Clinical trial NCT04495283
Conditions: Postoperative Pain
Sponsor: Nevakar, Inc.
Start date: 2020-07-28; Completion date: 2020-11-12
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy

Detailed description:
A Phase 2, Randomized, Double-Blind, Placebo- and Comparator-Controlled Trial to Evaluate the Safety and Efficacy of Combination Pregabalin and Acetaminophen Compared to Acetaminophen and Placebo in Subjects Undergoing Bunionectomy

Up to 80 subjects will be randomized (32 in each active treatment group, 16 placebo).

To evaluate the efficacy of combination pregabalin (PGB) and acetaminophen (APAP) administered vs. placebo for pain control in subjects undergoing bunionectomy.

The placebo will be the saline solution.

Arms: arm 1: Group A receives PGB plus APAP prior to surgery and placebo 1 post-surgery. arm 2: Group B receives placebo 2 prior to surgery and APAP post-surgery. arm 3: Group C receives placebo 1 prior to surgery and placebo 2 post-surgery.
Interventions: intervention 1: Pregabalin intervention 2: Acetaminophen intervention 3: Placebo 1 intervention 4: Placebo 2
Intervention descriptions: intervention 1: Pregabalin is a structural derivative of the inhibitory neurotransmitter gamma aminobutyric acid with anticonvulsant, anxiolytic and sleep-modulating properties. intervention 2: Acetaminophen is a non-salicylate antipyretic and non-opioid analgesic agent. intervention 3: Placebo for APAP intervention 4: Placebo for combination

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
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