Clinical trial NCT03670953
Conditions: Parkinson's Disease (Disorder)
Keywords: Idiopathic Parkinson's Disease Lewy Body Parkinson's Disease Paralysis Agitans Primary Parkinsonism
Sponsor: Impax Laboratories, LLC
Start date: 2018-11-06; Completion date: 2021-06-15
Enrollment: 630 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To evaluate the safety and efficacy of IPX203 (carbidopa and levodopa) extended-release capsules (IPX203 ER CD-LD) in comparison to immediate release (IR) CD-LD in the treatment of CD-LD-experienced participants with Parkinson's disease (PD) who have motor fluctuations.

Detailed description:
This was a multicenter, randomized, double-blind, double-dummy, active-controlled, parallel-group study. The study consisted of a 3-week, open-label IR CD-LD dose adjustment period; a 4-week, open-label period for conversion to IPX203; followed by a 13-week double-blind treatment period with participants randomized in a 1:1 ratio, stratified by center, to receive either IPX203 (with matching IR CD-LD placebo) or IR CD-LD (with matching IPX203 placebo).

Arms: arm 1: Participants started on the same dose as the pre-study dosing regimen of IR CD-LD and then received dose adjusted IR CD-LD tablets daily orally, for a period of 3 weeks. If the participant was taking controlled release carbidopa-levodopa (CR CD-LD), the CR CD-LD was discontinued and substituted with a 1:1 milligram-equivalent dose of IR CD-LD. arm 2: Participants received extended release (ER) CD-LD (IPX203) capsules orally, every 6 - 12 hours for a period of 4 weeks at a dose based on their most frequent stable dose of IR CD-LD in dose adjustment period. Participant with most frequent stable dose of 25-100 milligrams (mg) IR CD-LD received 70 - 280 mg IPX203 thrice daily (TID); \>25-100 - 37.5-150 mg IR CD-LD received 105-420 mg IPX203 TID; \>37.5-150 - 50-200 mg IR CD-LD received 140-560 mg IPX203 TID; \>50 - 200 mg IR CD-LD received 175-700 mg IPX203 TID. Participants who received a daily total dose of less than 125-500 mg IR CD-LD in dose adjustment received IPX203 every 12 hours. After initial dose conversion from IR CD-LD to IPX203 as per above mentioned dose conversion schedule, the dose of IPX203 could be further adjusted during the 4 week dose conversion period. arm 3: Participants received IPX203 capsules orally, every 6 - 12 hours for 13 weeks at a stable dose established at the end of dose conversion period along with placebo matched to IR CD-LD. arm 4: Participants received IR CD-LD tablets daily orally, for 13 weeks at a stable dose established at the end of dose adjustment period along with placebo matched to IPX203.
Interventions: intervention 1: IR CD-LD intervention 2: IPX203 ER CD-LD intervention 3: Placebo Matching IPX203 intervention 4: Placebo Matching IR CD-LD
Intervention descriptions: intervention 1: Active comparator - IR CD-LD intervention 2: Investigational formulation - ER CD-LD intervention 3: Double dummy placebo capsules intervention 4: Double dummy placebo tablets

Protocol documents:
Prot_000.pdf: 
Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1  of 1 5 9  
 
I P X 2 0 3 ( C A R BI D O P A-L E V O D O P A)  
E X T E N D E D- R E L E A S E C A P S U L E S  
I P X 2 0 3- B 1 6- 0 2 
A R A N D O MI Z E D C O N T R O L L E D S T U D Y T O 
C O M P A R E T H E S A F E T Y A N D E F FI C A C Y O F I P X 2 0 3 
WI T H I M M E DI A T E-R E L E A S E C A R BI D O P A -
L E V O D O P A I N P A R KI N S O N’ S DI S E A S E P A TI E N T S 
WI T H M O T O R F L U C T U A TI O N S  
S P O N S O R  
I m pa x La b orat ories, L L C  
4 0 0 Cr ossi n g B o ul e var d, T hir d Fl o or 
Bri d ge w ater, NJ 0 8 8 0 7- 2 8 6 3 
Ori gi nal Pr ot oc ol, Ma y 1 8, 2 0 1 7 
A me n d me nt 1, A u g ust 3 0, 2 0 1 7 
A me n d me nt 2, Oct o ber 2 3, 2 0 1 7 
A me n d me nt 3, Dece m ber 0 7, 2 0 1 7 
A me n d me nt 4, Se pte m ber 2 8, 2 0 1 8 
C O N FI D E N TI A LI T Y S T A T E M E N T  
All i nf or mati o n pr o vi de d is t he pr o pert y of I m p a x La b orat ories, L L C  a n d ma y n ot be di v ul ge d, 
p u blis he d or ot her wise discl ose d wit h o ut writte n c o nse nt of I m pa x.  All i nf or mati o n pr o vi de d t o 
t he I n vesti gat or b y t he S p o ns or, i ncl u di n g cli nical o bser vati o ns at t he i n vesti gati ve site, s hall b e 
hel d strictl y c o nfi de ntial a n d c o nfi ne d t o t he cli nical pers o n nel i n v ol ve d i n c o n d ucti n g t he st u d y, 
u n der  t he  s u p er v isi o n  of  t he  I n vesti gat or.    T his  i ncl u des  b ut  is  n ot  li mite d  t o  precli nical  d ata, 
pr ot oc ols,  case  re p ort  f or ms,  a n d  ver b al  or  writte n  c o m m u nicati o ns.    T his  i nf or mati o n  ma y  be 
relate d  i n  c o nfi d e nce  t o  t he  I nstit uti o nal  Re vie w  B oar d  or  ot her  c o m mittees  f u ncti o ni n g  i n  a 
si milar ca pacit y.  All re p orts, s u bject sa m ples, data p u blis he d or s u b mitte d t o t hir d parties will be 
i de ntifie d b y a c o de d n u m ber a n d i nitials o nl y i n or der t o mai ntai n s u bject c o nfi de ntialit y. 




Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 3  of 1 5 9  
 
I N V E S TI G A T O R’ S A G R E EM E N T  
 
Pr ot oc ol N o.:   
I P X 2 0 3-B 1 6 - 0 2 
Pr ot oc ol Title:   
A Ra n d o mize d C o ntr olle d St u d y t o C o m pare t he Safet y a n d Efficac y of 
I P X 2 0 3 wit h  I m me diat e-Release Car bi d o p a - Le v o d o pa i n Par ki ns o n’s Disease 
Patie nts wit h M ot or Fl uct uati o ns 
 
 
I h a ve r ea d t his pr ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d herei n, c o m pl yi n g wit h t he 
o bli gati o ns a n d r e q uire m e nts of cli nical i n vesti gat ors a n d all ot her re q uire me nts of I nter nati o nal 
C o nfere nce o n Har m o nizati o n (I C H), G o o d Cli nical Practice ( G C P), a n d t h e a p pr o pri ate 
re g ulat or y a ut h orit y. 
I will pr o vi de c o pies of t he pr ot oc ol a n d all perti ne nt i nf or mati o n t o all i n di vi d uals res p o nsi ble t o 
me w h o assist i n t he c o n d uct of t his cli nical st u d y.  I will disc uss t his material wit h t he m t o 
e ns ure t hat t he y are f ull y i nf or me d re gar di n g t he st u d y me dicati o n, t he c o n d uct of t he st u d y, a n d 
t he o bli gati o ns of c o nfi de ntialit y. 
 
 
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Pri nci pal I n v esti gat or’s si g nat ur e  
Date  
 
 
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Pri nci pal I n v esti gat or’s pri nte d na me 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 4  of 1 5 9  
 
S T U D Y C O N T A C T I N F O R M A TI O N 
C ha n ges i n I m p a x st u d y pers o n nel liste d o n t his pa ge d o n ot re q uire a pr ot oc ol a me n d me nt. 
R ole  
N a me a n d C o nt act I nf or m ati o n 
S p o ns or 
I m pa x La b orat ories, L L C  
4 0 0 Cr ossi n g B o ul e var d, T hir d Fl o or 
Bri d ge w ater, NJ 0 8 8 0 7- 2 8 6 3 
( 7 3 2) 5 9 5- 4 6 0 0 
Me dical M o nit or 
Statisticia n  
Cli nical P har mac ol o g y  
Cli nical Researc h Ass o ciates  
Seri o us A d verse E v e nt 
Re p orti n g 
F A X:  ( 8 6 6) 9 5 4- 2 0 6 4 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 5  of 1 5 9  
 
1.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:   I m pa x La b orat ories, L L C  (I m pa x) 
N a me of I n vesti g ati o n al Pr o d uct:   I P X 2 0 3 (car bi d o pa-le v o d o pa) E xte n de d-Release Ca ps ules  
N a me of Acti ve I n gre die nt s:  car bi d o pa ( C D), le v o d o pa ( L D) 
P r ot oc ol Title :  A Ra n d o mize d C o ntr olle d St u d y t o C o m pare t he Safet y a n d Efficac y of I P X 2 0 3 wit h 
I m me diate-Release Car bi d o pa - Le v o d o pa i n Par ki ns o n’s Disease Patie nts wit h M ot or Fl uct uati o ns 
P r ot oc ol N o.:   I P X 2 0 3-B 1 6 - 0 2 
St u d y ce nter(s):   M ultice nter  
P h ase of De vel o p me nt:   P hase 3  
O bjecti ves:  T o e val uate t he safet y a n d efficac y of I P X 2 0 3 i n c o m paris o n t o I R C D - L D i n t he 
treat me nt of C D-L D -e x perie nce d s u bjects wit h Par ki ns o n’s disease ( P D)  w h o ha ve m ot or fl uct uati o ns.  
Met h o d ol o g y:   T his is a m ultice nter, ra n d o mize d, d o u ble- bli n d, d o u ble- d u m m y, acti ve -c o ntr olle d, 
parallel - gr o u p st u d y.  T he st u d y will c o nsist of a 3 - wee k, o pe n-la bel I R C D -L D d ose a dj ust me nt 
peri o d; a 4- wee k , o pe n-la bel peri o d f or c o n versi o n  t o I P X 2 0 3; f oll o we d b y a 1 3- wee k d o u ble- bli n d 
treat me nt peri o d wit h s u bj ects ra n d o mize d i n a 1: 1  rati o, stratifie d b y ce nter, t o recei ve eit her I P X 2 0 3 
(wit h matc hi n g I R C D -L D place b o) or I R  C D -L D  (wit h matc hi n g I P X 2 0 3 place b o). 
S u bj ects will  c o nti n ue t o ta ke per mitte d n o n- C D -L D - b ase d P D me dicati o ns t hr o u g h o ut t he st u d y if 
d oc u me nte d i n t heir prest u d y re gi me n a n d if d osi n g re gi me ns ha ve bee n sta ble f or at least 4  wee ks 
pri or t o Visit 1 .  A “sta ble d osi n g re gi me n” mea ns n o c ha n ge i n d ose or i n d osi n g fre q ue nc y . 
•  
Wit hi n 4 wee ks f oll o wi n g t he Scree ni n g  visit , eli gi ble s u bj ects will c o m plete t heir P D Diaries  
o n eac h o f t he 3 c o nsec uti ve da ys i m me diatel y pri or t o Visit  1. 
•  
F oll o wi n g Visit 1 , q ualifie d s u bjects will e nter a 3-wee k , o pe n-la bel I R C D -L D treat me nt 
peri o d all o wi n g f or d ose a dj ust me nt.  T he d osi n g re gi me n of I R C D -L D  m a y be a dj uste d 
d uri n g t he d ose a dj ust me nt peri o d  t o mi ni mize “ Off” ti me wit h o ut ca usi n g tr o u bles o me 
d ys ki nesia .  T he d oses a n d re gi me ns of t he s u bj ect’s ot her n o n -C D -L D P D me dicati o ns 
( d o pa mi ne a g o nists, M A O- B i n hi bit ors, a ma nta di ne, a ntic h oli ner gics) s h o ul d re mai n sta ble 
t hr o u g h o ut t his st u d y.  A n y adj ust me nts t o t he I R C D -L D d osi n g re gi me n will be d o ne i n 
c o ns ultati o n wit h t he I n vesti gat or or q ualifie d site pers o n nel a n d will be rec or de d.  T he 
I R C D -L D  d osi n g re gi me n s h o ul d be sta ble f or at least 5 da ys pri or t o ret ur ni n g f or Visit 2.  
Resc ue wit h a d diti o nal or m o difie d d oses of c o nc o mita nt P D me dicati o ns or wit h use of 
C D - L D pr o d ucts ot her t ha n t he dis pe nse d st u d y me dicati o ns is n ot per mitte d  a n d will tri g ger 
disc o nti n uati o n fr o m t he st u d y.  S u bj ects  will c o m plete t heir 3 - da y P D Diaries  o n eac h of t he 
3 c o nsec uti ve  da ys  i m me diatel y pri or t o Visit  2. 
•  
F oll o w i n g c o m pleti o n of t he I R C D -L D  d ose a dj ust me nt peri o d, s u bjects will be gi n a 4- wee k 
o pe n- la bel peri o d f or c o n versi o n t o I P X 2 0 3.  T he i nitial d osi n g re gi me n of I P X 2 0 3 will be 
base d o n t he m ost fre q ue nt d ose of t he s u bject’s d osi n g re gi me n of I R C D -L D  at t he e n d of t he 
d ose a dj ust me nt peri o d  ( Visit 2).  A 2 5 - 1 0 0 m g  d ose of I R C D -L D c o n verts t o a 7 0 - 2 8 0 m g  
C D -L D d ose of I P X 2 0 3 ( 2 ca ps ules of 3 5 - 1 4 0 m g C D-L D I P X 2 0 3) , a n d a 1 2. 5- 5 0 m g d ose of 
I R C D -L D c o n verts t o a 3 5- 1 4 0 m g C D -L D d ose of I P X 2 0 3, b ut wit h a l o n ger d urati o n of 
effect .  It is rec o m me n de d t hat I P X 2 0 3 s h o ul d be d ose d a p pr o xi matel y e ver y 8 h o urs wit h t he 
e xce pti o n t hat s u bjects w h o are c urre ntl y recei vi n g a t otal dail y d ose of less t ha n 1 2 5 -5 0 0 m g 
I R C D -L D at t he e n d of t he d ose a dj ust me nt peri o d will be i nitiall y a d mi nistere d e ver y 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 6  of 1 5 9  
 
1 2  h o urs .  T he d osi n g i nter val ma y be re d uce d t o a p pr o xi matel y e ver y 8 h o urs if t he s u bject 
d oes n ot ac hie ve a n acce pta ble d urati o n of effect .  T he d osi n g re gi me n of I P X 2 0 3 m a y be 
a dj uste d d uri n g t he d ose c o n versi o n peri o d  t o ac hie ve t he o pti mal bala nce of efficac y a n d 
t olera bilit y ( mi ni mize “ Off” ti me wit h o ut ca usi n g tr o u bles o me d ys ki nesia or ot her 
d o pa mi ner gic si de effects).  T he d oses a n d re gi me ns of t he s u bject’s ot her n o n -C D -L D P D 
me dicati o ns ( d o pa mi ne a g o nists, M A O -B i n hi bit ors, a ma nta di ne, a ntic h oli ner gics) s h o ul d 
re mai n sta ble t hr o u g h o ut t his st u d y.  T he s u bject m ust be o n a sta ble d osi n g re gi me n of 
I P X 2 0 3 ( n o c ha n ge i n d ose or i n d osi n g fre q ue nc y) f or at least 5 da ys pri or t o ret ur ni n g f or 
Visit  4.  A n y a dj ust me nts t o t he I P X 2 0 3 d osi n g re gi me n will be d o ne i n c o ns ultati o n wit h t h e 
I n vesti gat or or q ualifie d site pers o n nel a n d will be rec or de d.  Resc ue wit h a d diti o nal or 
m o difie d d oses of c o nc o mita nt P D me dicati o ns or wit h use of C D -L D pr o d ucts ot her t ha n t he 
dis pe nse d st u d y me dicati o ns is n ot per mitte d  a n d will tri g ger disc o nti n uati o n fr o m t he st u d y.  
S u bj ects will ret ur n t o t he cli nic i n 2 wee ks f or Visit 3 f oll o we d b y Visit 4 , 2 wee ks later.   
S u bj ects will c o m plete t heir 3 -da y P D  Diaries  o n eac h of t he 3 c o nsec uti ve da ys i m me diatel y  
pri or t o  Visit  4. 
•  
S u bj ects w h o s uccessf ull y c o m plete t he I P X 2 0 3 d ose c o n versi o n peri o d will be ra n d o mize d i n 
1: 1 rati o, stratifie d b y ce nter, at Visit 4 i nt o o ne  of t w o parallel treat me nt ar ms of I P X 2 0 3 ( wit h 
matc hi n g I R  C D -L D place b o) or I R C D -L D  (wit h matc hi n g I P X 2 0 3 place b o) .  T he s u bjects 
will  u n der g o 1 3 wee ks of d o u ble- bli n d mai nte na nce t hera p y  wit h t he sta ble d osi n g re gi me n 
esta blis he d at t he e n d of Wee k 3 ( Visit 2) f or I R C D -L D  a n d at t he e n d of Wee k 7 ( Visit 4) f or 
I P X 2 0 3.  Resc ue wit h a d diti o nal or m o difie d d oses of c o nc o mita nt P D me dicati o ns or wit h use 
of C D - L D pr o d ucts ot her t ha n t he dis pe nse d st u d y me dicati o ns is n ot per mitte d  a n d will tri g ger 
disc o nti n uati o n fr o m t he st u d y.  S u bj ects will ret ur n t o t he cli nic f or 3 visits (Visits 5, 6, a n d 7 ) 
a n d will c o m plete t heir 3 -d a y P D  Diaries  o n eac h of t he  3 c o nsec uti ve  da ys i m me diatel y  pri or 
t o eac h of t hese visits. 
N u m ber of p atie nts ( pl a n ne d):  Ass u mi n g a p pr o xi matel y a n  1 8 % prera n d o mizati o n dr o p -o ut, 
a p pr o xi matel y 5 1 0  s u bjects will  be e nr olle d t o ra n d o mize 4 2 0 s u bjects. 
Di a g n osis a n d m ai n criteri a f or i ncl usi o n:  
I ncl usi o n Criteria 
•  
Male or fe male s u bjects dia g n ose d at a ge ≥ 4 0 years wit h P D , c o nsiste nt wit h t he U nite d Ki n g d o m 
Par ki ns o n’s Disease S ociet y Brai n Ba n k Dia g n ostic Criteria  a n d w h o are bei n g treate d wit h sta ble 
re gi me ns of C D- L D b ut e x perie nci n g m ot or fl uct uati o ns. 
•  
H oe h n a n d Ya hr Sta ges 1, 2, 3, or 4 i n t he “ O n” state ( part of M o ve me nt Dis or ders S ociet y versi o n 
of t he U nifie d Par ki ns o n’s Disease Rati n g Scale [ M D S -U P D R S]  Part III)  
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M o ntreal C o g niti ve Assess me nt ( M o C A) sc ore ≥ 2 4 at Scree ni n g Visit i n “ O n” state.  
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B y hist or y, f or t he 4 wee ks pri or t o Scree ni n g, t he s u bject e x perie nces dail y “ weari n g -off” e pis o des 
wit h peri o ds of bra d y ki nesia i n c o m bi nati o n wit h at least o ne of rest tre m or or ri gi dit y, e x perie nces 
a n “ Off” state u p o n a wa ke ni n g o n m ost m or ni n gs, a n d re p orts a n a vera ge of at least 2. 5 c u m ulati ve 
h o urs per da y of “ O ff” ti me d uri n g t he wa ki n g h o urs. 
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A ble t o differe ntiate “ O n” state fr o m “ O ff” state as deter mi ne d b y at least 7 5 % c o nc or da nce wit h a 
trai ne d rater i n “O n/ O ff” rati n gs f or 8 rati n gs o ver a 4- h o ur trai ni n g peri o d.  T he c o nc or da nce m ust 
i ncl u de at least 1 “ O n” a n d 1 “ Off” rati n g a n d m ust be ac hie ve d wit hi n t w o 4- h o ur trai ni n g 
sessi o ns. 
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At Visit 1, re vie w of t he 3 -da y P D Diaries  c o nfir ms t he f oll o wi n g:  t hat t he s u bject is a ble t o 
pr o perl y c o m plete t he Diaries  wit h vali d e ntries; a n d t hat t he s u bj ect has a n a vera ge of at least 
2. 5 h o urs  per da y of “ Off” ti me d uri n g wa ki n g h o urs o ver t he 3 da ys wit h at least 1. 5 h o urs of 
c u m ulati ve “ Off” ti me o n eac h da y.  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 7  of 1 5 9  
 
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Res p o nsi ve t o C D -L D t hera p y a n d c urre ntl y bei n g treate d o n a sta ble re gi me n wit h C D -L D f or at 
least 4 wee ks pri or t o Visit 1 a n d: 
− Re q uires at least 1 0 0  m g of L D fr o m I R C D -L D f or t he first m or ni n g d ose 
− R e q uires a t otal dail y d ose of at least 4 0 0 m g of L D  a n d ta kes a ma xi m u m t otal dail y d ose 
of 2 4 0 0 m g L D, fr o m I R C D -L D  al o ne or I R C D -L D i n c o m bi nati o n wit h a si n gle dail y 
be dti me d ose of C R C D -L D  
− Has a d osi n g fre q ue nc y of 4 t o 9 ti mes dail y of C D-L D  
− B y hist or y, t y picall y e x perie nces a n “ O n” res p o nse wit h t he first d ose of I R C D -L D  of t he 
da y, b ut t he efficac y of t his d ose t y picall y lasts less t ha n 4 h o urs . 
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At Scree ni n g, t he s u bject has pre dicta ble “ Off” peri o ds defi ne d b y a sc ore of 1 or 2 o n Ite m # 4. 5 
( C o m ple xit y of M ot or Fl uct uati o ns) of t he M D S -U P D R S Part I V B ( M ot or Fl uct uati o ns). 
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At Scree ni n g, t he M D S -U P D R S Part III t otal sc ore i n t he “ Off” state is at least 2 0 u nits.  
E xcl usi o n Criteria 
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Use d a n y d oses of c o ntr olle d- release ( C R) C D-L D a part fr o m a si n gle dail y be dti me d ose wit hi n  
4 wee ks pri or t o Visit 1.  
•  
Use d a n y d ose of R ytar y f or t he past 4 wee ks pri or t o Visit 1  or were c o nsi dere d I P X 0 6 6 or R ytar y 
fail ures f or reas o ns of efficac y or safet y. 
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Ha d pri or ne ur os ur gical treat me nt f or P D or if s uc h pr oce d ure is pla n ne d or a ntici pate d d uri n g t he 
st u d y peri o d. 
•  
Aller gic t o a n y e xci pie nt i n t he st u d y dr u gs. 
•  
Hist or y of gla uc o ma wit h i ntra oc ular press ures t hat are ele vate d des pite a p pr o priate me dical 
ma na ge me nt.  
•  
Hist or y of seiz ure or e pile ps y a n d e x perie nce d at least 1 seiz ure d uri n g t he past 1 2  m o nt hs or has 
n ot bee n c o m plia nt wit h me dicall y rec o m me n de d t hera p y or visits. 
•  
Hist or y of m y ocar dial i nfarcti o n wit h resi d ual atrial, n o dal, or ve ntric ular arr h yt h mias t hat are n ot 
c o ntr olle d wit h me dical a n d/ or s ur gical i nter ve nti o ns.  A rece nt ( ≤ 1 2 m o nt hs) hist or y of 
m y ocar dial i nfarcti o n wit h sec o n dar y arr h yt h mias is e xcl usi o nar y re gar dless of t he t hera pe utic 
c o ntr ol. 
•  
Recei ve d wit hi n 4 wee ks of Scree ni n g or pla n ni n g t o ta ke d uri n g partici pati o n i n t he cli nical st u d y: 
− A n y d oses of a C R  C D -L D a part fr o m a si n gle dail y be dti me d ose , a n y d oses of R ytar y, 
a d diti o nal C D (e g, L o d os y n) or be nserazi de (e g, Serazi de), or catec h ol- O- met h yl 
tra nsferase i n hi bit ors (e ntaca p o ne or t olca p o ne) or me dicati o ns c o ntai ni n g t hese i n hi bit ors 
( Stale v o), 
− N o nselecti ve m o n oa mi ne o xi dase i n hi bit ors ( M A O I), a p o m or p hi ne, or a ntid o pa mi ner gic 
a ge nts, i ncl u di n g a ntie metics. 
•  
S u bj ects w h o ha ve pre vi o usl y partici pate d i n a n I P X 2 0 3 st u d y. 
I n vesti g ati o n al pr o d uct, d os a ge a n d m o de of a d mi nistr ati o n:  I P X 2 0 3 (car bi d o pa-le v o d o pa) 
E xte n de d- Release ca ps ules, c o ntai ni n g 3 5- 1 4 0 m g  of C D -L D  a n d matc hi n g place b o, f or oral 
a d mi nistrati o n . 
Ref ere nce t her a p y, d os a ge a n d m o de of a d mi nistr ati o n:  I m me diate-Release car bi d o pa-le v o d o pa 
(I R C D -L D) ta blet s c o ntai ni n g 2 5- 1 0 0 m g of C D -L D , a n d matc hi n g place b o , f or oral a d mi nistrati o n. 
D ur ati o n of tre at me nt:   A p pr o xi matel y 2 4 wee ks , i ncl u di n g u p t o 4 wee ks f oll o wi n g Scree ni n g, 
3  wee ks of I R  C D -L D  d ose a dj ust me nt, 4 wee ks of I P X 2 0 3 d ose c o n versi o n, a n d 1 3 wee ks of d o u ble -


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 8  of 1 5 9  
 
bli n d t hera p y f oll o wi n g ra n d o mizati o n.  
Criteri a f or e v al u ati o n:  
Baseli ne is defi ne d as assess me nts d o ne at Visit 4 (ra n d o mizati o n visit).  St u d y E ntr y is defi ne d as 
assess me nts d o ne at Visit 1 (st u d y e ntr y visit).  
Effic ac y:  
•  
Pri mar y  e n d p oi nt:  C ha n ge fr o m baseli ne i n “ G o o d o n” ti me i n h o urs per da y, a vera ge d o ver 
t he P D D iar y da ys, at t he e n d of d o u ble -bli n d treat me nt peri o d ( Visit 7 or earl y ter mi nati o n) .  
“ G o o d o n” ti me is deri ve d fr o m t he 3-da y P D Diar ies a n d is defi ne d as t he s u m of “ O n” ti me 
wit h o ut d ys ki nesia a n d “ O n” ti me wit h n o ntr o u bles o me d ys ki nesia. 
•  
Ke y sec o n dar y e n d p oi nts: 
− C ha n ge fr o m baseli ne i n “ O ff” ti me i n h o urs per da y , a vera ged o ver  t he P D Diar y da ys  
at t he e n d of d o u ble- bli n d treat me nt peri o d ( Visit 7 or earl y ter mi nati o n) 
− Pr o p orti o n of s u bjects wit h eit her “ m uc h i m pr o ve d” or “ ver y m uc h i m pr o ve d” i n 
Patie nt Gl o bal I m pressi o n  of C ha n ge ( P GI- C) sc ores at t he e n d of d o u ble- bli n d 
treat me nt peri o d ( Visit 7 or earl y ter mi nati o n)  
− C ha n ge fr o m baseli ne i n t he M D S - U P D R S Part III at t he e n d of d o u ble- bli n d treat me nt 
peri o d ( Visit 7 or earl y ter mi nati o n)  
− C ha n ge fr o m baseli ne i n t he s u m of M D S -U P D R S Part s II a n d III at t he e n d of d o u ble-
bli n d treat me nt peri o d ( Visit 7 or earl y ter mi nati o n) 
•  
A d diti o nal e n d p oi nts :  
T he f oll o wi n g e n d p oi nts will be e val uate d (at t he p ost- ra n d o mizati o n visits) as c ha n ge fr o m 
base li ne ( Visit 4) as well as c ha n ge fr o m t he st u d y e ntr y ( Visit 1), w he n a p plica ble, b y visits : 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 9  of 1 5 9  
 
•  
S af et y:  electr ocar di o gra ms ( E C Gs), cli nical la b orat or y t ests, p h ysical e xa mi nati o ns, C ol u m bia-
S uici de Se verit y Rati n g Scale  ( C-S S R S ), a n d s u pi ne a n d sta n di n g ort h ostatic vital si g ns; 
a d verse e ve nts a n d c o nc o mita nt me dicati o ns e val uate d t hr o u g h o ut t he c o urse of t he st u d y . 
St atistic al met h o ds:   F or t he pri mar y e n d p oi nt, ass u mi n g a differe nce of 1 h o ur bet wee n I P X 2 0 3 a n d 
I R C D -L D i n “ G o o d o n” ti me a n d a sta n dar d de viati o n of t he treat me nt differe nce t o be 3. 0 h o urs, a 
sa m ple size of 2 1 0 per ar m will be nee de d t o e ns ure at least 9 0 % p o wer at a 0. 0 5 si g nifica nce le vel.  
Ass u mi n g a p pr o xi matel y a n 1 8 % prera n d o mizati o n dr o p- o ut, a p pr o xi matel y 5 1 0 s u bj ects w o ul d nee d 
t o be e nr olle d t o ra n d o mize 4 2 0 s u bjects. 
T he pri mar y efficac y e n d p oi nt of c ha n ge fr o m baseli ne i n “ G o o d o n” ti me will be a nal yze d usi n g a 
mi xe d m o del f or re peate d meas ures (M M R M ) m o del.  T he m o del will i ncl u de baseli ne ( Visit 4) “ G o o d 
o n” ti me as a c o variate , treat me nt, visit, a n d p o ole d ce nter as fi xe d effects, a n d a treat me nt - b y-visit 
i nteracti o n.  T he m o del will e m pl o y a n u nstr uct ure d wit hi n s u bject c o varia nce matri x a n d a restricte d 
ma xi m u m li keli h o o d ( Re M L ) esti mati o n met h o d.  T he de gree - of-free d o m of t he de n o mi nat or will be 
esti mate d usi n g t he Ke n war d -R o ger met h o d.  
T he ke y sec o n dar y e n d p oi nts (c ha n ge fr o m baseli ne i n “ Off ” ti me, c ha n ge fr o m baseli ne i n 
M D S -U P D R S Part III , a n d c ha n ge fr o m baseli ne i n t he s u m of t he M D S -U P D R S Part s II a n d III) will 
be a nal yze d usi n g M M R M m o dels si milar t o t he pri mar y a nal ysis m o del.   T he pr o p orti o n of s u bj ects 
wit h eit her “ m uc h i m pr o ve d” or “ ver y m uc h i m pr o ve d” o n t he P GI- C will be a nal yze d usi n g C oc hra n-
Ma ntel -Hae n szel test t o c o m pare t he t w o treat me nt gr o u ps wit h p o ole d ce nter as  a stratificati o n fact or. 
I n or der t o c o ntr ol t he t y pe I err or rate, t he pri mar y a n d ke y sec o n dar y e n d p oi nts will be teste d i n a 
si n gle hierarc hical or der: ( 1) c ha n ge fr o m baseli ne i n “ G o o d o n” ti me, ( 2) c ha n ge fr o m baseli ne i n 
“ Off” ti me, ( 3) pr o p orti o n of s u bjects wit h eit her “ m uc h i m pr o ve d” or “ ver y m uc h i m pr o ve d” i n 
P GI -C, ( 4) c ha n ge fr o m baseli ne i n t he M D S -U P D R S Part III , ( 5) c ha n ge fr o m baseli ne i n t he s u m of 
M D S -U P D R S Parts II a n d III.  
Q ua ntitati ve safet y data will be s u m marize d usi n g descri pti ve statistics  a n d fre q ue nc y distri b uti o ns.  
Q ualitati ve safet y data will be s u m marize d b y fre q ue ncies a n d perce nta ges.  All s u m maries will be 
prese nte d b y treat me nt ar ms.  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 0  of 1 5 9  
 
2.  
T A B L E O F C O N T E N T S, LI S T O F T A B L E S, A N D LI S T O F 
FI G U R E S  
T A B L E O F C O N T E N T S  
1.  
S Y N O P SI S  ................................................................................................................... 5 
2.  
T A B L E O F C O N T E N T S, L I S T O F T A B L E S, A N D LI S T O F FI G U R E S ............... 1 0 
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S ............................. 1 6 
4.  
I N T R O D U C TI O N ...................................................................................................... 1 9 
5.  
T RI A L O BJ E C TI V E S  ................................................................................................ 2 3 
6.  
I N V E S TI G A TI O N A L P L A N ..................................................................................... 2 4 
6. 1.  
O verall St u d y Desi g n  .................................................................................................. 2 4 
6. 2.  
N u m ber of S u bjects  .................................................................................................... 2 5 
6. 3.  
Treat me nt Assi g n me nt  ................................................................................................ 2 6 
6. 4.  
D osi n g a n d D ose Det er mi nati o n Criteria  ................................................................... 2 6 
6. 4. 1.  
I R C D - L D D ose A dj ust me nt Peri o d ........................................................................... 2 6 
6. 4. 2.  
I P X 2 0 3 D os e C o n versi o n Peri o d ................................................................................ 2 6 
6. 4. 3.  
D o u ble- Bli n d Mai nte n a n ce Peri o d  ............................................................................. 2 8 
6. 5.  
Criteria f or St u d y Ter mi nati o n  ................................................................................... 2 8 
7.  
S E L E C TI O N A N D WI T H D R A W A L O F S U BJ E C T S  .............................................. 2 9 
7. 1.  
S u bject I n cl usi o n Criteria  ........................................................................................... 2 9 
7. 2.  
S u bject E x cl usi o n Criteria  .......................................................................................... 3 0 
7. 3.  
S u bject Wit h dra wal Criteria  ....................................................................................... 3 1 
8.  
S T U D Y P R O C E D U R E S  ............................................................................................ 3 3 
8. 1.  
Scree ni n g Visit  ............................................................................................................ 3 7 
8. 2.  
Visit 1 – Start of I R C D - L D D ose A dj ust me nt........................................................... 3 8 
8. 2. 1.  
Pri or t o Visit 1  ............................................................................................................ 3 8 
8. 2. 2.  
At Visit 1 ..................................................................................................................... 3 8 
8. 2. 3.  
P ost Visit 1  .................................................................................................................. 3 9 
8. 3.  
Visits 2 ( Wee k 3) a n d Visit 3 ( Wee k 5) – I P X 2 0 3 D ose C o n versi o n  ........................ 3 9 
8. 3. 1.  
Pri or t o Visit 2  ............................................................................................................ 3 9 
8. 3. 2.  
Pri or t o Visit 3  ............................................................................................................ 3 9 
8. 3. 3.  
At Visits 2 a n d 3  ......................................................................................................... 3 9 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 1  of 1 5 9  
 
8. 3. 4.  
P ost Visits 2 a n d 3  ...................................................................................................... 4 0 
8. 4.  
Visit 4 ( Wee k 7) – Ra n d o mizati o n  ............................................................................. 4 0 
8. 4. 1.  
Pri or t o Visit 4  ............................................................................................................ 4 0 
8. 4. 2.  
At Visit 4 ..................................................................................................................... 4 0 
8. 5.  
Visit 5 ( Wee k 1 0) a n d Visit 6 ( Wee k 1 5)  ................................................................... 4 1 
8. 5. 1.  
Pri or t o Visit 5 a n d 6  ................................................................................................... 4 1 
8. 5. 2.  
At Visit 5 a n d 6  ........................................................................................................... 4 1 
8. 6.  
Visit 7 ( Wee k 2 0) – E n d of St u d y/ St u d y E xit  ............................................................ 4 2 
8. 6. 1.  
Pri or t o Visit 7  ............................................................................................................ 4 2 
8. 6. 2.  
At Visit 7 ..................................................................................................................... 4 2 
8. 7.  
Earl y Ter mi nati o n  ....................................................................................................... 4 3 
8. 7. 1.  
S u bjects W h o Ter mi nate Pri or t o Ra n d o mizati o n  ...................................................... 4 3 
8. 7. 2.  
S u bjects W h o Ter mi nate Earl y after Ra n d o mizati o n  ................................................. 4 4 
8. 8.  
Bl o o d V ol u me  ............................................................................................................. 4 4 
9.  
T R E A T M E N T O F S U BJ E C T S  .................................................................................. 4 5 
9. 1.  
Descri pti o n of St u d y Dr u g  .......................................................................................... 4 5 
9. 2.  
C o nc o mita nt Me dicati o ns  ........................................................................................... 4 5 
9. 2. 1.  
Per mitte d P D Me dicati o ns  .......................................................................................... 4 5 
9. 2. 2.  
Pr o hi bite d Me dicati o ns a n d Pr oce d ures  ..................................................................... 4 5 
9. 2. 3.  
Resc ue Me dicati o ns  .................................................................................................... 4 6 
9. 3.  
Treat me nt C o m plia nce  ................................................................................................ 4 6 
9. 4.  
Ra n d o mizati o n a n d Bli n di n g  ...................................................................................... 4 6 
1 0.  
S T U D Y D R U G M A T E RI A L S  A N D M A N A G E M E N T  ........................................... 4 7 
1 0. 1.  
St u d y Dr u g  .................................................................................................................. 4 7 
1 0. 2.  
St u d y Dr u g Pac k a gi n g a n d La b eli n g  .......................................................................... 4 7 
1 0. 3.  
St u d y Dr u g St ora ge  ..................................................................................................... 4 7 
1 0. 4.  
St u d y Dr u g A d mi nistrati o n ......................................................................................... 4 8 
1 0. 5.  
St u d y Dr u g Dis pe nsi n g a n d Acc o u nta bilit y  ............................................................... 4 8 
1 0. 6.  
St u d y Dr u g H a n dli n g a n d Dis p osal  ............................................................................ 4 8 
1 1.  
A S S E S S M E N T O F E F FI C A C Y  ................................................................................ 4 9 
1 1. 1.  
Par ki ns o n’s Disease Di ar y  .......................................................................................... 4 9 
1 1. 2.  
Patie nt a n d I n v esti gat or Gl o bal Assess me nts  ............................................................. 4 9 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 2  of 1 5 9  
 
1 1. 3.  
M o ve me nt Dis or ders S ociet y V ersi o n of U nifie d P ar ki ns o n’s Diseas e Rati n g 
Scale  ............................................................................................................................ 4 9 
1 1. 4.  
A d diti o nal Ass ess me nts  .............................................................................................. 5 0 
1 2.  
A S S E S S M E N T O F S A F E T Y  ..................................................................................... 5 1 
1 2. 1.  
Safet y Para met ers  ....................................................................................................... 5 1 
1 2. 2.  
A d verse E v e nts  ........................................................................................................... 5 1 
1 2. 2. 1.  
Defi niti o n of A d vers e E v e nt  ....................................................................................... 5 1 
1 2. 2. 2.  
Rec or di n g A d verse E ve nts  ......................................................................................... 5 1 
1 2. 2. 3.  
F oll o w- u p  .................................................................................................................... 5 2 
1 2. 2. 4.  
Relati o ns hi p t o St u d y Dr u g  ........................................................................................ 5 2 
1 2. 2. 5.  
Assess me nt of Se verit y  ............................................................................................... 5 2 
1 2. 3.  
Seri o us A d verse E v e nts  .............................................................................................. 5 2 
1 2. 3. 1.  
Defi niti o n of Seri o us A d verse E ve nt  .......................................................................... 5 2 
1 2. 3. 2.  
Re p orti n g Seri o us A d v erse E ve nts  ............................................................................. 5 3 
1 2. 4.  
Pre g n a nc y  ................................................................................................................... 5 3 
1 2. 5.  
Ot her Safet y Para meters a n d Relate d I nf or mati o n  ..................................................... 5 4 
1 3.  
S T A TI S TI C S  .............................................................................................................. 5 5 
1 3. 1.  
St u d y Desi g n a n d Sa m pl e Size Esti mati o n  ................................................................. 5 5 
1 3. 2.  
De m o gra p hics/ Baseli ne C o m para bilit y  ...................................................................... 5 5 
1 3. 3.  
Efficac y E n d p oi nts  ...................................................................................................... 5 5 
1 3. 4.  
A nal ysis of Efficac y D ata  ........................................................................................... 5 7 
1 3. 4. 1.  
Pri mar y Efficac y E n d p oi nt  ......................................................................................... 5 7 
1 3. 4. 2.  
Ke y Sec o n dar y Effi cac y E n d p oi nts  ............................................................................ 5 7 
1 3. 4. 3.  
A d diti o nal Efficac y E n d p oi nts  ................................................................................... 5 8 
1 3. 5.  
Ce nter P o oli n g Al g orit h m ........................................................................................... 5 8 
1 3. 6.  
Se nsiti vit y A nal ys es of t he Pri mar y E n d p oi nt a n d Ke y Sec o n dar y E n d p oi nts  .......... 5 9 
1 3. 6. 1.  
Assessi n g Ass u m pti o ns of t he Mi x e d M o del f or Re peate d M eas ures 
( M M R M) .................................................................................................................... 5 9 
1 3. 6. 2.  
C o m plete Case A nal ysis  ............................................................................................. 5 9 
1 3. 6. 3.  
Si n gle L O C F/ B L O C F I m p utati o n  .............................................................................. 5 9 
1 3. 6. 4.  
Patter n - Mi xt ure M o del ............................................................................................... 6 0 
1 3. 7.  
S u b gr o u p A n al ys es  ..................................................................................................... 6 1 
1 3. 8.  
M ulti plicit y A dj ust me nts  ............................................................................................ 6 1 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 3  of 1 5 9  
 
1 3. 9.  
A nal ysis P o p ulati o ns  .................................................................................................. 6 2 
1 3. 9. 1.  
Safet y A nal ysis Set  ..................................................................................................... 6 2 
1 3. 9. 2.  
I nte nt-t o-Treat A nal ysis Set  ........................................................................................ 6 2 
1 3. 9. 3.  
M o difie d I nte nt -t o-Tr eat A nal ysis Set  ........................................................................ 6 2 
1 3. 9. 4.  
C o m pleters A nal ysis Set  ............................................................................................. 6 2 
1 3. 1 0.  
Ha n dli n g of Missi n g Dat a  ........................................................................................... 6 2 
1 3. 1 0. 1.  
Missi n g Data f or P D Diaries  ....................................................................................... 6 2 
1 3. 1 0. 2.  
Missi n g Data f or Gl o bal Assess me nts ( P GI -C, 
.............. 6 3 
1 3. 1 0. 3.  
Missi n g Data f or M D S -U P D R S  ................................................................................. 6 3 
1 3. 1 1.  
A nal ysis of Safet y  ....................................................................................................... 6 4 
1 4.  
A D MI NI S T R A TI V E P R O C E D U R E S  ....................................................................... 6 5 
1 4. 1.  
G ui deli nes f or G o o d Cli nical Practice  ........................................................................ 6 5 
1 4. 2.  
I nstit uti o nal Re vie w B oar d A p pr o val ......................................................................... 6 5 
1 4. 3.  
I nf or me d C o nse nt ....................................................................................................... 6 5 
1 4. 4.  
St u d y M o nit ori n g  ........................................................................................................ 6 5 
1 4. 5.  
Pr ot oc ol A me n d me nts  ................................................................................................ 6 5 
1 4. 6.  
Ter mi nati o n of St u d y  .................................................................................................. 6 6 
1 4. 7.  
Case Re p ort F or ms  ..................................................................................................... 6 6 
1 4. 8.  
I n v esti gat or’s Fi nal C o n d uct Re p ort ........................................................................... 6 6 
1 4. 9.  
Rec or ds Rete nti o n  ....................................................................................................... 6 6 
1 5.  
P U B LI C A TI O N P O LI C Y  .......................................................................................... 6 7 
1 6.  
LI S T O F R E F E R E N C E S  ............................................................................................ 6 8 
1 7.  
A P P E N DI C E S  ............................................................................................................ 7 0 
A P P E N DI X  A.  P R E S C RI BI N G I N F O R M A T I O N F O R I R C D-L D  ......................................... 7 0 
A P P E N DI X  B.  I N S T R U C TI O N S F O R D O S E C O N V E R SI O N T O I P X 20 3  ............................ 8 2 
A P P E N DI X  C.  U NI T E D KI N G D O M P A R KI N S O N’ S DI S E A S E S O CI E T Y B R AI N 
B A N K DI A G N O S TI C C RI T E RI A F O R P A R KI N S O N’ S  DI S E A S E  ...................... 8 4 
A P P E N DI X  D.  M O N T R E A L C O G NI TI V E A S S E S S M E N T ( M O C A)  .................................... 8 5 
A P P E N DI X  E.  M O V E M E N T DI S O R D E R S S O CI E T Y V E R SI O N O F U N I FI E D 
P A R KI N S O N’ S DI S E A S E R A TI N G S C A L E ( M D S -U P D R S)  ................................ 9 1 
A P P E N DI X  F.  P A TI E N T G L O B A L I M P R E S SI O N O F C H A N G E ( P GI -C)  ......................... 1 2 5 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 4  of 1 5 9  
 
A P P E N DI X  K.  G A S T R O P A R E SI S C A R DI N A L S Y M P T O M I N D E X ( G C SI) ..................... 1 3 5 
A P P E N DI X  O.  C O L U M BI A -S UI CI D E S E V E RI T Y R A TI N G S C A L E ( C -S S R S)  ................ 1 4 6 
A P P E N DI X  P.  P A R KI N S O N’ S DI S E A S E DI A R Y  ................................................................ 1 5 3 
A P P E N DI X  Q.  E X CI PI E N T S I N I P X 2 0 3 , I P X 2 0 3 P L A C E B O, I R C D -L D, A N D I R 
P L A C E B O  ................................................................................................................ 1 5 7 
A P P E N DI X  R.  C LI NI C A L L A B O R A T O R Y S T U DI E S  ......................................................... 1 5 8 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 5  of 1 5 9  
 
 
LI S T O F T A B L E S  
Ta ble 1:  
A b bre viati o ns a n d S peci alist Ter ms  ........................................................................... 1 6 
Ta ble  2: 
L D D osa ge i n St u d y I P X 2 0 3- B 1 4 - 0 2 ......................................................................... 2 0 
Ta ble  3: 
Rec o m me n de d Starti n g I P X 2 0 3 L D D osi n g Re gi me n Bas e d o n t he D osi n g 
Re gi me n of I R C D - L D at t he E n d of t he D ose A dj ust me nt Peri o d ............................ 2 7 
Ta ble  4: 
E ve nts Sc he d ule f or I m p a x St u d y I P X 2 0 3- B 1 6 - 0 2 .................................................... 3 4 
Ta ble 5:  
St u d y Dr u gs f or St u d y I P X 2 0 3- B 1 6 - 0 2 ..................................................................... 4 5 
 
 
L I S T O F FI G U R E S  
Fi g ure  1: 
St u d y Fl o w C hart  ........................................................................................................ 2 5 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 6  of 1 5 9  
 
3.  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S 
T he f oll o wi n g a b bre vi ati o ns a n d s pecialist ter ms are use d i n t his st u d y pr ot oc ol. 
T a ble 1: 
A b bre vi ati o ns a n d S peci alist Ter ms  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
A A D C  
ar o matic a mi n o aci d decar b o x ylase  
A D L  
acti vities of dail y li vi n g 
A E  
a d verse e ve nt 
A N C O V A  
a nal ysis of c o varia nce 
A N O V A  
a nal ysis of varia nce 
B L O C F  
baseli ne o bser vati o n carrie d f or war d  
B MI  
b o d y mass i n de x 
C D  
car bi d o pa 
C R  
c o ntr olle d release 
C R F  
case re p ort f or m 
C- S S R S  
C ol u m bia- S uici de Se verit y Rati n g Scale  
E C G  
electr ocar di o gra m 
E R  
e xte n de d release 
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
G C P  
G o o d Cli nical Practice  
G C SI  
Gastr o paresis Car di nal S y m pt o m I n de x 
HI P A A  
Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I E C 
i n de pe n de nt et hics c o m mittee 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 7  of 1 5 9  
 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
I R 
i m me diate release 
I R B 
i nstit uti o nal re vie w b oar d 
I W R S 
i nteracti ve we b res p o nse s yste m 
L D  
le v o d o pa 
L O C F  
last o bser vati o n carrie d f or war d 
M A O I 
m o n oa mi ne o xi dase i n hi bit ors  
M A R  
missi n g at ra n d o m 
M- E D L  
M ot or As pects of E x perie nces of Dail y Li vi n g  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
M D S -U P D R S  
M o ve me nt Dis or ders S ociet y versi o n of t he U nifie d  Par ki ns o n’s 
Disease Rati n g Scale  
mI T T  
m o difie d i nte nt -t o-treat 
M M R M  
mi xe d m o del f or re peate d meas ures  
M N A R  
missi n g n ot at ra n d o m 
M o C A  
M o ntreal C o g niti ve Assess me nt  
n M- E D L  
N o n -M ot or As pects of E x perie nces of Dail y Li vi n g  
P D  
Par ki ns o n’s disease  
P GI - C 
Patie nt Gl o bal I m pressi o n  of C ha n ge 
P K  
p har mac o ki netic (a djecti ve)  
p har mac o ki netics (si n g ular n o u n)  
PI  
pri nci pal i n vesti gat or  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 8  of 1 5 9  
 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n 
P M M  
patter n - mi xt ure m o dels 
Re M L  
restricte d ma xi m u m li keli h o o d  
S A E  
seri o us a d verse e ve nt 
S A P  
statistical a nal ysis pla n 
S D  
sta n dar d de viati o n 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
U S  
U nite d States  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 9  of 1 5 9  
 
4.  
I N T R O D U C TI O N 
Par ki ns o n’s disease ( P D) is a pr o gressi ve n e ur o de ge n erati ve dis or d er of t h e e xtra p yra mi dal 
ner v o us s yst e m.  Le v o d o pa ( L D) us e d i n c o m bi nati o n wit h car bi d o pa ( C D) is c o nsi dere d t he 
g ol d sta n dar d f or t he s y m pt o matic treat me nt of P D.  L D is a d o p a mi ne prec urs or c o n verte d t o 
d o pa mi ne b y ar o matic a mi n o aci d decar b o x yl ase ( A A D C).  Car bi d o p a is a n A A D C i n hi bit or t hat 
d oes n ot cr oss t he bl o o d- brai n barri er.  W he n use d i n c o m bi nati o n wit h L D, C D i ncrea ses t h e 
plas ma half -life of L D fr o m 5 0 mi n utes t o 1. 5 h o urs.  Car bi d o pa i n hi bits t he c o n versi o n of L D 
i nt o d o pa mi ne i n t he peri p her y, t her e b y re d u ci n g t he peri p heral si de-effects ca use d b y d o p a mi ne 
a n d i ncreasi n g t h e a m o u nt of L D a vaila ble f or tra ns p ort i nt o t he brai n.  T he a d mi nistrati o n of C D 
wit h L D r e d uces t he d ose of L D re q uir e d t o pr o d u ce a d o p a mi ner gic res p o nse b y a b o ut 
7 5 perce nt ( Si ne met pres cri bi n g i nf or mati o n ; A p pe n di x A ). 
D ue t o its pr o ve n efficac y, L D is pr escri b e d e ve nt uall y t o m ost s u bjects wit h P D.  H o we ver, 
l o n g-ter m use of L D is ass ociate d wit h certai n c o m plicati o ns, i ncl u di n g “ weari n g-off” or “e n d-
of- d ose effect,” w here s y m pt o m c o ntr ol decreases ca usi n g t h e dr u g effects t o wear off s o o ner.  
As t he disease pr o gresses f urt her, m ot or c o m plicati o ns, na mel y d ys ki nesias a n d m ot or “ O n/ O ff” 
fl uct uati o ns, de vel o p i n a b o ut 5 0 % of t he patie nts after 5 years of treat me nt ( Fa h n 1 9 9 9 ).  S uc h 
m ot or c o m plicati o ns ca n be a si g nifica nt s o urce of disa bilit y a n d t heir ma na ge m e nt is a maj or 
u n met nee d i n t he treat me nt of P D. 
Mec ha nis ms u n derl yi n g m ot or c o m plicati o ns i n v ol vi n g d ys ki nesias a n d “ O n/ Off” fl uct uati o ns i n 
P D are u nclear.  T h e p ulsatile nat ure of sta n d ar d orall y a d mi nistere d L D is t h o u g ht t o c o ntri b ute 
t o t he a p pear a nce of m ot or c o m plicati o ns.  C hr o nic i nter mitte nt p ulsatile sti m ulati o n of t he 
d o pa mi ne rece pt ors t hat are u n der t o nic c o ntr ol c o ntri b utes t o t he de vel o p me nt of d ys ki nesia i n 
P D a ni mal m o dels as c o m pare d t o a ni mals treate d wit h c o nti n u o us i nf usi o n ( J u nc os et al 
1 9 8 9 , E n g b er et al 1 9 8 9 , Bla nc h et et al 1 9 9 5 ).  I n a d diti o n, u nrelia ble a bs or pti o n of L D 
p ote ntiall y d ue t o erratic gastri c e m pti n g a n d vari a ble i n vi v o diss ol uti o n of L D pr o d ucts is 
t h o u g ht t o c o ntri b ute t o t he dela y or i na d e q uate res p o nse after oral d osi n g wit h sta n dar d C D-L D 
pr o d ucts ( Mela me d et al 1 9 8 6 , K urla n et al 1 9 8 8 , St occ hi et al 1 9 9 4 ).  T hes e fi n di n gs s u g gest 
t hat m ot or c o m plicati o ns i n patie nts wit h P D ma y be less li kel y t o de v el o p wit h c o nti n u o us 
d o pa mi ner gic sti m ulati o n.  
I ntr a d u o de n al i nf usi o n of L D h as bee n s h o w n t o si g nifica ntl y re d uce m ot or c o m plicati o ns a n d t o 
re d uce “Off” ti me.  T he fi n di n gs of i nf usi o n st u dies i n P D patie nts i n dicate t hat t he mai nte na nce 
of sta ble plas ma L D c o nce ntrati o ns a n d t he a v oi d a nce of l o w tr o u g h le v els are effecti ve i n 
re d uci n g “O ff” h o urs, i ncreasi n g “O n ” h o urs wit h o ut disa bli n g d ys ki n esia, a n d re d uci n g t he 
se verit y of d ys ki nesia vers us sta n dar d oral L D f or m ulati o ns (Miz u n o 2 0 0 7 , Nilss o n et al 
2 0 0 1 , N y h ol m et al 2 0 0 5 , St occ hi et al 2 0 0 5 ).  T hese fi n di n gs pr o vi d e a str o n g rati o nale f or t h e 
de vel o p me nt of a n e xte n de d- rel ease ( E R) oral d os a ge f or m t hat d eli vers a c o nsta nt L D plas ma 
c o nce ntr ati o n i n or der t o o pti mize relief of P D s y m pt o ms, a n d t o mi ni mize “ O ff” ti me a n d 
d ys ki nesia.  
I P X 2 0 3 is a n i n vesti gati o nal pr o d uct c o ntai ni n g C D- L D t hat is bei n g de vel o pe d b y I m pa x 
La b orat ories, L L C  (I m pa x).  T he pri mar y o bj ecti v e of t he I P X 2 0 3 pr o gra m is t o de vel o p a n 
e xte n de d -release pr o d u ct t hat ca n attai n t hera pe uti c L D plas ma c o n ce ntrati o ns ra pi dl y a n d 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 0  of 1 5 9  
 
mai ntai n c o nsta nt L D plas ma c o nce ntr ati o ns f or a l o n ger d urati o n t ha n c urre ntl y a p pr o ve d 
pr o d ucts wit h mi ni mal pea k -t o-tr o u g h fl uct uati o ns.  I P X 2 0 3 is desi g ne d t o be d ose d 
a p pr o xi matel y e ver y 8 h o urs. 
I m pa x c haract erize d t he P K a n d p har mac o d y na mics of I P X 2 0 3 i n St u d y I P X 2 0 3 -B 1 4 - 0 2, a 
si n gle d ose trial i n s u bjects wit h a d va nce d P D vers us I R C D -L D a n d R yt ar y  (car bi d o p a a n d 
le v o d o pa) e xte n de d-r elease ca ps ules.  T w e nt y-si x ( 2 6) s u bjects were  ra n d o mize d wit h 
2 5 s u bjects c o m pleti n g all 3 treat me nts .  O ne s u bject disc o nti n ue d st u d y earl y d ue t o s u bject 
wit h dra wal.  T he d os es of I P X 2 0 3 a n d R yt ar y w ere deter mi ne d o n t he b asis of eac h s u bj ect’s 
prest u d y b aseli ne m or ni n g d ose of I R C D -L D ( Ta ble  2). 
T a ble 2:  
L D D os a ge i n St u d y I P X 2 0 3- B 1 4- 0 2 
P rest u d y B aseli ne 
M or ni n g  
I R L D ( m g) 
I R L D  
( m g) 
R yt ar y 
L D ( m g) 
I P X 2 0 3 
L D ( m g) 
1 0 0  
1 0 0  
3 4 0  
3 6 0  
1 5 0  
1 5 0  
4 8 5  
5 4 0  
2 0 0  
2 0 0  
6 3 0  
7 2 0  
2 5 0  
2 5 0  
7 8 0  
8 1 0  
A d mi nistrati o n of I P X 2 0 3 yiel de d a n i nitial i ncrease i n L D pl as ma c o nce ntrati o ns t hat was 
si milar t o I R C D -L D  b ut mai ntai ne d L D c o nce ntrati o ns f or a l o n ger d urati o n t ha n eit her 
I R C D -L D or R yt ar y.  T h e bi oa vaila bilit y of L D ( b ase d o n A U C ∞) fr o m I P X 2 0 3 was 8 8% 
relati ve t o I R C D- L D a n d a b o ut 1 1% m ore t ha n R yt ar y.  Plas ma e x p os ure t o L D ( Cma x  a n d 
A U C ∞) f oll o wi n g I P X 2 0 3 i ncreas e d i n a n a p pr o xi matel y d ose- pr o p orti o nal ma n ner.  
P har mac o d y na mic eff ects as meas ure d b y c ha n ge fr o m baseli ne sc ores o n M D S -U P D R S Part III 
were c o nsiste nt wit h t he P K pr ofiles of L D.  F oll o wi n g I P X 2 0 3 treat me nt, decre m e nts i n t he 
Part  III t otal sc or e (r eflecti n g i m pr o ve me nts i n m ot or s y m pt o ms) laste d f or a l o n ger d urati o n 
t ha n eit her I R C D -L D or R yt ar y.  I P X 2 0 3 pr o vi de d a l o n ger d urati o n of effect c o m pare d wit h 
I R C D - L D a n d R yt ar y, i ncl u di n g “ Off ” ti me a n d “ G o o d o n” ti me  base d o n t he Assess me nt of 
S u bject’s M ot or State a n d o n a ra n ge of i m pr o ve me nt t hres h ol ds of t he M D S- U P D R S Part III.  
T he res ults were c o nsiste nt wit h t he pr ol o n ge d L D plas ma c o nce ntrati o n pr ofile wit h I P X 2 0 3 
c o m pare d t o I R C D - L D or R ytar y a n d s u p p ort a d osi n g i nter val of a p pr o xi matel y 8 h o urs. 
Of t he 2 6 s u bjects w h o r ecei ve d at least o ne of t h e 3 treat me nts, 9 ( 3 4. 6 %) re p orte d at least o ne 
treat me nt-e mer ge nt a d v erse e ve nt ( A E).  N o n e of t hese s u bjects re p orte d a seri o us A E (S A E ) n or 
di d a n y s u bjects pre mat urel y dis c o nti n ue t he st u d y beca use of a n A E.  A d verse e v e nts were 
re p orte d b y m or e s u bjects d uri n g I R ( 2 8. 0 %) a n d I P X 2 0 3 ( 1 9. 2 %) t ha n d uri n g R yt ar y ( 8. 0 %) 
treat me nt.  N o ne of t he r e p orte d A Es w ere classifie d as “se v ere.”  A d verse e ve nts re p ort e d b y 
2 or m ore s u bjects i ncl u d e: Dizzi ness ( 3 s u bjects), na usea ( 2 s u bj ects), a n d h y perte nsi o n 
( 2 s u bjects).  T he n u m bers of s u bjects re p orti n g t h ese A Es d uri n g a n y si n gl e treat me nt peri o d 
were s mall ( 0 t o 2 s u bjects).  T w o s u bjects re p orte d dizzi ness d uri n g I R C D -L D  treat me nt a n d 
o ne s u bject eac h d uri n g I P X 2 0 3 a n d R ytar y treat me nts.  H y p erte nsi o n was re p orte d b y a t otal of 
2 s u bjects, b ot h re p orti n g t his A E d uri n g I P X 2 0 3 a n d I R C D -L D  treat me nts a n d 1 s u bject d uri n g 
R yt ar y tr eat me nt.  T w o s u bjects re p orte d n a usea o nl y d uri n g t he I R C D -L D  treat me nt peri o d.  Of 
t he 9 s u bjects re p orti n g A Es, 6/ 2 6 ( 2 3. 1 %) of s u bjects re p orte d A Es t hat w ere ass esse d as relate d 
t o treat me nt, i ncl u di n g all of t he re p orts of dizzi ness, na usea, a n d d ys ki nesi a ( 1 s u bject). 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 1  of 1 5 9  
 
St u d y I P X 2 0 3-B 1 6 - 0 1 is a ra n d o mize d, o pe n-la b el, rater- bli n de d, m ultice nt er, 2-treat me nt, 
2- peri o d, m ulti ple- d ose cr oss o ver st u d y t hat has c o m plete d d osi n g.  T w e nt y -ei g ht ( N = 2 8) 
a d va nce d P D s u bjects were ra n d o mize d t o 1 of 2  d osi n g se q ue n ces , wit h eac h treat me nt peri o d 
lasti n g 1 5 da ys a n d s e par ate d b y a 1-w ee k was h - o ut peri o d w here s u bjects ret ur n t o t heir us ual 
sta ble pre-st u d y C D-L D re gi me n .  T he o bjecti ves of t his st u d y are t o c o m p are t he P K, 
p har mac o d y n a mics, efficac y, a n d safet y of I P X 2 0 3 wit h I R C D- L D after si n gle a n d m ulti ple 
d osi n g.  S u bjects were per mitte d t o ta ke all o we d n o n-C D - L D bas e d P D me dicati o ns t hr o u g h o ut 
t he st u d y if d osi n g re gi m e ns ha d  bee n st a ble f or at least 4 wee ks .  S u bjects were i nstr uct e d t o 
ta ke t heir last d ose of C D- L D n o later t ha n 1 0: 0 0 P M o n t he e ve ni n g pri or t o Da y 1 of eac h 
treat me nt peri o d a n d t o wit h h ol d d osi n g f or at least 5 h o urs bef ore arri vi n g at t he site o n Da y 1 5 of 
eac h treat me nt peri o d .  O n Da y  1 of t he I R C D - L D treat me nt peri o d, s u bjects were starte d wit h a 
si n gle d ose of t heir us ual prest u d y first m or ni n g I R C D - L D d os e.  O n Da y 1 of t he I P X 2 0 3 
treat me nt peri o d, s u bjects were  starte d wit h a si n gle d ose of I P X 2 0 3 bas e d o n t heir us ual 
prest u d y first m or ni n g I R C D - L D d ose usi n g a L D c o n versi o n of 1 0 0 m g I R L D t o 3 6 0 m g of 
I P X2 0 3 L D .  D uri n g t he I R C D -L D treat me nt p eri o d, t he i nitial d osi n g re gi me n of I R  C D -L D 
was t he sa me as t he s u bject’s sta ble pr est u d y re gi me n.   D uri n g t he I P X 2 0 3 treat me nt peri o d, t he 
I P X 2 0 3 r e gi me n f or s u bs e q ue nt d oses f or t h e da y was deter mi ne d b y i d e ntif yi n g t he m ost 
fre q ue nt pr est u d y I R L D d ose i n milli gra ms t hat t he s u bject recei ve d i n t he after n o o n a n d 
e ve ni n g a n d a d mi nister i n g I P X 2 0 3 usi n g a L D c o n versi o n of 1 0 0 m g I R L D t o 2 7 0 m g of 
I P X2 0 3 L D .  T he pr ot oc ol rec o m me n de d t hat I P X 2 0 3 be d ose d a p pr o xi matel y e ver y 7 t o 
8 h o urs.  D uri n g Da ys 1 t hr o u g h 9 of b ot h treat me nt peri o ds, i n vesti gat ors ha d t he o p p ort u nit y t o 
a dj ust eac h s u bject’s st u d y me dicati o n re gi me n if necessar y t o o pti mize efficac y a n d s afet y.   
P har mac o ki netics a n d p h ar mac o d y n a mics ( M D S -U P D R S Part III a n d Assess me nts of S u bject’s 
M ot or State) were peri o di call y e val uate d o n Da y 1 a n d Da y 1 5 o f eac h treat me nt peri o d b y 
q ualifie d cli nical staff w h o were bli n de d t o d osi n g.  
Data fr o m t his m ulti ple - d ose st u d y c o nfir me d t he P K a n d p har mac o d y na mic res ults o bser v e d i n 
t he si n gle d ose st u d y wit h I P X 2 0 3: 
•  P K d ata fr o m 2 7 s u bjects i n dicates I P X 2 0 3 s h o ws a ra pi d i ncrease i n L D 
c o nce ntr ati o ns f oll o we d b y e xte n de d- release c h aracteristics.  F oll o wi n g I P X 2 0 3; 
i nitial i ncreases i n L D c o nce ntrati o ns were c o m p ara ble t o t hat fr o m I R C D -L D.  
Bi oa vaila bilit y of L D f oll o wi n g I P X 2 0 3 w as ~ 8 9 % relati ve t o I R C D -L D.  L D 
plas ma c o nce ntrati o ns w ere s ustai ne d l o n ger aft er I P X 2 0 3 treat me nt t ha n after 
I R C D - L D a n d s u p p ort d osi n g e ver y 8 h o urs.  N o acc u m ulati o n of L D was e vi de nt at 
stea d y-state f oll o wi n g I P X 2 0 3 or I R C D -L D.  Plas ma L D c o nce ntrati o ns f oll o wi n g 
I P X 2 03 w ere c haracterize d b y l o w er p ea k -t o-tr o u g h fl uct u ati o n.  N o ti me - varia nt or 
ti me- de pe n de nt c h a n ges were n ote d i n P K of C D or L D f oll o wi n g I P X 2 0 3. 
•  I P X 2 0 3 d e m o nstrate d a n o nset of effect t hat w as c o m para ble t o I R C D -L D i n 
M D S -U P D R S Part III s c ores.  I P X 2 0 3 pr ol o n ge d t he d urati o n o ver w hi c h 
M D S - U P D R S Part III s c ores were i m pr o ve d b y pres pecifi e d t hres h ol d c h a n ges fr o m 
baseli ne ( ≥4, ≥7, a n d ≥1 3 u nits ). 
•  I P X 2 0 3 pr o vi d es a si g nifica nt decreas e i n “ Off” ti me a n d a si g nifica nt i ncrease i n 
“ G o o d o n” ti me c o m pare d t o I R  C D - L D treat me nt o n Da y 1 a n d D a y 1 5 w he n 
assesse d b y t he I n v esti gat or’s Assess me nt of S u bject’s M ot or State.  S u bjects treate d 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 2  of 1 5 9  
 
wit h I P X 2 0 3 di d n ot e x perie nce a si g nifica nt i ncrease i n “ O n ” ti me wit h tr o u bles o me 
d ys ki nesia c o m pare d t o I R C D -L D.  
•  S u bjects ac hie ve d  si g nifi ca nt i m pr o ve me nts i n “ Off” ti me, “ G o o d o n ” ti me, a n d 
fre q ue n c y of m ot or state fl uct uati o ns base d o n t he 3-da y P D Diar ies. 
•  T we nt y - ei g ht s u bjects w ere e nr olle d i n t he m ulti ple d ose st u d y a n d 2 7 s u bjects 
c o m plete d b ot h treat me nts.  Sa fet y res ults were as f oll o ws: 
− O ne s u bject disc o nti n ue d d uri n g t he I P X 2 0 3 treat me nt peri o d d ue t o a n A E 
( ort h ostatic h y p erte nsi o n) t hat was c o nsi dere d p ossi bl y relat e d t o treat me nt. 
− A t otal of 3 9. 3 % ( 1 1/ 2 8 ) of treate d s u bjects re p orte d at least o ne treat me nt 
e mer ge nt A E, i n cl u di n g 3 5. 7% ( 1 0/ 2 8) d uri n g I P X 2 0 3 treat me nt a n d 7. 4 % ( 2/2 7 ) 
d uri n g I R C D -L D  treat me nt.  Ei g ht  s u bjects re p orte d A Es t hat were rel ate d t o 
treat me nt (8 s u bjects d uri n g I P X 2 0 3 treat me nt a n d 1 d uri n g I R C D -L D  
treat me nt). 
− T w o s u bjects e x perie nce d seri o us a d vers e e v e nts ( S A Es).  O ne s u bject re p orte d 
i ncreas e d h y perte nsi o n of m il d se verit y d uri n g I P X 2 0 3 treat me nt t hat was 
c o nsi dere d u nrelate d t o treat me nt a n d res ol ve d.  A sec o n d s u bject re p orte d 
m o derate t o se v ere  d e h y drati o n , diarr hea, a n d atri al fi brillati o n d uri n g t he 
was h o ut peri o d t hat were c o nsi dere d u nrelate d t o treat me nt  a n d res ol ve d . 
− A Es re p orte d i n 2 or m ore s u bjects i ncl u de d na us ea ( 2), dizzi ness ( 2), a n d 
d ys ki nesia ( 5), all of mil d or m o derate s e verit y, a n d all d uri n g t he I P X 2 0 3 
treat me nt. 
T he c urr e nt pr ot oc ol, St u d y I P X 2 0 3- B 1 6 - 0 2, is a m ultice nter, ra n d o mize d, d o u ble- bli n d, d o u ble-
d u m m y, acti ve-c o ntr olle d, parallel- gr o u p, P has e 3 st u d y.  It is desi g ne d t o c o m pare t he effi cac y, 
safet y a n d t oler a bilit y of I P X 2 0 3 wit h I R C D - L D f oll o wi n g m ulti ple d oses o ver 1 3 wee ks.  The 
f oll o wi n g I P X 2 0 3 d osi n g g ui deli nes will be utilize d i n t he prese nt st u d y ( I P X 2 0 3-B 1 6 - 0 2): 
•  T he i nitial re gi me n of I P X 2 0 3 is base d o n t he m ost fre q ue nt d ose of t he s u bject’s 
d osi n g re gi me n of I R C D -L D at t he e n d of d ose a dj ust me nt peri o d ( Visit 2); 
•  A 2 5- 1 0 0 m g d os e of I R C D- L D will be c o n verte d t o a 7 0- 2 8 0 m g C D- L D d ose of 
I P X 2 0 3; 
•  I P X 2 0 3 will be a d mi nistere d a p pr o xi matel y e v er y 8 h o urs f or m ost s u bjects; 
•  I n v esti gat ors ma y a dj ust t he I P X 2 0 3 re gi me n d uri n g t he d os e c o n versi o n peri o d t o 
o pti mize t he t hera pe utic effect ( mi ni mize “ Off” ti me wit h o ut ca usi n g tr o u bles o me 
d ys ki nesia or ot her d o pa mi ner gic si d e effects) . 
T he pr o p ose d d ose c o n versi o n sc he me f or t his st u d y has b ee n d e vel o pe d b ase d o n a si milar d ose 
c o n versi o n fr o m I R C D- L D t o I P X 2 0 3 t hat w as  st u die d i n t he c o m plete d P hase 2a st u d y 
(I P X 2 0 3-B 1 4 - 0 2, n = 2 5) a n d t he P hase 2 b st u d y (I P X 2 0 3-B 1 6 - 0 1, n = 2 8), b ot h c o n d ucte d i n 
s u bjects wit h a d va nce d P D usi n g si milar e ntr y criteria t o t he prese nt st u d y.  T he d oses of I P X 2 0 3 
are e x pecte d t o b e c o m para ble t o ot her E R C D - L D pr o d ucts, s uc h as R ytar y  a n d D u o pa. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 3  of 1 5 9  
 
5.  
T RI A L O B J E C TI V E S  
T o e val uate t he s afet y a n d efficac y of I P X 2 0 3 i n c o m paris o n t o I R C D -L D i n t he treat me nt of 
C D -L D e x perie nce d s u bjects wit h Par ki ns o n’s d isease ( P D) w h o ha v e m ot or fl uct uati o ns. 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 4  of 1 5 9  
 
6.  
I N V E S TI G A TI O N A L PL A N  
6. 1.  
O ver all St u d y Desi g n  
T his is a m ultice nter, ra n d o mize d, d o u ble- bli n d, d o u ble- d u m m y, acti ve-c o ntr olle d, parallel -
gr o u p st u d y.  S u bjects will  c o nti n ue t o ta ke per mitte d  n o n-C D -L D -b ase d P D me dicati o ns 
t hr o u g h o ut t he st u d y if d oc u me nte d i n t heir prest u d y re gi me n a n d if d osi n g re gi me ns ha ve b ee n 
sta ble f or at least 4 wee ks pri or t o Visit 1 .  A “sta ble d osi n g re gi me n” mea ns n o c ha n ge i n d ose 
or i n d osi n g fr e q ue n c y.  Wit hi n 4 wee ks f oll o wi n g t he Scree ni n g visit, eli gi ble s u bjects will 
c o m plete t heir P D  Diari es o n eac h of t h e 3 c o nsec uti ve da ys i m me diatel y pri or t o Visit  1. 
F oll o wi n g Visit 1, q ualifi e d s u bjects will e nter a 3 -wee k, o p e n -la b el I R C D -L D treat me nt p eri o d 
all o wi n g f or d ose a dj ust me nt.  D uri n g t he I R C D - L D d ose a dj ust me nt peri o d, t he i nitial d osi n g 
re gi me n of I R C D -L D will be t he sa me as t he s u bj ect’s sta ble prest u d y re gi me n u nless  t he 
s u bject is ta ki n g a si n gle dail y be dti me d ose of C R C D - L D, i n w hic h case, t he C R C D -L D d o s e 
will be disc o nti n ue d a n d s u bstit ute d wit h a 1: 1 milli gra m -e q ui vale nt d ose of I R C D -L D.  A 
“ be dti me d ose” is defi ne d as t he last da yti me d ose of C D-L D ta k e n wit hi n 1 h o ur of o nset of t he 
s u bject’s n or mal ni g htti me slee p peri o d.  T he d osi n g re gi me n of I R C D -L D m a y be a dj uste d 
d uri n g t he d ose a dj ust me nt peri o d  t o mi ni mize “ Off” ti me wit h o ut ca usi n g tr o u bles o me 
d ys ki nesia.  T h e d oses a n d re gi me ns of t he s u bject’s ot her n o n- C D - L D Par ki ns o n’s disease 
me dicati o ns ( d o pa mi ne a g o nists, M A O- B i n hi bit ors, a ma nta di ne, a ntic h oli ner gics) s h o ul d 
re mai n sta ble t hr o u g h o ut t his st u d y.  An y  a dj ust me nts t o t he I R C D -L D  d osi n g re gi me n will be 
d o ne i n c o ns ultati o n wit h t he I n v esti gat or or q u alifie d site pers o n nel a n d will  be rec or de d .  T he 
s u bject m ust be o n a sta ble d osi n g r e gi me n ( n o c h a n ge i n d ose or i n d osi n g fre q ue n c y) of 
I R C D -L D f or at least 5 da ys pri or t o ret ur ni n g f or Visit 2.  Resc ue wit h a d diti o nal or m o difie d 
d oses of c o nc o mita nt P D me dicati o ns or wit h use of C D- L D pr o d u cts ot her t ha n t he dis pe nse d 
st u d y me dicati o ns is n ot per mitte d a n d will tri g ger disc o nti n uati o n fr o m t he st u d y.  S u bjects will 
c o m plete t heir 3 -d a y P D  Diaries o n eac h of t he 3 c o nsec uti ve da ys i m me diatel y pri or t o Visit 1. 
F oll o wi n g c o m pleti o n of t he I R C D -L D  d ose a dj ust me nt peri o d, s u bjects will be gi n a 4-wee k 
o pe n-la bel peri o d f or c o n versi o n t o I P X 2 0 3.  T h e i nitial d osi n g re gi me n of I P X 2 0 3 d uri n g t he 
c o n versi o n peri o d will be base d o n t he s u bject’s d osi n g re gi me n of I R C D -L D at t he e n d of t h e 
d ose a dj ust me nt peri o d ( Visit 2)  selecti n g t he m ost fre q ue nt d ose acc or di n g t o  Ta ble  3.  A 
2 5- 1 0 0 m g d ose of I R C D -L D c o n v erts t o a 7 0- 2 8 0 m g  C D -L D d os e of I P X 2 0 3 b ut wit h a l o n ger 
d urati o n of effect.  It is r ec o m me n de d t hat I P X 2 0 3 s h o ul d be d ose d a p pr o xi matel y e v er y 8 h o urs 
wit h t he e x ce pti o n t hat s u bjects w h o are c urre ntl y recei vi n g a t otal d ail y d ose of less t ha n 
1 2 5- 5 0 0 m g I R C D - L D at t he e n d of t he d ose a dj ust me nt peri o d will be i nitiall y a d mi nistere d 
I P X 2 0 3 e ver y 1 2 h o urs.  T he d osi n g i nter v al ma y be re d uce d t o a p pr o xi matel y e ver y 8 h o urs if 
t he s u bject d oes n ot ac hi e ve a n acce pta ble d urati o n of effect.  T he d osi n g re gi me n of I P X 2 0 3 
m a y be a dj uste d d uri n g t he d ose c o n versi o n peri o d  t o ac hie ve t he o pti mal bala nce of efficac y 
a n d t olera bilit y ( mi ni mize “ O ff” ti me wit h o ut ca usi n g tr o u bles o me d ys ki nesia or ot her 
d o pa mi ner gic si de effects).   An y  a dj ust me nts t o t he I P X 2 0 3 d osi n g re gi m e n will be  rec or de d.  
Resc ue wit h a d diti o nal or m o difie d d oses of c o n c o mita nt P D me dicati o ns or wit h use of C D- L D 
pr o d ucts ot her t ha n t he dis pe nse d st u d y m e dicati o ns is n ot per mitte d a n d will tri g ger 
disc o nti n uati o n fr o m t he st u d y.  S u bjects will ret ur n t o t he cli nic i n t w o wee ks f or Visit 3 
f oll o we d b y Visit 4 t w o wee ks later .  T he s u bject m ust be o n a sta ble d osi n g re gi me n of I P X 2 0 3 




Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 6  of 1 5 9  
 
6. 3.  
Tre at me nt Assi g n me nt  
I n v esti gati o nal pr o d uct:  I P X 2 0 3 ( car bi d o pa-le v o d o pa) E xte n de d-Releas e Ca ps ules c o ntai ni n g 
3 5- 1 4 0 m g  of C D -L D, f or oral a d mi nistrati o n.  
Refere n ce t hera p y:  I m m e diate -Release car bi d o pa-le v o d o pa (I R C D -L D) ta blet s c o ntai ni n g 
2 5- 1 0 0 m g of C D -L D, f or oral a d mi nistrati o n.  
S u bjects will be ra n d o ml y assi g ne d t o o n e of t w o parallel treat me nt ar ms t o recei v e eit her 
I P X 2 0 3 (wit h matc hi n g I R  C D -L D  place b o ) or I R C D -L D (wit h matc hi n g I P X 2 0 3  place b o ) 
d uri n g t he d o u ble- bli n d mai nte na nce t hera p y p orti o n of t he st u d y. 
6. 4.  
D osi n g a n d D ose Deter mi n ati o n Criteri a  
I R C D -L D will be s u p plie d as ta blets c o ntai ni n g 2 5 - 1 0 0 m g of C D -L D.  I R  C D -L D ta blets ma y 
be s plit t o ac hie ve t he r e q uire d d ose. 
I P X 2 0 3 will be s u p plie d as ca ps ules c o ntai ni n g 3 5- 1 4 0 m g  of C D - L D.  T he s u g geste d d os es a n d 
re gi me n of I P X 2 0 3 are i nte n de d t o pr o vi de a n o ns et of effect c o m p ara ble t o t he s u bject’s 
prest u d y I R L D re gi me n a n d t o e xte n d t he d urati o n of effect.  A 2 5- 1 0 0 m g d ose of I R C D -L D 
c o n verts t o a 7 0- 2 8 0 m g  C D -L D d ose of I P X 2 0 3. 
6. 4. 1.  
I R C D -L D D ose A dj ust me nt Peri o d  
D uri n g t h e 3- wee k I R C D - L D d ose a dj ust me nt peri o d, t he i nitial d osi n g re gi me n of I R C D -L D 
will be t he sa me as t he s u bject’s sta ble prest u d y re gi me n u nless t he s u bject is ta ki n g a si n gle 
dail y be dti me d ose of C R C D - L D, i n w hic h case, t he C R C D - L D d os e will be disc o nti n ue d a n d 
s u bstit ute d wit h a 1: 1 milli gra m- e q ui vale nt d ose of I R C D -L D.   A “ b e dti me d ose” is defi n e d as 
t he last da yti me d os e of C D - L D ta ke n wit hi n 1 h o ur of o nset of t he s u bject’s n or mal ni g htti me 
slee p peri o d.  S u bjects w h o we re recei vi n g I R C D -L D as a 1: 1 0 C D-L D f or m ulati o n will be 
starte d o n I R C D -L D wit h  a 1: 4 rati o at t he sa me fre q ue nc y a n d L D d os e.  T he d osi n g re gi me n 
of I R C D -L D m a y be a dj uste d d uri n g t he d ose a dj ust me nt peri o d  t o mi ni mize “ Off” ti me 
wit h o ut ca usi n g tr o u bles o me d ys ki nesia.  T h e d os es a n d re gi me ns of t he s u bject’s ot her 
n o n- C D - L D Par ki ns o n’s disease me dicati o ns ( d o pa mi ne a g o nists, M A O- B i n hi bit ors, 
a ma nta di ne, a ntic h oli ner gics) s h o ul d r e mai n sta bl e t hr o u g h o ut t his st u d y.  A n y a dj ust me nts t o 
t he I R C D -L D  d osi n g re gi me n  will be d o ne i n c o ns ultati o n wit h t he I n vesti gat or or q ualifie d site 
pers o n nel a n d will be r ec or de d.  T he s u bject m ust be o n a sta ble d osi n g re gi me n ( n o c ha n ge i n 
d ose or i n d osi n g fre q u e n c y) of I R C D -L D  f or at least 5 da ys pri or t o ret ur ni n g f or Visit 2. 
6. 4. 2.  
I P X 2 0 3 D os e C o n versi o n Peri o d 
D uri n g t h e 4- wee k I P X 2 0 3 d ose c o n versi o n p eri o d, t he s u g geste d i nitial d osi n g re gi me n of 
I P X 2 0 3 will be b ase d o n t he m ost fre q ue nt d ose of t he s u bject’s d osi n g re gi me n of I R  C D -L D at 
t he e n d of t he d ose a dj ust me nt peri o d ( Visit 2).  A 2 5- 1 0 0 m g d ose of I R C D -L D c o n v erts t o a 
7 0- 2 8 0 m g C D -L D d ose of I P X 2 0 3,  a n d a h alf ta blet ( 1 2. 5- 5 0 m g d os e of I R C D - L D) c o n verts 
t o a 3 5- 1 4 0 m g C D -L D d ose of I P X 2 0 3.  T o facilitate c o n versi o n of s u bjects fr o m I R C D -L D t o 
I P X 2 0 3, T a ble  3 pr ese nts rec o m me n de d st arti n g  d ose re gi me ns .  It is rec o m me n de d t hat I P X 2 0 3 
s h o ul d be d ose d a p pr o xi matel y e ver y 8 h o urs wit h t he e x ce pti o n t hat s u bjects w h o are c urre ntl y 
recei vi n g a t otal d ail y d ose of less t ha n 1 2 5- 5 0 0 m g I R C D -L D at t he e n d of t he d ose a dj ust me nt 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 7  of 1 5 9  
 
peri o d will be  i nitiall y a d mi nistere d I P X 2 0 3 e ver y 1 2 h o urs.  T he d osi n g i nter val ma y be re d uce d 
t o a p pr o xi matel y e ver y 8 h o urs if t he s u bject d oes n ot ac hie ve a n acce pta bl e d urati o n of effect .  
T he d osi n g re gi me n of I P X 2 0 3 m a y be a dj uste d d uri n g t he d ose c o n versi o n peri o d t o 
ac hie ve t h e o pti mal bala nce of efficac y a n d t olera bilit y ( mi ni mize “ Off” ti me wit h o ut ca usi n g 
tr o u bles o me d ys ki nesi a or ot her d o pa mi ner gi c si de effects).  T h e ma xi m u m rec o m me n de d d ail y 
d ose of I P X 2 0 3 is 6 0 0- 2 4 0 0 m g C D- L D.   T h e  d oses a n d re gi me ns of t he s u bject’s ot her n o n-C D -
L D Par ki ns o n’s disease me dicati o ns ( d o pa mi ne a g o nists, M A O- B i n hi bit ors, a ma nta di ne, 
a ntic h oli ner gics) s h o ul d r e mai n sta ble t hr o u g h o ut t his st u d y.  T he s u bject m ust be o n a sta ble 
d osi n g re gi me n of I P X 2 0 3 ( n o c ha n ge i n d os e or i n d osi n g fre q ue n c y) f or at least 5 da ys pri or t o 
ret ur ni n g f or Visit 4. 
T a ble 3: 
Rec o m me n de d St arti n g I P X 2 0 3 L D D osi n g Re gi me n B ase d o n t he D osi n g 
Re gi me n of I R C D-L D  at t he E n d of t he D ose A dj ust me nt Peri o d  
M ost F re q ue nt  I R C D-L D U nit  D ose 
( m g) 
Rec o m me n de d St arti n g I P X 2 0 3 D ail y D osi n g Re gi me n 
C D -L D ( m g)  E ver y 8 H o urs 
2 5- 1 0 0 a 
7 0- 2 8 0 m g  ( 2 × 3 5- 1 4 0 m g ) 
> 2 5- 1 0 0 – 3 7. 5- 1 5 0 
1 0 5- 4 2 0 m g ( 3 × 3 5- 1 4 0 m g) 
> 3 7. 5- 1 5 0 – 5 0- 2 0 0 
1 4 0- 5 6 0 m g ( 4 × 3 5- 1 4 0 m g) 
> 5 0- 2 0 0 
1 7 5- 7 0 0 m g ( 5 × 3 5- 1 4 0 m g) 
a S u bj ect s w h o are o n a t otal dail y d ose of less t ha n 1 2 5 -5 0 0 m g C D -L D fr o m I R  C D -L D s h o ul d be a d vise d t o 
i nitiall y ta ke I P X 2 0 3 e ver y 1 2 h o urs.  T he d osi n g i nter val ma y be re d uce d t o a p pr o xi matel y e ver y 8 h o urs  if t he 
s u bj ect d oes n ot ac hie ve a n ac ce pta ble d urati o n of effect. 
 
D uri n g t h e d ose c o n v ersi o n t o I P X 2 0 3, t he I n v esti gat or or site staff are a d vise d t o be i n fre q ue nt 
c o ntact (e v er y 1 t o 3 da ys) wit h t he s u bject es peciall y d uri n g t he i nitial d ose c o n versi o n t o ass ess 
t he nee d f or d osa ge a dj ust me nt wit h t he g oal of mi ni mizi n g “ Off” ti me wit h o ut ca usi n g 
tr o u bles o me d ys ki nesi a.  A n y c ha n ges t o t he d osi n g re gi me n s h o ul d o nl y b e ma de b y  t he 
I n v esti gat or or q ualifie d site pers o n nel.  If t he s u bject e x perie nces tr o u bl es o me d ys ki nesias 
d uri n g i nitial d ose c o n v ersi o n, c o nsi der re d uci n g t he d ose b y o ne ca ps ule ( 3 5- 1 4 0 m g I P X 2 0 3 
C D - L D) bef ore i ncreasi n g t he d osi n g i nter v al.  If t urni n g “ O n” is sl o w f oll o wi n g t he first 
m or ni n g d ose, c o nsi der t a ki n g t he m or ni n g d os e i n t he faste d state a n d/ or i ncreasi n g t he d os e b y 
o ne ca ps ule ( 3 5- 1 4 0 m g I P X 2 0 3 C D- L D).  If t ur ni n g “ O n” is sl o w later i n t he da y or t o re d uce 
“e n d- of-d ose” “ Off” ti me, c o nsi der i ncreasi n g t he d ose b y o n e ca ps ule ( 3 5- 1 4 0 m g I P X 2 0 3 
C D -L D).  
W he n t w o or m ore I R  C D - L D d oses c orres p o n d t o t he m ost fre q ue nt I R C D -L D d ose, t he 
s u g geste d I P X 2 0 3 c o n versi o n s h o ul d be base d o n t he hi g her of t he I R C D -L D  d os es. 
A s u m mar y of t he i nstr ucti o ns f or d ose c o n versi o n t o I P X 2 0 3 is pr o vi de d i n A p pe n di x B . 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 8  of 1 5 9  
 
6. 4. 3.  
D o u ble -Bli n d M ai nte n a nce Peri o d  
D uri n g t h e 1 3- wee k d o u ble- bli n d d o u ble- d u m m y mai nte na nce p eri o d, s u bj ects recei ve eit her 
I P X 2 0 3 ( wit h matc hi n g I R C D - L D place b o) or I R C D - L D ( wit h matc hi n g I P X 2 0 3 place b o) wit h 
t he sta ble d osi n g r e gi me n esta blis he d at t he e n d of Wee k 3 ( Visit 2) f or I R C D - L D a n d at t he e n d 
of Wee k  7 ( Visit 4) f or I P X 2 0 3. 
6. 5.  
Criteri a f or St u d y Ter mi n ati o n  
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y a n d re m o ve all st u d y material fr o m t he st u d y 
site at a n y ti me f or me dical or a d mi nistrati ve reas o ns.  T he S p o ns or will e n dea v or t o gi ve 
a de q uate n otice t o all o w safe wit h dra wal of s u bjects fr o m t he st u d y.  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 2 9  of 1 5 9  
 
7.  
S E L E C TI O N A N D WI T H D R A W A L O F S U B J E C T S 
S u bject s m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o q ualif y f or e nr oll me nt.   S u bjects w h o 
ha ve a n y of t h e f oll o wi n g e x cl usi o n criteria will n ot be e nr olle d i n t he st u d y.  
7. 1.  
S u bject I ncl usi o n Criteri a  
1.  Male or fe m ale s u bjects dia g n ose d at a ge ≥ 4 0 ye ars wit h P D , c o nsiste nt wit h t he U nite d 
Ki n g d o m Par ki ns o n’s Disease S ociet y Brai n Ba n k Dia g n ostic Criteria ( A p p e n di x C ) a n d 
w h o are b ei n g treat e d wit h sta ble re gi me ns of C D - L D b ut e x perie n ci n g m ot or 
fl uct uati o ns. 
2.  A ble t o pr o vi de writte n i nf or me d c o ns e nt pri or t o t he c o n d uct of a n y st u d y- s pecific 
pr oce d ur es. 
3.  Fe male s u bjects of c hil d beari n g p ote ntial m ust ha ve a ne gati ve uri ne pre g n a nc y test at 
Scree ni n g Visit.  
4.  Ne gati ve uri ne s cree n f or dr u gs of a b use a n d ne gati ve alc o h ol breat h tes t at Scree ni n g. 
5.  H oe h n a n d Y a hr Sta ges 1, 2, 3, or 4 i n t he “ O n” st ate ( part of M o ve me nt Dis or ders 
S ociet y versi o n of t he U nifie d Par ki ns o n’s Diseas e Rati n g Scale [ M D S- U P D R S] Part 
III; A p pe n di x E ). 
6.  A grees t o use a me dicall y acce pta ble met h o d of c o ntrace pti o n t hr o u g h o ut t he st u d y a n d 
f or 6 wee ks after c o m pleti n g t he st u d y.  Me dicall y acce pta ble met h o ds of c o ntrace pti o n 
t hat ma y b e use d b y t he s u bject a n d/ or part ner i ncl u de b ut are n ot li mite d t o:  a bsti ne nce, 
oral c o ntrace pti o n, N u va Ri n g or tra ns d er mal s yste ms, dia p hra g m wit h va gi nal 
s per mici de, i ntra uteri ne de vice, c o n d o m a n d part ner usi n g v a gi nal s per mi ci de, s ur gical 
sterilizati o n ( 6 m o nt hs), pr o gesti n i m pla nt or i njecti o n, or p ost me n o pa usal fe male ( n o 
me nstr ual peri o d f or ˃ 2 years) or vasect o m y ( ˃ 6 m o nt hs). 
7.  M o ntreal C o g niti ve Assess me nt ( M o C A) sc ore ≥ 2 4 a t Scree ni n g Visit i n “O n” state 
(A p pe n di x D ). 
8.  B y hist or y, f or t he 4 wee ks pri or t o Scree ni n g, t he s u bject e x perie nces d ail y “ weari n g -
off” e pis o des wit h peri o ds of bra d y ki nesia i n c o m bi nati o n wit h at least o ne of rest tre m or 
or ri gi dit y, e x perie nces a n “Off ” state u p o n a wa ke ni n g o n m ost m or ni n gs, a n d re p orts a n 
a vera ge of at least 2. 5  c u m ulati ve h o urs per da y of “Off ” ti me d uri n g t he w a ki n g h o urs. 
9.  A ble t o differ e ntiate “ O n ” state fr o m “ O ff” state as deter mi ne d b y at least 7 5 % 
c o nc or da n ce wit h a trai n e d rater i n “ O n/ O ff” rati n gs f or 8 rati n gs o ver t h e 4- h o ur trai ni n g 
peri o d.  T he c o n c or da n ce m ust i ncl u de at least 1 “ O n” a n d 1 “ Off” rati n g a n d m ust be 
ac hie ve d wit hi n t w o 4- h o ur trai ni n g s essi o ns. 
1 0.  At Visit 1, re vie w of t he 3 -da y P D Diaries c o nfir ms t he f oll o wi n g:  t hat t he s u bject is a ble 
t o pr o perl y c o m plete t he diaries wit h vali d e ntries; a n d t hat t he s u bject has a n a vera ge of 
at least 2. 5 h o urs  per d a y of “ Off” ti me d uri n g t he wa ki n g h o urs o ver t h e 3 da ys wit h at 
least 1. 5 h o urs of c u m ulati ve “ Off” ti me o n eac h d a y.  I na bilit y t o pr o p erl y c o m plete t he 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 3 0  of 1 5 9  
 
d iaries is i n dicate d w he n m ore t ha n 1 da y of a d iar y is n ot ret ur n e d or w h e n m ore t ha n 
2 h o urs ( 4 half - h o ur peri o ds) of o ne 2 4- h o ur diar y da y are missi n g ( A p p e n di x P ). 
1 1.  Res p o nsi ve t o C D- L D t h era p y a n d c urre ntl y b ei n g treate d o n a st a ble re gi me n wit h 
C D -L D f or at least 4 wee ks pri or t o Visit 1 a n d: 
a. R e q uires at least 1 0 0 m g of L D fr o m I R C D - L D f or t he first m or ni n g d os e 
b.  R e q uires a t otal dail y d os e of at least 4 0 0 m g of L D  a n d ta kes a m a xi m u m t otal dail y 
d ose of 2 4 0 0 m g L D, fr o m I R C D - L D al o ne or I R C D - L D i n c o m bi nati o n wit h a 
si n gle dail y be dti me d ose of C R C D -L D  
c. H as a d osi n g fr e q ue nc y of 4 t o 9 ti mes dail y of C D-L D  
d.  B y hist or y, t y picall y e x perie nces a n “ O n” res p o ns e wit h t he first d ose of I R C D -L D 
of t he da y, b ut t he efficac y of t his d ose t y picall y lasts less t ha n 4 h o urs. 
1 2.  At Scree ni n g, t he s u bject has pre dicta bl e “ O ff” p eri o ds defi ne d b y a s c ore of 1 or 2 o n 
Ite m # 4. 5 ( C o m ple xit y of M ot or Fl uct uati o ns) of t he M D S-U P D R S Part I V B ( M ot or 
Fl uct uati o ns) ( A p p e n di x E ). 
1 3.  At Scree ni n g, t he M D S -U P D R S Part III t otal sc ore i n t he “ Off” stat e is at least 2 0 u nits. 
1 4.  A ble a n d willi n g t o c o m pl y wit h t he pr ot oc ol, i ncl u di n g c o m pleti o n of diaries a n d 
a vaila bilit y f or all st u d y visits.  
7. 2.  
S u bject  E xcl usi o n Criteri a  
1.  Use d a n y d oses of c o ntr olle d -release ( C R) C D-L D a part fr o m a si n gl e dail y be dti me d ose 
wit hi n 4 wee ks pri or t o Visit 1. 
2.  Use d  a n y d oses of R ytar y f or t he past 4 w ee ks pri or t o Visit 1 or c o nsi dere d I P X 0 6 6 or 
R yt ar y f ail ures f or reas o ns of efficac y or s afet y.  
3.  Recei ve d a n y i n v esti gati o nal me dicati o ns wit hi n 3 0  da ys or 5 ti mes t he half -life, 
w hic he ver is l o n ger, pri or t o Visit 1. 
4.  Fe male s u bjects w h o ar e c urre ntl y breastfee di n g or lactati n g.  
5.  Ha d pri or ne ur os ur gical treat me nt f or P D or if s uc h pr oce d ure is pla n ne d or a ntici pate d 
d uri n g t he st u d y peri o d. 
6.  Aller gi c t o a n y e x ci pie nt i n t he st u d y dr u gs ( See A p pe n di x Q ). 
7.  Hist or y of m e dical c o n diti o ns or of a pri or s ur gical pr oce d ure t hat w o ul d i nterfere wit h 
L D a bs or pti o n, s uc h as gastrect o m y, pr o xi mal s mall -b o wel res ecti o n , or bariatric s ur ger y. 
8.  Hist or y of u p p er gastr oi ntesti nal he m orr ha ge i n p atie nts wit h pe ptic ulcer disease wit hi n 
t he past 5 years.  
9.  Hist or y of gl a uc o ma wit h i ntra oc ular press ures t h at are ele vate d d es pite a p pr o priate 
me dical ma na ge m e nt.  
1 0.  Hist or y of s eiz ure or e pil e ps y a n d e x perie nce d at l ea st 1 seiz ure d uri n g t he past 
1 2 m o nt hs or has n ot bee n c o m plia nt wit h me dicall y rec o m me n de d t hera p y or visits. 
1 1.  Hist or y of m y o car dial i nf arcti o n wit h resi d ual atrial, n o dal, or ve ntric ul ar arr h yt h mias 
t hat are n ot c o ntr olle d wit h me dical a n d/ or s ur gical i nter ve nti o ns.  A rece nt 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 3 1  of 1 5 9  
 
( ≤ 1 2 m o nt hs) hist or y of m y ocar dial i nfarcti o n wit h sec o n dar y arr h yt h mias is 
e x cl usi o nar y r e gar dl ess of t he t hera p e utic c o ntr ol.  
1 2.  Hist or y of n e ur ole ptic m ali g na nt s y n dr o m e or of n o ntra u matic r ha b d o m y ol ysis. 
1 3.  Li ver e nz y m e val ues ≥ 2. 5 ti mes t he u p per li mit of n or mal; or hist or y of s e v ere he p atic 
i m pair me nt. 
1 4.  Ser u m creati ni ne le vel ≥ 1. 7 5 ti mes t he u p per li mit of n or mal; or re q uires dial ysis at t he 
ti me of Scree ni n g. 
1 5.  S u bject wit h a hist or y of mali g na nt mela n o ma or wit h a s us pici o us u n dia g n ose d s ki n 
lesi o n w hic h i n t he o pi ni o n of t he i n vesti gat or c o ul d be mela n o ma. 
1 6.  Hist or y of dr u g or al c o h ol a b use wit hi n t he 1 2 m o nt hs pri or t o Scree ni n g. 
1 7.  Recei ve d wit hi n 4 wee ks of Visit 1 or pla n ni n g t o ta ke d uri n g partic i p ati o n i n t he cli nical 
st u d y: 
a. a n y d os es of a c o ntr olle d -release ( C R) L D a part fr o m a si n gle dail y be dti m e d ose, a n y 
d oses of R ytar y, a d diti o nal C D (e g, L o d os y n) or b e nserazi de (e g, Serazi de), or 
catec h ol - O- met h yl tra nsf erase i n hi bit ors (e nt aca p o ne or t olca p o ne) or me dicati o ns 
c o ntai ni n g t hes e i n hi bit ors ( Stale v o),  
b.  n o nselecti ve m o n oa mi ne o xi dase i n hi bit ors ( M A OI), a p o m or p hi ne, or 
a nti d o pa mi ner gic a ge nts, i ncl u di n g a ntie metics . 
1 8.  Treat me nt wit h a n y d o p a mi ne a nta g o nist f or t he p ur p oses of treati n g ps yc h osis or bi p olar 
dis or der wit hi n t he last 2 years or a n y hist or y of ps yc h osis wit hi n t he past 1 0 years 
re gar dl ess of treat me nt.  A brief, self -li mite d e pis o de of ps yc h osis preci pitate d b y a 
me dical i nter ve nti o n wit h ret ur n t o n or mal me ntati o n is n ot e x cl usi o nar y.  Mil d 
P D -ass ociate d ill usi o ns are n ot e x cl usi o nar y pr o vi de d t hat t he y d o n ot occ ur m ore t ha n 
t wice per w ee k a n d t he s u bject d oes n ot l ose i nsi g ht. 
1 9.  E m pl o yees or fa mil y me m bers of t he i n vesti gat or, st u d y site, or s p o ns or. 
2 0.  S u bjects w h o ha ve pr e vi o usl y partici p ate d i n a n I P X 2 0 3 st u d y. 
2 1.  S u bjects w h o, i n t he o pi ni o n of t he cli nical i n vesti gat or, s h o ul d n ot partici pate i n t he 
st u d y. 
2 2.  Base d o n cli nical assess me nt, s u bject d oes n ot a d e q uatel y c o m pre he n d t he ter mi n ol o g y 
nee de d t o c o m plet e t he P D diar y.  
7. 3.  
S u bject Wit h dr a w al Criter i a 
Site pers o n nel s h o ul d ma ke e ver y eff ort t o c o n d uct all pr ot oc ol- s pecific pr o ce d ures t o c o m plete 
t he st u d y.  A s u bject ma y be disc o nti n ue d fr o m t he st u d y d ue t o t he f oll o wi n g reas o ns: 
1.  Wit h dra wal b y s u bject 
2.  A d verse e ve nt ( A E)  
3.  Lac k of efficac y  
4.  St u d y t er mi nate d b y S p o ns or 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 3 2  of 1 5 9  
 
5.  Pr ot oc ol de viati o n 
6.  N o nc o m plia nce wit h st u d y dr u g 
7.  L ost t o f oll o w- u p 
8.  Deat h  
9.  Ot her  
S u bjects w h o wit h dra w earl y fr o m t he st u d y will n ot be re place d.  T he reas o n or reas o ns f or 
disc o nti n uati o n will be s pecifie d a n d d o c u me nte d.  E m pt y me dica ti o n b ottles a n d a n y u n use d 
st u d y dr u g u p o n disc o nti n uati o n will be c ollecte d .  St u d y m e dicati o n dis pe nse d t o a disc o nti n ue d 
s u bject ma y n ot b e re dis p e nse d t o a differe nt s u bject. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 3 3  of 1 5 9  
 
8.  
S T U D Y P R O C E D U R E S  
T he pr oce d ures t o be p erf or me d at eac h st u d y visit are des cri be d bel o w a n d s u m marize d 
i n Ta ble  4. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b or at ories, L L C 
 
Pa ge 3 4  of 1 5 9  
 
T a ble 4: 
E ve nts Sc he d ule f or I m p a x St u d y I P X 2 0 3 - B 1 6- 0 2 
Assess me nt  
Scree ni n g  
3 Wee ks of  
I R C D -L D 
D ose 
A dj ust me nt  
4 Wee ks of  
I P X 2 0 3 D ose C o n versi o n  
1 3 Wee ks of  
D o u ble -Bli n d T her a p y  
Visit 1  
Visit 2  
Visit 3  
Visit 4  
R a n d o miz ati o n  
Visit 5  
Visit 6  
Visit 7  / St u d y 
E xit/ E ar l y 
Ter mi n ati o n b  
St u d y W ee k a 
– 4 
0 
3 
5 
7 
1 0  
1 5  
2 0  
I C F & HI P A A A ut h orizati o nc 
X 
 
 
 
 
 
 
 
C o ntact I W R S  
X 
X 
X 
X 
X 
X 
X 
X 
Ra n d o mizati o n  
 
 
 
 
X 
 
 
 
I ncl usi o n/ E xcl usi o n 
X 
X 
 
 
 
 
 
 
Me dical Hist or y  
X 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n  
X 
 
 
 
 
 
 
X 
Vital Si g ns d  
X 
X 
X 
X 
X 
X 
X 
X 
Hei g ht a n d W ei g ht  
X 
 
 
 
 
X e 
 
X e 
C- S S R S f 
X 
X 
X 
X 
X 
X 
X 
X 
Cli nical La b orat or y T ests g 
X 
 
 
 
 
X 
 
X 
Uri ne Pre g na nc y T est  
X 
 
 
 
 
 
 
 
Uri ne Scree n f or Dr u g A b use  
X 
 
 
 
 
 
 
 
Alc o h ol Breat h T est  
X 
 
 
 
 
 
 
 
E C G  
X 
 
 
 
 
X 
 
X 
M o C A
h 
X 
 
 
 
 
 
 
 
M D S -U P D R S P arts I -I V 
X i 
X 
X 
 
X 
X 
X 
X 
P GI - Cj 
 
 
 
 
 
X 
X 
X 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b or at ories, L L C 
 
Pa ge 3 5  of 1 5 9  
 
Assess me nt  
Scree ni n g  
3 Wee ks of  
I R C D -L D 
D ose 
A dj us t me nt 
4 Wee ks of  
I P X 2 0 3 D ose Co n versi o n  
1 3 Wee ks of  
D o u ble -Bli n d T her a p y  
Visit 1  
Visit 2  
Visit 3  
Visit 4  
R a n d o miz ati o n  
Visit 5  
Visit 6  
Visit 7  / St u d y 
E xit/ E arl y 
Ter mi n ati o n b  
St u d y W ee k a 
– 4 
0 
3 
5 
7 
1 0  
1 5  
2 0  
G C SI o 
 
X 
 
 
 
 
 
X 
P D Diar y Trai ni n g; P erf or m 
C o nc or da nce T esti n g at 
Scree ni n g O nl y s 
X 
X 
X 
X 
X 
X 
X 
 
Dis pe nse P D Diaries t 
X 
X 
 
X 
X 
X 
X 
 
Re vie w P D Diaries u 
 
X 
X 
 
X 
X 
X 
X 
Re mi n der p h o ne calls v, w 
X v 
X w  
X w  
X w  
X w  
X 
X 
X 
Dis pe nse st u d y me dicati o n  
 
X 
X 
X 
X 
X 
X 
 
C ollect e m pt y me dicati o n b ottles 
a n d a n y u n use d st u d y 
dr u g/ P erf or m st u d y dr u g 
acc o u nta bilit y  
 
 
X 
X 
X 
X 
X 
X 
A d verse E ve nts  
X 
X 
X 
X 
X 
X 
X 
X 
C o nc o mita nt Me dicati o ns  
X 
X 
X 
X 
X 
X 
X 
X 
 C- S S R S = C ol u m bia -S uici de Se verit y Rati n g Scale, E C G = electr ocar di o gra m, 
G C SI = Gastr o paresis Car di nal S y m pt o m I n de x , HI P A A = H ealt h I ns ura n ce P orta bilit y a n d Ac c o u nta bilit y Act, I C F = i nf or me d c o nse nt f or m,  I W R S = i nteracti ve we b res p o nse 
s yste m, M D S -U P D R S = M D S versi o n of U nifie d P ar ki ns o n’s Disease Rati n g Scale, M o C A = M o ntreal C o g niti ve Ass ess me nt,
 P D = Par ki ns o n’s 
disease,
 
 P GI - C = 
P atie nt Gl o bal I m pressi o n  of C ha n ge , 
a 
T he i nter val bet we e n Scree ni n g a n d Visit  1 ( Da y  1) s h o ul d n ot e xcee d 4 wee ks .  St u d y visits s h o ul d o cc ur wit hi n ± 3 d a ys of t heir s pecifie d ti mi n g . 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber  2 8, 2 0 1 8 
I m pa x La b or at ories, L L C 
 
Pa ge 3 6  of 1 5 9  
 
b 
St u d y E xit pr oce d ures t o be c o n d ucte d at t he e n d of Visit 7 or d uri n g a n earl y ter mi n ati o n visit.  
c  
Su bjects e nr olle d at sites i n t he U nite d States ( U S) m ust si g n HI P A A a ut h orizati o n pri or t o t h e c o n d uct of a n y st u d y -s p ecific pr oce d ures. 
d 
Rec or d vital si g ns ( bl o o d press ure, heart rate, res pirat or y rate, a n d te m p er at ure [ Scree ni n g a n d St u d y E xit o nl y]) after s u bject has bee n resti n g s u pi ne f or at least 5 mi n utes, 
t he n rec or d ort h ostatic bl o o d press ure a n d h eart rate after s u bject has b ee n sta n di n g f or a p pr o xi mat el y 2 mi n utes.   At Visits 1 a n d 4, ort h ostatic vital si g ns ( bl o o d press ure a n d 
heart rate) will be perf or me d i n tri plicate, eac h set se p arate d b y at least 1 5 mi n utes fr o m t h e pre vi o us set.  
e 
Wei g ht o nl y.  
f  
C-S S R S: C ol u m bia S uici de Se verit y Rati n g Scale.  See  A p p e n di x  O. 
g 
See  A p pe n di x  R. 
h 
M o ntreal C o g niti ve Assess me nt i n t he “ O n” state: see A p p e n di x  D. 
i 
At Scree ni n g M D S -U P D R S P arts I t hr o u g h I V  will b e d o n e i n b ot h t h e “ O n ” a n d “ Off” state (se e A p p e n di x  E). 
j 
See A p pe n di x  F. 
k 
l 
m  
n 
o 
See A p pe n di x  K. 
p 
q 
r 
s 
Trai n at Scree ni n g a n d t he n as nee de d at s u bse q u e nt visits.   P erf or m c o n c or d a n ce testi n g at Scree ni n g. 
t 
Dis pe nse P D Diaries  at Scree ni n g a n d Visits 1, 3, 4, 5, a n d 6 .  Call su bjects 4 d a ys pri or t o Visits 1, 2 a n d 4 -7 t o re mi n d t he m t o c o m plete P D Diaries .  S u bjects rec or d diar y 
i nf or mati o n f or 3 c o nsec uti ve da ys i m me diatel y pri or t o eac h of t h e visits ( Da ys -3, -2, a n d -1).  Call s u bjects t h e d a y pri or t o eac h visit t o re mi n d t he m t o bri n g t he P D Diaries , 
e m pt y me dicati o n b ottles, a n d a n y u n use d st u d y dr u g  t o t h e office. 
u 
Re vie w P D Diaries  at Visits 1, 2, a n d 4 - 7. 
v 
P ost -Scree ni n g re mi n der p h o ne call :  N otif y i n di vi d u als w h o s u ccessf ull y c o m plete scree ni n g pr o ce d ures f oll o wi n g re vie w of all st u d y e ntr y criteria a n d cli nical lab orat or y 
res ults t hat t he y ma y c o nti n ue i n t he st u d y.  T h e i nter val b et wee n Scree ni n g a n d Visit 1 s h o ul d n ot e xcee d 4 we e ks.  
w  Re mi n der p h o ne calls  f or Visits 1 t hr o u g h 4:  I n a d diti o n t o t h e calls disc usse d a b o ve, ma ke re g ular p h o n e calls (a p pr o xi matel y e ver y 1 t o 3 da ys) t o s u bjects t hr o u g h o ut t he 
I R C D-L D d ose -a dj ust me nt a n d I P X 2 0 3 d ose -c o n versi o n p eri o ds t o e val u ate eac h s u bject’s a dj ust me nt t o t h e st u d y me dicati o n  re gi me n. 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 3 7  of 1 5 9  
 
8. 1.  
Scree ni n g Visit  
After t he s u bject has si g n e d t he i nf or me d c o nse nt (a n d HI P A A a ut h orizati o n f or U S s u bjects 
o nl y), c o m plet e t he f oll o wi n g pr o ce d ures a n d a ssess me nts: 
•  O btai n a n i de ntificati o n n u m ber fr o m t he I nt eracti ve We b Res p o nse S yste m (I W R S).  
T he I W R S will assi g n a 6 - di git I D n u m ber t o eac h s u bject, c o nsisti n g of a 3-di git 
n u m ber re pr ese nti n g t he i n vesti gati ve site a n d a 3 -di git se q ue ntial s u bject n u m b er. 
•  Re vie w a n d r ec or d st u d y e ntr y criteri a ( Secti o n  7 ). 
•  Perf or m uri ne pre g na n c y test f or fe mal es of c hil d beari n g p ote ntial.  
•  Perf or m uri ne s cree n f or dr u gs of a b use.  
•  Perf or m alc o h ol br eat h test. 
•  C o m plete me dical hist or y.  
•  Perf or m p h ysical e x a mi nat i o n, i ncl u di n g hei g ht a n d wei g ht. 
•  Assess vital si g ns aft er s u bject is s u pi ne f or at least 5 mi n utes ( bl o o d press ure, heart 
rate, te m perat ure a n d res pirat or y rate) a n d t he n assess ort h ostatic bl o o d press ure a n d 
heart r ate aft er s u bject is sta n di n g (f or a p pr o xi matel y 2  mi n utes).  
•  Rec or d c urre nt C D - L D r e gi me n, ot h er P D me dicati o ns a n d t heir d osi n g sc h e d ule, a n d 
ot her c o nc o mita nt me dicati o ns. 
•  Rec or d A Es.  
•  Perf or m  a 1 2-l ea d E C G.  
•  A d mi nister C -S S R S ( A p pe n di x O ). 
•  Deter mi ne M o C A Sc or e i n t he “ O n” state ( A p pe n di x D ). 
•  C ollect bl o o d a n d uri ne sa m ples f or cli nical la b orat or y st u dies (A p p e n di x R ). 
•  Deter mi ne H o e h n a n d Y a hr sta gi n g of P D i n t he “ O n” state ( p art of M D S -U P D R S 
Part III M ot or E x a mi nati o n ) (A p pe n di x E ). 
•  A d mi nister M D S - U P D R S Parts I t hr o u g h I V i n t he “ O n” a n d “ Off” stat e 
(A p pe n d i x E). 
•  Trai n t he s u bject h o w t o c o m plete t he P D D iaries t o assess his/ her “ O n” a n d “ Off” 
states, i ncl u di n g ass ess me nt of a n y d ys ki nesia.  After trai ni n g t he s u bject, perf or m t he 
c o nc or da n ce testi n g.  T h e s u bject’s “ O n ”/”Off” rati n gs m ust a gree at least 7 5 % of t he 
ti me wit h t he trai ne d rater d uri n g t h e trai ni n g sessi o ns.  T hat is, t he s u bject’s 
“ O n”/”Off” rati n gs m ust a gree wit h t he trai ne d rat er’s rati n gs o n at least 7 5 % 
“ O n”/“Off ” stat es i n a si n gle sessi o n t o q ualif y f or st u d y i ncl usi o n.  T he 7 5 % 
c o nc or da n ce rate m ust be base d o n 8 rati n gs, a n d m ust i ncl u de at least o ne “ O n” a n d 
o ne “ Off” state.  T h e rati n gs s h o ul d occ ur e v er y 3 0  mi n utes a n d eac h s essi o n s h o ul d 
last u p t o 4 h o urs.  If t he s u bject fails t he first trai ni n g sessi o n, t he s u bject ma y b e 
trai ne d f or o n e a d diti o nal 4- h o ur trai ni n g sessi o n.  T his re peat testi n g s h o ul d n ot be 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 3 8  of 1 5 9  
 
perf or me d o n t h e sa me d a y as t he first sessi o n a n d ca n ta ke pl ace fr o m 1 da y t o 
3 wee ks p ost Scree ni n g visit . 
•  Dis pe nse P D D iaries a n d i nstr uct t he s u bject t o c o m plete t he P D D iaries o n 
3 c o nsec uti ve da ys i m me diatel y pri or t o Visit 1.  
N otif y i n di vi d uals w h o s uccessf ull y c o m plete s cree ni n g pr oce d ures f oll o wi n g re vi e w of all st u d y 
e ntr y criteri a a n d cli nical la b orat or y r es ults.  
T he i nter val bet w ee n Scr ee ni n g a n d Visit  1 ( Da y  1) s h o ul d n ot e x cee d 4 w ee ks.  
8. 2.  
Visit 1 – St art of I R C D-L D D ose A dj ust me nt  
8. 2. 1.  
Pri o r t o Visit 1  
C o ntact t he s u bject at least 4 da ys pri or t o Visit 1 t o re mi n d hi m/ her t o c o m plete t he 3- da y 
P D  Diaries starti n g 3 c o nsec uti ve da ys i m me diatel y pri or t o Visit  1. 
T he da y pri or t o Visit 1, re mi n d s u bjects t o: 
•  B ri n g t heir c o m plet e d 3-da y P D D i aries t o t he cli nic. 
8. 2. 2.  
At Visit 1  
F or Visit 1 c o m plete t he f oll o wi n g pr o ce d ures: 
•  C ollect a n d re vie w t h e s u bject’s 3 -da y P D  Di aries.  E ns ure t hat t he s u bject is 
a vera gi n g at least 2. 5 h o urs per da y of “ Off” ti me o ver 3 da ys a n d at least 1. 5 h o urs of 
“ Off ” ti me o n eac h da y b ase d o n t he 3 da y P D Di aries.  If t he s u bject ca n n ot pr o perl y 
c o m plete t he diar y, e g, if m ore t ha n 1 da y of t h e diar y is n ot ret ur ne d or if m ore t ha n 
1 da y of t he diar y is n ot vali d (ie, m ore t ha n 2 h o urs [ 4 half peri o ds] of t he 2 4- h o ur 
diar y ar e missi n g) , he/s h e will n ot c o nti n ue i n t he st u d y. 
•  Re vie w i ncl usi o n a n d e x cl usi o n criteria t o e ns ure t hat t he s u bject c o nti n ues t o meet 
t hese criteri a.  
•  Re vie w i nstr ucti o n of 3-da y P D D i aries if n ee de d. 
•  Meas ure vital si g ns (r es pirat or y rate, bl o o d press ure, a n d heart rate after s u pi ne f or at 
least 5 mi n utes , a n d ort h ostatic p ulse a n d bl o o d press ure after sta n di n g f or 
a p pr o xi matel y 2  mi n utes).   Ort h ostatic vital si g n m eas ure me nts ( bl o o d press ure a n d 
heart r ate) will be perf or me d i n tri plicate, eac h set se parate d b y at least 1 5 mi n utes 
fr o m t he pre vi o us set. 
•  A d mi nister C -S S R S ( A p pe n di x O ). 
•  A d mi nister M D S - U P D R S Parts I t hr o u g h I V (A p pe n di x E ). 
•  
•  
•  
•  C o m p lete G C SI ( A p p e n di x K ). 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 3 9  of 1 5 9  
 
•  
•  
•  
•  Re c or d a n y A Es a n d u p d ate c ha n ges i n c o nc o mita nt me dicati o n si nce t he pre vi o us 
visit.  
•  Dis pe nse P D D iaries. 
•  C o ntact I W R S a n d d is pe nse st u d y me dicati o n per I W R S i nstr ucti o ns. 
8. 2. 3.  
P ost Visit 1  
•  Ma ke re g ul ar p h o ne calls (a p pr o xi matel y e v er y 1 t o 3 da ys)  w hile t he I R C D - L D d ose 
is bei n g a dj uste d.  T h e I R C D - L D d osi n g re gi me n s h o ul d be sta ble f or at l east 5 da ys 
pri or t o ret ur ni n g f or Visit 2. 
8. 3.  
Visit s 2 ( Wee k 3) a n d Visit 3  ( Wee k 5) – I P X 2 0 3 D ose C o n versi o n 
8. 3. 1.  
Pri o r t o Visit 2  
•  Call s u bjects 4 da ys pri or t o Visit 2 a n d re mi n d t he m t o c o m plete t heir P D Diaries.  
•  Call s u bjects t he da y pri or t o Visit 2 t o re mi n d t he m t o bri n g t he P D Diari es,  e m pt y 
me dicati o n b ottles, a n d a n y u n use d st u d y dr u g t o t he office. 
8. 3. 2.  
Pri o r t o Visit 3  
•  Call s u bjects t he da y pri or t o Visit 3 t o re mi n d t he m t o bri n g b ac k e m pt y m e dicati o n 
b ottles a n d a n y u n us e d st u d y dr u g t o t he office. 
8. 3. 3.  
At Visits 2 a n d 3  
F or Visits 2 a n d 3 c o m pl ete t he f oll o wi n g pr oce d ures: 
•  Meas ure vital si g ns (r es pirat or y rate, bl o o d press ure, a n d heart rate after s u pi ne f or at 
least 5 mi n utes , a n d ort h ostatic p ulse a n d bl o o d press ure after sta n di n g f or 
a p pr o xi matel y 2  mi n utes).  
•  A d mi nister C -S S R S ( A p pe n di x O ). 
•  C ollect e m pt y me dicati o n b ottles a n d a n y u n us e d st u d y dr u g ; perf or m st u d y dr u g 
acc o u nta bilit y.  
•  Rec or d a n d u p d ate A Es a n d c o nc o mita nt me dicati o ns. 
•  C o ntact I W R S a n d d is pe nse st u d y me dicati o n per I W R S i nstr ucti o ns. 
A d diti o n al Assess me nt s at Visit 2 O nl y  
•  A d mi nister M D S - U P D R S Parts I t hr o u g h I V (A p pe n di x E ). 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 0  of 1 5 9  
 
•  Re vie w P D D iaries.  T h e s u bject will be ter mi nate d fr o m t he st u d y if t h e s u bject d oes 
n ot a vera ge at least 2. 5 h o urs per da y of “ Off” ti m e o ver 3 da ys a n d at least 1. 5 h o urs 
of “ O ff” ti me on eac h da y bas e d o n t he 3 da y P D D iaries a n d/ or if t h e s u bject ca n n ot 
pr o perl y c o m plete t h e diar y, e g, if m ore t ha n 1 da y of t he di ar y is n ot ret ur ne d or if 
m ore t ha n 1 da y of t h e diar y is n ot vali d (ie, m ore t ha n 2 h o urs [ 4 half peri o ds] of t he 
2 4 h o ur di ar y are missi n g).  
•  E ns ure t hat t he s u bject h as bee n o n a st a ble d osi n g re gi me n f or at least 5 d a ys pri or t o 
d ose c o n versi o n t o I P X 2 0 3.  If t he s u bject is n ot a ble t o ac hie ve a sta ble d osi n g 
re gi me n lasti n g at least 5 da ys, t he s u bject will be disc o nti n ue d. 
•  C o n d uct P D D iaries trai ni n g, if nee de d. 
A d diti o n al Acti vities  at Visit 3 O nl y  
•  Dis pe nse P D D iaries. 
•  Re vie w i nstr ucti o n of 3- da y P D D i aries if n ee de d. 
8. 3. 4.  
P ost Visits 2 a n d 3 
Ma ke re g ul ar p h o ne calls (a p pr o xi matel y e v er y 1 t o 3 da ys) t o s u bjects t hr o u g h o ut t he d ose 
c o n versi o n peri o d, as nee de d, t o e val uate eac h s u bject’s a dj ust me nt t o t he st u d y me dicati o n.  T he 
I P X 2 0 3 d osi n g r e gi me n s h o ul d be sta ble f or at least 5 da ys pri or t o ret ur ni n g f or Visit 4. 
8. 4.  
Visit 4 ( Wee k 7)  – R a n d o miz ati o n  
8. 4. 1.  
Pri o r t o Visit 4  
•  Call s u bject s 4 da ys pri or t o Visit 4 t o re mi n d t he m t o c o m plete t heir P D D iaries. 
•  C o ntact s u bjects 1 da y pri or t o Visit 4  t o re mi n d t he m t o bri n g bac k t he P D D iaries, 
e m pt y me dicati o n b ottles, a n d a n y u n use d st u d y dr u g t o t he office. 
8. 4. 2.  
At Visit 4  
F or Visit 4 c o m plete t he f oll o wi n g pr o ce d ures: 
•  Re vie w P D Diaries .  At l east 1 da y of v ali d diar y data (ie, less  t ha n 2 h o urs [ 4 half 
peri o ds] of t he 2 4- h o ur diar y are missi n g) m ust be a vaila ble, ot her wise t he s u bject 
will be ter mi nate d fr o m t he st u d y . 
•  E ns ure t hat t he s u bject h as bee n o n a st a ble d osi n g re gi me n f or at least 5 d a ys pri or t o 
ra n d o mizati o n.  If t he s u bject is n ot a ble t o ac hie v e a sta ble d osi n g re gi me n lasti n g at 
least 5 da ys, t he s u bject will be disc o nti n ue d. 
•  Meas ure vital si g ns (r es pirat or y rate, bl o o d press ure,  a n d heart rate after s u pi ne f or at 
least 5 mi n utes , a n d ort h ostatic p ulse a n d bl o o d press ure after sta n din g f or 
a p pr o xi matel y 2  mi n utes ).  Ort h ostatic vital si g n meas ure me nts ( bl o o d press ure a n d 
heart r ate) will be perf or me d i n tri plicate, eac h set se para te d by at least 1 5 mi n utes 
fr o m t he pre vi o us set. 
•  A d mi nister C -S S R S ( A p pe n di x O ). 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 1  of 1 5 9  
 
•  A d mi nister M D S - U P D R S Parts I t hr o u g h I V (A p pe n di x E ). 
•  
•  
•  
•  
•  
•  
•  Rec or d a n d u p d ate A Es a n d c o nc o mita nt me dicati o ns. 
•  C o n d uct P D d iaries trai ni n g, if nee de d. 
•  C ollect e m pt y me dicati o n b ottles a n d a n y u n us e d st u d y dr u g; pe rf or m st u d y dr u g 
acc o u nta bilit y. 
•  C o ntact I W R S f or ra n d o mizati o n a n d dis pe nse me dicati o n per I W R S i nstr ucti o ns. 
•  Dis pe nse P D d iaries. 
8. 5.  
Visit 5 ( Wee k 1 0) a n d Visit 6 ( Wee k 1 5)  
8. 5. 1.  
Pri o r t o Visit 5 a n d 6 
•  Call s u bjects 4 da ys pri or t o Visits 5 a n d 6 t o re mi n d t he m t o be gi n rec or di n g i n t heir 
P D d iaries o n eac h of t he 3 c o nsec uti ve da ys i m m e diatel y pri or t o eac h of t hese visits. 
•  Call t he s u bjects t he da y pri or t o Visits 5 a n d 6 t o re mi n d t he s u bjects t o bri n g i n t heir 
P D d iaries, e m pt y m e dicati o n b ottles, a n d a n y u n use d st u d y dr u g t o t he office. 
8. 5. 2.  
At Visit 5 a n d 6  
F or Visits 5 a n d 6 c o m pl ete t he f oll o wi n g pr oce d ures ( n ote visit- s pecifi c tas ks bel o w): 
•  Meas ure vital si g ns (r es pirat or y rate, bl o o d press ure, a n d heart rate after s u pi ne f or at 
least 5 mi n utes , a n d ort h ostatic p ulse a n d bl o o d press ure after sta n din g f or 
a p pr o xi matel y 2  mi n utes) . 
•  A d mi nister C -S S R S ( A p pe n di x O ). 
•  A d mi nister M D S - U P D R S Parts I t hr o u g h I V (A p pe n di x E ). 
•  C o m plete P G I- C (A p pe n di x F ). 
•  C o m plete C GI - C (A p pe n di x G ). 
•  Re vie w P D d iaries. 
•  C o n d uct P D d iaries trai ni n g, if nee de d. 
•  Dis pe nse P D d iaries. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 2  of 1 5 9  
 
•  C ollect e m pt y me dicati o n b ottles a n d a n y u n us e d st u d y dr u g ; perf or m st u d y dr u g 
acc o u nta bilit y. 
•  C o ntact I W R S a n d d is pe nse st u d y me dicati o n per I W R S i nstr ucti o ns. 
•  Rec or d a n y A Es a n d u p d ate c ha n ges i n c o nc o mita nt me dicati o n si nce t he pre vi o us 
visit.  
A d diti o n al Acti vities at Visit 5 O nl y : 
•  Rec or d wei g ht.  
•  Perf or m a 1 2 -l ea d E C G. 
•  C ollect bl o o d a n d uri ne sa m ples f or cli nical la b orat or y st u dies ( A p p e n di x R ). 
A d diti o n al Acti vities at Visit 6 O nl y:  
•  
•  
•  
•  
8. 6.  
Visit 7 ( Wee k 2 0) – E n d of St u d y /St u d y E xit  
8. 6. 1.  
Pri o r t o Visit 7 
•  Call s u bjects 4 da ys pri or t o Visit 7 t o re mi n d t he m t o be gi n rec or di n g i n t heir 
P D  Diaries  o n eac h of t h e 3 c o nsec uti ve d a ys i m me diatel y  pri or t o V isit 7. 
•  Call t he s u bjects t he da y pri or t o Visit 7 t o re mi n d t he s u bjects t o bri n g i n t heir 
P D  Diaries , e m pt y me dicati o n b ottles, a n d a n y u n use d st u d y dr u g t o t he office. 
8. 6. 2.  
At Visit 7 
All e nr olle d s u bjects m ust c o m plete St u d y E xit pr oce d ures at t he e n d of Visit 7 or d uri n g a n 
earl y ter mi nati o n visit:  
•  Perf or m p h ysica l e x a mi nati o n, i ncl u di n g wei g ht. 
•  Meas ure vital si g ns (te m perat ure, res pirat or y rat e, bl o o d press ure, a n d h eart rate aft er 
s u pi ne f or at least 5 mi n utes , a n d ort h ostatic p ulse a n d bl o o d press ure after sta n din g 
f or a p pr o xi matel y 2 mi n utes) . 
•  C ollect a n d re vie w 3- da y P D Diaries . 
•  A d mi nister C -S S R S ( A p pe n di x O ). 
•  A d mi nister M D S - U P D R S Parts I t hr o u g h I V (A p pe n di x E ). 
•  C o m plete P GI - C (A p pe n di x F ). 
•  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 3  of 1 5 9  
 
•  
•  
•  
•  
•  
•  
•  C o m plete G C SI ( A p p e n di x K ). 
•  C ollect e m pt y me dicati o n b ottles a n d a n y u n us e d st u d y dr u g ; perf or m st u d y dr u g 
acc o u nta bilit y. 
•  Rec or d a n d u p d ate A Es a n d c o nc o mita nt me dicati o ns. 
•  C ollect bl o o d a n d uri ne sa m ples f or cli nical la b orat or y st u dies ( A p p e n di x R ). 
•  Perf or m a 1 2 -l ea d E C G. 
•  C o ntact I W R S t o rec or d s u bject dis p ositi o n. 
8. 7.  
E arl y Ter mi n ati o n  
8. 7. 1.  
S u bjects W h o T er mi n ate Pri or t o R a n d o miz ati o n 
If t he s u bject disc o nti n ues t he st u d y pri or t o ra n d o mizati o n ( Visit 4) t he s u bject s h o ul d c o m plete 
t he f oll o wi n g ass ess me nts: 
•  Perf or m p h ysical e x a mi nati o n, i ncl u di n g wei g ht. 
•  Meas ure vital si g ns (te m perat ure, res pirat or y rat e, bl o o d press ure, a n d h eart rate aft er 
s u pi ne f or at least 5 mi n utes , a n d ort h ostatic p ulse a n d bl o o d press ure after sta n di n g 
f or a p pr o xi matel y 2 mi n utes) . 
•  C ollect a n d re vie w 3 -da y P D Diaries  w he n a vaila ble . 
•  A d mi nister C -S S R S ( A p pe n di x O ). 
•  A d mi nister M D S -U P D R S Parts I t hr o u g h I V ( A p pe n di x E ). 
•  C ollect e m pt y me dicati o n b ottles a n d a n y u n us e d st u d y dr u g ; perf or m st u d y dr u g 
acc o u nta bilit y. 
•  Rec or d a n d u p d ate A Es a n d c o nc o mita nt me dicati o ns. 
•  C ollect bl o o d a n d uri ne sa m ples f or cli nical la b orat or y st u dies ( A p p e n di x R ). 
•  Perf or m a 1 2 -l ea d E C G. 
•  C o ntact I W R S t o rec or d s u bject dis p ositi o n. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 4  of 1 5 9  
 
8. 7. 2.  
S u bjects W h o Ter mi n ate E arl y after R a n d o mi z ati o n 
If t he s u bject disc o nti n ues t he st u d y after ra n d o mizati o n ( Visit 4), t he s u bject s h o ul d c o m plete all 
assess me nts descri b e d i n Secti o n  8. 6. 2 . 
8. 8.  
Bl o o d V ol u me  
Safet y bl o o d dra ws:  A p pr o xi matel y 1 0 m L of bl o o d will be dra w n at Scree ni n g , Visit 5, a n d at 
St u d y E xit, f or a c o m bi ne d t otal of 3 0 m L.  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 5  of 1 5 9  
 
9.  
T R E A T M E N T O F S U B J E C T S 
9. 1.  
Descri pti o n of St u d y Dr u g  
St u d y dr u gs will be pr o vi de d b y I m pa x f or t his st u d y: 
•  I P X 2 0 3 ( car bi d o pa-le v o d o pa) E xte n de d-Releas e Ca ps ules  c o ntai ni n g 3 5- 1 4 0 m g  of 
C D -L D  f or or al a d mi nistrati o n.  T he C D -L D rati o is 1: 4.  I n a d diti o n, matc hi n g 
place b o ca ps ules wi ll als o be pr o vi de d. 
•  I m me diat e-r elease car bi d o pa-le v o d o pa (I R C D -L D) ta blet c o ntai ni n g 2 5- 1 0 0 m g of 
C D - L D, f or or al a d mi nistrati o n.  I n a d diti o n, matc hi n g place b o ta blets will als o be 
pr o vi de d. 
T a ble 5: 
St u d y Dr u gs f or St u d y I P X 2 0 3- B 1 6- 0 2 
I n vesti g ati o n al Pr o d uct 
D os a ge Stre n gt h ( m g C D- L D)  a n d F or m  
I P X 2 0 3 (car bi d o pa-le v o d o pa) E xte n de d-
Release ca ps ules  
3 5- 1 4 0 m g  
Ca ps ules f or oral a d mi nistrati o n  
I R C D- L D (car bi d o pa-le v o d o pa) ta blets 
2 5- 1 0 0 m g  
T a blets f or oral a d mi nistrati o n  
I P X 2 0 3 Place b o ca ps ules  
Ca ps ules f or oral a d mi nistrati o n  
I R C D-L D Place b o ta blets  
T a blets f or oral a d mi nistrati o n  
9. 2.  
C o nc o mit a nt Me dic ati o ns  
9. 2. 1.  
Per mitte d P D Me dic ati o ns  
C o nc o mita nt t hera p y wit h a ma nta di ne, selecti ve m o n oa mi ne o xi dase ( M A O) t y p e B i n hi bit ors 
(e g, selegili ne, r asa gili ne), a ntic h oli ner gic P D me dicati o ns (e g, be nztr o pi ne, tri he x y p he ni d yl), 
a n d/ or d o pa mi ne a g o nists (e x ce pt a p o m or p hi ne) is all o we d pr o vi de d t he d oses a n d re gi me ns 
ha ve bee n sta ble f or at least 4 wee ks pri or t o Visit 1 a n d t he t hera p y is i nte n de d t o be c o nsta nt 
t hr o u g h o ut t he c o urse of t he st u d y. 
9. 2. 2.  
Pr o hi bite d Me dic ati o ns  a n d Pr oce d ures  
Pr o hi bite d me dicati o ns a n d pr oce d ur es i ncl u de t h e f oll o wi n g: 
•  Recei ve d wit hi n 4 wee ks of Visit 1 or pla n ni n g t o ta ke d uri n g partici p ati o n i n t he 
cli nical st u d y:  a n y d os es of a c o ntr olle d- release ( C R) C D -L D a part fr o m a si n gle 
dail y be dti me d ose or a n y d oses of R ytar y, a d diti o nal C D (e g, L o d os y n) or 
be nserazi de ( e g, Serazi de), or cat ec h ol - O-met h yl tra nsferase i n hi bit ors (e nt aca p o n e or 
t olca p o ne) or m e dicati o ns c o ntai ni n g t hes e i n hi bit ors ( Stale v o). 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 6  of 1 5 9  
 
•  Resc ue wit h a d diti o nal or m o difie d d oses of c o n c o mita nt P D me dicati o ns or wit h use 
of C D - L D pr o d u cts ot her t ha n t he dis pe nse d st u d y me dicati o ns is n ot per mitte d a n d 
will tri g ger disc o nti n uati o n fr o m t he st u d y.  
•  Recei ve d wit hi n 4 wee ks of Visit 1 or pla n ni n g t o ta ke d uri n g partici p ati o n i n t he 
cli nical st u d y:  n o nselecti ve M A OI, sel ecti ve M A O t y pe A i n hi bit or (e g, p he nelzi ne, 
m ocl o be mi de, pirli n d ole, bife mela ne, t ol o x at o ne) , a p o m or p hi ne, or a nti d o p a mi ner gic 
a ge nts i ncl u di n g a ntie metics. 
•  Treat me nt wit h a n y d o p a mi ne a nta g o nist a nti ps yc h otic a ge nts f or t he p ur p oses of 
ps yc h osis or bi p olar dis or der wit hi n t he last 2 years.  Use of a nti ps yc h otics t o treat 
c o n diti o ns ot her t ha n ps yc h osis or bi p olar dis or ders ma y be all o we d o nl y after 
c o ns ultati o n wit h t he me dical m o nit or.  
•  A n y n e ur os ur gical pr oce d ure f or t he treat me nt of P D d uri n g t he c o urse of t he st u d y. 
A s u bject w h o re p orts t he use of a n y pr o hi bite d me dicati o ns or pr oce d ure will be disc o nti n ue d. 
All me dicati o ns ta ke n wi t hi n 3 0 da ys pri or t o si g ni n g t he i nf or m e d c o nse nt f or m (I C F) a n d all 
c o nc o mita nt me dicati o ns ta ke n d uri n g t he st u d y will be rec or d e d o n t he case re p ort f or m ( C R F). 
9. 2. 3.  
Resc ue  Me dic ati o ns  
Resc ue wit h a d diti o nal or m o difie d d oses of c o n c o mita nt n o n- C D -L D P D me d icati o ns is n ot 
per mitte d a n d will tri g ger disc o nti n uati o n fr o m t he st u d y.   D uri n g t h e d ose a dj ust me nt a n d d ose 
c o n versi o n peri o ds, resc u e wit h C D- L D pr o d ucts ot her t ha n t he dis pe nse d st u d y me dicati o ns is 
n ot per mitte d a n d will tri g ger disc o nti n uati o n fr o m  t he st u d y.  N o me dicati o n a dj ust me nts are 
all o we d f oll o wi n g ra n d o mizati o n a n d d uri n g t he d o u ble- bli n d p hase of t he st u d y a n d will tri g ger 
disc o nti n uati o n fr o m t he st u d y. 
9. 3.  
Tre at me nt C o m pli a nce  
St u d y dr u g acc o u nta bilit y a n d rec o n ciliati o n will be perf or me d b y t he st u d y staff a n d t he st u d y 
m o nit or (s). 
9. 4.  
R a n d o miz ati o n a n d Bli n di n g  
At Visit  4, s u bjects will be ra n d o mize d , stratifie d b y ce nter, i n a 1: 1 rati o i nt o o ne of t w o d o u ble-
bli n d parallel treat me nt ar ms of I P X 2 0 3 (a n d mat c hi n g I R C D -L D  pl ace b o) or I R  C D -L D (a n d 
matc hi n g I P X 2 0 3 place b o). 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 7  of 1 5 9  
 
1 0.  
S T U D Y D R U G M A T E RI A L S A N D M A N A G E M E N T  
1 0. 1.  
St u d y Dr u g  
St u d y dr u gs i ncl u de t he i n vesti gati o nal treat me nt I P X 2 0 3 3 5- 1 4 0 m g C D-L D  (a n d matc hi n g 
place b o ca p sules) a n d t h e acti ve c o m parat or  treat me nt I R 2 5- 1 0 0 m g C D -L D , (a n d matc hi n g 
place b o ta blets) . 
I P X 2 0 3 is a n e xte n de d-release ( E R) ca ps ule f or m ulati o n of C D-L D.   I m pa x will ma n ufact ure 
a n d pr o vi de t he I P X 2 0 3 a n d matc hi n g place b o. 
I R C D -L D is c o m merciall y a v aila ble a n d will be pr o vi de d b y I m pa x.  Matc hi n g place b o ta blets 
will be ma n u fact ur e d a n d pr o vi de d b y I m pa x.  
1 0. 2.  
St u d y Dr u g P ac k a gi n g a n d L a beli n g  
I m pa x or desi g nee will pr o vi de st u d y me di cati o ns i n b ottles wit h a p pr o priate la beli n g affi x e d. 
La b els o n t he st u d y m e dicati o n ma y i ncl u de t he f oll o wi n g i nf or mati o n: 
•  na me, a d dr ess, a n d p h o n e n u m ber of t he s p o ns or 
•  p har mace utical d osa ge f or m/r o ute of a d mi nistrati o n, q ua ntit y of d osa ge u nits, t he 
na me/i de ntifier , a n d str e n gt h/ p ote nc y 
•  batc h a n d/ or c o d e n u m ber t o i de ntif y t he c o nte nts a n d pac k a gi n g o p erati o n 
•  trial refere n ce c o d e (pr ot oc ol n u m ber) 
•  trial s u bject i de ntificati o n n u m ber/treat me nt n u m ber a n d w h ere rele v a nt, t he visit 
n u m ber 
•  na me of i n vesti gat or 
•  directi o ns f or use: T a ke t a blet(s) or ca ps ule(s) orall y wit h water as directe d.  
•  f or cli nical trial use o nl y 
•  st ora ge i nf or mati o n:  St ore at 2 5° C ( 7 7° F), wit h e x c ursi o ns per mitte d t o 1 5° C t o 3 0° C 
( 5 9° F t o 8 6° F).  Pr otect fr o m li g ht a n d m oist ure. 
•  peri o d of use ( us e- b y dat e, e x pir y date or ret est date as a p plica ble), i n m o nt h/ year 
f or mat a n d i n a ma n n er t hat a v oi ds a n y a m bi g uit y. 
•  kee p o ut of r eac h of c hil dre n 
•  ca uti o n state me nt:  Ca uti o n: Ne w Dr u g — Li mite d b y Fe deral ( or U nite d States) la w t o 
i n vesti gati o nal use. 
1 0. 3.  
St u d y Dr u g St or a ge  
T he cli nical site s h o ul d st ore t he st u d y dr u g at 2 5° C ( 7 7° F), wit h e x c ursi o ns per mitte d t o 1 5° C t o 
3 0° C ( 5 9° F t o 8 6° F).  T h e st u d y dr u g s h o ul d b e st ore d i n a ti g htl y cl os e d c o ntai ner, pr otecte d 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 8  of 1 5 9  
 
fr o m li g ht a n d m oist ure.  St ora ge t e m perat ure e x c ursi o ns a b o ve 3 0° C ( 8 6° F) s h o ul d be re p orte d 
b y t he cli nical site t o I m p a x or its desi g nee . 
1 0. 4.  
St u d y Dr u g A d mi nistr ati o n  
S u bjects will be  i nstr ucte d t o ta ke t heir me dicati o ns wit h a p pr o xi matel y 2 4 0 m L of r o o m-
te m perat ur e water.  T he ca ps ules or ta blets s h o ul d n ot be cr us he d or c he w e d. 
I R C D -L D ta blets ma y b e s plit t o ac hie ve t he re q uire d d oses. 
1 0. 5.  
St u d y Dr u g Dis pe nsi n g a n d Acc o u nt a bilit y  
T he I n vesti gat or m ust e ns ure t hat all st u d y me di cati o n recei ve d at t he st u d y site is i n ve nt orie d 
a n d acc o u nte d f or, a n d t h at dis pe nse d st u d y me di cati o n is rec or de d i n t he s u bject’s s o urce 
d oc u me nts, t he C R F, a n d t he st u d y me dicati o n i n ve nt or y l o g.  Site pers o n n el m ust n ot rela bel or 
reassi g n st u d y m e dicati o n t o ot her s u bjects or t o i n di vi d uals n ot e nr olle d i n t he st u d y.  T he st u d y 
m o nit or verifies me dicati o n acc o u nta bilit y d uri n g m o nit ori n g visits.  
1 0. 6.  
St u d y Dr u g H a n dli n g a n d Dis p os al  
T he I n vesti gat or m ust ret ai n a n d pr o perl y st ore all partiall y us e d a n d u n use d st u d y me dicati o n 
u ntil a ut h orize d b y I m pa x re gar di n g dis p ositi o n. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 4 9  of 1 5 9  
 
1 1.  
A S S E S S M E N T O F E F FI C A C Y  
1 1. 1.  
P ar ki ns o n’s Dise ase Di ar y  
S u bject s are t o rec or d “aslee p,” “ Off,” a n d “ O n” wit h o ut or wit h ( n o ntr o u bles o me or 
tr o u bles o me) d ys ki nesias d uri n g w a ki n g h o urs e v er y 3 0 mi n utes o ver a 2 4- h o ur da y.  I n t he 
P D  Diaries, s u bjects are i nstr ucte d t o i n dicate f or eac h half- h o ur t heir pre d o mi na nt state d uri n g 
m ost of t hat peri o d.  “ Off ” is defi ne d as t he t y pical f u ncti o nal state w he n t h e me dicati o n is n o 
l o n ger pr o vi di n g b e nefit wit h re gar d t o m o bilit y, sl o w ness, a n d stiff ness i n s pite of ta ki n g 
me dicati o ns.  “ O n” is defi ne d as t he t y pi cal f u n cti o nal state w he n a s u bj ect has recei ve d 
me dicati o n a n d t he me di cati o n is pr o vi di n g be n efit wit h re gar d t o m o bilit y, sl o w ness, a n d 
stiff ness.  D ys ki n esias ar e defi ne d as i n v ol u ntar y a n d irre g ular t wisti n g a n d/ or t ur ni n g 
m o ve me nts.  D ys ki nesia m o ve me nts are us uall y a n effect of me dicati o n a n d occ ur d uri n g “ O n” 
ti me.  N o ntr o u bles o me d ys ki nesias d o n ot i nterfere wit h f u ncti o n or d o n ot ca use mea ni n gf ul 
disc o mf ort.  Tr o u bles o m e d ys ki nesi as d o i nterfere wit h f u ncti o n or d o ca us e mea ni n gf ul 
disc o mf ort. 
1 1. 2.  
P atie nt a n d
Gl o b al Assess me nts  
•  Patie nt Gl o bal I m pr essi o n of C ha n ge ( A p p e n di x F ):  T he patie nt will c o m pare his/ her 
c o n diti o n fr o m t he start of t he st u d y o n a 7-p oi nt scale ra n gi n g fr o m “ V er y m uc h 
w orse” ( 1) t o “ V er y m uc h i m pr o ve d” ( 7) at t he ti me of t he assess me nt. 
1 1. 3.  
M o ve me nt Dis or ders S ociet y V ersi o n of U nifie d P ar ki ns o n’s Dise ase 
R ati n g Sc ale  
T he M D S -U P D R S has 4 parts:  
•  Part I:  N o n - M ot or As pects of E x perie nces of Dail y Li vi n g ( n M -E D L) has 
2 c o m p o ne nts.  C o m p o ne nt I A c o ntai ns a n u m ber of be ha vi ors ass esse d b y t he 
i n vesti gat or wit h all perti ne nt i nf or mati o n fr o m t h e patie nts a n d care gi vers.  
C o m p o ne nt I B is c o m plete d b y t he p atie nt wit h or wit h o ut hel p fr o m t he care gi ver b ut 
i n de pe n de nt of t he i n vesti gat or.  T h ese secti o ns ca n be re vie w e d b y t he rater t o e ns ure 
all q uesti o ns are a ns w ere d clearl y a n d t h e rater ca n hel p e x plai n a n y a m bi g uities.  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 0  of 1 5 9  
 
•  Part II:  M ot or As pects of E x perie nces of Dail y Li vi n g ( M -E D L) is a self -
a d mi nistere d q uesti o n naire b ut ca n b e re vi e we d b y t he i n vesti gat or t o e ns ure 
c o m plete ness a n d cla rit y. 
•  Part III:  M ot or E x a mi nati o n assesses t he m ot or si g ns of P D a n d h as i nstr u cti o ns f or 
t he rater t o gi ve t o or t o d e m o nstrate t o t he patie nt.  It is c o m plete d b y t h e rater.  
•  Part I V:  M ot or C o m plicati o ns i nte grates patie nt - deri ve 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 ge me nts a n d is c o m plete d b y t he rat er.  It c o nt ai ns 
i nstr ucti o ns f or t he rater a n d i nstr ucti o ns t o be rea d t o t he patie nt. 
1 1. 4.  
A d diti o n al Assess me nts  
•  
•  
•  
•  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 1  of 1 5 9  
 
1 2.  
A S S E S S M E N T O F S A F E T Y  
1 2. 1.  
S afet y P ar a meters  
Safet y will be assesse d b y t he f oll o wi n g para met ers:  
•  Electr ocar di o gra ms ( E C Gs), cli nical la b orat or y tests, p h ysical e x a mi nati o ns, t he 
C ol u m bia- S uici de Se verit y Rati n g Scale ( C - S S R S), a n d vital si g ns , i ncl u di n g s u pi ne 
a n d sta n di n g ort h ostatic bl o o d press ure a n d h eart rate. 
•  A d verse e ve nts a n d c o nc o mita nt me dicati o ns will be e val uat e d t hr o u g h o ut t he c o urse 
of t he st u d y. 
1 2. 2.  
A d verse E ve nts 
1 2. 2. 1.  
Defi niti o n of A d verse E ve nt  
A n a d vers e e ve nt (a d vers e e x perie nce) is a n y u nt o war d me dical occ urre n ce i n a patie n t or 
cli nical trial s u bject a d mi nistere d a me dici n al pr o d uct a n d w hic h d oes n ot n ecessaril y h a ve t o 
ha ve a ca usal r elati o ns hi p wit h t his treat me nt.  A n a d verse e ve nt ca n t heref ore be a n y 
u nfa v ora bl e a n d u ni nte n d e d si g n ( e g, a n a b n or mal la b orat or y fi n di n g), s y m pt o m, or disease 
te m p orall y ass ociate d wit h t he use of a me di ci nal pr o d uct, w het her or n ot c o nsi dere d rel ate d t o 
t he me dici nal pr o d uct. 
All A Es a n d a n y cli nicall y si g nifica nt p h ysical e x a mi nati o n fi n di n gs, 1 2 -lea d E C G 
a b n or malities, or cli nical la b orat or y meas ure me nts occ urri n g d uri n g t he st u d y t hat w ere n ot 
prese nt pri or t o a d mi nistr ati o n of st u d y me dicati o n a n d t hat c o nti n ue at St u d y E xit s h o ul d be 
f oll o we d a n d e v al uate d wit h a d diti o nal tests, if necessar y, u ntil t he A Es are me dicall y sta ble or 
res ol ve d.  F oll o w- u p o n t hese A Es s h o ul d be rec or de d o n t he s o urce d oc u m e nts a n d re p ort e d t o 
I m pa x. 
1 2. 2. 2.  
Rec or di n g A d verse E ve nts  
Elicit i nf or mati o n a b o ut A Es wit h n o nselecti ve q uesti o ns s uc h as:  “ Ha v e y o u e x perie n ce d a n y 
c ha n ges i n y o ur h ealt h stat us si nce y o ur las t visit?”  E nc o ura ge s u bjects t o re p ort A Es at o ns et. 
Rec or d i nf or mati o n f or a n y A E t h at e mer ges fr o m t he ti me t he s u bject si g ns t he I C F u ntil St u d y 
E xit.  
M o nit or eac h s u bject cl osel y f or t he de v el o p me nt of A Es a n d rec or d all s uc h e ve nts o n t he A E 
pa ge of t he C R F.  W he ne ver p ossi ble, gr o u p si g ns a n d s y m pt o ms t hat c o nstit ute a si n gle 
dia g n osis.  F or e x a m ple, c o u g h, r hi nitis, a n d s neezi n g mi g ht b e gr o u pe d as u p per res pirat or y 
i nfecti o n. 
F or eac h A E, rec or d t he o nset date, se verit y, s eri o us ness, relati o ns hi p t o st u d y me dicati o n, date 
of res ol uti o n ( or c o nti n ui n g), acti o n ta ke n, a n d o utc o me i n t he C R F.  T he I n vesti gat or is t o ma ke 
a ca usalit y assess me nt (r elati o n s hi p t o st u d y m e dicati o n) f or e ver y A E. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 2  of 1 5 9  
 
1 2. 2. 3.  
F oll o w- u p  
T he I n vesti gat or m ust f oll o w eac h A E u ntil res ol ve d or me dicall y sta ble. 
1 2. 2. 4.  
Rel ati o ns hi p t o St u d y Dr u g  
T he I n vesti gat or d o c u me nts his/ her o pi ni o n of t he relati o ns hi p of t he A E t o t he st u d y me dicati o n 
as f oll o ws: 
•  N ot Relate d — t he e x perie nce ca n be rea dil y e x plai ne d b y t h e s u bject’s u n derl yi n g 
me dical c o n diti o n or c o n c o mita nt me dicati o ns a n d n o relati o ns hi p e xists bet wee n t he 
st u d y me dicati o n a n d t h e e x perie nce. 
•  U nli kel y Relate d — t h e te m p oral relati o ns hi p bet w ee n the A E a n d t he a d mi nistrati o n 
of t he st u d y me di cati o n is u ncertai n a n d it is li kel y t hat t he A E ca n b e e x plai ne d b y 
t he s u bject’s me dical c o n diti o n or ot her t hera pies. 
•  P ossi bl y Relate d — t h ere is s o me l o gical te m p oral relati o ns hi p bet wee n t he A E a n d 
t he a d mi nistrati o n of t he st u d y me dicati o n a n d t h e e x perie nce is u nli kel y t o be 
e x plai ne d b y t he s u bject’s me dical c o n diti o n or ot her t hera pies. 
•  Relate d — t he te m p oral r elati o ns hi p is c o m pelli n g bet wee n t he a d mi nistrati o n of t he 
st u d y me dicati o n a n d t h e A E ca n n ot be e x plai ne d b y t he s u bject’s me dical c o n diti o n 
or ot her t her a pies. 
1 2. 2. 5.  
Assess me nt of Se verit y  
Gra de eac h A E f or s e verit y a n d n ote i n t he d escri pti o n of t he A E.  Deter mi n e t he se verit y 
cate g or y of mil d, m o derate, or se ver e, as d efi ne d b el o w, a n d e nter t he i nf or mati o n o n t he A E 
pa ge of t he C R F. 
•  Mil d — ca usi n g n o li mitati o n of us ual acti vities  
•  M o derate — ca usi n g s o me li mitati o n of us ual acti vities  
•  Se vere — ca usi n g i na bilit y t o carr y o ut us ual acti vities  
1 2. 3.  
Seri o us A d verse E ve nts  
1 2. 3. 1.  
Defi niti o n of Seri o us A d verse E ve nt  
A seri o us a d verse e v e nt ( S A E) is a n y A E occ urri n g at a n y d ose t hat res ults i n a n y of t h e 
f oll o wi n g o utc o mes, r e gar dless of relati o ns hi p t o t he st u d y me dicati o n: 
•  Deat h  
•  A life -t hreate ni n g a d vers e dr u g e x perie nce 
•  I n p atie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  A persiste nt or si g nifica nt disa bilit y/i nca p acit y  
•  A c o n ge nital a n o mal y/ birt h defect  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 3  of 1 5 9  
 
•  I m p ort a nt me dical e v e nts t hat ma y n ot res ult i n deat h, be life-t hreate ni n g, or re q uire 
h os pitalizati o n ma y be c o nsi dere d a n S A E w h e n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o p ar dize t he s u bject a n d ma y re q uire me di cal or s ur gical 
i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d i n t his defi niti o n. 
1 2. 3. 2.  
Re p orti n g Seri o us A d verse E ve nts  
A n y S A E t hat o cc urs fr o m t he ti me t he s u bject si g ns a n I C F u ntil 3 0 da ys after ta ki n g t he fi nal 
d ose of st u d y m e dicati o n m ust be re p orte d b y t he i n vesti gati ve staff t o t he S p o ns or or t he 
S p o ns or’s re pres e ntati ve wit hi n 2 4 h o urs of k n o wle d ge of t he e ve nt (see  St u d y C o ntact 
I nf or mati o n). 
A n S A E f or m m ust be c o m plete d a n d se nt t o t he S p o ns or a n d/ or t he S p o ns or’s re prese ntati ve.  
All S A Es m ust als o be rec or de d o n t he A E pa ge of t he C R F.  A d diti o nall y, all S A Es m ust be 
re p orte d t o t he i nstit uti o nal re vie w b o ar d (I R B) p er t he I RB’s re q uire me nts.  
T h ose S A Es t hat are c o nsi dere d b ot h seri o us a n d u ne x pecte d a n d rel ate d t o t he st u d y dr u g are 
s u bject t o e x pe dite d re p orti n g.  A n “ u ne x pecte d A E” is a n y A E w h ere t he n at ure or se v erit y is 
n ot c o nsiste nt wit h t he c urre nt i n vesti gat or br o c h ure (I B) or if a n I B is n ot re q uire d or a v aila ble, 
t he s pecificit y or se v erit y is n ot c o nsiste nt wit h t he pr o vi de d ris k i nf or mati o n. 
U ne x pecte d fatal or life -t hreate ni n g S A Es relate d t o t he st u d y dr u g m ust be re p orte d b y t he 
S p o ns or t o t he a p pr o priat e re g ulat or y a ut h orit y i n a n e x pe dite d ma n ner (i e, first re p ort wit hi n 
7 da ys of first k n o wle d ge b y t he S p o ns or).  T h e S p o ns or will pr o vi de a fi nal writte n re p ort t o t hat 
a ut h orit y wit hi n 1 5 da ys of i nitial recei pt of i nf or mati o n o n t he e ve nt.  T he S p o ns or or t he 
S p o ns or’s re pres e ntati ve will als o i nf or m all partici pati n g I n vesti gat ors of t he S A E.  
U ne x pecte d S A Es t hat ar e n ot fatal or life -t hreate ni n g m ust be re p orte d b y t he S p o ns or t o t he 
a p pr o priate re g ulat or y a ut h orit y as s o o n as p ossi bl e b ut n o later t ha n 1 5 c al e n dar da ys after first 
k n o wle d ge of t he S A E b y t he S p o ns or.  T h e S p o ns or or t he S p o ns or’s re prese ntati ve als o 
i nf or ms all partici pati n g I n v esti gat ors of t he S A E. 
S u bjects wit h dra w n fr o m t he st u d y d ue t o a n y S A E will be f oll o we d u ntil t he S A E is res ol ve d or 
me dicall y sta bl e.  Rec or d all S A Es, re gar dless of se verit y a n d w h et her or n ot relate d t o t he st u d y 
me dicati o n, o n t he a p pr o priate pa ge of t he C R F. 
T he I n vesti gat or m ust deter mi ne w het her t he seri o us ness of t he e ve nt w arra nts re m o val of t he 
s u bject fr o m t he st u d y.  He/s he s h o ul d, i n a n y cas e, i nstit ute a p pr o priate di a g n ostic a n d 
t hera pe utic meas ures a n d kee p t he s u bject u n d er o bser vati o n f or as l o n g as is me dicall y 
i n dicate d, or r efer t he s u bject t o a p pr o priat e healt h pr ofessi o nals. 
1 2. 4.  
Pre g n a nc y  
A n y pre g na n c y t hat occ urs fr o m t he ti me t he s u bject si g ns a n I C F u ntil 3 0  da ys after t a ki n g t h e 
fi nal d ose of st u d y me dicati o n m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or or t he S p o ns or’s 
re pres e ntati ve a n d t he s u bject s h o ul d be ter mi nate d fr o m t he st u d y.  All preg na n cies will be 
f oll o we d t hr o u g h t o deli ver y of t he i nf a nt.  If t he s u bject e x perie nces a ter mi nati o n of t he 
pre g na nc y, it s h o ul d be r e p orte d as d efi ne d i n Secti o n  1 2. 3. 2 . 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 4  of 1 5 9  
 
1 2. 5.  
Ot her S afet y P ar a meters a n d Rel ate d I nf or m ati o n  
A d diti o nal safet y par a meters (la b or at or y tests, 1 2-lea d E C Gs, p h ysi cal e x a mi nati o ns, a n d vital 
si g ns), t he C-S S R S, t he G C SI , a n d c o nc o mita nt me dicati o ns are c ollecte d as s h o w n i n t he 
Sc he d ule of Assess me nts i n Ta ble  4.  Cli nical la b orat or y assess me nt s are liste d i n A p pe n di x R . 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 5  of 1 5 9  
 
1 3.  
S T A TI S TI C S  
1 3. 1.  
St u d y Desi g n a n d S a m ple Size Esti m ati o n  
T his is a m ultice nter, ra n d o mize d, d o u ble- bli n d, d o u ble- d u m m y, acti ve-c o ntr olle d, parallel -
gr o u p st u d y.  Ass u mi n g a differ e nce of 1 h o ur b et wee n I P X 2 0 3 a n d I R C D -L D i n “ G o o d o n” 
ti me a n d a sta n dar d d e viati o n of t he treat me nt differe nces t o be 3. 0 h o urs, a sa m ple size of 
2 1 0 s u bj ects per ar m will be nee d e d t o e ns ure at least 9 0 % p o wer at a 0. 0 5 si g nifica n ce le v el. 
Ass u mi n g a p pr o xi matel y a n 1 8 % prera n d o mizati o n dr o p- o ut, a p pr o xi matel y 5 1 0 s u bjects w o ul d 
nee d t o be e nr olle d t o ra n d o mize 4 2 0 s u bjects. 
1 3. 2.  
De m o gr a p hics/ B aseli ne C o m p ar a bil it y 
T he de m o gra p hi cs a n d b aseli ne c haracteristics will be s u m marize d b y treat me nt ar ms a n d o verall 
usi n g descri pti ve statistics.  De m o gra p hics i nf or mati o n i ncl u de s a ge, se x, a n d race.  Baseli ne 
disease c h aracteristics i n cl u de M D S -U P D R S P arts I, II, III, a n d I V, H oe h n a n d Ya hr sta ge, 
M o C A sc ores, a n d a ge of o nset of P D .  Distri b uti o ns of d osi n g i nf or m ati o n, i ncl u di n g L D d oses 
a n d years o n L D, will als o be s u m marize d.  
1 3. 3.  
Effic ac y E n d p oi nts  
•  Pri mar y e n d p oi nt:  C ha n ge fr o m baseli ne i n “ G o o d o n” ti me i n h o urs per d a y, a vera ge d o v er 
t he P D Diar y da ys, at t he e n d of d o u ble-bli n d treat me nt peri o d ( Visit 7 or earl y t er mi nati o n).  
“ G o o d o n” ti me is deri ve d fr o m t he 3- da y P D Di aries  a n d is defi ne d as t he s u m of “ O n” ti me 
wit h o ut d ys ki nesia a n d “ O n” ti me wit h n o ntr o u bles o me d ys ki n esia.  
•  Ke y sec o n d ar y e n d p oi nts: 
− C ha n ge fr o m bas eli ne i n “ Off” ti me i n h o urs per d a y, a vera ge d o v er t he P D Diar y 
da ys at t he e n d of d o u bl e- bli n d treat me nt peri o d ( Visit 7 or earl y ter mi nati o n)  
− Pr o p orti o n of s u bjects wit h eit her “ m uc h i m pr o ve d” or “ ver y m uc h i m pr o v e d” i n 
Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI- C) sc ores at t he e n d of d o u ble- bli n d 
treat me nt peri o d ( Visit 7 or earl y ter mi nati o n) 
− C ha n ge fr o m bas eli ne i n t he M D S- U P D R S Part III at t he e n d of d o u bl e- bli n d 
treat me nt peri o d ( Visit 7 or earl y ter mi nati o n) 
− C ha n ge fr o m bas eli ne i n t he s u m of M D S- U P D R S Parts II a n d III at t he e n d of 
d o u ble- bli n d treat me nt p eri o d ( Visit 7 or earl y t er mi nati o n)  
•  A d diti o nal e n d p oi nts:  
T he f oll o wi n g e n d p oi nts will be e val uate d (at t he p ost- ra n d o mizati o n visits) as c ha n ge fr o m 
baseli ne ( Visit 4) as w ell as c ha n ge fr o m t he st u d y e ntr y ( Visit 1), w he n a p plica ble, b y visits:  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 6  of 1 5 9  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 7  of 1 5 9  
 
1 3. 4.  
A n al ysis of Effic ac y D at a  
I n or der t o c o ntr ol t he t y pe I err or r ate, t he pri mar y efficac y e n d p oi nt a n d k e y s ec o n dar y efficac y 
e n d p oi nts will be teste d i n a si n gle hierarc hical or der as det aile d i n Secti o n  1 3. 8 . 
1 3. 4. 1.  
Pri m ar y Effic ac y E n d p oi nt 
T he pri mar y efficac y e n d p oi nt is t he mea n c ha n ge fr o m baseli ne i n “ G o o d o n” t i me i n h o urs per 
da y, a ver a ge d o v er t he P D D iar y da ys,  at t he e n d of t he d o u ble-bli n d t hera p y ( Visit 7  or earl y 
ter mi nati o n).  “G o o d o n” t i me is deri ve d fr o m t he 3-da y P D  Diaries .  F or eac h da y, “ G o o d o n ” 
ti me is calc ulate d b y  a d di n g t he n u m ber of half- h o ur i nter vals i n w hic h eit h er a n “ O n wit h o ut 
d ys ki nesia” or “ O n wit h n o ntr o u bles o me d ys ki nesia” is c hec k e d. 
T he pri mar y efficac y e n d p oi nt will be a nal yze d usi n g a mi x e d m o del f or re peate d meas ures 
(M M R M ).  T he m o del will i ncl u de baseli ne ( Visit 4 ) “ G o o d o n” ti me as a c o variate, treat me nt, 
visit,  a n d p o ole d ce nter as fi x e d effects, a n d a treat me nt-b y -visit i nteracti o n .  T he m o del will 
e m pl o y a n u nstr u ct ure d wit hi n s u bject c o varia n ce matri x a n d a restricte d ma xi m u m li keli h o o d 
( ReM L ) esti mati o n met h o d.  T he de gree-of -free d o m of t he de n o mi nat or will be esti mate d usi n g 
t he Ke n war d-R o ger m et h o d ( Ke n w ar d a n d R o ger 1 9 9 7 ).  T he  pri mar y a nal ysis p o p ulati o n will 
be t he m o difie d i nte nt- t o-treat as d efi ne d i n Secti o n 1 3. 9 .  Missi n g data will be ha n dle d as i n 
Secti o n  1 3. 1 0 . 
If t he m o del fails t o c o n v er ge d ue t o t he u nstr u ct ure d c o vari a nce m atri x, a si m pler c o varia n ce 
matri x will be e m pl o ye d i n t he or der of 1) heter o ge ne o us T oe plitz [ S A S P R O C MI X E D t y p e = 
T O E P H], 2) heter o ge n e o us a ut ore gressi v e of or d er 1 [t y p e = A R H( 1)], 3) h eter o ge n e o us 
c o m p o u n d s y m metr y [t y pe = C S H], 4) T oe plitz [t y p e = T O E P], 5) a ut ore gressi ve of or d er 
1 [t y pe = A R( 1)], 6) c o m p o u n d s y m metr y [t y pe = C S].  T he first c o varia nce str uct ure  t hat d o es 
n ot ha ve a c o n v er ge n ce pr o ble m will be t he o ne us e d f or t he pri mar y a n al ysis . 
1 3. 4. 2.  
Ke y Sec o n d ar y Effic ac y E n d p oi nt s 
T he first ke y sec o n dar y e n d p oi nt is t he mea n c ha n ge fr o m baseli ne i n “Off ” ti me i n h o urs per 
da y, a ver a ge d o v er t he P D D iar y da ys, at t he e n d of t he d o u ble-bli n d t hera p y ( Visit 7  or earl y 
ter mi nati o n).  “ Off” ti me is deri ve d fr o m t he 3 - da y P D D iaries.  F or eac h d a y, “ Off” ti me is 
calc ulate d b y a d di n g t he n u m ber of half- h o ur i nter vals i n w hic h a n “ Off” is c hec k e d.  T his 
e n d p oi nt will be a nal yze d usi n g a M M R M  m o del wit h baseli ne ( Visit 4 ) “Off ” ti me as a 
c o variate, treat me nt, visit, a n d p o ole d ce nt er as fi x e d effects, a n d a treat me nt -b y -visit i nteracti o n .  
T he m o del will e m pl o y a n u nstr uct ure d wit hi n s u bject c o vari a nce m atri x a n d a restricte d 
ma xi m u m li keli h o o d ( R eM L) esti mati o n met h o d .  T he de gree-of -free d o m of t he de n o mi nat or 
will be es ti mate d usi n g t he Ke n w ar d-R o ger met h o d ( Ke n w ar d a n d R o ger 1 9 9 7 ). 
T he pr o p orti o n of s u bjects wit h eit her “ m uc h i m pr o ve d” or “ v er y m uc h i m pr o ve d” i n P GI -C 
sc ores at t he e n d of t he d o u ble- bli n d t hera p y ( Visit 7  or earl y ter mi nati o n ), t he sec o n d ke y 
sec o n dar y e n d p oi nt, will be a nal yz e d usi n g a C oc hra n -Ma ntel -Hae n szel test t o c o m pare t he t w o 
treat me nt gr o u ps wit h p o ole d ce nter as a stratificati o n fact or. 
T he mea n c h a n ge fr o m b aseli ne i n t he  M D S -U P D R S Part III  at the e n d of t he d o u ble- bli n d 
t hera p y ( Visit 7 or earl y t er mi nati o n) is t he t hir d  ke y s ec o n dar y e n d p oi nt.  T his e n d p oi nt will be 
a nal yze d usi n g a n M M R M m o del wit h baseli ne ( Visit 4) M D S -U P D R S Part III  as a c o v ariat e, 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 8  of 1 5 9  
 
treat me nt, visit, a n d p o ole d ce nter as fi xe d effects, a n d a treat me nt -b y -visit i nteracti o n.   T he 
m o del will e m pl o y a n u nstr uct ure d wit hi n s u bject c o varia n ce matri x a n d a restricte d ma xi m u m 
li keli h o o d ( ReM L) esti mati o n met h o d .  T he de gree- of-free d o m of t he de n o mi nat or will be 
esti mate d usi n g t he K e n war d -R o ger met h o d ( K e n war d a n d R o ger 1 9 9 7 ). 
T he mea n c h a n ge fr o m b aseli ne i n s u m of t he M D S - U P D R S Parts II a n d III at t he e n d of t he 
d o u ble- bli n d t hera p y ( Visit 7 or earl y ter mi nati o n) is t he f o urt h ke y sec o n d ar y e n d p oi nt.  T his 
e n d p oi nt will be a nal yze d usi n g a n M M R M m o del wit h baseli ne ( Visit 4) M D S- U P D R S Parts II 
a n d III c o m bi ne d as c o v ariates, treat me nt, visit, a n d p o ole d ce nter as fi x e d effects, a n d a 
treat me nt-b y -visit i nteracti o n.   T he m o del will e m pl o y a n u nstr u ct ure d wit hi n s u bject c o varia n ce 
matri x a n d a restricte d m a xi m u m li keli h o o d ( R eM L) esti mati o n met h o d .  T he de gree- of-free d o m 
of t he de n o mi nat or will b e esti mate d usi n g t h e Ke n war d -R o ger met h o d ( K e n war d a n d R o ger  
1 9 9 7 ). 
F or t he 4 k e y sec o n d ar y e n d p oi nts, t he a nal ysis p o p ulati o n will be t he m o difie d i nte nt- t o-treat as 
defi ne d i n Secti o n 1 3. 9 .  Missi n g data will be ha n dle d as i n  Secti o n 1 3. 1 0 . 
1 3. 4. 3.  
A d diti o n al  Effic ac y E n d p oi nts 
I n ge ner al, c o nti n u o us e n d p oi nts will be s u m marize d b y sta n dar d d escri pti v e statistics ( mea n, 
sta n dar d de viati o n, me di a n, mi ni m u m, a n d ma xi m u m).  Cate g ori cal e n d p oi nts will be 
s u m marize d b y fr e q ue n cies a n d per ce nta ges.  C o m paris o ns bet wee n t he t w o ar ms will be 
e x pl ore d usi n g a p pr o priate statistical met h o d ol o gies.  Deta ils will be pr o vi de d i n t he S A P. 
T he pri mar y e n d p oi nt, ke y sec o n dar y e n d p oi nts, as well as ot her efficac y e n d p oi nts will be 
prese nte d b y visit o ver t h e w h ole bli n de d treat me nt peri o d fr o m Baseli ne ( Visit 4) t o t he e n d of 
t he d o u ble- bli n d treat me nt peri o d (Visit 7).  
Ot her a d diti o nal efficac y e n d p oi nts c ollecte d p ostra n d o mizati o n will be a nal yze d b y visit i n a 
fas hi o n si milar t o t he pri mar y a n d ke y s ec o n dar y e n d p oi nts. 
A d diti o nall y t he P GI- C a n d  
 will be a nal yz e d usi n g a nal ysis of varia nce ( A N O V A) wit h 
treat me nt a n d p o ole d ce nter as fact ors.  
1 3. 5.  
Ce nter P o oli n g  Al g orit h m  
T he ce nter p o oli n g al g orit h m is as f oll o ws. 
1.  S ort ce nters fr o m eac h c o u ntr y fr o m s mallest t o lar gest bas e d o n t he n u m ber of s u bjects 
i n t he m o difie d i nte nt-t o-treat a nal ysis set ( mI T T). 
2.  Ce nters  wit h less t ha n 5 mI T T s u bjects or at least o ne mI T T s u bject per treat me nt gr o u p 
will be p o ole d wit h t he ne xt s mallest ce nter i n t he sa me c o u ntr y u ntil t he c o m bi ne d ce nter 
( na mel y, pse u d o-ce nter) has m ore t ha n 5 mI T T s u bjects a n d at least o n e mI T T s u bject 
per treat me nt gr o u p. 
3.  If after p o oli n g wit hi n t he sa me c o u ntr y, t h e pse u d o-ce nter still has less t ha n 5 mI T T 
s u bjects or still has zer o s u bjects i n o ne of t he treat me nt gr o u p, t h at pse u d o-ce nter will be 
p o ole d wit h t he ne xt s mallest ce nter i n t he sa me ge o gra p hical re gi o n ( West er n E ur o pe, 
Easter n E ur o p e, N ort h A merica).  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 5 9  of 1 5 9  
 
4.  If after p o oli n g wit hi n t he sa me ge o gra p hical re gi o n, t he pse u d o-ce nter still has less t ha n 
5 mI T T s u bjects or still has zer o s u bjects i n o ne of t he treat me nt gr o u p, t hat pse u d o-
ce nter will be p o ole d wit h t he ne xt s mallest ce nter i n a n y re gi o n.  
T he pr ocess c o nti n ues u ntil all p o ole d pse u d o- ce nt ers ha ve at least 5 mI T T s u bjects a n d at least 
o ne mI T T s u bject per treat me nt gr o u p.  T hese p o ole d ce nters will be use d i n a nal ys es t hat a dj ust 
f or p o oled ce nters.  
T his p o oli n g al g orit h m will be detaile d i n t he Statistical A nal ysis Pla n ( S A P).  
1 3. 6.  
Se nsiti vit y A n al yses of t he Pri m ar y E n d p oi nt  a n d Ke y Sec o n d ar y 
E n d p oi nts  
S e nsiti vit y a n al ys es will be perf or me d wit h res p ect t o t he pri mar y effi cac y e n d p oi nt  a n d 
c o nti n u o us ke y s ec o n dar y e n d p oi nts (“ Off” ti me, M D S -U P D R S Part III , a n d M D S-U P D R S Parts 
II a n d III c o m bi ne d) as f oll o ws. 
1 3. 6. 1.  
Assessi n g A ss u m pti o ns of t he M i xe d M o del f or R e pe ate d M e as ures ( M M R M)  
a. T he n or malit y a n d h o m osce dasticit y ass u m pti o ns will be e x a mi ne d t hr o u g h resi d ual 
a nal ys es.  T he n or malit y a n d h o m osce dasticit y ass u m pti o ns will f urt her be teste d via 
S ha pir o- Wil k ( S ha pir o a n d Wil k 1 9 6 5 ) a n d Le v e ne (Le v e ne 1 9 6 0 ) tests, res pecti vel y, at a 
0. 0 5 le vel of si g nifi ca nce.  If n or malit y a n d/ or h o m osce dasticit y ass u m pti o n a p pears vi olat e d, 
t he n: 
i. N o n para metric Wilc o x o n Ra n k S u m test will be perf or me d t o c o m pare t he t w o treat me nt 
gr o u ps, wit h missi n g d ata i m p ute d b y t he l ast o bser vati o n carrie d f or war d ( L O C F) 
met h o d. 
ii. M ulti ple i m p utati o n ra n k base d a nal ysis: i nstea d of missi n g data i m p ute d b y t he L O C F 
met h o d, i n t his a nal ysis, missi n g data at Visit 7 will be i m p ute d m ulti ple ti mes t o creat e 
5 0 c o m plete datasets.  T h e m ulti ple i m p uta ti o n pr oce d ure is d escri be d i n Secti o n 1 3. 6. 4  
( part of t he p atter n-mi xt ure m o del), usi n g f = 0 %.  T he Wilc o x o n Ra n k S u m test will be 
perf or me d o n eac h of t he 5 0 datasets.  T he res ults are t he n c o m bi ne d usi n g R u bi n’s r ule 
(R u bi n 1 9 8 7 ) via S A S P R O C MI A N A L Y Z E. 
b.  Missi n g at Ra n d o m ( M A R) ass u m pti o n wil l be e val uate d as disc usse d i n S ecti o n 1 3. 6. 4 . 
1 3. 6. 2.  
C o m plete C as e A n al ysis  
T he pri mar y e n d p oi nt will be a nal yze d usi n g a n A N C O V A m o del wit h “ G o o d o n” ti me at 
baseli ne ( Visit 4) as a c o variate, p o ole d ce nter a n d treat me nt as fact ors.  T he m o del will be 
perf or me d o n s u bj ects wit h b ot h  baseli ne “ G o o d o n” ti me a n d Visit 7 “ G o o d o n” ti me. 
1 3. 6. 3.  
Si n gle L O C F/ B L O C F Im p ut ati o n  
T he pri mar y efficac y e n d p oi nt will be a nal yze d usi n g a n A N C O V A m o del wit h “ G o o d o n” ti me 
at Visit 4 as a c o vari ate, p o ole d ce nter a n d treat me nt as fact ors.  Missi n g d ata will be i m p ute d b y 
t he L O C F a n d b aseli ne o bser vati o n carried f or war d ( B L O C F) met h o ds.  T h ese a nal ys es will be 
perf or me d o n t h e mI T T p o p ulati o n. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 0  of 1 5 9  
 
1 3. 6. 4.  
P atter n - Mi xt ure M o del  
If a n o verall dr o p o ut rat e p ostra n d o mizati o n is > 1 5 %, patter n-mi xt ure m o dels ( P M M) will be 
e m pl o ye d t o assess t he r o b ust ness of t he res ults u n der t he missi n g n ot at ra n d o m ( M N A R) 
ass u m pti o n.  T he patter n f or P M M is defi ne d b y p atie nts’ last visit wit h a n o bser ve d pri mar y 
efficac y e n d p oi nt a n d t h e reas o n f or dr o p o ut. 
M ulti ple i m p utati o n wit h mi x e d missi n g data mec ha nis m ( M N A R f or a missi n g data p atter n a n d 
M A R f or ot hers) will be use d t o i n vesti gate t h e r o b ust ness of t he pri mar y res ult.  F o ur s pecific 
data patter ns will be e x a mi ne d:  
1.  Dr o p o ut at Visit 5 a n d reas o n = Lac k of ef ficac y i n I P X 2 0 3 treat me nt ar m, 
2.  Dr o p o ut at Visit 5 a n d reas o n = Lac k of efficac y or a d vers e e ve nts i n I P X 2 0 3 treat me nt 
ar m, 
3.  Dr o p o ut at Visit 6 a n d reas o n = Lac k of ef ficac y i n I P X 2 0 3 treat me nt ar m, 
4.  Dr o p o ut at Visit 6 a n d reas o n = Lac k of efficac y or a d vers e e ve nts i n I P X 2 0 3 treat me nt 
arm.  
T he missi n g val ues will be i m p ute d 5 0 ti mes ( m ulti ple i m p utati o n) u n der t he ass u m pti o n t hat t he 
distri b uti o n of t he missi n g val u es is t he sa me as t h at of t he o bser v e d val ues.  T he P M M t he n 
i n vesti gates the d e part ure fr o m t he M A R ass u m pti o n b y pr o gressi vel y decreasi n g t h e o utc o me 
(t he “ pe n alt y”) f or t h ose o n I P X 2 0 3 ar m w h o fall i nt o a n ass u me d M N A R patter n a b o ve.  F or t h e 
dr o p o ut s u bjects o n I P X 2 0 3 ar m t hat fall i nt o o ne of t he patter ns a b o v e, t he “ pe nalt y” is o btai ne d 
b y s u btracti n g t h e i m p ute d missi n g data aft er dr o p o ut b y a fact or f, wit h f starts fr o m 0 %, 5 %, 
1 0 %, 1 5 %, 2 0 %, 2 5 %, 3 0 %, …, 1 0 0 % of t he treat me nt differe n ce see n i n t he pri mar y m o del.  
T his pr ocess c o nti n ues u ntil t he c o ncl usi o n fr o m t he pri mar y a n al ysis is o v ert ur ne d (a ti p pi n g 
p oi nt).  I n ot her w or ds, if t he dr o p o ut s u bject is fr o m I P X 2 0 3 ar m a n d t he dr o p o ut patter n falls 
i nt o o ne of t he 4 patter ns a b o ve, t he n t he s u bject’s i m p ute d val ue will be a dj uste d d o w n war d b y 
a fact or f, w her e f g o es fr o m 0 % t o 1 0 0 % of t he treat me nt differe nce see n i n t he pri mar y m o del.  
N ote t hat if 0 % i s use d, t he a nal ysis is esse ntiall y m ulti ple i m p utati o n u n der M A R ass u m pti o n.  
O n t he ot her ha n d, if 1 0 0 % is use d, t he n t he a nal ysis is esse ntiall y a “j u m p t o refere nce” w h ere 
o utc o me o n I P X 2 0 3 ar m is ass u me d t o be t he sa m e as o utc o me o n I R C D -L D.  After 
im p utati o ns, t he dataset will be a nal yze d usi n g a n M M R M m o del si milar t o t he pri mar y a n al ysis 
m o del.  T he res ults will t he n be c o m bi ne d usi n g t he R u bi n’s r ule ( R u bi n 1 9 8 7 ) via S A S P R O C 
MI A N A L Y Z E.  
T he pr oce d ure will be carrie d o ut i n S A S as f oll o ws: 
a. Use M o nte Carl o Mar k o v C hai n ( M C M C) met h o d i n S A S P R O C MI b y treat me nt 
gr o u p t o i m p ute t he i nter mitte nt missi n g data t o f or m m o n ot o ne missi n g ness.  
b.  Use M A R -base d m ulti ple i m p utati o n i n S A S P R O C MI t o i m p ute t he missi n g data 
( S A S M O N O T O N E state me nt).  
c. F or dr o p o ut s u bjects i n I P X 2 0 3 ar m w h o fall i nt o a n M N A R patter n s pecifi e d a b o ve, 
a delta w hic h e q uals t o f ti mes t he treat me nt differe nce o btai n e d fr o m t he pri mar y 
M M R M a nal ysis at Visit 7 will be s u btracte d fr o m t heir i m p ute d val ues f or all visits 
after t he dr o p o ut (“ p e nali zi n g” I P X 2 0 3 ar m). 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 1  of 1 5 9  
 
d.  After i m p utati o n, use t he M M R M m o del as i n t he pri mar y a nal ysis m o del t o a nal yze 
t he c o m plete data al o n g wit h t he i m p ute d data. 
e. Re peat ste ps a  t hr o u g h d 5 0 ti mes. 
C o m bi ne res ults usi n g R u bi n’s r ul e (R u bi n 1 9 8 7 ) via S A S P R O C MI A N A L Y Z E. 
1 3. 7.  
S u b gr o u p A n al yses  
T he pri mar y, ke y s ec o n d ar y e n d p oi nts, as w ell as o verall s u m mar y of a d verse e ve nts, will be 
e x a mi ne d f or t he f oll o wi n g s u b gr o u ps. 
•  A ge: < 6 5, ≥ 6 5 years ol d at st u d y e ntr y  
•  Se x: Males, Fe males  
•  Race: Ca ucasia ns, n o n -C a ucasia ns  
A d diti o nall y, t he f oll o wi n g s u b gr o u ps ma y b e e x a mi ne d: 
•  Re gi o n  
•  Et h nicit y  
•  C o nc o mita nt me dicati o ns  
•  Wei g ht  
•  B o d y mass i n de x ( B MI ) 
•  P D d urati o n 
•  A ge of P D o nset 
•  “ G o o d O n” ti me a n d “ Off” ti me at st u d y e ntr y.  
F or all s u b gr o u p efficac y a nal ys es, t he sa me a nal ysis met h o ds as t he pri mar y a n d k e y sec o n dar y 
e n d p oi nts will be a p plie d, u nless t he sa m ple size i n o ne of t he s u b gr o u ps b ec o mes t o o s mall t o 
hi n der t he statistical a nal ysis.  I n t hat case, n o i nfere ntial statistics will be pr o vi de d f or s uc h a 
s u b gr o u p.  T h e details f or fi nal s u b gr o u p a n al ys es will be d oc u me nte d i n t he S A P. 
1 3. 8.  
M ulti plicit y A dj ust me nts  
T he pri mar y e n d p oi nt a n d 4 ke y s ec o n d ar y e n d p oi nts will be teste d i n a se q ue ntial hierarc hical 
or d er as f oll o ws . 
1.  T he pri mar y e n d p oi nt, t h e mea n c h a n ge fr o m baseli ne i n “ G o o d o n” ti me ( h o urs per da y), 
will be teste d first at a 0. 0 5 le vel of si g nifi ca nce.  
2.  If statistical si g nifica nce is de m o nstrate d, t he n t he first ke y s ec o n d ar y e n d p oi nt, t he mea n 
c ha n ge fr o m baseli ne i n “Off ” ti me ( h o urs per da y), will be teste d ne xt at a 0. 0 5 le vel of 
si g nifica n ce. 
3.  If statistical si g nifica nce is de m o nstrate d, t he n t he sec o n d ke y sec o n dar y e n d p oi nt, t he 
pr o p orti o n of s u bjects wit h eit her “ m uc h i m pr o ve d” or “ ver y m uc h i m pr o v e d ” o n t he 
P GI - C, will be teste d n e xt at a 0. 0 5 le vel of si g nifi ca nce. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 2  of 1 5 9  
 
4.  If statistical si g nifica nce is de m o nstrate d, t he n t he t hir d ke y s ec o n dar y e n d p oi nt, t he 
mea n c ha n ge fr o m b aseli ne i n t he M D S -U P D R S Part III , will be teste d at a 0. 0 5 le vel of 
si g nifica n ce. 
5.  If statistical si g nifica nce is de m o nstrate d, t he n t he f o urt h ke y sec o n dar y e n d p oi nt, t he 
mea n c ha n ge fr o m b aseli ne i n t he s u m of t he M D S - U P D R S Parts II a n d III c o m bi ne d 
will be teste d ne xt at a 0. 0 5 le vel of si g nifi ca nce.  
F or t he ot her effica c y e n d p oi nt s, n o a dj ust me nt will be ma de . 
1 3. 9.  
A n al ysi s P o p ul ati o ns 
1 3. 9. 1.  
S af et y A n al ysis Set 
T he Safet y A n al ysis set will i ncl u de all s u bjects w h o were treat e d wit h a n y st u d y dr u g.  
1 3. 9. 2.  
I nte nt-t o- Tre at A n al ysis Set 
T he I nte nt -t o-tr eat A nal ysis Set will i ncl u de all s u bjects w h o were ra n d o mize d a n d treate d wit h 
a n y st u d y dr u g a n d ha v e a baseli ne a n d at least o n e p ost baseli ne efficac y assess me nt . 
1 3. 9. 3.  
M o difie d I nte nt -t o- Tre at A n al ysis Set 
T he M o difie d I nte nt- t o-tr eat A nal ysis Set will i ncl u de all s u bjects w h o were ra n d o mize d a n d 
treate d a n d h a ve a vali d baseli ne P D Diar y a n d at least o ne vali d  p ostra n d o mizati o n P D Diar y .  
T his a nal ysis set will be use d f or t he pri mar y a nal ysis  a n d ke y s ec o n d ar y a nal yses . 
1 3. 9. 4.  
C o m pleters A n al ysis Set  
T he C o m pleters A nal ysis Set will i ncl u de all s u bjects  w h o were ra n d o mize d a n d treate d a n d 
c o m plete t he st u d y.  
1 3. 1 0.  
H a n dli n g of Missi n g D at a  
1 3. 1 0. 1.  
Missi n g D at a f or P D Di aries  
A n M M R M a p pr oac h will be use d t o ha n dle missi n g visit data.  M M R M a n al ysis will use all 
a vaila ble vali d visit data, i ncl u di n g s u bjects wit h s o me missi n g visit data, i n or der t o arri ve at a n 
esti mate of t he mea n tr eat me nt effect.  
A P D Diar y is vali d if at least 1 da y of diar y d ata is a vaila ble usi n g t he r ules defi ne d bel o w. 
Im p utati o n of missi n g d ata f or a P D Diar y da y  will be re q uire d if a P D D iar y is n ot c o m plete d 
f or a f ull da y ( 6 a m t o 5: 3 0 a m).  I n t his case, t h e met h o d of i m p utati o n will be de pe n de nt u p o n 
t he a m o u nt a n d patter n of missi n g data. 
•  F or s u bjects wit h m ore t h a n 1 da y of diar y data, t h e f oll o wi n g r ules will a p pl y: 
1.  If m ore t ha n 4 h alf -h o ur ti me i nter vals are missi n g, t he n t hat partic ular d a y will n ot be 
i ncl u de d i n t he a nal ysis.  T he missi n g data will be ha n dle d i n t he M M R M m o del. 
2.  If a o ne- half h o ur ti me i nter val is missi n g a n d t he o bser vati o ns o n eit her si de of t he 
ti me i nter val are n ot missi n g, t he n t he missi n g ti m e i nter val will be i m p ute d b y 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 3  of 1 5 9  
 
assi g ni n g a v al ue of t he pre vi o us meas ure me nt f or t he first 1 5 mi n utes a n d t he val ue 
of t he ne xt meas ure me nt f or t he sec o n d 1 5 mi n utes. 
3.  If 2, 3, or 4 c o ns ec uti ve h alf -h o ur ti me i nter v als are missi n g, a n d t hese ti me i nter vals 
are a v aila ble fr o m ot her da ys of t he visit t he n t he f oll o wi n g r ules will be a p plie d:  
a. F or missi n g ti me i nter v als o n Da y 1, data fr o m Da y 2 will be use d f or i m p utati o n 
f or t he sa me ti me i nter v als.  If Da y 2 dat a is als o i nc o m plete or n ot a vaila bl e, t he n 
Da y 3 data will be use d. 
b.  F or missi n g ti me i nter v als o n Da y 2, data fr o m Da y 3 will be use d f or i m p utati o n 
if a vaila ble; ot her wise D a y 1 d ata will be use d.  
c. Data fr o m D a y 2 will be use d f or i m p uti n g missi n g ti me i nter vals o n D a y 3.  If 
data fr o m D a y 2 is n ot a vaila ble, t he n Da y 1 d ata will be use d f or i m p utati o n. 
d.  If data at t he sa me ti me p eri o d are missi n g acr oss all da ys , t he n t h e a p pr o ac h will 
be t o s plit t he i n di vi d ual missi n g half - h o ur i nter vals i nt o 2 peri o ds, wit h t he first-
half i nter val bei n g i m p ute d wit h data fr o m t he i m me diate pre vi o us n o n missi n g 
ti me peri o d a n d t he sec o n d- half i nter val b ei n g i m p ute d wit h t he ne xt n o n missi n g 
ti me i nter val. 
•  F or s u bjects wit h o nl y 1 da y of diar y d ata, t he f oll o wi n g r ul es will a p pl y: 
1.  If m ore t ha n 4 h alf-h o ur ti me i nter vals are missi n g, t he n t hat partic ular d a y will n ot be 
i ncl u de d i n t he a nal ysis.  T he missi n g data will be ha n dle d i n t he M M R M m o del. 
2.  If a o ne- half h o ur ti me i nter val is missi n g a n d t he o bser vati o ns o n eit her si de of t he 
ti me i nter val are n ot missi n g, t he n t he missi n g ti m e i nter val will be i m p ute d b y 
assi g ni n g a v al ue of t he pre vi o us meas ure me nt f or t he first 1 5 mi n utes a n d t he val ue 
of t he ne xt meas ure me nt f or t he sec o n d 1 5 mi n utes. 
3.  If 2, 3, or 4 c o ns ec uti ve h alf - h o ur i nter v als are missi n g, t he n t he a p pr oac h will be t o 
s plit t he i n di vi d ual missi n g half- h o ur i nter v als i nt o 2 peri o ds, wit h t he first-half 
i nter val bei n g i m p ute d wit h data fr o m t he i m me diate pre vi o us n o n missi n g ti me 
peri o d a n d t he sec o n d- half i nter val bei n g i m p ute d wit h t he ne xt n o n missi n g ti me 
i nter val. 
1 3. 1 0. 2.  
Missi n g D at a f or Gl o b al Assess me nts (P GI - C,
 
F or s u bjects wit h missi n g P GI -C or 
f or a partic ular visit, t he data will be i m p ute d as 
n o nres p o n ders (ie, n ot bei n g “ m uc h i m pr o v e d” or “ ver y m uc h i m pr o v e d” ). 
1 3. 1 0. 3.  
Missi n g D at a f or M D S-U P D R S  
If t he M D S-U P D R S are missi n g f or t he partic ular visit, t he  missi n g data will be ha n dle d via  t he 
M M R M m o del . 
If c o m p o ne nt q uesti o ns are missi n g f or a partic ular part of t he M D S- U P D R S q uesti o n naire, t he 
missi n g ite ms are assi g ne d t he a ver a ge val u e f or ot her ite ms i n t hat part  as f oll o ws (G oetz 2 0 1 5 ): 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 4  of 1 5 9  
 
•  F or Part I ( 1 3 q uesti o ns): u p t o 1 missi n g q uesti o n will be i m p ute d usi n g t he a vera ge 
val ue of t he r e mai ni n g 1 2 q uesti o ns. 
•  F or Part II ( 1 3 q uesti o ns): u p t o 2 missi n g q uesti o n s will be i m p ute d usi n g t he 
a vera ge val ue of t he r e mai ni n g 1 1 q uesti o ns. 
•  F or Part III ( 3 3 q u esti o ns): u p t o 7 missi n g q uesti o ns will be i m p ute d usi n g t he 
a vera ge val ue of t he r e mai ni n g 2 6 q uesti o ns. 
•  Part I V ( 6 q uesti o ns): n o i m p utati o n is d o ne. 
If m ore  c o m p o n e nt q uesti o ns are missi n g t ha n a b o ve f or a p artic ular part of t he M D S-U P D R S 
q uesti o n naire, t he e ntir e q uesti o n naire will n ot be i ncl u de d i n t he a nal ysis f or t hat partic ular 
assess me nt.  Missi n g dat a will be ha n dle d i n a fas hi o n si milar t o P D Diar y data ( Secti o n  1 3. 1 0. 1 ) 
usi n g t he M M R M m o del. 
F or q ualit y- of-life e n d p oi nts, missi n g res p o nses wit hi n a q uesti o n naire will n ot be i m p ute d. 
1 3. 1 1.  
A n al ysis of S afet y  
T he safet y a nal ysis will i ncl u de all s u bjects w h o recei ve at least 1 d ose of st u d y me dicati o n.  
Re p orte d A Es will be c o de d usi n g t he M e dical Di cti o nar y f or Re g ul at or y Acti vities ( Me d D R A).  
All A Es will be s u m marize d b y s yste m or ga n class a n d preferre d ter ms wit hi n s yste m or ga n 
class.  T he se v erit y, s eri o us ness, a n d relati o ns hi p t o st u d y me dicati o n will als o be s u m marize d 
b y treat me nt ar ms.  E ac h A E ( base d o n preferre d t er m) is c o u nte d o nce f or a gi v e n s u bject.  If 
t he sa me A E occ urr e d o n m ulti ple occasi o ns, t he hi g hest se v erit y a n d least c o m pli me ntar y 
relati o ns hi p will be ass u me d. 
T he i nci de nce of treat me nt- e mer ge nt A Es a n d seri o us A Es will be s u m marize d  b y treat me nt 
ar ms. 
A d diti o nall y, la b orat or y test data, p h ysical e x a mi nati o n s, vital si g ns, E C Gs, C -S S R S , a n d G C SI 
will be s u m marize d b y  tr eat me nt ar ms. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 5  of 1 5 9  
 
1 4.  
A D MI NI S T R A TI V E P R O C E D U R E S  
1 4. 1.  
G ui deli nes f or G o o d Cli nic al Pr actice  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h pri nci ples of G o o d Cli nical Practice ( G C P) as 
pr o m ul gate d b y t h e I C H.  G o o d Cli nical Practice is a n i nter nati o nal et hical a n d scie ntific q ualit y 
sta n dar d f or d esi g ni n g, c o n d ucti n g, r ec or di n g, a n d re p orti n g trials t hat i n v ol ve t he partici pati o n 
of h u ma n s u bjects.  C o m plia nce wit h t his sta n dar d pr o vi des p u blic ass ura n ce t hat t he ri g hts, 
safet y, a n d w ell- bei n g of h u ma n s u bjects are pr otecte d u n der c urre nt et hical pri nci ples, a n d t hat 
t he cli nical trial data are cre di ble.  C urre nt G C P sta n dar ds ma y b e f o u n d i n I C H G ui d a nce E 6 
( G o o d Cli nical Practice:  C o ns oli date d G ui da nce).  T his g ui da nce descri bes t he pri nci ples of 
G C P a n d t he o bli gati o ns of t he i nstit uti o nal re vie w b oar d (I R B), t he I n vesti gat or a n d t h e S p o ns or 
i n c o n d ucti n g t his st u d y i n acc or d a nce wit h t h ose pri nci ples. 
1 4. 2.  
I nstit uti o n al Re vie w B o ar d A p pr o v al 
T he re vie w of t his pr ot oc ol b y a n I R B a n d t he p erf or ma nce of all as pects of t he st u d y, i ncl u di n g 
t he met h o ds use d f or o bt ai ni n g i nf or m e d c o nse nt, m ust be i n acc or d a nce wit h pri nci ples 
e n u nciate d i n t he I C H a n d G C P G ui deli nes a n d b y t he a p pr o priat e re g ulat or y a ut h orities. 
T he I n vesti gat or is r es p o nsi ble f or pre p ari n g d oc u me nts f or s u b missi o n t o t he rele v a nt I R B a n d 
o btai ni n g writte n a p pr o v al f or t his st u d y.  I nstit uti o nal Re vie w B o ar d a p pr o val m ust be o btai ne d 
pri or t o t he i nitiati o n of t he st u d y.  T h e I n vesti gat or’s c o nti n ue d partici pati o n i n t he st u d y is 
c o nti n ge nt o n r e ne wi n g a p pr o val wit h t he I R B at least a n n uall y.  
1 4. 3.  
I nf or me d C o nse nt 
Site pers o n nel s h o ul d pre pare a n I nf or m e d C o nse nt F or m (I C F) i nc or p orati n g t he n ecess ar y 
ele me nts of c o nse nt.  T h e I C F is t o be a p pr o ve d b y I m pa x pri or t o s u b missi o n t o t he I R B.  T he 
I n v esti gat or or his/ her staff m ust e x plai n t he nat ure of t he i n vesti gati o n a n d t he ris ks i n v ol ve d t o 
eac h s u bject pri or t o scr ee ni n g, a n d o btai n a si g ne d I C F.  T he s u bject s h o ul d als o be i nf or me d 
t hat he/s he is free t o v ol u ntaril y wit h dra w fr o m t h e st u d y at a n y ti me. 
1 4. 4.  
St u d y M o nit ori n g  
I m pa x re pr ese ntati ves or desi g nees will c o n d uct site visits t o t he i n vesti gati o nal facilities f or t he 
p ur p ose of m o nit ori n g t h e st u d y.  T h e I n vesti gat or a grees t o all o w t he m o nit or t o i ns pect t he 
dr u g st or a ge area, st u d y dr u g st oc ks, dr u g acc o u nta bilit y rec or ds, s u bject c harts a n d st u d y s o urce 
d oc u me nts, a n d ot her r ec or ds rele va nt t o st u d y c o n d uct.  T he I n vesti gat or m ust per mit access t o 
s uc h rec or ds if a r e g ulat or y or c o m plia nce a u dit is re q uire d. 
1 4. 5.  
Pr ot oc ol A me n d me nts  
All a me n d me nts t o t he pr ot oc ol m ust be d oc u me nte d i n writi n g, re vie w e d a n d a p pr o ve d b y t he 
S p o ns or a n d I n vesti gat or, a n d s u b mitte d t o t he I R B f or a p pr o val pri or t o i m ple me ntati o n.  If t he 
pr ot oc ol a me n d me nt s u bsta ntiall y alters t he st u d y desi g n or p ot e ntial ris k t o t he s u bject, a ne w 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 6  of 1 5 9  
 
writte n I C F f or c o nti n ue d partici pati o n i n t he st u d y m ust be o btai ne d fr o m eac h s u bject affecte d 
b y t he c ha n ge.  
1 4. 6.  
Ter mi n ati o n of St u d y  
T he S p o ns or has t he ri g ht t o ter mi nate t his st u d y a n d re m o ve all st u d y material fr o m t he site at 
a n y ti me f or me dical or a d m i nistrati ve reas o ns.  I n t his e ve nt, t he S p o ns or will e n dea v or t o gi ve 
a de q uate n otice t o all o w safe wit h dra wal of s u bjects fr o m t he st u d y. 
1 4. 7.  
C ase Re p ort F or ms  
Site pers o n nel s h o ul d c ollect a n d rec or d d ata f or t he st u d y as s o urce d o c u me nts, a n d tra nsfer t he 
data i nt o t he C R F. 
T he I n vesti gat or m ust e ns ure t hat c o m plete d ata f or t he cli nical st u d y are c ollecte d a n d 
acc ur atel y d oc u me nt e d i n t he a p pr o priat e secti o ns of t he C R F a n d a d e q uat el y s u p p ort e d b y t he 
a p pr o priate s o urce d o c u me ntati o n.  I n a d diti o n, it is t he I n v esti gat or’s res p o nsi bilit y t o pr o vi de 
si g nat ur es w her e r e q uest e d i n dicati n g c o nc urre n ce wit h data i n t he C R F. 
1 4. 8.  
I n vesti g at or’s Fi n al C o n d uct Re p ort 
At t he c o m pleti o n of t he st u d y, t he I n v esti gat or m ust pr o vi de I m p a x a c o p y of t he fi nal c o n d u ct 
re p ort that was s u b mitte d t o t heir I R B, i ncl u di n g a re vie w of A Es.  
1 4. 9.  
Rec or ds Rete nti o n  
I nter nati o nal C o nfere nce o n Har m o nizati o n, G C P, a n d U S F D A g ui deli nes re q uire t hat esse ntial 
d oc u me nts be ret ai ne d u ntil at least 2 years after t he last a p pr o val of a mar keti n g a p plicati o n a n d 
u ntil t here are n o p e n di n g or c o nte m plate d mar keti n g a p plicati o ns, or at least 2 years ha ve 
ela pse d si nce t h e f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he i n vesti gati o nal pr o d uct. 
H o we ver, t he esse ntial d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d if re q uire d b y t he 
a p plica ble r e g ulat or y r e q uire me nts or b y a n a gree me nt wit h t he S p o ns or.  Rec or ds s h o ul d ne ver 
be destr o ye d wit h o ut writte n a p pr o val fr o m t he S p o ns or. 
If a n I n v esti gat or lea v es t he i nstit uti o n, he/s he m ust tra nsfer res po nsi bilities f or rec or d rete nti o n 
t o a n ot her i n di vi d ual willi n g t o acce pt t he m.  T he I n v esti gat or m ust n otif y t he S p o ns or i n writi n g 
of t he tra nsf er of st u d y d oc u me nts bef ore t he tra nsfer of t he st u d y d o c u me nts. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 7  of 1 5 9  
 
1 5.  
P U B LI C A TI O N P O LI C Y  
St u d y res ults ma y n ot be p u blis he d wit h o ut pri or writte n a p pr o val fr o m I m pa x. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 8  of 1 5 9  
 
1 6.  
LI S T O F R E F E R E N C E S  
Bla nc h et PJ, Cal o n F, Martel J C, et al. C o nti n u o us a d mi nistrati o n decreases a n d p ulsatile 
a d mi nistrati o n i ncreases be ha vi oral se nsiti vit y t o a n o vel d o pa mi ne D 2 a g o nist ( U- 9 1 3 5 6 A) i n 
M P T P -e x p ose d m o n ke ys. J P har mac ol E x p T her. 1 9 9 5; 2 7 2: 8 5 4- 8 5 9. 
E n g ber T M, S usel Z, J u nc os J L, C has e T N. C o nti n u o us a n d i nter mitte nt le v o d o pa differe ntiall y 
affect r otati o n i n d uce d b y D- 1 a n d D- 2 d o p a mi ne a g o nists. E ur o p ea n J o ur nal of P har mac ol o g y. 
1 9 8 9; 1 6 8: 2 9 1- 2 9 8. 
Fa h n S. Par ki ns o n diseas e, t he effect of l e v o d o pa, a n d t he E L L D O P A trial. Earlier vs Lat er L 
D O P A. Arc h N e ur ol. 1 9 9 9 Ma y; 5 6( 5): 5 2 9- 3 5. 
F o o d a n d Dr u g A d mi nistrati o n 2 0 0 3.  G ui da nce f or I n d ustr y.  Bi o a vaila bilit y a n d 
Bi oe q ui vale n ce St u dies f or Orall y A d mi nistere d Dr u g Pr o d ucts — Ge n eral C o nsi derati o ns.  U. S. 
De part me nt of Healt h a n d H u ma n Ser vices.  F o o d a n d Dr u g A d mi nistrati o n. Ce nter f or Dr u g 
E val uati o n a n d Researc h ( C D E R). Marc h 2 0 0 3. 
G oetz C G,  L u o S, Wa n g L, Tille y B C, La Pelle N R, Ste b bi ns G T. Ha n dli n g missi n g v al ues i n t he 
M D S - U P D R S. M o v Dis or d. 2 0 1 5 Oct; 3 0( 1 2): 1 6 3 2- 8. 
J u nc os J L, E n g b er T M, Rais ma n R, et al. C o nti n u o us a n d i nter mitte nt le v o d o pa differe ntiall y 
affect basal ga n glia f u ncti o n. A n n  Ne ur ol. 1 9 8 9; 2 5: 4 7 3- 4 7 8. 
Ke n war d M G a n d R o ger J H.  S mall sa m ple i nfere nce f or fi x e d effects fr o m restricte d ma xi m u m 
li keli h o o d. Bi o metrics. 1 9 9 7; 5 3: 9 8 3- 9 9 7. 
K urla n R, R ot hfiel d K P, W o o d war d W R, N utt J G, Miller C, Lic hter D, et al. Erratic gastri c 
e m pt yi n g of le v o d o p a ma y ca use “r a n d o m” fl uct u ati o ns of par ki ns o nia n m o bilit y. N e ur ol o g y. 
1 9 8 8; 3 8( 3): 4 1 9- 2 1. 
Le v e ne H.  I n c o ntri b uti o ns t o pr o ba bilit y a n d statistics: Essa ys i n h o n or of Har ol d H otelli n g, I. 
Ol ki n et al. e ds. Sta nf or d U ni versit y Pr ess. 1 9 6 0: 2 7 8- 2 9 2. 
Mela me d E, Bitt o n V, Zeli g O. Del a ye d o nset of res p o nses t o si n gle d os es of L- d o pa i n 
par ki ns o nia n fl uct uat ors o n l o n g- ter m L- d o pa t hera p y. Cli n Ne ur o p har mac ol. 1 9 8 6; 9( 2): 1 8 2- 8. 
Miz u n o Y. W here d o we sta n d i n t he treat me nt of Par ki ns o n's diseas e? Ne ur ol o g y. 2 0 0 7; 2 5 4: 1 3-
1 8. 
Nilss o n D, N y h ol m D, A q uil o ni us S- M. D u o de nal le v o d o pa i nf usi o n i n Par ki ns o n's disease --
l o n g-ter m e x perie nce. Acta Ne ur ol o gica Sca n di na vica. 2 0 0 1; 1 0 4: 3 4 3- 3 4 8. 
N y h ol m D, Nilss o n Re m a hl AI, Diz dar N, et al. D u o de nal le v o d o pa i nf usi o n m o n ot hera p y vs 
oral p ol y p h ar mac y i n a d va nce d Par ki ns o n disease. Ne ur ol o g y. 2 0 0 5; 6 4: 2 1 6- 2 2 3. 
R u bi n D B. M ulti ple I m p utati o n i n N o nres p o nse i n S ur ve ys. Sa n Fra ncisc o, C A: Wile y; 1 9 8 7. 
S ha pir o S S a n d Wil k M B.  A n a nal ysis of vari a nce test f or n or malit y (c o m plete sa m ples). 
Bi o metri ka. 1 9 6 5; 5 2( 3- 4): 5 9 1- 6 1 1. 
Si ne met ( Car bi d o pa- Le v o d o pa) Ta blets Pres cri bi n g I nf or mati o n. W hite h o use Stati o n, NJ: 
Ma n ufact ur e d b y Merc k & C o., I nc.; Mar kete d b y Brist ol- M yers S q ui b b C o m pa n y; 2 0 1 3. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 6 9  of 1 5 9  
 
St occ hi F, Q ui n n N P, Bar bat o L, Patsal os P N, O’ C o n nel M T, R u g gieri S, et al. C o m paris o n 
bet wee n a fast a n d a sl o w releas e pre p arati o n of le v o d o pa a n d a c o m bi nati o n of t he t w o:  a 
cli nical a n d p har m ac o ki n etic st u d y. Cli nical Ne ur o p har mac ol. 1 9 9 4; 1 7( 1): 3 8- 4 4. 
St occ hi F, Vacca L, et al. I nter mitte nt vs c o nti n u o us le v o d o pa a d mi nistrati o n i n patie nts wit h 
a d va nce d Par ki ns o n disease: a cli nical a n d p har m ac o ki netic st u d y. Arc h N e ur ol. 2 0 0 5: 6 2( 6): 9 0 5-
9 1 0. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 0  of 1 5 9  
 
1 7.  
A P P E N DI C E S  
 
 
A P P E N DI X  A.  P R E S C RI BI N G I N F O R M A TI O N F O R I R C D - L D 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 1  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
   
  
 
 
  
 
   
 
  
 
   
 
 
  
 
 
 
 
  
 
 
    
  
 
 
 
 
 
  
  
  
  
    
 
 
 
 
 
   
 
 
 
 
  
 
  
 
 
 
   
 
 
 
 
  
   
 
 
 
 
  
 
   
 
  
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
    
 
 
 
 
  
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
    
  
 
 
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
    
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 2  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
   
 
  
 
 
 
 
 
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 3  of 1 5 9  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 4  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 5  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
   
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 6  of 1 5 9  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 7  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 8  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 7 9  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 0  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
  
   
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 1  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 2  of 1 5 9  
 
A P P E N DI X  B. I N S T R U C TI O N S F O R D O S E C O N V E R SI O N T O I P X 20 3  
 
T he g o al of t he d ose c o n versi o n peri o d is t o esta blis h a d osi n g re gi me n f or I P X 2 0 3 t hat 
mi ni mizes “ Off” ti me wit h o ut ca usi n g tr o u bles o m e d ys ki nesi as.  
T he i nitial d ose of I P X 2 0 3 is base d o n t he s u bject’s m ost fre q ue nt I R C D - L D d ose esta blis he d 
d uri n g t he 3- wee k I R  C D - L D d ose a dj ust me nt peri o d. 
T a b le B- 1  
Rec o m me n de d St arti n g I P X 2 0 3 L D D osi n g Re gi me n B ase d o n t he D osi n g 
Re gi me n of I R C D -L D at t he E n d of t he D ose A dj ust me nt Peri o d  
M ost F re q ue nt I R C D -L D U nit 
D ose ( m g)  
Rec o m me n de d St arti n g I P X 2 0 3 D ail y D osi n g Re gi me n 
C D -L D ( m g) E ver y 8 H o urs  
2 5- 1 0 0 a 
7 0- 2 8 0 m g ( 2 × 3 5- 1 4 0 m g)  
> 2 5- 1 0 0 – 3 7. 5- 1 5 0 
1 0 5- 4 2 0 m g ( 3 × 3 5- 1 4 0 m g) 
> 3 7. 5- 1 5 0 – 5 0- 2 0 0 
1 4 0- 5 6 0 m g ( 4 × 3 5- 1 4 0 m g) 
> 5 0- 2 0 0 
1 7 5- 7 0 0 m g ( 5 × 3 5- 1 4 0 m g) 
a 
S u bj ects w h o are o n a t otal dail y d ose of less t ha n 1 2 5 -5 0 0 m g C D -L D fr o m I R C D -L D s h o ul d be a d vise d 
t o i nitiall y ta ke I P X 2 0 3 e ver y 1 2 h o urs.  T he d osi n g i nter val ma y be re d uce d t o a p pr o xi mat el y e ver y 
8 h o urs if t he s u bj ect d oes n ot ac hie ve a n acce pta ble d urati o n of effect.  
 
C o n versi o n I nstr u cti o ns:  
1.  C o n vert t he s u bject’s m ost fre q ue nt dail y d ose of I R C D - L D t o t he c orres p o n di n g d ose of 
I P X 2 0 3 acc or di n g t o t he a b o ve ta ble.  It is rec o m me n de d t hat t he s u bject t a kes I P X 2 0 3 
d oses a p pr o xi matel y e v er y 8 h o urs a part (f or e x a m ple, a s u bject ma y ta k e I P X 2 0 3 at 
6 A M, 2 P M, a n d 1 0 P M).  S o me s u bjects ma y b e nefit fr o m a s h orter or l o n ger d osi n g 
i nter val.  T he d osi n g i nter val ma y var y b ut s h o ul d n ot be m ore fre q ue nt t ha n e ver y 
6 h o urs.  T he ma xi m u m rec o m me n de d d ail y d ose of I P X 2 0 3 is 6 0 0- 2 4 0 0 m g C D- L D.  
2.  S u b jects w h o are o n a t otal dail y d ose of less t ha n 1 2 5- 5 0 0 m g C D -L D fr o m I R C D -L D 
s h o ul d be a d vise d t o i nitiall y ta k e I P X 2 0 3 e ver y 1 2 h o urs.  T he d osi n g i nter val ma y be 
re d uce d t o a p pr o xi matel y e ver y 8 h o urs if t h e s u bject d oes n ot ac hi e ve a n acce pta bl e 
d urati o n of effect. 
3.  T he In vesti gat or or t h eir staff are a d vise d t o  be i n tele p h o ne c o ntact wit h t he s u bject, 
es peciall y d uri n g t he i nitial d ose c o n versi o n t o assess t he nee d f or d osa ge a dj ust me nt 
wit h t he g oal of mi ni mizi n g “ Off” ti me wit h o ut ca usi n g tr o u bles o me d ys ki nesia or ot her 
d o pa mi ner gic si de effects.  Calls t o t h e s u bject ca n be re d uce d a p pr o priatel y w h e n t he 
s u bject reac hes a st a ble d osi n g re gi me n. 
4.  If d ose a dj ust me nt is necessar y, c o nsi der t he f oll o wi n g o pti o ns rec o g nizi n g t hat t he 
n u m ber of ca ps ules at eac h d ose ma y be v arie d t o ac hie ve a n o pti mal res p o nse. 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 3  of 1 5 9  
 
a. If tur ni n g “ O n ” is sl o w f oll o wi n g t he first m or ni n g d ose, c o nsi der ta ki n g t he m or ni n g 
I P X 2 0 3 d ose i n t he faste d state a n d/ or i ncreasi n g t he d ose b y o ne ca ps ule ( 3 5- 1 4 0 m g 
I P X 2 0 3 C D-L D).  
b.  If t ur ni n g “ O n ” is sl o w later i n t he da y or t o re d uce “e n d-of -d ose” “ Off” ti me, 
c o nsi der i ncr easi n g t he d ose b y o n e ca ps ule ( 3 5 - 1 4 0 m g I P X 2 0 3 C D-L D) bef ore 
re d uci n g t he d osi n g i nter val. 
5.  I n case of tr o u bles o me d ys ki nesias, use t h e f oll o wi n g g ui deli nes:  
a. C o nsi der re d uci n g t he d ose b y o n e ca ps ul e ( 3 5- 1 4 0 m g I P X 2 0 3 C D- L D).  
b.  C o nsi der i ncreasi n g t he d osi n g i nter val. 
6.  T he s u bject m ust be o n a sta ble d osi n g re gi me n of I P X 2 0 3 ( n o c ha n ge i n d ose or i n 
d osi n g fr e q ue n c y) f or at least 5 da ys pri or t o Visit 4 (ra n d o mizati o n). 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 4  of 1 5 9  
 
A P P E N DI X  C.  U NI T E D KI N G D O M P A R KI N S O N’ S DI S E A S E S O CI E T Y 
B R AI N B A N K DI A G N O S TI C C RI T E RI A F O R 
P A R KI N S O N’ S DI S E A S E  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 5  of 1 5 9  
 
A P P E N DI X  D.  M O N T R E A L C O G NI TI V E A S S E S S M E N T ( M O C A)  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 6  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
 
 
 
 
  
  
   
   
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 7  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
 
 
 
 
   
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
   
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 8  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
  
  
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 8 9  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 0  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
         
   
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
   
 
  
 
  
 
   
 
   
 
   
 
   
 
 
 
 
   
 
 
 
    
  
  
  
  
  
 
 
   
 
 
 
  
 
 
 
 
    
 
 
 
 
 
 
 
 
 
  
 
  
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
  
 
  
 
   
  
 
 
   
 
   
 
 
 
 
 
  
 
 
 
   
   
 
 
   
 
   
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 1  of 1 5 9  
 
A P P E N DI X  E. M O V E M E N T DI S O R D E R S S O CI E T Y V E R SI O N O F 
U NI FI E D P A R KI N S O N’ S DI S E A S E R A TI N G S C A L E  
(M D S -U P D R S ) 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 2  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 3  of 1 5 9  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 4  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
   
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 5  of 1 5 9  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
      
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
  
 
  
   
 
 
 
 
  
 
 
 
 
 
 
 
 
  
   
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 6  of 1 5 9  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 7  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 8  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 9 9  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 0  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 1  of 1 5 9  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 2  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 3  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 4  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 5  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 6  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 7  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 8  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 0 9  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
  
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 0  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 1  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 2  of 1 5 9  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 3  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 4  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 5  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 6  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 7  of 1 5 9  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
  
 
 
  
  
 
  
 
  
 
 
 
 
  
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 8  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
  
 
  
 
 
  
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
   
  
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
  
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 1 9  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 0  of 1 5 9  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
  
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
   
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
    
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 1  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
    
  
  
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
  
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 2  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 3  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 4  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 5  of 1 5 9  
 
A P P E N DI X  F.  P A TI E N T G L O B A L I M P R E S SI O N  O F C H A N G E  ( P GI- C) 
 
T he s u bject will i n de pe n de ntl y r ate t he f oll o wi n g q uesti o n of Patie nt Gl o bal I m pressi o n of 
C ha n ge ( P GI- C) b ase d o n his/ her o verall i m pressi o n at Visit 5 ( Wee k 1 0) , Visit 6 ( Wee k 1 5), 
a n d Visit 7 ( Wee k 2 0) or earl y disc o nti n uati o n. 
 
P ati e nt Gl o b al I m pressi o n of C h a n ge : 
C o m pare d t o y o ur c o n diti o n pri or t o y o ur starti n g o n t his st u d y, h o w m u c h has y o ur c o n diti o n 
c ha n ge d wit h y o ur c urr e nt treat me nt? 
 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
Ver y 
M uc h 
W orse  
M uc h 
W orse  
Mi ni mall y 
W orse  
N o  
C ha n ge 
Mi ni mall y 
I m pr o v e d 
M uc h 
I m pr o v e d 
Ver y 
M uc h 
I m pr o v e d 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 6  of 1 5 9  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 7  of 1 5 9  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 8  of 1 5 9  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 2 9  of 1 5 9  
 
 












Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 3 5  of 1 5 9  
 
A P P E N DI X  K. G A S T R O P A R E SI S C A R DI N A L S Y M P T O M I N D E X 
( G C SI) 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 3 6  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
  
     
 
 
 
  
  
 
 
 
  
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
    
 
 
 
  
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 3 7  of 1 5 9  
 






Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 4 0  of 1 5 9  
 




Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 4 2  of 1 5 9  
 
 








Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 4 6  of 1 5 9  
 
A P P E N DI X  O. C O L U M BI A -S UI CI D E S E V E RI T Y R A TI N G S C A L E  
( C-S S R S)  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 4 7  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
     
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 4 8  of 1 5 9  
 
 
 
 
  
  
 
 
 
 
  
 
 
  
 
  
 
 
 
   
 
 
   
  
 
 
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 4 9  of 1 5 9  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
  
 
 
  
  
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
  
 
  
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
  
  
 
 
 
   
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 5 0  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
   
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 5 1  of 1 5 9  
 
 
 
 
  
  
 
 
 
 
  
 
 
  
 
  
   
 
 
 
 
   
  
  
  
  
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
  
 
  
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 5 2  of 1 5 9  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
  
 
 
 
 
  
 
 
  
  
 
 
 
 
 
 
 
  
   
  
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
   
 
 
  
 
 
 
 
 
  
 
 
 
 
 
   
 
 
  
  
 
 
 
 
 
 
  
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
  
 
 
 
 
 
  
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
  
 
 
  
    
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
  
  
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
  
 
  
 
  
  
 
 
 
  
 
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 5 3  of 1 5 9  
 
A P P E N DI X  P.  P A R KI N S O N’ S DI S E A S E DI A R Y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
  
 
 
 
 
 
 
 
 
  
 
   
 
 
 
 
 
 
 
 
 
 
 
    


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b or at ories, L L C 
 
Pa ge 1 5 4  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b or at ories, L L C 
 
Pa ge 1 5 5  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
  


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b or at ories, L L C 
 
Pa ge 1 5 6  of 1 5 9  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 5 7  of 1 5 9  
 
A P P E N DI X  Q. E X CI PI E N T S I N I P X 2 0 3, I P X 2 0 3 P L A C E B O, I R C D-L D, 
A N D I R P L A C E B O  
 
I P X 2 0 3 
( V ari o us Stre n gt hs) 
I P X 2 0 3 Pl ace b o 
I R C D- L D 
(2 5 -1 0 0 m g)  
I R Pl ace b o 
Micr ocr ystalli ne Cell ul ose, 
N F  
Micr o cr ystalli n e Cell ul ose, 
N F  
Cr os p o vi d o n e  
Micr o cr ystalli n e cell ul ose, 
N F  
Cr oscar mell ose S o di u m, N F  
Talc, U S P  
H y dr o x y pr o p yl Cell ul ose  
Ma g n esi u m Stearate, N F  
Ma g nesi u m Stearate, N F  
Ma g n esi u m Stearate, N F  
Ma g n esi u m Stearate  
Q ui n oli n e yell o w E 1 0 4  
Ma n nit ol, U S P  
S u gar S p h eres, N F  
Micr o cr ystalli n e cell ul ose  
 
S o di u m La ur yl S ulfate, N F  
Met h acr ylic a ci d c o p ol y mer 
T y p e A, N F  
Starc h (c or n)  
 
P o vi d o ne, U S P  
Triet h yl citrate, N F  
D & C Yell o w N o. 1 0  
 
Cell ul ose Acetate  
Har d gelati n ca ps ules 
Al u mi n u m O xi d e  
 
C o p o vi d o ne, N F  
 
 
 
A mi n o Met hacr yl ate 
C o p ol y mer, N F  
 
 
 
Met hacr ylic a ci d c o p ol y mer 
T y pe A, N F  
 
 
 
Triet h yl Citrate, N F  
 
 
 
Talc, U S P  
 
 
 
Har d gelati n ca ps ules  
 
 
 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4 : Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C 
 
Pa ge 1 5 8  of 1 5 9  
 
A P P E N DI X  R.  C LI NI C A L L A B O R A T O R Y S T U DI E S  
 
H E M A T O L O G Y  
he m o gl o bi n 
he mat ocrit  
re d bl o o d cell c o u nt 
w hite bl o o d cell c o u nt 
% ne utr o p hils 
% l y m p h oc ytes 
% m o n oc yt es 
% bas o p hils 
% e osi n o p hils 
a bs ol ute ne utr o p hils 
a bs ol ute l y m p h oc ytes 
a bs ol ute m o n oc yt es 
a bs ol ute bas o p hils 
a bs ol ute e osi n o p hils 
platelet c o u nt  
C H E MI S T R Y  
s o di u m 
p otassi u m 
c hl ori de 
car b o n di o xi de 
bl o o d urea nitr o ge n ( B U N)  
creati ni ne  
gl uc ose 
calci u m  
p h os p h or o us 
al b u mi n 
t otal pr otei n 
uric aci d  
t otal bilir u bi n 
direct bilir u bi n  
i n direct bilir u bi n 
al kali ne p h os p hatase 
ala ni ne a mi n otra nsferas e 
( A L T, S G P T) 
as partate a mi n otra nsferas e 
( A S T, S G O T) 
creati ne p h os p h o ki n ase 
lactate de h y dr o ge nas e 
U RI N A L Y SI S  
p H 
s pecific gr a vit y 
bl o o d 
gl uc ose 
ket o nes 
micr osc o pic e x a m ( R B C 
a n d W B C, o nl y w h e n 
i n dicate d) 
le u k oc yt e esterase 
pr otei n
U RI N E D R U G T E S T  
a m p heta mi nes  
bar bit urates  
ca n na bi n oi ds 
c ocai ne m eta b olites  
o piates  
p he nc ycli di nes 
be nz o diaze pi nes 


Pr ot oc ol N o. I P X 2 0 3- B 1 6 - 0 2 
C O N FI D E N TI A L  
A me n d me nt 4: Se pte m ber 2 8, 2 0 1 8 
I m pa x La b orat ories, L L C  
 
Pa ge 1 5 9  of 1 5 9  
A L C O H O L B R E A T H T E S T  
P R E G N A N C Y T E S T  
Uri ne pre g n a nc y test (t o be c o m plete d o n site) f or fe male s u bjects of c hil d beari n g p ote ntial.  

SAP_001.pdf: 
I P X 2 0 3– B 1 6 -0 2  
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S T A TI S TI C A L A N A L Y SI S P L A N 
 
 
 
 
St u d y Title:  
A R A N D O MI Z E D C O N T R O L L E D S T U D Y T O 
C O M P A R E T H E S A F E T Y A N D E F FI C A C Y O F 
I P X 2 0 3 WI T H I M M E DI A T E-R E L E A S E 
C A R BI D O P A -L E V O D O P A I N P A R KI N S O N’ S 
DI S E A S E  P A TI E N T S WI T H M O T O R 
F L U C T U A TI O N S  
N a me of Test Dr u g:  
I P X 2 0 3 
Pr ot oc ol N u m ber:  
I P X 2 0 3-B 1 6 -0 2  
Pr ot oc ol V ersi o n ( D ate):  
Ori gi nal Pr ot oc ol, Ma y 1 8, 2 0 1 7  
A me n d me nt 1, A u g ust 3 0, 2 0 1 7  
A me n d me nt 2, Oct o ber 2 3, 2 0 1 7  
A me n d me nt 3, Dece m ber 0 7, 2 0 1 7  
A me n d me nt 4, Se pte m ber 2 8, 2 0 1 8  
A n al ysis T y pe:  
Fi nal  
A n al ysis Pl a n Versi o n:  
A me n d me nt 4  Fi nal  
A n al ysis Pl a n D ate:  
2 3J ul 2 0 2 1  
A n al ysis Pl a n A ut h or:  
 
 
 
 
 
 
S P O N S O R 
I m pa x La b orat ories, L L C 
4 0 0 Cr ossi n g B o ul e var d, T hir d Fl o or 
Bri d ge water, NJ 0 8 8 0 7- 2 8 6 3 
 
C O N FI D E N TI A L A N D P R O P RI E T A R Y I N F O R M A TI O N 


I P X 2 0 3– B 1 6 -0 2  
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SI G N A T U R E P A G E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
( J ul 2 3, 2 0 2 1 1 5: 5 9 G M T + 3)
( J ul 2 3, 2 0 2 1 0 9: 3 3 E D T)


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T A B L E O F C O N T E N T S 
1  
I N T R O D U C TI O N 
8  
1. 1  
St u dy  O bj ectiv es  
8  
1. 2  
St u dy D esi g n  
8  
1. 3  
S a m pl e Siz e a n d  P o w er  
1 0  
2  
G E N E R AL C O N SI D E R A TI O N S F O R D A T A  A N AL Y SI S  
1 0  
2. 1  
D efi niti o ns of B as eli n e  
1 1  
2. 2  
A n alysis  S ets  
1 1  
2. 2. 1  
S af et y A n al ysis S et 
1 2  
2. 2. 2  
R a n d o miz e d A n al ysis S et 
1 2  
2. 2. 3  
I nt e nt-t o- Tr e at A n al ysis S et 
1 2  
2. 2. 4  
M o difi e d I nt e nt- t o- Tr e at A n al ysis S et 
1 2  
2. 2. 5  
C o m pl et ers A n al ysis S et 
1 2  
2. 2. 6  
P er- Pr ot oc ol A nalysis S et 
1 2  
2. 3  
R a n d o miz ati o n a n d Bli n di n g  
1 3  
2. 4  
Ex a mi n ati o n of S u bj ect  S u b gr o u ps  
1 3  
3  
S U BJ E C T  DI S P O SI TI O N A N D B A S ELI N E C H A R A C T E RI S TI C S  
1 3  
3. 1  
S u bj ect E nr oll m e nt a n d  Dis p ositi o n  
1 3  
3. 2  
D e m o gr a p hics a n d B as eli n e C h ar act eristics  
1 4  
3. 3  
Pr e -st u dy L ev o d o p a D osi n g  
1 5  
3. 4  
St u dy Dr u g  Ex p os ur e  
1 5  
3. 5  
Pr ot oc ol  D evi ati o ns  
1 6  
3. 6  
M e dic al Hist ory  
1 7  
4  
E F FI C A C Y A N AL Y S E S  
1 7  
4. 1  
I m p ut ati o n of missi n g d at a  
1 7  
4. 1. 1  
I m p ut ati o n M et h o d f or P D Di ar y D at a 
1 7  
4. 1. 2  
Missi n g D at a f or M D S- U P D R S 
1 8  
4. 1. 3  
Missi n g D at a f or Gl o b al Ass ess m e nts ( P GI- C, 
) 
1 9  
4. 1. 4  
H a n dli n g of Missi n g Visit D at a 
1 9  
4. 2  
Visit Wi n d o ws f or Effic ac y A n alys es  
1 9  
4. 3  
C e nt er P o oli n g Al g orit h m  
1 9  
4. 4  
Pri m ary  E n d p oi nt  
2 0  
4. 4. 1  
C alc ul ati o n of t h e pri m ar y e n d p oi nt 
2 0  
4. 4. 2  
A n al ysis of t h e pri m ar y e n d p oi nt 
2 1  
4. 5  
A n alysis of t h e K ey S ec o n d ary  E n d p oi nts  
2 1  




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5. 1  
Visit Wi n d o ws f or S af ety Ass ess m e nts 
3 0  
5. 2  
A dv ers e E v e nts  
3 0  
5. 3  
L a b or at ory E v al u ati o ns  
3 2  
5. 4  
Vit al  Si g ns  
3 3  
5. 5  
El ectr oc ar di o gr a m  
3 4  
5. 6  
P h ysic al  Ex a mi n ati o n  
3 5  
5. 7  
C -S S R S  
3 5  
5. 8  
G CSI  
3 5  
5. 9  
Pri or a n d C o nc o mit a n t M e dic ati o ns  
3 6  
6  
C O VI D -1 9 c o nsi d er ati o ns f or a n al ys es  
3 6  
7  
C h a n g es Fr o m Pr ot oc ol -S p ecifi e d A n al ys es  
3 7  
8  
R E F E R E N C E S  
3 8  
9  
A P P E N DI C E S  
3 9  
9. 1  
Sc h e d ul e of e v e nts  
3 9  
9. 2  
C o d e Fr a g m e nts  
4 2  
9. 2. 1  
M M R M A n al ysis of t h e Pri m ar y E n d p oi nt a n d C o nti n u o us S ec o n d ar y E n d p oi nts 
4 2  
9. 2. 2  
C M H T est f or C at e g oric al E n d p oi nts 
4 2  
9. 2. 3  
N or m alit y T est f or R esi d u als 
4 3  
9. 2. 4  
H o m o g e n eit y of V ari a nc e T est 
4 3  
9. 2. 5  
Wilc ox o n R a n k- S u m T est f or S e nsiti vit y A n al ysis 
4 3  
9. 2. 6  
A N C O V A M o d el f or C o m pl et e C as e or Si n gl e L O C F/ B O C F I m p ut ati o n A n al ys es 
4 3  
9. 2. 7  
Sit e as Fix e d Eff ect 
4 4  
9. 2. 8  
P att er n- Mixt ur e M o d el 
4 4  
9. 2. 9  
M ulti pl e I m p ut ati o n R a n k- B as e d A n al ysis 
4 5  
 
 


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LI S T O F A B B R E VI A TI O N S 
 
A b bre vi ati o n  
E x pl a n ati o n  
A E  
A d verse E v e nt  
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 N O V A  
A nal ysis of Varia n ce  
A S T  
As partate Tra nsa mi nas e  
A T C  
A nat o mic -t hera pe utic-c h e mical  
B L O C F  
Baseli ne O bser vati o n Carrie d F or war d  
B MI  
B o d y Mass I n d e x  
C D -L D  
Car bi d o pa -Le v o d o p a  
C M H  
C oc hra n -Ma nt el -Hae nszel  
C R  
C o ntr olle d Release  
C S  
Cli nicall y Si g nifica nt  
C S R  
Cli nical St u d y Re p ort  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
E T  
Earl y ter mi nati o n  
G C SI  
Gastr o paresis Car di nal S y m pt o m I n de x  
I R 
I m me diat e Releas e 
I T T 
I nte nt-t o-Treat  
L D  
Le v o d o p a  
L L C  
Li mite d Lia bilit y C o m pa n y  
L O C F  
Last O bs er vati o n Carrie d F or war d  
M A O -B  
M o n oa mi ne o xi dase B  
M A R  
Missi n g At Ra n d o m  
M D S -U P D R S  
M o ve me nt Dis or der S oci et y v ersi o n of t he U nifi e d Par ki ns o n’s 
Disease  Rati n g Scale  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
mI T T  
M o difie d I nte nt -t o-Treat  
M M R M  
Mi x e d M o del f or Re peate d Meas ures  
M N A R  
Missi n g N ot At Ra n d o m  
N C S  
N ot Cli nicall y Si g nifica nt  
P D  
Par ki ns o n Disease  
P GI -C  
Patie nt Gl o bal I m pr essi o n of C ha n ge  
P M M  
Patter n -Mi xt ure M o del  
P T  
Preferre d Ter m  
R B C  
Re d Bl o o d Cells  


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Re M L  
Restricte d Ma xi m u m Li k eli h o o d  
S A P  
Statistical A nal ysis Pla n  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T L Fs  
Ta bles, Listi n gs a n d Fi g ures  
W B C  
W hite Bl o o d Cells  
W H O  
W orl d Healt h Or ga nizati o n  


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1  I N T R O D U C TI O N 
T his statistical a nal ysis pla n ( S A P) descri bes t h e statistical a nal ysis met h o ds a n d data 
prese ntati o ns t o be use d i n ta bles, listi n gs, a n d fi g ures ( T L Fs) i n t he cli nical st u d y re p ort 
( C S R) f or St u d y I P X 2 0 3- B 1 6- 0 2. T his S A P is bas e d o n t he st u d y pr ot oc ol a me n d me nt 4 
da te d 2 8 Se p 2 0 1 8. T he S A P will be fi nalize d bef ore data base l oc k. A n y c h a n ges ma de after 
t he fi naliz ati o n of t he S A P will be d oc u me nte d i n t he C S R. 
1. 1  
S t u d y O bjecti ves 
T he o bjecti ve of t his st u d y is t o e val uat e t he safet y a n d effi cac y of I P X 2 0 3 i n c o m paris o n t o I R 
C D - L D i n t he treat me nt of C D- L D e x perie n ce d s u bjects wit h Par ki ns o n’s disease ( P D) w h o ha ve 
m ot or fl uct uati o ns. 
1. 2  
S t u d y Desi g n 
T his is a m ultice nter, ra n d o mize d, d o u ble- bli n d, d o u ble- d u m m y, acti ve-c o ntr olle d, parallel-
gr o u p st u d y. S u bjects will c o nti n ue t o ta ke per mitte d n o n- C D -L D - base d P D me dicati o ns 
t hr o u g h o ut t he st u d y if d oc u me nte d i n t heir prest u d y re gi me n a n d if d osi n g re gi me ns ha ve b ee n 
sta ble f or at least 4 wee ks pri or t o Visit 1. A “sta ble d osi n g re gi me n” mea ns n o c ha n ge i n d ose or 
i n d osi n g fre q ue nc y. Wit hi n 4 wee ks f oll o wi n g t he Scree ni n g visit, eli gi ble s u bjects will 
c o m plete t heir P D Diari es o n eac h of t h e 3 c o nsec uti ve da ys i m me diatel y pri or t o Visit 1. 
F oll o wi n g Visit 1, q ualifi e d s u bjects will e nter a 3- wee k, o p e n-la bel I R C D- L D treat me nt p eri o d 
all o wi n g f or d ose a dj ust me nt. D uri n g t he I R C D- L D d os e a dj ust me nt peri o d, t he i nitial d osi n g 
re gi me n of I R C D- L D will be t he sa me as t he s u bj ect’s sta ble prest u d y re gi me n u nless t he 
s u bject is ta ki n g a si n gle dail y be dti me d ose of C R C D- L D, i n w hic h case, t he C R C D- L D d os e 
will be disc o nti n ue d a n d s u bstit ute d wit h a 1: 1 milli gra m-e q ui vale nt d ose of I R C D- L D. A 
“ be dti me d ose” is defi ne d as t he last da yti me d ose of C D- L D ta k e n wit hi n 1 h o ur of o nset of t he 
s u bject’s n or mal ni g htti me slee p peri o d. T he d osi n g re gi me n of I R C D- L D ma y b e a dj uste d 
d uri n g t he d os e a dj ust me nt peri o d t o mi ni mize “ Off” ti me wit h o ut ca usi n g tr o u bles o me 
d ys ki nesia. T he d oses a n d re gi me ns of t he s u bject’s ot her n o n- C D - L D Par ki ns o n’s disease 
me dicati o ns ( d o pa mi ne a g o nists, M A O- B i n hi bit ors, a ma nta di ne, a ntic h oli ner gics) s h o ul d 
re mai n sta ble t hr o u g h o ut t his st u d y. A n y a dj ust me nts t o t he I R C D- L D d osi n g re gi me n will be 
d o ne i n c o ns ultati o n wit h t he I n v esti gat or or q u alifie d site pers o n nel a n d will be rec or de d. T he 
s u bject m ust be o n a sta ble d osi n g re gi me n ( n o c h a n ge i n d ose or i n d osi n g fre q ue n c y) of I R C D-
L D f or at least 5 da ys pri or t o ret ur ni n g f or Visit 2. Resc ue wit h a d diti o nal or m o difie d d oses of 
co nc o mita nt P D me dicati o ns or wit h use of C D- L D pr o d ucts ot her t ha n t he dis pe nse d st u d y 
me dic ati o ns is n ot per mitte d a n d will tri g ger disc o nti n uati o n fr o m t he st u d y. S u bjects will 
c o m plete t heir 3- d a y P D Diaries o n eac h of t he 3 c o nsec uti ve da ys i m me diatel y pri or t o Visit 1. 
F oll o wi n g c o m pleti o n of t he I R C D- L D d ose a dj ust me nt peri o d, s u bjects will be gi n a 4- wee k 
o pe n-la bel peri o d f or c o n versi o n t o I P X 2 0 3. T h e i nitial d osi n g re gi me n of I P X 2 0 3 d uri n g t he 
co n versi o n peri o d will be base d o n t he s u bject’s d osi n g re gi me n of I R C D- L D at t he e n d of t h e 
d ose a dj ust me nt peri o d ( Visit 2) selecti n g t he m ost fre q ue nt d ose acc or di n g t o Ta ble 1 . A 2 5- 1 0 0 
m g  d ose of IR C D- L D c o n verts t o a 7 0- 2 8 0 m g C D- L D d ose of I P X 2 0 3 b ut wit h a l o n ger 
d ura ti o n of effect. It is r ec o m me n de d t hat I P X 2 0 3 be d ose d a p pr o xi matel y e ver y 8 h o urs wit h t he 
e x ce pti o n t hat s u bjects w h o are c urre ntl y recei vi n g a t otal d ail y d ose of less t ha n 1 2 5- 5 0 0 m g I R 
C D -L D at t he e n d of t he d ose a dj ust me nt peri o d will be i nitiall y a d mi nist ere d I P X 2 0 3 e ver y 1 2 
h o urs. T he d osi n g i nter val ma y be re d uce d t o a p pr o xi matel y e v er y 8 h o urs if t he s u bject d oes n ot 


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ac hie ve a n acce pta bl e d urati o n of effect. T h e d osi n g re gi me n of I P X 2 0 3 m a y b e a dj uste d d uri n g 
t he d ose c o n versi o n peri o d t o ac hie ve t he o pti mal bala nce of efficac y a n d t olera bilit y ( mi ni mize 
“Off” ti me wit h o ut ca usi n g tr o u bles o me d ys ki nesi a or ot her d o p a mi ner gic si de effects). A n y 
adj ust me nts t o t he I P X 2 0 3 d osi n g re gi me n will be rec or de d. Resc u e wit h a d diti o nal or m o difie d 
d ose s of c o nc o mita nt P D me dicati o ns or wit h use of C D-L D  pr o d ucts ot her t ha n t he dis pe nse d 
st u dy me dicati o ns is n ot per mitte d a n d will tri g ger disc o nti n uati o n fr o m t he st u d y. S u bjects will 
ret ur n t o t he cli nic i n t w o wee ks f or Visit 3 f oll o we d b y Visit 4 t w o wee ks l ater. T he s u bject 
m ust  be o n a sta ble d osi n g re gi me n of I P X 2 0 3 ( n o c ha n ge i n d ose or i n d osi n g fre q ue n c y) f or at 
least 5 da ys pri or t o ret ur ni n g f or Visit 4. S u bjects will als o be i nstr ucte d t o c o m plete t heir 3- d a y 
P D Diaries o n eac h of t h e 3 c o nsec uti ve d a ys i m me diatel y pri or t o Visit 4. 
T he st u d y staff will call t he s u bjects fre q ue ntl y (a p pr o xi matel y e ver y 1 t o 3 da ys) d uri n g t he I R 
C D - L D d ose a dj ust me nt a n d I P X 2 0 3 d ose c o n v ersi o n peri o ds. T he calls are t o e ns ure ti mel y a n d 
a p pr o priate d osi n g a dj ust me nts a n d t o e ns ure t hat t he s u bject is a ble t o f oll o w a n d a d here t o t he 
d osi n g i nstr ucti o ns. T he c o ntacts ma y be less fre q ue nt after i nitial d ose a dj ust me nts ha ve bee n 
ma de. A n y c h a n ges i n t he d osi n g re gi me n will be i n c o ns ultati o n wit h t he I n vesti gat or or 
q ualifie d site pers o n nel a n d will be d oc u me nte d. 
S u bjects w h o s uccessf ull y c o m plet e t he I P X 2 0 3 d ose c o n versi o n p eri o d will be ra n d o mize d, 
stratifie d b y ce nter, i n a 1: 1 rati o at Visit 4 i nt o o ne of t w o parallel treat me nt ar ms of I P X 2 0 3 
( wit h matc hi n g I R C D- L D place b o) or I R C D- L D ( wit h matc hi n g I P X 2 0 3 place b o). T h e s u bjects 
will u n der g o 1 3 wee ks of d o u ble- bli n d, d o u ble- d u m m y mai nte na n ce t hera p y wit h t he sta ble 
d osi n g re gi me n esta blis he d at t he e n d of Wee k 3 ( Visit 2) f or I R C D- L D a n d at t he e n d of Wee k 
7 ( Visit 4) f or I P X 2 0 3. S u bjects will ret ur n t o t he cli nic f or 3 visits ( Visits 5, 6, a n d 7) a n d will 
be i nstr ucte d t o c o m plete t heir 3- da y P D Diaries o n 3 c o nsec uti ve da ys i m me diatel y pri or t o eac h 
of t he 3 visits. Resc ue wit h a d diti o nal or m o difie d d oses of c o nc o mita nt P D me dicati o ns or use 
of C D- L D pr o d u cts ot her t ha n t he dis pe nse d st u d y me dicati o n is n ot per mitte d a n d will tri g ger 
disc o nti n uati o n fr o m t he st u d y. 
Fi g ure 1 St u d y Fl o w c h art 
 


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T a ble 1 Rec o m me n de d St arti n g I P X 2 0 3 L D D osi n g Re gi me n B ase d o n t he D osi n g Re gi me n 
of I R C D- L D at t he E n d of t he D ose A dj ust me nt Peri o d 
M ost Fre q ue nt I R C D -L D U nit 
D ose ( m g)  
Rec o m me n de d St arti n g I P X 2 0 3 D ail y 
D osi n g Re gi me n C D -L D ( m g) E ver y 8 
H o urs  
2 5 -1 0 0 a 
7 0 -2 8 0 m g ( 2 × 3 5 -1 4 0 m g)  
> 2 5 -1 0 0 –  3 7. 5 -1 5 0  
1 0 5 -4 2 0 m g ( 3 × 3 5 -1 4 0 m g)  
> 3 7. 5 -1 5 0 –  5 0 -2 0 0  
1 4 0 -5 6 0 m g ( 4 × 3 5 -1 4 0 m g)  
> 5 0 -2 0 0  
1 7 5 -7 0 0 m g ( 5 × 3 5 -1 4 0 m g)  
a S u bj ects w h o are o n a t otal dail y d ose of less t ha n 1 2 5- 5 0 0 m g C D- L D fr o m I R C D- L D s h o ul d be a d vise d t o 
i nitiall y ta ke I P X 2 0 3 e ver y 1 2 h o urs. T he d osi n g i nter val ma y be re d uce d t o a p pr o xi matel y e ver y 8 h o urs if t he 
s u bj ect d oes n ot ac hie ve a n ac ce pta ble d urati o n of effect. 
1. 3  
S a m ple Size a n d P o w er 
Ass u mi n g a differe nce of 1 h o ur bet wee n I P X 2 0 3 a n d I R C D- L D i n “ G o o d o n” ti me a n d a 
sta n dar d de viati o n of t he treat me nt differe nces t o be 3. 0 h o urs, a sa m ple si ze of 2 1 0 s u bjects per 
ar m will be nee d e d t o e ns ure at least 9 0 % p o wer at a 0. 0 5 si g nifi ca nce le vel. 
Ass u mi n g a p pr o xi matel y a n 1 8 % pre-ra n d o mizati o n dr o p- o ut, a p pr o xi matel y 5 1 0 s u bjects w o ul d 
nee d t o be e nr olle d t o ra n d o mize 4 2 0 s u bjects. 
 
2  G E N E R A L C O N SI D E R A TI O N S F O R D A T A A N A L Y SI S 
T he data bas e will be l oc k e d a n d fi nal a nal ysis of t he data will be perf or me d after all 
s u bjects ha ve c o m plet e d t he st u d y, o utsta n di n g data q ueries ha v e bee n res ol ve d or 
a dj u dicate d as u nres ol va ble, a n d t he data ha ve b ee n clea n e d a n d fi n alize d. T he statistical 
anal ys es will be perf or m e d b y Q uartesi a n L L C, wit h a p pr o val of t he S p o ns or, usi n g S A S 
Ve rsi o n 9. 4 ( or hi g her).  
All ta bles, fi g ures a n d listi n gs will be pr o d uce d i n la n dsca pe f or mat.  
I n ge neral, all data will b e liste d b y s u bject a n d visit/ti me p oi nt w here a p pr o priate. 
T he s u m mar y ta bles will be stratifie d b y, or ha ve c ol u m ns c orres p o n di n g t o, 
treat me nt gr o u ps i n t he ra n d o mize d d o u ble- bli n d treat me nt peri o d, i.e. I P X 2 0 3 a n d 
I R C D- L D. A nal yses of s afet y ma y als o h a ve a c ol u m n f or s u bjects w h o were n ot 
ran d o mize d. 
T he t otal n u m ber of s u bj ects i n t he treat me nt gr o u p ( N) u n der t he state d p o p ulati o n 
will  be dis pla ye d i n t he h ea der of s u m mar y ta bles. 
Data will be s u m marize d usi n g descri pti ve statistics f or c o nti n u o us varia bles. 
U nless ot her wise s pecifie d, descri pti ve statistics will i ncl u de n u m ber of s u bjects, 
mea n, sta n dar d de viati o n, mi ni m u m, me dia n a n d ma xi m u m. N u m ber of s u bjects 
wit h missi n g val ues will als o be dis pla ye d, b ut o nl y if n o n-zer o. T he mi ni m u m a n d 


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ma xi m u m statistics will be prese nt e d t o t he sa me n u m ber of deci mal places as t he 
ori gi nal dat a. T he me a n a n d me dia n will be prese nte d t o o ne m ore deci mal place 
t ha n t he ori gi n al data. T h e sta n dar d de viati o n will be prese nt e d t o t w o m ore 
deci mal places t h a n t he ori gi nal dat a. 
I n s u m mar y ta bles of cat e g orical varia bles, c o u nts a n d perce nta ges will be 
dis pla ye d. T h e c o u nt [ n] i n dicates t he act u al n u m ber of s u bjects i n a p artic ular 
cate g or y, w hi c h s h o ul d al wa ys b e less t ha n or e q u al t o t he t otal n u m ber of s u bjects 
i n t he res pecti ve st u d y gr o u p wit h k n o w n ( n o n- missi n g) cate g or y [ M]. Perce nta ge 
will be o btai ne d b y: % = n/ M * 1 0 0. U nless ot her wise s pecifie d, all perce nta ges will 
be e x presse d t o o ne deci mal place. 
All statistical tests will be t w o-si de d at a si g nifica nce le vel of α = 0. 0 5, u nl ess 
ot her wise s pecifie d.   
I n b y- visit s u m maries, o nl y data c ollecte d o n s c he d ule d visits/ti me p oi nts will be 
s u m marize d. Data fr o m u nsc he d ule d ass ess me nts will be i ncl u de d i n listi n gs a n d 
ma y b e use d i n deter mi nati o n of baseli ne if a p plica ble. 
Relati ve da ys will be cal c ulate d rel ati ve t o date of t he first st u d y dr u g d os e i n t he 
D ose A dj ust me nt peri o d. Relati ve da ys will be cal c ulate d as f oll o ws o nl y w he n t he 
f ull assess me nt date is k n o w n (i.e., partial d ates will ha ve missi n g relati ve da ys). 
F or ass ess me nt o n or aft er t he da y of first st u d y dr u g d ose: 
Relati ve Da y = D ate of Assess me nt – Date of First St u d y Dr u g D ose + 1. 
F or ass ess me nt bef ore t h e da y of first st u d y dr u g d ose: 
Relati ve Da y = D ate of Assess me nt – Date of First St u d y Dr u g D ose. 
All date s will be dis pla ye d i n D D M M M Y Y Y Y f or mat. 
2. 1  
Defi niti o ns of B aseli ne 
T here will be t w o t y pes of baseli ne defi ne d, st u d y e ntr y b aseli ne a n d d o u ble- bli n d baseli ne. 
St u d y e ntr y bas eli ne is defi ne d as t he l ast assess me nt o btai ne d pri or t o t he first d ose of t he 
st u d y dr u g (I R C D- L D) i n t he D ose A dj ust me nt peri o d. 
D o u ble- bli n d baseli ne is ge n erall y defi ne d as t he l ast assess me nt o btai ne d pri or t o t he first 
d ose of t he ra n d o mize d st u d y dr u g i n t he d o u ble- bli n d treat me nt peri o d. F or t he P D Diar y-
deri ve d e n d p oi nts, d o u bl e- bli n d baseli ne will be d eri ve d fr o m t he P D Diar y c oll ecte d at Visit 
4 (ra n d o mizati o n visit). 
U nless ot her wise s pecifie d, “ baseli ne” will refer t o t he d o u ble- bli n d baseli n e. 
Efficac y e n d p oi nts will be s u m mariz e d relati vel y t o t he d o u ble- bli n d baseli ne. S o me select 
e n d p oi nts ma y be s u m marize d als o relati ve t o t he st u d y e ntr y b aseli ne, as d etaile d i n secti o n 
4. 6  of t his S A P. Safet y p ara meters will be s u m marize d relati ve t o t he st u d y e ntr y b aseli ne, 
u nless ot her wise s pecifie d. 
2. 2  
A n al ysis Sets 
A nal ysis sets defi ne t he s u bjects t o be i ncl u de d i n a n a nal ysis. A nal ysis sets a n d t heir 


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defi niti o ns are pr o vi de d i n t his secti o n. T he a nal ysis set will be i de ntifie d a n d i ncl u de d as a 
s u btitle of eac h ta ble, listi n g, a n d fi g ure. 
2. 2. 1  S af et y A n al y si s S et 
T he Safet y A n al ysis set will i ncl u de all s u bjects w h o were treat e d wit h a n y st u d y dr u g (I P X 2 0 3 
or I R C D- L D). 
2. 2. 2  R a n d o mi z e d A n al y si s S et 
T he Ra n d o mize d A nal ysis set will i ncl u de all s u bjects w h o were ra n d o mize d. 
2. 2. 3  I nt e nt-t o- T r e at A n al ysi s S et 
T he I nte nt- t o-tr eat A nal ysis Set (I T T) will i ncl u de all s u bjects w h o were ra n d o mize d a n d treate d 
wit h a n y st u d y dr u g a n d ha ve a b aseli ne a n d at least o ne p ost- baseli ne efficac y assess me nt ( usi n g 
d o u ble- bli n d baseli ne, as defi ne d i n secti o n 2. 1 ). 
2. 2. 4  M o difi e d I nt e nt- t o- T r e at A n al y si s S et 
T he M o difie d I nte nt- t o-tr eat A nal ysis ( mI T T) Set will i ncl u de all s u bjects w h o were ra n d o mize d 
a n d treate d a n d ha v e a vali d baseli ne P D Diar y a n d at least o ne vali d p ost-ra n d o mizati o n P D 
Diar y ( usi n g d o u ble- bli n d P D Diar y baseli ne, as d efi ne d i n secti o n 2. 1 ). T his a nal ysis set will be 
use d f or t he pri mar y a nal ysis a n d ke y s ec o n d ar y a nal yses. 
2. 2. 5  C o m pl et e r s A n al y si s S et 
T he C o m pleters A nal ysis Set will i ncl u de all s u bjects w h o were ra n d o mize d a n d treate d a n d 
c o m plete d t he st u d y, atte n de d t heir Visit 7 n o earlier t ha n 1 8 wee ks after Visit 1 a n d n o earlier 
t ha n 1 1 wee ks after Visit 4, a n d ha ve v ali d P D Diaries at t he d o u ble- bli n d baseli ne ( Visit 4) a n d 
at Visit 7. 
2. 2. 6  P e r- P r ot o c ol A n al ysis S et 
T he Per- Pr ot oc ol A n al ysis Set will i ncl u de all s u bjects i n t he mI T T set w h o d o n ot ha ve a n y 
maj or pr ot oc ol de viati o ns of t he f oll o wi n g cate g ories: 
1.  S u bject di d n ot meet eli gi bilit y criteri o n b ut was e nr olle d i n t he st u d y 
2.  S u bject met wit h dra wal criteria b ut was n ot wit h dr a w n 
3.  T he site dis pe nse d t he i n c orrect I P b ottle a n d/ or kit t o t he s u bject 
4.  I P w as n ot dis pe nse d/a d mi nistere d as per  pr ot o c ol 
5.  Pr o hi bite d me dicati o ns a d mi nistere d/ta ke n 
6.  W as h o ut of re q uire d Me ds 
7.  Treate d a n d n ot Ra n d o mize d 
8.  D ose A dj ust me nt peri o d e xte n de d b y m ore t h a n 5 0 % (i.e. l o n ger t ha n 3 1 d a ys) 
9.  I P X 2 0 3 C o n versi o n peri o d e xte n de d b y m ore t h a n 5 0 % (i.e. l o n ger tha n 4 2 da ys). 
See secti o n 3. 5  f or m ore i nf or mati o n o n pr ot oc ol de viati o ns. T his a nal ysis set will be use d f or t he 
se nsiti vit y a nal ysis of t he pri mar y a n d ke y s ec o n d ar y e n d p oi nts. 


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2. 3  
R a n d o miz ati o n a n d Bli n di n g 
At Visit 4, s u bjects will be ra n d o mize d, stratifie d b y ce nter, i n a 1: 1 rati o i nt o o ne of t w o d o u ble-
bli n d parallel treat me nt ar ms of I P X 2 0 3 (a n d mat c hi n g I R C D- L D pl ace b o) or I R C D- L D (a n d 
matc hi n g I P X 2 0 3 place b o). 
2. 4  
E x a mi n ati o n of S u bject S u b gr o u ps 
T he pri mar y, ke y s ec o n d ar y e n d p oi nts, as w ell as o verall s u m mar y of a d verse e ve nts, will be 
e x a mi ne d f or t he f oll o wi n g s u b gr o u ps. 
 A ge: < 6 5, ≥ 6 5 years ol d at st u d y e ntr y 
 Se x: Males, Fe males 
 Race: Ca ucasia ns, n o n- C a ucasia ns 
A d diti o nall y, t he f oll o wi n g s u b gr o u ps ma y b e e x a mi ne d: 
 Re gi o n: N ort h A merica or E ur o pe 
 Et h nicit y: His pa nic, N o n- His pa nic or U n k n o w n 
 C o nc o mita nt me dicati o ns: t he f oll o wi n g n o n-e x cl usi ve s u b gr o u ps will be defi ne d f or 
s u bjects ta ki n g c o nc o mita nt me dicati o ns of t he f oll o wi n g cate g ories: 
o  A ma nta di ne 
o  selecti ve M A O B i n hi bit ors 
o  antic h oli ner gic P D me dicati o ns 
o  d o pa mi ne a g o nists 
o  ot her s 
 Wei g ht: < 7 5 k g or ≥7 5 k g 
 B o d y mass i n de x ( B MI): < 2 5 k g/ m 2 or ≥2 5 k g/ m2 
 P D d urati o n at scree ni n g: < 8 years or ≥8 years 
 A ge of P D o nset: < 6 5 years or ≥6 5 years 
 “ G o o d O n” ti me at st u d y e ntr y: a vera ge  < 9 h or ≥9 h per da y  
 “ Off” ti me at st u d y e ntr y: a vera ge  < 6 h or ≥6 h p er da y 
3  S U B J E C T DI S P O SI TI O N A N D B A S E LI N E C H A R A C T E RI S TI C S 
3. 1  
S u bject E nr oll me nt a n d Dis p ositi o n 
S u bject dis p ositi o n pri or t o ra n d o mizati o n will be prese nte d f or t he o verall s u bject p o p ulati o n 
wit h o ut brea k d o w n b y tr eat me nt gr o u p a n d will i ncl u de t he n u m ber of s u bjects scree ne d, 
scree n faile d, e nr olle d i n t he st u d y, n u m ber a n d perce nta ge of s u bjects w h o e ntere d t he D ose 
A dj ust me nt peri o d, disc o nti n ue d d uri n g t his peri o d ( wit h brea k d o w n b y reas o n f or 
disc o nti n uati o n), e ntere d t he I P X 2 0 3 C o n versi o n peri o d a n d disc o nti n ue d d uri n g t his peri o d 
( wit h brea k d o w n b y reas o n f or disc o nti n uati o n). Perce nt a ges will be bas e d o n t he n u m ber of 
e nr olle d s u bjects (e x ce pt f or reas o ns f or disc o nti n uati o ns, f or w hic h t he perce nta ge will be 


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base d o n t he n u m ber of s u bjects disc o nti n ue d i n peri o d). 
S u bject dis p ositi o n after t he ra n d o mizati o n will be prese nt e d b y treat me nt gr o u p a n d o verall 
a n d will i ncl u de t he n u m ber of s u bjects t hat w ere ra n d o mize d, n u m ber a n d perce nt a ge of 
s u bjects w h o were treate d i n t he d o u ble- bli n d peri o d, i ncl u de d i n t he Safet y, I T T, mIT T an d 
C o m pleters a nal ysis sets, c o m plete d t he st u d y a n d pre mat urel y disc o nti n ue d fr o m t he st u d y 
after ra n d o mizati o n ( wit h t he brea k d o w n b y t he pri mar y reas o n f or disc o nti n uati o n). 
Perce nta ges will be base d o n t he n u m ber of ra n d o mize d s u bjects i n eac h tr eat me nt gr o u p, 
ex ce pt perce nt a ges f or t he reas o ns f or disc o nti n uati o n, w hic h will be base d o n t he n u m ber of 
s u bjects w h o disc o nti n ue d earl y. 
I n t he s u m mar y of reas o ns f or disc o nti n uati o n a se parate li ne will be pr o vi de d f or 
disc o nti n uati o ns relate d t o C O VI D- 1 9 pa n d e mic. 
A n o verall s u m mar y of t he n u m ber of s u bjects i n eac h a nal ysis set b y site will be creat e d. 
All di s p ositi o n i nf or mati o n will be liste d. A d diti o nall y, a listi n g of s u bjects w h o disc o nti n ue d 
fr o m t he st u d y pre mat urel y will be create d, i n cl u di n g dat e of disc o nti n uati o n a n d pri mar y 
reas o n. Als o a listi n g of e nr oll me nt details will pr o vi de t he date of i nf or me d c o nse nt a n d 
i ncl usi o n/e x cl usi o n criteria n ot met, if a n y. 
3. 2  
De m o gr a p hics a n d B aseli ne C h ar acteristics 
De m o gra p hic c haracteristics will i ncl u de: 
 
a ge at Scree ni n g 
 
se x 
 
race 
 
et h nicit y 
Baseli ne p h ysic al c haracteristics will i ncl u de: 
 
hei g ht at st u d y e ntr y b aseli ne 
 
wei g ht at st u d y e ntr y bas eli ne 
 
B MI at st u d y e ntr y b aseli ne 
B aseli ne dise ase c haracteristics i ncl u de 
 
M D S- U P D R S Parts I, II, III, a n d I V t otal sc ores at st u d y e ntr y b aseli ne, b ot h 
i n “ O n” a n d “ Off” states 
 
H oe h n a n d Y a hr sta ge (at “ O n” state) 
 
M o C A sc ore at Scree ni n g as c o nti n u o us varia ble a n d cate g orize d as < 2 4, 2 4 
t o < 2 6, 2 6 t o < 2 8, 2 8 t o < 3 0, 3 0 
 
A ge of o nset of P D as c o nti n u o us varia ble a n d cat e g orize d as < 6 5 or ≥ 6 5 
y ears. 
De scri pti ve statistics will be prese nt e d f or c o nti n u o us varia bles. Fre q u e nc y c o u nts a n d 


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perce nt a ge will be prese nte d f or cate g orical varia bles. Hei g ht will be re p ort e d i n ce nti meters, 
wei g ht i n kil o gra ms a n d B MI i n k g/ m 2. 
A ge  will be deri ve d fr o m I nf or me d C o nse nt Date a n d Date of Birt h as t h e n u m ber of w h ole years 
bet wee n t h ose t w o d ates. 
T hese a n al ys es will be perf or me d f or t he Safet y, I T T a n d mI T T a n al ysis sets. T he s u m maries 
will  be prese nte d f or t he t w o treat me nt gr o u p a n d t otal; t he s u m mar y f or t he Safet y a n al ysis set 
will als o i ncl u de a se parate c ol u m n f or t he s u bjects w h o were n ot ra n d o mize d. 
T he s u m mar y of de m o gra p hic a n d bas eli ne c haracteristics will als o be prese nte d f or s u bjects 
w h o disc o nti n ue d d uri n g t he D ose A dj ust me nt peri o d, I P X 2 0 3 C o n versi o n peri o d a n d D o u ble-
Bli n d peri o d, b y peri o d. 
All de m o gra p hic para met ers a n d bas eli ne c haracteristics will be prese nte d i n t he b y-s u bj ect 
listi n gs. 
3. 3  
P re-st u d y Le v o d o p a D osi n g 
T he  f oll o wi n g c haracteristics of pre-st u d y le v o d o pa d osi n g will be s u m marize d f or t he Safet y, 
I T T a n d mI T T a nal ysis sets: 
 
D urati o n of pre-st u d y le v o d o pa (t otal, I R a n d C R) d osi n g i n years, as 
c o nti n u o us varia ble a n d cate g orize d as < 3, 3 t o < 6, 6 t o < 9, 9 t o < 1 2, ≥ 1 2 
years. 
 
T ota l dail y d ose of pre-st u d y le v o d o pa (t otal, I R a n d C R) i n m g, as 
c o nti n u o us varia ble a n d cate g orize d as < 4 0 0, 4 0 0 t o < 8 0 0, 8 0 0 t o < 
1 2 0 0, 1 2 0 0 t o < 1 6 0 0, 1 6 0 0 t o < = 2 4 0 0, a n d > 2 4 0 0 m g 
 
Fre q u e nc y of C D- L D d osi n g  
 
First m or ni n g d os e of I R C D- L D (i n m g) 
T he s u m maries wil l be prese nte d f or t h e t w o treat me nt gr o u p a n d t otal; t he s u m mar y f or t he 
Safet y a nal ysis set will als o i ncl u de a se parate c ol u m n f or t he s u bjects w h o were n ot r a n d o mize d. 
All i nf or mati o n will be liste d. 
3. 4  
S t u d y Dr u g E x p os ure 
A ve ra ge dail y d ose a n d t otal d ose of L D recei v e d b y s u bjects, as well as a v era ge d ail y d osi n g 
fre q ue n c y will be s u m marize d descri pti vel y f or t h e D ose A dj ust me nt peri o d, I P X 2 0 3 C o n versi o n 
pe ri o d a n d D o u ble- Bli n d treat me nt peri o d ( b y treat me nt gr o u p). 
A vera ge dail y d ose will als o b y s u m marize d cate g oricall y, cate g orize d as < 4 0 0, 4 0 0 t o < 8 0 0, 
8 0 0 t o < 1 2 0 0, 1 2 0 0 t o < 1 6 0 0, 1 6 0 0 t o < = 2 4 0 0 m g , an d > 2 4 0 0 m g. 
Treat me nt d ur ati o n (calc ulate d as Date of Last D ose – Date of First D ose + 1) will be 
s u m marize d descri pti vel y b y treat me nt gr o u p f or t he D o u ble- Bli n d treat me nt peri o d. 
T he n u m ber of titrati o n ste ps t o sta ble d osi n g a n d t he n u m ber of da ys t o sta ble d osi n g will be 
s u m marize d descri pti vel y f or I R C D- L D i n t he D ose A dj ust me nt peri o d a n d f or I P X 2 0 3 i n t he 
I P X 2 0 3 C o n versi o n peri o d f or s u bjects w h o ac hie ve sta ble d osi n g. T h e n u m ber of ste ps will als o 
be  cate g orize d as 0, 1 t o 2, 3 t o 4, 5 t o 6, a n d > 6 ste ps a n d t he n u m ber of d a ys as 0, 1 t o 2 da ys, 


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3 t o 4 da ys, 5 t o 6 da ys, 7 t o 9 da ys, a n d > 9 da ys, a n d b ot h para met ers will be s u m marize d 
cate g oricall y. 
N u m ber a n d p erce nta ges of s u bjects w h o d o n ot ac hie ve sta ble d osi n g will be s u m marize d 
se parat el y. 
S u m maries f or t he D ose A dj ust me nt peri o d a n d I P X 2 0 3 C o n versi o n peri o d will be d o ne o n t he 
Safet y a nal ysis set. S u m maries f or t he D o u ble- Bli n d treat me nt peri o d will be d o ne f or all 
s u bjects treate d i n t his peri o d a n d f or t he I T T p o p ulati o n. 
T otal dail y d ose of le v o d o pa, t he n u m ber of d ail y d oses a n d t he m ost fre q u e ntl y use d d os e will 
be  s u m mariz e d descri pti vel y at t he f oll o wi n g ti m e p oi nts: 
 Start of D ose A dj ust me nt peri o d ( pre-st u d y re gi me n of I R C D- L D) 
 E n d of  D ose A dj ust me nt peri o d (sta ble re gi me n of I R C D- L D) 
 S tart of I P X 2 0 3 C o n versi o n peri o d (starti n g I P X 2 0 3 re gi me n) 
 E n d of  I P X 2 0 3 C o n versi o n peri o d (sta ble I P X 2 0 3 re gi me n) 
T his a nal ysis will be d o n e f or t he Ra n d o mize d A nal ysis Set. 
T he rati o of t he sta bl e I P X 2 0 3 t otal dail y d ose t o I R C D- L D t otal dail y d os e as well as t he rati o 
of t he sta ble I P X 2 0 3 m ost fre q ue nt d ose t o I R C D- L D m ost fre q ue nt d ose will be s u m marize d 
descri pti vel y b y t he ra n ge of I R C D- L D t otal dail y d ose a n d o verall. T he s a me ra n ges will be 
use d as f or t he s u m mar y of t he a vera ge d ail y d os e: < 4 0 0, 4 0 0 t o < 8 0 0, 8 0 0 t o < 1 2 0 0, 1 2 0 0 t o < 
1 6 0 0, 1 6 0 0 t o < = 2 4 0 0 m g, a n d > 2 4 0 0 m g.  
T he pr ot oc ol rec o m me n ds t he starti n g I P X 2 0 3 re gi me n base d o n t he m ost fre q ue ntl y use d I R 
C D - L D d ose i n t he sta ble I R C D- L D re gi me n after t he D ose A dj ust me nt peri o d. T he relati o ns hi p 
of t he  m ost fre q ue ntl y us e d I R C D- L D d ose i n t he sta ble I R C D- L D re gi me n t o t he starti n g 
I P X 2 0 3 re gi me n a n d t o t he sta ble I P X 2 0 3 re gi me n (after I P X 2 0 3 C o n versi o n) will be e x pl ore d. 
T he m ost fre q ue ntl y use d I R C D- L D d ose i n t he st a ble I R C D- L D re gi me n will be cate g orize d i n 
ter ms of L D d ose: 1 0 0, > 1 0 0- 1 5 0, > 1 5 0- 2 0 0 a n d > 2 0 0 m g. F or eac h cate g or y t he n u m ber a n d 
pe rce nt a ge of s u bjects wit h eac h starti n g I P X 2 0 3 re gi me n a n d eac h sta ble I P X 2 0 3 re gi me n will 
be prese nt e d. T he perce nta ges will be base d o n t h e n u m ber of s u bjects wit hi n eac h cate g or y of 
m ost fre q ue nt I R C D- L D d ose. 
T he relati o ns hi p bet wee n t he n sta ble I R C D- L D t otal dail y d ose a n d sta ble I P X 2 0 3 t otal dail y 
d ose will als o be prese nt e d gra p hic all y. A s catter pl ot will be create d wit h X-a xis re prese nti n g 
t he sta ble I R C D- L D t otal dail y d ose a n d Y-a xis re prese nti n g sta ble I P X 2 0 3 t otal dail y d ose. 
T h ese a n al ys es will be d o ne f or t he Ra n d o mize d A nal ysis Set. 
3. 5  
P r ot oc ol De vi ati o ns 
Pr ot oc ol de viati o ns, s uc h as s u bjects w h o di d n ot meet eli gi bilit y criteria at st u d y e ntr y a n d 
t h ose occ urri n g after s u bj ects e ntere d t he st u d y, are d oc u me nte d d uri n g r o uti ne m o nit ori n g 
a n d t hr o u g h o ut t he st u d y. T he pr ocess f or t he ma n a ge me nt of pr ot o c ol de vi ati o ns is defi ne d i n 
t he Pr ot oc ol De viati o n a n d N o n-c o m plia nce M a n a ge me nt Pla n. Details of pr ot oc ol de viati o ns 
f or eac h st u d y site are d o c u me nte d a n d re vie we d re g ul arl y, a n d will be pr o vi de d b y t he 
Cli nical O perati o ns Gr o u p t o t he Statistics a n d Data Ma na ge me nt Gr o u p pri or t o data base 
fi nalizati o n. T hese pr ot oc ol de viati o ns will be liste d. De viati o ns rel ate d t o C O VI D- 1 9 will be 


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i de ntifie d i n t he listi n g. 
3. 6  
M e dic al Hist or y 
Me dical hist or y will be s u m mariz e d b y Me d D R A S yste m Or ga n Class a n d Preferre d Ter m. 
Eac h s u bject will be c o u nte d o nce wit hi n eac h a p plica ble Preferre d Ter m a n d S yste m 
Or ga n Class. T his s u m mar y will be perf or me d f or t he Safet y a nal ysis set b y treat me nt 
gr o u p a n d f or s u bjects w h o were n ot r a n d o mize d, as w ell as f or all s u bjects o verall.  
All m e dical hist or y i nf or mati o n will be liste d.  
4  E F FI C A C Y A N A L Y S E S 
4. 1  
I mp ut ati o n of missi n g d at a 
4. 1. 1  I m p ut ati o n M et h o d f o r P D Di a r y D at a 
F or all e n d p oi nts base d o n t he P D Diaries t he f oll o wi n g i m p utati o n of missi n g diar y e ntries 
will be a p plie d. 
A P D Diar y is vali d if at least 1 da y of diar y d ata is a vaila ble usi n g t he r ules defi ne d bel o w. 
I m p utati o n of missi n g d ata f or s u bject P D diari es will be re q uire d if t he P D diar y is n ot 
c o m plete d f or a f ull da y (fr o m 6: 0 0 a m t o 6: 0 0 a m t he ne xt da y). I n t his case, t he met h o d of 
i m p utati o n de pe n ds o n t he a m o u nt a n d patter n of missi n g data: 
 F or s u bjects wit h m ore t h a n 1 da y of diar y data, t h e f oll o wi n g r ules will a p pl y: 
 If m ore t ha n 4 h alf- h o ur ti me i nter vals are missi n g, t he n t hat partic ular d a y will 
n ot be i ncl u de d i n t he a n al ysis. T he missi n g d ata will be ha n dle d i n t he M M R M 
m o del. 
 If a half- h o ur ti me i nter v al is missi n g a n d t he o bs er vati o ns o n eit her si de of t he 
ti me i nter val are n ot missi n g, t he n t he missi n g ti m e i nter val will be i m p ute d b y 
assi g ni n g a val u e of t he pre vi o us meas ure me nt f or t he first 1 5 mi n utes a n d t he 
val ue of t he ne xt meas ur e me nt f or t he sec o n d 1 5 mi n utes. 
 If 2, 3 or 4 half- h o ur ti me i nter vals are missi n g, a n d t hese ti me i nter vals are 
a vaila ble fr o m ot her da ys of t he visit, t he n t he f oll o wi n g r ul es will be a p plie d: 
 F or missi n g v al ues o n Da y - 3, d ata fr o m Da y - 2 will be use d f or i m p utati o n f or 
t he sa me ti me i nter vals. If Da y - 2 d ata is als o i nc o m plete or n ot a vaila ble, t he n 
Da y - 1 data will be use d. 
 F or missi n g v al ues o n Da y - 2, d ata fr o m Da y - 1 will be use d f or i m p utati o n 
if a vaila ble; ot her wise D a y - 3 data will be us e d. 
 F or missi n g v al ues o n Da y - 1, d ata fr o m Da y - 2 will be use d f or i m p utati o n 
if a vaila ble; ot her wise D a y - 3 data will be us e d f or i m p utati o n. 
 If data at t he sa me ti me p eri o d are missi n g acr oss all da ys, t he n t h e a p pr oac h 
will  be t o s plit t he i n di vi d ual missi n g half- h o ur i nter vals i nt o 2 peri o ds, wit h t he 
first half-i nter val bei n g i m p ute d wit h data fr o m t h e i m me diate pre vi o us n o n-
missi n g ti me peri o d a n d t he sec o n d half-i nter val bei n g i m p ute d wit h t he ne xt 


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n o n- missi n g ti me i nter val. If t h e missi n g peri o d st arts wit h t he ver y first or e n ds 
wit h t he ver y last i nter val of t he diar y, t he n t he e ntire missi n g peri o d will be 
i m p ute d wit h t he data fr o m t he i m me diate a djace nt n o n- missi n g i nter val. 
 F or s u bjects wit h o nl y 1 da y of diar y d ata (i nstea d of 3 da y), t he f oll o wi n g r ules will 
a p pl y: 
 If m ore t ha n 4 h alf- h o ur ti me i nter vals are missi n g, t he n t hat partic ular d a y will 
n ot be i ncl u de d i n t he a n al ysis. T he missi n g d ata will be ha n dle d i n t he M M R M 
m o del. 
 If a o ne- half h o ur ti me i nter val is missi n g a n d t he o bser vati o ns o n eit her si de of 
+t he ti me i nter val are n ot missi n g, t he n t he missi n g ti me i nter val will be 
i m p ute d b y assi g ni n g a v al ue of t he pre vi o us meas ure me nt f or t he first 1 5 
mi n utes a n d t he val ue of t he ne xt meas ure me nt f or t he sec o n d 1 5 mi n utes.  
 If 2, 3, or 4 c o ns ec uti ve h alf- h o ur i nter vals are missi n g, t he n t he a p pr oac h will 
be t o s plit t he i n di vi d ual missi n g half- h o ur i nter vals i nt o 2 peri o ds, wit h t he 
first half-i nter val bei n g i m p ute d wit h data fr o m t h e i m me diate pre vi o us n o n-
missi n g ti me peri o d a n d t he sec o n d half-i nter val bei n g i m p ute d wit h t he ne xt 
n o n- missi n g ti me i nter val. If t h e missi n g peri o d st arts wit h t he ver y first or e n d 
wit h t he ver y last i nter val of t he diar y, t he n t he e ntire missi n g peri o d will be 
i mp ute d wit h t he data fr o m t he i m me diate a djace nt n o n- missi n g i nter val. 
4. 1. 2  Mi s si n g D at a f o r M D S- U P D R S 
F or all e n d p oi nts base d i n M D S- U P D R S q uesti o n naire t he f oll o wi n g i m p utati o n of missi n g 
res p o nses will be use d. 
If t he M D S- U P D R S are missi n g f or t he partic ular visit, t he missi n g data will be ha n dle d via t he 
M M R M m o del. 
If c o m p o ne nt q uesti o ns are missi n g f or a partic ular part of t he M D S- U P D R S q uesti o n naire, t he 
missi n g ite ms are assi g ne d t he a vera ge val u e f or ot her ite ms i n t h at part as f oll o ws: 
 
F or Part I ( 1 3 q uesti o ns): u p t o 1 missi n g q uesti o n will be i m p ute d usi n g t he 
a vera ge val ue of t he re mai ni n g 1 2 q uesti o ns. 
 
F or Part II ( 1 3 q uesti o ns): u p t o 2 missi n g q uesti o ns will be i m p ute d usi n g t he 
a vera ge val ue of t he re mai ni n g 1 1 q uesti o ns. 
 
F or Part III ( 3 3 q u esti o ns): u p t o 7 missi n g q uesti o ns will be i m p ute d usi n g 
t he a vera ge val u e of t he re mai ni n g 2 6 q u esti o ns. 
 
F or Part I V ( 6 q uesti o ns): n o i m p utati o n is d o ne. 
If m ore c o m p o n e nt q uesti o ns are missi n g t ha n a b o ve f or a p artic ular part of t he M D S- U P D R S 
q uesti o n naire, t he e ntire q uesti o n naire a n d t he affecte d part will n ot be i ncl u de d i n t he a nal ysis 
f or t hat partic ular assess me nt. Missi n g data will be ha n dle d i n a fas hi o n si milar t o P D Diar y d ata 
usi n g t he M M R M m o del. 


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4. 1. 3  Mi s si n g D at a f o r Gl o b al A s s e s s m e nt s ( P GI- C,
F or all e n d p oi nts base d o n P GI- C, 
gl o bal assess me nts t he f oll o wi n g 
i m p utati o n r ules will be a p plie d. 
F or s u bjects wit h missi n g P GI- C or  
f or a partic ular visit, t he data will be i m p ute d as n o n-
res p o n ders (i.e., n ot bei n g “ m u c h i m pr o ve d” or “ v er y m uc h i m pr o ve d ”). 
4. 1. 4  H a n dli n g of Mi s si n g Vi sit D at a 
A n M M R M a p pr oac h will be use d t o ha n dle missi n g visit data f or c o nti n u o us e n d p oi nts. 
M M R M a nal ysis will use all a vaila ble vali d visit d ata, i ncl u di n g s u bjects wit h s o me missi n g visit 
data, i n or der t o arri ve at a n esti mate of t he mea n treat me nt effect. 
4. 2  
Visi t Wi n d o ws f or Effic ac y A n al yses 
It is a ntici pate d t hat a n u m ber of s u bjects i n t his st u d y mi g ht atte n d t heir visits o ut of sc he d ule 
d ue t o C O VI D- 1 9 p a n de mic a n d a n u m ber of u nsc he d ule d visits mi g ht be a d de d.  
Efficac y a ssess me nts c oll ecte d at u nsc h e d ule d visits will be ma p pe d t o sc he d ule d visits if t he 
f oll o wi n g c o n diti o ns h ol d: 
 T he u nsc he d ule d visit falls i nt o a p pr o priate visit wi n d o w f or a sc h e d ule d visit 
 It oc c urs n o later t ha n t he s u bject’s Visit 7/ E T if o ne e xists 
 N o c orres p o n di n g s c he d ule d visit e xists at all or wit hi n t he a p pr o priate wi n d o w. If t he 
sche d ule d visit e xists, b ut is o ut of wi n d o w, t he o ut- of- wi n d o w sc h e d ule d visit will be 
treate d as u ns c he d ule d a n d will be re place d b y t he i n- wi n d o w u nsc he d ul e d visit f or 
a nal ysis.  
T he  f oll o wi n g wi n d o ws will be use d: 
Visit  
Wi n d o w i n d a ys after Visit 4 
5  
2 1 +/ - 3 da ys  
6  
5 6 +/ - 3 da ys  
7  
9 1 +/ - 3 da ys  
I n a d diti o n, if t he s u bject's last visit ( b y d ate) is u nsc he d ule d a n d t here is n o sc he d ule d Visit 
7/ E T, t he last u nsc he d ule d visit will be ma p pe d t o Visit 7/ E T. 
4. 3  
Ce nter P o oli n g Al g orit h m 
I n all a nal ysis m o dels w h ere p o ole d ce nter is a fact or, p o ole d ce nter will be deter mi ne d as 
f oll o ws. 
1.  
S ort ce nters fr o m eac h c o u ntr y fr o m s mallest t o lar gest bas e d o n t he n u m ber of s u bjects 
i n t he m o difie d i nte nt-t o-treat a nal ysis set ( mI T T). 
2.  
Ce nters t hat ha ve less t ha n 5 mI T T s u bjects i n t otal or d o n ot ha ve at least o ne mI T T 
s u bject per treat me nt gr o u p will be p o ole d wit h t he s mallest a m o n g t h e ot her ce nt ers i n 


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t he sa me c o u ntr y u ntil t he c o m bi ne d ce nter ( na mel y, pse u d o-ce nter) has m ore t ha n 5 
mI T T s u bjects a n d at least o ne mI T T s u bject per treat me nt gr o u p. 
3.  
If after p o oli n g wit hi n t he sa me c o u ntr y, t h e ps e u d o-ce nter still has less t ha n 5 mI T T 
s u bjects or still has zer o s u bjects i n o ne of t he treat me nt gr o u p, t h at pse u d o-ce nter will 
be p o ole d wit h t he s mallest ot her ce nt er i n t he sa me ge o gra p hical re gi o n ( Wester n 
E ur o pe, Easter n E ur o pe, N ort h A merica). 
4.  
If after p o oli n g wit hi n t he sa me ge o gra p hical re gi o n, t he pse u d o-ce nter still has less 
t ha n 5 mI T T s u bj ects or still has zer o s u bjects i n o ne of t he treat me nt gr o u p, t hat 
pse u d oce nter will be p o ole d wit h t he s mallest ot her ce nter i n a n y re gi o n.  
T he  pr ocess c o nti n ues u ntil all p o ole d pse u d o-ce nt ers ha ve at least 5 mI T T s u bjects a n d at least 
o ne mI T T s u bject per treat me nt gr o u p. T hese p o ol e d ce nters will be use d i n a nal ys es t hat a dj ust 
f or p o ole d ce nters. 
4. 4  
P ri m ar y E n d p oi nt 
T he pri mar y effic ac y e n d p oi nt is t he mea n c ha n ge fr o m baseli ne i n “ G o o d o n” ti me i n h o urs per 
da y, a vera ge d o v er t he P D Diar y da ys, at t he e n d of t he d o u ble- bli n d t hera p y ( Visit 7 or earl y 
ter mi nati o n).  
4. 4. 1  C al c ul ati o n of t h e p ri m a r y e n d p oi nt 
“ G o o d o n” ti me is deri ve d fr o m t he 3- da y P D Di aries c o m plete d pri or t o Visits 4, 5, 6 a n d 7 or 
earl y ter mi nati o n, res pecti vel y. S u bjects will als o c o m plete P D Diaries pri or t o Visits 1 a n d 2, 
b ut t hese will n ot be use d i n t he calc ulati o n of t he pri mar y e n d p oi nt. 
W he n m ore t ha n o ne stat e s are c hec ke d at a partic ular ti me p oi nt i n t he P D Diar y, t he w orse 
res ult is selecte d as t he fi nal re p orte d o ut c o me. T h e selecti o n or d er (fr o m t he w orst t o t he 
best) is defi ne d bel o w: 
2.  Off 
3.  O n wit h Tr o u bles o me D ys ki nesia 
4.  Aslee p 
5.  O n wit h N o ntr o u bles o me D ys ki nesia 
6.  O n wit h o ut D ys ki nesia 
If a n y half- h o ur i nter val i n t he P D Diar y has a missi n g res p o ns e, t he al g orit h m i n t he secti o n 
4. 1. 1  will be use d t o i m p ute missi n g val ues. 
A P D Dia r y is vali d if at least 1 f ull da y (fr o m 6: 0 0 a m t o 6: 0 0 a m t he ne xt da y) of diar y data is 
a vaila ble after t he i m p utati o ns me nti o ne d a b o ve. F or visits wit h n o vali d P D Diar y “ G o o d o n” 
ti me will n ot be deri ve d (a n d missi n g val ue will be ha n dle d b y t he M M R M pr oce d ure). 
F or eac h da y, “ G o o d o n ” ti me is calc ulate d b y a d di n g t he n u m ber of half- h o ur i nter vals i n w hic h 
eit her a n “ O n wit h o ut d ys ki nesia” or “ O n wit h n o ntr o u bles o me d ys ki nesi a” is c hec k e d. T he n t he 
time is a vera ge d acr oss all da ys wit h a vaila bl e dat a i n t he P D Diar y f or t he gi ve n visit. 
T he  baseli ne will be t he “ G o o d o n” ti me fr o m t he P D Diar y c ollecte d pri or t o Visit 4. C ha n ge 
fro m baseli ne at eac h s u bse q ue nt visit will be calc ulate d as “ G o o d o n” ti me at t hat visit mi n us 
t he baseli ne “ G o o d o n ” ti me. 


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4. 4. 2   A n al y si s of t h e p ri m a r y e n d p oi nt 
“G o o n o n” ti me a n d its c ha n ge fr o m b aseli ne will be s u m marize d descri pti vel y b y p ost-
ra n d omiz ati o n visit a n d treat me nt gr o u p. 
T he  pri mar y effic ac y e n d p oi nt will be a nal yze d usi n g a mi x e d m o del f or re peate d meas ures 
( M M R M). T he m o del will i ncl u de baseli ne ( Visit 4) “ G o o d o n” ti me as a c o variate, treat me nt 
(I P X 2 0 3 or I R C D- L D) a n d visit ( 5, 6 or 7/ E T) as fi x e d effects, p o ole d ce nt er (see secti o n 4. 3 ) as 
ran d o m effect a n d a treat me nt- b y - visit i nteracti o n. T he m o del will e m pl o y a n u nstr uct ure d 
wit hi n s u bject c o varia n ce matri x a n d a restricte d ma xi m u m li keli h o o d ( Re M L) esti mati o n 
met h o d. T he de gree- of -free d o m of t he de n o mi nat or will be esti mate d usi n g t he Ke n war d- R o ger 
met h o d. T he pri mar y a n al ysis set will be t he m o difie d i nte nt- t o-treat ( mI T T) as defi ne d i n 
Secti o n 2. 2. 4 . See ap pe n di x 9. 2. 1  f or S A S c o de sa m ples. 
If t he m o del fails t o c o n v er ge wit h t he u nstr uct ure d c o varia n ce matri x, a si m pler c o vari a nce 
matri x will be e m pl o ye d i n t he or der of 1) heter o ge ne o us T oe plitz [ S A S P R O C MI X E D t y p e 
= T O E P H], 2) heter o ge ne o us a ut ore gressi v e of or d er 1 [t y pe = A R H( 1)], 3) heter o ge n e o us 
c o m p o u n d s y m metr y [t y pe = C S H], 4) T oe plitz [t y p e = T O E P], 5) a ut or e gressi ve of or d er 1 
[t y pe = A R( 1)], 6) c o m p o u n d s y m metr y [t y pe = C S]. T he first c o varia nce str uct ure t hat d oes n ot 
ha ve a c o n ver ge nce pr o ble m will be t he o ne use d f or t he pri mar y a nal ysis. 
L S Mea n esti mates f or eac h treat me nt gr o u p at Visit 7/earl y ter mi nati o n will be pr o d uce d fr o m 
t he M M R M m o del, al o n g wit h t heir sta n dar d err ors ( S E) a n d 9 5 % c o nfi de nce i nter val. L S Mea n 
differe n ce b et wee n t h e I P X 2 0 3 a n d I R C D- L D treat me nts will als o be esti mate d al o n g wit h its 
S E a n d 9 5 % c o nfi de n ce i nter val. P- val ue f or t he h y p ot hesis of n o treat me nt differe n ce will be 
pr o vi de d. 
Mea n ( +/- S E) “ G o o d o n ” ti me will als o be pl otte d b y visit a n d b y treat me nt gr o u p. 
4. 5  
A n al ysis of t he Ke y Sec o n d ar y E n d p oi nts 
A nal ysis of t h e ke y sec o n dar y e n d p oi nts will be p erf or me d o n t h e mI T T p o p ulati o n.  
4. 5. 1  C h a n g e f r o m b a s eli n e i n “ Off” ti m e at t h e e n d of d o u bl e - bli n d t r e at m e nt p e ri o d 
( Vi sit 7 o r e a rl y t e r mi n ati o n) 
T his sec o n dar y e n d p oi nt will be calc ulate d si milar t o t he pri mar y e n d p oi nt, s u m mi n g t he ti me 
peri o d c hec ke d as “ Off”. It will a nal yze d i n t he sa me ma n ner as t h e pri mar y e n d p oi nt. 
4. 5. 2  P r o p o rti o n of s u bj e ct s wit h eit h e r “ m u c h i m p r o v e d” o r “ v e r y m u c h i m p r o v e d” 
i n P GI- C s c o r e s at t h e e n d of d o u bl e- bli n d t r e at m e nt p e ri o d ( Vi sit 7 o r e a rl y 
t e r mi n ati o n) 
T he patie nt will c o m pare his/ her c o n diti o n fr o m t he start of t he st u d y o n a 7- p oi nt scale ra n gi n g 
fr o m “ Ver y m uc h w ors e” ( 1) t o “ Ver y m uc h i m pr o ve d” ( 7) at t he ti me of t he assess me nt. 
T his assess me nt will be perf or me d at Visits 5, 6 a n d 7 ( or earl y t er mi nati o n). 
T he n u m ber a n d p erce nta ge of s u bjects wit h eac h P GI- C res p o nse will be dis pla ye d b y visit 
(starti n g wit h Visit 5) a n d treat me nt gr o u p. T he n u m ber a n d perce nt a ge of s u bjects wit h eit her 
“m uc h i m pr o ve d” or “ ver y m uc h i m pr o v e d” res p o nse will als o be pr o vi de d, wit h i m p utati o ns f or 
missi n g data as des cri be d i n t he secti o n 4. 1. 3 . 
C oc hra n- Ma nt el- Hae nszel ( C M H) test stratifie d b y t he p o ole d ce nter will be use d t o c o m pare t he 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 2  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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pr o p orti o n of s u bjects wit h eit her “ m uc h i m pr o ve d” or “ ver y m uc h i m pr o v e d” res p o ns e at t he 
e n d of t he d o u ble- bli n d t hera p y ( Visit 7 or earl y t er mi nati o n) bet wee n t he t w o treat me nt gr o u ps; 
p - val ue f or t h e h y p ot hesis of e q ual pr o p orti o ns will be s h o w n. Perce nt differe nce bet w ee n t he 
I P X 2 0 3 a n d I R C D- L D gr o u ps will be s h o w n wit h its 9 5 % c o nfi de nce i nter val. See a p pe n di x 
9. 2. 2  f or SA S c o de details. 
4. 5. 3  C h a n g e f r o m b a s eli n e i n t h e M D S- U P D R S P a rt III at t h e e n d of d o u bl e- bli n d 
t r e at m e nt p e ri o d ( Vi sit 7 o r e a rl y t e r mi n ati o n) 
M D S- U P D R S will be a d mi nistere d at Scree ni n g visit (i n “ O n” a n d “ Off” st ates) a n d Visits 1, 2, 
4, 5, 6 a n d 7 ( or earl y ter mi nati o n) (i n a n y stat e).  
P art III t otal sc ore will be deri ve d as t he s u m of t he a ns wers f or all q uesti o ns i n t his part of t he 
q ue sti o n naire. Missi n g d ata will be i m p ute d as descri be d i n t he secti o n 4. 1. 2 . 
D o u ble - bli n d baseli ne, as defi ne d i n secti o n 2. 1  will be use d f or all visits aft er Visit 4. C ha n ge 
fro m baseli ne will be cal c ulate d as t he res ult at t he visit mi n us t he baseli ne val ue. 
C ha n ge fr o m bas eli ne i n M D S- U P D R S Part III s c ore will be a nal yze d i n t h e sa me ma n ner as t he 
pri mar y e n d p oi nt, as des cri be d i n t he secti o n 4. 4. 2 . 
4. 5. 4  C h a n g e f r o m b a s eli n e i n t h e s u m of M D S- U P D R S P a rt II a n d III at t h e e n d of 
d o u bl e- bli n d t r e at m e nt p e ri o d ( Vi sit 7 o r e a rl y t e r mi n ati o n) 
T his e n d p oi nt will be calc ulate d as t he s u m of all a ns wers i n Parts II a n d III of t he M D S- U P D R S 
q uesti o n naire. It will be a nal yze d i n t he sa me m a n ner as M D S- U P D R S Part III. 
4. 6  
A d d iti o n al E n d p oi nts 
I n ge neral, c o nti n u o us e n d p oi nts will be s u m marize d b y sta n dar d descri pti v e statistics ( mea n, 
sta n dar d de viati o n, me di a n, mi ni m u m, a n d ma xi m u m) b y visit (starti n g wit h Visit 4) a n d 
treat me nt gr o u p. Cate g orical e n d p oi nts will be s u m marize d b y fre q ue n cies a n d perce nta ges. 
D o u ble- bli n d baseli ne will be use d. F or s o me e n d p oi nts st u d y e ntr y baseli ne will als o be use d, as 
s pecifie d i n t he s u bse cti o ns bel o w.  
T hese a n al ys es will be perf or me d o n t he mI T T p o p ulati o n (f or e n d p oi nts relate d t o P D diar y) or 
IT T p o p ul ati o n (f or e n d p oi nts n ot relate d t o t he P D diar y) as a p pr o pri ate. 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 3  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 4  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 5  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 6  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 7  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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4. 7  
S e nsiti vit y A n al yses 
Se nsiti vit y a n al ys es will be perf or me d wit h res p ect t o t he pri mar y effi cac y e n d p oi nt a n d 
c o nti n u o us ke y s ec o n dar y e n d p oi nts ( “ Off” ti me, M D S- U P D R S Part III, a n d M D S- U P D R S Parts 
II a n d III c o m bi ne d) as f oll o ws. 
4. 7. 1  A s s e s si n g A s s u m pti o n s of t h e Mi x e d M o d el f o r R e p e at e d M e a s u r es ( M M R M) 
T he n or malit y a n d h o m os ce dasticit y ass u m pti o ns will be e x a mi ne d t hr o u g h resi d ual a nal yses. 
T he resi d uals fr o m t he pri mar y a nal ysis m o dels will be teste d f or n or malit y usi n g S ha pir o- Wil k 
statistic. T he ass u m pti o n of h o m osce dasticit y ( h o m o ge n eit y of varia n ce) will be teste d f or 
o u tc o mes fr o m Visit 7/earl y ter mi nati o n usi n g a o ne- wa y A N O V A m o d el wit h t he fact or of 
treat me nt wit h Le ve n e’s test. See A p pe n dices 9. 2. 3  an d 9. 2. 4  f or SA S c o de sa m ples. 
If eit her of t he tests is si g nifica nt at t he 0. 0 5 le vel, t he f oll o wi n g n o n- p ara m etric a nal ys es will be 
perf or me d. 
I. 
N o n para metric Wilc o x o n Ra n k S u m test will be perf or me d t o c o m pare t he t w o 
treat me nt gr o u ps at Visit 7, wit h missi n g data i m p ute d b y t he l ast o bser vati o n carri e d 
f orwar d ( L O C F) met h o d (t hat is, t he latest a vaila ble res ult o btai ne d p ost-ra n d o mizati o n 
will be carri e d f or w ar d t o i m p ute t he missi n g Visit 7 res ult). 
II. 
M ulti ple i m p utati o n ra n k base d a nal ysis: i nstea d of missi n g data i m p ute d b y t he L O C F 
met h o d, i n t his a nal ysis, missi n g data at Visit 7 will be i m p ute d m ulti ple ti mes t o creat e 
5 0 c o m plete datasets. T h e m ulti ple i m p utati o n pr oce d ure is d escri be d i n Secti o n 4. 7. 8  
( part of t he p atter n- mi xt ure m o del), usi n g f = 0 %. T he Wilc o x o n Ra n k S u m test will be 
pe rf or me d o n eac h of t he 5 0 datasets. T he res ults are t he n c o m bi ne d usi n g R u bi n’s r ule 
via S A S  P R O C MI A N A L Y Z E. 
See a p pe n dic es 9. 2. 5  a n d 9. 2. 9  f or S A S c o de sa m ples. 
Missi n g at Ra n d o m ( M A R) ass u m pti o n will be e val uate d as disc usse d i n S ecti o n 4. 7. 8 . 
4. 7. 2  C o m pl et e C a s e A n al y si s 
T he pri mar y e n d p oi nt will be a nal yze d usi n g a n A N C O V A m o del wit h “ G o o d o n” ti me at 
d o u ble- bli n d baseli ne as a c o vari ate, p o ole d ce nter a n d treat me nt as fact ors. T he a nal ysis will be 
perf or me d o n t h e C o m pleters A nal ysis Set. 
Si milar t o t he pri mar y a n al ysis, L S Mea n esti mates f or eac h treat me nt gr o u p will be pr o d uce d 
fr o m t he A N C O V A m o d el, al o n g wit h t heir sta n dar d err ors ( S E) a n d 9 5 % c o nfi de nce i nter val. 
L S Mea n differe nce bet w ee n t he I P X 2 0 3 a n d I R C D- L D treat me nts will als o be esti mate d al o n g 
wit h its S E a n d 9 5 % c o nfi de nce i nter val. P- val ue f or t he h y p ot hesis of n o treat me nt differe nce 
will be pr o vi de d. See a p p e n di x 9. 2. 6  f or S A S c o de sa m ples. 
4. 7. 3  Si n gl e L O C F / B L O C F I m p ut ati o n 
T he pri mar y effic ac y e n d p oi nt will be a nal yze d usi n g a n A N C O V A m o del wit h “ G o o d o n” ti me 
at d o u ble- bli n d baseli ne as a c o variate, p o ole d ce nter a n d treat me nt as fact ors. Missi n g data will 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 8  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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be i m p ute d b y t he L O C F a n d baseli ne o bser vati o n carri e d f or war d ( B L O C F) met h o ds: 
 I n t he L O C F met h o d t he latest a vaila ble res ult o btai ne d p ost-ra n d o mizati o n will be 
carri e d f or w ar d t o i m p ute t he missi n g Visit 7 res ult 
 I n t he B L O C F met h o d missi n g Visit 7 “ G o o d o n” ti me will be re place d wit h t he 
ba seli ne res ult, i n ot her w or ds, c ha n ge fr o m bas eli ne will be i m p ute d as zer o. 
T hese a n al ys es will be perf or me d o n t he mI T T p o p ulati o n. See a p pe n di x 9. 2. 6  f or S A S c o de 
sam ples. 
4. 7. 4  Sit e a s Fi x e d Eff e ct 
T he pri mar y effic ac y e n d p oi nt will be s u m marize d wit h t he M M R M m o del si milar t o t he 
pri ma r y a nal ysis, e x ce pt p o ole d site will be use d as a fi x e d effect rat her t ha n ra n d o m. See 
ap pe n di x 9. 2. 7  f or S A S c o de. 
4. 7. 5  R e gi o n Eff e ct  
T he pri mar y effic ac y e n d p oi nt will be s u m marize d wit h t he M M R M m o del si milar t o t he 
pri mar y a nal ysis, e x ce pt ge o gra p hic re gi o n ( N ort h A merica or E ur o pe) will be use d as a fi x e d 
effect i nstea d of p o ole d site as ra n d o m effect. See a p pe n di x 9. 2. 7  f or S A S c o de, re placi n g p o ol e d 
site wit h re gi o n. 
4. 7. 6  P e r- P r ot o c ol A n al y si s 
T he a nal ysis of t he pri mar y a n d ke y sec o n dar y e n d p oi nts will be re peate d o n t he Per- Pr ot oc ol 
A nal ysis Set. 
4. 7. 7  E x cl u si o n of L at e Vi sit 7 
Pri mar y a nal ysis of t he pri mar y e n d p oi nt will be re peate d e x cl u di n g o ut- of- wi n d o w Visit 7 
assess me nts. I n t his a nal ysis P D Diaries c ollecte d f or Visit 7 will be e x cl u de d fr o m a n al ysis if 
t he first da y i n t he diar y is m ore t ha n 3 da ys later t ha n pla n ne d, i.e. m ore t ha n 9 1 da ys aft er 
ra n d o mizati o n. 
4. 7. 8  P att e r n- Mi xt u r e M o d el 
If a n o verall dr o p o ut rat e p ost-ra n d o mizati o n is > 1 5 %, patter n- mi xt ure m o dels ( P M M) will be 
e m pl o ye d t o assess t he r o b ust ness of t he res ults u n der t he missi n g n ot at ra n d o m ( M N A R) 
ass u m pti o n. T he patter n f or P M M is defi ne d b y p atie nts’ last visit wit h a n o bser ve d pri mar y 
effic ac y e n d p oi nt a n d t h e reas o n f or dr o p o ut. 
M ulti ple i m p utati o ns wit h mi x e d missi n g data mec ha nis m ( M N A R f or a missi n g data patter n a n d 
M A R  f or ot hers) will be use d t o i n vesti gate t h e r o b ust ness of t he pri mar y res ult. F o ur s pecific 
data patter ns will be e x a mi ne d: 
1.  Dr o p o ut at Visit 5 a n d reas o n = Lac k of efficac y i n I P X 2 0 3 treat me nt ar m, 
2.  Dr o p o ut at Visit 5 a n d reas o n = Lac k of efficac y or a d vers e e ve nts i n I P X 2 0 3 
treat me nt ar m, 
3.  Dr o p o ut at Visit 6 a n d reas o n = Lac k of efficac y i n I P X 2 0 3 treat me nt ar m, 
4.  Dr o p o ut at Visit 6 a n d reas o n = Lac k of efficac y or a d verse e ve nts i n I P X 2 0 3 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 2 9  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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treat me nt ar m. 
T he patter- mi xt ure a nal ysis will be perf or me d se p aratel y f or eac h of t he p atter ns a b o ve. 
F or eac h patter n, t he missi n g val ues will be i m p ut e d 5 0 ti mes ( m ulti ple i m p utati o n) u n der t he 
ass u m pti o n t hat t he distri b uti o n of t he missi n g val ues is t he sa me as t hat of t he o bser ve d v al ues. 
T he P M M t he n i n vesti gates t he de part ure fr o m t h e M A R ass u m pti o n b y pr o gressi vel y decreasi n g 
t he o utc o me (t he “ p e nalt y”) f or t h ose o n I P X 2 0 3 ar m w h o fall i nt o a n ass u me d M N A R patter n 
a b o ve. F or t he dr o p o ut s u bjects o n I P X 2 0 3 ar m t hat fall i nt o o ne of t he patter ns a b o ve, t he 
“ pe nalt y” is o btai ne d b y s u btracti n g t h e i m p ute d missi n g data aft er dr o p o ut b y a fact or f, wit h f 
ra n ges 0 % t o 1 0 0 % , wit h t he i ncre me nt b y 5 %, of t he treat me nt differe nce see n i n t he pri mar y 
m o del. T his pr ocess c o nti n ues u ntil t he c o ncl usi o n fr o m t he pri mar y a nal ysis is o vert ur ne d (a 
ti p pi n g p oi nt). I n ot her w or ds, if t he dr o p o ut s u bject is fr o m I P X 2 0 3 ar m a n d t he dr o p o ut patter n 
falls i nt o o ne of t he 4 patter ns a b o ve, t he n t h e s u bject’s i m p ute d val ue will be a dj uste d 
d o w n war d b y a fact or f, w here f g oes fr o m 0 % t o 1 0 0 % of t he treat me nt differe nce s ee n i n t he 
pri mar y m o del. N ote t hat if 0 % is use d, t he a nal ysis is esse ntiall y m ulti ple i m p utati o ns u n der 
M A R ass u m pt i o n. O n t he ot her ha n d, if 1 0 0 % is use d, t he n t he a nal ysis is esse ntiall y a “j u m p t o 
refere nce” w h ere o utc o m e o n I P X 2 0 3 ar m is ass u me d t o be t he sa me as o utc o me o n I R C D- L D. 
After i m p utati o ns, t he dataset will be a nal yz e d usi n g a n M M R M m o del si milar t o t he pri mar y 
a nal ysis m o del. T h e res ults will t he n be c o m bi ne d usi n g t he R u bi n’s r ule vi a S A S P R O C 
MI A N A L Y Z E. 
T he pr oce d ure will be carrie d o ut i n S A S as descri be d i n a p pe n di x 9. 2. 8 .  
If i n t he M M R M a nal ysis a c o vari a nce str u ct ure ot her t ha n U nstr uct ure d is selecte d d ue t o 
c o n ver ge n ce iss ues, t he s a me str uct ure s h o ul d b e use d f or all i m p utati o ns. I n ot her w or ds, if a 
c o varia n ce str uct ure res ults i n c o n ver ge nce pr o ble ms f or at least o ne of t h e m ulti ple i m p utati o ns, 
t he ne xt str uct ure fr o m t he list s pecifie d i n secti o n 4. 4. 2  s h o ul d be trie d u ntil a str uct ure is f o u n d 
t hat co n ver ges f or all i m p utati o ns. 
4. 8  
S u b gr o u p a n al yses 
T he pri mar y a n d k e y sec o n dar y e n d p oi nts will be s u m marize d f or t he s u b gr o u ps i de ntifie d i n 
secti o n 2. 4 . T he sa me a n al ysis met h o ds as t he pri mar y a n d ke y s ec o n dar y e n d p oi nts will be 
ap plie d, u nless t he sa m ple siz e i n o ne of t he s u b gr o u ps bec o mes t o o s mall t o hi n der t he statistical 
a nal ysis. I n t hat cas e, n o i nfere ntial statistics will be pr o vi de d f or s uc h a s u b gr o u p. 
4. 9  
M ulti plicit y A dj ust me nts 
T he pri mar y e n d p oi nt a n d 5  ke y/i m p orta nt sec o n d ar y e n d p oi nts will be teste d i n a se q ue ntial 
hier arc hical or d er as f oll o ws. 
1.  T he pri mar y e n d p oi nt, t h e mea n c h a n ge fr o m baseli ne i n “ G o o d o n” ti me ( h o urs per 
da y), will be teste d first at a 0. 0 5 le vel of si g nifica nce. 
2.  If statistical si g nifica nce is de m o nstrate d, t he n t he first ke y s ec o n d ar y e n d p oi nt, t he 
mea n c ha n ge fr o m b aseli ne i n “ Off” ti me ( h o urs per da y), will be teste d ne xt at a 0. 0 5 
le vel of si g nifi ca nce. 
3.  If statistical si g nifica n ce is de m o nstrate d, t he n t he sec o n d ke y sec o n dar y e n d p oi nt, t he 
pr o p orti o n of s u bjects wit h eit her “ m uc h i m pr o ve d” or “ ver y m uc h i m pr o v e d” o n t he 
P GI- C, will be teste d n e xt at a 0. 0 5 le vel of si g nifi ca nce. 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 0  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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4.  If statistical si g nifica nce is de m o nstrate d, t he n t he t hir d ke y s ec o n dar y e n d p oi nt, t he 
mea n c ha n ge fr o m b aseli ne i n t he M D S- U P D R S Part III, will be teste d at a 0. 0 5 le vel 
of si g nifica nce. 
5.  If statistical si g nifica nce is de m o nstrate d, t he n t he f o urt h ke y sec o n dar y e n d p oi nt, t he 
mea n c ha n ge fr o m b aseli ne i n t he s u m of t he M D S- U P D R S Parts II a n d III c o m bi ne d 
will  be teste d ne xt at a 0. 0 5 le vel of si g nifi ca nce. 
6.  If statistical si g nifica nce is de m o nstrate d, t he n t he i m p orta nt sec o n dar y e n d p oi nt, bei n g 
“o n” u p o n a w a ke ni n g will be teste d ne xt at a 0. 0 5 le vel of si g nifi ca nce. 
F or t he ot her efficac y e n d p oi nts, n o a dj ust me nt will be ma de.  
5  S A F E T Y A N A L Y S E S 
Safet y a nal yses will be perf or me d o n t h e Safet y A nal ysis Set a n d Ra n d o mi ze d A nal ysis Set. T he 
anal ysis o n t he Safet y A n al ysis Set will i ncl u de a s e parat e c ol u m n f or s u bjects w h o were n ot 
ra n d o mize d. 
F or safet y para meters t h at are c ollecte d b y visit a n d ha ve t heir first p ost-st u d y-e ntr y- bas eli ne 
assess me nt after ra n d o mi zati o n, st u d y e ntr y baseli ne val ues will be s u m marize d f or t he Safet y 
A nal ysis Set a n d all p ost-ra n d o mizati o n val ues will be s u m marize d f or t he Ra n d o mize d A nal ysis 
S et. 
F or safet y para meters t h at are c ollecte d at visits after t he st u d y e ntr y bas eli ne, b ut pri or t o 
ra n d o mizati o n, t heir val ues will be s u m marize d f or t he Safet y A nal ysis Set. 
N o i m p utati o n will be perf or me d f or missi n g safet y dat a. I n b y- visit s u m maries, if a s u bject d o es 
n ot ha ve a val u e c ollecte d at a gi ve n visit, t his s u bject will be s u m marize d at t hat visit. Data fr o m 
t he Earl y Ter mi nati o n visits will n ot be use d i n t he b y- visit s u m maries, b ut will be liste d a n d 
ma y p artici pate i n t he sel ecti o n of t he last p ost- bas eli ne assess me nt if a p plica ble. 
5. 1  
Visi t Wi n d o ws f or S afet y Assess me nts 
Sa m ples f or la b orat or y t ests a n d E C Gs are sc h e d ul e d t o be c ollecte d at Visits 1, 5 a n d 7/ E T, 
H o we ver, if at t he ti me of Visit 4 it is a ntici pate d t hat t he s u bject w o ul d n ot be a ble t o tra v el t o 
t he site d ue t o C O VI D- 1 9 relate d restricti o ns, t hese assess me nts ca n b e c ollecte d at Visit 4. If 
t hese assess me nts were n ot c ollecte d at Visit 4 or Visit 5, t he y ca n b e c ollecte d at Visit 6. 
T heref ore f or s u bjects w h o d o n ot ha ve la b orat or y or E C G para m eters c oll ecte d u n der Visit 5, 
assess me nts c ollecte d u n der Visit 4, Visit 6 or U nsc he d ule d visit will be ma p pe d t o Vis it 5 f or 
anal ysis u n d er t he f oll o wi n g cir c u msta nces 
1.  
S u bject c o m plete d t he st u d y or disc o nti n ue d l ater t ha n 1 8 da ys after Visit 4 (i.e. after t he 
start of t he wi n d o w f or Visit 5) 
2.  
T he assess me nt w as perf or me d at Visit 4, Visit 6 or at U nsc he d ul e d visits t hat occ urre d 
after Visit 4 a n d n o later t ha n da y 5 9 after Visit 4 (e n d of visit wi n d o w f or Visit 6). 
3.  
T he  U nsc he d ul e d assess me nt occ urre d n o later t h a n t he s u bject’s Visit 7/ E T if o n e e xists. 
5. 2  
A d ver se E ve nts 
A d verse E v e nts will be c o de d usi n g t he M e dical Dicti o nar y of Re g ulat or y Acti vities ( Me d D R A) 
versi o n 2 2. 0 A E c o di n g s yste m f or p ur p oses of s u m marizati o n. 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 1  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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O nl y Treat me nt E mer ge nt A d verse E ve nts ( T E A E) will be use d f or t he s u m mar y a nal ysis. A n 
A E will be c o nsi dere d as treat me nt-e mer ge nt if t h e date of o ns et is o n or after t he first st u d y dr u g 
a d mi nistrati o n date (I R C D- L D i n t he D ose A dj ust me nt peri o d) a n d n o lat er t ha n 1 da y after t he 
last d ose of t he st u d y dr u g (I R C D- L D or I P X 2 0 3). A Es wit h u n k n o w n start dates will be 
co u nte d as treat me nt-e m er ge nt u nless t he A E res ol uti o n date is pri or t o t he first st u d y dr u g 
a d mi nistrati o n date. If t h e A E start date is p artiall y missi n g, t he A E will be c o nsi dere d tr eat me nt-
e mer ge nt, u nless t he m o nt h a n d year ( w he n a vaila ble) r ule o ut t he p ossi bilit y t hat t he e v e nt 
occ urre d p ost start of t he st u d y dr u g n o later t ha n 1 da y after t he last d ose of t he st u d y dr u g. 
All A Es will  be assi g ne d t o st u d y peri o ds f or t he p ur p oses of t he ta b ulati o ns: 
D ose A dj ust me nt Peri o d : All T E A Es wit h o nset t hat meets t hese criteria: 
 o n or after t h e date of t he first I R C D- L D a d mi nistrati o n i n t he D ose A dj ust me nt peri o d  
 If t he s u bject pr o cee ds i nt o I P X 2 0 3 C o n versi o n peri o d, t he n pri or t o t he first d ose of 
I P X 2 0 3 i n t he I P X 2 0 3 C o n versi o n peri o d. Ot her wise, u p t o 1 da y after t he last st u d y 
dr u g  d os e 
I P X 2 0 3 C o nversi o n Peri o d: All T E A Es wit h o nset t hat meets t hese criteri a: 
 o n or after t h e date of t he first I P X 2 0 3 a d mi nistrati o n i n t he I P X 2 0 3 C o n versi o n  peri o d  
 If t he s u bject pr o cee ds i nt o D o u ble- bli n d peri o d, t he n pri or t o t he first d ose of t he 
ra n d o mize d dr u g i n t he D o u ble- bli n d peri o d. Ot h er wise, u p t o 1 da y after t he last st u d y 
dr u g  d os e 
D o u ble- Bli n d Peri o d : All T E A E s wit h o nset t hat meets t hese criteria: 
 o n or after t h e date of t he first ra n d o mize d dr u g a d mi nistrati o n i n t he D o u ble- bli n d 
peri o d  
 u p t o 1 da y after t h e last st u d y dr u g d ose 
F or t he p ur p os es of assi g ni n g T E A Es t o st u d y peri o ds partial o nset dates will be i m p ute d as t he 
latest p ossi ble date c o m p ati ble wit h t he k n o w n partial i nf or mati o n; t h us i n case of a m bi g uit y 
T E A Es will be assi g n e d t o t he later peri o d.  
A T E A E is defi ne d as treat me nt-relate d if it is rec or de d as “ p ossi bl y relate d” or “relate d ” t o t he 
st u dy me dicati o n o n t he e C R F. A Es rec or de d as “ n ot relate d” or “ u nli kel y relate d” will be 
c o nsi dere d n ot r elate d. I n case t he relate d n ess was n ot assesse d, t he m ost c o nser vati ve res ult 
(relate d) will be c h ose n f or t he a nal ysis.  
I n s u m maries of T E A Es a s u bject e x perie nci n g t h e sa me A E ( wit h t he sa m e preferre d ter m) 
m ul ti ple ti mes wit hi n t he sa me st u d y p eri o d will o nl y be c o u nte d o nce f or t hat preferre d ter m a n d 
st u dy peri o d. Si milarl y, if a s u bject e x perie n ces m ulti ple A Es wit hi n t he sa me s yste m or ga n class 
i n t he sa me st u d y p eri o d, t hat s u bject will be c o u nte d o nl y o nce i n t hat s yst e m or ga n class f or 
t hat st u d y peri o d. W he n s u m marizi n g A Es b y s e v erit y, o nl y t he m ost se vere occ urre n ce wit hi n 
t he preferre d ter m or s yst e m or ga n class a n d st u d y peri o d will be use d. Si milarl y, w he n 
s u m marizi n g A Es b y relati o ns hi p t o st u d y dr u g, o nl y t he m ost relat e d occ urre nce wit hi n t he 
preferre d t er m or s yste m or ga n class a n d st u d y p eri o d will be selecte d f or dis pla ys i n s u m mar y 
ta bles. 
A Es will be s u m mariz e d b y st u d y peri o d, a n d f or t he D o u ble- Bli n d peri o d als o b y treat me nt 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 2  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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gr o u p. 
A n o verall s u m mar y will i ncl u de, b y st u d y peri o d a n d b y tr eat me nt gr o u p a n d o verall, t he 
n u m ber a n d perce nt a ge of s u bjects re p orti n g at least 1 T E A E i n t he f oll o wi n g cate g ories: 
 A n y T E A E 
 Treat me nt-relate d T E A E 
 Seri o us T E A E 
 T E A E lea di n g t o disc o nti n uati o n of t he st u d y dr u g 
 T E A E lea di n g t o deat h. 
T his o verall s u m mar y will als o be prese nte d f or s u b gr o u ps of s u bjects i de ntifie d i n secti o n 2. 4 . 
T he  f oll o wi n g T E A E fre q ue nc y ta bles will be pre pare d s u m marizi n g t he o verall n u m ber of 
T E A Es, t he n u m ber a n d perce nt a ge of s u bjects re p orti n g at least o ne T E A E b y Me d D R A S yste m 
Or ga n Class ( S O C) a n d preferre d t er m ( P T), b y treat me nt gr o u p a n d b y st u d y peri o d: 
 All T E A Es 
 Seri o us T E A Es 
 Treat me nt-relate d T E A Es 
 A Es lea di n g t o disc o nti n uati o n of t he st u d y me di cati o n 
 T E A Es i n s u bjects wit h C O VI D- 1 9 
 T E A Es b y s e verit y 
 T E A Es b y relati o ns hi p t o st u d y dr u g. 
T he  s u m maries b y S O C a n d P T will be or dere d al p ha beticall y b y S O C a n d P T. 
A d diti o nall y n u m ber a n d perce nt a ge of s u bjects wit h T E A E will be prese nt e d b y preferre d ter m 
o nl y i n t he desce n di n g or der of t otal fre q ue n c y. Pr o p orti o n of s u bjects e x perie nci n g T E A Es t hat 
occ ur i n at least 5 % of s u bjects i n eit her treat me nt gr o u p will be c o m pare d bet wee n t hes e gr o u ps 
usi n g Fis her’s e x act test. 
All i nf or mati o n pertai ni n g t o a d v erse e ve nts n ote d d uri n g t he st u d y will be liste d b y s u bject, 
detaili n g ver bati m, preferre d ter m, s yste m or ga n cl ass, start date, st o p date, se verit y, o utc o me, 
acti o n ta ke n a n d ca usal relati o ns hi p t o t he st u d y dr u g.  
5. 3  
L a b or at or y E v al u ati o ns 
T he f oll o wi n g l a b orat or y tests will be perf or me d at Scree ni n g, Visit 5 a n d Visit 7/ Earl y 
Te r mi nati o n: 
H E M A T O L O G Y: he m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt, % 
ne utr o p hils,  
% l y m p h oc ytes, % m o n oc yt es, % bas o p hils, % e osi n o p hils, a bs ol ute ne utr o p hils, a bs ol ute 
l y m p h oc ytes, a bs ol ute m o n oc yt es, a bs ol ute bas o p hils, a bs ol ute e osi n o p hils, platelet c o u nt 
C H E MI S T R Y: s o di u m, p otassi u m, c hl ori de, car b o n di o xi de, bl o o d urea nitr o ge n ( B U N), 
creati ni ne, gl uc os e, cal ci u m, p h os p h or us, al b u mi n, t otal pr otei n, uric aci d, t otal bilir u bi n, direct 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 3  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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bilir u bi n, i n direct bilir u bi n, al kali ne p h os p hatase, ala ni ne a mi n otra nsferas e, ( A L T, S G P T), 
as partate a mi n otra nsferas e ( A S T, S G O T), creati ne p h os p h o ki nase, lactate d e h y dr o ge nas e 
U R I N A L Y SI S: p H, s pecific gra vit y, bl o o d, gl u c ose, ket o nes, micr osc o pi c e x a m ( R B C a n d 
W B C, o nl y w he n i n dicate d), le u k oc yte esterase, pr otei n 
Uri ne dr u g test (f or a m p h eta mi nes, bar bit urat es, ca n na bi n oi ds, c ocai ne met a b olites, o piates, 
p he nc ycli di nes, be nz o dia ze pi nes), uri ne pre g n a nc y test a n d alc o h ol breat h test will be perf or me d 
at scree ni n g. 
F or he mat ol o g y, c h e mistr y a n d uri nal ysis baseli ne val ues will be s u m marize d f or t he Safet y 
A nal ysis Set. Act u al val u es a n d c ha n ges fr o m b aseli ne will be s u m marize d descri pti vel y b y visit 
a n d treat me nt gr o u p f or t he Ra n d o mize d A nal ysis Set. St u d y e ntr y baseli ne will be use d. 
A d diti o nall y, n u meric h e mat ol o g y, c h e mistr y a n d uri nal ysis res ults will be classifie d as L o w 
( bel o w t he reference ra n ge), N or mal ( wit hi n t he refere nce ra n ge) or Hi g h (a b o ve t he refere nce 
ra n ge). Cat e g orical Uri nal ysis res ults will be classifie d as N or mal or A b n or mal. S hifts a m o n g 
t hese cate g ories bet w ee n st u d y e ntr y b aseli ne a n d l ast a vaila ble p ost- bas eli ne assess me nt will be 
pr o vi de d. 
All res ults will be liste d. 
A d diti o nall y, s u bject listi n gs will be pr o vi de d f or t he f oll o wi n g o cc urre nces d uri n g a n y peri o d of 
t he trial.  
1.  L i ver e nz y m e ( A L T or A S T) val ues ≥ 2. 5 ti mes t he u p per li mit of n or mal; 
2.  S er u m creati ni ne le vel ≥ 1. 7 5 ti mes t he u p per li mit of n or mal.  
F or s u bjects/tests t hat meet t he a b o ve criteria at least o nce d uri n g t he st u d y, res ults fr o m al l 
a vaila ble visits will be s h o w n. 
5. 4  
Vit al  Si g ns 
Vital si g ns will be c ollect e d at all visits. Bl o o d press ure, heart rate a n d res pirat or y rat e will be 
c ollecte d at all visits, te m perat ur e at Scree ni n g a n d Visit 7/ Earl y ter mi nati o n o nl y.  Bl o o d 
press ure a n d heart rate will be rec or de d at t w o p ositi o ns: s u pi ne a n d sta n di n g. At Visits 1 a n d 4, 
ort h ostatic vital si g ns ( bl o o d press ure a n d heart rate) will be perf or me d i n tri plicate, eac h set 
se parat e d b y at least 1 5 mi n utes fr o m t he pre vi o us s et. T hese tri plicate assess me nts will be 
avera ge d a n d t he a vera ge will be use d i n a nal ysis. 
W ei g ht will be meas ur e d at Scree ni n g, Visit 5 a n d Visit 7/ Earl y Ter mi nati o n. 
Vital si g ns (i ncl u di n g wei g ht) a n d t heir c ha n ges fr o m st u d y e ntr y bas eli ne will be s u m m arize d 
descri pti vel y b y visit, p ositi o n a n d treat me nt gr o u p (i ncl u di n g “ N ot ra n d o mize d” gr o u p f or visits 
pri or t o Visit 4). 
Vital si g ns will als o be cl assifie d as f oll o ws: 
 S yst olic bl o o d press ure: < 9 0 m m H g, 9 0 t o < 1 4 0 m m H g, a n d ≥ 1 4 0 m m H g. 
 Diast olic bl o o d press ure:  < 6 0 m m H g, 6 0 t o < 9 0 m m H g, a n d ≥ 9 0 m m H g. 
 Heart rate: < 6 0 b eats/ mi n, 6 0 t o < 1 0 0 beats/ mi n, a n d ≥ 1 0 0 beats/ mi n. 
 Res pirat or y rate: < 9 breat hs/ mi n, 9 t o < 2 0 breat hs/ mi n, ≥ 2 0 breat hs/ mi n. 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 4  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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 B o d y te m perat ure < 3 6. 5º C, 3 6. 5º C t o < 3 7. 5º C, 3 7. 5º C t o < 3 8. 5º C, a n d ≥ 3 8. 5 º C 
S u bjects will be s u m marize d wit h c o u nts a n d perce nta ges b y t hese cate g ories. 
Ort h ostatic h y p ot e nsi o n is defi ne d as a s yst olic bl o o d press ure d ecrease of ≥ 2 0 m m H g or a 
diast ol ic bl o o d press ure decrease of ≥ 1 0 m m H g wit hi n 3 mi n utes of sta n di n g. At visits w he n 
ort h ostatic vital si g ns are perf or me d at tri plicate, a s u bject will be defi ne d as ha vi n g ort h ostatic 
h y p ote nsi o n if it occ urre d bet wee n a n y pair of t h e s u pi ne a n d sta n di n g m eas ure me nts. 
N u m ber a n d p erce nta ge of s u bjects wit h ort h ostatic h y p ote nsi o n will be prese nte d b y treat me nt 
g r o u p a n d visit, as well as at least after t he st u d y e ntr y bas eli ne. 
All vital si g ns will be liste d. 
5. 5  
E lectr oc a r di o gr a m 
E C G will be perf or me d at Scree ni n g, Visit 5 a n d Visit 7/ Earl y ter mi nati o n. T he f oll o wi n g 
para meters will be rec or de d: Ve ntric ular Rate ( b eats/ mi n), P R I nter v al ( msec), Q R S D urati o n 
( msec), Q T I nter v al ( msec), R R I nt er val ( msec), R h yt h m Assess me nt ( N or mal Si n us R h yt h m V R 
6 0- 1 0 0 b p m, Si n us Bra d ycar dia V R less t ha n 6 0 b p m, Si n us Tac h ycar dia V R greater t h a n 1 0 0 
b p m or Ot he r) a n d O verall I nter pretati o n ( N or mal, A b n or mal N ot Cli nicall y Si g nifica nt ( N C S) 
or A b n or mal Cli nicall y Si g nifica nt ( C S)). 
Q T I nter val c orrecte d usi n g Fri deri cia’s f or m ula ( Q Tc F) will be cal c ulate d as f oll o ws: 
𝑄𝑇𝑐𝐹=
𝑄𝑇
√( 𝑅𝑅
1 0 0 0 )
3
 
Ve ntric ular rate a n d E C G i nter vals will be s u m marize d descri pti vel y wit h t heir c ha n ges fr o m 
st u d y e ntr y b aseli ne b y visit a n d treat me nt gr o u p f or t he Ra n d o mize d A nal ysis Set. St u d y 
ba seli ne val ues will als o be s u m mariz e d f or t he Safet y A nal ysis Set. 
R h yt h m assess me nt a n d o verall i nter pretati o n will be s u m marize d cate g ori call y b y visit a n d 
treat me nt gr o u p. 
S h ifts i n o verall i nter pret ati o n fr o m st u d y e ntr y baseli ne t o t he last a vaila bl e p ost- baseli ne 
assess me nt will be ta b ulate d. 
A d diti o nall y, E C G para meters will be classifie d as f oll o ws: 
P ar a meter  
C ate g ories of v al ue  
C ate g ories of c h a n ge fr o m 
b aseli ne  
Ve ntric ular rate  
< 6 0 beats/ mi n, 6 0 t o 1 0 0 
beats/ mi n, a n d > 1 0 0 
beats/ mi n  
< -1 0 beats/ mi n, -1 0 t o < 0 
beats/ mi n, 0 t o < 1 0 
beats/ mi n, a n d ≥ 1 0 
beats/ mi n.  
P R I nter v al  
< 1 2 0 msec, 1 2 0 t o 2 0 0 msec, 
a n d > 2 0 0 msec  
< -1 msec, -1 t o 5 msec, a n d ≥ 
5 msec  
Q R S I nter v al  
< 6 0 msec, 6 0 t o 1 0 0 msec, 
a n d > 1 0 0 msec  
< 0 msec, 0 t o < 3 msec, a n d 
≥ 3 msec  
Q T I nter val  
< 2 0 0 msec, 2 0 0 t o 4 3 0 msec, 
> 4 3 0 t o 4 5 0 msec, > 4 5 0 t o 
5 0 0 msec, a n d > 5 0 0 msec  
< 3 0 msec, 3 0 t o < 6 0 ms ec, 
a n d ≥ 6 0 msec  


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 5  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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R R I nter v al  
< 6 0 0 msec, 6 0 0 t o 1 0 0 0 
mse c, a n d > 1 0 0 0 msec  
< -3 3 msec, - 3 3 t o < 1 2 
msec, a n d ≥ 1 2 msec  
Q Tc F I nter val  
< 2 0 0 msec, 2 0 0 t o 4 3 0 msec, 
> 4 3 0 t o 4 5 0 msec, > 4 5 0 t o 
5 0 0 msec, a n d > 5 0 0 msec  
< 3 0 msec, 3 0 t o < 6 0 ms ec, 
a n d ≥ 6 0 msec  
S u bjects will be s u m marize d b y n u m ber a n d perce nta ge i n eac h of t he cate g ories a b o ve b y visit 
an d treat me nt gr o u p. 
All res ults will be liste d. 
5. 6  
P h ysic al E x a mi n ati o n 
P h ysical e x a mi nati o n will be perf or m e d at Scree ni n g a n d Visit 7/ Earl y T er mi nati o n. T he 
f oll o wi n g b o d y s yste ms will be e x a mi ne d: Gastr oi ntesti nal; Re pr o d ucti ve/ Breast; 
Car di o vasc ular; E n d o cri ne; Ge neral A p peara n ce; Hea d, E yes, E ars, N os e, T hr oat; 
M usc ul os keletal; Ne ur ol o gic; Peri p heral V asc ular; Ps yc hiatric; Ge nit o uri nar y/ R e nal; 
Res pirat or y; Der mat ol o gic. Eac h s yste m will be cl assifie d as N or m al, A b n or mal N ot Cli nicall y 
Si g nifica nt ( N C S) or A b n or mal Cli nicall y Si g nifi ca nt ( C S). 
N u m ber a n d p erce nta ge of s u bjects wit h eac h ass ess me nt res ult will be ta b ulate d b y b o d y 
s yste m, visit a n d treat me nt gr o u p f or t he Ra n d o mi ze d A nal ysis Set. St u d y Baseli ne Val ues will 
als o be s u m marize d f or t he Safet y A nal ysis Set. 
All res ults will be liste d. 
5. 7  
C - S S R S 
C ol u m ba S uici de Se verit y Rati n g Scale will be a d mi nistere d at eac h visit. Baseli ne/ Scree ni n g 
ve rsi o n will be a d mi nistere d at t he scree ni n g visit a n d Si nce Last Visit versi o n at all s u bse q ue nt 
visits. 
N u m ber a n d pr o p orti o n of s u bjects wit h a n y s uici d al i deati o n or a n d a n y s ui ci dal be ha vi or will 
be prese nt e d b y visit a n d treat me nt gr o u p. 
Ti me fr o m st u d y e ntr y baseli ne t o t he first a p peara nce of s uici dal i deati o n or s uici dal be ha vi or 
will be s u m mariz e d descri pti vel y f or t h os e s u bjects w h o de vel o p s uici dal i deati o n or s uici dal 
be ha vi or d uri n g t he st u d y (i.e. d o n ot ha ve s uici d al i deati o n or s uici dal be ha vi or at st u d y e ntr y 
baseli ne, b ut re p ort it d uri n g t he st u d y). 
All re s ults will be liste d. 
5. 8  
G C SI 
Gastr o paresis Car di nal S y m pt o m I n de x ( G C SI) q uesti o n naire will be a d mi nistere d at Visit 1 a n d 
Visit 7/ Earl y Ter mi nati o n. G C SI c o ntai ns 3 s u bsc ales: p ost- pra n dial f ull ness/earl y s atiet y 
( q uesti o ns 4- 7), na usea/ v o miti n g ( q uesti o ns 1- 3) a n d bl oati n g ( q uesti o ns 8- 9).  
T otal sc ores will be calc ulate d f or t he e ntire q uesti o n naire a n d eac h s u bs cal e. If at least o ne 
q uesti o n is n ot a ns were d t he n t he t otal sc ore a n d t he affecte d s u bs cale sc ore will n ot be 
calc ulate d. 
I n di vi d ual q uesti o n sc ores, t otal sc ore a n d s u bscale t otal sc ores as well as t heir c ha n ges fr o m t he 
st u d y e ntr y b aseli ne will be s u m mariz e d descri pti vel y b y visit a n d treat me nt gr o u p f or t he 
R a n d o mize d A nal ysis Set. St u d y e ntr y baseli ne v al ues will als o be s u m marize d f or t he Safet y 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 6  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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P o p ulati o n. 
All res ults will be liste d. 
5. 9  
P ri o r a n d C o nc o mit a nt Me dic ati o ns 
Pri or me dicati o ns are d efi ne d as me dicati o ns ta ke n pri or t o t he st u d y a n d st o p pe d bef ore t he 
first d ose of t he st u d y dr u g (I R C D- L D i n t he D ose A dj ust me nt peri o d).  C o nc o mita nt 
me dicati o ns are d efi ne d as me dicati o ns ta ke n w hile a s u bject t o o k st u d y dr u g, i.e. 
me dicati o ns wit h st o p date o n or after t he date of t he first a d mi nistrati o n of t he st u d y dr u g or 
t h ose t hat are o n g oi n g. 
Pri or a n d c o nc o mita nt m e dicati o ns will be c o de d usi n g W H O Dr u g Dicti o nar y versi o n 
Marc h 2 0 1 9.  
Use of pri or a n d c o nc o mita nt me dicati o ns will be se parat el y s u m marize d b y A T C class (t he 
hi g hest a v aila ble le vel), preferre d n a me, treat me nt gr o u p a n d st u d y p eri o d ( D ose 
A dj ust me nt, I P X 2 0 3 C o n versi o n a n d D o u ble- Bli n d treat me nt). A me di cati o n will be 
assi g ne d t o all peri o ds d uri n g w hic h it was ta ke n at least o nce. A s u bject re p orti n g t he sa m e 
me dicati o n m ore t ha n o n ce will be c o u nte d o nl y o nce f or t h at me dicati o n n a me; si milarl y, a 
s u bject re p orti n g se v eral me dicati o ns i n a n A T C class will be c o u nte d o nce f or t hat class. 
T he s u m mar y will be or dere d al p h a beticall y b y A T C class a n d preferre d n a me. 
C o nc o mita nt me dicati o ns will als o be gr o u pe d i nt o vari o us a nti- P D me dicati o n classes: 
 A ma nta di ne 
 selecti ve M A O- B i n hi bit ors 
 a ntic h oli ner gic P D me dicati o ns 
 d o pa mi ne a g o nists 
 ot hers 
as well as a nti de pressa nts, slee p ai ds, a n d ot hers. 
Fre q u e ncies a n d perce nta ges of s u bjects ta ki n g t hese classes of m e dicati o ns as well as eac h 
me dicati o n preferre d na me u n der t he cl ass will be s u m marize d b y tr eat me nt gr o u p a n d st u d y 
peri o d.  
All pri or a n d c o nc o mita nt me dicati o ns will be liste d. 
6  C O VI D -1 9 c o nsi der ati o ns f or a n al yses  
As t he st u d y will be partl y c o n d u cte d d uri n g t he C O VI D- 1 9 p a n de mic, a n u m ber of visits were 
dela ye d, ca ncelle d or c o n d ucte d re m otel y. T o acc o u nt f or t hese cir c u msta nces t he f oll o wi n g 
c ha n ges w ere i m ple me nt e d i n a nal ysis: 
1.  A ne w se nsiti vit y a n al ysis will be c o n d ucte d e x cl u di n g t he P D Diaries c ollecte d at Visit 
7/ E T t hat oc c urre d later t ha n pla n ne d ( secti o n 4. 7. 7 ) 
2.  S u bjects wit h D ose A dj ust me nt a n d I P X 2 0 3 C o n v ersi o n peri o ds e xte n de d b y m ore t h a n 
5 0 % of t he pla n ne d ti me will be e x cl u de d fr o m t he Per Pr ot oc ol p o p ulati o n ( secti o n 2. 2. 6 ) 
3.  Sa m ples f or la b orat or y t ests a n d E C G f or Visit 5 ca n be c ollecte d at Visits 4 or 6 ( secti o n 
5. 1 ) 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 7  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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4.  S u bjects w h o disc o nti n ue d f or reas o ns relat e d t o C O VI D- 1 9 p a n de mic will be s u m marize d 
se parat el y i n t he dis p ositi o n ta bles (secti o n 3. 1 ) 
5.  A d verse e ve nts i n s u bjects wit h C O VI D - 1 9 will be s u m marize d se paratel y (secti o n 5. 2 ). 
6.  Pr ot oc ol de viati o ns relate d t o C O VI D- 1 9 will be i de ntifie d i n t he listi n g ( secti o n 3. 5 ) 
7  C h a n ges Fr o m Pr ot oc ol- S pecifie d A n al yses 
T here are n o d e viati o ns fr o m t he pr ot oc ol-s pecifie d safet y a n al ys es. 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 3 8  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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8  R E F E R E N C E S 
St u d y pr ot oc ol: A Ra n d o mize d C o ntr olle d St u d y t o C o m pare t he Safet y a n d Efficac y of 
I P X 2 0 3 wit h I m me diat e- Release Car bi d o p a- Le v o d o pa i n Par ki ns o n’s Disease Patie nts wit h 
M ot or Fl uct uati o ns, A me n d me nt 4, Se pte m ber 2 8, 2 0 1 8. 


I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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9  A P P E N DI C E S 
9. 1  
Sc he d ule of e ve nts 
T a ble 2 Sc he d ule of E ve nts 
Assess me nt  
Scree ni n g  
3 Wee ks of 
I R C D-L D 
D ose 
A dj ust me nt  
4 Wee ks of I P X 2 0 3 D ose 
C o n versi o n  
1 3 Wee ks of D o u ble -Bli n d 
T her a p y  
Visit 1  
Visit 2  
Visit 3  
Visit 4 
R a n d o miz ati o n  
Visit 5  
Visit 6  
Visit 7/ St u d y 
E xit/ E arl y 
Ter mi n ati o n b  
St u d y Wee k a  
– 4  
0  
3  
5  
7  
1 0  
1 5  
2 0  
I C F & HI P A A A ut h ori z ati o nc   
X  
 
 
 
 
 
 
 
C o nt a ct I W R S  
X  
X  
X  
X  
X  
X  
X  
X  
R a n d o mi z ati o n  
 
 
 
 
X  
 
 
 
I n cl usi o n/ E x cl usi o n  
X  
X  
 
 
 
 
 
 
M e di c al Hist or y  
X  
 
 
 
 
 
 
 
P h ysi c al E x a mi n ati o n  
X  
 
 
 
 
 
 
X  
Vit al Si g ns d   
X  
X  
X  
X  
X  
X  
X  
X  
H ei g ht a n d W ei g ht  
X  
 
 
 
 
X e 
 
X e 
C -S S R S f  
X  
X  
X  
X  
X  
X  
X  
X  
Cli ni c al L a b or at or y T ests g   
X  
 
 
 
 
X  
 
X  
Uri n e Pr e g n a n c y T est  
X  
 
 
 
 
 
 
 
Uri n e S cr e e n f or Dr u g A b us e  
X  
 
 
 
 
 
 
 
Al c o h ol Br e at h T est  
X  
 
 
 
 
 
 
 
E C G  
X  
 
 
 
 
X  
 
X  
M o C A h   
X  
 
 
 
 
 
 
 
M D S -U P D R S P arts I -I V  
X i 
X  
X  
 
X  
X  
X  
X  




I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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b St u d y E xit pr oce d ures t o be c o n d ucte d at t he e n d of Visit 7 or d uri n g a n earl y ter mi nati o n visit. 
c S u bj ects e nr olle d at sites i n t he U nite d States ( U S) m ust si g n HI P A A a ut h orizati o n pri or t o t he c o n d uct of a n y st u d y-s p ecific pr oce d ures. 
d Rec or d vital si g ns ( bl o o d press ure, heart rate, res pirat or y rate, a n d te m perat ure [ Scree ni n g a n d St u d y E xit o nl y]) after s u bj ect has bee n resti n g s u pi ne 
f or at least 5 mi n utes, t he n rec or d ort h ostatic bl o o d press ure a n d heart rate after s u bj ect has bee n sta n di n g f or a p pr o xi mat el y 2 mi n utes. At Visits 1 a n d 
4, ort h ostatic vital si g ns ( bl o o d press ure a n d heart rate) will be perf or me d i n tri plicate, eac h set se parate d b y at least 1 5 mi n utes fr o m t he pre vi o us set. 
e Wei g ht o nl y. 
f C- S S R S: C ol u m bia S uici de Se verit y Rati n g Scale. See A p pe n di x O of t he pr ot oc ol. 
g See A p pe n di x R of t he pr ot oc ol. 
h M o ntreal C o g niti ve Assess me nt i n t he “ O n” state: see A p pe n di x D of t he pr ot oc ol. 
i At Scree ni n g M D S- U P D R S P arts I t hr o u g h I V will be d o ne i n b ot h t he “ O n” a n d “ Off” state (see A p pe n di x E) of t he pr ot oc ol. 
j See A p pe n di x F of t he pr ot oc ol. 
k
l 
m
n
o See A p pe n di x K of t he pr ot oc ol. 
p
q
r 
s Trai n at Scree ni n g a n d t he n as nee de d at s u bse q ue nt visits. P erf or m c o nc or da nce testi n g at Scree ni n g. 
t Dis pe nse P D Diaries at Scree ni n g a n d Visits 1, 3, 4, 5, a n d 6. Call s u bj ects 4 da ys pri or t o Visits 1, 2 a n d 4- 7 t o re mi n d t he m t o c o m plete P D Diaries. 
S u bj ects rec or d diar y i nf or mati o n f or 3 c o nsec uti ve da ys i m me diatel y pri or t o eac h of t he visits ( Da ys - 3, - 2, a n d - 1). Call s u bj ects t he da y pri or t o eac h 
visit t o re mi n d t he m t o bri n g t he P D Diaries, e m pt y me dicati o n b ottles, a n d a n y u n use d st u d y dr u g t o t he office. 
u Re vie w P D Diaries at Visits 1, 2, a n d 4- 7.  
v P ost- Scree ni n g re mi n der p h o ne call: N otif y i n di vi d uals w h o s uccessf ull y c o m plete scre e ni n g pr oce d ures f oll o wi n g re vie w of all st u d y e ntr y criteria 
a n d cli nical la b o rat or y res ults t hat t he y ma y c o nti n ue i n t he st u d y. T he i nter val bet wee n Scree ni n g a n d Visit 1 s h o ul d n ot e xcee d 4 wee ks. 
w Re mi n der p h o ne calls f or Visits 1 t hr o u g h 4: I n a d diti o n t o t he calls disc usse d a b o ve, ma ke re g ular p h o ne calls (a p pr o xi mat el y e ver y 1 t o 3 da ys) t o 
s u bj ects t hr o u g h o ut t he I R C D- L D d ose-a dj ust me nt a n d I P X 2 0 3 d ose-c o n versi o n peri o ds t o e val uate eac h s u bj ect’s a dj ust me nt t o t he st u d y me dicati o n 
re gi me n. 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 4 2  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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9. 2  
C o de F r a g me nts 
9. 2. 1  M M R M A n al y si s of t h e P ri m a r y E n d p oi nt a n d C o nti n u o u s S e c o n d a r y E n d p oi nt s 
 
p r o c  m i x e d  d a t a = … ;  
  c l a s s  t r t p n  s i t e g r 1  v i s i t n u m  u s u b j i d ;  
  m o d e l  c h g  =  b a s e  t r t p n  v i s i t n u m  t r t p n * v i s i t n u m  /  d d f m = k r  r e s i d u a l  
o u t p = r e s i d ;  
  r e p e a t e d  v i s i t n u m  /  s u b j e c t = u s u b j i d  t y p e = U N ;  
  r a n d o m  s i t e g r 1 ;  
  l s m e a n s  t r t p n * v i s i t n u m  /  d i f f ;  
r u n ;  
 
N otes: 
4.  
T he i n p ut dataset i ncl u des o ne rec or d per s u bj ect per visit. 
5.  
Mea ni n g of t he varia bles: 
 T R T P N: treat me nt gr o u p 
 SI T E G R 1: p o ole d ce nter 
 VI SI T N U M: visit n u m ber 
 U S U BJI D: u ni q ue s u bject i de ntifier 
 C H G: val ue of t he e n d p oi nt 
 B A S E: baseli ne val u e of t he e n d p oi nt 
6.  
If t he m o del d oes n ot c o n ver ge wit h t y pe = U N, f urt her c o varia nc e str uct ur e t y p es are t o 
be trie d as e x plai ne d i n secti o n 4. 4. 2 . 
7.  
F or c o v aria n ce str uct ur es ot her t ha n U N a n d C S, a n a d diti o nal state me nt “ra n d o m 
us u bji d” nee ds t o be a d d e d. 
8.  
O U T P o pti o n sa ves resi d uals f or n or malit y tests (see secti o n 9. 2. 3 ). 
9. 2. 2  C M H T e st f o r C at e g o ri c al E n d p oi nt s 
 
p r o c  f r e q  d a t a = . . . ;  
  t a b l e s  s i t e g r 1 * t r t p n * a v a l c  /  c m h ;  
r u n ;  
 
Perce nt differe n ce wit h 9 5 % c o nfi de n ce i nter val: 
p r o c  f r e q  d a t a = . . . ;  
  t a b l e s  t r t p n * a v a l c  /  r i s k d i f f ;  
r u n ;  
N otes: 
1.  
T he i n p ut dataset i ncl u des o ne rec or d per s u bj ect 
2.  
Mea ni n g of t he varia bles: 
 T R T P N: treat me nt gr o u p 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 4 3  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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 SI T E G R 1: p o ole d ce nter 
 A V A L C: o utc o m e (e. g. Y or N) 
9. 2. 3  N o r m alit y T e st f o r R e si d u al s 
p r o c  u n i v a r i a t e  d a t a = r e s i d u a l s  n o r m a l ;  
  v a r  r e s i d ;  
r u n ;  
N otes: i n p ut datasets c o mes fr o m t he O U T P o pti o n i n t he mai n a nal ysis m o del. 
9. 2. 4  H o m o g e n eit y of V a ri a n c e T e st 
p r o c  g l m  d a t a = … ;  
  c l a s s  t r t p n ;  
  m o d e l  c h g  =  t r t p n ;  
  m e a n s  t r t p n  /  h o v t e s t ;  
r u n ;  q u i t ;  
N otes: 
1.  
T he i n p ut dataset i ncl u des o ne rec or d per s u bj ect fr o m Visit 7/ E T o nl y. 
2.  
Me a ni n g of t he varia bles is t he sa me as i n secti o n 9. 2. 1 . 
9. 2. 5  Wi l c o x o n R a n k- S u m T e st f o r S e n siti vit y A n al y si s 
p r o c  n p a r 1 w a y  w i l c o x o n  d a t a = … ;  
  c l a s s  t r t p n ;  
  v a r  c h g ;  
  o u t p u t  o u t = W i l c o x o n O u t ;  
r u n ;  
N otes: 
1.  
I n p ut dat aset i ncl u des o n e rec or d per s u bj ect fr o m Visit 7 wit h i m p utati o ns 
2.  
Mea ni n g of t he varia bles is t he sa me as i n secti o n 9. 2. 1 . 
9. 2. 6  A N C O V A M o d el f o r C o m pl et e C a s e o r Si n gl e L O C F / B O C F I m p ut ati o n A n al y s e s 
p r o c  m i x e d  d a t a = . . . ;  
  c l a s s  t r t p n  s i t e g r 1 ;  
  m o d e l  c h g  =  b a s e  t r t p n   /  s s 3 ;  
  r a n d o m  s i t e g r 1 ;  
  l s m e a n s  t r t p n  /  d i f f ;  
r u n ;  
N otes: 
1.  
T he i n p ut dataset i ncl u des o ne rec or d per s u bj ect fr o m Visit 7 o nl y. 
2.  
F or t he C o m plete Case a nal ysis o nl y s u bjects fr o m t he C o m pleters A nal ysis Set are use d 
3.  
F or t he Si n gle L O C F/ B O C F i m p utati o n a nal ysis C H G at Visit 7 ma y b e i m p ute d if 
a p plica ble. 
4.  
Mea ni n g of t he varia bles is t he sa me as i n secti o n 9. 2. 1 . 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 4 4  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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9. 2. 7  Sit e a s Fi x e d Eff e ct 
p r o c  m i x e d  d a t a = … ;  
  c l a s s  t r t p n  s i t e g r 1  v i s i t n u m  u s u b j i d ;  
  m o d e l  c h g  =  b a s e  t r t p n  v i s i t n u m  s i t e g r 1  t r t p n * v i s i t n u m  /  d d f m = k r ;  
  r e p e a t e d  v i s i t n u m  /  s u b j e c t = u s u b j i d  t y p e = U N ;  
  l s m e a n s  t r t p n * v i s i t n u m  /  d i f f ;  
r u n ;  
All n otes t o t he pri mar y a nal ysis ( s ecti o n 9. 2. 1 ) are a p plica bl e. 
9. 2. 8  P att e r n- Mi xt u r e M o d el 
T he f oll o wi n g ste ps n ee d t o be re peate d f or eac h of t he 4 dr o p o ut patter ns s pecifie d i n secti o n 
4. 7. 8 . 
S te p 1. Efficac y data n ee ds t o be tra ns p ose d t o o n e rec or d per s u bj ect str uct ure wit h res p o nses 
fr o m differe nt visits i n differe nt varia bl es. I n t he e x a m ples bel o w res p o nses fr o m Visits 5, 6 a n d 
7 are de n ot e d as C H G 5, C H G 6 a n d C H G 7. 
Ste p 2 . I m p ute i nter mitte nt missi n g val ues 5 0 ti mes: 
p r o c  m i  d a t a = . .  o u t = . . .  n i m p u t e = 5 0  s e e d = 2 0 3 1 6 0 2 ;  
  v a r  c h g 5 - c h g 7 ;  
  m c m c  c h a i n = m u l t i p l e  i m p u t e = m o n o t o n e ;   
r u n ;  
N ote: pre -s pecifie d see d is necessar y t o e ns ure res ults are re p eata ble a n d a me na ble t o vali dati o n 
b y d o u ble -pr o gra m mi n g.  T he val ue is c h ose n ar bitraril y b ase d o n t he pr ot oc ol n u m ber.  
Ste p 3 . I m p ute tr aili n g missi n g data (after dis c o nti n uati o n): 
p r o c  m i  d a t a = . . .  o u t = . . .  n i m p u t e = 1  s e e d = 2 0 3 1 6 0 2 ;  
  v a r  t r t p n  s i t e g r 1  b a s e  c h g 5 - c h g 7 ;  
  c l a s s  t r t p n  s i t e g r 1 ;  
  m o n o t o n e  r e g ( c h g 5 - c h g 7 ) ;  
r u n ;  
N otes: 
1.  
T he i n p ut dataset is t he o ut p ut fr o m t he pre vi o us ste p. 
2.  
T he mea ni n g of t he v aria bles is t he sa me as i n t he pri mar y m o del ( secti o n 9. 2. 1 ). 
3.  
Missi n g val ues are i m p ute d base d o n re gressi o n usi n g t he fact ors fr o m t he pri mar y 
m o del. 
Ste p 4 . Tra ns p ose t he o ut p ut dataset bac k t o vertical str uct ure. 
Ste p 5 . Pe nalizati o n. F or eac h s u bject i n t he I P X 2 0 3 treat me nt gr o u p i n t he c urre nt dr o p -o ut 
patter n, f or eac h i m p ute d val ue after t he s u bject’s disc o nti n uati o n, ge nerate 2 1 pe nalize d rec or ds. 
F or t he p e nalizati o n fact or p f ra n gi n g fr o m 0 % t o 1 0 0 % i n 5 % i ncre me nts, re d uce t h e e n d p oi nt 
val ue b y pf  * E F F E C T _ SI Z E / 1 0 0 %, w here E F F E C T _ SI Z E is t he L S Mea n differe n ce b et wee n 
I P X 2 0 3 a n d I R C D-L D ar ms fr o m t he pri mar y m o del ( secti o n 9. 2. 1 ). 
S te p 6. A nal ysis of i m p ute d data. F or eac h of t he 5 0 i m p utati o ns a n d 2 1 pe nalizati o n fact ors 
perf or m t he pri mar y a n al ysis as i n secti o n 9. 2. 1 . 
S te p 7. C o m bi ne m ulti ple i m p utati o n res ults f or eac h pe n alizati o n fact or: 


I m pa x La b orat ories, I n c 
C O N FI D E N TI A L  
Pa ge 4 5  of 4 5  
 
I P X 2 0 3– B 1 6 -0 2  
Statistical A nal ysis Pla n  
 
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p r o c  m i a n a l y z e  p a r m s = … ;  
   b y  p f ;  
   m o d e l e f f e c t s  t r t p n * v i s i t n u m ;  
r u n ;  
N otes: 
1.  
T he i n p ut dataset ( par ms o pti o n) is L S Mea ns or L S Mea ns Differe nces ( Diffs) datas et 
fr o m t he pri mar y m o del fr o m t he pre vi o us ste p. 
2.  
pf  is t he pe nalizati o n fact or. 
9. 2. 9  M ulti pl e I m p ut ati o n R a n k- B a s e d A n al y si s 
Ste ps 1- 4  of t his pr ocess will t he sa me as i n t he Patter n Mi xt ure M o del (secti o n 9. 2. 8 ). 
Ste p 5 . A nal ysis of i m p ute d data. F or eac h of t he 5 0 i m p utati o ns perf or m t he ra n k- b ase d a n al ysis 
as i n secti o n 9. 2. 5 . 
S te p 6. I n or der t o c o m bi ne t he m ulti ple i m p utati o n res ults i n t he ne xt ste p, a d d a vari a ble St d Err 
t o t he o ut p ut dataset ( Wilc o x o n O ut) fr o m t he pre vi o us ste p, e q ual 1 o n all r ec or ds. T his r eflects 
t he fact t hat Wilc o x o n statistic has as y m pt otic sta n dar d n or mal distri b uti o n ( wit h mea n of 0 a n d 
sta n dar d de viati o n of 1) u n der t he n ull h y p ot h esis of n o treat me nt effect. 
S te p 7. C o m bi ne m ulti ple i m p utati o n res ults: 
p r o c  m i a n a l y z e  d a t a = W i l c o x o n O u t ;  
   m o d e l e f f e c t s  Z _ W I L ;  
   S t d E r r  S t d E r r ;  
r u n ;