A Dose-Blinded Extension Study to Evaluate the Long-Term Efficacy, Safety, and Tolerability of UCB0599 in Study Participants With Parkinson's Disease
Phase: PHASE2
Conditions: Parkinson's Disease
Sponsor: UCB Biopharma SRL

U C B  
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
C o nfi de ntial  
Pa ge 1  of 1 3 3  
A D O S E -B LI N D E D E X T E N SI O N S T U D Y T O E V A L U A T E T H E 
L O N G -T E R M E F FI C A C Y, S A F E T Y, A N D T O L E R A BI LI T Y O F 
U C B 0 5 9 9 I N S T U D Y P A R TI CI P A N T S WI T H P A R KI N S O N’ S 
DI S E A S E  
P R O T O C O L P D 0 0 5 5  A M E N D M E N T 4  
P H A S E 2  
S H O R T TI T L E:  
A n e xte nsi o n st u d y t o e val uate t he l o n g -ter m efficac y a n d safet y of mi nzas ol mi n ( U C B 0 5 9 9) i n 
st u d y partici pa nts wit h Par ki ns o n’s disease 
S p o ns or:  
U C B Bi o p har ma S R L  
Allée de la Rec herc he 6 0  
1 0 7 0 Br ussels  
B E L GI U M  
Re g ul at or y a ge nc y i de ntif yi n g n u m bers: 
E U C T N u m ber:  
2 0 2 2 -5 0 0 4 2 4 -3 0 -0 0  
E U D A M E D N u m ber:  
N ot a p plica ble  
I N D N u m ber: 
1 4 1 0 0 3  
I D E N u m ber: 
N ot a p plica ble  
N C T N u m ber:  
N C T 0 5 5 4 3 2 5 2  
C o nfi de nti al M ateri al  
C o nfi de nti al  
T his d oc u me nt is t he pr o pert y of U C B a n d m a y n ot –  i n f ull or i n p art –  be p asse d o n, 
re pr o d uce d, p u blis he d, or ot her wise use d wit h o ut t he e x press per missi o n of U C B.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2  of 1 3 3  
P R O T O C O L A M E N D M E N T S U M M A R Y O F C H A N G E S T A B L E  
D oc u me nt Hist or y  
D oc u me nt  
D ate  
T y pe of a me n d me nt  
A me n d me nt 4  
0 9  Oct 2 0 2 4  
S u bsta ntial  
A me n d me nt 3  
1 8 Se p 2 0 2 3  
S u bsta ntial  
A me n d me nt 2  
3 0 J u n 2 0 2 3  
S u bsta ntial  
A me n d me nt 1  
0 7 N o v 2 0 2 2  
N ot a p plica ble  
Ori gi nal Pr ot oc ol  
2 9 A pr 2 0 2 2  
N ot a p plica ble  
 
A me n d me nt 4 ( 0 9  Oct 2 0 2 4 ) 
O ver all R ati o n ale f or t he A me n d me nt  
P D 0 0 5 5 Pr ot oc ol A me n d me nt 4 was c o m plete d t o e xte n d t he st u d y d urati o n b y a n a d diti o nal 
3 0  m o nt hs t o M o nt h 6 0 t o c ollect l o n ger ter m effi cac y, safet y, a n d t olera bilit y data.  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n  Article 1 0(a) of 
Directi ve 2 0 0 1/ 2 0/ E C of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Title pa ge  
N C T n u m ber was a d de d.  
T o c o m plete t he ta ble wit h 
re g ulat or y a ge nc y i de ntif yi n g 
n u m bers.  
Gl o bal  
Ti me p oi nts of a nal ysis a n d refere nces t o t he 
E O T were u p date d t hr o u g h o ut:  
•  
Secti o n  1. 1  ‘ O verall desi g n’ a n d 
‘ Treat me nt gr o u ps a n d d urati o n’ 
•  
O bjecti ves a n d e n d p oi nts ta bles (refer 
t o c ha n ges descri be d f or Secti o n 1. 1  
a n d Secti o n  3  bel o w)  
•  
Secti o n  4. 1  O verall  desi g n ( 1 3 t h 
para gra p h)  
•  
Secti o n  9. 3  Pla n ne d efficac y/ o utc o me 
a nal yses (refer t o c ha n ges descri be d 
bel o w)  
T o reflect t he e xte n de d st u d y 
d urati o n t o M o nt h 6 0.  
Gl o bal  
W here t he e xter nal c o ntr ol ar m is 
descri be d, ‘e xter nal be nc h mar k/refere nce 
data’ was c ha n ge d t o ‘e xter nal real -w orl d 
data.’  
T o pr o vi de clarificati o n f or t he 
e xter nal c o ntr ol ar m i n t he 
st u d y. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  1. 1  S y n o psis - 
O bjecti ves a n d 
e n d p oi nts 
a n d  
Secti o n  3  
O BJ E C TI V E S A N D 
E N D P OI N T S  
P D 0 0 5 5 M o nt h 6 0 was a d de d as ti me p oi nt 
of a nal ysis f or t he Pri mar y Efficac y 
E n d p oi nt ( Da T -S P E C T w h ole striat u m 
S B R) a n d t he Sec o n dar y Efficac y E n d p oi nt 
(c u m ulati ve L E D D).  
T o reflect t he e xte n de d st u d y 
d urati o n t o M o n t h 6 0. 
 
U n der E x pl orat or y o bjecti ves I, II, a n d III, 
t he te xt i n b ol d  was a d de d t o t he f oll o wi n g 
e n d p oi nts: 
•  
M D S -U P D R S Part II s u bscale ( or 
selecte d ite ms a n d  e mer gi n g 
s y m pt o ms) 
•  
M D S -U P D R S Part III s u bscale ( or 
selecte d ite ms/s u bsc ore) 
T o clarif y t he e x pl orat or y 
efficac y e n d p oi nts f oll o wi n g 
P D 0 0 5 3 Pr ot oc ol 
A me n d me nt  6.  
 
 
T he w or di n g of t he E x pl orat or y o bjecti ve 
II. Effecti ve ness was re vise d f or clarit y: 
‘ P har mac o d y na mic effect’ was re w or de d t o 
‘effecti ve ness.’ I n a d diti o n, ‘ 3-years p ost 
dia g n osis a n d be y o n d’  was re vise d t o 
‘ be y o n d 1 8-m o nt hs d urati o n of P D 0 0 5 3’ t o 
acc o u nt f or partici pa nts w h o ma y ha ve less 
t ha n 3 years P D d urati o n w he n e nr olle d i n 
P D 0 0 5 5.  
T o clarif y t he e x pl orat or y 
o bjecti ve usi n g m ore 
a p pr o priate w or di n g a n d t o 
pr o vi de a m ore o bjecti ve a n d 
clearer descri pti o n of t he 
p o p ulati o n a n d peri o d 
e val uate d. 
 
I n t he list of ‘ E x pl orat or y E n d p oi nts 
( Cli nical O utc o mes)’ f or E x pl orat or y 
o bjecti ves I, II, a n d III, t he M D S -U P D R S 
Part III -relate d e n d p oi nt was re vise d t o 
re m o ve t he refere nce t o O N a n d O F F states.  
T o ali g n wit h w hat is act uall y 
bei n g d o ne i n practice d uri n g 
t he st u d y. 
 
I n t he list of ‘ E x pl orat or y E n d p oi nts 
( Cli nical O utc o mes)’ f or E x pl orat or y 
o bjecti ve II. Effecti ve ness, t he M o C A was 
a d de d bel o w L E D D. 
T he M o C A is alrea d y i ncl u de d 
as a n e n d p oi nt i n P D 0 0 5 5 
E x pl orat or y o bjecti ve I. It is 
a d de d i n E x pl orat or y o bjecti ve 
II t o c o m plete t he list of 
e n d p oi nts t hat s u p p ort t his 
e x pl orat or y st u d y o bjecti ve.   
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  1. 1  S y n o psis - 
O bjecti ves a n d 
e n d p oi nts 
a n d  
Secti o n  3  
O BJ E C TI V E S A N D 
E N D P OI N T S  
T he w or di n g of t he E x pl orat or y o bjecti ve 
III. Efficac y was re vise d f or clarit y (b ol d  
te xt a d de d): 
T o esti mate t he p har mac o d y na mic effects 
of E arl y -st art mi nzas ol mi n ( U C B 0 5 9 9) 
3 6 0 m g vers us E arl y -st art mi nzas ol mi n 
( U C B 0 5 9 9) 1 8 0 m g o n t he cli nical c o urse of 
P D, nee d f or S T a n d brai n pat h o p h ysi ol o g y 
i n partici pa nts ori gi nall y dia g n ose d wit h 
ne w o nset P D  
T o clarif y t he e x pl orat or y 
o bjecti ve . 
 
P D 0 0 5 5 M o nt h 6 0 was a d de d as ti me p oi nt 
of a nal ysis f or t he E x pl orat or y o bjecti ve I V. 
At y pical Par ki ns o nis m.  
T o reflect t he e xte n de d st u d y 
d urati o n t o M o nt h 6 0.  
Secti o n  1. 1  S y n o psis - 
O verall desi g n  
I n t he sec o n d para gra p h, i n t he f o urt h 
se nte nce s u m marizi n g t he e x pl orat or y st u d y 
o bjecti ves  a n d relate d t o o bjecti ves 
assessi n g met h o d ol o g y , ‘i de ntificati o n of 
e n d poi nts n ot affecte d b y S T ’ was c ha n ge d 
t o ‘i de ntificati o n of n o vel e n d p oi nts.’ 
T he sa me c ha n ge was ma de i n Secti o n  4. 1  
O verall desi g n . 
T o  i m ple me nt m ore 
a p pr o priate w or di n g .  
 
I n t he f o urt h para gra p h, t he descri pti o n of 
t he effecti ve ness esti mati o n usi n g e xter nal 
real-w orl d data was re vise d.  
T o clarif y h o w effecti ve ness 
will be e val uate d a n d t o ali g n 
wit h t he u p date d w or di n g of 
E x pl orat or y  o bjecti ve II. 
Effecti ve ness . 
Secti o n  1. 1  S y n o psis - 
N u m ber of partici pa nts  
E nr oll me nt a n d e x pecte d st u d y c o m pleti o n 
n u m bers at P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 
6 0  were u p date d.  
T he sa me c ha n ges were i m ple me nte d i n 
Secti o n  4. 1  O verall desi g n a n d Secti o n  9. 8  
Deter mi nati o n of sa m ple size.  
T o u p date partici pa nt n u m bers 
after P D 0 0 5 3 st u d y 
c o m pleti o n. 
Secti o n  1. 2  Sc he ma  
Fi g ures were u p date d.  
T o reflect t he e xte n de d st u d y 
d urati o n t o M o nt h 6 0.  
 
T he f oll o wi n g n ote was a d de d bel o w 
Fi g ure  1 -3  L o w d ose -ar m desi g n: 
N ote: Data of st u d y partici pa nts 
tra nsiti o ni n g fr o m t he place b o ar m t o t he 
3 6 0 m g ar m will n ot be part of t he 
c o m paris o n of t he 3 6 0 m g a n d 1 8 0 m g 
treat me nt ar ms. 
T o clarif y t he pla n ne d 
c o m paris o ns. 
 
T he n ote wit h a n asteris k ( *) bel o w 
Fi g ure  1 -4  E xter nal real -w orl d data was 
re vise d. 
T o ali g n wit h u p date d w or di n g 
of E x pl orat or y  o bjecti ve II. 
Effecti ve ness . 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  1. 2  Sc he ma  
A n a d diti o nal n ote was a d de d bel o w 
Fi g ure  1 -4  E xter nal real -w orl d data:  
N ote: Data of st u d y partici pa nts 
tra nsiti o ni n g fr o m t he place b o or 1 8 0 m g 
ar m t o t he 3 6 0 m g ar m will n ot be part of 
t he c o m paris o n of t he 3 6 0 m g treat me nt ar m 
t o t he e xter nal refere nce ar m. 
T o clarif y t he pla n ne d 
c o m paris o ns. 
Secti o n  1. 3  Sc he d ule 
of Acti vities  
V 1 1 ( M 3 6), V 1 2 ( M 4 2), V 1 3 ( M 4 8), V 1 4 
( M 5 4), a n d V 1 5/ E O T/ E T ( M 6 0) were 
a d de d. 
T o reflect t he e xte n de d st u d y 
d urati o n t o M o nt h 6 0.  
 
‘ E O T/ E T’ was m o ve d fr o m V 1 0 t o V 1 5. 
T o reflect t hat V 1 5 ( M o nt h 6 0 
i n P D 0 0 5 5) is n o w t he e n d-of -
treat me nt visit. 
 
A ne w i nf or me d c o nse nt pr oce d ure was 
a d de d f or st u d y partici pa nts t o pr o vi de 
writte n c o nse nt t o partici pate i n t he o pti o nal 
i n-st u d y patie nt inter vie ws (a p plica ble t o 
U S a n d U K sites o nl y).  
T o i m ple me nt a c ha n ge fr o m 
l ocal pr ot oc ol a me n d me nts 3. 2 
( U K) a n d 3. 3 ( U S) date d 
J u n 2 0 2 4 i n t he gl o bal pr ot oc ol 
a me n d me nt 4. 
 
A ne w assess me nt was a d de d:  
‘ O pti o nal i n-st u d y patie nt i nter vie ws ( U S 
a n d U K o nl y)’  
T o i m ple me nt a c ha n ge fr o m 
l ocal pr ot oc ol a me n d me nts 3. 2 
( U K) a n d 3. 3 ( U S) date d 
J u n 2 0 2 4 i n t he gl o bal pr ot oc ol 
a me n d me nt 4. 
 
A se nte nce was a d de d t o f o ot n ote ‘i’ t o 
clarif y t hat t he Da T -S P E C T at V 8 ( M 1 8) 
a n d V 1 5/ E O T/ E T ( M 6 0) ca n be d o ne 
wit hi n a ti me wi n d o w of ± 2 8 da ys.  
T o clarif y pr ot oc ol pr oce d ures.  
 
T he letter ‘ k’ was a d de d t o t he ne w M o C A 
assess me nts at V 1 1 ( M 3 6) a n d 
V 1 5/ E O T/ E T ( M 6 0) .  
F o ot n ote ‘ k’ was re vise d t o s pecif y t he 
M o C A versi o ns t o be use d at t he differe nt 
visits.  
T o clarif y t he M o C A versi o n 
t o be use d at t he ne w 
ti me p oi nts of assess me nt. 
 
Ne w f o ot n ote ‘s’ was a d de d t o f urt her 
clarif y t he ti me p oi nt of assess me nt f or t he 
i n-st u d y patie nt i nter vie ws (a p plica ble t o 
U S a n d U K sites o nl y).  
T o i m ple me nt a c ha n ge fr o m 
l ocal pr ot oc ol a me n d me nts 3. 2 
( U K) a n d 3. 3 ( U S) date d 
J u n 2 0 2 4 i n t he gl o bal pr ot oc ol 
a me n d me nt 4. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  4. 1  O verall 
desi g n  
I n t he se ve nt h para gra p h, t he descri pti o n of 
t he effecti ve ness esti mati o n usi n g e xter nal 
real-w orl d data was re vise d.  
T he f oll o wi n g se nte nce was re m o ve d:  
T his is s u bject t o detaile d feasi bilit y 
assess me nt of e xter nal data s o urces t o 
e val uate t heir s uita bilit y t o a d dress t he 
E x pl orat or y O bjecti ve II (refer t o Secti o n 
3).  
T o clarif y h o w effecti ve ness 
will be e val uate d a n d t o ali g n 
wit h t he u p date d w or di n g of 
E x pl orat or y o bjecti ve II. 
Effecti ve ness.  
 
T he last se nte nce i n t he secti o n was 
re m o ve d: 
T he S p o ns or ma y deci de t o e xte n d t he 
treat me nt d urati o n be y o n d t he 3 0 m o nt h 
peri o d via a pr ot oc ol a me n d me nt de pe n di n g 
o n t he dr u g de vel o p me nt strate g y.  
T o re m o ve te xt t hat n o l o n ger 
a p plies. 
Secti o n  4. 2  Scie ntific 
rati o nale f or st u d y 
desi g n  
T he fift h para gra p h descri bi n g t he 
e x pl orat or y o bjecti ve  III (of efficac y) was 
re vise d. 
T o clarif y t he st u d y o bjecti ve.  
Secti o n  6. 5. 2  
Pr o hi bite d 
c o nc o mita nt 
treat me nts 
( me dicati o ns a n d 
t hera pies) 
T he last se nte nce  bel o w t he list of 
treat me nts n ot all o we d d uri n g t he 5 0 da ys 
bef ore Da T -S P E C T i ma gi n g wa s re m o ve d: 
If a pr ot oc ol de viati o n is t o occ ur, a 
Was h o ut Peri o d of 5 0 h o urs ( or 5 half
li ves) m ust be c o m plete d pri or t o 
perf or mi n g t he Da T S P E C T meas ure me nt.  
T o re m o ve re d u n da nc y.  
 
 
 
 
 
 
Secti o n  6. 9  Di gital 
Healt h Tec h n ol o g y  
T he title of t he last s u bsecti o n ‘ E n d of 
st u d y’ was c ha n ge d t o ‘ E n d of Di gital 
Healt h Tec h n ol o g y use.’  
T o reflect t hat e n d of Di gital 
Healt h Tec h n ol o g y use at M 1 8 
is n o l o n ger at t he e n d of t he 
st u d y. 
Secti o n  8. 1. 1. 1  Da T -
S P E C T  
I n t he sec o n d para gra p h, t he n u m ber of 
i njecti o ns, ma xi m u m t otal effecti ve d ose, 
a n d ris k le vel (I C R 6 2) were u p date d.  
T o reflect t he a d diti o nal Da T -
S P E C T at M o nt h 6 0.  
Secti o n  8. 1. 3  I n-st u d y 
patie nt i nter vie ws ( U S 
a n d U K o nl y) 
Ne w secti o n was a d de d t o descri be t he 
o pti o nal i n-st u d y patie nt i nter vie ws 
(a p plica ble t o U S a n d U K sites o nl y ). 
T he s u bse q ue nt secti o n was re n u m bere d t o 
8. 1. 4 K o ne ksa Ne ur oscie n ce T o ol kit. 
T o i m ple me nt a c ha n ge fr o m 
l ocal pr ot oc ol a me n d me nts 3. 2 
( U K) a n d 3. 3 ( U S) date d 
J u n 2 0 2 4 i n t he gl o bal pr ot oc ol 
a me n d me nt 4. 
Secti o n  8. 3. 8  Safet y 
re p orti n g f or i n-st u d y 
patie nt i nter vie ws ( U S 
a n d U K o nl y) 
Ne w secti o n was a d de d t o clarif y t he safet y 
re p orti n g f or e ve nts re p orte d d uri n g i n-
st u d y patie nt i nter vie ws (a p plica ble t o U S 
a n d U K sites o nl y). 
T o i m ple me nt a c ha n ge fr o m 
l ocal pr ot oc ol a me n d me nts 3. 2 
( U K) a n d 3. 3 ( U S) date d 
J u n 2 0 2 4 i n t he gl o bal pr ot oc ol 
a me n d me nt 4. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  9. 2. 1  
Descri pti ve statistics 
a n d m o deli n g 
T he b ullets i n t he t hir d para gra p h were 
re vise d t o a d d t he a nal ysis at P D 0 0 5 5 
M o nt h  6 0.  
T he last se nte nce i n t he secti o n was re vise d 
t o n ote t hat a nal yses will be a dj uste d f or 
ge n der a n d a ge b ut n o l o n ger f or disease 
d urati o n, i n li ne wit h t he u p date d P D 0 0 5 3 
a nal ysis. 
T o reflect t he e xte nsi o n of t he 
st u d y t o M o nt h 6 0, clarif y t he 
pla n ne d c o m paris o ns,  a n d 
ali g n wit h u p dates t o t he 
P D 0 0 5 3 a nal ysis.  
Secti o n  9. 3  Pla n ne d 
efficac y/ o utc o me 
a nal yses 
T h r o u g h o ut t he secti o n, lists of a nal ysis 
ti me p oi nts w ere re place d b y “all a vaila ble 
ti me p oi nts” f or t he f oll o wi n g assess me nts: 
•  
Da T -S P E C T  
•  
W O Q -9  
•  
M o C A  
•  
F A TI G U E -P R O  
•  
M D S -N M S  
•  
M D S -U P D R S Parts I, II, III  s u bscales 
or selecte d ite ms  
•  
M D S -U P D R S Parts I -III s u m sc ore 
•  
Earl y P D F u ncti o n Sl o w ness a n d Earl y 
P D M o bilit y P R Os  
•  
C S F A S Y N  
•  
E Q -5 D -5 L  
T o si m plif y t he descri pti o n i n 
t he pr ot oc ol. 
 
Refere nces t o t he ‘ P D 0 0 5 5 E x pl orat or y 
A nal ysis Pla n’ were u p date d t o ‘ P D 0 0 5 5 
E x pl orat or y Effic ac y  A nal ysis Pla n’ 
t hr o u g h o ut. 
Mi n or clarificati o n.  
Secti o n  9. 3. 1. 1  Da T -
S P E C T  
Te xt u n der ‘ Mai n a nal ytical a p pr oac h’ was 
u p date d.  
T o a d d t he a nal ysis at P D 0 0 5 5 
M o nt h 6 0 a n d t o ali g n wit h 
u p dates t o t he P D 0 0 5 3 
a nal ysis. 
 
T he last se nte nce i n t he secti o n was re vise d 
(stri ket hr o u g h te xt re m o ve d; b ol d  te xt 
a d de d): 
A n y n oise t o si g nal i m pr o ve me nt 
e x pl orat or y i n vesti gati o ns b ase d o n 
a d v a nce d i m a ge a n al ysis met h o ds  will be 
detaile d i n a se parate P D 0 0 5 5 A nal ysis 
Pla n.  
T o clarif y t he pla n ne d 
e x pl orat or y a nal yses.  
Secti o n  9. 3. 2. 1  L E D D  
Ti me p oi nts of a nal ysis were u p date d 
t hr o u g h o ut. 
T o a d d t he a nal ysis at P D 0 0 5 5 
M o nt h 6 0.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  9. 3. 3. 2  M o C A  
Refere nces t o M o C A versi o ns were 
re m o ve d; t hese are pr o vi de d i n f o ot n ote ‘ k’ 
bel o w t he Sc he d ule of Acti vities.  
T o re d uce re d u n da nc y wit h 
ot her pr ot oc ol secti o ns.  
Sec ti o n 9. 3. 4. 2  Use of 
e xter nal real -w orl d 
data  
Secti o n was re vise d t o u p date t he 
descri pti o n of t he e xter nal, real -w orl d 
c o m parat or ar m. 
T o clarif y t h e use of e xter nal 
real-w orl d data t o e val uate t he 
effecti ve ness of mi nzas ol mi n 
vers us S o C o n cli nical a n d 
Q o L o utc o mes.  
Secti o n  9. 4. 2  Ot her 
a nal yse s 
A se nte nce was a d de d t o descri be t he 
a nal yses relate d t o t he i n -st u d y patie nt 
i nter vie ws ( U S a n d U K o nl y). 
T o i m ple me nt a c ha n ge fr o m 
l ocal pr ot oc ol a me n d me nts 3. 2 
( U K) a n d 3. 3 ( U S) date d 
J u n 2 0 2 4 i n t he gl o bal pr ot oc ol 
a me n d me nt 4. Te xt fr o m t he 
l ocal a me n d me nts was re vise d 
f or clarit y. 
Secti o n  9. 7  Pla n ne d 
a nal ysis a n d data 
m o nit ori n g  
Secti o n was re vise d t o a d d t he P D 0 0 5 5 
M o nt h 6 0 a nal ysis a n d clarif y t hat 
a d diti o nal a nal yses ma y be c o n d ucte d.  
T o reflect t he e xte nsi o n of t he 
st u d y t o M o nt h 6 0 a n d t o 
clar if y t hat a d diti o nal a nal yses 
ma y be d o ne f or p u blicati o n 
p ur p oses a n d t o s u p p ort 
re g ulat or y i nteracti o ns. 
Secti o n  1 0. 1. 6  
Disse mi nati o n of 
cli nical s t u d y data 
Secti o n was re vise d t o u p date t he 
descri pti o n of res ults p osti n g o n p u blic 
re gistries. 
T o reflect c urre nt U C B 
sta n dar d f or res ults re p orti n g. 
Secti o n  1 0. 6  A p pe n di x 
6: Li ver safet y –  
s u g geste d acti o ns a n d 
f oll o w-u p assess me nts  
A b bre viati o ns a n d f o ot n otes bel o w 
Ta ble  1 0 -1 : P hase 2 li ver c he mistr y 
st o p pi n g criteria a n d f oll o w-u p assess me nts 
were a d de d bac k.  
C orrecti o n (te xt was 
u ni nte nti o nall y re m o ve d i n 
pr ot oc ol a me n d me nt 3)  
Secti o n  1 0. 9  A p pe n di x 
9: C o u ntr y -s pecific 
re q uire me nts 
Secti o n  1 0 . 9. 1 was a d de d t o pr o vi de a n 
o ver vie w of t he c ha n ges fr o m l ocal 
pr ot oc ol a me n d me nts 3. 2 ( U K)  a n d 3. 3 
( U S). 
T o s u m marize c o u ntr y -s pecific 
pr ot oc ol c ha n ges a p plica ble i n 
t he U K a n d U S. 
Secti o n  1 1  
R E F E R E N C E S  
Ne w refere nce cite d i n Secti o n  8. 1. 3  was 
a d de d. 
Mi n or a d mi nistrati ve c ha n ge.  
T hr o u g h o ut  
Mi n or e dit orial a n d d oc u me nt f or matti n g 
re visi o ns. 
Mi n or, t heref ore ha ve n ot bee n 
s u m marize d. 
 
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 9  of 1 3 3  
S E RI O U S A D V E R S E E V E N T R E P O R TI N G  
Seri o us a d verse e ve nt re p orti n g ( 2 4 h)  
F a x  
E ur o pe a n d Rest of t he W orl d: + 3 2 2 3 8 6 2 4 2 1  
U S a n d C a n a d a: + 1 8 0 0 8 8 0 6 9 4 9 or + 1 8 6 6 8 9 0 3 1 7 5  
E m ail  
Gl o b al:  D S _I C T @ uc b.c o m (f or i nter ve nti o nal cli nical st u dies)  
 
R E P O R TI N G O F A D V E R S E D E VI C E E F F E C T S ( S E RI O U S A N D 
N O N S E RI O U S) A N D D E VI C E D E FI CI E N CI E S  
Re p orti n g of a d verse de vice effects (seri o us a n d n o nseri o us) a n d de vice 
deficie ncies f or n o n‑ U C B de vices use d i n t h e st u d y ( 2 4 h) 
E m ail  
C o m plete pa per A d v erse E ve nt a n d De vice Defici e nc y F or m a n d 
e mail t o hel p @ k o ne ksa h ealt h.c o m.  
N ote: De vice d eficie ncies f or n o n -U C B de vices s h o ul d n ot be 
ca pt ure d i n t he electr o nic data c ollecti o n t o ol.  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0  of 1 3 3  
T A B L E O F C O N T E N T S  
1  
P R O T O C O L S U M M A R Y  ............................................................................................... 1 6  
1. 1  
S y n o psis  ....................................................................................................................... 1 6  
1. 2  
Sc he ma  ......................................................................................................................... 2 1  
1. 3  
Sc he d ule of A cti vities  .................................................................................................. 2 3  
2  
I N T R O D U C TI O N ........................................................................................................... 2 9  
2. 1  
St u d y rati o nale  ............................................................................................................. 2 9  
2. 2  
Bac k gr o u n d  .................................................................................................................. 2 9  
2. 3  
Be nefit/ri s k assess me nt ................................................................................................ 3 0  
2. 3. 1  
C or o na vir us Disease -2 0 1 9 be nefit/ris k assess me nt  ............................................. 3 1  
2. 3. 1. 1  
C O VI D -1 9 ris k miti gati o n meas ures  ......................................................... 3 2  
2. 3. 1. 2  
C O VI D -1 9 be n efit/ris k c o ncl usi o n  ........................................................... 3 2  
2. 3. 2  
Di gital Healt h Tec h n ol o g y be nefit/ris k assess me nt  ............................................ 3 3  
3  
O BJ E C TI V E S A N D E N D P OI N T S  ................................................................................. 3 5  
4  
S T U D Y D E SI G N  ............................................................................................................. 3 7  
4. 1  
O verall desi g n  .............................................................................................................. 3 7  
4. 2  
Scie ntific rati o nale f or st u d y desi g n  ............................................................................ 3 9  
4. 2. 1  
Patie nt i n p ut i nt o desi g n  ...................................................................................... 3 9  
4. 3  
J ustificati o n f or d ose .................................................................................................... 4 0  
4. 4  
E n d of st u d y defi niti o n ................................................................................................. 4 0  
5  
S T U D Y P O P U L A TI O N  .................................................................................................. 4 0  
5. 1  
I n cl usi o n criteria .......................................................................................................... 4 0  
5. 2  
E xcl usi o n criteria  ......................................................................................................... 4 1  
5. 3  
Lifest yle restricti o ns ..................................................................................................... 4 2  
5. 3. 1  
Meals a n d diet ar y restricti o ns  .............................................................................. 4 2  
5. 3. 2  
Caffei ne, alc o h ol, a n d t o bacc o  ............................................................................. 4 2  
5. 3. 3  
Acti vit y  ................................................................................................................ 4 2  
5. 4  
Scree n fai l ures .............................................................................................................. 4 2  
6  
S T U D Y T R E A T M E N T S/I N V E S TI G A TI O N A L D E VI C E  ............................................ 4 2  
6. 1  
Treat me nts a d mi nistere d  .............................................................................................. 4 3  
6. 2  
Pre parati o n, ha n dli n g, st ora ge, a n d acc o u nta bilit y re q uire me nts  ................................ 4 3  
6. 2. 1  
Dr u g acc o u nta bilit y  ............................................................................................. 4 4  
6. 3  
Meas ures t o mi ni mize bi as: ra n d o mizati o n a n d bli n di n g  ............................................ 4 4  
6. 3. 1  
Pr oce d ures f or mai ntai ni n g a n d brea ki n g t he treat me nt bli n d  ............................. 4 5  
6. 3. 1. 1  
Mai nte na nce of st u d y treat me nt bli n d  ....................................................... 4 5  
6. 3. 1. 2  
Brea ki n g t he d ose bli n d i n a n e mer g e nc y si t uati o n ................................... 4 5  
6. 4  
Treat me nt c o m plia nce  .................................................................................................. 4 5  
6. 5  
C o nc o mita nt me dicati o n(s)/treat me nt(s)  ..................................................................... 4 6  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1  of 1 3 3  
6. 5. 1  
Per mitte d c o nc o mita nt treat me nts ( me dicati o ns a n d t hera pies)  .......................... 4 6  
6. 5. 1. 1  
Per mitte d (a u xiliar y) treat me nts f or perf or mi n g meas ure m e nts  ............... 4 6  
6. 5. 1. 2  
Per mitte d C o r o na vir us Disease-2 0 1 9 v acci nati o n ..................................... 4 6  
6. 5. 2  
Pr o hi bite d c o nc o mita nt treat me nts ( me dicati o ns a n d t hera pies)  ......................... 4 6  
6. 5. 3  
C o nc o mita nt S T  ................................................................................................... 4 7  
6. 6  
D ose m o dificati o n  ........................................................................................................ 4 7  
6. 7  
Criteria f or st u d y h ol d or d osi n g st o p pa ge  ................................................................... 4 7  
6. 8  
Treat me nt after t he e n d of t he st u d y  ............................................................................ 4 8  
6. 9  
Di gital Healt h Tec h n ol o g y  ........................................................................................... 4 8  
7  
DI S C O N TI N U A TI O N O F S T U D Y M E DI C A 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/ WI T H D R A W A L  ........................................................................ 5 0  
7. 1  
Disc o nti n uati o n of st u d y me dicati o n  ........................................................................... 5 0  
7. 1. 1  
H y perse nsiti vit y reacti o ns (s uc h as ras h, a n gi oe de ma, or a na p h yla xis)  .............. 5 0  
7. 1. 2  
Li ver c he mistr y st o p pi n g criteria  ......................................................................... 5 0  
7. 1. 3  
Q T c orrecte d st o p pi n g criteria  ............................................................................. 5 1  
7. 1. 4  
Te m p orar y disc o nti n uati o n  .................................................................................. 5 2  
7. 1. 5  
Rec halle n ge  .......................................................................................................... 5 2  
7. 2  
Partic i pa nt disc o nti n uati o n/ wit h dra wal fr o m t he st u d y ............................................... 5 2  
7. 3  
L ost t o f oll o w u p  .......................................................................................................... 5 3  
7. 4  
Disc o nti n uati o n  of Di gital Healt h Tec h n ol o g y  ............................................................ 5 4  
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  ........................................................... 5 4  
8. 1  
Efficac y assess me nts  .................................................................................................... 5 5  
8. 1. 1  
Cli nical assess me nts  ............................................................................................ 5 5  
8. 1. 1. 1  
Da T -S P E C T  ............................................................................................... 5 5  
8. 1. 1. 2  
L E D D  ........................................................................................................ 5 5  
8. 1. 1. 3  
N o n m ot or s y m pt o ms  ................................................................................. 5 6  
8. 1. 1. 4  
M ot or s y m pt o ms, acti vities of dail y li vi n g & Q o L  ................................... 5 6  
8. 1. 1. 5  
M o difie d H oe h n a n d Ya hr sta gi n g  ............................................................ 5 7  
8. 1. 1. 6  
M o ntreal C o g niti ve Assess me nt  ................................................................ 5 7  
8. 1. 2  
Patie nt -re p orte d o utc o m es ................................................................................... 5 8  
8. 1. 2. 1  
Earl y P D F u ncti o n Sl o w ness P R O  ............................................................ 5 8  
8. 1. 2. 2  
Earl y P D M o bilit y P R O  ............................................................................ 5 8  
8. 1. 2. 3  
F A TI G U E -P R O  ......................................................................................... 5 9  
8. 1. 2. 4  
W O Q -9  ...................................................................................................... 5 9  
8. 1. 2. 5  
E Q -5 D -5 L  .................................................................................................. 5 9  
8. 1. 3  
I n-st u d y patie nt i nter vie ws ( U S a n d U K o nl y) .................................................... 6 0  
8. 1. 4  
K o ne ksa N e ur oscie n ce T o ol kit  ............................................................................ 6 0  
8. 2  
Safet y assess me nts  ....................................................................................................... 6 2  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2  of 1 3 3  
8. 2. 1  
P h ysical e xa mi nati o n  ........................................................................................... 6 2  
8. 2. 2  
Ne ur ol o gical e x a mi nati o n  .................................................................................... 6 2  
8. 2. 3  
Vital si g ns  ............................................................................................................ 6 2  
8. 2. 4  
E C Gs  .................................................................................................................... 6 3  
8. 2. 5  
Cli nical safet y la b orat or y assess me nts  ................................................................ 6 3  
8. 2. 6  
S uici dal ris k m o nit ori n g  ...................................................................................... 6 3  
8. 3  
A d verse e ve nts a n d seri o us a d verse e ve nts  ................................................................. 6 4  
8. 3. 1  
Ti me peri o d a n d fre q ue n c y f or c ollecti n g A E a n d S A E i nf or mati o n  .................. 6 4  
8. 3. 2  
Met h o d of detecti n g A Es a n d S A Es  .................................................................... 6 5  
8. 3. 3  
F oll o w -u p of A Es a n d S A Es  ................................................................................ 6 5  
8. 3. 4  
Re g ulat or y re p orti n g r e q uire me nts f or S A Es  ...................................................... 6 5  
8. 3. 5  
Pre g na nc y  ............................................................................................................ 6 6  
8. 3. 6  
A E SI  .................................................................................................................... 6 6  
8. 3. 6. 1  
H y perse nsiti vit y reacti o n m o nit ori n g a n d ma na ge me nt  ............................ 6 6  
8. 3. 6. 2  
Re nal f u ncti o n safet y m o nit ori n g a n d ma na ge me nt  .................................. 6 9  
8. 3. 7  
Di gital Healt h Tec h n ol o g y safet y re p orti n g  ........................................................ 7 0  
8. 3. 7. 1  
Ti me peri o d f or safet y r e p orti n g  ............................................................... 7 0  
8. 3. 7. 2  
F oll o w -u p of A Es, A D Es, a n d de vice d eficie ncies  ................................... 7 1  
8. 3. 7. 3  
Re p orti n g of A Es, A D Es, a n d de vice d eficie ncies  .................................... 7 1  
8. 3. 8  
Safet y re p orti n g f or i n -st u d y patie nt i nter vie ws ( U S a n d U K o nl y)  .................... 7 1  
8. 4  
Safet y si g nal detecti o n  ................................................................................................. 7 1  
8. 5  
Treat me nt of o v er d ose  ................................................................................................. 7 2  
8. 6  
P har mac o ki netics  ......................................................................................................... 7 2  
8. 7  
Ge ne tics........................................................................................................................ 7 2  
8. 8  
P har mac o d y na mics  ...................................................................................................... 7 2  
8. 9  
Bi o mar kers  ................................................................................................................... 7 2  
8. 1 0  
U ni versit y of Pe n ns yl va nia S mell I de ntificati o n Test  ................................................. 7 3  
8. 1 1  
Me dical res o urce utilizati o n a n d healt h ec o n o mics  ..................................................... 7 3  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  ............................................................................. 7 4  
9. 1  
Defi niti o n of a nal ysis sets  ............................................................................................ 7 4  
9. 2  
Ge neral statistical c o nsi derati o ns  ................................................................................. 7 4  
9. 2. 1  
Descri pti ve statistics a n d m o deli n g  ..................................................................... 7 4  
9. 2. 2  
Ha n dli n g of i nterc urre nt e ve nts, pr ot oc ol de viati o ns, a n d res ulti n g missi n g data 7 5  
9. 2. 2. 1  
I C Es p ote ntiall y affecti n g t he i nter pretati o n of meas ure me nts ................. 7 7  
9. 2. 2. 2  
I C Es p ote ntiall y affecti n g t he e xiste nce of meas ure me nts ........................ 7 7  
9. 2. 2. 3  
Pr ot oc ol de viati o ns  .................................................................................... 7 8  
9. 2. 2. 4  
C o nfir me d or s us pecte d C O VI D -1 9 a n d C O VI D -1 9 vacci nati o n  ............. 7 8  
9. 3  
Pla n ne d effic ac y/ o utc o m e a nal yses  ............................................................................. 7 9  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 3  of 1 3 3  
9. 3. 1  
Pri mar y effic ac y o bje cti ve (a n d e x pl orat or y efficac y o bjecti ve III): pri mar y 
effic ac y esti ma n d  ................................................................................................. 7 9  
9. 3. 1. 1  
Da T -S P E C T  ............................................................................................... 7 9  
9. 3. 2  
Sec o n dar y effic ac y o bje cti ve a n d e x pl orat or y effi cac y o bjecti ves I (III): 
Sec o n dar y esti ma n d  ............................................................................................. 8 2  
9. 3. 2. 1  
L E D D  ........................................................................................................ 8 2  
9. 3. 3  
Sec o n dar y effic ac y o bje cti ve a n d e x pl orat or y effi cac y o bjecti ve I (III): 
E x pl orat or y esti ma n ds/e n d p oi nts  ......................................................................... 8 2  
9. 3. 3. 1  
W O Q -9  ...................................................................................................... 8 2  
9. 3. 3. 2  
M o C A  ........................................................................................................ 8 3  
9. 3. 3. 3  
F A TI G U E -P R O  ......................................................................................... 8 3  
9. 3. 3. 4  
N o n m ot or s y m pt o ms  ................................................................................. 8 4  
9. 3. 3. 5  
M ot or s y m pt o ms, acti vities of dail y li vi n g, a n d Q O L  .............................. 8 4  
9. 3. 3. 6  
Di gital Healt h Tec h n ol o g y  ........................................................................ 8 7  
9. 3. 4  
E x pl orat or y O bjecti ve II  ...................................................................................... 8 7  
9. 3. 4. 1  
E Q -5 D -5 L  .................................................................................................. 8 7  
9. 3. 4. 2  
Use of e xter nal r eal -w orl d data  ................................................................. 8 7  
9. 3. 5  
E x pl orat or y O bjecti ve I V: At y pical Par ki ns o nis m  .............................................. 8 8  
9. 3. 5. 1  
Descri pti ve statistics a n d vis ualizati o n  ...................................................... 8 8  
9. 3. 5. 2  
P D 0 0 5 3/ P D 0 0 5 5 se nsiti vit y a nal yses  ........................................................ 8 8  
9. 4  
Pla n ne d safet y a n d ot h er a nal yses ................................................................................ 8 8  
9. 4. 1  
Safet y a nal yses  ..................................................................................................... 8 8  
9. 4. 2  
Ot her a nal ys es  ...................................................................................................... 8 8  
9. 5  
Ha n dli n g of pr ot oc ol de viati o ns ................................................................................... 8 8  
9. 6  
Ha n dli n g of dr o p o uts or missi n g data  .......................................................................... 8 8  
9. 7  
Pla n ne d a nal ysis a n d dat a m o nit ori n g .......................................................................... 8 8  
9. 8  
Deter mi nati o n of sa m ple size  ....................................................................................... 8 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 ... 9 0  
1 0. 1  
A p pe n di x 1: Re g ulat or y, et hical, a n d st u d y o versi g ht c o nsi derati o ns  ......................... 9 0  
1 0. 1. 1  
Re g ulat or y a n d et hical c o nsi derati o ns  ................................................................. 9 0  
1 0. 1. 2  
Fi na ncial discl os ur e  ............................................................................................. 9 0  
1 0. 1. 3  
I nf or me d c o ns e nt pr ocess .................................................................................... 9 1  
1 0. 1. 4  
Data pr ote cti o n  ..................................................................................................... 9 1  
1 0. 1. 5  
C o m mittees str uct ures  ......................................................................................... 9 2  
1 0. 1. 6  
Disse mi nati o n of cli nical st u d y data  .................................................................... 9 2  
1 0. 1. 7  
Data q ualit y ass ura n ce  ......................................................................................... 9 2  
1 0. 1. 7. 1  
e C R F c o m pleti o n  ....................................................................................... 9 3  
1 0. 1 . 7. 2 
A p ps  ........................................................................................................... 9 3  
1 0. 1. 8  
S o urce d oc u me nts  ................................................................................................ 9 3  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 4  of 1 3 3  
1 0. 1. 9  
St u d y a n d site start a n d cl os ure  ........................................................................... 9 4  
1 0. 1. 1 0  P u blicati o n p olic y  ................................................................................................ 9 4  
1 0. 2  
A p pe n di x 2: Cli nical la b orat or y tests  .......................................................................... 9 5  
1 0. 3  
A p pe n di x 3: A d verse e ve nts –  Defi niti o ns a n d pr oce d ures f or rec or di n g, e v al uati n g, 
f oll o w-u p, a n d re p orti n g  .............................................................................................. 9 7  
1 0. 4  
A p pe n di x 4: C o ntrace pti ve g ui da nce a n d c ollecti o n of pre g na n c y i nf or mati o n  ....... 1 0 3  
1 0. 5  
A p pe n di x 5: Ge netics  ................................................................................................. 1 0 6  
1 0. 6  
A p pe n di x 6: Li ver safet y –  s u g geste d acti o ns a n d f oll o w-u p assess me nts  ............... 1 0 7  
1 0. 7  
A p pe n di x 7: Di gital Healt h Tec h n ol o g y A Es, S A Es, A D Es, S A D Es, a n d de vice 
deficie nci es: Defi niti o n 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 ..................................................................................................................... 1 1 0  
1 0. 7. 1  
Safet y re p orti n g f o r t he K o ne ksa m o bile s oft ware a p plicati o n a n d A p ple i P h o ne1 1 0  
1 0. 7. 1. 1  
A d verse e ve nts of t he K o ne ksa m o bile s oft ware a p plicati o n  a n d A p ple 
i P h o ne ...................................................................................................... 1 1 0  
1 0. 7. 1. 2  
Deficie n cies of t he K o n e ksa m o bile s oft ware a p plicati o n a n d A p ple 
i P h o ne ...................................................................................................... 1 1 0  
1 0. 7. 2  
Safet y re p orti n g f or t he Acti Gra p h C PI W a n d t he Data H u b  ............................ 1 1 0  
1 0. 7. 2. 1  
Defi niti o n of A D E  ................................................................................... 1 1 1  
1 0. 7. 2. 2  
Defi niti o n of S A D E a n d U S A D E  ............................................................ 1 1 1  
1 0. 7. 2. 3  
Defi niti o n of de vice d efi cie nc y  ............................................................... 1 1 1  
1 0. 7. 2. 4  
Rec or di n g a n d f oll o w -u p of A D E/ S A D E/ de vice d eficie nc y ................... 1 1 1  
1 0. 7. 2. 5  
Re p orti n g of A D E/ S A D E/ de vice deficie nc y  ........................................... 1 1 3  
1 0. 8  
A p pe n di x 8: Ra pi d alert pr oce d ures  .......................................................................... 1 1 4  
1 0. 9  
A p pe n di x 9: C o u ntr y -s pecific re q uir e me nts .............................................................. 1 1 5  
1 0. 9. 1  
C o u ntr y -s pecific re q uire me nts f or U S a n d U K ................................................. 1 1 5  
1 0. 1 0  A p pe n di x 1 0: A b bre viati o ns a n d tra de mar ks  ............................................................ 1 1 6  
1 0. 1 1  A p pe n di x 1 1: Pr ot oc ol a me n d me nt hist or y  ............................................................... 1 1 9  
1 0. 1 1. 1  A me n d me nt 3 ( 1 8 Se p 2 0 2 3)  ............................................................................. 1 1 9  
1 0. 1 1. 2  A me n d me nt 2 ( 3 0 J u n 2 0 2 3)  ............................................................................. 1 2 7  
1 0. 1 1. 3  A me n d me nt 1 ( 0 7 N o v 2 0 2 2)  ............................................................................ 1 2 8  
1 1  R E F E R E N C E S  .............................................................................................................. 1 3 1  
S P O N S O R D E C L A R A TI O N  ................................................................................................ 1 3 3  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 5  of 1 3 3  
LI S T O F T A B L E S  
Ta ble  2 ‒ 1:  
P ote ntial ris ks a n d miti gati o n strate gies f or K o ne ksa Ne ur oscie nce 
T o ol kit  .............................................................................................................. 3 3  
Ta ble  8 ‒ 1:  
Acti vities t o be perf or m e d wit h t he K o ne ksa Ne ur oscie nce T o ol kit  ............... 6 1  
Ta ble  9 -1:  
O ver vie w of ha n dli n g strate gies f or I C Es a n d a p pr oac h i n cas e of st u d y 
ter mi nati o n ....................................................................................................... 7 6  
Ta ble  1 0 -1:  
P hase 2 li ver c he mistr y st o p pi n g criteria a n d f oll o w -u p assess me nts  ........... 1 0 7  
 
LI S T O F FI G U R E S  
Fi g ure  1 -1:  
St u d y o ver vie w  ................................................................................................ 2 1  
Fi g ure  1 -2:  
Dela ye d -st art ar m d esi g n ................................................................................. 2 1  
Fi g ure  1 -3:  
L o w -d ose ar m desi g n  ....................................................................................... 2 2  
Fi g ure  1 -4:  
E xter nal real -w orl d d ata  ................................................................................... 2 2  
Fi g ure  7 -1:  
P hase 2 li ver c he mistr y st o p pi n g criteria a n d i ncrease d m o nit ori n g 
al g orit h m  .......................................................................................................... 5 1  
Fi g ure  9 -1:  
Dela ye d -st art desi g n (first 1 8 m o nt hs) ............................................................. 8 1  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 6  of 1 3 3  
1  
P R O T O C O L S U M M A R Y  
1. 1  
S y n o p si s  
Pr ot oc ol titl e:  
A d ose -bli n de d e xte nsi o n st u d y t o e val uate t he l o n g -ter m efficac y, safet y, a n d t olera bilit y of 
mi nzas ol mi n ( U C B 0 5 9 9) i n st u d y partici pa nts wit h Par ki ns o n’s disease  
S h ort title:  
A n e xte nsi o n st u d y t o e val uate t he l o n g -ter m efficac y a n d safet y of mi nzas ol mi n ( U C B 0 5 9 9) i n 
st u d y partici pa nts wit h Par ki ns o n’s disease 
R ati o n ale : 
Mi nzas ol mi n ( U C B 0 5 9 9) is a n orall y a vaila bl e i n hi bit or of al p ha -s y n uclei n ( A S Y N) misf ol di n g 
a n d d o w nstrea m a g gre g ati o n. A g gre gate d f or ms of A S Y N are t he hall mar k fi brillar pr otei n 
de p osits i n Par ki ns o n’s disease ( P D) a n d ot her s y n uclei n o pat hies, a n d e vi d e nce s u g gests t hat it is 
t he misf ol de d f or ms of A S Y N t hat pr o pa gate t hr o u g h t he ce ntral n er v o us s yste m ( C N S) d uri n g 
disease pr o gressi o n. T hese acc u m ulati o ns of A S Y N c o ntai ni n g ne ur o nal i n cl usi o ns f or m 
Le w y  b o dies a n d L e w y n e urites.  
A first -i n-h u ma n st u d y, U P 0 0 3 0, usi n g mi nzas ol mi n ( U C B 0 5 9 9), c o n d ucte d i n healt h y el derl y 
partici pa nts ( defi ne d as ≥5 5 t o ≤7 5 years of a g e), pr o vi de d t he safet y, t olera bilit y, a n d 
p har mac o ki netics ( P K) i nf or mati o n f or si n gle d os e e x p os ures u p t o 4 5 0 m g a n d m ulti ple d ose 
e x p os ures of 1 8 0 m g/ da y f or u p t o 2 1  da ys. T he first st u d y i n t he tar get p o p ulati o n, U P 0 0 7 7, 
pr o vi de d safet y, t olera bilit y, a n d P K i nf or mati o n f or m ulti ple d ose e x p os ures of 1 8 0 m g/ da y a n d 
3 6 0 m g/ da y f or 2 8 da ys i n st u d y partici pa nts wit h P D. A n o n g oi n g d o u ble -bli n d, p lace b o-
c o ntr olle d, ra n d o mize d, P hase 2a st u d y, P D 0 0 5 3, i n partici pa nts wit h earl y-sta ge P D, is desi g ne d 
t o pr o vi de pr o of-of -c o n ce pt f or t he efficac y of t he A S Y N misf ol di n g i n hi bit or 
mi nzas ol mi n  ( U C B 0 5 9 9) at d oses of 1 8 0 m g/ da y or 3 6 0 m g/ da y i n sl o wi n g disease pr o gressi o n 
a n d t o i nstr uct later sta ge de vel o p me nt.  
P D 0 0 5 5, a d ose -bli n de d e xte nsi o n st u d y of P D 0 0 5 3, is desi g ne d t o pr o vi de f urt her e vi de nce a n d 
u n dersta n di n g of t he effi cac y, safet y, a n d t olera bilit y of mi nzas ol mi n ( U C B 0 5 9 9) i n sl o wi n g t he 
pr o gressi o n  of P D st u d y partici pa nts w h o ha v e c o m plete d 1 8  m o nt hs of treat me nt i n P D 0 0 5 3.  
O bjecti ves a n d e n d p oi nts  
O bjecti ves  
E n d p oi nts  
Pri m ar y Effic ac y O bjecti ve  
T o esti mate t he p har mac o d y na mic effects of 
mi nzas ol mi n ( U C B 0 5 9 9) o n brai n 
pat h o p h ysi ol o g y i n Earl y -start vers us 
Dela ye d -st art partici pa nts ori gi nall y 
dia g n ose d wit h ne w o nset P D  
Pri m ar y Effic ac y E n d p oi nt  
•  Baseli ne a-a dj uste d Da T -S P E C T w h ole 
striat u m S B R at P D 0 0 5 5 M o nt h 1 8 a n d 
M o nt h 6 0  
E x pl or at or y Effic ac y E n d p oi nts  
•  Da T -S P E C T striatal s u b -re gi o ns S B R 
•  C S F t otal A S Y N  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 7  of 1 3 3  
O bjecti ves  
E n d p oi nts  
•  C S F A S Y N oli g o mers/see di n g ca pacit y  
Sec o n d ar y Effic ac y O bjecti ve  
T o esti mate t he p har mac o d y na mic effects of 
mi nzas ol mi n ( U C B 0 5 9 9) o n t he nee d f or S T 
i n Earl y-start vers us Dela ye d-start 
partici pa nts ori gi nall y dia g n ose d wit h ne w 
o nset P D  
Sec o n d ar y Effic ac y E n d p oi nt  
•  C u m ulati ve L E D D at P D 0 0 5 5 M o nt h 1 8 
a n d M o nt h 6 0  
E x pl or at or y Effic ac y E n d p oi nts  
•  W O Q -9  
Sec o n d ar y S afet y O bjecti ve  
T o assess t he safet y a n d t olera bilit y of 
mi nzas ol mi n ( U C B 0 5 9 9) i n partici pa nts 
ori gi nall y dia g n ose d wit h ne w o nset P D  
Sec o n d ar y S afet y E n d p oi nts  
•  I n ci de nce of T E A Es 
•  I n ci de nce of S A Es 
•  I n ci de nce of T E A Es l ea di n g t o 
wit h dra wal fr o m st u d y  
E x pl or at or y O bjecti ves  
I. Met h o d ol o g y: T o i de ntif y cli nical 
e n d p oi nts a ble t o detect t he 
p har mac o d y n a mic effects of 
mi nzas ol mi n ( U C B 0 5 9 9) o n t he cli nical 
c o urse of P D after i nitiati o n of S T i n 
Earl y -start vers us Dela y e d-start 
partici pa nts ori gi nall y dia g n ose d wit h 
ne w o nset P D  
E x pl or at or y E n d p oi nts ( Cli nic al 
O utc o mes)  
•  M o C A  
•  M D S -N M S ( or selecte d ite ms)  
•  M D S -U P D R S Parts I -III s u m sc ore 
•  M D S -U P D R S Part I s u bs cale ( or select e d 
ite ms) 
•  M D S -U P D R S Part II s u bscale ( or select e d 
ite ms a n d e mer gi n g s y m pt o ms)  
•  M D S -U P D R S Part III s u bsc ale ( or 
selecte d ite ms/s u bsc ore)  
•  M o difie d H & Y  
•  F A TI G U E -P R O  
•  Earl y P D F u ncti o n Sl o w ness P R O  
•  Earl y P D M o bilit y P R O  
E x pl or at or y E n d p oi nts ( Ot her)  
•  K o ne ksa Ne ur oscie nce T o ol kit  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 8  of 1 3 3  
O bjecti ves  
E n d p oi nts  
II. Effecti ve n ess: T o esti mate t he 
effecti ve ness of mi nzas ol mi n ( U C B 0 5 9 9) 
vers us S o C o n cli nical o utc o mes a n d Q o L 
be y o n d 1 8 m o nt hs d urati o n of P D 0 0 5 3, 
usi n g e xter nal real -w orl d data ( w here 
a vaila ble)  
E x pl or at or y E n d p oi nts ( Cli nic al 
O utc o mes)  
•  E Q -5 D -5 L  
•  L E D D  
•  M o C A  
•  M D S -U P D R S Parts I -III s u m sc ore 
•  M D S -U P D R S Part I V  
•  M D S -U P D R S Part I s u bs cale ( or select e d 
ite ms) 
•  M D S -U P D R S Part II s u bscale ( or select e d 
ite ms a n d e mer gi n g s y m pt o ms) 
•  M D S -U P D R S Part III s u bscale ( or 
selecte d ite ms/s u bsc ore) 
•  M o difie d H & Y  
III. Efficac y: T o esti mate t he 
p har mac o d y n a mic effects of E arl y-start 
mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g vers us 
E arl y-start mi nzas ol mi n ( U C B 0 5 9 9) 
1 8 0 m g o n t he cli nical c o urse of P D, nee d 
f or S T a n d brai n p at h o p h ysi ol o g y i n 
partici pa nts ori gi nall y dia g n ose d wit h ne w 
o n set P D 
E x pl or at or y E n d p oi nts ( Cli nic al 
O utc o mes)  
•  L E D D  
•  W O Q -9  
•  M o C A  
•  M D S -N M S ( or selecte d ite ms)  
•  M D S -U P D R S Parts I -III s u m sc ore 
•  M D S -U P D R S Part I s u bs cale ( or select e d 
ite ms) 
•  M D S -U P D R S Part II s u bscale ( or select e d 
ite ms a n d e mer gi n g s y m pt o ms) 
•  M D S -U P D R S Part I II s u bscale ( or 
selecte d ite ms/s u bsc ore)  
•  M o difie d H & Y  
•  F A TI G U E -P R O  
•  Earl y P D F u ncti o n Sl o w ness P R O  
•  Earl y P D M o bilit y P R O  
E x pl or at or y E n d p oi nts ( Bi o m ar kers)  
•  Da T -S P E C T w h ole striat u m S B R (a n d 
striatal s u b-re gi o ns S B R) 
•  C S F t otal A S Y N  
•  C S F A S Y N oli g o mers/see di n g  ca pacit y  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 9  of 1 3 3  
O bjecti ves  
E n d p oi nts  
I V. At y pical Par ki ns o nis m: Re visi o n of P D 
cli nical dia g n osis; i de ntificati o n of 
partici pa nts wit h At y pical Par ki ns o nia n 
Dis or ders  b at P D 0 0 5 5 Baseli ne Visit a n d 
at P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 6 0  
E x pl or at or y Assess m e nts  
•  Re -c o nfir me d P D dia g n osis stat us  
A S Y N =al p ha -s y n uclei n; C S F =cere br os pi nal fl ui d; Da T-S P E C T = D o pa mi ne Tra ns p orter I ma gi n g wit h Si n gle 
P h ot o n E missi o n C o m p ute d T o m o gra p h y; E Q -5 D -5 L = E ur o Q ualit y of life 5 -Di me nsi o ns 5 -Le vel; 
H & Y = H oe h n a n d Ya hr; L E D D = Le v o d o pa E q ui vale nt Dail y D ose; M D S -N M S = M o ve me nt Dis or der S ociet y 
N o n -M ot or Rati n g Scale; M D S -U P D R S = M o ve me nt Dis or der S ociet y U nifie d Par ki ns o n's Disease Rati n g 
Scale; M o C A = M o ntre al C o g niti ve Assess me nt; P R O = patie nt -re p orte d o utc o me; P D = Par ki ns o n’s disease; 
Q o L = Q ualit y of Life; S A E =seri o us a d verse e ve nt; S B R =s pe cific bi n di n g rati o; S o C =sta n dar d of care; 
S T =s y m pt o matic treat me nt; T E A E =treat me nt -e mer ge nt a d verse e ve nt; W O Q -9 = Weari n g -off Q uesti o n naire -9  
a Baseli ne will refer t o P D 0 0 5 3 Baseli ne Visit data ( or Scree ni n g Visit data w here a p plica ble).  
b M ost fre q ue nt At y pical Par ki ns o nia n Dis or ders are:  
•  
C ortic o basal d e g e n erati o n ( C B D): Ta u (al p ha -s y n) 
•  
De m e ntia wit h Le w y b o dies ( L B D): Al p h a-s y n de p ositi o n i n c ortical ne ur o ns 
•  
M ulti ple s yste m atr o p h y ( M S A): Al p ha -s y n de p ositi o n i n glial cells/ oli g o de n dr oc ytes 
•  
Pr o gressi ve s u pra n uclear pals y ( P S P): Ta u  
O ver all desi g n  
P D 0 0 5 5, a d ose -bli n de d, P hase 2, e xte nsi o n st u d y of P D 0 0 5 3, will e val uate t he l o n g -ter m 
effic ac y, safet y, a n d t olera bilit y of mi nzas ol mi n ( U C B 0 5 9 9) i n st u d y partici pa nts w h o were 
dia g n ose d wit h ne w o nset P D w he n e nteri n g P D 0 0 5 3, t he pr o of -of -c o n ce pt st u d y.  
T he pri mar y o bje cti ve of P D 0 0 5 5 is t o esti mate t he p har mac o d y na mic effects of mi nzas ol mi n 
( U C B 0 5 9 9) o n brai n pat h o p h ysi ol o g y i n Earl y-start vers us D ela ye d-start partici pa nts ori gi nall y 
dia g n ose d wit h ne w o nset P D. T he sec o n dar y efficac y o bjecti ve of t he e xte nsi o n st u d y is t o 
esti mate t he p har mac o d y na mic effects of mi nzas ol mi n ( U C B 0 5 9 9) o n t he nee d f or s y m pt o matic 
treat me nt ( S T) i n partici p a nts ori gi nall y dia g n ose d wit h ne w o nset P D, ta ki n g a d va nta ge of t he 
Earl y -start vers us Dela y e d-start ar ms desi g n. T he sec o n dar y safet y o bjecti ve of t he st u d y is t o 
assess t he safet y a n d t olera bilit y of mi nzas ol mi n ( U C B 0 5 9 9) i n partici pa nts ori gi nall y dia g n ose d 
wit h ne w o nset P D a n d will i ncl u de rec or di n g of i nci de nces of treat me nt -e mer ge nt a d verse 
e ve nts ( T E A Es), seri o us a d verse e ve nts ( S A Es), a n d T E A Es lea di n g t o wit h dra wal fr o m st u d y. 
T he e x pl orat or y o bj ecti v es of t he st u d y i ncl u de assess me nts of met h o d ol o g y (ie, i de ntificati o n of 
n o vel e n d p oi nts), effecti ve ness (stre n gt h e ni n g of t he patie nt val ue ste m mi n g fr o m i m pact o n  ke y 
m ot or o utc o mes), effi cac y (esti mati o n of p har mac o d y na mic effects of mi nzas ol mi n ( U C B 0 5 9 9) 
t hat ma y i nf or m a n y d ose-res p o nse m o deli n g), a n d i de ntificati o n of partici p a nts wit h At y pical 
Par ki ns o nis m t o perf or m se nsiti vit y a nal yses.  
A st u d y o ver vie w of P D 0 0 5 5 is pr o vi de d i n Fi g ure  1 -1 . T he st u d y will c o m prise 3 e m be d de d 
desi g ns. T he acti ve ar m will be c o nsi dere d t o be mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g. T w o 
c o m parat or ar ms will be use d t o pr o vi de f urt her i nsi g ht i nt o t he efficac y of mi nzas ol mi n 
( U C B 0 5 9 9): 
•  Dela ye d -st art ar m ( 3 6 0 m g) (Fi g ur e  1 -2 ) 
•  L o w -d ose ar m ( 1 8 0 m g) ( Fi g ure  1 -3 ) 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 0  of 1 3 3  
I n a d diti o n, e xter nal r eal -w orl d data ( w h ere a vaila ble) will be use d t o esti mate t he effecti ve ness 
of mi nzas ol mi n ( U C B 0 5 9 9) (select e d e n d p oi nts o nl y) vers us t he S o C be y o n d t he 1 8 m o nt hs 
d urati o n of t he fee der st u d y P D 0 0 5 3 ( Fi g ure  1 -4 ). 
T he pri mar y a n d s ec o n d ar y effic ac y o bjecti ves of t he st u d y will ma ke use of t he Dela ye d -start 
ar m. 
St u d y partici pa nts will be all o we d t o recei ve S T (ie, t he y will eit her c o nti n ue S T fr o m  P D 0 0 5 3 
or t he y will be free t o re q uest t he i nitiati o n of S T i n c olla b orati o n wit h t he st u d y p h ysicia n) a n d 
will recei ve i n vesti gati o n al me dici nal pr o d uct (I M P) f or u p t o 6 0 m o nt hs. Partici pa nts w h o ha v e 
bee n treate d wit h mi nzas ol mi n ( U C B 0 5 9 9) 1 8 0 m g/ da y d u ri n g P D 0 0 5 3 will c o nti n ue t o recei v e 
mi nzas ol mi n ( U C B 0 5 9 9) 1 8 0 m g/ da y i n e xte nsi o n st u d y P D 0 0 5 5. Partici pa nts w h o ha ve bee n 
treate d wit h mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y d uri n g P D 0 0 5 3 will c o nti n ue t o recei ve 
mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y i n P D 0 0 5 5. Partic i pa nts w h o recei ve d place b o d uri n g 
P D 0 0 5 3 will recei ve mi n zas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y i n P D 0 0 5 5.  
After c o m pleti n g, at t he mi ni m u m, t he M o nt h 1 8 Visit i n P D 0 0 5 5, partici pa nts will be s witc he d 
t o t he best d ose, as deter mi ne d fr o m t he res ults of P D 0 0 5 3. All st u d y partici pa nts a n d 
I n v esti gat ors will re mai n bli n de d t o treat me nt/ d ose recei ve d i n P D 0 0 5 3 a n d P D 0 0 5 5 at least u ntil 
all partici pa nts ha ve c o m plete d t he M o nt h 1 8 assess me nts i n P D 0 0 5 5. T hereafter, P D 0 0 5 5 will 
be o pe n la bel.  
T hr o u g h o ut t he st u d y, data w ill be re vie we d o n a n o n g oi n g basis b y a Data M o nit ori n g 
C o m mittee ( D M C) a n d a Safet y M o nit ori n g C o m mittee ( S M C).  
P D 0 0 5 5 ai ms t o pr o vi de f urt her e vi d e nce a n d u n d ersta n di n g of t he efficac y, safet y, a n d 
t olera bilit y of mi nzas ol mi n ( U C B 0 5 9 9) i n st u d y partici pa nts w h o c o m plete d 1 8 m o nt hs of 
treat me nt i n P D 0 0 5 3. 
N u m ber of p artici p a nts  
A t otal of 4 9 3 partici pa nts were d os e d i n P D 0 0 5 3. Of t he 4 3 1 partici p a nts w h o c o m plete d 
P D 0 0 5 3, 4 2 8 tra nsiti o ne d i nt o P D 0 0 5 5. Ass u mi n g t hat 1 5 % of P D 0 0 5 5 partici pa nts w h o were 
ra n do mize d t o place b o i n P D 0 0 5 3 dr o p o ut wit hi n t he first fe w m o nt hs of r olli n g o ver i nt o 
P D 0 0 5 5 d ue t o a d verse e ve nts ( A Es) u p o n i nitiati n g mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y (ie, 
ar o u n d 2 0  partici p a nts n ot c o m pleti n g t heir M o nt h 3 visit), a n d t hat a n ot her 5 % of  partici pa nts 
acr oss all treat me nt ar ms dr o p o ut or are l ost t o f oll o w u p i n a n y gi ve n year, ar o u n d 3 7 4 a n d 3 1 4 
partici pa nts w o ul d be e x pecte d t o reac h P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 6 0, res pecti vel y.  
Tre at me nt gr o u ps a n d d ur ati o n  
P D 0 0 5 5 i ncl u des a Scree ni n g Pe ri o d of u p t o 6 0 da ys ( o verla p pi n g wit h t he Treat me nt Peri o d of 
P D 0 0 5 3), f oll o we d b y a Treat me nt Peri o d of 6 0  m o nt hs a n d a Safet y F oll o w -u p ( S F U) Visit 
3 0  da ys after t h e last d ose.  
Partici pa nts will recei ve eit her mi nzas ol mi n ( U C B 0 5 9 9) 1 8 0 m g/ da y ( 9 0 m g t wic e dail y [ BI D]) or 
mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y ( 1 8 0 m g BI D) u ntil t he y reac h M o nt h 1 8. O nce t he best 
d ose is defi ne d bas e d o n res ults fr o m P D 0 0 5 3, all partici pa nts i n P D 0 0 5 5 will be tra nsiti o ne d t o 
t hat d ose as l o n g as t he y ha ve c o m plete d t h eir M o nt h 1 8 Visit.  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 1  of 1 3 3  
1. 2  
S c h e m a  
Fi g ur e  1 -1 : St u d y o v er vi e w  
 
B L = P D 0 0 5 5 Baseli ne Visit; D = d a y; E O T = E n d of Treat me nt; M = m o nt h; P D = Par ki ns o n’s disease; S F U = Safet y F oll o w -u p Visit; V = visit  
* St u d y partici pa nts will be s witc he d t o t he best d ose o nce t he d ose has bee n selecte d, b ut n ot bef ore t he y c o m plete d t he M 1 8  Visit.  
Fi g ur e  1 -2 : D el a y e d -st art ar m d e si g n  
 
B L = P D 0 0 5 5 Baseli ne Visit; D = d a y; E O T = E n d of Treat me nt; M = m o nt h; V = visit  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 2  of 1 3 3  
Fi g ur e  1 -3 : L o w -d o s e ar m d e si g n  
 
B L = P D 0 0 5 5 Baseli ne Visit; D = d a y; E O T = E n d of Treat me nt; M = m o nt h; V = visit  
N ote: Data of st u d y partici pa nts tra nsiti o ni n g fr o m t he place b o ar m t o t he 3 6 0 m g ar m will n ot be part of t he c o m paris o n of t he 3 6 0 m g a n d 1 8 0 m g treat me nt 
ar ms.  
Fi g ur e  1 -4 : E xt er n al r e al -w orl d d at a  
B L = P D 0 0 5 5 Baseli ne Visit; D = d a y; E O T = E n d of Treat me nt; M = m o nt h; P D = Par ki ns o n’s disease; V = visit  
* E xter nal real -w orl d data ( w here a v aila ble) will i ncl u de o bser vati o nal data f or t he sa me P D p o p ulati o n.  
N ote: Data of st u d y partici pa nts tra nsiti o ni n g fr o m t he place b o or 1 8 0 m g ar m t o t he 3 6 0 m g ar m will n ot be part of t he c o m pari s o n of t he 3 6 0 m g treat me nt ar m t o 
t he e xter nal refere nce ar m. 
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 3  of 1 3 3  
1. 3  
S c h e d ul e of A cti viti e s  
Pr oce d ure  
Scr  
Tre at me nt Peri o d  
 
V 1 a 
V 2 b  
V 3  
V 4  
V 4 a
m  
V 5  
V 5 a
m  
V 5 b
m  
V 6  
V 7  
V 8  
V 9  
V 1 0  
V 1 1  
V 1 2  
V 1 3  
V 1 4  
V 1 5/  
E O T/  
E T  
S F U  
 
B L  
P C  
M 1  
M 2  
M 3  
M 4  
M 5  
M 6  
M 1 2  
M 1 8  
M 2 4  
M 3 0  
M 3 6  
M 4 2  
M 4 8  
M 5 4  
M 6 0  
 
D a y  
-6 0 
t o 
D a y 
-1 0  
D a y  
0  
D a y  
1 0 
± 2 d  
D a y  
3 0 
± 5 d  
D a y  
6 0 
± 5 d  
D a y  
9 0 
± 5 d  
D a y  
1 2 0 
± 5 d  
D a y  
1 5 0 
± 5 d  
D a y  
1 8 0 
± 7 d  
D a y  
3 6 0 
± 1 4 d  
D a y  
5 4 0 
± 1 4 d  
D a y  
7 2 0 
± 1 4 d  
D a y  
9 0 0 
± 1 4 d  
D a y  
1 0 8 0 
± 1 4 d  
D a y  
1 2 6 0 
± 1 4 d  
D a y  
1 4 4 0 
± 1 4 d  
D a y  
1 6 2 0 
± 1 4 d  
D a y  
1 8 0 0  
± 1 4 d  
3 0 d 
after 
l ast 
d ose  
I nf or me d 
c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I nf or me d 
c o nse nt f or 
o pti o nal 
i n-st u d y 
patie nt 
i nter vie ws 
( U S a n d U K 
o nl y) s 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Verificati o n 
of i n cl usi o n/ 
e xcl usi o n 
criteria  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Wit h dra wal 
criteria c  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Vital si g ns d  
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Wei g ht  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical 
e xa mi n ati o n 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Ne ur ol o gical 
e xa mi n ati o n 
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse 
e ve nts e 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 4  of 1 3 3  
Pr oce d ure  
Scr  
Tre at me nt Peri o d  
 
V 1 a 
V 2 b  
V 3  
V 4  
V 4 a
m  
V 5  
V 5 a
m  
V 5 b
m  
V 6  
V 7  
V 8  
V 9  
V 1 0  
V 1 1  
V 1 2  
V 1 3  
V 1 4  
V 1 5/  
E O T/  
E T  
S F U  
 
B L  
P C  
M 1  
M 2  
M 3  
M 4  
M 5  
M 6  
M 1 2  
M 1 8  
M 2 4  
M 3 0  
M 3 6  
M 4 2  
M 4 8  
M 5 4  
M 6 0  
 
D a y  
-6 0 
t o 
D a y 
-1 0  
D a y  
0  
D a y  
1 0 
± 2 d  
D a y  
3 0 
± 5 d  
D a y  
6 0 
± 5 d  
D a y  
9 0 
± 5 d  
D a y  
1 2 0 
± 5 d  
D a y  
1 5 0 
± 5 d  
D a y  
1 8 0 
± 7 d  
D a y  
3 6 0 
± 1 4 d  
D a y  
5 4 0 
± 1 4 d  
D a y  
7 2 0 
± 1 4 d  
D a y  
9 0 0 
± 1 4 d  
D a y  
1 0 8 0 
± 1 4 d  
D a y  
1 2 6 0 
± 1 4 d  
D a y  
1 4 4 0 
± 1 4 d  
D a y  
1 6 2 0 
± 1 4 d  
D a y  
1 8 0 0  
± 1 4 d  
3 0 d 
after 
l ast 
d ose  
K o ne ksa 
Ne ur oscie nce 
T o ol kit safet y  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
C -S S R S  
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o nc o mita nt 
me dicati o n  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Bl o o d 
sa m pli n g f or 
c he mistr y, 
he mat ol o g y, 
c oa g ulati o n 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Uri nal ysis  
 
X  
 
X  
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -lea d E C Gf 
 
X  
 
X  
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Uri ne 
pre g na nc y 
testg 
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
C o ntact I R T  
X  
X  
 
 
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
I M P 
dis pe nsi n g/ 
ret ur nh 
 
X  
 
 
 
X  
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Da T -S P E C T i 
 
X  
 
 
 
 
 
 
 
 
X  
 
 
 
 
 
 
X  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 5  of 1 3 3  
Pr oce d ure  
Scr  
Tre at me nt Peri o d  
 
V 1 a 
V 2 b  
V 3  
V 4  
V 4 a
m  
V 5  
V 5 a
m  
V 5 b
m  
V 6  
V 7  
V 8  
V 9  
V 1 0  
V 1 1  
V 1 2  
V 1 3  
V 1 4  
V 1 5/  
E O T/  
E T  
S F U  
 
B L  
P C  
M 1  
M 2  
M 3  
M 4  
M 5  
M 6  
M 1 2  
M 1 8  
M 2 4  
M 3 0  
M 3 6  
M 4 2  
M 4 8  
M 5 4  
M 6 0  
 
D a y  
-6 0 
t o 
D a y 
-1 0  
D a y  
0  
D a y  
1 0 
± 2 d  
D a y  
3 0 
± 5 d  
D a y  
6 0 
± 5 d  
D a y  
9 0 
± 5 d  
D a y  
1 2 0 
± 5 d  
D a y  
1 5 0 
± 5 d  
D a y  
1 8 0 
± 7 d  
D a y  
3 6 0 
± 1 4 d  
D a y  
5 4 0 
± 1 4 d  
D a y  
7 2 0 
± 1 4 d  
D a y  
9 0 0 
± 1 4 d  
D a y  
1 0 8 0 
± 1 4 d  
D a y  
1 2 6 0 
± 1 4 d  
D a y  
1 4 4 0 
± 1 4 d  
D a y  
1 6 2 0 
± 1 4 d  
D a y  
1 8 0 0  
± 1 4 d  
3 0 d 
after 
l ast 
d ose  
K o ne ksa 
Ne ur oscie nce 
T o ol kit 
c o nse nt a n d 
trai ni n gn 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
De pl o y me nt 
of K o ne ksa 
Ne ur oscie nce 
T o ol kit  
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Detaile d 
c hec k o n 
K o ne ksa 
Ne ur oscie nce 
T o ol kit usa ge 
a n d re-
trai ni n g 
 
 
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acti ve 
K o ne ksa 
Ne ur oscie nce 
T o ol kit tests 
o n cell p h o ne 
at h o me  
 
X ( wee kl y - o nce i n “ O F F” state a n d o nce i n “ O N” state f or partici pa nts o n S T 
me dicati o n a n d o nce wee kl y f or partici p a nts n ot o n S T me dicati o n)  
 
 
 
 
 
 
 
 
Passi v e 
K o ne ksa 
Ne ur oscie nce 
T o ol kit data 
c ollecti o n via 
s mart watc h  
 
X ( o nce wee kl y f or a p pr o xi matel y 2 4  h o urs)  
 
 
 
 
 
 
 
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 6  of 1 3 3  
Pr oce d ure  
Scr  
Tre at me nt Peri o d  
 
V 1 a 
V 2 b  
V 3  
V 4  
V 4 a
m  
V 5  
V 5 a
m  
V 5 b
m  
V 6  
V 7  
V 8  
V 9  
V 1 0  
V 1 1  
V 1 2  
V 1 3  
V 1 4  
V 1 5/  
E O T/  
E T  
S F U  
 
B L  
P C  
M 1  
M 2  
M 3  
M 4  
M 5  
M 6  
M 1 2  
M 1 8  
M 2 4  
M 3 0  
M 3 6  
M 4 2  
M 4 8  
M 5 4  
M 6 0  
 
D a y  
-6 0 
t o 
D a y 
-1 0  
D a y  
0  
D a y  
1 0 
± 2 d  
D a y  
3 0 
± 5 d  
D a y  
6 0 
± 5 d  
D a y  
9 0 
± 5 d  
D a y  
1 2 0 
± 5 d  
D a y  
1 5 0 
± 5 d  
D a y  
1 8 0 
± 7 d  
D a y  
3 6 0 
± 1 4 d  
D a y  
5 4 0 
± 1 4 d  
D a y  
7 2 0 
± 1 4 d  
D a y  
9 0 0 
± 1 4 d  
D a y  
1 0 8 0 
± 1 4 d  
D a y  
1 2 6 0 
± 1 4 d  
D a y  
1 4 4 0 
± 1 4 d  
D a y  
1 6 2 0 
± 1 4 d  
D a y  
1 8 0 0  
± 1 4 d  
3 0 d 
after 
l ast 
d ose  
Ret ur n of 
K o ne ksa 
Ne ur oscie nce 
T o ol kit  
 
 
 
 
 
 
 
 
 
 
X o  
 
X p  
 
 
 
 
 
 
L E D D 
(c u m ulati v e) 
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
W O Q -9 q  
 
X  
 
 
 
 
 
 
X  
X  
X  
 
 
X  
  
  
  
X  
 
M D S -U P D R S 
Part  I 
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
M D S -U P D R S 
Part  II 
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
M D S -U P D R S 
Part  III 
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
M D S -U P D R S 
Part  I V 
 
X  
 
 
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
 
M o difie d 
H & Y  
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
M D S -N M S  
 
X  
 
 
 
 
 
 
X  
X  
X  
 
 
X  
  
  
  
X  
 
M o C A  
 
X j  
 
 
 
 
 
 
 
 
X k  
 
 
X k 
 
 
 
X k 
 
Earl y P D 
f u ncti o n 
sl o w ness P R O 
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
Earl y P D 
m o bilit y P R O  
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 7  of 1 3 3  
Pr oce d ure  
Scr  
Tre at me nt Peri o d  
 
V 1 a 
V 2 b  
V 3  
V 4  
V 4 a
m  
V 5  
V 5 a
m  
V 5 b
m  
V 6  
V 7  
V 8  
V 9  
V 1 0  
V 1 1  
V 1 2  
V 1 3  
V 1 4  
V 1 5/  
E O T/  
E T  
S F U  
 
B L  
P C  
M 1  
M 2  
M 3  
M 4  
M 5  
M 6  
M 1 2  
M 1 8  
M 2 4  
M 3 0  
M 3 6  
M 4 2  
M 4 8  
M 5 4  
M 6 0  
 
D a y  
-6 0 
t o 
D a y 
-1 0  
D a y  
0  
D a y  
1 0 
± 2 d  
D a y  
3 0 
± 5 d  
D a y  
6 0 
± 5 d  
D a y  
9 0 
± 5 d  
D a y  
1 2 0 
± 5 d  
D a y  
1 5 0 
± 5 d  
D a y  
1 8 0 
± 7 d  
D a y  
3 6 0 
± 1 4 d  
D a y  
5 4 0 
± 1 4 d  
D a y  
7 2 0 
± 1 4 d  
D a y  
9 0 0 
± 1 4 d  
D a y  
1 0 8 0 
± 1 4 d  
D a y  
1 2 6 0 
± 1 4 d  
D a y  
1 4 4 0 
± 1 4 d  
D a y  
1 6 2 0 
± 1 4 d  
D a y  
1 8 0 0  
± 1 4 d  
3 0 d 
after 
l ast 
d ose  
F A TI G U E -
P R O  
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
E Q -5 D -5 L  
 
X  
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
O pti o nal i n -
st u d y patie nt 
i nter vie ws 
( U S a n d U K 
o nl y)  s 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U P SI T r 
 
 
 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C S F sa m pli n g 
( o pti o nal)l 
 
X  
 
 
 
 
 
 
 
 
X  
 
X  
 
 
 
 
X  
 
Bl o o d 
sa m pli n g f or 
R N A 
bi o mar kers  
 
X  
 
 
 
 
 
 
 
 
X  
 
X  
 
 
 
 
X  
 
Bl o o d 
sa m pli n g f or 
ot h er 
bi o mar kers  
 
X  
 
 
 
 
 
 
 
 
X  
 
X  
 
 
 
 
X  
 
B L = Baseli ne Visit; B P = bl o o d press ure; C -S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale; C O VI D -1 9 = C or o na vir us Disease -2 0 1 9; C S F =cere br os pi n al fl ui d; d = da ys; 
Da T -S P E C T = D o pa mi n e Tra ns p orter I ma gi n g Wit h Si n gle P h ot o n E missi o n C o m p ute d T o m o gra p h y; E C G =ele ctr o car di o gra m; e C R F =electr o nic Case Re p ort f or m; E O T = E n d of 
Treat me nt; E Q -5 D -5 L = E ur o Q ualit y of life 5 -Di me nsi o ns 5 -Le vel; E T = Earl y Ter mi n ati o n; H & Y = H oe h n a n d Ya hr; I M P =i n vesti gati o nal me dici nal pr o d uct; I R T =i nteracti ve 
res p o nse tec h n ol o g y; L E D D = Le v o d o pa E q ui vale nt Dail y D ose; M = m o nt h; M D S -N M S = M o ve me nt Dis or der S ociet y N o n -M ot or Rati n g Scale; M D S -U P D R S = M o ve me nt Dis or der 
S ociet y U nifie d Par ki ns o n’s Disease Rati n g Scale; M o C A = M o ntreal C o g niti ve Assess me nt; P C = P h o ne call; P D = Par ki n s o n’s disease; P R O = patie nt-re p orte d o utc o me; 
R N A =ri b o n ucleic aci d; Scr = Scree ni n g; S F U = Safet y F oll o w -u p; S T =s y m pt o matic treat me nt; U P SI T = U ni v ersit y of Pe n ns yl v a nia S mell I de ntificati o n Test; V = Visit; W O Q -
9 = Weari n g -off Q uesti o n naire – 9  
a Visit 1 ma y c oi n ci d e wit h V 1 4 of P D 0 0 5 3.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 8  of 1 3 3  
Pr oce d ure  
Scr  
Tre at me nt Peri o d  
 
V 1 a 
V 2 b  
V 3  
V 4  
V 4 a
m  
V 5  
V 5 a
m  
V 5 b
m  
V 6  
V 7  
V 8  
V 9  
V 1 0  
V 1 1  
V 1 2  
V 1 3  
V 1 4  
V 1 5/  
E O T/  
E T  
S F U  
 
B L  
P C  
M 1  
M 2  
M 3  
M 4  
M 5  
M 6  
M 1 2  
M 1 8  
M 2 4  
M 3 0  
M 3 6  
M 4 2  
M 4 8  
M 5 4  
M 6 0  
 
D a y  
-6 0 
t o 
D a y 
-1 0  
D a y  
0  
D a y  
1 0 
± 2 d  
D a y  
3 0 
± 5 d  
D a y  
6 0 
± 5 d  
D a y  
9 0 
± 5 d  
D a y  
1 2 0 
± 5 d  
D a y  
1 5 0 
± 5 d  
D a y  
1 8 0 
± 7 d  
D a y  
3 6 0 
± 1 4 d  
D a y  
5 4 0 
± 1 4 d  
D a y  
7 2 0 
± 1 4 d  
D a y  
9 0 0 
± 1 4 d  
D a y  
1 0 8 0 
± 1 4 d  
D a y  
1 2 6 0 
± 1 4 d  
D a y  
1 4 4 0 
± 1 4 d  
D a y  
1 6 2 0 
± 1 4 d  
D a y  
1 8 0 0  
± 1 4 d  
3 0 d 
after 
l ast 
d ose  
b Visit 2 ( P D 0 0 5 5 Baseli ne Visit) t y picall y c oi nci d es wit h V 1 5 ( M 1 8) of P D 0 0 5 3. O nl y assess me nts n ot d o ne at V 1 5 i n P D 0 0 5 3 will  nee d t o be c o m plete d f or P D 0 0 5 5 V 2. If P D 0 0 5 5 
V 2 is c o n d ucte d m ore t ha n 2 wee ks after V 1 5 of P D 0 0 5 3, all ass ess me nts (e xce pt Da T -S P E C T, C S F sa m pli n g, a n d sa m pli n g f or bi o mar kers) will nee d t o be re peate d. Partici p a nts 
w h o ne wl y c o nse nte d t o pr o vi d e C S F sa m ples i n P D 0 0 5 5 nee d t o u n der g o C S F sa m pli n g at V 2.  
c All st u d y partici p a nts pre mat urel y ter mi n ati n g fr o m t h e  st u d y s h o ul d be e nc o ura ge d t o u n der g o fi n al e val u ati o n pr oce d ures i n acc or da nce wit h t he E O T/ E T  Visit a n d S F U Visit 
sc he d ule ( 3 0 da ys after t he last d ose), as s o o n as p ossi ble after t h e last d ose of st u d y me dicati o n.  
d Bl o o d press ure has t o be meas ure d i n  t h e s u pi ne a n d erect p ositi o ns t o assess a ut o n o m o us d ysre g ulati o n ( Tre n dele n b ur g test). Vital si g ns (t o be ta ke n bef ore bl o o d c ollecti o n f or 
la b orat or y tests) will c o nsist of 3 p ulse a n d 3 B P meas ure me nts ( 3 c o nsec uti ve B P rea di n gs will be rec or de d at i nt er vals of at least 1  mi n ute).  
e Q uesti o ni n g at t h e ti me of partici p a nt visits s h o ul d be e x plicit re gar di n g s y m pt o ms of h y perse nsiti vit y, he patic a n d/ or re nal  d ysf u ncti o n, a n d si g ns a n d s y m pt o ms of C O VI D -1 9.  
f Electr o car di o gra m rec or di n gs will be si n gle rea ds b ut ca n be re peate d i n tri plicate if cli nicall y i n dicate d. T h e st u d y partici p a nt s h o ul d be resti n g i n t he s u pi n e p ositi o n f or at least 
1 0  mi n utes bef ore rec or di n g.  
g Pre g na nc y test o nl y f or w o me n of c hil d -beari n g p ote ntial. A p ositi ve uri n e test s h o ul d be c o nfir me d wit h a bl o o d test.  
h First da y of mi nzas ol mi n ( U C B 0 5 9 9) a d mi nistrati o n will be Da y 1; last a d mi nistrati o n will be i n t h e m or ni n g of t he E O T Visit.  
i I n case of earl y ter mi n ati o n of I M P bef ore t he M 6 0 Visit, t he Da T-S P E C T will occ ur at t h e E O T/ E T Visit, pr o vi d e d t h at t he last Da T -S P E C T occ urre d m ore t ha n 6  m o nt hs pri or t o 
t h e E O T/ E T Visit. T he Da T-S P E C T at M 1 8 ( V 8) a n d M 6 0 ( V 1 5/ E O T/ E T) ca n be d o ne wit hi n a ti me wi n d o w of ± 2 8 da ys.  
j T h e V 2 ( P D 0 0 5 5 Baseli ne Visit) assess me nt (t y picall y c oi nci di n g wit h P D 0 0 5 3 M 1 8) will be d o ne base d o n M o C A v ersi o n 7. 2.  
k T h e V 8 ( M 1 8), V 1 1 ( M 3 6), a n d V 1 5/ E O T/ E T ( M 6 0) assess me nts will be d o ne base d o n M o C A versi o ns 8. 2, 8. 1, a n d 8. 3, res pecti vel y . 
l O pti o nal C S F sa m pli n g f or all partici p a nts re gar dless of t heir c o nse nti n g t o C S F sa m pli n g i n P D 0 0 5 3. Partici p a nts h a ve t he o p p ort u nit y t o o pt o ut of C S F sa m pli n g. T he C S F 
sa m pli n g s h o ul d occ ur at t he sa me ti me of da y as i n P D 0 0 5 3 a n d s h o ul d be ti me d wit h bl o o d sa m pli n g. T h ese sa m ples s h o ul d be c ollecte d o nl y after all  ot h er assess me nts of t he visit 
ha ve bee n perf or me d.  
m  D ata res ulti n g fr o m Visits 4a, 5a, a n d 5 b will be d oc u me nte d as a n u nsc he d ule d visit i n t he e C R F u ntil t h e rele va nt e C R F pa ges  f or t h ese visits are a vaila ble. 
n K o ne ksa Ne ur oscie nce T o ol kit c o nse nti n g a n d trai ni n g ca n be d o ne at a n y ti me fr o m Visit 1 t o Visit 2, if nee de d as a n u nsc he d ule d visit.  
o If a st u d y partici pa nt deci d es t o st o p usi n g t he Di gital Healt h Tec h n ol o g y pri or t o V 8 ( M 1 8) t he reas o n nee ds t o be d oc u me nte d i n t he C R F.  
p A p plies o nl y i n t he case of E T. 
q  T h e W O Q -9 will o nl y be c o m plete d b y st u d y partici p a nts w h o ha ve i nitiate d S T.  
r St u d y partici p a nts w h o ha ve alrea d y c o m plete d V 4 ( M 1) will c o m plete t h e U P SI T at t h e ne xt visit.  
s U S a n d U K o nl y : I n-st u d y patie nt i nter vie ws will be o pti o nal, s u bject t o t h e partici p a nt ha vi n g si g ne d t h e s pecific i nf or me d c o nse nt, a n d will be c o n d ucte d wit hi n 1 0 da ys after 
Baseli ne ( V 2). If t he partici pa nt has alrea d y c o m plete d t he Baseli ne visit, t h e i nter vie w s h o ul d be perf or me d wit hi n 1 0 da ys after t he M o n t h 1 visit ( V 4). 
 
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 2 9  of 1 3 3  
2  
I N T R O D U C TI O N 
2. 1  
St u d y r ati o n al e  
Mi nzas ol mi n ( U C B 0 5 9 9) is a n orall y a vaila bl e i n hi bit or of A S Y N misf ol di n g a n d d o w nstrea m 
a g gre gati o n. A g gre gat e d f or ms of A S Y N are t he hall mar k fi brillar pr otei n d e p osits i n P D a n d 
ot her s y n uclei n o pat hies, a n d e vi de nce s u g gests t hat it is t he misf ol de d f or ms of A S Y N t hat 
pr o pa gate t hr o u g h t h e C N S d uri n g disease pr o gressi o n. T hese acc u m ulati o ns of 
A S Y N -c o ntai ni n g ne ur o nal i ncl usi o ns f or m Le w y b o dies a n d Le w y ne urites.  
N o ncli nical a n d i n vi v o p har mac ol o g y st u dies ha v e pr o vi de d scie ntific e vi d e nce s u g gesti n g t hat 
mi nzas ol mi n ( U C B 0 5 9 9) ma y sl o w d o w n disease pr o gressi o n i n P D, w hic h re mai ns t he ma i n 
u n met me dical nee d i n t his c o n diti o n. A first -i n-h u ma n st u d y, U P 0 0 3 0, usi n g mi nzas ol mi n 
( U C B 0 5 9 9), c o n d ucte d i n healt h y el derl y partici pa nts ( defi ne d as ≥5 5 t o ≤7 5 years of a ge), 
pr o vi de d t he safet y, t olera bilit y, a n d P K i nf or mati o n f or si n gle d ose e x p o s ures u p t o 4 5 0 m g a n d 
m ulti ple d ose e x p os ures of 1 8 0 m g/ da y f or u p t o 2 1  da ys. T he first st u d y i n t he tar get p o p ulati o n, 
U P 0 0 7 7, pr o vi de d safet y, t olera bilit y, a n d P K i nf or mati o n f or m ulti ple d ose e x p os ures of 
1 8 0 m g/ da y a n d 3 6 0 m g/ da y f or 2 8 da ys i n st u d y p a rtici pa nts wit h P D. A n o n g oi n g d o u ble -bli n d, 
place b o -c o ntr olle d, ra n d o mize d, P hase 2a  st u d y, P D 0 0 5 3, i n partici pa nts wit h earl y-sta ge P D, is 
desi g ne d t o pr o vi de pr o of -of -c o nce pt f or t he efficac y of t he A S Y N misf ol di n g i n hi bit or 
mi nzas ol mi n ( U C B 0 5 9 9) i n sl o wi n g disease pr o gressi o n at d oses of 1 8 0 m g/ da y or 3 6 0 m g/ da y 
a n d t o i nstr uct later sta ges of de vel o p me nt.  
T he c urre nt e xte nsi o n st u d y, P D 0 0 5 5, is desi g ne d t o pr o vi de f urt her l o n g er -ter m e vi de nce a n d 
u n dersta n di n g of t he effi cac y, safet y, a n d t olera bilit y of  mi nzas ol mi n ( U C B 0 5 9 9) i n sl o wi n g t he 
pr o gressi o n of P D i n st u d y partici pa nts w h o ha v e c o m plete d 1 8 m o nt hs of treat me nt i n P D 0 0 5 3.  
2. 2  
B a c k gr o u n d  
Par ki ns o n’s disease is a pr o gressi ve ne ur o de g e nerati ve dis or der t hat pr ese nts wit h a s pectr u m of 
m ot or a n d n o n m ot o r si g ns a n d s y m pt o ms. T he mea n a ge at o nset is 6 0 years. T he cli nical 
dia g n osis of P D relies o n t he prese n ce of t he car di nal m ot or si g ns: bra d y ki nesia, ri gi dit y, tre m or, 
a n d p ost ural i nsta bilit y. H o we ver, n o n m ot or s y m pt o ms s uc h as l oss of s mell, de pressi o n , 
c o nsti pati o n, a n d ra pi d e ye m o ve me nt slee p be h a vi or dis or der ca n occ ur se veral y ears bef ore t he 
o nset of m ot or s y m pt o ms.  
Earl y P D is c haracteri ze d b y mil d, ma na gea ble m ot or s y m pt o ms t hat ma y n ot re q uire S T, or t hat 
s h o w a g o o d res p o nse t o l o w-d ose le v o d o pa, w hi c h re pres e nts sta n dar d of care ( S o C)first -li ne 
treat me nt. Ot her c o m m o nl y use d S o C me dicati o ns i ncl u de d o pa mi ne a g o nists, m o n oa mi ne 
o xi dase -B i n hi bit ors, a n d catec h ol -O -met h yltra nsferase ( C O M T) i n hi bit ors. As P D pr o gresses, 
t he m ot or a n d n o n m ot or s y m pt o ms bec o me m ore b ot hers o me, a n d patie nts ma y start 
e x perie n ci n g m ot or c o m plicati o ns. After 2 t o 5 years of treat me nt wit h  le v o d o pa, 3 0 % t o 5 0 % of 
patie nts de vel o p m ot or fl uct uati o ns. A d va nce d P D is c haracterize d b y mar k e d m ot or disa bilit y 
wit h l oss of i n de pe n de nt a m b ulati o n. After ≥1 0  years si nce o nset, m ost pati e nts s uffer fr o m 
diffic ult -t o-treat m ot or s y m pt o ms (e g, falls, freezi n g of gait, d ysart hria, a n d d ys p ha gia) a n d fr o m 
n o n m ot or s y m pt o ms f or w hic h treat me nt o pti o ns are li mite d (e g, de m e ntia, ps yc h osis, 
de pressi o n, a ut o n o mic d ysf u ncti o n, a n d pai n). Patie nts are ofte n b e dri d de n after 1 0 t o 1 4  years 
( P oe we, 2 0 0 6). T o t his d a y, sl o wi n g disease pr o gressi o n re mai ns t he mai n u n met me dical nee d 
i n P D. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 0  of 1 3 3  
Par ki ns o n’s disease is pat h ol o gicall y c haracterize d b y t he l oss of d o pa mi ner gic ne ur o ns i n t he  
s u bsta ntia ni gra, ass ociat e d wit h A S Y N pat h ol o g y ( ne ur o nal c yt os olic i ncl usi o ns call e d Le w y 
b o dies w hic h c o nsist of misf ol de d, pat h ol o gical a g gre gates of A S Y N).  Treat me nts t hat pre ve nt 
misf ol di n g a n d a g gre gati o n of A S Y N ma y sl o w t h e ne ur o de g e nerati o n i n P D, res ulti n g i n sl o wer 
pr o gressi o n of m ot or s y m pt o ms, t h us pr o vi di n g a t hera pe utic b e nefit t o patie nts wit h P D.  
Mi nzas ol mi n ( U C B 0 5 9 9) is a n orall y a vaila bl e i n hi bit or of A S Y N misf ol di n g a n d d o w nstrea m 
A S Y N a g gre g ati o n.  I n vi v o a n d n o ncli nical p har m ac ol o g y data s u g gest mi n zas ol mi n ( U C B 0 5 9 9) 
ma y sl o w ne ur o de g e nerati o n i n P D, res ulti n g i n sl o wer diseas e pr o gressi o n, t h us pr o vi di n g a 
t hera pe utic b e nefit t o patie nts wit h P D. 
Mi nzas ol mi n ( U C B 0 5 9 9) has n ot bee n a p pr o ve d b y a n y healt h a ut h orities w orl d wi de as of t h e 
date of t his d oc u me nt. U C B has c o n d ucte d 5  P has e  1 cli nical st u dies t o s u p p ort t he de vel o p me nt 
of mi nzas ol mi n ( U C B 0 5 9 9) t hat ha ve de m o nstr ate d g o o d P K pr o perties a n d a n acce pta ble s afet y 
a n d t olera bilit y pr ofile ( U P 0 0 2 3, U P 0 0 3 0, T M 0 0 1 7, a n d U P 0 0 7 7) as well as a mi ni mal f o o d 
effect o n t he P K pr ofile f or mi nzas ol mi n ( U C B 0 5 9 9)  ( U P 0 0 7 8). F urt her i nf or mati o n re gar di n g 
U P 0 0 2 3, U P 0 0 3 0, T M 0 0 1 7, U P 0 0 7 7, a n d U P 0 0 7 8 is pr o vi de d i n t he I n v esti gat or’s Br oc h ure 
(I B). 
2. 3  
B e n efit/ri s k a s s e s s m e nt  
Par ki ns o n’s disease w as c h ose n as t he tar get i n dicati o n o n t he basis of a str o n g scie ntific 
rati o nale a n d a si g nifica nt u n met me dical nee d. 
T he c urre ntl y a vaila ble treat me nts f or P D are m ost effecti ve i n treati n g t he m ot or s y m pt o ms i n 
t he earl y sta g es; h o we ver, t he y d o n ot sl o w/st o p t he disease pr o gressi o n a n d pr o vi de li mite d 
be nefit i n later sta g es of t he disease d u e t o t he c o nti n ui n g ne ur o nal l oss. T o date, t here are n o 
a p pr o ve d tr eat me nts t o st o p or sl o w d o w n t he cli nical pr o gressi o n of t he disease i n patie nts wit h 
earl y P D, w hic h re mai ns a lar ge u n met me di cal nee d.  
Fi n di n gs fr o m ge netic, cli nical pat h ol o g y, a n d a ni mal m o del st u dies i n dicate t hat t he ne ur o nal 
acc u m ulati o n of t o xic a g gre gates of a s y na ptic pr otei n calle d A S Y N c o ntri b utes t o t he 
u n derl yi n g pat h o p h ysi ol o g y of P D. T h us, a t hera pe utic a ge nt t hat pr e ve nts t he f or mati o n, or 
e n ha nces t he cle ar a n ce, of t hese t o xic f or ms of A S Y N ma y pre v e nt or sl o w ne ur o de ge n erati ve 
pr ocesses i n P D a n d relat e d dis or ders.  
N o ncli nical p har ma c ol o gic st u dies de m o nstrate t h at mi nzas ol mi n ( U C B 0 5 9 9) i nteracts directl y 
wit h A S Y N t o re d uce t h e misf ol di n g a n d t he f or mati o n  of A S Y N a g gre gates a n d, m ore 
s pecificall y, t o re d u ce t h e f or mati o n of oli g o meri c A S Y N str uct ur es ass ociate d wit h A S Y N -
me diate d cell ular t o xicit y.  
T he i m p orta nt i de ntifie d ris k is dr u g h y perse nsiti vit y, a n d t he p ote ntial ris ks are he p at ot o xicit y 
( base d o n cli nic al data) a n d car diac effects. Re n al la b orat or y a b n or malities are als o k e pt u n der 
cl ose safet y m o nit ori n g.  
I n P has e 1 de vel o p me nt of mi nzas ol mi n ( U C B 0 5 9 9), 5 st u dies ( U P 0 0 3 0, T M 0 0 1 7, U P 0 0 2 3, 
U P 0 0 7 7, a n d U P 0 0 7 8) de m o nstrate d t hat mi nzas ol mi n ( U C B 0 5 9 9) has acce pta ble safet y, P K, 
a n d t olera bilit y pr ofiles f or f urt her cli nical de vel o p me nt. O verall, t he maj orit y of T E A Es were 
mil d or m o derate i n i nte nsit y a n d res ol ve d. I n U P 0 0 3 0, 2 e ve nts of h y perse nsiti vit y were 
re p orte d. A n a d diti o nal 2 e ve nts of h y perse nsiti vit y occ urre d i n st u d y partici pa nts w h o recei ve d 
mi nzas ol mi n ( U C B 0 5 9 9) i n U P 0 0 7 7. A ca usal rel ati o ns hi p bet wee n t he re p orte d e ve nts of dr u g 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 1  of 1 3 3  
h y perse nsiti vit y a n d mi nzas ol mi n ( U C B 0 5 9 9) is c o nsi dere d pla usi ble. T he h y perse nsiti vit y 
reacti o ns are f urt her descri be d i n t he I B. As a res ult of t hese cli nical data, dr u g h y perse nsiti vit y 
is n o w c o nsi dere d a n i m p orta nt i de ntifie d ris k b y t he S p o ns or a n d, t heref ore, f urt her m eas ures of 
ris k m o nit ori n g a n d mi ni mizati o n are i ncl u de d. 
Sites will be i nf or me d a n d trai ne d a p pr o priatel y a b o ut t he ris k of a h y perse nsiti vit y reacti o n 
(s uc h as r as h, a n gi oe d e ma, or a na p h yl a xis) a n d t h e acti o ns t hat nee d t o b e ta ke n i n cas e of a 
h y perse nsiti vit y reacti o n. T he partici pa nt will be i nf or me d b y t he I n v esti gat or d uri n g t he c o nse nt 
p r oce d ure a b o ut t he ris k of a h y pers e nsiti vit y reacti o n (s uc h as ras h, a n gi oe de ma, or 
a na p h yla xis) a n d ot h er i m p orta nt p ote ntial ris ks f or mi nzas ol mi n ( U C B 0 5 9 9). Ris k miti gati o n 
meas ures i ncl u de usi n g a sta n dar d a p pr oac h of: ( 1) o btai ni n g a detaile d hist or y  of t he 
h y perse nsiti vit y reacti o n a n d its e v ol uti o n; ( 2) res p o nse wit h a p pr o priate treat me nt, if nee d e d; ( 3) 
a detaile d p h ysical e xa mi nati o n a n d re g ular m o nit ori n g of vital si g ns; a n d ( 4) t he a d diti o n of a 
g ui da nce f or t he e v al uati o n of s us pecte d h y perse ns iti vit y reacti o ns ( please refer t o 
Secti o n  8. 3. 6. 1 ) a n d re p orti n g of t he s us pecte d h y perse nsiti vit y reacti o n as a n a d verse e v e nt of 
s pecial i nterest ( AE SI).  
T o m o nit or t he p ote ntial ris k of he pat ot o xicit y, m o nt hl y r o uti ne li ver f u ncti o n tests are ma n date d 
d uri n g t he first 6 m o nt hs of treat me nt f or st u d y partici pa nts w h o recei ve m ulti ple d oses of st u d y 
me dicati o n ( see Sc h e d ule of Acti vities, Secti o n  1. 3 ). I n a d diti o n, a n y cases meeti n g H y´s la w 
criteria m ust be re p orte d as a n A E SI. Sites will be i nf or me d a n d trai n e d a p pr o priatel y . 
Wit h t he c urre nt ri s k ma na ge me nt meas ures f or mi nzas ol mi n ( U C B 0 5 9 9), t he be nefit-ris k pr ofile 
a p pears t o b e fa v ora ble f or f urt her de vel o p me nt. T he li mite d cli nical data c ollecte d t h us far ha ve 
n ot i de ntifie d a n y safet y c o ncer ns t h at w o ul d precl u de f urt her de vel o p me nt of mi nz as ol mi n 
( U C B 0 5 9 9) i n P D. 
M ore detaile d i nf or mati o n a b o ut t he k n o w n a n d e x pecte d be n efits a n d ris ks a n d reas o n a bl y 
e x pecte d a d vers e reacti o ns of mi nzas ol mi n ( U C B 0 5 9 9)  is pr o vi de d i n t he I B. 
2. 3. 1  
C or o n a vir u s Di s e a s e -2 0 1 9 b e n efit/ri s k a s s e s s m e nt  
Mi nzas ol mi n ( U C B 0 5 9 9) is n ot k n o w n t o e xert a n effect o n t he i m m u ne or res pirat or y s yste ms, 
a n d its mec ha nis m of acti o n is n ot li n ke d t o i m m u ne or res pir at or y s yste m a g o nis m or i n hi biti o n.  
T o date, n o i ncrease d ris k of i nfecti o n or res pirat or y pr o ble ms has  bee n i de ntifie d i n ass ociati o n 
wit h cli nical mi nzas ol mi n ( U C B 0 5 9 9) a d mi nistrati o n. N o s uc h ris ks ha ve b ee n i de ntifie d 
t hr o u g h re g ular re vie w of p u blis he d literat ure. P D 0 0 5 5 will i ncl u de st u d y partici pa nts wit h earl y-
sta ge P D w h o c o m plete d t he Treat me nt Peri o d of P D 0 0 5 3. 
Alt h o u g h t here is s o me e vi de nce t hat se v ere ac ute res pirat or y s y n dr o m e c or o na vir us -2 
( S A R S-C o V -2) mi g ht affect t he C N S, t here is n o reas o n t o ass u me o n t he basis of t he 
mec ha nis m of acti o n t hat mi nzas ol mi n ( U C B 0 5 9 9) will ha ve a n y s u bsta ntia l effect t o w orse n a 
C or o na vir us Disease -2 0 1 9 ( C O VI D -1 9) i nfecti o n or i ncrease t he ris k of C N S a n d ot her 
c o m plicati o ns i n case a st u d y partici pa nt wit h P D ac q uires S A R S -C o V -2. T here is n o e vi de nce 
t hat A S Y N pla ys a r ole i n i m m u n ol o gical pat h wa ys of t he C N S. F urt her m ore, t here is n o reas o n 
t o ass u me t hat mi nzas ol mi n ( U C B 0 5 9 9) ma y e n ha nce t he i nfecti o n ris k or t he disease 
ma nifestati o n.  
T heref ore, mi nzas ol mi n ( U C B 0 5 9 9) is n ot e x pecte d t o p ose a n a d diti o nal ris k of c o m plicati o ns 
or p o or pr o g n osis of C O VI D -1 9.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 2  of 1 3 3  
C o nsi deri n g t he mec ha nis m of acti o n, t he i ncl usi o n a n d e xcl usi o n criteria, a n d t he meas ures t o 
miti gate ris ks descri be d i n t his pr ot oc ol, t he ris k t o st u d y partici pa nts i n P D 0 0 5 5, b ot h i n ter ms 
of e x p os ure t o S A R S -C o V -2 a n d m or bi dit y fr o m C O VI D -1 9, is n ot e x pecte d t o be si g nifica ntl y 
differe nt fr o m t he ge n eral p o p ulati o n of i n di vi d uals wit h P D. T he be nefit -ris k pr ofile of 
mi nzas ol mi n ( U C B 0 5 9 9) i n P D 0 0 5 5 i n t he c o nte xt of C O VI D -1 9 vacci nati o n re mai ns p ositi ve.  
C o nse q ue ntl y, t here are n o restricti o ns o n C O VI D -1 9 vacci nati o n d uri n g P D 0 0 5 5 (ie, st u d y 
partici pa nts s h o ul d be free t o recei ve C O VI D -1 9 v acci nati o n as p er l ocal or nati o nal 
g ui da nce/re g ul ati o ns).  
2. 3. 1. 1  
C O VI D -1 9 ri s k miti g ati o n m e a s ur e s  
•  C urre nt nati o nal la ws a n d l ocal rec o m me n d ati o ns f or t he pre v e nti o n a n d c o ntr ol of t he 
pa n de mic will be strictl y a d here d t o.  
•  Partici pa nts are as ke d t o f oll o w t he visit sc he d ule t o t he e xte nt p ossi ble. If t he y are u n a ble t o 
c o me t o t he st u d y site, t he I n vesti gat or ma y c o ntact t he partici pa nt directl y via tele p h o ne 
a n d/ or vi de o co nfere n ce calls. If partici pa nts visit a n ot her facilit y f or a me dical iss ue ( or ha v e 
t o s witc h st u d y sites f or a C O VI D-1 9 -relate d reas o n), t he y are as ke d t o i nf or m t he 
I n v esti gat or t o o btai n t he details of t heir c o n diti o n a n d t heir partici p ati o n. 
•  Partici pa nts will be cl osel y m o nit ore d f or a n d e n c o ura ge d t o r e p ort a n y si g ns a n d s y m pt o ms 
of C O VI D -1 9.  T h e I n vesti gat or will c o nsi der t he i n di vi d ual be nefit/ris k of t he st u d y 
partici pa nt u p o n i de ntificati o n of a n y si g ns  a n d s y m pt o ms  of C O VI D -1 9 i nfecti o n 
(e g, c o nti n uati o n of d osi n g, site visits). 
•  C O VI D -1 9  testi n g b y o pti o nal la b orat or y ass ess me nt will be c o n d ucte d base d o n a vaila bilit y 
a n d ot her practical c o nsi derati o ns (e g,  test ca pacit y a n d t ur nar o u n d ti me) of a p pr o ve d t ests 
a n d at t he I n vesti gat or’s discreti o n.  T he I n v esti gat or will c o nsi der t he i n di vi d ual be nefit/ris k 
of t he st u d y partici pa nt  i n case of a p ositi ve C O VI D -1 9  test. 
•  T he p ossi bilit y of vir us tra ns missi o n will be c o ntr olle d as m uc h as p ossi ble b y:  
− A d visi n g partici pa nts t o a d here t o l ocal re q uir e me nts f or re d ucti o n of e x p os ure t o t he 
p u blic w hile a m b ulat or y.  
− A d visi n g partici pa nts t o a d here t o cli nical site re q uire me nts f or re d ucti o n of e x p os ure 
w hile at t he site or i nteracti n g wit h site staff. T his a d vice will be i ncl u de d i n t he I nf or me d 
C o nse nt f or m (I C F).  
•  C O VI D -1 9 testi n g f or cli nical staff will be c o n d u cte d if re q uire d b y l o cal g ui deli nes.  
2. 3. 1. 2  
C O VI D -1 9 b e n efit/ri s k c o n cl u si o n  
C o nsi deri n g t he mec ha nis m of acti o n of mi nzas ol mi n ( U C B 0 5 9 9), t he i ncl usi o n a n d e xcl usi o n 
criteria, a n d t he meas ures t o miti gate ris ks descri be d i n t his pr ot oc ol, t he ris k t o st u d y 
partici pa nts i n P D 0 0 5 5, b ot h i n ter ms of e x p os ure t o S A R S -C o V -2 a n d m or bi dit y fr o m C O VI D -
1 9, is n ot e x pecte d t o be si g nifica ntl y differe nt fr o m t he ge neral p o p ulati o n of i n di vi d uals wit h 
P D.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 3  of 1 3 3  
2. 3. 2  
Di git al H e alt h T e c h n ol o g y b e n efit/ri s k a s s e s s m e nt  
I n t his st u d y, t he K o ne ks a Ne ur os cie nce T o ol kit is use d as n o ni n vasi ve Di gital Healt h 
Tec h n ol o g y t o c ollect dat a o n si g ns a n d s y m pt o ms of P D. Briefl y, t he K o ne ksa Ne ur oscie nce 
T o ol kit c o nsists of a m o bile s oft ware a p plicati o n w hic h is e xec ute d o n a n A p ple i P h o ne; t he 
K o ne ksa N e ur oscie n ce T o ol kit als o utilizes t he Acti Gra p h Ce ntre P oi nt ®  I nsi g ht Watc h ( C PI W), 
a wrist -w or n s mart watc h, a n d t he Acti Gra p h C PI W Data  H u b f or dat a tra nsfer. Refer t o 
Secti o n  6. 9  a n d Secti o n  8. 1. 4  f or detaile d descri pti o ns of t he K o ne ksa Ne ur oscie nce T o ol kit.  
T here are l o n g -t er m be nefits f or t he P D patie nt c o m m u nit y ass ociate d wit h i ncreasi n g t he 
e vi de nce b ase re gar di n g t he utilit y of t he Di gital Healt h Tec h n ol o g y ( e g, K o ne ks a Ne ur oscie nce 
T o ol kit) t o ca pt ure c h a n g es i n t he si g ns a n d s y m pt o ms of P D o ver ti me.  
T he K o ne ksa Ne ur os cie n ce T o ol kit is desi g ne d f or use at h o me a n d all o ws f or a n o bjecti ve 
assess me nt of si g ns a n d s y m pt o ms of P D wit h o ut re q uiri n g st u d y partici pa nts t o vi sit t he cli nical 
site, p ote ntiall y mi ni mizi n g patie nt b ur de n b y re d uci n g site visits i n f ut ure cli nical st u dies.  
T he ris ks ass ociate d wit h t he K o ne ksa Ne ur osci e n ce T o ol kit are mi ni mal. T he acti ve 
assess me nts are s oft ware a p plicati o n base d a n d h a ve bee n sel ecte d c o nsi deri n g t he safet y of 
st u d y partici pa nts w hile perf or mi n g t he ass ess me nt i n a n u ns u per vise d e n vir o n me nt. T he 
p ote ntial ris ks a n d t he ass ociate d miti gati o n strate gies are liste d i n Ta ble  2 ‒ 1 . 
T a bl e  2 ‒ 1 : 
P ot e nti al ri s k s a n d miti g ati o n str at e gi e s f or K o n e k s a N e ur o s ci e n c e 
T o ol kit  
Ris k  
Descri pti o n  
Falli n g w hile perf or mi n g a n 
assess me nt a n d c o nf usi o n 
a n d/ or e m barrass me nt a n d 
fati g ue a n d/ or pai n 
T he ris k ass ociate d wit h falli n g ma y be prese nt d uri n g t he acti ve gait 
a n d bala nce assess me nt. T he a p plicati o n has bee n desi g ne d t o pr o m pt 
t he user t o o nl y c om plete t he assess me nt if t he y ca n safel y perf or m t his 
tas k wit h o ut falli n g. St u d y partici pa nts will e x plicitl y res p o n d if t he y 
feel t he y ca n or ca n n ot c o m plete t he gait a n d bala nce assess me nt 
safel y. If st u d y partici pa nts res p o n d t he y ca n n ot c o m plete t he t as k 
safel y, t he y will n ot be as ke d t o c o m plete t he assess me nt, a n d t his will 
n ot be c o nsi dere d a c o m plia nce fail ure.  
Har m ass ociate d wit h use of t he K o ne ksa Ne ur oscie nce T o ol kit i n 
acc or da nce wit h t he pr ot oc ol ma y als o i ncl u de c o nf usi o n a n d/ or 
e m barrass me n t, a n d fati g ue a n d/ or pai n. T hese ris ks are miti gate d b y 
pr o per st u d y partici pa nt scree ni n g a n d trai ni n g, a p plicati o n desi g n 
facilitates use f or assess me nts, patie nt s u p p ort t hr o u g h q uic k start 
g ui de, patie nt g ui de, vi de o a n d p h o ne s u p p ort, t he o pti o n t o m ar k t he 
tas k as n ot safe pri or t o t he start of t he tas k, a n d st o p pi n g a n y ti me 
d uri n g t he tas ks.  
Aller gic reacti o n t o t he 
Acti Gra p h C PI W s mart watc h 
a n d wrist ba n d 
T here is a ris k t hat s ki n reacti o ns (e g, irritati o n, itc hi ness, ras h) ma y 
occ ur d uri n g pr ol o n ge d use a n d s ki n c o ntact wit h t he Acti Gra p h 
C PI W. H o we ver, t he Acti Gra p h C PI W is c o m p ose d of materials wit h a 
l o w p ote ntial of aller gic reacti o ns a n d has bee n wi del y use d. If a 
partici pa nt has a k n o w n aller g y t o c o p ol y mer materials, t he y s h o ul d 
see k me dical a d vice bef ore usi n g t he Acti Gra p h C PI W. A d diti o nall y, 
t he Acti Gra p h C PI W a n d t he K o ne ksa Ne ur oscie nce T o ol kit patie nt 
g ui des pr o vi de i nstr ucti o ns f or ha n dli n g cases of s ki n reacti o ns.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 4  of 1 3 3  
T a bl e  2 ‒ 1 : 
P ot e nti al ri s k s a n d miti g ati o n str at e gi e s f or K o n e k s a N e ur o s ci e n c e 
T o ol kit  
Ris k  
Descri pti o n  
S h oc k d ue t o electr o ma g netic 
ra diati o n fr o m Acti Gra p h 
C PI W  
It is unli kel y t hat st u d y partici pa nts will e x perie nce disc o mf ort or 
s h oc k d ue t o electr o ma g netic ra diati o n fr o m t he Acti Gra p h C PI W 
gi ve n t he c o nf or mit y of t his s mart watc h wit h C E Mar k ( E U a n d U K) 
( E N 6 0 6 0 1-1) a n d re gistrati o ns Part 1 5. 1 0 9, Part 1 5. 2 4 9 ( U S), a n d 
IC E S -0 0 3 ( Ca na da).  
Electr o ma g netic i nterfere nce 
wit h a n y ki n d of i m pla nta ble 
acti ve de vices 
T he A p ple i P h o ne c o ntai ns ma g nets, as well as c o m p o ne nts a n d/ or 
wireless ele me nts t hat ge nerate electr o ma g netic fiel ds. T hese ma g nets 
a n d electr o ma g netic fiel ds ca n  ca use i nterfere nce wit h me dical de vices, 
s uc h as i m pla nte d pace ma kers a n d defi brillat ors, w hic h ma y c o ntai n 
se ns ors t hat res p o n d t o ma g nets or ra di o ele me nts w he n i n cl ose 
c o ntact. P ote ntial i nteracti o n wit h t hese i m pla nte d de vices c o ul d occ ur 
if t he A p ple i P h o ne c o mes cl oser t ha n 3 0c m t o t he i m pla nte d de vice. 
T heref ore, st u d y partici pa nts wit h a n y i m pla nte d acti ve me dical de vice 
are e xcl u de d fr o m usi n g t he K o ne ksa Ne ur oscie nce T o ol kit.  
P h ysical disc o mf ort s uc h 
as cra m ps, fai nti n g, e ye 
ac hes, or hea d ac hes  
St u d y partici pa nts ma y e x perie nce p h ysical disc o mf ort s uc h as cra m ps, 
fai nti n g, e ye ac hes, or hea dac hes, w hic h ma y be d ue t o t he use of t he 
A p ple i P h o ne. St u d y partici pa nts will be ca uti o ne d t o st o p usi n g t he 
K o ne ksa Ne ur oscie nce T o ol kit i n case of p h ysical disc o mf ort a n d t o 
c o ntact a n d see k g ui da nce fr o m t he I n vesti gat or.  
Data sec urit y  
T here are ris ks ass ociate d wit h sec urit y breac hes affecti n g data pri vac y 
a n d/ or i nte grit y. T hese are m i ni mize d b y se veral meas ures. N o 
pers o nal i de ntifia ble i nf or mati o n is ca pt ure d o n t he platf or m; all 
pers o nal data are pse u d o n y mize d. Data are e ncr y pte d at rest a n d i n 
tra nsit usi n g a 2 0 4 8-bit e ncr y pti o n. Bac ke n d access t o t he platf or m is 
li mite d f oll o wi n g a least pri vile ge d/r ole -base d a p pr oac h. Fi nall y, t he 
res ult of patie nt assess me nt ca n o nl y be assesse d wit hi n t he K o ne ksa 
a p plicati o n. 
C E = C o nf or mité E ur o pée n ne; C PI W = Ce ntre P oi nt I nsi g ht Watc h  
Besi des t he ris k a n d miti gati o ns descri be d a b o v e, n o f urt her ri s ks ass o ciate d t o t he m o bile 
s oft ware a p plicati o n, t he A p ple i P h o ne, a n d t he Acti Gra p h C PI W a n d its D ata H u b were 
i de ntifie d base d o n i nf or mati o n a vaila ble t o U C B. Please refer t o t he A p pl e i P h o ne User G ui de 
(a vaila ble at: htt ps://s u p p ort.a p ple.c o m/ g ui de/ip h o ne/ welc o me/i os), Acti Gra p h C PI W User 
G ui de ( Ce ntre P oi nt I nsi g ht Watc h User G ui de. Pe nsac ola, F L: Acti Gra p h, L L C; 2 0 2 3), a n d 
Acti Gra p h C PI W D ata H u b User G ui de ( Ce ntre P oi nt Data H u b User G ui de. Pe nsac ola, F L: 
Acti Gra p h, L L C; 2 0 2 3).  
C o nsi deri n g t he ris k m iti gati o n meas ures i n place, t he K o ne ksa Ne ur osci e n ce T o ol kit  d oes n ot 
p ose si g nifica nt ris ks t o st u d y partici pa nts. T he o v erall resi d ual ris k is acce pta ble f or t he 
K o ne ksa N e ur oscie n ce T o ol kit ’s i nte n de d use i n t his i n vesti gati o nal cli nical st u d y. Base d o n t he 
i nf or mati o n a vaila ble t o U C B a n d gi ve n t he u n met me dical nee d, p ote ntial f or be nefit, ris ks, a n d 
ris k miti gati o n meas ures, t he be nefit-ris k f or i ncl usi o n of t he K o ne ksa Ne ur oscie nce T o ol kit  is 
c o nsi dere d p ositi ve.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 5  of 1 3 3  
3  
O B J E C TI V E S A N D E N D P OI N T S  
O bje cti ves  
E n d p oi nts  
Pri m ar y Effic ac y O bjecti ve  
T o esti mate t he p har mac o d y na mic effects of 
mi nzas ol mi n ( U C B 0 5 9 9) o n brai n 
pat h o p h ysi ol o g y i n Earl y -start vers us 
Dela ye d -st art partici pa nts ori gi nall y 
dia g n ose d wit h ne w o nset P D  
Pri m ar y Effic ac y E n d p oi nt  
•  Baseli ne a-a dj uste d Da T -S P E C T w h ole 
striat u m S B R at P D 0 0 5 5 M o nt h 1 8 a n d 
M o nt h 6 0  
E x pl or at or y Effic ac y E n d p oi nts  
•  Da T -S P E C T striatal s u b -re gi o ns S B R 
•  C S F t otal A S Y N  
•  C S F A S Y N oli g o mers/see di n g ca pacit y  
Sec o n d ar y Effic ac y O bjecti ve  
T o esti mate t he p h ar mac o d y na mic effects of 
mi nzas ol mi n ( U C B 0 5 9 9) o n t he nee d f or S T 
i n Earl y-start vers us Dela ye d-start 
partici pa nts ori gi nall y dia g n ose d wit h ne w 
o nset P D  
Sec o n d ar y Effic ac y E n d p oi nt  
•  C u m ulati ve L E D D at P D 0 0 5 5 M o nt h 1 8 
a n d M o nt h 6 0  
E x pl or at or y Effic ac y E n d p o i nts 
•  W O Q -9  
Sec o n d ar y S afet y O bjecti ve  
T o assess t he safet y a n d t olera bilit y of 
mi nzas ol mi n ( U C B 0 5 9 9) i n partici pa nts 
ori gi nall y dia g n ose d wit h ne w o nset P D  
Sec o n d ar y S afet y E n d p oi nts  
•  I n ci de nce of T E A Es 
•  I n ci de nce of S A Es 
•  I n ci de nce of T E A Es l ea di n g t o 
wit h dra wal fr o m st u d y  
E x pl or at or y O bjecti ves  
I. Met h o d ol o g y: T o i de ntif y cli nical 
e n d p oi nts a ble t o detect t he 
p har mac o d y n a mic effects of mi nzas ol mi n 
( U C B 0 5 9 9) o n t he cli nic al c o urse of 
Par ki ns o n’s disease after i nitiati o n of S T 
i n Earl y-start vers us Dela yed -start 
partici pa nts ori gi nall y dia g n ose d wit h ne w 
o nset P D  
E x pl or at or y E n d p oi nts ( Cli nic al 
O utc o mes)  
•  M o C A  
•  M D S -N M S ( or selecte d ite ms)  
•  M D S -U P D R S Parts I -III s u m sc ore 
•  M D S -U P D R S Part I s u bs cale ( or select e d 
ite ms) 
•  M D S -U P D R S Part II s u bscale ( or s elect e d 
ite ms a n d e mer gi n g s y m pt o ms) 
•  M D S -U P D R S Part III s u bscale ( or 
selecte d ite ms/s u bsc ore)  
•  M o difie d H & Y  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 6  of 1 3 3  
O bje cti ves  
E n d p oi nts  
•  F A TI G U E -P R O  
•  Earl y P D F u ncti o n Sl o w ness P R O  
•  Earl y P D M o bilit y P R O  
E x pl or at or y E n d p oi nts ( Ot her)  
•  K o ne ksa Ne ur oscie nce T o ol kit  
II. Effecti ve n ess: T o esti mate t he effecti ve ness 
of mi nzas ol mi n ( U C B 0 5 9 9) vers us S o C 
o n  cli nical o utc o mes a n d Q o L be y o n d 1 8 
m o nt hs d urati o n of P D 0 0 5 3 , usi n g e xter nal 
real-w orl d  data ( w here a v aila ble)  
E x pl or at or y E n d p oi nts ( Cli nic al 
O utc o mes)  
•  E Q -5 D -5 L  
•  L E D D  
•  M o C A  
•  M D S -U P D R S Parts I-III s u m sc ore 
•  M D S -U P D R S Part I V  
•  M D S -U P D R S Part I s u bs cale ( or select e d 
ite ms) 
•  M D S -U P D R S Part II s u bscale ( or select e d 
ite ms a n d e mer gi n g s y m pt o ms) 
•  M D S -U P D R S Part III s u bscale ( or 
selecte d ite ms/s u bsc ore) 
•  M o difie d H & Y  
III. Efficac y: T o esti mate t he 
p har mac o d y n a mic effects of Ea rl y-start 
mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g vers us 
E arl y-start mi nzas ol mi n ( U C B 0 5 9 9) 
1 8 0 m g o n t he cli nical c o urse of P D, nee d 
f or S T a n d brai n p at h o p h ysi ol o g y i n 
partici pa nts ori gi nall y dia g n ose d wit h ne w 
o n set P D 
E x pl or at or y E n d p oi nts ( Cli nic al 
O utc o mes)  
•  L E D D  
•  W O Q -9  
•  M o C A  
•  M D S -N M S ( or selecte d ite ms)  
•  M D S -U P D R S Parts I -III s u m sc ore 
•  M D S -U P D R S Part I s u bs cale ( or select e d 
ite ms) 
•  M D S -U P D R S Part II s u bscale ( or select e d 
ite ms a n d e mer gi n g s y m pt o ms) 
•  M D S -U P D R S Part III s u bscale ( or 
selecte d ite ms/s u bsc ore)  
•  M o difie d H & Y  
•  F A TI G U E -P R O  
•  Earl y P D F u ncti o n Sl o w ness P R O  
•  Earl y P D M o bilit y P R O  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 7  of 1 3 3  
O bje cti ves  
E n d p oi nts  
E x pl or at or y E n d p oi nts ( Bi o m ar kers)  
•  Da T -S P E C T w h ole striat u m S B R (a n d 
striatal s u b-re gi o ns S B R) 
•  C S F t otal A S Y N  
•  C S F A S Y N o li g o mers/see di n g ca pacit y 
I V. At y pical Par ki ns o nis m: Re visi o n of P D 
cli nical dia g n osis; i de ntificati o n of 
partici pa nts wit h At y pical Par ki ns o nia n 
Dis or ders  b at P D 0 0 5 5 Baseli ne Visit a n d 
at P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 6 0  
E x pl or at or y Assess m e nts  
•  Re -c o nfir me d P D dia g n osis stat us  
A S Y N =al p ha -s y n uclei n; C S F =cere br os pi nal fl ui d; Da T-S P E C T = D o pa mi ne Tra ns p orter I ma gi n g wit h Si n gle 
P h ot o n E missi o n C o m p ute d T o m o gra p h y; E Q -5 D -5 L = E ur o Q ualit y of life 5 -Di me nsi o ns 5 -Le vel; 
H & Y = H oe h n a n d Ya hr; L E D D = Le v o d o pa E q ui vale nt Dail y D ose; M D S -N M S = M o ve me nt Dis or der S ociet y 
N o n -M ot or Rati n g Scale; M D S -U P D R S = M o ve me nt Dis or der S ociet y U nifie d Par ki ns o n's Disease Rati n g 
Scale; M o C A = M o ntreal C o g niti ve Assess me nt; P R O = patie nt -re p orte d o utc o me; P D = Par ki ns o n’s disease; 
Q o L = Q ualit y of Life; S A E =seri o us a d verse e ve nt; S B R =s pe cific bi n di n g rati o; S o C =sta n dar d of care; 
S T =s y m pt o matic treat me nt; T E A E =treat me nt -e mer ge nt a d verse e ve nt; W O Q -9 = Weari n g -off  Q uesti o n naire -9  
a Baseli ne will refer t o P D 0 0 5 3 Baseli ne Visit data ( or Scree ni n g Visit data w here a p plica ble).  
b M ost fre q ue nt At y pical Par ki ns o nia n Dis or ders are:  
•  
Pr o gressi ve s u pra n uclear pals y ( P S P): Ta u  
•  
C ortic o basal d e g e n erati o n ( C B D): Ta u (al p ha -s y n) 
•  
M ulti ple s yste m atr o p h y ( M S A): Al p ha -s y n de p ositi o n i n glial cells/ oli g o de n dr oc ytes 
•  
De m e ntia wit h Le w y b o dies ( L B D): Al p ha -s y n de p ositi o n i n c ortical ne ur o ns 
4  
S T U D Y D E SI G N  
4. 1  
O v er all d e si g n  
P D 0 0 5 5, a d ose -bli n de d, P hase 2, e xte nsi o n st u d y of P D 0 0 5 3, will e va l uate t he l o n g-ter m 
effic ac y, safet y, a n d t olera bilit y of mi nzas ol mi n ( U C B 0 5 9 9) i n st u d y partici pa nts w h o were 
dia g n ose d wit h ne w o nset P D w he n e nteri n g P D 0 0 5 3, t he pr o of -of -c o n ce pt st u d y. St u d y 
partici pa nts will be all o w e d t o recei ve S T (ie, t he y will eit her c o nti n ue S T fr o m P D 0 0 5 3 or t he y 
will be free t o r e q uest t he i nitiati o n of S T i n c olla b orati o n wit h t he st u d y p h ysicia n) a n d will 
recei v e I M P f or u p t o 6 0 m o nt hs. Par ki ns o n’s disease cli nical dia g n osis will be re vie we d at t he 
P D 0 0 5 5 Baseli ne Visit a n d a t P D 0 0 5 5 M o nt h 1 8 (ie,  3 6  m o nt hs p ost P D 0 0 5 3 Scree ni n g).  
A t otal of 4 9 3 partici pa nts were d os e d i n P D 0 0 5 3. Of t he 4 3 1 partici p a nts w h o c o m plete d 
P D 0 0 5 3, 4 2 8 tra nsiti o ne d i nt o P D 0 0 5 5. Ass u mi n g t hat 1 5 % of P D 0 0 5 5 partici pa nts w h o were 
ra n d o mize d t o place b o in P D 0 0 5 3 dr o p o ut wit hi n t he first fe w m o nt hs of r olli n g o ver i nt o 
P D 0 0 5 5 d ue t o A Es u p o n i nitiati n g mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y (ie, ar o u n d 
2 0  partici pa nts n ot c o m pleti n g t heir M o nt h 3 visit), a n d t hat a n ot her 5 % of partici pa nts acr oss all 
treat me nt ar ms dr o p o ut or are l ost t o f oll o w u p i n a n y gi ve n year, ar o u n d 3 7 4 a n d 3 1 4 
partici pa nts w o ul d be e x pecte d t o reac h P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 6 0, res pecti vel y.  
Partici pa nts w h o ha ve b ee n treate d wit h mi nzas ol mi n ( U C B 0 5 9 9) 1 8 0 m g/ da y d uri n g P D 0 0 5 3 
will c o nti n ue t o recei ve mi nzas ol mi n ( U C B 0 5 9 9) 1 8 0 m g/ da y i n e xte nsi o n st u d y P D 0 0 5 5. 
Partici pa nts w h o ha ve b ee n treate d wit h mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y d uri n g P D 0 0 5 3 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 8  of 1 3 3  
will c o nti n ue t o recei ve mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y i n P D 0 0 5 5. Partici pa nts w h o 
recei v e d place b o d uri n g P D 0 0 5 3 will recei ve mi n zas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y i n P D 0 0 5 5.  
After c o m pleti n g, at t he mi ni m u m, t he M o nt h 1 8 Visit i n P D 0 0 5 5, partici pa nts will b e s witc he d 
t o t he best d ose, as deter mi ne d fr o m t he res ults of P D 0 0 5 3. All st u d y partici pa nts a n d 
I n v esti gat ors will re mai n bli n de d t o treat me nt/ d ose recei ve d i n P D 0 0 5 3 a n d P D 0 0 5 5 at least u ntil 
all partici pa nts ha ve c o m plete d t he M o nt h 1 8 assess me nts i n P D 0 0 5 5. T hereafter, P D 0 0 5 5 will 
be o pe n la bel.  
T hr o u g h o ut t he st u d y, data will be re vie we d o n a n o n g oi n g basis b y a D M C a n d a S M C. Refer t o 
Secti o n  9. 7  f or details o n s pecific dat a re vie w a n d ti mi n gs. 
A st u d y o ver vie w of P D 0 0 5 5 is pr o vi de d i n Fi g ure  1 -1 . T he st u d y will c o m prise 3 e m be d de d 
desi g ns. T he acti ve ar m will be c o nsi dere d t o be mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g. T w o 
c o m parat or ar ms will be use d t o pr o vi de f urt her i nsi g ht i nt o t he efficac y/effecti ve ness of 
mi nzas ol mi n ( U C B 0 5 9 9):  
•  Dela ye d -start ar m ( 3 6 0 m g) ( Fi g ur e  1 -2 ) 
•  L o w -d ose ar m ( 1 8 0 m g) ( Fi g ure  1 -3 ) 
I n a d diti o n, e xter nal r eal-w orl d data ( w h ere a vaila ble) will be use d t o esti mate t he effecti ve ness 
of mi nzas ol mi n ( U C B 0 5 9 9) (select e d e n d p oi nts o nl y) vers us t he S o C be y o n d t he 1 8 m o nt hs 
d urati o n of t he fee der st u d y P D 0 0 5 3 ( Fi g ure  1 -4 ). 
T he pri mar y o bje cti ve of P D 0 0 5 5 is t o esti mate t he p har mac o d y na mic effects of mi nzas ol mi n 
( U C B 0 5 9 9) o n brai n pat h o p h ysi ol o g y i n Earl y-start vers us D ela ye d-start partici pa nts ori gi nall y 
dia g n ose d wit h ne w o nset P D. T he Dela ye d -start partici pa nts will recei ve t he e q ui vale nt of h alf 
t he c u m ulati ve d ose of mi nzas ol mi n ( U C B 0 5 9 9) c o m pare d wit h t he Earl y-start partici pa nts; t he y 
will als o i nitiate mi nzas ol mi n ( U C B 0 5 9 9) at  a later p hase wit h r es pect t o t h eir P D dia g n osis.  
T he sec o n d ar y efficac y o bjecti ve of t he e xt e nsi o n st u d y is t o esti mate t he p har mac o d y n a mic 
effects of mi nzas ol mi n ( U C B 0 5 9 9) o n t he nee d f or S T i n partici pa nts ori gi nall y dia g n ose d wit h 
ne w o nset P D, ta ki n g  a d va nta ge of t he Earl y -start vers us Dela ye d-start ar ms desi g n. T he 
sec o n dar y safet y o bjecti ve of t he st u d y is t o assess t he safet y a n d t olera bilit y of mi nzas ol mi n 
( U C B 0 5 9 9) i n partici pa nts ori gi nall y dia g n ose d wit h ne w-o nset P D a n d will i ncl u de rec or di n g of 
i nci de nces of T E A Es, S A Es, a n d T E A Es lea di n g t o wit h dra wal fr o m t he st u d y. 
T he e x pl orat or y o bj ecti v es of t he st u d y i ncl u de assess me nts of met h o d ol o g y (ie, i de ntificati o n of 
n o vel e n d p oi nts), effecti ve ness (stre n gt h e ni n g of t he patie nt val ue ste m mi n g fr o m i m pact o n ke y 
m ot or o utc o mes), effi cac y (esti mati o n of p har mac o d y na mic effects of mi nzas ol mi n ( U C B 0 5 9 9) 
t hat ma y i nf or m a n y d ose-res p o nse m o deli n g), a n d i de ntificati o n of partici p a nts wit h At y pical 
Par ki ns o nis m.  
T he pri mar y a n d s ec o n d ar y effic ac y o bjecti ves of t he st u d y, as well as t he e x pl orat or y 
met h o d ol o g y o bjecti ve, will ma ke use of t he Dela ye d -start ar m (Fi g ure  1 -2 ). T he e x pl or at or y 
effic ac y o bje cti ve will ma ke use of t h e L o w -d os e ar m ( Fi g ure  1 -3 ). Fi nall y, t he e x pl orat or y 
effecti ve ness o bjecti ve will ma ke use of t he e xter nal real -w orl d data ( Fi g ur e  1 -4 ). 
T he a nal yses t o be p erf or me d f or t he pri mar y a n d sec o n dar y effi cac y o bj ecti ves, f or t he 
e x pl orat or y o bjecti ves I ( met h o d ol o g y) a n d II (effec ti ve ness), as well as f or safet y a nal yses will 
use all st u d y data ( u p t o 6 0 m o nt hs p ost P D 0 0 5 5 Baseli ne Visit).  T he a nal yses t o be perf or me d 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 3 9  of 1 3 3  
f or t he e x pl or at or y o bjecti ve III (effi cac y [ d ose c o m paris o n]) will use data fr o m t he first 
1 8  m o nt hs of P D 0 0 5 5 o nl y.  
P D 0 0 5 5 i ncl u des a Scree ni n g Peri o d of u p t o 6 0 da ys ( o verla p pi n g wit h t he Treat me nt Peri o d of 
P D 0 0 5 3) f oll o we d b y a Treat me nt Peri o d of 6 0 m o nt hs a n d a n S F U Visit 3 0 da ys after t h e last 
d ose. St u d y partici pa nts w h o c o m plete d t he Treat me nt Peri o d of P D 0 0 5 3 are eli gi ble f or 
e nr oll me nt i n P D 0 0 5 5.  
4. 2  
S ci e ntifi c r ati o n al e f or st u d y d e si g n  
T he pri mar y o bje cti ve of t he P D 0 0 5 5 e xte nsi o n st u d y is t o a d dress a q uesti o n c o m ple me ntar y t o 
t he o ne a ns were d b y t he pri mar y o bjecti ve of t h e pr o of-of -c o nce pt st u d y, P D 0 0 5 3. T he 
D o pa mi ne Tra ns p orter I ma gi n g wit h Si n gle P h ot o n E missi o n C o m p ute d T o m o gra p h y 
( Da T-S P E C T) w h ole stri at u m s pecific bi n di n g rati o ( S B R) si g nal was selecte d as t he bi o mar ker 
e n d p oi nt of c h oice t o meas ure t he i m pact of mi nzas ol mi n ( U C B 0 5 9 9) o n t he i nte grit y of 
d o pa mi ner gic ner ves ter mi nals ( Fi g ure  1 -2 ). T he bi o mar ker Da T-S P E C T is t he best esta blis he d 
i n vi v o met h o d t o m o nit or d o pa mi ner gic n e ur o de g e nerati o n. It h as bee n re p orte d i n t he literat ure 
t hat Da T-S P E C T res ults are n ot i m pacte d ( or are o nl y mar gi nall y i m pacte d) b y usi n g S T 
(I ke da et al, 2 0 1 9). I n p arallel, le vels of A S Y N i n t he cere br os pi nal fl ui d ( C S F) will be use d as 
e x pl orat or y e n d p oi nts t o e val uate  t he i m pact of mi nzas ol mi n ( U C B 0 5 9 9) o n A S Y N meta b olis m 
i n t he brai n. 
T he sec o n d ar y o bjecti ve of P D 0 0 5 5 is t o esti mate t he p har mac o d y n a mic effects of mi nzas ol mi n 
( U C B 0 5 9 9) o n t he nee d f or S T i n Earl y-start vers us Dela ye d-start partici pa nts. T he c u m ulati ve 
Le v o d o pa E q ui vale nt D ail y D ose ( L E D D) a n d t he Weari n g -off Q uesti o n naire -9 ( W O Q -9) were 
selecte d as cli nical o utc o mes of c h oice t o meas ure t he i m pact of mi nzas ol mi n ( U C B 0 5 9 9) o n t he 
S T b ur de n a n d t he weari n g -off ( W O) of d o p a mi ner gic treat me nt.  
T o a d dress t h e e x pl orat or y o bjecti ve I ( of m et h o d ol o g y), m ot or a n d n o n m ot or o utc o mes were 
selecte d bas e d o n res earc h w or k at U C B t o de vel o p ne w e n d p oi nts w hic h w o ul d be m ost rele va nt 
t o P D patie nts a n d be a s uita ble se nsiti ve e n d p oi nt i n l o n git u di nal cli nical st u dies perf or m e d i n 
t he earl y P D p o p ulati o n u n der S T (le v o d o pa). I n a d diti o n, s uita bilit y of usi n g Di gital Healt h 
Tec h n ol o g y as a n o n -i n vasi ve met h o d t o c ollect d ata o n si g ns a n d s y m pt o ms of P D is e x pl ore d. 
T he res ults fr o m t he e x pl orat or y o bjecti ve II ( of effecti ve ness) will all o w t he stre n gt he ni n g of t he 
patie nt val ue ste m mi n g fr o m i m pact o n ke y m ot or o utc o mes t hr o u g h ( p ote ntiall y) s h o wi n g a n 
i m pact als o o n Q ualit y of Life ( Q o L) o utc o mes. Researc h wit h nati o nal pa y ers i n dicates t hat t his 
c o m bi nati o n w o ul d be part ic ularl y i m pactf ul i n de m o nstrati n g patie nt val ue. 
T he res ults o btai ne d fr o m t he e x pl orat or y o bjecti ve III ( of efficac y) ma y i nf or m a n y 
d ose -res p o ns e m o deli n g, c o nfir m a n y differe n ce s ee n i n efficac y i n P D 0 0 5 3 , or i nf or m o n a n y 
l o n ger ter m i m pact of t he c u m ulati ve d ose of mi nzas ol mi n ( U C B 0 5 9 9) . 
Fi nall y, t he e x pl orat or y o bjecti ve I V, w h ere t h e i nitial P D cli nical dia g n osis will be re -ass esse d, 
will all o w t he e xcl usi o n of partici pa nts w h o are n o l o n ger belie ve d t o ha ve a cli nical dia g n osis of 
P D fr o m pri mar y a n al yses i n P D 0 0 5 3 a n d P D 0 0 5 5 (se nsiti vit y a nal yses).  
4. 2. 1  
P ati e nt i n p ut i nt o d e si g n  
T here w as n o patie nt i n p ut i n t he st u d y desi g n of P D 0 0 5 5 ( P D 0 0 5 3 e xte nsi o n).  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 0  of 1 3 3  
4. 3  
J u stifi c ati o n f or d o s e  
T he rati o nale f or testi n g t he pr o p ose d cli nical d ose le vels of mi nzas ol mi n  ( U C B 0 5 9 9) 
1 8 0 m g/ da y ( 9 0 m g BI D) a n d 3 6 0 m g/ da y ( 1 8 0 m g BI D) i n e xte nsi o n st u d y P D 0 0 5 5 is t o all o w 
partici pa nts t o c o nti n ue i nt o P D 0 0 5 5 o n t he sa me d ose le vel as t he y were ra n d o ml y assi g ne d t o 
i n P D 0 0 5 3. 
T he d oses i n P D 0 0 5 3 were base d o n ( 1) t he s afet y mar gi n  esti mates c o m pari n g s yste mic 
e x p os ures at t he n o o bs er ve d a d vers e effect le vel i n m o n ke y wit h h u ma n o bser ve d e x p os ures i n 
st u d y partici pa nts wit h P D treate d i n U P 0 0 7 7, a n d ( 2) e x p os ures t hat ha ve s h o w n 
p har mac ol o gical acti vit y i n tra ns ge nic mice t hat o ver e x press t he h u ma n wil dt y pe A S Y N ge ne 
(s y n uclei n al p ha) i n t he C N S. U p war d or d o w n titrati o n of mi nzas ol mi n ( U C B 0 5 9 9) d ose is n ot 
necessar y. T he ma xi m u m dail y d ose teste d i n t he pr o gra m is mi nzas ol mi n ( U C B 0 5 9 9) 
3 6 0 m g/ da y ( 1 8 0 m g BI D).  
All partici pa nts fr o m t he place b o ar m of P D 0 0 5 3 will be assi g ne d t o a si n gle d ose le vel of 
mi nzas ol mi n ( U C B 0 5 9 9) i n P D 0 0 5 5, w hic h will be t he d ose c urre ntl y belie ve d t o pr o vi de m ost 
effic ac y, ie, 3 6 0 m g/ da y. T his desi g n will all o w t he n u m ber of partici pa nts i ncl u de d i n t he 
Dela ye d -st art a nal ysis t o be ma xi mize d.  
After c o m pleti n g, at t he mi ni m u m, t he M o nt h 1 8 Visit i n P D 0 0 5 5, partici pa nts will be s witc he d 
t o t he best d ose. T he best d ose will be deci de d b y U C B base d u p o n effi cac y a n d safet y d ata fr o m 
c o m plete d P D 0 0 5 3 a n d s afet y i n p ut fr o m t he D M C.  
P ote ntial f o o d effect, as well as p ote ntial dr u g -dr u g i nteracti o n wit h itrac o naz ole, a str o n g 
c yt oc hr o me P 4 5 0 3 A 4 ( C Y P 3 A 4) i n hi bit or, were e val uate d i n P hase 1 st u d y U P 0 0 7 8 after a 
si n gle d ose of mi nzas ol mi n ( U C B 0 5 9 9) 1 8 0 m g. Data fr o m U P 0 07 8 c o nfir me d t hat n o f o o d 
effect -re q uiri n g d ose a dj ust me nt is nee de d i n P D 0 0 5 5. H o we ver, str o n g C Y P 3 A 4 i n hi bit ors (a n d 
i n d ucers) s h o ul d n ot be c o-a d mi nistere d wit h mi nzas ol mi n ( U C B 0 5 9 9).  
4. 4  
E n d of st u d y d efi niti o n  
A partici pa nt is c o nsi dere d t o ha ve c o m plet e d t he st u d y if he/s he has c o m plete d all peri o ds of t he 
st u d y i ncl u di n g t he S F U Visit ( 3 0 da ys after last d ose). 
T he gl o bal e n d of t he st u d y is defi ne d as t he dat e of t he last visit of t he last partici pa nt i n t he 
st u d y. 
5  
S T U D Y P O P U L A TI O N  
Pr os pecti ve a p pr o val of pr ot oc ol de viati o ns t o recr uit me nt a n d e nr oll me nt criteria, als o k n o w n as 
pr ot oc ol wai vers or e xe m pti o ns, is n ot per mitte d.  
5. 1  
I n cl u si o n crit eri a 
Partici pa nts are eli gi ble t o be i ncl u de d i n t he st u d y o nl y if all of t he f oll o wi n g criteria a p pl y:  
T y p e of p arti ci p a nt a n d di s e a s e c h ar a ct eri sti c s  
1.  Partici pa nt c o m plete d t he Treat me nt Peri o d of P D 0 0 5 3. T he Baseli ne Visit f or P D 0 0 5 5 
( Visit 2) s h o ul d be n o later t ha n 4 wee ks f oll o wi n g t he E O T Visit i n P D 0 0 5 3.  A n y dela y 
nee ds t o be j ustifie d b y t he I n vesti g at or a n d a p pr o ve d b y t he S p o ns or.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 1  of 1 3 3  
S e x  
2.  C o ntrace pti o n  
− A male st u d y partici pa nt m ust a gree t o use c o ntrace pti o n as detaile d i n A p pe n di x  4 
(Secti o n  1 0. 4 ) d uri n g t he Treat me nt Peri o d a n d f or at least 9 0 da ys after t h e last d ose of 
t he I M P a n d refrai n fr o m d o nati n g s per m d uri n g t his peri o d. 
− A fe male st u d y partici pa nt is eli gi ble t o partici pate if s he is n ot pre g na nt, n ot 
breastfee di n g, a n d at least 1 of t he  f oll o wi n g c o n diti o ns a p plies: 
◦ 
N ot a w o ma n of c hil d beari n g p ote ntial ( W O C B P) as defi ne d i n A p p e n di x  4 
(Secti o n  1 0. 4  ) 
O R  
A W O C B P w h o a grees t o f oll o w t he c o ntrace pti v e g ui da nce d uri n g t he Treat me nt 
Peri o d a n d f or at least  1 m o nt h  after t he last d ose of I M P. T he st u d y partici pa nt m ust 
ha ve a n e gati ve uri ne pre g na nc y test at Scree ni n g ( Visit  1), w hic h is t o be c o nfir me d 
ne gati ve b y uri ne testi n g pri or t o t he first d ose of I M P at P D 0 0 5 5 Baseli ne Visit. If 
oral c o ntrace pti o n is use d, a n a d diti o nal barri er m et h o d will be re q uire d d uri n g t he 
st u d y as a n I M P-relate d gastr oi ntesti nal u pset or a dr u g i nteracti o n b y C Y P 3 A 4 
i n d ucti o n c o ul d i nterfere wit h efficac y. 
I nf or m e d c o n s e nt 
3.  Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt as d es cri be d i n A p pe n di x 1  (Secti o n  1 0. 1. 3 ) 
w hic h i ncl u des c o m plia n ce wit h t he re q uire me nts a n d restricti o ns liste d i n t he I C F a n d i n t his 
pr ot oc ol.  
5. 2  
E x cl u si o n crit eri a  
Partici pa nts are e xcl u de d fr o m t he st u d y if a n y of t he f oll o wi n g criteria a p pl y:  
Me dic al c o n diti o ns  
1.  St u d y partici pa nt has a n y me dical or ps yc hiatri c c o n diti o n t hat, i n t he o pi ni o n of t he 
I n v esti gat or, c o ul d je o par dize or w o ul d c o m pr o mise t he st u d y partici pa nt’s a bilit y t o 
partici pate i n t his st u d y.  
2.  A fe male st u d y partici pa nt w h o  tests p ositi ve f or pre g na nc y, pl a ns t o get pre g na nt d uri n g t he 
partici pati o n i n t he st u d y, or w h o is breastf ee di n g.  
Ot her e xcl usi o ns  
3.  St u d y partici pa nt ha d pre vi o usl y partici pate d i n P D 0 0 5 5.  
4.  St u d y partici pa nt meets a n y wit h dra wal criteria i n P D 0 0 5 3.  
5.  St u d y partici pa nts weari n g a n y ki n d of i m pla nta ble acti ve d e vice, i ncl u di n g car diac 
pace ma k ers, p u m ps, a n d i m pla nta ble car di o verters, will be e xcl u de d fr o m usi n g t he K o ne ksa 
Ne ur oscie n ce T o ol kit , b ut ma y partici pate i n t he mai n st u d y. 
6.  St u d y partici pa nt d oes n ot a gree t o r efrai n fr o m d o nati n g bl o o d or bl o o d pr o d ucts or ot her 
b o d y fl ui ds.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 2  of 1 3 3  
5. 3  
Lif e st yl e r e stri cti o n s  
5. 3. 1  
M e al s a n d di et ar y r e stri cti o n s  
T he st u d y partici pa nt m ust n ot i n gest gra pefr uit, starfr uit, or pa w pa w (as be vera ge, fr uit, or 
s u pple me nts) t hr o u g h o ut t he st u d y.  
5. 3. 2  
C aff ei n e, al c o h ol, a n d t o b a c c o  
T here are n o restricti o ns f or caffei n e or t o bacc o d uri n g t he st u d y. Pri or d oc u me ntati o n of alc o h ol 
a b use was a n e xcl usi o n criteri o n f or P D 0 0 5 3. St u d y partici pa nts are re q u este d t o li mit alc o h ol  
c o ns u m pti o n ( n o m ore t ha n m o derate alc o h ol c o ns u m pti o n).  
5. 3. 3  
A cti vit y  
T here are n o restricti o ns o n a n y acti vities.  
5. 4  
S cr e e n f ail ur e s  
Scree n fail ures are defi ne d as partici pa nts w h o c o nse nt t o partici pate i n t he cli nical st u d y b ut are 
n ot s u bse q ue ntl y ra n d o ml y a ssi g ne d t o I M P i n t he st u d y. A mi ni mal set of scree n fail ure 
i nf or mati o n is re q uire d t o e ns ure tra ns p are nt re p orti n g of scree n fail ure partici pa nts t o meet t he 
C o ns oli date d Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uire me nts a n d t o res p o n d t o q ueries 
fr om re g ulat or y a ut h orities. Mi ni mal i nf or mati o n i ncl u des de m o gra p h y, scree n fail ure det ails, 
eli gi bilit y criteria, a n d a n y S A E.  
T here will be n o rescree ni n g i n P D 0 0 5 5.  
6  
S T U D Y T R E A T M E N T S/I N V E S TI G A TI O N A L D E VI C E  
St u d y treat me nt is defi ne d as a n y i n vesti gati o nal treat me nt(s), m ar kete d pr o d uct(s), place b o, or 
me dical de vice (s) i nte n d e d t o be a d mi nistere d t o a st u d y partici pa nt acc or di n g t o t he st u d y 
pr ot oc ol.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 3  of 1 3 3  
6. 1  
Tr e at m e nt s a d mi ni st er e d  
Ar m N a me  
Mi nzas ol mi n ( U C B 0 5 9 9) 
1 8 0 m g/ da y  
Mi nzas ol mi n ( U C B 0 5 9 9) 
3 6 0 m g/ da y  
I nter ve nti o n n a me 
Mi nzas ol mi n ( U C B 0 5 9 9)  
Mi nzas ol mi n ( U C B 0 5 9 9)  
T y pe  
Dr u g  
Dr u g  
D ose f or m ul ati o n  
Gra n ules i n ca ps ules a n d matc hi n g 
place b o ca ps ules  
Gra n ules i n ca ps ules  
U nit d ose stre n gt h(s)  
9 0 m g a n d 0 m g  
9 0 m g  
D os a ge le vel(s)  
1 8 0 m g/ da y ( 9 0 m g BI D)  
3 6 0 m g/ da y ( 1 8 0 m g BI D)  
R o ute of 
a d mi nistr ati o n  
Oral –  2 ca ps ules 9 0 m g a n d 2 
matc hi n g place b o ca ps ules per da y 
BI D a p pr o xi matel y 1 2  h o urs a part  
Oral –  4 ca ps ules 9 0 m g per da y BI D 
a p pr o xi matel y 1 2  h o urs a part  
Use  
E x peri me ntal  
E x peri me n tal 
I M P a n d NI M P/ A x M P 
I M P  
I M P  
S o urci n g  
I M P will be s u p plie d b y U C B 
Cli nical Trial S u p pl y or desi g nee.  
I M P will be s u p plie d b y U C B 
Cli nical Trial S u p pl y or desi g nee.  
P ac k a gi n g a n d l a beli n g  T he I M P is ma n ufact ure d, 
pac ka ge d, a n d la bele d acc or di n g t o 
G M P g ui deli nes a n d i n acc or da nce 
wit h all a p plica ble la ws or 
re g ulati o ns. Eac h I M P cart o n will be 
la bele d acc or di n g t o i n di vi d ual 
c o u ntr y re q uire me nts. Details of t he 
pac ka gi n g a n d la beli n g will b e 
pr o vi de d i n t he I M P Ha n dli n g 
Ma n ual.  
T he I M P is ma n ufact ure d, 
pac ka ge d, a n d la bele d acc or di n g t o 
G M P g ui deli nes a n d i n acc or da nce 
wit h all a p plica ble la ws or 
re g ulati o ns. Eac h I M P cart o n will be 
la bele d acc or di n g t o i n di vi d ual 
c o u ntr y re q uire me nts. Detai ls of t he 
pac ka gi n g a n d la beli n g will be 
pr o vi de d i n t he I M P Ha n dli n g 
Ma n ual.  
C urre nt/ F or mer 
n a me(s) or ali as(es)  
N A  
N A  
A x M P =a u xiliar y me dici nal pr o d uct; BI D =t wice dail y; G M P = G o o d Ma n ufact uri n g Practices; I M P =i n vesti gati o nal 
me dici nal pr o d uct; N A = n ot a p plica ble; NI M P = n o ni n vesti gati o nal me dici nal pr o d uct  
6. 2  
Pr e p ar ati o n, h a n dli n g, st or a g e, a n d a c c o u nt a bilit y r e q uir e m e nt s  
T he I n vesti gat or or d esi g nee m ust c o nfir m t hat a p pr o priate te m perat ure c o n diti o ns ha ve bee n 
mai ntai ne d d uri n g tra nsit f or all I M P r ecei ve d a n d a n y discre p a ncies are re p orte d a n d res ol ve d 
bef ore us e of t he st u d y tr eat me nt.  
O nl y partici pa nts e nr olle d i n t he st u d y ma y recei v e t he I M P a n d o nl y a ut h orize d site staff m a y 
s u p pl y or a d mi nister t he I M P. All I M P m ust be st ore d i n a sec ure, e n vir o n me ntall y c o ntr olle d, 
a n d m o nit ore d ( ma n ual or a ut o mate d) area i n acc or da nce wit h t he la bele d st ora ge c o n diti o ns, 
wit h access li mite d t o t he I n v esti gat or a n d a ut h orize d site staff.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 4  of 1 3 3  
T he I n vesti gat or, i nstit uti o n, or t he hea d of t he me dical i nstit uti o n ( w h ere a p plica ble) is 
res p o nsi ble f or I M P acc o u nta bilit y, rec o nciliati o n, a n d rec or d mai nte na n ce (ie, recei pt, 
rec o nciliati o n, a n d fi nal dis p ositi o n rec or ds). 
I n case a n o ut-of -ra n g e te m perat ure is n ote d, it m ust be i m me diatel y re p orte d as per i nstr ucti o ns 
c ontai ne d i n t he I M P Ha n dli n g Ma n ual.  
T he I n vesti gat or ( or desi g nee) will i nstr uct t he partici pa nt t o st ore t he I M P f oll o wi n g t he 
i nstr ucti o ns o n t he la bel. 
F urt her g ui d a nce a n d i nf or mati o n f or t he fi nal dis p ositi o n of u n use d I M P are pr o vi de d i n t he 
I M P Ha n dli n g Ma n u al. 
6. 2. 1  
Dr u g a c c o u nt a bilit y  
A Dr u g Acc o u nta bilit y f or m will be use d t o rec or d I M P dis pe nsi n g a n d ret ur n i nf or mati o n o n a 
b y -partici pa nt basis a n d will ser ve as s o ur ce d oc u me ntati o n d uri n g t he c o urse of t he st u d y. 
Details of a n y I M P l ost, da ma ge d ( d ue t o brea ka g e or wasta g e), n ot use d, p artiall y use d, 
dis p ose d of at t he st u d y site, or ret ur ne d t o t he S p o ns or or desi g nee m ust als o be rec or de d o n t he 
a p pr o priate f or ms. All s u p plies a n d p har mac y d oc u me ntati o n m ust be ma de a vaila ble t hr o u g h o ut 
t he st u d y f or U C B ( or desi g nee) t o re vie w.  
T he I n vesti gat or ( or desi g nee) is res p o nsi ble f or retai ni n g all use d, u n use d, a n d partiall y use d 
c o ntai ners of I M P u ntil ret ur ne d or destr o ye d.  
T he I n vesti gat or ma y assi g n s o me of t he I n vesti gat or’s d uties f or dr u g acc o u nta bil it y at t he st u d y 
site t o a n a p pr o priate p h ar macist/ desi g nee. 
T he I n vesti gat or m ust e ns ure t hat t he I M P is use d o nl y i n acc or da n ce wit h t he pr ot oc ol.  
Peri o dicall y, a n d/ or aft er c o m pleti o n of t he cli nical p hase of t he st u d y, all use d (i ncl u di n g e m pt y 
c o ntai ners/ partiall y use d), u n use d, da ma ge d, a n d/ or e x pire d I M P m ust be rec o ncile d a n d eit her 
destr o ye d at t he site acc or di n g t o l ocal la ws, re g ul ati o ns, a n d U C B sta n dar d o perati n g pr oce d ures 
( S O Ps) or ret ur ne d t o U C B ( or desi g nee). I n vesti g ati o nal me dici nal pr o duct i nte n de d f or t he 
st u d y ca n n ot be use d f or a n y ot her p ur p os e t ha n t hat descri be d i n t his pr ot o c ol.  
6. 3  
M e a s ur e s t o mi ni mi z e bi a s: r a n d o mi z ati o n a n d bli n di n g  
T he ra n d o mize d st u d y partici pa nts i n P D 0 0 5 3 w h o c h o ose t o e nter P D 0 0 5 5 will retai n t heir 
P D 0 0 5 3 ra n d o mizati o n n u m ber a n d st u d y partici p a nt n u m ber.  
Partici pa nts will ha ve alr ea d y bee n ra n d o mize d t o a treat me nt r e gi me n i n P D 0 0 5 3, a n d t heir 
P D 0 0 5 5 treat me nt assi g n me nt is deter mi ne d base d o n t he treat me nt r ecei ve d i n t he fee der st u d y. 
T here is n o rera n d o miza ti o n i n P D 0 0 5 5. A n i nteracti ve res p o nse tec h n ol o g y (I R T) will be use d 
f or assi g ni n g eli gi ble partici pa nts t o a treat me nt re gi me n (as a p plica bl e) bas e d o n a 
pre deter mi ne d pr o d ucti o n pac ka gi n g sc h e d ule pr o vi de d b y U C B ( or desi g n ee). T h e I R T will 
ge nerat e i n d i vi d ual assi g n me nts f or kits of I M P, as a p pr o priate, acc or di n g t o t he visit sc he d ule. 
T he partici pa nt n u m ber will be re q uire d i n all c o m m u nicati o n bet wee n t h e I n vesti gat or or 
desi g nee a n d t he I R T re g ar di n g a partic ular partici pa nt. Partici pa nt n u m bers a n d kit n u m bers will 
be trac k e d via t he I R T. T he I R T will all ocate kit n u m bers t o t he partici pa nt base d o n t he 
partici pa nt n u m ber d uri n g t he c o urse of t he st u d y. T he ra n d o mizati o n n u m ber m ust be 
i nc or p orate d i nt o t he electr o nic Case Re p ort f or m (e C R F). 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 5  of 1 3 3  
All partici pa nt treat me nt details will be all ocate d a n d mai ntai ne d b y t he I R T. T he f oll o wi n g 
i n di vi d uals will ha ve recei ve d t he ra n d o mizati o n c o de at t he start of t he P D 0 0 5 3 st u d y: 
•  Desi g nate d c o ntr act r esearc h or ga nizati o n ( C R O) bi oa nal ytical staff a nal yzi n g sa m ples  
•  S p o ns or cli nical st u d y s u p pl y staff  
•  I R T pr o vi d er 
T he f oll o wi n g i n di vi d uals ma y ha ve access t o t he ra n d o mizati o n c o de as i n dicate d:  
•  S p o ns or patie nt safet y staff as n ee de d f or re p orti n g S A Es t o re g ulat or y a ut h orities  
•  O n re q uest, me m bers of t he D M C  w h o partici pate i n u n bli n de d (cl ose d) sessi o ns will be 
gi ve n i nf or mati o n a b o ut t he I M P all ocati o n f or t h ose partici pa nts f or w h o m data are pr o vi de d 
at t hese sessi o ns  
•  U n bli n de d C R O staff s u p p orti n g pre parati o n of t he data o ut p uts f or t he D M C re vie w  
6. 3. 1  
Pr o c e d u r e s f or m ai nt ai ni n g a n d br e a ki n g t h e tr e at m e nt bli n d 
6. 3. 1. 1  
M ai nt e n a n c e of st u d y tr e at m e nt bli n d  
All partici pa nt treat me nt details will be all ocate d a n d mai ntai ne d b y t he I R T s yste m.  
All st u d y partici pa nts a n d I n v esti gat ors will re mai n bli n de d t o treat me nt/ d ose r ecei ve d i n 
P D 0 0 5 3 a n d P D 0 0 5 5 at least u ntil all partici pa nts ha ve c o m plete d t h e M o nt h 1 8 assess me nts i n 
P D 0 0 5 5. T hereafter, P D 0 0 5 5 will be o pe n la bel.  
W he n P D 0 0 5 3 is u n bli n de d, t he S p o ns or will bec o me u n bli n de d t o t he P D 0 0 5 5 treat me nt 
assi g n me nt.  
6. 3. 1. 2  
Br e a ki n g t h e d o s e bli n d i n a n e m er g e n c y sit u ati o n 
All partici pa nts are o n acti ve treat me nt; as s uc h, u n bli n di n g will n ot be necessar y i n a n 
e mer ge n c y sit uati o n.  
6. 4  
Tr e at m e nt c o m pli a n c e  
At eac h visit after t he I M P is dis pe nse d, partici pa nts m ust ret ur n all u n use d I M P a n d e m pt y I M P 
c o ntai ners. Dr u g acc o u nta bilit y m ust be d o ne i n t he partici pa nt’s prese n ce i n or der t o o btai n 
e x pla nati o ns re g ar di n g discre pa n cies i n c o m plia nce wit h t he d osi n g re gi me n. Dr u g 
acc o u nta bilit y m ust be rec or de d o n t he Dr u g Acc o u nta bilit y f or m.  
If a partici pa nt is f o u n d t o be persiste ntl y n o nc o m plia nt ( < 8 0 % or > 1 2 0 % c o m plia nt), t he 
S p o ns or, i n c o nj u ncti o n wit h t he I n v esti gat or, will ma ke a decisi o n as t o w het her t he partici pa nt 
s h o ul d be wit h dra w n fr o m t he st u d y. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 6  of 1 3 3  
6. 5  
C o n c o mit a nt m e di c ati o n( s)/tr e at m e nt ( s) 
6. 5. 1  
P er mitt e d c o n c o mit a nt tr e at m e nt s ( m e di c ati o n s a n d t h er a pi e s)  
6. 5. 1. 1  
P er mitt e d ( a u xili ar y) tr e at m e nt s f or p erf or mi n g m e a s ur e m e nt s  
6. 5. 1. 1. 1  
D a T -S P E C T  
T he Da Tsca n ®  tracer f or Da T-S P E C T ( A nat o mical T hera pe utic C he mical [ A T C] c o de: 
) i ma gi n g will be s o urce d fr o m G E-Healt hcare via I n vicr o o n be half of U C B. T he 
tracer is a p pr o ve d f or c o m mercial use i n E ur o pe, U S, a n d Ca na da a n d will be use d acc or di n g t o 
t he pr o d uct la bel. A p pr o xi mate ra di oacti vit y per d ose is 1 8 5 M B q.  
I o di ne-base d t h yr oi d pr otecti n g s ol uti o ns (e g, L u g o l’s s ol uti o n) m ust be a d mi nistere d bef ore 
Da T -S P E C T. T hese s ol uti o ns will be s o urce d b y t he sites.  
6. 5. 1. 2  
P er mitt e d C or o n a vir u s Di s e a s e -2 0 1 9 v a c ci n ati o n  
S h o ul d a C O VI D -1 9 vacci ne be a d mi nistere d d uri n g st u d y partici pati o n, f ull details will be 
rec or de d i n t he c o n c o mita nt me dicati o n e C R F pa g e. T he s pecific na me of t he vacci ne a n d t he 
e xact dat e of a d mi nistrati o n s h o ul d be rec or de d, as i nstr ucte d i n t he c o m p leti o n g ui deli ne. 
6. 5. 2  
Pr o hi bit e d c o n c o mit a nt tr e at m e nt s ( m e di c ati o n s a n d t h er a pi e s)  
F or resc ue tr eat me nt of P D s y m pt o ms, refer t o Secti o n  6. 5. 3 . 
Str o n g C Y P 3 A 4 i n hi bit ors a n d i n d ucers, as well as se nsiti ve C Y P 3 A 4 s u bstrates wit h narr o w 
t hera pe utic i n de x are n ot all o we d d uri n g t he st u d y. 
T he f oll o wi n g me dicati o ns are n ot all o we d d uri n g t he 5 0 da ys bef ore Da T -S P E C T i ma gi n g d ue 
t o k n o w n i nteracti o ns: 
•  Met ocl o pra mi de  
•  Al p ha met h yl d o pa  
•  Cl oza pi ne  
•  Ola nza pi ne  
•  Fl u narizi ne  
•  A m o xa pi ne  
•  A m p heta mi ne deri vati ves  
•  Reser pi ne  
•  B u pr o pi o n  
•  B us pir o ne  
•  C ocai ne  
•  Mazi n d ol  
•  Met h yla m p heta mi ne  
•  Met h yl p he ni date  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 7  of 1 3 3  
•  N ore p he dri ne  
•  P he nter mi ne  
•  P he n yl pr o pa n ola mi ne  
•  M o dafi nil  
6. 5. 3  
C o n c o mit a nt S T  
I n v esti gat ors will be e nc o ura ge d t o c aref ull y d oc u me nt all c ha n ges a n d d ose a da ptati o ns, 
partic ularl y w h e n c o nsi d eri n g S T i nitiati o n, w hic h s h o ul d al wa ys c o nsi der t he i n di vi d ual 
partici pa nt nee ds a n d S o C  rec o m me n dati o ns. 
Le v o d o pa is deter mi ne d as t he first  c h oice f or p artici pa nts w h o are d eter mi ne d t o re q uire S T. 
Ot her S T o pti o ns (ie, d o pa mi ne a g o nists) are o nl y per mitte d w here le v o d o pa has a n 
u nsatisfact or y effect, w h ere c o ntrai n dicati o ns a g ai nst le v o d o pa are i de ntifi e d b y t he I n vesti gat or, 
or w here a n alt er nati ve S T dr u g is me dicall y i n dicate d f or a n y ot her reas o n.  
M o n oa mi ne o xi dase -B i n hi bit ors a n d t heir meta b olites (a m p heta mi ne deri v ati ves) will n ot be 
all o we d d ue t o t heir p ote ntial i m pact o n disease pr o gressi o n.  
T he date a n d ti me of o nset of resc u e me dicati o n a d mi nistrati o n, as well as t he na me a n d d osa g e 
re gi me n of t he resc u e me dicati o n, m ust be rec or de d i n t he e C R F. A n y d ose a dj ust me nts als o 
nee d t o be rec or de d.  T his will e na ble t he cal c ulati o n of t he c u m ulati ve  L E D D (sec o n d ar y 
effic ac y e n d p oi nt; refer t o Secti o n  9. 3. 2. 1 ). 
F or all sc h e d ule d visits, st u d y partici pa nts w h o start t o recei v e S T i n P D 0 0 5 5 will b e as ke d t o 
refrai n fr o m ta ki n g S T f or at least 1 2 h o urs bef ore t he cli nic visit a n d t o bri n g t he me dicati o n t o 
t he site. A 1 2-h o ur Was h o ut Peri o d is c o nsi dere d s ufficie nt t o ac hie ve a practicall y defi n e d 
“ O F F” -state a n d h as pr o ve n t olera ble i n cli nical practice ( Bl oe m et al, 2 0 1 9). All tests w hic h are 
e x pecte d t o b e se nsiti ve t o t he effects of S T will ta ke place t hr o u g h o ut t he first part of t he st u d y 
visit t o all o w res u mi n g d osi n g of S T at t he earliest p ossi ble p oi nt. If a p artici pa nt d oes n ot 
c o m pl y wit h t he 1 2 -h o ur S T Was h o ut Peri o d pri or t o a n y visit, t his will be rec or de d.  
6. 6  
D o s e m o difi c ati o n  
T here is n o d ose m o dificati o n i n P D 0 0 5 5 a part fr o m w he n t he best d ose is defi ne d bas e d o n 
P D 0 0 5 3 data.  
6. 7  
Crit eri a f or st u d y h ol d or d o si n g st o p p a g e  
U C B will halt f urt he r d osi n g f or all st u d y partici pa nts at all sites if t he f oll o wi n g criteria are met 
d uri n g t he c o urse of t he st u d y a n d f oll o wi n g case re vie w t o c o nfir m ca usalit y a n d seri o us ness 
a n d/ or se verit y of re p ort e d e ve nts.  
P ossi ble reas o ns f or disc o nti n uati o n or s us pe nsi o n of t he st u d y i ncl u de ( b ut are n ot li mite d t o):  
1.  A patter n of a d vers e e ve nts ( A Es), a b n or mal la b res ults, or ot her safet y fi n di n gs t hat w o ul d 
be u nacce pta ble f or t his patie nt p o p ulati o n.  
2.  A patter n of h y p erse nsiti vit y reacti o ns t hat are c o nsi dere d I M P -relate d a n d t hat w o ul d be 
u nacce pta ble f or t his patie nt p o p ulati o n.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 8  of 1 3 3  
3.  If t he S p o ns or ( or desi g nee) j u d ges it necessar y f or me dical, safet y, re g ul at or y, or a n y ot her 
reas o ns c o nsiste nt wit h a p plica ble la ws, re g ulati o ns, a n d G o o d Cli nical Practices ( G C P). 
4.  S p o ns or’s decisi o n t hat c o nti n uati o n of t he st u d y is u nj ustifia ble f or me dical or et hical 
reas o ns. 
5.  Disc o nti n uati o n of de vel o p me nt of t he S p o ns or’s I M P.  
If a n y criteri o n is p ote ntiall y met, t he S M C will re q uest f or t he D M C t o meet as s o o n as p ossi ble 
t o ma ke a rec o m me n dati o n t o t he S p o ns or as t o w het her disc o nti n uati o n, p a usi n g, or s us pe nsi o n 
of I M P d osi n g or t he st u d y s h o ul d occ ur.  
C o nsi derati o n will be gi ve n t o se verit y a n d relate d ness of e ve nts. F urt her details o n t he r ole a n d 
pr ocess of e ns uri n g cl ose safet y m o nit ori n g t hr o u g h t he S M C a n d D M C are pr o vi de d i n t he 
res pecti ve c hart ers. 
Detaile d pr oce d ures f or re p orti n g S A Es a n d ot her safet y e ve nts w hic h ma y meet st u d y h ol d 
criteria are pr o vi de d i n A p pe n di x 3 ( Secti o n  1 0. 3 ). 
6. 8  
Tr e at m e nt aft er t h e e n d of t h e st u d y  
Per t he c urre nt pr ot oc ol, t here is n o mi nzas ol mi n ( U C B 0 5 9 9) treat me nt pla n ne d after t he st u d y.  
T he I n vesti gat or will disc uss t he best trea t me nt o pti o n wit h t he st u d y partici pa nt after E O T i n 
P D 0 0 5 5, w hic h c o ul d i ncl u de t he p ossi bilit y of e xte n di n g treat me nt i n t his st u d y or j oi ni n g 
a n ot her st u d y wit h mi nzas ol mi n ( U C B 0 5 9 9).  
6. 9  
Di git al H e alt h T e c h n ol o g y  
T his st u d y utilizes t he K o ne ksa Ne ur oscie nc e T o ol kit  as n o ni n vasi ve Di gital Healt h Tec h n ol o g y 
f or at-h o me d ata c ollecti o n of P D s y m pt o ms of m ot or f u ncti o n, s peec h, p h ysical acti vit y, a n d 
slee p ( o pti o nal) fr o m st u d y partici pa nts. T he K o ne ksa Ne ur oscie nce T o ol kit  is pr o visi o ne d b y 
K o ne ksa H ealt h I nc.  
P ote ntial ris ks relate d t o t he Di gital Healt h Tec h n ol o g y are pr o vi de d i n Secti o n  2. 3. 2 . 
K o ne ks a Ne ur oscie nce T o ol kit pr o d uct descri pti o n  
T he K o ne ksa Ne ur os cie n ce T o ol kit  c o nsists of t he f oll o wi n g c o m p o ne nts:  
•  T he K o ne ksa M o bile A p plicati o n f or acti ve m ot or assess me nts a n d c ollecti o n of 
patie nt -re p ort e d data ( K o ne ksa Healt h I nc.) i nte grati n g t he A ural A nal ytics S peec h M o d ule 
( A ural A n al ytics I nc.). 
•  T he Acti Gra p h C PI W ( Acti Gra p h L L C) is a s mart watc h t hat has a C o nf or mité E ur o pée n ne 
( C E) Mar k a n d F o o d a n d Dr u g A d mi nistrati o n ( F D A) 5 1 0( k) cleara nce u n der K 1 8 1 0 7 7; it is 
r o uti nel y use d i n cli nical st u dies t o meas ure acti vit y a n d slee p. It is pr o vi de d to get her wit h a 
Data H u b f or data tra nsfer, w hic h has a C E M ar k a n d is F D A 5 1 0( k) e xe m pt.  
•  T he A p ple i P h o ne ( A p pl e I nc.) is a s m art p h o ne t h at has a C E Mar k a n d c o m plies wit h 
Part  1 5 of t he Fe deral C o m m u nicati o ns C o m missi o n ( F C C) r ules.  
T he m o bile s oft ware a p plicati o n is e xec ute d o n t h e c o m merci all y a vaila ble A p ple i P h o ne a n d 
le vera g es data fr o m t he Acti Gra p h C PI W s mart watc h. S mart p h o ne a n d s m art watc h are g e neral 
p ur p ose platf or ms a n d us e b uilt -i n o perati n g s yste ms a n d acceler o meter se ns ors as t heir pri mar y 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 4 9  of 1 3 3  
s ource of i n p ut. A d diti o nall y, t he Acti Gra p h C PI W c o mes wit h a d oc ki n g stati o n f or c har gi n g 
t he wrist-w or n s mart watc h a n d data tra nsfer. T h e acc urac y a n d s e nsiti vit y of t he acceler o meters 
i n t he Acti Gra p h C PI W a n d A p ple i P h o ne was verifie d i n be nc h testi n g acr oss t he ra n ge of 
accelerati o ns o bser ve d i n h u ma n m oti o n.  
K o ne ks a Ne ur oscie nce T o ol kit use i n t he st u d y  
T he K o ne ksa Ne ur os cie n ce T o ol kit is t o be use d t o ca pt ure P D m ot or s y m pt o ms i n t he c o nte xt of 
a s u per vise d cli nic al st u d y. It is n ot i nte n de d as a dia g n ostic t o ol a n d is n ot use d t o i nf or m 
treat me nt or ot her m e dic al decisi o ns d uri n g t he c o urse of t he st u d y.  
I n t his st u d y, t he K o ne ks a Ne ur os cie nce T o ol kit is use d f or at-h o m e data c ollecti o n of P D 
s y m pt o ms of m ot or f u ncti o n, s peec h, p h ysical acti vit y, a n d slee p ( o pti o nal) fr o m st u d y 
partici pa nts. I n a d diti o n, a n electr o ni c versi o n of t he M D S -U P D R S Part II (acti vities of dail y 
li vi n g), q uesti o ns o n S T me dicati o n i nta ke i ncl u di n g O N/ O F F stat us, a n d sl ee pi n g h o urs of st u d y 
partici pa nts will be ca pt ure d. S t u d y partici pa nt fee d bac k a b o ut t he usa bilit y of t he K o ne ksa 
Ne ur oscie n ce T o ol kit will be c ollecte d via a n electr o nic q uesti o n naire.  
M ot or f u ncti o n a n d s peec h will be assesse d t hr o u g h a batter y of acti ve tas ks usi n g t he m o bile 
s oft ware a p plicati o n e xec ute d o n t he A p ple i P h o ne. I n a d diti o n, patie nt -re p orte d data will be 
c ollecte d via t he A p ple i P h o ne as well.  
P h ysical acti vit y a n d ( o pti o nal) slee p data will be c ollecte d passi vel y usi n g t he Acti Gra p h C PI W.  
T he data c ollecte d b y t he K o ne ksa N e ur oscie nce T o ol k it is n ot s hare d wit h t he st u d y partici pa nt 
or t he I n vesti gat or a n d will n ot be use d f or me dical treat me nt decisi o n ma ki n g or f or partici pa nt 
ma na ge me nt d uri n g t he st u d y.  
T he o btai ne d data are ass esse d o nl y as part of e x pl orat or y a n al yses.  
St u d y partici p a nts will be ca uti o ne d t o f oll o w i nstr ucti o ns gi ve n i n t he Di gital Healt h 
Tec h n ol o g y user ma n u als f or a p pr o priate use a n d st ora ge of t he differe nt c o m p o ne nts of t he 
K o ne ksa N e ur oscie n ce T o ol kit.  
St u d y partici pa nts are free t o wit h dra w fr o m usi n g t he Di git al Healt h Tec h n ol o g y at a n y ti me 
d uri n g t he st u d y wit h o ut bei n g e xcl u de d fr o m st u d y partici pati o n.  
Scree ni n g/ E nr oll me nt/ B aseli ne Visit  
St u d y partici pa nts will be offere d t o use t he K o ne ksa Ne ur oscie nce T o ol kit d uri n g t he 1 8 -m o nt h 
d ose -bli n de d Treat me nt Per i o d a n d will be a p pr oac he d d uri n g t he Scree ni n g Peri o d ( or n o later 
t ha n t he Baseli ne Visit) if t he y are dee m e d eli gi ble b y t he I n vesti gat or. If p artici pa nts c o nse nt t o 
K o ne ksa N e ur oscie n ce T o ol kit use, t he y will be trai ne d o n its pr o per use pri or t o or at  Visit 2 
( Baseli ne Visit). Trai ni n g i ncl u des a K o ne ks a Ne ur oscie nce T o ol kit t ut orial a n d practice usi n g 
t he K o ne ksa N e ur osci e nce T o ol kit u n der cli nical s u per visi o n. F oll o wi n g Visit 2 ( Baseli ne Visit), 
partici pa nts will c o m plete t he K o ne ksa Ne ur oscie nce T o o l kit assess me nts at h o me. Pr o per use of 
t he K o ne ksa N e ur osci e nce T o ol kit will be cl osel y m o nit ore d b y cli nical site staff u ntil Visit 4 
( M o nt h 1).  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 0  of 1 3 3  
E n d of Di git al He alt h Tec h n ol o g y use  
St u d y partici pa nts nee d t o ret ur n t he K o n e ksa Ne ur oscie nce T o ol kit t o t he cli nical site at t he ne xt 
re g ular site visit after st o p pi n g use of t he Di gital Healt h Tec h n ol o g y (at M o nt h 1 8). 
7  
DI S C O N TI N U A TI O N O F S T U D Y M E DI C A 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/ WI T H D R A W A L  
7. 1  
Di s c o nti n u ati o n of st u d y m e di c ati o n  
St u d y me dicati o n will be s t o p pe d if t he st u d y partici pa nt de vel o ps a me di cal c o n diti o n ( or 
la b orat or y a b n or malit y or electr o car di o gra m [ E C G] c ha n g e) t hat, i n t he o pi ni o n of t he 
I n v esti gat or, c o m pr o mises t he st u d y partici pa nt’s a bilit y t o partici pate or c o m pr o mises t he st u d y 
partici pa nt’s safet y . 
A n y ne w cli nicall y rele v a nt safet y fi n di n g s h o ul d be re p ort e d as a n A E.  
I n all cases, t he st u d y p artici pa nt s h o ul d be f oll o we d u ntil t he c o n diti o n has res ol ve d as a gree d 
b y t he I n vesti gat or a n d t h e U C B st u d y p h ysicia n.  
See t he Sc he d ule of Acti vities ( Secti o n  1. 3 ) f or data t o be c ollecte d at t he ti me of treat me nt 
disc o nti n uati o n a n d f oll o w u p a n d f or a n y f urt her e val uati o ns t hat nee d t o b e c o m plete d.  
7. 1. 1  
H y p er s e n siti vit y r e a cti o n s ( s u c h a s r a s h, a n gi o e d e m a, or 
a n a p h yl a xi s)  
St u d y partici pa nts wi ll be i nf or me d t hat if t he y d e vel o p a n y s y m pt o ms s u g gesti ve of a 
h y perse nsiti vit y reacti o n (e g, ras h, a n gi oe de ma, or a na p h yla xis) t he y s h o ul d c o ntact t he 
I n v esti gat or i m me diatel y. 
T he I n vesti gat or s h o ul d assess t he prese nti n g s y m pt o ms t o deter mi ne if t his is p ossi bl y a 
h y perse nsiti vit y reacti o n.  
If t he e v e nt is n ot c o nsi dere d t o be a h y perse nsiti vit y reacti o n (e g, a ras h d u e t o a n ot her ca use) 
t he I n v esti gat or s h o ul d d oc u me nt t his, a n d t he partici pa nt ma y c o nti n ue d osi n g. 
If t he e v e nt is p ossi bl y a h y perse nsiti vit y reacti o n t he I n v esti gat or s h o ul d a d vise t he partici pa nt 
t o wit h h ol d d osi n g a n d arra n ge a d diti o nal i n vesti g ati o ns as per Secti o n  8. 3. 6. 1 . T he eve nt s h o ul d 
be re p ort e d t o U C B as a n A E SI. I n t his sce nari o d osi n g ma y o nl y be rec o m me nce d f oll o wi n g 
a gree m e nt of t he I n v esti gat or a n d t he S M C.  
7. 1. 2  
Li v er c h e mi str y st o p pi n g crit eri a  
Disc o nti n uati o n of st u d y treat me nt f or a b n or mal li ver f u ncti o n s h o ul d be c o nsi dere d b y t he 
I n v esti gat or w he n a st u d y partici pa nt meets o ne of t he c o n diti o ns o utli ne d i n Fi g ure  7 -1  or if t he 
I n v esti gat or belie ves t h at it is i n best i nterest of t he partici pa nt.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 1  of 1 3 3  
Fi g ur e  7 -1 : P h a s e 2 li v er c h e mi str y st o p pi n g crit eri a a n d i n cr e a s e d m o nit ori n g 
al g orit h m  
 
A L T =ala ni ne a mi n otra nsferase; A S T =as partate a mi n otra nsferase; I N R =i nter nati o nal n or malize d rati o; S A E =seri o us 
a d verse e ve nt; U L N = u p per li mit of n or mal.  
S pecific assess me nts a n d f oll o w -u p acti o ns f or p ot e ntial dr u g -i n d uce d li ver i nj ur y ( P DI LI) are 
pr o vi de d i n A p pe n di x 6 ( Secti o n  1 0. 6 ). 
7. 1. 3  
Q T c orr e ct e d st o p pi n g crit eri a  
A st u d y partici pa nt w h o meets eit her b ullete d criteri o n will be wit h dra w n fr o m I M P. 
C o nfir mati o n of t he b ullete d criteri o n s h o ul d be base d o n t he a vera ge of tri plicate 1 2 -lea d E C G 
rea di n gs. 
•  Q T c orrecte d f or heart rate usi n g Fri derici a's f or m ula ( Q Tc F) > 5 0 0 ms O R U nc orrecte d  Q T 
> 6 0 0 ms  
•  C ha n ge fr o m Baseli ne of Q Tc F > 6 0 ms  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 2  of 1 3 3  
F or partici pa nts wit h u n derl yi n g b u n dle bra n c h bl oc k, f oll o w t he disc o nti n uati o n criteria liste d 
bel o w : 
B aseli ne Q Tc wit h b u n dle br a nc h bl oc k  
Disc o nti n u ati o n Q Tc t hres h ol d wit h b u n dle 
br a nc h bl oc k  
< 4 5 0 ms  
> 5 0 0 ms  
4 5 0 t o 4 8 0 ms  
≥5 3 0 ms  
Q Tc = Q T c orrecte d  
If a cli nic all y si g nifica nt fi n di n g is i de ntifie d (i ncl u di n g, b ut n ot li mite d t o, c ha n ges fr o m 
Baseli ne i n Q Tc F after e nr oll me nt) t he I n vesti gat or or q ualifie d desi g n ee will deter mi ne if t he 
partici pa nt ca n c o nti n ue i n t he st u d y a n d if a n y c h a n ge i n partic i pa nt ma na ge me nt is nee de d. 
T his re vie w of t he E C G pri nte d at t he ti me of c oll ecti o n m ust be d oc u me nt e d.  
7. 1. 4  
T e m p or ar y di s c o nti n u ati o n  
T he I n vesti gat or, S M C, or D M C ma y c o nsi der te m p orar y disc o nti n uati o n of d osi n g of st u d y 
partici pa nts o n a case -b y -case b asis.  
7. 1. 5  
R e c h all e n g e  
T he I n vesti gat or after a gree me nt wit h t he S M C (a n d e n d orse me nt b y t he D M C if re q ueste d b y 
t he S M C) ma y c o nsi der rec halle n g e of st u d y parti ci pa nts o n a cas e-b y -case basis  
7. 2  
P arti ci p a nt di s c o nti n u ati o n/ wit h dr a w al fr o m t h e st u d y  
St u d y partici pa nts are free t o wit h dra w fr o m t he st u d y at a n y ti me, wit h o ut prej u dice t o t heir 
c o nti n ue d care.  
A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n v esti gat or, S M C, or D M C f or safet y, be ha vi oral, 
c o m plia nce, or a d mi nistrati ve reas o ns.  If a st u d y p artici pa nt wit h dra ws or is wit h dra w n, he/s he 
s h o ul d be e nc o ura ge d t o perf or m t he E O T/ Earl y Ter mi nati o n ( E T) Visit a n d t he S F U Visit 
a p pr o xi matel y 3 0 da ys after last d ose of I M P.  
If a partici pa nt wit h dra ws fr o m t he st u d y, he/s he ma y re q uest destr u cti o n of a n y sa m ples ta ke n 
a n d n ot teste d, a n d t he I n vesti gat or m ust d oc u me nt t his i n t he site st u d y rec or ds.  
See t he Sc he d ule of Acti vities ( Secti o n  1. 3 ) f or data t o be c ollecte d at t he ti me of st u d y 
disc o nti n uati o n a n d f oll o w u p, a n d f or a n y f urt her e val uati o ns t hat nee d t o be c o m plete d. T he 
Da T -S P E C T will occ ur at E O T, pr o vi de d t hat t he pre vi o us Da T-S P E C T occ urre d m or e t ha n 
6  m o nt hs pri or t o E O T Visit.  
Partici pa nts s h o ul d be wit h dra w n fr o m t he st u d y if a n y of t he f oll o wi n g e v e nts occ ur:  
1.  Wit h dra wal of c o nse nt b y t he st u d y partici pa nt  
2.  A re g ulat or y a ge nc y re q u ests wit h dra wal of t he p artici pa nt fr o m t he st u d y  
3.  L oss of a bilit y t o freel y pr o vi de c o nse nt t hr o u g h i m pris o n me nt or i n v ol u ntar y c o nfi n e me nt 
f or treat me nt of eit her a ps yc hiatric or p h ysical (e g, i nfecti o us disease) ill n ess or t hr o u g h o ut 
q uara nti ne c o n diti o ns.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 3  of 1 3 3  
Partici pa nts m ust b e disc o nti n ue d fr o m I M P ( b ut n ot necessaril y fr o m t he st u d y) if a n y of t he 
f oll o wi n g occ urs: 
1.  St u d y partici pa nt de vel o ps a n ill ness t hat w o ul d i nterfere wit h his/ her c o nti n ue d d osi n g.  
2.  St u d y partici pa nt ta kes pr o hi bite d c o nc o mita nt me dicati o ns as defi n e d i n t he pr ot oc ol. 
O utc o me s h o ul d be deci d e d o n a case -b y -cas e basis.  
3.  T here is c o nfir mati o n of a pre g na n c y d uri n g t he st u d y, as e vi de nce d b y a p ositi ve pre g na nc y 
test. 
4.  St u d y partici pa nt has act ual s uici dal i deati o n si nce last visit as i n dicate d b y a p ositi ve 
res p o nse (“ Yes ”) t o eit her Q uesti o n 4 or Q uesti o n 5 of t he “ Si nce L ast Visit” versi o n of t he 
C ol u m bia -S uici de Se verit y Rati n g Scale ( C -S S R S). T he st u d y partici pa nt s h o ul d be referre d 
i m me diatel y t o a me ntal healt hcare pr ofessi o nal a n d m ust be disc o nti n ue d fro m I M P.  
5.  St u d y partici pa nt is c o nfir me d p ositi ve f or recreati o nal dr u g use or f or alc o h ol at t he P D 0 0 5 5 
Baseli ne Visit ( Da y 0), w hic h is dee me d si g nifica nt e n o u g h t o i m pair t he st u d y partici pa nt’s 
safet y or t he q u alit y of t he c ollecte d data. O utc o m e s h o ul d be deci de d o n a case -b y -cas e 
basis.  
6.  Re nal t o xicit y c o nsi dere d p ossi bl y relate d t o t he I M P. La b orat or y tests s u g gesti ve of re n al 
t o xicit y w hic h s h o ul d tri g ger f urt her assess me nt ma y i ncl u de: 
•  I n crease i n ser u m creati ni ne ≥0. 3 m g/ d L O R 
•  I n crease i n ser u m creatini ne t o ≥1. 5 ti mes fr o m Baseli ne O R  
•  Ne w persiste nt al b u mi n uria or cli nicall y si g nifica nt i ncrease i n pr e -e xisti n g al b u mi n uria, 
o ver 6 c o nsec uti ve wee ks  
A n y cli nicall y si g nifica nt fi n di n gs i n la b orat or y res ults f or re nal f u n cti o n will be m o nit ore d 
u ntil res ol uti o n or sta bilizati o n.  
7.  T he S p o ns or re q uests wit h dra wal of t h e partici pa nt.  
8.  St u d y partici pa nt ta kes p art i n a n y ot her i nter ve nti o nal st u d y d uri n g t he d urati o n of t his 
st u d y. 
I n v esti gat ors s h o ul d c o ntact t he Me dical M o nit or, w he ne ver p ossi ble, t o disc uss t he wit h dra wal 
of a partici p a nt i n a d va nce.  
7. 3  
L o st 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 visits a n d is u na ble t o be c o ntacte d b y t he st u d y site. 
T he f oll o wi n g acti o ns m ust be ta k e n if a p artici pa nt fails t o ret ur n t o t he cli nic f or a re q uire d 
st u d y visit: 
•  T he site m ust atte m pt t o c o ntact t he partici pa nt a n d resc he d ul e t he misse d visit as s o o n as 
p ossi ble a n d 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 vis it 
sc he d ule a n d ascertai n w het her or n ot t he p artici p a 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. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 4  of 1 3 3  
•  Bef ore a p artici 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 (at least 1 p h o ne call a n d 1 writte n messa ge 
t o t he partici pa nt) a n d d o c u me nt his/ her eff ort ( dat e a n d s u m mar y of t he p h o ne call a n d c o p y 
of t he writte n messa g e i n t he s o urce d o c u me nts), t o c o m plete t he fi nal e val uati o n . All res ults 
of t hese e v al uati o ns a n d o bser vati o ns, t o get her wit h a narrati ve descri pti o n of t he reas o n(s) 
f or re m o vi n g t he partici p a nt, m ust be rec or de d i n t he s o urce d o c u me nts. T h e e C R F m ust 
d oc u me nt t he pri mar y reas o n f or wit h dra wal.  
S h o ul d t he partici pa nt c o nti n ue t o be u nreac ha ble, he/s he will be c o nsi dere d t o ha ve wit h dra w n 
fr o m t he st u d y wit h a pri mar y reas o n of l ost t o f oll o w u p d oc u me nte d i n t he e C R F. 
7. 4  
Di s c o nti n u ati o n  of Di git al H e alt h T e c h n ol o g y  
St u d y partici pa nts ca n st o p usi n g t he K o ne ksa Ne ur oscie nce T o ol kit  at t heir discreti o n a n d 
wit h o ut c o nse q ue nces o n f urt her st u d y partici pati o n at a n y ti me d uri n g t he st u d y.  
T he I n vesti gat or ma y d eci de t o disc o nti n ue use of t he K o ne ksa Ne ur osci e nce T o ol kit if t he st u d y 
partici pa nt de vel o ps a me dical c o n diti o n t hat, i n t he  o pi ni o n of t he I n vesti gat or, c o m pr o mises t he 
st u d y partici pa nt’s a bilit y t o use t he K o ne ksa Ne ur oscie nce T o ol kit or c o m pr o mises t he st u d y 
partici pa nt’s safet y.  
A st u d y partici pa nt m ust disc o nti n ue use of t he K o ne ksa Ne ur oscie nce T o ol kit  if t he y i nitiate use 
of a n y ki n d of i m pla nta bl e acti ve d e vice, i ncl u di n g car diac pace ma kers, p u m ps, a n d i m pla nta ble 
car di o verters.  
T he reas o n f or disc o nti n uati o n nee ds t o be d oc u m e nte d i n t he e C R F.  
A n y ne wl y i de ntifie d safet y i nf or mati o n s h o ul d be d oc u me n te d a n d re p orte d i n li ne wit h 
Secti o n  8. 3. 7  a n d A p pe n di x 7 ( Secti o n  1 0. 7 ). 
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  
T he or der of assess me nts is o pti mize d f or c o nsiste nc y, l o gistic re q uire me nts b y t he site, a n d 
mi ni mize d partici pa nt b ur de n. Sli g ht variati o ns a m o n g t he sites d o n ot c o nstit ute a pr ot oc ol 
de v iati o n, w hile sites are e nc o ura g e d t o kee p t h e or der of assess me nts c o nsiste nt o ver ti me. 
As a ge neral r ule, all assess me nts wit h a hi g h li keli h o o d of bei n g se nsiti ve t o pre vi o us i nta ke of 
S T nee d t o be c o n d uct e d i n a practicall y defi ne d off -state (as defin e d i n Secti o n  6. 5. 3 ) bef ore 
i nta ke of S T is res u me d. T he assess me nts prece di n g i nta ke of S T s h o ul d i ncl u de: 
•  Patie nt -re p orte d o utc o m es ( P R Os) 
•  M o ve me nt Dis or der S oci et y  U nifie d Par ki ns o n’s Disease Rati n g Scale ( M D S -U P D R S) 
(all parts)  
•  E C Gs  
•  La b orat or y bl o o d sa m pli n g  
•  Vital si g ns  
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 t he Sc he d ule of Acti vities ( Secti o n  1. 3 ). 
Pr ot oc ol wai vers or e xe m pti o ns are n ot all o we d.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 5  of 1 3 3  
I m me diat e safet y c o ncer ns s h o ul d be disc usse d wit h t he S p o ns or i m me diatel y u p o n occ urre nce 
or a ware ness t o det er mi ne if t he partici pa nt s h o ul d c o nti n ue or disc o nti n ue I M P.  
A d here n ce t o t he st u d y d esi g n re q uire me nts, i ncl u di n g t h ose s pecifie d i n t he Sc he d ule of 
Acti vities ( Secti o n  1. 3 ), is esse ntial a n d re q uir e d f or st u d y c o n d uct. 
All Scree ni n g e val u ati o ns m ust be c o m plete d a n d re vie we d t o c o nfir m t hat p ote ntial partici pa nts 
meet all eli gi bilit y criteria. T he I n v esti gat or will mai ntai n a Scree ni n g l o g t o rec or d details of all 
partici pa nts scree ne d a n d t o c o nfir m eli gi bilit y or rec or d reas o ns f or Scree ni n g fail ure, as 
a p plica ble.  
Pr oce d ures c o n d ucte d as part of t he partici pa nt’s r o uti ne cli nical ma na ge m e nt (e g, bl o o d c o u nt) 
a n d o btai ne d bef ore si g ni n g of t he I C F ma y be utilize d f or Scree ni n g or Bas eli ne p ur p oses 
pr o vi de d t he pr oce d ures met t he pr ot oc ol -s pecifie d criteria a n d were perf or me d wit hi n t he ti me 
fra me d efi ne d i n t he Sc h e d ule of Acti vities (Secti o n  1. 3 ). 
T he ma xi m u m a m o u nt of bl o o d c ollecte d fr o m eac h partici pa nt will n ot e xcee d 5 0 m L at a n y 
visit a n d will n ot e xcee d 5 0 0 m L o ver t he d urati o n of t he st u d y, i ncl u di n g  a n y e xtra assess m e nts 
t hat ma y be re q uir e d. Re peat or u nsc h e d ule d sa m ples ma y be ta ke n f or safet y reas o ns or f or 
tec h nical iss ues wit h t he sa m ples. 
8. 1  
Effi c a c y a s s e s s m e nt s  
Pla n ne d ti me p oi nts f or all efficac y assess me nts are pr o vi de d i n t he Sc he d ul e of Acti v ities 
(Secti o n  1. 3 ). 
8. 1. 1  
Cli ni c al a s s e s s m e nt s  
8. 1. 1. 1  
D a T -S P E C T  
1 2 3I-I ofl u pa n e ( Da Tsca n, G E Healt hcare) is a ra di o p har mace utical a p pr o v e d i n t he E U, Ca na da, 
a n d U S. 
Eac h st u d y partici pa nt will recei ve a ma xi m u m of 3 i nject i o ns of 1 2 3I-I ofl u p a ne d uri n g t he st u d y, 
acc or di n g t o t he a p pr o ve d la bel. T he tar g et si n gle i njecti o n d ose of 1 8 5 M B q is esti mate d t o 
res ult i n a ra diati o n b ur d e n of 4. 6 3 m S v a n d t he t otal effecti ve d ose f or t he st u d y will be a 
ma xi m u m of 1 4 m S v. T his is cate g orize d as a cate g or y III m o derate ris k le vel (I C R 6 2), w hic h is 
bala nce d b y t h e s u bsta ntial s ocietal be nefit fr o m t he res ults of t his cli nical st u d y.  
O n sca n ni n g da ys, st u d y partici pa nts will be a d mitte d t o t he i ma gi n g ce nter. A d ose of a 
t h yr oi d-bl oc ki n g a ge nt will be gi ve n bef ore t h e ra di otracer d ose. A p pr o xi matel y 4 h o urs pri or t o 
sca n ni n g, a ve n o us ca n ul a will be i nserte d i nt o a n ar m vei n a n d fr o m 1 1 1 t o 1 8 5 M B q Da Tsca n 
will be i njecte d. H y drati o n s h o ul d be e nc o ura ge d b ef ore t h e i njecti o n, as well as g o o d h y drati o n 
a n d fre q u e nt v oi di n g f or 4 8 h o urs after t h e sca n.  
A p pr o xi matel y 4 h o urs p ost i njecti o n of Da Tsca n, st u d y partici pa nts will be place d s u pi ne i n t he 
Si n gle P h ot o n E missi o n C o m p ute d T o m o gra p h y sca n ner a n d p ositi o ne d wit h c o mf orta ble hea d 
fi xati o n. A si n gle sca n will be ac q uire d o ver a p pr o xi matel y 3 0 t o 4 5 mi n utes. 
8. 1. 1. 2  
L E D D  
T he c u m ulati ve L E D D will be calc ulate d f or eac h partici pa nt at eac h visit a n d at t he e n d of 
st u d y. T his is t he s u m of all t he L E D Ds ta ke n u p t o t hat visit, ie, if a partici pa nt is ta ki n g 3 0 0 m g 
of le v o d o pa a d a y, t heir c u m ulati ve d ose o ver 1 0 da ys w o ul d be 3 0 0 0 m g. A n y c ha n ges i n 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 6  of 1 3 3  
me dicati o n (t y pe, d ose, or d osi n g re gi me n) s h o ul d be acc o u nte d f or w he n calc ulati n g c u m ulati ve 
d oses.  
Par ki ns o n’s disease me di cati o n will rec or de d t hr o u g h o ut t he st u d y (see Sc he d ule of Acti vities, 
Secti o n  1. 3 ), a n d t he L E D D will be calc ul ate d as d o ne i n t he Par ki ns o n's Pr o gressi o n Mar kers 
I nitiative ( Sc ha de et al, 2 0 2 0; T o mli ns o n et al, 2 0 1 0).  
8. 1. 1. 3  
N o n m ot or s y m pt o m s  
8. 1. 1. 3. 1  
M o v e m e nt Di s or d er S o ci et y N o n -M ot or R ati n g S c al e  
T he M o ve me nt Dis or der S ociet y N o n -M ot or Rati n g Scale ( M D S -N M S; Marti nez -Marti n et al, 
2 0 1 9) is a re visi o n of t he N o n -M ot or S y m pt o ms Scale. T h e rater-a d mi nistere d scal e meas ures 
fre q ue n c y a n d se v erit y of 1 3 n o n-m ot or d o mai ns ( A -M) wit h o ver 5 2 ite ms, c o veri n g a ra n ge of 
ke y n o n -m ot or s y m pt o ms t hat are P D a n d tr eat me nt relate d.  
I n a d diti o n, t he scale als o i ncl u des a ne w 8-d o mai n N o n -M ot or Fl uct u a ti o ns s u bscale t o assess 
c ha n ges i n n o n -m ot or s y m pt o ms i n relati o n t o t he ti mi n g of a nti -P D me dicati o ns.  
8. 1. 1. 3. 2  
M D S -U P D R S P art I s u b s c al e or s el e ct e d it e m s  
T he M D S -U P D R S Part  I s u bscale ( n o n-m ot or e x p erie nces of dail y li vi n g, G oetz et al, 2 0 0 8) h as 
2 c o m p o ne nts:  
− Part I A i ncl u des c o g niti v e i m pair me nt, hall uci nati o ns a n d ps yc h osis, de presse d m o o d, 
a n xi o us m o o d, a pat h y, a n d feat ur es of d o pa mi ne d ysre g ulati o n s y n dr o me; it is assesse d 
b y t he rater wit h all perti ne nt i nf or mati o n fr o m st u d y partici pa nts a n d care gi vers (i e, 
cli nicia n-re p orte d o utc o me [ Cli n R O]). 
− Part I B i ncl u des slee p pr o ble ms, da yti me slee pi ness, pai n a n d ot her se ns ati o n, uri nar y 
pr o ble ms, c o nsti pati o n pr o ble ms, li g ht hea de d ness o n sta n di n g, a n d fati g ue; it is 
c o m plete d b y t he st u d y partici pa nt wit h or wit h o ut t he ai d of t he care gi ver, b ut 
i n de pe n de ntl y of t he rater (ie, P R O). 
B ot h secti o ns ca n be re vie we d b y t he rater t o e ns ure t hat all q uesti o ns are a ns were d clearl y, a n d 
t he rater ca n h el p e x plai n a n y percei ve d a m bi g uities. 
8. 1. 1. 4  
M ot or s y m pt o m s, a cti viti e s of d a il y li vi n g & Q o L 
8. 1. 1. 4. 1  
M D S -U P D R S P art II s u b s c al e or s el e ct e d it e m s  
T he M D S -U P D R S Part II s u bs cale ( m ot or e x peri e nces of dail y li vi n g, G oet z et al, 2 0 0 8):  
− Is d esi g ne d t o be a s elf -a d mi nistere d q uesti o n nair e li ke Part I B (ie, P R O), b ut ca n be 
re vie we d b y t h e rat er t o e ns ure c o m plete ness a n d clarit y. 
− I n cl u des s peec h, sali va a n d dr o oli n g, c he wi n g a n d s wall o wi n g, eati n g tas ks (c utti n g f o o d 
a n d ha n dli n g ute nsils), dressi n g, h y gie ne, ha n d writi n g, d oi n g h o b bies a n d ot her acti vities, 
t ur ni n g i n be d, tre m or, getti n g o ut of be d, a car or a dee p c hair, wal ki n g a n d bala nce, a n d 
freezi n g. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 7  of 1 3 3  
8. 1. 1. 4. 2  
M D S -U P D R S P art III s u b s c al e or s el e ct e d it e m s  
T he M D S -U P D R S Part III s u bscale ( m ot or e xa mi nati o n, G oetz et al, 2 0 0 8):  
− Has i nstr ucti o ns f or t he rater t o gi ve or de m o nstrate t o t he st u d y partic i pa nt; it is 
c o m plete d b y t he rat er (i e, Cli n R O).  
− I n cl u des s peec h, facial e x pressi o n, ri gi dit y, fi n ger ta p pi n g, ha n d m o ve me nts, 
pr o nati o n -s u pi nati o n m o ve me nts of ha n ds, t oe ta p pi n g, le g a gilit y, arisi n g fr o m c hair, 
gait, freezi n g of gait, p ost ural sta bilit y, p ost ure, gl o bal s p o nta neit y of m o ve me nt ( b o d y 
bra d y ki nesia), p ost ural tre m or of t he ha n ds, ki neti c tre m or of t he ha n ds, rest tre m or 
a m plit u de, a n d c o nsta nc y of rest tre m or. M ot or f u ncti o n will be meas ure d i n a n off -stat e 
wit h re gar d t o S T i nta ke ( Secti o n  6. 5. 3 ; Bl oe m et al, 2 0 1 9). 
8. 1. 1. 4. 3  
M D S -U P D R S P art I V s u b s c al e or s el e ct e d it e m s  
T he M D S -U P D R S Part I V ( m ot or c o m plicati o ns, G oetz et al, 2 0 0 8):  
− I n cl u des ti me s pe nt wit h d ys ki nesias, f u ncti o nal i m pact of d ys ki nesias, ti me s pe nt i n t he 
" O F F" state, i m pact of fl uct uati o ns, c o m ple xit y of m ot or fl uct uati o ns, a n d pai nf ul " O F F" 
state d yst o nia. 
− Has i nstr ucti o ns f or t he rater a n d als o i nstr ucti o ns t o be rea d t o t he st u d y partici pa nt. T his 
part i nte grates st u d y partici pa nt -deri v e d i nf or mati o n wit h t he rater's cli nical o bser vati o ns 
a n d j u d g me nts a n d is c o m plete d b y t he rater.  
8. 1. 1. 5  
M o difi e d H o e h n a n d Y a hr st a gi n g  
T he H oe h n a n d Ya hr ( H & Y) scale ( H oe h n a n d Ya hr, 1 9 6 7) des cri bes h o w t he s y m pt o ms of P D 
pr o gress t hr o u g h 5 sta ges: Sta ge 1 = u nilateral disease; Sta ge 2 = bilateral disease wit h o ut 
i m pair me nt of bala nce; Sta ge 3 = mil d t o m o derate bilateral disease, s o m e p ost ural i nsta bilit y, 
p h ysicall y i n de pe n de nt; Sta ge 4 =se vere disa bilit y, still a ble t o wal k or sta n d u nassiste d; a n d 
Sta ge  5 = w heelc hair b o u n d or be dri d de n u nless ai de d. T he H & Y scale has si nce bee n m o difie d 
wit h t he a d diti o n of sta ges 1. 5 ( u nilateral a n d a xial i n v ol ve me nt) a n d 2. 5 ( mil d bilateral disease 
wit h rec o ver y o n p ull test) t o acc o u nt f or t he i nter me diate c o urse of P D . 
8. 1. 1. 6  
M o ntr e al C o g niti v e A s s e s s m e nt  
T he M o ntreal C o g niti ve Assess me nt ( M o C A; Nasre d di ne et al, 2 0 0 5) assesses differe nt 
c o g niti ve d o mai ns ( vis u os patial/e xec uti ve, na mi n g, me m or y, atte nti o n, la n g ua ge, a bstr acti o n, 
dela ye d recall, a n d orie nt ati o n). Partici pa nts are assesse d o n a 3 0 -p oi nt scale . A sc ore of 2 6 or 
a b o ve is c o nsi dere d n or mal.  
I n a st u d y of 3 7 0 6 partici pa nts a ge d 6 3 t o 6 5 years ol d fr o m t he ge neral p o p ulati o n of N or wa y, 
t he mea n M o C A sc ore w as 2 5. 3 ( 9 5 % c o nfi de nce i nter val [ CI]: 2 5. 2 t o 2 5. 4), a n d 4 9 % of t h e 
partici pa nts sc ore d bel o w t he s u g geste d c ut off s c ore of 2 6 p oi nts. T he e d ucati o n le vel ha d a 
si g nifica nt i m pact o n t he test res ults ( > 1 2 years e d ucati o n; mea n 2 6. 2, 9 5 % CI: 2 6. 1 t o 2 6. 3, 
me dia n 2 7 vers us ≤1 2 years e d ucati o n; mea n 2 4. 4, 9 5 % CI: 2 4. 3 t o 2 4. 6, m e dia n 2 5, p < 0. 0 0 1). 
T he a ut h ors s u g geste d t h at t he c ut off sc ore of 2 6 f or mil d c o g niti ve i m pair me nt ( M CI) ma y ha ve 
bee n set t o o hi g h t o disti n g uis h n or mal c o g niti ve f u ncti o n fr o m M CI (I hle -Ha nse n et al, 2 0 1 7).  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 8  of 1 3 3  
T o decrease t he l ear ni n g effect fr o m m ulti ple a d mi nistrati o ns of t h e M o C A o ver a s h ort p eri o d of 
ti me, alter nate versi o ns ha ve bee n ma de a vaila ble. T he f ull test has als o bee n a da pte d f or pe o ple 
wit h disa bilities i ncl u di n g b ot h p h ysical a n d me ntal. T he latest f ull versi o n of t he test is n o w 
a vaila ble o n a n i Pa d ( htt ps:// w w w. m ocatest. or g/a b o ut/).  
T he M o C A will be assesse d at t he visits s pecifie d i n t he Sc he d ule of Acti vities ( Secti o n  1. 3 ). 
8. 1. 2  
P ati e nt -r e p ort e d o ut c o m e s 
Pat ie nt-re p orte d o utc o m es m ust be c o m plete d as p er ti me p oi nts me nti o ne d i n t he Sc he d ule of 
Acti vities ( Secti o n  1. 3 ). 
Patie nt -re p orte d o utc o m es m ust be c o m plete d b y st u d y partici pa nts i n a q uiet place b y 
t he msel ves wit h o ut t he hel p of a part ner or care gi ver, bef ore a n y cli nical e xa mi nati o n ta kes 
place. D uri n g t he Treat me nt Peri o d, P R Os will be c o m plete d pri or t o d osi n g wit h S T.  
St u d y partici pa nts s h o ul d be i nf or me d of t he i m p orta nce of t he P R O q uesti o n naires a n d s h o ul d 
be i nstr ucte d t o rea d t he P R O ite ms a n d i nstr ucti o ns caref ull y. T he y s h o ul d be i nf or me d t hat 
t here are n o ri g ht or wr o n g a ns wers. 
St u d y pers o n nel are n ot all o we d t o i nter pret t he ite ms f or t he partici pa nt. If a partici pa nt as ks f or 
g ui da nce, st u d y pers o n n el s h o ul d i nstr uct hi m/ her t o res p o n d acc or di n g t o t heir best 
u n dersta n di n g of t he ite m.  
Patie nt -re p orte d o utc o m es s h o ul d o nl y be c hec ke d f or c o m plete ness b y st u d y pers o n nel. I n t he 
e ve nt a fe w q uesti o n nair e ite ms ha ve n ot bee n c o m plete d, st u d y pers o n nel s h o ul d merel y e n q uire 
t o t he st u d y partici pa nt if t his res ults fr o m a n o missi o n. St u d y pers o n nel s hall neit her c o m plete 
missi n g data n or s u g gest c ha n ges t o partici pa nt res p o nses. Li ke a n y ot h er st u d y data, res p o ns es 
t o t he q uesti o n naire s h o ul d be treate d as c o nfi de ntial i nf or mati o n. Data pri v ac y c o nsi derati o ns 
a p pl y. 
T he P R Os s h o ul d be c o m plete d i n t he f oll o wi n g or der: Earl y P D F u ncti o n Sl o w ness P R O; Earl y 
P D M o bilit y P R O; F A TI G U E -P R O; W O Q -9; a n d E ur o Q ualit y of life 5 -Di me nsi o ns 5 -Le vel 
( E Q-5 D -5 L).  
Ti me re q uire d t o c o m plet e t he first 3 P R Os liste d a b o ve was teste d wit h a s a m ple of 
6  partici pa nts wit h earl y -sta ge P D i n P D 0 0 5 3 a n d was a p pr o xi matel y 1 2 t o 1 5 mi n utes. 
C o m pleti o n of E Q -5 D -5 L re q uires a p pr o xi matel y 1 0 a d diti o nal mi n utes.  
8. 1. 2. 1  
E arl y P D F u n cti o n Sl o w n e s s P R O  
T he Earl y P D F u ncti o n Sl o w ness P R O i nstr u me nt c o nsists of 4 5 ite ms acr oss 4 d o mai ns: 
1 9  m ot or ( u p per li m b) ite ms, 9 m ot or (c o m ple x or l o wer li m b) ite ms, 9 c o m ple x acti vit ies ( m ot or 
a n d c o g niti ve) ite ms a n d 8 c o g niti ve ite ms. Partici pa nts are as ke d t o sc ore eac h ite m base d o n 
h o w sl o w t he y ma y ha ve bee n w he n p erf or mi n g dail y acti vities o ver t he past 7 da ys, usi n g a 
5 -p oi nt Li kert scale (“ N ot at all” t o “ E xtre mel y sl o w”). Be i n g a n e x pl orat or y P R O i nstr u me nt, n o 
sc ori n g al g orit h m c urre ntl y e xists. Fi nal P R O c o nte nt a n d sc ori n g str uct ur e will be i nf or me d b y 
a nal yses perf or me d o n e xter nal data as well as o n P D 0 0 5 3 data.  
8. 1. 2. 2  
E arl y P D M o bilit y P R O  
T he Earl y P D M o bilit y P R O i nstr u me nt c o nsists of 2 3 ite ms. Partici pa nts are as ke d t o sc ore eac h 
ite m base d o n w het her t he y ha ve e x perie n ce d a n y iss ue wit h wal ki n g a n d m o vi n g o ver t he past 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 5 9  of 1 3 3  
7  da ys, usi n g a 5 -p oi nt Li kert scale (“ N ot at all” t o “ E xtre mel y”). Bei n g a n e x pl orat or y P R O 
i nstr u me nt, n o sc ori n g al g orit h m c urre ntl y e xists. Fi nal P R O c o nte nt a n d sc ori n g str uct ure will 
be i nf or me d b y a n al yses perf or me d o n e xter n al data as well as o n P D 0 0 5 3 data.  
8. 1. 2. 3  
F A TI G U E -P R O  
T he F A TI G U E -P R O is a P R O i nstr u me nt t hat q ua ntifies fati g ue, ori gi nall y de vel o pe d f or 
S yste mic L u p us Er yt he mat os us. It c o nsists of 3 1 ite ms acr oss 3 scales: ‘ p h ysical fati g ue’ 
( 9 ite ms; 1 t o 9), ‘ me ntal a n d c o g niti ve’ ( 1 1 ite ms; 1 0 t o 2 0), a n d ‘s usce pti bilit y t o fati g ue’ 
( 1 1 ite ms; 2 1 t o 3 1). St u d y partici pa nts are as ke d t o rate eac h ite m base d o n h o w fre q u e ntl y t he y 
e x perie n ce d it o ver t he p ast 7 da ys, usi n g a 5 -p oi nt Li kert scale ra n gi n g fr o m ‘ n o ne of t he ti me’ 
t o ‘all of t he ti me’. T he F A TI G U E-P R O c urre ntl y d oes n ot tra nslate i nt o a t otal sc ore s u m mar y. 
Scale sc ores are tra nsf or me d i n t o a sc ore ra n gi n g fr o m 0 t o 1 0 0, wit h hi g her sc ores i n dicati n g 
hi g her le vels of fati g ue . 
8. 1. 2. 4  
W O Q -9  
T he well -des cri be d W O p he n o me n o n is t he s h orte ni n g effect of le v o d o p a, w hic h ca n b e 
ma na ge d wit h d osa ge a dj ust me nt or a dj u va nt t hera p y, s uc h as C O M T i n hi bit ors ( Pa h wa a n d 
L y o ns, 2 0 0 9).  
T he q uesti o n naire s electe d f or t his st u d y is t he W O Q -9 c o ntai ni n g t he m ost val ua ble q uesti o ns 
f or P D patie nts of all sta ges f or t he f oll o wi n g 9 it e ms: Tre m or, A n y Sl o w n ess, A n y Stiff ness, 
M uscle cra m pi n g, Re d u ce d de xterit y, A n xiet y / Pa nic attac ks, M o o d c ha n ges, Cl o u d y mi n d/ Sl o w 
t hi n ki n g, a n d Pai n/ Ac hi n g ( Stac y et al, 2 0 0 6).  
T he W O Q -9 has bee n rec o g nize d b y a tas k f orce of t he M o ve me nt Dis or der S ociet y as a 
rec o m me n de d di a g n ostic scree ni n g t o ol f or its a bilit y t o detect W O i n P D patients 
( A nt o ni ni et al, 2 0 1 1).  
T he W O Q -9 defi n es t he prese nce of W O as t he prese nce of at least 1 s y m pt o m  wit h 
i m pr o ve me nt after t h e ne xt d ose of a nti par ki ns o ni a n me dicati o n ( Stac y et al, 2 0 0 8, C O M P A S S-I 
st u d y). 
T he W O Q -9 will be assesse d after i nitiati o n of S T at t he visits s pecifie d i n t he Sc he d ule of 
Acti vities ( Secti o n  1. 3 ). 
8. 1. 2. 5  
E Q -5 D -5 L  
T he E Q -5 D -5 L c o nsists of t he E ur o Q ualit y of life 5 -Di me nsi o ns descri pti ve s yste m a n d t he 
E ur o Q ualit y of life  vis ual a nal o g ue scal e ( E Q V A S) ( De vli n a n d Br o o ks, 2 0 1 7). T he E Q -5 D -5 L 
descri pti ve s yste m c o m prises 5 di me nsi o ns: 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 sc ore d acc or di n g t o 5 le vels: n o pr o ble ms, sli g ht pr o ble ms, m o derate 
pr o ble ms, se vere pr o ble ms, a n d e xtre me pr o bl e ms. T hese le vels are e x presse d as a 1 -di git 
n u m ber, a n d t he di gits f or t he 5 di me nsi o ns are c o m bi ne d i nt o a 5 -di git n u m ber t hat descri b es t he 
partici pa nt’s healt h state (e g, 1 3 4 1 4). T h e 1 -di git n u m bers f or eac h of t he 5 di me nsi o ns will be 
s u m marize d cate g oric all y b y visit, treat me nt gr o u p, o verall a n d b y ge n d er. S hift ta bles will als o 
be pr o d uce d b y di me nsi o n. T he 5 -di git n u m b ers will be use d i n t he listi n gs.  
T he E Q -5 D -5 L all o ws deri vati o n of utilit y sc ores fr o m c o u ntr y -s pecific val ue sets t hat are t h e n 
i nc or p orate d i nt o he alt h ec o n o mic m o dels (c ost-utilit y a nal yses) as use d i n healt h tec h n ol o g y 
assess me nts i n se veral c o u ntries  ar o u n d t he w orl d. T he E Q -5 D -5 L utilit y wei g hts ra n ge fr o m 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 0  of 1 3 3  
1. 0  ( perfect he alt h) t o 0 ( deat h) a n d ca n e v e n des cri be healt h-relate d Q o L states bel o w 0, ie, a 
state w orse t ha n d eat h (t his is rare). 
T he E Q V A S rec or ds a p atie nt’s self -rate d healt h o n a vertical vis ual a nal o g scale; it ra n ges fr o m 
0 t o 1 0 0 ( wit h 1 0 0 re pres e nti n g t he “ best healt h y o u ca n i ma gi ne” a n d 0 re prese nti n g “ T he w orst 
healt h y o u ca n i ma gi ne ”).  
8. 1. 3  
I n-st u d y p ati e nt i nt er vi e w s ( U S a n d U K o nl y)  
A tar get of u p t o 3 0 i n -st u d y patie nt i nter vie ws will be c o n d ucte d wit h a sa m ple of U S a n d/ or 
U K st u d y partici pa nts mai nl y t o ge nerate a d diti o nal e vi de nce o n t he a de q u ac y of U C B’s ne wl y 
de vel o pe d P R O i nstr u me nts i n earl y -sta ge P D. 
I nter vie ws will be o pti o n al a n d will be c o n d uct e d bet wee n Bas eli ne a n d u p t o 1 m o nt h i nt o t he 
st u d y. Partici pa nts will be as ke d t o si g n t he s pecific i nf or me d c o nse nt t o partici pate i n t he 
i nter vie w. O bjecti ves are 3-f ol d: c o g niti ve de briefi n g of t he Earl y P D F u n cti o n Sl o w ness a n d 
M o bilit y P R O ite ms as well as s o me M D S -U P D R S Part I II ite ms, ge nerati o n of earl y e vi de nce 
o n cli nicall y mea ni n gf ul c ha n ge, a n d disc ussi o n o n st u d y partici pati o n e x perie nce.  
I nter vie ws will be or g a ni ze d a n d c o n d ucte d b y i n d e pe n de nt s pe cialist q ualitati ve s ocial res earc h 
scie ntists (refer t o F D A Patie nt-F oc u s e d Dr u g De v el o p me nt P u blic W or ks h o p G ui da nce 2 
Disc ussi o n D oc u me nt –  A p pe n dices [ A p pe n di x 3 Secti o n B]).  
8. 1. 4  
K o n e k s a N e ur o s ci e n c e T o ol kit  
T he K o ne ksa Ne ur os cie n ce T o ol kit will be use d t o c ollect data relate d t o P D m ot or s y m pt o ms 
a n d i m pacts o n dail y li vi n g. I n a d diti o n, st u d y partici pa nt fee d bac k a b o ut t he usa bilit y of t he 
K o ne ksa N e ur oscie n ce T o ol kit will be c ollecte d via a n electr o nic q uesti o n n aire t hat will be 
c o m plete d d uri n g t he st u d y at Visit 4 ( M o nt h 1), Visit 6 ( M o nt h 6), a n d Visit 8 ( M o nt h 1 8).  
T he d ata c ollecte d a n d a n al yze d d o n ot g ui de t he t hera p y a d mi nistere d or g ui de a n y ot her 
me dical decisi o ns d uri n g t his st u d y. T he o btai ne d data are assesse d o nl y as e x pl orat or y 
e n d p oi nts.  
Details o n acti ve a n d p assi ve assess me nts t o be perf or me d wit h t he K o ne ks a Ne ur oscie nce 
T o ol kit are s u m marize d i n Ta ble  8 ‒ 1 . 
Acti ve tests are p erf or me d  t hr o u g h t he i P h o ne. S pecificall y, st u d y partici p a nts will c o n d uct a n 
“acti ve test” e ver y wee k at a p pr o xi matel y t he sa m e ti me, o nce i n t he practi call y defi ne d “ O F F” 
state a n d o nce i n t he “ O N” state. T his will be a s et of r o uti ne, eas y-t o-perf or m acti vities , t hat 
reflect h o w partici pa nts are a ble t o perf or m wit h re gar d t o m ot or f u ncti o n a n d s peec h. T h e acti ve 
test c o nsists of a s h ort, prec o nfi g ure d sc he d ule of t as ks t hat ca pt ure P D s y m pt o ms. St u d y 
partici pa nts w h o are n ot o n a n y S T will c o n d uct o ne assess me n t u p o n wa ki n g. S mart p h o ne 
se ns or data will be rec or de d c o nti n u o usl y, t hr o u g h o ut t he acti ve tests.  
Passi ve tests are perf or m e d t hr o u g h t he C PI W. As part of passi ve tr ac ki n g of dail y acti vities a n d 
slee p ( o pti o nal), st u d y partici pa nts will be i nstr ucte d t o wear t h e pr o visi o ne d s mart watc h o n t heir 
m ost affecte d si d e starti n g i n t he e ve ni n g of t he da y pri or t o t he acti ve tests a n d e n di n g i n t he 
e ve ni n g of t he acti ve tests da y. S mart watc h se ns or data will be rec or de d c o nti n u o usl y t hr o u g h o ut 
t he acti ve tests. If p artici pa nts d o n ot wa nt t o wear t he s mart watc h d uri n g slee p, t he y will be 
as ke d t o wear it fr o m a wa ke ni n g pri or t o t he acti ve assess me nts t o t he e ve ni n g after t he acti ve 
assess me nts.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 1  of 1 3 3  
I n a d diti o n, patie nt-re p orte d data will be c ollect e d t hr o u g h t he i P h o ne. T hese i ncl u de a n 
electr o nic v ersi o n of t he M D S -U P D R S Part II (acti vities of dail y li vi n g), S T me dicati o n i nta ke, 
slee pi n g h o urs, a n d O N/ O F F st at us of st u d y parti ci pa nts. 
T a bl e  8 ‒ 1 : 
A cti viti e s t o b e p erf or m e d wit h t h e K o n e k s a N e ur o s ci e n c e T o ol kit  
 
I nstr u me nt/ Me as ure 
Fre q ue nc y  
H ar d w are  
Acti ve Tests  
2 0 -sec o n d w al k test assess me nt 
1 da y/ wee k;  
f or partici pa nts o n S T 
me dicati o n 2 x/ da y, first 
i n “ O F F” state, t he n i n 
“ O N” state;  
f or partici pa nts n ot o n 
S T me dicati o n, o nce per 
da y  
i P h o ne 
Pr o nati o n/s u pi nati o n assess me nt  
P ost ural, ki netic, a n d resti n g tre m or 
assess me nts  
Fi n ger ta p assess me nt  
A ural A nal ytics s peec h assess me nt  
P assi ve Tests  
Acti gra p h y de vic e w or n f or s pecifi c 
m o nit ori n g peri o ds; wal k peri o ds 
a nal yze d f or gait a n d b al a nce feat ur es  
Passi ve  
1 2 t o 2 4 hrs, 1 da y/ wee k  
C PI W  
T otal slee p ti me a n d # of wa ke b o uts per 
w or n e p oc h vi a acti gra p h y de vice w or n 
f or s pecifi c m o nit ori n g peri o ds 
Ste ps per da y  
P atie nt -
Re p orte d D at a  
C o nfir m ti me p oi nt of m ost rece nt 
s y m pt o matic treat me nt i nta ke 
Wee kl y ali g ne d wit h 
m or ni n g m ot or 
assess me nts  
i P h o ne 
C o nfir m slee p ti me  
Wee kl y ali g ne d wit h 
m or ni n g m ot or 
assess me nts  
i P h o ne 
Electr o nic M D S -U P D R S Part 2  
Wee kl y ali g ne d wit h 
m ot or assess me nts i n 
“ O F F” stat e  
i P h o ne 
Usa bilit y a n d E x perie nce Q uesti o n naire  
3 ti mes per st u d y  
i P h o ne 
C PI W = Ce ntre P oi nt I nsi g ht Watc h; M D S -U P D R S = M o ve me nt Dis or der S ociet y U nifie d Par ki ns o n's Disease Rati n g 
Scale; S T =s y m pt o matic treat me nt  
St u d y partici pa nts will be c o nse nte d a n d trai ne d t o use t he K o ne ksa Ne ur oscie nce T o ol kit d uri n g 
t he st u d y as descri be d i n Secti o n  6. 9 . T he K o ne ks a Ne ur oscie nce T o ol kit will be ha n de d o ver t o 
partici pa nts at Visit 2 ( Baseli ne Visit). F oll o wi n g Visit 2 ( Baseli ne Visit), partici pa nts will use 
t he K o ne ksa N e ur osci e nce T o ol kit at h o me. 
Baseli ne assess me nts will ta ke place fr o m t he e v e ni n g of Da y 0 ( Visit 2 [ B aseli ne Visit]) t o t he 
e ve ni n g of Treat me nt Peri o d Da y 1. St u d y partici pa nts will be as ke d t o wear t he Acti Gra p h 
C PI W (ie, s mart watc h) as of t he e ve ni n g of Da y 0 ( Visit 2 [ Baseli ne Visit]).  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 2  of 1 3 3  
Acti ve Baseli ne tests are d o ne o n Treat me nt Peri o d Da y 1. " O F F" assess me nts are d o ne pri or t o 
t he i nta ke of t he first I M P i n t he m or ni n g of Da y 1. " O N" assess me nts are d o ne after t he first 
i nta ke of I M P a n d i nta ke of S T. 
All s u bse q ue nt acti ve tests will be d o ne o n a wee kl y basis after i nta ke of t he m or ni n g d ose of 
I M P at a p pr o xi matel y t he sa me ti me. 
T he K o ne ksa Ne ur os cie n ce T o ol kit will g ui de/alert st u d y partici pa nts o n re q uire d acti vi ties wit h 
re gar ds t o passi v e a n d acti ve assess me nts. 
St u d y partici pa nts will be e nc o ura ge d t o a d here t o t he dail y sc he d ule of t as ks as m uc h as 
p ossi ble; h o we ver, partici pa nts will n ot be e xcl u de d fr o m t he st u d y if t he y d o n ot a d here t o t he 
pla n ne d acti viti es.  
Detaile d i nstr ucti o ns c o n cer ni n g t he K o n e ksa Ne ur oscie nce T o ol kit will be pr o vi de d t o t he 
partici pati n g I n vesti gat ors i n a se parat e ma n ual pri or t o t he start of K o ne ks a Ne ur oscie nce 
T o ol kit de pl o y me nt i n t he st u d y.  
8. 2  
S af et y a s s e s s m e nt s  
Pla n ne d ti me p oi n ts f or all safet y assess me nts are pr o vi de d i n t he Sc he d ule of Acti vities 
(Secti o n  1. 3 ). 
8. 2. 1  
P h y si c al e x a mi n ati o n  
A c o m plete p h ysical e x a mi nati o n will i ncl u de, at a mi ni m u m, ge neral a p peara nce; ear, n ose, a n d 
t hr oat; e yes, hair, a n d s ki n; a n d assess me nts of t he car di o vas c ular, res pirat or y, gastr oi ntesti nal, 
m usc ul os keletal, a n d he p atic s yste ms.  
I n v esti gat ors a n d site staff s h o ul d pa y s pecial atte nti o n t o cli nical si g ns relate d t o pre vi o us 
seri o us ill nesses a n d h y p erse nsiti vit y reacti o n (s uc h as ras h, a n gi oe de ma, or a na p h yla xis). F or 
a n y e mer g e nt lesi o n or a b n or malit y o n t he s ki n, a f ull e xa mi nati o n of s ki n a n d cl ose o b ser vati o n 
is re q uire d t o e xcl u d e p ossi bilit y of a h y perse nsiti vit y reacti o n as per Secti o n  8. 3. 6. 1 . 
Cli nicall y rele va nt fi n di n gs or w orse ni n g of pre vi o us fi n di n gs will be rec or de d as A Es.  
Wei g ht will be meas ur e d a n d rec or de d at Visit 2 wit h t he st u d y partici pa nt weari n g li g ht cl ot hi n g 
a n d wit h o ut weari n g s h o es; t he o utc o me will be r o u n de d t o t he nearest 0. 1 k g.  
8. 2. 2  
N e ur ol o gi c al e x a mi n ati o n  
T he c o m plete ne ur ol o gic al e xa mi nati o n will i ncl u de selecte d assess me nt of ge neral n e ur ol o gical 
stat us (le vel of c o nsci o us ness, me ntal stat us, s peec h), cra ni al ner ves, refl e xes, m ot or s yste m 
( ge neral m ot or stat us, m uscle stre n gt h, m uscle t o n e), c o or di n ati o n/cere b ellar f u ncti on, a n d 
se nsati o n. T he da y bef ore or t he da y of t he l u m bar p u nct ure, a c o m plete ne ur ol o gical 
e xa mi nati o n s h o ul d be perf or me d i n acc or da n ce wit h l ocal safet y pr o ce d ures a n d res ults s h o ul d 
be a vaila ble pri or t o perf or mi n g t he l u m bar p u nct ure.  
Cli nicall y si g ni fica nt ne ur ol o gical e xa mi nati o n fi n di n gs will be rec or de d as A Es. 
8. 2. 3  
Vit al si g n s  
Vital si g ns (t o be ta ke n b ef ore bl o o d c ollecti o n f or la b orat or y tests) will c o nsist of 3 p ulse a n d 
3  bl o o d press ure ( B P) meas ure me nts ( 3 c o nsec uti v e B P rea di n gs will be rec or de d at i nter v als of 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 3  of 1 3 3  
at least 1  mi n ute). Bl o o d press ure h as t o be meas ure d i n t he s u pi ne a n d erect p ositi o ns t o assess 
a ut o n o m o us d ysre g ulati o n ( Tre n del e n b ur g test).  
All p ulse a n d B P rea di n gs will be rec or de d o n t he e C R F, a n d t he a v era g e will be deri ve d f or 
a nal yses.  
8. 2. 4  
E C G s  
Electr ocar di o gra m r ec or di n gs will be o btai ne d as o utli ne d i n t he Sc he d ule of Acti vities 
(Secti o n  1. 3 ). 
T he st u d y partici pa nt s h o ul d be  resti n g i n t he s u pi ne p ositi o n f or at least 1 0 mi n utes bef ore t he 
start of t he rec or di n gs. El ectr ocar di o gra m rec or di n gs will be si n gle rea ds b ut ca n be re peat e d i n 
tri plicate if cli nicall y i n dicate d. 
T he I n vesti gat or s h o ul d r e vie w all E C G rec or di n gs a n d, if t here are a b n or m alities t hat are 
c o nsi dere d cli nicall y si g nifica nt f or a p artic ular st u d y partici pa nt, t he n t he I n vesti gat or s h o ul d 
i nitiate a re vie w b y a s pecialist of all E C G data pertai ni n g t o t hat st u d y partici pa nt. T he 
f oll o wi n g E C G para meters will be rec or de d i n t he e C R F: heart rate, P R i nter val, Q R S d urati o n, 
Q T i nter val, Q Tc F, a n d I n vesti gat or’s c o ncl usi o n o n E C G pr ofile.  
8. 2. 5  
Cli ni c al s af et y l a b or at or y a s s e s s m e nt s  
See A p pe n di x 2 ( Secti o n  1 0. 2 ) f or t he list of cli nical la b orat or y tests t o be p erf or me d a n d t he 
Sc he d ule of A cti vities ( Secti o n  1. 3 ) f or t he ti mi n g a n d fre q u e nc 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 i n t he A E secti o n of t he e C R F. T he 
la b orat or y re p orts m ust be file d wit h t he s o urce d o c u me nts. Cli nicall y si g nifica nt a b n or m al 
la b orat or y fi n di n gs are t h ose w hic h are 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 vesti gat or t o be m ore se vere t ha n e x p e cte d f or t he partici p a nt's c o n diti o n.  
All la b orat or y tests wit h val ues c o nsi dere d cli nicall y si g nifica ntl y a b n or mal d uri n g partici pati o n 
i n t he st u d y or wit hi n 3 0 da ys after t h e last d ose of I M P s h o ul d be re peat e d u ntil t he val ues 
ret ur n t o n or mal or Bas eli ne or are n o l o n ger c o nsi dere d cli nicall y si g nifica nt b y t he I n v esti gat or 
or Me dical M o nit or.  
If s uc h val ues d o n ot ret ur n t o n or mal/ Baseli ne wit hi n a peri o d of ti me j u d g e d reas o n a ble b y t he 
I n v esti gat or, t he eti ol o g y s h o ul d be i de ntifie d, a n d t he S p o ns or n otifie d.  
All pr ot oc ol -re q uir e d la b orat or y assess me nts, as defi ne d i n A p pe n di x 2 (Secti o n  1 0. 2 ), m ust be 
c o n d ucte d i n acc or da nce wit h t he la b orat or y ma n ual a n d t he Sc he d ule of Acti vities ( Secti o n  1. 3 ). 
If la b orat or y val ues fr o m n o n-pr ot oc ol s pecifi e d la b orat or y assess me nts perf or me d at t he 
i nstit uti o n’s l ocal la b orat or y re q uire a c h a n ge i n p artici pa nt ma na g e me nt or are c o nsi d ere d 
cli nicall y si g nifica nt b y t he I n vesti gat or (e g, S A E or A E), t he n t he res ults m ust be rec or de d i n 
t he e C R F. 
8. 2. 6  
S ui ci d al ri s k m o nit ori n g  
Mi nzas ol mi n ( U C B 0 5 9 9) is a C N S -acti ve I M P. T here has b ee n c o ncer n t hat s o me C N S -acti ve 
I M Ps ma y be ass ociate d wit h a n i ncreas e d ris k of s uici dal i deati o n or be ha vi or w he n gi ve n t o 
s o me partici pa nts wit h P D. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 4  of 1 3 3  
S uici dalit y will be assesse d b y trai ne d site st u d y p ers o n nel usi n g t he C -S S R S 
( P os ner et al, 2 0 1 1). T his scale will be use d t o ass ess s uici dal i deati o n a n d be ha vi or t hat ma y 
occ ur d uri n g t he st u d y. All st u d y partici pa nts will c o m plete t he “ Si nce L ast Visit” versi o n at t he 
visits i n dicate d o n t he Sc he d ule of Acti vities ( Secti o n  1. 3 ). 
Partici pa nts bei n g treate d wit h mi nzas ol mi n ( U C B 0 5 9 9) s h o ul d be m o nit ore d a p pr o pri atel y a n d 
o bser ve d cl os el y f or s uici dal i deati o n a n d be ha vi or or a n y ot her u n us ual c ha n ges i n be ha vi or. 
Fa milies a n d care gi v ers of partici pa nts bei n g treate d wit h mi nzas ol mi n ( U C B 0 5 9 9) s h o ul d be 
i nstr ucte d t o m o nit or partici pa nts f or t he e mer ge n ce of u n us ual c ha n ges i n b e ha vi or, as w ell as 
t he e mer ge n ce of s uici dal i deati o n a n d be ha vi or, a n d t o re p ort s uc h s y m pt o ms i m me diatel y t o t he 
st u d y I n vesti gat or. C o nsi derati o n s h o ul d be gi ve n t o disc o nti n ui n g mi nzas ol mi n ( U C B 0 5 9 9) i n 
partici pa nts w h o e x p erie nce si g ns of s uici dal i deati o n or be ha vi or. St u d y st o p pi n g be ha vi or f or 
st u d y partici pa nts wit h s uici dal i deati o n or be ha vi or is descri be d i n Secti o n  7. 2 . 
8. 3  
A d v er s e e v e nt s a n d s eri o u s a d v er s e e v e nt s  
T he defi niti o ns of a n A E or S A E ca n be f o u n d i n A p pe n di x 3 ( Secti o n  1 0. 3 ). 
A d verse e ve nts will be re p orte d b y t he partici p a nt ( or, w he n a p pr o priat e, b y a care gi ver or 
s urr o gate). 
T he I n vesti gat or a n d a n y desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d rec or di n g 
e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g u p A Es 
t hat are seri o us, c o nsi dere d relate d t o t he I M P or st u d y pr oce d ures, or t hat ca use d t he partici pa nt 
t o disc o nti n ue mi nzas ol mi n ( U C B 0 5 9 9) or P D 0 0 5 5 (see Secti o n  7 ). 
O n t he A E e C R F p a ge, t here is t he p ossi bilit y t o assess  ca us alit y t o t he I M P a n d t o a n y 
c o nc o mita nt me dicati o n. If a n A E is c o nsi d ere d relate d t o C O VI D -1 9 v acci ne, a ca usalit y 
assess me nt s h o ul d be e nt ere d i n t he A E e C R F.  
N ote t hat i n t his case t he nati o nal rec o m me n d ati o n f or re p orti n g A Es relate d t o C O VI D -1 9 
vacci nes s h o ul d be f oll o we d.  
If a n A E is t he res ult of a n i nteracti o n bet wee n a C O VI D-1 9 v acci n e a n d I M P i n t he st u d y, t he n 
t he cli nical st u d y ca usal ass ociati o n s h o ul d be f or b ot h I M P a n d C O VI D-1 9 vacci ne.  
F or res ults discl os ure o n p u blic re gistr ies (e g, Cli nical Trials. g o v), T E A Es a n d 
treat me nt-e mer ge nt S A Es will be p u blis he d.  
8. 3. 1  
Ti m e p eri o d a n d fr e q u e n c y f or c oll e cti n g A E a n d S A E i nf or m ati o n  
All A Es a n d S A Es will be c ollecte d fr o m t he si g ni n g of t he I C F u ntil t he S F U Visit at t he ti me 
p oi nts s pecifi e d i n t he Sc he d ule of Acti vities ( Secti o n  1. 3 ). 
I n or der t o e ns ure c o m plete safet y data c ollecti o n, all A Es occ urri n g d uri n g t he st u d y (ie, after 
t he si g ni n g of t he I C F), i ncl u di n g a n y pretr eat me nt a n d p osttreat me nt peri o ds re q uire d b y t he 
pr ot oc ol, m ust be re p orte d i n t he e C R F e ve n if n o I M P was t a ke n b ut s pecific st u d y pr oce d ures 
were c o n d ucte d. T his i ncl u des all A Es n ot prese nt pri or t o t he i nitial visit a n d all A Es t hat 
rec urre d or w orse n e d aft er t he i nitial visit. 
All S A Es will be rec or de d a n d re p ort e d t o t he S p o ns or or desi g nee wit hi n 2 4 h o urs, as i n dicate d 
i n A p pe n di x 3 (Secti o n  1 0. 3 ). T he I n vesti gat or will s u b mit a n y u p date d S A E data t o t he S p o ns or 
wit h o ut u n d ue dela y b ut n ot later t ha n wit hi n 2 4  h o urs of it bei n g a vaila ble.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 5  of 1 3 3  
T he I n vesti gat or is s pecificall y re q ueste d t o c ollect a n d re p ort t o U C B ( or its re pres e ntati ve) a n y 
S A Es (e ve n if t he I n vesti gat or is certai n t hat t he y are i n n o wa y ass ociate d wit h t he I M P), u p t o 
3 0 da ys fr o m t he e n d of t he st u d y f or eac h partici pa nt, a n d t o als o i nf or m partici pa nts of t he nee d 
t o i nf or m t he I n v esti gat or of a n y S A E wit hi n t his peri o d. Seri o us A Es t hat t he I n v esti gat or t hi n ks 
ma y be ass ociat e d wit h t he I M P m ust be re p orte d t o U C B re gar dless of t he ti me bet wee n  t he 
e ve nt a n d t he e n d of t he st u d y.  
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 A Es a n d S A Es 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 de d i n A p pe n di x  3 
(Secti o n  1 0. 3 ). 
8. 3. 2  
M et h o d of d et e cti n g A E s a n d S A E s  
Care will be ta ke n n ot t o i ntr o d uce bias w he n d etecti n g A Es a n d/ or S A Es. O pe n -e n d e d a n d 
n o nlea di n g ver bal q u esti o ni n g of t he partici pa nt is t he preferre d m e t h o d t o i n q uire a b o ut 
A E  occ urre nces.  
8. 3. 3  
F oll o w -u p of A E s a n d S A E s  
After t he i nitial A 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 A Es, S A Es, a n d A E SIs (as defi ne d i n Secti o n  8. 3. 6 ) 
will be f oll o we d u ntil res ol uti o n, sta bilizati o n, t he I n v esti gat or deter mi nes t hat it is n o l o n ger 
cli nicall y si g nifica nt, t he e ve nt is ot her w ise 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. 3 ). F urt her i nf or mati o n o n f oll o w u p pr oce d ures is gi ve n i n A p pe n di x 3 
(Secti o n  1 0. 3 ). 
8. 3. 4  
R e g ul at or y r e p orti n g r e q uir e m e nt s f or S A E s  
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 n S A E is esse nti al s o 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 nts a n d t he safet y of a n I M P 
u n der cli nical i n vesti gati o n are met.  
F urt her t o t he re p orti n g of a n S A E fr o m t he I n vesti gat or t o t he S p o ns or, a n e x pecte d ness 
assess me nt will be ma d e per t he I B, as refere n ce s afet y i nf or mati o n f or t his st u d y, a n d rele va nt 
S p o ns or’s S O Ps a n d a p pr o priate re p orti n g of s us pecte d u ne x p ecte d s eri o us a d verse reacti o ns 
( S U S A Rs) will be carrie d o ut t o healt h a ut h orities as per I C H a n d l ocal r e g ulat or y re q uirem e nts.  
I n v esti gat or safet y re p orts m ust be pre pare d f or S U S A Rs acc or di n g t o l ocal re g ulat or y 
re q uire me nts a n d S p o ns or p olic y a n d f or war de d t o I n v esti gat ors as necessar y. 
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 n I M P 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 ul at or y re q uir e m e nts relati n g t o safet y r e 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)/I n d e pen d e nt Et hics C o m mittees (I E Cs) , 
a n d I n vesti gat ors.  
A n I n vesti gat or w h o recei ves a n I n vesti gat or safet y re p ort descri bi n g a 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 S A Es) fr o m t he S p o ns or will re vie w a n d t he n file it 
al o n g wit h t h e I B a n d will n otif y t he I R B/I E C, if a p pr o priate acc or di n g t o l ocal re q uir e me nts.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 6  of 1 3 3  
8. 3. 5  
Pr e g n a n c y  
Details of all pre g n a ncies i n fe male partici pa nts a n d, if i n dicate d, fe m ale part ners of male 
partici pa nts will be c ollecte d after t he start of I M P a n d u ntil at leas t 1 2 m o nt hs after t he deli ver y 
date.  
If a pre g na nc y is r e p orte d, t he I n v esti gat or m ust i m me diatel y i nf or m t he S p o ns or wit hi n 2 4 h o urs 
of lear ni n g of t he pre g n a nc y a n d s h o ul d f oll o w t he pr oce d ures o utli ne d i n A p pe n di x 4 
(Secti o n  1 0. 4 ). 
T he partici pa nt s h o ul d be wit h dra w n fr o m t he st u d y as s o o n as pre g n a nc y is k n o w n ( b y p ositi ve 
pre g na nc y t est [ie, a p ositi ve uri ne test c o nfir me d wit h a bl o o d test]), a n d t he f oll o wi n g s h o ul d be 
c o m plete d:  
•  T he partici pa nt s h o ul d ret ur n f or a n earl y disc o nti n uati o n visit.  
•  T he partici pa nt s h o ul d i m me diatel y st o p t he i nta ke of t he I M P as i nstr uct e d at t he earl y 
disc o nti n uati o n visit.  
•  A n S F U Visit s h o ul d be sc he d ule d 1 4 da ys after t he partici pa nt has disc o nti n ue d her I M P.  
A b n or mal pre g n a nc y o ut c o mes (e g, s p o nta n e o us a b orti o n, fetal deat h, still birt h, c o n ge nital 
a n o malies, ect o pic pre g n a nc y) are c o nsi dere d S A Es.  
8. 3. 6  
A E SI  
A n A E SI is a n y A E t hat a re g ulat or y a ut h orit y has ma n date d be re p orte d o n a n e x pe dite d b asis, 
re gar dl ess of t he seri o us ness, e x pect e d ness, or relate d ness of t he A E t o t he a d mi nistrati o n of a 
U C B pr o d uct/c o m p o u n d.  
F or mi nzas ol mi n ( U C B 0 5 9 9), t he f oll o wi n g e v e nts re q uire i m me diate re p orti n g ( wit hi n 2 4 h o urs 
re gar dl ess of seri o us ness) t o U C B: 
•  H y’s La w  
− P ote ntial H y’s La w, defi ne d as ≥3 x u p per li mit of n or mal ( U L N) ala ni ne 
a mi n otra nsferase ( A L T) or as partat e a mi n otra nsferase ( A S T) wit h c oe xisti n g ≥2 x U L N 
t otal bilir u bi n i n t he a bse nce of ≥2 x U L N al kali ne p h os p hatase, wit h n o alter nati ve 
e x pla nati o n f or t he bi o c h e mical a b n or malit y (ie, wit h o ut waiti n g f or a n y a d diti o nal 
eti ol o gic i n vesti gati o ns t o ha ve bee n c o ncl u d e d). F oll o w -u p i nf or mati o n s h o ul d be 
re p orte d if a n alter nati ve eti ol o g y is i de ntifie d d uri n g i n vesti gati o n a n d m o nit ori n g of t he 
partici pa nt.  
•  H y perse nsiti vit y reacti o ns (s uc h as ras h, a n gi oe de ma, or a na p h yla xis)  
8. 3. 6. 1  
H y p er s e n siti vit y r e a cti o n m o nit ori n g a n d m a n a g e m e nt  
If a st u d y partici p a nt e x p erie nces a h y persensiti vit y reacti o n (s uc h as ras h, a n gi oe de ma, or 
a na p h yla xis), he or s he will c o ntact t he cli nical site i m me diatel y ( 2 4 h o urs a da y) or s ee k ur ge nt 
me dical a d vice i n acc or da nce wit h i nstr ucti o ns fr o m t he I n v esti gat or.  
T he a d vice will be base d o n t he cli nic al pres e ntati o n a n d ma y be t o pres e nt t o t he cli nical site or 
see k me dical atte nti o n i n t he c o m m u nit y. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 7  of 1 3 3  
T he st u d y partici pa nt s h o ul d be ra pi dl y a n d t h or o u g hl y assesse d i n li ne wit h t he acti o ns bel o w.  
H y perse nsiti vit y reacti o ns (s uc h as r as h, a n gi oe de ma, or a na p h yla xis) will be A E SIs a n d re q uire 
e x pe dite d re p orti n g t o U C B, re gar dless of seri o us ness, e x pect e d ness, or rel ate d ness i n li ne wit h 
Secti o n  8. 3. 6 . T his will all o w f or ra pi d e val uati o n. 
I n case of a s us pe cte d h y perse nsiti vit y reacti o n (s uc h as ras h, a n gi oe de ma, or a na p h yla xis) or 
a n y cli nical i n dicati o n of a n u ne x pecte d i m m u ne res p o nse, t he p oi nts descri be d i n 
Secti o ns  8. 3. 6. 1. 1 t hr o u g h 8. 3. 6. 1. 4 s h o ul d be o bser ve d.  
C o nsi derati o n f or restarti n g I M P is pr o vi de d i n Secti o n  7. 1. 1 . 
8. 3. 6. 1. 1  
M e di c al hi st or y  
Detaile d hist or y of t he h y perse nsiti vit y reacti o n (e g, ras h, a n gi oe de ma, or a na p h yla xis) wit h 
o nset ti me of s y m pt o ms a n d si g ns, l ocati o n of s y m pt o ms a n d si g ns, first a p peara n ce, its 
e v ol uti o n (e g, w here t he ras h a p peare d a n d t o w here it s prea d), a n y ot her s y m pt o ms (e g, pr urit us, 
s welli n g, breat hless ness), es peciall y if s h o wi n g a s yste mic i n v ol ve me nt (a n a p h yla xis), will be 
rec or de d. T he criteria f or a na p h yla xis are descri be d i n Secti o n  8. 3. 6. 1. 1. 1 . 
T he cli nical pr o gressi o n of t he h y perse nsiti vit y reacti o ns s y m pt o ms s h o ul d be rec or de d a n d a n y 
c ha n ge i n s y m pt o ms or se verit y s h o ul d als o be rec or de d t o get her wit h t he ti mi n g.  
All A Es re p orte d c o nc urre ntl y s h o ul d be i ncl u de d wit hi n t he  re vie w. 
It will als o be i m p orta nt t o i n vesti gate a n y rece nt i nta ke of ne w m e dicati o ns, her bs, s u p ple me nts, 
or t he rece nt use of a n y t o pical s u bsta nces.  
8. 3. 6. 1. 1. 1  
A n a p h yl a xi s  
Sa m ps o n et al. liste d criteria f or t h e dia g n osis of a na p h yla xis. T his was de v el o pe d at t he Sec o n d 
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas e/ F o o d Aller g y a n d A na p h yla xis Net w or k 
s y m p osi u m ( Sa m ps o n et al, 2 0 0 6). 
Ac ute o nset = mi n utes t o a fe w h o urs.  
Criteria f or dia g n osis -1 or m ore of t he f oll o wi n g:  
•  Ac ute o nset of a n ill ness wit h s y m pt o m c o m ple x 1 (see bel o w)  
•  Ac ute o nset of s y m pt o m c o m ple x 2 (see b el o w) after e x p os ure t o a li kel y aller ge n  
•  Ac ute o nset of a re d u ce d s yst olic bl o o d press ure ( S B P) after e x p os ure t o a k n o w n aller ge n 
f or t he partici p a nt. 
S y m pt o m c o m ple x 1: b ot h of t he f oll o wi n g: 
•  At least 1 of t he f oll o wi n g:  
− S ki n i n v ol ve me nt ( ge neralize d hi ves, pr uritis, fl us hi n g)  
− M uc o us me m bra ne i n v ol ve me nt (s w olle n li ps, s w olle n t o n g ue, s w olle n u v ula)  
•  At least 1 of t he f oll o wi n g:  
− Res pirat or y c o m pr o mise ( d ys p nea, w heezi n g, br o nc h os pas m,  stri d or, re d u ce d pea k 
e x pirat or y fl o w, h y p o x e mia)  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 8  of 1 3 3  
− Re d uce d S B P, c olla pse, s y nc o pe, i nc o nti ne nce or ot her s y m pt o m of e n d -or ga n 
d ysf u ncti o n  
S y m pt o m c o m ple x 2: T w o or m ore of t he f oll o wi n g:  
•  S ki n or m uc o us me m bra nes (as a b o v e)  
•  Res pirat or y c o m pr o mise (as a b o ve)  
•  Re d uce d B P (as a b o v e)  
•  Persiste nt gastr oi ntesti nal tract s y m pt o ms (cra m pi n g, a b d o mi nal pai n, v o miti n g)  
Re d uce d S B P is i n dicate d b y 1 of t he f oll o wi n g:  
•  B P < 7 0 % of Baseli ne S B P  
•  A ge ≥1 1 years A N D < 9 0 m m H g  
Li mitati o ns:  
Tre u dler et al. f o u n d t hat t he crite ria ma y n ot perf or m as well as ot hers f or t he rec o g niti o n of 
se vere, i m me diate reacti o ns ( Tre u dler et al, 2 0 0 8). 
8. 3. 6. 1. 2  
C o m pl et e p h y si c al e x a mi n ati o n  
E val uati o n of a p ossi ble h y perse nsiti vit y reacti o n (s uc h as ras h, a n gi oe de ma, or a na p h yl a xis) 
i ncl u des a c o m plete p h ysical e xa mi nati o n of t he e ntire b o d y as s o o n as feasi ble after re p orti n g b y 
t he st u d y partici pa nt. T he c o m plete p h ysical e xa mi nati o n i ncl u des a detaile d descri pti o n of t he 
si g ns s uc h as ras h or a n gi oe de ma, t he l ocati o n of t he si g ns, a n d a n e x a mi nati o n f or ot her p ossi ble 
si g ns, s uc h as: 
•  Bla nc he d or fl us he d s ki n  
•  M uc o us me m bra ne er osi o ns or ulcerati o n  
•  Mac ulae  
•  Pa p ulae  
•  Blisters  
•  C o nfl ue nt er yt he ma  
•  A n gi oe de ma: face, li ps, a n d/ or t o n g ue s welli n g, als o bac k of ha n ds or feet  
•  W heeze, stri d or, d ys p nea  
•  Pal pa ble p ur p ura  
•  L y m p ha de n o pat h y  
A n e xa mi nati o n of t he e ntire s ki n s urface, n ot j ust l ocal t o t he site of reacti o n, is re q uire d.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 6 9  of 1 3 3  
F urt her m ore, a c o m plete p h ysical e xa mi nati o n will als o i ncl u de:  
•  Vital si g ns ( hi g h fe ver, d ys p nea, or h y p ote nsi o n)  
− Vital si g ns ( p ulse rate, S B P, diast olic B P, res pirat or y rate, b o d y te m p erat ur e, a n d o x y ge n 
sat urati o n) will be ta ke n w he n t he A E of h y p erse nsiti vit y is re p orte d a n d at re g ular 
i nter vals (a p pr o xi mat el y 2 0 t o 3 0 mi n utes) f or a mi ni m u m of 2 h o urs. T he fre q ue nc y 
t hereafter will be bas e d o n cli nical j u d ge me nt. If t here is w ors e ni n g of cli nical stat us, t he 
I n v esti gat or will a p pl y t he a p pr o pri ate treat me nt a n d safet y pr oce d ures (e g, call 
e mer ge n c y) a n d c o ntact t he U C B st u d y p h ysicia n.  
•  P h ot o gra p h y of ras h a n d ot her s y m pt o ms at t he first o p p ort u nit y a n d wit h reas o na ble ti me 
se q ue nce t o d o c u me nt res ol uti o n. If ti mel y site visit is n ot p ossi ble t he partici pa nt ma y be 
re q ueste d t o ta k e p h ot os t o e ns ure p h ot os of acti ve s y m pt o ms. If partici pa nt is re q ueste d t o 
pr o vi de p h ot os t he I n ve sti gat or s h o ul d a d vise t he partici pa nt i n data pr otecti o n re q uire me nts 
(e g, a v oi da n ce of i d e ntif yi n g feat ures s u c h as c h aracteristic tatt o os, parts of t he face). T h e 
I n v esti gat or will e ns ure t hat i de ntifia ble c haract eristics are re m o ve d / hi d de n bef ore s h ari n g 
t he pict ures wit h t he S p o ns or. 
•  Re -e xa mi nati o n s h o ul d t he s y m pt o ms si g nifica ntl y w orse n  
•  Occ urre nce of ot her rece nt or c urre nt s y m pt o ms, e ve n if t he y a p p ear n ot relate d  
8. 3. 6. 1. 3  
A d diti o n al i n v e sti g ati o n s  
I n v esti gat ors s h o ul d arra n ge f or t he f oll o wi n g i n v esti gatio ns; f urt her i n vesti gati o ns ma y be 
re q ueste d after c o ns ultati o n wit h t he Me dical M o nit or: 
•  A d diti o nal bl o o d sa m pli n g f or e xte n de d eti ol o gical c haracterizati o n of t he h y perse nsiti vit y 
reacti o n i ncl u di n g: 
− Bas o p hil Acti vati o n Test  
− L y m p h oc yte Tra nsf or mati o n Tes t assa ys 
− Tr y ptase  
− I m m u n o gl o b uli n E 
•  Ra pi d referral t o e x p erts (ie, der mat ol o gist, aller gist, or i m m u n ol o gist)  
A d diti o nall y, a s ki n bi o ps y s h o ul d be c o nsi dere d f oll o wi n g re vie w b y e x pert.  
8. 3. 6. 1. 4  
Tr e at m e nt  
I n v esti gat ors will a d mi nister t he a p pr o priate treat me nt as dee me d necess ar y i n cases of 
h y perse nsiti vit y. T his i ncl u des t he use of a nti hista mi nes f or urticari a a n d t h e a p pr o pri ate 
ma na ge me nt i n cas e of p ote ntiall y life -t hreate ni n g e ve nts s uc h as a na p h yla xis, Ste ve ns-J o h ns o n 
S y n dr o me, a n d t o xic e pi der mal necr ol ysis.  
8. 3. 6. 2  
R e n al f u n cti o n s af et y m o nit ori n g a n d m a n a g e m e nt  
If a partici pa nt de vel o ps cli nicall y si g nifica nt re nal d ysf u ncti o n, re peat la b orat or y testi n g s h o ul d 
be u n derta k e n as s o o n as p ossi ble a n d ot her a p pr o priate i n vesti gati o ns ma y be arra n ge d. A n 
i ncreas e i n ser u m creati ni ne of > 2 5 % fr o m t he pre vi o us val ue will tri g ger re peat testi n g wit hi n 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 0  of 1 3 3  
4 8 h o urs. T he Me dic al M o nit or s h o ul d be n otifie d, a n d c o nsi derati o n s h o ul d be gi ve n t o m ore 
fre q ue nt m o nit ori n g. 
Cli nicall y si g nifica nt re nal d ysf u ncti o n will t ri g ger a n S M C a n d D M C re vi e w. 
Partici pa nts m ust be disc o nti n ue d fr o m I M P ( b ut n ot necessaril y fr o m t he st u d y) if la b orat or y 
tests s u g gest e vi de nce of re nal t o xicit y (see Secti o n  7. 2 ). A n y cli nicall y si g nifica nt fi n di n gs i n 
la b orat or y res ults f or re n al f u ncti o n will be m o nit ore d u ntil res ol uti o n or sta bilizati o n. 
T he S M C a n d D M C c harters will i ncl u de f urt her d etails re gar di n g t he assess me nt of re nal 
f u ncti o n. 
8. 3. 7  
Di git al H e alt h T e c h n ol o g y s af et y r e p orti n g  
T he K o ne ksa Ne ur os cie n ce T o ol kit is bei n g pr o vi de d as a n o ni n vasi ve e x pl orat or y t o ol f or 
assessi n g m ot or f u ncti o n, s peec h, p h ysical acti vit y, a n d slee p ( o pti o nal) i n st u d y partici pa nts 
w h o v ol u nteer t o use i t. 
T o f ulfill re g ulat or y o bli gati o ns w orl d wi de, t he I n vesti gat or is res p o nsi ble f or detecti n g a n d 
d oc u me nti n g e ve nts ass o ciate d wit h t he use of t h e K o ne ksa Ne ur oscie nce T o ol kit a n d n otif yi n g 
K o ne ksa H ealt h I nc. of s uc h e ve nts, if t he y meet t he defi niti o ns of i nci de nt or malf u ncti o n a n d 
occ ur d uri n g t he st u d y wit h t he K o ne ksa Ne ur osci e nce T o ol kit.  
T he pr ocesses f or detecti n g, rec or di n g, a n d re p orti n g of A Es a n d S A Es are o utli ne d i n 
Secti o n  8. 3  a n d als o pert ai n t o a n y A E or S A E o bser ve d d uri n g t he st u d y a n d relate d t o t he 
K o ne ksa N e ur oscie n ce T o ol kit. T he pr ocesses o utli ne d bel o w descri b e a d diti o nal acti vities f or 
A Es a n d S A Es relat e d t o t he c o m p o ne nts of t he K o ne ksa Ne ur oscie nce T o ol kit as well  as 
deficie nci es relat e d t o t he K o ne ksa Ne ur oscie nce T o ol kit.  
F or A Es, S A Es, a n d d efi cie ncies relate d t o t he m o bile s oft ware a p plicati o n a n d t he A p ple i P h o ne 
c o m p o ne nts of t he K o ne ksa Ne ur os cie nce T o ol kit, t he I n v esti gat or is res p o nsi ble f or n otif yi n g 
K o ne ksa H ealt h I nc. ( via a messa ge t o hel p @ k o n e ksa healt h.c o m).  
F or a d v erse d e vice effects ( A D Es) relate d t o t he Acti Gra p h C PI W (i ncl u di n g its Data H u b) 
c o m p o ne nt of t he K o ne ksa Ne ur os cie nce T o ol kit, t he I n v esti gat or is res p o nsi ble f or n otif yi n g 
K o ne ksa H ealt h I nc. ( via a messa ge t o hel p @ k o n e ksa healt h.c o m). Refer t o A p pe n di x 7 
( Secti o n 1 0. 7 ) f or defi niti o ns of A D E, seri o us A D E ( S A D E), a n d d e vice d eficie nc y. 
Of n ote, e ve nts f ulfilli n g t he defi niti o n of a n A E/ S A E will als o f oll o w t he pr ocesses o utli ne d i n 
Secti o n  8. 3. 3  a n d A p pe n di x 3 ( Secti o n  1 0. 3 ). 
K o ne ksa H ealt h I nc. will s u p p ort t he S p o ns or o n a n y f oll o w -u p f or A D Es/ S A D Es a n d 
deficie nci es relat e d t o t he K o ne ksa Ne ur oscie nce T o ol kit t hat occ ur d uri n g t he st u d y.  
8. 3. 7. 1  
Ti m e p eri o d f or s af et y r e p orti n g  
A d verse e ve nts will be c ollecte d at t he ti me p oi nts s pecifie d i n t he Sc he d ul e of Acti vities 
( Secti o n 1. 3 ; K o ne ksa N e ur oscie n ce T o ol kit safet y). 
A d verse e ve nts, A D Es, a n d de vice deficie nci es will be detecte d, d oc u me nte d, a n d re p ort e d 
d uri n g all peri o ds of t he st u d y i n w hic h t he K o ne ksa Ne ur oscie n ce T o ol kit is use d.  
If t he I n vesti gat or l ear ns of a n y safet y i nf or mati o n or deficie nc y rel ate d t o t he K o ne ksa 
Ne ur oscie n ce T o ol kit at a n y ti me after a st u d y partici pa nt has bee n disc h ar ge d fr o m t he st u d y, 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 1  of 1 3 3  
a n d s uc h e ve nt(s) is/are c o nsi dere d reas o na bl y r ela te d t o t he K o ne ksa Ne ur oscie nce T o ol kit, t he 
I n v esti gat or will pr o m ptl y n otif y K o ne ksa Healt h I n c. ( via a messa ge t o 
hel p @ k o ne ksa healt h.c o m) if t he st u d y is o n g oi n g.  If t he S p o ns or bec o m es a ware of a n y 
A D E/ S A D E or defi cie nc y relate d t o t he use of t he K o ne k sa Ne ur oscie nce t o ol kit after st u d y 
c o m pleti o n, t he S p o ns or will i nf or m K o ne ksa Healt h I nc.  
I n all cases, K o ne ksa H ealt h I n c. will s u p p ort t he S p o ns or o n a n y s u bse q ue nt f oll o w-u p.  
T he  pr ocess f or d oc u m e ntati o n  is pr o vi de d i n A p pe n di x 7 ( Secti o n  1 0. 7 ). 
8. 3. 7. 2  
F oll o w -u p of A E s, A D E s, a n d d e vi c e d efi ci e n ci e s  
F oll o w -u p a p plies t o all st u d y partici pa nts, i ncl u di n g t h ose w h o disc o nti n ue st u d y me dicati o n 
a n d/ or t he st u d y. 
T he I n vesti gat or is r es p o nsi ble f or e ns uri n g t hat f oll o w -u p i ncl u des a n y s u p ple me ntal 
i n vesti gati o ns as i n dicate d t o el uci date t he nat ur e a n d/ or ca us alit y of t he A E, A D E, or deficie nc y . 
Ne w or u p d ate d i nf or mati o n will be  f or war de d t o K o ne ksa Healt h I nc. a n d d oc u me nte d as per 
A p pe n di x 7 ( Secti o n  1 0. 7 ). 
8. 3. 7. 3  
R e p orti n g of A E s, A D E s, a n d d e vi c e d efi ci e n ci e s  
T he I n vesti gat or wi ll n otif y A Es (i ncl u di n g S A Es) a n d deficie ncies ass o ciat e d wit h t he m o bile 
s oft ware a p plicati o n or t he A p ple i P h o ne, as w ell as A D Es (i ncl u di n g S A D Es) a n d de vice 
deficie nci es ass ociate d wit h t he Acti Gra p h C PI W t o K o ne ksa Healt h I nc. ( via a messa ge t o 
hel p @ k o ne ksa healt h.c o m) wit hi n 2 4 h o urs after t he I n v esti gat or deter mi nes t hat t he e ve nt meets 
t he pr ot oc ol defi niti o n of a n e ve nt t hat s h o ul d be re p orte d. T he d efi niti o ns a n d t he pr ocess f or 
d oc u me ntati o n are pr o vi de d i n A p pe n di x 7 ( Secti o n  1 0. 7 ).  
T he I n vesti gat or will pr o vi de K o ne ksa Healt h I nc. ( via a n attac h me nt t o a messa ge t o 
hel p @ k o ne ksa healt h.c o m) wit h t he res pecti ve i nf or mati o n usi n g t he A d verse E ve nt a n d De vice 
Deficie n c y F or m s u p plie d b y t he S p o ns or. K o ne ksa Healt h I n c. is res p o nsi ble f or t he s u bse q ue nt 
re p orti n g t o t he res p ecti v e ma n ufact urers as a p plica ble. 
8. 3. 8  
S af et y r e p orti n g f or i n -st u d y p ati e nt i nt er vi e w s ( U S a n d U K o nl y)  
A n y p ote ntial A E re p or t e d b y partici pa nts d uri n g a q ualitati ve i nter vie w will be re p orte d t o t he 
site fr o m w hic h t he partici pa nt was r ecr uite d, a n d t he site will be res p o nsi ble f or c h ec ki n g t heir 
rec or ds if t h e A E has alrea d y bee n re p orte d b y t h e partici pa nt d uri n g t he cli nical st u d y. If it has 
alrea d y b ee n re p orte d b y t he partici pa nt, t he A E will be c o nsi dere d rec o ncil e d. If t he A E has n ot 
bee n pre vi o usl y r e p orte d, t he site will be res p o nsi ble f or re p orti n g t he A E i n t he e C R F acc or di n g 
t o t he A E re p orti n g pr o ce d ures i n A p pe n di x 3 ( Secti o n  1 0. 3 ). 
8. 4  
S af et y si g n al d et e cti o n  
Selecte d data fr o m t his st u d y will be re vie we d p eri o dicall y t o detect as earl y as p ossi ble a n y 
safet y c o n cer n(s) rel ate d t o t he I M P s o t hat I n vesti gat ors, cli nical st u d y partici pa nts, re g ulat or y 
a ut h orities, a n d I R Bs/I E Cs will be i nf or me d a p pr o priatel y a n d  as earl y as p ossi ble.  
T he st u d y p h ysicia n or m e dicall y q ualifie d desi g n ee/e q ui vale nt will c o n d u ct a n o n g oi n g re vie w 
of S A Es a n d perf or m o n g oi n g S A E rec o nciliati o ns i n c olla b orati o n wit h t he Patie nt Safet y 
re pres e ntati ve. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 2  of 1 3 3  
As a p pr o priat e f or t he sta ge of de vel o p me nt a n d acc u m ulate d e x p erie n ce wit h t he I M P, 
me dicall y q ualifie d pers o n nel at U C B ma y i de ntif y a d diti o nal safet y meas ures (e g,  A Es, vital 
si g ns, la b orat or y or E C G res ults) f or w hic h data will be peri o dicall y re vie we d d uri n g t he c o urse 
of t he st u d y.  
8. 5  
T r e at m e nt of o v er d o s e 
F or t his st u d y, a n y a d mi nistrati o n of mi nzas ol mi n ( U C B 0 5 9 9) t otali n g greater t ha n 3 6 0 m g 
wit hi n a p pr o xi matel y a 2 4 -h o ur ti me peri o d will be c o nsi dere d a n o ver d ose.  
O ver d ose e ve nts are o nl y c o nsi dere d A Es or S A Es if t here are ass o ciate d cli nical si g ns a n d 
s y m pt o ms or if t he act of ta ki n g t he e xcess I M P itself is a n A E or S A E (e g, s uici de atte m pt).  
U C B  d oes n ot rec o m me n d s pecific treat me nt f or a n o ver d ose . 
I n t he e ve nt of a n o ver d ose, t he I n vesti gat or or treati n g p h ysicia n s h o ul d: 
•  St o p d os i n g a n d c o ntact t he Me dical M o nit or i m me diatel y. 
•  Cl osel y m o nit or t he partici pa nt f or a n y A E/ S A E a n d la b orat or y a b n or malities u ntil 
mi nzas ol mi n ( U C B 0 5 9 9) ca n n o l o n ger b e detecte d s yste micall y (a p pr o xi m atel y  5  da ys).  
•  D oc u me nt t he q ua ntit y of t he e xcess d ose  as w ell as t he d urati o n of t he o ver d ose i n t he 
e C R F. 
Decisi o ns re g ar di n g d ose i nterr u pti o ns or m o dificati o ns will be ma de b y t he I n vesti gat or i n 
c o ns ultati o n wit h t he Me dical M o nit or base d o n t he cli nical e val u ati o n of t he partici pa nt.  
8. 6  
P h ar m a c o ki n eti c s  
P har mac o ki netic para met ers will n ot be e val uat e d i n t his st u d y.  
8. 7  
G e n eti c s  
Ge netic bl o o d sa m ples w ere c ollecte d i n P D 0 0 5 3.  
8. 8  
P h ar m a c o d y n a mi c s  
Da T -S P E C T ( Secti o n  8. 1. 1. 1 ) a n d C S F A S Y N (Secti o n  8. 9 ) will be use d as p har mac o d y n a mic 
bi o mar kers t o e val u ate t h e bi ol o gical res p o nse t o mi nzas ol mi n ( U C B 0 5 9 9) treat me nt. 
8. 9  
Bi o m ar k er s  
I ma gi n g bi o mar ker Da T-S P E C T assess me nt is disc usse d i n Secti o n  8. 1. 1. 1 . C ollecti o n of C S F 
a n d bl o o d sa m ples f or p ote ntial e x pl orat or y bi o mar ker researc h f or ms part of t he st u d y 
o bjecti ves.  
T he A S Y N see di n g assa y i n C S F has bee n rece ntl y de m o nstrate d ( Si der o wf et  al, 2 0 2 3) t o be a 
r o b ust ( q ualitati ve - Yes/ N o) bi o mar ker of Le w y b o d y pat h ol o g y i n P D. Acti ve a n d vi g or o us 
ste ps are bei n g ta k e n i n t he fiel d t o de vel o p a q ua ntitati ve assa y of t he bi o mar ker. T his pr o misi n g 
q ua ntitati ve assa y c o ul d p ote ntiall y be a mar ke r of disease pr o gressi o n/res p o nse t o t hera p y i n t he 
near f ut ur e f or dr u gs tar geti n g A S Y N, i ncl u di n g mi nzas ol mi n ( U C B 0 5 9 9; t he acti ve I M P i n t his 
st u d y). Si nce fe w st u d y p artici pa nts o pte d t o c o nse nt t o C S F sa m pli n g i n P D 0 0 5 3, a re n e we d 
atte m pt  (still o pti onal f or st u d y partici pa nts) will be ma de i n P D 0 0 5 5 t o c ollect C S F sa m ples t o 
ser ve as a bi o mar ker t hat ma y hel p gai n val ua ble i nsi g hts f or P hase 2 rea d o ut a n d f or P hase 3 
pla n ni n g a n d assa y de v el o p me nt.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 3  of 1 3 3  
T he C S F sa m ples will be c ollecte d f or assess me nt of A S Y N mar kers, ie, t otal A S Y N a n d A S Y N 
oli g o merizati o n. Al p ha -s y n uclei n oli g o merizati o n is belie ve d t o res ult i nt o t he t o xic s pecies 
res p o nsi ble f or t he n e ur o nal s prea d of pat h ol o g y u n derl yi n g t he A S Y N pat h ol o g y i n brai n a n d 
pr o ba bl y als o t he decreas e of t o tal A S Y N rel ease i nt o t he C S F of patie nts. T otal A S Y N le vels i n 
C S F will be assesse d usi n g a c o m merci all y a vaila ble e nz y me -li n ke d i m m u n os or be nt assa y. 
Pat h ol o gical A S Y N s pecies (e g, A S Y N see ds) ma y als o be assesse d.  
Bl o o d sa m ples are c ollecte d f or p ote ntia l e x pl orat or y bi o mar ker researc h w hic h ca n i ncl u d e b ut 
are n ot li mite d t o ri b o n ucleic aci d, pr otei n, a n d meta b olites.  
All c ollecte d sa m ples ma y be use d f or researc h p ur p oses f oc usi n g o n met h o d de vel o p me nt a n d 
assa y de vel o p me nt or t o better u n dersta n d t h e a ss ociati o n bet wee n bi o mar kers a n d diseas e 
pr o gressi o n, cli nical p he n ot y pes, or t he c orrelati o n bet wee n differe nt bi o mar kers or bi o mar kers 
a n d cli nical scal es. C ollecti o n of t hese sa m ples will e na ble e val uati o n of bi o mar kers relati ve t o 
disease bi ol o g y a n d pr o gressi o n, I M P treat me nt a n d res p o nse, a n d/ or m ec h a nis m of acti o n of t he 
I M P treat me nt. 
Cere br os pi nal fl ui d a n d bl o o d sa m ples f or meas ure me nt of bi o mar kers will be c ollecte d at t he 
ti me p oi nts s pecifie d i n t he sc he d ule of Sc he d ule of Acti vities (Secti o n  1. 3 ). T hese sa m ples 
s h o ul d be c ollecte d o nl y after all ot her assess me nts of t he visit ha ve bee n p erf or me d. As part of 
eac h i n di vi d ual C S F sa m pli n g pr oce d ure, a ma xi m u m of 1 2 m L of C S F d uri n g eac h l u m bar 
p u nct ure will be c ollecte d a n d a C S F q ualit y c o ntr ol c hec k (t otal cell c o u nt a n d/ or he m o gl o bi n 
meas ure me nt) will be d o ne t o i de ntif y a p ossi ble c o nta mi nati o n wit h bl o o d ca use d b y l u m bar 
p u nct ure.  
I nstr u cti o ns pertai ni n g t o sa m ple c ollecti o n, pr ocessi n g, st ora ge, la beli n g, a n d s hi p pi n g are 
pr o vi de d i n t he P D 0 0 5 5  La b orat or y M a n ual f or t his st u d y.  
8. 1 0  
U ni v er sit y of P e n n s yl v a ni a S m ell I d e ntifi c ati o n T e st  
Olfact or y i m pair me nt, e g, h y p os mia, is a c o m m o n fi n di n g i n P D. T he U ni versit y of 
Pe n ns yl va nia S mell I de ntificati o n Test ( U P SI T) is a well -esta blis he d 4 0 -ite m olfact or y test t hat 
all o ws f or deter mi ni n g t he a bs ol ute val ue of a n os mia a n d mil d, m o derate, or se vere h y p os mia. It 
is a wi del y use d s mell test f or assessi n g h y p os mia i n i n di vi d uals wit h P D ( D ot y, 2 0 1 2; 
D ot y  et al, 1 9 8 4). T he U P SI T will be c o m plete d as s pecifie d i n t he Sc he d ul e of Acti vities 
( Secti o n 1. 3 ) a n d t he Us er Ma n ual f or f urt her c haracterizati o n of t he st u d y p o p ulati o n. Site staff 
will perf or m t he U P SI T wit h eac h st u d y partici p a nt o nce d uri n g t he Treat me nt Peri o d a n d rec or d 
res ults i n t he e C R F. Site staff will d oc u me nt if t he u n derl yi n g ca use f or h y p os mia ma y be d ue t o 
ot her u n derl yi n g c o n diti o ns t ha n P D, e g, C O VI D -1 9. T he U P SI T will n ot be use d f or me dical 
treat me nt decisi o n ma ki n g or f or partici pa nt ma na ge me nt d uri n g t he st u d y. 
8. 1 1  
M e di c al r e s o ur c e utili z ati o n a n d h e alt h e c o n o mi c s  
N ot a p plica ble.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 4  of 1 3 3  
9  
S T A TI S TI C A L C O N SI D E R A TI O N S  
A descri pti o n of statistical met h o ds f oll o ws a n d will be descri be d i n m ore detail i n t he statistical 
a nal ysis pla n ( S A P).  
9. 1  
D efi niti o n of a n al y si s s et s  
T he f oll o wi n g a nal ysis sets will be use d:  
•  All St u d y Partici pa nts Set ( A S P S): All st u d y partici pa nts w h o were ra n d o mize d i nt o P D 0 0 5 3 
a n d w h o si g n t he I C F f or P D 0 0 5 5.  
•  Safet y Set ( S S): All st u d y partici pa nts w h o were ra n d o mize d i n P D 0 0 5 3 a n d w h o recei ve at 
least a partial d ose of P D 0 0 5 5 I M P. T he S S will be use d f or d e mo gra p hic, safet y, a n d 
effic ac y a n al yses.  
F or efficac y, a n al yses will be base d o n treat me nt assi g ne d i n P D 0 0 5 5; f or safet y, a nal yses will 
be base d o n tr eat me nt a ct uall y recei v e d i n P D 0 0 5 5.  
N ote: A F ull A nal ysis Set will n ot be defi ne d i n t his st u d y.  
9. 2  
G e n er al  st ati sti c al c o n si d er ati o n s  
All a nal yses will be perf or me d usi n g S A S ®  versi o n 9. 4 or later ( S A S I nstit ute, Car y, N C, U S).  
9. 2. 1  
D e s cri pti v e st ati sti c s a n d m o d eli n g  
F or c o nti n u o us varia bles, s u m mar y statistics will i ncl u de t he n u m ber of st u d y partici pa nts, mea n, 
me dia n, sta n dar d de viati o n ( S D), mi ni m u m, a n d ma xi m u m, u nless state d ot her wise. Cate g ori cal 
e n d p oi nts will be s u m marize d usi n g fre q ue nc y c o u nts a n d perce nta ges. F urt her details o n w hic h 
s u m mar y statistics will be prese nt e d f or eac h v ari a ble t y pe will be give n i n t he S A P.  
Baseli ne will refer t o P D 0 0 5 3 Baseli ne Visit data ( or Scree ni n g Visit data w here a p plica ble).  
L o n git u di nal a nal yses will i ncl u de data fr o m t he P D 0 0 5 3 Baseli ne/ Scree ni n g Visits (as 
a p plica ble).  All ti me p oi nts will be s pecifie d wit h refere nc e t o t he P D 0 0 5 3 Baseli ne/ Scree ni n g 
Visits.  
T he esti mati o ns f or t he treat me nt of i nterest f or t h e Pri mar y Efficac y O bj ecti ve/ Esti ma n d a n d f or 
t he E x pl orat or y Efficac y O bjecti ve III ( d ose c o m paris o n) ca n b e o btai ne d fr o m a si n gle a nal ysis 
usi n g a 3 -cate g or y treat me nt effect: t he “ E arl y-start 3 6 0 m g/ da y” ar m, t he “ Earl y-start 
1 8 0 m g/ da y” ar m, a n d t he “ Dela y e d -start 3 6 0 m g/ d a y” ar m. T h e esti mati o ns will be, res pecti vel y:  
•  Differe nce at 3 6 m o nt hs (“ P D 0 0 5 5 M o nt h 1 8 a nal ysis”) a n d at 7 8 m o nt hs (“ P D 0 0 5 5 
M o nt h  6 0 a nal ys is”) bet wee n t he Earl y-start mi n zas ol mi n ( U C B 0 5 9 9) ( 3 6 0 m g/ da y) ar m a n d 
t he 1 8‑ m o nt h Dela ye d-start mi nzas ol mi n ( U C B 0 5 9 9) ( 3 6 0 m g/ da y) ar m, e q ui vale nt t o half-
c u m ulati ve d ose  
A N D  
•  Differe nce at 3 6 m o nt hs (“ P D 0 0 5 5 M o nt h 1 8 a nal ysis”) a n d at 7 8 m o nt hs (“ P D 0 0 5 5 
M o nt h  6 0 a nal ysis”) bet wee n t he Earl y -start mi n zas ol mi n ( U C B 0 5 9 9) ( 3 6 0 m g/ da y) ar m a n d 
t he Earl y‑start mi nz as ol mi n ( U C B 0 5 9 9) ( 1 8 0 m g/ da y) ar m. Here, t h e “ P D 0 0 5 5 M o nt h 1 8 
a nal ysis” will be a c o m p aris o n t o a n e q ui vale nt h alf -c u m ulati ve d ose, w hereas at t he 
“ P D 00 5 5 M o nt h 6 0 a nal ysis” t he c o m paris o n of c u m ulati ve d oses will de pe n d o n t he best 
d ose selecte d.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 5  of 1 3 3  
All a nal yses will be a dj uste d f or ge n der a n d a ge.  
9. 2. 2  
H a n dli n g of i nt er c urr e nt e v e nt s, pr ot o c ol d e vi ati o n s, a n d r e s ulti n g 
mi s si n g d at a  
T he strate gies/a p pr oac h es f o r ha n dli n g i nterc urre nt e ve nts (I C Es) a n d pr ot oc ol de viati o ns will be 
as f oll o ws:  
•  Treat me nt P olic y : All ( pre I C E a n d p ost I C E) dat a will be i ncl u de d i n t he a nal ysis, re gar dless 
of w het her t h e partici pa nt re mai ns o n t he assi g ne d i n vesti gati o nal treat me nt or  disc o nti n ue d.  
T his a p pr oac h will reflect t he treat me nt effect r e g ar dless of t he I C E.  
•  H y p ot hetical : Data will b e m o difie d t o mirr or its val ue ha d a n I C E n ot o cc urre d ( u n d er s o me 
h y p ot hetical c o n diti o ns).  
O ne s uc h h y p ot hetical c o n diti o n is t hat t he I C E prese nte d c o m pletel y at ra n d o m. I n t his cas e, 
all p ost I C E data are s et t o missi n g (re m o ve d) a n d i m p ute d u n der t he ass u m pti o n of missi n g 
c o m pletel y at ra n d o m. T his strate g y ca n be a p plie d t o I C Es w hic h are c o nsi dere d 
u ni nf or mati ve wit h res pect t o t he effec t of i nterest, ie, treat me nt efficac y. As a defa ult 
a p pr oac h, t his strat e g y will be a p plie d t o a n y occ urre nce of a n I C E affecti n g t he e xiste nce of 
meas ure me nts.  
Alter nati ve i m p utati o n a p pr oac hes will als o be c o nsi dere d f or I C Es w hic h are c o nsi d ere d t o 
be i nf or mati ve wit h res p ect t o t he effect of i nterest, ie, treat me nt -relate d st u d y ter mi nati o n 
a n d treat me nt disc o nti n u ati o n, s uc h as refere nce -b ase d i m p utati o n ( R BI) a p pr oac hes (see 
S A P f or details).  
T his a p pr oac h will reflect t he treat me nt effect h a d t he I C E  n ot occ urre d.  
•  C o m p osite : I C E data will be i nc or p orate d i nt o t he e n d p oi nt bei n g a nal yze d. T his a p pr oac h 
will reflect t he tr eat me nt effect i n t he pres e nce of t he I C E.  
F or t he pri mar y a n d sec o n dar y O bjecti ves/ Esti ma n ds, a n o ver vie w of t he h a n dli n g strate gies  f or 
I C Es, pr ot o c ol de viati o ns, st u d y ter mi nati o n/l oss t o f oll o w u p, a n d res ulti n g missi n g data is 
prese nte d i n Ta bl e  9 -1 . 
I m p utati o n a p pr oac h es t o deal wit h missi n g data, ce ns ore d dat a, a n d re m o ve d data d ue t o t he 
“ H y p ot hetical” h a n dli n g strate g y will be descri be d i n detail i n t he S A P.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 6  of 1 3 3  
T a bl e  9 -1 : 
O v er vi e w of h a n dli n g  str at e gi e s f or I C E s a n d a p pr o a c h i n c a s e of 
st u d y t er mi n ati o n  
 
D a T -S P E C T w h ole stri at u m 
S B R  
C u m ul ati ve L E D D  
Esti m a n d  
Pri m ar y  
Sec o n d ar y  
 
Re g ar dless of S T i niti ati o n / 
t y pe / d ose 
S T i niti ati o n / t y pe / d ose as 
i nte gr al p art 
I C E 
S T  
Treat me nt p olic y  
(I ncl u de p ost I C E data) 
C o m p osite  
(I C E data i nc or p orate d i nt o 
e n d p oi nt) 
A E -relate d treat me nt 
disc o nti n uati o n  
Treat me nt p olic y  
(I ncl u de p ost I C E data) 
i d 
Treat me nt disc o nti n uati o n  
(all ot her ca uses) 
Treat me nt p olic y  
(I ncl u de p ost I C E data)  
i d 
Ot her pr ot oc ol de viati o ns - 
I m p orta nt 
H y p ot hetical  
(I m p ute p ost I C E data a) 
i d 
Ot her pr ot oc ol de viati o ns - 
N ot i m p orta nt  
Treat me nt p olic y  
(I ncl u de p ost I C E data) 
i d 
Deat h or seri o us i nj ur y (all 
ca uses) 
H y p ot hetical  
(I m p ute p ost I C E data a) 
i d 
C o nfir me d or s us pecte d cases 
of C O VI D -1 9 wit h o ut 
treat me nt disc o nti n uati o n or 
st u d y ter mi nati o n 
Treat me nt p olic y  
(I ncl u de p ost I C E data) 
i d 
C O VI D -1 9 vacci nati o n  
Treat me nt p olic y  
(I ncl u de p ost I C E data) 
i d 
St u d y ter mi n ati o n a n d l oss t o f oll o w-u p  
Treat me nt relate d  
H y p ot hetical  
(I m p ute p ost ter mi nati o n data a) 
i d 
Ot her/ u n k n o w n ca uses  
H y p ot hetical  
(I m p ute p ost ter mi nati o n data a) 
i d 
A E =a d verse e ve nt; C O VI D -1 9 = C or o na vir us Disease -2 0 1 9; Da T -S P E C T = D o pa mi ne Tra ns p orter I ma gi n g wit h 
Si n gle P h ot o n E missi o n C o m p uterize d T o m o gra p h y; I C E =i nterc urre nt e ve nt; i d =i de m, “t he sa me” acr oss r o ws; 
L E D D = Le v o d o pa E q ui vale nt Dail y D ose; W O Q -9 = Weari n g -Off  Q uesti o n naire  - 9; S B R =s pecific bi n di n g rati o; 
S A P =statistical a n al ysis pla n; S T =s y m pt o matic treat me nt  
N ote: T he ha n dli n g strate gies are defi ne d as f oll o ws: “ Treat me nt p olic y” –  i ncl u de p ost I C E data; “ H y p ot hetical” –  
re m o ve p ost I C E data a n d i m p ute missin g data.  
a A p pr oac h t o data i m p utati o n will be detaile d i n t he S A P.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 7  of 1 3 3  
9. 2. 2. 1  
I C E s p ot e nti all y aff e cti n g t h e i nt er pr et ati o n of m e a s ur e m e nt s 
T he mai n I C E affecti n g t he i nter pret ati o n of meas ure me nts will be i nitiati o n of S T as well as a n y 
c ha n ge i n t y pe or d os e t hr o u g h o ut P D 0 0 5 3 a n d P D 0 0 5 5.  
9. 2. 2. 1. 1  
S T i niti ati o n  
9. 2. 2. 1. 1. 1  
D a T -S P E C T  
I n t his st u d y, it will be ass u me d t hat Da T-S P E C T si g nal is n ot affecte d b y i nitiati o n or d ose of 
le v o d o pa (re vie we d i n I k e da et al, 2 0 1 9). I nitiati o n of le v o d o pa, d o pa mi ne a g o nists, a n d C O M T 
i n hi bit ors as well as c ha n ge i n d ose or t y pe will be c o nsi dere d N O T t o i m pact t he effect of 
i nterest f or D a T-S P E C T, a n d t he p ost I C E data will be i ncl u de d i n t he mai n esti ma n d a nal ysis 
‘re gar dless of S T i nitiati o n/t y pe/ d ose’ (“ Treat me nt p olic y” strate g y –  see details i n Ta ble  9 -1 ). 
M o n oa mi ne o xi dase -B i n hi bit ors will n ot be all o we d i n t his st u d y (see Secti o n  6. 5. 2  a n d 
Secti o n  6. 5. 3 ). A Was h o ut Peri o d of 5 0 h o urs ( or 5 half-li ves) m ust be c o m plete d pri or t o 
perf or mi n g t he D a T -S P E C T meas ure me nt. If was h o ut was n ot res pecte d, p ost I C E Da T -S P E C T 
data will be re m o ve d (“ H y p ot hetical” ha n dli n g strate g y) a n d missi n g data will be i m p ute d 
ass u mi n g missi n g at ra n d o m ness ( M A R) i n t he pri mar y a nal ysis.  
Missi n g data d ue t o sca n n ot ha vi n g ta ke n place at t he partici pa nt’s or I n vesti gat or’s discreti o n 
will be treate d as M A R.  
9. 2. 2. 1. 1. 2  
C u m ul ati v e L E D D  
I nitiati o n of, t y pe, d ose, a n d/ or c ha n g e i n S T will be c o nsi dere d t o be a n i nte gral part of t h e 
calc ulati o n of t he L E D D o utc o m e; t heref ore, a “ C o m p osite” ha n dli n g strate g y will be a p plie d.  
9. 2. 2. 1. 2  
Tr e at m e nt di s c o nti n u ati o n ( wit h o ut c o n s e nt 
wit h dr a w al)/ n o n a d h er e n c e  
Partici pa nt -le d or I n v esti gat or-le d (s ee det ails o n st o p pi n g criteria i n Secti o n  7 ) treat me nt 
disc o nti n uati o n ma y be relate d t o assi g ne d i n vesti gati o nal treat me nt (t o lac k of efficac y/ A Es) or 
u nrelate d (i n cl u di n g C O VI D -1 9 pa n d e mic).  
Treat me nt disc o nti n uati o n will n ot be c o nsi dere d t o i m pact t he effect of i nt erest, a n d t he p ost 
I C E dat a will be i ncl u de d i n t he a nal yses (“ Treat me nt p olic y” ha n dli n g strat e g y - see S A P f or 
details).  
Mi n or treat me nt n o na d here nce ( missi n g a d ose or ta ki n g a d ose at a differe nt ti me of t he da y) or 
mi n or dr u g a d mi nistrati o n err or will n ot be c o nsi dere d t o i m pact t he effect of i nterest, a n d t he 
p ost I C E data will be i ncl u de d i n t he a nal yses (“ Treat me nt p ol ic y” ha n dli n g strate g y –  see S A P 
f or details). 
Maj or treat me nt n o na d h ere nce or dr u g a d mi nistrati o n err or will be c o nsi d ere d u ni nf or mati ve 
wit h res pect t o t he effect of i nterest, a n d t he p ost I C E data will be re m o ve d i n t he a nal yses a n d 
t he p ost I C E missi n g data will be i m p ute d (“ H y p ot hetical” ha n dli n g strate g y –  see S A P f or 
details).  
9. 2. 2. 2  
I C E s p ot e nti all y aff e cti n g t h e e xi st e n c e of m e a s ur e m e nt s 
I n a d diti o n, bias ma y be i ntr o d uce d t hr o u g h dr o p o ut, l oss t o f oll o w u p, a n d disse nt t o e nter t he 
e xte nsi o n st u d y P D 0 0 5 5 f oll o wi n g t he pr o of -of -c o nce pt st u d y P D 0 0 5 3.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 8  of 1 3 3  
9. 2. 2. 2. 1  
St u d y t er mi n ati o n a n d l o s s t o f oll o w u p  
A partici pa nt ma y wit h dra w fr o m t he st u d y at a n y ti me at his/ her o w n re q uest or ma y be 
wit h dra w n at a n y ti me at t he discreti o n of t he I n v esti gat or f or safet y, be ha vi oral , c o m plia nce, or 
a d mi nistrati ve reas o ns (s ee Secti o n  7. 2 ). 
W here t h e ca us e f or st u d y ter mi nati o n is k n o w n t o be u nrelate d t o assi g ne d i n vesti gati o nal 
treat me nt or u n k n o w n (i n cl u di n g l oss t o f oll o w u p), st u d y ter mi nati o n will be c o nsi dere d 
u ni nf or mati ve wit h res pect t o t he effect of i nterest, a n d t he p ost I C E data will be i m p ute d 
ass u mi n g M A R as t he defa ult a p pr oac h (“ H y p ot hetical” ha n dli n g strate g y –  see S A P f or details ). 
9. 2. 2. 2. 2  
D e at h or s eri o u s i nj ur y  
L ocal i nj uries, e g, t o he a d f or Da T -S P E C T, t o ar ms/ ha n ds/le gs/feet f or cli nical o utc o mes, a n d/ or 
s yste mic ac ute c o n diti o ns s uc h as a str o ke or a n acci de nt-relate d c o m a, ma y pre ve nt t he ta ki n g of 
meas ure me nts. St u d y -rel ate d deat h or d eat h d ue t o ot her ca us es (i ncl u di n g C O VI D-1 9) ma y 
occ ur d uri n g t he st u d y. D eat h d ue t o P D is u nli kel y, as partici pa nts ha v e bee n selecte d i n t he 
earl y sta ge of t he diseas e, alt h o u g h a n acci de nt ma y be t he c o ns e q ue nce of P D s y m pt o ms.  
B ot h P D -relate d a n d n o n-P D -relate d s eri o us i nj ur y or deat h will be c o nsi d ere d u ni nf or m ati ve 
wit h res pect t o t he effect of i nterest, t he I C E i g n ore d, a n d t he p ost I C E data i m p ute d i n t he 
a nal yses (“ H y p ot hetical” ha n dli n g strate g y –  see S A P f or details).  
9. 2. 2. 3  
Pr ot o c ol d e vi ati o n s  
Pr ot oc ol de viati o ns w hic h are n ot alrea d y pre defi ne d as I C Es (e g, n o n a d here nce) c o ul d als o 
affect t he c o n d u ct of t he st u d y a n d/ or i m pact st u d y partici pa nt safet y as well as ke y efficac y 
e n d p oi nt meas ure me nts.  
T he criteri a f or i de ntif yi n g i m p o rta nt pr ot oc ol de viati o ns will be defi ne d wit hi n t he rele va nt 
pr ot oc ol de viati o n s pecifi cati o n d oc u me nt, w hic h is part of t he data clea ni n g pla n. All pr ot oc ol 
de viati o ns will be re vie we d as part of t h e o n g oi n g data clea ni n g pr ocess a n d all i m p orta nt 
de viat i o ns will be i de ntifie d a n d d oc u me nte d b ef ore u n bli n di n g t o c o nfir m e xcl usi o n fr o m 
a nal ysis sets. I m p orta nt pr ot oc ol de viati o ns will be liste d a n d s u m marize d.  
I m p ort a nt pr ot oc ol de viati o ns ( n ot pre defi ne d as I C Es) will be c o nsi dere d u ni nf or mati ve wit h 
res pect t o t he effect of i nterest a n d t he p ost I C E d ata i m p ute d ass u mi n g M A R as t he defa ult 
a p pr oac h (“ H y p ot h etical ” ha n dli n g strate g y –  see S A P f or details). 
Mi n or pr ot oc ol de viati o ns ( n ot pre defi n e d as I C Es) will be c o nsi dere d n ot t o i m pact t he effect of 
i nterest a n d t he p ost I C E data i ncl u de d i n t he a n al yses (“ Treat me nt p olic y” ha n dli n g strate g y –
see S A P f or details). 
9. 2. 2. 4  
C o nfir m e d or s u s p e ct e d C O VI D -1 9 a n d C O VI D -1 9 v a c ci n ati o n  
C o nfir me d or s us pecte d cases of C O VI D -1 9 will n ot be c o nsi dere d t o i m p act t he effect of 
i nterest, a n d t he p ost I C E data will be i ncl u de d i n t he a nal yses (“ Treat me nt p olic y” ha n dli n g 
strate g y). T his is ass u mi n g t hat t he partici pa nt re m ai ns i n t he st u d y. 
Ot her I C Es or pr ot o c ol de viati o ns relate d t o C O VI D -1 9 (treat me nt or st u d y disc o nti n uati o n) 
s h o ul d be ha n dle d usi n g t he a p pr oac hes o utli ne d i n t he secti o ns a b o ve.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 7 9  of 1 3 3  
St u d y partici pa nts are per mitte d t o recei ve t he C O VI D -1 9 vacci ne at a n y p oi nt i n t he st u d y. A 
“ Treat me nt p olic y” ha n dli n g strate g y will be use d f or t his I C E w h ere p ost vacci nati o n dat a are 
ke pt as part of t he a nal ys es.  
9. 3  
Pl a n n e d effi c a c y/ o ut c o m e a n al y s e s  
9. 3. 1  
Pri m ar y effi c a c y o bj e cti v e ( a n d e x pl or at or y effi c a c y o bj e cti v e III): 
pri m ar y effi c a c y e sti m a n d  
9. 3. 1. 1  
D a T -S P E C T  
T he mai n a nal ysis will be base d o n t he S B R of w h ole striat u m calc ulate d as t he a vera ge of t he 
S B R data val ues f or t he 4 f oll o wi n g “s mall” re gi o ns: “left ca u d ate s mall,” “left p uta me n s mall,” 
“ri g ht ca u dat e s mall,” a n d “ri g ht p uta me n s mall.”  
F or eac h re gi o n, t he S B R will be calc ulate d wit h t he occi pital c ort e x as t he refere nce re gi o n,  
w here a l o wer S B R i n dicates w orse dise ase. T h e f oll o wi n g f or m ula will be use d t o calc ulate t his:  
( A v er a g e ( S m all r e gi o n) –  A v er a g e ( Occi pit al r e gi o n)) / ( A v er a g e ( Occi pit al r e gi o n))  
T he partici pa nt -l e vel e n d p oi nt will be Da T-S P E C T w h ole striat u m S B R at 3 6 a n d 7 8  m o nt hs 
p ost P D 0 0 5 3 Scree ni n g, re gar dl ess of S T i nitiati o n of, t y pe, d ose, a n d/ or c ha n ge i n S T. F or 
Da T -S P E C T, Baseli ne is t he val ue rec or de d at P D 0 0 5 3 Scree ni n g.  
Descri pti ve statistics a n d vis ualizati o n  
Descri pti ve statistics f or o bser ve d res ults a n d c ha n ges fr o m Baseli ne i n Da T-S P E C T w h ole 
striat u m S B R at P D 0 0 5 3 Scree ni n g/ Baseli ne a n d at all a vaila ble ti me p oi nts p ost P D 0 0 5 3 
Baseli ne will be prese nt e d. S u m mar y ta bles will be pr o d uce d b y treat me nt gr o u p a n d visit at 
P D 0 0 5 3 Scree ni n g/ Baseli ne a n d at all a vaila bl e ti me p oi nts p ost P D 0 0 5 3 Baseli ne), o verall a n d 
b y ge n der a n d a ge at P D 0 0 5 3 Baseli ne (a ge cate g ories t o be defi ne d i n S A P).  
Pl ots of i n di vi d ual traject ories o ver ti me will als o be pr o d uce d. T o ma ke t h ese pl ots i nter preta bl e 
gi ve n t he lar ge s a m ple size, pl ots will be pr o d uce d b y treat me nt gr o u p ( E arl y -start 3 6 0 m g, 
Earl y -start 1 8 0 m g, a n d D ela ye d-start 3 6 0 m g), ge n der, a n d a g e cate g or y at P D 0 0 5 3 Baseli ne. 
Traject ori es will be c ol or c o de d t o clearl y i n dicate w he n a partici pa nt i nitiates S T.  
I n a d diti o n t o t hese i n di vi d ual pl ots, l o n git u di nal pl ots of mea n o bser ve d Da T -S P E C T w h ole 
striat u m S B R will be pr o d uce d b y treat me nt gr o u p, o verall as w ell as b y ge n der a n d/ or a ge 
cate g or y at P D 0 0 5 3 Baseli ne . T hese pl ots will i ncl u de err or bars ( ± S D) a n d all treat me nt gr o u ps 
will be o verlai d o n t he sa me pl ot.  
Mai n a nal ytical a p pr oac h  
A li near mi xe d effects m o del ( L M E M) f or a nal ysis of c o varia n ce ( A N C O V A) f or re peate d 
meas ures will be use d t o a nal yze t h e l o n git u di nal o bser ve d dat a. Treat me nt, ti me ( visit, 
cate g orical) a n d tr eat me nt b y ti me (i nteracti o n ter m bet wee n treat me nt a n d visit) will be i ncl u de d 
as fi xe d effects, a n d Baseli ne Da T -S P E C T Striat u m S B R will be i ncl u de d as a c o variate.  A 
varia nce -c o v aria n ce matri x str uct ure will be pres p ecifie d t o acc o u nt f o r re p eate d meas ures 
wit hi n a partici pa nt.  
Ha n dli n g of t he mai n I C E, ie, i nitiati o n/i nta ke of S T, will be “ Treat me nt p olic y” (i ncl u de 
p ost  I C E data). Ha n dli n g of ot her I C Es a n d pr ot oc ol de viati o ns is s u m marize d i n Ta ble  9 -1 . 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 0  of 1 3 3  
M o nt h 1 8 a n alysis  
At t he P D 0 0 5 5 M o nt h 1 8 a nal ysis data c ut, t he m o del will be a p plie d t o P D 0 0 5 3 Scree ni n g a n d 
1 2 -, 1 8-, a n d 3 6-m o nt h p ost -P D 0 0 5 3 Baseli ne data.  
M o nt h 6 0 a n alysis  
At t he P D 0 0 5 5 M o nt h 6 0 a nal ysis data c ut, t he m o del will be a p plie d t o P D 0 0 5 3 Scree ni n g a n d 
1 2 -, 1 8-, 3 6-, a n d 7 8-m o nt h p ost -P D 0 0 5 3 Baseli ne data.  
T he p o p ulati o n -le vel s u m mar y of i nterest will be t he Baseli ne-a dj uste d differe n ce i n tar get 
p o p ulati o n mea n i n Da T -S P E C T Striat u m S B R at 3 6 m o nt hs ( P D 0 0 5 5 M o nt h 1 8 a nal ysis) a n d at 
7 8 m o nt hs ( P D 0 0 5 5 M o nt h 6 0 a nal ysis) re gar dless of S T i nitiati o n bet wee n:  
•  Earl y -start mi nzas ol mi n ( U C B 0 5 9 9) ( 3 6 0 m g/ da y) ar m a n d 1 8-m o nt h Del a y e d -start 
mi nzas ol mi n ( U C B 0 5 9 9) ( 3 6 0 m g/ da y) ar m; a n d  
•  Earl y -start mi nzas ol mi n ( U C B 0 5 9 9) ( 3 6 0 m g/ da y) ar m a n d Earl y-start mi nzas ol mi n 
( U C B 0 5 9 9) ( 1 8 0 m g/ da y) ar m. 
A s u m mar y ta ble pres e nti n g t he esti mates of t he tr eat me nt effects at all a vaila ble ti me p oi nts a n d 
c orres p o n di n g 9 5 % CIs fr o m t his m o del will be prese nte d.  
A pl ot dis pla yi n g t he a dj uste d mea n a n d 9 5 % CI f or eac h treat me nt gr o u p fr o m t his m o del 
( L M E M o ver all a v aila bl e ti me p oi nts ) will be pr o d uce d. 
T he descri pti ve statistics a n d a nal yses will be re peate d f or t he stri atal s u b -re gi o ns. 
Se n siti vit y a nal yses 
F or b ot h t he P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 6 0 a nal yses, t he mai n a nal ysis will be re peat e d after 
e xcl usi o n of At y pical Par ki ns o nia n Dis or ders parti ci pa nts (see Secti o n  9. 3. 5 ). 
S u p p orti n g a nal yses (f or P D 0 0 5 5 M o nt h 1 8 a nal ysis o nl y)  
•  O bser ve d a bs ol ute c ha n g e fr o m Baseli ne ( m ea n a n d S D) o ver 1 8  m o nt hs i n Da T -S P E C T 
w h ole striat u m S B R f or eac h of t he f oll o wi n g gr o u ps (see Fi g ure  9 -1 ): 
− 1 8 -m o nt h mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y i nitiate d m ore t ha n  2 years p ost dia g n osis 
( p ur ple li ne) 
− 1 8 -m o nt h mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y i nitiate d wit hi n  2 years of dia g n osis 
( na v y li ne) 
− 1 8 -m o nt h place b o ar m ( p artici pa nts wit hi n 2 years of dia g n osis at Baseli ne) (li g ht bl ue 
li ne) 
I n a d diti o n, partici pa nt c haract eristics s uc h as g e n der, a ge at Baseli ne, a n d disease d urati o n at 
Baseli ne will be s u m marize d f or eac h of t he 3 gr o u ps.  
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y A nal ysis Pla n. 
A n y e x pl orat or y i n vesti g ati o ns base d o n a d va n ce d i ma ge a nal ysis met h o ds will be detaile d i n a 
se parat e P D 0 0 5 5 A nal ysis Pla n. 
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 1  of 1 3 3  
Fi g ur e  9 -1 : D el a y e d -st art d e si g n (fir st 1 8 m o nt h s)  
 
B L = P D 0 0 5 5 Baseli ne Visit; D = d a y; E O T = E n d of Treat me nt; M = m o nt h; V = visit  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 2  of 1 3 3  
9. 3. 2  
S e c o n d ar y effi c a c y o bj e cti v e a n d e x pl or at or y effi c a c y o bj e cti v e s I 
(III): S e c o n d ar y e sti m a n d 
9. 3. 2. 1  
L E D D  
T he partici pa nt -l e vel e n d p oi nt will be c u m ulati ve L E D D u p t o 7 8 m o nt hs p ost P D 0 0 5 3 Baseli ne. 
N o Baseli ne data will be a vaila ble as p artici pa nts were  “ S T-naï ve” at P D 0 0 5 3 Baseli ne.  
Descri pti ve statistics a n d vis ualizati o n  
A listi n g of c u m ulati ve L E D D will be pr o d uce d b y visit a n d treat me nt gr o u p base d o n t he S S, 
o nl y partici pa nts wit h n o nzer o dat a will be pres e nte d i n t his listi n g. C o nti n u o us s u m mar y 
statistics will be prese nte d b y visit, treat me nt gr o u p, o verall a n d b y ge n d er. S u m mar y statistics 
will be calc ulate d at M o nt hs 1 2, 1 8, 2 4, 3 6, a n d 7 8 p ost P D 0 0 5 3 Baseli ne. F or partici pa nts w h o 
ha ve n ot starte d S T b y a partic ular visit, t heir c u m ulati ve L E D D will be 0 m g a n d t his will be 
i ncl u de d i n t he calc ulati o n of s u m mar y statistics. As part of t he s u m mar y statistics, t he n u m ber 
of partici pa nts w h o ha v e i nitiate d S T b y eac h visit will be i ncl u de d. I n a d diti o n t o t he s u m mar y 
ta bles, pl ots of i n di vi d ual traject ories of L E D D will be pr o d uce d b y tr eat me nt gr o u p, ge n der, a n d 
a ge cate g or y at Bas e li ne. 
Mai n a nal ytical a p pr oac h  
A n A N C O V A will be us e d t o a nal yz e t he 3 6 -m o nt h o bser ve d data  at t he P D 0 0 5 5 M o nt h 1 8 
a nal ysis data c ut a n d a se parate A N C O V A will be use d t o a nal yze t h e 7 8 -m o nt h o bser ve d data at 
t he P D 0 0 5 5 M o nt h 6 0 a nal ysis data c ut. Treat me nt will be i ncl u de d i n t he m o del as a cat e g orical 
fi xe d effect. 
T he p o p ulati o n -le vel s u m mar y of i nterest will be t he differe nces i n tar get p o p ulati o n mea n 
c u m ulati ve L E D D at 3 6 or at 7 8 m o nt hs, de pe n di n g o n t he a nal ysis data c ut f or t he treat me nt 
c o m paris o ns (see  Secti o n  9. 2. 2 ). S y m pt o matic treat me nt d ose is a n i nte gral part of o utc o me. 
Ha n dli n g of I C Es a n d pr ot oc ol de viati o ns are s u m marize d i n Ta ble  9 -1 . 
A s u m mar y ta ble pres e nti n g t he m o del esti mates of t hese differe n ces a n d c orres p o n di n g 9 5 % CIs 
will be prese nte d. A pl ot dis pla yi n g t he a dj uste d mea n a n d 9 5 % CI f or eac h treat me nt gr o u p will 
be pr o d uce d.  
Se nsiti vit y a nal yses  
F or b ot h t he P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 6 0 a nal yses, t he mai n a nal ysis will be re peat e d after 
e xcl usi o n of At y pical Par ki ns o nia n Dis or der partici pa nts (see Secti o n  9. 3. 5 ). 
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y A nal ysis Pla n. 
9. 3. 3  
S e c o n d ar y effi c a c y o bj e cti v e a n d e x pl or at or y effi c a c y o bj e cti v e I (III): 
E x pl or at or y e sti m a n d s/ e n d p oi nt s  
9. 3. 3. 1  
W O Q -9  
F or W O Q -9, n o Baseli ne data will be a vaila ble as partici pa nts were “ S T -n aï ve” at P D 0 0 5 3 
Baseli ne.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 3  of 1 3 3  
Descri pti ve statistics a n d vis ualizati o n  
Descri pti ve statistics f or o bser ve d res ults at all a v aila ble ti me p oi nts will be prese nte d. S u m mar y 
ta bles will be pr o d uce d b y treatme nt gr o u p a n d visit, o verall a n d b y ge n der a n d a ge at P D 0 0 5 3 
Baseli ne (a ge cate g ories t o be defi ne d i n S A P).  
Details of t he pl ots will be gi ve n i n t he S A P.  
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y A nal ysis Pla n.  
9. 3. 3. 2  
M o C A  
Descri pti ve statistics a n d vis ualizati o n  
Descri pti ve statistics f or o bser ve d sc ores at all a vaila ble ti me p oi nts p ost P D 0 0 5 3 Baseli ne will 
be prese nt e d. S u m mar y ta bles will be pr o d uce d b y treat me nt gr o u p a n d visit, o verall a n d b y 
ge n de r a n d a ge at P D 0 0 5 3 Baseli ne. 
Pl ots of i n di vi d ual traject ories o ver ti me will als o be pr o d uce d. T o ma ke t h ese pl ots i nter preta bl e 
wit h o ur lar ge sa m ple siz e, pl ots will be pr o d uce d b y treat me nt gr o u p, ge n d er, a n d a g e at 
Baseli ne. Traje ct ories will be c ol or  c o de d t o cl earl y i n dicate w he n a partici pa nt i nitiates S T.  
I n a d diti o n t o t hese i n di vi d ual pl ots, l o n git u di nal pl ots of mea n o bser ve d M o C A will be 
pr o d uce d b y tr eat me nt gr o u p, o verall as w ell as b y ge n der a n d a ge at Baseli ne. T hese pl ots will 
i ncl u de err or bars ( ± S D) a n d all treat me nt gr o u ps will be o verlai d o n t he sa me pl ot. 
Se nsiti vit y a nal yses  
N o ne pla n ne d.  
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y  A nal ysis Pla n.  
9. 3. 3. 3  
F A TI G U E -P R O  
T he partici pa nt -l e vel e n d p oi nt will be t he fati g ue s u bscales sc ore at all a vaila ble ti me p oi nts p ost 
P D 0 0 5 3 Baseli ne. P D 0 0 5 3 Baseli ne data will be a vaila ble.  
Descri pti ve statistics a n d vis ualizati o n  
T his P R O will be s u m marize d usi n g c o nti n u o us s u m mar y statistics b y visit, treat me nt gr o u p, 
o verall a n d b y ge n d er. T he s u m mar y will be pres e nte d o verall a n d f or partici pa nts w h o are n ot 
yet o n S T. T his s u m mar y will be re peat e d f or t he tra nsf or me d s c ore, s e paratel y f or eac h scal e, 
w here tr a nsf or me d sc ore is calc ulate d as:  
𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒
𝑟𝑎𝑤 𝑠𝑐𝑜𝑟𝑒 𝑟𝑎𝑛𝑔𝑒×
𝑡𝑜𝑡𝑎𝑙 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑖𝑡𝑒𝑚𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑐𝑎𝑙𝑒
𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑛𝑜𝑛−𝑚𝑖𝑠𝑠𝑖𝑛𝑔 𝑖𝑡𝑒𝑚𝑠 𝑖𝑛 𝑡ℎ𝑒 𝑠𝑐𝑎𝑙𝑒× 1 0 0  
Pl ots of i n di vi d ual traject ories o ver ti me will als o be pr o d uce d b ase d o n t he ra w sc ore of eac h of 
t he 3 fati g ue scales. T o ma ke t hese pl ots i nter preta ble wit h o ur lar ge s a m ple size, pl ots will be 
pr o d uce d b y tr eat me nt gr o u p, ge n der, a n d a ge cate g or y (t he cate g ories will be defi ne d i n t he 
S A P). Traject ories will be c ol o r c o d e d t o clearl y i n dicate w he n a partici p a nt is a n d is n ot o n S T. 
I n a d diti o n t o t hese i n di vi d ual pl ots, pl ots of o bser ve d mea n a n d m ea n c h a n ge fr o m Baseli ne will 
be pr o d uce d f or eac h fati g ue scale, o n b ot h t he ra w a n d tra nsf or me d scale, b y treat me nt gr o u p 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 4  of 1 3 3  
a n d S T i nitiati o n ti mi n g cate g or y, o v erall, a n d b y ge n der. T h ese pl ots will i ncl u de err or bars 
( ± S D) a n d all treat me nt gr o u ps will be o verlai d o n t he sa me pl ot. 
E x pl orat or y a nal ys es  
T he F A TI G U E -P R O is li kel y t o re q uire a da ptati o n t o better re prese nt t he  P D p o p ulati o n 
fati g ue-relate d s y m pt o ms.  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y  A nal ysis Pla n.  
9. 3. 3. 4  
N o n m ot or s y m pt o m s  
9. 3. 3. 4. 1  
M D S -N M S  
T he partici pa nt -l e vel e n d p oi nt will be M D S-N M S at all a vaila ble ti me p oi nts p ost  P D 0 0 5 3 
Baseli ne. P D 0 0 5 3 Baseli ne data will be a v aila ble.  
Descri pti ve statistics a n d vis ualizati o n  
C o nti n u o us s u m mar y statistics will be prese nte d f or t he M D S -N M S t otal sc ores (t otal fre q ue nc y 
a n d t otal se verit y sc ores) b y treat me nt gr o u p, ge n d er, a n d visit. T he data li sti n g f or M D S-N M S 
will be gr o u pe d b y d o mai n, wit h fre q ue nc y a n d se verit y res ults a p peari n g si de b y si de.  
A pl ot of i n di vi d ual traject ories o ver ti me will be pr o d uce d f or t he t otal sc ore, usi n g t he sa me b y 
varia bles a n d c ol or -c o di n g descri be d f or t he P R O tr aject or y pl ots.  
Res ults f or t he n o n m ot or fl uct uati o ns s u bscale secti o n will be liste d o nl y.  
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y  A nal ysis Pla n.  
9. 3. 3. 4. 2  
M D S -U P D R S P art I s u b s c al e or s el e ct e d it e m s  
T he partici pa nt -l e vel e n d p oi nt will be M D S -U P D R S Part I  s u bsc ore/ite m sc ore at all a vaila ble 
ti me p oi nts p ost P D 0 0 5 3 Baseli ne. P D 0 0 5 3 Baseli ne sc ore will be a vaila ble. 
Descri pti ve statistics  
Descri pti ve statistics a n d vis ualizati o ns will be pr o d uce d f or t h e M D S -U P D R S Part I s u bsc ore 
(as descri be d f or M D S-U P D R S Part I -III s u m sc ore, Secti o n  9. 3. 3. 5. 3 ). A h eat ma p of t he 
ite m-le vel res p o nses will be pr o d uce d, f urt her det ails o n t his heat ma p a n d t he descri pti ve 
statistics will be prese nte d i n t he S A P. 
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y  A nal ysis Pla n.  
9. 3. 3. 5  
M ot or s y m pt o m s, a cti viti e s of d ail y li vi n g, a n d Q O L  
Descri pti ve statistics a n d vis ualizati o ns will be pr o d uce d f or t h e f oll o wi n g e n d p oi nts:  
9. 3. 3. 5. 1  
M D S -U P D R S P art II s u b s c al e or s el e ct e d it e m s  
T he partici pa nt -l e vel e n d p oi nt will be M D S -U P D R S Part II  s u bsc ore/ite m sc ore at all a vaila ble 
ti me p oi nts p ost P D 0 0 5 3 Baseli ne. P D 0 0 5 3 Baseli ne sc ore will be a vaila ble. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 5  of 1 3 3  
Descri pti ve statistics  
Descri pti ve statistics a n d vis ualizati o ns will be pr o d uce d f or t h e M D S -U P D R S Part II s u bsc ore 
(as descri be d f or M D S-U P D R S Part I -III s u m sc ore, Secti o n  9. 3. 3. 5. 3 ). A h eat ma p of t he 
ite m-le vel res p o nses will be pr o d uce d, f urt her det ails o n t his heat ma p a n d the descri pti ve 
statistics will be prese nte d i n t he S A P. 
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y A nal ysis Pla n.  
9. 3. 3. 5. 2  
M D S -U P D R S P art III s u b s c al e or s el e ct e d it e m s  
T he partici pa nt -l e vel e n d p oi nt will be M D S -U P D R S Part III s u bs c ore/ite m sc ore at all a vaila ble 
ti me p oi nts p ost P D 0 0 5 3 Baseli ne. P D 0 0 5 3 Baseli ne sc ore will be a vaila ble. 
Descri pti ve statistics  
Descri pti ve statis tics a n d vis ualizati o ns will be pr o d uce d f or t h e M D S-U P D R S Part III s u bsc ore 
(as descri be d f or M D S-U P D R S Part I -III s u m sc ore, Secti o n  9. 3. 3. 5. 3 ). A h eat ma p of t he 
ite m-le vel res p o nses will be pr o d uce d, f urt her det ails o n t his heat ma p a n d t he descri pti ve 
statistics will be prese nte d i n t he S A P. 
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y A nal y sis Pla n. 
9. 3. 3. 5. 3  
M D S -U P D R S P art s I -III s u m s c or e 
T he partici pa nt -l e vel e n d p oi nt will be M D S -U P D R S Parts I -III s u m sc ore at all a vaila ble 
ti me p oi nts p ost P D 0 0 5 3 Baseli ne. P D 0 0 5 3 Baseli ne sc ore will be a vaila ble. 
Descri pti ve statistics a n d vis ualizati o n  
S u m mar y ta b les prese nti n g t he o bser ve d mea n a n d mea n c ha n g e fr o m Bas eli ne i n M D S-U P D R S 
Parts I -III s u m sc ore b y treat me nt gr o u p a n d visit, o verall a n d b y ge n d er will be pr o d uce d. T his 
s u m mar y will be pr o d uce d o verall a n d b y S T stat us, w here S T stat us is defi ne d as ha vi n g or n ot 
ha vi n g starte d S T b y eac h visit. F or all s u m mar y ta bles a n d listi n gs w here t his S T stat us fla g is 
use d a n d pres e nte d, t he ass u m pti o n is ma de t hat o nce a p artici pa nt starts S T, t he y re mai n o n S T 
f or all st u d y visits after t heir i nitiati o n date. 
Pl ots of i n di vi d ual M D S -U P D R S Parts I -III s u m s c ores o ver ti me b y treat m e nt gr o u p a n d ge n d er 
will be prese nte d, c ol or c o de d t o clearl y i n dicate w he n a partici pa nt is a n d is n ot o n S T . T hese 
pl ots will be gr o u pe d b y S T i nitiati o n ti mi n g, t he cate g ories h ere  will be partici pa nts w h o starte d 
S T:  
•  b y M o nt h 1 2 (i ncl usi ve)  
•  bet wee n M o nt hs 1 2 a n d 1 8 (i ncl usi ve)  
•  bet wee n M o nt hs 1 8 a n d 2 4 (i ncl usi ve)  
•  bet wee n M o nt hs 2 4 a n d 3 0 (i ncl usi ve)  
•  bet wee n M o nt hs 3 0 a n d 3 6 (i ncl usi ve)  
•  bet wee n M o nt hs 3 6 a n d 4 2 (i ncl usi ve)  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 6  of 1 3 3  
•  bet wee n M o nt hs 4 2 a n d 4 8 (i ncl usi ve)  
•  bet wee n M o nt hs 4 8 a n d 5 4 (i ncl usi ve)  
•  bet wee n M o nt hs 5 4 a n d 6 0 (i ncl usi ve)  
•  bet wee n M o nt hs 6 0 a n d 6 6 (i ncl usi ve)  
•  bet wee n M o nt hs 6 6 a n d 7 2 (i ncl usi ve)  
•  bet wee n M o nt hs 7 2 a n d 7 8 (i ncl usi ve)  
•  n ot starte d b y 7 8 m o nt hs (if a p plica ble)  
I n a d diti o n t o t hese i n di vi d ual pl ots, pl ots of o bser ve d mea n M D S -U P D R S Parts I -III s u m sc ore 
will be pr o d uce d b y tr eat me nt gr o u p a n d S T i nitiati o n ti mi n g cate g or y, o verall a n d b y ge n der. 
T hese pl ots will i ncl u de err or bars ( ± S D) a n d all treat me nt gr o u ps wil l be o verlai d o n t he sa me 
pl ot.  
All pla n ne d s u m mar y ta bles a n d pl ots of M D S -U P D R S Parts I -III s u m sc ore will als o be 
pr o d uce d f or t he s u m sc ores of eac h i n di vi d ual s u bscale ( Part I, II, a n d III).  
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y  A nal ysis Pla n.  
9. 3. 3. 5. 4  
M o difi e d H & Y  
T he partici pa nt -l e vel e n d p oi nt will be t he H & Y sc ore at 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, 4 8, 5 4, 6 0, 6 6, 7 2, 
a n d 7 8 m o nt hs p ost P D 0 0 5 3 Baseli ne. P D 0 0 5 3 Basel i ne sc ore will be a vaila ble. 
Descri pti ve statistics a n d vis ualizati o n  
M o difie d H & Y sta gi n g r es ults will be s u m marize d descri pti vel y usi n g fre q ue nc y c o u nts a n d 
perce nt a ges. Sc ores/rati n gs will be prese nte d o verall a n d f or partici pa nts w h o are n ot yet o n S T 
at a partic ular visit ( w here a p plica ble), b y treat me nt gr o u p, ge n der, a n d visit.  
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y A nal ysis Pla n.  
9. 3. 3. 5. 5  
E arl y P D F u n cti o n Sl o w n e s s a n d E arl y P D M o bilit y P R O s  
T he p artici pa nt-l e vel e n d p oi nt will be P R O fi nal sc ore at all a vaila ble ti me p oi nts p ost P D 0 0 5 3 
Baseli ne. P D 0 0 5 3 Baseli ne data will be a v aila ble.  
Descri pti ve statistics a n d vis ualizati o n  
Data f or t h ese P R Os will be liste d o nl y.  
E x pl orat or y a nal ys es  
E x pl orat or y e fficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y Effi cac y A nal ysis Pla n. 
9. 3. 3. 5. 6  
C S F A S Y N  
T otal A S Y N a n d A S Y N oli g o mers/see di n g ca pacit y will be meas ure d i n C S F sa m ples i n 
c o nse nti n g partici pa nts, as well as i n C S F sa m ples o btai ne d fr o m P D 0 0 5 5 partici pa nt s w h o 
i nitiall y di d n ot c o nse nt i n P D 0 0 5 3.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 7  of 1 3 3  
Descri pti ve statistics a n d vis ualizati o n  
T he C S F t otal A S Y N c o nti n u o us s u m mar y statistics will be prese nte d b y visit (all a vaila ble 
ti me p oi nts p ost P D 0 0 5 3 Scree ni n g/ Baseli ne), treat me nt gr o u p, o verall, a n d b y ge nder. A 
traject or y pl ot will als o be pr o d uce d. Pl ots of o bser ve d mea n will be pr o d uce d b y treat me nt 
gr o u p, o verall, a n d b y g e n der. T hese pl ots will i ncl u de err or bars ( ± S D) a n d all treat me nt gr o u ps 
will be o verlai d o n t he sa me pl ot.  
Se parate ta b ul ate d a n d g ra p hical s u m maries will b e pr o d uce d f or st u d y partici pa nts w h o 
c o nse nte d o nl y fr o m P D 0 0 5 5 Baseli ne.  
E x pl orat or y a nal ys es  
E x pl orat or y efficac y a nal yses will be detaile d i n a P D 0 0 5 5 E x pl orat or y A nal ysis Pla n.  
9. 3. 3. 6  
Di git al H e alt h T e c h n ol o g y  
T he a nal ysis of Di gital  H ealt h Tec h n ol o g y dat a will be descri be d i n a s e parate P D 0 0 5 5 Di gital 
A nal ysis Pla n ( K o ne ksa Healt h I nc.). T he dat a will be a nal yze d s e paratel y fr o m t he st u d y 
a nal ysis. A n y a nal ysis of data o btai ne d fr o m t he Di gital Healt h Tec h n ol o g y will be perf or me d 
after data base l o c k a n d u n bli n di n g of t he P D 0 0 5 3 st u d y.  
9. 3. 4  
E x pl or at or y O bj e cti v e II  
9. 3. 4. 1  
E Q -5 D -5 L  
T he partici pa nt -l e vel e n d p oi nt will be E Q -5 D -5 L sc ore at all a vaila ble ti me p oi nts p ost P D 0 0 5 3 
Baseli ne. P D 0 0 5 3 Baseli ne data will be a v aila ble. T hese data all o w meeti n g pa yer e x p ectati o ns 
of s h o wi n g ass ociati o ns bet wee n i m pr o ve m e nts i n ke y cli nical o utc o mes (e g, M D S -U P D R S) a n d 
i m pr o ve me nts i n Q o L. Si x-m o nt hl y c ollecti o ns of t hese data als o ali g n wit h t he c ost -utilit y 
m o del c ycle le n gt hs c o m m o nl y use d i n healt h ec o n o mic a n al yses i n P D. 
Descri pti ve statistics a n d vis ualizati o n  
T he E Q V A S sc ores will be s u m marize d usi n g c o nti n u o us descri pti ve statistics prese nte d b y visit 
a n d treat me nt gr o u p, o v erall a n d b y ge n der. F or b ot h sets of E ur o Q ualit y of life sc ores/rati n gs, 
data wi ll be s u m marize d o verall a n d f or partici p a nts w h o are n ot yet o n S T (if a p plica ble). 
I n a d diti o n t o t he s u m mar y ta ble, pl ots of i n di vi d ual traject ories f or t he E Q V A S sc ore will be 
pr o d uce d b y tr eat me nt gr o u p, ge n der, a n d a ge cate g or y.  
E x pl orat or y a nal ys es  
E x pl orat or y effecti ve n ess a nal yses will be detaile d i n a P D 0 0 5 5 Trial E m ulati o n A nal ysis Pla n.  
9. 3. 4. 2  
U s e of e xt er n al r e al -w orl d d at a  
A n e xter nal, real -w orl d c o m parat or ar m will be desi g ne d t o esti mate t he effecti ve ness of 
mi nzas ol mi n vers us t he S o C o n cli nical a n d Q o L o utc o mes (li mite d t o M D S -U P D R S Part I -I V, 
m o difie d H & Y, c u m ulati ve L E D D, E Q -5 D -5 L, M o C A) be y o n d t he 1 8 m o nt hs d urati o n of t he 
fee der st u d y P D 0 0 5 3. 
Statistical a nal yses f or t h ese data will be descri be d i n a P D 0 0 5 5 Trial E m ulati o n A nal ysis Pla n. 
A detaile d feasi bilit y assess me nt of p ote ntial accessi ble data s o urces t o meet t his e x pl orat or y 
o bjecti ve has bee n fi nalize d a n d is a vaila ble as a s e parat e re p ort.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 8  of 1 3 3  
9. 3. 5  
E x pl or at or y O bj e cti v e I V: At y pi c al P ar ki n s o ni s m  
9. 3. 5. 1  
D e s cri pti v e st ati sti c s a n d vi s u ali z ati o n  
P D 0 0 5 3 Scree ni n g/ Baseli ne data f or partici pa nts n ot re -c o nfir me d t o ha ve a dia g n osis of P D will 
be s u m marize d a n d pl otte d ( details t o be pr o vi de d i n t he P D 0 0 5 5 S A P).  
T o c haracteri ze partici pa nt res p o nse t o mi nzas ol mi n ( U C B 0 5 9 9), data f or partici pa nts n ot 
re-c o nfir me d t o ha v e a di a g n osis of P D will be c ol ore d differe ntiall y ( det ails t o be s pecifie d i n 
t he P D 0 0 5 5 S A P). 
9. 3. 5. 2  
P D 0 0 5 3/ P D 0 0 5 5 s e n siti vit y a n al y s e s  
Selecte d P D 0 0 5 3/ P D 0 0 5 5 a nal yses will be re p eat e d after e xcl usi o n of p artici pa nts wit h At y pical 
Par ki ns o nia n Dis or der di a g n oses (t o be s pecifie d i n a P D 0 0 5 3 E x pl orat or y A nal ysis Pla n or i n 
t he P D 0 0 5 5 pr ot oc ol/ S A P as se nsiti vit y a nal yses). 
9. 4  
Pl a n n e d s af et y a n d ot h er a n al y s e s  
9. 4. 1  
S af et y a n al y s e s  
Safet y will be assesse d b y a nal yzi n g i nci de n ce of a n y T E A E, S A E, a n d st u d y partici pa nt 
wit h dra wals, a n d c ha n ges i n differe nt para meters s uc h as vital si g ns, safet y la b orat or y dat a, 
1 2 -lea d E C G ass ess me nt, p h ysical e xa mi nati o n fi n di n gs, ne ur ol o gical e xa mi nati o n fi n di n gs, a n d 
s uici dalit y usi n g t he C-S S R S.  
F urt her details o n t he pla n ne d safet y a nal yses will be gi ve n i n t he S A P.  
9. 4. 2  
Ot h er a n al y s e s  
A nal ysis of t he q ualitati ve data ge n erat e d as part of t he i n -st u d y patie nt i nter vie ws descri be d i n 
Secti o n  8. 1. 3  (U S a n d U K o nl y ) will f oll o w t he g ui deli nes fr o m t he mi xe d-met h o ds a nal ysis 
pr ot oc ol f or t he refi ne me nt of t he Earl y P D F u n cti o n Sl o w ness a n d M o bilit y P R O i nstr u me nts.  
9. 5  
H a n dli n g of pr ot o c ol d e vi ati o n s  
Refer t o Secti o n  9. 2. 2  f or details of ha n dli n g of pr ot oc ol de viati o ns. 
9. 6  
H a n dli n g of dr o p o ut s or mi s si n g d at a  
Refer t o Secti o n  9. 2. 2  f or details of ha n dli n g of missi n g data. 
9. 7  
Pl a n n e d a n al y si s a n d d at a m o nit ori n g  
Di gital Healt h Tec h n ol o g y will be a nal yze d as des cri be d i n Secti o n  9. 3. 3 . 6. 
T he a nal yses t o be p erf or me d f or t he pri mar y a n d sec o n dar y effi cac y o bj ecti ves ( dela ye d -start 
desi g n), as well as f or t he e x pl orat or y effi cac y o bj ecti ve II ( d ose c o m p aris o n) use data fr o m t he 
first 1 8 m o nt hs of t he st u d y ( P D 0 0 5 5 M o nt h 1 8 a nal ysis); t heref ore, t hese a nal yses will be 
carri e d o ut o nce all partici pa nts ha ve c o m plete d t h eir M o nt h 1 8 Visit. T his will be a f or mal 
a nal ysis b ut will n ot be c o nsi dere d a n i nteri m a n al ysis as t he res ults will n ot i m pact st u d y 
c o n d uct. Care will be ta k e n t o e ns ure t hat all st u d y partici pa nts a n d I n v esti gat ors will re mai n 
bli n de d t o treat me nt/ d ose recei v e d i n P D 0 0 5 3 a n d P D 0 0 5 5, at least u ntil all partici pa nts ha ve 
c o m plete d t he M o nt h 1 8 assess me nts i n P D 0 0 5 5.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 8 9  of 1 3 3  
T he a nal yses f or t he pri m ar y a n d sec o n dar y effi cac y o bjecti ves ( dela ye d -st art desi g n), will be 
re peat e d usi n g data fr o m all 6 0 m o nt hs of t he st u d y ( P D 0 0 5 5 M o nt h 6 0 a nal ysis).  
Descri pti ve statistics a n d vis ualizati o ns will be pr o vi de d at b ot h a nal ysis data c uts f or all 
e n d p oi nts, i ncl u di n g e x pl orat or y e n d p oi nts. F urt her details will be pr o vi de d i n t he S A P .  
Details of a nal yses f or ot her e x pl or at or y o bjecti ves will be pr o vi de d i n t he s pecifie d a n al ysis 
pla ns.  
A d diti o nal a nal yses ma y be c o n d ucte d f or p u blicati o n p ur p oses a n d t o s u p p ort re g ulat or y 
i nteracti o ns. 
D M C a n d S M C : 
A n i n de pe n de nt D M C will c o n d uct safet y i nteri m re vie ws of all a vaila ble s afet y data. A vaila ble 
data fr o m P D 0 0 5 5 will be re vie we d at D M C meeti n gs f or P D 0 0 5 3 . 
T he D M C will re vie w t h e safet y d ata of P D 0 0 5 5 w he n t he last partici p a nt fr o m P D 0 0 5 3 
tra nsiti o ne d i nt o P D 0 0 5 5, a n d t he n e ver y 1 8 m o nt hs t hereaft er. T he D M C will pr o vi de a 
rec o m me n dati o n o n t he c o nti n uati o n of t he st u d y. T he acti vities of t he D M C will be descri be d i n 
a se parate c h arter.  
A vaila ble data fr o m P D 0 0 5 5 will be re vie we d at S M C mee ti n gs f or P D 0 0 5 3 . 
T he S M C will re vie w t he safet y data of P D 0 0 5 5 w he n t he last partici pa nt fr o m P D 0 0 5 3 
tra nsiti o ne d i nt o P D 0 0 5 5, a n d t he n e ver y 6 m o nt hs t hereaft er. Meeti n gs ma y be a dj uste d as 
re q uire d b ase d o n recr uit me nt rates. A d-h o c S M C meeti n gs ma y be sc he d ule d i n a d diti o n. 
Details will be descri be d i n a se parate c h arter.  
9. 8  
D et er mi n ati o n of s a m pl e si z e  
N o f or mal sa m ple siz e esti mati o n will be pr o vi de d as t he sa m ple size f or t his st u d y will be 
deter mi ne d acc or di n g t o t he n u m ber of partici pa nts c o m pleti n g t he Treat me nt Peri o d of P D 0 0 5 3, 
meeti n g t he eli gi bilit y re q uire me nts f or P D 0 0 5 5 a n d c o nse nti n g t o partici p ate i n P D 0 0 5 5.  
A t otal of 4 9 3 partici pa nts were d os e d i n P D 0 0 5 3. Of t he 4 3 1 partici p a nts w h o c o m plete d 
P D 0 0 5 3, 4 2 8 tra nsiti o ne d i nt o P D 0 0 5 5. Ass u mi n g t hat 1 5 % of P D 0 0 5 5 partici pa nts w h o were 
ra n d o mize d t o place b o i n P D 0 0 5 3 dr o p o ut wit hi n t he first fe w m o nt hs of r olli n g o ver i nt o 
P D 0 0 5 5 d ue t o A Es u p o n i nitiati n g mi nzas ol mi n ( U C B 0 5 9 9) 3 6 0 m g/ da y (ie, ar o u n d 
2 0  partici pa nts n ot c o m pleti n g t heir M o nt h 3 vis it), a n d t hat a n ot her 5 % of partici pa nts acr oss all 
treat me nt ar ms dr o p o ut or are l ost t o f oll o w u p i n a n y gi ve n year, ar o u n d 3 7 4 a n d 3 1 4 
partici pa nts w o ul d be e x pecte d t o reac h P D 0 0 5 5 M o nt h 1 8 a n d M o nt h 6 0, res pecti vel y.  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 9 0  of 1 3 3  
1 0  
S U P P O R TI N G D O C U M E N T A TI O N A N D O P E R A TI O N A L 
C O N SI D E R A TI O N S  
1 0. 1  
A p p e n di x 1: R e g ul at or y, et hi c al, a n d st u d y o v er si g ht 
c o n si d er ati o n s  
1 0. 1. 1  
R e g ul at or y a n d et hi c al c o n si d er ati o n s  
T he st u d y will be c o n d ucte d u n der t he a us pi ces of a c o m pete nt a ut h orit y ( C A) a n d or I R B/I E C, 
as defi ne d i n l ocal re g ulati o ns, I nter n ati o nal C o u ncil f or Har m o nisati o n (I C H)-G C P, a n d i n 
acc or da nce wit h t he et hical pri nci ples t hat ha ve t h eir ori gi n i n t he Decl arati o n of Helsi n ki.  
T he I n vesti gat or/ U C B will e ns ure t hat a C A a n d a n a p pr o priatel y c o nstit ute d I R B/I E C t hat 
c o m plies wit h t he re q uire me nts of t he c urre nt I C H -G C P versi o n or a p plica ble c o u ntr y -s pecific 
re g ulati o ns 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 a n d a p pr o val of t he cli nical 
st u d y. Pri or t o i nitiati o n of t he st u d y, t he I n vesti g at or/ U C B will f or war d c o pi es of t he pr ot oc ol, 
I C F, I B, I n vesti gat or’s c urric ul u m vitae (if a p plica ble), a d v ertise me nt (if a p plica ble), a n d all 
ot her partici pa nt -relate d d oc u me nts t o be use d f or t he st u d y t o t he C A/I R B/I E C f or t h eir re vi e w 
a n d a p pr o val.  
Bef ore i nitiati n g a st u d y, t h e I n v esti gat or will ha ve writte n a n d date d f ull a p pr o val fr o m t he 
res p o nsi ble C A/I R B/I E C f or t he pr ot oc ol. 
T he I n vesti gat or will als o pr o m ptl y re p ort t o t he I R B/I E C all c ha n ges i n t h e st u d y, all 
u na ntici pate d pr o ble ms i n v ol vi n g ris ks t o partici pa nts or ot h ers, a n d a n y pr ot oc ol de viati o ns, t o 
eli mi nate i m me diate hazar ds t o partici pa nts. T he S p o ns or will s u b mit rele va nt i nf or mati o n t o t he 
C A i n acc or da nce wit h re g ulat or y re q uire m e nts.  
T he S p o ns or will n ot ma ke a n y c h a n ges i n t he st u d y or st u d y c o n d uct wit h o ut  C A/I R B/I E C 
a p pr o val, e x ce pt w here n ecessar y t o eli mi nate a p p are nt i m me diate hazar ds t o t he partici pa nts. 
F or mi n or c h a n ges t o a pre vi o usl y a p pr o ve d pr ot oc ol d uri n g t he peri o d c o v ere d b y t he ori gi nal 
a p pr o val, it ma y be p ossi ble f or t he S p o ns or t o o btai n a n e x pe dite d re vie w b y t he C A/I R B/I E C 
as all o we d.  
As part of t he C A/I R B/I E C re q uire me nts f or c o nti n ui n g re vie w of a p pr o ve d st u dies, t he S p o ns or 
will be res p o nsi ble f or s u b mitti n g peri o dic pr o gress re p orts acc or di n g t o re g ulat or y re q uire m e nts, 
at i nter vals a p pr o priate t o t he de gree of partici pa nt ris k i n v ol ve d, b ut n o less t ha n o nce per year. 
T he S p o ns or s h o ul d pr o vi de a fi nal r e p ort t o t he C A/I R B/I E C f oll o wi n g st u d y c o m pleti o n.  
U C B ( or its re prese nt ati ve) will c o m m u nicate safet y i nf or mati o n t o t he C A a n d all  acti ve 
I n v esti gat ors i n acc or da n ce wit h a p plica ble re g ulat or y re q uire me nts. T h e a p pr o priate I R B/I E C 
will als o be i nf or me d b y t he I n v esti gat or or t he S p o ns or, as s pecifi e d b y t he a p plica ble re g ulat or y 
re q uire me nts i n eac h c o n cer ne d c o u ntr y. W h ere a p plica ble, I n vesti gat ors are t o pr o vi de t he 
S p o ns or ( or its re pres e ntati ve) wit h e vi de nce of s uc h I R B/I E C n otificati o n.  
1 0. 1. 2  
Fi n a n ci al di s cl o s ur e  
I ns ura nce c o vera g e will be ha n dle d acc or di n g t o l ocal re q uir e me nts. 
Fi na nce a n d i ns ura n ce are a d dress e d i n t he I n vesti gat or  a n d/ or C R O a gree me nts, as a p plica ble.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 9 1  of 1 3 3  
1 0. 1. 3  
I nf or m e d c o n s e nt pr o c e s s 
Partici pa nt’s i nf or me d c o nse nt m ust be o btai ne d a n d d oc u me nte d i n acc or da nce wit h l ocal 
re g ulati o ns, I C H-G C P re q uire me nts, a n d t he et hical pri nci ples t hat ha ve t h eir ori gi n i n t he 
pri nci ples o f t he Declarati o n of Helsi n ki. 
Pri or t o o btai ni n g i nf or me d c o nse nt, i nf or mati o n s h o ul d be gi ve n i n a la n g u a ge a n d at a le vel of 
c o m ple xit y u n dersta n da ble t o t he partici pa nt i n b ot h oral a n d writte n f or m b y t he I n vesti gat or ( or 
desi g nee). T h e partici p a nt wi ll be gi ve n as m uc h ti me as nee d e d t o deci de w het her or n ot t he y 
wis h t o ta ke part i n t he st u d y. Eac h partici pa nt will ha ve t he o p p ort u nit y t o disc uss t he st u d y a n d 
its alter nati ves wit h t he I n vesti gat or or see k a d diti o nal a d vice. T h e a m o u nt of ti me a p otential 
partici pa nt ta kes t o deci de w het her t o p artici pate or n ot will var y per partici pa nt. T he p ote ntial 
partici pa nts will be u n der n o press ure t o ma k e a decisi o n.  
Pri or t o partici pati o n i n t he st u d y, t he I C F s h o ul d be si g ne d a n d pers o nall y date d b y t he 
p artici pa nt a n d b y t he p ers o n w h o c o n d ucte d t he i nf or me d c o nse nt disc ussi o n (I n vesti gat or or 
desi g nee). T h e partici p a nt m ust recei ve a c o p y of t he si g ne d a n d date d I C F. As part of t he 
c o nse nt pr ocess, eac h partici pa nt m ust c o nse nt t o direct access t o his/ he r m e dical rec or ds f or 
st u d y-relate d m o nit ori n g, a u diti n g, I R B/I E C re vie w, a n d re g ulat or y i ns pecti o n. Re m ote c o nse nt 
(e C o nse nt) is per mitte d d uri n g t his st u d y, b ut n ot re q uire d. F or t h ose partici pa nts w h o are 
assesse d as pr eli mi naril y eli gi ble per t he I R B/I E C -a p pr o ve d pre Scree ni n g s cri pt, c o ntact 
i nf or mati o n will be c ollecte d, i ncl u di n g a vali d e mail a d dress of t he partici pa nt. 
If t he I C F is a me n de d d uri n g t he st u d y, t he I n v esti gat or ( or t he s p o ns or, if a p plica ble) m ust 
f oll o w all a p plica ble re g ulat or y re q uire m e nts pert ai ni n g t o t he a p pr o val of t he a me n de d I C F b y 
t he I R B/I E C a n d use of t he a me n de d f or m. 
All st u dies c o n d ucte d at c e nters i n t he U S m ust i ncl u de t he use of a Healt h I ns ura nce P orta bilit y 
a n d Acc o u nt a bilit y Act a ut h orizati o n f or m.  
T he partici pa nt ma y wit h dra w his/ her c o nse nt t o partici pate i n t he st u d y at a n y ti me. A 
partici pa nt is c o nsi dere d as e nr olle d i n t he st u d y w h e n he/s he h as si g ne d t he I C F. T h e e C R F 
m ust n ot be starte d, n or ma y a n y st u d y s pecific pr oce d ure be p erf or m e d f or a gi ve n partici pa nt, 
wit h o ut ha vi n g o btai ne d his/ her writte n c o nse nt t o partici pate i n t he st u d y.  
1 0. 1. 4  
D at a pr ot e cti o n  
U C B staff ( or desi g ne e) will  affir m a n d u p h ol d t he partici pa nt’s c o nfi de nti alit y. Partici pa nts will 
be assi g ne d a u ni q ue i d e ntifier b y t he S p o ns or. A n y partici pa nt rec or ds or datasets t hat are 
tra nsferre d t o t he S p o ns or will c o ntai n t he i de ntifier o nl y; partici pa nt na mes or a n y i nf ormati o n 
w hic h w o ul d ma ke t he p artici pa nt i de ntifia ble will n ot be tra nsferre d.  
T he I n vesti gat or a grees t hat re prese ntati ves of U C B, its desi g nee, re pres e nt ati ves of t he rel e va nt 
I R B/I E C, or re pres e ntati ves of re g ulat or y a ut h orities will be all o we d t o re vie w t hat p orti o n of t he 
partici pa nt’s pri mar y m e dical rec or ds t hat directl y c o ncer ns t his st u d y (i ncl u di n g, b ut n ot li mite d 
t o, la b orat or y test res ult re p orts, E C G re p orts, a d missi o n/ disc har ge s u m maries f or h os pital 
a d missi o ns occ urri n g d uri n g a partici pa nt’s  st u d y partici pati o n, a n d a ut o ps y re p orts f or deat hs 
occ urri n g d uri n g t he st u d y).  
T he partici pa nt will be i nf or me d h o w his/ her pers o nal st u d y -relate d d ata will be use d b y t he 
S p o ns or a n d t hat it will be use d i n acc or da n ce wit h l ocal data pr otecti o n la w. T h e le vel of 
discl os ure will als o be e x plai ne d t o t he partici pa nt.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 9 2  of 1 3 3  
T he partici pa nt will be i nf or me d t hat his/ her me di cal 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 /I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
T he c o ntract bet wee n U C B a n d st u d y sites s pecifies res p o nsi bilities of t he parties a n d t he 
ti meli nes relate d t o data pr otecti o n, i ncl u di n g ha n dli n g of data sec urit y breac hes a n d res pecti ve 
c o m m u nicati o n a n d c o o p erati o n of t he parties i n or der t o miti gate t he p ossi ble deleteri o us 
c o nse q ue nces f or t h e partici pa nts.  
I nf or mati o n tec h n ol o g y s yste ms use d t o c ollect, pr ocess, a n d st ore st u d y-rel ate d data are s ec ure d 
b y tec h nical a n d or ga niz ati o nal sec uri t y meas ures desi g ne d t o pr otect s uc h data a gai nst 
acci de nt al or u nla wf ul l oss, alterati o n, or u na ut h orize d discl os ure or access.  
1 0. 1. 5  
C o m mitt e e s str u ct ur e s  
A n i n de pe n de nt D M C will c o n d uct safet y i nteri m re vie ws of all a vaila ble u n bli n de d safet y data 
a n d a n S M C will re g ularl y re vie w t he a vaila ble bli n de d safet y d ata as des cri be d i n Secti o n  9. 7 . 
1 0. 1. 6  
Di s s e mi n ati o n of cli ni c al st u d y d at a  
T his st u d y will be re gistere d a n d res ults p oste d o n p u blic re gistries as re q uir e d a n d i n li ne wit h 
U C B p olicies. A plai n la n g ua ge s u m mar y of res ults ma y als o be writte n. I n vesti gat ors ma y 
re q uest a ccess t o a n o n y mize d i n di vi d ual partici pa nt-le vel data a n d re dacte d st u d y d oc u me nts 
after pr o d u ct a p pr o v al i n t he U nite d States a n d E ur o pe. H o we v er, o nce t he st u d y c o m pletes, if 
t he ris k of re-i d e ntif yi n g st u d y partici pa nts is deter mi ne d t o be t o o hi g h, t he n i n di vi d ual 
partici pa nt -le vel d ata will n ot be ma de a vaila ble. 
F or res ults discl os ure o n p u blic re gistries (e g, Cli nical Trials. g o v), T E A Es a n d 
treat me nt-e mer ge nt S A Es will be p u blis he d.  
A s u m mar y of t he res ults is pla n ne d t o be p oste d t o t he E U data bas e wit hi n 1 year of st u d y 
c o m pleti o n, i n acc or da nce wit h i nter nati o nal sta n d ar ds a n d irres pecti ve of t he o utc o me of t he 
cli nical st u d y.  
1 0. 1. 7  
D at a q u alit y a s s ur a n c e  
All partici pa nt data relati n g t o t he st u d y will be rec or d e d o n pri nte d or e C R F u nless tra ns mitte d 
t o t he S p o ns or or desi g ne e electr o ni call y (e g, la b orat or y data). T h e I n v esti gat or is res p o nsi ble f or 
verif 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 
e C R F. 
T he I n vesti gat or m ust mai ntai n acc urate d oc 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 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/I E C re vie w, a n d re g ul at 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 or desi g ne e 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 d ata.  
St u d y m o nit ors will perf or m o n g oi n g s o urce data verificati o n t o c o nfir m t hat data e ntere d i nt o 
t he e C R F b y a ut h orize d site pers o n nel are acc urate, le gi ble, c o nte m p ora n e o us, ori gi nal, a n d 
attri b uta 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 nts are bei n g pr otecte d; 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 9 3  of 1 3 3  
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 oc ol a n d a n y 
ot her st u d y a gree me 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.  
All esse ntial d oc u me nts m ust be retai ne d b y t he I n vesti gat or f or t he mi ni m u m rete nti o n peri o d 
ma n dat or y u n der t h e a p plica ble l ocal la ws a n d re g ulati o ns. T he I n v esti gat or wil l c o ntact U C B 
f or a ut h orizati o n pri or t o t he destr ucti o n of a n y st u d y rec or ds or i n t he e ve nt of acci d e ntal l oss or 
destr ucti o n of a n y st u d y rec or ds. T he I n vesti gat or will als o n otif y U C B s h o ul d he/s he rel ocate or 
m o ve t he st u d y -relate d files t o a l ocati o n ot her t ha n t hat s pecifie d i n t he S p o ns or’s trial master 
file. 
Q ualit y t olera nce li mits will be esta blis he d f or t h e st u d y usi n g para meters relate d t o patie nt 
safet y re p orti n g a n d relia bilit y of st u d y res ults. T he para m eters will be m o nit ore d t hr o u g h o ut t he  
st u d y t o i de ntif y s yste matic iss ues. Para meters use d, para meter val ues, i m p orta nt de viati o ns fr o m 
t he q ualit y t olera nce li mits, a n d acti o ns ta ke n will be s u m marize d i n t he cli nical st u d y re p ort. 
1 0. 1. 7. 1  
e C R F c o m pl eti o n  
T he I n vesti gat or is r es p o nsi ble f or pr o m pt r e p orti n g of acc urate, c o m plete, a n d le gi ble data i n t he 
e C R Fs a n d i n all re q uir e d re p orts.  
A n y c ha n ge or c orrecti o n t o t he e C R F after sa vi n g m ust be acc o m pa nie d b y a reas o n f or t he 
c ha n ge.  
C orrecti o ns ma de after t h e I n vesti gat or’s re vie w a n d a p pr o val ( b y m ea ns of a 
pass w or d/electr o nic si g nat ure) will be rea p pr o ve d b y t he I n vesti gat or.  
T he I n vesti gat or s h o ul d mai ntai n a list of pers o n nel a ut h orize d t o e nt er dat a i nt o t he e C R F.  
Detaile d i nstr ucti o ns will be pr o vi de d i n t he e C R F C o m pleti o n G ui deli nes.  
1 0. 1. 7. 2  
A p p s  
N ot a p plica ble.  
1 0. 1. 8  
S o ur c e d o c u m e nt s  
All s o urce d oc u me nts m ust be acc urate, clear, u na m bi g u o us, per ma ne nt, a n d ca pa ble of bei n g 
a u dite d. T he y s h o ul d be ma de usi n g s o me per ma n e nt f or m of rec or di n g (i n k, t y pi n g, pri nti n g, 
o ptical disc). T he y s h o ul d n ot be o bsc ure d b y c orrecti o n fl ui d or ha ve t e m p orar y attac h me nts 
(s uc h as r e m o va ble self-stic k n otes). P h ot oc o pies a n d/ or pri nt o uts of e C R Fs are n ot c o nsi dere d 
acce pta ble s o ur ce d oc u m e nts.  
S o urce d oc u me nts are ori gi nal rec or ds i n w hic h ra w data are first r ec or de d. T hese ma y i ncl u de 
h os pital/cli nic/ ge neral pr actiti o ner rec or ds, c h arts, diaries, x -ra ys, la b orat or y res ults, pri nt o uts, 
p har mac y rec or ds, care rec or ds, E C G, or ot h er pri nt o uts, c o m plete d scales, Q o L q uesti o n naires, 
or vi de o, f or e xa m ple. S o urce d oc u m e nts s h o ul d be ke pt i n a sec ure, li mite d access area.  
S o urce d oc u me nts t hat are c o m p uter ge n erate d a n d st ore d electr o ni call y m ust be pri nte d f or 
re vie w b y t he m o nit or (e g, E C G re p orts). O nce pri nte d, t hese c o pies s h o ul d be si g ne d a n d date d 
b y t he I n vesti gat or a n d b ec o me a p er ma n e nt part of t he partici pa nt’s s o urce d oc u me nts. T he 
I n v esti gat or will facilitat e t he pr ocess f or e na bli n g t he m o nit or t o c o m pare t he c o nte nt of t he 
pri nt o ut a n d t h e data st or e d i n t he c o m p uter t o e ns ure all data are c o nsiste nt.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 9 4  of 1 3 3  
Electr o nic data rec or ds, s uc h as H olter m o nit or rec or ds or electr oe nce p hal o gra m rec or ds, m ust 
be sa ve d a n d st ore d as i nstr ucte d b y U C B ( or desi g nee).  
1 0. 1. 9  
St u d y a n d sit e st art a n d cl o s ur e  
T he st ar t of recr uit me nt 
T he start of recr uit me nt is t he first partici pa nt’s first visit a n d is als o t he start date of t he cli nical 
st u d y. 
St u d y/site ter mi n ati o n  
T he S p o ns or or desi g ne e reser ves t he ri g ht t o cl ose t he st u d y 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. A st u d y site is c o nsi dere d cl ose d w he n all re q uire d d o c u me nts a n d st u d y s u p plies 
ha ve bee n c ollecte d a n d a st u d y -site cl os ure visit has bee n perf orm e d.  
T he I n vesti gat or ma y i nitiate st u d y -site cl os ure at a n y ti me, pr o vi de d t here is reas o na ble ca use 
a n d s ufficie nt n otice is gi ve n i n a d va nce of t he i nt e n de d ter mi nati o n.  
Reas o ns f or t he earl y cl os ure of a st u d y site b y t he S p o ns or or I n v esti gat or ma y i n cl 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 uir e me nts of t he I R B/I E C or 
l ocal healt 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 v esti gat or 
•  Disc o nti n uati o n of f urt her I M P de vel o p me nt  
1 0. 1. 1 0  
P u bli c ati o n p oli c y  
T he res ults of t his st u d y ma y be p u blis he d or pres e nte d at scie ntific meeti n gs. If t his is f oresee n, 
t he I n v esti gat or a grees t o s u b mit all ma n uscri pts or a bstracts t o t he S p o ns or bef ore s u b missi o n. 
T his all o ws t he S p o ns or t o pr otect pr o priet ar y i nf or mati o n a n d t o pr o vi de c o m me nts.  
T he S p o ns or will c o m pl y wit h t he re q uire me nts f or p u blicati o n of st u d y res ults. I n acc or da nce 
wit h sta n dar d e dit orial a n d et hical practice, t he S p o ns or will ge nerall y s u p p or t p u blicati o n of 
m ultice nter st u dies o nl y i n t heir e ntiret y a n d n ot as i n di vi d ual site data. I n t his case, a 
c o or di nati n g I n vesti gat or will be desi g nate d b y m ut ual a gree m e nt.  
A ut h ors hi p will be deter mi ne d b y m ut ual a gree m e nt a n d i n li ne wit h I nt er nati o nal C o m mittee of 
Me dical J o ur nal E dit ors a ut h ors hi p re q uire m e nts.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0 3  of 1 3 3  
1 0. 4  
A p p e n di x 4: C o ntr a c e pti v e g u i d a n c e a n d c oll e cti o n of 
pr e g n a n c y i nf or m ati o n  
D efi niti o n s  
W O C B P  
A w o ma n is c o nsi dere d fertile f oll o wi n g me narc h e a n d u ntil bec o mi n g p ost me n o pa usal u nless 
per ma ne ntl y sterile. I n case of sterilizati o n, it s h o ul d ha ve ta ke n place bef ore t he start of t he 
Scr ee ni n g Peri o d a n d t h e me dical rec or ds of t he partici pa nt s h o ul d i ncl u de t he met h o d of 
sterilizati o n, al o n g wit h t he date of sterilizati o n, as pr o of of t he c o ntrace pti o n. 
W o me n i n t he f oll o wi n g cate g ories a re n ot c o nsi dere d W O C B P : 
1.  Pre me narc hal  
2.  Pre me n o pa usal  fe male wit h 1 of t he f oll o wi n g: 
− D oc u me nte d h ysterect o m y  
− D oc u me nte d bilateral sal pi n gect o m y  
− D oc u me nte d bilateral o o p h orect o m y  
N ote: D oc u me ntati o n ca n c o me fr o m t he site pers o n nel’s re vie w of t he partici pa nt’s me dical 
rec or ds, me di cal e x a mi nati o n, or me dical hist or y i nter vie w.  
3.  P ost me n o pa usal fe male  
− A p ost me n o pa usal state is defi ne d as n o me ns es f or 1 2 m o nt hs wit h o ut a n alter nati ve 
me dical ca us e. A hi g h f ollicle sti m ulati n g h or m o ne ( F S H) l e vel i n t he p ost me n o pa usal 
ra n ge ma y b e use d t o c o nfir m a p ost me n o pa usal st ate i n w o me n n ot usi n g h or m o nal 
c o ntrace pti o n or h or m o n al re place me nt t hera p y ( H R T). H o we v er, i n t he a bse nce of 
1 2  m o nt hs of a me n orr hea, a si n gle F S H meas ure me nt is i ns ufficie nt.  
− Fe males o n H R T a n d w h ose me n o pa usal stat us is i n d o u bt will be re q uire d t o use 1 of t he 
n o nestr o ge n h or m o nal hi g hl y effecti ve c o ntrace pti o n met h o ds if t he y wis h t o c o nti n ue 
t heir H R T d uri n g t he st u d y. Ot her wise, t he y m ust disc o nti n ue H R T t o all o w c o nfir mati o n 
of p ost me n o pa usal stat us bef ore st u d y e nr oll me nt.  
C o ntr ace pti o n g ui d a nce  
M ale p artici p a nts  
Male partici pa nts wit h fe male part ners of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y 
a gree t o O N E of t he f oll o wi n g:  
•  Are a bsti ne nt fr o m pe nile -va gi nal i nterc o urse as t heir us ual a n d preferre d life st yle (a bsti ne nt 
o n a l o n g -ter m a n d p ersiste nt basis) a n d a gree t o r e mai n a bsti ne nt. 
•  A gree t o use a male c o n d o m pl us part ner use of a c o ntrace pti ve met h o d wit h a fail ure rate of 
< 1 % per year as des cri be d i n t he ta ble bel o w  w he n ha vi n g pe nile -va gi nal i nterc o urse wit h a 
W O C B P  w h o is n ot c urre ntl y pre g na nt.  
I n a d diti o n, male partici p a nts m ust refrai n fr o m d o nati n g s per m f or t he d urati o n of t he st u d y a n d 
f or 3 m o nt hs after t he l ast d ose of st u d y me dicati o n. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0 4  of 1 3 3  
Male partici pa nts wit h a pre g na nt or breastf ee di n g par t ner m ust a gree t o r e mai n a bsti ne nt fr o m 
pe nile -va gi nal i nterc o urs e or use a m ale c o n d o m d uri n g eac h e pis o de of pe nile pe netrati o n 
d uri n g t he pr ot oc ol -defi ne d ti me fra me a n d f or 3 m o nt hs after t he last d ose of st u d y me dicati o n . 
Fe m ale p artici p a nts  
Fe male p artici pa nts of c hil d beari n g p ote ntial are eli gi ble t o partici pate if t he y a gree t o use a 
hi g hl y effecti ve m et h o d of c o ntrace pti o n c o nsiste ntl y a n d c orrectl y as descri be d i n t he ta ble 
bel o w.  
Hi g hl y effecti ve c o ntr ace pti ve met h o ds 
a 
Hi g hl y effecti ve c o ntr ace pti ve met h o ds t h at are user de pe n de nt b  
Fail ure rate of < 1 % per year w he n use d c o nsiste ntl y a n d c orrectl y.  
C o m bi ne d (estr o ge n a n d pr o gest o ge n c o ntai ni n g) h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of 
o v ulati o n c 
•  
Oral  
•  
I ntra va gi nal 
•  
Tra ns der mal  
Pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  
Oral  
•  
I njecta ble 
Hi g hl y effecti ve met h o ds t h at are user i n de pe n de nt 
c 
 
I m pla nta ble pr o gest o ge n o nl y h or m o nal c o ntrace pti o n ass ociate d wit h i n hi biti o n of o v ulati o n  
•  
I ntra uteri ne de vice (I U D) 
•  
I ntra uteri ne h or m o ne-releasi n g s yste m 
•  
Bilateral t u bal occl usi o n  
V asect o mize d p art ner  
A vasect o mize d part ner is a hi g hl y effecti ve c o ntrace pti o n met h o d pr o vi de d t hat t he part ner is t he s ole 
male se x ual part ner of t he W O C B P, a n d t he a bse nce of s per m has bee n c o nfir me d. If n ot, a n a d diti o nal 
hi g hl y effecti ve met h o d of c o ntrace pti o n s h o ul d be use d.  
Se x u al a bsti ne nce  
Se x ual a bsti ne nce is c o nsi dere d a hi g hl y effecti ve met h o d o nl y if defi ne d as refrai ni n g fr o m heter ose x ual 
i nterc o urse d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y me dicati o n. T he relia bilit y of se x ual 
a bsti ne nce nee ds t o be e val uate d i n relat i o n t o t he d urati o n of t he st u d y a n d t he preferre d a n d us ual 
lifest yle of t he partici pa nt. 
N O T E S:  
a) I n case of ne wl y starte d c o ntrace pti o n pills/I U Ds, t he I n vesti gat or s h o ul d c o nsi der t he c orrect ti mi n g of 
starti n g/a p pl yi n g s uc h met h o ds i n relati o n t o t he me nstr ual c ycle a n d t he ma n ufact uri n g i nstr ucti o n as t o w he n 
t hese ne wl y starte d met h o ds w o ul d bec o me effecti ve. 
b) T y pical use fail ure rates ma y differ fr o m t h ose w he n use d c o nsiste ntl y a n d c orrectl y. Use s h o ul d be c o nsiste nt 
wit h l ocal re g ulati o ns re ga r di n g t he use of c o ntrace pti ve met h o ds f or partici pa nts partici pati n g i n cli nical st u dies. 
c) If oral c o ntrace pti o n is use d, a n a d diti o nal barrier met h o d will be re q uire d d uri n g t he Treat me nt Peri o d a n d f or at 
least 3 0 da ys after t he last d ose of st u d y me dicati o n. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0 5  of 1 3 3  
Pre g n a nc y testi n g  
•  A W O C B P s h o ul d o nl y be i ncl u de d aft er a c o nfir me d me nstr ual peri o d a n d a ne gati ve uri n e 
pre g na nc y t est.  
•  A d diti o nal pre g na nc y testi n g s h o ul d be perf or me d at eac h visit d uri n g t he Treat me nt Peri o d 
a n d at t he S F U Visit a n d as re q uire d l o call y. 
•  Pre g na nc y testi n g will be perf or me d w he ne ver a me nstr ual c ycle is misse d or w he n 
pre g na nc y is ot her wise s us pecte d.  
•  A p ositi ve uri ne test s h o ul d be c o nfir me d b y a bl o o d test wit h a se nsiti vit y of 2 5 mI U/ m L . 
M ale p artici p a nts wit h p art ners w h o bec o me pre g n a nt  
•  T he I n vesti gat or will atte m pt t o c ollect pre g na nc y i nf or mati o n o n a n y male partici pa nt’s 
fe male part ner w h o b ec o mes pre g na nt w hile t he male partici pa nt is i n t his st u d y. T his a p plies 
o nl y t o male partici pa nts w h o recei ve st u d y me dicati on . 
•  After o btai ni n g t he necessar y si g ne d i nf or me d c o nse nt fr o m t he pre g n a nt fe male part ner 
directl y, t he I n vesti gat or will rec or d pre g na nc y i nf or mati o n o n t he a p pr o pri ate f or m a n d 
s u b mit it t o t he S p o ns or wit hi n 1 w or ki n g da y of lear ni n g of t he part ner’s pre g n a nc y. T he 
fe male part ner will als o b e f oll o we d t o deter mi ne t he o utc o me of t he pre g na nc y. I nf or mati o n 
o n t he stat us of t he m ot her a n d c hil d will be f or war de d t o t he S p o ns or. Ge nerall y, t he f oll o w 
u p will be at least 1 2 m o nt hs after t he deli ver y dat e. A n y t er mi nati o n of t he pre g na nc y will 
be re p ort e d re g ar dless of fetal stat us ( pres e nce or a bse nce of a n o malies) or i n dicati o n f or t he 
pr oce d ure.  
Fe m ale p artici p a nts w h o bec o me pre g n a nt  
•  A n y fe male p artici pa nt w h o bec o mes pre g na nt w hile partici pati n g i n t he st u d y  will 
disc o nti n ue st u d y me dicati o n.  
•  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 p artici 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. I nf or mati o n will be rec or de d o n t he a p pr o pri ate 
f or m a n d s u b mitte d t o t he S p o ns or wit hi n 1 w or ki n g da y  of lear ni n g of a p artici pa nt's 
pre g na nc y. T he partici pa nt will be f oll o we d t o deter mi ne t he o utc o me of t he pre g na n c y. T he 
I n v esti 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 warde d t o t he S p o ns or. Ge nerall y, t he f oll o w -u p will be at least 
1 2  m o nt hs after t he deli v er y date. A n y t er mi nati o n of pre g na n c y will be re p orte d, re g ar dless 
of fetal stat us ( prese nce or a bse nce of a n o m alies) or i n dicati o n f or t he pr oce d ure.  
•  W hile pre g na n c y i tself is n ot c o nsi dere d t o be a n A E or S A E, a n y pre g na n c y c o m plicati o n or 
electi ve ter mi nati o n of a pre g na nc y will be re p ort e d as a n A E or S A E. A s p o nta ne o us 
a b orti o n is al wa ys c o nsi d ere d t o be a S A E a n d will be re p orte d as s uc h. A n y p ostst u d y 
pre g na nc y -rel ate d S A E c o nsi dere d reas o na bl y r elate d t o t he st u d y me dicati o n b y t he 
I n v esti gat or will be re p orte d t o t he S p o ns or as des cri be d i n Secti o n 8. 3. 5 . W hile t he 
I n v esti gat or is n ot o bli gate d t o acti vel y see k t his i nf or mati o n i n f or mer st u d y partici pa nts, he 
or s he ma y lear n of a S A E t hr o u g h s p o nta ne o us re p orti n g.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0 6  of 1 3 3  
1 0. 5  
A p p e n di x 5: G e n eti c s  
N ot a p plica ble.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0 7  of 1 3 3  
1 0. 6  
A p p e n di x 6: Li v er s af et y –  s u g g e st e d a cti o n s a n d f oll o w -u p 
a s s e s s m e nt s  
Partici pa nts wit h p ote ntial dr u g -i n d uce d li ver i nj ur y m ust be assesse d t o det er mi ne if st u d y 
me dicati o n m ust be disc o nti n ue d. I n a d diti o n, all c o nc o mita nt me dicati o ns a n d her bal 
s u p ple me nts t hat are n ot me dicall y necess ar y s h o ul d als o be disco nti n ue d.  
I n v esti gat ors s h o ul d atte m pt t o o btai n i nf or mati o n o n st u d y partici pa nts i n t he case of st u d y 
me dicati o n disc o nti n uati o n t o c o m plete t he fi nal e val uati o n.  
St u d y partici pa nts wit h p ote ntial dr u g -i n d uce d li v er i nj ur y s h o ul d n ot be wit h dra w n fr o m t he 
st u d y u ntil i n vesti gati o n a n d m o nit ori n g are c o m plete. All res ults of t hese e val uati o ns a n d 
o bser vati o ns, as well as t he reas o n(s) f or st u d y me dicati o n disc o nti n uati o n a n d/ or partici pa nt 
wit h dra wal (if a p plica ble), m ust be rec or de d i n t he s o urce d oc u m e nt s. T he e C R F m ust d oc u me nt 
t he pri mar y reas o n f or disc o nti n uati o n of st u d y me dicati o n. 
A s pecific m o nit ori n g pla n m ust be a gree d bet w ee n t he U C B st u d y p h ysicia n a n d t he 
I n v esti gat or f or st u d y partici pa nts w h o ha ve A L T > 5 x U L N. T he m o nit ori n g pla n s h o ul d i nclu de 
a n y necessar y f oll o w -u p assess me nts ( u ntil res ol uti o n of t he a b n or mal la b v al ues).  
P hase 2 li ver c he mistr y st o p pi n g criteria are desi g ne d t o ass ure p artici pa nt safet y a n d t o e v al uate 
li ver e ve nt eti ol o g y (Secti o n  7. 1. 2 ). 
T a bl e  1 0 -1 : P h a s e 2 li v er c h e mi str y st o p pi n g crit eri a  a n d f oll o w -u p 
a s s e s s m e nt s  
Li ver C he mistr y St o p pi n g Criteri a  
A L T -a bs ol ute  
A L T 5 x U L N  
A L T I ncre ase  
A L T 3 x U L N persists f or 4 wee ks  
Bilir u bi n a,b 
A L T 3 x U L N a n d  bilir u bi n 2 x U L N ( > 3 5 % direct bilir u bi n)  
I N Rb 
A L T 3 x U L N a n d  i nter nati o nal n or malize d rati o (I N R) > 1. 5, if I N R meas ure d 
C a n n ot M o nit or  A L T 3 x U L N a n d ca n n ot be m o nit ore d wee kl y f or 4 wee ks  
S y m pt o m atic c 
A L T 3 x U L N ass ociate d wit h s y m pt o ms ( ne w or w orse ni n g) belie ve d t o be relate d 
t o li ver i nj ur y or h y perse nsiti vit y 
S u g geste d Acti o ns a n d F oll o w -u p Assess me nts  
Acti o ns  
F oll o w -U p Assess me nts  
•  
I m me di atel y disc o nti n ue st u d y me dicati o n.  
•  
Re p ort t he e ve nt t o t he S p o ns or wit hi n 2 4 h o urs.  
•  
C o m plete t he li ver e ve nt e C R F a n d c o m plete a n 
S A E data c ollecti o n t o ol if t he e ve nt als o met t he 
criteria f or a n S A E. b 
•  
Perf or m li ver c he mistr y f oll o w -u p assess me nts.  
•  
Viral he patitis ser ol o g y d 
•  
O btai n I N R a n d rec hec k wit h eac h li ver 
c he mistr y assess me nt u ntil t he 
tra nsa mi nases val ues s h o w d o w n war d 
tre n d 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0 8  of 1 3 3  
T a bl e  1 0 -1 : P h a s e 2 li v er c h e mi str y st o p pi n g crit eri a  a n d f oll o w -u p 
a s s e s s m e nt s  
Li ver C he mistr y St o p pi n g Criteri a  
•  
M o nit or t he partici pa nt u ntil li ver c he mistr y test 
a b n or malities res ol ve, sta bilize, or ret ur n t o 
Baseli ne (see M O NI T O RI N G ). 
•  
D o n ot rest art/rec h alle n ge  partici pa nt wit h st u d y 
me dicati o n u nless all o we d per pr ot oc ol a n d 
S p o ns or a p pr o val is gra nte d  
•  
If restart/rec halle n ge n ot all o we d per pr ot oc o l or 
n ot gr a nte d , per ma ne ntl y disc o nti n ue st u d y 
me dicati o n a n d c o nti n ue partici pa nt i n t he st u d y 
f or a n y pr ot oc ol s pecifie d f oll o w-u p assess me nts  
•  
C o nsi der t he nee d f or a t o xic ol o g y Scree ni n g  
M O NI T O RI N G : 
If A L T 3 x U L N A N D bilir u bi n 2 x U L N or I N R 
> 1. 5:  
•  
Re pea t li ver c he mistr y tests (i ncl u de A L T, 
as partate tra nsa mi nase [ A S T], al kali ne 
p h os p hatase, bilir u bi n)  a n d perf or m li ver e ve nt 
f oll o w-u p assess me nts wit hi n 2 4 h o urs.  
•  
M o nit or partici pa nt t wice wee kl y u ntil li ver 
c he mistr y test a b n or malities res ol ve, sta bilize , or 
ret ur n t o Baseli ne. 
•  
A s pecialist or he pat ol o g y c o ns ultati o n is 
rec o m me n de d. 
If A L T 3 x U L N A N D bilir u bi n < 2 x U L N a n d I N R 
1. 5:  
•  
Re peat li ver c he mistr y tests (i ncl u de A L T, A S T, 
al kali ne p h os p hatase, bilir u bi n) a n d perf or m li ver 
c he mistr y f oll o w -u p assess me nts wit hi n 2 4 t o 
7 2  h o urs.  
•  
M o nit or partici pa nts wee kl y u ntil li ver c he mistr y 
a b n or malities res ol ve, sta bilize, or ret ur n t o 
Baseli ne.  
•  
O btai n bl o o d sa m ple f or p har mac o ki netic 
( P K) a nal ysis as s o o n as p ossi ble after 
t he m ost rece nt d ose e 
•  
Ser u m creati ne p h os p h o ki nase ( C P K) 
a n d lactate de h y dr o ge nase ( L D H)  
•  
Fracti o nate bilir u bi n, if t otal bilir u bi n 
 2 x U L N  
•  
O btai n c o m plete bl o o d c o u nt wit h 
differe ntial t o assess e osi n o p hilia  
•  
Rec or d t he a p peara nce or w orse ni n g of 
cli nical s y m pt o ms of li ver i nj ur y (e g, 
fati g ue, na usea, v o miti n g, ri g ht u p per 
q ua dra nt pai n), or h y perse nsiti vit y, o n 
t he a d verse e ve nt ( A E) re p ort f or m 
•  
Rec or d use of c o nc o mita nt me dicati o ns 
(i ncl u di n g aceta mi n o p he n, her bal 
re me dies, a n d ot her o ver-t he-c o u nter 
me dicati o ns) o n t he c o nc o mita nt 
me dicati o ns e C R F  
•  
Rec or d alc o h ol use o n t he li ver e ve nt 
alc o h ol i nta ke e C R F  
•  
E xcl u de pre g na nc y  
If A L T 3 x U L N A N D bilir u bi n 2 x U L N 
or I N R  > 1. 5:  
•  
A nti -n uclear a nti b o d y, a nti -s m o ot h 
m uscle a nti b o d y, T y pe 1 a nti -li ver 
ki d ne y micr os o mal a nti b o dies, a n d 
q ua ntitati ve t otal i m m u n o gl o b uli n G 
(I g G) or ga m ma gl o b uli ns 
•  
Ser u m aceta mi n o p he n ( E A N 
paraceta m ol)  
•  
Li ver i ma gi n g ( ul tras o u n d, ma g netic 
res o na nce, or c o m p uterize d t o m o gra p h y) 
a n d/ or li ver bi o ps y t o e val uate li ver 
disease; c o m plete li ver  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 0 9  of 1 3 3  
T a bl e  1 0 -1 : P h a s e 2 li v er c h e mi str y st o p pi n g crit eri a  a n d f oll o w -u p 
a s s e s s m e nt s  
Li ver C he mistr y St o p pi n g Criteri a  
A E =a d verse e ve nt; A L T =ala ni ne a mi n otra nsferase; A S T =as partate a mi n otra nsferase; C P K =creati ne 
p h os p h o ki nase; E A N =I nter nati o nal Article N u m ber; e C R F =electr o nic case re p ort f or m; H Bc A b = he patitis B 
c ore a nti b o d y; H Bs A g = h e p atitis B vir us s urface a nti ge n; H P L C = h i g h perf or ma nce li q ui d c hr o mat o gra p h y; 
I g G =i m m u n o gl o bi n G; I g M =i m m u n o gl o bi n M; I N R =i nter nati o nal n or malize d rati o; L D H =lactate 
de h y dr o ge nase; P B O = place b o; P K = p har mac o ki netic; R N A =ri b o n ucleic aci d; S A E =seri o us a d verse e ve nt; 
U L N = u p per li mit of n or mal.  
a Ser u m bilir u bi n fracti o nati o n s h o ul d be perf or me d if testi n g is a vaila ble. If ser u m bilir u bi n fracti o nati o n is n ot 
i m me diatel y a vaila ble, disc o nti n ue st u d y me dicati o n if A L T ≥3 x U L N a n d  bilir u bi n ≥2 x U L N. A d diti o nall y, if 
ser u m bilir u bi n fracti o nati o n testi n g is u na vaila ble, rec or d t he a bse nce/ prese nce of detect a ble uri n ar y 
bilir u bi n o n di pstic k  w hic h is i n dicati ve of direct bilir u bi n ele v ati o ns s u g gesti n g li ver i nj ur y.  
b All e ve nts of A L T ≥3 x U L N a n d  bilir u bi n ≥2 x U L N ( > 3 5 % direct bilir u bi n) or A L T ≥3 x U L N a n d I N R  > 1. 5 ma y 
i n dicate se vere li ver i nj ur y ( p ossi ble ‘ H y’s L a w’) a n d m ust be re p orte d as a n S A E (e xcl u di n g st u dies of 
he p atic i m p air m e nt or cirr h osis) . T he I N R meas ure me nt is n ot re q uire d, a n d t he state d t hres h ol d val ue will 
n ot a p pl y t o partici pa nts recei vi n g  a ntic oa g ula nts. 
c Ne w or w orse ni n g s y m pt o ms belie v e d t o be relate d t o li ver i nj ur y (s uc h as fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dra nt p ai n or te n der ness, or ja u n dice) or h y perse nsiti vit y (s uc h as ras h, a n gi oe de ma, or a na p h yla xis)  
d I ncl u des: He patitis A i m m u n o gl o b uli n M (I g M) a nti b o d y; H Bs A g a n d H Bc A b; he patitis C R N A; 
c yt o me g al o vir us I g M a nti b o d y; E pstei n -Barr viral ca psi d a nti ge n I g M a nti b o d y ( or if u na vaila ble, heter o p hile 
a nti b o d y or m o n os p ot testi n g); a n d he patitis E I g M a nti b o d y.  
e Rec or d t he d ate/ti me of t he P K bl o o d sa m ple dra w a n d t he date/ti me of t he last d ose of st u d y me dicati o n pri or 
t o t he bl o o d sa m ple dra w o n t he e C R F. If t he date or ti me of t he last d ose is u nclear, pr o vi de t he partici pa nt’s 
best a p pr o xi mati o n. If t he date/ti me of t he l ast d ose ca n n ot be a p pr o xi mate d O R a P K sa m ple ca n n ot be 
c ollecte d i n t he ti me peri o d i n dicate d a b o ve, d o n ot o btai n a P K sa m ple. I nstr ucti o ns f or sa m ple ha n dli n g a n d 
s hi p pi n g are i n t he St u d y Refere n ce Ma n ual 
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1 0  of 1 3 3  
1 0. 7  
A p p e n di x 7: Di git al H e alt h T e c h n ol o g y A E s, S A E s, A D E s, 
S A D E s, a n d d e vi c e d efi ci e n ci e s: D efi niti o n a n d pr o c e d ur e s f or 
r e c or di n g, e v al u ati n g, f oll o w-u p, a n d r e p orti n g  
T hr o u g h o ut t he st u d y, safet y i nf or mati o n will be rec or de d a n d re p orte d acc or di n g t o t he 
pr oce d ures o utli ne d i n Secti o n  8. 3 , A p pe n di x 3 ( Secti o n 1 0. 3 ), a n d bel o w f or t he differe nt 
c o mp o ne nts of t he K o ne ksa Ne ur os cie nce T o ol kit.  
1 0. 7. 1  
S af et y r e p orti n g f or t h e K o n e k s a m o bil e s oft w ar e a p pli c ati o n a n d 
A p pl e i P h o n e  
1 0. 7. 1. 1  
A d v er s e e v e nt s of t h e K o n e k s a m o bil e s oft w ar e a p pli c ati o n a n d 
A p pl e i P h o n e  
T he I n vesti gat or is e x p ecte d t o rec or d a n y A Es a n d S A Es re late d t o t he K o ne ksa m o bile s oft ware 
a p plicati o n a n d t he A p pl e i P h o ne i n t he e C R F. T h e e C R F pa g e will all o w t he I n vesti gat or t o 
assess ca us alit y.  
T he S p o ns or a n d/ or I n v esti gat or will se n d re p orts of A Es a n d S A Es rel ate d t o t he K o ne ksa 
m o bile s oft ware a p plicati o n a n d t he A p ple i P h o ne t o K o ne ksa Healt h I nc. ( via a messa ge t o 
hel p @ k o ne ksa healt h.c o m).  
1 0. 7. 1. 2  
D efi ci e n ci e s of t h e K o n e k s a m o bil e s oft w ar e a p pli c ati o n a n d A p pl e 
i P h o n e 
Deficie n cies of t he K o n e ksa m o bile s oft ware a p plicati o n a n d A p ple i P h o ne ar e defi ne d as 
i na de q uaci es wit h res pect t o t heir i de ntit y, q ualit y, d ura bilit y, relia bilit y, safet y, or perf or ma nce. 
U p o n i de ntificati o n of s u c h deficie n cies, st u d y partici pa nts will be pr o vi de d wit h a re place me nt. 
T he affecte d t ec h n ol o g y will be ret ur ne d, w he n p ossi ble, t o K o ne ksa Healt h I n c. f or fail ure 
a nal ysis i n vesti gati o n.  
T he I n vesti gat or will se n d re p orts of deficie nci es of t he K o ne ksa m o bile s oft ware a p plicati o n 
a n d A p ple i P h o ne t o K o n e ksa Healt h I nc. ( via a m essa ge t o hel p @ k o ne ks a healt h.c o m).  
1 0. 7. 2  
S af et y r e p orti n g f or t h e A cti Gr a p h C PI W a n d t h e D at a H u b  
T he Acti Gra p h C PI W ( Acti Gra p h L L C) is a s mart watc h t hat has a C E M ar k a n d F D A 5 1 0( k) 
cleara nce u n d er K 1 8 1 0 7 7. T heref ore, t he bel o w s afet y r e p orti n g re q uir e me nts a p pl y.  
F or t he f oll o wi n g s u bse cti o ns, t he A cti Gra p h C PI W a n d Dat a H u b are des cri be d j oi ntl y as t he 
Acti Gra p h C PI W.  
T he I n vesti gat or m ust n otif y A D Es/ S A D Es/ de vice deficie ncies ass o ciate d wit h t he use of t he 
Acti Gra p h C PI W dir ectl y t o K o ne ksa Healt h I nc. ( via a messa g e t o hel p @ k o ne ksa healt h.c o m) 
usi n g t he A d verse E v e nt a n d De vic e Defi cie nc y F or m.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1 4  of 1 3 3  
1 0. 8  
A p p e n di x 8: R a pi d al ert pr o c e d ur e s  
N ot a p plica ble.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1 5  of 1 3 3  
1 0. 9  
A p p e n di x 9: C o u ntr y -s p e cifi c r e q uir e m e nt s  
1 0. 9. 1  
C o u ntr y -s p e cifi c r e q uir e m e nt s f or U S a n d U K 
A n o pti o nal i n -st u d y patie nt i nter vie w was a d de d wit h pr ot oc ol a me n d me nt 3. 2 i n t he U K a n d 
wit h pr ot oc ol a me n d me nt 3. 3 i n t he U S.  
T he f oll o wi n g u p dates were ma d e i n gl o bal pr ot oc ol a me n d me nt 4 t o i m ple me nt t he c o u ntr y -
s pecific c ha n ges i n t he gl o bal pr ot oc ol:  
•  Secti o n  1. 3 : O pti o nal i n-st u d y patie nt i nter vie ws a n d ass ociate d i nf or me d c o nse nt pr oce d ure 
were a d de d i n t he sc h e d ule of acti vities.  
•  Secti o n  8. 1. 3 : A descri pti o n of t he o pti o nal i n-st u d y patie nt i nter vie w was a d de d. 
•  Secti o n  8. 3. 8 : Ne w secti o n was a d de d t o clarif y t he safet y r e p orti n g f or e v e nts re p orte d 
d uri n g i n -st u d y patie nt i nter vie ws. 
•  Secti o n  9. 4. 2 : A n ote o n t he ha n dli n g of t he data ge nerat e d fr o m t he o pti o n al i n-st u d y patie nt 
i nter vie ws was a d de d. 
T hese c h a n ges a p pl y t o U S a n d U K sites o nl y, as n ote d i n t he res pecti ve secti o ns t hr o u g h o ut t he 
pr ot oc ol.  
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1 6  of 1 3 3  
1 0. 1 0  
A p p e n di x 1 0: A b br e vi ati o n s a n d tr a d e m ar k s  
A D E  
a d verse d e vice effect  
A E  
a d verse e ve nt  
A E SI  
a d verse e ve nt of s p ecial i nterest  
A L T  
ala ni ne a mi n otra nsferas e  
A N C O V A  
a nal ysis of c o varia nce  
A S P S  
All St u d y Partici pa nts Set  
A S T  
as partate a mi n otra nsferas e  
A S Y N  
al p ha-s y n uclei n 
A T C  
A nat o mical T hera pe utic C he mical  
BI D  
t wice dail y 
B P  
bl o o d press ure  
C A  
c o m pete nt a ut h orit y  
C E  
C o nf or mité E ur o pée n n e  
CI  
c o nfi de nce i nter val  
Cli n R O  
cli nicia n -re p orte d o utc o me 
C N S  
ce ntral ner v o us s yste m  
C O M T  
catec h ol -O -met h yltra nsferase  
C O VI D -1 9  
C or o na vir us Disease -2 0 1 9  
C PI W  
Acti Gra p h Ce ntr e P oi nt ®  I nsi g ht Watc h 
C R F  
Case Re p ort f or m  
C R O  
c o ntract r esearc h or ga nizati o n  
C S F  
cere br os pi nal fl ui d  
C -S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
C Y P 3 A 4  
c yt oc hr o me P 4 5 0 3 A 4  
Da T -S P E C T  
D o pa mi ne Tra ns p orter I ma gi n g wit h Si n gle P h ot o n E missi o n 
C o m p ute d T o m o gra p h y  
D M C  
Data M o nit ori n g C o m mittee  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic Cas e Re p ort f or m  
E O T  
E n d of Treat me nt  
E T  
Earl y Ter mi nati o n  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1 7  of 1 3 3  
E Q -5 D -5 L  
E ur o Q ualit y of life 5 -Di me nsi o ns 5 -Le vel  
E Q V A S  
E ur o Q ualit y of life vis ual a nal o g ue scal e  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
f ollicle sti m ulati n g h or m o ne 
G C P  
G o o d Cli nical Practices  
H & Y  
H oe h n a n d Y a hr  
H R T  
h or m o nal re place me nt t h era p y  
I B 
I n v esti gat or’s Br oc h ure 
I C E 
i nterc urre nt e ve nt 
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 nisati o n 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
I R T 
i nteracti ve res p o nse tec h n ol o g y 
I U D 
i ntra uteri ne de vice 
L E D D  
Le v o d o pa E q ui vale nt D ail y D ose  
L M E M  
li near mi xe d effects m o d el 
M A R  
missi n g at ra n d o m  
M CI  
mil d c o g niti ve i m pair me nt 
M D S -N M S  
M o ve me nt Dis or der S oci et y N o n -M ot or Rati n g Scale  
M D S -U P D R S  
M o ve me nt Dis or der S oci et y  U nifie d Par ki ns o n’s Disease Rati n g Scale  
M o C A  
M o ntreal C o g niti ve Assess me nts  
P D  
Par ki ns o n’s disease  
P K  
p har mac o ki netics  
P R O  
patie nt -re p ort e d o utc o mes 
Q o L  
Q ualit y of Life  
Q Tc  
Q T c orrecte d  
Q Tc F  
Q T c orrecte d f or heart rate usi n g Fri derici a's f or m ula  
S A E  
seri o us a d vers e e v e nt 
S A D E  
seri o us a d vers e de vice effect 
S A P  
statistical a nal ysis pla n 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1 8  of 1 3 3  
S A R S -C o V -2  
se vere ac ute res pirat or y s y n dr o me c or o na vir us-2  
S B P  
s yst olic bl o o d press ure 
S B R  
s pecific bi n di n g rati o 
S D  
sta n dar d de viati o n 
S F U  
Safet y F oll o w -u p  
S M C  
Safet y M o nit ori n g C o m mittee  
S o C  
sta n dar d of care 
S S  
Safet y Set  
S T  
s y m pt o matic treat me nt 
S U S A R  
s us pecte d u ne x p ecte d seri o us a d verse reacti o n 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
U L N  
u p per li mit of n or mal  
U P SI T  
U ni versit y of Pe n ns yl va nia S mell I de ntificati o n Test  
U S A D E  
u na ntici pate d seri o us a d v erse de vi ce effect  
W O  
weari n g -off  
W O C B P  
w o ma n/ w o me n of c hil d b eari n g p ote ntial  
W O Q -9  
Weari n g -off Q uesti o n naire -9  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 1 9  of 1 3 3  
1 0. 1 1  
A p p e n di x 1 1: Pr ot o c ol a m e n d m e nt hi st or y  
T he Pr ot oc ol A me n d me nt S u m mar y of C ha n ges Ta ble f or t he c urre nt a me n d me nt is l ocate d 
directl y bef ore t he Ta bl e of C o nte nts . 
1 0. 1 1. 1  
A m e n d m e nt 3 ( 1 8 S e p 2 0 2 3)  
O ver all R ati o n ale f or t he A me n d me nt  
P D 0 0 5 5 Pr ot oc ol A me n d me nt 3 was c o m plete d t o i m ple me nt Di gital Healt h Tec h n ol o g y i n t he 
st u d y. I n a d diti o n, t he i nt er nati o nal n o n pr o pri etar y na me mi nzas ol mi n was i ntr o d uce d a n d 
f urt her cl arific ati o n of pr ot oc ol pr oce d ures was pr o vi de d.  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 2( 1 3) of 
Re g ulati o n N o 5 3 6/ 2 0 1 4  of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Gl o bal  
U C B 0 5 9 9 was c ha n ge d t o “ mi nzas ol mi n 
( U C B 0 5 9 9)” t hr o u g h o ut. 
T o i ntr o d uce t he 
i nter nati o nal n o n pr o prietar y 
na me f or U C B 0 5 9 9.  
R E P O R TI N G O F 
A D V E R S E D E VI C E 
E F F E C T S ( S E RI O U S A N D 
N O N S E RI O U S) A N D 
D E VI C E D E FI CI E N CI E S  
Ta ble wit h re p orti n g i nf or mati o n f or 
a d verse de vice effects a n d de vice 
deficie ncies was a d de d.  
T o pr o vi de c o ntact 
i nf or mati o n f or a d verse 
de vice effects a n d de vice 
deficie ncies re p orti n g.  
Secti o n  1. 1  S y n o psis - 
O bjecti ves a n d e n d p oi nts  
a n d 
Secti o n  3  O BJ E C TI V E S 
A N D E N D P OI N T S  
I n t he E x pl orat or y O bjecti ves, the b ullet 
“ F A TI G U E-P R O (a n d s u bsc ores)” was 
c ha n ge d i n 2 places t o 
“ F A TI G U E-P R O.”  
T o re m o ve u n necessar y 
detail; t here is n o c ha n ge t o 
t he pla n ne d a nal ysis. 
I n t he E x pl orat or y O bjecti ves u n der I. 
Met h o d ol o g y, “ K o ne ksa Ne ur oscie nce 
T o ol kit” was a d de d as a n " E x pl orat or y 
E n d p oi nt ( Ot her)."  
T o i m ple me nt Di gital 
Healt h Tec h n ol o g y i n t he 
st u d y. 
I n t he E x pl orat or y O bjecti ves u n der I V. 
At y pical Par ki ns o nis m, t he E x pl orat or y 
E n d p oi nt “ Perce nta ge of partici pa nts 
wit h t hese dia g n oses fr o m 
P D 0 0 5 3/ P D 0 0 5 5 a nal yses” was c ha n ge d 
t o a n “ E x pl orat or y Assess me nt” of “ Re-
c o nfir me d P D dia g n osis stat us.”  
T o clarif y t he assess me nt.  
Secti o n  1. 1  S y n o psis - 
O verall desi g n  
A preca uti o n t o all o w a d ose s witc h fr o m 
3 6 0 m g/ da y t o 1 8 0 m g/ da y i n case of 
safet y c o ncer ns at t he ti me t he first 
partici pa nt was pla n ne d t o tra nsiti o n i nt o 
P D 0 0 5 5 wa s re m o ve d. 
T o re m o ve i nf or mati o n t hat 
n o l o n ger a p plies after First 
Partici pa nt First Visit i n 
P D 0 0 5 5; a s witc h i n d ose 
was n ot re q uire d bef ore 
First Partici pa nt First Visit 
i n P D 0 0 5 5 was c o n d ucte d. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 0  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  1. 1  S y n o psis - 
N u m ber of partici pa nts  
a n d 
Secti o n  4. 1  O verall desi g n  
N u m ber of partici pa nts was u p date d 
fr o m “ All st u d y partici pa nts 
(a p pr o xi matel y 4 5 0) ca n r oll o ver fr o m 
P D 0 0 5 3. Ass u mi n g t hat 6 0 % of P D 0 0 5 3 
partici pa nts ( 2 7 0) c h o ose t o r oll o ver i nt o 
P D 0 0 5 5, a n d 1 5 % of t he P D 0 0 5 3 
partici pa nts dr o p o ut or are l ost t o f oll o w 
u p, t he n 2 0 2 partici pa nts w o ul d be 
e x pecte d t o reac h E n d of Treat me nt 
( E O T)” t o “ All st u d y partici pa nts 
(a p pr o xi matel y 4 9 0) ca n r oll o ver fr o m 
P D 0 0 5 3. Ass u mi n g t hat 1 5 % of P D 0 0 5 3 
partici pa nts dr o p o ut or are l ost t o f oll o w 
u p o ver 1 8 m o nt hs a n d 9 0 % of t he 
re mai ni n g 4 1 6 partici pa nts w h o c o m plete 
P D 0 0 5 3 c h o ose t o r oll o ver i nt o P D 0 0 5 5, 
t he n 3 7 4 partici pa nts w o ul d be e x pecte d 
t o e nter t he e xte nsi o n st u d y. Ass u mi n g 
t hat 1 5 % of P D 0 0 5 5 partici pa nts dr o p 
o ut or are l ost t o f oll o w u p o v er 
1 8  m o nt hs, 3 1 8  partici pa nts w o ul d be 
e x pecte d t o reac h P D 0 0 5 5 E n d of 
Treat me nt ( E O T).”  
T o u p date t he n u m ber of 
partici pa nts e x pecte d t o r oll 
o ver fr o m P D 0 0 5 3 base d o n 
o bser vati o ns i n P D 0 0 5 5.  
Secti o n  1. 2  Sc he ma  
T he f o ot n ote i n Fi g ure 1 -1 t hat t he d ose 
ma y be s witc he d fr o m 3 6 0 m g/ da y t o 
1 8 0 m g/ da y was re m o ve d.  
Base d o n P D 0 0 5 3 
i nf or mati o n, a s witc h i n 
d ose was n ot re q uire d 
bef ore First Partici pa nt Firs t 
Visit i n P D 0 0 5 5 was 
c o n d ucte d. 
Secti o n  1. 3  Sc he d ule of 
Acti vities  
T he Earl y Ter mi nati o n ( E T) la bel was 
m o ve d fr o m V 9 t o V 1 0/ E O T i n t he 
Sc he d ule of Acti vities t o clarif y t hat t he 
E O T Visit pr oce d ures a p pl y f or st u d y 
partici pa nts w h o te r mi nate t he st u d y 
pre mat urel y, i n li ne wit h f o ot n ote ‘c’. 
F o ot n otes ‘c’ a n d ‘i’ were u p date d t o 
refer t o t he E O T/ E T Visit. 
T o clarif y w hic h pr oce d ures 
a p pl y if partici pa nts 
disc o nti n ue or are 
wit h dra w n fr o m t he st u d y.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 1  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  1. 3  Sc he d ule of 
Acti vities  
T he f oll o wi n g assess me nts were a d de d:  
•  
K o ne ksa Ne ur oscie nce T o ol kit 
safet y 
•  
K o ne ksa Ne ur oscie nce T o ol kit 
c o nse nt a n d trai ni ng  
•  
De pl o y me nt of K o ne ksa 
Ne ur oscie nce T o ol kit  
•  
Detaile d c hec k o n K o ne ksa 
Ne ur oscie nce T o ol kit usa ge a n d 
re-trai ni n g 
•  
Acti ve K o ne ksa Ne ur oscie nce 
T o ol kit tests o n cell p h o ne at h o me  
•  
Passi ve K o ne ksa Ne ur oscie nce 
T o ol kit data c ollecti o n via 
s mart watc h 
•  
Ret ur n of K o ne ksa Ne ur oscie nce 
T o ol kit  
T o i m ple me nt Di gital 
Healt h Tec h n ol o g y i n t he 
st u d y. 
A d de d t he earl y P D f u ncti o n sl o w ness 
P R O a n d earl y P D m o bilit y assess me nts 
t o V 9 ( M 2 4) a n d V 1 0/ E O T/ E T ( M 3 0) 
a n d a d de d t he F A TI G U E -P R O 
assess me nt t o V 9 ( M 2 4).  
T o g e nerate l o n ger ter m 
data.  
A d de d t he U P SI T at V 4 ( M 1).  
T o better c haracterize t he 
tar get p o p ulati o n. 
F o ot n ote “ b” was re vise d t o i ncl u de te xt 
descri bi n g C S F sa m pli n g at V 2 ( Baseli ne 
Visit) f or partici pa nts ne wl y c o nse nti n g 
t o C S F sa m pli n g i n P D 0 0 5 5. 
T o clarif y pr oce d ure f or 
C S F sa m pli n g at V 2.  
F o ot n ote “l” was re vise d t o all o w 
o pti o nal C S F sa m pli n g f or all 
partici pa nts re gar dless of t heir 
c o nse nti n g  t o C S F sa m pli n g i n P D 0 0 5 3.  
T o all o w C S F sa m pli n g f or 
t h ose partici pa nts 
c o nse nti n g i n P D 0 0 5 5, 
i n de pe n de nt of t heir c o nse nt 
decisi o n i n P D 0 0 5 3, i n or der 
t o i ncrease t he n u m ber of 
C S F sa m ples f or bi o mar ker 
a nal yses, w hic h are 
c o nsi dere d t o pr o vi de 
a d diti o nal mea ni n gf ul 
i nf or mati o n. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 2  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  1. 3  Sc he d ule of 
Acti vities  
 
Ne w f o ot n ote “ n” was a d de d t o clarif y  
t he ti mi n g of K o ne ksa Ne ur oscie nce 
T o ol kit c o nse nt a n d trai ni n g: at a n y ti me 
fr o m V 1 t o V 2, if nee de d as a n 
u nsc he d ule d visit.  
T o i m ple me nt Di gital 
Healt h Tec h n ol o g y i n t he 
st u d y; t o clarif y ti mes of 
pr oce d ures.  
Ne w f o ot n ote “ o” was a d de d  t o “Ret ur n 
of K o ne ksa Ne ur oscie nce T o ol kit” at V 8 
t o clarif y t hat if a st u d y partici pa nt st o ps 
usi n g t he Di gital Healt h Tec h n ol o g y 
pri or t o V 8 t he reas o n nee ds t o be 
d oc u me nte d i n t he C R F.  
T o i m ple me nt Di gital 
Healt h Tec h n ol o g y i n t he 
st u d y; t o clarif y pr oce d ure. 
Ne w f o ot n ote “ p” was a d de d t o t he 
V 1 0/ E O T/ E T c ol u m n t o clarif y t hat t he 
ret ur n of t he K o ne ksa Ne ur oscie nce 
T o ol kit o nl y a p plies at E T.  
T o i m ple me nt Di gital 
Healt h Tec h n ol o g y i n t he 
st u d y; t o clarif y occ urre nce 
of pr oce d ure.  
Ne w f o ot n ote “ q” was a d de d t o clarif y 
t hat t he W O Q-9 will o nl y be c o m plete d 
b y partici pa nts w h o ha ve i nitiate d S T.  
T o clarif y use of t he 
W O Q -9 i n t he st u d y.  
Ne w f o ot n ote “r” was a d de d t o pr o vi de 
i nstr ucti o ns t hat st u d y partici pa nts w h o 
ha ve alrea d y c o m plete d V 4 ( M 1) will 
c o m plete t he U P SI T at t he ne xt visit.  
T o pr o vi de i nstr ucti o ns f or 
t he ti mi n g of t he U P SI T. 
Secti o n  2. 3. 2  Di gital Healt h 
Tec h n ol o g y be nefit/ris k 
assessme nt  
Ne w secti o n was a d de d o n p ote ntial 
be nefits a n d ris ks ass ociate d wit h t he 
Di gital Healt h Tec h n ol o g y use d i n t he 
st u d y ( K o ne ksa Ne ur oscie nce T o ol kit). 
T o pr o vi de be nefit/ris k 
assess me nt f or t he Di gital 
Healt h Tec h n ol o g y.  
Secti o n  4. 2  Scie ntific 
rati o nale f or st u d y desi g n 
A se nte nce was a d de d at t he e n d of t he 
t hir d para gra p h t o i ntr o d uce t he use of 
Di gital Healt h Tec h n ol o g y i n t he st u d y.  
T o ali g n wit h t he a d diti o n of 
t he Di gital Healt h 
Tec h n ol o g y.  
Secti o n  5. 1  I ncl usi o n 
criteria 
I ncl usi o n criteri o n # 1 was re vise d fr o m 
“ P D 0 0 5 5 Baseli ne Visit nee ds t o be 
wit hi n 4 wee ks f oll o wi n g t he E O T Visit 
i n P D 0 0 5 3” t o “ P D 0 0 5 5 Baseli ne Visit 
s h o ul d be n o later t ha n 4 wee ks 
f oll o wi n g t he E O T Visit i n P D 0 0 5 3. A n y 
dela y nee ds t o be j ustifie d b y t he  
I n vesti gat or a n d a p pr o ve d b y t he 
S p o ns or.”  
T o clarif y t he criteri o n f or 
st u d y e ntr y. 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 3  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  5. 2  E xcl usi o n 
criteria 
E xcl usi o n criteri o n # 5 was a d d e d: 
“ St u d y partici pa nts weari n g a n y ki n d of 
i m pla nta ble acti ve de vice, i ncl u di n g 
car diac pace ma kers, p u m ps, a n d 
i m pla nta ble car di o verters, will be 
e xcl u de d fr o m usi n g t he K o ne ksa 
Ne ur oscie nce T o ol kit, b ut ma y 
partici pate i n t he mai n st u d y.”  
T o a d d e xcl usi o n criteri o n 
f or partici pa nts wit h acti ve 
i m pla nta ble de vices. 
Secti o n  5. 2  E xcl usi o n 
criteria 
E xcl usi o n criteri o n # 6 was a d de d: 
“ St u d y partici pa nt d oes n ot a gree t o 
refrai n fr o m d o nati n g bl o o d or bl o o d 
pr o d ucts or ot her b o d y fl ui ds.”  
T o a d d e xcl usi o n criteri o n 
f or partici pa nts w h o d o n ot 
a gree t o refrai n fr o m 
bl o o d/ bl o o d pr o d uct or ot her 
b o d y fl ui ds d o nati o n as t he 
pr o d uct is n ot yet f ull y 
c haracteriz e d. 
Secti o n  6. 5. 2  Pr o hi bite d 
c o nc o mita nt treat me nts 
( me dicati o ns a n d t hera pies) 
B u pr o pi o n was a d de d t o t he list of 
me dicati o ns t hat are n ot all o we d d uri n g 
t he 5 0 da ys bef ore a Da T-S P E C T 
i ma gi n g. 
T o c o m plete t h e list of dr u gs 
t hat ma y affect t he 
Da T -S P E C T sca n.  
Secti o n  6. 9  Di gital Healt h 
Tec h n ol o g y  
Ne w secti o n was a d de d wit h pr o d uct 
descri pti o n a n d use i n t he st u d y of t he 
Di gital Healt h Tec h n ol o g y ( K o ne ksa 
Ne ur oscie nce T o ol kit).  
T o i m ple me nt Di gital 
Healt h Tec h n ol o g y i n t he 
st u d y. 
Secti o n  7. 2  Partici pa nt 
disc o nti n uati o n/ wit h dra wal 
fr o m t he st u d y 
Refere nce t o E O T Visit was u p date d t o 
“ E O T/ Earl y Ter mi nati o n ( E T) Visit.”  
T o clarif y w hic h pr oce d ures 
a p pl y if partici pa nts 
disc o nti n ue or are 
wit h dra w n f r o m t he st u d y. 
Secti o n  7. 4  Disc o nti n uati o n 
of Di gital Healt h 
Tec h n ol o g y  
Ne w secti o n was a d de d t o descri be 
disc o nti n uati o n of Di gital Healt h 
Tec h n ol o g y.  
T o reflect t he a d diti o n of t he 
Di gital Healt h Tec h n ol o g y 
a n d a da pt st u d y pr oce d ures.  
Secti o n  8. 1. 1. 1  Da T -S P E C T  T he esti mate d ra diati o n b ur de n i n 
P D 0 0 5 5 was c ha n ge d fr o m 1 3. 8 9 m S v t o 
“a ma xi m u m of 9. 2 6 m S v” reflecti n g a 
ma xi m u m of 2  sca ns d o ne i n t he st u d y 
wit h a ra diati o n d ose esti mate of 
4. 6 3 m S v per sca n ( per E U la bel). N ote 
t hat t his i ncl u des t he P D 0 0 5 3 M o nt h 1 8 
sca n t hat is use d as P D 0 0 5 5 Baseli ne. 
T he cate g or y ris k le vel was c ha n ge d 
fr o m “III s u bsta ntial” t o “II b 
i nter me diate.” 
T o c orrect t he esti mate d 
ra diati o n b ur de n, w hic h has 
bee n calc u late d base d o n t he 
a p pr o ve d d ose per sca n 
( ma x 4. 6 3 m S v) m ulti plie d 
b y 2 ( ma x 2 sca ns).  
Base d o n t his, t he cate g or y 
ris k le vel i n P D 0 0 5 5 has 
bee n a da pte d.  
Secti o n  8. 1. 1. 2  L E D D  
Literat ure refere nces were u p date d.  
T o u p date refere nces f or 
L E D D calc ulati o n.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 4  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  8. 1. 2  
Patie nt -re p orte d o utc o mes 
T he last se nte nce of t he sec o n d 
para gra p h was re vise d t o clarif y t hat 
P R Os will be c o m plete d pri or t o d osi n g 
wit h S T.  
T o clarif y t he se q ue nce of 
P R O c o m pleti o n a n d d osi n g 
wit h S T . 
Secti o n  8. 1. 2. 4  W O Q -9  
T he last se nte nce was re vise d t o clarif y 
t hat t he W O Q-9 will be assesse d after 
i nitiati o n of S T. 
T o clarif y use of t he 
W O Q -9 i n t he st u d y.  
Secti o n  8. 1. 2. 5  E Q -5 D -5 L  
Literat ure refere nce was u p date d.  
T o u p date refere nce f or 
E Q -5 D -5 L.  
Secti o n  8. 1. 4  K o ne ksa 
Ne ur oscie nce T o ol kit  
Ne w secti o n was a d de d t o descri be 
assess me nts perf or me d wit h t he K o ne ksa 
Ne ur oscie nce T o ol kit.  
T o i m ple me nt Di gita l 
Healt h Tec h n ol o g y i n t he 
st u d y. 
Secti o n  8. 2. 1  P h ysical 
e xa mi nati o n 
Refere nce t o a brief ne ur ol o gical 
e xa mi nati o n perf or me d as part of t he 
p h ysical e xa mi nati o n was re m o ve d 
beca use it di d n ot a p pl y (all visits wit h 
p h ysical e xa mi nati o n als o ha ve a 
ne ur ol o gical e xa mi nati o n pla n ne d).  
T o re m o ve re d u n da nc y.  
Secti o n  8. 3. 7  Di gital Healt h 
Tec h n ol o g y safet y re p orti n g  
Ne w secti o n was a d de d t o descri be t he 
safet y re p orti n g ass ociate d wit h t he 
Di gital Healt h Tec h n ol o g y ( K o ne ksa 
Ne ur oscie nce T o ol kit).  
T o reflect t he a d diti o n of t he 
Di gital Healt h Tec h n ol o g y 
a n d a da pt st u d y pr oce d ures.  
Secti o n  8. 9  Bi o mar kers  
Sec o n d para gra p h was a d de d t o pr o vi de 
j ustificati o n f or t he c ollecti o n of 
a d diti o nal C S F sa m ples f or t he 
assess me nt of A S Y N mar kers.  
T o i ncrease mea ni n gf ul ness 
of bi o mar ker a nal ysis.  
Last se nte nce of t hir d para gra p h was 
re vise d t o clarif y t hat pat h ol o gical 
A S Y N s pecies (e g, A S Y N see ds) ma y 
als o be assesse d (i n a d diti o n t o t otal 
A S Y N le vels).  
T o clarif y pla n ne d 
assess me nt of f urt her A S Y N 
mar kers i n C S F sa m ples.  
Secti o n  8. 1 0  U ni versit y of 
Pe n ns yl va nia S mell 
I de ntificati o n Test 
 
Ne w secti o n was a d de d f or t he U P SI T.  
T o better c haracterize t he 
tar get p o p ulati o n. 
Secti o n  9. 3  Pla n ne d 
efficac y/ o utc o me a nal yses  
 
Te xt was re vise d fr o m “ E x pl orat or y 
a nal yses” t o “ E x pl orat or y efficac y 
a nal yses” i n m ulti ple places. I n a d diti o n, 
te xt was a d de d t o clarif y details of t he 
e xpl orat or y efficac y a nal yses i n m ulti ple 
places.  
A d mi nistrati ve c ha n ge.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 5  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  9. 3. 3. 1  W O Q -9  
T he ti me p oi nts at w hic h W O Q -9 will be 
meas ure d were c ha n ge d fr o m “ 2 6, 3 0, 
a n d 3 6 m o nt hs p ost P D 0 0 5 3 Baseli ne” t o 
“ 2 4, 3 0, a n d 3 6 m o nt hs p ost P D 0 0 5 3 
Baseli ne” t o ali g n wit h t he Sc he d ule of 
Acti vities ( 2 places).  
T o c orrect 1 ti me p oi nt f or 
W O Q -9 meas ure me nts.  
Secti o n  9. 3. 3. 3  
F A TI G U E -P R O  
T he ti me p oi nts at w hic h t he fati g ue 
s u bscale sc ore will be t he 
partici pa nt -le vel e n d p oi nt was c ha n ge d 
fr o m “ 6, 1 2, 1 8, 2 4, 3 0, a n d 3 6 m o nt hs” 
t o “ 6, 1 2, 1 8, 2 4, 3 0, 3 6, 4 2, a n d 
4 8  m o nt hs” t o ali g n wit h c ha n ges ma de 
i n t he Sc he d ule of Acti vities. 
T o ge nerate l o n ger ter m 
data; t o ali g n wit h c ha n ges 
ma de i n t he Sc he d ule of 
Acti vities.  
Secti o n  9. 3. 3. 5. 5  Earl y P D 
F u ncti o n Sl o w ness a n d P D 
M o bilit y P R Os  
 
T he ti me p oi nts at w hic h t he P R O fi nal 
sc ore will be t he partici pa nt-le vel 
e n d p oi nt was c ha n ge d fr o m “ 6, 1 2, 1 8, 
2 4, 3 0, a n d 3 6 m o nt hs” t o “ 6, 1 2, 1 8, 2 4, 
3 0, 3 6, 4 2, a n d 4 8  m o nt hs” t o ali g n wit h 
c ha n ges ma de i n t he Sc he d ule of 
Acti vities.  
T o ge nerate l o n ger ter m 
data; t o ali g n wit h c ha n ges 
ma de i n t he Sc he d ule of 
Acti vities.  
Secti o n  9. 3. 3. 5. 6  C S F 
A S Y N  
Te xt was a d de d t o t he first se nte nce t o 
state t hat t otal A S Y N a n d A S Y N 
oli g o mers/see di n g ca pacit y will als o be 
meas ure d i n C S F sa m ples o btai ne d fr o m 
P D 0 0 5 5 partici pa nts w h o i nitiall y di d n ot 
c o nse nt i n P D 0 0 5 3, ie, at P D 0 0 5 5 
Baseli ne ( M o nt h 1 8 p ost P D 0 0 5 3 
Baseli ne) a n d M o nt hs 1 8 a n d 3 0 p ost 
P D 0 0 5 5 Baseli ne.  
T o i ncrease mea ni n gf ul ness 
of bi o mar ker a nal ysis.  
Te xt was a d de d u n der Descri ptive 
st atistics a n d vis u aliz ati o n t o state t hat 
se parate ta b ulate d a n d gra p hical 
s u m maries will be pr o d uce d f or st u d y 
partici pa nts w h o c o nse nte d o nl y fr o m 
P D 0 0 5 5 Baseli ne.  
Secti o n  9. 3. 3. 6  Di gital 
Healt h Tec h n ol o g y  
Ne w secti o n was a d de d t o descri be 
a nal yses relate d t o t he Di gital Healt h 
Tec h n ol o g y.  
T o pr o vi de i nf or mati o n o n 
a nal ysis of Di gital Healt h 
Tec h n ol o g y data.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 6  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  9. 3. 5  E x pl orat or y 
O bjecti ve I V: At y pical 
Par ki ns o nis m  
S u bsecti o ns were re vise d t o clarif y t he 
pla n ne d a nal yses a n d u p date refere nces 
t o S A Ps f or f urther details.  
S ecti o n 9. 3. 5. 1  Descri ptive st atistics a n d 
vis u aliz ati o n was a d de d.  
F or mer Secti o n 9. 3. 5. 1 P D 0 0 5 3/ P D 0 0 5 5 
se nsitivity a n alyses was re n u m bere d t o 
S ecti o n 9. 3. 5. 2 . 
Secti o n 9. 3. 5. 3 I de ntific ati o n of Aty pic al 
P arki ns o ni a n Dis or der p artici p a nts’ 
B aseli ne c h ar acteristics  was re m o ve d.  
T o clarif y t he pla n ne d 
a nal ysis f or E x pl orat or y 
O bjecti ve I V.  
Secti o n  9. 7  Pla n ne d 
a nal ysis a n d data 
m o nit ori n g  
Te xt was a d de d at t he start of t he secti o n 
t o pr o vi de a refere nce t o t he a nal yses 
relate d t o t he Di gital Healt h Tec h n ol o g y 
descri be d i n Secti o n 9. 3. 3. 6.  
T o pr o vi de i nf or mati o n o n 
a nal ysis of Di gital Healt h 
Tec h n ol o g y data.  
T he se nte nce “ Care will be ta ke n t o 
e ns ure t hat t he bli n de d st u d y tea m 
re mai ns bli n de d f or t he t otal d urati o n of 
t he st u d y” was re vise d t o “ Care will be 
ta ke n t o e ns ure t hat all st u d y partici pa nts 
a n d I n vesti gat ors will re mai n bli n de d t o 
treat me nt/ d ose recei ved i n P D 0 0 5 3 a n d 
P D 0 0 5 5 at least u ntil all partici pa nts 
ha ve c o m plete d t he M o nt h 1 8 
assess me nts i n P D 0 0 5 5.”  
T o clarif y t he d urati o n of 
bli n di n g a n d ali g n wit h 
Secti o ns 4. 1 a n d 6. 3. 1. 1.  
Secti o n  9. 8  Deter mi nati o n 
of sa m ple size  
T he sec o n d para gra p h was c ha n ge d fr o m 
“ Ass u mi n g t hat 6 0 % of P D 0 0 5 3 
partici pa nts ( 2 7 0) c h o ose t o r oll o ver i nt o 
P D 0 0 5 5, a n d 1 5 % of t he P D 0 0 5 3 
partici pa nts dr o p o ut or are l ost t o f oll o w 
u p, t he n 2 0 2 partici pa nts w o ul d be 
e x pecte d t o reac h t he E O T” t o “ All st u d y 
partici pa nts (a p pr o xi matel y 4 9 0) ca n r oll 
o ver fr o m P D 0 0 5 3. Ass u mi n g t hat 1 5 % 
of P D 0 0 5 3 partici pa nts dr o p o ut or are 
l ost t o f oll o w u p o ver 1 8 m o nt hs a n d 
9 0 % of t he re mai ni n g 4 1 6 partici pa nts 
w h o c o m plete P D 0 0 5 3 c h o ose t o r oll 
o ver i nt o P D 0 0 5 5, t he n 3 7 4 partici pa nts 
w o ul d be e x pecte d t o e nter t he e xte nsi o n 
st u d y. Ass u mi n g t hat 1 5 % of P D 0 0 5 5 
partici pa nts dr o p o ut or are l ost t o f oll o w 
u p o ver 1 8 m o nt hs, 3 1 8 partici pa nts 
w o ul d be e x pecte d t o reac h P D 0 0 5 5 
E O T.”  
T o u p date t he n u m ber of 
partici pa nts e x pecte d t o r oll 
o ver fr o m P D 0 0 5 3 base d o n 
o bser vati o ns i n P D 0 0 5 5.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 7  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
B rief r ati o n ale 
Secti o n  1 0. 7  A p pe n di x 7: 
Di gital Healt h Tec h n ol o g y 
A Es, S A Es, A D Es, S A D Es, 
a n d de vice deficie ncies: 
Defi niti o n 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  
A p pe n di x 7 was a d de d t o pr o vi de 
defi niti o ns a n d pr oce d ures f or safet y 
re p orti n g ass ociate d wit h t he K o ne ksa 
Ne ur oscie nce T o ol kit.  
T o reflect t he a d diti o n of t he 
Di gital Healt h Tec h n ol o g y 
a n d a da pt st u d y pr oce d ures.  
Secti o n  1 0. 1 1  A p pe n di x 1 1: 
Pr ot oc ol a me n d me nt hist or y  
T he Pr ot oc ol A me n d me nt S u m mar y of 
C ha n ges Ta ble f or t he pre vi o us 
a me n d me nt was m o ve d t o A p pe n di x  1 1.  
Mi n or a d mi nistrati ve 
c ha n ge. 
Secti o n  1 1  R E F E R E N C E S  
T he f oll o wi n g refere nces were a d de d:  
•  
A p ple i P h o ne User G ui de  
•  
Ce ntre P oi nt Data H u b User G ui de  
•  
Ce ntre P oi nt I nsi g ht Watc h User 
G ui de  
•  
De vli n a n d Br o o ks, 2 0 1 7  
•  
D ot y, 2 0 1 2  
•  
D ot y et al, 1 9 8 4  
•  
Sc ha de et al, 2 0 2 0  
•  
Si der o wf et al, 2 0 2 3  
•  
T o mli ns o n et al, 2 0 1 0  
T o u p date refere nces cite d 
i n t he pr ot oc ol. 
T hr o u g h o ut  
C orrecti o n of a fe w t y p o gra p hical a n d 
f or matti n g err ors. 
Mi n or, t heref ore ha ve n ot 
bee n s u m marize d.  
1 0. 1 1. 2  
A m e n d m e nt 2 ( 3 0 J u n 2 0 2 3)  
O ver all R ati o n ale f or t he A me n d me nt  
P D 0 0 5 5 Pr ot oc ol A me n d me nt 2 was e nacte d t o i nc or p orat e a d diti o nal la b orat or y tests at Da y  6 0, 
Da y  1 2 0, a n d D a y  1 5 0 i n or der t o all o w f or cl ose m o nit ori n g of li ver f u ncti o n test para meters.  
T his a me n d me nt is c o nsi dere d t o be s u bsta ntial base d o n t he criteri a set f ort h i n Article 2( 1 3) of 
Re g ulati o n N o 5 3 6/ 2 0 1 4 of t he E ur o pea n Parlia me nt a n d t he C o u ncil of t he E ur o pea n U ni o n.  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  1. 3 Sc he d ule of 
Acti vities  
I n-cli nic visits at Da y  6 0 ( M o nt h 2), Da y  1 2 0 
( M o nt h 4), a n d Da y 1 5 0 ( M o nt h 5) 
( Visits 4a, 5a, a n d 5 b, res pecti vel y) were 
a d de d. 
T o i ncrease t he m o nit ori n g 
of li ver f u ncti o n test 
para meters a n d ali g n 
m o nit ori n g at treat me nt 
start wit h t he fee der st u d y 
P D 0 0 5 3.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 8  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  2. 3 Be nefit/ris k 
assess me nt 
Te xt was u p date d t o a d d he pat ot o xicit y t o t he 
list of p ote ntial ris ks, t o a d d t hat re nal 
la b orat or y a b n or malities are ke pt u n der cl ose 
safet y m o nit ori n g, a n d t o clarif y t he 
meas ures t o miti gate t he p ote ntial ris k of  
he pat ot o xicit y.  
T o ali g n wit h t he war ni n gs 
a n d preca uti o ns pr o vi de d 
i n t he u p date d 
Secti o n  6. 3. 4 of t he 
I n vesti gat or’s Br oc h ure. 
S ecti o n 1 0. 1 1 
A p pe n di x  1 1: Pr ot oc ol 
a me n d me nt hist or y 
T he Pr ot oc ol A me n d me nt S u m mar y of 
C ha n ges Ta ble f or t he pre vi o us a me n d m e nt 
has bee n a d de d.  
Mi n or a d mi nistrati ve 
c ha n ge. 
T hr o u g h o ut  
Mi n or e dit orial a n d d oc u me nt f or matti n g 
re visi o ns. 
Mi n or, t heref ore ha ve n ot 
bee n s u m marize d.  
1 0. 1 1. 3  
A m e n d m e nt 1 ( 0 7 N o v 2 0 2 2 ) 
O ver all R ati o n ale f or t he A me n d me nt  
P D 0 0 5 5 Pr ot oc ol A me n d me nt 1 was c o m plete d t o u p date t he pr ot oc ol bas e d o n Re q uests f or 
I nf or mati o n recei ve d d uri n g t he i nitial Cli nical Trial A p plicati o n. 
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Gl o bal  
T he pr ot oc ol was u p date d t o re m o ve t he ter m 
“i n di vi d ual” i n t he c o nte xt of s witc hi n g t o 
t he best d ose u p o n P hase 3 d ose selecti o n, t o 
clarif y t hat all partici pa nts will be s witc he d 
t o t he best d ose. 
T o clarif y d oses 
a d mi nistere d i n P D 0 0 5 5  
Secti o n  2. 3. 1 
C or o na vir us Disease -
2 0 1 9 be nefit/ris k 
assess me nt 
Secti o n 2. 3. 1 was a d de d t o pr o vi de a 
C O VI D -1 9 be nefit/ris k assess me nt.  
T o a d d a be nefit/ris k 
assess me nt f or C O VI D -1 9  
Secti o n  4. 1 O verall 
desi g n  
T he f oll o wi n g se nte nce was re m o ve d as n o 
safet y c o ncer n was i de ntifie d i n P D 0 0 5 3 
pri or t o t he first st u d y partici pa nt e nteri n g 
P D 0 0 5 5: “ H o we ver, i n case of safet y 
c o ncer ns wit h res pect t o t he 3 6 0 m g/ da y d ose 
at t he ti me t he first partici pa nt is pla n ne d t o 
tra nsiti o n i nt o P D 0 0 5 5, t he d ose t o s witc h 
b ot h place b o a n d U C B 0 5 9 9 3 6 0 m g/ da y 
partici pa nts t o ma y be re vise d t o be 
U C B 0 5 9 9 1 8 0 m g/ da y i nstea d.”  
T o re m o ve a preca uti o n 
t hat n o l o n ger a p plies 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 2 9  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  4. 3 J ustificati o n 
f or d ose 
T he f oll o wi n g se nte nce was re m o ve d as n o 
safet y c o ncer n was i de ntifie d i n P D 0 0 5 3 
pri or t o t he first st u d y partici pa nt e nteri n g 
P D 0 0 5 5: “I n case of safet y c o ncer ns wit h 
res pect t o t he U C B 0 5 9 9 3 6 0 m g/ da y d ose at 
t he ti me t he first partici pa nt is pla n ne d t o 
tra nsiti o n i nt o P D 0 0 5 5, t he d ose t o s witc h 
place b o partici pa nts t o ma y be selecte d t o be 
U C B 0 5 9 9 1 8 0 m g/ da y  i nstea d.” 
T o re m o ve a preca uti o n 
t hat n o l o n ger a p plies 
Secti o n  8. 3. 1 Ti me 
peri o d a n d fre q ue nc y f or 
c ollecti n g A E a n d S A E 
i nf or mati o n 
Te xt was u p date d t o clarif y t hat t he 
I n vesti gat or will s u b mit a n y u p date d S A E 
data t o t he S p o ns or wit h o ut u n d ue del a y 
b u t n ot l ater t h a n wit hi n 2 4  h o urs of it 
bei n g a vaila ble.  
T o ali g n pr ot oc ol w or di n g 
wit h Re g ulati o n ( E U) N o. 
5 3 6/ 2 0 1 4 Article 4 1, N o. 2  
Secti o n  8. 3. 3 F oll o w -u p 
of A Es a n d S A Es  
Te xt was re vise d t o clarif y t hat f oll o w -u p 
pr oce d ures a p pl y t o “all A Es, S A Es, a n d 
A E SIs” (i nstea d of “all S A Es, a n d n o nseri o us 
A E SIs”).  
T o re m o ve a n 
i nc o nsiste nc y wit h 
A p pe n di x  1 0. 3  
Secti o n  8. 3. 4 Re g ulat or y 
re p orti n g re q uire me nts 
f or S A Es 
T he f oll o wi n g se nte nce was a d de d: “ F urt her 
t o t he re p orti n g of a n S A E fr o m t he 
I n vesti gat or t o the S p o ns or, a n e x pecte d ness 
assess me nt will be ma de per t he I B, as 
refere nce safet y i nf or mati o n f or t his st u d y, 
a n d rele va nt S p o ns or’s S O Ps a n d a p pr o priate 
re p orti n g of s us pecte d u ne x pecte d seri o us 
a d verse reacti o ns ( S U S A Rs) will be carrie d 
o ut t o healt h a ut h orities as per I C H a n d l ocal 
re g ulat or y re q uire me nts.”  
I n a d diti o n, t he f oll o wi n g se nte nce was 
m o ve d u p i n t he secti o n t o a p pear bel o w t he 
ne w se nte nce a b o ve: “I n vesti gat or safet y 
re p orts m ust be pre pare d f or S U S A Rs 
acc or di n g t o l ocal re g ulat or y re q uire me 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 necessar y.”  
T o f urt her clarif y re p orti n g 
of S U S A Rs  
Secti o n  9. 8 
Deter mi nati o n of sa m ple 
size 
T he f oll o wi n g te xt was re m o ve d: “ H o we ver, 
esti mates of p o wer will be pr o vi de d. Details 
of t hese will be descri be d i n a n 
acc o m pa n yi n g w hite pa per e ntitle d “ Sa m ple 
Size D oc u me ntati o n F or m” as per s o p -af-
1 0 4 0 4 0.”  
T o re m o ve te xt o n 
esti mates of p o wer w hic h 
d oes n ot a p pl y f or P D 0 0 5 5  
Secti o n  1 0. 1. 1 
Re g ulat or y a n d et hical 
c o nsi derati o ns 
Te xt was u p date d wit h t he c o m pete nt 
a ut h orit y w here ver a p plica ble.  
T o clarif y res p o ns i bilities 
i n differe nt re gi o ns 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 3 0  of 1 3 3  
Secti o n # a n d n a me  
Descri pti o n of c h a n ge  
Brief r ati o n ale  
Secti o n  1 0. 1. 3 I nf or me d 
c o nse nt pr ocess  
T he f oll o wi n g se nte nce was re m o ve d at t he 
e n d of t he sec o n d para gra p h: “I n Fra nce, 
partici pa nts will be gi ve n at least 3 da ys of 
reflecti o n ti me bef ore si g ni n g t he I C F.” 
T o re m o ve a c o u ntr y-
s pecific re q uire me nt 
(relate d t o a Part II R FI 
re q uest recei ve d d uri n g t he 
i nitial Cli nical Trial 
A p plicati o n)  
Secti o n  1 0. 1. 4 Data 
pr otecti o n  
Te xt was u p date d.  
T o f urt her clarif y pers o nal 
data pr otecti o n  
Secti o n  1 0. 1. 6 
Disse mi nati o n of 
cli nical st u d y data 
T he f oll o wi n g se nte nce was a d de d: “ A 
s u m mar y of t he res ults is als o pla n ne d t o be 
p oste d t o t he E U data base wit hi n 1 year of 
st u d y c o m pleti o n, i n acc or da nce wit h 
i nter nati o nal sta n dar ds a n d irres pecti ve of t he 
o utc o me of t he cli nical st u d y.”  
T o f urt her clarif y res ults 
p osti n g f oll o wi n g st u d y 
c o m pleti o n 
Secti o n  1 0. 4  
A p pe n di x  4: 
C o ntrace pti ve g ui da nce 
a n d c ollecti o n of 
pre g na nc y i nf or mati o n  
T he f oll o wi n g te xt was a d de d: “ I n case of 
sterilizati o n, it s h o ul d ha ve ta ke n place 
bef ore t he start of t he Scree ni n g Peri o d a n d 
t he me dical rec or ds of t he partici pa nt s h o ul d 
i ncl u de t he met h o d of sterilizati o n, al o n g 
wit h t he date of sterilizati o n, as pr o of of t he 
c o ntrace pti o n.” 
T o pr o vi de f urt her 
clarificati o n o n sterilizati o n 
f or W O C B P relate d t o a 
Part II R FI re q uest recei ve d 
d uri n g t he i nitial Cli nical 
Trial A p plicati o n  
Secti o n  1 0. 1 1 Pr ot oc ol 
a me n d me nt hist or y 
A n ote was a d de d t hat t he Pr ot oc ol 
A me n d me nt S u m mar y of C ha n ges Ta ble f or 
t he c urre nt a me n d me nt is l ocate d directl y 
bef ore t he Ta ble of C o nte nts.  
Mi n or a d mi nistrati ve 
c ha n ge 
 
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 3 1  of 1 3 3  
1 1  
R E F E R E N C E S  
A nt o ni ni A, Marti nez -M arti n P, C ha u d h uri R K, et al. Weari n g -off s cales i n Par ki ns o n's disease: 
criti q ue a n d rec o m me n dati o ns. M o v Dis or d. 2 0 1 1; 2 6( 1 2): 2 1 6 9 -7 5.  
Bl oe m B R, Mar ks WJ Jr, Sil va de Li ma A L, et al. T he Pers o nalize d Par ki ns o n Pr oject: 
e xa mi ni n g disease pr o gressi o n t hr o u g h br oa d bi o mar kers i n earl y Par ki ns o n's disease. B M C 
Ne ur ol. 2 0 1 9; 1 9( 1): 1 6 0.  
Ce ntre P oi nt Data H u b User G ui de. Pe nsac ol a, F L: Acti Gra p h, L L C; 2 0 2 3.  
Ce ntre P oi nt I nsi g ht Wat c h User G ui de. Pe ns ac ola, F L: Acti Gra p h, L L C; 2 0 2 3.  
De vli n NJ, Br o o ks R. E Q -5 D a n d t he E ur o Q ol Gr o u p: Past, Prese nt a n d F ut ure. A p pl Healt h 
Ec o n Healt h P olic y. 2 0 1 7; 1 5( 2): 1 2 7 -3 7.  
D ot y R L. Olfacti o n i n Par ki ns o n’s disease a n d rel ate d dis or ders. Ne ur o bi ol Dis. 
2 0 1 2; 4 6( 3): 5 2 7 -5 2.  
D ot y R L, S ha ma n P, Da n n M. De vel o p me nt of t he U ni versit y of Pe n ns yl va nia S mell 
I d e ntificati o n Test: a sta n dar dize d micr oe nca ps ulate d test of olfact or y f u ncti o n. P h ysi ol Be ha v. 
1 9 8 4; 3 2( 3): 4 8 9 -5 0 2.  
F o o d a n d Dr u g A d mi nistrati o n. Patie nt -F oc us e d Dr u g De v el o p me nt P u blic W or ks h o p 
G ui da nce  2 Dis c ussi o n D oc u me nt - A p pe n dices. Met h o ds t o I d e ntif y W hat is I m p orta nt t o 
Patie nts & Select, De vel o p or M o dif y Fit -f or-P ur p ose Cli nical O utc o mes Assess me nts. 
W or ks h o p Date: 1 5 -1 6 O ct 2 0 1 8. A vaila ble at: htt ps:// w w w.f da. g o v/ me dia/ 1 1 6 2 5 9/ d o w nl oa d 
(accesse d 0 6 J u n 2 0 2 4).  
G oetz C G, Tille y B C, S haft ma n S R, et al. M o ve me nt Dis or der S ociet y -s p o ns ore d re visi o n of t he 
U nifie d Par ki ns o n's Dise ase Rati n g Scale ( M D S-U P D R S): scale prese nt ati o n a n d cli ni metric 
testi n g res ults. M o v Dis or d. 2 0 0 8 N o v 1 5; 2 3( 1 5): 2 1 2 9-7 0.  
Gra y R, Patel S, I ves N, et al. L o n g -ter m effecti ve ness of a dj u va nt treat me nt wit h catec h ol-O -
met h yltra nsferase or m o n oa mi ne o xi dase b i n hi bit ors c o m pa re d wit h d o pa mi ne a g o nists a m o n g 
patie nts wit h Par ki ns o n disease u nc o ntr olle d b y le v o d o pa t hera p y - T he P D M E D ra n d o mize d 
cli nical trial. J A M A Ne ur ol. 2 0 2 2; 7 9( 2): 1 3 1 -4 0.  
H oe h n M M, Ya hr M D. Par ki ns o nis m: o nset, pr o gressi o n a n d m ortalit y. Ne ur ol o g y. 1 9 6 7 
Ma y ; 1 7( 5): 4 2 7-4 2.  
I hle-Ha ns e n H, Vi ge n T, Ber ge T, et al. M o ntreal C o g niti ve Assess me nt i n a 6 3 - t o 6 5-year -ol d 
N or we gia n c o h ort fr o m t he ge neral p o p ulati o n: data fr o m t he A kers h us Car diac E xa mi nati o n 
1 9 5 0 st u d y. De me nt Geri atr C o g n Dis or d E xtra. 2 0 1 7; 7( 3): 3 1 8 – 2 7.  
I k e da K, E bi n a J, Ka w a b e K, et al. D o pa mi ne tra ns p orter i ma gi n g i n Par ki ns o n disease: 
pr o gressi ve c h a n ges a n d t hera pe utic m o dificati o n after a nti -par ki ns o nia n m e dicati o ns. I nter n 
Me d. 2 0 1 9; 5 8( 1 2): 1 6 6 5 -7 2.  
i P h o ne User G ui de. A p pl e I nc. https://s u p p ort.a p ple.c o m/ g ui de/i p h o ne/ welc o me/i os. Accesse d 
1 8 J ul 2 0 2 3.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 3 2  of 1 3 3  
Marti nez -M arti n P, Sc hra g A, Wei ntra u b D, et al. Pil ot st u d y of t he I nter nati o nal Par ki ns o n a n d 
M o ve me nt Dis or der S oci et y -s p o ns ore d N o n-M ot or Rati n g Scale ( M D S -N M S). M o v Dis or d Cli n 
Pra ct. 2 0 1 9; 6( 3): 2 2 7 -3 4.  
Nasre d di ne Z S, P hilli ps N A, Bé diria n V, et al. T he M o ntreal C o g niti ve Assess me nt, M o C A: a 
brief scree ni n g t o ol f or mil d c o g niti ve i m pair me nt. J A m Geriatr S oc. 2 0 0 5; 5 3( 4): 6 9 5 -9.  
Pa h wa R, L y o ns K E. Le v o d o pa -rel ate d weari n g-off i n Par ki ns o n's disease: i de ntificati o n a n d 
ma na ge me nt. C urr M e d Res O pi n. 2 0 0 9; 2 5( 4): 8 4 1 -9.  
P oe we W. T h e nat ural hist or y of Par ki ns o n’s disease. J Ne ur ol. 2 0 0 6; 2 5 3( S u p pl 7): VII/ 2 -VII/ 6.  
P os ner K, Br o w n G K, St a nle y B, et al. T he C ol u m bia -S uici de Se verit y Rati n g Sca le: i nitial 
vali dit y a n d i nter nal c o nsiste nc y fi n di n gs fr o m t hree m ultisite st u dies wit h a d olesce nts a n d 
a d ults. A m J Ps yc hiatr y. 2 0 1 1 Dec; 1 6 8( 1 2): 1 2 6 6 -7 7.  
Sa m ps o n H A, M u ñ oz -F url o n g A, Ca m p bell R L, et al. Sec o n d s y m p osi u m o n t he defi niti o n a n d 
ma na ge me nt o f a na p h yla xis: s u m mar y re p ort--Sec o n d Nati o nal I nstit ute of Aller g y a n d 
I nfecti o us Dise ase/ F o o d Aller g y a n d A na p h yla xis Net w or k s y m p osi u m. J Aller g y Cli n I m m u n ol. 
2 0 0 6 Fe b; 1 1 7( 2): 3 9 1 -7.  
Sc ha de S, M olle n ha uer B, Tre n k wal d er C. Le v o d o pa e q ui vale nt d ose c o n ve rsi o n fact ors: a n 
u p date d pr o p osal i ncl u di n g o pica p o ne a n d s afi na mi de. M o v Dis or d Cli n Pract. 
2 0 2 0; 7( 3): 3 4 3 -4 5.  
Si der o wf A, C o nc ha -Mara m bi o L, Laf o nta nt D E, et al. Assess me nt of heter o ge neit y a m o n g 
partici pa nts i n t he Par ki ns o n’s Pr o gressi o n Mar kers I nitia ti ve c o h ort usi n g α-s y n uclei n see d 
a m plificati o n: a cr oss -s ecti o nal st u d y. La ncet Ne ur ol. 2 0 2 3; 2 2( 5): 4 0 7 -1 7.  
Stac y M, Ha user R, O ert el W, et al. E n d -of -d ose weari n g off i n Par ki ns o n disease: a 9 -q u esti o n 
s ur ve y assess me nt. Cli n Ne ur o p har mac ol. 2 0 0 6; 2 9( 6): 3 1 2 -2 1.  
Stac y M A, M ur p h y J M, Greele y D R, et al. T he s e nsiti vit y a n d s pecificit y of t he 9 -ite m Weari n g-
off Q uesti o n nair e. Par ki ns o nis m Relat Dis or d. 2 0 0 8; 1 4( 3): 2 0 5 -1 2.  
T o mli ns o n C L, St o we R, Patel S, et al. S yste matic re vie w of l e v o d o pa d ose e q ui vale nc y 
re p orti n g i n Par ki ns o n's disease. M o v Dis or d. 2 0 1 0; 2 5( 1 5): 2 6 4 9-5 3.  
Tre u dler R, K o z o vs ka Y, Si m o n J C. Se vere i m me diate t y pe h y perse nsiti vit y reacti o ns i n 
1 0 5  Ger ma n a d ults: w he n t o dia g n ose a na p h yla xis. J I n v esti g Aller g ol Cli n I m m u n ol. 
2 0 0 8; 1 8( 1): 5 2 -8.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

U C B  
 
0 9 Oct 2 0 2 4  
Cli nical St u d y Pr ot oc ol A me n d me nt 4  
Mi nzas ol mi n ( U C B 0 5 9 9)  
P D 0 0 5 5  
 
 
 
C o nfi de ntial  
Pa ge 1 3 3  of 1 3 3  
S P O N S O R  D E C L A R A TI O N  
I c o nfir m t hat I h a ve caref ull y rea d a n d u n d ersta n d t his pr ot oc ol a n d a gree t o c o n d uct t his 
cli nical st u d y as o utli ne d i n t his pr ot oc ol, acc or di n g t o Cli nical Trial Re g ulati o n E U 5 3 6/ 2 0 1 4, 
a n d acc or di n g t o c urre nt G C P.  
P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of 

P U B LI C C O P Y 
T hi s d o c u m e nt c a n n ot b e u s e d t o s u p p ort a n y m ar k eti n g a ut h ori z ati o n a p pli c ati o n 
a n d a n y e xt e n si o n s or v ari ati o n s t h er e of