A Phase 2 Randomized Double-Blind Placebo-Controlled Trial to Evaluate the Efficacy and Safety of BHV-4157 in Patients With Mild to Moderate Alzheimer's Disease
Phase: PHASE2
Conditions: Alzheimer Disease
Sponsor: Biohaven Pharmaceuticals, Inc.

PROTOCOL TITLE: A Phase 2 Randomized Double-Blind Placebo-Controlled Trial to Evaluate the
Efficacy and Safety of BHV-4157 in Patients With Mild to Moderate Alzheimer's Disease
NCT NUMBER: NCT03605667
DATE: 12-September-2020

C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 1  of 9 6  
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
C LI NI C A L S T U D Y P R O T O C O L  
St u d y Title:  
A P hase 2 Ra n d o mize d D o u bl e -Bli n d Pl ace b o -C o ntr olle d 
Trial t o E val uat e t he Effica c y a n d Safet y of B H V -4 1 5 7  i n 
Patie nts wit h Mil d t o M o derate Alz h ei m er’s  Disease  
S p o ns or:  
Bi o ha ve n P har mace uticals , I nc. 
2 1 5  C h urc h Street  
Ne w Ha ve n, C T 0 6 5 1 1
Pr ot oc ol  N u m ber:  
U S I N D  #:  
B H V 4 1 5 7 -2 0 3  
 
A D C S  Refere nce #:  
 
Pr oject  Direct or:  
C o or di n ati n g  Ce nter:  
H o war d Fel d ma n, M D  
Alz hei mer’s Disease C o o perati ve St u d y 
 U ni versit y of Calif or nia, Sa n Di e g o  
 M C 0 9 4 9 
La J olla, C A 9 2 0 9 3 -0 9 4 9  
 
Tel: 
 
H o war d Fel d m a n, M D  
Direct or a n d Pri n ci pal I n vesti gat or  
Alz hei mer’s Disease C o o perati ve St u d y 
 U ni versit y of Calif or nia, Sa n Di e g o  
 M C 0 9 4 9 
La J olla, C A 9 2 0 9 3 -0 9 4 9  
 
Tel: 
 
C CI
C CI
P P D
P P D
P P D
P P D
P P D
P P D

C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2  of 9 6  
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
Me dic al  E mer ge ncies:     
 
 
A D C S 
 
Alz hei mer’s Disease C o o perati ve St u d y 
U ni versit y of Calif or nia, Sa n Die g o  
 
Cell: 
 
 
 
Bi o ha ve n 
 
 
Cell: 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D

Confidential
Protocol BHV4157-203 
Page 3 of 96
Amendment 5, Version 6.0 dd. 12SEP2020 
CONFIDENTIALITY STATEMENT 
The information in this document contains trade secrets and commercial information that are 
privileged or confidential and may not be disclosed unless such disclosure is required by applicable 
laws and regulations. In any event, persons to whom the information is disclosed must be informed 
that the information is privileged or confidential and may not be further disclosed by them. These 
restrictions on disclosure will apply equally to all future information supplied to you, which is 
indicated as privileged or confidential. 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
 
 
SI G N A T U R E P A G E  
 
( SI G N A T U R E S O N FI L E  A T A D C S)  
 
 
 
 
 
 
 
 
 
 
Date  (D D M M M Y Y Y Y ) 
 of 
 
Bi o ha ve n P har mace uticals , I nc. 
 
 
 
 
 
 
 
 
 
Date  (D D M M M Y Y Y Y ) 
  
Alz hei mer's  Disease  C o o perati ve St u d y  
U ni versit y of Calif or nia Sa n Di e g o  
 
 
 
 
 
 
H o war d Fel d m a n, M D  
Date  (D D M M M Y Y Y Y ) 
Pr oject  Direct or  a n d Pri nci pal I n vesti gat or 
Alz hei mer's  Disease  C o o perati ve St u d y  
U ni versit y of Calif or nia Sa n Die g o  
 
 
 
 
 
P P D
P P D
P P D
P P D
P P D
P P D
P P D

Confidential
Protocol BHV4157-203 
Page 5 of 96
Amendment 5, Version 6.0 dd. 12SEP2020 
STUDY SUMMARY 
Title 
A Phase 2 Randomized Double-Blind Placebo-Controlled Trial to Evaluate 
the Efficacy and Safety of BHV-4157 in Patients with Mild to Moderate 
Alzheimer’s Disease 
Rationale 
BHV-4157 is a new chemical entity 3rd-generation prodrug of the 
glutamate modulator, riluzole, which has been designed to bypass first-
pass metabolism therein providing greater bioavailability, diminished PK 
variability, lower hepatic burden, lack of food effect, longer half-life and 
once daily dosing. Preclinical models suggest that riluzole, the active 
metabolite of BHV-4157, may protect from AD-related pathology and 
cognitive dysfunction. 
Target 
Population 
Male and females, age 50 to 85 years (inclusive at screening), diagnosed 
with Alzheimer’s Disease (in accordance with NIA/Alzheimer’s 
Association Guidelines) of mild to moderate severity including MMSE 
score 14-24 at the screening visit.  
Eligible participants should be receiving a stable dose of FDA-approved 
AD medication(s) (acetylcholinesterase inhibitors (AchEI) and/or 
memantine) for at least 3 months prior to screening and willing to remain 
on same dose(s) for trial duration. Those participants with 
contraindications or failed treatment with either AchEI and/or memantine 
will be eligible for inclusion.  
Number of 
Participants 
Approximately 336 participants will be randomly allocated using a 1:1 
allocation to active treatment or placebo.  
Drug Dosage 
& Treatment 
Duration 
Titrated dose of BHV-4157 to 280 mg, or placebo, taken orally once daily. 
Duration of double-blind treatment is approximately 48 weeks. There is 
also a screening period of up to 42 days; and a 4-week post-treatment 
observation period. 
Eligible subjects will have the opportunity to continue in a 48-week open- 
label extension phase (once it is open for recruitment at their investigative 
site). 
Objectives 
Randomized Double-Blind Treatment Phase 
The co-primary objectives are to: evaluate the efficacy of BHV-4157 as 
measured by a) ADAS-Cog 11, and b) CDR-Sum of Boxes. 
The secondary objectives are to: (1) evaluate the efficacy of BHV-4157 
as measured by: volumetric MRI (Quarc bilateral hippocampal volume)  

 
 
 
C o nfi de nti al  
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A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
Ne ur o ps yc hiatri c I n ve nt or y ( N PI), A D C S -A D L, a n d Mi ni -Me ntal St a te 
E xa mi n ati o n ( M M S E) . (2 ) e val uate t he safet y a n d t olera bilit y of B H V -
4 1 5 7  as meas ure d b y m ortalit y rat es, seri o us a d verse e ve nts, a d verse 
e ve nts, cli nic al safet y la b orat ories, p h ysic al e x a mi n ati o ns a n d si g nifi ca nt 
E C G  c h a n ges. 
E x pl or at or y o bjecti ves are t o  assess : (1) Efficac y of B H V -4 1 5 7 assesse d 
b y t he M o ntre al C o g niti ve Assess me nt ( M o C A) ; (2) e ffica c y of B H V-4 1 5 7 
o n perf or ma nce usi n g t he A D C o m p osite Sc ore ( A D C O M S) ; (3) v ol u metric 
M RI ( bilater al later al v e ntricles a n d w h ol e brai n v ol u me) ; (4 ) effic ac y of 
B H V -4 1 5 7 o n perf or ma nc e o n a c o g niti v e c o m p osite o utc o m e c o m p ute d 
usi n g meas ures fr o m t h e N A C C Ne ur o ps yc h ol o gical Test Batter y ; (5) 
p har mac o ki netics of B H V -4 1 5 7 a n d ril u z ole i n plas ma ; (6) t r eat me nt 
res p o nse b y A p o E ge n ot y pe; a n d ( 7) C S F, ser u m a n d plas ma bi o mar k ers 
( A ß 4 2, A ß 4 2/ 4 0 rati o, t otal ta u, p-t a u-1 8 1, ne ur o gra ni n, Nf L, Y K L -4 0, 
VI LI P, S N A P -2 5, s T R E M 2, G F A P) at scree ni n g, wee k 2 4 a n d wee k 4 8 of 
t he d o u ble-bli n d p hase. C S F will b e assesse d i n a s u bset of t he st u d y 
p o p ulati o n ( esti m ate d n = 5 0 acti ve, n = 5 0 pl ace b o) . 
E x pl or at or y 
O pe n -L a bel E xte nsi o n  ( O L E) P h ase o bjecti ve is t o 
e val uate t he safet y a n d t olera bilit y of B H V -4 1 5 7 as meas ure d b y m ortalit y 
rates, seri o us a d verse e ve nts, a d verse e ve nts, cli nic al safet y l a b orat ories, 
p h ysical 
e xa mi nati o ns 
a n d si g nifi ca nt 
E C G 
c ha n ges. 
A d diti o nal 
e x pl orat or y o bjecti ve of e val uati n g l o n g -ter m effects o n cli ni cal o utc o me 
meas ures . 
St u d y Desi g n  
& St atistic al 
Pl a n  
T his is a p hase 2 m ulti -ce nt er, ra n d o mi ze d, d o u bl e bli n d, plac e b o -
c o ntr oll e d, parallel gr o u p st u d y  f oll o we d b y a n o pti o nal 4 8 wee k O pe n -
La bel E xte nsi o n  p h ase . Stratificati o n fa ct ors will b e site a n d M M S E  sc ore 
at scree ni n g (m o derate A D: 1 4  t o 1 9; mil d A D: 2 0  t o 2 4 ). 
T he c o -pri mar y e n d p oi nts are m ea n wit hi n -partici p a nt c ha n ge i n A D A S -
C o g 1 1 a n d C D R S u m of B o xes fr o m baseli n e t o we e k 4 8  of t he d o u bl e -
bli n d p hase , c o m pare d b et wee n t h e tre at m e nt a n d pla ce b o ar ms. T h e 
pri mar y o bj ecti ve of t he trial is met if b ot h c o -pri m ar y e n d p oi nts are 
si g nifica ntl y i n f a v or of treat me nt at t he 5 % l e vel.  
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C o nfi de nti al  
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A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
O ver all st u d y p o wer  at t he fi n al a n al ysis  of t he 4 8 wee k d o u ble -bli n d 
p h ase : 
T he st u d y has at least 8 0 % p o wer t o dete ct a differe n ce bet we e n t he B H V -
4 1 5 7 ar m a n d t h e pla ce b o ar m i n me a n 1 2 m o nt h c ha n ge of 2. 6 4 p oi nts o n 
t he A D A S-C o g 1 1 a n d of 0. 9 5 p oi nts i n C D R S u m of B o xes, u n der a ra n ge 
of i nteri m effe ct sizes w hic h gi ve 9 3. 7 % pr o ba bilit y of pr ocee di n g at t h e 
i nteri m a nal ysis.  
St atistic al met h o ds : 
B ot h t he i nteri m a n d fi n al a n al ysis of t he 4 8 wee k d o u ble -bli n d p h ase will 
use a mi xe d effects re p eat e d me as ures m o del . T he c o -pri mar y e n d p oi nts at 
t he fi nal a nal ysis are b ot h re q uire d t o att ai n 5 % si g nifica nc e le vel i n or der 
t o be re p ort e d. If b ot h c o-pri mar y o ut c o mes ar e si g nifica nt, t he n t h e 
re mai n d er of t he sec o n d ar y o utc o mes will b e test e d at o verall 5 % 
si g nifica n ce l e vel usi n g a H ol m ste p-d o w n test. T his will preser ve al p ha at 
5 % o verall f or all e n d p oi nts re p ort e d.  
T he pri m ar y a nal ysis f or t he st u d y will ta ke plac e aft er all s u bj ects ha v e 
c o m plete d all visits i n t he d o u ble -bli n d p hase.  
C o -Pri m ar y 
E n d p oi nt s  
T he me a n c ha n ge i n A D A S -C o g 1 1 fr o m baseli ne  t o wee k  4 8  of t he 
d o u ble -bli n d p h ase , c o m p are d bet we e n t he B H V -4 1 5 7  treat me nt gr o u p a n d 
t he pla ce b o gr o u p. 
T he me a n c ha n ge i n C D R -S u m of B o xes fr o m baseli ne t o wee k 4 8  of t h e 
d o u ble -bli n d p h ase , c o m p are d bet we e n t he B H V -4 1 5 7 treat me nt gr o u p a n d 
t he pla ce b o gr o u p. 
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Protocol BHV4157-203 
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Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
Secondary 
Endpoints 
The change in the NPI total score from baseline to week 48 of the double-
blind phase. 
The change in ADCS-ADL total score from baseline to week 48 of the 
double-blind phase. 
The change in MMSE from baseline to week 48 of the double-blind phase. 
The change in MRI Quarc bilateral hippocampal volume from screening to 
week 48 of the double-blind phase. 
The change in safety and tolerability measures including: (1) adverse 
events; (2) clinical laboratory tests; (3) vital signs; (4) physical 
examinations; (5) ECGs. 
Exploratory 
Endpoints 
Exploratory endpoints include: (1) the change in MoCA scores from 
baseline to week 48 of the double-blind phase; (2) the change in ADCOMS 
total score from baseline to week 48 of the double-blind phase; (3) the 
change in MRI Quarc bilateral lateral ventricles and whole brain volume 
from screening to week 48 of the double-blind phase; (4) the change in 
composite z score from baseline to week 48 of the double-blind phase on 
the cognitive composite outcome computed using measures from the 
NACC Neuropsychological Test Battery; (5) BHV-4157 and riluzole 
pharmacokinetics; (6) treatment response in participants by Apo E 
genotype; and (7) CSF, serum and plasma biomarker panel (Aß42, 
Aß42/40 ratio, total tau, p-tau-181, neurogranin, NfL, YKL-40, VILIP, 
SNAP-25, sTREM2, GFAP) will be assessed at screening, week 24, and 
week 48.  CSF will be assessed in a subset of the study population 
(estimated n=50 active, n=50 placebo). 
Interim 
Analysis 
Endpoints 
 
The mean change in ADAS-Cog 11 from baseline to week 24 of the 
double-blind phase, compared between the BHV-4157 treatment group and 
the placebo group. 
The mean change in MRI Quarc hippocampal volume from screening to 
week 24 of the double-blind phase, compared between the BHV-4157 
treatment group and the placebo group. 
 
Exploratory 
Open-Label 
Extension 
Endpoint 
 
The safety and tolerability measures in the Open-Label Extension include 
rates of: (1) adverse events; serious adverse events, suspected unexpected 
serious adverse reactions (2) clinically abnormal laboratory tests; (3) shifts 
in vital signs; (4) physical examination abnormalities; (5) ECG 
abnormalities. Additional exploratory endpoint of evaluating long-term 
effects on clinical outcome measures. 
 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
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A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
 
P R O T O C O L S U M M A R Y O F C H A N G E S  
 
N u m b er  
Brief d escri pti o n s u m m ar y of c h a n ges  
D ate  
Versi o n 0 1 – Ori gi nal 
Draft  
N ot A p plica ble  
2 6 A pril 2 0 1 8  
Versi o n 0 2  
A d mi nistrati ve u p dates, refi ne me nt of 
i ncl usi o n/e xcl usi o n criteria, a d diti o n of  
c o nc o mita nt me dicati o n c o nsi derati o ns.  
1 4 J u n 2 0 1 8  
Versi o n 0 3  
M o dificati o n of Pri mar y a n d S ec o n dar y O bjecti ves 
a n d E n d p oi nts, t o i ncl u de a C o -Pri mar y  E n d p oi nt. 
I ncre ase i n sa m ple size. S A P u p date t o matc h 
c ha n ge i n e n d p oi nts. Clarificati o n of  
 
 pla ns. U nsc he d ule d visit a d de d t o 
pr ot oc ol. A d mi nistrati ve clarificati o ns/ u p dates.  
0 1 Oct 2 0 1 9  
Versi o n 0 4  
A d de d a d diti o nal wi n d o w f or Wee k 4 8 visit i n 
or der t o pr oacti vel y acc o u nt f or a n y s u bjects t hat 
ma y p ote ntiall y be o ut of visit wi n d o w d ue t o 
c o ncer ns relate d t o C O VI D -1 9 pa n de mic. 
All o wi n g re m ote safet y visits if nee de d d ue t o 
C O VI D -1 9.  
1 6 -M A R -2 0 2 0  
Versi o n 0 5  
 
A d de d O pe n -L a bel E xte nsi o n P hase a n d ma de 
mi n or  e dits t o t he C O VI D -1 9 la n g ua ge  
2 4 -A pr -2 0 2 0  
Versi o n 0 6  
M o ve d t he v ol u metric M RI ( Q uarc bilat eral 
later al ve ntricles a n d w h ole brai n v ol u m e)a n d 
ne ur o ps yc h ol o gical test batter y fr o m sec o n dar y t o 
e x pl orat or y o utc o me. Clarificati o n of mI T T 
p o p ulati o n.  
1 0 -S E P -2 0 2 0  
 
 
 
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2 BS T U D Y S C H E M A TI C  
 
 
 
 
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T A B L E O F C O N T E N T S  
 
S T U D Y S U M M A R Y  ..........................................................................................................5  
P R O T O C O L S U M M A R Y O F C H A N G E S  .....................................................................9  
2 B S T U D Y S C H E M A TI C  ................................................................................................1 0  
T A B L E O F C O N T E N T S  ................................................................................................1 1  
LI S T O F A B B R E VI A TI O N S  .........................................................................................1 5  
1  
I N T R O D U C TI O N ....................................................................................................1 7  
1. 1  
B ac k gr o u n d  ..........................................................................................................1 7  
1. 2  
Precli nic al & Scie ntific R ati o n ale  .......................................................................1 8  
1. 3  
Mec h a nis m of A cti o n  ...........................................................................................2 0  
1. 4  
 ....................................................................................2 1  
1. 5  
 .................................................................................................2 2  
1. 6  
P ote nti al f or Dr u g -Dr u g I nter acti o ns  ................................................................2 3  
1. 7  
Cli nic al E x perie nce  ..............................................................................................2 4  
1. 7. 1  
A d verse E ve nt Pr ofil e  ....................................................................................2 4  
1. 8  
 .......................................................................................................2 8  
1. 9  
P ote nti al Ris k t o Fet al De v el o p me nt  ..................................................................3 0  
2  
S T U D Y D E SI G N  ......................................................................................................3 1  
3  
O B J E C TI V E S  ...........................................................................................................3 3  
3. 1  
C o -Pri m ar y O bje cti ves  ........................................................................................3 3  
3. 2  
Sec o n d ar y O bjecti ves ...........................................................................................3 3  
3. 2. 1  
Effic ac y ............................................................................................................3 3  
3. 2. 2  
S afet y a n d T oler a bilit y  ..................................................................................3 3  
3. 3  
E x pl or at or y O bjecti ves  ........................................................................................3 3  
3. 3. 1  
E x pl or at or y O pe n -L a bel E xte nsi o n P h ase O bjecti ve  .................................3 4  
4  
E N D P OI N T S  .............................................................................................................3 4  
4. 1  
C o -Pri m ar y E n d p oi nts  ........................................................................................3 4  
4. 2  
Sec o n d ar y E n d p oi nts  ...........................................................................................3 4  
4. 2. 1  
Effic ac y ............................................................................................................3 4  
4. 2. 2  
S afet y a n d T oler a bilit y  ..................................................................................3 5  
4. 3  
E x pl or at or y E n d p oi nts  ........................................................................................3 5  
4. 4  
 ................................................................................3 6  
5  
E T HI C S A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ........................................3 6  
5. 1  
G o o d Cli nic al P r acti ce  .........................................................................................3 6  
5. 2  
I nstit uti o n al Re vie w B o ar d .................................................................................3 6  
5. 3  
I nf or me d C o nse nt a n d HI P A A C o m pli a nce......................................................3 7  
5. 4  
P artici p a nt C o nfi de nti alit y │ HI P A A  ................................................................3 7  
5. 5  
P ote nti al Ris ks a n d Be nefits Ass oci ate d wit h t his St u d y  ..................................3 8  
5. 5. 1  
P ote nti al Ris ks  ................................................................................................3 8  
5. 5. 2  
P ote nti al Be nefits  ...........................................................................................3 8  
6  
S T U D Y D R U G  ..........................................................................................................3 8  
6. 1  
St u d y Me dic ati o n  .................................................................................................3 8  
6. 2  
 ............................................................................3 8  
6. 3  
.................................................................................................3 9  
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Protocol BHV4157-203 
Page 12 of 96
 
Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
6.4 
Missed Doses .........................................................................................................40 
6.5 
Coding and Packing .............................................................................................40 
6.6 
Blinding .................................................................................................................40 
6.7 
Randomization and Medication Ordering System ...........................................41 
6.8 
Labeling ................................................................................................................41 
6.9 
Drug Accountability.............................................................................................41 
7 
PARTICIPANT SELECTION AND CONCOMITANT MEDICATIONS ........42 
7.1 
Inclusion Criteria .................................................................................................42 
7.2 
Exclusion Criteria ................................................................................................43 
7.3 
Concomitant AD Medication ..............................................................................45 
7.4 
Other Concomitant Medication ..........................................................................45 
7.4.1 
Permitted Concomitant Medications ...........................................................45 
7.4.2 
Prohibited Concomitant Medications for double-blind phase but 
conditional for Open-Label Extension phase ..............................................46 
7.4.3 
Prohibited Medications, both in double blind and 0pen-label extension 
phases . ............................................................................................................47 
8 
STUDY PROCEDURES ..........................................................................................48 
8.1 
Study Visits ...........................................................................................................48 
8.1.1 
Screening (within 42 days prior to baseline) ...............................................48 
8.1.2 
Baseline (Week 0) ...........................................................................................50 
8.1.3 
Week 2 (+ 3 days) ...........................................................................................51 
8.1.4 
Week 4 (+ 7 days) ...........................................................................................51 
8.1.5 
Week 8 (+ 7 days) ...........................................................................................52 
8.1.6 
Week 12 (+ 7 days) .........................................................................................52 
8.1.7 
Week 24 (+ 7 days) .........................................................................................53 
8.1.8 
Week 36 (+ 7 days) .........................................................................................54 
8.1.9 
Week 48 or Early Termination (+ 7 days) ...................................................54 
8.1.10 
Week 52 Safety Follow-up (+ 7 days) ...........................................................56 
8.1.11 
Unscheduled Visit...........................................................................................56 
8.1.12 
Open-Label Extension Phase (as applicable) ..............................................56 
8.2 
Laboratory Safety Assessments ..........................................................................58 
8.3 
Pharmacokinetic Assessments ............................................................................59 
8.4 
Physical and Neurological Examination ............................................................59 
8.5 
Genotyping............................................................................................................59 
8.6 
Electrocardiogram ...............................................................................................60 
8.7 
vMRI Assessments ...............................................................................................60 
8.8 
CSF, Serum and Plasma Sub-study Assessments .............................................61 
9 
STUDY-SPECIFIC INSTRUMENTS ....................................................................62 
9.1 
Cognitive Measures ..............................................................................................62 
9.1.1 
Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog 11)62 
9.1.2 
Mini-Mental State Examination (MMSE) ...................................................62 
9.1.3 
Montreal Cognitive Assessment (MoCA) ....................................................62 
9.1.4 
Neuropsychological Test Battery (NTB) ......................................................63 
9.2 
Behavioral and Functional Measures.................................................................64 
9.2.1 
Clinical Dementia Rating (CDR) Scale – Sum of Boxes (SOB) .................64 
9.2.2 
ADCS-Activities of Daily Living (ADCS-ADL) Scale.................................64 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 1 3  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
9. 2. 3  
Ne ur o ps yc hi atric I n ve nt or y ( N PI) ................................................................6 5  
9. 3  
M o difie d H ac hi ns ki  ..............................................................................................6 5  
9. 4  
S hee h a n S uici d alit y Tr ac ki n g Sc ale ( S hee h a n S T S)  .........................................6 5  
9. 5  
Rese arc h S atisf acti o n S ur ve y  ..............................................................................6 5  
9. 6  
Tre at me nt Bli n di n g Q uesti o n n aire  ....................................................................6 5  
1 0  E A R L Y DI S C O N TI N U A TI O N/ WI T H D R A W A L P R O C E D U R E S  ...................6 6  
1 1  D E FI NI TI O N O F A D V E R S E E V E N T S  ................................................................6 7  
1 1. 1  
E v al u ati o n a n d Re p orti n g of A d v erse E ve nts ...................................................6 7  
1 1. 2  
Assess me nt of A d verse E ve nts  ............................................................................6 7  
1 1. 3  
C ollecti o n a n d Re p orti n g of Seri o us A d verse E ve nts  .......................................6 9  
1 1. 4  
O ver d ose Re p orti n g Re q uire me nts  ....................................................................7 1  
1 1. 5  
Cli nic al L a b or at or y A b n or m alities a n d Ot her A b n or m al Assess me nts  .........7 1  
1 1. 6  
Pre g n a nc y a n d Bre ast Fee di n g  ...........................................................................7 1  
1 2  S T A TI S TI C A L M E T H O D S  ....................................................................................7 1  
1 2. 1  
S a m ple Size a n d P o we r Deter mi n ati o n  ..............................................................7 2  
1 2. 1. 1  
O ver all St u d y P o wer  ......................................................................................7 2  
1 2. 1. 2  
 .............................................................................................7 3  
1 2. 2  
A n al ysis P o p ul ati o ns  ............................................................................................7 3  
1 2. 3  
A n al ysis of t he C o -Pri m ar y E n d p oi nts  ..............................................................7 4  
1 2. 4  
A n al ysis of Sec o n d ar y E n d p oi nts  .......................................................................7 5  
1 2. 5  
A n al ysis of E x pl or at or y E n d p oi nts  ....................................................................7 5  
1 2. 6  
 ...............................................................................7 5  
1 2. 7  
O pe n -L a bel E xte nsi o n P h ase A n al ysis  ...............................................................7 6  
1 2. 7. 1  
Effic ac y A n al ysis  ............................................................................................7 6  
1 2. 7. 2  
S afet y A n al ysis  ...............................................................................................7 6  
1 2. 7. 3  
A d verse E ve nts  ...............................................................................................7 6  
1 2. 7. 4  
L a b or at or y P ar a met ers  .................................................................................7 7  
1 2. 7. 5  
Ot h er S afet y P ar a m eters  ...............................................................................7 7  
1 2. 8  
R a n d o miz ati o n a n d Str atific ati o n  ......................................................................7 7  
1 2. 9  
Pr ot oc ol De vi ati o ns, D at a Bli n d Re vie w, a n d U n bli n di n g  ...............................7 7  
1 3  R E C O R DI N G A N D C O L L E C TI O N O F D A T A  ...................................................7 8  
1 3. 1  
C ase Re p ort F or m  ................................................................................................7 8  
1 3. 2  
St u d y Files a n d P artici p a nt S o urce D oc u me nts  ................................................7 8  
1 3. 3  
R ater Tr ai ni n g  ......................................................................................................7 9  
1 3. 4  
M o nit ori n g  ............................................................................................................7 9  
1 3. 5  
A u dit  ......................................................................................................................7 9  
1 3. 6  
Rete nti o n of D at a  .................................................................................................8 0  
1 3. 7  
Re p orti n g of St u d y Res ults  .................................................................................8 0  
1 3. 8  
Q u alit y Ass ur a nce/ Q u alit y C o ntr ol ....................................................................8 0  
1 4  D A T A S A F E T Y M O NI T O RI N G B O A R D  ............................................................8 0  
1 5  S T U D Y S T E E RI N G C O M MI T T E E  ......................................................................8 1  
1 6  P U B LI C A TI O N S P O LI C Y A N D S H A RI N G O F D A T A  .....................................8 1  
1 7  R E F E R E N C E S  .........................................................................................................8 1  
1 8  A P P E N DI C E S  ...........................................................................................................8 5  
1 8. 1  
A P P E N DI X I –  S T U D Y P L A N A N D P R O C E D U R E S A T E A C H VI SI T  ......8 5  
1 8. 2  
A P P E N DI X II - NI A/ A A G UI D E LI N E S  ...........................................................9 0  
C CI
C CI

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18.3 
APPENDIX III – CYP INHIBITORS AND INDUCERS OF INTEREST ....93 
18.4 
APPENDIX IV – CONSORT CHECKLIST & DIAGRAM (v2010) ..............94 
 
 
 

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LIST OF ABBREVIATIONS 
Aβ 
β-Amyloid 
AchEI 
Acetylcholinesterase Inhibitor 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale-Cognitive (subscale) 
ADCOMS 
Alzheimer’s Disease Composite Score 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study - Activities of Daily Living Inventory 
ADME 
Absorption, Distribution, Metabolism, Excretion 
AICD 
Automatic Implanted Cardioverter Defibrillator 
AUC 
Area Under the Curve 
AE 
Adverse Event 
AIDS 
Acquired Immunodeficiency Syndrome 
ALS 
Amyotrophic Lateral Sclerosis 
ALT 
Alanine Aminotransferase 
ApoE 
Apolipoprotein E 
AST 
Aspartate Aminotransferase 
BDNF 
Brain-derived Neurotrophic Factor 
BID 
Twice per day 
BUN 
Blood Urea Nitrogen 
CDR-SOB 
Clinical Dementia Rating- Sum of Boxes 
CFR 
Code of Federal Regulations 
CJD 
Creutzfeldt-Jakob Disease 
CONSORT 
Consolidated Standards of Reporting Trials 
CPK 
Creatinine Phosphokinase 
CSF 
Cerebrospinal Fluid 
CYP 
Cytochrome P450  
DMP 
Data Management Plan 
DSM 
Diagnostic and Statistical Manual of Mental Disorders 
DSMB 
Data Safety & Monitoring Board 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
 
EDC 
Electronic Data Capture  
FDA 
Food & Drug Administration 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transferase 
GMP 
Good Manufacturing Practice 
HCV 
Hepatitis C Virus 
HDL 
High-Density Lipoprotein 
HIPAA 
Health Insurance Portability & Accountability Act 
hr (unit) 
Hour 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent-To-Treat 
kg (unit) 
Kilogram 
LAR 
Legally Authorized Representative 

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LBD 
Lewy Bodies Dementia 
LDH 
Lactate Dehydrogenase 
LDL 
Low-Density Lipoprotein 
LFT 
Liver Function Test 
LP 
Lumbar Puncture 
MAD 
Multiple Ascending Dose 
MCI 
Multiple Cerebral Infarctions 
MINT 
Multi-lingual Naming Test 
mITT 
Modified Intent-To-Treat 
mg (unit) 
Milligram 
ml (unit) 
Milliliter  
MMSE 
Mini-Mental State Examination 
MoCA 
Montreal Cognitive Assessment 
MRI 
Magnetic Resonance Imaging 
NfL 
Neurofilament Light (Protein) 
ng (unit) 
Nanogram 
NIA 
National Institute on Aging 
NOAEL 
No-observed-adverse-effect-level 
NPH 
Normal Pressure Hydrocephalus 
NPI 
Neuropsychiatric Inventory 
OHRP 
Office of Human Research Protection 
PHI 
Personal Health Information 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PSP 
Progressive Supranuclear Palsy 
QD 
Once per day 
Quarc 
Quantitative Anatomical Regional Change 
RBC 
Red Blood Cell 
SAD 
Single Ascending Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCA 
Spinocerebellar Ataxia 
SD 
Standard Deviation 
SSC 
Study Steering Committee 
sTREM2 
Soluble Variant Triggering Receptor Expressed on Myeloid Cells 2 
TEAE 
Treatment Emergent Adverse Event 
ULN 
Upper Limit of Normal 
USPI 
United States Prescribing Information 
VILIP 
Visinin-Like Protein 
vMRI 
Volumetric Magnetic Resonance Imaging 
WBC 
White Blood Cell 
 

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1 INTRODUCTION  
1.1 
Background 
More than 5 million people are afflicted with Alzheimer’s disease (AD) in the United States, 
and by 2050 this number could rise as high as 16 million (Dementia, 2017). Recent data suggests 
that AD affects twice as many females as males, and is thought to be associated with multiple 
biological and genetic factors. The emotional and financial burden of AD to patients, family 
members, and society is enormous, and is predicted to grow exponentially as the median 
population age increases. The potential to preserve, or even improve, cognition in adults at high 
risk of cognitive decline due to AD clearly has important implications, not only for the affected 
individual, but also for the support system that bears the social and financial burdens of long-term 
caregiving.  
There are medications currently approved for symptomatic treatment of AD, but they have small 
effect sizes and generally limited clinical benefits. An urgent need exists to find effective 
treatments for AD that can arrest or reverse the disease before its advanced stages. Therapeutic 
strategies aimed at restoring synaptic and extra synaptic glutamate levels, offer potential 
therapeutic benefit in AD, in cognition, as well as in the neuroprotection of synapses, conferring 
the potential for disease modification. The significance of clinical research directed at this 
preclinical validated synaptic target cannot be overstated, given the lack of therapeutic progress in 
symptomatic and disease-modifying treatments since 2003.  
Biohaven Pharmaceuticals, Inc. [Biohaven] is developing a new drug, BHV-4157, for the potential 
treatment of mild to moderate Alzheimer’s Disease as well as for other neurologic and psychiatric 
disorders. BHV-4157 is a novel and optimized prodrug of the glutamatergic agent riluzole. The 
FDA originally approved riluzole (RILUTEK®) 50 mg twice-a-day (NDA #20-599) for the 
treatment of patients with amyotrophic lateral sclerosis (ALS). Riluzole is only indicated for ALS 
and has a number of non-desirable attributes that have limited its clinical use. BHV-4157 is a 
tripeptide prodrug of the glutamate modulating agent riluzole that has been optimized for improved 
bioavailability, pharmacokinetics and dosing.  
More specifically, BHV-4157 was developed to address the limitations of riluzole that have 
restricted its broader clinical application. Riluzole tablets have 60% bioavailability, attributed to 
high first-pass metabolism in the liver. This is thought to be related to metabolism by the 
heterogeneously expressed CYP1A2 enzyme, which also accounts for the high PK variability 
associated with riluzole (Carlsson, 2000; Pittenger, 2015a, 2015b). In addition, riluzole is 
associated with reduced exposure when taken with meals (i.e.,  a negative food effect), resulting 
in the guidance to take riluzole within a three hour fast (one hour before or two hours after a meal). 
Riluzole is also dosed twice a day, has dose-dependent effects on liver function tests and the drug 
substance itself has other intrinsic limitations including: very low solubility in water, poor oral 
palatability, pH dependent chemical stability, and intense oral numbness if administered directly 
to the oral mucosa. 
Based on the preclinical features of BHV-4157, we anticipate the clinical pharmacology to offer 
favorable properties as compared to available riluzole. These include: 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 1 8  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  I m pr o ve d Bi o a v ail a bilit y— B H V -4 1 5 7 is a s u bstrate f or t he g ut tra ns p orters ( Pe p T 1). 
T his is t h o u g ht t o c o ntri b ute t o its i ncreased  bi oa v aila bilit y as c o m pare d t o or all y -d ose d 
ril uz ol e, me a ni n g t hat m ore of t he c o m p o u n d is a bs or be d b y t he b o d y i nt o t h e bl o o d str ea m 
a n d ca n ha ve a n acti v e effect. St u dies ha ve s h o w n t hat a d mi nistr ati o n of a ge nts t hr o u g h 
pe pti de tra ns p orters si g nific a ntl y i ncr eases t he a bs or pti o n of dr u gs wit h ot her wise p o or oral 
bi oa vaila bilit y.  
•  N o Ne g ati ve F o o d Effect — B H V -4 1 5 7 s h o ws n o f o o d effect i n h u m a n st u di es, me a ni n g 
t hat t h e dr u g will n ot b e ass oci ate d wit h s peci al meal r estricti o ns, a p he n o me n o n p ot e nti all y 
attri b uta bl e t o e n ha nc e d u pta ke b y i nt esti nal tra ns p orters s pecific t o t h e pe pti d e -c o nt ai ni n g 
m o iet y of B H V -4 1 5 7 . T his is i n c o ntrast t o oral ril uz ole t a blets, w hic h re q uir e a 3-h o ur 
wi n d o w of fasti n g ar o u n d its t w o dail y d oses t o rea c h t hera p e uti c le v els, c urr e ntl y a d ose -
li miti n g fa ct or of ril uz ol e. 
•  L o wer O v er all Dr u g B ur de n t o t he Li ver —  as  a pr o dr u g t hat miti g ates first-pass li ver 
meta b olis m a n d e n h a nces bi o a vaila bilit y, t h era p e utic c o n ce ntr ati o ns of t h e acti ve 
meta b olit e ril u z ole c a n be a c hie v e d wit h a l o wer dr u g d ose as c o m pare d t o ril uz ole t a blets. 
I n a d diti o n, r elease of t he a cti v e meta b olite o ver ti m e will res ult i n a re d uc e d b ol us he patic 
c o nce ntr ati o n as c o m p are d t o t hat ass ociate d wit h ril uz ol e ta bl ets. Ta ke n t o g et her, we 
belie v e t hese attri b utes of B H V -4 1 5 7  will re d uc e t he p ote nti al f or a d v erse li ver effects.  
•  O pti mize d D osi n g Re gi m e n a n d C o m pli a nce — B H V -4 1 5 7 has bee n  de v el o pe d as a 
c o n ve nie nt o nce dail y d ose, w hic h c o ul d i m pr o v e r e gi me n c o m pli a nce f or patie nts. W e 
belie v e t hese are i m p o rta nt feat ures t o o pti mi ze l o n g-ter m he alt h o utc o m es i n t he treat me nt 
of patie nts wit h c hr o ni c diseases.   
1. 2  
P recli nic al & Scie ntific R ati o n ale  
S y na ptic l oss is a f u n d a me ntal a n d c o nsist e nt pat h o bi ol o gical feat ure of A D. I n dee d, s y na ptic l oss 
i n t he hi p p oc a m p us a n d ne oc orte x pr o vi des t he str o n gest a nat o mic al c orrelati o ns t o disease 
se verit y ( Terr y et al., 1 9 9 1). F urt her m or e, t h ere is i n creasi n g e vi de n ce fr o m p ost -m orte m st u dies 
i m pli cati n g gl ut a mater gi c s y na pt ot o xicit y i n A D, res ulti n g i n decre ase d s y na pti c pl asticit y. I n A D , 
t here is re d uc e d f u ncti o nal gl ut a mate tra ns p orter c o n ce ntrati o n ( e xcitat or y a mi n o aci d tr a ns p orter 
2: E A A T 2), wit h res ult a nt ele vat e d s y na pti c e xtr acell ular gl uta m ate.  
A ne ur ot o xic c ycle of i ncre ase d e xtrac ell ular gl ut a m ate acti vat es N M D A rece pt ors a n d lea ds t o a 
re d ucti o n i n d o w nstrea m tr o p hi c eff ect ors, i ncl u di n g C R E B a n d B D N F, ca usi n g cell deat h a n d 
atr o p h y ( Har di n g ha m, 2 0 0 6). I n crease d e xtra cell ular gl uta mat e als o lea ds t o i n crease d a m yl oi d-
beta ( A β ) pr o d ucti o n ( B or dji, B ecerril-Orte ga, Ni c ole, & B uiss o n , 2 0 1 0), w hic h ca n f urt her 
i ncrease gl uta m ate release wit h re d uc e d s y na ptic u pta ke ( C hi n et al., 2 0 0 7; Mat os, A u g ust o, 
Oli veira, & A g osti n h o, 2 0 0 8; Sci me mi et al., 2 0 1 3)  a n d i ncrease d t a u rele ase ( H u ns ber ger et al., 
2 0 1 5) . Decreases i n E A A T 2 c orrelat e t o s y na ptic l oss a n d disease se verit y.  
A ni mal m o del data i n cl u di n g be h a vi oral o bser vati o ns f urt her s u p p ort a n d e xte n d t hese fi n di n gs. 
I n o ne e x peri m e ntal m o del, a d o u ble tr ans ge nic m o use ( T G) wit h a m yl oi d o ver pr o d ucti o n 
(A β P P s we/ P S 1 E Δ 9) lac ki n g o ne all ele f or t he E A A T 2 s h o we d accelerate d a n d i n crease d c o g niti v e 

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impairment compared to TG mice with both EAAT2 alleles (Mookherjee et al., 2011). In another 
study, a TG mouse approach crossing EAAT2 transgenic mice with APPSw,Ind mice and a 
pharmacological approach using an EAAT2 translational activator were conducted. Findings from 
both approaches demonstrated that restored EAAT2 protein function improved pathology, while 
the APPSw,Ind using an EAAT2 translational activator approach also improved clinical phenotype 
and pathology (Takahashi et al., 2015). Thus, there is model support for EAAT2 as a therapeutic 
target to impact glutamatergic synaptic NMDA interactions. 
Glutamate transporter 1 (GLT-1), the mouse homologue of the EAAT2, expresses predominately 
on astrocytes and is responsible for regulating 90% of glutamate levels in the synapses. In a study 
by Zumkehr et al. using a triple transgenic mouse model of AD (3xTg-AD), GLT-1 was 
pharmacologically overexpressed by administering ceftriaxone, and results showed that the 
chronic upregulation of GLT-1 significantly attenuated tau pathology, restored synaptic proteins, 
and rescued cognition without affecting Aβ pathology (Zumkehr et al., 2015). Specifically, on a 
behavioral basis, ceftriaxone-treated mice had better memory performance (Morris Water Maze 
and Novel Object Recognition). In this paradigm, the GLT-1 dysfunction and improvement did 
not appear to be related to amyloid species or pathology. This behavioral finding was further 
supported on a molecular basis via ELISA and histological analyses showing that GLT-1 
dysfunction did not affect amyloid precursor protein (APP) processing, overall Aβ species levels, 
or plaque pathology in 3xTg-AD mice. Of further interest was the histopathological finding that 
ceftriaxone-treated 3xTg-AD mice had significantly less CP13-positive tau (pSer202) bearing 
neurons in the cortex and hippocampus. Similarly, the mean intensity from immunofluorescence 
staining with the PHF-1 antibody (pSer396/Ser404) was significantly less than the vehicle group 
in the CA1 region of the hippocampus. Quantitative analysis of fluorescent signals revealed that 
synaptic proteins detected by SYP and PSD-95 antibodies were significantly preserved in the CA3 
region of the hippocampus of ceftriaxone-treated 3xTg-AD mice. Furthermore, a significant 
restoration of PSD-95 immunoreactivity in the CA1 region of the hippocampus was also observed 
in ceftriaxone-treated 3xTg-AD mice. Restoration of PSD-95 also showed a correlation with 
augmented cognitive performance by the Morris Water Maze. Overall, these findings indicate that 
increasing GLT-1 may play a pivotal role in preserving synapses and neuron-to-neuron 
communication in AD.  
In the P301L tauopathy mouse model, Hunsberger et al (2015) demonstrated that treatment with 
riluzole at 12 mg/kg/day improved memory performance and that improvement was associated 
with a decrease in glutamate release and an increase in glutamate uptake in the dentate gyrus region 
of the hippocampus. Riluzole treatment also reduced tau pathology and increased hippocampal 
GLT-1 and PSD-95 expression. 
In aged rats, GLT-1 gene expression is significantly reduced and treatment with riluzole 
significantly increases GLT-1 gene expression and decreases hippocampal cytokine levels. This 
highlights the therapeutic potential of enhancing glutamate transport in diseases characterized by 
neuroinflammation and neurodegeneration (Brothers et al., 2013). RNA sequencing, validated by 
qRT-PCR open arrays, has been used to confirm increases in GLT-1 gene expression in response 
to riluzole treatment (Pereira et al., 2017). Another study, investigating the effects of riluzole on 
memory decline in aged rats (10-months old) treated with riluzole or vehicle for 17 weeks (Pereira 
et al., 2014), found that the aged riluzole-treated rats did not exhibit age-related cognitive decline 

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over time in the Y-maze test (a hippocampal-dependent task) compared with aged-control rats. 
Moreover, memory performance was correlated with the density of thin spines on apical dendrites 
in the CA1 region of the hippocampus. Riluzole-treated rats had an increase in clustering of thin 
spines that correlated with memory performance and was specific to the apical, but not basilar, 
dendrites of CA1. Other studies investigating the effect of riluzole on glutamate uptake in rat 
astrocyte cultures have showed a biphasic concentration-dependent effect on basal glutamate 
uptake with low concentrations (1 and 10 microM) of riluzole significantly increasing glutamate 
uptake (Frizzo, Dall'Onder, Dalcin, & Souza, 2004). 
Neuronal hyper excitation occurs in transgenic mouse models overexpressing APP and its 
pathogenic product, Aβ protein. The cellular basis of this has been pursued in rat models using 
brain tissue slices with bath application of soluble Aβ1-42 and with riluzole treatment to investigate 
whether a persistent sodium current (INaP) may, in part, account for the Aβ-induced neuronal 
hyperexcitation (Ren et al., 2014). Results showed that soluble Aβ1-42 increased neuronal 
excitability in a concentration-dependent manner and increased the amplitude of INaP without 
significantly affecting its activation properties. In the presence of riluzole, the Aβ1-42 induced 
neuronal hyperexcitation and INaP augmentation were significantly inhibited. These findings 
suggest that soluble Aβ1-42 may induce neuronal hyperexcitation by increasing the amplitude of 
INaP and that riluzole can inhibit the Aβ1-42-induced abnormal neuronal activity. 
1.3 
Mechanism of Action 
The active metabolite of BHV-4157, riluzole, has been documented to have a wide range of 
pharmacological actions, including interactions with several types of ion channels, cellular 
signaling mechanisms, and facilitation of glutamate reuptake. The figure below illustrates the 
potential targets related to riluzole’s mechanism of action: (1) Reducing presynaptic glutamate 
release through actions at the voltage-gated ion channels, (2) Facilitation of glutamate uptake via 
EAATs located on glial cells, (3) Enhanced transmission through synaptic AMPA receptors, (4) 
Altering GABAergic neurotransmission (5) Effects on neurotrophic agents such as BDNF. Several 
of these actions of riluzole balance abnormalities observed in human post-mortem tissue as well 
as in animal models. As such, BHV-4157 potentially offers neuroprotective effects at the level of 
the synapse as well as improved synaptic functioning, mechanisms that could exert both 
symptomatic and disease-modifying effects in AD.  
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 1  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
Fi g ure 1. M ec h a nis m of A cti o n  ( Ril uz ole)  
 
 
 
1. 4  
  
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 2  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1. 5  
  
 
C CI
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 3  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1. 6  
P ote nti al f or Dr u g -Dr u g I nter acti o ns  
B H V -4 1 5 7 : B H V-4 1 5 7, itself, is n ot e x pecte d t o i nterfere wit h dr u g m eta b olis m , a n d its cl ea va g e 
via pl as ma pe pti d ases re n der s it u nli k el y t o b e aff e cte d si g nific a ntl y b y li ver c yt o c hr o me P 4 5 0 
i n hi bit ors. B H V-4 1 5 7 has t he f oll o wi n g k n o w n p har mac o ki n eti c/ m eta b olis m para met ers:  
•  N ot a n i n hi bit or of C Y P 3 A 4, C Y P 1 A 2, or  C Y P 2 D 6  
•  I n C Y P i n d ucti o n st u di es: 
o  T he esti mat e d E C 5 0 a n d E ma x  f or C Y P 1 A 2 m R N A was 1. 4 4 μ M a n d 3. 4 7-f ol d 
i n d ucti o n, res pe cti v el y 
o  T he esti mate d E C 5 0  a n d E ma x  f or C Y P 2 B 6 m R N A was 1 2. 6 μ M a n d 2 7. 0-f ol d 
i n d ucti o n, r es pecti vel y 
o  B H V -4 1 5 7 di d n ot i ncrease C Y P 3 A 4 m R N A at d oses u p  t o 3 0 μ M  
Ril uz ol e Met a b olis m:  B H V -4 1 5 7 met a b oli zes t o ril uz ole. As per t he U S PI, ril u z ole meta b olis m 
has bee n assesse d i n s pecial p o p ulati o ns, c hara cterize d b y he patic i m pair me nt ( 2 t o 3 f ol d i ncrease 
i n A U C wit h C hil d-P u g h Sc ores of A a n d B), re nal i m pai r m e nt ( n o effect), a g e ( n o effect), se x ( n o 
effect), s m o k ers ( 2 0 % faster eli mi n ati o n) a n d rac e (Ja pa nese c o m pare d t o C a ucasi a ns: n o effe ct).  
Effect of ot h er dr u gs o n ril uz ol e m eta b olis m: I n vitr o st u di es usi n g h u m a n li ver micr os o m al 
pre parati o ns s u g gest t h at C Y P 1 A 2 is t he pri nci p al is oz y m e i n v ol v e d i n t he i nitial o xi dati ve 
meta b olis m of ril uz ole a n d, t her ef ore, p ote ntial i nt eracti o ns ma y occ ur w he n ril uz ole is gi ve n 
c o nc urre ntl y wit h a ge nts t hat affe ct C Y P 1 A 2 acti vit y. P ote ntial i n hi bit ors of C Y P 1 A 2 (e. g., 
ci pr ofl o x a ci n, e n o x a ci n, fl u v o x a mi n e, 
m et h o xs al e n, 
m e xil eti n e, 
or al c o ntr a c e pti v es, 
t hi a b e n d a z ol e, v e m ur af e ni b, zil e ut o n) c o ul d decr ease t he rate of ril u z ole eli mi n ati o n, w hil e 
i n d ucers of C Y P 1 A 2 (e. g., ci garette s m o ke, c harc oal-br oile d f o o d, rifa m pici n, a n d o me pr az ol e) 
c o ul d i ncr ease t h e rate of ril uz ole eli mi nati o n.  
Effect of r il uz ole o n t h e meta b olis m of ot her dr u gs: C Y P 1 A 2 is t he pri nci pal is oe nz y m e i n v ol v e d 
i n t he i nitial o xi dati ve met a b olis m of ril u z ole; p ot e ntial i nt eracti o ns ma y occ ur w he n ril uz ole is 
gi ve n c o nc urr e ntl y wit h ot her a ge nts w hic h are als o meta b oliz e d pri m aril y b y C Y P 1 A 2 (e. g., 
t he o p h ylli ne, caffei ne, a n d tacri ne). C urre ntl y, it is n ot k n o w n w het her ril uz ole has a n y p ote nti al 
f or e nz y me i n d ucti o n i n h u m a ns. 
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 4  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
It is p ossi ble t hat BH V -4 1 5 7 ma y re d uce t he efficac y of c o -a d mi nistere d dr u gs t hat are se nsiti v e 
s u bstrates of C Y P 1 A 2 a n d C Y P 2 B 6. 
1. 7  
Cli nic al E x perie nce  
T o dat e, B H V -4 1 5 7 has be e n well t olerate d a n d n o n e w t oler a bilit y or safet y si g nals c o m par e d t o 
t he pre vi o usl y a p pr o v e d ril uz ole h a ve b ee n o bser v e d.  Data fr o m cli nical st u di es  of B H V -4 1 5 7  are 
briefl y s u m marize d bel o w.  Please refer t o t h e I n vesti gat or’s B r oc h ure f or a d diti o nal cli nical 
i nf or mati o n.  
1. 7. 1  
A dverse Eve nt Pr ofile  
1. 7. 1. 1  
B H V -4 1 5 7  
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 5  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
St u d y B H V 4 1 5 7 -2 0 1 was  a d o u bl e-bli n d, pla ce b o -c o ntr olle d st u d y c o n d u cte d wit h B H V -4 1 5 7 t o 
assess safet y, t ol era bilit y a n d effic ac y i n partici pa nt s wit h S C A, w hic h is a pr o gr essi ve, ge n eti c, 
de ge nerati ve ne ur ol o gi cal disease. Parti ci pa nt s rec ei ve d B H V-4 1 5 7 1 4 0 m g o n ce d ail y or pl ace b o 
f or 8 wee ks. A t otal of 1 4 1 partici pa nt s were e nr olle d i nt o t he st u d y. O verall, B H V-4 1 5 7 1 4 0 m g 
o nce dail y f or 8  wee ks was well t oler ate d i n a d ult partici p a nt s wit h S C A. T he maj orit y of a d verse 
e ve nts were mil d or m o d erat e  i n se verit y. T h ere were n o deat hs re p orte d i n t his st u d y. Tre at m e nt-
e mer ge nt S A Es 
were re p orte d f or 5 ( 3. 5 5 %) p artici pa nt s, i ncl u di n g 4  B H V -4 1 5 7 -treat e d 
partici pa nt s (ast h e nia, atri al fi brill ati o n, bl o o d cre ati ni ne p h os p h o ki nase i n crease d, d e h y drati o n, 
bac k pai n a n d cere br al i nf arcti o n), a n d 1  pl ace b o -tre ate d partici pa nt  (c h est disc o mf ort). N o S A E 
re p orte d i n t h e B H V-4 1 5 7 gr o u p was j u d g e d b y t he i n vesti gat or t o b e tr eat me nt rel ate d. T he 
c o m pleti o n r ate was 9 0. 1 4 % ( 6 4/ 7 1 partici p a nt s) i n t he B H V-4 1 5 7 gr o u p a n d 9 7. 1 4 % ( 6 8/ 7 0 
partici pa nt s) i n t he plac e b o gr o u p. T he fre q ue n c y of tr eat me nt-e mer ge nt A Es t hat l e d t o 
wit h dra wal fr o m st u d y dr u g was 4. 2 3 % ( 3/ 7 1 partici p a nt s) i n t h e B H V-4 1 5 7 gr o u p a n d n o 
partici pa nt  i n t he place b o gr o u p. T h e m aj orit y of tre at me nt -e mer ge nt A Es d uri n g t h e D o u ble -Bli n d 
Ra n d o miz ati o n p hase ( Safet y A nal ysis Set) were mil d or m o derate i n se verit y, n ot relat e d t o st u d y 
t hera p y, a n d res ol v e d s p o nta ne o usl y b y t he e n d of tr e at me nt. T he m ost fre q u e ntl y ( ≥ 5 %) re p orte d 
treat me nt-e mer ge nt A Es were:  
T re at m e nt -e mer ge nt A E 
N u m ber of P artici p a nts ( %)  
St u d y Gr o u p  
Dizzi ness  
8 ( 1 1. 2 7 %)  
1 ( 1. 4 3 %)  
B H V -4 1 5 7  
Place b o  
Fati g ue  
6 ( 8. 4 5 %)  
3 ( 4. 2 9 %)  
B H V -4 1 5 7  
Place b o  
Fall  
5 ( 7. 0 4 %)  
1 ( 1. 4 3 %)  
B H V -4 1 5 7  
Place b o  
Hea dac he  
4 ( 5. 6 3 %)  
4 ( 5. 7 1 %)  
B H V -4 1 5 7  
Place b o  
Na us ea  
4 ( 5. 6 3 %)  
4 ( 5. 7 1 %)  
B H V -4 1 5 7  
Place b o  
M us cle S pas ms  
4 ( 5. 6 3 %)  
2 ( 2. 8 6 %)  
B H V -4 1 5 7  
Place b o  
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 6  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
N o cli nicall y me a ni n gf ul tr e n ds i n la b orat or y val u es were i de ntifi e d i n t his st u d y. N o partici pa nt  
ha d A S T or A L T la b orat or y a b n or malities > 3 X U L N. Partici pa nt s c o m pleti n g t he d o u ble-bli n d 
treat me nt p hase were offere d 4 8 wee ks of o pe n -la bel treat m e nt with B H V -4 1 5 7 ( 1 4 0 m g P O Q D) 
i n a n O pe n -L a bel E xt e nsi o n p hase . O ne h u n dre d a n d t hirt y-o n e ( 1 3 1) partici pa nt s c o nti n u e d i nt o 
t he O pe n -La b el E xte nsi o n p hase . T he safet y pr ofile of B H V-4 1 5 7 1 4 0 m g Q D d uri n g l o n g -ter m 
treat me nt (ra n d o miz ati o n a n d e xte nsi o n p hases t hr o u g h t he 0 7-Se p -2 0 1 8 data c ut off date) was 
c o nsiste nt wit h t he B H V -4 1 5 7 safet y pr ofile o bser ve d d uri n g t he d o u bl e bli n d treat me nt p hase.  
1. 7. 1. 2  
Ril uz ole  
Cli nic al i nf or m ati o n o n ril uz ole, as reflect e d i n t he U S PI, is pre d o mi na ntl y base d o n e x peri e nce 
fr o m a p pr o xi mat el y 4 0 0 0 pati e nts gi ve n ril uz ole f or A L S. Refer t o t he U S PI  w here greater details 
o n t he a d verse e ve nt pr ofile of ril uz ole ca n be f o u n d.  T he f oll o wi n g s u m mariz es rele va nt 
i nf or mati o n. 
O ver all, ril uz ole ta blets ha ve bee n 
well t oler ate d i n p o p ulati o ns 
wit h 
A L S a n d di verse 
ne ur o ps yc hiatric c o n diti o ns t h at i n cl u de maj or d e pr essi ve dis or der, ge ner ali ze d a n xiet y dis or der  
a n d s pi n ocere bellar at a xia . I n ra n d o mi ze d c o ntr olle d trials c o m pari n g a 1 0 0 m g dail y d ose of 
ril uz ol e wit h pl ace b o, n o A Es occ urre d at rates greater t ha n 5 % a n d t wice t hat of plac e b o. T he A Es 
occ urri n g great er t ha n 5 % a n d at le ast 2 % m ore t ha n place b o i ncl u de d ast he nia ( 1 8 % vs 1 2 % 
place b o) a n d na use a ( 1 4 % vs 9 %). T hese t w o A Es s h o we d tre n ds f or a d ose res p o nse  ( Lac o m blez, 
Be nsi m o n, Lei g h, G uillet, & Mei ni n ger, 1 9 9 6) . T h e p u blis he d literat ur e o n t he use of ril uz ole 
ta blets i n ps yc hiatric dis or ders, w hile ge ner all y c o m prise d of case -series, is c o nsiste nt wit h t his 
t olera bilit y pr ofil e. 
T he m ost c o m m o nl y o bser ve d A Es ass ociate d wit h t h e use of ril uz ole ta blets m ore fre q ue ntl y t ha n 
place b o treate d patie nts were:  
•  ast he nia  
•  na usea  
•  dizzi n ess  
•  decrease d l u n g  f u n cti o n  
•  diarr hea  
•  a b d o mi nal pai n  
•  p ne u m o nia  
•  v o miti n g  
•  verti g o  
•  circ u m or al parest hesi a  
•  a n ore xia   
•  s o m n ole nce 
A p pr o xi matel y 1 4 % ( n = 1 4 1) of t he 9 8 2 i n di vi d u als wit h A L S w h o recei ve d ril uz ole i n pr e -
mar keti n g cli nic al trials disc o nti n ue d treat me nt bec a use of a n a d verse e x p erie n ce. Of t h ose patie nts 
w h o disc o nti n ue d d ue t o a d verse e ve nts, t he m ost c o m m o nl y re p ort e d were: na usea, a b d o mi n al 
pai n, c o nsti pati o n, a n d A L T el e vati o ns. I n a d ose r es p o nse st u d y i n A L S patie nts, t he rat es of 
disc o nti n uati o n of RI L U T E K ®  f or ast h e nia, n a usea, a b d o mi nal p ai n, a n d A L T ele vati o n were d ose 

Confidential
Protocol BHV4157-203 
Page 27 of 96
 
Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
related. The AEs of asthenia, nausea, dizziness, diarrhea, anorexia, vertigo, somnolence, and 
circumoral paresthesia were dose related. Assessment of pulmonary AEs is confounded by the 
underlying illness, ALS, which is associated with respiratory symptoms. 
1.7.1.3 
Elevations in Liver Function Tests 
BHV-4157 has not been associated with significant changes in liver function or pathology in 
nonclinical toxicology studies to date, as reflected in the Investigator’s Brochure. No clinically 
significant LFT changes were observed on study drug in BHV4157-101. No participant had AST 
or ALT laboratory abnormalities > 3 X ULN in BHV4157-102, BHV4157-103 or BHV4157-201. 
BHV4157-203, BHV4157-206, and BHV4157-207 are blinded and ongoing. Preliminary safety 
findings are based on available randomized, double-blind data. As of 22-Jan-2020, 1 subject 
discontinued from BHV4157-207 and 1 subject discontinued from BHV4157-203 due to increased 
liver function tests.  
Riluzole is associated with elevations in aminotransferases that have been reflected in monitoring 
precautions that will be followed within this protocol. Experience in almost 800 ALS patients 
indicates that about 50% of riluzole-treated patients will experience at least one ALT/SGPT level 
above the upper limit of normal, about 8% will have elevations > 3 X ULN, and about 2% of 
patients will have elevations > 5 X ULN. A single non-ALS patient with epilepsy treated with 
concomitant carbamazepine and phenobarbital experienced marked, rapid elevations of liver 
enzymes with jaundice (ALT 26 X ULN, AST 17 X ULN, and bilirubin 11 X ULN) four months 
after starting riluzole; these returned to normal 7 weeks after treatment discontinuation. Maximum 
increases in serum ALT usually occurred within 3 months after the start of riluzole therapy and 
were usually transient when < 5 X ULN. In trials, if ALT levels were < 5 X ULN, treatment 
continued and ALT levels usually returned to below 2 X ULN within 2 to 6 months. Treatment in 
studies was discontinued, however, if ALT levels exceeded 5 X ULN, so that there is no experience 
with continued treatment of ALS patients once ALT values exceed 5 X ULN. There were rare 
instances of jaundice. There is limited experience with rechallenge of patients who have had 
riluzole discontinued for ALT > 5 X ULN, but there is the possibility of increased ALT values 
reoccurring. Therefore, rechallenge is not recommended. In post-marketing experience, cases of 
clinical hepatitis associated with riluzole have been reported, including one with fatal outcome. 
1.7.1.4 
Neutropenia 
BHV-4157 has not been associated with hematologic findings in nonclinical toxicology studies to 
date. In Study BHV4157-101, one participant in the 17.5 mg BID cohort experienced transient and 
mildly decreased white blood cell count after three days of treatment; however, this participant 
evidenced moderate decline during the screening period prior to medication administration. The 
participant’s count increased while on continued study drug and normalized within 6 days after 
onset. No clinically meaningful trends in laboratory values were identified in Study BHV4157-
201. 
For riluzole, according to the USPI, rare cases of neutropenia were reported. Among 
approximately 4,000 patients given riluzole for ALS in clinical trials, there were three cases of 
marked neutropenia (absolute neutrophil count less than 500/mm3), all seen within the first 2 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 8  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
m o nt hs of ril uz ole tr eat me nt. I n o n e case, n e utr o p hil c o u nts r os e o n c o nti n ue d treat me nt. I n a 
sec o n d case, c o u nts r ose after t hera p y was st o p p e d. A t hir d case was m ore c o m pl e x, wit h mar ke d 
a ne mi a as well as ne utr o pe ni a , a n d t he eti ol o g y of b ot h is u ncertai n. Patie nts s h o ul d be war n e d t o 
re p ort a n y fe brile ill ness t o their p h ysicia ns. T he re p ort of a fe brile ill ness s h o ul d pr o m pt treati n g 
p h ysicia ns t o c h ec k w hit e bl o o d cell c o u nts.  
1. 7. 1. 5  
I nterstiti al L u n g Dise ase 
B H V -4 1 5 7 has n ot bee n ass ociat e d wit h p ul m o nar y fi n di n gs i n n o ncli nic al t o xic ol o g y st u dies t o 
date  a n d n o cli nica ll y si g nifica nt p ul m o nar y fi n di n gs t o date i n cli nic al st u di es. 
 
F or ril uz ol e , a cc or di n g t o t he U S PI, rare c ases of i nterstitial l u n g disease ha v e be e n re p orte d, s o m e 
of t he m se vere; u p o n f urt her i n vesti gati o n, ma n y of t h ese cases were h y perse nsiti vit y p ne u m o nitis. 
If res pirat or y s y m pt o ms de vel o p s uc h as dr y c o u g h a n d/ or d ys p nea, c hest ra di o gra p h y s h o ul d be 
perf or me d, a n d i n c ase of fi n di n gs s u g gesti ve of i nterstitial l u n g disease or h y p erse nsiti vit y 
p ne u m o nitis (e. g.  bilat eral diff us e l u n g o pa cities), ril u z ole s h o ul d be disc o nti n u e d i m m e diatel y. I n 
t he maj orit y of t he re p orte d c ases, s y m pt o ms res ol ve d after dr u g disc o nti n u ati o n a n d s y m pt o matic 
treat me nt. 
1. 8  
 
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 2 9  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 0  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1. 9  
P ote nti al Ris k t o Fet al De v el o p me nt  
B H V -4 1 5 7 has n ot yet bee n assesse d i n fertilit y a n d fetal d e vel o p me nt st u dies.  
Ril uz ol e has bee n assesse d pre vi o usl y a n d has bee n c haract eriz e d as a Cate g or y C dr u g. As 
descri be d i n t h e U S PI, oral a d mi nistr ati o n of ril uz ole t o pre g na nt a ni mals d uri n g t h e peri o d of 
or ga n o ge nesis ca use d e m br y o t o xicit y  i n rats a n d ra b bits at d oses of 2 7 m g/ k g a n d 6 0 m g/ k g, 
res pecti v el y, or 2. 6 a n d 1 1. 5 ti mes, res pecti vel y, t he rec o m me n de d m a xi m u m h u ma n dail y d ose 
o n a m g/ m 2 basis. E vi d e nce of m ater nal t o xi cit y was als o o bser ve d at t hese d oses. 
W he n 
a d mi nist ere d t o rats pri or t o a n d d uri n g mati n g ( mal es  a n d fe m ales) a n d t hr o u g h o ut gest ati o n a n d 
lact ati o n (fe mal es), ril uz ol e pr o d uce d a d v erse effe cts o n pre g na nc y ( decr ease d i m pla nt ati o ns, 
i ncrease d i ntra uteri ne deat h) a n d offs pri n g via bilit y a n d gr o wt h at a n oral d ose of 1 5 m g/ k g or 1. 5 
ti mes t he ma xi m u m dail y d ose o n a m g/ m2 basis. T her e are n o a de q uate a n d well -c o ntr olle d st u dies 
i n pre g na nt w o me n. Ril uz ol e s h o ul d be use d d uri n g pre g na nc y o nl y if t h e p ote ntial be nefit j ustifi es 
t he p ote ntial ris k t o t h e fet us. 
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 1  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
2  S T U D Y D E SI G N  
T his is a p hase  2  m ulti -ce nter, 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 
i n patie nts  wit h  mil d  t o m o derate  Alz hei mer’s  disease .  
P artici p a nts  will be ra n d o mize d t o o ne of t w o gr o u ps: 2 8 0  m g of B H V -4 1 5 7 or place b o. T he 
B H V -4 1 5 7 treat m e nt d ose of 2 8 0  m g was sel ect e d f or e val u ati o n i n t he c urre nt st u d y base d o n 
e vi de nc e s u m mariz e d i n  Secti o n 1. 8 . D o u ble -bli n d t r eat m e nt d urati o n is a p pr o xi mat el y 4 8 w ee ks 
( 1 2 m o nt hs). T h ere is a scree ni n g peri o d of u p t o 4 2 d a ys a n d a 4 -wee k p ost -treat me nt o bser vati o n 
peri o d  (f or s u bjects w h o d o n ot partici pat e i n t h e O pe n-La bel E xt e nsi o n p hase) . 
 
 
 
 
  
I n a d diti o n, s u bj ects w h o ar e c o m pleti n g or ha ve c o m plet e d t he D o u bl e-bli n d treat me nt p hase 
ma y be offer e d t h e o p p ort u nit y t o e nr oll i n a n O pe n -La bel E xt e nsi o n p h ase, i n w hic h s u bjects 
will recei ve o pe n -la b el tre at m e nt wit h B H V-4 1 5 7 f or a p pr o xi m at el y 4 8 wee ks. E nr oll me nt i nt o 
t he O pe n -La b el E xte nsi o n p hase f or all s u bjects is c o nti n ge nt o n t he PI’s j u d ge m e nt t hat o p e n -
la bel tre at m e nt offers a n a cce pta bl e ris k-be nefit pr ofil e f or e ac h i n di vi d ual. All s u bjects w h o e nt er 
t he O pe n-La b el E xte nsi o n p hase will nee d t o si g n a ne w i nf or me d c o nse nt f or m.  
•  Partici p a nts  w h o are c o m pleti n g t h e d o u ble -bli n d tr e at me nt p hase m a y dire ctl y e nter t he 
O pe n -La bel E xte nsi o n p hase. T hese partici p a nts  s h o ul d n ot c o m plete t he f oll o w-u p safet y 
visit at W ee k 5 2 ( of t he d o u ble -bli n d tr eat me nt p has e). I nstea d, t hese partici p a nts  s h oul d 
c o nti n ue directl y i nt o t he O pe n -La bel E xt e nsi o n p has e starti n g at W ee k 4 8  ( of t h e d o u ble-
bli n d treat me nt p hase).  T he W ee k 4 8 visit will ser ve as t he Baseli ne visit i n t he  O pe n -
La bel E xte nsi o n p h ase  f or partici p a nts w h o are g oi n g directl y fr o m t he d o u bl e-bli n d 
treat me nt p hase t o t he O L E. T her eaft er, partici pa nts will u n der g o visits at Wee k 4, Wee k 
8, Wee k 1 2,  a n d t he n e v er y 1 2 wee ks of t he O pe n -L a bel E xt e nsi o n p hase as o utli ne d i n 
Ta ble 3 ( Sc h e d ule of Assess me nts/ Ti me & E ve nts - E xte nsi o n P hase).  
•  Partici p a nts w h o pre vi o usl y c o m plete d t h e d o u ble -bli n d tre at m e nt p hase pri or t o t h e 
O pe n -La bel E xte nsi o n p hase of t h e st u d y bei n g o pe n f or recr uit m e nt at t h eir st u d y ce nt er, 
ma y als o e nter t h e O pe n -La bel E xt e nsi o n p hase.  
o  F or partici p a nts w h o will h a ve b ee n off of  t he st u d y dr u g f or less t ha n or e q ual t o 
4 wee ks, t he s u bj ect s h o ul d c o me i nt o t he i n vesti gati ve site f or a n A b bre vi ate d 
Dr u g Dis pe nsati o n Visit  (als o “ A b bre viate d O L E Baseli ne Visit ”) , at w hic h ti m e 
a n y maj or me di cal or m e dic ati o ns c ha n ges will be r e vie w e d pri or t o dis pe nsi n g 
ril uz ol eI n t his c ase, m ost pr oce d ur es fr o m t he We e k 4 8 visit will als o ser ve as t h e 
O pe n -La bel E xt e nsi o n p hase Baseli n e visit , as o utli ne d i n Ta ble 3 ( Sc he d ule of 
Assess me nts/ Ti me & E ve nts - E xte nsi o n P hase) . T hereafter, partici pa nts  will 
u n der g o visits at Wee k 4, W ee k 8,  We e k 1 2,  a n d t he n e v er y 1 2 we e ks of t h e 
E xte nsi o n P hase . 
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 2  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
o  F or partici pa nts w h o ha ve bee n off t h e st u d y dr u g f or great er t h a n 4 wee ks,  t hese 
partici pa nts s h o ul d be re-assesse d a n d re -c o nse nte d b y t he PI d uri n g a n O pe n -
La bel E xte nsi o n Baseli ne Visit. Fr o m t he dat e t hat  t he O pe n -La bel  E xte nsi o n is 
o pe n f or recr uit m e nt at t h e st u d y sit e, t hese partici pa nts t hat c o m pl ete d t he st u d y 
pri or will ha ve u p t o a p pr o xi m atel y 1 2  wee ks  t o c o m plet e t he O pe n -La b el 
E xte nsi o n Baseli ne Visit . T h ereaft er, parti ci pa nts will u n der g o visits at W ee k 4,  
Wee k 8 , We e k 1 2,  a n d  t he n e ver y 1 2 wee ks of t he O pe n-La bel E xt e nsi o n p hase 
as o utli ne d i n Ta bl e 3 ( Sc he d ule of Assess me nts/ Ti me & E ve nts - E xte nsi o n 
P hase). All pre vi o us c o m pleters of t he d o u ble -bli n d p hase will ha v e a  1 2 -we e k 
wi n d o w of o p p ort u nit y t o baseli ne i nt o t he O L E, r e gar dless of t heir dat e of d o u ble -
bli n d p hase c o m pleti o n.  I n t h e e ve nt sites o p e n f or O pe n-La bel r ecr uit me nt, t he n 
cl ose d ue t o C O VI D -1 9  bef ore e nr olli n g all pri or c o m plet ers, e xc e pti o ns t o t h e 
1 2 -wee k wi n d o w will be c o nsi dere d o n a case -b y -cas e basis  f oll o wi n g disc ussi o n 
wit h t he S p o ns or Me dical M o nit o r: 
 
S p o ns or Me dic al M o nit or  
 
 
Cell: 
 
 
 
•  As wit h t he d o u bl e -bli n d p hase, c ertai n pr o visi o ns ma y be i m pl e me nte d, i n or der t o 
mi ni mize p ote ntial haz ar ds t o st u d y partici pa nts d ue t o C O VI D -1 9. T hese pr o visi o ns m a y 
all o w alt er nati ves t o i n -pers o n st u d y visits a n d i ncl u d e b ut are n ot li mite d t o t he f o ll o wi n g: 
c o n d ucti n g re m ote visits via p h o ne/tel e me dici n e vi de o, f oc usi n g o n safet y assess me nts 
d uri n g re m ot e visits, perf or mi n g safet y la bs vi a l ocal la bs or pr ofessi o nal i n h o me 
p hle b ot o m y ve n d ors, a n d s hi p pi n g st u d y me dicati o n t o st u d y p arti ci pa nts  if n ee de d. A n y 
p ote nti al iss ues s h o ul d be disc usse d wit h t he S p o ns or a n d will b e a d dresse d o n a n 
i n di vi d ualiz e d basis. 
•  Partici p a nts  w h o earl y -ter mi nat e d fro m  t he d o u ble-bli n d p hase trial or disc o nti n ue d t he 
st u d y dr u g f or a n y re as o n will n ot be eli gi ble f or e nr oll me nt i n t he O pe n -L a bel E xt e nsi o n 
p hase.  
•  All partici pa nts  m ust h a ve t h eir Wee k 4 8 visit i n -p ers o n pri or t o e nr olli n g i n t he O pe n -
La bel E xte nsi o n p h ase. ( D ue t o C O VI D -1 9,  t he ti mi n g of t his visit m a y be dela ye d) . 
All s u bjects e nteri n g t he O pe n -La b el E xt e n si o n p hase will start wit h o ne ca ps ul e of B H V-4 1 5 7 
( 1 4 0 m g) per d a y a n d titrate t o t w o ca ps ul es per da y after wee k t w o ( 2 8 0 m g). T his will b e d o ne 
s o t hat all p arti ci pa nts will b e o n o pe n-la bel m e dic ati o n a n d will safel y c o nti n u e fr o m eit her a cti v e 
B H V -4 1 5 7 or place b o.   
All s u bjects i n t he O pe n -La bel E xte nsi o n p hase are pla n ne d t o u n der g o a ter mi nati o n visit t w o 
wee ks after t h e last d ose of st u d y dr u g.  
P P D
P P D
P P D
P P D

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 3  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
3  O B J E C TI V E S   
3. 1  
C o -Pri m ar y O bje cti ve s 
T here ar e t w o c o -pri m ar y o bje cti v es:  
•  E val uate t h e effic ac y of B H V -4 1 5 7 a s meas ure d b y A D A S-C o g 1 1  
•  E val uate t h e effic ac y of B H V -4 1 5 7 as meas ure d b y C D R -S u m of B o xes  
3. 2  
Sec o n d ar y O bjecti ves  
T he sec o n d ar y o bj ecti ves ar e t o e val uat e t h e effica c y, safet y a n d t oler a bilit y of B H V -4 1 5 7 as 
o utli ne d b el o w.  
3. 2. 1  
Effic acy  
T he effi cac y of B H V -4 1 5 7 will be assesse d  b y  t he f oll o wi n g me as ures : 
•  V ol u metri c M RI ( Q uarc bil ateral hi p p oc a m pal v ol u me)  
•  Ne ur o ps yc hiatric I n ve nt or y ( N PI)  
•  Alz hei mer’s Disease C o o perati ve St u d y - Acti vities of Dail y Li vi n g ( A D C S -A D L )  
•  Mi ni -Me ntal State E xa mi nati o n ( M M S E)  
3. 2. 2  
S afety a n d T oler a bilit y  
T he  safet y a n d t ol era bilit y of B H V-4 1 5 7 will be assesse d  b y  t he f oll o wi n g m eas ures: 
•  M ortalit y rates  
•  S eri o us a d verse e ve nt rates  
•  A d verse e ve nts  
•  Cli nical safet y la b orat ories  
•  V ital si g ns  
•  P h ysical e xa mi nati o ns  
•  E C Gs  
•  U se of c o nc o mita nt me dicati o ns 
3. 3  
E x pl or at or y  O b jecti ves  
E x pl orat or y o bjecti ves are t o assess:  
•  Effica c y of B H V -4 1 5 7 assesse d b y t he M o ntreal C o g niti ve Assess me nt ( M o C A)  
•  E val uate t h e effica c y of B H V -4 1 5 7 o n perf or m a n ce usi n g t h e A D C o m p osit e Sc ore 
( A D C O M S) 
•  V ol u metri c M RI ( bilateral lat eral v e ntri cles a n d  w h ole brai n v ol u me)  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 4  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  A c o g niti ve c o m p osit e o utc o me c o m p ute d usi n g m eas ures fr o m t he N A C C 
Ne ur o ps yc h ol o gical Test B atter y [ Cr aft St or y 2 1 Re call (I m me diat e & Dela y e d); Be ns o n 
C o m ple x Fi g ure ( C o p y & Dela y e d Recall); M ultili n g ual Na mi n g Test; Letter & C ate g or y 
Fl ue n c y; Tr ail Ma ki n g Test A & B; N u m ber S pa n F or war d a n d Bac k war d]  
•  P har mac o ki n eti cs of B H V -4 1 5 7 a n d ril uz ole i n plas ma  
•  T reat me nt r es p o nse b y A p o E ge n ot y pe 
•  C S F, ser u m a n d plas ma bi o mar kers ( A ß 4 2, 
A ß 4 2/ 4 0 rati o, t otal t a u, p -t a u-1 8 1, 
ne ur o gra ni n, Nf L, Y K L -4 0, VI LI P, S N A P -2 5 , s T R E M 2, G F A P) at scree ni n g, wee k 2 4 
a n d wee k 4 8 of t he d o u bl e -bli n d p hase. C S F will b e assesse d i n a s u bset of t he st u d y 
p o p ulati o n ( esti m ate d n = 5 0 acti ve, n = 5 0 pl ace b o)  
3. 3. 1  
E x pl or at ory O pe n -L a bel E xt e nsi o n P h ase O bjecti v e  
E x pl orat or y O pe n -L a bel E xte nsi o n P h ase o bj ecti ve  is t o e val uate t h e safet y a n d t oler a bilit y of 
B H V -4 1 5 7 as meas ure d b y m ort alit y rates, seri o us a d verse e ve nts, a d v erse e v e nts, cli nic al safet y  
la b orat ories, p h ysical e xa mi nati o ns a n d si g nifi ca nt E C G c ha n g es. 
4  E N D P OI N T S  
4. 1  
C o -Pri m ar y  E n d p oi nt s 
T here ar e t w o pri mar y effic ac y e n d p oi nts:  
•  W it hi n-p arti ci pa nt  c ha n ge i n A D A S -C o g 1 1 fr o m baseli ne  t o we e k  4 8  of t he d o u ble -bli n d 
p hase,  c o m par e d  bet wee n t he tr eat me nt gr o u p a n d t h e plac e b o gr o u p . 
•  W it hi n-p arti ci pa nt c ha n ge i n C D R -S u m of B o xes fr o m  baseli n e t o wee k 4 8  of t he 
d o u ble -bli n d p h ase,  c o m p are d bet we e n t he treat me nt gr o u p a n d t he pl ace b o gr o u p.  
4. 2  
Sec o n d ar y E n d p oi nts  
T he sec o n d ar y e n d p oi nts will me as ure t h e effica c y, a n d safet y a n d t olera bilit y of B H V-4 1 5 7 as 
o utli ne d b el o w.  
4. 2. 1  
Effic acy  
T he eff i cac y of B H V-4 1 5 7 will be assesse d b y  t he wit hi n-partici pa nt c ha n ge s fr o m baseli ne t o 
wee k 4 8  of t he d o u bl e -bli n d p h ase,  c o m par e d  bet we e n t he  tr eat me nt gr o u p a n d t he pl ace b o 
gr o u p , o n t he f oll o wi n g : 
•  V ol u metri c M RI ( Q uarc bil ateral hi p p oc a m pal v ol u me)  
•  Ne ur o ps yc hiatric I n ve nt or y ( N PI)  sc ores 
•  Alz hei mer’s Disease C o o perati ve St u d y ( A D C S) -Acti vities of Dail y Li vi n g ( A D C S -A D L)  
sc ores 
•  Mi ni -Me ntal State E xa mi nati o n ( M M S E)  sc ores 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 5  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
4. 2. 2  
S afety a n d T oler a bilit y  
T he f oll o wi n g saf et y a n d t olera bilit y me as ures  will b e assesse d f or differe nces bet wee n t h e 
treat me nt gr o u p a n d t he place b o gr o u p: 
•  Occ urre nce  of m ortalit y e v e nts  
•  Occ urre nce of seri o us a d v erse e ve nts ( S A Es)  
•  Occ urre nce of a d v erse e ve nts ( A Es)  
•  Cl i nic al l a b orat or y tests 
•  Vital si g ns  
•  P h ysical e xa mi nati o ns  
•  E C G s 
•  Use of c o nc o mit a nt m e dicati o ns  
4. 3  
E x pl or at or y E n d p oi nts  
T he f oll o wi n g will be assesse d :  
•  Efficac y of B H V -4 1 5 7 assesse d b y t he wit hi n -partici pa nt c ha n ges fr o m baseli ne t o wee k 
4 8, c o m pare d bet wee n t he treat me nt gr o u p a n d t he place b o gr o u p, o n M o ntreal C o g niti ve 
Assess me nt ( M o C A) sc ores  
 
•  Effica c y of B H V -4 1 5 7 assesse d b y t he wit hi n -p arti ci pa nt c h a n ges fr o m b aseli ne t o wee k 
4 8, c o m par e d bet we e n t h e tr eat m e nt gr o u p a n d t he place b o gr o u p, o n perf or ma nc e usi n g 
t he A D C o m p osite Sc ore ( A D C O M S), a c o m p osite o utc o me c o m p ute d usi n g 4 A D A S-C o g 
s u bscale it e ms, 2 M M S E ite ms, a n d t he C D R S u m of B o xes ( Wa n g et al., 2 0 1 6)  
 
•  Efficac y of B H V -4 1 5 7 assesse d b y t he wit hi n -partici pa nt c ha n ges fr o m baseli ne t o wee k 
4 8, c o m pare d bet wee n t he treat me nt gr o u p a n d t he place b o gr o u p, o n  v ol u metric M RI 
( bilateral lateral ve ntricles a n d w h ole brai n v ol u me) 
•  Efficac y of B H V -4 1 5 7 assesse d b y t he wit hi n -partici pa nt c ha n ges fr o m baseli ne t o wee k 
4 8, c o m pare d bet wee n t he treat me nt gr o u p a n d t he place b o gr o u p, o n a c o g niti ve c o m p osite 
o utc o me c o m p ute d usi n g me as ures fr o m t he N A C C Ne ur o ps yc h ol o gical T est Batt er y 
[ Craft St or y 2 1 Recall (I m me di ate & Del a ye d); Be ns o n C o m ple x Fi g ur e ( C o p y & Dela ye d 
Recall); M ultili n g ual Na mi n g Test; Letter &  C ate g or y Fl u e nc y; Trail Ma ki n g Test A & B; 
N u m ber S pa n F or war d a n d B ac k war d]  
•  P har mac o ki n eti cs of B H V -4 1 5 7  a n d ril uz ole i n plas ma 
•  Treat me nt  r es p o nse b y A P O E ge n ot y pe  ( Qi u et al., 2 0 1 9) 
•  C S F, ser u m a n d plas ma bi o m ar ker pa nel ( A ß 4 2, A ß 4 2/ 4 0 rati o, t otal ta u,  p -ta u-1 8 1, 
ne ur o gra ni n, Nf L, Y K L -4 0, VI LI P, S N A P -2 5, s T R E M 2, G F A P) will b e assesse d at 
scree ni n g, wee k 2 4, a n d wee k 4 8.  C S F will be assesse d i n a s u bset of t he st u d y p o p ul ati o n 
(esti mate d n = 5 0 a cti v e, n = 5 0 pla ce b o) 
 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 6  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
4. 3. 1 O pe n -L a bel Ex pl or at ory E n d p oi nts  
T he c ha n g e i n safet y a n d t ol era bilit y meas ures i n cl u di n g: ( 1) a d verse e ve nts; ( 2) cli ni cal 
la b orat or y tests; ( 3) vital si g ns; ( 4) p h ysi cal e x a mi n ati o ns; ( 5) E C Gs. A d diti o nal e x pl or at or y 
e n d p oi nt of e v al uati n g  l o n g-ter m eff ects o n cli ni cal o utc o me meas ures . 
4. 4  
 
5  E T HI C S A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
5. 1  
G o o d Cli nic al P r acti ce  
T his st u d y  will be  c o n d u cte d i n acc or da nce wit h:  
•  Pri nci ples  of  t he Declarati o n  of  Helsi n ki  (re vise d v ersi o n  of  F ortaleza , Brazil  Oct o ber  
of 2 0 1 3 ) 
•  G o o d  Cli nical  Practice  ( G C P) g ui deli nes,  as  defi ne d  b y  t he I nter nati o nal C o nfere nce  o n  
Har m o niz ati o n (I C H) G ui deli ne,  T o pic  E 6,  t h e U nite d  States  C o d e  of  Fe deral  
Re g ulati o ns,  Title  2 1,  Part  5 0  ( 2 1 C F R 5 0) –  Pr otecti o n  of  H u ma n  S u bjects  a n d Part  
5 6  
•  I nstit uti o nal Re vie w  B oar ds  (I R Bs), Healt h  I ns ura nce P orta bilit y  a n d Acc o u nta bilit y  
Act  ( HI P A A), a n d all ot her  a p plica ble l ocal re g ul at or y re q uire me nts a n d la ws 
St u d y  pers o n nel  i n v ol ve d i n c o n d ucti n g  t his st u d y will  b e q ualifie d  b y  e d uc ati o n,  trai ni n g a n d  
e x perie nce t o perf or m t heir res pecti ve tas k(s) i n acc or da nce wit h G C P.  
5. 2  
I nstit uti o n al Re vie w B o ar d 
I nstit uti o nal Re vie w  B oar ds  a n d Researc h  Et hics  B oar ds  m ust  be  c o nstit ut e d  a n d t heir 
a ut h orit y  dele gate d  t hr o u g h t he i nstit uti o n's n or mal  pr ocess  of  g o ver na nce  acc or di n g  t o 
a p plica ble State  a n d Fe deral  re q uire me nts f or eac h partici p ati n g  l ocati o n. Eac h  partici pati n g  
i nstit uti o n m ust  pr o vi de  f or t he re vie w a n d a p pr o val of  t his pr ot oc ol  a n d t he ass ociate d  i nf or me d 
c o nse nt d oc u me nts  a n d recr uit me nt materials  b y  a n  a p pr o priate I R B re gistere d wit h  t he Office  
f or H u ma n  Researc h  Pr otecti o ns  ( O H R P). T he  pr ot oc ol  will  b e  s u b mitte d f or a p pr o val t o t he 
a p pr o priate I R B f or eac h st u d y site. T he  st u d y will  n ot  c o m me nce at a n y site u ntil  writte n  
a p pr o val f or i n vesti gati o nal pr o d uct release a n d a p pr o val t o e nr oll is o btai ne d  fr o m A D C S 
Re g ulat or y  Affairs.  
T he  i n vesti gat or m ust  o btai n  a p pr o val fr o m t he I R B f or all pr ot oc ol  a me n d me nts  a n d, w he n  
warra nte d,  c ha n ges t o t he  i nf or me d c o nse nt d oc u me nt.  Pr ot oc ol  a n d i nf or me d c o nse nt f or m 
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 7  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
a me n d m e nts  ca n be  m a de  o nl y  wit h  t he pri or  a p pr o val of  t he A D C S  a n d S p o ns or.  T he  
i n vesti gat or ma y  n ot i m ple me nt a n y pr ot oc ol de viati o n  e xce pt w here  necessar y  t o eli mi nate a n 
i m me diat e haz ar d  t o st u d y partici pa nt s, or  w he n  c ha n ge(s)  i n v ol ve o nl y  l o gistical or  
a d mi nistrati ve as pects  of  t he trial, i.e.,  c ha n ge of  m o nit or(s)  or  tele p h o ne n u m ber(s)  (I C H 4. 5. 2).  
T he i n vesti gat or s hall n otif y  t he I R B of  de viati o ns  fr o m t he pr ot oc ol  or  seri o us a d verse e ve nts  
occ urri n g  at t he site, i n acc or da nce wit h  l ocal pr oce d ures.  
5. 3  
I nf or me d C o nse nt a n d HI P A A C o m pli a nce 
N o  st u d y-s pecific pr oce d ure  will  be  u n derta ke n  o n  a n i n di vi d ual partici pa nt  u ntil  t h at partici pa nt  
or  t he partici pa nt ’s L A R  has  gi ve n  writte n i nf or me d c o nse nt t o ta ke part  i n t he st u d y. T he st u d y 
part ner m ust als o partici pate i n t he c o nse nti n g pr ocess.  
It will  be  ma de  clear  t o eac h p ote ntial  p artici pa nt, t h eir L A R if a p plica ble, a n d st u d y part ner t hat 
i nf or me d c o nse nt ma y  be  wit h dra w n  at a n y ti me wit h o u t nee di n g  t o gi ve  a reas o n a n d t hat s uc h 
wit h dra wal  will  n ot  c o m pr o mise t he relati o ns hi p bet wee n  t he partici pa nt  a n d t he I n vesti gat or n or  
t he partici pa nt ’s f ut ure treat me nt. 
I nf or me d c o nse nt will  be  o btai ne d  i n acc or da nce  wit h  U S  2 1  C F R  5 0. 2 5  a n d I C H G o o d  Cli nical  
Practice.  A p plica ble  HI P A A  pri vac y  n otificati o ns  will  be  i m ple me nte d a n d HI P A A  
a ut h orizati o ns  si g ne d bef ore  pr ot oc ol  pr oce d ures  are carrie d  o ut.  I nf or mati o n s h o ul d be gi ve n  
i n b ot h oral a n d writte n  f or m. 
C o nse nt  f or ms m ust  be  i n a la n g ua ge f ull y c o m pre he nsi ble  t o t he pr os pecti ve  p artici pa nts 
a n d/ or  t heir L A Rs,  a n d st u d y part ners , a n d am ple  o p p ort u nit y  m ust  be gi v e n  t o i n q uire a b o ut 
t he details  of  t he st u d y. Pri or  t o a partici pa nt ’s partici p ati o n  i n t he trial, t he writte n  i nf or me d 
c o nse nt f or m s h o ul d be  si g ne d a n d pers o nall y  date d  b y  t he partici pa nt  or  b y  t he p artici pa nt ’s 
L A R,  a n d b y  t he pers o n  w h o  c o n d ucte d t he i nf or m e d c o nse nt disc ussi o n.  Partici pa nt s or  t heir 
L A R  m ust  be  pr o vi de d  a c o p y of  t he si g ne d I C F. St u d y  p art ners  m a y  als o be r e q uire d t o  si g n 
t he i nf or me d c o nse nt pri or  t o st u d y partici pati o n  at t he discreti o n of t he res p o nsi ble I R B 
re vie wi n g t his researc h. 
T he  c o nse nt f or st ora ge will  i ncl u de c o nse nt t o ac cess  st ore d data,  bi ol o gical  sa m ples, a n d 
i ma gi n g data  f or sec o n dar y a nal yses.  C o nse nt  f or ms will  s pecif y t hat D N A  a n d bi o mar ker  
sa m ples are f or researc h p ur p oses  o nl y;  t he tests o n  t he D N A  a n d bi o mar ker  sa m ples are n ot  
dia g n ostic  i n nat ure  a n d p a rti ci pa nts will  n ot  recei ve res ults. M RI  sca n fi n di n gs of  cli nical  
si g nifica nce, deter mi ne d  b y  t h e sit e ra di ol o gist, ca n be  s hare d wit h  pa rtici pa nts per  site 
cli nicia n  discreti o n.  
5. 4  
P artici p a nt  C o nfi de nti alit y │ HI P A A  
I nf or mati o n a b o ut st u d y pa rtici pa nts will  be  ke pt  c o nfi de ntial a n d ma na ge d  acc or di n g  t o t he 
re q uire me nts of  HI P A A.  T h ose  re g ulati o ns re q uire a si g ne d partici pa nt  HI P A A  A ut h orizati o n  
i nf or mi n g t he partici pa nt  of  t he f oll o wi n g: 
 
•  W hat  pr otecte d  healt h  i nf or mati o n ( P HI) will  be  c olle cte d  fr o m partici pa nt s i n t his st u d y 
•  W h o will ha ve access  t o t hat i nf or mati o n a n d w h y  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 8  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  W h o will use or  discl ose  t hat i nf or mati o n 
•  T he  ri g hts of  a researc h partici pa nt  t o re v o ke t heir a ut h orizati o n  f or use  of  t heir P HI  
I n t he e ve nt t hat a pa rti ci pa nt re v o kes a ut h orizati o n  t o c ollect or  use  P HI,  t he i n vesti gat or, b y  
re g ulati o n, retai ns t he a bilit y t o use  all i nf or mati o n c ollecte d  pri or  t o t he re v ocati o n of  
p artici pa nt a ut h orizati o n.  Eac h  site PI,  u n der  t he g ui da nce  of  his/ her  I R B, is res p o nsi ble f or 
e ns uri n g  t hat all a p plic a ble HI P A A re g ulati o ns  a n d s tate la ws are met.  
5. 5  
P ote nti al  Ris ks a n d Be nefits Ass oci ate d w it h t his St u d y 
5. 5. 1  
P ote nti al Ris ks  
Ris ks  ass ociate d  wit h  st u d y partici pati o n  are  t h e p ote nti al  f or a d verse r eacti o ns t o t h e st u d y 
me dic ati o n  (see Se cti o n 1. 7. 1 ), c o nc o mit a nt me dicati o ns,  i n vasi ve st u d y assess me nts  li ke bl o o d  
dra ws  a n d l u m bar p u nct ure,  a n d ris ks relate d t o t he pr ocess  of  u n der g oi n g  brai n  M RI  sca ns a n d 
ne ur o ps yc h ol o gical  testi n g.  
5. 5. 2  
P ote nti al Be nefits  
Partici pa nts  i n t his st u d y ma y  e x perie nce  a n i m pr o ve me nt i n t heir A D  s y m pt o ms, e ve n 
t h o u g h s uc h i m pr o ve me nt ca n n ot be  pre dicte d  wit h  a n y s uret y. T his  st u d y is e x pecte d  t o 
be nefit  t h e A D  c o m m u nit y  b y  f urt heri n g t he de vel o p me nt  of  a  ne w  t h era p y a n d pr o vi di n g  m ore  
i nf or mati o n t o t h ose st u d yi n g p ote ntial treat me nts f or A D.  
6  S T U D Y D R U G  
6. 1  
St u d y Me dic ati o n  
T he  d o u bl e -bli n d p hase  me dicati o n  will  be  prese nte d  as  o ne  of t he  f oll o wi n g: 
•  
B H V -4 1 5 7,  1 or 2 ca ps ules (size 1) of 1 4 0 m g eac h , de pe n di n g o n assi g ne d d ose , a n d 
•  
1 or 2 ca ps ules of matc hi n g Place b o  
T he O pe n -La bel E xte nsi o n p hase me dicati o n will be:  
•  B H V -4 1 5 7,  1 or 2 ca ps ules (size 1) of 1 4 0 m g eac h   
T he st u d y me dicati o n c a ps ule s h o ul d n ot be o p e ne d.  
T he  st u d y me dicati o n  will  be  sec urel y st ore d at t he st u d y site i n acc or da nce wit h  t he 
c o n diti o ns  s pecifie d o n  t he la bel, se paratel y fr o m ot h er dr u gs.  T he  st u d y me dicati o n  ma y  n ot be 
use d  f or a n y p ur p ose ot her  t ha n t his st u d y. 
6. 2  
 
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 3 9  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
6. 3  
  
C CI
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 0  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
6. 4  
Misse d D oses  
If a partici pa nt  misses  a d ose  of  st u d y dr u g  a n d re me m bers wit hi n t he sa me cale n dar  da y , t he 
d ose  m a y b e t a k e n. If a p arti ci p a nt miss es a d os e of st u d y dr u g a n d d o es n ot r e m e m b er 
u ntil t h e n e xt c al e n d ar d a y, t h e d os e will  be  s ki p pe d (i.e.,  s h o ul d n ot be ma de u p) a n d d osi n g 
res u me d at t he n or mal d osi n g ti me f or t hat cale n dar da y.  
6. 5  
C o di n g a n d P ac ki n g  
As si g n me nt of  st u d y me dicati o n  kits  t o treat me nt gr o u ps  will  be  d o ne  wit h  a n all ocati o n rati o 
of 1: 1  b y  a c o m p uter  ge nerate d  ra n d o m se q ue nce. 
T he  st u d y me dicati o n  will  be  pac ka ge d  i n b ottles.  Eac h b ottle will c o ntai n 3 5 ca ps ul es.  A n  
a p pr o priate n u m ber  of  b ottles (t o pr o vi de  st u d y dr u g  bet wee n  visits) will be  pr o vi de d t o t he 
p artici pa nt at eac h st u d y visit  (see A p pe n di x  1  f or Sc he d ule  of  St u d y  Visits).   
N ote:  Eac h  pa rtici pa nt c o m pleti n g  t his st u d y will  ta ke t h e st u d y dr u g f or 4 7  t o 4 9  wee ks  i n t he 
d o u ble -bli n d p h ase , de pe n di n g  o n sc he d uli n g of t h e  E n d of  Treat me nt  Visit (wee k  4 8 ± 7 da ys)  
a n d a n a d diti o nal 4 7-4 9 wee ks if t he y c o nti n ue i n t he O pe n -La bel E xte nsi o n p hase.  
N ote: If a bs ol utel y necessar y, treat me nt d urati o n  ma y be l o n ger d ue t o t he C O VI D -1 9 pa n de mic  
as detaile d i n t he Sc h e d ule of Assess me nts a n d E ve nts i n A p pe n di x 1 . U n der t hese circ u msta nces, 
the sp o ns or me dical m o nit or  ( or desi g nee) s h o ul d be c o ns ulte d  b y t he s ite i n vesti gat or (or 
desi g nee ). 
6. 6  
Bli n di n g  
T his  is a d o u ble -bli n d place b o -c o ntr olle d  trial. Treat me nts  will  be  bli n de d  t o t he p artici pa nts  
a n d st u d y pers o n nel  t hr o u g h o ut t he d o u ble -bli n d p hase . Treat me nt  bli n d  will  be  mai ntai ne d  
b y  use  of  matc hi n g  place b o  me dic ati o n.  I n or der t o mi ni miz e u n ne cessar y a nal ysis of pl ace b o 
bl o o d P K sa m ples, t he bi oa nal ytic al scie ntist will b e u n bli n de d t o tre at m e nt pri or t o u n bli n di n g 
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 1  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
f or t he pri mar y e n d p oi nt. Res ults of t he bl o o d c o nce ntrati o n assa y will be ke pt sec ure u ntil 
data base l oc k  a n d u n bli n di n g  f or t h e pri m ar y e n d p oi nt.  
O nl y i n t he case of a n e mer g e nc y, w he n k n o wle d ge of w het her t he partici pa nt has re cei v e d t h e 
i n vesti gati o nal pr o d uct is esse ntial f or t he cli nical ma na ge me nt or welfare of t he partici p a nt, ma y 
t he I n vesti gat or u n bli n d a partici pa nt’s tr eat me nt assi g n me nt. Pr oce d ur es f or e mer ge n c y 
u n bli n di n g ar e i nitiate d b y c o ntacti n g t he A D C S Me dical M o nit or . 
T he i nteri m a nal ysis will be carrie d o ut b y t he u n bli n de d safet y bi ostatistics t ea m a n d t h e re p ort 
will be pr e pare d f or t he  D S M B. T he D S M B will re vi e w all d ata pertai ni n g t o t h e 
 
a n d will be u n bli n d e d. T he D S M B will c o n ve y t o t h e St u d y Steeri n g C o m mitt ee ( S S C ) w het her 
or n ot t he  st o p pi n g crit eria h a ve bee n met.  
T he St u d y Steeri n g C o m mitt ee ( S S C) t hat is o verseei n g t he trial will re cei ve t he 
rec o m m e n dati o n of t he D S M B a n d ha ve f ull ac cess t o data s u m m aries pr o vi d e d t o t h e D S M B. 
See  Secti o n 1 5 a n d  t he S S C C hart er f or a d diti o nal d etails.  
All parti ci pa nt s e nteri n g t he O pe n-L a bel E xte nsi o n p hase will n ot b e bli n d e d a n d will be o n 
acti v e tre at me nt .  
6. 7  
R a n d o miz ati o n a n d Me dic ati o n Or deri n g S yste m  
A  stratifie d per m ute d  bl oc k r a n d o mizati o n  pr oce d ure  will  be  use d wit h scree ni n g M M S E 
[m o derat e A D: 1 4  t o 1 9; mil d A D: 2 0  t o 2 4 ] a n d Site as  stratificati o n fact ors.  
T he  I n vesti gat or will  use  t he A D C S  E D C  s yste m t o e nter scree ni n g i nf or mati o n o n  eac h  
pa rtici pa nt. F or t h ose pa rtici pa nts w h o q ualif y,  t he s yste m will iss ue a  me dicati o n  kit n u m ber.  
Pa rtici pa nts will  be  ra n d o mize d at  t h e baseli ne visit , after scree ni n g is c o m plete d  a n d it is 
deter mi ne d  t hat t he pa rtici pa nt is eli gi ble f or t he st u d y. 
6. 8  
L a beli n g  
La bels  will  be  i n acc or da nce wit h  all a p plica ble r e g ulat or y re q uire me nts f or t he la beli n g of  
acti ve p har mace utical  i n gre die nts a n d wit h  A n ne x  1 3  of  G M P . La bels  will  c o ntai n t he dr u g  
na me,  pr ot oc ol n u m ber,  date  of  ma n ufact ure,  st ora ge c o n diti o ns  a n d a ca uti o n  state me nt t hat 
t he dr u g is f or cli nical i n vesti gati o nal use o nl y.  
6. 9  
Dr u g Acc o u nt a bilit y  
T he  I n vesti gat or or  his/ her  desi g nate d  re prese ntati ves will  dis pe nse  st u d y dr u g  o nl y  t o 
pa rtici pa nts ra n d o mize d t o treat me nt i n t he st u d y. 
T he  I n vesti gat or ( or, as  a p pr o priate, p har macist/i n di vi d ual  w h o  is desi g nate d  b y  
t he 
I n vesti gat or/i nstit uti o n) m ust  mai ntai n  rec or ds of  t he deli ver y  of  t he st u d y me dicati o n  t o t he trial 
site, t he i n ve nt or y at  t he site, t he use  b y  eac h  pa rtici pa nt, a n d t h e ret ur n t o t he dr u g  distri b ut or  
u nless t he y are a ble t o destr o y o n site . 
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 2  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
At eac h  visit, pa rtici pa nts a n d t heir st u d y part ners  s h o ul d bri n g i n all u n use d dr u g a n d e m pt y or  
partiall y  f ull c o ntai ners . After  t he dru g has bee n re vi e we d b y t h e m o nit or , e ac h  sit e will  d estr o y 
all u n use d  st u d y me dicati o n a n d e m pt y or  parti all y  f ull c o ntai ners  c ollecte d  fr o m eac h partici pa nt, 
or  ret ur n t he st u d y me di cati o n a n d c o ntai n ers t o t h e dr u g  distri b ut or if t h e y are u n a ble t o destr o y 
o n site.  
If t he st u d y site nee ds t o se n d dr u g o ver ni g ht vi a c ertifie d a n d trac k e d c o urier w here p ossi ble, 
a n d t his is a cce pta bl e t o t he i nstit uti o n be ca use a visit is a bs ol utel y n ot p ossi ble t o b e c o m pl ete d 
d ue t o t he C O VI D -1 9 pa n de mi c , t his is per missi ble per st u d y. T he sp o ns or s h o ul d be c o ns ulte d 
pri or t o s hi p pi n g dr u g.  
7  P A R TI CI P A N T  S E L E C TI O N  A N D C O N C O MI T A N T  M E DI C A TI O N S  
7. 1  
I ncl usi o n Criteri a 
 
Partici p a nt s m ust m eet all of t he f oll o wi n g i ncl usi o n criteria t o b e eli gi ble f or e nr oll me nt:  
 
1.  A ge 5 0  t o 8 5 (i ncl usi v e) at scre e ni n g. 
 
2.  Dia g n ose d 
wit h pr o ba ble 
Al z hei mer’s disease  d e me ntia: 
C or e cli nical criteri a  i n 
acc or da n ce wit h NI A/ Alz hei mer’s Ass ociati o n G ui d eli nes (see A p pe n di x II ). 
 
3.  Li vi n g i n t he c o m m u nit y (i ncl u d es assiste d li vi n g f aciliti es, b ut e xcl u des l o n g -t er m care 
n ursi n g faciliti es).  
 
4.  A m b ulat or y, or a ble t o wal k wit h a n assisti ve de vi ce, s uc h as a ca ne or wal k er.  
 
5.  Partici p a nt s 
m ust ha v e a st u d y part ner 
w h o h as fre q ue nt i nteracti o n 
wit h t he m 
(a p pr o xi matel y > 3 -4 ti mes per wee k) , will be prese nt f or all cli ni c visits, a n d ca n assist i n 
c om pli a nce wit h st u d y pr oce d ures . 
 
6.  Fe m ale patie nts m ust be  p ost -me n o pa usal f or at le ast 2 c o nsec uti v e years or s ur gicall y 
sterile ( bilateral t u bal li g ati o n, h yst erect o m y or bil ateral o o p h orect o m y) f or at least 6 
m o nt hs pri or t o scre e ni n g.  
 
7.  A m o difie d Hac hi ns ki sc ore of 4 or less at scr ee ni n g.  
 
8.  A n M M S E sc ore of 1 4  t o 2 4 , i ncl usi ve, at scree ni n g. 
 
9.  A brai n  M RI sc a n wit hi n 6 m o nt hs of scree ni n g c o nsiste nt wit h a dia g n osis of Alz hei m er’s 
disease .  
 
1 0.  B o d y mass i n de x ( B MI) ≤ 4 0  k g/ m 2 at scre e ni n g. 
 
1 1.  Partici p a nt s s h o ul d be tre ate d wit h a st a ble d osa ge  re gi m e n o f F D A -a p pr o ve d A D 
me dic ati o ns  (a cet ylc h oli n esterase i n hi bit ors ( Ac h EI) a n d/or me ma nti ne)  f or at least 3 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 3  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
m o nt hs pri or t o scree ni n g. Parti ci pa nt s s h o ul d be e x pecte d t o re mai n o n a sta bl e d osa ge 
re gi me n of t hese me dicati o ns f or t he d ur ati o n of t h e trial . T h e A D me dicati o n d ose m a y be 
c ha n ge d d uri n g t h e O pe n -La b el E xte nsi o n p hase if n ee de d , b ut it is pr eferre d  t o wait u ntil 
t he E xt e nsi o n P hase We e k 1 2 visit if p ossi ble. 
 
a. P artici p a nts w h o ar e n ot bei n g tre ate d wit h F D A -a p pr o ve d A D me di cati o ns at t he 
ti me of scree ni n g, beca use t h e y ha ve  c o ntr ai n di cati o ns t o t hese me dicati o ns, or  
beca use t h e y ha v e pre vi o usl y  faile d tr eat me nt wit h t hese m e dic ati o ns,  ar e als o 
eli gi ble f or i ncl usi o n , if it is e x pect e d t hat t he y will n ot be treat e d wit h t hese 
me dic ati o ns f or t h e d urati o n of t he trial.  
 
1 2.  A bilit y ( p ati e nts a n d t heir st u d y part ners) t o re a d, s pe a k a n d u n d ersta n d E n glis h  or S pa nis h  
t o e ns ure c o m plia n ce wit h c o g niti v e testi n g a n d st u d y visit pr oce d ur es.  
 
1 3.  Pr o visi o n of i nf or m e d c o nse nt fr o m  t h e partici pa nt  (or t he p arti ci pa nt ’s le g all y a ut h orize d 
re prese ntati ve ( L A R) if u n a ble t o pr o vi de c o nse nt ) a n d t he st u d y part n er. 
7. 2  
E xcl usi o n Criteri a  
Patie nts m eeti n g a n y of t h e f oll o wi n g criteria m ust n ot be i ncl u de d i n t he st u d y:   
 
1.  Hist or y of  brai n a m yl oi d i ma gi n g (e. g., A m y l oi d P ositr o n E missi o n T o m o gra p h y sca n) or 
cere br os pi nal fl ui d res ults (e. g., base d o n t a u a n d a m yl oi d c o n ce ntr ati o ns) t hat are n ot 
c o nsiste nt wit h a m yl oi d o pat h y or Alz hei mer’s disease . H o we ver, s uc h tests ma y be 
re peat e d i n or der t o det er mi n e eli gi bilit y, if disc usse d a n d a p pr o ve d b y t he Me dical 
M o nit or.  
2.  Use of pr o hi bite d m e dic ati o ns as defi n e d i n  Secti o n 7. 4. 2 .  
3.  C o ntrai n di cati o n t o M RI , i ncl u di n g b ut n ot li mit e d t o:  
a. Cli nic al hist or y or e xa mi nati o n fi n di n g t h at, w o ul d p ose a p ote ntial hazar d f or 
c o n d ucti n g a n M RI, i n t he j u d g me nt of t he pri nci pal i n vesti gat or. 
b.   I m pla nt de vi ces n ot c o m pati ble i n t he ma g netic res o na nce e n vir o n m e nt, s uc h as; 
AI C Ds; c oc hlear i m pl a nts; cer e bral a n e ur ys m cli ps; i m pla nte d i nf usi o n p u m ps; 
i m pla nte d ner v e sti m ulat ors; 
met allic s pli nters i n t he e ye; ot her 
ma g netic, 
electr o nic, or me c ha nic al i m pl a nts . Pace makers are per mitte d o nl y if la be le d as 
c o n diti o n al car diac i m pl a nta ble el ectr o nic de vices ( C I E Ds), ha ve bee n a p pr o ve d 
f or M RI use b y t he F D A, v erifie d b y t he pac e ma ker’s ma n ufact urer as a p pr o v e d 
f or M RI use, a n d deter mi ne d t o be s uita bl e b y t he site’s ra di ol o gist a n d pri nci p al 
i n vesti gat or. 
4.  C urre nt 
seri o us 
or 
u nsta ble ill ness i ncl u di n g 
car di o vasc ul ar, 
he patic, 
re n al, 
gastr oe nter ol o gic, r es pirat or y, e n d ocri n ol o gic, ne ur ol o gic, ps yc hi atri c, i m m u n ol o gic, or 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 4  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
he mat ol o gic disease or ot her c o n diti o ns t hat, i n t he i n vesti g at or’s or s p o ns or’s o pi ni o n, 
c o ul d i nt erfere wit h t he i nter pretati o n of safet y a n d a ssess me nt of effica c y i n t his st u d y.   
5.  He patic i m pair me nt defi ne d as  C hil d -P u g h cl ass of A or m ore se vere li ver i m p air m e nt. 
6.  Ala ni ne a mi n otr a nsferase ( A L T/ S G P T) val u es > 1. 5 X t he u p per li mit of n or m al ( U L N) of 
t he perf or mi n g la b orat or y, as part ate a mi n otr a nsferase ( A S T/ S G O T) val ues > 1. 5 X U L N, or 
t otal bilir u bi n val ues > 1 X U L N ( partici pa nts wit h Gil bert’s s y n dr o me ar e all o we d i n t he 
st u d y). 
7.  Ot her ne ur o de ge n erati ve diseases  a n d ca uses of de m e ntias, i ncl u di n g Par ki ns o n’s disease 
a n d H u nti n gt o n’s diseas e, vasc ular de m e nti a, CJ D ( Cre utzfel dt -Ja k o b disease), L B D 
( Le w y 
B o dy  de me ntia), P S P ( Pr o gressi ve S u pr a n ucle ar Pals y), 
AI D S ( Ac q uire d 
I m m u n o defi cie n c y S y n dr o me), or N P H ( n or mal press ure h y dr oce p hal us). 
8.  Brai n M RI at scree ni n g s h o ws e vi de nce of i nfecti o n,  t um or, c ortical  i nfarcti o n, e xte nsi ve 
w hite m att er dise ase  ( Faz e kas sc ore > 2), or m ulti ple l ac u nes i n prefr o ntal or critical 
me m or y re gi o ns; i nc o n cl usi ve fi n di n gs ma y be s u bject t o re vie w b y t he A D C S I ma gi n g 
C ore.  
 
9.  Hist or y of a maj or d e pressi ve e pis o de  wit h i n t h e past 6 m o nt hs of scree ni n g . 
1 0.  Hist or y of s c hiz o p hre ni a  dia g n osis .  
1 1.  Hist or y of bi p olar dis or der . 
1 2.  Hist or y of s eiz ure s wit hi n 2 y ears of scree ni n g. 
1 3.  Hist or y of alc o h ol a b use or de pe n de n ce or dr u g a b us e i n t he p ast 5 years.  
1 4.  Ins uli n -de pe n de nt dia b etes or u nc o ntr olle d dia betes  wit h H b A 1c val ue  > 8 . 0 %.  
1 5.  He patitis B, C, or HI V i nfecti o n . 
1 6.  Cli nic all y si g nifica nt la b orat or y a b n or malities t hat ma y i nfl ue n ce st u d y assess me nts as 
deter mi ne d b y t h e i n vesti gat or.   
1 7.  U ntreate d or i ns ufficie nt l y tr eat e d h y p ot h yr oi dis m, vita mi n B 1 2 or f olate  deficie n c y .  
1 8.  E C G o btai ne d d uri n g scree ni n g t hat, i n t he o pi ni o n of t he i n vesti gat or, is cli ni call y 
si g nifica nt wit h re gar d t o t he parti ci pa nt ’s partici pati o n i n t he st u d y. C orrecte d Q T i nter val  
( Q TcF ) m ust b e e val uat e d usi n g Fri dericia’s f or m ul a, a n d m ust n ot e x cee d 4 8 0  msec . 
1 9.  Ca ncer or a mali g n a nt t u m or wit hi n t he past 3 ye ars, e xce pt pati e nts w h o u n der we nt 
p ote nti all y c urati ve t hera p y wit h n o e vi de nce of re c urre nce  f or > 3 y ears. Patie nts wit h 
sta ble prostate c a ncer o r n o n -m ela n o ma s ki n c a ncers are n ot e x cl u de d . 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 5  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
2 0.  Partici p ati o n i n a n ot her cli nical tri al f or a n i n v esti gati o nal a ge nt a n d h a vi n g t a ke n at le ast 
o ne d ose of st u d y me dicati o n, u nl ess c o nfir me d as ha vi n g bee n o n place b o, wit hi n 1 2 
wee ks pri or t o s cree ni n g. T h e e n d of a pre vi o us i n v esti gati o n al trial is defi n e d as t he d ate 
of t he last d ose of a n i n vesti gati o nal a g e nt.  
2 1.  Ha vi n g recei ve d ril uz ol e f or m ore t ha n 4 wee ks pri or t o scree ni n g or wit h k n o w n 
t olera bilit y diffi c ulties t o ril uz ole. 
7. 3  
C o nc o mit a nt A D  Me dic ati o n  
 
Partici p a nts s h o ul d be treat e d wit h a sta ble d osa ge re gi me n of F D A -a p pr o ve d A D me dic ati o ns 
(acet ylc h oli nesterase i n hi bit ors ( Ac h EI) a n d/ or m e ma nti ne) f or at le ast 3 m o nt hs pri or t o 
scree ni n g. Partici pa nts s h o ul d be e x pe cte d t o re mai n o n a st a b le d osa ge r e gi m e n of t hese 
me dic ati o ns f or t he d urati o n of t he trial.  T h e A D me dic ati o n d ose m a y be c ha n g e d d uri n g t he 
O pe n -La bel E xt e nsi o n p hase if n ee de d , b ut it is pref erre d  t o wait u ntil t h e E xte nsi o n P hase W ee k 
1 2 visit if p ossi ble.  
 
Partici p a nts w h o are n ot bei n g tr eat e d wit h F D A -a p pr o ve d A D me dicati o ns at t he ti m e of 
scree ni n g, be ca use t h e y ha ve c o ntrai n dicati o ns t o t hese me dicati o ns, or bec a use t he y h a ve 
pre vi o usl y faile d tr eat me nt wit h t hese me di cati o ns,  are als o eli gi bl e f or i ncl usi o n, if it is e x pe cte d 
t hat t he y will n ot be treate d wit h t h ese me di cati o ns f or t he d urati o n of t h e d o u ble -bli n d  p hase of 
t he tri al. 
7. 4  
Ot her C o nc o mit a nt Me dic ati o n  
7. 4. 1  
Per mitte d C o nc o mit a nt Me di c ati o ns  
T he  f oll o wi n g c o nc o mita nt me dicati o ns  are per mitte d:  
•  Me dical  f o o ds a n d s o y-base d s u p ple me nts,  e xce pt as descri be d i n  Secti o n 7. 4. 2 .  
•  F o o d  s u p ple me nts i n ge neral  
•  Vita mi ns i n ge neral  
•  N o n -se dati n g a nti hista mi nes 
T he patie nt’s  c o n diti o n  m ust be  st a ble w hile o n t he prescri be d  me dicati o ns:  
•  
A nti de pressa nts  starti n g at le ast t w o m o nt hs  pri or  t o scree ni n g  e xce pt t he pr o hi bite d  
me dic ati o ns  as  descri be d  i n Secti o n 7. 4. 2 .  
•  
Beta -bl oc kers  use d  f or car di o vasc ular reas o ns starti n g at least 2 m o nt hs  pri or  t o 
scree ni n g 
T he  f oll o wi n g c o nc o mita nt me dicati o n s are per mitte d  o n  a n i nter mitte nt basis.  
•  
S h ort  t o me di u m -acti n g be nz o diaze pi nes  (estaz ola m, l oraze pa m, 
mi daz ola m, 
o xaze pa m, te maze pa m, triaz ola m, al praz ola m)  ta ke n n o m ore t ha n t wice wee kl y 
•  
Ra melte o n  ( u p t o 8  m g),  esz o picl o n e  ( u p t o 2  m g),  zale pl o n  ( u p t o 5  m g) or  z ol pi de m 
tartrate ( ≤6. 2 5 m g  C R a n d ≤1 0  m g  ta blet) ta ke n n o m ore t ha n t wice wee kl y 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 6  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  
Se dati n g  a nti-aller g y  me dicati o ns  (e. g. di p he n h y dra mi ne)  ta ke n n o m ore t ha n t wice 
wee kl y  
•  
L o w d ose a ntic o n v ulsa nt dr u gs use d f or n o n -e pile ptic i n dicati o ns w hic h ha v e bee n 
starte d a n d ha v e bee n sta bl e f or at l east 2 m o nt hs pri or t o scree ni n g: De pa k ote 2 5 0 m g, 
Ga ba p e nti n 3 0 0 m g, O xcar baz e pi ne 6 0 0 m g, Pre ga b ali n 1 0 0 m g, La m otri gi n e 7 5 m g)  
A n y c o nc o mit a nt me dicati o ns  m ust be rec or de d i n t he e C R F, n oti n g  t he na me  of  me dicati o n,  t h e 
d ose,  d urati o n, a n d i n dicati o n. H o we ver, a n y of t hese per mitte d c o nc o mita nt me dicati o ns use d o n 
a n i nt er mitte nt basis  s h o ul d n ot  be  ta ke n less t ha n 1 2  h o urs  pri or  t o a n y sc he d ule d visits  t hat 
i ncl u de a n y  c o g niti ve tests. 
7. 4. 2  
Pr o hi bite d C o nc o mit a nt Me di c ati o ns  f or d o u ble-bli n d p h ase b ut c o n diti o n al f or 
O pe n -L a bel  E xte nsi o n  p h ase  
T he  f oll o wi n g c o nc o mita nt me dicati o ns  are n ot  per mitte d  fr o m scree ni n g t hr o u g h t he e n d of  t he 
Ra n d o mize d D o u ble -Bli n d p hase of t he  st u d y. H o w e v er, t h e y ar e all o w e d p er i n v esti g at or 
j u d g e m e nt f or t h e O p en -L a b el E xt e nsi o n p h as e u nl ess ot h er wis e n ot e d i n 7. 4. 3.  
•  
Tric yclic a nti d e pressa nts (e. g. a mitri pt yli ne, a m o xa pi n e, cl o mi pra mi ne,  desi pra mi ne,  
d o xe pi n, i mi pra mi ne, n ortri pt yli ne,  pr otri pt yli ne,  tri mi pra mi ne) 
•  
M o n oa mi ne  o xi dase  i n hi bit ors (e. g. is ocar b o xazi d, p he nelzi ne,  tra n ylc y pr o mi ne, 
sele gili ne, rasa gili ne) 
•  
L o n g -acti n g  b e nz o diaze pi nes   
•  
C o n ve nti o nal  a n d at y pical a nti ps yc h otics  ( E X C E P T ≤ 5 0  m g/ d  of  q uetia pi ne  a n d ≤ 0. 5 
m g/ d  of  ris peri d o ne) 
•  
M o o d -sta bilizi n g ps yc h otr o pic a ge nts  (e. g. lit hi u m salts) 
•  
Prescri pti o n  se dati ves (e. g. bar bit urates,  met ha q ual o ne,  m e pr o ba mate;  E X C E P T  
ra melte o n, esz o picl o ne,  zale pl o n  a n d z ol pi de m tartr ate u n der  t he c o n diti o n  descri be d 
i n Secti o n 7. 4. 1 . 
•  
Ps yc h osti m ula nts (e. g. a m p heta mi nes,  m o dafi nil -relate d c o m p o u n ds li ke ar m o dafi nil)  
•  
D o pa mi ne a g o nists  (e. g. a p o m or p hi ne,  pra mi pe x ole,  r o pi nir ole, r oti g oti ne) 
•  
A ntic h oli ner gics  (e. g. be nztr o pi ne mes ylate,  tri he x y p he ni d yl H C L;  E X C E P T  i n hale d 
i pratr o pi u m, i n hale d ti otr o pi u m, o x y b uty ni n , darif e naci n,  tr os pi u m, s olife naci n a n d 
t olter o di ne) 
•  
A ntic o n v ulsa nt  me dicati o ns  use d t o treat seiz ures or e pile ps y w hic h i nterfere wit h 
c o g niti ve f u ncti o n or w h ose  usa ge has n ot bee n sta ble f or 6 m o nt hs or l o n ger  ( E X C E P T 
ga ba pe nti n at ≤ 3 0 0 m g Q D f or i n dicati o ns ot her t ha n seiz ures)  
•  
C hr o nic or re g ular use of o piate  a nal gesics  (e. g. m or p hi ne, c o dei ne,  h y dr o m or p h o ne,  
h y dr oc o d o ne,  me peri di ne,  o x yc o d o ne ) 
•  
I m m u n os u p pressi ve me dicati o ns  E X C E P T  i n hale d, t o pical, i ntra-nasal  ster oi ds, a n d 
l o w d ose met h otre xate f or r he u mat oi d art hritis or ps oriasis) 
•  
C he m ot hera pe utic  a ge nts  f or mali g na ncies 
•  
Me dical or recreati o nal marij ua na  
•  
Gl ut a mate r gi c a ge nts  ( E X C E P T me m a nti n e) 
•  
He pat ot o xi c dr u gs (e. g. all o p uri n ol, met h yl d o pa, s ulf asalazi ne) w hic h ma y i ncr ease t he 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 7  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
ris k f or he pat o xi cit y 
•  
A x o na ® a n d S o u ve nai d ®  ( E X C E P T w he n pa tie nts are usi n g A x o na ® or S o u ve nai d ® at 
t he ti me of scree ni n g a n d c o nti n ued  use  is a d vised b y treati n g p h ysicia n or Pri nci pal  
I n v esti g at or a n d is e x p e ct e d t o c o nti n u e t hr o u g h o ut t h e st u d y ) 
 
Partici pa nts  w h o are acti vel y bei n g treate d wit h l o w d ose acet ylsalic ylic a ci d ( A S A)  ma y u n der g o 
l u m bar p u nct ure, at t he discreti o n of t he i n vesti g at or. Partici pa nts  w h o are acti vel y  bei n g treate d 
wit h d ual a nti platel et  t h era p y or wit h a n y a ntic oa g ulati o n  me dicati o ns  (e. g. he pari n,  warfari n,  
t hr o m bi n i n hi bit ors, Fact or  X a  i n hi bit ors) s h o ul d n ot  u n der g o l u m bar p u nct ure.  Platelet c o u nts 
s h o ul d be > 1 0 0, 0 0 0, a n d P T T a n d I N R l e vels c hec ke d  a n d i n n or mal ra n ge bef ore t he l u m b ar 
p u nct ure is perf or m e d.  T he A D C S Me dical M o nit or s h o ul d be c o ntacte d if t here are a n y q uesti o ns.  
If, d uri n g  t he cli nical st u d y, t he a d mi nistrati o n  of  a n o n -per mitt e d  c o nc o mita nt me dicati o n  
bec o mes  necessar y,  t he Me dical  M o nit or m ust be c o nta cte d t o deter mi ne  if t h e p artici pa nt  
nee ds t o be  pre m at urel y  disc o nti n ue d fr o m acti ve treat me nt (see Secti o n 1 0 ). 
 
7. 4. 3  
Pr o hi bite d Me di c ati o ns, b ot h i n d o u ble bli n d a n d 0 pe n -la bel exte nsi o n  p h ases .  
T he  f oll o wi n g c o nc o mita nt m e dicati o ns  are neit h er p er mitt e d i n t h e d o u ble bli n d n or t he o pe n -
la bel exte nsi o n  p hase of t he St u d y:  
 
•  
He pat ot o xi c dr u gs (e. g., all o p uri n ol, m et h yl d o p a, s ulf asalazi ne) w hic h m a y i ncr ease t h e 
ris k f or he pat o xi cit y 
•  Se nsiti ve a n d m o deratel y  se nsiti ve s u bstrates of t he C Y P 2 B 6, C Y P 2 C 8, C Y P 2 C 9, a n d 
C Y P 2 C 1 9 e nz y mes ( please se e t he ta ble b el o w).  
E nz y me  
Se nsiti ve S u bstr ates  
M o der atel y Se nsiti v e S u bstr ates  
C Y P 2 B 6  
B u pr o pi o n  
efa vire n z  
C Y P 2 C 8  
Re pa gli ni de  
m o ntel u k ast, pi o glita z o ne, r osi glita z o ne  
C Y P 2 C 9  
Celec o xi b  
gli me piri de, p h e n yt oi n, t ol b ut a mi d e, 
warfari n  
C Y P 2 C 1 9  
S -me p he n yt oi n, o me pra z ole  
diaze p a m, l a ns o praz ole, r a be pra z ole, 
v oric o naz ole  
T he f oll o wi n g me di cati o ns are pr o hi bite d at le ast 1 4 da ys pri or t o ra n d o mizati o n or 5 half -li ves 
( w hic he ver is l o n g er) pri or t o ra n d o miz ati o n, a n d d uri n g t he d o u bl e -bli n d a n d O pe n -La bel 
E xte nsi o n  p hases of t h e st u d y, d ue t o t he p ot e ntial f or dr u g i ntera cti o ns:  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 8  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  Str o n g t o m o derate C Y P 1 A 2 i n hi bit ors, s uc h as a mi o dar o ne, ci meti di ne, a n d 
ci pr ofl o xa ci n w hic h ma y i ncr ease t h e ris k of ril u z ole -ass ociate d a d verse e ve nts ( See 
A p pe n di x III  f or detaile d m e dic ati o n listi n g) 
•  C hr o nic use of str o n g t o m o d erat e C Y P 1 A 2 i n d ucers, s uc h as car ba m aze pi n e, m o dafi nil 
a n d o me pra z ole, w hic h ma y res ult i n de crease d effic ac y ( See A p pe n di x  III f or detaile d 
me dic ati o n listi n g)  
8  S T U D Y P R O C E D U R E S  
8. 1  
St u d y Visits  
T he sc he d ul e of s t u d y visits  a n d pr oce d ures  t o be  perf or me d  at eac h  visit  ar e o utli n e d b el o w 
a n d a t a bl e ca n be  f o u n d i n A p pe n di x  1 . 
E ver y eff ort s h o ul d be m a de t o c o n d uct t he st u d y  visit s as pla n n e d . H o we ver, d ue t o c o nc er ns 
relat e d t o t h e C O VI D-1 9 pa n de mic, st u d y p arti ci pa nts ma y be u na bl e t o c o me i nt o t he office f or 
t heir st u d y sc h e d ule d visit, i n or der t o mi ni miz e a n y p ote nti al ris ks t o st u d y partici pa nt saf et y a n d 
t o c o m pl y wit h g o ver n m e ntal a n d l oc al i nstit uti o nal g ui da nce (e. g., st u d y site has a p oli c y t hat a 
cli ni cal r esearc h visit m ust be dela ye d). U n der t h ese circ u msta nc es , t he i n vesti g at or s h o ul d 
c o ntact t he s p o ns or m e dic al m o nit or ( or desi g nee)  t o disc uss  t he m ost a p pr o priate c o urse of 
acti o n. F or visits  ot her t ha n t h e  We e k  4 8 visit, r e m ot e safet y visits will b e all o we d o n a c ase b y 
case basis, if a partici pa nt  is u na bl e t o c o me t o t he site f or e val u ati o n i n cl u di n g p h ysic al 
e xa mi n ati o n or if saf et y l a bs ca n n ot be p erf or me d d ue t o t h e C O VI D -1 9 pa n de mi c . T h e sit e 
i n vesti gat or s h o ul d disc uss t he s pecific re q uire me nts f or t he re m ote safet y visit wit h t he S p o ns or  
M e dical M o nit or, w hic h will be b ase d o n t h e st u d y visit n u m b er a n d t h e cli nic al stat us of t he 
partici pa nt , wit h c o nsi d erati o n of t heir trial c o m plia nce t o st u d y me di cati o n, pre vi o us la bs a n d 
ot her ris k fact ors. S hi p pi n g of st u d y dr u g fr o m t he site t o t h e partici p a nt  vi a  o ver ni g ht  tra c ke d 
a n d certifie d c o urier , w here p ossi bl e will als o be all o we d.   
S p o ns or Me dic al M o nit or  
 
 
Cell: 
 
 
 
8. 1. 1  
S cree ni n g  ( wit hi n 4 2  d ays  pri or t o b aseli ne ) 
Partici p a nt s w h om  t he I n v esti gat or c o nsi ders t o b e a p pr o priate f or t he st u d y, will ha ve t he st u d y 
e x plai n e d t o t he m , t heir L A R if a p plica ble, a n d t heir st u d y part ner  b y t h e I n vesti g at or or his/ her 
desi g nee a n d will be gi ve n a c o p y of t he writt e n I nf or me d C o nse nt F or m (I C F). W he n t he y ha ve 
ha d s ufficie nt ti me t o st u d y t his i nf or mati o n a n d t he o p p ort u nit y t o as k a n y q uesti o ns t he y wis h, 
t he y will be i n vite d t o gi v e t heir c o nse nt t o partici p ati o n b y si g ni n g t he I C F. T he st u d y part n er 
P P D
P P D
P P D
P P D

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 4 9  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
ma y  als o be re q uire d t o si g n t he I C F at t he discr eti o n of t he res p o nsi ble I R B re vie wi n g t his 
researc h. Parti ci pa nt s w h o are willi n g t o p arti ci pate i n t he C S F s u b-st u d y will s o i n di cat e i n t he 
secti o n pr o vi d e d o n t he I C F. 
O nce t he partici pa nt  or L A R  (a n d st u d y part ner  if re q uire d) ha v e gi ve n c o nse nt, t h e f oll o wi n g 
pr oce d ures will b e u n derta k e n  d uri n g t h e scree ni n g p eri o d.  
•  C o nfir mati o n of pr o ba bl e Alz hei mer’s dise ase usi n g t he NI A/ Alz hei mer’s Ass ociati o n 
G ui deli nes  (see A p pe n di x II ) 
•  M M S E  (sc ore bet wee n 1 4 t o 2 4 , i n cl usi ve) 
•  D oc u me ntati o n of de m o gra p hics, m e dic al hist or y, s m o ki n g ha bits a n d e d uc ati o n  
•  M o difie d Hac hi ns ki isc he mic t est (sc ore of 4 or less)  
•  Ne ur o l o gical e xa m  
•  P h ysical e xa m i nati o n 
•  V ital si g ns (sitti n g bl o o d press ure , p ulse, te m p erat ur e, res pirati o n rat e) 
•  W ei g ht  
•  Hei g ht  
•  D oc u me ntati o n of c o n c urre nt pat h ol o gi es a n d c o nc o mita nt tre at m e nt  
•  D oc u me ntati o n of a d verse e v e nts fr o m ti me of c o nse nt . A d verse e ve nts t hat o cc ur pri or t o 
i niti ati o n of st u d y dr u g will be d o c u me nte d as me dic al hist or y. 
•  Bl o o d sa m ples f or : 
o  C li nic al saf et y la b orat or y tests ( h e mat ol o g y a n d s er u m c h e mistr y, as list e d i n 
Secti o n 8. 2 ). 
o  HI V, H Bs A g, H C V  a nti b o d y  
o  A p o E  (e 4 +/-) ge n ot y pi n g  
•  Uri nal ysis (see  Secti o n 8. 2 ) 
•  Resti n g 1 2 -le a d E C G 
•  V ol u metri c M RI per pr ot oc ol i m a gi n g re q uir eme nts ;  
o  If a parti ci pa nt  has n ot ha d a n  M RI perf or me d wit hi n 6 m o nt hs  of scree ni n g ( i.e.,  
wit hi n 6 m o nt hs fr o m t he dat e of i nf or me d c o nse nt),  t h e n a n 
M RI m ust b e 
perf or me d as part of t h e scree ni n g re q uire m e nts f or t his st u d y, per t he i ma gi n g 
pr ot oc ol, a n d  s h o ul d be o ne of t he last scr ee ni n g pr o ce d ures perf or me d  t o deter mi ne 
fi nal eli gi bilit y i n or der t o pre ve nt partici pa nt s fr o m u n der g oi n g u n necessar y  M RI s.  
o  If a partici pa nt  has  ha d a n  M RI wit hi n 6 m o nt hs  of scree ni n g ( i.e.,  wit hi n 6 m o nt hs 
fr o m t he dat e of i nf or me d c o nse nt) b ut t h e M RI d oes n ot f oll o w t he st u d y -s pecific 
i ma gi n g pr ot oc ol, t hat M RI ca n be use d t o hel p deter mi n e eli gi bilit y; h o we ver,  
a n ot her M RI m ust be perf or me d  p er t he i ma gi n g pr ot oc ol, a n d m ust occ ur as cl os e 
t o, a n d pri or t o, t he b aseli n e visit, after all ot her eli gi bilit y  criteri a ha ve b ee n 
c o nfir me d . 
•  L u m bar p u nct ure *  
•  P ost l u m bar p u nct ur e safet y tele p h o n e f oll o w -u p  ( 1 t o 3 da ys after l u m bar p u nct ure) 
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
* N O T E:  Pa rtici pa nts w h o  ha ve  c o nse nte d  t o partici p ate  i n t he C S F  s u b-st u d y s h o ul d u n der g o  a 
l u m bar p u nct ure  t o o btai n  sa m ples of  C S F n o  m ore  t ha n 1 4  da ys  pri or  t o t heir first d ose  of  st u d y 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 0  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
dr u g  at b aseli ne. T he partici pa nt’s vitals s h o ul d be assesse d bef ore a n d after t he pr oce d ure, or per 
sta n dar d l ocal practice. I N R, P T, P T T a n d platelets s h o ul d be assesse d at t he site’s l ocal la b orat or y 
at least 2 4 h o urs, a n d wit hi n n or mal ra n ge, pri or t o t he l u m bar p u nct ur e. T he l u m bar p u nct ure 
s h o ul d be d o ne after  t he M RI sca n if perf or me d o n t he sa me da y. If t he l u m bar p u nct ure is 
perf or me d o n a se p ar ate d a y fr o m t he M RI a n d occ urs bef ore  t he M RI, t he n t here m ust be at least 
a 3-da y wi n d o w bet wee n t he l u m bar p u nct ure a n d t he M RI. If t he l u m bar p u nct ure is perf or me d 
o n a se parate da y fr o m t he M RI a n d occ urs after  t he M RI, t he n t here is n o wi n d o w ( waiti n g peri o d) 
bet wee n t he M RI a n d l u m bar p u nct ure . B ot h t he l u m bar p u nct ure a n d v M RI s h o ul d occ ur after all 
ot her eli gi bilit y c riteria ha ve bee n c o nfir me d. 
F oll o wi n g c o m pleti o n of all scre e ni n g assess me nts, r es ults f or p a rti ci pa nts w h o me et all i n cl usi o n 
a n d n o ne of t he e xcl usi o n criteri a will be s u b mitte d  via t he A D C S  E D C  f or ce ntral c o nfir mati o n 
of eli gi bilit y. If c o nfir me d t o b e eli gi ble, per missi o n t o ra n d o mi ze will be iss ue d a n d t he pa rtici p a nt 
ma y be ra n d o miz e d . 
Ra n d o miz ati o n m ust occ ur at t he b aseli n e visit ; ot h er wise , t he p artici p a nt will be c o nsi d ere d a 
scree n fail ure. 
R e -scree ni n g  
 
A si n gle f ull re-scree n (re-c o nse nt partici p a nt, assi g n ne w Partici p a nt I D a n d perf or m all  scree ni n g  
assess me nts) ma y be c o n d ucte d m ore t ha n 1 4  da ys after t he last assess me nt of a  scree ni n g  fail ure. 
 
If t he parti ci pa nt is fail e d a gai n at re-scre e ni n g, f urt her re-scree ni n g a n d its mi ni m u m i nt er val fr o m 
t he pre vi o us o ne, ma y b e d o ne if t he PI a n d Ce ntral Re vie w Me di cal M o nit or are i n a gre e me nt t o 
d o s o.  
 
F or re -scree ni n g, v M RI ta ke n at t he 1st scree ni n g (s cree ni n g fail ure) ca n be use d if it will be less 
t ha n 3 m o nt hs ol d at t h e ti me of ra n d o mizati o n. Ot her wise, v M RI nee ds t o be  re peate d. 
 
If t he partici p a nt  is partici pati n g i n t he C S F su b -st u d y a n d t he l u m bar p u n ct ure was d o ne b ef ore 
scree ni n g fail ur e, please as k A D C S if l u m bar p u nct ure s h o ul d be re -ta ke n w he n t he partici pa nt  is 
re-scree ne d a n d r a n d o mi ze d. 
8. 1. 2  
B aseli ne  (W ee k 0)  
At  b aseli ne, eli gi bl e p a rti ci pa nts will  be  ra n d o mize d i nt o t he st u d y. Eac h  will  u n der g o  t he 
f oll o wi n g pr oce d ures  pri or  t o first d ose  of  st u d y me dicati o n:  
•  Verificati o n  of  I ncl usi o n/ E xcl usi o n criteria 
•  Ra n d o mizati o n  i n E D C  
•  P h ysical e xa m  
•  Vital si g ns (sitti n g bl o o d press ure, p ulse, te m p erat ur e, res pirati o n rat e) 
•  Wei g ht  
•  D oc u me ntati o n  of  c o nc o mita nt treat me nt 
•  D oc u me ntati o n  of  a d verse e ve nts . A d verse e ve nts t hat occ ur pri or t o i nitiati o n of st u d y 
dr u g will be d oc u me nte d as me dical hist or y.   

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 1  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  Bl o o d  sa m ples f or: 
o  Safet y  la b orat or y tests ( he m at ol o g y a n d ser u m c he mistr y,  as  liste d i n Secti o n 
8. 2 ). 
o  P har mac o ki n eti cs  i n plas m a 
o  Bi o mar ker/ ba n ki n g  
•  Uri nal ysis  (see Secti o n 8. 2 ) 
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
•  A D A S -C o g  1 1  
•  C D R -S O B  
•  N PI  
•  A D C S -A D L  
•  Ne ur o ps yc h ol o gical Test Batter y  
o  Craft St or y 2 1 Recall (I m me diate a n d Dela ye d)  
o  Be ns o n C o m ple x Fi g ure  
o  M ultili n g ual Na mi n g Test ( MI N T)  
o  Letter & Cate g or y Fl ue nc y  
o  Trail Ma ki n g Test A & B  
o  N u m ber S pa n Test  
•  M M S E  
•  M o ntreal C o g niti ve Assess me nt ( M o C A)  
•  Researc h Satisfacti o n S ur ve y  
First  d ose  of  st u d y me dicati o n  will  b e  gi ve n  i n t he cli nic at a n y ti me after c o m pleti o n  of  all  
of t he  a b o ve.  
At  t his visit,  all pa rtici pa nts will  recei ve a s u p pl y of  st u d y dr u g  wit h  i nstr ucti o ns o n  h o w  t o 
ta ke it. Pa rtici pa nts will be  gi ve n a n a p p oi nt me nt t o ret ur n at wee k  4 ( ± 7 da ys).  
8. 1. 3  
Wee k 2  (+  3  d ays)  
P artici p a nts will r ecei ve a p h o ne call d uri n g W ee k 2 fr o m site st u d y pers o n nel i n or der t o assess 
st u d y dr u g t olera bilit y. If t ol era ble, t he n t h e partici p a nt will be i nstr uct e d t o pr oc ee d wit h d ose 
escalati o n . T h e f oll o wi n g pr oc e d ures m ust oc c ur: 
•  D oc u me ntati o n of c o n c o mita nt treat me nt  
•  D oc u me ntati o n of a d v erse e ve nts  
•  I nstr ucti o n o n dr u g d osi n g re gi me n 
8. 1. 4  
W ee k 4 ( +  7 d ays)  
All pa rti ci pa nts ret ur ni n g f or wee k  4 will u n der g o t h e f oll o wi n g pr oc e d ures:  
•  P h ysical e xa m  
•  Vital si g ns (sitti n g bl o o d press ure, p uls e, te m p erat ur e, res pirati o n rat e) 
•  Wei g ht  
•  D oc u me ntati o n of c o n c o mita nt treat me nt  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 2  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  D oc u me ntati o n of a d v erse e ve nts  
•  Bl o o d sa m ples f or : 
o  S afet y la b or at or y t ests ( he mat ol o g y a n d ser u m c he mistr y, as liste d i n  Secti o n 8. 2 ) 
o  P har mac o ki n eti cs  (i n plas m a) 
•  Uri nal ysis ( see Secti o n 8. 2 ) 
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
At eac h visit, pa rtici p a nts will re cei v e a s u p pl y of st u d y dr u g wit h i nstr ucti o ns o n h o w t o ta ke it. 
Pa rtici p a nts will b e gi ve n a n a p p oi nt me nt t o ret ur n i n 4 wee ks ( +  7 da ys) . 
8. 1. 5  
W ee k 8 ( +  7 d ays)  
All pa rti ci pa nts ret ur ni n g f or wee k  8  will u n der g o t h e f oll o wi n g pr oc e d ures:  
•  P h ysical e xa m  
•  Vital si g ns (sitti n g bl o o d press ure, p ulse, te m p erat ur e, res pirati o n rat e) 
•  Wei g ht  
•  D oc u me ntati o n of c o n c o mita nt treat me nt  
•  D oc u me ntati o n of a d v erse e ve nts  
•  Bl o o d sa m ples f or : 
o  S afet y la b or at or y t ests ( he mat ol o g y a n d ser u m c he mistr y, as liste d i n  Secti o n 8. 2 ) 
o  P har mac o ki n eti cs  (i n plas m a) 
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
At  t his visit,  pa rtici pa nts will  recei ve a s u p pl y of  st u d y dr u g  wit h  i nstr ucti o ns o n  h o w  t o ta k e 
it. Pa rti ci pa nts will be gi ve n a n a p p oi nt me nt t o ret ur n i n 4 wee ks ( +  7 da ys).  
8. 1. 6  
W ee k 1 2 ( +  7 d ays)  
All pa rti ci pa nts ret ur ni n g f or wee k  1 2  will u n der g o  t he f oll o wi n g pr oc e d ures: 
•  P h ysical e xa m  
•  Vital si g ns (sitti n g bl o o d press ure, p ulse,  te m p erat ur e, res pirati o n rat e) 
•  Wei g ht  
•  D oc u me ntati o n of c o n c o mita nt treat me nt  
•  D oc u me ntati o n of a d v erse e ve nts  
•  Bl o o d sa m ples f or : 
o  S afet y la b or at or y t ests ( he mat ol o g y a n d ser u m c he mistr y, as liste d i n  Secti o n 8. 2 ) 
o  P har mac o ki n eti cs  (i n plas m a) 
•  Uri nal ysis ( see Secti o n 8. 2 )  
•  Resti n g 1 2 -le a d E C G 
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
•  A D A S -C o g 1 1  
•  C D R -S O B  
•  Researc h Satisfacti o n S ur ve y  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 3  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
At  t his visit,  pa rtici pa nts will  recei ve a s u p pl y of  st u d y dr u g  wit h  i nstr ucti o ns o n  h o w  t o ta k e 
it. Pa rtici pa nts will be  gi ve n  a n a p p oi nt me nt t o ret ur n i n 1 2 wee ks (+  7 da ys).   
8. 1. 7  
W ee k 2 4 ( +  7 d ays)  
All p arti ci pa nts  ret ur ni n g f or wee k  2 4 will u n der g o t he f oll o wi n g pr oc e d ures:  
•  P h ysical e xa m  
•  Vital si g ns (sitti n g bl o o d press ure, p ulse, te m p erat ur e, res pirati o n rat e)  
•  Wei g ht  
•  D oc u me ntati o n  of  c o nc o mita nt treat me nt 
•  D oc u me ntati o n  of  a d verse e ve nts 
•  Bl o o d  sa m ples f or: 
o  Safet y  la b orat or y  tests ( h e mat ol o g y a n d ser u m c he mistr y,  as  liste d i n Secti o n 8. 2 ) 
o  P har mac o ki n eti cs  (i n plas m a) 
o  Bi o mar ker /bi o ba n ki n g  
•  Uri nal ysis  (see Secti o n 8. 2 )  
•  Resti n g 1 2 -le a d E C G 
•  L u m bar p u nct ure * ( +  1 4 da ys of wee k  2 4 )  
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
•  A D A S -C o g 1 1  
•  C D R -S O B  
•  V ol u metri c M RI  (+  1 4 da ys of wee k  2 4)  
•  N PI   
•  A D C S -A D L  
•  M M S E  
•  M o C A  
•  Researc h Satisfacti o n S ur ve y  
 
At  t his visit,  p artici pa nts will  recei ve a s u p pl y of  st u d y dr u g  wit h  i nstr ucti o ns o n  h o w  t o ta k e 
it. Pa rtici pa nts will be  gi ve n  a n a p p oi nt me nt t o ret ur n i n 1 2 wee ks (+  7 da ys).   
* N O T E:  Partici pa nts  w h o  ha ve  c o nse nte d  t o partici pate  i n t he C S F  s u b-st u d y will  u n der g o  a 
l u m bar p u nct ure  f or C S F wit hi n  1 4  da ys  pri or  t o t his visit. Plas ma sa m ples f or P K f or t his s u bset 
of partici pa nts  s h o ul d be dra w n at t he ti me of l u m bar p u nct ure. T he partici pa nt’s vitals s h o ul d be 
assesse d bef ore a n d after t he pr oce d ure, or per sta n dar d l ocal practice. I N R, P T, P T T a n d platelets 
s h o ul d be assesse d at t he site’s l ocal la b orat or y at least 2 4 h o urs, a n d  wit hi n n or mal ra n ge, pri or 
t o t he l u m bar p u nct ure. T he l u m bar p u nct ure s h o ul d be d o ne after  t he M RI sca n if perf or me d o n 
t he sa me da y. If t he l u m bar p u nct ure is perf or me d o n a se p ar ate d a y fr o m t he M RI a n d occ urs 
bef ore t he M RI, t he n t here m ust be at least a 3-da y wi n d o w bet wee n t he l u m bar p u nct ure a n d t he 
M RI.  If t he l u m bar p u nct ure is perf or me d o n a se p ar ate d a y fr o m t he M RI a n d occ urs after  t he 
M RI, t he n t here is n o wi n d o w ( waiti n g peri o d) bet wee n t he M RI a n d l u m bar p u nct ure. If a 
partici pa nt i n t he  C S F s u b-st u d y is ter mi nati n g earl y, t he y d o n ot nee d t o u n der g o t his l u m bar 
p u nct ure. H o we ver, e ver y eff ort will be ma de t o e nc o ura ge t he partici pa nt’s o n g oi n g v ol u ntar y 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 4  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
partici pati o n a n d t o e x plai n t hat C S F c ollecti o n ma y pr o vi de i nf or mati ve i nf or mati o n i n t he f ut ure 
f or t he fiel d of A D.  
8. 1. 8  
W ee k 3 6 ( +  7 d ays)  
All p arti ci pa nts ret ur ni n g f or wee k  3 6 will u n der g o t he f oll o wi n g pr oc e d ures:  
•  P h ysical e xa m  
•  Vital si g ns (sitti n g bl o o d press ure, p ulse, te m p erat ur e, res pirati o n rat e)  
•  Wei g ht  
•  D oc u me ntati o n of c o n c o mita nt treat me nt  
•  D oc u me ntati o n of a d v erse e ve nts  
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
•  A D A S -C o g 1 1  
•  C D R -S O B  
•  Researc h Satisfacti o n S ur ve y  
At eac h visit, pa rtici p a nts will re cei v e a s u p pl y of st u d y dr u g wit h i nstr ucti o ns o n h o w t o ta ke it. 
Pa rtici p a nts will  b e gi v e n a n a p p oi nt me nt t o ret ur n i n 1 2  wee ks ( +  7 da ys).  
8. 1. 9  
W ee k 4 8  or E arly Ter mi n ati o n  (+  7 d ays)  
E ver y eff ort s h o ul d be ma de t o c o n d uct t he We e k 4 8 visit a n d mai ntai n t he +/ - 7 da y wi n d o w . 
H o we ver, d ue t o c o n cer ns rel ate d t o t he C O VI D -1 9  pa n de mi c , the  Wee k 4 8 visit wi n d o w ma y be 
m o difi e d be y o n d t he +/ - 7 da y wi n d o w , i n or d er t o mi ni miz e a n y p ote ntial ris ks t o st u d y p arti ci pa nt 
safet y a n d t o c o m pl y wit h g o ver n me nt al a n d l ocal i nstit uti o nal g ui da nc e  (e.g ., st u d y site has a 
p olic y t hat a clinic al r esearc h  visit m ust be d ela y e d).  U n der t hese circ u msta nc es, t he visit wi n d o w 
ma y be e xt e n de d ( u p t o  a ma xi m u m tr eat me nt d ur ati o n of 6 0  wee ks ), b ut e ver y atte m pt s h o ul d be 
ma de t o c o n d uct t h e visit as cl ose t o t he date t he visit is d ue as p ossi ble . If t he visit wi n d o w is 
m o difie d , partici pa nts s h o ul d be e val uate d re m ot el y (e. g., via p h o ne ) at t he ti me of t he sc he d ule d 
Wee k 4 8 visit t o perf or m a n d d o c u me nt a p pr o priat e s afet y assess me nts. St u d y me dic ati o n m a y be 
se nt t o t h e partici p a nt via tr ac ke d c o urier.  F or a n y s uc h cases, t h e i n vesti gat or s h o ul d disc uss t he 
s pecific circ u mst a nces of eac h c ase wit h t he s p o ns or  me dical m o nit or  ( or desi g nee) w h o m ust 
a p pr o ve t he re q uest pri or t o a n y m o dificati o n of t he visit wi n d o w . 
S p o ns or Me dic al M o nit or  
 
 
Cell: 
 
 
 
All pa rti ci pa nts ret ur ni n g f or wee k  4 8 will u n der g o t he f oll o wi n g pr oc e d ures:  
P P D
P P D
P P D
P P D

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 5  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
•  P h ysical e xa m  
•  Vital si g ns (sitti n g bl o o d press ure, p ulse, te m p erat ur e, res pirati o n rat e)  
•  Wei g ht  
•  D oc u me ntati o n  of  c o nc o mita nt treat me nt 
•  D oc u me ntati o n  of  a d verse e ve nts 
•  Bl o o d  sa m ples f or: 
o  Safet y  la b orat or y tests ( h e mat ol o g y a n d ser u m c he mistr y,  as  liste d i n Secti o n 8. 2 ) 
o  P har mac o ki n eti cs *  (i n plas m a) 
o  Bi o mar ker/ ba n ki n g  
•  Uri nal ysis  (see Secti o n 8. 2 ) 
•  Resti n g 1 2 -le a d E C G 
•  L u m bar p u nct ure *  (+  1 4 da ys of wee k  4 8)  
•  P ost l u m bar p u nct ur e safet y tele p h o n e f oll o w -u p  ( 1 t o 3 da ys after l u m bar p u nct ure) 
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
•  A D A S -C o g 1 1  
•  C D R -S O B  
•  V ol u metri c M RI ( +  1 4 da ys of wee k  4 8)  
•  N PI  
•  A D C S -A D L  
•  Ne ur o ps yc h ol o gical Test Batter y  
o  Craft St or y 2 1 (I m me diate a n d Dela ye d)  
o  Be ns o n C o m ple x Fi g ure  
o  M ultili n g ual Na mi n g Test ( MI N T)  
o  Letter & Cate g or y Fl ue nc y  
o  Trail Ma ki n g Test A & B  
o  N u m ber S pa n Test  
•  M M S E  
•  M o ntreal C o g niti ve Assess me nt ( M o C A)   
•  Researc h Satisfacti o n S ur ve y  
* N O T E:  Pa rtici pa nts w h o  ha ve  c o nse nte d  t o partici pate  i n t he C S F  s u b-st u d y will  u n der g o  a 
l u m bar p u nct ure  f or C S F wit hi n  1 4  da ys  pri or  t o t his visit. Plas ma sa m ples f or P K  f or t his s u bset 
of p artici pa nts s h o ul d be dra w n at t he ti me of l u m bar p u nct ure. T he partici pa nt’s vitals s h o ul d be 
assesse d bef ore a n d after t he pr oce d ure, or per sta n dar d l ocal practice. I N R, P T, P T T a n d platelets 
s h o ul d be assesse d at t he site’s l ocal la b orat or y at least 2 4 h o urs, a n d wit hi n n or mal ra n ge, pri or 
t o t he l u m bar p u nct ure. T he l u m bar p u nct ure s h o ul d be d o ne after  t he M RI sca n if perf or me d o n 
t he sa me da y. If t he l u m bar p u nct ure is perf or me d o n a se p ar ate d a y fr o m t he M RI a n d occ urs 
bef ore t he M RI, t he n t here m ust be at least a 3-da y wi n d o w bet wee n t he l u m bar p u nct ure a n d t he 
M RI.  If t he l u m bar p u nct ure is perf or me d o n a se p ar ate d a y fr o m t he M RI a n d occ urs after  t he 
M RI, t he n t here is n o wi n d o w ( waiti n g peri o d) bet wee n t he M RI a n d l u m bar p u nct ure. If a 
partici pa nt i n t he C S F s u bst u d y is ter mi nati n g earl y, t he y d o n ot nee d t o u n der g o t his l u m bar 
p u nct ure.  H o we ver, e ver y eff ort will be ma de  t o e nc o ura ge t he partici pa nt’s o n g oi n g v ol u ntar y 
partici pati o n a n d t o e x plai n t hat C S F c ollecti o n ma y pr o vi de i nf or mati ve i nf or mati o n i n t he f ut ure 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 6  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
f or t he fiel d of A D. Pa rtici pa nts will b e gi ve n a n a p p oi nt me nt t o ret ur n i n 4 we e ks ( +  7 da ys)  
u nless t his  ser ves as t heir Earl y Ter mi n ati o n visit. 
8. 1. 1 0  
W ee k 5 2  S afety F oll o w -u p  (+  7 d ays)  
All pa rti ci pa nts ret ur ni n g f or wee k  5 2 ( w h o ar e n ot g oi n g i nt o t h e O pe n-La b el E xte nsi o n p hase) 
will  u n der g o t h e f oll o wi n g pr o ce d ures  aft er t he Wee k 4 8 visit is c o m plet e d i n pers o n : 
•  P h ysical e xa m  
•  Vital si g ns ( sitti n g bl o o d press ure, p ulse, te m p erat ur e, res pirati o n rat e) 
•  Wei g ht  
•  D oc u me ntati o n of c o n c o mita nt treat me nt  
•  D oc u me ntati o n of a d v erse e ve nts  
•  Bl o o d sa m ples f or s afet y la b or at or y tests ( he mat ol o g y a n d ser u m c he mistr y, as liste d i n  
Secti o n 8. 2 ) 
•  Resti n g 1 2 -le a d E C G 
•  S hee ha n S uici d alit y Tra c ki n g Scal e  
8. 1. 1 1  
U nsc he d ule d Visit  
D oc u me ntati o n of c o nc o mita nt me dicati o n, a d verse e ve nts, a n d  vital si g ns will be c oll ecte d  at all 
u nsc he d ule d visits , a n d a d diti o nal cli nical safet y la b orat ories ma y be c o m plete d at t h e discreti o n 
of t he PI or at t he r e q uest of t he me dical m o nit or.  Partici pa nts ret ur ni n g t o c o n d u ct a n u nsc he d ule d 
visit o utsi d e of  t he pr ot o c ol’s visit sc he d ule ma y h a ve missi n g or a d diti o nal st u d y pr o ce d ures 
perf or me d b y sit e pers o n nel.  
8. 1. 1 2  
O pe n -L a bel E xte nsi o n P h ase ( as a p plic a ble)  
T he E xte nsi o n P hase is a n o pti o nal o pe n -la b el 4 8-wee k treat me nt p hase. T he i n vesti g at or will b e 
res p o nsi ble f or e val u ati n g a n y maj or c ha nges i n t he partici pa nt’s stat us t o deter mi ne t heir 
partici pati o n i n t he o pe n -la bel e xt e nsi o n. T his s h o ul d be base d o n t he stat us of t he parti ci pa nt at 
t he e n d of t he d o u ble-bli n d p hase, t he partici p a nt’s ris k -be nefit pr ofil e as d eter mi ne d b y t he site 
PI, t he c o nse nt of t h e partici pa nt , a n d t h e i nt e grit y of t he tri al.  
If t he partici pa nt has c o m plet e d t h e d o u bl e bli n d treat me nt p hase pri or t o t he O pe n -La bel 
E xte nsi o n P hase bei n g a p pr o ve d at t heir st u d y c e nter, t he y ca n re -c o nse nt a n d start t he st u d y as 
l o n g as t he i n vesti g at or d eter mi nes t hat o pe n -la bel treat me nt offers a n acc e pta ble ris k-be nefit 
pr ofile f or t h e i n di vi d ual. O nce t he st u d y sit e is o pe n f or recr uit me nt f or t h e O pe n-La b el e xte nsi o n, 
partici pa nts t h at c o m pl ete d t he st u d y pri or will ha ve u p t o 1 2  wee ks t o e nr oll i n t he O pe n -La bel 
st u d y. 
W he n sites ha ve o pe ne d f or recr uit me nt f or t he 
O pe n -La bel E xte nsi o n  P hase,  partici p a nts 
c o m pleti n g t he d o u ble -bli n d treat me nt p hase m ust g o directl y fr o m t he We e k 4 8 visit i nt o t he 
E xte nsi o n P hase if t he y c h o ose a n d are eli gi ble  t o c o nti n ue. 
•  Partici p a nts w h o are c o m pleti n g t h e d o u ble -bli n d tr e at me nt p hase m a y dire ctl y e nter t he 
O pe n -La bel E xt e nsi o n p hase. T hese partici p a nts s h o ul d n ot c o m plete t he f oll o w-u p safet y 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 7  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
visit at W ee k 5 2 ( of t he d o u ble -bli n d tr eat me nt p has e). I nstea d, t hese partici p a nts s h o ul d 
c o nti n ue directl y i nt o t he O pe n -La bel E xt e nsi o n p has e starti n g at W ee k 4 8 ( of t h e d o u ble -
bl i n d tr eat me nt p hase). T he Wee k 4 8 visit will als o ser ve as t he B aseli n e visit i n t h e 
E xte nsi o n P hase f or partici p a nts w h o ar e g oi n g directl y fr o m t he d o u ble -bli n d tr eat me nt 
p hase t o t h e O L E. T h ereafter, partici pa nts will u n der g o visits at Wee k 4, Wee k 8, W e e k 
1 2,  a n d t he n e ver y 1 2 wee ks of t he E xte nsi o n P hase as o utli ne d i n Ta ble 3 ( Sc he d ule of 
Assess me nts/ Ti me & E ve nts - E xte nsi o n P hase).  
•  Partici p a nts w h o pre vi o usl y c o m plete d t h e  d o u ble -bli n d tre at m e nt p hase pri or t o t h e 
O pe n -La bel E xte nsi o n p hase of t he st u d y bei n g o pe n f or recr uit m e nt at t h eir st u d y ce nt er, 
ma y als o e nter t h e O pe n -La bel E xt e nsi o n  ( O L E) p hase.  
o  F or partici p a nts w h o will h a ve b ee n off of t he st u d y dr u g f or less t ha n or e q ual t o 
4 wee ks, t he s u bj ect s h o ul d c o me i nt o t he i n vesti gati ve site f or a n Ab bre vi ate d 
Dr u g Dis pe nsati o n Visit  (als o “ A b bre viate d O L E Baseli ne Visit ”), at w hic h ti m e 
a n y maj or me di cal or m e dic ati o ns c ha n ges will be r e vie we d pri or t o dis pe nsi n g 
ril uz ol e. I n t his case, m ost pr oc e d ures fr o m t he W e e k 4 8 visit will als o ser ve as 
t he O L E 
 P hase  Baseli ne visit , as o utli ne d i n 
Ta ble 3 ( Sc he d ule of 
Assess me nts/ Ti me 
& E ve nts -E xte nsi o n P hase). T hereaft er, partici p a nts  will 
u n der g o visits at Wee k 4, W ee k 8, W ee k 1 2, a n d t he n e ver y 1 2 wee ks of t he O L E  
P hase . 
o  F or parti ci pa nts w h o ha ve bee n off t h e st u d y dr u g f or great er t h a n 4 wee ks, t hese 
partici pa nts s h o ul d be r e -assesse d a n d re -c o nse nte d b y t he PI d uri n g a n O L E  
Baseli ne Visit. Fr o m t he date t hat  t he O pe n -La bel  E xte nsi o n is o pe n f or 
recr uit me nt at t h e st u d y site, t hese partici pa nts t hat c o m plet e d t he st u d y pri or will 
ha ve u p t o a p pr o xi matel y 1 2 wee ks  t o c o m pl et e t he O L E  Baseli n e Visit . 
T hereafter, parti ci pa nts will u n der g o visits at We e k 4,  Wee k 8 , Wee k 1 2,  a n d t he n 
e ver y 1 2 wee ks of t he O L E  p hase as o utli ne d i n Ta ble 3 ( Sc he d ule of 
Assess me nts/ Ti me & E ve nts -E xte nsi o n P hase). All pre vi o us c o m plet ers of t he 
d o u ble -bli n d p hase will ha v e a 1 2 -we e k wi n d o w of o p p ort u nit y t o baseli ne i nt o 
t he O L E, r e gar dl ess of t heir d ate of d o u ble-bli n d p h ase c o m p l eti o n. I n t he e ve nt 
sites o pe n f or O L E  recr uit m e nt, t he n cl ose d ue t o C O VI D-1 9  bef ore e nr olli n g all 
pri or c o m pleters, e xce pti o ns t o t he 1 2 -wee k wi n d o w will be c o nsi dere d o n a c ase -
b y -case basis, f oll o wi n g disc ussi o n wit h t he S p o ns or Me dical M o nit or:  
 
S p o n s or Me dic al M o nit or 
 
 
Cell: 
 
 
 
•  As wit h t he d o u bl e -bli n d p hase,  c ertai n pr o visi o ns ma y be i m pl e me nte d, i n or d er t o 
mi ni mize p ote ntial haz ar ds t o st u d y partici pa nts d ue t o C O VI D -1 9. T hese pr o visi o ns m a y 
all o w alt er nati ves t o i n -pers o n st u d y visits a n d i ncl u d e b ut are n ot li mite d t o t he f oll o wi n g: 
c o n d ucti n g re m ote visits via p h o ne/tel e me dici n e vi de o, f oc usi n g o n s afet y assess me nts 
d uri n g re m ot e visits, perf or mi n g safet y la bs vi a l ocal la bs or pr ofessi o nal i n h o me 
P P D
P P D
P P D
P P D

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 5 8  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
p hle b ot o m y ve n d ors, a n d s hi p pi n g st u d y me dic ati o n t o st u d y s u bjects if nee de d. A n y 
p ote nti al iss ues s h o ul d be disc usse d wit h t he S p o ns or a n d will b e a d dre sse d o n a n 
i n di vi d ualiz e d basis. 
o  O L E visits ma y be c o m plet e d re m ot el y, if nec essar y d ue t o C O VI D -1 9. H o we ver, 
partici pa nts s h o ul d n ot be o n st u d y dr u g f or gre ater t ha n 2 4 we e ks  wit h o ut 
c o m pleti n g a n i n -pers o n visit . F or t hese partici p a nts, I P s h o ul d be held or t he 
partici pa nt disc o nti n u e d.  
•  Partici p a nts w h o e arl y -t er mi n ate d fr o m t he d o u ble-bli n d p hase tri al or disc o nti n ue d t he 
st u d y dr u g f or a n y reas o n will n ot eli gi bl e f or e nr oll me nt i n t o t he O L E  p hase.  
•  All partici p a nts m ust h a ve t heir Wee k 4 8 visit i n pers o n pri or t o e nr olli n g i n t he O L E  p hase. 
( D ue t o C O VI D-1 9,  t he ti mi n g of t his visit ma y be  d ela ye d)  
All partici pa nts e nt eri n g t h e O L E  p hase will start wit h o ne ca ps ule of B H V -4 1 5 7 per da y a n d 
titrate t o t w o ca ps ules per da y after we e k t w o. T his will be d o n e s o t hat all p arti ci pa nts will be o n 
o pe n -la bel me dicati o n a n d will safel y c o nti n u e fr o m eit her acti ve B H V-4 1 5 7 or place b o.  
All parti ci pa nts  i n t he O pe n-La bel E xte nsi o n p h ase are pla n ne d t o  u n der g o a ter mi n ati o n visit 
tw o wee ks after t h e last d ose of st u d y dr u g.  
8. 2  
L a b or at or y S afet y Assess me nts  
Cli nic al Safet y La b or at or y t ests will be p erf or me d b y a Ce ntral L a bor at or y . Assess me nts i ncl u d e 
t he f oll o wi n g:  
H e m at ol o g y : 
He m o gl o bi n, he mat ocrit, plat elet c o u nt , R B C, 
W B C, differe nti al c o u n t a n d 
a bs ol ute ne utr o p hil c o u nt  
C he mistr y:  
S o di u m, p otassi u m, c hl ori d e, cal ci u m, A L T, A S T, L D H, al kali ne p h os p hatase, 
G G T, p h os p h or o us, bicar b o n ate, C P K, t otal pr otei n, al b u mi n,  dire ct bilir u bi n, 
i n direct bilir u bi n, t otal bilir u bi n, gl uc ose, creati ni ne, B U N, uric aci d, t ot al 
c h olester ol, L D L, H D L, tri gl yc eri des  (li pi ds c olle cte d o nl y d uri n g d o u bl e-bli n d 
p hase) , B 1 2 (at scree ni n g o nl y), f ol ate  ( at scre e ni n g o nl y) 
Uri n al ysis:  
p H, s pecific gra vit y, pr ot ei n, gl uc ose, k et o nes, ur o bili n o ge n, bili r u bi n, bl o o d 
A n a p pr o xi mate bl o o d v ol u me of 9. 5 ml at scree ni n g a n d 7 m L  at s u bse q ue nt st u d y visits  ( baseli ne, 
wee k 4, wee k 8, wee k 1 2, we e k 2 4, a n d w ee k 4 8, O pe n -La bel E xt e nsi o n p hase wee k 4, we e k 8, 
wee k 1 2, wee k 2 4, wee k 3 6, a n d wee k 4 8 ), will be c ollecte d f or ser u m c he m istr y a n d he mat ol o g y 
a nal yses. If vita mi n B 1 2 is bel o w n or mal a n d t he I n vesti gat or t hi n ks it nec essar y, a n a d diti o nal 
bl o o d (a p pr o xi mat el y 5 ml) m a y be ta k e n t o me as ure ser u m m et h yl mal o nic aci d l e vels at a n ot her  
visit d uri n g scre e ni n g peri o d.   
Uri ne will be c oll ect e d f or uri nal ysis at scre e ni n g, b aseli ne , we e k  4, wee k  1 2, wee k  2 4 a n d wee k  
4 8 , a n d O pe n-La bel E xte nsi o n p hase wee k 4, wee k 8, wee k 1 2, wee k 2 4, a n d wee k 4 8.  

Confidential
Protocol BHV4157-203 
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Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
The Central Laboratory will provide the investigational sites with all appropriate materials for 
specimen collection, sample processing, packaging and shipping. Full details of sampling (blood 
and urine), sample preparation and storage methods will be given in the laboratory manual. 
If a participant is unable to come in to the study site and needs to have safety labs conducted 
locally, this is acceptable. The study site should provide the participant or local laboratory with a 
requisition and should collect the results. A home phlebotomist may also be an option for 
participants if needed.  
8.3 
Pharmacokinetic Assessments 
A plasma sample for pharmacokinetic (PK) should be collected at baseline, week 4, week 8, week 
12, week 24, and week 48 of the double-blind phase of the trial. Participants should take their dose 
at their routine time on the days of these visits. Date and time of last dose should be collected in 
case report forms for entry into the EDC system. Participants who are able to be scheduled for a 
morning visit should be instructed to hold their dose of study drug that morning until after a PK 
trough sample is obtained, if possible and appropriate in the judgment of the investigator. 
PK samples should be drawn if there are any SAEs that could possibly be drug-related or severe 
AEs that could be drug-related. 
In addition, for participants undergoing lumbar puncture, plasma samples for PK should be drawn 
at the time of lumbar puncture for Week 24 and Week 48 visits for the double blind placebo phase. 
Date and time of last dose should be collected in case report forms for entry into the EDC system. 
There is no PK sampling during the OLE phase. 
8.4 
Physical and Neurological Examination 
A physical examination will be performed by a medically qualified professional at every study 
visit. A review of the major body systems will be performed and vital signs will be assessed. A 
neurological examination will only be performed at screening and will include assessment of motor 
strength, sensory, deep tendon, tremor, cerebellar, cranial, and mental status. 
8.5 
Genotyping 
ApoE (e4 +/-) genotype is associated with the risk and age of onset of AD. ApoE genotyping 
will be performed at screening. The blood collection will total approximately 10 mL. Results 
of ApoE genotyping will be used in exploratory subgroup analyses to explore the relationship 
between ApoE genotype clinical course and response to treatment. 
If a participant has agreed to allow his/her sample to be banked, then the DNA sample will be 
stored at the UCSD and used for additional genetic testing. Samples will be de-identified prior 
to being shared with outside investigators to preserve the confidentiality of participants. 
Participants can request in writing any time to have their samples destroyed. Results of this testing 
are for research purposes only and will not be disclosed to the participant or study partner. 

Confidential
Protocol BHV4157-203 
Page 60 of 96
 
Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
8.6 
Electrocardiogram 
A standard 12-lead resting ECG will be performed during screening, week 12, week 24, and week 
48 of the double-blind phase, and week 12, week 24, and week 48 of the Open-Label Extension 
phase. The Investigator or designee will review the 12-lead ECG and findings will be recorded in 
the eCRF as normal, abnormal but not clinically significant, or abnormal and clinically significant. 
Any clinically significant abnormalities on ECGs recorded after administration of the 
investigational product will also be documented as AEs and entered on the AE page of the eCRF. 
Clinically significant abnormalities on ECGs prior to administration of the investigational product, 
will be recorded as medical history. 
8.7 
vMRI Assessments 
Brain structural change is seen in normal aging, but is accelerated in neurodegenerative 
disease, including AD. Atrophy in AD arises from neuron and synapse loss that begins in the 
entorhinal cortex. The pathology then spreads throughout the limbic regions of the temporal 
lobe, including the hippocampal formation. Subsequently, neuron loss and atrophy is observed 
throughout neocortical association areas in temporal, parietal and frontal lobes. 
vMRI allows the in vivo assessment of brain structure volume and provides a measure of atrophy 
rate. Results from vMRI studies suggest that the patterns of atrophy in AD, which mirror 
the pathological progression of the disease, can reliably be detected and tracked across time. 
Atrophy of the medial temporal lobe, including hippocampus and entorhinal cortex, has long 
been described in vMRI studies of AD. Hippocampal volume derived from MRI correlates 
with histological hippocampal volume and degree of neuronal loss and AD pathology, and 
entorhinal cortical thickness change appears to be an early and sensitive indicator of 
neurodegeneration associated with AD (Holland et al., 2009; Jack et al., 2004). Longitudinal 
MRI measures of regional and whole-brain volumetric change provide a valuable complement 
to cognitive measures in that they are not influenced by temporary symptomatic improvements, 
and they provide an early index of the study drug’s ability to reach the target organ and have 
an effect on AD-related atrophy.  
Participants will undergo vMRI scans of the brain at screening,  week 24 and week 48 (and 
Extension Phase baseline and week 48) in order to assess for changes in brain volumes that 
may be associated with clinical change due to treatment with BHV-4157.  
Volumetric MRI scans will use the same imaging protocol, which will include a localizer scan, 
a 3D T1- weighted sagittal acquisition (MPRAGE or IR-SPGR), a T2-weighted FLAIR axial 
acquisition, a T2* gradient recalled echo axial acquisition for magnetic susceptibility, and a 
diffusion weighted axial acquisition to assess for restricted diffusion. 
Images will be checked for image quality and adherence to scanning protocols. 3D T1- 
weighted datasets passing quality checks will be corrected for spatial distortion and for 
intensity variation. Screening and follow-up datasets for each participant will be spatially 
registered to one another using rigid-body registration followed by nonlinear registration and 
neuroanatomic parcellation to quantify whole-brain and subregional volumetric change on a 
patient-by-patient basis.  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 6 1  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
T he l ocal M RI res ults  will deter mi ne eli gi bilit y f or eac h partici pa nt i n t he  d o u ble bli n d treat me nt 
p hase of t he trial w he n t he PI  will c o nfir m if M RI res ults are c o nsiste nt wit h A D, meet t he 
s pecifie d i ncl usi o n criteria, a n d d o n ot ha ve e xcl usi o nar y fi n di n gs as defi ne d b y t he pr ot oc ol.  It is 
t he res p o nsi bilit y of t he PI t o ma ke t his deter mi nati o n f oll o wi n g re vie w of t he M RI, a n d t o si g n 
as well as date t he l ocal ra di ol o g y re p ort or t he PI’s o w n brai n M RI writte n e val uati o n t o 
ac k n o wle d ge t heir re vie w . T he PI is at li bert y t o c o ns ult wit h a l ocal ne ur ora di ol o gist, h o we ver 
t here is n o re q uire me nt f or a f or mal M RI rea d fr o m a ne ur ora di ol o gist.  T he A D C S Me dical Safet y 
tea m, or A D C S I ma gi n g c ore are a vaila ble t o a d dress a n y q uesti o ns s urr o u n di n g M RI eli gi bilit y. 
If t here are safet y c o ncer ns i de ntifie d o n t his 
M RI , t he PI s h o ul d c o m m u nicate wit h t he 
partici pa nt’s Pri mar y Care P h ysicia n a n d c o ns ult wit h A D C S Me dical M o nit or, A D C S Direct or, 
a n d A D C S I ma gi n g C ore.  
W h ole  brai n  v ol u me  ( W B V, e xcl u di n g cere bell u m), bilateral ve ntric ular  v ol u m e  a n d bilateral 
hi p p oca m pal  v ol u me  will be  meas ure d. Q ua ntitati ve a nat o mical re gi o nal c ha n ge ( Q uarc) will be 
use d as t he c o m p utati o nal 
M R i ma ge pr ocessi n g a p plicati o n. 
D etail f or t he statistical 
c o m p uta ti o ns is gi ve n i n t he Sta tistical A nal ytical Pla n ( S A P). 
If perf or me d o n t he sa me da y as a l u m bar p u nct ure, t he v M RI  s h o ul d be  c o n d ucte d  b ef ore  t he 
l u m bar p u nct ur e. Ot her wise, at le ast a 3 -da y  wi n d o w bet wee n v M RI a n d t he l u m bar p u nct ure  is 
re q uire d. Sca n ners  t hat ha ve  passe d  t he st u d y’s q ualificati o n  pr oce d ures  will  be  use d.  
Pa rtici p a nts m ust  be  sca n ne d b y  t he sa m e sca n ner t hr o u g h o ut t he st u d y. 
P artici pa nts wit h a c o ntrai n dicati o n  t o M RI at t he ti me of scre e ni n g ar e dee me d i neli gi ble t o 
partici pat e i n t his st u d y. Pa rtici pa nts ma y c o nti n ue t o partici pat e o n t h e st u d y if t h e y ha ve alr ea d y 
bee n ra n d o mize d b ut  de vel o p a c o ntr ai n di cati o n  t o M RI d uri n g t he c o urse of t h e st u d y. 
8. 8  
C S F , Ser u m a n d Pl a s m a S u b -st u d y Assess me nts  
C S F , ser u m a n d plas ma will  be  ta ke n at scree ni n g wit hi n  1 4 da ys  pri or  t o first d ose  of  st u d y 
dr u g  a n d wit hi n  1 4 da ys  pri or  t o wee k s 2 4 a n d 4 8  t o meas ure  bi o mar kers  (e. g., A ß 4 2, A ß 4 2/ 4 0 
rati o, t ot al t au, p -ta u-1 8 1 , ne ur o gra ni n, Nf L, Y K L -4 0, VI LI P , S N A P-2 5, s T R E M 2 , G F A P) i n t he 
d o u ble -bli n d treat me nt p hase of t he trial . F or t he O L E  p hase, ser u m a n d plas ma will be ta ke n at 
wee ks 2 4 a n d 4 8.  T hese sa m ples will be ba n ke d at a ce ntral bi ore p osit or y f or f ut ure e x pl orat or y 
bi o mar ker a nal yses.  
C S F  sa m ples s h o ul d be  c ollecte d  at t h e sa me ti me of  da y,  eit her m or ni n g  ( bet wee n 8  a n d 1 0 A M)  
or  after n o o n  ( bet wee n 1  a n d 3 P M).  T he  first l u m bar p u nct ure  m ust be  c o n d ucte d pri or  t o i nitiati o n 
of st u d y  dr u g.  Plas ma sa m ples f or P K s h o ul d be dra w n at t he ti me of l u m b ar p u nct ure. Date a n d 
ti me of d oses o n t he da y of l u m bar p u n ct ure a n d da y pri or s h o ul d be c olle cte d i n c ase re p ort f or ms, 
f or e ntr y i nt o t he E D C s yste m.  
T he esti m ate d 1 0 0 pa rtici pa nts ( n = 50  acti ve, n = 50 place b o)  w h o are wit hi n t he se nti nel c o h ort  of 
t he d o u bl e-bli n d tre at m e nt p hase of t he tri al will c o nstit ute t he st u d y sa m ple f or t h e
 
a n dwill als o ha ve t h e o p p ort u nit y t o partici pat e i n a C S F, ser u m, a n d plas m a  s u b-st u d y, wit h 
sa m ples dra w n i n t he scree ni n g peri o d a n d at wee k 2 4, wit h t he o pti o n f or a t hir d sa m pli n g ti me p oi nt 
at wee k 4 8. 
C CI

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In addition to the sentinel sub-study participants, other consenting trial participants will be 
approached to undergo a blood draw to provide serum and plasma biomarkers. For CSF, 
consenting participants will undergo a lumbar puncture at screening within 14 days prior to first 
dose of study drug and within 14 days prior to week 48 to measure the CSF biomarkers in the 
double-blind treatment phase of the trial. 
Anti-platelet and anticoagulant medications and lumbar puncture are addressed above in in 
(Prohibited Concomitant Medications, Section 7.4.2). Participants who are taking anticoagulants 
or dual antiplatelet drugs are excluded from the CSF sub-study. 
Details of the CSF sampling are contained in the Study Procedures Manual. 
The unused portion of CSF may be transferred to the National Cell Repository for Alzheimer’s 
Disease (NCRAD) for future research. Participants will be given the choice to allow such sample 
retention and further investigation of their CSF. 
9 STUDY-SPECIFIC INSTRUMENTS 
9.1 
Cognitive Measures 
9.1.1 
Alzheimer’s Disease Assessment Scale Cognitive Subscale (ADAS-Cog 11) 
The ADAS-Cog 11 (Rosen, Mohs, & Davis, 1984) is a structured scale that evaluates memory 
(word recall, word recognition), reasoning (following commands), language (naming, 
comprehension), orientation, ideational praxis (placing a letter in an envelope) and constructional 
praxis (copying geometric designs). Ratings of spoken language, language comprehension, word 
finding difficulty, and ability to remember test instructions are also obtained. The test is scored in 
terms of errors, with higher scores reflecting poorer performance and greater impairment. Scores 
can range from 0 (best) to 70 (worse). 
9.1.2 
Mini-Mental State Examination (MMSE) 
The MMSE is a frequently used screening instrument for Alzheimer’s disease drug trials. It 
evaluates orientation, memory, attention, concentration, naming, repetition, comprehension, and 
ability to create a sentence and to copy two intersecting pentagons (Folstein, Folstein, & McHugh, 
1975). A lower score indicates more cognitive impairment. The highest (best) score is 30.  
9.1.3 
Montreal Cognitive Assessment (MoCA) 
The MoCA is a brief mental status exam which was designed to be more sensitive to mild cognitive 
impairment and early dementia than the MMSE (Nasreddine et al., 2005). It assesses numerous 
cognitive domains, including attention and concentration, executive functions, memory, language, 
visuoconstructional skills, conceptual thinking, calculations, and orientation. Like the MMSE, the 
highest (best) score is 30. Administering both the MoCA and the MMSE in this trial will allow 
comparisons of the utility within the setting of a clinical trial. 

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9.1.4 
Neuropsychological Test Battery (NTB) 
The neuropsychological battery from the Uniform Data Set (v3.0 – Form C2) of the National 
Alzheimer’s Coordinating Center (NACC) (Weintraub et al., 2009) will be administered to provide 
a more detailed assessment of cognition. The battery includes brief measures of attention, 
processing speed, executive function, episodic memory, and language. Exploratory analyses will 
evaluate the treatment effects on a composite measure of this neuropsychological battery between 
baseline and endpoint . As described in the manual for test administration and scoring (Version 
3.0, March 2015), Form C2 of the NACC UDS battery includes the following measures: 
9.1.4.1 
Craft Story 21 Recall (Immediate and Delayed) 
This is a measure of verbal episodic memory (Craft et al., 1996). A brief story is read to the 
participant, who is then asked to retell it immediately from memory. The primary measure of 
performance is the number of story units recalled. Delayed recall of the story is assessed 20 
minutes after immediate recall. Other neuropsychological measures are administered during the 
delay interval (Range: 0-25 for each recall trial). 
9.1.4.2 
Benson Complex Figure Copy & Recall 
This test is a simplified form of the Rey-Osterrieth Complex Figure (Possin, Laluz, Alcantar, 
Miller, & Kramer, 2011). The purpose is to assess visuoconstructional and visual memory 
functions. In this test, the participant is presented with a figure composed of geometric shapes. The 
participant is then asked to reproduce (i.e.,  copy) the figure on the same page. The accuracy of 
each shape and its placement are recorded. The primary measure of performance is the total score 
for copying the figure (Range: 0-17). Approximately 10-15 minutes after the participant copies the 
figure, visual memory is assessed by asking the participant to draw the figure again, from memory, 
on a blank page. The accuracy of each shape and its placement are recorded. The primary measure 
of performance is the total score for the delayed drawing of the Benson figure (Range: 0-17). 
9.1.4.3 
Multilingual Naming Test (MINT) 
The MINT is a test of visual confrontation naming (Ivanova, Salmon, & Gollan, 2013). 
Participants are required to identify (i.e.,  name) line drawings of objects. If the initial response is 
incorrect, semantic and/or phonemic cues are provided, as appropriate. Items are counted as correct 
if spontaneously named after semantic cuing (Range: 0-32). 
9.1.4.4 
Trail Making Test (Trails A and B)  
The Trail Making Test is a test of processing speed and executive function. Trails A consists of 25 
circles numbered 1 through 25 distributed over a white sheet of paper. The participant is instructed 
to draw a line to connect the circles in ascending numerical order as quickly as possible (150 
second maximum). Trails B consists of 25 circles containing either numbers (1 through 13) or 
letters (A through L) that are randomly distributed across the page, and participants are instructed 
to connect the circles in alternating and ascending order (e.g., 1 to A; 2 to B). Performance is 
judged in terms of time to complete each trial. Time to complete Trails B (300 second maximum), 

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adjusted for the time taken to complete Trails A to control for sensorimotor demands of the task, 
is a sensitive measure of executive function and working memory. 
9.1.4.5 
Verbal Fluency – Category Fluency 
Category fluency assesses semantic memory and language fluency in which participants name as 
many different exemplars of a given semantic category as rapidly as possible. Participants will be 
given 60 seconds to name exemplars in each of two categories: animals and vegetables.  
9.1.4.6 
Verbal Fluency – Phonemic Fluency 
Phonemic Fluency is a measure of word generation that may be sensitive to dysfunction in the 
dominant frontal lobe. Participants will be given 60 seconds to name exemplars that begin with 
each of the two letters: F and L.  
9.1.4.7 
Number Span Forward and Backward 
Number Span assesses two different working memory constructs: Forward Number Span measures 
the capacity for retaining information very briefly for the purpose of repeating it exactly, while 
Backward Number Span measures the ability not only to retain the information but also to mentally 
manipulate the numbers and recite them in reverse sequence. Numbers for both forward and 
backward span tests are presented with sequences ranging from 2 to 9 numbers. Two trials are 
administered at each sequence length. Two scores are reported for each task: number of correct 
trials and longest sequence repeated correctly prior to failing two consecutive trials of the same 
length.  
9.2 
Behavioral and Functional Measures 
9.2.1 
Clinical Dementia Rating (CDR) Scale – Sum of Boxes (SOB) 
The CDR-SOB (Hughes, Berg, Danziger, Coben, & Martin, 1982) is a validated composite rating 
of cognition and everyday functioning used in longitudinal AD research which incorporates both 
informant input and direct assessment of performance. It assesses through semi structured 
interview 3 cognitive domains including memory, orientation, and judgement/problem solving and 
3 everyday functional domains including community affairs, home and hobbies and personal care. 
There are 5 levels of impairment from none CDR=0 to severe CDR=3. The individual domain 
scores are added to create a sum of the box scores.  
9.2.2 
ADCS-Activities of Daily Living (ADCS-ADL) Scale  
The ADCS-ADL scale is a questionnaire developed by the ADCS to assess functional performance 
in participants with AD (Galasko et al., 1997). Scores range from 0 to 75, with higher scores 
indicating better function. 

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9.2.3 
Neuropsychiatric Inventory (NPI) 
The NPI is a well-validated, reliable, multi-item instrument to assess psychopathology in AD 
dementia based on the results of an interview with the study partner (Cummings, 1997). The NPI 
evaluates both the frequency and severity of 10 neuropsychiatric features, including delusions, 
hallucinations, agitation/aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability 
and lability, and aberrant motor behavior, as well as evaluates sleep and appetite/eating disorders. 
Frequency assessments range from 1 (occasionally, less than once per week) to 4 (very frequently, 
once or more per day or continuously). Severity assessments range from 1 (mild) to 3 (severe). 
The score for each subscale is the product of severity and frequency and the total score is the sum 
of all subscales. 
9.3 
Modified Hachinski 
This brief questionnaire, conducted by a clinician, incorporates information regarding medical 
history, cognitive symptoms and features of stroke, reported by a study partner as well as the 
neurological examination, and neuroimaging studies (Rosen, Terry, Fuld, Katzman, & Peck, 
1980). 
9.4 
Sheehan Suicidality Tracking Scale (Sheehan STS) 
The Sheehan STS (S-STS) is a prospective, participant self-reported or clinician administered 
rating scale that contains 16 questions to track both treatment-emergent suicidal ideation and 
behaviors (Sheehan, Alphs, et al., 2014; Sheehan, Giddens, & Sheehan, 2014). The S-STS will be 
completed on a paper form at the site. At the screening visit, the recall period for completing the 
S-STS is 12 months prior; at all other visits, the recall period for completing the S-STS is since 
the last visit. Subjects who have an S-STS score > 0 should be evaluated by the investigator. If the 
investigator determines that a subject is at risk of suicide or self-harm, appropriate measures to 
ensure the subject’s safety and obtain mental health evaluation must be implemented. The subject 
must immediately be discontinued from the study. The event should be recorded as either an AE 
or SAE as determined by the investigator and reported within 24 hours to the Sponsor. 
9.5 
Research Satisfaction Survey 
A Research Satisfaction Survey will be administered to the participant and study partner to 
evaluate satisfaction with the study. The survey may reveal specific aspects of the study that 
participants dislike, which can inform efforts to improve their experiences when participating in 
future studies. Past studies show that participant input and feedback is important for retention 
(Miller, Duncan, Sorrell, & Brown, 2005). 
9.6 
Treatment Blinding Questionnaire 
Following the week 48 clinic assessment, the site Investigator and Raters will each complete a 
Treatment Blinding Questionnaire to document knowledge of intervention group assignment per 
participant.  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 6 6  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1 0  E A R L Y DI S C O N TI N U A TI O N/ WI T H D R A W A L P R O C E D U R E S  
T he e ntire st u d y 
ma y be disc o nti n ue d at t he discreti o n of A D C S or Bi o ha ve n . I n t hese 
circ u mst a nces t h e I n vesti gat or will arra n ge f or all o n g oi n g partici pa nts  t o b e see n a n d f or t h eir 
st u d y me dic ati o n t o be disc o nti n ue d as s o o n as is safel y p ossi ble.  
Pa rtici p a nts are free t o wit h dra w fr o m st u d y partici p ati o n at a n y ti me, f or a n y reas o n, a n d wit h o ut 
prej u dic e.  
Disc o nti n uati o n of st u d y tr eat m e nt a n d/ or t h e partici p ati o n of a n i n di vi d ual p arti ci pa nt  i n t h e st u d y 
will be t er mi n ate d i n t he f oll o wi n g cir c u msta n ces:  
1.  Wit h dra wal of i nf or me d c o nse nt b y t he p arti ci pa nt  or L A R. If t he st u d y part n er wit h dr a ws 
his/ her c o nse nt t o partici p ate t h e n att e m pts will b e ma de t o fi n d a re plac e me nt. I n a n y e ve nt 
t he parti ci pa nt  will be c o nti n u e d  i n t he st u d y i n s o far as p ossi ble. Partici pa nt s w h o 
wit h dra w c o nse nt will be a d vise d b y t he I n vesti gat or re gar di n g s u bse q ue nt treat me nt a n d 
i n vesti gati o n. 
2.  Treat me nt of a partici pa nt  wit h a n o n -per mitte d c o n c o mit a nt me di cati o n m a y n ecessitate 
disc o nti n uat i o n fr o m st u d y me dic ati o ns, a n d will b e det er mi n e d b y t h e I n vesti gat or i n 
c o nj u ncti o n wit h t h e Me dic al M o nit or.   
3.  A d verse e ve nt or ot her si g nifica nt m e dic al c o n diti o n w hic h, i n t he o pi ni o n of t he 
I n vesti gat or r e n der it necessar y t o disc o nti n u e st u d y me dic ati o n. 
4.  T he partici p a nt  e x p erie nc es a me dical e m er ge nc y t hat ne cessitates u n bli n di n g t heir 
treat me nt assi g n me nt. ( Se e Secti o n 6. 6 ).  
5.  A n y ot her occ urre nc e t hat, i n t he I n v esti gat or’s o pi ni o n, ma kes c o nti n ue d partici pati o n 
c o ntrar y t o t he partici p a nt ’s best i nterests. 
6.  M o ve me nt of parti ci pa nt  i nt o a l o n g-ter m car e n ursi n g facilit y.  M o ve me nt i nt o a n assiste d 
li vi n g fa cilit y is n ot ca use f or disc o nti n uati o n fr o m t he st u d y . 
Partici p a nts w h o disc o nti n ue a cti v e  tre at m e nt f or a n y reas o n will h a ve t h e o p p ort u nit y t o c o nti n u e 
o n t he pr ot oc ol wit h f urt her visits per pr ot oc ol t o t h e e n d of t h e d o u bl e -bli n d p hase of t h e st u d y 
wit h  t heir o n g oi n g c o nse nt. T heir c o nti n ue d p arti ci pati o n will b e e nc o ur a ge d.  
T he I n vesti gat ors at eac h sit e will m a ke e ver y reas o n a ble eff ort t o ma xi mize pa rtici pa nt ret e nti o n, 
e ve n if t he st u d y treat me nt is disc o nti n u e d bef ore wee k 4 8 . H o we ver, if a n i n vesti gat or re m o ves a 
p artici pa nt fr o m st u d y, or if a partici pa nt  de cli n es all f urt her st u d y partici pati o n d uri n g t he st u d y , 
a n Earl y T er mi n ati o n  Visit will be c o m pl ete d as cl ose as p ossi ble t o t h e ti me of st u d y 
disc o nti n uati o n. T he Earl y Ter mi nati o n  Visit  ma y c o ntai n t he sa me asse ss me nts as wee k  4 8 , t o 
all o w c olle cti o n of t he mai n o utc o me meas ures. F or f urt her d etail please refer t o t he Pr oce d ures 
Ma n ual.  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 6 7  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1 1  D E FI NI TI O N O F A D V E R S E E V E N T S  
A n  a d verse e ve nt ( A E) or  a d verse  e x perie nce  is a n y u nt o war d  me di cal  occ urre nce  i n a st u d y 
partici pa nt  w h o  is a d mi nistere d  a me dici nal  pr o d uct , t hat d oes  n ot  nec essaril y  ha ve  a ca usal  
relati o ns hi p wit h  t he st u d y treat me nt, a n d t hat occ ur s after i nf or me d c o nse nt is si g ne d a n d u p  t o 
3 0  da ys  after t he st u d y dr u g  has  bee n  disc o nti n u e d.  A n  A E  ca n t heref ore be  a n y  u nfa v ora ble  
a n d u ni nte n de d  si g n, s y m pt o m, or  disease  te m p orall y ass ociate d  wit h  t he use  of  a me dici nal  
pr o d uct,  w het her  or  n ot  c o nsi dere d  relate d t o t he me dici nal  pr o d uct.  Pre -e xisti n g  c o n diti o ns, 
w hic h  i ncrease i n fre q ue nc y or  se verit y or  w orse n  i n nat ure  d uri n g , or  as a c o nse q ue nce of , use  
of  a dr u g  i n h u ma n  cli nical trials, will  als o be  c o nsi dere d  a d verse e x perie nces.  A d verse  e ve nts  
ma y  als o i ncl u de pre - or  p ost - treat me nt c o m plicati o ns  t hat occ ur  as  a res ult of  pr ot oc ol -
ma n date d  pr oce d ures  (e. g. i n vasi ve pr oce d ures  s uc h as  bi o psies).   
A n A E d oes  n ot  i ncl u de: 
•  Me dical  or s ur gical pr oce d ures  (e. g., s ur ger y, e n d osc o p y,  t o ot h e xtracti o n,  tra nsf usi o n). 
T he c o n diti o n  t hat lea ds t o t he pr oc e d ure is t he A E.  
•  Sit uati o ns   w here   a n  u nt o war d   me dical   occ urre nce   has   n ot   occ urre d  (e. g., 
h os pitali zati o n f or electi ve s ur ger y,  s ocial a n d/ or c o n ve nie nce a d missi o ns).  
•  W orse ni n g  of  s y m pt o ms ass ociate d  wit h  e x pecte d  decli ne  i n Alz hei mer’s  disease  is n ot 
c o nsi dere d  a n a d verse e ve nt i n t his st u d y. 
•  O ver d ose  of  eit her st u d y dr u g  or  c o nc o mit a nt me dicati o n  wit h o ut  a n y si g ns or  
s y m pt o ms u nless  t he pa rti ci pa nt is h os pitalize d  f or o bser vati o n.  O ver d oses  s h o ul d be  
re p orte d as  o utli ne d  i n Secti o n 1 1. 4 . 
A treat me nt e m er ge nt a d v erse e ve nt ( T E A E) is defi n e d as a n y A E t hat de vel o pe d, w orse ne d, or 
beca m e seri o us after first d ose of st u d y dr u g a n d pri or t o 3 0 d a ys aft er t h e l ast d ose of st u d y dr u g.  
1 1. 1  
E v al u ati o n a n d Re p orti n g of A d verse E ve nts  
All  A Es  (i.e., a ne w  e ve nt or  a n e xacer bati o n  of  a pre -e xisti n g  c o n diti o n)  t hat occ ur  fr o m t h e 
ti m e i nf or m e d c o n s e nt is si g n e d a n d u p  t o 3 0  da ys  after t he st u d y dr u g  has  bee n  
disc o nti n ue d  m ust  be  rec or de d as a n A E  o n t he A E e C R F. T he  I n vesti gat or m ust  f oll o w all A Es  
u ntil  t h e A E  res ol ves, or  u ntil  t he I n vesti gat or a n d/ or  t he Me dical  M o nit or  deter mi ne  t he e ve nt  
is c hr o nic or  cli nicall y  sta ble. If a n A E  re m ai ns u nres ol ve d  at t he c o ncl usi o n  of  t he st u d y, t he 
I n vesti gat or a n d Me dical  M o nit or  will  ma ke  a  cli nical assess me nt  t o deter mi ne  w het her  
c o nti n ue d  f oll o w-u p  of  t he A E  is warra nt e d.  All  p artici pa nts  w h o  ha ve  recei ve d at  l east o ne  
e x p os ure t o st u d y t her a p y will b e  e val uate d  f or safet y of  st u d y treat me nt. 
T he  I n vesti gat or s h o ul d atte m pt t o esta blis h  a dia g n osis  of  t he e ve nt base d  o n  si g ns, 
s y m pt o ms a n d/ or  ot her  cli nical i nf or mati o n. I n s uc h cases,  t he dia g n osis  s h o ul d be  
d oc u me nte d  as  t he A E a n d n ot t he i n di vi d ual si g ns/s y m pt o ms. 
1 1. 2  
Assess me nt of A d verse E ve nts  
All  A Es  m ust  be  pr o m ptl y  d oc u me nte d  o n  t he A d verse  E ve nt  e C R F a n d assesse d  b y  t h e 
I n vesti gat or. Details  of  t he e ve nt m ust  i ncl u de t he dates  of  o nset  a n d res ol uti o n, se verit y, 

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relationship to study drug, seriousness, and whether the event caused the participant to 
withdraw from the study, outcome and timing with regard to administration of the study drug. 
Severity: Severity should be graded and recorded according to the table below. 
 
Severity 
Definition 
Mild 
Awareness of event but easily tolerated 
Moderate 
Discomfort enough to cause interference with usual activity 
Severe 
Inability to carry out usual activity, incapacitating, requires medical 
intervention 
 
 
 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 6 9  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
Rel ati o ns hi p: T he  relati o ns hi p of t he A d verse  E ve nt t o t he  st u d y dr u g  will be  d eter mi ne d  b y  t he 
Pri nci pal  I n vesti gat or, a n d assesse d usi n g  t he f oll o wi n g defi niti o ns:  
R el ate d ness 
D escri pti o n 
 
N ot  Relate d  
T here  is n o  e vi de nce  of  a  ca usal relati o ns hi p a n d a ca usal  relati o ns hi p ca n n ot  be  
reas o na bl y attri b ute d  t o t he st u d y treat me nt or pr oce d ures.  T he  e ve nt is clearl y d ue  t o 
e xtra ne o us  ca us es. 
 
U nli kel y  Relate d  
A  p o or  te m p oral relati o ns hi p e xists  bet wee n  t he e ve nt o nset  a n d a d mi nistrati o n of  
i nter ve nti o n. T he  e ve nt c o ul d easil y be  e x plai ne d  b y  t he partici pa nt’s  cli nical state, 
i nterc urre nt ill ness, or  c o nc o mita nt  t hera pies. 
 
P ossi bl y  R elate d  
A  relati o ns hi p ca n n ot be  r ule d o ut  wit h  certai nt y  a n d t he e ve nt ma y  be  relate d. T here  is 
s o me e vi de nce  t o s u g gest a  ca us al relati o ns hi p b ut  t he i nfl ue nce of  ot her  fact ors ma y  
ha ve  c o ntri b ute d  t o t he e ve nt, s uc h as  t he partici pa nt’s  cli nical c o n diti o n  or  c o nc o mita nt  
treat me nt. 
 
Pr o ba bl y  Relate d  
T he  e ve nt is li kel y relate d t o t he i nter ve nti o n. T here  is e vi de nce  t o s u g gest a  ca usal 
relati o ns hi p, s uc h as  reas o na ble te m p oral se q ue nce fr o m treat me nt a d mi nistrati o n or  
pr oce d ure.  T he  i nfl ue nce of  ot her  fact ors is u nli kel y.  
Defi nitel y  Relate d  
T he  e ve nt is clearl y relate d t o t he i nter ve nti o n. T here  is clear e vi de nce  t o s u g gest a  
ca us al  relati o ns hi p. T he  i nfl ue nce of  ot her  fact ors ca n be  r ule d o ut.  
T hese  criteria, i n a d diti o n t o g o o d  cli nical j u d g me nt, s h o ul d be  use d  as  a  g ui de  f or 
deter mi ni n g  t he ca usal assess me nt.  If it is felt t hat t h e e ve nt is n ot  relate d t o st u d y dr u g  t hera p y, 
t he n a n alter nati ve e x pla nati o n  s h o ul d be pr o vi de d.  
1 1. 3  
C ollecti o n a n d Re p orti n g  of  Seri o us A d verse E ve nts  
F oll o wi n g writte n c o nse nt t o partici pate i n t he st u d y, all S A Es, w het her relate d or n ot relate d t o 
st u d y dr u g, m ust be c ollecte d, i ncl u di n g t h ose t h o u g ht t o be ass ociate d wit h pr ot oc ol -s pecific 
pr oce d ures. T he re p orti n g peri o d e n ds  3 0 da ys after disc o nti n u ati o n of d osi n g. I n a d diti o n, the 
i n vesti gat or s h o ul d re p ort a n y S A E occ urri n g after t his ti me peri o d t hat is belie ve d t o be relate d 
t o st u d y dr u g or pr ot oc ol-s pecific pr oce d ures. Seri o us a d verse e ve nts t hat occ ur pri or t o i nitiati o n 
of st u d y dr u g will be d oc u me nte d i n t he E D C as me dical hist or y, b ut will still nee d t o  be  re p orte d 
t o 
 o n a n S A E f or m as descri be d bel o w. 
A n S A E is a n  A E fr o m t his st u d y t hat res ults i n a n y of t he f oll o wi n g  o utc o mes:  
•  Deat h  
•  Life -t hreate ni n g sit uati o n (pa rtici pa nt is at i m me diate ris k of deat h ) 
•  I n patie nt h os pitalizati o n  or  pr ol o n gati o n  of  e xisti n g  h os pitali zati o n  
•  Persiste nt  or si g nifica nt disa bilit y/i nca pacit y  
•  C o n ge nital  a n o mal y/ birt h  defect  i n t he offs pri n g  of  a  partici pa nt  w h o  recei ve d st u d y dr u g  
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•  C o nsi dere d  si g nifica nt b y  t he i n vesti gat or f or a n y ot h er  reas o n 
A n S A E re p ort s h o ul d be c o m plete d f or a n y e ve nt w here d o u bt e xists re gar di n g its stat us of 
seri o us ness.  
If t he i n vesti gat or belie ves t hat a n S A E is n ot relate d t o t he st u d y dr u g, b ut is p ote ntiall y relate d t o 
t he c o n diti o ns of t he st u d y (s uc h as a wit h dra wal of pre vi o us t hera p y or a c o m plicati o n relate d t o 
st u d y pr oce d ure), t he relati o ns hi p s h o ul d be s pecifie d i n t he narrati ve secti o n of t he S A E Re p ort 
F or m.  
S A Es, w het her relate d or n ot r elate d t o st u d y dr u g, o ver d ose, a n d p ote ntial dr u g i n d uce d li ver i nj ur y 
m ust be re p orte d wit hi n 2 4 h o urs of t he I n vesti gat or bec o mi n g a ware of t he e ve nt. F or t his st u d y 
we will be ca pt uri n g S A Es t hr o u g h b ot h t he A D C S E lectr o nic D ata C a pt ure ( E D C) s yste m a nd o n 
a n S A E re p ort f or m pr o vi de d b y 
 I n a d diti o n, all a p plica ble S A Es 
m ust be re p orte d b y t he Site I n vesti gat or t o t he I nstit uti o nal Re vie w B oar d (I R B) of rec or d 
acc or di n g t o I R B’s re p orti n g re q uire me nts f or s uc h e ve nts.  
T he Sit e I n vesti gat or is res p o nsi ble f or re p orti n g all S A Es a n d all Ot her I m p orta nt Me dical E ve nts 
t o 
 via tele p h o ne, i m me diatel y or n o later t ha n 2 4 h o urs after a ware ness of t he e ve nt. A  
 
re prese ntati ve will t he n i m me diatel y n otif y t he Bi o ha ve n Me dical M o n it or. A n S A E f or m m ust 
t he n be s u b mitte d t o 
 wit hi n 2 4 h o urs  via t he fa x n u m ber i n dicate d bel o w .  
 Safet y H otli ne N u m ber  f or S A E tele p h o ne re p orts: 
•  N ort h A merica:  
 
 Facsi mile (fa x) n u m ber f or 
 S A E re p ort f or m s, t o be se nt  wit hi n 2 4 h o urs  after 
a ware ness of t he e ve nt : 
•  N ort h A merica:  
 
T he Site I n vesti gat or, or desi g nate d staff, is als o res p o nsi ble f or e nteri n g t he S A E i nf or mati o n i n 
t he A D C S Electr o nic Data Ca pt ure ( E D C) s yste m ( i.e.,  e ve nt ter m, start  st o p dates, ca usalit y, a n d 
se verit y) acc or di n g t o st u d y -s pecific e C R F C o m pleti o n G ui deli nes. T he A D C S Me dical M o nit or 
a n d A D C S Pr oject Direct or will be a ut o maticall y n otifie d via e mail u p o n e ntr y of a n S A E i nt o t he 
A D C S E D C s yste m. A me m ber of t he A D C S Me dical Safet y tea m will i nf or m t he D S M B of t he 
occ urre nce of a n y S A Es wit hi n 7 da ys of bei n g re p orte d . T he D S M B ma y at a n y ti me re q uest 
a d diti o n al i nf or mati o n fr o m t h e A D C S i n relati o n t o a re p orte d e ve nt.  
If o nl y li mite d i nf or mati o n is i nitiall y a vaila ble, f oll o w-u p re p orts are re q uire d. If a n o n g oi n g S A E 
c ha n ges i n its i nte nsit y or relati o ns hi p t o st u d y dr u g or if ne w i nf or mati o n bec o mes a vaila ble, a 
f oll o w-u p S A E re p ort s h o ul d be se nt t o  
 wit hi n 2 4 h o urs of t he I n vesti gat or bec o mi n g a ware 
of t he u p date d i nf or mati o n usi n g t he sa me pr oce d ure use d f or t he tra ns missi o n of t he i nitial S A E 
a n d t he sa me e ve nt ter m s h o ul d be use d.  I n a d diti o n, ne w or re vise d e ve nt i nf or mati o n m ust be 
e ntere d i nt o t he A D C S E D C at t he sa me ti me.  
All S A Es s h o ul d be f oll o we d t o res ol uti o n or sta bilizati o n. F or  a n y q uesti o ns relati n g t o S A Es, 
please c o ntact t he A D C S Me dical M o nit or via tele p h o ne or e mail at t he n u m ber liste d o n t he 
pr ot oc ol face pa ge.  
 
 
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A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
S us pecte d U ne x pecte d Seri o us A d verse Re acti o ns  
S us pecte d u ne x pecte d seri o us a d v erse reacti o ns ( S U S A Rs) are ser i o us a d verse e ve nts t hat are n ot 
liste d i n t he I n vesti gat or’s Br oc h ure  as a n e x pecte d A E a n d t hat t he In vesti g at or assesses  as 
p ossi bl y relat e d or pr o ba bl y r elate d or defi nit el y relat e d t o st u d y dr u g or st u d y pr oc e d ure. U nit e d 
States 2 1 C F R 3 1 2. 3 2 a n d E ur o pea n U ni o n Cli nical Tri al Directi ve 2 0 0 1/ 2 0/ E C a n d t he 
ass ociate d d etaile d g ui da n ce  or n ati o n al r e g ulat or y re q uire me nts i n partici pati n g c o u ntries re q uire 
t he re p orti n g of S U S A Rs t o re g ulat or y a ut h orities. As t he cli nical trial s p o ns or, Bi o ha ve n  is 
res p o nsi ble f or, a n d has pr oce d ure s c o nsiste nt wit h re g ulati o ns t hat will be f oll o we d f or, 
e x pe dit e d re p orti n g of S U S A Rs.  
1 1. 4  
O ver d ose Re p orti n g Re q uire me nts  
F or  t he p ur p oses  of  t his st u d y, a n o ver d ose  is t h e a c ci d e nt al or i nt e nti o n al a d mi nistr ati o n of 
a n y d os e of st u d y dr u g gr e at er t h a n t h e hi g h est d ail y d os e ( eit h er 1 4 0 or 2 8 0 m g as 
pr es cri b e d p er pr ot o c ol) wit hi n a c al e n d ar d a y. A n y o v er d os e m ust b e r e p ort e d o n t h e e C R F. 
A n o v er d os e is n ot a n A E u nl ess i t r es ults i n u nt o w ar d eff e cts. A n y A Es r el at e d t o t h e 
o v er d os e m ust b e r e p ort e d o n t h e A E a n d/ or S A E p a g e of t h e e C R F. N o s p e cifi c a nti d ot e 
f or t h e o v er d os e of B H V -4 1 5 7  is k n o w n. Si g ns a n d s y m pt o ms of o v er d os e s h o ul d b e tr e at e d 
a c c or di n g t o st a n d ar d of c ar e.   
1 1. 5  
Cli nic al L a b or at or y A b n or m alities a n d Ot her A b n or m al Assess me nts  
La b orat or y  a b n or malities  are us uall y  n ot  rec or de d as  A E s u nless  c o nsi dere d  t o be  cli nicall y  
si g nifica nt b y  t he sit e cli nici a n.  A n  a b n or mal la b orat or y res ult will  be  c o nsi dere d  a n A E  if it 
is ass oci ate d wit h  cli ni cal si g ns or  s y m pt o ms, if t h e a b n or malit y  is of  a de gree  t hat re q uires acti ve 
ma na ge me nt  (e. g., disc o nti n uati o n of  t he st u d y dr u g,  d ose  m o dificati o n)  or  w he n  t he e ve nt is 
re q uiri n g treat me nt or  ot her  t hera pe utic i nter ve nti o n (e. g., ir o n s u p ple me nts, bl o o d tra nsf usi o n, 
etc.). 
T he  I n vesti gat or will  e val uate t h e relati o ns hi p of  a n y si g nifica ntl y a b n or mal res ult t o 
pr ot oc ol  treat me nt a n d cli nical c o n diti o n,  if p ossi ble.  All  cli nic all y  si g nifica nt a b n or mal  
la b orat or y r es ults will b e f oll o we d u ntil t he y  ret ur n t o n or mal  or bec o me  sta biliz e d. 
1 1. 6  
Pre g n a nc y a n d Bre ast Fee di n g  
B H V -4 1 5 7  s h o ul d n ot  be  use d  d uri n g  pre g na nc y  or  w hile  breast -fee di n g. T he  l o wer a ge li mit 
f or t his st u d y is 5 0  years,  a n d w o me n  m ust  be  p ost -me n o pa usal  f or at l east 2 c o nsec uti ve years  
or  s ur gicall y steril e ( bil ateral t u bal li g ati o n, h ysterect o m y or bilateral o o p h orect o m y) f or at least 
6 m o nt hs pri or t o scre e ni n g  t o be eli gi ble f or t his st u d y. 
1 2  S T A TI S TI C A L M E T H O D S  
T his is a m ulti -ce nt er d o u ble -bli n d place b o -c o ntr olle d trial of 2 8 0 m g of B H V -4 1 5 7 vs place b o  
ta ke n f or a p pr o xi matel y  4 8 wee ks  wit h a n o pti o n al 4 8 wee k o pe n -la b el e xte nsi o n p h ase. T her e is 
a n 
 
 
 As t he i nteri m a n al ysis will n ot st o p t he st u d y f or s uccess , we h a ve 
n ot a dj uste d t he fi nal a nal ysis a n d ha ve  mai ntai n e d t h e al p ha at 5 %  i n or der t o a v oi d i nflati n g t h e 
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C o nfi de nti al  
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pr o ba bilit y of a t y p e 1 err or. C o m plete  details  of t h e i nteri m,  effica c y,  a n d safet y a nal yses  are  
pr o vi de d  i n a se parate Statistical  A nal ysis  Pla n ( S A P), w hic h is mai ntai ne d b y A D C S i n 
c o ns ultati o n wit h Bi o ha ve n. 
1 2. 1  
S a m ple Size  a n d P o we r  Deter mi n ati o n  
1 2. 1. 1  
Over all St u dy  P o wer  
Usi n g a p pr o xi matel y 3 3 6 ra n d o miz e d partici pa nt s ( wit h a 1: 1 assi g n me nt 1 6 8 p er ar m ), t his st u d y 
has at least 8 0 % p o wer t o reject t h e n ull h y p ot h esis of n o effi cac y i n f a v or of t he alt er nati ve t hat 
B H V -4 1 5 7 is efficaci o us , gi ve n t he ass u m pti o n of a differe nc e i n t he me a n c ha n ge fr o m baseli ne 
t o 1 2 m o nt hs b et wee n t he B H V -4 1 5 7 ar m a n d pl ace b o ar m of 2. 6 4 p oi nts o n t h e A D A S -C o g  1 1 , 
a n d 0. 9 5 p oi nts i n C D R -S u m of B o xes, a n d u n der a ra n ge of effect siz es w hic h gi ve 9 3. 7 % 
pr o ba bilit y of pr oce e di n g at t he i nteri m a nal ysis.  
T his calc ulati o n ass u mes n o m ore t ha n a 2 6 % dr o p o ut rate , w hic h w o ul d lea v e 3 3 6 X 0. 7 4 = 2 4 8 
partici pa nts a vaila ble at t h e fi nal a n al ysis, or 1 2 4 per ar m. T he calc ul ati o n  als o ass u mes a sta n dar d 
de viati o n of 6 p oi nts o n t he c ha n ge i n A D A S -C o g 1 1 i n eac h ar m at b ot h 6 m o nt hs a n d 1 2 m o nt hs, 
a n d a s ta n dar d de vi ati o n of 2. 3 p oi nts o n t he c ha n ge i n C D R S u m of B o xes at 1 2 m o nt hs; i n 
a d diti o n,  a c orrel ati o n of 4 5 % b et wee n 1 2 m o nt h c ha n ge o n t he c o -pri m ar y A D A S -C o g 1 1 a n d 
C D R S u m of B o xes e n d p oi nts ar e ass u me d . T hes e ass u m pti o ns are s u p p ort e d b y p u blis he d  
retr os pecti ve data fr o m hist oric al A D C S st u dies ( T h o mas, Al bert, Pet ers o n, & Aise n, 2 0 1 6). T he 
c o m p utati o n s use a 2 -si de d 2-sa m ple t-test at 5 % al p ha t o a p pr o xi mat e p o wer.  
Briefl y, t h e statistic al reas o ni n g is as f oll o ws:  
1.  P( pass o verall) = P( pass fi nal | p ass i nteri m) P( pass i nteri m)  ≥ P( pass fi nal) P ( pass 
i nteri m) 
2.  P( pass fi nal) = P( pass fi nal A D A S ) P( pass fi nal C D R | pass  fi nal A D A S )  
3.  N u merical i nte gr ati o n s h o ws t hat P( pass fi nal C D R | pass A D A S ) is a b o ut 3 % greater 
t ha n P( pass fi nal C D R ), gi ve n t he ass u me d 4 5 % c orrelati o n bet we e n t hese e n d p oi nts.  
He nce, if P( pass i nt eri m ) = 0. 9 3 7, P( pass fi nal A D A S) = 0. 9 2, a n d P( pass fi nal C D R ) = 0. 9 0 , t he n 
P( pass o verall) ≥ 0. 9 2 x ( 1. 0 3 x 0. 9 0 ) x 0. 9 3 7 = 0. 8 0. 
Wit h 1 2 4 s u bjects per ar m, t h e u nc o n diti o nal p o wer f or t he A D A S -C O G e n d p oi nt is 9 2 %, if t he 
mea n differe n ce i n c ha n g e is 2. 6 4 p oi nts wit h st a n dar d de viati o n of 6 p oi nts wit hi n ea c h ar m.  At 
t his sa m ple si ze, t h e u nc o n diti o nal p o wer f or t h e C D R-S O B e n d p oi nt is 9 0 %, if t he mea n 
differe nc e is 0. 9 5 p oi nts wit h sta n d ar d de viati o n of  2. 3 p oi nts wit hi n eac h ar m.  He nce, if t h e 
i nteri m a nal ysis has p o wer 0. 9 3 7 or great er t o pass, t he o verall p o wer is 8 0 % or m or e f oll o wi n g 
t he statistic al re as o ni n g gi ve n a b o v e. 
F or pers pecti ve, we n ote t hat t he ass u me d diff ere nc e of  2. 6 4 p oi nts o n A D A S -C o g is 6 8 % of t he 
decli n e o bser ve d i n t he place b o ar m of 3. 9 p oi nts i n st u dies of mil d t o m o derat e A D fr o m ( T h o mas, 

 
 
 
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Al bert, Pet erse n, & Aise n, 2 0 1 6) . T he ass u me d diff ere nce of 0. 9 5 p oi nts o n C D R -S O B is 5 9 % of 
t he decli ne o bser v e d i n t he plac e b o ar m of 1. 6 p oi nts ( T h o mas, Al bert, Peterse n, & Aise n, 2 0 1 6). 
1 2. 1. 2  
 
1 2. 2  
A n al ysis P o p ul ati o ns  
A nal ysis  p o p ulati o ns are  defi ne d  as f oll o ws: 
•  E nr olle d Partici pa nts:  Parti ci pa nts w h o si g ne d a n i nf or me d c o nse nt f or m a n d were assi g ne d 
a Partici pa nt I d e ntificati o n n u m ber ( PI D).  
•  Ra n d o miz e d Parti ci pa nts:  E nr olle d partici pa nts w h o recei v e d a tr eat me nt assi g n me nt. T his 
gr o u p f or ms t he I T T p o p ulati o n.  
•  Treat e d Partici p a nts:  E nr olle d a n d ra n d o miz e d parti ci pa nts w h o recei ve d at le ast 1 d ose of 
bli n de d st u d y t hera p y ( B H V -4 1 5 7 or place b o). T his will be t he pri mar y a n al ysis p o p ulati o n 
use d f or s afet y s u m maries.  
 
•  T he  m o difie d  I nte nt-t o-Treat  ( mI T T) p o p ulati o n  will  i n cl u de all  ra n d o mize d partici pa nts  
w h o  t o o k at least o ne  d ose  of  t he st u d y m e dic ati o n, w h o ha ve a baseli ne assess me nt of 
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t he c o-pri m ar y effic ac y e n d p oi nts,  a n d w h o  ha ve at least o ne  efficac y  e v al uati o n f oll o wi n g  
baseli ne.  T his will b e t he pri mar y a n al ysis p o p ulati o n use d f or t he effi cac y a n al yses.  
•  O pe n -La bel E xte nsi o n Tr eate d Partici pa nts: Partici pa nts e nr olle d i n t he e xte nsi o n p has e 
w h o recei v e d at l east 1 d ose of o pe n -l a bel e xt e nsi o n p hase st u d y t h era p y ( B H V-4 1 5 7). T his 
will be  use d f or s afet y s u m maries of t he e xte nsi o n  p hase  
•  T he  m o difie d  I nte nt-t o-Treat  ( mI T T) p o p ulati o n  f or t h e E xt e nsi o n P h as e will  i ncl u de all  
O pe n -La bel E xte nsi o n p hase partici pa nts  w h o  t o o k at least o ne  d ose  of  E xte nsi o n p has e 
st u d y me di cati o n , w h o  ha v e  at  least o ne  effica c y  e val uati o n d uri n g t he e xt e nsi o n p hase . 
T his will be t he a nal ysis p o p ulati o n use d f or t he effic ac y s u m m aries f or t he e xte nsi o n p hase  
•  All B H V -4 1 5 7 Treate d Partici pa nts: Partici p a nts e nr olle d w h o recei v e d at le ast 1 d ose of 
B H V -4 1 5 7 i n eit her Ra n d o mizati o n or E xt e nsi o n P hase of t he st u d y. T his will b e  use d f or 
safet y s u m maries of t he e xte nsi o n  p hase  
 
T he  pri mar y  p o p ulati o n  f or all effica c y  a nal ys es i n t he d o u ble -bli n d treat me nt p hase  is t he mI T T  
p o p ulati o n , wit h o ut i m p ut ati o n f or missi n g val ues . A se nsiti vit y us es t he mI T T p o p ulati o n wit h 
m ulti ple i m p utati o n . T h e Tre ate d Partici p a nts  will b e  use d  f or a nal yses  of safet y  e n d p oi nts.  
1 2. 3  
A n al ysis  of t he C o -Pri m ar y E n d p oi nt s 
T he pri mar y st u d y h y p ot hesis is t h at treat m e nt wit h B H V -4 1 5 7 will res ult i n a r e d ucti o n i n t ot al 
wit hi n -partici p a nt  c h a n ge fr o m b aseli n e o n t he A D A S -C o g  1 1  sc ore a n d als o o n t he C D R S u m 
of B o xes , rel ati v e t o t he pla ce b o gr o u p at wee k  4 8  of t he d o u ble -bli n d tr eat me nt p hase  i n t he 
mI T T p o p ul ati o n. T he c o -pri mar y e n d p oi nts at t he fi n al a nal ysis will be teste d usi n g a hier arc hi cal 
gate ke e per str ate g y: if A D A S -C o g 1 1 is si g nifica nt at t he 5 % le vel, t he n C D R -S O B will als o be 
teste d at 5 % si g nifi ca nce l e vel. If A D A S-c o g is n ot sig nifica nt at t he 5 % le vel, t he n C D R -S O B 
will n ot be i ncl u d e d i n t he pri mar y a n al ysis, a n d will be prese nte d f or d escri pti ve p ur p oses o nl y. 
T he pri m ar y o bje cti ve of t he trial is met o nl y w he n b ot h c o pri m ar y e n d p oi nts are si g nifica nt.  
T he pri mar y a n al ysis for eac h  o ut c o me  uses  a mi x e d effects re pe ate d m eas ures m o del, i n cl u di n g 
all a vaila ble i n-cli nic o ut c o mes d uri n g t he d o u ble -bli n d p hase i n t he mI T T p o p ul ati o n. F i xe d 
effects  i n t h e m o d el are A P O E stat us  (e 4 carri er vs e 4 n o ncarrier), M M S E ( mil d vs m o derate) 
stat us, site, baseli ne  sc or e ( A D A S-c o g or C D R -S O B) , treat me nt gr o u p  ( acti ve vs pla ce b o), visit, 
visit x baseli ne sc ore, a n d visit x tre at m e nt gr o u p i nteracti o n. Visit is tr eat e d as a cat e g oric al 
varia bl e. Sites wit h o nl y o ne s u bje ct will be p o ole d . 
A ra n d o m effect will be i n cl u de d f or partici p a nt . T he wit hi n s u bject c o varia nc e will be 
u nstr uct ure d . If t h e m o del f ails t o c o n ver ge, M M S E stat us will be r e m o ve d fr o m t he m o d el. If 
t he m o del still d oes n ot c o n ver ge, t he f oll o wi n g c o varia nc e str uct ures will be fit, se q ue ntiall y, 
u ntil t he  str uct ure is f o u n d t hat r es ults i n c o n ver g e nce of t he m o d el: H u y n h -Fel dt, T oe plitz, 
A ut ore gressi ve ( 1), a n d C o m p o u n d  S y m metr y.  Err or de grees of free d o m will be calc ul ate d usi n g 
Ke n war d -R o ger a p pr o xi mati o n if a n u nstr uct ur e d c o varia n ce str uct ur e fits a p pr o priat el y; 
ot her wise, a sa n d wi c h esti mat or will b e utili ze d t o esti mate t h e c o v aria n ce str uct ure a n d de gre es 
of free d o m will be calc ul ate d usi n g t he bet wee n -wit hi n met h o d  ( Sc hl uter & El as h off, 1 9 9 0).  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 7 5  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
Eac h c o-pri mar y e n d p oi nt is test e d usi n g m o del -a dj uste d least s q uares mea ns at t he w ee k 4 8 visit  
of t he d o u ble -bli n d treat me nt p hase.  P oi nt esti mates, sta n dar d err ors, 9 5 % c o nfi de nce i nter vals, 
a n d p-val ues will be prese nte d.  
F urt her  details of t he pri mar y a nal ysis, i ncl u di n g se nsiti vit y a n al ysis a n d met h o ds f or ha n dli n g 
missi n g data, are prese nte d i n t h e statistic al a n al ysis pla n . 
1 2. 4  
A n al ysis of Sec o n d ar y E n d p oi nts  
If b ot h t he c o-pri mar y e n d p oi nts are  si g nifica nt, me a n c ha n ges i n t h e sec o n dar y e n d p oi nts fr o m 
baseli ne  t o wee k  4 8  of t he d o u ble -bli n d tr eat me nt p h ase are c o m pare d usi n g t he a nal ysis strate g y 
o utli ne d a b o v e , or if a p pr o priate, a t w o-si de d, t w o-sa m ple t-t est. F or t h ese sec on da ry e n d p oi nts, a 
H ol m ste p -d o w n test is c o n d uct e d at 5 % le vel t o c o ntr ol t he fa mil y wise err or rat e . T hese e n d p oi nts 
are: bil ateral hi p p oca m pal  v ol u me as meas ure d b y v ol u metri c M RI;  N PI t otal sc ores; A D C S -A D L; 
a n d M M S E sc ores.  
If t he c o-pri mar y e n d p oi nt s fail t o b ot h reac h si g nifi ca nce, t h e n t he sec o n dar y e n dp oi nts, will be 
a nal yz e d as e x pl orat or y usi n g t he sa me strate g y o utli ne d a b o ve.  
Cate g ori cal vari a bles are s u m mari ze d  b y tr eat m e nt  gr o u p usi n g fre q ue n c y distri b uti o n: n u m ber of 
n o n -missi n g o bser vati o ns a n d p erce nt a ges  will b e gi ve n . C o nti n u o us varia bl es are s u m marize d 
usi n g sta n dar d q ua ntitati ve st atistics: n u m b er of n o n -missi n g o bser vati o ns, m ea n, sta n d ar d 
de viati o n, me dia n a n d ra n g e ( mi ni m u m a n d ma xi m u m o bser ve d val u es).  
1 2. 5  
A n al ysis of E x pl or at or y E n d p oi nts  
T he e x pl orat or y e n d p oi nts  i ncl u de: ( 1) cha n ge i n M o C A sc ores fr o m baseli ne t o wee k 4 8; ( 2) 
c ha n ge i n A D C O M S t otal sc ore fr o m baseli n e t o wee k 4 8; ( 3) bilateral lateral v e ntri cles a n d w h ol e 
brai n v ol u me  as meas ure d b y v ol u metric M RI; ( 4)  a c o g niti ve c o m p osite o utc o me c o m p ute d usi n g  
meas ures fr o m t he N A C C Ne ur o ps yc h ol o gical Test Batter y   ( Craft St or y 2 1 Recall  (I m m e diate & 
Dela ye d), Be ns o n Fi g ure ( C o p y & Dela ye d Re call), M ultili n g u al Na mi n g Test ( MI N T), Letter & 
Cate g or y Fl u e nc y, Trail Ma ki n g Test A & B, N u m ber S pa n F or war d & Bac k war d ;  (5 ) B H V-4 1 5 7 
p har mac o ki netics ; (6 ) tre at m e nt res p o nse b y A p o E ge n ot y pe; a n d (7 ) C S F, ser u m a n d plas ma 
bi o mar ker pa nel ( A ß 4 2, A ß 4 2/ 4 0 rati o, t otal t a u, p -t a u-1 8 1 , ne ur o gra ni n, Nf L, Y K L-4 0, VI LI P, 
S N A P -2 5, s T R E M 2 , G F A P) at wee k 2 4 a n d wee k 4 8 . C S F will be assesse d  i n a s u bset of t h e st u d y 
p o p ulati o n ( esti m ate d n = 5 0 acti ve, n = 5 0 pl ace b o) . T heir a nal yses are i ncl u de d i n t he S A P .  
1 2. 6  
 
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 7 6  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1 2. 7  
O pe n -L a bel E xte nsi o n P h ase  A n al ysis  
A n y a nal yses of effica c y e n d p oi nts fr o m t he e xte nsi o n p hase will be e x pl orat or y o nl y.  
1 2. 7. 1  
Effic acy  A n al ysis  
Effica c y e n d p oi nts will be s u m mari ze d wit h descri pti ve statistics f or t he O pe n -La bel E xte nsi o n 
P hase b y treat me nt gr o u p a n d wee k. F or t he e xte nsi o n p hase, s u bjects will be s u m mariz e d b y t he 
ori gi nal r a n d o mi ze d tre at m e nt gr o u p a n d will refl ect 1) c o nti n ue d B H V -4 1 2 5 7 tre at m e nt a n d 2) 
Place b o s u bjects s witc he d t o o pe n -l a bel B H V-4 1 5 7. A d diti o nal e x pl or at or y e n d p oi nt of e val uati n g 
l o n g-ter m effects o n cli ni cal o utc o m e me as ures  
1 2. 7. 2  
S afety A n aly sis 
Safet y e n d p oi nts i ncl u de a d verse e ve nts, p h ysical e xa m, vit al si g ns, healt h stat us, 1 2 le a d E C G, 
la b orat or y deter mi nati o ns a n d partici p a nt wit h dra w als. Safet y a n d t olera bilit y data  as well as 
de m o gra p hi c data  will be s u m m ariz e d i n ta b ular a n d/ or gra p hi cal f or mat f or eac h treat me nt gr o u p. 
T he i nci d e nce of all la b orat or y test a b n or m alities a n d t he me dia n  c h a n ges fr o m baseli n e will be 
ta b ulate d b y treat me nt re gi me n a n d ti m e p oi nt. T he safet y p o p ulati o n will be use d f or t hese 
a nal yses.  
Safet y will be pr ese n te d se parat el y f or t he d o u ble -bli n d  p hase a n d f or t he o pe n -la bel e xte nsi o n 
p hase, o verall a n d b y ra n d o mize d ar m.  
1 2. 7. 3  
A dverse Eve nts  
Treat me nt e mer ge nt a d verse  e ve nts  ( A E) occ urri n g , or i nte nsif yi n g, after t he start of  st u d y dr u g  
d osi n g  a r e  s u m marize d descri pti vel y  f or t he safet y p o p ulati o n.  A listi n g is pre p are d of Seri o us 
A d verse E ve nts occ urri n g i n s u bje cts t hat are e nr olle d b ut n ot tre ate d.  All  A Es  are c o de d 
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 7 7  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
acc or di n g  t o s yste m or ga n  class  ( S O C) a n d preferre d  ter m ( P T) usi n g  t he Me dical  Dicti o nar y  
f or Re g ulat or y  Acti vities ( Me d D R A). S u m mar y  ta bl es s h o wi n g t he n u m ber  of  pa rtici pa nts a n d 
perce nt  of u ni q ue s u bjects  wit hi n  eac h cate g or y  are ge nerate d f or eac h of  t he f oll o wi n g t y pes of  
a d verse e ve nts  a n d its relati o ns hi p t o st u d y treat me nt (relate d t o st u d y treat me nt): 
•  All e ve nts  
•  Seri o us  e ve nts 
•  Deat hs  
•  E ve nts  lea di n g t o disc o nti n uati o n of treat me nt  
•  Se vere  e ve nts  
•  E ve nts occ urri n g wit h a fre q u e nc y of m or e t ha n 5 % i n eit her treat me nt gr o u p  
1 2. 7. 4  
L a b or at ory P ar a m eters  
La b orat or y  para meters  ar e s u m m ari z e d  b y  visit.  Fre q ue ncies  of  hi g h  a n d l o w val ues  wit h  
res pect t o t he n or mal  ra n ge are dis pla ye d,  as  are s hift ta bles c o m pari n g eac h treat me nt visit  
( wee ks  4,  8,  1 2,  2 4,  3 6,  a n d 4 8)  a n d b aseli ne visit  b y  ti m e p oi nt  a n d treat m e nt gr o u p.   
1 2. 7. 5  
Ot her S afety P ar a m eters  
Vital  si g ns a n d E C G  para meters  are s u m m ari z e d  acr oss  gr o u ps  b y  visit  usi n g  descri pti ve 
statistics, a n d at eac h o utc o me visit a n d at e n d of st u d y. 
P h ysical  e xa mi nati o n  fi n di n gs a n d n u m ber  of  pa rtici pa nts are s u m marize d as t h e c o u nt a n d 
perce nta ge  of  pa rti ci pa nts b y  e C R F pre -d efi ne d  cate g ories  at last visit.  C o nc o mita nt  
me dic ati o ns  are s u m mariz e d b y  treat m e nt gr o u p,  dr u g  class  a n d preferre d  ter m. Vital  si g ns 
are s u m marize d  b y visit  usi n g  descri pti ve statistics. 
O verall i nter pretati o n res ults f or E C Gs a n d t he I n vesti gat or i nter pretati o n res ults are c ollecte d as 
n or mal, a b n or mal n ot cli nicall y si g nifica nt, a n d a b n or mal cli nicall y si g nifica nt. Partici pa nts w h ose 
i nter pretati o n s hifts fr o m n or mal t o a b n ormal are liste d se paratel y i ncl u di n g descri pti o n of t he 
a b n or malit y a n d a n y ass ociate d c o m me nts.  
1 2. 8  
R a n d o miz ati o n a n d Str atific ati o n  
St u d y parti ci p a nts  are r a n d o ml y all ocate d  i n a 1: 1  rati o i nt o o ne  of  t he 2  gr o u ps:  treat me nt wit h  
2 8 0  m g B H V -4 1 5 7 or  place b o.  A  ra n d o mizati o n sc he d ule will  be  ge nerate d  a n d i nc or p or ate d 
i nt o t he Electr o nic  Data  Ca pt ure  s yste m ( E D C) a n d t he ra n d o mizati o n I D will  be  assi g ne d  w he n  
t he site ra n d o mizes t he partici pa nt.  A  ce ntr ali ze d  eli gi bilit y e val uati o n  pr oce d ure  will  be  a p plie d  
f or eac h  partici pa nt.  A  stratifie d per m ute d  bl oc k r a n d o mizati o n  pr oce d ure  will  be  use d.  
Scree ni n g  M M S E  [m o derate A D: 1 4  t o 1 9; mil d A D: 2 0  t o 2 4]  a n d Site will  be  stratificati o n 
fact ors. 
1 2. 9  
Pr ot oc ol De vi ati o ns, D at a Bli n d Re vie w, a n d U n bli n di n g  
A n y si g nifica nt e ve nt t hat d oes n ot c o m pl y  wit h t he i ncl usi o n/e xcl usi o n criteria, st u d y c o n d uct 
(e. g., i na de q uate i nf or me d c o nse nt, u nre p orte d S A Es), or st u d y pr oce d ures (e. g., use of pr o hi bite d 
me dicati o ns as defi ne d b y t he pr ot oc ol; i m pr o per b rea ki n g of t he bli n d) will be d oc u me nte d as a 
rele va nt de viati o n. 

Confidential
Protocol BHV4157-203 
Page 78 of 96
 
Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
 
The sponsor, or designee, will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file), which will be finalized prior to database lock. This file will 
include site, participant ID, deviation date, deviation type, status (major vs. minor), and a 
description of the protocol deviation. 
 
Classification of deviations from the protocol as minor or major will be decided on a case-by-
case basis without knowledge of the treatment assigned and before the database lock (Data Blind 
Review). After database lock, the responsible statistician will request the treatment codes, the 
study will be unblinded, and the statistical analysis will be conducted. The bioanalytical 
scientist, IWRS vendor, and pharmacovigilance roles may be unblinded before data are unblinded 
for the primary endpoint and all subjects complete the study. 
 
13 RECORDING AND COLLECTION OF DATA 
13.1 
Case Report Form 
The Investigator or designee will record all data collected on the electronic Case Report Form 
(eCRF) provided for that purpose. The site will be suitably trained on the use of the eCRF 
and appropriate site personnel will be provided electronic signatures. 
All site entries will be made in a secured web site and the Principal Investigator will review 
the record for completeness. Upon completion of the review, the PI will sign electronically 
in the signature page of the eCRF. 
The Investigator or designee will make necessary eCRF corrections. The investigator must 
authorize the corrections to the entered data on eCRF. 
Completed eCRFs will be submitted according to the ADCS's instructions, and reviewed by 
the ADCS to determine their acceptability. If necessary, data correction requests will be 
generated for resolution by the study site. 
13.2 
Study Files and Participant Source Documents 
Participant confidentiality is strictly held in trust by the participating investigators, research 
staff, and the sponsoring institution and their agents. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Authorized representatives of the sponsoring institution may inspect all documents 
and records required to be maintained by the Investigator, including but not limited to, medical 
records (office, clinic or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. Any data, specimens, forms, reports, video 
recordings, and other records that leave the site will be identified only by a participant 
identification number to maintain confidentiality. 
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented and the study data to be subsequently verified. These documents 

Confidential
Protocol BHV4157-203 
Page 79 of 96
 
Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
include Investigators’ Study Files and original participant clinical source documents 
generated at the study site. The term “original” means the first recording of the data. 
The Investigator will ensure the site master files are maintained, including the study 
protocol and its amendments, IRB and regulatory approvals with associated correspondence, 
informed consents, study drug records, staff curriculum vitae, all correspondence, and other 
appropriate documents. 
Participant clinical source documents may include, but are not limited to, participant 
hospital/clinic records, physicians’ and nurses’ notes, appointment books, laboratory reports, 
ECGs, MRI images, pathology and special assessment reports. The Investigator must assure 
that all original source documents are available to support monitoring activities. 
13.3 
Rater Training 
Site staff will be trained on the assessments and certified on the study specific cognitive, functional 
and behavioral measures as described in Section 9. The sites will have training at the Investigator 
meeting and possible online training and didactic training as needed. Throughout the trial the site 
staff administering the assessments may have limited scales audiotaped in order to ensure ratings 
are being consistently administered across sites. Most scales will be collected on paper and entered 
via the electronic data capture system (EDC). However, some scales may be collected via an 
electronic capture of assessments (eCOA). Details will be provided with your rater training 
instructions. As the study is extended, sites must monitor their raters’ certifications, and obtain re-
certification before any current certifications expire. 
13.4 
Monitoring 
During the study each site will be visited by an ADCS clinical research monitor according 
to the specifications in the monitoring plan for the double-blind and Open-Label Extension 
phases. The monitoring visits must be conducted according to the applicable ICH and GCP 
guidelines to ensure protocol adherence, quality of data, drug accountability, compliance with 
regulatory requirements and continued adequacy of the investigational site and its facilities. 
The Investigator will co-operate in the monitoring process by ensuring the availability of the 
eCRFs, source documents and other necessary documents at the time of the monitoring visits 
and by prompt attention to any matters brought to his/her attention by the monitor. 
13.5 
Audit 
ICH guidelines for GCP require independent inspection of clinical program activities. Such 
inspections may be performed at any time- before, during and/or after the study. The 
Investigator and study staff are responsible for maintaining the site master file containing 
all study-related regulatory documentation as outlined by ADCS Regulatory Affairs that will 
be suitable for inspection at any time by ADCS, Biohaven, its designees, and/or regulatory 
agencies. The Investigator understands and agrees to give access to the necessary documentation 
and files. 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 8 0  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1 3. 6  
Rete nti o n of D at a  
All  rec or ds c o n necte d  wit h  t his cli nical st u d y will  be  retai ne d f or at least t w o years  
f oll o wi n g t he dat e  of  a n a p pr o ve d  mar keti n g  a p plicati o n  [ 2 1 C F R  3 1 2. 6 2(c)];  or  at least t hree 
years  fr o m t he f or mal disc o nti n uati o n  of  B H V -4 1 5 7 de vel o p me nt;  or  se ve n years  fr o m t he e n d 
of  t he st u d y, w hic he ver  is l o n ger. Pri or  t o rec or d dis p osal,  A D C S  a n d Bi o ha ve n  ma y  elect t o 
e xte n d  t he rete nti o n peri o d.  T o  e ns ure t hat t hese sta n dar ds are a p plie d, writte n  per missi o n  
m ust  be  gra nte d  fr o m Bi o ha ve n  bef ore  rec or d dis p osal.  All  l ocal la ws re gar di n g rete nti o n of  
rec or ds m ust  als o be  f oll o we d. St u d y  sites are re q uire d t o retai n all rec or ds u ntil writte n  
n otific ati o n all o wi n g  destr ucti o n is recei ve d fr o m t he A D C S.  
1 3. 7  
Re p orti n g of St u d y Res ults  
Bi o ha ve n,  i n c o o perati o n  wit h  A D C S,  will  pr o d uce  a n i nte grate d Cli nical  St u d y  Re p ort,  w hic h  
will be s u b mitte d  f or a p pr o val t o t he Pr oject  Direct or  a n d t he A D C S  Pri nci pal  I n vesti gat or.  
1 3. 8  
Q u alit y Ass ur a nce/ Q u alit y C o ntr ol  
A D C S  Sta n dar d  O perati n g  Pr oce d ures  ( S O Ps) will  be  a d here d  t o f or all acti viti es rele va nt t o t he 
q ualit y  of t he  st u d y. 
D oc u me ntati o n  of  all q ualit y  c o ntr ol pr oce d ures  will  be  o utli n e d  i n t h e Dat a  Ma na ge me nt  Pla n  
( D M P). E dit  c hec ks  a n d listi n gs will  be  r u n a n d use d  i n c o nj u ncti o n  wit h  t he e C R F pa ges  t o 
s u p p ort a cli nical re vie w of  t he data.  D oc u me ntati o n  of  all q ualit y  c o ntr ol pr oce d ures  will 
be  o utli ne d i n t he D M P.  
1 4  D A T A S A F E T Y M O NI T O RI N G  B O A R D  
 
A n  i n de pe n de nt Data  Safet y  M o nit ori n g  B oar d  ( D S M B) will  be  utiliz e d  f or t his st u d y. T he  
A D C S  c urre ntl y  has  a D S M B  t hat re vie ws t he safet y of  all partici pa nt s e nr olle d  i n trials o n a n  
o n -g oi n g  basis.  
T he  D S M B  will  re vie w t he pr ot oc ol,  a n d will  i de ntif y t he data  para meters  a n d f or mat of  t he 
i nf or mati o n t o b e  re g ul arl y re p orte d. T he  D S M B  will  meet  i n pers o n  or  b y  c o nfere nce call 
a p pr o xi matel y  q u arterl y.  T he  D S M B  will t y pi call y recei v e re p orts wit h data  b y treat me nt gr o u p 
(e. g. se mi-bli n de d gr o u p A, gr o u p B  etc.) or, if re q ueste d b y t he D S M B, c o m pletel y u n bli n de d . 
T he  D S M B  w ill als o be  i nf or me d of  S U S A Rs as t he y are bei n g re p orte d t o re g ulat or y a ut h orities 
a n d I n vesti gat ors.  
Base d  o n  t he re vie w of  safet y data,  t he D S M B  will  ma k e  rec o m me n dati o ns re gar di n g t he 
c o n d uct of  t he st u d y t o t he St u d y Steeri n g C o m mittee ( S S C). T hese  ma y  i ncl u de c o nti n ui n g  
t he st u d y as  desi g ne d,  a me n di n g  safet y m o nit ori n g  pr oce d ures,  m o dif yi n g  t he pr ot oc ol  or  t he 
i nf or me d c o nse nt f or m, or r e c o m m e n di n g t h e t er mi n ati o n of t h e st u d y.  
T he i nteri m a nal ysis will b e carrie d o ut b y t he u n bli n de d safet y bi ost atistics t ea m, a n d a r e p or t 
will be pre pare d f or t he D S M B. T he  D S M B will re vie w all data pertai ni n g t o t he 
 
 T he D S M B 
will t he n i n dic ate w het her or n ot t he  
 criteri a ha ve bee n met t o t he S S C t hat is o verseei n g 
t he tri al a n d pr o vi de its me m b ers t he sa me d ata s u m maries f or re vie w.  
F or  f urt her details,  please refer t o t h e D S M B  c harter.  
C CI
C CI

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 8 1  of 9 6  
 
 
 
 
A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1 5  S T U D Y S T E E RI N G C O M MI T T E E  
T he S S C me m bers hi p will c o nsist of 5 me m b ers (a c hair pers o n a n d a d visi n g bi ostatisticia n b ot h 
i n de pe nde nt  fr o m Bi o ha v e n a n d A D C S, t w o p h ysicia n scie ntists fr o m A D C S wit h n o direct or 
i n direct i n v ol ve me nt i n t h e st u d y a n d o ne se ni or re prese ntati ve f or Bi o ha ve n wit h n o dire ct 
i n v ol ve m e nt i n t he o n g oi n g ma n a ge m e nt of t he st u d y. T he St u d y Ste eri n g C o m mitte e ( S S C) will  
recei v e t he rec o m me n d ati o n of t he D S M B a n d ha ve f ull a ccess t o d ata s u m maries pr o vi de d t o 
t he D S M B base d o n t he wee k 2 4 data c ut. T he r ole of t he S S C is t o pr o vi de cli nical a n d scie ntific 
a d vice t o Bi o h a ve n. T he se ni or re prese nt ati v e f or Bi o ha ve n t o t h e S S C will h a ve t he fi n al  
res p onsi bilit y f or ma ki n g t he de cisi o n t o c o nti n ue or t o  ter mi nate t he trial. See S S C C harter f or 
a d diti o n al details.  
If t he  
 criteria s pecifi e d i n t he i nteri m a nal ysis are n ot met, t he S S C will re mai n a vaila bl e 
t o recei ve fe e d bac k a n d/ or n o n -bi n di n g re c o m m e n d ati o ns fr o m t he D S M B re gar di n g t he st u d y. 
If p ote ntial safet y c o n cer ns arise, t h e S S C will a d vise Bi o ha ve n o n w het h er t o c o nti n ue t he st u d y, 
c o nsi der tri al m o dific ati o n, or c o nsi d er earl y ter mi nati o n.  
1 6  P U B LI C A TI O N S P O LI C Y A N D S H A RI N G O F D A T A  
A D C S , i n c olla b orati o n wit h Bi o ha ve n, will  p u blis h  t he st u d y res ults i n acc or d a nce wit h t h e 
2 0 1 0 C O N S O R T g ui deli nes  ( Sc h ulz, Alt m a n, Mo her, & Gr o u p, 2 0 1 0) . See A p pe n di x I V  f or t he 
C O N S O R T C hec klist a n d Fl o wc hart.  
 
As  t here are e x pecte d  t o be  t o o fe w pa rtici pa nts st u die d at  eac h site f or i n di vi d ual site’s res ults 
t o be  statistic all y vali d,  t h e res ults of  t his st u d y will  be  discl ose d  or  p u blis he d  o nl y  i n c o m bi ne d  
f or m base d  u p o n  t he statistical a nal ysis  perf or me d  b y  A D C S  a n d Bi o ha ve n  a n d will  be  
c o or di nate d  b y  A D C S  a n d Bi o ha ve n . N o  discl os ure  of  st u d y res ults will  be  per mitte d  e xce pt  
as  s pecifie d i n a se parate, writte n  a gree me nt bet wee n  Bi o ha ve n  a n d t he I n vesti gat or. T his  st u d y 
will  be  re gistere d at w w w. Cli nical Trials. g o v  after a p pr o val of  t he desi g nate d  I R B a n d pri or  t o 
e nr oll me nt of  t he first pa rtici pa nt, as  re q uire d f or p u blicati o n  b y  t he I nter nati o nal C o m mittee  
of  Me dical  J o ur nal E dit ors (I C MJ E). 
Res ults  will be  p oste d  o n cli nicaltrials. g o v  i n acc or da nce wit h re q uire me nts.   
1 7  R E F E R E N C E S  
B or dji, K., B ecerril -Orte ga, J., Nic ole, O., & B uiss o n, A. ( 2 0 1 0). Acti vati o n of e xtras y na ptic, b ut 
n ot s y na ptic, N M D A rece pt ors m o difies a m yl oi d pr e c urs or pr otei n e x pressi o n  patter n a n d 
i ncreases  
a m yl oi d-ß  
pr o d ucti o n. 
J  
Ne ur osci,  
3 0 ( 4 7),  
1 5 9 2 7-1 5 9 4 2. 
d oi: 1 0. 1 5 2 3/J N E U R O S CI. 3 0 2 1 -1 0. 2 0 1 0  
Br ot hers, H. M., Bar d o u, I., H o p p, S. C., Kaerc her, R. M., C or o na, A. W., Fe n n, A. M., . . . W e n k, 
G. L. ( 2 0 1 3). Ril u z ole p arti all y resc ues a g e -ass ociate d, b ut n ot L P S -i n d uce d, l oss of 
gl uta m ate tr a ns p orters a n d s patial me m or y. J Ne ur oi m m u ne P h ar m ac ol, 8 ( 5), 1 0 9 8-1 1 0 5. 
d oi: 1 0. 1 0 0 7/s 1 1 4 8 1 -0 1 3 -9 4 7 6 -2  
Carlss o n, M. L. ( 2 0 0 0). O n t he r ole of c ortical gl ut a mat e i n o bsessi ve -c o m p ulsi ve dis or der a n d 
attenti o n -deficit h y pera cti vit y dis or der, t w o p h e n o me n ol o gi call y a ntit h etic al c o n diti o ns. 
Act a Psy c hi atr Sc a n d, 1 0 2 ( 6), 4 0 1-4 1 3.  
C CI

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Chin, J., Massaro, C. M., Palop, J. J., Thwin, M. T., Yu, G. Q., Bien-Ly, N., . . . Mucke, L. (2007). 
Reelin depletion in the entorhinal cortex of human amyloid precursor protein transgenic 
mice and humans with Alzheimer's disease. J Neurosci, 27(11), 2727-2733. 
doi:10.1523/JNEUROSCI.3758-06.2007 
Craft, S., Newcomer, J., Kanne, S., Dagogo-Jack, S., Cryer, P., Sheline, Y., . . . Alderson, A. 
(1996). Memory improvement following induced hyperinsulinemia in Alzheimer's disease. 
Neurobiol Aging, 17(1), 123-130.  
Cummings, J. L. (1997). The Neuropsychiatric Inventory: assessing psychopathology in dementia 
participants. Neurology, 48(5 Suppl 6), S10-16.  
Dementia, A. (2017). 2017 Alzheimer's disease facts and figures. Alzheimer's Association; The 
Journal of the Alzheimer's Association.  
Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). "Mini-mental state". A practical method 
for grading the cognitive state of participants for the clinician. J Psychiatr Res, 12(3), 189-
198.  
Frizzo, M. E., Dall'Onder, L. P., Dalcin, K. B., & Souza, D. O. (2004). Riluzole enhances 
glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol, 24(1), 123-128.  
Galasko, D., Bennett, D., Sano, M., Ernesto, C., Thomas, R., Grundman, M., & Ferris, S. (1997). 
An inventory to assess activities of daily living for clinical trials in Alzheimer's disease. 
The Alzheimer's Disease Cooperative Study. Alzheimer Dis Assoc Disord, 11 Suppl 2, S33-
39.  
Hardingham, G. E. (2006). Pro-survival signalling from the NMDA receptor. Biochem Soc Trans, 
34(Pt 5), 936-938. doi:10.1042/BST0340936 
Holland, D., Brewer, J. B., Hagler, D. J., Fennema-Notestine, C., Fenema-Notestine, C., Dale, A. 
M., & Initiative, A. s. D. N. (2009). Subregional neuroanatomical change as a biomarker 
for Alzheimer's disease. Proc Natl Acad Sci U S A, 106(49), 20954-20959.  
Hughes, C. P., Berg, L., Danziger, W. L., Coben, L. A., & Martin, R. L. (1982). A new clinical 
scale for the staging of dementia. Br J Psychiatry, 140, 566-572.  
Hunsberger, H. C., Weitzner, D. S., Rudy, C. C., Hickman, J. E., Libell, E. M., Speer, R. R., . . . 
Reed, M. N. (2015). Riluzole rescues glutamate alterations, cognitive deficits, and tau 
pathology associated with P301L tau expression. J Neurochem, 135(2), 381-394. 
doi:10.1111/jnc.13230 
Ivanova, I., Salmon, D. P., & Gollan, T. H. (2013). The multilingual naming test in Alzheimer's 
disease: clues to the origin of naming impairments. J Int Neuropsychol Soc, 19(3), 272-
283. doi:10.1017/S1355617712001282 
Jack, C. R., Shiung, M. M., Gunter, J. L., O'Brien, P. C., Weigand, S. D., Knopman, D. S., . . . 
Petersen, R. C. (2004). Comparison of different MRI brain atrophy rate measures with 
clinical disease progression in AD. Neurology, 62(4), 591-600.  
Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P., & Meininger, V. (1996). Dose-ranging 
study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole 
Study Group II. Lancet, 347(9013), 1425-1431.  
Matos, M., Augusto, E., Oliveira, C. R., & Agostinho, P. (2008). Amyloid-beta peptide decreases 
glutamate uptake in cultured astrocytes: involvement of oxidative stress and mitogen-
activated 
protein 
kinase 
cascades. 
Neuroscience, 
156(4), 
898-910. 
doi:10.1016/j.neuroscience.2008.08.022 
Miller, S. D., Duncan, B. L., Sorrell, R., & Brown, G. S. (2005). The partners for change outcome 
management system. J Clin Psychol, 61(2), 199-208. doi:10.1002/jclp.20111 

Confidential
Protocol BHV4157-203 
Page 83 of 96
 
Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
Mookherjee, P., Green, P. S., Watson, G. S., Marques, M. A., Tanaka, K., Meeker, K. D., . . . 
Cook, D. G. (2011). GLT-1 loss accelerates cognitive deficit onset in an Alzheimer's 
disease animal model. J Alzheimers Dis, 26(3), 447-455. doi:10.3233/JAD-2011-110503 
Nasreddine, Z. S., Phillips, N. A., Bédirian, V., Charbonneau, S., Whitehead, V., Collin, I., . . . 
Chertkow, H. (2005). The Montreal Cognitive Assessment, MoCA: a brief screening tool 
for mild cognitive impairment. J Am Geriatr Soc, 53(4), 695-699. doi:10.1111/j.1532-
5415.2005.53221.x 
Pereira, A. C., Gray, J. D., Kogan, J. F., Davidson, R. L., Rubin, T. G., Okamoto, M., . . . McEwen, 
B. S. (2017). Age and Alzheimer's disease gene expression profiles reversed by the 
glutamate modulator riluzole. Mol Psychiatry, 22(2), 296-305. doi:10.1038/mp.2016.33 
Pereira, A. C., Lambert, H. K., Grossman, Y. S., Dumitriu, D., Waldman, R., Jannetty, S. K., . . . 
Morrison, J. H. (2014). Glutamatergic regulation prevents hippocampal-dependent age-
related cognitive decline through dendritic spine clustering. Proc Natl Acad Sci U S A, 
111(52), 18733-18738. doi:10.1073/pnas.1421285111 
Pittenger, C. (2015a). Glutamate modulators in the treatment of obsessive-compulsive disorder. 
Psychiatr Ann, 45(6), 308-315. doi:10.3928/00485713-20150602-06 
Pittenger, C. (2015b). Glutamatergic agents for OCD and related disorders. Curr Treat Options 
Psychiatry, 2(3), 271-283. doi:10.1007/s40501-015-0051-8 
Possin, K. L., Laluz, V. R., Alcantar, O. Z., Miller, B. L., & Kramer, J. H. (2011). Distinct 
neuroanatomical substrates and cognitive mechanisms of figure copy performance in 
Alzheimer's disease and behavioral variant frontotemporal dementia. Neuropsychologia, 
49(1), 43-48. doi:10.1016/j.neuropsychologia.2010.10.026 
Qiu, Y., Jacobs, D.M., Messer, K., Salmon, D.P., Feldman, H.H. (2019). Cognitive heterogeneity 
in probable Alzheimer's disease: Clinical and neuropathologic features. Neurology. 93(8), 
e778-e790. doi: 10.1212/WNL.0000000000007967 
Quinn, J. F., Raman, R., Thomas, R. G., Yurko-Mauro, K., Nelson, E. B., Van Dyck, C., . . . Aisen, 
P. S. (2010). Docosahexaenoic acid supplementation and cognitive decline in Alzheimer 
disease: a randomized trial. JAMA, 304(17), 1903-1911. doi:10.1001/jama.2010.1510 
Ren, S. C., Chen, P. Z., Jiang, H. H., Mi, Z., Xu, F., Hu, B., . . . Zhu, Z. R. (2014). Persistent 
sodium currents contribute to Aβ1-42-induced hyperexcitation of hippocampal CA1 
pyramidal neurons. Neurosci Lett, 580, 62-67. doi:10.1016/j.neulet.2014.07.050 
Rosen, W. G., Mohs, R. C., & Davis, K. L. (1984). A new rating scale for Alzheimer's disease. Am 
J Psychiatry, 141(11), 1356-1364. doi:10.1176/ajp.141.11.1356 
Rosen, W. G., Terry, R. D., Fuld, P. A., Katzman, R., & Peck, A. (1980). Pathological verification 
of ischemic score in differentiation of dementias. Ann Neurol, 7(5), 486-488. 
doi:10.1002/ana.410070516 
Scheltens, N. M. E., Tijms, B. M., Koene, T., Barkhof, F., Teunissen, C. E., Wolfsgruber, S., . . . 
Cohort, A. D. (2017). Cognitive subtypes of probable Alzheimer's disease robustly 
identified 
in four 
cohorts. 
Alzheimers 
Dement, 
13(11), 
1226-1236. 
doi:10.1016/j.jalz.2017.03.002 
Schluchter, M. D. & Elashoff, J. D. (1990). Small-sample adjustments to tests with unbalanced 
repeated measures assuming several covariance structures. J Statist Comput Simulation, 
37(1-2), 69–87. 
Schulz, K. F., Altman, D. G., Moher, D., & Group, C. (2010). CONSORT 2010 Statement: 
Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol, 63(8), 
834-840. doi:10.1016/j.jclinepi.2010.02.005 

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Amendment 5, Version 6.0 dd. 12SEP2020 
 
 
Scimemi, A., Meabon, J. S., Woltjer, R. L., Sullivan, J. M., Diamond, J. S., & Cook, D. G. (2013). 
Amyloid-β1-42 slows clearance of synaptically released glutamate by mislocalizing 
astrocytic GLT-1. J Neurosci, 33(12), 5312-5318. doi:10.1523/JNEUROSCI.5274-
12.2013 
Sheehan, D. V., Alphs, L. D., Mao, L., Li, Q., May, R. S., Bruer, E. H., . . . Williamson, D. J. 
(2014). Comparative Validation of the S-STS, the ISST-Plus, and the C-SSRS for 
Assessing the Suicidal Thinking and Behavior FDA 2012 Suicidality Categories. Innov 
Clin Neurosci, 11(9-10), 32-46.  
Sheehan, D. V., Giddens, J. M., & Sheehan, I. S. (2014). Status Update on the Sheehan-Suicidality 
Tracking Scale (S-STS) 2014. Innov Clin Neurosci, 11(9-10), 93-140.  
Terry, R. D., Masliah, E., Salmon, D. P., Butters, N., DeTeresa, R., Hill, R., . . . Katzman, R. 
(1991). Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the 
major 
correlate 
of 
cognitive 
impairment. 
Ann 
Neurol, 
30(4), 
572-580. 
doi:10.1002/ana.410300410 
Thomas, R. G., Albert, M., Petersen, R. C., & Aisen, P. S. (2016). Longitudinal decline in mild-
to-moderate Alzheimer's disease: Analyses of placebo data from clinical trials. Alzheimers 
Dement, 12(5), 598-603. doi:10.1016/j.jalz.2016.01.002 
Turner, R. S., Thomas, R. G., Craft, S., van Dyck, C. H., Mintzer, J., Reynolds, B. A., . . . 
Alzheimer's Dis Cooperative, S. (2015). A randomized, double-blind, placebo-controlled 
trial 
of 
resveratrol 
for 
Alzheimer 
disease. 
Neurology, 
85(16), 
1383-1391. 
doi:10.1212/wnl.0000000000002035 
Wang, J., Logovinski, V., Hendrix, S.B., Stanworth, S.H., Perdomo, C., Xu, L., Dhadda, S., Do, 
I., Rabe, M., Luthman, J., Cummings, J. (2016). ADCOMS: a composite clinical outcome 
for prodromal Alzheimer's disease trials. J Neurol Neurosurg Psychiatry, 87(9), 993-9. 
Weintraub, S., Salmon, D., Mercaldo, N., Ferris, S., Graff-Radford, N. R., Chui, H., . . . Morris, J. 
C. (2009). The Alzheimer's Disease Centers' Uniform Data Set (UDS): the 
neuropsychologic test battery. 
Alzheimer Dis Assoc Disord, 23(2), 91-101. 
doi:10.1097/WAD.0b013e318191c7dd 
Zumkehr, J., Rodriguez-Ortiz, C. J., Cheng, D., Kieu, Z., Wai, T., Hawkins, C., . . . Kitazawa, M. 
(2015). Ceftriaxone ameliorates tau pathology and cognitive decline via restoration of glial 
glutamate transporter in a mouse model of Alzheimer's disease. Neurobiol Aging, 36(7), 
2260-2271. doi:10.1016/j.neurobiolaging.2015.04.005 
 
 

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18 APPENDICES  
18.1 
APPENDIX I – STUDY PLAN AND PROCEDURES AT EACH VISIT 
Table 1: 
Schedule of Assessments and Events – Double-Blind Phase 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 or 
Early Term 
10 
 
Study Visit Time Point 
Screening 
(within 42 
days prior 
to baseline) 
 
Baseline 
(Week 0) 
 
Week 2 
(±3 days) 
 
Week 4 
(±7 days) 
 
Week 8 
(±7 days) 
 
Week 12 
(±7 days) 
 
Week 24 
(±7 days) 
 
Week 36 
(±7 days) 
 
Week 481 
(±7 days) 
Follow-Up 
Week 52 
(±7 days) 
Unscheduled 
Visit2 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
X 
 
 
 
 
 
 
 
 
 
Randomization3 
 
X 
 
 
 
 
 
 
 
 
 
Med History/Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Modified Hachinski Ischemic 
Scale 
X 
 
 
 
 
 
 
 
 
 
 
Height4 & Weight 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Physical Examination 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Neurological Examination 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs5 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECG (resting) 
X 
 
 
 
 
X 
X 
 
X 
X 
 
Clinical Safety Blood Tests7 
X 
X 
 
X 
X 
X 
X 
X8 
X 
X 
 
B12 (blood test) 
X 
 
 
 
 
 
 
 
 
 
 
Urinalysis9 
X 
X 
 
X 
 
X 
X 
 
X 
 
 
HIV, HBsAg, HCV antibody 
X 
 
 
 
 
 
 
 
 
 
 
ApoE4 (blood test) 
X 
 
 
 
 
 
 
 
 
 
 
Blood Collection for 
Biomarker Banking 
 
X 
 
 
 
 
X 
 
X 
 
 
Blood Collection for 
Pharmacokinetics10 
 
X 
 
X 
X 
X 
X 
 
X 
 
 
 
 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
 
Pa ge 8 6  of 9 6  
 
 
 
 A me n d me nt 5, Versi o n 6. 0 d d. 1 2 Se p 2 0 2 0  
 
 
 
 
 
Visit N u m ber  
1  
2  
3  
4  
5  
6  
7  
 
 
 
 
8  
9  or  
Earl y  T er m  
1 0  
 
 
St u d y Visit Ti m e P oi nt  
Scree ni n g  
( wit hi n 4 2  da ys  
pri or t o 
baseli ne ) 
 
B as eli ne  
( Wee k 0)  
 
Wee k 2  
( ± 3 da ys)  
 
Wee k  4  
( ± 7 da ys) 
 
Wee k  8  
( ± 7 da ys) 
 
Wee k  1 2  
( ± 7 da ys) 
 
Wee k  2 4  
( ± 7 da ys) 
 
Wee k  3 6  
( ± 7 da ys) 
 
Wee k  4 8  
( ± 7 da ys) 
F oll o w -U p  
wee k  5 2  
( ± 7 da ys) 
U ns c he d ule d 
Visit  
V ol u metric M RI 1 1 
X  
 
 
 
 
 
X  
 
X  
 
 
L u m bar P u nct ure ( L P) 1 1, 1 2  
X  
 
 
 
 
 
X  
 
X  
 
 
C S F Bi o mar kers 1 3 
X  
 
 
 
 
 
X  
 
X  
 
 
P ost -L P Safet y T ele p h o ne 1 4 
F oll o w -u p 7 
X  
 
 
 
 
 
X  
 
X  
 
 
S hee ha n S uici dalit y Trac ki n g 
Scale  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
 
A D A S -C o g 1 1  
 
X  
 
 
 
X  
X  
X  
X  
 
 
C D R -S O B  
 
X  
 
 
 
X  
X  
X  
X  
 
 
N PI  
 
X  
 
 
 
 
X  
 
X  
 
 
A D C S -A D L  
 
X  
 
 
 
 
X  
 
X  
 
 
Craft St or y  2 1 R ecall  
 
X  
 
 
 
 
 
 
X  
 
 
B e ns o n C o m ple x Fi g ure  
 
X  
 
 
 
 
 
 
X  
 
 
MI N T  
 
X  
 
 
 
 
 
 
X  
 
 
Letter & C ate g or y Fl ue nc y  
 
X  
 
 
 
 
 
 
X  
 
 
Trail M a ki n g Test A & B  
 
X  
 
 
 
 
 
 
X  
 
 
N u m ber S pa n T est  
 
X  
 
 
 
 
 
 
X  
 
 
M M S E  
X  
X  
 
 
 
 
X  
 
X  
 
 
M o C A  
 
X  
 
 
 
 
X  
 
X  
 
 
R es earc h Satisfacti o n S ur ve y  
 
X  
 
 
 
X  
X  
X  
X  
 
 
Dis pe ns e St u d y Dr u g 1 5 
 
X  
 
X  
X  
X  
X  
X  
 
 
 
St u d y Dr u g I nstr ucti o n  P h o ne 
C all 1 6 
 
 
X  
 
 
 
 
 
 
 
 
St u d y  Dr u g Acc o u nta bilit y  
 
 
 
X  
X  
X  
X  
X  
X  
 
 
Treat me nt Bli n di n g 
Q uesti o n naire 1 7 
 
 
 
 
 
 
 
 
X  
 
 
1  
E ver y eff ort s h o ul d be ma de t o c o n d uct t he Wee k 4 8 visit a n d mai ntai n t he +/ - 7 da y wi n d o w. H o we ver, d ue t o c o ncer ns relate d t o t he C O VI D -1 9 pa n de mic, 
t he Wee k 4 8 visit wi n d o w ma y be m o difie d be y o n d t he +/- 7 da y wi n d o w, i n or der t o mi ni mize a n y p ote ntial ris ks t o st u d y partici pa nt s afet y a n d t o c o m pl y 
wit h g o ver n me ntal a n d l ocal i nstit uti o nal g ui da nce (e. g., st u d y site has a p olic y t hat a cli nical researc h visit m ust be dela ye d). U n der t hes e circ u msta nces, t he 
visit wi n d o w ma y be e xte n de d ( u p t o a ma xi m u m treat me nt d urati o n of 6 0 we e ks), b ut e ver y atte m pt s h o ul d be ma de t o c o n d uct t he visit as cl os e t o t he date 
t he visit is d ue as p ossi ble. If t he visit wi n d o w is m o difie d, partici pa nts s h o ul d be e val uate d re m otel y (e. g., via p h o ne) at t he ti me of t he s c he d ule d Wee k 4 8 
visit t o perf or m a n d d oc u me nt a p pr o priate s afet y ass ess me nts. St u d y me dicati o n ma y be s e nt t o t he partici pa nt via trac ke d a n d  certifie d c o urier. F or a n y s uc h 
cas es, t he i n vesti gat or s h o ul d dis c uss t he s pecific circ u msta nces of eac h cas e wit h t h e s p o ns or me dical m o nit or ( or desi g nee) w h o m ust a p pr o ve t he re q uest 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
 
Pa ge 8 7  of 9 6  
 
 
 
 A me n d me nt 5, Versi o n 6. 0 d d. 1 2 Se p 2 0 2 0  
 
 
 
 
 
pri or t o a n y m o dificati o n of t he visit wi n d o w: 
  
 C ell 
 
 
2  
T he f oll o wi n g m ust be c ollecte d at a n y u ns c he d ule d  visit: vital si g ns, pri or a n d c o nc o mita nt me dicati o ns, a d vers e e ve nts, a n d pr ot oc ol de viati o ns. All ot her 
u ns c he d ule d visit pr oce d ures are s u bject t o PI dis creti o n or re q uest fr o m t he M e dical M o nit or.  
3  
R a n d o mizati o n m ust occ ur at t he bas eli ne visit after eli gi bilit y is c o nfir me d . 
4  
Hei g ht is d o ne  at scree ni n g o nl y.  
5  
Vital si g ns i ncl u de sitti n g bl o o d press ure, p uls e, te m perat ure, res pirati o n rate, a n d wei g ht.  
6  
T he S A E re p orti n g peri o d starts at t he s cree ni n g visit (i.e., w he n t he partici pa nt or L A R si g ns c o ns e nt). T he re p orti n g peri o d f or n o n -s eri o us A Es starts at t he 
bas eli ne visit at t he ti me of recei vi n g t he first d os e of st u d y dr u g. T he e n d of t he re p orti n g peri o d f or b ot h S A Es a n d A Es is 3 0 da ys after t he st u d y dr u g has 
bee n dis c o nti n ue d.  
7  
Cli nical Safet y La b orat or y T ests will be perf or me d b y a C e ntral La b orat or y. Ass ess me nt i ncl u des t he f oll o wi n g: He mat ol o g y ( he m o gl o bi n, he mat ocrit, 
platelets, R B C, W B C, differe ntial c o u nt, a n d a bs ol ute ne utr o p hil c o u nt), C he mistr y (s o di u m, p otassi u m, c hl ori de, calci u m, A L T, A S T, L D H, al kali ne 
p h os p hatas e, G G T, p h os p h or us, bicar b o nate, C P K, t otal pr otei n, al b u mi n, i n direct bilir u bi n, direct bilir u bi n, t otal bilir u bi n , gl u c os e, creati ni ne, B U N, uric 
ac i d, t otal c h olester ol, L D L, H D L, tri gl yceri des, f olate).  
8  
Perf or mi n g a d diti o nal s afet y la bs at Wee k 3 6 is n o w str o n gl y e nc o ura ge d, gi ve n t he C O VI D -1 9 pa n de mic a n d u na ntici pate d iss ues relate d t o c ollecti n g la b 
s a m ples t hat ma y p ote ntiall y arise. 
9  
Uri nal ysis  t o i ncl u de: p H, s pecific gra vit y, pr otei n, gl uc os e, ket o nes, ur o bili n o ge n, bilir u bi n, bl o o d  
1 0  
A bl o o d sa m ple f or p har mac o ki netic ( P K) meas ures i n plas ma s h o ul d be c ollecte d at baseli ne, wee k  4, wee k  8, wee k  1 2, wee k  2 4, a n d wee k  4 8. Partici pa nts  
s h o ul d ta ke t heir d ose at t heir r o uti ne ti me o n t he da ys of t hese visits. Date a n d ti me of last d ose s h o ul d be c ollecte d i n cas e re p ort f or ms f or e ntr y i nt o t he E D C 
s yste m. Partici pa nts  w h o are a ble sc he d ule d f or a m or ni n g visit s h o ul d be i nstr ucte d t o h o l d t heir d ose of st u d y dr u g t hat m or ni n g u ntil after a P K tr o u g h s a m ple 
is o btai ne d, if p ossi ble a n d a p pr o priate i n t he j u d g me nt of t he i n vesti gat or.  Bl o o d sa m ples f or P K  i n plas ma s h o ul d be dra w n if t here are a n y S A Es t hat c o ul d 
p ossi bl y be dr u g -relate d or se vere A Es t hat c o ul d be dr u g-relate d. I n a d diti o n, f or partici pa nts  t hat are u n der g oi n g l u m bar p u nct ure, P K sa m ples s h o ul d be dra w n 
at t he ti me of l u m bar p u nct ure. Date a n d ti me of d oses o n t he da y of l u m bar p u nct ure a n d da y pri or s h o ul d be c ollecte d i n  case re p ort f or ms, f or e ntr y i nt o t he 
E D C s yste m.  
1 1  
All v M RIs m ust be perf or me d per i ma gi n g pr ot oc ol a n d m ust use t he s a me sca n ner t hr o u g h o ut st u d y.  
o  
S cree ni n g  v M RI:  if a partici pa nt  has n ot  ha d a n M RI perf or me d wit hi n 6 m o nt hs of s cree ni n g ( i.e.,  wit hi n 6 m o nt hs fr o m t he date of i nf or me d 
c o nse nt), t he n a n M RI m ust be perf or me d as part of t he scree ni n g re q uire me nts f or t his st u d y, per t he i ma gi n g pr ot oc ol, a n d s h o ul d be o ne of t he last 
s cree ni n g pr oce d ures perf or me d t o deter mi ne fi nal eli gi bilit y in or der t o pre ve nt partici pa nt s fr o m u n der g oi n g u n necess ar y M RIs. If a partici pa nt  h as  
ha d a n M RI wit hi n 6 m o nt hs of scree ni n g ( i.e.,  wit hi n 6 m o nt hs fr o m t he date of i nf or me d c o ns e nt) b ut t he M RI d oes n ot f oll o w t he st u d y-s pecific 
i ma gi n g pr ot oc ol, t hat M RI ca n be us e d t o hel p deter mi ne eli gi bilit y; h o we ver, a n ot her M RI m ust be perf or me d per t he i ma gi n g pr ot oc ol, a n d m ust 
occ ur as cl os e t o, a n d pri or t o, t he bas eli ne visit, after all ot her eli gi bilit y criteria ha ve bee n c o nfir me d.  
o  
W ee k 2 4 a n d  wee k  4 8 v M RI : the pr ot oc ol wi n d o w  f or v M RI  at wee k  2 4 a n d wee k  4 8 is 1 4  da ys  bef ore  a n d u p t o 1 4 da ys  after t he cli nic visit.  If 
partici pa nt  is ter mi nati n g earl y at 3 6  wee k  or after,  o btai n v M RI.  If M RI is perf or me d o n t he sa me da y as a l u m bar p u nct ure at wee k  4 8 , t he v M RI 
m ust be c o n d ucte d bef ore t he l u m bar p u nct ure. Ot her wis e, at least a 3 -da y wi n d o w bet wee n v M RI a n d t he l u m bar p u nct ure is re q uire d.  
1 2  
It is a ntici pate d t hat l u m bar p u nct ure wil l be perf or me d o n a n esti mate d 1 0 0  st u d y partici pa nts as part of a s u b-st ud y  (s e parate i nf or me d c o nse nt re q uire d). 
1 3  
O nl y  f or t he C S F  s u b-st u d y. Visit  wi n d o ws  f or C S F  are: u p  t o 1 4  da ys  pri or t o first d os e of st u d y  me dicati o n a n d  u p  t o 1 4 da ys  pri or  t o wee k s 2 4 a n d 4 8.  If a  
partici pa nt  i n t he C S F  s u b-st u d y is ter mi nati n g earl y, t he y d o  n ot  nee d t o u n der g o  l u m bar p u nct ure.  
1 4  
P ost l u m bar p u nct ure s afet y f oll o w u p tele p h o ne call m ust occ ur 1 t o 3 da ys after t he l u m bar p u nct ure is perf or me d.  
1 5  
First d os e of st u d y me dicati o n will be gi ve n i n t he cli nic at t he bas eli ne cli nic visit after c o m pleti o n of t he baseli ne visit pr oce d ures.  
1 6  
Partici pa nts will recei ve a p h o ne call d uri n g Wee k 2 fr o m site st u d y pers o n nel i n or der t o ass ess st u d y dr u g t olera bilit y. If  t olera ble, t he n t he partici pa nt will 
be i nstr ucte d t o pr ocee d wit h d os e es calati o n .  
1 7  
Treat me nt bli n di n g q uesti o n naire t o be a d mi ni stere d t o site PI a n d R aters. 
 
P P D
P P D
P P D
P P D

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
 
Pa ge 8 8  of 9 6  
 
 
 
 A me n d me nt 5, Versi o n 6. 0 d d. 1 2 Se p 2 0 2 0  
 
 
 
 
 
T a ble 3 : 
Sc he d ule of Assess me nts a n d E ve nts –  O pe n -L a bel E xte nsi o n P h ase  
Visit N u m ber  
1  
2  
3  
4  
5  
6  
7  
8  
9  
1 0  
 
St u d y Visit Ti m e p oi nt  
B as eli ne 1  
A b bre v -
iate d 
Dr u g 
Dis pe ns at
i o n Visit2  
E xt  
W ee k 2  
( +/- 7 da ys)  
E xt  
W ee k  4  
( +/- 7 da ys)  
E xt 
Wee k 8
3  
( +/- 7 da ys)  
E xt  
W ee k 1 2  
( +/- 7 da ys)  
E xt  
W ee k 2 4  
( +/- 7 da ys)  
E xt  
W ee k 3 6  
( +/- 7 da ys)  
E xt  
W ee k 4 8 
or E arl y 
T er m 
( +/- 7 da ys)  
W ee k 2 
P ost last 
d os e  
( +/- 7 da ys)  
U ns c he d -
ule d 
Visit 4  
( +/- 7 da ys)  
I nf or me d C o ns e nt  
X  
X  
 
 
 
 
 
 
 
 
 
M e dical Hist or y  
X  
 
 
 
 
 
 
 
 
 
 
A d vers e E ve nt Assess me nt  
X  
X  
X  
X  
X 3  
X  
X  
X  
X  
X  
X  
T ele p h o ne C hec k -i n5  
I n cl u d es A E ass ess m e nt a n d c o n c o mit a nt 
m e di c ati o n r e vi e w  
 
 
X  
 
X 3  
 
 
 
 
 
 
La b orat or y Ass ess me nts 6 
X  
 
 
X  
X 3  
X  
X  
X  
X  
 
 
Uri nal ysis  
X  
 
 
 
 
 
X  
 
X  
 
 
P h ysical E xa m  
X  
 
 
 
 
 
 
 
X  
 
 
P h ysical M eas ure me nt - Wei g ht  
X  
 
 
 
 
 
X  
 
X  
 
 
Vital Si g ns  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
1 2 -Lea d E C G  
X  
 
 
 
 
X  
X  
 
X  
 
 
C o nc o mita nt M e dicati o n R e vie w  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
S hee ha n S uici dalit y Trac ki n g 
Scale ( S -S T S)  
X  
X  
 
X  
 
X  
X  
X  
X  
X  
 
Dis pe ns e St u d y Dr u g  
X  
X  
 
X  
 
X  
X  
X  
 
 
 
V ol u metric M RI 7 
X  
 
 
 
 
 
 
 
X  
 
 
A D A S -C o g 1 1  
X  
 
 
 
 
 
X  
 
X  
 
 
C D R -S O B  
X  
 
 
 
 
 
X  
 
X  
 
 
St u d y  Dr u g Acc o u nta bilit y  
 
 
 
X  
 
X  
X  
X  
X  
 
 
Bl o o d C ollecti o n f or Bi o mar ker 
B a n ki n g  
 
 
 
 
 
 
 
X  
 
 
X  
 
 
Craft St or y 2 1 R ecall  
X  
 
 
 
 
 
X  
 
X  
 
 
Letter & C ate g or y Fl ue nc y  
X  
 
 
 
 
 
X  
 
X  
 
 
N u m ber S pa n T est  
X  
 
 
 
 
 
X  
 
X  
 
 
M o C A  
X  
 
 
 
 
 
X  
 
X  
 
 
1.  
B as eli ne visit f or t he E xte nsi o n P has e is o nl y re q uire d if t here is a n e xte n de d brea k ( ≥4 wee ks) i n d osi n g bet wee n t he Ra n d o m izati o n a n d E xte nsi o n P has es. 
2.  
 F or partici pa nts w h o will ha ve bee n off of t he st u d y dr u g f or less t ha n or e q ual t o 4 wee ks, t he s u bject s h o ul d c o me i nt o t he  i n vesti gati ve site f or a n 
A b bre viate d Dr u g Dis pe ns ati o n Visit (als o “ A b bre viate d O L E B as eli ne Visit”), at w hic h ti me a n y maj or me d ical or me dicati o ns c ha n ges will be re vie we d 
pri or t o dis pe nsi n g ril uz ole. I n t his cas e, m ost pr oce d ures fr o m t he Wee k 4 8 visit will als o s er ve as t he O pe n -La bel E xte nsi o n P has e  B as eli ne visit  

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
 
Pa ge 8 9  of 9 6  
 
 
 
 A me n d me nt 5, Versi o n 6. 0 d d. 1 2 Se p 2 0 2 0  
 
 
 
 
 
3.  
E xte nsi o n Wee k 8 is pri maril y t o c ollect Li ver F u ncti o n tests. If a partici pa nt prefers n ot t o c o me i nt o t he office, t hes e ca n be c ollecte d at a l ocal la b orat or y, 
wit h a tele p h o ne call c o nfir mi n g t hes e were c ollecte d as well as a re vie w of c o nc o mita nt me dicati o ns a n d a n ass ess me nt of a n y  a d vers e e ve nts. If t he 
partici pa nt c o mes i nt o t he ce nter, a n assess me nt of a d vers e e ve nts a n d Li ver f u ncti o n tests will be c o m plete d. Alt h o u g h all ot her vi sits ca n be c o n d ucte d 
re m otel y as nee de d d ue t o C O VI D-1 9 restricti o ns, u n der re g ular circ u msta nces visits are t o be c o m plete d i n -pe rs o n. See Pr ot oc ol Secti o n 8. 1. 1 2, O pe n -
La bel E xte nsi o n P has e , f or f urt her details a n d re q uire me nts re gar di n g re m ote visit c o m pleti o n d ue t o C O VI D-1 9.  
4.  
T he f oll o wi n g m ust be c ol lecte d at a n y u ns c he d ule d visit: vital si g ns, pri or a n d c o nc o mita nt me dicati o ns, a d vers e e ve nts, a n d pr ot oc ol de viati o ns. All ot her 
u ns c he d ule d visit pr oce d ures are s u bject t o PI dis creti o n or re q uest fr o m t he M e dical M o nit or.  
5.  
T ele p h o ne calls t o s u bjects w ill be ma de bet wee n visits d uri n g E xte nsi o n P has e ( Wee ks 2 a n d 8) t o m o nit or s u bject c o n diti o n, re vie w c o nc o mita nt 
me dicati o ns a n d ass ess a n y a d vers e e ve nts.  
6.  
Cli nical Safet y La b orat or y T ests will be perf or me d b y a C e ntral La b orat or y. Ass ess me nt i ncl u des t h e f oll o wi n g: He mat ol o g y ( he m o gl o bi n, he mat ocrit, 
platelets, R B C, W B C, differe ntial c o u nt, a n d a bs ol ute ne utr o p hil c o u nt), C he mistr y (s o di u m, p otassi u m, c hl ori de, calci u m, A L T , A S T, L D H, al kali ne 
p h os p hatas e, G G T, p h os p h or us, bicar b o nate, C P K, t otal pr otei n , al b u mi n, i n direct bilir u bi n, direct bilir u bi n, t otal bilir u bi n, gl u c os e, creati ni ne, B U N, uric 
aci d, f olate).  
7.  
V ol u metric M RI is n ot re q uire d if t he partici pa nt’s D o u ble -Bli n d Wee k 4 8 M RI s ca n occ urre d less t ha n t ha n 3 m o nt hs pri or t o t heir j oi ni n g t he O p e n-La bel 
E xte nsi o n P has e.  
 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
 
Pa ge 9 0  of 9 6  
 
 
 
 A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
1 8. 2  
A P P E N DI X II  - NI A/ A A G UI D E LI N E S  
Criteri a f o r all -c a use de me nti a: C or e cli nic al crit eri a  
1.  I nterfere wit h t he a bilit y t o f u ncti o n at w ork or at us ual acti vities ; a n d 
2.  Re prese nt a d ecli ne fr o m pre vi o us le vels of f u ncti o ni n g a n d perf or mi n g; a n d  
3.  Are n ot e x plai ne d b y deliri u m or maj or ps yc hiatric dis or der;  
4.  C o g niti ve i m pair me nt is detecte d a n d dia g n ose d t hr o u g h a c o m bi nati o n of ( 1) 
hist or y -ta ki n g fr o m t h e patie nt a n d a k n o wl e d ge a ble i nf or ma nt a n d ( 2) a n 
o bjecti ve c o g niti v e assess me nt, eit h er a “ be dsi de ” m e ntal st at us e x a mi n ati o n or 
ne ur o ps yc h ol o gic al testi n g. Ne ur o ps yc h ol o gi cal testi n g s h o ul d b e perf or me d 
w he n t he r o uti ne hist or y a n d b e dsi de me ntal stat us e x a mi nati o n c a n n ot pr o vi de a 
c o nfi de nt dia g n osis.  
5.  T he c o g niti ve or b e ha vi oral i m p air m e nt i n v ol ves a mi ni m u m of t w o of t he 
f oll o wi n g d o mai ns: 
a. I m paire d a bilit y t o ac q uire a n d re me m ber ne w i nf or mati o n – – s y m pt o ms 
i ncl u de: re p etiti ve q uesti o ns or c o n versati o ns, 
mis placi n g pers o nal 
bel o n gi n gs, f or getti n g e ve nts or a p p oi nt m e nts, getti n g l ost o n a fa miliar 
r o ute. 
b.  I m paire d reas o ni n g a n d ha n dli n g of c o m ple x t as ks, p o or j u d g me nt– –
sy m pt o ms i ncl u de: p o or u n derst a n di n g of safet y ris ks, i na bilit y t o ma na g e 
fi na nces, p o or decisi o n-m a ki n g a bilit y, a n d i na bilit y  t o pla n c o m ple x or 
se q ue ntial acti vities. 
c. I m paire d vis u os pati al a biliti es– – s y m pt o ms i n cl u de: i na bilit y t o rec o g nize 
faces or c o m mo n o bjects or t o fi n d o bj ects i n dir ect vie w d es pite g o o d 
ac uit y, i na bilit y t o o perate si m ple i m ple me nts, or orie nt cl ot hi n g t o t he 
b o d y.  
d.  I m paire d la n g ua g e f u ncti o ns (s pea ki n g, r ea di n g, writi n g)– – s y m pt o ms 
i ncl u de: diffic ult y t hi n ki n g of c o m m o n w or ds w hil e s pea ki n g, hesitati o ns; 
s peec h, s pelli n g, a n d writi n g err ors. 
e. C ha n ges i n pers o nalit y, b e ha vi or, or c o m p ort me nt – – s y m pt o ms i ncl u d e: 
u nc haracteristic 
m o o d fl uct uati o ns 
s uc h 
as 
a gitati o n, i m pair e d 
m oti vati o n, i niti ati v e, a pat h y, l o ss of dri ve, s ocial wit h dra wal, decr ease d 
i nterest i n pre vi o us acti vities, l oss of e m pat h y, c o m p ulsi ve or o bsessi ve 
be ha vi ors, a n d s oci all y  u n acce pta bl e be ha vi ors.  
 
 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
 
Pa ge 9 1  of 9 6  
 
 
 
 A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
A.  I nsi di o us o nset. S y m pt o ms ha ve a gra d ual o nset o ver m o nt hs t o years, n ot 
s u d de n o ver h o urs or da ys; 
B.  Clear -c ut hist or y of w orse ni n g of c o g niti o n b y re p ort or o bser vati o n; a n d  
C.  T he i nitial a n d m ost pr o mi ne nt c o g niti ve deficits are e vi de nt o n hist or y a n d 
e xa mi n ati o n i n o ne of t h e f oll o wi n g c ate g ories:  
a. A m nestic prese ntati o n: It is t h e m ost c o m m o n s y n dr o mic prese ntati o n  of 
A D de me ntia. T he d eficits s h o ul d i n cl u de i m p air m e nt i n lear ni n g a n d 
recall of rece ntl y l ear ne d i nf or mati o n. T here s h o ul d als o be e vi de nce of 
c o g niti v e d ysf u ncti o n i n at le ast o ne ot her c o g niti ve d o mai n, as defi n e d 
i n a b o ve secti o n ( Criteria f or all-ca use de me ntia: C or e cli nical criteria).  
b.  N o na m nestic pr ese ntati o ns:  
•  La n g ua ge prese ntati o n: T he m ost pr o mi ne nt d eficits are i n w or d -
fi n di n g, b ut defi cits i n ot h er c o g niti ve d o mai ns s h o ul d be prese nt. 
•  Vis u os patial prese nt ati o n: T he m ost pr o mi n e nt deficits are i n 
s patial c o g niti o n, i ncl u di n g o bj ect a g n osia, i m paire d f ace 
rec o g niti o n, si m ulta n a g n osia, a n d ale xia. 
Deficits i n ot h er 
c o g niti v e d o mai ns s h o ul d be prese nt.  
•  E xec uti ve d ysf u ncti o n: T he m ost pr o mi n e nt deficits are i m paire d 
reas o ni n g, j u d g me nt, a n d pr o ble m s ol vi n g. Defi cits i n ot her 
c o g niti v e d o mai ns s h o ul d be prese nt.  
D.  T he dia g n osis of pr o ba bl e A D de me ntia s h o ul d n ot be a p plie d w he n t her e is 
e vi de nc e of : (a) s u bsta ntial c o nc o mita nt c ere br o vas c ular disease, d efi ne d b y a 
hist or y of a str o ke te m p or all y relat e d t o t he o nset or w orse ni n g of c o g niti ve 
i m pair me nt; or t he pr ese nce of m ulti ple or e xte nsi ve i nfarcts or se vere w hite 
matt er h y peri nte nsit y b ur de n; or ( b) c or e feat ures of De me nti a wit h Le w y b o di es 
ot her t ha n de me ntia itself; or ( c) pr o mi ne nt f eat ures of be ha vi oral v aria nt 
fr o nt ote m p or al de me ntia; or ( d) pr o mi ne nt feat ures of se ma nti c vari a nt pri mar y 
pr o gressi ve a p hasia or n o nfl ue nt/a gr a m matic v aria nt pri m ar y pr o gressi ve 
a p hasia; or (e) e vi d e nce f or a n ot h er c o nc urre nt, a cti v e ne ur ol o gic al diseas e, or a 
n o n -ne ur ol o gic al m e dic al c o m or bi dit y or use of m e dicati o n t h at c o ul d h a ve a 
s u bsta ntial effect o n c o g niti o n. 
Pr o b a ble A D de me nti a: C ore cli nic al crite ri a  
Meets crit eri a f o r de me nti a o utli ne d a b o ve, a n d i n a d diti o n, h as t he f oll o wi n g 
c h ar acterist ics:  
A.  I nsi di o us o nset. S y m pt o ms ha v e a gr a d ual o nset o ver m o nt hs t o y ears, n ot 
s u d de n o ver h o urs or da ys; 

 
 
 
C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
 
Pa ge 9 2  of 9 6  
 
 
 
 A me n d me nt 5, Versi o n 6. 0 d d. 1 2 S E P 2 0 2 0  
 
 
 
 
 
B.  Clear -c ut hist or y of w orse ni n g of c o g niti o n b y re p ort or o bser vati o n; a n d  
 
C.  T he i nitial a n d m ost pr o mi ne nt c o g niti ve deficits are e vi de nt o n hist or y a n d 
e xa mi n ati o n i n o ne of t h e f oll o wi n g c ate g ories:  
 
a. A m nestic prese nt ati o n: It is t he m ost c o m m o n s y n dr o mic prese nt ati o n 
of A D de me ntia. T he deficits s h o ul d i ncl u d e i m p air m e nt i n l ear ni n g a n d 
recall of r ece ntl y lear n e d i nf or mati o n. T h ere s h o ul d als o be e vi de nc e of 
c o g niti v e d ysf u ncti o n i n at le ast o ne ot her c o g niti ve d o mai n, as defi ne d 
i n a b o ve secti o n ( Criteria f or all-ca use de me nt i a: C or e cli nic al crit eria). 
 
b.  N o na m nestic pr ese ntati o n s: 
 
•  La n g ua ge pr ese ntati o n: T he m ost pr o mi ne nt d eficits are i n 
w or d -fi n di n g, b ut d eficits i n ot h er c o g nitiv e d o m ai ns s h o ul d 
be prese nt.  
 
•  Vis u os patial prese ntati o n: T he m ost pr o mi n e nt deficits are i n 
s patial c o g niti o n, i ncl u di n g o bje ct a g n osi a, i m p aire d face  
rec o g niti o n, si m ulta na g n osia, a n d al e xia. Deficits i n ot her 
c o g nitiv e d o mai ns s h o ul d be prese nt.  
 
•  E xec uti ve d ysf u ncti o n: T he 
m ost pr o mi ne nt d eficits are 
i m pair e d reas o ni n g, j u d g me nt, a n d pr o ble m s ol vi n g. Deficits 
i n ot her c o g niti v e d o mai ns s h o ul d be prese nt.  
 
D.  T he di a g n osis of pr o ba bl e A D de me ntia s h o ul d n ot be a p plie d w he n t here is 
e vi de nc e of: (a) s u bsta nti al c o nc o mit a nt c ere br o vasc ular disease, defi ne d b y a 
hist or y of a str o ke te m p or all y rel ate d t o t he o nset or w orse ni n g of c o g niti ve 
i m pair me nt; or t he pr ese nce of m ulti ple or e xte nsi v e i nfarcts or se vere w hit e 
matt er h y peri nt e nsit y b ur de n; or ( b) c or e feat ur es of De me ntia wit h Le w y 
b o dies ot her t ha n d e me ntia itself; or ( c) pr o mi ne nt f eat ures of be ha vi oral vari a nt 
fr o nt ote m p or al d e me ntia; or ( d) pr o mi ne nt feat ures of se ma ntic v aria nt pri mar y 
pr o gressi ve a p hasi a or n o nfl ue nt/a gra m matic vari a nt pri mar y p r o gr essi ve 
a p hasia; or (e) e vi de nc e f or a n ot her c o nc urre nt, acti v e ne ur ol o gic al dise ase, or 
a n o n-ne ur ol o gic al me dical c o m or bi dit y or use of me dicati o n t hat c o ul d ha ve a 
s u bsta ntial effect o n c o g niti o n. 

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18.3 
APPENDIX III – CYP INHIBITORS AND INDUCERS OF INTEREST 
 
CYP1A2 Potent and Moderate Inhibitors 
Amiodarone 
Artemisinin 
Atazanavir 
Cimetidine 
Ciprofloxacin 
Efavirenz 
Enoxacin 
Fluoroquinolones 
Furafylline 
Interferon 
Methoxsalen 
Mexiletine 
Mibefradil 
Tacrine 
Thiabendazole 
Ticlopidine 
Vemurafenib 
Zileuton 
 
CYP1A2 Potent and Moderate Inducers 
Barbiturates 
Beta-naphthoflavone 
Carbamazepine 
Insulin 
Methylcholanthrene 
Modafinil 
Nafcillin 
Omeprazole 
Primidone 
Rifampin 
 
 
Sensitive and moderately sensitive substrates of CYP2B6, CYP2C8, CYP2C9, and 
CYP2C19: 
Enzyme 
Sensitive Substrates 
Moderately Sensitive Substrates 
CYP2B6 
bupropion 
efavirenz 
CYP2C8 
repaglinide 
montelukast, pioglitazone, rosiglitazone 
CYP2C9 
celecoxib 
glimepiride, phenytoin, tolbutamide, warfarin 
CYP2C19 
S-mephenytoin, omeprazole 
diazepam, lansoprazole, rabeprazole, voriconazole 
 

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18.4 
APPENDIX IV – CONSORT CHECKLIST & DIAGRAM (v2010) 
 
 
Section/Topic 
Item No 
Checklist item 
Reported 
on page 
Title and abstract 
 
1a 
Identification as a randomized trial in the title 
 
1b 
Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for 
abstracts) 
 
Introduction 
Background and 
objectives 
2a 
Scientific background and explanation of rationale 
 
2b 
Specific objectives or hypotheses 
 
Methods 
Trial design 
3a 
Description of trial design (such as parallel, factorial) including allocation ratio 
 
3b 
Important changes to methods after trial commencement (such as eligibility criteria), with reasons 
 
Participants 
4a 
Eligibility criteria for participants 
 
4b 
Settings and locations where the data were collected 
 
Interventions 
5 
The interventions for each group with sufficient details to allow replication, including how and when they were 
actually administered 
 
Outcomes 
6a 
Completely defined pre-specified primary and secondary outcome measures, including how and when they were 
assessed 
 
6b 
Any changes to trial outcomes after the trial commenced, with reasons 
 
Sample size 
7a 
How sample size was determined 
 
7b 
When applicable, explanation of any interim analyses and stopping guidelines 
 
Randomization: 
 
 
 
 Sequence 
generation 
8a 
Method used to generate the random allocation sequence 
 
8b 
Type of randomization; details of any restriction (such as blocking and block size) 
 
 Allocation 
concealment 
mechanism 
9 
Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), 
describing any steps taken to conceal the sequence until interventions were assigned 
 
 Implementation 
10 
Who generated the random allocation sequence, who enrolled participants, and who assigned participants to 
interventions 
 
Blinding 
11a 
If done, who was blinded after assignment to interventions (for example, participants, care providers, those 
assessing outcomes) and how 
 
11b 
If relevant, description of the similarity of interventions 
 

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Statistical methods 
12a 
Statistical methods used to compare groups for primary and secondary outcomes 
 
12b 
Methods for additional analyses, such as subgroup analyses and adjusted analyses 
 
Results 
Participant flow (a 
diagram is strongly 
recommended) 
13a 
For each group, the numbers of participants who were randomly assigned, received intended treatment, and were 
analyzed for the primary outcome 
 
13b 
For each group, losses and exclusions after randomization, together with reasons 
 
Recruitment 
14a 
Dates defining the periods of recruitment and follow-up 
 
14b 
Why the trial ended or was stopped 
 
baseline data 
15 
A table showing baseline demographic and clinical characteristics for each group 
 
Numbers analyzed 
16 
For each group, number of participants (denominator) included in each analysis and whether the analysis was by 
original assigned groups 
 
Outcomes and 
estimation 
17a 
For each primary and secondary outcome, results for each group, and the estimated effect size and its precision 
(such as 95% confidence interval) 
 
17b 
For binary outcomes, presentation of both absolute and relative effect sizes is recommended 
 
Ancillary analyses 
18 
Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-
specified from exploratory 
 
Harms 
19 
All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) 
 
Discussion 
Limitations 
20 
Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 
 
Generalizability 
21 
Generalizability (external validity, applicability) of the trial findings 
 
Interpretation 
22 
Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence 
 
Other information 
 
Registration 
23 
Registration number and name of trial registry 
 
Protocol 
24 
Where the full trial protocol can be accessed, if available 
 
Funding 
25 
Sources of funding and other support (such as supply of drugs), role of funders 
 
 
 

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CONSORT Flow Diagram (v2010) 
 
 
Consented (n=) 
Excluded (n= ) 
  Not meeting inclusion criteria 
(n= ) 
  Declined to participate (n= ) 
Analyzed (n= ) 
 Excluded from analysis (give reasons) 
(n= ) 
Lost to follow-up (give reasons) (n= ) 
Discontinued BHV-4157 (give reasons) 
(n= ) 
Allocated to BHV-4157 (n= ) 
 Received BHV-4157 (n= ) 
 Did not receive BHV-4157 (give 
reasons) (n= ) 
Lost to follow-up (give reasons) (n= ) 
Discontinued placebo (give reasons) (n= ) 
Allocated to placebo (n= ) 
 Received placebo (n= ) 
 Did not receive placebo (give reasons) 
(n= ) 
Analyzed (n= ) 
 Excluded from analysis (give reasons) 
(n= ) 
Allocation 
Analysis 
Follow-Up 
Randomized (n= ) 
Enrollment