A 6-Month Extension Study Following Protocol VMDN-003-2 - An Adaptive, Phase 3, Double-Blind, Randomized, Placebo-Controlled, Multicenter Study to Assess Engensis in Participants With Painful Diabetic Peripheral Neuropathy
Phase: PHASE3
Conditions: Diabetic Peripheral Neuropathy
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 D N- 0 0 3- 2 – A n 
A d a pti ve, P h ase 3, D o u ble -Bli n d, R a n d o mize d, Pl ace b o - C o ntr olle d, 
M ultice nter St u d y t o Assess t he S afet y a n d Effic ac y of E n ge nsis i n 
P artici p a nts  wit h P ai nf ul Di a betic Peri p her al Ne ur o p at h y  
Pr ot oc ol N u m ber:  V M D N - 0 0 3- 2 b 
Versi o n N u m ber:   1. 0 
A p pr o v al D ate :  
1 1 Fe b  2 0 2 1 
C o m p o u n d :   
E n ge nsis  
St u d y P h ase:    
3 
S h ort Title :  
A 6- M o nt h P hase 3 E xte nsi o n of a St u d y t o Assess Safet y a n d Efficac y of 
E n ge nsis i n Pai nf ul Dia betic Peri p heral Ne ur o pat h y 
Acr o n y m : 
R E G Ai N - 1 B  
Re g ul at or y A ge nc y I de ntifier N u m ber:  I N D 1 3 9 3 8 
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. 0 
1 1 Fe b  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 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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 
Fi nal: 1 1 Fe b 2 0 2 1 
T A B L E O F C O N T E N T S  
1.  
Pr ot oc ol S u m m ar y .......................................................................................................... 8 
 
S y n o psis ............................................................................................................................ 8 
 
St u d y Sc he ma ................................................................................................................. 1 3  
 
Sc he d ule of A cti vities ( S o A) .......................................................................................... 1 4  
2.  
I N T R O D U C TI O N ........................................................................................................ 1 7 
 
St u d y Rati o nale ............................................................................................................... 1 7  
 
Bac k gr o u n d ..................................................................................................................... 1 8  
2. 2. 1.  
Pat h o p h ysi ol o g y of Dia betic Peri p heral Ne ur o p at h y ..................................................... 1 8  
2. 2. 2.  
C urre nt Treat me nt  O pti o ns ............................................................................................. 2 0 
2. 2. 3.  
U n met Cli nical  Nee d  ....................................................................................................... 2 1 
2. 2. 4.  
He pat oc yte Gr o wt h Fact or f or t he Treat me nt of Dia betic  
Ne ur o pat h y ...................................................................................................................... 2 1  
2. 2. 5.  
E n ge nsis .......................................................................................................................... 2 2  
2. 2. 6.  
Precli nical  Data  ............................................................................................................... 2 3 
2. 2. 7.  
Cli nical  Data  ................................................................................................................... 2 3 
 
Be nefit/ Ris k Assess me nt  ................................................................................................ 2 4 
2. 3. 1.  
Ris k  Assess me nt  ............................................................................................................. 2 4 
2. 3. 2.  
Be nefit  Assess me nt  ......................................................................................................... 2 6 
2. 3. 3.  
O verall Be nefit/ Ris k  C o ncl usi o ns ................................................................................... 2 6 
3.  
O B J E C TI V E S A N D  E N D P OI N T S  ............................................................................. 2 7 
4.  
S T U D Y D E SI G N ........................................................................................................... 3 0 
 
O verall Desi g n  ................................................................................................................ 3 0 
 
Scie ntific Rati o nale f or St u d y Desi g n  ............................................................................ 3 0 
 
Partici pa nt I n p ut i nt o Desi g n .......................................................................................... 3 0  
 
J ustificati o n f or D ose ...................................................................................................... 3 0 
 
E n d of St u d y Defi niti o n .................................................................................................. 3 0  
 
St u d y C o m pleti o n  ........................................................................................................... 3 0 
 
C o m plete d Partici pa nts  ................................................................................................... 3 0 
5.  
S T U D Y P O P U L A TI O N  ............................................................................................... 3 1 
 
Partici pa nt I de ntificati o n ................................................................................................. 3 1 
 
Lifest yle C o nsi derati o ns ................................................................................................. 3 1  
5. 2. 1.  
Meals a n d Dietar y Restri cti o ns  ....................................................................................... 3 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 
Fi nal: 1 1 Fe b 2 0 2 1 
5. 2. 2.  
Caffei ne, Al c o h ol, a n d T o bacc o ..................................................................................... 3 1  
5. 2. 3.  
S u p ple me nts .................................................................................................................... 3 1  
5. 2. 4.  
Acti vit y  ........................................................................................................................... 3 1 
6.  
S T U D Y I N T E R V E N TI O N  .......................................................................................... 3 2 
 
Meas ures t o Mi ni mize Bias  ............................................................................................ 3 2 
6. 1. 1.  
Ra n d o mizati o n ................................................................................................................ 3 2  
6. 1. 2.  
Stratificati o n  .................................................................................................................... 3 2 
6. 1. 3.  
Bli n di n g........................................................................................................................... 3 2  
6. 1. 4.  
Mai nte na nce of t he  Bli n d  ................................................................................................ 3 2 
 
C o nc o mita nt T hera p y ..................................................................................................... 3 2  
6. 2. 1.  
Resc ue Me dici ne  ............................................................................................................. 3 3 
 
Pr o hi bite d a n d Restricte d Me dicati o ns a n d Pr oce d ures ................................................. 3 3  
6. 3. 1.  
Me dicati o ns T hat Ma y I nterfere wit h E n ge nsis  Bi o acti vit y  ........................................... 3 3 
6. 3. 2.  
Me dicati o ns a n d Pr oce d ures T hat Ma y I nterfere wit h Assess me nt 
of Pai n  ............................................................................................................................. 3 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 ................................. 3 4  
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 DI S C O N TI N U A TI O N  ..................................................................... 3 5 
 
Partici pa nt Disc o nti n uati o n/ Wit h dra wal/ Earl y T er mi nati o n fr o m 
t he St u d y ......................................................................................................................... 3 5 
 
L ost t o F oll o w- u p............................................................................................................ 3 6  
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 7 
 
Partici pa nt Trai ni n g  ........................................................................................................ 3 7 
8. 1. 1.  
Acc ur ate Pai n Re p orti n g  ................................................................................................. 3 7 
8. 1. 2.  
Place b o Res p o nse Re d ucti o n .......................................................................................... 3 7  
 
Efficac y Assess me nts a n d Pr oce d ures  ............................................................................ 3 7 
8. 2. 1.  
Brief Pai n I n ve nt or y f or Dia betic Pai nf ul Ne ur o pat h y ................................................... 3 7  
8. 2. 2.  
Q ualit y of Life/ Partici pa nt Re p orte d O utc o me Meas ures  .............................................. 3 8 
8. 2. 3.  
Be dsi de Se ns or y Testi n g ................................................................................................. 3 9  
8. 2. 4.  
Mic hi ga n Ne ur o p at h y Scree ni n g I nstr u me nt .................................................................. 3 9  
 
Safet y Assess me nts  ......................................................................................................... 3 9 
8. 3. 1.  
P h ysical  E xa mi nati o ns .................................................................................................... 3 9 
8. 3. 2.  
Me dical Hist or y a n d Fa milial Hist or y of Ca ncer  ............................................................ 3 9 
8. 3. 3.  
1 2- Lea d Electr ocar di o gr a ms  ........................................................................................... 4 0 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 
Fi nal: 1 1 Fe b 2 0 2 1 
8. 3. 4.  
Vital Si g ns  ....................................................................................................................... 4 0 
8. 3. 5.  
Cli nical La b orat or y Assess me nts  .................................................................................... 4 0 
8. 3. 6.  
Reti nal F u n d osc o p y ........................................................................................................ 4 1  
 
Safet y Assess me nts  ......................................................................................................... 4 2 
8. 4. 1.  
Treat me nt - e mer ge nt A d v erse E ve nts a n d Seri o us A d verse E v e nts ................................ 4 2 
8. 4. 2.  
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 mati o n ..................................................................................................................... 4 2 
8. 4. 3.  
Met h o d of Re p orti n g T E A Es a n d T E S A Es  .................................................................... 4 2 
8. 4. 4.  
T E S A E Re p orti n g t o t he S p o ns or or Desi g nee ............................................................... 4 2  
8. 4. 5.  
A d verse E v e nts of S peci al I nt erest  ................................................................................. 4 2 
8. 4. 6.  
F oll o w- u p of T E A Es a n d T E S A Es  ................................................................................. 4 4 
8. 4. 7.  
Re g ulat or y Re p orti n g Re q uire me nts f or T E S A Es .......................................................... 4 4  
8. 4. 8.  
Pre g na nc y a n d C o ntrace pti o n ......................................................................................... 4 5  
8. 4. 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 T E A Es or T E S A Es  ................................................................................... 4 6 
9.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ........................................................................ 4 7 
 
Sa m ple Size Deter mi nati o n  ............................................................................................ 4 7 
 
P o p ulati o ns f or A nal yses ................................................................................................ 4 7  
9. 2. 1.  
I nte nt-T o -Tr eat  P o p ulati o n ............................................................................................. 4 7 
9. 2. 2.  
Safet y  P o p ulati o n ............................................................................................................ 4 7 
9. 2. 3.  
M o difie d I T T  P o p ulati o n ................................................................................................ 4 7 
9. 2. 4.  
Per Pr ot oc ol ( P P)  P o p ulati o n .......................................................................................... 4 7 
 
Statistical A nal yses  ......................................................................................................... 4 8 
9. 3. 1.  
Pri mar y  E n d p oi nt(s) ........................................................................................................ 4 8 
9. 3. 2.  
Sec o n dar y E n d p oi nts ...................................................................................................... 4 8  
9. 3. 3.  
E x pl orat or y Effi cac y E n d p oi nts ...................................................................................... 4 8  
9. 3. 4.  
Safet y  A nal yses  ............................................................................................................... 4 9 
9. 3. 5.  
I nteri m A nal ysis .............................................................................................................. 4 9 
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  .................................................................................................... 5 0 
 
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 ................................................................................................................ 5 0  
1 0. 1. 1.  Re g ulat or y a n d Et hical C o nsi derati o ns ........................................................................... 5 0  
1 0. 1. 2.  Fi na ncial Discl os ur e ........................................................................................................ 5 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
6 
Fi nal: 1 1 Fe b 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 ..................................................... 5 2  
1 0. 1. 4.  Data Pr otecti o n a n d C o nfi de ntialit y ................................................................................ 5 2 
1 0. 1. 5.  C o m mittee Str uct ure  ....................................................................................................... 5 4 
1 0. 1. 6.  Data Q ualit y Ass ur a nce .................................................................................................. 5 4  
1 0. 1. 7.  Data  Ma na ge m e nt  ........................................................................................................... 5 7 
1 0. 1. 8.  Rec or d kee pi n g a n d Rete nti o n  ......................................................................................... 5 8 
1 0. 1. 9.  St u d y a n d Site Start a n d Cl os ure .................................................................................... 5 9  
1 0. 1. 1 0.  P u blicati o n P olic y  ........................................................................................................... 5 9 
1 0. 1. 1 1.  I ns ura nce ......................................................................................................................... 6 0 
 
A p pe n di x 2. A d vers e E v e 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 ......................................................... 6 1  
1 0. 2. 1.  Defi niti o n of A E ............................................................................................................. 6 1  
1 0. 2. 2.  Defi niti o n of T E A E......................................................................................................... 6 2  
1 0. 2. 3.  Defi niti o n of T E S A E ...................................................................................................... 6 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/ or T E S A Es  ................................................... 6 3 
1 0. 2. 5.  Re p orti n g of S A Es .......................................................................................................... 6 5  
 
A p pe n di x 3. Pr o hi bite d Me dicati o ns a n d Pr oce d ures ..................................................... 6 6  
 
A p pe n di x 4. A b bre vi ati o ns a n d Defi niti o ns ................................................................... 6 7  
1 0. 4. 1.  A b bre viati o ns .................................................................................................................. 6 7  
1 0. 4. 2.  Defi niti o ns ....................................................................................................................... 7 0 
 
A p pe n di x 5. Brief Pai n I n ve nt or y f or Partici p a nts wit h Dia betic 
Peri p heral N e ur o pat h y ( B PI- D P N)  ................................................................................. 7 1 
 
A p pe n di x 6. Patie nt Gl o bal I m pressi o n of C ha n ge ........................................................ 7 3  
 
A p pe n di x 7. S h ort F or m Healt h S ur ve y ( S F- 3 6) ............................................................ 7 4  
 
A p pe n di x 8. E ur o Q ol Healt h Utilities I n de x ( E Q- 5 D)  ................................................... 7 9 
 
A p pe n di x 9. Be dsi de Se ns or y Testi n g ( B S T) ................................................................. 8 2 
 
A p pe n di x 1 0. Mic hi ga n Ne ur o pat h y Scree ni n g I nstr u me nt ........................................... 8 5  
 
A p pe n di x 1 1. Pr ot oc ol A me n d me nt Hist or y .................................................................. 8 9  
1 1.  
R E F E R E N C E S .............................................................................................................. 9 0 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 
Fi nal: 1 1 Fe b 2 0 2 1 
List of T a bles  
Ta ble 1  
P ote ntial Ris ks of Cli nical Si g nifica nce  ............................................................. 2 4 
Ta ble 2  
Pr o hi bite d Me dicati o ns – Ster oi ds ..................................................................... 6 6  
Ta ble 3  
Pr o hi bite d Me dicati o ns a n d Pr oce d ures – O pi oi ds a n d Ot her T h era pies  ........... 6 6 
List of Fi g ures  
Fi g ure 1  
T he Ne ur o d estr ucti ve Effects of  Hy per gl y ce mia  ............................................... 1 9 
Fi g ure 2  
V M 2 0 2 C o nstr uct ............................................................................................... 2 2  
 
 

 
 
 
Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
1 1 
Fi nal: 1 1 Fe b 2 0 2 1 
O ver all Desi g n  
V M D N - 0 0 3- 2 b is a 6- m o nt h e xte nsi o n st u d y f oll o wi n g St u d y V M D N- 0 0 3- 2, w hic h is an 
a da pti ve, P hase 3, 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 efficac y a n d safet y of E n ge nsis (c o ntai ni n g t he acti ve p har m ace utical i n gre die nt 
V M 2 0 2) i n Partici pa nts wit h pai nf ul D P N.  
T he p ur p ose of t his st u d y is t o assess t he d ura bilit y of efficac y a n d  l o n g-ter m safet y of E n ge nsis 
c o m pare d t o Place b o as meas ure d b y c ha n ges i n A vera g e Dail y Pai n Sc ore ( A D P S) of t he f ull 
Brief Pai n I n ve nt or y f or Dia betic Peri p heral Ne ur o pat h y ( B PI -D P N ), Be dsi de Se ns or y Testi n g 
(B S T ), p h ysical e xa mi nati o ns, la b orat or y assess m e nts, vital si g ns, treat me nt-e mer ge nt a d vers e 
e ve 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 n d a d verse e ve nts of 
s pecial i nterest ( A E SIs). 
Partici pa nts will be e nr olle d i n t he V M D N- 0 0 3- 2 b st u d y at c o m pleti o n of t he Da y  1 8 0 Visit  of 
St u d y V M D N- 0 0 3- 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 
a n d t he sa me tr eat me nt gr o u p ( E n ge nsis or Place b o) assi g ne d b y ra n d o mizati o n i n St u d y 
V M D N - 0 0 3- 2. N o st u d y dr u g or treat me nt will be a d mi nistere d i n t his V M D N - 0 0 3- 2 b e xt e nsi o n 
st u d y. T he d o u ble-bli n d treat me nt assi g n me nt fr o m t he pri or st u d y will be mai ntai ne d  f or 
I n v esti gat ors a n d Partici p a nts d uri n g t his e xte nsi o n st u d y. 
Assess me nts t o be c o n d u cte d d uri n g t his V M D N - 0 0 3- 2 b e xte nsi o n st u d y are as f oll o ws: vital 
si g ns, wei g ht, B MI , p h ysical e xa mi nati o n, reti nal f u n d osc o p y ( b y a n o p ht h al m ol o gist), 1 2-lea d 
electr ocar di o gr a m ( E C G), la b orat or y ass ess me nts, H B A 1c le vels, c o n c o mita nt me dicati o ns a n d 
pr oce d ur es, uri ne dr u g a n al ysis, uri ne pre g na n c y test f or fe males of c hil d beari n g p ote ntial, 
Acc ur ate Pai n Re p orti n g ( A P R) , Place b o Res p o ns e Re d ucti o n ( P R R), t he Mic hi ga n Ne ur o p at h y 
Scree ni n g I nstr u me nt ( M N SI), p artial a n d f ull B PI -D P N , B S T, a n d q ualit y of life i nstr u me nts 
( 3 6-ite m S h ort F or m Healt h S ur ve y [ S F- 3 6] a n d E ur o Q ol Healt h Utilities I n de x [ E Q-5 D]) . 
Assess me nts of T E A E s, T E S A Es,  A E SI s, a n d cli nicall y si g nifica nt la b orat or y val ues will start as 
of t he Da y  1 8 0 Visit of St u d y V M D N- 0 0 3- 2 a n d c o nti n ue t hr o u g h o ut t he V M D N - 0 0 3- 2 b 
e xte nsi o n st u d y t hr o u g h Da y 3 6 5/ E T. 
D uri n g t he last 7 da ys pri or t o  t he Da y 2 7 0 a n d Da y 3 6 5/ E T Visits, Partici pa nts m ust c o m plete 
t he f ull B PI -D P N  o n a n eP R O  f or deter mi ni n g t he A D P S f or at least 5  o ut of t he last 7 da ys. 
F oll o w- u p St u d y Visits will be c o n d ucte d o n D a ys 2 7 0, 3 0 0, a n d 3 6 5/ E T . At t he Da y 3 6 5/ E T 
Visit (e n d of st u d y), t he f oll o wi n g assess me nts will be c o n d ucte d: t he f ull B PI- D P N ( perf or me d 
d uri n g t he 7 da ys pri or t o t he Visit), M N SI, B S T, Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C), 
S F - 3 6 a n d E Q-5 D q ualit y of life assess me nts, uri ne dr u g a nal ysis, reti nal f u n d osc o p y, p h ysical 
e xa mi nati o n, c o nc o mita nt me dicati o ns a n d pr oce d ures, T E A Es , a n d A E SIs. Bl o o d will be dra w n 
f or deter mi nati o n of s er u m c he mistr y, li pi d pr ofile, pre g na nc y st at us, he mat ol o g y, a n d H b A 1c 
le vels. 

 
 
 
Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
1 2 
Fi nal: 1 1 Fe b 2 0 2 1 
St u d y a n d Tre at m e nt D ur ati o n:  
T he ti mi n g f or visits i n t he V M D N - 0 0 3- 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 
St u d y V M D N- 0 0 3- 2. Partici pa nts i n St u d y V M D N- 0 0 3- 2 b will be f oll o we d fr o m t he Da y 1 8 0 
Visit  (V M D N - 0 0 3- 2) t o Da y 3 6 5/ E T. T he V M D N- 0 0 3- 2 b st u d y d urati o n is 6 m o nt hs.  
N o st u d y dr u g or treat me nt will be a d mi nistere d i n St u d y V M D N- 0 0 3- 2 b. 
Visit Fre q ue nc y:  
T here will be  3 visits t o t he Cli nical Site d uri n g t he e xte nsi o n st u d y ( aft er t he Da y 1 8 0 Visit fr o m 
St u d y V M D N- 0 0 3- 2) o n Da y s 2 7 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 w o treat me nt gr o u ps of Partici pa nts ( E n ge nsis or Place b o) fr o m St u d y V M D N- 0 0 3- 2 will be 
f oll o we d i n a d o u ble- bli n d fas hi o n fr o m Da y  1 8 0 Visit  ( St u d y V M D N- 0 0 3- 2) t hr o u g h 
Da y  3 6 5/ E T of t his e xte nsi o n pr ot oc ol. N o st u d y dr u g ( E n ge nsis or Place b o) will be 
a d mi nistere d  i n t he V M D N - 0 0 3- 2 b 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 6- m o nt h 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 m plete t he Da y 1 8 0 Visit i n St u d y V M D N- 0 0 3- 2 a n d pr o vi de 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 or d uri n g t heir Da y  1 8 0 Visit  i n t he 
V M D N - 0 0 3- 2 st u d y). 
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 ata Safet 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.  

 
 
 
Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
1 3 
Fi nal: 1 1 Fe b 2 0 2 1 
 
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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
1 5 
Fi nal: 1 1 Fe b 2 0 2 1 
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. 
2.  C o m plete P h ysic al E x a mi n ati o n s will be perf or me d o n Da ys 2 7 0, 3 0 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: hea d, e yes, ears, n ose, a n d t hr oat ( H E E N T); heart; l u n gs; a b d o me n; e xtre mities; l y m p h 
n o des; ne ur ol o gical; a n d s ki n/i nte g u me ntar y s yste ms. 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 a d verse e ve nts 
usi n g a p pr o priate me dical ter mi n ol o g y .  
3.  Reti n al F u n d osc o p y will be perf or me d b y a n o p ht hal m ol o gist u p t o 3 0 da ys bef ore t he Da y  2 7 0 a n d 3 6 5  Visit s 
(a n d, if p ossi ble, u p o n Earl y Ter mi nati o n if t he Partici pa nt disc o nti n ues pri or t o  t he Da y 3 6 5  Visit) . Res ults of 
t he f u n d osc o p y e xa mi nati o ns at t he Da y  2 7 0 a n d Da y 3 6 5  Visits c o m pare d t o res ults at t he Da y  1 8 0  Visit 
(St u d y V M D N -0 0 3 -2)  will be assesse d b y t he  I n vesti gat or. 
4.  1 2 -Le a d Electr oc ar di o gr a m ( E C G) will be perf or me d o n Da ys 2 7 0 a n d 3 6 5/ E T. T he E C G rec or di n g a n d 
i nter pretati o n will be pri nte d o ut a n d st ore d wit h t he Partici pa nt’s rec or ds.  A n y ne wl y i de ntifie d a b n or malities 
are t o be rec or de d as a d verse e ve nts.  
5.  Ser u m  C he mistr y,  He m at ol o g y, a n d Li pi d Pr ofile:  T hese  la b orat or y assess me nts will  be  e val uate d  o n 
Da ys  2 7 0 a n d 3 6 5/ E T . 
•  
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  
o  
Ki d ne y f u ncti o n tests ( bl o o d urea nitr o ge n, creati ni ne)  
o  
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 
•  Li pi d Pr ofile i ncl u des t otal c h olester ol, hi g h-de nsit y li p o pr otei n c h olester ol ( H D L -C), l o w -de nsit y 
li p o pr otei n c h olester ol ( L D L-C), a n d tri gl yceri des  
6.  Uri ne  Pre g n a nc y  Test:  Pre g na nc y tests f or w o me n  of  c hil d beari n g  p ote ntial  will be c o n d ucte d  i n t he cli nic o n 
Da y  3 6 5/ E T . 
7.  Uri ne Dr u g A n al ysis i ncl u des a m p heta mi nes ( met ha m p heta mi ne), bar bit urates, be nz o diaze pi nes, 
b u pre n or p hi ne, ca n na bi n oi d ( T H C), c ocai ne, o x yc o d o ne, met ha d o ne,  o piates, p he nc ycli di ne ( P C P), tric yclics 
( T C A), a n d et h yl alc o h ol. Ca n na bi n oi d detecti o n is n ot a n e xcl usi o n criteri o n b ut ma y be use d i n e x pl orat or y 
a nal yses. T he uri ne dr u g a nal yses will be c o n d ucte d o n Da ys  2 7 0, 3 0 0, a n d 3 6 5/ E T . Dr u g a nal yses will be 
perf or me d b y t he ce ntral la b orat or y.  
8.  H b A 1c le vels will be meas ure d o n  Da y  3 6 5/ E T . 
9.  C o nc o mit a nt Me dic ati o ns a n d Pr oce d ures : A ll 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 recei ves will be 
rec or de d o n Da ys  2 7 0,  3 0 0, a n d 3 6 5/ E T . 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 or 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.  
1 0.  Acc ur ate P ai n Re p orti n g ( A P R):  T he Acc urate Pai n Re p orti n g trai ni n g will be c o n d ucte d o n Da ys  2 7 0, 3 0 0 , 
a n d 3 6 5/ E T. 
Pl ace b o Res p o nse Re d ucti o n ( P R R): T he Place b o Res p o nse Re d ucti o n trai ni n g will be c o n d ucte d o n 
Da ys  2 7 0, 3 0 0 , a n d 3 6 5/ E T. 
1 1.  Brief P ai n I n ve nt or y ( B PI -D P N) – F ull Q uesti o n n aire will be  a d mi nistere d t hr o u g h t he e P R O  dail y starti n g 
at 7 da ys  pri or t o  Da y 2 7 0 a n d Da y 3 6 5/ E T . T he mea n of t he A vera ge Dail y Pai n Sc ores ( A D P Ss, use d f or t he 
pri mar y e n d p oi nt) is t he mea n fr o m a mi ni m u m of 5  A D P Ss rec or de d i n t he 7 da ys pri or t o t he Da y s 2 7 0  a n d 
3 6 5 / E T Visits. If t he e P R O  c o ntai ns fe wer t ha n 5 dail y e ntries o ver t he 7  da ys pri or t o t he Da y  2 7 0 a n d 
Da y  3 6 5/ E T  Visits , t he v isit m ust be resc he d ule d ( u p t o 3 da ys later) s o t hat t he Partici pa n t ca n rec or d 5 dail y 
e ntries o ver t he 7 da ys.  
1 2.  Brief P ai n I n ve nt or y ( B PI) - P arti al Q uesti o n n aire ( q uesti o ns 3, 5, a n d 9a fr o m t he f ull q uesti o n naire) will 
be c o m plete d o n t he e P R O  e ver y  da y t hat t he f ull B PI is n ot  c o n d ucte d  fr o m t he Da y  1 8 0  Visit (V M D N -0 0 3 -2, 
I nitial Visit f or t his e xte nsi o n st u d y) t o t he Da y 3 6 5/ E T  Visit.  

 
 
 
Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
1 6 
Fi nal: 1 1 Fe b 2 0 2 1 
1 3.  Q u alit y  of  Life  Questi o n n aires  ( S F-3 6,  E Q -5 D)  will  be  a d mi nistere d  o n  Da y 2 7 0 a n d Da y  3 6 5/ E T . T he st u d y 
c o or di nat or will c hec k t he q uesti o n naires 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 
clarifie d b y t he Partici pa nt pri or t o lea vi n g t he cli nic.  
1 4.  P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C) will be a d mi nistere d o n Da ys 2 7 0 a n d 3 6 5/ E T.  
1 5.  Tre at m e nt -em er ge nt A d verse E ve nts ( T E A Es)  will be m o nit ore d  t hr o u g h o ut t he st u d y a n d will be rec or de d 
after fr o m t he Da y 1 8 0 Visit ( V M D N-0 0 3 -2) u ntil Da y  3 6 5/ E T i n t h is e xte nsi o n st u d y. A n y T E A Es t hat starte d 
d uri n g St u d y V M D N -0 0 3 -2 a n d were  o n g oi n g at t he Da y  1 8 0  Visit will c o nti n ue t o be f oll o we d after Da y  1 8 0  
d uri n g t his e xte nsi o n pr ot oc ol.  A d verse e ve nts t hat occ ur i n t his pr ot oc ol will be referre d t o as T E A Es . 
Tre at m e nt -e m er ge nt Seri o us A d verse E ve nts ( T E S A Es ) will be rec or de d a n d re p orte d t o t he S p o ns or 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.  
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 . 
1 6.  Mic hi g a n  Ne ur o p at h y  Scree ni n g  I nstr u m e nt ( M N SI) will  be  a d mi nistere d  o n Da y 2 7 0 a n d Da y 3 6 5/ E T  f or 
assessi n g disease pr o gressi o n d uri n g t he  st u d y. 
1 7.  Be dsi de Se ns or y Testi n g ( B S T) will be a d mi nistere d o n Da y 2 7 0 a n d Da y 3 6 5/ E T  t o pr o vi de a d diti o nal 
i nf or mati o n t hat will all o w e x pl orat or y a nal ysis of B S T se ns or y pr ofiles.  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
1 7 
Fi nal: 1 1 Fe b 2 0 2 1 
2.  
IN T R O D U C TI O N  
E n ge nsis is a n o vel ge ne t hera p y treat me nt bei n g de vel o pe d f or pr ol o n g e d treat me nt of patie nts 
wit h pai nf ul dia betic peri p heral ne ur o pat h y ( D P N). T he acti ve p h ar mace utical i n gre die nt of 
E n ge nsis is V M 2 0 2 ( d o na per mi n o ge ne s elt o plas mi d), a plas mi d de o x yri b o n ucleic 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, t hat 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 well 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 n erati o n i n dia betics i n w h o m l oss of micr o vasc ulat ure m a y accelerate ne ur o n al l oss ( 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). 
C o m pare d wit h alter nat e m o des of deli ver y of e x o ge n o us H G F i nt o t he s yst e mic circ ulati o n, 
w hic h is i m pe de d b y ra pi d clear a nce b y t h e li ver, direct a d mi nistrati o n of t he plas mi d D N A i n 
E n ge nsis i nt o tar get tiss ues is f oll o we d b y e x press i o n of H G F i n sit u, w hic h res ults i n a l o were d 
ris k of ge n o mic i nte grati o n ( partic ularl y i n s kel etal m uscle tiss ue) a n d a p p are nt lac k of i m m u ne 
res p o nses (s uc h as o bser ve d wit h viral vect or d eli ver y s yste ms) , ma k i n g it a n attracti ve o pti o n 
f or l ocal tar g ete d deli ver y. I n a d diti o n, E n ge nsis c o ntai ns bi ol o gical a ge nts ( pr o m oters a n d 
c o ntr ollers of ge n e tra ns cri pti o n), i ncl u di n g t he u ni q ue plas ma vect or p C K t hat ma kes t he 
e x pressi o n fr o m s kel etal m uscle m ore efficie nt (s ee t he I B f or f ull des cri pti o n of a d diti o nal 
acti vities i de ntifie d f or E n ge nsis). E n ge nsis is detecta ble a n d e x presses H G F f or u p t o 3 0 d a ys  
after dir ect s keletal m uscle i njecti o n.  
 
St u d y R ati o n ale 
Dia betic peri p h eral ne ur o pat h y  is a bilateral ne ur o pat h y. Base d o n t he fa v ora ble safet y pr ofile of 
E n ge nsis o bser ve d i n t he P hase 1 a n d P hase 2 critical li m b isc he mia ( C LI) st u dies, preli mi nar y 
efficac y dat a fr o m t he P h ase 1/ 2 st u dies , a n d safet y data fr o m t he P hase 1/ 2 st u dies a n d t he 
P hase  3 st u dies of E n ge nsis i n Partici pa nt s wit h D P N, we pr o p ose c o nti n ue d f oll o w- u p of 
bilateral treat me nt  of t he feet a n d l o w er le gs  i n t his P hase 3 e xte nsi o n st u d y. 
T he p ur p ose of t his st u d y is t o f urt her e val u ate t he d ura bilit y of efficac y o n pai n a n d t he 
l o n g-ter m safet y of I M a d mi nistrati o n of E n ge nsis i n Partici pa nt s wit h pai nf ul D P N i n t he feet 
a n d l o wer le gs, as c o m pare d t o Place b o,  i n t his 6- m o nt h e xte nsi o n i n Partici pa nts w h o c o m plete 
t he Da y 1 8 0 Visit i n  St u d y V M D N- 0 0 3- 2. 
E n ge nsis will be teste d a gai nst Place b o. T here will be n o st u d y dr u g a d mi nistrati o n i n t his 
V M D N - 0 0 3- 2 b e xte nsi o n st u d y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
1 8 
Fi nal: 1 1 Fe b 2 0 2 1 
 
B ac k gr o u n d 
2. 2. 1.  P at h o p h ysi ol o g y of Di a betic Peri p her al N e ur o p at h y 
Dia betic peri p h eral ne ur o pat h y ( D P N) is a bilateral, partic ularl y de bilitati n g c o m plicati o n of 
dia betes c haracterize d b y pai n t hat is b ur ni n g, la nci nati n g, ti n gli n g, or s h o oti n g (electric 
s h oc k-li ke), occ urri n g wit h parest hesia, a n d is t y pi call y w orse at ni g ht. T he pai n ca n eit her be 
tri g gere d b y a n e xter n al sti m ul us or be i n de pe n de nt of e xter nal i n p ut. U nli k e ot her pai nf ul 
se nsati o ns, w hic h si g nal a war ni n g i n res p o nse t o a har mf ul sti m ul us, ne ur o pat hic pai n is 
mala da pti ve. Dia b etic peri p heral ne ur o pat h y acc o u nts f or si g nifica nt m or bi dit y b y pre dis p osi n g 
t he f o ot t o ulcerati o n a n d l o wer e xtr e mit y a m p utati o n. 
Dia betic peri p h eral ne ur o pat h y ma nifests as t hree br oa d cat e g ories: se ns or y, m ot or, a n d 
a ut o n o mic, wit h t he m ost pre vale nt f or m bei n g s o matic or se ns ori m ot or ne ur o pat h y. S y m pt o ms 
(e. g., b ur ni n g, ti n gli n g, sta b bi n g, or pi ns-a n d-n ee dles) ofte n e x hi bit a dist al s y m metric patter n, 
be gi n ni n g at t he base of t he t oes a n d as ce n di n g pr o xi mall y u p t he l o wer le g as t he disease 
pr o gresses. Patie nts ma y als o dis pla y m uscle wea k ness, lac k of c o or di nati o n a n d ata xia, a n d l oss 
of pai n per ce pti o n. L oss of pr otecti ve se ns ati o n ca n lea d t o t he f or mati o n of f o ot ulcerati o ns, 
i nfecti o ns, a n d a m p utati o ns. 
T he se q ue n ce of p h ysi ol o gical e ve nts t hat res ult i n D P N is p o orl y u n derst o o d. T he pat h o ge nesis 
of dia betic ne ur o pat h y li kel y i n v ol ves t he i nter pla y of h y per gl yce mia, isc h e mia, a n d o xi dati ve 
stress. Fi g ure 1  p ortra ys t he relati o ns hi p of h y per gl yce mia t o o xi dati ve stress, meta b olic 
alterati o ns, vasc ular d ysf u ncti o n, a n d ne ural da ma ge.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
2 0 
Fi nal: 1 1 Fe b 2 0 2 1 
O xi d ative Stress. Gl uc ose ca n ca use si g nifica nt o xi dati ve stress a n d da ma ge w he n prese nt i n 
e xcess. U n d er p h ysi ol o gical c o n diti o ns, aer o bi c res pirati o n is ass ociate d wit h t he f or mati o n of a 
s mall n u m ber of free r a dicals or R O S. I n a h y per gl yce mic state, h o w e ver, p artic ularl y i n 
e n d ot helial cells, w hic h d o n ot ha ve t he a bilit y t o li mit gl uc ose e ntr y i nt o t he cell, gl uc ose 
acc u m ulati o n e xcee ds t h e le vels t hat gl yc ol ytic e n z y mes ca n h a n dle. 2 ,3  T he fl o o d of e xcess 
gl uc ose i nt o e n d ot helial cells is s h u nte d i nt o alter nate meta b olic pat h w a ys (e. g., p ol y ol pat h wa y, 
gl yc os ylati o n, he x osa mi ne pat h wa y, t he di ac yl gl ycer ol acti vati o n of pr ot ei n ki nase C [ P K C]). 
T hese pat h w a ys, partic ul arl y P K C, pr o d uce si g nifica ntl y lar ger a m o u nts of R O S t ha n aer o bic 
res pirati o n, o ver w hel mi n g c o m pe nsat or y a nti o xi d a nt mec ha nis ms. 4 ,5 ,6 ,7 ,8 ,9 ,1 0 ,1 1 T he res ulti n g 
h y per gl yce mic o xi dati ve stress c o ntri b utes t o e n d ot helial d ysf u ncti o n b y i n hi biti n g e n d ot helial 
nitric o xi de pr o d ucti o n a n d b y i nitiati n g a n d pr o m oti n g t he de p ositi o n of m o difie d li pi ds i n t he 
s u be n d ot heli u m. T hese f act ors accel erate at her os cler otic macr o v asc ular disease a n d are 
ass ociate d wit h t he de v el o p me nt of a p o pt osis i n ne ur o ns a n d s u p p orti n g glial cells. 1 2   
V asc ul ar D a m a ge . Ner v e tiss ue de pe n ds o n a d e q uate bl o o d fl o w t o deli ver n utrie nts a n d re m o v e 
meta b olic waste. N or mall y, t he ca pillar y bas e me nt me m bra ne all o ws t he p assa ge of n utri e nts 
i nt o t he cell a n d per mits t he re m o val of waste pr o d ucts. I n p atie nts wit h pr ol o n ge d 
h y per gl yce mia, gl uc os e is m ore li kel y t o be de p osite d i n t he base me nt me m bra ne, t h us 
decreasi n g its per mea bilit y. Decrease d p er mea bilit y res ults i n t he b uil d u p of t o xic meta b olites, 
res ulti n g i n p o or cell ular meta b olis m, f urt her free ra dical f or mati o n, a p o pt osis, a n d a decli ne i n 
vasc ularizati o n of ner v o us tiss ues. 
2. 2. 2.  C urre nt Tre at m e nt  O pti o ns  
C urre ntl y n o a p pr o ve d dr u gs or i nter ve nti o nal strate gies are k n o w n t o halt or re verse t he 
pr o gressi o n of D P N. Tr eat me nts tar get pai n re d ucti o n, p h ysical f u ncti o n i m pr o ve me nt, re d u cti o n 
of ps yc h ol o gical distress, a n d q ualit y of life i m pr o ve me nts. 
L o n g-ter m c o m plicati o ns of b ot h t y pe 1 a n d t y pe 2 dia betes ca n b e re d uce d b y ti g ht gl yce mic 
c o ntr ol. T o date, t his is t he o nl y i nter ve nti o n s pecificall y s h o w n t o arrest or p ost p o ne t he o nset 
a n d se verit y of p eri p her al ne ur o pat h y. T he c o nse q ue nces of D P N ca n b e a meli orate d b y t he 
e d ucati o n of patie nts a n d t heir car e pr o vi ders as t o f o ot care, pr o per f o ot wear, a n d of 
h y p ose nsiti ve areas a n d press ure p oi nts, all t o pre ve nt t he occ urre n ce of ul cers a n d t o l o w er t he 
ris k of i nfecti o n of s oft tiss ue a n d b o ne. 1 3   
T he i nci de nce of ne ur o pat h y is als o ass ociate d wit h p ote ntiall y m o difia ble car di o vas c ular ris k 
fact ors, i ncl u di n g a n ele v ate d tri gl yceri de l e vel, a hi g h b o d y mass i n de x ( B MI), s m o ki n g, a n d 
h y perte nsi o n. 
O nl y t hree dr u gs h a ve bee n 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) s pecifi call y 
f or t he treat me nt of t he s y m pt o ms of D P N: N uc y nta E R (ta pe nta d ol), a n o pi oi d me dicati o n; 
C y m balta ( d ul o xeti ne), a ser ot o ni n a n d n ore pi ne p hri ne re u pta k e i n hi bit or; a n d L yrica 
( pre ga b ali n), a n a ntic o n v ulsa nt dr u g. All are prescri be d f or t he ma n a ge me nt of pai n ass ociate d 
wit h D P N . 
See t he I B f or prese ntati o n of g ui deli nes iss ue d b y i nter nati o nal or ga nizati o ns f or D P N treat me nt 
o pti o ns. 
A n ot her treat me nt o pti o n is α -li p oic aci d, a n at urall y occ urri n g a nti o xi da nt c o m p o u n d f o u n d i n 
s pi nac h a n d br o cc oli. α-Li p oic aci d was rece ntl y st u die d i n a m ultice nter, place b o -c o ntr olle d 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
2 1 
Fi nal: 1 1 Fe b 2 0 2 1 
st u d y of Partici pa nts wit h t y pe 2 dia betes a n d s y m pt o matic ne ur o pat h y. O ne h u n dre d ei g ht y- o ne 
( 1 8 1) Partici pa nts were gi ve n dail y oral d oses of 6 0 0, 1 2 0 0, or 1 8 0 0 m g of α-li p oic aci d or 
place b o. Aft er 5  w ee ks, n e ur o pat hic s y m pt o ms i m pr o ve d i n t h ose Partici pa nts w h o recei v e d 
α -li p oic aci d. T h e 6 0 0- m g d ose a p peare d t o pr o vi de t he o pti m u m ris k-t o-be nefit rati o. 1 4   
T here are als o i n vasi ve tr eat me nt o pti o ns. O ne o pti o n is s ur gical dec o m pressi o n of t he 
l o wer-e xtr e mit y peri p her al ner ves i n patie nts wit h D P N b ut t his is still c o nsi dere d a n 
e x peri me ntal i nter v e nti o n (see I B f or details). Pa n creatic tra ns pla ntati o n i n pati e nts wit h dia betes 
ca n sta bilize ne ur o pat h y a n d, i n s o me i nsta nces, i m pr o ve m ot or, se ns or y, a n d a ut o n o mic 
f u ncti o n. 
Ot her treat me nts i ncl u de off -la bel us e of se v eral dr u gs a n d de vices. Dr u gs c o m m o nl y prescri b e d 
t o ma na ge pai n s y m pt o ms i ncl u de tric yclic a nti de pressa nts ( T C As), sel ecti ve ser ot o ni n re u pta k e 
i n hi bit ors ( S S RIs), a n d ser ot o ni n – n ore pi ne p hri n e re u pta ke i n hi bit ors ( S N RIs). Ot her treat me nt 
strate gies s uc h as ac u p u n ct ure, tra ns c uta ne o us electrical ner ve sti m ulati o n ( T E N S), ca ps aici n 
patc hes a n d crea ms, t o pical a nest hetics, a n d is os or bi de di nitrate (I S D N) s pra y ma y als o be us e d. 
Eac h of t hes e ca n alle viat e s o me of t he pai n s y m pt o ms. N o ne de m o nstrate a n y a bilit y t o i m pr o ve 
t he u n derl yi n g ne ur o pat h y. 
2. 2. 3.  U n m et Cli nic al  Nee d  
Dia betic peri p h eral ne ur o pat h y is a seri o us c o m plicati o n of dia betes m ellit us ( D M), wit h pai nf ul 
D P N bei n g a fr e q ue nt ma nifestati o n of ne ur o p at h y. Ti g ht gl yce mic c o ntr ol a n d treat me nt of 
car di o vas c ular ris k f act ors are effecti ve pre v e nti ve meas ures, b ut D P N re mai ns t he m ost 
c o m m o n c o m plicati o n of D M, aff ecti n g 6 0 % t o 7 0 % of dia betics. Pr o gressi ve D P N ma y res ult i n 
l oss of f u ncti o n i n affecte d le gs, seri o us i nfecti on c o m plicati o ns , a n d a m p utati o n. 
C urre nt treat me nts pr o vi de s y m pt o matic relief of t he pai n ass ociate d wit h D P N. A clear u n met 
me dical nee d e xists f or tr eat me nts t hat a d dress t he u n derl yi n g pat h ol o g y of D P N a n d pre v e nt t he 
pr o gressi ve destr u cti o n a n d l oss of f u ncti o n ass oci ate d wit h t his d isease. 
2. 2. 4.  He p at oc yte Gr o wt h F act or f or t he Tre at me nt of Di a betic  N e ur o p at h y  
He pat oc yte gr o wt h fact or ( H G F) is a m ultif u ncti o nal pr otei n wit h hi g hl y p ote nt a n gi o ge nic a n d 
ne ur otr o p hic pr o p erties pr o d uce d b y vari o us cell t y pes of mese n c h y mal ori gi n s uc h as 
fi br o blasts, macr o p ha g es, a n d str o mal cells. 1 5 ,1 6 ,1 7 ,1 8 ,1 9 Its bi ol o gical f u ncti o n is me diate d b y its 
rece pt or c- M et, w hic h is a me m ber of t h e rece pt or t yr osi ne ki nase fa mil y. I n t he peri p heral 
ner v o us s yste m a n d its ass ociate d tiss ues, c- Met is e x presse d i n se ns or y ne ur o ns, Sc h wa n n cells, 
e n d ot helial cells, a n d s m o ot h m uscle cells a m o n g ot hers, 2 0 ,2 1 whic h all pla y i m p orta nt r oles i n 
t he f u ncti o ns of t he peri p heral ner ve a n d its re ge n erati o n aft er pat h ol o gical i ns ults. I n dee d, H G F 
has bee n r e p orte d t o act o n se ns or y a n d m ot or ne ur o ns t o e n ha nce t heir s ur vi va bilit y a n d ne urite 
o ut gr o wt h, a n d als o pr o d uces a ne ur o pr otecti ve effect i n i nj ure d se ns or y n e ur o ns. 2 2 ,2 3 ,2 4 ,2 5 ,2 6 
L ocal a p plicati o n of e x o ge n o us H G F h as bee n s h o w n t o pr o m ote t he gr o wt h of s y m pat hetic 
n e ur o ns, 2 7 ,2 8 ,2 9 ,3 0 ,3 1 ,3 2 a n d t o i n d uce t he f or mati o n of c ollateral vessels a n d i ncreas e d bl o o d fl o w 
b ot h i n dia betic a n d n o n- dia betic  rat m o dels. 3 3   
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 i n r o de nt bl o o d of less t ha n 1 5 mi n utes. 3 4 O ne a p pr o ac h t o mai ntai ni n g a 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
2 6 
Fi nal: 1 1 Fe b 2 0 2 1 
2. 3. 2.  Be nefit  Assess m e nt  
Dia betic peri p h eral ne ur o pat h y is o ne of t he m ost-c o m m o nl y e nc o u ntere d  n e ur o pat hic pai n 
s y n dr o mes a n d affects nearl y half of all dia betic p atie nts. T hr o u g h its effects o n m ot or or 
se ns ori m ot or ne ur o ns, disa bli n g c o nse q ue nces o n f u ncti o n a n d q ualit y of life pre d o mi nat e t hat 
i ncl u de slee p dist ur ba nces, de pe n de nce o n narc oti c a nal gesics f or pai n, as well as tra u ma a n d 
i nfecti o n fr o m se ns or y i m pair me nt. 
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 re pair, h as t he p ote ntial t o i m pr o ve 
o utc o mes i n dia betic pati e nts, as s u g geste d b y prece di n g st u dies.  
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 st u d y i n its ai m t o meet t he u n met nee ds of D P N 
patie nts.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 0 
Fi nal: 1 1 Fe b 2 0 2 1 
4.  
S T U D Y D E SI G N  
 
O ver all Desi g n  
V M D N - 0 0 3- 2 b is a 6- m o nt h, P hase 3, d o u ble- bli n d, ra n d o mize d, place b o-c o ntr olle d, 
m ultice nter , e xte nsi o n st u d y t o t he V M D N- 0 0 3-2 st u d y  a n d is desi g ne d t o assess t he d ura bilit y 
of efficac y a n d t he l o n g-t er m safet y of E n 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 pai nf ul D P N as c o m pare d t o Place b o . N o Partici pa nts i n t his  
V M D N - 0 0 3- 2 b St u d y e xte nsi o n st u d y will recei ve st u d y dr u g. Refer t o t he S o A i n Secti o n 1. 3  
f or ti mi n g of all assess me nts a n d treat me nts d uri n g t his e xte nsi o n st u d y. 
 
Scie ntific R ati o n ale f or St u d y Desi g n  
V M D N - 0 0 3- 2 is desi g ne d as a well- c o ntr olle d P hase 3  st u d y, 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 hat is s ufficie ntl y size d i n n u m bers of Partici pa nt s t o 
e val uate t he p ote ntial a bilit y of E n ge nsis t o re d uce ne ur o pat hic pai n a n d disa bilit y i n Partici pa nt s 
wit h pai nf ul D P N. V M D N - 0 0 3- 2 b is a 6- m o nt h f oll o w- o n t o t hat st u d y. 
C ollecti o n of efficac y dat a will be c o n d ucte d vi a e -Diaries , w hic h will be use d t o re mi n d 
Partici pa nts t o rec or d t h eir efficac y dat a dail y a n d i n real ti me. 
 
P artici p a nt I n p ut i nt o Desi g n  
Partici pa nt i n p ut i nt o t he desi g n of t his st u d y was n ot c ollecte d, as  t he s a me met h o ds were use d 
i n pre vi o us st u dies wit h E n ge nsis a n d di d n ot lea d t o u nacce pt a ble n u m bers of Partici pa nt s 
disc o nti n ui n g t he st u dies. I n a d diti o n, t he met h o ds use d t o assess pai n re d u cti o n ( B PI- D P N) a n d 
patie nt gl o bal i m pressi o n of c ha n ge ( P GI C) ha v e bee n vali date d a n d are t h e t o ols rec o m me n de d 
b y re g ulat or y a ut h orities t o assess efficac y ( pai n re d ucti o n) a n d res p o nse (cli nical be nefit) i n 
patie nts wit h pai nf ul D P N.  
 
J ustific ati o n f or D ose 
Partici pa nts will n ot be a d mi nistere d st u d y dr u g i n t h is V M D N - 0 0 3- 2 b st u d y. 
 
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/ E T Visit  or is disc o nti n ue d. 
 
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 S p o ns or a p pr o val of t h e cli nical st u d y re p ort.  
 
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/ E T Visit  a n d has at least 5 da ys of t he m ost rece nt 7 da ys wit h electr o nic diar y (e Diar y ) 
e ntries pri or t o t he D a y 3 6 5/ E T Visit . 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 1 
Fi nal: 1 1 Fe b 2 0 2 1 
5.  
S T U D Y P O P U L A TI O N  
Partici pa nts f or t his 6 - m o nt h e xte nsi o n st u d y will c o me fr o m t he mai n st u d y ( St u d y 
V M D N - 0 0 3- 2) i n w hic h Partici pa nts c o m plete t he Da y  1 8 0 Visit  a n d gi ve si g ne d i nf or me d 
c o nse nt f or t he e xte nsi o n st u d y.  
T he n u m ber of Partici pa nts w h o meet t hese q ualificati o ns will deter mi ne t he n u m ber of 
Partici pa nts f or t his e xte nsi o n st u d y.  
 
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 a n d ori gi nal me dical rec or ds . All Partici pa nt s 
w h o si g n t he i nf or me d c o nse nt f or m f or t he V M D N- 0 0 3- 2 b st u d y will c o nti n ue t o use t he sa me 
u ni q ue i de ntifier assi g ne d t o t he Partici pa nt i n t he V M D N- 0 0 3- 2 st u d y. 
 
Lifest yle C o nsi der ati o ns  
5. 2. 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. 2. 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. 2. 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 ( eC R F ) as c o nc o mita nt 
me dicati o ns.  
5. 2. 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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 2 
Fi nal: 1 1 Fe b 2 0 2 1 
6.  
S T U D Y I N T E R V E N TI O N  
N o st u d y dr u g will be a d mi nistere d t o Partici pa nts i n t his V M D N - 0 0 3- 2 b e xte nsi o n st u d y.  
 
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 h is V M D N - 0 0 3- 2 b e xte nsi o n st u d y. All 
Partici pa nts  w h o are e ntere d i nt o t he V M D N- 0 0 3- 2 b e xte nsi o n st u d y will  c o nti n ue t o be 
f oll o we d fr o m t he V M D N- 0 0 3- 0 2 st u d y i n a bli n de d fas hi o n. 
6. 1. 2.  Str atific ati o n  
T here will be n o str atificati o n of Partici pa nts  i n t he V M D N- 0 0 3- 2 b e xte nsi o n st u d y as all 
Partici pa nts  w h o are e ntere d i nt o t he V M D N- 0 0 3- 2 b e xte nsi o n st u d y are t o c o nti n ue i n t he 
stratificati o n t he y were assi g ne d i n t he V M D N- 0 0 3- 2 st u d y. 
6. 1. 3.  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 o r 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. 4.  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 I nteracti ve We b 
Res p o nse S yste m (I W R S ) at ra n d o mizati o n i n t he V M D N- 0 0 3- 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 D N - 0 0 3- 2 b e xt e 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. 
 
C o nc o mit a nt T her a p y 
All c o nc o mita nt t hera pies s h o ul d be ca pt ure d i n t he C o nc o mita nt T hera p y secti o n of t he e C R F. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 3 
Fi nal: 1 1 Fe b 2 0 2 1 
6. 2. 1.  Resc ue Me dici ne  
T he o nl y all o we d r esc ue me dicati o n is aceta mi n o p he n i n t he V M D N- 0 0 3- 2 b e xte nsi o n st u d y. O n 
Da y  1 8 0 of t he V M D N- 0 0 3- 2 b e xte nsi o n st u d y, t he Site  will dis pe nse e xtra -stre n gt h 
aceta mi n o p he n ( 5 0 0 m g) pr o vi de d b y t he S p o ns or. T he Partici pa nt  will be i nstr ucte d t o ta ke u p 
t o 2 ca plets e ver y 6 h o urs as nee de d f or D P N pai n f or a ma xi m u m of 6 ca plets ( 3 gra ms)/ da y. 
T he st u d y-iss ue d aceta mi n o p he n is o nl y t o be use d f or D P N pai n, a n d t he P artici pa nt  is n ot t o 
use a n y ot her s o ur ce of aceta mi n o p he n f or D P N p ai n. T he Par tici pa nt ma y use u p t o 1 gra m per 
da y of a s o ur ce of aceta mi n o p he n ot her t ha n t he st u d y-iss ue d T yle n ol f or c o n diti o ns ot her t ha n 
D P N pai n.  T he Partici pa nt  will be pr o vi de d wit h a n e Diar y t o rec or d t heir pai n le vel 
( N R S = 0- 1 0 scale) bef or e use, t he date a n d ti me of use, a n d t he a m o u nt of aceta mi n o p he n us e d. 
T he Partici pa nt  will be as ke d t o ret ur n t he e Diar y a n d t he u n use d resc ue m e dicati o n at eac h 
Visit . At eac h Visit , t he Site  will rec o ncile h o w ma n y ca plets were use d, as d oc u me nte d i n t he 
e Diar y, wit h h o w ma n y ca plets re mai n i n t he b ottle(s). N e w b ottle(s) of aceta mi n o p he n will t he n 
be dis pe nse d b y t he Site  t o t he Partici pa nt o n Da y s 2 7 0 a n d 3 0 0 of t his e xte nsi o n st u d y. 
 
Pr o hi bite d a n d Restrict e d Me dic ati o ns  a n d Pr oce d ures  
Pr o hi bite d me dicati o ns a n d pr oce d ur es are liste d i n Secti o n 1 0. 3 , A p pe n di x 3. 
6. 3. 1.  Me dic ati o n s T h at M a y I nterfere wit h E n ge nsis  Bi o acti vit y 
Certai n ster oi ds (e x ce pt i n hale d, oc ular, or i ntra-artic ular ster oi ds)  ma y i nterfere wit h t he 
bi oacti vit y of E n ge nsis a n d are t heref ore pr o hi bite d fr o m use d uri n g t he st u d y. Partici pa nts m ust 
a gree t o n ot ta k e a n y of t hese dr u gs f or t he d urati o n of t he V M D N - 0 0 3- 2 b e xte nsi o n st u d y. A list 
of t he pr o hi bite d me dicati o ns i n t his cate g or y ca n be f o u n d i n  Secti o n 1 0. 3 , A p pe n di x 3. 
6. 3. 2.  Me dic ati o ns a n d Pr oce d ures T h at M a y I nterfere wit h Assess me nt of P ai n  
Partici pa nts  m ust refrai n fr o m use of t hes e t hera pi es f or t he d urati o n of t he V M D N - 0 0 3- 2 b 
e xte nsi o n st u d y: 
•  s keletal m uscle r ela xa nts 
•  o pi oi ds 
•  be nz o diaze pi nes ( e xce pt f or sta ble be dti me d os e) 
•  i njecta ble ster oi ds 
•  ca psaici n a p plie d t o t he l o wer le gs or feet 
•  l ocal a nest hetic crea ms a n d patc hes a p plie d t o t he l o wer le gs or feet (e xce pt l ocal/t o pical 
a nest hetic crea m a p plie d i m me diatel y pri or t o st u d y dr u g i njecti o ns 
•  I S D N s pra y a p plie d t o t h e l o wer le gs or feet 
•  tra nsc uta ne o us electrical ner ve sti m ulati o n ( T E N S), ac u p u nct ure 
A list of pr o hi bite d me dicati o ns  a n d pr oce d ures i n t his cate g or y ca n be f o u n d i n Secti o n  1 0. 3 , 
A p pe n di x 3. 
If n ot usi n g a sta ble d ose of d ul o xeti ne ( C y m balta), a n y a nti de press a nts (e. g., a mitri pt yli ne a n d 
ve nlafa xi ne), or a n y ot h er a ntie pile ptics (e. g., v al pr oic aci d, car b a maze pi n e, a n d vi ga batri n) 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 4 
Fi nal: 1 1 Fe b 2 0 2 1 
d uri n g t he V M D N- 0 0 3- 2 st u d y, Partici pa nt s m ust a gree t o n ot start t hes e dr u gs d uri n g t he 
V M D N - 0 0 3-2 b e xte nsi o n st u d y. Partici pa nt s o n t hese me dicati o ns o n a sta ble d ose d uri n g t he 
V M D N - 0 0 3- 2 st u d y are t o c o nti n ue t hese me dicati o ns at t he sta ble d ose a d mi nistere d i n t he 
V M D N - 0 0 3- 2 st u d y i n t h e V M D N- 0 0 3- 2 b e xte nsi o n st u d y. Partici pa nts  ma y n ot use pre ga b ali n 
( L yrica) or ga b a pe nti n ( Ne ur o nti n) at a n y ti me d uri n g t he V M D N - 0 0 3- 2 b st u d y. 
 
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  
Me dicati o ns a n d t reat me nts rec or de d at t he Da y 1 8 0 Visit of t he V M D N - 0 0 3- 2 st u d y will be 
mi grate d t o t he  Me dicati o n a n d Hist or y e C R F of t he V M D N - 0 0 3- 2 b e xte nsi o n st u d y. A n y 
me dicati o n or vacci ne, i n cl 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 t o pical a nest hetics f or p ost-i njecti o n pai n 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 V M D N - 0 0 3-2 b e xte nsi o n st u d y m ust 
be rec or de 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  
•  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 
•  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 
T he Me dical M o nit or will 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. Aceta mi n o p he n is t he o nl y resc ue me dicati o n all o we d i n t his st u d y. U p t o 3 gra ms per 
da y will be all o we d. Use of resc u e me dicati o n will be rec or de d eac h d a y i n t he e Diar y.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 5 
Fi nal: 1 1 Fe b 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  DI S C O N TI N U A TI O N  
 
P artici p a nt  Disc o nti n u ati o n/ Wit h dr a w al/ E arl y Ter mi n ati o n fr o m t he St u d y 
A n y Partici pa nt  ma y v ol u ntaril y disc o nti n ue t he V M D N - 0 0 3-2 b e xte nsi o n st u d y at a n y ti me 
wit h o ut prej u dice. T he I n vesti 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 v esti 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 mai 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 ’s decisi o n  
•  I n v esti gat or’s decisi o n  
•  A d verse e ve nt  
•  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. 
T he f oll o wi n g assess me nts will be perf or me d, if p ossi ble, f or Partici pa nt s w h o disc o nti n ue pri or 
t o t he V M D N - 0 0 3- 2 b e xte nsi o n st u d y Da y 3 6 5/ Earl y Ter mi nati o n Visit ( E T; see Secti o n 1. 3 , 
S o A) . 
•  A P R a n d P R R  
•  F ull B PI -D P N  
•  M N SI  
•  B S T  
•  P GI C  
•  S F - 3 6 a n d E Q- 5 D 
•  C o m plete  p h ysical e xa mi nati o n 
•  Vital si g ns,  wei g ht 
•  Reti nal  f u n d osc o p y 
•  Ser u m c he mistr y , li pi d pr ofile, a n d he mat ol o g y  
•  E C G  
•  Uri n e p re g n a nc y test  
•  Uri ne dr u g a n al ysis  
•  H b A 1c  
•  C o nc o mita nt me dicati o ns  / pr oce d ures 
•  A d verse e ve nts  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 6 
Fi nal: 1 1 Fe b 2 0 2 1 
 
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 b y Da y 3 6 5/ E T ( + 7 da ys) i n t he 
V M D N - 0 0 3- 2 b e xte nsi o n st u d y. 
T he f oll o wi n g acti o ns m ust be ta ke n if a Partici p a 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 m ai ntai ni n g t he 
assi g ne d Visit  sc he d ule a n d ascert ai n w het her t h e 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 he Partici pa nt’s r elati ves or his/ her ge n eral  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 r e gai 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 hese 
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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 7 
Fi nal: 1 1 Fe b 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  
St u d y pr oce d ures a n d t heir ti mi n g are s u m marize d i n Secti o n 1. 3  ( S o A). 
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, 
i ncl u di n g t h ose s pecifie d i n t he S o A, is esse ntial. 
 
P artici p a nt Tr ai ni n g  
8. 1. 1.  Acc ur at e P ai n Re p orti n g  
T he Acc urate Pai n Re p orti n g ( A P R) trai ni n g i nstr ucts Partici pa nt s h o w t o re p ort pai n sc ores 
acc ur atel y a n d relia bl y, a n d o n t he pr o per us e of p ai n scales, wit h t he ai m of i ncreasi n g t he 
re p orti n g acc urac y of Partici pa nt  pai n. Partici pa nts will  recei ve trai ni n g o n Da ys 2 7 0, 3 0 0, a n d 
3 6 5/ E T. 
8. 1. 2.  Pl ace b o Res p o nse Re d ucti o n  
T he Place b o Res p o nse R e d ucti o n ( P R R ) trai ni n g teac h es t he Partici pa nt a b o ut t he a p pr o priate 
e x pectati o ns of p ers o nal be nefit w hile partici pati n g i n a cli nical trial. T he p ur p ose is t o pr o vi de 
Partici pa nt s wit h tr ut hf ul i nf or mati o n t hat will ne utralize t he t y picall y e x cessi ve e x pectati o ns 
t hat dri ve hi g h place b o res p o nses i n cli nical st u dies. Partici pa nts will recei v e trai ni n g o n 
Da ys  2 7 0, 3 0 0, a n d 3 6 5/ E T. 
 
Effic ac y Assess m e nt s a n d Pr oce d ures  
8. 2. 1.  Brief P ai n I n ve nt or y f o r Di a betic P ai nf ul Ne ur o p at h y 
T he Brief Pai n I n ve nt or y f or Dia betic Pai nf ul N e ur o pat h y ( B PI-D P N ) ass ess me nt t o ol 
( Secti o n 1 0. 5 , A p pe n di x 5) will be a d mi nistere d t hr o u g h use of a n e Diar 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 e Diar y 
a n d t o c o m plete t he ass ess me nt t o ol pr o perl y bef ore data c ollecti o n be gi ns. T he B PI -D P N will be 
c o n d ucte d usi n g t he F ull B PI- D P N q uesti o n naire a n d t he Partial B PI- D P N q uesti o n naire  
Sc ores o btai ne d fr o m t he F ull B PI-D P N d uri n g  t he 7 da ys pri or t o t he D a y 2 7 0 a n d Da y 3 6 5 / E T 
Visits will be use d t o deter mi ne A D P Ss. T he A D P S is t he mea n of at least 5  dail y pai n sc ores 
rec or d e d i n t he e Di ar y. If t he e Diar y c o ntai ns fe w er t ha n 5 dail y e ntries o ver t he 7 da ys pri or t o 
t he Da y 2 7 0 or t he Da y 3 6 5 / E T Visits , t he Visit m ust be resc he d ule d s o t hat t he Partici pa nt ca n 
rec or d 5 d ail y e ntries o ver t he 7 da ys pri or t o t he resc he d ule d Visit.  
Partici pa nts will use t he e Diar y t o r ate t heir A v era ge Dail y Pai n a n d W orst Dail y Pai n  i ncl u de d 
i n t he Brief B PI-D P N o n a dail y basis fr o m t he D a y  1 8 0 Visit ( St u d y V M D N- 0 0 3-2) t o t he 
Da y  3 6 5/ E T Visit of t his e xte nsi o n st u d y t o all o w a n assess me nt of t he le v el a n d d urati o n of pai n 
relief i n t he acti ve treat me nt gr o u p vers us Place b o. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 8 
Fi nal: 1 1 Fe b 2 0 2 1 
8. 2. 2.  Q u alit y of Life/ P artici p a nt Re p orte d O utc o me Me as ures  
8. 2. 2. 1.  
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 after treat me nt will be meas ure d wit h t he Patie nt Gl o bal 
I m pr essi o n of C ha n ge (P GI C ) q uesti o n naire t hr o u g h use of a n e Diar y. T h e I n v esti gat or s h o ul d 
e ns ure t hat t he Partici p a 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 e Diar y 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 ( Secti o n 1 0. 6 , A p pe n di x 6). 
T his q uesti o n naire meas ures t he Partici pa nt’s p erce pti o n of h o w treat me nt has affecte d 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. Eac h des cri pt or is ra n ke d o n a n 
i nte nsit y scale of 1 = V er y M uc h I m pr o ve d; 2 = M uc h I m pr o ve d; 3 = Mi ni mall y I m pr o v e d; 
4 = N o C ha n ge; 5 = Mi ni mall y W orse; 6 = M uc h W orse; 7 = V er y M uc h W orse. T he t est will be 
self-a d mi nistere d d uri n g t he Da y 2 7 0 a n d D a y 3 6 5/ E T Visits . 
U p o n c o m pleti o n of t he q uesti o n naire, t he st u d y c o or di nat or will c hec k t h e 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 clarifie d b y t h e Partici pa nt  pri or t o 
lea vi n g t he cli nic. 
8. 2. 2. 2.  
S h ort F or m He alt h S ur ve y  
T he 3 6-ite m S h ort F or m Healt h S ur ve y ( S F- 3 6; Secti o n 1 0. 7 , A p pe n di x 7) will be a d mi nistere d 
t hr o u g h use of a n e Diar y. T he I n vesti gat or s h o ul d e ns ure t hat t he Partici p a 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 e Diar y 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 t o meas ure t he Partici pa nt ’s perce pti o n of t h eir o verall healt h stat us o n t he 
Da y 2 7 0 a n d D a y 3 6 5 / E T Visits. T his 3 6- q uesti o n s ur ve y meas ures t he Partici pa nt ’s perce pti o n 
of vitalit y, p h ysical f u ncti o ni n g, b o dil y pai n, ge neral healt h perce pti o ns, p h ysical r ole 
f u ncti o ni n g, e m oti o nal r ole f u ncti o ni n g, s ocial r ole f u ncti o ni n g, a n d me ntal healt h. 
U p o n c o m pleti o n of t he q uesti o n naire, t he st u d y c o or di nat or will c hec k t h e 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 clarifie d b y t h e Partici pa nt  pri or t o 
lea vi n g t he cli nic. 
8. 2. 2. 3.  
E ur o Q ol He alt h Utilities I n de x  
T he E ur o Q ol H ealt h Utilities I n de x ( E Q -5 D ) i nstr u me nt ( Secti o n 1 0. 8 , A p pe n di x 8) will als o be 
a d mi nistere d t hr o u g h use of a n e Diar 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 e Diar y a n d t o c o m plete t he assess me nt t o ol 
pr o perl y bef ore d ata c oll ecti o n be gi ns t o meas ure t he Partici pa nt ’s perce pti o n of t heir o verall 
healt h stat us o n t he Da y 2 7 0 a n d Da y  3 6 5/ E T Visits . T he i nstr u me nt has t w o parts – t he 
descri pti ve s yste m t hat meas ures m o bilit y, self -care, us ual acti vities, pai n/ disc o mf ort, a n d 
a n xiet y/ de pressi o n; a n d t he vis ual a nal o g scale ( V A S) t hat rec or ds t he P artici pa nt’s self -rate d 
healt h . 
U p o n c o m pleti o n of t he q uesti o n naire, t he st u d y c o or di nat or will c hec k t h e 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 clarifie d b y t h e Partici pa nt  pri or t o 
lea vi n g t he cli nic. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
3 9 
Fi nal: 1 1 Fe b 2 0 2 1 
8. 2. 3.  Be dsi de Se ns or y Testi n g  
Se ns or y tests will be perf or me d at 3 pre d efi ne d l o cati o ns: d ors u m of t he f o ot, mi d-s hi n, a n d 
mi d -t hi g h, e xce pt l o w t hr es h ol d mec ha n orece pti ve f u ncti o n, w hic h will be c o n d ucte d at t he 
b ott o m of t he f o ot o nl y o n t he Da y 2 7 0 a n d D a y  3 6 5/ E T Visits . T he I n v esti gat or s h o ul d e ns ure 
t hat t he Partici pa nt is seate d c o mf orta bl y bef ore d ata c ollecti o n be gi ns.  
T he Be dsi de Se ns or y Testi n g is prese nte d i n Secti o n 1 0. 9 , A p pe n di x 9. 
8. 2. 4.  Mic hi g a n Ne ur o p at h y Scree ni n g I nstr u me nt  
T he Mic hi ga n Ne ur o pat h y Scree ni n g I nstr u me nt ( M N SI ) (Secti o n  1 0. 1 0 , A p pe n di x 1 0) will be 
a d mi nistere d t hr o u g h use of a n e Diar y (f or t he Partici pa nt) or a n electr o nic ta blet (f or t he Site ) 
o n Da y 2 7 0 a n d D a y  36 5/ E T  t o trac k disease pr o gressi o n. T he I n v esti 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 e Diar y a n d t o c o m plete t he 
assess me nt t o ol pr o perl y bef ore d ata c ollecti o n be gi ns. T he M N SI c o m prises a Partici pa nt  
q uesti o n naire ( 1 5 q uesti o ns) a n d a p h ysical e val uati o n t hat i ncl u des a f o ot i ns pecti o n, vi brati o n 
se nsati o n testi n g, m uscle stretc h refle xes, a n d m o n ofila me nt testi n g. 
U p o n c o m pleti o n of t he M N SI q uesti o n naire, t he st u d y c o or di nat or will c h ec k t he q uesti o n naire 
f or c o m plete n ess. A n y o missi o ns or a m bi g u o us a ns wers will be clarifie d b y t he Partici pa nt  pri or 
t o lea vi n g t he cli nic. T he Partici pa nt  will be re q uire d t o electr o nicall y si g n  a n d date t he 
q uesti o n naire. 
 
S afet y Assess m e nts  
8. 3. 1.  P h ysic al E x a mi n ati o ns  
C o m plete p h ysical e xa mi nati o ns ( P Es) will be perf or me d at t he Da y 2 7 0, D a y 3 0 0, a n d Da y 
3 6 5 / E T Visits; a n d at t he last Visit if t he Partici pa nt  disc o nti n ues pri or t o Da y 3 6 5. 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 pear a nce, hea d, n ec 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 us c 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 bas eli ne stat us or e val uat e s y m pt o ms or T E A E s. A n y p h ysical e xa mi nati o n 
a b n or malities c o nsi der e d t o be cli nicall y si g nifica nt ( C S) s h o ul d be a d de d t o T E A Es usi n g 
me dical l y a p pr o pri ate ter mi n ol o g y. 
8. 3. 2.  Me dic al Hist or y  a n d F a mili al Hist or y of C a ncer 
Me dical hist or y f or t his e xte nsi o n st u d y will be base d o n t he me dical hist or y i nf or mati o n 
rec or d e d at Scr ee ni n g f or St u d y V M D N- 0 0 3- 2. 
M e dicati o n hist or y will be base d o n r ec or d e d me di cati o ns wit hi n 3 0 da ys pri or t o t he Da y 1 8 0 
Visit of St u d y V M D N - 0 0 3- 2. 
Ele vate d ris ks of ca ncer f or t y pe 2 dia betes or o b esit y are detaile d i n Secti o n  8. 4. 5 , A d verse 
E ve nts of S pecial I nterest.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 0 
Fi nal: 1 1 Fe b 2 0 2 1 
8. 3. 3.  1 2- Le a d Electr oc a r di o gr a ms  
1 2- Lea d electr o car di o gr a ms ( E C Gs) will be perf or me d o n Da ys 2 7 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 be re p orte d as a d v erse e v e nts. T he E C G rec or di n g will be 
pri nte d, a n d t he i n vesti gat or or dele gat e d staff will i nitial a n d date t he pri nt o ut t o i n dicate t heir 
re vie w of t h e fi n di n gs. T he trace a n d t he i nter pret ati o n will t he n be  st ore d wit h t he Partici pa nt ’s 
rec or ds. 
8. 3. 4.  Vit al Si g ns  
Vital si g ns will be meas ure d at t he D a y 2 7 0, 3 0 0, a n d 3 6 5 / E T Visit s. After resti n g i n t he seate d 
p ositi o n f or 5 mi n utes, vital si g ns meas ure d will i ncl u de te m perat ure, sitti n g bl o o d press ure, 
heart r ate, res pir at or y r ate, a n d o x y ge n s at 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. 3. 5.  Cli nic al L a b or at or y Assess m e nts 
See Secti o n  1. 3  ( S o A) f or t he ti mi n g a n d fre q ue n c y. 
8. 3. 5. 1.  
Ce ntr al L a b or at or y Ass ess me nts  
All la b orat or y assess me nts  at t he Da y 2 7 0 a n d 3 6 5/ E T Visits will be perf or me d b y t he ce ntral 
la borat or y . 
T he I n vesti gat or m ust re vie w t he la b orat or y re p ort, 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 ha n g es 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 a n d u pl oa de d i nt o t he E D C. 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. 
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. 
8. 3. 5. 1. 1.  He m at ol o gy 
•  W hite bl o o d cell c o u nt 
•  Ne utr o p hil (i ncl u di n g cal c 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. 3. 5. 1. 2.  Ki d ney F u ncti o n Tests  
•  Bl o o d urea nitr o ge n ( B U N) 
•  Creati ni ne  
8. 3. 5. 1. 3.  Liver F u ncti o n Tests  
•  As partate a mi n otra nsferase  ( A S T) 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 1 
Fi nal: 1 1 Fe b 2 0 2 1 
•  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. 3. 5. 1. 4.  Cli nic al C he mistry  
•  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 
•  H b A 1c  
8. 3. 5. 1. 5.  Li pi d Pr ofile  
•  T otal c h olester ol  
•  Hi g h - de nsit y li p o pr otei n c h olester ol ( H D L- C) 
•  L o w - de nsit y li p o pr otei n c h olester ol ( L D L-C)  
•  Tri gl yceri des  
8. 3. 5. 1. 6.  A d diti o n al Tests  
•  Uri ne pre g n a nc y  t est 
•  Uri ne dr u g a nal ysis  
8. 3. 6.  Reti n al F u n d osc o p y  
Pr oliferati ve dia betic reti n o pat h y, defi ne d as t h e prese nce of ne w pr oliferati n g bl o o d vessels 
( ne o vasc ul arizati o n) arisi n g fr o m t he reti na or o ptic disc a n d gr o wi n g o n t h e reti nal s urface or 
i nt o t he vitre o us ca vit y, will be assesse d b y reti nal f u n d osc o p y at Da y 2 7 0 a n d Da y 3 6 5/ E T. 
Reti nal f u n d osc o p y m ust be perf or me d b y a n o p ht hal m ol o gist u p t o 3 0 da ys bef ore t he Da y 2 7 0 
a n d Da y 3 6 5 Visits a n d, if p ossi ble, u p o n E T. T he sa me o p ht hal m ol o g y practice s h o ul d be use d 
f or all meas ur e me nts of i n di vi d ual partici pati o n. I n cases w h ere f u n d osc o p y al o ne is dee me d 
i ns ufficie nt, fl u ores cei n a n gi o gra p h y ma y be perf or me d. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 2 
Fi nal: 1 1 Fe b 2 0 2 1 
 
S afet y Assess m e nts  
8. 4. 1.  Tre at m e nt -e m er g e nt A d verse E ve nts a n d 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. 4. 2.  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 fr o m t he Da y 1 8 0 Visit  ( St u d y V M D N- 0 0 3-2) t hr o u g h 
Da y 3 6 5 / E T of V M D N - 0 0 3- 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 . T he I n vesti gat or will 
s u b mit a n y u p date d T E S A E  data 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 E s or T E S A E s 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 har g e 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. 4. 3.  Met h o d of Re p orti n g  T E A Es , T E S A Es  a n d A E SIs  
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 , T E S A E s, a n d A E SIs, 
a n d t he pr oce d ures 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 d e 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 i d e ntif yi n g T E A Es a n d/ or T E S A Es. O pe n -e n d e d 
a n d n o n-lea di n g ver bal 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 a n d T E S A E occ urre nces.  
8. 4. 4.  T E S A E Re p orti n g t o t he S p o ns or  or Desi g nee  
All T E 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 h e 
T E S A E occ urri n g. 
8. 4. 5.  A d verse E ve nts of S peci al I nterest  
C ate g ories of A E SIs  
T here are t hr ee mai n cate g ories of A E SIs: 1) t h ose c o nsi dere 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 me dical pr o bl e ms i n t his patie nt p o p ulati o n, a n d 3) C O VI D - 1 9 
i nfecti o ns occ urri n g i n Partici pa nts d uri n g t he st u d y. 
8. 4. 5. 1.  
A E SIs Rel ate d t o A n gi o ge nesis  
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 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 3 
Fi nal: 1 1 Fe b 2 0 2 1 
is a n gi o ge nesis- de pe n d e nt.3 5 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 or cere bral v asc ular 
disease fr o m  t he Da y 1 8 0 Visit ( V M D N- 0 0 3-2) t o t he Da y 3 6 5/ E T Visit ( V M D N- 0 0 3- 2 b) will 
be e val uat e d as A E SIs.  
Pr oliferati ve dia betic reti n o pat h y  
Ne o vasc ularizati o n is a n a d va nce d sta ge of di a beti c reti n o pat h y t hat is d ue t o rele ntless a b n or m al 
fi br o vasc ular pr olifer ati o n.3 6 Beca use t h e a n gi o ge ni c p ote ntial of E n ge nsis m a y pr o m ote t he 
de vel o p me nt of or sti m ulate a b n or mal fi br o vasc ul ar pr oliferati o n i n t he reti na, ne w f u n d os c o pic 
c ha n ges or s y m pt o ms of pr oliferati ve dia b etic reti n o pat h y t hat occ ur fr o m t he Da y 1 8 0 Visit 
( V M D N- 0 0 3- 2) t o Da y 3 6 5/ E T ( V M D N- 0 0 3-2 b) are c o nsi d ere d 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. 3 7 All t y pes of ca ncer r e p orte d b et wee n t h e Da y  1 8 0 Visit ( V M D N- 0 0 3- 2) t o Da y 
3 6 5/ E T ( V M D N- 0 0 3- 2 b) will be dee me d t o be A E SIs.  
Dia betes mellit us a n d o b esit y ( B MI ≥3 0) eac h i n creases t he ris k of se v eral t y pes of ca n cer .3 8 ,3 9 
I n t y pe 2 D M, t her e is a 2- t o 3-f ol d i ncrease d ris k f or pa ncreatic ca n cer, a 2-f ol d i ncrease d ris k 
f or he pat o biliar y a n d e n d o metrial ca ncers, a 5 0 % i ncreas e d i nci de n ce of c ol orectal ca ncer, a n d a 
2 0 % i ncrease d ris k f or br east ca n cer .4 0 O bese p ost me n o pa usal w o me n h a ve a n i ncreas e d ris k of 
breast ca ncer ,4 1 a n d o besit y is ass ociate d wit h a m o destl y i ncrease d ris k of c ol orectal ca ncer ,4 2 ,4 3 
pa ncreatic ca ncer ,4 4 a n d pr ostate ca ncer .4 5 
8. 4. 5. 2.  
A E SIs Rel ate d t o Ot her Me dic al Pr o ble ms  
Se veral me dical pr o ble ms are fre q ue ntl y o bser ve d i n patie nts wit h dia betic peri p heral ne ur o pat h y 
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 b y t y pe of me dical 
pr o ble m. 
I nfecti o ns a n d I nfestati o ns; S ki n a n d S u bc uta ne o us Dis or ders  
Beca use p atie nts wit h dia betic peri p heral ne ur o p at h y are at a n i ncrease d ris k t o de vel o p s ki n 
lesi o ns (e. g., blisters, ulcers) a n d v ari o us l o wer li m b i nfecti o us c o m plicati o ns (e. g., cell ulitis, 
oste o m yelitis) t hat ma y be ass ociate d wit h s yste mic i nfecti o ns (e. g ., b actere mia, se psis, or se ptic 
s h oc k), all of t hese t y p es of me dical pr o ble ms t hat occ ur bet w ee n t he Da y  1 8 0 ( V M D N- 0 0 3- 0 2) 
a n d t he Da y 3 6 5/ E T ( V M D N- 0 0 3- 2 b) Visits will be c o nsi dere d A E SIs. I n a d diti o n, a n y 
a m p utati o ns i n v ol vi n g t he l o wer e xtre mit y, de vel o p me nt of C harc ot f o ot, or ot her si milar 
c o m plicati o ns will als o be c o nsi der e d A E SIs. 
Peri p heral A rt erial D isease 
A n o verla p of D P N a n d peri p her al arter y disease ( P A D ) a p pare ntl y e xists i n t y pe 2 dia betic 
patie nts. 4 6 Beca us e Partici pa nt s wit h D P N ma y de v el o p si g ns or s y m pt o ms of P A D bet wee n t he 
Da y  1 8 0 ( V M D N- 0 0 3- 2) a n d t he Da y 3 6 5/ E T ( V M D N- 0 0 3- 2 b) Visits , detaile d e val uati o ns of 
Partici pa nt s c o nsi dere d t o ha ve P A D 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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 4 
Fi nal: 1 1 Fe b 2 0 2 1 
Dia betic N e ur o pat hies  
Beca use Partici p a nt s i n t his st u d y ma y de vel o p ot her t y pes of dia b etic peri p heral ne ur o pat hies 
w hile i n t he st u d y, t he f oll o wi n g e ve nts will be c o nsi dere d t o be A E SIs i n Partici pa nt s wit h 
D P N: dia betic m o n o ne ur o pat h y, dia betic m o n o ne ur o pat h y m ulti ple x, a n d dia betic 
p ol yra dic ul o pat h y. T he o cc urr e nce of t hese ot h er t y pes of peri p h eral ne ur o pat hies i n a 
Partici pa nt  wit h D P N ma y i n dicate a m ore s e vere f or m of D P N .  
Beca use Partici p a nt s i n t his st u d y ma y de vel o p vari o us ma nifestati o ns of a ut o n o mic ne ur o pat h y 
(t y picall y i n v ol ves t he gastr oi ntesti nal, ge nit o uri nar y tract, car di o vas c ular s yste ms) after 
ra n d o mizati o n, t he cli nical ma nifestati o ns of dia b etic a ut o n o mic ne ur o p at h y will be c o nsi dere d 
t o be A E SIs.  
Gl yce mic C o ntr ol 
H y p o gl yce mia, h y per gl y ce mia, h y perli pi de mia, h y perc h olester ole mia, a n d h y pertri gl yceri d e mia 
are t o be liste d as A E SIs base d o n t he C o m m o n Ter mi n ol o g y Criteria f or A d verse E v e nts 
( C T C A E) gra di n g if t he y are Gra des 3 or 4. 
Meta b olic c o m plicati o ns of D M  (s uc h as di a betic ket oaci d osis [ D K A], h y p er gl yce mic 
h y per os m olar n o n- k et otic c o ma, lactic aci d osis, meta b olic aci d osis [ o verla ps wit h D K A]) are t o 
be liste d as A E SIs.  
8. 4. 5. 3.  
C O VI D - 1 9 I nfecti o ns 
A dia g n osis of a 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 ke d. 
8. 4. 6.  F oll o w- u p of T E A Es  a n d  T E S A Es  
After t he i nitial T E A E/ T E S A E re p ort, t he I n v esti gat or is re q uire d t o pr o acti 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 SI s (see Secti o n 8. 4. 5 ) 
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 7. 2 ). 
8. 4. 7.  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 t he S p o ns or of a T E 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 pa 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. 
T he S p o ns or has a le g al r es 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 S afet 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 S p o ns or p olic y a n d 
f or war de d t o I n vesti gat ors as necess ar y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 5 
Fi nal: 1 1 Fe b 2 0 2 1 
A n I n vesti gat or w h o r ecei ves a n I n vesti gat or S afet 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. 4. 7. 1.  
S p o ns or’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 F R 3 1 2). Per t he 2 0 1 0 F D A G ui d a nce D o c u me nt f or I n d ustr y a n d I n vesti gat ors 
“ Safet y Re p orti n g Re q uir e me nts f or I N Ds a n d B A/ B E St u dies,” e ve nts cate g orize d as “ p ossi bl y” 
or “ pr o ba bl y ” relat e d will be treate d as “s us pecte d a d verse reacti o ns.” E ve nts cate g orize d as 
“ defi nitel y” r elate d will be treate d as a n “a d verse reacti o n.”  
All seri o us a n d u ne x pecte d st u d y- dr u g- relate d or s us pecte d a d v erse reacti o ns will be re p orte d t o 
F D A a n d t o all partici pati n g I n vesti gat ors as 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 aft er t he S p o ns or deter mi nes t hat t he s us pecte d a d v erse 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, or s us pecte d 
a d verse reacti o n will be r e p orte d t o t he A ge n c y wit hi n 7 cale n dar d a ys after t he S p o ns or’s i nitial 
recei pt of t h e i nf or mati o n. 
T he S p o ns or will n otif y all partici pati n g I n v esti gat ors of a n y ne w safet y i nf or mati o n t hat alters 
t he c urr e nt ris k- be nefit assess me nt of t he st u d y me dicati o n or t hat w o ul d b e 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. 4. 8.  Pre g n a nc y  a n d C o ntr ace pti o n 
8. 4. 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 2 8 da ys pri or t o r a n d o mizati o n a n d/ or t heir last c o nfir me d me nstr u al peri o d pri or t o st u d y 
ra n d o mizati o n ( w hic h e ver is l o n ger) u ntil 2 m o nt hs after st u d y c o m pleti o n. Male Partici pa nts 
m ust als o a gree t o use d o u ble- barri er c o ntrace pti o n u ntil 2 m o nt hs after st u d y c o m pleti o n. Male 
Partici pa nts m ust als o a gree t o use d o u ble- barrier c o ntrace pti o n u ntil 2 m o nt hs after st u d y 
c o m pleti o n. 
D o u ble- barrier f e male 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, dia p hra g m wit h s per mici de, cer vical ca p wit h 
s per mici de. T he r h yt h m met h o d a n d c o ntrace pti o n b y a part ner are n ot c o nsi dere d acce pt a ble 
met h o ds of c o ntrace pti o n. 
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 or t he last St u d y Visit  t o e val uate w het her t he Partici pa nt is 
pre g na nt. 
8. 4. 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 
S p o ns or wit hi n 2 4 h o urs of lear ni n g of a Partici pa nt ’s pre g na nc y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 6 
Fi nal: 1 1 Fe b 2 0 2 1 
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 t he S p o ns or. 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. 
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 n A E or 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 g estati o nal a ge) or still birt h ( occ urri n g at 
> 2 2 wee ks g estati o nal a ge) is al wa ys c o nsi dere d t o be a n T E S A E  a n d will be re p ort e 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 S A Es a n d will be re p ort e d. 
A n y p ost-st u d y pre g na nc y- relate d T E S A E  c o nsi dere d p ossi bl y, pr o ba bl y, or defi nitel y relat e d t o 
t he st u d y dr u g b y t he I n v esti gat or will be re p ort e d t o t he S p o ns or. W hile t he I n vesti 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 
T E S A E  t hr o u g h v ol u ntar y re 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. 4. 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 T E A Es 
or T E S A Es  
E xce pt f or si g ns a n d s y m pt o ms of dia betic peri p heral ne ur o p at h y (i.e., n u m b ness, pai n, ti n gli n g 
or b ur ni n g se nsati o n, cr a m ps, a n d i ncreas e d se nsiti vit y t o t o uc h), all disease -rel ate d e v e nts or 
disease -r elate d o utc o m es q ualify 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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 7 
Fi nal: 1 1 Fe b 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).  
 
S a m ple Size Deter mi n ati o n  
T he N u m ber of Partici pa nts t o be e nr olle d i n St u d y V M D N- 0 0 3- 2 b after c o m pleti o n of t he 
Da y  1 8 0 Visit i n St u d y V M D N - 0 0 3-2 w as base d o n t he sa m ple size esti mat e d f or e nr oll me nt 
i nt o St u d y V M D N- 0 0 3- 2, w hic h was bas e d o n t he h y p ot hesis f or t he pri mar y efficac y e n d p oi nt 
i n St u d y V M D N- 0 0 3- 2 (see Pr ot oc ol V M D N- 0 0 3-2).  
 
P o p ul ati o ns f or A n al yses 
9. 2. 1.  I nte nt-T o -Tre at  P o p ul ati o n 
T his s u bset i ncl u des all e nr olle d Partici pa nt s i n t his st u d y w h o start t his e xte nsi o n st u d y at t he 
Da y 1 8 0 Visit ( St u d y V M D N- 0 0 3- 2). Partici pa nts  i n t he I T T p o p ul ati o n will be a nal yze d 
acc or di n g t o ori gi nal tr eat me nt assi g n me nt i n St u d y V M D N- 0 0 3- 2 , re gar dless of act ual treat me nt 
recei v e d. T he pri mar y a n al yses of t he pri mar y a n d sec o n dar y effi cac y e n d p oi nts will be base d o n 
t his I T T p o p ulati o n. 
9. 2. 2.  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 e nr olle d Partici pa nt s. 
9. 2. 3.  M o difie d I T T  P o p ul ati o n 
T he m o difie d I T T ( mI T T) p o p ulati o n i ncl u des all Partici pa nt s w h o meet t h e f oll o wi n g:  
•  U n der w e nt (a n y) i njecti o ns ( E n ge nsis or Place b o) i n St u d y V M D N- 0 0 3- 2 
•  C orrectl y c o m plete d t he B PI -D P N e Diar y at Bas eli ne  a n d t he 1 2- m o nt h f oll o w- u p i n 
St u d y V M D N- 0 0 3- 2 b 
Partici pa nts  will be gr o u pe d base d o n t he ra n d o ml y assi g ne d treat me nts, n ot t he act ual treat me nt 
recei v e d. T he mI T T p o p ulati o n will be use d i n t he se nsiti vit y a nal yses f or t he pri mar y a n d 
sec o n dar y effi cac y e n d p oi nts. 
9. 2. 4.  Per Pr ot oc ol ( P P)  P o p ul ati o n 
T he Per Pr ot oc ol p o p ulati o n is a s u bset of mI T T. It i ncl u des all mI T T Partici pa nt s w h o met all 
t he f oll o wi n g criteria f or St u d y V M D N - 0 0 3- 2 a n d St u d y V M D N - 0 0 3- 2 b: 
•  T he Partici pa nt  met maj or pr ot oc ol eli gi bilit y criteria  i n St u d y V M D N- 0 0 3- 2 
•  T he Partici pa nt  recei ve d all i njecti o ns i n St u d y V M D N- 0 0 3- 2, bas e d o n t he ra n d o mize d 
treat me nts, a n d ha d a Da y  3 6 5/ E T Visit , i ncl u di n g a 7- da y A D P S. 
A d diti o nal criteria, if a n y, will be esta blis he d bef ore u n bli n di n g t he ra n d o mizati o n c o de b y t he 
i n de pe n de nt C D R C t hat is mas ke d t o t he treat me nt i nf or mati o n of eac h Partici pa nt .  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 8 
Fi nal: 1 1 Fe b 2 0 2 1 
T he P P p o p ulati o n will be use d i n t he se nsiti vit y a nal yses f or t he pri mar y a n d sec o n dar y effi cac y 
e n d p oi nts.  
 
St atistic al A n al yses 
T he S tatistical A nal ysis P la n 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 descri be 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 a n d t he statistical a nal yses. 
9. 3. 1.  Pri m ar y  E n d p oi nt(s)  
As descri be d i n Secti o n 3 , t he pri mar y efficac y e n d p oi nt is: 
•  
C ha n ge i n t he mea ns of t he A D P S s fr o m t he f ull B PI-D P N fr o m  t he 7 da ys pri or t o t he 
Da y  0 Visit ( St u d y V M D N- 0 0 3-2) t o t he 7 d a ys pri or t o t he Da y 3 6 5 Visit i n t he 
i nte nt-t o-treat (I T T) p o p ulati o n. 
9. 3. 2.  Sec o n d ar y E n d p oi nts  
T he s ec o n d ar y efficac y e n d p oi nts i ncl u de t he f oll o wi n g: 
•  C ha n ge i n t he mea ns of t he W orst Pai n sc ores fr o m t he f ull B PI- D P N fr o m t he 7 da ys 
pri or t o t he Da y 0 Visit ( St u d y V M D N 0 0 3 2) t o t he 7 da ys pri or t o t he D a y 2 7 0 Visit a n d 
t he 7 da ys pri or t o t he Da y 3 6 5 Visit f or E n ge nsis c o m pare d t o Place b o 
•  Pr o p orti o n of Res p o n ders ( ≥ 5 0 % re d u cti o n i n t he A D P Ss fr o m t he f ull B PI -D P N ) fr o m 
t he 7 da ys pri or t o t he Da y 0 Visit ( St u d y V M D N- 0 0 3- 2) t o t he 7 da ys pri or t o t he 
Da y  2 7 0 Visit a n d t he 7 da ys pri or t o t he Da y 3 6 5 Visit f or E n ge nsis c o m pare d t o 
Place b o  
Sec o n dar y safet y e n d p oi nts i ncl u de: 
•  I n ci de nce of T E A Es a n d T E S A Es f or E n ge nsis c o m pare d t o Place b o  
•  I n ci de nce of cli nicall y si g nifica nt la b orat or y v al u es f or E n ge nsis c o m p are d t o Place b o 
9. 3. 3.  E x pl or at or y Effic ac y E n d p oi nts  
E x pl orat or y efficac y e n d p oi nts i ncl u de: 
•  
Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI C) o n Da y 2 7 0 a n d D a y 3 6 5 f or E n ge nsis 
c o m pare d t o Place b o  
•  
Pr o p orti o n of Res p o n ders ( ≥ 5 0 % re d u cti o n i n t he A D P Ss  fr o m t he f ull B PI-D P N ) d uri n g 
t he 7 da ys pri or t o t he Da y 2 7 0 Visit a n d t he 7 da ys pri or t o t he Da y 3 6 5 Visit w h o were 
Res p o n ders o n Da y 1 0 4 (fi nal i njecti o n visit i n St u d y V M D N 0 0 3 2) f or E n ge nsis 
c o m pare d t o Place b o  
•  
C ha n ge i n t he B S T fr o m t he Da y 0  Visit ( St u d y V M D N 0 0 3- 2) t o Da y 2 7 0 a n d t o 
Da y  3 6 5 Visit 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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
4 9 
Fi nal: 1 1 Fe b 2 0 2 1 
•  
Pr o p orti o n of Res p o n ders ( ≥ 2 0, 3 0, 4 0, 6 0, a n d 7 0 % re d ucti o n i n t he A D P Ss fr o m t he 
f ull B PI-D P N ) fr o m t he 7 da ys pri or t o t he Da y 0 Visit ( St u d y V M D N 0 0 3- 2) t o t he 
7 da ys pri or t o t he Da y 2 7 0 Visit a n d t he 7 da ys pri or t o t he Da y 3 6 5 Visit f or E n ge nsis 
c o m pare d t o Place b o  
•  
C ha n ge i n t he mea ns of t he A D P Ss fr o m t he f ull B PI- D P N fr o m t he 7 da ys pri or t o t he 
Da y  0 Visit ( St u d y V M D N- 0 0 3- 2) t o t he 7 d a ys pri or t o t he Da y 2 7 0 Visit f or E n ge nsis 
c o m pare d t o Place b o  
•  
C ha n ges i n t he se verit y s c ores (fr o m t he f ull B PI- D P N) fr o m  t he 7 da ys pri or t o t he 
Da y  0 Visit ( St u d y V M D N- 0 0 3- 2) t o 7 da ys pri or t o t he Da y 2 7 0 Visit a n d t o 7 da ys pri or 
t o t he Da y 3 6 5 Visit f or E n ge nsis c o m pare d t o Pl ace b o 
•  
C ha n ges i n M N SI assess me nts fr o m t he Da y 0  Visit ( St u d y V M D N 0 0 3 2) t o Da y 2 7 0 
a n d Da y 3 6 5 f or E n ge nsis c o m pare d t o Place b o 
•  
C ha n ges i n t he S F- 3 6 fr o m t he Da y 0  Visit ( St u d y V M D N 0 0 3 2) t o Da y 2 7 0 a n d t o 
Da y  3 6 5 f or E n g e nsis c o m pare d t o Place b o  
•  
C ha n ges i n t he E Q- 5 D fr o m t he Da y 0 V isit ( St u d y V M D N- 0 0 3-2) t o D a y 2 7 0 a n d t o 
Da y 3 6 5 f or E n g e nsis c o m pare d t o Place b o 
•  
C ha n ges i n t he mea ns of t he dail y use of res c ue m e dicati o n fr o m t he D a y 1 8 0 Visit 
( St u d y V M D N- 0 0 3- 2) t o Da y 2 7 0 a n d t o Da y 3 6 5 f or E n ge nsis c o m pare d t o Place b o 
9. 3. 4.  S afet y  A n al yses 
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 as c o m pare d t o  Place b o. 
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 Partici pa nt s i n t he 
safet y s u bset will be i ncl u de d i n t hese a nal ys es. Partici pa nts  will be gr o u pe d b y treat me nt 
recei v e d. All s u m maries will be deri ve d bas e d o n a vaila ble data. 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 ys es will be ma de o n t he Safet y P o p ulati o n. 
9. 3. 5.  I nteri m A n al ysis 
T here will be n o i nteri m a nal ysis d uri n g t his 6- m o nt h e xte nsi o n st u d y. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 0 
Fi nal: 1 1 Fe b 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  
 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  of t h e 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 o c u me nt t he i nf or me d c o nse nt pr ocess i n t he 
Partici pa nt ’s c hart. 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 ele me nts of 
i nf or me d c o nse nt m ust b e ge ner ate d b y t he I n vesti gat or. After a p pr o val 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 n e 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 dical 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 
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 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 1 
Fi nal: 1 1 Fe b 2 0 2 1 
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 In 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 S p o ns or a n d t he I n vesti g at or 
T he S p o ns or a n d I n vesti 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 
i n vesti gati o nal pr o d uct, cli nical researc h, i nf or m e 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 nts’ pr otecte d healt h i nf or mati o n ( P HI), a n d I R B re g ul ati o ns. T he S p o ns or will 
n otif y t he I n v esti 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 t he S p o ns or 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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 2 
Fi nal: 1 1 Fe b 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 ut 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 
T he I n vesti gat or will scr ee n Partici pa nt s w h o meet t he eli gi bilit y criteria. T he I n vesti gat or will 
n ot e xercise s electi vit y, s o t hat bias is pre ve nte d. All Partici pa nt s m ust si g n a n I C F t hat has b ee n 
a p pr o ve d b ot h b y t he S p o ns or a n d b y t he re vie wi n g I E C/I R B. T he i nf or m e d c o nse nt s h o ul d be i n 
acc or d a nce wit h t he c urr e nt re visi o n of t he Declarati o n of Helsi n ki as well as c urre nt I C H a n d 
G o o d Cli nical Practice ( G C P ) g ui deli nes. 
Partici pa nts will recei ve a c o m pre h e nsi ve e x pla n ati o n of t he 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, a n y k n o w n A Es, t he i n vesti gati o nal stat us of t he pr o d uct, a n d t he ot her ele m e 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 nts will als o recei ve a 
detaile d e x pla nati o n of t h e pr o p ose d use a n d discl os ure of t heir pr otecte d h ealt 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 ples. 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 p ati o n i n t he st u d y after ha 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 p at or y state me nts. T he I C F a n d a n y se parate 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 S p o ns or pri or t o I R B/I E C s u b missi o n. 
T he S p o ns or 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 mati 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 P artici 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, if necessar y.  
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 t he S p o ns or 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 t he S p o ns or. 
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 t he S p o ns or. 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 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 3 
Fi nal: 1 1 Fe b 2 0 2 1 
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 mati o n ge n erate 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 t he data will be release d t o a n y u n a ut h orize d t hir d part y 
wit h o ut pri or writte n a p pr o val of t he S p o ns or. 
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 t he S p o ns or, re prese ntati 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 
C li 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 S p o ns or 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 Site s 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 nati o nal dat a 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 stri ctl 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 t he S p o ns or 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 t he S p o ns or 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, a n d, i n 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 nti alit 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 t he 
S p o ns or i n acc or d a nce wit h l ocal data pr otecti o n l a w. T he le v el 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 d ata t o be 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 t he S p o ns or, 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. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 4 
Fi nal: 1 1 Fe b 2 0 2 1 
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 ata Saf et y M o nit ori n g B oar d ( D S M B ) has bee n c hartere 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 uar 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 h e 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 t he S p o ns or r e 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 ta bles a n d/ or listi n gs, i ncl u di n g all re p orte d T E A Es a n d 
T E S A Es . 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; n o data will be releas e d t o t he S p o ns or a n d 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. Eac h data ele me nt t hat t he D S M B re q uires t o assess t he 
safet y of E n g e nsis will be a gree d u p o n pri or t o st u d y start. R o uti ne D S M B meeti n gs will be 
re g ularl y sc h e d ule d per t he D S M B C hair t o re vie w safet y a n d 1 2- wee k p o ole d all-ca us e 
m ortalit y data, i ncl u di n g u n bli n de d Partici pa nt  narrati ves. T he 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 derst a n d a safet y tre 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 n cer n. T he D S M B will 
pr o vi de rec o m me n dati o ns t o t he S p o ns or i n acc or da 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  
T he S p o ns or 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, Marc 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 S p o ns or’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 v esti gat or. T he cli nical m o nit ors will 
visit (i n pers o n or re m otel y) Cli nical Site s at a p pr o priate i nter vals t o e ns ure c o m plia nce wit h t he 
pr ot oc ol a n d t o 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. 
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 t he S p o ns or. T he cli nical m o nit or or ot her a ut h orize d 
re pres e ntati ves of t he S p o ns or ma y i ns pect all dat a, d oc u me nts, a n d rec or ds re 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 r ec 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 h e I n vesti gat or will o btai n, as part of t he i nf or me d c o ns e 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 va nt P HI a n d p er missi o n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 5 
Fi nal: 1 1 Fe b 2 0 2 1 
f or a ut h orize d re prese nt ati ves of t he S p o ns or, 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 rec 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  
T he S p o ns or or its desi g nee will  m o nit or t he pr o gress of t his st u d y. T he cli nical m o nit or, as a 
re pres e ntati ve of t he S p o ns or, has t he o bli gati o n t o f oll o w t his st u d y cl osel y. 
T he S p o ns or or its desi g nee ma y meet wit h I n v esti gat 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 pect 
t o t he nee ds of t he st u d y, a n d t o fa miliarize t he I n vesti gat or wit h t he st u d y pr ot oc ol. 
T he S p o ns or or its desi g nee ma y meet wit h t he I n v esti gat or(s) at t he ti me t h at 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 ED 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 t he S p o ns or or its re pr ese 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 he 
o bjecti ves of t his visit are t o c o nfir m  t hat all re g ul at or y rec or ds a n d re p orts are c o m plet e a n d  
e ns ure t hat t he I n v esti gat or is a war e of his/ her res 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 o ce d ures will be i m ple me nte d be gi n ni n g wit h t he data e ntr y s yste m, a n d 
data Q C c hec ks t hat will be r u n o n t he data b ase will be ge nerat e d. 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. 
F oll o wi n g writte n Sta n dar d O per ati n g Pr oce d ures ( S O Ps), 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 ar e ge 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), G o o d Ma n ufact uri n g Practices 
( G M 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 t he S p o ns or, 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.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 6 
Fi nal: 1 1 Fe b 2 0 2 1 
T he I n vesti gat or at t he 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  
T he S p o ns or ’s e m pl o yees a n d/ or t heir c o ntracte d re pres e 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 pare d t o t he hi g h est 
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 t he S p o ns or 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. 
All Partici pa nt  data relati n g t o t he st u d y will be rec or de d o n a n electr o nic C R F (e C R F) u nless 
tra ns mitte d t o t he S p o ns or or desi g nee electr o nicall y (e. g., la b orat or y d ata). T he I n vesti gat or is 
res p o nsi ble f or v erif yi n g t hat data e ntries are acc urate a n d c orrect b y p h ysicall y or electr o nicall y 
si g ni n g t he 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 C 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. 
T he S p o ns or is res p o nsi ble f or t he dat a ma na ge m e 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 data. 
T he S p o ns or ass u mes acc o u nta bilit y f or acti o ns d ele 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).  
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 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 verifia 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. 
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 t he S p o ns or or its desi g nee. T he data bas e will be a ut h orize 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.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 7 
Fi nal: 1 1 Fe b 2 0 2 1 
T he Cli nical  Site  will be pr o vi de d wit h e C R Fs a n d e P R O/e C O A de vices  i n w hic h t o rec or d all 
t he pr ot oc ol-s pecifie d dat a f or eac h Partici p a 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 o c u me nts, or i n certai n circ u msta nces as directe d b y t he S p o ns or, e ntries will 
ha ve bee n directl y e nt ere d i nt o t he e C R F; i n s uc h cases, 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 data. D ata r e 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 me nts or t he discre pa ncies s h o ul d be e x pl ai ne d. T he I n v esti gat or 
will be res p o nsi ble f or r e 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 nate d 
pa ges i n eac h  Partici pa nt ’s e C R F, verif yi n g t hat t h e i nf or mati o n is tr ue a n d c orrect. Q ueri es 
ge nerat e d b y Data M a 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 Me dical M o nit or o n be half of t he S p o ns or e xce pt i n t he case of a m e dical e mer ge 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 . 
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 Me 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. 
Pr ot oc ol de viati o ns will be trac k e d t hr o u g h t he E D C. 
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 
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, de p e n di n g o n 
t he st u d y. Curre 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.  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 8 
Fi nal: 1 1 Fe b 2 0 2 1 
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 file area a n d be accessi ble o nl y 
t o re prese nt ati ves of t he Cli nical Site , t he S p o ns or a n d its re pres e ntati ves, a n d F D A/rele va nt 
healt h a ut h orities/re g ulat or y a ge nci es. 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 v esti 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 o f c o nfi de ntialit y. 
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 t he F D A/r el e 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 ueste 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 de 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 g e n c y, t he I n vesti gat or will c o ntact t he S p o ns or i m me diatel y. T he 
I n v esti gat or will als o gra nt t he S p o ns or ’s re pres e ntati ves t he sa me pri vile ges offere d t o t he 
F D A/r ele va nt healt h a ut h orit y or re g ulat or y a ge nts/ officers/e m pl o yees. 
T he I n vesti gat or m ust pr o vi de t he S p o ns or 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  
•  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 D H H S Ge neral Ass ura nce N u m b er (if t he I R B has  a n 
Ass ura nce 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 B C f or c o n d ucti n g t he st u d y, if a p plica ble. 
Re ne wals, wit h c o nti n ua nce of t he 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 f or t h e recei pt  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:  
•  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 
•  A c o p y of del e gati o n of a ut h orit y l o g 
•  All ori gi nal I C Fs wit h re q uire d si g nat ures 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
5 9 
Fi nal: 1 1 Fe b 2 0 2 1 
•  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, A Es, a d vertise me nts, ne wsletters ) 
•  All I B C  c orres p o n d e nce 
•  A c o p y of t he St u d y Visit  L o g  
•  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 he S p o ns or a n d t he Site  
•  C o pies of all T E S A E  re p orts s u b mitte d t o t he S p o ns or 
•  C o pies of all I n v esti gat or S afet y Re p orts s u b mitte d t o t he Site  b y t he S p o ns or 
•  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 te m p or aril y s us pe n de d or pre mat urel y ter mi nate d if t here is s ufficie nt 
reas o na bl e ca us e. Writte n n otificati o n d oc u me nti n g t he reas o n f or 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 S p o ns or t o I n vesti gat ors a n d re g ul at 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 de d, t h e I n vesti 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 t er 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 be i nf or me d of c ha n ges t o St u d y Vis it sc he d ules. 
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y f or a n y safet y, et hical, or a d mi nistrati ve 
reas o n at a n y ti me. 
T he S p o ns or or desi g nee reser v es 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 reas o n at t he s ole discreti o n of t he S p o ns or. 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 t he S p o ns or or I n vesti 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, t he S p o ns or’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, t he S p o ns or 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 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
6 0 
Fi nal: 1 1 Fe b 2 0 2 1 
re g ulati o ns as defi n e d i n t he a gree me nt bet wee n t he S p o ns or 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 
S p o ns or 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  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
6 6 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x  3. Pr o hi bite d  Me dic ati o ns  a n d Pr oce d ures  
T a ble 2 
Pr o hi bite d Me dic ati o ns  – Ster oi ds  
Dr u g  
E x a m ple of C o m m o n 
N a m e(s)  
M a xi m u m D ose All o we d 
D uri n g St u d y  
Ster oi ds  
I njecte d or oral 
c ortic oster oi ds a 
p re d nis o ne, 
beta met has o ne,  
de xa met has o ne,  
c ortis o ne,  
h y dr oc ortis o ne, 
tria mci n ol o ne 
N o ne  
T o pical c ortic oster oi ds o n 
t he l o wer le gs or feet 
p re d nis o ne,  
beta met has o ne, 
de xa met has o ne,  
c ortis o ne,  
h y dr oc ortis o ne, 
tria mci n ol o ne 
N o ne o n t he l o wer le gs or 
feetb 
a I n hale d, o c ular, a n d i ntra-artic ular ster oi ds are all o we d.  
b T o pical c ortic oster oi d use is all o we d o n b o d y s urfaces ot h er t h a n t h e l o wer le gs a n d feet.  
 
T a ble 3 
Pr o hi bite d Me dic ati o ns  a n d Pr oce d ures – O pi oi ds a n d Ot her  T her a pies  
Dr u g or Pr oce d ure  
M a xi m u m D ose All o we d D uri n g St u d y  
Ac u p u nct ure  
N o ne  
A nest hetic crea ms (f or use o nl y d uri n g i njecti o ns) a n d 
patc hes, i ncl u di n g ca psaici n, o n l o wer le gs a n d feet  
N o ne  
Be nz o diaze pi nes  
N o ne, e xce pt f or sta ble be dti me d ose  
Ga ba pe nti n, pre ga bali n  
N o ne  
Is os or bi de di nitrate s pra y o n l o wer le gs a n d feet 
N o ne  
O pi oi ds (e. g., m or p hi ne, o x yc o d o ne, tra ma d ol, 
met ha d o ne, fe nta n yl)  
N o ne, e xce pt after tra u ma or s ur ger y  
S keletal m uscle rela xa nts (e. g., c ycl o be nza pri ne, 
meta xal o ne, c hl orz o xaz o ne)  
N o ne  
Tra nsc uta ne o us electrical ner ve sti m ulati o n  
N o ne  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
6 7 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x 4.  A b bre vi ati o ns a n d Defi niti o ns  
1 0. 4. 1.  A b bre vi ati o ns 
A b bre vi ati o n  
Defi niti o n  
A D P S  
A vera ge Dail y Pai n Sc ore  
A E  
a d verse e ve nt 
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 T  
ala ni ne tra nsa mi nase ( S G P T)  
A P R  
Acc urate Pai n Re p orti n g  
A S T  
as partate tra nsa mi nase ( S G O T)  
β -H C G  
Beta h u ma n c h ori o nic g o na d otr o pi n  
B MI  
b o d y mass i n de x  
B P  
bl o o d press ure  
B PI -D P N  
Brief Pai n I n ve nt or y f or Dia betic Peri p heral Ne ur o pat h y  
B U N  
bl o o d urea nitr o ge n  
B S T  
Be dsi de Se ns or y Testi n g  
C A B G  
c or o nar y arter y b y pass grafti n g  
c D N A  
c o m ple me ntar y D N A  
C D R C  
Cli nical Data Re vie w C o m mittee  
C F R  
C o de of Fe deral Re g ulati o ns  
C K D -E PI  
c hr o nic ki d ne y disease e pi de mi ol o g y c olla b orati o n  
C LI  
critical li m b isc he mia  
C R F  
case re p ort f or m 
C R O  
cli nical researc h or ga nizati o n  
C S  
cli nicall y si g nifica nt  
C T  
C o m p ute d T o m o gra p h y  
DI P  
distal i nter p hala n geal  
D K A  
dia betic ket oaci d osis  
D M  
dia betes mellit us  
D M C  
Data M o nit ori n g C o m mittee  
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  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
6 8 
Fi nal: 1 1 Fe b 2 0 2 1 
A b bre vi ati o n  
Defi niti o n  
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 Diar y  
electr o nic diar y 
e G F R  
esti mate d gl o mer ular filtrati o n rate  
E Q -5 D  
E ur o Q ol Healt h Utilities I n de x  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -gl uta m yl tra ns pe pti dase  
G L P  
G o o d La b orat or y Practice  
H b A 1c  
He m o gl o bi n A 1c  
H D L - C 
hi g h -de nsit y li p o pr otei n c h olester ol  
H E E N T  
hea d, e yes, ears, n ose, a n d t hr oat  
H G F  
he pat oc yte gr o wt h fact or  
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 C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o u ncil f or Har m o ni sati o n  of Tec h nical Re q uire me nts f or 
P har mace uticals f or H u ma n Use  
I H D 
isc he mic heart disease 
I M 
i ntra m usc ular 
I N D 
I n vesti gati o nal Ne w Dr u g a p plicati o n 
I R B 
I nstit uti o nal Re vie w B oar d 
I S D N 
is os or bi de di nitrate  
I T T 
i nte nt-t o-treat 
I U D 
i ntra uteri ne de vice 
I W R S 
I nteracti ve We b Res p o nse S yste m 
L D L - C 
l o w-de nsit y li p o pr otei n c h olester ol  
mI T T  
m o difie d i nte nt -t o-treat 
M N SI  
Mic hi ga n Ne ur o pat h y Scree ni n g I nstr u me nt  
N C S  
n ot cli nicall y si g nifica nt 
N H U  
n o n heali n g f o ot ulcer  
NI H  
Nati o nal I nstit utes of Healt h  
N R S  
N u merical Rati n g Scale  

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
6 9 
Fi nal: 1 1 Fe b 2 0 2 1 
A b bre vi ati o n  
Defi niti o n  
O S P  
Office of Scie nce P olic y  
P A D  
peri p heral arterial disease  
P C R  
p ol y merase c hai n reacti o n  
P C P  
p he nc ycli di ne  
P E  
p h ysical e xa mi nati o n  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
P HI  
pr otecte d healt h i nf or mati o n  
PI  
Pri nci pal I n vesti gat or  
P K C  
Pr otei n ki nase C  
P P  
per pr ot oc ol  
P R R  
Place b o Res p o nse Re d ucti o n  
Q C  
q ualit y c o ntr ol  
Q o L  
Q ualit y of Life  
R O S  
reacti ve o x y ge n s pecies 
S A P  
statistical a nal ysis pla n 
S F -3 6  
3 6 -Ite m S h ort F or m Healt h S ur ve y 
S o A  
S c he d ule  of A cti vities 
S O P  
sta n dar d o perati n g pr oce d ure 
S S RI  
selecti ve ser ot o ni n re u pta ke i n hi bit or 
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n 
T C A  
tric yclic a nti de pressa nts  
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 E N S  
tra nsc uta ne o us electrical ner ve sti m ulati o n 
T H C  
ca n na bi n oi d 
V A S  
Vis ual A nal o g Scale  
V E G F  
vasc ular e n d ot helial gr o wt h fact or  
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 0 
Fi nal: 1 1 Fe b 2 0 2 1 
1 0. 4. 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 
A vera ge Dail y Pai n Sc ore  
( A D P S) 
T he mea n of at least 5 dail y pai n sc ores rec or de d f or Q uesti o n 5 of t he 
B PI -D P N ( Secti o n 1 0. 5 ) i n e Diar y d uri n g t he 7 da ys  pri or t o t he Visit s o n 
Da y s 2 7 0 a n d 3 6 5/ E T  
W orst Dail y Pai n Sc ore  
T he mea n of at least 5 w orst dail y pai n sc ores rec or de d f or Q uesti o n 3 of t he 
B PI -D P N ( Secti o n 1 0. 5 ) i n e Diar y d uri n g t he 7 da ys  pri or t o t he Visit s o n 
Da y s 2 7 0 a n d 3 6 5/ E T  
Da y 1 4, etc.  
Da y 1 4 (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 1 4 Visit, a n d n ot t o t he 1 4 t h da y of t he st u d y f or a 
Partici pa nt . 
Dr u g A b use  
T he ha bit ual ta ki n g of a d dicti ve or ille gal dr u gs  
Dr u gs of A b use  
A m p heta mi ne s, bar bit urates, be nz o diaze pi nes, b u pre n or p hi ne, c ocai ne, 
fe nta n yl, me peri di ne, met ha d o ne, o piates, o x yc o d o ne, o x y m or p h o ne, 
p he nc ycli di ne, a n d tra ma d ol 
E M L A Crea m  
A mi xt ure of li d ocai ne 2. 5 % a n d pril ocai ne 2. 5 %  
First -de gree relati ve  
Pare nt , si bli n g, or c hil d 
Hi g hl y Effecti ve C o ntrace pti o n 
Met h o d  
See Secti o n  8. 4. 8  
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 
L o wer Le g  
T he part of t he le g bet wee n t he k nee j oi nt a n d t he a n kle j oi nt. D oes n ot 
i ncl u de t he f o ot. 
Me dical M o nit or  
T he Res p o nsi ble Me dical Officer or desi g nee  
Partici pa nt  
A n i n di vi d ual w h o has si g ne d i nf or me d c o nse nt t o be e ntere d i nt o t he st u d y  
Place b o  
Place b o c o m prises 4 5 m g s o di u m c hl ori de a n d 5 5 m g s ucr ose i n 5 m L of 
water f or i njecti o n. E n ge nsis vials c o ntai n t he sa me e xci pie nts.  
Safet y A nal ysis P o p ulati o n  
All Partici pa nt s w h o recei ve a St u d y I njecti o n  
Site  
A cli nical researc h facilit y partici pati n g i n t he V M D N -0 0 3 -2 b  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 
Sta ble D osi n g Re gi me n  
≤ 5 0 % c ha n ge i n t otal dail y d ose relati ve t o d osi n g at baseli ne of 
a n y me dicati o n 
Sta ge 4 or 5 Ki d ne y Disease  
e G F R < 3 0 m L/ mi n/ 1. 7 3 m 2  
St u d y Dr u g  
E n ge nsis or Place b o  
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 1 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x 5. Brief P ai n I n ve nt or y f o r P artici p a nts wit h Di a betic Peri p her al 
Ne ur o p at h y ( B PI- D P N)  
T he pa per versi o n of t he B PI- D P N S h ort F or m is s h o w n bel o w. Partici pa nts will be usi n g a n 
e P R O versi o n, w hic h will be de vel o pe d pri or t o st u d y start u p. 
. 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 2 
Fi nal: 1 1 Fe b 2 0 2 1 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 3 
Fi nal: 1 1 Fe b 2 0 2 1 
 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 
P atie nt Gl o b al I m pressi o n of C h a n ge ( P GI C) Sc ale 
Si nce t he start of t he st u d y, m y o verall stat us is: C hec k ( ) o ne b o x o nl y: 
Ver y M uc h I m pr o ve d 
1 
 
M uc h I m pr o ve d  
2 
 
Mi ni mall y I m pr o ve d  
3 
 
N o C ha n ge 
4 
 
Mi ni mall y W orse  
5 
 
M uc h W orse 
6 
 
Ver y M uc h W orse 
7 
 
 
 
Partici pa nt’s  I nitials:    
Date:  _ _ _ _ _ _ _ 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 4 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x 7. S h ort F or m He alt h S ur ve y ( S F- 3 6) E x a m ple 
S h ort F or m 3 6 ( S F- 3 6) Q u alit y of Life Sc ale 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 5 
Fi nal: 1 1 Fe b 2 0 2 1 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 7 
Fi nal: 1 1 Fe b 2 0 2 1 
 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 8 
Fi nal: 1 1 Fe b 2 0 2 1 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
7 9 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x 8 . E ur o Q ol He alt h Utilities I n de x ( E Q-5 D)  
E ur o pe a n Q u alit y of Life ( E Q- 5 D) Q u alit y of Life Sc ale 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 0 
Fi nal: 1 1 Fe b 2 0 2 1 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 1 
Fi nal: 1 1 Fe b 2 0 2 1 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 2 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x 9. Be dsi de Se ns or y Testi n g  ( B S T) 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 3 
Fi nal: 1 1 Fe b 2 0 2 1 
B S T St aff S o urce W or ks heet ( C o nti n ue d)  
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 4 
Fi nal: 1 1 Fe b 2 0 2 1 
A d mi nisteri n g Be dsi de Se ns or y Testi n g ( B S T)  
A d mi nistr ati o n. A n I n v esti gat or s h o ul d a d mi nister B S T o n Da ys 2 2 5, 2 7 0, 3 1 5, a n d 3 6 5 / E T. 
All se ns or y tests are b ei n g perf or me d at 3 pre d efi n e d l ocati o ns: d ors u m of t he f o ot, mi d-s hi n, 
a n d mi d-t hi g h, e xce pt l o w t hres h ol d mec ha n orece pti ve f u ncti o n, w hic h will be c o n d ucte d at t he 
b ott o m of t he f o ot o nl y. 
T he Partici pa nt s h o ul d be seate d c o mf orta bl y d uri n g all fi ve pr oce d ures of t he B S T. 
Pr oce d ure 1: Ne ur o pe n Test. T he Ne ur o pe n test all o ws assess me nt of t he e xte nt of da ma g e of 
t he l o w t hres h ol d mec ha n orece pti ve s m all fi bers. 
Met h o d of A d mi nistr ati o n. A p plicati o n of t he v o n Fre y fila me nt ( 1 0 g) t o te n ra n d o m l ocati o ns 
o n t he b ott o m of t he f o ot 
S u m m ar y Sc ore. Fre q u e nc y c o u nt of v o n Fre y sti m uli detecte d (ra n ge 0- 1 0; 0 = n o ne detecte d; 
1 0 = all detect e d) f or b ott o m of t he f o ot; t he n re verse sc ore fre q ue nc y c o u nt t o ali g n wit h 
i nter pretati o n of ot her se ns or y tests. 
Pr oce d ure 2: F o a m Br us h Test. All o d y nia, a p he n o me n o n i n w hic h e x p os ure t o a n o n- p ai nf ul 
sti m ul us is percei ve d as pai nf ul, is ass ociate d wit h s mall fi ber ne ur o p at h y. T he f oa m br us h test 
all o ws f or assess me nt of D y na mic Mec h a nical All o d y nia.  
Met h o d of A d mi nistr ati o n. Str o ke eac h a n at o mical l ocati o n wit h br us h ma ki n g pl us s ha pe. 
S u m m ar y Sc ore. Si n gle 0- 1 0 N R S pai n i nte nsit y rati n g f or eac h a n at o mical l ocati o n 
Pr oce d ure 3: S afet y Pi n Test. H y per al gesia, a p h e n o me n o n i n w hic h e x p os ure t o a pai nf ul 
sti m ul us is percei ve d as m ore pai nf ul t ha n it s h o ul d be, is ass ociate d wit h s mall fi ber ne ur o p at h y. 
T he safet y pi n test all o ws f or t he assess me nt of p u nctate h y peral gesia.  
Met h o d of a d mi nistr ati o n. Ta p safet y pi n fi ve ti mes wit hi n eac h a n at o mical l ocati o n  
S u m m ar y Sc ore. A vera ge of fi ve 0- 1 0 N R S pai n i nte nsit y rati n gs i n eac h a nat o mical l ocati o n  
Pr oce d ure 4: V o n Fre y Fil a m e nt Test. Te m p oral S u m mati o n is a p he n o me n o n i n w hic h 
e x p os ure t o t he a p plicati o n of c o nsec uti ve re peate d sti m uli is percei ve d as m ore pai nf ul t ha n 
e x p os ure t o a si n gle sti m ul us. T he V o n Fre y fila m e nt test all o ws f or q ua ntificati o n of Te m p oral 
S u m mati o n.  
Met h o d of A d mi nistr ati o n. A p pl y v o n Fre y fila me nt fi ve ti mes i n ra pi d s uccessi o n wit hi n eac h 
a nat o mical l ocati o n  
S u m m ar y Sc ore. Delta bet wee n first a n d last 0 - 1 0 N R S pai n i nte nsit y rati n g i n eac h a n at o mical 
l ocati o n 
Pr oce d ure 5: T u ni n g F or k Test. All o d y nia, a p he n o me n o n i n w hic h e x p os ure t o a n o n- p ai nf ul 
sti m ul us is percei ve d as pai nf ul, is ass ociate d wit h s mall fi ber ne ur o p at h y. T he t u ni n g f or k test 
all o ws f or assess me nt of C ol d All o d y nia. 
Met h o d of A d mi nistr ati o n. A p pl y t u ni n g f or k f or 1 0 sec o n ds at eac h a n at o mical l ocati o n. 
S u m m ar y Sc ore. Si n gle 0- 1 0 N R S pai n i nte nsit y rati n g f or eac h a n at o mical l ocati o n 
 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 5 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x  1 0. Mic hi g a n Ne ur o p at h y Scree ni n g I nstr u me nt 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 6 
Fi nal: 1 1 Fe b 2 0 2 1 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 7 
Fi nal: 1 1 Fe b 2 0 2 1 
H o w t o Use t he Mic hi g a n Ne ur o p at h y Scree ni n g I nstr u me nt  
Hist ory. T he hist or y q uesti o n naire is self-a d mi nistere d b y t he Partici pa nt . Res p o nses are a d de d 
t o o btai n t he t otal sc ore. Res p o nses of “ yes ” t o ite ms 1- 3, 5- 6, 8- 9, 1 1-1 2, 1 4 - 1 5 are eac h c o u nte d 
as o ne p oi nt. A “ n o” res p o nse o n ite ms 7 a n d 1 3 c o u nts as 1 p oi nt. Ite m # 4 is a meas ure of 
i m paire d circ ulati o n a n d ite m # 1 0 is a measure of ge neral aest he nia a n d are n ot i ncl u de d i n 
sc ori n g. T o decreas e t he p ote ntial f or bias, all sc ori n g i nf or mati o n has bee n eli mi nate d fr o m t he 
Partici pa nt  versi o n. 
U p o n c o m pleti o n of t he q uesti o n naire, t he st u d y c o or di nat or will c hec k t h e q uesti o n naire f or 
c o m plete ness. N ote, t he Partici pa nt  will be as ke d t o i nitial a n d date t he q uesti o n naire. 
P hysic al Assess me nt. F or all assess me nts, t he f o ot s h o ul d be war m ( > 3 0° C). 
F o ot I ns pecti o n: T he feet are i ns pecte d f or e vi de nce of e x cessi vel y dr y s ki n, call o us f or mati o n, 
fiss ures, fr a n k ulcer ati o n or def or mities. Def or mities i ncl u de flat feet, ha m mer t oes, o verla p pi n g 
t oes, hall u x val g us, j oi nt s u bl u xati o n, pr o mi ne nt metatarsal hea ds, me dial c o n ve xit y ( C harc ot 
f o ot) a n d a m p utati o n. 
Vi br ati o n Se ns ati o n:  Vi bra ti o n se nsati o n s h o ul d be perf or me d wit h t he great t oe u ns u p p orte d. 
Vi brati o n se nsati o n will be teste d bilaterall y usi n g a 1 2 8 Hz t u ni n g f or k pl ace d o v er t he d ors u m 
of t he great t oe o n t he b o ne y pr o mi ne nce of t he distal i nter p hala n geal ( DI P) j oi nt. Partici pa nts , 
w h ose e yes are cl ose d, will be as ke d t o i n dicate w he n t he y ca n n o l o n g er se nse t he vi brati o n 
fr o m t he vi brati n g t u ni n g f or k. I n ge n eral, t he e xa mi ner s h o ul d be a ble t o feel vi brati o n fr o m t he 
ha n d- hel d t u ni n g f or k f or 5 sec on ds l o n ger o n his distal f orefi n ger t h a n a n or mal Partici pa nt  ca n 
at t he great t oe (e . g., e xa mi ner’s DI P j oi nt of t he first fi n ger vers us Partici p a nt ’s t oe). If t h e 
e xa mi ner f eels vi brati o n f or 1 0 or m ore s ec o n ds o n his or her fi n ger, t he n vi brati o n is c o nsi dere d 
decrease d. A st u d y s h o ul d be gi ve n w he n t he t u ni n g f or k is n ot vi brati n g t o be cert ai n t hat t he 
Partici pa nt  is res p o n di n g t o vi brati o n a n d n ot press ure or s o me ot her cl ue. Vi brati o n is sc ore d as 
1) prese nt if t he e xa mi ner se nses t he vi brati o n o n hi s or her fi n ger f or < 1 0 sec o n ds, 2) re d uce d if 
se nse d f or ≥ 1 0 or 3) a bs e nt ( n o vi brati o n detecti o n.)  
M uscle Stret c h Refl e xes:  T he a n k le refl e xes will be e xa mi ne d usi n g a n a p pr o priate refle x 
ha m mer (e. g., Tr o m mer or Q uee n s q u are). T he a n kle refle x es s h o ul d be eli cite d i n t he sitti n g 
p ositi o n wit h t he f o ot de pe n de nt a n d t he Partici p a nt  rela xe d. F or t he refle x, t he f o ot s h o ul d be 
passi vel y p ositi o ne d, a n d t he f o ot d orsifle xe d sli g htl y t o o btai n o pti mal stretc h of t he m uscle. 
T he Ac hilles te n d o n s h o ul d be perc uss e d directl y. If t he refle x is o btai ne d, it is gra de d as pres e nt. 
If t he refle x is a bse nt, t he Partici pa nt  is as ke d t o perf or m t he J e n drassic ma ne u ver (i. e., h o o ki n g 
t he fi n gers t o get her a n d p ulli n g). Refle xes elicite d wit h t he Je n drassic ma n e u ver al o ne are 
desi g nate d “ pr ese nt wit h rei nf orce me nt.” If t he refle x is a bse nt, e ve n i n t he face of t he Je n drassic 
ma ne u ver, t he refl e x is c o nsi dere d a bse nt.  
M o n ofil a m e nt Testi n g: F or t h is e xa mi nati o n, it is i m p orta nt t hat t he Partici pa nt ’s f o ot be 
s u p p orte d (i.e., all o w t he s ole of t he f o ot t o rest o n a flat, war m s urface). T h e 1 0-gra m fila m e nt 
s h o ul d i nitiall y be pre-stresse d ( 4- 6 p er pe n di c ular a p plicati o ns t o t he d ors u m of t he e xa mi ner’s 
first fi n ger). T h e fila me nt is t he n a p plie d t o t he d ors u m of t he great t oe mi d wa y bet wee n t he nail 
f ol d a n d t he DI P j oi nt. D o n ot h ol d t he t oe directl y. T he fila me nt is a p plie d per pe n dic ularl y a n d 
briefl y, ( < 1 s ec o n d) wit h a n e ve n pr ess ure. W he n t he fila me nt be n ds, t he f orce of 1 0 gra ms has 
bee n a p plie d. T h e Partici pa nt, w h ose e y es are cl os e d, is as ke d t o res p o n d y es if he/s he feels t he 
fila me nt. Ei g ht c orrect res p o nses o ut of 1 0 a p plicati o ns are c o nsi dere d n or mal, o ne t o se ve n 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 8 
Fi nal: 1 1 Fe b 2 0 2 1 
c orrect res p o nses i n dicat e re d uce d se nsati o n, a n d n o c orrect a ns wers tra nsl ates i nt o a bse nt 
se nsati o n. 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
8 9 
Fi nal: 1 1 Fe b 2 0 2 1 
 A p pe n di x 1 1. P r ot oc ol A m e n d me nt Hist or y  
T here are n o a me n d me nts t o t his pr ot oc ol. 
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
9 0 
Fi nal: 1 1 Fe b 2 0 2 1 
1 1.  
R E F E R E N C E S  
 
1 Fi g uer oa -R o mer o C, Sa di di M, Fel d ma n E L. Mec ha nis ms of disease. T he o xi dati ve stress t he or y of dia betic 
ne ur o pat h y. Rev E n d ocr Met a b Dis or d. 2 0 0 8; 9( 4): 3 0 1 -1 4.  
2 K u ma gai A K. Gl uc ose tra ns p ort i n brai n a n d reti na: i m plicati o ns i n t he ma na ge me nt a n d c o m plicati o ns of 
dia betes. Di a betes Met a b Res Rev . 1 9 9 9; 1 5( 4): 2 6 1-7 3.  
3 Tie n T, Barrette K F, C hr o n o p o ul os A, R o y S. Effects of hi g h gl uc ose -i n d uce d C x 4 3 d o w nre g ulati o n o n occl u di n 
a n d Z O-1 e x pressi o n a n d ti g ht j u ncti o n barrier f u ncti o n i n reti nal e n d ot helial cells. I nvest O p ht h al m ol Vis Sci. 
2 0 1 3; 5 4( 1 0): 6 5 1 8 -2 5.  
4 Br o w nlee M. Bi oc he mistr y a n d m olec ular cell bi ol o g y of dia betic c o m plicati o ns. N at ure . 2 0 0 1; 4 1 4( 6 8 6 5): 8 1 3-2 0.  
5 de M Ba n deira S, da F o nseca LJ S, da S G ue des G, Ra bel o L A, G o ulart M O F, Vasc o ncel os S M L. O xi dati ve stress 
as a n u n derl yi n g c o ntri b ut or i n t he de vel o p me nt of c hr o nic c o m plicati o ns i n dia betes mellit us. I nt J M ol Sci. 
2 0 1 3; 1 4: 3 2 6 5 -8 4.  
6 Ya na gi da K, Maeji ma Y, Sa nt os o P, et al. He x osa mi ne pat h wa y b ut n ot i nterstitial c ha n ges me diates gl uc ot o xicit y 
i n pa ncreatic β-cells as assess e d b y c yt os olic Ca 2 + res p o nse t o gl uc ose. A gi n g . 2 0 1 4; 6( 3): 2 0 7-1 4.  
7 Ta n g W H, Marti n K A, H wa J. Al d ose re d uctase, o xi dati ve stress, a n d dia betic mellit us. Fr o nt P h ar m ac ol . 
2 0 1 2; 3: 8 7.  
8 Ve da nt ha m S, A na nt ha kris h na n R, Sc h mi dt A M, Ra masa m y R. Al d ose re d uctase, o xi dati ve stress a n d dia betic 
car di o vasc ular c o m plicati o ns. C ar di ov asc He m at ol A ge nts Me d C he m . 2 0 1 2; 1 0( 3): 2 3 4-4 0.  
9 Gra y S P, Di Marc o E, O ka be J, et al. N A D P H o xi dase 1 pla ys a ke y r ole i n dia betes mellit us -accelerate d 
at her oscler osis. Circ ul ati o n . 2 0 1 3; 1 2 7( 1 8): 1 8 8 8-9 0 2.  
1 0 Na u di A, J o ve M, A yala V, et al. Cell ular d ysf u ncti o n i n dia betes as mala da pti ve res p o nse t o mit oc h o n drial 
o xi dati ve stress. Ex p Di a betes Res . 2 0 1 2; 2 0 1 2: 6 9 6 2 1 5. 
1 1 Si vitz WI, Y ore k M A. Mit oc h o n drial d ysf u ncti o n i n dia betes: fr o m m olec ular mec ha nis ms t o f u ncti o nal 
si g nifica nce a n d t hera pe utic o p p ort u nities. A nti oxi d Re d ox Si g n al . 2 0 1 0; 1 2( 4): 5 3 7-7 7.  
1 2 Zie gler D, S o hr C G, N o ur o oz -Za de h J. O xi dati ve stress a n d a nti o xi da nt defe nse i n relati o n t o t he se verit y of 
dia betic p ol y ne ur o pat h y a n d car di o vasc ular a ut o n o mic ne ur o pat h y.  Di a betes C are . 2 0 0 4; 2 7( 9): 2 1 7 8-8 3.  
1 3 Far ber D C, Far ber J S. Office -base d scree ni n g, pre ve nti o n, a n d ma na ge me nt of dia betic f o ot dis or ders. Pri m C are . 
2 0 0 7; 3 4( 4): 8 7 3 -8 5, vii -viii.  
1 4 Zie gler D, A met o v A, Bari n o v A, et al. Oral treat me nt wit h al p ha -li p oic aci d i m pr o ves s y m pt o matic dia betic 
p ol y ne ur o pat h y: t he S Y D N E Y 2 trial. Di a betes C are . 2 0 0 6; 2 9( 1 1): 2 3 6 5-7 0.  
1 5 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( 3): 6 2 9-4 1.  
1 6 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( 3): 5 1 3-9.  
1 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( 4): 5 9 1 -6 0 0.  
1 8 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( 6): 1 1 6 0-5.  
1 9 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( 3): 2 7 3-8 4.  
2 0 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( 7): 1 4 0 3-7.  
2 1 Jia n g W, Hisc o x S, Mats u m ot o K, Na ka m ura T. He pat oc yte gr o wt h fact or/scatter fact or, its m olec ular, cell ular 
a n d cli nical i m plicati o ns i n ca ncer. Crit Rev O nc ol He m at ol . 1 9 9 9; 2 9( 3): 2 0 9-4 8.  
2 2 E be ns A, Br ose K, Le o nar d o E D, et al. He pat oc yte gr o wt h fact or/scatter fact or is a n a x o nal c he m oattracta nt a n d a 
ne ur otr o p hic fact or f or s pi nal m ot or ne ur o ns.  Ne ur o n . 1 9 9 6; 1 7( 6): 1 1 5 7-1 1 7 2.  
2 3 Gasc o n E, Gaillar d S, Mala pert P, et al. He pat oc yte gr o wt h fact or -Met si g nali n g is re q uire d f or R u n x 1 e xti ncti o n 
a n d pe pti der gic differe ntiati o n i n pri mar y n ocice pti ve ne ur o ns. J Ne ur osci. 2 0 1 0; 3 0( 3 7): 1 2 4 1 4-2 3.  
2 4 Mai na F, Hilt o n M C, A n dres R, W yatt S, Klei n R, Da vies A M. M ulti ple r oles f or he pat oc yte gr o wt h fact or i n 
s y m pat hetic ne ur o n de vel o p me nt. Ne ur o n . 1 9 9 8: 2 0( 5): 8 3 5-4 6.  
 

Heli x mit h C o., Lt d. 
C O N FI D E N TI A L  
V M D N - 0 0 3- 2 b 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
Versi o n 1. 0 
9 1 
Fi nal: 1 1 Fe b 2 0 2 1 
 
2 5 Mai na F, Hilt o n M C, P o nzett o C, Da vies A M, Klei n R . Met rece pt or si g nali n g is re q uire d f or se ns or y ner ve 
de vel o p me nt a n d H G F pr o m otes a x o nal gr o wt h a n d s ur vi val of se ns or y ne ur o ns. Ge nes Dev . 
1 9 9 7; 1 1( 2 4): 3 3 4 1 -5 0.  
2 6 Ya n g X M, T o ma J G, Ba mji S X, et al. A ut ocri ne he pat oc yte gr o wt h fact or pr o vi des a l ocal mec ha nis m f or 
pr o m oti n g a x o nal gr o wt h. J Ne ur osci . 1 9 9 8; 1 8( 2 0): 8 3 6 9-8 1.  
2 7 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( 2): 4 3 1 -4 5.  
2 8 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.  
2 9 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( 6): 7 7 9-8 1.  
3 0 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 8; 1 7( 1): 4 2-5 0.  
3 1 T ön 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 Ne ur oc he m . 2 0 1 1; 1 1 7: 8 9 2-9 0 3.  
3 2 Ta ni ya ma Y, M oris hita R, A o ki M, et al. T hera pe utic a n gi o ge nesis i n d uce d b y h u ma n he pat oc yte gr o wt h fact or 
ge ne i n rat a n d ra b bit hi n dli m b isc he mia m o dels: precli nical st u d y f or treat me nt of peri p heral arterial disease. 
Ge ne  T her . 2 0 0 1; 8: 1 8 1-9.  
3 3 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 oc N atl Ac a d Sci U S A . 1 9 9 4; 9 1: 4 3 5 7-6 1.  
3 4 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): 1 2 9-4 0.  
3 5 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.  
3 6 Si m ó R, Carrasc o E, García -Ra mírez M, Her ná n dez C. A n gi o ge nic a n d a ntia n gi o ge nic fact ors i n pr oliferati ve 
dia betic reti n o pat h y. C urr Di a betes Rev . 2 0 0 6; 2( 1): 7 1-9 8.  
3 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.  
3 8 K ol b R, S utter walla F S, Z ha n g W. O besit y a n d ca ncer: i nfla m mati o n bri d ges t he t w o. C urr O pi n P h ar m ac ol . 
2 0 1 6; 2 9: 7 7 – 8 9. d oi: 1 0. 1 0 1 6/j.c o p h. 2 0 1 6. 0 7. 0 0 5.  
3 9 S hl o mai G, Neel B, Le R oit h D, et al. T y pe 2 dia betes mellit us a n d ca ncer: T he r ole of p har mac ot hera p y. J Cli n 
O nc ol . 2 0 1 6; 3 4( 3 5): 4 2 6 1-9.  
4 0 Tsili dis K K, Kasi mis J C, L o pez D S, Ntza ni E E, I oa n ni dis J P . T y pe 2 dia betes a n d ca ncer: U m brella re vie w of 
meta -a nal yses of o bser vati o nal st u dies. B MJ . 2 0 1 5; 3 5 0: g 7 6 0 7. 
4 1 M u nsell M F, S pra g ue B L, Berr y D A, C his h ol m G, Tre nt ha m -Dietz A . B o d y mass i n de x a n d breast ca ncer ris k 
acc or di n g t o p ost me n o pa usal estr o ge n -pr o gesti n use a n d h or m o ne rece pt or stat us. E pi de mi ol Rev . 
2 0 1 4; 3 6: 1 1 4 -3 6.  
4 2 G u h D P, Z ha n g W, Ba ns bac k N, A marsi Z, Bir mi n g ha m C L, A nis A H . T he i nci de nce of c o-m or bi dities relate d t o 
o besit y a n d o ver wei g ht: a s yste matic re vie w a n d meta -a nal ysis. B M C P u blic He alt h . 2 0 0 9; 9: 8 8.  
4 3 Calle E E, R o dri g uez C, Wal ker -T h ur m o n d K, T h u n MJ. O ver wei g ht, o besit y, a n d m ortalit y fr o m ca ncer i n a 
pr os pecti vel y st u die d c o h ort of U. S. a d ults. N E n gl J Me d . 2 0 0 3; 3 4 8: 1 6 2 5– 3 8.  
4 4 Wise ma n M. T he sec o n d W orl d Ca ncer Researc h F u n d/ A merica n I nstit ute f or Ca ncer Researc h e x pert re p ort. 
F o o d, n utriti o n, p h ysical acti vit y, a n d t he pre ve nti o n of ca ncer: a gl o bal pers pecti ve. Pr oc N utr S oc . 2 0 0 8; 6: 2 5 3-6.  
4 5 H u M B, Li u S H, Jia n g H W, Bai P D, Di n g Q . O besit y affects t he bi o ps y-me diate d detecti o n of pr ostate ca ncer, 
partic ularl y hi g h -gra de pr ostate ca ncer: a d ose -res p o nse meta-a nal ysis of 2 9, 4 6 4 patie nts. P L o S O ne . 
2 0 1 4; 9( 9):e 1 0 6 6 7 7.  
4 6 C harles M, Ejs kjaer N, Witte D R, B orc h -J o h nse n K, La uritze n T, Sa n d bae k A. Pre vale nce of ne ur o pat h y a n d 
peri p heral arterial disease a n d t he i m pact of treat me nt i n pe o ple wit h scree n -detecte d t y pe 2 dia betes: t he 
A D DI TI O N -De n mar k st u d y. Di a betes C are . 2 0 1 1; 3 4: 2 2 4 4-9.