Clinical trial NCT04682353
Conditions: Contraception
Keywords: Pharmacokinetics
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2020-12-14; Completion date: 2023-01-12
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this study is to evaluate and compare the pharmacokinetic profile of Medroxyprogesterone acetate following subcutaneous administration of 3 different doses of TV-46046 and a dose of Depo-subQ Provera in healthy female participants.

The secondary objectives of the study are to evaluate and compare the safety, local tolerability, and acceptability of a subcutaneous injection of 3 different doses of TV-46046 and a dose of Depo-subQ Provera in healthy female participants.

The total duration of the study for each participant is expected to be up to 19.5 months.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None
Interventions: intervention 1: TV-46046 intervention 2: Depo-subQ Provera
Intervention descriptions: intervention 1: SC injection of 300 mg/mL (120 mg/0.4mL; 180 mg/0.6mL; 240 mg/0.8mL) intervention 2: SC injection of 104 mg/0.65 mL

Protocol documents:
Prot_000.pdf: 
 
 
 
Cli nic al St u d y Pr ot oc ol  
 
 
A Ra n d o mize d, D ose -ra n ge Fi n di n g St u d y t o E val uate P har mac o ki netics of 
Me dr o x y pr o gester o ne Acetate F oll o wi n g a Si n gle  S u bc uta ne o us A d mi nistrati o n of  
T V -4 6 0 4 6 i n Healt h y W o me n of Re pr o d ucti ve A ge  
 
 
St u d y N u m ber T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
 
N C T 0 4 6 8 2 3 5 3  
 
 
Pr ot oc ol wit h A me n d me nt 0 2  A p pr o val Date: 1 6 Marc h 2 0 2 1  


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1  
 
 
Cli nic al St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y N u m ber  T V 4 6 0 4 6 -W H -1 0 1 5 9  
F HI 3 6 0 St u d y N u m ber 1 4 4 9 0 4 8  
A R a n d o miz e d, D ose -r a n ge Fi n di n g St u d y t o E v al u ate P h ar m ac o ki netics of 
Me dr o x y pr o gest er o ne Acet ate F oll o wi n g a Si n gle S u bc ut a ne o us A d mi nistr ati o n of  
T V -4 6 0 4 6 i n He alt h y W o me n of Re pr o d ucti ve A ge  
P h ase 1  
I N D n u m ber: 1 2 6 2 4 9 
E u dr a C T n u m ber: N ot a p plic a ble  
Cl i nic al St u d y Pr ot oc ol wit h A me n d me nt 0 2 Versi o n D ate: 1 6  M a rc h  2 0 2 1   
 
S p o ns or  
M o nit or  
Te va Bra n d e d P har mace utical  
Pr o d ucts R & D, I nc.  
1 4 5 Bra n d y wi n e P ark w ay,  
West C hester, Pe n ns yl va nia  1 9 3 8 0  
U nite d States  
F HI 3 6 0  
 
 
A ut h orize d Re pres e nt ati ve  
 
 
Te va Bra n d e d P har mace utical  
Pr o d ucts R & D, I nc.  
1 4 5 Bra n d y wi n e P ark w ay,  
West C hester, Pe n ns yl va nia  1 9 3 8 0  
U nite d States  
S p o ns or’s Me dic al E x pert  
S p o ns or’s S afet y Re prese nt ati ve  
 
 
N u ve ntra, I n c. ™ 
 
 
 
 
 
  
Gl o bal Patie nt  Safet y & 
P har mac o vi gila nce  
Te va Bra n d e d P har mace utical  
Pr o d ucts R & D, I nc.  
Tel: 
 
T his cli nical st u d y will be c o n d ucte d i n acc or da nce wit h c urre nt G o o d Cli nical Practice ( G C P) as directe d 
b y t he pr o visi o ns of t he I nter nati o nal C o u ncil f or Har m o nisati o n (I C H); U nite d States ( U S) C o de of 
Fe deral Re g ulati o ns ( C F R), a n d E ur o pea n U ni o n ( E U) Directi ves a n d Re g ulati o ns (as a p plica ble i n t he 
re gi o n of t he st u d y); nati o nal c o u ntr y le gislati o n; a n d t he s p o ns or’s Sta n dar d O perati n g Pr oce d ures 
( S O Ps). 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2  
C o nfi de nti alit y St ate me nt  
T his d oc u me nt c o ntai ns c o nfi de ntial a n d pr o prietar y i nf or mati o n (i ncl u di n g c o nfi de ntial c o m mercial 
i nf or mati o n p urs ua nt t o 2 1 C F R § 2 0. 6 1) a nd is a c o nfi de ntial c o m m u nicati o n of © 2 0 2 1 T e va Bra n de d 
P har mace utical Pr o d ucts R & D, I nc a n d/ or its affiliates. T he reci pie nt a grees t hat n o i nf or mati o n 
c o ntai ne d herei n ma y be p u blis he d or discl ose d wit h o ut writte n a p pr o val fr o m t he s p o ns or.  
© 2 0 2 1 T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc. Al l ri g hts reser ve d. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3  
D O C U M E N T HI S T O R Y  
 
A me n d me nt 0 2  
1 6  Marc h  2 0 2 1  
1 0 s u bj ects e nr olle d t o date  
A me n d me nt  0 1  
0 2 J ul y 2 0 2 0  
0 s u bj ects e nr olle d t o date. 
Ori gi nal Pr ot oc ol  
0 4 Marc h 2 0 2 0  
T he S u m mar y of C ha n ges t o t he Pr ot oc ol i ncl u des t he c orres p o n di n g reas o n/j ustificati o n f or 
eac h c ha n ge a n d is pr o vi de d i n Secti o n 1 7 .   
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4  
S P O N S O R P R O T O C O L A P P R O V A L  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
A Ra n d o mize d, D ose -ra n ge Fi n di n g St u d y t o E val uate P har mac o ki n etics of 
Me dr o x y pr o gester o ne A cetate F oll o wi n g a Si n gle S u bc uta ne o us A d mi nistrati o n of T V -4 6 0 4 6 i n 
Healt h y W o me n of Re pr o d ucti ve A ge  
 
Versi o n Date: 1 6  M arc h  2 0 2 1  
 
I h a ve rea d t he pr ot oc ol wit h A me n d me nt 0 2 a n d a p pr o ve t he desi g n of t his st u d y.  
 
S p o ns or’s A ut h orize d 
Re prese nt ati ve  
 
 
 
 
 
 
Si g n at ure  
D ate  
E xec ute d si g n at ure p a ges are m ai nt ai ne d wit hi n t he Tri al M aster File  
 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5  
I N V E S TI G A T O R A G R E E M EN T  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
A Ra n d o mize d, D ose -ra n ge Fi n di n g St u d y t o E val uate P har mac o ki n etics of 
Me dr o x y pr o gester o ne A cetate F oll o wi n g a Si n gle S u bc uta ne o us A d mi nistrati o n of T V -4 6 0 4 6 i n 
Healt h y W o me n of Re pr o d ucti ve A ge  
Versi o n Date: 1 6  M arc h  2 0 2 1  
Pri nci p al I n vesti g at or:   
Title:  
 
A d dress of I n vesti g ati o n al Ce nter:  
 
 
 
 
 
Tel:  
 
I h a ve rea d t he pr ot oc ol wit h A me n d me nt 0 2 a n d a gree t h at it c o ntai ns all necessar y details f or 
carr yi n g o ut t his st u d y. I a m q ualifie d b y e d ucati o n, e x perie nce, a n d trai ni n g t o c o n d uct t his 
cli nical researc h st u d y. T he si g nat ure bel o w c o nstit utes a gree m e n t wit h t his pr ot oc ol a n d 
attac h me nts, a n d pr o vi d es ass ura nce t hat t his st u d y will be c o n d u cte d acc or di n g t o all 
sti p ulati o ns of t he pr ot oc ol, i ncl u di n g all state me nts re gar di n g c o nfi de ntialit y, a n d acc or di n g t o 
nati o nal or l ocal le gal a n d re g ulat or y re q uir e me nts a n d a p plica ble re g ulati o ns a n d g ui d eli nes.  
I will ma ke a vaila ble t h e pr ot oc ol a n d all i nf or mati o n o n t he i n vesti gati o nal me dici nal pr o d uct 
(I M P) t hat were f ur nis he d t o me b y t he s p o ns or t o all p h ysicia ns a n d ot her st u d y pers o n nel 
re p orti n g t o me w h o parti ci pate i n t his st u d y a n d will disc uss t his material wit h t he m t o e ns ure 
t hat t he y are f ull y i nf or me d re gar di n g t he I M P a n d t he c o n d uct of t he st u d y. I a gree t o kee p 
rec or ds o n all s u bject i nf or mati o n, I M P s hi p me nt a n d ret ur n f or ms, a n d all ot her i nf or mati o n 
c ollecte d d uri n g t he st u d y, i n a cc or da nce wit h nati o nal a n d l ocal G o o d Cli nical Practice ( G C P) 
re g ulati o ns as well as all ot her nati o nal a n d i nter n ati o nal la ws a n d re g ulati o ns. 
Pri nci p al I n vesti g at or 
 
 
Si g n at ure  
D ate  
E xec ute d si g n at ure p a ges are m ai nt ai ne d wit hi n t he I n vesti g at or Site File a n d t he Tri al 
M aster File  
 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6  
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S  
Wit h A me n d me nt 0 2  
St u d y: T V 4 6 0 4 6 -W H -1 0 1 5 9  
Title of St u d y: A Ra n d o mize d, D ose -ra n ge Fi n di n g St u d y t o E v al uate P har mac o ki netics of 
Me dr o x y pr o gester o ne A c etate F oll o wi n g a Si n gle S u bc uta ne o us A d mi nistrati o n of T V -4 6 0 4 6 i n 
Healt h y W o me n of Re pr o d ucti ve A ge   
S p o ns or:  Te va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
I n vesti g ati o n al Ne w Dr u g (I N D) N u m ber: 1 2 6 2 4 9  
N a me of Test I n vesti g ati o n al Me dici n al Pr o d uct (I M P): de p ot me dr o x y pr o gester o ne acetate 
( D M P A [ T V-4 6 0 4 6])  
Acti ve S u bst a nce : me dr o x y pr o gester o n e acetate ( M P A)  
E u dr a Vi gil a nce ( E V) c o de f or t he I M P: N ot A p plic a ble  
T y pe of St u d y:  P har mac o ki netic ( P K) St u d y  
P h ase of Cli nic al De vel o p me nt:  1  
N u m ber of I n vesti g ati o n al Ce nters Pl a n ne d: 3 i n vesti gati o nal ce nters  
C o u ntries Pl a n ne d: U nite d States of A merica, D o mi nica n Re p u blic  
Pl a n ne d St u d y Peri o d: T he st u d y is e x pecte d t o start i n Q uarter 0 4 2 0 2 0 (first s u bject scree ne d) 
a n d ha ve a d urati o n peri o d  of a p pr o xi matel y 2 6 m o nt hs (t hr o u g h last s u bject o ut).  
Pri m ar y O bjecti ve(s): T he pri mar y o bjecti ve of t his st u d y is t o e v al uate a n d c o m pare t he 
p har mac o ki netic pr ofile of M P A f oll o wi n g s u bc uta ne o us a d mi nistrati o n of 3 d oses of T V -4 6 0 4 6 
3 0 0 m g/ m L ( 1 2 0 m g/ 0 . 4 m L; 1 8 0 m g/ 0. 6 m L; 2 4 0 m g/ 0. 8 m L), a n d 1 0 4 m g/ 0. 6 5 m L of De p o-
s u b Q Pr o vera i n he alt h y fe male s u bjects. 
Sec o n d ar y O bjecti ve(s):  T he sec o n d ar y o bjecti ves of t he st u d y are t o e val uate a n d c o m p are t he 
safet y, l ocal t olera bilit y, a n d acce pta bilit y of a s u b c uta ne o us i njecti o n of 3 d oses of  
T V -4 6 0 4 6 3 0 0 m g/ m L ( 1 2 0 m g/ 0. 4 m L; 1 8 0 m g/ 0. 6 m L; 2 4 0 m g/ 0. 8 m L) a n d 1 0 4 m g/ 0. 6 5 m L of 
De p o -s u b Q Pr o vera i n he alt h y fe male s u bjects. 
Ge ner al St u d y Desi g n a n d Met h o d ol o g y:  T his is a ra n d o mize d, partiall y -bli n de d d ose -ra n ge 
fi n di n g st u d y t o e val uat e a n d c o m pare t he p har mac o ki netics of M P A, safet y, l ocal t olera bilit y, 
a n d acce pta bilit y of t he si n gle s u bc uta ne o us a d mi nistrati o n of 3 d oses of T V -4 6 0 4 6 3 0 0 m g/ m L 
( 1 2 0 m g/ 0. 4 m L, 1 8 0 m g/ 0. 6 m L or 2 4 0 m g/ 0. 8 m L), a n d 1 0 4 m g/ 0. 6 5 m L of De p o-s u b Q 
Pr o vera i n he alt h y fe mal e s u bjects of re pr o d ucti v e a ge. T h e ulti mate g o al is t o select f or f urt her 
i n vesti gati o n a d ose of T V-4 6 0 4 6 t hat is b ot h safe a n d well t olerate d, a n d h as a P K pr ofile 
c o nsiste nt wit h c o ntrace pti ve pr otecti o n w he n i njecte d s u bc uta ne o usl y e ver y 6 m o nt hs.  
St u d y p artici pati o n will c o nsist of a scree ni n g p eri o d ( a p pr o xi matel y 1. 5 m o nt hs, or 6 wee ks), 
treat me nt i nitiati o n ( Da y 0) a n d f oll o w-u p ( u p t o 1 8 m o nt hs or 7 8 wee ks).  
 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7  
I n vesti g ati o n al Me dici n al Pr o d ucts (I M Ps): D ose, P h ar m aceuti c al F o r m, R o ute of 
A d mi nistr ati o n, a n d A d mi nistr ati o n R ate  
Test I M P:  T V -4 6 0 4 6 ( Me dr o x y pr o gester o ne acetate i njecta ble s us p e nsi o n 3 0 0 m g/ m L)   
Refere nce I M P: D e p o – s u b Q Pr o vera 1 0 4 ®  ( Me dr o x y pr o gester o n e acetate i njecta ble 
s us pe nsi o n [ 1 0 4 m g/ 0. 6 5 m L f or s c use]) 
St u d y P o p ul ati o n a n d N u m ber of S u bjects Pl a n ne d:  A p pr o xi matel y si xt y ( 6 0) h ealt h y fe m ale 
s u bjects of re pr o d ucti ve a ge at l o w ris k of pre g na nc y wit h n o c o ntrai n dicati o ns f or M P A -
c o ntai ni n g pr o d u cts will be ra n d o mize d t o 1 of 3 d oses of T V -4 6 0 4 6 3 0 0 m g/ m L ( 1 2 0, 1 8 0, 2 4 0 
m g) or 1 d os e of De p o -s u b Q Pr o vera ( 1 0 4 m g/ 0. 6 5 m L) (a p pr o xi matel y 1 5 w o me n per gr o u p).  
D ur ati o n of S u bject P a rtici p ati o n:  T otal d urati o n of t he st u d y f or eac h s u bj ect is e x pecte d t o 
be a p pr o xi matel y 1 9. 5 m o nt hs, i ncl u di n g a p pr o xi matel y 1. 5 m o nt hs of scree ni n g a n d u p t o 1 8 
m o nt hs of f oll o w -u p after st u d y tr eat me nt i nitiati o n.  
M ai n Criteri a f or I ncl usi o n: S u bjects ma y be i n cl u de d i n t he st u d y o nl y if t he y m eet all of t he 
st u d y i ncl usi o n criteri a. T he mai n i ncl usi o n criteria are:  
a. willi n g a n d ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt  
b.  fe male of 1 8 t o 4 5 years of a ge (i n cl usi ve) 
c. healt h y b ase d o n res ults of p h ysic al e xa mi nati o n, me dical hist or y, vital si g ns tests, 
a n d Pa p s mear res ults 
d.  has re g ular m e nstr ual c ycle ( 2 1 t o 3 5 da ys)  
e. has a l o w ris k of pre g na n c y (ie, sterilize d, i n e xcl usi vel y sa me -se x part ners hi p, 
a bsti ne nt, i n m o n o ga m o us relati o ns hi p wit h vasect o mize d part ner, usi n g n o n -
h or m o nal i ntra uteri ne d e vice (I U D), or c o nsiste ntl y usi n g barrier met h o ds of 
c o ntrace pti o n)  
f. ha d a n or mal ma m m o gra m wit hi n t he last year, if 4 0 years of a ge or ol d er  
g.  has a b o d y mass i n de x ( B MI) of 1 8 t o 3 5, i ncl usi ve  
h.  has he m o gl o bi n ≥1 0. 5 g/ d L  
i. is willi n g a n d a ble t o c o m pl y wit h all st u d y re q uire me nts a n d ret ur n t o t he 
i n vesti gati o nal c e nter f or t he f oll o w-u p pr oce d ures a n d assess me nts as s pecifie d i n 
t his pr ot oc ol 
M ai n Criteri a f or E xcl usi o n: S u bjects will be e xcl u de d fr o m partici pati n g i n t his st u d y if t he y 
meet a n y of t he st u d y e x cl usi o n  criteria. T h e mai n e x cl usi o n criteria are:  
a. has h y p erte nsi o n wit h:  
○ s yst olic bl o o d press ur e  (B P ) ≥1 6 0  m m H g or diast olic B P ≥1 0 0  m m H g  
○ vasc ular dise ase  
b.  has a n a b n or m al Pa p res ult t hat re q uires treat me nt or i n t he o pi ni o n of a n i n vesti gat or 
w o ul d ma ke st u d y p artici pati o n u nsafe or c o m plicate data i nter pretati o n   
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
8  
c. has m ulti ple ris k fact ors f or car di o v asc ular dise ase (e g, s m o ki n g, o b esit y, 
h y perte nsi o n, k n o w n l o w hi g h de nsit y li p o pr otei n [ H D L ], hi g h l o w de nsit y 
li p o pr otei n [L D L ], or hi g h tri gl yceri de le vels) 
d.  has c urre nt or hist or y of isc he mic heart disease  
e. has acti ve t hr o m b o p hle bitis, c urre nt or past hist or y of t hr o m b o e m b olic dis or ders, 
cere bral vas c ular dise ase or str o ke  
f. has s yste mic l u p us er yt h e mat os us  
g.  has r he u mat oi d art hritis o n i m m u n os u p pressi ve t hera p y  
h.  h as u ne x plai ne d va gi n al blee di n g  
i. has dia betes  
j. has str o n g fa mil y hist or y of breast c a ncer ( d efi ne d as o ne or m ore first de gree 
relati ves wit h breast ca n cer, breast ca n cer occ urri n g bef ore m e n o pa use i n t hree or 
m ore fa mil y me m bers, re gar dless of de gree of rel ati o ns hi p, a n d a n y male fa mil y 
me m ber wit h breast ca ncer), or  
k.  has c urre nt or hist or y of breast c a ncer, or u n dia g n ose d mass detecte d b y breast e x a m  
l. has c urre nt or hist or y of cer vical ca n cer  
m.  has cirr h osis or li ver t u m ors  
n.  has o ne or m ore baseli ne li ver f u nct i o n test(s) o utsi de t he l ocal la b orat or y’s n or mal 
ra n ge 
o.  has k n o w n oste o p or osis or oste o pe nia  
p.  has hist or y of di a g n ose d cli nical de pressi o n or bi p olar dis or der, wit h or wit h o ut 
s uici dal i deati o n, a n d/ or hist or y of s uici de atte m pt, e x ce pt s h ort-li ve d sit uati onal 
de pressi o n t hat di d n ot re q uire me dicati o n a n d h as n ot rec urre d i n last fi ve years  
q.  has hist or y of ps yc hiatric dis or der t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d ma ke 
st u d y partici p ati o n u nsafe, w o ul d i nterfere wit h a d here nce t o st u d y re q uir e me nts or 
c o m plicate data i nter pret ati o n  
r. use d M P A -c o ntai ni n g i njecta ble pr o d u cts i n t he past 1 2 m o nt hs  
s. use d a c o m bi ne d i nject a ble c o ntrace pti ve i n t he past 6  m o nt hs  
t. use d a n y of t he f oll o wi n g me dicati o ns wit hi n 1 m o nt h pri or t o e nr oll me nt:  
○ a n y i n v esti gati o nal dr u g  
○ pr o hi bite d dr u gs p er pr ot oc ol  
○ oral c o ntrace pti ves, c o ntrace pti ve ri n g or patc h  
○ le v o n or gestrel i ntra ut eri n e s yste m ( L N G I U S) or c o ntrace pti ve i m pla nt 
u.  is partici pati n g i n a n ot her cli nical trial  
v.  is pre g n a nt 
w.  desires t o bec o me pre g n a nt i n s u bse q ue nt 2 4 m o nt hs  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
9  
x.  has bee n pre g na nt i n last 3 m o nt hs  
y.  is c urre ntl y lactati n g 
z. is usi n g or pla n ni n g t o use pr o hi bite d dr u gs per pr ot oc ol i n t he ne xt 1 2 m o nt hs 
aa.  has k n o w n se nsiti vit y t o M P A or i nacti ve i n gre die nts  
b b.  pla ns t o  m o ve t o a n ot her l ocati o n i n t he ne xt 1 2 m o nt hs  
cc.  has a n y c o n diti o n (s ocial or me dical), w hi c h i n t he o pi ni o n of t he i n vesti gat or w o ul d 
ma ke st u d y p artici pati o n u nsafe, w o ul d i nterfere wit h a d here nce t o t he cli ni cal st u d y 
re q uire me nts or c o m plicate data i nter pretati o n 
St u d y E v al u ati o ns  
P h ar m a c o ki netic Assess me nts:  Bl o o d s a m ples (a p pr o xi matel y 5 m L) will be c ollecte d bef ore 
a n d u p t o 5 2 wee ks ( 3 6 5 da ys) after I M P a d mi nistrati o n f or t he det er mi nati o n of ser u m M P A.  
S afet y Assess me nts:  Safet y a n d l ocal t olera bilit y e val uati o n will be base d o n t he f oll o wi n g:  
•  occ urre nce of a d v erse e v e nts  
•  use of c o nc o mita nt me di cati o n  
•  c ha n ge i n vital si g ns a n d b o d y wei g ht  
•  va gi n al blee di n g patter n  
•  c ha n ge i n m o o d  
•  c ha n ge i n li ver f u ncti o n tests  
•  Estra di ol ( E 2) le vels  
•  dela ye d ret ur n t o o v ulati o n ( > 1 2 m o nt hs after treat me nt i nit iati o n) w here o v ulati o n is 
defi ne d as a si n gle pr o gester o ne ( P ) ≥4. 7 n g/ m L  
•  occ urre nce of i njecti o n site reacti o ns (I S Rs)  
Acce pt a bilit y assess me nts: Acce pta bilit y will be e val uat e d base d o n t he s u bject’s res p o nses t o 
acce pta bilit y q uesti o ns.  
St atistic al Met h o ds  
S a m ple Size D eter mi n ati o n: T he g oal of t he st u d y is t o select a d ose of T V -4 6 0 4 6 t hat is safe 
a n d well t olerate d, a n d h as a P K pr ofile c o nsiste nt wit h c o ntrace pti ve pr otecti o n w he n i njecte d 
e ver y 6 m o nt hs. Rec o g ni zi n g t hat t here is n o f or m al h y p ot h esis test o n w hi c h t o base sa m ple siz e 
calc ulati o ns, 1 5 s u bjects per treat me nt gr o u p (a p pr o xi matel y 6 0 i n t otal) are e x pecte d t o be 
s ufficie nt t o i nf or m d ose selecti o n base d o n d ata fr o m rece nt P K st u dies of M P A deli vere d 
s u bc uta ne o usl y. 
 
T he i nte nt of t he st u d y is t o ha ve a mi ni m u m of 5 4 s u bjects wit h e val ua ble data c o m plete 3 2 
wee ks per pr ot oc ol. A d diti o nal s u bjects ma y  b e e nr olle d t o c o m plete t he mi ni m u m n u m ber of 
e val ua ble s u bjects at t he discreti o n of t he S p o ns or.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 0  
P h ar m a c o ki netic Me as ures/ P a r a meters:  
T he f oll o wi n g pri mar y p har mac o ki netic  p ara m eters will be calc ulat e d fr o m c o nce ntr ati o n -ti me 
data:  
•  ti me t o ma xi m u m o bser ve d ser u m dr u g c o nce ntr ati o n (tma x ) 
•  ma xi m u m o bser ve d ser u m dr u g c o nce ntr ati o n  ( Cma x ) 
•  ser u m M P A c o nce ntr ati o ns at da y 9 1 ( C 9 1), da y 1 8 2 ( C1 8 2), a n d da y 2 1 0 ( C2 1 0) 
•  area u n d er t he s er u m c o n ce ntrati o n -ti me c ur ve ( A U C) fr o m ti me 0 t o da y 1 8 2  
( A U C0 -1 8 2); A U C fr o m ti me 0 t o da y 2 1 0 ( A U C0 -2 1 0); a n d A U C e xtra p olate d t o 
i nfi nit y ( A U C0 -∞) 
•  a p pare nt ter mi nal half -life (t½ ) 
A n al yses  
P h ar m a c o ki netic A n al ysis:  N o n -c o m part me ntal met h o ds will be use d t o esti mate A U C val ues 
a n d t ½ . T he ot her esti mates (tma x , Cma x , C9 1, C1 8 2, a n d C2 1 0) will be base d o n o bser ve d val u es 
w here p ossi ble. N o f or m al h y p ot hesis  tests of p har mac o ki netic dat a are pla n ne d. Para meter 
esti mates will be s u m mariz e d b y treat me nt gr o u p f or eac h d os e le vel usi n g descri pti ve statistics, 
i ncl u di n g n u m ber ( n), me a n, sta n dar d de viati o n ( S D), ge o metric m ea n, ge o metric c oefficie nt of 
variati o n , har m o nic mea n (f or t ½ ), me dia n, mi ni m u m, ma xi m u m, a n d ass ociate d 9 5 % c o nfi d e nce 
i nter vals ( CIs). Gra p hical dis pla ys will i ncl u de i n di vi d ual a n d ge o metric mea n p har mac o ki netics 
pr ofiles o n u n -tra nsf or me d a n d se mi-l o g ( base 1 0) data. Descri pti ve c o m paris o ns  of P K 
para meters bet wee n test a n d refere n ce gr o u ps will be base d o n ge o metric mea n rati os a n d 9 0 % 
CIs.  
S afet y Me as ure me nts:  
T he safet y me as ure m e nts f or t his st u d y i ncl u de:  
•  occ urre nce of a d v erse e v e nts  
•  use of c o nc o mita nt me di cati o n  
•  vital si g ns a n d b o d y wei g ht meas ure me nt  
•  va gi n al blee di n g patter n  
•  assess me nt of m o o d b y Patie nt Healt h Q uesti o n naire -9  ( P H Q-9)  
•  li ver f u ncti o n tests 
•  E 2 meas ure me nts t hr o u g h o ut t he st u d y  
•  P meas ure me nts at W ee ks 4 8, 4 9, 5 0, 5 1, a n d 5 2  
•  occ urre nce of I S Rs  
T he acce pta bilit y p ara m eters  are:  
•  s u bject’s res p o nses t o acce pta bilit y q u esti o ns 
S afet y A n al ysis: N o f or mal h y p ot hesis tests of safet y d ata are pla n ne d. All safet y data will be 
s u m marize d b y treat me nt gr o u p usi n g des cri pti ve statistics ( n, mea n, S D, sta n dar d err or, m e dia n, 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 1  
mi ni m u m, a n d ma xi m u m f or c o nti n u o us varia bl es, a n d fre q u e nc y a n d perce nta ge f or cate g ori cal 
varia bles). S pecificall y, t he n u m ber a n d p erce nta ge of s u bjects e x perie n ci n g treat me nt -e mer ge nt 
a d verse e ve nts will be prese nte d b y treat me nt gr o u p, o verall, b y se verit y gra de, a n d b y 
relate d ness t o tr eat me nt. A d verse e ve nts will be f urt her s u mmarize d i n listi n gs or fre q u e nc y 
ta bles acc or di n g t o s yste m or ga n class a n d preferre d ter m. Seri o us a d verse e ve nts a n d a d v erse 
e ve nts lea di n g t o wit h dra wal fr o m t he st u d y will be liste d se parat el y. C o n c o mita nt me dicati o n 
use will be s u m mariz e d b y treat me nt  gr o u p i n fre q ue nc y ta bles, b y t hera pe utic class a n d 
me dici ne cate g or y. C ha n ge i n vital si g ns ( B P [s yst olic/ diast olic], p ulse, b o d y te m perat ur e a n d 
res pirati o n) a n d b o d y wei g ht fr o m D a y 0 t o Da y 7, Wee ks 1 3, 2 6, a n d 5 2 will be descri be d i n 
s hift ta bles. T he perce nta ge of w o me n e x perie nci n g a m e n orr h ea or va gi nal blee di n g dist ur ba nces 
(irre g ular va gi nal blee di n g or s p otti n g) will li ke wise be s u m marize d descri pti vel y a n d c o m pare d 
bet wee n tr eat me nt gr o u ps. M o o d data will be s u m marize d o ver ti me usi n g fre q ue n c y ta bles a n d 
gra p hical dis pla ys . Li ver f u ncti o n will be assesse d b y ta b ulati n g c h a n ge i n li ver f u ncti o n tests 
fr o m baseli ne t o Da y 7, Wee ks 1 3, 2 6, a n d 5 2. Rates of ret ur n t o o v ulati o n b y 1 2 m o nt hs ( Wee k 
5 2), w here o v ulati o n is defi ne d as a si n gle P  ≥4. 7 n g/ m L, will be pr o vi de d b y treat me nt gr o u p. 
Estra di ol c o nce ntr ati o ns will be s u m marize d f or eac h gr o u p usi n g mea ns, sta n dar d de viati o ns, 
a n d gra p hical dis pla ys t hr o u g h Wee k 5 2. T he I S R data will be pr o vi de d b y gr o u p i n fre q u e nc y 
ta bles (if a p plica bl e) a n d usin g s u bject -d ata listi n gs. T he res p o nses t o acce pta bilit y q u esti o ns will 
be descri pti vel y c o m p are d bet wee n tr eat me nt gr o u ps.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 2  
T A B L E O F C O N T E N T S  
TI T L E P A G E  ...................................................................................................................................1  
D O C U M E N T HI S T O R Y .................................................................................................................3  
S P O N S O R P R O T O C O L A P P R O V A L  ...........................................................................................4  
I N V E S TI G A T O R A G R E E M EN T ...................................................................................................5  
C LI NI C A L S T U D Y P R O T O C O L S Y N O P SI S ...............................................................................6  
LI S T O F T A B L E S  .........................................................................................................................1 6  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F  T E R M S  ................................................1 8  
1.  
B A C K G R O U N D I N F O R M A TI O N  ...........................................................................2 0  
1. 1.  
I ntr o d u cti o n .................................................................................................................2 0  
1. 2.  
Fi n di n gs fr o m N o ncli nic al a n d Cli nical St u dies  .........................................................2 0  
1. 2. 1.  
N o ncli nical St u dies  .....................................................................................................2 0  
1. 2. 2.  
Cli nical St u dies  ...........................................................................................................2 0  
1. 2. 2. 1.  
Cli nical P har mac ol o g y St u dies  ...................................................................................2 0  
1. 2. 2. 2.  
Cli nical Efficac y a n d Safet y St u dies  ..........................................................................2 1  
1. 3.  
K n o w n a n d P ote ntial Be nefits a n d Ris ks  ....................................................................2 1  
1. 3. 1.  
O verall P ote ntial Be nefits a n d Ris ks  ..........................................................................2 1  
1. 3. 2.  
K n o w n a n d P ote ntial Ris ks of T V -4 6 0 4 6  ...................................................................2 2  
1. 4.  
St u d y Desi g n Rati o nale  ..............................................................................................2 2  
1. 4. 1.  
Ge neral St u d y D esi g n Rati o nale  .................................................................................2 2  
1. 4. 2.  
D osa ge Rati o nale  ........................................................................................................2 2  
2.  
S T U D Y O BJ E C TI V E S A N D M E A S U R E S/ P A R A M E T E R S  ...................................2 4  
2. 1.  
Pri mar y a n d Sec o n dar y St u d y O bjecti ves a n d Meas ures/ Para meters  ........................2 4  
3.  
I N V E S TI G A TI O N A L P L A N .....................................................................................2 5  
3. 1.  
Ge neral St u d y D esi g n  .................................................................................................2 5  
3. 2.  
S u bject Eli gi bilit y  .......................................................................................................2 5  
3. 2. 1.  
S u bject I n cl usi o n Criteria  ...........................................................................................2 5  
3. 2. 2.  
S u bject E x cl usi o n Criteria  ..........................................................................................2 6  
3. 3.  
D urati o n of S u bject Parti ci pati o n  ...............................................................................2 7  
3. 4.  
St u d y Pr oce d ures  ........................................................................................................2 7  
3. 4. 1.  
Pr oce d ures f or Scree ni n g  ............................................................................................3 0  
3. 4. 2.  
Pr oce d ures f or E nr oll me nt ( Da y 0)  .............................................................................3 0  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 3  
3. 4. 3.  
Pr oce d ures f or F oll o w -U p  ..........................................................................................3 0  
3. 4. 4.  
U nsc he d ule d Pr oce d ures a n d Visits  ............................................................................3 1  
4.  
T R E A T M E N T O F S U BJ E C T S  ..................................................................................3 2  
4. 1.  
I n v esti gati o nal Me dici nal Pr o d ucts A d mi nistere d D uri n g t h e St u d y .........................3 2  
4. 1. 1.  
Test I n v esti gati o nal Me dici nal Pr o d uct  ......................................................................3 2  
4. 1. 2.  
Refere n ce I n vesti gati o nal Me dici nal Pr o d uct  .............................................................3 2  
4. 2.  
Treat me nt of S u bjects  .................................................................................................3 2  
4. 3.  
Bli n di n g/ U n bli n di n g  ...................................................................................................3 3  
4. 3. 1.  
U n bli n di n g D uri n g t he St u d y ......................................................................................3 4  
4. 4.  
St o p pi n g R ules a n d Disc o nti n uati o n Criteria  .............................................................3 4  
4. 5.  
I nteri m Data Re vie ws .................................................................................................3 5  
4. 6.  
Pri or a n d C o nc o mita nt T hera p y or Me dicati o n  ..........................................................3 5  
4. 7.  
Pr oce d ures f or M o nit ori n g S u bject C o m plia nce  ........................................................3 5  
4. 8.  
T otal Bl o o d V ol u me  ...................................................................................................3 5  
4. 9.  
Wit h d ra wal of S u bjects ...............................................................................................3 6  
4. 9. 1.  
S u bject Wit h dra wal Criteria a n d Pr oce d ures  ..............................................................3 6  
4. 9. 2.  
L ost t o F oll o w -u p  .......................................................................................................3 6  
5.  
S A F E T Y M E A S U R E M E N T S A N D A S S E S S M E N T S  .............................................3 8  
5. 1.  
Safet y a n d T olera bilit y Meas ure me nts  .......................................................................3 8  
5. 1. 1.  
A d verse E v e nts  ...........................................................................................................3 8  
5. 1. 2.  
C o nc o mita nt Me dicati o n Use  .....................................................................................3 8  
5. 1. 3.  
Vital Si g ns a n d B o d y Wei g ht Meas ure me nt  ..............................................................3 8  
5. 1. 4.  
Assess me nt of Va gi nal Blee di n g  ................................................................................3 9  
5. 1. 5.  
Assess me nt of M o o d  ...................................................................................................3 9  
5. 1. 6.  
L i ver F u n cti o n Tests ...................................................................................................3 9  
5. 1. 7.  
Estra di ol Meas ure m e nt  ...............................................................................................3 9  
5. 1. 8.  
Assess me nt of Ret ur n t o O v ulati o n at 5 2 Wee ks  .......................................................4 0  
5. 1. 9.  
I nje cti o n Site Reacti o ns ..............................................................................................4 0  
5. 1. 1 0.  
P h ysical E x a mi nati o ns  ................................................................................................4 1  
5. 2.  
Safet y Assess me nts  .....................................................................................................4 1  
5. 2. 1.  
Defi niti o n of a n A d verse E ve nt  ..................................................................................4 1  
5. 2. 2.  
Rec or di n g a n d Re p orti n g A d verse E v e nts  ..................................................................4 2  
5. 2. 3.  
Se verit y of a n A d v erse E ve nt  .....................................................................................4 2  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 4  
5. 2. 4.  
Relati o ns hi p of a n A d verse E ve nt t o t he I M P  ............................................................4 3  
5. 2. 5.  
Seri o us A d verse E v e nts  ..............................................................................................4 3  
5. 2. 5. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  .......................................................................4 3  
5. 2. 5. 2.  
E x pecte d ness  ...............................................................................................................4 4  
5. 2. 5. 3.  
Seri o us A d verse E v e nt Ma na ge me nt Pla n  ..................................................................4 4  
5. 2. 6.  
Pr ot oc ol Defi ne d A d v ers e E ve nts f or E x pe dite d Re p orti n g  .......................................4 6  
5. 2. 7.  
Me dicati o n Err or a n d S pecial Sit uati o ns Relat e d t o t he I n v esti gati o nal 
Me dici nal Pr o d ucts  .....................................................................................................4 6  
5. 2. 8.  
Pr ot oc ol De viati o ns Beca use of a n A d verse E v e nt  ....................................................4 7  
5. 2. 9.  
Pre g n a nc y  ...................................................................................................................4 7  
6.  
P H A R M A C O KI N E TI C  M E A S U R E M E N T S A N D A S S E S S M E N T S ......................4 8  
6. 1.  
Ti mi n g of P har ma c o ki netic Sa m pli n g  ........................................................................4 8  
6. 2.  
P har mac o ki netic Para meters  .......................................................................................4 8  
7.  
P H A R M A C O D Y N A M I C M E A S U R E M E N T S A N D A S S E S S M E N T S  ..................4 9  
7. 1.  
P har mac o d y na mics  .....................................................................................................4 9  
8.  
A C C E P T A BI LI T Y A S S E S S M E N T S  ........................................................................5 0  
9.  
S T A TI S TI C S  ..............................................................................................................5 1  
9. 1.  
Sa m ple Siz e Det er mi nati o n a n d Rati o nale  .................................................................5 1  
9. 2.  
Met h o d of Ra n d o miz ati o n a n d Bli n di n g  ....................................................................5 1  
9. 3.  
A nal ysis Sets  ...............................................................................................................5 2  
9. 3. 1.  
Scree ne d A nal ysis Set  .................................................................................................5 2  
9. 3. 2.  
Ra n d o mize d A nal ysis Set  ...........................................................................................5 2  
9. 3. 3.  
Safet y A nal ysis Set  .....................................................................................................5 2  
9. 3. 4.  
P har mac o ki netic A n al ysis Set  ....................................................................................5 2  
9. 4.  
Data Ha n dli n g C o n ve nti o ns  ........................................................................................5 2  
9. 4. 1.  
Ha n dli n g Wit h dra wals a n d Missi n g Data  ...................................................................5 2  
9. 5.  
St u d y P o p ulati o n  .........................................................................................................5 2  
9. 5. 1.  
S u bject Dis p ositi o n  .....................................................................................................5 3  
9. 5. 2.  
De m o gra p hics, C o ntrace pti ve a n d Re pr o d ucti ve Hist or y  ..........................................5 3  
9. 6.  
Safet y A nal ysis  ...........................................................................................................5 3  
9. 7.  
P har mac o ki netic A n al ysis  ..........................................................................................5 4  
9. 8.  
Acce pt a bilit y A nal ysis  ................................................................................................5 5  
9. 9.  
Pla n ne d I nteri m A nal ysis  ............................................................................................5 5  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 5  
1 0.  
I N V E S TI G A TI O N A L M E DICI N A L P R O D U C T I N F O R M A TI O N  ........................5 6  
1 0. 1.  
I n v esti gati o nal Me dici nal Pr o d uct St ora ge a n d Sec urit y ............................................5 6  
1 0. 2.  
I n v esti gati o nal Me dici nal Pr o d uct Acc o u nta bilit y  .....................................................5 6  
1 1.  
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  .........................................5 7  
1 1. 1.  
Pr ot oc ol A me n d me nts, Pr ot oc ol De viati o ns, a n d I m p orta nt Pr ot oc ol 
De viati o ns  ...................................................................................................................5 7  
1 1. 1. 1.  
Pr ot oc ol A me n d me nts  ................................................................................................5 7  
1 1. 1. 2 . 
I m p ort a nt Pr ot oc ol De viati o ns ....................................................................................5 7  
1 1. 2.  
St u d y M o nit ori n g  ........................................................................................................5 7  
1 1. 3.  
Cli nical Pr o d uct C o m plai nts  .......................................................................................5 8  
1 1. 3. 1.  
Pr o d uct C o m plai nt I nf or mati o n Nee de d fr o m t he I n v esti gati o nal Ce nter  ..................5 8  
1 1. 3. 2.  
Ha n dli n g t he Pr o d u ct C o m plai nt I M P at t he I n vesti gati o nal Ce nter  ..........................5 9  
1 1. 3. 3.  
D oc u me nti n g a Pr o d uct C o m plai nt  ............................................................................5 9  
1 1. 4.  
Data Q ualit y C o ntr ol  ...................................................................................................5 9  
1 1. 5.  
A u dit a n d I ns pecti o n  ...................................................................................................6 0  
1 2.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ..........................................6 1  
1 2. 1.  
Healt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o nal Re vie w 
B oar ds  .........................................................................................................................6 1  
1 2. 2.  
I nf or me d C o nse nt .......................................................................................................6 1  
1 2. 3.  
S u bject C o nfi de ntialit y  ...............................................................................................6 2  
1 2. 4.  
Declarati o n of t he E n d of t he Cli nical St u d y  ..............................................................6 2  
1 2. 5.  
Re gistrati o n of t he Cli nical St u d y ...............................................................................6 2  
1 3.  
S T U D Y D O C U M E N T A TI O N  ...................................................................................6 3  
1 3. 1.  
S o urce Data a n d Case Re p ort F or ms  ..........................................................................6 3  
1 3. 2.  
Arc hi vi n g of St u d y D o c u me ntati o n  ............................................................................6 3  
1 3. 2. 1.  
F HI 3 6 0 Res p o nsi bilities  ............................................................................................6 3  
1 3. 2. 2.  
I n v esti gat or Res p o nsi bilities .......................................................................................6 3  
1 4.  
FI N A N CI N G A N D I N S U R A N C E  .............................................................................6 5  
1 5.  
R E P O R TI N G A N D P U B LI C A TI O N O F R E S U L T S  ................................................6 6  
1 6.  
R E F E R E N C E S  ...........................................................................................................6 7  
1 7.  
S U M M A R Y O F  C H A N G E S T O P R O T O C O L  .........................................................6 8  
1 7. 1.  
Pr ot oc ol A me n d me nt 0 2 Date d 1 6 Marc h 2 0 2 1  .........................................................6 8  
1 7. 2.  
Pr ot oc ol A me n d me nt 0 1 Date d 0 2 J ul y 2 0 2 0  .............................................................7 5  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 6  
A P P E N DI X  A.  S T U D Y R E S P O N SI BI LI TI E S  ..........................................................................8 3  
A P P E N DI X  B.  S P E CI M E N S A M P LI N G A N D H A N D LI N G  ..................................................8 5  
LI S T O F T A B L E S  
Ta ble  1:  
St u d y Pr oce d ures a n d Assess me nts  ............................................................................2 8  
Ta ble  2:  
Tar get Ti me Wi n d o ws f or F oll o w -u p Visits  ..............................................................3 1  
Ta ble  3:  
I n v esti gati o nal Me dici nal Pr o d ucts Use d i n t he St u d y ...............................................3 3  
Ta ble  4:  
A p pr o xi mate Bl o o d V ol u mes  .....................................................................................3 6  
 
 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 7  
LI S T O F FI G U R E S  
Fi g ure  1:  
O verall St u d y Sc h e matic Dia gra m  .............................................................................2 5  
 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 8  
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   
A b bre vi ati o n  
Ter m  
A E  
a d verse e ve nt  
A L P  
al kali ne p h os p hatase  
A L T  
ala ni ne a mi n otra nsferase  
A S T  
as partate a mi n otra nsferase  
A U C  
area u n der t he ser u m dr u g c o nce ntrati o n -ti me c ur ve 
A U C 0 – 1 8 2 
area u n der t he ser u m c o nce ntr ati o n -ti me c ur ve fr o m ti me 0 t o da y 1 8 2 
A U C 0 – 2 1 0 
area u n der t he ser u m c o nce ntr ati o n -ti me c ur ve fr o m ti me 0 t o da y 2 1 0 
A U C 0 -∞  
area u n der t he ser u m c o nce ntr ati o n -ti me c ur ve e xtra p olate d t o i nfi nit y  
B P  
b l o o d press ure 
B MI  
b o d y mass i n de x  
C D M S  
cli nical data ma na ge me nt s yst e m  
C F R  
C o de of Fe deral Re g ulati o ns ( U S)  
CI  
c o ntrace pti ve i nj ecti o n  
C 9 1 
ser u m M P A c o nce ntrati o n at da y 9 1 
C 1 8 2 
ser u m M P A c o nce ntrati o n at da y 1 8 2 
C 2 1 0 
ser u m M P A c o nce ntrati o n at da y 2 1 0 
C ma x  
ma xi m u m o bser ve d ser u m dr u g c o nce ntrati o n  
C R F  
case re p ort f or m  
D M P A  
de p ot me dr o x y pr o gester o ne acetate  
E 2  
estra di ol  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
G C P  
G o o d Cli nical Practice  
G L P  
G o o d La b orat or y Practice  
H D L  
hi g h de nsit y li p o pr otei n  
I B 
I n vesti gat or’s Br oc h ure  
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 H ar m o nisati o n 
I E C 
I n de p e n de nt Et hics C o m mitte e 
I M P 
i n vesti gati o nal me dici nal pr o d uct 
I R B 
I nstit uti o nal Re vie w B oar d  
I S R 
I nj ecti o n site reacti o n  
I U D 
i ntra uteri ne de vice 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
1 9  
A b bre vi ati o n  
Ter m  
L D L  
l o w de nsit y li p o pr otei n 
M P A  
me dr o x y pr o gester o ne acetate  
P  
pr o gester o ne  
P H Q -9  
P atie nt Healt h Q uesti o n naire -9   
P K  
p har mac o ki netics  
S D  
sta n dar d de viati o n 
S O P  
sta n dar d o perati n g pr oce d ure  
S M P  
Seri o us A d verse E ve nt Ma na ge me nt Pla n  
S R C  
St u d y Re vie w C o m mittee  
S U S A R  
s us pecte d u ne x pecte d seri o us a d verse reacti o n  
t1/ 2 
a p pare nt ter mi nal half -life  
tma x  
ti me t o ma xi m u m ser u m o bser ve d dr u g c o nce ntrati o n 
U L N  
u p per li mit of t he n or mal ra n ge  
U S( A)  
U nite d States ( of A merica)  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 0  
1.  
B A C K G R O U N D I N F O R M A TI O N  
1. 1.  
I ntr o d ucti o n  
Te va a n d F HI 3 6 0 are i n c olla b orati o n t o de vel o p T V -4 6 0 4 6, a f or m ulati o n of de p ot 
me dr o x y pr o gester o ne acetate  ( D M P A), f or t he pre ve nti o n of pre g n a nc y w he n i njecte d e v er y 
6  m o nt hs. De p o -s u b Q Pr o vera 1 0 4 a n d De p o Pr o vera C o ntrace pti ve I njecti o n ( CI ) are t he 
2  pr o p ose d liste d dr u gs f or t he T V -4 6 0 4 6 d e vel o p me nt pr o gra m. M ore d etaile d i nf or mati o n is 
pr o vi de d i n t he c ur re nt v ersi o n of t he I n v esti gat or’s Br oc h ure (I B). 
T he o bjecti ve of t his st u d y is t o e val uat e a n d c o m p are t he p har mac o ki netic pr ofile of 
me dr o x y pr o gester o ne acetate ( M P A), safet y a n d l ocal t olera bilit y, a n d acce pta bilit y f oll o wi n g 
s u bc uta ne o us a d mi nistrati on of o ne of 3 d oses of T V -4 6 0 4 6 or De p o -s u b Q Pr o vera 1 0 4 i n 
healt h y fe male s u bj ects.  
1. 2.  
Fi n di n gs fr o m N o ncli nic al a n d Cli nic al St u dies  
Brief s u m maries of n o ncli nical p har mac ol o g y, p h ar mac o ki netic, t o xic ol o g y, a n d cli nical st u dies 
are pr o vi d e d i n t he f oll o wi n g  secti o ns. M ore detaile d i nf or mati o n is pr o vi de d i n t he c urre nt 
versi o n of t he I B.  
1. 2. 1.  
N o ncli nic al St u dies  
De p ot me dr o x y pr o gester o ne acetate  / me dr o x y pr o gester o ne acet ate ( D M P A/ M P A) has bee n 
e xte nsi vel y i n v esti gate d i n a n u m ber of a ni mal s pe cies. C o nse q ue ntl y,  t h e n o ncli nical 
p har mac ol o g y a n d t o xic ol o g y pr ofiles of D M P A/ M P A ha ve bee n well esta blis he d. P u blis he d 
n o ncli nical p har ma c ol o gi cal a n d t o xic ol o gical st u dies e val uati n g n o ncli nical bi ol o gical a n d 
t o xic ol o gical/t o xic o ki netic acti vities of D M P A are s u m marized i n t he c urre nt versi o n of t he I B 
t o s u p p ort t he c o ntrace pti o n i n dicati o n f or T V-4 6 0 4 6.  
Te va’s c urre nt n o n cli nical t o xic ol o g y pr o gra m c o nsists of 5 i n vi v o n o ncli nical st u dies: a G o o d 
La b orat or y Practice ( G L P) fe male ra b bit s u bc uta ne o us l ocal t olera n ce/ di sta nt tar get or ga n tiss ue 
e val uati o n wit h l o n g-t er m t o xic o ki netic st u d y ( St u d y D S -2 0 1 5 -0 0 9); a G L P m uri ne l ocal l y m p h 
n o de assa y st u d y ( St u d y  D S -2 0 1 5 -0 1 7); a n o n -G L P m uri ne l ocal l y m p h n o de assa y st u d y 
( St u d y D S -2 0 1 4 -0 6 4); a si n gle d ose n o n -G L P feasi bilit y  st u d y of s u bc uta ne o us i njecti o n ( St u d y 
D S -2 0 1 8 -0 0 8); a n d a n o n -G L P fe male ra b bit s u bc uta ne o us p har mac o ki neti c a n d gr oss 
t olera bilit y st u d y ( St u d y D P -2 0 1 4 -1 3 5). T he res ults of t hese st u dies are s u m marize d i n t he 
c urre nt v ersi o n of I B.  
1. 2. 2.  
Cli nic al St u dies  
1. 2. 2. 1.  
Cli nic al P h ar m ac ol o g y St u dies  
T he p har mac o ki netics ( P K) of M P A f oll o wi n g a si n gle s u bc uta ne o us i njecti o n of u n dil ute d a n d 
sali ne dil ute d 1 2 0 m g T V-4 6 0 4 6 has bee n e val uat e d i n a si n gle P hase 1 st u d y w hic h i n cl u de d 1 2 
healt h y s u bjects ( St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5). All s u bjects, e x ce pt 1 i n t he u n dil ute d T V -4 6 0 4 6 
gr o u p,  h a d ser u m M P A l e vels greater t ha n 0. 2 0 n g/ m L 2 4 h o urs after treat me nt i nitiati o n. 
Ma xi m u m o bser ve d ser u m dr u g c o nce ntr ati o n  ( Cma x ) i n t he u n dil ute d T V -4 6 0 4 6 gr o u p  a n d t he 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 1  
sali ne-dil ute d T V -4 6 0 4 6 gr o u p  were 0. 5 3 n g/ m L a n d 0. 9 7 n g/ m L, res p ecti v el y. Areas u n d er t he 
c o nce ntr ati o n c ur ve ( A U C 0 -∞) of t he u n dil ute d T V -4 6 0 4 6 gr o u p  a n d t he s ali ne-dil ute d T V -4 6 0 4 6 
gr o u p were 9 4. 5 6 da ys * n g/ m L a n d 1 1 4. 1 3 da ys * n g/ m L, res p ecti vel y. All e val ua ble s u bjects i n 
t he u n dilute d  
T V -4 6 0 4 6 gr o u p  a n d all e x ce pt 1 s u bject i n t he sali ne -dil ute d T V -4 6 0 4 6 gr o u p ha d ser u m M P A 
c o nce ntr ati o ns e x cee di n g 0. 1 0 n g/ m L o n Da y 1 8 2. T he a p pare nt half -li ves of t he u n dil ute d  
T V -4 6 0 4 6 gr o u p  a n d t h e sali ne -dil ute d T V -4 6 0 4 6 gr o u p were 8 2. 8 7 a n d 4 2. 3 4 da ys, 
res pecti vel y. 
1. 2. 2. 2.  
Cli nic al Effic ac y a n d S afet y St u dies  
T he effi cac y of T V -4 6 0 4 6 has n ot bee n e v al uate d.  
Safet y was e v al uate d i n St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5. T he safet y d ata i n dicate d t hat treat me nt 
wit h 1 2 0 m g T V -4 6 0 4 6 was well t olerat e d. N o deat h, treat me nt rel ate d seri o us a d verse e ve nt 
( S A E), or wit h dra wal d u e t o a d vers e e ve nt ( A E) occ urre d i n t his st u d y. T wel ve ( 1 0 0 %) of t he 1 2 
s u bjects re p orte d at least o ne A E d uri n g t he c o urse of t he st u d y. A t otal of 5 1 A Es occ urre d 
t hr o u g h o ut t he st u d y, t he maj ority of w hi c h ( 8 0. 4 %) occ urre d wit hi n 7. 5 m o nt hs of treat me nt 
i nitiati o n. I nj ecti o n site reacti o n (I S R) was t he m ost fre q ue ntl y re p orte d A E ( 9 [ 7 5. 0 %] s u bjects). 
T he rate of I S Rs ass ociat e d wit h s u bc uta ne o us i nj ecti o n of T V -4 6 0 4 6 a p peare d t o be hi g her 
c o m pared t o hist orical d ata o n t he a p pr o ve d D M P A pr o d ucts. H o we v er, m ost of t he I S Rs i n t he 
st u d y were mil d, tra nsie nt, a n d res ol ve d wit h o ut se q uelae. T w o s u bjects de vel o pe d s ki n 
disc ol orati o n ( h y p o pi g m e ntati o n) at t he site of i nj ecti o n. O ne s u bject d e vel o pe d 
h y p o pi g me ntati o n a p pr o xi matel y 4 m o nt hs after t he i njecti o n w hic h was still prese nt at st u d y 
e xit a p pr o xi matel y o ne year after o ns et; t he ot her s u bject de vel o pe d h y p o pi g me ntati o n 
a p pr o xi matel y 3 m o nt hs after t he i njecti o n w hic h c o m pletel y res ol ve d a p pr o xi mate l y o ne year 
after o nset.  
Vital si g ns of all b ut o ne s u bject were wit hi n n or mal ra n ges a n d re mai n e d lar gel y u n c ha n ge d 
d uri n g t he st u d y c o m p are d t o t he baseli ne. Wit h t he e x ce pti o n of o ne s u bject i n t he u n dil ute d 
T V -4 6 0 4 6 gr o u p  w h o was l ost t o f oll o w -u p o n D a y 2 0 1, all s u bjects i n b ot h gr o u ps ret ur ne d t o 
o v ulati o n wit hi n 1 5 m o nt hs of treat me nt i nitiati o n.  
1. 3.  
K n o w n a n d P ote nti al Be nefits a n d Ris ks  
1. 3. 1.  
O ver all P ote nti al Be nefits a n d Ris ks  
T he st u d y will be c o n d ucte d i n healt h y s u bjects. S u bjects will u n der g o a p h ysic al e x a m, Pa p 
s mear e v al uati o n a n d he m o gl o bi n testi n g at s cree ni n g. Li ver e nz y mes testi n g will be c o n d u cte d 
at scree ni n g a n d d uri n g t he st u d y. M o o d e v al uati o n will be c o n d ucte d at e nr oll me nt a n d d uri n g 
t he st u d y. W o me n 4 0 years of a ge or ol der will ha ve a ma m m o gra m perf or me d u nless t he y h a ve 
ha d o ne i n t he last year pri or t o e nr oll me nt. N o ot her direct healt h be nefits are e x pecte d i n t his 
st u d y p o p ulati o n. T he st u d y desi g n, i ncl usi o n/e xcl usi o n criteria, a n d pr oce d ures ha ve b ee n 
de vel o pe d i n a ma n n er t o pr ote ct s u bject safet y. T he res ults of t his st u d y m a y facilitate t he 
de vel o p me nt of a n e w l o n ger -acti n g i njecta ble c o ntrace pti ve.   
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 2  
1. 3. 2.  
K n o w n a n d P ote nti al Ris ks of T V -4 6 0 4 6  
S pecific ris ks f or T V -4 6 0 4 6 i ncl u de t he ris k of p ossi ble s ki n disc ol orati o n (i ncl u di n g 
h y p o p i g me ntati o n). A d diti o nal i nf or mati o n re gar di n g ris ks t o s u bjects ma y be f o u n d i n t he I B. 
1. 4.  
St u d y Desi g n R ati o n ale  
1. 4. 1.  
Ge ner al St u d y Desi g n R ati o n ale  
T his is a ra n d o mize d, partiall y -bli n de d d ose -ra n ge fi n di n g st u d y t o e val uat e a n d c o m pare t he 
p har mac o ki netics of  M P A, safet y a n d l o cal t olera bilit y, a n d acce pta bilit y of t he si n gle 
s u bc uta ne o us a d mi nistrati o n of 3 d oses of T V-4 6 0 4 6 3 0 0 m g/ m L ( 1 2 0 m g/ 0. 4 m L,  
1 8 0 m g/ 0. 6 m L, or a n d 2 4 0 m g/ 0. 8 m L), a n d 1 0 4 m g/ 0. 6 5 m L of De p o -s u b Q Pr o vera 1 0 4 i n 
healt h y fe male s u bj ects o f re pr o d ucti ve a ge. 
St u d y p artici pati o n will c o nsist of a scree ni n g p eri o d ( a p pr o xi matel y 1. 5 m o nt hs, or 6 wee ks), 
treat me nt i nitiati o n ( Da y 0), a n d at least 5 2 wee ks of f oll o w-u p. S u bjects wit h u nres ol ve d I S R(s) 
at W ee k 5 2 will be f oll o we d e ver y 3 m o nt hs t hr o u g h t he res ol uti o n of I S R(s) or Wee k 7 8, 
w hic he ver c o mes first. A p pr o xi matel y 6 0 eli gi ble s u bjects will be e nr olle d i nt o t he st u d y a n d 
ra n d o ml y assi g n e d i n a 1: 1: 1: 1 rati o t o recei ve o ne of t he 4 st u d y treat me nts: 1 2 0 m g/ 0. 4 m L, 
1 8 0  m g/ 0. 6  m L or 2 4 0 m g / 0. 8 m L of T V-4 6 0 4 6, or 1 0 4 m g/ 0. 6 5 m L of De p o -s u b Q Pr o vera 1 0 4 
(a p pr o xi matel y 1 5 w o me n per gr o u p). After tr eat me nt i nitiati o n, s u bjects will be f oll o we d f or 
5 2  wee ks a n d pr o vi de bl o o d sa m ples f or M P A, pr o gester o ne ( P, a n d estra di ol  ( E 2) as s h o w n i n 
Ta ble  1 . 
I n a d diti o n t o fre q ue nt la b orat or y visits t here will be f o ur sc h e d ule d f oll o w-u p visits at Wee k 1 
( Da y 7), Wee k 1 3, Wee k 2 6, a n d Wee k 5 2, d uri n g w hic h s u bjects will be e val uate d f or vital 
si g ns, b o d y wei g ht, li ver e nz y mes, a n d I S Rs. Va gi nal blee di n g patter n, acce pta bilit y, a n d m o o d 
will be assesse d t hr o u g h o ut t he st u d y at pr e defi ne d ti me p oi nts . Uri ne pre g na nc y test will be 
perf or me d p eri o dicall y a n d i nf or mati o n o n a d verse e ve nts a n d c o nc o mita nt me dici nes will be 
c ollecte d t hr o u g h o ut t he st u d y.  
T he st u d y s c he matic dia gra m is s h o w n i n Fi g ure  1 . St u d y pr oce d ures a n d assess me nts wit h 
sc he d ule d ti me p oi nts are s h o w n i n Ta ble  1 . 
1. 4. 2.  
D os a ge R ati o n ale  
T his st u d y is desi g n e d t o e val uate a n d c o m pare t he p har mac o ki netics of M P A, safet y a n d l o cal 
t olera bilit y, a n d acce pta bilit y of t h e si n gl e s u bc uta ne o us a d mi nistrati o n of o ne 3 d oses of  
T V -4 6 0 4 6 3 0 0 m g/ m L ( 1 2 0 m g/ 0. 4 m L, 1 8 0 m g/ 0. 6 m L or 2 4 0 m g/ 0. 8 m L) or 1 0 4 m g/ 0. 6 5 m L 
of De p o -s u b Q Pr o v era 1 0 4 i n healt h y fe male s u bj ects of re pr o d ucti ve a ge. T he g o al is t o select a 
d ose of T V -4 6 0 4 6 t hat is b ot h safe a n d h as P K pr ofile c o nsiste nt wit h c o ntrace pti ve pr otecti o n 
w he n i njecte d s u bc ut a ne o usl y e ver y 6  m o nt hs.  
T he select e d d ose ra n ge of T V -4 6 0 4 6 was c h ose n t o ha ve a hi g h pr o ba bilit y of brac k eti n g t h e 
d ose necess ar y t o 1) t o ac hie ve a c o m para ble ge o metric mea n 6 -m o nt h tr o u g h c o n ce ntr ati o n as 
t he 3-m o nt h tr o u g h of t h e refere n ce dr u g ( 0. 3 5 t o 0. 4 0 n g/ m L), a n d 2) t o e ns ure a l o w (e g, 5 % or 
less) ris k of ret ur n t o o v ulati o n wit hi n 7 m o nt hs of treat me nt i njecti o n. B ot h criteria are e x pecte d 
t o be met f or b y a d ose of T V-4 6 0 4 6 bet w ee n 1 2 0 m g/ 0. 4 m L a n d 2 4 0 m g/ 0. 8 m L bas e d o n 
res ults of St u d y T V 4 6 0 4 6 -W H -1 0 0 7 5  (N C T 0 2 8 1 7 4 6 4 ), St u d y 7 0 2 1 7 9 ( N C T 0 2 4 5 6 5 8 4 ), a n d t he 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 3  
P K/ P D st u dies w hic h i nf or me d t he la bel f or De p o -s u b Q Pr o vera 1 0 4  (J ai n et al 2 0 0 4, T o h et al 
2 0 0 4 ). A d ose of T V -4 6 0 4 6 i n t he selecte d ra n ge is als o e x pecte d t o be safe w he n i njecte d 
s u bc uta ne o usl y e ver y 6 m o nt hs. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 4  
2.  
 S T U D Y O B J E C TI V E S A N D M E A S U R E S/ P A R A M E T E R S  
2. 1.  
Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves a n d Me as ures/ P ar a meters  
O bjecti ves  
M e as ures/ P ar a meters  
T he pri m ar y o bjecti ve  of t his st u d y is 
t o e val uate a n d c o m pare t he 
p har mac o ki netic pr ofile of 
me dr o x y pr o gester o ne acetate  (M P A ) 
f oll o wi n g s u bc uta ne o us a d mi nistrati o n 
of 3 d oses of T V -4 6 0 4 6 3 0 0 m g/ m L 
( 1 2 0 m g/ 0. 4 m L; 1 8 0 m g/ 0. 6 m L; 2 4 0 
m g/ 0. 8 m L), a n d 1 0 4 m g/ 0. 6 5 m L of 
De p o -s u b Q Pr o vera 1 0 4 i n healt h y 
fe male s u bj ects.  
 
T he f oll o wi n g n o n -e x ha usti ve list of p har mac o ki netic para meters will be 
e val uate d t o s u p p ort t he pri mar y o bj ecti ve of t he st u d y:  
•  C ma x  ( ma xi m u m o bser ve d ser u m c o nce ntrati o n) 
•  T ma x  (ti me t o Cma x ) 
•  Ser u m M P A c o nce ntrati o ns at treat me nt da ys 9 1, 1 8 2, a n d 2 1 0 ( C
9 1, 
C 1 8 2, C2 1 0) 
•  A U C 0 -1 8 2 (area u n der t he ser u m dr u g c o nce ntrati o n-ti me c ur ve fr o m 
ti me 0 t o da y 1 8 2); A U C0 -2 1 0 ( A U C fr o m ti me 0 t o da y 2 1 0); a n d 
A U C 0 -∞ ( A U C e xtra p olate d t o i nfi nit y) 
•  A p pare nt ter mi nal  half -life (t½ ) 
T he sec o n d ar y o bjecti ves of t he st u d y 
are:  
1)  t o e val uate a n d c o m pare t he 
safet y a n d l ocal t olera bilit y of 
a s u bc uta ne o us i nj ecti o n of 3 
d oses of T V -4 6 0 4 6 3 0 0 
m g/ m L ( 1 2 0 m g/ 0. 4 m L; 1 8 0 
m g/ 0. 6 m L; 2 4 0 m g/ 0. 8 m L) 
a n d 1 0 4 m g/ 0. 6 5 m L of De p o -
s u b Q Pr o vera 1 0 4 i n healt h y 
fe male s u bj ects. 
2)  t o e val uate t he acce pta bilit y of 
a s u bc uta ne o us i nj ecti o n of 
T V -4 6 0 4 6 o ver t he ra n ge of 
differe nt d oses.  
T he safet y a n d l ocal t olera bilit y meas ures/ para meters are:  
•  occ urre nce of a d verse e ve nts  
•  use of c o nc o mita nt me dicati o n  
•  vital si g ns a n d b o d y wei g ht meas ure me nt  
•  va gi nal blee di n g patter n  
•  assess me nt of m o o d b y P atie nt Healt h Q uesti o n naire -9 ( P H Q -9)  
•  li ver f u ncti o n tests 
•  estra di ol ( E 2 ) meas ure me nts t hr o u g h o ut t he st u d y   
•  pr o gester o ne ( P) meas ure me nts at Wee ks 4 8, 4 9, 5 0, 5 1, a n d 5 2  
•  occ urre nce of i nj ecti o n site reacti o ns (I S Rs)  
T he acce pta bilit y para meters are:  
•  s u bj ect’s res p o nses t o acce pta bilit y q uesti o ns 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 5  
3.  
I N V E S TI G A TI O N A L P L A N 
3. 1.  
Ge ner al St u d y Desi g n  
T he assess me nts a n d pr oce d ures p erf or me d d uri n g eac h st u d y visit are d etaile d i n Ta ble  1  a n d 
Secti o n  3. 4 . 
T he st u d y s c he matic dia gra m is prese nte d i n  Fi g ure  1 .  
Fi g ure  1 : 
O ver all St u d y Sc he m ati c Di a gr a m  
 
 
 
3. 2.  
S u bject Eli gi bilit y  
Pr os pecti ve wai vers (e x ce pti o ns) fr o m st u d y eli gi bilit y criteria t o all o w s u bjects t o  e nter a st u d y 
are n ot gra nte d b y Te v a (see Secti o n  1 1. 1. 2 ). 
3. 2. 1.  
S u bject I ncl usi o n Criteri a  
S u bjects ma y be i n cl u de d i n t he st u d y if t he y meet all of t h e f oll o wi n g criteria:  
a. willi n g a n d ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt  
b.  fe male of 1 8 t o 4 5 years of a ge (i n cl usi ve) 
c. healt h y b ase d o n res ults of p h ysic al e xa mi nati o n, me dical hist or y, vital si g ns tests, 
a n d Pa p s mear res ults  
d.  has re g ular m e nstr ual c ycl e ( 2 1 t o 3 5 da ys)  
e. has a l o w ris k of pre g na n c y (ie, sterilize d, i n e xcl usi vel y sa me -se x part ners hi p, 
a bsti ne nt, i n m o n o ga m o us relati o ns hi p wit h vasect o mize d part ner, usi n g n o n -
h or m o nal i ntra uteri ne d e vice (I U D), or c o nsiste ntl y usi n g barrier met h o ds of 
c o ntrace pti o n)  
f. ha d a n or mal ma m m o gra m wit hi n t he last year, if 4 0 years of a ge or ol d er  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 6  
g.  has a b o d y mass i n de x ( B MI) of 1 8 t o 3 5, i ncl usi ve  
h.  has he m o gl o bi n ≥1 0. 5 g/ d L  
i. is willi n g a n d a ble t o c o m pl y wit h all st u d y re q uire me nts a n d ret ur n t o t he 
i n vesti gati o nal c e nter f or t he f oll o w-u p pr oce d ures a n d assess me nts as s pecifie d i n 
t his pr ot oc ol 
3. 2. 2.  
S u bject E xcl usi o n Criteri a  
S u bjects will be e x cl u de d fr o m partici pati n g i n t his st u d y if t he y meet a n y of t he f oll o wi n g 
criteria:  
a. has h y p erte nsi o n wit h:  
○ s yst olic B P ≥1 6 0 m m H g or diast olic B P ≥1 0 0  m m H g  
○ vasc ular dise ase  
b.  has a n a b n or m al Pa p res ult t hat re q uires treat me nt or i n t he o pi ni o n of a n i n vesti gat or 
w o ul d ma ke st u d y p artici pati o n u nsafe or c o m plicate data i nter pretati o n   
c. has m ulti ple ris k fact ors f or ca r di o v asc ular dise ase (e g, s m o ki n g, o b esit y, 
h y perte nsi o n, k n o w n l o w  hi g h de nsit y li p o pr otei n  (H D L ), hi g h l o w de nsit y 
li p o pr otei n (L D L ), or hi g h tri gl yceri de le vels) 
d.  has c urre nt or hist or y of isc he mic heart disease  
e. has acti ve t hr o m b o p hle bitis, c urre nt or p ast hist or y of t hr o m b o e m b olic dis or ders, 
cere bral vas c ular dise ase or str o ke  
f. has s yste mic l u p us er yt h e mat os us  
g.  has r he u mat oi d art hritis o n i m m u n os u p pressi ve t hera p y  
h.  has u ne x plai ne d va gi n al blee di n g  
i. has dia betes  
j. has str o n g fa mil y hist or y of breast c a ncer ( d e fi ne d as o ne or m ore first de gree 
relati ves wit h breast ca n cer, breast ca n cer occ urri n g bef ore m e n o pa use i n t hree or 
m ore fa mil y me m bers, re gar dless of de gree of relati o ns hi p, a n d a n y male fa mil y 
me m ber wit h breast ca ncer)  
k.  has c urre nt or hist or y of breast  ca ncer, or u n dia g n ose d mass detecte d b y breast e x a m  
l. has c urre nt or hist or y of cer vical ca n cer  
m.  has cirr h osis or li ver t u m ors  
n.  has o ne or m ore baseli ne li ver f u ncti o n test(s) o utsi de t he l ocal la b orat or y’s n or mal 
ra n ge 
o.  has k n o w n oste o p or osis or oste o pe nia  
p.  ha s hist or y of di a g n ose d cli nical de pressi o n or bi p olar dis or der, wit h or wit h o ut 
s uici dal i deati o n, a n d/ or hist or y of s uici de atte m pt, e x ce pt s h ort-li ve d sit uati o nal 
de pressi o n t hat di d n ot re q uire me dicati o n a n d h as n ot rec urre d i n last fi ve years  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 7  
q.  has his t or y of ps yc hiatric dis or der t hat i n t he o pi ni o n of t he i n vesti gat or w o ul d ma ke 
st u d y partici p ati o n u nsafe, w o ul d i nterfere wit h a d here nce t o st u d y re q uir e me nts or 
c o m plicate data i nter pret ati o n  
r. use d M P A -c o ntai ni n g i njecta ble pr o d u cts i n t he past 1 2 m o nt hs  
s. use d a c o m bi ne d i nject a ble c o ntrace pti ve i n t he past 6  m o nt hs  
t. use d a n y of t he f oll o wi n g me dicati o ns wit hi n 1 m o nt h pri or t o e nr oll me nt:  
○ a n y i n v esti gati o nal dr u g  
○ pr o hi bite d dr u gs p er pr ot oc ol  
○ oral c o ntrace pti ves, c o ntrace pti ve ri n g or patc h  
○ le v o n or gestrel i ntra ut eri n e s yste m or c o ntrace pti ve i m pla nt 
u.  is partici pati n g i n a n ot her cli nical trial  
v.  is pre g n a nt 
w.  desires t o bec o me pre g n a nt i n s u bse q ue nt 2 4 m o nt hs  
x.  has bee n pre g na nt i n last 3 m o nt hs  
y.  is c urre ntl y lactati n g 
z. is usi n g or pla n ni n g t o use pr o hi bite d dr u gs per pr ot oc ol i n t he ne xt 1 2 m o nt hs  
aa.  has k n o w n se nsiti vit y t o M P A or i nacti ve i n gre die nts  
b b.  pla ns t o  m o ve t o a n ot her l ocati o n i n t he ne xt 1 2 m o nt hs  
cc.  has a n y c o n diti o n (s ocial or me dical), w hi c h i n t he o pi ni o n of t he i n vesti gat or w o ul d 
ma ke st u d y p artici pati o n u nsafe, w o ul d i nterfere wit h a d here nce t o t he cli ni cal st u d y 
re q uire me nts or c o m plicate data i nter pretati o n 
3. 3.  
D ur ati o n of S u bject P artici p ati o n  
T otal d urati o n of t he st u d y f or eac h s u bject is e x pecte d t o be a p pr o xi matel y 1 9. 5 m o nt hs, 
i ncl u di n g a p pr o xi matel y 1. 5 m o nt hs of scree ni n g a n d u p t o 1 8 m o nt hs of f oll o w -u p after st u d y 
treat me nt i nitiati o n. All s u bjects will be f oll o we d f or at least 5 2 wee ks aft er treat me nt 
i nitiati o n. If s u bjects ha v e u nres ol ve d I S R(s) at Wee k 5 2, t he y will be f oll o we d u ntil I S R 
res ol uti o n or Wee k 7 8, w hic he ver c o mes first. T heref ore, t he mi ni mal d urati o n of s u bject 
partici pati o n is 5 2 wee ks a n d t he ma xi m u m 7 8 wee ks after treat me nt i nitiati o n.  
See Secti o n  1 2. 4  f or t he defi niti o n of t he e n d of t he st u d y. 
3. 4.  
St u d y Pr oce d ures  
St u d y pr oce d ures a n d ass ess me nts wit h t heir ti mi n g are s u m marize d i n Ta bl e  1 . Detaile d 
descri pti o ns of eac h assess me nt are pr o vi de d i n S ecti o n  5  (safet y assess me nts) a n d Secti o n 6  
( p har mac o ki netic assess me nts).  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 8  
T a ble  1 : 
St u d y Pr oce d ures a n d Assess me nts  
Pr o ce d ures a n d 
assess me nts  
Scree ni n g  
E nr oll me nt  
F oll o w -U p  
( 6 Wee ks bef ore 
R a n d o miz ati o n)  
D a y 0  
D a y 1 t o Wee k 5 2  
( D a y 3 6 5) 
Wee ks 
6 5 a n d 
7 8  
 
 
Sc he d ule d 
F oll o w -u p 
( D a y 7, Wee ks 
1 3, 2 6, a n d 5 2)  
L a b 
visits a  
 
I nf or me d c o ns e nt 
X  
 
 
 
 
Me dical hist or y  
X  
 
 
 
 
I n cl usi o n a n d 
e x cl usi o n criteria  
X  
X  
 
 
 
De m o gra p hics, 
c o ntrace pti ve a n d 
re pr o d ucti ve 
hist or y  
X  
 
 
 
 
Hei g ht  
X  
 
 
 
 
Vital si g ns 
meas ure me nt  
X  
X  
X  
 
 
B o d y wei g ht  
X  
X  
X  
 
 
P h ysical e x a m  
X  
 
 
 
 
Uri ne pre g n a nc y 
test b 
 
X  
X  
X  
X  
Ra n d o mizati o n  
 
X  
 
 
 
St u d y dr u g 
a d mi nistrati o n  
 
X  
 
 
 
E 2  c 
 
X  
X  
X  
 
P  c 
 
X  
X  
X  
 
Ser u m M P A  d 
 
X  
X  
X  
 
I nje cti o n site 
reacti o ns e 
 
X  
X  
 
X  
A d verse e ve nt 
i n q uir y f 
 
X  
X  
 
X  
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
2 9  
Pr o ce d ures a n d 
assess me nts  
Scree ni n g  
E nr oll me nt  
F oll o w -U p  
( 6 Wee ks bef ore 
R a n d o miz ati o n)  
D a y 0  
D a y 1 t o Wee k 5 2  
( D a y 3 6 5) 
Wee ks 
6 5 a n d 
7 8  
 
 
Sc he d ule d 
F oll o w -u p 
( D a y 7, Wee ks 
1 3, 2 6, a n d 5 2)  
L a b 
visits a  
 
C o nc o mita nt 
me dicati o n 
i n q uir y f 
 
X  
X  
 
 X  
He m o gl o bi n  
X  
 
 
 
 
Li ver f u ncti o n 
testi n g g 
X  
 
X  
 
 
M o o d e val uati o n 
h 
 
X  
X  
X  
 
Va gi nal blee di n g 
patter n i 
 
 
X  
 
 
Ma m m o gra m 
j 
X  
 
 
 
 
Pa p s mear k  
X  
 
 
 
 
Acce pt a bilit y l  
 
 
X  
 
 
a S u bj ects will ret ur n f or la b orat or y visits at pre -defi ne d ti me p oi nts: Da ys 0, 1, 2, 3, 5, 7, 1 0, 1 2, 1 4, 1 8, 2 1, a n d 2 8; 
W ee ks 6, 8, 1 0, 1 2, 1 3, 1 5, 1 7, 1 9, 2 1, 2 3, 2 5, 2 6, 2 8, 3 0, a n d 3 2; a n d t he n e ver y 2 8 da ys t hr o u g h Wee k 5 2.  
b A n uri ne pre g na nc y test will be perf or me d o n Da y 0; W ee ks 2 6, 3 2, 3 6, 4 0, 4 4, 4 8, a n d 5 2; a n d at Wee ks 6 5 a n d 
7 8 if a p plica ble, a n d at a n y ot her ti mes w he n i n dicate d.  
c Bl o o d sa m ples f or P a n d E 2 will be c ollecte d at Da y 0 a n d at Wee ks 4 8, 4 9, 5 0, 5 1, a n d 5 2. Bl o o d sa m ples f or E 2 
will b e c ollecte d at all visits w he n M P A or P is teste d starti n g o n Da y 2 8.  
d Bl o o d sa m ples f or M P A will be c ollecte d o n Da ys 0, 1, 2, 3, 5, 7, 1 0, 1 2, 1 4, 1 8, 2 1, a n d 2 8; W ee ks 6, 8, 1 0, 1 2, 
1 3, 1 5, 1 7, 1 9, 2 1, 2 3, 2 5, 2 6, 2 8, 3 0, a n d 3 2; a n d t he n e ver y 2 8 da ys t hr o u g h Wee k 5 2.  
e I S Rs will b e e val uate d o n Da y 0 i m me diatel y (ie, as s o o n as p ossi ble b ut n o later t ha n 1 0 mi n utes u p o n re m o vi n g 
t he nee dle) a n d 1 h o ur ( ± 5 mi n utes) after i nj ecti o n; Da y 7; at W ee ks 1 3, 2 6, a n d 5 2 an d at ot her visits, if i n dicate d. 
S u bj ects w h o ha ve I S R(s) at W ee k 5 2 will be f oll o we d e ver y 3 m o nt hs (at Wee ks 6 5 a n d 7 8) u ntil I S R res ol uti o n 
or W ee k 7 8, w hic he ver is earli er. If t he s u bj ect d oes n ot ha ve a n y I S Rs at Wee k 5 2 it will b e her fi nal visit. A ll 
s u bj ects will be i nstr ucte d t o ret ur n t o t he cli nic if a n y I S Rs de vel o p after t heir fi nal visit.  
f D uri n g la b orat or y visits, i nf or mati o n o n a d verse e ve nts a n d c o nc o mita nt me dicati o ns will n ot b e s olicite d, b ut will 
be d oc u me nte d if self -re p orte d b y t he s u bj ect. A d verse e ve nts a n d use of c o nc o mita nt me dicati o ns will als o be 
e val uate d d uri n g a d diti o nal I S R f oll o w u p at Wee ks 6 5 a n d 7 8.  
g L i ver f u ncti o n testi n g will b e d o ne at Scree ni n g, Da y 7 a n d at t he Wee ks 1 3, 2 6, a n d 5 2.  
h M o o d will b e e val uate d o n Da ys 0 a n d 2 8; W ee ks 8, 1 3, 1 7, 2 1, 2 6, 3 2, 3 6, 4 0, 4 4, 4 8, a n d 5 2.  
i Va gi nal blee di n g patter n will be assesse d at Wee ks 1 3, 2 6, a n d 5 2.  
j N or mal ma m m o gra m res ults fr o m wit hi n t he last year m ust be prese nte d pri or t o e nr oll me nt f or w o me n 4 0 years 
of a ge or ol der.  
 k  P a p test will be c o m plete d f or w o me n w h o d o n ot ha ve res ults of t heir pre vi o us P a p test t hat are wit hi n A merica n 
C olle ge of O bstetricia ns a n d G y nec o l o gists ( A C O G) P a p test sta n dar d of care re q uire me nts. If a d diti o nal testi n g is 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 0  
re q uire d base d o n P a p res ults, t his s h o ul d be c o m plete d pri or t o e nr oll me nt (i n acc or da nce wit h C o m mittee o n 
Practice B ulleti ns G y nec ol o g y 2 0 1 6 ). 
l Acce pta bilit y data will be c ollecte d at W ee ks 2 6 a n d 5 2.  
E 2 = Estra di ol; I S R =i nj ecti o n site reacti o n; La b = la b orat or y; M P A = me dr o x y pr o gester o ne acetate; P = Pr o gester o ne  
3. 4. 1.  
Pr o ce d ures f or Scree ni n g  
A si g ne d a n d date d i nf or me d c o nse nt f or m (I C F) will be o btai ne d bef ore s cree ni n g pr oce d ures 
c o m me nce (s ee Secti o n  1 2. 2 ).  
After i nf or m e d c o nse nt is o btai ne d, s u bjects will be assi g n e d a s u bject i de ntificati o n n u m ber i n 
c o nsec uti ve or der wit hi n eac h i n vesti gati o nal ce nt er.  
De m o gra p hic d ata as w ell as c o ntrace pti ve a n d re pr o d ucti ve hist or y will be c ollecte d a n d 
d oc u me nte d. Scree ni n g f or eli gi bilit y  will i ncl u de , re vie w of eli gi bilit y criteria a n d me dical 
hist or y, meas ure me nt of he m o gl o bi n a n d li ver e nz y m es, a n d p h ysi cal e xa mi nati o n t hat will 
i ncl u de, at mi ni m u m: hea d/ nec k, ears, e yes, n os e, t hr oat, c hest a n d l u n gs, car di o vasc ular, 
a b d o me n, s ki n, l y m p h n o des a n d breast assess me nts. B MI will be cal c ulate d base d o n t he 
meas ure d w ei g ht a n d hei g ht. 
 
 
 
 I n a d diti o n, a ma m m o gra m will be perf or me d f or 
w o me n 4 0 years of a ge or ol der if ma m m o gra m r es ults fr o m wit hi n t he last year are n ot 
a vaila ble. A Pa p test will be perf or me d if re q uire d, f oll o wi n g A merica n C olle ge of O bstetricia ns 
a n d G y nec ol o gists  Pa p test g ui deli nes ( C o m mittee o n Practice B ulleti ns G y nec ol o g y  2 0 1 6 ). I n 
a d diti o n, i n vesti gati o nal ce n ters ma y p erf or m a d diti o nal scree ni n g pr oce d ures per t heir sta n dar d 
of care pr oce d ures (e g, S TI t esti n g, uri n e dr u g scree ni n g). All scree ni n g pr oce d ures a n d tests will 
be c o m plete d wit hi n 6 w ee ks bef ore ra n d o mizati o n.  
3. 4. 2.  
Pr o ce d ures f or E nr oll me nt  ( D a y 0) 
E nr o ll me nt visits will be sc he d ule d t o occ ur d uri n g t he first 5 da ys of t he me nstr ual c ycle. O n 
t hat da y, a uri ne pre g na n c y t est will be c o m plete d i n all s u bjects t o r ule o ut pre g na nc y. I n 
a d diti o n, a n assess me nt of vital si g ns, b o d y wei g ht a n d B MI, m o o d, E 2 a n d P, a n d M P A will be 
perf or me d. A d vers e e v e nts a n d c o nc o mita nt me dicati o ns will be e val uate d.  
All eli gi bilit y criteria will be verifie d pri or t o ra n d o mizati o n.  
Eli gi ble s u bjects will be e nr olle d i nt o t he st u d y a n d ra n d o ml y assi g n e d i n a 1: 1: 1: 1 rati o t o  
recei v e o ne of t h e 4 st u d y treat me nts: 1 2 0 m g/ 0. 4 m L, 1 8 0 m g/ 0. 6 m L or 2 4 0 m g/ 0. 8 m L of T V-
4 6 0 4 6, or 1 0 4 m g/ 0. 6 5 m L of De p o -s u b Q Pr o v era 1 0 4. Eac h st u d y treat me nt will c o nsist of a 
si n gle s u bc uta n e o us i njecti o n i n t he a b d o me n. T he i njecti o n site l ocati o n will be mar ke d a n d 
p h ot o gra p he d f or refere n ce. T he i njecti o n site will be o bser ve d f or I S Rs i m me diatel y (ie, as s o o n 
as p ossi ble b ut n o later t ha n 1 0 mi n utes u p o n re m o vi n g t he nee dle) a n d 1 h o ur ( ± 5 mi n utes) after 
t he i njecti o n.  
3. 4. 3.  
Pr o ce d ures f or F oll o w -U p  
St u d y f oll o w -u p will last f or at least 5 2 wee ks fr o m treat me nt i nitiati o n. T here will be f o ur 
sc he d ule d f oll o w-u p visits at W ee k 1 ( Da y 7), Wee k 1 3, Wee k 2 6, a n d Wee k 5 2, d uri n g w hic h 
s u bjects will be e val uate d f or vital si g ns, b o d y wei g ht, li ver e nz y m es, I S Rs, a d verse e ve nts a n d 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 1  
use of c o nc o mita nt me di cati o ns. Va gi nal blee di n g patter n, acce pta bilit y a n d m o o d will be 
e val uate d t hr o u g h o ut  t he st u d y at pr e-defi ne d ti me p oi nts ( See Ta ble  1 ). Uri ne pre g na n c y tests 
will be a d mi nistere d peri o dicall y starti n g at Wee k 2 6 t hr o u g h t he e n d of t h e st u d y.  
I n a d diti o n t o t he sc he d ul e d f oll o w-u p visits, s u bjects will ret ur n f or la b orat or y visits t o pr o vi de 
bl o o d sa m ples f or M P A, P, a n d E 2 at pre -d efi ne d ti me p oi nts (see Ta ble  1 ). 
If t he s u bject has n e w or o n g oi n g I S Rs at Wee k 5 2, s he will be f oll o we d e ver y 3 m o nt hs (at 
Wee ks 6 5 a n d 7 8) u ntil I S R res ol uti o n or M o nt h 1 8 ( Wee k 7 8), w hic h e ver is earlier. If t he 
s u bject d oes n ot ha ve a n y I S Rs at W ee k 5 2 it will be her fi n al visit. H o we ver, all s u bjects will be 
i nstr ucte d t o ret ur n t o t he cli nic if a n y I S Rs de vel o p after t heir fi nal visit. I n t hat case, t heir stat us 
will c ha n ge fr o m c o m plete d t he st u d y t o acti ve a n d t he y will be f oll o w e d p er t he sc h e d ule a b o v e 
u ntil I S R res ol uti o n or Wee k 7 8, w hic h e ver is earlier.  
F oll o w u p visits s h o ul d be sc he d ule d usi n g t he tar get wi n d o w p er i o ds bel o w. H o we ver, if a 
s u bject ca n n ot atte n d a visit wit hi n t he tar get wi n d o w bel o w, t he visit pr oce d ures s h o ul d be 
c o n d ucte d as s o o n as p ossi ble re gar dless of ti mi n g.  
T a ble  2 : 
T ar get Ti me Wi n d o ws f or F oll o w -u p Visit s  
T ar g et visit d ate  
T ar get ti me wi n d o w 
Da ys 1, 2  
±  1 h o ur  
Da ys 3, 5, 7  
±  3 h o urs  
Da ys 1 0, 1 2, 1 4, 1 8  
±  2 4 h o urs  
A n y sc he d ule d cli nic or la b orat or y visit p ast Da y 2 1  
±  4 8 h o urs  
3. 4. 4.  
U nsc he d ule d Pr oce d ures a n d Visits  
A n u nsc he d ule d pr o ce d ure or visit ma y b e perf or me d at a n y ti me d uri n g t he st u d y at t he 
s u bject’s re q u est or as dee me d necessar y b y t he i n vesti gat or.  
U nsc he d ule d pr o ce d ures ma y i ncl u d e t he f oll o wi n g:  
•  c o nc o mita nt me dicati o n re vie w  
•  vital si g ns meas ur e me nts  
•  ad verse e ve nt i n q uir y  
•  st u d y c o m plia nce re vi e w 
•  uri ne pre g n a nc y test  
Ot her pr oce d ures m a y be perf or me d at t he discreti o n of t he i n vesti gat or a n d i n c o ns ult wit h t he 
s p o ns or. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2  
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 2  
4.  
T R E A T M E N T O F S U B J E C T S  
4. 1.  
I n vesti g ati o n al Me dici n al Pr o d ucts A d mi nistere d D uri n g t he St u d y  
T he I M Ps use d i n t his st u d y are des cri be d i n T a ble  3 . 
4. 1. 1.  
Test I n vesti g ati o n al Me dici n al Pr o d uct  
A p pr o xi matel y 6 0 s u bj ects will be ra n d o mize d i n a 1 : 1: 1: 1 rati o t o recei ve o ne of t he 4 st u d y 
treat me nts: 1 2 0 m g/ 0. 4 m L, 1 8 0 m g/ 0. 6 m L or 2 4 0 m g/ 0. 8 m L of T V-4 6 0 4 6, or 1 0 4 m g/ 0. 6 5 m L 
of De p o -s u b Q Pr o v era 1 0 4, stratifie d b y site. 
4. 1. 2.  
Refere nce I n vesti g ati o n al Me dici n al Pr o d uct  
De p o -s u b Q Pr o vera  1 0 4 is t he refere nce i n vesti gati o nal me dici nal pr o d uct (I M P). F or t his st u d y, 
De p o -s u b Q Pr o vera  1 0 4 will be s u p plie d as a si n gle -u nit d ose of 1 0 4 m g/ 0. 6 5 m L prefille d glass 
s yri n ges pre-p ac k a ge d wit h 2 6 ga u ge 3/ 8” nee dle. Detaile d c o m p ositi o n a n d i njecti o n 
i nstr ucti o ns are c o ntai n e d i n t he De p o-s u b Q Pr o vera  1 0 4 Pres cri bi n g I nf or mati o n ( De p o -s u b Q 
Pr o vera 1 0 4 U S Prescri bi n g I nf or mati o n 2 0 1 6 ). 
4. 2.  
Tre at me nt of S u bjects  
T V -4 6 0 4 6 will be a d mi nistere d b y a st u d y staff me m ber as a si n gle s u b c uta ne o us i njecti o n i n t he 
a b d o me n d uri n g t he first 5  da ys of t he me nstr ual c ycl e usi n g a 2 3  ga u ge 3/ 8  i nc h nee dle 
f oll o wi n g t he s p o ns or’s i nstr ucti o ns f or a d mi nisteri n g a s u b c uta ne o us i njecti o n. T he cli nical staff 
pre pari n g t he d os e a n d pr o vi di n g t he i n jecti o ns will be trai ne d t o s hiel d t he s yri n ge fr o m vie w of 
t he s u bject a n d a n y bli n d e d st u d y staff pri or t o a n d at t he ti me of i njecti o n.  
 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 3  
T a ble  3 : 
I n vesti g ati o n al Me dici n al Pr o d ucts Us e d i n t he St u d y 
I M P n a me 
T V -4 6 0 4 6  
Refere nce I M P  
Tr a de n a me a n d I N N, if 
a p plic a ble, or c o m p a n y 
assi g ne d n u m ber  
Me dr o x y pr o gester o ne acetate i nj ecta ble 
s us pe nsi o n 3 0 0 m g/ m L 
De p o – S u b Q Pr o vera 1 0 4 ®  
Me dr o x y pr o gester o ne acetate i nj ecta ble 
s us pe nsi o n ( 1 0 4 m g/ 0. 6 5 m L f or sc use) 
F or m ul ati o n  
 
Me dr o x y -pr o gester o ne 
Acetate  
3 0 0 m g  
Me dr o x y -
pr o gester o ne acetate  
1 0 4 m g  
D oc usate s o di u m  
0. 6 0 m g  
Met h yl para be n  
1. 0 4 0 m g  
P ol yet h yle ne gl yc ol 
3 3 5 0  
2 0. 0 0 m g  
Pr o p yl para be n  
0. 0 9 8 m g  
S o di u m s ulfate a n h.  
1 3. 0 0 m g  
S o di u m C hl ori de  
5. 2 0 0 m g  
M o n o basic s o di u m 
p h os p hate a n h.  
0. 6 0 m g  
P ol yet h yle ne Gl yc ol  
1 8. 6 8 8 m g  
Di basic S o di u m 
p h os p hate a n h.  
0. 2 3 m g  
P ol ys or bate 8 0  
1. 9 5 0 m g  
L -Met hi o ni ne  
1. 5 0 m g  
M o n o basic S o di u m 
P h os p hate ∙ H 2O  
0. 4 5 1 m g  
W ater f or I nj ecti o n ( u p 
t o 1 m L) 
qs  
Di basic S o di u m 
P h os p hate ∙ 1 2 H 2O  
0. 3 8 2 m g  
N A  
N A  
Met hi o ni ne  
0. 9 7 5 m g  
N A  
N A  
P o vi d o ne  
3. 2 5 0 m g  
N A  
N A  
Water f or i nj ecti o n  
( u p t o 0. 6 5 m L) 
qs  
U nit d ose 
stre n gt h(s)/ D os a ge 
le vel(s) 
1 2 0 m g/ 0. 4 m L  
1 8 0 m g/ 0. 6 m L  
2 4 0 m g/ 0. 8 m L  
1 0 4 m g/ 0. 6 5 m L  
R o ute of a d mi nistr ati o n  
 
S C i nj ecti o n  
S C i nj ecti o n  
a n h =a n h y dr o us; H 2O  = water; I M P = i n vesti gati o nal me dici nal pr o d uct; I N N = i nter nati o nal n o n pr o prietar y na me; 
N A = n ot a p plica ble; qs = q ua ntit y s ufficie nt; S C =s u bc uta ne o us  
4. 3.  
Bli n di n g/ U n bli n di n g  
T his st u d y will be partiall y -bli n de d d ue t o differe nces i n a p peara n ce a n d v ol u me of t he 
treat me nts. Desi g nate d u n bli n de d st u d y staff will c o n d uct ra n d o mizati o n pr oce d ures. T he staff 
pre pari n g a n d a d mi nisteri n g st u d y i njecti o ns will be u n bli n de d b ut will be trai ne d t o s hiel d t he 
s yri n ge pri or t o a n d at t h e ti me of i njecti o n fr o m vie w of t he s u bject a n d a n y ot her bli n de d st u d y 
staff. F HI 3 6 0 a n d s p o ns or pr oject tea m me m bers i n v ol ve d i n assess me nt of a d verse e ve nts, d ata 
a nal ysis or res ults i nter pretati o n will be bli n de d t o treat me nt assi g n me nt u ntil t he pla n ne d i nteri m 
a nal ysis, after w hic h o nl y i n vesti gati o nal ce nter staff perf or mi n g s u bjec t i nter vie ws a n d 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 4  
assessi n g s afet y o utc o mes will re mai n bli n de d. La b pers o n nel perf or mi n g M P A testi n g will 
re mai n bli n de d t o treat m e nt assi g n me nt t hr o u g h o ut t he st u d y. 
4. 3. 1.  
U n bli n di n g D uri n g t he St u d y  
A descri pti o n of t he e m er ge n c y u n bli n di n g pr oce d ures will be i ncl u de d i n t he st u d y p h ar mac y 
ma n ual.  
F or a d v erse e ve nts t hat are defi n e d as a S us pecte d U ne x pecte d Seri o us A d verse Reacti o n 
( S U S A R) (ie, reas o na ble p ossi bilit y t hat a d v erse e ve nt is relate d t o treat me nt; Secti o n 5. 2. 5 ), 
Gl o bal Patie nt Safet y a n d P har mac o vi gila nce will re q uest t hat t he treat me nt c o de be re veal e d t o 
c o m pl y wit h re g ul at or y re q uire me nts. T he re p ort will be pr o vi de d i n a n u n bli n de d ma n ner  f or 
re g ulat or y s u b missi o n. I n t he case of a S U S A R, o nl y t he s p o ns or a n d a desi g nat e d u n bli n de d 
F HI 3 6 0 staff will recei v e t he u n bli n de d re p ort f or re g ulat or y s u b missi o n; ot her staff will recei ve 
a bli n de d re p ort i n a cc or da nce wit h s p o ns or's c urre nt pr oce dures . 
All cases of i na d v erte nt u n bli n di n g will be ha n dle d per F HI 3 6 0’s sta n d ar d o perati n g pr oce d ures 
( S O Ps).  
4. 4.  
St o p pi n g R ules a n d Disc o nti n u ati o n Criteri a  
If, at a n y ti me o ne of t he f oll o wi n g occ urs: t w o or m ore I S Rs gra de d as se vere a d v erse e ve nts, 1 5 
cases of s ki n disc ol or ati o n at i njecti o n site (e g, h y p o pi g me ntati o n) o n g oi n g f or m ore t ha n 7 da ys, 
or t w o seri o us a n d relate d a d verse e ve nts i n t he st u d y acr oss all treat me nt gr o u ps, a n u n pla n ne d 
re vie w of i nteri m data b y a St u d y Re vie w C o m mittee ( S R C), will occ ur, at w hic h ti me a 
rec o m me n dati o n ma y b e ma de t o pa use e nr oll me nt or halt t he st u d y. Ot her pla n ne d re vie ws will 
ta ke place as sc h e d ule d (see Secti o n 9. 8 ), at w hi c h ti me t he S R C c o ul d a d vise t hat t he st u d y st o p 
or be m o difie d base d o n c o ncer ns f or safet y of s u bjects or defi niti ve c o n cl usi o ns.  
Si nce m ost of t he st u d y dr u gs are e x pecte d t o re m ai n i n t he b o d y m o nt hs after i njecti o n, st u d y 
disc o nti n ua ti o n will n ot be t he sa me as tr eat me nt disc o nti n uati o n. St u d y st aff will e x plai n t o 
s u bjects w h o wis h t o disc o nti n ue t he st u d y earl y t h at it is i m p orta nt t o sta y i n t he st u d y u ntil 
safet y assess me nts are c o m plete d. H o we ver, a s u bject ma y disc o nti n ue partic i 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 (e g, wit h dra wal of c o ns e nt or a n a d v erse e ve nt) wit h o ut l oss of ot her 
be nefits or ser vices t o w hic h t he y m a y be e ntitle d. All s u bjects w h o disc o nti n ue earl y will be 
f oll o we d acc or di n g t o S u bject Wit h dra wal Criteria a n d Pr oce d ures ( Secti o n 4. 9. 1 ). Reas o ns f or 
disc o nti n uati o n fr o m t he st u d y will be rec or de d o n t he a p pr o priat e electr o nic case re p ort f or m 
(eC R F ) 
Ot hers reas o ns t he st u d y ma y b e st o p pe d i ncl u de:  
•  I nstit uti o nal Re vie w B oar d (I R B)/ I n de p e n de nt Et hics C o m mittee (I E C) rec o m me n d 
ter mi nati n g t he st u d y 
•  T he F o o d a n d Dr u g A d mi nistrati o n ( F D A ) re q uests t hat t he st u d y be disc o nti n ue d or 
place d o n h ol d.   
•  T he s p o ns or deci d es t o re d uce t he sc o p e (e g, re d uce sa m ple siz e, dr o p o ne or m ore 
st u d y gr o u ps) or ter mi nat e t he st u d y. T h e s p o ns or ma y ter mi nate t he st u d y at a n y ti me 
f or a n y reas o n.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 5  
If t he w h ole st u d y is st o p pe d, t he s u bjects t hat are ter mi nate d earl y will be f oll o we d acc or di n g t o 
S u bject Wit h dra wal Criteria a n d Pr oce d ures ( Secti o n  4. 9. 1 ).  
4. 5.  
I nteri m D at a Re vie ws 
T he st u d y will be o v ersee n b y a n i nter nal S R C, t he c o m p ositi o n a n d res p o nsi bilities of w hic h 
will be detaile d i n a se parate S R C O perati o nal Pla n.  E xter nal c o ns ulta nts wit h rele va nt 
s pecialties ma y als o be e n ga ge d as part of t his S R C . 
T he S R C will c o n ve ne f or at least o ne re vie w of i nteri m data after  at least 8 0 % of s u bjects ha v e 
ha d a c h a nce t o c o m plete 7. 5 m o nt hs after treat me nt i nitiati o n. T his a nal ysis is i nte n de d t o hel p 
i nf or m t he decisi o n t o m o ve t o, a n d select t he d os e f or, a pi v otal st u d y. I n a d diti o n, u n pla n ne d 
re vie ws ma y b e tri g gere d b y t he o cc urre nce of I S Rs, i njecti o n site disc ol orati o n 
( h y p o pi g me ntati o n) e ve nts a n d/ or seri o us a n d relate d a d verse e ve nts. At t h e ti me of a n y pla n ne d 
or u n pla n ne d i nteri m re vi e w of data, t h e S R C ma y rec o m me n d t hat t he trial be m o difie d or 
halte d t o e ns ure t he  s afet y a n d well-bei n g of st u d y s u bjects. T here will be n o a dj ust me nt t o t y p e I 
err or t o acc o u nt f or a n y i nteri m re vie ws of st u d y d ata.  
4. 6.  
Pri or a n d C o nc o mit a nt T her a p y or Me dic ati o n  
A n y pri or or c o n c o mita nt me dicati o n a s u bject  has ha d wit hi n 3 0 da ys b ef ore st u d y dr u g 
a d mi nistrati o n a n d u p t o t he fi nal visit will be rec or de d as a c o nc o mita nt me dicati o n o n t he 
a p pr o priate C R F. D uri n g t he f o ur sc he d ule d f oll o w -u p visits t he i n vesti gat or will as k s u bjects 
w het her t he y h a ve ta k e n a n y m e dicati o ns, i ncl u di n g o ver -the -c o u nter m e dicati o ns, vita mi ns, or 
her bal or n utriti o nal s u p ple me nts, si nce t he pre vi o us visit. D uri n g all ot her visits i nf or mati o n o n 
t he use of c o n c o mita nt me dicati o ns will be d oc u m e nte d o nl y if s elf-re p orte d b y t he s u bject. 
Ge neric or tra d e na me, i n di cati o n, r o ute of a d mi nistrati o n, d osa ge, a n d start a n d e n d dates will be 
rec or de d. 
T he f oll o wi n g m e dicati o ns s h o ul d n ot be use d d uri n g t his st u d y: a mi n o gl utet hi mi de; ster oi d 
h or m o nes (estr o ge ns, pr o gesti ns a n d a n dr o ge ns); a n d a ntiretr o viral dr u gs i n cl u di n g  n o n -
n ucle osi de re v erse tr a nscri ptase i n hi bit ors (efa vir e nz a n d ne vira pi ne) a n d rit o na vir -b o oste d 
pr otease i n hi bit ors. T he use of pr o hi bite d dr u gs will be d oc u me nte d as a n i m p orta nt pr ot oc ol 
de viati o n. I n a d diti o n, a p plicati o n of ba n da ges t o i njecti o n site s will be disc o ura ge d. 
4. 7.  
Pr oce d ures f or M o nit ori n g S u bject C o m pli a nce  
All I M Ps will be i njecte d b y t he i n vesti gat or or ot her cli nical pers o n nel at t he i n vesti gati o nal 
ce nter; t heref ore, m o nit ori n g of s u bj ect c o m plia nce will n ot be necess ar y.  
4. 8.  
T ot al Bl o o d V ol u me  
T he t otal v ol u me of bl o o d t o be c ollecte d f or eac h s u bject i n t his st u d y is a p pr o xi matel y 3 4 5 m L 
as detaile d i n Ta ble  4 .  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 6  
T a ble  4 : 
A p pr o xi m ate Bl o o d V ol u mes  
Assess me nts  
V ol u me per s a m ple ( m L)  
T ot al n u m ber of s a m ples  
T ot al v ol u me ( m L)  
P har mac o ki netics  
M P A: a b o ut 5 m L  
3 2  
1 6 0 m L  
Cli nical la b orat or y  
He m o gl o bi n: a b o ut 5 m L  
Li ver e nz y mes: a b o ut 5 m L  
P: a b o ut 5 m L  
E 2: a b o ut 5 m L  
 
He m o gl o bi n: 1  
Li ver e nz y mes: 5  
P: 6  
E 2: 2 5  
He m o gl o bi n: 5 m L  
Li ver e nz y mes: 2 5 
m L  
P: 3 0 m L  
E 2: 1 2 5 m L  
A p pr o xi m ate T ot al  
 
6 9  
3 4 5 m L  
M P A: Me dr o x y pr o gester o ne acetate  
4. 9.  
Wit h dr a w al of S u bjects  
4. 9. 1.  
S u bject Wit h dr a w al Criteri a a n d Pr o ce d ures  
I n acc or da n ce wit h t he D eclarati o n of Helsi n ki, eac h s u bject is free t o wit h dra w fr o m t he st u d y at 
a n y ti me. T h e i n vesti gat or als o has t he ri g ht t o wit h dra w a s u b ject fr o m t he st u d y i n t he e ve nt of 
i nterc urre nt ill ness, a d verse e ve nts, pre g na nc y (see Secti o n  5. 1 ) or ot her reas o ns c o ncer ni n g t he 
healt h or well -b e i n g of t he s u bject, or i n t he e v e nt of lac k of c o o perati o n.  
S h o ul d a s u bject deci de t o wit h dra w fr o m t he st u d y, or s h o ul d t he i n vesti gat or deci de t o 
wit h dra w t he s u bject, e ver y reas o n a ble eff ort will be ma de t o assess i nf or mati o n rele va nt t o t he 
e n d p oi nts  at t he ti me of disc o nti n uati o n. T his ma y i ncl u de b ut ma y n ot b e li mite d t o M P A 
testi n g, pre g n a nc y testi n g, ass ess me nt of I S Rs a n d/ or acce pta bilit y. T he fi nal visit pr oce d ures 
will be f oll o we d f or all s u bjects w h o  wit h dra w, if p ossi ble (see  Secti o n  3. 4 ).  
T he reas o n f or a n d date of wit h dra wal fr o m t he st u d y m ust be rec or de d o n t he s o urce 
d oc u me ntati o n a n d tra ns cri be d o nt o t he C R F. If a s u bject wit h dra ws c o ns e nt, e ver y atte m pt will 
be ma de t o deter mi ne t he reas o n.  
If t he i n vesti gat or det er mi nes t hat a n a d verse e v e nt is relate d t o t he test I M P, m o nit ori n g will 
c o nti n ue u ntil t he a d vers e e ve nt has res ol ve d or st a bilize d, t he s u bject e xite d t he st u d y or t he 
s u bject has reac he d t h e e n d of t he f oll o w-u p peri o d. T he i n vesti gat or m ust i nf or m F HI 3 6 0 as 
s o o n as p ossi ble of all s u bjects w h o are bei n g c o nsi dere d f or wit h dra wal d ue t o a d verse e ve nts. 
A d diti o nal re p orts m ust be pr o vi de d w h e n re q u este d.  
T he st u d y pr o d uct re m ai ns i n t he b o d y m o nt hs aft er t he i njecti o n, t heref ore, pr o m pt wit h dra wal 
fr o m t he st u d y tr eat me nt is n ot p ossi ble, a n d disc o nti n uati o n fr o m t he st u d y will n ot be t he sa me 
as wit h dra wal fr o m treat me nt. St u d y staff will e x plai n t o s u bjects w h o wi s h t o disc o nti n ue fr o m 
t he st u d y earl y t hat it is i m p ossi ble t o disc o nti n ue t he treat me nt a n d t hat it is i m p orta nt t o sta y i n 
t he st u d y u ntil safet y ass ess me nts are c o m plete d. 
4. 9. 2.  
L ost t o F oll o w -u p  
If a s u bject fails t o a p pear f or a s c he d ule d visit, at least 3 atte m pts t o c o ntact t he s u bject will be 
ma de. If s he d oes n ot ret ur n t o cli nic w hile t he st u d y is o n g oi n g t he n s he will be c o nsi dere d 
“ pres u me d l ost t o f oll o w -u p”, b ut her file will re mai n o pe n u ntil st u d y cl ose o ut. If t he s u bject 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 7  
d oes n ot ret ur n bef ore t h e st u d y is cl ose d, s h e will be classifie d as l ost t o f oll o w -u p. T he l ost t o 
f oll o w-u p desi g nati o n will n ot be ma de f or a n y s u bject u ntil t he cl osi n g dat e of t he st u d y.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 8  
5.  
S A F E T Y M E A S U R E M E N T S A N D A S S E S S M E N T S  
5. 1.  
S afet y a n d T oler a bilit y Me as ure me nts  
T he f oll o wi n g s afet y a n d l ocal t olera bilit y meas ures will be i m ple me nte d t hr o u g h o ut t he st u d y at 
t he ti me p oi nts liste d i n Ta ble  1 : 
•  occ urre nce of a d v erse e v e nts  
•  use o f c o nc o mita nt me di cati o n  
•  vital si g ns a n d b o d y wei g ht meas ure me nts  
•  va gi n al blee di n g patter n  
•  assess me nt of m o o d b y Patie nt Healt h Q uesti o n naire -9 ( P H Q -9)  
•  li ver f u ncti o n tests 
•  E 2 le vels  t hr o u g h o ut t he st u d y  
•  P meas ure me nts at W ee ks 4 8, 4 9, 5 0, 5 1, a n d 5 2  
•  o cc urre nce of I S Rs  
5. 1. 1.  
A d verse E ve nts  
I nf or mati o n o n a d verse e ve nts will be m o nit ore d t hr o u g h o ut t he st u d y as d etaile d i n Ta ble  1 . 
D uri n g s c he d ule d f oll o w -u p  visits, st u d y staff will pr oacti vel y as k st u d y s u bjects a b o ut a n y ne w 
or w orse ni n g me dical iss ues si nce t he pre vi o us visit. At all ot her visits i nf or mati o n o n a d verse 
e ve nts will be rec or de d if self -re p orte d b y st u d y s u bjects. 
See Secti o n  5. 2  f or det ails o n a d verse e ve nt r ec or di n g a n d re p orti n g. 
5. 1. 2.  
C o nc o mit a nt Me dic ati o n Use  
C o nc o mita nt t hera p y or me dicati o n usa ge will be m o nit ore d t hr o u g h o ut t he st u d y as  det aile d i n 
Ta ble  1 . 
D uri n g s c he d ule d f oll o w -u p visits, st u d y staff will pr oacti vel y as k st u d y s u bjects a b o ut a n y ne w 
me dicati o n si nce t he pre vi o us vis it. At all ot her visits i nf or mati o n o n c o nc o mita nt me dicati o n use 
will be rec or de d if self -re p orte d b y st u d y s u bjects. Details of pr o hi bite d me dicati o ns are f o u n d i n 
Secti o n  4. 6 .  
5. 1. 3.  
 Vit al Si g ns a n d B o d y Wei g ht Me as ure me nt  
Vital si g ns ( B P [s yst olic/ diast olic], te m perat ure, p ulse a n d res pir ati o n rate) a n d wei g ht will be 
meas ure d as detaile d i n  T a ble  1 . 
Bef ore p ulse a n d B P are meas ure d, t he s u bject m ust be i n a s u pi ne or se mi -erect/seate d p ositi o n 
a n d resti n g f or at least 5  mi n utes. T he sa me p ositi o n a n d ar m s h o ul d be use d eac h ti me vital 
si g ns are meas ure d f or a gi ve n s u bject. A n y vital si g n val ue t h at is j u d ge d b y t he i n vesti gat or as a 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
3 9  
p ote ntiall y cli nicall y si g nifica nt c ha n ge ( w orse ni n g) fr o m Da y 0 will be c o nsi dere d a n a d verse 
e ve nt.  
Wei g ht gai n or l oss will be d oc u me nte d as a n a d v erse e v e nt if c o nsi dere d cli nicall y si g nifica nt 
b y t he site i n vesti gat or.  
5. 1. 4.  
Assess me nt of V a gi n al Blee di n g  
St u d y s u bj ects will be as ke d a b o ut t heir va gi nal bl ee di n g patter n si nce last assess me nt d uri n g t he 
sc he d ule d f oll o w-u p visits at W ee ks 1 3, 2 6, a n d 5 2. I nte r vie w ite ms will i ncl u de date of l ast 
blee di n g, d escri pti o n of blee di n g p atter n si nce last visit, a n d its acce pta bilit y.  
5. 1. 5.  
Assess me nt of M o o d  
S u bjects  will be i nter vie we d a b o ut as p ects of a n d c ha n ges i n m o o d at e nr oll me nt a n d at pre -
defi ne d ti me p oi nts t hr o u g h o ut t he st u d y ( Ta bl e  1 ). T o meas ure d e pressi on or ps yc h ol o gi cal 
distress, a selecte d v ali date d scale bas e d o n t he 1 0 -ite m P H Q-9 ( Kr o e n ke  et al 2 0 0 1 ) will be use d 
t o ascertai n t he fre q u e nc y of a vari et y of s o matic a n d e m oti o nal i n dicat ors of well-bei n g a n d 
pr o d uce a n o v erall  sc ore f or t he se verit y of de pressi o n t hat will be c o m pare d bet wee n Da y 0 a n d 
differe nt ti me p oi nts i n t he st u d y.  
5. 1. 6.  
Li ver F u ncti o n Tests  
Li ver f u ncti o n testi n g will be perf or m e d b y t he i n v esti gati o nal ce nter la b orat or y as d etaile d i n 
Ta ble  1 . 
T he f oll o wi n g t ests will be i ncl u de d i n t he li ver pa nel:  
•  Al kali ne p h os p hatase ( A L P)  
•  As partate a mi n otra nsferase ( A S T)  
•  Ala ni ne a mi n otra nsf eras e ( A L T) 
•  T otal pr otei n  
•  Al b u mi n  
•  T otal a n d direct bilir u bi n  
All occ urre nces of p ossi ble dr u g i n d u ce d li ver i nj ur y t hat meet H y’s la w criteria, defi n e d as all of 
t he bel o w, m ust be re p ort e d b y t h e i n vesti gat or t o t he s p o ns or as a s eri o us a d verse e v e nt: 
•   A L T or A S T i ncrease of > 3 x t he u p per li mit of n or mal ( U L N)  
•  t otal bilir u bi n i ncrease of > 2 x U L N 
•  a bse nce of i nitial fi n di n gs of c h olestasis (ie, n o s u bsta ntial i ncrease of A L P)  
5. 1. 7.  
Estr a di ol Me as ure me nt  
All e nr olle d s u bjects will pr o vi de bl o o d f or E 2 meas ure me nt bef or e t h e i njecti o n t o d oc u me nt t he 
baseli ne le vel. D uri n g t h e st u d y, all s u bjects will ret ur n f or ser u m E 2 testi n g acc or di n g t o t he 
pre -defi ne d sc h e d ule ( T a ble  1 ). 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 0  
5. 1. 8.  
Assess me nt of Ret ur n t o O v ul ati o n at 5 2 Wee ks  
All e nr olle d s u bjects will pr o vi de bl o o d f or P meas ure me nt bef ore t he i njecti o n. D uri n g t he 
st u d y, all s u bjects will ret ur n f or ser u m P testi n g acc or di n g t o t he pre-defi ne d sc he d ule ( Ta ble  1 ).  
D uri n g t h e treat me nt p h ase of t he st u d y, if P is ≥4. 7  n g/ m L i n a si n gle sa m ple o v ulati o n will be 
c o nsi dere d c o nfir me d f or t he p ur p ose of t he  a nal ysis.  
5. 1. 9.  
I njecti o n Site Re acti o ns  
I nje cti o n site reacti o n (I S R) will be e val uate d as detaile d i n  Ta ble  1 . 
L ocal t olera bilit y will be assesse d b y occ urre nce of I S Rs i ncl u di n g b ut n ot li mite d t o er yt he ma 
(re d ness), s welli n g, pr urit us (itc hi n g), blee di n g, br uisi n g, i njecti o n site disc ol orati o n (e g, 
h y p o pi g me ntati o n), atr o p h y (ie, di m ple) or i njecti o n site pai n. F or t he p ur p ose of t his pr ot oc ol, 
i njecti o n site pai n will i ncl u de pai n ass oci ate d wit h i njecti o n a n d a n y pai n or te n der ness 
at/ar o u n d t he i njecti o n site.  
T he site of i njecti o n will be e val uat e d f or p ossi ble I S Rs after t he i njecti o n at least t wice d uri n g 
t he i njecti o n visit i m me diatel y (i e, as s o o n as p ossi ble b ut n o later t ha n 1 0 mi n utes u p o n 
re m o vi n g t he n ee dle) a n d 1 h o ur ( ± 5 mi n utes) after t he i njecti o n. I njecti o n sites will be 
m o nit ore d f or t he pr o gress of o n g oi n g a n d/ or o cc urre nce of ne w I S Rs. I f t he s u bject has ne w or 
o n g oi n g I S R at W ee k 5 2, s he will be f oll o we d e v er y 3 m o nt hs (at Wee ks 6 5 a n d 7 8) u ntil I S R 
res ol uti o n or Wee k 7 8, w hic he ver is earlier. All o n g oi n g I S Rs will be e x a mi ne d d uri n g t he ne xt 
cli nic visit, re gar dless of visit t y pe, or m ore fre q u e ntl y at t he discreti o n of t he i n vesti gat or, u ntil 
I S R res ol uti o n, or t he fi n al visit, w hic he ver occ urs first.  
I S Rs will be e val uat e d at all st u d y ti me p oi nts liste d i n Ta ble  1  b y s u bj ect’s self -re p orts a n d 
vis ual e x a mi nati o n of t he site of i njecti o n b y bli n d e d st u d y staff. T he st u d y staff will be 
i nstr ucte d t o use n o n-lea di n g q uesti o ns (e g, “ D o y o u ha v e a n y n e w me dical iss ues si nce pre vi o us 
visit? ”) f or I S R ascertai n me nt.  If t he s u bject r e p orts injecti o n site pai n at a n y ti me d uri n g t he 
st u d y, s he will be as k e d t o assess t he pai n usi n g a n 1 1-p oi nt N u meric Rati n g Scal e ( N R S) b y 
i n dicati n g a n u m b er bet w ee n 0 ( n o pai n) a n d 1 0 ( w orst pai n).  
All fi n di n gs will be rec or de d o n t he a p pr o priate st u d y C R Fs a n d cli nical n otes. P h ot os of t he 
i njecti o n site ma y be t a ke n t o s u p ple me nt d oc u me ntati o n of I S Rs a n y ti me d uri n g t he st u d y. All 
cases of i nje cti o n site disc ol orati o n ( h y p o pi g me nt ati o n) will be p h ot o gra p h e d. If necessar y, a 
c o ns ultati o n wit h a n a p pr o priate  cli nical e x pert ma y be s c he d ule d.  
T he f oll o wi n g I S Rs will be d oc u me nte d as a d verse e ve nts:  
•  I nje cti o n site pai n wit h a n N R S sc ore of 7 t o 1 0 
•  I nje cti o n site pr urit us/itc hi n g if itc hi n g l ocalize d t o t he i njecti o n site re q uiri n g ≥4 8 
h o urs of treat me nt O R ge neralize d itc hi n g ca usi n g i na bilit y t o p erf or m us u al s ocial 
a n d f u ncti o nal a cti vities  
•  I nje cti o n site er yt he ma/r e d ness of ≥5 c m i n dia met er ( or ≥ 2 5 c m 2 s urface area) or 
greater t ha n mi ni mal i nterfere nce wit h us ual s ocial a n d f u ncti o nal acti vities  
•  I nje ctio n site i n d urati o n/s welli n g of ≥5 c m i n dia meter ( or ≥ 2 5 c m 2 s urface area) or 
greater t ha n mi ni mal i nterfere nce wit h us ual s ocial a n d f u ncti o nal acti vities  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 1  
•  A n y I S R t hat meets t he d efi niti o n of “seri o us a d v erse e ve nt ”  
5. 1. 1 0.  
P h ysic al E x a mi n ati o ns  
P h ysical e x a mi n ati o n will be perf or m e d at scree ni n g t o defi n e i ncl usi o n/e xcl usi o n.  
5. 2.  
S afet y Assess me nts  
5. 2. 1.  
Defi niti o n of a n A d verse E ve nt  
A n a d vers e e ve nt is a n y u nt o war d me dical o cc urre nce i n a s u bject a d mi nistere d a p h ar mace utical 
pr o d uct, re gar dless of w h et her it has a ca usal r elati o ns hi p wit h t he treat me nt.  
I n t his st u d y, a n y a d v erse e ve nt occ urri n g aft er t he cli nical st u d y s u bject has si g ne d t he I C F 
t hr o u g h t he e n d of t he f oll o w-u p peri o d s h o ul d be rec or de d a n d re p orte d as a n a d verse e v e nt. A n 
a d verse e ve nt oc c urri n g d u ri n g or after st u d y i njecti o n is referre d t o as a tr eat me nt e mer ge nt 
a d verse e ve nt  
A ne w c o n diti o n or t he w orse ni n g of a pre -e xisti n g c o n diti o n will be c o nsi dere d a n a d verse 
e ve nt. Sta ble c hr o nic c o n diti o ns (s uc h as art hritis) t hat are prese nt bef ore st u d y  e ntr y a n d d o n ot 
w orse n d uri n g t his st u d y will n ot be c o nsi dere d a d verse e v e nts.  
Acc or di n gl y, a n a d vers e e ve nt ca n i n cl u de a n y of t he f oll o wi n g:  
•  i nterc urre nt ill nesses 
•  p h ysical i nj uries  
•  e ve nts p ossi bl y relate d t o c o nc o mita nt me dicati o n  
•  si g nifica nt w orse ni n g (c h a n ge i n nat ure, s e verit y, or fre q u e nc y) of pre-e xisti n g 
c o n diti o ns ( N ote: A c o n diti o n rec or de d as pre -e xisti n g t hat is i nter mitte ntl y 
s y m pt o matic [e g, h ea d ac he] a n d t hat occ urs d uri n g t his st u d y s h o ul d be rec or de d as 
a n a d vers e e v e nt.)  
•  dr u g i nteract i o ns 
•  e ve nts occ urri n g d uri n g dia g n ostic pr o ce d ures  
•  la b orat or y or dia g n ostic t est a b n or malities, t hat res ult i n t he wit h dra wal of t he s u bject 
fr o m t he st u d y, are ass ociate d wit h cli nical si g ns a n d s y m pt o ms or a seri o us a d verse 
e ve nt, or re q uire me dical tre at me nt or f urt her dia g n ostic w or k -u p, or are c o nsi dere d 
b y t he i n vesti gat or t o b e cli nicall y si g nifica nt ( N ote: A b n or mal la b orat or y t est res ults 
at t he scree ni n g visit t hat precl u de a s u bject fr o m e nteri n g t he st u d y or recei vi n g 
st u d y treat me nt are n ot c o nsi dere d a d v erse e ve nts.)  
•  all e ve nts of p ossi ble dr u g i n d uce d li ver i nj ur y ( Secti o n 5. 1. 6  ) 
•  a n y p h ysi cal e x a mi nati o n, vital si g ns meas ure me nt, electr ocar di o gra m, or ot her safet y 
assess me nt fi n di n g t hat is j u d ge d b y t he i n vesti gat or as a cli nicall y si g nifica nt c ha n ge 
( w orse ni n g) c o m pare d wit h a baseli ne val ue will be c o nsi dere d a n a d v erse e ve nt  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 2  
•  F or t he p ur p os e of t his st u d y, irre g ular v a gi nal blee di n g will n ot be c o nsi dere d a n 
a d verse e ve nt u nless it re q uires me dical i nter v e nti o n or meets t he defi niti o n of 
“seri o us a d verse e ve nt” ( See Secti o n  5. 2. 5 ). 
5. 2. 2.  
Rec or di n g a n d Re p orti n g A d verse E ve nts  
F or a d v erse e ve nt r ec or di n g, t he st u d y peri o d is defi ne d f or eac h s u bject as t hat ti me peri o d fr o m 
si g nat ur e of t he I C F t hr o u g h t he e n d of t he f oll o w-u p per i o d. F or t his st u d y, t he f oll o w-u p peri o d 
is defi ne d as u p t o 7 8 wee ks after t h e last d ose of I M P.   
All a d verse e ve nts t hat o cc ur d uri n g t he defi ne d st u d y peri o d m ust be rec or de d o n t he s o urce 
d oc u me ntati o n a n d tra ns cri be d o nt o t he C R F, re gar dless of t he s e verit y of t he e ve nt or j u d ge d 
relati o ns hi p t o t he I M P. F or seri o us a d verse e ve nts, a Seri o us a n d Pr ot oc ol Defi ne d A d verse 
E ve nt F or m m ust als o be c o m plete d a n d m ust be re p orte d i m me diatel y.  T h e i n vesti gat or d oes n ot 
nee d t o acti vel y m o nit or s u bjects f or ad v erse e ve nts o nce t heir f oll o w -u p p eri o d has e n d e d. 
Seri o us a d verse e ve nts o cc urri n g i n a s u bject aft er st u d y disc o nti n uati o n will be re p orte d t o t he 
s p o ns or if t he i n vesti gat or bec o mes a ware of t he m, f oll o wi n g t he pr o ce d ures descri be d i n 
Secti o n  5. 2. 5. 3 . 
At t he sc he d ule d visits, t he i n vesti gat or will q uesti o n t he s u bject a b o ut a d v erse e v e nts b y as ki n g 
a n o pe n-e n d e d q uesti o n s uc h as, “ H a ve y o u h a d a n y u n us ual s y m pt o ms or me dical pr o ble ms 
si nce t he last visit? If yes, please des cri be.” At all ot her visits i nf or mati o n o n a d verse e ve nts will 
be rec or de d if s elf -re p ort e d b y st u d y s u bjects. All o bser ve d or re p ort e d si g ns a n d s y m pt o ms will 
be rec or de d i n di vi d uall y, e x ce pt w he n c o nsi dere d ma nifestati o ns of a me di cal c o n diti o n or 
disease state. A precise dia g n osis will be rec or de d w he ne ver p ossi ble. W he n s uc h a dia g n osis is 
ma de, all relat e d si g ns, s y m pt o ms, a n d a n y test fi n di n gs will be rec or de d c ollecti vel y as  a si n gle 
dia g n osis o n t he C R F a n d, if it is a seri o us or pr ot oc ol defi ne d a d v erse e ve nt, o n t he Seri o us 
A d verse E v e nt F or m.  
T he cli nical c o urs e of eac h a d vers e e v e nt will be m o nit ore d at s uita ble i nter vals u ntil res ol ve d or 
sta bilize d or ret ur ne d t o baseli ne, t hr o u g h t he s u bject’s fi nal st u d y visit. 
T he o nset a n d e n d d ates a n d ti mes, acti o n ta ke n re gar di n g I M P, treat me nt a d mi nistere d, a n d 
o utc o me f or eac h a d vers e e ve nt m ust be rec or de d o n t he s o urce d o c u me ntati o n a n d tra nscri be d 
o nt o t he C R F.  
T he relati o ns hi p of eac h a d verse e ve nt t o I M P a n d st u d y pr oce d ures, a n d t h e se verit y a n d 
seri o us ness of eac h a d v erse e ve nt, as j u d ge d b y t h e i n vesti gat or, m ust be rec or de d as d escri b e d 
i n Secti o n 5. 2. 3 , Secti o n 5. 2. 4 , a n d Secti o n 5. 2. 5 . 
5. 2. 3.  
Se verit y of a n A d verse E ve nt  
T he se verit y of eac h a d v erse e v e nt m ust be rec or de d as 1 of t he c h oices o n t he f oll o wi n g scale:  
Mil d:  
  
N o li mitati o n of us ual acti vities  
M o der ate:  
S o me li mitati o n of us ual acti vities  
Se vere:    
I n a bilit y t o carr y o ut us u al acti vities 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 3  
5. 2. 4.  
Rel ati o ns hi p of a n A d verse E ve nt t o t he I M P  
T he relati o ns hi p of a n a d verse e v e nt t o t he I M P is c haracterize d as f oll o ws:  
Ter m  
Defi niti o n  
Cl arific ati o n  
N o reas o na ble 
p ossi bilit y  
( n ot relate d) 
T his cate g or y a p plies t o a d verse 
e ve nts t hat, after caref ul 
c o nsi derati o n, are clearl y d ue t o 
e xtra ne o us ca uses ( disea se, 
e n vir o n me nt, etc.) or t o a d verse 
e ve nts t hat, after caref ul me di cal 
c o nsi derati o n at t he ti me t he y are 
e val uate d, are j u d ge d t o be 
u nrelate d t o t he I M P.  
T he relati o ns hi p of a n a d verse e ve nt ma y be c o nsi dere d “ n o 
reas o na ble p ossi bilit y” if it is clearl y d ue t o e xtra ne o us ca us es 
or if at least 2 of t he f oll o wi n g a p pl y:  
•  
It d oes n ot f oll o w a reas o na bl e te m p oral se q ue nce fr o m 
t he a d mi nistrati o n of t he I M P. 
•  
It c o ul d rea dil y ha ve bee n pr o d uce d b y t he s u bj ect’s 
cli nical state, e n vir o n me ntal, or t o xic fact ors, or ot her 
m o des of t hera p y a d mi nistere d t o t he s u bj ect.  
•  
It d oes n ot f oll o w a k n o w n patter n of res p o nse t o t he 
I M P.  
•  
It d oes n ot rea p pear or w orse n w he n t he I M P is 
re-a d mi nistere d.  
Reas o na ble 
p ossi bilit y  
(relate d) 
T his cate g or y a p plies t o a d verse 
e ve nts f or w hic h, after caref ul 
me dical c o nsi derati o n at t he ti me 
t he y are e val uate d, a c o n necti o n 
wit h t he I M P a d mi nistrati o n 
ca n n ot b e r ule d o ut wit h 
certai nt y.  
T he relati o ns hi p of a n a d verse e ve nt ma y be c o nsi dere d 
“reas o na ble p ossi bilit y” if at l east 2 of t he  f oll o wi n g a p pl y: 
•  
It f oll o ws a reas o na ble te m p or al se q ue nce fr o m 
a d mi nistrati o n of t he I M P.  
•  
It ca n n ot be reas o na bl y e x plai ne d b y t he k n o w n 
c haracteristics of t he s u bj ect’s cli nical state, 
e n vir o n me ntal or t o xic fact ors or ot her m o des of t hera p y 
a d mi nistere d t o t he s u bj ect.  
•  
It disa p pears or decreases o n cessati o n or re d ucti o n i n 
d ose. T here are i m p orta nt e xc e pti o ns w he n a n a d verse 
e ve nt d oes n ot disa p pear u p o n disc o nti n uati o n of t he I M P, 
yet a n I M P relati o ns hi p clearl y e xists. 
•  
It f oll o ws a k n o w n patter n of res p o nse t o t he I M P.  
5. 2. 5.  
Seri o us A d verse E ve nts  
5. 2. 5. 1.  
Defi niti o n of a Seri o us A d verse E ve nt  
A seri o us a d verse e v e nt is a n a d vers e e ve nt o cc urri n g at a n y d os e t hat res ults i n a n y of t he 
f oll o wi n g o utc o mes or acti o ns: 
•  deat h  
•  a life-t hreate ni n g a d v erse e ve nt (ie, t he s u bject was at i m me diate ris k of deat h fr o m 
t he e ve nt as it occ urre d); d oes n ot i ncl u de a n e v e nt t hat, ha d it occ urre d i n a m ore 
se vere f or m, mi g ht h a ve ca use d deat h 
•  i n patie nt h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n, w hic h mea ns t hat 
h o s pital i n patie nt a d missi o n a n d/ or pr ol o n gati o n of h os pital sta y were re q uire d f or 
treat me nt of a n a d vers e e ve nt, or t hat t he y occ urre d as a c o nse q u e nce of t he e ve nt. 
H os pitalizati o ns sc he d ule d pri or t o st u d y e ntr y will n ot be c o nsi dere d seri o us a d verse 
e vents, u nless t here was w orse ni n g of t he pree xisti n g c o n diti o n d uri n g t he s u bject’s 
partici pati o n i n t his st u d y   
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 4  
•  persiste nt or si g nifi ca nt disa bilit y or i nca p acit y (refers t o a s u bsta ntial disr u pti o n of 
o ne’s a bilit y t o c o n d u ct n or mal life f u ncti o ns)  
•  a c o n genital a n o m al y/ birt h defect  
•  a n i m p orta nt me dical e v e nt t hat ma y n ot res ult i n deat h, be life -t hreat e ni n g, or re q uire 
h os pitaliz ati o n, b ut ma y j e o par dize t he s u bject a n d ma y re q uire m e dical i nter ve nti o n 
t o pre ve nt o ne of t h e o utc o mes liste d i n t his defi niti on. E x a m ples of s uc h e ve nts are 
i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me f or aller gi c br o nc h os pas m; 
bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; or t he 
de vel o p me nt of dr u g d e p e n de nc y or dr u g a b us e. N ote: A n y s us p ecte d tr a ns missi o n of 
a n i nfecti o us a ge nt via a me dici nal pr o d uct is c o nsi dere d a n i m p orta nt me dical e ve nt  
A n a d vers e e ve nt t hat d o es n ot meet a n y of t he criteria f or seri o us ness liste d a b o ve will be 
re gar de d as a n o ns eri o us a d verse e ve nt. 
5. 2. 5. 2.  
E x pecte d ness  
A seri o us a d verse e v e nt t hat is n ot i ncl u de d i n t he A d verse Reacti o n Secti o n  of t he rele va nt 
refere nce safet y i nf or mati o n ( R SI) b y its s pecificit y, se v erit y, o utc o me, or fre q ue nc y is 
c o nsi dere d a n u ne x pecte d a d verse e ve nt. T he R SI f or t his st u d y is t he c urre nt I B f or  T V -4 6 0 4 6, 
a n d U S prescri bi n g i nf or mati o n f or De p o -S u b Q Pr o vera 1 0 4, De p o -Pr o vera CI a n d  
De p o Pr o vera 4 0 0 m g/ m L ( De p o -s u b Q Pr o vera 1 0 4 U S prescri bi n g i nf or mati o n 2 0 1 6 , De p o -
Pr o vera  CI U S pr escri bi n g i nf or m ati o n 2 0 1 6 , a n d De p o -Pr o vera  Sterile A q ue o us S us pe nsi o n U S 
prescri bi n g i nf or mati o n 2 0 1 7 ).  
T he s p o ns or’s P har mac o vi gila nce De p art me nt will deter mi ne t he e x pecte d ness f or all seri o us 
a d verse e ve nts.  
F or t he p ur p os e of S U S A R re p orti n g, t he v ersi o n of t he I B at t he ti me of o cc urre nce of t he 
S U S A R a p plies.  
5. 2. 5. 3.  
Seri o us A d verse E ve nt M a n a ge me nt Pl a n  
T he o bjecti ve of t h e Seri o us A d verse E v e nt Ma na ge m e nt Pla n ( S M P) is t o esta blis h t he 
res p o nsi bilities a n d pr oce d ures f or recei vi n g, pr ocessi n g, re p orti ng, rec o nciliati o n a n d f oll o wi n g 
u p of seri o us a d verse e v e nts.  T he S M P will be fi nalize d pri or t o st u d y i nitiati o n.  
5. 2. 5. 3. 1.  I n vesti g at or Res p o nsi bilit y 
All seri o us a d vers e e ve nts t hat occ ur d uri n g t he st u d y peri o d (i ncl u di n g t he pr ot oc ol defi ne d 
f oll o w-u p peri o d, re gar dl ess of j u d ge d rel ati o ns hi p t o treat me nt wit h t he st u d y dr u g), m ust be 
re p orte d t o t he s p o ns or b y t he i n vesti gat or p er t he pr oce d ures s pecifi e d i n t he S M P. T he e ve nt 
m ust be re p orte d wit hi n 2 4 h o urs of w he n t he i n v esti gat or l ear ns a b o ut it. C o m pleti n g t he 
Seri o us a n d Pr ot oc ol Defi ne d A d verse E ve nt F or m a n d re p orti n g t he e v e nt m ust n ot be dela ye d, 
e ve n if n ot all t he i nf or m ati o n is a vaila ble.  
T he f oll o wi n g i nf or mati o n s h o ul d be pr o vi de d t o rec or d t he e ve nt acc uratel y a n d c o m pletel y:  
•  st u d y n u m ber 
•  i n vesti gat or a n d i n vesti gati o nal ce nter i d e ntificati o n 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 5  
•  s u bject i de ntificati o n n u m ber 
•  o nset date a n d det aile d d escri pti o n of a d verse e v e nt  
•  i n vesti gat or's ass ess me nt of t he relati o ns hi p of t he a d verse e ve nt t o t he st u d y dr u g ( n o 
reas o na bl e p ossi bilit y, reas o na ble p ossi bilit y)  
A d diti o nal i nf or mati o n ma y i ncl u d e t he f oll o wi n g:  
•  a ge a n d se x of s u bject  
•  date of st u d y dr u g i njecti o n  
•  acti o n ta ke n  
•  o utc o me, if k n o w n  
•  se verit y 
•  e x pla nati o n of assess me nt of relate d n ess  
•  c o nc o mita nt t hera p y (i ncl u di n g d oses, r o utes a n d re gi me ns) a n d tr eat me nt of t he 
e ve nt  
− perti ne nt la b orat or y or ot her dia g n ostic test data  
− me dical hist or y  
− f or a n a d v erse e ve nt r es ulti n g i n deat h: 
○ ca use of deat h ( w het her or n ot t he deat h was relat e d t o st u d y dr u g)  
○ a ut o ps y fi n di n gs (if a vail a ble)  
T he i n vesti gat or d oe s n ot nee d t o acti vel y m o nit or s u bjects f or a d v erse e ve nts o nce t heir f oll o w -
u p peri o d has e n d e d. Seri o us a d verse e ve nts oc c urri n g after st u d y disc o nti n uati o n will be 
re p orte d t o t he s p o ns or wit hi n 2 4 h o urs fr o m w he n t he i n vesti gat or b ec o mes a ware of t he m, 
f oll o wi n g t he pr o ce d ures descri be d i n Secti o n 5. 2. 5. 3 . 
Eac h re p ort of a s eri o us a d verse e v e nt will be re vi e we d a n d e val uat e d b y t he i n vesti gat or a n d t he 
s p o ns or t o assess t he nat ure of t he e ve nt a n d t he relati o ns hi p of t he e ve nt t o t he st u d y dr u g, a n d 
st u d y pr oce d ures.  
If a d diti o nal (f oll o w-u p) i nf or mati o n a b o ut a seri o us a d verse e ve nt bec o mes a vaila ble, t he 
i n vesti gat or will f or war d it t o t he s p o ns or wit hi n 2 4 h o urs. 
Bli n di n g will be mai ntai ne d f or t he p e o ple w h o are directl y i n v ol ve d i n t h e st u d y e x ce pt f or 
a ut h orize d u n bli n de d staff. I n t he case of a S U S A R,  o nl y t he s p o ns or a n d a desi g nat e d u n bli n de d 
F HI 3 6 0 staff will recei v e t he u n bli n de d re p ort f or re g ulat or y s u b missi o n; ot her staff will recei ve 
a bli n de d re p ort.  
5. 2. 5. 3. 2.  S p o ns or Res p o nsi bilit y  
If a seri o us u ne x pecte d a d verse e v e nt is belie ve d t o be relate d t o t he st u d y dr u g or st u d y 
pr oce d ures, t he s p o ns or will ta ke a p pr o priat e ste ps t o n otif y all i n vesti gat ors partici pati n g i n 
s p o ns ore d cli nical st u dies of T V-4 6 0 4 6 a n d t he a p pr o priate healt h a ut h orities a n d I R B/I E C, if 
a p pr o priate.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 6  
I n a d diti o n t o n otif yi n g t he in vesti gat ors a n d healt h a ut h orities (a n d I R B/I E C, if a p pr o priate), 
ot her meas ur es ma y be re q uire d, i ncl u di n g t he f oll o wi n g:  
•  a me n di n g t h e pr ot oc ol  
•  disc o nti n ui n g or s us pe n di n g t he st u d y  
•  i nf or mi n g c urre nt st u d y s u bjects of ne w fi n di n gs b y a m e n di n g t h e e xistin g I C F  a n d 
re-c o ns e nti n g all s u bjects  
•  m o dif yi n g listi n gs of e x pecte d t o xicities t o i ncl u de a d verse e v e nts ne wl y i de ntifie d as 
relate d t o T V-4 6 0 4 6  
5. 2. 6.  
Pr ot oc ol D efi ne d A d verse E ve nts f or E x pe dite d Re p orti n g  
N o pr ot oc ol -defi ne d a d v erse e v e nts f or e x pe dite d re p or ti n g t o Te va are i d e ntifie d f or t his st u d y. 
5. 2. 7.  
Me dic ati o n Err or a n d S peci al Sit u ati o ns Rel ate d t o t he I n vesti g ati o n al 
Me dici n al Pr o d ucts  
A n y a d mi nistrati o n of I M P t hat is n ot i n acc or da nce wit h t he st u d y pr ot oc ol  will be rec or de d as a 
de viati o n. If it meets t he i m p orta nt pr ot oc ol de viati o n  criteria, t he i nc orrect I M P a d mi nistrati o n 
will be cate g orize d as “ N o n -C o m plia nce t o I n vesti gati o nal Me di ci nal Pr o d uct ( I M P).” 
T he f oll o wi n g are t y p es of me dicati o n err ors a n d s pecial sit uati o ns:  
•  Me dicati o n err or: A n y u ni nte nti o nal err or i n t he prescri bi n g, dis pe nsi n g, or 
a d mi nistrati o n of a me dici nal pr o d uct w hile i n t he c o ntr ol of t he healt hcare 
pr ofessi o nal, patie nt, or c o ns u mer.  
•  O ver d ose: A d mi nistrati o n of a q ua ntit y of a me di ci nal pr o d uct gi ve n per 
a d mi nistrati o n or c u m u lati vel y w hic h is a b o v e t he ma xi m u m rec o m me n de d d ose 
acc or di n g t o t he a ut h orize d pr o d uct i nf or mati o n. Cli nical j u d g me nt s h o ul d al wa ys be 
a p plie d. A n y d ose of I M P ( w het her t he test I M P, refere nce I M P, or place b o I M P), 
w het her ta k e n i nte nti o nall y or u ni nte nt i o nall y, i n e x cess of t hat prescri be d m ust be 
i m me diatel y re p orte d t o t he s p o ns or.  
•  Mis use: A n y i nte nti o nal t hera pe utic us e of a dr u g pr o d uct i n a n i na p pr o pri ate wa y or 
o pi oi d use c o ntrar y t o t he directe d or prescri be d patter n of use, re gar dless of t he 
pre se nce or a bs e nce of har m or a d v erse effects. E x a m ples: u n der usa ge, erratic or 
dis or ga niz e d use, i na p pr o priate use (f or a n xiet y), i n c o nj u ncti o n wit h alc o h ol or 
ille gal s u bsta nces, o ver us e. 
•  A b use: A n y i nte nti o nal, n o nt hera pe utic us e of a dr u g pr o d uct or s u bsta n ce, e ve n 
o nce, f or t h e p ur p ose of ac hie vi n g a desir a ble ps yc h ol o gical or p h ysi ol o gical effect, 
or i nte nti o nal use of t he o pi oi d f or a n o n me dical p ur p ose, s uc h as e u p h ori a or alteri n g 
o ne’s state of c o nsci o us n ess.  
•  Off -la b el use: Sit uati o ns w here a n I M P is i nte nti o nall y use d f or a me di cal p ur p ose n ot 
i n acc or da nce wit h t he a ut h orize d pr o d uct i nf or mati o n. 
•  Occ u pati o nal e x p os ure: E x p os ure t o a n I M P, as a res ult of o ne’s pr ofessi o nal or 
n o n -pr ofessi o nal o cc u pati o n.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 7  
•  Breastfee di n g: S us pect e d a d verse e ve nts w hic h o cc ur i n i nfa nts f oll o wi n g e x p os ure t o 
a me dici nal pr o d uct fr o m breast mil k.  
5. 2. 8.  
Pr ot oc ol D e vi ati o ns Bec a use of a n A d verse E ve nt  
If a s u bject e x perie nces a n a d verse e ve nt or me di cal e mer ge n c y, de p art ures fr o m t he pr ot oc ol 
ma y b e all o we d o n a cas e -b y -case basis. After sta bilizati o n a n d/ or treat me n t has bee n 
a d mi nistere d t o e ns ure s u bject safet y, t he i n v esti gat or or ot her p h ysicia n i n atte n da nce m ust 
c o ntact t he p h ysicia n i de ntifie d i n t he Cli nical St u d y Pers o n nel C o ntact I nf or mati o n secti o n  of 
t his pr ot oc ol (A p pe n di x  A ) as s o o n as p ossi ble t o disc uss t he sit uati o n. T he i n vesti gat or, i n 
c o ns ultati o n wit h t he s p o ns or, will deci de w het h er t he s u bject s h o ul d c o nti n ue t o partici pate i n 
t he st u d y. 
5. 2. 9.  
Pre g n a nc y  
T he ris k of pre g na nc y is mi ni mal d ue t o t he fact t hat o nl y w o me n w h o are at l o w ris k of 
pre g na nc y will be e nr olle d i n t he st u d y (see Secti o n  3. 2. 1  f or I ncl usi o n Criteria). O nl y w o m e n 
w h o are n ot pr e g na nt o n t he da y of t he st u d y i njecti o n a n d d o n ot wa nt t o bec o me pre g na nt i n t he 
ne xt 2 4 m o nt hs will be e nr olle d i n t he st u d y. D uri n g t he st u d y, a pre g na n c y  test will be 
perf or me d as detaile d i n Ta ble  1 , a n d at a n y ti me t he w o ma n is e x perie nci n g a n y s y m pt o ms or 
si g ns of pre g na nc y, or t hi n ks s he ma y b e pre g na nt. I n t he u nli kel y e ve nt of pre g na nc y, a n y 
s u bject bec o mi n g pre g n a nt d uri n g t he st u d y will be wit h dra w n a n d pre g n a n c y rec or de d as reas o n 
f or disc o nti n uati o n o n a p pr o priate st u d y C R Fs. Pre g n a nc y will be re p orte d i m me diatel y t o t he 
i n di vi d ual i de ntifie d i n t he cli nical st u d y p ers o n nel c o ntact i nf or mati o n se cti o n of t his pr ot oc ol, 
a n d t he i n vesti gat or m ust pr o vi de t he s p o ns or wit h t he pre g na n c y f or m. T h e pr ocess f or re p orti n g 
a pre g na n c y is t he sa me as t hat f or re p orti n g a seri o us a d verse e ve nt b ut usi n g t he  pre g na nc y 
f or m. T he i n vesti gat or is n ot re q uire d t o re p ort s u bjects w h o are f o u n d t o be pre g na nt bet wee n 
scree ni n g a n d e nr oll me nt.  
All s u bjects w h o bec o me pre g na nt will be m o nit ore d  f or t he o utc o m e of t he pre g na nc y 
(i ncl u di n g s p o nta n e o us, electi ve, or v ol u ntar y a b orti o n). If t he pre g na nc y c o nti n ues t o ter m, t he 
o utc o me ( healt h of t h e i nfa nt u p t o 8  wee ks of a ge), i ncl u di n g det ails of birt h a n d prese n ce or 
a bse nce of a n y birt h defect, c o n ge nital a b n or m alities, or mater nal a n d ne w b or n c o m plicati o ns, 
will be  re p orte d t o t he s p o ns or. A n y c o m plicati o n of pre g na n c y d uri n g t he st u d y a n d a n y 
c o m plicati o n of pre g n a nc y t hat t he i n vesti gat or b ec o mes a ware of after wit h dra wal fr o m t he 
st u d y will be re p orte d as a n a d vers e e v e nt or seri o us a d verse e ve nt, as a p pr o priate.  
If t he pre g n a nc y i n t he w o ma n partici pati n g i n t he st u d y d oes n ot c o nti n ue t o ter m, 1 of t he 
f oll o wi n g acti o ns will be ta ke n: 
•  F or a s p o nta n e o us a b orti o n, re p ort as a seri o us a d verse e v e nt.  
•  F or a n electi ve a b orti o n d ue t o de vel o p me ntal a n o malies, re p ort as  a seri o us a d verse 
e ve nt.  
•  F or a n electi ve a b orti o n n ot  d ue t o de vel o p me ntal a n o malies, re p ort o n t he pre g na nc y 
f or m; d o n ot re p ort as a n a d verse e ve nt. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 8  
6.  
P H A R M A C O KI N E TI C  M E A S U R E M E N T S A N D A S S E S S M E N T S  
6. 1.  
Ti mi n g of P h ar m ac o ki netic S a m pli n g  
Bl o o d sa m ples (a p pr o xi matel y 5 m L) will be o btai ne d via ve ni p u nct ure or i n d welli n g cat heter 
bef ore a n d t hr o u g h 5 2 w ee ks ( 3 6 5 da ys) aft er T V -4 6 0 4 6 a d mi nistrati o n f or deter mi nati o n of 
ser u m c o nce ntrati o n of M P A at t he ti me p oi nts detaile d i n Ta ble  1 . S peci me n c ollecti o n, 
pr ocessi n g, a n d h a n dli n g re q uire me nts are d etaile d i n A p pe n di x  B . W he n t he p har mac o ki netic 
bl o o d sa m ple c ollecti o n c oi nci des wit h vital si g n assess me nt, assess me nt of vital si g ns s h o ul d 
prece d e p har mac o ki netic bl o o d sa m pli n g.  
6. 2.  
P h ar m ac o ki netic P ar a meters  
T he f oll o wi n g p h ar mac o ki netic pa ra met ers will be calc ul ate d fr o m c o n ce ntrati o n-ti me data usi n g 
n o n -c o m part me ntal met h o ds, w he n p ossi ble:  
T he f oll o wi n g n o n -e x ha usti ve list of p har mac o ki n etic para m eters will be e val uate d t o s u p p ort t he 
pri mar y o bjecti ve of t h e st u d y:  
•  C ma x  (ma xi m u m o bser ve d  ser u m dr u g c o n ce ntrati o n) 
•  T ma x  (ti me t o Cma x ) 
•  Ser u m M P A c o nce ntr ati o ns at treat me nt da ys 9 1, 1 8 2, a n d 2 1 0 ( C 9 1, C1 8 2, C2 1 0) 
•  A U C 0 -1 8 2 (area u n d er t he ser u m dr u g c o n ce ntrati o n-ti me c ur ve fr o m ti me 0 t o da y 
1 8 2); A U C 0 -2 1 0 ( A U C fr o m ti me 0 t o da y 2 1 0); a n d A U C 0 -∞ ( A U C e xtra p olate d t o 
i nfi nit y) 
•  A p pare nt ter mi nal half -life (t½ )  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
4 9  
7.  
P H A R M A C O D Y N A M I C M E A S U R E M E N T S A N D A S S E S S M E N T S   
7. 1.  
P h ar m ac o d y n a mics  
Please refer t o Secti o n  5  f or a des cri pti o n of E 2 a n d P assess me nts. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 0  
8.  
A C C E P T A BI LI T Y A S S E S S M E N T S   
T he acce pta bilit y of t he differe nt i nje cti o n d oses a n d treat me nt gr o u ps will be assesse d a n d 
rec or de d o n a p pr o priate st u d y C R Fs at Wee ks 2 6 a n d 5 2 b y bli n de d staff. Acce pta bilit y 
q uesti o ns will i ncl u de b ut n ot be li mite d t o q uesti o ns a b o ut w hat s he li kes a n d disli kes m ost 
a b o ut t his met h o d, a n d w het her s he w o ul d us e t his met h o d i n t he f ut ure a n d/ or rec o m me n d it t o a 
frie n d. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 1  
9.  
S T A TI S TI C S  
T his secti o n descri bes t h e statistical a nal ysis as f oresee n at t he ti me of pla n ni n g t he st u d y. 
C ha n ges, a d diti o ns, a n d f urt her details a b o ut t he a nal yses will be descri b e d i n t he statistical 
a nal ysis pla n. A n y s u bse q ue nt a d diti o nal a nal yses or c ha n ges t o a nal yses t hat ma y b e re q uire d 
will be f u ll y discl ose d i n t he cli nical st u d y re p ort.  
9. 1.  
S a m ple Size Deter mi n ati o n a n d R ati o n ale  
T he g o al of t he st u d y is t o select a d ose of T V -4 6 0 4 6 t hat is safe a n d well t olerate d, a n d h as a P K 
pr ofile c o nsiste nt wit h c o ntrace pti ve pr otecti o n w he n i njecte d e v er y 6 m o nt hs. Rec o g nizi n g t h at 
t here is n o f or mal h y p ot h esis test o n w hic h t o base sa me size calc ulati o ns, 1 5 s u bjects per 
treat me nt gr o u p (a p pr o xi matel y 6 0 i n t otal) are e x pecte d t o be s ufficie nt t o i nf or m d ose selecti o n 
b ase d o n data fr o m rece nt P K st u dies of M P A deli vere d s u bc ut a ne o usl y. 
 
 
 
 
 
 
 
 
 
T he i nte nt of t he  st u d y is t o ha ve a mi ni m u m of 5 4 s u bjects wit h e val ua ble data c o m plete 3 2 
wee ks per pr ot oc ol. A d diti o nal s u bjects ma y  b e e nr olle d t o c o m plete t he mi ni m u m n u m ber of 
e val ua ble s u bjects at t he discreti o n of t he S p o ns or. S R C will pr o vi de g ui da nce re gar di n g t h e 
val ue of e x pa n di n g e nr oll me nt a n d size of s uc h e x pa nsi o n t o hel p e ns ure t h at at least 5 4 s u bjects 
c o m plete 3 2 wee ks per pr ot oc ol.  
9. 2.  
Met h o d of R a n d o miz ati o n a n d Bli n di n g  
T his is a ra n d o mize d, partiall y -bli n de d st u d y. A p pr o xi matel y 6 0 s u bjects will be ra n d o m ize d i n a 
1: 1: 1: 1 rati o t o t he 4 treat me nt gr o u ps, str atifie d b y site. T he ra n d o mizati o n se q ue nce will be 
de vel o pe d b y a n F HI 3 6 0 Ra n d o mizati o n Statisticia n n ot ot her wise i n v ol ve d i n t he st u d y usi n g a 
vali date d pr o gra m writte n i n S A S ® . 
F HI 3 6 0 a n d s p o ns or pr oject tea m me m bers i n v ol ve d i n assess me nt of a d v erse e v e nts, data 
a nal ysis or res ults i nter pretati o n will be bli n de d t o treat me nt assi g n me nt u ntil t he pla n ne d i nteri m 
a nal ysis, after w hic h o nl y site staff perf or mi n g s u bject i nter vie ws a n d assessi n g safet y o ut c o mes 
will re mai n bli n de d.  
A descri pti o n of e mer ge n c y u n bli n di n g pr oce d ures will be descri be d i n t he st u d y p har m ac y 
ma n ual.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 2  
9. 3.  
A n al ysis Sets  
9. 3. 1.  
Scree ne d A n al ysis Set  
T he Scree ne d A n al ysis S et will i ncl u de all s u bjects w h o are s cree ne d f or st u d y partici pati o n, 
re gar dl ess of w het h er t he y are e nr olle d a n d ra n d o mize d. I n t his a nal ysis set, a nal ys es will be 
perf or me d acc or di n g t o e nr oll me nt stat us.  
9. 3. 2.  
R a n d o mize d A n al ysis Set  
T he Ra n d o mize d A nal ysis Set will i ncl u de all ra n d o mize d s u bjects, re gar dless of w het her t he y 
recei v e d a d ose of st u d y dr u g. T h e Ra n d o mize d A nal ysis Set will be use d f or assess me nt of 
s u bject dis p ositi o n. 
9. 3. 3.  
S afet y A n al ysis Set  
T he Safet y A n al ysis Set will be a s u bset of t he Ra n d o mize d A nal ysis Set, e x cl u di n g a n y s u bject 
w h o faile d t o recei ve a n i nj ecti o n of st u d y dr u g. S u bjects will be a nal yz e d acc or di n g t o treat me nt 
recei v e d, re gar dless of a n y all ocati o n err ors. T he S afet y A nal ysis Set will be use d f or all 
assess me nts of baseli ne, safet y, a n d acce pta bilit y data, as well as s e nsiti vit y a n al ys es of 
p har mac o ki netics d ata t h at i ncl u de all treat e d s u bjects, re gar dless of a n y e x cl usi o ns fr o m t he 
pri mar y p har mac o ki netics a nal ys es.  
9. 3. 4.  
P h ar m a c o ki netic A n al ysis Set  
T he P har mac o ki n etic A n al ysis Set will be a s u bset of t he  Safet y A nal ysis Set, e xcl u di n g a n y 
s u bjects w h o ha d a b aseli ne M P A c o nce ntr ati o n t hat e x cee de d 5 % of t heir i n di vi d ual Cma x , ha d 
a n i m p orta nt pr ot oc ol de viati o n t hat ma y affect i nter pretati o n of t he M P A data, or faile d t o 
pr o vi de at least o ne e val u a ble p ost -treat me nt M P A s peci me n. T he a nal ysis set will e x cl u de M P A 
data c ollecte d d uri n g ti me peri o ds w he n s u bj ects use d a c o nc o mita nt me di cati o n k n o w n t o 
i m pact t he p har mac o ki netics of M P A. I n t his a n al ysis set, s u bjects will be a nal yze d acc or di n g t o 
treat me nt recei ve d, re gar dless of a n y all ocati o n err ors. 
9. 4.  
D at a H a n dli n g C o n ve nti o ns  
Missi n g M P A c o nce ntr ati o ns at ke y ti me p oi nts (e g, start - a n d e n d -ti mes of partial areas u n der 
t he c o nce ntr ati o n-ti me c ur ve) will be i m p ute d, as a p pr o priate, usi n g met h o ds s pecifie d i n t he 
statistical a nal ysis pla n. 
9. 4. 1.  
H a n dli n g W it h dr a w als a n d Missi n g D at a 
I n c o m plete a d v erse e ve nt o nset or c o nc o mita nt me dicati o n use dates ma y als o be i m p ute d or 
a dj u dicate d t o assess safet y or w h e n ce ns ori n g s u bjects fr o m  a nal ys es d ue t o pr o hi bite d 
me dicati o n use.  
N o ot her missi n g data will be i m p ute d u nless s pecifie d i n t he detaile d statistical a nal ysis pla n.  
9. 5.  
St u d y P o p ul ati o n  
T his st u d y will recr uit healt h y s u bjects t o eli mi nat e c o nf o u n di n g fact ors (c o m or bi dities, 
c o me dicati o ns) wit h p ote ntial i m pact o n st u d y o utc o me. Si nce T V -4 6 0 4 6 is a h or m o nal 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 3  
c o ntrace pti ve, o nl y w o me n will be e nr olle d i n t he st u d y. Si nce t he c o ntrace pti ve d ose a n d 
d urati o n of T V -4 6 0 4 6 is u n k n o w n, we will e nr oll w o me n w h o are n ot pre g na nt, n ot wa nti n g t o 
bec o me pre g na nt i n t he n e xt 2 4 m o nt hs, a n d w h o are at l o w ris k of pre g n a nc y  b eca use t he y are 
steriliz e d, i n e x cl usi vel y sa me-se x part ners hi p, a bsti ne nt, i n m o n o ga m o us relati o ns hi p wit h 
vasect o miz e d part ner, usi n g n o n - h or m o nal I U D, c o nsiste nt use of c o n d o ms or ot her barrier 
met h o ds of c o ntrace pti o n.  
9. 5. 1.  
S u bject Dis p ositi o n  
Data fr o m s u bjects scree ne d, s u bjects scree ne d b ut n ot ra n d o mize d a n d reas o n n ot ra n d o mize d, 
s u bjects w h o are ra n d o miz e d/e nr olle d, s u bjects ra n d o mize d/e nr olle d b ut n ot treate d a n d reas o n, 
p har mac o ki netic, a n d safet y a nal ysis sets, s u bjects w h o c o m plete t he st u d y, a n d s u bjects w h o 
wit h dra w fr o m t he st u d y will be s u m marize d usi n g des cri pti ve statistics. Data fr o m s u bjects w h o 
wit h dra w fr o m t he st u d y will als o be s u m marize d b y reas o n f or wit h dra wal usi n g descri pti ve 
statistics. 
9. 5. 2.  
De m o gr a p hic s, C o ntr a ce pti ve a n d Re pr o d uctive Hist or y   
S u bject de m o gra p hi cs, c o ntrace pti ve a n d re pr o d ucti ve hist or y  will be e x a mi ne d t o assess t he 
c o m para bilit y of t he treat me nts a n d will be s u m marize d usi n g descri pti ve statistics. F or 
c o nti n u o us varia bles, des cri pti ve statistics ( n u m ber [ n], mea n,  sta n dar d de viati o n ( S D), me dia n, 
mi ni m u m, a n d ma xi m u m) will be pr o vi de d. F or cate g ori cal varia bles, s u bject c o u nts a n d 
perce nt a ges will be pr o vi de d. Cate g ories f or missi n g dat a will be pres e nte d if necessar y.  
9. 6.  
S afet y A n al ysis  
Safet y a nal yses will be perf or me d o n t h e safet y a n al ysis set. Safet y m eas ures a n d ti me p oi nts are 
pr o vi de d i n Ta ble  1 .  
Safet y a n d l ocal t olera bilit y e val u ati o n will be base d o n t he  f oll o wi n g: 
•  occ urre nce of a d v erse e v e nts  
•  use of c o nc o mita nt me di cati o n  
•  c ha n ge i n vital si g ns a n d b o d y wei g ht  
•  va gi n al blee di n g patter n  
•  c ha n ge i n m o o d  
•  c ha n ge i n li ver f u ncti o n tests  
•  E 2 le vels  
•  dela ye d ret ur n t o o v ulati o n ( > 1 2 m o nt hs after treat me nt i nitia ti o n) w here o v ulati o n is 
defi ne d as a si n gle P  ≥4. 7 n g/ m L  
•  occ urre nce of I S Rs  
N o f or mal h y p ot hesis tests of safet y data are pl a n ne d. All safet y dat a will be s u m marize d b y 
treat me nt gr o u p usi n g descri pti ve statistics ( n, mea n, S D, S E, me dia n, mi ni m u m, a n d ma xi m u m 
f or c o nti n u o us varia bl es, a n d fre q u e nc y a n d perce nta ge f or cate g ori cal vari a bles). S pecificall y, 
t he n u m ber a n d perce nta ge of s u bjects e x perie n ci n g treat me nt-e mer ge nt a d verse e v e nts will be 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 4  
prese nte d b y tr eat me nt gr o u p, o verall, b y se verit y gra de, a n d b y relat e d ness t o treat me nt. 
A d verse e ve nts will be f urt her s u m marize d i n listi n gs or fre q u e nc y ta bles acc or di n g t o s yste m 
or ga n class a n d preferre d ter m. Seri o us a d verse e v e nts a n d a d verse e v e nts lea di n g t o wit h dra wal 
fr o m t he st u d y will be liste d se paratel y. C o nc o mita nt me dicati o n use will be s u m marize d b y 
treat me nt gr o u p i n fre q ue nc y t a bles, b y t hera pe utic class a n d me dici ne cate g or y. C ha n ge i n vital 
si g ns ( B P [s yst olic/ diast olic], p ulse, b o d y t e m perat ure a n d res pirati o n) a n d b o d y wei g ht fr o m 
Da y 0 t o  Da y 7, Wee k 1 3, Wee k 2 6, a n d Wee k 5 2 will be descri be d i n s hift ta bles. T he 
perce nt a ge of w o me n e x perie nci n g a m e n orr h ea or va gi nal blee di n g dist ur ba nces (irre g ular 
va gi n al blee di n g or s p otti n g) will li ke wise be s u m marize d descri pti vel y a n d c o m pare d b et wee n 
t he test a n d refere nce gr o u ps. M o o d data will be s u m marize d o ver ti me fr o m Da y 0 usi n g 
fre q ue n c y ta bles a n d gra p hical dis pla ys. Li ver f u n cti o n will be assesse d b y ta b ulati n g c h a n ge i n 
li ver f u ncti o n tests fr o m baseli ne t o Da y 7, Wee ks 1 3, 2 6, a n d 5 2. Rates of ret ur n t o o v ulati o n b y 
1 2 m o nt hs ( Wee k 5 2), w here o v ulati o n is defi ne d as a si n gl e P ≥4. 7 n g/ m L, will be pr o vi de d b y 
treat me nt gr o u p. Estra di ol c o nce ntrati o ns will be s u m marize d f or eac h gr o u p usi n g mea ns, 
sta n dar d de viati o ns, a n d gra p hical dis pla ys t hr o u g h Wee k 5 2. T he I S R data will be pr o vi de d b y 
gr o u p i n fre q u e nc y ta bles (if a p plica ble) a n d usi n g s u bject -data listi n gs.  
9. 7.  
P h ar m ac o ki netic A n al ysis  
T he f oll o wi n g pri mar y p har mac o ki netic  p ara m eters will be calc ulat e d fr o m c o nce ntr ati o n -ti me 
data base d o n t he P har mac o ki netic A nal ysis Set: 
•  ti me t o ma xi m u m o bser ve d ser u m dr u g c o nce ntr ati o n (tma x ) 
•  ma xi m u m o bser ve d ser u m dr u g c o nce ntr ati o n  ( Cma x ) 
•  ser u m M P A c o nce ntr ati o n at da y 9 1 ( C 9 1), da y 1 8 2 ( C1 8 2), a n d da y 2 1 0 ( C2 1 0) 
•   A U C 0 -1 8 2 (area u n d er t he ser u m dr u g c o n ce ntrati o n -ti me c ur ve fr o m ti me 0 t o da y 
1 8 2); A U C 0 -2 1 0 ( A U C fr o m ti me 0 t o da y 2 1 0); a n d A U C0 -∞ ( A U C e xtra p olate d t o 
i nfi nit y) 
•  a p pare nt ter mi nal half -life (t½ ) 
A m o n g t hes e pri mar y p h ar mac o ki netics p ara m eters, n o n -c o m part me nt al met h o ds will be use d t o 
esti mate A U C val ues a n d t ½ . T he ot her esti mates (tma x , Cma x , C9 1, C1 8 2, a n d C2 1 0) will be base d o n 
o bser ve d val u es w here p ossi ble. N o f or mal h y p ot hesis tests of p har mac o ki netic data are pla n ne d. 
Para meter esti mates will be s u m mariz e d b y tr eat m e nt gr o u p f or eac h d os e le vel usi n g d escri pti ve 
statistics, i ncl u di n g n, mea n, S D, sta n dar d err or, ge o metric mea n, ge o metri c c oefficie nt of 
variati o n, har m o nic mea n (f or t ½ ), me dia n, mi ni m u m, ma xi m u m, a n d 9 5 % c o nfi de nce i nter vals 
( CIs) f or mea ns. Gra p hic al dis pla ys will i ncl u de i n di vi d ual a n d ge o metric mea n 
p har mac o ki netics pr ofiles.  
P K c o m paris o ns bet wee n eac h d ose of test f or m ul ati o n ( T V 4 6 0 4 6) a n d t he refere nce pr o d u ct 
( De p o-s u b Q Pr o v era 1 0 4) will be ma de bas e d o n ge o m etric mea n rati os (test/refere nce) a n d 9 0 % 
CIs wit h t he f oll o wi n g M P A e x p os ure para meters: C ma x , C9 1, C1 8 2, C2 1 0, A U C 0 -1 8 2, A U C 0 -2 1 0, a n d 
A U C 0 -∞. 
Ot her p har m ac o ki netic p ara meters (e g, ste a d y -stat e tr o u g h c o nce ntrati o ns) ma y b e cal c ulate d 
usi n g n o n -c o m p art me ntal met h o ds or n o n -li near mi x e d effects m o dels to i nf or m d ose selecti o n.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 5  
Effects of s u bj ect c h aracteristics (e g, B MI) o n p h ar mac o ki netics of M P A will li ke wise be 
e x pl ore d usi n g n o n -li near mi x e d effects m o dels as t he data per mits. 
9. 8.  
Acce pt a bilit y A n al ysis  
T he res p o nses t o acce pta bilit y q u esti o ns at Wee ks 2 6 a n d 5 2, i ncl u di n g li kes a n d disli kes of t he 
met h o d a n d willi n g ness t o use t he pr o d uct i n t he f ut ure will be ta b ulate d i n fre q ue n c y ta bles a n d 
c o m pare d b et wee n t h e test a n d t he refere n ce gr o u ps usi n g descri pti ve C hi -s q uare d tests. 
9. 9.  
Pl a n ne d I nteri m A n al ysi s 
At least o ne i nteri m re vie w is pla n ne d t o occ ur aft er at least 8 0 % of s u bjects ha ve ha d a c ha n ce 
t o c o m plete 7. 5 m o nt hs after treat me nt i nitiati o n. T his a nal ysis is i nte n de d t o hel p i nf or m t he 
decisi o n t o m o ve t o, a n d select t he d ose f or, a pi v otal st u d y . T hese i nteri m data ma y be use d t o 
i nf or m t he e n d of P hase 1 meeti n g wit h t he F D A.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 6  
1 0.  
I N V E S TI G A TI O N A L M E DI CI N A L P R O D U C T I N F O R M A TI O N 
1 0. 1.  
I n vesti g ati o n al Me dici n al Pr o d uct St or a ge a n d Sec urit y 
All I M Ps m ust be st ore d acc or di n g t o t he ma n ufact urer’s dr u g pr o d uct s ti p ulati o n, i n a dr y place, 
a n d i n a sec urel y l oc ke d, s u bsta ntiall y c o nstr uct e d ca bi net or e n cl os ure.  T V -4 6 0 4 6 s h o ul d be 
st ore d at c o ntr olle d r o o m te m perat ur e 2 0° C t o 2 5° C ( 6 8° F t o 7 7° F). 
T he i n vesti gat or m ust c o nfir m a p pr o priat e te m perat ure c o n diti o ns ha v e b ee n mai ntai ne d f or all 
I M Ps recei ve d. T he i n vesti gat or m ust re p ort a n d res ol ve a n y discre p a ncies b ef ore us e of t he 
I M Ps. 
1 0. 2.  
I n vesti g ati o n al Me dici n al Pr o d uct Acc o u nt a bilit y 
Eac h I M P s hi p me nt will i ncl u de a pac ki n g sli p listi n g t he c o nt e nts of t he s hi p me nt a n d a n y 
a p plica ble f or ms. T he i n vesti gat or is r es p o nsi ble f or e ns uri n g t hat deli veries of I M P a n d ot her 
st u d y materi als fr o m t he s p o ns or are c orrectl y recei ve d, rec or de d, h a n dle d a n d st ore d safel y a n d 
pr o perl y i n acc or da n ce wit h t he C F R or l ocal re g ulati o n s, a n d use d i n acc or da nce wit h t his 
pr ot oc ol.  
A rec or d of I M P acc o u nt a bilit y (ie, I M P a n d ot her materials recei ve d, us e d, retai ne d, ret ur ne d, or 
destr o ye d) m ust be pre pare d a n d si g ne d b y t he i n v esti gat or, wit h a n acc o u nt gi ve n f or a n y 
discre pa n cies. E m pt y  a n d partiall y us e d c o ntai ners of I M P will be destr o ye d at t he 
i n vesti gati o nal c e nter i n acc or da nce wit h i n vesti gati o nal ce nter S O Ps, wit h s p o ns or a p pr o val. I n 
t he e ve nt t he i n vesti gati o nal ce nter is u n a ble t o destr o y t he e m pt y a n d/ or u n use d u nits of I M P, 
t he I M P will be dis p ose d of, retai ne d, or ret ur n e d t o t he s p o ns or or desi g nee per F HI 3 6 0 
i nstr ucti o ns. 
I M P acc o u nta bilit y i n cl u des mai ntai ni n g acc urate rec or ds of q ua ntit y of pr o d ucts recei ve d, date 
of recei pt, c o n diti o n at recei pt, te m perat ur e n ote d d uri n g tr a nsit, l ot n u m ber of cli nical st u d y 
pr o d ucts recei ve d a n d dis pe nse d, descri pti o n of da ma ge d u nits if a n y, dis pe nsati o n, a n d pr o d uct 
dis p ositi o n or destr ucti o n. St ora ge t e m perat ure c o nti n uit y tr ac ki n g will occ ur f or cli nical st u d y 
pr o d ucts d uri n g st ora ge a n d tra nsit ti me. St u d y p ers o n nel are res p o nsi ble f or dail y te m p erat ur e 
m o nit ori n g a n d safe st ora ge of t he st u d y pr o d ucts.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 7  
1 1.  
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  
1 1. 1.  
Pr ot oc ol A me n d me nts, Pr ot oc ol De vi ati o ns, a n d I m p ort a nt Pr ot oc ol 
De vi ati o ns  
1 1. 1. 1.  
Pr ot oc ol A me n d me nts  
N o c ha n ges fr o m t he fi nal a p pr o ve d (si g ne d) pr ot o c ol will be i nitiate d wit h o ut t he pri or writte n 
a p pr o val or fa v ora ble o pi ni o n of a writte n a me n d me nt b y t he I R B/I E C a n d l ocal healt h 
a ut h orities, as a p plica ble, e x ce pt w he n necessar y t o a d dress i m me diate  safet y c o n cer ns t o t he 
s u bjects or w he n t he c ha n ge i n v ol ves o nl y n o ns u bsta ntial l o gistics or a d mi nistrati o n. T he 
i n vesti gat or, c o or di nati n g i n vesti gat or a n d t he s p o ns or will si g n t he pr ot oc ol a me n d me nt.  
1 1. 1. 2.  
I m p ort a nt Pr ot oc ol De vi ati o ns  
A n y d e viati o n fr o m t he pr ot oc ol t hat affects, t o a si g nifica nt d e gree, (a) t he safet y, p h ysical, or 
me ntal i nte grit y of t he s u bjects i n t he st u d y a n d/ or ( b) t he scie ntific v al ue of t he st u d y will be 
c o nsi dere d a n i m p orta nt pr ot oc ol de viati o n. I m p orta nt pr ot oc ol de viati o ns ma y  i ncl u d e n o n-
a d here n ce o n t he p art of t he s u bject, t he i n vesti gat or, or t he s p o ns or t o pr ot oc ol -s pecific 
i ncl usi o n a n d e x cl usi o n criteria, pri mar y o bj ecti ve varia ble criteria, or G C P g ui deli nes; or 
n o nc o m plia nce t o I M P a d mi nistrati o n. I m p orta nt pr ot oc ol de viati o ns will be i de ntifie d a n d 
rec or de d b y st u d y staff o n a C R F a n d will be re p orte d t o t he res p o nsi ble I R B/I E C, as re q uire d. 
W he n a n i m p orta nt pr ot oc ol de viati o n is re p orte d, F HI 3 6 0 i n c o ns ultati o n wit h t he s p o ns or will 
deter mi ne w het h er t o disc o nti n ue t he s u bject fr o m t he st u d y or per mit t he s u bject t o c o nti n ue i n 
t he st u d y. T he d ecisi o n will be base d o n e ns uri n g t he safet y of t he s u bj ect a n d preser vi n g t he 
i nte grit y of t he st u d y. 
C ha n ges i n t he i n cl usi o n a n d e x cl usi o n criteria of t he pr ot oc ol are n ot p r os pecti vel y gra nte d b y 
t he s p o ns or. If st u d y staff lear n t hat a s u bject w h o di d n ot meet pr ot oc ol i ncl usi o n a n d e x cl usi o n 
criteria w as e ntere d i n a st u d y, t he y m ust i m me diatel y i nf or m F HI 3 6 0 of t h e i m p orta nt pr ot oc ol 
de viati o n. If s uc h a s u bj ect has alre a d y c o m plete d t he st u d y or has wit h dra w n earl y, n o acti o n 
will be ta ke n b ut t he i m p orta nt pr ot oc ol de viati o n will be rec or de d.  
F HI 3 6 0 will rec or d mi n or pr ot oc ol de viati o ns, ie t h ose t hat d o n ot si g nifica ntl y affect s u bject 
safet y or sci e ntific val ue of t he data, o n a Pr ot o c ol De viati o n L o g. T he c u m ulati ve l o g will be 
s u b mitte d t o t he res p o nsi ble I R B/I E C at a n n u al re vie ws, if/as re q uir e d.  
1 1. 2.  
St u d y M o nit ori n g  
T o e ns ure c o m plia n ce wit h G C P g ui deli nes, t he st u d y m o nit or or re pres e ntati ve is res p o nsi ble 
f or e ns urin g t hat s u bjects ha ve si g ne d t he I C F a n d t he st u d y is c o n d uct e d i n acc or da nce wit h 
a p plica ble S O Ps, t he pr ot oc ol, a n d ot her writte n i nstr ucti o ns a n d re g ulat or y g ui deli nes. Details of 
t he m o nit ori n g pr oce d ures are o utli ne d i n t he st u d y's cli nical m o nit ori n g pl a n w hic h is 
mai ntai ne d b y F HI 3 6 0.  
T he mai n res p o nsi bilities of t he st u d y m o nit or are t o e ns ure a d h ere n ce t o t h e pr ot oc ol, t hat all 
data are c orrectl y a n d c o m pletel y rec or de d a n d re p orte d, a n d t hat i nf or me d c o nse nt is o btai ne d 
a n d rec or de d f or all s u bje cts bef ore t h e y partici p ate i n t he st u d y a n d w he n c ha n ges t o t he c o nse nt 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 8  
f or m are warra nte d, i n acc or da nce wit h I R B/I E C a p pr o vals. T he st u d y m o nit or will be per mitte d 
t o c hec k a n d v erif y t he v ari o us rec or ds ( C R Fs a n d ot her perti ne nt s o urce data rec or ds), incl u di n g 
s pecific el ectr o nic s o ur ce d oc u me ntati o n (see Secti o n 1 3. 1 ) relati n g t o t he st u d y t o verif y 
a d here n ce t o t he pr ot oc ol a n d t o e ns ure t he c o m p lete ness, c o nsiste nc y, a n d acc urac y of t he data 
bei n g rec or de d.  
As part of t he s u per visi o n of st u d y pr o gress, ot her s p o ns or or F HI 3 6 0 pers o n nel ma y, o n 
re q uest, a cc o m pa n y t he st u d y m o nit or o n visits t o t he i n vesti gati o nal ce nter. T he i n vesti gat or a n d 
assisti n g staff m ust a gree t o c o o perate wit h t he st u d y m o nit or t o res ol ve a n y pr o ble ms, err ors, or 
p ossi ble mis u n dersta n di n gs c o n cer ni n g t he fi n di n gs detecte d d uri n g t hes e m o nit ori n g visits 
a n d/ or pr o vi de d i n f oll o w -u p writte n c o m m u nicati o n.  
1 1. 3.  
Cli nic al Pr o d uct C o m pl ai nts  
A cli nical pr o d uct c o m pl ai nt is defi ne d as a pr o ble m or p ote ntial pr o ble m wit h t he p h ysical 
q ualit y or c h aracteristics of cli nical I M P s u p plies a n d/ or cli nical de vice s u p plies use d i n a 
s p o ns or’s cli nical res earc h st u d y. E x a m ples of a pr o d uct c om plai nt i ncl u de b ut are n ot li mite d t o 
t he f oll o wi n g:  
•  s us pecte d c o nta mi nati o n 
•  q uesti o na ble sta bilit y (e g, c ol or c ha n ge, fla ki n g, cr u m bli n g, etc.)  
•  defecti ve c o m p o ne nts  
•  missi n g or e xtra u nits (e g, pri mar y c o ntai ner is recei ve d at t he i n vesti gati o n al ce nter 
wit h m ore or less t ha n t h e desi g n ate d n u m ber of u nits i nsi de)  
•  i nc orrect pac k a gi n g or i nc orrect or missi n g la beli n g/la bels 
•  u ne x pecte d or u na ntici pate d taste or o d or, or b ot h  
•  de vice n ot w or ki n g c orrectl y or a p pears defecti ve i n s o me ma n ner  
Eac h i n vesti gati o n al ce nt er will be res p o nsi ble f or re p orti n g a p ossi ble cli ni cal pr o d uct c o m plai nt 
b y c o m pleti n g t he Pr o d u ct C o m plai nt F or m pr o vi de d b y t h e s p o ns or a n d e maili n g it t o 
 wit hi n 4 8 h o urs of bec o mi n g a ware of t he iss ue. 
F or c o m plai nts i n v ol vi n g a de vice or ot her retrie v a ble ite m, it is re q uire d t hat t he de vice ( or 
ite m) be se nt bac k t o t he s p o ns or f or i n vesti gati ve testi n g w he n e ver p ossi bl e. F or c o m plai nts 
i n v ol vi n g a n I M P, all rel e va nt sa m ples (e g, t h e re mai n der of t he s ubject’s I M P s u p pl y) s h o ul d be 
se nt bac k t o t he s p o ns or f or i n vesti gati ve t esti n g u p o n s p o ns or’s re q uest.  
1 1. 3. 1.  
Pr o d uct C o m pl ai nt I nf or m ati o n Nee de d fr o m t he I n vesti g ati o n al Ce nter  
I n t he e ve nt t hat t he Pr o d uct C o m plai nt F or m ca n n ot be c o m plete d, t he i n v esti gat or will o btai n 
t he f oll o wi n g i nf or m ati o n, as a vaila ble: 
•  i n vesti gati o nal c e nter n u m ber a n d i n vesti gat or na me 
•  na me, p h o ne n u m ber, a n d a d dress of t he s o urce of t he c o m plai nt  
•  cli nical pr ot oc ol n u m ber  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
5 9  
•  s u bject i de ntifier (s u bject st u d y n u m ber) a n d c orres p o n di n g visit n u m bers, if 
a p plica ble  
•  pr o d uct na me a n d stre n gt h f or o pe n la bel st u dies  
•  s u bject n u m ber, b ottle, a n d kit n u m bers (if a p plica ble) f or d o u bl e-bli n d or o pe n la bel 
st u dies 
•  pr o d uct a vaila ble f or ret ur n Yes/ N o  
•  pr o d uct was ta k e n or use d i n acc or da nce wit h t h e pr ot oc ol Yes/ N o  
•  descri pti o n or nat ur e of c o m plai nt  
•  ass ociate d seri o us a d vers e e ve nt Y es/ N o  
•  cli nical s u p plies u n bli n de d (f or bli n de d st u dies) Yes/ N o  
•  date a n d na m e of pers o n recei vi n g t he c o m plai nt  
N ote: Re p orti n g a c o m pl ai nt m ust n ot be dela ye d e ve n if n ot all t he re q uire d i nf or mati o n ca n be 
i m me diatel y o btai ne d. K n o w n i nf or mati o n m ust be i m me diatel y re p orte d. T he s p o ns or will 
c olla b orate wit h t he i n vesti gat or t o o btai n a n y o utsta n di n g i nf or mati o n.  
1 1. 3. 2.  
H a n dli n g t he Pr o d uct C o m pl ai nt I M P at t he I n vesti g ati o n al  Ce nter  
T he i n vesti gat or is res p o nsi ble f or retai ni n g t he I M P relate d t o t he pr o d uct c o m plai nt i n a 
l ocati o n se parate fr o m t h e i n vesti gat or’s cli nical st u d y s u p plies. T he s p o ns or ma y re q u est t hat t he 
i n vesti gat or ret ur n t he pr o d uct f or f urt h er e v al uati o n an d/ or a nal ysis. If t his is necessar y, t h e 
cli nical st u d y m o nit or or desi g nee will pr o vi de t he i nf or mati o n nee de d f or ret ur ni n g t he I M P.  
If it is deter mi ne d t hat t he i n vesti gati o nal ce nter m ust ret ur n all I M P, t he s p o ns or will pr o vi de t he 
i nf or mati o n nee de d t o h a n dle t he ret ur n. 
T he i nte grit y of t he ra n d o mizati o n c o de a n d c orres p o n di n g bli n de d cli nical s u p plies will be 
mai ntai ne d w he ne v er p ossi ble.  
1 1. 3. 3.  
D oc u me nti n g a Pr o d uct C o m pl ai nt  
T he i n vesti gat or will rec or d a descri pti o n of t he pr o d uct c o m plai nt i n t he s o u rce d oc u m e ntati o n, 
al o n g wit h a n y acti o ns ta ke n t o res ol ve t he c o m plai nt a n d t o preser ve t he s afet y of t he s u bject. 
O nce t he c o m plai nt has bee n i n vesti gate d b y t he s p o ns or a n d t he i n vesti gat or, if necessar y, a n 
e ve nt cl os ure l etter ma y be se nt t o t he i n ves ti gati o nal ce nter w here t he c o m plai nt ori gi nate d or t o 
all i n vesti gati o nal c e nters usi n g t he pr o d u ct.  
1 1. 4.  
D at a Q u alit y C o ntr ol   
T he i n vesti gat or is res p o nsi ble f or t he acc urac y, q ualit y, c o m plete ness, a n d i nter nal c o nsiste nc y 
of t he data fr o m t his st u d y. D ata ha n dli n g, i ncl u di n g dat a q ualit y c o ntr ol, will c o m pl y wit h 
i nter nati o nal re g ulat or y g ui deli nes, i ncl u di n g I nter nati o nal C o u ncil f or Har m o nisati o n (I C H) 
G C P g ui deli nes. Data m a na ge me nt a n d c o ntr ol pr ocesses s pecific t o t his st u d y, al o n g wit h all 
ste ps a n d acti o ns ta ke n re gar di n g d ata ma n a ge me nt a n d data q ualit y c o ntr ol, will be descri be d i n 
a data ma n a ge me nt pla n.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 0  
Data will be verifie d b y t he st u d y m o nit or usi n g t he data s o urce, a n d re vie we d b y Data 
Ma na ge me nt usi n g b ot h a ut o mate d l o gi cal c hec ks a n d ma n ual r e vi e w. Dat a i de ntifie d as 
err o ne o us, or data t hat are missi n g, will be referre d t o t he i n vesti gati o nal ce nter f or res ol uti o n 
t hr o u g h d ata q ueri es. A n y necessar y c ha n ges will be ma de i n t he cli nical d ata base, a n d data 
re vie w a n d v ali dati o n pr oce d ures will be re peate d as nee de d.  
Case re p ort f or ms will be pr ocesse d a n d re vi e we d f or c o m plete ness, c o nsiste nc y, a n d t he 
prese nce of ma n d at or y v al ues. A p plica ble ter ms will be c o de d acc or di n g t o t he c o di n g 
c o n ve nti o ns f or t his st u d y. L o gic al c hec ks will be i m ple me nte d t o e ns ure d ata q ualit y a n d 
acc urac y. A n y n ecessar y c ha n ges will be ma de i n t he cli nical data b ase, a n d data re vie w a n d 
vali dati o n pr oce d ures will be re peate d as n ee de d. Data fr o m e xter nal s o urces will be c o m pare d 
wit h t he i nf or mati o n a vaila ble i n t he C D M S . Discre pa ncies f o u n d will be q uerie d. 
At t he c o ncl usi o n of t he st u d y, t he C D M S a n d all ot her st u d y d ata will be l oc ke d t o f urt her 
a d diti o ns or c orrecti o ns. L oc ki n g t he st u d y d ata re prese nts t he ac k n o wle d ge me nt t hat all data 
ha ve bee n ca pt ur e d a n d c o nfir me d as acc urate. All data c ollecte d will be a p pr o ve d b y t he 
i n vesti gat or at t he i n vesti gati o nal ce nter.  
1 1. 5.  
A u dit a n d I ns pecti o n  
T he s p o ns or or F HI 3 6 0 ma y a u dit t he i n vesti gati o nal ce nter t o e val uate st u d y c o n d u ct a n d 
c o m plia nce wit h pr ot oc ols, S O Ps, G C Ps, a n d  a p plica ble re g ulat or y re q uire me nts. T he s p o ns or’s 
Gl o bal Cli nical Q ualit y Ass ura nce de part me nt, i n de pe n de nt of t he Gl o bal Cli nical De vel o p me nt 
de part me nt, is res p o nsi bl e f or det er mi ni n g t he nee d f or (a n d ti mi n g of) a n i n vesti gati o nal ce nter 
a u dit. 
T he i n v esti gat or m ust acce pt t hat healt h a ut h orities a n d s p o ns or re prese ntati ves ma y c o n d uct 
i ns pecti o ns t o verif y c o m plia nce wit h G C P g ui deli nes. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 1  
1 2.  
E T HI C A L A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
T his st u d y will be c o n d u cte d i n f ull acc or da nce wit h t he I C H Har m o nise d Tri par tite G ui deli ne 
f or G o o d Cli nical Practice ( G C P) E 6 a n d a n y a p plica ble nati o nal a n d l ocal la ws a n d re g ul ati o ns 
(e g, Title 2 1 C o de of Fe d eral Re g ulati o ns [ 2 1 C F R] Parts 1 1, 5 0, 5 4, 5 6, 3 1 2, a n d  3 1 4, Directi ve 
2 0 0 1/ 2 0/ E C of t he E u r o pea n Parlia me nt a n d of t he Co u ncil o n t he a p pr o xi mati o n of t he la ws, 
re g ulati o ns a n d a d mi nistrati ve pr o visi o ns of t he Me m ber States rel ati n g t o t he i m ple me ntati o n of 
G C P i n t he c o n d uct of cli nical st u dies o n me dici nal pr o d ucts f or h u ma n use). A n y e pis o de of 
n o nc o m plia nce will be d oc u me nte d.  
T he i n vesti gat or has t he o verall res p o nsi bilit y f or t he c o n d uct a n d a d mi nistrati o n of t he cli nical 
st u d y a n d f or c o nta cts wit h st u d y ma na ge m e nt, wit h t he I R B/I E C, a n d wit h healt h a ut h orities.  
T he i n vesti gat or is res p o nsi ble f or perf or mi n g t h e cli ni cal st u d y i n acc or da nce wit h t his pr ot oc ol 
a n d t he a p plica ble G C P g ui deli nes refere n ce d a b o ve f or c ollecti n g, rec or di n g, a n d re p orti n g t he 
data acc urat el y a n d pr o p erl y. A gree me nt of t he i n vesti gat or t o c o n d uct a n d a d mi nister t his 
cli nical st u d y i n a cc or da n ce wit h t he pr ot oc ol will be d oc u me nte d i n se parate cli nical st u d y 
a gree m e nts wit h F HI 3 6 0 a n d ot her f or ms as re q uire d b y nati o nal healt h a ut h orities  i n t he 
c o u ntr y w here eac h i n vesti gati o nal ce nt er is l ocate d.  
T he i n vesti gat or is res p o nsi ble f or e ns uri n g t he pri vac y, healt h, a n d welfare of t he s u bjects 
d uri n g a n d after t he cli ni cal st u d y; a n d m ust e ns ure t hat trai ne d pers o n nel are i m me diatel y 
a vaila ble i n t he e v e nt of a me dical e mer ge n c y. T h e i n vesti gat or a n d t he i n v ol ve d cli nical st u d y 
pers o n nel m ust be f a mili ar wit h t he bac k gr o u n d a n d re q uire me nts of t h e st u d y; a n d wit h t he 
pr o perties of t he I M Ps as descri be d i n t he I B or prescri bi n g i nf or mati o n.  
T he i n vesti gat or is res p o nsi ble f or gi vi n g i nf or m ati o n a b o ut t he st u d y t o all staff me m bers 
i n v ol ve d i n t he stu d y or i n a n y ele me nt of s u bject ma na ge me nt, b ot h bef ore starti n g t he st u d y 
a n d d uri n g t he st u d y (e g, w he n ne w staff bec o me i n v ol ve d). T he i n vesti gat or m ust e ns ure t hat all 
st u d y pers o n n el are q ualifie d b y e d ucati o n, e x perie nce, a n d trai ni n g t o perf or m t he ir s pecific 
res p o nsi bilities. T hese st u d y pers o n nel m ust be liste d o n t he ce nter’s staff dele gati o n l o g, w hic h 
i ncl u des a cle ar des cri pti o n of eac h st aff me m b er’s res p o nsi bilities a n d a p pr o priatel y dele gate d 
si g nifica nt st u d y-relate d res p o nsi bilities. T his list m ust be u p date d t hr o u g h o ut t he st u d y, as 
necessar y.  
1 2. 1.  
He alt h A ut h orities a n d I n de pe n de nt Et hics C o m mittees/I nstit uti o n al 
Re vie w B o ar ds  
Bef ore t his st u d y starts, t he pr ot oc ol will be s u b mitte d t o healt h a ut h orities, if re q uire d, a n d t o 
eac h I R B/I E C f or re vie w. As re q uire d, t h e st u d y will n ot start at t he i n vesti gati o nal ce nters 
bef ore t h e I R B/I E C a n d healt h a ut h orit y (as a p pli ca ble) f or t he ce nter gi ve writte n a p pr o val or a 
fa v ora bl e o pi ni o n. 
1 2. 2.  
I nf or me d C o nse nt 
T he i n vesti gat or, or a q u alifie d pers o n desi g n ate d b y t he i n vesti gat or, will f ull y i nf or m t he 
s u bject of all perti ne nt as pects of t he st u d y, i ncl u di n g t he writte n i nf or mati o n a p pr o ve d b y t he 
I R B/I E C. All writte n a n d oral i nf or mati o n a b o ut t he st u d y will be pr o vi d e d i n a la n g u a ge as 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 2  
n o ntec h nical as pr actical a n d u n derst o o d b y t he s u bject. T he s u bject will be gi ve n a m ple ti me 
a n d o p p ort u nit y t o i n q uir e a b o ut details of t he st u d y a n d t o d eci de w h et her t o partici pate i n t he 
st u d y. T he a b o ve will be detaile d i n t he s o urce d oc u me ntati o n. 
Writte n i nf or me d c o nse nt will be o btai ne d fr o m eac h s u bject bef ore a n y st u d y s pecific 
pr oce d ures or ass ess me nts are d o ne a n d aft er t he ai ms, met h o ds, a ntici pate d be nefits, a n d 
p ote ntial hazar ds are e x plai ne d, i n acc or da nce wit h a p plica ble re g ulat or y re q uire me nts. T he 
s u bject’s willi n g ness t o p artici pate i n t he st u d y will be d oc u me nte d i n a n I C F, w hic h will be 
si g ne d a n d pers o n all y dat e d b y t h e s u bject a n d b y t he pers o n w h o c o n d ucte d t he i nf or me d 
c o nse nt disc ussi o n. T he i n vesti gat or will kee p t he ori gi nal c o ns e nt f or ms, a n d c o pies will be 
gi ve n t o t he s u bject. It will als o be e x plai ne d t o t he s u bject t hat t he s u bject is free t o r ef use e ntr y 
i nt o t he st u d y a n d free t o wit h dra w fr o m t he st u d y at a n y ti me wit h o ut prej u dice t o f ut ure 
treat me nt. 
1 2. 3.  
S u bject C o nfi de nti alit y  
T he i n vesti g at or m ust e ns ure t hat t he pri vac y of t he s u bjects, i ncl u di n g t h eir i de ntit y a n d all 
pers o nal me dic al i nf or mati o n, will be mai ntai ne d at all ti mes. I n C R Fs a n d ot her d oc u me nts or 
i ma ge m aterial s u b mitte d t o t he s p o ns or, s u bjects will be i de ntifie d n ot b y t heir na mes, b ut b y a n 
i de ntificati o n c o de (ie, s u bject n u m ber). 
Pers o nal me dical i nf or m ati o n ma y b e re vie we d f or s u bject safet y a n d f or verif yi n g data i n t he 
s o urce a n d tr a nscri b e d o nt o t he C R F. T his re vie w ma y b e c o n d uct e d b y t he st u d y m o nit or, 
pr o perl y a u t h orize d pers o ns o n be half of t he s p o ns or or F HI 3 6 0, Gl o bal Q ualit y Ass ura nce 
( G Q A), or healt h a ut h orities. Pers o nal me dical i nf or mati o n will al wa ys b e treate d as 
c o nfi de ntial.  
1 2. 4.  
Decl ar ati o n of t he E n d of t he Cli nic al St u d y  
L ocal re g ul ati o ns will be f oll o we d t o deter mi ne t h e e n d of t he st u d y.  
1 2. 5.  
Re gistr ati o n of t he Cli nic al St u d y  
I n c o m plia nce wit h l ocal re g ulati o ns a n d i n acc or da nce wit h t he s p o ns or’s sta n dar d pr o ce d ures, 
t his cli nical st u d y will be re gistere d o n cli nicaltrials. g o v. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 3  
1 3.  
S T U D Y D O C U M E N T A TI O N  
1 3. 1.  
S o urce  D at a a n d C ase Re p ort F or ms  
Data will be c ollecte d at t he i n vesti gati o nal ce nter b y a p pr o priatel y d esi g n ate d a n d trai ne d 
pers o n nel. T he i n vesti gat or m ust mai ntai n t he ori gi nal rec or ds (ie, s o urce d oc u me nts) of eac h 
s u bject’s data at all ti mes. T he i n vesti g at or will mai ntai n a c o nfi de ntial s u bject i de ntificati o n list 
t hat all o ws t he u na m bi g u o us i de ntificati o n of eac h s u bject. S u bject i de ntit y will n ot be 
discer ni ble fr o m t he d ata pr o vi de d o n C R Fs.  
E x a m ples of s o urce d oc u me nts are h os pital rec or ds, office vi sit rec or ds, e x a mi ni n g p h ysicia n’s 
fi n di n g or n otes, la b orat or y re p orts, dr u g i n v e nt or y, I M P la bel rec or ds, a n d w or ks heets t hat are 
use d as t he s o urce.  
S o me data ma y be rec or de d directl y o nt o t he C R F, if i nstr ucte d b y F HI 3 6 0; t he i n vesti gati o nal 
ce nter will ge n erate a d o c u me nt s pecif yi n g w hic h data are rec or de d directl y o nt o C R Fs. “ Cas e 
re p ort f or m ” mea ns a n y C R F, w het her p a per or el ectr o nic. 
T he me dical e x perts, st u d y m o nit ors, a u dit ors, I R B/I E C, a n d i ns pect ors fr o m healt h a ut h orities 
( or t heir a ge nts) will be gi ve n direct a ccess t o s o urce data a n d d oc u me nts (e g, me dical 
c harts/rec or ds, la b orat or y test res ults, pri nt o uts) f or s o urce d ata verificati o n, pr o vi de d t hat 
s u bject c o nfi de ntialit y is mai ntai ne d i n acc or da nce wit h nati o nal a n d l ocal r e q uire me nts.  
Al l data c ollecte d will be a p pr o ve d b y t he i n vesti gat or at t he i n vesti gati o nal ce nter. T his 
a p pr o val a c k n o wle d ges t he i n vesti gat or’s re vi e w a n d acce pta nce of t he d at a as bei n g c o m plete 
a n d acc urate.  
T he data c ollecte d o n C R Fs will be e ntere d i n a C D M S t hat meets t he tec h nical re q uir e me nts 
descri be d i n 2 1 C F R  Part  1 1 ( U S A) a n d d oc u m e nts of ot her c o n cer ne d healt h a ut h orities. T he 
C D M S will be f ull y v ali date d t o e ns ure t h at it meets t he scie ntific, re g ulat or y, a n d l o gistical 
re q uire me nts of t h e st u d y bef ore it is use d t o ca pt ure data fr o m t his st u d y. Bef ore usi n g t he 
C D M S, all users will recei ve trai ni n g o n t he s yste m a n d st u d y s pecific trai ni n g. Aft er t he y are 
trai ne d, users will be pr o vi de d wit h i n di vi d ual s yste m access ri g hts. 
F or s u bjects w h o si g n a n I C F b ut d o n ot meet eli gi bilit y criteria, at a mi ni m u m, data f or scree n 
fail ure reas o n, de m o gra p h y, a n d a d verse e v e nts fr o m t he ti me of i nf or me d c o nse nt will be 
e ntere d o nt o a C R F.  
1 3. 2.  
Arc hi vi n g of St u d y D oc u me nt ati o n  
1 3. 2. 1.  
F HI 3 6 0 Res p o nsi bilities  
All data ma na ge m e nt tas k s f or t his st u d y are dele gat e d t o F HI 3 6 0. T he ori gi nal C R Fs will be 
st ore d at t he res p ecti ve i n vesti gati o nal ce nters u ntil t he e n d of t he st u d y.  
1 3. 2. 2.  
I n vesti g at or Res p o nsi bilities 
T he i n vesti gat or m ust mai ntai n all writte n a n d electr o nic rec or ds, acc o u nts, n o tes, re p orts, a n d 
data relat e d t o t he st u d y a n d a n y a d diti o nal rec or ds re q uire d t o be mai ntai n e d u n der c o u ntr y, 
state/ pr o vi nce, or nati o nal a n d l ocal la ws, i ncl u di n g, b ut n ot li mite d t o: 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 4  
•  f ull case hist ories 
•  si g ne d I C Fs 
•  s u bject i de ntificati o n lists 
•  case re p ort f or ms f or eac h s u bject o n a per -visit basis  
•  data fr o m ot her s o urces (e g, e xter nal la b orat or y)  
•  safet y re p orts 
•  re p orts of recei pt, use, a n d dis p ositi o n of t he I M Ps 
•  c o pies of all c orres p o n de nce wit h F HI 3 6 0, t he I R B/I E C, a n d a n y h ealt h a ut h orit y  
T he i n ves ti gat or will retai n all rec or ds relate d t o t he st u d y a n d a n y a d diti o nal rec or ds re q uir e d, as 
i n dicate d b y t he pr ot oc ol a n d acc or di n g t o a p plica ble la ws a n d re g ulati o ns, u ntil F HI 3 6 0 or 
s p o ns or n otifies t he i nstit uti o n i n writi n g t hat rec or ds ma y b e destr o ye d. If, after 2 5  years fr o m 
st u d y c o m pleti o n, or earlier i n t he cas e of t he i n vesti gati o nal ce nt er cl osi n g or g oi n g o ut of 
b usi ness, t he i n vesti gat or reas o na bl y d eter mi nes t hat st u d y rec or d rete nti o n has bec o me u n d ul y 
b ur de ns o me, a n d F HI 3 6 0 has n ot pr o vi de d writte n n otificati o n of destr ucti o n, t he n t he 
i n vesti gat or ma y s u b mit a writte n re q u est t o F HI 3 6 0 at least 6 0 da ys bef ore a n y pla n ne d 
dis p ositi o n of st u d y rec or ds. After recei pt of s uc h re q uest, F HI 3 6 0 ma y arra n ge f or a p pr o priate 
arc hi val or dis p osit i o n, i ncl u di n g re q uiri n g t hat t he i n vesti gat or d eli ver s uc h rec or ds t o t he 
s p o ns or or F HI 3 6 0. T he i n vesti gat or s hall n otif y F HI 3 6 0 of a n y acci de ntal l oss or destr ucti o n of 
st u d y rec or ds. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 5  
1 4.  
FI N A N CI N G A N D I N S U R A N C E  
A se parate cli nical st u d y a gree m e nt, i ncl u d i n g a st u d y b u d get, will be e ntere d i nt o bet wee n eac h 
i n vesti gat or a n d F HI 3 6 0 bef ore t h e st u d y dr u g is deli vere d. 
T his cli nical st u d y is i ns ure d i n acc or da n ce wit h t h e c orres p o n di n g l ocal le gal pr o visi o ns. T he 
p olic y c o v era ge is s u bject t o t he f ull p olic y  ter ms, c o n diti o ns, e xte nsi o ns, a n d e x cl usi o ns. 
E x cl u de d fr o m t he i ns ura nce c o v era ge are i nter ali a, da ma ges t o healt h, a n d w orse ni n g of 
pre vi o us e xisti n g disease t hat w o ul d ha ve occ urre d or c o nti n ue d if t he s u bj ect ha d n ot ta ke n p art 
i n t he cli nical st u d y.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 6  
1 5.  
R E P O R TI N G A N D P U B LI C A TI O N O F R E S U L T S  
T he s p o ns or is res p o nsi ble f or e ns uri n g t h at t he p u blic has access t o t he a p pr o priate i nf or m ati o n 
a b o ut t he st u d y b y c o nf or mi n g t o l ocal a n d re gi o nal re q uire me nts a n d re g ulati o ns f or re gistrati o n 
a n d p osti n g of res ults, a n d t o re q uire me nts o utli ne d i n a n y c urre nt or f ut ure a gree m e nts bet wee n 
t he s p o ns or a n d F HI 3 6 0.  
F HI 3 6 0 will pre p are t he cli nical st u d y re p ort, i n c o o perati o n wit h t he s p o ns or. T he fi nal r e p ort is 
si g ne d b y t he s p o ns or a n d F HI 3 6 0.  
W he n t he s p o ns or ge nerates re p orts fr o m t he data c ollecte d i n t his st u d y f or prese ntati o n t o 
healt h a ut h orities, drafts will be circ ulate d t o F HI  3 6 0  f or c o m me nts a n d s u g gesti o ns.  
N o u n p u blis he d i nf or mati o n s hall be p u blis he d or discl ose d t o a t hir d part y wit h o ut t he pri or 
writte n c o nse nt of t he s p o ns or a n d F HI  3 6 0. T he pri mar y p u blicati o n fr o m t his st u d y will re p ort 
t he res ults of t he st u d y i n acc or da nce wit h t he c urre nt “ Rec o m me n dati o ns f or t he C o n d uct, 
Re p orti n g, E diti n g, a n d P u blicati o n of Sc h olarl y W or k i n Me d ical J o ur nals” ( w w w.I C MJ E. or g). 
P u blicati o n of t he res ults will occ ur i n a ti mel y m a n ner acc or di n g t o a p plica ble re g ulati o ns. 
A ut h ors hi p will be base d o n meeti n g all t he f oll o wi n g 4  criteria:  
•  s u bsta ntial c o ntri b uti o ns t o t he c o nce pti o n or desi g n of t he w ork; or t he ac q uisiti o n, 
a nal ysis, or i nter pret ati o n of data f or t h e w or k  
•  drafti n g t he w or k or re visi n g it criticall y f or i m p ort a nt i ntellect ual c o nte nt  
•  fi nal a p pr o val of t h e versi o n t o be p u blis he d 
•  a gree m e nt t o be acc o u nta ble f or all as pects of t he w or k i n e ns uri n g t hat q uesti o ns 
relate d t o t he acc urac y or i nte grit y of a n y part of t he w or k are a p pr o priatel y 
i n vesti gate d a n d res ol ve d. 
A j oi nt p u blicati o ns c o m mittee will be esta blis he d b y t he s p o ns or a n d F HI  3 6 0 t o o versee t his 
pr ocess. A d diti o nal p u blicati o ns  ma y f oll o w u p o n t he a gree me nt of t he c o m mittee. P olicies 
re gar di n g t he p u blic ati o n of t he st u d y res ults are f urt her defi n e d i n a c olla b orati o n a gree me nt 
bet wee n t he s p o ns or a n d F HI  3 6 0. A n y dis p utes or iss ues a b o ut p u blicati o n will be referre d t o 
t he E x ecuti ve C o m mittee, as descri be d i n t hat a gree me nt.  
N o pate nt a p plicati o ns base d o n t he res ults of t he st u d y ma y be m a de b y t he i n vesti gat or n or m a y 
assista nce be gi ve n t o a n y t hir d part y t o ma k e s uc h a n a p plicati o n wit h o ut t he writte n 
a ut h orizati o n of t he s p o ns or.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 7  
1 6.  
R E F E R E N C E S  
C o m mittee o n Practice B ulleti ns G y nec ol o g y. Practice B ulleti n N o. 1 6 8: C er vical Ca n cer 
Scree ni n g a n d Pre ve nti o n. O bstet G y n ec ol 2 0 1 6; 1 2 8( 4):e 1 1 1 -3 0.  
De p o -Pr o vera C o ntrace pti ve I nje cti o n U S prescri bi n g i nf or mati o n. N e w Y or k, N Y: Pfizer I nc ; 
2 0 1 6.  
De p o -Pr o vera me dr o x y pr o gester o ne acetate i njecti o n, sterile a q ue o us s us pe nsi o n U S prescri bi n g 
i nf or mati o n. Ne w Y or k, N Y: Pfizer I n c; 2 0 1 7. 
De p o -s u b Q Pr o vera 1 0 4 U S prescri bi n g i nf or mati o n. Ne w Y or k, N Y: Pfizer I nc; 2 0 1 6.  
J ai n J, D utt o n C, Nic osia A, Wajsz cz u k C, B o de F R, Mis hell D R Jr. P har mac o ki netics, o v ulati o n 
s u p pressi o n a n d ret ur n t o o v ulati o n f oll o wi n g a l o wer d ose s u b c uta ne o us f or m ulati o n of De p o -
Pr o vera. C o ntrace pti o n. 2 0 0 4; 7 0( 1): 1 1 -8.  
Kr oe n ke K, S pitz er R L, Willia ms J B. T he P H Q -9: vali dit y of a bri ef de pressi o n se verit y 
meas ure. J Ge n I nter n Me d 2 0 0 1; 1 6( 9): 6 0 6 -1 3.  
T o h Y C, J ai n J, Ra h n n y M H, B o de F R, R oss D. S u p pressi o n of o v ulati o n b y a n e w s u bc ut a ne o us 
de p ot me dr o x y pr o gester o ne acetate ( 1 0 4  m g/ 0. 6 5  m L) c o ntrace pti ve f or m ulati o n i n Asia n 
w o m e n. Cli nical T hera p e utics. 2 0 0 4; 2 6( 1 1): 1 8 4 5 -5 4.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 8  
1 7.  
S U M M A R Y O F C H A N G E S T O P R O T O C O L  
1 7. 1.  
Pr ot oc ol A me n d me nt 0 2 D ate d 1 6  M arc h  2 0 2 1  
T he pri mar y reas o ns f or t his a me n d me nt are t o u p date t he assess me nt ti me p oi nts i n Ta ble  1  a n d 
t o m o dif y t he defi niti o n of irre g ular va gi nal blee di n g as a n a d verse e v e nt. I n a d diti o n, 
i nf or mati o n was a d de d o n e nr oll me nt e x pa nsi o n a n d o n c ollecti o n of c o ntr ace pti ve a n d 
re pr o d ucti ve hist or y d uri n g t he scree ni n g p h ase . 
A ta ble s h o wi n g t he c ha n ges fr o m t he Pr ot oc ol wit h A me n d me nt 0 1 t o A me n d me nt 0 2 is 
pr o vi de d bel o w. All maj or c ha n ges t o t he pr ot oc ol b o d y are liste d bel o w i n t he ta ble, a n d are 
reflecte d i n t he s y n o psis, as a p plica ble. Pre vi o us te xt wit h c ha n ges i n dicate d is prese nte d i n t he 
c ol u m n title d " Ori gi nal te xt wit h c ha n ges s h o w n", a n d t he fi nal te xt is prese nte d i n t he c ol u m n 
title d " Ne w w or di n g." A d de d te xt is s h o w n i n u n derli ne a n d del eti o ns are s h o w n i n stri ke-
t hr o u g h. 
Ta ble 1 ( St u d y Pr oce d ures a n d Assess me nts) h as bee n re vis e d t o refl ect c ha n ges descri be d 
bel o w.  
Mi n or e dit orial c ha n ges (t y p os, p u nct uati o n, r e placi n g te xt wit h a b bre viati o ns, etc) ha v e bee n 
ma de t o t he pr ot oc ol a n d pr ot oc ol s y n o psis, as a p pr o priate.  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
Secti o n 1. 3. 1 O ver all P ote nti al B e nefits a n d Ris ks   
M o o d e val uati o n will b e c o n d ucte d at 
e nr oll me nt  baseli ne  a n d d uri n g t he st u d y.  
M o o d e val uati o n will be c o n d ucte d at 
e nr oll me nt a n d d uri n g t he st u d y.  
U p date. Ti mi n g of 
assess me nts u p date d.  
Secti o n 1. 4. 1 Ge ner al St u d y Desi g n R ati o n ale  
St u d y partici pati o n will c o nsist of a 
scree ni n g peri o d ( u p t o  a p pr o xi matel y 1. 5 
m o nt hs, or 6 wee ks),  
St u d y partici pati o n will c o nsist of a 
scree ni n g peri o d ( a p pr o xi mat el y 1. 5 
m o nt hs, or 6 wee ks),  
U p date. Descri pti o n of 
scree ni n g p hase peri o d 
u p date d  
Secti o n 2. 1 Pri m ar y a n d Sec o n d ar y St u d y O bjecti ves a n d M e as ures/ P ar a meters  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
6 9  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
T he safet y a n d l ocal t olera bilit y 
meas ures/ para meters are : 
•  c ha n ge i n vital si g ns ( bl o o d press ure, 
res pirat or y rate, b o d y te m perat ure, 
a n d p ulse) a n d b o d y wei g ht 
meas ure me nt  
•  c ha n ge i n b o d y wei g ht  
•  c ha n ge i n va gi nal blee di n g patter n  
•  c ha n ge i n m o o d assess me nt of m o o d 
b y P atie nt Healt h Q uesti o n naire -9 
( P H Q-9)  
•  c ha n ge i n li ver f u ncti o n tests 
•  c ha n ge i n estra di ol ( E 2) le vels 
meas ure me nts t hr o u g h o ut t he st u d y  
•  dela ye d ret ur n t o o v ulati o n ( > 1 2 
m o nt hs after treat me nt i nitiati o n) 
w here o v ulati o n is defi ne d as a si n gle 
P ≥4. 7 n g/ m L pr o gester o ne ( P) 
meas ure me nts at W ee ks 4 8, 4 9, 5 0 , 
5 1, a n d 5 2  
T he safet y a n d l ocal t olera bilit y 
meas ures/ para meters are : 
•  vital si g ns a n d b o d y wei g ht 
meas ure me nt  
•  va gi nal blee di n g patter n  
•  assess me nt of m o o d b y P atie nt 
Healt h Q uesti o n naire -9 ( P H Q -9)  
•  li ver f u ncti o n tests 
•  estra di ol ( E 2) meas ure me nts 
t hr o u g h o ut t he st u d y 
•  pr o gester o ne ( P) meas ure me nts at 
Wee ks 4 8, 4 9, 5 0, 5 1, a n d 5 2  
U p date. D efi niti o n of t he 
safet y a n d l ocal t olera bilit y 
meas ures/ para meters 
u p date d . 
 
Secti o n 3. 3 D ur ati o n of S u bject P artici p ati o n  
T otal d urati o n of t he st u d y f or eac h s u bj ect 
is e x pecte d t o be u p t o  a p pr o xi matel y1 9. 5 
m o nt hs, i ncl u di n g u p t o  a p pr o xi matel y 1. 5 
m o nt hs of scree ni n g a n d u p t o 1 8 m o nt hs of 
f oll o w-u p after st u d y treat me nt i nitiati o n.  
T otal d urati o n of t he st u d y f or eac h s u b j ect 
is e x pecte d t o be a p pr o xi matel y  1 9. 5 
m o nt hs, i ncl u di n g a p pr o xi mat el y 1. 5 
m o nt hs of scree ni n g a n d u p t o 1 8 m o nt hs 
of f oll o w -u p after st u d y treat me nt 
i nitiati o n. 
U p date. Descri pti o n of 
scree ni n g p hase peri o d 
u p date d  
Secti o n 3. 4 St u d y Pr o ce d ures  
T a ble 1. St u d y Pr o ce d ures a n d Assess me nts  
See Ne w w or di n g c ol u m n  
T a ble 1 ( St u d y Pr oce d ures a n d 
Assess me nts) has bee n re vise d as descri be d 
bel o w:  
•  
Me dical hist or y re m o ve d fr o m 
e nr oll me nt p hase  da y 0) i n T a ble 
1  
•  
De m o gra p hics, c o ntrace pti ve a n d 
re pr o d ucti ve hist or y re m o ve d 
fr o m enr oll me nt p hase ( Da y 0) i n 
T a ble 1  
•  
M o o d eval uati o n re m o ve d fr o m  
scree ni n g p hase  ( 6 wee ks bef ore 
Ra n d o mizati o n)  i n T a ble 1 
•  
Va gi nal blee di n g patter n 
re m o ve d fr o m scree ni n g p has e  ( 6 
U p date. Assess me nt s 
re m o ve d fr o m t he s pecifie d 
ti me p oi nts i n T a ble 1. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 0  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
wee ks bef ore Ra n d o mizati o n) 
a n d la b v isits ( F oll o w-U p)  i n 
T a bl e 1 
De m o gra p hics , cco ntrace pti ve a n d 
rre pr o d ucti ve h h ist or y a n d bas eli ne 
c haracteristics  
De m o gra p hics, c o ntrace pti ve a n d 
re pr o d ucti ve hist or y 
U p date. Descri pti o n of 
pr oce d ure u p date d.  
Secti o n 3. 4. 1 Pr oce d ures f or Scree ni n g  
De m o gra p hic data as well as c o ntrace pti ve 
a n d re pr o d ucti ve hist or y will be c ollecte d 
a n d d oc u me nte d . Scree ni n g f or eli gi bilit y  
will i ncl u de re vie w of eli gi bilit y criteriaa n d 
me dical hist or y  de m o gra p hics, re vie w of 
m e dical hist or y, meas ure me nt of 
he m o gl o bi n a n d li ver e nz y mes, a n d 
p h ysical e xa mi nati o n t hat will i ncl u de, at 
mi ni m u m: hea d/ nec k, ears, e yes, n ose, 
t hr oat, c hest a n d l u n gs, car di o vasc ular, 
a b d o me n, s ki n, l y m p h n o des a n d breast 
assess me nts.  
De m o gra p hic data a s well as c o ntrace pti ve 
a n d re pr o d ucti ve hist or y will be c ollecte d 
a n d d oc u me nte d. Scree ni n g f or eli gi bilit y, 
will i ncl u de  re vie w of eli gi bilit y criteria 
a n d me dical hist or y,  meas ure me nt of 
he m o gl o bi n a n d li ver e nz y mes, a n d 
p h ysical e xa mi nati o n t hat will i ncl u de, at 
mi ni m u m: hea d/ nec k, ears, e yes, n ose, 
t hr oat, c hest a n d l u n gs, car di o vasc ular, 
a b d o me n, s ki n, l y m p h n o des a n d breast 
assess me nts.  
A d diti o n a n d u p date. 
Re q uire me nt f or 
de m o gra p hic data a n d 
c o ntrace pti ve a n d 
re pr o d ucti ve hist or y 
c ollecti o n was a d d e d t o 
scree ni n g p hase .  
Scree ni n g f or e li gi bilit y 
u p date d.  
B MI will be calc ulate d base d o n t he 
meas ure d wei g ht a n d hei g ht.  
 
 
 
 
 
 
 
 
 
B MI will be calc ulate d base d o n t he 
meas ure d wei g ht a n d hei g ht.  
 
 
 
 
 
 
 
 
 
A d diti o n. 
 
  
 
 
 
Secti o n 3. 4. 2. Pr o ce d ures f or E nr oll me nt  ( D a y 0) 
Secti o n 3. 4. 2. Pr o ce d ures f or Tre at me nt 
I niti ati o n E nr oll me nt  ( D a y 0) 
Secti o n 3. 4. 2. Pr oce d ures f or E nr oll me nt 
( D a y 0) 
Title of Secti o n 3. 4. 2 
u p date d  
I n a d diti o n, a n assess me nt of vital si g ns, 
b o d y wei g ht a n d B MI , m o o d, E 2 a n d P, 
a n d M P A will be perf or me d . Rele va nt 
me dical hist or y i ncl u di n g pre
e xisti n g 
c o n diti o ns will be re vie we d a n d 
d oc u me nte d. A d verse e ve nts a n d 
c o nc o mita nt me dicati o ns will als o be 
eval uate d.   
All eli gi bilit y criteria will be verifie d a n d 
c o nfir me d  pri or t o ra n d o mizati o n  
I n a d diti o n, a n assess me nt of vital si g ns, 
b o d y wei g ht a n d B MI, m o o d, E 2 a n d P, 
a n d M P A will be perf or me d. A d verse 
e ve nts a n d c o nc o mita nt me dic ati o ns will 
be e val uate d.  
All eli gi bilit y criteria will be verifie d pri or 
t o ra n d o mizati o n 
A d diti o n. B MI a d de d t o 
vital si g n assess me nt f or 
enr oll me nt p hase . Me dical 
hist or y a d de d f or re vie we d 
d oc u me nts f or t his p hase .  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 1  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
T he i nj ecti o n site l ocati o n will be mar ke d 
a n d p h ot o gra p he d f or refere nc e. 
 
 
 
 
 T he 
i nj ecti o n site will be o bser ve d f or i nj ecti o n 
site reacti o ns (I S Rs) i m me diat el y (ie, as 
s o o n as p ossi ble b ut n o later t ha n 1 0 
mi n utes u p o n re m o vi n g t he n e e dle) a n d 1 
h o ur ( ± 5 mi n utes) after t he i nj ecti o n . 
T he i nj ecti o n site l ocati o n will be mar ke d 
a n d p h ot o gra p he d f or refere nc e. T he 
i nj ecti o n site will be o bser ve d f or i nj ecti o n 
site reacti o ns (I S Rs) i m me diat el y (ie, as 
s o o n as p ossi ble b ut n o later t ha n 1 0 
mi n utes u p o n re m o vi n g t he ne e dle) a n d 1 
h o ur ( ± 5 mi n utes) after t he i nj ecti o n . 
Deleti o n. 
 
 
 
 
Secti o n 5. 1 S afet y a n d T oler a bilit y M e as ure me nts  
T he f oll o wi n g safet y a n d l ocal t olera bilit y 
meas ures will b e i m ple me nte d t hr o u g h o ut 
t he st u d y at t he ti me p oi nts list e d i n 
T a ble  1 : 
•  i nci de nce occ urre nce  of a d verse 
e ve nts  
•  use of  c o nc o mita nt me dicati o n use  
•  c ha n ge i n b o d y wei g ht  
•  assess me nt of va gi nal blee di n g 
patter n  
•  assess me nt of m o o d  b y P atie nt 
Healt h Q uesti o n naire -9 ( P H Q -9)  
•  E 2 c o nce ntrati o n  le vels t hr o u g h o ut 
t he st u d y 
•  assess me nt of ret ur n t o o v ulati o n at 
5 2 wee ks as meas ure d b y P 
meas ure me nts at W ee ks 4 8, 4 9, 5 0, 
5 1, a n d 5 2  
•  i nci de nce occ urre nce  of i nj ecti o n site 
reacti o ns (I S Rs) 
T he f oll o wi n g safet y a n d l ocal t olera bilit y 
meas ures will be i m ple me nte d t hr o u g h o ut 
t he st u d y at t he ti me p oi nts list e d i n 
T a ble  1 : 
•  occ urre nce of a d verse e ve nts  
•  use of c o nc o mita nt me dicati o n  
•  va gi nal blee di n g patter n  
•  assess me nt of m o o d b y P atie nt 
Hea lt h Q uesti o n naire-9 ( P H Q -9)  
•  E 2 le vels t hr o u g h o ut t he st u d y  
•  P meas ure me nts at Wee ks 4 8, 4 9, 5 0, 
5 1, a n d 5 2  
•  occ urre nce of i nj ecti o n site reacti o ns 
(I S Rs) 
U p date. Defi niti o n of t he 
safet y a n d l ocal t olera bilit y 
meas ures u p date d . 
 
Secti o n 5. 1. 5 Assess me nt of M o o d  
S u bj ects will be i nter vie we d a b o ut as pects 
of a n d c ha n ges i n m o o d at e nr oll me nt  
scree ni n g a n d at pre -defi ne d ti me p oi nts 
t hr o u g h o ut t he st u d y (T a ble 1 ). 
S u bj ects will be i nter vie we d a b o ut as pects 
of a n d c ha n ges i n m o o d at e nr oll me nt a n d 
at pre -defi ne d  ti me p oi nts t hr o u g h o ut t he 
st u d y (T a ble 1 ). 
U p date. Ti mi n g of s u bj ects’ 
i nter vie w o n m o o d c ha n ges 
u p date d  
Secti o n 5. 2. 1 Defi niti o n of a n A d verse E ve nt  
• F or t he p ur p ose of t his st u d y, irre g ular 
va gi nal blee di n g will n ot b e c o nsi dere d a n 
a d verse e ve nt u nless it re q uires me dical 
i nter ve nti o n or meets t he defi niti o n of 
“seri o us a d verse e ve nt” ( See S ecti o n 5. 2. 5 ) 
• F or t he p ur p ose of t his st u d y, irre g ular 
va gi nal blee di n g will n ot be c o nsi dere d a n 
a d verse e ve nt u nless it re q uires me dical 
i nter ve nti o n or meets t he defi niti o n of 
“seri o us a d verse e ve nt”  ( See S ecti o n 5. 2. 5 )  
A d diti o n. Clarificati o n o n 
irre g ular va gi nal blee di n g as 
a n a d verse e ve nt a d de d.  
Secti o n 9. 1 S a m ple Size Dete r mi n ati o n a n d R ati o n ale  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 2  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
T he i nte nt of t he st u d y is t o ha ve a 
mi ni m u m of 5 4 s u bj ects wit h e val ua ble 
data c o m plete 3 2 wee ks per pr ot oc ol. 
A d diti o nal s u bj ects ma y  be e nr olle d t o 
c o m plete t he mi ni m u m n u m ber of 
e val ua ble s u bj ects at t he discr eti o n of t he 
S p o ns or. S R C will pr o vi de g ui da nce 
re gar di n g t he val ue of e x pa n di n g 
e nr oll me nt a n d size of s uc h e x pa nsi o n t o 
hel p e ns ure t hat at least 5 4 s u bj ects 
c o m plete 3 2 wee ks per pr ot oc ol.  
T he i nte nt of t he st u d y is t o ha ve a 
mi ni m u m of 5 4 s u bj ects wit h e val ua ble 
data c o m plete 3 2 wee ks per pr ot oc ol. 
A d diti o nal s u bj ects ma y  be e nr olle d t o 
c o m plete t he mi ni m u m n u m ber of 
e val ua ble s u bj ects at t he discr eti o n of t he 
S p o ns or. S R C will pr o vi de g ui da nce 
re gar di n g t he val ue of e x pa n di n g 
e nr oll me nt a n d size of s uc h e x pa nsi o n t o 
hel p e ns ure t hat at least 5 4 s u bj ects 
c o m plete 3 2 wee ks per pr ot oc ol.  
A d diti o n.  State me nt o n 
e nr oll me nt e x pa nsi o n 
a d de d. 
9. 5. 2 De m o gr a p hic s, C o ntr a ce pti v e a n d 
Re pr o d ucti ve Hist or y  a n d B aseli ne 
C h ar a cteristics  
9. 5. 2 De m o gr a p hics, C o ntr a ce pti ve a n d 
Re pr o d ucti ve Hist or y  
Title of secti o n 9. 5. 2 
u p d ate d  
S u bj ect d e m o gra p hic s, c o ntra ce pti ve a n d 
re pr o d ucti ve hist or y a n d baseli ne 
c haracteristics  will be e xa mi ne d t o assess 
t he c o m para bilit y of t he treat me nts a n d will 
be s u m marize d usi n g descri pti ve statistics.  
S u bj ect de m o gra p hics, c o ntra ce pti ve a n d 
re pr o d ucti ve hist or y will be e xami ne d t o 
assess t he c o m para bilit y of t he treat me nts 
a n d will be s u m marize d usi n g descri pti ve 
statistics. 
U p d ate. S u bject’s 
c h ar acteristics re q uire d  
f or assess me nt of 
tre at me nt c o m p ar a bilit y 
u p d ate d  
Secti o n 9. 6 S afet y A n al ysis  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 3  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
Safet y a n d l ocal t olera bilit y e val uati o n will 
be base d o n t he f oll o wi n g:  
•  
occ urre nce  i nci de nce of 
a d verse e ve nts  
•  
use of  c o nc o mita nt 
me dicati o n use  
•  
c ha n ge i n vital si g ns a n d 
b o d y wei g ht meas ure me nt  
•  
c ha n ge i n assess me nt of  
m o o d  
•  
c ha n ge i n li ver f u ncti o n tests 
•  
c ha n ge i n E 2 le vels 
c o nce ntrati o n meas ure me nt   
•  
dela ye d  assess me nt of  ret ur n 
t o o v ulati o n ( > 1 2 m o nt hs 
after treat me nt i nitiati o n) 
w here o v u lati o n is defi ne d as 
a si n gle P ≥4. 7 n g/ m L  at 5 2 
wee ks as meas ure d b y 
P  ≥ 4. 7 n g/ m L  
•  
occ urre nce of  i nci de nce of 
I S Rs 
Safet y a n d l oca l t olera bilit y e val uati o n 
will be base d o n t he f oll o wi n g:  
•  
occ urre nce of a d verse e ve nts  
•  
use of c o nc o mita nt 
me dicati o n  
•  
c ha n ge i n vital si g ns a n d 
b o d y wei g ht  
•  
c ha n ge i n m o o d  
•  
c ha n ge i n li ver f u ncti o n tests  
•  
E 2 le vels  
•  
dela ye d ret ur n t o o v ulati o n 
( > 1 2 m o nt hs after treat me nt 
i nitiati o n) w here o v ulati o n is 
defi ne d as a si n gle P ≥4. 7 
n g/ m L  
•  
occ urre nce of I S Rs  
 
U p date. Clarificati o n o n 
defi niti o n of safet y a n d 
l ocal t olera bilit y e val uati o n 
meas ure me nts.  
Seri o us a d verse e ve nts a n d a d verse e ve nts 
lea di n g t o wit h dra wal fr o m t he st u d y will 
be liste d se p aratel y. C o nc o mit a nt 
me dicati o n use will be s u m marize d b y 
treat me nt gr o u p i n fre q ue nc y t a bles, b y 
t hera p e utic class a n d me dici ne cate g or y. 
Seri o us a d verse e ve n ts a n d a d verse e ve nts 
lea di n g t o wit h dra wal fr o m t he st u d y will 
be liste d se paratel y. C o nc o mit a nt 
me dicati o n use will be s u m marize d b y 
treat me nt gr o u p i n fre q ue nc y t a bles, b y 
t hera pe utic class a n d me dici ne cate g or y. 
A d diti o n. Clarificati o n o n 
s u m maries classificati o n of 
c o nc o mita nt me dicati o n use 
a d de d. 
M o o d data will be s u m marize d o ver ti me 
fr o m i n ta bles at Da y 0 usi n g fre q ue nc y 
ta bles a n d gra p hical dis pla ys  at f oll o w u p 
visits . 
M o o d data will be s u m marize d o ver ti me 
fr o m Da y 0 usi n g fre q ue nc y ta bles a n d 
gra p hical dis pla ys.  
U p date. Clarificati o n o n 
dis pla y of m o o d data o ver 
ti me. 
A p pe n di x A S T U D Y R E S P O N SI BI LI TI E S  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 4  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
I nstit uti o n al Re vie w B o ar ds 
Mi dla n ds  W C G  I R B 
1 0 1 9 3 9t h A ve., S E  
S uite 1 2 0  
P u yall u p, W A 9 8 3 7 4  
8 2 0 7 Melr ose Dri ve, S uite 2 0 5  
Le ne xa, Ka nsas 6 6 2 1 4  
U nite d States of A merica  
I nstit uti o n al Re vie w B o ar ds 
W C G I R B  
1 0 1 9 3 9t h A ve., S E  
S uite 1 2 0  
P u yall u p, W A 9 8 3 7 4  
U nite d States of A merica  
U p date d a d dress  
A p pe n di x B S P E CI M E N S A M P LI N G A N D H A N D LI N G  
Sa m ple pr ocessi n g (ser u m):  
1. C ollect sa m ples (a p pr o xi matel y 5 m L) 
i nt o Vac utai ner®  t u bes (t u be r e d t o p, 1 3 x 
7 5 m m, silic o ne c o ate d i nteri or)  c o ntai ni n g 
n o a ntic oa g ula nt  
2. I m me diatel y after t he sa m pl e is dra w n, 
ge ntl y i n vert t he t u be 5 ti mes . All o w t u bes 
t o sit at r o o m te m perat ure f or 1 5 t o 3 0  at 
least 2 0  mi n utes ( n o m ore t ha n 4 0 
mi n utes)  
3. Ce ntrif u ge ~ 1 0 -1 5  mi n utes ( at r o o m 
te m perat ure at 2 5 0 0 t o 3 0 0 0 r p m 
[a p pr o xi matel y 6 5 0 t o 1 4 5 0 x g ] 4 °C t o 
8 °C, 2 0 0 0 g ) t o ac hie ve a clear ser u m la yer 
o ver t he cl otte d re d cells (t he s pee d a n d 
ti me ma y be varie d acc or di n g t o t he ma ke 
a n d m o del of ce ntrif u ge use d)  
Sa m ple pr ocessi n g (ser u m):  
1. C ollect sa m ples (a p pr o xi matel y 5 m L) 
i nt o Vac utai ner®  t u bes (t u be r e d t o p, 1 3 x 
7 5 m m, silic o ne c oate d i nteri or) c o ntai ni n g 
n o a ntic oa g ula nt  
2. I m me diatel y after t he sa m pl e is dra w n, 
ge ntl y i n vert t he t u be 5 ti mes. All o w t u bes 
t o sit at r o o m te m perat ure f or at least 2 0 
mi n utes ( n o m ore t ha n 4 0 mi n utes)  
3. Ce ntrif u ge ~ 1 0 -1 5 mi n utes (at r o o m 
te m perat ure at 2 5 0 0 t o 3 0 0 0 r p m 
[a p pr o xi matel y 6 5 0 t o 1 4 5 0 x g]) t o 
ac hie ve a clear ser u m la yer o ver t he cl otte d 
re d cells (t he s pee d a n d ti me ma y be varie d 
acc or di n g t o t he ma ke a n d m o del of 
ce ntrif u ge use d)  
A d diti o n a n d u p date. 
I nf or mati o n a d de d o n t y pe 
of sa m ple t u be, t u be 
ha n dli n g a n d ce ntrif u ge.  
St ora g e:  
Sa m ples will be st ore d at a te m perat ure of 
– 2 7 0° C i n a n u pri g ht p ositi o n u ntil t he y are 
s hi p pe d t o t he bi oa nal ytical la b orat or y. 
St ora ge:  
Sa m ples will be st ore d at a te m perat ure of 
– 2 0° C i n a n u pri g ht p ositi o n u ntil t he y are 
s hi p pe d t o t he bi oa nal ytical la b orat or y. 
U p date. St ora ge te m perat ure 
of ser u m sa m ple u p date d  
St ora ge:  
F or e ver y M P A bl o o d dra w, b atc h o ne 
ali q u ot (“ali q u ot 1 ”) f or e ve nt ual s hi p me nt 
t o P P D st ore, a n d o ne ali q u ot (“ali q u ot 2 ”) 
t o be st ore d o n site d uri n g t he st u d y as bac k 
u p i n case a d diti o nal testi n g is nee de d . 
St ora ge at 1 5° C t o 2 5° C wit h o ut a n y 
freeze/t ha w is acce pta ble f or a peri o d of u p 
t o 4 da ys if a freezer wit h a te m perat ure of 
≤6 5° C is n ot a vaila ble.  
St ora ge:  
F or e ver y M P A bl o o d dra w, b atc h o ne 
ali q u ot (“ali q u ot 1”) f or e v e nt ual s hi p me nt 
t o P P D st ore, a n d o ne ali q u ot (“ali q u ot 2”) 
t o be st ore d o n site d uri n g t he st u d y as 
bac k u p i n case a d diti o nal testi n g is 
nee de d.  
U p date. State me nt o n 
sa m ple ali q u ots a d de d a n d 
i nf or mati o n o n acce pta ble 
peri o d of freeze/t ha w 
re m o ve d. 
 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 5  
1 7. 2.  
Pr ot oc ol A me n d me nt 0 1 D ate d 0 2 J ul y 2 0 2 0  
T he pri mar y reas o n f or t his a me n d me nt is t o e xte n d t he d urati o n of t his st u d y.  
A ta ble s h o wi n g t he c ha n ges fr o m t he Pr ot oc ol t o A me n d me nt 0 1 is pr o vi de d bel o w. All maj or 
c ha n ges t o t he pr ot o c ol b o d y are liste d bel o w i n t h e ta ble, a n d are reflecte d i n t he s y n o psis, as 
a p plica ble. Pre vi o us te xt wit h c ha n ges i n dicate d is prese nte d i n t h e c ol u m n title d " Ori gi nal te xt 
wit h c ha n ges s h o w n", a n d t he fi nal te xt is prese nte d i n t he c ol u m n title d " Ne w w or di n g." A d de d 
te xt is s h o w n i n u n derli ne a n d deleti o ns are s h o w n i n stri ke-t hr o u g h.  
T he Sc he d ule of Pr oce d ures a n d Assess me nts ta bl e ( Ta ble 1) has bee n re vise d t o reflect t he 
c ha n ges des cri be d b el o w as a p plica ble. Listi n gs of i n di vi d ual c ollecti o n or assess me nt ti mes 
ha ve bee n re pla ce d wit h a refere n ce t o T a ble 1. O nl y t he title of a n a d diti o nal ta ble a d de d t o t he 
b o d y of t h e pr ot oc ol has bee n i n cl u de d i n t he s u m mar y of c h a n ges.  
Mi n or e dit orial c ha n ges (t y p os, p u nct uati o n, r e placi n g te xt wit h a b bre viati o ns, etc) ha v e bee n 
ma de t o t he pr ot oc ol a n d pr ot oc ol s y n o psis, as a p pr o priate.  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
Secti o n 1. 4. 1.  
Ge ner al St u d y Desi g n R ati o n ale  
St u d y partici pati o n will c o nsist of a 
scree ni n g peri o d ( u p t o 1. 5 m o nt hs, or 6 
wee ks), treat me nt i nitiati o n ( D a y 0), a n d at 
least 5 2 wee ks of f oll o w -u p  
St u d y partici pati o n will c o nsist of a 
scree ni n g peri o d ( u p t o 1. 5 m o nt hs, or 6 
wee ks), treat me nt i nitiati o n ( D a y 0), a n d at 
least 5 2 wee ks of f oll o w-u p  
U p date. St u d y d urati o n 
e xte n de d.  
S u bj ects wit h u nres ol ve d I S R(s) at W ee k 5 2 
will b e f oll o we d e ver y 3 m o nt hs t hr o u g h t he 
res ol uti o n of I S R(s) or W ee k 7 8, w hic he ver 
c o mes first.  
S u bj ects wit h u nres ol ve d I S R(s) at Wee k 
5 2 will be f oll o we d e ver y 3 m o nt hs 
t hr o u g h t he res ol uti o n of I S R(s) or Wee k 
7 8, w hic he ver c o mes first.  
U p date. St u d y d urati o n 
e xte n de d.  
After treat me nt i nitiati o n , s u bj ects will be 
f oll o we d f or 5 2 wee ks a n d pr o vi de bl o o d 
sa m ples f or M P A at t he f oll o wi n g ti me 
p oi nts: Da ys 0, 1, 2, 3, 5, 7, 1 0, 1 2, 1 4, 1 8, 
2 1, a n d 2 8; Wee ks 6, 8, 1 0, 1 2, 1 3, 1 5, 1 7, 
1 9, 2 1, 2 3, 2 5, 2 6, 2 8, 3 0, a n d 3 2; a n d t he n 
e ver y 2 8 da ys t hr o u g h W ee k 5 2. Bl o o d 
sa m ples f or pr o gester o ne, (P ,) will b e 
c ollecte d at W ee ks 4 8, 4 9, 5 0, 5 1 a n d 5 2. I n 
a d diti o n, starti n g o n Da y 2 8 bl o o d sa m ples 
f or a n d  estra di ol ( E 2) as s h o w n i n T a ble 
1. will be c ollecte d e ver y ti me M P A or P is 
meas ure d.  
After treat me nt i nitiati o n, s u bj ects wi ll be 
f oll o we d f or 5 2 wee ks a n d pr o vi de bl o o d 
sa m ples f or M P A, P, a n d estra di ol  ( E 2) as 
s h o w n i n T a ble 1. 
U p date. Ti me p oi nts 
re m o ve d a n d refere nce 
ma de t o T a ble 1.  
Va gi nal blee di n g patter n, acce pta bilit y, a n d 
m o o d will be assesse d t hr o u g h o ut t he st u d y 
at pre d efi ne d ti me p oi nts . a n d acce pta bilit y 
will b e assesse d at W ee ks 1 3, 2 6, a n d 5 2. 
M o o d will b e e val uate d usi n g a brief 
sta n dar dize d q uesti o n naire e v er y 2 8 da ys 
t hr o u g h o ut t he st u d y. 
Va gi nal blee di n g patter n, acce pta bilit y, 
a n d m o o d will be assesse d t hr o u g h o ut t he 
st u d y at pre defi ne d ti me p oi nts. 
U p date. Ti me p oi nts 
re m o ve d a n d refere nce 
ma de t o pre defi ne d ti me 
p oi nts.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 6  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
Uri ne pre g na nc y test will be perf or me d 
e ver y 2 8 da ys starti n g at t he W ee k 2 6 visit 
t hr o u g h t he e n d of t he st u d y p eri o dicall y 
a n d  . Ii nf or mati o n o n a d verse e ve nts a n d 
c o nc o mita nt me dici nes will be c ollecte d 
t hr o u g h o ut t he st u d y. 
Uri ne pre g na nc y test will be perf or me d 
peri o dicall y a n d i nf or mati o n o n a d verse 
e ve nts a n d c o nc o mita nt me dici nes will be 
c ollecte d t hr o u g h o ut t he st u d y.  
U p date. Ti mi n g of 
assess me nts u p date d.  
T he st u d y staff will pr o vi de assess me nt o n 
t he ease of dr u g re s us pe nsi o n a n d i nj ecti o n. 
T he st u d y sc he matic dia gra m is s h o w n i n 
Fi g ure 1.  
T he st u d y sc he matic dia gra m is s h o w n i n 
Fi g ure 1.  
U p date. State me nt 
re gar di n g assess me nt of  
dr u g re -s us pe nsi o n a n d 
i nj ecti o n re m o ve d. 
Secti o n 3. 1. Ge ner al St u d y Desi g n ( Fi g ure 1)  
F oll o w -u p ( 1 2 m o nt hs  u p t o 1 8 m o nt hs ) 
F oll o w -u p ( u p t o 1 8 m o nt hs)  
U p date. D urati o n of st u d y 
e xte n de d.  
Secti o n 3. 2. 2.  
S u bject E xcl usi o n Criteri a  
aa.  has k n o w n se nsiti vit y t o M P A or 
i nacti ve i n gre die nts 
b b. has s ki n dis or ders or s ki n aller gies 
w hic h i n t he o pi ni o n of t he i n vesti gat or 
w o ul d ma ke st u d y partici pati o n u nsafe or 
c o m plicate data i nter pretati o n  
cc. pla ns t o m o ve t o a n ot her l ocati o n i n t he 
ne xt 1 2 m o nt hs  
aa.  has k n o w n se nsiti vit y t o M P A or 
i nacti ve i n gre die nts 
b b. pla ns t o m o ve t o a n ot her l ocati o n i n 
t he ne xt 1 2 m o nt hs 
 
Clarificati o n. T his is n ot t he 
pri mar y o bj ecti ve of t he 
st u d y.   
Secti o n 3. 3.  D ur ati o n of S u bject P artici p ati o n  
T otal d urati o n of t he st u d y f or eac h s u bj ect 
is e x pecte d t o be u p t o 1 3 1 9. 5 m o nt hs, 
i ncl u di n g u p t o 1. 5 m o nt hs of scree ni n g a n d 
1 2 1 8  m o nt hs of f oll o w -u p aft er st u d y 
treat me nt i nitiati o n. All s u bj ects will be 
f oll o we d f or at least 5 2 wee ks after 
treat me nt i nitiati o n. If s u bj ects ha ve 
u nres ol ve d I S R(s) at W ee k 5 2, t he y will b e 
f oll o we d u ntil I S R res ol uti o n or W ee k 7 8, 
w hic he ver c o mes first. T heref ore, t he 
mi ni mal d urati o n of s u bj ect p artici pati o n is 
5 2 wee ks a n d t he ma xi m u m 7 8 wee ks after 
treat me nt i nitiati on.  
T otal d urati o n of t he st u d y f or eac h 
s u bj ect is e x pecte d t o be u p t o 1 9. 5 
m o nt hs, i ncl u di n g u p t o 1. 5 m o nt hs of 
scree ni n g a n d 1 8 m o nt hs of f oll o w-u p 
after st u d y treat me nt i nitiati o n. All 
s u bj ects will be f oll o we d f or at least 5 2 
wee ks after treat me nt i n itiati o n. If s u bj ects 
ha ve u nres ol ve d I S R(s) at Wee k 5 2, t he y 
will be f oll o we d u ntil I S R res ol uti o n or 
Wee k 7 8, w hic he ver c o mes first. 
T heref ore, t he mi ni mal d urati o n of s u bj ect 
partici pati o n is 5 2 wee ks a n d t he 
ma xi m u m 7 8 wee ks after treat me nt 
i nitiati o n. 
U p date. D urati o n of st u d y 
e xte n de d.  
Secti o n 3. 4.  St u d y Pr o ce d ures ( T a ble 1)  
a S u bj ects will ret ur n f or la b orat or y visits at 
pre -defi ne d ti me p oi nts: Da ys 0, 1, 2, 3, 5, 
7, 1 0, 1 2, 1 4, 1 8, 2 1, a n d 2 8; W ee ks 6, 8, 
1 0, 1 2, 1 3, 1 5, 1 7, 1 9, 2 1, 2 3, 2 5, 2 6, 2 8, 
3 0, a n d 3 2; a n d t he n e ver y 2 8 da ys t hr o u g h 
W ee k 5 2.  
a S u bj ects will ret ur n f o r la b orat or y visits 
at pre -defi ne d ti me p oi nts: Da ys 0, 1, 2, 3, 
5, 7, 1 0, 1 2, 1 4, 1 8, 2 1, a n d 2 8; W ee ks 6, 
8, 1 0, 1 2, 1 3, 1 5, 1 7, 1 9, 2 1, 2 3, 2 5, 2 6, 
2 8, 3 0, a n d 3 2; a n d t he n e ver y 2 8 da ys 
t hr o u g h Wee k 5 2. 
U p date. F o ot n ote a d di n g 
ti me p oi nts f or la b visits 
u p date d.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 7  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
a b A uri ne pre g na nc y test will be perf or me d 
o n Da y 0; W ee ks 2 6, 3 2, 3 6, 4 0, 4 4, 4 8, a n d 
5 2; a n d at W ee ks 6 5 a n d 7 8 if a p plica ble, 
a n d at a n y ot her ti mes w he n i n dicate d. A 
uri ne pre g na nc y test will be perf or me d at 
Da y 0; e ver y 2 8 da ys starti n g a t W ee k 2 6 
a n d at a n y ot her ti mes w he n i n dicate d.  
b A uri ne pre g na nc y test will be 
perf or me d o n Da y 0; W ee ks 2 6, 3 2, 3 6, 
4 0, 4 4, 4 8, a n d 5 2; a n d at Wee ks 6 5 a n d 
7 8 if a p plica ble, a n d at a n y ot her ti mes 
w he n i n dicate d.  
U p date. F o ot n ote descri bi n g 
ti mi n g of pre g na nc y tests 
u p date d.  
edI S Rs will be e val uate d o n D a y 0 
i m me diatel y (ie, as s o o n as p ossi ble b ut n o 
later t ha n 1 0 mi n utes u p o n re m o vi n g t he 
nee dle) a n d 1 h o ur ( ± 5 mi n utes) after 
i nj ecti o n; Da y 7; at W ee ks 1 3, 2 6, a n d 5 2 
a n d at ot her visits, if i n dicate d. S u bj ects 
w h o ha ve I S R(s) at W ee k 5 2 will b e 
f oll o we d e ver y 3 m o nt hs (at W ee ks 6 5 a n d 
7 8) u ntil I S R res ol uti o n or W ee k 7 8, 
w hic he ver is earlier. If t he s u bj ect d oes n ot 
ha ve a n y I S Rs at W ee k 5 2 it will b e her 
fi nal visit. All s u bj ects will be i nstr ucte d t o 
ret ur n t o t he cli nic if a n y I S Rs de vel o p after 
t heir fi nal visit. 
eI S Rs will be e val uate d o n Da y 0 
i m me diatel y (ie, as s o o n as p ossi ble b ut 
n o later t ha n 1 0 mi n utes u p o n re m o vi n g 
t he nee dle) a n d 1 h o ur ( ± 5 mi n utes) after 
i nj ecti o n; Da y 7; at W ee ks 1 3, 26, a n d 5 2 
a n d at ot her visits, if i n dicate d. S u bj ects 
w h o ha ve I S R(s) at Wee k 5 2 will be 
f oll o we d e ver y 3 m o nt hs (at Wee ks 6 5 
a n d 7 8) u ntil I S R res ol uti o n or Wee k 7 8, 
w hic he ver is earlier. If t he s u bj ect d oes 
n ot ha ve a n y I S Rs at Wee k 5 2 it will be 
her fi n al visit. All s u bj ects will be 
i nstr ucte d t o ret ur n t o t he cli ni c if a n y 
I S Rs de vel o p after t heir fi nal visit. 
U p date. F o ot n ote descri bi n g 
assess me nt of I S Rs d uri n g 
t he f oll o w-u p peri o d 
u p date d.  
feD uri n g la b orat or y visits, i nf or mati o n o n 
a d verse e ve nts a n d c o nc o mita nt 
me dicati o ns will n ot b e s olicit e d, b ut will 
be d oc u me nte d if self -re p orte d b y t he 
s u bj ect. A d verse e ve nts a n d use of 
c o nc o mita nt me dicati o ns will als o be 
e val uate d d uri n g a d diti o nal I S R f oll o w u p 
at W ee ks 6 5 a n d 7 8.  
fD uri n g la b orat or y visits,  i nf or mati o n o n 
a d verse e ve nts a n d c o nc o mita nt 
me dicati o ns will n ot be s olicit e d, b ut will 
be d oc u me nte d if self -re p orte d b y t he 
s u bj ect. A d verse e ve nts a n d use of 
c o nc o mita nt me dicati o ns will als o be 
e val uate d d uri n g a d diti o nal I S R f oll o w u p 
at Wee ks 6 5 a n d 7 8.  
U p date. F o ot n ote descri bi n g 
t he d oc u me ntati o n of 
a d verse e ve nts a n d 
c o nc o mita nt me dicati o ns 
d uri n g t he f oll o w -u p peri o d 
u p date d.  
h gM o o d will be e val uate d o n Da ys 0 a n d 2 8; 
W ee ks 8, 1 3, 1 7, 2 1, 2 6, 3 2, 3 6, 4 0, 4 4, 4 8, 
5 2.  M o o d will b e e val uate d at Da y 0 a n d 
e ver y 2 8 da ys t hr o u g h o ut t he st u d y.  
hM o o d will be e val uate d o n Da ys 0 a n d 
2 8; W ee ks 8, 1 3, 1 7, 2 1, 2 6, 3 2, 3 6, 4 0, 
4 4, 4 8, a n d 5 2.   
U p date. Ti mi n g of m o o d 
assess me nts u p date d.  
ihVa gi nal blee di n g patter n dat a will be 
assesse d c ollecte d at Scree ni n g, a n d  at 
W ee ks 1 3, 2 6, a n d 5 2.
 
iVa gi nal blee di n g patter n will be assesse d 
at Wee ks 1 3, 2 6, a n d 5 2.  
U p date. Ti mi n g of va gi nal 
blee di n g patter n 
assess me nts u p date d.  
Secti o n 3. 4. 3. Pr o ce d ures f or F oll o w -U p  
St u d y f oll o w -u p will last f or at least 5 2 
wee ks fr o m treat me nt i nitiati o n.  
St u d y f oll o w -u p will last f or at least 5 2 
wee ks fr o m treat me nt i nitiati o n.  
U p date. D urati o n of f oll o w -
u p peri o d e xte n de d.  
Va gi nal blee di n g patter n a n d , acce pta bilit y 
a n d m o o d  will be e val uate d t hr o u g h o ut t he 
st u d y at pre-defi ne d ti me p oi nts . at W ee ks 
1 3, 2 6, a n d 5 2. M o o d will be e val uate d 
usi n g a brief sta n dar dize d q uesti o n naire 
e ver y 2 8 da ys t hr o u g h o ut t he st u d y.  Uri ne 
pre g na nc y tests will b e a d mi nistere d e ver y 
2 8 da ys  peri o dicall y  starti n g at W ee k 2 6 
t hr o u g h t he e n d of t he st u d y. 
Va gi nal blee di n g patter n, acce pta bilit y 
a n d m o o d will be e val uate d t hr o u g h o ut 
t he st u d y at pre-defi ne d ti me p oi nts ( See 
T a ble 1). Uri ne pre g na nc y tests will be 
a d mi nistere d peri o dicall y starti n g at 
Wee k 2 6 t hr o u g h t he e n d of t he st u d y.  
U p date.  Assess me nt of 
m o o d a d de d t o f oll o w -u p 
peri o d.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 8  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
I n a d diti o n t o t he sc he d ule d f oll o w-u p 
visits, s u bj ects will ret ur n f or la b orat or y 
visits t o pr o vi de bl o o d sa m ples f or M P A, P 
a n d E 2 at t he f oll o wi n g ti me p oi nts: Da ys 0, 
1, 2, 3, 5, 7, 1 0, 1 2, 1 4, 1 8, 2 1, a n d 2 8; 
W ee ks 6, 8, 1 0, 1 2, 1 3, 1 5, 1 7, 1 9, 2 1, 2 3, 
2 5, 2 6, 2 8, 3 0, a n d 3 2; a n d t he n e ver y 2 8 
da ys t hr o u g h W ee k 5 2. Bl o o d sa m ples f or P 
will b e c ollecte d at W ee ks 4 8, 4 9, 5 0, 5 1 
a n d 5 2. I n a d diti o n, starti n g o n Da y 2 8 
bl o o d sa m ples f or E 2 will be c ollecte d 
ever y ti me M P A or P is meas ure d.  at pre -
defi ne d ti me p oi nts (see T a ble 1).  
I n a d diti o n t o t he sc he d ule d f oll o w-u p 
visits, s u bj ects will ret ur n f or la b orat or y 
visits t o pr o vi de bl o o d sa m ples f or M P A, 
P a n d E 2 at pre -defi ne d ti me p oi nts (see 
T a ble 1).  
U p date.  C ollecti o n ti mes 
re m o ve d a n d re place wit h a 
refere nce t o T a ble 1. 
If t he s u bj ect has ne w or o n g oi n g I S R at 
W ee k 5 2, s he will be f oll o we d e ver y 3 
m o nt hs (at W ee ks 6 5 a n d 7 8) u ntil I S R 
res ol uti o n or M o nt h 1 8 ( W ee k 7 8), 
w hic he ver is earlier. If t he s u bj ect d oes n ot 
ha ve a n y I S Rs at W ee k 5 2 it will b e her 
fi nal visit. H o we ver, all s u bj ects will be 
i nstr ucte d t o ret ur n t o t he cli ni c if a n y I S Rs 
de vel o p after t heir fi nal visit. I n t hat case, 
t heir stat us will c ha n ge fr o m c o m plete d t he 
st u d y t o acti ve a n d t he y will b e f oll o we d 
per t he sc he d ule a b o ve u ntil I S R res ol uti o n 
or W ee k 7 8, w hic he ver is earli er.  
If t he s u bj ect has ne w or o n g oi n g I S Rs at 
Wee k 5 2, s he will be f oll o we d e ver y 3 
m o nt hs (at Wee ks 6 5 a n d 7 8) u ntil I S R 
res ol uti o n or M o nt h 1 8 ( Wee k 7 8), 
w hic he ver is earlier. If t he s u bj ect d oes 
n ot ha ve a n y I S Rs at Wee k 5 2 it will be 
her fi nal visit. H o we ver, all s u bj ects will 
be i nstr ucte d t o ret ur n t o t he cli nic if a n y 
I S Rs de vel o p after t heir fi nal visit. I n t hat 
case, t heir stat us will c ha n ge fr o m 
c o m plete d t he  st u d y t o acti ve a n d t he y 
will be f oll o we d per t he sc he d ule a b o ve 
u ntil I S R res ol uti o n or Wee k 7 8, 
w hic he ver is earlier.  
U p date. Pr o ce d ures f or 
re p orti n g a n d rec or di n g 
I S Rs d uri n g t he f oll o w-u p 
peri o d.  
F oll o w u p visits s h o ul d be sc h e d ule d usi n g 
t he tar get wi n d o w peri o ds bel o w. H o we ver, 
if a s u bj ect ca n n ot atte n d a visit wit hi n t he 
tar get wi n d o w bel o w, t he visit pr oce d ures 
s h o ul d be c o n d ucte d as s o o n as p ossi ble 
re gar dless of ti mi n g. 
F oll o w u p visits s h o ul d be sc he d ule d 
usi n g t he tar get wi n d o w peri o ds bel o w . 
H o we ver, if a s u bj ect ca n n ot atte n d a visit 
wit hi n t he tar get wi n d o w bel o w, t he visit 
pr oce d ures s h o ul d be c o n d uct e d as s o o n 
as p ossi ble re gar dless of ti mi n g.  
A d diti o n. A descri pti o n of 
t he ta ble i ncl u di n g t he 
tar get ti me wi n d o ws. 
T a ble 2. T ar get Ti me Wi n d o ws f or F oll o w -
u p Visits  
T a ble 2. T ar get Ti me Wi n d o ws f or 
F oll o w -u p Visits  
A d diti o n. T a ble 2 was 
a d de d t o i ncl u de t he tar get 
ti me wi n d o ws f or f oll o w-u p 
visits  
Secti o n 4. 5.  I nteri m D at a Re vie ws 
T he S R C will c o n ve ne f or at l east si n gle 
pla n ne d o ne re vie w of i nteri m data after at 
least 8 0 % of s u bj ects ha ve ha d a c ha nce t o 
c o m plete 7. 5 m o nt hs after treat me nt 
i nitiati o n. 
T he S R C will c o n ve ne f or at l east o ne 
re vie w of i nteri m data after at least 8 0 % 
of s u bj ects ha ve ha d a c ha nce t o c o m plete 
7. 5 m o nt hs after treat me nt i nitiati o n.  
Clarificati o n. Ti mi n g of 
i nteri m data re vie w 
u p date d.  
Secti o n 5. 1. 5.  Assess me nt Of M o o d  
S u bj ects will be i nter vie we d a b o ut as pects 
of a n d c ha n ges i n m o o d at scree ni n g a n d at 
pre -defi ne d  o n a re g ular basis  ti me p oi nts 
t hr o u g h o ut t he st u d y ( T a ble 1). 
S u bj ects will be i nter vie we d a b o ut as pects 
of a n d c ha n ges i n m o o d at scree ni n g a n d 
at pre -defi ne d ti me p oi nts  t hr o u g h o ut t he 
st u d y ( T a ble 1). 
Clarificati o n. Ti me of 
assess me nts u p date d t o pre -
defi ne d ti me p oi nts  
Secti o n 5. 1. 9 .  I njecti o n Site Re a cti o ns (I S Rs) 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
7 9  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
I nj ecti o n site reacti o n (I S R) will be 
e val uate d  meas ure d as detaile d i n T a ble 1.  
I nj ecti o n site reacti o n (I S R) will be 
e val uate d as detaile d i n T a ble 1.  
Clarificati o n.  
F or t he p ur p ose of t his pr ot oc ol, i nj ecti o n 
site pai n will i ncl u de pai n ass ociate d wit h 
i nj ecti o n a n d a n y pai n or te n d er ness 
at/ar o u n d t he i nj ecti o n site.  F or t he p ur p ose 
of t his pr ot oc ol, i nj ecti o n site pai n will 
i ncl u de pai n ass ociate d wit h i nserti o n of t he 
nee dle, i nj ecti n g of t he dr u g, a n d a n y pai n 
o r te n der ness at/ar o u n d t he i nj ecti o n site. 
F or t he p ur p ose of t his pr ot oc ol, i nj ecti o n 
site pai n will i ncl u de pai n ass ociate d wit h 
i nj ecti o n a n d a n y pai n or te n d er ness 
at/ar o u n d t he i nj ecti o n site.  
U p date. I nj ecti o n site 
descri pti o n u p date d.  
I nj ecti o n sites will be m o nit or e d f or t he 
pr o gress of o n g oi n g a n d/ or occ urre nce of 
ne w I S Rs. If t he s u bj ect has ne w or o n g oi n g 
I S R at W ee k 5 2, s he will be f oll o we d e ver y 
3 m o nt hs (at W ee ks 6 5 a n d 7 8) u ntil I S R 
res ol uti o n or W ee k 7 8, w hic he ver is earlier.   
I nj ecti o n sites will be m o nit or e d f or t he 
pr o gress of o n g oi n g a n d/ or occ urre nce of 
ne w I S Rs. If t he s u bj ect has ne w or 
o n g oi n g I S R at Wee k 5 2, s he will be 
f oll o we d e ver y 3 m o nt hs (at Wee ks 6 5 
a n d 7 8) u ntil I S R res ol uti o n or Wee k 7 8, 
w hic he ver is earlier.   
U p date. Pr o ce d ures relate d 
t o I S R m o nit ori n g u p date d.  
I S Rs will b e e val uate d at all st u d y 
ti me p oi nts liste d i n T a ble 1 b y s u bj ect’s 
self-re p orts a n d vis ual e xa mi nati o n of t he 
site of i nj ecti o n b y bli n de d st u d y staff. 
I S Rs will be e val uate d at all st u d y 
ti me p oi nts liste d i n T a ble 1 b y s u bj ect’s 
self-re p orts a n d vis ual e xa mi nati o n of t he 
site of i nj ecti o n b y bli n de d st u d y staff. 
Clarificati o n. T a ble 1 is 
liste d as a refere nce f or 
ti me p oi nts.  
T he st u d y staff will be i nstr uct e d t o use 
n o n -lea di n g q uesti o ns (e g, “D o y o u ha ve 
a n y ne w me dical iss ues si nce pre vi o us 
visit? ” ) h o w d oes t he i nj ecti o n site feel, d o 
y o u ha ve a n y ne w c o m plai nts a b o ut t he 
i nj ecti o n site si nce last visit) f or I S R 
ascertai n me nt. I nj ecti o n site p ai n will be 
e val uate d b y self re p orts. 
T he  st u d y staff will be i nstr uct e d t o use 
n o n -lea di n g q uesti o ns (e g, “ D o y o u ha ve 
a n y ne w me dical iss ues si nce pre vi o us 
visit? ”) f or I S R ascertai n me nt.  
U p date. Q uesti o ns 
re gar di n g I S Rs re m o ve d. 
State me nt re gar ds self -
re p orts of I S Rs re m o ve d. 
If necessar y, a c o ns ultati o n wit h a n 
a p pr o priate cli nical e x pert ma y be 
sc he d ule d. All cases of i nj ecti o n site 
disc ol orati o n ( h y p o pi g me ntati o n) will b e 
p h ot o gra p he d a n d c o ns ulte d b y a 
der mat ol o gist.  If necessar y, a c o ns ultati o n 
wit h a n a p pr o priate cli nical e x pert ma y be 
sc he d ule d.  
All cases of i nj ecti o n site disc ol orati o n 
( h y p o pi g me ntati o n) will be p h ot o gra p he d. 
If necessar y, a c o ns ultati o n wit h a n 
a p pr o priate cli nical e x pert ma y be 
sc he d ule d. 
U p date. Details descri bi n g 
I S R d oc u me ntati o n a n d 
e val uati o n u p date d.  
Secti o n 5. 2. 2.  
Rec or di n g a n d Re p orti n g A d verse E ve nts  
F or t his st u d y, t he f oll o w u p peri o d is 
defi ne d as u p t o 7 8  5 2 wee ks after t he last 
d ose of I M P.  
F or t his st u d y, t he f oll o w u p peri o d is 
defi ne d as u p t o 7 8 wee ks after t he last 
d ose of I M P.  
U p date. T he f oll o w-u p 
peri o d of t he st u d y u p date d.  
At t he sc he d ule d W ee k 1 ( Da y 7) a n d W ee k 
1 3, 2 6, a n d 5 2  visits, t he i n vesti gat or will 
q uesti o n t he s u bj ect a b o ut a d verse e ve nts 
b y as ki n g a n o pe n -e n de d q uesti o n s uc h as, 
“ Ha ve y o u ha d a n y u n us ual s y m pt o ms or 
me dical pr o ble ms si nce t he last visit? If 
yes, please descri be.”  
At t he sc he d ule d visits, t he i n vesti gat or 
will q uesti o n t he s u bj ect a b o ut a d verse 
e ve nts b y as ki n g a n o pe n -e n de d q uesti o n 
s uc h as, “ Ha ve y o u ha d a n y u n us ual 
s y m pt o ms or me dical pr o ble ms si nce t he 
last visit? If yes, please descri be.” 
U p date. Da ys re m o ve d.  
Secti o n 5. 2. 5. 3. 1.  I n vesti g at or Res p o nsi bilit y 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
8 0  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
T he i n vesti gat or d oes n ot nee d t o acti vel y 
m o nit or s u bj ects f or a d verse e ve nts o nce 
t his st u d y has e n de d. Seri o us a d verse e ve nts 
occ urri n g t o a s u bj ect after t he treat me nt of 
t hat s u bj ect has e n de d will be re p orte d t o 
t he s p o ns or, wit hi n 2 4 h o urs, fr o m w he n t he 
i n vesti gat or bec o mes a ware of t he m. 
T he i n vesti gat or d oes n ot nee d t o acti vel y 
m o nit or s u bj ects f or a d verse e ve nts o nce 
t heir f oll o w-u p peri o d has e n d e d. Seri o us 
a d verse e ve nts occ urri n g after st u d y 
disc o nti n uati o n will be re p orte d t o t he 
s p o ns or wit hi n 2 4 h o urs fr o m w he n t he 
i n vesti gat or bec o mes a ware of t he m, 
f oll o wi n g t he pr oce d ures descri be d i n 
Secti o n 5. 2. 5. 3.  
T he i n vesti gat or d oes n o t nee d t o acti vel y 
m o nit or s u bj ects f or a d verse e ve nts o nce 
t heir f oll o w-u p peri o d has e n d e d. Seri o us 
a d verse e ve nts occ urri n g after st u d y 
disc o nti n uati o n will be re p orte d t o t he 
s p o ns or wit hi n 2 4 h o urs fr o m w he n t he 
i n vesti gat or bec o mes a ware of t he m, 
f oll o wi n g t he pr oce d ures descri be d i n 
Secti o n 5. 2. 5. 3.  
U p date. I n vesti gat or 
res p o nsi bilities after a 
s u bj ect’s f oll o w-u p peri o d 
u p date d.  
Secti o n 5. 2. 9.  Pre g n a nc y  
D uri n g t he st u d y , a pre g na nc y test will be 
perf or me d if t he w o ma n is e x perie nci n g 
a n y s y m pt o ms or si g ns of pre g na nc y, or 
t hi n ks s he ma y be pre g na nt, a n d e ver y 2 8 
da ys bet wee n W ee ks 2 6 a n d 5 2.  as detaile d 
i n T a ble 1, a n d at a n y ti me t he w o ma n is 
e x perie nci n g a n y s y m pt o ms or si g ns of 
pre g na nc y, or t hi n ks s he ma y be pre g na nt.  
D uri n g t he st u d y , a pre g na nc y test will be 
perf or me d as detaile d i n T a ble 1 , a n d at 
a n y ti me t he w o ma n is e x perie nci n g a n y 
s y m pt o ms or si g ns of pre g na nc y, or 
t hi n ks s he ma y be pre g na nt. 
U p date. A d diti o nal ti mes 
f or pre g na nc y tests 
i ncl u de d. 
Secti o n 8.  A C C E P T A BI LI T Y A S S E S S M E N T S  
T he acce pta bilit y of t he differ e nt i nj ecti o n 
d oses a n d treat me nt gr o u ps will be assesse d 
a n d rec or de d o n a p pr o priate st u d y C R Fs at 
W ee ks 1 3,  2 6 , a n d 5 2 b y bli n de d staff. 
Acce pta bilit y q uesti o ns will i ncl u de b ut n ot 
be li mite d t o q uesti o ns a b o ut a cce pta bilit y 
of t he blee di n g patter ns a n d ot her si de 
effects, w hat s he li kes a n d disli kes m ost 
a b o ut t his met h o d, a n d w het her s he w o ul d 
use t his met h o d i n t he f ut ure a n d/ or 
rec o m me n d it t o a frie n d. 
T he acce pta bilit y of t he differ e nt i nj ecti o n 
d oses a n d t reat me nt gr o u ps will be 
assesse d a n d rec or de d o n a p pr o priate 
st u d y C R Fs at Wee ks 2 6 a n d 5 2 b y 
bli n de d staff. Acce pta bilit y q uesti o ns will 
i ncl u de b ut n ot be li mite d t o q uesti o ns 
a b o ut w hat s he li kes a n d disli kes m ost 
a b o ut t his met h o d, a n d w het her s he w o ul d 
use t his met h o d i n t he f ut ure a n d/ or 
rec o m me n d it t o a frie n d. 
U p date. Ti mi n g of 
acce pta bilit y assess me nts 
u p date d. Q uesti o ns i ncl u de d 
i n t he assess me nt u p date d. 
Secti o n 9. 3. 4.  P h ar m ac o ki n etic A n al ysis Set  
F oll o w u p ti me will als o be ce ns ore d after a 
s u bj ect i nitiates use of a c o nc o mita nt 
me dicati o n k n o w n t o i m pact t he 
p har mac o ki netics of M P A.  T he a nal ysis set 
will e xcl u de M P A data c ollect e d d uri n g 
ti me peri o ds w he n s u bj ects us e d a 
c o nc o mita nt me dicati o n k n o w n t o i m pact 
t he p har mac o ki netics of M P A. 
T h e a nal ysis set will e xcl u de M P A data 
c ollecte d d uri n g ti me peri o ds w he n 
s u bj ects use d a c o nc o mita nt me dicati o n 
k n o w n t o i m pact t he p har mac o ki netics of 
M P A.  
U p date. Data e xcl u de d fr o m 
t he a nal ysis set u p date d.  
Secti o n 9. 5. 2.  
De m o gr a p hic a n d B aseli ne C h ar a cteristics  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
8 1  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
S u bj ect d e m o gra p hic a n d baseli ne 
c haracteristics, i ncl u di n g me di cal hist or y, 
a n d pri or me dicati o ns  will be e xa mi ne d t o 
assess t he c o m para bilit y of t he treat me nts 
a n d will be s u m marize d usi n g descri pti ve 
statistics. 
S u bj ect de m o gra p hic a n d baseli ne 
c haracteristics, will be e xa mi ne d t o assess 
t he c o m para bilit y of t he treat me nts a n d 
will be s u m marize d usi n g des cri pti ve 
statistics. 
U p date. De m o gra p hics data 
c ollecte d u p date d.  
Secti o n 9. 6.  S afet y A n al ysis  
T he perce nta ge of w o me n e x p erie nci n g 
a me n orr hea or va gi nal blee di n g 
dist ur ba nces (irre g ular va gi nal blee di n g or 
s p otti n g) will li ke wise be s u m marize d 
descri pti vel y a n d c o m pare d bet wee n t he 
test a n d refere nce treat me nt gr o u ps. M o o d 
data will be s u m marize d i n ta bles at 
a p pr o xi matel y m o nt hl y Da y 0 a n d at 
f oll o w-u p visits.  
T he perce nta ge of w o me n e x p erie nci n g 
a me n orr hea or va gi nal blee di n g 
dist ur ba nces (irre g ular va gi nal blee di n g 
or s p otti n g) will li ke wise be s u m marize d 
descri pti vel y a n d c o m pare d bet wee n t he 
test a n d refere nce gr o u ps. M o o d data will 
be s u m marize d i n ta bles at Da y 0 a n d at 
f oll o w-u p visits.  
U p date.  “ T est a n d 
refere nce” gr o u p a d de d. 
Ti mi n g of m o o d data 
s u m maries u p date d. 
Secti o n 9. 8.  Acce pt a bilit y A n al ysis  
T he res p o nses t o acce pta bilit y q uesti o ns at 
W ee ks 2 6 a n d 5 2, i ncl u di n g li kes a n d 
disli kes of t he met h o d a n d willi n g ness t o 
use t he pr o d uct i n t he f ut ure will be 
ta b ulate d i n fre q ue nc y ta bles a n d c o m pare d 
bet wee n t he test a n d t he refere nce gr o u ps 
usi n g descri pti ve C hi -s q uare d tests. 
T he res p o nses t o acce pta bilit y q uesti o ns 
at Wee ks 2 6 a n d 5 2, i ncl u di n g li kes a n d 
disli kes of t he met h o d a n d willi n g ness t o 
use t he pr o d uct i n t he f ut ure will be 
ta b ulate d i n fre q ue nc y ta bles a n d 
c o m pare d bet wee n t he test a n d t he 
refere nce gr o u ps usi n g descri pti ve C hi-
s q uare d tests. 
A d diti o n. Acce pta bilit y 
a nal ysis a d de d.  
Secti o n 9. 9.   Pl a n ne d I nteri m A n al ysis  
At least  O o ne i nteri m re vie w is pla n ne d t o 
occ ur after at least 8 0 % of s u bj ects ha ve 
ha d a c ha nce t o c o m plete 7. 5 m o nt hs after 
treat me nt i nitiati o n. T his a nal ysis is 
i nte n de d t o hel p i nf or m t he de cisi o n t o 
m o ve t o, a n d select t he d ose f or, a pi v otal 
st u d y. T hese i nt eri m data ma y be use d t o 
i nf or m t he e n d of P hase 1 meeti n g wit h t he 
F D A.  
At least o ne i nteri m re vie w is pla n ne d t o 
occ ur after at least 8 0 % of s u bj ects ha ve 
ha d a c ha nce t o c o m plete 7. 5 m o nt hs after 
treat me nt i nitiati o n. T his a nal ysis is 
i nte n de d t o hel p inf or m t he de cisi o n t o 
m o ve t o, a n d select t he d ose f or, a pi v otal 
st u d y. T hese i nteri m data ma y be use d t o 
i nf or m t he e n d of P hase 1 meeti n g wit h 
t he F D A. 
U p date. Fre q ue nc y of  
pla n ne d i nteri m re vie w 
u p date d.  
A P P E N DI X A.  St u d y Res p o nsi bilities  
Site I n vesti gat ors 
Site I n vesti gat ors  
U p date. M ulti ple site 
i n vesti gat ors a d de d. 
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
8 2  
Ori gi n al te xt wit h c h a n ges s h o w n  
Ne w w or di n g  
Re as o n/ J ustific ati o n f or 
c h a n ge  
 
 
 
As ociaci ó n D o mi nica na Pr o Bie nestar de la 
Fa milia, I nc. ( P R O F A MI LI A)  
  
 
 
 
 
I C O N 
 
 
 
 
  
W C C T  
 
 
 
 
 
As ociaci ó n D o mi nica na Pr o Bie nestar de 
la Fa milia, I nc. ( P R O F A MI LI A)  
  
 
 
 
 
I C O N 
 
 
 
 
ti gat or  
W C C T  
 
 
U p date. A d diti o nal 
i n vesti gat ors i ncl u de d. 
  
F HI 3 6 0  
   
  
 
  
F HI 3 6 0  
   
  
 
U p date. Title c ha n ge d.  
Ce ntral  I nstit uti o nal Re vie w B oar ds 
I nstit uti o nal Re vie w B oar ds 
U p date. Ce ntral I R B 
re m o ve d. 
Mi dla n ds I R B  
8 2 0 7 Melr ose Dri ve, S uite 2 0 5  
Le ne xa, Ka nsas 6 6 2 1 4  
U nite d States of A merica  
 
Et hical C o m mittee of Pr ofa milia  
Clí nica A bre u, Calle B eller # 4 2 es q. A ve. 
I n de p e n de ncia 
Sa nt o D o mi n g o, D o mi nica n R e p u blic  
 
C O N A BI O S  
A ve. B olí var # 9 0 2, La J ulia  
Sa nt o D o mi n g o, D o mi nica n R e p u blic  
Pr otecti o n of H u ma n S u bj ects C o m mittee  
F HI 3 6 0  
 
 
 
Mi dla n ds I R B  
8 2 0 7 Melr ose Dri ve, S uite 2 0 5  
Le ne xa, Ka nsas 6 6 2 1 4  
U nite d States of A merica  
 
Et hical C o m mittee of Pr ofa milia  
Clí nica A bre u, Calle Beller # 4 2  es q. A ve. 
I n de pe n de ncia 
Sa nt o D o mi n g o, D o mi nica n Re p u blic  
 
C O N A BI O S  
A ve. B olí var # 9 0 2, La J ulia  
Sa nt o D o mi n g o, D o mi nica n Re p u blic  
 
U p date. I R Bs a d de d.  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
8 3  
A P P E N DI X  A.  S T U D Y R E S P O N SI BI LI TI E S   
S p o ns or’s A ut h orize d Re prese nt ati ve  
 
  
 
  
S p o ns or’s M e dic al E x pert   
 
 
N u ve ntra, I nc. ™ 
 
 
 
S p o ns or’s S afet y Re prese nt ati ve  
 
 
T e va Bra n de d P har mace utical Pr o d ucts R & D, I nc.  
 
 
 
Site I n vesti g at ors  
 
 
As ociaci ó n D o mi nica na Pr o Bie nestar de la Fa milia, I nc. 
( P R O F A MI LI A)  
  
 
 
 
 
I C O N 
 
 
 
 
  
W C C T  
 
 
C o or di n ati n g I n vesti g at or  
  
F HI 3 6 0  
   
  
 
M o nit o r  
F HI 3 6 0  
 
 
 
Tri al S u p pl y M a n a ge me nt ( T S M) Ve n d or  
Acta vis La b orat ories U T, I nc  
5 7 7 C hi peta Wa y  
Salt La ke Cit y, U T 8 4 1 0 8, U S A  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
8 4  
I nstit uti o n al Re vie w B o ar ds 
W C G I R B 
1 0 1 9 3 9t h A ve., S E  
S uite 1 2 0  
P u yall u p, W A 9 8 3 7 4  
U nite d States of A merica  
 
Et hical C o m mittee of Pr ofa milia  
Clí nica A bre u, Calle Beller # 4 2 es q. A ve. I n de pe n de ncia  
Sa nt o D o mi n g o, D o mi nica n Re p u blic  
 
C O N A BI O S  
A ve. B olí var # 9 0 2, La J ulia  
Sa nt o D o mi n g o, D o mi nica n Re p u blic  
V V- 0 0 0 4 3 7 1 1 v 4. 0


 
P har mac o ki netic St u d y –  Healt h y S u bjects  
Cli nical St u d y Pr ot oc ol wit h A me n d me nt 0 2   
St u d y T V 4 6 0 4 6 -W H -1 0 1 5 9  
 
8 5  
A P P E N DI X  B.  S P E CI M E N S A M P LI N G A N D H A N D LI N G  
P h ar m a c o ki netic Ser u m C ollecti o n a n d Pr o cessi n g I nstr ucti o ns  
Ve ni p u nct ure a n d 
tra nsfer t u b e la bel 
i nf or mati o n 
St u d y n u m b er, s u bject r a n d o mizati o n n u m ber, sa m ple t y pe (e g, P K), st u d y 
peri o d (if a p plica ble), n o mi nal c ollecti o n ti me, sa m ple set ( A or B)  
Sa m ple 
pr ocessi n g 
(ser u m) 
1.  C ollect sa m ples (a p pr o xi matel y 5 m L) i nt o V ac ut ai ner ®  t u bes (t u be 
re d t o p, 1 3 x 7 5 m m, silic o ne c o ate d i nteri or) c o ntai ni n g n o 
a ntic oa g ula nt  
2.  I m me diat el y after t he sa m ple is dra w n,  ge ntl y  i n vert t he t u be 5  ti mes. 
All o w t u bes t o sit at r o o m te m perat ure f or at least 2 0 mi n utes ( n o 
m ore t ha n 4 0 mi n utes)  
3.  Ce ntrif u ge ~ 1 0 -1 5 mi n utes (at r o o m te m perat ure at 2 5 0 0  t o 3 0 0 0  r p m 
[a p pr o xi matel y 6 5 0  t o 1 4 5 0  x  g] ) t o ac hie ve a clear ser u m la yer o ver  
t he cl otte d re d cells (t he s pee d a n d ti me ma y  be  v arie d  acc or di n g t o 
t he ma ke  a n d m o del  of  ce ntrif u ge use d)  
4.  Tra nsfer a p pr o xi matel y e q ual p orti o ns of se parate d ser u m (at least 
1  m L) i nt o 2 la bel e d, p ol y pr o p yle ne tra nsfer t u bes (sets  A  a n d B)  
St ora ge  
Sa m ples will be st ore d at a te m pe rat ure of – 2 0° C i n a n u pri g ht p ositi o n u ntil 
t he y are s hi p pe d t o t he bi oa nal yti cal la b orat or y. F or e ver y M P A  bl o o d dr a w, 
batc h o ne ali q u ot (“ali q u ot 1”) f or e v e nt ual s hi p me nt t o P P D st ore, a n d o ne 
ali q u ot (“ali q u ot 2”) t o b e st ore d o n site d uri n g t h e st u d y  as b ac k u p i n cas e 
a d diti o nal testi n g is nee d e d.   
S hi p pi n g  
T he bi oa nal ytical la b orat or y will be n otifie d pri or t o t he s hi p me nt of t he 
sa m ples. Pri mar y a n d bac k u p sa m ples are n ot t o be se nt i n t he sa me s hi p me nt.  
A n electr o nic file c o ntai ni n g sa m ple c ollec ti o n dat es will be e maile d t o t he 
bi oa nal ytical la b orat or y a n d t he s p o ns or’s bi oa nal ytical d e part me nt 
re pres e ntati ve f or eac h s hi p me nt. 
 
V V- 0 0 0 4 3 7 1 1 v 4. 0

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan 
 
 
A Randomized, Dose-range Finding Study to Evaluate Pharmacokinetics of 
Medroxyprogesterone Acetate Following a Single Subcutaneous Administration of 
TV-46046 in Healthy Women of Reproductive Age 
 
 
Study Number TV46046-WH-10159 
 
 
NCT04682353 
 
 
SAP Approval Date: 15 February 2023 


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
1 
 
 
Statistical Analysis Plan 
Teva Study Number: TV46046-WH-10159 
FHI 360 Study Number: 1449048 
 
A Randomized, Dose-range Finding Study to Evaluate Pharmacokinetics of 
Medroxyprogesterone Acetate Following a Single Subcutaneous Administration of  
TV-46046 in Healthy Women of Reproductive Age 
 
Phase 1 
IND Number: 126249 
EudraCT number: Not applicable 
Initial Approval Date: 18 November 2020 
Version 5.0 Date: 15 February 2023  
 
Study Sponsor 
Teva Branded Pharmaceutical Products R&D, Inc 
145 Brandywine Pkwy,  
West Chester, PA 19380 
United States of America 
 
Study Implementation 
FHI 360  
 
 
 
 
 
 
 
Prepared by: 
  
                        FHI 360 
 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
2 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
Study No.: 
TV46046-WH-10159 
Study Title: A Randomized, Dose-range Finding Study to Evaluate Pharmacokinetics of 
Medroxyprogesterone Acetate Following a Single Subcutaneous Administration 
of TV-46046 in Healthy Women of Reproductive Age 
  
 
Statistical Analysis Plan for: 
 
 Interim Analysis  
 
 Integrated Summary of Efficacy 
 
 Final Analysis 
 
 
 Integrated Summary of Safety 
 
 
Author: 
  
                        
 
                        FHI 360 
 
 
 
 
Approver signatures and dates: 
 
 
______________________________________________________________________________
                                                        
 
 
, FHI 360 
 
____________________________________________ 
                    
 
, FHI 360 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
3 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................5 
INTRODUCTION ...........................................................................................................................6 
1. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................7 
1.1. 
Primary Study Objective and Endpoints .......................................................................7 
1.1.1. 
Primary Objective .........................................................................................................7 
1.1.2. 
Primary Endpoints ........................................................................................................7 
1.2. 
Secondary Study Objectives and Endpoints .................................................................7 
1.2.1. 
Secondary Objectives ...................................................................................................7 
1.2.2. 
Secondary Endpoints ....................................................................................................8 
2. 
STUDY DESIGN .........................................................................................................9 
2.1. 
General Design .............................................................................................................9 
2.2. 
Randomization, Allocation Concealment, and Blinding ..............................................9 
2.3. 
Blinded Data Review ..................................................................................................10 
2.4. 
Interim Monitoring .....................................................................................................10 
2.5. 
Sample Size and Power Considerations .....................................................................10 
2.6. 
Sequence of Planned Analyses ...................................................................................11 
2.6.1. 
Planned Interim Analysis ............................................................................................11 
2.6.2. 
Final Analysis and Reporting .....................................................................................11 
3. 
ANALYSIS SETS ......................................................................................................12 
3.1. 
Screened Analysis Set .................................................................................................12 
3.2. 
Randomized Analysis Set ...........................................................................................12 
3.3. 
Safety Analysis Set .....................................................................................................12 
3.4. 
Pharmacokinetic Analysis Set ....................................................................................12 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................13 
4.1. 
Descriptive Statistics ..................................................................................................13 
4.2. 
Specification of Baseline Values ................................................................................13 
4.3. 
Handling of Withdrawals and Missing Data ..............................................................13 
4.3.1. 
Discontinuation and Missing Data ..............................................................................13 
4.3.2. 
Imputed Data ..............................................................................................................13 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
4 
4.4. 
Study Days and Visits .................................................................................................14 
5. 
STUDY POPULATION .............................................................................................15 
5.1. 
General ........................................................................................................................15 
5.2. 
Subject Disposition .....................................................................................................15 
5.3. 
Demographic and Baseline Characteristics ................................................................15 
5.4. 
Protocol Deviations ....................................................................................................15 
6. 
EFFICACY ANALYSIS ............................................................................................16 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................17 
8. 
SAFETY ANALYSIS ................................................................................................18 
8.1. 
General ........................................................................................................................18 
8.2. 
Compliance to Study Drug .........................................................................................18 
8.3. 
Adverse Events ...........................................................................................................18 
8.4. 
Injection Site Reactions ..............................................................................................18 
8.5. 
Delayed Return to Ovulation ......................................................................................19 
8.6. 
Vaginal Bleeding ........................................................................................................19 
8.7. 
Liver Function Tests ...................................................................................................19 
8.8. 
Mood ...........................................................................................................................19 
8.9. 
Vital Signs and Body Weight .....................................................................................19 
8.10. 
Estradiol ......................................................................................................................19 
8.11. 
Concomitant Medications or Therapies ......................................................................19 
9. 
ACCEPTABILITY DATA ANALYSIS ....................................................................21 
10. 
PHARMACOKINETICS ANALYSIS .......................................................................22 
10.1. 
MPA Concentrations below the LLOQ ......................................................................22 
10.2. 
Intercurrent Events ......................................................................................................22 
10.3. 
Descriptive Pharmacokinetic Summaries ...................................................................22 
10.4. 
Noncompartmental Analysis ......................................................................................23 
10.5. 
Treatment Group Comparisons ...................................................................................24 
10.6. 
Planned Sensitivity Analyses ......................................................................................24 
10.7. 
Exploratory Analyses ..................................................................................................24 
11. 
STATISTICAL SOFTWARE ....................................................................................25 
12. 
CHANGES TO PLANNED ANALYSES..................................................................26 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
Abbreviation 
Term 
λ 
terminal phase rate constant 
AUC0-x 
area under the serum drug concentration by time curve from time 0 to day x 
AUC0-∞ 
area under the serum drug concentration by time curve from time 0 to infinity 
BMI 
body mass index 
Cx 
serum drug concentration at day x post-treatment initiation 
Clast 
last quantifiable serum drug concentration 
Cmax 
maximum serum drug concentration 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
%CV 
percent coefficient of variation 
E2 
Estradiol 
GM 
geometric mean 
IcE 
intercurrent event 
ISR 
injection site reaction 
LLOQ 
lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MPA 
medroxyprogesterone acetate 
NCA 
non-compartmental analysis 
NRS 
numeric rating scale 
P 
progesterone 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
SE 
standard error 
t1/2 
apparent terminal half-life 
Tlast 
time (in days) to last quantifiable MPA measurement 
Tmax 
time (in days) to maximum serum drug concentration 
TEAE 
treatment emergent adverse event 
WY 
women-years 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
6 
INTRODUCTION 
This Statistical Analysis Plan (SAP) describes the planned analysis for A Randomized, Dose-
range Finding Study to Evaluate Pharmacokinetics of Medroxyprogesterone Acetate Following a 
Single Subcutaneous Administration of TV-46046 in Healthy Women of Reproductive Age. The 
study is sponsored by Teva Branded Pharmaceutical Products R&D, Inc. and is implemented by 
FHI 360.  
The reader of this SAP is encouraged to read the protocol for details on the conduct of this study, 
the operational aspects of clinical assessments, and the timing for completing the participation of 
a subject in this study. Version 1.0 of the SAP expands upon the analysis of primary and 
secondary endpoints outlined in Protocol Amendment 01 (the current version at the time of first 
subject enrolled), including definitions of estimands and methods for handling missing data and 
intercurrent events. When differences exist in descriptions or explanations provided in the study 
protocol and this Statistical Analysis Plan, the SAP prevails; any such differences will be 
explained in the Clinical Study Report (CSR).  
Future changes to the SAP (e.g., to address amendments to the protocol) and their temporal 
relationship to unblinding will be documented in Section 12 and detailed in the CSR. Mock 
tables, figures and listings will be approved by the Coordinating Investigator prior to un-blinding 
of study statisticians and maintained in a separate document.  
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
7 
1. 
STUDY OBJECTIVES AND ENDPOINTS 
The overall goal of this study is to select a dose of TV-46046 (medroxyprogesterone acetate 
[MPA] injectable suspension 300 mg/mL) that is safe, well tolerated, and has a pharmacokinetics 
profile consistent with contraceptive protection when injected every 6 months. 
1.1. 
Primary Study Objective and Endpoints 
1.1.1. 
Primary Objective 
The primary objective of this study is to evaluate and compare the pharmacokinetics profile of 
MPA following subcutaneous administration of 3 doses of TV-46046 300 mg/mL (120 
mg/0.4mL; 180 mg/0.6mL; 240 mg/0.8mL), and 104 mg/0.65 mL Depo-subQ Provera 104 in 
healthy female subjects. 
1.1.2. 
Primary Endpoints 
The following non-exhaustive list of pharmacokinetics parameters will be evaluated to support 
the primary objective of the study: 
 Cmax (maximum observed serum concentration) 
 Tmax (time to Cmax) 
 Serum MPA concentrations at treatment days 91, 182, and 210 (C91, C182, C210) 
 AUC0-182 (area under the serum drug concentration-time curve from time 0 to day 182) 
 AUC0-210 (area under the serum drug concentration-time curve from time 0 to day 210) 
 AUC0-∞ (area under the serum drug concentration-time curve extrapolated to infinity) 
 Apparent terminal half-life (t½) 
1.2. 
Secondary Study Objectives and Endpoints 
1.2.1. 
Secondary Objectives 
The secondary objectives of the study are: 
1) to evaluate and compare the safety and local tolerability of a subcutaneous injection of 3 
doses of TV-46046 300 mg/mL (120 mg/0.4mL; 180 mg/0.6mL; 240 mg/0.8mL) and Depo-
subQ Provera 104 in healthy female subjects 
2) to evaluate the acceptability of a subcutaneous injection of TV-46046 over the range of 
different doses 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
8 
1.2.2. 
Secondary Endpoints 
The safety and local tolerability measures/parameters are: 
 occurrence of adverse events 
 use of concomitant medication 
 vital signs 
 body weight measurement 
 vaginal bleeding pattern 
 assessment of mood by Patient Health Questionnaire-9 (PHQ-9) 
 liver function tests 
 estradiol (E2) measurements throughout the study 
 progesterone (P) measurements at Weeks 48, 49, 50, 51, and 52 
 occurrence of injection site reactions (ISRs)  
 subjects’ responses to acceptability questions 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
9 
2. 
STUDY DESIGN 
2.1. 
General Design 
This is a randomized, partially-blinded dose-range finding study to evaluate and compare the 
pharmacokinetics, safety, local tolerability, and acceptability of the subcutaneous administration 
of 3 different doses of TV-46046 300 mg/mL (120 mg/0.4 mL, 180 mg/0.6 mL, or 240 mg/0.8 
mL) and the reference product Depo-subQ Provera 104 (104 mg/0.65mL) in healthy female 
subjects. 
Study procedures and their timing in relation to treatment initiation are summarized in Table 1 of 
the protocol.1 Briefly, study participation will consist of a screening period, treatment initiation 
and 52 weeks of primary follow-up. Enrolled subjects will provide blood samples for MPA 
testing at baseline (Day 0, prior to injection of study drug); Day 1, 2, 3, 5, 7, 10, 12, 14, 18, 21, 
and 28 post-injection; and Week 6, 8, 10, 12, 13, 15, 17, 19, 21, 23, 25, 26, 28, 30, 32, 36, 40, 44, 
48, and 52 post-injection. Specimens for P and E2 measurement will be collected at Day 0 and 
Weeks 48, 49, 50, 51 and 52, and specimens for E2 measurement will be collected at all visits 
where samples for MPA or P are taken starting on Day 28. 
Subjects will be evaluated for vital signs, body weight, liver enzymes, and ISRs at Weeks 1, 13, 
26, and 52 post-injection; vaginal bleeding patterns will be assessed at Weeks 13, 26, and 52; 
acceptability will be assessed at Weeks 26 and 52; and mood will be evaluated on Days 0 and 28 
and Weeks 8, 13, 17, 21, 26, 32, 36, 40, 44, 48, and 52. Subjects with unresolved ISRs at Week 
52 or who report a new ISR after Week 52 will be followed every 3 months through ISR 
resolution or Week 78, whichever comes first (adverse events and concomitant medication use 
will also be evaluated at post-week 52 visits, as relevant). 
2.2. 
Randomization, Allocation Concealment, and Blinding 
Subjects will be randomized in a 1:1:1:1 allocation ratio to one of the 3 TV-46046 test groups or 
the Depo-subQ 104 reference group, using a permuted block design stratified by investigational 
center. The randomization sequence will be developed by an FHI 360 programmer not otherwise 
involved in the study using a validated SAS/STAT® program (version 9.4). Randomized subjects 
who discontinue early will not be replaced. Additional details (including block sizes) are 
maintained in a separate document.  
Allocation will be concealed using opaque, sequentially numbered randomization envelopes 
provided to each investigational center. Trained staff will open the next available envelope, and 
allocate the next treatment assignment, only after a subject has completed all other baseline 
procedures and is determined to be eligible for treatment. Randomization envelopes will be 
                                                 
1 The study protocol defines day of treatment initiation as Day 0. Noting that the day of treatment initiation is 
defined as Day 1 in CDISC, protocol Day X will be mapped to treatment Day X+1 when creating ADaM data. 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
10 
maintained in a secure location at each center, with access limited to authorized personnel per 
center-specific study procedures.  
The study will only be partially blinded due to differences in appearance of the investigational 
products. Investigational center staff preparing and administering injections will not be blinded 
but will be trained to shield the syringe from view of the subject. FHI 360 and sponsor study 
team members involved in assessment of adverse events, data analysis, and results interpretation 
will be blinded to treatment assignment until the first interim analysis, after which time only 
investigational center staff assessing safety outcomes or performing subject interviews will 
remain blinded. Lab personnel performing MPA testing will remain blinded throughout the 
study. Emergency unblinding procedures for medical reasons are described in the study 
Pharmacy Manual and Safety Management Plan. Any instances of unscheduled unblinding will 
be described in the CSR. 
2.3. 
Blinded Data Review 
Prior to the first planned interim analysis, study data will be reviewed by the Coordinating 
Investigator and Lead Biostatistician or their designee(s) to inform analysis decisions. The Lead 
Biostatistician will be responsible for developing blinded listings for this review and will 
document the Coordinating Investigator’s decisions prior to unblinding. These reviews will 
include (but not necessarily be limited to) important protocol deviations for inclusion/exclusion 
of subjects and/or data points from the primary analysis sets, assessment of potential outliers, and 
any necessary adjustments to imputation rules for missing MPA results due to out of window 
visits. Blinded data reviews may likewise occur to inform clinical queries to the site. 
2.4. 
Interim Monitoring 
A Study Review Committee (SRC) composed of FHI 360 and Sponsor staff will convene for one 
or more interim data reviews after at least 80% of treated subjects have had an opportunity to 
complete 7.5 months of follow-up. Unplanned reviews may be triggered by the occurrence of 
ISRs and/or serious and related adverse events as specified in the protocol and detailed in a 
separate SRC Operational Plan. The SRC may recommend that the trial be modified or halted to 
ensure the safety and well-being of study subjects at the time of any planned or unplanned 
interim analysis. There will be no adjustment to type I error or the coverage of confidence 
intervals (CIs) to account for interim reviews of data. 
2.5. 
Sample Size and Power Considerations 
There are no hypothesis tests in this phase 1 pharmacokinetics study, and the sample size was not 
based on formal power calculations. Rather, 60 treated subjects (15 per group) was determined to 
be sufficient to inform the selection of a dose of TV-46046 for future pivotal study based on the 
results of two recent trials of MPA products implemented under similar protocols. 
 
 
 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
11 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.6. 
Sequence of Planned Analyses 
2.6.1. 
Planned Interim Analysis 
A planned review of interim data will occur when at least 80% of treated subjects have had an 
opportunity to complete 7.5 months of follow-up. This interim analysis is intended to inform the 
decision to move to - and the dose selection for - a future pivotal study. If recommended by the 
SRC, additional interim analyses of pharmacokinetic data may be performed in advance of an 
end of phase 2 meeting. Unplanned interim analyses for purposes of monitoring participant 
safety may be triggered by safety endpoints or otherwise made at the discretion of the SRC.  
2.6.2. 
Final Analysis and Reporting 
All final analyses will be performed after the last subject has completed the study. 
 
 
  
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
12 
3. 
ANALYSIS SETS 
3.1. 
Screened Analysis Set 
The Screened Analysis Set will include all subjects who are screened for study participation, 
regardless of whether they are enrolled and randomized. In this analysis set, analyses will be 
performed according to enrollment status. 
3.2. 
Randomized Analysis Set 
The Randomized Analysis Set will include all randomized subjects, regardless of whether they 
received a dose of study drug. The Randomized Analysis Set will be used for assessment of 
subject disposition. 
3.3. 
Safety Analysis Set 
The Safety Analysis Set will be a subset of the Randomized Analysis Set, excluding any subject 
who failed to receive an injection of study drug. Subjects will be analyzed according to treatment 
received, regardless of any allocation errors. The Safety Analysis Set will be used for all 
assessments of baseline, safety, and acceptability data, as well as sensitivity analyses of 
pharmacokinetics data that include all treated subjects, regardless of any exclusions from the 
primary pharmacokinetics analyses. 
3.4. 
Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set will be a subset of the Safety Analysis Set, excluding any 
subjects who had a baseline MPA concentration that exceeded 5% of their individual Cmax, had 
an important protocol deviation that may affect interpretation of their MPA data, or failed to 
provide at least one evaluable post-treatment MPA specimen. The Pharmacokinetic Set will be 
analyzed according to treatment received. Failure to follow the intention-to-treat principle will be 
justified on the grounds that the study is not intended to make definitive conclusions regarding 
the efficacy of TV-46046. 
A single intercurrent event (IcE) relevant to pharmacokinetic analyses is anticipated as possible 
for this study: the use of concomitant medications known to impact the pharmacokinetics of 
MPA (e.g. inducers or inhibitors of CYP3A4).2 The strategy for handling this potential IcE is to 
exclude MPA results obtained during periods of relevant medication use (and assume that the 
excluded drug concentration data are missing completely at random) when defining estimands 
and constructing estimators based on non-compartmental analysis (NCA) methods. Additional 
details regarding the impact of IcEs on estimands and estimators are provided in Section 10. 
                                                 
2 Intercurrent events typical to other studies, such as discontinuing treatment and treatment switching, are not 
relevant given that each subject is administered only a single dose of drug which can’t be discontinued.   
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
13 
4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
Descriptive Statistics 
Descriptive statistics pertinent to pharmacokinetic analyses are described in Section 10. For all 
other analyses, continuous variables will be summarized using the number [n] of non-missing 
values, the mean, standard deviation (SD), median, minimum, maximum and other descriptive 
statistics, as relevant. Categorical data will be summarized using the number and percentage of 
subjects with a specific level of the variable. Measures of central tendency and dispersion will be 
reported to one decimal place greater than the original data; the minimum, maximum, and 
percentiles other than the median will be reported to the same number of decimal places as the 
original data. Proportions will be presented to three decimal places and percentages to one 
decimal place. 
4.2. 
Specification of Baseline Values 
The baseline value for any measurement is the last value prior to injection of study drug.  
4.3. 
Handling of Withdrawals and Missing Data 
4.3.1. 
Discontinuation and Missing Data 
Subjects who are discontinued from the study after being randomized will not be replaced. All 
available data up to the time of discontinuation will be included in relevant analyses. Except as 
noted in Section 4.3.2, missing data will not be estimated or imputed. 
4.3.2. 
Imputed Data 
Missing MPA concentrations at key time points (e.g., end-times of partial AUCs) and MPA 
concentrations that fall below the lower limit of quantification (LLOQ) will be imputed using 
methods specified in Section 10. Other laboratory measurements that fall below an applicable 
LLOQ will be imputed as half the LLOQ when summarizing continuous variables. If required to 
interpret safety, incomplete adverse event onset, resolution, or concomitant medication use dates 
may be imputed as follows: 
 If the month of adverse event onset or initiation of medication use is known but the day is 
missing, then the onset/initiation date may be imputed as the first day of the month.  
 If the month of adverse event resolution or medication use stop-date is known but the day 
is missing, then the resolution/stop data may be imputed as the last day of the month. 
Other imputation rules may be required on a case-by-case basis, as determined by the 
Coordinating Investigator or delegated staff member. Imputation decisions will be documented 
in the CSR as occurring after unblinding, as applicable.  
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
14 
4.4. 
Study Days and Visits 
For purposes of analysis, the number of days post-injection on which an event occurs or an 
outcome is assessed will be calculated as the date of the event or outcome, minus the date of 
treatment initiation; a negative day indicates an event prior to study drug administration. When 
appropriate, fractions of study days will be computed based on the time (in hours and minutes) of 
a subject’s injection and the time of her event or outcome assessment. 
Although actual MPA sampling times will be used in applicable pharmacokinetics analyses (e.g., 
when computing AUC values), sampling times will be assigned to visit windows when reporting 
by-visit summaries of MPA concentrations (e.g., C182). In order to maximize available data, the 
window periods used in these by-visit summaries may be wider than the target visit windows 
specified in the protocol (see Table 2).  
Table 2. Pharmacokinetic data visit windows 
 
Visit Window 
Days since Treatment Initiation 
Protocol Target 
Visit-specific Analyses 
1, 2 
 1 hour 
+/- 3 hours 
3, 5, 7 
 3 hours 
+/- 6 hours 
10, 12, 14, 18 
 24 hours 
+/- 24 hours 
21 and after (except days 91 and 182) 
 48 hours 
+/- 168 hours 
91, 182 
 48 hours 
-84 / +168 hours 
 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
15 
5. 
STUDY POPULATION 
5.1. 
General 
This study will recruit healthy subjects to eliminate confounding factors (comorbidities, 
comedications) with potential impact on study outcome. Since TV-46046 is a hormonal 
contraceptive, only women will be enrolled in the study. Since the contraceptive dose and 
duration action of TV-46046 is unknown, we will enroll women who are not pregnant, not 
wanting to become pregnant in the next 24 months, and who are at low risk of pregnancy 
because they are sterilized, in exclusively same-sex partnership, abstinent, in monogamous 
relationship with vasectomized partner, using non-hormonal IUD, consistent use of condoms or 
other barrier methods of contraception. Enrolled women will be 18 to 45 years of age and with 
body mass index (BMI) 18 to 35 kg/m2 (inclusive).  
5.2. 
Subject Disposition 
Summaries of subject disposition will include the numbers and percentages of screened subjects 
who are enrolled, randomized, and contribute to the Randomized, Safety and Pharmacokinetic 
Analysis Sets; reasons for exclusion from analysis sets; women-years (WY) of follow-up 
contributed (for Randomized and Safety analysis sets) and WY of MPA testing contributed (for 
Pharmacokinetic analysis set); and the numbers and percentages of subjects who complete the 
study, discontinue early (overall and by reason), or are lost to follow-up. Disposition will be 
summarized by treatment group, investigational site and overall. 
5.3. 
Demographic and Baseline Characteristics 
Summary statistics appropriate for the measurement scale will be used to describe baseline data. 
Continuous variables may also be described using categorical levels based on previous 
experience with similar studies. Baseline data will be presented for the Safety Analysis Set and 
the Pharmacokinetic Analysis Set (the later only if any subjects are excluded from the Safety 
Set). Summaries will be provided by treatment group within each investigational center and 
pooled across centers and treatment groups. No statistical tests will be performed to compare 
baseline characteristics between treatment groups. 
 
 
 
 
5.4. 
Protocol Deviations 
Protocol deviations will be tabulated by treatment group (as relevant) according to categories of 
deviations and described in data listings, including any action taken in response to the deviation.  
 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
16 
6. 
EFFICACY ANALYSIS 
N/A. Efficacy will not be evaluated in this study. 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
17 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No adjustments will be made for planned or unplanned multiple comparisons of study endpoints. 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
18 
8. 
SAFETY ANALYSIS 
8.1. 
General 
An adverse event with onset during or after injection of study drug, or a worsening of an existing 
condition during or after injection, is considered a treatment emergent adverse event (TEAE); 
only TEAEs will be included in the safety analysis. All safety and local tolerability endpoints 
will be summarized for the Safety Analysis Set. 
8.2. 
Compliance to Study Drug 
All treated subjects will by definition be 100% compliant, as they are administered a single dose 
of drug which can’t be discontinued. 
8.3. 
Adverse Events 
A summary table of TEAEs will include numbers of events, and numbers and percentages of 
subjects, experiencing: any TEAEs; serious TEAEs; related TEAEs; TEAEs by severity; TEAEs 
leading to study discontinuation; and TEAEs leading to death. Treatment-group differences in 
the percentages of subjects experiencing each TEAE category will be explored using descriptive 
Fisher’s Exact tests. The summary table will be repeated when restricted to TEAEs with onset on 
or before week 52 (the end of routine follow-up). 
TEAEs will be further grouped by System Organ Class (SOC) and preferred term using 
MedDRA™ (v23.0 or higher). Results will be displayed in order of decreasing frequency, both 
across SOCs and within each SOC term, by treatment group. TEAEs will also be tabulated by 
severity (mild, moderate, severe) and relationship to study drug, by SOC and preferred term. 
TEAEs (preferred term) which occur in at least 10% of subjects will be summarized separately.  
Listings of TEAEs will include verbatim event description, SOC and preferred term, duration, 
relatedness, seriousness, severity, outcome, whether onset was during the first 52 weeks of 
follow-up, and whether the subject withdrew from the study as a result of the event. Information 
on any deaths will be described in subject narratives included in the CSR. 
8.4. 
Injection Site Reactions 
A summary table of ISRs will include numbers of events, and numbers and percentages of 
subjects, experiencing a) any ISR; b) ISRs documented as adverse events on CRF data (per 
protocol criteria); and c) hypopigmentation events. Exact Cochran-Armitage tests of trend will 
be used to explore relationships between MPA dose and the probability of experiencing ISRs.  
ISRs will be further tabulated according to specific categories, including but not necessarily 
limited to erythema, swelling, pruritus, bleeding, bruising, hypopigmentation, atrophy, and 
injection site pain. The maximum recorded size of ISRs (if applicable) will be summarized using 
descriptive statistics for continuous variables. An 11-point numeric rating scale will be used to 
describe reports of injection site pain. Listings of ISRs will include time to onset, duration, 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
19 
outcome, and whether the ISR was self-reported by the subject or noted by clinic staff when 
performing an assessment of the injection site. 
8.5. 
Delayed Return to Ovulation 
The number and percentage of subjects with no evidence of ovulation (i.e. no observed P ≥ 4.7 
ng/mL) in the 12th month of follow-up, and an exact 95% CI for the probability of delayed return 
to ovulation based on a binomial distribution assumption, will be reported by treatment group. 
These calculations will exclude subjects with 1 or more missing progesterone measurements at 
weeks 48, 49, 50, 51 or 52 unless ovulation was detected at one of their non-missing visits.  
8.6. 
Vaginal Bleeding 
Subjects’ responses to questions about their vaginal bleeding patterns since last visit will be 
summarized in frequency tables at Weeks 13, 26, and 52.  
8.7. 
Liver Function Tests 
Liver function (ALP, AST, ALT, total protein, albumin, and total and direct bilirubin) will be 
summarized by treatment group by tabulating mean, SD, median, minimum and maximum 
values at Day 7, Week 13, Week 26, and Week 52. Mean, standard error (SE), minimum and 
maximum change from baseline will be summarized using shift-tables, by treatment group.  
8.8. 
Mood 
A 10-item Patient Health Questionnaire will be used to produce an overall depression severity 
score. Depression scores will be summarized by treatment group in frequency tables (based on a 
5-point Likert scale) at Day 0, Day 28, and Weeks 13, 26, and 52, and displayed graphically over 
time. 
8.9. 
Vital Signs and Body Weight 
Pulse, temperature, systolic and diastolic blood pressure, respiration rate, body weight, and BMI 
will be tabulated by treatment group using descriptive statistics at baseline and Day 7, Week 13, 
Week 26, and Week 52. Change from baseline in vital signs and body weight will be described 
in shift tables using mean, SE, minimum, and maximum values, by treatment group.  
8.10. 
Estradiol  
Individual E2 concentrations will be displayed graphically from pre-treatment through Week 52. 
E2 data will also be tabulated for each treatment group using mean, SD, median, minimum and 
maximum values at Day 28 and Weeks 13, 26, 30, and 52, by treatment group. 
8.11. 
Concomitant Medications or Therapies  
Concomitant medications used in 30 days prior to treatment and after treatment initiation will be 
summarized separately by treatment group in frequency tables, by therapeutic class and medicine 
category (per the WHO Drug Dictionary). Listings of medication use, including those initiated 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
20 
after week 52 of follow-up (among the subset of subjects monitored for ISRs after week 52) will 
include indication and start and stop dates. 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
21 
9. 
ACCEPTABILITY DATA ANALYSIS 
Responses to acceptability questionnaire items at Week 26 and Week 52 will be summarized 
using frequency tables and compared between test and reference groups using descriptive 
Pearson’s Chi-square tests.  
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
22 
10. 
PHARMACOKINETICS ANALYSIS 
10.1. 
General 
All pharmacokinetic analyses will be presented for the Pharmacokinetic Analysis Set unless 
otherwise specified.  
10.2. 
MPA Concentrations below the LLOQ   
The following rules will be applied to account for MPA concentrations below the LLOQ:  
 Baseline values below the LLOQ will be imputed as 0 ng/mL 
 Values that fall below the LLOQ after Day 0 will be imputed as ½ the LLOQ when 
summarizing visit-specific MPA concentration data. However, any below LLOQ value that 
occurs after the day of a woman’s last quantifiable measure (Tlast) will be imputed as zero 
when computing AUC values, and ignored when computing the terminal rate constant (λ).      
10.3. 
Intercurrent Events  
A single IcE is anticipated as possibly occurring in this study: the use of concomitant 
medications known to impact the pharmacokinetics of MPA. Any MPA results obtained from a 
subject between the initiation date of a relevant medication and the last date that the medication 
may have impacted the pharmacokinetics of MPA will be excluded from the Pharmacokinetics 
Analysis Set. This strategy corresponds to the hypothetical scenario in which the IcE did not 
occur when defining pharmacokinetic estimands, and the corresponding estimators will be 
(asymptotically) unbiased under the assumption that the excluded data are missing completely at 
random (i.e., the reason for use of the medication is independent of the pharmacokinetics of 
MPA). The precise dates of exclusion will be adjudicated by the Lead Biostatistician and 
Clinical Investigator in blind review whenever possible. The impact of exclusions on 
pharmacokinetic parameter estimators are described further in Section 10.4.  
10.4. 
Descriptive Pharmacokinetic Summaries 
Overlays of individual MPA profiles will be displayed by treatment group in the original scale 
and using semi-log[base 10] plots. Serum MPA concentrations will be summarized by treatment 
group using the mean (SD), median, minimum, maximum, percent below 0.2 ng/mL, and percent 
below the LLOQ at select sampling timepoints, including but not limited to: Baseline, Day 1, 
Day 91 (Month 3), Day 182 (Month 6), Day 210 (Month 7), and Day 364 (Month 12). Geometric 
Mean (GM) +/- geometric SD concentrations will be graphically displayed by treatment group at 
all sampling visits through Week 52 (Day 364). A graphical overlay of treatment-group GMs 
(with 95% CIs computed based on log-normality assumptions) will also be provided. If a subject 
has more than one MPA result in the same visit window (Table 2) then the value closest to the 
nominal time will be used when describing visit-level data. Summary measures of visit-specific 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
23 
drug concentration data will be reported to the same number of decimal places as the original 
data. 
10.5. 
Noncompartmental Analysis   
The following protocol-specified pharmacokinetic parameters will be estimated based on NCA: 
Cmax, Tmax, C91, C182, C210, AUC0-182, AUC0-210, AUC0-∞, and the apparent terminal half-life 
(computed as loge[2]/ λ). Additional estimates will include AUC through day of last quantifiable 
sample (AUC0-last), and time above 0.2 ng/mL (extrapolated to infinity). Detailed rules used to 
estimate these parameters, and conditions that must be met to report the estimate, are as follows:  
 Cmax will be based on the maximum observed MPA concentration for subjects who a) 
provide at least one MPA result after their highest observed concentration and b) do not use 
a concomitant medication known to impact the pharmacokinetics of MPA before the 
occurrence of Cmax. Values of Cmax for subjects who fail to meet these two criteria will be 
considered non-evaluable and excluded from the primary pharmacokinetic analysis.  
 Tmax will be based on the day (rounded to the first decimal place) when Cmax was initially 
observed. Values of Tmax for subjects who’s Cmax is non-evaluable (per above) will be 
excluded from primary analyses. 
 C91, C182, and C210 will be based on evaluable results in the corresponding pre-defined visit 
windows (Table 2). If a subject has more than one MPA result in the same visit window, 
then the value closest to the nominal time will be used. 
 λ will be estimated as minus the slope of the terminal phase, based on the last three or more 
log-transformed MPA concentrations after Cmax but on or before Tlast, regressed on time. 
The specific number of time points used to compute λ will be determined based on the 
unweighted regression with largest adjusted R2. If the estimated slope is not negative, or if 
fewer than three time points are available for estimating λ, then no value will be reported. 
 Partial AUC values will be computed using the ‘linear up log down’ rule as implemented in 
Phoenix WinNonLin (version 8.3 or higher). No AUC value will be reported if Cmax was 
not estimable per above. 
 AUC0-∞ will be computed as AUC0-last + Clast/ λ, where Clast is the last quantifiable drug 
concetration measurement  
 Time at or above 0.2 ng/mL will be computed using linear up log down interpolation if the 
0.2 ng/ml threshold is crossed between two sampling time points, and log down 
interpolation when extrapolating to infinity.    
Except for t1/2, the primary measure of central tendency and dispersion for each pharmacokinetic 
parameter estimate will be the GM and geometric %CV; for t1/2, the harmonic mean and %CV 
based on a jackknife estimate of SD will be reported. Additional summaries will include mean, 
SD, SE, median, minimum, maximum, and 95% CIs for means. Measures of AUC, Tmax, and t1/2 
will be reported to one decimal place. Drug concentration parameter estimates (e.g. Cmax and 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
24 
C182) will be summarized using the same number of decimal places as the original data. Subject 
listings will include each of the above parameter estimates as well as the percent of AUC 
extrapolated to infinity.   
10.6. 
Treatment Group Comparisons   
Comparisons between each dose of TV-46046 and the Depo-subQ reference product will be 
made based on GM ratios (test/reference) and 90% CIs for GM ratios, for the following exposure 
parameters: Cmax, C91, C182, C210, AUC0-182, AUC0-210, AUC0-∞, and trough concentrations (C182 
for each TV-46046 test group and C91 for the Depo-subQ provera 104 reference). Confidence 
intervals will be computed based on the antilog of corresponding limits for the difference in 
mean log concentrations (computed assuming a student-t distribution for log-transformed 
values). The assumptions of log-normality and homogeneity of variance will be assessed by 
inspection of quantile-to-quantile plots, residuals, and tests of departure from these assumptions. 
The lead biostatistician will use these results to determine whether either assumption is violated 
to a degree that alternative methods (e.g. boostrap resampling) should be employed when 
reporting CIs for GM ratios. 
10.7. 
Planned Sensitivity Analyses   
The NCA analysis will be repeated based on the Safety Set (not excluding any subjects or data 
points, regardless of IcEs or violations of entry criteria). In addition, if more than 10% of 
subjects have missing data on visit Day 91, 182, or 210 then the primary comparison of those 
outcomes between test and reference groups will be repeated based on imputed C91, C182, or C210 
values, using the same imputation rules as for the end-times of partial AUCs.  
10.8. 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
25 
11. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS/STAT® 
(version 9.4 or later) or Phoenix WinNonlin® (version 8.3 or later). 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


 
 Pharmacokinetics Study–Healthy Subjects 
Statistical Analysis Plan Version 5.0 
Study TV46046-WH-10159 
26 
12. 
CHANGES TO PLANNED ANALYSES 
12.1. 
Changed from V1.0 of the SAP   
The following cumulative changes were made from Version 1.0 of the SAP, prior to unblinding: 
Version 2.0 (May 18, 2021) 
 Section 1.2.2: Safety and local tolerability measures/parameters updated to be consistent 
with changes made in Protocol Amendment 02. 
 Section 2.1: revised to reflect updates to assessment timepoints in Table 1 of the protocol. 
Specifically, addition of collection of P specimens and mood evaluation on Day 0; 
specimens for E2 collected on Day 0 and weeks 48, 49, 50, 51 and 52; and clarifying 
which visits E2 specimens will be collected if MPA or P samples are taken (starting on 
Day 28). 
 Section 10.7: 
. 
Version 3.0 (April 12, 2022)  
Version 3.0 of the SAP was created to document that the above changes took place. 
Version 4.0 (June 29, 2022)  
Version 4.0 of the SAP clarified computation methods for apparent half-life and time above 0.2 
ng/mL. The imputation of partial AE and concomintant medication start and stop dates using 
previous visit dates was removed as reporting date for these events was not collected. Changes to 
planned analyses were documented and approved prior to unblinding. 
Version 5.0 (February 15, 2023)  
Version 5.0 of the SAP expanded the analysis visit windows in Table 2 after blinded review of 
samples excluded for being out of window. These changes were not implemented for the interim 
analysis but were documented and approved prior to unblinding. In section 8.5, the definition of 
ovulation in month 12 was added as well as a definition of which subjects would be included in 
the denominator for the percentage calculations. 
 
DocuSign Envelope ID: 16B2332D-2490-446E-BC28-3C9E93E0087A


Certificate Of Completion
Envelope Id: 16B2332D2490446EBC283C9E93E0087A
Status: Completed
Subject: TV46046-10159  SAP V5.0.doc
CF02: 
Project Code/Charge Code: FP0205.C01.004.004.001
Source Envelope: 
Document Pages: 26
Signatures: 2
Envelope Originator: 
Certificate Pages: 5
Initials: 0
AutoNav: Enabled
EnvelopeId Stamping: Enabled
Time Zone: (UTC-05:00) Eastern Time (US & Canada)
IP Address: 
   
Record Tracking
Status: Original
             2/15/2023 10:56:37 AM
Holder: 
             
Location: DocuSign
Signer Events
Signature
Timestamp
Family Health International Inc - Part 11
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
CD1A4605-A615-4A76-9A07-F2E6D22D38CF
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 2/15/2023 10:58:30 AM
Viewed: 2/17/2023 9:32:59 AM 
Signed: 2/17/2023 9:34:03 AM
Electronic Record and Signature Disclosure: 
      Accepted: 12/6/2019 10:47:18 AM
      ID: 822c8224-6c32-474e-86c1-b06bacca3778
FHI360
Security Level: Email, Account Authentication 
(Required)
Signature Adoption: Pre-selected Style
Signature ID: 
A8BED2E7-E466-4DAB-AD27-0B685C6E44DD
Using IP Address: 
With Signing Authentication via DocuSign password
With Signing Reasons (on each tab): 
   I approve this document
Sent: 2/15/2023 10:58:30 AM
Viewed: 2/15/2023 12:44:32 PM 
Signed: 2/15/2023 12:45:10 PM
Electronic Record and Signature Disclosure: 
      Accepted: 11/8/2019 9:32:09 AM
      ID: ebe536cf-51e6-4beb-b20d-1b08d1bc938a
In Person Signer Events
Signature
Timestamp
Editor Delivery Events
Status
Timestamp
Agent Delivery Events
Status
Timestamp
Intermediary Delivery Events
Status
Timestamp


Certified Delivery Events
Status
Timestamp
Carbon Copy Events
Status
Timestamp
Witness Events
Signature
Timestamp
Notary Events
Signature
Timestamp
Envelope Summary Events
Status
Timestamps
Envelope Sent
Hashed/Encrypted
2/15/2023 10:58:31 AM
Certified Delivered
Security Checked
2/15/2023 12:44:32 PM
Signing Complete
Security Checked
2/15/2023 12:45:10 PM
Completed
Security Checked
2/17/2023 9:34:03 AM
Payment Events
Status
Timestamps
Electronic Record and Signature Disclosure


ELECTRONIC RECORD AND SIGNATURE DISCLOSURE  
From time to time, Family Health International Inc - Part 11 (we, us or Company) may be 
required by law to provide to you certain written notices or disclosures. Described below are the 
terms and conditions for providing to you such notices and disclosures electronically through the 
DocuSign system. Please read the information below carefully and thoroughly, and if you can 
access this information electronically to your satisfaction and agree to this Electronic Record and 
Signature Disclosure (ERSD), please confirm your agreement by selecting the check-box next to 
‘I agree to use electronic records and signatures’ before clicking ‘CONTINUE’ within the 
DocuSign system. 
 
Getting paper copies  
At any time, you may request from us a paper copy of any record provided or made available 
electronically to you by us. You will have the ability to download and print documents we send 
to you through the DocuSign system during and immediately after the signing session and, if you 
elect to create a DocuSign account, you may access the documents for a limited period of time 
(usually 30 days) after such documents are first sent to you. After such time, if you wish for us to 
send you paper copies of any such documents from our office to you, you will be charged a 
$0.00 per-page fee. You may request delivery of such paper copies from us by following the 
procedure described below. 
 
Withdrawing your consent  
If you decide to receive notices and disclosures from us electronically, you may at any time 
change your mind and tell us that thereafter you want to receive required notices and disclosures 
only in paper format. How you must inform us of your decision to receive future notices and 
disclosure in paper format and withdraw your consent to receive notices and disclosures 
electronically is described below. 
 
Consequences of changing your mind  
If you elect to receive required notices and disclosures only in paper format, it will slow the 
speed at which we can complete certain steps in transactions with you and delivering services to 
you because we will need first to send the required notices or disclosures to you in paper format, 
and then wait until we receive back from you your acknowledgment of your receipt of such 
paper notices or disclosures. Further, you will no longer be able to use the DocuSign system to 
receive required notices and consents electronically from us or to sign electronically documents 
from us. 
 
All notices and disclosures will be sent to you electronically  
Electronic Record and Signature Disclosure created on: 11/6/2019 11:30:00 AM
Parties agreed to: 


Unless you tell us otherwise in accordance with the procedures described herein, we will provide 
electronically to you through the DocuSign system all required notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided or made 
available to you during the course of our relationship with you. To reduce the chance of you 
inadvertently not receiving any notice or disclosure, we prefer to provide all of the required 
notices and disclosures to you by the same method and to the same address that you have given 
us. Thus, you can receive all the disclosures and notices electronically or in paper format through 
the paper mail delivery system. If you do not agree with this process, please let us know as 
described below. Please also see the paragraph immediately above that describes the 
consequences of your electing not to receive delivery of the notices and disclosures 
electronically from us. 
 
How to contact Family Health International Inc - Part 11:  
You may contact us to let us know of your changes as to how we may contact you electronically, 
to request paper copies of certain information from us, and to withdraw your prior consent to 
receive notices and disclosures electronically as follows: 
To contact us by email send messages to: 
 
 
To advise Family Health International Inc - Part 11 of your new email address  
To let us know of a change in your email address where we should send notices and disclosures 
electronically to you, you must send an email message to us at 
 and in 
the body of such request you must state: your previous email address, your new email 
address.  We do not require any other information from you to change your email address.  
If you created a DocuSign account, you may update it with your new email address through your 
account preferences.  
 
To request paper copies from Family Health International Inc - Part 11  
To request delivery from us of paper copies of the notices and disclosures previously provided 
by us to you electronically, you must send us an email to 
 and in the 
body of such request you must state your email address, full name, mailing address, and 
telephone number. We will bill you for any fees at that time, if any. 
 
To withdraw your consent with Family Health International Inc - Part 11  
To inform us that you no longer wish to receive future notices and disclosures in electronic 
format you may: 


i. decline to sign a document from within your signing session, and on the subsequent page, 
select the check-box indicating you wish to withdraw your consent, or you may; 
ii. send us an email to 
 and in the body of such request you must state 
your email, full name, mailing address, and telephone number. We do not need any other 
information from you to withdraw consent..  The consequences of your withdrawing consent for 
online documents will be that transactions may take a longer time to process.. 
 
Required hardware and software  
The minimum system requirements for using the DocuSign system may change over time. The 
current system requirements are found here: https://support.docusign.com/guides/signer-guide-
signing-system-requirements.  
 
Acknowledging your access and consent to receive and sign documents electronically  
To confirm to us that you can access this information electronically, which will be similar to 
other electronic notices and disclosures that we will provide to you, please confirm that you have 
read this ERSD, and (i) that you are able to print on paper or electronically save this ERSD for 
your future reference and access; or (ii) that you are able to email this ERSD to an email address 
where you will be able to print on paper or save it for your future reference and access. Further, 
if you consent to receiving notices and disclosures exclusively in electronic format as described 
herein, then select the check-box next to ‘I agree to use electronic records and signatures’ before 
clicking ‘CONTINUE’ within the DocuSign system. 
By selecting the check-box next to ‘I agree to use electronic records and signatures’, you confirm 
that: 
 
You can access and read this Electronic Record and Signature Disclosure; and 
 
You can print on paper this Electronic Record and Signature Disclosure, or save or send 
this Electronic Record and Disclosure to a location where you can print it, for future 
reference and access; and 
 
Until or unless you notify Family Health International Inc - Part 11 as described above, 
you consent to receive exclusively through electronic means all notices, disclosures, 
authorizations, acknowledgements, and other documents that are required to be provided 
or made available to you by Family Health International Inc - Part 11 during the course of 
your relationship with Family Health International Inc - Part 11.