A 6-Month Extension Study Following Protocol VMALS-002-2 (A Phase 2a, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess the Safety of Engensis in Participants With Amyotrophic Lateral Sclerosis)
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis
Sponsor: Helixmith Co., Ltd.

 
 
Pr ot oc ol Title:   
A 6-M o nt h  E xte nsi o n St u d y F oll o wi n g Pr ot oc ol V M A L S- 0 0 2- 2 
( A P h ase 2 a, D o u ble- Bli n d , R a n d o mize d, Pl ace b o - C o ntr olle d, 
M ulti ce nter St u d y t o Assess t he S afet y  of E n ge nsis i n P artici p a nts  
wit h A m y otr o p hic L ater al Scler osis ) 
Pr ot oc ol N u m ber : 
V M A L S - 0 0 2- 2 b 
Versi o n N u m ber:  
1. 1 
A p pr o v al D ate:   
1 2 Oct 2 0 2 1 
C o m p o u n d:   
E n ge nsis 
St u d y P h ase:    
2a 
S h ort Title:  
A 6- M o nt h E xte nsi o n St u d y  t o Assess t he L o n g- T er m Safet y of E n g e nsis 
i n A m y otr o p hic Lateral Scler osis  
Acr o n y m:  
R E Vi V A L S - 1 B 
Re g ul at or y A ge nc y I de ntifier N u m ber : 
I N D 1 5 7 6 1  
S p o ns or C o nt act: 
Tele p h o ne N o.: 8 5 8- 8 1 5- 1 3 1 0 
 
 
Versi o n  
D ate  
Versi o n 1. 1 
1 2 Oct 2 0 2 1 
 
 
 
 
 
 
 
 
 
 
DI S C L O S U R E S T A T E M E N T  
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, U S C o de of Fe deral Re g ulati o ns 
a p plica ble t o cli nical st u dies, pri nci ples of I C H G o o d Cli nical Practice , the Declarati o n of 
Helsi n ki, a n d all a p plica ble re g ulat or y re q uire m e nts. T his pr ot oc ol is t he c o nfi de ntial 
i nf or mati o n of Heli x mit h C o. Lt d. a n d is i nte n de d s olel y f or t he g ui da nce of t he cli nical 
i n vesti gati o n. T his pr ot oc ol ma y n ot be discl ose d t o parties n ot ass ociate d wit h t he cli nical 
i n vesti gati o n or use d f or a n y p ur p ose wit h o ut t he pri or writte n c o nse nt of Heli x mit h.  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 
Fi nal : 1 2 Oct 2 0 2 1 
 
T a ble of C o nte nts  
1.  
P R O T O C O L S U M M A R Y  ............................................................................................ 7 
1. 1.  
S y n o psis ........................................................................................................................ 7 
1. 2.  
St u d y Sc he ma ............................................................................................................. 1 0  
1. 3.  
Sc he d ule of A cti vities ( S o A) ...................................................................................... 1 1  
2.  
I N T R O D U C TI O N ...................................................................................................... 1 3 
2. 1.  
St u d y Rati o nale ........................................................................................................... 1 3  
2. 2.  
Bac k gr o u n d ................................................................................................................. 1 3  
2. 2. 1.  
Pat h o p h ysi ol o g y of A m y otr o p hic Lateral Scler osis ................................................... 1 3  
2. 2. 2.  
C urre nt Treat me nt O pti o ns, Treat me nt A p pr o ac h es, a n d U n met Cli nical 
Nee d  ............................................................................................................................ 1 5 
2. 2. 3.  
He pat oc yte Gr o wt h Fact or f or Treat me nt of A m y otr o p hic Lateral Scler osis  ............ 1 6 
2. 2. 4.  
E n ge nsis a n d V M 2 0 2 .................................................................................................. 1 7  
2. 2. 5.  
N o ncli nical Data  ......................................................................................................... 1 8 
2. 2. 6.  
Cli nical Data  ............................................................................................................... 1 8 
2. 2. 6. 1.  
P hase 1/ 2 St u d y i n Partici pa nts wit h A m y otr o p hic Lateral Scler osis ........................ 1 9  
2. 2. 6. 2.  
Ot her E n ge nsis Cli nical St u dies  ................................................................................. 1 9 
2. 3.  
Be nefit/ Ris k Assess me nt  ............................................................................................ 2 0 
2. 3. 1.  
Ris k Assess me nt  ......................................................................................................... 2 0 
2. 3. 2.  
Be nefit Assess me nt  ..................................................................................................... 2 1 
2. 3. 3.  
O verall Be nefit / Ris k C o ncl usi o ns  ............................................................................ 2 1 
3.  
O BJ E C TI V E S A N D E N D P OI N T S  ............................................................................ 2 2 
4.  
S T U D Y D E SI G N  ....................................................................................................... 2 4 
4. 1.  
O verall Desi g n  ............................................................................................................ 2 4 
4. 2.  
Scie ntific Rati o nale f or St u d y Desi g n ........................................................................ 2 4  
4. 3.  
J ustificati o n f or D ose .................................................................................................. 2 4 
4. 4.  
Ra n d o mizati o n ............................................................................................................ 2 4  
4. 5.  
E n d of St u d y Defi niti o n .............................................................................................. 2 4  
4. 6.  
St u d y C o m pleti o n ....................................................................................................... 2 4  
4. 7.  
C o m plete d Partici pa nts  ............................................................................................... 2 4 
5.  
S T U D Y P O P U L A TI O N  ............................................................................................. 2 5 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 
Fi nal : 1 2 Oct 2 0 2 1 
5. 1.  
N u m ber of Partici pa nts ............................................................................................... 2 5  
5. 2.  
Partici pa nt I de ntificati o n  ............................................................................................ 2 5 
5. 3.  
Lifest yle C o nsi derati o ns ............................................................................................. 2 5  
5. 3. 1.  
Meals a n d Dietar y Restri cti o ns  ................................................................................... 2 5 
5. 3. 2.  
Caffei ne, Al c o h ol, a n d T o bacc o ................................................................................. 2 5  
5. 3. 3.  
S u p ple me nts ................................................................................................................ 2 5  
5. 3. 4.  
Acti vit y  ....................................................................................................................... 2 5 
6.  
S T U D Y I N T E R V E N TI O N  ........................................................................................ 2 6 
6. 1.  
Meas ures t o Mi ni mize Bias  ........................................................................................ 2 6 
6. 1. 1.  
Ra n d o mizati o n ............................................................................................................ 2 6  
6. 1. 2.  
Bli n di n g ...................................................................................................................... 2 6  
6. 1. 3.  
Mai nte na nce of t he Bli n d  ............................................................................................ 2 6 
6. 2.  
C o nc o mita nt T hera p y ................................................................................................. 2 6  
6. 3.  
Pri or a n d C o nc o mita nt Me dicati o ns, Treat me nts, a n d Pr oce d ures ............................. 2 6  
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D 
P A R TI CI P A N T WI T H D R A W A L  ............................................................................. 2 8 
7. 1.  
Partici pa nt Wit h dra w al/ Disc o nti n uati o n  .................................................................... 2 8 
7. 2.  
L ost t o F oll o w- u p ....................................................................................................... 2 8  
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  ...................................................... 3 0 
8. 1.  
Safet y Assess me nts  ..................................................................................................... 3 0 
8. 1. 1.  
C o m plete P h ysical E xa mi nati o ns  ............................................................................... 3 0 
8. 1. 2.  
1 2- Lea d Electr ocar di o gr a ms  ....................................................................................... 3 0 
8. 1. 3.  
Vital Si g ns  .................................................................................................................. 3 0 
8. 1. 4.  
Cli nical La b orat or y Assess me nts  ............................................................................... 3 0 
8. 1. 5.  
Sl o w Vital Ca pacit y  .................................................................................................... 3 1 
8. 2.  
Ot her Assess me nts a n d Pr oce d ures  ............................................................................ 3 2 
8. 2. 1.  
Re vise d A m y otr o p hic Lateral Scler osis F u n cti o nal Rati n g........................................ 3 2  
8. 2. 2.  
Ha n d hel d D y na m o metr y ............................................................................................. 3 2  
8. 2. 3.  
Q ualit y of Life Assess me nt, Patie nt Re p orte d O utc o mes, a n d Cli nical 
Re p orte d O utc o mes .................................................................................................... 3 2  
8. 2. 3. 1.  
A m y otr o p hic Later al Scler osis Assess me nt Q uesti o n naire ........................................ 3 2  
8. 2. 3. 2.  
Patie nt Gl o bal I m pr essi o n of C ha n ge ......................................................................... 3 2  
8. 2. 3. 3.  
Cli nical Gl o bal I m pr essi o n of C ha n ge ....................................................................... 3 3  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 
Fi nal : 1 2 Oct 2 0 2 1 
8. 3.  
Treat me nt -e mer ge nt A d v erse E ve nts a n d Treat me nt -e mer ge nt Seri o us 
A d verse E v e nts  ........................................................................................................... 3 3 
8. 3. 1.  
Ti me Peri o d a n d Fr e q ue n c y f or C ollecti n g T E A E a n d T E S A E I nf or m ati o n ............. 3 3  
8. 3. 2.  
Met h o d of Detecti n g T E A Es a n d T E S A Es ................................................................ 3 3  
8. 3. 3.  
S A E Re p orti n g t o t he S p o ns or or Desi g nee ............................................................... 3 4  
8. 3. 4.  
A d verse E v e nts of S peci al I nt erest  ............................................................................. 3 4 
8. 3. 4. 1.  
A E SI C o nsi der e d Relate d t o A n gi o ge nesis ................................................................ 3 4  
8. 3. 4. 2.  
Ot her Me dical Pr o ble ms i n A L S Patie nts  ................................................................... 3 4 
8. 3. 4. 3.  
C O VI D -1 9 I nfecti o ns  ................................................................................................. 3 5 
8. 3. 5.  
F oll o w- u p of T E A Es, T E S A Es, a n d A E SIs ............................................................... 3 5  
8. 3. 6.  
Re g ulat or y Re p orti n g Re q uire me nts f or T E S A Es ...................................................... 3 5  
8. 3. 7.  
Heli x mit h’s  Res p o nsi bilit y ......................................................................................... 3 5 
8. 3. 8.  
Pre g na nc y a n d C o ntrace pti o n ..................................................................................... 3 6  
8. 3. 8. 1.  
Pre g na nc y T est ( W o me n of C hil d beari n g P ote ntial O nl y) a n d C o ntrace pti o n .......... 3 6  
8. 3. 8. 2.  
Pre g na nc y  ................................................................................................................... 3 6 
8. 3. 9.  
Disease -Rel ate d E ve nts a n d/ or Disease - R elate d O utc o mes N ot Q ualif yi n g as 
A Es or S A Es  ............................................................................................................... 3 7 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ....................................................................... 3 8 
9. 1.  
Sa m ple Size Deter mi nati o n  ........................................................................................ 3 8 
9. 2.  
P o p ulati o n f or A nal ysis: Safet y P o p ulati o n ................................................................ 3 8  
9. 3.  
Statistical A nal yses  ..................................................................................................... 3 8 
9. 3. 1.  
Pri mar y E n d p oi nts ...................................................................................................... 3 8  
9. 4.  
Data Safet y M o nit ori n g B oar d .................................................................................... 3 8  
1 0.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  .................................................................................................. 3 9 
1 0. 1.  
A p pe n di x 1. Re g ulat or y, Et hical, a n d St u d y O versi g ht C o nsi derati o ns..................... 3 9  
1 0. 1. 1.  
Re g ulat or y a n d Et hical C o nsi derati o ns ...................................................................... 3 9  
1 0. 1. 1. 1.  
I nstit uti o nal Re vie w B oar d  ......................................................................................... 3 9 
1 0. 1. 1. 2.  
I nf or me d C o nse nt Pr ocess  .......................................................................................... 3 9 
1 0. 1. 1. 3.  
O bli gati o ns of t he Heli x mit h a n d t he I n v esti gat or...................................................... 4 0  
1 0. 1. 2.  
Fi na ncial Discl os ur e  ................................................................................................... 4 0 
1 0. 1. 2. 1.  
C o nflict of I nt erest P olic y  ........................................................................................... 4 0 
1 0. 1. 2. 2.  
Fi na ncial Discl os ur e  ................................................................................................... 4 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
5 
Fi nal : 1 2 Oct 2 0 2 1 
1 0. 1. 3.  
Partici pa nt Selecti o n a n d I nf or me d C o nse nt Pr ocess ................................................. 4 1  
1 0. 1. 4.  
Data Pr otecti o n a n d C o nfi de ntialit y  ........................................................................... 4 1 
1 0. 1. 4. 1.  
C o nfi de ntialit y  ............................................................................................................ 4 2 
1 0. 1. 4. 2.  
Data  Pr otecti o n  ........................................................................................................... 4 2 
1 0. 1. 5.  
C o m mittee Str uct ure  ................................................................................................... 4 3 
1 0. 1. 5. 1.  
Data Safet y M o nit ori n g B oar d .................................................................................... 4 3  
1 0. 1. 6.  
Data Q ualit y Ass ur a nce  .............................................................................................. 4 3 
1 0. 1. 6. 1.  
Cli nical M o nit ori n g  .................................................................................................... 4 3 
1 0. 1. 6. 2.  
Access t o St u d y D oc u me nts a n d St u d y M o nit ori n g ................................................... 4 4  
1 0. 1. 6. 3.  
Q ualit y Ass ura nce a n d Q ualit y C o ntr ol ...................................................................... 4 4  
1 0. 1. 6. 4.  
Data Q ualit y  Ass ura n ce  .............................................................................................. 4 5 
1 0. 1. 6. 5.  
Data C ollecti o n a n d Ma n a ge me nt  Res p o nsi bilities  .................................................... 4 6 
1 0. 1. 6. 6.  
Pr ot oc ol De viati o ns .................................................................................................... 4 6  
1 0. 1. 6. 7.  
S o urce D oc u m e nts ...................................................................................................... 4 6  
1 0. 1. 7.  
Data  Ma na ge m e nt  ....................................................................................................... 4 7 
1 0. 1. 8.  
Rec or d kee pi n g a n d Rete nti o n  ..................................................................................... 4 7 
1 0. 1. 9.  
St u d y a n d Site Start a n d Cl os ure ................................................................................ 4 8  
1 0. 1. 1 0.  
P u blicati o n P olic y  ....................................................................................................... 4 9 
1 0. 1. 1 1.  
I ns ura nce ..................................................................................................................... 4 9 
1 0. 2.  
A p pe n di x 2. Treat me nt- E mer ge nt A d verse E ve nts: Defi niti o ns a n d 
Pr oce d ures f or Rec or di n g, E val uati n g, F oll o w- u p, a n d Re p orti n g ............................ 5 0  
1 0. 2. 1.  
Defi niti o n of T E A Es ................................................................................................... 5 0  
1 0. 2. 2.  
Criteria f or D efi ni n g a T E S A E  ................................................................................... 5 1 
1 0. 2. 3.  
Defi niti o n of T E S A E .................................................................................................. 5 2  
1 0. 2. 4.  
Rec or di n g a n d F oll o w- U p of T E A Es a n d T E S A Es  ................................................... 5 2 
1 0. 2. 5.  
Re p orti n g of T E S A Es ................................................................................................. 5 4  
1 0. 3.  
A p pe n di x 3. List of A b br e viati o ns a n d Defi niti o ns .................................................... 5 5  
1 0. 3. 1.  
A b bre viati o ns .............................................................................................................. 5 5  
1 0. 3. 2.  
Defi niti o ns  .................................................................................................................. 5 7 
1 0. 4.  
A p pe n di x 4. Re vise d A m y otr o p hic Lateral Scler osis F u ncti o nal Rati n g Scale ......... 5 8  
1 0. 5.  
A p pe n di x 5. A m y otr o p hic Lateral Scler osis Assess me nt Q uesti o n naire ................... 5 9  
1 0. 6.  
A p pe n di x 6. Patie nt Gl o bal I m pressi o n of C ha n ge a n d Cli nical I m pressi o n 
of C ha n ge .................................................................................................................... 6 4  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 
Fi nal : 1 2 Oct 2 0 2 1 
1 1.  
R E F E R E N C E S  ........................................................................................................... 6 6 
 
List of Fi g ures  
Fi g ure 1:  
M olec ular Mec ha nis ms of M ot or Ne ur o n I nj ur y i n A L S ........................................... 1 5  
Fi g ure 2:  
V M 2 0 2 C o nstr uct ....................................................................................................... 1 8  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
7 
Fi nal : 1 2 Oct 2 0 2 1 
1.  
P R O T O C O L  S U M M A R Y  
T he f oll o wi n g secti o ns prese nt a n o v er vie w of t he st u d y, st u d y sc he ma, a n d Sc he d ule of 
A cti vities ( S o A). A list of a b bre vi ati o ns is prese nt e d i n Secti o n 1 0. 3 , A p pe n di x 3. 
1. 1.  
S y n o psis  
Pr ot oc ol Title:  A 6 - M o nt h E xte nsi o n St u d y F oll o wi n g Pr ot oc ol V M A L S- 0 0 2- 2 ( A P has e 2a, 
D o u ble- Bli n d, Ra n d o mize d, Place b o- C o ntr olle d, M ultice nter St u d y t o Assess t he Safet y of 
E n ge nsis i n Partici pa nts wit h A m y otr o p hic Lateral Scler osis ) 
S h ort Title:   A 6- M o nt h E xte nsi o n St u d y t o Assess t he Safet y of E n ge nsis i n A m y otr o p hic 
Lateral Scler osis  
R ati o n ale: 
T he p ur p ose of t his st u d y is t o e val uate t he l o n g- ter m safet y of i ntra m us c ular (I M) a d mi nistrati o n 
of E n ge nsis i n Partici pa nts wit h A m y otr o p hic Lateral Scler osis ( A L S) w h o  were pre vi o usl y 
ra n d o mize d, r ecei ve d treat me nt, a n d c o m plete d t h e Da y 1 8 0 Visit of St u d y V M A L S- 0 0 2- 2. 
Safet y will be assesse d b y i nci de nces of treat me nt -e mer g e nt a d vers e e v e nts ( T E A Es) , 
treat me nt-e mer ge nt seri o us a d verse e ve nts (T E S A Es) , a d vers e e ve nts of s pecial i nterest ( A E SIs), 
a n d t he cli nicall y si g nifica nt la b orat or y v al ues. See t he ta ble bel o w f or a d diti o nal, e x pl orat or y 
e n d p oi nts. 
E n ge nsis c o ntai ns t he acti ve p har mace utical i n gre die nt V M 2 0 2, a n o vel ge n o mic c o m ple me ntar y 
de o x yri b o n ucleic aci d  ( c D N A) h y bri d h u ma n h e p at oc yte gr o wt h fact or ( H G F ) c o di n g se q ue nce 
( H G F- X 7) e x pressi n g t w o is of or ms of H G F, H G F7 2 8 a n d H G F 7 2 3, bei n g de vel o pe d b y Heli x mit h 
f or treat me nt of A L S. 
D ata fr o m H eli x mit h’s first cli nical trial i n A L S, t he P hase 1/ 2 st u d y ( V M A L S- 0 0 1) t hat 
i ncl u de d 1 8 Partici pa nts w h o wer e f oll o we d f or 9 m o nt hs, s u g geste d t hat tar gete d deli ver y of 
H G F t o m ot or ne ur o ns vi a i ntra m usc ular (I M) i njecti o ns of E n ge nsis was safe a n d w ell -t olerate d. 
Safet y assess me nts d uri n g t he st u d y i ncl u de d re p orts of 7 9 a d vers e e v e nts ( A Es) i n 
1 7 Partici pa nts ( 9 4. 4 %), i ncl u di n g 2 6 mil d i njecti o n site reacti o ns ( Gra de 1). Fi ve S A Es w ere 
re p orte d i n 3 Partici pa nts. O nl y a n i njecti o n site reacti on w as c o nsi dere d rel ate d t o st u d y 
treat me nt. F oll o wi n g i njecti o ns u ntil Da y 9 0, a platea u or a relati ve sl o wi n g i n t he decli ne of t he 
Re vise d A m y otr o p hic Lateral Scler osis F u n cti o n Rati n g ( A L S F R S - R) sc ores a n d m uscle 
stre n gt h was n ote d, s u g g esti n g a sl o wi n g of disease pr o gressi o n. Aft er 9 0  da ys, t he platea u w as 
n o l o n ger o bser v e d i n t he A L S F R S- R,  wit h t he n ota ble e xce pti o n of a tre n d t o war d better 
preser v ati o n of b ul bar a n d breat hi n g f u ncti o ns as meas ure d b y t he A L S F R S -R.  
Data f or Partici pa nts at st u d y visits i n St u d y V M A L S- 0 0 2- 2 will be use d as refere nce p oi nts f or 
c ha n ges i n saf et y assess me nts d uri n g t he e xte nsi o n st u d y V M A L S - 0 0 2- 2 b.  
O bjecti ves a n d e n d p oi nts f or t his e xte nsi o n st u d y are prese nte d i n t he f oll o wi n g ta ble. N ote t hat 
t here will be n o E n ge nsis or Place b o treat me nts i n V M A L S- 0 0 2- 2 b. T heref ore, t he c o m paris o ns 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
9 
Fi nal : 1 2 Oct 2 0 2 1 
O bjecti ves  
E n d p oi nts  
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has effects o n res pirat or y 
f u ncti o n i n A L S Partici pa nts 
•  C ha n ge fr o m Baseli ne ( St u d y 
V M A L S - 0 0 2- 2 Da y 0) i n Sl o w Vital 
Ca pacit y ( S V C) at Da y 3 6 5 f or E n ge nsis 
c o m pare d t o Place b o  
•  Ti me t o trac he ost o m y f or E n ge nsis  
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has p ositi ve effects o n 
s ur vi val i n A L S Partici pa nts 
•  Ti me t o all -ca use m ortalit y  c o m pare d t o 
Place b o  
•  T o e val uate Q u alit y of Life i m pr o ve me nt 
f oll o wi n g E n ge nsis i njecti o ns i n A L S 
Partici pa nts c o m pare d t o Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n Q ualit y 
of Life ( Q o L) usi n g t he A L S Assess me nt 
Q uesti o n naire ( A L S A Q; wit h 4 0 ite ms, 
A L S A Q 4 0) o n Da y 3 6 5 f or E n ge nsis 
c o m pare d t o Place b o  
•  T o e val uate Patie nt a n d Cli nical Re p orte d 
O utc o me i m pr o ve me nt f oll o wi n g 
E n ge nsis i njecti o ns i n A L S Partici pa nts 
c o m pare d t o Place b o  
•  Patie nt Gl o bal I m pressi o n of C ha n ge 
( P GI C) a n d Cli nical Gl o bal I m pressi o n of 
C ha n ge ( C GI C) at D a y 3 6 5 f or E n ge nsis 
c o m pare d t o Place b o  
 
O ver all Desi g n  
V M A L S - 0 0 2- 0 2 b is a P hase 2a , 6- m o nt h e xt e nsi o n st u d y, multi ce nter st u d y desi g ne d t o assess 
t he l o n g-ter m saf et y of En ge nsis (c o ntai ni n g t he acti ve p har mace utical i n gre die nt V M 2 0 2) i n 
Partici pa nt s wit h A L S.  
Partici pa nts will be e nr olle d i n t he V M A L S - 0 0 2- 2 b st u d y f oll o wi n g t he c o m pleti o n of t he 
Da y  1 8 0 Visit of  St u d y V M A L S- 0 0 2- 2. Partici pa nts will c o nti n ue t o be i de ntifie d b y t he sa me 
Partici pa nt n u m ber. 
Assess me nts t o be c o n d u cte d d uri n g t his V M A L S- 0 0 2- 2 b e xte nsi o n st u d y are as f oll o ws: vital 
si g ns; wei g ht a n d hei g ht; c o m plete p h ysical e x a mi nati o n ; a rec or d of all c o nc o mita nt 
me dicati o ns a n d pr oce d ures; A L S F R S - R; Ha n d hel d D y na m o metr y ( H H D ); Sl o w Vital Ca pacit y 
(S V C ); A m y otr o p hic Lateral Scler osis Assess me nt Q uesti o n naire , 4 0 q uesti o ns (A L S A Q - 4 0); 
Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI C ); Cli nical Gl o bal I m pressi o n of C ha n ge (C GI C ); 
a n d uri ne pr e g na nc y t est f or fe mal es of c hil d beari n g p ote ntial. Assess me nts of T E A Es, T E S A Es, 
A E SIs, a n d cli nicall y si g nifica nt la b orat or y v al ues will c o nti n ue fr o m t he D a y 1 8 0 Visit of St u d y 
V M A L S - 0 0 2- 2 t hr o u g h o ut t he V M A L S- 0 0 2- 2 b e xte nsi o n st u d y, t o Da y 3 6 5. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
1 0 
Fi nal : 1 2 Oct 2 0 2 1 
St u d y a n d Tre at m e nt D ur ati o n : 
T he re will be n o tr eat me nts d uri n g t his e xte nsi o n st u d y. T he ti mi n g f or visits i n t he V M A L S-
0 0 2- 2 b st u d y starts at t he c o ncl usi o n of t he Da y 1 8 0 Visit i n V M A L S- 0 0 2- 2. Partici pa nts i n 
V M A L S - 0 0 2- 2 b will be f oll o we d f or 1 8 0 d a ys t o Da y 3 6 5.  
Visit Fre q ue nc y:  
C o nse nte d Partici pa nts will be see n a n d e v al uate d f or  safet y at visits e ver y 6 0 da ys ( Da ys 2 4 0, 
3 0 0, a n d 3 6 5 / E T).  
I nter ve nti o n Gr o u ps a n d D ur ati o n: 
T here will be n o E n g e nsis treat me nts a d mi nistere d d uri n g t his 1 8 0- da y e xte nsi o n st u d y.  
N u m ber of P artici p a nts:  
T he n u m ber of Partici pa nts t o be e nr olle d i n t his e xte nsi o n st u d y de pe n ds u p o n t he n u m ber of 
s u bjects w h o c o mp lete t h e Da y 1 8 0 Visit i n V M A L S- 0 0 2- 2 ( pri or t o, d uri n g, or after t h eir Da y 
1 8 0 Visit) a n d w h o pr o vi de writte n i nf or me d c o ns e nt. T he ma xi m u m p ote ntial Partici pa nts i n 
V M A L S - 0 0 2- 2 b is 1 8, base d o n e nr oll me nt i n V M A L S- 0 0 2- 2. 
D at a S afet y M o nit ori n g B o ar d: 
A n  i n de pe n de nt D ata Saf et y M o nit ori n g B oar d ( D S M B) will peri o dicall y re vie w a li mite d set of 
u n bli n de d ( n o nc o m par ati ve) ta bles a n d/ or listi n gs, i ncl u di n g all re p orte d T E A Es, T E S A Es, a n d 
A E SIs.  
1. 2.  
St u d y Sc he m a  
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
1 2 
Fi nal : 1 2 Oct 2 0 2 1 
3.  C o m plete P h ysic al E x a m i n ati o n will be perf or me d  o n Da ys 2 4 0  a n d 3 6 5 / E T. T he e xa mi nati o n will i ncl u de 
t he f oll o wi n g: a n e xa mi nati o n of t he s ki n/i nte g u me ntar y s yste ms, ge neral a p peara nce, hea d, nec k (i ncl u di n g 
t h yr oi d), e yes, ears, n ose, t hr oat, l y m p h n o des, c hest (l u n gs), heart, a b d o me n, m usc ul os keletal s yste m, 
ne ur ol o gical s yste m, a n d a n y a d diti o nal assess me nts nee de d t o esta blis h Baseli ne stat us or e val uate s y m pt o ms 
or T E A Es.  A n y a b n or malities s h o ul d be cate g orize d as cli nicall y si g nifica nt ( C S) or n ot cli nicall y si g nifica nt 
( N C S), a n d t he a b n or malities s h o ul d be rec or de d as T E A Es, T E S A Es, or A E SIs . 
4.  1 2 -Le a d Electr oc ar di o gr a m ( E C G) will be perf or me d at Da y s 2 4 0  a n d 3 6 5 / E T. Cli nicall y si g nifica nt 
a b n or malities are t o be rec or de d as a d verse e ve nts. T he E C G rec or di n g m ust be  st ore d wit h t he Partici pa nt ’s 
rec or ds. 
5.  Ser u m C he mistr y  a n d  He m at ol o g y: Bl o o d sa m ples will be c ollecte d f or ser u m c he mistr y a n d he mat ol o g y  
assess me nts o n Da ys  2 4 0  a n d 3 6 5 / E T. Test res ults will be re vie we d a n d assesse d b y t he I n vesti gat or f or 
cli nicall y si g nifica nt a b n or mal la b orat or y fi n di n gs , w hic h s h o ul d be rec or de d as T E A Es, T E S A Es, a n d  A E SIs.  
C he mistr y i ncl u des s o di u m, p otassi u m, c hl ori de, bicar b o nate, calci u m, i n or ga nic p h os p hate, ma g nesi u m, 
gl uc ose, a m ylase, li pase, creati ne ki nase, lactate de h y dr o ge nase, a n d : 
a. 
Ki d ne y f u ncti o n tests ( bl o o d urea nitr o ge n, creati ni ne)  
b.  Li ver f u ncti o n  tests (as partate a mi n otra nsferase [ A S T], ala ni ne a mi n otra nsferase [ A L T], al kali ne 
p h os p hatase, ga m ma -gl uta m yl tra ns pe pti dase [ G G T], t otal bilir u bi n, t otal pr otei n, a n d al b u mi n) 
He m at ol o g y i ncl u des platelet c o u nt, he m o gl o bi n, he mat ocrit, w hite bl o o d cell c o u nt, a n d ne utr o p hil c o u nt 
6.  C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures  will be rec or de d o n Da ys 2 4 0, 3 0 0, a n d 3 6 5/ E T, a n d will i ncl u de  
all me dicati o ns or vacci nes, i ncl u di n g o ver -t he-c o u nter or prescri pti o n me dici nes, vita mi ns, her bal s u p ple me nts , 
a n d pr oce d ures t hat t he Partici pa nt  was recei v e d . F or eac h me dicati o n, treat me nt, or pr oce d ure , t he f oll o wi n g 
i nf or mati o n will be c ollecte d: Me dicati o n tra de or ge neric na me, t y pe of pr oce d ure, i n dicati o n, start date, st o p 
date or o n g oi n g, d ose, u nits, fre q ue nc y, a n d r o ute  of a d mi nistrati o n . 
7.  Uri ne Pre g n a nc y Test  will b e c o n d ucte d f or w o me n of c hil d beari n g p ote ntial  o n  Da y 3 6 5 / E T.   
8.  Sl o w Vit al C a p acit y ( S V C ) will be meas ure d  o n Da ys 2 4 0 , 3 0 0, a n d 3 6 5 / E T. 
9.  A L S F R S - R: Re vise d A m y otr o p hic L ater al Scler osis F u n cti o n al R ati n g Sc ale will be perf or me d o n Da ys 
2 4 0 , 3 0 0, a n d 3 6 5. 
1 0.  H a n d hel d  D y n a m o m etr y ( H H D)  will be meas ure d o n Da ys 2 4 0 , 3 0 0, a n d 3 6 5 / E T: 
1 1.  A L S A Q -4 0 : A m y otr o p hic L ater al Scler osis Assess m e nt Q uesti o n n aire, 4 0 q uesti o ns ( A L S A Q -4 0)  will be 
meas ure d o n Da y s 2 4 0  a n d 3 6 5 / E T.  
1 2.  P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C)  a n d  Cli nic al Gl o b al I m pressi o n of C h a n ge  ( C GIC)  will be 
c o n d ucte d o n Da ys 2 4 0  a n d 3 6 5 / E T.   
1 3.  Tre at m e nt -E m er ge nt A d verse E ve nts ( T E A Es)  a n d Tre at m e nt -E m er ge nt Seri o us A d verse E ve nts 
( T E S A Es): T E A Es / T E S A Es will be rec or de d after i nf or me d c o nse nt o n  Da y 1 8 0  of V M A L S -0 0 2 -0 2  f or 
Partici pa nts i n V M A L S -0 0 2 -2 b . All T E S A Es d uri n g  t his e xte nsi o n st u d y will be rec or de d a n d  re p orte d t o t he 
S p o ns or/ desi g nee  wit hi n 2 4 h o urs of a ware ness of t he T E S A E b y t he  Site . 
1 4.  A d verse E ve nts of S peci al I nterest  ( A E SIs): All A E SIs will be c o nti n u o usl y m o nit ore d t hr o u g h o ut t he st u d y.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
1 3 
Fi nal : 1 2 Oct 2 0 2 1 
2.  
I N T R O D U C TI O N 
E n ge nsis is a n o vel ge ne t hera p y bei n g de v el o pe d f or treat me nt of A L S. T h e acti ve 
p har mace utical i n gre die nt of E n ge nsis is V M 2 0 2, a plas mi d de o x yri b o n ucl eic aci d ( D N A) 
desi g ne d as a g e ne tra nsf er met h o d t o si m ulta ne o usl y e x press t w o is of or ms of h u ma n he pat oc yt e 
gr o wt h fact or ( H G F), H G F 7 2 8 a n d H G F 7 2 3, w hic h  are i de ntical t o wil d -t y pe h u ma n f or ms. 
He pat oc yte gr o wt h fact or is a p ote nt a n gi o ge nic a n d vasc ul o ge nic gr o wt h fact or sti m ulati n g t he 
gr o wt h of e n d ot helial cells a n d mi grati o n of vasc ular s m o ot h m uscle cells. As a m ultif u ncti o nal 
mese nc h y me - d eri ve d c yt o ki ne, it has p ote nt a n gi o ge nic a n d a nti-a p o pt otic effects, i ncl u di n g t hat 
of t he l y m p hatic s yste m. I n a d diti o n, H G F u pre g ul ates t he e x pressi o n of vas c ular e n d ot helial 
gr o wt h fact or ( V E G F) a n d ot her fact ors a n d de m o nstrates greater mit o ge ni c acti vit y t ha n t hat of 
V E G F al o ne i n h u ma n a ortic e n d ot hel ial cells i n vitr o. H G F is als o i m p orta nt i n t he 
pat h o p h ysi ol o g y of i ns uli n resista nce, as a ne ur otr o p hic fact or pr o m oti n g a x o nal gr o wt h a n d 
re ge nerati o n i n dia betics i n w h o m l oss of micr o vasc ulat ure ma y accelerate ne ur o nal l oss, m ore 
s o t ha n e x o ge n o us V E G F (see t he I n v esti gat or’s Br oc h ure [I B] f or m ore d etaile d i nf or mati o n). 
2. 1.  
St u d y R ati o n ale 
V M A L S - 0 0 2- 2 b is a saf et y e xte nsi o n of V M A L S- 0 0 2- 2, a well -c o ntr olle d st u d y t o e val uate t he 
l o n g-ter m safet y of I M a d mi nistrati o n of E n ge nsis t o Partici pa nt s wit h A L S .  
2. 2.  
B ac k gr o u n d 
2. 2. 1.  
P at h o p h ysi ol o g y of A m y otr o p hic L ater al Scler osis  
A m y otr o p hic Later al Scler osis ( A L S) is a n a d ult- o nset ne ur o de g e nerati ve dis or der c haracterize d 
b y t he l oss of u p per a n d l o wer m ot or ne ur o ns. T he disease is di verse i n its prese ntati o n, ca use, 
a n d pr o gressi o n, b ut i n g e neral, A L S prese nts cli nicall y as as y m metric m us cle wea k ness, 
wasti n g, s pasticit y, wei g ht l oss, d ys p ha gia, a n d paral ysis; i n 1 0 % t o  1 5 % of patie nts; c o g niti ve 
i m pair me nt ma y arise bef ore or f oll o wi n g t hat of m ot or ne ur o n d ysf u ncti o n. Pat h ol o gicall y, A L S 
is c haracterize d b y pr o gr essi ve de ge n erati o n a n d l oss of m ot or ne ur o ns i n t he s pi nal c or d, 
brai nste m, a n d cere bral c orte x . Fr o m t he ti me of dia g n osis, me dia n s ur vi val is 3 t o 5 years ; a b o ut 
1 0 % of patie nts ca n s ur vi ve f or ≥1 0 years . W hile m ost A L S cases are s p ora dic ( pri mar y or 
i di o pat hic), a b o ut 5% t o  1 0 % of patie nts ha ve a p ositi ve fa mil y hist or y (fa milial A L S), 1 ,2 wit h a 
m utati o n i n t he C u/ Z n s u per o xi de dis m utase 1 ( S O D 1 ) ge n e acc o u nti n g f or 1 0 % of fa milial 
A L S. 3 
Esti mates of t he i nci de nce of A L S w orl d wi de ra n g e fr o m 1 t o 3 cas es per 1 0 0, 0 0 0 pe o ple 
a n n uall y, wit h a hi g her i nci de nce i n Ca u casia ns, 4 ,5 ,6 ,7 ,8 i n pe o ple w h o s m o ke,9 ,1 0  a n d i n se veral 
ge o gra p hic re gi o ns i n w hic h e n vir o n me ntal t o xi ns are s us pecte d. 1 1 ,1 2 ,1 3 ,1 4 T he A L S Ass ociati o n, 
t he Ce nters f or Disease C o ntr ol a n d Pre ve nti o n, a n d t he Nati o nal I nstit ute of Ne ur ol o gical 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
1 4 
Fi nal : 1 2 Oct 2 0 2 1 
Dis or ders a n d Str o ke esti mate t hat as ma n y as 3 0, 0 0 0 A merica ns ma y h a ve t he disease at a n y 
gi ve n ti me , wit h a p pr o xi matel y 5, 6 0 0 ne wl y dia g n ose d patie nts a n n uall y.* 
M ulti ple mec ha nis ms f or t he selecti ve v ul nera bilit y , de ge nerati o n, a n d earl y d yi n g-bac k 
a x o n o pat h y of m ot or ne ur o ns ha ve bee n pr o p ose d a n d i n vesti gate d. T he y i n cl u de pr otei n 
misf ol di n g, mit oc h o n drial d ysf u ncti o n, o xi dati ve da ma ge, defecti ve a x o nal tra ns p ort, 
e xcit ot o xicit y, i ns ufficie nt gr o wt h fact or si g nali n g, a n d i nfla m mati o n .1 5 ,1 6 ,1 7 ,1 8 ,1 9 ,2 0 T o xicit y 
res ults fr o m a c o m bi nati o n of da ma ge i nc urre d directl y wit hi n m ot or ne ur o ns a n d t hr o u g h 
da ma ge i nc urre d b y n o n- ne ur o nal nei g h b ors, i ncl u di n g astr oc ytes a n d micr o glia, w h ose acti o ns 
a m plif y t he i nitial da ma ge a n d dri ve disease pr o gressi o n a n d s prea d. Mi cr o glia acti vate a n 
i nfla m mat or y casca de vi a secr eti o n of m o n oc yte c he m oattracta nt pr otei n 1 ( M C P- 1) a n d ot her 
c yt o ki nes. Astr oc ytes c o ntri b ute t o ne ur o n i nj ur y b y releasi n g i nfla m mat or y me diat ors s uc h as 
nitric o xi de ( N O) a n d pr osta gla n di n E 2 ( P G E 2 ), re d uce d lact ate rel ease, acti vati o n of 
pr o -N G F - p 7 5 ( n er ve gr o wt h fact or) rece pt or si g n ali n g a n d re d uce d acti vit y of t he gl uta mate 
re u pta ke tr a ns p orter e xcit at or y a mi n o aci d tra ns p orter 2 ( E A A T 2). M ot or n e ur o ns mi g ht als o 
u n der g o tra ns cri pti o nal d ysre g ulati o n a n d a b n or m al ri b o n ucleic aci d ( R N A ) pr ocessi n g, w hic h , 
t o get her wit h o ver pr o d u cti o n of reacti ve o x y g e n s pecies, c o ntri b utes t o a b erra nt pr otei n f ol di n g. 
A berr a nt pr otei ns ca n f or m a g gre gates, l ea di n g t o pr oteas o me i m pair me nt a n d e n d o plas mic 
retic ul u m stress. T he r es ulti n g mit oc h o n drial i m pair me nt a n d d ysre g ul ati o n of calci u m ha n dli n g 
tri g ger a ut o p ha g y a n d t he a p o pt otic cas ca de.2 1 ,2 2 T he pr ocess is “c o nt a gi o us” a n d 
self- per p et uati n g, affecti n g t he d y na mics of cell deat h i n nei g h b ori n g cells d ue t o releas e of 
i nterle u ki n- 1β  , t u m or necr osis fact or al p ha (T N F -α ), a n d free ra dicals.2 3 Fi g ure 1  de picts t he 
m olec ular pr o cesses i n v ol ve d i n m ot or ne ur o n i nj ur y i n A L S. 
 
* htt p:// w w w.alsa. or g/a b o ut -als/ w h o -gets -als. ht ml (accesse d Oct o ber 1 2, 2 0 1 5) 
htt p:// w w w n.c dc. g o v/als/ W hatis A L S.as p x  (accesse d Oct o ber 1 2, 2 0 1 5) 
htt p:// w w w. ni n ds. ni h. g o v/ dis or ders/a m y otr o p hiclateralscler osis/ detail _ A L S. ht m  (accesse d Oct o ber 1 2, 2 0 1 5) 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
1 6 
Fi nal : 1 2 Oct 2 0 2 1 
a n d/ or ti me t o trac he ost o m y, wit h o ut pr o vi di n g a statisticall y si g nifica nt differe nces i n m uscle 
stre n gt h or ne ur ol o gical f u ncti o n. 3 0  
E dara v o n e was a p pr o ve d b y t he F o o d a n d Dr u g A d mi nistrati o n ( F D A ) o n Ma y 5, 2 0 1 7, f or 
patie nts wit h A L S . T he dr u g is a d mi nistere d i ntra ve n o usl y a n d belie ve d t o re d uce o xi d ati ve 
stress i n t he ner v o us s yste m, a pr ocess t hat kills ne ur o ns i n patie nts wit h A L S. E dara v o ne was 
a p pr o ve d bas e d o n t he r es ults of a P hase  3 cli nical trial i n Ja pa n a n d S o ut h K orea i n w hic h 
1 3 7 A L S patie nts were gi ve n eit her e d ara v o ne  or p lace b o. T he gr o u p gi ve n e dara v o n e 
e x perie n ce d a 3 3 % re d u cti o n i n t he decli ne of t heir p h ysical li mitati o ns c o m pare d wit h  t he 
p lace b o gr o u p. Statistical si g nifica nce w as o nl y reac he d i n Partici pa nts dia g n ose d less t ha n t w o 
years earlier a n d wit h ra pi d pr o gressi o n of s y m pt o ms, h o we ver; 2 ot her P hase 3 st u dies faile d t o 
s h o w a n y cli nical be n efit of  e dar a v o ne, a n d s ur vi v al was n ot de m o nstrate d t o be pr ol o n ge d wit h 
its use.   
Neit her r il uz ole n or e dar a v o ne pre v e nt or c orrect t he u n derl yi n g ca us es of A L S. Clearl y, a 
t hera p y t hat c o ul d i m pe d e or re v erse n e ur o de g e nerati o n is nee de d f or patie nts wit h A L S. 
E n ge nsis pr o d uces H G F, w hic h  acts as a ne ur otr o p hic fact or t h at ai ds i n t he de vel o p me nt a n d 
re ge nerati o n of peri p her al ner ves; it acti vates Sc h wa n n  cells t o bec o m e re p air -t y pe cells a n d 
e n ha nces t he re m y eli nati o n pr ocess, c o ns e q ue ntl y lea di n g t o t he pr o per re g e nerati o n of i nj ure d 
peri p her al  ner ves  i n a ni mal m o dels (see t he I B f or m ore i nf or mati o n). 
Treat me nt a p pr oac h es base d o n a nat o mic deli ver y strate gies ha ve als o bee n pr o p ose d f or 
treat me nt of A L S or ot her ne ur o de g e nerati ve diseases.3 1 ,3 2 F or e x a m ple, base d o n o bser vati o ns 
of retr o gr a de n e ural tr a ns p ort of bi ot hera pe utics f oll o wi n g I M i njecti o n i n a ni mal m o dels, a 
deli ver y a p pr o ac h of I M i njecti o ns of ste m cells has bee n a p plie d i n cli nical trials of vari o us 
a d ult ste m cell p o p ulati o ns, all wit h a li mite d n u m ber of i njecti o ns a n d fe w m uscle tar gets.3 3 ,3 4 ,3 5 
A m uc h br oa d er a n at o mic deli ver y strat e g y is bei n g use d f or E n ge nsis i njecti o ns bei n g e val uate d 
i n Heli x mit h cli nical trials. 
2. 2. 3.  
He p at oc yte Gr o wt h F act or f or Tre at me nt of A m y otr o p hic L ater al Scler osis  
He pat oc yte gr o wt h fact or ( H G F) is a m ulti -f u ncti o nal mese nc h y me- deri ve d c yt o ki ne. It is a 
rec o g nize d p ote nt a n gi o g e nic gr o wt h fact or a n d a nti-a p o pt osis a ge nt, sti m ulati n g t he gr o wt h of 
e n d ot helial cells  a n d t he mi grati o n of vasc ular s m o ot h m uscle cells.3 6 ,3 7 ,3 8 ,3 9 H G F sti m ulates 
D N A, R N A , a n d pr otei n s y nt hesis b y e n d ot helial cells i n a d ose- de p e n de nt ma n ner, u pre g ulates 
V E G F e x pressi o n, a n d e x hi bits  greater mit o ge nic acti vit y t ha n t hat of V E G F al o ne i n h u ma n 
a ortic e n d ot helial cells i n vitr o.4 0 ,4 1 ,4 2 
Alt h o u g h lar gel y t h o u g ht of as a n a n gi o g e nic a g e nt, H G F has b ee n rece ntl y i de ntifie d as a 
ne ur otr o p hic f act or. 4 3 ,4 4 ,4 5 ,4 6 ,4 7 ,4 8 ,4 9   H G F  a n d its c o g n ate rece pt or (t he c-M et rece pt or ) are 
e x presse d i n t he p eri p her al ner v o us s yste m as w ell as i n vari o us re gi o ns of t he brai n a n d s pi nal 
c or d. S u n et al. ( 2 0 0 2) f o u n d t hat l ocal s ustai ne d H G F pr o d u cti o n i n ne ural tiss ue i n S O DG 9 3 A  
mice  (tra ns ge ni c A L S m o del) alle viated t he s y m pt o ms of A L S b y direct ne ur otr o p hic acti vities 
o n m ot o r ne ur o ns a n d i n direct acti vities o n glial cells. 4 7 T he y f o u n d t hat H G F was 
ne ur o pr otecti ve. S O D mice tra nsf ecte d wit h a si n gle c o p y of t he H G F g e ne ( G 9 3 A/ H G F) 
retai ne d a si g nifica ntl y lar ger n u m ber of s pi nal m ot o r ne ur o ns wit h a healt hier m or p h ol o g y t ha n 
S O D mice wit h o ut t he H G F ge n e ( G 9 3 A si n gle tra ns ge nic).  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
1 7 
Fi nal : 1 2 Oct 2 0 2 1 
G 9 3 A/ H G F mice als o e x perie nce d i m pr o ve d m ot or perf or ma nce, si g nifica ntl y dela ye d o nset i n 
paral ysis , a n d s ur vi ve d l o n ger t ha n G 9 3 A mice. Researc hers als o f o u n d i n direct e vi de n ce t hat 
H G F s u p pr esses micr o gli osis (i nte nse reacti o n of ce ntral ner v o us s yste m [C N S ] micr o glia t o 
pat h o ge nic i ns ults) a n d astr oc yt osis (a b n or mal i ncrease i n t he n u m b er of astr oc ytes), b ot h of 
w hic h c o ntri b ute t o m ot or ne ur o n de g e nerati o n b y pr o d uci n g c yt ot o xic c yt o ki nes a n d e ve nt ual 
glial scar f or m ati o n .5 0 ,5 1 
It has b ee n d e m o nstrate d t hat H G F ca n pr o m ote ne ur o ge nesis, a n gi o ge n esis, a n d s y na pt o ge nesis 
a n d t hat it ca n i n hi bit fi br otic c ha n ges i n isc he mic re gi o ns better t ha n glial cell li ne -deri ve d  
ne ur otr o p hic f act or ( G D N F). 5 2 
H G F ma y als o ha ve pr ot ecti ve effects a gai nst e xcit ot o xic i nj uries , beca use it has bee n s h o w n t o 
atte n uate a x o n al de ge n er ati o n b y re d uci n g e x cit ot o xicit y t hr o u g h m o d ulati o n of t he e x pressi o n 
of t he scaff ol di n g pr otei n ( me m bers of t he si g nali n g casca d e d o w nstrea m of cell s urface 
rece pt ors) of t he N-met h yl - D-as partate (N M D A ) rece pt or at t he s y na ps e.5 3 ,5 4 
Fi nall y, H G F m a y sta ve off cell deat h a n d halt t he casca d e of n ei g h b ori n g cell da ma ge b y 
i n hi biti n g cas pase si g nali n g directl y i n m ot or ne ur o ns a n d i n directl y b y its effects o n 
astr oc ytes. 5 5 I n A L S patie nts, c hr o nic, s u blet hal acti vati o n of cas pas e a p pears t o me diate cell 
d ysf u ncti o n, w hic h prece des cell deat h .5 6 ,5 7 Cell d ysf u ncti o n of s u bsta ntial ma g nit u de, occ urri n g 
bef ore cell deat h, mi g ht res ult i n s y m pt o matic disease . Gi ve n t hat cas pases ma y be acti ve i n 
i n di vi d ual ne ur o ns f or a l o n g peri o d ( p ote ntiall y w ee ks t o m o nt hs), i n hi biti o n of cas pas e i n t hese 
circ u msta nces c o ul d re d u ce cell d ysf u ncti o n a n d d ela y cell deat h. 5 4 T heref ore, t he ne ur otr o p hic 
acti o n of H G F o n m ot o r ne ur o ns is, at least i n part, pr o m ote d b y pre ve nti n g cas p ase -me diate d 
cell deat h si g nals.  
H G F o vere x pr essi o n als o atte n uates m o n oc yte c he m oattracta nt pr otei n- 1 ( M C P - 1, o ne of t he 
i m p orta nt c he m o ki nes t hat c o ntr ols mi grati o n a n d i nfiltrati o n of m o n oc ytes a n d macr o p h a ges 
d uri n g i nfla m mati o n ) i n d ucti o n i n astr oc ytes, w hic h res ults i n a re d ucti o n i n micr o glial 
acc u m ulati o n, a h all mar k i nfla m mat or y pr ocess i n A L S. 5 8  
T he c halle n g e ass ociat e d wit h deli veri n g a tar g ete d s ustai ne d d ose of e x o g e n o us H G F is i n 
o verc o mi n g t he i nsta bilit y of H G F i n bl o o d circ ul ati o n a n d its ra pi d cleara nce b y t he li ver; H G F 
has a n i n vi v o half -life of less t ha n 1 5 mi n utes.5 9 ,6 0 
O ne a p pr o ac h t o i ncr easi n g H G F a v aila ble t o ne ur o ns is t o de vel o p a ge ne tra nsfer strate g y t hat 
w o ul d all o w f or persiste nt e x pressi o n of H G F pr ot ei n i n vi v o. Alt h o u g h plas mi d D N A is o ne of 
t he least effi cie nt ge ne tr a nsfer s yste ms c urre ntl y i n use, t he fact t hat it is ass ociate d wit h li mite d 
persiste nce a n d n o pr o pe nsit y f or ge n o mic i nte grati o n ( partic ularl y i n s keletal m uscle tiss ue) 
ma kes it a n attracti ve o pti o n f or l ocal tar g ete d deli ver y .  
2. 2. 4.  
E n ge nsis  a n d V M 2 0 2 
T he i n vesti gati o nal a ge nt (st u d y dr u g) bei n g st u die d i n t his pr ot oc ol is E n ge nsis, w hic h c o ntai ns 
t he acti ve p har mace utical i n gre die nt V M 2 0 2. V M 2 0 2 is a plas mi d D N A t hat c o ntai ns t he n o vel 
ge n o mic c o m ple me ntar y D N A  (c D N A) h y bri d h u ma n H G F c o di n g se q ue n ce ( H G F-X 7) 
e x pressi n g t w o is of or ms of H G F, H G F 7 2 8 a n d H G F 7 2 3 (Fi g ure 2 ). 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
1 9 
Fi nal : 1 2 Oct 2 0 2 1 
arter y disease ( P has e 2), o ne st u d y i n c or o nar y art er y disease ( P hase 1), f o ur st u dies ( P hase 1/ 2, 
P hase 2, a n d t w o P hase 3) i n Partici pa nt s wit h pai nf ul dia betic peri p h eral n e ur o pat h y (D P N ), a 
st u d y ( P hase 1/ 2) i n A L S, a n d o ne ( P hase 3) st u d y i n dia betic Partici pa nt s wit h c hr o nic 
n o n heali n g f o ot ulcers ( N H U). E n ge nsis w as well t olerate d a n d t he m ost fre q ue nt reacti o n w as  
pai n at i njecti o n sites i n 1 -4 % of Partici pa nt s, w hi c h was si milar t o t hat o bser ve d i n t he place b o 
gr o u ps. N o  s yste mic eff ects ha ve bee n attri b ute d t o E n ge nsis. 
2. 2. 6. 1.  
P h ase 1/ 2 St u d y i n P artici p a nts wit h A m y otr o p hic L ater al Scler osis  
A P hase 1/ 2, o pe n la bel, si n gle ce nter st u d y i n 1 8 P artici pa nt s dia g n ose d wit h cli nicall y defi nite, 
cli nicall y pr o ba ble, or cli nicall y pr o ba ble-l a b orat or y s u p p orte d A L S ( V M A L S- 0 0 1; 
N C T 0 2 0 3 9 4 0 1) lasti n g 9 m o nt hs was c o m plete d .6 1  Pr i or t o i njecti o ns o n Da y 0, Partici pa nt s 
were assesse d usi n g t he A L S F R S -R, t he Me dical Researc h C o u n cil ( M R C) scale f or m us cle 
stre n gt h testi n g, d y na m o metr y, f orce d vital ca p acit y ( F V C), a n d m uscl e circ u mfere nce of treate d 
m uscles .  
All Partici pa nt s ( 1 8 Partici pa nts) recei ve d a t otal of 6 4 m g of E n ge nsis I M i n t he u p per li m bs 
(a b d uct or p ollicis bre vis, first d orsal i nter osse o us, bice ps, delt oi d, e xte ns or car pi ra dialis, fle x or 
car pi ul naris, a n d fle x or car pi r a dialis) a n d l o wer li m bs ( q ua drice ps, gastr o c ne mi us, a n d ti bialis 
a nteri or).  
E n ge nsis was a d mi nister e d o ver t he c o urse of f o ur v isits: Da ys 0, 7, 1 4, a n d 3 0. As i n pre vi o us 
E n ge nsis st u dies, t he fi nal d ose of E n ge nsis f or eac h tar get m uscle gr o u p w a s di vi de d a n d 
a d mi nistere d 2 wee ks a p art  wit h  i njecti o n of t he u p per li m bs at se parate v isits f oll o we d b y 
i njecti o n of t he l o wer li m bs. 
P ost-i njecti o n, A L S F R S- R, F V C , a n d m uscle stre n gt h ( deter mi ne d b y t he M R C scale) were 
assesse d at D a y s 3 0, 6 0, a n d 9 0, a n d at 6 a n d 9 m o nt hs. M uscle circ u mfere nce a n d d y n a m o metr y 
were c o n d ucte d o n Da y s 6 0 a n d 9 0, a n d at 6 a n d 9 m o nt hs. Partici pa nt s were c o ntact e d t hr o u g h 
3 6 m o nt hs b y p h o ne t o assess s ur vi val. 
After E n ge nsis or Place b o i njecti o ns t hr o u g h Da y 3 0, s e ve ntee n ( 1 7) Partici pa nts c o m plete d t he 
9- m o nt h f oll o w- u p; o ne Partici pa nt  die d pri or t o t he 9- m o nt h visit. T hree ( 3) Partici pa nt s 
c o m plete d t he st u d y ( 3 6- m o nt h f oll o w- u p), w hile 1 4 Partici pa nt s die d f oll o wi n g t he 9- m o nt h 
v isit; all decease d Partici pa nt s die d d ue t o res pirat or y fail ure ass ociate d wit h A L S. F o ur 
a d diti o nal seri o us a d vers e e ve nts (S A Es ) t h at re q uire d h os pitalizati o n were re p orte d. All deat hs 
a n d S A Es wer e classifie d as u nrelate d t o t he st u d y dr u g . I njecti o n site reacti o ns were  li mite d t o 
pai n a n d/ or br uisi n g a n d n o ne e xcee de d gra de 2 s e verit y. 
2. 2. 6. 2.  
Ot her E n ge nsis Cli nic al St u dies  
See t he I B f or d etaile d pr ese ntati o n of res ults fr o m all 1 0 cli nical st u dies i n t he U S A a n d K orea 
(see Secti o n 2. 2. 6 ). Als o, see Secti o n  4. 3  ( D os e J ustificati o n) f or des cri pti o ns of pri or cli nical 
st u dies wit h E n ge nsis t hat c o ntri b ute d t o t he selecti o n of d oses a n d d osi n g re gi me n f or t his 
c urre nt st u d y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 1 
Fi nal : 1 2 Oct 2 0 2 1 
S A Es  re p orte d as p ossi bl y relate d i n t he V M D N- 0 0 3 trial i ncl u de d: 
•  Vitre o us he m orr h a ge of t he e ye (cate g orize d as p ossi bl y relate d t o t he st u d y dr u g b ut 
was pr o ba bl y r elate d t o u n derl yi n g disease) 
•  M y ocar dial i nfarcti o n (cate g orize d b y H eli x mit h as p ossi bl y relate d t o t he st u d y dr u g, 
alt h o u g h cate g orize d b y t he i n vesti gat or as n ot rel ate d t o t he st u d y dr u g) 
•  A de n ocarci n o ma ( cate g orize d as p ossi bl y relat e d t o t he st u d y dr u g b y t he i n vesti gat or 
a n d n ot relate d t o t he st u d y dr u g b y Heli x mit h) 
2. 3. 2.  
Be nefit  Assess m e nt  
I n A L S, s ustai ne d, l ocal pr o d ucti o n of H G F i n ne ural tiss ue ma y alle viate s y m pt o ms b y direct 
ne ur otr o p hic a n d i n dir ect ne ur o pr otecti ve acti vities o n m ot or ne ur o ns. H G F has als o bee n 
re p orte d t o pla y a n i m p orta nt r ole i n re versi n g or li miti n g m uscle da ma ge a n d m usc ular atr o p h y; 
e x o ge n o us treat me nt of H G F a m eli orate d s kel etal m uscle atr o p h y a n d i ncrease d t he g e nerati o n 
of ne w m uscle fi bers.  
E n ge nsis i n d uces relati vel y ra pi d a n d pr ol o n ge d pr o d ucti o n of H G F, w hic h, t hr o u g h its m ulti ple 
mec ha nis ms of acti o ns o n micr o vasc ular a n d ne ural tiss ue re pair, h as t he p ote ntial t o i m pr o ve 
o utc o mes i n A L S  patie nts, as s u g geste d b y prece di n g st u dies. If E n g e nsis s h o ws fa v ora ble 
o utc o me s i n t his st u d y, it ma y be c o nsi dere d a n i m p orta nt a ge nt wit h a d ura ble t hera pe utic effect 
f or A L S patie nts. 
2. 3. 3.  
O ver all Be nefit / Ris k C o ncl usi o ns  
T he o ver all pr ofile of p ot e ntial be nefits a n d a p pare nt safet y f or E n ge nsis pr o vi de s ufficie nt 
s u p p ort t o j ustif y t he c o n d uct of t he pres e nt e xte nsi o n st u d y i n its ai m t o meet t he u n met nee ds of 
A L S  patie nts.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 3 
Fi nal : 1 2 Oct 2 0 2 1 
O bjecti ves  
E n d p oi nts  
•  T o e val uate m uscl e stre n gt h c ha n ges 
f oll o wi n g E n ge nsis i njecti o ns i n A L S 
Partici pa nts  
•  C ha n ge fr o m Baseli ne ( St u d y 
V M A L S - 0 0 2- 2 Da y 0) i n m uscle stre n gt h 
assesse d bilaterall y b y Ha n d h el d 
D y na m o metr y ( H H D) i n m uscles i n t he 
u p per a n d l o w er e xtre mities at Da y 3 6 5 
f or E n ge nsis c o m pare d t o Place b o  
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has effects o n res pirat or y 
f u ncti o n i n A L S Partici pa nts 
•  C ha n ge fr o m Baseli ne ( St u d y 
V M A L S - 0 0 2- 2 Da y 0) i n Sl o w Vital 
Ca pacit y ( S V C) at Da y 3 6 5 f or E n ge nsis 
c o m pare d t o Place b o  
•  Ti me t o trac he ost o m y f or E n ge nsis  
•  T o deter mi ne w h et her I M a d mi nistrati o n 
of E n ge nsis has p ositi ve effects o n 
s ur vi val i n A L S Partici pa nts 
•  Ti me t o all -ca use m ortalit y  c o m pare d t o 
Place b o  
•  T o e val uate Q u alit y of Life i m pr o ve me nt 
f oll o wi n g E n ge nsis i njecti o ns i n A L S 
Partici pa nts c o m pare d t o Place b o  
•  C ha n ge fr o m Baseli ne ( Da y 0) i n Q ualit y 
of Life ( Q o L) usi n g t he A L S Assess me nt 
Q uesti o n naire ( A L S A Q; wit h 4 0 ite ms, 
A L S A Q 4 0) o n Da y 3 6 5 f or E n ge nsis 
c o m pare d t o Place b o  
•  T o e val uate Patie nt a n d Cli nical Re p orte d 
O utc o me i m pr o ve me nt f oll o wi n g 
E n ge nsis i njecti o ns i n A L S Partici pa nts 
c o m pare d t o Place b o  
•  Patie nt Gl o bal I m pressi o n of C ha n ge 
( P GI C) a n d Cli nical Gl o bal I m pressi o n of 
C ha n ge ( C GI C) at D a y 3 6 5 f or E n ge nsis 
c o m pare d t o Place b o  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 4 
Fi nal : 1 2 Oct 2 0 2 1 
4.  
S T U D Y D E SI G N  
4. 1.  
O ver all  Desi g n  
V M A L S - 0 0 2- 2 b is a saf et y e xte nsi o n st u d y f oll o wi n g V M A L S- 0 0 2- 2 ( A P hase  2a, d o u ble- bli n d, 
ra n d o mize d, place b o - c o ntr olle d, m ultice nter  st u d y desi g ne d t o assess t he safet y of I M 
a d mi nistrati o n of E n ge nsis i n Partici pa nt s wit h A L S ). F oll o wi n g c o m pleti o n of t he Da y 1 8 0 visit 
i n V M A L S- 0 0 2- 2 a n d si g ni n g of writte n i nf or me d c o nse nt, Partici pa nts ma y be e nr olle d i n t his 
a p pr o xi matel y 1 8 0- da y e xte nsi o n st u d y.  
4. 2.  
Scie ntific R ati o n ale f or St u d y Desi g n  
V M A L S - 0 0 2- 2 b is desi g ne d as a safet y e xte nsi o n st u d y t o e val uate t he l o n g-ter m safet y pr ofile 
of E n ge nsis f oll o wi n g t he mai n st u d y, V M A L S- 0 0 2- 2, w hic h is a well -c o ntr olle d P hase 2 a st u d y 
i n A L S Partici pa nts, as it is a d o u ble- bli n d, ra n d o mize d, place b o -c o ntr olle d, a n d m ultice nter 
st u d y t o e val uate m uscle bi o mar kers a n d t he s afet y pr ofile of E n ge nsis i n Partici pa nt s wit h A L S.  
4. 3.  
J ustific ati o n f or D ose 
N o treat me nts will be a d mi nistere d d uri n g t his e xte nsi o n st u d y. 
4. 4.  
R a n d o miz ati o n 
T here  is n o r a n d o mizati o n i n t his st u d y. 
4. 5.  
E n d of St u d y Defi niti o n  
T he e n d of t he st u d y is d efi ne d as t he d ate o n w hi c h t he last Partici pa nt  i n t he st u d y c o m pletes 
t he Da y 3 6 5 Visit , is ter mi nate d, or disc o nti n ue d earl y fr o m t he st u d y (earl y ter mi nati o n). 
4. 6.  
St u d y C o m pleti o n  
T he st u d y will be c o nsi dere d c o m plet e u p o n Heli x mit h ’s a p pr o val of t he cli nical st u d y re p ort. 
4. 7.  
C o m plete d  P artici p a nts  
A Partici pa nt  is c o nsi der e d t o ha ve c o m plet e d t he st u d y if t he Partici pa nt  c o m pletes t he Da y 
3 6 5 Visit.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 5 
Fi nal : 1 2 Oct 2 0 2 1 
5.  
S T U D Y P O P U L A TI O N  
Partici pa n ts w h o c o m plet e t he Da y 1 8 0 Visit i n V M A L S- 0 0 2- 2 are eli gi ble t o e nr oll i n t his 
e xte nsi o n st u d y, V M A L S- 0 0 2- 2 b. 
5. 1.  
N u m ber of P artici p a nts  
T he n u m ber of Partici pa nts t o be e nr olle d i n t his e xte nsi o n st u d y de pe n ds u p o n t he n u m ber of 
Partici pa nt s w h o c o m plet e t he Da y 1 8 0 Visit i n V M A L S- 0 0 2- 2 a n d pr o vi d e writte n i nf or me d 
c o nse nt f or t his e xte nsi o n pr ot oc ol ( pri or t o, d uri n g , or after t h eir Da y 1 8 0 Visit i n t he 
V M A L S - 0 0 2- 2 st u d y). 
5. 2.  
P artici p a nt I de ntific ati o n  
T o mai ntai n c o nfi de ntialit y, t he na me of t he Partici pa nt  s h o ul d n ot be rec or de d o n a n y st u d y 
d oc u me nt ot her t ha n t he i nf or me d c o ns e nt f or m. All Partici pa nt s w h o si g n t he i nf or me d c o ns e nt 
f or m will be i de ntifie d b y t he sa me u ni q ue i de ntifier/ n u m ber t he y w ere assi g ne d i n 
V M A L S - 0 0 2- 2. 
5. 3.  
Lifest yle C o nsi der ati o ns  
5. 3. 1.  
Me als a n d Diet ar y Rest ricti o ns  
T here are n o meal or diet ar y restri cti o ns f or t his st u d y. 
5. 3. 2.  
C affei ne, Alc o h ol, a n d T o b acc o 
T here are n o caffei ne, t o bacc o, or alc o h ol restricti o ns f or t his st u d y.  
5. 3. 3.  
S u p ple m e nts  
T here are n o restricti o ns o n her bal me dici nes or dietar y s u p ple me nts or c ha n ges i n t heir use 
d uri n g t he st u d y. T he use of a n y s u p ple me nts d uri n g t he st u d y will be rec or de d o n t he 
Partici pa nt’s me dical r ec or d a n d t he electr o nic cas e re p ort f or m (e C R F) as c o nc o mita nt 
me dicati o ns.  
5. 3. 4.  
Acti vit y  
T here are n o restricti o ns o n acti vit y. Partici pa nts s h o ul d be a d vise d t o c o nti n ue t heir n or mal 
acti vit y le vel d uri n g t he st u d y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 6 
Fi nal : 1 2 Oct 2 0 2 1 
6.  
S T U D Y I N T E R V E N TI O N  
T here will be n o tr eat me nt a d mi nistere d d uri n g t his st u d y. 
6. 1.  
Me as ures t o Mi ni mize Bi as  
6. 1. 1.  
R a n d o miz ati o n 
T here will be n o r a n d o mizati o n of Partici pa nts i n t his V M A L S- 0 0 2- 2 b e xte nsi o n st u d y ; 
Partici pa nts w h o are e ntere d i nt o t h is e xte nsi o n st u d y will c o nti n ue t o be f oll o we d i n a bli n de d 
fas hi o n.  
6. 1. 2.  
Bli n di n g  
Partici pa nts, I n v esti gat ors, Site staff, C R O staff, a n d S p o ns or staff will re m ai n bli n de d t o 
treat me nt assi g n me nts e x ce pt f or t he d esi g nate d u n bli n de d Cli nical Researc h Ass ociate ( C R A) 
a n d t he u n bli n de d Me dical M o nit or. 
T o a v oi d p ote ntial bias, I n vesti gat ors a n d st u d y staff are e x p ecte d t o refrai n fr o m s hari n g safet y 
a n d treat me nt o utc o mes wit h ot her partici pati n g Sites.  
T he D S M B, i n de pe n de nt of t he S p o ns or, ma y re vi e w i n di vi d ual u n bli n de d Partici pa nt narrati ves 
i n t he case of a n S A E or m ulti ple  S A Es f or  w hic h t he D S M B C hair  re q uests u n bli n di n g, b ut will 
n ot ha ve access t o u n bli n de d ta bles a n d listi n gs u nless re q ueste d b y t he D S M B C hair  w he n 
assessi n g a p ote ntial saf et y si g nal. W hile  t he st u d y is o n g oi n g a n d pri or t o data base l oc k, t h e 
datasets will re mai n bli n de d wit h n o preli mi nar y  s u m mar y of t he st u d y b y t he i n di vi d ual 
treat me nt ar ms e x ce pt w he n re q uest e d b y t he D S M B C hair. 
6. 1. 3.  
M ai nte n a nce of t he Bli n d  
T he treat me nt assi g n me nt f or eac h Partici pa nt t hat was deter mi ne d b y t h e ra n d o mizati o n  m o d ule 
i n t he V M A L S - 0 0 2- 2 st u d y will be c o nti n ue d f or eac h Partici p a nt i n t he V M A L S - 0 0 2- 2 b 
e xte nsi o n st u d y. 
I N C A S E O F E M E R G E N C Y (i.e., S E RI O U S A D V E R S E E V E N T [ S A E]) A N D O N L Y W H E N 
T HI S I N F O R M A TI O N I N F L U E N C E S T H E P A R TI CI P A N T' S M E DI C A L M A N A G E M E N T,  
t he I n v esti gat or ma y c o nt act t he desi g nate d u n bli n de d Me dical M o nit or t o re q uest u n bli n di n g of 
t he treat me nt assi g n me nt. T he date a n d reas o n f or u n bli n di n g will be d oc u me nte d i n t he 
electr o nic d ata ca pt ure ( E D C) s yste m.  
6. 2.  
C o nc o mit a nt T her a p y  
Sta n dar d of care f or A L S  is prese nte d i n t he A merica n Aca de m y of N e ur ol o g y ( A A N) g ui deli ne 
re gar di n g ma n a ge me nt a n d care of t he patie nt wit h A L S. 6 3 Rec o m me n dati o ns are prese nte d f or 
m ulti disci pli nar y care, s y m pt o m ma na ge me nt, a n d t he treat me nt of c o g niti ve/ be ha vi oral 
i m pair me nt. 
6. 3.  
P ri or a n d C o nc o mit a nt Me dic ati o ns, Tre at me nts, a n d Pr oce d ures  
C o nc o mita nt me dicati o ns a n d pr oce d ures  d uri n g V M A L S - 0 0 2- 2 b fr o m D a y 1 8 0 of 
V M A L S - 0 0 2- 2 t o Da y 3 6 5 of t his e xte nsi o n st u d y will be rec or d e d o n t he Me dicati o n a n d 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 7 
Fi nal : 1 2 Oct 2 0 2 1 
Hist or y e C R F o n t he Da ys 2 4 0, 3 0 0, a n d 3 6 5/ E T. A n y me dicati o n or vacci ne, i ncl u di n g 
o ver-t he- c o u nter or pres cri pti o n me dici nes, vita mi ns, her bal s u p ple me nts, a n d pr oce d ures t hat 
t he Partici pa nt is recei vi n g at t he ti me of e nr oll me nt or recei ves d uri n g t he st u d y m ust be 
rec or d e d o n t he C o nc o mita nt Me dicati o ns or C o nc o mita nt Pr oce d ures e C R F. F or eac h 
me dicati o n or treat me nt, t he f oll o wi n g i nf or mati o n will be c ollecte d:  
•  Me dicati o n tra de or ge neric na me, or  pr oce d ure  na me 
•  I n dicati o n f or w hic h t h e me dicati o n/ pr oce d ure w as gi ve n 
•  D ose/stre n gt h, r o ute, a n d fre q ue n c y of a d mi nistrati o n  of me dicati o ns 
•  Date starte d a n d date st o p pe d ( or c o nti n uati o n at st u d y e xit) 
•  Reas o n f or use of c o nc o mita nt me dicati o ns or pr oce d ures 
T he me dical m o nit or m ust be c o ntacte d if t h ere are a n y q uesti o ns  re gar di n g c o nc o mita nt or pri or 
t hera p y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 8 
Fi nal : 1 2 Oct 2 0 2 1 
7.  
DI S C O N TI N U A TI O N O F S T U D Y I N T E R V E N TI O N A N D P A R TI CI P A N T 
WI T H D R A W A L  
7. 1.  
P artici p a nt  Wit h dr a w al/ Disc o nti n u ati o n 
A n y Partici pa nt  ma y v ol u ntaril y disc o nti n ue t he st u d y at a n y ti me wit h o ut prej u dice. T h e 
I n v esti gat or ma y disc o nti n ue a Partici pa nt  fr o m t he st u d y at a n y ti me if, i n t he I n vesti gat or’s 
j u d g me nt, t he Partici pa nt’s healt h or safet y w o ul d be c o m pr o mise d b y re m ai ni n g i n t he st u d y. 
S pecific  reas o ns f or st u d y disc o nti n uati o n i ncl u de t he f oll o wi n g: 
•  Partici pa nt  decisi o n  
•  I n v esti gat or’s decisi o n 
•  T E A E s or T E S A E s 
•  
I ns ufficie nt c o m plia n ce wit h st u d y re q uire me nts 
•  L ost t o f oll o w- u p 
•  Ot her  
T he  s pecific reas o ns f or Partici pa nt  disc o nti n uati o n will be rec or d e d i n t he eC R Fs . 
T he f oll o wi n g assess me nts will be perf or me d  at a n Earl y Ter mi nati o n ( E T) V isit, if p ossi ble, f or 
Partici pa nt s w h o disc o nti n ue pri or t o t he Da y 3 6 5 Visit . 
•  C o m plete P h ysical e xa m i nati o n 
•  Vital si g ns, wei g ht, hei g ht 
•  1 2- lea d EC G 
•  Ser u m che mistr y  a n d he mat ol o g y 
•  C o nc o mita nt me dicati o ns  a n d pr oce d ures 
•  A L S F R S - R 
•  S V C  
•  H H D  
•  A L S A Q - 4 0 
•  P GI C  
•  C GI C  
•  T E A Es , T E S A Es , a n d A E SIs 
7. 2.  
L ost t o F oll o w- u p 
A Partici pa nt  will be c o nsi dere d l ost t o f oll o w - u p if he or s he re peate dl y fails t o ret ur n f or 
sc he d ule d Visit s a n d is u na ble t o be c o ntacte d b y t he Site bet wee n t he D a y 1 8 0 of V M A L S - 0 0 2-
2 a n d t he Da y 3 6 5 ( + 7 da ys) of V M A L S - 0 0 2- 2 b. 
T he f oll o wi n g acti o ns m ust be ta ke n a n d rec or d e d if a Partici pa nt  fails t o ret ur n t o t he cli nic f or a 
re q uire d st u d y Visit : 
•  T he site m ust atte m pt t o c o ntact t he Partici pa nt  a n d resc he d ul e t he misse d Visit  as 
s o o n as p ossi ble. T he site m ust  c o u nsel t he Partici pa nt  o n t he i m p orta nce of 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
2 9 
Fi nal : 1 2 Oct 2 0 2 1 
mai ntai ni n g t he assi g ne d Visit  sc he d ule a n d ascert ai n w het her or n ot t he Partici pa nt  
wis hes t o a n d/ or s h o ul d c o nti n ue i n t he st u d y. 
•  If n o res p o ns e is o btai ne d fr o m t he Partici pa nt, t h e I n vesti gat or is e n c o ura ge d t o 
c o ntact o ne of t h e Partici pa nt ’s relati ves or his/ her ge neral practiti o ner.  
•  Bef ore a Partici pa nt  is dee me d l ost t o f oll o w u p, t he I n vesti gat or or d esi g nee m ust 
ma ke e ver y eff ort t o re g ai n c o ntact wit h t he Partici pa nt , i ncl u di n g at least t hree 
tele p h o ne calls a n d, fi nall y, a certifie d letter t o t he Partici pa nt ’s last k n o w n maili n g 
a d dress . T hes e c o ntact atte m pts s h o ul d be d oc u me nte d i n t he s o urce rec or ds. 
•  S h o ul d t he Partici pa nt  c o nti n ue t o be u nreac ha ble, t he Partici pa nt will be c o nsi dere d 
l ost t o f oll o w- u p.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 0 
Fi nal : 1 2 Oct 2 0 2 1 
8.  
S T U D Y A S S E S S M E N T S A N D P R O C E D U R E S  
All s t u d y pr oce d ures a n d assess me nts t o get her wit h t heir ti mi n g are s u m marize d i n t he S o A i n 
Secti o n 1. 3 . 
Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d. A d here n ce t o t he pr ot o c ol re q uire me nts is 
esse ntial. 
8. 1.  
S afet y Assess m e nts  
T he safet y assess me nts liste d i n Secti o n 1. 3  s h o ul d be f oll o we d d uri n g t he 1 8 0- da y e xte nsi o n 
st u d y. 
8. 1. 1.  
C o m plete P h ysic al E x a mi n ati o ns 
A c o m plete p h ysical e x a mi nati o n ( P E) will be perf or me d o n Da ys 2 4 0 a n d 3 6 5/ E T . T he 
c o m plete P E will i ncl u de t he f oll o wi n g: a n e xa mi nati o n of t he s ki n/i nte g u me ntar y s yste ms, 
ge neral a p peara n ce, hea d, nec k (i ncl u di n g t h yr oi d), e yes, ears, n ose, t hr o at, l y m p h n o des, c hest 
(l u n gs), heart, a b d o me n, m usc ul os keletal s yste m, ne ur ol o gical s yste m, a n d a n y a d diti o nal 
assess me nts nee d e d t o esta blis h Baseli ne  stat us or e val uate s y m pt o ms or T E A Es . A n y 
a b n or malities s h o ul d be cate g orize d as cli nicall y si g nifica nt ( C S) or n ot cli nicall y si g nifica nt 
( N C S), a n d cli nicall y si g nifica nt  a b n or malities s h o ul d be rec or de d as T E A Es, T E S A Es, or 
A E SIs.  I n v esti gat or or q u alifie d me dical pers o n nel w h o r o uti nel y perf or m t hese e val u ati o ns i n 
patie nts wit h A L S will c o n d uct t he e xa mi nati o n, deter mi ne fi n di n gs, a n d assess a n y 
a b n or malities as t o t heir cli nical si g nifica nce.  
8. 1. 2.  
1 2- Le a d Electr oc a r di o gr a ms  
1 2- Lea d E C Gs will be perf or me d  o n D a ys 2 4 0 a n d 3 6 5 / E T. A n y cli nicall y si g nifica nt 
a b n or malities are t o b e rec or de d  as T E A Es . T he E C G rec or di n g will be pri nte d o ut a n d st ore d 
wit h t he Partici pa nt ’s rec or ds. 
8. 1. 3.  
Vit al Si g ns  
Vital si g ns will be meas ure d o n Da y s 2 4 0, 3 0 0, a n d 3 6 5 / E T. After resti n g i n t he seate d p ositi o n 
f or 5 mi n utes, vital si g ns will be rec or d e d  i ncl u di n g te m perat ure, sitti n g bl o o d press ure, h eart 
rate, r es pirat or y r ate, a n d o x y ge n sat urati o n o n r o o m air. T he met h o d of te m perat ure 
meas ure me nt s h o ul d be acc or di n g t o t he Site ’s p olic y a n d s h o ul d be c o nsiste ntl y a p plie d. 
8. 1. 4.  
Cli nic al L a b or at or y Assess me nts 
T he I n vesti gat or m ust re vie w t he Partici pa nt’s la b orat or y test res ults re p orts, d oc u me nt t his 
re vie w, a n d rec or d a n y cli nicall y rele va nt c h a n ges occ urri n g d uri n g t he st u d y. T he la b orat or y 
re p orts m ust be file d wit h t he s o urce d o c u me nts. Cli nicall y si g nifica nt a b n or mal la b orat or y 
fi n di n gs are t h ose t hat ar e n ot ass ociate d wit h t he u n derl yi n g disease, u nless j u d ge d b y t he 
I n v esti gat or t o be m ore s e vere t h a n e x pecte d f or t he Partici pa nt’s c o n diti o n. Cli nicall y 
si g nifica nt a b n or mal la b orat or y fi n di n gs s h o ul d be rec or d e d as T E A Es, T E S A Es, or A E SIs usi n g 
a n a p pr o pri ate me dical di a g n osis.  
Bl o o d sa m ple f or la b orat or y assess me nts will be c ollecte d o n Da ys 2 4 0 a n d 3 6 5 / E T. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 1 
Fi nal : 1 2 Oct 2 0 2 1 
All pr ot oc ol-re q uir e d la b orat or y assess me nts m ust be perf or me d i n acc or d a nce wit h t he 
la b orat or y ma n u al a n d t h e S o A. T he la b orat or y re p orts m ust be file d wit h t he s o urce d o c u me nts. 
8. 1. 4. 1. 1.  He m at ol o g y 
•  W hite bl o o d cell c o u nt 
•  Ne utr o p hil c o u nt (i ncl u di n g calc ulate d a bs ol ute ne utr o p hil c o u nt) 
•  He m o gl o bi n 
•  He mat ocrit  
•  Platelet  c o u nt 
8. 1. 4. 1. 2.  Ki d ne y F u ncti o n Tests  
•  Bl o o d urea nitr o ge n ( B U N) 
•  Creati ni ne  
8. 1. 4. 1. 3.  Li ver F u ncti o n Tests  
•  As partate a mi n otra nsferase  ( A S T) 
•  Ala ni ne a mi n otra nsf eras e  ( A L T) 
•  Al kali ne  p h os p hatase 
•  Ga m ma - gl uta m yl tra ns pe pti dase ( G G T) 
•  T otal  bilir u bi n  
•  T otal  pr otei n 
•  Al b u mi n  
8. 1. 4. 1. 4.  Cli nic al C he mistr y  
•  Electr ol ytes (s o di u m, p otassi u m, c hl ori de, bicar b o nate, cal ci u m, i n or ga nic p h os p hate, 
ma g nesi u m) 
•  Gl uc ose (r a n d o m c ollecti o n, i.e., n ot necessaril y fasti n g) 
•  A m ylase  
•  Li pase  
•  Lactate  d e h y dr o ge n ase 
•  Creati ne  ki nase 
8. 1. 5.  
Sl o w Vit al C a p acit y  
Sl o w vital ca pacit y is a p ul m o nar y f u ncti o n test t hat q ua ntifies t he v ol u me of air t hat ca n be 
sl o wl y e x hale d aft er sl o w ma xi m u m i n halati o n. S V C will be meas ure d a n d rec or d e d  o n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 2 
Fi nal : 1 2 Oct 2 0 2 1 
Da ys  2 4 0, 3 0 0, a n d 3 6 5/ E T. Cli nicall y si g nifica nt a b n or mal  S V C  fi n di n gs s h o ul d be rec or de d as 
T E A Es, T E S A Es, or A E SIs.  
8. 2.  
Ot her Assess m e nts a n d Pr oce d ures  
8. 2. 1.  
Re vise d A m y otr o p hic L ater al Scler osis F u ncti o n al R ati n g  
T he A L S F R S -R is a vali date d rati n g scale f or m eas uri n g t he gl o bal f u ncti o n of patie nts wit h 
A L S. It pr o vi d es a healt h pr ofessi o nal- g e nerate d esti mate of t he patie nt’s d e gree of f u ncti o nal 
i m pair me nt, w hic h ca n b e e val uat e d seriall y t o o bjecti vel y assess a n y res p o nse t o treat me nt or 
pr o gressi o n of diseas e. T he A L S F R S - R i ncl u des t wel ve q uesti o ns t hat as k t he I n v esti gat or t o rat e 
his/ her i m pressi o n of t he patie nt’s le vel of f u n cti o nal i m pair me nt i n perf or mi n g o ne of t wel ve 
c o m m o n tas ks, e. g., cli m bi n g stairs. Eac h tas k is rate d o n a fi ve- p oi nt scale fr o m 0 (ca n't d o) t o 
4 ( n or mal a bilit y). I n di vi d ual ite m sc ores are s u m me d t o pr o d uce a re p ort e d sc ore bet w ee n 
0 = w orst a n d 4 8 = b est. T h e A L S F R S- R will be c o n d ucte d  o n Da ys 2 4 0, 3 0 0, a n d 3 6 5 / E T. Details 
a b o ut t he scale ca n be f o u n d i n Secti o n 1 0. 4 , A p pe n di x 4. 
8. 2. 2.  
H a n d hel d D y n a m o m etr y  
M uscle stre n gt h will be meas ure d q u a ntitati vel y b y H H D a n d t he c ha n ge fr o m baseli ne ( Da y 0, 
V M A L S - 0 0 2- 2) i n H H D f oll o wi n g E n ge nsis i njecti o ns as c o m pare d t o Place b o. H H D is a 
pr oce d ur e b y w hic h a d y na m o meter is a p plie d t o t he b o d y of a n i n di vi d ual bei n g teste d. 6 4 
A n o n- A C p o wer e d d y na m o meter ( ma n ufact ure d b y H o g ga n Healt h I n d ustries, I nc) will be use d 
at all cli nical sites. T hese meas ure me nts will be perf or me d o n D a ys 2 4 0, 3 0 0, a n d 3 6 5 / E T. 
Stre n gt h meas ure me nts will be e val uate d f or i n di vi d ual m uscles.6 5 
8. 2. 3.  
Q u alit y of Life Assess me nt, P atie nt Re p orte d O utc o mes, a n d Cli nic al Re p orte d 
O utc o m es  
8. 2. 3. 1.  
A m y otr o p hic L ater al Scler osis Assess me nt Q uesti o n n aire  
T he A L S A Q - 4 0 is a disease-s pecific, Partici pa nt s elf-re p ort healt h stat us, or electr o ni c 
patie nt -re p ort e d o utc o me (e P R O). T here are 4 0 q u esti o ns i n t he A L S A Q- 4 0 wit h 5 discrete 
scales: p h ysical m o bilit y ( 1 0 q uesti o ns), acti vities of dail y li vi n g a n d i n de pe n de nce 
( 1 0 q uesti o ns), eati n g a n d dri n ki n g ( 3 q uesti o ns), c o m m u nicati o n ( 7 q uesti o ns), a n d e m oti o nal 
reacti o ns ( 1 0 q u esti o ns). T he A L S A Q- 4 0 will be meas ure d o n D a ys 2 4 0 a n d 3 6 5/ E T. See 
Secti o n  1 0. 5 , A p pe n di x 5, f or t he A L S A Q- 4 0 q u esti o n naire. 
Partici pa nts are as ke d t o t hi n k a b o ut t he diffic ulties t hat t he y ma y ha ve e x p erie nce d d uri n g t he 
last t w o wee ks ( e. g., “I h a ve f o u n d it diffic ult t o fee d m yself”). Partici pa nts are as k e d t o i n dicate 
t he fre q u e nc y of eac h e v e nt b y selecti n g o ne of 5 o pti o ns ( Li kert scale): n e ver, rarel y, 
s o meti mes, ofte n, al wa ys, or ca n n ot d o at all. 
8. 2. 3. 2.  
P atie nt Gl o b al I m pressi o n of C h a n ge 
T he Partici pa nt’s i m pressi o n of c ha n ge at Da ys 24 0 a n d 3 6 5/ E T will be meas ure d wit h t he P GI C 
q uesti o n naire t hr o u g h us e of t he e P R O. T his q uesti o n naire meas ures t he Partici pa nt’s perce pti o n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 3 
Fi nal : 1 2 Oct 2 0 2 1 
of t heir le vel of acti vit y, s y m pt o ms, e m oti o ns, a n d o verall q ualit y of life d uri n g t he st u d y . Eac h 
descri pt or is ra n k e d o n a 1 0- p oi nt scale, w here M u c h W orse = 0, N o C ha n g e = 5, a n d M u c h 
Better = 1 0 . T he P GI C q uesti o n naire is prese nt e d i n Secti o n 1 0. 6 , A p pe n di x 6. 
U p o n c o m pleti o n of t he q uesti o n naire b y t he Partici pa nt, t he st u d y c o or di n at or will c hec k t he 
q uesti o n naire f or c o m plete ness. A n y o missi o ns or a m bi g u o us a ns wers will be clarifi e d b y t he 
Partici pa nt pri or t o lea vi n g t he cli nic.  
8. 2. 3. 3.  
Cli nic al Gl o b al I m pressi o n of C h a n ge  
T he C GI C is a vali date d i nstr u me nt c o m plete d b y o bser vers as a n ass ess me nt of Q o L. T he C GI C 
is a 8- p oi nt scale wit h sc ores t hat ra n g e fr o m 0 ( n ot c o n d ucte d) t o 1 ( v er y m uc h i m pr o ve d) t o 
7 ( ver y m uc h w orse). T h e test will be a d mi nistere d d uri n g t he Da ys 2 4 0 a n d 3 6 5 / E T Visits. T he 
C GI C q uesti o n nair e is pr ese nte d i n Secti o n 1 0. 6 , A p pe n di x 6. 
8. 3.  
Tre at m e nt -e m er g e nt A d verse E ve nts a n d Tre at me nt -e mer ge nt Seri o us A d verse 
E ve nts  
T he defi niti o ns of T E A Es  a n d T E S A Es  ca n b e f o u n d i n Secti o n  1 0. 2 , A p pe n di x 2. 
8. 3. 1.  
Ti m e Peri o d a n d Fre q ue nc y f or C ollecti n g T E A E  a n d T E S A E  I nf or m ati o n 
All T E A Es  a n d T E S A Es  will be c ollecte d after si g ni n g i nf or me d c o nse nt pri or t o, o n , or after 
Da y 1 8 0 of t he St u d y V M A L S- 0 0 2- 2 u ntil t he ti me t hat t he Partici pa nt c o m pletes or wit h dra ws 
c o nse nt f or V M A L S- 0 0 2- 2 b (see d efi niti o n of T E A E, Secti o n  1 0. 2 ).  
All T E S A Es will be rec or de d a n d r e p orte d t o t he S p o ns or or desi g nee i m me diatel y a n d u n der n o 
circ u msta nce s h o ul d t his e xcee d 2 4 h o urs, as i n dicate d i n Secti o n 1 0. 2. 5 , A p pe n di x 2. T he 
I n v esti gat or will s u b mit a n y u p date d T E S A E dat a t o t he S p o ns or wit hi n 2 4 h o urs of its 
a vaila bilit y. 
I n v esti gat ors ar e n ot o bli gate d t o acti vel y see k T E A Es or T E S A Es after c o ncl usi o n of t he st u d y 
partici pati o n. H o we v er, if t he I n vesti gat or lear ns of a n y T E S A E, i ncl u di n g a deat h, at a n y ti me 
after a Partici pa nt  has b ee n disc o nti n ue d fr o m t he st u d y, a n d he/s he c o nsi ders t he e ve nt t o be 
p ossi bl y, pr o ba bl y, or defi nitel y relate d t o t he st u d y i nter ve nti o n or st u d y partici pati o n, t he 
I n v esti gat or m ust pr o m ptl y n otif y t he S p o ns or. 
8. 3. 2.  
Met h o d of Detecti n g T E A Es  a n d T E S A Es  
T he met h o d of rec or di n g, e val uati n g, a n d ass essi n g ca usalit y of T E A Es a n d T E S A Es , a n d t he 
pr oce d ur es f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n Secti o n 1 0. 2 , 
A p pe n di x 2. 
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g T E A Es a n d/ or T E S A Es. O pe n -e n de d a n d 
n o n-lea di n g ver b al q uesti o ni n g of t he Partici pa nt  is t he preferre d m et h o d t o i n q uire a b o ut T E A E 
occ urr e nces.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 4 
Fi nal : 1 2 Oct 2 0 2 1 
8. 3. 3.  
S A E Re p orti n g t o t he S p o ns or or Desi g nee  
All S A Es s h o ul d be re p orte d t o t he S p o ns or or desi g nee wit hi n 2 4 h o urs of k n o wle d ge of t he 
S A E occ urri n g (s ee Secti o n  1 0. 2 , A p pe n di x 2). 
8. 3. 4.  
A d verse E ve nts of S peci al I nterest  
A n y of t he A E SI s t hat occ ur d uri n g t he st u d y, as d escri be d b el o w , m ust be rec or d e d  as A E SI a n d  
a n y of t he A E SI t hat meet t he criteria f or a seri o us e ve nt ( Secti o n 8. 3 ) m ust be re p ort e d as a 
T E S A E a n d i de ntifie d as a n A E SI.  
C ate g ories of A E SIs  
T here are t w o  mai n cate g ories of A E SIs  as prese nt e d bel o w : 1) t h ose c o nsi d ere d t o be relate d t o 
t he a n gi o ge nesis p ote ntial of E n ge nsis, 2) ot her m e dical pr o ble ms i n t his patie nt p o p ulati o n, a n d 
3) C O VI D - 1 9 i nf ecti o ns occ urri n g i n Partici pa nts d uri n g t he st u d y. 
8. 3. 4. 1.  
A E SI C o nsi dere d Rel ate d t o A n gi o ge n esis 
At her oscler osis  
H y per plasia of t he vasa v as or u m i n t he earl y sta g es of at her oscl er osis is i n de pe n de nt of 
a n gi o ge nesis, b ut t he i nti mal ne o vasc ularizati o n t hat f oll o ws t he h y per plasia of t he vasa v as or u m 
is a n gi o ge nesis- de pe n d e nt.6 6 A n gi o ge nesis i ncreas es o x y ge n a n d n utrie nts t o t he arter y wall a n d 
s u p p orts i nitial pla q ue gr o wt h. O nce t he at her oscl er otic pla q ue d e vel o ps, i nti mal a n gi o ge nesis is 
t h o u g ht t o c o ntri b ute t o c haract eristics of a n u nsta ble pla q ue, pla q ue h e m orr ha ge, a n d pl a q ue 
r u pt ure. T heref ore, dia g n oses s u g gesti ve of rece nt c or o nar y arter y disease si nce Baseli ne  will be 
e val uate d as A E SIs.  
Ca ncer  
A n gi o ge nesis pla ys a n i m p orta nt r ole i n t he pr oliferati o n a n d m etastatic s prea d of ca n cer as t hese 
pr ocesses are d e pe n de nt o n a n a de q u ate s u p pl y of o x y ge n a n d n utrie nts a n d re m o val of w aste 
pr o d ucts. 6 7 All t y pes of ca ncer r e p orte d d uri n g t he st u d y will be dee me d t o be A E SIs.  
8. 3. 4. 2.  
Ot her Me dic al Pr o ble ms  i n A L S P atie nts 
Se veral me dical pr o ble ms are fre q ue ntl y o bser ve d i n patie nts wit h A L S t hat s h o ul d be 
c o nsi dere d A E SIs. T h ese me dical pr o ble ms are liste d bel o w.  
•  P ul m o nar y Me dical Pr o ble ms: Beca use patie nts wit h A L S are at a n i ncreas e d ris k t o 
de vel o p p ul m o nar y me di al pr o ble ms s uc h as as pirati o n of f o o d or li q ui ds. p ne u m o nia, 
a n d res pirat or y arrest, all e ve nts of t his t y pe t hat occ ur d uri n g t he st u d y will be 
c o nsi dere d A E SIs. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 5 
Fi nal : 1 2 Oct 2 0 2 1 
•  Pr o gressi ve M uscle Wea k ness:  Beca use s o me p atie nts wit h A L S ma y de vel o p ra pi dl y 
pr o gressi ve m uscle wea k ness t hat res ults i n l oss of a bilit y t o care f or self, d ec u bit us 
ulcers, or w ei g ht l oss d ue t o i m paire d de gl utiti o n; all e ve nts of t his t y pe t hat occ ur d uri n g 
t he st u d y will be c o nsi dere d A E SIs. 
•  B ul bar Disease:  Partici pa nts ma y de vel o p b ul bar disease or w orse ni n g o n b ul bar disease 
d uri n g t he st u d y, ma nifeste d as c halle n g es wit h d ysart hria, facial w ea k ness, i m paire d 
t o n g ue p ulsi o n or palate ele vati o n, a n d i m paire d masticati o n a n d s wall o wi n g; all of t hese 
t y pes of e ve nts t hat occ ur d uri n g t he st u d y will be c o nsi dere d A E SIs.  
8. 3. 4. 3.  
C O VI D - 1 9 I nfecti o ns 
A dia g n osis of a C or o na Vir us Disease 2 0 1 9 ( C O VI D - 1 9) i nfecti o n occ urri n g i n Partici pa nts will 
be rec or de d as a n A E SI a n d t heir dis p ositi o n d uri n g t he trial f oll o wi n g t he dia g n osis of t he 
C O VI D - 1 9 i nfecti o n will be trac k e d. 
8. 3. 5.  
F oll o w- u p of T E A Es,  T E S A Es, a n d A E SIs  
After t he i nitial T E A E  or T E S A E re p ort, t he I n v esti gat or is re q uire d t o pr oacti vel y f oll o w eac h 
Partici pa nt  at s u bse q ue nt Visits/c o ntacts. All T E A Es, T E S A Es , a n d A E SIs  (see Secti o n 8. 3. 4 ) 
will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he e ve nt is ot her wise e x pl ai ne d, or t he Partici pa nt  
is l ost t o f oll o w- u p (as defi ne d i n Secti o n  1 0. 2. 3 , A p pe n di x 2 ). 
8. 3. 6.  
Re g ul at or y Re p orti n g Re q uire me nts f or T E S A Es  
Pr o m pt n otificati o n b y t he I n vesti gat or t o Heli x mit h of a n S A E is esse ntial t o e ns ure t hat le gal 
o bli gati o ns a n d et hical res p o nsi bilities t o war ds t he safet y of Partici p a nt s a n d t he safet y of a st u d y 
dr u g u n der cli nical i n vesti gati o n are met. 
Heli x mit h  has a le gal res p o nsi bilit y t o n otif y b ot h t he l ocal re g ulat or y a ut h orit y a n d ot her 
re g ulat or y a g e ncies a b o ut t he safet y of a st u d y dr u g u n der cli nical i n vesti gati o n. T he S p o ns or 
will c o m pl y wit h c o u ntr y -s pecific re g ulat or y re q uire me nts relati n g t o safet y re p orti n g t o t he 
re g ulat or y a ut h orit y, I nstit uti o nal Re vie w B oar ds (I R Bs), a n d I n vesti gat ors.  
F or all st u dies, I n vesti gat or Safet y Re p orts m ust be pre pare d f or s us pect e d u ne x pecte d s eri o us 
a d verse reacti o ns ( S U S A Rs) acc or di n g t o l ocal re g ulat or y re q uire m e nts a n d Heli x mit h’s  p olic y 
a n d f or w ar de d t o I n v esti gat ors as necessar y. 
A n I n vesti gat or w h o r ecei ves a n I n vesti gat or Safet y Re p ort descri bi n g a T E S A E or ot her s pecific 
safet y i nf or mati o n ( e. g., s u m mar y or listi n g of T E S A Es) fr o m t he S p o ns or will re vie w a n d t he n 
n otif y t he I R B if a p pr o priate acc or di n g t o l ocal re q uire me nts. 
8. 3. 7.  
Heli x mit h’s  Res p o nsi bilit y  
All T E A Es a n d T E S A Es will be re p orte d o n a n a n n ual basis t o F D A i n acc or da nce wit h t he I N D 
re g ulati o n ( 2 1 C o de of Fe deral Re g ul ati o ns [C F R ] 3 1 2). Per t he 2 0 1 0 F D A G ui da nce D o c u me nt 
f or I n d ustr y a n d I n vesti g at ors “ Safet y Re p orti n g Re q uire me nts f or I N Ds a n d bi oa vaila bilit y 
(B A )/ bi oe q ui vale nce (B E ) St u dies,” e ve nts cate g orize d as “ p ossi bl y” or “ pr o ba bl y” relate d will 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 6 
Fi nal : 1 2 Oct 2 0 2 1 
be treate d as “s us pecte d a d verse reacti o ns.” E ve nts cate g orize d as “ d efi nitel y” relate d will be 
treate d as a n “a d vers e reacti o n” (a d verse dr u g reacti o n, A D R). 
All seri o us a n d u ne x pecte d st u d y- dr u g- relate d a d verse reacti o ns ( S U S A Rs)  or s us pecte d a d verse 
dr u g reacti o ns ( S A D Rs) will be re p orte d  t o F D A a n d t o all partici pati n g I n v esti gat ors i n a n I N D 
Safet y Re p ort wit hi n 1 5 cale n dar da ys of t he e ve nt after H eli x mit h deter mi nes t hat t he s us pecte d 
a d verse reacti o n q ualifies f or re p orti n g ( 2 1 C F R 3 1 2. 3 2). A n y u ne x pecte d fatal or life-
t hreate ni n g st u d y- dr u g-relate d a d vers e reacti o n  or s us pecte d a d v erse reacti o n will be re p orte d t o 
t he A ge nc y wit hi n 7 cale n dar da ys after t he S p o ns or’s i nitial recei pt of t he i nf or mati o n. 
Heli x mit h will n otif y all partici pati n g I n vesti gat ors of a n y ne w s afet y i nf or mati o n t hat alters t he 
c urre nt ris k - b e nefit assess me nt of t he st u d y me dicati o n or t hat w o ul d be s ufficie nt t o c o nsi der 
c ha n ges i n E n ge nsis a d mi nistrati o n or i n t he o verall c o n d uct of t he st u d y. 
8. 3. 8.  
Pre g n a nc y a n d C o ntr ace pti o n 
8. 3. 8. 1.  
Pre g n a nc y Test ( W o m e n of C hil d be ari n g P ote nti al O nl y) a n d C o ntr ace pti o n 
Fe male Partici pa nt s m ust be n o n pre g na nt, n o nlact ati n g, a n d eit her p ost me n o pa usal f or at least 
1 year, or s ur gicall y sterile f or at least 3 m o nt hs, or a gree t o use d o u ble- b arrier c o ntrace pti o n 
fr o m 1 4 da ys pri or t o D a y 1 8 0 visit i n V M A L S -0 0 2 - 2 a n d/ or t heir last c o nfir me d me nstr ual 
peri o d pri or t o Da y 1 8 0 ( w hic he ver is l o n ger) u ntil 2 m o nt hs after t he last visit o n Da y 3 6 5 / E T. 
D o u ble- barrier c o ntrace pti o n ma y i ncl u de, b ut is n ot li mite d t o, i ntra uteri ne de vice wit h 
s per mici de, fe m ale c o n d o m wit h s per mici de, d ia p hra g m wit h s per mici de, cer vical ca p wit h 
s per mici de; ha vi n g a mal e se x ual part ner w h o a grees t o use a mal e c o n d o m wit h s per mici de; or 
ha vi n g a sterile se x u al part ner.  
F or w o me n of c hil d beari n g p ote ntial, a uri ne beta h u ma n c h ori o nic g o na d otr o pi n ( β -H C G) test 
will be perf or me d o n Da y 3 6 5 / E T t o e val uate w h et her t he Partici pa nt  is pre g na nt. 
T he r h yt h m met h o d, a bsti ne nce, o uter c o urse, or celi bac y are n ot c o nsi dere d acce pta ble met h o d 
of c o ntrace pti o n. 
8. 3. 8. 2.  
Pre g n a nc y  
T he I n vesti gat or will c oll ect pre g n a nc y i nf or m ati o n o n a n y fe male Partici pa nt  w h o bec o mes 
pre g na nt w hile partici pati n g i n t his st u d y. T he i nitial i nf or mati o n will be s u b mitte d t o t he 
Heli x mit h wit hi n 2 4 h o urs of lear ni n g of a Partici p a nt ’s pre g na n c y. 
F urt her d osi n g will be disc o nti n ue d f or a n y fe mal e Partici pa nt  w h o bec o mes pre g na nt d uri n g t he 
st u d y. 
T he Partici pa nt  will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. T he I n vesti gat or 
will c ollect f oll o w - u p i nf or mati o n o n t he Partici pa nt  a n d t he ne o nate, a n d t he i nf or mati o n will be 
f or war de d t o Heli x mit h . Ge ner all y, f oll o w- u p will n ot be re q uire d f or l o n ger t ha n 6 t o 8 wee ks 
be y o n d t he esti mate d deli ver y date. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 7 
Fi nal : 1 2 Oct 2 0 2 1 
W hile pre g na n c y itself is n ot c o nsi dere d t o be a T E A E or T E S A E, a n y pre g na nc y c o m plicati o n 
or electi ve ter mi nati o n of a pre g na n c y f or m e dical reas o ns will be re p orte d as a T E A E or 
T E S A E. A s p o nta ne o us a b orti o n ( occ urri n g at < 2 2 wee ks gestati o nal a ge) or still birt h ( occ urri n g 
at > 2 2 wee ks gestati o nal a ge) is al w a ys c o nsi dere d t o be a T E S A E a n d will be re p orte d as s uc h. 
Ot her a b n or m al pre g na n c y o utc o mes (e. g., fetal deat h, c o n ge nital a n o malies, ect o pic pre g n a nc y) 
are als o c o nsi dere d T E S A Es a n d will be re p or te d. 
A n y p ost-st u d y pre g na nc y-relate d S A E c o nsi dere d p ossi bl y, pr o ba bl y, or defi nitel y relate d t o t he 
st u d y dr u g b y t he I n vesti gat or will be re p ort e d t o t he Heli x mit h . W hile t he I n v esti gat or is n ot 
o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y Partici pa nt s, he or s he ma y lear n of a n 
S A E t hr o u g h v ol u ntar y r e p orti n g. 
T he I n vesti gat or will rec or d a narrati ve des cri pti o n of t he c o urs e of eac h pre g na nc y a n d its 
o utc o me. 
8. 3. 9.  
Dise ase -R el ate d E ve nts a n d/ or Dise ase - Rel ate d O utc o mes N ot Q u alif yi n g as A Es 
or S A Es  
E xce pt f or si g ns a n d s y m pt o ms of A L S , all disease -rel ate d e v e nts or diseas e-rel ate d o utc o mes 
q ualif y as T E A Es or T E S A Es.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 8 
Fi nal : 1 2 Oct 2 0 2 1 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  
Detaile d statistical met h o ds are des cri be d i n t he St atistical A nal ysis Pla n ( S A P) . 
9. 1.  
S a m ple Size Deter mi n ati o n  
T he n u m ber of Partici pa nts i n t his st u d y will be deter mi ne d b y t he n u m ber w h o c o m plete t he 
Da y 1 8 0 Visit i n V M A L S- 0 0 2- 2.  
9. 2.  
P o p ul ati o n f or A n al ysis: S afet y P o p ul ati o n 
T he safet y a nal ysis p o p ulati o n will c o ntai n all P artici pa nt s w h o e nr oll i n V M A L S - 0 0 2- 2 b. 
9. 3.  
St atistic a l A n al yses 
T he S A P will be fi nalize d pri or t o data base l o c k a n d will i ncl u de a m ore tec h nical a n d d etaile d 
descri pti o n of t he statistical a nal yses d escri b e d i n t his secti o n . T his secti o n is a s u m mar y of t he 
pla n ne d e n d p oi nts. 
9. 3. 1.  
Pri m ar y E n d p oi nt s 
Safet y a nal yses i n t his st u d y will e val uate t he safet y pr ofile of E n ge nsis. T he pri mar y e n d p oi nts 
f or saf et y are as f oll o ws: 
•  I n ci de nce of T E A Es, T E S A Es , a n d A E SIs 
•  I n ci de nce of cli nicall y si g nifica nt la b orat or y v al u es 
N o f or mal statistical testi n g will be c o n d ucte d f or t he safet y a n al yses . All P artici pa nt s i n t he 
S afet y P o p ulati o n wi ll be i ncl u de d i n t hese a nal ys es. F or d ata a n al ysis, Partici pa nt s will be 
gr o u pe d b y t he treat me nt recei v e d d uri n g V M A L S- 0 0 2- 2. All s u m maries will be deri ve d fr o m 
a n d base d o n a vaila ble d ata . N o i m p utati o n will be perf or me d f or missi n g val ues. All safet y 
a nal yses will be ma de o n t he Safet y P o p ulati o n. 
9. 4.  
D at a S afet y M o nit ori n g B o ar d 
T he i n de pe n de nt D S M B will als o perf or m a Safet y Re vie w, usi n g a li mite d set of u n bli n de d 
ta bles a n d/ or listi n gs of all safet y data, i ncl u di n g all re p orte d A E SIs, T E A Es, a n d T E S A Es. T he 
D S M B ma y perf or m m ulti ple u n bli n de d a nal yses f or safet y d uri n g t he st u d y.  
T he o bjecti ves of t he D S M B meeti n gs are t o re vie w t he safet y o utc o m es of t he st u d y a n d pr o vi de 
g ui da nce t o Heli x mit h  re gar di n g t he safet y of E n g e nsis. T he data a n al yses f or t he D S M B 
meeti n gs will be directl y pr o vi de d t o t he D S M B me m bers , a n d n o d ata will be release d t o t he 
st u d y s p o ns or or bli n de d desi g nees. I nf or mati o n will o nl y be s hare d wit h H eli x mit h  or t he 
Heli x mit h Pr oject Steeri n g C o m mittee w he n t he D S M B rec o m me n ds a te m p orar y s us pe nsi o n or 
ter mi nati o n of t he st u d y. N o  a dj ust me nt will be ma de  f or m ulti ple testi n g d ue t o t he D S M B data 
re vie ws. F urt her d etails of D S M B res p o nsi bilities are i ncl u de d i n t he D S M B C harter.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
3 9 
Fi nal : 1 2 Oct 2 0 2 1 
1 0.  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
1 0. 1.  
A p pe n di x 1 . Re g ul at or y, Et hic al , a n d St u d y O versi g ht C o nsi der ati o ns 
1 0. 1. 1.  
Re g ul at or y a n d Et hic al C o nsi der ati o ns 
1 0. 1. 1. 1.  I nstit uti o n al Re vie w  B o ar d 
Pri or t o t he i nitiati o n of t he st u d y, t he pr ot oc ol, t he i nf or me d c o ns e nt f or m, a n d I n vesti gat or’s 
Br oc h ure will be s u b mitte d t o t he I R B f or a p pr o v al. B y si g ni n g t he “ State me nt of I n vesti gat or” 
f or m ( F or m F D A 1 5 7 2), t he I n v esti gat or is e ns uri n g t hat a n I R B c o m plia nt wit h t he re q uire me nts 
set f ort h i n 2 1 C F R 5 6 will be res p o nsi ble f or t he i nitial a n d c o nti n ui n g re vie w of t he pr o p os e d 
cli nical st u d y. A c o p y of t he I R B a p pr o val letter f or t he pr ot oc ol, t he i nf or me d c o nse nt, a n d t he 
pr ot oc ol si g nat ure pa g e m ust be s u b mitte d t o t he S p o ns or pri or t o releas e of i n vesti gati o nal 
s u p plies t o t he St u d y Site. T he a p pr o v al letter m ust refer t o t he s p ecific pr ot oc ol a n d t he 
i nf or me d c o nse nt f or m. T he St u d y Site m ust mai ntai n a n acc urate a n d c o m plete rec or d of all 
re p orts, d oc u me nts, a n d ot her s u b missi o ns ma de t o t he I R B c o n cer ni n g t his pr ot oc ol. A list of 
t he I R B me m bers, t heir titles or occ u pati o ns, a n d t heir i nstit uti o nal affiliati o n, or a n I R B 
ass ura nce n u m ber m ust b e pr o vi de d t o t he S p o ns or pri or t o release of st u d y s u p plies.  
Healt h a ut h orit y re g ul ati o ns re q uire t hat all a d v ertise me nts f or Partici pa nt  recr uit me nt be 
a p pr o ve d b y a n I R B pri or t o i m ple me ntati o n. T he c o m plete te xt a n d f or mat m ust be s u b mitte d t o 
t he S p o ns or f or a p pr o v al pri or t o I R B s u b missi o n. 
T he I n vesti gat or is r es p o nsi ble f or n otif yi n g t he I R B of a n y S A Es as re q uire d b y t he I R B. A 
c o p y of t he n otificati o n m ust be f or war d e d t o t he S p o ns or or its desi g nee. 
Stat us re p orts m ust be s u b mitte d t o t he I R B at least o nce a year ( or m ore fre q ue ntl y as re q uire d 
b y t he I R B), a n d t he I R B m ust be n otifie d of c o m pleti o n or ter mi nati o n of t he st u d y. 
1 0. 1. 1. 2.  I nf or m e d C o nse nt  Pr ocess  
T he I n vesti gat or h as t he r es p o nsi bilit y t o i nf or m eac h Partici pa nt, pri or t o , o n, or a fter t h e Da y 
1 8 0 Visit i n V M A L S- 0 0 2- 2, of t he p ur p ose of t his cli nical st u d y, i ncl u di n g p ossi ble ris ks a n d 
be nefits, a n d d oc u m e nt t he i nf or me d c o ns e nt pr ocess i n t he Partici pa nt’s c h art. A n i nf or me d 
c o nse nt f or m (I C F) c o ntai ni n g t he re q uire d G C P ele me nts of i nf or me d c o ns e nt m ust be 
ge nerat e d b y t he I n v esti gat or. After a p pr o v al b y t he S p o ns or, t he I C F m ust be s u b mitte d t o a n d 
a p pr o ve d b y a n I R B. Pri or t o e ntr y i nt o t he st u d y or i nitiati o n of a n y st u d y- relate d pr o ce d ur es, 
t he Partici pa nt m ust rea d, si g n, a n d date t he I C F. T he pers o n e x ec uti n g t he c o nse nt m ust als o 
si g n a n d date t he I R B-a p pr o ve d I C F. O ne ori gi nal I C F is t o be retai n e d b y t he St u d y Site, a n d a 
c o p y is t o be gi ve n t o t he Partici pa nt. T he i nf or me d c o nse nt pr ocess m ust be d oc u me nte d i n t he 
Partici pa nt’s s o urce/ me di cal rec or d.  
T he I C F m ust be writte n i n a la n g ua ge i n w hic h t h e Partici pa nt  is fl ue nt. If a f orei g n la n g u a ge 
tra nslati o n is re q uire d, a state me nt of certificati o n of t he tra nslati o n m ust be iss ue d. Re g ulati o ns 
re q uire t hat f orei g n la n g u a ge I C Fs b e s u b mitte d t o t he I R B f or a p pr o v al. T he I n vesti gat or m ust 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 0 
Fi nal : 1 2 Oct 2 0 2 1 
f or war d a c o p y of t he I C F, t he certifie d f orei g n la n g ua ge tra nslati o n, a n d a n I R B a p pr o v al letter 
t o t he S p o ns or. 
T he I n vesti gat or will e x plai n t he st u d y p ur p ose, pr oce d ures, a n d Partici pa nt ’s res p o nsi bilities t o 
t he Partici pa nt. T he Parti ci pa nt ’s willi n g ness a n d a bilit y t o meet t he f oll o w- u p re q uire m e nts will 
be deter mi ne d a n d writte n i nf or me d c o nse nt will be o btai ne d. T he Partici pa nt  will si g n a n d date 
t he I C F. T he I n vesti gat or or a q ualifie d d esi g nee will als o si g n a n d date t he I C F. T h e ori gi nal 
I C F will be retai n e d wit h t he Partici pa nt ’s rec or ds; a c o p y will be pr o vi de d t o t he Partici pa nt .  
If t he I C F is a me n de d d uri n g t he st u d y, t he I n v esti gat or or a q u alifie d desi g nee m ust f oll o w all 
a p plica ble r e g ulat or y r e q uire me nts pertai ni n g t o a p pr o val of t he a m e n de d I C F b y t he I R B. F or 
eac h n e w versi o n of t he I C F, t he I R B will be c o ns ulte d t o deter mi ne if Partici pa nt s w h o ha ve n ot 
c o m plete d t he st u d y m ust be re- c o nse nte d t o t he n e w I C F.  
1 0. 1. 1. 3.  O bli g ati o ns of t he Heli x mit h  a n d t he  I n vesti g at or 
Heli x mit h  a n d t he I n v esti gat or m ust c o m pl y wit h all a p plica ble re g ulati o ns. I n a d diti o n, t he 
I n v esti gat or m ust f oll o w l ocal a n d i nstit uti o nal re q uire me nts pertai ni n g, b ut n ot li mite d, t o 
cli nical researc h, i nf or me d c o nse nt i ncl u di n g t he use a n d discl os ure of t he Partici pa nt s’ pr otecte d 
healt h i nf or mati o n ( P HI), a n d I R B re g ulati o ns. Heli x mit h will n otif y t he I n vesti gat or of pr ot oc ol 
a n d a me n d me nt a p pr o vals b y re g ulat or y a ut h orities w he n a p plica ble. 
T he I n vesti gat or a n d cli nical researc h c o or di nat or will be a vaila ble t o res p o n d t o reas o na ble 
re q uests a n d a u dit q ueries ma de b y t he a ut h orize d re g ulat or y a g e nc y re prese ntati ves. T he 
I n v esti gat or a n d cli nical researc h c o or di nat or will pr o vi de Heli x mit h  wit h a d va nce writte n 
n otificati o n if t he y pla n t o rel ocate t o a n ot her i nstit uti o n.  
E xce pt w here t he I n v esti gat or’s si g nat ure is s pecificall y re q uire d, t he ter m “I n vesti gat or” as use d 
i n t his pr ot oc ol a n d pr ot oc ol-relat e d d oc u me nts is u n derst o o d t o refer t o t he Pri nci pal 
I n v esti gat or ( PI) or a p pr o priate St u d y Site pers o n nel w h o m t he PI d esi g nates t o perf or m a certai n 
d ut y. T his dele gati o n of a ut h orit y nee ds t o be d oc u me nte d a p pr o pri atel y a n d si g ne d b y t he PI. 
T he PI is ulti matel y res p o nsi ble f or t he c o n d uct of all as pects of t h e cli nical  st u d y. 
S u b-i n vesti gat ors or ot her a p pr o priat e St u d y Site pers o n nel (e. g., liste d o n t he F or m F D A 1 5 7 2) 
are eli gi ble t o si g n f or t h e PI o n la b orat or y re p orts a n d ma y be desi g nat e d t o verif y a n d 
electr o nicall y si g n e C R Fs.  
1 0. 1. 2.  
Fi n a nci al Discl os ure  
1 0. 1. 2. 1.  C o nflict of I nterest P oli c y  
T he i n de pe n de n ce of t he st u d y fr o m a n y act ual or percei v e d i nfl ue nce is critical. T heref ore, a n y 
act ual c o nflict of i nterest or fi na ncial i nterest of pers o ns w h o ha ve a r ole i n t he desi g n, c o n d uct, 
a nal ysis, p u blicati o n, or a n y as pect of t his st u d y s h o ul d be discl ose d. F urt h er m ore, p ers o ns w h o 
ha ve a p ercei ve d c o nflict of i nterest or fi na n cial i nterest will be re q uire d t o ha ve s uc h c o nflicts 
ma na ge d i n a w a y t hat is a p pr o priate t o t heir p artici pati o n i n t he desi g n a n d c o n d uct of t his 
st u d y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 1 
Fi nal : 1 2 Oct 2 0 2 1 
1 0. 1. 2. 2.  Fi n a nci al Discl os ure  
I n v esti gat ors a n d s u b-i n v esti gat ors will pr o vi de t he S p o ns or wit h s ufficie nt, acc urate fi n a ncial 
i nf or mati o n as re q u este d t o all o w t he S p o ns or t o s u b mit c o m plete a n d acc urate fi na n cial 
certificati o n or discl os ure state me nts t o t he a p pr o priate re g ul at or y a u t h orities. I n v esti gat ors are 
res p o nsi ble f or pr o vi di n g i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urs e of t he st u d y a n d f or 
1 year after c o m pleti o n of t he st u d y. 
1 0. 1. 3.  
P artici p a nt Selecti o n a n d I nf or me d C o nse nt Pr ocess  
Partici pa nt s w h o c o m plet e d t he Da y 1 8 0 visit i n V M A L S - 0 0 2- 2 a n d are pla n ne d f or e nr oll me nt 
i n V M A L S- 0 0 2- 2 b, m ust si g n a n I C F t hat has bee n a p pr o ve d b ot h b y H eli x mit h a n d re vie we d  b y 
t he I n d e pe n d e nt Et hics C o m mittee (I E C)/I R B. T h e i nf or me d c o ns e nt s h o ul d be i n acc or da nce 
wit h t he c urre nt r e visi o n of t he Decl arati o n of H elsi n ki as well as c urre nt I C H a n d G C P 
g ui deli nes. 
O n Da y 1 8 0 of t he V M A L S - 0 0 2- 2 st u d y, Partici pa nts will recei ve a c o m pre he nsi ve e x pla n ati o n 
of t he V M A L S - 0 0 2- 2 b st u d y i ncl u di n g t he nat ure a n d ris ks of t he st u d y, alter nate t hera pies, a n y 
k n o w n A Es, a n d t he ot her ele me nts t hat are part of o btai ni n g pr o per i nf or m e d c o nse nt. P ote ntial 
Partici pa nt s will als o recei ve a det aile d e x pla nati o n of t he pr o p ose d use a n d discl os ure of t heir 
pr otecte d healt h i nf or mati o n, i ncl u di n g s pecificall y a n y sa ve d bl o o d sa m pl es. P ote ntial 
Partici pa nt s will be all o we d s ufficie nt ti me t o c o nsi der partici pati o n i n t he st u d y after h a vi n g t he 
nat ure a n d ris ks of t he st u d y e x plai ne d t o t he m. T he I C F m ust n ot i ncl u de a n y e xc ul pat or y 
state me nts. T he I C F a n d a n y se par ate H ealt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
( HI P A A) a ut h orizati o n f or m, if a p plica ble, s h o ul d be re vie w e d a n d a p pr o ve d b y t he Heli x mit h  
pri or t o I R B/I E C s u b missi o n. 
Heli x mit h  will pr o vi de t o t he I n v esti gat or, i n writi n g, a n y ne w i nf or m ati o n t hat si g nifica ntl y 
bears o n t he Partici pa nt s’ ris k i n recei vi n g t he st u d y dr u g. T his ne w i nf or mati o n will be 
c o m m u nicate d b y t he I n v esti gat or t o Partici pa nts i n acc or d a nce wit h I R B/I E C re q uire me nts. T he 
I C F will be u p date d, a n d Partici pa nt s will be re-c o nse nte d.  
Site staff ma y c o n d uct st a n dar d -of -care pr oce d ures a n d e m pl o y recr uit me nt eff orts pri or t o 
Partici pa nt  c o nse nt; h o w e ver, bef ore a n y pr ot oc ol-s pecifie d pr oce d ures are perf or me d t o 
deter mi ne pr ot oc ol eli gi bilit y, a n I C F m ust be si g n e d. Partici pa nts will be gi ve n a c o p y of all 
c o nse nt f or ms t hat t he y si g n. 
B y si g ni n g t he I C F, t he P artici pa nt  a grees t o c o m plete all e val uati o ns re q uire d b y t he st u d y 
u nless t he Partici pa nt  wit h dra ws v ol u ntaril y or is ter mi nate d fr o m t he st u d y f or a n y reas o n. 
1 0. 1. 4.  
D at a Pr ot ecti o n a n d C o nfi de nti alit y 
T he data r es ulti n g fr o m t his st u d y will be t he pr o prietar y i nf or m ati o n of Heli x mit h  a n d ma y be 
ma de p u blic after all data ha ve bee n a nal y ze d a n d t he st u d y res ults are a v aila ble. At t he e n d of 
t he st u d y, a cli nical st u d y re p ort will be writte n b y Heli x mit h . 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 2 
Fi nal : 1 2 Oct 2 0 2 1 
1 0. 1. 4. 1.  C o nfi de nti alit y  
Partici pa nt c o nfi de ntialit y a n d pri vac y are stri ctl y hel d i n tr ust b y t he I n v esti gat ors, t heir staff, 
a n d Heli x mit h . T his c o nfi de ntialit y is e xte n de d t o c o ver testi n g of bi ol o gical sa m ples i n a d diti o n 
t o t he cli nical i nf or mati o n relati n g t o Partici pa nt s. T heref ore, t he st u d y pr ot oc ol, d oc u me ntati o n, 
data, a n d all ot her i nf or m ati o n ge nerat e d will be h el d i n strict c o nfi de nce. N o i nf or mati o n 
c o ncer ni n g t he st u d y or d ata will be release d t o a n y u na ut h orize d t hir d part y wit h o ut pri or 
writte n a p pr o val of Heli x mit h . 
All resear c h acti vities will be c o n d ucte d i n as pri v ate a setti n g as p ossi ble.  
T he st u d y m o nit or, ot her a ut h orize d r e pres e ntati ves of Heli x mit h , re prese nt ati ves of t he I R B, 
re g ulat or y a g e ncies, or p har mace utical c o m pa ni es s u p pl yi n g st u d y pr o d uct ma y i ns pect all 
d oc u me nts a n d rec or ds r e q uire d t o be mai ntai ne d b y t he I n vesti gat or i ncl u di n g, b ut n ot li mite d 
t o, me dical rec or ds ( office, cli nic, or h os pital) a n d p har mac y rec or ds f or Partici pa nt s. T he 
Cli nical St u d y Site will per mit access t o s uc h rec or ds.  
T he Partici pa nt ’s c o nt act i nf or mati o n will be sec urel y st ore d at eac h Cli nical Site f or i nter nal use 
d uri n g t he st u d y. At t he e n d of t he st u d y, all rec or ds will c o nti n ue t o be ke pt i n a sec ure l o cati o n 
f or as l o n g a p eri o d as di ctate d b y t he re vie wi n g I R B/I E C, a p plica ble re g ul at or y a ge n cies, 
i nstit uti o nal p olicies, a n d/ or Heli x mit h  re q uire me nts. 
Partici pa nt researc h d ata, w hic h is f or p ur p oses of statistical a nal ysis a n d scie ntific re p orti n g, 
will be tra ns mitte d t o a n d st ore d b y t he S p o ns or or t heir desi g nee. T his will n ot i ncl u de t he 
Partici pa nt ’s c o ntact or i de ntif yi n g i nf or mati o n. Rat her, i n di vi d ual Partici pa nts a n d t heir res earc h 
data will be i de ntifie d b y a u ni q ue st u d y i de ntificati o n n u m ber. T he st u d y data e ntr y a n d st u d y 
ma na ge me nt s yste ms use d b y Cli nical Sites a n d b y researc h staff will be sec ure d a n d p ass w or d 
pr otecte d. At t he e n d of t he st u d y, all st u d y data bases will be de-i de ntifie d a n d arc hi v e d. 
1 0. 1. 4. 2.  D at a  Pr ot ecti o n  
I n acc or da n ce wit h G C P a n d wit h t he i nter nati o nal/ nati o nal data pr otecti o n la ws, all i nf or mati o n 
c o ncer ni n g t he Partici pa nts i n t he st u d y m ust be treate d as strictl y c o nfi de ntial b y all pers o ns 
i n v ol ve d i n t he st u d y. 
T he I n vesti gat or ac k n o wl e d ges t hat a n y a n d all i nf or mati o n ac q uire d fr o m Heli x mit h  or 
de vel o pe d or ac q uir e d i n c o n necti o n wit h t he st u d y is strictl y c o nfi de ntial. T he I n vesti gat or will 
n ot discl ose a n y c o nfi de ntial i nf or mati o n t o a n y t hir d part y n or use c o nfi de ntial i nf or mati o n f or 
a n y p ur p ose wit h o ut first o btai ni n g t he c o nse nt of Heli x mit h  i n writi n g. S uc h c o nse nt will be 
dee me d t o ha v e bee n gi v e n f or discl os ure t o a n y p ers o n f or w h o m t he I n vesti gat or is res p o nsi ble 
at his/ her ce nter, b ut o nl y s o far as re q uire d f or t he p ur p oses of t he st u d y . In t he case of 
discl os ures t o staff, o nl y if s uc h staff are b o u n d b y o bli gati o ns of c o nfi de ntialit y n o less strict 
t ha n t h ose set o ut herei n. 
P ote ntial Partici pa nt s m ust be i nf or me d t hat t heir pers o nal st u d y-relate d data will be use d b y 
Heli x mit h  i n acc or da n ce wit h G C P, i nter nati o nal/ nati o nal, a n d l ocal data pr otecti o n la w. T he 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 3 
Fi nal : 1 2 Oct 2 0 2 1 
le vel of discl os ure m ust als o be e x plai ne d t o t he Partici pa nt  w h o will be re q uire d t o gi ve c o nse nt 
f or t heir data t o b e use d as descri be d i n t he I C F. 
P ote ntial Partici pa nt s m ust be i nf or me d t hat t heir me dical rec or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y Heli x mit h , b y a p pr o priate 
I R B me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
1 0. 1. 5.  
C o m mittee Str uct ure  
1 0. 1. 5. 1.  D at a S afet y M o nit ori n g B o ar d 
A n i n de pe n de nt D S M B has bee n c h artere d f or t his st u d y t o re vie w all safet y data d uri n g t he 
st u d y a n d safe g u ar d t he i nterests of t he Partici pa nt s. T he o bjecti ves of t he D S M B meeti n gs are t o 
re vie w t he s afet y o utc o m es of t he st u d y a n d pr o vi de g ui da nce t o t he S p o ns or re gar di n g t he safet y 
of E n ge nsis. T he D S M B will meet peri o dicall y a n d re vie w a li mite d set of u n bli n de d or 
n o nc o m parati ve ta bl es a n d/ or listi n gs of all re p orte d T E A Es, T E S A Es, a n d A E SIs . If a safet y 
si g nal is i de ntifie d d uri n g t he n o nc o m parati ve a n al ysis, t his will be f oll o we d b y a c o m parati ve 
a nal ysis as pr o m pte d b y o bser vati o ns. T he dat a a n al yses f or t he D S M B meeti n gs will be directl y 
pr o vi de d t o t he D S M B me m bers; n o data will be release d t o t he S p o ns or or bli n de d desi g nees. 
N o a dj ust me nt will be ma de f or m ulti ple testi n g d ue t o t he D S M B data re vie w.  
T he D S M B will c o nsist of t w o p h ysicia ns wit h e x pertise i n cli nical st u dies a n d o ne statisticia n. 
Me m bers of t he D S M B will be i n de pe n de nt of st u d y c o n d uct a n d free of c o nflict of i nterest, or 
meas ures s h o ul d be i n pl ace t o mi ni mize percei ve d c o nflicts of i nterest. A n i n de pe n de nt 
bi ostatisticia n will be a vaila ble f or c o ns ultati o n.  
T he D S M B will o perate u n der t he r ules of t he c h arter, w hic h h a ve bee n re vie we d at 
or ga nizati o nal meeti n gs of t he D S M B. R o uti ne D S M B meeti n gs will be re g ularl y sc he d ule d p er 
t he D S M B C hair t o re vie w safet y a n d p o ol e d all-ca use m ortalit y data, i ncl u di n g u n bli n de d 
Partici pa nt  narr ati ves . T h e D S M B C hair ma y re q u est a d diti o nal u n bli n de d i nf or mati o n at a n y 
ti me t o f urt her u n dersta n d a safet y tr e n d. A d h oc D S M B meeti n gs ca n be c o n ve ne d at a n y ti me at 
t he discreti o n of t he D S M B C hair or t he S p o ns or. H o we ver, t he D S M B C hair ma y n ot s hare a n y 
u n bli n de d i nf or mati o n wit h t he S p o ns or u nless it is dee me d necessar y f or t he S p o ns or t o a d dress 
a p ote ntial safet y c o ncer n. T he D S M B will pr o vi de rec o m me n d ati o ns t o t he S p o ns or i n 
acc or d a nce wit h t he D S M B C harter.  
1 0. 1. 6.  
D at a Q u alit y Ass ur a nce 
1 0. 1. 6. 1.  Cli nic al M o nit ori n g  
Heli x mit h  or desi g nee will visit (i n pers o n or re m otel y, acc or di n g t o F D A G ui da nce o n C o n d uct 
of Cli nical Trials of Me dical Pr o d uct d uri n g C O VI D- 1 9 Pa n de mic, M arc h 2 0 2 0, u p date d 0 3 J u n 
2 0 2 0) t he Cli nical Site f or m o nit ori n g. T he Heli x mit h’s cli nical m o nit or s hall e ns ure t hat t he 
I n v esti gat or u n dersta n ds t he i n vesti gati o nal stat us of t he pr o d uct, all pr ot oc ol re q uire me nts, a n d 
his/ her re g ulat or y r es p o nsi bilities as a n I n vesti gat or. T he cli nical m o nit ors will visit (i n pers o n or 
re m otel y) Cli nical Sites at a ppr o priate i nter v als t o e ns ure c o m plia n ce wit h t he pr ot oc ol a n d t o 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 4 
Fi nal : 1 2 Oct 2 0 2 1 
verif y t he acc ur ac y, c o m plete ness, a n d c orrect ness of data re p orte d a n d acc o u nta bilit y of 
E n ge nsis s u p plies. 
T he cli nical m o nit or s hall be a vaila ble f or c o ns ult ati o n b y t he I n v esti gat or a n d ser ves as a liais o n 
bet wee n t he Cli nical Site a n d Heli x mit h . T he cli nical m o nit or or ot her a ut h orize d re pres e ntati ves 
of Heli x mit h  ma y i ns pect all data, d oc u me nts, a n d rec or ds re q uire d t o b e mai ntai ne d b y t he 
I n v esti gat or i ncl u di n g, b ut n ot li mite d t o, me dical rec or ds ( office, cli nic, or h os pital) a n d 
p har mac y rec or ds f or Partici pa nt s. T he Cli nical Site will per mit access t o s uc h rec or ds. T he 
I n v esti gat or will o btai n, as part of t he i nf or me d c o nse nt pr ocess, HI P A A-c o m plia nt a ut h orizati o n 
fr o m Partici pa nt s t o use a n d discl ose t he re q uisite a n d rele v a nt P HI a n d per missi o n f or 
a ut h orize d r e pres e ntati ves of Heli x mit h , or re g ulat or y a ut h orities i ncl u di n g t he F D A, t o re vie w, 
i n c o nfi de nce, a n y r ec or ds i de ntif yi n g Partici pa nt s i n t he cli nical st u d y. 
1 0. 1. 6. 2.  Access t o St u d y D oc u me nts a n d St u d y  M o nit ori n g  
Heli x mit h  has desi g nate d a C o ntract  Researc h Or g a nizati o n  (C R O ) t o m o nit or t he pr o gress of 
t his st u d y. T he C R O cli nical m o nit or, as a re prese ntati ve of Heli x mit h , has t he o bli gati o n t o 
f oll o w t his st u d y cl osel y. Heli x mit h  or its desi g nee ma y meet wit h I n vesti g at ors pri or t o t he 
i nitiati o n of t he st u d y i n or der t o re vi e w t he a d e q u ac y of t he Partici pa nt  p o p ulati o n, facilities, 
a n d e q ui p me nt wit h res p ect t o t he nee ds of t he st u d y, a n d t o fa miliarize t he I n v esti gat or wit h t he 
st u d y pr ot oc ol. 
Heli x mit h  or its desi g nee ma y meet wit h t he I n vesti gat or(s) at t he ti me t hat st u d y Partici pa nt s 
be gi n t o be e nr olle d t o e ns ure t hat Partici pa nt s are bei n g pr o perl y selecte d a n d t hat st u d y data are 
bei n g c orr ectl y rec or de d. 
D uri n g t he st u d y, t he cli nical m o nit or will visit (i n pers o n or re m otel y) t he st u d y facilities 
re g ularl y a n d us e tele p h o ne a n d writte n c o m m u nicati o ns o n a n o n g oi n g basis t o mai ntai n c urre nt 
k n o wle d ge of t he st u d y. D uri n g peri o dic visits t o t he Cli nical Site (i n pers o n or re m otel y), t he 
m o nit or will re vie w t he s o urce d oc u m e nts use d f or data e ntr y i n t he E D C s yste m t o verif y t he 
acc ur ac y a n d c o m plete n ess of t he i nf or mati o n c o ntai ne d i n t h ose re p orts i n pre parati o n f or 
retrie val. S o urce d oc u me nts m ust c o ntai n all data e ntere d i n t he E D C s yste m. All data ge nerate d 
d uri n g t his st u d y a n d t he s o urce d oc u m e nts fr o m w hic h t he y ori gi nate d are s u bject t o i ns pecti o n 
b y Heli x mit h  or its re prese ntati ves, a n d t he F D A a n d ot her re g ulat or y a g e ncies. 
U p o n c o m pleti o n of t he st u d y, t he cli nical m o nit or will c o n d uct a fi nal visit (cl ose o ut) t o t he 
Site. T he o bjecti ves of t his visit are t o ascertai n t h at all re g ulat or y rec or ds are c o m plete, v erif y 
t hat st u d y dr u g a n d ot her s u p plies ha ve bee n acc o u nte d f or, a n d e ns ure t hat t he I n v esti gat or is 
a war e of his/ her r es p o nsi bilities p ost-st u d y. 
1 0. 1. 6. 3.  Q u alit y Ass ur a nce a n d Q u alit y C o ntr ol 
Eac h Cli nical Site will perf or m i nter nal q u alit y ma na ge me nt of st u d y c o n d u ct, data a n d 
bi ol o gical s peci me n c ollecti o n, d oc u me ntati o n, a n d c o m pleti o n. 
Q ualit y C o ntr ol ( Q C) pr oce d ures will be c o n d ucte d wit hi n t he E D C. A n y missi n g data or data 
a n o malies will be c o m m u nicate d t o t he sites f or clarificati o n/res ol uti o n.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 5 
Fi nal : 1 2 Oct 2 0 2 1 
F oll o wi n g writte n Sta n dar d O per ati n g Pr oce d ures ( S O Ps) b y t he C R O , t he m o nit ors will verif y 
t hat t he cli nical st u d y is c o n d ucte d, data are g e nerate d, a n d bi ol o gical s peci me ns are c ollecte d, 
d oc u me nte d (r ec or d e d), a n d re p ort e d i n c o m plia n ce wit h t he pr ot oc ol, I C H G C P, a n d a p plica ble 
re g ulat or y r e q uire me nts ( e. g., G o o d La b orat or y Practices [G L P ]). 
T he Cli nical Site will pr o vi de direct access t o all st u d y -relate d s o urce d ata d oc u me nts a n d 
re p orts f or t he p ur p ose of m o nit ori n g a n d a u diti n g b y Heli x mit h , a n d i ns pecti o n b y l ocal a n d 
re g ulat or y a ut h orities. 
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he pri nci ples of G C Ps: 2 1 C F R 5 0, 2 1 C F R 5 4, 
2 1 C F R 5 6, a n d 2 1 C F R 3 1 2, S u b part D; t he 2 0 1 6 I C H G ui d eli ne o n G o o d Cli nical Practice 
(I C H E 6( R 2)); a n d  HI P A A.  
T he I n vesti gat or at a Cli nical Site m ust si g n t he I n vesti gat or State me nt of  A gree me nt.  
1 0. 1. 6. 4.  D at a Q u alit y Ass ur a nce  
Heli x mit h ’s e m pl o yees a n d/ or t heir c o ntracte d re prese ntati ves use S O Ps desi g ne d t o e ns ure t hat 
researc h pr o ce d ur es a n d d oc u me ntati o n are c o nsiste ntl y c o n d ucte d/ pre p are d t o t he hi g hest 
q ualit y sta n dar ds. T hese S O Ps als o re q uire c o m plia nce wit h H ealt h A ut h orit y re g ulati o ns a n d 
G C P g ui da nce. 
A q ualit y ass ura nce a u dit ma y be c o n d uct e d b y Heli x mit h  or its desi g nee at a n y ti me d uri n g or 
after c o m pleti o n of a st u d y. T he I n vesti gat or will be gi ve n a de q u ate n otice if he/s he is selecte d 
f or a n a u dit. T he a u dit will i ncl u de, b ut is n ot li mite d t o, a re vie w of all I C Fs, s o urce d oc u m e nts, 
me dical rec or ds, a n d re g ulat or y d oc u me ntati o n; a n assess me nt of st u d y c o n d uct a n d pr ot oc ol 
c o m plia nce. At t he c o ncl usi o n of a n a u dit, t he a u dit or will c o n d uct a brief meeti n g wit h t he 
I n v esti gat or t o re vie w t he n ote d o bser v ati o ns. 
All Partici pa nt  data relati n g t o t he st u d y will be rec or de d o n e C R Fs u nless tra ns mitte d t o t he 
Heli x mit h  or desi g nee el ectr o nicall y (e. g., la b orat or y data). T h e I n vesti gat or is res p o nsi ble f or 
verif yi n g t hat e C R F dat a e ntries ar e acc urate , c orrect , a n d c o m plete b y p h ysicall y or 
electr o nicall y si g ni n g t he e C R F.  
T he I n vesti gat or m ust mai ntai n acc urate d o c u me ntati o n (s o urce dat a) t hat s u p p orts t he 
i nf or mati o n e ntere d i n t h e eC R F.  
T he I n vesti gat or m ust per mit st u d y-relate d m o nit ori n g, a u dits, I R B re vi e w, a n d re g ulat or y 
a ge nc y i ns pecti o ns a n d pr o vi de direct access t o s o urce dat a d oc u me nts. 
Heli x mit h  is res p o nsi ble f or t he data m a na ge me nt of t his st u d y i ncl u di n g q ualit y c hec ki n g of t he 
e C R F data.  
Heli x mit h  ass u mes acc o u nta bilit y f or acti o ns dele gate d t o ot her i n di vi d uals (e. g., C o ntract 
Researc h Or ga ni zati o ns).  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 6 
Fi nal : 1 2 Oct 2 0 2 1 
St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d i nt o 
t he e C R F b y a ut h orize d Site pers o n nel are acc urate, c o m plete, a n d v erifia ble fr o m s o urce 
d oc u me nts; t hat t he safet y a n d ri g hts of Partici pa nt s are bei n g pr otecte d; a n d t hat t he st u d y is 
bei n g c o n d ucte d i n acc or da nce wit h t he c urre ntl y a p pr o ve d pr ot o c ol a n d a n y ot her st u d y 
a gree m e nts, I C H G C P, a n d all a p plica ble re g ulat or y re q uire m e nts. 
1 0. 1. 6. 5.  D at a C ollecti o n a n d M a n a ge me nt Res p o nsi bilities  
Data c ollecti o n is t he res p o nsi bilit y of t he cli nical st u d y staff u n der t he s u p er visi o n of t he 
I n v esti gat or. D uri n g t he st u d y, t he I n v esti gat or will mai ntai n c o m plete a n d acc urate 
d oc u me ntati o n f or t he st u d y. T he I n vesti gat or s h o ul d e ns ure t hat t he Partici pa nt is pr o vi de d wit h 
i nstr ucti o ns a n d is trai ne d t o use t he eP R O  a n d t o c o m plete t he assess me nt t o ol pr o perl y bef ore 
data c ollecti o n be gi ns. 
All e C R F data will be e ntere d i nt o a vali date d d at a base c o m plia nt wit h 2 1 C F R Part 1 1. 
La b orat or y d ata will be eit her ma n uall y e ntere d or i m p orte d t o t he cli nical data base 
electr o nicall y. All data e ntr y, verificati o n, a n d v ali dati o n will be perf or me d i n ac c or d a nce wit h 
t he c urr e nt S O Ps of Heli x mit h  or its desi g nee. T he data bas e will be a ut h ori ze d f or l o c k o nce n o 
data q ueries are o utsta n di n g, all st u d y data are c o nsi dere d clea n, a n d all defi ne d pr oce d ures are 
c o m plete d.  
T he Cli nical Site will be pr o vi de d wit h e C R Fs i n w hic h t o rec or d all t he pr ot oc ol- s pecifie d d ata 
f or eac h Partici pa nt. E ntries ma de i n t he e C R F m ust be verifia ble a gai nst s o urce d oc u m e nts, or 
i n certai n cir c u msta nces as directe d b y t h e Heli x mit h , e ntries will ha ve bee n directl y e ntere d i nt o 
t he e C R F; i n s uc h cas es, t he e ntr y i n t he e C R F will be c o nsi dere d as t he s o urce dat a. Data 
re p orte d i n t he e C R F t hat are deri ve d fr o m s o urce d oc u me nts s h o ul d be c o nsiste nt wit h t he 
s o urce d oc u m e nts or t he discre pa n cies sh o ul d be e x plai ne d. T he I n v esti gat or will be res p o nsi ble 
f or re vie wi n g all data a n d e C R F e ntries a n d will si g n a n d date t he desi g nat e d pa ges i n eac h 
Partici pa nt ’s e C R F, verif yi n g t hat t he i nf or mati o n is tr ue a n d c orrect. Q u eri es ge nerate d b y D ata 
Ma na ge me nt will be se nt t o t he Cli nical Site f or res ol uti o n. T he I n vesti gat or is res p o nsi ble f or 
t he re vie w a n d a p pr o v al of all res p o nses t o e C R F q ueries. 
1 0. 1. 6. 6.  Pr ot oc ol D e vi ati o ns 
T he I n vesti gat or will n ot de viate fr o m t his pr ot oc ol f or a n y reas o n wit h o ut pri or writte n a p pr o v al 
b y t he M e dical M o nit or o n be half of t he Heli x mit h  e xce pt i n t he case of a me dical e mer g e nc y 
w he n t he c h a n ge is necessar y t o eli mi nate a n a p p are nt a n d i m me diate hazar d t o t he Partici pa nt . 
Pr ot oc ol de viati o ns are t o be rec or de d i n s o urce d oc u me nts a n d will be trac ke d t hr o u g h t he E D C. 
I n t he e ve nt of s u c h a n e mer ge nc y, t he I n vesti gat or will n otif y t he Me dical M o nit or i m me diatel y 
b y p h o ne, n otif y t he I R B, a n d c o nfir m wit h t he M e dical M o nit or i n writi n g wit hi n 5  w or ki n g 
da ys of t he c h a n ge bei n g i m ple me nte d. 
1 0. 1. 6. 7.  S o urce D oc u m e nts  
As defi ne d i n t he I C H G ui deli nes f or G o o d Cli nical Practice E 6( R 2), Secti o n 1. 5 2, s o urce 
d oc u me nts ma y i ncl u de: ori gi nal d oc u me nts, data, a n d rec or ds (e. g., h os pit al rec or ds, cli nical 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 7 
Fi nal : 1 2 Oct 2 0 2 1 
a n d office c harts, la b orat or y n otes, me m ora n da, P artici pa nt ’s diaries or e v al uati o n c hec klists, 
p har mac y dis pe nsi n g r ec or ds, rec or de d dat a fr o m a ut o mate d i nstr u me nts, c o pies or tra nscri pti o ns 
certifie d after v erificati o n as bei n g acc urat e a n d c o m plete, micr ofic hes, p h ot o gra p hic ne gati ves, 
micr ofil m or ma g netic m e d ia, x ra ys, Partici pa nt  files, a n d rec or ds ke pt at t he p har mac y, at t he 
la b orat ories, a n d at me di c o-tec h nical de part me nts i n v ol ve d i n t he cli nical st u d y). 
S o urce d oc u me nts pr o vi d e e vi de nce f or t h e e xiste n ce of t he Partici pa nt  a n d s u bsta ntiate t he 
i nte grit y of t he data c ollecte d. S o urce d o c u me nts are file d at t he I n vesti gat or’s Site. 
T he I n vesti gat or ma y n ee d t o re q uest pre vi o us me dical rec or ds or tra nsfer rec or ds. C urre nt 
me dical rec or ds m ust als o be a vaila ble.  
1 0. 1. 7.  
D at a  M a n a ge m e nt  
All Partici pa nt  data will be e nter e d i nt o a pass w or d - pr otecte d v ali date d E D C s yste m b y 
a ut h orize d Site pers o n n el acc or di n g t o t he C R O’s S O Ps.  
Data discr e pa nci es i de ntifie d via pr o gr a m me d e dit c hec ks, ma n u al data re vi e w or disc o vere d 
d uri n g data m o nit ori n g will be a d dresse d a n d res ol ve d. A n a u dit trail i n t he E D C s yste m will list 
all c ha n ges ma d e t o t he d ata, wit h a date/ti me sta m p a n d user i niti als. U p o n data base l oc k, 
occ urri n g after d ata are d eclar e d clea n a n d e C R Fs ha ve bee n a p pr o v e d b y t he I n vesti gat or, t he 
C R O will pr o vi de S A S datasets t o t he S p o ns or a n d desi g nate d Statisticia n f or data a nal ysis via 
sec ure d ata tra nsfer s p ecifie d i n t he St u d y Data M a na ge me nt Pla n.  
1 0. 1. 8.  
Rec or d kee pi n g a n d  Ret e nti o n  
Data ge n erate d f or t he st u d y s h o ul d be st ore d i n a li mite d- access a n d s ec ure d -access file area a n d 
be accessi ble o nl y t o re pr ese ntati ves of t he Cli nical Site, Heli x mit h  a n d its re prese nt ati ves, a n d 
F D A/r ele va nt healt h a ut h orities/re g ulat or y a g e ncies. All re p orts a n d c o m m u nicati o ns relati n g t o 
Partici pa nt s will i de ntif y Partici pa nt s o nl y b y Partici pa nt  i de ntificati o n n u m ber. C o m plete 
Partici pa nt  i de ntificati o n will be ke pt b y t he I n vesti gat or. T his i nf or mati o n will be treate d wit h 
strict a d here n ce t o pr ofessi o nal sta n dar ds of c o nfi de ntialit y  a n d pers o nal d ata pr otecti o n la ws. 
T he I n vesti gat or m ust i n reas o na bl e ti me, u p o n re q uest fr o m a n y pr o p erl y a ut h orize d officer or 
e m pl o yee of F D A/r ele va nt healt h a ut h orit y/re g ulat or y a ge nc y, p er mit s uc h officer or e m pl o yee 
t o ha ve access t o re q u est e d rec or ds a n d re p orts, a n d c o p y a n d verif y a n y rec or ds or re p orts ma d e 
b y t he I n vesti gat or. U p o n n otificati o n of a visit b y t he F D A/rele va nt healt h a ut h orit y/re g ulat or y 
a ge nc y, t he I n vesti gat or will c o ntact Heli x mit h  i m me diatel y. T he I n vesti gat or will als o gra nt 
Heli x mit h ’s re prese nt ati ves t he sa me pri vile ges offere d t o F D A/rel e va nt healt h a ut h orit y or 
re g ulat or y a g e nts/ officers/e m pl o yees. 
T he I n vesti gat or m ust pr o vi de Heli x mit h  or its desi g nee wit h t he f oll o wi n g d oc u me nts pri or t o 
st u d y i nitiati o n a n d retai n a c o p y i n t he st u d y file: 
•  A c o m plete d a n d si g ne d F or m F D A 1 5 7 2. If, d uri n g t he st u d y, a n y c ha n ges occ ur t hat are 
n ot reflect e d o n t he c urre nt 1 5 7 2, a ne w 1 5 7 2 m ust be c o m plete d a n d ret ur n e d t o t he 
S p o ns or or its desi g nee f or s u b missi o n t o t he F D A  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 8 
Fi nal : 1 2 Oct 2 0 2 1 
•  C urre nt si g ne d c urric ula vitae ( wit hi n 2 years pri or t o st u d y i nitiati o n) a n d c urre nt 
me dical lice nses f or t he I n vesti gat or a n d all c o -I n vesti gat ors liste d o n t he 1 5 7 2 
•  A c o p y of t he ori gi nal a p pr o val b y t he I R B f or c o n d ucti n g t he st u d y. Re ne wals, wit h 
c o nti n ua nce of t h e st u d y, m ust be s u b mitte d at yearl y i nter vals or as re q uire d b y I R B 
p olic y 
•  A c o p y of t he I R B- a p pr o ve d I C F  
•  T he I R B me m ber list a n d/ or U S De part me nt of H u ma n Healt h Ser vices ( D H H S ) Ge neral 
Ass ura nce N u m ber (if t he I R B has a n Ass ura n ce n u m ber) 
•  A c o p y of t he ori gi nal a p pr o val b y t he I nstit uti o nal Bi osafet y C o m mittee (I B C) f or 
c o n d ucti n g t he st u d y, if a p plica ble. Re ne w als, wit h c o nti n ua nce of t h e st u d y, m ust be 
s u b mitte d at yearl y i nter vals or as re q uire d b y I B C p olic y 
•  Si g ne d Fi na ncial Discl os ure F or ms f or all pers o n n el liste d o n t he 1 5 7 2 wit h a state me nt 
of n o n- v oti n g b y st u d y staff 
•  T he si g nat ure pa g e of t his pr ot oc ol si g ne d a n d dat e d b y t he I n v esti g at or 
•  T he si g nat ure pa g e of t he I B si g ne d a n d date d b y t he I n vesti gat or 
•  I n a d diti o n t o t he d oc u me nts liste d a b o ve, t he Cli nical Site will als o retai n t he f oll o wi n g 
ite ms: 
o  Certificati o ns a n d la b or at or y refere n ce ra n ges f or all l ocal la b orat ories us e d f or 
t his st u d y 
o  A c o p y of del e gati o n of a ut h orit y l o g 
o  C o pies of t he i nitiati o n visit re p ort, t he pr ot oc ol, I B, e nr ol me nt l o gs, s u bject 
i de ntifier (I D) list ( n ot pr o vi de d t o s p o ns or/ C R O), i n vesti gati o nal pr o d uct 
acc o u nta bilit y rec or ds 
o  All ori gi nal I C Fs wit h re q uire d  si g nat ures 
o  All I R B c orres p o n de n ce (e. g., i nf or me d c o nse nt [i ncl u di n g a n y a p pr o ve d 
re visi o ns], pr ot oc ol, T E A E, a d vertise me nts,  ne wsl etters)  
o  A c o p y of t he St u d y M o nit ori n g L o g  
o  Cli nical a n d n o ncli nical s u p pl y s hi p me nt f or ms 
o  C o pies of all perti ne nt c orres p o n de n ce pertai ni n g t o t he st u d y (e xce pt b u d g et 
iss ues) bet wee n t h e S p o ns or, C R O, a n d t he Site  
o  C o pies of all S A E re p orts s u b mitte d t o t he S p o ns or 
o  C o pies of all I n v esti gat or Safet y Re p orts s u b mitte d t o t he Site b y  t he S p o ns or 
o  C o pies of a p pr o ve d p ac k a ge la belli n g, if a p plica bl e 
1 0. 1. 9.  
St u d y a n d Site St art a n d Cl os ure  
T he st u d y ma y be s us pe n de d te m p oraril y or ter mi nate d pre mat urel y  b y Heli x mit h  f or a n y safet y, 
et hical, or a d mi nistrati o n reas o n at a n y ti me.  Writte n n otificati o n d oc u me nti n g t he reas o n f or 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
4 9 
Fi nal : 1 2 Oct 2 0 2 1 
st u d y s us pe nsi o n or ter mi nati o n will be pr o vi de d b y t he Heli x mit h  t o I n vesti gat ors a n d 
re g ulat or y a ut h orities. If t he st u d y is pre mat urel y ter mi nate d or s us pe n d e d, t he I n v esti gat or will 
pr o m ptl y i nf or m Partici pa nt s a n d t he I R B a n d will pr o vi de t he reas o ns f or t he ter mi nati o n or 
s us pe nsi o n. Partici pa nts will be c o ntacte d, as a p plica ble, a n d b e i nf or me d of c ha n ges t o St u d y 
Visit  sc he d ules. 
Heli x mit h  or desi g nee reser ves t he ri g ht t o cl ose a Cli nical Site or ter mi nate t he st u d y at a n y ti me 
f or a n y r eas o n at t he s ole discreti o n of Heli x mit h . St u d y sites will be cl ose d u p o n st u d y 
c o m pleti o n. 
T he I n vesti gat or ma y i nitiate Cli nical Site cl os ure at a n y ti me, pr o vi de d reas o na ble ca us e a n d 
s ufficie nt n otice is gi ve n i n a d va nce of t he i nte n de d ter mi nati o n. 
Reas o ns f or t he earl y cl os ure of a Cli nical Site b y Heli x mit h  or I n v esti gat or ma y i ncl u de b ut are 
n ot li mite d t o:  
•  Fail ure of t he I n vesti gat or t o c o m pl y wit h t he pr ot oc ol, t he re q uire me nts of t he 
I R B/I E C or l ocal h ealt h a ut h orities, Heli x mit h’s pr oce d ures, or G C P g ui deli nes 
•  I n a de q uat e recr uit me nt of Partici pa nts b y t he I n vesti gat or 
•  Disc o nti n uati o n of f urt her st u d y dr u g de vel o p me nt 
If t he st u d y is pre mat ur el y ter mi nate d or s us pe n d e d, Heli x mit h  will pr o m ptl y i nf or m t he 
I n v esti gat ors, I R Bs, t he r e g ulat or y a ut h orities, a n d a n y C R Os use d i n t he st u d y of t he reas o n f or 
ter mi nati o n or s us pe nsi o n, as s pecifie d b y t he a p plica ble re g ulat or y re q uire me nts. T he 
I n v esti gat or will pr o m ptl y i nf or m t he Partici pa nt s a n d s h o ul d e ns ure a p pr o priate Partici pa nt  
t hera p y a n d/ or f oll o w- u p. 
1 0. 1. 1 0.  
P u blic ati o n P olic y  
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he p u blicati o n a n d data s h ari n g p olicies a n d 
re g ulati o ns as defi n e d i n t he a gree me nt bet wee n H eli x mit h  a n d t he i nstit uti o n. I n a d diti o n, t his 
st u d y will be re gistere d at w w w. Cli nical Trials. g o v a n d i n a n y ot her pr ot o c ol re gistries re q uire d 
b y t he re gi o ns i n w hic h t he st u d y is c o n d ucte d, a n d t he res ults fr o m t his st u d y will bec o me 
p u blicl y a vaila ble. 
N o ne of t he d ata res ulti n g fr o m t his st u d y will be all o we d t o be pres e nte d or p u blis he d i n a n y 
f or m b y t he I n vesti gat or or a n y ot her p ers o n wit h o ut t he pri or writte n a p pr o val of t he S p o ns or. 
1 0. 1. 1 1.  
I ns ur a nce 
Matters relati n g t o i ns ura nce f or t his st u d y are t o be defi ne d i n t he a gree me nt bet wee n t he 
Heli x mit h  a n d t he i nstit uti o n.  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
5 5 
Fi nal : 1 2 Oct 2 0 2 1 
1 0. 3.  
A p pe n di x  3. List of A b bre vi ati o ns a n d Defi niti o ns  
1 0. 3. 1.  
A b bre vi ati o ns 
A b bre vi ati o n  
Defi niti o n  
A A N  
A merica n Aca de m y of Ne ur ol o g y  
A E SI  
A d verse e ve nt of s pecial i nterest  
A L S  
a m y otr o p hic lateral scler osis  
A L S A Q  
A m y otr o p hic Lateral Scler osis Assess me nt Q uest io n naire  
A L T  
ala ni ne tra nsa mi nase ( S G P T)  
A L S F R S - R 
Re vise d A m y otr o p hic Lateral Scler osis F u ncti o nal Rati n g Scale  
A S T  
as partate tra nsa mi nase ( S G O T) 
B A  
bi oa vaila bilit y  
B E  
bi oe q ui vale nce  
β -H C G  
beta h u ma n c h ori o nic g o na d otr o pi n  
B U N  
bl o o d urea nitr o ge n  
c D N A  
C o m pli me ntar y de o x yri b ose n ucleic aci d  
C F R  
C o de of Fe deral Re g ulati o n  
C LI  
critical li m b isc he mia  
C O N S O R T  
C o ns oli date d Sta n dar ds of Re p orti n g Trials  
C O VI D -1 9  
C or o na Vir us Disease 2 0 1 9  
C GI C  
Cli nical Gl o bal I m pressi o n of C ha n ge  
C N S  
ce ntral ner v o us s yste m  
C R A  
Cli nical Researc h Ass ociate  
C R O  
co ntract  researc h or ga nizati o n 
C S  
cli nicall y si g nifica nt  
D H H S  
U S De part me nt of Healt h a n d H u ma n Ser vices  
D N A  
de o x yri b o n ucleic aci d  
D P N  
dia betic peri p heral ne ur o pat h y  
D S M B  
Data Safet y M o nit ori n g B oar d  
E A A T 2  
excitat or y a mi n o aci d tra ns p orter 2  
E C G  
electr ocar di o gra m 
e C R F  
electr o nic case re p ort f or m 
E D C  
electr o nic data ca pt ure s yste m  
e P R O  
electr o nic patie nt re p orte d o utc o me  
E T  
earl y ter mi nati o n fr o m t he st u d y  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F V C  
f orce d vital ca pacit y 
G C P  
g o o d cli nical p ractices 
G D N F  
glial cell li ne ne ur otr o p hic Fact or  
G G T  
ga m ma -gl uta m yl tra ns pe pti dase  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
5 6 
Fi nal : 1 2 Oct 2 0 2 1 
A b bre vi ati o n  
Defi niti o n  
G L P  
g o o d la b orat or y practices  
H C G  
h u ma n c h ori o nic g o na d otr o pi n  
H E E N T  
hea d, e yes, ears, n ose, a n d t hr oat  
H G F  
he pat o c yte gr o wt h fact or 
H G F -X 7  
h y bri d he patic gr o wt h fact or c o di n g se q ue nce e x pressi n g t w o is of or ms of 
H G F, H G F 7 2 8 a n d H G F 7 2 3 
H H D  
Ha n d hel d D y na m o meter  
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act  
I B 
I n vesti gat or’s Br oc h ure 
I B C 
I nstit uti o nal Bi osafet y C o m mittee 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D 
i de ntifier 
I E C 
I n de pe n de nt Et hics C o m mittee 
I M 
i ntra m usc ular 
I N D 
I n vesti gati o nal Ne w Dr u g 
I R B 
I nstit uti o nal Re vie w B oar d 
I S R 
I njecti o n site reacti o n 
L L O Q  
l o wer li mit of q ua ntitati o n  
M C P - 1 
m o n oc yte c he m oattracta nt pr otei n 1  
M R C  
Me dical Researc h C o u ncil  
N C S  
n ot cli nicall y si g nifica nt  
N G F  
ner ve gr o wt h fact or  
N D A  
Ne w Dr u g A p plicati o n  
N H U  
n o n heali n g f o ot ulcers  
N M D A  
N- met h yl - D-as partate 
N O  
nitr o us o xi de  
P A D  
peri p heral arterial disease  
P E  
p h ysical e xa mi nati o n  
P G E 2  
pr osta gla n di n E 2  
P HI  
pr otecte d healt h i nf or mati o n  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
PI  
Pri nci pal I n vesti gat or  
P R O  
patie nt re p orte d o utc o me  
P T T  
partial pr ot hr o m bi n ti me  
Q C  
q ualit y c o ntr ol  
Q o L  
Q ualit y of Life  
R N A  
ri b o n ucleic aci d 
S A D R  
S us pecte d a d verse dr u g reacti o n  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
5 7 
Fi nal : 1 2 Oct 2 0 2 1 
A b bre vi ati o n  
Defi niti o n  
S A E  
seri o us a d verse e ve nt 
S A P  
Statistical A nal ysis Pla n  
S A S  
Statistical A nal ysis S yste m  
S o A  
Sc he d ule of A cti vities 
S O D 1  
s u per o xi de dis m utase 1 
S O P  
sta n dar d o perati n g pr oce d ure 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
S V C  
Sl o w Vital Ca pacit y  
T E A E  
treat me nt-e mer ge nt a d verse e ve nt 
T E S A E  
treat me nt-e mer ge nt seri o us a d verse e ve nt  
T N F  
t u m or necr osis fact or 
U S  
U nite d States  
V E G F  
vasc ular e n d ot helial gr o wt h fact or  
 
1 0. 3. 2.  
Defi niti o ns  
Acti ve I nfecti o n  
C hr o nic i nfecti o n or se vere acti ve i nfecti o n t hat ma y c o m pr o mise t he 
Partici pa nt ’s well bei n g or partici pati o n i n t he st u d y, i n t he I n vesti gat or’s 
j u d g me nt 
Da y 2 4 0 , etc. 
Da y 2 4 0  (f or e xa m ple) refers s pecificall y t o t he act ual da y of t he Visit  
desi g nate d as t he Da y 2 4 0  Visit, a n d n ot t o t he 2 4 0 t h da y of t he st u d y f or a 
Partici pa nt . 
E n d of St u d y  
C o m pleti o n of t he last Visit  ( Da y 3 6 5) or pr oce d ure s s h o w n i n t he So A  f or t he 
last Partici pa nt re mai ni n g i n t he st u d y 
Hi g hl y Effecti ve C o ntrace pti o n 
Met h o d  
See C o ntrace pti ve G ui da nce  
I n vesti gat or 
T he PI or a p pr o priate st u d y site pers o n nel w h o m t he PI desi g nates t o perf or m a 
certai n d ut y 
Safet y A nal ysis P o p ulati o n  
All Partici pa nt s i n t he st u d y 
S p o ns or  
Heli x mit h C o., Lt d. a n d its re prese ntati ves c o ntracte d t o pr o vi de ser vices f or 
st u d y c o n d uct 
Partici pa nt  
A n y o ne w h o is c o nse nte d f or t he Safet y E val uati o n d uri n g V M A L S -0 0 2 -2 b o n 
or pri or t o Da y 1 8 0 of V M A L S -0 0 2 - 2 
V M 2 0 2  
T he acti ve p har mace utical i n gre die nt of E n ge nsis: a n o vel ge n o mic 
c o m ple me ntar y de o x yri b o n ucleic aci d (c D N A) h y bri d h u ma n he pat oc yte 
gr o wt h fact or ( H G F) c o di n g se q ue nce ( H G F -X 7) e x pressi n g t w o is of or ms of 
H G F, H G F 7 2 8 a n d H G F 7 2 3 
 
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
5 8 
Fi nal : 1 2 Oct 2 0 2 1 
1 0. 4.  
A p pe n di x 4. Re vise d A m y otr o p hic L ater al Scler osis F u ncti o n al R ati n g Sc ale  
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
5 9 
Fi nal : 1 2 Oct 2 0 2 1 
1 0. 5.  
A p pe n di x 5 . A m y otr o p hic L ater al Scler osis Assess me nt Q uesti o n n aire 
T he f oll o wi n g is a n e xa m ple of t he A L S A Q- 4 0 
Ple ase c o m plete t his q uesti o n n aire as s o o n as p ossi ble . If y o u ha v e a n y diffic ulties filli n g i n 
t he q uesti o n naire b y y o urself, please g et s o me o ne else t o hel p y o u wit h it. H o we ver, it is y o ur 
res p o nses t hat we ar e i ntereste d i n. 
T he q uesti o n naire c o nsists of a n u m ber of st ate me nts a b o ut diffic ulties t hat y o u ma y ha ve 
e x perie n ce d d uri n g t he l ast 2 wee ks. T here are n o ri g ht or wr o n g a ns w ers: y o ur first res p o nse is 
li kel y t o be t he m ost acc urate f or y o u. Please tic k t he b o x w hic h best descri bes y o ur o w n 
e x perie n ce or feeli n gs.  
Please tr y t o a ns wer e ver y q uesti o n e ve n t h o u g h s o me ma y see m rat her si milar t o ot hers or ma y 
n ot see m rele v a nt t o y o u. 
All t he i nf or mati o n y o u gi ve will be treate d i n t he strictest c o nfi de nce.  
T he f oll o wi n g state me nts all refer t o diffic ulties t hat y o u  
ma y ha ve ha d d uri n g t he l ast 2 wee ks . 
Please i n dicate, b y tic ki n g t he a p pr o priat e b o x, h o w ofte n 
t he f oll o wi n g state me nts ha ve bee n tr ue f or y o u. 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 0 
Fi nal : 1 2 Oct 2 0 2 1 
T he f oll o wi n g st ate m e nts all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
If y o u c a n n ot w alk at all  
please tic k Al w a ys/c a n n ot w al k at all . 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue ? 
Ple ase tick o ne b o x f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys or 
c a n n ot w al k 
at all  
1.  I h a ve f o u n d it diffic ult t o w al k s h ort 
dist a nces, e. g. ar o u n d t he h o use.  
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2.  I h a ve f alle n o ver w hile w al ki n g. 
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3.  I h a ve st u m ble d or tri p pe d w hile 
w al ki n g.  
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4.  I h a ve l ost m y b al a nce w hile w al ki n g.  
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5.  I h a ve h a d t o c o nce ntr ate w hile 
w al ki n g.  
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Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n  
bef ore g oi n g t o t he ne xt set of q uesti o ns  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
T he f oll o wi n g st ate m e nts all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
If y o u c a n n ot d o t he activities at all 
ple ase tick Al w a ys/c a n n ot d o at all . 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue ? 
Ple ase tick o ne b o x  f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys or 
c a n n ot d o at 
all  
6.  W al ki n g h as tire d m e o ut.  
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7.  I h a ve h a d p ai ns i n m y le gs w hile w al ki n g. 
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8.  I h a ve f o u n d it diffic ult t o g o u p a n d d o w n 
st airs. 
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9.  I f o u n d it diffic ult t o st a n d u p. 
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1 0.  I h a ve f o u n d it diffic ult t o get m yself u p o ut 
of c h airs.  
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Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n  
bef ore g oi n g t o t he ne xt set of q uesti o ns  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 1 
Fi nal : 1 2 Oct 2 0 2 1 
T he f oll o wi n g st ate m e nt all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
If y o u c a n n ot d o t he activities at all 
ple ase tick Al w a ys/c a n n ot d o at all . 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue ? 
Ple ase tick o ne b o x  f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys or 
c a n n ot d o at 
all  
1 1.  I h a ve h a d diffic ult y usi n g m y ar ms 
a n d h a n ds.  
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1 2.  I h a ve f o u n d t ur ni n g a n d m o vi n g i n 
be d diffic ult.  
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1 3.  I h a ve f o u n d pic ki n g u p t hi n gs 
diffic ult.  
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1 4.  I f o u n d h ol di n g b o o ks a n d 
ne ws p a pers, or t ur ni n g p a ges, 
diffic ult.  
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1 5.  I h a ve diffic ult y writi n g cle arl y. 
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Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n  
 bef ore g oi n g t o t he ne xt set of q uesti o ns  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T he f oll o wi n g st ate m e nt all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
If y o u c a n n ot d o t he activities at all 
ple ase tick Al w a ys/c a n n ot d o at all . 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue ? 
Ple ase tick o ne b o x  f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys or 
c a n n ot d o at 
all  
1 6.  I h a ve f o u n d it diffic ult t o d o j o bs 
ar o u n d t he h o use.  
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1 7.  I h a ve f o u n d it diffic ult t o fee d 
m yself.  
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1 8.  I h a ve h a d diffic ult y c o m bi n g m y h air 
or cle a ni n g m y teet h.  
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1 9.  I h a ve h a d diffic ult y getti n g dresse d.  
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2 0.  I h a ve diffic ult y w as hi n g t he h a n d 
b asi n.  
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 
Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n  
bef ore g oi n g t o t he ne xt set of q uesti o ns  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 2 
Fi nal : 1 2 Oct 2 0 2 1 
T he f oll o wi n g st ate m e nt all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
If y o u c a n n ot d o t he activities at all 
ple ase tick Al w a ys/c a n n ot d o at all . 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue ? 
Ple ase tick o ne b o x  f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys or 
c a n n ot d o 
at all  
2 1.  I h a ve h a d diffic ult y s w all o wi n g. 
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2 2.  I h a ve h a d diffic ult y e ati n g s ol d 
f o o ds. 
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2 3.  I h a ve f o u n d it diffic ult t o dri n k 
li q ui ds. 
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2 4.  I h a ve f o u n d it diffic ult t o p artici p ate 
i n c o n vers ati o ns. 
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2 5.  I h a ve felt t h at m y s peec h h as n ot 
bee n e as y t o u n derst a n d.  
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Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n  
bef ore g oi n g t o t he ne xt set of q uesti o ns  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T he f oll o wi n g st ate m e nt all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
If y o u c a n n ot d o t he activities at all 
ple ase tick Al w a ys/c a n n ot d o at all . 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue ? 
Ple ase tick o ne b o x  f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys or 
c a n n ot d o 
at all  
2 6.  I h a ve sl urre d or st uttere d w hile 
s pe a ki n g. 
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2 7.  I h a ve h a d t o t al k ver y sl o wl y. 
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2 8.  I h a ve t al k e d less t h a n I use d t o d o. 
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2 9.  I h a ve bee n fr ustr ate d b y m y s peec h. 
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3 0.  I h a ve felt self-c o nsci o us a b o ut m y 
s peec h. 
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Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n  
bef ore g oi n g t o t he ne xt pa ge  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 3 
Fi nal : 1 2 Oct 2 0 2 1 
T he f oll o wi n g st ate m e nt all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue: 
Ple ase ti ck o ne b o x  f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys  
3 1.  
I h a ve felt l o nel y. 
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3 2.  
I h a ve bee n b ore d. 
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3 3.  
I h a ve felt e m b arr asse d i n s o ci al 
sit u ati o ns. 
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3 4.  
I h a ve felt h o peless a b o ut t he 
f ut ure. 
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3 5.  
I h a ve w orrie d t h at I a m a b ur de n 
t o ot her pe o ple. 
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Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n  
bef ore g oi n g t o t he ne xt set of q uesti o ns  
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
T he f oll o wi n g st ate m e nt all refer t o cert ai n diffic ulties t h at y o u m a y h a ve h a d d uri n g t he 
l ast 2 wee ks. Ple ase i n dic ate, b y tic ki n g t he a p pr o pri ate b o x, h o w ofte n t he f oll o wi n g 
st ate m e nts h a ve bee n tr ue f or y o u. 
H o w ofte n d uri n g t he l ast 2 wee ks h ave t he f oll o wi n g bee n tr ue: 
Ple ase ti ck o ne b o x  f or e ac h q uesti o n 
 
Ne ver  
R arel y  
S o m eti m es  
Ofte n  
Al w a ys  
3 6.  I h a ve w o n dere d w h y I k ee p g oi n g. 
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3 7.  I h a ve felt a n gr y bec a use of t he 
dise ase.  
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3 8.  I h a ve felt de presse d. 
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3 9.  I h a ve w orrie d a b o ut h o w t he 
dise ase will affect me i n t he f ut ure.  
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4 0.  I h a ve felt as if I h a ve n o free d o m. 
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Please ma ke s ure t hat y o u ha ve tic ke d o ne b o x f or e ac h q uesti o n.  
T h a n k y o u f or c o m pleti n g t his q uesti o n n aire.  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 4 
Fi nal : 1 2 Oct 2 0 2 1 
1 0. 6.  
A p pe n di x 6. P atie nt Gl o b al I m pressi o n of C h a n ge a n d Cli nic al I m pressi o n of 
C h a n ge 
P GI C Sc ale:  
Si nce be gi n ni n g treat me nt at t his cli nic, h o w w o ul d y o u descri be t he c ha n g e (if a n y) i n acti vit y 
li mitati o ns, s y m pt o ms, e m oti o ns, a n d o verall q ualit y of life, relate d t o y o ur pai nf ul c o n diti o n? 
(tic k O N E b o x) 
N o c ha n ge ( or c o n diti o n has g ot w orse)  
 
1  
Al m ost t he sa me, har dl y a n y c ha n ge at all  
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2  
A  little better, b ut n o n oticea ble c ha n ge 
 
3  
S o me w hat better, b ut t he c ha n ge has n ot ma de a n y real differe nce  
 
4  
M o deratel y better, a n d a sli g ht b ut n oticea ble c ha n ge  
 
5  
Better, a n d a defi nite i m pr o ve me nt t hat has ma de a real a n d w ort h w hile differe nce  
 
6  
A great deal better, a n d a c o nsi dera ble i m pr o ve me nt t hat has ma de all t he differe nce  
 
7  
 
I n a si milar wa y, please circle t he n u m ber b el o w, t hat matc hes y o ur d e gree of c ha n ge si n ce 
be gi n ni n g care at t his cli nic: 
M uc h  
W orse  
 
 
 
 
N o 
C ha n ge  
 
 
 
 
M uc h  
Better  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
1 0  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 5 
Fi nal : 1 2 Oct 2 0 2 1 
Cli nic al I m pressi o n of C h a n ge Sc ale  
1. C GI C - Gl o b al I m pr o ve m e nt: Rate t otal i m pr o ve me nt w het her or n ot, i n y o ur j u d ge me nt, it 
is d ue e ntirel y t o dr u g treat me nt. 
C o m pare d t o his/ her c o n diti o n at a d missi o n t o t he pr oject, h o w m uc h has h e/s he c ha n g e d? 
0 = N ot assesse d    
 
4 = N o c ha n ge  
1 = Ver y m uc h i m pr o ve d    
5 = Mi ni mall y w orse  
2 = M uc h i m pr o ve d   
 
6 = M uc h w orse  
3 = Mi ni mall y i m pr o ve d    
7 = Ver y m uc h w orse  
2. Effic ac y i n de x: Rate t his ite m o n t he basis of dr u g effect o nl y . 
Select t he ter ms w hic h b est descri be t he d e grees of t hera p e utic effect a n d si de effects a n d 
rec or d t h e n u m ber i n t he b o x w here t he t w o ite ms i ntersect. 
E X A M P L E: T hera p e utic effect is rate d as ‘ M o derate’ a n d si de effects are j u d ge d ‘ D o n ot 
si g nifica ntl y i nterfer e wit h patie nt’s f u ncti o ni n g’. 
T her a pe utic effect  
Si de effects  
 
 
N o ne  
D oes n ot 
si g nific a ntly 
i nterfere wit h 
p atie nt’s 
f u ncti o ni n g 
Si g nific a ntly 
i nterferes wit h 
p atie nt’s 
f u ncti o ni n g 
O ut wei g hs 
t her a pe utic effect 
M ar k e d  
Vast i m pr o ve me nt. C o m plete or 
nearl y c o m plete re missi o n of all 
s y m pt o ms 
0 1  
0 2  
0 3  
0 4  
M o der ate  
Deci de d I m pr o ve me nt. Partial 
re missi o n of  
s y m pt o ms 
0 5  
0 6  
0 7  
0 8  
Mi ni m al  
Sli g ht i m pr o ve me nt w hic h 
d oes n’t alter stat us 
 of care of patie nt  
0 9  
1 0  
1 1  
1 2  
U nc h a n ge d or w orse  
1 3  
1 4  
1 5  
1 6  
N ot assesse d = 0 0  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 6 
Fi nal : 1 2 Oct 2 0 2 1 
1 1.  
Refere nces  
 
1 Nels o n L M. E pi de mi ol o g y of A L S. Cli nic al Ne ur oscie nce . 1 9 9 5; 3: 3 2 7 -3 1.  
2 Har di ma n O, va n de n Ber g L H, Kier na n M C. Cli nical dia g n osis a n d ma na ge me nt of a m y otr o p hic lateral scler osis. 
N at ure revie ws Ne ur ol o gy . 2 0 1 1; 7: 6 3 9 -4 9.  
3 R ose n D R, Si d di q ue T, Patters o n D, et al. M utati o ns i n C u/ Z n s u per o xi de dis m utase ge ne are ass ociate d wit h 
fa milial a m y otr o p hic lateral scler osis. N at ure . 1 9 9 3;  3 6 2: 5 9 -6 2.  
4 L o gr osci n o G, Tra y n or BJ, Har di ma n O, et al. I nci de nce of a m y otr o p hic lateral scler osis i n E ur o pe. J o ur n al of 
N e ur ol o gy, N e ur os ur gery, a n d P syc hi atry. 2 0 1 0;  8 1: 3 8 5 -9 0.  
5 Cr o ni n S, Har di ma n O, Tra y n or BJ. Et h nic variati o n i n t he i nci de nce of A L S: a s yste matic re vie w. Ne ur ol o gy . 
2 0 0 7; 6 8: 1 0 0 2 -7.  
6 Fact or -Lit va k P, Al -C hala bi A, Asc heri o A, et al. C urre nt pat h wa ys f or e pi de mi ol o gical researc h i n a m y otr o p hic 
lateral scler osis. A my otr o p hic L ater al S cler osis & F r o nt ote m p or al D e ge ner ati o n . 2 0 1 3; 1 4 S u p pl 1: 3 3 -4 3.  
7 Zal di var T, G utierrez J, Lara G, et al. Re d uce d fre q ue nc y of A L S i n a n et h nicall y mi xe d p o p ulati o n: a p o p ulati o n -
base d m ortalit y st u d y. Ne ur ol o gy . 2 0 0 9; 7 2: 1 6 4 0 -5.  
8 He nr y K A, Fa glia n o J, J or da n H M, et al. Ge o gra p hic v ariati o n of am y otr o p hic lateral scler osis inci de nce i n Ne w 
Jerse y, 2 0 0 9-2 0 1 1. A m J E pi de mi ol . 2 0 1 5; 1 8 2: 5 1 2 -9.  
9 Wa n g H, O' Reill y EJ, Weiss k o pf M G, et al. S m o ki n g a n d ris k of a m y otr o p hic lateral scler osis: a p o ole d a nal ysis of 
5 pr os pecti ve c o h orts. Arc hives of Ne ur ol o gy . 2 0 1 1; 6 8: 2 0 7 1 3.  
1 0 de J o n g S W, H uis ma n M H, S ute dja N A, et al. S m o ki n g, alc o h ol c o ns u m pti o n, a n d t he ris k of a m y otr o p hic lateral 
scler osis: a p o p ulati o n-base d st u d y. A meric a n J o ur n al of E pi de mi ol o gy . 2 0 1 2; 1 7 6: 2 3 3 -9.  
1 1 Bra dle y W G, Mas h D C. Be y o n d G ua m: t he c ya n o bacteria/ B M A A h y p ot hesis of t he ca use of A L S a n d ot her 
ne ur o de ge nerati ve diseases. A my otr o p hic L ater al S cler osis: O ffici al Pu blic ati o n of t he W orl d Fe der ati o n of 
Ne ur ol o gy Rese arc h Gr o u p o n M ot or Ne ur o n Dise ases . 2 0 0 9; 1 0 S u p pl 2: 7 -2 0.  
1 2 Caller T A, D o oli n J W, Ha ne y J F, et al. A cl uster of a m y otr o p hic lateral scler osis i n Ne w Ha m ps hire: a p ossi ble 
r ole f or t o xic c ya n o bacteria bl o o ms. A my otr o p hic L ater al Scler osis: Offici al P u blic ati o n of t he W orl d Fe der ati o n of 
Ne ur ol o gy Rese arc h Gr o u p o n M ot or Ne ur o n Dise ases . 2 0 0 9; 1 0 S u p pl 2: 1 0 1 -8.  
1 3 Caller T A, Fiel d N C, C hi p ma n J W, et al. S patial cl usteri n g of a m y otr o p hic lateral scler osis a n d t he p ote ntial r ole 
of B M A A. A my otr o p hic L ater al Scler osis: Offici al P u blic ati o n of t he W orl d Fe der ati o n of Ne ur ol o gy Rese arc h 
Gr o u p o n M ot or Ne ur o n Dise ases . 2 0 1 2; 1 3: 2 5 -3 2.  
1 4 Ki hira T, Y os hi da S, K o n d o T, et al. A n i ncrease i n A L S i nci de nce o n t he Kii Pe ni ns ula, 1 9 6 0 -2 0 0 9: a p ossi ble 
li n k t o c ha n ge i n dri n ki n g water s o urce. A my otr o p hic L ater al Scler osis: Offici al P u blic ati o n of t he W orl d 
Fe der ati o n of Ne ur ol o gy Rese arc h Gr o u p o n M ot or Ne ur o n Dise ases . 2 0 1 2;  1 3: 3 4 7 -5 0.  
1 5 Jar o ne n M, Ve h vilai ne n P, Mal m T, et al. Pr otei n dis ulfi de is o merase i n A L S m o use glia li n ks pr otei n misf ol di n g 
wit h N A D P H o xi dase -catal yze d s u per o xi de pr o d ucti o n. H u m M ol Ge net. 2 0 1 3; 2 2: 6 4 6 -5 5 . 
1 6 C ozz oli n o M, Ferri A, Valle C, Carri M T. Mit oc h o n dria a n d A L S: I m plicati o ns fr o m n o vel ge nes a n d pat h wa ys. 
M ol Cell Ne ur osci. 2 0 1 2 3; 5 5: 4 4 -4 9 . 
1 7 Bar ber S C, S ha w PJ. O xi dati ve stress i n A L S: ke y r ole i n m ot or ne ur o n i nj ur y a n d t hera pe utic tar get. Free 
R a dic al Bi ol o gy & Me dici ne . 2 0 1 0; 4 8: 6 2 9 -4 1.  
1 8 Pa pa di mitri o u D, Le Verc he V, Jac q uier A, et al. I nfla m mati o n i n A L S a n d S M A: s orti n g o ut t he g o o d fr o m t he 
e vil. Ne ur o bi ol o gy of Dise ase . 2 0 1 0; 3 7: 4 9 3 -5 0 2.  
1 9 Mc C o m be P A, He n ders o n R D. T he R ole of i m m u ne a n d i nfla m mat or y mec ha nis ms i n A L S. C urre nt M olec ul ar 
Me dici ne . 2 0 1 1; 1 1: 2 4 6 -5 4.  
2 0 Wallis N, Za ga mi CJ, Beart P M, O' S hea R D. C o m bi ne d e xcit ot o xic -o xi dati ve stress a n d t he c o nce pt of n o n -cell 
a ut o n o m o us pat h ol o g y of A L S: i nsi g hts i nt o m ot o ne ur o n a x o n o pat h y a n d astr o gli osis. Ne ur oc he mistry 
I nter n ati o n al. 2 0 1 2; 6 1: 5 2 3 -3 0.  
2 1 B oillee S, Va n de Vel de C, Cl e vela n d D W. A L S: a disease of m ot or ne ur o ns a n d t heir n o n ne ur o nal nei g h b ors. 
Ne ur o n . 2 0 0 6; 5 2: 3 9 -5 9  
2 2 Ferrai u ol o L, Kir b y J, Griers o n AJ, et al. M olec ular pat h wa ys of m ot or ne ur o n i nj ur y i n a m y otr o p hic lateral 
scler osis. N at ure Revie ws Ne ur ol o gy . 2 0 1 1; 7: 6 1 6 -3 0.  
2 3 Frie dla n der R M. A p o pt osis a n d cas pases i n ne ur o de ge nerati ve diseases. T he Ne w E n gl a n d J o ur n al of Me dici ne . 
2 0 0 3; 3 4 8: 1 3 6 5 -7 5.  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 7 
Fi nal : 1 2 Oct 2 0 2 1 
 
2 4 Ferrai u ol o L, Kir b y J, Griers o n AJ, et al. M olec ular pat h wa ys of m ot or ne ur o n i nj ur y i n a m y otr o p hic lateral 
scler osis. N at ure Revie ws Ne ur ol o gy . 2 0 1 1; 7: 6 1 6 -3 0.  
2 5 Frie dla n der R M, Br o w n R H, Ga gliar di ni V, et al. I n hi biti o n of I C E sl o ws A L S i n mice. N at ure . 1 9 9 7; 3 8 8: 3 1.  
2 6 Li M, O na V O, G ue ga n C, et al. F u ncti o nal r ole of cas pase -1 a n d cas pase -3 i n a n A L S tra ns ge nic m o use m o del. 
Scie nce . 2 0 0 0;  2 8 8: 3 3 5 -9.  
2 7 Pasi nelli P, H o use weart M K, Br o w n R H, Jr., Cle vela n d D W. Cas pase -1 a n d -3 are se q ue ntiall y acti vate d i n m ot or 
ne ur o n deat h i n C u, Z n s u per o xi de dis m utase -me diate d fa milial a m y otr o p hic lateral scler osis. Pr ocee di n gs of t he 
N ati o n al Ac a de my of Scie nces of t he U nite d St ates of A meric a . 2 0 0 0; 9 7: 1 3 9 0 1 -6.  
2 8 Y ua n J, Ya n k ner B A. A p o pt osis i n t he ner v o us s yste m. N at ure . 2 0 0 0; 4 0 7: 8 0 2 -9.  
2 9 Marti n LJ. Ne ur o nal deat h i n a m y otr o p hic lateral scler osis is a p o pt osis: p ossi ble c o ntri b uti o n of a pr o gra m me d 
cell deat h mec ha nis m. J o ur n al of Ne ur o p at h ol o gy a n d Ex peri me nt al Ne ur ol o gy . 1 9 9 9; 5 8: 4 5 9 -7 1.  
3 0 Miller R G, Mitc hell J D, M o ore D H. Ril uz ole f or a m y otr o p hic lateral scler osis ( A L S)/ m ot or ne ur o n disease 
( M N D). C oc hr a ne D at a b ase of Syste m atic Revie ws . 2 0 1 2; 3: C D 0 0 1 4 4 7.  
3 1 Fe derici T, B o ulis N M. Ge ne -base d treat me nt of m ot or ne ur o n diseases. M uscle Nerve . 2 0 0 6; 3 3: 3 0 2 -2 3.  
3 2 Sa da n O, S he mes h N, C o he n Y, Mela me d E, Offe n D. A d ult ne ur otr o p hic fact or -secreti n g ste m cells: a p ote ntial 
n o vel t hera p y f or ne ur o de ge nerati ve diseases. Isr Me d Ass oc J . 2 0 0 9; 1 1: 2 0 1 -4.  
3 3 Berr y J D, C u d k o wicz M E, Wi n de ba n k AJ, et al. N ur O w n, p hase 2, ra n d o mize d, cli nical trial i n patie nts wit h 
A L S: Safet y, cli nical, a n d bi o mar ker res ults. Ne ur ol o g y 2 0 1 9; 9 3:e 2 2 9 4 -e 3 0 5. 
3 4 Geij o -Barrie nt os E, Past ore -Ol me d o C, De Mi n g o P, et al. I ntra m usc ular injecti o n of b o ne m arr o w ste m cells i n 
am y otr o p hic lateral scler osis p atie nts: a ra n d o mize d cli nical trial. Fr o nt Ne ur osci. 2 0 2 0; 1 4: 1 -1 4 . 
3 5 Petr o u P, G ot helf Y, Ar g o v Z, et al. Safet y a n d cli nical effects of m ese nc h y mal ste m cells secreti n g n e ur otr o p hic 
fact or tra ns pla ntati o n i n p atie nts w it h am y otr o p hic lateral scler osis: res ults of p hase 1/ 2 a n d 2a cli nical trials. J A M A. 
Ne ur ol . 2 0 1 6; 7 3: 3 3 7 -4 4.  
3 6 B uss oli n o F, Di Re nz o M F, Zic he M, et al. He pat oc yte gr o wt h fact or is a p ote nt a n gi o ge nic fact or w hic h 
sti m ulates e n d ot helial cell m otilit y a n d gr o wt h. J Cell Bi ol. 1 9 9 2; 1 1 9: 6 2 9 -4 1.  
3 7 Mats u m ot o K, Na ka m ura T. E mer gi n g m ulti p ote nt as pects of he pat oc yte gr o wt h fact or. J Bi oc he m . 
1 9 9 6; 1 1 9: 5 9 1 -6 0 0.  
3 8 Ja yasa n kar V, W o o YJ, Pir olli TJ, et al. I n d ucti o n of a n gi o ge nesis a n d i n hi biti o n of a p o pt osis b y he pat oc yte 
gr o wt h fact or effecti vel y treats p ostisc he mic heart fail ure. J C ar d S ur g . 2 0 0 5; 2 0: 9 3 -1 0 1.  
3 9 Na ka ga mi H, Ka ne da Y, O gi hara T, M oris hita R. He pat oc yte gr o wt h fact or as p ote ntial car di o vasc ular t hera p y. 
Ex pert Rev C ar di ov asc T her . 2 0 0 5; 3: 5 1 3 -9.  
4 0 Gille J, K hali k M, K o ni g V, Ka uf ma n n R. He pat oc yte gr o wt h fact or/scatter fact or ( H G F/ S F) i n d uces vasc ular 
per mea bilit y fact or ( V P F/ V E G F) e x pressi o n b y c ult ure d kerati n oc ytes. J I nvest Der m at ol. 1 9 9 8; 1 1 1: 1 1 6 0 -5.  
4 1 M oris hita R, A o ki M, Y o Y, O gi hara T. He pat oc yte gr o wt h fact or as car di o vasc ular h or m o ne: r ole of H G F i n t he 
pat h o ge nesis of car di o vasc ular disease . E n d ocr J. 2 0 0 2; 4 9: 2 7 3 -8 4 . 
4 2 Ja yasa n kar V, W o o YJ, Bis h L T, et al. Ge ne tra nsfer of he pat oc yte gr o wt h fact or atte n uates p osti nfarcti o n heart 
fail ure. Circ ul ati o n. 2 0 0 3; 1 0 8 S u p pl 1:II 2 3 0 -6.  
4 3 Has hi m ot o N, Ya ma na ka H, F u k u o ka T, et al. E x pressi o n of H G F a n d c Met i n t he peri p heral ner v o us s yste m of 
a d ult rats f oll o wi n g sciatic ner ve i nj ur y. Ne ur ore p ort . 2 0 0 1; 1 2: 1 4 0 3 -7.  
4 4 Giac o bi ni P, Messi na A, Wra y S, et al. He pat oc yte gr o wt h fact or acts as a m ot o ge n a n d g ui da nce si g nal f or 
g o na d otr o pi n h or m o ne -releasi n g h or m o ne-1 ne ur o nal mi grati o n. J Ne ur osci. 2 0 0 7; 2 7: 4 3 1 -4 5.  
4 5 Kat o N, Ne m ot o K, Na ka nis hi K, et al. N o n viral ge ne tra nsfer of h u ma n he pat oc yte gr o wt h fact or i m pr o ves 
stre pt oz ot oci n-i n d uce d dia betic ne ur o pat h y i n rats. Di a betes . 2 0 0 5; 5 4: 8 4 6 -5 4.  
4 6 K oi ke H, M oris hita R, I g uc hi S, et al. E n ha nce d a n gi o ge nesis a n d i m pr o ve me nt of ne ur o pat h y b y c otra nsfecti o n 
of h u ma n he pat oc yte gr o wt h fact or a n d pr ostac ycli n s y nt hase ge ne. F A S E B J . 2 0 0 3; 1 7: 7 7 9 -8 1.  
4 7 Ts uc hi hara T, O gata S, Ne m ot o K, et al. N o n viral Retr o gra de Ge ne Tra nsfer of H u ma n He pat oc yte Gr o wt h Fact or 
I m pr o ves Ne ur o pat hic Pai n-relate d P he n o me na i n Rats. M ol T her. 2 0 0 9; 1 7: 4 2 -5 0 . 
4 8 T o n ges L, Oste n d orf T, La m balle F, et al. He pat oc yte gr o wt h fact or pr otects reti nal ga n gli o n cells b y i ncreasi n g 
ne ur o nal s ur vi val a n d a x o nal re ge nerati o n i n vitr o a n d i n vi v o. J o ur n al of Ne ur oc he mistry . 2 0 1 1; 1 1 7: 8 9 2 -9 0 3.  
4 9 Kita m ura K, I wa na mi A, Na ka m ura M, et al. He pat oc yte gr o wt h fact or pr o m otes e n d o ge n o us re pair a n d 
f u ncti o nal rec o ver y after s pi nal c or d i nj ur y. J Ne ur osci Res. 2 0 0 7; 8 5: 2 3 3 2 -4 2.  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L   
Pr ot oc ol: V M A L S- 0 0 2- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 1 
6 8 
Fi nal : 1 2 Oct 2 0 2 1 
 
5 0 Ka d o ya ma K, F u na k os hi H, O h ya W, Na ka m ura T. He pat oc yte gr o wt h fact or ( H G F) atte n uates gli osis a n d 
m ot o ne ur o nal de ge nerati o n i n t he brai nste m m ot or n uclei of a tra ns ge nic m o use m o del of A L S. Ne ur oscie nce 
Rese arc h . 2 0 0 7; 5 9: 4 4 6 -5 6.  
5 1 T y n dall SJ, Wali k o nis R S. Si g nali n g b y he pat oc yte gr o wt h fact or i n ne ur o ns is i n d uce d b y p har mac ol o gical 
sti m ulati o n of s y na ptic acti vit y. Sy n a pse . 2 0 0 7; 6 1: 1 9 9 -2 0 4.  
5 2 S ha n g J, De g uc hi K, O hta Y, et al. Str o n g ne ur o ge nesis, a n gi o ge nesis, s y na pt o ge nesis, a n d a ntifi br osis of 
he pat oc yte gr o wt h fact or i n rats brai n after tra nsie nt mi d dle cere bral arter y occl usi o n. J o ur n al of Ne ur oscie nce 
Rese arc h.  2 0 1 1; 8 9: 8 6 -9 5.  
5 3 A kita H, Ta ka gi N, Is hi hara N, et al. He pat oc yte gr o wt h fact or i m pr o ves s y na ptic l ocalizati o n of t he N M D A 
rece pt or a n d i ntracell ular si g nali n g after e xcit ot o xic i nj ur y i n c ult ure d hi p p oca m pal ne ur o ns. Ex peri me nt al 
Ne ur ol o gy . 2 0 0 8; 2 1 0: 8 3 -9 4.  
5 4 Is hi hara N, Ta ka gi N, Nii m ura M, et al. I n hi biti o n of a p o pt osis-i n d uci n g fact or tra nsl ocati o n is i n v ol ve d i n 
pr otecti ve effects of he pat oc yte gr o wt h fact or a gai nst e xcit ot o xic cell deat h i n c ult ure d hi p p oca m pal ne ur o ns. 
J o ur n al of Ne ur oc he mistry . 2 0 0 5; 9 5: 1 2 7 7 -8 6.  
5 5 Is hi ga ki A, A o ki M, Na gai M, et al. I ntrat hecal deli ver y of he pat oc yte gr o wt h fact or fr o m a m y otr o p hic lateral 
scler osis o nset s u p presses dise ase pr o gressi o n i n rat a m y otr o p hic lateral scler osis m o del. J o ur n al of Ne ur o p at h ol o gy 
a n d Ex peri me nt al  Ne ur ol o gy . 2 0 0 7; 6 6: 1 0 3 7 -4 4.  
5 6 Li M, O na V O, G ue ga n C, et al. F u ncti o nal r ole of cas pase -1 a n d cas pase -3 i n a n A L S tra ns ge nic m o use m o del. 
Scie nce . 2 0 0 0; 2 8 8: 3 3 5 -9.  
5 7 Pasi nelli P, H o use weart M K, Br o w n R H, Jr., Cle vela n d D W. Cas pase -1 a n d -3 are se q ue ntiall y acti vate d i n m ot or 
ne ur o n deat h i n C u, Z n s u per o xi de dis m utase -me diate d fa milial a m y otr o p hic lateral scler osis. Pr ocee di n gs of t he 
N ati o n al Ac a de my of Scie nces of t he U nite d St ates of A meric a . 2 0 0 0; 9 7: 1 3 9 0 1 -6.  
5 8 Ka d o ya ma K, F u na k os hi H, O h ya W, Na ka m ura T. He pat oc yte gr o wt h fact or ( H G F) atte n uates gli osis a n d 
m ot o ne ur o nal de ge nerati o n i n t he brai nste m m ot or n uclei of a tra ns ge nic m o use m o del of A L S. Ne ur osci Res . 
2 0 0 7; 5 9: 4 4 6 -5 6.  
5 9 Ka wai da K, Mats u m ot o K, S hi maz u H, Na ka m ura T. He pat oc yte gr o wt h fact or pre ve nts ac ute re nal fail ure a n d 
accelerates re nal re ge nerati o n i n mice. Pr ocee di n gs of t he N ati o n al Ac a de my of Scie nces of t he U nite d St ates of 
A meric a . 1 9 9 4; 9 1: 4 3 5 7 -6 1.  
6 0 Li u M L, Mars W M, Zar ne gar R, Mic hal o p o ul os G K. U pta ke a n d distri b uti o n of he pat oc yte gr o wt h fact or i n 
n or mal a n d re ge nerati n g a d ult rat li ver. A m J P at h ol . 1 9 9 4; 1 4 4: 1 2 9 -4 0.  
6 1 S ufit R L, Ajr o u d -Driss S, Case y P, Kessler J A. O pe n la bel st u d y t o assess t he safet y of V M 2 0 2 i n Partici pa nt s 
wit h a m y otr o p hic lateral scler osis. A my otr o p h L ater al Scler Fr o nt ote m p or al De ge ner . 2 0 1 7; 1 8( 3-4): 2 6 9 -2 7 8.  
6 2 Bri n k ma n n J R, A n dres P, Me n d oza M, Sa nja k M. G ui deli nes f or t he use a n d perf or ma nce of q ua ntitati ve o utc o me 
meas ures i n A L S cli nical trials. J o ur n al of t he N e ur ol o gic al Scie nces. 1 9 9 7; 1 4 7: 9 7 -1 1 1.  
6 3 Miller R G, Jac ks o n C E, Kasars kis EJ, et al. Practice para meter u p date: t he care of t he patie nt wit h a m y otr o p hic 
lateral scler osis: m ulti disci pli n ar y care, s y m pt o m ma na ge me nt, a n d c o g niti ve/ be ha vi oral i m pair me nt (a n e vi de nce-
base d re vie w). Ne ur ol o gy . 2 0 0 9; 7 3: 1 2 2 7-1 2 3 3. ( Reaffir me d b y t he A merica n Ass ociati o n of Ne ur o m usc ular a n d 
Electr o dia g n ostic Me dici ne , Ja n uar y 1 1, 2 0 2 0) 
6 4 Bri n k ma n n J R, A n dres P, Me n d oza M, Sa nja k M. G ui deli nes f or t he use a n d perf or ma nce of q ua ntitati ve o utc o me 
meas ures i n A L S cli nical trials. J o ur n al of t he Ne ur ol o gic al Scie nces . 1 9 9 7; 1 4 7: 9 7 -1 1 1.  
6 5 S hef ner J M, Li u D, Leit ner M L, et al. Q ua ntitate stre n gt h testi n g i n A L S cli nical trials. Ne ur ol o gy . 
2 0 1 6; 8 7: 6 1 7 -2 4.  
6 6 Patel A. D oes t he r ole of a n gi o ge nesis pla y a r ole i n at her oscler osis a n d pla q ue i nsta bilit y? A n at P hysi ol . 
2 0 1 4; 4( 3). d oi: 1 0. 4 1 7 2/ 2 1 6 1 -0 9 4 0. 1 0 0 0 1 4 7.  
6 7 Nis hi da T, Ts uji S, Ts ujii M, et al. Oral gl uc ose t olera nce test pre dicts pr o g n osis of patie nts wit h li ver cirr h osis. 
A m J G astr oe nter ol . 2 0 0 6; 1 0 1( 1): 7 0-5.