Clinical trial NCT03952806
Conditions: Multiple System Atrophy
Keywords: Multiple System Atrophy (MSA)
Sponsor: Biohaven Pharmaceuticals, Inc.
Start date: 2019-07-29; Completion date: 2022-06-30
Enrollment: 421 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to compare the efficacy of verdiperstat (BHV-3241) versus placebo in participants with Multiple System Atrophy

Detailed description:

Arms: arm 1: Participants received verdiperstat 300 mg tablet orally once daily for 1 week, followed by 300 mg twice daily for 1 week, and then 600 mg twice daily for the remaining 46 weeks of the double-blind phase.

Participants who completed the double-blind phase were offered the opportunity to enroll in an open-label extension (OLE) phase to continue verdiperstat 600 mg twice daily for 48 weeks. arm 2: Participants received placebo matching with verdiperstat for 48 weeks. Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to receive verdiperstat 600 mg tablet orally twice daily for 48 weeks.
Interventions: intervention 1: Verdiperstat intervention 2: Placebo
Intervention descriptions: intervention 1: 300mg 2 oral tablets, twice daily intervention 2: Matching placebo

Protocol documents:
Prot_000.pdf: 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 1 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
D R U G:
B H V- 3 2 4 1
S T U D Y N U M B E R:
B H V 3 2 4 1- 3 0 1
P R O T O C O L TI T L E:
Ra n d o mize d, D o u ble- Bli n d, Plac e b o- C o ntr olle d, 
Parallel- Gr o u p St u d y t o E val uat e t he Efficac y a n d S afet y 
of B H V- 3 2 4 1 i n S u bjects wit h M ulti ple S yste m Atr o p h y 
( M- S T A R St u d y)
I N D N U M B E R:
E u dr a C T N U M B E R:
1 0 7, 3 9 8
2 0 1 9- 0 0 1 1 0 0- 3 8
S P O N S O R:
Bi o ha ve n P har m ace uticals, I nc
2 1 5 C h urc h Street
Ne w Ha ve n, C T 0 6 5 1 0
U S A
O RI GI N A L P R O T O C O L 
D A T E:
1 9 Dec 2 0 1 8
V E R SI O N N U M B E R:
V 0 7
V E R SI O N D A T E:
2 0 J a n 2 0 2 1


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 2 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
S U M M A R Y O F C H A N G E S
V ersi o n N u m ber
Brief des cri 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 plic a ble
1 9 De c 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 criteri a, a n d 
assess me nt s c he d ule pri or t o E C s u b missi o n.
1 5 Ja n 2 0 1 9
Versi o n 0 3
M o dific ati o n of Pri mar y a n d Sec o n d ar y O bjecti ves a n d 
E n d p oi nts, a d diti o n of P GI- S, refi ne me nt of eli gi bilit y 
criteria a n d d ose m o dific ati o n g ui deli nes, a d diti o n of W ee k 
4 8 p h o n e c all, a d diti o n of B e n efit/ Ris k se cti o n, 
a d mi nistrati ve clarifi cati o ns/ u p dates.
1 8 A pr 2 0 1 9
Versi o n 0 3. 1
U K c o u ntr y s pe cific a me n d me nt- m o dificati o ns p er re q uest 
of M H R A
2 2 N o v 2 0 1 9
Versi o n 0 3. 2
Fra n ce c o u ntr y s pe cific a me n d me nt- m o dificati o ns per 
re q uest of A N S M
0 2 D ec 2 0 1 9
Versi o n 0 3. 3
Ger ma n y c o u ntr y s p ecific a m e n d me nt- m o dificati o ns p er 
re q uest of Bf Ar M
1 8 D ec 2 0 1 9
Versi o n 0 4
O nl y s u b mitt e d t o U S sites -M o dific ati o n of U M S A R S 
a nal ysis per F D A, f urt her refi ne me nt of eli gi bilit y criteria 
a n d clarifi cati o n of pr o hi bite d/restricte d c o nc o mita nt 
me dicati o ns /ti mi n g of re q uire d w as h o ut f or pr o hi bit e d 
me dicati o ns t o a d dress li mitati o ns i n t his rare dise as e 
p o p ulati o n of ver y ill patie nts wit h m ulti ple c o m or bi dities, 
s pecificati o n of o pti o n t o R es cre e n patie nts, i nc or p orati o n of 
A d mi nistrati ve Letter s 1, 2 a n d 3 t o u p d ate 
 me dic al 
m o nit or i nf or mati o n a n d clarif y I P st ora ge te m perat ure a n d 
e xc ursi o n re p orti n g, a n d a d mi nistrati ve 
clarificati o ns/ u p dates.
2 0 N o v 2 0 1 9
Versi o n 0 5
C o ns oli dati o n of c o u ntr y s pecific pr ot oc ol versi o ns 3. 1, 3. 2, 
a n d 3. 3 wit h v ersi o n 4. 0.
3 1 Ja n 2 0 2 0
Versi o n 0 6
1 6 J ul 2 0 2 0
Versi o n 0 7
2 0 Ja n 2 0 2 1
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B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
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B H V 3 2 4 1- 3 0 1 
R A N D O MI Z E D, D O U B L E- B LI N D, P L A C E B O- C O N T R O L L E D, 
P A R A L L E L- G R O U P S T U D Y T O E V A L U A T E T H E E F FI C A C Y A N D 
S A F E T Y O F B H V- 3 2 4 1 I N S U B J E C T S WI T H M U L TI P L E S Y S T E M 
A T R O P H Y ( M- S T A R S T U D Y)
C O N FI D E N TI A LI T Y A N D I N V E S TI G A T O R S T A T E M E N T 
T he i nf or m ati o n c o ntai ne d i n t his pr ot oc ol a n d all ot her i nf or mati o n rele va nt t o B H V- 3 2 4 1 are 
t he c o nfi d e nti al a n d pr o pri etar y i nf or mati o n of Bi o h a ve n P har ma ce uticals, I nc., a n d e xc e pt as 
ma y be re q uire d b y fe der al, state or l o cal la ws or re g ulati o n, ma y n ot b e dis cl ose d t o ot hers 
wit h o ut pri or writte n per missi o n of Bi o ha v e n P har m ace uticals, I nc.
I ha ve rea d t he pr ot oc ol, i ncl u di n g all a p p e n dic es, a n d I a gree t h at it c o ntai ns all of t he 
necessar y i nf or m ati o n f or m e a n d m y st aff t o c o n d u ct t his st u d y as des cri b e d. I will c o n d uct 
t his st u d y as o utli n e d herei n, i n acc or da nce wit h t h e re g ulati o ns state d i n t he Fe d eral C o de of 
Re g ulati o ns f or G o o d Cli nic al Practices a n d I nter nati o nal C o nfere n ce o n Har m o ni zati o n 
g ui deli n es, a n d will ma ke a reas o na bl e eff ort t o c o m plete t he st u d y wit hi n t he ti m e desi g nate d.  
I will pr o vi de all st u d y p ers o n nel u n der m y s u per visi o n c o pies of t he pr ot oc ol a n d a n y 
a me n d m e nts, a n d access t o all i nf or m ati o n pr o vi de d b y Bi o ha ve n P har m ace uticals, I nc. or 
s pecifie d d esi g nees. I will disc uss t he materi al wit h t he m t o e ns ure t hat t he y are f ull y i nf or me d 
a b o ut B H V- 3 2 4 1 a n d t he st u d y. 
 
 
 
 
 
 
 
 
 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
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Pa g e 4 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
S T U D Y S U M M A R Y ( S Y N O P SI S)
 
M ulti ple-s yste m atr o p h y ( M S A) is a n a d ult- o ns et, fat al ne ur o de g e nerati ve 
dis eas e t hat is c har acterize d p at h ol o gicall y b y oli v o p o nt ocere b ell ar a n d 
striat o ni gr al atr o p h y, ne ur o de ge n erati ve c h a n ges affe cti n g t h e ce ntral 
a ut o n o mi c ner v o us s yste m, a n d t he prese nc e of glial c yt o plas mic i n cl usi o ns 
-s y n ucl ei n pr ot ei n i n oli g o de n dr oc yt es. T h e
f or mati o n of G CIs is ass ociate d wit h o xi dati ve stress, ne ur oi nfla m mati o n, l oss 
of ne ur otr o p hic s u p p ort, a n d ulti matel y ne ur o n al c ell deat h.
M yel o per o xi das e ( M P O) is a n e nz y me t hat ge ner ates c yt ot o xi c o xi da nts a n d 
acts as a ke y dri ver of o xi dati ve a n d ne ur oi nfla m mat or y pr ocesses t hat 
u n derlie n e ur o de ge ner ati o n. T he l e vels of M P O are si g nific a ntl y i ncre as e d i n 
acti v ate d i m m u n e cells, s uc h as micr o glia, i n brai ns fr o m M S A patie nts, a n d 
t hese el e vati o ns i n M P O are belie v e d t o pr o m ote ne ur o de ge nerati o n. B y 
i n hi biti n g M P O acti vit y, t her e b y re d uci n g t he ge n erati o n of c yt ot o xic 
o xi dizi n g s pecies, B H V- 3 2 4 1 has t he p ot e ntial t o sl o w t he pr o gressi o n of 
ne ur o de ge nerati o n i n M S A.
I n a m o us e m o del of M S A, treat m e nt wit h B H V- 3 2 4 1 was f o u n d t o ha ve 
ne ur o pr otecti ve effects, i n cl u di n g t he f oll o wi n g: s u p pressi o n of micr o glial 
acti v ati o n ( n e ur oi nfla m mati o n); r e d ucti o n of al p h a-s y n uclei n p at h ol o g y; 
ne ur o pr otecti o n i n s e v eral brai n re gi o ns aff ect e d i n M S A, i ncl u di n g s u bsta ntia 
ni gra a n d stri atal pr ojecti o n ne ur o ns; a n d be nefici al effects o n m ot or f u n cti o n.
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B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa g e 5  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
 
 
 
 
 
 
 
 T o e val u ate t he effi cac y of B H V- 3 2 4 1, c o m p are d t o place b o, as meas ure d 
b y a c ha n ge fr o m bas eli n e i n a m o difi e d U nifie d M S A Rati n g Scal e 
( U M S A R S), c o nsisti n g of a s u bset of ite ms fr o m Part I a n d P art II, at 
Wee k 4 8. 
 T o assess t he safet y a n d t olera bilit y of B H V- 3 2 4 1, relati v e t o pl ace b o, i n 
s u bjects wit h M S A. 
 
 T o e val u ate t he effi cac y of B H V- 3 2 4 1, c o m p are d t o place b o, as meas ure d 
b y t he Cli nical Gl o bal I m pressi o n of I m pr o ve m e nt ( C GI-I) s c ore at Wee k 
4 8. 
 T o e val u ate t he i m pact of B H V- 3 2 4 1 o n q ualit y of life, c o m par e d t o 
place b o, as meas ure d b y a c ha n ge fr o m baseli ne i n t he m ot or s u bs cal e of 
t he M S A- Q ualit y of Lif e ( M S A- Q o L) s cale at W ee k 4 8. 
 T o e val u ate t he i m pact of B H V- 3 2 4 1 o n q ualit y of life, c o m par e d t o 
place b o, as meas ure d b y a c ha n ge fr o m baseli ne i n t he n o n- m ot or s u bs cal e 
of  t he M S A- Q o L s cale at Wee k 4 8. 
 T o e val u ate t he effi cac y of B H V- 3 2 4 1, c o m p are d t o place b o, as meas ure d 
b y a c ha n ge fr o m bas eli n e i n t h e U M S A R S P art I a n d Part II t otal s c ore at 
Wee k 4 8. 
 
 T o ass ess t he i m pa ct of B H V- 3 2 4 1, relati ve t o plac e b o, as meas ure d b y a 
c ha n ge fr o m b as eli ne at W ee k 4 8 i n t he f oll o wi n g i nstr u me nts: 
 Patie nt Gl o b al I m pr essi o n of S e verit y ( P GI- S), 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
Cli nic al Gl o bal I m pressi o n of Se verit y ( C GI- S),
U M S A R S Part III,
U M S A R S Part I V.
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B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 7 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
Fi g ur e 1:
St u d y S c h e m ati c
 
 
 
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B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 8 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
T A B L E O F C O N T E N T S
 
S U M M A R Y O F C H A N G E S  ..................................................................................................... 2 
C O N FI D E N TI A LI T Y A N D I N V E S TI G A T O R S T A T E M E N T  ............................................ 3 
S T U D Y S U M M A R Y ( S Y N O P SI S)  ........................................................................................... 4 
T A B L E O F C O N T E N T S  ........................................................................................................... 8 
LI S T O F T A B L E S  ................................................................................................................... 1 0 
LI S T O F FI G U R E S  ................................................................................................................. 1 0 
LI S T O F A B B R E VI A TI O N S  .................................................................................................. 1 1 
1  
I N T R O D U C TI O N A N D R A TI O N A L E .......................................................................... 1 5 
1. 1  
B ac k gr o u n d  ................................................................................................................... 1 5 
1. 1. 1  
M ulti ple S yste m Atr o p h y ( M S A)  .......................................................................... 1 5 
 
1. 1. 3  
B H V- 3 2 4 1  ................................................................................................................ 1 6 
 
1. 1. 5  
Cli nic al A d vers e E ve nt P r ofil e  .............................................................................. 2 9 
1. 1. 6  
P ote nti al Ris k t o Fet al De v el o p me nt  .................................................................... 3 5 
1. 2  
St u d y R ati o n ale ............................................................................................................. 3 5 
1. 2. 1  
St u d y D esi g n R ati o n ale  .......................................................................................... 3 5 
1. 3  
D ose Selecti o n  ............................................................................................................... 3 6 
1. 4  
Be n efit- Ris k ................................................................................................................... 3 7 
2  
S T U D Y O B J E C TI V E S  ..................................................................................................... 4 0 
2. 1  
Pri m ar y  ......................................................................................................................... 4 0 
2. 2  
Sec o n d ar y  ...................................................................................................................... 4 0 
 
3  
S T U D Y E N D P OI N T S  ....................................................................................................... 4 2 
3. 1  
Pri m ar y  ......................................................................................................................... 4 2 
3. 2  
Sec o n d ar y  ...................................................................................................................... 4 2 
4  
S T U D Y P L A N  ................................................................................................................... 4 3 
4. 1  
St u d y D esi g n a n d D ur ati o n  ......................................................................................... 4 3 
4. 2  
St u d y Sc he m atic  ........................................................................................................... 4 3 
4. 3  
Sc he d ule of Assess me nts  .............................................................................................. 4 4 
4. 3. 1  
C O VI D- 1 9 P u blic He alt h E mer ge nc y  .................................................................. 4 4 
4. 3. 2  
Scree ni n g P h as e  ...................................................................................................... 5 4 
4. 3. 3  
R a n d o miz ati o n P h as e  ............................................................................................. 5 4 
4. 4  
E n d of Tre at me nt  ......................................................................................................... 5 5 
4. 5  
P ost St u d y A ccess t o T her a p y/ O pe n- L a bel E xte nsi o n P h ase  ................................... 5 6 
4. 5. 1  
O pe n- L a bel E xte nsi o n P h ase Eli gi bilit y Crite ri a  ................................................ 5 6 
4. 5. 2  
O pe n- L a bel E xte nsi o n P h ase Pr oce d ures  ............................................................ 5 7 
5  
P O P U L A TI O N  .................................................................................................................. 5 8 
5. 1  
N u m ber of S u bjects  ...................................................................................................... 5 8 
5. 2  
I ncl usi o n Criteri a ......................................................................................................... 5 8 
5. 3  
E xcl usi o n Criteri a  ........................................................................................................ 6 0 
5. 4  
Pr o hi bite d a n d R estricte d C o n c o mit a nt Me dic ati o n  ................................................ 6 5 
5. 4. 1  
Ot h er R estricti o ns a n d Prec a uti o ns ...................................................................... 6 7 
5. 5  
W o m a n of C hil d be ari n g P ote nti al ( W O C B P)  ........................................................... 6 8 
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B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
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A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
5. 6
D e vi ati o n fr o m I ncl usi o n/ E xcl usi o n Criteri a ............................................................. 6 9
6  
S T U D Y C O N D U C T A N D D E S C RI P TI O N O F S T U D Y P R O C E D U R E S  .................. 6 9 
6. 1  
St u d y M ateri als  ............................................................................................................ 6 9 
6. 2  
Eli gi bilit y a n d S afet y Ass ess me nts  .............................................................................. 6 9 
6. 2. 1  
Me dic al a n d Ps yc hi atric Hist or y ........................................................................... 6 9 
6. 2. 2  
S afet y Assess me nts  ................................................................................................. 6 9 
6. 2. 3  
Cli nic al O utc o m e Assess me nts  .............................................................................. 7 3 
6. 3  
Ot h er Ass ess me nts ........................................................................................................ 7 6 
 
6. 3. 2  
P h ar m ac o ki netic Assess me nts ............................................................................... 7 7 
 
6. 3. 5  
C S F C ollecti o n ( O pti o n al)  ..................................................................................... 7 9 
6. 4  
E arl y Dis c o nti n u ati o n fr o m t he St u d y  ....................................................................... 7 9 
7  
S T U D Y D R U G M A N A G E M E N T  ................................................................................... 8 1 
7. 1  
D es cri pti o n of St u d y D r u g  ........................................................................................... 8 1 
7. 1. 1  
I n vesti g ati o n al Pr o d uct .......................................................................................... 8 1 
7. 1. 2  
P ac k a gi n g, S hi p me nt a n d St or a ge  ........................................................................ 8 1 
7. 2  
D ose a n d A d mi nistr ati o n  ............................................................................................. 8 2 
7. 2. 1  
Met h o d of Assi g ni n g P atie nt I d e ntific ati o n  ......................................................... 8 2 
7. 2. 2  
Selecti o n a n d Ti mi n g of D ose a n d A d mi nistr ati o n  ............................................. 8 3 
7. 2. 3  
D ose M o dific ati o ns  ................................................................................................. 8 4 
7. 3  
Bli n di n g a n d U n bli n di n g ............................................................................................. 8 5 
7. 4  
Tre at me nt C o m pli a n ce  ................................................................................................ 8 6 
7. 5  
D estr ucti o n a n d R et ur n of St u d y Dr u g  ...................................................................... 8 6 
8  
A D V E R S E E V E N T S  ......................................................................................................... 8 6 
8. 1  
Seri o us A d verse E ve nts  ................................................................................................ 8 7 
8. 1. 1  
D efi niti o n of Seri o us A d verse E ve nt ( S A E)  ......................................................... 8 7 
8. 1. 2  
D efi niti o n of Ter ms  ................................................................................................ 8 7 
8. 1. 3  
Cl assific ati o n of A d vers e E ve nts  ........................................................................... 8 8 
8. 1. 4  
C ollecti o n a n d R e p orti n g S eri o us A d vers e E ve nts .............................................. 8 9 
8. 1. 5  
O ver d ose  .................................................................................................................. 9 1 
8. 1. 6  
Pre g n a nc y  ................................................................................................................ 9 1 
8. 1. 7  
P ote nti al D r u g I n d uce d Li ver I nj ur y ( DI LI)  ....................................................... 9 2 
8. 1. 8  
A d vers e E ve nt of S peci al I nterest- T h yr oi d F u n cti o n  ......................................... 9 2 
8. 2  
N o n-s eri o us A d vers e E ve nts  ........................................................................................ 9 3 
8. 2. 1  
C ollecti o n a n d R e p orti n g of N o n- Seri o us A d verse E ve nts  ................................. 9 3 
8. 2. 2  
L a b or at or y Test A b n or m alities  ............................................................................ 9 3 
9  
S T A TI S TI C S  ..................................................................................................................... 9 4 
9. 1  
Ge ner al Pr oce d ures  ...................................................................................................... 9 4 
9. 2  
S a m ple Size  ................................................................................................................... 9 4 
9. 3  
P o p ul ati o ns f or A n al ysis  .............................................................................................. 9 4 
9. 4  
St atistic al Met h o ds  ....................................................................................................... 9 5 
9. 4. 1  
D e m o gr a p hic a n d B aseli n e C h ar acteristi cs  ......................................................... 9 5 
9. 4. 2  
Pri m ar y E n d p oi nt(s)  .............................................................................................. 9 5 
9. 4. 3  
Sec o n d ar y E n d p oi nt(s)  ........................................................................................... 9 6 
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B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
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B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 1 0  of 1 0 6  
 
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9. 4. 4
E xte nsi o n P h as e A n al ysis ....................................................................................... 9 6
9. 4. 5  
A dj ust me nt f or M ulti plicit y  .................................................................................. 9 6 
9. 4. 6  
Missi n g D at a  ........................................................................................................... 9 6 
9. 4. 7  
A n al ysis of S afet y  ................................................................................................... 9 7 
9. 5  
Sc he d ule of A n al ys es  .................................................................................................... 9 7 
1 0  E T HI C S A N D R E S P O N SI BI LI TI E S  ............................................................................. 9 7 
1 0. 1  
G o o d Cli nic al P r acti ce  ................................................................................................. 9 7 
1 0. 2  
D at a M o nit ori n g C o m mittee  ....................................................................................... 9 8 
1 0. 3  
I nstit uti o n al R e vie w B o ar d/I n d e pe n d e nt Et hics C o m mittee  ................................... 9 8 
1 0. 4  
I nf or me d C o ns e nt ......................................................................................................... 9 9 
1 0. 5  
C ase R e p ort F or ms ..................................................................................................... 1 0 0 
1 0. 6
R ec or ds M a n a ge me nt a n d Rete nti o n ....................................................................... 1 0 0
1 0. 7  
S o urce D oc u me nt ati o n  ............................................................................................... 1 0 1 
1 0. 8  
St u d y Files a n d R ec or d R ete nti o n  ............................................................................ 1 0 1 
1 1  A M E N D M E N T S  ............................................................................................................. 1 0 1 
1 2  S T U D Y R E P O R T A N D P U B LI C A TI O N S  .................................................................. 1 0 2 
1 3  S T U D Y DI S C O N TI N U A TI O N  ..................................................................................... 1 0 2 
1 4  C O N FI D E N TI A LI T Y  .................................................................................................... 1 0 2 
1 5  A P P E N DI C E S  ................................................................................................................. 1 0 3 
1 5. 1  
A P P E N DI X I - N a mes of St u d y Pers o n nel ............................................................... 1 0 3 
1 6  R E F E R E N C E S CI T E D  .................................................................................................. 1 0 4 
C LI NI C A L P R O T O C O L A P P R O V A L F O R M .................................................................. 1 0 6 
 
LI S T O F T A B L E S 
T a ble 1:  
Sc he d ule of Assess me nts a n d E ve nts - R a n d o mize d D o u ble- bli n d P h as e  ... 4 7 
T a ble 2:  
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  ......... 5 1 
 
LI S T O F FI G U R E S 
Fi g u re 1: 
St u d y Sc he m atic ................................................................................................. 7
Fi g u re 2:  
St u d y Sc he m atic  ............................................................................................... 4 3 
 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 1 1 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
LI S T O F A B B R E VI A TI O N S
C CI
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 1 2  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 1 3 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI
C CI
C CI
C CI
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 1 4 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
 
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 1 5  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
1 I N T R O D U C TI O N A N D R A TI O N A L E 
1. 1 
B a c k gr o u n d 
Bi o ha ve n P har m ace uticals, I nc [ Bi o ha v e n] is de vel o pi n g a ne w dr u g, B H V- 3 2 4 1, als o k n o w n 
as V er di perstat, f or t he tre at m e nt of m ulti ple s yste m atr o p h y ( M S A). B H V- 3 2 4 1 is a n 
irre versi bl e i n hi bit or of t h e m yel o p er o xi das e ( M P O) e nz y me t hat g e nerat es c yt ot o xic o xi dizi n g 
a n d nitr os ylati n g c o m p o u n ds.  T he pr o p os e d st u d y is bas e d o n c u m ul ati v e precli nic al, cli ni cal, 
a n d ne ur oi m a gi n g st u di es t hat i m plicate M P O acti vit y i n t he o ns et a n d pr o gressi o n of 
ne ur o de ge nerati ve dis eas es, i ncl u di n g M S A, s u g gesti n g treat me nt wit h B H V- 3 2 4 1 has t he 
p ote nti al t o sl o w ne ur o d e ge nerati o n i n M S A. T he hi g h u n met nee d f or a n effecti v e tre at m e nt, 
t o get her wit h t he a vaila ble d ata, pr o vi de a c o m pelli n g rati o nale f or t h e de vel o p me nt of B H V-
3 2 4 1 as a treat me nt f or M S A.  
1. 1. 1
M ulti pl e S y st e m Atr o p h y ( M S A) 
M S A is a n or p ha n diseas e ( Or p ha n n u m ber: O R P H A 1 0 2 [ w w w. or p ha. net]) t hat is a n a d ult-
o ns et, fatal ne ur o de ge n erati ve dise as e 1. O nset of M S A us uall y occ urs d uri n g t he si xt h dec a de 
of life, a n d i n vari a bl y le a ds t o deat h aft er a n a v era ge of 6 t o 1 0 years fr o m s y m pt o m o nset, wit h 
t he ca us es of de at h c o m m o nl y bei n g br o nc h o p ne u m o nia, ur ose psis, a n d s u d de n deat h. N o 
dis eas e m o dif yi n g tre at m e nt c urre ntl y e xists, o nl y s y m pt o matic a n d palliati ve a p pr o ac hes ar e 
a vail a ble 1. 
T he defi ni n g ne ur o pat h ol o g y of M S A o n p ost- m orte m e xa mi nati o n i ncl u des varia ble de gr ees 
of oli v o p o nt ocere bellar atr o p h y a n d stri at o ni gr al de g e nerati o n, w hic h refl ect t he prese n ce of 
ata xi a a n d par ki ns o nis m, res pecti vel y, d uri n g lif e. I n a d diti o n, n e ur o de ge n erati v e c ha n g es 
affect t he ce ntral a ut o n o mic ner v o us s yste m, i ncl u di n g t he h y p ot hala m us, n ora dr e ner gic a n d 
s er ot o ni ner gi c brai n-st e m n ucl ei, d ors al n u cle us of t h e va g us ner ve, n ucle us a m bi g u us, 
i nter m e di ol ater al c ol u m ns of t he s pi nal c or d, a n d O n uf n ucle us. T he d efi ni n g m olec ular a n d 
cell ular ne ur o pat h ol o g y of M S A is t he wi des prea d pr es e nce of glial c yt o plas mi c i ncl usi o ns 
( G CIs) c o ntai ni n g fi brili ze
-s y n ucl ei n pr ot ei n i n oli g o de n dr oc yt es 2- 4. M S A is t h us 
-s y n uclei n o p at h y, 
eas e a n d de m e nti a wit h Le w y b o di es, 
alt h o u g h it has ver y disti nct p at h ol o gical a n d cli nic al feat ures. 
M S A is a s p ora dic dis eas e of u n k n o w n eti ol o g y. Alt h o u g h t he pat h o p h ysi ol o gic al m ec ha nis ms 
u n derl yi n g M S A re mai n u n cle ar, e vi de n ce fr o m pr ecli nic al m o d els a n d p ost- m orte m st u dies 
s u g gests t hat t he f or mati o n of G CIs is ass oci ate d wit h o xi dati v e stress, ne ur oi nfl a m m ati o n, l oss 
of ne ur otr o p hic s u p p ort, a n d ulti matel y ne ur o n al c ell deat h.  
M S A is c haracteri ze d cli nic all y b y pr o gr essi ve a ut o n o mic fail ure, p ar ki ns o nia n fe at ures, a n d 
cere bellar a n d p yr a mi d al fe at ures i n v ari o us c o m bi nati o ns 1. Patie nts wit h M S A are di vi de d 
i nt o 2 s u bt y pes base d o n t h eir pre d o mi na nt s y m pt o ms: 1) M S A- P patie nts ha ve pre d o mi na ntl y 
par ki ns o nia n feat ures; a n d 2) M S A- C pati e nts ha ve cere bellar ata xia as t he pre d o mi na nt 
s y m pt o m. Bas e d o n t h e re vis e d crit eria f or t h e dia g n osis of M S A t hat were esta blis he d at a 
c o nse ns us c o nfere nce i n 2 0 0 7 5, t he di a g n osis of M S A i ncl u des 3 cate g ori es: 1) Defi nit e M S A; 
2) Pr o ba ble M S A; a n d 3) P ossi ble M S A. As t he pre d o mi na nt f eat ur es of M S A ma y c ha n ge 
o ver ti m e, t he d esi g nati o n of M S A- P or M S A- C f or a gi ve n patie nt ma y c ha n ge d uri n g t he 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 1 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
c o urs e of t he dis e as e. A p pr o xi mat el y 6 0- 8 0 % of M S A patie nts i n E ur o pe a n d N ort h A m erica 
ha ve t he M S A- P s u bt y pe 6, w hereas 6 5- 8 5 % of M S A patie nts i n Ja pa n a n d K orea h a ve t h e 
M S A- C s u bt y pe 
7, 8.
M S A has a n esti mate d p oi nt pre v ale nc e of 3. 4 t o 4. 9 cas es per 1 0 0, 0 0 0, i ncre asi n g t o 7. 8 per 
1 0 0, 0 0 0 a m o n g pers o ns ol der t h a n 4 0 years of a g e 9. Cas es of M S A- P o ut n u m ber cases of 
M S A- C b y 2: 1 t o 4: 1 i n m ost c o u ntries
1 0- 1 2, wit h M S A- C bei n g m ore pre vale nt i n J a pa n 1 3 a n d 
li kel y i nfl ue n ce d b y ge netic a n d e pi g e netic fa ct ors.
1. 1. 3
B H V- 3 2 4 1
B H V- 3 2 4 1 is a n irre versi ble, mec ha nis m- base d M P O i n hi bit or t h at is h y p ot h esize d t o s u p press 
t he ge ner ati o n of c yt ot o xic o xi di zi n g a n d nitr os ylati n g c o m p o u n ds, t here b y sl o wi n g t he 
pr o gressi o n of M S A-ass ociate d ne ur o de ge ner ati o n. T he e nz y me, M P O, is a n o xi dati ve he m e 
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 1 7 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
pr otei n release d pri maril y b y acti vate d ne utr o p hils, b ut is als o e x presse d i n p h a g oc ytic cells, 
i ncl u di n g micr o glia, a n d le a ds t o t he pr o d ucti o n of h y p oc hl oric aci d, a p ote nt o xi da nt. M P O 
o xi dizes nitrit e t o re acti ve nitr o g e n s peci es a n d c o n v erts t yr osi ne t o t yr os yl ra di cal, a r eacti ve 
i nter
- dit yr osi ne f or mati o n a n d i nitiat es li pi d p er o xi dati o n. 
1. 1. 3. 1
Pr e- Cli ni c al St u di e s
S u m maries of rele va nt fi n di n gs fr o m pre- cli nical st u dies c o n d uct e d wit h B H V- 3 2 4 1 are 
pr o vi de d. Please r efer t o t h e I n vesti g at or Br oc h ur e f or a d diti o n al i nf or mati o n. 
1. 1. 3. 1. 1
Pri m ar y P h ar m a c o d y n a mi c s
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 1 8 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 1 9 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 0 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 1 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 2 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1. 1. 3. 2
Cli ni c al E x p eri e n c e
T o date, se v e n cli nical st u dies (f o ur P hase 1 st u di es i n healt h y s u bj ects; t w o P hase 2 st u dies i n 
s u bject
s u bjects wit h M S A) ha ve be e n 
c o n d ucte d wit h B H V- 3 2 4 1, wit h a p pr o xi m atel y 2 3 4 s u bjects ha vi n g r ecei ve d B H V- 3 2 4 1 i n 
t hese cli nic al st u di es. Refer t o t h e I n vesti g at or Br oc h ure f or detaile d i nf or mati o n o n t hese 
st u dies. 
1. 1. 3. 2. 1
B H V- 3 2 4 1 P h a s e I 
Refer t o t h e I n vesti g at or Br oc h ure f or d etaile d i nf or mati o n o n t he P has e 1 st u di es. 
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 3 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 4 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 5 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1. 1. 3. 2. 2. 3
St u d y D 0 4 9 0 C 0 0 0 2 3
T his P hase 2 1 2- w ee k, m ultice nter, ra n d o miz e d, parallel- gr o u p st u d y i n patie nts wit h M S A was 
desi g ne d t o ass ess t he eff ect o n s afet y, t ol era bilit y, p har mac o ki netics, mi cr o glial acti vati o n 
(assess e d b y P E T i ma gi n g), bi o mar k er effects, a n d efficac y of t w o d osa ges of B H V- 3 2 4 1 ( 3 0 0 
m g a n d 6 0 0 m g BI D). Recr uite d s u bj ects were m ale a n d fe male, 3 0 t o 8 0 y ears of a ge, 
i ncl usi ve, at Scre e ni n g, w h o met t he criteria f or di a g n osis of pr o ba ble or p ossi ble M S A 
acc or di n g t o c o ns e ns us cli nical crit eria. 5 9 s u bj ects were act u all y ra n d o miz e d a n d tr eat e d ( 1 9,
B H V- 3 2 4 1 3 0 0 m g BI D; 2 0, B H V- 3 2 4 1 6 0 0 m g BI D; a n d 2 0, plac e b o BI D); a n d 4 6 s u bjects 
c o m plete d t h e st u d y ( 1 4, B H V- 3 2 4 1 3 0 0 m g BI D; 1 7 B H V- 3 2 4 1 6 0 0 m g BI D; a n d 1 5 place b o 
BI D). 
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 7 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
P E T i ma gi n g: B H V- 3 2 4 1 treat me nt at eit her d osa g e ( 3 0 0 m g or 6 0 0 m g) ha d n o statisti call y 
si g nifica nt effe ct o n micr o gli al a cti v ati o n, b as e d o n c ha n ge i n t h e re gi o n al t otal distri b uti o n 
T ) meas ure d b y P E T i ma gi n g of ra di oli ga n d [1 1C]
P B R 2 8 bi n di n g t o tra nsl o cat or pr otei n. I m p orta ntl y, t he lac k of st atisticall y si g nifica nt 
differe nce bet w ee n B H V- 3 2 4 1 tre at m e nt ar ms a n d pl ace b o ar ms o n [ 1 1C] P B R 2 8 bi n di n g t o 
T S P O is n ot i nc o nsiste nt wit h a p ote ntial tre at m e nt effect i n M S A. T he relati vel y l ar ge 
treat me nt effect si ze i n St u d y D 0 4 9 0 C 0 0 0 0 4
was us e d t o 
deter mi ne t h e s a m pl e size f or t his st u d y i n patie nts wit h M S A, a n d ma y ha ve b ee n a n 
o veresti m ate. I n a d diti o n, t here are k n o w n iss ues wit h t his P E T i m a gi n g t ec h ni q u e, i ncl u di n g 
heter o ge n e o us a n d n o n-s pecifi c bi n di n g a n d si g nal-t o- n ois e rati o.
Plas ma M P O acti vit y: B H V- 3 2 4 1 treat me nt f or 1 2 wee ks (at d os es of eit her 3 0 0 m g BI D or 
6 0 0 m g BI D) s h o w e d statistic all y si g nific a nt re d ucti o ns i n meas ures of M P O acti vit y i n 
plas ma. F or s pecific M P O acti vit y ( M P O acti vit y/ M P O pr otei n), t here were statisticall y 
si g nifica nt re d ucti o ns of a p pr o xi matel y 1 0 % bet we e n bas eli ne a n d p ost- d os e ass ess me nts at 
Wee k 1 2, f or t h e B H V- 3 2 4 1 3 0 0 m g BI D a n d B H V- 3 2 4 1 6 0 0 m g BI D treat e d gr o u ps 
( p = 0. 0 1 3 8 a n d p = 0. 0 0 0 3, res pecti vel y). Pair wise c o m paris o ns bet wee n t he B H V- 3 2 4 1 treat e d 
gr o u ps a n d place b o w ere st atisticall y si g nifica nt ( p = 0. 0 1 6 6 a n d p = 0. 0 0 2 6 f or t he 3 0 0 m g BI D 
a n d 6 0 0 m g BI D gr o u ps, res pecti v el y). T hes e cli nical trial res ults s u p p ort t h e i nt e n de d 
mec ha nis m of acti o n of B H V- 3 2 4 1.
P K:
M S A s u bjects treate d wit h B H V- 3 2 4 1 3 0 0 m g BI D f or 1 2 wee ks ha d t he f oll o wi n g st ea d y 
ma x of 2. 3 8 
( C V: 4 6. 4 %). M S A s u bjects treate d wit h B H V- 3 2 4 1 6 0 0 m g BI D f or 1 2 wee ks ha d t he 
f oll o wi n g stea d y st ate, g e o metric m ea n e x p os ures: A U C of 3
C V: 4 3. 8 %) a n d 
C ma x o
V: 4 1. 6 %).
Safet y/ T olera bilit y: B H V- 3 2 4 1 treat me nt was ge n erall y safe a n d well-t olerat e d i n M S A 
s u bjects at d os es of 3 0 0 m g a n d 6 0 0 m g BI D.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 8 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 2 9 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1. 1. 5
Cli ni c al A d v er s e E v e nt Pr ofil e
T o date, a p pr o xi m atel y 2 3 4 s u bjects ha v e rec ei ve d B H V- 3 2 4 1 i n s e ve n cli ni cal st u dies: f o ur 
P hase 1 st u dies i n healt h y s u bje cts, a P hase 2 P E T i ma gi n g st u d y i n 
dis eas e ( St u d y D 0 4 9 0 C 0 0 0 0 4), a P has e 2 safet y a n d t olera bilit y st u d y i n s u bje cts wit h 
dis eas e ( St u d y D 0 4 9 0 C 0 0 0 0 5), a n d a P has e 2 P E T i m a gi n g st u d y i n s u bj ects wit h 
M S A ( St u d y D 0 4 9 0 C 0 0 0 2 3). I n t he P hase 1 st u dies, treat me nt wit h m ulti pl e d os es of u p t o 9 0 0 
m g B H V- 3 2 4 1 BI D w as ge nerall y safe a n d well t ol erate d. I n t h e P hase 2 st u dies i n s u bj ects 
dis eas e a n d M S A, treat me nt wit h B H V- 3 2 4 1 at d oses of u p t o 6 0 0 m g BI D
f or 8- 1 2 w ee ks w as ge nerall y s afe a n d well t oler ate d.
1. 1. 5. 1
B H V- 3 2 4 1 P h a s e 1 St u di e s
T o date, 4 P hase 1 st u dies ha ve b ee n c o n d ucte d wit h B H V- 3 2 4 1. Ke y safet y-relate d fi n di n gs 
fr o m t hes e st u di es are pres e nt e d bel o w.
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 3 0 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 3 1 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1. 1. 5. 2
B H V- 3 2 4 1:  P h a s e 2 Cli ni c al A d v er s e E v e nt Pr ofil e
T o date, 3 P hase 2 st u dies ha ve b ee n c o n d ucte d wit h B H V- 3 2 4 1 . Ke y safet y-relate d fi n di n gs 
fr o m t hes e st u di es are pres e nt e d bel o w.
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 3 2 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1. 1. 5. 2. 3
St u d y D 0 4 9 0 C 0 0 0 2 3
I n t his st u d y i n M S A patie nts, tr eat me nt wit h B H V- 3 2 4 1 ( 6 0 0 m g BI D a n d 3 0 0 m g BI D) f or 1 2 
w ee ks w as ge nerall y safe a n d w ell t oler ate d. T here were 2 deat hs i n t his st u d y d ue t o A Es of 
M S A disease pr o gressi o n ( B H V- 3 2 4 1 6 0 0 m g) a n d c h o ki n g o n f o o d ( plac e b o); b ot h e ve nts 
w ere c o nsi dere d se ver e a n d j u d g e d n ot relat e d t o B H V- 3 2 4 1. T hree s u bjects e x perie n ce d 
S A Es. O ne s u bject i n t he B H V- 3 2 4 1 3 0 0 m g tr eat e d gr o u p ha d a n S A E of fract ure d ri g ht hi p 
t hat w as c o nsi der e d se vere, j u d g e d n ot relat e d t o st u d y dr u g, a n d le d t o dis c o nti n u ati o n. T w o 
s u bjects ha d S A Es of M S A dis eas e pr o gressi o n a n d c h o ki n g w hic h l e d t o deat h (see a b o v e). 
F o ur s u bjects, 3 recei vi n g B H V- 3 2 4 1 3 0 0 m g a n d 1 recei vi n g place b o, disc o nti n ue d t h e st u d y 
d ue t o A Es. T he A Es t hat le d t o dis c o nti n uati o n of tr eat m e nt wit h B H V- 3 2 4 1 3 0 0 m g i n cl u de d 
mil d-t o- m o derate bala nce dis or der, s y nc o pe, fe eli n g jitt er y, a n d e pista xis i n 1 s u bj ect; fract ur e d 
ri g ht hi p (se v er e) i n a sec o n d s u bj ect; a n d d ys p ha gi a (se vere) i n a t hir d s u bject. T he s u bj ect 
recei vi n g place b o dis c o nti n ue d fr o m t he st u d y d ue t o ge neral disc o mf ort ( m o derat e) a n d 
hea dac h e ( mil d). All of t he e ve nts l ea di n g t o dis c o nti n uati o n, e x ce pt f or e pista xis a n d hi p 
fract ure, w ere c o nsi dere d b y t he I n vesti gat or- t o be r elat e d t o st u d y dr u g a d mi nistr ati o n. T he 
o verall i nci d e nce of T E A Es w as si milar acr oss t he tr eat m e nt gr o u ps, ra n gi n g fr o m 7 8. 9 % t o 
8 4. 2 %. T he m ost c o m m o n A E w as uri nar y tract i nfe cti o n, re p orte d wit h a hi g her i n ci de n ce i n 
t he B H V- 3 2 4 1 3 0 0- m g gr o u p ( 2 6. 3 %) t ha n i n t he B H V- 3 2 4 1 6 0 0 m g ( 1 5. 0 %) or place b o 
( 1 5. 8 %) gr o u ps. Fati g u e w as re p orte d wit h a si milar i nci de n ce i n t he B H V- 3 2 4 1 3 0 0 m g 
( 1 5. 8 %) a n d 6 0 0 m g ( 1 5. 0 %) gr o u ps, b ut wit h a l o wer i nci d e nce i n t he pl ace b o gr o u p ( 5. 3 %).
Ort h ostatic h y p ote nsi o n w as m ore fre q u e nt a m o n g s u bjects i n t he B H V- 3 2 4 1 6 0 0 m g gr o u p 
( 1 5. 0 %) t ha n i n t h e B H V- 3 2 4 1 3 0 0 m g ( 5. 3 %) a n d place b o ( 0) gr o u ps. Si milarl y, falls a n d 
pres y nc o pe e ve nts w ere m ore fre q u e nt a m o n g s u bjects i n t he B H V- 3 2 4 1 6 0 0 m g gr o u p ( 2 0. 0 % 
a n d 1 0. 0 %, res pecti vel y) t ha n i n t h e B H V- 3 2 4 1 3 0 0 m g ( 5. 3 % f or b ot h e ve nts) a n d plac e b o 
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 3 3 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
( 5. 3 % a n d 0, res pecti vel y) gr o u ps. T he maj orit y of A Es re p orte d i n t his st u d y were mil d 
( 6 3. 2 % of e ve nts i n b ot h t he pl ace b o a n d B H V- 3 2 4 1 3 0 0 m g gr o u ps a n d 6 0. 0 % of e ve nts i n t he 
B H V- 3 2 4 1 6 0 0 m g gr o u p). Se vere T E A Es were re p orte d i n 1 s u bje ct e ac h i n t he B H V- 3 2 4 1
6 0 0 m g ( 5. 0 %) a n d pla ce b o ( 5. 3 %) gr o u ps a n d i n 4 s u bjects i n t he B H V- 3 2 4 1 3 0 0 m g gr o u p 
( 2 1. 1 %). T he s e vere T E A Es i n t he B H V- 3 2 4 1 3 0 0 m g gr o u p were d ys p ha gia, t h er mal b ur n, hi p 
fract ure, a n d hea da c he; a n d t he s e v ere A E i n t he B H V- 3 2 4 1 6 0 0 m g gr o u p was M S A 
( w ors e ni n g). C h o ki n g w as t he se vere A E i n t he pl ace b o gr o u p. T he maj orit y of A Es were 
j u d ge d u nrel ate d t o st u d y treat me nt b y t he I n v esti gat ors, ra n gi n g fr o m 7 0. 0 % t o 7 3. 7 % a cr oss 
t he tre at m e nt gr o u ps. Treat me nt-rel ate d A Es were r e p orte d i n 6 ( 3 1. 6 %) s u bjects i n t h e B H V-
3 2 4 1 3 0 0 m g gr o u p, 5 ( 2 5. 0 %) s u bjects i n t he B H V- 3 2 4 1 6 0 0 m g gr o u p, a n d 4 ( 2 1. 1 %) 
s u bjects i n t h e place b o gr o u p.
La b orat or y v al ues t h at met p ote ntiall y cli ni call y si g nifica nt ( P C S) criteria were i nfr e q ue nt i n 
t his st u d y. Of 1 7 s u bjects wit h P C S la b orat or y val u es, 7 recei ve d place b o, 6 r ecei ve d B H V-
3 2 4 1 3 0 0 m g BI D, a n d 4 recei ve d B H V- 3 2 4 1 6 0 0 m g BI D. T hree ( 1 6. 7 %) s u bjects i n t he 
B H V- 3 2 4 1 3 0 0 m g gr o u p ha d p ote nti all y cli nicall y si g nific a nt T S H le v els: 1 s u bject ha d l o w 
T S H at t he e arl y t er mi nati o n ( 0. 1 8 uI U/ m L) a n d f oll o w- u p ( 0. 3 3 uI U/ m L; refere n ce ra n g e: 
0. 3 4- 5. 6) visits; 1 ot her s u bj ect h a d hi g h T S H at Wee ks 2, 3, 4, 8, a n d 1 2 (ra n gi n g fr o m 6. 5 8 t o 
9. 3 3 uI U/ m L); a n d t he t hir d s u bject ha d hi g h T S H be gi n ni n g at Wee k 4 ( 9. 1 1 uI U/ m L) a n d 
decreasi n g at We e k 8 ( 7. 4 3 uI U/ m L) a n d We e k 1 2 ( 6. 2 8 uI U/ m L). O ne ( 5. 3 %) s u bject i n t he 
B H V- 3 2 4 1 6 0 0 m g BI D gr o u p ha d hi g h T S H at Wee k 1 2 ( 9. 3 1 uI U/ m L) a n d t h e F oll o w- u p
visit ( 7. 2 5 uI U/ m L). T w o ( 1 1. 1 %) s u bjects i n t he B H V- 3 2 4 1 3 0 0 m g BI D gr o u p a n d 1 ( 5. 3 %) 
s u bject i n t he B H V- 3 2 4 1 6 0 0 m g BI D gr o u p ha d hi g h uri ne pr otei n.
T here w ere n o cli ni call y si g nifi ca nt differe n ces i n E C G res ults bet wee n eit her of t he B H V-
3 2 4 1 gr o u ps a n d place b o.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 3 4 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 3 5 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1. 1. 6
P ot e nti al Ri s k t o F et al D e v el o p m e nt
O n t he basis of t he re pr o d u cti ve a n d de vel o p me ntal t o xicit y st u dies des cri b e d a b o ve, w o me n of 
c hil d be ari n g p ot e nti al ( W O C B P) ma y be i ncl u d e d i n t he cli nical trials pr o vi d e d t he y ar e n ot 
pre g na nt or l act ati n g at a d missi o n a n d s uffici e nt c o ntrace pti ve pr ot ecti o n is use d. T here is a 
p ote nti al ris k of dr u g- dr u g i nteracti o ns wit h h or m o n al c o ntr ace pti ve m et h o ds s e nsiti v e t o 
i n d ucti o n of C Y P 3 A 4 wit h B H V- 3 2 4 1. C o nse q ue ntl y, st u d y I n vesti gat ors s h o ul d ke e p t his 
p ote nti al of re d u ce d h or m o nal c o ntr ace pti ve effecti v e ness i n mi n d f or w o me n usi n g 
c o ntrac e pti v e c o ntr ol me di ci nes a n d d e vices c o ntai ni n g estr o ge n/ pr o gest er o ne. Estr o ge n a n d 
pr o gester o ne h or m o n al c o ntrace pti ves as a s ol e met h o d of c o ntrac e pti o n are pr o hi bite d. 
1. 2
St u d y R ati o n al e
1. 2. 1
St u d y D e si g n R ati o n al e
T he p ur p os e of t his P has e 3 st u d y is t o d e m o nstrate t he efficac y of B H V- 3 2 4 1 i n t he tr eat me nt 
of M S A a n d c haracteri ze its s afet y/t oler a bilit y pr ofil e.
T he st u d y is a ra n d o miz e d, d o u ble- bli n d, 2-ar m, plac e b o-c o ntr olle d, parallel- gr o u p st u d y i n 
s u bjects wit h M S A treat e d wit h B H V- 3 2 4 1 f or 4 8 wee ks. If a bs ol utel y necessar y d ue t o t he 
C O VI D- 1 9 p u blic healt h e mer ge n c y, tre at m e nt d urati o n ma y be l o n ger, wit h a n e x pa n de d
Wee k 4 8 visit wi n d o w u p t o a m a xi m u m treat me nt d urati o n of 6 0 wee ks, as detaile d i n t h e 
Sc he d ule of Ass ess me nts a n d E ve nts ta bl es ( Ta ble 1 , Ta ble 2 ). U n der t hese cir c u msta n ces, t he 
s p o ns or me dical m o nit or ( or d esi g nee) s h o ul d be c o ns ulte d a n d m ust a p pr o ve t h e re q uest t o 
e xte n d t h e treat me nt d urati o n. 
D uri n g t he ra n d o mize d d o u ble- bli n d treat me nt p hase, t he use of pla ce b o c o ntr ol will f acilit ate 
t he i de ntifi cati o n of a tre at m e nt eff ect r elate d t o a d mi nistrati o n of B H V- 3 2 4 1. T he us e of 
place b o is j ustifi e d beca use t here is n o c urre nt st a n dar d t hera p y f or M S A a n d s u bjects i n t his 
st u d y will be all o w e d t o c o nti n u e t heir bac k gr o u n d s y m pt o matic treat me nts f or M S A ( wit h t he 
e xce pti o n of e xcl u de d me dicati o ns). T he p o p ulati o n i ncl u des s u bje cts wit h M S A ( M S A- P a n d 
M S A- C).  B ot h ha ve t he s a me u n d erl yi n g diseas e pr ocess a n d t he sa m e rate of dis eas e 
pr o gressi o n as meas ure d b y cli nic al rati n g scales (i.e., U M S A R S).  M ore o ver, b ot h s u bt y pes 
are e q uall y li kel y t o be nefit fr o m M P O i n hi biti o n b y B H V- 3 2 4 1 a n d de m o nstrate d t he p ot e ntial 
t o be res p o nsi ve t o treat me nt wit h B H V- 3 2 4 1 i n t he pre vi o us P hase 2 st u d y i n M S A s u bjects 
( St u d y D 0 4 9 0 C 0 0 0 2 3). 
S u bjects w h o are c o m pleti n g or ha ve c o m pl ete d Wee k 4 8 of t he ra n d o mize d d o u ble- bli n d 
treat me nt p h ase ma y be off ere 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 xte nsi o n ( O L E) 
p hase, i n w hic h s u bje cts will r ecei v e o pe n-l a bel treat me nt wit h B H V- 3 2 4 1 f or a p pr o xi mat el y 
4 8 w ee ks. E nr oll m e nt i nt o t he O L E
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 3 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
j u d ge me nt t hat o pe n-l a bel treat me nt off ers a n ac ce pt a ble ris k- be n efit pr ofile f or e ac h 
i n di vi d ual. 
T he pri m ar y o utc o me vari a ble i n t his st u d y is a m o difie d U M S A R S s c ore c o m prise d of a
s u bset of ite ms fr o m t he U M S A R S ( U M S A R S I: Acti viti es of Dail y Li vi n g & U M S A R S II: 
M ot or E xa mi n ati o n). T he U M S A R S is a cli nic al rati n g scale t h at has bee n de vel o p e d a n d 
vali date d f or m eas uri n g f u ncti o nal i m pair me nt i n M S A o ver 4 8 wee ks. It is t he sta n dar d 
o utc o me v ar ia ble use d i n l o n git u di nal nat ural hist or y st u dies a n d i nt er ve nti o nal st u dies. T he 
ke y s ec o n dar y o ut c o me varia bl es are t h e Cli nical Gl o bal I m pressi o n of I m pr o v e me nt ( C GI-I)
a n d M S A -Q ualit y of Life ( M S A -Q o L) m ot or a n d n o n -m ot or s u b s cales, w hic h ass ess 
c o m ple me nt ar y as pects of dis a bilit y i n M S A a n d ha v e als o pre vi o usl y b ee n vali dat e d i n M S A 
st u dies t o m o nit or disease pr o gr essi o n, as well as t he U M S A R S Part I a n d P art II t otal s c ore at 
Wee k 4 8 .
 P har mac o ki netic par a meters a n d P D effects, s uc h as M P O acti vit y, are 
als o i ncl u d e d.
1. 3
D o s e S el e cti o n
T he d os e s electe d f or e v al uati o n i n t his P hase 3 B H V- 3 2 4 1- 3 0 1 st u d y is 6 0 0 m g BI D. T his 
d os e s electi o n w as base d o n c u m ulati v e cli nical a n d n o ncli ni cal e x perie n ce wit h B H V- 3 2 4 1,
i ncl u di n g n o n cli nical t o xi c ol o g y a n d s afet y a n d effic ac y dat a i n M S A s u bjects.
T he n o ncli nic al t o xic ol o g y pr o gra m f or B H V- 3 2 4 1 is c o m pre he nsi ve a n d s u p p orts oral 
a d mi nistr ati o n i n t he cli nic f or c hr o ni c tre at m e nt.  I n cl u de d i n t he t o xic ol o g y pr o gr a m are: 
si n gle a n d re p eat- d os e t o xicit y st u dies i n r ats a n d d o gs, ge n ot o xicit y st u dies, re pr o d u cti v e 
t o xicit y st u dies, p h ot ot o xicit y st u di es, a n d safet y p h ar mac ol o g y st u dies.  B H V- 3 2 4 1 d os es i n 
t he prese nt st u d y are pre di cte d t o pr o d uce p h ar ma c o ki neti c e x p os ures bel o w t h e e x p os ure 
li mits s et o n t he b asis of n o ncli nical t o xi c ol o g y data.
T o date, a p pr o xi m atel y 2 3 4 s u bjects ha v e rec ei ve d B H V- 3 2 4 1 i n s e ve n cli ni cal st u dies: f o ur 
D 0 4 9 0 C 0 0 0 0 4), a P hase 2 safet y
( St u d y D 0 4 9 0 C 0 0 0 0 5), a n d a P hase 2 P E T i m a gi n g st u d y i n s u bjects wit h M S A ( St u d y 
D 0 4 9 0 C 0 0 0 2 3). I n t he P hase 1 st u dies, tre at m e nt wit h m ulti ple d os es of u p t o 9 0 0 m g B H V-
3 2 4 1 BI D w as ge nerall y safe a n d w ell t olerate d. I n t he P hase 2 st u dies i n s u bjects wit h 
- 3 2 4 1 at d oses of u p t o 6 0 0 m g BI D f or 8-
1 2 w ee ks w as ge nerall y s afe a n d w ell t oler ate d.
T he s ele cte d d ose of B H V -3 2 4 1 a d mi nistere d 6 0 0 m g BI D is b ase d o n t he fi n di n gs i n t he P hase 
1 a n d 2 st u dies re gar di n g safet y a n d t oler a bilit y of B H V -3 2 4 1 at 6 0 0 m g BI D; 
 
 a n d t h e d ose-
de pe n de nt f a v ora ble tre n ds o n cli nical effica c y me as ures i n t he P has e 2 st u d y i n M S A. Ta ke n 
t o get her, t he safet y, t oler a bilit y, P K, a n d P D data ge nerate d i n cli nical st u dies wit h B H V-3 2 4 1,
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 3 7  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
al o n g wit h t h e precli ni cal p har mac ol o g y, P K, a n d s afet y dat a, s u p p ort t he f urt her e val uati o n of 
B H V- 3 2 4 1 i n M S A patie nts i n a P hase 3 st u d y. 
 
1. 4 
B e n efit- Ri s k 
Be n efit- Ris k Assess me nt  
T he c urre nt be nefit-ris k a nal ysis is base d o n t he a vaila ble d ata wit h B H V- 3 2 4 1 fr o m precli nical 
a n d M S A s u bjects). It is c o nsi dere d t hat t he be nefits of e val uati n g B H V- 3 2 4 1 as a p ote ntial 
treat me nt f or M S A o ut w ei g h t h e ris ks. 
Precli ni cal st u dies s afet y a n d t o xic ol o g y st u dies ar e descri be d i n Se cti o n 1. 1. 3. 1. 3 a n d Secti o n 
1. 1. 3. 1. 5, res pecti v el y. Safet y p har ma c ol o g y st u di es were perf or me d assessi n g t he ce ntr al 
ner v o us, res pirat or y, car di o vas c ul ar a n d gastr oi ntesti nal s yste ms. A c o m pre h e nsi ve t o xic ol o g y 
data pac ka ge has bee n de vel o pe d o n B H V- 3 2 4 1 i ncl u di n g si n gle d os e t o xicit y, re pe at- d os e 
t o xicit y (i ncl u di n g c hr o nic t o xicit y i n rats a n d d o gs), ge neti c t o xi cit y, r e pr o d ucti v e a n d 
de vel o p m e ntal t o xi cit y, a n d s pecial t o xi cit y. 
T he cli nic al e x perie nc e wit h B H V- 3 2 4 1 is des cri be d i n detail i n S e cti o n 1. 1. 3. 2. T he a d v erse 
e ve nt pr ofile o bser ve d i n t hes e cli ni cal st u dies wit h B H V- 3 2 4 1 is des cri be d i n Secti o n 1. 1. 5. 
T o date, se v e n cli nical st u dies (f o ur P hase 1 st u di es i n healt h y s u bj ects; t w o P has e 2 st u dies i n 
ha ve be e n 
c o n d ucte d wit h B H V- 3 2 4 1, wit h a p pr o xi m atel y 2 3 4 s u bjects ha vi n g r ecei ve d B H V- 3 2 4 1 i n 
t hese cli nic al st u di es.  
E x p os u re 
T he e x p os ure li mits f or B H V- 3 2 4 1 i n cli ni cal st u dies ha ve pre vi o usl y b ee n a C ma x  of 4 0 
µ m ol/ L a n d a n A U C( 0-
 base d o n t he hist o pat h ol o gi cal fi n di n gs i n t h e 
t h yr oi d gla n d i n t he r at 6- m o nt h st u d y. I n t he P hase 2 b st u d y ( D 0 4 9 0 C 0 0 0 2 3), M S A s u bjects 
treat e d wit h B H V- 3 2 4 1 6 0 0 m g BI D f or 1 2 wee ks ha d t he f oll o wi n g st ea d y state, ge o metri c 
mea n e x p os ures: A U C of 3 9. 5 µ m
ma x  
T h us, t he e x p os ures of B H V- 3 2 4 1 i n pla n ne d cli nical trials are pr oj ecte d t o be bel o w t he 
N O A E L. 
S afet y a n d T oler a bilit y i n Cli ni c al St u dies 
I n t he P has e 1 st u dies, B H V- 3 2 4 1 has bee n ge ner all y well t ol erat e d w he n a d mi nistere d t hr o u g h 
titrati o n as m ulti ple d os es u p t o 9 0 0 m g BI D. I n t h e P hase 2 st u dies i n s u bjects wit h 
- 3 2 4 1 at d oses of u p t o 6 0 0 m g BI D f or 8 t o 
1 2 w ee ks w as ge nerall y s afe a n d w ell t oler ate d. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 3 8  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
P ote nti al Be nefits
T he rati o nal e f or t he pr o p ose d st u d y is base d o n c u m ulati v e precli ni cal a n d cli nical st u dies t h at 
i m pli cat e M P O acti vit y i n t h e o nset a n d pr o gressi o n of M S A a n d s u g gest treat me nt wit h B H V-
3 2 4 1 has t he p ote ntial t o sl o w ne ur o de ge n erati o n i n M S A. 
I n partic ular, i n a P has e 2 b st u d y, s u bjects wit h M S A were ra n d o mi ze d t o re cei v e B H V- 3 2 4 1 
3 0 0 m g BI D, B H V- 3 2 4 1 6 0 0 m g BI D, or place b o f or 1 2 wee ks. T he B H V- 3 2 4 1 gr o u ps 
e x hi bit e d n u merical, b ut n ot st atisticall y si g nifi ca nt, i m pr o ve m e nts c o m p are d t o t he pla ce b o 
gr o u p t hat w ere d ose-relat e d, bas e d o n c h a n ges i n t h e U nifie d M S A Rati n g Scale sc ores fr o m 
baseli ne t o Wee k 1 2. Place b o-treate d s u bje cts w ors e ne d b y 4. 6 p oi nts, w hile B H V- 3 2 4 1 tre ate d 
s u bjects s h o w e d less w orse ni n g of 3. 7 p oi nts at t he 3 0 0- m g d os e a n d 2. 6 p oi nts at t he 6 0 0- m g 
d os e, s u g gesti n g a d ose-res p o nse relati o ns hi p. B H V- 3 2 4 1 treat me nt f or 1 2 wee ks (at d os es of 
3 0 0 m g BI D a n d 6 0 0 m g BI D) s h o we d statisti call y si g nifica nt re d ucti o ns i n m eas ures of M P O 
acti vit y i n plas ma. T hes e res ults s u p p ort t he i nt e n de d mec ha nis m of acti o n of B H V- 3 2 4 1 a n d 
p ote nti al f or efficac y i n M S A. 
P ote nti al Ris ks
Precli ni cal a n d cli nical st u dies ha v e de m o nstr ate d a n acce pta bl e safet y a n d t oler a bilit y pr ofile 
f or B H V- 3 2 4 1 b ut d o s u g gest s pecific p ot e nti al ris ks. T he pres e nt st u d y i ncl u d es ge neral a n d 
s pecific s af et y pr oce d ur es a nti ci pate d t o mi ni miz e a n y p ote nti al ris ks. 
Ge ner al pr oce d ur es will i n cl u de fr e q ue nt s af et y assess me nts b y I n vesti gat ors, t h or o u g h 
e val uati o ns a n d re vie w of A Es a n d S A Es o n a n o n g oi n g basis t o m o nit or f or a n y safet y si g nals 
or tre n ds b y t he S p o ns or a n d Me dic al M o nit or, a n d D M C re vie w of t he be nefit-ris k of t he 
st u d y f or s u bjects. 
T h yr oi d 
I n precli nical st u dies, re versi ble hist o p at h ol o gical c h a n ges i n t he t h yr oi d gl a n d a n d re versi ble 
t h yr oi d h or m o ne c ha n ges w ere o bser ve d. I n cli nical st u dies, B H V- 3 2 4 1 has bee n ass ociat e d 
wit h la b orat or y c ha n g es i n dicati ve of d ecre ase d t h yr oi d f u ncti o n. S pe cifi call y, t here h a ve be e n 
i ncreases o ver ti m e i n mea n T S H le vels a n d s o me de creases o ver ti me i n mea n fr ee T 4 a n d 
mea n fre e T 3 le v els rel ati v e t o pl ace b o. M ost s u bje cts di d n ot ha ve t h yr oi d f u ncti o n test v al ues 
o utsi de t he n or mal r a n ge, a n d t h e a b n or m alities t h at occ urre d were mil d. C ha n g es i n t h yr oi d 
f u ncti o n t ests ass ociat e d wit h B H V- 3 2 4 1 ret ur n e d t o war d baseli ne le vels d uri n g t he peri o d of 
o bs er vati o n f oll o wi n g disc o nti n uati o n of B H V- 3 2 4 1. 
T he pres e nt st u d y will i n v ol ve m o nit ori n g of t h yr oi d f u ncti o n. T h yr oi d f u ncti o n test 
a b n or maliti es i n dicati n g cli nicall y si g nifi ca nt t h yr oi d h or m o ne defi cie n c y ar e re a dil y treata bl e 
wit h t h yr oi d h or m o n e re pl ace m e nt. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 3 9  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
R e n al
Re versi ble r e nal fi n di n gs were o bs er ve d i n t he 1- m o nt h precli nic al st u di es i n fe male rats at 
hi g h d os es, a n d n o re nal c ha n ges w ere n ot e d i n t h e 6- m o nt h st u d y. I n cli nic al st u di es, B H V-
3 2 4 1 has bee n ass ociate d wit h de creas es i n mea n uri c aci d le vels o ver ti me rel ati v e t o pl ace b o. 
A varia ble pr o p orti o n of s u bjects recei vi n g B H V- 3 2 4 1 ha ve ha d pl as ma uri c aci d le vels bel o w 
t he l o w er li mit of n or mal. D ecreases i n uric aci d l e vels ass ociate d wit h B H V- 3 2 4 1 ha ve te n de d 
t o ret ur n t o war d b as eli n e f oll o wi n g t h e disc o nti n uati o n of d osi n g. I n dices of re nal f u ncti o n 
ha ve n ot s h o w n a n y a b n or m alities ass ociate d wit h B H V- 3 2 4 1. T he mec ha nis m of t he c h a n ges 
i n uric a ci d l e vels is u nclear b ut c o ul d i n cl u de d ecre ase d uric aci d pr o d ucti o n or decreas e d 
re nal t u b ular rea bs or pti o n. H y p o urice mia is t h o u g ht t o be a bi oc h e mi call y defi ne d dis or der 
wit h n o k n o w n cli ni cal si g nific a nce.  
T he pres e nt st u d y will i n v ol ve m o nit ori n g of uric aci d le vels a n d i n dices of re nal f u ncti o n.
C ar di o v as c ul ar 
I ncreases i n heart rat e w ere o bser ve d i n d o gs d uri n g t he precli ni cal st u dies. H o we ver, B H V-
3 2 4 1 ha d n o effect o n bl o o d press ure or o n E C G par a met ers at a n y d ose. T w o st u dies 
e val uati n g c ar di o vasc ul ar res p o nse t o ort h ost ati c tilt i n d o gs were als o perf or me d; n o 
i nci de n ces of ort h ostatic h y p ote nsi o n were o bser ve d f oll o wi n g a d mi nistrati o n of B H V- 3 2 4 1. 
T he first S A D cli ni cal st u d y ( D 0 4 9 0 C 0 0 0 0 1) was dis c o nti n ue d o n t he basis of A Es t hat 
i ncl u de d s y nc o p e ass ociate d wit h bri ef si n us pa uses detecte d o n c ar diac tel e metr y. T w o of t he 
cas es of s y nc o pe w ere ass ociate d wit h ort h ostatic t esti n g. T her e was n ot a relati o ns hi p b et wee n 
t hese e ve nts a n d B H V- 3 2 4 1 c o nce ntrati o ns. T her e was n o e vi de nce of direct pr oarr h yt h mic or 
ot her car di ot o xi c effects. It was c o nsi dere d t hat e ve nts of s y nc o pe ma y ha v e re pres e nt e d a n 
e xa g gerate d p h ysi ol o gical r es p o nse t o st u d y pr oce d ures, i n v ol vi n g s y nc o pe of 
ne ur ocar di o g e nic ori gi n. H o we ver, a n eff ect of B H V- 3 2 4 1 c o ul d n ot be r ule d o ut. A sec o n d 
S A D st u d y w as c o n d ucte d wit h 2 m o difi cati o ns desi g ne d t o re d uc e t he ris k of s y nc o pe: ( 1) t he 
e xcl usi o n of s u bje cts wit h a hist or y of rec urre nt pres y nc o pe a n d/ or s y nc o p e i n c o n ne cti o n wit h 
ort h ostati c c halle n g e, a n d ( 2) fracti o nate d d osi n g. I n t his s ec o n d S A D st u d y, t here were n o 
e pis o des of pres y nc o pe or s y nc o pe, a n d n o cli nicall y rele va nt fi n di n gs i n v ol vi n g vital si g ns or 
E C G par a meters. S u bs e q ue nt cli nic al st u di es ha ve us e d E R f or m ul ati o ns a n d t here ha v e bee n 
n o cas es of s y nc o pe i n s u bje cts recei vi n g B H V- 3 2 4 1. T here ha v e bee n s o me A Es p ot e nti all y 
relat e d t o s y nc o pe (e. g., dizzi ness, ort h ostatic h y p ot e nsi o n). O verall, t h ere ha ve b ee n n o 
cli ni call y rel e va nt fi n di n gs i n v ol vi n g vital si g ns or E C Gs, wit h t he e xce pti o n of s o me d ecreas es 
i n t he m ea n R R i nter val o bser ve d i n t he B H V- 3 2 4 1 6 0 0- m g BI D gr o u p i n t he s afet y/t olera bilit y 
I n a g gre gat e, t he cli ni cal d ata d o n ot s h o w clear e vi d e nce of si g nifica nt car di o v asc ular 
a b n or maliti es ass ociat e d wit h a d mi nistrati o n of B H V- 3 2 4 1 E R f or m ulati o ns at t he d oses us e d. 
T he pres e nt st u d y will i n v ol ve m o nit ori n g of vital si g ns, i ncl u di n g ort h ost ati c me as ure me nts, 
a n d E C Gs. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 4 0  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
Li ver
Mi ni mall y n o n-a d verse, i ncreas e d ala ni ne a mi n otr a nsferase a n d sli g ht ( a da pti ve) 
hist o pat h ol o gical effects i n t he li ver w er e o bser ve d i n rats d uri n g t he pr ecli nical st u dies; t hes e 
are li k el y relate d t o e nz y me i n d u cti o n ( e. g., C Y P 2 B 1 i n d ucti o n). I n t he M A D st u d y 
( D 0 4 9 0 C 0 0 0 0 2), s e veral s u bjects, i ncl u di n g t h ose re cei vi n g B H V- 3 2 4 1 a n d pl ace b o, ha d 
i ncreases i n h e patic tra nsa mi n ases. H o we ver, i n s u bs e q ue nt st u di es t here h a ve bee n n o 
cli ni call y rel e va nt fi n di n gs i n v ol vi n g he patic f u ncti o n.  
I n a g gre gat e, t he cli ni cal d ata d o n ot s h o w a cle ar ass ociati o n of he patic a b n or maliti es wit h 
B H V- 3 2 4 1. T he pres e nt st u d y will i n v ol ve m o nit ori n g of li ver f u ncti o n t ests. 
O ver all Be nefit- Ris k Assess me nt 
M S A is a n a d ult- o ns et, fat al ne ur o d e ge nerati ve dis eas e. N o diseas e m o dif yi n g treat me nt 
c urre ntl y e xists, o nl y s y m pt o matic a n d p alliati v e a p pr oac hes are a v ail a ble. B H V- 3 2 4 1 is a n 
irre versi bl e i n hi bit or of t h e M P O e nz y me t hat pr o m otes o xi dati ve stress a n d 
ne ur oi nfla m mati o n. T h e hi g h u n m et nee d f or a n effe cti ve treat me nt f or M S A, t o get her wit h t h e 
a vail a ble pr ecli nical a n d cli ni cal d ata wit h B H V- 3 2 4 1, pr o vi de a c o m pelli n g a n d fa v or a ble 
o verall b e nefit-ris k ass ess me nt f or t he d e vel o p me nt of B H V- 3 2 4 1 at t he 6 0 0 m g BI D d os e as a 
treat me nt f or M S A. T he s afet y m o nit ori n g i n t h e pla n ne d cli nical st u d y will mi ni miz e t he 
p ote nti al ris ks t o st u d y s u bjects. 
2 
S T U D Y O B J E C TI V E S 
2. 1 
Pri m ar y 
 T o e val u ate t he effi cac y of B H V- 3 2 4 1, c o m p are d t o place b o, as meas ure d b y a c ha n ge 
fr o m bas eli n e i n a m o difi e d U nifie d M S A Rati n g Sc ale ( U M S A R S), c o nsisti n g of a s u bset 
of ite ms fr o m Part I a n d P art II, at Wee k 4 8. 
 T o assess t he safet y a n d t olera bilit y of B H V- 3 2 4 1, relati v e t o pl ace b o, i n s u bjects wit h 
M S A. 
2. 2 
S e c o n d ar y 
Ke y Sec o n d ar y  
 T o e val u ate t he effi cac y of B H V- 3 2 4 1, c o m p are d t o place b o, as meas ure d b y t h e Cli nical 
Gl o bal I m pressi o n of I m pr o v e me nt ( C GI-I) s c ore at Wee k 4 8. 
 T o e val u ate t he i m pact of B H V- 3 2 4 1 o n q ualit y of life, c o m par e d t o pl ace b o, as m eas ure d 
b y a c ha n ge fr o m bas eli n e i n t h e m ot or s u bs cale of t he M S A- Q ualit y of Life ( M S A- Q o L) 
s cale at Wee k 4 8. 
 T o e val u ate t he i m pact of B H V- 3 2 4 1 o n q ualit y of life, c o m par e d t o pl ace b o, as m eas ure d 
b y a c ha n g e fr o m bas eli n e i n t h e n o n- m ot or s u bs cale of t he M S A- Q o L s cale at Wee k 4 8. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 4 1 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
T o e val u ate t he effi cac y of B H V- 3 2 4 1, c o m p are d t o place b o, as meas ure d b y a c ha n ge 
fr o m bas eli n e i n t h e U M S A R S Part I a n d Part II t otal sc ore at W ee k 4 8.
Ot h er Sec o n d ar y
T o ass ess t he i m pa ct of B H V- 3 2 4 1, relati ve t o plac e b o, as meas ure d b y a c ha n ge fr o m 
baseli ne at W ee k 4 8 i n t h e f oll o wi n g i nstr u me nts:
Patie nt Gl o b al I m pr essi o n of Se verit y ( P GI- S),
Cli nic al Gl o bal I m pressi o n of Se verit y ( C GI- S),
U M S A R S Part III,
U M S A R S Part I V.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 4 2 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
3
S T U D Y E N D P OI N T S
3. 1
Pri m ar y
C ha n ge fr o m baseli ne i n a m o difie d U M S A R S s c ore, base d o n a s u bs et of it e ms fr o m Part I 
a n d II, at W ee k 4 8 (s ee S ecti o n 9. 4. 2).
T he fre q ue n c y of u ni q ue s u bjects wit h: seri o us a d vers e e ve nts; a d v ers e e ve nts l ea di n g t o 
dis c o nti n uati o n; a d vers e e ve nts j u d ge d t o b e rel ate d t o st u d y me dic ati o n; cli nic all y 
si g nifica nt E C G a b n or m alities a n d cli ni call y si g nifi c a nt la b or at or y a b n or malities.
3. 2
S e c o n d ar y
Ke y Sec o n d ar y
T he C GI-I s c or e at W ee k 4 8
C ha n ge fr o m bas eli ne i n t he M S A- Q o L m ot or s u bs cale at Wee k 4 8 
C ha n ge fr o m bas eli ne i n t he M S A- Q o L n o n- m ot or s u bs cale at Wee k 4 8
C ha n ge fr o m bas eli ne i n U M S A R S Part I a n d II t otal s c ore at W ee k 4 8 
Ot h er Sec o n d ar y
C ha n ge fr o m baseli ne at We e k 4 8 o n t he f oll o wi n g i nstr u me nts:
P GI- S,
C GI- S,
U M S A R S Part III,
U M S A R S Part I V.
 
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 4 3  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
4 
S T U D Y P L A N 
4. 1 
St u d y D e si g n a n d D ur ati o n 
B H V 3 2 4 1- 3 0 1 is a P has e 3, m ultic e nter, r a n d o miz e d, d o u ble- bli n d, 2- ar m pl ace b o-c o ntr oll e d 
parall el- gr o u p st u d y desi g n e d t o e val uat e t he effic ac y a n d s afet y of B H V- 3 2 4 1 i n a p o p ul ati o n 
of patie nts wit h M S A ( M S A- C a n d M S A- P). T he st u d y is pla n ne d t o c o nsist of a Scre e ni n g 
p hase lasti n g a ma xi m u m of a p pr o xi matel y 6 we e ks a n d a ra n d o mize d d o u ble- bli n d treat me nt 
p hase of a p pr o xi m atel y 4 8 w ee ks, per  Fi g ure 2. It is a ntici pat e d t hat t he R a n d o miz ati o n p h ase 
will i ncl u de a d os e titr ati o n p eri o d of a p pr o xi mat el y 2 wee ks f oll o we d b y a f ull d os e peri o d of 
a p pr o xi matel y 4 6 w ee ks. A p pr o xi matel y 3 2 5 s u bjects i n t otal are pl a n ne d t o b e ra n d o mi ze d i n 
a 1: 1 rati o t o re cei ve eit h er B H V- 3 2 4 1 6 0 0 m g BI D, or matc hi n g pla ce b o BI D. It is a ntici p ate d 
t hat s u bje cts will b e ass esse d at cli nic visits, per t h e Sc he d ule of Ass ess me nts & E ve nts ( Ta bl e 
1 ).  I n a d diti o n, s u bj ects w h o are c o m pleti n g or ha v e c o m plete d W ee k 4 8 of t he d o u ble- bli n d 
treat me nt p h ase ma y be off ere 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 xte nsi o n p h as e, i n 
w hic h s u bjects will rec ei ve o pe n-la bel tre at m e nt wit h B H V- 3 2 4 1 f or a p pr o xi matel y 4 8 wee ks. 
(Ta ble 2 ) 
4. 2 
St u d y S c h e m ati c 
Fi g ur e 2:  
St u d y S c h e m ati c 
 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 4 4 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
4. 3
S c h e d ul e of A s s e s s m e nt s
4. 3. 1
C O VI D- 1 9 P u bli c H e alt h E m er g e n c y
I n b ot h t he d o u bl e- bli n d p h ase a n d O L E p has e of t he st u d y, e ver y eff ort s h o ul d b e ma de t o 
c o n d uct pr ot o c ol-s pecifie d i n- p ers o n st u d y visits as pla n ne d a n d as cl ose t o t he dat e of t he 
s c he d ule d visit as p ossi ble.  H o w e ver, d ue t o t he C O VI D- 1 9 p u blic healt h e m er ge nc y, i n or d er 
t o mi ni mize p ote ntial ris ks t o t he s af et y of st u d y partici pa nts a n d st u d y site p ers o n nel a n d t o 
c o m pl y wit h g o v er n me nt a n d l o cal he alt h care i nstit uti o n g ui da n ce a n d r estricti o ns, st u d y 
partici pa nts m a y be u na ble t o atte n d st u d y sc h e d ule d pr ot oc ol re q uire d visits i n pers o n (e. g., 
s helter i n plac e restricti o ns, st u d y site p olic y t hat cli nical r esearc h visits m ust be dela ye d). 
U n der t hese cir c u msta nc es, if a st u d y partici pa nt is u na ble t o att e n d a n i n p ers o n pr ot oc ol-
re q uire d e v al uati o n at t he st u d y sit e at t he s c he d ule d ti me, t he sit e I n vesti g at or s h o ul d disc uss 
t he a p pr o pri ate c o urse of acti o n a n d s pecific r e q uire me nts f or re m ote safet y visits o n a c ase b y 
cas e basis wit h t h e S p o ns or M e dical M o nit or ( or desi g nee), base d o n t he s pecific st u d y visit, 
t he cli nic al stat us of t he partici p a nt, c o nsi d erati o n of t heir c o m pli a nce t o st u d y me dicati o n, 
pre vi o us la b res ults a n d ot her ris k fact ors.  
P ote ntial c o urs es of acti o n i n cl u de e x p a nsi o n of t he visit wi n d o w, c o n d uct of a re m ote [ via 
p h o ne or te l e me dici ne vi de o] visit, f oc usi n g o n s afet y assess me nts d uri n g re m ot e visits ,
i ncl u di n g st u d y dr u g c o m plia nce, c o nc o mita nt me dic ati o n re vie w, a d vers e e v e nt m o nit ori n g, 
S hee ha n S uici d alit y Tra c ki n g Scal e, U M S A R S Part I a n d Ti m e t o E v e nt M eas ures , perf or mi n g 
s afet y la bs vi a l ocal la bs or 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 di cati o n t o 
st u d y partici pa nts, if n ee de d. Vital si g ns, p h ysical e xa ms , a n d cli nicia n-rat e d o utc o me 
meas ures (e. g., U M S A R S Part II, C GI -I/ S) will n ot b e c o n d uct e d re m otel y.  E C Gs ma y b e 
c o n d ucte d at a l ocal h ealt h facilit y ot her t ha n t h e st u d y site, w it h s u bse q ue nt s u b missi o n t o 
 (ce ntral E C G v e n d or). S cree ni n g, B as eli n e a n d Wee k 4 8 visits m ust be c o n d u cte d i n 
pers o n a n d la b a n al ys es s h o ul d be c o n d ucte d b y 
 ce ntral la b .
F or o n -tre at m e nt st u d y visits ( n ot Scree ni n g, Baseli n e or Wee k 4 8) , if t he C O VI D-1 9 p u blic 
healt h e mer g e nc y pre ve nts st u d y s u bjects fr o m b ei n g a ble t o h a ve bl o o d a n d uri ne l a b sa m pl es 
c olle cte d at t h e st u d y site f or s hi p me nt t o 
 ce ntral la b f or a nal ysis, t h e s a m ples m a y be 
c olle cte d at l o cati o ns ot her t ha n t he st u d y sit e (l oc al l a b, pri mar y care pra cti ce, i n-h o me 
p hle b ot o m y s er vice) a n d ma y be a nal y ze d b y a l ocal la b.  T he st u d y site will c ollect a n y l oc al 
la b res ults f or re vie w a n d e ntr y i nt o t h e e D C e C R F. T he s afet y la b s a m ples c oll ect e d a n d 
a nal yze d i n t h ese cas es of re m ote ass ess me nts will b e li mite d t o safet y la bs specifie d b y t he 
S p o ns or (s ee Secti o n 6. 2. 2. 4 ).  P har ma c o ki netic a n d 
will n ot be c oll ect e d.  
 
C CI
C CI
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 4 5 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
4. 3. 1. 1
Crit eri a f or T e m p or ar y I nt err u pti o n of I n v e sti g ati o n al Pr o d u ct (I P)
T he visit wi n d o ws f or c ollecti o n of B H V 3 2 4 1- 3 0 1 pr ot oc ol-re q uire d s afet y la bs d uri n g t h e 
C O VI D- 1 9 e mer ge nc y, a n d t he crit eria f or te m p or ar y i nterr u pti o n of I P d ue t o i n a bilit y t o 
m o nit or patie nt s afet y via l a b a nal yses ar e as f oll o ws:
Wee k 4 or W ee k 4- E xt e nsi o n s afet y la bs- nee d t o be c o n d ucte d wit hi n a 1 0 d a y wi n d o w of 
Wee k 4 or W ee k 4- E xt e nsi o n. If n ot, nee d t o t e m p or aril y i nterr u pt I P u ntil l a bs are 
c o n d ucte d.
Wee k 1 2 or W ee k 1 2- E xt e nsi o n s afet y la bs- nee d t o be c o n d uct e d wit hi n a 8- wee k wi n d o w 
of Wee k 1 2- E xte nsi o n (ass u mi n g n o cli ni call y si g nifica nt la b a b n or maliti es at Wee k 8 or
Wee k 8- E xte nsi o n). F or s u bjects w h o di d n ot ha ve Wee k 8 or W ee k 8 - E xt e nsi o n la bs 
c o n d ucte d, b ut w h o ha d Wee k 4 or Wee k 4- E xte nsi o n la bs c o n d uct e d wit h n o cli ni call y 
si g nifica nt la b a b n or malities, t he n Wee k 1 2 or W ee k 1 2- E xte nsi o n l a bs nee d t o b e 
c o n d ucte d wit hi n a 4 w e e k wi n d o w of Wee k 1 2 or Wee k 1 2- E xte nsi o n. If n ot, nee d t o 
te m p oraril y i nterr u pt I P u ntil l a bs are c o n d ucte d.
Wee k 2 4 or W ee k 2 4- E xt e nsi o n s afet y la bs- nee d t o be c o n d uct e d wit hi n a 1 2- wee k wi n d o w 
of Wee k 2 4 or
Wee k 2 4- E xt e nsi o n (ass u mi n g n o cli nicall y si g nifi ca nt la b a b n or malities at 
Wee k 1 2 or W ee k 1 2- E xt e nsi o n). If n ot, ne e d t o t e m p oraril y i nterr u pt I P u ntil l a bs are 
c o n d ucte d.
4. 3. 1. 2
W e e k 1 8 A s s e s s m e nt
If a s u bject h as n ot bee n ass ess e d at a n i n pers o n visit at W ee k 1 2 or We e k 1 2 -E xt e nsi o n ,
c hec ki n g i n wit h t h e s u bject re m ot el y ( b y p h o ne or vi de o) bet we e n Wee k 1 2 or Wee k 1 2 -
E xte nsi o n a n d Wee k 2 4 or W ee k 2 4 -E xte nsi o n (at a p pr o xi mat el y t h e Wee k 1 8 or Wee k 1 8 -
E xte nsi o n ti me p oi nt) a n d o btai ni n g s afet y la bs is str o n gl y e nc o ura g e d.  T hes e l a bs ma y be 
c o n d ucte d usi n g t he 
 ce ntral la b U nsc he d ule d Visit la b kit or t he y ma y be c oll ecte d at a 
visiti n g p hl e b ot o m y s er v ice) a n d ma y be a nal y ze d b y a l ocal la b.
4. 3. 1. 3
S hi p m e nt of St u d y M e di c ati o n t o St u d y P arti ci p a nt s
I n t hes e cases of re m ote assess me nts, w he n a n i n- pers o n st u d y visit is n ot p ossi ble d ue t o t he 
C O VI D- 1 9 p u blic healt h e mer ge n c y, o ver ni g ht s hi p me nt of st u d y m e dic ati o n fr o m t he site t o 
t he st u d y partici p a nt vi a certifie d a n d tra c ka bl e c o uri er u n der a m bie nt c o n diti o ns (f oll o wi n g 
Re m ote Visit W or kar o u n d G ui d eli n es pr o vi de d t o sit es), is per missi ble, if ac ce pta ble t o t he 
C o nfir mati o n t h at t h e st u d y dr u g s hi p me nt was rec ei ve d b y t he st u d y 
partici pa nt s h o ul d b e retai n e d as d oc u me nt ati o n, e. g., trac ki n g c o nfir m ati o n pri nt o ut fr o m t he 
c o urier, writte n d oc u me ntati o n of c o ntact wit h t h e s u bject ( b y p h o n e, e m ail, te xt), s u bject 
si g nat ure o n pac ki n g list, et c.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 4 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
4. 3. 1. 4
R e m ot e M o nit ori n g/ S o ur c e D at a V erifi c ati o n
T he o n -site r e vie w a n d verific ati o n of st u d y s o urc e d oc u me nts b y t h e S p o ns or a n d its 
re pres e ntati ves m a y be affe cte d b y C O VI D-1 9 p u bli c healt h e m er ge nc y restricti o ns li miti n g 
access t o t h e st u d y site.  If it is s pecificall y all o we d a cc or di n g t o h ealt h a ut h orit y, I R B/ E C a n d 
data pr ot ecti o n a ge nc y r e g ulati o ns, re m ote s o urce d ata verificati o n m a y be c o n d ucte d t hr o u g h 
Re m ote M o nit ori n g, wit h st u d y d o c u me nts access e d electr o nic all y wit h o ut brea ki n g st u d y
o perati n g pr oce d ure.  
 
 
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
 
Pa ge 4 7  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
T a bl e 1:  
S c h e d ul e of A s s e s s m e nt s a n d E v e nt s - R a n d o mi z e d D o u bl e- bli n d P h a s e  
Visit 
Scr ee ni n g 
B as eli ne 
( Pre- d os e) 
2 a 
3 
3- 1 
4 
5
6 
7 9 
 
D a y ( Visit pr oc e d ures c o n d ucte d wit hi n a +/- 
3 d a y wi n d o w, u nl ess ot her wis e s pecifie d)
M a xi m u m 
of 4 2 d a ys 
(- 4 2 t o - 1)
1
1 4
2 9
5 7
8 5
1 6 9
2 5 3
3 3 7 ( +/- 7 
d a ys)
 
We e k 
 
0 
2 
4 
8 
1 2 
2 4 
3 6 
4 8 
( E a rl y D/ C) 9 
We e k 4 8 
P h o ne C all 
(if a p plic a ble)1 0  
Eli gi bilit y Ass ess m e nts 
 
 
 
 
 
 
 
 
 
 
I nf or me d C o ns e nt (s u bje ct a n d c are gi v er) 
X 
 
 
 
 
 
 
 
 
 
I ncl usi o n/ E x cl usi o n Criteria 
X 
X 
 
 
 
 
 
 
 
 
M e dical Hist or y 
X 
 
 
 
 
 
 
 
 
 
De m o gra p hic Dat a 
X 
 
 
 
 
 
 
 
 
 
C o n c o mita nt M e dicati o n re vie w 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
S af et y Assess m e nts 
 
 
 
 
 
 
 
 
 
 
P h ysi cal E xa mi nati o n * 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
P h ysi cal M eas ure me nts 1 
X 
X 
 
 
X 
 
Vital Si g ns 2  
X 
X 
X 
X 
 
X 
X 
X 
X 
 
E C G ( 1 2-lea d) 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
La b orat or y T ests 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pre g n a n c y T est 3 
X 
X 
 
X 
 
X 
X 
X 
X 
 
S h ee h a n S uici dalit y Trac ki n g Scale 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
A d verse E ve nt Re p orti n g 
 
 
 
 
 
 
 
 
 
 
M o nit or f or N o ns eri o us A Es 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
M o nit or f or S A Es 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 4 8 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
Visit
Scr ee ni n g
B as eli ne
( Pre- d ose)
2 a
3
3- 1
4
5
6
7 9
D a y ( Visit pr oce d ur es c o n d ucte d wit hi n a +/-
3 d a y wi n d o w, u nless ot her wise s pecifi e d)
M a xi m u m 
of 4 2 d a ys 
(- 4 2 t o - 1)
1
1 4
2 9
5 7
8 5
1 6 9
2 5 3
3 3 7 ( +/- 7
d a ys)
We e k
0
2
4
8
1 2
2 4
3 6
4 8
( E a rl y 
D/ C) 9
We e k 4 8 
P h o ne C all
(if a p plic a ble)1 0
Effic ac y Ass ess m e nts
U nifie d M S A Rati n g Sc ale Parts I-I V *
X
X
X
X
X
X
X
Cli nical Gl o bal I m pressi o n of Se v erit y ( C GI- S)
X
X
X
X
X
X
Cli nical Gl o bal I m pressi o n of I m pr o ve me nt 
( C GI-I)
X
X
X
X
X
Patie nt Gl o bal I m pressi o n of Se v erit y ( P GI- S)
X
X
X
X
X
X
M S A Q ualit y of Life
X
X
X
Ti me-t o-e v e nt meas ures of dise ase pr o gressi o n 
X
X
X
X
X
X
X 1 0
Ot he r Ass ess m e nts
L u m b ar P u nct ure 5
X
X
P h ar m ac o ki neti c Ass ess m e nts
Bl o o d P K Sa m pli n g 6
X
X
X
X
X
X
C CI
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 4 9 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
Visit
Scr ee ni n g
B as eli ne
( Pre- d ose)
2 a
3
3- 1
4
5
6
7 9
D a y ( Visit pr oce d ur es c o n d ucte d wit hi n a +/-
3 d a y wi n d o w, u nless ot her wise s pecifi e d)
M a xi m u m 
of 4 2 d a ys 
(- 4 2 t o - 1)
1
1 4
2 9
5 7
8 5
1 6 9
2 5 3
3 3 7 ( +/- 7
d a ys)
We e k
0
2
4
8
1 2
2 4
3 6
4 8
( E a rl y 
D/ C) 9
We e k 4 8 
P h o ne C all
(if a p plic a ble)1 0
 
  
  
 
  
 
  
  
  
  
 
Ra n d o mize
X
Dis pe ns e St u d y Dr u g
X
X
X
X
X
St u d y Dr u g C o m plia nce Ass ess me nt 8
X
X a
X
X
X
X
X
U n der re g ular circ u msta n ces, visits are t o b e c o m plet e d i n- p ers o n, u nless ot h er wis e s p ecifie d. S o me visits ca n b e c o n d uct e d re m otel y, as n ee de d, d ue t o 
C O VI D- 1 9 restricti o ns. See Pr ot o c ol Secti o n 4. 3. 1, C O VI D- 1 9 P u blic H ealt h E mer ge nc y, f or f urt her details a n d re q uire me nts re g ar di n g c o n d uct of re m ote 
visits d ue t o C O VI D- 1 9.
a T he Wee k 2 ass ess me nt s h o ul d ge nerall y be c o n d ucte d at t he st u d y site. Per I n vesti g at or j u d g e m e nt, a d diti o n al e val uati o ns/ pr oc e d ures ma y be c o n d ucte d at 
t his ti me p oi nt as a p pr o priate.
*I ncl u di n g n e ur ol o gic e xa m as a c o m p o n e nt of g e n eral p h ysical e xa m a n d U M S A R S
1 Hei g ht at Scre e ni n g a n d We e k 4 8; wei g ht at Scree ni n g, Baseli ne, a n d Wee k 4 8.
2 S u bje cts s h o ul d be seate d a n d resti n g f or a p pr o xi matel y 5 mi n utes pri or t o vital si g n me as ure me nts - te m p erat ure, bl o o d press ure, a n d he art rate. Tilt ta ble 
ma y be use d, if a v aila ble.
3 Ser u m pre g na n c y test will be c o n d ucte d i n W O C B P (s e e s ecti o n 5. 5) at all s c h e d ule d visits.  Uri n e pre g na nc y test will be p erf or me d o n W O C B P (i n 
a d diti o n t o ser u m) at Bas eli ne ( wit hi n 2 4 h o urs pri or t o first d ose).
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 5 0 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
6 O n e P K s a m ple s h o ul d b e c ollecte d pre- d os e a n d o n e P K s a m ple s h o ul d be c ollecte d p ost- d os e. T he ti me of t h e last B H V- 3 2 4 1/ place b o d os e pri or t o t h e 
s a m ple c ollecti o n a n d ti me of t he P K sa m ple c ollecti o n a n d ti me of m ost rec e nt me al s h o ul d be re p ort e d o n t he C R F. At W ee ks 4, 1 2, 2 4, 3 6 a n d 4 8, t h e 
m or ni n g d os e of st u d y dr u g s h o ul d be h el d a n d a d mi nistere d i n t he cli nic/ offi ce d uri n g t he st u d y visit, s o t hat o ne pre- d os e (tr o u g h) a n d o ne p ost- d os e P K 
s a m ple c a n b e c ollecte d. T he p ost- d ose s a m ple s h o ul d be c ollecte d wit hi n a ti me wi n d o w of a p pr o xi m atel y 2 t o 4 h o urs. C ollecti o n of P K s a m ples is n ot 
re q uire d at t h e Earl y Dis c o nti n uati o n visit.
8 S u bje cts s h o ul d ta ke t he first d os e of i n vesti g ati o n al pr o d u ct (I P) w hile i n t h e offic e/cli nic o n t h e d a y of t h e B aseli n e visit a n d sta y at t h e cli nic f or ~ 4 h o urs 
f or o bs er vati o n. Fr o m st art t o e n d of
We e k 1, s u bje cts will i n gest eit her 3 0 0 m g Q D of B H V- 3 2 4 1 or matc hi n g plac e b o Q D.  Fr o m st art t o e n d of
Wee k 2, 
s u bjects will i n gest eit h er 3 0 0 m g BI D of B H V- 3 2 4 1 or matc hi n g plac e b o BI D.  Starti n g wit h We e k 3 a n d f or t h e re mai n der of t he d o u ble- bli n d p orti o n of 
t he st u d y, s u bje cts will i n gest eit h er 6 0 0 m g BI D of B H V- 3 2 4 1 or matc hi n g place b o BI D. 
9 T he Wee k 4 8 ass ess me nts/ pr oc e d ures s h o ul d b e c o n d u ct e d as a n i n p ers o n visit at t he st u d y site.
E v er y eff ort s h o ul d b e ma d e t o c o n d uct t he Wee k 4 8 visit 
a n d mai ntai n a +/- 7 da y wi n d o w. H o we ver, d u e t o t he C O VI D- 1 9 p u blic h ealt h e mer ge nc y, if a bs ol utel y necess ar y, i n or der t o mi ni mize p ote ntial ris ks t o 
st u d y p artici pa nt safet y a n d t o c o m pl y wit h g o v er n me ntal a n d l ocal i nstit uti o n al g ui da n ce (e. g., st u d y site h as a p olic y t hat a n i n p ers o n cli nical res earc h visit 
m ust be d ela ye d), t h e Wee k 4 8 visit wi n d o w ma y b e e x pa n de d u p t o a n a d diti o nal 1 2 we e ks ( ma xi m u m treat me nt d urati o n of 6 0 wee ks).  H o we ver, e ver y 
atte m pt s h o ul d b e ma de t o c o n d u ct t he visit as cl os e as p ossi ble t o t he d at e t hat t he visit is d u e. U n der t h es e circ u msta nces, t he I n v esti gat or s h o ul d dis c uss t h e 
s pecific circ u msta nces of t hese c ases wit h t he s p o ns or me dic al m o nit or ( or desi g nee), w h o m ust a p pr o v e t h e re q uest t o e xte n d t h e treat me nt d urati o n, pri or t o 
a n y m o difi cati o n of t he visit wi n d o w. If t he We e k 4 8 visit wi n d o w is m o difie d, partici pa nts s h o ul d ha ve s afet y ass ess me nts e v al uate d re m otel y (e. g., via 
p h o ne) a n d safet y la bs c o n d ucte d (at a l ocal la b) at t h e ti me of t he s c he d ule d Wee k 4 8 visit. 
S u bje cts w h o dis c o nti n ue fr o m st u d y me dicati o n pri or t o W ee k 4 8 will h a v e a n Earl y Dis c o nti n uati o n visit.  De pe n di n g o n t he r eas o n f or t he earl y 
dis c o nti n uati o n (e. g., d e cli ni n g patie nt stat us), s o me pr oce d ures, f or e x a m ple, P K s a m ples, P D s a m ples, l u m b ar p u nct ure, m a y n ot be c o n d u ct e d at t his visit.  
C o n d u ct of all pr o ce d ures, if p ossi ble, is e nc o ura g e d.
1 0 F or s u bjects w h o dis c o nti n ue st u d y me di cati o n earl y ( pri or t o Wee k 4 8), t h e site s h o ul d c o ntact t h e s u bject b y p h o n e call at a p pr o xi matel y We e k 4 8 t o 
c ollect i nf or mati o n o n cli nical stat us (i n cl u di n g Ti me t o E ve nt meas ures of dis ease pr o gressi o n, a n d if a p plica ble, A Es, S A Es).
 
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
 
Pa ge 5 1  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
T a bl e 2: 
S c h e d ul e of A s s e s s m e nt s a n d E v e nt s - O p e n- L a b el E xt e n si o n P h a s e  
Visit 
B as eli ne 
E xt 1 
( Pre- d ose) 
A b bre vi ate d 
Dr u g 
Dis pe ns ati o n 
Visit 2 
2 E xt 
( p h o ne) 
3 E xt 7 
(c a n be 
re m ote) 
4 E xt 7 
(c a n be 
re m ote) 
5 E xt 
6 E xt 
7 E xt 
8 E xt 8 
D a y ( Visit pr oc e d ures c o n d ucte d 
wit hi n a +/- 7 d a y wi n d o w, u nl ess 
ot her wis e s pe cifie d) 
1 
 
1 4 
2 9 
5 7 
8 5 
1 6 9 
2 5 3 
3 3 7 
We e k 
0 
 
2 E xt 
4 E xt 
8 E xt 
1 2 
E xt 
2 4 
E xt 
3 6 
E xt 
4 8 E xt / E a rl y 
Dis c o nti n u ati o n 8  
Eli gi bilit y Ass ess me nts 
  
 
  
 
  
  
  
  
 
I nf or me d C o ns e nt (s u bject) 
X  
X 
  
 
  
 
 
  
 
M e dical Hist or y 
X  
 
  
 
  
 
 
  
 
C o n c o mita nt M e dicati o n re vie w 
X 
X 
 
 
 
X 
X 
X 
X 
S af et y Assess m e nts 
  
 
  
 
  
  
  
  
 
P h ysi cal E xa mi nati o n 3 
X 
 
 
 
 
X 
X 
X 
X 
P h ysi cal M eas ure me nts 4 
X 
 
  
 
  
 
 
 
X 
Vital Si g ns 5  
X 
X 
 
 
 
X 
X 
X 
X 
E C G ( 1 2-lea d) 
X 
 
 
X 
if visit is 
c o n d u cte d 
i n p ers o n 
X 
 if visit is 
c o n d u cte d 
i n p ers o n 
X 
X 
X 
X 
La b orat or y T ests 
X 
 
 
X 
X 
X 
X 
X 
X 
Pre g n a n c y T est 6 
X 
 
 
X 
X 
X 
X 
X 
X 
S h ee h a n S uici dalit y Trac ki n g Scale 
X 
 
X 
 
 
X 
X 
X 
X 
A d verse E ve nt Re p orti n g
M o nit or f or N o ns eri o us A Es a n d S A Es
X
X
X
X
X
X
X
X
X
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
 
Pa ge 5 2  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
Visit 
B as eli ne 
E xt 1 
( Pre- d ose) 
A b bre vi ate d 
Dr u g 
Dis pe ns ati o n 
Visit 2 
2 E xt 
( p h o ne) 
3 E xt 7 
(c a n be 
re m ote) 
4 E xt 7 
(c a n be 
re m ote) 
5 E xt 
6 E xt 
7 E xt 
8 E xt 8 
D a y ( Visit pr oc e d ures c o n d ucte d 
wit hi n a +/- 7 d a y wi n d o w, u nl ess 
ot her wis e s pe cifie d) 
1 
 
1 4 
2 9 
5 7 
8 5 
1 6 9 
2 5 3 
3 3 7 
We e k 
0 
 
2 E xt 
4 E xt 
8 E xt 
1 2 
E xt 
2 4 
E xt 
3 6 E xt 
4 8 E xt / E a rl y 
Dis c o nti n u ati o n 8  
Effic ac y Ass ess m e nts 
  
 
  
 
  
  
  
  
 
U nifie d M S A Rati n g Sc ale Parts I-I V 3 
(if visit is c o n d ucte d re m otel y [ b y 
p h o ne], o nl y c o n d uct Part I) 
X 
 
 
 
 
X 
X 
X 
X 
M S A Q ualit y of Life 
X 
 
 
 
 
X 
X 
X 
X 
Ti me-t o-e v e nt meas ures of dise ase 
pr o gressi o n  
X 
 
 
 
 
X 
X 
X 
X 
Dis pe ns e St u d y Dr u g 
X 
X 
 
 
 
X 
X 
X 
 
St u d y Dr u g C o m plia nce Assess me nt 
X 
 
X 
 
 
X 
X 
X 
X 
U n der re g ular circ u msta n ces, visits are t o b e c o m plet e d i n- p ers o n, u nless ot h er wis e s p ecifie d.  S o me visits ca n b e c o n d uct e d re m otel y, as n ee de d, d ue t o 
C O VI D- 1 9 restricti o ns.  See Pr ot o c ol Secti o n 4. 3. 1, C O VI D- 1 9 P u blic H ealt h E mer ge nc y, f or f urt her d et ails a n d re q uire me nts re gar di n g c o n d uct of re m ote 
visits d ue t o C O VI D- 1 9. 
1 Baseli ne visit f or t h e O L E P hase is o nl y re q uire d if t here is a n e xte n d e d bre a k (
4 wee ks) i n d osi n g bet wee n t he d o u ble- bli n d a n d O L E P has es.  Ot her wis e, 
t he d o u ble- bli n d Wee k 4 8 visit will ta ke t h e place of t h e B aseli ne- E xte nsi o n visit. S u bjects s h o ul d ta k e t he first d ose of I P w hile i n t h e office/cli nic o n t he da y 
of t h e Bas eli ne- E xte nsi o n visit a n d sta y at t he cli nic f or ~ 4 h o urs f or o bs er vati o n. Fr o m st art t o e n d of We e k 1- E xte nsi o n, s u bje cts will i n gest 3 0 0 m g Q D of 
B H V- 3 2 4 1.  Fr o m st art t o e n d of W ee k 2- E xte nsi o n, s u bje cts will i n gest 3 0 0 m g BI D of B H V- 3 2 4 1.  Starti n g wit h W ee k 3- E xt e nsi o n a n d f or t h e re mai n d er of 
t he O L E, s u bje cts will i n gest 6 0 0 m g BI D of B H V- 3 2 4 1.  
2 A b bre viate d visit o nl y n ee de d f or p atie nts w h o c o m plete d d osi n g i n t h e d o u ble- bli n d p has e < 4 w ee ks pri or t o e nteri n g t he O L E P h as e. T he d o u ble- bli n d 
We e k 4 8 Visit ser ves as t h e B as eli ne- E xte nsi o n visit. T his visit is pri maril y t o dis pe ns e st u d y dr u g. S u bjects s h o ul d ta k e t he first d os e of I P w hile i n t h e 
office/cli nic o n t he da y of t he Bas eli ne- E xte nsi o n visit a n d sta y at t h e cli nic f or ~ 4 h o urs f or o bs er v ati o n. Fr o m start t o e n d of Wee k 1, s u bjects will i n gest 3 0 0 
m g Q D of B H V- 3 2 4 1.  Fr o m st art t o e n d of We e k 2, s u bje cts will i n gest 3 0 0 m g BI D of B H V- 3 2 4 1.  Starti n g wit h We e k 3 a n d f or t he re m ai n der of t he O L E, 
s u bjects will i n gest 6 0 0 m g BI D of B H V- 3 2 4 1.  
3I ncl u di n g n e ur ol o gic e xa m as a c o m p o ne nt of ge n eral p h ysical e x a m a n d U M S A R S. 
4 Hei g ht a n d wei g ht. 
5 S u bje cts s h o ul d be seate d a n d resti n g f or a p pr o xi matel y 5 mi n utes pri or t o vital si g n meas ure me nts - te m p erat ure, bl o o d press ure, a n d heart rate. Tilt ta ble 
ma y be use d, if a v aila ble. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
 
Pa ge 5 3  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
6 Ser u m pre g n a n c y test will b e c o n d ucte d i n W O C B P (se e secti o n 5. 5) at all s c he d ule d visits.  Uri n e pre g na nc y test will be perf or m e d o n W O C B P (i n a d diti o n 
t o s er u m) at B as eli ne- E xte nsi o n ( wit hi n 2 4 h o urs pri or t o first d os e of o pe n-la b el B H V- 3 2 4 1). 
7 W ee k 4- E xte nsi o n a n d W ee k 8- E xte nsi o n are pri maril y t o c oll ect la b tests a n d, if c o n d u cte d i n t he cli nic/st u d y site, t o c o n d uct a n E C G. If t h e patie nt atte n ds 
t he visit at t h e cli nic/st u d y site, a n ass ess me nt of a d v ers e e ve nts, c o n d uct of a n E C G a n d c ollecti o n of s a m ples f or la b a n al yses will b e c o m plete d.  If a 
p artici pa nt prefers t o n ot atte n d t he visit at t he cli nic/st u d y site, t he la b s a m ples ca n b e c ollecte d/c o n d u ct e d at a l o cal la b orat or y/l o cati o n a n d a tele p h o ne call 
t o c o nfir m t h es e were c ollecte d, as well t o ass ess a n y a d vers e e v e nts, will ta k e plac e. 
8 S u bje cts w h o dis c o nti n ue fr o m st u d y me dic ati o n pri or t o Wee k 4 8- E xte nsi o n will h a v e a n Earl y Dis c o nti n u ati o n visit 
 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 5 4  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
4. 3. 2
S cr e e ni n g P h a s e
T he p ur p os e of t he Scr ee ni n g p hase is t o e ns ure t h at t he a p pr o pri ate s u bj ects are e nter e d i nt o 
t he tri al a n d r e mai n sta ble d uri n g t he pr e-tre at m e nt p eri o d. It is esti mate d t h at a p pr o xi matel y 
3 6 0 s u bjects will e nter t he S cree ni n g p hase of t h e tri al. T he I n v esti gat or will d eter mi ne t h at t h e 
s u bject m eets eli gi bilit y criteria a n d will c oll ect d e m o gra p hic a n d me di cal data prese nti n g a f ull 
c haracteriz ati o n of t he s u bject. All att e m pts s h o ul d b e ma de t o o btai n me dical a n d p har m ac y 
rec or ds t o c o nfir m t he s u bj ect s me dical a n d m e dic ati o n treat me nt hist or y. D uri n g Scree ni n g, 
Bi o ha ve n ( or desi g n ee) ma y r e vie w rele va nt cli nic al i nf or mati o n t o c o nfir m t h e dia g n osis a n d 
s u bt y pe of M S A, f or st u d y eli gi bilit y a n d str atificati o n pri or t o ra n d o mizati o n. 
Scree ni n g will ra n ge fr o m a mi ni m u m of 1 d a y t o a ma xi m u m of 4 2 da ys. Please r efer t o t h e 
Sc he d ule of Ass ess me nts  & E ve nts ( Ta bl e 1 ) f or Scree ni n g pr oc e d ure det ails.  
If i niti al Scre e ni n g l a b s a m ple r es ults d o n ot m eet pr ot oc ol-s pecifie d eli gi bilit y criteri a a n d t h e 
I n vesti gat or d eter mi nes t hat a re p eat s a m ple ma y m e et t he r a n ge re q uire d f or eli gi bilit y, a 
re peat la b s a m ple ma y b e c ollecte d ( o ne r e peat c olle cti o n/ a nal ysis all o we d).  
R escree ni n g:  After o btai ni n g S p o ns or a p pr o val, a s u bject w h o d o es n ot meet pr ot oc ol re q uire d 
eli gi bilit y criteri a d uri n g Scree ni n g b ut w h o ma y p ot e ntiall y bec o me eli gi ble (e. g., l o gisti cal 
reas o ns s uc h as e xcee di n g s cr ee ni n g wi n d o w t o acc o m m o dat e ti me re q uire d f or 
a dj ust me nt/sta bilit y of c o nc o mit a nt m e dicati o n, was h o ut of pr o hi bit e d me dicati o n or re peat 
pr oce d ures t o all o w f or rec hec k/c o nfir mati o n of a n a b n or malit y t hat ma y meet t he re q uire d 
ra n ge i n a r eas o na ble a m o u nt of ti m e), ma y b e e nt ere d as a Scree n Fail ure i n I W R S a n d t he n 
rescree ne d o ne ti m e (e nt ere d as a Scr ee n Fail ure a n d Res cree n i n I W R S a n d e C R F).  If t he 
S p o ns or a p pr o ves Rescree ni n g f or a s u bje ct, i nstr u cti o ns will be pr o vi de d t o t he site re g ar di n g 
t he s pecific Scree ni n g pr oce d ur es/e val uati o ns t hat will nee d t o be re p eate d f or R escree ni n g, as 
t his is de pe n de nt o n t he a m o u nt of ti m e ela pse d. 
4. 3. 3
R a n d o mi z ati o n P h a s e 
S u bjects w h o are deter mi ne d t o be eli gi ble f or t he st u d y will be ra n d o miz e d i nt o t he trial. It is 
esti mate d t h at a p pr o xi matel y 3 2 5 s u bjects will b e ra n d o mize d a n d assi g ne d t o r ecei v e B H V-
3 2 4 1 ( 6 0 0 m g BI D) or matc hi n g pla ce b o ( BI D) i n a 1: 1 rati o, wit h ra n d o mizati o n stratifie d b y 
dis eas e s u bt y pe of eit her M S A- P vs. M S A- C, dia g n ostic cate g or y of eit her p ossi ble M S A vs. 
pr o ba ble M S A, a n d c o u ntr y. 
S u bjects s h o ul d be a d mi nistere d t he D a y 1/first d os e of st u d y me dic ati o n ( 3 0 0 m g Q D or 
m atc hi n g pl ace b o Q D) w hil e i n t he offic e/cli nic o n t he d a y of t he B as eli ne visit. S u bjects 
s h o ul d st a y at t he office/cli nic f o r m o nit ori n g f or a p pr o xi m atel y 4 h o urs. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 5 5  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
D ose titrati o n peri o d: F or t he rest of W ee k 1, s u bjects will i n gest eit her 3 0 0 m g Q D of B H V-
3 2 4 1 or matc hi n g pla ce b o Q D. Fr o m st art t o e n d of Wee k 2, s u bjects will i n gest eit her 3 0 0 m g 
BI D of B H V- 3 2 4 1 or matc hi n g pla ce b o BI D.  S u bje cts s h o ul d ta ke t he st u d y dr u g t wi ce a da y; 
d osi n g i n t he m or ni n g a n d e v e ni n g a p pr o xi matel y 1 2 h o urs a part.  If t here is a del a y i n d osi n g, 
t he i nt er val b et wee n t w o d oses s h o ul d be n o l ess t ha n 6 h o urs. 
A n e n d of Wee k 2 ass ess me nt of c o m pli a nce a n d t ol era nce t o t his d ose titrati o n sc he d ul e will 
be c o n d uct e d.  Per I n vesti gat or j u d ge me nt, a d diti o nal e val u ati o ns/ pr o ce d ures ma y b e 
c o n d ucte d at t his ti m e p oi nt as a p pr o priat e.  If t ol era bilit y iss ues are e x perie nce d wit h 3 0 0 m g 
Q D or 3 0 0 m g BI D d osi n g, t he titrati o n sc he d ule m a y be m o difi e d (s ee Secti o n  7. 2. 3). 
F ull d os e p eri o d: St arti n g wit h We e k 3 a n d f or t he r e mai n der of t he st u d y, s u bje cts will i n gest 
eit her 6 0 0 m g BI D of B H V- 3 2 4 1 or matc hi n g place b o BI D. S u bjects s h o ul d ta ke t he st u d y 
dr u g t wice a d a y; d osi n g i n t he m or ni n gs a n d e ve ni n gs a p pr o xi mat el y 1 2 h o urs a part.  
At Wee ks 4, 1 2, 2 4, 3 6 a n d 4 8, t h e m or ni n g d os e of st u d y me dicati o n s h o ul d n ot be t a ke n o n 
t he da y of t h e st u d y visit u ntil it is a d mi nist ere d b y site pers o n nel d uri n g t he st u d y visit, s o t hat 
o ne pre- d os e (tr o u g h) a n d o ne p ost- d os e P K s a m pl e ca n be c olle cte d a p pr o xi matel y 2- 4 h o urs 
p ost- d os e (s ee Secti o n 6. 3. 2).  
T he t a blets s h o ul d be s w all o we d w h ol e wit h a dri n k of w ater. T he t a blets s h o ul d n ot be 
s plit, c he we d, or cr us he d. 
St u d y me dic ati o n ca n be ta ke n wit h o ut re gar d t o meals, h o we ver, t he last m ealti me pri or t o 
c olle cti o n of P K sa m pl es s h o ul d be o btai ne d. 
If s u bjects ha ve diffic ult y t olerati n g B H V- 3 2 4 1 6 0 0 m g BI D, t he n t he d os e ma y be a dj uste d 
(s ee Secti o n 7. 2. 3).  
T here is a +/- 3 da y visit a n d pr oc e d ure wi n d o w d uri n g t he st u d y, u nless ot her wise s pecifi e d. 
Please refer t o t he Sc he d ule of Assess me nts & E ve nts ( Ta ble 1 ) f or details o n pr oce d ures.  
4. 4 
E n d of Tr e at m e nt 
Patie nts will ha ve a Wee k 4 8/ Earl y Disc o nti n u ati o n visit w he n t he y eit h er c o m plete t he st u d y 
at Wee k 4 8 or dis c o nti n ue fr o m st u d y m e dic ati o n earl y ( pri or t o Wee k 4 8).  T he Wee k 
4 8/ Earl y Dis c o nti n uati o n ass ess me nts/ pr o ce d ures s h o ul d be c o n d ucte d as a n i n pers o n visit at 
t he st u d y site.  E ver y eff ort s h o ul d be ma d e t o c o n d u ct t he Wee k 4 8 visit a n d mai ntai n a +/- 7 
da y wi n d o w. H o w e ver, d ue t o t he C O VI D- 1 9 p u blic healt h e mer g e nc y, if a bs ol utel y n ecess ar y, 
i n or der t o mi ni mize p ote ntial ris ks t o st u d y partici 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 n ce (e. g., st u d y site has a p olic y t hat a n i n pers o n 
cli ni cal r es earc h visit m ust be d ela y e d), t he Wee k 4 8 visit wi n d o w ma y be e x pa n de d b e y o n d 
t he +/- 7 da y wi n d o w u p t o a n a d diti o nal 1 2 wee ks ( ma xi m u m tre at m e nt d urati o n of 6 0 wee ks).  
H o w e ver, e ver y att e m pt s h o ul d b e ma d e t o c o n d u ct t he visit as cl ose as p ossi ble t o t he date t hat 
t he visit is d ue. U n der t hese circ u msta nces, t h e I n vesti gat or s h o ul d dis c uss t he s pecific 
circ u mst a nces of t h ese cas es wit h t h e s p o ns or me dic al m o nit or ( or desi g ne e), w h o m ust 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 5 6  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
a p pr o ve t he r e q uest t o e xte n d t h e tre at m e nt d urati o n, pri or t o a n y m o dific ati o n of t he visit 
wi n d o w. 
If t he Wee k 4 8 visit wi n d o w is m o difie d, partici pa nts s h o ul d ha ve s afet y ass ess me nts e v al uat e d 
re m otel y (e. g., vi a p h o ne) a n d safet y la bs c o n d u cte d (at a l o cal la b) at t he ti me of t he sc he d ule d 
Wee k 4 8 visit. 
F or s u bjects w h o dis c o nti n ue earl y, d e pe n di n g o n t h e reas o n f or earl y dis c o nti n u ati o n ( e. g., 
decli ni n g patie nt st at us), s o me pr oce d ur es (f or e xa m ple, P K sa m ples, P D sa m ples, l u m b ar 
p u nct ure), m a y n ot be c o n d ucte d at t his visit.  C o n d u ct of all pr oce d ures, if p ossi ble, is 
e nc o ura ge d.  If p ossi bl e, t he s u bje cts w h o dis c o nti n u e fr o m st u d y me dicati o n pri or t o Wee k 4 8 
s h o ul d be c o nta cte d b y a f oll o w u p p h o ne c all at t h e a p pr o xi mate ti me of t heir W ee k 4 8 visit, 
t o c oll ect i nf or mati o n o n cli nic al stat us (i ncl u di n g Ti me t o E v e nt m eas ures of dis ease 
pr o gressi o n, a n d if a p plica ble, A Es, S A E S). 
4. 5 
P o st St u d y A c c e s s t o T h er a p y/ O p e n- L a b el E xt e n si o n P h a s e  
T he O L E P hase is a n o pti o nal 4 8 w ee k o pe n-l a bel tr eat m e nt p has e f oll o wi n g t h e d o u ble- bli n d 
p hase of t he st u d y.  
4. 5. 1  
O pe n- L a bel E xte nsi o n P h ase Eli gi bilit y Crite ri a 
ris k- be nefit pr ofile, t he c o ns e nt of t he partici pa nt a n d t he i nt e grit y of t he trial, t o deter mi ne 
w het her a st u d y partici pa nt is a p pr o priat e a n d eli gi bl e t o c o nti n ue partici pati o n i n t he o pti o nal 
O L E P has e, bas e d o n cli nical j u d ge me nt, t he restrict e d a n d pr o hi bite d m e dicati o n criteria 
s pecifie d i n pr ot oc ol s ecti o n 5. 4, t he disc o nti n uati o n criteria g ui d a nce s pecifie d i n pr ot oc ol 
s ecti o n 6. 4  a n d r e vie w of t he f oll o wi n g criteria:  
 C o m pleti o n of t he 4 8 w ee k D o u ble- Bli n d ra n d o mize d p has e of t he st u d y. Partici p a nts w h o 
earl y-t er mi n ate d fr o m t he d o u bl e- bli n d p h ase of t he trial or w h o disc o nti n ue d t h e st u d y 
me dic ati o n 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 he O L E p h as e. All 
partici pa nts m ust h a ve t h eir We e 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 h ase. 
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.  
 St u d y partici pa nts m ust b e:  
o  a ble t o c o nti n u e t o s w all o w w h ole st u d y me dic ati o n ta blets  
o  willi n g a n d a ble t o c o nti n ue t o  
 a d here t o t he st u d y dr u g re gi me n  
 t o parti ci pate i n all pr ot oc ol s pecific ass ess me nts, a n d 
 t o c o m pl y wit h t he st u d y visit s c he d ule. 
 Pr o vi de i nf or me d c o ns e nt t o p artici pat e i n t h e O L E p hase.  All s u bjects w h o e nter t h e O L E 
p hase will si g n a n e w i nf or me d c o ns e nt f or m.  


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 5 7  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
4. 5. 2
O pe n- L a bel E xte nsi o n P h ase Pr oce d ures
W he n a sit e is o pe n f or recr uit m e nt t o t he O L E P has e, parti ci pa nts c o m pl eti n g t he d o u ble- bli n d 
treat me nt p h ase w h o c h o os e t o partici p ate i n t he O L E p has e a n d ar e eli gi ble t o c o nti n ue, m ust 
c o nse nt t o t h e O L E p has e a n d directl y e nter t h e O L E p has e starti n g at W ee k 4 8 visit of t he 
d o u ble- bli n d treat me nt p hase. T he Wee k 4 8 visit will s er ve as t he B aseli n e- E xte nsi o n visit i n 
t he O L E p has e f or p artici pa nts w h o m o ve directl y fr o m t he d o u bl e- bli n d treat me nt p hase t o t h e 
O L E. T here after, partici pa nts will u n der g o visits at Wee k 2- E xte nsi o n, Wee k 4- E xt e nsi o n, 
Wee k 8- E xte nsi o n, Wee k 1 2- E xt e nsi o n, a n d t h e n e v er y 1 2 wee ks of t he O L E p has e as o utli n e d 
i n Ta bl e 2  ( Sc he d ul e of Ass ess me nts & E ve nts- E xt e nsi o n P hase).  
A partici p a nt w h o has c o m plete d t he d o u bl e- bli n d tr eat m e nt p hase of t he st u d y pri or t o t he 
O L E p hase of t he st u d y b ei n g a p pr o ve d a n d o pe n f or recr uit me nt at t h e st u d y ce nt er w here t h e y 
are partici p ati n g, c a n rec o ns e nt a n d start t he O L E p h as e as l o n g as t he i n vesti g at or det er mi n es 
t hat o pe n-la bel treat me nt offers a n a cce pta bl e ris k- be nefit pr ofile f or t h e parti ci pa nt. O nce t h e 
st u d y site is o pe n f or recr uit me nt f or t h e O L E, st u d y partici pa nts w h o pre vi o usl y c o m pl ete d t h e 
d o u ble- bli n d p h ase of t he st u d y will ha v e u p t o a p pr o xi mat el y 1 2 wee ks (fr o m t he dat e of O L E 
o pe ni n g at t he sit e) t o e nr oll a n d c o m plete t h e O L E B aseli ne- E xte nsi o n Visit, re gar dless of 
t heir date of d o u bl e- bli n d p hase c o m pl eti o n.  
F or partici p a nts w h o ha ve bee n off of t he st u d y dr u g f or less t ha n 4 wee ks, t he s u bj ect s h o ul d 
atte n d a n A b bre viate d Dr u g Dis pe ns ati o n Visit at t h e i n vesti gati ve site, w he n m e dical a n d/ or 
me dic ati o n c ha n ges will be re vi e w e d pri or t o dis pe nsi n g o pe n-la b el B H V- 3 2 4 1.  I n t his cas e, 
f or t hes e partici p a nts, t he Wee k 4 8 visit will als o s er ve as t he Baseli ne- E xte nsi o n visit i n t he 
O L E P has e.  T here after, partici pa nts will u n der g o visits at We e k 2- E xt e nsi o n, Wee k 4-
E xte nsi o n, W ee k 8- E xte nsi o n, Wee k 1 2- E xt e nsi o n, a n d t he n e ver y 1 2 we e ks of t he E xt e nsi o n 
P hase as o utli ne d i n Ta ble 2  ( Sc he d ule of Ass ess me nts & E ve nts- E xte nsi o n P hase). 
F or partici p a nts w h o will ha v e bee n off of t h e st u d y dr u g f or greater t ha n or e q ual t o 4 wee ks, 
t hese partici p a nts s h o ul d be re-ass esse d a n d re- c o nse nte d b y t he I n v esti gat or d uri n g a n O L E 
Bas eli ne- E xte nsi o n Visit. Fr o m t he d ate t hat t he O L E is o pe n f or recr uit m e nt at t heir 
i n vesti gati ve site, t h es e partici pa nts will ha v e u p t o a p pr o xi mat el y 1 2 wee ks t o c o m pl ete t h e 
O L E Bas eli n e- E xt e nsi o n Visit. T h ereaft er, partici p a nts will u n der g o visits at W ee k 2-
E xte nsi o n, Wee k 4- E xte nsi o n, We e k 8- E xt e nsi o n, W ee k 1 2- E xt e nsi o n, a n d t h e n e ver y 1 2 
w ee ks of t he E xt e nsi o n P hase as o utli ne d i n T a ble 2  ( Sc he d ule of Ass ess me nts & E ve nts- 
E xte nsi o n P hase).
D ose Titr ati o n:  S u bjects e nteri n g t he O L E p has e of t he st u d y will r ecei ve o pe n-l a bel acti ve 
B H V- 3 2 4 1 a n d will f oll o w t he s a me d os e titrati o n sc he d ule as t h e titrati o n i n t h e d o u ble- bli n d 
p hase of t he st u d y, t o e ns ure t hat all p arti ci pa nts s afel y c o nti n u e fr o m eit her a cti v e B H V- 3 2 4 1 
or place b o t o o pe n-l a bel B H V- 3 2 4 1. 
S u bjects s h o ul d be a d mi nistere d t he D a y 1/first d os e of o pe n-l a bel B H V- 3 2 4 1 ( 3 0 0 m g 
Q D) w hile i n t he office/cli nic o n t h e d a y of t he B aseli ne- E xte nsi o n visit.  S u bjects s h o ul d 
st a y at t h e office/cli nic f or m o nit ori n g f or a p pr o xi m atel y 4 h o urs. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 5 8  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
F or t he r est of We e k 1- E xte nsi o n of t he O L E p h as e, s u bjects will i n gest o ne ta bl et of B H V-
3 2 4 1 ( 3 0 0 m g) per da y i n t he m or ni n g f or o ne wee k.  Fr o m start t o e n d of Wee k 2- E xte nsi o n, 
s u bjects will i n gest 3 0 0 m g BI D of B H V- 3 2 4 1.  S u bjects s h o ul d ta k e o ne 3 0 0 m g ta bl et of 
B H V- 3 2 4 1 t wice a da y ( 6 0 0 m g p er da y); i n t he m or ni n gs a n d e ve ni n gs, a p pr o xi matel y 1 2 
h o urs a part.  If t here is a del a y i n d osi n g, t h e i nt er val bet wee n t w o d os es s h o ul d be n o l ess t ha n 
6 h o urs.
A n e n d of Wee k 2- E xte nsi o n ass ess me nt of c o m pli a nce a n d t olera nce t o t his d ose titr ati o n 
s c he d ule will be c o n d u cte d.  Per I n vesti gat or j u d ge m e nt, a d diti o nal e val uati o ns/ pr oce d ures 
ma y be c o n d u cte d at t his ti m e p oi nt as a p pr o priat e.  If t olera bilit y iss ues are e x perie nc e d wit h 
3 0 0 m g Q D or 3 0 0 m g BI D d osi n g, t he titr ati o n sc h e d ule ma y b e m o difi e d (s ee Secti o n  7. 2. 3). 
Starti n g wit h Wee k 3- E xte nsi o n a n d f or t he re mai n d er of t he O L E p h as e of t he st u d y 
(a d diti o n al 4 6 w ee ks), s u bjects will i n gest 6 0 0 m g BI D of B H V- 3 2 4 1. S u bjects s h o ul d ta ke t w o 
3 0 0 m g ta bl ets of B H V- 3 2 4 1 t wice a d a y ( 1 2 0 0 m g per da y); i n t he m or ni n gs a n d e ve ni n gs, 
a p pr o xi matel y 1 2 h o urs a p art.  
S u bjects w h o w ere ta ki n g a re d uc e d d ose of 3 0 0 m g BI D ( o ne ta blet t wic e a da y) of t h e bli n d e d 
st u d y me dicati o n d u e t o t olera bilit y iss ues w he n t he y c o m plete d t h e d o u ble- bli n d p hase of t h e 
pr ot oc ol, m a y c o nti n ue t a ki n g 3 0 0 m g BI D d uri n g t h e O L E. 
5 
P O P U L A TI O N 
5. 1 
N u m b er of S u bj e ct s 
A p pr o xi matel y 3 2 5 s u bjects are e x pe cte d t o be ra n d o mize d i n t his st u d y.  
5. 2 
I n cl u si o n Crit eri a 
1.  I nf or me d C o nse nt 
a. S u bjects m ust pr o vi d e a writte n si g ne d a n d date d i nf or me d c o ns e nt f or m/f or ms 
(I R B/ E C s pecific) i n acc or da n ce wit h r e g ulat or y a n d i nstit uti o nal g ui deli nes, pri or t o 
t he i nitiati o n of a n y pr ot oc ol r e q uire d pr oc e d ures.  O nl y pati e nts wit h t h e ca p acit y t o 
u n dersta n d t he n at ure, si g nifica n ce a n d sc o p e of t he cli ni cal trial i nt er ve nti o ns a n d t o 
e x press t heir wis hes acc or di n gl y m a y pr o vi de c o nse nt t o partici p ate i n t he st u d y. 
b.  Care gi vers m ust b e willi n g t o si g n a n d d ate a n I R B/ E C-a p pr o ve d writte n i nf or me d 
c o nse nt f or m t h at o utli nes t h e care gi ver e x p ect ati o ns a n d res p o nsi bilities i n t his st u d y 
(s ee I ncl usi o n criteri o n 3 k), i n acc or da nc e wit h re g ul at or y a n d i nstit uti o nal g ui deli nes, 
as a p pr o priat e. 
2.  A ge a n d Se x 
a. M ale a n d fe mal e s u bjects bet wee n t h e a ges of > 4 0 t o < 8 0 years at ti me of Scr ee ni n g. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 5 9  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
3.
T ar get P o p ul ati o n
a. Dia g n osis of pr o ba ble or p ossi ble M S A acc or di n g t o c o ns e ns us cli nical criteri a ( Gil m a n 
et al 2 0 0 8), i ncl u di n g s u bjects wit h M S A of eit her s u bt y pe ( M S A- P or M S A- C).
b.  A ble t o a m b ulat e wit h o ut t he assista n ce of a n ot h er p ers o n, defi ne d as t h e a bilit y t o ta ke 
at le ast 1 0 ste ps. Use of assisti ve de vices (e. g., wal k er or ca ne) is all o we d.
c. A ntici pate d s ur vi val of at least 3 ye ars at t h e ti me of S cree ni n g, as j u d g e d b y t he 
I n vesti gat or.
d.  A brai n M RI s ca n (c o n d ucte d wit hi n t he 1 4 da ys pri or t o Bas eli n e/ Da y 1, 
a p pr o xi matel y) t hat d o es n ot r ule o ut a dia g n osis of M S A.  
e. A ble t o t ol erat e M RI. 
f. B o d y mass i n de x ( B MI) < 4 0 k g/ m 2 at Scree ni n g. 
g.  A ble t o s w all o w ta blets w h ole a n d a ntici pate d t o b e a ble t o d o s o t hr o u g h o ut t he 
d urati o n of t h e st u d y. 
h.  Willi n g a n d a ble t o a d here t o t he st u d y dr u g re gi me n. 
i. Willi n g a n d a ble t o p erf or m all pr ot oc ol-s pecifie d ass ess me nts a n d c o m pl y wit h t he 
st u d y visit s c he d ul e.  
j. A ble t o rea d, u n d ersta n d, a n d s pea k l ocal la n g u a ge fl ue ntl y t o e ns ure c o m pr e he nsi o n of 
i nf or me d c o ns e nt a n d pr ot o c ol-s pecifie d ass ess me nts. 
k.  M ust ha ve reli a ble care gi v er t o a cc o m p a n y s u bject t o st u d y visits, wit h t he sa me 
care gi v er c o m pleti n g care gi ver ass ess me nts at Bas eli ne, Wee k 2 4 a n d Wee k 4 8/ Earl y 
Disc o nti n uati o n, w he n p ossi ble. Car e gi ver m ust be a ble t o re a d, u n dersta n d, a n d s pe a k 
l ocal la n g ua g e fl ue ntl y t o e ns ure c o m pre h e nsi o n of i nf or me d c o ns e nt a n d pr ot oc ol-
s pecifie d ass ess me nts. Care gi ver m ust als o ha v e fre q ue nt c o nt act wit h s u bject (at l east 3 
h o urs per w ee k at o ne ti me or differe nt ti mes) a n d be willi n g t o m o nit or t he s u bje ct's 
healt h a n d c o nc o mit a nt me dicati o ns t hr o u g h o ut t he st u d y. 
l. If s u bject is recei vi n g treat me nt f or M S A, t he d oses m ust ha ve bee n sta bl e f or at l east 
3 0 da ys pri or t o Bas eli ne/ R a n d o mi zati o n a n d me dicati o ns pres e nt at Baseli ne e x pecte d 
t o re mai n rel ati v el y sta ble d uri n g t h e st u d y peri o d. T his ma y i ncl u de m e dic ati o ns 
c o m m o nl y us e d f or Par ki ns o n's disease (e. g., c oe nz y me Q 1 0, le v o d o pa/car bi d o pa, 
le v o d o pa/ b e ns erazi de, fa va b ea n e xtract, a d o pa mi ne a g o nist, catec h ol- 0-
met h yltra nsferase i n hi bit or, a ma nta di n e) or t h ose f or a ut o n o mi c d ysf u ncti o n ( e. g., 
e p he dri ne, mi d o dri n e, fl u dr oc ortis o ne, octr e oti d e, des m o pressi n, o x y b ut y ni ne, 
dr o xi d o pa). 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 6 0 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
m. Sta ble o n ot h er c hr o ni c me dicati o ns a n d s u p ple m e nts f or at least 3 0 d a ys pri or t o
Bas eli ne/ Ra n d o mizati o n a n d e x pect e d t o re mai n r elati vel y st a ble d uri n g t he st u d y 
peri o d.
n.
W o me n of c hil d beari n g p ote ntial ( W O C B P) [s ee pr ot oc ol secti o n 5. 5] a n d f ertile me n 
(i ncl u di n g t h os e vas ect o mi ze d f or less t ha n 6 m o nt hs) wit h fe male part ners w h o are 
W O C B P ( n ot s ur gicall y st eril e a n d n ot p ost me n o pa us al) [s ee pr ot oc ol s ecti o n 5. 5] m ust 
a gree t o use hi g hl y effe cti v e birt h c o ntr ol, i ncl u di n g t w o met h o ds of c o ntr ace pti o n, f or 
t he d urati o n of t he st u d y (i.e., be gi n ni n g 3 0 da ys pri or t o Bas eli n e/ Ra n d o mizati o n a n d 
e xte n di n g t o 3 0 da ys f or w o me n a n d 9 0 da ys f or m e n after t he last d os e of st u d y dr u g). 
T he t w o met h o ds of c o ntra ce pti o n s h o ul d i ncl u d e:
i.
o ne barrier met h o d (e. g. dia p hra g m wit h s per mici d e, c o n d o m wit h s per mici d al gel, 
cer vical ca p); 
ii.
a n d o ne ot her met h o d t hat c o ul d i ncl u de h or m o n al c o ntrace pti ves (e. g. oral 
c o ntrac e pti v es, i njecta bl e c o ntr ace pti ves, c o ntrace pti ve i m pl a nt, patc h) use d f or at 
least 4 w ee ks pri or t o se x ual i nterc o urse ( Se cti o n 5. 5); 
o.
W O C B P m ust ha ve a ne g ati v e s er u m pre g na n c y test at S cree ni n g a n d a ne g ati v e uri ne 
pre g na nc y t est wit hi n a p pr o xi matel y 2 4 h o urs pri or t o d osi n g at 
Bas eli ne/ Ra n d o mizati o n.
5. 3
E x cl u si o n Crit eri a
1.
T ar get Dis e ase E xce pti o ns
a.
S u bjects ha vi n g a d va nc e d disease, defi ne d b y t h e prese nce of o ne or m ore of t he 
f oll o wi n g o n t he U M S A R S Part I:
i.
S peec h i m p air m e nt, as assesse d b y a sc ore gre ater t h a n or e q ual t o 3, Q uesti o n 1;
ii.
S w all o wi n g i m pair me nt, as ass ess e d b y a s c ore of gr eater t ha n or e q ual t o 3 o n 
Q uesti o n 2;
iii. Falli n g m or e fre q ue ntl y t h a n o nce per wee k, as ass ess e d b y a s c ore of great er t ha n 
or e q ual t o 3 o n Q uesti o n 8; or 
2.
Me dic al Hist or y E xcl usi o ns
a.
i nstr ucti o ns, pl ace t he s u bje ct at u n acc e pta ble ris k, a n d/ or c o nf o u n d t he i nter pr etati o n of 
s afet y or effi cac y data fr o m t he st u d y, as j u d g e d b y t he I n vesti gat or.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 6 1  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
b.
Dia g n osis of ne ur ol o gic al dis or ders, ot h er t ha n M S A, i ncl u di n g ( b ut n ot li mite d t o) t he 
f oll o wi n g:
i. I di o pat hi c Par ki ns o n's dis eas e or a n ot her f or m of par ki ns o nis m (e. g., de m e nti a wit h 
Le w y b o dies, dr u g-i n d uc e d, p ost-e nce p h alitic, v asc ular), w hic h has n ot 
s u bse q ue ntl y re vise d t o a di a g n osis of M S A, 
ii. A n y ot her ne ur o de ge ner ati v e dis eas e ( e. g., Alz hei mer's dis ease, fr o nt ote m p oral 
de me ntia, a m y otr o p hi c lateral s cler osis, pri o n dis eas e),
iii. A n y ot her cli nicall y si g nifica nt ne ur ol o gi cal dis or der (e. g., hist or y of str o ke, hist or y 
of hea d i nj ur y wit h l oss of c o nsci o us ness f or at least 1 5 mi n utes wit hi n t he p ast 2 0 
years, hist or y of s eiz ur e dis or der, brai n t u m or, or ot h er s pace- occ u p yi n g lesi o n). 
c. Hist or y of or S cree ni n g brai n M RI sca n i n dicati v e of si g nifica nt a b n or m alit y, i ncl u di n g 
( b ut n ot li mit e d t o) t h e f oll o wi n g: pri or he m orr ha ge or i nfarct gr eater t ha n 1 c m 3; 3 or 
m ore la c u nar i nfar cts; cere bral c o nt usi o n; e nc e p hal o malacia; a ne ur ys m; vasc ular 
malf or m ati o n; s u b d ural he mat o ma; h y dr oc e p hal us; s pace- oc c u p yi n g lesi o n (e. g., 
a bscess or brai n t u m or). 
d.  C o ntrai n di cati o n t o M RI e xa mi nati o n f or a n y re as o n. 
e. F or t h ose partici pati n g i n t h e o pti o n al C S F s u b-st u d y, c o ntrai n dicati o n t o u n d er g oi n g a n 
L P i ncl u di n g, b ut n ot li mite d t o: i na bilit y t o t olerate a n a p pr o priatel y fle xe d p ositi o n f or 
t he ti me ne cess ar y t o perf or m a n L P; i nf ecti o n at t he desire d L P site; ta ki n g 
a nti pl atelet/a ntic oa g ul a nt m e dicati o ns t h at ca n n ot be disc o nti n ue d f or a s h ort peri o d of 
ti me pri or t o perf or mi n g t h e L P; de ge n erati ve art hritis of t he l u m bar s pi n e; s us pect e d 
n o n-c o m m u ni cati n g h y dr oce p hal us or i ntra cra ni al m ass; pri or hist or y of s pi nal mass or 
tra u ma. 
f. Pres e nce of cli nicall y si g nifica nt t h yr oi d disease wit h a b n or mal fr ee T 4 le vels a n d T S H 
> 1 0 mI U/ L ( des pit e tre at m e nt) at Scree ni n g, c o nfir m e d b y re peat .   
g.  Wit hi n 1 y ear pri or t o S cree ni n g or b et wee n S cr ee ni n g a n d Bas eli n e ( Da y - 1), a n y of 
t he f oll o wi n g: m y oc ar dial i nfarcti o n; h os pitalizati o n f or c o n gesti ve h eart fail ure; 
h os pitali zati o n f or, or s y m pt o ms of, u nsta ble a n gi na; or s y nc o pe n ot rel ate d t o M S A. 
h.  Dia g n osis of cli ni call y si g nifi ca nt ps yc hiatri c dis or d er i ncl u di n g ( b ut n ot li mite d t o) t he 
f oll o wi n g: a n y ps yc h otic dis or der, s e vere bi p olar or u ni p olar de pr essi o n, pri or hist or y 
of s uici dal t h o u g hts or be ha vi or t hat are belie v e d t o r e prese nt a c urre nt safet y ris k.  
i. Hist or y of s u bsta nce us e dis or der ( dr u g or al c o h ol) i n t he last 1 2 m o nt hs, wit h t h e 
e xce pti o n of nic oti ne, as defi ne d b y D S M- V criteri a. 
j. Hist or y or pres e nce of gastr oi ntesti n al or ot h er disease k n o w n t o i nterfer e wit h 
a bs or pti o n, distri b uti o n, m eta b olis m, or e x creti o n of dr u gs, or a hist or y of s ur ger y 
k n o w n t o i nterfer e wit h a bs or pti o n or e xcreti o n of dr u gs (i.e., gastric b y p ass). 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 6 2  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
k.
Hist or y of a n y ot her cli ni call y si g nifica nt dis e as e (e. g., a ut oi m m u ne, c ar di o vasc ular, 
e n d ocri ne, g astr oi nt esti nal, he mat ol o gi cal, h e patic, i m m u n ol o gi cal, i nfecti o us, 
ne ur ol o gic al, p ul m o nar y, ps yc hiatric, or r e nal) t hat, bas e d o n t he j u d g me nt of t he 
I n vesti gat or, is cli nicall y u nsta ble, is li kel y t o deteri orate d uri n g t he c o urse of t h e st u d y, 
c o ul d p ut t h e patie nt at ris k bec a us e of partici p ati o n i n t he st u d y, c o ul d affect t he 
 
l. Hist or y of h u ma n i m m u n o defi cie n c y vir us i nfecti o n. 
m.  H e mat ol o gic or s oli d mali g na nc y dia g n osis wit hi n 5 years pri or t o Scre e ni n g. [ N ote: 
S u bjects wit h a hist or y of l oc ali ze d s ki n ca n cer, bas al cell or s q ua m o us cell car ci n o m a, 
ma y be e nr olle d i n t he st u d y as l o n g as t he y ar e ca n c er free pri or t o ra n d o mi zati o n. 
S u bjects wit h ot h er l oc ali ze d ca n cers ( wit h o ut met astati c s prea d) w h o ha ve pre vi o usl y 
c o m plete d t h eir c o urse of tr eat me nt m ore t h a n 5 years pri or t o Scree ni n g, are n ot 
c urre ntl y r ecei vi n g tre at m e nt a n d h a ve be e n i n re missi o n ma y be e nr olle d o nl y if, i n t he 
o pi ni o n of t he I n v esti gat or, t here is n o e x pectati o n f or rec urre nce or f urt her c a ncer 
treat me nt d uri n g t he st u d y p eri o d. A nti h or m o nal t h er a p y (e. g., ta m o xife n) is all o we d if 
t he s u bject's c a ncer is i n r e missi o n a n d t he s u bje ct is o n sta ble m ai nt e na nce t hera p y t o 
re d uce t h eir ris k of rec urr e nce.] 
n.  A n y maj or s ur ger y wit hi n 4 we e ks of Scree ni n g. 
o.  Bl o o d tra nsf usi o n wit hi n 4 we e ks of Scree ni n g. 
p.  Hist or y of brai n s ur ger y f or Par ki ns o nis m (i. e., dee p- brai n sti m ulati o n).
q.  Hist or y of ste m-cell tr eat me nt. 
r. W o me n w h o are pre g n a nt or breastfee di n g. 
s. S u bjects or pris o ners w h o are i n v ol u ntaril y det ai ne d or i ncarcerate d f or treat me nt of 
eit her a ps yc hiatric or p h ysical ill ness m ust n ot b e e nr olle d i nt o t he st u d y. 
t. A n y me dical c o n diti o n, base d o n t he j u d ge me nt of t h e I n vesti gat or, t hat w o ul d 
c o nf o u n d t he a bilit y t o a d e q uatel y ass ess s afet y a n d efficac y o utc o me meas ures 
3.  P h ysic al a n d L a b or at o r y Test Fi n di n gs 
a. E vi de nc e of or ga n d ysf u ncti o n or a n y cli nicall y si g nifica nt d e viati o n fr o m n or mal i n 
p h ysical e x a mi n ati o n, vital si g ns, E C G, or cli nical la b orat or y det er mi n ati o ns be y o n d 
w hat is c o nsiste nt wit h t he tar get p o p ulati o n. 
b.  Cli nic all y si g nifica nt a b n or malit y o n 1 2-le a d E C G pri or t o st u d y dr u g a d mi nistrati o n 
be y o n d w hat is c o nsiste nt wit h t h e tar g et p o p ulati o n, c o nfir me d b y r e peat. 
c. 
 Scr ee ni n g/ B as eli n e peri o d or 
u nc o ntr oll e d arr h yt h mia or fre q u e nt pre mat ur e ve ntri c ular c o ntracti o n ( P V Cs) ( > 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 6 3  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
5/ mi n ut e) or M o bitz T y pe II sec o n d or t hir d de gre e atri o ve ntric ul ar ( A V) bl oc k or left 
b u n dle bra nc h bl oc k, or ri g ht b u n dle bra n c h bl oc k wit h a Q R S 
or s u b-ac ute m y o car dial i nfar cti o n or isc he mia or ot h er E C G fi n di n gs t hat, i n t h e 
d y. 
d.  A b n or mal free T 4 le vels a n d T S H > 1 0 mI U/ L ( des pite tr eat me nt) at Scree ni n g, 
c o nfir me d b y r e peat. 
e. T otal bilir u bi n, al a ni ne a mi n otra nsferas e ( A L T) or as partat e a mi n otra nsferas e ( A S T) 
greater t ha n 2 ti mes t he u p p er li mit of n or mal ( U L N), c o nfir me d b y r e p eat.  If t he 
M e dical M o nit or. 
f. Pat h ol o gic r e nal fi n di n gs at S cr ee ni n g as defi ne d b y t he pres e nc e of eit h er of t he 
f oll o wi n g criteri a: 
i. Esti mate d gl o mer ul ar filtrati o n r ate ( e G F R) acc or di n g t o t he re- e x press e d 
a b bre viate d (f o ur- vari a ble) M o dificati o n of Diet i n R e nal Disease ( M D R D) St u d y 
e q uati o n < 3 0 ml/ mi n/ 1. 7 3 m 2; T h e M D R D esti mati o n is calc ulat e d as f oll o ws: 
e G F R ( m L/ mi n/ 1. 7 3 m 2) = 1 7 5 x (sta n d ar diz e d S cr)- 1. 1 5 4 x ( A ge)- 0. 2 0 3 x ( 0. 7 4 2 if 
fe mal e) x ( 1. 2 1 2 if Bl ac k). [ Scr: Sta n d ar diz e d s er u m creati ni ne]; 
ii. 
g.  H e mat ol o gic a b n or maliti es at Scree ni n g: 
i. H e m o gl o bi n < 1 0 g/ d L; or 
ii. W B C < 3. 0 x 1 0 3/ m m 3; or 
iii. Platel et c o u nt < 1 0 0, 0 0 0/ m m 3; or 
i v. 
/ m m3 
h.  H e m o gl o bi n A 1 C > 7. 5 %, c o nfir me d b y re p eat. 
i. Uri ne dr u g s cree n p ositi ve f or a dr u g of a b us e, f or w hic h t he p ati e nt d oes n ot h a ve a 
vali d pres cri pti o n a n d is s us pecte d of a b usi n g, i n t he j u d ge me nt of t he I n v esti gat or.  
N ote: uri ne dr u g s cr ee n p ositi ve f or ca n n a bis is e xcl usi o nar y u nless t he I n vesti gat or a n d 
M e dical M o nit or a gree t hat t he s u bje ct c a n a bstai n fr o m use f or t he d urati o n of t h e 
st u d y, or if t he s u bje ct has a v ali d me dic al prescri pti o n. 
j. H u ma n I m m u n o defici e nc y Vir us ( HI V) p ositi ve at S cree ni n g (i n dic ate d b y p ositi ve 
c o nfir mat or y West er n Bl ot);


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 6 4  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
k.
H Bs A g or H C V p ositi ve at Scre e ni n g;
l. F or W O C B P, p
- h C G w hic h is i n dicati ve of pre g na n c y a n d n ot fals e 
p ositi ve at Scree ni n g or a p ositi ve uri ne pr e g na nc y test at Bas eli ne. 
4.  Pr o hi bite d a n d R estricte d Tre at m e nts a n d/ or T her a pies (c a n be w as he d o ut d uri n g 
Scree ni n g) 
a. Partici p ati o n i n a n ot h er cli nical tri al f or a n i n vesti g ati o nal a g e nt a n d h a vi n g t a ke n at 
least o ne d ose of st u d y me di cati o n, u nless c o nfir m e d as ha vi n g bee n o n place b o, is 
e xcl u de d wit hi n 9 0 da ys or 5 half-li ves ( w hic h e ver is l o n ger) pri or t o 
Bas eli ne/ Ra n d o mizati o n. T h e e n d of a pre vi o us i n vesti gati o n al trial is defi ne d as t he 
date of t h e last d os e of a n i n vesti g ati o n al a g e nt.  
b.  D o pa mi ne a nta g o nists, i n cl u di n g met o cl o pra mi de a n d a nti ps yc h otic m e dicati o ns are 
e xcl u de d. 
i. Q uetia pi n e a n d cl oza pi n e are all o we d if t he d oses ar e sta ble f or at l east 3 0 da ys 
pri or t o Bas eli ne/ R a n d o mi zati o n
c. I n hi bit ors of C Y P 1 A 2 - Str o n g i n hi bit ors of C Y P 1 A 2 (i.e., ci pr ofl o xaci n, e n o xaci n, 
fl u v o xa mi n e, zafirl u kast) c o ul d p ote ntiall y i n crease B H V- 3 2 4 1 le vels a n d are e x cl u de d 
f or c hr o nic/l o n g-ter m ( > 2 wee ks) us e.  Str o n g i n hi bit ors of C Y P 1 A 2 f or ac ute/s h ort-
ter m us e s h o ul d be a v oi de d, if p ossi ble, or use d wit h ca uti o n, b ase d o n t he cli nical 
j u d ge me nt of t he i n vesti g at or.  M o derat e i n hi bit ors of C Y P 1 A 2 (i.e., met h o xs ale n) 
c o ul d p ote ntiall y i n creas e B H V- 3 2 4 1 le vels a n d s h o ul d be us e d wit h c a uti o n f or 
c hr o nic/l o n g-ter m us e, base d o n t he cli nical j u d ge me nt of t he i n v esti gat or.   
d.  I n d ucers of C Y P 1 A 2 - Str o n g i n d ucers of C Y P 1 A 2 (i.e., p he n yt oi n, rifa m pi n) c o ul d 
re d uce B H V- 3 2 4 1 le vels a n d s h o ul d be use d wit h c a uti o n, base d o n t h e cli nical 
j u d ge me nt of t he i n vesti g at or.  
e. I n hi bit ors of C Y P 3 A 4 - Str o n g i n hi bit ors of C Y P 3 A 4 (i.e., c o ni v a pta n, gr a pefr uit j uice, 
itrac o n az ol e, ket oc o n az ol e, p os ac o na z ole, tr olea n d o m yci n, v ori c o naz ole, 
clarit hr o m yci n, diltiaze m, i d elalisi b, nef az o d o ne, a n d a nti vir al a g e nts [c o bicistat, 
da n o pre vir, rit o na vir, el vite gra vir, i n di na vir, l o pi n a vir, parita pr e vir, o m bitas vir, 
dasa b u vir, s a q ui na vir, ti pr a na vir, nelfi na vir]) c o ul d p ote nti all y i ncre ase B H V- 3 2 4 1 
le vels a n d are e xcl u de d f or c hr o nic/l o n g-ter m ( > 2 wee ks) us e.  Str o n g i n hi bit ors of 
C Y P 3 A 4 f or ac ute/s h ort-ter m us e s h o ul d be a v oi d e d, if p ossi ble, or us e d wit h c a uti o n, 
base d o n t he cli ni cal j u d ge me nt of t he i n vesti g at or.  M o derate i n hi bit ors of C Y P 3 A 4 
(i.e., a pre pita nt, ci meti di ne, cl otri maz ole, criz oti ni b, c ycl os p ori ne, dr o n e dar o ne, 
er yt hr o m yci n, fl uc o n az ole, i mati ni b, t ofis o pa m, v era pa mil) c o ul d p ot e nti all y i ncreas e 
B H V- 3 2 4 1 le vels a n d s h o ul d be use d wit h ca uti o n f or c hr o nic/l o n g-ter m us e, base d o n 
t he cli nic al j u d g e me nt of t he i n v esti gat or.   


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 6 5  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
f.
I n d ucers of C Y P 3 A 4
Str o n g i n d ucers of C Y P 3 A 4 (i.e., car b a maz e pi ne, e nzal uta mi de, 
mit ot a ne, 
 c o ul d re d uce B H V- 3 2 4 1 le vels a n d 
s h o ul d be use d wit h ca uti o n, base d o n t h e cli nical j u d ge me nt of t he i n v esti gat or. 
g.  Dr u gs pri nci pall y met a b oli ze d b y C Y P 2 B 6 (i.e., b u pr o pi o n, c ycl o p h os p ha mi de, 
efa vire n z, if os p ha mi de, met ha d o ne, a n d s orafe ni b) s h o ul d be us e d wit h ca uti o n, b ase d 
o n t he cli nical j u d g e me nt of t he i n v esti gat or. 
h.
Dr u gs pri nci pall y met a b oli ze d b y C Y P 3 A 4 (i.e., clarit hr o m yci n, er yt hr o m yci n, 
et hi n yl estra di ol [ h or m o nal c o ntra ce pti ves], telit hr o m yci n, q ui ni di ne, t h e o p h ylli ne, 
tiza ni di ne, v era pa mil, w arfari n, zile ut o n, a n d z ol mitri pta n) s h o ul d be us e d wit h ca uti o n, 
base d o n t he cli ni cal j u d ge me nt of t he i n vesti g at or. N ote: h or m o nal c o ntr ace pti ve 
effecti ve ness ma y p ote nti all y b e re d uce d; t h us d os e a dj ust me nt, us e of alt er nati ve 
a n d/ or a d diti o nal met h o ds of birt h c o ntr ol is re q uir e d f or W O C B P.
i. C hr o nic/l o n g-ter m ( > 2 w ee ks) us e of i m m u n o m o d ul at or y me dicati o ns is e xcl u de d, 
i ncl u di n g t he f oll o wi n g: a zat hi o pri ne, c hl ora m b u cil, c ycl o p h os p ha mi de, fi n g oli m o d 
(a n d ot her S 1 P rece pt or m o d ul at ors), i b u dil ast, met h otre xat e, m o nt el u kast, 
m yc o p he n ol ate m ofetil, t acr oli m us, sir oli m us (ra p a m yci n), a n d m o n o cl o nal a nti b o dies 
or relat e d bi ol o gical a ge nts (i. e., a batac e pt, a d ali m u ma b, a na ki nra, basili xi ma b, 
beli m u ma b, ca na ki n u ma b, cert oli z u ma b, d acliz u m a b, eta ner ce pt, i nfli xi ma b, 
nataliz u m a b, ocreliz u m a b, t ocili z u ma b, rit u xi ma b, tr ast uz u ma b, a n d uste ki n u ma b).  
N O T E: As piri n, a n d n o nster oi d al a nti-i nfla m m at or y me dic ati o ns, ar e all o we d 
5. 4 
Pr o hi bit e d a n d R e stri ct e d C o n c o mit a nt M e di c ati o n 
D uri n g t he c o urse of t h e st u d y (fr o m Bas eli ne/ R a n d o mizati o n t o e n d of tre at me nt), patie nts 
s h o ul d sta y o n t heir us ual me dicati o n re gi mes (i.e. t h ose n ot e xcl u d e d b y t he pr ot oc ol) at 
relati vel y st a ble d os es. 
Use of t he f oll o wi n g m e dic ati o ns is pr o hi bite d or restrict e d as f oll o ws. S u bjects recei vi n g s uc h 
me dic ati o ns c hr o nic/l o n g-ter m at e nr oll m e nt s h o ul d u n der g o a 4 wee k was h o ut peri o d pri or t o 
Baseli ne/ Ra n d o mizati o n u nl ess ot her wise n ote d or m e dicall y c o ntrai n dicat e d: 
1.  A n y ot her i n vesti g ati o n al a g e nt is pr o hi bite d (re q uires mi ni m u m was h o ut of 9 0 d a ys or 5 
half-li v es [ w hic he ver is l o n ger], pri or t o B as eli n e/ Ra n d o mizati o n) 
2.  D o pa mi ne a nta g o nists, i n cl u di n g met o cl o pra mi de a n d a nti ps yc h otic m e dic ati o ns are 
pr o hi bite d. 
a. Q uetia pi n e a n d cl oza pi n e are all o we d if t he d os es ar e sta ble f or at l east 3 0 da ys pri or t o 
Bas eli ne/ Ra n d o mizati o n  


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 6 6  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
3. I n hi bit ors of C Y P 1 A 2 - Str o n g i n hi bit ors of C Y P 1 A 2 (i.e., ci pr ofl o xaci n, e n o xaci n, 
fl u v o xa mi n e, zafirl u kast) c o ul d p ote ntiall y i n creas e B H V- 3 2 4 1 le vels a n d are pr o hi bite d 
f or c hr o nic/l o n g-ter m ( > 2 wee ks) us e.  Str o n g i n hi bit ors of C Y P 1 A 2 f or ac ute/s h ort-ter m 
us e s h o ul d be a v oi de d, if p ossi ble, or us e d wit h ca uti o n, base d o n t he cli ni cal j u d ge me nt of 
t he i n vesti gat or.  M o der ate i n hi bit ors of C Y P 1 A 2 (i.e., met h o xs ale n) c o ul d p ote ntiall y 
i ncrease B H V- 3 2 4 1 le vels a n d s h o ul d be us e d wit h c a uti o n f or c hr o nic/l o n g-ter m us e, 
base d o n t he cli ni cal j u d ge me nt of t he i n vesti g at or.   
4.  I n d ucers of C Y P 1 A 2 - Str o n g i n d ucers of C Y P 1 A 2 (i.e., p he n yt oi n, rifa m pi n) c o ul d re d uce 
B H V- 3 2 4 1 le vels a n d s h o ul d be us e d wit h ca uti o n, b as e d o n t he cli ni cal j u d ge me nt of t he 
i n vesti gat or.  
5.  I n hi bit ors of C Y P 3 A 4 - Str o n g i n hi bit ors of C Y P 3 A 4 (i.e., c o ni v a pta n, gr a pefr uit j uic e, 
itrac o n az ol e, ket oc o n az ol e, p os ac o na z ole, tr olea n d o m yci n, v ori c o naz ole, cl arit hr o m yci n, 
dilti aze m, i delalisi b, nefaz o d o n e, a n d a nti vir al a g e nts [c o bicistat, da n o pre vir, rit o na vir, 
el vit e gra vir, i n di na vir, l o pi n a vir, parita pre vir, o m bitas vir, das a b u vir, s a q ui na vir, ti pr a na vir, 
nelfi na vir) c o ul d p ote ntiall y i ncre as e B H V- 3 2 4 1 le v els a n d are pr o hi bit e d f or c hr o nic/l o n g-
ter m ( > 2 wee ks) us e.  Str o n g i n hi bit ors of C Y P 3 A 4 f or ac ute/s h ort-ter m us e s h o ul d be 
a v oi de d, if p ossi bl e, or us e d wit h ca uti o n, base d o n t he cli nical j u d ge me nt of t he 
i n vesti gat or.  M o derat e i n hi bit ors of C Y P 3 A 4 (i.e., a pre pita nt, ci meti di ne, cl otri maz ole, 
criz oti ni b, c y cl os p ori ne, dr o ne d ar o ne, er yt hr o m yci n, fl uc o naz ole, i mati ni b, t ofis o pa m, 
vera pa mil) c o ul d p ote ntiall y i ncr eas e B H V- 3 2 4 1 le v els a n d s h o ul d be us e d wit h ca uti o n f or 
c hr o nic/l o n g-ter m us e, bas e d o n t he cli nical j u d ge me nt of t he i n v esti gat or.   
6.  I n d ucers of C Y P 3 A 4  Str o n g i n d ucers of C Y P 3 A 4 (i.e., car b a maz e pi ne, e nzal uta mi de, 
mit ot a ne, p he n yt oi n, rif a m pi n, St. J o h n's w ort) c o ul d re d uce B H V- 3 2 4 1 le vels a n d s h o ul d 
be use d wit h ca uti o n, bas e d o n t he cli nic al j u d g e me nt of t he i n v esti gat or.  
7.  Dr u gs pri nci pall y met a b oli ze d b y C Y P 2 B 6 (i.e., b u pr o pi o n, c ycl o p h os p ha mi de, efa vire n z, 
if os p ha mi de, met h a d o ne, a n d s orafe ni b) s h o ul d be us e d wit h ca uti o n, base d o n t h e cli nical 
j u d ge me nt of t he i n vesti g at or. 
8.  Dr u gs pri nci pall y met a b oli ze d b y C Y P 3 A 4 (i. e., clarit hr o m yci n, er yt hr o m yci n, 
et hi n yl estra di ol [ h or m o nal c o ntra ce pti ves], telit hr o m yci n, q ui ni di ne, t h e o p h ylli ne, 
tiza ni di ne, v era pa mil, w arfari n, zile ut o n, a n d z ol mitri pta n) s h o ul d be us e d wit h ca uti o n, 
base d o n t he cli ni cal j u d ge me nt of t he i n vesti g at or.  N ote: h or m o nal c o ntr ace pti ve 
effecti ve ness ma y p ote nti all y b e re d uce d; t h us d os e a dj ust me nt, us e of alt er nati ve a n d/ or 
a d diti o n al m et h o ds of birt h c o ntr ol is re q uire d f or W O C B P. 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 6 7 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
9.
C hr o nic ( > 2 wee ks) us e of i m m u n o m o d ul at or y m e di cati o ns, i n cl u di n g t he f oll o wi n g: 
azat hi o pri ne, c hl ora m b u cil, c ycl o p h os p ha mi de, fi n g oli m o d (a n d ot her S 1 P rece pt or 
m o d ulat ors), i b u dilast, met h otre xate, m o ntel u kast, m yc o p he n olate m of etil, tacr oli m us, 
sir oli m us (ra pa m yci n), a n d m o n ocl o nal a nti b o di es or relat e d bi ol o gical a ge nts (i. e., 
a batace pt, a dali m u ma b, a na ki nr a, basili xi m a b, beli m u ma b, ca n a ki n u m a b, cert oliz u ma b, 
dacli z u ma b, eta ner ce pt, i nfli xi ma b, n ataliz u ma b, ocr eliz u ma b, t o ciliz u m a b, rit u xi ma b, 
trast uz u m a b, a n d uste ki n u ma b) is pr o hi bite d.
N O T E: As piri n a n d n o nster oi d al a nti-i nfla m m at or y me dic ati o ns ar e all o we d.
T he a b o ve me di cati o ns, if us e d f or t he s h ort-t er m tr eat me nt of i nt erc urre nt ill n ess, are all o we d 
if nee de d, at t h e discreti o n of t he I n v esti gat or, pr o vi d e d t he y ar e n ot ot h er wise pr o hi bit e d as 
n ote d a b o ve.
T he ge neric na me ( w here p ossi ble), st art date, e n d d ate a n d d osi n g i nf or mati o n f or a n y 
me dic ati o n ( pr escri pti o ns or n o n- pres cri pti o n) ta ke n b y t he s u bject wit hi n 1 m o nt h pri or t o 
c o nc o mita nt me di cati o n ele ctr o ni c case r e p ort f or m.
5. 4. 1
Ot h er R e stri cti o n s a n d Pr e c a uti o n s
M e dicati o ns pres cri be d b y a n ot her p h ysicia n: I n or d er t o e ns ure t h at a p pr o pri ate c o nc o mita nt 
t hera p y is a d mi nist ere d, it is esse nti al t hat s u bjects be i nstr uct e d n ot t o ta ke a n y me di cati o n, 
eit her n o n- pr es cri pti o n or pres cri pti o n t her a p y prescri be d b y a n ot h er p h ysici a n, wit h o ut pri or 
c o ns ultati o n wit h t h e I n vesti g at or.
P h ysical re ha bilitati o n: Partici p ati o n i n p h ysical r e ha bilit ati o n pr o gr a ms is per mitt e d if t h es e 
ha ve bee n o n g oi n g pri or t o st arti n g t he st u d y a n d ar e pla n ne d t o c o nti n u e t hr o u g h o ut t he 
d urati o n o
partici pati o n s h o ul d be li mite d i n a n atte m pt t o mai nt ai n a sta ble re gi me n, w he ne v er p ossi ble, 
as cli ni call y a p pr o priate.
Electi ve me di cal pr oc e d ures: S u bje cts s h o ul d n ot u n der g o a n y el ecti ve me dical pr oce d ur es
wit h o ut pri or c o ns ultati o n wit h t h e I n vesti g at or. A n electi ve pr o ce d ure (e. g., mi n or s ur ger y, 
de ntal s ur ger y, ort h o pe di c s ur ger y) t hat mi g ht r e q uir e h os pitalizati o n or a n est hesia s h o ul d be 
deferre d u ntil after t he st u d y, w he n cli nicall y a p pr o priate.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 6 8  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
5. 5
W o m a n of C hil d b e ari n g P ot e nti al ( W O C B P)
W O C B P i ncl u de a n y f e male w h o has e x peri e nce d m e narc he a n d w h o has n ot u n der g o ne 
s uccessf ul s ur gical st erilizati o n ( h ystere ct o m y, bilateral t u bal li g ati o n, or bilateral 
o o p h orect o m y) or is n ot p ost me n o p a us al. P ost me n o p a us al is defi n e d as: 
 A me n orr hea greater t h a n or e q ual t o 1 2 c o ns ec uti v e m o nt hs wit h o ut a n ot her c a use a n d a 
d oc u me nt e d s er u m f ollicle sti m ulati n g h or m o ne ( F S H) le vel > 3 5 mI U/ m L. A hi g h f ollicle 
sti m ulati n g h or m o n e ( F S H) le v el i n t he p ost m e n o pa us al ra n ge m a y be us e d t o c o nfir m a 
p ost me n o pa us al st ate i n w o me n n ot usi n g h or m o nal c o ntrac e pti o n or h or m o nal re plac e me nt 
t hera p y. H o we ver i n t he a bse nc e of 1 2 m o nt hs of a m e n orr hea, a si n gle F S H meas ure me nt is 
i ns ufficie nt. 
N O T E: F S H le vel testi n g is n ot re q uire d f or w o me n greater t ha n or e q ual t o 6 2 years ol d 
wit h a me n orr h ea of greater t h a n or e q ual t o o ne year. 
T he re q uisite dr u g i nteracti o n st u di es t o det er mi n e t h e i nter acti o n of B H V- 3 2 4 1 wit h oral 
c o ntrac e pti v es ha ve n ot be e n c o m plet e d t o date. It is t heref ore n ot p ossi ble t o d eter mi ne t h e 
effica c y of oral c o ntrac e pti v es as a n effe cti ve met h o d of c o ntrac e pti o n f or W O C B P w h o are 
partici pati n g i n t his st u d y. Si nce h or m o n al c o ntrace pti ve eff ecti ve ness ma y be r e d uce d, 
estr o ge n a n d pr o gest er o ne h or m o nal c o ntr ace pti ves as a s ole met h o d of c o ntra ce pti o n are 
t heref ore pr o hi bit e d.  
It is re q uire d t hat all W O C B P us e t w o met h o ds of c o ntrace pti o n t o a v oi d pre g na n c y f or t he 
d urati o n of t h e st u d y (i.e., b e gi n ni n g at 3 0 da ys pri or t o bas eli n e) t hr o u g h 3 0 da ys after t he l ast 
d os e of i n vesti gati o nal pr o d uct i n s uc h a ma n n er t hat ris k of pre g na nc y is mi ni mize d. T he t w o 
met h o ds s h o ul d i ncl u de o ne b arrier m et h o d (e. g., dia p hra g m wit h s per mici d al gel, c o n d o m wit h 
s per mici d al gel, cer vi cal ca p) a n d o n e ot her met h o d. T he ot h er met h o d c o ul d i n cl u de h or m o n al 
c o ntrac e pti v es (e. g., oral c o ntrac e pti v es, i nje cta ble c o ntrace pti ves, patc h, or c o ntr ace pti ve 
i m pla nt) us e d si nce at l east 4 w ee ks pri or t o se x u al i nterc o urs e.  
A n y male w h o has a fe male p art ner of W O C B P m ust a v oi d pre g na n c y w hile partici pati n g i n 
t his st u d y. If mal e s u bjects are se x uall y acti ve a n d n ot vasect o miz e d f or at l east 6 m o nt hs, a n d 
f oll o wi n g ac ce pt e d met h o ds of c o ntrac e pti o n s h o ul d be us e d t hr o u g h o ut t h e st u d y a n d f or 9 0 
da ys after t h e last st u d y dr u g a d mi nistrati o n: 
 Si m ulta n e o us use of mal e c o n d o m wit h s per mi ci dal gel, a n d f or t h e fe male part ner, 
h or m o nal c o ntrac e pti ves (e. g., birt h c o ntr ol pills, i m pla nts, pat c h, de p ot i nje cti o n, use d 
si nce at least 4 w e e ks) or i ntra- ut eri ne c o ntra ce pti ve de vice plac e d si nce at le ast 4 wee ks 
bef ore s e x ual i nterc o urs e; 
O R 
 Si m ulta n e o us use of mal e c o n d o m, a n d f or t he fe mal e part ner cer vical c a p or dia p hr a g m 
wit h i ntra v a gi nall y a p plie d s per mici d e. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 6 9 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
5. 6
D e vi ati o n fr o m I n cl u si o n/ E x cl u si o n Crit eri a
A n y si g nifica nt e ve nt t hat d o es n ot c o m pl y wit h t he i ncl usi o n e xcl usi o n criteri a, st u d y c o n d uct, 
or st u d y pr oce d ures will b e d oc u me nte d as a d e viati o n. De viati o ns will be d oc u me nt e d a n d 
re p orte d t hr o u g h t he cli nic al m o nit ori n g of t he trial. De viati o ns will be re p orte d t o t he I R B/ E C 
at t he fr e q ue nc y re q uire d b y t h e I R B/ E C. N o pr ot o c ol e xce pti o ns rel ate d t o I ncl usi o n/ E xcl usi o n 
criteria will be gra nt e d b y t he S p o ns or.
6
S T U D Y C O N D U C T A N D D E S C RI P TI O N O F S T U D Y P R O C E D U R E S
6. 1
St u d y M at eri al s
Bi o ha ve n will pr o vi de t he I P, w hic h will i ncl u de B H V- 3 2 4 1 3 0 0 m g E R ta bl ets a n d m atc hi n g 
place b o ta bl ets.
Sites will als o be pr o vi de d wit h a Re g ulat or y bi n der, I W R S M a n ual, C S F c olle cti o n ma n ual 
a n d 
I ma gi n g M a n ual. S o urce d o c u me nt cre ati o n is t he res p o nsi bilit y of t h e site. 
I nstr ucti o ns o n all s peci me ns c ollect e d will b e pr o vi de d b y a ce ntral la b orat or y.
All sites will us e a n El ectr o nic D ata C a pt ure ( E D C) t o ol t o s u b mit st u d y d ata. Ele ctr o ni c Cas e 
Re p ort F or ms (e C R Fs) will be pre p are d f or all dat a c ollecti o ns.
Sites will be pr o vi de d wit h a st u d y pr ot oc ol a n d a n y a me n d m e nts.
T he I n vesti g at or will be re q uir e d t o ha v e a ce ntrif u g e ( prefera bl y r efri ger ate d), a sec ure l oc ke d 
ca bi net or si milar (f or dr u g st ora ge), as well as freez er (-2 0 C or -7 0 t o -8 0 C ; s ee 
la b 
ma n ual a n d C S F S ub -st u d y C oll ecti o n a n d Pr ocessi n g ma n ual f or s pecifi c i nstr ucti o ns 
re gar di n g st ora g e of la b sa m ples), a p pr o pri ate c o ntai ners a n d dr y ice f or s hi p me nt a n d st or a ge 
of bl o o d, plas ma a n d uri ne s a m ples. T he s a me c e ntrif u ge a n d freez er at a site s h o ul d b e us e d 
co nsiste ntl y f or pr e parati o n a n d st ora g e of s a m pl es fr o m st u d y s u bjects.  S ufficie nt dr y ice, 
w he n i n dicate d, s h o ul d be utilize d t o all o w sa m ples t o arri ve at t heir desi g nat e d la b or at or y i n a 
fr oze n stat e.
6. 2
Eli gi bilit y a n d S af et y A s s e s s m e nt s
6. 2. 1
M e di c al a n d P s y c hi atri c Hi st or y
A f ull me di cal hist or y will b e o btai ne d at Scr ee ni n g. T his will i n cl u de, b ut is n ot li mite d t o, 
s m o ki n g hist or y, car di o vas c ul ar disease, patie nt hist or y of M S A a n d ot her me dic al a n d 
ps yc hiatri c hist or y.
6. 2. 2
S af et y A s s e s s m e nt s
Safet y a n d t olera bilit y will b e e val u ate d b y r e p ort of A Es a n d b y e val uati o n of a b n or malities 
a n d cli nicall y si g nifica nt c ha n ges i n p h ysi cal e xa mi n ati o ns, E C Gs, vital si g ns, S hee ha n 
S uici dalit y Tr ac ki n g Sc ale ( S- S T S), a n d la b or at or y t ests.
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 7 0  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
6. 2. 2. 1
Vit al Si g n s a n d P h y si c al M e a s ur e m e nt s ( H ei g ht a n d W ei g ht)
Vital si g n m eas ure m e nts (te m perat ur e, bl o o d press ur e, a n d heart rate) will be r ec or de d at e v er y 
i n- pers o n visit as s pecifie d i n t he Sc he d ule of Assess me nts & E v e nts (Ta ble 1  a n d Ta ble 2 ). 
S u bjects s h o ul d be s eate d a n d r esti n g f or a p pr o xi mat el y 5 mi n utes pri or t o p erf or mi n g vital 
si g n meas ure m e nts (tilt t a ble ma y be use d, if a vaila bl e).  
H ei g ht will b e rec or d e d at Scre e ni n g a n d Wee k 4 8 a n d/ or earl y dis c o nti n u ati o n.  B o d y wei g ht 
will be re c or de d at S cree ni n g, B aseli n e, a n d W ee k 4 8 a n d/ or earl y dis c o nti n uati o n. I n t he O L E 
p hase, hei g ht a n d wei g ht will be re c or de d at Bas eli n e- E xte nsi o n a n d Wee k 4 8- E xte nsi o n/ Earl y 
Disc o nti n uati o n. T he f oll o wi n g g ui d eli n es will ai d i n t he sta n dar dizati o n of t hese 
meas ure m e nts: 
1.  T he s a me s cale s h o ul d b e us e d t o wei g h a gi ve n s u bj ect t hr o u g h o ut t he st u d y; 
2.  Scales s h o ul d be c ali br ate d a n d zer oe d p er site g ui deli nes. 
6. 2. 2. 2 
P h y si c al E x a m 
S u bjects will u n d er g o a c o m plete p h ysical e xa m at e ac h i n- pers o n st u d y visit. T he p h ysi cal 
e xa m s h o ul d i n cl u de at l east t he f oll o wi n g c o m p o ne nts: H E E N T ( hea d, e yes, ears, n os e, a n d 
t hr oat), nec k, l y m p h n o d es, l u n gs, car di o vasc ular, a b d o me n, s ki n, m us c ul os kelet al a n d 
ne ur ol o gic e val u ati o n b y t he Pri nci p al I n vesti gat or or a me di call y q ualifie d dele gate.  If a 
s u bject is dis c o nti n ue d f or a n y reas o n, a n atte m pt s h o ul d be ma d e t o c o n d u ct a fi n al p h ysic al 
e xa m.  
6. 2. 2. 3 
El e ctr o c ar di o gr a m ( E C G) 
A 1 2- Lea d E C G will b e rec or de d at Scre e ni n g, Bas eli ne, We e k 2, 4, 1 2, 2 4, 3 6, a n d 4 8, 
Bas eli ne- E xte nsi o n, Wee k 4- E xte nsi o n (if i n pers o n visit is c o n d ucte d), W ee k 8- E xt e nsi o n (if 
i n pers o n visit is c o n d u cte d), Wee k 1 2- E xte nsi o n, 2 4- E xte nsi o n, 3 6- E xte nsi o n a n d 4 8-
E xte nsi o n a n d/ or earl y dis c o nti n uati o n, as s pecifi e d i n t he Sc he d ul e of Ass ess me nts & E ve nts 
(Ta ble 1  a n d Ta ble 2 ) a n d as m e dic all y n ecess ar y.  If a s u bject is dis c o nti n u e d f or a n y reas o n, 
a n att e m pt s h o ul d b e ma d e t o c o n d uct a fi n al E C G.  
6. 2. 2. 4 
L a b or at or y A s s e s s m e nt s 
La b orat or y testi n g will be c o n d ucte d at Scre e ni n g, B aseli ne, a n d Wee ks 2, 4, 8, 1 2, 2 4, 3 6, a n d 
4 8, Bas eli ne- E xte nsi o n, Wee k 4- E xte nsi o n, Wee k 8- E xte nsi o n, W ee k 1 2- E xte nsi o n, Wee k 2 4-
E xte nsi o n, Wee k 3 6- E xte nsi o n, We e k 4 8- E xt e nsi o n a n d/ or earl y dis c o nti n uati o n, as s pecifi e d 
(a n d as me di call y necess ar y), t o i ncl u d e t he f oll o wi n g ( Refer t o Sc he d ule of Ass ess me nts & 
E ve nts [ Ta ble 1  a n d Ta ble 2 ]): 
a. H e mat ol o g y: he m o gl o bi n, he mat o crit, platelets, C B C wit h differe ntial a n d a bs ol ute 
ne utr o p hil c o u nt, R B C c o u nt a n d i n dices. At Scree ni n g a n d pri or t o l u m bar p u nct ure: 
I N R, P T a n d partial P T.   


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 7 1  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
b.
Ser u m C he mistr y: s o di u m, p ot assi u m, c hl ori de, calci u m, ma g nesi u m, A L T, A S T, L D H, 
A L P, G G T, p h os p h or us, bic ar b o nat e, C P K, t otal pr ot ei n, al b u mi n, t otal bilir u bi n (if 
greater t ha n 2 m g/ dl bilir u bi n will be fra cti o n ate d), gl uc os e, creati ni ne, B U N, uric aci d. 
T S H, free T 3 a n d free T 4. Als o, a nti- T P O a nti b o di es at Bas eli ne, W ee k 2, Wee k 4, 
Wee k 8, W ee k 1 2, We e k 2 4, Wee k 3 6, Wee k 4 8, Bas eli ne- E xte nsi o n, W ee k 4-
E xte nsi o n, Wee k 8- E xte nsi o n, We e k 1 2- E xt e nsi o n, Wee k 2 4- E xte nsi o n, Wee k 3 6-
E xte nsi o n, Wee k 4 8- E xte nsi o n a n d w he ne v er T S H is o utsi de of n or mal ra n ge.  
A d diti o nall y, at Scr ee ni n g: t ot al c h ol ester ol, L D L, H D L, tri gl yceri des, f ol ate, H b A 1c, 
P- A m ylase or Li pas e; Esti mat e d gl o m er ular filtrati o n rate (e G F R) 
c. Uri nal ysis (c oll ect uri ne s peci me n j ust pri or t o o bt ai ni n g wei g ht): macr osc o pic 
e xa mi n ati o n, p H, s pecific gra vit y, ket o nes, nitrites, ur o bili n o ge n, le u k oc yte est eras e, 
pr otei n, cr eati ni ne, gl uc os e, a n d oc c ult bl o o d. If bl o o d, pr otei n, or l e u k oc yt es are 
p ositi ve, micr os c o pi c e xa mi nati o n will be perf or m e d o n a b n or mal fi n di n gs; 
d.  S er u m pr e g n a n c y t est will b e c o n d u ct e d o n W O C B P ( p er s e cti o n 5. 5) at S cr e e ni n g, 
B as eli n e, a n d W e e ks 4, 1 2, 2 4, 3 6 a n d 4 8, B as eli n e- E xt e nsi o n, W e e k 4- E xt e nsi o n, 
W e e k 1 2- E xt e nsi o n, W e e k 2 4- E xt e nsi o n, W ee k 3 6- E xt e nsi o n, W e e k 4 8- E xt e nsi o n 
a n d e arl y dis c o nti n u ati o n.  Uri n e pre g na n c y tests will be p erf or me d ( as well as s er u m) 
at Bas eli ne a n d B as eli n e- E xte nsi o n ( pri or t o d osi n g) o n W O C B P a n d at t he discreti o n 
of t he I n vesti g at or. F S H is t o be c o n d ucte d o n p ost m e n o pa usal w o me n at Scree ni n g t o 
c o nfir m p ost m e n o pa us al st at us (s ee Secti o n  5. 5).  
e. At Scree ni n g O nl y: H Bs A g, H C V (refle x H C V- R N A after a p ositi ve H C V A b), HI V 
a nti b o d y detecti o n, a n d ra pi d plas m a rea gi n ( R P R).  Refle x t esti n g will be d o ne f or a n y 
p ositi ve R P R. 
f. At Scree ni n g, Bas eli ne a n d Bas eli n e- E xt e nsi o n O nl y: Uri ne Dr u g Scree n f or ca n n a bis 
( me dic al a n d r ecreati o nal), a m p h eta mi nes (i n cl u di n g M D M A/ecstas y), c ocai ne, 
bar bit urate, P C P, be nz o di aze pi n es, tric y cli c a nti de pr essa nts, a n d/ or o piates. Refl e x 
c o nfir mat or y testi n g will b e c o n d uct e d o n all p ositi v e uri ne dr u g scree n sa m ples.  
g.  At Scree ni n g O nl y: Uri n e al c o h ol le v el. 
h.  F or t h ose partici pati n g i n t h e o pti o n al C S F s u b-st u d y, a nal ysis c o n d ucte d b y l o cal la b of 
cell c o u nts ( w hite bl o o d cells a n d re d bl o o d cells [ wit h refle x e d differe ntial if eit her of 
t he c o u nts is a b n or mal], C S F pr otei n a n d C S F gl uc os e.  
If i niti al Scre e ni n g l a b sa m ple r es ults d o n ot m eet pr ot oc ol-s pecifie d eli gi bilit y criteri a a n d t h e 
I n vesti gat or d eter mi nes t hat a re p eat s a m ple ma y m e et eli gi bilit y crit eria, re p eat la b sa m ples 
ma y be c olle cte d ( o ne r e peat c ollecti o n/ a nal ysis all o we d).   


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 7 2 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
If la b sa m pl es are c ollecte d a n d a nal y ze d b y a l ocal l a b rat her t ha n 
 ce ntral la b, d u e t o 
C O VI D -1 9 restricti o ns pre ve nti n g a st u d y partici p a nt fr o m atte n di n g a n i n pers o n visit at t he 
st u d y site, t he f oll o wi n g s afet y la b a nal yses s h o ul d b e or dere d:
T S H
Free T 3
Free T 4
A nti- T P O a nti b o di es
H e mat ol o g y p a nel- H e mat ol o g y: he m o gl o bi n, he mat ocrit, pl atelets, C B C wit h differe ntial 
a n d a bs ol ute n e utr o p hil c o u nt, R B C c o u nt a n d i n dices
C he mistr y Pa nel- Direct Bili R E F L E X, I n dir ect Bili R E F L E X, Ser u m C he mistr y: s o di u m, 
p otassi u m, c hl ori de, c alci u m, m a g nesi u m, A L T, A S T, L D H, A L P, 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, t otal bilir u bi n (if greater t h a n 2 m g/ dl bilir u bi n 
will be fra cti o n ate d), gl u c ose, cre ati ni ne, B U N, uric aci d
Uri nal ysis P a nel wit h Uri n e Creati ni n e- macr osc o pic e xa mi n ati o n, p H, s pecific gra vit y,
ket o nes, nitrites, ur o bili n o g e n, le u k oc yte ester as e, pr otei n, cr eati ni ne, gl uc ose, a n d oc c ult
bl o o d. If bl o o d, pr otei n, or le u k o c ytes are p ositi ve, micr os c o pi c e xa mi nati o n will be 
perf or me d o n a b n or mal fi n di n gs.
Ser u m pre g na nc y test f or all W O C B P.
Cli nic all y si g nifica nt l a b orat or y a b n or maliti es will b e i de ntifie d as Gra de 3 t o 4 la b or at or y t est 
res ults gra de d a cc or di n g t o n u meri c la b or at or y t est criteri a i n C o m m o n Ter mi n ol o g y Criteria 
f or A d vers e E ve nts ( C T C A E) V ersi o n 5. 0 ( 2 0 1 7)1 8.  F or t h ose n ot a vaila bl e i n C T C A E,
acc or di n g t o Di visi o n of AI D S ( D AI D S) Ta ble f or Gra di n g t he S e v erit y of A d ult a n d Pe diatric 
A d verse E ve nts C orrecte d V ersi o n 2. 1 ( 2 0 1 7) 1 9.
6. 2. 2. 5
S h e e h a n S ui ci d alit y Tr a c ki n g S c al e ( S h e e h a n- S T S)
T he S hee ha n S T S ( S- S T S) is a pr os pecti ve, cli nicia n a d mi nist ere d rati n g s cale t hat c o nt ai ns 1 6 
q uesti o ns t o tra c k b ot h tr eat me nt-e mer ge nt s uici d al i deati o n a n d be ha vi ors 2 0, 2 1. T he S- S T S will 
be c o m pl ete d o n a pa per f or m at t h e site at Scre e ni n g, Bas eli ne a n d eac h st u d y visit, i ncl u di n g 
Wee k 4 8, Bas eli ne- E xte nsi o n, W ee k 2- E xte nsi o n, W ee k 1 2- E xt e nsi o n, Wee k 2 4- E xte nsi o n, 
Wee k 3 6- E xte nsi o n, Wee k 4 8- E xt e nsi o n, or earl y wit h dra wal. At Scre e ni n g, t h e recall peri o d 
f or c o m pleti n g t h e S- S T S is 6 m o nt hs pri or; at all ot her visits, t he r ecall peri o d f or c o m pl eti n g 
t he S- S T S is si nce t he last visit (t w o s e parate versi o ns will be pr o vi de d). S u bj ects w h o ha ve a 
S- S T S s c ore > 0 s h o ul d be e val uate d b y t h e I n vesti g at or.  If t he I n v esti gat or deter mi nes t h at a 
s u bject is at ris k of s uici d e or s elf-
o btai n m e ntal healt h e val uati o n m ust be i m pl e me nte d a n d t he I n vesti gat or s h o ul d e val uate if 
t he patie nt s h o ul d b e disc o nti n ue d fr o m t he st u d y.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 7 3  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
6. 2. 3
Cli ni c al O ut c o m e A s s e s s m e nt s
Eac h of t h e Cli nici a n Re p orte d O ut c o me ( Cli n R O) meas ures des cri b e d bel o w s h o ul d be 
perf or me d b y a n a p pr o priat el y q ualifi e d i n di vi d ual. S pecific q u alificati o n re q uir e me nts f or 
raters will b e d oc u m e nte d a n d a p pr o priate tr ai ni n g will be pr o vi de d t hr o u g h di dactic, vi de o 
certificati o n, a n d/ or o nli ne trai ni n g. W he n e ver p ossi ble, f or a n y i n di vi d ual s u bject, eac h of 
t hese ass ess me nts s h o ul d be perf or me d b y t he s a me r ater t hr o u g h o ut t he c o urse of t he st u d y. 
T he Pati e nt Re p orte d O utc o me ( P R O) meas ures des cri be d bel o w s h o ul d be directl y prese nt e d 
t o t he patie nt o n pa per.  As a bac k- u p o pti o n, e ac h of t he P R O meas ures ma y b e a d mi nistere d 
as Cli nicia n Re p orte d O utc o me meas ures w here all o w a ble b y t he assess me nt 
a ut h or/ de v el o per
mea ni n g t hat t he assess me nts will be pres e nt e d t o t h e patie nt ver b all y b y a 
q ualifi e d me m ber of t he site staff, w h o will rec or d t h e res p o ns es c olle cte d fr o m t he s u bje ct
i n 
or der t o pr o m ot e c o nsiste nt q ualit y, sta n dar dizati o n, a n d mi ni miz e b ur de n o n t h e st u d y s u bject. 
Care gi vers s h o ul d n ot c o m pl ete t he P R O meas ures o n be half of patie nts.  
F or a n y i n di vi d ual s u bject, ea c h of t he care gi v er assess me nts s h o ul d be c o m pl ete d b y t he sa m e 
care gi v er t hr o u g h o ut t he c o urse of t h e st u d y, w he n p ossi ble. Care gi v er faci n g s cales s h o ul d be 
directl y pres e nt e d t o t he care gi ver o n pa p er. As a bac k- u p o pti o n, ea c h of t he care gi v er 
meas ures ma y b e a d mi nistere d as Cli ni cia n R e p orte d O utc o me m eas ures w here all o wa ble b y 
t he ass ess me nt a ut h or/ de v el o per- m ea ni n g t hat t he ass ess me nts will be prese nte d t o t he 
care gi v er ver ball y b y a q ualifi e d me m ber of t h e site staff, w h o will rec or d t he res p o ns es 
c olle cte d fr o m t he care gi v er-i n or der t o pr o m ot e c o nsiste nt q ualit y, sta n d ar diz ati o n, a n d 
mi ni mize b ur d e n o n t he care gi v er.  Care gi vers m ust be willi n g t o si g n a n d date a n I R B/ E C-
a p pr o ve d writt e n i nf or m e d c o ns e nt f or m i n ac c or da n ce wit h re g ulat or y a n d i nstit uti o n al 
g ui deli n es, as a p pr o priate. Care gi ver i nf or mati o n will be rec or d e d o n t he C R F.   
T he U M S A R S s h o ul d be t he first Cli n R O c o m plet e d, w he ne ver p ossi ble.  T h e M S A- Q o L 
a n d/ or P GI- S s h o ul d be t h e first P R Os c o m plete d, w he ne ver p ossi ble.  
6. 2. 3. 1 
U nifi e d M ulti pl e S y st e m Atr o p h y R ati n g S c al e ( U M S A R S) 
T he U M S A R S is a cli nici a n-rat e d scale c o m prise d of f o ur parts 2 2.  Part I, Hist orical Re vie w, is 
a n assess me nt of f u ncti o ni n g acr oss vari o us areas.  Part II is a M ot or E x a mi n ati o n.  P art III is 
a n A ut o n o mic E xa mi nati o n, a n d i n cl u des s u pi ne a n d sta n di n g vit al si g ns, ort h ostatic c ha n ge, 
a n d ort h ostatic s y m pt o ms.  Tilt ta ble m a y be use d, if a vail a ble.  Part I V is a Gl o bal Dis a bilit y 
Scale. N ote: T he U M S A R S will be use d t o c olle ct data i n t his st u d y. H o we ver, t he pri mar y 
o utc o me v aria ble f or t he st u d y will be a m o difie d U M S A R S, c o m p ose d of a s u bs et of ite ms 
fr o m U M S A R S Part I a n d Part II, wit h t h e it e ms s electe d base d o n f ee d bac k fr o m Healt h 
A ut h orities, e x p ert o pi ni o n, a n d a nal ysis of data fr o m pre vi o us cli nical trials i n M S A. 
T he U M S A R S is ass esse d d uri n g t he Scree ni n g p has e t o det er mi n e eli gi bilit y f or st u d y e ntr y 
a n d will s u bs e q ue ntl y be a d mi nist ere d at Baseli n e, a n d Wee ks 4, 1 2, 2 4, 3 6 a n d 4 8, Bas eli ne-
E xte nsi o n, Wee k 1 2- E xte nsi o n, We e k 2 4- E xt e nsi o n, Wee k 3 6- E xte nsi o n, Wee k 4 8- E xt e nsi o n  
a n d/ or earl y dis c o nti n uati o n.  


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 7 4 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
If t he U M S A R S is a d mi nistere d re m otel y ( b y p h o ne/ vi de o) d ue t o C O VI D- 1 9 re m ot e visit 
all o w a nc es, o nl y P art I s h o ul d be c o n d ucte d a n d e nt ere d i n t he e C R F.
6. 2. 3. 2
Cli ni c al Gl o b al I m pr e s si o n of S e v erit y ( C GI- S) a n d Cli ni c al Gl o b al 
I m pr e s si o n of I m pr o v e m e nt ( C GI-I)
T h e C GI- S s cal e is a cli nicia n-rate d scale m eas uri n g t h e s e v erit y of
ill n ess. It is 
s c ore d o n a 7- p oi nt s cale ra n gi n g fr o m 1 ( n or mal, n ot ill at all) t o 7 ( a m o n g t h e m ost e xtre mel y 
ill patie nts). T h e C GI- S will b e a d mi nist er e d at B as eli n e a n d W e e ks 4, 1 2, 2 4, 3 6 a n d 4 8 
a n d/ or e arl y dis c o nti n u ati o n. T h e C GI- S will n ot be a d mi nist ere d d uri n g t he O L E.
T he C GI-I s cale is a cli nici a n-rat e d scal e me as uri n g
fr o m a s pecific p oi nt i n ti me. It is s c ore d o n a 7- p oi nt s cale, r a n gi n g fr o m 1 ( ver y m uc h 
i m pr o ve d) t o 7 ( v er y m uc h w orse), wit h a s c or e of 4 i n dicati n g n o c h a n ge. T he C GI-I s h o ul d be 
ass esse d relati v e t o t h e C GI- S at t he Wee k 0 ( Da y 1) visit as t he r efere nc e. T h e C GI-I will b e 
a d mi nist er e d at W ee ks 4, 1 2, 2 4, 3 6 a n d 4 8 a n d/ or e arl y dis c o nti n u ati o n. T he C GI-I will n ot 
be a d mi nistere d d uri n g t he O L E.
C GI rati n gs. F or a n y i n di vi d ual 
s u bject, t h ese ass ess me nts s h o ul d be perf or m e d b y t h e sa me rater t hr o u g h o ut t he st u d y.
6. 2. 3. 3
M S A Q u alit y of Lif e S c al e ( M S A- Q o L)
T h e M S A- Q o L is a p ati e nt-r at e d s cal e t h at w as d esi g n e d t o m e as ur e h e alt h-r el at e d q u alit y 
of lif e s p e cifi c all y i n M S A 2 3. It ass ess es a cti viti es of d ail y li vi n g a n d h as s u bs c al es f or 
m ot or, n o n m ot or, a n d e m oti o n al/s o ci al d o m ai ns.
T h e M S A- Q o L will b e a d mi nist er e d at B as eli n e,
W e e k 2 4 a n d 4 8, B as eli n e- E xt e nsi o n, 
W e e k 1 2- E xt e nsi o n, W e e k 2 4- E xt e nsi o n, W e e k 3 6- E xt e nsi o n, W e e k 4 8- E xt e nsi o n a n d/ or
e arl y dis c o nti n u ati o n.
6. 2. 3. 4
P ati e nt Gl o b al I m pr e s si o n of S e v erit y ( P GI- S)
T h e P GI- S is a p ati e nt-r at e d s c al e a n d will b e a d mi nist er e d at B as eli n e a n d W e e ks 4, 1 2,
2 4, 3 6 a n d 4 8 a n d/ or e arl y dis c o nti n u ati o n. T h e p ati e nt will r at e h o w t h e y p er cei v e t h e 
s e v erit y of t h eir ill n ess. T he P GI- S will n ot be a d mi nistere d d uri n g t he O L E.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 7 5 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 7 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
6. 3
Ot h er A s s e s s m e nt s 
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 7 7 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 7 8 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 7 9 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
6. 4
E arl y Di s c o nti n u ati o n fr o m t h e St u d y
S u bjects M U S T dis c o nti n ue t he I P (a n d n o n-i n v esti g ati o nal pr o d uct at t h e dis creti o n of t he 
I n vesti gat or) f or a n y of t he f oll o wi n g reas o ns:
A n y cli nic al a d v ers e e ve nt ( A E), E C G, a n d la b or at or y a b n or maliti es (c o nfir me d b y r e peat 
if a p pr o priate) or i nterc urre nt ill ness w hic h, i n t h e o pi ni o n of t he I n v esti gat or or s p o ns or, 
i n dicates t hat c o nti n ue d partici p ati o n i n t he st u d y is n ot i n t he b est i nt erest of t h e s u bject.
T his ma y i n cl u de t he f oll o wi n g:
i.
Treat me nt- e mer ge nt E C G a b n or m alities
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 0  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Disease pr o gressi o n, w hic h, i n t h e o pi ni o n of t he I n v esti gat or or s p o ns or, i n di cat es t hat 
c o nti n ue d p arti ci pati o n i n t he st u d y is n ot i n t he best i nterest of t he s u bje ct 
 Pre g na nc y 
 Ter mi n ati o n of t he st u d y b y Bi o h a ve n P har mace utic als 
 L oss of a bilit y t o freel y pr o vi de c o nse nt t hr o u g h i m pris o n me nt or i n v ol u ntar y i ncarc erati o n 
f or treat me nt of eit her a ps yc hiatric or p h ysi cal ( e. g., i nfecti o us disease) ill ness 
All s u bjects w h o disc o nti n ue st u d y tr eat me nt earli er t ha n Wee k 4 8 or Wee k 4 8- E xt s h o ul d 
c o m pl y wit h pr ot oc ol s pecifi e d Earl y Dis c o nti n uati o n pr oce d ures as a p pr o priate, o utli ne d i n t he 
Sc he d ule of Ass ess me nts & E ve nts ( Ta bl e 1 , Ta bl e 2 ). De pe n di n g o n t he r eas o n f or t he earl y 
dis c o nti n uati o n (e. g., d ecli ni n g patie nt stat us), s o me pr oce d ures, f or e xa m ple, P K sa m ples, P D 
s a m ples, l u m b ar p u nct ur e, ma y n ot be c o n d ucte d at t his visit.  C o n d uct of all pr o ce d ures, if 
p ossi ble, is e nc o ura g e d. If p ossi ble, t h e s u bjects w h o disc o nti n ue fr o m st u d y me dicati o n pri or 
t o Wee k 4 8 s h o ul d b e c o nt acte d b y a f oll o w u p p h o n e call at t he a p pr o xi mat e ti me of t h eir 
Wee k 4 8 visit, t o c olle ct i nf or mati o n o n cli nical stat us (i ncl u di n g Ti me t o E ve nt me as ures of 
dis eas e pr o gressi o n a n d if a p plica ble, a d verse e v e nts, S A Es).  
A n e xce pti o n t o t he r e q uire m e nt f or E n d of Treat me nt pr oce d ures is w he n a s u bj ect wit h dr a ws 
c o nse nt f or all st u d y pr oce d ures or l oses t h e a bilit y t o c o ns e nt freel y (i.e., is i m pris o ne d or 
i n v ol u ntaril y i n carc erate d f or t he tr eat me nt of eit h er a ps yc hiatric or p h ysic al ill ness).  


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 1  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
7 
S T U D Y D R U G M A N A G E M E N T
7. 1 
D e s cri pti o n of St u d y Dr u g 
7. 1. 1
I n v e sti g ati o n al Pr o d u ct
A n I n vesti gati o n al Pr o d uct (I P), als o k n o w n as I n vesti gati o nal Me dici n al Pr o d uct i n s o me 
re gi o ns, is defi ne d as f oll o ws: 
A p har mace utical f or m of a n acti ve s u bsta nce or pla ce b o bei n g teste d or use d as a r efere n ce i n 
a cli nical st u d y, i ncl u di n g pr o d ucts alrea d y wit h a m ar keti n g a ut h ori zati o n b ut us e d or 
ass e m ble d (f or m ulat e d or pac ka g e d) i n a wa y differe nt fr o m t he a ut h ori ze d f or m, or use d f or a n 
u na ut h oriz e d i n di cati o n, or w he n us e d t o gai n f urt her i nf or mati o n a b o ut t he a ut h orize d f or m.
T he I P s h o ul d be st ore d i n a s ec ure ar ea a cc or di n g t o l ocal r e g ulati o ns. It is t h e res p o nsi bilit y of 
t he I n vesti g at or t o e ns ure t hat t he I P is o nl y dis pe ns e d t o st u d y pati e nts. T he I P m ust b e 
dis pe ns e d o nl y fr o m offi cial st u d y sites b y a ut h orize d pers o n nel ac c or di n g t o l oc al r e g ulati o ns. 
I n t his pr ot oc ol, t he I P is B H V- 3 2 4 1 3 0 0 m g ta bl ets a n d mat c hi n g pl ace b o ta blets.  
T he I P d uri n g t he O L E p hase of t he st u d y is B H V- 3 2 4 1 3 0 0 m g ta bl ets.
7. 1. 2
P a c k a gi n g, S hi p m e nt a n d St or a g e 
T he dr u g pr o d uct is pres e nte d as B H V- 3 2 4 1 E xte n d e d Releas e ( E R) Ta blets t hat are r e d dis h-
bei ge, fil m c o ate d a n d o v al ( 3 0 0 m g str e n gt h). T h e ta blets ea c h c o nsist of 3 0 0 m g of B H V-
3 2 4 1 dr u g s u bsta nce as free base, a n d ge ner all y r ec o g nize d as s afe ( G R A S) e xci pi e nts f or oral 
d os a ge f or ms i ncl u di n g h y dr o x y pr o p yl m et h yl cell ul ose, micr ocr yst alli ne cell ul os e, 
h y dr o x y pr o p yl cell ul os e, s o di u m st ear yl f u marat e a n d ora n ge c ol or. M atc hi n g place b o ta bl ets 
c o ntai n micr o cr ystalli ne c ell ul ose a n d s o di u m st ear yl f u marat e a n d are fil m- c oat e d wit h 
O P A D R Y ®  ( mi xt ure of h y pr o m ell os e, p ol yet h yle ne gl yc ol a n d tit a ni u m di o xi de) a n d ir o n 
o xi de t o gi v e re d dis h- bei ge c ol or.  T he t a blets are pa c ke d i n hi g h- d e nsit y p ol y et h yl e ne ( H D P E) 
b ottles.  T h e b ottles are i n d ucti o n seale d a n d cl os e d wit h c hil d r esista nt p ol y pr o p yle n e ( P P) 
s cre w ca ps.  
All i n vesti g ati o n al pr o d ucts s h o ul d be ke pt i n a sec ur e area wit h li mit e d acc ess u n der 
a p pr o priat e st ora ge c o n diti o ns. C o ntai ner(s) of i n v esti gati o nal pr o d u ct will bear a la bel 
c o ntai ni n g (at a mi ni m u m) t he na m e of t he st u d y dr u g, l ot a n d/ or b atc h n u m ber a n d a p pr o priat e 
st ora ge c o n diti o ns ( 1 5°- 2 5° C [ 5 9°- 7 7° F] i n a ti g htl y cl os e d c o nt ai ner, pr otect e d fr o m li g ht).   
St ora ge te m perat ure e xc ursi o ns s h o ul d be r e p orte d p er P har mac y M a n u al i nstr ucti o ns.  Te m p-
Tale U S B m o nit ors will be i ncl u d e d i n s hi p m e nts of i n vesti gati o nal me dicati o n t o st u d y sites 
a n d u p o n recei pt, st u d y pers o n nel m ust retrie ve, pri nt a n d e m ail t he T e m p- Tale m o nit or re p ort 
i n or d er t o c o nfir m t h at u nac ce pt a ble e xc ursi o ns di d n ot occ ur d uri n g s hi p me nt. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 2  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
7. 2
D o s e a n d A d mi ni str ati o n
7. 2. 1
M et h o d of A s si g ni n g P ati e nt I d e ntifi c ati o n 
T he I n vesti g at or or desi g n ee will n ee d t o acc ess a n I nteracti ve We b- base d Res p o nse S yste m 
(I W R S) i n or der t o re gister eac h s u bject. I nitiall y, aft er i nf or me d c o ns e nt is o bt ai ne d at t he 
Scree ni n g Visit, t he I n vesti gat or or desi g n ee will e nt er t he s u bje ct i nt o t he st u d y a n d o btai n a 
s u bject n u m b er assi g n me nt. After c o m pleti o n of S cr ee ni n g e v al uati o ns, all eli gi ble s u bj ects 
will be ra n d o miz e d, i n a 1: 1 rati o t o rec ei ve eit h er B H V- 3 2 4 1 ( 6 0 0 m g BI D) or matc hi n g 
place b o. R a n d o mi zati o n will b e stratifie d b y dis eas e s u bt y pe of eit h er M S A- P vs. M S A- C, 
dia g n ostic cat e g or y of p ossi ble M S A vs. pr o ba ble M S A, a n d c o u ntr y.  C o ntai n er assi g n me nts 
will be o bt ai ne d b y t he I n vesti gat or ( or desi g n ee) vi a t he I W R S s yste m. 
I n vesti gati o nal sites will access t he I W R S at eac h sc he d ule d visit t hr o u g h o ut t he d o u bl e- bli n d 
p hase of t he st u d y (e x ce pt f or W ee ks 2, 8 a n d 4 8) t o trac k patie nt e nr oll me nt a n d dis pe ns e 
dr u g. St u d y me dic ati o n will be assi g ne d via t he I W R S s yste m; t he s yste m will assi g n s pecific 
c o ntai n er n u m bers f or all bli n d e d st u d y dr u g t o be dis pe nse d t o t he s u bje ct. O nce a c o ntai ner 
has bee n assi g ne d it ca n n ot be dis pe nse d t o a n ot her st u d y s u bject.  
After a s u bject has pr o vi de d i nf or me d c o nse nt t o partici p ate i n t he O L E p hase, t he I n v esti gat or 
 a n d at eac h 
s c he d ule d visit t hr o u g h o ut t he O L E p h as e of t he st u d y (e xce pt f or Wee ks 2- E xt, 4- E xt, 8- E xt 
a n d 4 8- E xt) t o trac k p atie nt e nr oll me nt a n d o bt ai n c o ntai ner n u m bers of o p e n-la b el B H V- 3 2 4 1 
t o be dis pe ns e d t o t he s u bject. O nce a c o ntai ner has bee n assi g ne d it ca n n ot be dis pe ns e d t o 
a n ot her st u d y s u bje ct.  
Sites will be r es p o nsi ble f or re c or di n g t he c o ntai ner n u m bers dis pe ns e d t o t h e s u bject o n t he 
Dr u g A cc o u nta bilit y F or m pr o vi d e d i n t h e Re g ulat or y Bi n der, as well as e ns ure a p pr o priate 
  
O nce a s u bject c o m pletes t h e st u d y, or if a s u bj ect is disc o nti n ue d earl y fr o m t he st u d y, t he 
I n vesti gat or or d esi g nee m ust acc ess t he I W R S t o d o c u me nt disc o nti n u ati o n of t he patie nt fr o m 
partici pati o n i n t h e st u d y. 
R escree ni n g:  If i nitial Scree ni n g la b s a m ple res ults d o n ot meet pr ot oc ol-s pecifie d eli gi bilit y 
criteria a n d t he I n vesti g at or deter mi nes t hat a re p eat sa m ple m a y me et t h e ra n ge re q uire d f or 
eli gi bilit y, a re p eat la b s a m pl e ma y b e c ollecte d ( o ne re peat c oll ecti o n/a nal ysis all o we d).  
After o btai ni n g S p o ns or a p pr o val, a s u bj ect w h o d o es n ot meet pr ot oc ol r e q uire d eli gi bilit y 
criteria d uri n g Scr ee ni n g b ut w h o m a y p ote ntiall y be c o me eli gi ble (e. g., l o gisti cal re as o ns s uc h 
as e xcee di n g s cree ni n g wi n d o w t o acc o m m o date ti m e re q uire d f or a dj ust me nt/sta bilit y of 
c o nc o mita nt me di cati o n, w as h o ut of pr o hi bit e d me di cati o n or r e peat pr oce d ures t o all o w f or 
rec hec k/c o nfir m ati o n of a n a b n or m alit y t hat ma y me et t he r e q uire d ra n g e i n a r eas o na bl e 
a m o u nt of ti me) ma y be e ntere d as a S cree n Fail ure i n I W R S a n d e C R F a n d res cree ne d o ne 
ti me ( e nter e d as a Res cree n i n I W R S a n d e C R F).  If t he S p o ns or a p pr o ves Rescree ni n g f or a 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 3  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
s u bject, i nstr u cti o ns will be pr o vi d e d t o t h e site re g ar di n g t he s pecific S cr ee ni n g 
pr oce d ures/e v al uati o ns t hat will ne e d t o be r e peate d f or Rescree ni n g, as t his is de pe n de nt o n 
t he a m o u nt of ti me ela ps e d. 
7. 2. 2
S el e cti o n a n d Ti mi n g of D o s e a n d A d mi ni str ati o n 
All s u bjects will be ra n d o mize d t o rec ei ve B H V- 3 2 4 1 6 0 0 m g BI D or matc hi n g pla ce b o BI D. 
S u bjects s h o ul d be a d mi nistere d t he D a y 1/first d os e of st u d y me dic ati o n ( 3 0 0 m g Q D or 
m atc hi n g pl ace b o Q D) w hil e i n t he offic e/cli nic o n t he d a y of t he B as eli ne visit. S u bjects 
s h o ul d st a y at t he office/cli nic f o r m o nit ori n g f or a p pr o xi m atel y 4 h o urs. 
T he t a blets s h o ul d be s w all o we d w h ol e wit h a dri n k of w ater. T he t a blets s h o ul d n ot be 
s plit, c he we d, or cr us h e d. 
St u d y me dic ati o n ca n be ta ke n wit h o ut re gar d t o meals.  
D os e titr ati o n peri o d - D o u ble- Bli n d P h ase:   
Fr o m t h e be gi n ni n g t o t h e e n d of W ee k 1 s u bjects s h o ul d i n gest eit her 3 0 0 m g Q D of B H V-
3 2 4 1 or matc hi n g pla ce b o Q D. Fr o m t he be gi n ni n g t o t he e n d of W ee k 2, s u bjects s h o ul d 
i n gest eit her 3 0 0 m g BI D of B H V- 3 2 4 1 or mat c hi n g place b o BI D.  S u bje cts s h o ul d ta k e t he 
st u d y dr u g t wice a d a y; d osi n g i n t he m or ni n g a n d e v e ni n g a p pr o xi mat el y 1 2 h o urs a part.   
At t he e n d of W ee k 2, a n ass ess me nt of c o m plia nc e a n d t oler a nce t o t his d ose titrati o n s c he d ul e 
will be c o n d u cte d.  Per I n v esti gat or j u d ge m e nt, a d diti o nal e v al uati o ns/ pr oc e d ures ma y be 
c o n d ucte d at t his ti m e p oi nt as a p pr o priat e.  If t ol era bilit y iss ues are e x perie nce d wit h 3 0 0 m g 
Q D or 3 0 0 m g BI D d osi n g, t he titrati o n sc he d ule m a y be m o difi e d (see S ecti o n 7. 2. 3). 
F ull d ose peri o d - D o u ble- Bli n d P h ase:  
Starti n g wit h t he be gi n ni n g of W ee k 3 a n d t hr o u g h o ut t he re mai n d er of t he st u d y, s u bje cts 
s h o ul d i n gest eit her 6 0 0 m g BI D of B H V- 3 2 4 1 or matc hi n g pl ace b o BI D. S u bje cts s h o ul d ta k e 
t he st u d y dr u g t wice a da y; d osi n g i n t h e m or ni n g a n d e ve ni n g a p pr o xi matel y 1 2 h o urs a part.  
At t he Wee ks 4, 1 2, 2 4, 3 6 a n d 4 8 st u d y visits, t h e m or ni n g d os e of st u d y me di cati o n s h o ul d be 
hel d o n t he d a y of t he st u d y visit a n d a d mi nistere d i n t he cli nic/ offic e d uri n g t he st u d y visit, s o 
t hat o ne pr e- d os e (tr o u g h) a n d o ne p ost- d os e P K s a m ple ca n b e c ollect e d a p pr o xi mat el y 2- 4 
h o urs p ost- d os e (see S ecti o n 6. 3. 2). 
D ose Titr ati o n Peri o d - O L E P h as e:
S u bjects e nt eri n g t h e O L E p has e of t h e st u d y will r e cei ve o p e n-la bel acti ve B H V- 3 2 4 1 a n d will  
f oll o w t he s a m e d os e titrati o n sc he d ule as t he titrati o n i n t he d o u bl e- bli n d p h ase of t he st u d y, t o 
e ns ure t hat all p artici pa nts s afel y c o nti n ue fr o m eit h er acti v e B H V- 3 2 4 1 or place b o t o o p e n-
la bel B H V- 3 2 4 1.  


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 4  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
S u bjects s h o ul d be a d mi nistere d t he D a y 1/first d os e of o pe n-l a bel B H V- 3 2 4 1 ( 3 0 0 m g 
Q D) w hile i n t he office/cli nic o n t h e d a y of t he B aseli ne - E xte nsi o n visit. S u bjects s h o ul d 
st a y at t h e office/cli nic f or m o nit ori n g f or a p pr o xi m atel y 4 h o urs.  
F or t he r est of We e k 1- E xte nsi o n of t he O L E p h as e, s u bjects will i n gest o ne ta bl et of B H V-
3 2 4 1 ( 3 0 0 m g) per da y i n t he m or ni n g f or o ne wee k.  Fr o m start t o e n d of Wee k 2- E xte nsi o n, 
s u bjects will i n gest 3 0 0 m g BI D of B H V- 3 2 4 1.  S u bjects s h o ul d ta k e o ne 3 0 0 m g ta bl et of 
B H V- 3 2 4 1 t wice a da y ( 6 0 0 m g p er da y); i n t he m or ni n gs a n d e ve ni n gs, a p pr o xi matel y 1 2 
h o urs a part. If t here is a del a y i n d osi n g, t h e i nt er val bet wee n t w o d oses s h o ul d be n o l ess t ha n 
6 h o urs.
A n e n d of Wee k 2- E xte nsi o n ass ess me nt of c o m pli a nce a n d t oler a nce t o t his d ose titr ati o n 
s c he d ule will be c o n d u cte d.  Per I n vesti gat or j u d ge m e nt, a d diti o nal e val uati o ns/ pr oce d ures 
ma y be c o n d u cte d at t his ti m e p oi nt as a p pr o priat e.  If t olera bilit y iss ues are e x perie nc e d wit h 
3 0 0 m g Q D or 3 0 0 m g BI D d osi n g, t he titr ati o n s c h e d ule ma y b e m o difie d (s ee Secti o n  7. 2. 3). 
F ull D ose Peri o d- O L E P h as e: 
Starti n g wit h Wee k 3- E xte nsi o n a n d f or t he re mai n d er of t he O L E p h as e of t he st u d y 
(a d diti o n al 4 6 w ee ks), s u bjects will i n gest 6 0 0 m g BI D of B H V- 3 2 4 1. S u bjects s h o ul d ta ke t w o 
3 0 0 m g ta bl ets of B H V- 3 2 4 1 t wice a d a y ( 1 2 0 0 m g per da y); i n t he m or ni n gs a n d e ve ni n gs, 
a p pr o xi matel y 1 2 h o urs a p art.  
S u bjects w h o w ere ta ki n g a re d uce d d os e of 3 0 0 m g BI D ( o ne ta blet t wice a da y) of t h e bli n d e d 
st u d y me dicati o n d u e t o t olera bilit y iss ues w he n t he y c o m plete d t h e d o u ble- bli n d p hase of t h e 
pr ot oc ol, m a y c o nti n ue t a ki n g t h at 3 0 0 m g BI D d uri n g t he O L E. 
7. 2. 3
D o s e M o difi c ati o n s 
S u bjects, al o n g wit h t heir care gi vers, will b e i nstr uct e d o n t he d osi n g re gi me n. 
If t olera bilit y iss ues are e x perie nc e d d uri n g t h e d ose titrati o n peri o d wit h t h e 3 0 0 m g Q D 
a n d/ or 3 0 0 m g BI D d oses ( or mat c hi n g pl ace b o), t h e titrati o n sc he d ule m a y be e xt e n de d (e. g., 
u p titrati o n t o t he ne xt d os e le v el del a ye d b y a n a d diti o nal wee k). P ot e nti al t olera bilit y iss u es 
ma y i ncl u de s u d de n, cli ni call y si g nific a nt c h a n ges fr o m bas eli n e i n s y m pt o ms of pres y nc o pe, 
s y nc o pe, ort h ostatic h y p ot e nsi o n, or falls t hat ar e n ot ot her wise e x pl ai ne d. T he I n vesti g at or 
m ust c o ns ult wit h t he Me di cal M o nit or if he or s he b elie v es t hat a c ha n ge t o t he d os e titr ati o n 
s c he d ule is w arra nte d; a n d, t he I n vesti gat or m ust d oc u me nt a n y s uc h c ha n ges t o t he d os e 
titrati o n sc he d ule.
D uri n g t he f ull d os e p eri o d of t h e st u d y, it is a nti ci pate d t hat all s u bjects will re cei ve eit h er 
B H V- 3 2 4 1 6 0 0 m g BI D or matc hi n g pl ace b o BI D. If s u bjects ha ve diffic ult y t olerati n g B H V-
3 2 4 1 6 0 0 m g BI D or matc hi n g pla ce b o BI D d osi n g, t he I n vesti g at or m a y per mit t he s u bject t o 
s witc h t o B H V- 3 2 4 1 3 0 0 m g BI D or matc hi n g pla ce b o BI D d osi n g (a n d d oc u me nt t his c ha n g e 
i n t he s u bj
P ote ntial t oler a bilit y iss ues ma y i ncl u de t h ose liste d a b o ve as well as 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 5  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
cli ni call y si g nifi ca nt la b orat or y a b n or malities (i.e., t h yr oi d a n d re nal f u ncti o n) t hat are n ot 
ot her wis e e x pl ai ne d. D o w n titrati o n t o B H V- 3 2 4 1 3 0 0 m g BI D or matc hi n g pla ce b o BI D will 
o nl y be all o we d t o a d dr ess t olera bilit y iss ues a n d o nl y wit h Me dical M o nit or a p pr o v al. If a 
s u bject is d o w n titrat e d t o t h e 3 0 0 m g BI D d ose, t he y ma y be all o we d t o r etr y t he 6 0 0 m g BI D 
d os e (re-c halle n ge), if d ee m e d a p pr o pri ate b y t he I n v esti gat or a n d M e dic al M o nit or. O nl y t w o 
re-c halle n ges are all o w e d. A n y s uc h c h a n ges m ust b e d oc u me nte d b y t h e I n vesti gat or. If a 
s witc h t o B H V- 3 2 4 1 3 0 0 m g BI D or matc hi n g pla ce b o BI D d osi n g d oes n ot res ult i n 
acce pta bl e t oler a bilit y, t h e n d osi n g s h o ul d be disc o nti n ue d.  
D ose m o dificati o n s h o ul d be c o nsi dere d if a patie nt e x perie n ces o ne of t he f oll o wi n g: 
a. Cli nic all y si g nific a nt c h a n ges i n fre q ue n c y a n d/ or s e verit y fr o m b as eli n e i n s y m pt o ms 
of pres y nc o pe, s y nc o pe, ort h ostatic h y p ote nsi o n, a n d/ or falls t h at ar e n ot e x plai ne d b y 
M S A disease pr o gressi o n or i nterc urre nt ill n ess a n d n ot a ble t o be a d e q uatel y treate d 
wit h s y m pt o matic p h ar ma c ol o gi cal a n d n o n- p h ar ma c ol o gical tr eat me nts, base d o n t h e 
j u d ge me nt of t he I n v esti gat or, 
b.  D e vel o p me nt of Gr a de 3 or Gr a de 4 h y p ot h yr oi dis m. Rec halle n ge ma y be atte m pte d, if 
w arra nte d, w he n i m pr o ve d t o l ess t ha n or e q ual t o Gra de 2 (i ncl usi ve of tre at m e nt wit h 
t h yr o xi ne re plac e me nt t hera p y. se e S ecti o n 8. 1. 8). 
c. D e vel o p me nt of a greater t h a n or e q ual t o Gra de 3 t o xicit y or a n i nt olera ble si de eff ect 
attri b ute d t o B H V- 3 2 4 1 base d o n t h e j u d ge me nt of t he I n vesti gat or. Rec h alle n g e ma y 
be att e m pt e d, if w arra nt e d, w he n s y m pt o ms i m pr o ve t o less t ha n or e q u al t o Gra d e 1. 
7. 3 
Bli n di n g a n d U n bli n di n g 
Bli n di n g is criti cal t o t he i nte grit y of t his cli nical st u d y. H o we ver, i n t he e v e nt of a m e dical 
e mer ge n c y or pre g na nc y i n a n i n di vi d ual s u bject, i n w hic h k n o wle d ge of t h e i n vesti gati o nal 
treati n g p h ysici a n. 
I n vesti gat or s h o ul d h a ve deter mi n e d t hat t he i nf or mati o n is nec ess ar y, i.e., t h at it will alter t he 
s clearl y 
n ot i n vesti g ati o n al pr o d uct rel ate d, t h e pr o ble m ma y be pr o perl y m a na ge d wit h o ut t he n ee d f or 
u n bli n di n g, b y ass u mi n g t hat t he s u bject is re cei vi n g acti v e pr o d uct. U n bli n di n g will be 
ma na ge d via t h e I W R S s yste m. T he cli nical s u p pl y ma na ger, p h ar mac o ki netic a n d 
p har mac o d y n a mi c ve n d ors, I W R S ve n d or, p har m ac o vi gila n ce a n d  D M C (if re q ueste d)  r oles 
ma y be u n bli n de d bef or e data are u n bli n de d f or t h e pri mar y e n d p oi nt a n d all s u bj ects c o m plet e 
t he st u d y. E xce pt as n ot e d a b o ve, ot h er me m bers of t he Bi o ha ve n r es earc h t ea m will re mai n 
bli n de d. I n c ases of acci d e ntal u n bli n di n g, c o nt act t h e M e dical M o nit or a n d e ns ure e ver y 
atte m pt is m a de t o pr es er ve t he bli n d. 
D uri n g t he O L E p has e, all p artici pa nts will n ot be bli n de d a n d will b e recei vi n g a cti v e B H V-
3 2 4 1. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 6  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
7. 4
Tr e at m e nt C o m pli a n c e
Res p o nsi ble st u d y pers o n nel will dis pe ns e t he st u d y dr u g. Acc o u nta bilit y a n d c o m plia nc e 
verific ati o n s h o ul d b e d oc u me nte d i n t he 
st u d y rec or ds. S u bjects will be c o u ns ele d o n 
t he i m p orta nc e of ta ki n g t he st u d y dr u g as dir ect e d at all st u d y visits.   
O ver ni g ht s hi p me nt of st u d y me dicati o n u n der a m bi e nt c o n diti o ns ( via certifie d a n d trac k e d 
c o urier a n d f oll o wi n g Re m ote Visit W or kar o u n d G ui deli nes pr o vi d e d t o sit es), fr o m t he st u d y 
site t o st u d y partici pa nts is per missi ble w he n a n i n- p ers o n st u d y visit is n ot p ossi ble d u e t o t h e 
C O VI D-
. T he 
s p 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. C o nfir mati o n t hat t he st u d y dr u g s hi p me nt 
w as recei ve d b y t he st u d y partici p a nt s h o ul d be r etai n e d as d oc u me ntati o n, e. g., tra c ki n g 
c o nfir mati o n pri nt o ut fr o m t he c o uri er, writt e n d oc u me ntati o n of c o ntact wit h t h e s u bject ( b y 
p h o ne, e mail, t e xt), s u bject si g nat ure o n pac ki n g list, etc.
If p o or c o m pli a nce c o nti n ues, (i. e., ta ki n g st u d y dr u g differe ntl y t ha n p er I n vesti gat or 
i nstr ucti o ns, m ulti ple misse d d os es res ulti n g i n less t ha n 8 0 % o verall c o m plia nce), 
dis c o nti n uati o n of t h e s u bject fr o m t h e trial s h o ul d b e c o nsi dere d a n d disc usse d wit h t he 
S p o ns or. 
7. 5 
D e str u cti o n a n d R et ur n of St u d y Dr u g 
All u n us e d a n d/ or partiall y us e d st u d y dr u g ca n b e se nt bac k t o t he dr u g de p ot f or destr ucti o n 
desi g nee. If it
t o e ns ure t hat arra n ge me nts ha v e bee n ma de f or t he dis p osal, pr oce d ures f or pr o per dis p os al 
ha ve bee n esta blis he d acc or di n g t o t h e a p plica ble re g ulati o ns, g ui d eli n es a n d i nstit uti o n al 
pr oce d ures, a n d a p pr o pri ate r ec or ds of t he dis p os al h a ve bee n d o c u me nte d. T he u n use d st u d y 
dr u gs ca n o nl y be destr o y e d after b ei n g i ns pecte d a n d rec o ncile d b y t h e res p o nsi ble St u d y 
 
8 
A D V E R S E E V E N T S 
A n A d verse E ve nt ( A E) is defi ne d as a n y ne w u nt o w ar d me di cal o cc urre nc e or w orse ni n g of a 
pre-e xisti n g me di cal c o n diti o n i n a patie nt or cli nic al i n vesti gati o n patie nt a d mi nister e d a n 
i n vesti gati o nal ( me dici n al) pr o d uct a n d t hat d oes n ot necess aril y h a ve a c a us al relati o ns hi p 
wit h t his tre at m e nt. A n A E ca n t heref ore b e a n y u nfa v ora ble a n d u ni nte n d e d si g n (i ncl u di n g a n 
a b n or mal la b orat or y fi n di n g, f or e x a m pl e) s y m pt o m, or dis eas e te m p orall y ass ociat e d wit h t h e 
us e of t he i n vesti gati o nal pr o d u ct, w het her or n ot c o nsi dere d rel ate d t o t he i n v esti gati o nal 
pr o d uct.  
If a s pecifi c dia g n osis or s y n dr o me is i de ntifie d b y t h e I n vesti gat or, t his s h o ul d be r ec or de d as 
t he A E, rat h er t ha n re c or di n g as s e par ate A Es t h e i n di vi d ual si g ns/s y m pt o ms or cli nicall y 
si g nifica nt la b or at or y a b n or m alities k n o w n t o be ass ociat e d wit h, a n d c o nsi dere d b y t h e 
I n vesti gat or t o be a c o m p o ne nt of, t he dis eas e/s y n dr o me.   


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 7  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
A d verse e ve nts ca n be s p o nt a ne o usl y re p orte d or elicite d d uri n g o p e n-e n de d q u esti o ni n g, 
e xa mi n ati o n, or e val uati o n of a p ati e nt. I n or der t o pr e ve nt re p orti n g bi as, patie nts s h o ul d n ot 
be q uesti o ne d r e gar di n g t he s pecific occ urre nce of o ne or m ore A Es. 
T here ar e t w o t y pes of A Es, Seri o us A d verse E ve nts ( S A Es) a n d N o n- Seri o us A Es. 
8. 1 
S eri o u s A d v er s e E v e nt s 
8. 1. 1
D efi niti o n of S eri o u s A d v er s e E v e nt ( S A E) 
A S A E is a n y e ve nt t hat me ets a n y of t he f oll o wi n g criteri a at a n y d ose:
 D eat h; 
 Life-t hr eat e ni n g; 
 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 nifi ca nt dis a bilit y/i nca p acit y; 
 C o n ge nital a n o m al y/ birt h def ect i n t he offs pri n g of a s u bject w h o recei ve d B H V- 3 2 4 1: 
 Ot her: I m p ort a nt m e dical e ve nts t hat ma y n ot r es ult i n deat h, be life-t hreat e ni n g, or re q uire 
h os pitali zati o n, ma y b e c o nsi dere d a n S A E w he n, bas e d u p o n a p pr o priat e me dical 
j u d g me nt, t he y m a y je o p ar dize t he s u bje ct a n d ma y r e q uire m e dic al or s ur gical i nt er ve nti o n 
t o pre ve nt o n e of t he o utc o mes liste d i n t his defi niti o n. E xa m pl es of s uc h e ve nts are ( b ut 
n ot li mite d t o): 
 I nte nsi ve tr eat me nt i n a n e m er ge nc y r o o m or at h o m e f or aller gi c br o nc h os pas m; 
 Bl o o d d yscrasias or c o n v ulsi o ns t h at d o n ot r es ult i n i n pati e nt h os pit ali zati o n; 
 D e vel o p me nt of dr u g de pe n de n c y or dr u g a b use; 
 
P ote ntial dr u g i n d uc e d li v er i nj ur y (s ee s ecti o n 8. 1. 7)  
8. 1. 2
D efi niti o n of T er m s 
Mil d: A mil d A E is us uall y tr a nsie nt a n d ma y r e q uir e o nl y mi ni mal treat m e nt or t her a pe utic 
i nter ve nti o n.  T h e e ve nt d oes n ot ge ner all y i nterf ere wit h us ual acti vities of dail y li vi n g. 
M o der ate: A m o derate A E is us uall y alle vi ate d wit h a d diti o n al s pecific t hera pe utic 
i nter ve nti o n. T h e e ve nt i nterf eres wit h us ual acti vities of dail y li vi n g, ca usi n g disc o mf ort b ut 
p os es n o si g nifica nt or p er ma n e nt ris k of har m t o t he s u bject. 
Se vere: A se vere A E i nterr u pts us ual acti vities of dail y li vi n g, si g nifi ca ntl y affe cts cli nical 
stat us, or ma y re q uire i nte nsi ve t hera pe utic i nter v e nti o n. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 8 8  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
Life t hre ate ni n g: A n A E is lif e t hreate ni n g if t he s u bject was at i m me di ate ris k of de at h fr o m 
t he e ve nt as it o cc urre d; i.e., it d oes n ot i n cl u de a rea cti o n t h at if it ha d o cc urre d i n a m ore 
s eri o us f or m mi g ht h a ve ca us e d deat h. F or e x a m pl e, dr u g i n d uce d he p atitis t hat res ol ve d 
wit h o ut e vi d e nce of h e pati c fail ure w o ul d n ot b e c o nsi dere d lif e t hre ate ni n g e ve n t h o u g h dr u g 
i n d uce d he p atitis ca n be f atal. 
H os pit aliz ati o n: A Es re q uiri n g h os pitaliz ati o n s h o ul d be c o nsi dere d S A Es. H os pitalizati o n f or 
electi ve s ur ger y or r o uti ne cli ni cal pr o ce d ures t h at ar e n ot t he r es ult of a n A E (e. g., electi v e 
s ur ger y f or a pre-e xisti n g c o n diti o n t hat has n ot w orse ne d) nee d n ot be c o nsi der e d A Es or 
S A Es. If a n yt hi n g u nt o war d is re p ort e d d uri n g t he pr oce d ure, t h at occ urr e nce m ust be re p orte d 
as a n A E, eit h er 'seri o us' or ' n o n-s eri o us' a cc or di n g t o t he us ual criteria.  
I n ge neral, h os pitalizati o n si g nifies t hat t he s u bject h as bee n det ai ne d ( us uall y i n v ol vi n g at least 
a n o ver ni g ht st a y) at t he h os pit al or e m er ge nc y war d f or o bser vati o n a n d/ or treat me nt t hat 
w o ul d n ot ha ve be e n a p pr o priate i n t he p h ysicia n's office or o ut p ati e nt s etti n g. W he n i n d o u bt 
as t o w het her ' h os pitaliz ati o n' occ urr e d or was necess ar y, t he A E s h o ul d be c o nsi d ere d s eri o us.  
T he f oll o wi n g h os pitalizati o ns are n ot c o nsi dere d S A Es i n Bi o ha ve n cli ni cal st u dies ( b ut m a y 
be c o nsi dere d n o n-s eri o us A Es): 
 A visit t o t he e mer g e nc y r o o m or ot her h os pital de part me nt < 2 4 h o urs t h at d oes n ot r es ult 
 
t hreat e ni n g); 
 Electi ve s ur ger y, pla n ne d pri or t o si g ni n g c o nse nt; 
 A d missi o ns as per pr ot oc ol f or a pla n ne d me dic al/s ur gical pr o ce d ure; 
 R o uti ne healt h ass ess me nt re q uiri n g a d missi o n (i.e., r o uti ne c ol o n osc o p y); 
 A d missi o n e nc o u nter e d f or a n ot her life circ u msta nc e t hat carries n o beari n g o n healt h a n d 
re q uires n o me dical i nter v e nti o n (i.e., l ac k of h o usi n g, care- gi v er res pite, f a mil y 
circ u mst a nces).
Dis a bilit y/i n c a p acit ati n g:  A n A E is i nca pa cit ati n g or disa bli n g if t he e x p erie nc e res ults i n a 
s u bsta ntial a n d/ or per ma ne nt disr u pti o n of t he s u bject's a bilit y t o carr y o ut n or mal life 
f u ncti o ns.
8. 1. 3
Cl a s sifi c ati o n of A d v er s e E v e nt s 
T he s e verit y of all A Es m ust be rec or d e d i n t h e e C R F a n d o n t h e S A E F or m, if a p plica ble. T h e 
acti viti es. T he s e verit y of e ve nts s h o ul d be gra de d as mil d, m o d erat e or se vere.  
T
pr ocess b ut is n ot a fact or i n d eter mi ni n g w hat is or is n ot re p orte d i n t he st u d y. If t h ere is a n y 
d o u bt as t o w het her a cli nical o bs er vati o n is a n A E, t he e ve nt s h o ul d b e re p orte d. T he 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 8 9 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
relati o ns hi p or ass ociati o n of t h e st u d y dr u g i n ca usi n g or c o ntri b uti n g t o t h e A E will b e 
c haracteriz e d as n ot relat e d, u nli k el y relat e d, p ossi bl y relat e d or relate d f or n o n-s eri o us A Es 
a n d as n ot rel ate d or relat e d f or S A Es.
Dis eas e relate d si g ns a n d s y m pt o ms, i ncl u di n g t h ose t hat ar e part of t he dia g n ostic criteria f or 
M S A, ma y be re p orte d as A Es as f oll o ws:
Disease relate d si g ns a n d s y m pt o ms t hat meet t he defi niti o n of a n S A E as o utli n e d i n
Secti o n 8. 1. 1 s h o ul d be r e p orte d as S A Es.
Disease relate d si g ns a n d s y m pt o ms n ot meeti n g t he defi niti o n of a n S A E, b ut re pr ese nti n g 
u nt o w ar d me di cal o cc urre nc es or c ha n ges i n t he c o n diti o n t h at ar e 
me dic all y si g nific a nt s h o ul d be re p orte d as A Es.
Disease relate d si g ns a n d s y m pt o ms ma y be m e dic all y si g nifica nt if t h e y
o
are u nc o m m o n a n d u ne x pe cte d f or t he sta g e of t he disease,
o
c ha n ge si g nifica ntl y i n t heir fre q u e nc y or i nte nsit y,
o
lea d t o t he i niti ati o n of a ne w t hera p y or m o difi cati o n of a n e xisti n g t hera p y, or
o
are ass ociate d wit h mea ni n gf ul se q uel ae.
8. 1. 4
C oll e cti o n a n d R e p orti n g S eri o u s A d v er s e E v e nt s
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 n cl u di n g t h os e t h o u g ht t o b e ass ociate d wit h 
pr ot oc ol-s pecific pr oc e d ures. All S A Es m ust be c ollecte d t h at oc c ur d uri n g t he Scr ee ni n g 
peri o d a n d wit hi n 3 0 da ys of dis c o nti n uati o n of d osi n g. T he I n vesti g at or s h o ul d re p ort a n y 
S A E occ urri n g aft er t hes e ti me p eri o ds t hat is belie v e d t o be relat e d t o st u d y dr u g or pr ot oc ol-
s pecific pr o ce d ures. 
A n S A E re p ort s h o ul d be c o m pl ete 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 
s eri o us ness. 
If t he I n vesti g at or belie ves t h at a n S A E is n ot r elate d t o t he st u d y dr u g, b ut is p ote ntiall y 
relat e d t o t h e 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 h era p y or a 
c o m pli cati o n rel ate 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 pecifi e d i n t h e narrati ve 
s ecti o n of t h e S A E Re p ort F or m. 
S A Es ( w het her relat e d or n ot rel ate d t o st u d y dr u g), o ver d ose, p ote ntial dr u g i n d uce d li ver 
i nj ur y a n d pre g n a nci es m ust be re p ort e d i m me di atel y or n o l ater t h a n wit hi n 2 4 h o urs of
t he I n vesti g at or a w are n ess of t he e ve nt t o t h e 
 de part me nt. 
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 9 0 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
T he I n vesti g at or is res p o nsi bl e 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
i m me diatel y u p o n o bser vi n g or lear ni n g of t h e e ve nt. 
 will t h e n i m me di atel y n otif y 
t he Bi o ha v e n M e dic al M o nit or of t he e ve nt. T he S A E f or m m ust t h e n be s u b mitte d t o
wit hi n o ne w or ki n g da y. 
If o nl y li mite d i nf or mati o n is i niti all 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 r elati 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 vail a ble, a f oll o w- u p S A E re p ort s h o ul d be s e nt wit hi n 2 4 h o urs of t he I n vesti g at or be c o mi n g 
a w are of t he u p date d i nf or mati o n usi n g t he s a me pr o ce d ure use d f or t he tra ns missi o n of t h e 
i niti al S A E a n d t h e s a me e ve nt ter m. 
All S A Es s h o ul d be f oll o w e d t o res ol uti o n or sta bili z ati o n.  
T he Seri o us A d verse E ve nt Re p ort F or m ( S A E R F) s h o ul d be s u b mitte d t o 
 b y 
facsi mile ( F A X). 
N ort h A meric a:
 
E U E M E A: 
 
If site pers o n nel d o n ot ha ve access t o a F A X mac hi ne d uri n g t he C O VI D-1 9 p u blic h ealt h 
e mer ge n c y, S A Es ma y be re p ort e d t o 
 b y e mail (e ncr y pt t h e d oc u m e nt bef ore e maili n g) t o
Re p orts ca n be ma de b y tele p h o n e via t he Safet y H otli ne N u m ber b el o w if a S A E R F ca n n ot be 
i m me diat el y s u b mitte d. 
N ort h A meric a:
 
E U E M E A: 
 
A d diti o nall y, t he I n v esti gat or, or desi g nate d staff, is res p o nsi ble f or e nt eri n g t h e S A E 
i nf or mati o n i n t h e El ectr o nic D ata C a pt ure ( E D C) s yste m (i.e.: e ve nt ter m, start st o p dates, 
ca us alit y, se verit y).  
re p orti n g re q uire m e nts. 
F or a n y q uesti o ns relati n g t o S A Es, ple ase c o nta ct t h e M e dical M o nit or vi a tele p h o ne:  
N ort h A meric a: Dr. 
E U E M E A : Dr. 
T he S p o ns or or s pecifie d d esi g nee/ a ut h ori ze d re pr es e ntati ve will re p ort s us pecte d u ne x pe cte d 
s eri o us a d verse reacti o ns ( S U S A Rs) i n a n e x pe dite d ma n ner ( wit h o ut del a y) t o t he Re g ulat or y 
A ut h orities a n d Et hi cs C o m mitte es c o ncer ne d, i n ac c or da nce wit h F o o d a n d Dr u g 
C CI
C CI
C CI
C CI
P P D
P P D
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 9 1 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
A d mi nistrati o n C o de of Fe der al Re g ulati o ns ( C F R) 2 1 C F R Parts 3 1 2 a n d 3 2 0, E ur o p ea n 
Directi v e 2 0 0 1/ 2 0/ E C a n d t h e D etaile d G ui da n ce o n c olle cti o n, v erifi cati o n a n d prese nt ati o n of
a d verse reacti o n re p orts arisi n g fr o m cli nical tri als o n I Ps f or h u ma n us e ( E N T R/ C T 3) a n d als o 
i n acc or d a nce wit h c o u ntr y-s pecific r e q uire me nts.
T he S p o ns or or s pecifie d d esi g nee/ a ut h ori ze d re pr es e ntati ve s hall n otif y t he I n vesti gat or of t h e 
f oll o wi n g i nf or m ati o n:
A n y A E t hat is b ot h seri o us a n d u n e x pecte d a n d is s us pecte d of bei n g relate d t o t he use of 
t he I P i n t his st u d y or i n ot her st u di es (i.e., S U S A R).
W here re q uire d b y l oc al l e gislati o n, t h e I n vesti g at or s hall n otif y his/ her I R B/ E C pr o m ptl y of 
t hese ne w seri o us a n d u ne x pe cte d A E(s) or si g nifica nt ris ks t o s u bjects.
8. 1. 5
O v er d o s e
A n o ver d ose is defi ne d as t h e acci de nt al or i nte nti o n al a d mi nistrati o n of a n y d os e of t he 
pr o d uct t hat is c o nsi der e d b ot h e xcessi ve a n d m e dic all y i m p orta nt. All occ urr e nces of 
me dic all y si g nifica nt o ver d os e (s us pect e d or c o nfir m e d a n d irres pe cti ve of w het her or n ot it 
i n v ol ve d B H V- 3 2 4 1) m ust be c o m m u ni cat e d t o Bi o h a ve n or a s pecifie d desi g n ee wit hi n 2 4 
h o urs of t he I n vesti gat or bec o mi n g a ware a n d be f ull y d oc u me nt e d as a n S A E. A n S A E is 
re p orte d f or o ver d ose w he n t h e i n vesti gat or f eels t h e o ver d os e was e xcessi ve a n d m e dic all y 
i m p orta nt. D etails of a n y si g ns or s y m pt o ms a n d t heir ma na g e me nt s h o ul d be rec or d e d 
i ncl u di n g d etails of a n y a nti d ot e(s) a d mi nist ere d.
8. 1. 6
Pr e g n a n c y
If, f oll o wi n g i nitiati o n of t h e I P, it is disc o v ere d t hat a st u d y s u bject is pre g na nt or ma y ha ve 
bee n pre g na nt at t he ti me of t h e I P e x p os ure, i ncl u di n g d uri n g at l east 6 half-li v es after I P 
a d mi nistr ati o n, t he I P will b e per m a ne ntl y disc o nti n u e d i n a n a p pr o priat e ma n ner (i.e., d os e 
ta peri n g, if nec ess ar y, f or patie nt safet y). Pr ot o c ol-re q uire d pr oce d ur es f or st u d y 
dis c o nti n uati o n a n d f oll o w u p will b e c o n d ucte d u nless c o ntrai n dic ate d b y t he pre g na n c y (i.e., 
x-ra y st u dies). Ot her a p pr o pri ate pr e g na nc y f oll o w- u p pr oce d ures s h o ul d be c o nsi d ere d if 
i n dicate d.
Sites s h o ul d i nstr uct p ati e nts t o c o ntact t he I n vesti gat or if t he y be c o me pre g n a nt d uri n g t he 
c o urs e of t he st u d y. T h e I n vesti gat or m ust i m me diat el y n otif y 
 of t he e v e nt wit hi n 2 4 h o urs 
of t he I n vesti g at or be c o mi n g a w ar e of t he i nf or mati o n a n d t he sit e m ust c o m plete a Pre g na n c y 
Re p ort F or m. F oll o w u p i nf or m ati o n r e gar di n g t he c o urs e of t he pre g na nc y, i ncl u di n g peri n atal 
a n d ne o nat al o ut c o me a n d, w her e a p plica ble, offs pri n g i nf or mati o n m ust als o be re p ort e d o n a 
Pre g na nc y Re p ort F or m.
A n y pre g na nc y t hat occ urs i n a f e male part ner of a m ale st u d y p arti ci pa nt s h o ul d als o be 
re p orte d t o 
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 9 2  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
8. 1. 7
P ot e nti al Dr u g I n d u c e d Li v er I nj ur y ( DI LI)
W here ver p ossi bl e, ti mel y c o nfir mati o n of t h e i nitial li ver-relat e d la b orat or y a b n or m alities 
s h o ul d occ ur pri or t o t he re p orti n g of a p ot e nti al dr u g i n d uce d li ver i nj ur y ( DI LI) e ve nt. All 
occ urre nces of p ot e nti al DI LIs, me eti n g t he defi ne d criteria, m ust b e re p orte d as S A Es as per 
Secti o n 8. 1. 4.  
P ote ntial dr u g i n d uc e d li v er i nj ur y is defi ne d as: 
 A mi n otra nsferases ( A L T or A S T) el e vati o n > 3 ti mes t he U L N; 
 
 T otal bilir u bi n ( T B L) > 2 ti m es U L N, wit h o ut i nitial fi n di n gs of c h olest asis (ele v ate d 
s er u m al kali ne p h os p hatas e); 
 
 N o ot her i m m e diatel y a p pare nt p ossi bl e ca us es of A L T or A S T ele v ati o n a n d 
h y per bilir u bi ne mia, i n cl u di n g, b ut n ot li mite d t o, vir al he patitis, pre-e xisti n g c hr o nic or 
ac ute li ver dis eas e, or t he a d mi nistrati o n of ot her dr u g(s) k n o w n t o be he pat ot o xic. 
If a n y p ote ntial DI LI is i de ntifie d a n d meets t he criteria a b o ve, t he Bi o h a ve n Me dic al M o nit or 
s h o ul d i m me diat el y be c o nta cte d f or f urt h er i nstr ucti o n o n d osi n g a dj ust me nts a n d w het her t he 
patie nt m ust disc o nti n ue fr o m t he trial a n d a p pr o pri ate f oll o w u p re q uire m e nts. 
8. 1. 8
A d v er s e E v e nt of S p e ci al I nt er e st- T h yr oi d F u n cti o n 
Re versi ble c ha n ges i n t h yr oi d f u ncti o n tests were o bs er ve d d uri n g t he pr ecli nical st u dies a n d 
cli ni cal st u dies wit h B H V- 3 2 4 1. P h ysical e x a mi n ati o n a n d la b orat or y m o nit ori n g of t h yr oi d 
f u ncti o n wit h s er u m trii o d ot h yr o ni n e (free T 3), t h yr o xi ne (free T 4), T S H, a n d a nti T P O 
a nti b o di es will be p erf or me d a n d d o c u me nte d t hr o u g h o ut t his st u d y. A n y si g nific a nt a b n or mal 
fi n di n gs s h o ul d be dis c uss e d wit h t h e st u d y Me dic al M o nit or a n d ma y b e f oll o we d u p as per 
l ocal pr actice (e. g., i n vesti g ati o ns a n d c o ns ultati o n wit h e n d ocri n ol o gist).  
I n cases of s us pecte d h y p ot h yr oi dis m, re pe at t h yr oi d f u ncti o n t ests s h o ul d be me as ure d a n d 
t h yr o xi ne re plac e me nt t hera p y s h o ul d b e c o nsi der e d. I nitiati o n of tr eat me nt is at t he discreti o n 
of t he I n vesti g at or. P ote ntial i nitiati o n of t h yr o xi ne r e place me nt t hera p y ma y be c o nsi dere d 
acc or di n g t o t he f oll o wi n g g ui d eli nes: 
 Mil d T S H i ncrease: 5. 0 t o 1 0 m U/ L (ass u mi n g a n or mal T S H ra n ge of 0. 4 t o 4. 9 m U/ L) a n d 
u nc ha n ge d free T 4 (a n d/ or fr ee T 3) 
 Wit h cli ni cal s y m pt o ms of h y p ot h yr oi dis m: C o nsi der t h yr o xi ne tr eat me nt if c o nfir m e d 
at 2 c o nsec uti ve o ccasi o ns a n d n ot e x plai ne d b y c o n c o mit a nt 
ill ness/fe v er/i nf ecti o n/s ur ger y 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 9 3  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
N o s y m pt o ms: C o nti n ue n or mal m o nit ori n g.
 T S H greater t h a n t he U L N a n d decrease d fr ee T 4 ( a n d/ or free T 3) b el o w n or mal r a n ge: 
 Re gar dless of s y m pt o ms, c o nsi d er i nitiati o n of t h yr o xi ne treat m e nt if c o nfir me d at 2 
c o nsec uti v e occasi o ns a n d n ot e x pl ai ne d b y c o nc o mita nt ill ness/fe v er/ i nf ecti o n/s ur ger y 
(if se vere s y m pt o ms, re peat sa m pli n g i n 2 wee ks). 
If si g ns/s y m pt o ms of h y p ot h yr oi dis m a n d/ or si g nific a nt c ha n g es i n t h yr oi d h or m o ne le v els 
(free T 3/free T 4/ T S H) de vel o p, c olle cti o n of f oll o w u p cli ni cal c he mistr y s a m pl es a n d/ or 
u ns c he d ule d st u d y visits ma y be w arr a nte d. 
Cli nic all y si g nifica nt l a b orat or y a b n or maliti es will b e i de ntifie d as Gra de 3 t o 4 la b or at or y t est 
res ults gra de d a cc or di n g t o n u meri c la b or at or y t est criteri a i n C o m m o n Ter mi n ol o g y Criteria 
f or A d vers e E ve nts ( C T C A E) V ersi o n 5. 0 ( 2 0 1 7)1 8.  F or t h ose n ot a vaila bl e i n C T C A E, 
acc or di n g t o Di visi o n of AI D S ( D AI D S) Ta ble f or Gra di n g t he Se v erit y of A d ult a n d Pe diatric 
A d verse E ve nts C orrecte d V ersi o n 2. 1 ( 2 0 1 7)
1 9.  
If t here are cli nicall y si g nifica nt iss ues wit h t ol era bilit y t hat are n ot a bl e t o be treat e d 
a de q uat el y wit h t h yr o xi ne re plac e me nt t her a p y, t he I n vesti gat or ma y c o nsi d er m o difi cati o ns t o 
t he d osa ge re gi me n. C o ns ultati o n wit h t h e Me dical M o nit or is re q uire d. M o dificati o ns ma y 
i ncl u de r e d uci n g t he d os e of B H V- 3 2 4 1/ mat c hi n g pl ace b o t o 3 0 0 m g BI D or ta ki n g a d os e 
h oli da y. A n y s uc h m o dificati o ns t o t h e d osa ge re gi m e n s h o ul d be n ote d i n t he C R F. 
8. 2 
N o n- s eri o u s A d v er s e E v e nt s 
A n o n-s eri o us a d verse e ve nt is a n A E n ot cl assifie d as a S A E.  
8. 2. 1
C oll e cti o n a n d R e p orti n g of N o n- S eri o u s A d v er s e E v e nt s 
T he c ollecti o n of n o n-s eri o us A E i nf or m ati o n s h o ul d be gi n at t he i niti ati o n of st u d y dr u g.  
N o n-s eri o us a d verse e ve nts s h o ul d be f oll o we d u ntil c o ncl usi o n or sta bili zati o n, or re p orte d as 
S A Es if t he y bec o m e s eri o us. F oll o w- u p is re q uir e d f or n o n-s eri o us A Es t hat ca us e i nterr u pti o n 
or dis c o nti n uati o n of st u d y dr u g or t h os e t hat are pres e nt at t h e e n d of st u d y tr eat me nt. 
8. 2. 2
L a b or at or y T e st A b n or m aliti e s 
T he f oll o wi n g la b orat or y test a b n or maliti es s h o ul d be ca pt ur e d o n t he n o n-s eri o us A E C R F 
pa ge or S A E Re p ort F or m ( pa p er or electr o ni c) as a p pr o priate: 
 A n y la b orat or y t est res ult t hat is cli nicall y si g nifi ca nt or meets t h e defi niti o n of a n S A E; 
 A n y la b orat or y a b n or malit y t hat re q uir e d t he p ati e nt t o ha ve t h e st u d y dr u g dis c o nti n ue d or 
i nterr u pt e d;
 A n y la b orat or y a b n or malit y t hat re q uir e d t he p ati e nt t o recei ve s pecific c orr ecti ve t h era p y. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 9 4  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
9 
S T A TI S TI C S 
D etail e d pla ns f or a nal ysis are s u m m ariz e d i n a s e p arate Statisti cal A nal ysis Pla n ( S A P) 
d oc u me nt. A s u m m ar y of statistical as pects of t he desi g n a n d i nte n d e d a nal ysis is pr o vi de d 
here.
9. 1 
G e n er al Pr o c e d ur e s 
Cate g ori cal v aria bl es are t a b ulate d wit h c o u nts a n d p erce nt a ges. C o nti n u o us varia bles ar e 
s u m mariz e d wit h u ni v ariate statistics (e. g., n, mea n, sta n dar d err or, m e dia n, mi ni m u m a n d 
ma xi m u m).   
F or t he cal c ulati o n of descri pti ve st atistics of o bser v e d data, s u bj ects m ust h a ve a baseli ne 
val ue t o b e e val ua ble f or e n d p oi nts bas e d o n v al ues a n d c ha n ges fr o m bas eli ne o ver ti m e. 
Ta b ulati o ns of t he f oll o wi n g e n d p oi nts prese nt t he n u m ber of u ni q ue s u bj ects wit h a n e ve nt: 
pr ot oc ol de viati o ns; n o n-st u d y me dicati o ns; a d vers e e ve nts; a n d la b orat or y a b n or malities. 
T h us, f or t hes e e n d p oi nts, m ulti ple o cc urre nc es of t h e sa me e v e nt are c o u nte d o nl y o nce p er 
s u bject. 
9. 2 
S a m pl e Si z e 
T he s a m pl e size f or t his st u d y will b e a p pr o xi m atel y 3 2 5 ra n d o miz e d s u bjects.  Bas e d o n 
u n p u blis he d dat a fr o m t h e Pr o mesa st u d y, st u d yi n g E G C G (e pi g all o cat ec hi n gallate) vs 
place b o 2 6 wit h a tr eat m e nt d urati o n of 4 8 wee ks, t h e place b o gr o u p h a d a 4. 8 8 p oi nt i ncre ase 
wit h a sta n dar d d e viati o n of 4. 8 5 i n t he m o difie d U M S A R S Part I a n d Part II t ot al s c ore. Wit h 
a n e x pecte d i m pr o ve me nt of 4 0 % at Wee k 4 8 f or B H V- 3 2 4 1 c o m pare d t o pl ace b o, a t otal of 
2 6 0 s u bjects ( 1 3 0 per gr o u p) pr o vi d es 9 0 % p o wer base d o n a 2-s a m ple, t w o-si de d t-t est.  Wit h 
a dr o p- o ut rat e of ~ 2 0 %, t he st u d y will ra n d o mize a p pr o xi mat el y 3 2 5 s u bjects. 
9. 3 
P o p ul ati o n s f or A n al y si s 
T he p o p ulati o n of i nterest, f or all esti ma n ds, ar e s u bj ects dia g n ose d wit h p ossi ble or pr o ba ble 
M S A.  
T he f oll o wi n g a nal ysis s ets ar e defi ne d f or t his pr ot o c ol:  
E nr olle d s u bj ects: S u bj ects w h o si g ne d a n i nf or me d c o ns e nt f or m a n d were assi g ne d a 
Patie nt I d e ntificati o n n u m b er ( PI D). 
Ra n d o mize d s u bjects: E nr olle d s u bjects w h o recei v e d a treat me nt assi g n me nt fr o m t he 
I nteracti ve We b Res p o ns e S yste m (I W R S). 
Treat e d/ Safet y: E nr olle d s u bje cts w h o recei ve d at le ast 1 d os e of bli n de d st u d y t hera p y 
( B H V- 3 2 4 1 or place b o).  


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 9 5  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
M o difie d I nte nt t o Tr eat ( mI T T) s u bjects: Ra n d o mize d s u bjects t h at re cei ve d at l east o ne 
d os e of bli n de d st u d y t h era p y a n d pr o vi de d a bas eli n e a n d at least o n e p ost- baseli n e 
effica c y assess me nt.
O pe n- La bel E xte nsi o n Treat e d s u bjects: E nr olle d s u bjects i n t he e xte nsi o n p hase 
 
B H V- 3 2 4 1 Treate d Partici pa nts: E nr olle d s u bjects w h o recei v e d at least 1 d os e of B H V-
3 2 4 1 ( bli n de d or o pe n-la bel). 
9. 4 
St ati sti c al M et h o d s 
9. 4. 1
D e m o gr a p hi c a n d B a s eli n e C h ar a ct eri sti c s 
Ta b ulati o ns of de m o gr a p hic a n d b aseli n e c har act eristics will b e s u m marize d b y treat me nt 
gr o u p a n d f or all treate d s u bjects.  A se parate s et of t a b ulati o ns will be ma de f or s u bj ects 
e nr olle d b ut n ot ra n d o miz e d. 
9. 4. 2
Pri m ar y E n d p oi nt( s) 
T he pri m ar y e n d p oi nt is t he c ha n ge fr o m b as eli n e i n t he m o difie d U M S A R S sc ore meas ure d at 
t he Wee k 4 8 visit. T he ite ms i n t he m o difie d U M S A R S will c o ntai n t he f oll o wi n g Part I ite ms: 
S peec h, C utti n g F o o d a n d H a n dli n g Ut e nsils, Dressi n g, H y gie ne, Wal ki n g a n d Uri nar y 
F u ncti o n. T he f oll o wi n g Part II ite ms will als o be i ncl u de d: Arisi n g fr o m C h air, P ost ure, a n d 
Gait. I n t he a nal ysis of all ite ms, t h e res p o nse cat e g ories of 0 a n d 1 will b e c o m bi ne d i nt o a 
si n gle cate g or y bef ore s u m mi n g t h e i n di vi d ual ite ms t o deri ve t he m o difie d U M S A R S.  
T he pri m ar y esti ma n d, f or t he pri mar y e n d p oi nt, will p urs ue a h y p ot hetical strate g y of 
esti mati n g t h e effect of B H V- 3 2 4 1 relati ve t o place b o ha d all s u bj ects sta y e d o n treat me nt.  
Usi n g t he mI T T p o p ulati o n, t he s u m mar y will be t h e differe nc e bet wee n plac e b o a n d B H V-
3 2 4 1 treat e d s u bjects at t he Wee k 4 8 visit. T h e s u m mar y will b e c o m p ute d usi n g a Mi x e d 
M o del f or Re peate d Meas ures ( M M R M) t hat will i n cl u de fi x e d effect fact ors f or treat me nt 
gr o u p, ra n d o mizati o n str ata ( M S A- C or M S A- P, P ossi ble or Pr o ba ble M S A dia g n osis, a n d 
c o u ntr y), visit, a n d t he treat me nt gr o u p b y visit i nter acti o n. B aseli n e m o difie d U M S A R S s c ore 
will e nt er t he m o del as a c o vari ate, a n d s u bject will b e a ra n d o m effect. I nterc urr e nt e v e nts t hat 
lea d t o disc o nti n u ati o n, or lac k of data, will be ha n dl e d b y o nl y usi n g t he- o n treat me nt data.  
M M R M- base d esti mates (i. e., least-s q uares mea n [ L S M] wit h c orres p o n di n g S D a n d 9 5 % CI) 
of val ues a n d c h a n ges fr o m bas eli ne will be pres e nte d b y treat me nt gr o u p a n d wee k. I n 
a d diti o n, t he L S M differ e nce i n c ha n ge fr o m bas eli n e bet wee n treat me nt gr o u ps ( B H V- 3 2 4 1  
place b o) at We e k 4 8 wit h c orr es p o n di n g S D, 9 5 % CI, a n d p- val ue fr o m M M R M will als o be 
pres e nte d.  Si nc e t he esti mate is c alc ulat e d usi n g a li keli h o o d- base d a p pr oac h, t h e a nal ysis is 
base d o n a Missi n g at Ra n d o m ( M A R) ass u m pti o n. Se nsiti vit y a nal ys es will i ncl u de m ulti ple 
i m p utati o n of missi n g data usi n g a c o p y i n cre me nt fr o m refere n ce met h o d.  


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 9 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
O bser ve d val ues a n d c ha n g es fr o m baseli ne i n t he m o difie d U M S A R S s c ores will als o be 
s u m mariz e d usi n g descri pti ve st atistics o ver ti me b y treat me nt gr o u p d uri n g t he R a n d o mizati o n 
P hase.
D etails of t h es e a nal yses are pr o vi de d i n t he S A P.
9. 4. 3
S e c o n d ar y E n d p oi nt( s)
T he s ec o n dar y e n d p oi nts, M S A- Q o L m ot or s u bscale a n d n o n- m ot or s u bscal e s c ores, U M S A R S 
Part I a n d P art II t otal s c ore, P GI- S, C GI- S, U M S A R S P art III, a n d U M S A R S Part I V are
c ha n ge-fr o m- baseli ne e n d p oi nts a n d will be a nal y ze d f or mI T T s u bje cts usi n g t he s a me 
strate g y as des cri be d f or t he pri mar y esti m a n d as t he pri mar y e n d p oi nt. T h e U M S A R S Part I 
a n d Part II t ot al sc ore will e xcl u de ite m 1 1 fr o m Part I (s e x ual f u ncti o n).
T he ot her s ec o n dar y e n d p oi nt, t he C GI-I, d oes n ot h a ve a bas eli ne val ue. T h e esti ma n d f or t his 
e n d p oi nt will p urs ue a h y p ot h eti cal strate g y of esti m ati n g t h e effe ct of B H V- 3 2 4 1 relati ve t o 
place b o h a d all s u bjects sta y e d o n tre at m e nt. T h e a nal ysis will us e t he mI T T p o p ulati o n.  T he 
p o p ulati o n s u m mar y will be t h e differe n ce i n t he C GI-I bet wee n pl ace b o a n d B H V- 3 2 4 1
treat e d s u bjects at t he Wee k 4 8 visit. T h e s u m mar y will be c o m p ute d usi n g a n a nal ysis of 
varia nce, t hat will i ncl u de fi xe d eff ect f act ors f or tr e at me nt gr o u p, baseli ne C GI- S s c ore, a n d 
ra n d o miz ati o n str ata ( M S A- C or M S A- P, P ossi ble or Pr o ba ble M S A dia g n osis a n d c o u ntr y).
I nterc urre nt e ve nts will be ha n dle d b y o nl y usi n g t he o n-treat me nt d ata.
F urt her d etails o n t he se c o n dar y a nal ys es are pr o vi d e d i n t he S A P.
9. 4. 4
E xt e n si o n P h a s e A n al y si s
9. 4. 5
A dj u st m e nt f or M ulti pli cit y
T y pe- 1 err or will be c o ntr olle d f or t he pri mar y a n d k e y s ec o n dar y effi cac y e n d p oi nts b y t esti n g 
t he m wit h a gat e- kee pi n g pr o ce d ure. T he pri mar y e n d p oi nt will b e test e d at a t w o-si de d al p ha 
le vel of 0. 0 5. If t his test is si g nific a nt, t h e n t he ke y s ec o n dar y efficac y e n d p oi nts will be t este d 
u na dj uste d p- val ues f or t he ke y s ec o n dar y e n d p oi nts will be pres e nte d o nl y f or d escri pti v e 
p ur p os es.
N o atte m pt will b e ma d e t o a dj ust f or m ulti plicit y w he n testi n g t he n o n -ke y se c o n dar y or 
 e n d p oi nts. A n y e n d p oi nts s u bjecte d t o si g nifica n ce t esti n g are e val u ate d at a n 
u na dj uste d t w o -si de d al p ha le vel of 0. 0 5.
9. 4. 6
Mi s si n g D at a
If m ore t ha n 1 0 % of t he s u bjects dis c o nti n u e, t he n t h e missi n g dat a will b e m ulti pl y i m p ut e d 
f or t he pri m ar y e n d p oi nt usi n g a c o p y i n cre m e nt fr o m refere n ce met h o d. 
C CI
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 9 7  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
9. 4. 7
A n al y si s of S af et y
T he I n vesti g at ors det er mi ne t he i nte nsit y of A Es a n d t he rel ati o ns hi p of A Es t o st u d y t hera p y. 
T he I n vesti g at o
of t he M e dic al Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A) a vaila bl e. A Es will be 
pres e nte d b y s yste m or g a n class a n d pref erre d t er m, or dere d b y t he o v erall fr e q ue nc y of e ve nts.  
If a s u bject h a d a n a d verse e ve nt wit h differ e nt i nte nsities o ver ti me, t he n o nl y t he greatest 
i nte nsit y is re p orte d. 
A Es are ta b ul ate d i n all treate d s u bje cts.  All de at hs a n d S A Es are liste d f or e nr olle d s u bjects 
wit h o ut re gar d t o o ns et. 
T he fre q ue n cies of t he f oll o wi n g safet y e ve nts are s u m mari ze d b y tr eat me nt gr o u p a n d o v erall 
f or treat e d s u bjects:  S A Es; all A Es, n o n-s eri o us A Es; A Es b y i nte nsit y; A Es b y relate d ness 
a n d cli nicall y rele va nt la b orat or y a b n or m alities. 
Gra p hi cal a n d ta b ular dis pla ys of o n-tr eat me nt li ver f u ncti o n t est res ults ar e pr o vi de d. 
Safet y will b e prese nt e d s e parat el y f or t h e d o u ble- bli n d p hase a n d f or t he o p e n-la bel e xt e nsi o n 
p hase, o verall a n d b y ra n d o mize d ar m. 
9. 5 
S c h e d ul e of A n al y s e s 
T he first s c he d ule d u n bli n de d a nal ysis will be t he pri mar y a nal ysis, w hic h will b e c o n d uct e d 
after t h e last s u bj ect c o m pletes t heir We e k 4 8 visit a n d t he dat a base has bee n l oc ke d.  T his will 
s u m mariz e all effic ac y, safet y, la b or at or y a n d ot her data c olle cte d t hr o u g h t he e ntire st u d y. I n 
a d diti o n, d ata ma y be l oc ke d, bli n de d a n al yses c o n d ucte d, a n d r e p orts pr o d uce d as re q uire d t o 
s u p p ort safet y m o nit ori n g or re g ulat or y re q uire m e nts. 
I n a d diti o n t o t he a b o ve, a D at a M o nit ori n g C o m mitt ee (s ee Secti o n 1 0. 2) will re vie w effica c y 
a n d s afet y data o n a peri o dic b asis, wit h acti vities f ull y des cri be d i n a D M C C harter. 
A fi nal a nal ysis will be c o n d ucte d at t h e e n d of t h e o pe n-la bel e xt e nsi o n p has e.
1 0 E T HI C S A N D R E S P O N SI BI LI TI E S
1 0. 1 
G o o d Cli ni c al Pr a cti c e 
T his st u d y will be c o n d uct e d i n c o m pli a nce wit h t he pr ot oc ol, G o o d Cli nical Practice ( G C P), 
G o o d La b or at or y Practice ( G L P), I nt er nati o nal C o nf ere nce o n Har m o nizati o n g ui d eli n es , a n d 
all a p plic a ble re g ulati o ns, i ncl u di n g t he Fe d eral F o o d, Dr u g a n d C os metic Act, U. S. a p plica ble 
C o de of Fe d eral R e g ulati o ns (title 2 1), a n y I E C re q uire me nts relati ve t o cli nical st u dies. T he 
st u d y will als o be c o n d uct e d i n c o m pli a nce wit h t he rec o m m e n dati o ns lai d d o w n i n t he m ost 
rece nt v ersi o n of t he D eclarati o n of Helsi n ki, wit h t h e e xce pti o n t h at re gistrati o n of s uc h P hase 
1 trials i n a p u bli cl y accessi ble d ata b ase is n ot m a n d at or y. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa ge 9 8  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
T his st u d y will be c o n d uct e d i n c o m pli a nce wit h t he pr ot oc ol. T h e pr ot oc ol, a n y a m e n d me nts 
a n d t he i nf or me d c o nse nt f or m(s) will re cei v e I nstit uti o nal R e vie w B oar d/I n de pe n de nt Et hics 
C o m mittee (I R B/I E C) a p pr o v al/f a v ora ble o pi ni o n pri or t o i nitiati o n of t h e st u d y. 
All s eri o us breac h es m ust be re p ort e d t o Bi o h a ve n ( or desi g nee) i m me diatel y. A seri o us br eac h 
is a breac h of t he c o n diti o ns a n d pri n ci pl es of G C P i n c o n necti o n wit h t h e st u d y or pr ot oc ol, 
w hic h is li kel y t o aff ect, t o a si g nifica nt d e gree, t he s afet y or p h ysic al or m e ntal i nte grit y of t h e 
patie nts of t he st u d y or t h e s cie ntific v al ue of t he st u d y. 
St u d y pers o n nel i n v ol v e d i n c o n d u cti n g t his st u d y will be q ualifi e d b y e d ucati o n, trai ni n g, a n d 
e x perie n ce t o perf or m t heir res pecti ve tas k(s). 
T his st u d y will n ot use t he ser vi ces of st u d y pers o n n el w here s a ncti o ns ha ve be e n i n v o ke d or 
w here t here has be e n scie ntifi c mis c o n d u ct or fra u d ( e. g., l oss of me dic al lice ns ure, 
de bar me nt). 
1 0. 2 
D at a M o nit ori n g C o m mitt e e
A n i n de pe n de nt D ata M o nit ori n g C o m mitt ee ( D M C) will be est a blis he d f or t his st u d y a n d its 
acti viti es, pr ocess es a n d g ui da nce f or t he o v ersi g ht a n d a d here nc e t o D M C practi ces will b e 
descri be d i n a se parat e D M C C harter. T h e D M C will be c o m p os e d of at least 2 i n de pe n d e nt 
p h ysicia ns a n d 1 i n d e pe n de nt statisticia n. I n t his st u d y, t he maj or res p o nsi biliti es of t he D M C 
will be t o m o nit or t he be n efit/ris k of B H V- 3 2 4 1, t o ass ess w het her t here are u na cce pta bl e 
s afet y fi n di n gs after a d mi nistrati o n of B H V- 3 2 4 1 t hat re q uire m o dif yi n g or st o p pi n g t he st u d y 
a n d p ote ntiall y t o a dj u dicate st u d y dr u g-relat e d ness of S A Es a n d deat hs t hat are u ne x pecte d 
a n d/ or at y pical f or parti ci pa nts wit h M S A. 
1 0. 3 I n stit uti o n al R e vi e w B o ar d/I n d e p e n d e nt Et hi c s C o m mitt e e 
T he I n vesti g at ors a gree t o pr o vi de t he I E C wit h all a p pr o priate d o c u me nts, i ncl u di n g a c o p y of 
t he pr ot oc ol/a me n d m e nts, I C Fs, a d v ertisi n g te xt (if a n y), I n vesti gat or br o c h ure (if a n y) a n d a n y 
ot her writt e n i nf or m ati o n pr o vi de d t o st u d y s u bj ects. T he tri al will n ot be gi n at a site u ntil t he 
I n vesti gat ors ha v e o btai ne d t he I E C fa v ora ble writte n a p pr o vals f or t he a b o ve- me nti o ne d st u d y 
d oc u me nts. A pr o perl y e xec ut e d writt e n I C F s hall be rea d, si g ne d a n d d ate d b y e ac h s u bje ct 
pri or t o e nt eri n g t h e tri al or pri or t o p erf or mi n g a n y st u d y pr oce d ure.  
I n t he e ve nt t hat t he pr ot oc ol is a me n de d, t he re vis e d pr ot oc ol m ust b e a p pr o ve d b y t he I E C 
pri or t o its i m ple me nt ati o n, u nless t he c h a n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve as pe cts 
of t he tri al. If a re vise d I C F is i ntr o d uc e d d uri n g t h e st u d y, t he ne w versi o n of t h e I C F m ust be 
be o btai n e d.  
a me n d m e nts (if a n y) b ef ore i nitiati n g t h e st u d y.  
I C Fs t o re g ul at or y a ut h orities w he n necessar y. 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa ge 9 9 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1 0. 4
I nf or m e d C o n s e nt
I n vesti gat ors m ust e ns ure t hat patie nts, or, i n t h os e sit uati o ns w here c o nse nt ca n n ot be gi v e n b y 
patie nts, t heir le gall y ac ce pt a ble r e prese nt ati v es, are clearl y a n d f ull y i nf or me d a b o ut t h e 
p ur p os e, p ote nti al ris ks, a n d ot h er critical iss ues re gar di n g cli nical st u dies i n w hi c h t he y 
v ol u nteer t o partici p ate.
Bi o ha ve n ( or desi g n ee) will pr o vi de t h e I n vesti g at or wit h a n a p pr o pri ate (i.e., Gl o bal or L ocal) 
s a m ple i nf or me d c o ns e nt f or m w hic h will i ncl u de all ele m e nts re q uir e d b y I C H, G C P a n d 
a p plic a ble r e g ulat or y r e q uire me nts. T h e s a m pl e i nf or me d c o ns e nt f or m will a d here t o t he 
et hic al pri n ci pl es t hat ha v e t heir ori gi n i n t he Declar ati o n of Helsi n ki.
Bef ore t he p ote ntial s u bj ect has u n der g o n e a n y st u d y-relat e d Scree ni n g pr o ce d ures, t h e nat ur e 
of t he st u d y a n d t h e p ote ntial ris ks ass ociate d wit h it will be e x plai n e d t o t h e s u bject, a n d t he 
s u bject will be gi v e n a n o p p ort u nit y t o as k q uesti o ns t o his or her s atisfacti o n. Aft er t he 
q uesti o ns are a ns w ere d, b ut bef ore pr ocee di n g f urt her, t he s u bject m ust rea d, si g n a n d dat e a n 
I R B/I E C a p pr o ve d writte n i nf or me d c o ns e nt f or m. T he si g ne d a n d date d I C F will b e retai ne d at 
A n y re visi o ns t o t he pr ot o c ol or I C F will b e re vi e we d a n d a p pr o ve d b y t h e I R B/I E C a n d 
s u bjects will b e i nf or m e d of I C F c ha n ges a n d d oc u m e nt c o nti n ui n g c o ns e nt b y si g ni n g a n d 
dati n g t h e re vise d v ersi o n of t he I C F.
di a n or le g all y acce pta bl e 
re pres e ntati ve, a n d t he patie nt s u bse q ue ntl y b ec o m es ca pa bl e of ma ki n g a n d c o m m u nic ati n g 
t heir i nf or me d c o ns e nt d uri n g t he st u d y, t he n t h e c o nse nt m ust a d diti o nall y be o btai n e d fr o m 
t he patie nt.
T he i nf or m e d c o ns e nt f or m m ust als o i ncl u de a stat e me nt t h at Bi o h a ve n a n d its re pres e nt ati v es 
a n d re g ulat or y a ut h orities ma y ha ve direct access t o patie nt rec or ds.
T he ri g hts, s afet y, a n d w ell- bei n g of st u d y patie nts are t he m ost i m p ort a nt c o nsi d erati o ns a n d 
s h o ul d pre vail o v er i nt erests of s cie nc e a n d s oci et y.
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 1 0 0 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1 0. 5
C a s e R e p ort F or m s
A n I n vesti gat or is re q uire d t o pre p are a n d mai ntai n a de q uate a n d acc ur ate case hist ories 
desi g ne d t o re c or d all o bs er vati o ns a n d ot her data perti ne nt t o t h e i n vesti g ati o n of eac h st u d y 
patie nt. D ata r e p orte d o n t h e C R F t hat are deri ve d fr o m s o urce d oc u m e nts m ust be c o nsiste nt 
wit h t he s o urce d o c u me nts or t he dis cre p a nci es m ust be e x plai ne d.
Electr o nic C R Fs will b e pre pare d f or all d ata c oll ecti o ns fiel ds w he n E D C is bei n g us e d.
T he c o nfi d e nti alit y of rec or ds t hat c o ul d i de ntif y pati e nts m ust be pr ot ect e d, res pecti n g t he 
pri vac y a n d c o nfi de ntialit y r ul es i n ac c or da nc e wit h t he a p pli ca bl e re g ulat or y re q uir e me nt(s).
T he I n vesti g at or m ust r etai n a c o p y of t h e C R Fs, i n cl u di n g rec or ds of c ha n ges a n d c orrecti o ns. 
If E D C is bei n g use d, si g nat ur es will be o btai ne d ele ctr o nic all y a n d a c o p y of t h e el ectr o nic 
C R Fs will be pr o vi de d ( or t h e dat a fr o m t h e C R Fs) f or f ut ure refere n ce.
1 0. 6
R e c or d s M a n a g e m e nt a n d R et e nti o n
I n acc or da nce wit h t h e pri nci ples of G C P a n d G L P, t he st u d y ma y be i ns pect e d b y re g ulat or y 
a ut h orities, t he S p o ns or a n d C R O. T he S p o ns or ( or s pecifi e d desi g ne e) is e ntitle d t o ac cess 
i nf or mati o n a b o ut t he stat us of t he st u d y a n d t o re vie w t he ori gi nal d oc u m e nts of t he st u d y.
T he I n vesti g at or m ust r etai n all st u d y rec or ds a n d s o urce d oc u m e nts f or t he ma xi m u m re q uir e d 
b y t he a p plica ble re g ul ati o ns a n d g ui deli nes, or i nstit uti o n pr oce d ur es or f or t he peri o d of ti m e 
s pecifie d b y t he s p o ns or, w hic he ver is l o n g er. T he I n vesti gat or m ust c o nt act t he S p o ns or pri or 
t o destr o yi n g a n y r ec or ds ass ociat e d wit h t his st u d y if n ot wit hi n t h ese g ui deli nes.
Bi o ha ve n will n otif y t he I n vesti gat ors w he n t he st u d y files f or t his st u d y ar e n o l o n ger n ee de d.
If t he I n vesti g at or wit h dr a ws fr o m t he st u d y (i.e., r etire me nt, r el oc ati o n), t h e rec or ds s hall be 
tra nsferre d t o a m ut uall y a gr ee d u p o n desi g n ee.  N oti ce of s uc h tra nsfer will be gi v e n i n writi n g 
t o Bi o ha ve n.
It is t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure t h at t he c urre nt dis p ositi o n rec or d of 
i n vesti gati o nal pr o d uct (t h ose s u p plie d b y t he s p o ns or) is mai nt ai ne d at eac h st u d y site w her e 
t he st u d y dr u g is i n ve nt orie d a n d dis pe ns e d. Rec or ds or l o gs m ust c o m pl y wit h a p plica ble 
re g ulati o ns a n d g ui deli nes a n d s h o ul d i ncl u de:
A m o u nt of st u d y dr u g recei ve d a n d place d i n st ora ge area;
La bel I D n u m b er or batc h n u m ber or Kit n u m ber as s pecifie d f or t he pr ot o c ol;
C CI


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa g e 1 0 1  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
 A m o u nt dis pe ns e d t o a n d r et ur ne d fr o m eac h patie nt; 
 A m o u nt tra nsferre d t o a n ot her area or site f or dis pe nsi n g or st ora ge if a p plic a ble;
 A m o u nt of dr u g l ost or w aste d; 
 A m o u nt destr o ye d at t he site if a p plica ble; 
 A m o u nt ret ur ne d t o s p o ns or, if a p plica ble; 
 Retai n e d s a m pl es f or bi oa vaila bilit y/ bi oe q ui val e nce, if a p pli ca bl e;
Rec or d of dat es a n d i nitials of pers o n nel res p o nsi ble f or I M dis pe nsi n g a n d acc o u nta bilit y.
1 0. 7 
S o ur c e D o c u m e nt ati o n 
A n I n vesti gat or is re q uire d t o pre p are a n d mai ntai n a de q uate a n d acc ur ate case hist ories 
desi g ne d t o re c or d all o bs er vati o ns a n d ot her data perti ne nt f or all s u bj ects o n st u d y.  
If s o urce d oc u me nts are cre ate d t o s u p p ort t he c oll ecti o n of st u d y i nf or m ati o n, t his m ust be 
retai n e d wit h t h e ot her perti ne nt me dical rec or d f or e ac h patie nt f or v erific ati o n of d ata p oi nts, 
u nless ot her wise i nstr ucte d b y t h e S p o ns or ( or s pecifie d desi g ne e) t o e nter dat a dire ctl y o n t he 
C R F. 
1 0. 8 
St u d y Fil e s a n d R e c or d R et e nti o n 
T he S p o ns or d oes n ot re q uire ori gi nal d oc u me nts t hat ha ve alrea d y be e n s ca n ne d a n d e nt ere d 
i nt o t he e T M F s yste m be f or w ar de d t o t he S p o ns or. A n y ori gi nal d oc u me nts (i. e., 1 5 7 2, si g ne d 
fi na nci al discl os ure, si g ne d I C F, etc.) will be r etai ne d i n t he re g ulat or y bi n der at t he st u d y site. 
T he C R O will d o a fi nal T M F rec o nciliati o n t o e ns ur e all st u d y files a n d r e g ulat or y d oc u me nts 
ha ve bee n c orrectl y u pl oa d e d t o t h e T M F pri or t o t h e cl ose or ter mi nati o n of t h e st u d y. A n y 
materials or d oc u me nts t o s u p p ort t he cli nical trial o utsi de of t he e T M F (i.e., rater trai ni n g 
ta pes) s h o ul d be m ai nt ai ne d b y t he C R O. T he S p o ns or will be c o ntacte d t o deter mi ne w het h er 
t he st u d y d oc u m e nts/ m aterials t h at are r etai ne d o utsi de of t he T M F will b e f or war de d t o t he 
S p o ns or, destr o ye d or ke pt at t he C R O or at a n ot her facilit y f or a l o n ger peri o d of ti m e at t he 
S p o ns or's e x pe nse. 
1 1 A M E N D M E N T S 
Pr ot oc ol m o dificati o ns, e xce pt t h os e i nte n de d t o re d uce i m me di ate ris k t o st u d y s u bjects, ma y 
be ma de o nl y b y t he S p o ns or ( or s pecifie d desi g nee). A pr ot oc ol c ha n g e i nt e n de d t o eli mi nat e 
a n a p pare nt i m me diate ha zar d t o s u bj ects m a y be i m ple me nte d i m me diat el y, pr o vi de d t he 
I R B/I E C is n otifie d wit hi n 5 da ys. 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa g e 1 0 2  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
A n y per ma ne nt c ha n ge t o t he pr ot o c ol m ust b e ha n dl e d as a pr ot oc ol a m e n d me nt. T he writte n 
a me n d m e nt m ust b e s u b mitte d t o t he I R B/I E C a n d t h e I n vesti gat or m ust a wait a p pr o val bef ore 
i m ple me nti n g t he c ha n ges. T he S p o ns or will s u b mit pr ot oc ol a me n d m e nts t o t h e a p pr o priate 
re g ulat or y a ut h orities f or a p pr o val. 
If i n t he j u d g me nt of t he I R B/I E C, t he I n vesti gat or, a n d/ or t he S p o ns or, t he a me n d m e nt t o t he 
pr ot oc ol s u bsta ntiall y c ha n g es t he st u d y desi g n a n d/ or i ncreas es t h e p ote ntial ris k t o t he s u bj ect 
a n d/ or has a n i m pact o n t he s u bje ct's i n v ol ve me nt as a st u d y parti ci pa nt, t he c urre ntl y a p pr o ve d 
writte n i nf or me d c o ns e nt f or m will re q uire si mil ar m o dificati o n. I n s uc h c ases, i nf or me d 
c o nse nt will b e re ne we d f or s u bje cts e nr olle d i n t he st u d y bef ore c o nti n ue d p artici pati o n. 
1 2 S T U D Y R E P O R T A N D P U B LI C A TI O N S 
T he S p o ns or ( or s pecifie d d esi g nee) is res p o nsi bl e f or pre pari n g a n d pr o vi di n g t h e a p pr o priate 
re g ulat or y a ut h orities wit h cli nical st u d y r e p orts acc or di n g t o t he a p pli ca bl e re g ulat or y 
re q uire m e nts.  
T he p u bli cati o n p oli c y of t he S p o ns or is disc uss e d i n t he I n vesti g at or's Cli ni cal R es earc h 
A gree me nt. 
1 3 S T U D Y DI S C O N TI N U A TI O N 
B ot h t he S p o ns or a n d t he Pri n ci pal I n vesti g at or reser ve t he ri g ht t o t er mi n ate t he st u d y at t he 
Pri nci pal I
t h e S p o ns or ( or s pecifie d 
desi g nee) will i nf or m t he a p pr o pri ate r e g ulat or y a ut h orities of t h e ter mi nati o n of t h e st u d y a n d 
t he reas o ns f or its t er mi n ati o n, a n d t he Pri nci pal I n v esti gat or will i nf or m t he I R B/I E C of t he 
s a me. I n ter mi nati n g t h e st u d y, t he S p o ns or a n d t he Pri nci pal I n v esti gat or will ass ure t hat 
i nt erests. 
1 4 C O N FI D E N TI A LI T Y 
All i nf or mati o n ge n erate d i n t his st u d y is c o nsi dere d hi g hl y c o nfi d e nti al a n d m ust n ot be 
dis cl os e d t o a n y p ers o n or e ntit y n ot dir ectl y i n v ol v e d wit h t he st u d y u nl ess pri or writte n 
c o nse nt is gai n e d fr o m t h e S p o ns or ( or s pecifie d desi g nee). H o we ver, a ut h ori ze d re g ulat or y 
officials, I R B/I E C pers o n nel, t he S p o ns or a n d its a ut h orize d re pr es e ntati ves are all o we d f ull 
access t o t h e rec or ds. 
I de ntifi cati o n of s u bjects a n d C R Fs s hall be b y S u bje ct n u m bers o nl y. If r e q uire d, t he s u bject's 
f ull na m e ma y b e ma de k n o w n t o a n a ut h orize d r e g ulat or y a g e nc y or ot h er a ut h ori ze d offi cial.  
T he S p o ns or ma y a p pr o ve t he s hari n g of de-i de ntifie d data fr o m t his st u d y t o be ma de 
a vail a ble t o res earc h ers f or t he p ur p ose of a d v a nci n g t he u n dersta n di n g of ne ur ol o gic or 
ps yc hiatri c ill ness, rati n g s c ales, or tri al m et h o d ol o g y f or t he affecte d p o p ul ati o n. I n a n y 
p u blicati o n of t his data, c o nfi de ntialit y of i n di vi d ual s u bjects will b e pr ote cte d. 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 1 0 3 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
1 5
A P P E N DI C E S
1 5. 1
A P P E N DI X I - N a m e s of St u d y P er s o n n el
S p o ns or:
Bi o ha ve n P h ar mace uticals, I n c.
2 1 5 C h urc h Stre et
Ne w Ha ve n, C T 0 6 5 1 0
M e dical M o nit ors a n d M e dical 
M o nit or B ac k- u p:
E U/ E M E A:
E m ail: 
P h o n e: 
N o rt h A m eric a:
E m ail: 
P h o n e: 
Ba c k- u ps:
Bi o ha v e n P h ar mac e uticals, I nc. 
Ne w Ha ve n, C o n nectic ut 0 6 5 1 0 
U S A
E m ail :
P h o n e: 
Bi o ha ve n P h ar mac e uticals, I nc.
Ne w Ha ve n, C o n ne ctic ut 0 6 5 1 0
U S A
E m ail: 
P h o n e: 
Cli nical R esearc h
Or ga nizati o n:
P P D
P P D
P P D
P P D
C CI
P P D
P P D
P P D
P P D
P P D
P P D
P P D
C CI
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
P P D
P P D
P P D
P P D
P P D
C CI
P P D


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa g e 1 0 4  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
1 6 R E F E R E N C E S CI T E D 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7 
C o nfi de nti al  
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y 
Pa g e 1 0 5  of 1 0 6  
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


B H V 3 2 4 1- 3 0 1; Cli nical Pr ot o c ol V 0 7
C o nfi de nti al
B H V- 3 2 4 1 i n A d ult S u bje cts wit h M ulti ple S yste m Atr o p h y
Pa g e 1 0 6 of 1 0 6
 
A p pr o v e d Versi o n 0 7; 2 0 J a n 2 0 2 1
C LI NI C A L P R O T O C O L A P P R O V A L F O R M
Pr ot o c ol Title: A R a n d o mize d, D o u ble- Bli n d, Pl a ce b o C o nt r olle d, P ar allel- Gr o u p St u d y t o E v al u ate t he 
Effic ac y a n d S af et y of B H V- 3 2 4 1 i n S u bjects wit h M ulti ple S yste m Atr o p h y ( M S A)
St u d y N o: B H V 3 2 4 1- 3 0 1
Dr aft O ri gi n al Pr ot o c ol D ate: 1 8 D ec 2 0 1 8
Pr ot o c ol Versi o n N o: V 0 7
Pr ot o c ol Ve rsi o n D ate: 2 0 J a n 2 0 2 1
T his st u d y pr ot oc ol w as s u bje ct t o critical re vie w a n d has bee n a p pr o ve d b y t he a p pr o pri ate 
pr ot oc ol re vie w c o m mittee of t h e s p o ns or.  T he i nf or mati o n c o ntai ne d i n t his pr ot oc ol is 
c o nsiste nt wit h:
-
T he c urre nt ris k- be nefit e val uati o n of t he i n vesti g ati o nal pr o d uct.
-
T he m oral, et hical a n d s cie ntifi c pri nci ples g o ver ni n g cli ni cal r esearc h as s et o ut i n t h e 
D eclarati o n of Helsi n ki, a n d pri nci ples of G C P as des cri be d i n 2 1 C F R parts 5 0, 5 4, 5 6 
a n d 3 1 2 a n d ac c or di n g t o a p plic a ble l ocal re q uir e me nts.
-
T he I n vesti g at or will be s u p pli e d wit h details of a n y si g nifica nt or ne w fi n di n gs, 
i ncl u di n g a d verse e v e nts, relati n g t o treat me nt wit h t he i n vesti g ati o n al pr o d uct.
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D ate
A ut h or/ Pr ot oc ol Writer:
 
 
Bi o ha v e n P h ar mac e uticals
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Cli nical O perati o ns:
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Bi ostatistics:
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M e dical Lea d:
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Re g ulat or y Affairs:
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