A Phase 2, Open-label, Dose-finding Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of Pharmaceutical Grade Synthetic Cannabidiol Oral Solution in Pediatric Patients With Treatment-Resistant Childhood Absence Seizures
Phase: PHASE2
Conditions: Childhood Absence Epilepsy
Sponsor: Radius Pharmaceuticals, Inc.

 
 
 
C LI NI C A L T RI A L P R O T O C O L  
 
 
A P h a s e 2, O p e n -l a b el, D o s e-fi n di n g St u d y t o A s s e s s t h e Effi c a c y, S af et y, 
T ol er a bilit y, a n d P h ar m a c o ki n eti c s of P h ar m a c e uti c al Gr a d e S y nt h eti c  
C a n n a bi di ol Or al S ol uti o n i n P e di atri c P ati e nt s wit h Tr e at m e nt -R e si st a nt  
C hil d h o o d A b s e n c e S ei z ur e s  
 
 
Pr ot oc ol N u m ber: I N S 0 1 1 - 1 7- 1 0 3 
Fi nal Pr ot oc ol Date : 0 6 Ma y 2 0 1 9 
Versi o n: 7. 0 
I n v esti gati o nal Pr o d uct: Ca n na bi di ol Oral S ol uti o n 
I N D N u m ber: I N D 1 2 3, 1 2 0 
 
Cli nical Trials. g o v I D:  N C T 0 3 3 3 6 2 4 2 

C LI NI C A L T RI A L P R O T O C O L  
 
A P h ase 2, O pe n -l a bel, D ose-fi n di n g St u d y t o Assess t he Effic ac y, S afet y, 
T oler a bilit y, a n d P h ar m ac o ki netics of P h ar m ace utic al Gr a de S y nt hetic  
C a n n a bi di ol Or al S ol uti o n i n Pe di atric P atie nt s wit h Tre at me nt -Resist a nt 
C hil d h o o d  A bse n ce Seiz ures  I T A G E 
 
Pr ot oc ol N u m ber:  I N S0 1 1 -1 7 -1 0 3  
Fi nal Pr ot oc ol Date:  0 6  Ma y  2 0 1 9   
Pr ot oc ol Versi o n:  7 . 0   
I n v esti gati o nal Pr o d uct: Ca n na bi di ol Oral S ol uti o n  
I N D N u m ber: 1 2 3, 1 2 0  
S p o ns or:  I ns ys De vel o p me nt C o m pa n y , I nc. 
1 3 3 3 S o ut h S pectr u m Bl v d, S uite  1 0 0  
C ha n dler, A Z 8 5 2 8 6  
Me dical M o nit or:  
M D 
I ns ys D e vel o p me nt C o m pa n y, I nc. 
, Cli nical De vel o p me nt  
P h o ne: 
Fa x: 
 
 
 
C o nfi de nti alit y St ate me nt  
T his st u d y will be perf or me d i n c o m plia nce wit h G o o d Cli ni cal Practices ( G C P) a n d a p plica ble 
re g ulat or y re q uire me nts. T he c o nfi de ntial i nf or mati o n i n t his d oc u me nt is pr o vi de d t o y o u as a n 
i n vesti gat or, p ote ntial i n vesti gat or or c o ns ulta nt f or re vie w b y y o u, y o ur staff a n d a p plica ble 
I n d e pe n de nt Et hics C o m mittee (I E C) or I nstit uti o nal Re vie w B o ar d (I R B). It is u n derst o o d t hat 
t he i nf or mati o n will n ot be discl ose d t o ot hers wit h o ut writte n a ut h orizati o n fr o m I ns ys 
De vel o p me nt C o m pa n y , I n c., e x ce pt t o t he e xte nt necessar y t o o btai n i nf or me d c o nse nt fr o m 
t h ose pers o ns t o w h o m t he dr u g ma y be a d mi nistere d. 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD
PPD
PPD
PPD
PPD

I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     3  
 P R O T O C O L S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  
I ns ys D e vel o p me nt C o m pa n y, I nc. 
N a me of I n vesti g ati o n al Pr o d uct:  
Ca n na bi di ol Oral S ol uti o n  
N a me of Acti ve I n gre die nt:  
Ca n na bi di ol  
Title of St u d y:  
A P hase 2, O pe n -l a bel, D ose-fi n di n g St u d y t o Ass ess t he Efficac y, Safet y, T olera bilit y, a n d 
P har mac o ki netics of P har mace utical Gra d e S y nt h etic Ca n na bi di ol Oral S ol uti o n i n Pe diatric 
Patie nts wit h Treat me nt -Resista nt C hil d h o o d A bse nce Seiz ures  
St u d y ce nter(s):  A p pr o xi matel y 8 sites i n t he U S. 
St u die d peri o d:  
Esti mate d date first patie nt e nr olle d: N o ve m ber  2 0 1 7  
Esti mate d date last patie nt c o m plete d: Se pte m ber  2 0 1 9  
P h as e of de vel o p me nt:  
P hase 2  
O bjecti ves:  
 
Pri m ar y  
•  T o assess t he efficac y of Ca n na bi di ol Oral S ol uti o n i n t he treat me nt of pe di atric 
patie nts wit h treat me nt -resista nt c hil d h o o d a bse nce seiz ures. 
 
Sec o n d ar y  
•  T o assess a n y i m pr o ve m e nt i n q ualitati ve assess me nt s of patie nt stat us o ver t he 
d urati o n of t he st u d y.  
•  T o assess t he safet y a n d t olera bilit y of Ca n n a bi di ol Oral S ol uti o n treat me nt i n 
pe diatric patie nts wit h treat me nt -resista nt c hil d h o o d a bse nce s eiz ures.  
•  T o assess t he p har m ac o ki netics of Ca n na bi di ol Oral S ol uti o n i n pe diatric patie nts 
wit h treat me nt -resista nt c hil d h o o d a bse nce seiz ures. 
Met h o d ol o g y:  
T his is a P hase 2, o pe n -la bel, d ose-fi n di n g st u d y d esi g ne d t o assess t he effi cac y, safet y, 
t olera bilit y, a n d p h ar mac o ki netics of t hree d os es ( 2 0, 3 0, a n d 1 0 m g/ k g/ da y ) of Ca n na bi di ol 
Oral S ol uti o n . D oses e x cee di n g 3 0 m g/ k g/ da y will n ot be e x a mi ne d i n t his st u d y.  
St u d y p artici pa nts will b e pe diatric p atie n ts a ge 3 t o 1 7 years  (i ncl usi ve) e x perie nci n g 
treat me nt-resista nt c hil d h o o d a bse nce s eiz ures w h o satisf y all i ncl usi o n/e xcl usi o n criteria. T he 
st u d y will c o nsist of a Scree ni n g Peri o d, a Titrati o n Peri o d, a Treat me nt Peri o d, a n d a F oll o w -
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     4  
U p Peri o d. A t otal of 3 0 patie nts will be e nr olle d i n t he st u d y. Te n p atie nts will be e nr olle d i n 
eac h of t hree d os e c o h orts, a n d n o patie nt will partici pate i n m ore t ha n o ne c o h ort . At 
c o m pleti o n , patie nts will ha ve t he o p p ort u nit y t o e nr oll i n a n o pe n -la bel l o n g-ter m safet y 
st u d y (I N S 0 1 1-1 7 -1 1 3) .  
Eac h patie nt will c o m plete a Scree ni n g Peri o d f or u p t o 2 8  ( ± 5) da ys. Eli gi ble patie nts will 
ha ve a b aseli ne 4 -hr vi d e o -electr o e nce p hal o gra p h y ( vi de o -E E G) t hat will i ncl u de 
h y per ve ntilati o n d uri n g t heir Baseli ne Visit. T he i n vesti gat or m a y use res ults of a pre vi o usl y 
o btai ne d E E G t o g ui de selecti o n of t he a p pr o priate patie nts b ut t he Baseli ne Visit vi de o -E E G  
will be use d f or deter mi nati o n of eli gi bilit y a n d  will be e val uate d b y a n electr o p h ysi ol o gist n ot 
i n v ol ve d i n t he st u d y. Details of t he vi de o-E E G assess me nt will be pr o vi de d i n t he vi de o -E E G 
C harter.  
T he st u d y dr u g will be a d de d t o  e xisti n g a ntie pile ptic dr u g ( A E D) t h era p y f or t he Treat me nt 
Peri o d. D osa ges of c o nc o mita nt A E Ds will be hel d c o nsta nt f or t he Scree ni n g a n d Treat me nt 
Peri o d s. 
Titr ati o n a n d Tre at me nt Peri o ds  
T hirt y patie nts i n t otal will be e nr olle d i n t o o ne of t hree d ose c o h orts ; te n patie nts per  c o h ort. 
P atie nts i n C o h ort 1 will be treate d b ef ore patie nts are tr eate d i n C o h ort 2, a n d patie nts i n 
C o h ort 2 will be treate d pri or t o patie nt s bei n g treate d i n C o h ort 3. Patie nts will be d ose d 
a p pr o xi matel y e ver y 1 2 h o urs wit h  f o o d t o hel p e ns ure c o nsiste nt plas ma l e vels are ac hi e ve d, 
e x ce pt f or Visit 6 ( Wee k 4, Da y 7 ) w h e n bl o o d f or fasti n g p h ar mac o ki n etic ( P K) a nal ysis will 
be dra w n pri or t o t he m or ni n g d ose.  
•  C o h ort 1: 2 0 m g/ k g/ da y di vi de d t wice dail y ( BI D) f or 4 wee ks.  
•  C o h or t 2: Titrati o n peri o d of 2 0 m g/ k g/ da y di vi de d BI D f or 5 da ys, f oll o w e d b y 
3 0  m g/ k g/ da y di vi de d BI D f or 4 wee ks.  
•  C o h ort 3: 1 0 m g/ k g/ da y di vi de d t wice dail y ( BI D) f or 4 wee ks.  
Eli gi ble patie nts will be pr o vi de d wit h t heir titrati o n d ose d uri n g t h eir Baseli ne  Visit ( 5 da ys at 
2 0 m g/ k g/ da y f or C o h orts 2 ).  
D uri n g t h e Treat me nt Peri o d, p atie nts will be d ose d f or 4 wee ks d uri n g w hic h t he i n vesti gat or 
will assess t olera bilit y a n d effect. Patie nts will ret ur n t o t he site at t he e n d of Wee k 2 ( Visit 4) 
t o e val uate me dic al stat us  (seiz ure diar y, vital si g ns, a n d ne ur ol o gical e x a m), cli nical 
la b orat or y ass ess me nts, a n d assess A Es .  
At Visit 5  ( Wee k 4, Da y 6 ), t he patie nt will ha ve a re peat 4-h o ur vi de o -E E G i ncl u di n g 
h y per ve ntilati o n t o c o u nt t he n u m ber of a bs e nce s eiz u res ca pt ure d, a n d bl o o d f or P K a nal ysis 
will be dra w n. Bl o o d f or P K a nal ys es will be dra w n at Visit 3, Visit 5 ( fe d; Wee k 4, Da y 6 ) 
a n d Visit 6 (faste d; Wee k 4, Da y 7 ), or t he Earl y Wit h dra wal Visit. T he i n vesti gat or will 
assess t olera bilit y a n d efficac y . 
F oll o wi n g t he c o m pleti o n of t he Treat me nt Peri o d ( Visit 6 ), patie nts will ha ve t he o pti o n t o 
c o nti n ue treat me nt i n a n o pe n -la bel l o n g-ter m safet y st u d y. Patie nts w h o c h o ose t o e nr oll i n 
t he l o n g-ter m safet y st u d y will n ot ha ve a f oll o w-u p p h o ne call. Patie nts w h o d o n ot c h o ose t o 
e nr oll i n t he l o n g-t er m safet y st u d y will ta per t he d ose of Ca n na bi di ol Oral S ol uti o n acc or di n g 
t o t he f oll o wi n g sc h e d ule: d oses bet wee n 2 0-3 0 m g/ k g/ da y will be re d uce d t o 2 0 m g/ k g/ d a y 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     5  
f or fi ve da ys a n d t he n dis c o nti n ue d; d oses ≤ 20 m g/ k g/ da y ca n be disc o nti n ue d wit h o ut 
titrati o n. T his ca n be m o difie d b y t he i n v esti gat or base d u p o n t he patie nt’s res p o nse. Patie nts 
will recei ve a f oll o w -u p p h o ne call 1 4 da ys  after c o m pleti n g Visit 6 ( E n d of St u d y).   
A vaila ble safet y data will be re vie w e d o n a n o n g oi n g basis t o e ns ure d oses  are ge n erall y well 
t olerate d. Det ails of t he s afet y data re vie w will be pr o vi de d i n t he Data M o nit ori n g  C harter.  
F oll o w -U p Peri o d  
A f oll o w -u p p h o ne call will occ ur 1 4 da ys  after Visit 6 ( E n d of St u d y) of t he st u d y t o assess 
A Es, A E Ds, a n d rec or d c o nc o mita nt me dicati o ns.  
St u d y Assess me nts  
Safet y assess me nts f or all patie nts will i ncl u de me dical hist or y, p h ysic al e xa mi nati o n, vital 
si g ns (seate d bl o o d press ure, p ulse rat e, te m perat ure, a n d res pirati o n rat e), cli nical l a b orat or y 
testi n g ( he m at ol o g y, c he mistr y, a n d uri nal ysis), 1 2-lea d E C G, pri or me di cati o n hist or y 
(assess me nt of past/c urre nt A E Ds a n d c o nc o mita nt me dicati o n s), C -S S R S, a n d A E 
assess me nts.  
A c o m plete p h ysical e x a mi nati o n  will be d o ne at Scree ni n g ( Visit 1).  A n e ur ol o gical 
e x a mi nati o n (c o m plete at Scree ni n g [ Visit 1] a n d brief at all ot her st u d y visits) a n d vital si g ns 
will be assesse d at Scree ni n g ( Visit  1), Baseli ne ( Visit 2), Treat me nt Peri o d ( Visits 3 [ Wee k 
1], 4 [ Wee k 2] , a n d 6 [ Wee k 4 , E n d of St u d y]), o r at t he Earl y Wit h dra wal Visit. Visit 6 is t he 
E n d of St u d y visit f or patie nts w h o c o m plete t he st u d y.  
Cli nical la b orat or y bl o o d tests  ( he mat ol o g y, c he mistr y) will be o btai ne d d uri n g t he Scree ni n g 
( Visit 1), Treat me nt Peri o d ( Visits 3, 4, a n d 6 [ E n d of St u d y]) or  at t he Earl y Wit h dra wal 
Visit. Uri nal ysis  will be o btai ne d d uri n g Scree ni n g ( Visit 1) a n d at Visit 6 ( E n d of St u d y)  or 
t he Earl y Wit h dra wal Visit . C o nc o mita nt A E D bl o o d le vels will be deter mi ne d at Bas eli ne 
( Visit 2), Visit 6 ( E n d of St u d y) , or t he E arl y Wit h dra wal Visit.  
A 1 2 -lea d el ectr o car di o gra m ( E C G), will be c o m plete d d uri n g  Scree ni n g ( Visit 1),  Treat me nt 
Peri o d  (Visit 6  [ E n d of St u d y]) or  at t he E arl y Wit h dra wal  Visit .  
F or patie nts a ge d 7 t o 1 7 years a n d if t h e de vel o p me ntal le vel is a p pr o priat e, t he C ol u m bia -
S uici de Se verit y Rati n g Scale [( C-S S R S) C hil dre n's  or A d ult’s  v ersi o n as a p pr o priate base d 
o n a ge] will be utilize d t o assess s uici dalit y at t he f oll o wi n g st u d y visits: Scree ni n g ( Visit 1) 
a n d Visit  5  ( Wee k 4, Da y 6) or t he Earl y Wit h d ra wal Visit. F or patie nts w h o are less t ha n 7 
years of a ge or f or w h o m t he C -S S R S is i na p pr o priate d ue t o t he patie nt’s d e vel o p me ntal 
f u ncti o ni n g, a cli nical ass ess me nt will be ma de.  
All a d verse e ve nts ( A Es) t hat arise d uri n g t he Scree ni n g, Titrati o n, Tre at me nt, a n d F oll o w -u p 
Peri o ds will be d oc u me nte d. C o nc o mita nt me dicati o ns will be re vie we d a n d d oc u me nte d at 
eac h visit. A meal diar y will be c o m plete d at Bas eli ne ( Visit 2) , a n d f or 2 4 h o urs bef ore eac h 
P K sa m pli n g visit at Visit 3 a n d Visit 5 ( Wee k 4, Da y 6).  
T o assess P K para m eters, bl o o d dra ws will be o btai ne d at Visit 3, Visit 5 (fe d; Wee k 4, Da y 6) 
a n d Visit 6 (faste d; Wee k 4, Da y 7), or t he Earl y Wit h dra wal Visit . Bl o o d dra ws f or P K v al ues 
at Visits 5 a n d 6 will occ ur as f oll o ws : 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     6  
F asti n g/ Fe d  
P K  
S a m pl e 
Visits   
Ti me p oi nts  
Fe d: Patie nts s h o ul d arri ve wit h o ut 
f o o d a n d t he m or ni n g d ose. Site 
pr o vi des a hi g h fat/ hi g h cal orie f o o d 
t he n d oses patie nt 
Visit 5  
( Wee k 4, 
Da y 6 ) 
Pre -d ose (b ef ore meal/ m or ni n g d ose ) 
a n d 2, 4, 6 h o urs aft er t he m or ni n g 
d ose ( b ut be f ore ne xt d ose) 
Faste d ( 2 h o urs bef ore d ose  u ntil 2 
h o urs after d os e ): Patie nts s h o ul d 
arri ve wit h o ut f o o d a n d t he m or ni n g 
d ose. Site pr o vi des a sta n dar d meal 2 
h o urs after d os e.  
Visit 6  
( Wee k 4, 
Da y 7 ) 
Pre -d ose a n d 2  ( bef ore m eal), 4, 6 
h o urs after t h e m or ni n g d ose ( b ut 
bef ore n e xt d ose)  
T o assess efficac y , a 4-h o ur vi de o -E E G i ncl u di n g h y per ve ntilati o n will be o btai ne d at t he 
Baseli ne Visit ( Visit 2), Visit 5 ( Wee k 4, Da y 6)  or  t he Earl y Wit h dra wal  Visit . A bse nce 
seiz ures will be c o u nte d b y a n electr o p h ysi ol o gist n ot i n v ol ve d wit h t he st u d y. F urt her details 
will be pr o vi de d i n t he vi de o -E E G C harter.   
Dail y seiz ure di aries will be c o m plete d t hr o u g h o ut t he Titrati o n a n d Treat me nt Peri o ds , or  t he 
Earl y Wit h dra wal Visit . T he dail y rec or d will as k: “H o w ma n y a bs e nce s eiz ures di d t he 
patie nt ha ve t o da y? ”. 
T o assess efficac y, t he Cli nical Gl o bal I m pressi o n –  Gl o bal I m pr o ve me nt  ( C GI-I) assess me nt 
will be c o m plete d b y t he i n vesti gat or at Visit 3 , Visit 5  ( Wee k 4, Da y 6) or  t he Earl y 
Wit h dra wal  Visit .  
N u m ber of p atie nts ( pl a n ne d):  
A p pr o xi matel y 3 0 p atie nts ( 1 0/c o h ort), 3 t o 1 2 ye ars of a ge (i ncl usi ve) at ti me of o nset, w h o 
are 3-1 7 years of a ge (i ncl usi ve) at ti me of c o nse nt, w h o ha ve treat me nt -resista nt c hil d h o o d 
a bse nce s eiz ures will be e nr olle d i n t he st u d y.  
Di a g n osis a n d m ai n criteri a f or i ncl usi o n:  
Patie nts will be male a n d n o n -pre g na nt fe male v ol u nteers bet w ee n 3 a n d 1 7 years of a ge 
(i ncl usi ve) at ti me of c o nse nt w h o were dia g n ose d wit h c hil d h o o d a bse nce e pile ps y ( C A E) 
bet wee n 3 a n d 1 2 years of a ge (i n cl u si ve), wei g h ≥ 1 0  k g, patie nt a n d/ or pare nt(s)/ care gi ver(s) 
are a bl e t o u n dersta n d a n d pr o vi de writte n c o nse nt, ha ve a d e q uate re nal a n d he patic f u ncti o n, 
a n d w h o meet all t he i ncl usi o n a n d n o ne of t he e x cl usi o n criteria.  
I n cl usi o n criteria 
1.  Patie nt a n d/ or p are nt(s)/care gi ver(s) f ull y c o m pr e h e n d t he i nf or me d c o nse nt f or m 
(I C F) a n d asse nt f or m, u n dersta n d all st u d y pr oce d ures, a n d ca n c o m m u nicate 
satisfact oril y wit h t he i n vesti gat or a n d st u d y co or di nat or , i n acc or da nce wit h 
a p plica ble la ws, re g ulati o ns, a n d l o cal re q uir e me nts.  
2.  Male or fe m ale bet w ee n 3 a n d 1 2 years (i ncl usi ve) at t he ti me of o nset a n d bet wee n 
3  a n d 1 7 years of a ge (i n cl usi ve) at t he ti me of c o nse nt.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     7  
3.  B o d y wei g ht ≥ 1 0  k g.  
4.  Dia g n os e d wit h c hil d h o o d a bse nce e pile ps y ( C A E), c o nfir me d b y E E G wit h at least 3 
b ursts of ge neral s pi ke w a ve ( G S W of 2. 7 t o 5 hertz lasti n g ≥ 3 sec o n ds)  d uri n g t he 4 -
h o ur E E G , a n d h as ha d a n a de q uate tri al of at least t w o ( 2) A E Ds a n d are tr eat m e nt-
resista nt t o at least o ne A E D.  
5.  Willi n g ness t o n ot start a ket o ge nic diet d uri n g t he Baseli ne or Treat me nt Peri o d.  
6.  A fe male p atie nt is eli gi ble t o partici pate i n t he st u d y if s he is:  
a. Pre me narc hal, or  
b.  Of c hil d beari n g p ot e ntial wit h a ne gati ve uri ne pre g na n c y test at t he Scree ni n g 
Visit. If se x uall y acti ve, s he m ust a gree t o f ulfill o ne of t he f oll o wi n g re q uire me nts:  
i. C o m plete a bsti ne nce fr o m i nterc o urse f or 2 4 wee ks pri or t o a d mi nistrati o n of t he 
first d ose of t he i n vesti gati o nal pr o d uct, t hr o u g h o ut t he Treat me nt Peri o d, a n d 2  
wee ks after c o m pleti o n or pre mat ure disc o nti n uati o n fr o m t he i n vesti gati o nal 
pr o d uct, a n d a gree m e nt t o use a d o u ble barrier m et h o d if s he bec o mes se x uall y 
acti ve.  
ii. Use of acce pt a ble met h o ds of c o ntrace pti o n t hr o u g h o ut t he st u d y a n d 2  wee ks 
after c o m pleti o n or pre m at ure disc o nti n uati o n fr o m i n vesti gati o nal pr o d uct. T he 
acce pta ble met h o d of c o ntrace pti o n is d o u ble barrier met h o d (i.e., c o n d o m pl us 
s per mici de or a c o n d o m pl us i ntra uteri ne de vice [I U D], dia p hra g m, or sta ble 
h or m o nal c o ntra ce pti ve use f or at least 3 m o nt hs bef ore s cree ni n g a n d t hr o u g h 2 8  
da y s after st u d y c o m pleti o n).  
7.  A se x uall y acti ve mal e p atie nt o r part ner of a n e nr olle d s u bject m ust be willi n g t o use 
acce pta ble met h o ds of c o ntrace pti o n t hr o u g h o ut t h e st u d y a n d f or 2  wee ks  after 
c o m pleti o n of st u d y partici pati o n or disc o nti n uati o n fr o m i n vesti gati o nal pr o d uct. T he 
acce pta ble met h o ds of birt h c o ntr ol are a bsti ne nce or d o u ble barrier birt h c o ntr ol (i.e., 
c o n d o m pl us s per mici de or a c o n d o m pl us o ne of t he met h o ds liste d i n [ 7] ). 
8.  I n t he o pi ni o n of t h e i n vesti gat or, t he p are nt(s)/care gi v er(s) is willi n g a n d a ble t o 
c o m pl y wit h t he st u d y pr oce d ures a n d visit sc he d ules, i ncl u di n g ve ni p u nct ure, a n d t he 
F oll o w -u p Visits.  
9.  Ge neral g o o d healt h ( defi ne d as t he a bse n ce of a n y cli nicall y r ele va nt a b n or malities as 
deter mi ne d b y t he i n vesti gat or) base d o n p h ysi cal a n d ne ur ol o gical e x a mi nati o ns, 
me dical hist or y, a n d cli nical la b orat or y val ues ( h e mat ol o g y, c h e mistr y, a n d uri nal ysis) 
c o m plete d d uri n g t he Scree ni n g Visit t hat w o ul d pr o hi bit t he p atie nt fr o m safel y 
partici pati n g i n t he tri al as j u d ge d b y t he i n vesti gat or.  
E x cl usi o n criteria  
1.  Patie nt or pare nt(s)/ care gi ver(s) ha v e dail y c o m mit me nts d uri n g t he st u d y d urati o n t hat 
w o ul d i nterfere wit h atte n di n g all st u d y visits.  
2.  Has a hist or y of acti ve n o nfe brile seiz ures ot her t ha n a bse nce seiz ures (e. g., t o nic, 
at o nic, or m y o cl o nic seiz ures).  Hist or y of a n y ot her seiz ure t y pe c urre ntl y i n re missi o n 
m ust be a dj u dicate d b y t he me dical m o nit or.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     8  
3.  Has a hist or y of fe brile s eiz ures after 3 years  of a ge. 
4.  Has a hist or y c o nsiste nt wit h j u ve nile a bse nce e pile ps y or j u v e nile m y o cl o nic e pile ps y.  
5.  C urre ntl y ta ki n g fel ba mate  
6.  C urre ntl y ta ki n g p h e n yt oi n, fl u v o x a mi ne, car ba maze pi ne, or St. J o h n’s W ort.  
7.  C urre ntl y ta ki n g c o nc o mita nt me dicati o ns t hat are str o n g i n hi bit ors/ i n d ucers/se nsiti ve 
s u bstrates wit h a narr o w t hera pe utic i n de x f or c yt oc hr o me P 4 5 0 3 A 4 ( C Y P 3 A 4), 
C Y P 2 C 9, or C Y P 2 C 1 9  [ N ote: Sta ble d oses of Val pr oic Aci d d uri n g t he scree ni n g, 
titrati o n, treat me nt, a n d f oll o w-u p peri o ds are per mitte d] . 
8.  C urre ntl y o n a ket o ge n ic diet. 
9.  I n t he o pi ni o n of t h e i n vesti gat or, a n y cli nicall y si g nifica nt, u nsta ble me dical 
a b n or malit y, c hr o nic dise ase, or a hist or y of a cli ni call y si g nifica nt a b n or malit y of t he 
car di o vas c ular, gastr oi nt esti nal, res pirat or y, h e patic, or re n al s yste ms.  
1 0.  Cl i nicall y si g nifica nt a b n or mal li ver f u ncti o n test ( L F T) val u es, i ncl u di n g: 
a.  Al b u mi n, direct bilir u bi n, t otal bilir u bi n, as partate a mi n otra nsferase ( A S T), 
a n d ala ni ne a mi n otra nsferase ( A L T) ≥3 ti mes t he u p per li mit of n or mal ( U L N).  
1 1.  Hist or y or prese n ce of a b n or mal E C Gs t hat are cli nicall y si g nifica nt i n t he o pi ni o n of 
t he i n vesti gator.  
1 2.  Has a c urre nt or hist or y of cli nicall y si g nifica nt i ntellect ual disa bilit y or maj or 
ps yc hiatric diseas e, i ncl u di n g a utis m s pectr u m dis or der, w hic h w o ul d i nterfere wit h 
c o m plia nce.  
1 3.  F or patie nts a ge d 7 t o 1 7 years of a ge a n d f or w h o m t he C -S S R S is de vel o p me ntall y 
a p pr o priate, a n affir mati ve a ns wer t o q ueries re gar di n g acti ve s uici dal i deati o n wit h 
s o me i nte nt t o act b ut wit h o ut a s pecific pla n or acti ve s uici dal i deati o n wit h a s pecific 
pla n a n d i nte nt o n t he C -S S R S assess me nt at t he Scree ni n g Visit. Pati e nts w h o ha ve 
si g nifica nt fi n di n gs f or s uici dal i deati o n as assess e d b y t h e C-S S R S m ust be referre d t o 
t he i n vesti gat or f or f oll o w-u p e val uati o n.  
1 4.  A n y hist or y of atte m pte d s uici de.  
1 5.  Pre vi o usl y recei ve d  a n y i n vesti gati o nal dr u g or de vice or i n vesti gati o nal t hera p y 
wit hi n 3 0 da ys bef ore  Scree ni n g.  
1 6.  Ta ke n a n y ca n na bi n oi ds (ca n na bi di ol, Δ 9-tetra h y dr oca n na bi n ol [ Δ9-T H C], he m p oil, 
Real m Oil , or marij ua na) i n t he 3 0 da ys pri or t o t he Scree ni n g Visit.  
1 7.  Hist or y of a n aller gi c reacti o n or a k n o w n or s us p ecte d se nsiti vit y t o a n y s u bsta nce t hat 
is c o ntai ne d i n t he i n vesti gati o nal pr o d u ct f or m ulati o n. 
1 8.  K n o w n i nfecti o n wit h he patitis B, he patitis C, or h u ma n i m m u n o deficie nc y vir us 
( HI V). 
1 9.  I n t he o pi ni o n of t h e i n vesti gat or, t he p atie nt is u ns uita ble i n a n y ot her wa y t o 
partici pate i n t his st u d y.  
2 0.  B o d y wei g ht < 1 0 k g  or > 9 0  k g.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     9  
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:  
Ca n na bi di ol Oral S ol uti o n: a n oral s ol uti o n c o ntai ni n g p har m ace utical gra d e ca n n a bi di ol 
( p har mace utical gra de, s y nt hetic). 
T he i n vesti gati o nal pr o d uct will be d ose d orall y i n t hree d ose c o h orts. T otal dail y d oses of 1 0, 
2 0, or 3 0  m g/ k g/ da y will be a d mi nistere d i n t w o dail y d oses of 5, 1 0, or 1 5  m g/ k g/ d ose. D oses 
hi g her t h a n 2 0  m g/ k g/ da y will be titrate d. Ca n na bi di ol Oral S ol uti o n will be a d mi nistere d wit h 
f o o d e x ce pt f or w h e n fasti n g P K val ues will be o bt ai ne d  (Visit 6 [ Wee k 4, Da y  7 ]). 
D ur ati o n of tre at me nt:  
T he ma xi m u m d urati o n of t he st u d y fr o m scree ni n g t o t he f oll o w-u p of A Es call will be 
a p pr o xi matel y 1 0  wee ks . 
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:  
N ot a p plic a ble.  
Criteri a f or e v al u ati o n:  
Effic ac y E n d p oi nts  
•  % c ha n ge i n a bse nce seiz ure c o u nts c o m pari n g treat me nt at Wee k 4 ( Visit 5 ) 
vi de o -E E G t o Baseli ne ( Visit 2) vi de o -E E G a n d c o m pari n g d os es.  
•  % c ha n ge i n ti me t o a bs e nce seiz ure d uri n g h y per ve ntilati o n testi n g  o n vi de o -E E G 
c o m pari n g treat me nt at Wee k 4 ( Visit 5 ) t o Baseli ne ( Visit 2) a n d c o m pari n g 
d oses.  
•  % patie nts seiz ure free at Wee k 4 ( Visit 5 ) base d o n seiz ure diar y,  c o m pari n g 
d oses.  
•  In v esti gat or C GI -I at W ee k 4 ( Visit 5 ) c o m pari n g d oses. 
S afet y E n d p oi nts  
•  In ci de nce, t y p e, a n d s e verit y of A Es a n d seri o us a d verse e v e nts ( S A Es) occ urri n g 
d uri n g t he Treat me nt Peri o d (i.e., treat me nt -e mer ge nt a d verse e ve nts [ T E A Es]).  
•  I n ci de nce, t y p e, ti mi n g, a n d se verit y of A Es a n d seri o us a d verse e v e nts ( S A Es) 
occ urri n g d uri n g t he Safet y Peri o d. (i.e., treat me nt -e mer ge nt a d verse e v e nts 
[ T E A Es]). 
•  C ha n ges fr o m Baseli ne ( Visit 2) i n vital si g ns d uri n g t he Treat me nt Peri o d. 
•  C ha n ges fr o m Scree ni n g (Visit 1 ) i n la b orat or y val ues ( he mat ol o g y, c h e mistr y, a n d 
uri nal ysis) d uri n g t he Treat m e nt Peri o d.  
P h ar m a c o ki netic E n d p oi nts  
•  C ma x  a n d d ose-n or malize d C ma x : fe d ( Visit 5 [ Wee k 4, Da y 6 ]) a n d faste d ( Visit 6 
[ Wee k 4, Da y 7 ]). 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     1 0  
•  Area u n d er t he plas ma c o nce ntrati o n c ur ve (A U C ( 0-t) a n d d ose n or malize d area 
u n der t he c ur ve (A U C ( 0-t) / Dose ): fe d ( Visit 5 [ Wee k 4, Da y 6 ]) a n d faste d ( Visit 6 
[ Wee k 4, Da y 7 ]). 
•  Tr o u g h pl as ma c o nce ntrati o n ( C tr o u g h) a n d d ose n or malize d  tr o u g h plas ma 
c o nce ntr ati o n  ( Ctr o u g h/ D ose): fe d ( Visit 5 [ Wee k 4, Da y 6 ]), a n d faste d ( Visit 6 
[ Wee k 4, Da y 7 ), Visit  3 , or t he Earl y Wit hdra wal Visit .  
St atistic al Met h o ds:  
Efficac y A nal ysis  
T he res ults of t he vi de o -E E G (i ncl u di n g prese n ce or a bse nce of h y p er ve ntilati o n), C GI -I, a n d 
seiz ure diar y assess me nts will be s u m marize d usi n g s u m mar y ta bl es, listi n gs, a n d fi g ures 
( T L Fs), as a p pr o priate.  C o nti n u o us varia bles will be s u m marize d usi n g descri pti ve statistics: 
sa m ple siz e ( n), mea n, st a n dar d de vi ati o n ( S D), or c oeffi cie nt of variati o n ( C V %) as 
a p pr o priate, m e dia n, i nter q uartile ra n ge, mi ni m u m a n d ma xi m u m.  Cate g orical vari a bles will 
be s u m marize d b y prese nti n g t he n u m ber (fre q ue n c y) a n d perce nta ge i n eac h cate g or y.  
Safet y A nal ysis  
All safet y assess me nts, i ncl u di n g A Es, cli nical la b orat or y e v al uati o ns, vital si g ns, 1 2 -lea d 
E C Gs, C -S S R S (c hil dre n a n d a d olesce nts a ge d 7 t o 1 7 years, if a p pr o priate), c o nc o mita nt 
A E D bl o o d le vels, p h ysical a n d ne ur ol o gi cal e xa mi nati o ns will be liste d. W he n a p pr o priate, 
t he y will be s u m mariz e d wit h descri pti ve statistics b y a ge a n d d os e c o h ort. T he Me dical 
Dicti o nar y f or Re g ul at or y A cti vities ( Me d D R A; Versi o n 2 0 . 0 or hi g her) will be use d t o 
classif y all a d verse e v e nts wit h res pect t o s yste m or ga n class a n d preferre d ter m. A d verse 
e ve nt s u m maries will i ncl u de o nl y T E A Es, w hic h will be s u m marize d f or eac h treat me nt 
gr o u p.  
Cli nical la b orat or y fi n di n gs a n d vital si g ns will be s u m marize d f or all patie nts f or o bser ve d 
val ues a n d c h a n ge fr o m baseli ne. S hifts fr o m bas eli ne acc or di n g t o n or mal ra n ge criteria will 
als o be prese nt e d f or all patie nts.  
T he ne ur ol o gic al e x a mi nati o n res ults will be liste d a n d s u m marize d descri p ti vel y. S hifts fr o m 
baseli ne acc or di n g t o n or mal a n d a b n or mal criteri a will als o be prese nt e d f or all patie nts i n t he 
safet y p o p ulati o n. 
Res ults of p h ysical e x a mi nati o ns c o n d ucte d t hr o u g h o ut t he st u d y will be prese nte d i n listi n gs 
a n d s u m mariz e d descri pti v el y. S hifts fr o m baseli n e acc or di n g t o n or mal a n d a b n or mal criteria 
will als o be prese nte d f or all patie nts i n t he safet y p o p ulati o n.  
Pri or me dicati o n a n d c o n c o mita nt me dicati o ns will be re p orte d i n t he d ata listi n gs.  
Statistical a nal yses will b e perf or me d  usi n g S A S ®  ( Versi o n 9. 3 or hi g her, S A S I nstit ute I nc.) 
or R ( Versi o n 3. 3 or hi g h er, R os well Par k Ca ncer I nstit ute).  
P har mac o ki netic A n al ysis  
T he P K p o p ulati o n will be use d f or P K data a n al ysis. T he P K p o p ulati o n c o nsists of patie nts 
w h o recei ve at least o ne d ose of Ca n na b a di ol Oral S ol uti o n a n d ha ve at least o ne usa ble C B D 
plas ma c o nce ntrati o n me as ure me nt.  Descri pti ve statistics of tr o u g h plas ma c o nce ntr ati o n a n d 
P K para meters data f or C B D a n d 7 -O H C B D b y Visit, D ose, a n d Res p o nse will be pr o vi de d. 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
 
 
 
 
 
 
     C O N FI D E N TI A L  
 
 
 
 
 
 
                     1 1  
T he f o ll o wi n g n o n c o m part me ntal P K para met ers will be esti mate d fr o m t he plas ma 
c o nce ntr ati o n -ti me data: area u n d er t he c ur ve fr o m ti me 0 t o t he last meas ure d c o nce ntrati o n 
( A U C0 -t) b y ma xi m u m plas ma c o nce ntrati o n ( Cma x ), a n d ti me t o reac h ma xi m u m plas ma 
c o nce ntr ati o n ( T ma x ) usi n g P h oe ni x Wi nN o nli n ®  ( Versi o n 7  or hi g her; P harsi g ht C or p orati o n, 
Car y, N C 2 7 5 1 8, U S A).  A d diti o nal P K para meters ma y be esti mate d, as a p pr o priate. 
E x pl orat or y a nal ysis of d ose (e x p os ure) -res p o nse relati o ns hi p will be perf or me d.  F urt h er 
p o p ulati o n P K a p pr oac h ma y b e use d f or P K para meter esti mati o n, as a p pr o priate.  
Missi n g D at a  
T here will be n o i m p utati o n of t he missi n g val ues f or t he efficac y, safet y, or P K p o p ulati o n. 
All assess me nts will be c o n d ucte d base d o n all t he o bser ve d dat a.   
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc.      
 
 
Pr ot oc ol N u m ber I N S 0 1 1-1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
                                           C O N FI D E N TI A L  
                    
                                1 2  
T a ble  1 : 
Sc he d ule of E ve nts  
A S S E S S M E N T S  
S C R E E NI N G 
P E RI O D a 
T I T R A TI O N P E RI O D  
T R E A T M E N T P E RI O D  
F O L L O W -
U P 
P E RI O D C  
Visit N u m b er  
1  
2  
B aseli ne  
C all / 
E m ail  
3  
4  
5  
6   
E n d of 
St u d y  
E arl y 
Wit h dr a w al  
Visit p  
7  
St u d y Ti me P oi nts  
D a ys -2 8  t o -1  
D a y  1  
0 -5 or 0 -1 0 
d a ys  
D a y 1  
Wee k 2  
Wee k 4 
( D a y 6 ) 
Wee k 4 
( D a y 7 ) 
 
Wee k 6  
Visit Wi n d o w ( Da ys)  
± 5  
± 5  
 
0  
0  
± 3  
± 3  
± 5  
± 5  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
Re vie w of 
i ncl usi o n/e xcl usi o n 
criteria  
X  
X  
 
 
 
 
 
 
 
Re vie w of hist oric 
seiz ure c o u nts 
X  
 
 
 
 
 
 
 
 
4 -h o ur vi de o -E E G d, e 
 
X b 
 
 
 
X  
 
X  
 
Seiz ure diar y f 
X  
X  
X  
X  
X  
X  
 
X  
 
Meal diar y
f 
 
X  
X  
X  
 
X  
 
X  
 
De m o gra p hics  
X  
 
 
 
 
 
 
 
 
Assess me nts of 
past/c urre nt A E Ds  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Me dical S ur gical 
Hist or y  
X  
 
 
 
 
 
 
 
 
C o nc o mita nt 
Me dicati o ns  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vi tal Si g nsg 
X  
X  
 
X  
X  
 
X  
X  
 
Cli nical La b orat or y 
Assess me nts h  
X  
 
 
X  
X  
 
X  
X  
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
                                        C O N FI D E N TI A L  
                                                     1 3  
A S S E S S M E N T S  
S C R E E NI N G 
P E RI O D a 
T I T R A TI O N P E RI O D  
T R E A T M E N T P E RI O D  
F O L L O W -
U P 
P E RI O D C  
Visit N u m b er  
1  
2  
B aseli ne  
C all / 
E m ail  
3  
4  
5  
6   
E n d of 
St u d y  
E arl y 
Wit h dr a w al  
Visit p  
7  
St u d y Ti me P oi nts  
D a ys -2 8  t o -1  
D a y  1  
0 -5 or 0 -1 0 
d a ys  
D a y 1  
Wee k 2  
Wee k 4 
( D a y 6 ) 
Wee k 4 
( D a y 7 ) 
 
Wee k 6  
Visit Wi n d o w ( Da ys)  
± 5  
± 5  
 
0  
0  
± 3  
± 3  
± 5  
± 5  
C o nc o mita nt A E D 
le vels 
 
X  
 
 
 
 
X  
X  
 
P K Sa m ples  
 
 
 
X i 
 
X i 
X i 
X j 
 
1 2 -lea d E C G 
X  
 
 
 
 
 
X  
X  
 
Uri ne A nal ysis  
X  
 
 
 
 
 
X  
X  
 
Uri ne pre g na nc y 
scree n f or p ost-
me narc hal fe males  
X  
 
 
 
 
 
 
 
 
P h ysical E xa mi nati o n k  
X  
 
 
 
 
 
 
 
 
Ne ur ol o gical 
E xa mi nati o n l 
X  
X  
 
X  
X  
 
X  
X  
 
Hei g ht/ Wei g ht  
X  
 
 
X  
 
 
X  
X  
 
C GI -I 
 
 
 
X  
 
X  
 
X  
 
C -S S R S  
X  
 
 
 
 
X  
 
X  
 
D osi n g wit h 
Ca n na bi di ol Oral 
S ol uti o n  
 
X m  
X  
X  
X  
X  
X n 
X o 
 
Dr u g Acc o u nta bilit y  
 
 
X  
X  
X  
 
X  
X  
 
A Es  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E n d of St u d y  
 
 
 
 
 
 
X q 
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
                                        C O N FI D E N TI A L  
                                                     1 4  
a Scree ni n g s h o ul d occ ur wit hi n 2 8  ( ± 5) da ys .  
b P atie nts  will ha ve a B aseli ne 4 -h o ur vi de o E E G (i ncl u di n g h y per ve ntilati o n) .  
c F oll o w -U p P eri o d Visit ( Visit 7 ) ma y be a p h o ne call.  
d  H y per ve ntilati o n testi n g will be c o n d ucte d d uri n g t he vi de o -E E G . 
e P atie nts  will ret ur n t o t he st u d y cli nic at Visit 5  or  t he Earl y Wit h dra wal  Visit  f or a re peat 4-h o ur vi de o -E E G .  
f Seiz ure diaries will be dis pe nse d d uri n g t he Scree ni n g Visit  ( Visit 1 ), re vie we d a n d ret ur ne d d uri n g Visits 2 t hr o u g h 5 , a n d c ollecte d d uri n g Visit 6 . A meal 
diar y will be c o m plete d at B aseli ne ( Visit 2); a n d  f or 2 4 h o urs bef ore eac h P K sa m pli n g visit at Visit 3 a n d Visit 5 ( W ee k 4, Da y 6) , or  t he Earl y Wit h dra wal 
Visit.  
g Vital si g ns will be ta ke n after a 5 -mi n ute seated rest. 
h  A uri ne di pstic k pre g na nc y t est will be perf or me d o n all fe male p ost -me narc hal patie nts d uri n g Scree ni n g ( Visit 1) . 
i Bl o o d f or p har mac o ki netic anal yses of C B D a n d 7 -O H C B D  will be dra w n at Visit 3 ( Da y 1) , Visit 5 ( Wee k 4, Da y 6 ), a n d Visit 6 (W ee k 4 , Da y 7 ). Bl o o d 
dra ws will b e ta ke n pre -d ose, 2, 4, a n d 6 h o urs after t he m or ni n g d ose ( b ut bef ore t he ne xt d ose).  I n t he Fe d state ( Visit 5, W ee k 4 Da y 6 ), pre-d ose bl o o d 
sa m ples s h o ul d be c ollecte d B E F O R E d osi n g wit h t he “ hi g h -fat” brea kfast (d ose w ill be a d mi nistere d wit hi n 3 0 mi n utes of start of brea kfast) .  I n t he F aste d state 
( Visit 6, W ee k 4 Da y 7 ), patie nts will be faste d f or 2 h o urs bef ore  t he d ose .   
j Tr o u g h val ues of C B D a n d 7 -O H C B D will be c ollecte d at t he Earl y Wit h dra wal Visit pri or t o d osi n g.  
k  T he p h ysical e xa mi nati o n will i ncl u de e val uati o n of ge neral a p peara nce, s ki n, e yes, ears, n ose, t hr oat, nec k, l y m p h n o des, c hest, heart, a b d o me n, a n d 
e xtre mities.  
l A  c o m plete ne ur ol o gical e xa m will be perf or me d d uri n g S cree ni n g ( Visit 1) a n d  bri ef ne ur ol o gical e xa mi nati o n ( me ntal stat us, cra nial ner ves, n ysta g m us, m ot or 
s yste m, se ns or y s yste m, refle xes, c o or di nati o n, gait, a n d stati o n) will be  perf or me d  at Visits 2  ( Baseli ne), 3, 4,  a n d 6  ( E n d of St u d y) or t he Earl y Wit h dra wal 
Visit.  
m  Titrati o n d ose of s t u d y dr u g will b e dis pe nse d after patie nt  q ualificati o n .  
n  A ris k/ be nefit assess me nt will b e ma d e a n d t he decisi o n o n w het her t o c o nti n ue t he patie nt t o t he l o n g-ter m safet y st u d y will be d oc u me nte d. If patie nt is n ot 
c o nti n ui n g i n t he safet y st ud y , dis pe nse Ca n na bi di ol Oral S ol uti o n f or T a per P eri o d.  P atie nts w h o d o n ot c h o ose t o e nr oll i n t he l o n g -ter m safet y st u d y will ta per 
t he d ose of Ca n na bi di ol Oral S ol uti o n acc or di n g t o t he f oll o wi n g sc he d ule: d oses bet wee n 2 0-3 0 m g/ k g/ da y will be re d uce d  t o 2 0 m g/ k g/ da y f or fi ve d a ys a n d 
t he n disc o nti n ue d; d oses ≤ 2 0 m g/ k g/ da y ca n be disc o nti n ue d wit h o ut titrati o n. T his ca n b e m o difie d b y t he i n vesti gat or base d u p o n t he patie nt’s res p o nse . 
o  St u d y dr u g will be c ollecte d  b ut n ot dis pe nse d.  
p If t he patie nt  wit h dra ws  pre mat urel y fr o m t he Treat me nt P eri o d, all E arl y W it h dra wal pr oce d ures s h o ul d be c o n d ucte d. Site staff will f oll o w u p wit h t he patie nt  
at 1 4 da ys  after c o m pleti o n of t he Earl y Wit h dra wal Visit via t he tele p h o ne t o c ollect i nf or mati o n re gar di n g A Es, A E Ds, a n d c o nc o mita nt me dicati o ns.  
q P atie nts ca n re -c o nse nt t o e nter t he l o n g -ter m safet y st u d y. If patie nt re-c o nse nts, t he n t he patie nt will c o nti n ue t o recei ve C B D at t heir c urre nt d ose.  
A E = a d verse e ve nt; A E D = a nti -e pile ptic dr u g; C GI -I = Cli nical Gl o bal  I m pressi o n –  Gl o bal I m pr o ve me nt; C -S S R S = C ol u m bia S uici de Se verit y Rati n g Scale; 
E E G = electr oe nce p hal o gra p h y;  P K = p har mac o ki netics.  
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc.      
 
   Pr ot oc ol N u m ber I N S 0 1 1-1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
                                                                 C O N FI D E N TI A L  
                                                    1 5  
      Fi g ure  1 :  St u d y Desi g n Sc he m ati c  
 
C O H O R T 1
 C B D 2 0 m g /k g / da y BI D f or 4 w ee ks
C O H O R T 2
1 . C B D  2 0 m g / k g/ da y BI D f or 5 da ys 
2 . C B D  3 0 m g /k g / da y BI D f or 4 w ee ks
C O H O R T 3  
 C B D 1 0 m g /k g / da y  BI D f or 4 w ee ks
S C R E E NI N G
N O T E : All patie nts i n C o h ort 1 will be tre ate d pri or t o i niti ati o n of e nr oll me nt i nt o
C o h ort 2 , a n d all patie nts i n C o h ort 2 will be  pri or t o i nitiati o n of e nr oll me nt i nt o C o h ort 3 . 
L O N G -T E R M  
S A F E T Y  ST U D Y ?
F O L L O W- U P 
P E RI O D 
N
L O N G- T E R M 
S A F E T Y S T U D Y 
I N S0 1 1 -1 7 -1 1 3
Y
F O L L O W - UP  PE RI O D : P ati e nts w h o d o 
n ot c h o ose t o e nr oll i n t he l o n g-ter m 
s afet y st u d y will t a per t heir d os e a n d 
rec ei ve a f oll o w- u p 4 w ee ks aft er ta per 
c o m plet e d.
 
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc.      
 
Pr ot oc ol N u m ber I N S 0 1 1-1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
1 6  
T A B L E O F C O N T E N T S  
P R O T O C O L A P P R O V A L P A G E  ...................................................................................................2  
P R O T O C O L S Y N O P SI S  ................................................................................................................3  
T A B L E O F C O N T E N T S  ...............................................................................................................1 6  
List of Ta bl es  .................................................................................................................................2 1  
List of Fi g ures  ................................................................................................................................2 1  
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  ................................................2 2  
1.  
I N T R O D U C TI O N ......................................................................................................2 5  
1. 1.  
Ca n na bi di ol  .................................................................................................................2 5  
1. 1. 1.  
Mec ha nis m of Acti o n  .................................................................................................2 5  
1. 1. 2.  
Meta b olis m a n d P ote ntial Dr u g I nteracti o ns  ..............................................................2 5  
1. 2.  
N o ncli nical E x perie nce  ...............................................................................................2 6  
1. 2. 1.  
Safet y  ..........................................................................................................................2 6  
1. 2. 2.  
Efficac y i n A ni mal M o dels of E pile ps y  .....................................................................2 6  
1. 3.  
Cli nical E x perie nce  .....................................................................................................2 6  
1. 3. 1.  
P har mac o ki netics  ........................................................................................................2 9  
1. 3. 2.  
O ver vie w of Safet y  .....................................................................................................3 0  
1. 3. 3.  
Cli nical Safet y D ata  ....................................................................................................3 0  
1. 3. 4.  
Efficac y i n H u ma n E pile ps y  .......................................................................................3 1  
1. 4.  
C hil d h o o d A bse nce E pile ps y  ......................................................................................3 1  
1. 5.  
D ose Selecti o n Rati o nale  ............................................................................................3 2  
1. 6.  
S u m mar y of P ote ntial Ris ks a n d Be n efits  ..................................................................3 5  
2.  
S T U D Y O BJ E C TI V E S  ..............................................................................................3 7  
2. 1.  
Pri mar y O bj ecti ve  .......................................................................................................3 7  
2. 2.  
Sec o n dar y O bj ecti ves  .................................................................................................3 7  
3.  
I N V E S TI G A TI O N A L P L A N .....................................................................................3 8  
3. 1.  
O verall St u d y Desi g n  ..................................................................................................3 8  
3. 1. 1.  
Titrati o n a n d Treat me nt Peri o ds  .................................................................................3 8  
3. 1. 2.  
F oll o w -U p Peri o d  .......................................................................................................3 9  
3. 1. 3.  
St u d y Assess me nts ......................................................................................................3 9  
3. 2.  
Patie nt Selecti o n  .........................................................................................................4 1  
3. 2. 1.  
I n cl usi o n Criteria ........................................................................................................4 1  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            1 7  
3. 2. 2.  
E x cl usi o n Criteria  .......................................................................................................4 2  
3. 3.  
Re m o val of Patie nts fr o m T hera p y or Assess me nt .....................................................4 3  
3. 4.  
D ose A dj ust me nt Criteria  ...........................................................................................4 3  
3. 5.  
St o p pi n g R ules  ............................................................................................................4 4  
4.  
T R E A T M E N T S  ..........................................................................................................4 5  
4. 1.  
Treat me nts A d mi nistere d  ............................................................................................4 5  
4. 2.  
I d e ntit y of I n vesti gati o nal Pr o d uct .............................................................................4 5  
4. 3.  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps  .................................................4 5  
4. 4.  
Selecti o n a n d Ti mi n g of D ose f or E ac h S u bject  .........................................................4 5  
4. 5.  
Bli n di n g a n d U n bli n di n g Treat me nt Assi g n me nt  .......................................................4 5  
4. 6.  
Treat me nt C o m plia nce  ................................................................................................4 6  
4. 7.  
Per mitte d a n d Pr o hi bite d T hera pies  ............................................................................4 6  
4. 7. 1.  
Per mitte d T hera pies  ....................................................................................................4 6  
4. 7. 2.  
Pr o hi bite d T hera pies  ...................................................................................................4 6  
4. 8.  
Treat me nt Aft er t he E n d of St u d y  ..............................................................................4 7  
5.  
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 8  
5. 1.  
La b eli n g a n d Pac k a gi n g  ..............................................................................................4 8  
5. 1. 1.  
La b eli n g  ......................................................................................................................4 8  
5. 1. 2.  
Pac ka gi n g  ....................................................................................................................4 8  
5. 2.  
Dis pe nsi n g a n d St or a ge  ..............................................................................................4 8  
5. 3.  
Dr u g S u p pl y a n d Acc o u nta bilit y  ................................................................................4 9  
6.  
S T U D Y A S S E S S M E N T S  ..........................................................................................5 0  
6. 1.  
Efficac y Assess me nts  .................................................................................................5 0  
6. 1. 1.  
Vi de o -Electr o e nce p hal o gra p h y ( Vi de o -E E G)  ............................................................5 0  
6. 1. 2.  
Cli nical Gl o ba l I m pr essi o n –  Gl o bal I m pr o ve me nt ( C GI -I) ......................................5 0  
6. 1. 3.  
Seiz ure Diaries  ............................................................................................................5 0  
6. 2.  
Safet y Assess me nts  .....................................................................................................5 0  
6. 2. 1.  
De m o gra p hics a n d Me di cal Hist or y  ...........................................................................5 0  
6. 2. 2.  
P h ysical E x a mi nati o ns  ................................................................................................5 0  
6. 2. 3.  
Ne ur ol o gical E x a mi nati o ns  ........................................................................................5 1  
6. 2. 4.  
Vital Si g ns  ..................................................................................................................5 1  
6. 2. 5.  
Electr ocar di o gra ms  .....................................................................................................5 1  
6. 2. 6.  
Cli nical La b orat or y Assess me n ts ...............................................................................5 1  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            1 8  
6. 2. 7.  
C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S)  ...................................................5 1  
6. 2. 8.  
A d verse E v e nts a n d Seri o us A d verse E v e nts  .............................................................5 2  
6. 2. 8. 1.  
Defi niti o n of A d vers e E v e nts  .....................................................................................5 2  
6. 2. 8. 2.  
Classificati o n of A d verse E ve nts  ................................................................................5 3  
6. 2. 8. 3.  
Ca usal it y/ Dr u g Relati o ns hi p Assess me nt ...................................................................5 3  
6. 2. 8. 4.  
Defi niti o n of Seri o us A d verse E ve nts  ........................................................................5 4  
6. 2. 8. 5.  
Seri o us A d verse E v e nts Acti o ns Ta ke n  ......................................................................5 4  
6. 2. 8. 6.  
Seri o us A d verse E v e nts O utc o me at t he Ti me of Last O bs er vati o n  ..........................5 4  
6. 2. 8. 7.  
A d verse E v e nt Rec or di n g a n d Re p orti n g  ...................................................................5 4  
6. 2. 8. 8.  
A d verse E v e nt F oll o w -U p  ..........................................................................................5 5  
6. 2. 8. 9.  
Safet y Data Re vi e w  ....................................................................................................5 5  
6. 2. 8. 1 0.  
S pecial C o nsi derati o ns  ................................................................................................5 6  
6. 2. 9.  
P har mac o ki netics Assess me nts  ..................................................................................5 6  
7.  
S T U D Y P R O C E D U R E S  ............................................................................................5 7  
7. 1.  
Scree ni n g  ....................................................................................................................5 7  
7. 2.  
Titrati o n Peri o d  ...........................................................................................................5 7  
7. 2. 1.  
Baseli ne ( Visit 2, Da y 1)  ............................................................................................5 7  
7. 3.  
Treat me nt Peri o d  ........................................................................................................5 8  
7. 3. 1.  
Visit 3 ( Da y 1)  ............................................................................................................5 8  
7. 3. 2.  
Visit 4 ( Wee k 2)  ..........................................................................................................5 8  
7. 3. 3.  
Visi t 5 ( Wee k 4, Da y 6) ..............................................................................................5 9  
7. 3. 4.  
E n d of St u d y: Visit 6 ( Wee k 4, Da y 7)  .......................................................................5 9  
7. 4.  
Earl y Wit h dra wal Visit  ...............................................................................................6 0  
7. 5.  
Visit 7 ( F oll o w -U p Peri o d)  .........................................................................................6 0  
8.  
S T A TI S TI C S  ..............................................................................................................6 1  
8. 1.  
Efficac y E n d p oi nts  ......................................................................................................6 1  
8. 2.  
Safet y E n d p oi nts  .........................................................................................................6 1  
8. 3.  
P har mac o ki netic E n d p oi nts  ........................................................................................6 1  
8. 4.  
Sa m ple Siz e Deter mi nati o n  ........................................................................................6 1  
8. 5.  
A nal ysis P o p ulati o ns  ..................................................................................................6 1  
8. 6.  
Statistical A nal yses  .....................................................................................................6 2  
8. 6. 1.  
St u d y S u bje cts a n d De m o gra p hics  .............................................................................6 2  
8. 6. 1. 1.  
Dis p ositi o n a n d Wit h dra wals  ......................................................................................6 2  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            1 9  
8. 6. 1. 2.  
Pr ot oc ol De viati o ns  ....................................................................................................6 2  
8. 6. 1. 3.  
De m o gra p hics a n d Ot her Baseli ne C haracteristics  .....................................................6 2  
8. 6. 2.  
E x p os ure a n d C o m plia nce  ..........................................................................................6 2  
8. 6. 3.  
Efficac y A nal yses  .......................................................................................................6 2  
8. 6. 4.  
Safet y a n d T olera bilit y A nal yses  ................................................................................6 3  
8. 6. 4. 1.  
A d verse E v e nts  ...........................................................................................................6 3  
8. 6. 4. 2.  
Cli nical La b orat or y E val uati o ns  .................................................................................6 3  
8. 6. 4. 3.  
Vital Si g ns  ..................................................................................................................6 3  
8. 6. 4. 4.  
Electr ocar di o gra ms  .....................................................................................................6 3  
8. 6. 4. 5.  
P h ys ical E x a mi nati o n Fi n di n gs ..................................................................................6 3  
8. 6. 4. 6.  
C ol u m bia S uici de Se verit y Rati n g Scale ( C -S S R S)  ...................................................6 4  
8. 6. 5.  
I nteri m A nal ysis ..........................................................................................................6 4  
8. 6. 6.  
P har mac o ki netic A n al ys es  ..........................................................................................6 4  
8. 6. 7.  
Missi n g Data  ...............................................................................................................6 4  
9.  
S T U D Y C O N D U C T  ...................................................................................................6 5  
9. 1.  
S p o ns or a n d I n vesti gat or Res p o nsi bilities  ..................................................................6 5  
9. 1. 1.  
S p o ns or Res p o nsi bilities  .............................................................................................6 5  
9. 1. 2.  
I n v esti gator Res p o nsi bilities  .......................................................................................6 5  
9. 2.  
Site I nitiati o n  ..............................................................................................................6 6  
9. 3.  
Scree n Fail ures  ............................................................................................................6 6  
9. 4.  
St u d y D oc u me nts  ........................................................................................................6 6  
9. 4. 1.  
I n v esti gat or’s Re g ulat or y D oc u me nts ........................................................................6 6  
9. 4. 2.  
Case Re p ort F or ms  .....................................................................................................6 6  
9. 4. 3.  
S o urce D oc u m e nts  ......................................................................................................6 7  
9. 5.  
St u d y Ter mi nati o n  ......................................................................................................6 7  
9. 6.  
St u d y Site Cl os ure  ......................................................................................................6 7  
9. 6. 1.  
Rec or d Rete nti o n  ........................................................................................................6 7  
9. 6. 2.  
P har mac o ki netic/ La b orat or y Sa m ple Ret e nti o n  .........................................................6 8  
1 0.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .........................................6 9  
1 0. 1.  
C ha n ges T o T he Pr ot oc ol  ...........................................................................................6 9  
1 0. 2.  
M o nit ori n g  ..................................................................................................................6 9  
1 0. 3.  
Data Re vie w M eeti n g  .................................................................................................6 9  
1 0. 4.  
Pr ot oc ol Vi olati o ns  .....................................................................................................6 9  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 0  
1 0. 5.  
Q ualit y Ass ura nce A u dit  .............................................................................................7 0  
1 1.  
R E G U L A T O R Y  A N D E T HI C A L C O N SI D E R A TI O N S  ..........................................7 1  
1 1. 1.  
Re g ulat or y A ut h orit y A p pr o val  ..................................................................................7 1  
1 1. 2.  
Et hical C o n d uct of t he St u d y  ......................................................................................7 1  
1 1. 3.  
State me nt of I n vesti gat or/ Dele gati o n of A ut h orit y  ....................................................7 1  
1 1. 4.  
Patie nt I nf or me d C o nse nt  ...........................................................................................7 1  
1 1. 5.  
I n v esti gator Re p orti n g Re q uire me nts  .........................................................................7 2  
1 2.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  ......................................................7 3  
1 2. 1.  
Data Ma na ge me nt  .......................................................................................................7 3  
1 2. 2.  
Case Re p ort F or ms a n d S o urce D oc u me nts  ...............................................................7 3  
1 2. 3.  
D oc u me ntati o n a n d Rete nti o n of Esse ntial D oc u me nts  .............................................7 3  
1 2. 4.  
Fi na ncial  Discl os ur e  ...................................................................................................7 3  
1 3.  
F A CI LI TI E S  ...............................................................................................................7 5  
1 4.  
U S E O F I N F O R M A TI O N A N D P U B LI C A TI O N P O LI C Y  .....................................7 6  
1 4. 1.  
Use of I nf or mati o n  ......................................................................................................7 6  
1 4. 2.  
P u blicati o n P olic y  .......................................................................................................7 6  
1 5.  
R E F E R E N C E S ( A V AI L A B L E U P O N R E Q U E S T)  ..................................................7 7  
1 6.  
I N V E S TI G A T O R SI G N A T UR E P A G E  ....................................................................8 0  
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc.      
 
Pr ot oc ol N u m ber I N S 0 1 1-1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
2 1  
List of T a bles  
Ta ble  1:  
Sc he d ule of E ve nts  .....................................................................................................1 2  
Ta ble  2:  
Ca n na bi di ol Oral S ol uti o n E x p os ure ( St u d y I N S 0 1 1 -1 4 -0 3 0)  ...................................3 3  
Ta ble 3:  
Ca n na bi di ol Oral S ol uti o n D ose Re d ucti o n b y I nitial Pla n ne d D ose ( St u d y 
I N S 0 1 1-1 4 -0 3 0)  ..........................................................................................................3 4  
Ta ble 4:  
Distri b uti o n of Patie nts b y Ca n na bi di ol Oral S ol uti o n D ose ( St u d y I N S 0 1 1 -
1 4 -0 3 0)  ........................................................................................................................3 4  
 
List of Fi g ures  
Fi g ure  1:  
St u d y Desi g n Sc he matic  .............................................................................................1 5  
 
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 2  
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 . 
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
5 -H T 1 a 
5 -h y dr o x ytr y pta mi ne 1 a 
A C T H  
a dre n oc ortic otr o pic h or m o ne  
A E  
a d verse e ve nt  
A E Ds  
a nti-e pile ptic dr u gs  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferas e  
A PI  
acti ve p har m ace utical i n gre die nt  
A S T  
as partate a mi n otra nsferas e  
A U C  
area u n d er t he c ur ve  
A U C 0 -t 
area u n d er t he c o nce ntrati o n -ti me c ur ve fr o m 0 
( pre d ose) t o t he last q ua ntifia ble c o nce ntr ati o n 
B MI  
b o d y mass i n de x  
BI D  
bis i n die (t wice a da y)  
B U N  
bl o o d urea nitr o ge n  
C A E  
c hil d h o o d a bse nce e pile ps y1 A 1  
C B 1  
ca n na bi n oi d rece pt or 1  
C B 2  
ca n na bi n o i d rece pt or 2 
C B D  
ca n na bi di ol  
C F R  
C o de of Fe d eral Re g ul ati o ns  
C GI -I 
Cli nical Gl o bal I m pr essi o n –  Gl o bal I m pr o ve me nt  
c G M P 
c urre nt G o o d M a n ufact uri n g Practices  
C L B  
cl o baza m  
C ma x  
ma xi m u m plas ma c o nce ntrati o n  
C tr o u g h 
plas ma tr o u g h c o nce ntrati o ns  
C N S  
central ner v o us s yste m  
C R F  
case re p ort f or m  
C R A  
cli nical researc h ass ociat e  
C R O  
c o ntract r esearc h or ga nizati o n  
C -S S R S  
C ol u m bia S uici de Se verit y Rati n g Scale  
C V %  
c oeffi cie nt of variati o n  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 3  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
C Y P  
c yt o c hr o me P 4 5 0  
C Y P 1 A 1  
C yt o c hr o me P 4 5 0 1 A 1  
C Y P 2 C 1 9  
C yt o c hr o me P 4 5 0 2 C 1 9  
C Y P 2 C 9  
C yt o c hr o me P 4 5 0 2 C 9  
C Y P 3 A 4  
C yt o c hr o me P 4 5 0 3 A 4  
C Y P 3 A 5  
C yt o c hr o me P 4 5 0 3 A 5  
D E A  
Dr u g E nf orce me nt A d mi nistrati o n  
E C G  
electr ocar di o gra m  
e C R F 
electr o nic case re p ort f or m  
E D C  
electr o nic d ata ca pt ure  
E E G  
electr oe n ce p h al o gra m  
E E N T  
e yes, ears, n ose, a n d t hr oat 
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  
HI V  
h u ma n i m m u n o deficie nc y vir us  
I B 
I n v esti gat or’s Br oc h ure 
I C D 
i nf or me d c o nse nt d oc u m e nt 
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
IE C  
I n d e pe n de nt Et hics C o m mittee 
I F N 
i nterfer o n 
I L-2  
i nterle u ki n-2  
I P 
I n v esti gati o nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d 
L D H  
lactate de h y dr o ge nas e 
M C T  
m e di u m c hai n tri gl yceri d es  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
O H  
h y dr o x y  
P K  
p har mac o ki netic(s)  
p Ka  
aci d diss ociati o n c o nsta nt  
P T  
preferre d t er m  
S A E  
seri o us a d verse e v e nt 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 4  
A b bre vi ati o n or S peci alist Ter m  
E x pl a n ati o n  
S A P  
Statistical A nal ysis Pla n  
S O P  
sta n dar d o perati n g pr oce d ure 
t ½ 
eli mi nati o n half -life 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  
T ma x  
ti me t o ma xi m u m plas ma c o nce ntr ati o n  
Δ 9-T H C  
Δ 9-tetra h y dr oca n na bi n ol 
T H C  
tetra h y dr oca n na bi n ol 
U S  
U nite d States  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 5  
1.  
I N T R O D U C TI O N 
Data pres e nte d i n t his secti o n i ncl u des o ver vie ws fr o m t he n o ncli nical a n d cli nical p u blis he d 
literat ure t hat re p orts o n vari o us ot her f or m ulati o ns of ca n na bi di ol ( C B D) ( pri maril y pla nt-
base d). A n al o g o us st u dies ha ve n ot bee n c o m plete d f or Ca n na bi di ol Oral S ol uti o n, t he s y nt h etic 
p har mace utical gra d e C B D t o be i n vesti gat e d i n t his st u d y.  
Please see t he I n vesti gat or’s Br oc h ure (I B) 1 f or m ore i nf or mati o n. 
1. 1.  
C a n n a bi di ol   
T he mai n acti ve c o nstit ue nt of ca n n a bis, Δ 9-tetra h y dr oca n na bi n ol ( Δ9-T H C) is t he pri nci pal 
ps yc h o acti ve c o nstit ue nt of marij ua na. Ca n n a bi di ol is n o n ps yc h oacti ve a n d t he sec o n d m ost 
a b u n da nt ca n n a bi n oi d . It has de m o nstrate d a p ot e ntial be nefit t o treati n g su bjects  wit h treat me nt -
resista nt e pile ps y.2 ,3 ,4 ,5  
I ns ys D e vel o p me nt C o m pa n y, I nc. ( hereafter referre d t o as t he S p o ns or) h as s uccessf ull y 
m a n ufact ur e d a p h ar mace utical gra d e , s y nt hetic C B D dr u g s u bsta n ce. It is ma n ufact ur e d i n 
I ns ys’ c urre nt G o o d Ma n ufact uri n g Practices (c G M P) ma n ufact uri n g facilit y. T his facilit y is 
a p pr o ve d b y t he Dr u g E nf orce m e nt A d mi nistrati o n ( D E A) a n d has bee n i ns pecte d  b y t he F o o d 
a n d Dr u g A d mi nistrati o n ( F D A). T his acti ve p h ar mace utical i n gre die nt is ≥ 9 9. 5 % p ure 6 a n d ca n 
be c o nsiste ntl y pr o d u ce d wit h o ut c o ncer n f or c o nt a mi na nt.  
1. 1. 1.  
Mec h a nis m of Acti o n  
T he m o de of acti o n of C B D is n ot f ull y u n d erst o o d. T he dr u g s u bsta nce ma nifests a l o w affi nit y 
f or e n d o ge n o us ca n n a bi n oi d rece pt ors 1 ( C B 1) a n d 2 ( C B 2). Ca n n a bi di ol acts as a n i n direct 
a nta g o nist of C B 1 a n d i n hi bits se veral C B 1 me diate d ∆9-T H C effects. 7 It als o sti m ulates t he 
va nill oi d rece pt or t y pe 1 8  a n d m o d ulates t he µ - a n d δ-o pi oi d rece pt ors. 9 It ma y als o i ncrease 
plas ma ∆9-T H C le vels b y i n hi biti n g he patic micr os o mal meta b olis m t hr o u g h c o m petiti vel y 
bi n di n g pr otei ns i n t he c yt oc hr o me P 4 5 0 ( C Y P) o xi dati ve s yste m. 1 0  Fi nall y, C B D ma y m o d ulate 
ne ur o nal h y pere x cita bilit y t hr o u g h o n e or m ore of t he f oll o wi n g mec ha nis ms:  
•  Bi directi o nal r e g ulati o n of calci u m h o me ostasis via t he mit oc h o n dri al 
s o di u m/calci u m e x c ha n ger. 1 1  
•  A g o nistic pr o p erties at 5 -h y dr o x ytr y pt a mi ne 1a ( 5 -H T 1a) rece pt ors.1 2 
•  E n ha nci n g e n d o ge n o us a de n osi ne le vels i n t he ce ntral ner v o us s yste m ( C N S) b y 
re d uci n g a d e n osi ne re -u pta ke. 1 3 ,1 4  
1. 1. 2.  
Met a b olis m a n d P ote nti al Dr u g I nter acti o ns  
T he maj or bi otra nsf or mati o n pat h wa y f or C B D is si milar t o t hat of ot her ca n na bi n oi ds a n d 
me diate d b y h y dr o x ylati o n wit h  c yt oc hr o me P 4 5 0 ( C Y P) pr otei ns. 1 5 Its i nteracti o ns wit h h u ma n 
dr u g met a b olizi n g e nz y m es (as a s u bstrate, i n hi bit or, or i n d ucer) were rece ntl y re vie we d. 1 6 ,1 7  
Ca n na bi di ol is meta b olize d pri maril y i n t he li ver b y C Y P 3 A 4 a n d t o a l esser e xte nt b y 
C Y P 2 C 1 9. S pecificall y, C B D i n hi bits C Y P 3 A 4, C Y P 3 A 5, a n d C Y P 1 A 1 i n vitr o. 1 8 ,1 9 ,2 0 It als o 
a p pears t o i n hi bit C Y P 2 C 9 2 1 a n d t he tra ns p ort pr otei n P -gl yc o pr ot ei n.  2 2 ,2 3     
F urt her details ma y be f o u n d i n t he I n v esti gat or ’s Br oc h ure (I B). 1 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 6  
1. 2.  
N o ncli nic al E x per ie nce 
1. 2. 1.  
S afet y  
I n a n o ncli nical setti n g, si n gle-d os e t o xic ol o g y st u dies of C B D re veal a rel ati vel y safe t o xic ol o g y 
pr ofile e x ce pt at ver y hi g h d oses of t he dr u g s u bst a nce. Re p eate d d os e t o xic ol o g y st u dies 
hi g hli g ht a p ote ntial i m pact of C B D o n s per mat o ge nesi s, f ollicle-sti m ulati n g h or m o n e le vels, 
a n d a s u bset of i m m u ne res p o nses. F ull detail of t hese res ults ma y be f o u n d i n t he I B. 1  
1. 2. 2.  
Effic ac y i n A ni m al M o dels of E pile ps y  
Pla nt -deri ve d C B D st u di es s h o w a ntie pile ptic, 2 4  a nti ps yc h otic, a nti -d yst o ni c, a nti -e metic, a n d 
a nti-i nfla m mat or y pr o perties i n a ni mal m o dels.2 5 T hese m o dels s u p p ort e x pl ori n g t he use of 
C B D f or t he treat me nt of e pile ps y. 2 6    
T he a ntic o n v ulsa nt a cti vit y of oral C B D was i n vesti gate d i n a d ult rat m o del of seiz ures (i n d uce d 
b y ma xi mal electr os h oc k or a u di o ge nic s o urces). 2 7 Ca n na bi di ol was effecti ve a gai nst ma xi mal 
electr os h oc k -i n d uce d s eiz ures ( me dia n effecti ve d ose [ E D 5 0] = 1 8 m g/ k g), b ut o nl y mi ni mall y 
effecti ve a gai nst a u di o ge nic -i n d uce d seiz ures ( E D5 0 ≥7 5 m g/ k g). T he ne ur ot o xicit y me dia n 
t olerate d d ose ( T D5 0) was > 1 0 0 m g/ k g. Ca n na bi di ol c o-a d mi nistere d wit h differe nt a nti -seiz ure 
dr u gs (e. g., p he n yt oi n or car ba m aze pi ne) i ncrease d or re d uce d t heir a ntic o n v ulsa nt acti vit y, 
i n dicati n g t hat s y ner gis m or a nta g o nis m wit h C B D was dr u g s pecific. 
1. 3.  
Cli nic al E x perie nce  
A P hase 1/ 2 st u d y t o assess t he p har mac o ki netics ( P K) a n d safet y of m ulti ple d oses 
( 1 0 m g/ k g/ da y, 2 0  m g/ k g/ da y, a n d 4 0 m g/ k g/ da y) of p har mace utical gra de , s y nt hetic 
Ca n na bi di ol Oral S ol uti o n i n 6 1 pe diatric s u bjects wit h treat me nt -resista nt seiz ure dis or ders a ge d 
1 year t o 1 7 years has b ee n c o m plete d b y t he S p o ns or ( Pr ot oc ol I N S 0 1 1 -1 4 -0 2 9). S u bjects  we re 
e x p ose d f or a peri o d of a p pr o xi matel y 1 1 d a ys bef ore q ualif yi n g t o partici p ate i n t he l o n g -ter m 
e xte nsi o n st u d y (I N S 0 1 1-1 4 -0 3 0). A n al ys es de m o nstrate d t hat: 
•  Ca n na bi di ol le vels o n Da y 1 0 a p p eare d t o i ncrease pr o p orti o nall y wit h w ei g ht -base d 
d ose acr oss t he d osi n g c o h orts, n ot wit hsta n di n g t he t w o differe nt f or m ulati o ns of t he 
i n vesti gati o nal pr o d u ct.   
•  Stea d y -st ate le vels of ca n na bi di ol a p peare d t o be attai ne d wit h a p pr o xi matel y 2 t o 6 
da ys of re p eate d BI D d osi n g wit h Ca n na bi di ol Oral S ol uti o n , wit h ge o met ric mea n 
area u n d er t he c o nce ntrati o n -ti me c ur ve i n plas ma d uri n g a d osi n g i nter val ( A U C( 0-
ta u)) of 5 0 7. 0 ( C o h ort 1 [ 1 0  m g/ k g/ da y]), 8 3 6. 0  ( C o h ort 2 [ 2 0 m g/ k g/ da y]), a n d 
2 1 0 8  n g∙h/ m L ( C o h ort 3 [ 4 0  m g/ k g/ da y]) f or all a ge cate g ories c o m bi ne d.  
•  Ge o metric mea n ma xi m u m plas ma c o nce ntr ati o ns ( C ma x ) of ca n n a bi di ol at 
stea d y-state w ere 9 1. 0 ( C o h ort 1 [ 1 0 m g/ k g/ da y]), 1 2 6. 0 ( C o h ort 2 [ 2 0  m g/ k g/ da y]), 
a n d 3 1 4. 5  n g/ m L ( C o h ort 3 [ 4 0  m g/ k g/ da y]) f or all a ge cate g ories c o m bi ne d.  
•  Me dia n ti me t o ma xi m u m plas ma c o nce ntr at i o n of ca n na bi di ol at stea d y-state ra n ge d 
fr o m 2. 0 t o 3. 0 h o urs f or all a ge cate g ories c o m bi n e d.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 7  
•  Ge o metric mea ns of ca n na bi di ol a p pare nt ter mi nal half -life (t1/ 2) ra n ge d fr o m 1 9.5  t o 
2 9. 6  h o urs f oll o wi n g a si n gle d ose of Ca n na bi di ol Oral S ol uti o n f or all a ge cate g ories 
c o m bi ne d.  
•  Acc u m ulati o n i n ca n n a bi di ol e x p os ures was a p pr o xi matel y 3 - t o 4-f ol d f or all a ge 
cate g ories c o m bi ne d. D osi n g c o h ort t otal ge o m etric mea ns ra n ge d fr o m 2. 6  t o 3. 1  f or 
acc u m ulati o n rati o f or C ma x  a n d fr o m 3. 6  t o 4. 4 f or acc u m ulati o n r ati o f or A U C ( 0-ta u). 
•  M ost of t he d osi n g c o h ort t otal varia bilit y i n ca n n a bi di ol e x p os ures after re peate d 
d osi n g ( Da y  1 0) was l o wer t ha n Da y 1. Si n gle a n d re peat e d a d mi nistrati o ns of 
Ca n na bi di ol Oral S ol uti o n res ulte d i n hi g hl y varia ble s yste mic e x p os ures o f 
ca n na bi di ol.  
•  T here w ere n o a p pare nt f or m ulati o n -relate d differe nces o bser ve d i n ter ms of t1/ 2, 
d ose -n or malize d e x p os ures, a n d vari a bilit y.  
•  T here w ere n o clear tre n ds f or a ge -relat e d differe nces i n ca n n a bi di ol e x p os ures, b ut 
e x p os ure i n i nfa nts te n de d t o be l o wer t ha n t hat i n c hil dre n a n d a d ol esce nts, 
a p pr o xi matel y half at t he hi g hest d ose ( 4 0 m g/ k g/ da y).  
•  A p pr o xi matel y 5 0 % of s u bjects e nrolle d were recei vi n g cl o b aza m. Cl o baza m a n d 
ca n na bi di ol ha ve a reci pr ocal dr u g -dr u g i nteracti o n lea di n g t o t he i n crease d mea n 
e x p os ures of b ot h ca n na bi di ol (a p pr o xi matel y 2. 5 -f ol d), a n d cl o baza m as well as 
n orcl o baza m (a p pr o xi matel y 3 -f ol d) at t he hi g hest d ose ( 4 0 m g/ k g/ da y). 
•  N o a p pare nt ge n der differe nces were o bser ve d f or ca n na bi di ol p har mac o ki netics 
( P K). 
•  P har mac o ki neti c res ults f or 7 -h y dr o x y ca n na bi di ol a n d its statistical e val uati o ns 
ge n erall y reflecte d t h ose o bser ve d f or pare nt ca n n a bi di ol.  
•  T here w ere n o q u a ntifia ble le vels Δ 9-T H C a n d 1 1 -h y dr o x y -Δ 9-T H C meas ure d 
f oll o wi n g ca n na bi di ol d osi n g.  
•  All d oses of t he i n vesti gati o nal pr o d uct were ge nerall y well -t olerat e d, alt h o u g h 
d ose -titrati o n was n ot e m pl o ye d. D os e-de p e n de nt a d verse e ve nts ( A Es) t hat occ urre d 
i n m ulti ple d osi n g c o h orts a n d i ncrease d as t he d ose of t he i n vesti gati o nal pr o d uct 
i ncreas e d i ncl u de d diarr hea, flat ule n ce, wei g ht i ncrease, s o m n ole nce, a n d 
ps yc h o m ot or h y p eracti vit y. E ve nts of s o m n ole nce were p ote ntiall y als o r el ate d t o 
c o nc o mita nt use of cl o b aza m wit h t he i n v esti gati o nal pr o d uct, b ut t his was n ot 
f or mall y i n v esti gat e d i n t his st u d y.  
•  T here w ere n o cli nicall y rele va nt differe nces i n t h e A E pr ofile a m o n g s u bj ects i n t he 
i nfa nt, c hil d, a n d a d oles ce nt a ge cate g ories. 
•  Seri o us a d verse e ve nts w ere re p orte d rarel y a n d  were c o nsiste nt wit h u n derl yi n g 
disease or pr o ce d ures.  
•  Alt h o u g h t his was n ot desi g ne d as a n efficac y st u d y, pare nt(s)/ care gi ver(s) a n d 
in vesti gat ors b ot h r e p orte d n ota ble re d ucti o ns i n se verit y of me ntal ill ness ( Cli nical 
Gl o bal I m pressi o n of Se verit y) a n d i m pr o ve me nt i n gl o bal s u bject stat us ( Cli nical 
Gl o bal I m pressi o n of I m pr o ve me nt).   
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 8  
•  T he a vera ge c ha n ge i n w ee kl y seiz ure rat es (seiz ures of all t y pes) was varia ble acr oss 
s u bjects, d osi n g c o h orts, a n d o ver ti me. Alt h o u g h t he mea n c h a n ge i n t he wee kl y rate 
t o nic seiz ures at t he e n d of t he st u d y c o m pare d wit h baseli ne ge nerall y decrease d i n a 
p ote ntiall y d ose -d e pe n d e nt ma n ner, n o patter n was o bser ve d f or t he ot her t y p es of 
seiz ures re p orte d. It was t h o u g ht t hat t o nic seiz ures were m ost re prese nt ati ve of 
seiz ure c o ntr ol i n t his st u d y.  
I n a d diti o n, a l o n g-ter m s afet y st u d y ( Pr ot oc ol I N S 0 1 1-1 4 -0 3 0) f or s u bjects e nr olle d i n t he P K 
st u d y a b o v e was rece ntl y c o m plete d. Fift y -t w o of 6 1 s u bjects fr o m I N S 0 1 1-1 4 -0 2 9 e nr olle d; 4 5 
s u bjects c o m plete d t he st u d y. T here were s e ve n earl y ter mi nati o n s u bjects (t w o f or wit h dra wal of 
c o nse nt, t w o f or A Es of a g gressi o ns a n d slee pi ness/irrita bilit y, o n e f or t he S A E of w orse ni n g 
seiz ures, o ne f or la c k of effic ac y, a n d o n e s u bject wit h a ge netic m utati o n die d fr o m s yst e mic 
se psis a nd m ulti -or ga n fail ure c o nsi dere d n o nrelat e d) . O verall, 9 1 % of t he s u bjects were t a ki n g 
d oses greater t ha n 2 0 m g/ k g/ da y, wit h 3 8 % of s u bjects t olerati n g 4 0 m g/ k g/ d a y. T h e m ost 
c o m m o n dr u g -relat e d A Es re p orte d w ere a ne mia ( 5 s u bjects), s o m n ole nce ( 4 s u bjects), a n d 
wei g ht i ncreas e d ( 4 s u bjects). H o we v er, t he wei g ht i ncreases ra n ge d fr o m a little o ver 2 l bs t o 
a p pr o xi matel y 7 l bs.   
D uri n g t h e st u d y, tr o u g h P K val ues were dra w n a n d i nteri m P K data f or C B D a n d 7-O H C B D 
fr o m Visit 5 ( Wee k 4) t o Visit 8 ( Wee k 2 4) were a nal yze d. D ose -n or malize d mea n tr o u g h C B D 
c o nce ntr ati o ns ra n ge d fr o m 1 1. 9 t o 1 6 ( n g/ m L)/( m g/ k g), s h o wi n g relati vel y sta ble le vels f or u p 
t o 6 m o nt hs d osi n g Ca n na bi di ol Oral S ol uti o n at vari o us d ose le vels. After o ne m o nt h of d osi n g, 
t here di d n ot a p pear t o be m uc h acc u m ulati o n, e v e n t h o u g h earl y acc u m ulati o n ha d li kel y 
ha p pe ne d w h e n c o m pare d wit h I N S 0 1 1 -1 4 -0 2 9 res ults. Hi g h varia bilit y i n tr o u g h C B D 
c o nce ntr ati o ns was o bser ve d, b ut t he e xte nt of varia bilit y b et wee n visits was si milar as re p orte d 
i n t he pre vi o us 0 2 9 st u d y.  
A n o pe n -la bel st u d y of C a n na bi di ol Oral S ol uti o n ( 2 0 m g/ k g/ da y a n d 4 0 m g/ k g/ da y) i n pe di atric 
s u bjects wit h i nfa ntile s pas ms refract or y t o A C T H a n d vi ga batri n rece ntl y was halte d d ue  t o 
f utilit y ( Pr ot oc ol I N S 0 1 1-1 5 -0 5 4)  beca use o nl y o n e o ut of ni ne patie nts a c hie ve d a c o m plete 
res p o nse. 
A f o o d effect st u d y of Ca n na bi di ol Oral S ol uti o n i n n or mal he alt h y a d ults ( Pr ot oc ol I N S 0 1 1 -1 5 -
0 4 3) rece ntl y c o m plete d a n d t he res ults are pres e nte d i n t he I B. A nal ysis d e m o nstrate d 
si g nifica ntl y hi g her C B D le vels w he n a d mi nistere d wit h f o o d.  
I N S 0 1 1-1 6 -0 9 3 e v al uate d t he effect of f o o d o n t h e bi oa vaila bilit y of m ulti ple  test f or m ulati o ns 
of Ca n na bi di ol Oral S ol uti o n: M C T Oil f or m ulati o n ( 1 0 0 m g/ m L ), Sesa m e See d Oil f or m ulati o n 
( 1 0 0 m g/ ml), a n d alc o h ol-c o ntai ni n g f or m ulati o n ( 8 0 m g/ mL ). T he Ses a me Oil f or m ulati o n was 
st u die d b ot h after s u bjects were fe d a hi g h fat diet a n d after a fast; t he ot her f or m ulati o ns were  
teste d after a hi g h-fat diet. C B D C ma x  was a p pr o xi matel y 1 2. 3 -f ol d hi g h er after a d mi nistrati o n of 
f o o d c o m pare d t o fasti n g. C o m pari n g t he Sesa m e Oil fasti n g le vels t o t he fe d f or m ulati o ns t here 
was a 1 2. 7 -f ol d hi g h er C B D Cma x  ( M C T f or m ulati o n) a n d 1 1. 2-f ol d hi g her Cma x  (alc o h ol-
c o ntai ni n g f or m ulati o n).  
Cli nical data descri be d i n t he f oll o wi n g secti o ns were c ollecte d f oll o wi n g a d mi nistrati o n of 
vari o us e xtracts of C B D as oral s ol uti o ns or s oli d f or m ulati o ns.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            2 9  
1. 3. 1.  
P h ar m a c o ki netics  
St u d y I N S 0 1 1 -1 4 -0 2 9 is a P hase 1/ 2 st u d y assessi n g t he P K a n d s afet y of m ulti ple d oses of 
C B D.  I n t his rece ntl y c o m plete d P K trial  usi n g s y nt hetic C B D ( Ca n n a bi di ol Oral S ol uti o n, I ns ys 
De vel o p me nt C o m pa n y, I n c.), eac h c o h ort c o nsiste d of 2 0 pe diatri c s u bjects fr o m 1 t o 1 7 years 
of a ge w h o recei ve d 1 0 m g/ k g/ da y, 2 0 m g/ k g/ d a y, or 4 0 m g/ k g/ da y o ver a peri o d of 1 0 d a ys. 
S u bjects  were d os e d as i n -s u bjects f or Da y 1 t hr o u g h Da y 8. S u bjects  were t he n offere d t he 
o p p ort u nit y t o be disc har ge d o n Da y 8 wit h r ea d missi o n o n Da y 1 0 a n d a fi nal st u d y visit o n 
Da y  1 1. C o h ort 1 recei ve d a f or m ulati o n c o ntai ni n g al c o h ol; C o h orts 2 a n d 3 recei v e d t he f i nal 
alc o h ol-free f or m ulati o n c o ntai ni n g me di u m c hai n tri gl yceri des ( M C T) oil. It w as desi g n e d t o 
ha ve t hree a ge gr o u ps c o nsisti n g of i nfa nts ( 1 -2 yrs: 5 s u bjects), c hil dre n ( 2 t o < 1 2 yrs: 9 
s u bjects), a n d a d oles ce nts ( 1 2 t o < 1 7 yrs: 6 s u bjects) i n eac h c oh ort.  
Si n gle oral a d mi nistrati o n of C B D at 5, 1 0, 2 0 m g/ k g per d ose res ulte d i n mea n pea k l e vels of 
a b o ut 5 9, 1 1 1, a n d 2 3 2 n g/ m L, res p ecti vel y, a n d t er mi nal half -life v al ue of a b o ut 1 7 t o 2 9 h o urs.  
T he P K of C B D i n differe nt a ge gr o u ps was c o m p ara ble at e ac h d ose le vel. Stea d y-st ate see m e d 
t o be ac hie v e d wit hi n 2 t o 4 da ys after dail y d os e of 1 0, 2 0, 4 0 m g/ k g/ da y C B D, wit h t y pical 
stea d y-state pea k le vels of a b o ut 1 2 0, 2 1 4, a n d 4 2 7 n g/ m L, res p ecti vel y, a n d a ter mi nal half -life 
of 4 t o 9 h o urs o n Da y 1 0.  
D ose pr o p orti o nal i ncrease i n C B D e x p os ures o n Da y 1 0 was clearl y o bs er ve d i n mea n C ma x,ss  
a n d A U C ta u e ve n if t w o differe nt f or m ulati o ns were use d i n t he st u d y. Acc u m ulati o n after 
re peat e d d oses was a b o ut 2-f ol d. Plas ma le vels of 7-h y d o x y ( 7 -O H) C B D were ge nerall y si milar 
t o t he pare nt dr u g. 
Ca n na bi di ol a n d cl o baza m ( C L B) a p p ear t o h a ve a dr u g -dr u g i nteracti o n b ase d o n t he o bser ve d 
plas ma le vels of b ot h dr u gs: I ncreas e i n mea n e x p os ures of cl o baza m o n D a y 1 0 b y ca n n a bi di ol 
was s h o w n i n a d ose -d e p e n de nt matte r ( × 1. 2, × 1. 5, × 2. 6 of cl o baza m f or 1 0, 2 0, 4 0 m g/ k g/ da y 
C B D, res p ecti vel y). Si milarl y , me a n N -d es met h yl C L B plas ma le vels f oll o wi n g 2 0 or 
4 0  m g/ k g/ da y of C B D were i ncreas e d b y C B D.  
H o we ver, t here were a p precia ble c ha n ges i n ca n n a bi di ol e x p os ures o n Da y 1 0 o nl y at t he hi g hest 
C B D d ose ( 4 0 m g/ k g/ da y), b ut n ot i n t he l o wer d oses, wit h c o -a d mi nistrati o n of cl o baza m.  
T he f o o d effect st u d y ( Pr ot oc ol I N S 0 1 1-1 5 -0 4 3) d e m o nstrates  a 1 5 t o 1 8 -f ol d a n d 8 5-f ol d hi g h er 
A U C a n d C ma x , res pecti v el y, i n t he fe d state vers us t he fasti n g stat e after si n gle a d mi nistrati o n of 
2 0  m g/ k g Ca n na bi di ol Oral S ol uti o n  ( 3 0 0 m g/ m L) i n healt h y a d ults. I nter-s u bject varia bilit y was 
dra maticall y re d u ce d wit h f o o d: 5 5 % C V fr o m 1 2 5 % f or C ma x  a n d 3 5 % C V fr o m 7 8 % f or A U C 0 -
i nf. Me dia n ti me t o ma xi m u m ca n na bi di ol e x p os ure ( T ma x ) occ urre d a p pr o xi matel y 6 h o urs earlier 
u n der fe d c o n diti o ns c o m pare d t o t hat after faste d c o n diti o ns ( 6. 0 0 h Fe d vs. 1 2. 0 0 h Faste d). 
T he hi g h est e x p os ures wit h f o o d i n ter ms of A U C a n d C ma x  were 2 4 0 4 0 h· n g/ m L a n d 4 1 9 0 
n g/ m L, res p ecti vel y.  
I N S 0 1 1-1 6 -0 9 3 e v al uate d t he effect of f o o d o n t h e bi oa vaila bilit y of m ulti ple  test f or m ulati o ns 
of Ca n na bi di ol Oral S ol uti o n: M C T Oil f or m ulati o n ( 1 0 0 m g/ m L ), Sesa m e See d Oil f or m ulati o n 
( 1 0 0 m g/ ml), a n d alc o h ol-c o ntai ni n g f or m ulati o n ( 8 0  m g/ m L ). T he Ses a me Oil f or m ulati o n was 
st u die d b ot h after s u bjects were fe d a hi g h fat diet a n d after a fast; t he ot her f or m ulati o ns were 
teste d after a hi g h-fat diet. C B D Cma x  was a p pr o xi matel y 1 2. 3 -f ol d hi g h er after a d mi nistrati o n of 
f o o d c o m pare d t o fasti n g. C o m pari n g t he Sesa m e Oil fasti n g le vels t o t he fe d f or m ulati o ns t here 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            3 0  
was a 1 2. 7 -f ol d hi g h er C B D Cma x  ( M C T f or m ulati o n) a n d 1 1. 2-f ol d hi g her Cma x  (alc o h ol-
c o ntai ni n g f or m ulati o n).  
As a c o m paris o n, me a n p ea k a n d t otal e x p os ures i n all a ge gr o u ps ( Pr o t oc ol I N S 0 1 1-1 4 -0 2 9) o n 
Da y 1 0 were wit hi n 1 6 t o 3 6 % t o d ose -a dj uste d e x p os ures i n fe d a d ults ( Pr ot oc ol I N S 0 1 1 -1 4 -
0 2 9).  
1. 3. 2.  
O ver vie w of S afet y  
Cli nical st u dies i n vari o us h u ma n p o p ulati o ns i n dicate t hat C B D has a fa v ora ble si de -effect 
pr ofile. D oses as hi g h as  1 5 0 0 m g are well t olerate d. 2 8 N o si g nifica nt reacti o ns or seri o us a d verse 
e ve nts ( S A Es) ha v e bee n re p orte d acr oss a wi de ra n ge of d osa ges i n b ot h ac ute a n d c hr o nic 
setti n gs.  Ber ga m asc hi et al. 1 7 rece ntl y re vie we d t he safet y of C B D i n h u m a ns e x a mi ne d i n 2 2 1 
s u bjects acr oss 2 1 st u dies. As detaile d i n t he I B 1, n o si g nifica nt safet y iss u es were re p orte d. 
Re gar di n g d oses of C B D t hat ha ve bee n e x a mi ne d i n ot her st u dies, dail y  d oses of 2 0 0 t o 3 0 0 m g 
C B D ( or p ote ntiall y m or e) ma y be s afe. 2 ,2 9 Cli nical e val uati o n a n d t hera pe utic ra n ges of C B D 
d oses ha ve bee n re p orte d t o be bet wee n 1 0 a n d 1 5 0 0 m g/ da y, wit h t he maj orit y of r e p orts 
e val uati n g d oses i n t he 3 0 0 t o 6 0 0 m g/ da y C B D ra n ge. F urt her m ore, bet w ee n 3 0 0 a n d 1 5 0 0 m g 
ha ve bee n use d i n h u ma ns wit h o ut t o xicit y or S A Es. 3 0 ,3 1 ,3 2    
1. 3. 3.  
Cli nic al S afet y D at a  
T he f oll o wi n g s p ecific e x a m ples detail selecte d st u dies of t he safet y of C B D use i n h u ma ns:  
•  Dail y d osi n g of 1 0 m g/ k g C B D was e val uate d i n a st u d y of 1 5 s u bj ects dia g n ose d 
wit h H u nti n gt o n's diseas e. 3 0 O nl y 1 5 a b n or mal  cli nical la b orat or y v al ues were 
ass ociate d wit h C B D treat me nt; t hese were l ar gel y li mite d t o 4 s u bjects a n d e x hi bite d 
n o o b vi o us patter n. N o si g nifica nt or cli nical differe nces i n C B D were o bser ve d i n a 
ca n na bis -s pecific si de-effect i n ve nt or y.  
•  C hr o nic ora l a d mi nistrati o n of 1 0 m g C B D dail y f or 2 1 da ys d oes n ot i n d u ce a n y 
c ha n ges i n ne ur ol o gi cal (i ncl u di n g electr oe n ce p hal o gra m [ E E G]), cli nical (i ncl u di n g 
electr ocar di o gra m [ E C G]), ps yc hiatric, bl o o d, or uri ne e x a mi nati o ns i n b ot h healt h y 
v ol u nteers a n d e pile ptic s u bjects.2  
•  Oral a d mi nistrati o n of C B D i n healt h y v ol u nteers ( 3 m g/ k g dail y f or 3 0 d a ys) a n d i n 
e pile ptic s u bjects ( 2 0 0 t o 3 0 0 m g dail y f or 1 3 5 d a ys) was well t olerate d. N o si g ns of 
t o xicit y or seri o us si de-effects were de t ecte d o n ne ur ol o gical a n d p h ysical 
e x a mi nati o ns, bl o o d a n d uri ne a nal ysis, E C G, or E E G. 2 ,2 9 
•  A d mi nistrati o n of si n gle a n d re peate d d oses of C B D f or u p t o 2 0 da ys at a d ose of 
1 2 0 0  m g/ da y d oes n ot i m pact p ulse rat e a n d bl o o d press ure i n h u ma n s u bjects wit h 
pre vi o us e x perie nce t o ca n na bis s m o ki n g. 3 4  
•  T hree s u bjects wit h treat me nt -resista nt sc hiz o p hre nia ha ve b ee n d ose d wit h 4 0 t o 
1 2 8 0  m g/ da y of C B D f or u p t o 4 wee ks wit h o ut  re p orti n g si de-effects. 3 5 
•  T w o s u bjects dia g n ose d wit h bi p olar affecti ve dis or der di d n ot re p ort a d verse effects 
u p o n recei vi n g 6 0 0 t o 1 2 0 0 m g/ da y of C B D f or u p t o 2 4 da ys. 3 6     
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            3 1  
•  In a d diti o n, a l o n g -ter m s afet y st u d y ( Pr ot oc ol I N S 0 1 1-1 4 -0 3 0) f or s u bjects e nr olle d 
i n t he P K st u d y a b o ve rece ntl y c o m plete d. Fift y -t w o of 6 1 s u bjects fr o m I N S 0 1 1-1 4 -
0 2 9 e nr olle d; 4 5 s u bjects c o m plete d t he st u d y . T h ere were s e ve n earl y ter mi nati o n 
s u bjects (t w o f or wit h dr a wal of c o nse nt, t w o f or A Es of a g gressi o ns a n d 
slee pi ness/irrita bilit y, o n e f or t he S A E of w orse ni n g seiz ures, o n e f or lac k of efficac y, 
a n d o ne s u bject wit h a ge netic m utati o n die d fr o m s yste mic se psis a n d m ulti -or ga n 
fail ure c o nsi dere d n o nrel ate d). O verall, 9 1 % of t h e s u bjects were ta ki n g d oses greater 
t ha n 2 0 m g/ k g/ da y, wit h 3 8 % of s u bjects t olerati n g 4 0 m g/ k g/ da y. T he m ost c o m m o n 
dr u g -relat e d A Es r e p orte d were a ne mia ( 5 s u bjects), s o m n ole nce ( 4 s u bjects), a n d 
wei g ht i ncreas e d ( 4 s u bjects). H o we v er, t he wei g ht i ncreases ra n ge d fr o m a little o ver 
2 l bs t o a p pr o xi matel y 7 l bs.  
1. 3. 4.  
Effic ac y i n H u m a n E pile ps y  
Se veral pr eli mi nar y st u di es of C B D re p ort re d ucti o ns i n seiz ure acti vit y f or a si g nifica nt s u bset 
of s u bjects.    
Pla nt -deri ve d C B D was e x a mi ne d as a n a dj u nct i ve t hera p y i n 1 5 s u bjects wit h sec o n dar y 
ge n eralize d e pile ps y wit h te m p oral f oc us w h o were refract or y t o c o n ve nti o nal treat me nt. 2 ,3  T he 
ei g ht s u bjects ra n d o mize d t o t he acti ve ar m recei ve d 2 0 0 t o 30 0 m g/ da y of C B D or place b o f or 
u p t o 4. 5 m o nt hs i n a d diti o n t o pre vi o usl y esta blis he d a ntie pile ptic dr u gs ( A E Ds). 2 ,2 9 S u bjects  
t olerate d C B D well, wit h n o si g ns of t o xicit y or seri o us si de-effects.  F o ur of t he ei g ht s u bjects 
recei vi n g C B D re m ai ne d al m ost free of c o n v ulsi ve crises t hr o u g h o ut t he st u d y a n d t hree ot hers 
e x perie nce d partial i m pr o ve me nt. T he cli nical c o n diti o n of se ve n s u bjects recei vi n g place b o 
re mai ne d u nc h a n ge d a n d o ne s u bject i m pr o ved.   
Pare nts of c hil dre n wit h treat me nt -resista nt e pile ps y ha v e s o u g ht C B D-e nri c he d ca n na bis f or 
treat me nt.4 I n a s ur ve y, t hese pare nts re p ort e d d os a ges of C B D ra n gi n g fr o m < 0. 5 t o 
2 8. 6  m g/ k g/ da y, as per res ults fr o m me dical ca n n a bis testi n g facilities. Si xtee n ( 8 4 %) of t he 
1 9  pare nts eli gi ble t o res p o n d t o t he s ur ve y re p orte d a re d u cti o n i n t heir c hil d's seiz ure fre q ue nc y 
w hile ta ki n g C B D -e nric h e d ca n n a bis. Of t hese, 2 ( 1 1 %) re p orte d c o m plete seiz ure -free d o m, 
8  ( 4 2 %) re p orte d >8 0 % re d ucti o n i n seiz ure fre q u e nc y, a n d 6 ( 3 2 %) re p ort e d a 2 5 % t o 6 0 % 
seiz ure re d ucti o n. Re p ort e d si de-effects i ncl u de d fati g ue a n d s o m n ole nce.   
Real m Oil is a n e xtract fr o m a strai n of ca n n a bis k n o w n as C harl otte’s We b a n d c o ntai ns a 
C B D: ∆9-T H C rati o > 2 0 : 1. Ge d de a n d M aa5 re p orte d o n a s mall gr o u p of pe diatric s u bjects 
dia g n ose d wit h vari o us t y p es of e pile ps y w h o t o o k Real m Oil f or ≥3 m o nt hs. Baseli ne s eiz ure 
fre q ue n c y f or t h ese s u bjects ra n ge d fr o m 5 t o 2 8 0 0 e ve nts per wee k.  Ei g ht ( 8, 7 3 %) of t hes e 
s u bjects re p orte d a 9 5 % t o 1 0 0 % re d ucti o n i n seiz ure occ urre n ce, 1 ( 9 %) re p orte d 7 5 % 
re d ucti o n, a n d 2 ( 1 8 %) re p orte d 2 0 % t o 4 5 % re d u cti o n. 
1. 4.  
C hil d h o o d A bse nce E pile ps y  
Alt h o u g h t here are c urre ntl y t w o dr u gs a p pr o ve d f or c hil d h o o d a bs e n ce e pile ps y ( C A E), 
val pr oate a n d et h os u xi mi de, n eit her are i deal. Val pr oate has p ote ntiall y seri o us si de effects, 
i ncl u di n g wei g ht gai n, p ol yc ystic o var y diseas e, li ver fail ure, a n d si g nifica nt terat o ge nic effects . 
E t h os u xi mi de d oes n ot c o ntr ol ge n eral to nic -cl o nic seiz ures t hat ca n c o -e xist wit h C A E. I n a 
rece nt st u d y c o m p ari n g et h os u xi mi de, val pr oic aci d, a n d la m otri gi ne, free d o m fr o m fail ure rates 
w here tr eat me nt f ail ure was defi ne d as persiste n ce of a bse n ce seiz ures at Wee k 1 6 or 2 0, a 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I N S 0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L         
                                            3 2  
ge n eralize d t o n ic-cl o nic seiz ure at a n y ti me, e x cessi ve dr u g -rel ate d s yste mic t o xicit y, d ose-
li miti n g t o xicit y after a si n gle d o w n war d d os e m o dificati o n, or wit h dra wal i nitiate d b y t he pare nt 
or p h ysici a n, was 5 3 % (et h os u xi mi de), 5 8 % ( val pr oic aci d), a n d 2 9 % (l a m otri gi ne ).3 7 T heref ore, 
t here is still a n u n met nee d f or m ore effecti ve a nti-e pile ptic dr u gs wit h less si de effects f or t hes e 
seiz ures. As C B D has b ee n de m o nstrate d t o be effecti ve i n t he treat me nt of c ortical me diate d 
e pile ptic e nce p h al o pat hies 3 8, I ns ys is pr o p osi n g a m ulti ple -site, o pe n-la bel, d ose-fi n di n g pr o of of 
c o nce pt st u d y of Ca n na bi di ol Oral S ol uti o n f or t he treat me nt of refract or y c hil d h o o d a bse nce 
e pile ps y. C hil dre n h a ve ma n y a bse nce seiz ures a da y, a n d seiz ures ma y be pr o v o ke d b y 
h y per ve ntilati o n d uri n g E E G, a 4 -h o ur vi d e o -E E G i ncl u di n g h y per ve ntilati o n will be utilize d as 
a bi o mar ker i n t his pr o of of c o nce pt st u d y . I n a d diti o n, a seiz ure diar y will be c ollecte d.  
1. 5.  
D ose Selecti o n R ati o n ale  
D oses u p  t o 4 0 m g/ k g/ da y w ere gi ve n i n t he P has e 1/ 2 P K st u d y ( Pr ot oc ol I N S 0 1 1 -1 4 -0 2 9) a n d 
t he l o n g-ter m safet y st u d y ( Pr ot oc ol I N S 0 1 1-1 4 -0 3 0). T he ma xi m u m d ose gi ve n was 
3 2 0 0  m g/ da y i n a n a d olesce nt. T hese d os es were ge n erall y well t olerate d e ve n wit h o ut titrati o n. 
O nl y si x s u bjects re q uire d a decreas e i n d ose d ue t o s o m n ole nce ( 2), a b d o mi nal pai n ( 1), 
diarr hea ( 1), irrita bilit y ( 1), a n d seiz ure ( 1).  
A n i nteri m safet y re p ort was ge nerate d f or t he l o n g-ter m safet y st u d y (I N S 0 1 1-1 4 -0 3 0 ) wit h a 
data c ut off -of 3 1 J a n 2 0 1 7. As of t he data c ut off, 5 2 patie nts ( 9 i nfa nts, 2 6 c hil dre n, a n d 1 7 
a d olesce nts) were e nr olle d a n d ha d recei ve d at least o ne d ose of t he i n vesti gati o nal pr o d u ct i n 
t his st u d y. As of t he data c ut-off, t he mea n m o dal d ose ( defi ne d as t he d ose wit h t h e l o n gest 
d urati o n) f or all patie nts was 2 3. 4 7 m g/ k g/ da y, a n d t he mea n n u m ber of da ys o n -st u d y f or all 
patie nts was 2 2 0. 6 ( Ta bl e  2 ). O verall, se ve n p atie nts ( 1 3. 5 %) ha d d ose re d ucti o ns res ulti n g fr o m 
a n A E, a n d 3 p atie nts ( 5. 8 %) ha d d ose re d ucti o ns d ue t o ot her reas o ns ( Ta ble 3 ). T he fre q ue n c y 
of d ose re d u cti o ns was greater i n t he p atie nts recei vi n g 4 0 m g/ k g/ d a y c o m p are d wit h patie nts 
recei vi n g 1 0 m g/ k g/ da y (se ve n patie nts [3 5. 0 %] a n d t w o patie nts [ 1 4. 3 %], res pecti vel y).  
O verall, o ne p atie nt ( 1. 9 %) was ta ki n g < 1 0  m g/ k g/ da y, 1 0 p atie nts ( 1 9. 2 %) were ta ki n g bet w ee n 
1 0 a n d < 2 0 m g/ k g/ d a y, 2 0 patie nts ( 3 8. 5 %) were t a ki n g b et wee n 2 0 a n d < 4 0 m g/ k g/ da y, a n d 2 0 
patie nts ( 3 8. 5 %) were ta ki n g 4 0 m g/ k g/ d a y as of t he data c ut-off ( T a ble 4 ). T heref ore, t his st u d y 
will e val uate t he d oses of 2 0  m g/ k g/ da y, 3 0  m g/ k g/ da y a n d 1 0  m g/ k g/ da y. D oses hi g h er t ha n 2 0  
m g/ k g/ da y will be titrate d.   
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
                                                                                  P r ot oc ol N u m ber I N S0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
                                                                 C O N FI D E N TI A L                                                                                       3 3  
T a ble  2 : 
C a n n a bi di ol Or al S ol uti o n E x p os ure ( St u d y I N S 0 1 1-1 4 -0 3 0 ) 
 
I nf a nts 
( N = 9) 
C hil dre n  
( N = 2 6) 
A d olesce nts  
( N = 1 7) 
All P atie nt s 
( N = 5 2) 
M o d al D ose ( m g/ k g/ d a y)
a 
 
 
 
 
n  
9  
2 6  
1 7  
5 2  
Mea n ( S D)  
3 1. 1 1  ( 1 0. 5 4 1) 
2 1. 1 7  ( 1 2. 7 1 9) 
2 2. 9 4  ( 1 2. 12 7)  
2 3. 4 7  ( 1 2. 4 8 8) 
Me dia n  
4 0. 0 0  
2 0. 0 0  
2 0. 0 0  
2 0. 0 0  
Mi n, Ma x  
2 0. 0,  4 0. 0  
0. 5,  4 0. 0  
1 0. 0,  4 0. 0  
0. 5,  4 0. 0  
 
 
 
 
 
T ot al D ur ati o n of St u d y Dr u g at A n y D ose ( D a ys)  
 
 
 
 
n  
9  
2 6  
1 7  
5 2  
Mea n ( S D)  
2 3 4. 1  ( 9 1. 7 3) 
2 1 0. 0  ( 1 1 8. 7 3) 
2 2 9. 7  ( 9 5. 4 7) 
2 2 0. 6  ( 1 0 5. 8 6) 
Me dia n  
2 5 3 . 0 
2 4 9. 0  
2 5 0. 0  
2 5 0. 5  
Mi n, Ma x  
1,  3 3 6  
1,  3 4 4  
1,  3 3 6  
1,  3 4 4  
A b bre viati o ns:  BI D = t wice dail y; Ma x = ma xi m u m; Mi n = mi ni m u m; N = t otal n u m ber; n = sa m ple size;  S D = sta n dar d de viati o n.  
a F or eac h patie nt , t he m o dal d ose c orres p o n ds t o t he d ose wit h t he l o ngest d urati o n.  
D urati o n = Date of last d ose –  date of first D ose + 1.  
T he st u d y dr u g is Ca n na bi di ol Oral S ol uti o n ( 3 0 0 m g/ m L) a d mi nistere d BI D  
A ge Cate g or y:  I nfa nts = 1 t o < 2 years of a ge, C hil dre n = 2 t o < 1 2 years of a ge, A d olesce nts = 1 2 t o ≤1 7 years of a ge.  A ge c ate g ories are base d o n t he 
patie nt ’s a ge at t he be gi n ni n g of t heir pre vi o us st u d y (I N S 0 1 1-1 4 -0 2 9).  
S o urce:  I nteri m Safet y Re p ort f or St u d y I N S 0 1 1 -1 4 -0 3 0.  
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
                                                                                  P r ot oc ol N u m ber I N S0 1 1 -1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
                                                                 C O N FI D E N TI A L                                                                                       3 4  
T a ble 3 : 
C a n n a bi di ol Or al S ol uti o n D ose Re d ucti o n b y I niti al Pl a n ne d D ose  ( St u d y I N S 0 1 1-1 4 -0 3 0 ) 
 
1 0 m g/ k g/ d a y  
( N = 1 4) 
2 0 m g/ k g/ d a y  
( N = 1 8) 
4 0 m g/ k g/ d a y  
( N = 2 0) 
All P atie nts  
( N = 5 2) 
N u m ber of p atie nts wit h ≥1 d ose re d ucti o ns  
2  ( 1 4. 3 %) 
0  
7  ( 3 5. 0 %) 
9  ( 1 7. 3 %) 
Re as o n f or d ose re d ucti o ns  
 
 
 
 
A d verse e ve nt  
1  ( 7. 1 %) 
0  
6  ( 3 0. 0 %) 
7  ( 1 3. 5 %) 
Lac k of efficac y  
0  
0  
0  
0  
P K  a nal ysis res ult  
0  
0  
0  
0  
Ot her  
1  ( 7. 1 %) 
0  
2  ( 1 0. 0 %) 
3  ( 5. 8 %) 
T he st u d y dr u g is Ca n na bi di ol Oral S ol uti o n ( 3 0 0 m g/ m L) a d mi nistere d BI D  
P atie nt s ha vi n g m ore t ha n 1 d ose re d ucti o n d ue t o t he sa me reas o n are c o u nte d o nl y o nce f or t his reas o n.  
P atie nt s ma y be i ncl u de d i n m ore t ha n 1 reas o n f or d ose re d ucti o n.  
S o urce:  I nteri m Safet y Re p ort f or St u d y I N S 0 1 1-1 4 -0 3 0.  
 
T a ble 4 : 
Distri b uti o n of P atie nt s b y C a n n a bi di ol Or al S ol uti o n D ose ( St u d y I N S 0 1 1-1 4 -0 3 0)  
 
I nf a nts 
( N = 9)  
C hil dre n  
( N = 2 6)  
A d olesce nts  
( N = 1 7)  
All P atie nts  
( N = 5 2)  
N u m ber of p atie nts  t a ki n g d ose as of c ut-off  
 
 
 
 
< 1 0 m g/ k g/ da y  
0  
1  ( 3. 8 %) 
0  
1  ( 1. 9 %) 
1 0 -< 2 0 m g/ k g/ da y  
0  
7  ( 2 6. 9 %) 
3  ( 1 7. 6 %) 
1 0  ( 1 9. 2 %) 
2 0 -< 4 0 m g/ k g/ da y  
3  ( 3 3. 3 %) 
9  ( 3 4. 6 %) 
8  ( 4 7. 1 %) 
2 0  ( 3 8. 5 %) 
≥4 0 m g/ k g/ da y  
6  ( 6 6. 7 %) 
8  ( 3 0. 8 %) 
6  ( 3 5. 3 %) 
2 0  ( 3 8. 5 %) 
T he st u d y dr u g is Ca n na bi di ol Oral S ol uti o n ( 3 0 0 m g/ m L) a d mi nistere d BI D  
A ge Cate g or y:  I nfa nts = 1 t o < 2 years of a ge, C hil dre n = 2 t o < 1 2 years of a ge, A d olesce nts = 1 2 t o ≤1 7 years of a ge.  A ge c ate g ories are base d o n t he 
patie nt ’s a ge at t he be gi n ni n g of t heir pre vi o us st u d y (I N S 0 1 1-1 4 -0 2 9).  
S o urce:  I nterim Safet y Re p ort f or St u d y I N S 0 1 1 -1 4 -0 3 0.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc.      
 
Pr ot oc ol N u m ber I N S 0 1 1-1 7 -1 0 3  
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
3 5  
1. 6.  
S u m m ar y of P ote nti al Ris ks a n d Be nefits  
As re vie we d i n Secti o n  1. 2  a n d Secti o n  1. 3 , n u mer o us n o ncli nical a n d cli ni cal st u dies ha ve 
e x a mi ne d ot her f or m ulati o ns of C B D. Se veral areas of p ote ntial c o ncer n ha ve bee n i de ntifie d 
wit h t he use of C B D, es p eciall y i n n o ncli nical st u dies. T hese i ncl u de:   
•  C o m petiti ve bi n di n g of C Y P pr otei ns (t h us, a n i m pact o n dr u g meta b olis m i n t he 
li ver). Ca n na bi di ol is meta b olize d pre d o mi na ntl y b y C Y P 3 A 4 a n d C Y P 2 C 1 9.  
Ca n na bi di ol ma y i n hi bit t hese 2 is oz y m es, as w ell as ha vi n g s mall effects o n 
C Y P 3 A 5, C Y P 1 A 1, a n d C Y P 2 C 9.  
•  P ote ntial d o w nre g ul ati o n of i m m u ne res p o nses i n v ol vi n g t he T, B, T -hel p er, a n d T 
c yt ot o xic s u bsets of le u k oc yt es a n d/ or t h ose de p e n de nt o n I L-2 or I F N -γ.  
Base d o n rece nt st u dies of ca n na bi n oi d a d mi nistrati o n i n h u ma ns, c o ntr olle d C B D ma y be s afe i n 
h u ma ns a n d a ni mals. H o we ver, f urt her st u dies are nee de d t o cl arif y t hese re p orte d i n vitr o  a n d i n 
vi v o si de -effects. 3 9  
T he i ncl usi o n/e x cl usi o n criteria, c o nc o mita nt me dicati o n g ui deli nes, a n d s afet y m o nit ori n g ( A Es, 
cli nical la b orat or y, vital si g ns, E C G, a n d p h ysic al e xa mi nati o n assess me nts) pla n ne d f or t his 
st u d y are i nte n de d t o mi ni miz e t hese p ote ntial safet y ris ks.   
Criteria f or re m o val of s u bjects fr o m t he st u d y will dictate disc o nti n uati o n of patie nt 
partici pati o n s h o ul d a safet y iss ue arise (see Secti o n  3. 3 ).  
T w o f acets of t he c urre nt treat me nt la n dsca pe f or pe diatric patie n ts wit h treat me nt -resista nt 
a bse nce s eiz ures s u p p ort t he p ote ntial be nefit f or s u bjects i n t his st u d y. First, pe diatric patie nts  
wit h treat me nt -resista nt a bse nce seiz ures c o nti n ue t o e x perie nce a si g nifica nt u n met me dical 
nee d des pite o n g oi n g treat me nt wit h c urre ntl y a v aila ble me dicati o ns a n d pr oce d ures. Patie nts  
i ncl u de d i n t his st u d y m a y p ote ntiall y be n efit fr o m treat me nt wit h Ca n na bi di ol Oral S ol uti o n.  
De vi ns k y et al. 4 0 rece ntl y n ote d t hat pe diatric s u bj ects wit h treat me nt -resista nt seiz ures are 
partic ularl y g o o d ca n di dates f or C B D i nter ve nti o n. Data re vi e we d i n Secti o n  1. 2. 2   a n d 
Secti o n  1. 3. 4  de m o nstrate t hat C B D has s h o w n preli mi nar y efficac y i n treati n g e pile ps y i n 
se veral earl y-sta ge n o ncli nical a n d cli nical st u dies, res pecti vel y. T his st u d y is e x pecte d t o ser ve 
as a critic al ste p i n t he de vel o p me nt of Ca n na bi di ol Oral S ol uti o n as a treat me nt f or refract or y 
c hil d h o o d a bse nce e pile ps y.   
Sec o n d, s y nt h etic p har m ace utical gra de Ca n n a bi di ol Oral S ol uti o n is e x pecte d t o ha ve se veral 
disti nct a d va nta ges o ver ca n na bis pla nt -d eri ve d e xtracts:  
•  A vaila bilit y of t he dr u g s u bsta nce d oes n ot de pe n d o n ca n na bis pla nt pr o d ucti o n. As 
s uc h, t he de vel o p me nt of Ca n na bi di ol Oral S ol uti o n will n ot s u p p ort gr o wt h a n d 
distri b uti o n of pla nts fr o m w hic h marij ua na is deri ve d.   
•  Ma n ufact ur e of Ca n n a bi di ol Oral S ol uti o n d oes n ot i n v ol ve a n e xtracti o n pr oc ess 
w here b y t he d eri ve d c o nstit ue nts c o ul d als o i ncl u de a si g nifica nt a m o u nt of Δ 9-T H C. 
T he ma n ufact uri n g pr ocess ca n be c o ntr olle d s o t hat mass q ua ntities ca n be pr o d uce d 
t hat are u nif or m i n q ualit y, p urit y, a n d c o nsiste nc y a n d ca n b e deli vere d i n k n o w n an d 
pre deter mi ne d q ua ntities.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
                        
P r ot oc ol N u m ber I N S0 1 1 -1 7 -1 0 3  
0 6  Ma y  2 0 1 9   
 
 
 
 
 
    C O N FI D E N TI A L                                                           3 6  
•  Varia bilit y i n c o n ce ntr ati o n a n d c o nstit ue nts s h o ul d be re d uce d a m o n g bat c hes, w hic h 
ma y i m pr o ve s afet y a n d t olera bilit y.  
•  Re d uce d c o n cer n f or c o nta mi nati o n b y Δ 9-T H C, h er bici des, pestici des, etc.  
  
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
                        
P r ot oc ol N u m ber I N S0 1 1 -1 7 -1 0 3  
0 6  Ma y  2 0 1 9   
 
 
 
 
 
    C O N FI D E N TI A L                                                           3 7  
2.  
S T U D Y  O B J E C TI V E S  
2. 1.  
Pri m ar y O b jecti ve 
•  T o assess t he efficac y of Ca n na bi di ol Oral S ol uti o n i n t he treat me nt of pe di atric 
patie nts wit h treat me nt -resista nt c hil d h o o d a bse nce seiz ures. 
2. 2.  
Sec o n d ar y O bjecti ves  
•  T o assess a n y i m pr o ve m e nt i n q ualitati ve assess me nts of patie nt  stat us o ver t he 
d ur ati o n of t he st u d y.  
•  T o assess t he safet y a n d t olera bilit y of Ca n n a bi di ol Oral S ol uti o n treat me nt i n 
pe diatric patie nts  wit h treat me nt -resista nt c hil d h o o d a bse nce s eiz ures.  
•  T o assess t he p har m ac o ki netics of Ca n na bi di ol Oral S ol uti o n i n pe diatric  patie nts 
w it h treat me nt-resista nt c hil d h o o d a bse nce seiz ures. 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
                        
P r ot oc ol N u m ber I N S0 1 1 -1 7 -1 0 3  
0 6  Ma y  2 0 1 9   
 
 
 
 
 
    C O N FI D E N TI A L                                                           3 8  
3.  
I N V E S TI G A TI O N A L P L A N 
3. 1.  
O ver all St u d y Desi g n  
T his is a P h ase 2, o pe n -la bel, d ose-fi n di n g st u d y d esi g ne d t o assess t he effi cac y, safet y, 
t olera bilit y, a n d p h ar mac o ki netics  of t hree d os es ( 2 0, 3 0 , a n d 1 0 m g/ k g / da y) of Ca n na bi di ol Oral 
S ol uti o n.  D oses e x cee di n g 3 0 m g/ k g/ da y wil l n ot be e x a mi ne d i n t his st u d y. T he st u d y d esi g n 
a n d patie nt  pr o gressi o n t hr o u g h t h e st u d y is o utli ne d i n  Fi g ure  1 . 
St u d y p artici pa nts will b e pe d iatric p atie n ts a ge 3 t o 1 7  (i ncl usi ve) e x perie nci n g tr eat me nt -
resista nt c hil d h o o d a bse n ce seiz ures w h o  satisf y all i ncl usi o n/e xcl usi o n criteria. T he st u d y will 
c o nsist of a Scree ni n g Peri o d, a  Titrati o n Peri o d, a  Treat me nt Peri o d , a n d a F oll o w -u p Peri o d. A 
t otal of 3 0 patie nts will be e nr olle d i n t he st u d y. T e n  patie nts will be e nr oll e d i n eac h of  t he t hree 
d ose c o h orts, a n d n o p atie nt will partici pate i n m ore t ha n o ne  c o h ort.   
Eac h patie nt will c o m plete a Scree ni n g Peri o d f or u p t o 2 8  ( ± 5) da ys. Eli gi bl e patie nts will ha ve 
a baseli ne 4 -h o u r vi de o-E E G t hat will i ncl u de h y per ve ntilati o n. T he i n vesti gat or ma y us e res ults 
of a pre vi o usl y o btai ne d E E G t o g ui de s electi o n of t he a p pr o pri ate patie nts b ut t he Baseli ne Visit 
vi de o -E E G will be use d f or deter mi nati o n of eli gi bilit y a n d will be e val uat e d b y a n 
electr o p h ysi ol o gist n ot i n v ol ve d i n t he st u d y. Det ails of t he vi de o -E E G assess me nt will be 
pr o vi de d i n t he vi de o -E E G C harter.   
T he st u d y dr u g will be a d de d t o e xisti n g a ntie pile ptic dr u g ( A E D) t h era p y f or t he Tr eat me nt 
Peri o d. D osa ges of c o nc o mita nt A E Ds will be hel d c o nsta nt f or t he Scree ni n g Peri o d a n d d uri n g 
t he Treat me nt Peri o d.  
3. 1. 1.  
Titr ati o n a n d Tre at me nt Peri o d s 
T hirt y patie nts i n t otal will be e nr olle d i nt o o ne of t hree d ose c o h orts ; te n patie nts per c o h ort . 
P atie nts i n C o h ort 1 will be treate d b ef ore patie nts are tr eate d i n C o h ort 2, a n d patie nts i n C o h ort 
2 will be treate d pri or t o patie nts bei n g tr eate d i n C o h ort 3. Patie nts will be d ose d a p pr o xi matel y 
e ver y 1 2 h o urs wit h f o o d t o hel p e ns ure c o nsiste nt plas m a le vels are ac hi e v e d, e x ce pt f or Visit 6 
( Wee k 4, Da y 7 ) w he n bl o o d f or fasti n g p har mac o ki netic ( P K) a nal ysis will be dra w n pri or t o 
t he m or ni n g d ose.  
•  C o h ort 1: 2 0 m g/ k g/ da y di vi de d t wice dail y ( BI D)  f or 4 wee ks . 
•  C o h ort 2: Titrati o n peri o d of 2 0 m g/ k g/ da y  di vi de d BI D f or 5  da ys , f oll o w e d b y 
3 0  m g/ k g/ da y  di vi de d BI D  f or 4 wee ks . 
•  C o h ort 3: 1 0 m g/ k g/ da y di vi de d t wice dail y ( BI D)  f or 4 wee ks.  Eli gi ble patie nts will 
be pr o vi de d wit h t heir titrati o n d ose d uri n g t heir Baseli ne Visit ( 5 da ys at 2 0 
m g/ k g/ da y f or C o h ort s 2 ).  
D uri n g t h e Treat me nt Peri o d, patie nts will be d ose d f or 4 wee ks d uri n g w hic h t he i n vesti gat or 
will assess t olera bilit y a n d effect. Patie nts will ret ur n t o t he site at t he e n d of Wee k 2 ( Visit 4) t o 
e val uate me dical stat us (seiz ure diar y, vital si g ns, a n d ne ur ol o gical e x a m), cli nical la b orat or y 
assess me nts, a n d assess A Es.  
At Visit 5  ( Wee k 4, Da y 6 ), t he patie nt will ha ve a re peat 4-h o ur vi de o -E E G i ncl u di n g 
h y per ve ntilati o n t o c o u nt t he n u m ber of a bs e nce s eiz ures ca pt ure d, a n d bl o o d f or P K a nal y sis 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
                        
P r ot oc ol N u m ber I N S0 1 1 -1 7 -1 0 3  
0 6  Ma y  2 0 1 9   
 
 
 
 
 
    C O N FI D E N TI A L                                                           3 9  
will be dra w n. Bl o o d f or P K a nal ys es will be dra w n at Visit 3, Visit 5 (fe d; Wee k 4, Da y 6) a n d 
Visit 6 (faste d; Wee k 4, Da y 7), or t he Earl y Wit h dra wal Visit . T he i n vesti gat or will assess 
t olera bilit y a n d effic ac y. 
F oll o wi n g t he c o m pleti o n of t he Trea t me nt Peri o d ( Visit 6), patie nts will ha ve t he o pti o n t o 
c o nti n ue treat me nt i n a n o pe n -la bel l o n g-ter m safet y st u d y. Patie nts w h o c h o ose t o e nr oll i n t he 
l o n g-ter m safet y st u d y will n ot ha ve a f oll o w-u p p h o ne call. Patie nts w h o d o n ot c h o ose t o e nr oll 
i n the l o n g -ter m safet y st u d y will ta per t h e d ose of Ca n na bi di ol Oral S ol uti o n acc or di n g t o t he 
f oll o wi n g sc h e d ule: d oses bet wee n 2 0-3 0 m g/ k g/ d a y will be re d uce d t o 2 0 m g/ k g/ da y f or fi ve 
da ys a n d t he n disc o nti n u e d; d oses ≤ 2 0 m g/ k g/ da y ca n be disc o nti n ue d wit h o ut titrati o n. T his 
ca n be m o difie d b y t he i n vesti gat or b ase d u p o n t he patie nt’s res p o nse. Patie nts will recei ve a 
f oll o w-u p p h o ne call 1 4 da ys  after c o m pleti n g Visit 6 ( E n d of St u d y).  
A vaila ble safet y data will be re vie we d o n a n o n g oi n g basis t o e ns ure d oses are ge n erall y well 
t olerate d. Det ails of t he s afet y data re vie w will be pr o vi de d i n t he Data M o nit ori n g  C harter.  
3. 1. 2.  
F oll o w -U p  Peri o d  
A f oll o w -u p p h o ne call will occ ur 1 4 da ys  after Visit 6 ( E n d of St u d y)  of t he st u d y dr u g  t o ass ess 
A Es, A E Ds, a n d rec or d c o nc o mita nt me dicati o ns . 
3. 1. 3.  
S t u d y Assess me nts   
Safet y assess me nts f or all patie nts will i ncl u de me dical hist or y, p h ysic al e xa mi nati o n, vital si g ns 
(seate d bl o o d press ure, p ulse rate, te m perat ure, a n d res pirati o n rat e), cli nical la b orat or y testi n g 
( he mat ol o g y, c he mistr y, a n d uri nal ysis), 1 2 -lea d E C G, pri or me dicati o n hist or y (assess me nts of 
past/c urre nt A E Ds a n d c o nc o mita nt me dicati o ns) , C-S S R S, a n d A E assess me nts.  
A c o m plete p h ysical e x a mi nati o n will be d o ne at Scree ni n g ( Visit 1). A n e ur ol o gical 
e x a mi nati o n (c o m plete at Scree ni n g [ Visit 1 ] a n d brief at all ot her st u d y visits ) a n d vital si g ns 
will be assesse d at Scree ni n g ( Visit 1), Baseli ne ( Visit 2), Treat me nt Peri o d ( Visits 3 [ Wee k 1], 4 
[ Wee k 2], a n d 6 [ Wee k 4, E n d of St u d y]), or at t he Earl y Wit h dra wal Visit. Visit 6 is t he E n d of 
St u d y visit f or p atie nts w h o c o m plete t he st u d y.  
Cli nical la b orat or y bl o o d tests ( he mat ol o g y, c he mistr y) will be o btai ne d d uri n g t he Scree ni n g 
( Visit 1), Treat me nt Peri o d ( Visits 3, 4, a n d 6 [ E n d of St u d y]) or at t he Earl y Wit h dra wal Visit. 
Uri nal ysis will be o btai n e d d uri n g Scree ni n g ( Visit 1), a n d at Visit 6 ( E n d of St u d y) or at t he 
Earl y Wit h dra wal Visit. C o nc o mita nt A E D bl o o d le vels will be deter mi ne d at Bas eli ne ( Visit 2), 
Visit 6 ( E n d of St u d y), or t he Earl y Wit h dra wal Visit .  
A 1 2 -lea d el ectr o car di o gra m ( E C G), will be c o m plete d d uri n g Scree ni n g ( Visit 1), Treat me nt 
Peri o d ( Visit 6 [ E n d of St u d y]) or at t he E arl y Wit h dra wal Visit.  
F or patie nts a ge d 7 t o 1 7 years a n d if t h e de vel o p me ntal le vel is a p pr o priat e, t he C ol u m bia -
S ui ci de Se verit y Rati n g Scale [( C-S S R S) C hil dre n's or A d ult’s v ersi o n as a p pr o priate base d o n 
a ge]  will be utilize d t o assess s uici dalit y at t he f oll o wi n g st u d y visits: Scree ni n g ( Visit 1) a n d 
Visit 5  ( Wee k 4, Da y 6) or t he Earl y Wit h dra wal Visit. F or patie nt s w h o are less t ha n 7 years of 
a ge or f or w h o m t he C -S S R S is i na p pr o priate d ue t o t he patie nt’s de vel o p m e ntal f u ncti o ni n g, a 
cli nical assess me nt will be ma de.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
                        
P r ot oc ol N u m ber I N S0 1 1 -1 7 -1 0 3  
0 6  Ma y  2 0 1 9   
 
 
 
 
 
    C O N FI D E N TI A L                                                           4 0  
All a d verse e ve nts ( A Es) t hat arise d uri n g t he Scree ni n g, Titrati o n, Treat me nt, a n d F oll o w -u p 
Pe ri o ds will be d oc u me nte d. C o nc o mita nt me dicati o ns will be re vie we d a n d d oc u me nte d at eac h 
visit. A meal diar y will be c o m plete d at Bas eli ne ( Visit 2) , a n d f or 2 4 h o urs bef ore eac h P K 
sa m pli n g visit at Visit 3 a n d Visit 5 ( Wee k 4, Da y 6) , or t he Earl y Wit h d ra wal Visit. 
T o assess P K para m eters, bl o o d dra ws will be o btai ne d at Visit 3, Visit 5 (fe d; Wee k 4, Da y 6) 
a n d Visit 6 (faste d; Wee k 4, Da y 7), or t he Earl y Wit h dra wal Visit . Bl o o d dra ws f or P K v al ues at 
Visits 5 a n d 6 will occ ur as f oll o ws:  
F asti n g/ Fe d  
P K  
S a m ple 
Visits   
Ti me p oi nts  
Fe d: Patie nts s h o ul d arri ve wit h o ut 
f o o d a n d t he m or ni n g d ose. Site 
pr o vi des a hi g h fat/ hi g h cal orie f o o d 
t he n d oses patie nt 
Visit 5  
( Wee k 4, 
Da y 6 ) 
Pre -d ose (b ef ore meal/ m or ni n g d ose ) 
a n d 2, 4, 6 h o urs aft er t he m or ni n g 
d ose ( b ut bef ore ne xt d ose) 
Faste d ( 2 h o urs bef ore d ose  u ntil 2 
h o urs after d os e ): Patie nts s h o ul d 
arri ve wit h o ut f o o d a n d t he m or ni n g 
d ose. Site pr o vi des a sta n dar d meal 2 
h o urs after d os e.  
Visit 6  
( Wee k 4, 
Da y 7 ) 
Pre -d ose a n d 2  ( bef ore m eal), 4, 6 
h o urs afte r t h e m or ni n g d ose ( b ut 
bef ore n e xt d ose)  
T o assess efficac y, a 4 -h o ur vi de o -E E G i ncl u di n g h y per ve ntilati o n will be o btai ne d at t he 
Baseli ne Visit ( Visit 2), Visit 5 ( Wee k 4, Da y 6)  or t he Earl y Wit h dra wal Visit. A bse nce seiz ures 
will be c o u nte d b y a n el e ctr o p h ysi ol o gist n ot i n v ol ve d wit h t he st u d y. F urt her details will be 
pr o vi de d i n t he vi de o -E E G C harter.   
Dail y seiz ure di aries will be c o m plete d t hr o u g h o ut t he Titrati o n a n d Treat me nt Peri o ds , or t he  
Earl y Wit h dra wal Visit . T he dail y rec or d will as k: “ H ow ma n y a bs e nce s eiz ures di d t he patie nt 
ha ve t o da y? ”.  
T o assess efficac y, t he Cli nical Gl o bal I m pressi o n –  Gl o bal I m pr o ve me nt ( C GI -I) assess me nt 
will be c o m plete d b y t he i n vesti gat or at Visit 3 , Visit 5  ( Wee k 4, Da y 6) or t he Earl y Wit h dra wal 
Visit. All sc ree ni n g, effi cac y, a n d safet y ass ess me nts  will be perf or me d acc or di n g t o t he 
sc he d ule of assess me nts s u m marize d i n T a ble 1 . 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 1  
3. 2.  
P atie nt  Selecti o n  
3. 2. 1.  
I ncl usi o n Criteri a 
Patie nts m ust meet all of t he f oll o wi n g i ncl usi o n c riteria 
1.  Patie nt a n d/ or pare nt(s)/care gi ver(s) f ull y c o m pr e h e n d t he i nf or me d c o nse nt f or m (I C F) 
a n d asse nt f or m, u n d ersta n d all st u d y pr oce d ures, a n d ca n c o m m u nicate satisfact oril y 
wit h t he i n vesti gat or a n d st u d y co or di n at or, i n acc or da nce wit h a p plica ble l a ws, 
re g ulati o ns, a n d l ocal r e q uire me nts. 
2.  Male or fe m ale bet w ee n 3 a n d 1 2 years (i ncl usi ve) at t he ti me of o nset a n d bet wee n 3 a n d 
1 7 years of a ge (i n cl usi ve) at t he ti me of c o nse nt.  
3.  B o d y wei g ht ≥ 1 0  k g.  
4.  Dia g n os e d wit h c hil d h o o d a bse nce e pile ps y ( C A E), c o n fir me d b y E E G wit h at least 3 
b ursts of ge neral s pi ke w a ve ( G S W of 2. 7 t o 5 hertz lasti n g ≥ 3 sec o n ds)  d uri n g t he 4 -
h o ur E E G , a n d h as ha d a n a de q uate tri al of at least 2 A E Ds a n d are treat me nt -resista nt t o 
at least o ne A E D.  
5.  Willi n g ness t o n ot start a ket o ge nic diet d uri n g t he Baseli ne or Treat me nt Peri o d.  
6.  A fe male p atie nt is eli gi ble t o partici pate i n t he st u d y if s he is:  
a. Pre me narc hal, or  
b.  Of c hil d beari n g p ot e ntial wit h a ne gati ve uri ne pre g na n c y test at t he Scree ni n g Visit. 
If se x uall y acti ve, s he m ust a gree t o f ulfill o ne of t he f oll o wi n g re q uire me nts:  
i. C o m plete a bsti ne nce fr o m i nterc o urse f or 2 4 wee ks pri or t o a d mi nistrati o n of t he 
first d ose of t he i n vesti gati o nal pr o d uct, t hr o u g h o ut t he Treat me nt Peri o d, a n d 2  
wee ks after c o m pleti o n or pre mat ure disc o nti n uati o n fr o m t he i n vesti gati o nal 
pr o d uct, a n d a gree m e nt t o use a d o u ble barrier m et h o d if s he bec o mes se x uall y 
acti ve.  
ii. Use of acce pt a ble met h o ds of c o ntrace pti o n t hr o u g h o ut t he st u d y a n d 2  wee ks after 
c o m pleti o n or pre mat ure disc o nti n uati o n fr o m i n vesti gat i o nal pr o d u ct. T he 
acce pta ble met h o d of c o ntrace pti o n is d o u ble barrier met h o d (i.e., c o n d o m pl us 
s per mici de or a c o n d o m pl us i ntra uteri ne de vice [I U D], dia p hra g m, or sta ble 
h or m o nal c o ntrace pti ve use f or at least 3 m o nt hs bef ore s cree ni n g a n d t hr o u g h 2 8  
d a ys after st u d y c o m pleti o n).  
7.  A se x uall y acti ve mal e p atie nt or part ner of a n e nr olle d s u bject m ust be willi n g t o use 
acce pta ble met h o ds of c o ntrace pti o n t hr o u g h o ut t h e st u d y a n d f or 2  wee ks after 
c o m pleti o n of st u d y partici pati o n or disc o nti n uati o n fr o m i n vesti gati o nal pr o d uct. T he 
acce pta ble met h o ds of birt h c o ntr ol are a bsti ne nce or d o u ble barrier birt h c o ntr ol (i.e., 
c o n d o m pl us s per mici de or a c o n d o m pl us o ne of t he met h o ds liste d i n [ 7] ). 
8.  I n t he o pi ni o n of t h e i n vesti gat or, t he p are nt(s)/care gi v er(s) is willi n g a n d a ble t o c o m pl y 
wit h t he st u d y pr oce d ures a n d visit sc he d ules, i ncl u di n g ve ni p u nct ure, a n d t he F oll o w -u p 
Visits.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 2  
9.  Ge neral g o o d healt h ( defi ne d as t he a bse n ce of a n y cli nicall y rele va nt a b n or malities as 
deter mi ne d b y t he i n vesti gat or) base d o n p h ysi cal a n d ne ur ol o gical e x a mi nati o ns, 
me dical hist or y, a n d cli nical la b orat or y val ues ( h e mat ol o g y, c h e mistr y, a n d uri nal ysis) 
c o m plete d d uri n g t he Scree ni n g Visit t hat w o ul d pr o hi bit t he patie nt fr o m safel y 
partici pati n g i n t he tri al as j u d ge d b y t he i n ve sti gat or. 
3. 2. 2.  
E xcl usi o n Criteri a  
1.  Patie nt or pare nt(s)/ care gi ver(s) ha v e dail y c o m mit me nts d uri n g t he st u d y d urati o n t hat 
 
w o ul d i nterfere wit h atte n di n g all st u d y visits.  
2.  Has a hist or y of acti ve n o nfe brile seiz ures ot her t ha n a bse nce seiz ures (e. g., t o ni c, at o nic, 
or  m y ocl o nic seiz ures).  Hist or y of a n y ot her seiz ure t y p e c urre ntl y i n r e missi o n m ust be 
a dj u dicate d b y t he me dic al m o nit or.  
3.  Has a hist or y of fe brile s eiz ures after 3 years of a ge.  
4.  Has a hist or y c o nsiste nt wit h j u ve nile a bse nce e pile ps y o r j u v e nile m y o cl o nic e pile ps y. 
5.  C urre ntl y ta ki n g fel ba mate  
6.  C urre ntl y ta ki n g p h e n yt oi n, fl u v o x a mi ne, car ba maze pi ne, or St. J o h n’s W ort.  
7.  C urre ntl y ta ki n g c o nc o mita nt me dicati o ns t hat are str o n g i n hi bit ors/i n d ucers/se nsiti ve 
 
s u bstrates wit h a narr o w t hera pe utic i n de x f or c yt oc hr o me P 4 5 0 3 A 4 ( C Y P 3 A 4), 
 
C Y P 2 C 9, or C Y P 2 C 1 9  [ N ote: Sta ble d oses of Val pr oic Aci d d uri n g t he scree ni n g, 
titrati o n, treat me nt, a n d f oll o w-u p peri o ds are per mitte d] . 
8.  C urre ntl y o n a ket o ge nic diet.  
9.  I n t he o pi ni o n of t h e i n vesti gat or, a n y cli nicall y si g nifica nt, u nsta ble me dical 
 
a b n or malit y, c hr o nic dise ase, or a hist or y of a cli ni call y si g nifica nt a b n or malit y of t he 
 
car di o vas c ular, gastr oi nt esti nal, res pirat or y, h e patic, or re n al s yste ms.  
1 0. Cli nicall y si g nifica nt a b n or mal li ver f u n cti o n test ( L F T) val ues, i ncl u di n g: 
a. Al b u mi n, direct bilir u bi n, t otal bilir u bi n, as partate a mi n otra nsferase ( A S T), a n d ala ni n e 
a mi n otra nsferase ( A L T) ≥3 ti mes t he u p per li mit of n or mal ( U L N).  
1 1 . Hist or y or prese n ce of a b n or mal E C Gs t hat are cli nicall y si g nifica nt i n t he o pi ni o n of t he 
 
i n vesti gat or. 
1 2 . Has a c urre nt or hist or y of cli nicall y si g nifica nt i ntelle ct ual disa bilit y or maj or ps yc hiatric 
 
disease, i ncl u di n g a utis m s pectr u m dis or der, w hic h w o ul d i nterfere wit h c o m plia nce.  
1 3 . F or patie nts a ge d 7 t o 1 7 years of a ge a n d f or w h o m t he C -S S R S is de vel o p me ntall y 
 
a p pr o priate, a n affir mati ve a ns wer t o q ueries re gar di n g acti ve s uici dal i deati o n wit h s o me 
 
i nte nt t o act b ut wit h o ut a s pecific pl a n or acti ve s uici dal i deati o n wit h a s pecific pla n a n d 
 
i nte nt o n t he C-S S R S assess me nt at t he Scree ni n g Visit. Patie nts w h o ha ve si g nifica nt 
 
fi n di n gs f or s ui ci dal i deati o n as assesse d b y t he C-S S R S m ust be referre d t o t he 
 
i n vesti gat or f or f oll o w-u p e val uati o n.  
1 4 . A n y hist or y of atte m pte d s uici de.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 3  
1 5 . Pre vi o usl y recei ve d a n y i n vesti gati o nal dr u g or de vice or i n vesti gati o nal t hera p y wit hi n 
 
3 0 da ys b ef ore Scree ni n g.  
1 6 . Ta ke n a n y ca n na bi n oi ds (ca n na bi di ol, Δ 9-tetra h y dr oca n na bi n ol [ Δ9-T H C], he m p oil, 
 
Real m Oil, or marij ua na) i n t he 3 0 da ys pri or t o t he Scree ni n g Visit.  
1 7 . Hist or y of a n aller gi c reacti o n or a k n o w n or s us p ecte d se nsiti vit y t o a n y s u bsta nce t hat is 
 
c o ntai ne d i n t he i n vesti gati o nal pr o d uct f or m ulati o n. 
1 8 . K n o w n i nfecti o n wit h he patitis B, he patitis C, or h u ma n i m m u n o deficie nc y vir us ( HI V).  
1 9 . I n t he o pi ni o n of t h e i n vesti gat or, t he p atie nt is u ns uita ble i n a n y ot her wa y t o partici pate 
 
i n t his st u d y. 
2 0 . B o d y wei g ht  < 1 0 k g or  > 9 0 k g.  
3. 3.  
Re m o v al of P atie nts fr o m T her a p y or Assess me nt 
Patie nts will be all o we d t o disc o nti n ue t heir partici pati o n i n t he st u d y at a n y ti me f or a n y reas o n 
( wit h dra wal of c o nse nt). F urt her m ore, partici pati o n i n t his cli nical st u d y ma y b e disc o nti n ue d b y 
t he in vesti gat or or b y t he s p o ns or f or a n y of t h e f oll o wi n g reas o ns:  
•  I nt olera ble si de effects of t he st u d y pr o d u ct. 
•  C ha n ges i n me di cal stat us or me dical c o n diti o n of t he patie nt s uc h t hat t he 
in vesti gat or b elie ves t hat patie nt safet y will be c o m pr o mise d or t hat it w o ul d be i n t he 
best i nterest of t he patie nt t o st o p treat me nt.  
•  Patie nt safet y or welfare is at ris k. 
•  N o n -c o m plia nce wit h st u d y visits, defi ne d as fail ure t o perf or m a n y p orti o n of 
sc he d ule d ass ess me nts or pr oce d ures. 
•  A n y u n f ores ee n e v e nt t hat i n t he o pi ni o n of t he treati n g p h ysici a n a n d/ or t he Pri nci pal 
in vesti gat or, will pre v e nt t he researc h p artici pa nt fr o m c o nti n ui n g i n t his st u d y.  
•  Patie nt d oes n ot t olerate 1 0 m g/ k g/ da y.  
•  S p o ns or deci des t o st o p t he st u d y.  
I n t he e ve nt of a patie n t’s wit h dra wal, t he in vesti gat or will pr o m ptl y n otif y t he s p o ns or.  E ver y 
eff ort will be ma d e t o c o m plete t he e n d -of -st u d y assess me nts. 
S h o ul d a n y patie nt c h o os e t o wit h dra w earl y fr o m t he st u d y, t he y will be a d vise d of t he safet y 
preca uti o ns t o be ta k e n a n d will be f oll o we d u ntil res ol uti o n of a n y A E or u ntil t he u nres ol ve d 
A Es are j u d ge d b y t he i n vesti gat or t o h a ve sta bilize d.  
3. 4.  
D ose A dj ust me nt Criteri a  
D oses will n ot be a dj uste d i n t his st u d y.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 4  
3. 5.  
St o p pi n g R ules  
T he in vesti gat or res er ves t he ri g ht t o ter mi nate t h e st u d y i n t he i nterests of patie nt  safet y a n d 
welfare. T he S p o ns or res er ves t he ri g ht t o ter mi nate t he st u d y at a n y ti me f or a d mi nistrati ve 
reas o ns. 
Patie nts will als o be disc o nti n ue d fr o m t he st u d y if t he y m eet t he f oll o wi n g criteria:  
•  A L T or A S T > 3 x U L N wit h ( or t he a p peara n ce of) fati g ue, n a usea, v o miti n g, ri g ht 
u p per q ua dra nt pai n or te n der ness, f e ver, ras h, a n d/ or e osi n o p hilia > 5 %  
•  A L T or A S T > 8 x U L N  
•  A L T or A S T > 5 x U L N f or m ore t ha n 2 wee ks  
•  A L T or A S T > 3 x U L N a n d bilir u bi n > 2 x U L N or  I N R > 1. 5 
F or patie nts meeti n g t he a b o ve criteria, t he i n vesti gat or will arra n ge f or t h e patie nt t o ret ur n t o 
t he i n vesti gati o nal site as s o o n as p ossi ble ( wit hi n 2 4 h o urs of n otice of a b n or mal res ults) f or 
re peat assess me nt of A L T, A S T, bilir u bi n, a n d alkali ne p h os p hatase ( A L P), detaile d hist or y, a n d 
p h ysical e x a mi nati o n. Patie nts will be f oll o we d u ntil all a b n or malities ha ve n or malize d (i n t he 
i n vesti gat or’s o pi ni o n) or ret ur ne d t o t he b aseli ne state. If t he patie nt is u na ble t o ret ur n t o t he 
i n vesti gatio nal site, re p eat assess me nts ma y b e perf or me d at a l o cal la b orat or y .  
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 5  
4.  
T R E A T M E N T S  
4. 1.  
Tre at me nts A d mi nistere d  
I n t he Treat me nt Peri o d, Ca n na bi di ol Oral S ol uti o n will be d ose d orall y i n t hree d ose c o h orts. 
Patie nts or pare nt/care gi v er will be i nstr ucte d h o w t o meas ure,  ta ke t heir d ose, a n d rec or d t heir 
d ose i n t he d osi n g diar y  w he n t he I P is dis pe nse d f or t he first ti me . 
T otal dail y d oses of 1 0, 2 0, or 3 0  m g/ k g/ da y will b e a d mi nistere d wit h f o o d i n t w o dail y d oses of 
5, 1 0, or 1 5  m g/ k g / d ose a p pr o xi matel y e ver y 1 2 h o urs . P atie nts i n C o h ort 1 will be treate d pri or 
t o i nitiati o n of e nr oll me nt i nt o C o h ort 2, a n d patie n ts i n C o h ort 2 will be treate d pri or t o 
i nitiati o n of e nr oll me nt i nt o C o h ort 3. D oses hi g h er t ha n 2 0 m g/ k g/ d a y will be titrate d  as 
descri be d i n Secti o n  4. 4 . Ca n na bi di ol Oral S ol uti o n will be a d mi nistere d wit hi n 3 0 mi n utes after 
a meal, e x ce pt d uri n g Visit 6 w he n fasti n g P K val ues will be o btai ne d.  
4. 2.  
I de ntit y of I n vesti g ati o n al Pr o d uct  
T he acti ve p h ar mace utical  i n gre die nt ( A PI) i n Ca n na bi di ol Oral S ol uti o n is a p har mace utical 
gra de s y nt hetic C B D ma n ufact ur e d acc or di n g t o c G M P. It is a n off -w hite t o pale yell o w resi n or 
cr ystal s u bsta nce t h at is s ol u ble i n se veral or ga nic s ol ve nts wit h a n aci d diss ociati o n c o nsta nt 
( p Ka) of 9. 6 4. T he s ol uti o n is a clear, c ol orless t o pale yell o w-br o w n c ol or e d s ol uti o n ( C B D 
c o nce ntr ati o n of 1 0 0 m g/ m L) fille d i nt o a 3 0 m L a m ber gl ass vial. M ore det aile d i nf or mati o n 
ma y b e f o u n d i n t he I B. 1  
4. 3.  
Met h o d of Assi g ni n g S u bjects  t o Tre at me nt Gr o u ps 
Eli gi ble patie nts  will be s e q ue ntiall y assi g n e d t o eac h d ose c o h ort.   T hat is, t he first 1 0 eli gi ble 
patie nts will be i n C o h ort 1, a n d s o o n.  
4. 4.  
Selecti o n a n d Ti mi n g of D ose f or E ac h S u bject  
Te n  patie nts  will be e nr olle d i n eac h of t hree d os e co h orts :  
•  C o h ort 1 : 2 0  m g/ k g/ da y di vi de d BI D f or 4 wee ks . 
•  C o h ort 2:  2 0 m g/ k g/ da y di vi de d BI D f or 5 da ys f oll o we d b y 3 0 m g/ k g/ da y di vi de d 
BI D f or 4 wee ks. 
•  C o h ort 3:  1 0  m g/ k g/ da y di vi de d BI D f or 4 wee ks.  
S u bjects  will ta ke eac h d ose a p pr o xi matel y e v er y 1 2 h o urs wit h f o o d i n or der t o e ns ure 
c o nsiste nt plas ma le vels are ac hie ve d , e x ce pt f or Visit 6  w he n bl o o d f or fasti n g p har mac o ki netic 
a nal ysis will be dra w n  pri or t o t he m or ni n g d ose . T he date a n d ti me of all i n vesti gati o nal pr o d u ct 
a d mi nistrati o ns will be d oc u me nte d i n t he  case re p ort f or m  (C R F ) fr o m t he seiz ure diar y. 
4. 5.  
Bli n di n g a n d U n bli n di n g Tre at me nt Assi g n me nt  
N ot a p plica ble.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 6  
4. 6.  
Tre at me nt C o m pli a nce  
T he prescri be d d osa ge, ti mi n g, a n d m o de of a d mi nistrati o n of I P ma y n ot be c ha n ge d u nless 
t here is a pr ot oc ol-s pecifi e d up titrati o n or a safet y c o ncer n or t o xicit y is i de ntifie d f or a patie nt .   
T he in vesti gat or, a me m b er of t he i n vesti gati o nal staff, or a h os pital p h ar macist m ust mai ntai n a n 
a de q uate rec or d of t he recei pt a n d distri b uti o n of all st u d y me dicati o n usi n g t he Dr u g 
Acc o u nta bilit y F or m. T h ese f or ms m ust be a v aila ble f or i ns pecti o n at a n y ti me.  
All s u p plies of I P s h o ul d be acc o u nte d f or at t he ter mi nati o n of t he st u d y a n d a writte n 
e x pla nati o n pr o vi de d f or discre pa n cies. All use d a n d u n use d s u p plies , a n d pac ka gi n g materials 
are t o be i n ve nt orie d a n d ret ur ne d t o t he S p o ns or or a desi g nee b y t he in vesti gat or. T he 
in vesti gat or is n ot per mitte d t o ret ur n or destr o y u n use d cli nical dr u g s u p plies or pac k a gi n g 
materials u nless a ut h oriz e d b y t h e S p o ns or or a d esi g nee.  
If the st u d y is ter mi nate d, disc o nti n ue d, s us pe n de d, or c o m plete d, all use d a n d u n use d s u p plies of 
t he i n vesti gati o nal pr o d u ct ma y b e destr o ye d via t he use of a t hir d-part y ve n d or or be ret ur ne d t o 
t he S p o ns or or a desi g nee after t he fi nal dr u g acc o u nta bilit y c hec k has bee n perf or me d. A 
certificate of destr u cti o n will be pr o vi de d t o t he S p o ns or.  
All re g ul ati o ns iss ue d b y t he D E A c o ncer ni n g t he acc o u nta bilit y of Sc he d ul e I me dicati o ns will 
be f oll o we d (e. g., pre v e nti o n of di versi o n).  
4. 7.  
Per mitte d a n d Pr o hi bite d T he r a pies 
4. 7. 1.  
Per mitte d T her a pies  
A n y me di cati o ns ( ot her t ha n t h ose e x cl u de d b y t h e pr ot oc ol, see Secti o n  4. 7. 2 ) t hat t he 
in vesti gat or c o nsi ders necessar y f or a p atie nt ’s welfare a n d will n ot i nterfere wit h t he 
i n vesti gati o nal pr o d u ct ma y b e a d mi nistere d  at t he in vesti gat or’s discreti o n.  
4. 7. 2.  
Pr o hi bite d T her a pies  
D uri n g t h e Scree ni n g, Titrati o n, Treat me nt,  a n d F oll o w -u p Peri o ds, patie nts  are n ot t o recei ve 
t he f oll o wi n g: 
•  A n y ca n na bi n oi ds besi des t he st u d y dr u g (ca n n a bi di ol , Δ9-T H C, he m p oil, Real m Oil 
or marij ua na).  
•  P he n yt oi n, fl u v o x a mi ne, car ba m aze pi ne, or St. J o h n’s W ort.  
•  M e dicati o ns t hat are str o n g i n hi bit ors/i n d ucers/se nsiti ve s u bstrates wit h a narr o w 
t hera pe utic i n de x f or C Y P 3 A 4 , C Y P 2 C 9, or C Y P 2 C 1 9 [ N ote: Sta ble d oses of 
Val pr oic Aci d d uri n g t h e scree ni n g, titrati o n, treat me nt, a n d f oll o w -u p peri o ds are 
per mitte d] .   
•  A n y ot her i n vesti gati o nal dr u g or i n vesti gati o nal de vice.  
•  I ntr o d u cti o n of ne w a nti-e pile ptic dr u gs ( A E Ds) or t hera pies ( V N S, ket o ge nic diet) 
d uri n g t he st u d y is pr o hi bite d  d uri n g t he Treat me nt Peri o d , b ut all o we d d uri n g t he 
Safet y Peri o d .    
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 7  
Alt h o u g h t he y are n ot pr o hi bite d, patie nts  ta ki n g c o nc o mita nt me dicati o ns ma y n ee d t o be 
m o nit ore d wit h s pecial care t o i de ntif y a n y A Es arisi n g d ue t o t he p ote ntial f o r altere d dr u g 
meta b olis m.  
4. 8.  
Tre at me nt After t he E n d of St u d y  
A fi nal f oll o w-u p p h o ne call will be c o n d ucte d 1 4 da ys  after c o m pleti o n of Visit 6 ( E n d of 
St u d y).  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 8  
5.  
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  
5. 1.  
L a beli n g a n d P ac k a gi n g  
5. 1. 1.  
L a beli n g  
T he la bels f or t h e i n vesti gat i o nal pr o d u ct will c o ntai n all i nf or mati o n acc or di n g t o re g ulat or y 
re q uire me nts. 
5. 1. 2.  
P ac k a gi n g  
T he i n vesti gati o nal pr o d uct will be s u p plie d i n 3 0 m L c o ntai n ers of a 1 0 0 m g/ m L str e n gt h (i.e., 
3 0 0 0 m g per c o ntai ner).  
N o n -pr o priet ar y or c o m m o n n a me of 
dr u g pr o d uc t 
Ca n na bi di ol Oral S ol uti o n, 1 0 0 m g/ m L  
D os a ge f or m  
Oral s ol uti o n  
Stre n gt h  
1 0 0 m g/ m L  
Please refer t o t he Ca n n a bi di ol Oral S ol uti o n I B 1 f or a d diti o nal i nf or mati o n o n t he dr u g 
f or m ulati o n.   
T he i n vesti gati o nal pr o d uct will be clearl y mar ke d acc or di n g t o F D A a n d/ or I C H re q uir e me nts 
re gar di n g use f or cli nical st u d y i n vesti gati o n o nl y a n d will be la bele d wit h t he i n vesti gati o nal 
pr o d uct na me, st u d y refere nce n u m b er, st ora ge c o n diti o ns, a n d e x pir y d ate. It is t he 
res p o nsi bilit y of t he in vesti gat or t o e ns ure t h at acc urate acc o u nta bilit y rec or ds are mai ntai ne d 
t hr o u g h o ut t he st u d y. St u d y ce nter staff will dis pe nse t he i n vesti gati o nal pr o d uct acc or di n g t o t he 
ha n dli n g i nstr ucti o ns.  
5. 2.  
Dis pe nsi n g a n d St or a ge  
I P will be st ore d at c o ntr olle d r o o m te m perat ur e ( 2 0 t o 2 5 de grees Celsi us, 6 8 t o 7 7 de grees 
Fa hre n heit) at t he st u d y ce nters.  
Ca n na bis a n d its c o nstit ue nts (i ncl u di n g C B D) are Sc he d ule I c o ntr olle d s u bsta nces a n d s u bject 
t o all a p plica ble l ocal a n d fe deral la ws a n d re g ulati o ns re gar di n g t hese pr o d ucts. T his i ncl u des 
sec urit y pr o visi o ns f or st ori n g t he c o ntr olle d s u bsta nces a n d f or dis pe nsi n g i n a ma n ner t o 
pre ve nt di versi o n. A d diti o nall y, t he S p o ns or or in vesti gat or m ust pr o vi de a state me nt of t he 
q ua ntit y t o be ma n ufact ure d a n d t he s o urces of t he c he micals t o be u se d or t he s u bsta nce. 
T he D E A re g ulati o ns det ail s pecific sec urit y re q uire me nts f or st or a ge of t h e i n vesti gati o nal 
pr o d uct. Li ce nse d practiti o ners m ust st ore c o ntr olle d s u bsta nces i n a “sec urel y l oc ke d, 
s u bsta ntiall y c o nstr uct e d ca bi net” a n d m ust n otif y t he D E A of t he t heft or si g nifica nt l oss of a n y 
c o ntr olle d s u bsta nces wit hi n o ne b usi ness da y of disc o veri n g s uc h l oss or t h eft. F urt h er m ore, all 
practiti o ners are pr o hi bit e d fr o m hiri n g e m pl o yees w h o ha ve bee n c o n vict e d of a dr u g -rel ate d 
fel o n y or w h o ha v e ha d a D E A re gistrati o n de ni e d or re v o ke d.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 4 9  
I n v esti gat ors are res p o nsi ble f or e ns uri n g t hat all a p plica ble lice ns ures are i n place a n d st ora ge 
c o n diti o ns are a p pr o priat e.   
D oses of I P will be a d mi nistere d fr o m t he Sc h e d ule I -lice nse d st u d y ce nter.   
T he st u d y ce nters are re q uire d t o pr o vi de c o m plet e i nf or mati o n, i ncl u di n g case re p ort f or ms 
( C R Fs) a n d fi nal o utc o m es, o n all i nsta nces of a d dicti o n, a b use, mis use, o ver d ose, dr u g 
di versi o n/ dr u g acc o u nt a bilit y, discre pa n cies i n a m o u nt of t he cli nical s u p plies of t he 
i n vesti gati o nal pr o d u ct, n o nc o m plia nce, pr ot oc ol vi olati o ns, lac k of effi cac y, i n di vi d uals l ost t o 
f oll o w-u p, a n d a n y ot her reas o ns w h y s u bjects dr o p pe d o ut of t he st u d y.  
5. 3.  
Dr u g S u p pl y a n d Acc o u nt a bilit y  
T he in vesti gat or, a me m b er of t he i n vesti gati o nal staff, or a h os pital p h ar macist m ust mai ntai n a n 
a de q uate rec or d of t he recei pt a n d distri b uti o n of all st u d y me dicati o n usi n g t he Dr u g 
Acc o u nta bilit y F or m. T h ese f or ms m ust be a v aila ble f or i ns pecti o n at a n y ti me.  
All s u p plies of Ca n na bi di ol Oral S ol uti o n  s h o ul d be acc o u nte d f or at t he ter mi nati o n of t he st u d y 
a n d a writte n e x pla nati o n pr o vi de d f or discre pa n cies. All u n use d s u p plies a n d pac ka gi n g 
materials are t o be i n ve nt orie d a n d ret ur ne d t o t he S p o ns or or a desi g nee b y t he in vesti gat or. T he 
in vesti gat or  is n ot per mitte d t o ret ur n or destr o y u n use d cli nical dr u g s u p plies or pac k a gi n g 
materials u nless a ut h oriz e d b y t h e S p o ns or or a d esi g nee.  
If t he st u d y is ter mi nate d, disc o nti n ue d, s us pe n de d, or c o m plete d, all u n us e d s u p plies of t he 
i n vesti gati o nal pr o d u ct ma y b e destr o ye d b y via t h e use of a t hir d-part y ve n d or or be ret ur ne d t o 
t he S p o ns or or a desi g nee after t he fi nal dr u g acc o u nta bilit y c hec k has bee n perf or me d.  A 
certificate of destr u cti o n will be pr o vi de d t o t he S p o ns or.  
All re g ul ati o ns iss ue d b y t he  D E A c o ncer ni n g t he acc o u nta bilit y of Sc he d ul e I me dicati o ns will 
be f oll o we d (e. g., pre v e nti o n of di versi o n).  
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
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o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 0  
6.  
S T U D Y A S S E S S M E N T S  
6. 1.  
Effic ac y Assess me nts  
6. 1. 1.  
Vi de o -E lectr o e nce p h al o gr a p h y (V i de o-E E G)  
A 4 -h o ur v i de o-E E G will be perf or me d f or all s u bjects at Baseli ne  ( Visit 2), Visit 5 ( Wee k 4, 
Da y 6) or  t he Earl y Wit h dra wal  V isit. H y per ve ntilati o n will be c o n d ucte d d uri n g t he vi de o -E E G.  
As o vert cli nical si g ns ma y or ma y n ot be prese nt d uri n g t he G S W b ursts, res p o nse testi n g 
d uri n g t he G S W b ursts is e nc o ura ge d, if p ossi ble, b ut n ot re q uire d.  
Details re gar di n g re q uir e me nts f or co n d ucti n g  t he vi de o-E E G a n d t he in d e p e n de nt ce ntr al 
rea der’s r e vie w a n d assess me nt of t he vi de o -E E G is o utli ne d i n t he E E G C harter.  
6. 1. 2.  
Cli nic al Gl o b al I m pressi o n –  Gl o b al I m pr o ve me nt  (C GI -I) 
T he C GI -I will be assess e d  b y t h e i n vesti gat or at Visit  3 , Visit  5 ( Wee k 4, Da y 6)  or  t he Earl y 
Wit h dra wal Visit . 
6. 1. 3.  
Seiz ure Di aries  
Seiz ure diaries will be dis pe nse d d uri n g t he Scree ni n g Visit ( Visit 1 ) t o c ollect dail y s eiz ure 
acti vit y t hr o u g h o ut t he S cree ni n g,  Titr ati o n , a n d Treat me nt Peri o d s, or t he  Earl y Wit h dra wal 
Visit . Eac h da y, t he patie nt or pare nt /care gi ver will res p o n d t o t he q uesti o n: “H o w ma n y  a bs e nce 
seiz ures di d t he patie nt ha ve t o da y? ”  
6. 2.  
S afet y Assess me nts  
Safet y assess me nts f or all patie nts  will i ncl u de me dical hist or y, p h ysic al e xa mi nati o n, vital si g ns 
(seate d bl o o d press ure, p ulse rate, te m perat ure, a n d res pirati o n rat e), cli nical la b orat or y testi n g 
(he mat ol o g y, c he mistr y, a n d uri nal ysis ), 1 2-lea d E C G, c o nc o mita nt A E D bl o o d le vels, pri or 
me dicati o n hist or y  (assess me nts of past/c urre nt A E Ds a n d c o nc o mita nt me dicati o ns), C -S S R S, 
a n d A E assess me nts.  
6. 2. 1.  
De m o gr a p hics a n d Me dic al Hist or y  
Eac h p ote ntial st u d y partici pa nt will ha ve t he f oll o wi n g ass ess me nts perf or me d b y t h e 
in vesti gat or or d esi g nee d uri n g t h e Scree ni n g Peri o d  ( Da ys -2 8 t o -1) : de m o gra p hic data, 
i ncl u di n g se x, date of birt h , race, et h nicit y, me di cal/s ur gical hist or y, esti mate of hist oric seiz ure 
c o u nt fr o m patie nt or pare nt, rec or d of past a n d c urre nt A E Ds , a n d c o nc o mita nt me dicati o ns. 
6. 2. 2.  
P h ysic a l E x a mi n ati o ns 
A p h ysic al e x a mi nati o n will be c o n d ucte d f or e ver y p atie nt d uri n g t he Scree ni n g Visit ( Visit 1). 
T he e x a mi na ti o n will i ncl u de e val uati o n of ge n eral a p peara nce, s ki n, e yes, ears, n ose, t hr o at, 
nec k, l y m p h n o d es, c hest,  h eart, a b d o me n, a n d e xtre mities. Hei g ht a n d wei g ht will be meas ure d 
d uri n g Visits 1, 3, 6 ( E n d of St u d y) or t h e Earl y Wit h dra wal Visit . 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 1  
6. 2. 3.  
Ne ur ol o gic al E x a mi n ati o ns  
A c o m plete ne ur ol o gic al e x a mi nati o n ( me ntal stat us, cra nial ner ves, n ysta g m us, m ot or s yst e m, 
se ns or y s yst e m, refl e x es, c o or di nati o n, gait, a n d st ati o n) will be c o n d ucte d d uri n g Scree ni n g 
( Visit 1). A brief n e ur ol o gic al e x a mi nati o n will be c o n d ucte d d uri n g Baseli ne ( Visit 2), 
Treat me nt Peri o d  (Visit s 3, 4 , a n d Visit 6  [E n d of St u d y ]) or t h e Earl y Wit h dra wal  Visit . 
6. 2. 4.  
Vit al S i g ns 
Vital si g ns (seate d bl o o d press ure, p ulse rate, te m p erat ur e a n d res pirati o n rate) will be meas ure d 
d uri n g Scree ni n g ( Visit 1) , Bas eli ne Visit ( Visit 2), Treat me nt  Peri o d ( Visit s 3,  4 , a n d 6 [E n d of 
St u d y ]) or t h e Earl y Wit h dra wal Visit.  
A d diti o nal vi tal si g n meas ure me nts ma y be perf or me d as dee me d m e dicall y necessar y b y 
researc h pers o n nel. 
6. 2. 5.  
Electr oc a r di o gr a ms  
A resti n g 1 2 -lea d E C G will be c o n d ucte d f or e ver y patie nt d uri n g Scree ni n g ( Visit 1), Treat me nt 
Peri o d ( Visit 6  [E n d of St u d y ]) or t he Earl y Wit hdra wal Visit .  
6. 2. 6.  
Cli nic al L a b or at or y Assess me nts  
Bl o o d sa m ples f or h e mat ol o g y a n d c he mistr y assess me nts will be c ollecte d d uri n g Scree ni n g 
( Visit 1), Treat me nt  Peri o d  (Visit s 3,  4 , a n d 6  [E n d of St u d y ]) or  t he Earl y Wit h dra wal Visit. 
Uri ne sa m ples f or uri nal ysis will be c ollect e d d uri n g Scree ni n g ( Visit 1), Treat me nt Peri o d 
( Visit 6  [E n d of St u d y ]) or  t he Earl y Wit h dra wal Visit. 
•  He mat ol o g y: h e m o gl o bi n, he mat ocrit, t otal a n d differe ntial le u k o c yte c o u nt, re d 
bl o o d cell ( R B C), a n d pl atelet c o u nt.  
•  C he mistr y: al bu mi n, bl o o d urea nitr o ge n ( B U N), creati ni ne, t otal bilir u bi n, al kali ne 
p h os p hatase ( A L P), as partate tra nsa mi nas e ( A S T), ala ni ne tra ns a mi nase ( A L T), 
s o di u m ( Na+ ), p otassi u m ( K+ ), c hl ori de ( Cl-), l actate de h y dr o ge n ase ( L D H), uric aci d, 
gl uc ose, a n d calci u m.  
•  Uri nal ysis: p H, s pecific gra vit y, pr otei n, gl uc ose, k et o nes, bilir u bi n, bl o o d, nitrite, 
le u k oc yt e esterase, a n d ur o bili n o ge n. If pr otei n, o cc ult bl o o d, nitrite, or le u k oc yt e 
esterase v al ues are o ut of ra n ge a micr osc o pic e x a mi nati o n will be perf or m e d.  
C o n c o mita nt A E D bl o o d le vels will be deter mi ne d at Bas eli ne ( Visit 2), Visit 6 ( E n d of St u d y), 
or t he Earl y Wit h dra wal Visit.   
6. 2. 7.  
C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)  
T he C -S S R S is a pr os pecti ve assess me nt t o ol r o uti nel y use d i n st u dies of dr u gs wit h a n y 
p ote ntial f or C N S effects. It c a pt ures t he o cc urre n ce, se verit y, a n d fre q ue n c y of s uici de -relate d 
t h o u g hts a n d be h a vi ors d uri n g t he assess me nt peri o d. F or patie nts a ge d 7 t o 1 7 years a n d if t he 
de vel o p me ntal le vel is a p pr o priate, the q u esti o n naire will  be c o m plete d at Scree ni n g ( Visit 1)  
a n d Visit  5  ( Wee k 4, Da y 6) or t he Earl y Wit h dra wal Visit . F or patie nts w h o are less t ha n 7 years 
or f or w h o m t he C -S S R S is i na p pr o priate d ue t o t he patie nt ’s de v el o p me ntal f u ncti o ni n g, a 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 2  
cli nical assess me nt will be ma d e f oll o wi n g F D A g ui deli nes. 
(htt ps:// w w w.f da. g o v/ d o w nl oa ds/ dr u gs/ g ui da nces/ uc m 2 2 5 1 3 0. p df ). 
6. 2. 8.  
A d verse E ve nts a n d Seri o us A d verse E ve nts  
6. 2. 8. 1.  
Defi niti o n of A d verse E ve nts  
A n A E is defi ne d a s a n y u nt o war d me dical o cc urre nce i n a p atie nt a d mi nistere d a p h ar mace utical 
pr o d uct d uri n g t he c o urs e of a cli nic al i n vesti gati o n. A n A E ca n t h eref ore be a n y u nfa v ora ble 
a n d u ni nte n de d si g n, s y m pt o m, or disease te m p orall y ass ociat e d wit h t he use of a n 
i n vesti gati o nal pr o d u ct, w het her or n ot t h o u g ht t o be relate d t o t he i n v esti gati o nal pr o d uct.  
Patie nts  will be m o nit ore d t hr o u g h o ut t he st u d y f or A Es. M o nit ori n g f or treat me nt -e mer ge nt A Es 
will be gi n as s o o n as t he patie nt  is d ose d. All A Es m ust be f oll o we d until t he y are res ol ve d or 
sta bilize d, or u ntil all atte m pts t o deter mi ne res ol uti o n of t he e ve nt are e x ha uste d. T he 
i n vesti gat or s h o ul d use t heir discreti o n i n or deri n g a d diti o nal tests as necessar y t o m o nit or t he 
pr o gress of s uc h e ve nts.  
A n A E ma y be:  
•  A n e w ill ness, n ot d oc u me nte d i n t he patie nt’s s m e dical hist or y; 
•  W orse ni n g of a c o nc o mit a nt ill ness;  
•  A n effect of t he st u d y me dicati o n; it c o ul d be a n a b n or mal la b orat or y v al ue, as well 
as a si g nifica nt s hift fr o m baseli ne wit hi n n or mal ra n ge w hic h t he q uali fie d 
i n vesti gat or or m e dical q ualifie d desi g nate c o nsi ders t o be cli nicall y i m p orta nt; 
•  A c o m bi nati o n of t w o or m ore of t hese fact ors.  
S ur gical pr oce d ures t he msel ves are n ot A Es. T he y are t hera pe utic meas ures f or c o n diti o ns t hat 
re q uire d s ur ger y. T h e c o n diti o n f or w hic h t he s ur ger y is re q uir e d is a n A E, if it occ urs or is 
detecte d d uri n g t he st u d y peri o d. Pla n ne d s ur gical meas ures per mitte d b y t h e cli nical st u d y 
pr ot oc ol a n d t he c o n diti o ns(s) lea di n g t o t hese meas ures are n ot A Es, if t he c o n diti o n(s) was 
( were) k n o w n b ef ore t he start of st u d y tr eat me nt. I n t he latter cas e, t he c o n diti o n s h o ul d be 
re p orte d as me dical hist or y. 
A bse nce s eiz ures will n ot be c o nsi dere d A E s. H o we ver, ne w seiz ure t y pes a n d i nj ur y res ulti n g 
fr o m a seiz ure will be ca pt ure d as A Es. 
Pat ie nts will be m o nit ore d t hr o u g h o ut t he st u d y f or A Es. All A Es m ust be f oll o we d u ntil t he y are 
res ol ve d or sta biliz e d, or u ntil all atte m pts t o deter mi ne res ol uti o n of t he e v e nt are e x ha uste d. 
T he i n vesti gat or s h o ul d use his/ her discreti o n i n or deri n g a d dit i o nal tests as necessar y t o m o nit or 
t he pr o gress of s u c h e ve nts. 
A d verse e ve nts re p orte d pri or t o d ose a d mi nistrati o n will be rec or de d as part of t he patie nt’s 
me dical hist or y.  
Pre vi o us cli nical trial e x perie nce has  s h o w n t hat s o m n ole nce, diarr hea, a n d transa mi nase 
ele vati o ns ma y be ass o ciate d wit h C B D treat me nt. T heref ore, I ns ys De vel o p me nt C o m pa n y has 
i de ntifie d t hese as A d v erse E ve nts  of S pecial I nt erest.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 3  
6. 2. 8. 2.  
Cl assific ati o n of A d verse E ve nts  
A d verse e ve nts are t o be rec or de d o n t he A E p a ge of t he patie n t’s case re p ort f or m ( C R F).  
Se verit y will be gra de d acc or di n g t o t he f oll o wi n g defi niti o ns:  
•  Mil d : T he patie nt  e x perie nces a ware n ess of s y m pt o ms b ut t hese are easil y t olerate d or 
ma na ge d wit h o ut s pecifi c treat me nt.  
•  M o derate : T he p atie nt e x perie nces disc o mf ort e n o u g h t o ca use i nterfere nce wit h 
us ual acti vit y, a n d/ or t he c o n diti o n re q uires s pecific treat me nt.  
•  Se vere : T he  p atie nt  is i nca pacitate d wit h i na bilit y t o w or k or d o us ual acti vit y, a n d/ or 
t he e ve nt re q uires si g nifica nt treat me nt meas ures. 
Acti o n ta ke n will  be cate g orize d as n o n e, st u d y dr u g disc o nti n ue d, d ose m o difie d, re q uire d 
c o nc o mita nt me dicati o n, re q uire d pr oce d ure, or ot her.  
E ve nt o utc o me at r es ol uti o n or ti me of last f oll o w -u p will rec or de d as e v e nt res ol ve d, res ol ve d 
wit h se q uelae, o n g oi n g, or deat h . 
6. 2. 8. 3.  
C a us alit y/ Dr u g Rel ati o ns hi p Assess me nt  
T he relati o ns hi p of t he e ve nt t o t he st u d y dr u g s h o ul d be deter mi ne d b y t h e i n vesti gat or 
acc or di n g t o t he f oll o wi n g criteria:   
•  Defi nitel y relate d : T h e e ve nt f oll o ws a reas o na ble te m p oral se q ue n ce fr o m t he ti me of 
dr u g a d mi nistrati o n t hat ca n n ot be e x plai ne d, f oll o ws a k n o w n or e x pecte d res p o nse 
patter n t o t he st u d y dr u g, t hat is c o nfir me d b y i m pr o ve me nt o n st o p pi n g a n d 
rea p peara nce of t he e v e nt o n re peate d e x p os ure a n d t hat c o ul d n ot be reas o na bl y 
e x plai ne d b y ot her fact ors s uc h as t he patie nt ’s cli nical c o n diti o n, i nterc urre nt ill ness, 
or c o nc o mita nt dr u gs.  
•  N ot relate d : T he e ve nt is m ost li kel y pr o d uce d b y ot her fact ors s uc h as t he patie n t’s 
cli nical c o n diti o n, i nterc urre nt ill ness, or c o nc o mita nt dr u gs, a n d d oes n ot  f oll o w a 
k n o w n res p o nse p atter n t o t he st u d y dr u g, or t he te m p oral rel ati o ns hi p of t he e ve nt t o 
st u d y dr u g a d mi nistrati o n ma kes a ca usal rel ati o ns hi p u nli kel y.  
•  P ossi bl y relate d : T he e ve nt f oll o ws a reas o n a ble te m p oral se q ue nce fr o m t h e ti me of 
dr u g a d mi ni strati o n, a n d/ or f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g, b ut 
c o ul d ha ve bee n pr o d uce d b y ot her fact ors s uc h as t he patie n t’s cli nical c o n diti o n, 
i nterc urre nt ill ness, or c o nc o mita nt dr u gs. 
•  U nli kel y relate d : T he e ve nt f oll o ws little or n o te m p oral se q ue n ce fr o m t he ti me of 
dr u g a d mi nistrati o n t hat ma kes a ca usal rel ati o ns hi p i m pr o ba ble a n d/ or ot h er fact ors 
s uc h as t he patie n t’s cli nical c o n diti o n, i nterc urre nt ill ness, or c o nc o mita nt dr u gs is a 
m ore li kel y alter nati ve.  
•  Pr o ba bl y relate d : T he e v e nt f oll o ws a reas o na ble t e m p oral se q ue n ce fr o m t he ti me of 
dr u g a d mi nistrati o n, a n d/ or f oll o ws a k n o w n res p o nse patter n t o t he st u d y dr u g, a n d 
ca n n ot be reas o na bl y e x plai ne d b y ot h er fact ors s u c h as t he patie n t’s cli nical 
c o n diti o n, i nterc urre nt ill ness, or c o nc o mita nt dr u gs.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 4  
6. 2. 8. 4.  
Defi niti o n of Seri o us A d verse E ve nts  
A seri o us A E ( S A E) is a n y A E t h at f ulfills a n y of t he f oll o wi n g criteria, as per 2 1 C F R 3 1 2. 3 2:  
•  Res ults i n deat h;  
•  Is life-t hreate ni n g; 
•  Re q uires i n -patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n;  
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y;  
•  Is a c o n ge nital a n o mal y or birt h defect; 
•  Is me di call y si g nifi ca nt or re q uires i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d 
a b o ve.  
Seri o us A Es will be ca pt ure d fr o m t he ti m e of c o nse nt t hr o u g h t he e n d of t he st u d y.  
6. 2. 8. 5.  
Seri o us A d verse E ve nts Acti o ns T a ke n  
Acti o ns ta ke n ma y c o nsist of:  
•  N o ne: N o acti o n ta k e n  
•  Treat me nt:  Sta n dar d of care meas ures i nstit ute d  
•  Dr u g wit h dra w n: St u d y me dicati o n was per ma ne ntl y disc o nti n ue d beca us e of t he  A E  
•  U n k n o w n: N ot k n o w n, n ot o bser ve d, n ot rec or de d, or ref use d  
6. 2. 8. 6.  
Seri o us A d verse E ve nts O utc o me at t he Ti me of L ast O bser v ati o n  
T he o utc o me at t he ti me of last o bser vati o n will be classifie d as:  
•  Rec o vere d/res ol ve d  
•  Rec o vere d/res ol ve d wit h se q uelae  
•  N ot rec o ver e d/ n ot res ol v e d  
•  Deat h  
•  U n k n o w n  
6. 2. 8. 7.  
A d verse E ve nt Rec or di n g a n d Re p orti n g  
A d verse e ve nts will be rec or de d t hr o u g h o ut t he st u d y i n t he s o urce d oc u m e nts a n d i n t he C R Fs. 
T he i n vesti gat or will rate A Es f or seri o us n ess, i nte nsit y, ca us alit y, acti o n ta ke n, a n d o utc o m e as 
descri be d i n t he pre vi o us secti o n.  
E x pe dite d re p orti n g is re q uire d f or seri o us u ne x pecte d a d verse dr u g reacti o ns. Fatal or 
life-t hreat e ni n g u n e x pecte d dr u g reacti o ns m ust be re p ort e d b y t he S p o ns or t o re g ulat or y 
a ge ncies n o m or e t ha n 7 da ys after t h e S p o ns or’s first k n o wle d ge of t he reacti o n; f oll o we d b y as 
c o m plete a re p ort as p ossi ble wit hi n 8 a d diti o nal da ys. U ne x pecte d dr u g reacti o ns m ust be 
re p orte d n o lat er t ha n 1 5 da ys after t h e S p o ns or’s first k n o wle d ge of t he reacti o n. I n or der t o 
c o m pl y wit h t hese re q uir e me nts, t he i n vesti gat or or dele gate m ust i nf or m t he S p o ns or 
i m me diatel y u p o n occ urre nce of a n y S A E. T he sit e will c o m plete t he S A E Re p ort F or m as 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 5  
t h or o u g hl y as p ossi ble a n d e-mail  it t o I ns ys wit hi n 2 4 h o urs of t he i n vesti gat ors first k n o wle d ge 
of t he e ve nt.  
S p o ns or c o ntact i nf or mati o n is liste d bel o w:  
Direct or of P h ar m ac o vi gil a nce  
I ns ys De vel o p me nt C o m p a n y, I nc.  
E m ail: cli nic al p v @i ns ysr x.c o m   
T hese S A E re p orts m ust c o ntai n t he f oll o wi n g i nf or mati o n:  
A.  St u d y na me/ n u m ber  
B.  
St u d y dr u g  
C.  
I n vesti gat or details ( na me, p h o ne, fa x, e-mail)  
D.  Patie nt n u m ber  
E.  
Patie nt i nitials 
F.  
Patie nt de m o gra p hics  
G.  Cli nical e ve nt  
1)  
Descri pti o n  
2)  
Date of o nset  
3)  
Treat me nt ( dr u g, d ose, d osa ge f or m)  
4)  
A d verse e ve nt relati o ns hi p t o st u d y dr u g  
5)  
Acti o n ta ke n re gar di n g st u d y dr u g i n direct relati o ns hi p t o t he A E  
H.  If t he A E was fatal or life-t hreate ni n g 
I. 
Ca use of deat h ( w het her or n ot t he deat h was relate d t o st u d y dr u g)  
J. 
A ut o ps y fi n di n gs (if a vaila ble)  
T he S p o ns or or its re prese ntati ve will be res p o nsi ble f or n otificati o n t o re g ulat or y  a ge nci es.  
6. 2. 8. 8.  
A d verse E ve nt F oll o w -U p  
All n o n -seri o us A Es t hat are n ot r elate d or u nli kel y t o be relate d t o st u d y tr eat me nt will be 
f oll o we d u ntil t he e n d of st u d y partici p ati o n. All S A Es or A Es t hat are c o nsi dere d as p ossi bl y, 
pr o ba bl y, or defi nitel y relate d  t o treat me nt will be f oll o we d u ntil res ol uti o n or sta bilizati o n. 
6. 2. 8. 9.  
S afet y  D at a Re vie w   
A vaila ble safet y data will be re vie we d o n a n o n g oi n g basis t o e ns ure d oses are ge n erall y well 
t olerate d. Det ails of t he s afet y data re vie w will be pr o vi de d i n t he Data M o nit ori n g  C harter.   
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 6  
6. 2. 8. 1 0.  S peci al C o nsi der ati o ns  
Ca n na bi di ol i n hi bits dr u g meta b olis m me diate d b y a s u bset of C Y P pr otei ns (see Secti o n 
Secti o n  1. 1. 2 ). T h us, t he in vesti gat or a n d st u d y ce nter staff s h o ul d m o nit or s u bjects w h o are 
ta ki n g c o n c o mita nt me dicati o ns t hat are m eta b olize d b y C Y P 2 C 1 9, C Y P 2 C 9, C Y P 2 D 6, 
C Y P 3 A 4, C Y P 1 A 2, or b y P -gl yc o pr ot ei n wit h s pecial care.  
6. 2. 9.  
P h ar m a c o ki netics Assess me nts  
T o assess P K para m eters, bl o o d dra ws will be o btai ne d at Visit 3, Visit 5 (fe d; Wee k 4, Da y 6) 
a n d Visit 6 (faste d; Wee k 4, Da y 7), or t he Earl y Wit h dra wal Visit . Bl o o d dra ws f or P K v al ues at 
Visits 5 a n d 6 will occ ur as f oll o ws:  
F asti n g/ Fe d  
P K S a m ple Visits  
Ti me p oi nts  
Fe d: Patie nts s h o ul d arri ve 
wit h o ut f o o d a n d t he m or ni n g 
d ose. S ite pr o vi des a hi g h 
fat/ hi g h cal orie f o o d t h e n d oses 
patie nt  
Visit 5 ( Wee k 4, Da y 6 ) 
Pre -d ose ( bef ore 
meal/ m or ni n g d ose) a n d 2, 
4, 6 h o urs after t h e m or ni n g 
d ose ( b ut bef ore ne xt d ose)  
Faste d ( 2 h o urs bef ore d ose  u ntil 
2 h o urs after d os e ): Patie nts 
s h o ul d arri ve wit h o ut f o o d a n d 
t he m or ni n g d ose. Site pr o vi des 
a sta n dar d meal 2 h o urs after 
d ose.  
Visit 6  ( Wee k 4, Da y 7 ) 
Pre -d ose a n d 2  ( bef ore 
meal) , 4, 6 h o urs after t h e 
m or ni n g d ose ( b ut bef ore 
ne xt d ose)  
W h ole bl o o d will be o btai ne d i n a Vac ut ai ner
®  t u be c o ntai ni n g K 2E D T A . S pecific sa m ple 
c ollecti o n i nstr ucti o ns will be pr o vi de d  i n a se parate p har mac o ki n etic ma n ual. 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 7  
7.  
S T U D Y P R O C E D U R E S  
T he assess me nts a n d pr oce d ures t h at will be c o n d ucte d d uri n g t his st u d y are s u m marize d i n 
T a ble 1 . 
7. 1.  
Scree ni n g   
P ote ntial st u d y s u bjects will be e x a mi ne d bef ore t he start of t he st u d y t o deter mi ne t heir 
eli gi bilit y f or partici pati o n. I nf or me d c o nse nt m ust be o btai ne d a n d si g ne d b ef ore i nitiati o n of 
scree ni n g acti vities. T he f oll o wi n g screeni n g pr oce d ures a n d assess me nts m ust be perf or me d 
wit hi n 2 8 ( +/ - 5) da ys  bef ore t he d a y of e nr oll me nt i n t he st u d y:  
•  O btai n writte n i nf or me d c o nse nt/asse nt (if a p pr o priate).  
•  Re vie w of i ncl usi o n a n d e x cl usi o n criteria. 
•  Re vie w of hist oric seiz ure c o u nts  base d  o n p atie nt a n d care gi ver re p orts . 
•  Dis pe nse seiz ure a n d me al diar y.  
•  Rec or d de m o gra p hics.  
•  Assess me nt of past/c urre nt A E Ds  a n d ot her c o nc o mita nt me dicati o ns . 
•  Rec or d me dical/s ur gi cal hist or y . 
•  Rec or d vital si g ns (s eate d bl o o d press ure, p ulse rate, te m perat ure,  a n d res pirati o n 
rate), i ncl u di n g hei g ht a n d wei g ht.  
•  C ollect bl o o d sa m ples (cli nical c he mistr y a n d he m at ol o g y ). 
•  Perf or m 1 2 -le a d E C G. 
•  C ollect uri ne sa m ple f or uri nal ysis .  
•  Uri ne di pstic k pre g na n c y test (all fe male s u bjects of c hil d beari n g p ote ntial).  
•  Perf or m a c o m plet e p h ysical e xa mi nati o n.  
•  Perf or m a c o m plet e ne ur ol o gical e x a mi nati o n.  
•  Meas ure a n d rec or d hei g ht a n d wei g ht.  
•  C o m plete C -S S R S.  
•  Re vie w A Es.  
7. 2.  
Titr ati o n Peri o d  
7. 2. 1.  
B aseli ne ( Visit 2, D a y 1) 
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d at t he Visit 2:  
•  Re vie w of i ncl usi o n a n d e x cl usi o n criteria.  
•  4 -h o ur vi de o -E E G.  
•  Re vie w a n d rec or d s eiz ure a n d meal diar y.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 8  
•  Dis pe nse meal diar y.  
•  Assess me nt of past/c urre nt A E Ds a n d c o nc o mita nt me dicati o ns . 
•  Rec or d vital si g ns (s eate d bl o o d press ure, p ulse rate, te m p erat ure, a n d res pirati o n 
rate).  
•  C o nc o mita nt A E D le vels.  
•  Perf or m a bri ef ne ur ol o gi cal e xa mi nati o n.  
•  If patie nt is i n C o h ort 2, dis pe nse st u d y dr u g f or t he Titrati o n Peri o d after eli gi bilit y is 
c o nfir me d, a n d tr ai n p ati e nt/care gi v er t o a d mi nister a n d rec or d treat me nts. 
•  Re vie w A Es . 
D uri n g t h e 5 -da y (f or C o h ort 2) Titrati o n Peri o d, t he seiz ure diar y s h o ul d b e c o m plete d dail y. 
T he meal diar y s h o ul d be c o m plete d f or 2 4 h o urs pri or t o Visit 3. T he i n vesti gat or or d esi g n ee 
will call or e -mail dail y a n d rec or d past/ c urre nt A E Ds, c o nc o mita nt me dicati o ns, a n d A Es.  
7. 3.  
Tre at me nt Peri o d  
7. 3. 1.  
Visit 3  ( D a y 1) 
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d  o n Da y 1 : 
•  R e vie w a n d rec or d s eiz ure diar y a n d meal diar y.  
•  Assess me nt of past/c urre nt A E Ds  a n d ot her c o nc o mita nt me d icati o ns. 
•  Rec or d vital si g ns (s eate d bl o o d press ure, p ulse rate, te m perat ure, a n d res pirati o n 
rate).  
•  C ollect bl o o d sa m ples (cli nical c he mistr y a n d he m at ol o g y , a n d P K s a m ple) 
•  Perf or m a bri ef ne ur ol o gi cal e xa mi nati o n.  
•  Rec or d hei g ht a n d wei g ht.  
•  C ollect, re vi e w, a n d dis p e nse Ca n na bi di ol Oral S ol uti o n. If patie nt is i n C o h ort 1 ( 2 0 
m g/ k g/ da y) or C o h ort 3 ( 1 0 m g/ k g/ da y) , tr ai n patie nt/care gi v er t o a d mi nister a n d 
rec or d tr eat me nts. 
•  Dis pe nse seiz ure diar y.  
•  I n v esti gat or c o m plete C GI-I. 
•  Re vie w A Es.  
7. 3. 2.  
Visit 4  ( Wee k 2) 
T he f oll o wi n g pr oce d ures a n d assess me nts will be perf or me d:  
•  R e vie w a n d rec or d s eiz ure diar y .  
•  Assess me nt of past/c urre nt A E Ds  a n d ot her c o nc o mita nt me dicati o ns . 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 5 9  
•  Rec or d vital si g ns (s eate d bl o o d press ure, p ulse rate, te m perat ure, a n d res pirati o n 
rate).  
•  C ol lect bl o o d sa m ples (cli nical c he mistr y a n d he m at ol o g y ). 
•  Perf or m a bri ef ne ur ol o gi cal e xa mi nati o n.  
•  Re vie w A Es.  
•  C ollect, re vie w, a n d dis p e nse Ca n na bi di ol Oral S ol uti o n.  
•  Dis pe nse meal a n d s eiz ure diar y.  
7. 3. 3.  
Visit 5  ( Wee k 4, D a y 6 ) 
T he patie nt s h o ul d c o m plete t hei r meal diar y f or 2 4 h o urs pri or t o Visit 5, bri n g t heir m or ni n g 
d ose of t he I P wit h t he m t o t he st u d y site a n d s h o ul d n ot eat brea kfast. T he f oll o wi n g pr oce d ures 
a n d assess me nts will be perf or me d:  
•  Re vie w a n d rec or d  s eiz ure a n d meal diar ies. 
•  4 -h o ur vi de o -E E G.  
•  Assess me nt of past/c urre nt A E Ds  a n d ot her c o nc o mita nt me dicati o ns . 
•  P K b l o o d dra ws will be ta ke n pre-d ose, 2, 4, a n d 6 h o urs after t h e m or ni n g d ose ( b ut 
bef ore t h e ne xt d ose). T he pre -d os e bl o o d sa m ple s h o ul d be c ollecte d B E F O R E 
d osi n g wit h “ hi g h -fat” brea kfast ( d os e will be a d mi nistere d wit hi n 3 0 mi n utes of start 
of brea kfast).  
•  D osi n g wit h Ca n na bi di ol Oral S ol uti o n.  
•  In v esti gat or c o m plete C GI -I. 
•  C o m plete C -S S R S  
•  Re vie w A Es.  
7. 3. 4.  
E n d of St u d y : Visit 6  ( Wee k 4, D a y 7 ) 
T he patie nt s h o ul d bri n g t heir m or ni n g d ose of me dicati o ns  wit h t he m t o t he st u d y site a n d 
s h o ul d n ot eat f or at least t w o h o urs pri or t o arri v al. T he f oll o wi n g pr oce d ures a n d ass ess me nts 
will be perf or me d:    
•  Rec or d vital si g ns (s eate d bl o o d press ure, p ulse rate, te m perat ure, a n d res pirati o n 
rate).  
•  Dra w bl o o d f or cli nical l a b orat or y tests ( cli nical c he mistr y a n d  h e mat ol o g y ) a n d 
c o nc o mita nt A E D le vel.  
•  P K b l o o d dra ws will be ta ke n pre-d ose, 2, 4, a n d 6 h o urs after t h e m or ni n g d ose ( b ut 
bef ore t h e ne xt d ose). P atie nt will be faste d f or 2 h o urs bef ore d ose. A sta n dar d 
brea kfast will be pr o vi de d 2 h o urs after t h e d ose, A F T E R t he 2 -h o ur bl o o d dra w.  
•  D osi n g wit h Ca n na bi di ol Oral S ol uti o n  ( patie nt s h o ul d n ot eat u ntil t w o h o urs after 
d ose  a n d t he 2-h o ur P K bl o o d is dra w n ). 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 0  
•  C ollect uri ne sa m ple f or uri nal ysis. 
•  Perf or m 1 2 -le a d E C G. 
•  Perf or m a bri ef ne ur ol o gi cal e xa mi nati o n.  
•  Rec or d hei g ht a n d wei g ht.  
•  Re vie w A Es.  
7. 4.  
E arl y Wit h dr a w al  Visit  
T he patie nt s h o ul d c o m plete t heir seiz ure diar y f or 7 da ys pri or t o t he visit, c o m plete t heir meal 
diar y f or 2 4 h o urs pri or t o t he visit, a n d bri n g t heir m or ni n g d os e of t he me dicati o ns wit h t he m t o 
t he st u d y. T he f oll o wi n g pr oce d ures a n d ass ess me nts will be perf or me d at Visit 7  or f oll o wi n g 
patie nt  wit h dra wal:  
•  4 -h o ur vi de o -E E G.  
•  Re vie w a n d c ollect seiz ure a n d meal diaries . 
•  Re vie w  a n d c ollect meal diar y.  
•  Assess me nt of past/c urre nt A E Ds  a n d ot her c o nc o mita nt me dicati o ns . 
•  C o nc o mita nt A E D le vels.  
•  Rec or d vital si g ns (s eate d bl o o d press ure, p ulse rate, te m perat ure, a n d res pirati o n 
rate).  
•  C ollect bl o o d sa m ples (cli nical c he mistr y a n d he m at ol o g y ). 
•  1 2 -lea d E C G. 
•  P K bl o o d sa m ple.  
•  C ollect uri ne sa m ple f or uri nal ysis. 
•  Perf or m a bri ef ne ur ol o gi cal e xa mi nati o n.  
•  Rec or d hei g ht  a n d w ei g ht.  
•  In v esti gat or c o m plete C GI -I. 
•  C o m plete C -S S R S.  
•  Re vie w/ C ollect  Ca n na bi di ol Oral S ol uti o n . 
•  Re vie w A Es.  
7. 5.  
Visit 7  (F oll o w -U p  Peri o d )  
F or patie nts w h o d o n ot c h o ose t o e nr oll i n t he l o n g -ter m safet y st u d y, the f oll o wi n g assess me nts 
will be perf or me d b y p h o ne call  at 1 4 da ys  after c o m pleti o n of Visit 6 ( E n d of St u d y) :  
•  Rec or d  past/c urre nt A E Ds  a n d ot her c o n c o mita nt me dicati o n s. 
•  Re vie w A Es.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 1  
8.  
S T A TI S TI C S  
8. 1.  
Effic ac y E n d p oi nts  
•  % c ha n ge i n a bse nce seiz ure c o u nts c o m pari n g treat me nt at Wee k 4 ( Visit 5 ) vi de o-
E E G t o B as eli ne ( Visit 2) vi de o -E E G a n d c o m pari n g d oses . 
•  % c ha n ge i n ti me t o a bs e nce seiz ure d uri n g h y per ve ntilati o n testi n g o n vi de o -E E G 
c o m pari n g treat me nt at Wee k 4 ( Visit 5 ) t o B aseli ne ( Visit 2) a n d c o m pari n g d oses . 
•  % patie nts seiz ure free at Wee k 4 ( Visit 5 ) base d o n seiz ure diar y, c o m pari n g d oses . 
•  In v esti gat or C GI -I at W ee k 4 ( Visit 5 ) c o m pari n g d oses. 
8. 2.  
S afet y E n d p oi nts  
C ha n ges  i n s afet y e n d p oi nts will be re p orte d as m ea n/ me dia n c h a n ge fr o m baseli ne at r ele va nt 
ti me p oi nts a n d as a listi n g of e ve nts t hat fall o utsi de n or mal li mits. 
•  I n ci de nce, t y p e, a n d s e verit y of A Es a n d seri o us a d verse e v e nts ( S A Es) occ urri n g 
d uri n g t he Treat m e nt Peri o d (i.e., treat me nt -e mer ge nt A E s [ T E A Es]). 
•  C ha n ges fr o m B aseli ne ( Visit 2) i n vital si g ns d uri n g t he Treat me nt  Peri o d . 
•  C ha n ges fr o m Scree ni n g  i n la b orat or y val ues ( he mat ol o g y, c h e mistr y, a n d uri nal ysis) 
d uri n g t he Treat me nt Peri o d . 
8. 3.  
P h ar m ac o ki netic E n d p oi nts  
•  C ma x  a n d d ose-n or malize d C ma x : fe d ( Visit 5  [Wee k 4 , D a y 6 ]) a n d faste d ( Visit 6  
[Wee k 4 , Da y 7 ]). 
•  Area u n d er t he plas ma c o nce ntrati o n c ur ve (A U C ( 0-t)) a n d d ose n or malize d area u n der 
t he c ur ve (A U C ( 0-t)/ Dose ): fe d ( Visit 5  [Wee k 4 , Da y 6 ]) a n d faste d (Visit 6  [Wee k  4 , 
Da y 7 ]). 
•  Tr o u g h  pl as ma c o nce ntrati o n ( Ctr o u g h) a n d d ose n or malize d tr o u g h plas ma 
c o nce ntr ati o n ( C tr o u g h/ D ose): fe d ( Visit 5 [Wee k 4 , Da y 6 ]) a n d faste d ( Visit 6 [Wee k 
4 , Da y 7 ], Visit  3 , or t he Earl y Wit h dra wal Visit. 
8. 4.  
S a m ple Size Det er mi n ati o n 
D ue t o t he e x pl orat or y nat ure of t he st u d y, t he sa m ple size is n ot base d o n f or mal statistical 
c o nsi derati o ns. T he sa m ple size is base d o n e x perie nce fr o m si milar st u dies t o o btai n a de q uate 
preli mi nar y efficac y, s afet y, a n d t olera bilit y d ata t o ac hie ve t he o bj ecti ves of t he st u d y.  
8. 5.  
A n al ysis P o p ul ati o ns  
Statistical a nal ysis will be c o n d ucte d o n all e nr oll e d s u bjects.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 2  
8. 6.  
St atistic al A n al yses  
T his secti o n prese nts a s u m mar y of t he pla n ne d statistical a nal ys es. A S tatistical A nal ysis P la n 
( S A P) t hat descri bes t he details of t he a nal yses t o be c o n d ucte d will be fi nalize d pri or t o data base 
l oc k. 
S u m mar y statistics will be pr o vi de d f or t he vari a bles descri be d as f oll o ws. F or c o nti n u o us 
varia bles, t hese st atistics will t y pi call y i ncl u de t he n u m ber of s u bjects, mea n, sta n dar d de viati o n, 
me dia n, mi ni m u m, a n d ma xi m u m. F or cate g orical varia bles, t hes e statistics will t y picall y i ncl u de 
t he n u m ber a n d perce nta ge of s u bjects i n eac h cate g or y. 
8. 6. 1.  
St u d y S u bjects  a n d De m o g r a p hics  
8. 6. 1. 1.  
Dis p ositi o n a n d Wit h dr a w als  
T he n u m bers of  s u bjects assi g ne d , c o m pleti n g, a n d wit h dra wi n g, al o n g wit h reas o ns f or 
wit h dra wal, will be ta b ul ate d o verall a n d b y treat me nt gr o u p. T h e n u m ber of s u bjects i n eac h 
a nal ysis p o p ulati o n will be re p ort e d.  
8. 6. 1. 2.  
Pr ot oc ol D e vi ati o ns  
Pr ot oc ol de viati o ns will be i de nt ifie d a n d cl assifie d as mi n or or maj or. 
8. 6. 1. 3.  
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics  
T hese a n al ys es will be c o n d ucte d f or t he s afet y p o p ulati o ns.  
De m o gra p hic a n d baseli n e c haracteristics (i ncl u di n g a ge, ge n d er, race, wei g ht, hei g ht, a n d B MI) 
will be s u m mariz e d b y tr eat me nt gr o u p a n d f or t h e o verall p o p ulati o n b y d escri pti ve statistics. 
N o f or mal statistical a nal ys es will be p erf or me d. Me dical hist or y, cli nical la b orat or y test res ults, 
a n d E C G assess me nts will be liste d  a n d s u m marize d b y d escri pti ve stati stics. 
Pri or a n d c o nc o mita nt m e dicati o ns will be s u m marize d b y treat me nt gr o u p a n d b y t h e n u m ber 
a n d perce nta ge of s u bjects ta ki n g eac h me dicati o n. T he y will als o be classifie d b y usi n g t he 
W orl d Healt h Or ga niz ati o n Dr u g Dicti o nar y A nat o mical T hera p e utic C he mical classes a n d 
preferre d t er ms.  
8. 6. 2.  
E x p os ure a n d C o m pli a nce  
T he e x p os ure t o st u d y m e dicati o n will be s u m marize d b y descri pti ve statistics. A n y c o m plia nce 
de viati o ns will be liste d.  
8. 6. 3.  
Effic ac y A n al yses  
T he res ults of t he vi de o -E E G (i ncl u di n g prese n ce or a bse nce of h y p er ve ntilati o n) , C GI -I, a n d 
seiz ure diar y assess me nts will be s u m marize d usi n g s u m mar y ta bl es, listi n gs, a n d fi g ures 
( T L Fs), as a p pr o priate. C o nti n u o us varia bles will be s u m marize d usi n g des cri pti ve statistics: 
sa m ple siz e ( n), mea n, st a n dar d de viati o n ( S D), or c oeffi cie nt of variati o n ( C V %) as 
a p pr o priate, m e dia n, i nter q uartile ra n ge, mi ni m u m a n d ma xi m u m. Cate g orical vari a bles will be 
s u m marize d b y pres e nti n g t he n u m ber (fre q ue n c y) a n d perce nta ge i n eac h cate g or y.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 3  
8. 6. 4.  
S afet y a n d T oler a bilit y A n al yses  
Safet y a nal yses will be c o n d ucte d usi n g d ata fr o m t he safet y p o p ulati o n. N o f or mal i nfere ntial 
a nal ys es will be c o n d u cte d f or safet y vari a bles. Data listi n gs will be pr o vi d e d f or pr ot oc ol -
s pecifie d safet y data.  
8. 6. 4. 1.  
A d verse E ve nts  
T he Me dical Di cti o nar y f or R e g ul at or y Acti vities ( Me d D R A, v ersi o n 2 0 .0 or hi g her) will be 
use d t o classif y all A Es. A d verse e ve nt s u m maries will i ncl u de o nl y T E A Es, w hic h will be 
s u m marize d f or eac h treat me nt gr o u p. 
T he n u m ber a n d p erce nta ge of s u bjects wit h A Es will be dis pla ye d f or  eac h treat me nt gr o u p b y 
s yste m or ga n class a n d preferre d t er m. S u m maries of A Es b y s e verit y a n d relati o ns hi p t o t he I P 
will als o be pr o vi de d. Seri o us A Es ( S A Es)  a n d A Es res ulti n g i n disc o nti n uati o n will be 
s u m marize d se paratel y i n a si milar ma n ner. Patie n t listi n gs of A Es a n d S A Es will be pr o d uce d. 
8. 6. 4. 2.  
Cli nic al L a b or at or y E v al u ati o ns  
F or t he c o nti n u o us he mat ol o g y a n d c he mistr y la b orat or y para meters, descri pti ve statistics will be 
prese nte d f or val ues c ollecte d at Scree ni n g ( Visit 1),  Treat me nt Peri o d  (Visit s 3 , 4, a n d 6  [ E n d of 
St u d y] ) or t h e Earl y Wit h dra wal  Visit , a n d f or a n y cli nicall y si g nifica nt c ha n ges fr o m Scree ni n g . 
F or uri nal ysis, d es cri pti ve statistics will be prese nte d f or val ues c ollecte d at Scree ni n g ( Visit 1), 
a n d at Visit 6 ( E n d of St u d y)  or t he Earl y Wit h dra wal  Visit,  a n d f or a n y cli nicall y si g nifica nt 
c ha n ges fr o m Scree ni n g  
8. 6. 4. 3.  
 Vit al Si g ns  
F or bl o o d press ure, p ulse rate, te m perat ure, a n d res pirati o n rate, des cri pti ve statistics will be 
prese nte d f or val ues c ollecte d at Scree ni n g ( Visit 1), Bas eli ne  ( Visit 2), Treat me nt Peri o d ( Visit s 
3, 4 , a n d 6  [ E n d of St u d y]) or t he Earl y Wit h dra wal Visit, a n d f or t he c h a n ges fr o m Baseli ne t o 
Visit 6 ( E n d of St u d y )/ E arl y Wit h dra wal. 
8. 6. 4. 4.  
Electr oc a r di o gr a ms  
F or t he c o nti n u o us E C G para meters, descri pti ve statistics will  be prese nte d f or val ues c ollecte d 
at Scree ni n g ( Visit 1) , Visit 6 ( E n d of St u d y) or t h e Earl y Wit h dra wal Visit,  a n d f or t he c ha n ges 
fr o m Scree ni n g ( Visit 1) t o Visit 6 ( E n d of St u d y )/ Earl y Wit h dra wal. 
A d diti o nall y, t he n u m ber a n d perce nta ge of s u bjects wi ll be prese nte d as s hift ta bles f or t he 
o verall i nter pretati o n fr o m S cree ni n g ( n or mal or a b n or mal, n ot cli nicall y si g nifica nt [ N C S]) t o 
E n d of S t u d y/E arl y W it h dra wal ( n or mal; a b n or mal, N C S; or a b n or mal, cli nicall y si g nifica nt 
[ C S]). 
8. 6. 4. 5.  
P h ysic al E x a mi n ati o n Fi n di n gs  
P h ysical e x a mi nati o n b o d y s yste ms will be pres e nte d as t he n u m ber a n d p erce nt a ge of s u bjects 
t hat ha ve n or mal or a b n or mal res ults at Scree ni n g ( Visit 1) . T he e x a mi nati o n will i ncl u de 
e val uati o n of ge n eral a p p eara n ce, s ki n, e yes, ears, n ose, t hr oat, nec k, l y m p h n o des, c hest, he art, 
a b d o me n, a n d e xtre mities.   
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 4  
8. 6. 4. 6.  
C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)  
C -S S R S cate g orizati o n base d o n C ol u m bia Classificati o n Al g orit h m of S uici de Assess me nt 
( C-C A S A ) cate g ories 1, 2, 3, 4, a n d 7 will be s u m marize d as d ic h ot o m o us e n d p oi nts at 
Scree ni n g ( Visit 1), Treat me nt Peri o d  ( Visit 5 ) or t he Earl y Wit h dra wal Visit . 
8. 6. 5.  
I nteri m A n al ysis 
N o i nteri m a nal yses are pla n ne d.   
8. 6. 6.  
P h ar m a c o ki netic A n al ys es 
Descri pti ve statistics of tr o u g h plas m a c o nce ntrati o n a n d P K para m eters data  f or C B D a n d 7-O H 
C B D b y Visit, D ose, a n d Res p o nse will be pr o vi de d. T he f oll o wi n g n o nc o m part me ntal P K 
para meters will be esti mate d fr o m t he plas ma c o n ce ntrati o n -ti me data: area u n der t he c ur ve fr o m 
ti me 0 t o t he last meas ure d c o nce ntrati o n ( A U C0 -t) b y ma xi m u m plas ma c o nce ntrati o n ( Cma x ), 
a n d ti me t o reac h m a xi m u m plas ma c o nce ntr ati o n ( T ma x ) usi n g P h oe ni x Wi n n o nli n ( Versi o n 6. 3 
or hi g her; P harsi g ht C or p orati o n, Car y, N C 2 7 5 1 8, U S A).  A d diti o nal P K para meters ma y b e 
esti mate d, as a p pr o priate. E x pl orat or y a nal ysis of d ose (e x p os ure) -res p o nse relati o ns hi p will be 
perf or me d. F urt h er p o p ul ati o n P K a p pr oac h ma y b e use d f or P K para met er esti mati o n, as 
a p pr o priate.  
8. 6. 7.  
Missi n g D at a  
T here will be n o i m p utati o n of t he missi n g val ues f or t he efficac y, safet y, or P K p o p ulat i o n. All 
assess me nts will be c o n d ucte d base d o n all t he o bser ve d dat a.   
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 5  
9.  
S T U D Y C O N D U C T  
Ste ps t o e ns ure t he acc urac y a n d relia bilit y of data i ncl u de t he selecti o n of q ualifie d i n vesti gat ors 
a n d a p pr o pri ate st u d y sit es, re vie w of pr ot oc ol pr oce d ures wit h t h e i n vesti gat or a n d ass o ciate d 
pers o n nel pri or t o t he st u d y, peri o dic m o nit ori n g visits, a n d metic ul o us data ma na ge me nt.  
9. 1.  
S p o ns or a n d I n vesti g at or Res p o nsi bilities  
9. 1. 1.  
S p o ns or Res p o nsi bilities  
T he s p o ns or, a n d/ or s p o ns or’s re prese ntati ve is o bli gate d t o c o n d u ct t he st u d y i n acc or da nce wit h 
strict et hical pri nci ples. T he s p o ns or res er ves t he ri g ht t o wit h dra w a patie nt  fr o m t he st u d y, t o 
ter mi nate partici pati o n of a st u d y site at a n y ti me, a n d/ or t o disc o nti n ue t he st u d y. 
T he s p o ns or, or s p o ns or’s re pres e ntati ve, a grees t o pr o vi de t he i n vesti gat or wit h s ufficie nt 
material a n d s u p p ort t o p er mit t he i n vesti gat or t o c o n d uct t he st u d y acc or di n g t o t he st u d y 
pr ot oc ol.  
9. 1. 2.  
I n vesti g at or Res p o nsi bilities 
B y si g ni n g t he I n vesti gat or’s A gree me nt, t he i n vesti gat or i n dicat es t hat s he/ he has caref ull y rea d 
t he pr ot oc ol, f ull y u n d ersta n ds t he re q uire m e nts, a n d a grees t o c o n d uct t he st u d y i n acc or da n ce 
wit h t he pr oce d ures a n d re q uire me nts descri be d i n t his pr ot oc ol.  
T he i n vesti gat or als o a grees t o c o n d uct t his st u d y i n acc or da nce wit h  all la ws, re g ulati o ns, a n d 
g ui deli nes of t h e perti ne nt re g ul at or y a ut h orities, i ncl u di n g a n d i n acc or da n ce wit h t he A pril 
1 9 9 6 I nter nati o nal C o nfere nce o n Har m o nisati o n (I C H) G ui da nce f or I n d ustr y E 6 G o o d Cli nical 
Practice ( G C P) a n d i n a gree me nt wit h t he 1 9 9 6 Versi o n of t he Declarati o n of Helsi n ki. W hile 
dele gati o n of certai n as p ects of t he st u d y t o s u b -i n vesti gat ors a n d st u d y c o or di nat ors is 
a p pr o priate, t h e i n vesti gat or will re mai n pers o nall y acc o u nta bl e f or cl osel y o verseei n g t he st u d y 
a n d f or e ns uri n g c o m plia nce wit h t he pr ot oc ol a n d all a p plica ble re g ulati o ns a n d g ui d eli nes. T he 
i n vesti gat or is r es p o nsi ble f or mai ntai ni n g a list of all pers o ns t hat ha ve b ee n dele gate d st u d y-
relate d res p o nsi bilities (e.g ., s u b-i n vesti gat ors a n d st u d y c o or di n at ors) a n d their s pecific st u d y -
relate d d uties. 
I n v esti gat ors s h o ul d e ns ure t hat all pers o ns w h o h a ve bee n dele gate d st u d y-relate d 
res p o nsi bilities are a de q u atel y q u alifie d a n d i nf or me d a b o ut t he pr ot oc ol, I Ps, a n d t heir s pecific 
d uties wit hi n t he c o nte xt of t he st u d y . I n vesti gat ors are res p o nsi ble f or pr o vi di n g C R O  wit h 
d oc u me ntati o n of t he q ualificati o ns, G C P trai ni n g, a n d researc h e x perie nce f or t he msel ves a n d 
t heir staff as re q uire d b y t he s p o ns or a n d t he rele va nt g o v er ni n g a ut h orities. 
T o e ns ure c o m plia n ce wit h t h e g ui deli nes, t he st u d y will be a u dite d b y a n i n de pe n de nt pers o n. 
T he i n vesti gat or a grees, b y writte n c o nse nt t o t his pr ot oc ol, t o c o o perate f ull y wit h c o m plia nce 
c hec ks b y all o wi n g access t o all st u d y d o c u me ntati o n b y a ut h orize d i n di vi d uals.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 6  
9. 2.  
Site I niti ati o n  
St u d y p ers o n nel ma y n ot scree n or e nr oll s u bjects i nt o t he st u d y u ntil after recei vi n g n otificati o n 
fr o m t he s p o ns or or s p o ns or’s re prese ntati ve t hat t he st u d y ca n be i nitiate d at t he st u d y site. T he 
st u d y site will n ot be a ut h orize d f or st u d y i nitiati on u ntil:  
•  T he st u d y site has recei v e d t he a p pr o priate i nstit uti o nal re vie w b oar d (I R B) a p pr o val 
f or t he pr ot oc ol a n d t h e a p pr o priate i nf or m e d c o ns e nt f or m (I C F). 
•   All re g ul at or y d oc u me nts ha ve bee n s u b mitte d t o a n d a p pr o ve d b y t he s p o ns or or 
s p o ns or’s re prese ntati ve. 
•  T he st u d y site has a cli ni cal trial a gree me nt i n place.  
•  St u d y site p ers o n nel, i ncl u di n g t he i n vesti gat or, h a ve partici pate d i n a st u d y i nitiati o n 
meeti n g.  
9. 3.  
Scree n F ail ures  
S u bjects  w h o scree n fail ma y b e re-scree ne d f or t h e st u d y if d ee me d a p pr o priate b y t he 
i n vesti gat or a n d a p pr o ve d b y t he s p o ns or. 
9. 4.  
St u d y D oc u me nts  
All d oc u me ntati o n a n d material pr o vi de d b y t h e s p o ns or, or s p o ns or’s re prese ntati ve f or t his 
st u d y are t o be retai ne d i n a sec ure l ocati o n a n d tr eate d as c o nfi de ntial mat erial.  
9. 4. 1.  
I n vesti gat or’s Re g ul at o r y D oc u me nts  
T he re g ulat or y d o c u me nts m ust be recei ve d fr o m t he i n vesti gat or a n d re vie we d a n d a p pr o ve d b y 
t he s p o ns or or s p o ns or’s re pres e ntati ve bef ore t he st u d y site ca n i nitiate t he st u d y a n d b ef ore t he 
s p o ns or, or s p o ns or’s r e prese ntati ve, will a ut h orize s hi p me nt of i n vesti gati o nal pr o d uct (I P) t o 
t he st u d y site. C o pies of t he i n vesti gat or’s re g ul at or y d o c u me nts m ust be ret ai ne d at t he st u d y 
site i n a sec ure l o cati o n. A d diti o nal d oc u me nts, i ncl u di n g a c o p y of t he pr ot oc ol a n d a p plica ble 
ame n d me nt(s), t he I B, C R F/electr o nic case re p ort f or m (e C R F) c o m pleti o n g ui deli nes, c o pi es of 
re g ulat or y refere nces, c o pies of I R B c orres p o n de nce, a n d I P acc o u nta bilit y rec or ds s h o ul d als o 
be retai ne d as part of t he i n vesti gat or’s re g ulat or y d oc u me nts. It i s t he i n vesti gat or’s 
res p o nsi bilit y t o e ns ure t hat c o pies of all re q uire d re g ulat or y d oc u m e nts are or ga nize d, c urre nt, 
a n d a vaila ble f or i ns pecti o n.  
9. 4. 2.  
C ase Re p ort F or ms  
B y si g ni n g t he I n vesti gat or’s A gree me nt , t he i n vesti gat or a grees t o mai ntai n acc urate 
C R F s/e C R Fs a n d s o urce d oc u me ntati o n as part of t he case hist ories f or all s u bjects w h o si g n a n 
I C F. 
Case re p ort f or ms are c o nsi dere d c o nfi d e ntial d oc u me nts a n d s h o ul d be ha n dle d a n d st ore d 
acc or di n gl y. T h e s p o ns or, or s p o ns or’s re prese nt ati ve, will pr o vi de t h e necessar y trai ni n g o n t he 
use of t he s pecific C R Fs/e C R F s yste m us e d d uri n g t he st u d y t o e ns ure t hat t he st u d y i nf or mati o n 
is ca pt ure d acc uratel y a n d a p pr o priatel y. 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 7  
T o e ns ure dat a acc urac y, C R F/e C R F data f or i n di vi d ual patie nt  visits s h o ul d be c o m plete d a s 
s o o n as p ossi ble after t he visit. All re q ueste d i nf or mati o n m ust be e ntere d i n t he C R F/electr o nic 
data ca pt ur e ( E D C) s yste m acc or di n g t o t he c o m pl eti o n g ui deli nes pr o vi d e d b y t he s p o ns or, or 
s p o ns or’s re prese ntati ve. 
9. 4. 3.  
S o urce D oc u me nts  
All i nf or mati o n rec o r de d i n t he C R F/ E D C s yste m m ust be s u p p orte d b y c orres p o n di n g s o urce 
d oc u me ntati o n. E x a m ples of acce pta ble s o urce d o c u me ntati o n i ncl u de, b ut are n ot li mite d t o, 
h os pital rec or ds, cli nic a n d office c harts, la b orat or y n otes, a n d rec or de d data fr o m a ut o mate d 
i nstr u me nts, me m ora n da, a n d p har mac y dis pe nsi n g rec or ds. 
D uri n g t h e st u d y, s elect C R F/e C R F data ma y be use d as ori gi nal data c ollecti o n t o ols as l o n g as 
a descri pti o n of t his d oc u me ntati o n pr ocess is mai ntai ne d i n t he i n vesti gat or’s st u d y files.  
Cli nical l a b orat or y data re q uire d b y t he pr ot o c ol will be electr o nicall y tr a nsferre d fr o m t he 
ce ntral la b orat or y t o t he s p o ns or or t he s p o ns or’s re prese nt ati ve. A pa p er c o p y of t he l a b orat or y 
res ults will be pr o vi de d t o t he st u d y site a n d s h o ul d be retai ne d wit h each s u bject’s s o urce data. 
T he i n vesti gat or will pr o vi de direct a ccess t o s o urce data a n d d oc u me nts f or trial -rel ate d 
m o nit ori n g, a u dits, I E C/I R B re vie w, a n d re g ulat or y re q uire me nts.  
9. 5.  
St u d y Ter mi n ati o n  
T he st u d y ma y b e ter mi n ate d at t he s p o ns or’s discreti o n a t a n y ti me a n d f or a n y reas o n. St u d y 
sites ma y be as ke d t o ha v e all s u bjects c urre ntl y partici pati n g i n t he st u d y c o m plete all of t he 
assess me nts f or t he tele p h o ne f oll o w -u p call.  
I n t he e ve nt of st u d y disc o nti n uati o n, st u d y sites ma y b e as ke d t o ha ve all s u bjects c urre ntl y 
partici pati n g i n t he st u d y c o m plete all of t he ass ess me nts f or t he Earl y Wit h dra wal  Visit.  
9. 6.  
St u d y Site Cl os ure  
At t he e n d of t he st u d y, all st u d y sites will be cl os e d. T he s p o ns or or s p o ns or’s re prese ntati ve 
ma y ter mi nate partici p ati o n of  a st u d y site at a n y ti me. E x a m ples of c o n diti o ns t hat ma y re q uire 
pre mat ure t er mi nati o n of a st u d y site i ncl u de, b ut are n ot li mite d t o, t he f oll o wi n g:  
•  N o nc o m plia nce wit h t he pr ot oc ol a n d/ or a p plica ble re g ulati o ns a n d g ui deli nes  
•  I n a de q uat e patie nt  e nr oll m e nt 
9. 6. 1.  
Rec or d R ete nti o n  
T he i n vesti gat or s hall ret ai n a n d pres er ve o n e  c o p y of all data ge n erate d d uri n g  t he c o urse of t he 
st u d y, s pecificall y i ncl u di n g, b ut n ot li mite d t o, t h ose defi ne d b y G C P as esse ntial u ntil t he 
f oll o wi n g occ ur: 
•  At least 2 years after t h e last mar keti n g a ut h orizati o n f or t he I n v esti gati o nal P r o d uct 
has bee n a p pr o ve d or t he s p o ns or has disc o nti n ue d its researc h wit h t he 
In v esti gati o nal P r o d uct, or 
•  At least 2 years h a ve el a pse d si nce t he f or mal disc o nti n uati o n of cli nical d e vel o p me nt 
of t h e I n vesti gati o nal Pr o d uct 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 8  
T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uire d b y t he a p plica ble 
re g ulat or y re q uire me nt(s) or if nee d e d b y t he s p o ns or. 
9. 6. 2.  
P h ar m a c o ki netic/ L a b or at or y S a m ple Rete nti o n  
La b orat or y s a m ples ma y be use d f or p ur p oses relate d t o t his researc h. T he s a m ples will be st ore d 
u ntil t he s p o ns or has deter mi ne d t hat s peci me ns are n o l o n ger nee de d a n d t he decisi o n has bee n 
ma de t hat n o ne of t he s a m ples nee ds t o be rea nal yz e d. I n a d diti o n, i de ntifi a ble sa m ples ca n be 
destr o ye d at a n y ti me at t he re q uest of t h e s u bject. 
 
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 6 9  
1 0.  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
T he s p o ns or or its desi g n ee will i m ple me nt a n d mai ntai n q ualit y c o ntr ol a n d q ualit y ass ur a nce 
pr oce d ures wit h writte n sta n dar d o perati n g pr oce d ures t o e ns ure t h e st u d y  is c o n d ucte d a n d d ata 
are ge n erate d, d oc u me nt e d, a n d re p orte d i n c o m plia nce wit h t he pr ot oc ol, G C P, a n d a p plica ble 
re g ulat or y re q uire me nts. T his trial will be c o n d ucte d i n acc or da nce wit h t he pr o visi o ns of t he 
Declarati o n of Helsi n ki ( Oct o ber 1 9 9 6) a n d al l re visi o ns t here of, a n d i n acc or da nce wit h t he 
F D A C F R 3 1 2. 5 0 a n d 3 1 2. 5 6, a n d wit h t he I C H g ui deli nes o n G C P ( C P M P/I C H/ 1 3 5/ 9 5).  
1 0. 1.  
C h a n ges T o T he Pr ot oc ol  
O nl y I ns ys ma y m o dif y t he pr ot oc ol. A me n d me nts t o t he pr ot oc ol will be ma de o nl y after 
c o ns ultati o n a n d  a gree me nt bet wee n t he s p o ns or a n d t he i n vesti gat or. T he o nl y e x ce pti o n is 
w he n t he i n vesti gat or ass esses a s u bject’s safet y will be c o m pr o mise d wit h o ut i m me diate acti o n. 
I n t hes e cir c u msta nces, i m me diate a p pr o val of t he c hair ma n of t he I E C/I R B m ust be s o ug ht, a n d 
t he i n vesti gat or s h o ul d i nf or m t he s p o ns or a n d t he f ull I E C/I R B wit hi n 5 w or ki n g da ys after t he 
e mer ge n c y occ urre d. All a me n d me nts t hat ha ve a n i m pact o n patie nt  ris k or t he st u d y o bjecti ves, 
or re q uire re visi o n of t he i nf or me d c o nse nt f or m, m ust recei ve a p pr o val fr o m t he I E C/I R B pri or 
t o t heir i m ple me ntati o n. 
1 0. 2.  
M o nit ori n g  
T he s p o ns or or s p o ns or’s re pres e ntati ve will c o n d uct site visits t o m o nit or t he st u d y a n d e ns ure 
c o m plia nce wit h t he pr ot oc ol, G C P, a n d a p plica bl e re g ulati o ns a n d g ui deli nes. T he a ssi g ne d 
cli nical researc h ass ociat e(s) ( C R A[s]) will visit t he i n vesti gat or a n d st u d y site at peri o dic 
i nter vals a n d mai ntai n peri o dic c o m m u nicati o n. T he i n vesti gat or a grees t o all o w t he C R A(s) a n d 
ot her a ut h orize d s p o ns or/c o ntract r esearc h or ga nizati o n ( C R O) pers o n nel access. T he C R A(s) 
will mai ntai n c urre nt pers o nal k n o wle d ge of t he st u d y t hr o u g h o bser vati o n, re vie w of st u d y 
rec or ds a n d s o urce d oc u me ntati o n, a n d disc ussi o n of t he c o n d uct of t h e st u d y wit h t he 
i n vesti gat or a n d staff. 
1 0. 3.  
D at a Re vie w Meeti n g  
T h e s p o ns or will re vie w all data re p orte d i n C R Fs of all s u bjects bef ore dat a base l oc k. T h e data 
re vie w me eti n g d eter mi n es w het her all e nr olle d s u bjects ca n be i n cl u de d i n t he a nal ysis 
p o p ulati o n acc or di n g t o t he s pecifie d d efi niti o n of a nal ysis p o p ulati o ns a n d e val uates w h et her or 
n ot me dical decisi o ns of t he in vesti gat or were a p pr o priate f or i m p orta nt dat a affecti n g t he safet y 
a n d effi cac y e n d p oi nt.  
1 0. 4.  
Pr ot oc ol Vi ol ati o ns  
T he in vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol a p pr o ve d b y t he I R B. 
M o dificati o ns t o t he pr ot oc ol s h o ul d n ot be perf or me d wit h o ut a gree me nt of b ot h t he 
in vesti gat or a n d t he s p o ns or. C ha n ges t o t he pr ot o c ol will re q uire writte n I R B a p pr o val pri or t o 
i m ple me ntati o n, e x ce pt w he n t he m o dificati o n is nee de d t o eli mi nate a n i m me diate hazar d(s) t o 
s u bjects. 
T he in vesti gat or or s u b -i n vesti gat or s h o ul d d oc u me nt a n y d e viati o n fr o m t he pr ot oc ol a n d t he 
reas o n. If t he in vesti gat or perf or ms a d e viati o n fr o m t he pr ot oc ol or a c h a n ge of t he pr ot oc ol t o 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 0  
eli mi nate a n i m me diate h azar d(s ) t o s u bjects, t he rec or d s h o ul d be i m me diatel y s u b mitte d t o t he 
s p o ns or, t he C R O , a n d t he I R B b y t he in vesti gat or a n d t he I R B will pr o vi de e x pe dite d re vie w 
a n d a p pr o val. After t he in vesti gat or h as o btai ne d a p pr o val of t he I R B, t he in vesti gat or s h o ul d 
o bta i n writte n per missi o n of t he C R O  a n d writte n a gree m e nt of t he s p o ns or.  
W he n de viati o n fr o m t he pr ot oc ol is re q uire d t o eli mi nate i m me diate hazar d(s) t o s u bjects, t he 
in vesti gat or will c o ntact t he s p o ns or, if cir c u msta nces per mit, t o disc uss t he pla n ne d c o u rse of 
acti o n. A n y de viati o ns fr o m t he pr ot oc ol m ust be f ull y d oc u me nt e d i n t he C R F a n d s o urce 
d oc u me ntati o n.  
1 0. 5.  
Q u alit y Ass ur a nce  A u dit  
T his st u d y will be s u bject t o a u dit b y t he s p o ns or, C R O, or desi g nee. 
T he s p o ns or or s p o ns or’s re pres e ntati ve ma y c o n d uct a u dits o n a selecti o n of st u d y sites, 
re q uiri n g access t o patie nt  n otes, st u d y d oc u me ntati o n, a n d facilities or la b orat ories use d f or t he 
st u d y. 
T he st u d y site, facilities, all data (i ncl u di n g s o urce data), a n d d o c u me ntati o n will be ma de 
a vaila ble f or a u di t b y q ualit y ass ura n ce a u dit ors a n d f or I R B or re g ul at or y a ut h orities acc or di n g 
t o G C P g ui deli nes. T he i n vesti gat or a grees t o c o o perate wit h t he a u dit or d uri n g t he visit a n d will 
be a vaila ble t o s u p pl y t he a u dit or wit h C R Fs or ot her files necessar y t o c o n d uct t hat a u dit. A n y 
fi n di n gs will be strictl y c o nfi de ntial. 
If a re g ulat or y a ut h orit y i nf or ms t he i n vesti gat or t hat it i nte n ds t o c o n d uct a n i ns pecti o n, t he 
i n vesti gat or s hall n otif y s p o ns or or s p o ns or’s re prese ntati ve i m me diatel y. 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 1  
1 1.  
R E G U L A T O R Y A N D E T HI C A L C O N SI D E R A TI O N S  
1 1. 1.  
Re g ul at or y A ut h orit y A p pr o v al  
T he i n vesti gat or will e ns ure t hat t he pr ot oc ol a n d c o nse nt f or m are re vie we d a n d a p pr o ve d b y t he 
a p pr o priate I n de pe n d e nt Et hics C o m mittee/I nstit uti o nal Re vie w B oar d (I E C/I R B) pri or t o t he 
start of a n y st u d y pr oced ures. T he I E C/I R B will be a p pr o pri atel y c o nstit ute d a n d will perf or m its 
f u ncti o ns i n acc or da nce wit h F o o d a n d Dr u g A d mi nistrati o n ( F D A) re g ulati o ns, 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) g ui deli nes, a n d l ocal 
re q uire me nts as a p plica bl e.  
I n a d diti o n, t he I R B will a p pr o ve all pr ot o c ol a me n d me nts (e x ce pt f or l o gistical or a d mi nistrati ve 
c ha n ges), writte n i nf or m e d c o nse nt d oc u me nts a n d d oc u me nt u p dates, pati e nt recr uit me nt 
pr oce d ures, writte n i nf or mati o n t o be pr o vi de d t o t he s u bjects, a vaila ble s afet y i nf or mati o n, 
i nf or mati o n a b o ut pa y me nt a n d c o m pe nsati o n a vaila ble t o s u bjects, t he i n vesti gat or’s c urric ul u m 
vitae a n d/ or ot her e vi de n ce of q ualifi cati o ns, a n d a n y ot h er d oc u me nts re q ueste d b y t h e I R B/I E C 
a n d re g ulat or y a ut h orit y, as a p plica ble.  
1 1. 2.  
Et hic al C o n d uct of t he St u d y  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he Decl arati o n of Helsi n ki a n d G C P acc or di n g 
t o I C H g ui deli nes. S pecificall y, t he st u d y will be c o n d ucte d u n der a pr ot oc ol re vie we d b y a n I R B 
or I E C; t he st u d y will be c o n d ucte d b y scie ntifi call y a n d me di call y q ualifie d pers o ns; t he 
be nefits of t he st u d y are i n pr o p orti o n t o t he ris ks; t he ri g hts a n d welfare of t he s u bjects will be 
res pect e d; t he p h ysi cia ns c o n d ucti n g t h e st u d y d o n ot fi n d t he hazar ds t o o ut wei g h t he p ot e ntial 
be nefits; a n d eac h patie nt will gi ve his or her writte n, i nf or me d c o ns e nt bef ore a n y pr ot o c ol -
dri ve n tests or e val u ati o ns are perf or me d.  
1 1. 3.  
St ate me nt of I n vesti g at or/ Dele g ati o n of A ut h orit y  
As a c o n diti o n f or c o n d u cti n g t he cli nical i n vesti gati o n, t he Pri nci pal I n vesti gat or will si g n t h e 
F D A F or m 1 5 7 2, State m e nt of I n vesti gat or ( 2 1 C o de of Fe deral Re g ulati o ns [ C F R] Part  3 1 2).  
T he Pri nci pal I n vesti gat or will e ns ure t hat all pers o ns assisti n g wit h t he trial are a d e q uatel y 
q ualifie d, i nf or me d a b o ut t he pr ot oc ol, a n y a me n d me nts t o t he pr ot oc ol, t he st u d y treat me nts, 
a n d t heir trial -relate d d uties a n d f u ncti o ns. T he q u alifie d i n vesti gat or will mai ntai n a list of 
s u b-i n vesti gat or a n d ot her a p pr o priat el y q u alifie d pers o ns t o w h o m t o dele gat e si g nifica nt 
trial-relate d d uties. S h o ul d t he q ualifie d i n vesti gat or dele gate t h e s u per visi o n of t he 
i n vesti gati o nal pr o d u ct a d mi nistrati o n t o a desi g n ate d pers o n, t his i n di vi d ual m ust ha ve t he 
a p pr o priate m e dical q ualificati o ns t o effecti vel y c o n d uct or s u per vise  a n y p ote ntial res uscitati o n 
pr oce d ures.  
1 1. 4.  
P atie nt I nf or me d C o nse nt 
T he i n vesti gat or or his/ her desi g nee will i nf or m t he patie nt of all as p ects p ertai ni n g t o t heir 
partici pati o n i n t he st u d y. T he pr ocess f or o btai ni n g patie nt i nf or me d c o nse nt will be i n 
acc or da nce wit h all a p plica ble re g ulat or y re q uire me nts (e. g., C F R Part 5 0 a n d I C H E 6 Secti o n 
4. 8). T he i n vesti gat or or his/ her desi g n ee a n d t h e patie nt m ust b ot h si g n a n d date t he i nf or me d 
c o nse nt d oc u me nt (I C D) bef ore t h e y  ca n p artici pat e i n t he st u d y. T h e pa tie nt will recei ve a c o p y 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 2  
of t he si g n e d a n d dat e d f or m, a n d t he ori gi nal will be retai ne d i n t he site’s st u d y rec or ds. T h e 
decisi o n t o partici pate i n t he st u d y t hat is ma de b y t he patie nt is e ntirel y v ol u ntar y. T he 
i n vesti gat or or his/ her desi g nee m ust e m ph asiz e t o t he patie nt t hat c o nse nt f or st u d y p artici pati o n 
ma y b e wit h dra w n at a n y ti me wit h o ut pe nalt y or l oss of be nefits t o w hic h t he patie nt is 
ot her wise e ntitle d. If t h e I C D is a m e n de d d uri n g t he st u d y t he i n vesti gat or m ust f oll o w all 
a p plica ble re g ul at or y re q uire me nts pertai ni n g t o a p pr o val of t he a m e n de d I C D b y t he I R B, a n d 
use of t he a me n d e d f or m, i ncl u di n g t he necessit y of re -c o nse nti n g o n g oi n g s u bjects. 
1 1. 5.  
I n vesti g at or Re p orti n g Re q uire me nts 
I n acc or da n ce wit h a p pli ca ble l ocal re g ulat or y re q uire me nts, t he i n vesti gat or ma y b e o bli gate d t o 
pr o vi de peri o dic safet y u p dates o n t he c o n d uct of t he st u d y at his/ her site a n d n otificati o n of 
st u d y cl os ur e t o t he I R B. S uc h peri o dic safet y u p d ates a n d n otificati o ns are t he res p o nsi bilit y of 
t he i n vesti gat or a n d not of I ns ys or its dele gate.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 3  
1 2.  
D A T A H A N D LI N G A N D R E C O R D K E E PI N G  
T he C R O  will be res p o nsi ble f or data ma n a ge me nt a n d a nal ysis. T he pr oce d ures will be 
s pecifie d i n t he D ata Ma na ge me nt Pla n. 
1 2. 1.  
D at a M a n a ge me nt  
T he C R O  will be res p o nsi ble f or acti vities ass ociat e d wit h t he data ma n a ge me nt of t his st u d y. 
T he sta n dar d pr oce d ures f or ha n dli n g a n d pr o cessi n g rec or ds will be f oll o we d per G C P a n d t he 
C R O’s S O Ps. A c o m pre he nsi ve Data M a na ge m e nt Pla n will be de vel o pe d i ncl u di n g a d ata 
ma na ge me nt o ver vie w, d ata base c o nte nts,  a n n otat e d C R F a n d c o nsiste nc y c hec ks.  St u d y site 
pers o n nel will be res p o nsi ble f or pr o vi di n g res ol uti o ns t o all data q ueries. T he i n vesti gat or will 
be re q uir e d t o d oc u me nt electr o nic d ata re vi e w t o e ns ure t he acc urac y of t h e c orrecte d a n d/ or 
clarifie d d at a. 
1 2. 2.  
C ase Re p ort F or ms a n d S o urce D oc u me nts  
T he C R Fs will be s u p plie d b y t he C R O data m a na ge m e nt ser vices. T he c o m plete C R Fs will be 
re vie we d, si g n e d, a n d dat e d b y t h e q ualifie d i n vesti gat or a n d a c o p y ret ur n e d t o t he S p o ns or wit h 
t he fi nal re p ort. 
S o urce d o c u me nts are defi ne d as ori gi nal d oc u me nts, data, a n d rec or ds. T his ma y i ncl u de 
h os pital rec or ds, cli nic al a n d office c harts, la b orat or y d ata/i nf or mati o n, s u bjects’ diaries or 
e val uati o n c hec klists, p har mac y dis pe nsi n g a n d ot her rec or ds, rec or de d dat a fr o m a ut o mate d 
i nstr u me nts, micr ofic hes, p h ot o gra p hic ne gati ves, micr ofil m or ma g n etic m e dia a n d/ or x ra ys. 
1 2. 3.  
D oc u me nt ati o n a n d Rete nti o n of Esse nti al D oc u me nts  
All d oc u me nts pertai ni n g t o t he st u d y, i ncl u di n g a c o p y of t he a p pr o ve d pr ot oc ol, c o p y of t he 
I C D, c o mplete d C R Fs, s o urce d oc u m e nts, dr u g acc o u nta bilit y a n d rete nti o n rec or ds, a n d ot her 
st u d y rel ate d d oc u me nts will be retai ne d i n t he per ma ne nt arc hi ves of t he st u d y site. T hese will 
be a vaila ble f or i ns pecti o n at a n y ti me b y t h e S p o ns or or t he F D A. Per 2 1 C F R 3 1 2, rec or d 
rete nti o n f or t his st u d y is re q uire d f or a p eri o d of t w o years f oll o wi n g t he date o n w hic h t his 
st u d y a ge nt is a p pr o ve d b y t he F D A f or t he mar keti n g p ur p oses t h at were t he s u bject of t his 
i n vesti gati o n; or, if n o a p plicati o n is t o be file d or if t he a p plicati o n is n ot a p pr o ve d f or s u c h 
i n dicati o n, u ntil t w o years f oll o wi n g t he dat e o n w hic h t he e ntire st u d y is c o m plete d, ter mi nate d, 
or disc o nti n ue d, a n d t he F D A is n otifie d.  
T he i n vesti gat or will pr o vi de direct a ccess t o s o urce data a n d d oc u me nts f or trial relate d 
m o nit ori n g, a u dits, I E C/I R B re vie w, a n d re g ulat or y re q uire me nts.  
1 2. 4.  
Fi n a nci al Discl os ure  
T hese iss ues will be a d dresse d i n a se p arate a gree me nt bet wee n t he s p o ns or a n d t he in vesti gat or.  
T he U S F D A Fi na n cial Discl os ure b y Cli nical I n vesti gat ors ( 2 1 C o de of Fe deral Re g ul ati o ns 
[ C F R] 5 4) re g ulati o ns re q uire s p o ns ors t o o btai n certai n fi n a ncial i nf or mati o n fr o m i n vesti gat ors 
partici pati n g i n c o vere d cli nical st u dies; eac h i n vesti gat or a n d s u b -i n vesti gat or is re q uire d t o 
pr o vi de t he re q uir e d f i na ncial i nf or mati o n a n d t o pr o m ptl y u p date I ns ys De vel o p me nt C o m pa n y, 
I n c., wit h a n y rele va nt c h a n ges t o t heir fi na ncial i nf or mati o n t hr o u g h o ut t he c o urse of t he cli nical 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 4  
st u d y a n d f or u p t o o ne year after its c o m pleti o n. T his r ule a p plies t o all i n vesti gat ors a n d s u b -
i n vesti gat ors partici pati n g i n c o v ere d cli nical st u dies t o be s u b mitte d t o t he F D A i n s u p p ort of a n 
a p plicati o n f or mar ket a p pr o val.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 5  
1 3.  
F A CI LI TI E S  
Selecti o n of s pecific st u d y ve n d ors is pe n di n g.  
Cli nical La b orat or y : Me d pace  
5 3 7 5 Me d pace Wa y  
Ci nc i n nati, O H 4 5 2 2 7 
Bi oa nal ytical La b orat or y : W orl d wi de Cli nical T rials Earl y P h ase 
Ser vice/ Bi o a nal ytical Sci e nces, I n c.  
8 6 0 9 Cr oss Par k Dri ve  
A usti n, Te x as 7 8 7 5 4  
P har mac o ki netic A nal yses : W orl d wi de Cli nical T rials Earl y P h ase 
Ser vice/ Bi o a nal ytical Sci e nces , I n c. 
8 6 0 9 Cr oss Par k Dri ve  
A usti n, Te x as 7 8 7 5 4  
Data Ma na ge me nt : P R A Healt h Scie nces  
4 1 3 0 Par k  La ke A ve n ue , S uite 4 0 0  
Ralei g h, N C 2 7 6 1 2  
Statistical Ser vices : P R A Healt h Scie nces  
4 1 3 0 Par k  La ke A ve n ue , S uite 4 0 0  
Ralei g h, N C 2 7 6 1 2  
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 6  
1 4.  
U S E O F I N F O R M A TI O N A N D  P U B LI C A TI O N P O LI C Y  
1 4. 1.  
Use o f I nf or m ati o n 
All i nf or mati o n c o ncer ni n g Ca n na bi di ol Oral S ol uti o n a n d I ns ys D e vel o p me nt C o m pa n y’s 
o perati o ns, s uc h as I ns ys’ pate nt a p plicati o ns, f or m ulas, ma n ufact uri n g pr ocesses, basic s cie ntific 
data, or f or m ulati o n i nf or mati o n , s u p plie d b y I ns ys De vel o p me nt C o m pa n y a n d n ot pre vi o usl y 
p u blis he d, is c o nsi dere d c o nfi de ntial i nf or mati o n.  
T his c o nfi de ntial i nf or mati o n s hall re mai n t he s ole pr o pert y of I ns ys D e vel o p me nt C o m pa n y, 
s hall n ot be discl ose d t o ot hers wit h o ut t he writte n c onse nt of I ns ys D e vel o p me nt C o m pa n y, a n d 
s hall n ot be use d e x ce pt i n t he perf or m a nce of t his st u d y. 
T he i n vesti gat or will mai ntai n a c o nfi de ntial patie nt i de ntificati o n c o de list of all s u bjects 
e nr olle d i n t he st u d y ( b y na me a n d patie nt n u m ber). T his list will be mai ntai ne d at t he site, a n d 
will n ot be retrie ve d b y I ns ys.  
1 4. 2.  
P u blic ati o n P olic y  
I ns ys D e vel o p me nt C o m pa n y, I nc. will ret ai n o w ners hi p of all data. All pr o p ose d p u blicati o ns 
base d o n t his st u d y will b e s u bject t o t he s p o ns or’s a p pr o val r e q uire me nts. 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 7  
1 5.  
R E F E R E N C E S  ( A V AI L A B L E U P O N R E QU E S T)  
1.  I n v esti gat or’s Br oc h ure  f or Ca n na bi di ol Oral S ol uti o n, E diti o n 6. 0 , 3 0  Se pte m ber  2 0 1 6.  
2.  C u n ha J M, Carli ni E A, Pereir a A E, Ra m os O L, Pi me ntel C, Ga gliar di R, et al. C hr o nic 
a d mi nistrati o n of ca n na bi di ol t o healt h y v ol u ntee rs a n d e pile ptic patie n ts. P h ar m ac ol . 
1 9 8 0; 2 1: 1 7 5 -1 8 5.  
3.  Carli ni E A, C u n ha J M. H y p n otic a n d a ntie pile ptic effects of ca n na bi di ol. J Cli n 
P h ar m ac ol . 1 9 8 1; 2 1: 4 1 7 S-4 2 7 S.  
4.  P orter B E, J ac o bs o n C. Re p ort of a p are nt s ur v e y of ca n na bi di ol -e nric he d ca n na bis use i n 
pe diatric treat me nt -resist a nt e pile ps y. E pile psy Be h av . 2 0 1 3; 2 9: 5 7 4-5 7 7.  
5.  Ge d de M M, Ma a E. W h ole ca n na bis e xtract of hi g h c o nce ntr ati o n ca n na bi di ol ma y cal m 
seiz ures i n hi g hl y refract or y p e diatric e pile psies. A meric a E pile psy S o ciety  Meeti n g 2 0 1 3; 
a bstract: 3. 3 0 0.  
6.  S p o ns or’s i nter nal d oc u me ntati o n of a nal ysis.  
7.  Z uar di A W, S hira ka wa I, Fi n kelfar b E, Kar ni ol I G. Acti o n of ca n n a bi di ol o n t he a n xiet y 
a n d ot her effects pr o d uce d b y delta 9 -T H C i n n or mal s u bjects. Psyc h o p h ar m ac ol o gy  
1 9 8 2; 7 6: 2 4 5 -2 5 0.  
8.  Bis o g n o T, Ha n us L, D e Petr ocellis L, et al. M ole c ular tar gets f or ca n na bi di ol a n d its 
s y nt hetic a n al o g ues: effect o n va nill oi d V R 1 rece pt ors a n d o n t he cell ular u pta ke a n d 
e nz y matic h y dr ol ysis of a na n da mi de . Br J P h ar m ac ol. 2 0 0 1; 1 3 4: 8 4 5 -8 5 2.  
9.  Kat h ma n n M, Fla u K, Re d mer A, Tra n kle C, Sc hlic ker E. Ca n n a bi di ol is a n all osteric 
m o d ulat or at m u - a n d delta-o pi oi d rece pt ors. N a u ny n Sc h mie d e ber gs Arc h P h ar m ac ol.  
2 0 0 6; 3 7 2: 3 5 4 -3 6 1.  
1 0.  B or n hei m L M, Grill o M P. C haracterizati o n of c yt oc hr o me P 4 5 0 3 A i nacti vati o n b y 
ca n na bi di ol: p ossi ble i n v ol ve me nt of ca n n a bi di ol -h y dr o x y q ui n o n e as a P 4 5 0 i nacti vat or. 
C he m Res T oxic ol . 1 9 9 8; 1 1: 1 2 0 9 1 2 1 6. 
1 1.  R ya n D, Dr ys dale AJ, Laf o urca d e C, Pert wee R G, Platt B. Ca n na bi di ol tar gets 
mit oc h o n dria t o re g ulate i ntracell ular Ca 2 + le vels. J Ne ur osci.  2 0 0 9 ; 2 9: 2 0 5 3-2 0 6 3.  
1 2.  R uss o E B, B ur nett A, Hall B, Par ker K K. A g o nistic pr o perties of ca n n a bi di ol at 5 -H T 1 A 
rece pt ors. Ne ur oc he m Res.  2 0 0 5; 3 0: 1 0 3 7 -1 0 4 3.  
1 3.  Carrier EJ, A uc ha m pa c h J A, Hillar d CJ. I n hi biti o n of a n e q uili brati ve n u cle osi de 
tra ns p orter b y ca n na bi di ol: a mec ha nis m of ca n na bi n oi d i m m u n os u p pressi o n. Pr oc N atl 
Ac a d Sci U S.  2 0 0 6; 1 0 3: 7 8 9 5 -7 9 0 0.  
1 4.  J o nes N A, Gl y n S E, A ki ya m a S, et al. Ca n na bi di ol e xerts a nti -c o n v ulsa nt effects i n 
a ni mal m o dels of te m p oral l o be a n d partial s eiz ures. Seiz ure.  2 0 1 2; 2 1: 3 4 4 -3 5 2 . 
1 5.  Har ve y DJ, Sa mara E, Mec h o ula m R. C o m parati v e meta b olis m of ca n n a bi di ol i n d o g, rat 
a n d ma n. P h ar m ac ol Bi o c he m Be h a v.  1 9 9 1; 4 0: 5 2 3 -5 3 2.  
1 6.  St o ut S M, Ci mi n o N M. E x o ge n o us ca n n a bi n oi ds as s u bstrates, i n hi bit ors, a n d i n d ucers of 
h u ma n dr u g meta b olizi n g e nz y me s: a s yste matic re vie w. Dr u g Met a b Rev.  2 0 1 4 Fe b; 4 6: 
8 6 -9 5.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 8  
1 7.  Ber ga masc hi M M, Q u eir oz R H, Z uar di A W, Cri p pa J A. Safet y a n d si d e -effects of 
ca n na bi di ol, a ca n na bis s ati va c o nstit ue nt. C urr Dr u g S af.  2 0 1 1 b; 6: 2 3 7 -2 4 9.  
1 8.  Ya ma ori S, E bisa wa J, O k us hi ma Y, Ya ma m o t o I, Wata na be K. P ote nt i n hi biti o n of 
h u ma n c yt o c hr o me P 4 5 0 3 A is of or ms b y ca n na bi di ol: r ole of p he n olic h y dr o x yl gr o u ps 
i n t he res orci n ol m oiet y. Life Sci.  2 0 1 1; 8 8: 7 3 0 -7 3 6.  
1 9.  Ya ma ori S, K us hi hara M, Ya ma m ot o I, Wata na be K. C haract erizati o n of maj or 
p h yt o ca n na bi n oi ds, ca n n a bi di ol a n d ca n na bi n ol, as is of or m -selecti ve a n d p ote nt 
i n hi bit ors of h u ma n C Y P 1 e nz y mes. Bi oc h e m P h ar m ac ol.  2 0 1 0; 7 9: 1 6 9 1 -1 6 9 8.  
2 0.  J o ha n nesse n SI, La n d m ar k CJ. A ntie pile ptic dr u g i nteracti o ns –  pri nci ples a n d cli nical 
i m plicati o ns. C urr Ne ur o p h ar m ac ol.  2 0 1 0; 8: 2 5 4 -2 6 7.   
2 1.  Ya ma ori S, K oe d a K, K us hi hara M, Ha d a Y, Ya ma m ot o I, Wata na be K. C o m paris o n i n 
t he i n vitr o i n hi bit or y effects of maj or p h yt oca n na bi n oi ds a n d p ol yc yclic ar o matic 
h y dr ocar b o ns c o ntai ne d i n marij ua na s m o ke o n c yt oc hr o me P 4 5 0  2 C 9 acti vit y. Dr u g 
Met a b P h ar m ac o ki net.  2 0 1 2; 2 7: 2 9 4 -3 0 0.  
2 2.  Z h u HJ, Wa n g J S, Mar k o witz J S, et al. C haracterizati o n of P -gl yc o pr otei n i n hi biti o n b y 
maj or ca n na bi n oi ds fr o m marij ua na. J P h ar m ac ol Ex p T her.  2 0 0 6; 3 1 7: 8 5 0 -8 5 7.  
2 3.  H olla n d M L, Pa n etta J A, H os ki ns J M, Be ba w y M, R o uf o galis B D, Alle n J D, et al. T he 
effects of ca n na bi n oi ds o n P -gl yc o pr ot ei n tra ns p ort a n d e x pressi o n i n m ulti dr u g resista nt 
cells. Bi oc he m P h ar m a c ol.  2 0 0 6; 7 1: 1 1 4 6 -1 1 5 4.  
2 4.  Carli ni E A, C u n ha J M. H y p n otic a n d a nti -e pile ptic effects of ca n na bi d i ol. J Cli n 
P h ar m ac ol . 1 9 8 1; 2 1: 4 1 7 S-4 2 7 S.  
2 5.  Mec h o ula m R, Ha n us L. Ca n na bi di ol: a n o ver vie w of s o me p har m ac ol o gical a s pects. J 
Cli n P h ar m ac ol . 2 0 0 2; 4 2: 1 1 S -1 9 S . 
2 6.  Massi P, Vacca ni A, Cer uti S, C ol o m b o A, A b bracc hi o M P, Par olar o D. A ntit u m or 
effects of ca n na b i di ol, a n o n ps yc h o acti ve ca n na bi n oi d, o n h u ma n gli o ma cell li nes. 
J P h ar m ac ol Ex p T her . 2 0 0 4; 3 0 8: 8 3 8-8 4 5.  
2 7.  C o nsr oe P, W ol ki n A. Ca n na bi di ol - a ntie pile ptic dr u g c o m paris o ns a n d i nt eracti o ns i n 
e x peri me ntall y i n d uce d s eiz ures i n rats. J P h ar m ac ol Ex p T her . 1 9 7 7; 2 0 1: 2 6 -3 2.  
2 8.  Z uar di A W, M orais S L, G ui marães F S, Mec h o ula m R. A nti ps yc h otic effect of 
ca n na bi di ol. J Cli n Psyc hi atry  1 9 9 5; 5 6: 4 8 5 -4 8 6.  
2 9.  Gl oss D, Vic kre y B. Ca n na bi n oi ds f or e pile ps y. C oc hr a ne D at a b ase Syst R ev.  2 0 1 4; 5; 3: 
C D 0 0 9 2 7 0.  
3 0.  C o nsr oe P, La g u n a J, Alle n der J, et al. C o ntr olle d cli nical trial of ca n n a bi di ol i n 
H u nti n gt o n's disease. P h ar m ac ol Bi oc he m Be h av . 1 9 9 1; 4 0: 7 0 1-7 0 8.  
3 1.  Z uar di A W, C os me R A, Graeff F G, G ui marães F S. Effects of i psa pir o n e a n d ca n na bi di ol 
o n h u ma n e x peri me ntal a n xiet y. J Ps yc h o p h ar m a c ol.  1 9 9 3a; 7: 8 2 -8 8.  
3 2.  B or g w ar dt SJ, Alle n P, B hattac har y ya S, et al. Ne ural basis of delta -9 -
tetra h y dr oca n na bi n ol a n d ca n na bi di ol: effects d uri n g res p o nse i n hi biti o n. Bi ol Psyc hi atry.  
2 0 0 8; 6 4: 9 6 6 -9 7 3.  
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 7 9  
3 3.  Z uar di A W. Ca n na bi di ol: fr o m a n i nacti ve ca n na bi n oi d t o a dr u g wit h wi de s pectr u m of 
acti o n. Rev Br as Psi q ui atr . 2 0 0 8; 3 0: 2 7 1-2 8 0.  
3 4.  G o n g H Jr, Tas h ki n D P, Si m m o ns M S, Cal varese B, S ha pir o BJ. Ac ute a n d s u bac ute 
br o nc hial effects of oral ca n na bi n oi ds. Cli n P h ar m ac ol a n d T her.  1 9 8 4; 3 5: 2 6 -3 2.  
3 5.  Z uar di A W, Halla k J E, D urs u n S M, et al. Ca n na bi di ol m o n ot hera p y f or treat me nt -
resista nt sc hiz o p hre nia. J Psyc h o p h ar m ac ol.  2 0 0 6; 2 0: 6 8 3 -6 8 6.  
3 6.  Z uar di A, Cri p pa J, D urs u n S, M orais S, Vilela J, Sa nc hes R, et al. Ca n na bi di ol was 
i neffecti ve f or ma nic e pis o de of bi p olar affecti ve dis or der. J Ps yc h o p h ar m ac ol. 2 0 1 0; 2 4: 
1 3 5 -1 3 7.  
3 7.  Gla user T A, C naa n A, S hi n nar S, et al. Et h os u xi mi de, val pr oic aci d, a n d la m otri gi ne i n 
c hil d h o o d a bse nce e pile ps y. N E n gl J. Me d . 2 0 1 0; 3 6 2: 7 9 0-7 9 9.  
3 8.  De vi ns k y O, Mars h E, Frie d ma n D, et al. Ca n na bi di ol i n s u bjects wit h treat me nt -resista nt 
e pile ps y: a n o p e n -la b el i nter ve nti o nal trial. L a ncet Ne ur ol . 2 0 1 6; 1 5: 2 7 0-8.  
3 9.  Bra ut -B o u c her F, Brae mer R, B olli ne A, Kre mers P. C o m parati ve t o xic ol o gical 
i n vesti gati o n of ca n na bi di ol usi n g t w o differe nt cell c ult ure s yste ms. E ur J Cell Bi ol . 
1 9 8 6; 4 2: C T 1 7 (a bstract).  
4 0.  De vi ns k y O, Cili o M R, Cr oss H, Fer na n dez -R uiz J, Fre nc h J, Hill C et al. Ca n na bi di ol: 
p har mac ol o g y a n d p ot e ntial t hera pe utic r ol e i n e pile ps y a n d ot her ne ur o ps yc hiatric 
dis or ders. E pile psi a  2 0 1 4; 5 5: 7 9 1 – 8 0 2.  
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD

I ns ys D e vel o p me nt C o m pa n y , I nc. 
 
Pr ot oc ol N u m ber I NS 0 1 1 -1 7 -1 0 3  
 
 
 
0 6 Ma y 2 0 1 9  
C O N FI D E N TI A L  
 8 0  
1 6.  
I N V E S TI G A T O R SI G N A T U R E P A G E  
 
TI T L E:  
A P hase 2, O pe n -l a bel, D ose-fi n di n g St u d y t o Ass ess t he 
Efficac y, Safet y, T olera bilit y, a n d P har mac o ki n etics of 
P har mace utical Gra d e S y nt hetic  Ca n na bi di ol Oral S ol uti o n i n 
Pe diatric S u bjects  wit h Treat me nt -Resist a nt C hil d h o o d A bse nce 
Seiz ures  
P R O T O C O L N U M B E R:  
I N S 0 1 1-1 7 -1 0 3  
P H A S E O F S T U D Y:  
P hase 2  
P R O T O C O L D A T E:  
0 6  Ma y  2 0 1 9   
S T U D Y S P O N S O R:  
I ns ys D e vel o p me nt C o m pa n y , I nc. 
1 3 3 3 S o ut h S pectr u m Bl v d, S uite 1 0 0  
C ha n dler, A Z 8 5 2 8 6  
 
 
 
 
P RI N CI P A L I N V E S TI G A T O R C O M MI T M E N T : 
 
I, t he u n d ersi g ne d Pri nci pal I n v esti gat or, s u b mit t his state me nt of c o m mit me nt as e vi de nce t hat I 
u n dersta n d m y res p o nsi bilities p urs ua nt t o t he C o de of Fe deral Re g ulati o ns ( 2 1 C F R § 3 1 2. 6 0 
t hr o u g h § 3 1 2. 7 0, 2 1 C F R § 1 1, 5 0, 5 4, 5 6) a n d I C H E 6 G o o d Cl i nical Practice g ui deli nes, as 
well as wit h a n y a n d all a p plica ble fe d eral, state a n d/ or l ocal la ws a n d re g ul ati o ns, a n d a gree t o 
c o n d uct t he st u d y i n acc or da nce wit h t he pr ot oc ol refere nce d herei n.  
 
 
 
 
 
 
 
Pri nci p al I n vesti g at or Pri nte d N a me  
 
 
 
 
 
Pri nc i p al I n vesti g at or Si g n at ure 
 
D ate  
 
 
 
I N S 0 1 1- 1 7- 1 0 3 FI N A L pr ot o 0 6 Ma y 2 0 1 9 | V V- T M F- 1 1 9 8 1 1 | 1. 0
A p pr o ve d
D o w nl oa de d b y 
o n 1 0/ 1 2/ 2 0 2 2
PPD