1 7. 8 ). It is a self-c o m plete d refere nce diar y desi g ne d 
t o se parate d ys ki nesia t hat ha d a ne gati ve i m pact o n patie nt-defi ne d f u ncti o nal  stat us fr o m d ys ki nesia t hat di d 
n ot. Wit h t his diar y, t he effect of a n i nter ve nti o n ca n be e x presse d as t he c ha n ge i n off -me dicati o n ti me a n d 
t he c ha n ge i n o n-me dicati o n ti me wit h tr o u bles o me d ys ki nesia ( ba d ti me). T he s u m ca n be use d as a n o utc o me 
varia bl e a n d c o m pare d t o baseli ne or acr oss gr o u ps. I n a f oll o w -u p st u d y t o t he ori gi nal e val uati o n of t he 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 2 9  of 9 9   
 
assess me nt, it was deter mi ne d t hat c o m plia nce di mi nis he d after 3 da ys, b ut diaries c o m plete d o n 3 
c o nsec uti ve da ys were si m ple, feasi ble, a n d i m pr o ve d c o m pl ia nce (Ha user 2 0 0 4 ). 
 
7. 2  
L A B O R A T O R Y P R O C E D U R E S/ E V A L U A TI O N S  
 
7. 2. 1  
C LI NI C A L L A B O R A T O R Y E V A L U A TI O N S  
 
Bi ol o gical sa m ples ( e. g., w h ole bl o o d, ser u m, uri ne) will be c ollecte d f or la b orat or y e val uati o ns i ncl u di n g 
pre g na nc y testi n g i n W O C B P i n acc or da nce wit h t he Sc he d ule of E ve nts . Refer t o t he st u d y’s la b orat or y 
ma n ual f or c o m plete i nf or mati o n re gar di n g all la b orat or y e val uati o ns t o be perf or me d, sa m ple c ollecti o n 
pr oce d ures, a n d relate d re q uire me nts.  
 
T he i n vesti gat or is res p o nsi ble f or deter mi ni n g a n d d oc u me nti n g w het her  o ut of ra n ge la b orat or y val ues are 
cli nicall y si g nifica nt . Al l cli nicall y si g nifica nt val ues will be rec or de d as A Es i n t he C R F a n d f oll o we d u ntil 
deter mi ne d t o be sta ble or res ol ve d u nless t he s u bject is l ost t o f oll o w u p . O nce res ol ve d, t he a p pr o priate C R F 
pa ge(s) will be u p date d.  
 
 
7. 2. 2  
O T H E R T E S T S  O R P R O C E D U R E S  
 
7. 2. 2. 1   
St u d y A ge nt C o nce ntr ati o n a n d P h ar m ac o ki netics  
Plas ma c o nce ntrati o n meas ure me nts of A K S T 4 2 9 0 a n d its  maj or  meta b olites will be c ollecte d t o assess 
s yste mic e x p os ure t o t he st u d y a ge nt. F or re q uire d a n d o pti o nal sa m pli n g ti me p oi nts a n d f urt her details, 
please refer t o  Secti o n  1 7. 1 2 .  
 
7. 2. 2 . 1. 1  P har mac o ki netic E n d p oi nts  
 
As far as feasi ble, t he f oll o wi n g P K para meter will be s u m marize d descri pti vel y:  
•  
C pre,ss, N  
Pre -d ose c o nce ntrati o n of A K S T 4 2 9 0 i n plas ma i m me diatel y bef ore   
                       a d mi nistrati o n of t he Nt h d ose  
 
7. 2. 2 .1. 2  Met h o ds of Sa m ple C ollecti o ns   
F or q ua ntificati o n of plas ma c o nce ntrati o ns of A K S T 4 2 9 0  a n d its maj or meta b olites, a n d f or bi o mar ker 
i n vesti gati o ns (see Secti o n 7. 2. 2. 3 ), o ne bl o o d sa m ple of a p pr o xi matel y 6 m L per sa m pli n g ti me p oi nt 
(see Secti o n 1 7. 1 2  Ta ble of P har mac o ki netic, Bi o mar ker, P har mac o ge n o mic , a n d F A C S Sa m pli n g ) will 
be ta ke n fr o m a n a ntec u bital or f orear m vei n i nt o a p otassi u m et h yle ne dia mi netetraacetic aci d ( E D T A)-
a ntic oa g ula nt bl o o d dra wi n g t u be.  
 
T he E D T A -a ntic oa g ulate d bl o o d sa m ples will be ce ntrif u ge d t o c ollect plas ma. F or P K  sa m ples o nl y, t he 
o btai ne d plas ma will be s plit i nt o 2 ali q u ots a n d st ore d i n p ol y pr o p yle ne t u bes. At t he selecte d ti me p oi nts 
wit h a d diti o nal bi o mar ker deter mi nati o ns, 5 i nstea d of 2 ali q u ots of at least 0. 5 m L plas ma eac h will be 
pre pare d fr o m t he bl o o d sa m ple. T he ti me fr o m bl o o d c ollecti o n u ntil t he tra nsfer of plas ma ali q u ots i nt o 
t he freezer s h o ul d n ot e xcee d 6 0 mi n utes, wit h interi m sa m ple st ora ge o n wet ice w he ne ver p ossi ble. 
Sa m ples will be p ositi o ne d u pri g ht a n d will be fr oze n at a p pr o xi matel y -2 0° C or bel o w u ntil s hi p me nt . 
T hese ali q u ots will be pr ocesse d b y t he ce ntral la b orat or y. Details of plas ma c ollecti o n, sa m ple ha n dl i n g, 
a n d s hi p me nt i nstr ucti o ns will be pr o vi de d i n t he La b Ma n ual.  
 
7. 2. 2. 1 . 3  A nal ytical Deter mi nati o ns  
 
C o nce ntrati o ns of A K S T 4 2 9 0 a n d meta b olites (if feasi ble) i n plas ma sa m ples will be deter mi ne d b y a 
vali date d hi g h -perf or ma nce li q ui d c hr o mat o gra p h y, t a n de m mass s pectr o metr y ( H P L C -M S/ M S) assa y . 
Left o ver sa m ples will be use d f or e x pl orat or y bi o mar ker assess me nt (see  Secti o n 7. 2. 2. 3 ). 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 0  of 9 9   
 
 
7. 2. 2. 2   
P h ar m ac o ge n o mic E v al u ati o ns  
P har mac o ge netic a nal ysis of pres pecifie d ge n es is a n e x pl orat or y e n d p oi nt. S a m ples f or de o x yri b o n ucleic 
aci d ( D N A) ba n ki n g will be c ollecte d if partici pa nts si g ne d a se parate inf or me d co nse nt a n d is n ot re q uire d 
f or st u d y partici pati o n.  
 
• Pres pecifie d ge nes: D N A will be e xtracte d fr o m o ne bl o o d sa m ple a n d ge n ot y pe d f or c o m m o n ge netic 
varia nts of t he f oll o wi n g ge nes: 
  
 
S e veral ge ne m utati o ns ha ve bee n i m plicate d i n Par ki ns o n’s  disease, n ota bl y t he al p ha -s y n uclei n ge ne 
( S N C A), le uci ne-ric h re peate d ki nase 2 ( L R R K 2) ge ne, a n d t he P A R K N ge ne. 
 
 
 
 Pres pecifie d a nal yses will be perf or me d at t he e n d of t he trial a n d t he data w ill be part 
of t he re p ort. All re mai ni n g sa m ples will be destr o ye d after t he e n d of t he trial.  
 
• D N A ba n ki n g  ( o pti o nal): O ne bl o o d sa m ple will be c ollecte d f or retr os pecti ve, e x pl orat or y ge n ot y pi n g 
(e. g., t o a nal yze disease or treat me nt-relate d ge ne variants).  F or i nf or mati o n re gar di n g f ut ure use of st ore d 
sa m ples, see Secti o n 1 2. 5 F ut ure Use of St ore d S peci me ns . 
 
7. 2. 2. 3   
Pl as m a Bi o m ar kers  
Meas ure me nt of bi o mar kers is e x pl orat or y. I n vesti gati o ns mi g ht i ncl u de mec ha nis m relate d mar kers
 
w hic h c o ul d i de ntif y s u bsets of s u bjects 
w h o ma y be nefit m ost fr o m t he treat me nt wit h A K S T 4 2 9 0. Ot her disease -relate d mar kers ma y i ncl u de 
i nfla m mat or y me diat ors or mar kers of o xi dati ve stress. Bi o mar kers will be meas ure d i n plas ma sa m ples t o 
i n vesti gate a n y c ha n ge i n res p o nse t o treat me nt. After c o m pleti o n of t he st u d y, left o ver sa m ples ma y be use d 
f or f urt her met h o d ol o gical a n d/ or ot her, n o n-ge netic bi o mar ker i n vesti gati o ns eit her b y t he s p o ns or, or 
desi g nee. T he st u d y sa m ples will be discar de d after c o m pleti o n of t he a d diti o nal i n vesti gati o ns, b ut n ot later 
t ha n 3 years after t he fi nal st u d y re p ort has bee n arc hi ve d. T he e x pl orat or y bi o mar ker meas ure me nts will  be 
c o n d ucte d eit her at t he s p o ns or’s la b orat orie s or at e xter nal C R Os usi n g a p pr o priate met h o d ol o g y (e. g., 
i m m u n oassa ys, m ulti ple x tec h n ol o g y). A La b orat or y  Ma n ual/I S F will descri be t he ha n dli n g of t he sa m ples.  
 
7. 2. 2. 4   
Bl o o d Bi o m ar kers b y Fl o w C yt o metr y  
C haracterizati o n of i m m u ne cells usi n g F A C S /c o m plete bl o o d c o u nt ( C B C ) is e x pl orat or y. F or t he 
i n vesti gati o ns, o ne bl o o d sa m ple of a p pr o xi matel y 6 m L per sa m pli n g ti me p oi nt will be c ollecte d. S peci me ns 
m ust be tra ns p orte d f or testi n g wit hi n a s pecifie d t i me peri o d. T he e x pl orat or y bi o mar ker meas ure me nts usi n g 
F A C S/ C B C will be c o n d ucte d eit her at t he s p o ns or’s la b or at ories or at e xter nal C R Os usi n g a p pr o priate 
met h o d ol o g y ( e. g., i m m u n oassa ys, m ulti ple x tec h n ol o g y). A La borat or y  Ma n ual/I S F will descri be t he 
ha n dli n g of t he sa m ples.  
 
7. 3  
S T U D Y S C H E D U L E  
 
7. 3 .1  
S C R E E NI N G  
 
7. 3. 1. 1 Visit 1, Scree ni n g Visit ( D a y -1 4  t o -7 ) 
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der: 
□ Si g ni n g of all a p plica ble i nf or me d c o nse nt s m ust be c o m plete d  pri or t o a n y st u d y -relate d assess me nts. 
□ Verif y dia g n osis of P D  acc or di n g t o M D S P D  criteria , i ncl u di n g m o difie d H oe h n a n d Ya hr sta ge . 
 
Re mai ni n g assess me nts (m ay be c o n d ucte d i n a ny or der): 
□ O bta i n me dical hist or y, i ncl u di n g me dical rec or ds a n d test res ults  t o s u p p ort P D  dia g n osis if a vaila ble . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 1  of 9 9   
 
□ C ollect de m o gra p hic i nf or mati o n . 
□ Re vie w s u bject’s c urre nt a n d pri or me dicati o ns . 
□ Re vie w pr o hi bite d me dicati o ns  a n d s u bsta nces wit h t he s u bject . 
□ C ollect vital si g ns . 
□ C ollect (scree ni n g) la b orat or y sa m ples . 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P . 
□ Perf or m f ull p h ysical e xa m i nati o n (i ncl u di n g hei g ht). 
□ Perf or m 1 2 -lea d E C G. 
□ Verif y t he s u bject f ulfills all t he i ncl usi o n criteria a n d n o ne of t he e x cl usi o n criteria . 
□ F or eli gi ble s u bjects, re vie w i nstr ucti o ns f or P D Q-3 9 a n d  Ha user 3 -Da y Patie nt Diar y a n d  pr o vi de 
ass ociate d i nf or mati o n a n d assess me nt materials; s u bjects s h o ul d be i nstr ucte d t o bri n g c o m plete d 
materials t o Visit  2 . 
□ F or eli gi ble s u bjects , set u p, re vie w i nstr ucti o ns f or, a n d pr o vi de t he h o me -base d weara ble se ns or 
de vice  t o be c ollecte d at Visit 2. 
□ F or c o nse nti n g  s u bjects, fecal sa m ple c ollecti o n ( o pti o nal).  
 
 
7 . 3. 2 
B A S E LI N E  
 
7. 3. 2. 1 Visit 2, B aseli ne (D a y  1 ) 
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der, u nless ot her wise i n dic ate d : 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P . 
□ C o nfir m s u bject meets all eli gi bilit y criteria . 
□ R a n d o mize t o A K S T 4 2 9 0 or place b o.  
□ C o nfir m off -me dicati o n state  ( off-le v o do pa) . 
□ A ssess me nts t o be c o n d ucte d i n t he off-me dicati o n ( off -le v o d o pa) state (m ay be c o n d ucte d i n a ny 
or der ):  
o  M D S -U P D R S Part 3.  
o  1 0 -meter ti me d wal k.  
□ A d mi nistrati o n of d o pa mi ner gic me dicati o n (c o m me nce o n -me dicati o n state) f or re mai ni n g 
assess me nts t hat da y.  
 
T he f oll o wi n g assess me nts ma y be c o n d ucte d  i n a n y or der, after r a n d o miz ati o n a n d pri or t o st u dy a ge nt 
a d mi nistr ati o n : 
□ C ollect t he weara ble se ns or de vice . 
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns.  
□ Perf or m tar gete d p h ysical e xa mi nati o n.  
□ C ollect vital si g ns.  
□ C ollect c o m plete d P D Q -3 9 a n d pr o vi de  f or t he ne xt visit. 
□ C ollect c o m plete d Ha user 3 -Da y Patie nt Diar y.  
□ C o nfir m ati o n of o n -me dicati o n state . 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state (m ay be c o n d ucte d  i n a ny or der ): 
o  M D S -U P D R S Parts 1 -4.  
o  M o C A.  
o  S E -A D L.  
o  CI SI -P D.  
o  S -S T S.  
o  1 0 -meter ti me d wal k.  
□ C ollect la b orat or y sa m ples.  
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 2  of 9 9   
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der, after all ot h er assess me nts are c o m plete d: 
□ C ollect i nitial P K  a n d bi o mar ker sa m ples 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n (see Secti o ns 
7. 2. 2. 1 , 7. 2. 2. 3 , 1 7. 1 2 ). 
□ C ollect i nitial F A C S/ C B C sa m ples 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n (see Secti o n s 
7. 2. 2. 4 , 1 7. 1 2 ). 
□ C ollect p har mac o ge n o mic sa m ple (see Secti o n s 7. 2. 2. 2 , 1 7. 1 2 ). 
□ Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0 or place b o.  
□ St u d y d r u g ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n ( d ose a d mi nistere d a p pr o xi matel y 1 5 mi nutes  after 
ac q uisiti o n of i nitial P K  sa m ple).  
□ St u d y a ge nt acc o u nta bilit y.  
□ C ollect P K  a n d bi o mar ker sa m ples 1 h o ur f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o ns 7. 2. 2. 1 , 
7. 2. 2. 3 , 1 7. 1 2 ). 
□ C ollect F A C S/ C B C sa m ples  1 h o ur f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o n s 7. 2. 2. 4 , 1 7. 1 2 ). 
□ C ollect (o pti o n al , wit h c o nse nt) P K  sa m ple 2 h o urs f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o n s 
7. 2. 2. 1 , 1 7. 1 2 ). 
 
 
7. 3. 3  
T R E A T M E N T  
 
T he e xa mi nati o ns of eac h visit are s pecifie d i n Secti o n 1 5 Sc he d ule of E ve nts . I n a d diti o n, please see Secti o n 
1 7. 1 2  Ta ble of P har mac o ki netic, Bi o mar ker , P har mac o ge n o mic , a n d F A C S  Sa m pli n g  f or detaile d i nf or mati o n 
re gar di n g t hese e val uati o ns. I m p orta nt n ote: t o e ns ure acc urac y of P K  sa m pli n g, st u d y a ge nt 
(A K S T 4 2 9 0/ place b o) s h o ul d be a d mi nistere d d uri n g t he st u d y v isit t o e na ble a p pr o priate ti mi n g of P K  sa m ple 
ac q uisiti o n . 
 
7. 3. 3. 1  Visit 3 ( D a y 1 4   2 ) a n d Visit 5 ( D a y 5 6   2)  
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der: 
□ C ollect la b orat or y sa m ples. 
□ C ollect P K  sa m ple 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n . 
□ St u d y a ge nt  ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n ( d ose a d mi nistere d a p pr o xi matel y 1 5 mi n utes 
f oll o wi n g ac q uisiti o n of P K  sa m ple). 
 
Re mai ni n g assess me nts (m ay be c o n d ucte d  i n a ny or der): 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P.  
□ St u d y a ge nt acc o u nta bilit y . 
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns . 
□ Perf or m tar gete d p h ysical e xa mi nati o n . 
□ C ollect vital si g ns . 
□ C ollect c o m plete d P D Q -3 9  a n d pr o vi de f or ne xt visit . 
□ Pr o vi de Ha user 3 -Da y  Patie nt Diar y f or ne xt visit ( Visit 5 o nl y ). 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state  (m ay be c o n d ucte d  i n a ny or der): 
o  M D S -U P D R S Parts 1 -4 .  
o  S E -A D L . 
o  CI SI -P D . 
o  1 0 -meter  ti me d wal k . 
□ Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0  or place b o ( Visit 5 O nl y ). 
□ C ollect weara ble se ns or de vice ( Visit 5 o nl y ). 
□ Pr o vi de weara ble se ns or de vice  t o be c ollecte d at Visit 6 (Visit 5 o nl y ). 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 3  of 9 9   
 
 
7. 3. 3. 2  Visit 4  ( D a y 2 8   2)  a n d Visit 6 –  E n d of Tre at me nt ( D a y 8 4  2)  or E arl y Ter mi n ati o n  
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der: 
□ C ollect la b orat or y sa m ples. 
□ C ollect i nitial P K sa m ple 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n. 
□ C ollect b i o mar ker sa m ple 1 5 mi n utes  pri or t o st u d y a ge nt a d mi nistrati o n  (Visit 6 O nl y ).  
□ C ollect F A C S/ C B C sa m ples 1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n (Visit 6 O nl y ).   
□ St u d y a ge nt  ( A K S T 4 2 90/ place b o) a d mi nistrati o n ( d ose a d mi nistere d a p pr o xi matel y 1 5 mi n utes  after 
ac q uisiti o n of i nitial P K  sa m ple).  
□ C o nfir mati o n of off -me dicati o n state ( ≥1 2 h o urs si nce last le v o d o pa d ose ). 
□ Assess me nts t o be c o n d ucte d i n t he off -me dicati o n ( off -le v o d o pa) state a n d 4 5 mi n utes ( 1 5 mi n utes ) 
after  st u d y a ge nt  a d mi nistrati o n  (m ay be c o n d ucte d  i n a ny or der):  
o  M D S -U P D R S Part 3.  
o  1 0 -meter ti me d wal k.  
□ A d mi nistrati o n of d o pa mi ner gic me dicati o n (c o m me nce o n -me dicati o n state) f or re mai ni n g 
assess me nts t hat da y.  
 
Re mai ni n g assess me nts (m ay be c o n d ucte d  i n a ny or der): 
□ C ollect vital si g ns.  
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P.  
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns.  
□ Perf or m tar gete d p h ysical e xa mi nati o n.  
□ C ollect c o m plete d P D Q -3 9 a n d pr o vi de f or ne xt visit.  
□ C ollect c o m plete d Ha user 3 -Da y Patie nt Diar y ( Visit 6 o nl y ).  
□ Perf or m 1 2 -lea d E C G.  
□ St u d y a ge nt acc o u nta bilit y.  
□ C ollect (o pti o n al , wit h c o nse nt) P K sa m ple 1  h o ur f oll o wi n g  st u d y a ge nt a d mi nistrati o n (see Secti o ns 
7. 2. 2. 1 , 7. 2. 2. 3 , 1 7. 1 2 ). 
□ Pr o vi de weara ble se ns or de vice ( Visit 4 o nl y ). 
□ C ollect weara ble se ns or de vice ( Visit 6 o nl y ). 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state: ( m ay be c o n d ucte d  i n a ny or der) 
o  M D S -U P D R S Parts 1 -4.  
o  M o C A ( Visit 6 O nl y ).  
o  S E -A D L.  
o  CI SI -P D.  
o  S -S T S ( Visit 6 O nl y ).  
o  1 0 -meter ti me d wal k.  
o  Fecal sa m ple c ollecti o n ( o pti o n al , wit h c o nse nt) (Visit 6 O nl y ).  
□ Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0 or place b o ( Visit 4 O nl y ).  
□ C ollect (o pti o n al , wit h c o nse nt) P K sa m ple 2  h o urs f oll o wi n g st u d y a ge nt a d mi nistrati o n (see Secti o n s 
7. 2. 2. 1 , 1 7. 1 2 ). 
 
 
7. 3. 4  
F O L L O W -U P  
 
7. 3. 4 .1  Visit 7  ( D a y 9 8   3  or 1 4 d a ys after E arl y Ter mi n ati o n ) 
 
Assess me nts t o be c o n d ucte d  i n t he f oll o wi n g or der, u nless ot her wise i n dic ate d : 
□ C o nfir m off -me dicati o n state ( ≥ 1 2 h o urs off le v o d o pa) . 
□ Assess me nts t o be c o n d ucte d i n t he off -me dicati o n ( off-le v o d o pa) state (m ay be c o n d ucte d  i n a ny 
or der ): 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 4  of 9 9   
 
o  M D S -U P D R S Part 3 . 
o  1 0 -meter ti me d wal k . 
□ A d mi nistrati o n of d o pa mi ner gic me dicati o n (c o m me nce o n -me dicati o n state) f or re mai ni n g 
assess me nts t hat da y.  
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns . 
□ Perf or m tar gete d p h ysical e xa mi nati o n . 
□ C ollect vital si g ns . 
□ C ollect la b orat or y, P K , a n d bi o mar ker sa m ples. 
□ Perf or m pre g na nc y testi n g a n d re vie w res ults i n W O C B P . 
□ C ollect c o m plete d P D Q -3 9 . 
□ Assess me nts t o be c o n d ucte d i n t he o n -me dicati o n state  (m ay be c o n d ucte d  i n a ny or der): 
o  M D S -U P D R S Parts 1 -4 .  
o  S E -A D L . 
o  CI SI -P D . 
o  1 0 -meter ti me d wal k. 
 
 
7. 3. 4 .2  S afet y F oll o w -U p: D oc u me nte d P h o ne C all  ( D a y 11 4   2  or 3 0  d a ys after E arl y Ter mi n ati o n ) 
 
□ Re vie w A Es a n d c o nc o mita nt me dicati o ns .  
 
7. 3. 5  
E A R L Y T E R MI N A TI O N  
 
I n cases of earl y ter mi nati o n, if a s u bject has recei ve d at least 1  d ose ( 4 0 0  m g) of A K S T 4 2 9 0  or place b o , t he 
site s h o ul d tr y t o perf or m all assess me nts sc he d ule d at t he Visit 6 - E n d of T reat me nt visit as well as t he 
s u bse q ue nt f oll o w u p visits u nless t he s u bject has wit h dra w n c o nse nt .  
 
7. 3. 6  
S C H E D U L E O F E V E N T S T A B L E  
 
A ta b ular s u m mar y of all pr oce d ures t hat wi ll be acc o m plis he d at eac h st u d y visit ca n be f o u n d i n Secti o n 1 5 
Sc he d ule of E ve nts.  
 
7. 3. 7  
E N D O F T RI A L/ E N D O F S T U D Y  
 
T he e n d of trial/e n d of st u d y will occ ur f oll o wi n g t he last s u bject’s last visit. T he a p pr o xi mate d urati o n t o 
c o n d uct t he trial t o s u p p ort f ull recr uit me nt is a p pr o xi matel y 1 0  m o nt hs.  
 
7. 4  
C O N C O MI T A N T M E DI C A TI O N S  
 
All prescri pti o n, o ver -t he-c o u nter, a n d n o n -prescri pti o n me dicati o ns (i ncl u di n g her bal t hera pies a n d s u p ple me nts) 
m ust be d oc u me nte d i n t he s o urce d oc u me nts a n d C R F . All s u bjects s h o ul d be mai ntai ne d o n t he sa me 
me dicati o ns at t he sa me d osa ge a n d a d mi nistrati o n t hr o u g h o ut t he e ntire st u d y peri o d, as me dicall y feasi ble, wit h 
n o i ntr o d ucti o n of ne w c hr o nic t hera pies. A n y c ha n ges i n m e dicati o ns s h o ul d be d oc u me nte d i n t he C R F wit h 
reas o n f or c ha n ge (e. g., A E ). 
 
7. 5  
P R O HI BI T E D M E DI C A TI O N S, T R E A T M E N T S, A N D P R O C E D U R E S  
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 5  of 9 9   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
8  
A S S E S S M E N T O F S A F E T Y  
 
Assess me nt of safet y will be c o n d ucte d b y bli n de d st u d y pers o n nel e xce pt i n e xtra or di nar y circ u msta nces w here 
k n o wle d ge of w het her A K S T 4 2 9 0  or place b o was  recei ve d b y a s u bject is esse ntial. A n y i nsta nces of u n bli n di n g 
will be ma na ge d as i n dicate d i n Secti o n 1 0. 6. 3 Brea ki n g t he St u d y Bli n d/ S u bject  C o de.  
 
8 .1  
S P E CI FI C A TI O N O F S A F E T Y P A R A M E T E R S  
 
8. 1. 1  
D E FI NI TI O N O F A D V E R S E E V E N T S ( A E)  
 
Per 2 1 C F R 3 1 2. 3 2(a) a n A E  is a n y u nt o war d ( u nfa v ora ble, har mf ul, or pat h ol o gic) me dical occ urre nce i n a 
s u bject a d mi nistere d a p har mace utical  (i n vesti gati o nal) pr o d uct e ve n if t he e ve nt d oes n ot necessaril y ha ve a 
ca usal relati o ns hi p wit h t his treat me nt .  
 
A n A E ca n t heref ore be a ny  u nfa v ora ble a n d u ni nte n de d si g n (i ncl u di n g a n a b n or mal la b orat or y fi n di n g t hat 
is dee me d cli nicall y si g nifica nt), s y m pt o m, or disease te m p orall y ass ociate d wit h t he use of a me dici nal 
(i n vesti gati o nal) pr o d uct w het her or n ot relate d t o t he me dici nal  (i n vesti gati o nal) pr o d uct.  
 
A n A E d oes i ncl u de a n y:  
• 
E xacer bati o n of a pre -e xisti n g ill ness . 
• 
S u bjecti ve or o bjecti ve s y m pt o ms s p o nta ne o usl y offere d b y t he s u bject a n d/ or o bser ve d b y t he 
i n vesti gat or or st u d y staff. 
• 
I ncrease i n fre q ue nc y or i nte nsit y of a pre-e xisti n g e pis o dic e ve nt or c o n diti o n . 
• 
C o n diti o n detecte d or dia g n ose d after st u d y a ge nt a d mi nistrati o n e ve n t h o u g h it ma y ha ve bee n 
prese nt pri or t o t he start of t he st u d y ( u nless it ca n be de m o nstrate d b y me dical rec or d re vie w t hat 
t he o nset of t he e ve nt prece de d t he date/ti me of inf or me d co nse nt ). 
• 
C o nti n u o us persiste nt disease or s y m pt o ms prese nt at baseli ne t hat w orse n f oll o wi n g t he start of t he 
st u d y. 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 6  of 9 9   
 
• 
S y m pt o ms ass ociate d wit h disease n ot pre vi o usl y re p orte d b y t he s u bject . 
• 
U nt o war d me dical  occ urre nces c o nsi dere d b y t he i n vesti gat or t o be relate d t o st u d y -ma n date d 
pr oce d ures . 
• 
A b n or mal assess me nts ( e. g., c ha n ge o n p h ysical e xa mi nati o n, E C G fi n di n gs), if t he y re prese nt a 
cli nicall y si g nifica nt fi n di n g, t hat were n ot prese nt at Baseli ne or w ors e ne d d uri n g t he c o urse of t he 
st u d y. 
• 
La b orat or y test a b n or malities, if t he y re prese nt a cli nicall y si g nifica nt fi n di n g, s y m pt o matic or n ot, 
w hic h were n ot prese nt at Baseli ne or w orse ne d d uri n g t he c o urse of t he st u d y . 
 
A n A E D O E S N O T i ncl u de a/a n:  
• 
Electi v e me dical or s ur gical pr oce d ure ( e. g., s ur ger y, e n d osc o p y, t o ot h e xtracti o n, tra nsf usi on) .  
• 
Pre -e xisti n g diseases or c o n diti o ns prese nt or detecte d at t he start of t he st u d y t hat d o n ot w orse n . 
• 
Sit uati o ns w here a n u nt o war d me dical occ urre nce has n ot occ urr e d (e. g., h os pitalizati o n f or c os metic 
electi ve s ur ger y, s ocial a n d/ or c o n ve nie nce a d missi o ns) . 
• 
O ver d ose of eit her st u d y a ge nt or c o nc urre nt me dicati o n wit h o ut a n y si g ns or s y m pt o ms.  
• 
Pre g na nc y . 
 
8. 1. 2  
D E FI NI TI O N O F S E RI O U S A D V E R S E E V E N T S  
 
N ote : if eit her t he i n vesti gat or or t he S p o ns or belie ves t hat t he e ve nt is seri o us, t he e ve nt m ust be c o nsi dere d 
seri o us a n d e val uate d f or e x pe dite d re p orti n g.  
N ote : t he ter ms “se vere” a n d “seri o us” are n ot s y n o n y m o us. Se verit y ( or i nte nsit y) refers t o t he gra de of a n 
A E . “ Seri o us” is a re g ulat or y defi niti o n .  
A seri o us a d verse e ve nt (e x perie nce) or reacti o n is a n u nt o war d me dical occ urre nce t hat , at a n y d ose , f ulfills 
o ne or m ore of t he f oll o wi n g criteria:  
a. Res ults i n deat h ( i.e., t he A E act uall y ca uses or lea ds t o deat h) . 
b.  Is life-t hreate ni n g. 
• 
A n A E  is c o nsi dere d “life-t hreate ni n g” if, i n t he vie w of eit her t he i n vesti gat or or S p o ns or, its 
occ urre nce places t he patie nt or s u bject at i m me diate ris k of deat h; it d oes n ot i ncl u de A Es  w hic h, 
ha d it occ urre d i n  a m ore se vere f or m, mi g ht ha ve ca use d deat h . 
c. Res ults i n 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.  
• 
H os pitalizati o n f or electi ve treat me nt of a pre -e xisti n g c o n diti o n t hat di d n ot w orse n d uri n g t he st u d y 
is n ot c o nsi dere d a n A E ; h os pitalizati o n f or partici pati n g i n t his st u d y is n ot c o nsi dere d a n A E. 
• 
C o m plicati o ns t hat occ ur d uri n g h os pitalizati o n are A Es; if a c o m plicati o n pr ol o n gs h os pitalizati o n, 
t he e ve nt is a n S A E. 
• 
“I n patie nt” h os pitalizati o n mea ns t he s u bject has bee n f o r mall y a d mitte d t o a h os pital f or me dical 
reas o ns t hat ma y or ma y n ot be o ver ni g ht; it d oes n ot i ncl u de prese ntati o n at a cas ualt y or e mer ge nc y 
r o o m u nless t he e ve nt meets t he defi niti o n of a n I m p orta nt Me dical E ve nt (i n t he o pi ni o n of t he 
I n vesti gat or or S p o ns or) . 
d.  Res ults i n persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct n or mal life 
f u ncti o ns. 
• 
T he ter m ‘ disa bilit y’ mea ns a s u bsta ntial disr u pti o n of a pers o n’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns; t his defi niti o n is n ot i nte n de d t o i ncl u de e x perie nces of relati vel y mi n or me dical 
si g nifica nce s uc h as u nc o m plicate d hea dac he, na usea, v o miti n g, diarr hea, i nfl ue nza, acci de ntal 
tra u ma (i.e., s prai ne d a n kle) t hat ma y i nterfere or pre ve nt e ver y da y life f u ncti o ns  b ut d o n ot c o nstit ute 
a s u bsta ntial disr u pti o n . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 8  of 9 9   
 
i n vesti gat or br oc h ure referre d o nl y t o ele vate d he patic e nz y mes or he patitis. Si milarl y, cere bral 
t hr o m b oe m b olis m a n d cere bral vasc ulitis w o ul d be u ne x pecte d ( b y virt ue of greater s pecificit y) if t he 
In vesti gat or ’s B r oc h ure liste d o nl y cere bral vasc ular acci de nts. " U ne x pecte d" as use d i n t his defi niti o n, als o 
refers t o A E s or s us pecte d a d verse reacti o ns t hat are me nti o ne d i n t he I n vesti gat or’s Br oc h ure as occ urri n g 
wit h a class of dr u gs or as a ntici pate d fr o m t he p har mac ol o gical pr o perties of t he dr u g b ut are n ot s pecificall y 
me nti o ne d as occ urri n g wit h t he partic ular dr u g u n der i n vesti gati o n . F or e xa m ple, alt h o u g h a n gi oe de ma is 
a ntici pate d t o occ ur i n s o me patie nts e x p ose d t o dr u gs i n t he an gi ote nsi n -c o n verti n g e nz y me  (A C E ) i n hi bit or 
class a n d a n gi oe de ma w o ul d be descri be d i n t he In vesti gat or ’s B r oc h ure as a class effect, t he first case of 
a n gi oe de ma o bser ve d wit h t he dr u g u n der i n vesti gati o n s h o ul d be c o nsi dere d u ne x pecte d f or re p orti n g 
p ur p oses  (F D A 2 0 1 2 ). 
 
T his defi niti o n of “ u ne x pecte d” relies e ntirel y o n  t he Refere nce Safet y I nf or mati on  i n t he I n vesti gat or’s 
Br oc h ure as t he basis f or deter mi ni n g if ne wl y ac q uire d i nf or mati o n ge nerate d fr o m cli nical tr ials or re p orte d 
fr o m ot her s o urces is u ne x pecte d. T he s us pecte d a d verse reacti o ns liste d i n t he In vesti gat or ’s B r oc h ure (i.e., 
“e x pecte d”) are t h ose o bser ve d wit h t he i n vesti gati o nal dr u g a n d f or w hic h a ca usal relati o ns hi p bet wee n t he 
e ve nt a n d t he dr u g is s us pecte d or c o nfir me d. 
 
S p o ns or assess me nt of e x pecte d ness a n d relati o ns hi p t o st u d y a ge nt/ca usalit y will deter mi ne t he nee d f or 
e x pe dite d re p orti n g of A Es.  
 
8. 3  
TI M E P E RI O D/ F R E Q U E N C Y F O R E V E N T A S S E S S M E N T/ F O L L O W -U P  
 
At e ver y cli nic visit, s u bjects w h o ha ve gi ve n i nf or me d c o nse nt will be assesse d f or A Es a n d S A Es . After t he 
s u bject has ha d a n o p p ort u nit y t o s p o nta ne o usl y me nti o n a n y pr o ble ms, t he i n vesti gat or s h o ul d i n q uire a b o ut A Es 
b y as ki n g a n o n -lea di n g q uesti o n s uc h as t he f oll o wi n g:  
1.  
“ H o w are y o u feeli n g?”  
2.  
“ Ha ve y o u ha d a n y c ha n ges si nce y o ur last assess me nt/ visit?”  
3.  
“ Ha ve y o u ta ke n a n y ne w me dici nes si nce y o ur last assess me nt/ visit?”  
 
8. 3 .1  
P O S T -S T U D Y A E A N D S A E  
 
T he i n vesti gat or is n ot o bli gate d t o acti ve l y see k S A E i nf or mati o n i n f or mer st u d y s u bjects, b ut t he 
i n vesti gat or is e nc o ura ge d t o n otif y Al ka hest, I nc. or t heir desi g nee of a n y A E or S A E occ urri n g wit hi n 
3 0  da ys after a s u bject c o m pletes t he st u d y ( or has t heir last visit) t hat t he i n vesti gat or j ud ges ma y be 
reas o na bl y relate d t o st u d y treat me nt or st u d y partici pati o n. 
 
8. 4  
R E P O R TI N G P R O C E D U R E S  
 
8. 4. 1  
A D V E R S E E V E N T R E P O R TI N G  
 
All s u bjects w h o ha ve gi ve n i nf or me d c o nse nt will be e val uate d f or A Es . All A Es t hat occ ur after t he ti me of 
treat me nt wit h t he st u d y a ge nt will be c o nsi dere d treat me nt emer ge nt A Es . S u bjects wit h treat me nt-emer ge nt 
A Es m ust be f oll o we d u ntil t he A E is res ol ve d or is sta ble, u nless t he s u bject is l ost t o f oll o w u p.  
 
Eac h A E or  s us pecte d a d verse reacti o n m ust be descri be d as f oll o ws: t he date of o nset, date of res ol uti o n, 
se verit y ( mil d, m o derate, se vere), fre q ue nc y of t he e ve nt (si n gle e pis o de, i nter mitte nt, c o nti n u o us), acti o n 
ta ke n wit h st u d y treat me nt ( n o acti o n ta ke n, treatme nt hel d, treat me nt disc o nti n ue d), o utc o me, ca usalit y * 
( u nrelate d, p ossi bl y relate d, defi nitel y relate d), a n d seri o us ness criteria. Eac h A E or s us pecte d a d verse 
reacti o n m ust be rec or de d se paratel y. 
 
* N ote : Ca usalit y assess me nt will be ma de o nl y w he n t he A E occ urs after t he s u bject has i nitiate d at least 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 3 9  of 9 9   
 
1  d ose  of t he st u d y a ge nt . A n A E occ urri n g bef ore t he s u bject’s e x p os ure t o st u d y a ge nt will al wa ys be 
la bele d as “ u nrelate d”. 
 
A n y A E occ urri n g d uri n g t he st u d y m ust be d oc u me nte d i n  t he s u bject’s me dical rec or ds a n d as a n A E i n t he 
C R F . A n y S A E occ urri n g d uri n g t he st u d y m ust be d oc u me nte d i n t he s u bject’s me dical rec or ds a n d as a n 
S A E i n t he C R F.  
 
A se parate set of S A E pa ges s h o ul d be use d f or e ac h S A E. H o we ver, if at t he ti me of i nitial re p orti n g, 
m ulti ple S A Es are prese nt t hat are te m p orall y a n d/ or cli nicall y relate d, t he y ma y be re p orte d o n t he sa me S A E 
pa ge.  
 
T he i n vesti gat or s h o ul d atte m pt t o esta blis h a dia g n osis of t he e ve nt (t hat meets t h e defi niti o n of a n A E or 
S A E) base d o n si g ns, s y m pt o ms, a n d/ or ot her cli nical i nf or mati o n . I n s uc h cases, t he dia g n osis s h o ul d be 
d oc u me nte d as t he A E a n d/ or S A E a n d n ot t he i n di vi d ual si g ns or s y m pt o ms . T he dia g n osis will bec o me t he 
basis f or t he ver bati m  ter m as re p orte d b y t he in vesti ga t or. If n o dia g n osis is k n o w n a n d cli nical si g ns a n d 
s y m pt o ms are n ot prese nt, t he a b n or mal fi n di n g s h o ul d be rec or de d. 
 
I n a d diti o n t o t he in vesti gat or’s o w n descri pti o n of t he A E , eac h A E will be e nc o de d acc or di n g t o t he 
Me d D R A . 
 
T he i n vesti gat or will ta ke all a p pr o priate a n d necessar y t hera pe utic meas ures re q uire d f or res ol uti o n of t he 
A E . A n y me dicati o n necessar y f or t he treat me nt of a n A E m ust be rec or de d o n t he c o nc o mita nt me dicati o n 
C R F .  
 
T he S A E pa ges of t he C R F s h o ul d be c o m plete d as t h or o u g hl y as p ossi ble a n d si g ne d b y t he i n vesti gat or or 
his/ her desi g nee bef ore tra ns mittal t o t he st u d y C o ntract Researc h Or ga nizati o n ( C R O) . It is ver y i m p orta nt 
t hat t he i n vesti gat or pr o vi de his/ her assess me nt of ca usalit y t o st u d y a ge nt  as well as a n a p plica ble dia g n osis 
at t he ti me of t he i nitial S A E re p ort.  
 
8. 4. 2  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  
 
8. 4. 2. 1  
Ti mefr a mes f or Re p orti n g S A Es  
U n der 2 1 C F R 3 1 2. 3 2(c), t he S p o ns or is re q uire d t o n otif y t he F D A , E M A, a n d all partici pati n g i n vesti gat ors 
i n a safet y re p ort of p ote ntiall y seri o us ris ks fr o m cli nical trials [i.e., S us pecte d U ne x pecte d Seri o us A d verse 
Reacti o ns ( S U S A R S) ], as s o o n as p ossi ble after t he S p o ns or recei ves t he safet y i nf or mati o n a n d deter mi nes 
t hat t he i nf or mati o n q ualifies f or re p orti n g: 
• 
N o later t ha n 7 cale n dar da ys f or e ve nts t hat are life t hreate ni n g (i n t he o pi ni o n of t he 
in vesti gat or or t he S p o ns or) or t hat i n v ol ve d eat h as a n o utc o me . 
• 
N o later t ha n 1 5 cale n dar da ys f or all ot her S U S A R S . 
 
As s uc h, pr o m pt n otificati o n of t he S p o ns or , a n d/ or t he S p o ns or’s re prese ntati ves, a n d pr o m ptl y pr o vi di n g 
re q ueste d f oll o w-u p i nf or mati o n re gar di n g S A Es is esse ntial s o t hat et hical a n d  re g ulat or y res p o nsi bilities a n d 
le gal o bli gati o ns ca n be satisfie d. I n vesti gat ors are res p o nsi ble f or re p orti n g S A Es acc or di n g t o t he f oll o wi n g 
ti mefra mes:  
 
•  
T he S A E Re p ort F or m a n d rele va nt s o urce d oc u me nts, if a p plica ble, m ust be c o m plete d a n d n otifie d, 
fa xe d, or e maile d t o  P P D P V G  i m me diatel y ( wit h o ut c ul pa ble dela y), b ut n o later t ha n 2 4 h o urs of 
o bser vati o n or lear ni n g of t he e ve nt.  
o  
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 0  of 9 9   
 
o  
 
•  
F oll o w -u p i nf or mati o n m ust  be se nt t o 
 i m me diatel y ( wit h o ut c ul pa ble dela y), b ut n o later 
t ha n 2 4 h o urs of recei pt of i nf or mati o n b y t he i n vesti gati o nal site.  
 
S A Es will be f oll o we d u ntil res ol uti o n, t he c o n diti o n sta bilizes, t he e ve nt is ot her wise e x plai ne d or is j u d ge d 
b y t he i n vesti gat or t o be n o l o n ger cli nicall y si g nifica nt, or u ntil t he s u bject is l ost t o f oll o w u p.  
 
8. 4. 2. 2  
S A E I nf or m ati o n t o Re p ort  
All i nf or mati o n a vaila ble re gar di n g a n S A E m ust be s u b mitte d i n t he ti mefra mes i n dicate d . At a mi ni m u m, 
S A E re p orts m ust c o ntai n t he s u bject I D, t he S A E  ver bati m ter m, o nset date, relati o ns hi p t o st u d y 
a ge nt/ca usalit y, a n d a brief narrati ve of t he e ve nt. Please n ote t hat rel ati o ns hi p t o st u d y a ge nt/c a us alit y as 
well as t he re p orte d ver b ati m ter m are ver y i m p ort a nt  a n d s h o ul d  be i ncl u de d i n t he i nitial re p ort as it 
ma y i m pact e x pe dite d re g ulat or y re p orti n g re q uire me nts f or t he e ve nt . T he date of S A E disc o ver y b y t he site 
staff s h o ul d be d oc u me nte d i n t he s o urce d oc u me nts. 
 
T he i n vesti gat or m ust rec or d all  rele va nt i nf or mati o n re gar di n g a n A E/ S A E i n t he a p plica ble secti o ns of t he 
C R F . It is n ot acce pta ble f or t he i n vesti gat or t o se n d p h ot oc o pies of t he s u bject’s me dical rec or ds i n lie u of 
c o m pleti o n of t he a p pr o priate A E/ S A E pa ges . H o we ver, t here ma y be i ns ta nces w he n c o pies of me dical 
rec or ds f or certai n cases are re q ueste d b y t he C R O a n d/ or t he S p o ns or. If me dical rec or ds are s u b mitte d t o t he 
C R O t he n all s u bject pers o nal i de ntifiers m ust be c o m pletel y a n d t h or o u g hl y re dacte d pri or t o s u b missi o n.  
 
A bla n k S A E Re p ort F or m a n d i nstr ucti o ns f or S A E re p orti n g will be pr o vi de d t o t he site a n d will be 
mai ntai ne d i n t he i n vesti gat or’s st u d y file. T he S A E Re p ort F or m m ust be c o m plete d a n d fa xe d or e maile d t o 
P P D  P V G  acc or di n g t o t he ti mefra mes s pecifie d i n Secti o n 8. 4. 2. 1 . T he S A E Re p ort F or m s h o ul d i ncl u de 
c o pies of rele va nt s o urce d oc u me nts, if a p plica ble . R ec o nciliati o n of a n y discre pa nc y n ote d d uri n g m o nit ori n g 
a n d a me n di n g t he e C R F is re q uire d.  
 
If ne w i nf or mati o n a b o ut a n S A E  is recei ve d or c orrecti o ns t o data are nee de d , t he i n vesti gat or s h o ul d 
c o m plete a ne w S A E Re p ort F or m a n d c hec k t he “f oll o w -u p” b o x o n t he f or m . T his f oll o w -u p S A E Re p ort 
F or m s h o ul d be s u b mitte d wit hi n 2 4 h o urs of lear ni n g of t he i nf or mati o n, es peciall y if t he ne w i nf or mati o n 
c o ncer ns seri o us ness, relate d ness, or t he e ve nt ter m of a n A E.  
 
Sites acti n g u n der t heir l ocal I R B/ IE C s h o ul d s u b mit all a p plica ble e ve nts, u na ntici pate d pr o ble ms, a n d safet y 
re p orts t o t he site’s l ocal I R B/IE C, if a p plica ble . All safet y re p ort i n g de viati o ns s h o ul d als o be s u b mitte d t o 
t heir l ocal I R B/IE C, if a p plica ble.  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 1  of 9 9   
 
8. 4. 4  
R E P O R TI N G O F P R E G N A N C Y  
 
W hile pre g na nc y itself is n ot c o nsi dere d a n A E, pre g na nc y occ urri n g i n a cli nical st u d y m ust be f oll o we d t o 
c ollect i nf or mati o n re gar di n g t he e x perie nces of gestati o n a n d pre g na nc y wit h st u d y a ge nt e x p os ure . T he 
i n vesti gat or must re p ort a n y pre g na nc y t hat occ urs i n a fe male st u d y s u bject  or fe male part ner of a male 
s u bject s u bse q ue nt t o first e x p os ure t o t he st u d y a ge nt u ntil E n d of St u d y, or 3 m o nt hs f oll o wi n g a s u bject’s 
last d ose i n t he e ve nt of earl y ter mi nati o n. All pre g na ncies will be re p orte d t o t he I R B /I E C, S p o ns or, a n d 
C R O . I n t he e ve nt of a pre g na nc y, treat me nt will be disc o nti n ue d, a n d t he s u bject will u n der g o c o nti n ue d 
safet y f oll o w-u p t hr o u g h pre g na nc y o utc o me.  T he st u d y bli n d ca n be br o ke n f or safet y reas o ns if t he  
i nf or mati o n is re q uire d f or t he ma na ge me nt of pre g na nc y . A n y n ote d i nte nti o nal or u ni nte nti o nal brea ki n g of 
t he bli n d s h o ul d be re p orte d t o t he S p o ns or’s St u d y Tea m Lea d a n d Q ualit y Gr o u p (see Secti o n 1 0. 6. 3 ). 
 
A n y pre g na nc y m ust be f oll o we d b y t he in vesti gat or u ntil deli ver y or t o t he e n d of pre g na nc y . A n y 
a n o malies, c o m plicati o ns, a b n or mal o utc o mes, or birt h defect (s) o bser ve d i n t he c hil d m ust be re p orte d as a n 
S A E wit hi n 2 4 h o urs of t he i n vesti gat or or st u d y pers o n nel’s first k n o wle d ge.  
 
8. 5  
S T U D Y H A L TI N G R U L E S  
 
If a n y of t he f oll o wi n g safet y e ve nts occ ur, a Safet y E val uati o n Meeti n g ( defi ne d bel o w) will be tri g gere d: 
•  
T hree or m ore S A Es i n t he sa me s yste m/ or ga n/class ( S O C) t hat are assesse d as p ossi bl y or  defi nitel y 
relate d t o t he st u d y age nt b y t he i n vesti gat or a n d c o nfir me d as s uc h b y t he S p o ns or  (see Secti o n 8. 2. 2 
Relati o ns hi p t o St u d y A ge nt ). 
•  
Wit hi n or bet wee n a n y of t he d osi n g gr o u ps: a n o verall patter n of s y m pt o matic, cli nical, or la b orat or y 
e ve nts ass ociate d wit h t he st u d y age nt t hat t he S p o ns or’s Pr o gra m P h ysicia n  or desi g nee c o nsi der a 
seri o us p ote ntial safet y c o ncer n (e. g., s us pici o us o verall patter n). 
E ve nts t hat are m ore li kel y relate d t o a s pecific st u d y pr oce d ure, will n ot be c o nsi dere d “ dr u g relate d” a n d will n ot 
c o ntri b ute t o t he c o u nt of defi nitel y -relate d S A Es t hat w o ul d tri g ger a Safet y E val uati o n Meeti n g. 
 
S afety Ev al u ati o n Meeti n g  
 
If safet y e ve nts of p ote ntial c o ncer n occ ur d uri n g t he trial (i.e., 3 relate d e ve nts i n t he sa me S O C or a s us pici o us 
o verall patter n, as defi ne d a b o ve) a Safet y E val uati o n Meeti n g will be tri g gere d, a n d d osi n g ma y be te m p oraril y 
halte d base d o n t he o bser vati o ns . T he S p o ns or will i nf or m i n vesti gat ors a n d t he F D A  a n d E M A i n t he e ve nt of 
a n y te m p orar y halt i n d osi n g at a n y ti me d uri n g t he c o n d uct of t he st u d y . T he p ur p ose of t he meeti n g is f or 
i n vesti gat ors, t he S p o ns or, a n d t he C R O Me dical M o nit or (s) t o disc uss a n d e val uate t he safet y of t he s u bjects 
usi n g a vaila ble a g gre gate d safet y data a n d wit h o ut c o m pr o misi n g st u d y bli n di n g , u nless t he S p o ns or dee ms 
u n bli n di n g necessar y f or safet y e val uati o n .  
 
Atte n da nts at t he Safet y E val uati o n  Meeti n g  will i ncl u de t he Pr o gra m P h ysicia n  of Al ka hest ( or his/ her desi g nee), 
t he C R O  me dical m o nit or(s) , a n d availa ble  acti ve i n vesti gat ors partici pati n g i n t he trial . After s ufficie nt data 
re vie w t he S p o ns or will c h o ose o ne of t he f oll o wi n g c o urses of acti o n:  
1.  C o nti n ue d osi n g wit h n o c ha n ge t o pr ot oc ol . 
2.  H alt d osi n g i n all gr o u p s a n d st o p t he st u d y.  
3.  C o nti n ue wit h a m o difie d pr ot oc ol desi g n a n d a me n d t he pr ot oc ol as a p pr o priate.  
 
8. 6  
S A F E T Y O V E R SI G H T  
 
Safet y o versi g ht will be pr o vi de d b y t he S p o ns or’s Pr o gra m P h ysicia n  or his or her desi g nee a n d t he C R O’s 
Me dical M o nit or (s) i n c o ncert wit h t he site in vesti gat ors . T here will be n o f or mal Data Safet y M o nit ori n g B oar d 
( D S M B) esta blis he d. As nee de d, Safet y E val uati o n Meeti n gs will be c o n ve ne d as des cri be d i n  Secti o n 8. 5  t o 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 2  of 9 9   
 
m o nit or t he o n g oi n g safet y of t he st u d y . T he S p o ns or’s Pr o gra m P h ysicia n  or desi g nee is t he fi nal a ut h orit y f or 
safet y o versi g ht i n t he st u d y. 
 
9  
C LI NI C A L M O NI T O RI N G  
 
Cli nical site m o nit ori n g is c o n d ucte d t o e ns ure t hat t he ri g hts a n d well -bei n g of h u ma n s u bjects are pr otecte d, t hat 
t he re p orte d trial data are acc urate, c o m plete, a n d verifia ble, a n d t hat t he c o n d uct of t he trial is i n c o m plia nce wit h 
t he c urre ntl y a p pr o ve d pr ot oc ol/ame n d me nt(s), wit h G C P, a n d wit h a p plica ble re g ulat or y re q uire me nt(s).  
 
• 
M o nit ori n g f or t his st u d y will be c o n d ucte d  b y t he st u d y C R O i n acc or da nce wit h t he Cli nical M o nit ori n g 
Pla n ( C M P) . 
• 
A mi x of o n -site a n d ce ntralize d ris k-base d m o nit ori n g will be c o n d ucte d t o ens ure t he safet y of cli nical 
s u bjects a n d t he acc urac y a n d c o m plete ness of st u d y data.  
• 
T he S p o ns or  will be pr o vi de d wit h c o pies of m o nit ori n g re p orts per t he ti meli nes s pecifie d wit hi n t he 
C M P . 
• 
Details of cli nical site m o nit ori n g tas ks a n d sc o pe are d oc u me nte d i n t he st u d y’s C M P . T he C M P 
descri bes i n detail w h o will c o n d uct m o nit ori n g, at w hat fre q ue nc y m o nit ori n g will be d o ne, at w hat le vel 
of detail m o nit ori n g will be c o n d ucte d , a n d t he distri b uti o n of m o nit ori n g re p orts. 
• 
I n de pe n de nt a u dits ma y  b e c o n d ucte d b y t he S p o ns or  i n acc or da nce wit h a st u d y-s pecific Qualit y 
Ass ura nce  P la n t o e ns ure m o nit ori n g practices are c o n d ucte d c o nsiste ntl y acr oss all partici pati n g sites , 
t hat m o nit ors are f oll o wi n g t he C M P a n d sites c o n d uct t he st u d y acc or di n g t o t he pr ot oc ol, G C P , a n d 
a p plica ble re g ulat or y re q uire me nt s. 
 
1 0  
S T A TI S TI C A L C O N SI D E R A TI O N S  
1 0 . 1 S T A TI S TI C A L D E SI G N M O D E L  A N D A N A L Y TI C A L P L A N S  
 
A Statistical A nal ysis Pla n ( S A P) wit h a nal ytical details a n d ass u m pti o n s will be de vel o pe d a n d fi nalize d  bef ore  
data base l oc k a n d u n bli n di n g of t he st u d y data.  
 
1 0 . 2 S T A TI S TI C A L H Y P O T H E S E S  
 
T he n ull a n d alter nati ve h y p ot heses f or t his st u d y are:  
H 0: µC  = µ T  
 vs  
H A : µC  ≠ µ T . 
N ote: T he s y m b ol “ µ ” de n otes t he mea n c ha n ge fr o m baseli ne i n m ot or f u ncti o n d uri n g t he practicall y defi ne d 
off -me dicati o n state at Wee k 1 2 as meas ure d b y t he M D S -U P D R S Part 3  f or t he c o ntr ol ( C) a n d treate d ( T) 
gr o u ps . 
 
1 0. 3  A N A L Y SI S D A T A S E T S  
 
St u d y data will be a nal yze d i n o ne of t he f oll o wi n g a nal ysis sets:  
•  
I nte nt-t o-Tre at (I T T)  set will i ncl u de all ra n d o mize d s u bjects. 
•  
M o difie d I nte nt -t o-Tre at ( mI T T) / E v al u a ble set will be a s u bset of t he I T T s u bjects wit h baseli ne 
a n d Wee k 1 2  val ue f or off -me dicati o n m ot or f u ncti o n as meas ure d b y t he M D S-U P D R S Part 3.  
•  
S afet y E v al u a ble  set will i ncl u de all ra n d o mize d s u bjects w h o recei ve at least 1 d ose of t he st u d y 
a ge nt. 
•  
Per -Pr ot oc ol ( P P) set is a s u bset of I T T s u bjects w h o f oll o w t he pr ot oc ol wit h o ut a n y major 
de viati o n(s). A detaile d descri pti o n of t he reas o ns f or e xcl usi o n fr o m t he P P p o p ulati o n will be 
i ncl u de d i n t he Statistical A nal ysis Pla n ( S A P) 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 3  of 9 9   
 
S u bjects will be a nal yze d i n t he treat me nt ar m assi g ne d at ra n d o mizati o n  f or t he I T T, mI T T, a n d P P sets. F o r t he 
Safet y E val ua ble set, s u bjects will be gr o u pe d acc or di n g t o act ual treat me nt recei ve d.  
 
1 0. 4  D E S C RI P TI O N O F S T A TI S TI C A L M E T H O D S  
 
1 0. 4. 1  
G E N E R A L A P P R O A C H  
 
S u bject dis p ositi o n a n d pr ot oc ol de viati o ns will be s u m marize d descri pti vel y b y treat me nt ar m. T he 
c o m para bilit y bet wee n t he treat me nt ar ms i n de m o gra p hics a n d baseli ne c haracteristics will be 
assesse d. Pri or a n d c o nc o mita nt me dicati o ns will als o be s u m marize d b y treat me nt ar m.  
 
All s u m mar y statistics will be descri pti ve u nless n ote d ot her wise . Descri pti ve s u m maries will i ncl u de 
mea n, sta n dar d de viati o n  ( S T D), me dia n, a n d ra n ge f or c o nti n u o us varia bles a n d c o u nts, a n d 
perce nta ges f or cate g orical varia bles. T w o -si de d 9 5 % c o nfi de nce i nter vals ( CIs) will be pr o vi de d f or 
t he mea ns a n d perce nta ges  as nee de d . F or ke y o utc o me meas ures, t he differe nce bet wee n t he treat me nt 
ar m a n d t he 9 5 % CI of t he differe nce will be c o m p ute d.  
 
Detaile d statistical met h o ds will be o utli ne d i n t he S A P f or t he st u d y.  
 
1 0. 4. 2  
A N A L Y SI S O F T H E P RI M A R Y E N D P OI N T  
 
T he pri mar y e n d p oi nt is c ha n ge fr o m baseli ne t o Wee k 1 2 i n t he off -me dicati o n m ot or f u ncti o n as meas ure d 
b y t he M D S -U P D R S Part 3 . T he mai n a nal ysis f or t he pri mar y efficac y varia ble will be a nal yze d usi n g mI T T 
s u bjects. 
 
A mi xe d -effect m o del f or re peate d m eas ures ( M M R M) will be e m pl o ye d t o a nal yze t he c ha n ge fr o m baseli ne 
sc ores at eac h visit o ver ti me u p t o Wee k 1 2. T he m o del will i ncl u de t he fi xe d effects of treat me nt  (stratifie d, 
b y se x) , baseli ne of t he e n d p oi nt, visit, a n d treat me nt b y visit i nteracti on. A n u nstr uct ure d c o varia nce 
str uct ure will be use d t o m o del t he wit hi n s u bject err or. Least -s q uare ( L S) mea n, sta n dar d err or ( S E), a n d 
9 5 % CI of t he L S mea n will be pr o vi de d f or eac h treat me nt ar m at eac h visit . T he differe nce i n L S mea ns 
bet wee n treat me nt ar ms a n d 9 5 % CI of t he differe nce will als o be calc ulate d . P -val ue f or testi n g w het her t he 
differe nce is e q ual t o zer o will be pr o vi de d . T he p -val ue at Wee k 1 2 will be c o m pare d a gai nst t he al p ha 
si g nifica nt le vel of 0. 1. 
 
T he mai n a nal ysis of t he pri mar y e n d p oi nt usi n g t he a b o ve M M R M will use all a vaila ble data. T o c hec k t he 
r o b ust ness of t he res ults, t he f oll o wi n g se nsiti vit y a nal yses will be perf or me d : 
•  
A nal ysis of c o varia nce ( A N C O V A) m o del o n t he o bser ve d c ha n ge fr o m baseli ne val ue at Wee k 1 2 . 
T he m o del i ncl u des treat me nt as t he fi xe d effect a n d baseli ne of t he e n d p oi nt as a c o variate.  
•  
T he sa me M M R M m o del o n data fr o m t he P P s u bjects.  
•  
De pe n di n g o n t he stat us of missi n g data, m ulti ple i m p utati o ns ma y be e m pl o ye d t o ha n dle missi n g 
data a n d a p pl y t he M M R M o n t he i m p ute d datasets.  
   
1 0. 4. 3  
A N A L Y SI S O F T H E S E C O N D A R Y E N D P OI N T S  
 
Sec o n dar y efficac y e n d p oi nts will be a nal yze d usi n g t he mI T T set. C o nti n u o us e n d p oi nts will be a nal yze d 
usi n g t he sa me M M R M m o del use d f or t he pri mar y e n d p oi nt. L o gistic re gr essi o n m o dels will be use d f or 
e n d p oi nts wit h cate g orical or or di nal res p o nses.  
 
Safet y data will be a nal yze d usi n g t he Safet y E val ua ble set. Treat me nt -e mer ge nt ad verse e ve nts will be 
s u m marize d b y Me d D R A c o di n g ter ms, a n d se parate ta b ulati o ns will be pr o d uce d f or treat me nt-relate d 
a d verse e ve nts, seri o us a d verse e ve nts , a n d disc o nti n uati o ns d ue t o a d verse e ve nts. Vital si g n data a n d 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 4  of 9 9   
 
fi n di n gs fr o m p h ysical e xa mi nati o ns will be ta b ulate d f or c ha n ges o ver ti me d uri n g t he  st u d y peri o d . 
La b orat or y para meters wi ll be s u m marize d f or c ha n ges acr oss t he st u d y peri o d  usi n g descri pti ve statistics.  
 
  
1 0. 4. 4  
P L A N N E D I N T E RI M A N A L Y S E S  
 
Safet y will be m o nit ore d o n a n o n g oi n g basis. If a Safet y E val uati o n Meeti n g is tri g gere d (see Sect i o n 8. 5), a n 
a d h oc i nteri m safet y a nal ysis will be perf or me d . If s uc h a n a d h oc safet y i nteri m a nal ysis is c o n d ucte d, t he 
treat me nt assi g n me nt will re mai n mas ke d, u nless u n bli n di n g is dee me d necessar y b y t he S p o ns or f or safet y 
e val uati o n.  
  
1 0. 4. 5  
M U L TI P L E C O M P A RI S O N/ M U L TI P LI CI T Y  
 
N o a dj ust me nts f or m ulti plicit y will be e m pl o ye d . All h y p ot hesis tests will be perf or me d  at a n al p ha le vel of 
0. 1.  
  
1 0. 4. 6   
E X P L O R A T O R Y A N A L Y S E S  
 
E x pl orat or y e n d p oi nts will be s u m marize d descri pti vel y . Treat me nt c o m paris o ns o n e x pl orat or y e n d p oi nts, if 
perf or me d , will be i n t he nat ure of h y p ot hesis ge nerati o n. 
  
1 0. 5  S A M P L E SI Z E  
 
A t otal of a p pr o xi matel y 1 2 0 s u bjects will be ra n d o mize d i n a 1: 1 rati o t o acti ve treat me nt (a p pr o xi matel y 6 0 
s u bjects) or place b o (a p pr o xi matel y 6 0 s u bjects), wit h t he i nte nt of o btai ni n g ~ 1 0 8  e val ua ble s u bjects.  
 
T he varia bilit y of c ha n ge fr o m baseli ne i n t he off -me dicati o n m ot or f u ncti o n as meas ure d b y M D S -U P D R S, 
Part  3 is a p pr o xi matel y 6. 4 a n d 7. 6 p oi nts at Wee ks 4 8 a n d 6 0, res pecti vel y, f or t he place b o gr o u p, a n d 
a p pr o xi matel y 4. 9 a n d 4. 8 i n a pre vi o us st u d y of t he c o m p o u n d E xe nati de ( At ha u da 2 0 1 7 ). Ass u mi n g t he 
varia bilit y at Wee k 1 2 is si milar t o t hat at Wee k 4 8, a n d ass u mi n g t he varia bilit y i n t he A K S T 4 2 9 0 treate d gr o u p 
is si milar t o t hat of E xenati de -treate d s u bjects, t he sa m ple size f or t he st u d y will base d o n S T D = 6. 4 a n d 4. 9 f or 
t he c o ntr ol a n d treate d res pecti vel y. Wit h n = 5 4  e val ua ble s u bjects i n eac h ar m, t he st u d y w ill ha ve m ore t ha n 8 5 % 
p o wer t o detect a differe nce i n mea ns bet wee n ar ms w he n t he tr ue differe nce is 3 p oi nts base d o n a t w o -si de d t-
test at a n al p ha of 0. 1. If t he tr ue differe nce is 4 p oi nts, t he p o wer i ncreases t o m ore t ha n  9 5 %.  
  
1 0. 6  M E A S U R E S T O MI NI MI Z E BI A S  
 
1 0. 6. 1  
E N R O L L M E N T/ R A N D O MI Z A TI O N/ M A S KI N G P R O C E D U R E S  
 
T o mi ni mize t he p ote ntial bias at t he ti me of ra n d o mizati o n, t he st u d y will be d o u ble -bli n de d a n d ra n d o mize d 
i n a 1: 1 rati o (acti ve: place b o) base d o n a bl oc k ra n d o mizati o n sc he ma stratifie d b y se x. T he ra n d o mizati o n 
will be we b -base d a n d ce ntralize d. T he ra n d o mizati o n c o des will be ge nerate d b y a statisticia n t hat has n o 
i n v ol veme nt i n t he st u d y ot her t ha n ge nerati o n a n d mai nte na nce of t he ra n d o mizati o n c o des.   
 
1 0. 6. 2  
E V A L U A TI O N O F S U C C E S S O F B LI N DI N G  
 
S uccess of bli n di n g will be assesse d base d o n all occ urre nces (i nte nti o nal or u ni nte nti o nal) of u n bli n di n g of 
bli n de d st u d y s u bjects or st u d y pers o n nel ( e. g., i n vesti gat ors, me dical pr o vi ders, c o g niti ve/ m ot or testi n g 
raters, t he S p o ns or or t heir re prese ntati ves). All i nte nti o nal a n d u ni nte nti o nal u n bli n di n g will be d oc u me nte d 
a n d re p orte d.  
  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 5  of 9 9   
 
1 0. 6. 3  
B R E A KI N G T H E S T U D Y B LI N D/ S U B J E C T C O D E  
 
T he st u d y bli n d ca n be br o ke n f or safet y reas o ns if t he i nf or mati o n is re q uire d f or t he ma na ge me nt o f S A Es, 
se vere A Es, or pre g na ncies . T he I n vesti gat or ca n o btai n t he treat me nt all ocati o n f or t heir s u bject t hr o u g h t he 
we b -base d ra n d o mizati o n s yste m  (I R T). In t he rare e ve nt t he we b -base d s yste m is u na vaila ble or t o c o ntact 
t he Me dical M o nit or, 
2 4 -h o ur e mer ge nc y Safet y H otli ne ma y be c o ntacte d at: 
 
 
  
 
 
Bef ore brea ki n g t he bli n d, e ver y atte m pt s h o ul d be ma de t o disc uss t he nee d wit h t he S p o ns or Pr o gra m 
P h ysicia n, or desi g nee. W he n s o me de gree of u n bli n di n g m ust occ ur, t his s h o ul d be li mite d t o t he fe west 
n u m ber of pe o ple o n a nee d -t o-k n o w basis.  
 
A n y n ote d i nte nti o nal or u ni nte nti o nal brea ki n g of t he bli n d s h o ul d be re p orte d t o t he S p o ns or’s St u d y Tea m 
Lea d  a n d Q ualit y Gr o u p . If u ni nte nti o nal u n bli n di n g occ urs d uri n g t he st u d y, r o ot ca use a nal ysis will be 
e val uate d, a n d c orrecti ve acti o ns i m ple me nte d.  
 
1 1  
S O U R C E D O C U M E N T S A N D A C C E S S T O S O U R C E D A T A/ D O C U M E N T S  
 
Eac h partici pati n g site will mai ntai n a p pr o priate me dical a n d researc h rec or ds f o r t his trial, i n c o m plia nce wit h  
I C H E 6 R 2 a n d re g ulat or y a n d i nstit uti o nal re q uire me nts f or t he pr otecti o n of c o nfi de ntialit y of s u bjects. Eac h site 
will per mit a ut h orize d re prese ntati ves of re g ulat or y a ge ncies, t he I R B/I E C, t he S p o ns or, or t he S p o ns or’s 
re prese ntati ves t o e xa mi ne (a n d w he n per mitte d b y a p plica ble la w, t o c o p y) cli nical rec or ds f or t he p ur p oses of 
q ualit y ass ura nce re vie ws, a u dits, a n d e val uati o n of t he st u d y safet y, pr o gress, a n d data vali dit y .  
 
S o urce data are all i nf or mati o n,  ori gi nal rec or ds of cli nical fi n di n gs, o bser vati o ns, or ot her acti vities i n a cli nical 
trial necessar y f or t he rec o nstr ucti o n a n d e val uati o n of t he trial. E xa m ples of t hese ori gi nal d oc u me nts a n d data 
rec or ds i ncl u de, b ut are n ot li mite d t o, h os pital rec or ds, cli nical a n d office c harts, la b orat or y n ot es, me m o ra n da, 
s u bject’s me m or y ai ds or e val uati o n c hec klists, p har mac y dis pe nsi n g rec or ds, rec or de d a u di o ta pes of c o u nseli n g 
sessi o ns, rec or de d data fr o m a ut o mate d i nstr u me nts, c o pies or tra nscri pti o ns certi fie d after verificati o n as bei n g 
attri b uta ble, le gi ble, acc urate a n d c o m plete, micr ofic hes, p h ot o gra p hic ne gati ves, micr ofil m or ma g netic me dia, x -
ra ys, a n d s u bject files a n d rec or ds ke pt at t he p har mac y, at t he la b orat ories, a n d me dic o-tec h nical de part me nts 
i n v ol ve d i n t he cli nical trial.  
 
It is n ot acce pta ble f or t he C R F t o be t he o nl y rec or d of a s u bject’s partici pati o n i n t he st u d y. T his is t o e ns ure t hat 
a n y o ne w h o w o ul d access t he s u bject’s me dical rec or d has a de q uate k n o wle d ge t hat t he s u bject is pa rtici pati n g i n a 
cli nical trial . S o urce d oc u me nt te m plates will be de vel o pe d f or t his st u d y.  
 
1 2  
E T HI C S/ P R O T E C TI O N O F H U M A N S U B J E C T S  
1 2 . 1 E T HI C A L S T A N D A R D  
 
T he i n vesti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o nf or mit y wit h Re g ulati o ns f or t he Pr otecti o n of 
H u ma n S u bjects of Researc h c o difie d i n 4 5 C F R Part 4 6, 2 1 C F R Part 5 0, 2 1 C F R Part 5 6, I C H E 6 R 2, 2 1 C F R, 
part 3 2 0, 1 9 9 3, Rete nti o n of Bi oa vaila bilit y a n d Bi oe q ui vale nce Testi n g Sa m ples a n d t he Declarati o n of Helsi n ki.  
 
1 2 . 2 I N S TI T U TI O N A L R E VI E W B O A R D 
 
T his pr ot oc ol a n d a n y acc o m pa n yi n g material t o be pr o vi de d t o t he s u bject (s uc h as a d vertise me nts, s u bject 
i nf or mati o n s heets, or descri pti o ns of t he st u d y use d t o o btai n i nf or me d c o nse nt) will be s u b mitte d b y t he 
i n vesti gat or t o a n I R B or IE C . A p pr o val fr o m t he I R B/ IE C m ust be o btai ne d bef ore starti n g t he st u d y a n d s h o ul d 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 6  of 9 9   
 
be d oc u me nte d i n a letter t o t he i n vesti gat or s pecif yi n g t he pr ot oc ol n u m ber, pr ot oc ol versi o n, d oc u me nts 
re vie we d, a n d date o n w hic h t he c o m mittee met a n d gra nte d t he a p pr o val.   
 
All c ha n ges t o t he c o nse nt f or m will be I R B /I E C a p pr o ve d; a deter mi nati o n will be ma de re gar di n g w het her 
pre vi o usl y c o nse nte d s u bjects nee d t o be re-c o nse nte d. 
 
A n y m o dificati o ns or a me n d me nt s t o t he pr ot oc ol m ust als o be s u b mitte d t o t he I R B/IE C f or a p pr o val pri or t o 
i m ple me ntati o n. 
 
1 2 . 3 I N F O R M E D C O N S E N T P R O C E S S 
 
1 2 . 3. 1 
C O N S E N T F O R M S  
 
C o nse nt f or ms descri bi n g i n detail t he st u d y a ge nt, st u d y pr oce d ures, a n d ris ks are gi ve n t o t he s u bject or 
h ealt hcare p o wer of att or ne y or e q ui vale nt le gal re prese ntati ve,  a n d writte n d oc u me ntati o n of i nf or me d 
c o nse nt is re q uire d pri or t o a n y st u d y -relate d pr oce d ures.  
 
1 2 . 3. 2 
C O N S E N T P R O C E D U R E S A N D D O C U M E N T A TI O N  
 
It is t he res p o nsi bilit y of t he i n vesti gat or or desi g nee t o o btai n writte n i nf or me d c o nse nt fr o m eac h s u bject 
partici pati n g i n t his st u d y after a de q uate e x pla nati o n of t he ai ms, met h o ds, o bjecti ves, a n d p ote ntial hazar ds 
of t he st u d y a n d pri or t o u n derta ki n g a n y st u d y -relate d pr oce d ures. 
 
S u bjects s h o ul d ha ve t he o p p ort u nit y t o disc uss t he st u d y wit h t heir fa mil y me m bers or ot her a d vis ors a n d t he 
ti me t o c o nsi der partici pati o n i n t he trial caref ull y. T he s u bjects ma y wit h dra w c o nse nt at a n y ti me t hr o u g h o ut 
t he c o urse of t he trial. T he ri g hts a n d welfare of t he s u bjects will be pr otecte d b y e m p hasizi n g t o t he m t hat t he 
q ualit y of t heir me dical care will n ot be a d versel y affecte d if t he y decli ne t o partici pate i n t his st u d y.  
 
T he i n vesti gat or or desi g nee m ust utilize a n I R B /I E C-a p pr o ve d c o ns e nt f or m t hat c o ntai ns t he ele me nts 
re q uire d b y I C H G C P a n d a p plica ble re g ulat or y re q uire me nts f or d oc u me nti n g writte n i nf or me d c o nse nt. 
Eac h i nf or me d c o nse nt will be a p pr o priatel y si g ne d a n d date d b y t he s u bject a n d t he pers o n o btai ni n g 
c o nse nt . A c o p y of  t he si g ne d c o nse nt f or m will be pr o vi de d t o t he s u bject. B y si g ni n g t he i nf or me d c o nse nt 
f or m, all parties a gree t he y will c o m plete t he e val uati o ns re q uire d b y t he st u d y, u nless t he y wit h dra w 
v ol u ntaril y or are ter mi nate d fr o m t he st u d y f or a n y reas o n.  
 
In vesti gat ors will be e x pecte d t o mai ntai n a scree ni n g l o g of all p ote ntial st u d y ca n di dates t hat i ncl u des 
li mite d i nf or mati o n a b o ut t he p ote ntial ca n di date (e. g., date of scree ni n g).  
 
All s u bjects w h o pr o vi de c o nse nt will be assi g ne d a u ni q ue st u d y n u m ber . T his n u m ber will be use d t o 
i de ntif y t he s u bject t hr o u g h o ut t he cli nical st u d y a n d m ust be use d o n all st u d y d oc u me ntati o n relate d t o t he 
st u d y s u bject. O nce a n u m ber is assi g ne d t o a s u bject, t hat n u m ber will re mai n wit h t hat st u d y s u bject a n d 
will n ot be re use d.  
 
If a n i n di vi d u al’s me di c al c h art or res ults of di a g n osti c t ests p erf or m e d  as part of a n i n di vi d u al’s r e g ular 
m e dic al  c ar e  ar e g oi n g  t o b e  us e d  f or s cre e ni n g, writt e n  i nf or me d c o nse nt  m ust  b e  o btai n e d  pri or  t o r e vie w 
of  t hat i nf or m ati o n i n a c c or d a n ce wit h HI P A A. 
 
1 2 . 4 P A R TI CI P A N T A N D D A T A C O N FI D E N TI A LI T Y  
 
S u bject c o nfi de ntialit y is hel d i n strict tr ust b y t he partici pati n g in vesti gat ors, t heir staff, t he S p o ns or , a n d t heir 
a ge nts . T his c o nfi de ntialit y is e xte n de d t o c o ver testi n g of bi ol o gical sa m ples a n d ge netic tests i n a d diti o n t o t he 
cli nical i nf or mati o n relati n g t o s u bjects. T heref ore, t he st u d y pr ot oc ol, d oc u me ntati o n, data, a n d all ot her 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 7  of 9 9   
 
i nf or mati o n ge nerate d will be hel d i n strict c o nfi de nce. N o i nf or mati o n c o ncer ni n g t he st u d y or data will be 
release d t o a n y u na ut h orize d t hir d part y wit h o ut pri or writte n a p pr o val of t he S p o ns or . 
 
T he st u d y m o nit or, ot her a ut h orize d re prese ntati ves of t he S p o ns or , re prese ntati ves of t he I R B/IE C , or 
g o ver n me nt re g ulat or y a ge ncies  ma y i ns pect d oc u me nts a n d rec or ds re q uire d t o be mai ntai ne d b y t he i n vesti gat or, 
i ncl u di n g b ut n ot li mite d t o, me dical rec or ds ( office, cli nic, or h os pital) a n d p har mac y rec or ds f or t he s u bjects i n 
t his st u d y. T he cli nical st u d y site will per mit  access t o s uc h rec or ds.  
 
T he i n vesti gat or m ust ass ure t hat s u bjects’ a n o n y mit y will be strictl y mai ntai ne d a n d t hat t heir i de ntities are 
pr otecte d fr o m u na ut h orize d parties . O nl y s u bject i nitials a n d a n i de ntificati o n c o de ( i.e., n ot na mes) s h o ul d be 
rec or de d o n n o n-l ocal la borat or y  sa m ples, re q uisiti o ns, a n d a n y d oc u me nts s u b mitte d t o t he C R O, S p o ns or , 
a n d/ or I R B /I E C. T he i n vesti gat or m ust kee p a s u bject l o g s h o wi n g c o des, na mes, a n d a d dresses f or all s u bjects 
scree ne d a n d for all s u bjects e nr olle d i n t he trial . T he st u d y s u bject’s c o ntact i nf or mati o n will be sec urel y st ore d 
at eac h cli nical site f or i nter nal use d uri n g t he st u d y . At t he e n d of t he st u d y, all rec or ds will c o nti n ue t o be ke pt i n 
a sec ure l ocati o n f or as l o n g a  peri o d as dictate d b y l ocal I R B /I E C a n d instit uti o nal re g ulati o ns. 
 
1 2 . 5 F U T U R E U S E O F S T O R E D S P E CI M E N S  
 
Wit h t he s u bject’s a p pr o val a n d as a p pr o ve d b y l ocal I R B /I E Cs, de-i de ntifie d bi ol o gical sa m ples ma y be st ore d at 
Al ka hest , or desi g nee, f or f ut ure use. T hese sa m ples c o ul d be use d f or researc h a n d t o i m pr o ve treat me nt . 
Al ka hest will als o be pr o vi de d wit h a c o de -li n k t hat will all o w li n ki n g t he bi ol o gical s peci me ns wit h t he s pecific 
data fr o m eac h s u bject, mai ntai ni n g t he mas ki n g of the i d e ntit y of t he st u d y s u bject. S u bjects ma y c h o ose w het her 
t he S p o ns or ca n st ore a n d use  sa m ples f or f urt her researc h.  
 
D uri n g t he c o n d uct of t he st u d y, a n i n di vi d ual s u bject ca n c h o ose t o wit h dra w c o nse nt t o ha ve bi ol o gical 
s peci me ns st ore d f or f ut ure researc h. H o we ver, wit h dra wal of c o nse nt f or bi os peci me n  st ora ge will n ot be 
p ossi ble after t he st u d y is c o m plete d.  
 
W he n t he st u d y is c o m plete d, access t o st u d y data a n d/ or sa m ples will be ma na ge d b y Al ka hest . I n t he e ve nt 
Al ka hest tra nsfers o w ners hi p t o a n ot her c o m mercial S p o ns or , o w ners hi p of t he sa m ples ma y be tra nsferre d as 
well.  
 
1 3  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
1 3 . 1 D A T A C O L L E C TI O N A N D M A N A G E M E N T R E S P O N SI BI LI TI E S  
 
Data c ollecti o n is t he res p o nsi bilit y of t he cli nical trial staff at t he site u n der t he s u per visi o n of t he site 
i n vesti gat or. T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he acc urac y, c o m plete ness, a n d ti meli ness of t he data 
re p orte d. 
 
S o urce d oc u me nts pr o vi de e vi de nce f or t he e xiste nce of t he s u bject a n d s u bsta ntiate t he  i nte grit y of t he data 
c ollecte d . S o urce d oc u me nts are file d at t he i n vesti gat or’s site . Data e ntere d i n t he C R F t hat are tra nscri be d fr o m 
s o urce d oc u me nts m ust be c o nsiste nt wit h t he s o ur ce d oc u me nts or t he discre pa ncies m ust be e x plai ne d . All 
s o urce d oc u me nts s h o ul d be c o m plete d i n a neat, le gi ble ma n ner t o e ns ure acc urate i nter pretati o n of data . Blac k 
or bl ue i n k is re q uire d t o e ns ure clarit y of re pr o d uce d c o pies . W he n ma ki n g c ha n ges or c orrecti o ns, cr oss o ut t he 
ori gi nal e ntr y wit h a si n gle li ne, a n d i nitial a n d date t he c ha n ge . D O N O T E R A S E, O V E R W RI T E, O R U S E 
C O R R E C TI O N F L UI D O R T A P E O N T H E O RI GI N A L . T he i n vesti gat or ma y nee d  t o re q uest pre vi o us me dical 
rec or ds or tra nsfer rec or ds, de pen di n g o n t he trial; als o , c urre nt  me dical rec or ds m ust be a vaila ble.  
 
F or eac h s u bject w h o recei ves t he st u d y a ge nt or place b o , t he C R F m ust be c o m plete d i n a ti mel y ma n ner . T he 
i n vesti gat or will re vie w a n d a p pr o ve t he C R F f or eac h st u d y s u bject after all data ha ve bee n e ntere d, t he C R Fs 
ha ve bee n s o u rce d oc u me nt verifie d, a n d all q ueries ha ve bee n res ol ve d. T his also a p plies t o rec or ds f or t h ose 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 8  of 9 9   
 
su bjects w h o fai l t o c o m plete t he st u d y. If a su bject wit h dra ws fr o m t he st u d y, t he reas o n m ust be n ote d o n t he 
C R F . If a s u bject is wit h dra w n fr o m t he st u d y beca use of a n A E, t h or o u g h eff orts s h o ul d be ma de t o clearl y 
d oc u me nt t he o utc o me.  
 
All data c ollecti o n a n d rec or d kee pi n g pr oce d ure s m ust be c o m plia nt  wit h a p plica ble I C H G C P.  
 
1 3 . 1. 1 
I N V E S TI G A T O R R E S P O N SI BI LI TI E S  
 
T he i n vesti gat or will c o m pl y wit h t he pr ot oc ol ( w hic h has bee n a p pr o ve d/ gi ve n fa v ora ble o pi ni o n b y a n 
I R B/IE C), I C H G C P, a n d a p plica ble re g ulat or y re q uire me nts . T he i n vesti gat or is ulti matel y res p o nsi ble f or 
t he c o n d uct of all as pects of t he st u d y at t he st u d y site a n d verifies b y si g nat ure t he i nte grit y of all data 
tra ns mitte d t o t he S p o ns or . T he ter m “i n vesti gat or” as use d i n t his pr ot oc ol as well as i n ot her st u d y 
d oc u me nts, refers t o t he i n vesti gat or or a ut h orize d st u d y pers o n nel t hat t he i n vesti gat or has desi g nate d t o 
perf or m certai n d uties . S u b -i n vesti gat ors or ot her a ut h orize d st u d y pers o n nel are eli gi ble t o si g n f or t he 
i n vesti gat or, e xce pt w here t he i n vesti gat or’s si g nat ure is s pecificall y re q uire d. 
 
1 3 . 1. 2 
S T U D Y FI L E S  
 
T he i n vesti gat or m ust mai ntai n a de q uate a n d acc urate rec or ds t o e na ble t he c o n d uct of t he st u d y t o be f ull y 
d oc u me nte d a n d t he st u d y data t o be s u bse q ue ntl y verifie d . T hese d oc u me nts s h o ul d be classifie d i nt o t w o 
se parate cate g ories (alt h o u g h n ot li mite d t o) t he f ollo wi n g: ( 1) i n vesti gat or’s st u d y file, a n d ( 2) s u bject 
cli nical s o urce d oc u me nts.  
 
T he i n vesti gat or’s st u d y file will c o ntai n t he pr ot oc ol/a me n d me nts, C R F, I R B/ IE C a p pr o val wit h 
c orres p o n de nce, i nf or me d c o nse nt s, dr u g rec or ds, staff c urric ul u m vitae a n d a uth orizati o n f or ms, a n d ot her 
a p pr o priate d oc u me nts a n d  st u d y-s pecific ma n uals (e. g., la borat or y  m a n ual) . 
 
S u bject cli nical s o urce d oc u me nts w o ul d i ncl u de (alt h o u g h are n ot li mite d t o) t he f oll o wi n g: s u bject 
h os pital/cli nic rec or ds, p h ysicia n’s a n d n urse’s n otes, a p p oi nt me nt b o o k, ori gi nal la b orat or y re p orts, E C G, 
ra di ol o gic i ma gi n g, x -ra y, pat h ol o g y a n d s pecial assess me nt re p orts, c o ns ulta nt letters, scree ni n g a n d 
e nr oll me nt l o g, etc. 
 
1 3 . 2 S T U D Y R E C O R D S R E T E N TI O N  
 
All cli nical st u d y d oc u me nts m ust be retai ne d b y t he i n vesti gat or u ntil t w o years after t he st u d y is disc o nti n ue d 
a n d re g ulat or y a ut h orities ha ve be e n n otifie d . Bef ore t he i n vesti gat or destr o ys a n y material relate d t o t he cli nical 
st u d y, he/s he m ust o btai n a p pr o val i n writi n g fr o m t he S p o ns or . 
 
T he i n vesti gat or s h o ul d kee p a file w here t he f ull na me a n d a d dress of t he s u bject a n d all si g ne d i nf or me d 
co nse nts are i ncl u de d f or at least 1 5 years after c o m pleti o n of t he trial . A n y ori gi nal st u d y -relate d i nf or mati o n t hat 
per mits verificati o n of i ncl usi o n a n d e xcl usi o n criteria, i ncl u di n g cli nical hist or y, a c o p y of all data c ollecti o n 
l o gs, a n d d oc u me nts o n t he use of t he st u d y a ge nt, m ust be st ore d f or as l o n g a ti me peri o d as per mitte d b y t he 
ce nter.  
 
S h o ul d t he i n vesti gat or wis h t o m o ve st u d y rec or ds t o a n ot her l ocati o n, arra n ge me nts m ust be ma de t o st ore t hese 
i n seale d c o ntai ners s o t hat t he y ca n be ret ur ne d seale d t o t he i n vesti gat or i n case of a re g ulat or y a u dit. W here 
s o urce d oc u me nts are re q uire d f or t he c o nti n ue d care of t he su bject, a p pr o priate c o pies s h o ul d be ma de f or st ora ge 
o utsi de of t he site.  
 
1 3 . 3 P R O T O C O L D E VI A TI O N S  
 
A p r ot oc ol d e viati o n is a n y n o nc o m plia nce wit h t he cli nical trial prot oc ol or  wit h  G C P . T he n o nc o m plia nce ma y 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 4 9  of 9 9   
 
be eit her o n t he part of t he s u bject, t he i n vesti gat or, or t he st u d y site staff. W he n de viati o ns  occ ur , c orrecti ve 
acti o ns are t o be de vel o pe d b y t he site a n d  i m ple me nte d pr o m ptl y. 
 
T hese practices are c o nsiste nt wit h I C H E 6:  
• 4. 5 C o m plia nce wit h Pr ot oc ol, secti o ns 4. 5. 1, 4. 5. 2, a n d  4. 5. 3 . 
• 5. 1 Q ualit y Ass ura nce a n d Q ualit y C o ntr ol, secti o n  5. 1. 1 . 
• 5. 2 0 N o nc o m plia nce, secti o ns 5. 2 0. 1, a n d  5. 2 0. 2.  
 
Pr ot oc ol d e viati o ns will be cate g orize d as eit her M aj or or M i n or a n d will be d efi ne d i n t he st u d y -s pecific Pr ot oc o l 
De viati o n Pla n  or e q ui vale nt d oc u me nt .  
 
M aj or Pr ot oc ol De vi ati o ns  are de part ure s fr o m t he a p pr o ve d pr ot oc ol relati n g t o t he c o n d uct of t he st u d y 
w hic h ma y affect t he ri g hts, safet y , a n d/ or well bei n g of st u d y partici pa nts or t he st u d y o utc o mes or data 
q ualit y . Maj or Pr ot oc ol De viati o ns ma y res ult i n data t hat are n ot dee me d e val ua ble f or t he per pr ot oc ol  
a nal ysis a n d/ or ma y re q uire t hat s u bjects are disc o nti n ue d fr o m t he st u d y . Maj or Pr ot oc ol De viati o ns are 
Si g nifica nt Cli nical Iss ues.   
N ote : O bserv ati o ns c ate g orize d as M aj or m ay i ncl u de t h ose sit u ati o ns w here t here is a p atter n of 
devi ati o n, n u mer o us M i n or o bserv ati o ns, or ot her si g nific a nt devi ati o n. 
 
Mi n or Pr ot oc ol De vi ati o ns  are de part ures fr o m t he a p pr o ve d pr ot oc ol relati n g t o t he c o n d uct of a st u d y 
t hat d oes n ot affect t he ri g hts, safet y, a n d/ or well bei n g of st u d y partici pa nts or t he st u d y o utc o mes or data 
q ualit y . Mi n or Pr ot oc ol De viati o ns d o n ot re q uire re vie w b y t he me dical m o nit or.  Mi n or Pr ot oc ol 
De viati o ns w o ul d n ot ge nerall y precl u de  s u bject data fr o m t he per pr ot oc ol  a nal ysis p o p ulati o n.   
N O T E: persiste ntly misse d  or i nc o m plete st u dy pr oce d ures  a n d / or st u dy ev al u ati o ns will be c o nsi dere d  
M aj or Pr ot oc ol Devi ati o n s. 
 
C or o n a vir us Dise ase 2 0 1 9 ( C O VI D-1 9) Pr ot oc ol De vi ati o ns  are de part ures fr o m t he a p pr o ve d pr ot oc ol 
relate d t o t he C O VI D -1 9 pa n de mic. Wi n d o w e xte nsi o ns a n d misse d pr ot oc ol assess me nts ma y be 
per mitte d t o re d uce t he ris k of C O VI D -1 9 e x p os ure . A n y de viati o n t o t he pr ot oc ol t o re d uce t he ris k of 
C O VI D -1 9 will be ca pt ured as a “Pr ot oc ol De viati o n relate d t o C O VI D -1 9 ” t o cate g orize t he a ntici pate d 
i ncrease i n pr ot oc ol de viati o ns d ue t o t he pa n de mic. I n a d diti o n, pr ot oc ol de viati o ns ha ve bee n 
pr os pecti vel y i de ntifie d t hat ca n be i m ple me nte d t o re d uce t he ris k of e x p os ure w h ile still mai ntai ni n g 
a p pr o priate safet y m o nit ori n g a n d i nte grit y of t he st u d y data. T hese pr os pecti ve de viati o ns (e. g. wi n d o w 
assess me nts a n d misse d assess me nts) are descri be d i n Secti o n 1 5 Sc he d ule of E ve nts.  T he se meas ur es are 
te m p orar y, a n d will be re peale d as s o o n as t he sit uati o n (e. g., g o ver n me ntal r ules, be nefit/ris k assess me nt 
f or t he trial, etc.) all o ws.  
 
All de viati o ns will be l o g ge d a n d trac ke d b y t he site a n d C R O . Peri o dic re vie w of p r ot oc ol d e viati o ns will ser ve 
a n i n dicat or  of site perf or ma nce.  
 
It is t he res p o nsi bilit y of t he site t o use c o nti n u o us vi gila nce t o i de ntif y a n d re p ort de viati o ns pr o m ptl y t o t he 
st u d y C R O a n d/ or S p o ns or. All de viati o ns m ust be a d dresse d i n st u d y s o urce d oc u me nts . N otificati o n of p r ot oc ol 
d e viati o ns m ust be se nt t o t he l ocal I R B/I E C per t heir g ui deli nes . T he site i n vesti gat or/st u d y staff is res p o nsi ble 
f or k n o wi n g a n d a d heri n g t o t heir I R B/I E C re q uire me nts. 
 
1 3 . 4 P U B LI C A TI O N A N D D A T A S H A RI N G P O LI C Y  
 
I n c o m plia nce wit h T he I nter nati o nal C o m mittee of Me dical J o ur nal E dit ors (I C MJ E) cli nical trials re gistrati o n 
p olic y a n d Secti o n 8 0 1 of t he F o o d a n d Dr u g A d mi nistrati o n A me n d me nts Act of 2 0 0 7, t his st u d y will be 
re gistere d b y t he S p o ns or i n Cli nical Trials. g o v, a p u blic trials re gistr y w hic h is s p o ns ore d b y t he Nati o nal Li brar y 
of Me dici ne.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 0  of 9 9   
 
 
N ot wit hsta n di n g t he S p o ns or’s re q uire me nts f or re gistrati o n a n d data s hari n g i n Cli nical Trials. g o v, a n y f or mal 
prese ntati o n or p u blicati o n of data c ollecte d as a direct or i n direct re s ult of t his trial will be c o nsi dere d as a j oi nt 
p u blicati o n b y t he i n vesti gat or(s) a n d t he S p o ns or . I n t he case of m ultice nter st u dies, it is ma n dat or y t hat t he first 
p u blicati o n be ma de base d o n t he t otalit y of data o btai ne d fr o m all ce nters, a nal yze d as  sti p ulate d i n t he pr ot oc ol, 
a n d prese nte d a n d i nter prete d as d oc u me nte d i n t he fi nal Cli nical St u d y Re p ort . T he res ulti n g p u blicati o n will 
na me i n vesti gat ors acc or di n g t o t he p olic y of t he c h ose n j o ur nal . W here it is n ot per mitte d f or all i n vesti gat ors t o  
be i ncl u de d as a ut h ors, t he p u blicati o n will na me all i n vesti gat ors wit hi n t he p u blicati o n.  
 
I n di vi d ual i n vesti gat ors ma y p u blis h data arisi n g fr o m t heir o w n s u bjects. T he i n vesti gat or will pr o vi de t he 
S p o ns or wit h c o pies of writte n p u blicati o ns (i ncl u di n g a bstracts a n d p osters) at least 6 0 da ys i n a d va nce of 
s u b missi o n. T his re vie w is t o per mit t he S p o ns or t o re vie w t he c o m m u nicati o n f or acc urac y (t h us a v oi di n g 
p ote ntial discre pa ncies wit h s u b missi o ns t o re g ulat or y a ut h orities), t o verif y t hat c o nfi de ntia l i nf or mati o n is n ot 
i na d verte ntl y di v ul ge d (i ncl u di n g pate nt pr otecti o n), t o all o w a de q uate i n p ut or s u p ple me ntar y i nf or mati o n t hat 
ma y n ot ha ve bee n a vaila ble t o t he i n vesti gat or, a n d t o all o w esta blis h me nt of c o -a ut h ors hi p. 
 
I n vesti gat ors partici pati n g i n m ultice nter st u dies m ust a gree n ot t o e n ga ge i n prese ntati o ns base d o n data gat here d 
i n di vi d uall y or b y a s u b gr o u p of ce nters bef ore p u blicati o n of t he first mai n p u blicati o n u nless t his has bee n 
a gree d ot her wise b y all ot her i n vesti gat ors a n d t he S p o ns or . H o we ver, i n t he e ve nt t hat n o p u blicati o n of t he 
o verall res ults has bee n s u b mitte d after a p pr o val of t he Cli nical St u d y Re p ort, i n vesti gat ors ma y p u blis h res ults of 
o ne or m ore ce nter’s s u bjects t o t he sa me re vie w as o utli ne d a b o ve . T he S p o ns or will c irc ulate pr o p ose d 
m ultice nter p u blicati o ns t o all i n vesti gat ors f or re vie w.  
 
Data will be re vie we d b y all partici pati n g i n vesti gat ors pri or t o p u blicati o n . T he st u d y S p o ns or will ha ve 9 0 da ys 
t o re vie w all defi niti ve p u blicati o ns, s uc h as ma n uscri pts a n d bo o k c ha pters, a n d a mi ni m u m of 3 0 da ys t o re vie w 
all a bstracts. 
 
1 4  
FI N A N CI A L DI S C L O S U R E A N D C O N F LI C T O F I N T E R E S T P O LI C Y  
 
A se parate fi na ncial discl os ure a gree me nt will be ma de bet wee n eac h P ri nci pal In vesti gat or a n d Al ka hest, I nc. or 
its a ut h orize d re prese ntati ve bef ore t he st u d y a ge nt  is s hi p pe d. Eac h i n vesti gat or will n otif y Al ka hest, I nc. or its 
a ut h orize d re prese ntati ve of a n y rele va nt c ha n ges d uri n g t he c o n d uct of t he st u d y a n d f or 1 year after t he st u d y has 
bee n c o m plete d . Al ka hest  a n d t he st u d y C R O  will e val uate a n y  discl ose d  c o nflicts of i nterest a n d will esta blis h a 
mec ha nis m f or t he ir ma na ge me nt.  
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 1  of 9 9   
 
1 5  
S C H E D U L E O F E V E N T S  
 
Scree ni n g/ B aseli ne  
Tre at me nt  
F oll o w -U p  
Visit N u m ber  
D a y  
Wi n d o w ( d a ys)a 
Wee k  
1  
-1 4 t o - 7   
2  
1  
 
3  
1 4  
± 2  
2  
4  
2 8  
± 2  
4  
5  
5 6  
± 2  
8  
6/ E O T  
8 4  
± 2  
1 2  
7  
9 8  
± 3  
1 4  
P h o ne  C all  
1 1 4  
± 2  
1 5  
I nf or me d C o nse nt1/O pti o nal C o nse nt: fecal sa m ple 
X  
 
 
 
 
 
 
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
Me dical hist or y  
X  
 
 
 
 
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
 
 
 
 
 
 
Ra n d o mizati o n t o A K S T 4 2 9 0 or place b o  
 
X  
 
 
 
 
 
 
M o difie d H oe h n a n d Ya hr  
X  
 
 
 
 
 
 
 
Pr o vi de P D Q -3 9 t o be c o m plete d pri or t o ne xt visit  
X  
X  
X  
X  
X  
X  
 
 
Pr o vi de Ha user 3 -Da y Diar y f or ne xt visit 
X  
 
 
 
X  
 
 
 
C o nfir mati o n of off -me dicati o n state  
 
X  
 
X  
 
X  
X  
 
F ull p h ysical e xa mi n ati o n  
X  
 
 
 
 
 
 
 
Tar gete d p h ysical e xa mi n ati o n  
 
X  
X  
X  
X  
X  
X  
 
Vital si g ns  
X  
X  
X  
X  
X  
X  
X  
 
La b orat or y tests  
X  
X  
X  
X  
X  
X  
X  
 
Pre g na nc y testi n g 2 
X  
X  
X  
X  
X  
X  
X  
 
1 2 -lea d E C G 
X  
 
 
X  
 
X  
 
 
M D S -U P D R S Part 3 –  O ff-me dicati o n  
 
X  
 
X  
 
X  
X  
 
1 0 -meter ti me d wal k  –  O ff-me dicati o n  
 
X  
 
X  
 
X  
X  
 
A d mi nistrati o n of d o pa mi n er gic me dicati o n  
 
X  
 
X  
 
X  
X  
 
M D S -U P D R S Part 1 -4  –  O n -me dicati o n  
 
X  
X  
X  
X  
X  
X  
 
1 0 -meter ti me d wal k  –  O n -me dicati o n  
 
X  
X  
X  
X  
X  
X  
 
M o C A  
 
X  
 
 
 
X  
 
 
S E -A D L  a n d CI SI -P D  
 
X  
X  
X  
X  
X  
X  
 
S -S T S  
 
X  
 
 
 
X  
 
 
C ollect P D Q -3 9  
 
X  
X  
X  
X  
X  
X  
 
C ollect Ha user 3 -Da y Patie nt Diar y  
 
X  
 
 
 
X  
 
 
Weara ble se ns or de vice
3 
X  
X  
 
X  
X  
X  
 
 
Fecal sa m ple ( o pti o nal)  
X  
 
 
 
 
X  
 
 
Dis pe nse 5 -wee k s u p pl y of A K S T 4 2 9 0/ p lace b o 
 
X  
 
X  
X  
 
 
 
St u d y a ge nt ad mi nistrati o n 4 
 
X  
X  
X  
X  
X  
 
 
St u d y a ge nt  acc o u nta bilit y 
 
X  
X  
X  
X  
X  
 
 
P har mac o ki n etics bl o o d sa m ple 5, 6  
 
X  
X  
X  
X  
X  
X  
 
B i o mar ker plas ma ali q u ots5, 6  
 
X  
 
 
 
X  
X  
 
F A C S / C B C bl o o d sa m ple 5 
 
X  
 
 
 
X  
 
 
P har mac o ge n o mics bl o o d sa m ple (a n d o pti o nal 
D N A ba n ki n g sa m ple)  
 
X  
 
 
 
 
 
 
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt me dicati o ns 7 
X  
X  
X  
X  
X  
X  
X  
X  
Trial c o m pleti o n  
 
 
 
 
 
 
 
X  
 N otes:  
  a.   Wi n d o w e xte nsi o ns a n d misse d pr ot oc ol assess me nts ma y be per mitte d t o re d uce t he ris k of C O VI D -1 9 e x p os ure. A n y de viati o n t o t he pr ot oc ol t o 
re d uce t he ris k of C O VI D-1 9 e x p os ure will be ca pt ure d as a “Pr ot oc ol De viati o n relate d t o C O VI D -1 9 ” t o cate g orize t he a ntici pate d i ncrease i n 
pr ot oc ol de viati o ns d ue t o t he pa n de mic. T hese meas ures are te m p orar y, a n d will be re peale d as s o o n as t he sit uati o n (e. g., g o ver n me ntal r ules, 
be nefit/ris k assess me nt f or t he trial, etc.) all o ws  (see Secti o n 1 3. 3 ). 
1.  All patie nts m ust si g n a n i nf or me d c o nse nt c o nsiste nt wit h I C H -G C P g ui deli nes pri or t o a n y trial relate d pr oce d ures, w hic h i ncl u des me dicati o n 
was h o uts a n d restricti o ns.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 2  of 9 9   
 
2.  Pre g na nc y testi n g ma y be perf or me d us i n g ser u m or uri ne . Test s h o ul d be perf or me d at t he site a n d res ults re vie we d . P ositi ve res ults s h o ul d be 
c o nfir m e d b y t he ce ntral la b. 
3.  A n at h o me  weara ble watc h will be pr o vi de d i n cli nic o n Visits 1, 4 a n d 5 . T he wat c h will be c ollecte d at Visits 2 , 5, a n d 6.  
4.  St u d y a ge nt ( A K S T 4 2 9 0/ place b o) will be self-a d mi nistere d i n t he cli nic u n der s u per visi o n of st u d y pers o n nel d uri n g e ver y v isit of t he treat me nt 
peri o d ( Visits 2 -6). Trai ni n g o n st u d y a ge nt  a d mi nistrati o n will be c o n d ucte d at Visit 2.  St u d y a ge nt  a d mi nistrati o n will be perf or me d after all 
assess me nts d uri n g Visit 2 a n d at visit start at re mai ni n g visits (after c ollecti o n of i nitial P K sa m ple  1 5 mi n utes pri or t o st u d y a ge nt a d mi nistrati o n , if 
a p plica ble).  Please Secti o n 7. 3  f or ti mi n g de pe n de ncies.  
5.  T h e P K  sa m ple is dra w n ~ 1 5 mi n utes pri or t o st u d y a ge nt ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n at Visit s 2 -6 . Bi o mar ker a n d F A C S / C B C sa m ples are 
dra w n ~ 1 5 mi n utes pri or t o st u d y a ge nt ( A K S T 4 2 9 0/ place b o) a d mi nistrati o n at Visits 2  a n d 6.  T he P K, b i o mar ker, a n d F A C S/ C B C sa m ples are 
dra w n ~ 1 h o ur after st u d y a ge nt a d mi nistrati o n  at Visit 2.  A d diti o nal (o pti o nal ) P K sa m ples are dra w n at ~ 2 h o ur s after st u d y a ge nt  a d mi nistrati o n  at 
Visit  2 . A d diti o nal (o pti o nal ) P K sa m ples are dra w n at ~ 1 h o ur a n d ~ 2 h o ur s after st u d y a ge nt  a d mi nistrati o n at Visit s 4  a n d 6 . F or a d diti o nal 
i nf or mati o n re gar di n g ti mi n g, see Secti o n 1 7. 1 2 . 
6.  Bi o mar ker plas ma ali q u ots are dra w n fr o m t he P K  bl o o d sa m ple.  
7.  
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 3  of 9 9   
 
1 6  
R E F E R E N C E S  
1 6 .1  P U B LI S H E D R E F E R E N C E S  
 
Al Da k heel A, Kalia L V, La n g A E . Pat h o ge nesis -tar gete d, disease-m o dif yi n g t hera pies i n Par ki ns o n disease . 
Ne ur ot hera pe utics . 2 0 1 4; 1 1: 6 -2 3.  
 
At ha u da D, Macla ga n K, S ke ne S S, Baj wa -J ose p h M, Letc hf or d D, C h o w d ur y K, et al. E xe nati de o nce wee kl y 
vers us place b o i n Par ki ns o n's disease: a ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d trial. La ncet. 
2 0 1 7; 3 9 0( 1 0 1 0 3): 1 6 6 4 -1 6 7 5.  
 
 
 
 
 
 
 
  
 
Be n ner EJ, Ba nerjee R, Re y n ol ds A D, S her ma n S, Pisare v V M, et al. Nitrate d α -s y n uclei n i m m u nit y accelerates 
de ge nerati o n of ni gral d o pa mi ner gic ne ur o ns. P L os O ne. 2 0 0 8; 3( 1): 1 -2 0.  
 
 
 
 
 
 
 
 
Cli nical Trial Facilitati o n Gr o u p . Rec o m me n dati o ns relate d t o c o ntrace pti o n a n d pre g na nc y testi n g i n cli nical 
trials. Versi o n 2 0 1 4-0 9 -1 5: 1 -1 3.  
 
C o n n oll y B S, La n g A E . P har mac ol o gical treat me nt of Par ki ns o n disease: a re vie w. J A M A. 2 0 1 4; 3 1 1( 1 6): 1 6 7 0-
1 6 8 3.  
 
D orse y E R, Bl oe m B R . T he Par ki ns o n pa n de mic –  a call t o acti o n . J A M A Ne ur ol. 2 0 1 8; 7 5: 9-1 0.  
 
Fa h n S, Elt o n R L. U nifie d Par ki ns o n’s disease rati n g scale. I n: Fa h n S, Mars de n C D, Cal ne D, G ol dstei n M, e ds. 
Rece nt Devel o p me nts i n P arki ns o n’s Dise ase . Fl or ha m Par k: Mac milla n Healt h Care I nf or mati o n. 1 9 8 7: 1 5 3 -1 6 3 .  
 
F o o d a n d Dr u g A d mi nistrati o n ( F D A), U. S. De part me nt of Healt h a n d H u ma n Ser vices. G ui da nce f or I n d ustr y 
a n d I n vesti gat ors: Safet y Re p orti n g Re q uire me nts f or I N Ds a n d B A/ B E St u dies. Dece m ber, 2 0 1 2.  
 
G oetz C G, Tille y B C, S haft ma n S R, Ste b bi ns G T, Fa h n S , Marti nez-Marti n P, et al. M o ve me nt Dis or der S ociet y -
s p o ns ore d re visi o n of the U nite d Par ki ns o n’s Disease Rati n g Scale ( M D S -U P D R S): Scale Prese n tati o n a n d 
Cli ni metric Testi n g Res ults. M o v Dis or ders. 2 0 0 8; 2 3( 1 5): 2 1 2 9 -2 1 7 0.  
 
G ol d ma n J G, Lit va n I . Mil d c o g niti ve i m pair me nt i n Par ki ns o n’s Disease . Mi ner va Me d. 2 0 1 1; 1 0 2: 4 4 1 -4 5 9.  
 
Ha user R A, Dec kers F, Le hert P. Par ki ns o n’s disease h o me diar y: f urt her vali dati o n a n d i m plicati o ns f or cli nical 
trials. M o v Dis or ders. 2 0 0 4; 1 9: 1 4 0 9-1 4 1 3.  
 
Ha user R A, Frie dla n der J, Zesie wicz T A, A dler C H, See ber ger L C, O’ Brie n C F, et al. A h o me diar y t o assess 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 4  of 9 9   
 
f u ncti o nal stat us i n patie nts wit h Par ki ns o n’s disease wit h m ot or fl uct uati o ns a n d d ys ki nesia. Cli n 
Ne ur o p har mac ol. 2 0 0 0; 2 3: 7 5 -8 1.  
 
Hirsc h E C, H u n ot  S . Ne ur oi nfla m mati o n i n Par ki ns o n's disease: a tar get f or ne ur o pr otecti o n? La ncet Ne ur ol. 
2 0 0 9; 8: 3 8 2 -3 9 7.  
 
 
 
 
Ja n vi n C C, Larse n J P, Aarsla n d D, H u g da hl K . S u bt y pes of mil d c o g niti ve i m pair me nt i n Par ki ns o n’s disease: 
pr o gressi o n t o de me ntia . M o v Dis or d. 2 0 0 6; 2 1: 1 3 4 3 -1 3 4 9.  
 
Lalli M A, Bettc her  B M , Arcila M L , Garcia G , G uz ma n C , Ma dri gal L , et al. W h ole -ge n o me se q ue nci n g s u g gests 
a c he m o ki ne ge ne cl uster t hat m o difies a ge at o nset i n fa milial Alz hei mer's disease. M ol Ps yc hiatr y . 
2 0 1 5; 2 0: 1 2 9 4 -1 3 0 0.  
 
La n g J T, Kassa n T O, De va ne y L L, C ol o n -Se me nza C, J ose p h M E. Test -retest relia bilit y a n d mi ni mal detecta ble 
c ha n ge f or t he 1 0 -meter wal k test i n ol der a d ults wit h Par ki ns o n’s disease. J Geriatr P h y T her. 2 0 1 6; 3 9: 1 6 5 -1 7 0.  
 
  
 
Marti nez -Marti n P, F orjaz MJ, C u b o E, Fra des B, de Pe dr o C uesta J, E L E P Pr oject Me m bers . Gl o bal vers us 
fact or-relate d i m pressi o n of se verit y i n Par ki ns o n’s disease: a ne w cli ni metric i n de x ( CI SI -P D). M o v Dis or d. 
2 0 0 6; 2 1: 2 0 8 -2 1 4.  
 
M urra y C, Sa n ders o n DJ, Bar k us C, Deac o n R M, Ra wli ns J N, Ba n ner ma n C M, et al. S yste mic i nfla m mati o n 
i n d uces ac ute w or ki n g me m or y deficits i n t he pri me d brai n: rele va nce f or deliri u m. Ne ur o bi ol A gi n g. 
2 0 1 2; 3 3( 3): 6 0 3 -6 1 6.  
 
Nasre d di ne Z S, P hilli ps N A, Be diria n V, C har b o n nea u S, W hite hea d V, C olli n I,  et al . T he M o ntreal C o g niti ve 
Assess me nt, M o C A: a brief scree ni n g t o ol f or mil d c o g niti ve i m pair me nt . A m Geriatr S oc . 2 0 0 5; 5 3: 6 9 5 -6 9 9.  
 
Ola n o w C W, Ster n M B, Set hi K . T he scie ntific a n d cli nical basis f or t he treat me nt of Par ki ns o n disease ( 2 0 0 9) . 
Ne ur ol o g y. 2 0 0 9; 7 2( S u p pl 4) S 2 -S 1 3 6.  
 
Par ki ns o n J . Essa y o n t he S ha ki n g Pals y . M o n o gra p h . L o n d o n: W hitti n g ha m a n d R o wla n d f or S her w o o d, Neel y 
a n d J o nes, 1 8 1 7. 
 
Pet o V, Je n ki ns o n C, Fitz patric k R . P D Q -3 0: a re vie w of t he de vel o p me nt, vali dati o n a n d a p plicati o n of a 
Par ki ns o n’s disease q ualit y of life q uesti o n naire a n d its ass ociate d meas ures . J Ne ur ol. 1 9 9 8; 2 4 5[ S u p pl 1]: S 1 0-
S 1 4.  
 
P o st u ma R B, Ber g D, Ster n M, P oe we W, Ola n o w C W, Oertel W, et al. M D S cli nical dia g n ostic criteria f or 
Par ki ns o n’s disease . M o v Dis or d. 2 0 1 5; 3 0: 1 5 9 1 -1 5 8 8.  
 
Sa vica R, Gr ossar dt B R, R occa W A, B o wer J H . Par ki ns o n disease wit h a n d wit h o ut de me ntia: a pre vale nce st u d y 
a n d f ut ure pr ojecti o ns . M o v Dis or d. 2 0 1 8 ; 3 3: 5 3 7-5 4 3 .  
 
Sc hlac hetz ki, J C, Wi n kler  J. T he i n nate i m m u ne s yste m i n Par ki ns o n's disease: a n o vel tar get pr o m oti n g 
e n d o ge n o us ne ur ore ge nerati o n. Ne ural Re ge n Res . 2 0 1 5; 1 0: 7 0 4 -7 0 6.  
 
Sc h nei der J S, Se n de k S, Y a n g C. Relati o ns hi p bet wee n m ot or s y m pt o ms, c o g niti o n, a n d de m o gra p hic 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 5  of 9 9   
 
c haracteristics i n treate d mil d/ m o derate Par ki ns o n’s disease . P L os O N E. 2 0 1 5; 1 0( 4):e 0 1 2 3 2 3 1.  
 
Sc h wa b R S,  E n gla n d  A C . Par ki ns o n s y n dr o me d ue t o vari o us a n d s pecific ca uses . I n: Vi n ki n PJ, Br u y n, e ds. 
H a n d b o ok of Cli nic al Ne ur ol o gy . A mster da m: Else vier N ort h H olla n d. 1 9 6 8: 2 2 7 -2 4 7.  
 
Sc h wiertz A, S pie gel J, Dill ma n n U, Gr u n d ma n n D, B ür ma n n J, Fa ß be n der  K, et al. Fecal mar kers of i ntesti nal 
i nfla m mati o n a n d i ntesti nal per mea bilit y are ele vate d i n Par ki ns o n’s disease. Par ki ns o nis m Relat Dis. 
2 0 1 8; 5 0: 1 0 4 -1 0 7.  
 
S hee ha n D V, Gi d de ns J M, S hee ha n I S . S hee ha n -S uici dalit y Trac ki n g Scale ( S -S T S ) 2 0 1 4. I n n o v Cli n Ne ur osci. 
2 0 1 4; 1 1( 9 -1 0) :9 3 -1 4 0.   
 
Si n g h  Y, El -Ha di di M, A d mar d J, Wass o u f Z, Sc h ulze-He ntric h J M, K hl h ofer U, et al. E nric he d e n vir o n me ntal 
c o n diti o ns m o dif y t he g ut micr o bi o me c o m p ositi o n a n d fecal mar kers of i nfla m mati o n i n Par ki ns o n’s disease. 
Fr o nt Ne ur osci. 2 0 1 9; 1 3: 1 0 3 2.  
 
S ulzer D, Alcala y  R N , Garretti F , C ote L , Ka nter E , A gi n-Lie bes  J, et al. T cells fr o m patie nts wit h Par ki ns o n's 
disease rec o g nize al p ha -s y n uclei n pe pti des. Nat ure. 2 0 1 7; 5 4 6: 6 5 6 -6 6 1.  
 
S ve n ni n gs s o n P, West ma n E, Ballar d C, Aarsla n d D . C o g niti ve i m pair me nt i n patie nts wit h Par ki ns o n’s disease: 
dia g n osis, bi o mar kers, a n d treat me nt . La ncet Ne ur ol. 2 0 1 2; 1 1: 6 9 7 -7 0 7.  
 
Ville da S A, L u o J, M os her KI, Z o u B, Britsc h gi M, Bieri G, et al . T he a gei n g s yste mic milie u ne gati vel y 
re g ulates ne ur o ge nesis a n d c o g niti ve f u ncti o n. Nat ure. 2 0 1 1; 4 7 7: 9 0-9 4.  
 
 
 
 
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 6  of 9 9   
 
1 6 .2  U N P U B LI S H E D R E F E R E N C E S  
 
 
 
 
 
 
D S U R: D e vel o p me nt  Safet y U p date Re p ort : Al ka hest, I nc.   
 
I n vesti gat or’s Br oc h ure –  A K S T 4 2 9 0.  Al ka hest,  I nc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 7  of 9 9   
 
1 7  
A P P E N DI C E S  
 
T he ne ur oc o g niti ve a n d m ot or assess me nts , as well as assess me nts of acti vities i n dail y li vi n g  i n t his secti o n a n d 
ass ociate d i nf or mati o n are pr o vi de d as E X A M P L E S O N L Y . T he act ual assess me nts, relate d s o urce d oc u me nts, 
a n d i nstr ucti o ns f or a d mi nistrati o n a n d sc ori n g are i ncl u de d i n a rater refere nce ma n ual or e q ui vale nt . 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 8  of 9 9   
 
1 7. 1   M O V E M E N T DI S O R D E R S O CI E T Y ’S U NI FI E D P A R KI N S O N ’S DI S E A S E R A TI N G 
S C A L E  
 
T he M D S -U P D R S ( Fa h n 1 9 8 7 , G oetz 2 0 0 8 ) was de vel o pe d as a n eff ort t o i nc or p orate ele me nts fr o m e xisti n g 
scales t o pr o vi de a c o m pre he nsi ve b ut efficie nt a n d fle xi ble mea ns t o m o nit or P D -relate d disa bilit y a n d 
i m pair me nt. T he M D S -U P D R S has f o ur c o m p o ne nts ( Part 1 , Me ntati o n, Be ha vi or, a n d M o o d; Part 2 , Acti vities of 
Dail y Li v i n g; Part 3 , M ot or; Part 4 , C o m plicati o ns). F or  Parts  1 -3 , the rati n g f or eac h ite m is fr o m 0 ( n or mal) t o 4 
(se vere). T he t otal sc ore f or eac h Part is o bta ine d fr o m t he s u m of t he c orres p o n di n g ite m sc ores . T he esti mate d 
ti me f or c o m pleti o n of Parts 1 -3  is 2 0-3 0 mi n utes . I n Part 4 m, t he rater uses hist orical a n d o bjecti ve i nf or mati o n t o 
assess t w o m ot or c o m plicati o ns, d ys ki nesias, a n d m ot or fl uct uati o ns t hat i ncl u de off -me dical state d yst o nia.  
 
U nifie d P ar ki ns o n’s Dise ase R ati n g Sc ale ( U P D R S)  P art s 1 -4  
 
P art 1 . Acti vities of D ail y L i vi n g 
 
I ntellect u al I m p air me nt 
0 = N or mal.  
1 = Mil d . C o nsiste nt f or getf ul ness wit h partial rec ollecti o n of e ve nts a n d n o ot her diffic ulties.  
2 = M o derate  me m or y l oss, wit h dis orie ntati o n a n d m o derate diffic ult y ha n dli n g c o m ple x pr o ble ms . Mil d b ut 
defi nite i m pair me nt of f u ncti o n at h o me wit h nee d of occasi o nal pr o m pti n g.   
3 = Se vere  me m or y l oss wit h dis orie ntati o n f or ti me a n d ofte n t o place . Se vere i m pair me nt i n ha n dli n g pr o ble ms.  
4 = Se vere me m or y l oss wit h orie ntati o n preser ve d t o pers o n o nl y . U na ble t o ma ke j u d ge me nts or s ol ve pr o ble ms . 
Re q uires m uc h hel p wit h pers o nal care . Ca n n ot be left al o ne at all.  
 
T h o u g ht Dis or der ( D ue t o de me nti a or dr u g i nt o xic ati o n.)  
0 = N o ne . 
1 = Vi vi d drea mi n g.  
2 = “ Be ni g n” hall uci nati o ns wit h i nsi g ht retai ne d.   
3 = Occasi o nal t o fre q ue nt hall uci nati o ns or del usi o ns; wit h o ut i nsi g ht; c o ul d i nterfere wi t h dail y acti vities. 
4 = Persiste nt hall uci nati o ns, del usi o ns, or fl ori d ps yc h osis . N ot a ble t o care f or self.  
 
De pressi o n  
0 = N o ne.  
1 = Peri o ds of sa d ness or g uilt greater t ha n n or mal, ne ver s ustai ne d f or da ys or wee ks.  
2  = S ustai ne d de pressi o n ( 1 wee k or  m ore).   
3 = S ustai ne d de pressi o n wit h ve getati ve s y m pt o ms (i ns o m nia, a n ore xia, wei g ht l oss, l oss of i nterest).  
4 = S ustai ne d de pressi o n wit h ve getati ve s y m pt o ms a n d s uici dal t h o u g hts or i nte nt.  
 
M oti v ati o n/i niti ati ve  
0 = N or mal.  
1 = Less asserti ve t ha n us ual; m ore passi ve.  
2  = L oss of i nitiati ve or disi nterest i n electi ve ( n o nr o uti ne) acti vities.   
3 = L oss of i nitiati ve or disi nterest i n da y t o da y (r o uti ne) acti vities.  
4 = Wit h dra w n, c o m plete l oss of m oti vati o n.  
 
 
P art 2 . Acti vities of D a il y L i vi n g 
 
S peec h  
0 = N or mal.  
1 = Mil dl y affecte d. N o diffic ult y bei n g u n derst o o d.  
2 = M o deratel y affecte d. S o meti mes as ke d t o re peat state me nts.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 5 9  of 9 9   
 
3 = Se verel y affecte d. Fre q ue ntl y as ke d t o re peat state me nts.  
4 = U ni ntelli gi ble m ost of t he ti me.  
  
S ali v ati o n  
0 = N or mal.  
1 = Sli g ht b ut defi nite e xcess of sali va i n m o ut h; ma y ha ve ni g htti me dr o oli n g.  
2 = M o deratel y e xcessi ve sali va; ma y ha ve mi ni mal dr o oli n g.  
3 = Mar ke d e xcess of sali va wit h s o me dr o oli n g.  
4 = Mar ke d dr o oli n g, re q uires c o nsta nt tiss ue or ha n d kerc hief.  
 
S w all o wi n g  
0 = N or mal.  
1 = Rare c h o ki n g.  
2 = Occasi o nal c h o ki n g.  
3 = Re q uires s oft f o o d.  
4 = Re q uires N G t u be or gastr ot o m y fee di n g.  
 
H a n d writi n g  
0 = N or mal.  
1 = Sli g htl y sl o w or s mall.  
2 = M o deratel y sl o w or s mall; all w or ds are le gi ble.  
3 = Se verel y affecte d; n ot all w or ds are le gi ble.  
4 = T he maj orit y of w or ds are n ot le gi ble.  
 
C utti n g F o o d a n d H a n dli n g U te nsils 
0 = N or mal.  
1 = S o me w hat sl o w a n d cl u ms y, b ut n o hel p nee de d.  
2 = Ca n c ut m ost f o o ds, alt h o u g h cl u ms y a n d sl o w; s o me hel p nee de d.  
3 = F o o d m ust be c ut b y s o me o ne b ut ca n still fee d sl o wl y.  
4 = Nee ds t o be fe d.  
 
Dressi n g  
0 = N or mal.  
1 = S o me w hat sl o w, b ut n o hel p nee de d.  
2 = Occasi o nal assista nce wit h b utt o ni n g, gett i n g ar ms i n slee ves.  
3 = C o nsi dera ble hel p re q uire d b ut ca n d o s o me t hi n gs al o ne.  
4 = Hel pless.  
 
 
H y gie ne  
0 = N or mal.  
1 = S o me w hat sl o w, b ut n o hel p nee de d.  
2 = Nee ds hel p t o s h o wer or bat he; or ver y sl o w i n h y gie nic care.  
3 = Re q uires assista nce f or was hi n g, br us hi n g teet h, c o m bi n g hair, g oi n g t o bat hr o o m.  
4 = F ole y cat heter or ot her mec ha nical ai ds.  
 
T ur ni n g i n B e d a n d A dj usti n g B e d C l ot hes 
0 = N or mal.  
1 = S o me w hat sl o w a n d cl u ms y, b ut n o hel p nee de d.  
2 = Ca n t ur n al o ne o r a dj ust s heets, b ut wit h great diffic ult y.  
3 = Ca n i nitiate, b ut n ot t ur n or a dj ust s heets al o ne.  
4 = Hel pless.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 0  of 9 9   
 
  
F alli n g ( U nrel ate d t o F reezi n g)  
0 = N o ne.  
1 = Rare falli n g.  
2 = Occasi o nall y falls, less t ha n o nce per da y.  
3 = Falls a n a vera ge of o nce dail y.  
4 = Falls m ore t ha n o nce dail y.  
 
Freezi n g W he n W al ki n g  
0 = N o ne.  
1 = Rare freezi n g w he n wal ki n g; ma y ha ve start  hesitati o n.  
2 = Occasi o nal freezi n g w he n wal ki n g.  
3 = Fre q ue nt freezi n g. Occasi o nall y falls fr o m freezi n g.  
4 = Fre q ue nt falls fr o m freezi n g.  
 
W al ki n g  
0 = N or mal.  
1 = Mil d diffic ult y. Ma y n ot s wi n g ar ms or ma y te n d t o dra g le g.  
2 = M o derate diffic ult y b ut re q uires little or n o assista nce.  
3 = Se vere dist ur ba nce of wal ki n g, re q uiri n g assista nce.  
4 = Ca n n ot wal k at all, e ve n wit h assista nce.  
 
Tre m or ( S y m pt o m atic co m pl ai nt of tre m or i n a n y p art of b o d y.)  
0 = A bse nt.  
1 = Sli g ht a n d i nfre q ue ntl y prese nt.  
2 = M o derate; b ot hers o me t o patie nt.  
3 = Se vere; i nterferes wit h ma n y acti vities.  
4 = Mar ke d; i nterferes wit h m ost acti vities.  
 
 
Se ns or y C o m pl ai nts R el ate d t o P ar ki ns o nis m  
0 = N o ne.  
1 = Occasi o nall y has n u m b ness, ti n gli n g, or mil d ac hi n g.  
2 = Fre q ue ntl y has n u m b ness, ti n gli n g, or ac hi n g; n ot distressi n g.  
3 = Fre q ue nt pai nf ul se nsati o ns.  
4 = E xcr uciati n g pai n.  
 
P art 3 . M ot or E x a mi n ati o n  
 
S peec h  
0 = N or mal.  
1 = Sli g ht l oss of e x pressi o n, dicti o n a n d/ or v ol u me.  
2 = M o n ot o ne, sl urre d b ut u n dersta n da ble; m o deratel y i m paire d.  
3 = Mar ke d  i m pair me nt, diffic ult t o u n dersta n d. 
4 = U ni ntelli gi ble.  
 
F aci al E x pressi o n  
0 = N or mal.  
1 = Mi ni mal h y p o mi mia, c o ul d be n or mal  “ P o ker Face .” 
2 = Sli g ht b ut defi nitel y a b n or mal di mi n uti o n of facial e x pressi o n  
3 = M o derate h y p o mi mia; li ps parte d s o me of t he ti me.  
4 = Mas ke d or fi xe d facies wit h se vere or c o m plete l oss of facial e x pressi o n; li ps parte d 1/ 4 i nc h or m ore. ( hea d, 
u p per a n d l o wer e xt re mities) 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 1  of 9 9   
 
  
Tre m or at R est 
0 = A bse nt.  
1 = Sli g ht a n d i nfre q ue ntl y prese nt.  
2 = Mil d i n a m plit u de a n d persiste nt. Or m o derate i n a m plit u de, b ut o nl y i nter mitte ntl y prese nt.  
3 = M o derate i n a m plit u de a n d prese nt m ost of t he ti me.  
4 = Mar ke d i n a m plit u de a n d prese nt m ost of t he ti me.  
 
Acti o n or P ost ur al T re m or of H a n ds  
0 = A bse nt.  
1 = Sli g ht; prese nt wit h acti o n.  
2 = M o derate i n a m plit u de, prese nt wit h acti o n.  
3 = M o derate i n a m plit u de wit h p ost ure h ol di n g as well as acti o n.  
4 = Mar ke d i n a m plit u de; i nterfe res wit h fee di n g. 
 
Ri gi dit y ( J u d ge d o n p assi ve m o ve me nt of m aj or joi nts wit h p atie nt rel a xe d i n sitti n g p ositi o n. c o g w heeli n g 
t o be ig n ore d.)  
0 = A bse nt.  
1 = Sli g ht or detecta ble o nl y w he n acti vate d b y mirr or or ot her m o ve me nts.  
2 = Mil d t o m o derate.  
3 = Mar ke d, b ut f ull ra n ge of m oti o n easil y ac hie ve d.  
4 = Se vere, ra n ge of m oti o n ac hie ve d wit h diffic ult y.  
 
Fi n ger T a ps ( P atie nt ta ps th u m b wit h in de x fi n ger i n ra pi d successi o n.)  
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de.  
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  
 
H a n d m o ve me nts ( P atie nt o pe ns a n d cl oses h a n ds i n ra pi d  s uccessi o n.)  
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de. 
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  
 
R a pi d Alter n ati n g M o ve me nts o f H a n ds (P r o n ati o n-s u pi n ati o n m o ve me nts o f h a n ds, vertic all y a n d 
h oriz o nt all y, wit h a s l ar ge a n a m plit u de a s p ossi ble, b ot h h a n ds si m ult a ne o usl y.) 
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de.  
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  
 
Le g A gilit y ( P atie nt t a ps heel o n the gr o u n d in r a pi d s uccessi o n pic ki n g u p e ntire le g . A m plit u de s h o ul d be 
at le ast 3 i nc hes.)  
0 = N or mal.  
1 = Mil d sl o wi n g a n d/ or re d ucti o n i n a m plit u de.  
2 = M o deratel y i m paire d. Defi nite a n d earl y fati g ui n g. Ma y ha ve occasi o nal arrests i n m o ve me nt.  
3 = Se verel y i m paire d. Fre q ue nt hesitati o n i n i nitiati n g m o ve me nts or arrests i n o n g oi n g m o ve me nt.  
4 = Ca n barel y perf or m t he tas k.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 2  of 9 9   
 
  
Arisi n g fr o m C h air ( P atie nt atte m pts to rise fr o m a  str ai g ht-b ac ke d c h air, wit h ar ms f ol de d acr oss c hest.)  
0 = N or mal.  
1 = Sl o w; or ma y nee d m ore t ha n o ne atte m pt.  
2 = P us hes self u p fr o m ar ms of seat.  
3 = Te n ds t o fall bac k a n d ma y ha ve t o tr y m ore t ha n o ne ti me b ut ca n get u p wit h o ut hel p.  
4 = U na ble t o arise wit h o ut hel p.  
 
P ost ure  
0 = N or mal erect.  
1 = N ot q ui te erect, sli g htl y st o o pe d p ost ure; c o ul d be n or mal f or ol der pers o n. 
2 = M o deratel y st o o pe d p ost ure, defi nitel y a b n or mal; ca n be sli g htl y lea ni n g t o o ne si de.  
3 = Se verel y st o o pe d p ost ure wit h k y p h osis; ca n be m o deratel y lea ni n g t o o ne si de.  
4 = Mar ke d f le xi o n wit h e xtre me a b n or malit y of p ost ure. 
 
G ait  
0 = N or mal.  
1 = Wal ks sl o wl y, ma y s h uffle wit h s h ort ste ps, b ut n o festi nati o n ( haste ni n g ste ps) or pr o p ulsi o n.  
2 = Wal ks wit h diffic ult y b ut re q uires little or n o assista nce; ma y ha ve s o me festi nati o n, s h ort ste ps, or pr o p ulsi o n. 
3 = Se vere dist ur ba nce of gait, re q uiri n g assista nce.  
4 = Ca n n ot wal k at all, e ve n wit h assista nce.  
 
P ost ur al S t a bilit y (R es p o nse t o s u d de n, str o n g p osteri or dis pl ace me nt pr o d uce d b y p ull o n s h o ul ders w hile 
p atie nt  erect wit h e yes o pe n a n d feet sli g htl y a p art. P atie nt is pre p are d.)  
0 = N or mal.  
1 = Retr o p ulsi o n b ut rec o vers u nai de d.  
2 = A bse nce of p ost ural res p o nse; w o ul d fall if n ot ca u g ht b y e xa mi ner.  
3 = Ver y u nsta ble, te n ds t o l ose bala nce s p o nta ne o usl y.  
4 = U na ble t o sta n d wit h o ut assista nce.  
 
B o d y B r a d y ki nesi a a n d H y p o ki nesi a ( C o m bi ni n g sl o w ness, hesit a nc y, decre ase d ar m  s wi n g, s m all 
a m plit u de, a n d p o vert y of m o ve me nt i n ge ner al.)  
0 = N o ne.  
1 = Mi ni mal sl o w ness, gi vi n g m o ve me nt a deli berate c haracter; c o ul d be n or mal f or s o me pers o ns. P ossi bl y 
re d uce d a m plit u de. 
2 = Mil d de gree of sl o w ness a n d p o vert y of m o ve me nt w hic h is defi nitel y a b n or mal. Alter nati vel y, s o me re d uce d 
a m plit u de. 
3 = M o derate sl o w ness, p o vert y or s mall a m plit u de of m o ve me nt.  
4 = Mar ke d sl o w ness, p o vert y or s mall a m plit u de of m o ve me nt.  
 
P art 4 . M ot or C o m plic ati o ns  
 
Ti me S pe nt wit h D ys ki nesi as  
0 = N or mal: N o  d ys ki nesias . 
1 = Sli g ht:  2 5 % of wa ki n g da y.  
2 = Mil d: 2 6 -5 0 % of wa ki n g da y.  
3 = M o derate : 5 1-7 5 % of wa ki n g da y.  
4 = Se vere: > 7 5 % of wa ki n g da y.  
 
F u ncti o n al I m p act of D ys ki nesi as  
0 = N or mal: N o  d ys ki nesias or n o i m pact b y d ys ki nesias o n acti vities or s ocial i nteracti o ns . 
1 = Sli g ht: D ys ki nesias i m pact a fe w acti vities, b ut patie nt is a ble t o perf or m all acti vities a n d partici pate i n all  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 3  of 9 9   
 
s ocial i nteracti o ns d uri n g d ys ki netic peri o ds. 
2 = Mil d: D ys ki nesias i m pact ma n y acti vities, b ut patie nt us uall y perf or ms all acti vities a n d partici pates i n all 
s ocial i nteracti o ns d uri n g d ys ki netic peri o ds. 
3 = M o derate : D ys ki nesias i m pact ma n y acti vities t o t he p oi nt t hat patie nt us uall y d oes n ot perf or m s o me acti vities 
or partici pate i n s o me s ocial acti vities d uri n g d ys ki netic e pis o des . 
4 = Se vere: D ys ki nesias i m pact f u ncti o n t o t he p oi nt t hat t he patie nt us uall y d oes n ot perf or m m ost acti vities or 
partici pate i n m ost s ocial i nteracti o ns d uri n g d ys ki netic e pis o des . 
 
Ti me S pe nt i n t he Off St ate  
0 = N or mal: N o  Off ti me . 
1 = Sli g ht:  2 5 % of wa ki n g da y.  
2 = Mil d: 2 6 -5 0 % of wa ki n g da y.  
3 = M o derate : 5 1-7 5 % of wa ki n g da y.  
4 = Se vere: > 7 5 % of wa ki n g da y.  
 
F u ncti o n al I m p act of Fl uct u ati o ns  
0 = N or mal: N o  fl uct uati o ns or n o i m pact b y fl uct uati o ns o n acti vities or s ocial i nteracti o ns. 
1 = S li g ht: Fl uct uati o ns i m pact o n a fe w acti vities, b ut d uri n g Off state, patie nt is a ble t o perf or m all acti vities a n d 
partici pate i n all s ocial i nteracti o ns t hat t y picall y occ ur i n t he O n state.  
2 = Mil d: Fl uct uati o ns i m pact ma n y acti vities, b ut d uri n g Off s tate, patie nt us uall y perf or ms all acti vities a n d 
partici pates i n all s ocial i nteracti o ns t hat t y picall y occ ur i n t he O n state.  
3 = M o derate : Fl uct uati o ns i m pact o n t he perf or ma nce of acti vities d uri n g t he Off state t o t he p oi nt t hat patie nt 
us uall y d oes n ot perf or m s o me acti vities or partici pate i n s o me s ocial i nteracti o ns t hat are perf or me d d uri n g 
O n peri o ds.  
4 = Se vere: Fl uct uati o ns i m pact o n f u ncti o n t o t he p oi nt t hat, d uri n g Off, t he patie nt us uall y d oes n ot perf or m m ost 
acti vities or partici pate i n m o st s ocial i nteracti o ns t hat are perf or me d d uri n g O n peri o ds. 
 
C o m ple xit y of M ot or Fl uct u ati o ns  
0 = N or mal: N o  m ot or fl uct uati o ns . 
1 = Sli g ht: Off ti mes are pre dicta ble all or al m ost all of t he ti me ( > 7 5 %). 
2 = Mil d: Off ti mes are pre dicta ble m ost of t he ti me ( 5 1 -7 5 %) . 
3 = M o derate : Off ti mes are pre dicta ble s o me of t he ti me ( 2 6 -5 0 % ). 
4 = Se vere: Off e pis o des are rarel y pre dica ble ( < 2 5 % ). 
 
P ai nf ul Off St ate D yst o ni a  
0 = N or mal: N o  d yst o nia or n o Off ti me . 
1 = Sli g ht:  2 5 % of ti me i n Off state.  
2 = Mil d: 2 6 -5 0 % of ti me i n Off state.  
3 = M o derate : 5 1-7 5 % of ti me i n Off state.  
4 = Se vere: > 7 5 % of ti me i n Off state.  
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 4  of 9 9   
 
1 7. 2  M O N T R E A L C O G NI TI V E A S S E S S M E N T  
 
T he M o C A ( Nasre d di ne 2 0 0 5 ) is a c o m m o nl y use d scree ni n g test easil y a d mi nistere d b y n o n-s pecialist staff. It 
assesses t he d o mai ns of atte nti o n a n d c o nce ntrati o n, e xec uti ve f u ncti o ns, me m or y, la n g ua ge, vis u oc o nstr ucti o nal 
s kills, c o nce pt ual t hi n ki n g, calc ulati o ns, a n d orie ntati o n. T he t otal p ossi ble sc ore is 3 0 p oi nts wit h a sc ore of 2 6 or 
m ore c o nsi dere d n or mal .  
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 5  of 9 9   
 
1 7. 3   S C H W A B A N D E N G L A N D A C TI VI TI E S O F D AI L Y LI VI N G  
 
T he S E -A D L e val uate s patie nts’ perce pti o n of gl o bal f u ncti o nal ca pacit y a n d de pe n de nce ( Sc h wa b 1 9 6 8 ). Sc ori n g 
is e x presse d i n ter ms of perce nta ge, i n 1 0 ste ps fr o m 1 0 0 t o 0 ( 1 0 0 %, n or mal stat us; 0 %, be dri d de n wit h ve getati ve 
d ysf u ncti o n), s o t hat t he l o wer t he sc ore, t he w orse t he f u ncti o nal stat us. T he rati n g is ma de b y a n 
o bser ver/ pr ofessi o nal.  
 
Sc h w a b A n d E n gl a n d Acti vities o f D ail y Li vi n g Sc ale 
 
1 0 0 % = C o m pletel y i n de pe n de nt. A ble t o d o all c h ores wit h o ut sl o w ness, diffic ult y or i m pair me nt. Esse ntiall y 
n or mal. U na ware of a n y diffic ult y.  
9 0 % = C o m pletel y i n de pe n de nt. A ble t o d o all c h ores wit h s o me de gree of sl o w ness, diffic ult y a n d i m pair me nt. 
Mi g ht ta ke t wice as l o n g. Be gi n ni n g t o be a ware of diffic ult y.  
8 0 % = C o m pletel y i n de pe n de nt i n m ost c h ores. Ta kes t wice as l o n g. C o nsci o us of diffic ult y a n d sl o w ness. 7 0 % = 
N ot c o m pletel y i n de pe n de nt. M ore diffic ult y wit h s o me c h ores. T hree t o f o ur ti mes as l o n g i n s o me. M ust 
s pe n d a lar ge part of t he da y wit h c h ores. 
6 0 % = S o me de pe n de nc y. Ca n d o m ost c h ores, b ut e xcee di n gl y sl o wl y a n d wit h m uc h eff ort. Err ors; s o me 
i m p ossi ble. 
5 0 % = M ore de pe n de nt. Hel p wit h half, sl o wer, etc. Diffic ult y wit h e ver yt hi n g. 4 0 % = Ver y de pe n de nt. Ca n assist 
wit h all c h ores, b ut fe w al o ne.  
3 0 % = Wit h eff ort, n o w a n d t he n d oes a fe w c h ores al o ne or be gi ns al o ne. M uc h hel p nee de d. 2 0 % = N ot hi n g 
al o ne. Ca n be a sli g ht hel p wit h s o me c h ores. Se vere i n vali d.  
1 0 % = T otall y de pe n de nt, hel pless. C o m plete i n vali d.  
0 %   = Ve getati ve f u ncti o ns s uc h as  s wall o wi n g, bla d der a n d b o wel f u ncti o ns are n ot f u ncti o ni n g. Be dri d de n. 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 6  of 9 9   
 
1 7. 4   C LI NI C A L I M P R E S SI O N O F S E V E RI T Y I N D E X –  P A R KI N S O N ’S DI S E A S E  
 
T he CI SI -P D is a se verit y i n de x f or me d b y f o ur ite ms ( m ot or si g ns, disa bilit y, m ot or c o m plicati o ns a n d c o g niti ve 
stat us), rate d 0 ( n ot at all) t o si x ( ver y se vere or se verel y disa ble d). A t otal sc ore is calc ulate d b y s u m mi n g t he ite m 
sc ores. T he scale is c o m plete d b y a cli nicia n at t he ti me of assess me nt . It ta kes a fe w sec o n ds t o c o m plete o nce t he 
state of t he patie nt is k n o w n ( Marti nez -Marti n 2 0 0 6 ). 
 
Cli nic al I m pressi o n of Se verit y I n de x ( CI SI -P D)  
 M ot or Si g ns  
0  
N or mal  
1  
Ver y mil d  
2  
Mil d  
3  
Mil d t o m o derate  
4  
M o derate  
5  
Se vere  
6  
Ver y se vere  
Dis a bilit y  
0  
N or mal  
1  
Mi ni mal sl o w ness a n d/ or cl u msi ness  
2  
Sl o w ness a n d/ or cl u msi ness. N o li mitati o ns  
3  
Li mitati o n f or de ma n di n g acti vities  
D oes n ot nee d hel p, or r arel y, f or b asic acti vities of d ail y li vi n g ( A D L)  
4  
Li mitati o n t o perf or m basic A D L Hel p is re q uire d f or s o me ba sic A D L 
5  
Great li mitati o n t o perf or m basic A D L Hel p is re q uire d f or m ost or all basic A D L  
6  
Se verel y disa ble d; hel pless C o m plete assista nce nee de d  
M ot or C o m plic ati o ns ( d ys ki nesi a a n d fl uct u ati o ns)  
0  
N ot at all  
1  
Ver y mil d  
2  
Mil d  
3  
Mil d t o m o derate  
4  
M o der ate 
5  
Se vere  
6  
Ver y se vere  
C o g niti ve St at us  
0  
N or mal  
1  
Mi ni mal c o g niti ve pr o ble ms  
2  
Mil d c o g niti ve pr o ble ms. N o li mitati o ns  
3  
Mil d t o m o derate c o g niti ve pr o ble ms. Li mitati o ns f or de ma n di n g acti vities. D oes n ot nee d hel p, or rarel y, 
f or basic acti vities 
4  
M o derate c o g niti ve pr o ble ms. Li mitati o ns f or basic acti vities. Hel p is nee de d f or s o me basic acti vities  
5  
Se vere c o g niti ve pr o ble ms. Ma n y li mitati o ns f or basic acti vities. Hel p is nee de d f or m ost or all basic A D L  
6  
Se verel y disa ble d; hel pless.  C o m plete a n d c o nti n ue d assista nce nee de d  
 
Sc ore  
M ot or si g ns  
 
 
 
 
 
_ _ _ _ _  
Dis a bilit y  
 
 
 
 
 
_ _ _ _ _  
M ot or C o m plic ati o ns    
 
 
 
_ _ _ _ _   
C o g niti ve St at us  
  
 
 
 
_ _ _ _ _  
CI SI -P D T ot al sc ore ( S u m of t he f o ur ite ms ( 0 -2 4)):  _ _ _ _ _  
 
  
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 7  of 9 9   
 
1 7. 5   P A R KI N S O N ’S DI S E A S E Q U A LI T Y O F LI F E Q U E S TI O N N AI R E -3 9  
 
T he P D Q -3 9 is a self -a d mi nistere d q uesti o n naire of 3 9 q uesti o ns relati n g t o 8 ke y areas of healt h a n d dail y 
acti vities, i ncl u di n g b ot h m ot or a n d n o n -m ot or s y m pt o ms ( Pet o 1 9 9 8 ). T he ei g ht di me nsi o ns i ncl u de: m o bilit y, 
acti vities of dail y li vi n g, e m oti o nal well -bei n g, sti g ma, s ocial s u p p ort, c o g niti o ns, c o m m u nicati o n, a n d b o dil y 
disc o mf ort . It is sc ore d o n a scale of 0-1 0 0 wit h l o wer sc ores i n dicati n g better healt h a n d hi g h sc ores  i n dicati n g 
m ore se vere s y m pt o ms .  
 
P ar ki ns o n’s Dise ase Q u ali t y of Life Q uesti o n n aire-3 9  
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 8  of 9 9   
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 6 9  of 9 9   
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 0  of 9 9   
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 1  of 9 9   
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 2  of 9 9   
 
1 7. 6  S H E E H A N S UI CI D A LI T Y T R A C KI N G S C A L E  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re pri nte d wit h per missi o n fr o m S hee ha n 2 0 1 4 . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 3  of 9 9   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re pri nte d wit h per missi o n fr o m S hee ha n 2 0 1 4 . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 4  of 9 9   
 
 
1 7. 7   M O V E M E N T DI S O R D E R S O CI E T Y ’S P A R KI N S O N ’S DI S E A S E C RI T E RI A  
 
 
 
 
 
Pr o vi de d f or use i n cli nical trial d oc u me ntati o n i n P ost u ma 2 0 1 5 . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 5  of 9 9   
 
1 7. 8   H A U S E R 3 -D A Y P A TI E N T DI A R Y  
 
T he Ha user patie nt diar y (Ha user  2 0 0 0 ) was de v el o pe d t o assess f u ncti o nal stat us o ver a peri o d of ti me i n patie nts 
wit h m ot or fl uct uati o ns a n d d ys ki nesia. It is a self -c o m plete d refere nce diar y desi g ne d t o se parate d ys ki nesia t hat 
ha d a n e gati ve i m pact o n patie nt -defi ne d f u ncti o nal stat us fr o m d ys ki nesia t hat di d n ot. Wit h t his diar y, t he effect 
of a n i nter ve nti o n ca n be e x presse d as t he c ha n ge i n off -me dicati o n ti me a n d t he c ha n ge i n o n -me dicati o n ti me 
wit h tr o u bles o me d ys ki nesia ( ba d ti m e). T he s u m ca n be use d as a n o utc o me varia ble a n d c o m pare d t o baseli ne or 
acr oss gr o u ps.   
 
 
 
 
Re pri nte d wit h per missi o n fr o m Ha user 2 0 0 0 . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 6  of 9 9   
 
1 7. 9  M O DI FI C A TI O N O F DI E T I N R E N A L DI S E A S E  F O R M U L A  
Gl o mer ular filtrati o n rate ( G F R) ma y be esti mate d base d o n t he M D R D  f or m ula:  
 
W he n ser u m creati ni ne is i n m g/ d L (c o n ve nti o nal u nits), t he G F R ma y be esti mate d base d o n t he 
f oll o wi n g M D R D f or m ula: 
G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 8 6 × (ser u m creati ni ne)– 1. 1 5 4 × ( A ge) – 0. 2 0 3 × ( 0. 7 4 2 if fe male) × ( 1. 2 1 0 if 
Africa n A merica n)  
 
W he n ser u m creati ni ne i s i n μ m ol/ L ( SI u nits), t he G F R ma y be esti mate d base d o n t he f oll o wi n g 
M D R D f or m ula:  
G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 8 6 × (ser u m creati ni ne/ 8 8. 4)– 1. 1 5 4 × ( A ge [ years])– 0. 2 0 3 × ( 0. 7 4 2 if fe male) × 
( 1. 2 1 0 if Africa n A merica n)  
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 8  of 9 9   
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
1 7. 1 1  C LI NI C A L E V A L U A TI O N O F LI V E R I N J U R Y  
 
1 7. 1 1 . 1 I N T R O D U C TI O N 
 
Alterati o ns of li ver la b orat or y para meters,
 are t o be 
f urt her e val uate d usi n g t he pr oce d ures descri be d bel o w. 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 7 9  of 9 9   
 
 
 
1 7. 1 1 . 2 P R O C E D U R E S  
Re peat t he f oll o wi n g la b orat or y tests: A L T, A S T, a n d bilir u bi n (t otal a n d direct) - wit hi n 4 8 t o 7 2 h o urs a n d 
pr o vi de a d diti o nal bl o o d sa m ple t o t he ce ntral la b orat or y f or a ut o mat ic refle x testi n g of t he bel o w liste d 
la b orat or y para meters. O nl y i n cases i n w hic h t he ce ntral la b orat or y is n ot i m me diatel y a vaila ble (e. g., if t he 
l o gistics are s uc h t hat t he s u bject´s re peat s peci me n w o ul d n ot reac h t he ce ntral la b orat or y i n a reas o na ble 
ti mefra me), A L T, A S T, a n d bilir u bi n (t otal a n d direct) will be e val uate d b y t he l ocal la b orat or y a n d res ults 
will be ma de a vaila ble t o t he i n vesti gat or a n d t o Al ka hest as s o o n as p ossi ble. If A L T a n d/ or A S T > 3 -f ol d 
U L N c o m bi ne d wit h a n ele vati o n of t ot al bilir u bi n > 2 -f ol d U L N are c o nfir me d, res ults of t he la b orat or y 
para meters descri be d bel o w m ust be ma de a vaila ble t o t he i n vesti gat or a n d t o Al ka hest as s o o n as p ossi ble.  
I n a d diti o n, t he f oll o wi n g s h o ul d be re p orte d i n t he C R F: 
•  
Detaile d hist or y of c urre nt s y m pt o ms a n d c o nc urre nt dia g n oses a n d me dical hist or y acc or di n g t o t he 
DI LI C hec klist pr o vi de d i n t he I S F . 
•  
Hist or y of c o nc o mita nt dr u g use (i ncl u di n g n o n -prescri pti o n me dicati o ns, her bal a n d dietar y 
s u p ple me nt pre parati o ns), alc o h ol use, recreati o nal dr u g use, a n d s pecial diets acc or di n g t o t he DI LI 
C hec klist pr o vi de d i n t he I S F . 
•  
Hist or y of e x p os ure t o e n vir o n me ntal c he mical a ge nts (c o nsi der h o me a n d w or k place e x p os ure) 
acc or di n g t o t he DI LI C hec klist pr o vi de d i n t he I S F . 
 
1 7. 1 1 .2. 1  Cli nic al C he mistr y  
•  
O btai n a n al kali ne p h os p hatase, al b u mi n, pr ot hr o m bi n ti me  or I N R, creati ni ne ki nase ( C K), creati ni ne 
ki nase M B test ( C K -M B,) cer ul o plas mi n, α -1 a ntitr y psi n, tra nsferri n a m ylase, li pase, gl uc ose, 
c h olester ol, tri gl yceri des . 
 
1 7. 1 1 . 2. 2  Se r ol o g y 
•  
O btai n a he patitis A (a nti -i m m u n o gl o b uli n M [I g M], a nti -I G M), he patitis B ( he patitis B a nti ge n, a nti-
H Bs, D N A), he patitis C (a nti -he patitis C vir us [H C V ]), ri b o n ucleic aci d ( R N A) if a nti-H C V p ositi ve), 
he patitis D (a nti -I g M, a nti-i m m u n o gl o b uli n G [Ig G ]), he patitis E (a nti -he patitis E vir us [H E V ]), a nti-
H E V I g M, R N A if a nti -H E V I g M p ositi ve), a nti -s m o ot h m uscle a nti b o d y (titer), a nti-n uclear 
a nti b o d y (titer), a nti -li ver-ki d ne y micr os o mes ( L K M) a nti b o d y, a nti mit oc h o n drial a nti b o d y, E pstei n 
Barr vir us ( vasc ularize d c o m p osite all otra ns pla ntati o n [V C A ] I g G, V C A I g M), c yt o me gal o vir us 
(I g G, I g M), her pes si m ple x vir us (I g G, I g M), varicella (I g G, I g M), par v o vir us (I g G, I g M), 
t o x o plas m osis (I g G, I g M). 
 
1 7. 1 1 . 2. 3  H or m o nes  
•  
T h yr oi d -sti m ulati n g h or m o ne. 
 
1 7. 1 1 . 2. 4  He m at ol o g y  
•  
T hr o m b oc ytes, 
. 
 
1 7. 1 1 . 2. 5  Ultr as o u n d  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 0  of 9 9   
 
•  
Pr o vi de a n a b d o mi nal ultras o u n d t o r ule o ut biliar y tract, pa ncreatic, or i ntra he patic pat h ol o g y ( e. g., 
bile d uct st o nes or ne o plas m) . 
 
1 7. 1 1 . 2. 6 O bser v ati o n/ Re pe at Testi n g 
•  
I nitiate cl ose obser vati o n of s u bjects b y re peat testi n g of A L T, A S T, a n d t otal bilir u bi n ( wit h 
fracti o nati o n b y t otal a n d direct) at least wee kl y u ntil t he la b orat or y A L T a n d/ or A S T a b n or malities 
sta bilize or ret ur n t o n or mal, t he n acc or di n g t o t he pr ot oc ol. De pe n di n g o n  f urt her la b orat or y c ha n ges, 
a d diti o nal para meters i de ntifie d e. g., b y refle x testi n g will be f oll o we d u p base d o n me dical j u d g me nt 
a n d G C P. 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 1  of 9 9   
 
1 7. 1 2  P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C , A N D F A C S 
S A M P LI N G  
 
1 7. 1 2 . 1 T A B L E O F P H A R M A C O KI N E TI C, BI O M A R K E R, P H A R M A C O G E N O MI C , a n d F A C S 
S A M P LI N G  
 
Visit  
Ti me P oi nt  
Ti me f or 
D at a b ase 
Set u p  
P K  
Bl o o d  
E xtr a Bi o m ar ker Ali q u ot fr o m 
P K Bl o o d S a m ple  
P G X 
Bl o o d  
F A C S & 
C B C  
2  
Pri or t o ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
-0: 1 5 h  
 
X  
 
X  
 
X  
 
X  
0: 0 0  
0: 0 0 h  
St u d y a ge nt a d mi nistrati o n  
 
1: 0 0 ± 1 5  mi n utes  
1: 0 0 h  
X  
X  
 
X  
2: 0 0 ± 3 0  mi n utes  ( o pti o nal) 
2: 0 0 h  
X  
 
 
 
3  
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
 
X  
 
 
 
4  
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
 
X  
 
 
 
 
0: 0 0  
0: 0 0 h 
St u d y a ge nt a d mi nistrati o n  
1: 0 0 ± 1 5  mi n utes  ( o pti o nal) 
1: 0 0 h 
X  
 
 
 
2: 0 0 ± 3 0  mi n utes  ( o pti o nal) 
2: 0 0 h 
X  
 
 
 
5  
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
 
X  
 
 
 
 
6 
( E O T) 
-0 0: 1 5 mi n ( i.e., wit hi n 1 5 mi n 
bef ore st u d y a ge nt 
a d mi nistrati o n) 
 
 
X  
 
X  
 
 
X  
0: 0 0  
0: 0 0 h 
St u d y a ge nt a d mi nistrati o n  
1: 0 0 ± 1 5  mi n utes  ( o pti o nal) 
1: 0 0 h 
X  
 
 
 
2: 0 0 ± 3 0  mi n utes  ( o pti o nal) 
2: 0 0 h 
X  
 
 
 
7  
A n y ti me d uri n g visit –  
prefera bl y at t he e n d of all visit 
pr oce d ures  
 
 
 
X  
 
X  
 
 
 
1 7. 1 3  P H A R M A C O KI N E TI C M E A S U R E S A N D E V A L U A TI O N  
 
1 7 . 13 . 1 TI MI N G O F P H A R M A C O KI N E TI C B L O O D S A M P LI N G  
F or t he ti me sc he d ules of p har mac o ki netic bl o o d sa m ples, please refer t o  Secti o n 1 7. 1 2 . 1.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 2  of 9 9   
 
 
1 7. 1 3 . 2 P H A R M A C O KI N E TI C S A M P L E H A N D LI N G A N D S HI P M E N T  
Met h o ds of p har mac o ki netic sa m ple c ollecti o n are descri be d i n  Secti o n 7. 2. 2. 1 . 2. F urt her i nstr ucti o ns f or 
sa m pli n g pr oce d ures, a n d f or ha n dli n g, st ora ge a n d s hi p me nt of t he sa m ples will be pr o vi de d i n t he 
La b orat or y  Ma n ual i n t he I S F .  
 
1 7. 1 3 . 3 P H A R M A C O KI N E TI C D A T A E V A L U A TI O N  
F or p har mac o ki netic a nal ysis a n d dis pla ys, c o nce ntrati o ns will be prese nte d i n t he sa me f or mat as re p orte d i n 
t he bi oa nal ytical re p ort. O nl y c o nce ntrati o ns wit hi n t he vali date d c o nce ntrati o n ra n ge a n d act ual sa m pli n g 
ti mes will be use d f or t he calc ulati o n of p har mac o ki netic para meters. 
 
1 7. 1 3 . 4 H A N D LI N G O F MI S SI N G BI O A N A L Y TI C A L D A T A  
I n t he n o nc o m part me ntal a nal ysis, c o nce ntrati o n data i de ntifie d wit h N O S, N O R, a n d N O A will n ot be 
c o nsi dere d. B L Q a n d N O P val ues i n t he la g p has e will be set t o zer o . T he la g p hase is defi ne d as t he peri o d 
bet wee n ti me zer o a n d t he first ti me p oi nt wit h a c o nce ntrati o n a b o ve t he q ua ntificati o n li mit. All ot her B L Q 
a n d/ or N O P val ues of t he pr ofile will be i g n ore d . E ver y eff ort will be ma de t o i ncl u d e all c o nce ntrati o n data 
i n a n a nal ysis. If n ot p ossi ble, a case t o case decisi o n is re q uire d w het her t he val ue s h o ul d be e xcl u de d. 
Descri pti ve statistics of c o nce ntrati o ns will be calc ulate d o nl y w he n at least 2/ 3 of t he i n di vi d uals ha ve 
c o nce ntrati o ns wi t hi n t he vali date d c o nce ntrati o n ra n ge. T he o verall sa m ple size t o deci de w het her t he ' 2/ 3' 
r ule is f ulfille d will be base d o n t he t otal n u m ber of sa m ples i nte n de d t o be dra w n f or t hat ti me p oi nt (i.e., 
B L Q, N O R, N O S, N O A, N O P are i ncl u de d) . Descri pti ve st atistics of para meters are calc ulate d o nl y w he n at 
least 2/ 3 of t he i n di vi d ual para meter esti mates of a certai n para meter are a vaila ble. 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 3  of 9 9   
 
1 8  
R E VI SI O N HI S T O R Y  
1 8. 1  S U M M A R Y O F C H A N G E S  
 
P r ot oc ol V ersi o n 4. 0  d ate d 2 2 M A Y 2 0 2 0  
Re pl aces: Pr ot oc ol V ersi o n 3 .1  d ate d 0 6 J A N 2 0 2 0  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 3. 1  ( date d 0 6J A N 2 0 2 0 ) wit h j ustificati o ns 
pr o vi de d.  
 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d :  V 3 .1 _ 0 6J A N 2 0 2 0  
 
N o w re a ds: V 4. 0 _ 2 2 M A Y 2 0 2 0  
Versi o n c o ntr ol. 
T hr o u g h o ut  
Mi n or gra m mar, c o nte nt, a n d st yle u p dates.  
Mi n or c o nte nt u p dates f or 
clarit y/acc urac y /st yle of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
P r ot oc ol 
S u m mar y, 
Sc he matic of 
St u d y Desi g n, 
4 . 1, 5. 3 
S u bject d urati o n is 1 8 wee ks  w hic h i ncl u des  
S cree ni n g (-1 4 t o -7  da ys pri or t o Baseli ne ), 
treat me nt ( 1 2 wee ks), a n d 4  wee k s of f oll o w-u p.  
C o nte nt re vise d f or acc urac y.  
Pr ot oc ol 
S u m mar y, 3, 
4. 2. 3, 7. 1. 1. 3, 
7. 1. 1. 3. 8 
(re m o ve d 
secti o n –  
s u bse q ue nt 
secti o ns 
re n u m bere d), 
7. 3, 1 5, 1 6. 1  
T he Ze n o wal k wa y assess me nt was  re m o ve d fr o m t he 
trial.  
T he Ze n o wal k wa y was n ot 
a vaila ble at a n y partici pati n g st u d y 
sites. 
5. 1  
•  
U p date d I ncl usi o n Criteri o n # 8 : 
o  Previ o usly re a d : “If o n a nti de pressa nt 
me dicati o ns, m ust be o n sta ble d osa ge f or 
at least 8 wee ks pri or t o e nr oll me nt. ” 
o  N o w re a ds: “If o n a nti de pressa nt 
me dicati o ns or ne ur ole ptic me dicati o ns, 
m ust be o n sta ble d osa ge f or at least 8 
wee ks pri or t o e nr oll me nt. ” 
 
Re m o ve d  
as a pr o hi bite d 
me dicati o n a n d i ncl u de d g ui da nce 
f or sta ble d osa ge of all ne ur ole ptic 
me dicati o ns 8 wee ks p ri or t o 
e nr oll me nt. 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 4  of 9 9   
 
5. 2  
•  
U p date d E xcl usi o n Criteri o n # 3 : 
o  Previ o usly re a d : “
 
 
 
 
 
 
o  N o w re a ds: “ 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 4 : 
o  
 
 
 
 
  
 
 
 
 
 
 
 
 
•  
U p da te d E xcl usi o n Criteri o n #5 : 
o  
 
 
 
 
 
  
 
 
 
 
 
•  
E xcl usi o n Criteri o n # 6  re m o ve d: 
o  
 
 
 
 
 
 
 
 
 
•  
E xcl usi o n Criteri o n # 7  re m o ve d: 
o  
 
 
 
E xcl usi o n re vise d t o pr o vi de 
narr o wer wi n d o w of pr o hi bite d 
me dicati o n  usa ge . 
 
 
 
 
 
 
 
 
 
 
 
U p date d e xcl usi o n  base d o n fi n di n gs 
fr o m a cli nical dr u g -dr u g i nteracti o n 
st u d y. 
 
 
 
 
 
 
 
 
 
 
U p date d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
 
 
 
 
Re m o ve d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
 
 
 
Re m o ve d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 5  of 9 9   
 
 
 
 
•  
   E xcl usi o n Criteri o n # 8  re m o ve d: 
o  
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 6 ( pre vi o us l y # 9): 
o  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 8 ( pre vi o usl y # 1 1 ): 
o  
 
  
 
 
 
 
•  
Pre vi o us E xcl usi o n Criteri a # 1 0 a n d # 1 2 -# 2 0  
re n u m bere d t o #7 a n d # 9 -# 1 7 , res pecti vel y, a n d 
a p pr o priate cr oss -refere nce were a d de d. 
 
 
 
Re m o ve d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
U p date d e xcl usi o n  base d o n 
fi n di n gs fr o m a cli nical dr u g -dr u g 
i nteracti o n st u d y. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Re m o ve d  
as a pr o hi bite d 
me dicati o n a n d i ncl u de d g ui da nce 
f or sta ble d osa ge of all ne ur ole ptic 
me dicati o ns 8 wee ks pri or t o 
e nr oll me nt. 
 
Re vise d n u m beri n g f or clarit y.  
 
 
 
7. 2. 2. 1 , 7. 3, 
1 5, 1 7. 1 2  
A d diti o nal o pti o nal P K e val uati o ns were a d de d at Visit 2 
(o pti o nal P K at + 2 h o urs)  a n d Visits 4 a n d 6 ( o pti o nal P K  
sa m ples at + 1 h o ur a n d + 2 h o urs).  
N e w ( o pti o nal) sa m ple c ollecti o ns 
a n d a nal yses  were a d de d t o i m pr o ve  
P K e val uati o n . 
7. 3, 1 5  
Te xt was m o difie d f or clarit y relate d t o or der of 
assess me nts. 
Clarificati o n of t he or der ( or lac k of 
s pecifie d or der) f or partic ular 
assess me nts. 
7. 5, 1 5, 1 7. 1 0  
C o nte nt u p dates ma de t o e ns ure all re visi o ns i n t he 
E xcl usi o n Criteria relate d t o pr o hi bite d me dicati o ns  a n d 
s u bsta nces, as well as preca uti o ns  a n d m o nit ori n g , were 
c orrectl y i ncl u de d/ descri be d. 
U p date d c o nte nt  base d o n fi n di n gs 
fr o m a cli nical dr u g -dr u g i nteracti o n 
st u d y. 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 6  of 9 9   
 
 
P r ot oc ol V ersi o n 3. 1  d ate d 0 6 J A N 2 0 2 0  
Re pl aces: Pr ot oc ol V ersi o n 3 . 0 d ate d 0 2 D E C 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 3. 0  ( date d 0 2 D E C 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
 
Pr ot oc ol V ersi o n 3. 0  d ate d 0 2 D E C 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 2. 0 d ate d 2 4 J U L 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 3. 0  ( date d 0 2 D E C 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
1 3. 3, 1 5 , 
1 7. 1 0  
C o nte nt a d de d re: fle xi bilit y f or wi n d o w e xte nsi o ns a n d 
misse d pr ot oc ol assess me nts relate d t o C O VI D -1 9.  A n y 
de viati o n t o t he pr ot oc ol t o re d uce t he ris k of C O VI D -1 9 
will be ca pt ure d as a “ Pr ot oc ol De viati o n relate d t o 
C O VI D -1 9” t o cate g orize t he a ntici pate d i ncrease i n 
pr ot oc ol de via ti o ns d ue t o t he pa n de mic.  T hese meas ures 
are te m p orar y, a n d will be re peale d as s o o n as t he 
sit uati o n (e. g., g o ver n me ntal r ules, be nefit/ris k assess me nt 
f or t he trial, etc.) all o ws.   
Ne w c o nte nt t o acc o u nt f or p ote ntial 
pr ot oc ol de viati o ns relate d t o 
C O VI D -1 9.  
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d :  V 3 . 0_ 0 2 D E C 2 0 1 9  
 
N o w re a ds : V 3 .1 _ 0 6 J A N 2 0 2 0 
Versi o n c o ntr ol. 
T hr o u g h o ut  
Mi n or gra m mar, c o nte nt, a n d st yle u p dates.  
Mi n or c o nte nt u p dates f or 
clarit y/acc urac y /st yle of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates. 
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
5. 1  
T he c o ntrace pti ve met h o d “se x ual a bsti ne nce” has 
bee n re m o ve d fr o m I ncl usi o n Criteri o n #1 0  as it is 
n ot c o nsi dere d a hi g hl y effecti ve c o ntrace pti ve 
met h o d  wit h o ut s u p ple me ntati o n.  
C o n te nt re visi o n f or ali g n me nt wit h 
re g ulat or y g ui da nce re gar di n g 
hi g hl y effecti ve met h o ds of 
c o ntrace pti o n. 
8. 4. 2. 1  
Pr ot oc ol pre vi o usl y i n dicate d t hat a n S A E Re p ort 
F or m a n d S A E f oll o w -u p i nf or mati o n c o ul d be se nt  
t o 
 wit hi n 2 4 h o urs  of recei pt of 
i nf or mati o n b y t he i n vesti gati o nal site. T he 
la n g ua ge has bee n a me n de d t o i n dicate t hat t hese 
ite ms m ust be se nt i m me diatel y ( wit h o ut c ul pa ble 
dela y), b ut n o later t ha n 2 4 h o urs of recei pt of 
i nf or mati o n b y t he i n vesti gati o nal site. 
C o nte nt re vi si o n t o pr o vi de clarit y 
of ur ge nc y of re p orti n g of S A E 
Re p ort F or ms a n d f oll o w -u p 
i nf or mati o n. 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d :  V 2. 0 _ 2 4 J U L2 0 1 9  
 
N o w re a ds : V 3 . 0_ 0 2 D E C 2 0 1 9  
Versi o n c o ntr ol. 
Ta ble of 
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 7  of 9 9   
 
C o nte nts  
re vise d c o nte nt. 
List of 
A b bre viati o ns  
Delete d  T B ; re vise d I R B defi niti o n, a d de d C P K 
(creati ne p h os p h o ki nase) a n d C R P ( C-reacti ve 
pr otei n).  
Mi n or u p dates re q uire d f or acc urac y 
a n d t o reflect re vise d c o nte nt. 
P r ot ocol 
S u m mar y, 
4. 2. 3 , 1 6. 1 
U p dates t o e x pl orat or y e n d p oi nt i n last b ullet:  
Previ o usly re a d :  
Pr ot oc ol S u m mar y: “ I n c o nse nti n g s u bjects ( o pti o nal): 
c ha n ges i n fecal mar kers of i ntesti nal i nfla m mati o n 
(cal pr otecti n a n d lact oferri n) a n d per mea bilit y (al p ha-1 
a ntitr y psi n a n d z o n uli n). ” 
Secti o n 4. 2. 3: “ I n c o nse nti n g s u bjects ( o pti o nal): 
c han ges i n fecal mar kers of i ntesti nal i nfla m mati o n 
(cal pr otecti n a n d lact oferri n) a n d per mea bilit y (al p ha-1 
a ntitr y psi n a n d z o n uli n ) (Sc h wiertz 2 0 1 8 ).” 
 
N o w re a ds:  
Pr ot oc ol S u m mar y: “ I n c o nse nti n g s u bjects 
( o pti o nal): c haracterizati o n of t he c o m p ositi o n a n d 
f u ncti o n of t he fecal g ut micr o bi o me.” 
Secti o n 4. 2. 3:  “ I n c o nse nti n g s u bjects ( o pti o nal): 
c haracterizati o n of t he c o m p ositi o n a n d f u ncti o n of 
t he fecal g ut micr o bi o me (S c h wiertz 2 0 1 8 , Si n g h 
2 0 1 9 ).” 
C o nte nt re vise d t o pr o vi de 
a d diti o nal fle xi bilit y i n e val uati o n of 
micr o bi o me; rece nt s u p p orti n g 
refere nce a d de d ( Si n g h 2 0 1 9). 
4. 1 , 7. 3. 1. 1, 
1 5  
C ha n ge d scree ni n g peri o d wi n d o w fr o m “ Da y -1 0 
t hr o u g h Da y -7” t o “ Da y -1 4 t hr o u g h Da y -7”  
 
Re vise d  t o all o w m ore ti me f or sites 
t o sc he d ule s u bjects. 
5 . 1 
•  I ncl usi o n Criteri o n # 1 0 : 
Previ o usly re a d:  
•  Fe male s u bjects m ust n ot be pre g na nt or 
breastfee di n g. W o me n  a n d me n  of c hil d beari n g 
p ote ntial ( W O C B P) m ust ha ve a ne gati ve 
pre g na nc y test at Scree ni n g. W O C B P a n d me n 
m ust a gree t o use hi g hl y effecti ve c o ntrace pti o n 
(Cli nical Trial Facilitati o n Gr o u p 2 0 1 4 ) pri or t o 
st u d y e ntr y. A w o ma n is c o nsi dere d of 
c hil d beari n g p ote ntial f oll o wi n g me narc he a n d 
u ntil bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d 
a w o ma n bec o me pre g na nt or s us pect s he is 
pre g na nt w hile s he or her part ner is parti ci pati n g i n 
t he st u d y, s he s h o ul d i nf or m her treati n g p h ysicia n 
i m me diatel y. Male s u bjects m ust be willi n g t o use 
a barrier met h o d c o ntrace pti o n w hile partici pati n g 
i n t he st u d y.  
N o w re a ds:  
•  Fe male s u bjects m ust n ot be pre g na nt or 
breastfee di n g. W o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve pre g na nc y test at 
Scree ni n g. W O C B P m ust a gree t o use hi g hl y 
effecti ve c o ntrace pti o n w hic h i ncl u des c o m bi ne d 
(estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal 
c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
Pr o vi de d a d diti o nal details 
re gar di n g hi g hl y effecti ve 
c o ntrace pti o n . 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 8  of 9 9   
 
o v ulat i o n ( oral, i ntra va gi nal, tra ns der mal), 
pr o gest o ge n -o nl y h or m o nal c o ntrace pti o n 
ass ociate d wit h i n hi biti o n of o v ulati o n ( oral, 
i njecta ble, i m pla nta ble), i ntra uteri ne de vice, 
i ntra uteri ne h or m o ne-releasi n g s yste m, bilateral 
t u bal occl usi o n, vasect o mize d partner, or se x ual 
a bsti ne nce ( Cli nical Trial Facilitati o n Gr o u p 2 0 1 4 ) 
pri or t o st u d y e ntr y. A w o ma n is c o nsi dere d of 
c hil d beari n g p ote ntial f oll o wi n g me narc he a n d 
u ntil bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d 
a w o ma n bec o me pre g na nt or s us pect s he is 
pre g na nt w hile s he or her part ner is partici pati n g i n 
t he st u d y, s he s h o ul d i nf or m her treati n g p h ysicia n 
i m me diatel y. Male s u bjects m ust be willi n g t o use 
a barrie r met h o d c o ntrace pti o n. 
5. 2  
•  
U p date d E xcl usi o n Criteri o n  # 2 t o re m o ve 
t u berc ul osis testi n g ( b y Q ua nti F E R O N testi n g) at 
scree ni n g. 
 
•  
U p date d E xcl usi o n Criteri o n # 4:  
o  
 
 
 
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Crit eri o n # 5: 
o  
 
 
 
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 6:  
o  
 
 
 
 
 
 
 
 
 
 
Delete d t u berc ul osis testi n g at 
scree ni n g si nce it is n ot re q uire d. 
 
 
C o nte nt re vise d t o pr o vi de cr oss -
refere nce t o listi n g of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 
 
 
C o nte nt re vise d t o clarif y p ote ntial 
dr u g i nteracti o ns  wit h cr oss -
refere nce t o listi n g of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 
 
C o nt e nt re vise d t o clarif y p ote ntial 
dr u g i nteracti o ns  wit h cr oss -
refere nce t o listi n g of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 8 9  of 9 9   
 
 
 
 
 
 
 
 
•  
U p date d E xcl usi o n Criteri o n # 7:  
o  
 
 
 
 
 
 
 
 
 
 
 
•  
   A d de d E xcl usi o n Criteri o n # 8:  
o  
 
 
 
 
 
 
•  
Pre vi o us E xcl usi o n Criteri a # 8 -# 1 9 re n u m bere d t o 
# 9 -# 2 0  a n d a p pr o priate cr oss -refere nce were 
a d de d . 
  
 
 
 
 
 
 
 
C o nte nt re vise d t o clarif y p ote ntial 
dr u g i nteracti o ns  wit h  cr oss-
refere nce t o list of pr o hi bite d 
me dicati o ns  a n d s u bsta nces. 
 
 
 
 
 
 
 
Criteria re n u m bere d d ue t o a d diti o n 
of E xcl usi o n Criteri o n # 8  a n d cr oss -
refere nce t o list of pr o hi bite d 
me dicati o ns  a n d s u bsta nces was 
a d de d. 
 
 
 
Criteria re n u m bere d d ue t o a d diti o n 
of E xcl usi o n Criteri o n # 8 a n d cr oss -
refere nce t o list of pr o hi bite d 
me dicati o ns a n d s u bsta nces were 
a d de d, as a p p ro priate.  
 
7. 1. 1. 2. 7  
•  
Re m o ve d Ser ol o g y testi n g f or T B fr o m Bl o o d a n d 
Uri ne C ollecti o n f or La b orat or y E val ua ti o ns 
 
•  
A d de d t he f oll o wi n g e xa mi nati o ns t o C he mistr y: 
creati ne p h os p h o ki nase ( C P K), c h olester ol (t otal), 
a n d C-reacti ve pr otei n. 
P ositi ve scree ni n g f or T B is  n o 
l o n ger a n E x cl usi o n C riterio n . 
 
A d diti o n of la b orat or y tests f or 
re q uire d m o nit ori n g.  
7. 5  
C o nte nt u p dates ma de t o e ns ure all pr o hi bite d me dicati o ns  
a n d s u bsta nces , per t he re vise d E xcl usi o n Criteria, were 
descri be d . 
C o nte nt re vise d t o clarif y a d diti o nal  
pr o hi bite d me dicati o ns a n d 
s u bsta nces. 
 
8. 4. 2. 1  
S A E Re p orti n g I nf or mati o n: 
Previ o usly re a d :  
•  
“ All S A Es occ urri n g d uri n g t he st u d y s h o ul d be 
re p orte d i m me diatel y. 
•  
T he S A E Re p ort F or m a n d rele va nt s o urce 
d oc u me nts, if a p plica ble, m ust be c o m plete d 
a n d e maile d t o
wit hi n 
2 4 h o urs of o bser vati o n or l ear ni n g of t he e ve nt.  
•  
F oll o w -u p i nf or mati o n m ust be se nt t o t he C R O 
wit hi n 2 4 h o urs of recei pt of i nf or mati o n b y t he 
Ti mefra me f or Re p orti n g S A Es 
ha ve bee n u p date d t o clarif y c o ntact 
i nf or mati o n. 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 0  of 9 9   
 
 
Pr ot oc ol V ersi o n 2. 0  d ate d 2 4 J U L 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 1. 2  d ate d 1 7 M A Y 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 1.2  ( date d 1 7 M A Y 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
i n vesti gati o nal site.” 
 
N o w re a ds:  
•  
“T he S A E Re p ort F or m a n d rele va nt s o urce 
d oc u me nts, if a p plica ble, m ust be c o m plete d a n d 
n otifie d, fa xe d, or e maile d t o  
 wit hi n 
2 4 h o urs of o bser vati o n or lear ni n g of t he e ve nt.  
o  
 
 
 
 
 
 
 
 
 
 
•  
F oll o w -u p i nf or mati o n m ust be se nt t o  
 
wit hi n 2 4 h o urs of recei pt of i nf or mati o n b y t he 
i n vesti gati o nal site.” 
 
8. 4. 2. 2  
S A E Re p orti n g I nf or mati o n:  
Previ o usly re a d : “T he S A E Re p ort F or m m ust be 
c o m plete d a n d e maile d t o
 
acc or di n g t o t he ti mefra mes s pecifie d i n  Secti o n 
8. 4. 2. 1 .” 
 
N o w re a ds : “T he S A E Re p ort F or m m ust be c o m plete d 
a n d fa xe d or e maile d t o  
 acc or di n g t o t he 
ti mefra mes s pecifie d i n Secti o n 8. 4. 2. 1 .” 
Re vise d si nce t he S A E re p orti n g 
i nf or mati o n was u p date d. 
1 7. 1 0, 
1 7. 1 0. 1  
C o nte nt a n d ta ble u p date d wit h e x pa n de d list of 
pr o hi bite d me dicati o ns a n d s u bsta nces d ue t o 
re vise d E xcl usi o n Criteria (see Secti o n 5. 2  re visi o ns 
descri be d a b o ve). 
C o nte nt  re vise d t o clarif y a d diti o nal 
pr o hi bite d me dicati o ns a n d 
s u bsta nces. 
 
1 7. 1 0. 2  
Ta ble a d de d wit h e x pa n de d list of pr o hi bite d 
me dicati o ns a n d s u bsta nces d ue t o re vise d 
E xcl usi o n Criteria (see Secti o n 5. 2  re visi o ns 
descri be d a b o ve ). 
C o nte nt de vel o pe d  t o clarif y 
a d diti o nal pr o hi bite d me dicati o ns 
a n d s u bsta nces.  
 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d : V 1. 2 _ 1 7 M A Y 2 0 1 9  
 
N o w re a ds : V 2 . 0_ 2 4 J U L2 0 1 9  
Versi o n c o ntr ol. 
T hr o u g h o ut  
Mi n or gra m mar a n d c o nte nt u p dates.  
Mi n or gra m mar/c o nte nt u p dates f or 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 1  of 9 9   
 
clarit y/acc urac y of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
List of 
A b bre viati o ns  
A d de d H B V , mI T T, a n d T B 
U p date d a b bre viati o ns t o i ncl u de 
He patitis B v ir us ( H BV) , M o difie d 
i nte nt-t o-treat ( mI T T), a n d 
T u berc ul osis  ( T B).  
Pr ot oc ol 
S u m mar y, 5 . 1 
C ha n ge d a ge ra n ge i ncl usi o n criteri o n fr o m “ 4 0 t o 
8 0 years of a ge” t o “ 5 0 t o 8 0 year s of a ge”  
Eff ort t o r e d uce n u m ber of W O C B P 
partici pati n g  i n t he st u d y t o re d uce 
pr o ba bilit y of pre g na n c y d uri n g t he 
trial. 
Pr ot oc ol 
S u m mar y, 4. 1  
N u m ber of Sites:  
Previ o usly re a d : “A p pr o xi matel y 1 0  i n t he U nite d 
States ( U S) a n d u p t o 1 0 i n Ger ma n y ” 
 
N o w re a ds : “A p pr o xi matel y 3 0 sites are pla n ne d 
gl o ball y ” 
E x pa n di n g ge o gra p hic ra n ge t o 
s u p p ort ti mel y recr uit me nt a n d 
a d diti o nal ge o gra p hic 
re prese ntati o n.   
5. 1  
U p date d I ncl usi o n Criteri o n # 1 0  f oll o ws: 
Previ o usly  re a d: 
•  
Fe male s u bjects m ust n ot be 
pre g na nt or breastfee di n g. 
W o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve 
pre g na nc y test at Scree ni n g. 
W O C B P a n d me n m ust a gree t o 
use hi g hl y effecti ve 
c o ntrace pti o n ( Cli nical Trial 
Facilitati o n Gr o u p 2 0 1 4 ) pri or t o 
st u d y e ntr y. Birt h c o ntr ol 
me t h o ds c o nsi dere d acce pta ble 
f or t his st u d y i ncl u de d o u ble-
barrier met h o ds; h or m o nal 
c o ntrace pti ves t hat are i njecte d, 
i m pla nte d, or ta ke n orall y; or a n 
i ntra uteri ne de vice. A w o ma n is 
c o nsi dere d of c hil d beari n g 
p ote ntial f oll o wi n g me narc he 
a n d u ntil bec o mi n g 
p ost me n o pa usal ( n o me nses f or 
at least 2 years wit h o ut a n 
alter nati ve ca use). S h o ul d a 
w o ma n bec o me pre g na nt or 
s us pect s he is pre g na nt w hile s he 
or her part ner is partici pati n g i n 
t he st u d y, s he s h o ul d i nf or m her 
treati n g p h ysicia n i m me diatel y. 
N o w  re ads:  
•  
Fe male s u bjects m ust n ot be 
pre g na nt or breastfee di n g. 
W o me n of c hil d beari n g p ote ntial 
( W O C B P) m ust ha ve a ne gati ve 
pre g na nc y test at Scree ni n g. 
Ali g n me nt w it h Cli nical T rial 
F acilitati o n G r o u p rec o m me n dati ons  
o n use of c o ntrace pti ve s i n cli nical 
trials. 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 2  of 9 9   
 
W O C B P a n d me n m ust a gree t o 
use hi g hl y effecti ve 
c o ntrace pti o n (Cli nical Trial 
Facilitati o n Gr o u p 2 0 1 4 ) pri or t o 
st u d y e ntr y. A w o ma n is 
c o nsi dere d of c hil d beari n g 
p ote ntial f oll o wi n g me narc he 
a n d u ntil bec o mi n g 
p ost me n o pa usal ( n o me nses f or 
at least 2 years wit h o ut a n 
alter nati ve ca use). S h o ul d a 
w o ma n bec o me pre g n a nt or 
s us pect s he is pre g na nt w hile s he 
or her part ner is partici pati n g i n 
t he st u d y, s he s h o ul d i nf or m her 
treati n g p h ysicia n i m me diatel y. 
Male s u bjects m ust be willi n g t o 
use a barrier met h o d 
c o ntrace pti o n w hile partici pati n g 
i n t he st u d y. 
  
5. 2  
U p date d E xcl usi o n Criteria as f oll o ws:  
 
•  E xcl usi o n Criteri o n # 2 , b ullet 5, re m o ve d: 
 
 
 
•  E xcl usi o n Criteri o n # 2 , b ullet 6 ( pre vi o usl y b ullet 7): 
Previ o usly re a d:  
•  He patic i m pair me nt.  
N o w re a ds:  
•  C urre nt, acti ve li ver disease: > 3 -f ol d ele vati o n of 
li ver e nz y mes (ala ni ne a mi n otra nsferase [ A L T] 
a n d as partate a mi n otra nsferase [ A S T] o ver u p per 
li mit of n or mal). 
 
•  E xcl usi o n Criteri o n # 2, b ullet 7 ( pre vi o usl y b ullet 8): 
Previ o usly  re a d: 
•  U nc o ntr olle d s yste mic h y perte nsi o n .  
N o w  re a ds: 
•  U nc o ntr olle d hi g h bl o o d press ure (s yst olic bl o o d 
press ure of 1 6 0 m m H g or hi g her a n d/ or diast olic 
bl o o d press ure of 1 0 0 m m H g or hi g her) des pite 
a de q uate treat me nt d uri n g t he 3 m o nt hs pri or t o 
d osi n g.  
 
•  E xcl usi o n Criteri o n # 4 : 
Previ o usly re a d:  
•  
 
 
  
N o w re a ds:  
 
 
E xcl usi o n was a carr y o ver fr o m 
earlier p hase st u d y. Warfari n a n d 
fact or Xa a ntic oa g ula nts a d de d t o 
E xcl usi o n Criteri o n # 4  as t hese are 
C Y P 3 A 4/ 5 a n d/ or P -g p s u bstrates 
t hat ha ve a narr o w t hera pe utic 
i n de x; als o clarifies t hat 
acet ylsalic ylic aci d is n ot p r o hi bite d. 
 
 
C riteri o n clarifie d wit h a d diti o nal 
descri pti ve c o nte nt  t o ai d 
i n vesti gat ors i n deter mi ni n g 
eli gi bilit y.   
 
 
 
 
 
C riteri o n clarifie d wit h a d diti o nal 
descri pti ve c o nte nt  t o ai d 
i n vesti gat ors i n deter mi ni n g 
eli gi bilit y.   
   
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 3  of 9 9   
 
•  
 
  
 
•  E xcl usi o n Criteri o n # 7 : 
Previ o usly re a d:  
•  
 
 
  
N o w re a ds:  
•  
 
 
  
 
C riteri o n clarifie d wit h a d diti o nal 
descri pti ve c o nte nt/e xa m ple s t o ai d 
i n vesti gat ors i n deter mi ni n g 
eli gi bilit y. 
 
 
 
 
 
 
Criteri o n clarifie d t o i ncl u de  
 
t o sta n dar dize 
wit h rec o m me n dati o ns i n t he 
I n vesti gat or’s Br oc h ure.   
 
5. 4. 2  
A d de d la n g ua ge t o clarif y t hat s u bjects w h o ha ve 
wit h dra w n d ue t o a d verse dr u g e ve nts or a d verse 
reacti o ns base d o n st u d y pr oce d ures will n ot be re place d.  
Pr o vi de clarificati o n ar o u n d 
ha n dli n g of partici pa nt wit h dra wal 
a n d s u bject re place me nt. 
7. 1. 1. 1. 9, 
7. 3. 2. 1, 
7. 3. 3. 2, 
7. 3. 4. 1  
A d de d / defi ne d A d mi nistrati o n of d o pa mi ner gic 
me dicati o n as a st u d y pr oce d ure  a n d u p date d la n g ua ge i n 
t he St u d y Sc he d ule secti o ns fr o m “ C o m me nce o n-
me dicati o n state” t o “ A d mi nistrati o n of d o pa mi ner gic 
me dicati o n”  
Ali g n wit h S c he d ule of E ve nts a n d 
pr o vi de clarificati o n ar o u n d t he 
a d mi nistrati o n of d o pa mi ner gic 
me dicati o n.  
7. 1. 1. 2. 7  
A d de d Ser ol o g y testi n g f or H B V, H C V, HI V, a n d T B t o 
Bl o o d a n d Uri ne C ollecti o n f or La b orat or y E val uati o ns  
P ositi ve scree ni n g f or H B V, H C V, 
HI V, a n d / or T B is a n E x cl usi o n 
C riterio n , b ut was missi n g fr o m t he 
la b orat or y e val uati o ns.  A d de d 
detail  t o clarif y t hese assess me nts  
wil l be perf or me d at Scree ni n g. 
7. 3. 7  
A d de d defi niti o n f or e n d of trial/e n d of st u d y.  
Clarif y defi niti o n e n d of trial/e n d of 
st u d y (last patie nt last visit) vs e n d 
of treat me nt (eac h s u bject’s last 
visit) . 
7. 5  
C o nte nt u p dates ma de t o e ns ure t hat all pr o hi bite d 
me dicati o ns, per t he E xcl usi o n Criteria, were descri be d . 
F urt her clarificati o n of all pr o hi bite d 
me dicati o ns  a n d ali g n me nt wit h 
I n vesti gat or’s Br oc h ure. 
8. 1. 1  
M o dificati o n of A E defi niti o n t o re m o ve la n g u a ge t hat 
i n dicate d w orse ni n g of P D s y m pt o ms  is n ot a n A E. 
Ali g n me nt  t o l ocal la w a n d E U r ules 
( 2 0 1 1/ C/ 1 7 2/ 0 1/ E C, C T-3) 
re gar di n g defi niti o n of A E as it 
pertai n s t o worse ni n g of a pre -
e xisti n g ill ness.  
1 0. 6. 3  
A d de d a d diti o nal detail o n u n bli n di n g pr oce d ures 
i ncl u di n g h o w t o pr ocee d if t he we b -base d ra n d o mizati o n 
s yste m is n ot a vaila ble.  
P r o vi de a d diti o nal details o n 
u n bli n d pr oce d ures  
1 7. 9  
M o difie d M D R D f or m ula t o i ncl u de t w o f or m ulas.  
O ne is use d w he n  ser u m creati ni ne  res ults are 
pr o vi de d i n SI u n its  ( μ m ol/ L)  a n d t he sec o n d w he n  
ser u m creati ni ne are pr o vi de d i n c o n ve nti o nal u nits  
( m g/ d L).   
Pr o vi de clarificati o n o n w hic h 
M D R D f or m ula t o use base d o n 
u nits of ser u m creati ni ne  res ults.   
1 7. 1 0  
I ntr o d uct or y c o nte nt a n d T a ble 1 7. 1 0. 1 u p date d t o 
i ncl u de m o derate as well as str o n g C Y P 3 A 4/ 5 
a n d/ or P-g p i n hi bit ors a n d i n d ucers.  
U p date d c o nte nt f or sta n dar dizati o n 
wit h I n vesti gat or’s Br oc h ure  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 4  of 9 9   
 
 
Pr ot oc ol V ersi o n 1. 2  d ate d 1 7 M A Y 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 1. 1  d ate d 1 8 A P R 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 1. 1  ( date d 1 8 A P R 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
Secti o n  
Descri pti o n  
J ustific ati o n  
C o ver pa ge  
A d diti o n of E u dr aC T N o.  
 
U p date A ut h orize d Re prese ntati ve fr o m J o nas 
Ha n nesta d t o Est her Ra w ner  
Re q uire d f or Ger ma n y . 
 
I nter nal pers o n nel c ha n ge  of 
res p o nsi bilities. 
T hr o u g h o ut  
Pr ot oc ol versi o n u p date.  
Previ o usly re a d : V 1. 1 _ 1 8 A P R 2 0 1 9  
 
N o w re a ds : V 1. 2 _ 1 7 M A Y 2 0 1 9  
Versi o n c o ntr ol.  
T hr o u g h o ut  
Mi n or gra m mar a n d c o nte nt u p dates.  
Mi n or gra m mar/c o nte nt u p dates f or 
clarit y/acc urac y of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
List of 
A b bre viati o ns  
E M A/ E ur o pea n Me dici nes A ge nc y a n d b.i. d. /t wice 
per da y a d de d t o list of a b bre viati o ns.  
Missi n g a b bre viati o n/ defi niti o n s 
a d de d. 
State me nt of 
C o m plia nce  
A d de d E M A/ E ur o pea n Me dici nes A ge nc y t o 
c o nte nt i n b ullets 3 a n d 5.  
A d de d per re g ulat or y re q uire me nts 
f or a gl o bal st u d y wit h E ur o pea n 
sites. 
Pr ot oc ol 
S u m mar y, 4. 1  
N u m ber of Sites:  
Previ o usly re a d : “A p pr o xi matel y 1 5 i n t he U nite d 
States ( U S) a n d u p t o 1 0 i n Ger ma n y ” 
 
N o w re a ds : “A p pr o xi matel y 1 0  i n t he U nite d States 
( U S) a n d u p t o 1 0 i n Ger ma n y” 
Pr o p ose d n u m ber of sites i n t he U S 
re d uce d. 
Pr ot oc ol 
S u m mar y , 
4. 2. 2  
Sec o n dar y E n d p oi nt a d de d:  
•  Ha user 3 -Da y Patie nt Diar y . 
A d diti o n of sec o n dar y e n d p oi nt t o 
meas ure c ha n ges i n o n/ off ti me . 
Pr ot oc ol 
S u m mar y , 
4. 2. 3  
E x pl orat or y E n d p oi nt a d de d:   
•  I n c o nse nti n g s u bjects ( o pti o nal): c ha n ges i n fecal 
mar kers of i ntesti nal i nfla m mati o n (cal pr otecti n a n d 
lact oferri n) a n d per mea bilit y (al p ha-1 a ntitr y psi n a n d 
z o n uli n). 
O pti o nal fecal sa m ple a d de d f or 
assess me nt of micr o bi o me.  
2. 2  
A d diti o nal details o n d ose selecti o n a d de d.  
Pr o vi de a d diti o nal  p har mac o ki netic 
data a n d  j ustificati o n f or d ose 
selecti o n. 
2. 2  
C o nte nt a d de d re: o pti o nal fecal sa m ple  f or 
assess me nt of micr o bi o me : 
“I n a d diti o n, a n o pti o nal assess me nt  will be 
c o n d ucte d i n c o nse nti n g s u bjects t o e val uate 
p ote ntial micr o bi o me c ha n ges as assesse d b y fecal 
mar kers of i ntesti nal i nfla m mati o n (cal pr otecti n a n d 
lact oferri n) a n d per mea bilit y (al p ha-1 a ntitr y psi n 
a n d z o n uli n) at scree ni n g a n d f oll o wi n g treat me n t 
(Sc h wiertz 2 0 1 8 ).”  
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 5  of 9 9   
 
3  
C o nte nt a d de d: re: o pti o nal fecal sa m ple f or assess me nt of 
micr o bi o me:  
“I n c o nse nti n g s u bjects, fecal sa m ples will be o btai ne d at 
scree ni n g a n d f oll o wi n g treat me nt t o assess p ote ntial 
micr o bi o me c ha n ges. “  
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  
4. 1  
C o nte nt re vise d re: o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me:  
Previ o usly re a d:  
“ D uri n g t he scree ni n g peri o d ( Da y -1 0 t hr o u g h Da y -7), 
s u bjects will u n der g o all scree ni n g assess me nts t o assess 
eli gi bilit y. ” 
N o w re a ds:  
“D uri n g t he scree ni n g peri o d ( Da y -1 0 t hr o u g h Da y -7), 
s u bjects will u n der g o all scree ni n g assess me nts t o assess 
eli gi bilit y. I n c o nse nti n g s u bjects, fecal sa m ples will als o 
be c ollecte d at scree ni n g f or micr o bi o me assess me nt. ” 
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  
 
 
 
 
 
 
 
5. 2  
U p date d  e xcl usi o n criteria # 2 t o i ncl u de t he f oll o wi n g:  
“ P ositi ve scree ni n g test res ult f or he patitis B, he patitis C, 
h u ma n i m m u n o deficie nc y vir us ( HI V), or t u berc ul osis ( b y 
Q ua nti F E R O N testi n g) .” 
A d de d f or a d diti o nal safet y a n d per 
re g ulat or y re q uire me nts f or a gl o bal 
st u d y wit h E ur o pea n sites. 
6. 2  
B ullet c o nte nt delete d:  
•     A vaila bilit y of a si g ne d F D A F or m(s) 1 5 7 2 a n d 
Fi na ncial Discl os ure F or m(s) f or t he pri nci pal 
i n vesti gat or a n d site s u b-i n vesti gat or(s) 
 
B ullet c o nte nt re vise d:  
Previ o usly re a d:  
•  A p pr o val of t he st u d y pr ot oc ol a n d inf or me d co nse nt 
b y t he I R B or I E C.  
 
N o w re a ds:  
•  A p pr o val of t he st u d y pr ot oc ol a n d inf or me d 
co nse nt (s) b y t he I R B or I E C.  
 
Previ o usly re a d:  
•  A p pr o val/ n otificati o n of t he a p pr o priate re g ulat or y 
a ut h orit y . 
 
N o w re a ds:  
•  A p pr o val/ n otificati o n of t he a p pr o priate re g ulat or y 
a ut h orit y (ies). 
 
C o nte nt is n ot a p plica ble t o all 
gl o bal sites; re m o ve d per re g ulat or y 
re q uest.  
 
 
C o nte nt re vise d t o reflect p ote ntial 
( o pti o nal) c o nse nt f or partici pati o n 
i n micr o bi o me assess me nt.  
 
 
 
 
 
 
C o nte nt re vise d t o reflect a d diti o n 
of E M A  as a  re g ulat or y a ut h orit y 
t hr o u g h o ut. 
7. 1. 1. 3  
C o nte nt re vise d:  
Previ o usly re a d:  
“Pr oce d ures t o assess efficac y i ncl u de m ot or a n d 
c o g niti ve f u ncti o n testi n g  a n d assess me nt of acti vities of 
dail y li vi n g . ” 
 
N o w re a ds:  
“Pr oce d ures t o assess efficac y i ncl u de m ot or a n d 
c o g niti ve f u ncti o n testi n g , assess me nt of acti vities of dail y 
C o nte nt a d de d re: fecal sa m ple 
a d de d assess me nt of micr o bi o me.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 6  of 9 9   
 
li vi n g, a n d, i n c o nse nti n g s u bjects, micr o bi o me 
assess me nt . ” 
 
Assess me nt s a d de d: 
“ 1 0. Fecal mar kers of i ntesti nal i nfla m mati o n a n d 
per mea bilit y  ( o pti o nal).”   
“ 1 1. Ha user 3 -Da y Patie nt Diar y.”  
7. 1. 1. 3. 1 0  
C o nte nt a d de d re: assess me nt of micr o bi o me:  
“7. 1. 1. 3. 1 0  
Fecal Mar kers of I ntesti nal I nfla m mati o n 
a n d Per mea bilit y 
I ntesti nal i nfla m mati o n a n d i ncrease i ntesti nal 
per mea bilit y ( b ot h p ossi bl y f uele d b y d ys bi osis) ha ve 
bee n i m plicate d i n t he m ultifact orial pat h o ge nesis of P D 
(Sc h wiertz 2 0 1 8 ). I n c o nse nti n g s u bjects, fecal sa m ples 
will be c ollecte d at scree ni n g a n d at e n d of treat me nt  a n d 
sa m ples will be flas h fr oze n f or assess me nt. F ull 
i nf or mati o n as t o pr oce d ure f or c ollecti o n a n d pr ocessi n g 
of sa m ples will be i ncl u de d i n t he I S F. ”   
A d de d descri pti ve c o nte nt re: 
o pti o nal fecal sa m ple f or assess me nt 
of micr o bi o me.  
7. 1. 1. 3, 
7. 1. 1. 3. 1 1 , 
7. 3. 1. 1, 
7. 3. 2. 1 , 
7. 3. 3. 1, 
7. 3. 3. 2  
Descri pti o n a n d assess me nt f or  Ha user 3 -Da y  Diar y a d de d  
T he 3 -Da y Ha user Diar y assess me nt 
was a d de d t o o btai n i nf or mati o n 
re gar di n g p ote ntial f u ncti o nal 
i m pr o ve me nt a n d/ or decreases o n 
off -ti me.  
7. 3. 1 . 1, 
7. 3. 3. 2  
O pti o nal fecal sa m ple a d de d.  
O pti o nal fecal sa m ple c ollect i o n 
a d de d f or assess me nt of 
micr o bi o me.  
7. 5  
A d diti o nal details o n pr o hi bite d me dicati o ns, treat me nts, 
a n d me dicati o ns a d de d.  
Pr o vi de clarificati o n o n pr o hi bite d 
oral s u p ple me nts.  
8. 4. 2. 1 , 
8. 5  
E M A a d de d t o c o nte nt. 
A d de d per re g ulat or y re q uire me nts 
f or a gl o bal st u d y wit h E ur o pea n 
sites. 
1 0. 3  
E val ua ble defi niti o n a d de d a n d clarificati o n t o 
mI T T/ E val ua ble set a d de d  
A d diti o n o f e val ua ble defi niti o n. 
1 3. 1. 1  
Previ o usly re a d:  “S u b -i n vesti gat ors as liste d o n F or m 
F D A 1 5 7 2, or ot her a ut h orize d st u d y pers o n nel are 
eli gi ble t o si g n f or t he i n vesti gat or, e xce pt w here t he 
i n vesti gat or’s si g nat ure is s pecificall y re q uire d.” 
 
N o w re a ds:  “S u b -i n vesti gat ors or ot her a ut h orize d st u d y 
pers o n nel are eli gi ble t o si g n f or t he i n vesti gat or, e xce pt 
w here t he  i n vesti gat or’s si g nat ure is s pecificall y 
re q uire d.” 
C o nte nt is n ot a p plica ble t o all 
gl o bal sites; re m o ve d per re g ulat or y 
re q uest. 
1 5  
Ha user 3 -Da y Patie nt Diar y a d de d t o pr o vi de 
q uesti o n naire at V 1 a n d V 5 a n d f or c ollecti o n of t he 
q uesti o n naire at V 2 a n d V 6  
 
O pti o nal c o nse nt f or fecal sa m ple a n d fecal sa m ple 
c ollecti o n (at scree ni n g [ V 2] a n d Visit 6 / E O T).  
A d diti o n of sec o n dar y e n d p oi nt t o 
meas ur e c ha n ges i n o n/ off ti me.  
 
 
 
O pti o nal fecal sa m ple c o nse nt a n d 
c ollecti o n a d de d f or assess me nt of 
micr o bi o me.  
1 6. 1 , 1 6. 2 
F ull refere nce s f or A L K 4 2 9 0 -1 0 1, Ha user 2 0 0, Ha user 
Ne w  refere nces a d de d t o list. 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 7  of 9 9   
 
 
 
Pr ot oc ol V ersi o n 1. 1 d ate d 1 8 A P R 2 0 1 9  
Re pl aces: Pr ot oc ol V ersi o n 1. 0 d ate d 1 0 J A N 2 0 1 9  
 
T he f oll o wi n g ta ble descri bes c ha n g es fr o m V ersi o n 1. 0 ( date d 1 0J A N 2 0 1 9) wit h j ustificati o ns 
pr o vi de d.  
 
2 0 0 4, Sc h wiertz 2 0 1 8 , a d de d t o list. 
F ull refere nce f or Ha user et all ( 2 0 0 0, 2 0 0 4)  a d de d t o list. 
 
 
 
1 7. 8  
I nserti o n of ne w A p pe n di x f or Ha user 3-Da y Diar y . 
S u bse q ue nt a p pe n dices, 1 7. 8 t hr o u g h 1 7. 1 2, se q ue ntiall y 
re n u m bere d t hr o u g h o ut pr ot oc ol. 
A d diti o n of A p pe n di x f or 3 -Da y 
Ha user Diar y . 
Secti o n  
Descri pti o n  
J ustific ati o n  
T hr o u g h o ut  
Pr ot oc ol versi o n u p da te.  
Previ o usly re a d : V 1. 0 _ 1 0J A N 2 0 1 9  
 
N o w re a ds : V 1. 1 _ 1 8 A P R 2 0 1 9  
Versi o n c o ntr ol.  
T hr o u g h o ut  
Mi n or gra m mar a n d c o nte nt u p dates.  
Mi n or gra m mar/c o nte nt u p dates f or 
clarit y/acc urac y of c o nte nt.  
Ta ble of 
C o nte nts  
Mi n or c o nte nt u p dates.  
Mi n or u p dates re q uire d t o reflect 
re vise d c o nte nt. 
List of 
A b bre viati o ns  
 w A M D / Wet a ge-relate d mac ular de ge nerati o n 
a d de d t o list of a b bre viati o ns.  
Missi n g a b bre viati o n / defi niti o n 
a d de d. 
Pr ot oc ol 
S u m mar y,  
4. 1  
N u m ber of Sites:  
Previ o usly re a d : “ A p pr o xi matel y 2 0 i n t he U nite d 
States ( U S) ” 
 
N o w re a ds : “A p pr o xi matel y 1 5 i n t he U nite d States ( U S) 
a n d u p t o 1 0 i n Ger ma n y ” 
N u m ber of site s i n U S re d uce d a n d 
u p t o 1 0 sites i n Ger ma n y a d de d.  
2. 3. 1  
Se nte nce re gar di n g trials:  
Previ o usly re a d : “ I n o ur o n g oi n g  E ur o pea n st u dies 
i n treat me nt-naï ve a n d refract or y s u bjects wit h 
w A M D …”  
 
N o w re a ds : “I n o ur rece ntl y c o m plete d E ur o pea n st u dies 
i n treat me nt-naï ve a n d refract or y s u bjects wit h 
w A M D …”  
C o nte nt u p date d t o i n dicate t hat 
st u dies i n w A M D ha ve bee n 
c o m plete d.  
5. 1, 5. 2  
Pre vi o us I ncl usi o n Criteria # 9 re m o ve d a n d i ncl u de d as 
E xcl usi o n Criteria # 8.  
 
 
 
C urre nt I ncl usi o n Criteria # 1 0:  
Previ o usly re a d:  “ … pri or t o st u d y e ntr y. A w o ma n is 
c o nsi dere d of c hil d beari n g p ote ntial f oll o wi n g me narc he 
a n d u ntil bec o mi n g p ost me n o pa usal ( n o me nses f or at 
least 2 years wit h o ut a n alter nati ve ca use). S h o ul d a 
w o ma n bec o me pre g na nt or s us pect s he is pre g na nt w hile 
s he or her part ner is partici pati n g i n t he st u d y, s he s h o ul d 
Re nal f u ncti o n re q uire me nts were 
pre vi o usl y s plit bet wee n 
I ncl usi o n/ E xcl usi o n Criteria, b ut are 
n o w c o m bi ne d t o pre ve nt c o nf usi o n.  
 
C o nte nt u p date d t o reflect gl o bal 
re g ulat or y re q uire me nts.  
 
 
 
 
 

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 8  of 9 9   
 
i nf or m her treati n g p h ysicia n i m me diatel y.” 
 
N o w re a ds:  “ … pri or t o st u d y e ntr y. Birt h c o ntr ol met h o ds 
c o nsi dere d acce pta ble f or t his st u d y i ncl u de d o u ble -
barrier met h o ds; h or m o nal c o ntrace pti ves t hat are 
i njecte d, i m pla nte d, or ta ke n orall y; or a n i ntra uteri ne 
de vice. A w o ma n is c o nsi dere d of c hil d beari n g p ote ntial 
f oll o wi n g me narc he a n d u ntil bec o mi n g p ost me n o pa usal 
( n o me nses f or at least 2 years wit h o ut a n alter nati ve 
ca use). S h o ul d a w o ma n bec o me pre g na nt or s us pect s he 
is pre g na nt w hile s he or her part ner is partici pati n g i n t he 
st u d y, s he s h o ul d i nf or m her treati n g p h ysicia n 
i m me diatel y.” 
 
B ullet s 2  a n d 9 u p date d i n E xcl usi o n Criteria # 2  
Previ o usly re a d:  “
 
  
 
N o w re a ds : “
 
  
 
Previ o usly re a d:  “P ositi ve scree ni n g f or  he patitis B, 
he patitis C, or h u ma n i m m u n o def icie nc y vir us ( HI V)” 
 
N o w re a ds: “K n o w n i nfecti o n wit h he patitis B, he patitis 
C, or h u ma n i m m u n o deficie nc y vir us ( HI V).” 
 
E xcl usi o n Criteria # 8:  
Previ o usly re a d : “ …
 
 
 
N o w re a ds:  “ …
 
 
 
B ullet 3 a d de d t o c urre nt E xcl usi o n Criteria # 1 1:  
“I ncl usi o n of v ul nera ble pers o ns b y l ocal re g ulati o n ( e. g., 
i m pris o ne d or i nstit uti o nalize d).” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C larificati o n of e xcl usi o n criteria 
a n d p u nct uati o n a d de d.  
 
 
 
 
 
 
 
 
 
 
 
 
C larificati o n of e xcl usi o n criteria. 
 
 
 
 
 
 
C o nte nt u p date d t o reflect gl o bal 
re g ulat or y re q uire me nts. 
 
5. 4. 1, 1 2. 3. 2, 
1 2. 5  
C o nte nt relate d t o “s u bject’s le gall y a ut h orize d 
re prese ntati ve” re m o ve d. 
S u bject s m ust be a ble t o pr o vi de 
c o nse nt; a s u bject’s le gall y 
a ut h orize d re prese ntati ves will n ot 
be all o we d t o pr o vi de c o nse nt 
a n d/ or ma ke decisi o ns o n be half of 
t he s u bject. 
7. 1. 1. 1, 
7. 1. 1. 1. 1, 
7. 3. 1, 1 5  
“ H oe h n a n d Ya hr” assess me nt c ha n ge d t o “ m o difie d 
H oe h n a n d Ya hr” assess me nt .  
C o nte nt u p date d t o reflect acc urate 
ter mi n ol o g y f or assess me nt. 
7. 1. 1. 1. 6  
C o nte nt re gar di n g t he ne ur ol o gical e xa m: 
Previ o usly re a d:  “T he ne ur ol o gical e xa m will i ncl u de 
cra nial ner ves ( vis ual fiel ds, f u n d osc o pic e xa m, p u pillar y 
li g ht refle x, e xtra oc ular m uscles, facial se nsati o n a n d 
s y m metr y, palate a n d t o n g ue, a n d hea d t ur ni n g a n d 
C o nte nt a d de d t o pr o vi de 
clarificati o n o n c o m p o ne nts of t he 
ne ur ol o gical e xa m.  

 
Pr ot oc ol  A K S T 4 2 9 0 -2 1 1                                                  
V 4. 0
2 2 M A Y 2 0 2 0  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
C O N FI D E N TI A L/ P R O P RI E T A R Y                                                                                                    Pa ge 9 9  of 9 9   
 
 
s h o ulder s hr u g); m uscle stre n gt h, t o ne, a n d b ul k; refle xes 
( bice ps, trice ps, k nees, a n kles, a n d pla ntar); c o or di nati o n 
(fi n ger-t o-n ose, heel -k nee -s hi n); se ns or y f u ncti o n (li g ht 
t o uc h a n d pi n pric k); a n d gait. ”   
 
N o w re a ds:   “T he ne ur ol o gical e xa m will i ncl u de  cra nial 
ner ves ( vis ual fiel ds, f u n d osc o pic e xa m, p u pillar y li g ht 
refle x, e xtra oc ular m uscles, facial se nsati o n a n d 
s y m metr y, palate a n d t o n g ue, a n d hea d t ur ni n g a n d 
s h o ul der s hr u g); m uscle stre n gt h, t o ne, b ul k, a n d 
a b n or mal m o ve me nts ; refle xes ( bice ps, trice ps, k nees, 
a n kles, a n d pla ntar); c o or di nati o n (fi n ger -t o-n ose, heel -
k nee -s hi n); se ns or y f u ncti o n (li g ht t o uc h, pi n pric k , a n d 
vi brati o n ); a n d gait.”   
7. 3. 3. 2  
S u b -b ullet # 2 u n d er “ Assess me nts t o be c o n d ucte d i n t he 
o n -me dicati o n state”:  
Previ o usly re a d :“ M o C A ” 
 
N o w re a ds : “M o C A ( Visit 6 O nl y )” 
C o nte nt u p date d t o reflect t hat 
M o C A will be c o n d ucte d a t Visit 6 
o nl y , rat her t ha n at Visit 4 a n d Visit 
6  as n ote d i n t he pre vi o us versi o n . 
1 5  
M o C A at Visit 4 re m o ve d.  
Assess me nt was n ot re q uire d at 
Visit 4.  
1 6. 1  
F ull refere nce f or At ha u da et al 2 0 1 7 a d de d t o list.  
Missi n g refere nce a d de d t o list.