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: PHASE1
Conditions: Contraception
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.

 
 
 
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  
 
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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).  
 
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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   
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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  
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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 
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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.  
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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 
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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 ). 
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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  
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•  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  
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•  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 
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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   
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•  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 
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•  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.  
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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.  
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•  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. 
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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 )  
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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. 
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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. 
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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.  
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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 
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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 
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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.  
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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.  
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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.  
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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 
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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  
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•  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.  
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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. 
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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 
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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. 
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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: 
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•  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. 
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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.  
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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.  
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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.  
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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  
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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. 
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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 .  
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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  
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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  
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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  
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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. 
 
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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.  
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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.  
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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