Clinical trial NCT03605667
Conditions: Alzheimer Disease
Sponsor: Biohaven Pharmaceuticals, Inc.
Start date: 2018-07-31; Completion date: 2021-12-23
Enrollment: 350 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Preclinical models suggest that riluzole, the active metabolite of BHV-4157, may protect from AD-related pathology and cognitive dysfunction. Titrated dose of BHV-4157 to 280 mg, or placebo, were administered orally once daily. Duration of treatment is 48 weeks in double-blind phase. There is also a screening period of up to 42 days; and a 4-week post-treatment observation period. Eligible participants who completed the double-blind treatment phase had the opportunity to receive open-label troriluzole for up to 48 weeks in an open-label extension (OLE) phase.

Detailed description:

Arms: arm 1: troriluzole, 280 mg (2 x 140 mg) capsules, QD arm 2: matching 280 mg (2 x 140 mg) placebo capsules, QD
Interventions: intervention 1: troriluzole intervention 2: Placebo oral capsule
Intervention descriptions: intervention 1: Oral BHV-4157 will be given daily for up to 48 weeks intervention 2: Oral matching placebo will be given daily for up to 48 weeks

Protocol documents:
Prot_000.pdf: 
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  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 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  
 
 
 
 
 
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.  
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  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 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 
Page 8 of 96
 
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  
Pa ge 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  
 
 
 
 
 
 
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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C o nfi de nti al  
Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 1 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  
 
 
 
 
 
 
 
 
 
 
2 BS T U D Y S C H E M A TI C  
 
 
 
 
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C o nfi de nti al  
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Pa ge 1 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 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 
Page 59 of 96
 
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 
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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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Pr ot oc ol B H V 4 1 5 7 -2 0 3  
Pa ge 7 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  
 
 
 
 
 
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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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). 
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mice and humans with Alzheimer's disease. J Neurosci, 27(11), 2727-2733. 
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Craft, S., Newcomer, J., Kanne, S., Dagogo-Jack, S., Cryer, P., Sheline, Y., . . . Alderson, A. 
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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 
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Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). "Mini-mental state". A practical method 
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glutamate uptake in rat astrocyte cultures. Cell Mol Neurobiol, 24(1), 123-128.  
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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 

SAP_001.pdf: 
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: 3-December-2020


 
 
ADCS and Biohaven Pharmaceuticals 
 
Protocol BHV4157-203 
 
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 
Statistical Analysis Plan 
Version 3.0 
Date: 3 December 2020 
 


SIGNATURE PAGE 
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 
Sponsor: 
Biohaven Pharmaceuticals, Inc. 
Protocol Number: 
BHV4157-203 
Document Version/Date: 
V3.0 3 December 2020 
 
Author:                    
 
 
 
 UCSD, for ADCS. 
Signature:____________________________________ 
Date:________________________________________ 
Sponsor Approval 
By signing this document, I acknowledge that I have read the document and approve of the 
planned statistical analyses described herein. I agree that the planned statistical analyses are 
appropriate for this study, are in accordance with the study objectives, and are consistent with 
the statistical methodology described in the protocol, clinical development plan, and all 
applicable regulatory guidances and guidelines. 
I have discussed any questions I have regarding the contents of this document with the 
biostatistical author. 
I also understand that any subsequent changes to the planned statistical analyses, as described 
herein, may have a regulatory impact and/or result in timeline adjustments. All changes to the 
planned analyses will be described in the clinical study report (CSR). 
Sponsor Signatories: 
 
 
  
 Biohaven 
Pharmaceuticals 
Signature:____________________________________ 
Date:________________________________________ 
 
 
 Biohaven 
Pharmaceuticals  
Signature:____________________________________ 
Date:________________________________________ 
Project Director/ Principal Investigator Signatory 
Howard Feldman, MD, Director, 
Alzheimer’s Disease Cooperative 
Study 
Signature:____________________________________ 
Date:________________________________________ 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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TABLE OF CONTENTS 
SIGNATURE PAGE ......................................................................................................... 2 
TABLE OF CONTENTS .................................................................................................. 3 
LIST OF TABLES (NOT APPENDIX TABLES) ......................................................... 5 
REVISION HISTORY ..................................................................................................... 6 
ABBREVIATIONS ........................................................................................................... 8 
1 
INTRODUCTION AND OBJECTIVES OF ANALYSIS ...................................... 9 
1.1 
Introduction ........................................................................................................... 9 
1.2 
Objectives of Statistical Analysis ......................................................................... 9 
1.2.1 
Primary Objective ........................................................................................... 9 
1.2.2 
Secondary Objectives ...................................................................................... 9 
1.2.3 
Exploratory Objectives ................................................................................. 10 
2 
STUDY DESIGN ...................................................................................................... 10 
2.1 
Synopsis of Study Design .................................................................................... 10 
2.2 
Randomization Methodology ............................................................................. 11 
2.3 
Unblinding ........................................................................................................... 11 
2.4 
Efficacy, Safety, and Other Variables ............................................................... 12 
2.4.1 
Co-Primary Endpoints ................................................................................. 12 
2.4.2 
Secondary Endpoints .................................................................................... 12 
2.4.3 
Exploratory Endpoints ................................................................................. 13 
3 
PARTICIPANT POPULATIONS .......................................................................... 14 
3.1 
Population Definitions ........................................................................................ 14 
3.2 
Protocol Deviations ............................................................................................. 14 
4 
STATISTICAL METHODS ................................................................................... 15 
4.1 
Sample Size Justification and Power ................................................................. 15 
4.2 
Overall Study Power ........................................................................................... 15 
4.2.1 
 ............................................................................................ 16 
4.3 
General Statistical Methods and Data Handling ............................................. 17 
4.3.1 
General Methods ........................................................................................... 17 
4.3.1.1 
Estimands, Intercurrent Events, and Missing Data ............................. 17 
4.3.1.2 
Data Handling ......................................................................................... 18 
4.3.2 
Computing Environment .............................................................................. 19 
4.3.3 
Adjustments for Covariates and Stratification .......................................... 19 
4.3.4 
Multiple Comparisons/Multiplicity ............................................................. 20 
4.3.5 
Subpopulations .............................................................................................. 20 
4.3.6 
Withdrawals, Dropouts, and Loss to Follow-up ......................................... 20 
4.3.7 
Missing, Unused, and Spurious Data .......................................................... 20 
4.3.8 
Visit Windows ................................................................................................ 21 
4.4 
Analysis Periods and Study Phases ................................................................... 24 
4.5 
Planned Analyses ................................................................................................. 25 
4.5.1 
 ........................................................................ 25 
4.5.2 
Primary Analysis After Double-blind Randomization Phase and Final Analysis 
After OL Extension Phase ............................................................................ 26 
4.6 
Participant Disposition ....................................................................................... 27 
CCI
CCI


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4.7 
Demographic and Baseline Characteristics ...................................................... 28 
4.8 
Efficacy Evaluation ............................................................................................. 29 
4.8.1 
ADAS-Cog ...................................................................................................... 29 
4.8.2 
CDR Sum of Boxes ........................................................................................ 29 
4.8.3 
Analysis of the Co-Primary Outcome Measures ........................................ 29 
4.8.4 
Secondary Efficacy Endpoints ..................................................................... 32 
4.8.4.1 
Volumetric MRI ...................................................................................... 32 
4.8.4.2 
ADCS-ADL .............................................................................................. 33 
4.8.4.3 
NPI Total Scores ...................................................................................... 33 
4.8.4.4 
MMSE Scores .......................................................................................... 34 
4.8.5 
Exploratory Efficacy Endpoints .................................................................. 35 
4.8.5.1 
MoCA Scores ........................................................................................... 35 
4.8.5.2 
Composite Neuropsychological Test Battery Score ............................. 35 
4.8.5.3 
ADCOMS ................................................................................................. 35 
4.8.5.4 
CSF, Serum and Plasma Biomarker Panel ........................................... 36 
4.9 
Pharmacokinetic Evaluations ............................................................................ 36 
4.10 
Safety and Other Analyses ................................................................................. 36 
4.10.1 
Extent of Exposure and Compliance to Study Treatment ........................ 37 
4.10.2 
Adverse Events .............................................................................................. 38 
4.10.3 
Laboratory Data ............................................................................................ 39 
4.10.4 
Physical Examinations .................................................................................. 42 
4.10.5 
Vital Signs and Physical Measurements ..................................................... 42 
4.10.6 
Electrocardiogram ........................................................................................ 42 
4.10.7 
Concomitant Medications ............................................................................. 43 
4.10.8 
Sheehan-Suicidality Tracking Scale (S-STS) .............................................. 43 
4.10.9 
Subjects Identified for Narratives ............................................................... 44 
5 
REFERENCES ......................................................................................................... 45 
APPENDIX ...................................................................................................................... 47 
APPENDIX 1 - Study Plan and Procedures at Each Visit .......................................... 47 
APPENDIX 2 - Calculating the ADAS-Cog Total Score when there are missing data54 
APPENDIX 3 - Calculating the composite neuropsychological test battery score when there 
are missing data ................................................................................................... 56 
 
 


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List of Tables (not Appendix Tables) 
 
Table 1:  
Analysis Windows for Efficacy Parameters: ADAS-cog and CDR in the 48 
week Randomization Phase .....................................................................22 
Table 2:  
Analysis Windows for All Other Efficacy Parameters Including NPI, ADCS-
ADL, MMSE, MoCA, Volumetric MRI, CSF Biomarkers and Blood 
Biomarkers and NACC measures in the 48 week Randomization Phase.
....................................................................................................................22 
Table 3:  
Analysis Windows for Safety Parameters: Sheehan Suicidal Tracking, Vital 
Signs, Lab Assessments, PK  and ECG ..................................................23 
Table 4:  
Analysis Windows for All efficacy assessments and the Volumetric MRI, in 
the 48 week Extension Phase ...................................................................23 
Table 5:  
Analysis Windows for Safety Parameters: Sheehan Suicidal Tracking, Vital 
Signs, Lab Assessments, and ECG in the 48 week Extension Phase ...24 
 
 
 


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REVISION HISTORY 
Version 
Description of Change 
1.0 
Original version based on Protocol Version 3.0, Amendment 2 
2.0 
Revised version based on Protocol Version 6.0. Amendment 5.  Revisions 
primarily include changes related to the potential impact of COVID-19 
pandemic crisis and the addition of an open label extension phase to the 
study.  These changes include: 
• Details on the summarization of data obtained from the CRF 
collecting information on the impact of COVID-19 pandemic crisis on 
study visits  
• Modifications on the analysis plans due to COVID-19 pandemic crisis 
including an expanded analysis window for the Week 48 to allow for 
delayed in clinic assessments and clarification on the assessments to 
be included in the primary analysis 
• Additional sensitivity analyses included to assess the impact of 
COVID-19 pandemic crisis on the primary and secondary endpoints as 
well as key safety domains.  
• Revised proration method for calculating total score when some 
subscales are missing on ADAS-cog 
• Specification on list of subjects for safety narratives 
• Details on the summarization of data collected in the new Open Label 
Extension phase  
• Additional edits and clarification on wording 
3.0 
Revised version including the following revisions, clarifications and 
corrections.  
• Clarification of mITT definition that criteria need only be met by 
at least one of the co-primary endpoints for a subject to be 
included. 
• Updating Meddra version to 23.0 
• Clarified the handling of missing APOE e4 status in subgroup 
definition. 
• Revised determination of baseline for CDR assessments (Table 1) 


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• Clarified in section 4.3.3 that site is also included as a stratification 
factor in models. 
• Specified  baseline MMSE status subgroup analyses for the co-
primary and secondary endpoints.  
• Revised statistical analysis of MRI parameters to be first focused 
on assessments in the Week 48 analysis window. Specified 
additional analyses as exploratory. 
• Corrected references to sections in section 4.10.2 
• Clarified calculation of ADAS-cog score when some performance 
subtest scores are missing. 
• Eliminated Summary of AEs “Associated with Study Treatment” 
• Clarified handling of multiple lab assessments with in a window 
for by week summaries. 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
ALT 
Alanine aminotransferase  
AST 
Aspartate aminotransferase  
BQL 
Below limit of quantification 
BUN 
Blood urine nitrogen  
CI 
Confidence interval 
CPK 
Creatine phosphokinase  
CRF 
Case Report Form 
CSR 
Clinical study report 
DILI 
Drug induced liver injury 
ECG 
Electrocardiogram 
HDL 
High-density lipoprotein  
GGT 
Gamma-glutamyl transferase  
LDH 
Lactate dehydrogenase  
LDL 
Low-density lipoprotein  
mITT 
Modified Intent to Treat 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed model for repeated measures 
MMSE 
Mini Mental State Exam 
PID 
Participant Identification Number 
PK 
Pharmacokinetic 
PP 
Per protocol set 
PT 
Preferred term 
QD 
Quaque die (once daily) 
S-STS 
Sheehan-Suicidality Tracking Scale 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDS 
Sheehan Disability Scale 
SOC 
System organ class 
ULN 
Upper limit of normal  
WHO Drug 
World Health Organization drug reference dictionary 
 


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1 INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1 
Introduction 
This document presents the statistical analysis plan (SAP) for Biohaven Pharmaceuticals, 
Protocol BHV4157-203: 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. 
This SAP is based on Version 6.0, Amendment 5, of the T2 Protocol dated September 12, 2020. 
It contains the analysis details and methodology to answer the study objectives, including 
planned summary tables, by-subject listings, and figures, which will provide the basis for the 
results section of the clinical study report (CSR). Operational aspects related to collection and 
timing of planned clinical assessments are not repeated in this SAP unless relevant to the 
planned analyses.  
1.2 
Objectives of Statistical Analysis 
1.2.1 
Primary Objective 
• To evaluate the efficacy of BHV-4157 as measured by ADAS-Cog 11 and CDR-Sum of 
Boxes (co-primary endpoints) 
1.2.2 
Secondary Objectives 
• To evaluate the efficacy, safety and tolerability of BHV-4157 
o The efficacy of BHV-4157 will be assessed by the following measures: 
 Volumetric MRI (Quarc bilateral hippocampal volume)  
 Neuropsychiatric Inventory (NPI) 
 Alzheimer’s Disease Cooperative Study (ADCS)-Activities of Daily Living (ADCS-
ADL) 
 Mini-Mental State Examination (MMSE) 
• The safety and tolerability of BHV-4157 will be assessed by: 
o Mortality rates 
o Serious adverse event rates 
o Adverse events 
o Clinical safety laboratories 
o Vital signs 


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o Physical examinations 
o ECGs 
• Use of concomitant medications 
1.2.3 
Exploratory Objectives 
• To evaluate the efficacy of BHV-4157 as assessed by the Montreal Cognitive Assessment 
(MoCA) 
• To evaluate the efficacy of BHV-4157 on performance using the AD Composite Score 
(ADCOMS) 
• To evaluate volumetric MRI (bilateral lateral ventricles and whole brain volume) 
• To evaluate the efficacy of BHV-4157 on performance on a cognitive composite outcome 
computed using measures from the NACC Neuropsychological Test Battery [Craft Story 21 
Recall (Immediate & Delayed); Benson Complex Figure (Copy & Delayed Recall); 
Multilingual Naming Test; Letter & Category Fluency; Trail Making Test A & B; Number 
Span Forward and Backward]  
• To analyze the pharmacokinetics of BHV-4157 and riluzole in plasma 
• To evaluate treatment response by Apo E genotype 
• To assess CSF, serum and plasma biomarkers (Aß42, Aß42/40 ratio, total tau, p-tau-181, 
neurogranin, NfL, YKL-40, VILIP, SNAP-25, sTREM2, GFAP) at screening, week 24 and 
week 48 of the double-blind phase. CSF will be assessed in a subset of the study population 
(estimated n=50 active, n=50 placebo) 
Exploratory Open-Label Extension Phase objective is to evaluate the safety and tolerability of 
BHV-4157 as measured by the change in safety and tolerability measures including: (1) adverse 
events; (2) clinical laboratory tests; (3) vital signs; (4) physical examinations; (5) ECGs. 
Additional exploratory endpoint of evaluating long-term effects on clinical outcome measures. 
2 STUDY DESIGN 
2.1 
Synopsis of Study Design 
This is a phase 2 multi-center, randomized, double-blind, placebo-controlled, parallel group 
study in participants with mild to moderate Alzheimer’s disease. Approximately 336 
participants will be randomized 1:1 to one of two groups: 280 mg of BHV-4157 or placebo. 
Treatment duration is 48 weeks (12 months). There is a screening period of up to 42 days and a 
4-week post-treatment observation period. An interim analysis for futility will be conducted 
when a sentinel cohort consisting of the first 100 randomized participants has had opportunity to 
receive 24 weeks of study treatment or longer.  


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In addition, subjects who are completing or have completed the double-blind treatment phase 
may be offered the opportunity to enroll in an Open-Label Extension phase, in which subjects 
will receive open-label treatment with BHV-4157 for approximately 48 weeks. Enrollment into 
the Open-Label Extension phase for all subjects is contingent on the PI’s judgement that open-
label treatment offers an acceptable risk-benefit profile for each individual. All subjects who 
enter the Open-Label Extension phase will need to sign a new informed consent form. All 
subjects entering the Open-Label Extension phase will start with one capsule of BHV-4157 (140 
mg) per day and titrate to two capsules per day after week two (280 mg).  
The primary estimand is the effect relative to placebo of treatment as actually taken for 48 
weeks, in the protocol-defined modified intent-to-treat study population. 
Figure 1 illustrates the study schematic. 
Figure 1: Study Schematic 
 
2.2 
Randomization Methodology 
After completion of all screening evaluations, eligible participants will be randomized in a 1:1 
ratio to one of 2 groups: treatment with 280 mg BHV-4157 or placebo. A randomization 
schedule will be generated and incorporated into the Electronic Data Capture system (EDC) and 
the randomization ID will be assigned when the site randomizes the participant. A centralized 
eligibility confirmation procedure will be applied for each participant. A stratified permuted 
block randomization procedure will be used. The stratification factors will be Screening Visit 
MMSE [14 to 19; 20 to 24] and Site.  
2.3 
Unblinding 
Blinding is critical to the integrity of this clinical study. However, in the event of a medical 
emergency in which knowledge of the investigational product is essential for management of the 
participant, the blind for that participant may be broken after consultation with the ADCS 
Medical Core.  
Unblinding will be managed via the ADCS Unblinded Informatics team. As part of ongoing 
safety monitoring, an ADCS Unblinded Informatics team member and a bioanalytical scientist 
designee may be unblinded before data are more generally unblinded after the double-blinded 
phase of the study has been completed and the database has been locked.  
CCI


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In order to minimize unnecessary analysis of placebo blood PK samples, the bioanalytical 
scientist will be unblinded to treatment prior to unblinding for the primary endpoint.  Results of 
the blood concentration assay will be kept secure until database lock and unblinding  for the 
primary endpoint. 
The interim analysis will be conducted on a locked unblinded data set by the unblinded safety 
ADCS biostatistician, who is not involved in the final study analysis and who is firewalled from 
the study team (see section 4.4.1). As part of the interim analysis review, an independent data 
monitoring committee will be unblinded (see section 4.4.1 for additional detail). Except as noted 
above, other members of the BHV and ADCS research teams will remain blinded.  
Once all participants have completed the double-blind phase of the study, the database will be 
cleaned, locked, and the data will be analyzed in an unblinded manner.  
In cases of accidental unblinding, the Medical Monitor will be contacted and every attempt will 
be made to preserve the blind. 
2.4 
Efficacy, Safety, and Other Variables 
2.4.1 
Co-Primary Endpoints 
• There are two primary efficacy endpoints: 
o Within-participant change in ADAS-Cog 11 from baseline to week 48 of the double-
blind phase, compared between the treatment group and the placebo group 
o Within-participant change in CDR-Sum of Boxes from baseline to week 48 of the 
double-blind phase, compared between the treatment group and the placebo group 
2.4.2 
Secondary Endpoints 
• The efficacy of BHV-4157 will be assessed by the within-participant changes from baseline 
to week 48 of the double-blind phase, compared between the treatment group and the 
placebo group, on the following: 
o Volumetric MRI (Quarc bilateral hippocampal volume)  
o Neuropsychiatric Inventory (NPI) scores 
o Alzheimer’s Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores 
o Mini-Mental State Examination (MMSE) 
• Safety and tolerability as assessed by:  
o Serious adverse events (SAEs) including deaths 
o Adverse events (AEs) leading to discontinuation 


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o AEs 
o AEs judged to be related to study medication 
o Clinical safety labs 
o Vital signs 
o Physical examinations 
o ECGs 
o Use of concomitant medications 
2.4.3 
Exploratory Endpoints 
The following will be assessed during the double-blind phase : 
• Efficacy of BHV-4157 assessed by the within-participant changes from baseline to week 48, 
compared between the treatment group and the placebo group, on Montreal Cognitive 
Assessment (MoCA) scores 
• Efficacy of BHV-4157 assessed by the within-participant changes from baseline to week 48, 
compared between the treatment group and the placebo group, on performance using the AD 
Composite Score (ADCOMS), a composite outcome computed using 4 ADAS-Cog subscale 
items, 2 MMSE items, and the CDR Sum of Boxes (Wang et al., 2016) 
• Efficacy of BHV-4157 assessed by the within-participant changes from baseline to week 48, 
compared between the treatment group and the placebo group, on volumetric MRI (bilateral 
lateral ventricles and whole brain volume) 
• Efficacy of BHV-4157 assessed by the within-participant changes from baseline to week 48, 
compared between the treatment group and the placebo group, on a cognitive composite 
outcome computed using measures from the NACC Neuropsychological Test Battery [Craft 
Story 21 Recall (Immediate & Delayed); Benson Complex Figure (Copy & Delayed Recall); 
Multilingual Naming Test; Letter & Category Fluency; Trail Making Test A & B; Number 
Span Forward and Backward]  
• Pharmacokinetics of BHV-4157 and riluzole in plasma 
• Treatment response by APOE genotype  
• 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) 
• Open Label Exploratory Endpoints The change in safety and tolerability measures including: 
(1) adverse events; (2) clinical laboratory tests; (3) vital signs; (4) physical examinations; (5) 


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ECGs. Additional exploratory endpoint of evaluating long-term effects on clinical outcome 
measures. 
3  PARTICIPANT POPULATIONS 
3.1 
Population Definitions 
The following populations will be evaluated and used for presentation and analysis of the data: 
• Enrolled Participants: Participants who signed an informed consent form and were assigned 
a Participant Identification number (PID) 
• Randomized Participants: Enrolled participants who received a randomized treatment 
assignment. This group forms the ITT population  
• Treated Participants: Enrolled and randomized participants who received at least 1 dose of 
blinded study therapy (BHV 4157 or placebo). This will be the primary analysis population 
used for safety summaries  
•   The modified Intent-to-Treat (mITT) population will include all randomized participants 
who took at least one dose of study medication, who have a baseline assessment of at 
least one of the co-primary endpoints, and who have at least one efficacy  evaluation visit 
during the double-blind phase following baseline. This will be the primary analysis 
population used for the efficacy analyses. 
• Treated Participants in Open Label Extension: Participants who received at least 1 dose of 
open label study therapy (BHV 4157) in the Extension Phase. This will be the primary 
analysis population used for safety summaries focusing on the Extension Phase 
•   The modified Intent-to-Treat (mITT) population for the Extension Phase will include all 
randomized participants who took at least one dose of o p e n  l a b e l  study therapy 
(BHV4157) in the Extension Phase, who have a baseline assessment for the extension phase, 
and who have at least one efficacy evaluation during the extension phase. This will be the 
primary analysis population used for the efficacy summaries in the extension phase 
•   Treated Participants in All Troriluzole Exposure. Participants who received at least 1 dose 
of Troriluzole in either the Randomization Phase or the Extension Phase. This will be the 
primary analysis population used for safety summaries focusing on All Troriluzole exposure 
The primary population for all efficacy analyses is the mITT population (subjects included in 
treatment group as randomized). The Treated Participants will be used for analyses of safety 
endpoints (subject included in treatment group as received). 
3.2 
Protocol Deviations 
Any significant event that does not comply with the inclusion/exclusion criteria, study conduct 
(e.g., inadequate informed consent, unreported SAEs), or study procedures (e.g., use of 


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prohibited medications as defined by the protocol; improper breaking of the blind) will be 
documented as a protocol deviation.  
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. 
Classification of deviations from the protocol as minor or major will be decided on a case-by-
case basis by the medical monitor without knowledge of the treatment assigned and before 
the database lock (Data Blind Review). This file will include site, participant ID, deviation 
date, deviation type, status (major vs. minor), and a description of the protocol deviation. 
All protocol deviations will be presented in a tabulation and data listing. Both the summary 
tabulation and the listing will include information regarding whether the deviation was 
potentially related to the COVID-19 global pandemic. 
4 STATISTICAL METHODS 
4.1 
Sample Size Justification and Power 
4.2 
Overall Study Power 
Using approximately 336 randomized participants (with a 1:1 assignment approximately 168 per 
arm), this study has at least 80% power to reject the null hypothesis of no efficacy in favor of 
the alternative that BHV4157 is efficacious, given the assumption of a difference in the mean 
change from baseline to 12 months between the BHV-4157 arm and placebo arm of 2.64 points 
on the ADAS-Cog 11 and 0.95 points in CDR-SOB, and under a range of interim effect sizes 
which give 93.7% probability of proceeding at the interim analysis.  
This calculation assumes no more than a 26% dropout rate, which would leave 336 X 0.74 = 
248 subjects available at the final analysis, or 124 per arm. The calculation also assumes a 
standard deviation of 6 points on the change in ADAS-Cog 11 in each arm at both 6 months and 
12 months, and a standard deviation of 2.3 points on the change in in CDR-SOB at 12 months; 
in addition a correlation of 45% between 12-month-change on the co-primary ADAS-Cog11 
and CDR-SOB endpoints is assumed. These assumptions are supported by published 
retrospective data from historical ADCS studies14. The computations use a 2-sided 2-sample t-
test at 5% alpha to approximate power.  
Briefly, the statistical reasoning is as follows: 
1. P(pass overall) = P(pass final | pass interim) P(pass interim) ≥ P(pass final) P(pass 
interim) 
2. P(pass final) = P(pass final ADAS) P(pass final CDR | pass final ADAS)  
3. Numerical integration shows that P(pass final CDR | pass ADAS) is about 3% greater 
than P(pass final CDR), given the assumed 45% correlation between these endpoints. 
Hence, if P(pass interim) = 0.937, P(pass final ADAS) = 0.92, and P(pass final CDR) =0.90, 
then P(pass overall) ≥ 0.92 x (1.03 x 0.90) x 0.937 = 0.80.  


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With 124 subjects per arm, the unconditional power for the ADAS-COG endpoint is 92%, if the 
mean difference in change is 2.64 points with standard deviation of 6 points within each arm. At 
this sample size, the unconditional power for the CDR-SOB endpoint is 90%, if the mean 
difference is 0.95 points with standard deviation of 2.3 points within each arm. Hence, if the 
interim analysis has power 0.937 or greater to pass, the overall power is 80% or more following 
the statistical reasoning given above. 
For perspective, we note that the assumed difference of 2.64 points on ADAS-Cog is 68% of the 
decline observed in the placebo arm of 3.9 points in studies of mild to moderate AD14. The 
assumed difference of 0.95 points on CDR-SOB is 59% of the decline observed in the placebo 
arm of 1.6 points14. 
4.2.1 
 
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4.3 
General Statistical Methods and Data Handling 
4.3.1 
General Methods 
Overview 
The primary study hypothesis is that treatment with BHV-4157 will result in a reduction in total 
within-participant change from baseline on the ADAS-Cog 11 score and also on the CDR Sum 
of Boxes, relative to the placebo group at week 48 in the mITT population. The co-primary 
endpoints at the final analysis will be tested using a hierarchical gatekeeper strategy: if ADAS-
Cog 11 is significant at the 5% level, then CDR-SOB will also be tested at 5% significance 
level. If ADAS-cog is not significant at the 5% level, then CDR-SOB will not be included in the 
primary analysis, and will be presented for descriptive purposes only. The primary objective of 
the trial is met only when both co-primary endpoints are significant. If both co-primary 
endpoints are significant, the remainder of the secondary endpoints will be tested at overall 5% 
significance level using a Holm-Bonferroni step down test. If the co-primary endpoints are not 
significant, the secondary endpoints will be presented for descriptive purposes only. This will 
preserve alpha at 5% overall for all endpoints tested. Both the interim and final analysis will use 
a mixed effects repeated measures model. The secondary endpoints will compare mean changes 
from baseline to week 48 using a similar analysis strategy. 
4.3.1.1 
Estimands, Intercurrent Events, and Missing Data 
This discussion follows the framework as in Ratitch et al.10.  
Summary of primary estimand:  
The effect relative to placebo of treatment as actually taken for 48 weeks during the double-
blind phase, in the protocol-defined mITT study population. 
1. Objective  
An estimate of efficacy which would potentially be supportive of registration; thus similar 
to an ITT, “as taken” estimand. 
2. Estimand 
A. The population is the mITT population as defined by the protocol’s inclusion and 
exclusion criteria. 
B. Efficacy is measured by the change from baseline to 48 weeks in the co-primary 
endpoints (ADAS-cog and CDR-SOB) 
C. The treatment evaluated is the randomized treatment as it was assigned to study subjects. 
All types of intercurrent events are incorporated using a treatment policy strategy, which 
evaluates the randomized treatment as taken including missed or modified doses, drug 
discontinuation, and concurrent treatments. Study dropout including those potentially 
related to the COVID-19  pandemic (and corresponding discontinuation of assessments) 
will be handled by a hypothetical strategy to estimate what the outcome would have 
been at the designated time point if all subjects were continued to be assessed. Deaths 
are not expected during the 48 week double-blind phase follow-up in the enrolled subject 
population. 


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D. The mean change from baseline between treatment and control arm on the 2 endpoints 
will be compared at 48 weeks between treatment and placebo arms. A significant 
difference in both endpoints at familywise error rate of 5% will be required for success. 
3. Primary estimator and missing data. 
The estimator is a MMRM using all available assessments. Under the assumption that data 
are MAR conditional on model covariates and observed assessments, this analysis 
estimates the treatment as taken in the mITT study population.  
 
Note that MAR assumes that subjects will follow the same trajectory after dropping out of 
the study as while on the study, conditional on the model covariates. However, if subjects 
tend to preferentially drop out after discontinuation of study drug, their post-dropout 
trajectory (off treatment) may differ from their pre-dropout trajectory (on treatment). In 
this case the MAR assumption may not hold. A sensitivity analyses is proposed to assess 
this scenario. 
4. Sensitivity analyses and missing data.  
MMRM, using multiple imputation from the control arm to complete assessments missing 
after discontinuation of study drug. This analysis assumes subjects who discontinue 
medication and are no longer assessed immediately become similar to subjects who never 
took any medication, and so provides a lower bound on efficacy, again under the MAR 
assumption that the time of stopping study medication depends only on past history and 
covariates 
4.3.1.2 
Data Handling 
All output will be incorporated into Microsoft Excel or Word files, sorted and labeled according 
to the International Conference on Harmonization (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced by randomized treatment group and overall, unless otherwise 
specified.  
Categorical variables will be tabulated with counts and percentages. Continuous variables will 
be summarized with univariate statistics (e.g., n, mean, standard deviation (SD), median, 
minimum, and maximum). The minimum and maximum will be presented with the same 
precision as the data, the mean and percentiles will be presented with the precision of the data + 
1 decimal place, and the SD will be presented with the precision of the data + 2 decimal places.  
Unless otherwise specified, all statistical tests will be 2-sided with alpha = 0.05. Tests will be 
declared statistically significant if the calculated p-value is ≤ 0.05. P-values < 0.0001 will be 
presented as “<0.0001”. Otherwise, p-values will be presented to 4 decimal places.  
Change from baseline is calculated by subtracting the baseline value from the observed post-
baseline value at any subsequent visit. Baseline (specific to the randomized phase or to the 
open-label phase) will be defined as last available assessment on or before the 1st day the 
participant receives study medication for that phase.  


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Tabulations of the following endpoints will present the number of unique participants with an 
event: protocol deviations; non-study medications; AEs; and laboratory abnormalities. Thus, for 
these endpoints, multiple occurrences of the same event are counted only once per participant. 
Unique Participant ID’s will take the form “BHV4157-203-site#-participant#”. By-participant 
listings will display unique PID and “(Age/Sex/Race)” stacked together in the same column 
using the following conventions:  
• Age at informed consent will be displayed truncated to an integer  
• Sex will be displayed abbreviated as “F” for female and “M” for male  
• Race will be abbreviated as “A” for Asian”, “B” for Black or African American, “I” for 
American Indian or Alaska Native, “M” for multiple, “N” for Native Hawaiian or Other 
Pacific Islander, and “W” for White 
A footnote will describe race abbreviations, e.g., “Race: A = Asian, B = Black or African 
American, I = American Indian or Alaska Native, M = Multiple, N = Native Hawaiian or Other 
Pacific Islander, W = White”. Participants who report more than one race will be counted only 
once in the “Multiple” category. Missing age, sex, or race will be displayed as a single blank 
space.  
Note that “(Age/Sex/Race)” will not be displayed in listings of randomization scheme and 
codes, batch numbers, and demographics. 
4.3.2 
Computing Environment 
All statistical analyses will be performed using SAS statistical software (Version 9.4) or R 
(Version 4.0.0), as specified. Medical history and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA, Version 23.) Concomitant medications will be 
coded with WHO Drug (Global March 2019) using the WHODrug Insight tool. Laboratory 
abnormalities will be classified as clinically significant if they are coded as Grade 3 or 4 
according to the numeric laboratory test criteria in Common Technical Criteria for Adverse 
Events (CTCAE) Version 5.0 (2017). For laboratory tests not included in CTCAE Version 5.0, 
abnormalities will be coded according to Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events Corrected Version 2.1 (2017). 
4.3.3 
Adjustments for Covariates and Stratification 
The analysis of the primary endpoints and other efficacy endpoints will be analyzed by 
comparing the change in efficacy outcome at week 48 between treatment groups using a mixed 
model with repeated measures (MMRM). Fixed effects in the model are APOE status (e4 carrier 
vs e4 noncarrier), MMSE (mild vs moderate) status, site, baseline value of the endpoint, 
treatment group (active vs. placebo), visit, visit x baseline and visit x treatment group 
interaction. Visit is treated as a categorical variable (see section 4.2.8 for definition of visit 
windows to be use). Subject will be included as random effects in the model. Sites with only one 
subject will be pooled together. 


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A stratified permuted block randomization procedure will be used. The stratification factors will 
be Screening Visit MMSE [mild: 20 to 24; moderate: 14 to 19] and Site.  
4.3.4 
Multiple Comparisons/Multiplicity 
Type 1 errors will be controlled for the co-primary and multiple secondary efficacy endpoints 
by testing these endpoints with a gate-keeping procedure at a family wise two-sided alpha level 
of 0.05. The co-primary endpoints, ADAS-Cog 11 and CDR-SOB, will be tested, first testing 
the ADAS-cog and then, if significant, testing the CDR-SOB. The primary objective of the trial 
is met only when both co-primary endpoints are significant. If the co-primary endpoints are 
significant, then the key secondary efficacy endpoints will be tested using the Holm-Bonferroni 
step down procedure, at family-wise significance level 5%.  
If the tests of the primary endpoints are not significant, then the adjusted and unadjusted p-
values for the secondary endpoints will be presented only for descriptive purposes, and no 
conclusions will be drawn from these results. 
No attempt will be made to adjust for multiplicity when testing the exploratory endpoints. Any 
exploratory endpoints subjected to significance testing are evaluated at an unadjusted two-sided 
alpha level of 0.05 and are presented for descriptive purposes only.  
4.3.5 
Subpopulations 
The subgroups of interest for this study are: 
• Sex  
• APOE (e4 vs no or missing) 
• Mild vs moderate (mild AD:MMSE 20 to 24; moderate AD: MMSE 14 to 19) 
• Participation during Covid-19 (opportunity to complete randomization phase before March 
13, 2020 vs on or after March 13, 2020) 
Except where indicated otherwise, descriptive summaries will be provided for the co-primary 
endpoints for each subgroup. 
4.3.6 
Withdrawals, Dropouts, and Loss to Follow-up 
Participants who withdraw from the study will not be replaced.  
4.3.7 
Missing, Unused, and Spurious Data 
Unless otherwise noted, efficacy analyses will be based on observed data only. No missing data 
will be imputed. Imputation will be done for sensitivity analyses only. 
For efficacy analyses, partial or missing dates will not be imputed. The relative study days, 
where determined, will be calculated for full dates only.  


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If the start date/time of an AE is partially or completely missing, the date/time will be compared 
as far as possible with the date/time of the start of administration of study drug. The AE will be 
assumed to be treatment-emergent if it cannot be definitively shown that the AE did not occur or 
worsen during the treatment-emergent period (worst-case approach).  
The following general rules will be used: 
• If the start time of an AE is missing but the start date is complete, an AE will only be 
excluded as being treatment-emergent if the start date is before the date of study drug 
administration or if the stop date/time is before study drug administration.  
• If the start time and day are missing but the start month and year are complete, an AE will 
only be excluded as being treatment-emergent if the start month/year is before the 
month/year of study drug administration or if the stop date/time is before study drug 
administration.  
• If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment-emergent if start year is before the year of study drug 
administration or if the stop date/time is before study drug administration.  
• If the start date is completely missing, an AE will be considered treatment-emergent unless 
the stop date/time is before study drug administration. 
4.3.8 
Visit Windows 
The protocol-specified in-clinic visit windows are ± 7 days during the Randomization Phase, 
however, analysis windows will be continuous to include all data. Refer to Appendix 1 for 
details on the expected evaluation intervals for the details on the schedule of assessments during 
the Randomization and Extension Phases. The data portal contains a report where all visits and 
their acceptable windows will be projected at the baseline visit. The baseline visit for the 
randomization phase is expected to be the date of randomization and first dose of randomized 
treatment.  
 


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On-Treatment Analysis Windows 
Table 1:  
Analysis Windows for Efficacy Parameters: ADAS-cog and CDR in 
the 48 week Randomization Phase 
 
Evaluation 
Protocol-Specified Day 
Analysis-Specified Interval 
Randomization Phase 
 
 
Week 12 
Day 84 
Day 2-126 
Week 24 
Day 168 
Day 127-210 
Week 36 
Day 252 
Day 211-294 
Week 48 
Day 336 
Day 295-420 
 
 
 
Note: Baseline assesment will be defined as the last available assessment on or before first day of randomization 
phase study drug [For CDR the window for baseline assessment will be extended to include assessments up to and 
including Day 2 of study drug as one subject completed the CDR after starting study treatment. This assessment 
was felt to still be a valid baseline assessment due to the limited treatment at the time of assessment. The Week 12 
window will be adjusted accordingly to Day 3-126.]. Days based on days from first day of randomization phase 
study drug. 
 
Table 2:  
Analysis Windows for All Other Efficacy Parameters Including NPI, 
ADCS-ADL, MMSE, MoCA, Volumetric MRI, CSF Biomarkers and 
Blood Biomarkers and NACC measures in the 48 week 
Randomization Phase. 
 
Evaluation 
Protocol-Specified Day 
Analysis-Specified Interval 
Randomization Phase 
 
 
Week 24 
Day 168 
Day 2-252 
Week 48 
Day 336 
Day 253-420 
 
 
 
Note: Baseline assesment will be defined as the last available assessment on or before first day of randomization 
phase study drug. Days based on days from first day of randomization phase study drug. 
 
 
 
 


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Table 3:  
Analysis Windows for Safety Parameters: Sheehan Suicidal 
Tracking, Vital Signs, Lab Assessments, PK  and ECG 
 
Evaluation 
Protocol-Specified Day 
Analysis-Specified Interval 
Randomization Phase 
 
 
Week 4 
Day 28 
Day 2-42 
Week 8 
Day 56 
Day 43-70 
Week 12 
Day 84 
Day 71-98 
Week 16 
Day 112 
Day 99-126 
Week 20 
Day 140 
Day 127-154 
Week 24 
Day 168 
Day 155-182 
Week 28 
Day 196 
Day 183-210 
Week 32 
Day 224 
Day 211-238 
Week 36 
Day 252 
Day 239-266 
Week 40 
Day 280 
Day 267-294 
Week 44 
Day 308 
Day 295-322 
Week 48 
Day 336 
Day 323-420 
Note: Baseline assesment will be defined as the last available assessment on or before first day of randomization 
phase study drug. Days based on days from first day of randomization phase study drug. 
If a participant has more than one record within an analysis window, the latest record within the 
window will be used in the analysis.  
Table 4:  
Analysis Windows for All efficacy assessments and the Volumetric 
MRI, in the 48 week Extension Phase 
 
Evaluation 
Protocol-Specified Day 
Analysis-Specified Interval 
Extension Phase 
 
 
Week 24 
Day 168 
Day 2-252 
Week 48 
Day 336 
Day 253-420 
Note: Baseline assesment will be defined as the last available assessment on or before first day of extension phase 
study drug as long as it is within 28 days of the first day of extension phase medication. Days based on days from 
first day of extension phase study drug. 
 
 
 


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Table 5:  
Analysis Windows for Safety Parameters: Sheehan Suicidal 
Tracking, Vital Signs, Lab Assessments, and ECG in the 48 week 
Extension Phase 
 
Evaluation 
Protocol-Specified Day 
Analysis-Specified Interval 
Extension Phase 
 
 
Week 4 
Day 28 
Day 2-42 
Week 8 
Day 56 
Day 43-70 
Week 12 
Day 84 
Day 71-126 
Week 24 
Day 168 
Day 127-210 
Week 36 
Day 252 
Day 211-294 
Week 48 
Day 336 
Day 295-420 
Note: Baseline assesment will be defined as the last available assessment on or before first day of extension phase 
study drug as long as it is within 28 days of the first day of extension phase medication. Days based on days from 
first day of extension phase study drug. 
4.4 
Analysis Periods and Study Phases 
Analysis periods and study phases are defined as follows: 
• Screening Phase: will include all assessments on or before the first day of study drug.  
• On-Treatment in Randomization Phase (Safety Assessments): except where indicated, "on-
treatment" in the Randomization Phase will include all assessments after first day of study 
drug and up to the first day of dosing of the Open Label Extension Phase study drug (for 
subjects entering extension) or up to the last day of Randomization Phase study drug + 30 
days, whichever comes first. For AEs, “on-treatment” in the Randomization Phase will 
include first day of dosing of the Randomization Phase study drug up to the last day of 
Randomization Phase study drug + 30 days for those not going into the Extension Phase or 
up to the day before the first day of dosing of Extension Phase medication for those subjects 
who do. 
• On-Treatment in Randomization Phase (Efficacy Assessments): except where indicated, 
"on-treatment" in the Randomization Phase will include all assessments after first day of 
study drug and up to the first day of dosing of the Open Label Extension Phase study drug 
(for subjects entering extension) or up to the last day of Randomization Phase study drug + 3 
days, whichever comes first. 
• On-Treatment in Open Label Extension Phase (Safety Assessments): except where 
indicated, "on-treatment" in the Open Label Extension Phase will include all assessments 
after first day of open label study drug and up to the last day of Open Label Extension Phase 
study drug + 30 days. For AEs, “on-treatment” in the Open Label Extension Phase will 
include first day of dosing of the Open Label Extension Phase study drug up to the last day 
of Open Label Extension Phase study drug + 30 days. 
• On-Treatment in Open Label Extension Phase (Efficacy Assessments): will include all 
efficacy assessments after the first day of dosing of OL Extension Phase study drug to the 


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last day of study drug +3 days. Baseline for the extension will be the last available 
assessment on or before the first day of  dosing of OL Extension Phase medication. 
• On-Treatment in Study (Safety Assessments): except where indicated, "on-treatment" for 
any Troriluzole treatment (combined Randomization Phase and Extension Phase) will 
include all assessments  after first day of Troriluzole and up to the last day of Troriluzole 
treatment + 30 days. For AE summaries for any Troriluzole treatment (combined 
Randomization Phase and Extension Phase), On-treatment (Troriluzole) will include AEs 
with start date on or after first day of dosing with Troriluzole up to last day of dosing with 
Troriluzole + 30 days. 
4.5 
Planned Analyses 
DSMB analyses of safety data will be performed quarterly throughout the trial period by an 
unblinded safety ADCS biostatistician who is not involved in the final study analysis. The 
quarterly analyses include an Executive Summary and a Study Summary (extracted from the 
protocol). These summaries are followed by tables and figures detailing elements of the current 
data base related to safety, specifically: Screening and Enrollment, Enrollment by MMSE, 
Enrollment by Month, Enrollment by Site, Inclusion and Exclusion, Screen Failure by Inclusion 
Criteria, Screen Failure by Exclusion Criteria, Early Discontinuation, Protocol Deviations, 
Demographics and Baseline Outcomes, Vital Signs, Safety, Adverse Events with Onset Prior to 
Randomization, Adverse Events with Onset Following Randomization, Adverse Events by 
Severity, AE by relatedness, Adverse Events summarized by MedDRA SOC–PT, Serious 
Adverse Events, and Safety Labs. 
4.5.1 
 
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4.5.2 
Primary Analysis After Double-blind Randomization Phase and Final Analysis 
After OL Extension Phase 
The primary efficacy (including the primary, secondary and exploratory endpoints of the 
Randomization Phase) and safety analysis will be conducted after the last subject completes 
their Week 48 visit, or discontinues from the Randomization Phase.  The study will be 
unblinded and the primary analyses will include all data from the double-blind Randomization 
Phase of the study, but will not include summaries of efficacy and safety data accumulated from 
the Extension Phase. 
Interim looks at data from the Extension Phase may be performed after the completion and 
unblinding of the Randomization Phase, particularly for safety purposes.  
A final analysis of the Open Label Extension Phase data will be completed after the last subject 
completes their last study visit.  This will summarize for descriptive purposes all efficacy data 
collected in the open-label Extension Phase as well as all safety, laboratory, and other data 
collect though the entire study.  Change from baseline will be based on the Extension Phase 
Baseline, unless otherwise specified. 
Additional analyses may be conducted during the open label Extension Phase of the study to 
support regulatory and administrative requirements.  
 
CCI


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4.6 
 Participant Disposition 
A summary of participant disposition will be tabulated for all participants by treatment group 
and overall, including: 
• Number of participants enrolled and signed informed consent form 
• Number of enrolled participants excluded from the study prior to randomization and reason 
for exclusion 
• Number of participants randomized  
• Number of participants treated in Randomization Phase 
• Number of mITT participants in Randomization Phase  
• Number of participants who completed the Randomization Phase 
• Number of participants who prematurely withdrew from the Randomization Phase and 
reasons for withdrawal 
• Number of subjects who entered the Extension Phase 
• Number of subjects treated in Extension Phase 
• Number of mITT subjects in Extension Phase  
• Number of subjects who completed the Extension Phase 
• Number of subjects who withdrew from the Extension Phase and reasons for withdrawal 
A special form will collect  information on whether a visit was impacted by the COVID-19 
pandemic crisis and will be used for all visits on or after March 1, 2020.  This form will collect 
the specific impact on the visit (i.e. missed visit, in-person visit not all assessments completed, 
in-person visit occurring earlier or delayed, remote visit video, and remote visit telephone) as 
well as how COVID-19 impacted on a given visit (i.e. subject diagnosed/quarantined, site 
closure/restricted access, subject unwilling/unable to come to site, other). If the subject is 
terminating the study prematurely the CRF will also collect whether the reason was related to 
COVID-19 (yes or no). 
An additional summary will present the disposition of subjects whose discontinuation was 
indicated as being related to the COVID-19 pandemic crisis on the COVID-19 CRF. 
For the randomized subjects active during COVID-19, the impact of the COVID-19 pandemic 
crisis  on the study will be summarized by presenting (by treatment and overall):  


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• number and percentage of randomized subjects active in the double-blind phase during the 
pandemic crisis, as referenced by having at least one visit in the double-blind phase on after 
the March 13, 2020 National Emergency declaration 
• number and percentage of randomized subjects reporting (on the CRF) at least one impact 
on a given visit (missed visit, in-person visit not all assessments completed, in-person visit 
occurring earlier or delayed, remote visit video, and remote visit telephone) a subjected will 
be included in each category they reported in the period 
o Summarize at any time in double-blind phase 
o Summarize by week (analysis window) 
• number and percentage of randomized subjects reporting (on the CRF) how COVID-19 
impacted on a given visit (diagnosed/quarantined, site closure/restricted access, subject 
unwilling/unable to come to site, other) a subjected will be included in each category they 
reported in the period 
o Summarize at any time in double-blind phase 
o Summarize by study week (analysis window) 
• Time of first visit impacted by COVID-19 pandemic crisis (based on the first visit date 
indicated as impacted from the COVID-19 CRF) 
• Duration  of time in double-bind phase impacted by COVID-19 pandemic crisis (duration = 
date of last visit impacted – date of first visit impacted + 1) (based on the first visit date 
indicated as impacted from the COVID-19 CRF) 
A by-subject listing of study completion information for both the Randomization and Extension 
Phases, including the reason for withdrawal and impact due to COVID-19, if applicable, will be 
presented. 
A listing of all subjects with at least one visit impacted by COVID-19 pandemic crisis with the 
impact and how the impact was related to COVID-19. 
4.7 
Demographic and Baseline Characteristics 
Tabulations of demographic and baseline characteristics, including age, sex, racial group, 
smoking habits, level of education, disease and medical history, and current standard of care 
treatment, will be made for all treated participants. A separate set of tabulations will be made for 
participants enrolled but not randomized. Demographic information will be summarized by 
treatment group and for all treatment groups combined.  
In addition to all Treated subjects additional summaries will be provided for: 


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• Subjects completing or discontinuing the double-blind randomization phase before March 
13, 2020 (the reference date for the start of the COVID-19 pandemic based on the date  
National Emergency declared) 
• Subjects still active in the double-blind randomization phase on or after March 13, 2020 
Demographic and other baseline data will also be provided in by-participant data listings. 
4.8 
Efficacy Evaluation 
Unless otherwise noted, all efficacy analyses will be conducted using all available in-clinic 
assessments from the mITT population during the double blind phase. Remote assessments 
during the double blind phase will be included in sensitivity analyses. All efficacy data will be 
included in listings by participant, treatment group, visit and phase (as applicable).  
4.8.1 
ADAS-Cog 
The ADAS-Cog is a rater-administered scale with eight performance subtests: Word Recall; 
Commands; Constructional Praxis; Naming; Ideational Praxis; Orientation; Word Recognition; 
Remembering Word Recognition Test Instructions11. Three examiner ratings, Spoken Language, 
Language Comprehension, and Word Finding Difficulty, also are 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 (worst).  
Please refer to Appendix 2 regarding prorating subtest scores when there are partially missing 
data. 
4.8.2 
CDR Sum of Boxes 
The CDR sum of boxes is a numeric scale used to quantify the severity of symptoms of 
dementia and it assesses a participant's cognitive and functional performance in six areas: 
memory, orientation, judgment & problem solving, community affairs, home & hobbies, and 
personal care. Scores in each of these are combined to obtain a composite score ranging from 0 
(best) to 18 (worst). If any item is missing, the assessment is considered missing. 
The CDR sum of boxes will be assessed at visits conducted in clinic or via remote 
communication. Only in-clinic assessments will be considered in the primary analysis; 
sensitivity analysis will include similar analysis including remote assessments. 
4.8.3 
Analysis of the Co-Primary Outcome Measures 
The primary analyses use the within-participant change in ADAS-Cog 11 and in CDR-SOB as 
the outcome in two separate similar mixed effects repeated measures models, including all 
available in-clinic outcomes during the double blind phase in the mITT population. Fixed 
effects in the models are APOE status (e4 carrier vs e4 noncarrier), MMSE (mild vs. moderate) 
status, site, baseline ADAS-Cog or CDR-SOB score, respectively, treatment group (active vs 
placebo), visit, visit x baseline score interaction, and visit x treatment group interaction. Visit is 
treated as a categorical variable. Sites with only one subject will be pooled together.   


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Descriptive statistics showing the timing of the primary outcome assessment will be presented 
by treatment arm as well as break-outs by baseline characteristics (e.g. APOE status, 
Mild/Moderate status based on MMSE, age group, and sex).  
A random effect will be included for participant. The within-participant covariance will be 
unstructured. If the model does not converge, MMSE status will be removed from the model. If 
the model still does not converge, the following structures for the within-subject covariance will 
be fit, sequentially, until the structure is found that results in convergence of the model: Huynh-
Feldt, Toeplitz, Autoregressive (1), and Compound Symmetry. Error degrees of freedom will be 
calculated using the Kenward-Roger approximation if an unstructured covariance is used; 
otherwise, a sandwich estimator will be utilized to estimate the covariance structure and degrees 
of freedom will be calculated using the between-within method13. For the ADAS-Cog 11and 
CDR-SOB, each primary endpoint will be tested using model-adjusted least squares means at 
the week 48 visit. Point estimates, standard errors, two-sided 95% confidence intervals, and p-
values will be presented. 
The two co-primary endpoints will be tested for significance using a hierarchical gatekeeper 
strategy which preserves a 5% family-wise type I error rate. If a significant improvement in 
ADAS-Cog 11 is found with BHV-4157 relative to placebo at 5% level, then a similar analysis 
to the above will be conducted comparing CDR-SOB between the BHV-4157 and placebo arms. 
If a significant difference is found in CDR-SOB at 5% level, then both ADAS-Cog 11 and 
CDR-SOB are declared significant at 5% joint significance level, using this hierarchical 
gatekeeper analysis strategy. If there is no significant difference in ADAS-Cog 11, then CDR-
SOB cannot be found to have a significant difference. A significant difference on both co-
primary endpoints (at the 5% level) must be found in order to meet the primary trial objective. 
The following sensitivity analysis will be conducted to support the principal analysis, following 
the same methods as above.  
1. Imputation for missing data. All available in-clinic data will be used. Multiple 
imputations will be used to fill in any missing assessments. The imputation model will 
be a MMRM model. The parameters of the imputation model will use data from the 
placebo arm only - a jump to reference approach as described by Ayela, Lipkovich, 
Molenberghs & Mallinckrodt1 and Carpenter, Roger & Kenward2. This model will be 
used as the imputation model for both the treated arm and the placebo arm, The 
imputation model will follow that specified in the primary analysis plan, however 
incorporating the additional baseline covariates of age, ADAS-COG, CDR-SOB, ADCS-
ADL, and the time-dependent COVID indicator specified below. Proper imputation from 
this model will be used, following Rubin12 and Tsiatis16, in that the mth imputation is 
based on a new parameter βˆm, drawn from a N(βˆ,Σˆ) distribution, where βˆ and Σˆ are 
the maximum likelihood estimates from the imputation model. The augmented data 
(observed data, completed by the imputed data) will then be analyzed as specified for the 
primary analysis. This analysis will provide a lower bound on the estimated efficacy, as 
described in section 4.2.1.1.  
Inference will use the rules for multiple imputation as outlined in Rubin12. 20 
imputations will be used. This analyses will be implemented in PROC MI in SAS with 
the MONOTONE option using predictive mean matching (option REGPMM) with 


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K=20, or in a similar manner in R. The outcome variable will be imputed in a monotone 
sequential manner. 
2. Investigation of the impact of COVID-19 will be conducted by the following separate 
analyses:   
i) 
A fixed effect to indicate an assessment occurring after March 13 (during the 
COVID pandemic) will be added to the model (“COVID indicator”), as well as 
the interaction of the COVID indicator x time.  If the model with the interaction 
term fails to converge, the interaction term will be omitted. 
ii) 
A fixed effect to indicate the timing of the Week 48 assessment will be included 
in the primary analysis model. The fixed effect will be subject-based and include 
2 levels. The subjects either discontinuing early or completing their in-clinic 
assessment within the originally specified week 48 window (Days 323-372) will 
be in one level of the effect and subjects with their week 48 assessment in the 
expanded portion of the window (days 373-420) in the another level. 
iii) 
Remote assessments will be included in the model, with the model as specified 
for the primary analysis. 
iv) 
Remote assessments will be included in the model, with the model as specified 
for the sensitivity analysis which includes the COVID indicator. 
Additional supplemental analyses will run the primary model for each of the co-primaries but 
only include in-clinic “on-treatment” assessments (i.e. done within 3 days of the final dose of 
double-blind medication – see Section 4.3).  These analysis will assess a more hypothetical 
estimand which focus on the effect of the study medication as intended. 
Subgroup Analyses  
Except where indicated, descriptive statistics for the two co-primary endpoints ADAS-Cog 11 
score and CDR-SOB score, and their change from baseline, will be tabulated by visit, 
separately, for the subgroups defined by: 
o Sex  
o Mild vs Moderate MMSE status 
o APOE e4 status  
o Participation during Covid-19 (opportunity to complete randomization phase before 
March 13, 2020 vs on or after March 13, 2020) 
As a further exploratory analysis, for Mild vs Moderate MMSE baseline status subgroups an 
MMRM analysis will be utilized  on  each subgroup using the model specification as described 
above. 
In addition, descriptive statistics will also be presented by visit in the Open Label Extension 
Phase, by original randomized group (BHV-4157 and Placebo to BHV4157). 
 


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4.8.4 
Secondary Efficacy Endpoints 
4.8.4.1 
Volumetric MRI 
Bilateral hippocampal volume (as well as the exploratory endpoints of bilateral lateral ventricles 
and whole brain volume) will be measured as volumetric MRI. MRI imaging of the brain will be 
performed in order to measure brain atrophy over time. Results from vMRI studies suggest that the 
patterns of atrophy in AD 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. 
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.  
The analysis of structural change will be performed through Quarc nonlinear registration (see 
Holland et al., 20116) comparing each participant’s follow-up scan to the initial baseline scan. 
For the interim analysis, the week 24 scan will be registered to the baseline scan, and for the 
final analysis, the latest timepoint scan will be registered to the baseline scan. The procedure 
provides percent deformation within regions of interest (ROIs) obtained through segmentation 
of the baseline scan. The registration of serially-acquired brain volumes yields a deformation 
field that represents the volumetric shift of internal structure required for optimal overlaying of 
the two scans. The anatomically-based segmentation is overlaid on the smoothed voxel-wise 
deformation field and an average percent deformation is created for each ROI. Visual QC of 
registration is performed and values from scans passing QC are returned to the statistical team 
for analysis.  
This treatment effect will be mean difference in change in volumetric MRI, compared between 
the BVH-4157 and placebo groups. 
Subjects who have a baseline MRI measure and at least one MRI evaluation on-treatment 
following baseline will form the mITT population for this analysis. The number of images 
which are not quantifiable due to scan alignment failure will be summarized by study arm. The 
percent deformation in volumetric MRI will first be analyzed using the mITT population via an 
analysis of covariance (ANCOVA) with baseline MMSE as a covariate based only on subjects 
with an assessment in the Week 48 analysis window as the main analysis.  As an exploratory 
analysis, an additional analysis also using the same ANCOVA model, however including all 
subjects  with a post-baseline assessment, will be conducted to compare between BHV-4157 
and placebo based on subject’s last post baseline MRI.   
Finally, although only the last assessed post-baseline MRI deformation will be available at time 
of database lock, the MRI processing team will remain blind and will process the remaining 
post-baseline MRIs.  A subsequent analysis utilizing all on-treatment post-baseline assessments 
will be done based on an MMRM analysis with the model including fixed effect terms for 
baseline MMSE score, visit, visit x baseline MMSE score interaction, and visit x treatment 
group interaction. Visit is treated as a categorical variable. A random effect will be included for 


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participant. The within-participant covariance will be unstructured. A similar approach to 
calculating degrees of freedom and convergence issues will be taken as done for the primary 
endpoint. 
As a further exploratory analysis, for Mild vs Moderate MMSE baseline status subgroups an 
analysis will be utilized  on  each subgroup using the model specification as described above. 
In addition, descriptive statistics will also be presented at endpoint in the Open Label Extension 
Phase, by original randomized group (BHV-4157 and Placebo to BHV4157). 
4.8.4.2 
ADCS-ADL 
The ADCS-ADL scale is a validated tool for assessing instrumental and basic activities of daily 
living based on a 23-item structured interview of the study partner. The scale has a range of 0 to 
78, with lower scores indicating greater impairment5.  
This treatment effect will be summarized as the difference in change from baseline in the 
ADCS-ADL total score between the BVH-4157 and placebo groups. 
The change from baseline ADCS-ADL total score will be analyzed using the mITT set via a 
MMRM analysis model using the same approach as in the primary analysis. 
As a further exploratory analysis, for Mild vs Moderate MMSE baseline status subgroups an 
MMRM analysis will be utilized  on  each subgroup using the model specification as described 
above. 
When computing the total score, if 25% or fewer of the questions are missing within a question 
category, the score for each missing question will be prorated using the average score of the 
completed questions, categorized by basic ADL and IADL: 
Basic ADL (questions 1-6) will be prorated using the average score of completed 
questions 1-6  (no more than 1 of these question can be prorated). 
Instrumental ADL (questions 7-23) will be prorated using the average score of 
completed questions 7-23 (no more than 4 of these questions can be prorated). 
If more than 25% of questions with in a subgroup are missing, the total score will be missing. 
The ADCS-ADL will be assessed at visits conducted in clinic or via remote communication.  
Only in-clinic assessments will be considered in the primary analysis; sensitivity analysis will 
include similar analysis including remote assessments. 
4.8.4.3 
NPI Total Scores  
The NPI is a validated, reliable, multi-item instrument to assess psychopathology in AD based 
on interview with the study partner3. The NPI evaluates both the frequency and severity of 12 
neuropsychiatric features, including delusions, hallucinations, agitation/aggression, dysphoria, 
anxiety, euphoria, apathy, disinhibition, irritability/lability, and aberrant motor behavior, as well 


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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) as well as severity (1 = mild, 2 = moderate, 3 = severe). The overall score and the 
score for each subscale are the product of severity and frequency. This treatment effect will be 
summarized as the difference in change from baseline in the NPI total score between the BVH-
4157 and placebo groups. 
As for the primary endpoint, the change from baseline in NPI total score will be analyzed using 
the mITT set via a MMRM analysis model using the same approach as in the primary analysis. 
As a further exploratory analysis, for Mild vs Moderate MMSE baseline status subgroups an 
MMRM analysis will be utilized  on  each subgroup using the model specification as described 
above. 
In the event that an NPI is partially, but not completely administered, individual NPI scores will 
be imputed within the scoring algorithm using the following guidelines: 
• If there are 4 or fewer items with missing data on an NPI (severity and/or frequency), and if 
the participant has a previous or subsequent complete NPI, the scores for each missing item 
will be used from the assessment completed on the date closest to the assessment with 
missing data (either the previous NPI or subsequent NPI) in order to calculate a total score.  
• If 5 or more questions are missing, the entire assessment will be considered as missing. 
The NPI will be assessed at visits conducted in clinic or via remote communication.  Only in-
clinic assessments will be considered in the primary analysis; sensitivity analysis will include a 
similar analysis including remote assessments. 
4.8.4.4 
MMSE Scores 
The MMSE is a validated, brief, frequently used screening instrument for Alzheimer’s disease 
drug studies4. The MMSE scale evaluates orientation, memory, attention, concentration, 
naming, repetition, comprehension, and ability to create a sentence and to copy two overlapping 
pentagons. The MMSE is scored as the number of correctly completed items with a lower score 
indicative of poorer performance and greater cognitive impairment. The total score ranges from 
0 (worse) to 30 (perfect performance). 
When computing the total score, if three or fewer of the 30 items on the MMSE are missing, the 
last non-missing observation for those items will be carried forward in order to calculate a total 
score. If four or more items are missing, the MMSE Total Score will be missing. 
The change from baseline in MMSE Total Score will be analyzed using the mITT set via a 
MMRM analysis model, similar to the primary endpoint.  
As a further exploratory analysis, for Mild vs Moderate MMSE status subgroups an MMRM 
analysis will be utilized  on  each subgroup using the model specification as described above. 
 


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4.8.5 
Exploratory Efficacy Endpoints 
4.8.5.1 
MoCA Scores 
The MoCA is a brief mental status screening instrument that evaluates orientation, memory, 
executive functions, visuospatial ability, language, abstraction, attention, and naming8. 
When computing the total score, if three or fewer of the 30 items on the MoCA are missing, the 
last non-missing observation for those items will be carried forward to compute a total score. If 
four or more items are missing, the MoCA Total Score will be missing. 
The change from baseline in MoCA Total Score will be analyzed using the mITT set via a 
MMRM analysis model. 
4.8.5.2 
Composite Neuropsychological Test Battery Score 
A cognitive composite outcome measure will be computed using measures from the NACC 
Neuropsychological Test Battery18. The composite outcome will comprise the overall average of 
the Z-scores from each of the following NACC subtest measures: Craft Story 21 total immediate 
Recall; Craft Story 21 total delayed recall; Benson Figure copy score; Benson Figure delayed 
recall; Multilingual Naming Test total correct; Letter Fluency total score; Category Fluency 
total score; Trail Making Test A time to completion; Trail Making Test B time to completion; 
Number Span Forward total correct; and Number Span Backward total correct. Z-scores for 
each participant on each measure will be calculated using the overall average of all participants 
at baseline as reference.  
The total composite neuropsychological test battery score will be calculated as the overall 
average Z-score from each of the completed subtests. If more than 2 NACC Neuropsychological 
Test Battery subtest measures are missing, the total composite neuropsychological test battery 
score will be missing. Please refer to Appendix 3 regarding prorating subtest scores when there 
are partially (i.e., item-level) missing data. 
The change from baseline in composite neuropsychological test battery score will be analyzed 
using the mITT set via a mixed model as above. However since there are no repeated measures 
on participants, there will not be a participant-level random effect. This analysis is exploratory 
for potential publication purposes only. 
In addition, descriptive statistics will also be presented by visit in the Open Label Extension 
Phase, by original randomized group (BHV-4157 and Placebo to BHV4157). 
4.8.5.3 
ADCOMS 
The AD Composite Score (ADCOMS) is a weighted composite outcome optimized for 
progression in an MCI stage of AD, and comprised of scores from 4 ADAS-Cog subscales 
(Delayed Word Recall, Orientation, Word Recognition, and Word Finding Difficulty), 2 MMSE 
items (Orientation to Time, and Intersecting Pentagons), and the CDR Sum of Boxes (Wang et 
al., 2016). Because Delayed Word Recall is not assessed within this trial, the ADCOMS cannot 
be calculated using the methods and weights described by Wang and colleagues (2016) and this 


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composite is not optimized for the mild-to-moderate population included in our study. However, 
exploratory analyses may be run using historical data from a similar mild-to-moderate 
population to combine and weight elements of the ADAS-Cog and MMSE with the CDR-SB to 
develop a composite score using similar methodology. Change from baseline to Week 48 on this 
composite outcome will be analyzed using the mITT set via an MMRM analysis model to assess 
impact on AD progression. 
4.8.5.4 
CSF, Serum and Plasma Biomarker Panel 
CSF, serum and plasma biomarker panel (including, for example, 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 collected and analyzed in a subset of the study 
population (estimated n=50 active, n=50 placebo) at screening, week 24 and week 48. 
 The change from baseline in the response through week 48 will be analyzed using the mITT 
population via a Mixed Model for Repeated Measures (MMRM) analysis model, similar to the 
primary analysis.  Fixed effects in the models are APOE status (e4 carrier vs e4 noncarrier), 
baseline score, treatment group (active vs placebo), visit, visit x baseline score, and visit x 
treatment group interaction. If appropriate, the response variable will be log transformed. 
Subjects who have a baseline measure and at least one  evaluation on-treatment following 
baseline will form the study population for this analysis. 
Summary statistics will be provided by arm. A p-value and 95% confidence interval for the 
estimated effect will be included in the summary. 
4.9 
Pharmacokinetic Evaluations 
All PK analyses will be conducted using the treated population. 
A PK sample will be collected at baseline, weeks 4, 8, 12, 24 and 48 of the Randomization 
Phase. Additionally, PK samples should be drawn if there are any SAEs that could possibly be 
drug related or severe AEs that could be drug related. Date and time of doses on the day of visits 
and day prior will be collected in the case report forms along with the time of last meal.  
Participants who are able to schedule a morning visit for baseline, weeks 2, 4, 8, 12, 24 and 48 
can be instructed to hold their dose of study drug that morning until after a PK trough sample is 
obtained, if possible and appropriate. 
Individual concentrations will be summarized by visit for the Randomization Phase. Plasma 
concentrations below the limit of quantification (BQL) will be considered to be 0 concentration. 
Missing values will not be imputed.  
Individual plasma concentration data will be displayed in listings for the Randomization Phase. 
4.10 
Safety and Other Analyses 
Safety and other exploratory analyses will be conducted on the Treated Participants Population 
for the respective phase. Separate summaries will be provide for Randomization and Extension 


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Phases.  In addition, where indicated safety summaries for the combined all BHV-4157 
exposure will be provided. 
Safety outcome measures include: AEs, laboratory assessments, physical examinations, vital 
signs, ECGs, concomitant medications, and the S-STS questionnaire.  
Continuous values will be summarized by descriptive statistics (mean, median, SD, minimum, 
maximum, and number of participants). Mean line plots over time may be displayed if 
applicable with separate lines for each treatment. 
Categorical variables will be summarized using the number and percentage of participants in 
each category for each treatment group and overall. The denominators for calculating the 
percentages will be based on the number of participants with non-missing assessments at a 
particular visit for the safety population. 
In order to assess the impact of the COVID-19 pandemic crisis on safety results, select safety 
summaries will be repeated separating subjects by whether they were active (on-treatment) in 
the double-blind Randomization phase on or after March 13, 2020 or only active prior to this 
date.  
4.10.1 
Extent of Exposure and Compliance to Study Treatment 
Participants will receive placebo (QD) or BHV-4157 (140 mg QD followed by 140 mg BID) 
during the Randomization Phase.  For the Extension Phase subjects will receive open label 
BHV-4157 (140 mg QD followed by 140 mg BID). 
For the Randomization Phase, the extent of participant exposure (including missed dose days) 
will be quantified as the number of days on study drug (placebo or BHV-4157) and measured 
from the time the participant received the first dose until the time the participant received the 
last dose (i.e., total days on randomized study medication = last day of double-blind randomized 
study medication – day 1 of double blind randomized study medication + 1). 
For the Extension Phase, the extent of participant exposure (including missed dose days) will be 
quantified as the number of days on study drug (open label BHV-4157) and measured from the 
time the participant received the first dose in the Extension Phase until the time the participant 
received the last dose (i.e., total days on open label medication = last day of open label study 
medication – day 1 of open label  study medication + 1). 
For combined exposure of BHV-4157 either the randomization and  the extension phase, the 
extent of participant exposure (including missed dose days) will be quantified as the number of 
days on study drug (BHV-4157) and measured from the time the participant received the first 
dose BHV-4157 until the time the participant received the last dose of BHV-4157 regardless of 
phase (i.e., total days on randomized study medication = last day of BHV-4157 study 
medication – day 1 of BHV-4157 study medication + 1). 
Extent of participant exposure for a given phase or overall for BHV4157 will also be calculated 
only including days where number of capsules taken was >0 (total days on study medication). 


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For the Randomization Phase, the number of participants on-treatment and their average daily 
dose (including minimum and maximum) will be summarized by 14-day intervals for the first 
28 days and then by month (28-day intervals) as well as overall for the randomization phase. For 
participants on placebo the number of capsules will be summarized. 
For the Randomization Phase, the extent of study medication exposure will also be summarized 
by a Kaplan-Meier plot presenting proportion of participants still on Randomization Phase study 
medication (including days of missed dose).  
For the Extension Phase and the entire study, the number of subjects on-treatment and their 
average daily dose (including minimum and maximum) will be summarized by month (30-day 
intervals) for the as well as overall for the Extension Phase and the entire study (BHV-4157 
exposure).  
Additionally, percent (%) compliance will be calculated and summarized as follows: 
• Randomization Phase % compliance = total days on study medication (i.e. number of days 
where number of capsules taken > 0) during the Randomization Phase / (last dose date in 
Randomization Phase– first dose date + 1) × 100 
•  Extension Phase % compliance = total days on BHV-4157 in Extension Phase / (last dose 
date – first dose date in Extension Phase + 1)  × 100 
• Overall % compliance = total days on BHV-4157 during the study / [(last BHV-4157 dose 
date – first BHV-4157 dose date + 1) – (number of days with a dosing break in dosing 
between the Randomization and Extension Phases)] 
Summaries on the Randomization Phase will be repeated for Treated subjects completing (or 
discontinuing) double-blind treatment prior to versus on or after start of COVID-19 pandemic 
crisis (March 13, 2020). 
Study drug administration and compliance will be listed in participant data listings. 
4.10.2 
Adverse Events 
AEs will be coded using MedDRA and displayed in tables and listings by system organ class 
(SOC) and preferred term (PT). 
Analyses of AEs will be performed for those events that are considered treatment-emergent 
(TEAE), where treatment-emergent is defined as events that first occurred or worsened on or 
after first dose of study medication. See section 4.4 for the detailed definition of “on-treatment” 
treatment-emergent AEs (TEAEs)  and see section 4.3.7 for additional details when onset date is 
partial.  
The number and percentage of participants with the following AEs will be summarized by 
treatment group and overall for the Randomization and Extension Phases, separately, as well as 
just overall for subjects after at least one dose of BHV-4157 in any phase.  


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• TEAEs 
• TEAEs Related, Probably Related or Possibly Related to Treatment (An AE is considered to 
be related to study drug if the relationship is either definitely, probably  or possibly related.) 
• Treatment-emergent SAEs  
• TEAEs leading to discontinuation of study treatment  
• TEAEs by highest severity (mild, moderate, severe) 
• TEAEs Related, Probably Related or Possibly Related to Treatment by highest severity 
(mild, moderate, severe) 
• TEAEs indicating potential Interstitial Lung Disease (using Standardized MedDRA Queries 
(SMQ) Interstitial Lung Disease including Eosinphilic Pneumonia and Hypersensitivity 
Pneumonitis) 
In the above tabulations, each participant will contribute only once for a given preferred term 
(i.e., the most related occurrence or the most severe occurrence) to each of the incidence rates in 
the descriptive analysis, regardless of the number of episodes. No formal hypothesis-testing 
analysis of AEs incidence rates will be performed.  
All AEs occurring pre-treatment, during the Randomization and Open Label Extension Phases, 
and throughout the entire study will be listed. Additional listings will be provided including all 
deaths, SAEs, and AEs leading to withdrawal of study drug. 
Listings will indicate whether subject was active during COVID-19 pandemic crisis and the date 
of first visit impacted. 
4.10.3 
Laboratory Data 
Clinical laboratory evaluations include: 
• Hematology: hemoglobin, hematocrit, platelets, complete blood count with differential and 
absolute neutrophil count 
• Serum Chemistry: sodium, potassium, chloride, calcium, ALT, AST, LDH, alkaline 
phosphatase, GGT, phosphorous, bicarbonate, CPK, total protein, albumin, direct bilirubin, 
indirect bilirubin, total bilirubin, glucose, creatinine, BUN, uric acid, total cholesterol, LDL, 
HDL, triglycerides 
• Urinalysis: pH, specific gravity, protein, glucose, ketones, urobilinogen, bilirubin, blood 
Clinical laboratory values will be expressed using conventional (US) and standard international 
(SI) units. In the event of repeat values within the same analysis visit, if any measurement has 
abnormal results, that measurement will be used for presentation in by-visit tables. If none of the 
measurements are abnormal, or all of them are abnormal, the worst measurement in the analysis 


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visit interval will be used for presentation in by-visit tables. All measurements will be presented 
in listings and considered for evaluation of potential drug- induced liver injury (DILI) or 
abnormalities.  
Due to the COVID-19 pandemic crisis some sites might utilize local laboratories for some visits.  
These local laboratory values will be combined with the centralized laboratory values by 
normalizing them to the central laboratory using methods described in Chuang-Stein 1992 
On-treatment laboratory abnormalities are those with an assessment date after the date/time of 
first dose of study drug and within 30 days after the last dose of study drug. For the 
Randomization Phase, treatment-emergent laboratory abnormalities will be assessed from the 
date of first dose of study drug until: 1) the first day of the Extension Phase or 2) if the subject 
did not continue into the Extension Phase, 30 days after the last dose of study drug. For the 
Extension Phase, treatment-emergent lab abnormalities will be assessed from the first dose 
during the Extension Phase until 30 days after the last dose of study drug. (See section 4.3) 
The observed value and change from baseline will be summarized for each continuous 
laboratory parameter for the Randomization and Extension Phases, separately, in both 
conventional and SI units.  
Clinical laboratory test results will be graded according to CTCAE version 5.0 if criteria for test 
available, otherwise according to DAIDS version 2.1 criteria, if available for test. The number 
and percent of participants with at least one on-treatment lab assessment by highest grade will 
be summarized for each treatment (regardless of baseline) for the Randomization and Extension 
Phases, separately as well as just overall for subjects after at least one dose of BHV-4157 in any 
phase. In addition, the shift from baseline to worst on-treatment lab (based on either normal 
limits or grading, where available) will be tabulated by visit and the overall minimum and 
maximum observed for treated subjects in the Randomization and Extension Phases, separately, 
as well as just overall for subjects after at least one dose of BHV-4157 in any phase. The shift 
tables will include only participants with a baseline assessment and at least one on-treatment 
assessment. 
For the liver function tests, AST, ALT, Alk Phos, and BILI the shift from baseline will also be 
presented by visit and to the maximum observed abnormality for the Randomization Phase and 
Extension Phases, separately, as well as just overall for subjects after at least one dose of BHV-
4157 in any phase. Baseline in the shift tables will be defined as per Section 4.2.8; the last 
available assessment on or before the first day of study treatment in that phase. Shift tables will 
only include treated participants with an assessment for the specific test of interest at baseline 
and on treatment. The following categories will be used to summarize the shift from baseline 
based on the upper limit of normal (ULN) range for ALT and AST:  
• <=ULN  
• >ULN to ≤ 3x ULN 
• >3x ULN to ≤ 5x ULN 
• >5x ULN 


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The following categories will be used to summarize the shift from baseline based on the ULN 
range for alkaline phosphatase:  
• <=ULN  
• >ULN to ≤ 1.5x ULN 
• >1.5x ULN to ≤ 2.5x ULN 
• >2.5x ULN 
For GGT, the following categories will be used to summarize the shift from baseline:  
• <=ULN 
• >ULN to ≤ 2.5x ULN 
• >2.5x ULN 
The following categories will be used to summarize the shift from baseline based on the ULN 
range for Total Bilirubin BILI:  
• <=ULN  
• >ULN to ≤ 1.5x ULN 
• >1.5x ULN to ≤ 2.0x ULN 
• >2.0x ULN 
An evaluation of drug-induced serious hepatotoxicity (eDISH) scatter plot will display the 
maximum TBL ratio of value to ULN on the y-axis versus the maximum ALT ratio of value to 
ULN on the x-axis, where the maxima is not necessarily concurrent, for treated subjects in the 
randomization phase and DB and OL BHV-4157 treated subjects. Both axes will be on the 
log10 scale. Ratios < 0.1 x ULN will be set to 0.1. Sample sizes in the legend will represent 
subjects with paired ratios. A horizontal reference line will be placed at 2 x ULN, and a vertical 
reference line will be placed at 3 x ULN. The lower left quadrant will be labeled “Normal 
Range”, the upper left quadrant will be labeled “Hyperbilirubinemia”, the lower right quadrant 
will be labeled “Temple’s Corollary”, and the upper right quadrant will be labeled “Possible 
Hy’s Law Range.” 
All laboratory data will be presented in data listings. Additional listings will be presented for all 
abnormal laboratory values considered potentially clinically significant (Grade 3 or 4) for the 
Randomization and Extension Phases. Participants with a maximum value of ALT or AST >3x 
ULN or a maximum total bilirubin value >2x ULN observed at any point during the entire study 
will also be presented in a listing. Note that these abnormalities do not need to occur on 
concurrent visits. 
The following summary for the Randomization Phase will be repeated for Treated subjects 
completing (or discontinuing) double-blind treatment prior to versus on or after start of COVID-
19 pandemic crisis (March 13, 2020): 


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The number and percent of subjects with at least one on-treatment lab assessment by highest 
grade will be summarized for each treatment (regardless of baseline) for the Randomization 
Phase 
4.10.4 
Physical Examinations 
Physical examination findings and number of participants are summarized as the count and 
percentage of participants by eCRF pre-defined categories at last visit. Results of Physical 
Examination will be included as a listing for each arm and overall. 
4.10.5 
Vital Signs and Physical Measurements 
The observed value and change from baseline in vital signs and physical measurements will be 
summarized for each arm at each visit for the Randomization and Extension Phases, separately. 
The summary will be based on the “on-treatment” data after the date/time of first dose of study 
drug and within 30 days after the last dose of study drug (see section 4.3 for  detailed definition 
of  “on-treatment”).  
In addition, the number and percentage of participants with at least one post-treatment vital sign 
measurement meeting any of these criteria will be summarized: 
• Systolic Blood Pressure: <90 mmHg, >140 mmHg, >160 mmHg 
• Diastolic Blood Pressure: <50 mmHg, >90 mmHg, >100 mmHg 
• Pulse Rate: <60 bpm, >100 bpm 
• Body Weight: decrease of ≥7% from baseline and increase of ≥7% from baseline 
• Temperature: >38.0 °C, <36.0 °C 
The number and percent of subjects meeting these criteria will be summarized for the 
Randomization and Extension Phase, separately as well as the overall BHV-4157 treated 
exposure. A subject listing will provide for each vital sign measure abnormality criteria listing 
any subject meeting the criteria with a complete list of all of their values that particular vital 
sign measure with the specific assessments that meet the criteria indicated. 
The criteria summarized for the Randomization Phase will also be repeated for Treated subjects 
completing (or discontinuing) double-blind treatment prior to versus on or after start of COVID-
19 pandemic crisis (March 13, 2020). 
4.10.6 
Electrocardiogram 
Descriptive statistics for ECG interval data (e.g., QRS, PR, QT, QTcF), and ventricular heart 
rate will also be reported by visit for the Randomization and Extension Phases, separately. The 
summary will be based on the data after the date/time of first dose of study drug and within 30 
days after the last dose of study drug (see section 4.3 for  detailed definition of  “on-treatment”).  


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In addition, the number and percentages of subjects with at least one post-treatment QTcF > 450 
ms, >480 ms, and >500 ms will be summarized for the Randomization and Extension Phase, 
separately, as well as the overall BHV-4157 treated exposure. Similar number and percentages 
will be presented for subjects with at least one post-baseline QTcF Change from baseline >= 30 
ms to < 60ms and those with at least one change from baseline >= 60 ms. A subject listing will 
provide each QTcF sign measure, specifying any subject meeting the criteria with a complete 
list of their QTcF assessments with the ones meeting the criteria indicated. 
The criteria summarized for the Randomization Phase will also be repeated for Treated subjects 
completing (or discontinuing) double-blind treatment prior to versus on or after start of COVID-
19 pandemic crisis (March 13, 2020). 
4.10.7 
Concomitant Medications 
Concomitant medications will be coded with WHODrug (Global March 2019) using the 
WHODrug Insight tool. Each codable concomitant medication will be assigned five values: 
Drug Name, Drug Record Number, SeqNum1, SeqNum 2, and Anatomic Therapeutic Class 
(ATC) code. Results will be tabulated by treatment group, ATC code, and Drug Name during 
the Randomization and Extension Phases, separately. Note that all concomitant medications 
with a given Drug Record Number will be assigned the same ATC code. 
Unless the start date of the medication is after the last study drug dose date, or the end date of 
the medication is prior to the start date of the study drug, the medication will be considered 
‘concomitant.’ Partial onset and dates need to be considered in the determination of the 
medication being concomitant or not. 
4.10.8 
Sheehan-Suicidality Tracking Scale (S-STS) 
The S-STS is a prospective, self-reported rating scale that contains 16 questions to track both 
treatment-emergent suicidal ideation and behaviors. In the event the participant is unavailable, 
the S-STS clinician-administered rating scale with 6 yes/no questions will be completed. 
Self-reported S-STS scores are calculated as follows: 
• Ideation subscale score: Sum of scores (0 – 4) for Questions 2 – 11 
• Behavior subscale score: Sum of scores (0 – 4) for Questions 1a, (highest of 12 or any row 
of 16), (highest of 14 or any row of 15), 17, and 20 based on the scoring used for the 2017 
version of scale used in this study. In addition, a Behavior subscale score based on the 2019 
version of the scoring will also be calculated where the score for a ‘Yes’ item 20 is 56 and 
the scores for 18, 19, 21 and 22 are used from the prior visit if applicable. 
• Total score: Sum of the ideation and behavior subscale scores. A Total score will be 
calculated based on both 2017 version and 2019 version 
The self-reported S-STS ideation subscale, behavior subscale, and total score will be 
summarized as the change from baseline (i.e., <-1, -1, no change, 1, >1) at each visit and at 
Maximum score in the Randomization and Extension Phases, presented separately. Both 


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versions of the Total score will be summarized. All S-STS assessments will be included in 
summaries regardless of being completed at study site or remote. 
4.10.9 
Subjects Identified for Narratives 
A safety narrative will be prepared for each subject who received at least one dose of troriluzole 
and experienced the following events (regardless of relationship to study drug) on-treatment 
with Troriluzole:  
• All deaths on-treatment and post-treatment through the end of the study  
• SAEs on-treatment, which includes up to 30 days after the last dose of study drug; SAEs that 
occur > 30 days (i.e., during the follow-up period) will be included per the clinical judgment 
of the Biohaven medical monitor  
• All premature discontinuations of study drug due to AEs (either identified through “action 
taken” or “end of treatment status”)  
• The following on-treatment events of special interest:  
o Neutropenia based on laboratory results and defined as minimum absolute neutrophil 
count < 500 per mm3  
o LFT abnormalities:  
o ALT or AST > 3x ULN  
o ALT or AST > 3x ULN, and serum total bilirubin > 2x ULN  
Interstitial lung disease Standardized MedDRA Query (SMQ) including eosinophilic 
pneumonia and hypersensitivity pneumonitis  
These select events are described in the current version (v3) of the Biohaven Safety Narrative 
Scope for BHV-4157 (troriluzole). Because select events may be subject to change, updates to 
the list of events or selection algorithms after database lock may be described in a Note to File 
(NTF) rather than amending the SAP.  
A by-subject listing of safety narrative subject identifiers will be presented for all troriluzole 
treated subjects with the select events as described above. 
 
 


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5 REFERENCES 
1. Ayela B, Lipkovich I, Molenberghs G, Mallinckrodt CH. (2014). A multiple imputation-
based approach to sensitivity analyses and effectiveness assessments in longitudinal 
clinical trials. Journal of Biopharmaceutical Statistics, 24(2). 211–228. 
 
2. Carpenter J, Roger J, Kenward M. Analysis of longitudinal trials with missing data: a 
framework for relevant, accessible assumptions, and inference via multiple imputation. 
Journal of Biopharmaceutical Statistics, 23 2013: 1352–1371. 
 
3. Cummings, J. L. (1997). The Neuropsychiatric Inventory: assessing psychopathology in 
dementia patients. Neurology, 48(5 Suppl 6), S10-16.  
 
4. Folstein, M. F., Folstein, S. E., & McHugh, P. R. (1975). "Mini-mental state". A practical 
method for grading the cognitive state of patients for the clinician. J Psychiatr Res, 12(3), 
189-198.  
 
5. Galasko D1, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, Ferris S. 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, 1997;11 Suppl 
2:S33-9. 
6. Holland, D., McEvoy, L. K., Dale, A. M., & Alzheimer's Dis, N. (2012). Unbiased 
comparison of sample size estimates from longitudinal structural measures in ADNI. 
Human Brain Mapping, 33(11), 2586-2602. doi:10.1002/hbm.21386 
 
7. Mallinckrodt, C., Molenberghs, G., and Rathmann, S. (Jan-Feb 2017). Choosing 
Estimands in Clinical Trials with Missing Data. Pharmaceutical Statistics, 16(1): 29-36. 
doi: https://doi.org/10.1002/pst.1765|  
8. Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, 
Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief 
screening tool for mild cognitive impairment. Journal of the American Geriatrics 
Society, 53(4), 695-9. 
 
9. Qiu Y, Jacobs DM, Messer K, Salmon DP, Feldman HH (2019). Cognitive heterogeneity 
in probable Alzheimer disease: Clinical and neuropathologic features. Neurology, 22: 
10-212. 
 
10. Ratitch, B., Bell, J., Mallinckrodt, C., Bartlett, JW., Goel, N., Molenberghs, G., O' Kelly, 
M., Singh, P., and Lipkovich, I (April 2019). Choosing Estimands in Clinical Trials: 
Putting the ICH E9(R1) Into Practice. Therapeutic Innovation & Regulatory Science, 4. 
doi: 10.1177/2168479019838827.  
 
11. 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 
 
12. Rubin, D. B. (1987). Multiple Imputation for Nonresponse in Surveys. Wiley and Sons, 
Harvard. 
 


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13. Schluchter, M. D., and Elashoff, J. D. (1990). “Small-Sample Adjustments to Tests with 
Unbalanced Repeated Measures Assuming Several Covariance Structures.” Journal of 
Statistical Computation and Simulation 37:69–87.  
 
14. Thomas RG, Albert M, Petersen RC, Aisen PS. 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. Epub 2016 Feb 23. 
15. 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 
 
16. Tsiatis, A. A. Semiparametric theory and missing data. Springer, 2006. 
 
17. Wang J, Logovinsky V, Hendrix SB, Stanworth SH, Perdomo C, Xu L, Dhadda S, Do I, 
Rabe M, Luthman J, Cummings J. ADCOMS: a composite clinical outcome for 
prodromal Alzheimer's disease trials. Journal Neuroly, Neurosurgy and Psychiatry. 2016 
Sep 1;87(9):993-9. 
18. Weintraub S, Besser L, Dodge HH, Teylan M, Ferris S, Goldstein FC, Giordani B, 
Kramer J, Loewenstein D, Marson D, Mungas D. Version 3 of the Alzheimer Disease 
Centers’ neuropsychological test battery in the Uniform Data Set (UDS). Alzheimer 
disease and associated disorders. 2018 Jan;32(1):10. 
 
19. Xiong et al (2017). Linear Combinations of Multiple Outcome Measures to Improve the 
Power of Efficacy Analysis ---Application to Clinical Trials on Early Stage Alzheimer 
Disease. Journal of Biostatistics and Epidemiology, 1(1): 36-58. 


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APPENDIX 
APPENDIX 1 - 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 
 
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 
 
 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 or 
Early Term 
10 
 
 


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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 48 
(±7 days) 
Follow-Up 
week 52 
(±7 days) 
Unscheduled 
Visit 
Volumetric MRI11 
X 
 
 
 
 
 
X 
 
X 
 
 
Lumbar Puncture (LP)11,12 
X 
 
 
 
 
 
X 
 
X 
 
 
CSF Biomarkers13 
X 
 
 
 
 
 
X 
 
X 
 
 
Post-LP Safety Telephone14 
X 
 
 
 
 
 
X 
 
X 
 
 
Sheehan Suicidality Tracking 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
ADAS-Cog 11 
 
X 
 
 
 
X 
X 
X 
X 
 
 
CDR-SOB 
 
X 
 
 
 
X 
X 
X 
X 
 
 
NPI 
 
X 
 
 
 
 
X 
 
X 
 
 
ADCS-ADL 
 
X 
 
 
 
 
X 
 
X 
 
 
Craft Story 21 Recall 
 
X 
 
 
 
 
 
 
X 
 
 
Benson Complex Figure 
 
X 
 
 
 
 
 
 
X 
 
 
MINT 
 
X 
 
 
 
 
 
 
X 
 
 
Letter & Category Fluency 
 
X 
 
 
 
 
 
 
X 
 
 
Trail Making Test A & B 
 
X 
 
 
 
 
 
 
X 
 
 
Number Span Test 
 
X 
 
 
 
 
 
 
X 
 
 
MMSE 
X 
X 
 
 
 
 
X 
 
X 
 
 
MoCA 
 
X 
 
 
 
 
X 
 
X 
 
 
Research Satisfaction Survey 
 
X 
 
 
 
X 
X 
X 
X 
 
 
Dispense Study Drug15 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
Study Drug Instruction Phone 
Call16 
 
 
X 
 
 
 
 
 
 
 
 
Study Drug Accountability 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
Treatment Blinding 
Questionnaire17 
 
 
 
 
 
 
 
 
X 
 
 
 
Every effort should be made to conduct the Week 48 visit and maintain the +/- 7 day window. However, due to concerns related to the COVID-19 
pandemic, the Week 48 visit window may be modified beyond the +/- 7 day window, in order to minimize any potential risks to study participant safety 
and to comply with governmental and local institutional guidance (e.g., study site has a policy that a clinical research visit must be delayed). Under these 
circumstances, the visit window may be extended (up to a maximum treatment duration of 60 weeks), but every attempt should be made to conduct the 
visit as close to the date the visit is due as possible. If the visit window is modified, participants should be evaluated remotely (e.g., via phone) at the time 
of the scheduled Week 48 visit to perform and document appropriate safety assessments. Study medication may be sent to the participant via tracked and 
certified courier. For any such cases, the investigator should discuss the specific circumstances of each case with the sponsor medical monitor (or 
designee) who must approve the request prior to any modification of the visit window:
Cell
1 
The following must be collected at any unscheduled visit: vital signs, prior and concomitant medications, adverse events, and protocol deviations. All 
other unscheduled visit procedures are subject to PI discretion or request from the Medical Monitor.  
PPD
PPD
PPD


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2 
Randomization must occur at the baseline visit after eligibility is confirmed. 
3 
Height is done at screening only. 
4 
Vital signs include sitting blood pressure, pulse, temperature, respiration rate, and weight. 
5 
The SAE reporting period starts at the screening visit (i.e., when the participant or LAR signs consent). The reporting period for non-serious AEs starts at 
the baseline visit at the time of receiving the first dose of study drug. The end of the reporting period for both SAEs and AEs is 30 days after the study 
drug has been discontinued. 
6 
Clinical Safety Laboratory Tests will be performed by a Central Laboratory. Assessment includes the following: Hematology (hemoglobin, hematocrit, 
platelets, RBC, WBC, differential count, and absolute neutrophil count), Chemistry (sodium, potassium, chloride, calcium, ALT, AST, LDH, alkaline 
phosphatase, GGT, phosphorus, bicarbonate, CPK, total protein, albumin, indirect bilirubin, direct bilirubin, total bilirubin, glucose, creatinine, BUN, uric 
acid, total cholesterol, LDL, HDL, triglycerides, folate).  
7 
Performing additional safety labs at Week 36 is now strongly encouraged, given the COVID-19 pandemic and unanticipated issues related to collecting 
lab samples that may potentially arise. 
8 
Urinalysis to include: pH, specific gravity, protein, glucose, ketones, urobilinogen, bilirubin, blood  
9 
A blood sample for pharmacokinetic (PK) measures in plasma should be collected at baseline, week 4, week 8, week 12, week 24, and week 48. 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 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. Blood samples for PK in plasma 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 that are undergoing lumbar puncture, PK 
samples should be drawn at the time of lumbar puncture. Date and time of doses on the day of lumbar puncture and day prior should be collected in case 
report forms, for entry into the EDC system. 
10 
All vMRIs must be performed per imaging protocol and must use the same scanner throughout study.  
o 
Screening vMRI: if a participant has not had an MRI performed within 6 months of screening (i.e.,  within 6 months from the date of informed 
consent), then an MRI must be performed as part of the screening requirements for this study, per the imaging protocol, and should be one of the 
last screening procedures performed to determine final eligibility in order to prevent participants from undergoing unnecessary MRIs. If a 
participant has had an MRI within 6 months of screening (i.e.,  within 6 months from the date of informed consent) but the MRI does not follow 
the study-specific imaging protocol, that MRI can be used to help determine eligibility; however, another MRI must be performed per the imaging 
protocol, and must occur as close to, and prior to, the baseline visit, after all other eligibility criteria have been confirmed. 
o 
Week 24 and week 48 vMRI: the protocol window for vMRI at week 24 and week 48 is 14 days before and up to14 days after the clinic visit. If 
participant is terminating early at 36 week or after, obtain vMRI. If MRI is performed on the same day as a lumbar puncture at week 48, the vMRI 
must be conducted before the lumbar puncture. Otherwise, at least a 3-day window between vMRI and the lumbar puncture is required. 
11 
It is anticipated that lumbar puncture will be performed on an estimated 100 study participants as part of a sub-study (separate informed consent required). 
12 
Only for the CSF sub-study. Visit windows for CSF are: up to 14 days prior to first dose of study medication and up to 14 days prior to weeks 24 and 48. If 
a participant in the CSF sub-study is terminating early, they do not need to undergo lumbar puncture.  
13 
Post lumbar puncture safety follow up telephone call must occur 1 to 3 days after the lumbar puncture is performed. 
14 
First dose of study medication will be given in the clinic at the baseline clinic visit after completion of the baseline visit procedures.  
15 
Participants will receive a phone call during Week 2 from site study personnel in order to assess study drug tolerability. If tolerable, then the participant 
will be instructed to proceed with dose escalation.  
16 
Treatment blinding questionnaire to be administered to site PI and Raters. 
 
 
 


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   Confidential   
03DEC2020 
 
50
Table 2: 
Schedule of Assessments and Events – Open-Label Extension Phase 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Study Visit Timepoint 
Baseline1 
Abbrev-
iated 
Drug 
Dispensat
ion Visit2 
Ext 
Week 2 
(+/- 7 days) 
Ext 
Week 4 
(+/- 7 days) 
Ext 
Week 83 
(+/- 7 days) 
Ext 
Week 12 
(+/- 7 days) 
Ext 
Week 24 
(+/- 7 days) 
Ext 
Week 36 
(+/- 7 days) 
Ext 
Week 48 
or Early 
Term 
(+/- 7 days) 
Week2 
Post last 
dose 
(+/- 7 days) 
Unsched-
uled 
Visit4 
(+/- 7 days) 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X 
 
Telephone Check-in5 
Includes AE assessment and concomitant 
medication review 
 
 
X 
 
X3 
 
 
 
 
 
 
Laboratory Assessments6 
X 
 
 
X 
X3 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
X 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
X 
 
 
Physical Measurement - Weight 
X 
 
 
 
 
 
X 
 
X 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
X 
X 
 
X 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sheehan Suicidality Tracking 
Scale (S-STS) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Dispense Study Drug 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
Volumetric MRI7 
X 
 
 
 
 
 
 
 
X 
 
 
ADAS-Cog 11 
X 
 
 
 
 
 
X 
 
X 
 
 
CDR-SOB 
X 
 
 
 
 
 
X 
 
X 
 
 
Study Drug Accountability 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Blood Collection for Biomarker 
Banking 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Craft Story 21 Recall 
X 
 
 
 
 
 
X 
 
X 
 
 
Letter & Category Fluency 
X 
 
 
 
 
 
X 
 
X 
 
 
Number Span Test 
X 
 
 
 
 
 
X 
 
X 
 
 
MoCA 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
 


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51
1. 
Baseline visit for the Extension Phase is only required if there is an extended break (≥4 weeks) in dosing between the Randomization and Extension 
Phases. 
2. 
 For participants who will have been off of the study drug for less than or equal to 4 weeks, the subject should come into the investigative site for an 
Abbreviated Drug Dispensation Visit (also “Abbreviated OLE Baseline Visit”), at which time any major medical or medications changes will be 
reviewed prior to dispensing riluzole. In this case, most procedures from the Week 48 visit will also serve as the Open-Label Extension Phase Baseline 
visit 
3. 
Extension Week 8 is primarily to collect Liver Function tests. If a participant prefers not to come into the office, these can be collected at a local 
laboratory, with a telephone call confirming these were collected as well as a review of concomitant medications and an assessment of any adverse 
events. If the participant comes into the center, an assessment of adverse events and Liver function tests will be completed. Although all other visits can 
be conducted remotely as needed due to COVID-19 restrictions, under regular circumstances visits are to be completed in-person. See Protocol Section 
8.1.12, Open-Label Extension Phase, for further details and requirements regarding remote visit completion due to COVID-19. 
4. 
The following must be collected at any unscheduled visit: vital signs, prior and concomitant medications, adverse events, and protocol deviations. All 
other unscheduled visit procedures are subject to PI discretion or request from the Medical Monitor. 
5. 
Telephone calls to subjects will be made between visits during Extension Phase (Weeks 2 and 8) to monitor subject condition, review concomitant 
medications and assess any adverse events. 
6. 
Clinical Safety Laboratory Tests will be performed by a Central Laboratory. Assessment includes the following: Hematology (hemoglobin, hematocrit, 
platelets, RBC, WBC, differential count, and absolute neutrophil count), Chemistry (sodium, potassium, chloride, calcium, ALT, AST, LDH, alkaline 
phosphatase, GGT, phosphorus, bicarbonate, CPK, total protein, albumin, indirect bilirubin, direct bilirubin, total bilirubin, glucose, creatinine, BUN, 
uric acid, folate). 
7. 
Volumetric MRI is not required if the participant’s Double-Blind Week 48 MRI scan occurred less than than 3 months prior to their joining the Open-
Label Extension Phase. 
 
 


ADCS & Biohaven Pharmaceuticals                  
Protocol BHV4157-203 
   Confidential   
03DEC2020 
 
52
Table 2: 
Schedule of Assessments and Events – Open-Label Extension Phase 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
 
Study Visit Timepoint 
Baseline1 
Abbrev-
iated 
Drug 
Dispensat
ion Visit2 
Ext 
Week 2 
(+/- 7 days) 
Ext 
Week 4 
(+/- 7 days) 
Ext 
Week 83 
(+/- 7 days) 
Ext 
Week 12 
(+/- 7 days) 
Ext 
Week 24 
(+/- 7 days) 
Ext 
Week 36 
(+/- 7 days) 
Ext 
Week 48 
or Early 
Term 
(+/- 7 days) 
Week2 
Post last 
dose 
(+/- 7 days) 
Unsched-
uled 
Visit4 
(+/- 7 days) 
Informed Consent 
X 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X 
 
Telephone Check-in5 
Includes AE assessment and concomitant 
medication review 
 
 
X 
 
X3 
 
 
 
 
 
 
Laboratory Assessments6 
X 
 
 
X 
X3 
X 
X 
X 
X 
 
 
Urinalysis 
X 
 
 
 
 
 
X 
 
X 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
X 
 
 
Physical Measurement - Weight 
X 
 
 
 
 
 
X 
 
X 
 
 
Vital Signs 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
12-Lead ECG 
X 
 
 
 
 
X 
X 
 
X 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Sheehan Suicidality Tracking 
Scale (S-STS) 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
Dispense Study Drug 
X 
X 
 
X 
 
X 
X 
X 
 
 
 
Volumetric MRI7 
X 
 
 
 
 
 
 
 
X 
 
 
ADAS-Cog 11 
X 
 
 
 
 
 
X 
 
X 
 
 
CDR-SOB 
X 
 
 
 
 
 
X 
 
X 
 
 
Study Drug Accountability 
 
 
 
X 
 
X 
X 
X 
X 
 
 
Blood Collection for Biomarker 
Banking 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
Craft Story 21 Recall 
X 
 
 
 
 
 
X 
 
X 
 
 
Letter & Category Fluency 
X 
 
 
 
 
 
X 
 
X 
 
 
Number Span Test 
X 
 
 
 
 
 
X 
 
X 
 
 
MoCA 
X 
 
 
 
 
 
X 
 
X 
 
 
 
 
8. 
Baseline visit for the Extension Phase is only required if there is an extended break (≥4 weeks) in dosing between the Randomization and Extension 
Phases. 


ADCS & Biohaven Pharmaceuticals                  
Protocol BHV4157-203 
   Confidential   
03DEC2020 
 
53
9. 
 For participants who will have been off of the study drug for less than or equal to 4 weeks, the subject should come into the investigative site for an 
Abbreviated Drug Dispensation Visit (also “Abbreviated OLE Baseline Visit”), at which time any major medical or medications changes will be 
reviewed prior to dispensing riluzole. In this case, most procedures from the Week 48 visit will also serve as the Open-Label Extension Phase Baseline 
visit 
10. 
Extension Week 8 is primarily to collect Liver Function tests. If a participant prefers not to come into the office, these can be collected at a local 
laboratory, with a telephone call confirming these were collected as well as a review of concomitant medications and an assessment of any adverse 
events. If the participant comes into the center, an assessment of adverse events and Liver function tests will be completed. Although all other visits can 
be conducted remotely as needed due to COVID-19 restrictions, under regular circumstances visits are to be completed in-person. See Protocol Section 
8.1.12, Open-Label Extension Phase, for further details and requirements regarding remote visit completion due to COVID-19. 
11. 
The following must be collected at any unscheduled visit: vital signs, prior and concomitant medications, adverse events, and protocol deviations. All 
other unscheduled visit procedures are subject to PI discretion or request from the Medical Monitor. 
12. 
Telephone calls to subjects will be made between visits during Extension Phase (Weeks 2 and 8) to monitor subject condition, review concomitant 
medications and assess any adverse events. 
13. 
Clinical Safety Laboratory Tests will be performed by a Central Laboratory. Assessment includes the following: Hematology (hemoglobin, hematocrit, 
platelets, RBC, WBC, differential count, and absolute neutrophil count), Chemistry (sodium, potassium, chloride, calcium, ALT, AST, LDH, alkaline 
phosphatase, GGT, phosphorus, bicarbonate, CPK, total protein, albumin, indirect bilirubin, direct bilirubin, total bilirubin, glucose, creatinine, BUN, 
uric acid, folate). 
14. 
Volumetric MRI is not required if the participant’s Double-Blind Week 48 MRI scan occurred less than than 3 months prior to their joining the Open-
Label Extension Phase. 


ADCS & Biohaven Pharmaceuticals                  
Protocol BHV4157-203 
   Confidential   
03DEC2020 
 
54
APPENDIX 2 - Calculating the ADAS-Cog Total Score when there are missing 
data 
The ADAS-Cog is a rater-administered scale with eight performance subtests: Word Recall; 
Commands; Constructional Praxis; Naming; Ideational Praxis; Orientation; Word Recognition; 
Remembering Word Recognition Test Instructions. Three examiner ratings, of Spoken 
Language, Language Comprehension, and Word Finding Difficulty, also are 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 (worst).  
If a participant is unable to complete any of the eight performance subtests, the rater must code 
the reason for incompletion: 
• Not done for reasons other than physical or cognitive 
• Participant refused 
• - Participant unable to complete for physical reasons 
• - Participant unable to complete for cognitive reasons 
When total scores for performance subtest measures are missing because the participant is 
unable to complete the task for cognitive reasons, the worst possible score for the measure will 
be assigned. 
Because Remembering Test Instructions is scored solely based on performance on Word 
Recognition, if Word Recognition was not completed for any reason, then Remembering Test 
Instructions must also be scored as not completed.  
For a given individual performance subtest: 
If 25% or fewer of the items within a subtest are missing, scores for the missing items will be 
prorated as the average of the completed items on that subtest. This procedure will be employed 
for a maximum of two performance subtests.  
If more than 25% of the items within any performance subtest are missing, the entire subtest is 
missing.  
For the ADAS-Cog Total Score 
The total score is the sum of 11 subscales (8 performance subtests and 3 examiner ratings). If 
more than two subscales (either performance subtest or examiner ratings) are missing  or  more 
than 2 performance subtests have partial missing data or if both the Word Recall and Word 
Recognition  subtests are missing, then the ADAS-Cog total score will be missing. Otherwise, 
the total score will be based on the sum of the scores from the non-missing subscales multiplied 
(prorated) by the ratio (max ADAS-cog Total Score of 70/max total possible from non-missing 
subscales). 


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55
For example, if the Word Recall performance subtest , which ranges from 0-10 (maximum=10), 
is missing, and another subtest Commands, which ranges from a score of 0-5 (maximum = 5) is 
also missing, then the total ADAS-cog score will be calculated as the sum from the 9 non-
missing subscales  multiplied by the ratio (70/(70 – (10 + 5)) = 70/55 = 1.27, the resulting 
prorated total score will be rounded up to the nearest integer 
 
 


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56
APPENDIX 3 - Calculating the composite neuropsychological test battery score 
when there are missing data 
A cognitive composite outcome measure will be computed using measures from the NACC 
Neuropsychological Test Battery. The composite outcome will comprise the overall average of 
the Z-scores from each of the following NACC subtest measures: Craft Story 21 total immediate 
Recall; Craft Story 21 total delayed recall; Benson Figure copy score; Benson Figure delayed 
recall; Multilingual Naming Test total correct; Letter Fluency total score; Category Fluency 
total score; Trail Making Test A time to completion; Trail Making Test B time to completion; 
Number Span Forward total correct; and Number Span Backward total correct. Z-scores for 
each participant on each measure will be calculated using the overall average of all participants 
at baseline as reference.  
Missing total scores for subtest measures from the NACC Neuropsychological Test Battery are 
designated as missing for the following reasons: 
• ·     Participant Unable for Cognitive Reasons 
• ·     Participant Unable for Other Reasons (Physical, auditory, etc.) 
• ·     Participant/Study Partner Refused 
• ·     Oversight 
• ·     Other Reason 
• ·     Unknown 
When total scores for subtest measures are missing because the participant was unable to 
complete the task for cognitive reasons, the worst possible score for the measure will be 
assigned. Total scores that are missing for any other reason will be treated as missing in 
calculating the composite neuropsychological test battery score. 
For partially missing (item-level) missing data, if fewer than 25% of items within a NACC 
subtest measure are missing, scores for the missing items will be prorated as the average of the 
completed items on that subtest. This procedure will be employed for a maximum of two NACC 
subtests. If more than 25% of the items within any NACC subtest are missing, the entire subtest 
is missing.  
The total composite neuropsychological test battery score will be calculated as the overall 
average Z-score from each of the completed subtests. If more than 2 NACC subtests are 
missing, the total composite neuropsychological test battery score will be missing.