Conditions: Alzheimer Disease
Keywords: Alzheimer's Disease ASN51
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 123
Healthy volunteers: no

Brief summary:
The main purpose of this study is to evaluate the safety, tolerability, and effect on biomarkers of disease pathophysiology and pathology, pharmacokinetics (PK), and preliminary effects on measures of clinical efficacy of multiple doses of ASN51 in adult participants with early Alzheimer's disease (AD).

Detailed description:

Arms:
arm 1: Participants were to receive low dose of ASN51 orally, once daily (QD) for up to 24 weeks in the double-blind placebo-controlled intervention period or up to 36 weeks long-term extension period. arm 2: Participants were to receive high dose of ASN51 orally, QD for up to 24 weeks in the double-blind placebo-controlled intervention period or up to 36 weeks long-term extension period. arm 3: Participants were to receive ASN51 matching placebo orally, QD for up to 24 weeks in the double-blind placebo-controlled intervention period.

Interventions: intervention 1: ASN51 intervention 2: Placebo
Intervention descriptions: intervention 1: Oral capsules intervention 2: Oral capsules

Protocol document:
Prot_SAP_000.pdf: 
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 
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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 
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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 
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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 
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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
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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
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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 o r 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 h e M RI res ults t o b ec 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 n cl u d e A P O E g e 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 p acit 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 b e 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 T a 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 v e d b y t he rele v a 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 p erf 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 n e 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 h ea wit h ot h er 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 p ecte 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 x a 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 h at 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 b e 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 h e 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 p artici 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 g es 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 u esti o n n aire 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 b e 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 p a 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 d a 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 k e 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 h as 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 p ati 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 p a 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 n cl 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, h e 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 k er st ora g e 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 k er 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 b e 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 h e 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 n ecessar 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 p e nse d. 
g  
W h e n e v er perf or m e d o n t h e 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 p artici 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 g es 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 b e 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 p a 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 k er st ora g e 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 h as b ee 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 h e 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 n cti 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 b e perf or me d. 
p  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, 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
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
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
 






A S N 5 1- 2 0 1
Asce ne ur o n S A
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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
Pr ot oc ol Versi o n 2. 0: 0 7 Oct o ber 2 0 2 4 
 
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 p artici 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 n al 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 n al 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 n er
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 v e 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 


A S N 5 1- 2 0 1
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7 0 
C o nfi de ntial 
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
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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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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
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 8 
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 g e 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 h e “ 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 v e a n d f u n cti o n al 
assess me nts s h o ul d be p erf or me d 
b ef ore pr o ce 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 n e a b o ut 1 b usi n ess da 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 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 h e I n vesti 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 partici p a nt 
pri or t o t he c o n d u ct 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 b es. 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 g e 
A P h ase 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.