Conditions: Childhood Absence Epilepsy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 20
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to assess the efficacy of Cannabidiol Oral Solution in the treatment of pediatric participants with treatment-resistant childhood absence seizures. This study will also assess safety, tolerability and pharmacokinetics of Cannabidiol Oral Solution, and any improvement in qualitative assessments of participant status over the duration of the study in pediatric participants with treatment-resistant childhood absence seizures. The study will include a 4-week Screening Period, a 5 or 10 day Titration Period (depending study Cohort), a 4-week Treatment Period followed by 5-day Tapering for doses \>20 mg/kg/day and a 4-week Follow-up Period.

Detailed description:

Arms:
arm 1: Treatment Period: Cannabidiol Oral Solution 20 milligrams per kilogram per day (mg/kg/day) divided twice daily (BID) for 4 weeks. arm 2: Titration Period: Cannabidiol Oral Solution 20 mg/kg/day divided BID for 5 days.

Treatment Period: Cannabidiol Oral Solution 30 mg/kg/day divided BID for 4 weeks. arm 3: Treatment Period: Cannabidiol Oral Solution 10 mg/kg/day divided BID for 4 weeks.

Interventions: intervention 1: Cannabidiol Oral Solution
Intervention descriptions: intervention 1: An oral solution containing pharmaceutical grade cannabidiol (nonplant-based).

Protocol document:
Prot_000.pdf: 
 
 
 
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
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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
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PPD
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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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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
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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
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o n 1 0/ 1 2/ 2 0 2 2
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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
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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 
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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  
 
 
 
 
 
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D ate  
 
 
 
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SAP_001.pdf: 
 
 
 
Statistical Analysis Plan 
 
 
 
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 
 
 
Protocol Number: INS011-17-103 
Final Protocol Date: 27 Sep 2017 
Version: 2.0 
Investigational Product: Cannabidiol Oral Solution 
IND Number: IND 123,120 
 
ClinicalTrials.gov ID: NCT03336242 


INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 1 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Statistical Analysis Plan 
Sponsor: 
Insys Development Company, Inc. 
Protocol No: 
INS011-17-103 
PRA Project Id: 
INY17103-17103X 
Version Date: 
27-Sep-2017 
Version No.: 
2.0 
Title: 
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 
CRF Version 
No./Date: 
0.1/27-Nov-2017
SAP No. 
1.0 
Approvals 
Sponsor 
Sponsor Name: 
Insys Development Company, Inc. 
Representative/ Title: 
 Director of Biostatistics 
Signature /Date: 
 
Representative/ Title: 
 Senior Director, Clinical Trials 
Signature /Date: 
 
Representative/ Title: 
 
 Regulatory Affairs 
Signature /Date: 
 
PRA 
Project Manager/Title: 
 Project Manager 
Signature /Date: 
 
Biostatistician / Title 
(Owner): 
 Principal Biostatistician 
Signature /Date: 
 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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d
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Pediatric Patients w
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Pediatric Patients
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A
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 2 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Table of Contents 
Approvals ................................................................................................................................... 1 
Table of Contents ....................................................................................................................... 2 
 Introduction .......................................................................................................................... 4 
 Study Objectives .................................................................................................................. 4 
Primary Objective ................................................................................................................... 4 
Secondary Objectives ............................................................................................................. 4 
 Study Design ........................................................................................................................ 4 
3.1 Sample Size Considerations ............................................................................................. 6 
3.2 Randomization.................................................................................................................. 6 
 Study Variables and Covariates ........................................................................................... 6 
4.1 Primary Efficacy Variable .................................................................................................. 6 
4.2 Secondary Variables ........................................................................................................ 6 
4.3 Safety ............................................................................................................................... 6 
4.4 Predetermined Covariates and Prognostic Factors ........................................................... 7 
 Definitions ............................................................................................................................ 7 
5.1 Baseline ........................................................................................................................... 7 
5.2 Change from Baseline ...................................................................................................... 7 
5.3 Missing values .................................................................................................................. 8 
5.4 Completers ....................................................................................................................... 8 
5.5 Primary variable calculation .............................................................................................. 8 
5.6 Secondary Variable calculation ......................................................................................... 8 
5.7 Treatment Emergent Adverse Events ............................................................................... 9 
5.8 Dates ................................................................................................................................ 9 
5.9 Age Groups ...................................................................................................................... 9 
5.10 Study Drug Consumed ..................................................................................................10 
5.11 Body Mass Index ...........................................................................................................10 
 Analysis Populations ...........................................................................................................10 
6.1 Intent-to-Treat ..................................................................................................................10 
6.2 Per Protocol .....................................................................................................................10 
6.3 Safety ..............................................................................................................................11 
6.4 PK ...................................................................................................................................11 
 Data Monitoring Committee .................................................................................................11 
 Statistical Methods ..............................................................................................................12 
General considerations ..........................................................................................................12 
8.1 Subject Disposition ..........................................................................................................12 
8.2 Important Protocol Deviations ..........................................................................................13 
8.3 Study Drug Exposure and Compliance ............................................................................14 
8.3.1 Dose Changes ..........................................................................................................14 
8.3.2 Compliance ...............................................................................................................14 
8.4 Prior and Concomitant Medications .................................................................................14 
8.5 Demographic and Baseline Characteristics .....................................................................15 
8.6 Efficacy Analyses ............................................................................................................15 
8.6.1 Primary Efficacy Analysis ..........................................................................................15 
8.6.2 Secondary Efficacy Analysis .....................................................................................16 
8.6.3 Exploratory Efficacy Analysis ....................................................................................18 
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 3 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
8.6.4 Methods for Handling Dropouts and Missing Data .....................................................18 
8.6.5 Multiplicity .................................................................................................................18 
8.6.6 Pooling of Sites .........................................................................................................18 
8.7 Safety Analyses ...............................................................................................................19 
8.7.1 Adverse Events .........................................................................................................19 
8.7.2 Deaths and Serious Adverse Events .........................................................................19 
8.7.3 Laboratory Data ........................................................................................................19 
8.7.4 Vital Signs .................................................................................................................20 
8.7.5 Physical Examinations, ECGs, and Other Observations Related to Safety ...............20 
8.7.6 C-SSRS ....................................................................................................................20 
8.8 Pharmacokinetic Analysis ................................................................................................21 
 Validation ............................................................................................................................21 
 References ........................................................................................................................22 
Appendix 1 Glossary of Abbreviations .......................................................................................23 
Appendix 2 Tables Figures, and Listings ...................................................................................25 
Appendix 3 Schedule of Events ................................................................................................29 
 
 
 
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 4 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 Introduction 
This Phase 2 study is designed to determine the effect CBD has on Childhood Absence Seizures, to 
inform future studies. 
The statistical analysis plan (SAP) is based on:  
• 
Protocol No. INS011-17-103, dated 27-Sep-2017 
• 
CRF dated 27-Nov-2017 
• 
ICH guidelines E4 (Dose-Response Information to Support Drug Registration) and E9 
(Statistical Principles for Clinical Trials)1,2 
• 
Discussions with the FDA  
The purpose of this document is to provide details on study populations and on how the variables will be 
derived, how missing data will be handled as well as details on statistical methods to be used to analyze 
the safety and efficacy data for Study Protocol No. INS011-17-103.  
The SAP is to be developed in two stages. The purpose is to “finalize” the SAP so that we can start 
programming earlier in the process. Versions of the SAP up to initial sponsor approval will be known as the 
SAP. Changes following approval of the SAP will be tracked in the SAP Change Log and a final version of 
the SAP, known as the Amended SAP, will be issued for sponsor approval prior to database lock. 
 Study Objectives 
Primary Objective 
• 
To assess the efficacy of Cannabidiol Oral Solution in the treatment of pediatric patients with 
treatment-resistant childhood absence seizures. 
Secondary Objectives 
• 
To assess any improvement in qualitative assessments of patient status over the duration of 
the study. 
• 
To assess the safety and tolerability of Cannabidiol Oral Solution treatment in pediatric 
patients with treatment-resistant childhood absence seizures.  
• 
To assess the pharmacokinetics of Cannabidiol Oral Solution in pediatric patients with 
treatment-resistant childhood absence seizures. 
 
 Study Design 
This is a Phase 2, open-label, dose-finding study designed to assess the efficacy, safety, tolerability, and 
pharmacokinetics of three doses (20, 30, and 40 mg/kg/day) of Cannabidiol Oral Solution in a sequential 
fashion. Doses exceeding 40 mg/kg/day will not be examined in this study. The study design and patient 
progression throughout the study is outlined in Figure 1. 
Figure 1: 
Study Design Schematic 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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App
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 5 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
COHORT 1
 CBD 20 mg/kg/day BID for 4 weeks
COHORT 2
1. CBD 20 mg/kg/day BID for 5 days 
2. CBD 30 mg/kg/day BID for 4 weeks
COHORT 3
 1. CBD 20 mg/kg/day BID for 5 days
 2. CBD 30 mg/kg/day BID for 5 days 
 3. CBD 40 mg/kg/day  BID for 4 weeks
SCREENING
NOTE: All patients in Cohort 1 will be treated for 4 weeks prior to initiation of 
enrollment into Cohort 2, and all patients in Cohort 2 will be treated for 4 weeks 
prior to initiation of enrollment into Cohort 3. 
LONG-TERM 
SAFETY STUDY?
FOLLOW-UP 
PERIOD 
N
LONG-TERM 
SAFETY STUDY 
INS011-17-113
Y
FOLLOW-UP PERIOD: Patients who do 
not choose to enroll in the long-term 
safety study will taper their dose and 
receive a follow-up 4 weeks after taper 
completed.
 
Eligible patients will have a Baseline video-EEG that will include hyperventilation. Video-EEG will be 
repeated at the end of the treatment period to assess efficacy. 
The study drug will be added to existing antiepileptic drug (AED) therapy for the Treatment Period. 
Dosages of concomitant AEDs will be held constant for the Screening Period and during the 4-week 
Treatment Period. 
The study will consist of 30 patients spread equally across the 3 dose cohorts and will be conducted in the  
United States of America across 8 study centers. Patient treatment group is not blinded in this study. 
Patients will be male and non-pregnant female volunteers between ages 3 and 17 years (inclusive) at 
time of consent who were diagnosed with childhood absence epilepsy (CAE) between ages 3 and 12 
(inclusive), have an average of ≥ 5 absence seizures per day, weigh ≥ 10 kg, patient and/or 
parent(s)/caregiver(s) are able to understand and provide written consent, have adequate renal and 
hepatic function, and who meet all the inclusion and exhibit none of the exclusion criteria.  
 
A Data Monitoring Committee (DMC) will meet after all patients in each dose cohort have been treated for 
at least 4 weeks and provide recommendations regarding escalation to the next dose cohort. This will 
ensure that the subsequent higher doses are likely to be tolerated. The DMC may also meet on an ad hoc 
basis if needed. Reference the DMC charter for this study for further detail. 
 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 6 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
3.1 Sample Size Considerations 
Due to the exploratory nature of the study, the sample size is not based on formal statistical 
considerations. Cannabidiol has been extensively studied for many indications, including other forms of 
childhood epilepsy, with favorable tolerability up to 25 mg/kg (Iffland and Grotenhermen, 2017)3. The 
sample size of 30 in an escalating dose design, based on experience from these similar studies to obtain 
adequate preliminary efficacy, safety, and tolerability data, is thus considered sufficient to achieve the 
objectives of the study.  
3.2 Randomization 
This is a non-randomized study.  Patients will be enrolled sequentially in escalating dose groups.  
 Study Variables and Covariates 
4.1 Primary Efficacy Variable 
The primary outcome variable is the percent change in absence seizure count using video-EEG collected 
at Baseline and Week 4 (Visit 5), comparing doses. 
4.2 Secondary Variables 
Efficacy assessments will also include: 
• 
percent change in time to first absence seizure after initiation of hyperventilation testing on  
video-EEG from Baseline to Week 4 (Visit 5) 
• 
percent of patients seizure free at Week 4 (Visit 5)  
• 
investigator CGI-I score at Week 4 (Visit 5) 
4.3 Safety 
Safety assessments will include medical history and conditions, prior and concomitant medications (AEDs 
and others), vital signs, C-SSRS4 and AE assessments, and physical and neurological examinations. 
Blood samples will be taken for clinical laboratory tests (chemistry and hematology), urine will be 
collected for urinalysis, and the 12-lead ECG will be performed according to the Schedule of Events 
(Figure 1).  
All adverse events will be documented at every visit. Adverse events will be classified by severity and 
relationship to study drug using The Medical Dictionary for Regulatory Activities (MedDRA, version 20.0 
or higher) as described in the protocol. The incidence, type, and severity of AEs and serious adverse 
events (SAEs) occurring during the Treatment Period (i.e., treatment-emergent adverse events [TEAEs]) 
will be summarized to meet safety endpoints. Overall summary of TEAE’s will be summarized by any 
TEAE, treatment-related TEAE, treatment-related and severe TEAE, TEAE leading to study drug 
discontinuation, any serious TEAE, any serious and treatment related TEAE and TEAE resulting in death. 
Summaries of AEs will include incidence of TEAEs and treatment-related TEAEs by MedDRA preferred 
term (PT) and system organ class (SOC). The TEAEs will also be summarized by severity, PT, and SOC. 
Subjects reporting more than one TEAE are counted once in each category at the maximum severity. 
AEs with a start date during the study will be summarized. Listings of all AEs, AEs leading to 
discontinuation of the study, AEs ongoing into the planned long term safety study, SAEs, and deaths, if 
any, will be provided. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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in absence seizure c
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in absence seizure 
absence seizure afte
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Week 4 (Visit 5)
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 7 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Vital signs will consist of seated blood pressure, pulse rate, temperature, and respiration rate 
measurements. Changes from Baseline (Visit 2) in vital signs during the Treatment Period will be 
summarized to meet safety endpoints. 
Hematology assessments include: hemoglobin, hematocrit, total and differential leukocyte count, red 
blood cell (RBC), and platelet count. Serum chemistry assessments include: albumin, blood urea nitrogen 
(BUN), creatinine, total bilirubin, alkaline phosphatase (ALP), aspartate transaminase (AST), alanine 
transaminase (ALT), sodium (Na+), potassium (K+), chloride (Cl-), lactate dehydrogenase (LDH), uric 
acid, glucose, and calcium. Urine assessments include: pH, specific gravity, protein, glucose, ketones, 
bilirubin, blood, nitrite, leukocyte esterase, and urobilinogen. Changes from Screening (Visit 1) in 
laboratory values (hematology, chemistry, and urinalysis) during the Treatment Period will be summarized 
to meet safety endpoints. 
4.4 Predetermined Covariates and Prognostic Factors 
For the primary efficacy endpoint of change in number of absence seizure counts, ANCOVA may be 
applied to compare treatment groups. Factors in the modeling include treatment group and Baseline 
seizure count from video-EEG recording. 
 
For the secondary efficacy endpoint of change in time to first absence seizure after initiation of 
hyperventilation testing on video-EEG from Baseline, ANCOVA may be applied to compare treatment 
groups. Factors in the modeling include treatment group and Baseline time to absence seizure from 
video-EEG recording.  
 Definitions 
5.1 Baseline 
The Baseline value of any measurement will the most recent valid value recorded prior to administration 
of the first dose of the study drug during Visit 3. Baseline assessments collected during the Screening 
Visit (Visit 1) include: historic seizure counts, medical/surgical history, clinical laboratory assessments, the 
12-lead ECG, urinalysis, physical examination, height, weight, and C-SSRS. Baseline assessments 
collected during Visit 2 include: 4-hour video-EEG, seizure diary, past/current AEDs, concomitant 
medications, concomitant AED blood levels, vital signs, neurological examination, and AEs. 
5.2 Change from Baseline 
For all study analysis variables Change from Baseline this will be calculated as: 
Change from Baseline = Post-Baseline value – Baseline value. 
Change from Baseline will only be calculated if both Baseline and post Baseline values are available, 
unless otherwise specified. 
Change from Baseline Status (normal or abnormal) for laboratory values will be defined for each measure 
based on the measures’ classifications as defined by the Central Laboratory. 
Visit windows are defined below. If visit timing falls outside of the defined window, the visit will be 
assigned to the scheduled visit that it occurs closest to. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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modeling include 
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 8 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Visit Windows (Days) Relative to the First Dose of Study Medication  
Visit 
Relative Target Day/Week 
Visit Window 
Visit 1 (Screening) 
Days -28 to -1 
± 5 
Visit 2 (Titration) 
Titration Days 0-5 or 0-10 
± 5 
Visit 3 (Treatment) 
Day 1 
0 
Visit 4 (Treatment) 
Week 2 
0 
Visit 5 (Treatment) 
Week 4, Day 6 
± 3 
Visit 6 (End of Study) 
Week 4, Day 7 
± 3 
Early Withdrawal 
 
± 5 
Follow-up visit 
Week 9 
± 5 
5.3 Missing values 
No imputation of missing endpoint values will be performed.  Analysis will be done on all patients in the 
ITT Population. Patients who are missing a second measurement for the primary efficacy measure will not 
be included in change from Baseline analyses, but all existing data will be used for analysis of other 
efficacy and safety measures. 
5.4 Completers 
A patient is considered to have completed the study if they complete all treatments per assigned cohort
and final assessments up to and including week 9, with no early withdrawal. 
5.5 Primary variable calculation 
The primary variable, percent change in absence seizure counts from video-EEG recording will be 
calculated by: 
Percent change = 100 x ((Count at week 4 – Count at Baseline) / Count at Baseline) 
A negative value indicates the percentage of reduction in absence seizures and a positive value indicates 
the percent increase in absence seizures from Baseline at Week 4 (Visit 5). 
5.6 Secondary Variable calculation 
The secondary efficacy variable, percent change in time to first absence seizure after initiation of 
hyperventilation testing on video-EEG from Baseline to Week 4 (Visit 5), will be calculated by: 
Percent change = 100 x ((time in seconds at Week 4 – time in seconds at Baseline) / time in seconds at 
Baseline) 
The secondary efficacy variable, percent of patients seizure free at Week 4 (Visit 5), will be calculated by: 
Number of patients with zero seizures recorded on seizure diary at Week 4/ Total patients in ITT 
population. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 9 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
5.7 Treatment Emergent Adverse Events 
Treatment Emergent Adverse Events (TEAEs) are defined as AEs that first occurred or worsened after 
the first administration of the investigational product, that is after study drug is dispensed and at least one 
dose is taken. Adverse events are considered treatment-related if the relationship to study drug is 
indicated as related. A missing relationship will be imputed as related to study drug and included in the 
summary. 
5.8 Dates 
Partial missing start dates will be imputed as follows: 
 
Missing Start 
Date Portion 
Prior to Treatment 
Same as Treatment Start 
Date 
After Treatment Start 
Date 
Day 
Month and Year < Month 
and Year of first treatment: 
 
Day = 1 
Month and Year = Month and 
Year of first treatment: 
 
Day = Day of first treatment 
Month and Year > Month 
and Year of First 
Treatment: 
 
Day = 1 
Day and Month 
Year < Year of first 
treatment: 
 
Day = 1, 
Month = July 
Year = Year of first treatment: 
 
Day = Day of first treatment, 
Month = Month of first 
treatment 
Year > Year of first 
treatment: 
 
Day = 1, 
Month = January 
Day, Month, and 
Year 
To be conservative, completely missing start dates will be set to the date of first 
treatment 
After following these imputation rules, if the start date is imputed as a date after the end date, the start 
date will be set to the end date to provide a positive duration for the event incidence.  These rules will 
also be applied to missing Adverse Event dates. Partially missing end dates will be imputed as the Study 
completion/early withdrawal date. 
This is intended to conservatively assign AE start dates relative to treatment start date, when AE start 
date is partially missing. That is, if the AE start date is partially missing and available information makes it 
possible that it started after the first day of treatment, then it should be included as a TEAE. 
 
Calculations Using Dates will be performed as follows: 
Age will be calculated as Age = Integer [(Date of enrollment – Date of Birth)/365.25]. 
Study day will be calculated as Study Day = (Date – Date of Visit 3) +1. 
Duration of medication with study drug will be calculated as:  
Duration* = (Date of last dose – Date of first dose [Visit 3]) +1. 
*Note: Missed doses will not be accounted for in the calculation of Duration. 
5.9 Age Groups 
Age will be categorized into 2 groups 3 to 7 and > 7 to 17 for demographic variable reporting.  
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Day = Day of first tre
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Year = Year of fi
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 10 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
5.10 Study Drug Consumed 
Given the liquid nature of the study drug, the following method will be used to calculate the amount of study 
drug used, per bottle, given the displacement of volume in the bottle: 
Weight indicates weight of the bottle in grams 
Amount consumed in mL = 
((Weight at dispensing - Weight at return of bottle) – 0.7 [adapter weight]) / 1.025 [density] 
The percent of subjects per treated visits will be calculated as subjects enrolled at each visit vs. total for 
ITT population 
Total amount of doses taken will be calculated as the total of amount consumed for each bottle for all ITT 
patients. 
Total number of doses taken will be calculated as total of both am and pm doses taken, and Dose 
intensity PDI (mL/week) will be calculated as Cumulative dose (mL) / Duration of medication (weeks) for 
all ITT patients. 
5.11 Body Mass Index 
BMI will be reported in kg/m2. Weight may be collected in kilograms (kg) or pounds (lb) and Height may be 
collected in centimeters (cm) or inches (in). 
For metric measurements kg and cm: 
BMI = Weight/[(Height*100)2] 
For English measurements lb and in: 
BMI = [Weight/(Height)2] x 703 
 Analysis Populations 
6.1 Intent-to-Treat 
The Intent to Treat (ITT) Population will include all subjects who were assigned to a treatment group and 
have a Baseline video-EEG administered. Patients who withdraw from the study after completion of the 
Baseline video-EEG will be included. 
The ITT Population will be used for all efficacy assessments and potential sensitivity analyses.   
6.2 Per Protocol 
The Per-Protocol Population (PP) will include all subjects who complete all treatments, visits, and 
assessments without major protocol violations.  Protocol violations are defined by the FDA as either 
“deviations that may significantly impact the completeness, accuracy, and/or reliability of the study data or 
that may significantly affect a subject’s rights, safety, or well-being”, or as “a change, divergence, or 
departure from the study requirements, whether by the subject or investigator, that resulted in a subject’s 
withdrawal from study participation.” 
For this study, a “major protocol violation” will be defined as:5,6,7 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
th am an
d
th am an
dose (mL) / 
d
dose (mL) / D
d
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collected in k
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collected in kilo
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in:
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s 
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 11 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
• 
Failure to provide valid informed consent 
• 
Violation of eligibility criteria discovered after study enrollment 
• 
Receipt of excluded concomitant treatments 
• 
Deviation of ± > 20% of the assigned study dose, including receipt of the wrong dose from the 
study center, under-dosing, over-dosing, missed doses, or extra doses. 
• 
Failure to complete one or more assessments required to calculated any of the primary or 
secondary efficacy endpoints 
• 
Unreported serious adverse events 
• 
Mishandled samples 
• 
More than 30% of study visits missed or outside permissible windows 
• 
Repeated subject non-compliance with study requirements 
Due to the small size of this study, analysis of the PP Population will be exploratory. 
 
6.3 Safety 
The Safety Population will include all subjects who were treated with at least one dose of the study drug. 
The Safety Population will be used for all safety assessments.   
6.4 PK 
The Pharmacokinetics Population will include all subjects who receive at least one dose of study drug and 
have at least one usable plasma concentration measurement. The Pharmacokinetics Analysis Population 
will be used for all Pharmacokinetics assessments. 
 Data Monitoring Committee 
No interim analysis is planned for this study. However, a DMC will meet on a periodic basis to review safety 
data. Refer to the DMC Charter for this study for the content, conduct, and timing of TFL delivery for these 
meetings. Data review meetings will occur after all patients in each dose cohort have been treated for at 
least 4 weeks. 
The DMC analysis will include: 
For Demographic data, listings for each patient including age, gender, race and ethnicity, historical seizure 
count, past and current anti-epileptic drugs, concomitant medications, co-morbid conditions, seizure type 
and discontinued early including reason for discontinuation. Data will be delivered using JReview listings if 
a DMC meeting occurs prior to TFLs programming completion.  
Safety endpoints data including AEs, changes in vital signs from Baseline, changes in lab values from 
screening will be provided. The incidence, type, and severity and description fields of AEs and SAEs will 
be presented for both Treatment and Follow-Up Periods sorted by incidence, and also sorted by severity. 
AEs will be classified as expected vs. unexpected, and unexpected AEs will be listed first for ease of 
identification per DMC request. The most common expected AEs are somnolence and diarrhea.  
  
Vital signs will be listed by subject showing Baseline, value at each visit where measured, and 
corresponding change. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
uirem
d
uirem
ulation will be e
d
ulation will be e
who were treated with
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who were treated with
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Ap
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 12 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Laboratory values will be listed by subject showing screening, value at each visit where measured and 
corresponding change. 
Data for the safety endpoints will be presented by treatment group side by side, based on stage of the study 
to evaluate progression to next highest dosing cohort. 
Other safety assessments including 12-lead ECG, C-SSRS, medical history, prior medication history, 
neurological and physical exams, will be listed. ECG data will be listed and presented by treatment group 
side by side, based on stage of the study to evaluate progression to next highest dosing cohort. If ECG 
abnormalities occur or QT interval is prolongated as dose escalates, this constitutes a potential stop signal 
for the study and the DMC may convene for an ad-hoc meeting. C-SSRS description fields will be listed for 
the DMC upon request.  
The following information will be presented by subject (listings only) and overall at the Final Closed Session, 
unless a signal is observed, which may be reported prior to the final session: 
Cmax maximum concentration
Ctrough plasma concentration 
Tmax time to maximum concentration 
AUC0-t Area under the curve 
 Statistical Methods 
Tables and data listings will be prepared using SAS Version 9.3 or higher. 
General considerations 
The results of this study will be reported using summary tables, listings, and figures (TFLs), as 
appropriate. Continuous variables will be summarized using descriptive statistics: sample size (n), mean, 
standard deviation (SD), coefficient of variation (CV %) (where appropriate), median, interquartile range, 
minimum and maximum. Categorical variables will be summarized by presenting the sample size (n), 
number of events (frequency), and percentage in each category. 
8.1 Subject Disposition 
Patients who fail screening are not eligible for the study and will not be entered into the database. 
The numbers of subjects enrolled, in the ITT Population, in the Safety Population, in the Per-Protocol 
Population, completing, ongoing to long term safety follow-up and subjects discontinued from the study 
along with reasons to discontinue from the study, will be tabulated overall and by treatment group. A 
tabulation of the number and percentage of subjects enrolled at each center will be presented. 
Summary tables for withdrawal reasons overall, by study site, and by treatment group will be presented. 
Withdrawal reasons are as follows: 
• 
Adverse Event 
• 
Death 
•
Lack of Efficacy
• 
Lost to Follow-up 
• 
Non-Compliance with Study Drug 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
nly
d
nly
he final s
d
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d using SAS Version
pro
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reported using summ
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 13 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
• 
Physician Decision 
• 
Pregnancy 
• 
Protocol Violation 
• 
Site Terminated by Sponsor 
• 
Study Terminated by Sponsor 
• 
Technical Problems 
• 
Withdrawal by Parent/Guardian 
• 
Withdrawal by Subject 
• 
Other 
8.2 Important Protocol Deviations 
A summary table of protocol deviations will also be presented. All protocol deviations along with patient’s 
eligibility criteria will be listed for the Safety Analysis Population. 
Per PRA processes, important protocol deviations data will be entered into our Clinical Trials 
Management System (CTMS). The study team and the sponsor will conduct on-going reviews of the 
deviation data from CTMS and the resulting set of evaluable subjects throughout the study, adjusting the 
deviation criteria as seems appropriate. The evaluable subjects set must be finalized at the post-freeze 
data review meeting (or earlier), prior to database lock. Non-evaluable subjects will not be included in 
efficacy analyses. 
The following important (clinically) protocol deviations, as identified in the clinical trial management 
system (CTMS), will be summarized by category: 
Major 
• 
Eligibility and Entry Criteria 
• 
Incorrect Dose 
• 
Informed Consent 
• 
Missed Efficacy Assessments 
• 
Significant alteration of study drug administration 
• 
Study Drug Compliance  
 
Minor 
• 
Missed Laboratory Assessment  
• 
Missed Scheduled Visit  
• 
Missed Study Procedures  
• 
Other  
• 
Prohibited Concomitant Medication  
 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
ented. All protocol d
ed
ented. All protoco
Populat
ed
Population.
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data will be entered
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 14 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
8.3 Study Drug Exposure and Compliance 
Thirty patients in total will be enrolled into one of three dose cohorts (20, 30, and 40 mg/kg/day); ten 
patients per cohort. Doses will be divided BID and taken within 30 minutes after a meal to ensure 
consistent plasma levels. 
During the Treatment Period, patients will be dosed for 4 weeks during which the investigator will assess 
tolerability and effect. 
Study drug exposure will be calculated in days using the difference between last dose date and first dose 
date plus one. Missed doses will not be subtracted from the total duration time. The percent of subjects 
per treated visits, total amount of study drug taken, dose intensity, and PDI will be reported. 
8.3.1 Dose Changes 
Dose changes are not permitted during this study; however, patients will receive different total doses 
based on their treatment group and weight.  Interruptions, compliance, and dose changes are not 
included in the calculation of duration of exposure. Study drug exposure data will be presented in a listing 
of: 
• 
date of first dose 
• 
date of last dose  
• 
total duration of therapy: (date of last dose – date of first dose) +1 
• 
whether each patient completed the full treatment duration 
• 
actual amount of dose in mL 
• 
total medication taken.  
Reported compliance issues will be listed and summarized to include:  
• 
unauthorized individual dose modification 
• 
unauthorized multiple dose change 
• 
dose interruption 
• 
dose permanently discontinued 
• 
reason (adverse event, lack of efficacy, PK-analysis result, other) 
A patient who experiences several dose modifications for the same reason will be counted only once for 
this reason. A patient who experiences several dose modifications due to different reasons will be 
counted once for each reason.   
8.3.2 Compliance 
Compliance will be assessed using a target of 90% of IP taken with a lower bound of 80% indicating 
compliance for the ITT population. Patient compliance will be presented in a listing and summarized overall 
and by treatment group.  
 
8.4 Prior and Concomitant Medications 
Prior and concomitant medications will be coded using World Health Organization Drug Dictionary (WHO-
DD), version March 2017 and will be summarized at each Visit by treatment group, by the number and 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
er, patients will 
d
er, patients will 
s, compliance, and 
ed
s, compliance, an
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udy drug exposure d
ed
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discontinu
t, la
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 15 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
percentage of subjects taking each medication, and separately by preferred term for the Safety Analysis 
Population.   
In the event the concomitant medication coincided with an AE, these instances will be listed along with the 
corresponding AE. 
Concomitant Antiepileptic Drugs will be summarized and listed by treatment group. 
 
8.5 Demographic and Baseline Characteristics 
Baseline assessments from Visit 1 (screening) will include demographics, past/current AEDs, medical and 
surgical history, concomitant medications (other than AEDs) vital signs, clinical labs, ECG results, 
urinalysis, physical and neurological examinations, C-SSRS results and AEs during screening. Baseline 
assessments from Visit 2 (efficacy Baseline) will include 4-hour video-EEG, seizure diary, meal diary, time 
to first absence seizure after initiation of hyperventilation. Data listings and summaries (overall and by 
treatment group) will be provided for both the ITT and Safety Populations.   
8.6 Efficacy Analyses 
8.6.1 Primary Efficacy Analysis 
• 
Percent change in absence seizure counts comparing treatment at Week 4 (Visit 5) video-EEG to 
Baseline (Visit 2) video-EEG and comparing doses. 
An absence seizure is defined by video-EEG as 3-5 bursts of Generalized Spike Wave (GSW) of 2.7 to 
5 hertz lasting ≥ 3 seconds. The number of seizures will be counted from the first seizure beginning 
after initiation of hyperventilation through the end of the EEG. 
 
The change in number of absence seizure counts will be compared between treatment groups using 
ANCOVA with Baseline value and treatment groups as factors.  
 
The total measurement time from the video-EEG will be recorded and reported in listings for each 
subject for both the Baseline and Week 4 (Visit 5) visits. Measurement time is defined as time from 
initiation of hyperventilation to end of the EEG. If measurement time differs substantially among doses 
based on their variances, an adjustment term may be included in the percent change in absence 
seizure counts to make them comparable between patients and between Baseline and Week 4. 
 
All efficacy endpoints will be analyzed using the ITT population. 
Primary Efficacy Variable 
A positive result for this study will be a reduction in absence seizure counts in any of the dose cohorts. 
The percent change in absence seizure counts comparing treatment at Week 4 (Visit 5) video-EEG to 
Baseline (Visit 2) video-EEG and doses will be analyzed using an ANCOVA procedure. 
− 
Null Hypothesis: There is no difference in the percent change in absence seizure counts 
between treatment groups. 
− 
Alternative Hypothesis: The percent change in absence seizure counts differs in at least 
one treatment group. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
proved
su
d
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ur video
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ur video
Data listings an
d
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afety Population
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 16 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
The Baseline number of absence seizures count, Visit 5 number of absence seizures, and change from 
Baseline (difference and percent change) will be listed and summarized by treatment group within 
dosing cohort using descriptive statistics (n, mean, SD, CV%, 90% CIs, median, minimum, and 
maximum). 
Results of the ANCOVA test will be presented in a table along with parameter estimates and the p-value 
for differences among treatment groups.  
Sensitivity analyses for the ANCOVA procedure may be employed if outliers occur, by removing the outliers 
if total number is small and minimal numbers occur per treatment, to determine the effect on the modeling 
procedure. Sensitivity analyses may also be employed for missing endpoint data as specified in Section 
8.6.4.  
Simulation studies have been conducted to show robustness of the ANCOVA procedure at sample size of 
10 per group8. If results of the ANCOVA analysis procedure yield a significant difference among treatment 
groups, corresponding power calculations for the detected difference will be presented.
The applicability of the ANCOVA procedure will be assessed through checking of the model assumptions: 
• 
Normally distributed response 
• 
Homogeneity of variance 
• 
Independence and linear relationship between the dependent variables and the covariates 
• 
Homogeneity of regression slopes 
These assumptions may be assessed using boxplots to compare treatment group responses and 
Baseline covariates distribution, quantile-quantile plots for normality of percent change from Baseline as 
response variable, normal probability plots for homogeneity of residuals, studentized residual plots for 
residuals across range of percent change responses per treatment group, and scatter plots with 
regression lines for each treatment group.   
The additional assumption of random independent samples will be examined by summarizing and 
comparing Baseline demographic variables (age, sex, and concomitant AED).  
If model assumptions are violated a non-parametric test, the Wilcoxon Mann-Whitney, may be used to 
perform pairwise comparisons of treatment groups as the primary efficacy analysis with known non-
normally distributed data. 
The applicability of ANCOVA procedure and comparability of Baseline characteristics will be performed 
during the study Dry Run meetings to finalize analysis for the SAP sign off and prior to database lock. 
8.6.2 Secondary Efficacy Analysis 
Secondary Efficacy Variables 
Number of daily seizures will be recorded using a seizure diary that captures the number of seizures 
every day from Screening through the End of Study.   
The CGI-I9 is a 7-point scale that scores the investigator’s impression of improvement from ‘very much 
improved’ to ‘very much worse’.  The CGI-I investigator score will be recorded at Week 4 (Visit 5). If a 
patient withdraws early and does not complete an Early Withdrawal Visit, the investigator will attempt to 
obtain the CGI-I assessment parents’ score at time of withdrawal.  
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
f th
d
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yield a si
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yield a si
difference will 
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 17 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
• 
The percent change in time to first absence seizure after initiation of hyperventilation testing on 
video-EEG comparing treatment at Week 4 (Visit 5) to Baseline (Visit 2) will be analyzed to 
compare doses using ANCOVA with the Baseline duration as a covariate. 
− 
Null Hypothesis: There is no difference in percent change in time to absence seizure 
between treatment groups. 
− 
Alternative Hypothesis: The percent change in time to absence seizure counts differs in 
at least one treatment group. 
• 
The percent of patients seizure free at Week 4 (Visit 5) defined as having had no absence 
seizures for all 7 days during the 4th week of the Treatment Period based on seizure diary, will be 
analyzed to compare doses using Fisher’s exact test.  
− 
Null Hypothesis: There is no difference in percent of seizure free patients between 
treatment groups. 
− 
Alternative Hypothesis: There is a significant difference in percent of seizure free patients 
in at least one treatment group. 
• 
Investigator CGI-I at Week 4 (Visit 5) comparing doses. 
The number of subjects and percentage of subjects within each point along the 7-point scale 
will be summarized by treatment group for the CGI-I completed by the investigator during 
Visit 5.  
Change from Visit 3 response will be summarized within treatment groups using descriptive 
statistics (n, mean, SD, CV%, 90% CIs, median, minimum, and maximum).  
Change in score will be compared between treatment groups using ANCOVA with Visit 3 
score as a covariate. 
− 
Null Hypothesis: The mean CGI-I score does not differ between treatment groups. 
− 
Alternative Hypothesis: the mean CGI-I score is different in at least one treatment group. 
Duration to first absence seizure after initiation of hyperventilation for both Baseline and Week 4 (Visit 5) 
and change from Baseline will be listed. The average time to first absence seizure after initiation of 
hyperventilation at Baseline and Week 4 (Visit 5) as well as difference from Baseline at Week 4 (Visit 5) 
will be summarized and compared by treatment group. The change from Baseline will be summarized by 
descriptive statistics (n, mean, SD, CV%, 90% CIs, median, minimum, and maximum) and value from the 
significance testing for the Null hypothesis average difference is equal to 0 vs. Alternative Hypothesis 
average difference is not equal to 0 will be presented. 
Number and percent of patients seizure free vs. not seizure free at visit 5 will be summarized by 
treatment, and the value from the significance testing will be presented. 
CGI-I responses completed by the investigator during Visit 5 will be summarized and presented using a 
histogram of the number and percentage of each point along the 7-point scale. Visit 3, Visit 5, and 
change from Visit 3 response will be summarized within treatment groups using descriptive statistics (n, 
mean, SD, CV%, 90% CIs, median, minimum, and maximum), and the value from the significance 
testing will be presented. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
proved
ercent of s
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 18 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
8.6.3 Exploratory Efficacy Analysis 
Time to freedom from seizures will be defined as the Study Day at which no further seizures were 
recorded for the rest of the Treatment Period. 
Number of seizure-free days per week will be defined as the number of days in each Week of Treatment 
(out of 7) with zero seizures recorded. 
Average number of seizures per week will be defined as the total number of seizures in each Week of 
Treatment, averaged across patients for each treatment group. 
Average time to freedom from seizures, number of seizure-free days per week, and number of absence 
seizures per week (for each of Weeks 1, 2, 3, and 4) will be summarized by treatment group. 
 
No inferential analyses will be conducted for these exploratory efficacy measures. 
8.6.4 Methods for Handling Dropouts and Missing Data 
Efficacy measures will not be imputed, and patients without a second video-EGG will not be included in 
analyses requiring the second video-EGG. Patients without a second video-EEG will be included in a 
sensitivity analysis to assess the impact of excluding missing values versus using imputed values for the 
final video-EEG as the median of the change from Baseline within treatment group. Impact will be 
measured as the change in significance in R2 and/or AIC between the two ANCOVA models.  
Missing dates will be imputed as specified in Section 5.8.  
8.6.5 Multiplicity 
Overall strong type I error control will be achieved for the primary and secondary efficacy endpoints 
using a fixed sequence closed testing procedure with fallback. Fallback procedures are closed testing 
procedures that maintain strong control of familywise error rate while allowing testing of all hypotheses 
even if one or more hypotheses are not rejected earlier in the testing sequence (Wiens and Dmitrienko, 
2005) 10. The primary endpoint and five secondary endpoints are ordered prospectively. In the fixed 
sequence procedure, each hypothesis is tested, in order, at α = 0.05, until a hypothesis fails to be 
rejected, after which testing stops. The fallback modification “reserves” a small alpha to be used for the 
next test in the sequence even if the prior hypothesis is not rejected.  
That is, with the hypotheses ordered as H1, H2, …, Hi, assign 𝛼𝛼𝑖𝑖
′ to the ith null hypothesis such that 
∑
𝛼𝛼𝑖𝑖
′
𝑖𝑖
𝑖𝑖=1
=  𝛼𝛼. H1 is tested at the level 𝛼𝛼𝑖𝑖
∗=𝛼𝛼𝑖𝑖
′. Subsequent hypotheses Hi are tested at the level 𝛼𝛼𝑖𝑖
∗ = 𝛼𝛼𝑖𝑖
′ if 
Hi−1 was not rejected, or 𝛼𝛼𝑖𝑖
∗ = 𝛼𝛼𝑖𝑖
′ + 𝛼𝛼𝑖𝑖−1
′
 if Hi−1 was rejected. Specifically, α will be distributed among the 
hypotheses as 𝛼𝛼𝑖𝑖
′ = 0.04, 0.003, 0.002, 0.002, 0.002, and 0.001, respectively.  If H1 is rejected with p < 
0.04, H2 (time to relapse) will be tested at 𝛼𝛼2
′= 0.04 + 0.003 = 0.043.  If H2 is rejected with p< 0.043, H3 
is tested at 𝛼𝛼3
′ = 0.043 + 0.002 = 0.045, and so on.  However, if H2 is not rejected (p≥ 0.043), H3 is 
tested at 𝛼𝛼3
′=0.002. 
8.6.6 Pooling of Sites 
Data will be pooled across sites for all analyses. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 19 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
8.7  Safety Analyses 
Safety evaluations will be based on the incidence, intensity, type of adverse events (AEs), clinically 
significant changes in the patient’s physical examination findings, electrocardiograms (ECGs), vital sign 
measurements, and clinical laboratory results.  
These analyses will be performed using the Safety population. 
No statistical inference is planned. 
 
8.7.1 Adverse Events
Overall summary of TEAE’s will be summarized by any TEAE, treatment-related TEAE, treatment-related 
and severe TEAE, TEAE leading to study drug discontinuation, any serious TEAE, any serious and 
treatment related TEAE, TEAE resulting in death, and TEAE leading to study discontinuation. Summaries 
of AEs will include incidence of TEAEs and treatment-related TEAEs by MedDRA preferred term (PT) and 
system organ class (SOC) by dose cohort. The TEAEs will also be summarized by severity, PT, and SOC 
by dose cohort.  
Missing values for severity will be assigned as “Severe” and missing values for relationship to study 
treatment will be considered as “Related” in the summary. Subjects reporting more than one TEAE are 
counted once in each category at the maximum severity. 
AEs with a start date during the study will be summarized. Listings of all AEs, AEs leading to 
discontinuation of the study drug, SAEs, TEAE leading to study discontinuation; and deaths, if any, will be 
provided. 
Adverse events that occur during the video EEG recording will be listed. 
Adverse events that occur during the administration of study drug will be listed. 
Adverse events that are reported during follow-up phone calls or emails will be listed. 
 
8.7.2 Deaths and Serious Adverse Events 
Any SAE, or death related to the study drug will be listed in a table by treatment group. 
8.7.3 Laboratory Data 
Blood samples will be taken for clinical laboratory tests (chemistry and hematology) and urine will be 
collected for urinalysis.  
The results of the Screening Visit laboratory chemistry, hematology and urinalysis values will be listed 
and summarized for the Safety Population. Results for subsequent visits will be listed as change from 
screening per visit, and any change to abnormal status (below LLN or above ULN) and shift tables will be 
listed and summarized by treatment group. Out of range values as defined by the Central Laboratory will 
also be listed. If multiple lab values occur on the same date the latest chronological sample per date will 
be used in the results. 
For the purposes of summarization in both the tables and listings, all laboratory values will be converted 
to standardized units. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
, an
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 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 20 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Parameters to be included are: 
• 
Hematology: hemoglobin, hematocrit, total and differential leukocyte count, red blood cell (RBC), 
and platelet count. 
• 
Chemistry: albumin, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline phosphatase 
(ALP), aspartate transaminase (AST), alanine transaminase (ALT), sodium (Na+), potassium 
(K+), chloride (Cl-), lactate dehydrogenase (LDH), uric acid, glucose, and calcium. 
• 
Urinalysis: pH, specific gravity, protein, glucose, ketones, bilirubin, blood, nitrite, leukocyte 
esterase, and urobilinogen.  
8.7.4 Vital Signs 
Vital signs measurements will be listed and summarized by treatment group for the Safety Population. 
Results for post Baseline visits will also be listed with change from Baseline per visit. 
8.7.5 Physical Examinations, ECGs, and Other Observations Related to Safety 
A 12-lead ECG will be completed during Screening and at End of Study or Early Withdrawal.  Each ECG 
will be evaluated for any clinically relevant cardiovascular conditions, defined as any clinically significant 
abnormalities identified by the reader related to coronary artery disease, coronary spasm, abnormal heart 
rhythm, hypertrophic cardiomyopathy, heart failure, rheumatic heart disease, or myocarditis, which will be 
listed and summarized by treatment group.   
The following ECG parameters will be captured: HR (Ventricular rate) (beats per minute), PR Interval 
(msec), QRS Interval (msec), QT Interval (msec), QTcF Interval (msec) [QT interval corrected by 
Fridericia], RR Interval (msec) and Overall assessment of ECG by the investigator (Normal, Abnormal, 
Not Clinically Significant (ANCS), Abnormal, Clinically Significant (ACS)). 
Abnormal values for QT interval and QTcF will be classified as > 450 msec and > 480 msec, respectively. 
ECG parameters will be listed as Baseline values, End of Study/Early Withdrawal values, and change 
from Baseline. Overall assessment of ECG by the investigator will be listed if there is a change to 
Abnormal results from Baseline. 
The neurological examination includes assessment of mental status, cranial nerves, nystagmus, motor 
system, sensory system, reflexes, coordination, gait, and station as ‘normal’ or ‘abnormal’. Neurological 
exam results will be listed by Body System for any abnormal findings along with description of any 
abnormal, clinically significant findings. 
A complete physical examination includes assessment of general appearance, skin, eyes, ears, nose, 
throat, neck, lymph nodes, chest, heart, abdomen, and extremities as ‘normal’ or ‘abnormal’. Physical 
exam results will be listed by Body System for any abnormal findings along with description of any 
abnormal, clinically significant findings. 
 
8.7.6 C-SSRS 
For patients aged 7 to 17 years and if the developmental level is appropriate, the Columbia-Suicide 
Severity Rating Scale (C-SSRS) Children's Version will be utilized to assess suicidality at Screening and 
End of Study or the Early Withdrawal Visit. For patients who are less than 7 years of age or for whom the 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
from
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from B
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Observations R
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Observations
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ed
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aptured: HR (Ventric
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rval (msec), QTcF In
pr
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Overall assessment
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val and QTcF will be
App
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A
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 21 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
C-SSRS is inappropriate due to the patient’s developmental functioning, a clinical assessment will be 
made. Results of the C-SSRS assessments will be presented in a listing to include outcomes of any 
clinically relevant findings.  
8.8 Pharmacokinetic Analysis 
The PK population will be used for PK data analysis. The PK population consists of patients 
who receive at least one dose of Cannabidiol Oral Solution and have at least one usable CBD 
plasma concentration measurement. Descriptive statistics of trough plasma concentration and 
PK parameters data for CBD and 7-OH CBD by Visit, Dose, and Response will be provided. 
 
The following noncompartmental PK parameters will be estimated from the plasma 
concentration-time data: area under the curve from time 0 to the last measured concentration 
(AUC0-t) by maximum plasma concentration (Cmax), and time to reach maximum plasma 
concentration (Tmax) using Phoenix WinNonlin® (Version 7 or higher; Pharsight Corporation, 
Cary, NC 27518, USA). Additional PK parameters may be estimated, as appropriate. 
Parameters will be summarized by dose cohort.  
Exploratory analysis of dose (exposure)-response relationship will be performed. Further 
population PK approach may be used for PK parameter estimation, as appropriate. 
 Validation 
PRA's goal is to ensure that each TFL delivery is submitted to the highest level of quality. Our quality control 
procedures will be documented separately in the study specific quality control plan.  
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
oved
to
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to
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or highe
estimated, as
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 22 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
 References 
1. ICH Harmonized Tripartite Guideline. Dose-Response Information to Support Drug Registration E4. 
International conference on harmonisation of technical requirements for registration of 
pharmaceuticals for human use. 10 March 1994.  
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E4/Step4/E4_Guideli
ne.pdf 
2. ICH Harmonized Tripartite Guideline. Statistical Principles for Clinical Trials E9. International 
conference on harmonisation of technical requirements for registration of pharmaceuticals for human 
use. 05 February 1998. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E9/Step4/E9_Guideli
ne.pdf
3. Iffland K, Grotenhermen F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical 
Data and Relevant Animal Studies. Cannabis and Cannabinoid Research. 2017;2(1):139-154. 
doi:10.1089/can.2016.0034. 
 
4. Posner K, Brown GK, Stanley B, Brent DA, Yershova KV, Oquendo MA, Currier GW, Melvin GA, 
Greenhill L, Shen S, Mann JJ. The Columbia-Suicide Severity Rating Scale: initial validity and internal 
consistency findings from three multisite studies with adolescents and adults. Am J Psychiatry. 2011 
Dec;168(12):1266-77. doi: 10.1176/appi.ajp.2011.10111704. PubMed PMID: 22193671; PubMed 
Central PMCID: PMC3893686. 
 
5. ICH Harmonized Tripartite Guideline. Structure and Content of Clinical Study Reports E3. 
International conference on harmonisation of technical requirements for registration of 
pharmaceuticals for human use. 30 November 1995. 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_Guideline.pdf 
6. E3 implementation Working Group: ICH E3 Guideline: Structure and Content of Clinical Study 
Reports. Questions and Answers. 7 June 2012 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E3/E3_QAs_R1_Ste
p4.pdf 
7. Arun Bhatt. Protocol deviation and violation. Perspectives in Clinical Research. 2012 Jul-Sep; 3(3): 
117. 
 
8. Vickers, A. J. Parametric versus non-parametric statistics in the analysis of randomized trials with 
non-normally distributed data. BMC Medical Research Methodology. 2005; 5(35). 
http://doi.org/10.1186/1471-2288-5-35 
9. Busner J, Targum SD. The Clinical Global Impressions Scale: Applying a Research Tool in Clinical 
Practice. Psychiatry (Edgmont). 2007;4(7):28-37. 
10. Wiens, Brian L.; Dmitrienko, Alexei Journal of Biopharmaceutical Statistics, 01 November 2005, 
Vol.15(6), p.929-942[Peer Reviewed Journal]: 10.1080/10543400500265660 The fallback procedure 
for evaluating a single family of hypotheses 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
proved
de Effects o
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nnabinoid Rese
shova KV, Oquendo
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shova KV, Oquendo
Suicide Severity Ra
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Suicide Severity Ra
udies with adolescen
ov
udies with adolescen
ajp.2011.10111704. 
ov
ajp.2011.10111704. 
e
p
e.
p
. S
p
Structure and 
pro
tructure and C
o
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onisation of technica
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Public_Web_Site/ICH
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 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 23 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Appendix 1 Glossary of Abbreviations 
Glossary of Abbreviations: 
ACS 
Abnormal Clinically Significant 
AE 
Adverse event 
AED 
Anti-Epileptic Drug 
AIC 
Akaike Information Criterion 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ANCS 
Abnormal Not Clinically Significant 
ANOVA 
Analysis of Variance 
AST 
Aspartate Transaminase 
AUC0-t   
Area Under the Concentration-time curve from 0 
BID 
Bis In Die (twice a day) 
BUN 
Blood Urea Nitrogen 
CAE 
Childhood Absence Epilepsy 
CBD 
Cannabidiol 
CGI-I 
Clinical Global Impression - Global Improvement 
CI 
Confidence Interval 
Cmax  
maximum plasma concentration 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CRF 
Case Report Form 
CTMS 
Clinical Trial Management System 
Ctrough 
plasma trough concentrations 
CV 
Coefficient of Variation 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EEG 
Electroencephalography 
GSW 
General Spike Wave 
HV 
Hyperventilation 
IP 
Investigational Product 
ITT 
Intention-to-treat 
LDH 
Lactate Dehydrogenase 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
ant
d
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entration-
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-time curve 
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day
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o
iol
p
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al Global Impression
p
al Global Impression
pr
nfidence Interval
pp
nfidence Interval
pp
maximum plasma c
App
maximum plasma c
App
Columbia
Ap
Columbia-
Ap
-Suicid
Ap
Suicid
Ap
A
Case Report 
A
Case Report 
A
nical
A
nical Tr
A
Tr
A
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 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018
PRS 005 T 17 F 
Page 24 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
LLN 
Lower Limit of Normal 
QTcF 
QT interval with Fridericia correction 
PDI 
Dose Intensity 
PK 
Pharmacokinetic 
PP 
Per Protocol 
PT 
Preferred Term 
RBC 
Red Blood Cell 
R2 
Coefficient of Determination 
SAP 
Statistical Analysis Plan 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SOC  
System Organ Class 
Tmax   
time to maximum concentration 
ULN 
Upper Limit of Normal 
WHO-DD 
World Health Organization Drug Dictionary 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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ed
centration
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 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 25 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Appendix 2 Tables Figures, and Listings 
Title 
Population  
Table 1.1 Subject Analysis Populations 
(All Screened Subjects) 
Table 1.2 Enrollment by Center 
(Intent to Treat Population) 
Table 1.3 Subject Disposition 
(Intent to Treat Population) 
Table 1.4 Important Protocol Deviations 
(Intent to Treat Population) 
Table 1.5.1 Demographic Characteristics 
(Intent to Treat Population) 
Table 1.5.2 Demographic Characteristics 
(Per Protocol Population) 
Table 1.5.3 Demographic Characteristics 
(Safety Population) 
Table 1.6 Past Medical History by System Organ Class and Preferred Term
(Intent to Treat Population) 
Table 1.7.1 Prior Medications by WHO Drug Dictionary Preferred Term  
(Intent to Treat Population) 
Table 1.7.2 Concomitant Medications by WHO Drug Dictionary Preferred Term   
(Intent to Treat Population) 
Table 1.7.3 Prior Anti-Epileptic Medications by WHO Drug Dictionary Preferred Term   
(Intent to Treat Population) 
Table 1.7.4 Concomitant Anti-Epileptic Medications by WHO Drug Dictionary Preferred Term   
(Intent to Treat Population) 
Table 1.8 Treatment Compliance 
(Intent to Treat Population) 
Table 2.1.1 Summary of Actual Response and Change from Baseline in Absence Seizure Counts 
(Intent to Treat Population) 
Figure 2.1.2 Scatter Plot of Absence Seizure Counts 
(Intent to Treat Population) 
Table 2.1.3 Model checking plots for Change from Baseline in Absence Seizure Counts ANCOVA 
(Intent to Treat Population) 
Table 2.1.4 Sensitivity Analysis for Change from Baseline in Absence Seizure Counts ANCOVA 
(Intent to Treat Population) 
Table 2.2.1 Summary of Time to First Absence Seizure after Initiation of Hyperventilation Testing Change from 
Baseline
(Intent to Treat Population) 
Table 2.2.2 Summary of Percent Patients Seizure Free During Week 4
(Intent to Treat Population)
Figure 2.2.3 Histogram of CGI-I 7 point scale by Cohort
(Intent to Treat Population)
Table 2.2.4 Multiplicity for Efficacy Endpoints Using a fixed sequence closed testing procedure with fallback
(Intent to Treat Population)
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
Approved
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ved
ove
Preferred Term
rov
Preferred Term
ov
y Preferred Term  
pro
y Preferred Term  
pro
rug Dictionary Preferred Te
ppr
rug Dictionary Preferred Te
pr
by WHO Drug Dictionary P
App
by WHO Drug Dictionary P
App
App
Medications by WHO Dru
App
Medications by WHO Dru
Ap
App
Ap
A
Change
A
Change
A
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 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 26 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Table 2.3 Pharmacokinetics Parameters 
(PK Population) 
Table 3.1.1 Summary of Exposure  
(Safety Population) 
Table 3.2.1 Overall Summary of Treatment-Emergent Adverse Events 
(Safety Population) 
Table 3.2.2 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
Table 3.2.3 Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(Intent to Treat Population) 
Table 3.3.1 Treatment-Related Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
Table 3.3.2 Treatment-Related Adverse Events by System Organ Class and Preferred Term 
(Intent to Treat Population) 
Table 3.4.1 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(Safety Population) 
Table 3.4.2 Serious Treatment-Emergent Adverse Events by System Organ Class and Preferred Term 
(Intent to Treat Population) 
Table 3.4.3 Serious Treatment-Related Adverse Events by System Organ Class and Preferred Term 
(Per Protocol Population) 
Table 3.4.4 Treatment-Emergent Adverse Events with an Outcome of Death by System Organ Class and Preferred 
Term 
(Safety Population) 
Table 3.5 Subjects with Treatment-Emergent Adverse Events with Outcome of Death 
(Safety Population) 
Table 3.6.1 Treatment-Emergent Adverse Events Leading to Study Medication Discontinuation by System Organ 
Class and Preferred Term 
(Safety Population) 
Table 3.6.2 Subjects Who Experienced Treatment-Emergent Adverse Events Leading to Discontinuation of Study 
Medication 
(Safety Population) 
Table 3.7.1 Hematology Results Change from Baseline 
(Safety Population) 
Table 3.7.2 Biochemistry Results by Time Point – General Chemistry 
(Safety Population) 
Table 3.7.3 Urinalysis Results Change from Baseline – Continuous Variables 
(Safety Population) 
Table 3.7.4 Vital Sign Results Change from Baseline 
(Safety Population) 
Table 4.1 Electrocardiogram Results 
(Safety Population) 
Listing 5.1.1 Discontinued Subjects 
(Intent to Treat Population) 
Listing 5.1.2 Protocol Deviations 
(Intent to Treat Population) 
Listing 5.2 Demographic and Baseline Data
(Intent to Treat Population) 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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d Term
d
d Term
d
eferred Term
ed
eferred Term
d
n Class and Preferred Te
ved
n Class and Preferred T
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Organ Class and Preferred
ve
Organ Class and Preferred
ve
em Organ Class and Prefe
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em Organ Class and Prefe
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Appr
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ppr
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Appr
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-Emergent A
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 27 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Listing 5.3.1 General Medical History 
(Intent to Treat Population) 
Listing 5.3.2 Seizure History 
(Intent to Treat Population) 
Listing 5.4.1 Prior and Concomitant Medications 
(Safety Population) 
Listing 5.4.2 Study Drug Administration 
(Safety Population) 
Listing 5.4.3 Treatment Compliance 
(Intent to Treat Population) 
Listing 5.5.1 Video Electroencephalography Results 
(Safety Population) 
Listing 5.5.2 Absence Seizure Diaries  
(Intent to Treat Population) 
Listing 5.5.3 Meal Diary 
(Intent to Treat Population) 
Listing 5.6 Clinical Global Impression – Global Improvement 
(Safety Population) 
Listing 5.7.1.1 Columbia-Suicide Severity Rating Scale Page 1A 
(Intent to Treat Population) 
Listing 5.7.1.2 Columbia-Suicide Severity Rating Scale Page 1B 
(Intent to Treat Population) 
Listing 5.7.1.3 Columbia-Suicide Severity Rating Scale Page 2 
(Intent to Treat Population) 
Listing 5.7.1.4 Columbia-Suicide Severity Rating Scale Page 3 
(Intent to Treat Population) 
Listing 5.7.1.5 Columbia-Suicide Severity Rating Scale Page 4 
(Intent to Treat Population) 
Listing 5.7.2.1 Children's Columbia-Suicide Severity Rating Scale Page 1A 
(Intent to Treat Population) 
Listing 5.7.2.2 Children's Columbia-Suicide Severity Rating Scale Page 1B 
(Intent to Treat Population) 
Listing 5.7.2.3 Children's Columbia-Suicide Severity Rating Scale Page 2 
(Intent to Treat Population) 
Listing 5.7.2.4 Children's Columbia-Suicide Severity Rating Scale Page 3 
(Intent to Treat Population) 
Listing 5.7.2.5 Children's Columbia-Suicide Severity Rating Scale Page 4 
(Intent to Treat Population) 
Listing 5.8.1 Adverse Events During video – EEG recording 
(Safety Population) 
Listing 5.8.2 Adverse Events During Administration of Study Drug 
(Safety Population) 
Listing 5.8.3 Adverse Events Reported at Follow-up (email or phone 
(Safety Population) 
Listing 5.8.4 Treatment-Emergent Adverse Events 
(Safety Population) 
Listing 5.8.5 Treatment-Emergent Adverse Events Leading to Study Drug Discontinuation 
(Safety Population) 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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pro
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App
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Rating Scale Page 4
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Severity Rating
Ap
Severity Rating
Ap
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verity R
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verity R
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 28 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Listing 5.8.6 Treatment-Emergent Adverse Events Ongoing to Follow-Up Study 
(Safety Population) 
Listing 5.8.7 Serious Treatment-Emergent Adverse Events 
(Safety Population) 
Listing 5.8.8 Treatment-Emergent Adverse Events Resulting in Death 
(Safety Population) 
Listing 5.8.9 Adverse Events Expected vs. Unexpected 
(Safety Population) 
Listing 5.9 Hematology Results and Change from Baseline 
(Safety Population) 
Listing 5.10 Biochemistry Results and Change from Baseline 
(Safety Population) 
Listing 5.11 Urinalysis Results and Change from Baseline 
(Safety Population) 
Listing 5.12 Pregnancy Test Results (Post-Menarchal Females only) 
(Safety Population) 
Listing 5.13 Vital Signs 
(Safety Population) 
Listing 5.14 Electrocardiogram Results 
(Safety Population) 
Listing 5.15.1 Physical Examinations
(Safety Population) 
Listing 5.15.2 Neurological Examinations 
(Safety Population) 
Listing 5.16 Pharmacokinetics 
(PK Population) 
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 29 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
Appendix 3 Schedule of Events 
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 30 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
ASSESSMENTS 
SCREENING 
PERIODa 
TITRATION PERIOD 
TREATMENT PERIOD 
FOLLOW- 
UP 
PERIODC 
Visit Number 
1 
2 
Baseline 
Call/ 
Email 
3 
4 
5 
6 
End of 
Study 
Early 
Withdrawal
Visitp 
7 
Study Time Points 
Days -28 to -1 
Day 1 
0-5 or 0-10 
days 
Day 1 
Week 2 
Week 4 
(Day 6) 
Week 4 
(Day 7) 
Week 9 
Visit Window (Days) 
± 5 
± 5 
0 
0 
± 3 
± 3 
± 5 
± 5 
Informed consent 
X 
Review of
inclusion/exclusion 
criteria 
X 
X 
Review of historic 
seizure counts 
X 
4-hour video-EEGd,e 
Xb 
X 
X 
Seizure diaryf 
X 
X 
X 
X 
X 
X 
X 
Meal diaryf 
X 
X 
X 
X 
X 
Demographics 
X 
Assessments of 
past/current AEDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical Surgical 
History 
X 
Concomitant 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signsg 
X 
X 
X 
X 
X 
X 
Clinical Laboratory 
Assessmentsh 
X 
X 
X 
X 
X 
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Week 2
d
Week 2
d
0
ed
0
d
ed
v d
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ppr
X
A
Xb
A
b
pp
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A
X
X
pp
X
Ap
Ap
App
App
X
A
X
X
p
X
Ap
Ap
Ap
Ap
A
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 31 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
ASSESSMENTS 
SCREENING 
PERIODa 
TITRATION PERIOD 
TREATMENT PERIOD 
FOLLOW- 
UP 
PERIODC 
Visit Number 
1 
2 
Baseline 
Call/ 
Email 
3
4 
5 
6 
End of 
Study 
Early 
Withdrawal 
Visitp 
7 
Study Time Points 
Days -28 to -1 
Day 1 
0-5 or 0-10 
days 
Day 1 
Week 2 
Week 4 
(Day 6) 
Week 4 
(Day 7) 
Week 9 
Visit Window (Days) 
± 5
± 5 
0
0 
± 3 
± 3 
± 5 
± 5 
Concomitant AED 
levels 
X 
X 
X 
PK Samples 
Xi 
Xi 
Xi 
Xj 
12-lead ECG 
X 
X 
X 
Urine Analysis 
X 
X 
X 
Urine pregnancy 
screen for post- 
menarchal females
X 
Physical Examinationk 
X 
Neurological 
Examinationl 
X 
X 
X 
X 
X 
X 
Height/Weight 
X 
X 
X 
X 
CGI-I 
X 
X 
X 
C-SSRS 
X 
X 
X 
Dosing with 
Cannabidiol Oral 
Solution 
Xm 
X 
X 
X 
X 
Xn 
Xo 
Drug Accountability 
X 
X 
X 
X 
X 
AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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Week 2
d
Week 2
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Ap
Ap
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X
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 32 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
End of Study 
Xq 
a Screening should occur within 28 (± 5) days. Patients in Cohort 2 and Cohort 3 may have a waiting period between Screening and Titration Periods while 
previous Cohort completes the Treatment Period and safety data is reviewed by the DMC. 
b Patients will have a Baseline 4-hour video EEG (including hyperventilation). 
c Follow-Up Period Visit (Visit 7) may be a phone call. 
d Hyperventilation testing will be conducted during the video-EEG. 
e Patients will return to the study clinic at Visit 5 or the Early Withdrawal Visit for a repeat 4-hour video-EEG.
f Seizure diaries will be dispensed during the Screening Visit (Visit 1), reviewed and returned during Visits 2 through 5, and collected during Visit 6. A 
meal diary will be completed at Baseline (Visit 2); and for 24 hours before each PK sampling visit at Visit 3 and Visit 5 (Week 4, Day 6), or the Early 
Withdrawal Visit. 
g Vital signs will be taken after a 5-minute seated rest. 
h A urine dipstick pregnancy test will be performed on all female post-menarchal patients during Screening (Visit 1). 
i Blood for pharmacokinetic analyses of CBD and 7-OH CBD will be drawn at Visit 3 (Day 1), Visit 5 (Week 4, Day 6), and Visit 6 (Week 4, Day 7). Blood 
draws will be taken pre-dose, 2, 4, and 6 hours after the morning dose (but before the next dose). In the Fed state (Visit 5, Week 4 Day 6), pre-dose blood
samples should be collected BEFORE dosing with the “high-fat” breakfast (dose will be administered within 30 minutes of start of breakfast). In the Fasted 
state (Visit 6, Week 4 Day 7), patients will be fasted for 2 hours before the dose. 
j Trough values of CBD and 7-OH CBD will be collected at the Early Withdrawal Visit prior to dosing. 
k The physical examination will include evaluation of general appearance, skin, eyes, ears, nose, throat, neck, lymph nodes, chest, heart, abdomen, and 
extremities. 
l A complete neurological exam will be performed during Screening (Visit 1) and brief neurological examination (mental status, cranial nerves, nystagmus, 
motor system, sensory system, reflexes, coordination, gait, and station) will be performed at Visits 2 (Baseline), 3, 4, and 6 (End of Study) or the Early 
Withdrawal Visit. 
m Titration dose of study drug will be dispensed after patient qualification. 
n A risk/benefit assessment will be made and the decision on whether to continue the patient to the long-term safety study will be documented. If patient is not
continuing in the safety study, dispense Cannabidiol Oral Solution for Taper Period. Patients who do not choose to enroll in the long-term safety study will 
taper the dose of Cannabidiol Oral Solution according to the following schedule: doses over 30 mg/kg/day will be reduced to 30 mg/kg/day for five days, 
then 30 mg/kg/day will be reduced to 20 mg/kg/day for five days and then discontinued; doses between 20-30 mg/kg/day will be reduced to 20 mg/kg/day for 
five days and then discontinued; doses ≤ 20 mg/kg/day can be discontinued without titration. This can be modified by the investigator based upon the 
patient’s response. 
o Study drug will be collected but not dispensed.
p If the patient withdraws prematurely from the Treatment Period, all Early Withdrawal procedures should be conducted. Site staff will follow up with the 
patient at 4 weeks after completion of treatment via the telephone to collect information regarding AEs, AEDs, and concomitant medications. 
q Patients can re-consent to enter the long-term safety study. If patient re-consents, then the patient will continue to receive CBD at their current dose. 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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hour
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Sponsor: Insys Development Company, Inc 
 Statistical Analysis Plan 
Protocol no: INS011-17-103 
Version Date: 07-Jun-2018 
PRS 005 T 17 F 
Page 33 of 33 
Strictly Confidential.  © 2004-2015, PRA Health Sciences.  All rights reserved. 
AE = adverse event; AED = anti-epileptic drug; CGI-I = Clinical Global Impression – Global Improvement; C-SSRS=Columbia Suicide Severity Rating 
Scale; EEG = electroencephalography; PK= pharmacokinetics. 
 
INS011-17-103 Statistical Analysis Plan v1.0 signed | VV-TMF-120943 | 1.0
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