A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study of ASN51 in Adults With Early Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer Disease
Sponsor: Asceneuron S.A.

Offi ci al Titl e:  
A P h a s e 2, R a n d o mi z e d, D o u bl e- Bli n d, Pl a c e b o- C o ntr oll e d, 
P ar all el Gr o u p St u d y of A S N 5 1 i n A d ult s Wit h E arl y Al z h ei m er' s 
Di s e a s e
N C T N u m b er:  
N C T 0 6 6 7 7 2 0 3
D o c u m e nt D at e:   
Pr ot o c ol V er si o n 2 : 0 7- O ct - 2 02 4

A S N 5 1- 2 0 1 
Asce ne ur o n S A
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C o nfi de ntial 
T A B L E O F C O N T E N T S
T A B L E O F C O N T E N T S ........................................................................................................................ 3
LI S T O F T A B L E S .................................................................................................................................. 8
LI S T O F FI G U R E S ................................................................................................................................ 8
1
P R O T O C O L S U M M A R Y ............................................................................................................... 9
1. 1
Pr ot oc ol S y n o psis ................................................................................................................... 9
1. 2
Trial Sc he ma ......................................................................................................................... 1 3
1. 3
Sc he d ule of Acti viti es ........................................................................................................... 1 4
2
I N T R O D U C TI O N .......................................................................................................................... 2 1
2. 1
P ur p ose of Trial .................................................................................................................... 2 1
2. 2
S u m mar y of Be nefits a n d Ris ks ............................................................................................ 2 1
2. 2. 1  
Be nefit S u m mar y ................................................................................................... 2 1
2. 2. 2  
Ris k S u m mar y ........................................................................................................ 2 2
2. 2. 3  
O verall Be nefit: Ris k C o ncl usi o n .......................................................................... 2 4
3  
O BJ E C TI V E S A N D E N D P OI N T S ................................................................................................ 2 5
4  
T RI A L D E SI G N ............................................................................................................................. 2 7
4. 1
Descri pti o n ............................................................................................................................ 2 7
4. 2
Rati o nale f or Trial Desi g n .................................................................................................... 2 8
4. 3
Start of Tri al a n d E n d of Trial .............................................................................................. 3 0
5  
P O P U L A TI O N ............................................................................................................................... 3 1
5. 1
Sel ecti o n of Trial P o p ul ati o n ................................................................................................ 3 1
5. 2
Rati o nale f or Trial P o p ulati o n .............................................................................................. 3 1
5. 3
I ncl usi o n Criteria .................................................................................................................. 3 1
5. 4
E xcl usi o n Crit eria ................................................................................................................. 3 3
5. 4. 1
E xcl usi o n Criteria b y Me dical Hist or y .................................................................. 3 3
5. 4. 2  
E xcl usi o n Criteri a b y Scree ni n g Assess me nts ....................................................... 3 4
5. 4. 3  
E xcl usi o n Criteri a b y C o nc o mit a nt Me dicati o ns/ Pri or T hera pies ......................... 3 5
5. 4. 4  
Pr oce d ural E xcl usi o ns ............................................................................................ 3 6
5. 4. 5  
Ot her E xcl usi o ns .................................................................................................... 3 7
5. 5
Lifest yle C o nsi derati o ns ....................................................................................................... 3 7
5. 5. 1  
Meals a n d Diet ar y Restricti o ns .............................................................................. 3 7
5. 5. 2  
P h ysical Acti vit y .................................................................................................... 3 7
5. 5. 3  
Ot her Acti vit y ........................................................................................................ 3 7
5. 6
Scree n Fail ures ...................................................................................................................... 3 8
6  
I N T E R V E N TI O N S A N D C O N C O MI T A N T T H E R A P Y ............................................................. 3 9

A S N 5 1- 2 0 1 
Asce ne ur o n S A
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C o nfi de ntial 
6. 1
Descri pti o n of Trial I nt er ve nti o n .......................................................................................... 3 9
6. 1. 1
I n vesti gati o nal Me dici nal Pr o d uct: A S N 5 1 ........................................................... 3 9
6. 1. 2  
C o ntr ol/ C o m parat or:  Pl ace b o ............................................................................... 3 9
6. 2
Rati o nale f or Trial I nt er ve nti o n ............................................................................................ 4 0
6. 3
D osi n g a n d A d mi nistrati o n ................................................................................................... 4 0
6. 4
Treat me nt of O ver d ose ......................................................................................................... 4 1
6. 5
Pre parati o n, Ha n dli n g, St ora ge, a n d Acc o u nt a bilit y ............................................................ 4 1
6. 5. 1
Pre parati o n of Trial I nter ve nti o n ............................................................................ 4 1
6. 5. 2
Ha n dli n g a n d St ora ge of Trial I nt er ve nti o n ........................................................... 4 1
6. 5. 3  
Acc o u nta bilit y of Trial I nter ve nti o n ...................................................................... 4 1
6. 6
Partici pa nt Assi g n me nt, Ra n d o mizati o n, a n d Bli n di n g ........................................................ 4 1
6. 6. 1  
Partici pa nt Assi g n me nt .......................................................................................... 4 1
6. 6. 2  
Bli n di n g a n d U n bli n di n g ........................................................................................ 4 2
6. 6. 3  
Ra n d o mizati o n ....................................................................................................... 4 2
6. 7
Trial I nt er ve nti o n C o m pli a nce .............................................................................................. 4 2
6. 8
C o nc o mita nt T hera p y ........................................................................................................... 4 2
6. 8. 1  
Pr o hi bit e d C o nc o mit a nt T hera p y ........................................................................... 4 3
6. 8. 2  
Per mitt e d C o nc o mita nt T hera p y ............................................................................ 4 3
6. 8. 3  
Resc ue T hera p y ...................................................................................................... 4 3
6. 8. 4  
A d diti o nal Pr ot oc ol- desi g nate d Pr o d ucts – P ositr o n E missi o n T o m o gra p h y 
I ma gi n g Ra di oli ga n ds ............................................................................................ 4 3
7  
DI S C O N TI N U A TI O N O F I N T E R V E N TI O N A N D P A R TI CI P A N T WI T H D R A W A L ............. 4 6
7. 1
Disc o nti n uati o n of Tri al I nter ve nti o n ................................................................................... 4 6
7. 1. 1  
Criteria f or Per ma ne nt Disc o nti n uati o n of Trial I nter ve nti o n ................................ 4 6
7. 1. 2  
Te m p orar y Disc o nti n uati o n ................................................................................... 4 7
7. 1. 3
Rec hall e n ge ............................................................................................................ 4 8
7. 2
Partici pa nt Wit h dra wal fr o m Tri al ........................................................................................ 4 8
7. 3
L ost t o F oll o w- u p ................................................................................................................. 4 8
7. 4
Trial St o p pi n g R ules ............................................................................................................. 4 8
8  
T RI A L A S S E S S M E N T S A N D P R O C E D U R E S ........................................................................... 5 0
8. 1
Scree ni n g/ Baseli ne Assess m e nts .......................................................................................... 5 0
8. 1. 1  
I nf or me d C o nse nt................................................................................................... 5 0
8. 1. 2  
Me dical Hist or y a n d De m o gra p hics ...................................................................... 5 1
8. 1. 3  
P h os p h or ylate d ta u- 2 1 7 ......................................................................................... 5 1
8. 1. 4  
A p oli p o pr otei n E Ge n ot y pi n g ................................................................................ 5 1
8. 1. 5  
Hei g ht ..................................................................................................................... 5 1

A S N 5 1- 2 0 1 
Asce ne ur o n S A
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C o nfi de ntial 
8. 1. 6  
Vir ol o g y Scree n ..................................................................................................... 5 2
8. 2
Efficac y Assess me nts ........................................................................................................... 5 2
8. 2. 1  
C o g niti ve a n d F u ncti o nal Assess me nts .................................................................. 5 2
8. 2. 2  
I ma gi n g Ass ess me nts ............................................................................................. 5 3
8. 3
Safet y Assess m e nts ............................................................................................................... 5 3
8. 3. 1  
P h ysical E xa mi nati o n ............................................................................................. 5 3
8. 3. 2  
Vital Si g ns .............................................................................................................. 5 4
8. 3. 3
Electr ocar di o gra m .................................................................................................. 5 4
8. 3. 4
Cli nical La b orat or y Assess m e nts ........................................................................... 5 4
8. 3. 5  
S ui ci dal I deati o n a n d Be ha vi or Ris k M o nit ori n g................................................... 5 5
8. 4
A d verse E ve nts a n d Seri o us A d verse E ve nts ....................................................................... 5 5
8. 4. 1  
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt I nf or m ati o n ............... 5 6
8. 4. 2  
I de ntif yi n g A d verse E ve nts a n d Seri o us A d verse E ve nts ...................................... 5 6
8. 4. 3  
A d verse E ve nts of S pecial I nterest ........................................................................ 5 6
8. 4. 4  
Disease-relat e d E ve nts or O utc o mes N ot Q ualif yi n g as A d verse E ve nts or 
Seri o us A d verse E ve nts ......................................................................................... 5 7
8. 5
Pre g na nc y a n d P ost part u m I nf or mati o n ............................................................................... 5 7
8. 5. 1  
Partici pa nts W h o Bec o me Pre g na nt D uri n g t he Tri al ............................................ 5 7
8. 5. 2  
Part ner Pre g na nc y .................................................................................................. 5 8
8. 6
Me dical De vice Pr o d uct C o m plai nts f or Dr u g/ De vice C o m bi nati o n Pr o d ucts .................... 5 8
8. 7
P har mac o ki netics .................................................................................................................. 5 8
8. 8
Ge neti cs ................................................................................................................................ 5 9
8. 8. 1  
P har mac o ge n o mics ................................................................................................ 5 9
8. 9
Bi o mar kers ............................................................................................................................ 5 9
8. 1 0  I m m u n o ge ni cit y .................................................................................................................... 6 0
8. 1 1
Me dical Res o urce Utili zati o n a n d Healt h Ec o n o mi cs .......................................................... 6 0
9  
S T A TI S TI C A L C O N SI D E R A TI O N S ........................................................................................... 6 1
9. 1
A nal ysis Sets ......................................................................................................................... 6 2
9. 1. 1  
M o difie d I nt e nt-t o- Treat ........................................................................................ 6 2
9. 1. 2  
Safet y A nal ysis Set ................................................................................................ 6 2
9. 1. 3  
Per Pr ot oc ol Set...................................................................................................... 6 2
9. 1. 4  
P har mac o ki netic A nal ysis Set ................................................................................ 6 2
9. 2
A nal ysis S u p p orti n g Pri mar y O bjecti ve - Safet y .................................................................. 6 2
9. 2. 1  
A d verse E ve nts ...................................................................................................... 6 4
9. 2. 2  
St atistical M o del, H y p ot hesis a n d Met h o d of A nal ysis ......................................... 6 4
9. 2. 3  
Ha n dli n g of Missi n g Dat a ...................................................................................... 6 4

A S N 5 1- 2 0 1 
Asce ne ur o n S A
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C o nfi de ntial 
9. 3
A nal ysis S u p p orti n g Ke y Sec o n dar y O bj ecti ves .................................................................. 6 4
9. 4
A nal ysis S u p p orti n g Ot her Sec o n dar y O bjecti ves ................................................................ 6 6
9. 4. 1  
1 8 F M K- 6 2 4 0 P E T Sca n ........................................................................................ 6 6
9. 4. 2  
A S N 5 1 P har m ac o ki netics ...................................................................................... 6 6
9. 5
A nal ysis of E x pl orat or y O bjecti ves ...................................................................................... 6 7
9. 6
A d diti o nal Safet y A nal ysis ................................................................................................... 6 7
9. 6. 1  
P h ysical E xa mi nati o n ............................................................................................. 6 7
9. 6. 2
B o d y Wei g ht .......................................................................................................... 6 7
9. 6. 3
Vital Si g ns .............................................................................................................. 6 8
9. 6. 4  
Electr ocar di o gra m Para m eters ............................................................................... 6 8
9. 6. 5  
Cli nical La b orat or y Pa nels ..................................................................................... 6 8
9. 6. 6  
C ol u m bia S uici de Se verit y Rati n g Scale ............................................................... 6 8
9. 7
Ot her A nal ysis ...................................................................................................................... 6 8
9. 8
A nal yses f or L o n g-t er m E xte nsi o n ....................................................................................... 6 9
9. 9
Ti mi n g of A nal ysis ............................................................................................................... 6 9
9. 1 0  Sa m ple Si ze Deter mi nati o n .................................................................................................. 6 9
9. 1 1  Pr ot oc ol De viati o ns .............................................................................................................. 6 9
1 0
G E N E R A L C O N SI D E R A TI O N S: R E G U L A T O R Y, E T HI C A L, A N D T RI A L O V E R SI G H T ... 7 1
1 0. 1  Re g ulat or y a n d Et hical C o nsi derati o ns ................................................................................. 7 1
1 0. 2  C o m mittees ........................................................................................................................... 7 1
1 0. 2. 1
Et hics C o m mittees ................................................................................................. 7 1
1 0. 2. 2
Safet y Re vi e w C o m mittee ..................................................................................... 7 1
1 0. 3  I nf or me d C o nse nt Pr ocess .................................................................................................... 7 2
1 0. 4  Dat a Pr otecti o n ..................................................................................................................... 7 2
1 0. 5  Earl y Site Cl os ure or Trial Ter mi nati o n ............................................................................... 7 2
1 1
G E N E R A L C O N SI D E R A TI O N S: RI S K M A N A G E M E N T A N D Q U A LI T Y A S S U R A N C E .... 7 4
1 1. 1  Q ualit y T olera nce Li mits ...................................................................................................... 7 4
1 1. 2  Dat a Q ualit y Ass ura nce ........................................................................................................ 7 4
1 1. 3  S o urce Dat a ........................................................................................................................... 7 4
1 1. 4  C o nti n ge nc y Pla ns D uri n g P u blic Healt h E mer ge ncies, Nat ural Disasters, or Ot her 
Nati o nal E m er ge ncies ........................................................................................................... 7 5
1 2
A P P E N DI X: A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E E V E N T S – D E FI NI TI O N S 
S E V E RI T Y A N D C A U S A LI T Y ................................................................................................... 7 6
1 2. 1  Defi niti o ns ............................................................................................................................ 7 6
1 2. 1. 1
A d verse E ve nt Ass ociate d wit h St u d y Pr oce d ures ................................................ 7 6
1 2. 1. 2
A d verse E ve nt ........................................................................................................ 7 6
1 2. 1. 3
Seri o us A d verse E ve nt ........................................................................................... 7 6

A S N 5 1- 2 0 1 
Asce ne ur o n S A
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C o nfi de ntial 
1 2. 2  Rec or di n g of A d verse E ve nts a n d Seri o us A d vers e E ve nts ................................................. 7 7
1 2. 2. 1
Se verit y .................................................................................................................. 7 7
1 2. 2. 2
Ca usalit y ................................................................................................................ 7 7
1 2. 2. 3
F oll o w U p .............................................................................................................. 7 8
1 2. 2. 4
O utc o me ................................................................................................................. 7 8
1 2. 3  Re p orti n g of Seri o us A d verse E ve nts ................................................................................... 7 8
1 2. 4  Re g ulat or y Re p orti n g Re q uire m e nts f or Seri o us A d verse E ve nts ........................................ 7 8
1 2. 5
Seri o us a n d U ne x pecte d A d verse Reacti o n Re p orti n g ......................................................... 7 9
1 3
A P P E N DI X:  D E FI NI TI O N S A N D S U P P O R TI N G O P E R A TI O N A L D E T AI L S ....................... 8 0
1 3. 1  C o ntrace pti o n a n d Pre g na nc y Testi n g .................................................................................. 8 0
1 3. 1. 1
Defi niti o ns Relate d t o C hil d beari n g P ote nti al ....................................................... 8 0
1 3. 1. 2
C o ntrace pti o n ......................................................................................................... 8 0
1 3. 1. 3
Pre g na nc y Testi n g .................................................................................................. 8 1
1 3. 2  Cli nical La b orat or y Tests...................................................................................................... 8 1
1 3. 3  C o u ntr y/ Re gi o n- S pecifi c Differe nces ................................................................................... 8 2
1 3. 4  Pri or Pr ot oc ol A me n d m e nts.................................................................................................. 8 2
1 4
A P P E N DI X:  R E F E R E N C E S ........................................................................................................ 8 3
1 5
A P P E N DI X:  G L O S S A R Y O F T E R M S ........................................................................................ 8 7
1 6
A P P E N DI X:  R E S T RI C T E D M E DI C A TI O N G UI D A N C E ......................................................... 8 9
I N V E S TI G A T O R A G R E E M E N T ........................................................................................................ 9 0
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S ............................................................... 9 1

A S N 5 1- 2 0 1
Asce ne ur o n S A
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C o nfi de ntial 
LI S T O F T A B L E S
Ta ble 1
Sc he d ule of Acti vities: Scree ni n g Peri o d...................................................... 1 4
Ta ble 2
Sc he d ule of Acti vities: D o u ble- bli n d I nt er ve nti o n Peri o d ............................ 1 6
Ta ble 3
Sc he d ule of Acti vities: L o n g-ter m E xte nsi o n Peri o d .................................... 1 9
Ta ble 4
Trial I nter v e nti o ns: Dail y D ose A d mi nistrati o n............................................ 3 9
Ta ble 5
O- Glc N Acase Occ u p a nc y i n Healt h y V ol u nteers......................................... 4 0
Ta ble 6
C o m m o nl y Re p orte d A d verse Reacti o ns wit h Ra di oli ga n ds Use d i n t he 
St u d y.............................................................................................................. 4 4
Ta ble 7
A d verse E v e nt Re p orti n g Peri o ds ................................................................. 5 6
Ta ble 8
Cli nical La b orat or y Tests.............................................................................. 8 1
LI S T O F FI G U R E S 
Fi g ure 1  
Trial Sc he ma .................................................................................................. 1 3

A S N 5 1- 2 0 1
Asce ne ur o n S A
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C o nfi de ntial 
A D = Alz h ei m er’s disease; C S F = cere br os pi n al fl ui d; C- S S R S = C ol u m bia- S uici d e Se verit y Rati n g Scale; E C G = electr ocar di o gra m;
e C R F = electr o nic case re p ort f or m; E U = E ur o pea n U ni o n; F S H = f ollicle-sti m ulati n g h or m o n e; H Bs A g = He patitis B vir us s urface 
a nti ge n; I V D R = i n vitr o dia g n ostic re g ulati o n; I W R S = i nteracti ve we b res p o nse s yste m; M M S E = Mi ni- M e ntal State E xa mi nati o n; 
M RI = m a g netic res o na nce i ma gi n g; P E T = p ositr o n e missi o n t o m o gra p h y 
C o ns ult Secti o n 8  f or g ui deli nes o n pr oce d ures a n d assess m e nts. C o ns ult t he St u d y Refere nce M a n u al f or a d diti o n al i nf or m ati o n, i ncl u di n g a 
rec o m m e n de d or der of (s pecific) assess m e nts f o r e a c h visit. 
a  T he Scree ni n g Peri o d ma y be u p t o 8 wee ks i n d urati o n t o all o w f or t h e c o m pleti o n of all scree ni n g assess me nts a n d f or t he e val uati o n of all la b orat or y, E C G, 
a n d i ma gi n g tests. Scree ni n g pr oce d ures will be c o m plete d o ver m ulti ple d a ys. If a d diti o n al ti m e is re q uire d, t his will be c o nsi dere d a n d a p pr o ve d o n a 
case- b y-case basis b y t he S p o ns or Me dial M o nit or. 
b  A n o n-c o ntrast brai n M RI is perf or me d as t h e fi n al test f or eli gi bilit y. If a brai n M RI sca n is n ot a vaila ble wit hi n t he scree ni n g wi n d o w (a n d a rece nt M RI is 
n ot a vaila ble f or eli gi bilit y deter mi nati o n), t he Scree ni n g Peri o d m a y b e e xte n d e d, if all ot her eli gi bilit y criteria ha ve bee n met, b y u p t o 1 4 da ys t o pr o vi de 
a d diti o nal ti me f or t he M RI res ults t o bec o me a v aila ble. If t he scree ni n g wi n d o w is e xte n d e d f or a n i n di vi d ual, re peat cli nical c he mistr y a n d he mat ol o g y 
la b orat or y tests s o res ults are a vaila ble wit hi n 6 wee ks of t he Da y 1 visit. Res ults of t he re p eate d la b orat or y tests are t o be re vie we d b y t he I n vesti gat or or a 
q ualifie d d esi g nee f or fi nal assess m e nt eli gi bilit y. 
c  
A n a b bre viate d scree ni n g i nf or me d c o nse nt m a y be utilize d t o c o n d u ct prescree ni n g (i.e., Tier 1 a n d Tier 2) pr oce d ures, if all o we d b y t he i n vesti gati ve site. 
C o nse nt s h o ul d i ncl u de A P O E ge n ot y pi n g. Ge nerall y, prescree ni n g c o nse nt d o es n ot re q uire t h e st u d y p art ner; h o we ver, if, i n t he I n vesti gat or’s o pi ni o n, a 
p artici pa nt lac ks ca pacit y t o c o nse nt, t he n t h e writte n i nf or m e d c o nse nt of a le g al re prese ntati ve s h o ul d b e o btai ne d. 
d  Partici pa nts w h o meet Tier 1 eli gi bilit y criteria, i n cl u di n g M M S E, s h o ul d pr ocee d t o Tier 2 ( plas ma p Ta u 2 1 7 a n d A P O E ge n ot y pe). Tier 1 a n d Tier 2 
assess me nts ma y ta ke place o n t he sa me da y. T h e ti me a n d date of t he plas ma p T a u 2 1 7 test s h o ul d be rec or de d o n t he La b Re q uisiti o n F or m. T he plas ma 
p Ta u 2 1 7 eli gi bilit y res ult is t o be re p orte d t o t he site. If t h e plas ma p T a u 2 1 7 res ult d oes n ot meet criteria f or eli gi bilit y, t he partici pa nt is n ot t o c o m plete a n y 
a d diti o nal scree ni n g. If plas ma p Ta u 2 1 7 is n ot a v aila ble d u e t o l ocal re g ulati o ns, a n A D dia g n ostic test p erf or m e d wit hi n n o m ore t ha n 5 2 wee ks of scree ni n g 
t hat h as b ee n a p pr o ve d b y t he rele va nt l ocal re g ulat or y a ut h orit y ma y b e s u bstit ute d (e. g., a n I V D R-c o m plia nt assa y s uc h as a m yl oi d P E T or C S F a b 4 2/ 4 0 i n 
E U c o u ntries perf or me d wit hi n 5 2 wee ks of scree ni n g); t he p artici pa nt m a y b e i n cl u de d if t he res ult is i nter prete d b y t he I n vesti gat or as c o nsiste nt wit h t he 
p at h ol o gical prese nce of a m yl oi d beta i n t h e brai n. T he res ult of a n y s u bstit ute d test s h o ul d be rec or d e d i n t he partici pa nt’s e C R F. A P O E ge n ot y pe ma y als o 
b e d o ne at Tier 3 if n ot feasi ble t o c o m plete at Tier 2 b ut m ust b e c o m plete d pri or t o ra n d o mizati o n. 
e  If i nf or me d c o nse nt f or t he f ull st u d y is n ot o btai n e d at Tier 1 a n d a n a b bre viate d c o nse nt f or m was use d f or Tier 1 a n d Tier 2 scree ni n g assess me nts, o btai n 
f ull i nf or m e d c o nse nt pri or t o i nitiati o n a n y Tier 3 scree ni n g pr oce d ures. 
f  
E C Gs s h o ul d be ta ke n s u pi ne i n tri plicate at a p pr o xi matel y 1- mi n ute i nter vals. Partici p a nts s h o ul d rest f or at least 5 mi n utes i n t he s u pi ne p ositi o n bef ore 
E C Gs are ta ke n. 
g  T he “ Scree n Versi o n” q uesti o n naire will be a d mi nistere d at Scree ni n g. T he “ Si nce Last Visit” q u esti o n n aire will be a d mi nistere d at all s u bse q ue nt visits.  
h  Re q uire d f or fe males o nl y. Fe m ales of n o n-c hil d beari n g p ote ntial are d efi ne d as meeti n g o n e of t h e f oll o wi n g criteria: p ost me n o pa usal ( defi ne d as 1 2 m o nt hs 
of s p o nta n e o us a me n orr hea wit h ot her i de ntifia ble ca use or 6 m o nt hs of s p o nta n e o us a me n orr h ea wit h ser u m F S H le vels > 4 0 mI U/ m L) or 6 wee ks 
p osts ur gical bilateral o o p h orect o m y wit h or wit h o ut h ysterect o m y c o nfir me d b y d o c u me ntati o n. 
i  
Partici p a nts wit h a s us pecte d or c o nfir m e d past hist or y of He patitis C are t o ha v e h e patitis C a nti b o d y test at V 1 a n d are e xcl u de d if t he test is p ositi ve. 
j  
Partici p a nts ma y pr ocee d t o Tier 4 o nly  after all criteria fr o m Tier 1, 2, a n d 3 ha ve b ee n met. 
k  
Ma y be sc he d ule d earlier at t he S p o ns or’s discreti o n t o facilitate ti m el y sc he d uli n g. S u b mit t h e M RI t o t he ce ntral M RI ve n d or f or fi nal deter mi nati o n of 
eli gi bilit y. Res ults of ce ntrall y rea d M RIs will be use d f or data a n al ysis; res ults will b e c o m m u nicate d b ac k t o t he site.  

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
1 7 
C o nfi de ntial 
Visit:
D a y 1 a, b
D a y 1 4
Wee k 4
Wee k 8
Wee k 1 2
Wee k 1 6
Wee k 2 0
Wee k 2 4
E T c
F U d
Visit Wi n d o w ( D a ys):  
- 
-4  
± 7  
± 7  
± 7  
± 7  
± 7
± 7  
± 7
4 wee ks 
( + 1 4 da ys)
p ost last 
d ose  
E C G = electr ocar di o gra m; e C R F = electr o nic case re p ort f or m; E T = earl y ter mi n ati o n; E U = E ur o p ea n U ni o n; F S H = f ollicle-sti m ulati n g h or m o ne; 
F U = f oll o w- u p; H Bs A g = He patitis B vir us s urface a nti ge n; I V D R = i n vitr o dia g n ostic re g ulati o n; I W R S = i nteracti ve we b res p o nse s yste m; M M S E = 
Mi ni -Me ntal State E xa mi nati o n; M RI  =  ma g n etic res o n a n ce i ma gi n g; P E T  = p ositr o n e missi o n t o m o gra p h y; P K  =  p har mac o ki netics.
C o ns ult Secti o n 8 f or g ui deli nes o n pr oce d ures a n d assess me nts. C o ns ult t he St u d y Refere nce M a n u al f or a d diti o n al i nf or m ati o n, i ncl u di n g a 
rec o m m e n de d or der of (s pecific) assess m e nts f o r e a c h visit. 
a  C o nfir m t hat all Scree ni n g Visit eli gi bilit y criteria ha ve b ee n met b ef ore pr ocee di n g t o a n y Da y 1 acti vities. 
b 
Sc h e d ule all re mai ni n g visits at Da y 1 visit. Visits ma y ta k e m ore t ha n 1 da y b ut s h o ul d ta ke place as cl ose t o t he tar get date as p ossi ble. Partici pa nts m ust 
c o m plete bi o mar ker assess me nts (e. g., M RI, ta u P E T, C S F, a n d plas ma) bef ore pr o cee di n g t o ra n d o mizati o n. 
c  E arl y ter mi nati o n e C R Fs s h o ul d be c o m plete d if a p artici p a nt disc o nti n u es b ef ore t he Wee k 2 4 Visit. Sc h e d ule F U visit 4 wee ks after t he last d ose of st u d y 
i nter v e nti o n. 
d 
Sc h e d ule t he F U visit 4 wee ks after t he last d ose of st u d y i nter v e nti o n f or safet y assess me nt. T he F U visit ma y be c o n d ucte d b y p h o ne; h o we ver, a n y 
p artici pa nt wit h a n o n g oi n g A E, or hist or y of a b n or m al E C Gs s h o ul d b e m o nit ore d b y t he I n v esti gat or a n d ma na ge d a p pr o priatel y ( wit h a n i n-cli nic visit, 
i ncl u di n g vital si g ns a n d E C G, if necessar y). 
e 
A S N 5 1 s h o ul d be ta ke n o nce dail y i n t he m or ni n g wit h or wit h o ut f o o d. T h e first d ose s h o ul d b e ta ke n at t he cli nic visit u n der s u per visi o n. Partici pa nts 
s h o ul d b e i nstr ucte d t o bri n g all st u d y m e dicati o n t o t he site at eac h i n dicate d visit t o assess c o m plia n ce. F or E T visit, n o st u d y i nter ve nti o n s h o ul d be 
dis pe nse d. 
f  
W h e n e v er perf or m e d o n t he sa m e da y, c o g niti v e a n d f u ncti o nal assess m e nts ( A D A S- C o g 1 3, C D R- S B, a n d M M S E) are t o be perf or me d bef ore pr oce d ures 
t hat ma y be stressf ul f or partici pa nts (f or e xa m ple, M RI, P E T, bl o o d dra w, or C S F sa m pli n g).  
g 
A n y cli nicall y si g nifica nt c ha n ges fr o m baseli ne i n t h e p h ysical e x a mi n ati o n s h o ul d b e n ote d as a n A E. 
h  “ Scree n Versi o n” q uesti o n naire will be a d mi nistere d at Scree ni n g. T h e “ Si n ce L ast Visit” q u esti o n naire will be a d mi nistere d at all s u bse q ue nt visits. 
i  
U nsc h e d ule d la b orat or y tests ma y be perf or m e d at a n y ti me at t h e discreti o n of t he I n v esti g at or if cli nicall y i n dicate d f or a s us pecte d A E. 
j  
Rec or d date a n d ti mes of sa m ple c ollecti o n o n t h e La b Re q uisiti o n F or m. O btai n wit hi n 1 2 wee ks of all l u m bar p u nct ures t o c o nfir m c oa g ulati o n stat us. 
k  
Wee ks 4, 1 2, a n d 2 4 visits o nl y: Partici pa nts will b e c o ntacte d b y tele p h o n e 1 d a y b ef ore sc h e d ule d P K sa m pli n g t o re mi n d t he m n ot t o ta ke trial i nter ve nti o n 
o n t h e m or ni n g of t heir ne xt visit, a n d t o i nstea d bri n g t he d ose t o cli nic t o ta k e u n d er s u per visi o n. D uri n g t he call, partici pa nts will be as ke d w hat ti me t heir 
st u d y m e dicati o n was ta ke n t hat da y, a n d t h e site is t o rec or d t h e last d ose a d mi nistrati o n ti m e pri or t o t h e P K sa m pli n g visit.  
l  
Da y 1, Wee k 4, Wee k 1 2, a n d Wee k 2 4 visits: A pre- d ose A S N 5 1 plas ma sa m ple will b e ta k e n. T he act u al ti me of d ose a d mi nistrati o n i n t he cli nic s h o ul d be 
rec or d e d i n t he partici pa nt’s e C R F. A p ost- d ose sa m ple will als o b e o btai ne d 1. 5 t o 4 h o urs after t h e p artici pa nt ta kes t he d ose of trial i nter ve nti o n at t he site 
a n d sites will rec or d if t he partici pa nt eats a f ull meal, as j u d ge d b y t h e I n vesti gat or, wit hi n ± 2 h o urs of t h e d ose a d mi nistrati o n. 
m  Bl o o d a n d C S F f or bi o mar ker st ora ge a n d bl o o d f or p h ar mac o ge n o mics will be o btai ne d, u nless c ollecti o n a n d/ or tra ns p ortati o n of t he sa m ple is pr o hi bite d 
d ue t o l o cal re g ulati o ns. At t he Da y 1 visit, p artici p a nts m ust ha ve c o m plete d t h e bl o o d a n d C S F c ollecti o n pr oce d ures bef ore ra n d o mizati o n. 
n  T he p har m ac o ge n o mic sa m ple ma y be ta ke n at a later visit if it ca n n ot b e c ollecte d at Da y 1 Visit. 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
1 8 
C o nfi de ntial 
o
O btai n vital si g ns w hile partici pa nt has bee n i n a seate d p ositi o n f or at least 5 mi n utes, prefera bl y bef ore ot her i n vasi ve pr oce d ures (e. g., bl o o d dra ws, l u m bar 
p u n ct ure). 
p  E C Gs s h o ul d be ta ke n i n tri plicate at a p pr o xi matel y 1- mi n ute i nter vals. Partici p a nts s h o ul d rest f or at least 5 mi n utes i n t he s u pi ne p ositi o n bef ore E C Gs are 
ta k e n. O btai n E C Gs a n d bl o o d sa m ples f or ser u m h or m o nes, t o t h e b est of t h e site a n d partici p a nts’ a bilit y, at a p pr o xi m atel y t he sa m e ti me of da y ( prefera bl y 
i n t h e m or ni n g) at eac h i n dicate d visit t o mi ni mize di ur n al v ariati o n. Rec or d t he ti me of c ollecti o n. A d diti o nal E C G assess m e nts m a y be perf or m e d at a n y 
ti m e d uri n g trial partici pati o n if cli nicall y i n dicate d. 
q  
M K- 6 2 4 0 ta u P E T sca n s h o ul d be sc he d ule d as s o o n as p ossi ble. D u e t o t h e p ote ntial f or sc he d uli n g c h alle n ges f or M K- 6 2 4 0 ta u P E T, or i n t he e ve nt of 
tracer fail ure, ra n d o mizati o n ma y be dela ye d, a n d t he scree ni n g peri o d e xte n de d b y 1 4 d a ys a n d t h e Wee k 2 4 de viati o n wi n d o w ma y be e xte n de d u p t o 
+ 2 1 d a ys, wit h S p o ns or Me dical M o nit or a p pr o v al, t h o u g h eff ort s h o ul d b e ma d e t o sc he d ule it as cl ose as p ossi ble t o eac h i n dicate d ti me p oi nt. T he Da y 1 
visit M K- 6 2 4 0 ta u P E T sca n ma y be perf or me d o nce a s u bject is dee m e d eli gi ble f or ra n d o mizati o n b ut n o earlier t ha n 2 1 da ys bef ore ra n d o mizati o n. At t he 
Da y 1 visit, partici pa nts m ust ha ve c o m plete d t he M K- 6 2 4 0 ta u P E T sca n pri or t o ra n d o mizati o n. 
r  
T he scree ni n g brai n M RI sca n ma y be use d as t h e b aseli n e v ol u metric M RI sca n f or a p artici p a nt. 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
1 9 
C o nfi de ntial 
T a ble 3 
Sc he d ule of Acti vities: L o n g- ter m E xte nsi o n Peri o d 
Visit:  
Wee k 
2 4 a, b
Wee k 
2 6  
Wee k
2 8  
Wee k 
3 2  
Wee k 
3 6  
Wee k 
4 0  
Wee k 
4 4  
Wee k 
4 8  
Wee k 
5 4
Wee k 
6 0  
E T c
F U d
Visit Wi n d o w ( D a ys):
± 7
-4
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
± 7
4 wee ks 
( + 1 4 da ys) 
p ost last d ose
C o ntact I W R S
X e 
X
X
X
X
P h ysical E xa mi nati o n (i ncl u di n g 
n e ur ol o gical) a n d Wei g ht
See 
Ta ble 2
 
 
 
 
 
 
X 
 
X 
X 
C o nc o mita nt Me dicati o ns
X
X
X
X
X
X
X
X
X
X
X
 Dis pe nse/ Re vie w A S N 5 1 C o m plia nce f
 
X  
X  
X  
X  
X  
X  
X
X  
X  
Effic a c y Me as ures
 A D A S -C o g 1 3 g 
 
 
 
X  
 
 
X  
 
X  
X  
 C D R -S B g 
 
 
 
X  
 
 
X  
 
X  
X  
M M S E
g
X
X
X
X
S afet y Assess me nt
A d verse E ve nts h
X
X
X
X
X
X
X
X
X
X
X
 C -S S R S i 
X  
X  
X  
X  
X  
X  
X  
X
X  
X  
X
L a b o r at or y S peci me ns j
Cli nical c he mistr y, he m at ol o g y k
X
X
X
X
X
X
X
X
X
X
X
 C o a g ulati o n pa nel  
 
 
 
 
 
 
X
 
X  
Uri nal ysis
X
X
X
X
Ser u m h or m o ne mar kers k
X
X
X
X
Plas m a f or bi o mar ker st ora ge l
X
X
X
X
X
Plas m a f or A S N 5 1 k
X
O pti o n al C S F f or bi o mar ker st ora ge k, l
X
X
Ot her S afet y Me as ures
V ital si g nsm
X
X
X
X
X
X
X
X
X
X
( X)
E C G i n tri plicate n
X
X
X
X
X
X
X
X
X
X
( X)
I m a gi n g Assess m e nts
Brai n M RI
o
X
X
1 8 F M K -6 2 4 0 P E T sca n p
X
X
A D = Alz h ei m er’s disease; A D A S- C o g 1 3 = Alz h ei m er’s Disease Assess me nt Scale – C o g niti ve Be h a vi or S u bscale 1 3; A E = a d verse e ve nt;  C D R- S B = Cli nical 
De me ntia Rati n g – S u m of B o xes; C S F = cere br os pi nal fl ui d; C- S S R S = C ol u m bia- S uici d e Se verit y Rati n g Scale; E C G = electr ocar di o gra m; e C R F = electr o nic case 
re p ort f or m; E T = earl y ter mi nati o n; E U = E ur o pea n U ni o n; F S H = f ollicle-sti m ulati n g h or m o ne; F U = f oll o w- u p; H Bs A g = He patitis B vir us s urface a nti ge n; I V D R = i n 
vitr o dia g n ostic re g ulati o n; I W R S = i nteracti ve we b res p o nse s yste m; L T E = L o n g-ter m E xte nsi o n; M M S E = Mi ni- Me ntal State E xa mi nati o n; M RI = m a g netic res o na nce 
i ma gi n g; P E T = p ositr o n e missi o n t o m o gra p h y; P K = p har mac o ki netics .
    
 
 
 
    
    
 
 
 
    
    
 
  
    
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
2 0 
C o nfi de ntial 
C o ns ult Secti o n 8 f or g ui deli nes o n pr oce d ures a n d assess me nts. C o ns ult t he St u d y Refere nce M a n u al f or a d diti o n al i nf or m ati o n, i ncl u di n g a 
rec o m m e n de d or der of (s pecific) assess m e nts f o r e a c h visit. 
a  Partici pa nts e nr olle d i n t he L T E Peri o d will b e dis p e nse d st u d y i nter ve nti o n at t he Wee k 2 4 visit. N o Wee k 2 4 assess me nts s h o ul d be re peate d fr o m t he mai n 
st u d y. 
b  Sc h e d ule all re mai ni n g visits at Wee k 2 4 visit. Visits ma y ta k e m ore t ha n 1 d a y b ut s h o ul d ta k e place as cl ose t o t he tar get date as p ossi ble. 
c  E arl y ter mi nati o n e C R Fs s h o ul d be c o m plete d if a p artici p a nt disc o nti n u es b ef ore t he Wee k 6 0 Visit. Sc h e d ule F U visit 4 wee ks after t he last d ose of A S N 5 1. 
d  Sc h e d ule t he F U visit 4 wee ks after t he last d ose of A S N 5 1 f or safet y assess me nt. T he F U visit ma y be c o n d ucte d b y p h o ne, h o we ver, a n y partici pa nt wit h a n 
o n g oi n g A E, or hist or y of a b n or mal E C Gs s h o ul d be m o nit ore d b y t he I n v esti gat or a n d ma na ge d a p pr o priatel y ( wit h a n i n-cli nic visit, i ncl u di n g vital si g ns 
a n d E C G, if necessar y).  
e  
A S N 5 1 s h o ul d be ta ke n o nce dail y i n t he m or ni n g wit h or wit h o ut f o o d. T h e first d ose s h o ul d b e ta ke n at t he cli nic visit u n der s u per visi o n. 
f  Partici pa nts s h o ul d be i nstr ucte d t o bri n g all st u d y m e dicati o n t o t he site at eac h i n dicate d visit t o assess c o m plia nce. If a n E Y visit, n o st u d y i nter ve nti o n 
( A S N 5 1) s h o ul d be dis pe nse d. 
g  
W h e n e v er perf or m e d o n t he sa m e da y, c o g niti v e a n d f u ncti o nal assess m e nts ( A D A S- C o g 1 3, C D R- S B, a n d M M S E) are t o be perf or me d bef ore pr oce d ures 
t hat ma y be stressf ul f or partici pa nts (f or e xa m ple, M RI, P E T, bl o o d dra w, or C S F sa m pli n g).  
h 
A n y cli nicall y si g nifica nt c ha n ges fr o m baseli ne i n t h e p h ysical e x a mi n ati o n s h o ul d b e n ote d as a n A E. 
i  
T he “ Si nce Last Visit” q uesti o n naire will b e a d mi nistere d at all s u bse q u e nt visits. 
j  
U nsc h e d ule d la b orat or y tests ma y be perf or m e d at a n y ti me at t h e discreti o n of t he I n v esti g at or if cli nicall y i n dicate d f or a s us pecte d a d verse e ve nt. 
k  Rec or d date a n d ti mes of sa m ple c ollecti o n o n t h e La b Re q uisiti o n F or m, f or all P K sa m ples, rec or d t h e d ate a n d ti m e of m ost rece nt A S N 5 1 d ose a n d 
w h et h er p artici pa nt is i n fe d or faste d state. 
l  
Bl o o d a n d C S F f or bi o mar ker st ora ge a n d are t o b e c ollecte d u nless c ollecti o n a n d/ or tra ns p ortati o n of t h e sa m ple is pr o hi bite d d ue t o l ocal re g ulati o ns. 
m  O btai n vital si g ns w hile partici pa nt has bee n i n a seate d p ositi o n f or at least 5 mi n utes. 
n  E C Gs s h o ul d be ta ke n i n tri plicate at a p pr o xi matel y 1- mi n ute i nter vals. Partici p a nts s h o ul d rest f or at least 5 mi n utes i n t he s u pi ne p ositi o n bef ore E C Gs are 
ta k e n. O btai n E C Gs, t o t he best of t he site a n d partici p a nts’ a bilit y, at a p pr o xi matel y t he sa me ti me of d a y at eac h visit t o mi ni mize di ur nal variati o n. 
A d diti o n al E C G assess m e nts m a y be perf or m e d at a n y ti me d uri n g trial partici p ati o n if cli nicall y i n dicate d. 
o  Perf or m M RI after a n y c o g niti ve a n d f u ncti o n al assess me nts. Alter nati v el y, M RI ma y b e perf or me d at least 1 da y bef ore c o g niti ve a n d f u ncti o nal 
assess me nts. V ol u metric M RI will be perf or me d. 
p  D u e t o t h e p ote ntial f or sc he d uli n g c halle n g es f or M K- 6 2 4 0 ta u P E T, or i n t he e ve nt of tracer fail ure, t he d e viati o n wi n d o w ma y be e xte n de d t o + 2 1 da ys of 
t he i n dicate d visits. 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
2 1 
C o nfi de ntial 
2
I N T R O D U C TI O N
2. 1  
P ur p ose of Tri al 
A S N 5 1 is a re versi ble a n d s u bstrate c o m petiti ve i n hi bit or of O-li n ke d
N-
acetyl gl uc osa mi ni dase ( O- Glc N Acase; O G A), w hic h is i n cli nical de vel o p me nt f or t he treat me nt 
of A D ca use d b y i ntracell ular brai n pr otei n o pat hies.
I n p atie nts wit h A D, t he f or mati o n of ne ur ofi brillar y ta n gles ( N F Ts) c o nsisti n g of t he pr otei n ta u 
is ti g htl y li n ke d t o t he o nset a n d pr o gressi o n of de me ntia s y m pt o ms (La J oie, Visa ni et al. 2 0 2 0 ).
I n hi biti o n of t he O G A e n z y me wit h A S N 5 1 sta bilizes a p ost-tra nslati o nal car b o h y drat e 
m o dificati o n of ta u calle d O- Glc N Ac b y pre ve nti n g its re m o val. I ncreasi n g t he le vel of O-
Glc N Ac m o dificati o n of ta u is h y p ot hesize d t o pre ve nt t he a g gre gati o n of ta u i nt o t o xic paire d 
helical fila me nts t hat de p osit as N F Ts i n t he brai ns of patie nts wit h A D. Orall y a d mi nistere d 
O G A i n hi bit ors ha ve bee n s h o w n t o sl o w t he de vel o p me nt of N F T pat h ol o g y i n precli nical 
m o dels of earl y A D b y u p t o 8 0 % i n s o me brai n re gi o ns a n d re prese nt a pr o misi n g ne w disease-
m o dif yi n g treat me nt a p pr oac h ( Y u z wa, S ha n et al. 2 0 1 2 , Gra ha m, Gra y et al. 2 0 1 4 , Y uz wa, S ha n 
et al. 2 0 1 4 , Hasti n gs, Wa n g et al. 2 0 1 7 , Wa n g, S mit h et al. 2 0 1 8 , Wa n g, Li et al. 2 0 2 0 , 
Per ma n ne, Sa n d et al. 2 0 2 2 , Pratt a n d V oca dl o 2 0 2 3 , R ost gaar d, J ul et al. 2 0 2 3 , Mer g ott 2 0 2 4, 
Ner y 2 0 2 4 ). 
A S N 5 1 has bee n a d mi nistere d t o healt h y v ol u nteers i n m ulti ple P hase 1 cli nical trials t o date a n d 
has bee n dee me d s uita ble f or c hr o nic d osi n g i n t his P hase 2 st u d y of earl y A D base d o n a vaila ble 
n o ncli nical a n d cli nical d ata as des cri be d i n t he I n vesti gat or’s Br oc h ure (I B). 
T he p ur p ose of t h e A S N 5 1- 2 0 1 trial is t o e val uate t he safet y, p har mac o ki netics ( P K), effect o n 
bi o mar kers of disease pat h o p h ysi ol o g y a n d pat h ol o g y, a n d preli mi nar y effects o n meas ures of 
cli nical efficac y of m ulti ple d oses of A S N 5 1 i n a d ults wit h earl y, s y m pt o matic A D. 
2. 2  
S u m m ar y of Be nefits a n d Ris ks 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
2 2 
C o nfi de ntial 
2. 2. 2  
Ris k S u m m ar y 
2. 2. 2. 1  
I nter ve nti o n Ris ks a n d Miti g ati o n 

A S N 5 1- 2 0 1
Asce ne ur o n S A
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2 3 
C o nfi de ntial 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
2 4 
C o nfi de ntial 
2. 2. 3
O ver all Be nefit: Ris k C o ncl usi o n
 

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2 7 
C o nfi de ntial 
4
T RI A L D E SI G N
4. 1  
Des cri pti o n 
A S N 5 1- 2 0 1 is a m ulti-site, place b o-c o ntr olle d, d o u ble- bli n d, ra n d o mize d, parallel gr o u p trial wit h 
a l o n g-ter m e xte nsi o n ( L T E). T he p ur p ose of t he trial is t o e val uate t he safet y, P K, effect o n 
bi o mar kers of disease p at h o p h ysi ol o g y a n d pat h ol o g y, a n d preli mi nar y effects o n meas ures of 
cli nical efficac y of m ulti ple d oses of A S N 5 1 i n a d ults wit h earl y A D.  
T he trial desi g n is de pict e d i n Secti o n 1. 2 .  
Scree ni n g f or eli gi bilit y will be c o n d ucte d usi n g a tiere d a p pr oac h a n d ma y be c o m plete d o ver 
m ulti ple da ys. A n a b bre viate d scree ni n g i nf or me d c o nse nt pr ocess ma y be utilize d t o c o n d uct 
i nitial prescree ni n g (i.e., de n ote d Tier 1 a n d Tier 2 per Ta ble 1), if all o we d at t he i n vesti gati ve 
site. Partici pa nts w h o meet Tier 1 eli gi bilit y criteria, i ncl u di n g M M S E, s h o ul d pr ocee d t o Tier 2 
( plas ma p Ta u 2 1 7). Ti er 1 a n d Tier 2 ass ess me nts ma y ta ke place o n t he sa me da y.
I nf or me d c o ns e nt f or t he f ull trial m ust be o btai ne d pri or t o perf or mi n g a n y Tier 3 a n d Tier 4 
scree ni n g pr o ce d ures 2 p er Ta ble 1. Partici pa nts ma y pr ocee d t o Tier 4 o nl y after all criteria fr o m 
Tier 1, 2, a n d 3 ha v e bee n met. 
T he d urati o n of t he Scree ni n g Peri o d ma y be u p t o 8 wee ks ( ma y be e xte n de d o n a case- b y-cas e 
basis b y t he S p o ns or Me dial M o nit or) t o all o w f or t he c o m pleti o n of assess me nts a n d f or t he 
e val uati o n of re q uire d la b orat or y, E C G, a n d i ma gi n g tests per t he Sc he d ule of Acti vities 
pr o vi de d i n Ta ble 1. 
D ose selecti o n has b ee n e na ble d b y t w o P hase 1 t ar get e n ga ge me nt trials t hat utilize d a n O G A 
e nz y me P E T li ga n d t o defi ne t he precise relati o ns hi p i n h u ma n bei n gs bet wee n plas ma 
c o nce ntrati o n a n d brai n t ar get occ u pa nc y. F urt her details o n d ose selecti o n ca n be f o u n d i n 
Secti o n  6. 2.
Eli gi ble partici pa nts will be ra n d o mize d i n a 1: 1: 1 rati o t o o ne of t he f oll o wi n g pla n ne d ar ms:
 A S N 5 1: 
 o nce dail y b y m o ut h 
 A S N 5 1: 
 o nce dail y b y m o ut h 
 Place b o o nce d ail y b y m o ut h.
Eli gi ble partici pa nts will self-a d mi nister A S N 5 1 o nce dail y at t he assi g ne d d ose le vel d uri n g a 
2 4- wee k D o u ble- bli n d ( D B) I nter ve nti o n Peri o d. T he partici pa nt (acc o m pa nie d b y a desi g nate d 
st u d y part ner) will be as ke d t o ret ur n t o t he i n vesti gati ve site a p pr o xi matel y e ver y 4 wee ks o ver 
t w o da ys as l o n g as all assess me nts are c o m plete d wit hi n t he visit wi n d o w. 
F oll o wi n g c o m pleti o n of t he D B I nt er ve nti o n Peri o d, all partici pa nts will be offere d c o nti n ue d 
A S N 5 1 i n t he 3 6- wee k L T E Peri o d. Partici pa nts i nitiall y ra n d o mize d t o place b o will recei ve 
A S N 5 1 (ra n d o mize d 1: 1 
) d uri n g t he L T E Peri o d. Partici pa nts ra n d o mize d t o 
 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
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2 8 
C o nfi de ntial 
A S N 5 1 will c o nti n ue at t he assi g ne d d ose le vel, u nless d ose m o dificati o n is rec o m me n de d base d 
o n e mer gi n g data.
A safet y F oll o w- u p Visit will ta ke place 4 wee ks after t he last d ose of A S N 5 1.  
A Sc he d ule of Acti vities f or t he D B I nter ve nti o n Peri o d a n d L T E Peri o d are pr o vi de d i n Ta ble 2  
a n d Ta ble 3, res pecti vel y. 
4. 2
R ati o n ale f or Tri al Desi g n
A S N 5 1- 2 0 1 is t he first trial t o i n vesti gate t he safet y, t olera bilit y, P K, effect o n bi o mar kers of 
pat h ol o g y a n d pat h o p h ysi ol o g y, a n d e x pl orat or y effect o n meas ures of c o g niti o n a n d f u ncti o n of 
A S N 5 1 i n a d ults wit h earl y A D. 
 
 
 
 
 
 
 
T he 2 4- wee k D B I nter ve nti o n Peri o d of c hr o nic a d mi nistrati o n of A S N 5 1 i n patie nts wit h earl y 
A D is a p pr o priat e t o esta blis h safet y a n d t olera bilit y of A S N 5 1 at m ulti ple d ose le vels as 
meas ure d b y c ha n ges i n l a b orat or y safet y ass ess me nts (i ncl u di n g cli nical c he mistr y, he mat ol o g y, 
uri nal ysis, a n d ser u m h or m o ne mar kers), vital si g ns, 1 2-lea d E C Gs, C ol u m bia- S uici de Se verit y 
Rati n g Scale ( C- S S R S), a n d p h ysical e xa mi nati o ns (i ncl u di n g ne ur ol o gical e xa mi nati o n).
T he 2 4- wee k D B I nter ve nti o n Peri o d is als o of s ufficie nt d urati o n t o perf or m a p o p ulati o n P K 
a nal ysis of tr o u g h ( C mi n ) a n d pea k ( Cma x ) P K at stea d y-state, t o o bser ve i nitial c ha n ges i n A D 
pat h o p h ysi ol o g y a n d pat h ol o g y as meas ure d b y fl ui d bi o mar kers, a n d t o o bser ve i nitial c ha n ges 
i n c o g niti ve f u ncti o n as assesse d b y A D cli nical o utc o me meas ures.

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
2 9 
C o nfi de ntial 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
3 0 
C o nfi de ntial 
4. 3
St a rt of Tri al a n d E n d of Tri al
T he Start of t he Trial is t he esti mate d date o n w hi c h t he cli nical trial will be o pe n f or recr uit me nt 
of partici pa nts. 
A partici pa nt will be c o nsi dere d e nr olle d i n t he trial o nce all scree ni n g pr oce d ures ha ve bee n 
c o m plete d, t he res ults e v al uate d b y t he I n vesti gat or t o c o nfir m eli gi bilit y, a n d t he partici pa nt is 
ra n d o mize d i nt o t he trial.
T he e n d of t he tri al is defi ne d as t he date of t he last pr ot oc ol-s pecifie d visit f or t he last 
partici pa nt partici pati n g i n t he trial. 
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he trial at a n y ti me f or a n y reas o n or disc o nti n ue 
partici pati o n of a n i n vesti gat or d ue t o p o or e nr oll me nt or n o nc o m plia nce ( Secti o n 1 0. 5 ).

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
3 1 
C o nfi de ntial 
5
P O P U L A TI O N
5. 1  
Selecti o n of Tri al P o p ul ati o n 
T his trial will be c o n d ucte d i n a d ults (a ge d 5 0 t o 8 0 years) wit h a dia g n osis of earl y A D. Eli gi ble 
patie nts s h o ul d meet dia g n ostic criteria f or mil d c o g niti ve i m pair me nt ( M CI) d ue t o A D or mil d 
A D di me ntia, c ollecti vel y referre d t o as earl y A D. All patie nts s h o ul d ha ve a plas ma p Ta u 2 1 7
c o nce ntrati o n a b o ve a pre- deter mi ne d c ut- off t o c o nfir m t he prese nce of brai n a m yl oi d 
pat h ol o g y. Mi ni Me ntal Stat us E xa mi nati o n 
 
 2 8 at 
baseli ne wit h a gl o bal Cli nical De me ntia Rati n g ( C D R) sc ore of 0. 5 or 1. 0. All partici pa nts 
s h o ul d meet Nati o nal I nstit ute o n A gi n g a n d t he Alz hei mer’s Ass ociati o n ( NI A- A A) dia g n ostic 
criteria f or M CI or mil d A D ( Jac k, B e n nett et al. 2 0 1 8) a n d ha ve a C D R me m or y b o x sc ore of 
0. 5 c o nfir mi n g e pis o dic me m or y i m pair me nt. 
5. 2  
R ati o n al e f or Tri al P o p ul ati o n 
Earl y A D patie nts are e x pecte d t o ha v e ta u pat h ol o g y prese nt at bas eli ne, ma xi mizi n g t he 
pr o ba bilit y of o bser vi n g a n a nti-ta u treat me nt effect wit h A S N 5 1. 
T he S p o ns or has ta ke n reas o na ble meas ures t o e ns ure t he pr otecti o n a n d safet y of t his p o p ulati o n 
i ncl u di n g s pecific criteria t o e xcl u de patie nts wit h si g nifica nt car di o vas c ular or ne ur ol o gical 
c o n diti o ns, or w h o re q uire c o nc o mita nt me dicati o ns f or c o n diti o ns w hic h ma y c o nf o u n d trial 
res ults. A d diti o nal criteri a relate d t o c o nc o mita nt me dicati o ns or a b n or mal c oa g ulati o n 
para meters were i ncl u de d t o miti gate ris ks ass ociate d wit h L P pr oce d ures. C o nsi derati o ns 
i ncl u de d c o m or bi dities li kel y prese nt i n t he select e d p o p ulati o n, a n d e mer gi n g safet y data fr o m 
P hase 1 cli nical trials. 
F or I n v esti gat or q uesti o ns re gar di n g partici pa nt eli gi bilit y or cli nical si g nifica nce of 
a b n or malities, disc ussi o n wit h t he st u d y Me dical M o nit or is str o n gl y e nc o ura ge d. 
I n di vi d uals w h o d o n ot meet criteria f or trial eli gi bilit y m ust n ot be e nr olle d; t here will be n o 
pr ot oc ol wai vers or e xe m pti o ns.
5. 3  
I ncl usi o n Criteri a  
T o be eli gi ble t o partici p ate i n t his trial, a n i n di vi d ual m ust meet all t he f oll o wi n g criteria:  
1.  Male or fe m ale a g e 5 0 t o 8 0 years i ncl usi ve at t he ti me of c o nse nt. 
2.  A bilit y of t he partici pa nt a n d/ or his/ her le gall y a ut h orize d re pres e ntati ve (e. g., pare nt, s p o use, 
or le gal g uar di a n, w here l ocal re g ulati o ns a n d i nstit uti o nal practices per mit), as a p pr o priate 
a n d a p plica ble, t o u n d ersta n d t he p ur p ose a n d ris ks of t he st u d y, t o pr o vi de i nf or me d c o nse nt, 
a n d t o a ut h orize t he us e of c o nfi de ntial healt h i nf or mati o n i n acc or da nce wit h nati o nal a n d 
l ocal pri vac y re g ulati o ns. 
   
   
   
   
   
  

A S N 5 1- 2 0 1
Asce ne ur o n S A
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3 2 
C o nfi de ntial 
3.
M ust c o nse nt t o A P O E ge n ot y pi n g. T he partici pa nt’s A P O E stat us ma y be discl ose d t o 
hi m/ her at t he I n vesti gat or’s discreti o n.
4.
M ust ha ve a care p art ner w h o, i n t he I n vesti gat or’s j u d g me nt, has fre q ue nt a n d s ufficie nt 
c o ntact wit h t he partici p a nt (at least 1 0 h o urs/ wee k) as t o be a ble t o pr o vi de acc urate 
i nf or mati o n a b o ut t he partici pa nt’s c o g niti ve a n d f u ncti o nal a bilities. T he care part ner m ust 
a gree t o acc o m p a n y t he p artici pa nt t o cli nic visits a n d/ or be a vaila ble b y tel e p h o ne at 
desi g nate d ti mes t o pr o vi de i nf or mati o n t o t he I n vesti gat or a n d st u d y staff a b o ut t he 
partici pa nt (a n d t o atte n d i n- pers o n cli nic visits t hat re q uire care part ner i n p ut f or scale 
c o m pleti o n) a n d m ust a gree t o m o nit or t he partici pa nt’s a d mi nistrati o n of a n y prescri be d 
me dicati o ns. A care part ner s h o ul d be a vaila ble f or t he d urati o n of t he st u d y, a n d t he 
partici pati o n of t he sa me care p art ner f or t he d urati o n of t he st u d y is a t o p pri orit y. T he care 
part ner m ust be literate a n d pr o vi de i nf or me d c o nse nt. 
5.
A plas ma p Ta u 2 1 7 res ult c o nsiste nt wit h t he prese nce of a m yl oi d pat h ol o g y ( defi ne d as 
> 0. 1 8 p g/ m L).
6.
A cli nical dia g n osis of A D at eit her t he mil d c o g niti ve i m pair me nt or mil d A D de me ntia 
sta ge per NI A- A A criteria (Jac k, Be n nett et al. 2 0 1 8), c o nsiste nt wit h Sta ge 3 a n d Sta ge 4 i n 
t he F D A draft g ui da n ce f or earl y A D ( F D A draft 2 0 2 4). 
7.
Gra d ual a n d pr o gressi ve c ha n ge i n c o g niti o n f or at least 6 m o nt hs as re p ort e d b y t he 
partici pa nt a n d st u d y part ner. 
8.
Gl o bal C D R of 0. 5 t o 
. 
9.
M M S E sc ore of 2 0 t o 2 8 (i ncl usi ve). 
1 0.  B o d y mass i n de x greater t ha n 1 8. 5 a n d less t ha n 3 5 at Scree ni n g. 
1 1. All me n, re gar dl ess of fertilit y stat us, wit h n o n- pre g na nt w o me n of c hil d beari n g p ote ntial 
part ners m ust a gree t o at least o ne of t he f oll o wi n g c o ntrace pti o n re q uire m e nts fr o m 2 8 da ys 
bef ore baseli ne ass ess me nt t hr o u g h 9 0 da ys after l ast st u d y dr u g a d mi nistrati o n: 
a. T otal a bsti ne nce: if i n li ne wit h t heir preferre d a n d us ual lifest yle
b.  Male sterilizati o n b y vas ect o m y wit h d oc u me ntati o n of t he pr oce d ure 
c. C o n d o m use
d.  A hi g hl y effecti ve met h o d of c o ntrace pti o n ( Secti o n 1 3. 1. 2 ) f or t he part ner of a male 
partici pa nt.  
1 2.  A part fr o m a cli nical dia g n osis of M CI d ue t o A D or mil d A D de me ntia, t he partici pa nt m ust 
be i n g o o d healt h as deter mi ne d b y t he I n vesti gat or, base d o n me dical hist or y a n d scree ni n g 
assess me nts. 
   
   
   
   
   
  
      
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
3 3 
C o nfi de ntial 
5. 4
E xcl usi o n Criteri a
A n i n di vi d ual w h o meets a n y of t he f oll o wi n g crit eria will be e xcl u de d fr o m partici pati o n i n t his 
trial:
5. 4. 1
E xcl usi o n Criteri a b y Me dic al Hist or y
1.  A n y me dical or ne ur ol o gical/ ne ur o de ge nerati ve c o n diti o n ( ot her t ha n A D) t hat, i n t he 
o pi ni o n of t he I n v esti gat or, mi g ht be a c o ntri b uti n g ca use t o t he partici pa nt’s c o g niti ve 
i m pair me nt (e. g., c urre nt hist or y of s u bsta nce a b us e, u nc o ntr olle d vita mi n B 1 2 deficie nc y or 
a b n or mal t h yr oi d f u ncti o n, str o ke or ot her cere br o vasc ular c o n diti o n, n or mal press ure 
h y dr oce p hal us, Par ki ns o n’s disease, Le w y b o d y de me ntia, cere bral a m yl oi d a n gi o pat h y, 
fr o nt ote m p oral de me ntia) or c o ul d lea d t o disc o nti n uati o n, lac k of c o m plia nce, i nterfere nce 
wit h st u d y assess me nts, or safet y c o ncer ns. 
2.  N o n-a m nestic prese ntati o n of A D as j u d ge d b y t he I n vesti gat or.
3.  W o ma n of c hil d beari n g p ote ntial ( per C T F G 2 0 2 0 ).  
4.  E xcessi ve alc o h ol us e ( d efi ne d as m ore t ha n 3 alc o h olic dri n ks per da y or 2 1 dri n ks per wee k 
f or me n a n d 2 alc o h olic dri n ks per da y or 1 4 dri n ks per wee k f or w o m e n) fr o m t he Scree ni n g 
Visit u ntil t he e n d of t he F oll o w- u p Peri o d. 
5.
Hist or y of ca n cer i n t he p ast 3 years. Exce pti o ns: n o n- metastatic basal a n d/ or s q ua m o us cell 
carci n o ma of t he s ki n, i n sit u cer vical ca ncer, n o n- pr o gressi ve pr ostat e ca ncer, partici pa nts 
wit h ca ncer i n re missi o n > 5 years, or ot her ca ncers wit h l o w ris k of rec urre nce or s prea d.
6.
Hist or y of h u ma n i m m u n o deficie nc y vir us i nfecti o n (acti ve or past), or acti ve he patitis C 
i nfecti o n. 
7.  Hist or y of li ver disease i ncl u di n g he patitis B, he patitis C, pri mar y biliar y c h ola n gitis, 
pri mar y scler osi n g c h ol a n gitis, al p ha- 1 a ntitr y psi n disease, alc o h olic li ver disease, Wils o n’s 
disease, he m oc hr o mat osis, p ortal h y perte nsi o n, bi o ps y- pr o ve n meta b olic ass ociate d 
steat o he patitis, a ut oi m m u ne he patitis, dr u g i n d uce d li ver disease. 
8.  Cli nicall y si g nifica nt s yste mic i nfecti o n or se vere i nfecti o n (e. g., p ne u m o nia, se ptice mia) 
wit hi n t he 3 0 da ys pri or t o Scree ni n g or bet wee n S cree ni n g a n d Da y - 1. 
9.  Hist or y of seiz ures wit hi n 1 0 years pri or t o Scree ni n g Visit 1 or hist or y of e pile ps y (e xce pt 
f or hist or y of fe brile seiz ures i n c hil d h o o d). 
1 0.  Prese nce of cli nicall y si g nifica nt a n d/ or u nsta ble ps yc hiatric ill ness, i n t he I n vesti gat or’s 
o pi ni o n (e. g., bi p olar dis or der), wit hi n t he 6 m o nt hs pri or t o Scree ni n g Visit 1 a n d/ or a 
d oc u me nte d pri or hist or y of c hr o nic sc hiz o p hre ni a. 
1 1.  Hist or y of maj or de pressi ve dis or der, bi p olar dis or der, or ge neralize d a n xiet y dis or der wit h 
a n acti ve e pis o de i n t he p ast 5 years. 

A S N 5 1- 2 0 1
Asce ne ur o n S A
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3 4 
C o nfi de ntial 
1 2. Hist or y of dia betes mellit us. Partici pa nts wit h well-c o ntr olle d dia bet es mellit us a n d a 
he m o gl o bi n A 1c < 7 % are per mitte d.
1 3. Bi oti n s u p ple me ntati o n
 fr o m 2 8 da ys pri or t o Scree ni n g t hr o u g h t he e n d of 
t he F oll o w- u p Peri o d  
1 4.  Hist or y of blee di n g dis or der or pre dis p osi n g c o n diti o ns, bl o o d cl otti n g, or cli nicall y 
si g nifica nt a b n or mal res ults o n c oa g ulati o n pr ofile at Scree ni n g, as deter mi ne d b y t he 
I n v esti gat or. 
1 5.  A n y maj or s ur ger y wit hi n 1 2 wee ks of Scree ni n g Visit 1 or d uri n g t he scree ni n g peri o d. 
1 6. Hist or y of u nsta ble a n gi n a, m y ocar dial i nfarcti o n, c hr o nic heart fail ure ( Ne w Y or k Heart 
Ass ociati o n Class III or I V), or cli nicall y si g nifica nt c o n d ucti o n a b n or malities (e. g., u nsta ble 
atrial fi brillati o n) wit hi n 1 year pri or t o Scree ni n g Visit 1.
1 7. U nc o ntr olle d h y pert e nsi o n defi ne d as a n a vera ge of 3 s yst olic/ diast olic bl o o d press ure 
rea di n gs > 1 6 5 m m H g a n d/ or > 1 0 0 m m H g, res pecti vel y, at Scree ni n g ( bl o o d press ure 
meas ure me nts e x cee di n g t hese li mits ma y be re peate d as warra nt e d b y t he I n vesti gat or, b ut 
val ues m ust be wit hi n t he s pecifie d li mits f or t he partici pa nt t o be eli gi ble f or t he st u d y) or 
persiste nt s yst olic/ diast olic bl o o d press ure rea di n gs > 1 8 0/ 1 0 0 m m H g wit hi n 1 2 wee ks pri or 
t o ra n d o mizati o n ( St u d y Da y 1) t hat, i n t he o pi ni o n of t he I n vesti gat or, are i n dicati ve of 
c hr o nic u nc o ntr olle d h y p erte nsi o n.
1 8.  Hist or y of se vere aller gi c or a na p h ylactic reacti o ns. 
1 9. K n o w n or s us pect e d hist or y of dr u g or alc o h ol a b use wit hi n 2 years pri or t o Scree ni n g. 
Be nz o diaze pi n e a n d o pi oi d use is per mitte d if i n t he cli nical o pi ni o n of t he I n vesti gat or t he 
use is f or a n a p pr o priate me dical c o n diti o n a n d n ot d ue t o dr u g a b use. 
2 0. C urre nt seri o us or u nsta ble ill ness, or a n y ot her c o n diti o n t hat, i n t he j u d ge me nt of t he 
I n v esti gat or, w o ul d i nterfere wit h t he a bilit y t o c o m plete t he st u d y, p ose si g nifica nt ris k t o 
partici pa nt safet y, or p ote ntiall y c o nf o u n d i nter pret ati o n of trial res ults.
5. 4. 2
E xcl usi o n Criteri a b y Scree ni n g Assess me nts 
2 1. A n y cli nicall y si g nifica nt a b n or malit y at scree ni n g i n p h ysical e xa mi nati o n, vital si g ns, E C G, 
or la b orat or y test res ults t hat c o ul d place t he partici pa nt at u n d ue ris k d uri n g t he st u d y, 
c o m pr o mise t he f ut ure i nter pretati o n of st u d y ass ess me nts, or t hat s u g gests a n alter nati ve 
eti ol o g y f or de me ntia ot h er t ha n A D. 
2 2. At ris k of s uici de base d o n a “ yes” res p o nse t o t he C ol u m bia S uici de Se verit y Rati n g Scale 
( C- S S R S) s uici dal i deati o n q uesti o n 4 or 5 or a n y s uici dal be ha vi or ass ess me nt wit hi n 6 
m o nt hs bef ore Scree ni n g, or has bee n h os pitalize d or treate d f or s uici dal be ha vi or wit hi n 5 
years of Scree ni n g. 
 
   
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
3 5 
C o nfi de ntial 
2 3.
Ma g netic res o n a nce i ma gi n g ( M RI) e vi de nce of vasc ular de me ntia or ot her fi n di n gs 
s u g gesti ve of a maj or n e ur ol o gic dis or der ot her t ha n A D.
2 4.  Si g nifica nt cla ustr o p h o bia d uri n g M RI t hat, i n t he o pi ni o n of t he I n vesti gat or, will pre ve nt 
s uccessf ul c o m pleti o n of re q uire d pr oce d ures. 
2 5.  Heart rate > 1 0 0 b eats per mi n ute after 5 mi n utes of rest, wit h o ut s olicitati o n.  
2 6.  C o nfir me d de m o nstrati o n of c orrecte d Q T i nter val usi n g Fri dericia’s c orrecti o n met h o d 
( Q Tc F) of > 4 5 0 ms f or males a n d > 4 6 0 ms f or fe males (as rea d b y t he ce ntral rea di n g 
facilit y). 
2 7.  Me dia n E C G (tri plicate) P R i nter val > 2 0 0 msec at Scree ni n g. 
2 8.  P ositi ve he patitis B vir us s urface a nti ge n a n d/ or he patitis B e-a nti ge n at Scree ni n g. 
2 9.  P ositi ve he patitis C a nti b o d y test res ult at Scree ni n g. 
3 0.  Prese nce of blee di n g dis or der or a b n or mal c oa g ul ati o n para meters at Scree ni n g, i ncl u di n g 
platelet c o u nt < 1 5 0, 0 0 0 cells/ µ L or i nter nati o nal n or malize d rati o (I N R) > 1. 5. 
3 1.  Esti mate d gl o mer ular filtrati o n rate < 6 0 m L/ mi n/ 1. 7 3 m 2 per C hr o nic Ki d ne y Disease 
E pi de mi ol o g y C olla b orati o n at Scree ni n g. 
3 2. Li ver f u ncti o n, a n y of t he f oll o wi n g
 1 × t he U L N, A S T 1 × U L N, t otal bilir u bi n 
 1 × 
 1 × U L N at scree ni n g. S u bjects wit h 
a n y de gree of h e patic i m pair me nt as defi ne d b y t he C hil d- P u g h classificati o n are als o 
e xcl u de d (e. g., classificati o n B or C). 
5. 4. 3  
E xcl usi o n Criteri a b y C o nc o mit a nt Me dic ati o ns/ Pri or T her a pies 
3 3. I nitiati o n or c h a n ge i n d ose of a n acet ylc h oli nesterase i n hi bit or a n d/ or me m a nti ne wit hi n less 
t ha n 8 wee ks pri or t o ra n d o mizati o n.
3 4.  P ositi ve uri ne dr u g test at Scree ni n g. Testi n g p ositi ve f or be nz o diaze pi nes or o pi oi ds i n uri ne 
dr u g testi n g is per mitte d if deter mi ne d b y t he I n vesti gat or t o be d ue t o a p pr o priate me dical 
use a n d n ot dr u g a b us e. Me dical ca n na bi di ol ( C B D) use is per mitte d if prescri be d b y a 
me dical pr o vi der i n acc or da nce wit h l ocal la ws a n d if i n t he o pi ni o n of t he I n vesti gat or its 
use d oes n ot p ose a ris k t o partici pa nt safet y or c o m pr o mise a partici pa nt’s perf or ma nce o n 
c o g niti ve assess me nts. 
3 5.  Ta ki n g me dicati o ns k n o w n t o pr ol o n g P R or Q T i nter vals (e. g., calci u m c ha n nel bl oc kers or 
beta bl oc kers) u nless o n a sta ble d ose of ( or titrati n g) wit hi n 1 2 wee ks pri or t o 
ra n d o mizati o n. 
3 6.  Use of a n y me di cati o ns t hat, i n t he o pi ni o n of t he I n vesti gat or, ma y c o ntri b ute t o c o g niti ve 
i m pair me nt, p ut t he partici pa nt at hi g her ris k f or A Es, or i m pair t he partici pa nt’s a bilit y t o 
perf or m c o g niti ve testi n g or c o m plete st u d y pr oce d ures.
   
 
 
   
  
      
   
   
  

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
3 6 
C o nfi de ntial 
3 7. A n y pri or or o n g oi n g e x p os ure t o acti ve or passi ve a nti-a m yl oi d i m m u n ot hera p y, a nti-ta u 
i m m u n ot hera p y, a n a nti-t a u a ntise nse oli g o n ucle oti de or ge ne t hera p y, or O- Glc N Acase 
i n hi bit or. 
3 8. If pre vi o usl y e x p os e d t o a n i n vesti gati o nal pr o d uct ot her t ha n acti ve or passi ve a nti-a m yl oi d 
i m m u n ot hera p y, a nti-ta u i m m u n ot hera p y, a n a nti-t a u a ntise nse oli g o n ucle oti de or ge ne 
t hera p y, or O- Glc N Acas e i n hi bit or, t he n 1 2 wee ks or 5 half-li ves ( w hi c he ver is l o n ger) m ust 
ha ve passe d pri or t o ra n d o mizati o n. 
3 9.  K n o w n aller g y t o a n y c o m p o ne nts of t he A S N 5 1 f or m ulati o n. 
4 0.  Re q uires use of a ntic oa g ula nts d uri n g trial partici pati o n (t o per mit safe C S F c ollecti o n). 
4 1.  Pri or use of a m o derate or str o n g i n hi bit or of C Y P 3 A 4 wit hi n a peri o d of 5 half-li ves of 
ra n d o mizati o n (refer t o A p pe n di x 1 6 ).  
4 2.  Pri or use of a m o derate or str o n g i n hi bit or of C Y P 2 C 1 9 wit hi n a peri o d of 5 half-li ves of 
ra n d o mizati o n (refer t o A p pe n di x 1 6 ). 
5. 4. 4  
Pr oce d ur al E xcl usi o ns 
4 3.  U na ble t o s wall o w  ca ps ules o nce dail y. 
4 4.  K n o w n se nsiti vit y t o 1 8 F- M K- 6 2 4 0. 
4 5.  P o or ve n o us access.  
4 6.  Has a n y of t he f oll o wi n g c o ntrai n dicati o ns t o ha vi n g a L P, i ncl u di n g, b ut n ot li mite d t o: 
 Scree ni n g val ues of platelet c o u nt a n d c oa g ul ati o n para meters i ncl u di n g I N R, 
pr ot hr o m bi n ti me, a n d partial t hr o m b o plasti n ti me or ot her c oa g ul o pat h y s h o ul d be 
wit hi n n or mal ra n ges. Partici pa nts wit h n o ncli nicall y si g nifica nt a n d sta ble o ut- of-ra n ge 
val ues ma y be eli gi ble t o e nr oll i n t he st u d y at t he discreti o n of t he I n vesti gat or. 
 A d mi nistrati o n of a n y a nti platelet or a ntic oa g ula nt me dicati o n (e. g., 
 3 2 5 
m g/ da y], cl o pi d o grel, di p yri da m ole, warfari n, da bi gatra n, ri var o xa ba n, a n d a pi xa ba n) t hat 
ca n n ot be safel y hel d bef ore a n d/ or after a n L P pr oce d ure acc or di n g t o l ocal or 
i nstit uti o nal g ui deli nes a n d/ or I n vesti gat or deter mi nati o n. 
 Prese nce of ris k f or i n crease d or u nc o ntr olle d blee di n g a n d/ or ris k of blee di n g t hat is n ot 
ma na ge d o pti mall y a n d c o ul d place a partici pa nt at a n i ncreas e d ris k f or pr oce d ural 
blee di n g. T hese c o ul d i ncl u de, b ut are n ot li mite d t o, k n o w n a nat o mical fact ors at or near 
t he L P site (e. g., vasc ular a b n or malities, ne o plas ms, or ot her a b n or m alities). 
 L u m bar s pi ne def or mit y a n d/ or k n o w n e vi de nce o n M RI c o ntrai n dicati n g L P. 
 Cli nical si g ns or s y m pt o ms detecte d d uri n g ne ur ol o gical e xa m (e. g., f ocal ne ur ol o gical 
si g ns, altere d me ntal stat us, pa pille de ma) or ra di o gra p hic e vi de nce (e. g., e nlar ge d 
ve ntricles, her ni ati o n, or mass effect) of i ncreas e d i ntracra ni al press ure. 
 
 
     
  
 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
3 7 
C o nfi de ntial 
A n y s y m pt o ms ca use d b y or relate d t o t he L P if perf or me d d uri n g Scree ni n g m ust be 
res ol ve d pri or t o ra n d o mizati o n.
4 7. C o ntrai n dicati o n t o M RI.
4 8. C o ntrai n dicati o n t o ha vi n g a P E T sca n (e. g., i na bilit y t o lie flat or still f or t he d urati o n of t he 
sca n) or i nt olera nce t o pre vi o us P E T sca ns (i.e., pre vi o us h y perse nsiti vit y reacti o ns t o a n y 
P E T ra di oli ga n d, i ma gi n g a ge nt, or a n y of t he e xci pie nts; fail ure t o partici pate i n a n d c o m pl y 
wit h pre vi o us P E T sca ns). 
4 9.  Pla n ne d or rece nt e x p os ure t o i o nizi n g ra diati o n t hat w he n c o m bi ne d wit h st u d y P E T 
i ma gi n g pr oce d ures w o ul d res ult i n a c u m ulati ve e x p os ure t o ra diati o n t hat e xcee ds l ocal 
li mits. 
5. 4. 5  
Ot her E xcl usi o ns 
5 0.  Partici pa nt li vi n g i n a n or ga nize d care facilit y wit h e xte nsi ve i nter ve nti o n a n d/ or s u p p ort of 
dail y li vi n g acti vities (e. g., a n ursi n g h o me). 
5 1.  Bl o o d d o nati o n ( 1 u nit or m ore) wit hi n 9 0 da ys pri or t o Scree ni n g Visit 1, plas ma d o nati o n 
fr o m 1 wee k pri or t o Scree ni n g Visit 1, a n d platel et d o nati o n fr o m 6 wee ks pri or t o 
Scree ni n g Visit 1.  
5 2.  I n a bilit y t o c o m pl y wit h st u d y re q uire me nts. 
5 3.  Ot her u ns pecifie d reas o ns t hat, i n t he o pi ni o n of t he I n vesti gat or or t he S p o ns or, ma ke t he 
partici pa nt u ns uita ble f or e nr oll me nt. 
5. 5  
Lifest yle C o nsi der ati o ns 
5. 5. 1
Me als a n d Diet ar y Restricti o ns
N o restricti o ns. 
5. 5. 2  
P h ysic al Acti vit y 
N o restricti o ns. 
5. 5. 3  
Ot her Acti vit y 
Partici pa nts m ust refrai n fr o m d o nati n g bl o o d or bl o o d pr o d ucts fr o m t he scree ni n g visit u ntil 1 
m o nt h after t he last d ose of A S N 5 1. 
Male partici pa nts s h o ul d refrai n fr o m s per m d o nati o n fr o m t he scree ni n g visit u ntil 9 0 da ys after 
t he last d ose of A S N 5 1.

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
3 8 
C o nfi de ntial 
5. 6
Scree n F ail ures
Pr os pecti ve partici pa nts will be e val uate d f or eli gi bilit y per i ncl usi o n a n d e xcl usi o n criteria 
( Secti o ns 5. 3 a n d 5. 4 ) as detaile d i n Secti o n 8. 1 a n d Ta ble 1 .
A n i n di vi d ual w h o d oes n ot meet a n y i ncl usi o n criteria or meets o ne or m ore e xcl usi o n criteria 
will be dee me d i neli gi ble; t he reas o n f or scree n fail ure will be d oc u me nte d. N o e xce pti o ns t o 
eli gi bilit y criteria (i.e., pr ot oc ol wai vers) will be gra nte d. 
Rescree ni n g ma y b e c o nsi dere d i n c o ns ultati o n wit h t he Me dical M o nit or if t here is a c ha n ge i n 
t he i n di vi d ual’s stat us. Rescree ni n g is n ot all o we d if t he reas o n f or scree n fail ure is a n i ma gi n g 
test f or A D or bi o mar ker u nless d ue t o tec h nical iss ue wit h sa m ple or pr ocessi n g. A n a b n or mal 
la b orat or y test res ult ma y be re peate d o nce wit hi n t he scree ni n g peri o d wit h o ut t he partici pa nt 
bei n g c o nsi dere d a res cree n. 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 0 
C o nfi de ntial 
6. 2
R ati o n ale f or Tri al I nter ve nti o n 
6. 3
D osi n g a n d A d mi nistr ati o n
All partici pa nts will ta ke a t otal of  A S N 5 1 a n d/ or place b o ca ps ules o nce dail y t o ac hie ve t he 
assi g ne d d ose le vel a n d mai ntai n t he bli n d.  
Partici pa nts will be pr o vi de d wit h d osi n g i nstr ucti o ns; ca ps ules will be ta ke n orall y , wit h or 
wit h o ut f o o d, a n d s h o ul d be a d mi nistere d a p pr o xi matel y t he sa me ti me eac h da y, prefera bl y i n 
t he m or ni n g. 
F or a n y d os e n ot ta ke n wit hi n 1 2 h o urs ( ± 2 h o urs) of t he us ual ti me, or wit hi n 1 2 h o urs 
( ± 2 h o urs) of pri or d os e partici pa nts will be i nstr ucte d t o wit h h ol d d osi n g o n t hat da y. 
Partici pa nts will be i nstr ucte d n ot t o ma ke u p t he misse d d oses.
If dr u g-relate d t olera bilit y iss ues are s us pecte d f or a n i n di vi d ual partici pa nt, c o ntact t he S p o ns or 
Me dical M o nit or f or g ui da nce. 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 1 
C o nfi de ntial 
6. 4
Tre at me nt of O ver d ose
N o a nti d otes or a nta g o nists e xist f or t he treat me nt of a p ote ntial A S N 5 1 o ver d ose. Cli nical 
s y m pt o ms will be treate d as dee me d a p pr o priat e b y t he I n vesti gat or a n d/ or treati n g p h ysicia n.
All A Es ass ociate d wit h o ver d ose s h o ul d be d oc u me nte d i n t he electr o ni c case re p ort f or m 
(e C R F) a n d re p ort e d f oll o wi n g pr oce d ures f or t he re p orti n g of Seri o us A d verse E ve nts ( S ecti o n 
1 2. 3 ).   
6. 5  
P re p ar ati o n, H a n dli n g, St or a ge, a n d Acc o u nt a bilit y 
6. 5. 1
Pre p ar ati o n of Tri al I nter ve nti o n
A S N 5 1 will be s u p plie d i n ca ps ule f or m a n d dis pe nse d t o t he partici pa nt.
D uri n g t he D B I nter v e nti o n Peri o d, matc he d place b o will be s u p plie d i n ca ps ule f or m a n d 
dis pe nse d t o t he partici pa nt as assi g ne d. 
6. 5. 2  
H a n dli n g a n d St or a ge of Tri al I nter ve nti o n 
At t he i n vesti gati ve site, I M P m ust be sec urel y st ore d u n der c o n diti o ns i n dicate d i n t he I B; I M P 
acc o u nta bilit y is t he res p o nsi bilit y of t he I n vesti gat or ( Secti o n 1 0. 5 ).  
Details o n ha n dli n g a n d st ora ge of A S N 5 1 ( place b o) ca ps ules are pr o vi de d i n t he St u d y 
Refere n ce M a n ual. 
6. 5. 3  
Acc o u nt a bilit y of Tri al I nter ve nti o n 
T he I n vesti gat or is res p o nsi ble f or e ns uri n g I M P is st ore d i n a sec ure li mite d access l ocati o n at 
c o ntr olle d te m perat ure as descri be d i n t he I B a n d acc or di n g t o pr o d uct pac ka gi n g.  T he st ora ge 
facilit y m ust be a vaila ble f or i ns pecti o n b y t he trial m o nit or at a n y ti me d uri n g t he trial. 
A dr u g acc o u nta bilit y rec or d m ust be mai ntai ne d f or all I M P recei ve d, dis pe nse d, ret ur ne d, 
a n d/ or l ost d uri n g t he trial. T his rec or d m ust be ke pt c urre nt a n d m a de a vaila ble t o t he trial 
m o nit or f or i ns pecti o n. F oll o wi n g t he cl ose- o ut of t he trial, all u n use d I M P m ust be ret ur ne d t o 
S p o ns or a n d/ or its desi g nee u nless ot her i nstr ucti o ns ha ve bee n pr o vi de d f or fi nal dis p ositi o n of 
t he I M P. 
6. 6  
P artici p a nt Assi g n me nt, R a n d o mi z ati o n, a n d Bli n di n g 
6. 6. 1
P artici p a nt Assi g n me nt 
Partici pa nts will be se q ue ntiall y assi g ne d a n i de ntificati o n n u m ber u p o n si g ni n g of i nf or me d 
c o nse nt.  
O nce eli gi bilit y is c o nfir me d, partici pa nts will be ra n d o mize d via a n I nteracti ve We b Res p o nse 
S yste m (I W R S). Ra n d o mizati o n will be stratifie d as descri be d i n Secti o n 4. 2 .   

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 2 
C o nfi de ntial 
6. 6. 2
Bli n di n g a n d U n bli n di n g
T he i nitial 2 4 wee ks of i nter ve nti o n will be a d mi nistere d i n a d o u ble- bli n d fas hi o n. Partici pa nts, 
I n v esti gat ors, site pers o n nel, a n d t he S p o ns or a n d/ or desi g nees will be bli n de d t o ra n d o mizati o n 
assi g n me nt.  
T he statisticia n(s) res p o nsi ble f or ge nerati n g t he ra n d o mizati o n sc he d ule, a n d pers o n nel 
res p o nsi ble f or pre pari n g trial i nter ve nti o n s u p plies will be u n bli n de d.  
Ra n d o mizati o n n u m bers will be assi g ne d se q ue nti all y. Eac h partici pa nt will be dis pe nse d 
bli n de d trial i nter ve nti o n ( A S N 5 1 or place b o), la bele d wit h t he partici pa nt’s u ni q ue 
ra n d o mizati o n n u m ber. U n bli n di n g mec ha nis ms will be a vaila ble b y I W R S. 
S h o ul d a n y trial st o p pi n g criteria ( Secti o n 7. 4 ) be tri g gere d t he i n v ol ve d partici pa nt(s) will be 
u n bli n de d t o ra n d o mizati o n assi g n me nt b y t he S R C t o deter mi ne if t he e ve nt was relate d t o I M P. 
I n t he e ve nt of a n e mer ge nc y, t he I n vesti gat or has t he s ole res p o nsi bilit y f or deter mi ni n g if 
u n bli n di n g of a partici pa nt’s ra n d o mizati o n assi g n me nt is warra nte d. T he safet y of t he 
partici pa nt will be t he first c o nsi derati o n i n ma ki n g s uc h a deter mi nati o n. If a partici pa nt’s 
ra n d o mizati o n assi g n me nt is u n bli n de d, t he S p o ns or Me dical M o nit or m ust be n otifie d wit hi n 2 4 
h o urs.  
F oll o wi n g c o m pleti o n of t he 2 4- wee k D B I nter ve nti o n Peri o d, data will be u n bli n de d after 
data base l oc k f or t he p ur p ose of data a nal ysis; h o we ver, partici pa nts, I n vesti gat ors, a n d st u d y  
site staff will re mai n bli n de d t o D B treat me nt assi g n me nt u ntil t he e n d of t he 3 6- wee k L T E 
Peri o d (e n d of t he st u d y). 
6. 6. 3
R a n d o miz ati o n
Partici pa nts will be ra n d o mize d ( 1: 1: 1) t o A S N 5 1 at 1 of 2 d ose le vels, or place b o.
T he ra n d o mizati o n sc he d ule will be c o m p uter ge nerate d b y t he S p o ns or or desi g nee. A n I W R S 
will be use d. 
6. 7  
Tri al I nter ve nti o n C o m pli a nce 
Site pers o n nel will mai ntai n a rec or d of all I M P dis pe nse d t o eac h partici pa nt. Partici pa nts will 
als o be i nstr ucte d t o bri n g all I M P c o ntai ners ( blister pac ks a n d/ or u n use d ca ps ules) t o eac h 
cli nic visit.
6. 8  
C o nc o mit a nt T her a p y 
I n v esti gat ors ma y pres cri be a n y c o n c o mita nt me dicati o ns or treat me nts dee me d necess ar y t o 
pr o vi de a de q u ate s u p p orti ve care, e xce pt t h ose s pecifie d as pr o hi bite d me di cati o ns 
( Secti o n 6. 8. 1).  

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 3 
C o nfi de ntial 
6. 8. 1
Pr o hi bite d C o nc o mit a nt T her a p y
T o be eli gi ble f or t he trial, partici pa nts m ust n ot re q uire c hr o nic dail y dr u g i nta ke of t he 
me dicati o ns liste d bel o w. If partici pa nts disc o nti n ue a n y of t hes e me dicati o ns pri or t o 
ra n d o mizati o n, a was h o ut peri o d of t he lesser of 5 half-li ves or 3 0 da ys is re q uire d.  
T he f oll o wi n g me dicati o ns will re mai n pr o hi bite d t hr o u g h o ut t he D B I nter ve nti o n Peri o d:   
 A n y i n vesti gati o nal pr o d uct i nte n de d f or A D (e. g., a nti-ta u a ntise nse oli g o n ucle oti de or 
ge ne t hera p y, acti ve or passi ve a nti-a m yl oi d i m m u n ot hera p y, acti ve or passi ve a nti-ta u 
i m m u n ot hera p y, O- Glc N Acase i n hi bit or, etc.) or ot her i n vesti gati o nal pr o d uct wit hi n 8 
wee ks pri or t o ra n d o mizati o n 
 A ntic oa g ula nts
 M o derate a n d str o n g i n hi bit ors of C Y P 3 A 4 a n d C Y P 2 C 1 9 (refer t o A p pe n di x 1 6 ).
D uri n g t he L T E Peri o d, use of pr o hi bite d/restrict e d me dicati o ns will be a d dresse d o n a case- b y-
case basis i n c o ns ultati o n wit h t he S p o ns or Me dical M o nit or. 
6. 8. 2  
Per mitte d C o nc o mit a nt T her a p y 
C o nc o mita nt t hera p y, partic ularl y me dicati o ns t hat c o ul d p ote ntiall y affect c o g niti o n, s h o ul d be 
mai ntai ne d at sta ble d oses t hr o u g h o ut t he trial, u nless a c ha n ge is me dicall y necessar y. 
Me dicati o ns (i n vesti gati o nal, prescri pti o n, o ver t he c o u nter, a n d her bal) a n d n utriti o nal 
s u p ple me nts ta ke n d uri n g t he 3 0 da ys pri or t o Da y 1 will be re vie we d a n d rec or de d as pri or 
me dicati o ns.  
All c o nc o mita nt me dicati o ns ta ke n d uri n g t he trial, a n d a n y c ha n ges si nce t he pre vi o us visit, will 
be rec or de d. D os e, r o ute, u nit fre q ue nc y of a d mi nistrati o n, i n dicati o n, a n d date(s) of 
a d mi nistrati o n will be ca pt ure d.  
If partici pa nt is ta ki n g hi g h d ose bi oti n s u p ple me nts (
g/ da y, f o u n d i n 
m ulti vita mi ns, bi oti n s u p ple me nts, a n d s u p ple me nts f or hair, s ki n, a n d nail gr o wt h), a was h o ut of 
1 wee k bef ore ra n d o mizati o n is per mitte d.
6. 8. 3
Resc ue T her a p y
N ot a p plica ble.
6. 8. 4
A d diti o n al Pr ot oc ol- desi g n ate d Pr o d ucts – P ositr o n E missi o n T o m o gr a p h y 
I m a gi n g R a di oli g a n ds
 
 
 
  
    

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
4 4 
C o nfi de ntial 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 5 
C o nfi de ntial 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 6 
C o nfi de ntial 
7
DI S C O N TI N U A TI O N O F I N T E R V E N TI O N A N D P A R TI CI P A N T 
WI T H D R A W A L 
7. 1  
Disc o nti n u ati o n of Tri al I nter ve nti o n 
7. 1. 1
Criteri a f or Per m a ne nt Disc o nti n u ati o n of Tri al I nter ve nti o n
T he I n vesti gat or a n d S p o ns or ha ve t he ri g ht t o re m o ve partici pa nts fr o m t he trial. T he S p o ns or 
als o reser v es t he ri g ht t o disc o nti n ue partici pati o n of a n i n di vi d ual partici pa nt. 
Cli nical j u d ge me nt 
Trial i nter ve nti o n ma y be disc o nti n ue d, a n d partici pa nts ma y be re m o ve d fr o m t he trial f or t he 
f oll o wi n g reas o ns: 
Occ urre nce of a n A E or S A E t hat precl u des f urt her partici pati o n  
 A n y c o n diti o n t hat, i n t he j u d g me nt of t he I n vesti gat or or S p o ns or, mi g ht place t he 
partici pa nt at ris k or i n vali date t he trial  
 At t he re q uest of t he p artici pa nt, I n vesti gat or, or S p o ns or, f or a d mi nistrati ve or ot her 
reas o ns
 Pr ot oc ol de viati o n or n o nc o m plia nce. 
He patic e v e nt or li ver test a b n or malit y 
Partici pa nts w h o are dis c o nti n ue d fr o m I M P d ue t o a he patic e ve nt or li ver test a b n or malit y 
s h o ul d ha ve a d diti o nal he patic safet y data c ollect e d a n d rec or de d i n t he e C R F as dee me d 
necessar y b y I n vesti gat or t o acc uratel y f oll o w e ve nt u ntil res ol uti o n or baseli ne ret ur n. 
Disc o nti n uati o n of I M P f or a li ver test a b n or malit y s h o ul d occ ur w he n a partici pa nt meets a n y of 
t he f oll o wi n g c o n diti o ns: 
 A L T or A S T > 8 × U L N 
 A L T or A S T > 5 × U L N f or m ore t ha n 2 wee ks 
 A L T or A S T > 3 × U L N a n d T B L > 2 × U L N or I N R > 1. 5 
 A L T or A S T > 3 × U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n or t e n der n ess, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) 
 A L P > 3 × U L N 
 A L P > 2. 5 × U L N a n d T B L > 2 × U L N 
 A L P > 2. 5 × U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt 
pai n or te n der n ess, fe v er, ras h, a n d/ or e osi n o p hilia ( > 5 %). 
 
 
 
 
 
 
 
 
 
 
 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 7 
C o nfi de ntial 
C- S S R S
I n a d diti o n, I M P ma y be disc o nti n ue d if partici pa nts: 
 A ns wer “ y es” t o Q u esti o n 4 or Q uesti o n 5 o n t he “ S uici dal I deati o n” p orti o n of t he C-
S S R S, or
 A ns wer “ y es” t o a n y of t he s uici de-relate d be ha vi ors o n t he S uici dal Be ha vi or p orti o n of 
t he C- S S R S. 
A ps yc hiatrist ma y assist i n t he decisi o n t o disc o nti n ue t he partici pa nt.
E C G
If a cli nicall y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g c ha n ges fr o m baseli ne i n Q Tc F) after 
e nr oll me nt, t he I n vesti gat or or q ualifie d desi g nee will deter mi ne if t he parti ci pa nt ma y c o nti n ue 
i n t he trial or if a c h a n ge i n partici pa nt ma na ge m e nt is re q uire d. Re vie w of E C Gs m ust be 
d oc u me nte d u p o n c ollecti o n a n d a n y ne w cli nicall y si g nifica nt E C G fi n di n g s h o ul d be re p orte d 
as a n A E. Ce ntral re vie w of E C Gs will als o be perf or me d (see Secti o n 8. 3. 3. 1 ). 
S h o ul d t he f oll o wi n g e ve nts occ ur i n a n i n di vi d ual partici pa nt d uri n g t he tri al, t he I n vesti gat or, i n 
c o ns ultati o n wit h t he S p o ns or’s Me dical M o nit or, will deci de if st u d y i nter ve nti o n s h o ul d be 
i nterr u pte d or per ma ne ntl y disc o nti n ue d: 
 If a partici pa nt has me dia n P R i nter val of 2 0 0 ms t o 2 2 0 ms A N D  a c ha n ge fr o m baseli ne 
i n P R i nter val of > 1 0 % (tri plicate meas ure me nts) 
 If a partici pa nt has me dia n P R i nter val > 2 2 0 ms (tri plicate meas ure me nts). 
S yste mic H y perse nsiti vit y Reacti o ns
If t he I n vesti gat or, after c o ns ultati o n wit h t he S p o ns or- desi g nate d M e dical M o nit or, deter mi nes 
t hat a s yste mic h y perse nsiti vit y reacti o n has occ urre d rel ate d t o I M P a d mi nistrati o n, t he 
partici pa nt s h o ul d be disc o nti n ue d. 
E xcl u de d T hera pe utic A ge nt 
If t he partici p a nt re q uires treat me nt wit h a n e xcl u de d t hera pe utic a ge nt a n d te m p orar y 
disc o nti n uati o n ca n n ot be met, I M P s h o ul d be disc o nti n ue d. 
If a partici pa nt disc o nti n ues fr o m t he trial pre mat urel y, reas o na ble eff orts s h o ul d be ma de t o 
perf or m t he E arl y Ter mi nati o n ( E T) visit pr oce d ures as s o o n as p ossi ble, a n d sc he d ule F oll o w- u p 
Visit pr oce d ures 4 wee ks after t he l ast d ose of A S N 5 1. 
7. 1. 2  
Te m p or ar y Disc o nti n u ati o n  
Dr u g h oli da ys of u p t o 4 da ys (i n a 1 2- wee k peri o d) are all o we d if t he parti ci pa nt e x peri e nces a n 
A E t hat necessitates a te m p orar y disc o nti n uati o n of trial i nter ve nti o n, base d o n cli nical j u d g me nt 
of t he I n vesti gat or. C o ns ult t he Me dical M o nit or s h o ul d t hese e ve nts occ ur. 
 
 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 8 
C o nfi de ntial 
A n y dr u g h oli da y ( pla n n e d or me dicall y i n dicat e d) e xcee di n g 7 c o nsec uti ve da ys i n d urati o n 
ma y res ult i n disc o nti n uati o n fr o m t he trial, at t he discreti o n of t he I n vesti gat or i n c o ns ultati o n 
wit h t he S p o ns or Me dical M o nit or. 
7. 1. 3
Rec h alle n ge
Ge nerall y, rec h alle n ge will n ot be all o we d.
7. 2
P artici p a nt Wit h dr a w al fr o m Tri al
I n acc or da nce wit h t he Declarati o n of Helsi n ki, partici pa nts ha ve t he ri g ht t o wit h dra w fr o m t he 
trial at a n y ti me f or a n y reas o n. T he S p o ns or s h o ul d be n otifie d of all partici pa nt wit h dra wals as 
s o o n as p ossi ble.
T he pri mar y reas o n f or t he partici pa nt’s wit h dra wal fr o m t he st u d y m ust be rec or de d i n t he 
partici pa nt’s e C R F.
Partici pa nts m ust u n der g o a n E T Visit u nless wit h dra wal is d ue t o deat h or wit h dra wal of 
c o nse nt. 
7. 3  
L ost t o F oll o w- u p 
If a partici pa nt misses o ne or m ore sc he d ule d visits, site pers o n nel will perf or m t he f oll o wi n g 
pri or t o disc o nti n uati o n as l ost t o f oll o w u p: 
 C o ntact t he partici pa nt t o resc he d ul e t he misse d visit a n d c o u nsel t he partici pa nt o n t he 
i m p orta nce of safet y m o nit ori n g 
 A mi ni m u m of 3 d oc u me nte d atte m pts t o c o ntact t he partici pa nt ( via tele p h o ne a n d 
writte n or electr o nic c o m m u nicati o n). T hese c o nt act atte m pts s h o ul d be d oc u me nte d i n 
t he partici pa nt’s me dical rec or d 
 S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, t hat partici pa nt will be c o nsi dere d t o 
ha ve wit h dra w n fr o m t he st u d y wit h a pri mar y reas o n of l ost t o f oll o w- u p.  
7. 4  
Tri al St o p pi n g R ules 
S h o ul d a n y of f oll o wi n g e ve nts occ ur, t he S R C, S p o ns or, a n d C o or di nati n g I n vesti gat or (al o n g 
wit h i n v ol ve d I n vesti gat or(s)) will c o n ve ne o n a d h oc  basis ( n ot t o e xcee d 5 b usi ness da ys after 
k n o wle d ge of t he e ve nt): 
 Deat h of a n y partici pa nt wit hi n 2 8 da ys of recei pt of I M P u nless i ne xtrica bl y relate d t o a n 
alter nati ve ca use 
 T w o or m ore p artici pa nts i n a gr o u p s h o w a 2 n d de gree A V bl oc k, or M o bit z t y pe 2 
c o nfir me d wit h 2 c o nsec uti ve E C Gs, or 3 r d de gree A V bl oc k 
 
 
 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
4 9 
C o nfi de ntial 
 H y’s la w is met f or o n e p artici pa nt, re q uiri n g all t he f oll o wi n g: 
o  A L T or A S T > 3 × U L N 
o  T B L > 2 × U L N 
o
A L P < 2 × U L N
o
N o ot her o b vi o us reas o n f or t he li ver i nj ur y, s uc h as viral he patitis, alc o h ol use, or 
a n ot her he p at ot o xic dr u g
A Es occ urri n g i n t he sa me S yste m Or ga n Class ( S O C; irres pecti ve of s e verit y or 
seri o us ness) lea di n g t o disc o nti n uati o n of trial i nter ve nti o n i n 3 or m ore partici pa nts.  
All a vaila ble i nf or mati o n re gar di n g t he e ve nt(s) will be e val uate d. Base d o n reas o na bl e cli nical 
j u d g me nt, a decisi o n will be ma de w h et her or n ot t he e ve nt(s) nee ds t o be f urt her c haracterize d 
wit h res pect t o pr o gressi o n a n d re versi bilit y; a n d w het her it is reas o na ble t o alter o n g oi n g 
treat me nt (criteria/ m o nit ori n g), rec o m me n d a pa use i n f urt her e nr oll me nt, or rec o m me n d 
st o p pi n g t he trial. 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 0 
C o nfi de ntial 
8
T RI A L A S S E S S M E N T S A N D P R O C E D U R E S
T he Sc he d ules of Acti vities f or t he Scree ni n g Peri o d a n d Treat me nt/ O bser vati o n Peri o ds, 
i ncl u di n g all o we d visit wi n d o ws, assess me nts, a n d pr oce d ures are detaile d i n:
Ta ble 1
Sc he d ule of Acti vities: Scree ni n g Peri o d
Ta ble 2
Sc he d ule of Acti vities: D o u ble- bli n d I nt er ve nti o n Peri o d
 Ta ble 3
Sc he d ule of Acti vities: L o n g- ter m E xte nsi o n Peri o d 
G ui deli nes f or st u d y pr oce d ures a n d assess me nts are disc usse d bri efl y i n t he f oll o wi n g secti o ns. 
C o ns ult t he St u d y Refere nce Ma n ual f or a d diti o nal i nf or mati o n, i ncl u di n g a rec o m me n de d or der 
of (s pecifi c) assess m e nts f or eac h visit. 
8. 1  
Scree ni n g/ B aseli ne Ass ess me nts 
Scree ni n g f or eli gi bilit y will be c o n d ucte d usi n g a tiere d a p pr oac h a n d ma y be c o m plete d o ver 
m ulti ple da ys (see Secti o n 4. 1 ). T he d urati o n of t he Scree ni n g Peri o d ma y be u p t o 8 wee ks t o 
all o w f or t he c o m pleti o n of assess me nts a n d f or t he e val uati o n of re q uire d l a b orat or y, E C G, a n d 
i ma gi n g tests. If a d diti o nal ti me is re q uire d t his will be c o nsi dere d a n d a p pr o ve d o n a case b y 
case basis b y t he S p o ns or Me dial M o nit or. 
A n o n-c o ntrast brai n M RI is perf or me d as t he fi nal test f or eli gi bilit y. If a brai n M RI or ta u P E T 
sca n is n ot a vaila ble wit hi n t he scree ni n g wi n d o w, t he Scree ni n g Peri o d ma y be e xte n de d, if all 
ot her eli gi bilit y criteria h a ve bee n met, b y u p t o 1 4 da ys t o pr o vi de a d diti o nal ti me f or t he 
i ma gi n g res ults t o bec o me a vaila ble. If t he scree ni n g wi n d o w is e xte n de d f or a n i n di vi d ual, 
re peat cli nical c he mistr y, he mat ol o g y, a n d c oa g ul ati o n pa nels. Res ults of t he re peate d la b orat or y
tests are t o be re vie we d b y t he I n v esti gat or or a q ualifie d desi g nee f or fi nal assess me nt of 
eli gi bilit y. 
T he I n vesti gat or m ust re vie w a n d c o nfir m eli gi bilit y pri or t o ra n d o mizati o n. O nce all eli gi bilit y 
criteria h a ve bee n met, t he Da y 1 visit s h o ul d be c o m plete d as s o o n as p ossi ble. 
8. 1. 1  
I nf or me d C o nse nt 
A n a b bre viat e d pres cree ni n g i nf or me d c o nse nt pr ocess ma y be utilize d t o c o n d uct i nitial 
prescree ni n g (i.e., d e n ote d Tier 1 a n d Tier 2 per Ta ble 1 ), if all o we d at t he i n vesti gati ve site. 
Prescree ni n g c o nse nt d oes n ot re q uire t he st u d y part ner. 
I nf or me d c o ns e nt f or t he f ull trial m ust be o btai ne d pri or t o perf or mi n g a n y Tier 3 a n d Tier 4 
scree ni n g pr o ce d ures per Ta ble 1 . I nf or me d c o nse nt will als o be o btai ne d fr o m a desi g nate d 
st u d y part ner pri or t o t he Da y 1 visit ( n ot re q uire d f or t he a b bre viate d prescree ni n g c o ns e nt). T he 
st u d y part ner s h o ul d be a n i n di vi d ual w h o is i n c o ntact wit h t he partici pa nt f or at least 1 0 h o urs 
eac h wee k, a n d a grees t o acc o m pa n y t he partici pa nt t o st u d y visits, or is a vaila ble b y tele p h o ne. 
 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 1 
C o nfi de ntial 
8. 1. 2
Me dic al Hist or y a n d De m o gr a p hics
Me dical hist or y i ncl u des acti ve c o n diti o ns, a n d a n y me dical ill nesses, dia g n oses, a n d s ur geries 
c o nsi dere d cli nicall y rele va nt b y t he I n vesti gat or.  
T he re vie w will als o i ncl u de a detaile d assess me nt of A D, i ncl u di n g: 
 date of s y m pt o m o nset a n d cli nical prese nt ati o n 
 date a n d met h o d of dia g n osis
 pri or a n d o n g oi n g treat m e nts, s ur geries, or t hera pi es 
pri or ( or c urre nt) partici p ati o n i n i nter ve nti o nal cli nical trials.
De m o gra p hic i nf or mati o n ( date of birt h, se x, race, et h nicit y) will be rec or de d at Scree ni n g (as 
all o we d b y l ocal re g ulati o ns).
8. 1. 3
P h os p h or yl ate d t a u- 2 1 7
Partici pa nts w h o meet Ti er 1 eli gi bilit y criteria, i ncl u di n g M M S E, s h o ul d pr ocee d t o Ti er 2 
(i ncl u des plas ma p Ta u 2 1 7). T he ti me a n d dat e of t he plas ma p Ta u 2 1 7 test s h o ul d be rec or de d o n 
t he La b Re q uisiti o n F or m. Partici pa nts ma y pr ocee d t o Tier 3 scree ni n g assess me nts o nce 
e vi de nce of q ualif yi n g p Ta u 2 1 7 is met.
Plas ma p h os p h or ylate d ta u 2 1 7 ( p Ta u 2 1 7) is a n o n-i n vasi ve dia g n ostic test s h o w n t o acc uratel y 
pre dict t he li keli h o o d f or a n i n di vi d ual t o ha ve Alz hei mer’s diseas e brai n a m yl oi d pat h ol o g y 
( As ht o n, Br u m et al. 2 0 2 4, T herria ult, W o o et al. 2 0 2 4). T he i nc or p orati o n of t he plas ma 
p Ta u 2 1 7 bi o mar ker i n A S N 5 1- 2 0 1 is i nte n de d t o i de ntif y earl y A D patie nts wit h e vi de nce of 
brai n a m yl oi d pat h ol o g y, t o facilitate trial scree ni n g, a n d t o e na ble t he recr uit me nt of di verse 
partici pa nts b y a v oi di n g tra diti o nal c ostl y a n d i n vasi ve dia g n ostic A D tests li ke a m yl oi d beta 
P E T i ma gi n g a n d C S F a m yl oi d testi n g.  
T he plas ma p Ta u 2 1 7 eli gi bilit y res ult is t o be re p orte d t o t he site i n t he u nits of p g/ m L. If t he 
plas ma p Ta u 2 1 7 res ult d oes n ot meet criteri a f or eli gi bilit y, t he partici pa nt is n ot t o c o m plete a n y 
a d diti o nal scree ni n g, a n d will be c o nsi dere d a scree n fail ure.    
F urt her d etails o n t he plas ma p Ta u 2 1 7 assa y ca n be f o u n d i n t he st u d y La b orat or y Ma n ual. 
8. 1. 4  
A p oli p o pr otei n E Ge n ot y pi n g 
Carriers of t h e a p oli p o pr otei n E ( A P O E) 
4 ge n ot y pe are at a n i ncreas e d ris k f or de vel o pi n g 
s p ora dic late- o ns et Alz hei mer’s disease a n d cere bral a m yl oi d a n gi o pat h y. A P O E 4 als o 
i nfl ue nces t he rate of cli nical pr o gressi o n of A D. A bl o o d sa m ple will be o btai ne d f or A P O E 
ge n ot y pi n g. A P O E stat us ma y be discl ose d t o t he I n vesti gat or a n d partici pa nt. 
8. 1. 5  
Hei g ht 
A sta n di n g hei g ht will be meas ure d a n d rec or de d usi n g a sta di o meter. 
 
 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 2 
C o nfi de ntial 
8. 1. 6
Vir ol o g y Scree n
Partici pa nts will be scree ne d f or he p atitis B s urface a nti ge n ( H bs A g) a n d he patitis C a nti b o d y.
8. 2  
Effi c ac y Assess me nts  
T he assess me nts a n d pr o ce d ures t o s u p p ort trial o bjecti ves a n d deri ve s pecifie d efficac y 
e n d p oi nts ( Secti o n 3 ) are briefl y descri be d i n t he f oll o wi n g secti o ns. Ti mi n g of assess me nts is 
s u m marize d i n Secti o n 1. 3 . C o ns ult t he St u d y Refere nce Ma n ual f or m ore i nf or mati o n.
8. 2. 1
C o g niti ve a n d F u ncti o n al Assess me nts 
W he ne v er perf or me d o n t he sa me da y, c o g niti ve a n d f u ncti o nal assess me nts s h o ul d be 
perf or me d b ef ore pr o ce d ures t hat ma y be stressf ul f or partici pa nts (e. g., M RI, P E T, bl o o d dra w, 
or C S F sa m pli n g).  
Raters i n v ol ve d i n a d mi nisteri n g t he c o g niti ve f u ncti o n assess me nts will be bli n de d t hr o u g h o ut 
t he trial. T o a v oi d iss ues wit h i nter-rater varia bilit y, efficac y ass ess me nts s h o ul d be a d mi nistere d 
b y t he sa me i n di vi d ual at t he i n vesti gati ve site at a p pr o xi matel y t he sa me ti me of da y t hr o u g h o ut 
t he d urati o n of partici p ati o n, w here p ossi ble.  
Data o btai ne d fr o m t he A D A S- C o g 1 3, M M S E, a n d C D R- S B will als o be use d t o deri ve t he 
A D C O M S. 
8. 2. 1. 1  
Mi ni- Me nt al St ate E x a m ( Versi o n 2) 
T he M M S E is a sta n dar dize d assess me nt of me nt al stat us a n d e val uates 7 c o g niti ve d o mai ns: 
orie ntati o n t o ti me a n d place; re gistrati o n a n d recall of 3 w or ds; atte nti o n a n d calc ulati o n; 
la n g ua ge; a n d vis ual c o nstr ucti o n ( F olstei n, F olst ei n et al. 1 9 7 5). T he i nstr u me nt is wi del y use d 
as a brief s cree n of c o g niti ve a bilities ( Hall, F orjaz et al. 2 0 1 5). A d mi nistrati o n ti me is 
a p pr o xi matel y 1 0 mi n utes. T he M M S E is als o a d mi nistere d d uri n g pre-s cree ni n g. 
8. 2. 1. 2
Alz hei mer's Dise ase Assess me nt Sc ale- C o g niti ve 1 3
T he m o difie d Alz hei mer's Disease Assess me nt Scale ( A D A S- C o g 1 3) ( M o hs, K n o p ma n et al. 
1 9 9 7) i ncl u des all ori gi nal A D A S- C o g ite ms a n d e xte n ds t he c o g niti ve d o mai ns a n d ra n ge of 
s y m pt o m se verit y wit h o ut a s u bsta ntial i ncreas e i n t he ti me re q uire d f or a d mi nistrati o n. T he 
A D A S- C o g 1 3 c o nsists of 1 3 ite ms t hat are c o m m o nl y i m paire d i n Alz hei mer’s Disease: 
orie ntati o n, ver bal me m or y, la n g ua ge, pra xis, dela ye d free recall, di git ca ncellati o n, a n d maze-
c o m pleti o n meas ures. Sc ores ra n g e fr o m 0 t o 8 5; hi g her sc ores i n dicate greater s e verit y. 
A d mi nistrati o n ti me is a p pr o xi matel y 3 0 mi n utes.
8. 2. 1. 3
Cli nic al De me nti a R ati n g – S u m of B o xes
T he Cli nical De me ntia R ati n g – S u m of B o xes ( C D R- S B) is a 5- p oi nt scale t o c haracterize 
6 d o mai ns of c o g niti ve a n d f u ncti o nal i m pair me nt si m ulta ne o usl y ( C ole y, A n drie u et al. 2 0 1 1 ). 
T he C D R is o btai ne d t hr o u g h se mi str uct ure d i nter vie ws of partici pa nts a n d st u d y part ners. T he 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 3 
C o nfi de ntial 
sc ore is use d t o c h aracterize a n d trac k t he le vel of i m pair me nt/ de me ntia. T he C D R- S B ca n be 
use d t o acc uratel y sta ge A D a n d discri mi nate bet wee n ver y earl y A D a n d t h ose wit h mil d 
c o g niti ve i m pair me nt ( O' Br ya nt, Wari n g et al. 2 0 0 8 ). 
8. 2. 2  
I m a gi n g Assess me nts 
Ac q uiri n g M RI i ma g es i n c o nj u ncti o n wit h 1 8F M K- 6 2 4 0 P E T is per mitte d if d ual P E T/ M RI 
i ma gi n g de vices are utilize d.
8. 2. 2. 1
1 8F M K- 6 2 4 0 P E T Sc a n 
P ositr o n e missi o n t o m o gra p h y ( P E T) i ma gi n g of N F T ta n gle pat h ol o g y wit h t he ta u tracer M K-
6 2 4 0 is a bi o mar ker met h o d t o meas ure t he effect of A S N 5 1 o n t he pr o gressi o n of A D ta u N F T 
pat h ol o g y. 
 
A d diti o nal i nf or mati o n is a vaila ble i n t he I ma gi n g Ma n ual.
8. 2. 2. 2  
V ol u metric M a g netic Res o n a nce I m a gi n g
A n M RI will be p erf or m e d as part of S cree ni n g. T he M RI s ca n will be s u b mitte d t o t he ce ntral 
M RI ve n d or f or fi nal det er mi nati o n of eli gi bilit y. Res ults of ce ntrall y rea d M RIs will be use d f or 
data a nal ysis a n d re p orts; rele va nt safet y a n d eli gi bilit y res ults will be c o m m u nicate d bac k t o t he 
site. V ol u metric M RI will be perf or m e d t o assess c ha n ges i n w h ole brai n, ve ntric ular a n d select 
re gi o n of i nterest a n d c ortical t hic k ness v ol u mes.
A d diti o nal i nf or mati o n is a vaila ble i n t he I ma gi n g Ma n ual. 
8. 3  
S afet y Assess me nts 
Assess me nts t o c haracterize safet y a n d t olera bilit y of A S N 5 1 are descri be d bel o w; ass ociate d 
safet y e n d p oi nts a n d pla n ne d a nal yses are descri be d i n Secti o n 3  a n d Secti o ns 9. 2 a n d 9. 6 , 
res pecti vel y. 
8. 3. 1  
P h ysic al E x a mi n ati o n  
C o m plete p h ysical e xa mi nati o ns will be perf or me d b y t he I n vesti gat or or desi g nate d lice nse d 
pr ofessi o nal ( M D, N P, R N, P A, or e q ui vale nt). 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 4 
C o nfi de ntial 
A c o m plete p h ysical e x a mi nati o n i ncl u des ge neral a p peara nce; hea d, e yes, ears, n ose, a n d t hr oat; 
a n d car di o v asc ular, d er m at ol o gic, res pirat or y, gastr oi ntesti nal, m usc ul os keletal, a n d ne ur ol o gic 
s yste ms (i ncl u de ne ur ol o gical assess me nt of cra ni al ner ves, m ot or, se ns ati o n, c o or di nati o n, 
refle x es, a n d gait). 
Fi n di n gs will be rec or d e d as n or mal/a b n or mal f or eac h para met er wit h a d diti o nal descri pti o n as 
i n dicate d.
8. 3. 1. 1  
Wei g ht
Wei g ht ( meas ure d i n kil o gra ms) a n d hei g ht (i n meters) will be meas ure d a n d rec or de d d uri n g 
eac h p h ysical e xa mi nati o n. Partici pa nts ma y re mai n i n cl ot hes.  
8. 3. 2
Vit al Si g ns 
Vital si g ns 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), res pirati o n rat e ( breat hs per mi n ute), a n d te m perat ure (° C). Meas ure me nts s h o ul d be 
o btai ne d after t he partici pa nt has bee n s eate d f or a mi ni m u m of 5 mi n utes, a n d bef ore a n y 
a d diti o nal assess me nts are c o m plete d.  
8. 3. 3  
Electr oc a r di o gr a m 
A r o uti ne 1 2-lea d E C G will be perf or me d after t he partici pa nt has reste d f or a mi ni m u m of 
5 mi n utes i n t he s u pi ne p ositi o n. All E C Gs m ust be perf or me d a n d rec or de d i n tri plicate. 
Tri plicate E C Gs s h o ul d be ta ke n at a p pr o xi matel y 1- mi n ute i nter vals. O btai n E C Gs, t o t he best 
of t he site a n d partici p a nts’ a bilit y, at a p pr o xi matel y t he sa me ti me of da y at eac h visit t o 
mi ni mize di ur nal variati o n. 
8. 3. 3. 1  
E C G P ar a meters  
E C G Para meters i ncl u d e P R i nter val, Q R S d urati o n, Q T i nter val, a n d Q Tc F. E C G a d mi nistrati o n 
pr oce d ures will be sta n dar dize d, a n d res ults will be rea d ce ntrall y b y q ualifie d pers o n nel bli n de d 
t o treat me nt assi g n me nt, ti me p oi nt, a n d partici pa nt data.  
E C Gs will be tra ns mitte d t o a n d i nter prete d b y a ce ntral ve n d or as n or mal or a b n or mal, wit h 
cli nical si g nifica nce d eter mi ne d b y t he I n vesti gat or.  
8. 3. 4  
Cli nic al L a b or at or y Assess me nts 
La b orat or y assess me nts will be use d r o uti nel y t o assess eli gi bilit y a n d I M P safet y i n all 
partici pa nts per T a ble 1 a n d Ta ble 2 , res pecti vel y. After i nitiati o n of I M P, cli nicall y si g nifica nt 
a b n or mal la b orat or y fi n di n gs m ust be d oc u me nte d as a n A E. Cli nical la b orat or y para meters t o be 
assesse d f or s afet y are liste d i n Secti o n 1 3. 2 . T he St u d y Refere nce Ma n ual pr o vi des details o n 
sa m ple c ollecti o n a n d pr ocessi n g.  
Fasti n g is n ot re q uire d; fasti n g stat us will be rec or de d.  
All la b orat or y assess me nts will be c o n d ucte d b y a ce ntral la b orat or y u nless ot her wise s pecifie d.  

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 5 
C o nfi de ntial 
8. 3. 4. 1
Ser u m C he mistr y
Bl o o d sa m ples will be o btai ne d f or ser u m c he mistr y para m eters (c o m pre he nsi ve meta b olic 
pa nel) as n ote d i n Secti o n 1 3. 2 .  
8. 3. 4. 2  
He m at ol o g y  
Bl o o d sa m ple will be o btai ne d f or h e mat ol o g y para meters (c o m plete bl o o d c o u nt wit h 
differe ntial) as n ote d i n Secti o n 1 3. 2 .  
8. 3. 4. 3  
Uri n al ysis 
A uri nal ysis pa nel ( di pstic k wit h micr osc o pic e xa mi nati o n o n p ositi ves) will be perf or me d wit h 
para meters as n ote d i n Secti o n 1 3. 2 . 
8. 3. 4. 4  
C o a g ul ati o n P a nel 
A c oa g ulati o n pa n el will be perf or me d wit h para m eters as n ote d i n Secti o n 1 3. 2 . 
8. 3. 4. 5  
Ser u m H or m o ne M ar kers
Ser u m h or m o ne mar kers will be o btai ne d as o utli ne d i n Secti o n 1 3. 2 .  
8. 3. 5  
S uici d al I de ati o n a n d Be h a vi or Ris k M o nit ori n g
8. 3. 5. 1  
C ol u m bi a S uici de Se verit y R ati n g Sc ale 
T o pr os pecti vel y assess s uici dal i deati o n a n d be ha vi or, t he C- S S R S will be a d mi nistere d b y site 
pers o n nel. T he “ Scree n Versi o n” q uesti o n naire will be a d mi nistere d at Scree ni n g. T he “ Si nce 
Last Visit” q uesti o n naire will be a d mi nistere d at all s u bse q ue nt visits. De pe n di n g o n t he 
c o g niti ve state of t he partici pa nt, s o me q uesti o ns wit hi n t he C- S S R S ma y be dee me d 
i na p pr o priate b y t he I n vesti gat or a n d/ or site pers o n nel a n d ma y be o mitte d.  
I nte grati o n of i nf or m ati o n fr o m ot her s o urces (e. g., fa mil y, frie n ds, or si g nifica nt ot hers; st u d y 
part ners or h ealt h pr ofessi o nals; h os pital or e mer ge nc y r o o m rec or ds) ma y be e val uat e d a n d 
i nte grate d i nt o t he assess me nt as a p pr o priat e. 
Res p o nses will be re vie we d d uri n g t he visit; if e mer ge nt s uici dal i deati o n or be ha vi or is 
i n dicate d, t he I n vesti gat or will pr o m ptl y e val uate t he partici pa nt t o e ns ure pr o per ma na ge me nt 
a n d partici pa nt safet y. 
8. 4  
A d v erse E ve nts a n d Seri o us A d vers e E ve nts 
Defi niti o ns, rec or di n g, f oll o w- u p, a n d re p orti n g re q uire me nts f or A Es a n d S A Es f oll o w r o uti ne 
p har mac o vi gila nce practice are pr o vi de d i n Secti o n  1 2.  
Trial-s pecifi c g ui da nce is pr o vi de d i n t he f oll o wi n g s u bsecti o ns. 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 6 
C o nfi de ntial 
8. 4. 1
Ti me Peri o d a n d Fre q ue nc y f or C ollecti n g A d verse E ve nt I nf or m ati o n
All A Es, S A Es, A E SI, a n d part ner pre g na ncies occ urri n g d uri n g t he pr ot oc ol-s pecifie d 
ti mefra mes (T a ble 7 ) will be assesse d a n d re p ort e d per g ui deli nes pr o vi de d i n Secti o n 1 2 .
T a ble 7 
A d verse E ve nt Re p orti n g Peri o ds 
E v e nt T y pe 
Re p orti n g Peri o d
A d diti o n al Re q uire me nts
A E/ S A E d uri n g Scree ni n g 
Peri o d
Date of partici pa nt i nf or m e d c o nse nt 
t hr o u g h start of Da y 1 Visit ( pri or t o first 
d ose of I M P) 
Re p ort as A E/ S A E o nl y if relate d t o 
trial-s pecifie d pr o ce d ure ( m e dical 
hist or y ot h er wise) 
Treat me nt-e mer ge nt A E/ S A E 
First d ose of I M P t hr o u g h 4 wee ks p ost 
fi nal d ose of I M P 
Re p ort S A Es o utsi d e of re p orti n g 
p eri o d if assesse d as relate d t o I M P 
A E SI 
First d ose of I M P t hr o u g h 4 wee ks p ost 
fi nal d ose of I M P
Re p ort A E SI o utsi d e of re p orti n g 
p eri o d if assesse d as relate d t o I M P
Pre g n a n c y of part ner
Date of partici p a nt i nf or me d c o nse nt 
t hr o u g h 4 wee ks p ost fi n al d ose of I M P 
O btai n c o nse nt t o f oll o w part ner 
pre g na n c y 
A E = a d v erse e ve nt; A E SI = a d verse e ve nt of s p ecial i nterest; I M P = i n v esti g ati o n al me dici n al pr o d u ct; 
S A E = seri o us a d verse e ve nt. 
Cli nicall y si g nifica nt c ha n ges fr o m baseli ne i n a n y safet y or cli nical la b orat or y para met er will be 
rec or d e d as A Es or S A Es, if dee me d a p pr o priate b y t he I n vesti gat or. 
8. 4. 2  
I de ntif yi n g A d verse E ve nts a n d Seri o us A d verse E ve nts 
At eac h visit, partici pa nts will be as ke d a b o ut a n y ne w or o n g oi n g A Es si nce t he pre vi o us visit. 
S p o nta ne o us re p orti n g of A Es a n d S A Es will be e nc o ura ge d. 
8. 4. 3  
A d verse E ve nts of S peci al I nterest 
E ve nts defi ne d bel o w are c o nsi dere d A E SI f or t his trial a n d s h o ul d be re p orte d f oll o wi n g S A E 
re p orti n g pr oce d ures ( Secti o n 1 2. 3 ). 
8. 4. 3. 1  
Dr u g I n d uce d P R Pr ol o n g ati o n 
Dr u g-i n d uce d P R pr ol o n gati o n wit h M o bitz t y pe 1 sec o n d de gree A V bl oc k ma y be a ris k 
ass ociate d wit h A S N 5 1. T E A Es wit h t he f oll o wi n g Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) Preferre d T er ms ( P Ts) will be c o nsi dere d a n A E SI f or t his trial: 
 A V bl oc k first de gree, A V bl oc k sec o n d de gree M o bitz t y pe I, A V bl oc k sec o n d de gree 
M o bitz t y pe II, a n d A V bl oc k t hir d de gree.  
8. 4. 3. 2  
Dr u g I n d uce d Li ver I nj ur y 
T he p ote ntial f or dr u g-i n d uce d li ver i nj ur y will be m o nit ore d usi n g assess me nts of li ver f u ncti o n 
via ser u m c he mistr y at re g ular i nter vals. If t he A S T or A L T is > 1 × U L N b ut < 2 × U L N, t he 
I n v esti gat or s h o ul d deter mi ne w het her m ore fre q ue nt testi n g is warra nte d. If t he A S T or A L T is 
 2 × U L N wit h or wit h o ut bilir u bi n or al kali ne p h os p hatase ele vati o n, b ut d o n ot meet t he 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
5 7 
C o nfi de ntial 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
5 8 
C o nfi de ntial 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
5 9 
C o nfi de ntial 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
6 0 
C o nfi de ntial 
8. 1 0
I m m u n o ge nicit y
N ot a p plica ble.
8. 1 1
Me di c al Res o urce Utili z ati o n a n d He alt h Ec o n o mics
N ot a p plica ble.

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
6 1 
C o nfi de ntial 
9
S T A TI S TI C A L C O N SI D E R A TI O N S
A ge neral descri pti o n of t he statistical met h o ds pla n ne d t o a nal yze t he safet y a n d preli mi nar y 
efficac y of t he I M P is o utli ne d bel o w. T he a nal ys es s pecifie d i n t his pr ot oc ol will be e x pa n de d i n 
t he Statistical A nal ysis Pla n ( S A P) t o i ncl u de a detaile d descri pti o n of t he a nal yses. T he S A P 
will be fi nalize d a n d a p pr o ve d pri or t o data base l oc k.  
Trial data will be re p orte d usi n g s u m mar y ta bles, fi g ures, a n d data listi n gs. Descri pti ve statistics 
will be use d t o s u m marize t he data. F or c o nti n u o us varia bles, t he mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m will be pr o vi de d. F or discrete data, i nci de nce a n d perce nta ges 
will be pr o vi de d. Statistical tests will be 1-si de d at t he al p ha le vel of 0. 1 0, u nless state d 
ot her wise. P- val ues will be use d descri pti vel y a n d will ha ve n o i nfere ntial val ue. All p- val ues 
will be re p orte d t o t he 3r d deci mal place. S u m mar y ta bles will i ncl u de t he data fr o m t he A S N 5 1 
 gr o u ps c o m bi ne d, i.e., Place b o a n d A S N 5 1 
 f or t he 
D B a n d L T E peri o ds, res pecti vel y. 
Baseli ne f or all cli nical l a b orat or y e val uati o ns, vital si g ns meas ure me nts, a n d 1 2-lea d E C Gs will 
be defi ne d as t he last e val uati o n bef ore I M P a d mi nistrati o n. T he ti mi n g of eac h 
pr ot oc ol-s pecifi e d assess me nt is pr o vi de d i n t he Sc he d ules of Acti vities ( Secti o n 1. 3 ). 
T w o sets of a nal ys es will be c o n d ucte d.  T he first set of a nal yses will be c o n d ucte d after all 
partici pa nts ha ve h a d t he o p p ort u nit y t o c o m plete t he Wee k 2 4 assess me nt or ha ve disc o nti n ue d 
t he st u d y ( pri mar y a n al ysis Secti o ns 9. 1  t hr o u g h 9. 7 ). T he sec o n d set of a nal yses will be 
c o n d ucte d w h e n all parti ci pa nts ha ve ha d t he o p p ort u nit y t o c o m plete t he L T E or disc o nti n ue d 
t he st u d y ( Secti o n 9. 8 ). 
F or e n d p oi nts c ollecte d o nl y o nce p ost- baseli ne, c ha n ges fr o m baseli ne will be a nal yze d usi n g a n 
a nal ysis of c o varia nce ( A N C O V A) m o del t hat i ncl u des t he cate g orical effects of A P O E 4 stat us, 
use of A D me dicati o n, treat me nt gr o u p, a n d t he c o nti n u o us c o variate of t he baseli ne val ue of t he 
varia ble bei n g a nal yze d. T he o ne-si de d p- val ue (t-test o n least s q uares mea ns at Wee k 2 4) a n d 
t w o-si de d 8 0 %, a n d 9 0 % c o nfi de nce li mits will be ta b ulate d. T he m o del will als o i ncl u de t he 
ra n d o mizati o n stratificati o n fact ors (i. e., A P O E 4 stat us a n d use of A D m e dicati o n).  
F or e n d p oi nts c ollecte d m ulti ple ti mes p ost- baseli ne, c ha n ges fr o m baseli ne will be a nal yze d 
usi n g a restricte d li keli h o o d- base d mi xe d effects m o del f or re peate d meas ures ( M M R M). C ha n ge 
fr o m baseli ne will be fit as t he de pe n d e nt varia bl e. I n de pe n de nt varia bles i ncl u de d i n t he a nal ysis 
m o del will be t he cate g orical fi xe d effects of A P O E 4 stat us, use of A D me dicati o n, treat me nt 
gr o u p, a n d t he treat me nt b y Visit i nteracti o n, al o n g wit h t he c o nti n u o us c o variates of t he baseli ne 
val ue of t he varia ble b ei n g a nal yze d a n d its i nteracti o n wit h Visit. T he m o del will als o i ncl u de 
t he ra n d o mizati o n stratifi cati o n fact ors (i.e., A P O E 4 stat us a n d use of A D me dicati o n). Wit hi n 
partici pa nt err ors will be m o dele d usi n g a n u nstr uct ure d c o varia nce matri x. If t his a nal ysis fails 
t o c o n verse, h eter o ge n e o us T oe plitz, heter o ge ne o us a ut o-re gressi ve, a n d heter o ge ne o us 
c o m p o u n d s y m metric str uct ures will be teste d i n t he liste d or der. T he first str uct ure t o yiel d 

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c o n ver ge n ce will be c o nsi dere d t he pri mar y a nal ysis. T he o ne-si de d p- val ue (t-test o n least 
s q uares mea ns at Wee k 2 4) a n d t w o-si de d 8 0 %, a n d 9 0 % c o nfi de nce li mits will be ta b ulate d. 
A nal ysis of P K para met ers ma y be des cri be d a n d s u m marize d i n a se parat e d oc u me nt o utsi de t he 
c o nte xt of t he S A P. 
Data a n al ysis will c o m pl y wit h pri nci ples set f ort h i n t he I nter nati o nal C o nfere nce o n 
Har m o nisati o n (I C H) E 9 G ui deli ne a n d I C H E 9( R 1) G ui deli ne. 
9. 1  
A n al ysis Sets 
T he n u m ber of p artici pa nts ra n d o mize d w h o c o m plete eac h trial Peri o d a n d w h o disc o nti n ue t he 
trial will be s u m marize d. Reas o ns f or disc o nti n uati o n will be s u m marize d. T he f oll o wi n g 
a nal ysis sets will be e m pl o ye d:
9. 1. 1
M o difie d I nte nt-t o- Tre at
T he m o difie d I nte nt-t o- Treat ( mI T T) A nal ysis Set will i ncl u de all partici pa nts w h o recei ve d at 
least o ne d ose of I M P. Partici pa nts will be i ncl u de d i n t he assi g ne d d ose c o h ort/ar m, re gar dless 
of t he act ual treat me nt recei ve d.  
9. 1. 2  
S afet y A n al ysis Set 
T he Safet y A n al ysis Set c o nsists of all partici pa nts w h o recei ve at least o ne d ose of I M P. T his 
a nal ysis set will be use d f or t he a n al yses of all safet y e n d p oi nts. Partici pa nts will be i ncl u de d 
base d o n t he act ual d ose le vel recei ve d. 
9. 1. 3  
Per Pr ot oc ol Set 
T he Per Pr ot oc ol A nal ysis Set will c o nsist of partici pa nts w h o di d n ot ha ve maj or pr ot oc ol 
vi olati o ns wit h re gar d t o e ntr y criteri a, a d here nce t o I M P d osi n g, disall o we d c o nc o mita nt 
me dicati o ns, a n d c o m pleti o n of st u d y visits a n d pr oce d ures. A detaile d list of partici pa nts wit h 
maj or pr ot oc ol vi olati o ns will be deter mi ne d a n d d oc u me nte d pri or t o u n bli n di n g.  
9. 1. 4  
P h ar m ac o ki netic A n al ysis Set 
T he P K A nal ysis Set will c o nsist of all partici pa nts fr o m w h o m plas ma or C S F sa m ples f or t he 
a nal ysis of A S N 5 1 were o btai ne d a n d w h o di d n ot ha ve maj or pr ot oc ol de viati o ns t hat w o ul d 
c o nf o u n d i nter pretati o n of P K a nal ysis.
9. 2  
A n al ysis S u p p orti n g Pri m ar y O bjecti ve - S afet y 
All safet y a nal yses will be c o n d ucte d i n t he Safet y A nal ysis Set.  

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A d verse E ve nts
Safet y will be e val uat e d b y e xa mi ni n g i nci de nce, t y pe, ca usalit y, a n d se verit y of T E A Es, 
i ncl u di n g S A Es a n d disc o nti n uati o n d ue t o T E A E.  
A d verse e ve nts will be cl assifie d acc or di n g t o t he latest a vaila ble Me d D R A versi o n, t o t he S O C 
a n d P T le vels. Treat me nt-e mer g e nt A Es ( hereafter referre d t o as A Es) are defi ne d as t h ose wit h 
o nset after t he first d ose of ra n d o mize d treat me nt i nter ve nti o n at Da y 1 or, if occ urri n g pri or t o 
a d mi nistrati o n of t he first d ose at Da y 1, w orse ne d after a d mi nistrati o n of t hat first d ose.
T he A E listi n gs will i n dicate w h et her t he e ve nt le d t o te m p orar y i nterr u pti o n of or per m a ne nt 
wit h dra wal of st u d y treat me nt. A n o verall s u m mar y will be prese nte d w hi c h gi ves t he n u m ber 
a n d perce nta ge of partici pa nts wit hi n eac h d ose gr o u p i n t he safet y p o p ulati o n t hat e x perie nce d 
a n y A E, e x perie nce d a n y treat me nt-relate d A E, te m p oraril y i nterr u pte d or per ma ne ntl y 
disc o nti n ue d treat me nt d ue t o a n A E, e x perie nce d a n S A E, a n d t hat die d.
I nci de nce of A d verse E ve nts 
T he n u m ber a n d p erce nta ge of partici p a nts e x peri e nci n g o ne or m ore A E wit hi n a Me d D R A 
S O C a n d P T wit h o ut re gar d t o i nte nsit y, relati o ns hi p, or seri o us ness will be ta b ulate d.  
Ta bles will als o be pre p are d t o dis pla y e ve nts b y S O C, P T, a n d ma xi m u m i nte nsit y or cl osest 
relati o ns hi p t o treat me nt. 
A gl ossar y listi n g t hat s h o ws t he ver bati m ter ms assi g ne d t o eac h S O C a n d P T will be pr o vi de d. 
Se verit y of A d verse E ve nts 
A s u m mar y of A Es b y se verit y will be prese nte d i n a ta ble b y i nci de nce of occ urre nce. T he 
se verit y t hat will be pres e nte d re prese nts t he m ost e xtre me se verit y ca pt ure d o n t he e C R F pa ge. 
T he se verit y will be ass esse d b y t he I n vesti gat or as “ Mil d,” “ M o derate,” or “ Se vere.” If a 
partici pa nt re p orts m ulti ple occ urre nces of t he sa m e A E (at t he P T wit hi n t he S O C le vel a n d at 
t he S O C le vel), o nl y t he m ost se vere will be prese nte d. 
Rel ati o ns hi p of A d verse E ve nts t o St u d y Tre at me nt 
A s u m mar y of A Es b y relati o ns hi p t o st u d y treat me nt will be prese nte d i n a ta ble b y i nci de nce of 
occ urre nce. T he relati o ns hi ps will be c ollecte d bas e d o n t he I n vesti gat or’s deter mi nati o n of 
li keli h o o d t hat st u d y treat me nt c o ul d ha ve ca use d t he e ve nt. T he p ossi ble relati o ns hi ps are 
“ U nrelat e d”, “ U nli kel y”, “ P ossi bl y,” “ Pr o ba bl y,” a n d “ Defi nitel y.” F or t he s u m mar y of 
relati o ns hi ps, t he cate g ories of “ P ossi bl y,” “ Pr o ba bl y,” a n d “ Defi nitel y” will be c o m bi ne d t o 
f or m a si n gle cat e g or y of “ Relate d.” I n t he A E rel ati o ns hi p ta ble, if a partici pa nt re p orts m ulti ple 
occ urre nces of t he sa me A E (at t he P T wit hi n S O C le vel a n d at t he S O C le vel), o nl y t he 
occ urre nce wit h t he greatest ca usal relati o ns hi p will be prese nte d. A Es t hat are missi n g 
relati o ns hi p data will be prese nte d i n t he s u m mar y ta ble as “ Relate d” b ut will be prese nte d i n t he 
data listi n g wit h a missi n g relati o ns hi p. 

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A d verse E ve nts Le a di n g t o Tre at me nt Disc o nti n u ati o n
All A Es f or w hic h t he acti o n “ St u d y treat me nt disc o nti n ue d” is rec or de d will be ta b ulate d.
Seri o us A d verse E ve nts
T he data f or S A Es will be prese nt e d i n a listi n g.  If a s uffici e nt n u m ber of S A Es are re p orte d, t he 
se verit y a n d relati o ns hi p ta bles ca n be s u bs ette d o n t he S A E s u b p o p ulati o n. 
De at h
T he data f or partici pa nt d eat hs, if a n y, will be pres e nte d i n a listi n g. 
C ha n ges fr o m bas eli ne i n cli nical la b orat or y test val ues, p h ysical a n d ne ur ol o gic e xa mi nati o n 
res ults, vital si g ns meas ure me nts, a n d 1 2-lea d E C Gs will be liste d a n d/ or s u m marize d t hr o u g h 
t he e n d of trial. 
9. 2. 1  
A d verse E ve nts 
T he ori gi nal ter ms use d i n t he e C R Fs b y i n vesti gat ors t o i de ntif y A Es will be c o de d usi n g t he 
latest a vaila ble Me d D R A versi o n. T he n u m ber a n d perce nt a ge of partici pa nts wit h T E A Es will 
be s u m marize d b y treat m e nt gr o u p. S u m maries will be de vel o pe d f or t h ose partici pa nts w h o 
disc o nti n ue d treat me nt d ue t o a n A E or w h o e x perie nce d a life-t hreate ni n g or 
treat me nt-e mer ge nt S A E. 
9. 2. 2  
St atistic al M o del, H y p ot hesis a n d Met h o d of A n al ysis 
Gi ve n t he e x pl orat or y nat ure of t he st u d y, n o f or m al statistical h y p ot hesis will be perf or me d. 
N o mi nal p- val ues f or s afet y e n d p oi nts will be re p orte d f or des cri pti ve p ur p oses. A nal yses will be 
base d o n Fis her’s E xact Test. 
9. 2. 3  
H a n dli n g of Missi n g D at a
A d verse e ve nts wit h missi n g or partial o nset date will be treate d as T E A Es u nless t he partial 
o nset date or e n d d ate of t he e ve nt is c o m plete e n o u g h t o i n dicate t hat t he e ve nt starte d or 
res ol ve d pri or t o t he first a d mi nistrati o n of t he st u d y i nter ve nti o n, i n w hic h case it will be 
d oc u me nte d i n me dical hist or y. If A E gra de or rel ati o ns hi p is missi n g i n a nal yses of gra de a n d 
ca usalit y, t he missi n g gra de will be set t o se vere, a n d relati o ns hi p will be set t o relate d f or 
ta b ulati o n p ur p oses. Pr oce d ures f or i m p utati o n of missi n g or partial A E start a n d e n d dates will 
be s pecifie d i n t he S A P.  
Ha n dli n g of missi n g data f or sec o n d ar y efficac y e n d p oi nts is descri be d i n Secti o n 9. 3 . 
9. 3  
A n al ysis S u p p orti n g Ke y Sec o n d ar y O bjecti ves 
T he f oll o wi n g fa mil y of e n d p oi nts t hat eac h ass ess ta u pat h o p h ysi ol o g y will be use d t o 
deter mi ne pr o of- of-c o nce pt. T hese e n d p oi nts will be teste d t o get her t o c o ntr ol t he fa mil y- wise 
err or rate at t he desire d al p ha of 0. 1 0. 

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Plas ma c o nce ntrati o ns of A S N 5 1 will be a nal yze d usi n g n o nc o m part me ntal met h o ds t o 
deter mi ne t he rele va nt P K para met ers. T he A S N 5 1 c o nce ntrati o ns a n d P K para meters will be 
liste d a n d s u m marize d b y st u d y da y (a n d ti me p oi nt, as a p pr o priate) a n d d ose gr o u p. I n di vi d ual 
a n d mea n c o n ce ntrati o n pr ofiles o ver ti me will be pr o vi de d b y partici pa nt/ d ose gr o u p a n d st u d y 
da y. 
Details o n t he P K a nal ys es will be i n t he S A P t hat will be fi nalize d bef ore data base l oc k. A n y 
i nte grate d a n al yses acr oss st u dies, s uc h as a p o p ul ati o n P K a nal ysis will be prese nte d se paratel y 
fr o m t he mai n C S R. 
9. 5  
A n al ysis of E x pl or at or y O bjecti ves  
A nal yses of e x pl orat or y bi o mar kers a n d efficac y e n d p oi nts will i ncl u de differe nce bet wee n 
treat me nts i n mea n c h a n ge fr o m baseli ne t o Wee k f or a d diti o nal C S F bi o mar kers (i ncl u di n g b ut 
 
A bs ol ute  val ues a n d c h a n ges fr o m baseli ne will be s u m marize d usi n g des cri pti ve statistics b y 
visit (a n d ti me p oi nt) a n d b y d ose gr o u p. S u p p orti ve pl ots will be ge nerat e d as a p pr o priat e. 
Details will be s pecifie d i n t he S A P w hic h will be fi nalize d bef ore data base l oc k f or t he D B 
I nter ve nti o n peri o d.  
9. 6  
A d diti o n al S afet y A n al ysis 
Descri be d i n Secti o n 9. 2  a n d f urt her deli neate d i n s u bsecti o ns bel o w. 
9. 6. 1
P h ysic al E x a mi n ati o n 
Baseli ne p h ysical e xa mi n ati o n will be s u m marize d i n a fre q ue nc y ta ble b y b o d y s yste m t o 
c haracteri ze t he e nr olle d Safet y A nal ysis Set. S hift ta bles will be prese nte d f or eac h b o d y s yste m 
s h o wi n g t he c ha n ge fr o m baseli ne i n stat us bet wee n N or mal/ A b n or mal at eac h assess me nt. 
9. 6. 2  
B o d y Wei g ht 
Baseli ne b o d y wei g ht will be s u m marize d usi n g t he descri pti ve statistics o utli ne d i n Secti o n 9 t o 
c haracteri ze t he e nr olle d Safet y P o p ulati o n.  C ha n ges fr o m baseli ne will be descri be d usi n g t he 
descri pti ve statistics f or c o nti n u o us o utc o mes. I n a d diti o n, p ote ntiall y cli nicall y mea ni n gf ul 
c ha n ges will be e v al uate d usi n g t he descri pti ve statistics f or cate g orical e n d p oi nts descri be d. T he 
defi niti o ns of cli nicall y mea ni n gf ul c ha n ges will be pr o vi de d i n t he S A P. 
   
    
 
 

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9. 6. 3
Vit al Si g ns
Vital si g ns i ncl u de bl o o d press ure, h eart rate, res pirati o n rate a n d b o d y t e m perat ure. Vital si g ns 
data will be liste d a n d s u m marize d usi n g descri pti ve statistics f or a bs ol ute val ues, a n d c ha n ges 
fr o m baseli ne b y visit a n d d ose gr o u p. I n a d diti o n, p ote ntiall y cli nicall y mea ni n gf ul c ha n ges will 
be e val uat e d usi n g t he descri pti ve statistics f or cat e g orical e n d p oi nts. T he defi niti o ns of 
cli nicall y mea ni n gf ul c ha n ges will be pr o vi de d i n t he S A P. 
9. 6. 4  
Electr oc a r di o gr a m P ar a meters 
E C G para meters of i nterest i ncl u de P R i nter val, Q R S d urati o n, Q T i nter val, a n d Q Tc F. Baseli ne 
val ues will be s u m marize d b y descri pti ve statistics t o c haracterize t he Safet y P o p ulati o n. 
C ha n ges fr o m bas eli ne will be s u m marize d usi n g t he descri pti ve statistics descri be d i n Secti o n 9 
f or c o nti n u o us o utc o mes. I n a d diti o n, p ote ntiall y cli nicall y mea ni n gf ul c ha n ges will be e val uate d 
usi n g t he descri pti ve statistics f or cate g orical e n d p oi nts. T he defi niti o ns of cli nicall y mea ni n gf ul 
c ha n ges will be pr o vi d e d i n t he S A P. 
9. 6. 5  
Cli nic al L a b or at or y P a nels 
Cli nical la b orat or y pa nels i ncl u de ser u m c he mistr y, he mat ol o g y, a n d uri nal ysis, as well as 
c oa g ulati o n a n d ser u m h or m o ne mar kers. Baseli ne val ues will be s u m mari ze d b y descri pti ve 
statistics or fre q ue n c y ta bles, w here a p pr o pri ate, t o c haracteri ze t he Safet y A nal ysis Set. C ha n ges 
fr o m baseli ne will be s u m marize d usi n g t he descri pti ve statistics descri be d i n Secti o n 9 f or 
c o nti n u o us o utc o mes. I n a d diti o n, t he c o u nt a n d perce nt a ge of partici pa nts wit h at least o ne 
cli nicall y si g nifica nt a b n or mal val ue b y visit a n d p ost treat me nt will be s u m marize d b y d ose 
gr o u p. Data listi n gs of a b n or malities will als o be pr o vi de d as a p pr o priate. 
9. 6. 6  
C ol u m bi a S uici de Se verit y R ati n g Sc ale 
Baseli ne a n d p ost- baseli n e res ults f or t he C- S S R S will pr o vi de d i n patie nt listi n gs. T he c o u nt a n d 
perce nt a ge of p artici pa nts wit h s uici dal be ha vi or a n d s uici dal i deati o n (as assesse d b y C- S S R S) 
will be s u m marize d b y visit a n d d ose gr o u p. 
9. 7  
Ot her A n al ysis 
De m o gra p hics (a ge, g e n der, race, et h nicit y, a n d re gi o n) a n d ot her baseli ne disease 
c haracteristics, i ncl u di n g A P O E 4 ge n ot y pe, will be s u m marize d usi n g des cri pti ve statistics. 
A nal yses of bi o mar k ers, p har mac o g e n o mic, a n d P K data will be descri be d i n se parate re p orts 
o utsi de t he c o nte xt of t he S A P.  

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9. 8
A n al yses f or L o n g-ter m E xte nsi o n
F or t he L T E, t h e i nci de n ce a n d se v erit y of A Es o ver t he place b o-c o ntr olle d a n d l o n g-ter m 
e xte nsi o n peri o ds of t he st u d y will be s u m marize d fr o m L T E baseli ne t o t he e n d of treat me nt b y 
D B I nter ve nti o n Peri o d treat me nt assi g n me nt a n d o verall. Ot her s afet y para meters will be 
s u m marize d as des cri be d f or t he D B I nter ve nti o n Peri o d pri mar y a nal ysis i n Secti o n 9. 6 . 
A nal yses f or t he L T E will use t he sa me met h o ds as descri be d f or t he D B I nter ve nti o n Peri o d 
a nal ysis i n Secti o ns 9. 3  t hr o u g h 9. 5 . S u m maries will be pr o vi de d f or c ha n ges fr o m L T E bas eli ne 
b y D B treat me nt assi g n me nt a n d o verall. F or partici pa nts s witc hi n g fr o m place b o t o acti ve 
treat me nt, a t w o-sl o pe ra n d o m c oeffici e nt m o del will be use d t o c o m pare t he c ha n ge i n 
bi o mar kers a n d efficac y assess me nts fr o m D B baseli ne t o Wee k 2 4 (e. g., e n d of D B I nter ve nti o n 
peri o d) a n d fr o m t he L T E baseli ne (e. g., Wee k 2 4) t o Wee k 6 0 (e n d of L T E). 
A f ull descri pti o n of L T E a nal yses will be pr o vi de d i n t he S A P. 
9. 9  
Ti mi n g of A n al ysis 
Re vie ws of safet y, P K, a n d cli nical efficac y data will be perf or me d as s pecifie d i n Secti o n 4. 1 .  
T he pri mar y a n al ysis will be c o n d ucte d f oll o wi n g c o m pleti o n of t he D B I nter ve nti o n Peri o d.
T he fi nal a n al ysis will be c o n d ucte d at t he e n d of t he L T E; res ults will be prese nte d i n a fi nal 
cli nical st u d y re p ort.
9. 1 0  S a m pl e Size Deter mi n ati o n  
T he sa m ple size was n ot deri ve d statisticall y, b ut e m piricall y deter mi ne d base d o n t he safet y 
o bjecti ves of t his d ose ra n gi n g trial. Wit h N = 2 1 per ar m (acc o u nti n g f or a 2 0 % dr o p o ut rate), 
t he r ule of 3 s u g gests t hat t he pr o ba bilit y of o bser vi n g at least 1 occ urre nce of i n di vi d ual A Es is 
at least 9 5 % if t he i nci de nce rat e is great er t ha n 1/( N/ 3), w hic h is a p pr o xi m atel y 1 4 %. 
F or t he plas ma a n d C S F ke y sec o n dar y bi o mar ker e n d p oi nts ( C S F p Ta u 2 1 7, plas ma p Ta u 2 1 7, 
a n d C S F t Ta u), t he st u d y has 9 0 % p o wer at a o ne-si de d al p ha of 0. 1 t o o bser ve a bas eli ne-
a dj uste d c ha n ge fr o m bas eli ne of 2 0 % relati ve t o place b o ass u mi n g a 2 5 % sta n dar d de viati o n 
(e. g., C o he n’s d of 0. 8). A differe nce of 2 0 % fr o m place b o has bee n o bser ve d f or C S F t Ta u a n d 
p Ta u wit h t he O G A i n hi bit or T hia met G i n t he r T g 4 5 1 0 ta u m o del ( Wa n g, S mit h et al. 2 0 1 8 ) a n d 
is a si milar effect size t o w hat has d oc u me nte d aft er 2 4- wee ks of treat me nt of earl y A D patie nts 
wit h a m yl oi d l o weri n g t hera pies li ke leca ne m a b a n d d o na ne ma b ( Sall o wa y 2 0 2 3 , va n D yc k, 
S wa ns o n et al. 2 0 2 3 ). 
9. 1 1  P r ot oc ol De vi ati o ns 
A n y de viati o ns i n t he st u d y pr ot oc ol will be d oc u me nte d a n d re p orte d i n acc or da nce wit h I R B 
re q uire me nts. N o d e viati o n fr o m t he pr ot oc ol will be i m ple me nte d wit h o ut t he pri or re vie w a n d 
a p pr o val of t he I R B/I E C e xce pt w h ere it ma y be necessar y t o eli mi nate a n i m me diate hazar d t o a 

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researc h partici pa nt. I n s uc h case, t h e de viati o n will be re p orte d t o t he I R B/I E C as s o o n as 
p ossi ble.

A S N 5 1- 2 0 1
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C o nfi de ntial 
1 0
G E N E R A L C O N SI D E R A TI O N S: R E G U L A T O R Y, E T HI C A L, A N D 
T RI A L O V E R SI G H T 
1 0. 1  Re g ul at or y a n d Et hic al C o nsi der ati o ns 
T he trial will be c o n d uct e d i n acc or da nce wit h t he c o nse ns us et hical pri nci ples deri ve d fr o m 
i nter nati o nal g ui deli nes i ncl u di n g t he Declarati o n of Helsi n ki, a p plica ble I C H G o o d Cli nical 
Practice ( G C P) G ui deli nes, a n d a p plica bl e l ocal l a ws a n d re g ulati o ns. S h o ul d a c o nflict arise, t he 
I n v esti gat or will f oll o w w hic he ver l a w or g ui deli ne aff or ds t he greater pr otecti o n t o t he 
i n di vi d ual partici pa nt.   
T he pr ot oc ol, pr ot oc ol a me n d me nts, I nf or me d C o nse nt F or m (I C F), I B, a n d ot her rele va nt 
d oc u me nts (e. g., a d v ertis e me nts) m ust be s u b mitte d t o a n I nstit uti o nal Re vie w B oar d (I R B)/ 
I n d e pe n de nt Et hics C o m mittee (I E C) b y t he I n vesti gat or a n d re vie we d a n d a p pr o ve d b y t he 
I R B/I E C bef ore t he trial is i nitiate d.
Pr ot oc ol a me n d me nts re q uire I R B/I E C a p pr o val bef ore i m ple me ntati o n of c ha n ges t o t he trial 
desi g n, e xce pt f or c ha n g es necessar y t o miti gate a n i m me diate hazar d t o partici pa nts. 
1 0. 2  C o m mittees 
1 0. 2. 1  
Et hics C o m mittees 
T he I R B/I E C m ust be a pr o perl y c o nstit ute d b oar d or c o m mittee o perati n g i n acc or da nce wit h 
2 1 C F R Part 5 6, "I nstit uti o nal Re vie w B oar ds."  T he pr ot oc ol, a n y pr ot oc ol a me n d me nts, a n d t he 
ass ociate d I C Fs m ust be re vie we d a n d a p pr o ve d b y t he I R B/I E C pri or t o scree ni n g of a n y 
p ote ntial partici pa nt. I M P ma y n ot be s hi p pe d t o t he I n vesti gat or u ntil S p o ns or, or its desi g nee 
has recei ve d a c o p y of t h e letter or certificate of a p pr o val fr o m t he I R B/I E C f or t he pr ot oc ol a n d 
a n y pr ot oc ol a me n d me nts, as a p plica ble. 
All partici pa nt recr uit me nt a n d/ or a d vertisi n g i nf or mati o n m ust be s u b mitte d t o t he I R B/I E C a n d 
S p o ns or or its desi g nee f or re vie w a n d a p pr o val pri or t o i m ple me ntati o n. I R B/I E C a p pr o val of 
a n y pr ot oc ol a me n d me nts m ust be recei ve d bef ore a n y of t he c ha n ges o utli ne d i n t he 
a me n d me nts are p ut i nt o effect, e xce pt w he n t he a me n d me nt has bee n e nacte d t o pr otect 
partici pa nt safet y.  I n s uc h cases, t he c hair of t he I R B/I E C s h o ul d be n otifie d i m me diatel y, a n d 
t he a me n d me nt f or war d e d t o t he I R B/I E C f or re vi e w a n d a p pr o val. 
1 0. 2. 2  
S afet y Re vie w C o m mittee 
T he S R C will be f or me d t o re vie w safet y a n d t olera bilit y data a n d will meet o n a n a d h oc basis if 
re q ueste d b y o n e of t he me m bers or if trial st o p pi n g r ules are m et as o utli ne d i n Secti o n 7. 4 . T he 
S R C will be c o m prise d of t he S p o ns or’s Me dical M o nit or, a p har mac o vi gila nce m o nit or, a n d t he 
trial I n v esti gat or. T he S R C ma y, base d o n t he nat ure, fre q ue nc y, a n d/ or se verit y of a n a d verse 
e ve nt rec o m me n d pr ot oc ol m o dificati o n(s), d ose s us pe nsi o n, d ose ter mi nati o n or st u d y 

A S N 5 1- 2 0 1
Asce ne ur o n S A
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C o nfi de ntial 
ter mi nati o n. A Safet y Re vie w C o m mittee c harter will pr o vi de f ull g ui da nce o n t he f u ncti o n a n d 
practices t o b e f oll o we d b y t he S R C.
1 0. 3  I nf or me d C o nse nt Pr ocess 
A p pr o priate f or ms f or d o c u me nti n g writte n i nf or me d c o nse nt will be re vi e we d a n d a p pr o ve d b y 
t he S p o ns or or its desi g nee pri or t o i n vesti gat or s u b missi o n t o t he I R B/I E C. T he S p o ns or or its 
desi g nee m ust recei ve a c o p y of t he I R B/I E C's a p pr o val of t he I C F bef ore t he s hi p me nt of I M P
t o t he trial site.
T he met h o d of o btai ni n g a n d d oc u me nti n g i nf or m e d c o nse nt a n d t he c o nte nts of t he I C F will 
c o m pl y wit h I C H G C P g ui deli nes, t he re q uire m e nts of 2 1 C F R Part 5 0, “ Pr otecti o n of H u ma n 
S u bjects,” t he Healt h I ns ura nce P ort a bilit y a n d Acc o u nta bilit y Act ( HI P A A) re g ulati o ns, a n d all 
ot her a p plica ble re g ulat or y re q uire m e nts.     
T he I n vesti gat or is res p o nsi ble f or o btai ni n g writte n i nf or me d c o ns e nt fr o m eac h p ote ntial trial 
partici pa nt a n d st u d y part ner pri or t o t he c o n d uct of a n y trial pr oce d ures. T he si g ne d I C F m ust be 
retai ne d i n eac h partici pa nt's trial file a n d be accessi ble t o t he trial m o nit or. Partici pa nts will be 
gi ve n a c o p y of t he si g n e d I C F a n d will be pr o vi de d wit h a n y ne w i nf or mati o n d uri n g t he c o urse 
of t he trial t hat mi g ht affect t heir c o nti n ue d partici pati o n i n t he trial. 
If t he pr ot oc ol is a me n d e d a n d t he I C F is re vise d, eac h partici pa nt will be re q uire d t o pr o vi de 
writte n i nf or me d c o ns e nt a gai n usi n g t he re vise d I C F. 
1 0. 4  D at a Pr otecti o n 
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y t he s p o ns or. A n y partici pa nt rec or ds, datasets, 
or bi ol o gical sa m ples t hat are tra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier o nl y; 
partici pa nt na mes or a n y i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be 
tra nsferre d. T h e partici pa nt will be i nf or me d t hat t heir pers o nal st u d y-relate d data will be use d 
b y t he S p o ns or i n acc or d a nce wit h l ocal data pr ot ecti o n la w. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici p a nt w h o will be re q uire d t o gi ve c o nse nt f or t heir data t o be use d as 
descri be d i n t he I C F. 
T he partici pa nt will be i nf or me d t hat t heir me dical rec or ds ma y be e xa mi ne d b y Cli nical Q ualit y 
Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y t he S p o ns or, b y a p pr o priate 
I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
1 0. 5  E arl y Site Cl os ure or Tri al Ter mi n ati o n 
T he I n vesti gat or will ha v e t he f oll o wi n g res p o nsi bilities:
 Pr o vi di n g o versi g ht of trial c o n d uct at t he site 
 A d heri n g t o 2 1 C F R, I C H g ui deli nes, I R B/I E C re q uire me nts, E ur o pea n Cli nical Trials 
Directi ve (if a p plica ble), a n d all ot her a p plica ble l ocal re g ulati o ns 
 
 

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C o nfi de ntial 
 Pr o m ptl y n otif yi n g t he I B R/ E C of si g nifica nt safet y fi n di n gs 
 Pr o vi di n g trial stat us u p dates t o t he I B R/ E C as re q uire d 
 Pr o vi de t he S p o ns or wit h re q uire d i nf or mati o n t o c o m plete fi na nci al certifi cati o n or 
discl os ure state me nt as re q uire d b y re g ulat or y a ut h orities. 
S h o ul d t he I n vesti gat or n ot c o m pl y wit h t hese res p o nsi bilities, t he site ma y be cl ose d. 
T he S p o ns or or desi g nee reser v es t he ri g ht t o cl ose a site or ter mi nate t he tri al at a n y ti me. 
Li ke wise, a n I n v esti gat or has t he ri g ht t o i nitiate site cl os ure. Reas o ns f or earl y site cl os ure of a 
st u d y site b y S p o ns or or I n v esti gat or i ncl u de b ut are n ot li mite d t o:
 Fail ure t o f oll o w I n v esti gat or res p o nsi bilities, as liste d a b o ve
 I n a de q uat e recr uit me nt b y t he I n vesti gat or 
 Disc o nti n uati o n of I M P de vel o p me nt. 
F oll o wi n g ter mi nati o n or s us pe nsi o n, t he S p o ns or a n d I n vesti gat or will e ns ure t he a p pr o priate 
et hics c o m mittee(s) a n d re g ulat or y a ut h orities are i nf or me d, a n d partici pa nts are n otifie d a n d 
tra nsiti o ne d, as a p pr o pri ate. 
 
 
 
 
 
 

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Asce ne ur o n S A
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C o nfi de ntial 
1 1
G E N E R A L C O N SI D E R A TI O N S: RI S K M A N A G E M E N T A N D 
Q U A LI T Y A S S U R A N C E 
1 1. 1  Q u alit y T oler a nce Li mits 
Q ualit y t olera nce li mits will be pre defi ne d b y t he S p o ns or a n d/ or its desi g nee i n a st u d y 
ma na ge me nt pla n. T h e pla n will i ncl u de a descri pti o n of m o nit ori n g a p pr oac hes a n d t he pr ocess 
f or ha n dli n g n o n-c o m plia nce wit h t he pr ot oc ol or I C H G C P g ui deli nes. 
1 1. 2
D at a Q u alit y Ass ur a nce
M o nit ori n g a n d a u diti n g pr oce d ures de vel o pe d b y S p o ns or a n d/ or its desi g nee will be 
i m ple me nte d t o e ns ure c o m plia nce wit h F D A a n d I C H G C P g ui deli nes. T he f oll o wi n g pri nci ples 
will be set f ort h t o e ns ure q ualit y of trial data:
T he S p o ns or ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals (e. g.,
C o ntract Researc h Or g a nizati o ns)
 T he S p o ns or or desi g nee is res p o nsi ble f or t he ma na ge me nt of trial data i ncl u di n g q ualit y 
c o ntr ol 
T he S p o ns or ( or desi g nee) will de vel o p a m o nit ori n g pla n t o detail met h o ds, 
res p o nsi bilities, a n d re q uire me nts (i ncl u di n g ha n dli n g of n o nc o m plia nce iss ues) 
 All partici pa nt data relati n g t o t he trial will be rec or de d o n t he e C R F u nless electr o nicall y 
tra ns mitte d directl y t o t he S p o ns or or desi g nee (e. g., la b orat or y dat a) 
 A n y c ha n ges t o t he d ata will be ma de o nl y b y S p o ns or-a ut h orize d users; c ha n ges will be 
ca pt ure d i n a n electr o ni c a u dit trail
 T he I n vesti gat or is res p o nsi ble f or verif yi n g t he acc urac y of data e ntere d at t he trial site 
 M o nit ors will e val uate t he site t o ass ure t he safet y a n d ri g hts of partici pa nts are bei n g 
pr otecte d; a n d t he trial is bei n g c o n d ucte d i n acc or da nce wit h t he c urre nt pr ot oc ol, trial 
a gree m e nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 
1 1. 3  S o urce D at a 
 T he I n vesti gat or will mai ntai n acc urate d oc u m e ntati o n (s o urce data) t hat s u p p orts 
i nf or mati o n e ntere d i n t h e e C R F
 T he I n vesti gat or m ust per mit trial-relate d m o nit ori n g, a u dits, I R B/I E C re vi e w, a n d 
re g ulat or y a g e nc y i ns pecti o ns, a n d pr o vi de direct access t o s o urce data d oc u me nts 
 M o nit ors will verif y s o urce data t o c o nfir m data e ntere d i nt o t he e C R F b y a ut h orize d site 
pers o n nel are acc urate, c o m plete, a n d verifi a ble  
 
 
 
 
 
 
 
 
 
 

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C o nfi de ntial 
 Rec or ds a n d d o c u me nts pertai ni n g t o t he c o n d uct of t his trial (i ncl u di n g ori gi nal si g ne d 
I C Fs), m ust be ret ai ne d b y t he I n vesti gat or f or 2 5 years after trial c o m pleti o n u nless l ocal 
re g ulati o ns or i nstit uti o nal p olicies re q uire a l o n ger ret e nti o n peri o d 
 N o rec or ds ma y be d estr o ye d d uri n g t he ret e nti o n peri o d wit h o ut t he writte n a p pr o val of 
t he S p o ns or.
 Writte n n otificati o n t o t he S p o ns or is re q uire d pri or t o a n y tra nsfer of rec or ds t o a n ot her 
l ocati o n or part y. 
1 1. 4
C o nti n ge nc y 
Pl a ns 
D uri n g 
P u blic 
He alt h 
E mer ge ncies, 
N at ur al 
Dis asters, or Ot her N ati o n al E mer ge ncies 
If a n i n vesti gati o nal site is affecte d b y a p u blic healt h e mer ge nc y, nat ural disaster, or ot her 
nati o nal e mer ge n c y d uri n g t he trial, t he S p o ns or will c o or di nate wit h t he I n vesti gat or/I nstit uti o n 
t o e ns ure t he safet y of tri al partici pa nts i n acc or da nce wit h G C P a n d a vaila ble re g ulat or y 
g ui da nce d oc u m e nts.  
T he S p o ns or will see k t o mai ntai n t he i nte grit y of t he trial, h o we ver mi ni mizati o n of ris k t o trial 
partici pa nts will be c o nsi dere d para m o u nt.
I n s u c h u n prece de nte d sit uati o ns, c o nti n ge ncies m a y i ncl u de:
 S us pe nsi o n of trial recr uit me nt
 Alter nate pr o visi o ns f or pr o vi di n g i n vesti gati o nal pr o d uct a n d s u p pl y c hai n ma na ge me nt 
 M o dificati o ns t o m o nit ori n g pr ocesses a n d pr oce d ures. 
T he S p o ns or will c o ns ult wit h I n v esti gat ors a n d I R B/I E Cs i n a ti mel y ma n ner t o deter mi ne 
acti o ns nee de d t o pr otect acti ve trial partici pa nts. H o we ver, c ha n ges t o pr otect t he safet y of trial 
partici pa nts ma y be i m ple me nte d wit h o ut pri or I R B/I E C a p pr o val, s uc h as: 
 Dela ye d a d mi nistrati o n of I M P (i.e., e xte n de d scree ni n g peri o ds) u ntil safet y f oll o w- u p 
ma y be c o n d uct e d  
 Alter nate met h o ds f or safet y assess me nts (e. g., tel e p h o ne, tele me dici ne, re m ote l ocati o n 
f or la b orat or y sa m ple ac q uisiti o n a n d/ or pr ocessi n g) 
 P ost p o ne me nt of certai n visits a n d/ or assess me nts dee me d less critical 
 E xce pti o ns t o pr ot oc ol-s pecifie d visit wi n d o ws. 
 
 
 
 
 
 
 
 
 
 
 

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C o nfi de ntial 
1 2
A P P E N DI X: A D V E R S E E V E N T S A N D S E RI O U S A D V E R S E 
E V E N T S – D E FI NI TI O N S S E V E RI T Y A N D C A U S A LI T Y 
1 2. 1  Defi niti o ns 
1 2. 1. 1
A d verse E ve nt Ass oci ate d wit h St u d y Pr oce d ures
A pr oce d ure-relate d A E is a n A E c o nsi dere d b y t he I n vesti gat or t o be relate d t o a pr oce d ure 
re q uire d b y t he pr ot oc ol (i.e., te m p orall y ass ociate d or k n o w n ris k of t he pr oce d ure). 
1 2. 1. 2  
A d verse E ve nt 
A n A E is a n y u nt o war d me dical occ urre nce ass ociate d wit h t he use of a dr u g i n h u ma ns, w het her 
or n ot c o nsi dere d dr u g relate d. T he ter m “a d verse e ve nt” c o ul d i ncl u de a n y of t he f oll o wi n g 
e ve nts t hat de vel o p or i n creas e i n se verit y d uri n g t he c o urse of t he trial. E xa m ples i ncl u de: 
 A n y si g n, s y m pt o m, or p h ysical e xa mi nati o n fi n di n g t hat w orse ns i n nat ure, se verit y, or 
fre q ue n c y c o m pare d t o b aseli ne irres pecti ve of ass ociati o n wit h t he c o n diti o n u n der st u d y
 A n y cli nicall y si g nifica nt la b orat or y a b n or malit y or la b orat or y a b n or malit y t hat re q uires 
me dicati o n or h os pitalizati o n 
 Reacti o ns t o I M P i ncl u di n g t h ose occ urri n g as a res ult of a n o ver d os e, a b use, wit h dra wal 
p he n o me na, se nsiti vit y, or t o xicit y 
 C o nc urre nt ill ness 
 I nj ur y or acci de nt. 
C o n diti o ns prese nt pri or t o e nr oll me nt are c o nsi dere d Me dical Hist or y. Pre-e xisti n g c o n diti o ns 
s h o ul d be re p orte d as a T E A E if t here is a c ha n ge i n t he fre q ue nc y, i nte nsit y, or t he c haract er of 
t he c o n diti o n. 
1 2. 1. 3
Seri o us A d verse E ve nt
A n S A E is a n A E t hat:
res ults i n deat h
is c o nsi dere d life t hreate ni n g
re q uires i n- p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n
res ults i n persiste nt/si g nifica nt disa bilit y/i nca pacit y
res ults i n a c o n ge nital a n o mal y/ birt h defect; or 
ot her me diall y i m p orta nt seri o us me dical e ve nt.
 
 
 
 
 
 
 
 
 
 
 

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C o nfi de ntial 
1 2. 2
Rec or di n g of A d vers e E ve nts a n d Seri o us A d verse E ve nts
1 2. 2. 1
Se verit y 
T he i nte nsit y of eac h A E s h o ul d be gra de d as mil d, m o derate, se vere, or p ote ntiall y 
life-t hreat e ni n g, usi n g t he f oll o wi n g cate g ories:
Mil d : as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; 
i nter ve nti o n ge nerall y n ot i n dicate d
 M o derate : mi ni mal, l ocal, or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g 
a ge-a p pr o priate i nstr u me ntal acti vities of dail y li vi n g
Se vere : i nterr u pts n or m al dail y acti vities a n d ge nerall y re q uires s yste mic dr u g t hera p y or 
ot her treat me nt; us uall y i nca pacitati n g.
Ma y als o be c o nsi dere d p ote ntiall y life-
t hreate ni n g or re q uire ur ge nt i nter ve nti o n t o pre ve nt per ma ne nt i m pair me nt, persiste nt 
disa bilit y, or deat h
Se verit y is n ot c o nsi dere d a g ui de f or defi ni n g re g ulat or y re p orti n g o bli gati o ns. 
1 2. 2. 2  
C a us alit y
T he I n vesti gat or s h o ul d c o ns ult t he I B w he n assessi n g relati o ns hi p t o I M P a n d c o nsi der all 
p ossi ble eti ol o gies f or t he A E. T he I n vesti gat or will assess t he ca usalit y of t he A E t o st u d y 
pr oce d ure or I M P as f oll o ws: 
Attri b uti o ns f or “ U nrelat e d” e v e nts: 
 U nrel ate d:  t he A E is cle arly n ot rel ate d t o t he I M P/ pr oce d ure, be y o n d a reas o na bl e 
d o u bt
 U nli kel y Relate d:  t he A E is d o u btf ull y relate d t o t he I M P/ pr oce d ure 
Attri b uti o ns f or “ Relate d ” e ve nts: 
 P ossi bl y Relate d: t he A E ma y be relat e d t o t he I M P/ pr oce d ure 
 Pr o ba bl y Relate d: t he A E is li kel y relate d t o t he I M P/ pr oce d ure 
 Defi nitel y Relate d: t he A E is clearl y relate d t o t he I M P/ pr oce d ure
F or t he p ur p os es of re p orti n g t o re g ulat or y a ge ncies, A Es dee m e d as Defi nitel y, Pr o ba bl y or 
P ossi bl y Relate d will be c o nsi dere d Relat e d a n d t h ose dee me d U nrelat e d or U nli kel y Relate d 
will be c o nsi dere d U nrel ate d. 
A Es liste d as relate d are c o nsi dere d t o ha ve a s us pecte d “reas o na ble ca usal relati o ns hi p” t o t he 
I M P/i nter ve nti o n (I C H E 2 A). T he e x pressi o n "reas o na ble ca us al relati o ns hi p" is mea nt t o 
c o n ve y i n ge neral t hat t h ere are facts (e vi de nce) or ar g u me nts t o s u g gest a ca usal relati o ns hi p.
 
 
 
 
 
 
 
 

A S N 5 1- 2 0 1
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C o nfi de ntial 
1 2. 2. 3
F oll o w U p
All A Es (i.e., a n y ne w or w orse ni n g i n se verit y or fre q ue nc y of a pree xisti n g c o n diti o n) wit h 
o nset after t he p artici pa nt si g ns c o nse nt f or trial partici pati o n m ust be pr o m ptl y d oc u me nte d o n 
t he A E e C R F via t he electr o nic data ca pt ure s yste m. Details of t he A E m ust i ncl u de se verit y, 
relati o ns hi p t o I M P, d urati o n, a n d o utc o me.  
Partici pa nts w h o disc o nti n ue d ue t o treat me nt-e mer ge nt S A E will be m o nit ore d f or s afet y as 
s pecifie d i n Secti o n 8. 4. 1 .
F oll o w- u p is re q uire d f or all partici pa nts wit h A Es u ntil t he e ve nt has bee n res ol ve d or t he 
c o n diti o n has sta bilize d. Cli nicall y si g nifica nt a b n or mal la b orat or y val ues s h o ul d be f oll o we d 
u ntil re peat tests ret ur n t o n or mal, sta bilize, or are n o l o n ger cli nicall y si g nifica nt. 
1 2. 2. 4  
O utc o me 
T he o utc o me of a n A E ass ociate d will be assesse d as f oll o ws:
 Rec o vere d/ Res ol ve d: t he e ve nt has i m pr o ve d or rec u perat e d 
 N ot rec o vere d/ N ot Res ol ve d: t he e ve nt has n ot i m pr o ve d or rec u perate d
 Rec o vere d/res ol ve d wit h se q uelae: t he partici pa nt rec u perate d b ut retai ne d pat h ol o gical 
c o n diti o ns res ulti n g fr o m t he pri or disease or i nj ur y 
 Fatal: ter mi nati o n of life as a res ult of a n A E  
 U n k n o w n: n ot k n o w n, n ot o bser ve d, n ot rec or de d 
1 2. 3  Re p orti n g of Seri o us A d verse E ve nts 
S A Es a n d A E SIs m ust be re p orte d t o t he S p o ns or ( or desi g nee) wit hi n 2 4 h o urs of t he 
k n o wle d ge of t he o cc urre nce.  
A n S A E re p ort will be c o m plete d as t h or o u g hl y as p ossi ble i ncl u di n g all a vaila ble details a b o ut 
t he e ve nt a n d t he si g nat ure of t he I n v esti gat or. T he S A E f or m will be u p date d w he n a d diti o nal 
i nf or mati o n is recei v e d.
A deat h occ urri n g d uri n g t he trial m ust be re p orte d t o S p o ns or or its desi g nee wit hi n 2 4 h o urs of 
k n o wle d ge of t he d eat h w het her or n ot it is c o nsi dere d treat me nt rel ate d.   
T he I n vesti gat or als o m ust n otif y t he I R B/I E C of t he occ urre nce of t he S A E, i n writi n g, as s o o n 
as is practica bl e a n d i n acc or da n ce wit h I R B/I E C re q uire me nts a n d l ocal la w.  A c o p y of t his 
n otificati o n m ust be pr o vi de d t o t he S p o ns or or its desi g nee.
1 2. 4  Re g ul at or y Re p orti n g Re q uire me nts f or Seri o us A d verse E ve nts 
I n v esti gat ors are re q uire d t o re p ort a n y ur ge nt safet y matters t o S p o ns or or its desi g nee wit hi n 2 4 
h o urs. T he I n vesti gat or will n otif y t he I R Bs/I E Cs of S A Es a n d ur ge nt safet y matters, i n 
 
 
 
 
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
7 9 
C o nfi de ntial 
acc or d a nce wit h I R B/I E C re q uire me nts a n d l ocal la ws a n d re g ul ati o ns. A c o p y of t his 
n otificati o n m ust be pr o vi de d t o t he S p o ns or or its desi g nee.
S A Es t hat are u ne x p ecte d a n d c o nsi dere d relat e d t o t he a d mi nistrati o n of t he I M P will be 
re p orte d b y t he S p o ns or ( or desi g nee) t o t he a p pr o priate re g ul at or y a ut h orities a n d ot her 
i n vesti gat ors i n t he f or m of a n e x pe dite d s afet y re p ort wit hi n 1 5 cale n dar da ys after recei vi n g 
i nf or mati o n o n t he S A E. T he i n vesti gat ors will n otif y t heir re vie wi n g I R B/I E C a n d ot her 
c o m mittee(s) as re q uire d b y i nstit uti o nal p olicies. 
1 2. 5
Seri o us a n d U ne x pecte d A d verse Re acti o n Re p orti n g
Fatal a n d life-t hreate ni n g s us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) will be 
s u b mitte d n o later t ha n 7-cale n d ar da ys of first k n o wle d ge of t he e ve nt a n d f oll o w- u p 
i nf or mati o n s u b mitte d wit hi n a n a d diti o nal ei g ht ( 8) da ys. T he S p o ns or will re p ort a n y 
u ne x pecte d life t hreat e ni n g or fatal S A Es t hat are c o nsi dere d relate d t o t he I M P t o t he 
a p pr o priate re g ulat or y a ut h orities wit hi n 7 da ys of recei vi n g t he i nf or mati o n.

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 0 
C o nfi de ntial 
1 3
A P P E N DI X:  D E FI NI TI O N S A N D S U P P O R TI N G O P E R A TI O N A L 
D E T AI L S 
1 3. 1  C o ntr ace pti o n a n d Pre g n a nc y Testi n g 
1 3. 1. 1
Defi niti o ns Rel ate d t o C hil d be ari n g P ote nti al
Fe males of C hil d beari n g P ote ntial: 
F or t he p ur p ose of t his d oc u me nt, a w o ma n is c o nsi dere d of c hil d beari n g p ote ntial ( W O C B P), i.e., 
fertile, 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 u nless per ma ne ntl y sterile. 
Per ma ne nt sterilizati o n met h o ds i ncl u de h ysterect o m y, bilateral sal pi n gect o m y a n d bilateral 
o o p h orect o m y.
N ote: W O C B P are e xcl u de d fr o m partici pati o n i n t his trial.
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical 
ca use. A hi g h f ollicle sti m ulati n g h or m o ne ( F S H) le vel i n t he p ost me n o pa usal ra n ge ma y be use d 
t o c o nfir m a p ost- me n o pa usal state i n w o me n n ot usi n g h or m o nal c o ntrace pti o n or h or m o nal 
re place me nt t hera p y. H o we ver, i n t he a bse nce of 1 2 m o nt hs of a me n orr hea, a si n gle F S H 
meas ure me nt is i ns ufficie nt. 
Fertile Males:
F or t he p ur p ose of t his d oc u me nt, a ma n is c o nsi dere d fertile after p u bert y u nless per ma ne ntl y 
sterile b y bilateral orc hi dect o m y. 
1 3. 1. 2  
C o ntr ace pti o n
Use of hi g hl y effecti ve c o ntrace pti o n is re q uire d as s pecifie d i n Secti o n 5. 3 . 
C o ntrace pti o n met h o ds wit h a fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y 
are c o nsi d ere d hi g hl y effecti ve. S uc h met h o ds i ncl u de: 
 C o m bi ne d (estr o ge n a n d pr o gest o ge n) 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 1: 
 
Oral
 
I ntra va gi nal 
 
Tra ns der m al
 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 1: 
 
Oral
 
I njecta ble
 
I m pla nta bl e2  
 I ntra uteri ne de vice (I U D) 2  
 
 
 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 2 
C o nfi de ntial 
1 3. 3  C o u ntr y/ Re gi o n- S pecifi c Differe nces 
W here differe nces i n re q uire me nts ca n n ot be rec o ncile d, c o u ntr y/re gi o n-s pecific a m e n d me nts or 
a d de n da will be iss ue d, if necessar y, or liste d bel o w wit h refere nce t o rel e va nt pr ot oc ol secti o n. 
1 3. 4  P ri or Pr ot oc ol A me n d me nts 
T his pr ot oc ol has n ot bee n pre vi o usl y a me n de d.

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 3 
C o nfi de ntial 
1 4
A P P E N DI X:  R E F E R E N C E S

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
8 4 
C o nfi de ntial 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 5 
C o nfi de ntial 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 6 
C o nfi de ntial 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 7 
C o nfi de ntial 
1 5
A P P E N DI X:  G L O S S A R Y O F T E R M S
A D 
Alz hei mer's Disease
A D A S- C o g 1 3
Alz hei mer's Disease Assess m e nt Scale- C o g niti ve 1 3
A E
A d verse e ve nt 
A E SI
A d verse e ve nt of s peci al i nterest
A L P 
Al kali ne p h os p hatase 
A L T
Ala ni ne a mi n otra nsferase
A N C O V A
A nal ysis of c o varia nce
A S N 5 1 
A S N 5 1 (i n vesti gati o nal m e dici nal pr o d uct; O-li n ke d-
- N-
acet yl gl uc osa mi ni dase i n hi bit or)
A S T 
As partate a mi n otra nsferase 
C B D
Ca n na bi di ol
C D R 
Cli nical De m e nti a Rati n g 
C D R- S B
Cli nical De m e nti a Rati n g – S u m of B o xes 
C ma x  
Ma xi m u m c o nce ntrati o n
C S F 
Cere br os pi nal fl ui d
C- S S R S
C ol u m bia S uici de Se verit y Rati n g Scal e
D B 
D o u ble- bli n d 
E C G
Electr ocar di o gra m 
e C R F
Electr o nic case re p ort f or m(s)
E T 
Earl y Ter mi nati o n 
E U
E ur o pea n U ni o n
F D A
F o o d a n d Dr u g A d mi nistrati o n, U nit e d St ates
F S H 
F ollicl e-sti m ulati n g h or m o ne
G C P
G o o d Cli ni cal Practice
H Bs A g
He patitis B vir us s urface a nti ge n
I B
I n vesti gat or’s Br oc h ure 
I C F 
I nf or me d C o nse nt F or m
I C H 
I nt er nati o nal C o nfere nce o n Har m o nisati o n of Tec h nical Re q uire me nts f or 
Re gistrati o n of P har mace uti cals f or H u ma n Us e
I E C 
I n de pe n de nt Et hics C o m mitt ee
I M P 
I n vesti gati o nal me dici nal pr o d uct 
I R B
I nstit uti o nal Re vie w B oar d 
I V
I ntra ve n o us 
I V D R 
I n vitr o dia g n osti c re g ul ati o n
I W R S 
I nt eracti ve we b res p o nse s yst e m
L H
L utei nizi n g h or m o ne
L P 
L u m bar p u nct ure
L S 
Least s q uares 
L T E 
L o n g-t er m E xte nsi o n 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 8 
C o nfi de ntial 
M CI
Mil d c o g niti ve i m pair me nt
Me d D R A
Me dical Dicti o nar y f or Re g ulat or y Acti vities 
M M R M
Mi xe d effects m o del f or re peate d meas ures
M M S E 
Mi ni Me ntal St ate E xa m
M RI
Ma g netic res o na nce i ma gi n g
N F L 
Ne ur ofila me nt li g ht c hai n
N F T 
Ne ur ofi brillar y ta n gles 
NI A- A A 
Nati o nal I nstit ute o n A gi n g a n d t he Alz hei mer’s Ass oci ati o n
O G A,  
O- Glc N Acas e
O-li n ke d-
- N-acet yl gl uc osa mi ni das e 
P E T 
P ositr o n e missi o n t o m o gra p h y
P K
P har m ac o ki netic(s)
P T 
Preferre d Ter m
Q Tc 
C orrecte d Q T i nter val (a dj uste d f or t he partici pa nt’s heart rat e 
Q Tc F
Q T i nter val c orrecte d usi n g Fri dericia’s f or m ula
R OI
Re gi o n of i nterest 
S A E 
Seri o us a d vers e e ve nt 
S A P 
Statistical A nal ysis Pla n
S R C 
Safet y Re vie w C o m mittee
S U S A R
S us pect e d u ne x pecte d seri o us a d verse reacti o ns
S U V R 
Sta n dar dize d u pta ke val ue rati o
T B L 
T otal bilir u bi n le vel
T E A E 
Treat me nt-e mer ge nt a d verse e ve nt
U L N 
U p per li mit of n or mal 
W O C B P 
W o ma n (fe male) of c hil d beari n g p ot e nti al 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
8 9 
C o nfi de ntial 
1 6
A P P E N DI X:  R E S T RI C T E D M E DI C A TI O N G UI D A N C E 
T he U S F o o d & Dr u g A d mi nistrati o n has pr o vi de d g ui da nce a n d e xa m ples of dr u gs t hat i nteract 
wit h c yt oc hr o me P- 4 5 0 ( C Y P) e nz y mes a n d tra ns p orter s yste ms: F or Healt hcare Pr ofessi o nals | 
F D A’s E x a m ples of Dr u gs t hat I nteract wit h C Y P E nz y mes a n d Tra ns p orter S yste ms | F D A
Briefl y, dr u g- dr u g i nteracti o ns ca n lea d t o c ha n ges i n s yste mic e x p os ure (e. g., ma xi m u m 
c o nce ntrati o n ( C ma x), area u n der t h e c o nce ntrati o n ti me c ur ve ( A U C), a vera ge stea d y state 
c o nce ntrati o n ( C pss) p ote ntiall y res ulti n g i n a d verse reacti o ns ( hi g her dr u g e x p os ure) or l oss of 
efficac y (l o wer dr u g e x p os ure).
C yt oc hr o me P- 4 5 0 ( C Y P) e nz y mes are res p o nsi ble f or t he met a b olis m of ma n y dr u gs, a n d 
- dr u g i nteracti o ns beca use of t heir effect 
o n a dr u g’s p har mac o ki n etics (e. g., dr u g e x p os ure). 
T he list bel o w is n ot a c o m pre he nsi ve list of all p ossi ble dr u gs a n d ot her s u bsta nces; c o ns ult t he 
Me dical M o nit or wit h q uesti o ns as nee de d. 
M o der ate 3 A 4 i n hi bit ors: 
A pre pita nt, ci pr ofl o x aci n, c o ni va pta n, cri z oti ni b, diltiaze m, dr o ne dar o ne, fl uc o naz ole, gra pefr uit 
j uice, i mati ni b, isa v uc o naz ole, a n d v era pa mil
Str o n g I n hi bit ors of C Y P 3 A 4 
Ceriti ni b, clarit hr o m yci n, c o bicistat, el vite gra vir, rit o na vir, i delalisi b, i n di na vir, itrac o naz ole, 
ket oc o naz ol e, l o pi na vir, nefaz o d o n e, nelfi na vir, parita pre vir, p os ac o naz ole, sa q ui na vir, 
ti pra na vir, v oric o n az ole, s u b o x o ne, telit hr o m yci n. 
M o der ate 2 C 1 9 i n hi bit ors:
Ce n o ba mate, fel ba mate, v oric o naz ole
Str o n g I n hi bit ors of C Y P 2 C 1 9 
Fl uc o naz ole, fl u o xeti ne, fl u v o xa mi ne, a n d ticl o pi di ne. 
 
  
   
   
      
 
 
   
   
   
   
   
 
   
   
   
      
   
      
 

A S N 5 1- 2 0 1
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
9 0 
C o nfi de ntial 
I N V E S TI G A T O R A G R E E M E N T
Pr ot oc ol Title:
A P hase 2, Ra n d o mize d, D o u ble- Bli n d, Place b o- C o ntr olle d, Parallel 
Gr o u p St u d y of A S N 5 1 i n A d ults wit h Earl y Alz hei mer’s Disease  
Pr ot oc ol N u m ber:    
A S N 5 1- 2 0 1 
Ori gi n al Pr ot oc ol: 
Versi o n 2. 0,  0 7 Oct o ber 2 0 2 4   
 
As a n i n vesti gat or, I a gree t o c o m pl y wit h all pr ot oc ol s pecificati o ns a n d e ns ure t he safet y of 
partici pa nts e nr olle d at m y site. I a gree t o c o n d uct t he trial i n acc or da nce wit h a p plica ble 
re g ulati o ns, I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee s pecificati o ns, a n d I C H 
G C P g ui da nce.  I will e ns ure site pers o n nel u n dersta n d t heir o bli gati o ns i n t he c o n d uct of t his 
trial a n d will pr o vi de site pers o n nel wit h all rele va nt i nf or mati o n t hat bec o mes a vaila ble d uri n g 
t he c o n d uct of t his trial.   
 
Pri nci pal I n v esti gat or Na me:  
I nstit uti o n A d dress: 
 
 
Pri nci pal I n v esti gat or Si g nat ure:  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
                                                                 
 
Date:  
 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
9 1 
C o nfi de ntial 
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S 
T his S u m mar y of C ha n ges details t he s u bsta nti ve c ha n ges t o pr ot oc ol A S N 5 1- 2 0 1 fr o m t he 
Ori gi nal Pr ot oc ol ( 1 A u g ust 2 0 2 4) t o Versi o n 2 ( 7 Oct o ber 2 0 2 4).  Mi n or c ha n ges f or e dit orial 
clarificati o ns, or f or a d mi nistrati ve c orrecti o ns of t y p o gra p hic err ors, ref or matti n g, a b bre viati o ns 
or secti o n/ta ble re- n u m b eri n g are n ot i ncl u de d i n t his s u m mar y.  Te xt re m o ve d fr o m t he ori gi nal 
versi o n ( Ori gi nal Pr ot oc ol) is i n dicate d wit h stri ket hr o u g h te xt.  Te xt a d de d t o t he ne w versi o n 
( Versi o n 2. 0) is i n dicate d b y b ol d te xt . C o m me nts s u m marizi n g c ha n ges affecti n g lar ge bl oc ks of 
te xt are it alicize d. 
Pr ot o c ol Secti o n 
Ori gi n al Te xt 
Re vise d Te xt
J ustific ati o n
1. 1 Pr ot o c ol 
S y n o psis Ke y 
Eli gi bilit y Criteri a 
A d de d:
• A n y e vi de nce of h e p atic 
i m p air me nt ( C hil d P u g h 
classificati o n B a n d C are 
e xcl u d e d) 
• Re q uires use of m o d erate or 
str o n g C Y P 3 A 4 i n hi bit ors 
d uri n g trial partici p ati o n 
• Re q uires use of m o d erate or 
str o n g C Y P 2 C 1 9 i n hi bit ors 
d uri n g trial partici p ati o n  
Mi n or. A d d e d 
clarificati o n. 
1. 3 Sc he d ule of 
Acti vities 
Tier 2 ( Prescree ni n g Peri o d)
Plas m a p Ta u 2 1 7 d 
Bl o o d f or A P O E ge n ot y pe 
F o ot n ote d m o ve d: 
Tier 2 ( Prescree ni n g 
Peri o d) d 
Plas m a p T a u 2 1 7 d 
Bl o o d f or A P O E g e n ot y pe 
Mi n or. 
A d de d 
clarificati o n t o 
f o ot n ote d t hat 
A P O E ge n ot y pe 
ma y als o be 
c o m plete d 
d uri n g Tier 3 of 
scree ni n g, s o 
l o n g as t h e 
res ult is 
a vaila ble pri or 
t o 
ra n d o mizati o n. 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
9 2 
C o nfi de ntial 
Pr ot o c ol Secti o n 
Ori gi n al Te xt 
Re vise d Te xt
J ustific ati o n
1. 3 Sc he d ule of 
Acti vities 
Tier 3 ( Scree ni n g Peri o d) – a d d e d 
ite m 
C D R- S B  
Mi n or. 
Clarificati o n. 
1. 3 Sc he d ule of 
Acti vities 
Tier 3 ( Scree ni n g Peri o d) – a d d e d 
ite m 
Cli nical c he mistr y, 
h e mat ol o g y, c oa g ulati o n 
p a n el, uri n al ysis , uri ne dr u g 
scree n 
Mi n or. 
A d de d uri ne 
dr u g scree n t o 
scree ni n g t o 
clarif y t his 
s h o ul d b e d o ne 
i n Tier 3 
1. 3 Sc he d ule of 
Acti vities a n d 
Secti o n 8. 3. 3 
Electr o c ar di o gr a m 
Ta ble 1; f o ot n ote f 
Ta ble 2; f o ot n ote p 
Ta ble 3; f o ot n ote n 
E C Gs s h o ul d b e ta k e n s u pi ne 
i n tri plicate at a p pr o xi m atel y 
5 1- mi n ute 
i nter v als. 
Partici p a nts s h o ul d rest f or at 
least 5 mi n utes i n t h e s u pi n e 
p ositi o n 
bef ore 
E C Gs 
are 
ta k e n. 
Mi n or.
Clarifie d E C G 
a d mi nistrati o n 
i nstr u cti o ns. 
1. 3 Sc he d ule of 
Acti vities 
Ta ble 2; f o ot n ote b 
Sc h e d ule all re m ai ni n g visits 
at Da y 1 visit. Visits ma y ta ke 
m ore t h a n 1 d a y b ut s h o ul d 
ta k e place as cl ose t o t h e tar get 
d ate as p ossi ble. Partici p a nts 
m ust 
c o m plete 
bi o m ar k er 
assess me nts (e. g., 
M RI, ta u 
P E T, C S F, a n d plas ma) b ef ore 
pr o cee di n g t o ra n d o mizati o n.  
Mi n or.  
E m p h asize d a n d 
clarifie d 
ra n d o mizati o n 
pr o ce d ure. 
1. 3 Sc he d ule of 
Acti vities a n d 
Pr ot o c ol Secti o n 
8. 3. 5. 1 
F or C- S S R S: 
Ta ble 1; f o ot n ote g 
Ta ble 2; f o ot n ote h 
 
T he “ Scree n Versi o n” q uesti o n naire 
will be a d mi nistere d at 
Scree ni n g a n d at t he Da y 1 visit.  
T h e 
“ Scree n 
Versi o n” 
q uesti o n n aire 
will 
be 
a d mi nistere d at Scree ni n g a n d 
at t h e Da y 1 visit.  
Mi n or. Si m plif y 
a n d clarif y trial 
pr o ce d ure. 
1. 3 Sc he d ule of 
Acti vities & Secti o n 
8. 7 
Ta ble 2; f o ot n ote l  
A p ost- d ose sa m ple will als o 
b e o btai ne d 1. 5 t o 4 h o urs 
after t h e partici p a nt ta k es t h e 
d ose of trial i nter v e nti o n at 
t he site a n d sites will rec or d if 
t he s u bject partici p a nt eats a 
f ull meal, as j u d g e d b y t h e 
I n v esti g at or, wit hi n ± 2 h o urs 
of t he p ost d ose P K sa m ple 
t he d ose a d mi nistrati o n. 
Mi n or. 
Clarifie d P K 
pr o ce d ure 
ti mi n g i n 
relati o n t o f o o d 
i nta ke. 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
9 3 
C o nfi de ntial 
Pr ot o c ol Secti o n 
Ori gi n al Te xt 
Re vise d Te xt
J ustific ati o n
1. 3 Sc he d ule of 
Acti vities 
Ta ble 2; f o ot n ote m
Bl o o d a n d C S F f or bi o mar k er 
st ora g e a n d bl o o d f or 
p har m ac o g e n o mics will be 
o btai n e d, u nless c ollecti o n 
a n d/ or tra ns p ortati o n of t h e 
sa m ple is pr o hi bite d d u e t o 
l ocal re g ulati o ns. At t h e Da y 1 
visit, partici p a nts m ust h a ve 
c o m plete d t h e bl o o d a n d C S F 
c ollecti o n pr o ce d ures b ef ore 
ra n d o mizati o n. 
Mi n or.  
E m p h asize d a n d 
clarifie d 
ra n d o mizati o n 
pr o ce d ure. 
1. 3 Sc he d ule of 
Acti vities a n d 
Pr ot o c ol Secti o n 
8. 2. 1 
Ta ble 2; f o ot n ote f 
Ta ble 3; f o ot n ote g 
 
C o g niti ve a n d f u ncti o n al 
assess me nts s h o ul d be p erf or me d 
bef ore pr oce d ures t h at ma y be 
stressf ul f or partici p a nts (e. g., M RI, 
P E T, bl o o d dra w, or C S F 
sa m pli n g).
W h e n e v er perf or m e d o n t h e 
sa me d a y, c Co g niti v e a n d 
f u n cti o nal assess me nts 
( A D A S- C o g 1 3, C D R- S B, a n d 
M M S E) are t o b e p erf or me d 
b ef ore pr o ce d ures t h at ma y be 
stressf ul f or p artici p a nts (f or 
e xa m ple, M RI, P E T, bl o o d 
dra w, or C S F sa m pli n g). 
Mi n or. Clarifie d 
pr ot oc ol 
la n g u a ge. 
1. 3 Sc he d ule of 
Acti vities a n d 
8. 2. 2. 1 1 8 F M K- 6 2 4 0 
P E T Sc a n 
Ta ble 2; f o ot n ote q  
M K- 6 2 4 0 ta u P E T sca n 
s h o ul d b e sc he d ule d as s o o n 
as p ossi ble. D u e t o t h e 
p ote ntial f or sc h e d uli n g 
c halle n g es f or M K- 6 2 4 0 ta u 
P E T, or i n t he e ve nt of tracer 
fail ure, ra n d o mizati o n ma y be 
d ela y e d, a n d t h e scree ni n g 
p eri o d e xte n d e d b y 1 4 d a ys 
a n d t he Wee k 2 4 de viati o n 
wi n d o w m a y b e e xte n d e d u p 
t o + 2 1 da ys, wit h S p o ns or 
Me dical M o nit or a p pr o v al, 
t h o u g h eff ort s h o ul d be m a d e 
t o sc he d ule it as cl ose as 
p ossi ble t o eac h i n dicate d 
ti m e p oi nt. T h e Da y 1 visit 
M K- 6 2 4 0 ta u P E T sca n ma y 
b e p erf or m e d o n ce a s u bject is 
d ee me d eli gi ble f or 
ra n d o mizati o n b ut n o earlier 
t ha n 2 1 d a ys bef ore 
ra n d o mizati o n. At t h e Da y 1 
Mi n or.  
E m p h asize d a n d 
clarifie d 
ra n d o mizati o n 
pr o ce d ure. 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
9 5 
C o nfi de ntial 
Pr ot o c ol Secti o n 
Ori gi n al Te xt 
Re vise d Te xt
J ustific ati o n
of ra n d o mizati o n 
(refer t o A p pe n di x 
1 6). 
A p pe n di x 1 6 u p d ate d t o 
i ncl u d e: 
M o derate 3 A 4 i n hi bit ors: 
A pre pita nt, ci pr ofl o xaci n, 
c o ni v a pta n, 
criz oti ni b, diltiaze m, 
dr o n e dar o ne, 
fl u c o n az ole, gra p efr uit j uice, 
i mati ni b, isa v u c o naz ole, 
a n d v era p a mil 
  
M o derate 2 C 1 9 i n hi bit ors: 
Ce n o b a m ate, fel b a m ate, 
v oric o naz ole 
 
8. 7 
P h ar m a c o ki netics 
Partici pa nts s h o ul d be c o ntacte d b y 
tele p h o ne a b o ut 1 b usi n ess da y 
bef ore i n dicate d visits t o re mi n d 
t he m t o bri n g I M P t o t h e 
i n vesti gati ve site f or a d mi nistrati o n 
d uri n g t he visit. 
Partici p a nts s h o ul d be 
c o ntacte d b y tele p h o n e a b o ut 
1 b usi n ess d a y b ef ore 
i n dicate d visits t o re mi n d 
t he m t o bri n g I M P t o t h e 
i n v esti g ati v e site f or 
a d mi nistrati o n d uri n g t he 
visit , a n d t o rec or d t h e ti me 
I M P is ta k e n o n t he d a y pri or 
t o t h e visit. 
Mi n or. Clarifie d 
P K pr o ce d ures. 
1 0. 3 I nf o r me d 
C o nse nt Pr o cess
T he I n vesti gat or is res p o nsi ble f or 
o btai ni n g writte n i nf or me d c o nse nt 
fr o m eac h p ote ntial trial partici p a nt 
pri or t o t he c o n d uct of a n y trial 
pr oce d ures. 
T h e I n v esti g at or is 
res p o nsi ble f or o btai ni n g 
writte n i nf or me d c o nse nt fr o m 
eac h p ote ntial trial p artici pa nt 
a n d st u d y p art ner pri or t o t he 
c o n d u ct of a n y trial 
pr o ce d ures.
Mi n or. N o 
c ha n g e t o 
c o nse nt pr ocess, 
o nl y u p dati n g 
te xt f or clarit y.
1 3. 2 Cli nic al 
L a b o r at or y Tests 
T a ble 8 Cli nic al 
L a b o r at or y Tests 
F ollicle sti m ulati n g h or m o n e 
( Scree ni n g; l ocal la b orat or y) 
F ollicle sti m ulati n g h or m o n e 
( Scree ni n g; l ocal or ce ntral 
la b orat or y) 
Mi n or. 
Clarificati o n of 
la b orat or y 
pr o ce d ure. 

A S N 5 1- 2 0 1 
Asce ne ur o n S A
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
9 6 
C o nfi de ntial 
Pr ot o c ol Secti o n 
Ori gi n al Te xt 
Re vise d Te xt
J ustific ati o n
1 3. 2 Cli nic al 
L a b o r at or y Tests 
T a ble 8 Cli nic al 
L a b o r at or y Tests 
C ollecti o n of C S F i n p ol y pr o p yle ne 
t u bes. Cell c o u nt, pr otei n, gl uc ose. 
C ollecti o n of C S F i n 
p ol y pr o p yle ne t u b es. Cell 
c o u nt ( w hite bl o o d cells wit h 
differe ntial a n d re d bl o o d 
cells) , pr otei n, gl uc ose.
Mi n or. 
Clarificati o n of 
la b orat or y 
testi n g. 
I n v esti g at o r 
Si g n at ure P a ge 
A P hase 2, D o u ble Bli n d, 
Ra n d o mize d, Place b o- C o ntr olle d 
D ose-ra n gi n g Safet y Trial of 
A S N 5 1 i n A d ults wit h Earl y 
Alz hei m er’s Disease 
A P h ase 2, Ra n d o mize d, 
D o u ble- Bli n d, Place b o-
C o ntr olle d, Parallel Gr o u p 
St u d y of A S N 5 1 i n A d ults 
wit h Earl y Alz hei m er’s 
Disease  
Mi n or. 
C orrecte d 
pr ot oc ol title o n 
i n v esti g at or 
si g nat ure pa ge.