A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination of Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy
Phase: PHASE2
Conditions: Postoperative Pain
Sponsor: Nevakar, Inc.

 
 
 
 
 
 
 
 
 
Cli ni c al Tri al Pr ot o c ol 
  
A P hase 2, Ra n d o mize d, D o u bl e- Bli n d, Place b o- a n d C o m p arat or- 
C o ntr olle d Trial t o E v al uate t h e Safet y a n d Efficac y of C o m bi nati o n 
 Pre ga bali n a n d Aceta mi n o p he n C o m pare d t o Aceta mi n o p he n 
a n d Place b o i n S u bjects U n der g oi n g B u ni o nect o m y 
Pr ot oc ol N u m ber:  C P- N V K 0 0 9- 0 0 0 5, Versi o n 2. 0, A me n d me nt 0 2 
D ate d:  0 8-J u n e- 2 0 2 0 
Cli nic al Tri als. g o v I de ntifier:  N C T 0 4 4 9 5 2 8 3 
S p o ns or:  Ne v a k ar, I nc. NJ 0 8 8 0 7 
 
 

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 3 5  of 1 0 3  
3.  
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
Ne va kar, I nc.  
N a me of I n vesti g ati o n al Pr o d uct:  
N V K 0 0 9 , a c o m bi nati o n of pre ga bali n ( P G B) 
 a n d 
 (aceta mi n o p he n [A P A P ] 
 
a d mi nistere d 
 (
 T he fi nal d ose of P G B is deter mi ne d b y t he C P-N V K 0 0 9 -0 0 0 4 st u d y . 
N a me of Acti ve I n gre die nts:  
Pre ga bali n ( P G B) a n d aceta mi n o p he n ( A P A P) 
Pr ot oc ol N u m ber:  
C P -N V K 0 0 9 -0 0 0 5  
Title of St u d y:  
A P hase 2, Ra n d o mize d, D o u ble -Bli n d, Place b o - a n d C o m parat or -C o ntr olle d Trial t o E val uate t he Safet y 
a n d Efficac y of C o m bi nati o n 
 Pre ga bali n a n d Aceta mi n o p he n C o m pare d t o Aceta mi n o p he n a n d 
Place b o  i n S u bjects U n der g oi n g B u ni o nect o m y 
St u d y Ce nter(s):  
1  t o 3 st u d y ce nters ( U S) 
St u die d Peri o d ( 3 m o nt hs ):  
Esti mate d date first s u bject e nr olle d: J ul y 2 0 2 0  
Esti mate d date last s u bject c o m plete d: Se pte m ber  2 0 2 0  
P h ase of De vel o p me nt:  
P hase 2  
O bjecti ves:  
Pri m ar y:  
• 
T o e val uate t he efficac y of c o m bi nati o n P G B 
 a n d A P A P  
 a d mi nistere d 
 vs . 
place b o f or pai n c o ntr ol i n s u bjects u n der g oi n g b u ni o nect o m y.  
Sec o n d ar y:  
• 
T o e val uate t he efficac y of c o m bi nati o n P G B 
 a n d A P A P  
 a d mi nistere d 
 vs. 
c o m parat or ( A P A P  
 al o ne) f or pai n c o ntr ol i n s u bjects u n der g oi n g b u ni o nect o m y.  
• 
T o e val uate t he safet y a n d t olera bilit y of a c o m bi nati o n of P G B 
 a n d A P A P  
 
a d mi nistere d 
 i n a p ost o perati ve p o p ulati o n. 
O utc o me Me as ures:  
Pri m ar y E n d p oi nt : 
• 
S u m me d pai n i nte nsit y ( S PI) meas ure d b y t he n u meric rati n g scale (N R S) (A p pe n di x  1 ) c o m pare d 
bet wee n a c o m bi nati o n of P G B 
 a n d A P A P  
 a d mi nistere d 
 a n d place b o 
fr o m H o ur 0 t o H o ur  4 8 ( S PI 0 -4 8). 
Sec o n d ar y E n d p oi nts : 
•  
S PI c o m pare d bet wee n a c o m bi nati o n of P G B 
 a n d A P A P  
 a d mi nistere d 
 
a n d c o m parat or ( A P A P  
 al o ne) fr o m H o ur 0 t o H o ur  4 8 ( S PI 0 -4 8); 
• 
S PI c o m pare d bet wee n a c o m bi nati o n of P G B 
 a n d A P A P  
 a d mi nistere d 
 
c o m parat or  ( A P A P 
 al o ne) , a n d place b o f or t he f oll o wi n g ti me i nter vals: 
o  0 – 1 2 h o urs ; 
o  1 2 – 2 4 h o urs ; 

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 3 6  of 1 0 3  
o  1 2 – 4 8 h o urs.  
• 
Perce nta ges of  s u bjects w h o are o pi oi d free o ver ti me ( 1 2 -2 4  h o urs  a n d 1 2 -4 8  h o urs ); 
• 
Perce nta ges of s u bjects w h o d o n ot ta ke o pi oi d resc ue  (are o pi oi d free ) o ver vari o us ti me peri o ds 
(1 2 -2 4  h o urs a n d 1 2 -4 8  h o urs) ; 
• 
T he t otal c o ns u m pti o n of o pi oi d resc ue a nal gesia t hr o u g h 2 4 h o urs a n d t hr o u g h 4 8  h o urs;  
• 
T he t otal c o ns u m pti o n of resc ue a nal gesia;  
• 
Ti me t o first use of resc ue me dicati o n fr o m H o ur 0 ; 
• 
Perce nta ge of s u bjects usi n g resc ue me dicati o n ; 
• 
Patie nt Gl o bal Assess me nt ( P G A) of pai n c o ntr ol at 4 8 h o urs  (A p pe n di x  2 ); 
• 
S PI o ver ti me . 
T he safet y o utc o mes of t he st u d y are : 
• 
T he i nci de nce a n d se verit y of treat me nt-e mer ge nt a d verse e ve nts ( T E A Es ), i ncl u di n g cli nicall y 
si g nifica nt vital si g ns, electr ocar di o gra ms ( E C Gs), a n d cli nical la b orat or y test res ults data . 
• 
T he i nci de nce a n d se verit y of s o m n ole nce a n d dizzi ness as deter mi ne d b y t he Rea di ness f or 
Disc har ge M o difie d Al drete Sc ori n g S yste m ( A p pe n di x  3 ), i nclu di n g Acti vit y, Res pirati o n, 
Circ ulati o n, C o nsci o us ness , O x y ge nati o n , a n d Dizzi ness ( A p pe n di x  4 ) q uesti o n naires . 
T he P K o utc o mes of t he st u d y are : 
T he plas ma P K e n d p oi nts f or P G B a n d A P A P , t o be calc ulate d fr o m sa m ples ta ke n pri or t o  a n d after eac h 
  
 i ncl u di n g: 
• 
Ma xi m u m o bser ve d c o nce ntrati o n ( C
ma x ); 
• 
Mi ni m u m o bser ve d c o nce ntrati o n ( C
mi n ). 
Met h o d ol o g y:  
T his is a p hase 2 , m ulti--ce nter, ra n d o mize d, d o u ble -bli n d, parallel -gr o u p, place b o - a n d c o m parat or -
c o ntr olle d st u d y . 
S u bjects will u n der g o a Scree ni n g Visit ( Da y -4 2 t o Da y -2 ). Pre -o perati ve assess me nts will be c o n d ucte d 
wit hi n 2 4 h o urs pri or t o s ur ger y  (o n eit her Da y  -1  or Da y 1 pri or t o s ur ger y ) a n d pri or t o a n y d osi n g. 
S u bjects sc he d ule d f or b u ni o nect o m y s ur ger y w h o meet all of t he i ncl usi o n criteria a n d n o ne of t he 
e xcl usi o n criteria state d bel o w will be e nr olle d a n d ra n d o mize d  ( Da y 1). S u bjects a n d all st u d y staff 
perf or mi n g st u d y assess me nts will be bli n de d t o treat me nt all ocati o n. 
O n Da y 1, t he first d ose of st u d y dr u g  or place b o will be a d mi nistere d a p pr o xi matel y 3 0  t o 9 0 mi n utes 
bef ore s ur ger y ( p re-S ur ger y  
 # 1 ) w he n t he s u bject is i n t he pre-o perati ve area . 
 are 
a p pr o xi matel y 1 5 mi n utes.  S ur ger y will b e perf or me d a p pr o xi matel y wit hi n t he ne xt h o ur, wit h e n d of 
s ur ger y (i.e., c o m pleti o n of last s ut ure) desi g nate d as H o ur  0 . T he sec o n d d ose of st u d y dr u g or place b o 
will be a d mi nistere d i n t he p ost -a nest hesia care u nit ( P A C U) at + 3 0 mi n utes ( ± 3 0 mi n utes) fr o m H o ur 0 
(p ost -s ur ger y 
 # 2). St u d y  dr u g  or place b o will be a d mi nistere d  e ver y 8 h o urs (± 2 mi n utes) relati ve 
t o pre -s ur ger y 
 # 1 a n d e ver y 6  h o urs (± 2  mi n utes) relati ve t o p ost -s ur ger y 
 # 2 c o nti n ui n g 
t hr o u g h 4 8 h o urs . T he A P A P d ose i n t he c o m bi nati o n  
 gi ve n e ver y 8 h o urs a n d t he A P A P d ose 
al o ne gi ve n e ver y 6 h m ust n ot e xcee d 4 0 0 0 m g i n a 2 4 -h o ur peri o d. ( 
  
 Pac ka ge I nsert, 
2 0 1 8).  T he Sc he d ule of  
 is prese nte d i n Ta ble 4 . S u bjects will re mai n i n t he researc h u nit f or at 
least 4 8  h o urs p ost -s ur ger y ( disc har ge) as l o n g as t he y are n o l o n ger se date d, a n d all assess m e nts are 
c o m plete d . S u bjects will be re q ueste d t o ret ur n t o t he cli nical researc h u nit ( C R U) o n Da y  7 ( ± 1  da y) f or a 
f oll o w-u p safet y visit . If a n A E relate d t o st u d y dr u g is re p orte d or is o n g oi n g at t he F oll o w-u p/ E n d of 
St u d y ( E O S) visit o n Da y 7, a s u bj ect s h o ul d be f oll o we d u ntil a p pr o priate res ol uti o n of t he A E(s) as 
descri be d i n t he pr ot oc ol ( Secti o n 1 0. 7 ). 
 

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 3 8  of 1 0 3  
R a n d o miz ati o n Pr oce d ure:  
Eli gi ble s u bjects will be ra n d o mize d o n Da y 1 i n a 2: 2: 1 rati o t o recei ve eit her a c o m bi nati o n of P G B 
 a n d A P A P  
 a d mi nistere d 
 ( Gr o u p A), A P A P  
 
 
 ( Gr o u p B), or  
 
place b o 
 ( Gr o u p C). Ra n d o mize d s u bjects will recei ve eit her dr u g or place b o per t heir treat me nt 
all ocati o n (see treat me nt gr o u ps bel o w) . All s u bjects will recei ve 
 
 of eit her st u d y dr u g or 
place b o e ver y 8 h o urs (± 2 mi n utes)  relati ve t o  
 # 1 a n d e ver y 6  h o urs  (± 2 mi n utes) relati ve t o 
 # 2.T he Sc he d ule of  
 is  prese nte d i n Ta ble 4 . T o mai ntai n bli n di n g, all  
 f or all 
st u d y ar ms will be of i de ntical v ol u me. 
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 Criteri a:  
T o be eli gi ble f or t his st u d y, a s u bject m ust meet all  t he f oll o wi n g i ncl usi o n criteria: 
1.  Pr o vi de i nf or me d c o nse nt b y si g ni n g t he i nf or me d c o nse nt f or m (I C F) a p pr o ve d b y t he 
I nstit uti o nal Re vie w B oar d (I R B); 
2.  Be male or fe male  a ge d 1 8 -6 5 years ; 
3.  Be sc he d ule d t o u n der g o u nilateral first metatarsal b u ni o nect o m y ; 
4.  Be i n g o o d healt h a n d ca pa ble of u n der g oi n g a b u ni o nect o m y u n der a nest hesia as descri be d i n t he 
st u d y s ur gical a n d a nest hetic pr ot oc ol; 
5.  Wei g h bet wee n 5 0 a n d 1 0 0 k g ( b o d y mass i n de x [ B MI] < 3 2 k g/ m
2); 
6.  Ha ve n o a d diti o nal pla n ne d s ur ge ries ot her t ha n b u ni o nect o m y d uri n g t he c o urse of t he st u d y; 
7.  Ha ve ne gati ve  uri ne dr u g scree n f or dr u gs i n dicati ve of illicit dr u g use ( u nless res ults ca n be 
e x plai ne d b y a c urre nt prescri pti o n or acce pta ble o ver -t he-c o u nter me dicati o n at scree ni n g as 
deter mi ne d b y t he i n vesti gat or)  a n d n o detecta ble res ults o n t he alc o h ol test ( breat h or sali va) 
i n dicati ve of alc o h ol a b use at scree ni n g, a n d/ or pri or t o sur ger y ( ma y be re peate d if t he I n vesti gat or 
s us pects a false-p ositi ve res ult) . 
N ote:  F or t h ose s u bjects w h o test p ositive f or tetr a hy dr oc a n n a bi n ol ( T H C), if t hey are willi n g t o 
a bst ai n fr o m use or c o ns u m pti o n of T H C -c o nt ai ni n g pr o d ucts fr o m scree ni n g t hr o u g h e n d of t he 
s u bject’s p artici p ati o n i n t he st u dy, t hey m ay be all o we d t o p artici p ate i n t he st u dy.  
8.  Bi ol o gical f e male s u bjects  m ust be n o n -lactati n g, sterile ( bilateral t u bal li gati o n, bilateral  
sal pi n gect o m y, or h ysterect o m y), p ost-me n o pa usal f or at least 2 years, ha ve a part ner t hat is sterile, 
be a bsti ne nt, use  a hi g hl y effecti ve d o u ble - c o ntrace pti o n  met h o d ( h or m o nal pr otecti o n is 
i ns ufficie nt), or use a n F D A-a p pr o ve d c o ntrace pti ve f or greater t ha n 2  m o nt hs pri or t o t he 
scree ni n g visit a n d c o m mit t o a n acce pta ble f or m of birt h c o ntr ol f or t he d urati o n of t he st u d y a n d 
f or 3 0 da ys after c o m pleti o n of t he st u d y ; 
9.  Be willi n g a n d a ble t o c o m plete t he st u d y pr oce d ures a n d pai n scales a n d c o m m u nicate 
mea ni n gf ull y i n E n glis h wit h st u d y pers o n nel . 
E xcl usi o n Criteri a:  
A s u bject w h o meets a ny of t he f oll o wi n g e xcl usi o n criteria m ust be e xcl u de d fr o m t he st u d y : 
1.  H a ve a m e dic al c o n diti o n or hist or y  t hat i n t he I n vesti gat or’s o pi ni o n c o ul d a d versel y i m pact t he 
s u bject’s partici pati o n or safet y or t he c o n d uct of t he st u d y, or i nterfere wit h t he pai n assess me nts, 
i ncl u di n g t he f oll o wi n g: 
a. Seri o us breat hi n g diffic ulties or res pirat or y ris k fact ors (i ncl u di n g use of o pi oi d pai n 
me dici nes a n d ot her dr u gs t hat de press t he ce ntral ner v o us s yste m), a n d c o n diti o ns s uc h as 
c hr o nic o bstr ucti ve p ul m o nar y disease t hat re d uce l u n g f u ncti o n.  

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 3 9  of 1 0 3  
b.  H y perte nsi o n  ( u nc o ntr olle d) , car di o vasc ular disease, or hist or y of cere br o vasc ular e ve nts. 
H y perte nsi o n m ust be c o ntr olle d wit h o ut  k n o w n e n d or ga n da ma ge.  
c. C o nc urre nt pai nf ul c o n diti o ns t hat ma y re q uire a nal gesic treat me nt d uri n g t he st u d y 
peri o d.  
d.  Hist or y of si g nifica ntl y  re d uce d he patic or re nal f u ncti o n, a n gle cl os ure gla uc o ma, or 
c o n v ulsi ve dis or der.  
e. Rece nt hist or y of uri nar y rete nti o n.  
f. O pi oi d t olera nt, i.e., t he s u bject is c urre ntl y ta ki n g or has ta ke n a c hr o nic o pi oi d at a d ose 
greater t ha n or e q ual t o 2 0  m g m or p hi ne milli gra m e q ui vale nts ( M M E)  per da y ( m ore t ha n 
3 0  c o nsec uti ve da ys of dail y use) f or pai n i n t he 2  m o nt hs pri or t o s ur ger y.  
g.  Acti ve c uta ne o us disease, or ot her disease, at t he s ur gical site.  
h.  Peri p heral vasc ular disease, sic kle cell disease, vasc ular grafts, or vas os pastic dis or ders.  
i. 
K n o w n blee di n g dis or der or is ta ki n g a ge nts affecti n g c oa g ulati o n pre o perati vel y . Dee p 
ve n o us t hr o m b osis ( D V T) pr o p h yla xis of t he s ur ge o n’s c h oice is per mitte d 
p ost o perati vel y.  
j. 
Dia betes mellit us  ( u nc o ntr olle d). Dia betes me llit us m ust be c o ntr olle d wit h o ut k n o w n e n d 
or ga n da ma ge.  
k.  Hist or y of mali g na nc y i n t he past 2 years wit h t he e xce pti o n of s q ua m o us cell carci n o ma 
or basal cell carci n o ma.  
l. 
Pri or b u ni o nect o m y o n t he i n de x f o ot or ot her f o ot s ur ger y o n t he i n de x f o ot t hat c o ul d 
i m pact t he s ur ger y or data c ollecti o n e n d p oi nts. 
2.  Use of dis all o we d me dic ati o ns i ncl u di n g t he f oll o wi n g: 
a. Pai n me dicati o n ( o pi oi ds, N S AI Ds, C O X -2 i n hi bit ors, tra ma d ol, keta mi ne, cl o ni di ne, 
ga ba pe nti n, pre ga bali n, or ca n na bi n oi ds) wit hi n 2  da ys pri or t o Da y  1 . 
b.  Ce ntral ner v o us s yste m ( C N S) acti ve dr u gs s uc h as be nz o diaze pi nes, tric yclic 
a nti de pressa nts, ser ot o ni n a n d n ore pi ne p hri ne re u pta ke i n hi bit ors ( S N RIs), or selecti ve 
ser ot o ni n re u pta ke i n hi bit ors ( S S RIs) f or pai n wit hi n se ve n da ys pri or t o Da y 1 . T he se 
dr u gs are per mitte d f or n o n -pai n i n dicati o ns if t he d ose has bee n sta ble f or at least 3 0  da ys 
pri or t o Da y 1  a n d is pla n ne d t o re mai n sta ble t hr o u g h o ut t he st u d y . T he use of l oraze pa m 
a n d ot her slee p me dicati o ns, e xce pt t h ose c o ntai ni n g a nal gesic pr o per ties, is per mitte d. 
c. Use of pare nteral or oral c ortic oster oi d(s) wit hi n 1 4  da ys pri or t o Da y 1 . 
d.  A nti h y perte nsi ve a ge nt or dia betic re gi me n at a d ose t hat has n ot bee n sta ble f or at least 
3 0  da ys, or w hic h is n ot e x pecte d t o re mai n sta ble t hr o u g h o ut t he st u d y.  
e. Di g o xi n, warfari n (see e xce pti o n bel o w), lit hi u m, t he o p h ylli ne pre parati o ns, 
a mi n o gl yc osi des, a n d all a ntiarr h yt h mics e xce pt beta -bl oc kers, a n d use of a ntic o n v ulsa nts 
e xce pt be nz o diaze pi nes wit hi n 7  da ys pri or t o Da y 1  a n d t hr o u g h o ut t he st u d y.  
- Use of warfari n is all o we d, at t he i n vesti gat or’s discreti o n, f or D V T pr o p h yla xis after t he 
s ur ger y. 
3.  Si g nifica nt hist or y of aller gic reacti o ns or k n o w n i nt olera nce t o pre ga bali n or a n y ga ba pe nti n oi d, t o 
A P A P , t o a n y resc ue me dicati o n use d i n t he st u d y, or a n y me dicati o n use d i n t he s ur gical a n d 
a nest hetic pr ot oc ol.  
4.  Fe male s u bjects  ( bi ol o gical fe males o nl y) w h o are pre g na nt or lactati n g, w h o pla n t o get pre g na nt, 
or w h o ha ve a p ositi ve ser u m pre g na nc y test at Scree ni n g  or a p ositi ve uri ne pre g na nc y test  at 
eit her Da y -1 or Da y 1 pri or t o s ur ger y . 

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 4 0  of 1 0 3  
5.  Partici pate d i n a n ot her cli nical trial wit hi n 3 0  da ys, or pre vi o usl y partici pate d i n a cli nical st u d y 
wit h a si milar i n vesti gati o nal pr o d uct.  
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:  
All s u bjects will recei ve 
  
 of matc hi n g v ol u me e ver y 8  h o urs ( ± 2  mi n utes)  relati ve t o pre-
s ur ger y  
 # 1 a n d e ver y 6 h o urs ( ± 2 mi n utes) relati ve t o p ost-s ur ger y  
 # 2. 
A.  T he  in vesti gati o nal pr o d uct  (I P) is a c o m bi nati o n of P G B 
 a n d A P A P  
 
a d mi nistere d 
 a d mi nistere d q  8  h o urs ( 3 2 s u bjects). N ote: T he fi n al d ose of P G B is deter mi ne d b y 
t he C P-N V K 0 0 9 -0 0 0 4 st u d y . 
• 
Treat me nt G r o u p A  will recei ve a c o m bi nati o n of P G B 
 a n d A P A P  
 
a d mi nistere d 
 e ver y 8 h o urs  (± 2  mi n utes)  relati ve t o pre -s ur ger y 
 # 1, a n d 
 place b o  
f or 
 
 e ver y 6  h o urs  (± 2  mi n utes)  relati ve t o p ost -s ur ger y 
 # 2. 
T he Sc he d ule of  
 is prese nte d i n Ta ble 4 .  
Refere nce T her a p y, D os a ge a n d M o de of A d mi nistr ati o n:  
T he refere nce t hera pies are t he acti ve c o m parat or A P A P  
 
 a n d 
 
 ( place b o). 
B.  A P A P  
 via 
  
 a d mi nistere d e ver y 6 h o urs  (± 2  mi n utes)  ( 3 2 s u bjects). 
• 
Treat me nt G r o u p B will recei ve A P A P  
 via 
  
 e ver y 6 h o urs  (± 2  mi n utes)  
relati ve t o p ost-s ur ger y  
 # 2, a n d  
 place b o via  
  
 e ver y 8 h o urs (± 2  mi n utes)  
relati ve t o pre-s ur ger y  
 # 1. 
C.  
 place b o f or 
  
 ( 1 6 s u bjects). 
• 
Treat me nt G r o u p C will recei ve 
 place b o f or 
 
 e ver y 6 h o urs  relati ve t o p ost-
s ur ger y  
 # 2 a n d e ver y 8 h o urs  (± 2  mi n utes)  relati ve t o pre-s ur ger y  
 # 1. 
T he Sc he d ule of  
 is prese nte d i n Ta ble 4 . 
D ur ati o n of Tre at me nt:  
U p t o 4 8 h o urs.  
Criteri a f or E v al u ati o n:  
Effic ac y:  
• 
N R S (A p pe n di x  1 ) at t he f oll o wi n g ti me p oi nts p ost -H o ur 0  ( n ote t hese ti mes are fr o m last s ut ure 
of s ur ger y, n ot e n d of i nitial st u d y dr u g 
 : 1,  2, 4, 6, 8, 1 0, 1 2, 1 4, 1 6, 1 8, a n d 2 0  h o urs  
(± 1 5  mi n utes) , t he n e ver y 4 h o urs (± 1 5 mi n utes) u ntil disc har ge or earl y ter mi nati o n.  N ote:  E ver y 
eff ort will be ma de t o e ns ure t w o c o nsec uti ve N R S assess me nts are n ot misse d  or s ki p pe d. 
H o we ver, s h o ul d t w o N R S assess me nts be misse d d ue t o n or mal slee pi n g h o urs , a de viati o n will 
n ot be i nc urre d . Pai n assess me nts s h o ul d al wa ys be perf or me d 5  t o 1 0 mi n utes after t he e n d of 
 a n d P K sa m pli n g a n d/ or safet y bl o o d dra ws t o a v oi d o verla p wit h a n y pai n ass ociate d 
wit h bl o o d dra ws.  
• 
Patie nt -re p orte d N R S pri or t o eac h use of o pi oi d resc ue me dicati o n.  
• 
P G A at 4 8 h o urs  or at Earl y Ter mi nati o n ( E T)  (A p pe n di x  2 ). 

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 4 1  of 1 0 3  
Criteri a f or E v al u ati o n (c o nti n ue d):  
S afet y:  
• 
M o nit ori n g of A Es a n d S A Es , i ncl u di n g cli nicall y si g nifica nt cli nical la b orat or y fi n di n gs 
( he mat ol o g y, bi oc he mistr y, a n d uri nal ysis/ uri ne micr osc o p y), p h ysical e xa mi nati o n fi n di n gs, vital 
si g ns, a n d 1 2-lea d E C Gs. 
• 
M o nit ori n g of t he M o difie d Al drete Sc ori n g S yste m ( A p pe n di x  3 ) i ncl u di n g Acti vit y, Res pirati o n, 
Circ ulati o n, C o nsci o us ness , a n d O x y ge nati o n. 
P h ar m ac o ki netics:  
D eter mi nati o n of plas ma c o nce ntrati o ns of P G B a n d A P A P  pri or t o d osi n g ( C mi n ) a n d at t he e n d of 
eac h d osi n g ( C ma x ). 
St atistic al Met h o ds:  
S a m ple Size  
All h y p ot hesis tests will be perf or me d at a o ne -si de d 1 0 % le vel of si g nifica nce. T he sa m ple size of 
8 0  e val ua ble s u bjects ( 3 2  s u bjects: a c o m bi nati o n of P G B  
 a n d A P A P  
 a d mi nistere d 
 3 2 s u bjects: A P A P  
 al o ne, a n d 1 6 s u bjects: place b o) will pr o vi de 8 1 % p o wer t o detect a 
sta n dar dize d effect size of 0. 5 4 bet wee n t he c o m bi nati o n of P G B 
 a n d A P A P  
 
a d mi nistere d 
 a n d A P A P  
 al o ne treat me nt gr o u ps, a n d 8 0 % p o wer t o detect a sta n dar dize d effect 
size of 0. 6 6 bet wee n t he c o m bi nati o n of P G B 
 a n d A P A P  
 a d mi nistere d 
 a n d 
place b o treat me nt gr o u ps.  
Ge ner al C o nsi der ati o ns  
Statistical met h o ds will be f urt her o utli ne d i n a Statistical A nal ysis Pla n ( S A P) . Pr oce d ures o utli ne d i n t h e 
S A P will s u perse de pr ot oc ol -s pecifie d statistical met h o ds i n t he e ve nt of di ver ge nce. 
Data prese ntati o ns ‘ b y treat me nt gr o u p’ o utli ne d bel o w are ta ke n t o be defi ne d as b y treat me nt gr o u p (a 
c o m bi nati o n of P G B 
 a n d A P A P  
 a d mi nistere d 
 A P A P 
 f or 
 
 or 
place b o  f or 
 
All h y p ot hesis tests will be o ne -si de d a n d perf or me d at t he 1 0 % le vel of si g nifica nce. All c o nfi de nce 
i nter vals will be o ne-si de d 9 0 % c o nfi de nce i nter vals. 
Descri pti ve statistics (arit h metic mea n, sta n dar d de viati o n [ S D], me dia n, mi ni m u m a n d ma xi m u m) will be 
calc ulate d f or c o nti n u o us data as well as f or t he differe nce fr o m baseli ne f or eac h a p plica ble visit, w he n 
a p pr o priate . Descri pti ve statistics will be pr o vi de d b y treat me nt gr o u p . Fre q ue nc y c o u nts a n d perce nta ges 
will be calc ulate d f or cate g orical data.  
A n alysis Sets  
T he F ull A nal y sis Set (F A S ) is defi ne d as all ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of st u d y 
dr u g.  Patie nts will be a nal yze d acc or di n g t o t he treat me nt gr o u p t o w hic h t he y were ra n d o mize d. 
T he Safet y A nal ysis Set is defi ne d as all s u bjects  w h o recei ved  st u d y dr u g.  S u bjects will be a nal yze d 
acc or di n g t o t he act ual treat me nt t he y recei ve d . 
Per -Pr ot oc ol ( P P) A nal ysis Set is defi ne d as t he s u bset of F A S s u bjects w h o ha ve n o  maj or pr ot oc ol 
vi olati o ns t hat c o ul d p ote ntiall y i m pact t he i nter pretati o n o f t heir efficac y data. S u bjects will be a nal yze d 
acc or di n g t o t he act ual treat me nt t he y recei ve d.   
T he P K A nal ysis Set is defi ne d as all ra n d o mize d s u bjects w h o recei ve d a n y a m o u nt of A P A P a n d P G B, 
ha d n o pr ot oc ol de viati o ns affecti n g t he P K varia bles , a n d ha d s ufficie nt data t o all o w e val uati o n of least 
o ne P K para meter, w hic h are  C mi n  a n d C ma x . 
 
 

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 4 2  of 1 0 3  
St atistic al Met h o ds  (c o nti n ue d): 
Pr ot oc ol vi olati o ns will  be re vie we d a n d cate g orize d pri or t o data base l oc k a n d t he P P A nal ysis Set will 
als o be i de ntifie d at t hat ti me. T he s u bset of t he list of maj or pr ot oc ol de viati o ns t hat res ult i n e xcl usi o n of 
a s u bject fr o m t he P P A nal ysis Set will be d oc u me nte d pri or t o  u n bli n di n g t he st u d y treat me nt all ocati o n 
c o des. 
S u bjects w h o recei ve mi xe d treat me nt(s) will be a nal yze d acc or di n g t o t he treat me nt gr o u p t he y were 
ra n d o mize d t o f or all anal ysis sets . Me m bers hi p i n t he a nal ysis sets will be deter mi ne d bef ore u n bli n di n g 
a n y st u d y treat me nt c o des. I n ge neral, data listi n gs will i ncl u de o nl y s u bjects w h o recei ve st u d y treat me nt 
( F A S a n d/ or Safet y A nal ysis Set ). 
Dis p ositi o n, E nr ol lme nt, De m o gr a p hics, a n d Me dic al Hist ory  
S u m mar y ta bles usi n g descri pti ve statistics b y treat me n t gr o u p  w here a p plica ble w o ul d be pr o vi de d f or 
dis p ositi o n a n d e nr ol me nt data f or all ra n d o mize d  s u bjects, al o n g wit h s u bject listi n gs.  
De m o gra p hics a n d me dical hist or y will be s u m marize d b y treat me nt gr o u p  usi n g descri pti ve statistics a n d 
liste d b y s u bject usi n g t he S afet y A nal ysis Set . 
Effic acy  
T he S PI  will be calc ulate d usi n g the tr apez o i dal met h o d as t he area u n der t he c ur ve [ A U C ] of pai n i nte nsit y 
as meas ure d usi n g t he N R S (A p pe n di x  1 ) t hr o u g h vari o us ti me i nter vals u p t o 4 8 h o urs. T he A U C will be 
calc ulate d usi n g t he act ual assess me nt ti mes . F or S PI 0 -4 8 calc ulati o n, all a vaila ble N R S pai n i nte nsit y  sc ores 
(sc he d ule d pai n i nte nsit y , u nsc he d ule d pai n i nte nsit y a n d pre -resc ue pai n i nte nsit y ) fr o m 0 t o 4 8 h o urs, 
i ncl u di n g a n y i m p ute d val ues, will be use d i n t he calc ulati o n. A wi n d o we d last o bser vati o n carrie d f or war d 
(w L O C F ) i m p utati o n usi n g t he pre-resc ue pai n i nte nsit y val ues will be perf or me d f or sc he d ule d pai n 
i nte nsit y acc or di n g t o t he resc ue fre q ue nc y all o we d d uri n g t he sc he d ule d ti mes (e. g., 2  h o urs f or 
o x yc o d o ne P O q 2 h, 4 h o urs f or o x yc o d o ne P O q 4 h).  
T he pri mar y efficac y varia ble, S PI 0 -4 8, will be a nal yze d usi n g a o ne -wa y a nal ysis of varia nce ( A N O V A ) 
m o del wit h treat me nt gr o u p as t he mai n effect . S u m mar y statistics ( n, mea n, S D, me dia n, mi ni m u m, a n d 
ma xi m u m) will be prese nte d . Least s q uares ( L S ) m ea ns a n d o ne -si de d 9 0 % co nfi de nce inter vals will be 
prese nte d al o n g wit h t he p -val ues fr o m t he A N O V A m o del .  
Ot her S PI a n d pai n i nte nsit y  e n d p oi nts will be prese nte d a n d a nal yze d si milarl y t o t he pri mar y e n d p oi nt 
a n d prese nte d gra p hicall y  as a p pr o priate . T he t otal c o ns u m pti o n of o pi oi d resc ue a nal gesia t hr o u g h 
2 4  h o urs a n d t hr o u g h 4 8  h o urs will be a nal yze d usi n g t he n o n para metric Wilc o x o n ra n k s u m test I P vs . 
place b o a n d acti ve c o m parat or c o m paris o n se paratel y .  
T he t otal c o ns u m pti o n of resc ue a nal gesia res ults will be prese nte d i n a s u m mar y ta ble wit h sta n dar d 
s u m mar y statistics as well as Wilc o x o n ra n k s u m mea ns, pair wise ra n k -s u m mea n differe nces a n d p-val ues 
a n d will als o be prese nte d gra p hicall y .  
T he perce nta ge of s u bjects t hat t o o k resc ue, as well as t he perce nta ge of s u bjects w h o d o n ot re q uir e o pi oi d 
resc ue me dicati o n will be a nal yze d usi n g a l o gistic re gressi o n wit h treat me nt gr o u p as t he mai n effect . T he 
a nal ysis will c o m pare t he o d ds rati os of t he pr o p orti o ns of o pi oi d -free s u bjects bet wee n eac h treat me nt 
gr o u p a n d t he place b o or acti ve c o m parat or gr o u p , res pecti vel y. A s u m mar y of fre q ue ncies as well as o d ds 
rati o, 90 % c o nfi de nce i nter vals a n d p -val ues will be prese nte d . 
Ti me t o first resc ue will be a nal yze d usi n g Ka pla n -Meier tec h ni q ues.  S u m mar y statistics will be prese nte d,  
a n d treat me nt gr o u ps  c o m pare d usi n g a l o g ra n k test.  A Ka pla n Meier gra p h will als o be prese nte d.  
T he P G A (A p pe n di x  2 ) res ults will be prese nte d i n a s u m mar y ta ble b y treat me nt gr o u p usi n g sta n dar d 
s u m mar y statistics as well as L S mea ns, pair wise L S mea n differe nces, sta n dar d err ors, c o nfi de nce 
i nter vals a n d p-val ues.  P -val ues will be calc ulate d usi n g a n A N O V A wit h treat me nt gr o u p as t he mai n 
effect. T he n u m ber ( %) of s u bjects a ns weri n g i n eac h cate g or y will als o be prese nte d b y treat me nt gr o u p.  

N V K 0 0 9 Pre ga bali n / Aceta mi n o p he n 
 
 
Pr ot oc ol N u m ber : C P-N V K 0 0 9 -0 0 0 5  
 
Ne va kar, I nc.  
Pr ot oc ol Versi o n 2. 0 _ 0 8 J u ne  2 0 2 0  
 
Pa ge 4 3  of 1 0 3  
St atistic al Met h o ds  (c o nti n ue d): 
S afety  
A d verse e ve nts will be c o de d usi n g t he m ost c urre nt Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A versi o n 2 2. 0 or hi g her ). A s u bject A E data listi n g, i ncl u di n g ver bati m ter m, preferre d ter m, 
s yste m or ga n class ( S O C), treat me nt gr o u p , se verit y, a n d relati o ns hi p t o st u d y dr u g, will be pr o vi de d . T he 
n u m ber of s u bjects e x perie nci n g T E A Es a n d n u m ber of i n di vi d ual T E A Es will be s u m marize d b y 
treat me nt gr o u p, S O C, a n d preferre d ter m. T E A Es will als o be s u m marize d b y treat me nt gr o u p, se verit y, 
a n d relati o ns hi p t o st u d y dr u g, w here a p plica ble . 
Cli nical l a b orat or y e val uati o ns a n d vit al si g ns assess me nts will be s u m marize d b y treat me nt gr o u p  at t he 
pr ot oc ol s pecifie d c ollecti o n ti me p oi nt usi n g descri pti ve statistics . A s u m mar y of c ha n ge fr o m baseli ne 
a n d c o u nts of n u m ber of val ues o ut of n or mal ra n ge at eac h pr ot oc ol -s pecifie d ti me p oi nt b y treat me nt 
gr o u p  will als o be prese nte d.  
Vital si g ns ( bl o o d press ure [s yst olic a n d diast olic], heart rate, res pirat or y rate, oral or te m p oral b o d y 
te m perat ure, a n d p ulse o xi metr y) will be s u m mariz e d b y treat me nt gr o u p.  O bser ve d a n d c ha n ge fr o m 
baseli ne val ues will be s u m marize d b y treat me nt gr o u p at eac h sc he d ule d visit. Listi n gs will als o be 
pr o vi de d.  
Cli nical assess me nt of E C G ( N or mal, A b n or mal N C S  [ n ot cli nicall y si g nifica nt], A b n or mal C S [cli nicall y 
si g nifica nt]) will be s u m marized b y treat me nt gr o u p  at eac h sc he d ule d visit , usi n g fre q ue nc y ta b ulati o ns. 
P h ysical e xa mi nati o n  fi n di n gs at eac h visit will be liste d. 
Pri or a n d c o nc o mita nt me dicati o ns will be c o de d usi n g t he m ost c urre nt W orl d Healt h Or ga nizati o n 
( W H O) dr u g dicti o nar y ( Versi o n B 3 Se pte m ber 2 0 1 8 Dr u g Gl o bal  or hi g her ). Pri or a n d c o nc o mita nt 
me dicati o ns will be s u m marize d b y a nat o mical t hera pe utic class a n d preferre d na me f or eac h treat me nt 
gr o u p . 
M o difie d Al drete Sc ori n g S yste m ( A p pe n di x  3 ) i ncl u di n g Acti vit y, Res pirati o n, Circ ulati o n, 
C o nsci o us ness , a n d O x y ge nati o n  will be s u m marize d b y treat me nt gr o u p  usi n g descri pti ve statis tics. 
S u bject listi n gs will als o be pr o vi de d.  
P h ar m ac oki netics  
Plas ma c o nce ntrati o n data will be s u m marize d b y sa m pli n g ti me a n d treat me nt gr o u p as a p pr o priate; P K 
para meters will be s u m marize d b y treat me nt gr o u p a n d sc he d ule d visit as a p pr o priate.  All i n d i vi d ual 
plas ma c o nce ntrati o ns a n d P K para meter esti mates of C mi n  a n d C ma x  will be liste d a n d s u m marize d.  
S u m mar y statistics will i ncl u de n u m ber of s u bjects, n u m ber bel o w t he li mit of q ua ntificati o n ( B L Q) 
(e xcl usi vel y f or c o nce ntrati o n s u m maries), arit h metic mea n, S D, c o -efficie nt of variati o n ( C V), me dia n, 
mi ni m u m a n d ma xi m u m.  I n a d diti o n, t he ge o metric mea n a n d ge o metric C V will be re p orte d. Bet wee n -
s u bject varia bilit y will be base d o n ge o metric mea n C V. Mea n c o nce ntrati o n o ver ti me will be prese nte d as 
gra p hs f or eac h treat me nt gr o u p o n t he ra w a n d li near scale. 

 
 
 
 
 
 
 
 
St atistic al A n al ysis Pl a n 
A P hase 2, Ra n d o mi ze d, D o u ble- Bli n d, Pl ace b o- a n d C o m p arat or- 
C o ntr olle d Trial t o E v al uat e t h e Safet y a n d Effi cac y of 
C o m bi n ati o n  
 Pre g a bali n a n d Aceta mi n o p he n 
C o m pare d t o Aceta mi n o p h e n a n d Pl ace b o i n S u bj ects U n d er g oi n g 
B u ni o nect o m y 
Versi o n 2. 0; Date d: 1 9- N o v e m ber- 2 0 2 0 
Pr ot oc ol n u m ber:  C P- N V K 0 0 9- 0 0 0 5  
S p o ns or:  Ne va k ar, I n c. NJ 0 8 8 0 7 

Ne va kar, I nc.  
 
C P -N V K 0 0 9 -0 0 0 5  
Statistical A nal ysis Pla n, Fi nal v 2 . 0                                                                           1 9 -N O V -2 0 2 0  
 
 
3  
 
 
  
 
 
T E C H NI C A L S U M M A R Y R E P O R T ( T S R)  
N a me of S p o ns or/ C o m p a n y  
Ne va kar, I nc.  
I n di vi d u al St u d y T a ble 
Referri n g t o P art of t he 
D ossier:  
V ol u me:  
( F or N ati o n al A ut h ority Use 
O nly) : 
N a me of Fi nis he d Pr o d uct : 
N V K 0 0 9, a c o m bi nati o n of 
pre ga bali n ( P G B) 
 a n d 
 (aceta mi n o p h e n 
[ A P A P]  
 
a d mi nistere d 
 
  
P a ge:  
 
N a me of Acti ve I n gre die nt:  
Pre ga bali n ( P G B) a n d 
aceta mi n o p he n ( A P A P)   
 
 
Title Of St u d y:  
A P hase 2, Ra n d o mize d, D o u ble -Bli n d, Place b o - a n d C o m parat or -C o ntr olle d Trial t o E val uate 
t he Safet y a n d Efficac y of C o m bi nati o n  
 Pre ga bali n a n d Aceta mi n o p he n 
C o m pare d t o Acet a mi n o p he n a n d Place b o i n S u bj ects U n der g oi n g B u ni o nect o m y  
I n vesti g at ors: 
St u d y Ce nter(s):  
1 t o 3 st u d y ce nters ( U S)  
St u die d peri o d ( ye ars): 
St u d y is e x pecte d be 
c o m plete d wit hi n 4 m o nt hs of 
t he first s u bject e ntr y.  
P h ase of de vel o p me nt:  
P hase 2  
O bjecti ves:  
Pri m ar y:  
• T o e val uate t he effi cac y of c o m bi nati o n P G B 
 a n d A P A P  
 a d mi nistere d 
 
vs. place b o f or pai n c o ntr ol i n s u bjects u n der g oi n g b u ni o nect o m y.  
 
Sec o n d ar y:  
• T o e val uate t he effi cac y of c o m bi nati o n P G B 
 a n d A P A P  
 a d mi nistere d 
 
vs. c o m parat or ( A P A P  
 al o ne) f or p ai n c o ntr ol i n s u bjects u n der g oi n g b u ni o nect o m y.  
• T o e val uate t he s afet y a n d t olera bilit y of a c o m bi nati o n of P G B 
 a n d A P A P  
 
a d mi nistere d 
 i n a p ost o perati ve p o p ulati o n.  
D o c u Si g n E n v el o p e I D: 1 4 A 9 4 1 E B- F E D D- 4 1 3 7- 8 1 F A- A C 2 9 7 5 0 F 4 0 7 9

Ne va kar, I nc.  
 
C P -N V K 0 0 9 -0 0 0 5  
Statistical A nal ysis Pla n, Fi nal v 2 . 0                                                                           1 9 -N O V -2 0 2 0  
 
 
4  
 
 
  
 
 
Met h o d ol o g y:  
C P -N V K 0 0 9 -0 0 0 5  is a p hase 2, m ulti-ce nter, ra n d o mize d, d o u ble -bli n d, parallel -gr o u p, 
place b o - a n d c o m parat or -c o ntr olle d st u d y.  
S u bjects will u n der g o a Scree ni n g Visit ( Da y -4 2 t o Da y -2). Pre -o perati ve assess me nts will be 
c o n d ucte d wit hi n 2 4 h o urs pri or t o s ur ger y ( o n eit her Da y -1 or Da y 1 pri or t o s ur ger y) a n d 
pri or t o a n y d osi n g. S u bjects sc he d ule d f or b u ni o nect o m y s ur ger y w h o meet all of t he 
i ncl usi o n criteria a n d n o n e of t he e x cl usi o n criteria state d bel o w will be e nr olle d a n d 
ra n d o mize d ( Da y 1). S u bjects a n d all st u d y staff perf or mi n g st u d y assess m e nts will be bli n de d 
t o treat me nt all ocati o n.  
O n Da y 1, t he first d ose of st u d y dr u g or place b o will be a d mi nistere d a p pr o xi matel y 3 0 t o 9 0 
mi n utes bef ore s ur g er y ( pre -S ur ger y  
 # 1) w he n t he s u bject is i n t he pre -o perati ve area. 
 are a p pr o xi mat el y 1 5 mi n utes. S ur ger y will be perf or me d a p pr o xi matel y wit hi n t he 
ne xt h o ur, wit h e n d of s ur ger y (i.e., c o m pleti o n of last s ut ure) desi g nate d as H o ur 0. T he 
sec o n d d ose of st u d y dr u g or place b o will be a d mi nistere d i n t he p ost-a nest hesia care u nit 
( P A C U) at + 3 0 mi n utes ( ± 3 0 mi n utes) fr o m H o ur 0 ( p ost-s ur ger y  
 # 2). St u d y dr u g or 
place b o will be a d mi nistere d e v er y 8 h o urs ( ± 2 mi n utes) relati ve t o pre -s ur ger y  
 # 1 
a n d e ver y 6 h o urs ( ± 2 mi n utes) relati ve t o p ost -s ur ger y  
 # 2 c o nti n ui n g t hr o u g h 4 8 
h o urs. T he A P A P d ose i n t he c o m bi nati o n  
 gi ve n e ver y 8 h o urs a n d t he A P A P d ose 
al o ne gi ve n e v er y 6 h m ust n ot e xcee d  
 i n a 2 4 -h o ur peri o d ( 
  
 
Pac ka ge I ns ert, 2 0 1 8). T he Sc he d ule of  
 is prese nte d i n Ta ble 4  of t he pr ot oc ol . 
S u bjects will re mai n i n t he researc h u nit f or at least 4 8 h o urs p ost -s ur ger y ( disc har ge) as l o n g 
as t he y are n o l o n ger se d ate d, a n d all ass ess me nts are c o m plet e d. S u bjects will be re q ueste d t o 
ret urn t o t he cli nical r esearc h u nit ( C R U) o n Da y 7 ( ± 1 da y) f or a f oll o w -u p safet y visit. If a n 
A E relate d t o st u d y dr u g is re p orte d or is o n g oi n g at t he F oll o w -u p/ E n d of St u d y ( E O S) visit 
o n Da y 7, a s u bject s h o ul d be f oll o we d u ntil a p pr o priate res ol uti o n of t he A E(s) as des cri be d 
i n t he pr ot oc ol ( Secti o n 1 0. 7).  
N u m ber of S u bjects ( pl a n ne d a n d a n al yze d):  
8 0 s u bjects ( 3 2 per  acti ve treat me nt gr o u p, 1 6 place b o).  
D o c u Si g n E n v el o p e I D: 1 4 A 9 4 1 E B- F E D D- 4 1 3 7- 8 1 F A- A C 2 9 7 5 0 F 4 0 7 9

Ne va kar, I nc.  
 
C P -N V K 0 0 9 -0 0 0 5  
Statistical A nal ysis Pla n, Fi nal v 2 . 0                                                                           1 9 -N O V -2 0 2 0  
 
 
5  
 
 
  
 
 
Di a g n osis a n d m ai n criteri a f or i ncl usi o n:  
Male a n d fe male bet w ee n 1 8 -6 5 years of a ge wit h wei g h bet wee n 5 0 a n d 1 0 0 k g ( b o d y mass 
i n de x [ B MI] < 3 2 k g/ m2) c o ul d partici pate i n t he st u d y. S u bjects  m ust be i n g o o d healt h a n d 
ca pa ble of u n der g oi n g a b u ni o nect o m y u n der a n est hesia as descri be d i n t he st u d y s ur gical a n d 
a nest hetic pr ot oc ol.  
T he y m ust be sc he d ule d t o u n der g o u nilateral first metatarsal b u ni o nect o m y a n d ha ve n o 
a d diti o nal pla n ne d s ur geries ot her t ha n b u ni o nect o m y d uri n g t he c o urse of t he st u d y .  S u bjects  
s h o ul d pr o vi de i nf or me d c o nse nt b y si g ni n g t he i nf or me d c o nse nt f or m (I C F) a p pr o ve d b y t he 
Instit uti o nal Re vie w B oar d (I R B), be willi n g a n d a ble t o c o m plete t he st u d y pr oce d ures a n d 
pai n scales a n d c o m m u nicate mea ni n gf ull y i n E n glis h wit h st u d y pers o n nel. T he i ncl usi o n 
criteria is t o ha ve n e gati v e uri ne dr u g s cree n f or dr u gs i n dicati ve of illicit dr u g use ( u nless 
res ults ca n be e x plai ne d b y a c urre nt pres cri pti o n or acce pta ble o v er-t he-c o u nter me dicati o n at 
scree ni n g as deter mi ne d b y t he i n vesti gat or) a n d n o detecta ble res ults o n t he alc o h ol test 
( breat h or s ali va) i n dicati ve of alc o h ol a b us e at scree ni n g, a n d/ or pri or t o s ur ger y ( ma y be 
re peat e d if t he I n v esti gat or s us pects a false-p ositi ve res ult).  
Bi ol o gical fe male s u bjects m ust be n o n -lactati n g, sterile ( bilateral t u bal li gati o n, bilateral 
sal pi n gect o m y, or h ysterect o m y), p ost-me n o pa us al f or at  least 2 years, ha ve a part n er t hat is 
sterile, be a bsti ne nt, use a hi g hl y effecti ve d o u ble- c o ntrace pti o n met h o d ( h or m o nal pr otecti o n 
is i ns ufficie nt), or use a n F D A-a p pr o ve d c o ntrace pti ve f or greater t ha n 2 m o nt hs pri or t o t he 
scree ni n g visit a n d c o m mit t o a n acce pta ble f or m of birt h c o ntr ol f or t he d urati o n of t he st u d y 
a n d f or 3 0 da ys after c o m pleti o n of t he st u d y .  
Test pr o d uct, d ose a n d m o de of a d mi nistr ati o n:  
All s u bjects will recei ve 
  
 of matc hi n g v ol u me e ver y 8 h o urs ( ± 2 mi n utes) relati ve 
t o pre-s ur ger y  
 # 1 a n d e ver y 6 h o urs ( ± 2 mi n utes) relati ve t o p ost-s ur ger y  
 # 2.  
Treat me nt Gr o u p A will recei v e a c o m bi nati o n of P G B 
 a n d A PA P  
 
a d mi nistere d 
 e v er y 8 h o urs ( ± 2 mi n utes) relati ve t o pre -s ur ger y  
 # 1, a n d 
 
place b o f or 
  
 e ver y 6 h o urs  ( ± 2 mi n utes) relati ve t o p ost-s ur ger y  
 # 2. 
N ote: T he fi n al d ose of P G B is deter mi ne d b y t he C P -N V K 0 0 9 -0 0 0 4 s t u d y.  
T he Sc he d ule of  
 is prese nte d i n Ta ble 4  of Pr ot oc ol .  
 
D ur ati o n of tre at me nt:  
T he st u d y will c o nsist of a scree ni n g peri o d of u p t o 4 0 da ys ( Da y -4 2 t o -2),  da y of a d missi o n 
( Da y -1 or H o ur -2 4), da y of s ur ger y ( Da y 1), Da y of disc har ge ( H o ur 4 8 relati ve t o H o ur 0 ) 
a n d f oll o w-u p  visit  ( Da y 7 ±1  da ys). D urati o n of tr eat me nt will be  u p t o 4 8  h o urs.  
D o c u Si g n E n v el o p e I D: 1 4 A 9 4 1 E B- F E D D- 4 1 3 7- 8 1 F A- A C 2 9 7 5 0 F 4 0 7 9

Ne va kar, I nc.  
 
C P -N V K 0 0 9 -0 0 0 5  
Statistical A nal ysis Pla n, Fi nal v 2 . 0                                                                           1 9 -N O V -2 0 2 0  
 
 
6  
 
 
  
 
 
Refere nce t her a p y, d ose a n d m o de of a d mi nistr ati o n:  
T he refere nce t h era pies are t he acti ve c o m parat or A P A P  
 
 a n d 
 
 
( place b o): 
•  Treat me nt Gr o u p B will recei ve A P A P  
 via 
  
 e v er y 6 h o urs ( ± 2 
mi n utes) relati ve t o p ost -s ur ger y  
 # 2, a n d  
 place b o via 
  
 e ver y 
8 h o urs ( ± 2 mi n utes) relati ve t o pre -s ur ger y  
 # 1.  
•  Treat me nt Gr o u p C will recei ve  
 place b o f or 
  
 e ver y 6 h o urs  ( ± 2 
mi n utes)  relati ve t o p ost-s ur ger y  
 # 2 a n d e ver y 8 h o urs ( ± 2 mi n utes) relati ve t o 
pre -s ur g er y  
 # 1.  
 
T he Sc he d ule of  
 is prese nte d i n Ta ble 4 of Pr ot oc ol.  
 
D o c u Si g n E n v el o p e I D: 1 4 A 9 4 1 E B- F E D D- 4 1 3 7- 8 1 F A- A C 2 9 7 5 0 F 4 0 7 9