An Open Label, 1-Year Trial, Including a Double-Blind Placebo-Controlled Withdrawal Period, of Setmelanotide (RM-493), a Melanocortin 4 Receptor (MC4R) Agonist, in Leptin Receptor (LEPR) Deficiency Obesity Due to Bi-Allelic Loss-of-Function LEPR Genetic Mutation
Phase: PHASE3
Conditions: Leptin Receptor Deficiency Obesity
Sponsor: Rhythm Pharmaceuticals, Inc.

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
C LI NI C A L S T U D Y P R O T O C O L  
 
Pr ot oc ol R M -4 9 3 -0 1 5  
 
A n O pe n L a bel, 1 -Ye ar  Tri al, i ncl u di n g a D o u ble -Bli n d Pl ace b o -C o ntr olle d 
Wit h dr a w al Peri o d, of Set mel a n oti de ( R M -4 9 3 ), a Mel a n oc orti n 4 Rece pt or 
( M C 4 R) A g o nist, i n Le pti n Rece pt or ( L E P R ) Deficie nc y O besit y d ue t o  
Bi- Allelic L oss -of -F u ncti o n L E P R  Ge netic M ut ati o n  
T his st u dy will be c o n d ucte d acc or di n g t o t he pr ot oc ol a n d i n c o m pli a nce wit h G o o d Cli nic al 
Pr actice, t he et hic al pri n ci ples st ate d i n t he Decl ar ati o n of Helsi nki,  
a n d ot her a p plic a ble re g ul at ory re q uire me nts. 
 
U S I N D N o.  1 1 2, 5 9 5 
E u dra C T N o. 2 0 1 7- 0 0 2 0 0 5- 3 6 
 
St u d y S p o ns or:   
 
R h yt h m P har mace uticals , I n c. 
5 0 0 B o ylst o n Street , 1 1t h Fl o or 
B ost o n, M A 0 2 1 1 6, U S A 
Tele p h o ne: 8 5 7. 2 6 4. 4 2 8 2 
Fa x: 8 5 7. 2 6 4. 4 2 9 9 
 
 
S p o ns or Si g nat or y:   
 
 
 
 
D oc u me nt Versi o n ( Date):   3 0 M A Y  2 0 1 7    Versi o n 1. 1 ( Gl o bal) 
  
  
  
  
1 1 Se pt 2 0 1 7 A me n d me nt 1 ( Fra n ce o nl y) 
  
  
  
  
2 7 Se pt  2 0 1 7 A me n d me nt 2 ( Ger ma n y o nl y) 
  
  
  
  
1 0 A pr 2 0 1 8 A me n d me nt 3 ( Gl o bal) 
  
  
  
  
3 1J ul y 2 0 1 8 A me n d me nt 4 ( Gl o bal) 
  
  
  
  
0 6 Se pt 2 0 1 8 A me n d me nt 5 ( Fra nce o nl y) 
  
  
  
  
1 0 Dec 2 0 1 8 A me n d m e nt 6 ( Ger ma n y o nl y) 
 
C O N FI D E N TI A LI T Y N O T E  
T he i nf or mati o n c o ntai ne d i n t his d oc u me nt is pri vile ge d a n d c o nfi d e ntial. A n y distri b uti o n, 
c o p yi n g, or discl os ure is strictl y pr o hi bite d u nless s uc h discl os ure is re q uire d b y fe deral 
re g ulati o ns or state la w.  Pers o ns t o w h o m t he i nf or mati o n is discl ose d m ust k n o w t hat it is 
c o nfi de ntial a n d t hat it ma y n ot b e  f urt her discl ose d b y t he m. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
I N V E S TI G A T O R S T A T E M EN T   
I u n d ersta n d t hat all d oc u me ntati o n pr o vi de d t o me b y R h yt h m P har mace uticals , I nc. ( R h yt h m) 
or its desi g nate d re pr ese ntati ve(s) c o ncer ni n g t his st u d y t hat has n ot bee n p u blis he d pre vi o usl y 
will be ke pt i n t he strictest c o nfi de nce.  T his d o c u me ntati o n i ncl u des t he st u d y pr ot o c ol, 
i n vesti gat or br o c h ur e (I B), case re p ort f or ms, a n d ot her scie ntific dat a. 
T his st u d y will n ot c o m me nce wit h o ut t he pri or writte n a p pr o val of a pr o perl y c o nstit ute d 
I nstit uti o nal Re vie w B oar d/ Et hics C o m mittee.  N o c ha n ges will be ma d e t o t he st u d y pr ot oc ol 
wit h o ut t he pri or writte n a p pr o val of R h yt h m a n d t he I nstit uti o nal Re vie w B oar d / Et hics 
C o m mittee , e x ce pt w here necessar y t o eli mi nate a n i m me diate hazar d t o t he patie nt. 
I h a ve r ea d, u n d erst o o d, a n d a gree t o a bi de b y all t he c o n diti o ns a n d i nstr ucti o ns c o ntai ne d i n 
t his pr ot oc ol.  
 
I n v esti gat or Na me 
 
I n v esti gat or Si g nat ure 
 
Date  
 
 
 
 
I n v esti gati o nal site or na me of i nstit uti o n a n d l ocati o n ( pri nte d) 
 
 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
C LI NI C A L S T U D Y S Y N O P SI S  
S p o ns or  
R h yt h m  P har mace uticals, I n c.  
I n vesti g ati o n al Dr u g 
Pr o d uct  
Set mela n oti de  ( R M-4 9 3, Mela n oc orti n -4 Rece pt or A g o nist)  
Pr ot oc ol N u m ber  
R M -4 9 3 -0 1 5  
Pr ot oc ol Title  
A n O pe n La b el, 1 -Year Trial, i ncl u di n g a D o u ble -Bli n d 
Place b o - C o ntr olle d Wit h dra wal Peri o d, of Set mela n oti de ( R M-
4 9 3), a Mela n o c orti n 4 Rece pt or ( M C 4 R) A g o nist, i n Le pti n 
Rece pt or  (L E P R ) D eficie nc y O besit y d ue t o Bi-Allelic L oss -
of- F u n cti o n L E P R  Ge netic M utati o n s 
Cli nic al P h ase/ Tri al T y pe  
Pi v otal, ~ 1 -year  o pe n la b el acti ve treat me nt wit h a d o u ble -
bli n d, place b o-c o ntr olle d wit h dra wal peri o d. 
Tre at me nt I n dic ati o n  
Treat me nt of L E P R D eficie nc y O b esit y   
O bjecti ve(s)  
Pri mar y  
•  T o de m o nstrate statisticall y si g nifi ca nt a n d cli nicall y 
mea ni n gf ul effects of s et mela n oti de o n perce nt b o d y 
wei g ht c ha n ge i n p atie nts wit h L E P R  deficie n c y 
o besit y d ue t o rare bi- allelic or l oss- of f u ncti o n 
m utati o ns at t he e n d of 1 year of treat me nt. 
Sec o n dar y  
T o assess t he effect of set mela n oti de , o ver o ne ye ar, o n: 
•  S afet y a n d t olera bilit y of set mela n oti de (i ncl u di n g 
bl o o d press ure [ B P ] a n d heart rate [ H R ]). 
•  H u n ger i n patie nts ≥1 2 years ol d .  
•  P erce nt c h a n ge i n  b od y fat mass.  
•  Gl uc ose para meters:  fasti n g gl uc ose, gl ycate d 
he m o gl o bi n ( H b A 1c ), oral gl uc os e t olerate test ( O G T T ) 
wit h f oc us o n para meters of i ns uli n se nsiti vit y. 
•  Waist circ u mfere n ce.  
•  D uri n g wit h dra wal fr o m dr u g: re vers al of w ei g ht a n d 
h u n ger re d u cti o n d uri n g t he d o u ble- bli n d place b o-
c o ntr olle d wit h dra w al peri o d.   

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
Tri al Desi g n  
 
T his is a pi v otal st u d y t o assess l o n g -ter m (~ 1 year) efficac y  of 
set mela n oti de i n L E P R d eficie nc y o b esit y.  T h e st u d y will 
be gi n wit h a n i nitial peri o d of d ose titrati o n lasti n g bet w ee n 2 
a n d 1 2 wee ks  w here t he i n di vi d ual patie nt’s t hera p e utic d ose 
will be esta blis he d  b y u p war ds d ose titrati o n i n 2-wee k 
i nter vals. T hereafter, pati e nts will c o nti n ue acti ve treat me nt at 
t heir i n di vi d uall y titrate d o pti mal t hera pe utic d ose f or a n 
a d diti o nal 1 0 wee ks, f or a t otal c o m bi ne d d osi n g d urati o n of 1 2 
wee ks at t he i n di vi d ual p atie nt’s t hera p e utic d ose [i.e., t he last 
2 wee ks d uri n g d ose titrati o n pl us 1 0 wee ks of o p e n la bel 
treat me nt]. F or patie nts w h o de m o nstrate at least 5 k g w ei g ht 
l oss ( or at least 5 % w ei g ht l oss if baseli ne b o d y w ei g ht < 1 0 0 
k g) at t he e n d of t h e O pe n La b el Treat me nt Peri o d, t he y will 
c o nti n ue o nt o t he d o u ble- bli n d, varia bl y- ti me d, place b o-
c o ntr olle d, wit h dra w al peri o d lasti n g 8 w ee ks  i ncl usi ve of a 4-
wee k peri o d of place b o treat me nt.  T he o nset of t h e place b o 
peri o d will be varia bl e f or eac h p atie nt t o mas k t he act ual 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
ti mi n g of t he wit h dra w al peri o d.  F oll o wi n g t he 8 -wee k 
wit h dra wal peri o d, patie nts will c o nti n ue d osi n g at t heir 
t hera pe utic d os e f or ~ 3 2 wee ks, res ulti n g i n a t otal of ~ 5 2 
wee ks d osi n g at t heir t hera pe utic d ose. 
W here feasi ble,  a n d f or p atie nts w h o a gree t o parti ci pate, t here 
St u d y P o p ul ati o n  
Male a n d fe mal e patie nts, 6 years of a ge  a n d a b o v e, wit h a 
c o nfir me d dia g n osis of L E P R D eficie nc y O b esit y d ue t o bi-
allelic, l oss- of-f u n cti o n L E P R  ge ne m utati o ns.   
N u m ber of P atie nts & 
St u d y Ce nters  
It is c urre ntl y a ntici pate d t hat a t otal of ~ 1 0  patie nts  will be 
e nr olle d i n t his st u d y.  T he t otal n u m ber of patie nts re q uire d 
f or re gistrati o n is yet t o b e c o nfir me d wit h a p plica ble 
re g ulat or y a ut h orities, gi ve n t hat tr ue pre vale nce of t his ultra-
rare disease is u ncertai n.  T heref ore, t he t otal n u m ber of 
patie nts ma y b e i ncrease d or decrease d t o s atisf y re g ulat or y 
re q uire me nts f or re gistrati o n, de pe n di n g u p o n t h e t otal n u m ber 
of aff ecte d p atie nts i de ntifie d.  
It is a ntici pate d t hat u p t o 1 0 ce nters l ocate d w orl d wi de will 
partici pate i n t his st u d y.  I f a d de d p at ie nts are t o be e nr olle d, 
a d diti o nal sites ma y be a d de d, as necessar y.  
I ncl usi o n Criteri a 
1.  Bi -allelic, h o m oz y g o us or c o m p o u n d heter oz y g o us (a 
differe nt ge ne m utati o n o n eac h allele) ge n etic stat us f or 
eit her t he L E P R ge n es, wit h t he l oss- of-f u ncti o n ( L O F) 
varia nt f or eac h allele c o nferri n g a s e vere o besit y 
p he n ot y p e.        
2.  A ge 6 years a n d a b o v e.    
3.  If a d ult a ge ≥1 8 years, o b esit y wit h b o d y mass i n d e x ( B MI ) 
≥ 3 0 k g/ m 2; if c hil d or a d olesce nt, o besit y wit h B MI ≥9 5t h 
perce ntile f or a ge o n gr o wt h c hart assess m e nt.  
4.  St u d y p artici pa nt a n d/ or pare nt or g u ar dia n ca n 
c o m m u nicate well wit h t he i n vesti gat or, t o u n dersta n d a n d 
c o m pl y wit h t he re q uire me nts of t he st u d y, a n d ca n 
u n dersta n d a n d si g n t he writte n i nf or me d c o ns e nt/asse nt, 
after b ei n g i nf or me d a b o ut t he st u d y.   
5.  F e male p artici pa nt s of c hil d-beari n g p ote ntial m ust a gree t o 
use c o ntrace pti o n as o utli ne d i n t he pr ot oc ol.  Fe male 
partici pa nt s of n o n-c hil d beari n g p ote ntial, defi ne d as 
s ur gicall y sterile (stat us p ost h ysterect o m y, bilat eral 
o o p h orect o m y, or bilateral t u bal li gati o n) or p ost-
me n o pa usal f or at least 1 2 m o nt hs (a n d c o nfir me d wit h a 
scree ni n g F S H le vel i n t h e p ost-me n o pa usal la b ra n ge),  or 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
dela ye d p u bertal de vel o p me nt a n d  fail ure t o h a ve ac hie ve d 
me narc h e, d o n ot re q uire c o ntrace pti o n d uri n g t h e st u d y.  
6.  Male  partici pa nt s wit h fe male part ners of c hil d beari n g 
p ote ntial m ust a gree t o a d o u ble barrier met h o d if t he y 
bec o me se x uall y acti v e d uri n g t he st u d y. Male p atie nts 
m ust n ot d o nate s per m d uri n g a n d f or 9 0 d a ys f oll o wi n g 
t heir partici pati o n i n t he st u d y. 
E xcl usi o n Criteri a  
 
1.  Rece nt i nte nsi ve ( wit hi n 2 m o nt hs) diet a n d/ or e x ercise 
re gi me n wit h or wit h o ut t he use of w ei g ht l oss a ge nts 
i ncl u di n g her b al me dicati o ns, t hat has res ulte d i n wei g ht 
l oss or wei g ht sta bilizati o n.  Patie nts ma y be rec o nsi dere d 
a p pr o xi matel y 1 m o nt h after cessati o n of s uc h i nte nsi ve 
re gi me ns.   
2.  Pri or gastri c b y pass s ur ger y res ulti n g i n > 1 0 % w ei g ht l oss 
d ura bl y m ai ntai ne d fr o m t he baseli ne pre- o perati v e wei g ht 
wit h n o e vi de nce of wei g ht re gai n.  S pecificall y, p atie nts 
ma y b e c o nsi dere d if  s ur ger y was n ot s uccessf ul, or 
res ulte d i n < 1 0 % w ei g ht l oss c o m pare d t o pre- o perati ve 
baseli ne wei g ht or clear e vi de nce of w ei g ht re gai n after a n 
i nitial res p o nse t o bariatric s ur ger y.  All patie nts wit h a 
hist or y of b ariatric s ur ger y m ust be disc usse d wit h, a n d 
recei v e a p pr o v al fr o m R h yt h m pri or t o e nr oll me nt.  
3.  Dia g n osis of s c hiz o p hre nia, bi p olar dis or der, p ers o nalit y 
dis or der or ot her Dia g n ostic a n d Statistical Ma n ual of 
Me ntal Dis or ders ( D S M -III) dis or d ers t hat t he i n v esti gat or 
belie ves will i nterfere si g nifica ntl y wit h st u d y c o m plia nce.  
4.  A Patie nt Healt h Q uesti o n naire - 9 (P H Q - 9) sc ore of ≥ 1 5. 
5.  A n y s uici d al i deati o n of t y p e 4 or 5 o n t he C ol u m bia 
S uici de Se verit y Rati n g Scale ( C- S S R S ).  A n y lifeti me 
hist or y of a s uici de atte m pt, or a n y s ui ci dal be ha vi or i n t he 
last m o nt h. 
6.  C urre nt, se vere sta ble restricti ve or o bstr ucti ve l u n g diseas e 
d ue t o e xtre me o besit y, e vi de nce of si g nifica nt heart fail ure 
( N Y H A Class 3 or greater), or o nc ol o gic disease , if t hese 
were s e vere e n o u g h t o i nterfere wit h t he st u d y a n d/ or 
w o ul d c o nf o u n d t he res ults. A n y s uc h p atie nts s h o ul d be 
disc usse d wit h t he s p o ns or pri or t o i ncl usi o n. 
7.  Hist or y of si g nifica nt li ver disease or li ver i nj ur y , or 
c urre nt li ver assess me nt f or a ca us e of a b n or mal li ver tests  
[ as i n dicate d b y a b n or mal li ver f u ncti o n tests, ala ni ne 
tra nsa mi nase ( A L T), as p artate tra nsa mi nase ( A S T), 
al kali ne p h os p hatase, or ser u m bilir u bi n ( > 2. 0 x u p per 
li mit of n or mal (U L N ) f or a n y of t hese t ests)] f or a n 
eti ol o g y ot her t ha n n o n- alc o h olic fatt y li ver diseas e 
( N A F L D).  T h us, a n y u n derl yi n g eti ol o g y besi d es N A F L D, 
i ncl u di n g dia g n ose d n o n-alc o h olic steat o he p atitis ( N A S H), 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
ot her ca us es of he p atitis,  or hist or y of h e patic cirr h osis  will 
be e x cl usi o nar y, b ut t he prese nce of N A F L D w o ul d n ot be 
e x cl usi o nar y.   
8.  Hist or y or prese n ce of i m paire d re nal f u ncti o n as i n dicate d 
b y cli nicall y si g nifica nt a b n or mal creati ni ne, bl o o d urea 
nitr o ge n ( B U N ), or uri nar y c o nstit ue nts (e. g., al b u mi n uria) 
or m o derate t o se v ere re n al d ysf u n cti o n as defi n e d b y t he 
C oc k cr oft Ga ult e q uati o n < 3 0 m L/ mi n  ( A p p e n di x 1 1. 1 0 ).  
9.  Hist or y or cl ose fa mil y hist or y ( par e nts or si bli n gs) of s ki n 
ca ncer or mel a n o ma, or p atie nt hist or y of o c ular-c uta ne o us 
al bi nis m. 
1 0.  Si g nifica nt der mat ol o gic fi n di n gs  relati n g t o mela n o ma or 
pre - mela n o m a s ki n lesi o ns, deter mi ne d as part of a 
scree ni n g c o m pre he nsi v e s ki n e val uati o n perf or me d b y a 
q ualifie d  der mat ol o gist.  A n y c o ncer ni n g lesi o ns i de ntifie d 
d uri n g t he s cree ni n g p eri o d will be bi o psie d a n d res u lts 
k n o w n t o be be ni g n pri or t o e nr oll me nt.  If t he pre-
treat me nt bi o ps y res ults are of c o ncer n, t he patie nt ma y 
nee d t o be e x cl u de d fr o m t he st u d y.   
1 1.  V ol u nteer is, i n t he o pi ni o n of t he St u d y I n v esti gat or, n ot 
s uita ble t o partici pate i n t he st u d y. 
1 2.  Partici pati o n i n a n y cli nical st u d y wit h a n i n vesti gati o nal 
dr u g/ de vi ce wit hi n 3 m o nt hs pri or t o t he first da y of 
d osi n g. 
1 3.  Pre vi o us hist or y of s i g nifica nt h y p erse nsiti vit y t o 
e x o ge n o usl y i njecte d pe pti des (e. g. urticaria, s h ort ness of 
breat h, or m ore se vere res p o nses i ncl u di n g a n a p h yl act oi d 
reacti o ns or a na p h yla xis). 
1 4.  I n a bilit y t o c o m pl y wit h Q D i njecti o n re gi me n. 
1 5.   Patie nts w h o ha ve bee n place d i n a n i nstit uti o n t hr o u g h 
a n d official or c o urt or d er, as well as t h ose w h o are 
de pe n de nt o n t he s p o ns or, I n v esti gat or, or st u d y site. 
S y n o psis of St u d y 
Acti vities  
 
After a n i nitial scree ni n g a n d c o nfir mati o n of eli gi bilit y 
i ncl usi ve of a n i n de pt h retr os pecti ve me di cal hist or y, p atie nts 
will e nter t he O pe n La bel D ose Titrati o n P hase lasti n g bet wee n 
2 a n d 1 2 wee ks ( de pe n di n g u p o n t he n u m ber of titrati o n ste ps 
a n d ma xi m u m all o wa ble d ose a p pr o ve d at t he partici pati n g 
site) w here t h e i n di vi d ual patie nt’s t hera p e utic d os e will be 
esta blis he d.  O nce t h e patie nt’s t hera pe utic d os e is deter mi ne d, 
t he patie nt will e nter a 10- wee k O pe n La b el Acti v e Treat me nt 
P hase.   
F oll o wi n g t he d os e titrati o n a n d 1 0- wee k o pe n la b el acti ve 
treat me nt p hases, p atie nts w h o l ose at least 5 k g of wei g ht fr o m 
baseli ne  ( or 5 % if < 1 0 0 k g at b aseli ne), a n d w h o c o nti n ue t o 
s h o w t olera bilit y t o set m ela n oti de, will c o nti n ue i nt o t he 8 -

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
wee k D o u ble -Bli n d Place b o C o ntr olle d Wit h dra wal p hase.  
Patie nts w h o d o n ot e x hi bit t he re q uire d w ei g ht l oss of at least 
5 k g will be wit h dra w n fr o m t he treat me nt, b ut s h o ul d c o nti n ue 
wit h t he st u d y assess me nts . 
D uri n g t hi s ti me, patie nts will be assi g ne d t o t he 4-wee k 
se q ue nce i n w hic h t he y recei ve pl ace b o i n a d o u ble- bli n de d 
se q ue nce. T he ke y o bj ecti ve of t his p hase is t o i m ple me nt t he 
o nl y d o u ble- bli n d, place b o-c o ntr olle d peri o d f or t his st u d y t h at 
will i nf or m patie nt’s s y m pt o matic h u n ger a n d w ei g ht c h a n ge 
res p o nses t o st o p pi n g a n d t he n restarti n g acti ve t hera p y wit h 
set mela n oti de wit h o ut a ware n ess of t he ti mi n g of t he 
wit h dra wal.   
Ne xt, patie nts will res u me wit h O pe n La b el Acti v e Treat me nt 
f or a n a d diti o nal ~ 3 2 w ee ks, f or a t otal of ~ 5 2 wee ks of 
treat me nt at t he i n di vi d ual patie nt’s t hera p e utic d ose (i ncl usi ve 
of t he 4- wee k place b o wit h dra wal). 
St u d y Pr oce d ures  
 
T he pri mar y efficac y e n d p oi nt is t he pr o p orti o n of patie nts i n 
t he f ull a nal ysis set (F A S ) w h o meet t he ≥1 0 % w ei g ht l oss 
t hres h ol d (res p o n d ers) after ~ 1 year of treat me nt, c o m pare d t o 
t he pr o p orti o n fr o m hist orical data (at m ost 5 % res p o n ders i n 
t he n ull p o p ulati o n). T heref ore, fre q ue nt wei g ht m eas ure m e nts 
will be o btai ne d t hr o u g h o ut t he c o urse of t he trial.  S u p p orti n g 
efficac y e n d p oi nts will i ncl u de: H u n ger  assesse d d ail y b y  a 
q uesti o n naire ( usi n g a  n u meric rati n g  scale f or p atie nts 1 2 
years or ol der a n d 
 
 as well as b y 2 Gl o bal H u n ger 
Q uesti o ns f or eac h patie nt o ver ti me, i ncl u di n g d uri n g t he 
Scree ni n g Peri o d; b o d y c o m p ositi o n assess me nts i ncl u di n g 
t otal b o d y wei g ht l oss, fat l oss, a n d 
, 
meas ure d i n  k g as well as perce nt c ha n ge fr o m baseli ne; a n d 
waist circ u mfere n ce.  
T he safet y a n d t olera bilit y of s et mela n oti de Q D S C i njecti o n 
will be assesse d b y t he fre q ue nc y a n d se verit y of a d verse 
e ve nts ( A Es) as well as c ha n ges i n p h ysi cal e x a mi n ati o ns, 
electr ocar di o gra ms ( E C Gs), vital si g ns  (i ncl u di n g resti n g B P 
a n d H R), la b orat or y e val uati o ns, a n d i njecti o n site reacti o ns.  
P ote ntial i m pr o ve me nts i n  
 
 as well as gl uc ose para meters as meas ure d b y 
fasti ng g l uc os e, H b A 1 c a n d O G T T wit h f oc us o n para meters of 
i ns uli n se nsiti vit y will be assesse d o ver ti me. 
.  As re q uire d b y F o o d a n d 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
Dr u g A d mi nistrati o n ( F D A ) f or ce ntral n er v o us s yste m ( C N S )-
acti ve o besit y me dicati o ns, c ha n ges i n
will be m o nit ore d  o ver 
t he e ntire c o urse of t he trial.    
St u d y Dr u g  a n d 
A d mi nistr ati o n  
All st u d y dr u gs are f or i n vesti gati o nal use o nl y a n d are t o be 
use d o nl y wit hi n t he c o nt e xt of t his pr ot oc ol .  All 
i n vesti gati o nal st u d y dr u gs (s et mela n oti de a n d place b o) will be 
s u p plie d b y R h yt h m. 
Set mela n oti de dr u g pr o d uct ( R M- 4 9 3-m P E G/ D S P E 
f or m ulati o n) is a sterile s ol uti o n f or i njecti o n.  T he pr o d uct is 
ma n ufact ure d at a c o nce ntrati o n of 1 0. 0 m g/ m L.   
Place b o will be ve hicle.   
Set mela n oti de a n d place b o will be a d mi nistere d as 
s u bc uta ne o us (S C ) i njecti o n o nce dail y .  
T here will be e xte nsi ve trai ni n g of p atie nts i n dr u g 
a d mi nistrati o n i ncl u di n g e d ucati o nal materials.   St u d y s pecific 
trai ni n g materials will be pr o vi de d t o b ot h t he i n vesti gati ve 
staff a n d st u d y partici pa nts a n d care gi vers.  R h yt h m will 
pr o vi de e xtra place b o s u p plies f or use d uri n g trai ni n g. 
St atistic al C o nsi der ati o ns  
T he o bjecti ve of t his st u d y is t o de m o nstrate statisticall y 
si g nifica nt a n d cli nicall y mea ni n gf ul wei g ht l oss i n patie nts 
wit h L E P R deficie n c y o b esit y after ~ 1 year of treat me nt.   
As patie nts re mai n o n treat me nt f or 1 year, m ore wei g ht l oss is 
e x pecte d. 
T he pri mar y e n d p oi nt is pr o p orti o n of patie nts i n t he F A S w h o 
de m o nstrate at least 1 0 % wei g ht l oss at ~ 1 year ( 1 0 - 1 4 m o nt hs 
p ost baseli ne) c o m pare d t o baseli ne.  Patie nts wit h missi n g 
data after 1 0 m o nt hs fr o m baseli ne will be c o u nte d as n ot 
ha vi n g 1 0 % wei g ht l oss at 1 year.  T h e pri mar y researc h 
h y p ot hesis is t hat t his pr o p orti o n is at least 5 %.  T he n ull 
h y p ot hesis is t hat t his pr o p orti o n is at m ost 5 %.  Si nce pri or 
data o n u ntreat e d L E P R deficie nt patie nts s u g gests n o ne will 
ha ve 1 0 % w ei g ht l oss at 1 year wit h o ut i nter ve nti o n, t he 5 % 
ass u me d n ull h y p ot hesis val ue is c o nser v ati ve. 
It is e x pecte d t hat treat m e nt wit h R M- 4 9 3 f or 1 year is 
ass ociate d wit h a T R U E u n derl yi n g pr o ba bilit y of at least 1 0 % 
wei g ht l oss at 1 year of at least 5 0 %.  T hat ass u m pti o n yi el ds at 
least 9 4 % p o wer t o yiel d a statisticall y si g nifica nt (al p ha = 0. 0 5 
a n d 0. 0 2 5 1-si de d, d ue t o discrete ness of t he bi n o mial 
distri b uti o n) differe nce fr o m t he n ull h y p ot hesis 5 % val ue f or 
N = 1 0 F A S patie nts.  If t h e T R U E pr o ba bilit y of at least 1 0 % 
wei g ht l oss at 1 year is 4 0 %, t he n p o wer is ~ 8 3 %.  T he 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
mi ni m u m O B S E R V E D pr o p orti o n of  N = 1 0 p atie nts wit h at 
least 1 0 % wei g ht l oss at 1 year t hat w o ul d yiel d st atistical 
si g nifica n ce (al p ha = 0. 0 5 a n d 0. 0 2 5 1-si de d, d ue t o discrete ness 
of t he bi n o mial distri b uti o n) is 0. 3 ( 3 of 1 0). 
 
As t he sa m ple size i n t his trial is li mite d d ue t o rare ness  of 
L E P R defici e nc y, o ne- sa m ple s u m mar y statistics a n d 
i n di vi d ual patie nt listi n gs will be pr o vi de d t o re p ort a n d assess 
t he data fr o m t he tri al.  D etails will be i n a se parate Statistical 
A nal ysis Pla n ( S A P) d oc u me nt.  
 
 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
T a ble of C o nte nts  
1.  
I N T R O D U C TI O N ................................................................................................................ 2 2 
1. 1.  
O ver vie w of M o n o ge nic Earl y -O nset E xtre me O b esit y  a n d t he I m p orta nce of L E P R i n 
t he P O M C- M C 4 R Pat h wa y ...................................................................................................... 2 2 
 
P O M C Deficie nc y O b esit y  ..................................................................................... 2 3 
 
L E P R Defi cie nc y O b esit y  ....................................................................................... 2 3 
1. 2.  
Rati o nale a n d J ustificati o n f or t he Pr o p osal t o Treat L E P R defi cie nt patie nts wit h a n 
M C 4 R a g o nist ........................................................................................................................... 2 4  
 
I nitial Cli nical Data i n T w o P O M C Deficie nc y O besit y Patie nts .......................... 2 5 
 
I nitial Cli nical Data i n T hree L E P R Deficie nc y O besit y Patie nts .......................... 2 7 
 
Cli nical Safet y i n P O M C a n d L E P R Deficie n c y  .................................................... 2 8 
 
Pr o of- of- C o nce pt S u m mar y .................................................................................... 2 9  
1. 3.  
Set mela n oti de Pr o perties a n d A d diti o nal Cli nical E x perie nce  ...................................... 2 9 
 
N o ncli nical E x perie nce  ........................................................................................... 2 9 
 
Mec ha nis m -Relate d A d v erse E x perie nces of I nterest  ............................................ 3 0 
 
Set mela n oti de Cli nical Safet y a n d T ol era bilit y S u m mar y  ...................................... 3 1 
2.  
S T U D Y O BJ E C TI V E S A N D E N D P OI N T S  ........................................................................ 3 2 
2. 1.  
St u d y O bjecti ves  ............................................................................................................ 3 2 
 
Pri mar y O bj ecti ve:  .................................................................................................. 3 2 
 
E x pl orat or y O bjecti ves ........................................................................................... 3 3  
2. 2.  
St u d y E n d p oi nts  ............................................................................................................. 3 3 
3.  
I N V E S TI G A TI O N A L P L A N ............................................................................................... 3 6 
3. 1.  
O verall Desi g n a n d Pla n of t he St u d y ............................................................................ 3 6  
3. 2.  
Rati o nale f or t he D os es  .................................................................................................. 3 7 
3. 3.  
J ustificati o n of t he St u d y Desi g n ................................................................................... 3 8 
3. 4.  
St u d y Ter mi nati o n  .......................................................................................................... 3 9 
4.  
S T U D Y P O P U L A TI O N  ....................................................................................................... 4 0 
4. 1.  
N u m ber of Patie nts ......................................................................................................... 4 0  
4. 2.  
I n cl usi o n Criteria: ........................................................................................................... 4 0 
4. 3.  
E x cl usi o n Criteria  ........................................................................................................... 4 0 
4. 4.  
Patie nt I de ntifi cati o n a n d Re gistrati o n  ........................................................................... 4 1 
4. 5.  
Wit h dra wal of Patie nts  ................................................................................................... 4 2 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
5.  
S T U D Y T R E A T M E N T S  ...................................................................................................... 4 3 
5. 1.  
St u d y Dr u gs  .................................................................................................................... 4 3 
5. 2.  
St u d y Dr u g D ose a n d A d mi nistrati o n  ............................................................................ 4 3 
 
D ose Titrati o n a n d A dj ust me nts ............................................................................. 4 4  
5. 3.  
Met h o d of Assi g ni n g Patie nts t o Treat me nt ................................................................... 4 4  
5. 4.  
Bli n di n g, Pac k a gi n g, a n d La b eli n g ................................................................................ 4 6  
 
Bli n di n g a n d Br ea ki n g t h e Bli n d ............................................................................ 4 6  
 
Pac ka gi n g a n d La b eli n g  .......................................................................................... 4 6 
5. 5.  
D urati o n of Patie nt Partici pati o n  .................................................................................... 4 6 
5. 6.  
Assess me nt of Treat me nt C o m plia nce  ........................................................................... 4 6 
5. 7.  
St u d y Dr u g A cc o u nta bilit y............................................................................................. 4 7  
5. 8.  
Pri or a n d C o nc o mita nt Treat me nt .................................................................................. 4 7  
 
Per mitte d Me dicati o n  .............................................................................................. 4 7 
 
Pr o hi bite d Me dicati o n a n d S u bsta nces ................................................................... 4 8  
 
C o nc o mita nt Pr oce d ures ......................................................................................... 4 8  
6.  
S T U D Y A S S E S S M E N T S  .................................................................................................... 4 9 
6. 1.  
O ver vie w of Sc he d ule of Assess me nts  .......................................................................... 4 9 
6. 2.  
Patie nt Re q uire me nts ...................................................................................................... 6 0 
 
C o ntrace pti o n .......................................................................................................... 6 0  
 
Pr otecti o n fr o m S u n ................................................................................................ 6 0  
6. 3.  
Efficac y Meas ure me nts  .................................................................................................. 6 0 
 
Wei g ht  ..................................................................................................................... 6 0 
 
Waist Circ u mfere nce  .............................................................................................. 6 1 
 
B o d y C o m p ositi o n .................................................................................................. 6 1  
6. 4.  
Cli nical Pr oce d ures a n d Safet y Assess me nts  ................................................................. 6 1 
 
I nf or me d C o nse nt/ Asse nt........................................................................................ 6 1 
 
De m o gra p hics a n d Me di cal Hist or y ....................................................................... 6 1  
 
P h ysical E x a mi nati o n, C o m pre he nsi ve S ki n E x a mi nati o n, a n d Hei g ht ................. 6 2  
 
Fitz patric k Scale ...................................................................................................... 6 3 
 
C o nc o mita nt Me dicati o n Re vie w ........................................................................... 6 3  
 
Vital Si g ns  ............................................................................................................... 6 3 
 
1 2- Lea d Electr ocar di o gr a m  .................................................................................... 6 3 
 
Cli nical La b or at or y Tests  ........................................................................................ 6 4 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
 
Oral Gl uc ose T olera n ce Test ( O G T T)  ................................................................ 6 5 
 
I njecti o n Site E val uati o n a n d Sc ori n g ................................................................. 6 6 
 
A nti -R M - 4 9 3 A nti b o d y ( A D A) Meas ure me nts .................................................. 6 6 
 
Patie nt Q uesti o n naires  ......................................................................................... 6 6 
 
Diet a n d N utriti o nal C o u nseli n g ......................................................................... 6 8  
 
A d verse E v e nts  .................................................................................................... 6 9 
 
O pti o nal S u b- St u dies........................................................................................... 6 9  
 
Or der of Assess me nts  .......................................................................................... 7 0 
7.  
A D V E R S E E V E N T S  ............................................................................................................ 7 2 
7. 1.  
Defi niti o ns, D oc u me ntati o n, a n d Re p orti n g .................................................................. 7 2  
7. 2.  
Pr oce d ures f or A E a n d S A E Re p orti n g .......................................................................... 7 2  
7. 3.  
A d verse E v e nts a n d Ris ks .............................................................................................. 7 4  
 
Me dical m o nit ori n g  ................................................................................................. 7 4 
7. 4.  
M o nit ori n g of A d v erse E ve nts a n d Peri o d of O bser vati o n ............................................ 7 5  
7. 5.  
G ui deli nes f or A d diti o nal M o nit ori n g a n d S us pe nsi o n of D osi n g f or a Pati e nt ............ 7 5  
 
De press i o n or S uici dalit y ........................................................................................ 7 5 
8.  
S T A TI S TI C A L P R O C E D U R E S  .......................................................................................... 7 6 
8. 1.  
Sa m ple Size Esti mati o n a n d Pri mar y P o wer State me nt  ................................................. 7 6 
8. 2.  
Statistical Met h o ds  ......................................................................................................... 7 7 
8. 3.  
Ti mi n g of A nal yses ........................................................................................................ 7 8  
8. 4.  
L o n g - T er m E xte nsi o ns a n d P o oli n g of Patie nts fr o m ot her St u dies .............................. 7 8 
8. 5.  
Statistical A nal ysis Pla n  ................................................................................................. 7 8 
9.  
A D MI NI S T R A TI V E R E Q UI R E M E N T S  ............................................................................ 7 9 
9. 1.  
G o o d Cli nical Practice  ................................................................................................... 7 9 
9. 2.  
Et hical C o nsi derati o ns.................................................................................................... 7 9  
9. 3.  
Patie nt I nf or mati o n a n d I nf or me d C o nse nt .................................................................... 7 9  
9. 4.  
Patie nt C o nfi de ntialit y .................................................................................................... 7 9 
9. 5.  
Pr ot oc ol C o m plia nce ...................................................................................................... 7 9  
9. 6.  
Data Ma na ge me nt  .......................................................................................................... 8 0 
 
D ata Ha n dli n g  ......................................................................................................... 8 0 
 
C o m p uter S yste ms  .................................................................................................. 8 0 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
 
Data E ntr y  ............................................................................................................... 8 0 
 
Me d ical I nf or mati o n C o di n g................................................................................... 8 0 
 
Data Vali dati o n  ....................................................................................................... 8 0 
9. 7.  
Direct Access t o S o urce Data  ......................................................................................... 8 0 
9. 8.  
S o urce D oc u m e nt/ Case Re p ort F or m C o m pleti o n ......................................................... 8 1  
9. 9.  
Rec or d Rete nti o n  ............................................................................................................ 8 1 
9. 1 0.  
Lia bilit y I ns ura n ce  ...................................................................................................... 8 1 
9. 1 1.  
P u blicati o n of St u d y Fi n di n gs a n d Us e of I nf or mati o n .............................................. 8 1  
1 0.  
R E F E R E N C E S  .................................................................................................................. 8 3 
1 1.  
A P P E N DI C E S  ................................................................................................................... 8 5 
1 1. 1.  
I njecti o n Site E val uati o ns ........................................................................................... 8 5 
1 1. 2.  
Fitz patric k Classificati o n Scale  .................................................................................. 8 6 
1 1. 3.  
Past Me dical Hist or y a n d Gr o wt h C ur ve I nf or mati o n................................................ 8 7  
1 1. 4.  
G ui da nce f or M o nit ori n g P ote ntial Treat me nt- Rel ate d De r m at ol o gical C ha n ges a n d 
S u g geste d Criteri a F or Disc o nti n uati o n of D osi n g ..................................................... 8 8  
1 1. 5.  
G ui da nce f or M o nit ori n g P ote ntial Treat me nt -Rel ate d Pe nile Erecti o ns a n d S u g geste d 
Criteria f or Disc o nti n uati o n of D osi n g ....................................................................... 9 0  
1 1. 6.  
E val uati o n of A b n or mal Li ver F u n cti o n Tests ( L F Ts)  ............................................... 9 1 
1 1. 7.  
Sta n dar dizati o n of Bl o o d Press ure Meas ure me nt ....................................................... 9 2  
1 1. 8.  
D ose Titrati o n G ui deli nes  ........................................................................................... 9 5 
1 1. 9.  
H u n ger Q u esti o ns ....................................................................................................... 9 8  
1 1. 1 0.  
Creati ni ne Cleara nce Esti mate b y C oc k cr oft - Ga ult E q uati o n .................................. 1 0 1 
1 1. 1 1.  
C o nsi derati o ns f or re d u ci n g pai n a n d distress i n t he pe diatric p o p ulati o n ............... 1 0 2  
1 1. 1 2.  
Bl o o d V ol u mes f or St u d y Tests................................................................................ 1 0 3  
1 1. 1 3.  
Declar ati o n of Helsi n ki  ............................................................................................. 1 0 5 
 
List of T a bles  
Ta ble 1: D ose Titrati o n S c he d ule ................................................................................................ 4 4  
Ta ble 6 - 1 A: Sc he d ul e of Assess me nts: Scree ni n g a n d D ose Titrati o n ........................................ 5 1  
Ta ble 6 -1 B: Sc he d ule of Assess me nts:  1 0 Wee k Acti ve Treat me nt a n d 8 Wee k D o u ble- Bli n d 
Place b o C o ntr olle d Wit h dra wal .............................................................................. 5 4  
Ta ble 6 - 1 C: Sc he d ule of Assess me nts: A d diti o nal 3 2 Wee k O pe n La b el Treat me nt ................. 5 5  
Ta ble 6 - 1: Sc he d ule of Assess me nts F o ot n otes ........................................................................... 5 6  
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
List of Fi g ures  
Fi g ure 1:    
Sc he matic o utli ne of h y p ot hala mic f o o d i nta ke c o ntr ol ...................................... 2 2 
Fi g u re 2:    
T he r ole of L E P R i n t he setti n g of rare ge netic dis or ders of o b esit y d u e 
t o defects i n t he u pstrea m part of t he M C 4 pat h w a y. .......................................... 2 3 
Fi g ure 3:    
Res ults f or H u n ger a n d Wei g ht l oss i n t he first P O M C deficie nc y 
patie nt after tr eat me nt wit h set mela n oti de.  .......................................................... 2 6 
Fi g ure 4:   
Res ults f or L E P R Patie nt # 1 i n St u d y R M- 4 9 3- 0 1 1 ............................................ 2 7  
Fi g ure 5  
Res ults f or L E P R Patie nt # 2 i n St u d y R M - 4 9 3- 0 1 1 ............................................ 2 8 
Fi g ure 6  
Res ults f or L E P R Patie nt # 3 i n St u d y R M- 4 9 3- 0 1 1 ............................................ 2 8  
Fi g ure 7:  
St u d y Sc h e ma ....................................................................................................... 3 7 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
LI S T O F A B B R E VI A TI O N S 
A b bre vi ati o n 
Defi niti o n  
A D A  
A nti -dr u g a nti b o d y  
A E  
A d verse e ve nt  
A g R P  
A g o uti- Relat e d Pe pti de  
A L T  
Ala ni ne tra nsa mi nas e  
a P T T 
Acti vate d partial t hr o m b o plasti n ti me  
A S T  
As partate tra nsa mi nase  
b- L P H  
β -li p otr o pi n 
Bf Ar M  
Fe deral I nstit ute f or Dr u gs a n d M e dical D e vices 
( B u n desi nstit ut f ür Arz nei mittel u n d Me dizi n pr o d u kte 
BI A  
Bi oelectrical i m pe da n ce  
B MI  
B o d y mass i n de x 
B P  
Bl o o d press ure 
B P M  
Beats p er mi n ute  
B U N  
Bl o o d urea nitr o ge n  
C B E R  
Ce nter f or Bi ol o gi cs E val uati o n a n d Researc h 
C D E R  
Ce nter f or Dr u g E val uati o n a n d Researc h  
C N S  
Ce ntra l ner v o us s yste m 
C O 2 
Car b o n di o xi de 
C P K  
Creati ne p h os p h o ki nase 
C R A  
Cli nical researc h ass oci ate  
C R F  
Case re p ort f or m  

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
A b bre vi ati o n 
Defi niti o n  
 
 
C S C  
Cli nical Safet y C o m mittee  
C T C A E  
C o m m o n Ter mi n ol o g y Criteria f or A d vers e E ve nts  
C V  
Car di o vasc ular  
C V D  
Car di o vasc ular disease  
D H E A - S 
De h y dr oe pia n dr oster o n e s ulfate  
D X A  
D ual -e ner g y x -ra y a bs or pti o metr y 
DI O  
Diet -i n d uce d o bes e 
D S M -III 
Dia g n ostic a n d Statistical Ma n ual of Me ntal Dis or ders 
Versi o n III  
E C 5 0 
Half ma xi mal  effecti ve c o nce ntrati o n  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
F A S  
F ull a n al ysis set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n 
F S H  
F ollicle Sti m ulati n g H or m o ne  
Free T 4  
Free t h yr o xi ne 
G C  
Gl uc oc ortic oi d  
G C P  
G o o d cli nical practice  
G G T  
Ga m ma -gl uta m yl  tra ns pe pti dase  
G H  
Gr o wt h h or m o ne 
GI  
Gastr oi ntesti nal  
G n R H  
G o na d otr o pi n- releasi n g h or m o ne 
H b A 1 c 
gl ycate d he m o gl o bi n 
H g  
Merc ur y  
HI V  
H u ma n i m m u n o deficie nc y vir us 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
A b bre vi ati o n 
Defi niti o n  
H R  
Heart rate  
I B 
I n v esti gat or Br oc h ure 
I C H 
I nter nati o nal C o nfere nce f or Har m o nizati o n  
I E C 
I n d e pe n de nt Et hics C o m mittee 
I N R 
I nter nati o nal n or malize d rati o 
I R B 
I nstit uti o nal Re vie w B oar d 
 
 
L D H  
Lactat e d e h y dr o ge n ase  
L E P R 
Le pti n Rece pt or  
L F T  
Li ver f u ncti o n tests 
L H  
L utei nizi n g h or m o n e  
M A D  
M ulti ple asce n di n g d os e 
M C  
Mela n oc orti n  
M C 1 R 
Mela n oc orti n Rece pt or t y p e 1  
M C 3 R 
Mela n oc orti n Rece pt or t y p e 3  
M C 4 R  
Mela n oc orti n Rece pt or t y p e 4  
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
M H P  
Me ntal healt h pr ofessi o nal 
M S H  
Mela n oc yte sti m ulati n g h or m o ne  
N A F L D  
N o n -alc o h olic fatt y li ver disease  
N A S H  
N o n -alc o h olic steat o he patitis 
N H L BI  
Nati o nal Heart, L u n g, a n d Bl o o d I nstit ute 
N O A E L  
N o o bser ve d a d vers e effects le vel  
N P Y  
H y p ot hal a mic ne ur o p e pti de Y 
O G T T  
Oral gl uc ose t olera nce test  

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R hyt h m P h ar m ace utic als, I nc. 
A b bre vi ati o n 
Defi niti o n  
P C S K 1  
Pr o pr otei n C o n vertase S u btilisi n/ Ke xi n T y p e 1  
P D  
P har mac o d y na mic  
 
 
P H Q -9  
Patie nt Healt h Q uesti o n naire 9  
P O M C  
Pr o - o pio mela n oc orti n 
P T  
Pr ot hr o m bi n Ti me 
P T T  
Partial t hr o m b o plasti n ti me  
P W S  
Pra der -Willi S y n dr o me  
P Y Y  
Pe pti de Y Y  
S A D  
Si n gle asce n di n g d os e 
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S B P  
S yst olic bl o o d press ure  
S C  
S u bc uta ne o us 
S D S 
Sta n dar d de viati o n sc ore 
S M B  
Safet y M o nit ori n g B oar d  
S O A  
Sc he d ule of ass ess me nts  
T E A E  
Treat me nt e mer ge nt a d v erse e ve nt  
T S H  
T h yr oi d sti m ulati n g h or m o ne  
U S  
U nite d States  
U L N  
U p per li mit of n or mal  
U V  
Ultra vi olet  

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
A b bre vi ati o n 
Defi niti o n  
W M A  
W orl d Me dical Ass ociati o n  
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
1.  I N T R O D U C TI O N 
1. 1.  O ver vie w of M o n o ge nic E arl y- O nset E xtre me O besit y a n d t he I m p ort a nce of L E P R i n  t he 
P O M C -M C 4 R P at h w a y   
Alt h o u g h h u ma n o besit y is rec o g nize d as bei n g i nfl ue nce d b y b ot h ge n etic a n d e n vir o n me ntal 
fact ors, e xtre me m or bi d o besit y wit h a n o nset i n i nfa nc y or earl y c hil d h o o d is ofte n f o u n d t o be m ore 
clearl y ca use d b y s pecifi c ge netic c o ntri b ut or s.  I n fact, t he i de ntificati o n of critical h y p ot hala mic 
pat h wa ys t hat res p o n d t o b ot h peri p heral d eri ve d h or m o nes (e. g., le pti n) a n d t o ot her ne ur o pe pti des 
a n d si g nali n g m olec ul es has s u bse q ue ntl y le d t o t he el uci dati o n of ma n y si n gle ge ne dis or ders 
i n v ol vi n g t hese sa me n e ur o pe pti de re g ul at ors (va n der Klaa u w 2 0 1 5 ).   
T h us, t he h y p ot hal a m us ser ves as a ke y i nte grati ve re gi o n of t he brai n a n d i ncl u des b ot h sti m ulat or y 
a n d i n hi bit or y pat h w a ys/re gi o ns t hat c o or di natel y re g ulate a p p etite, cal ori c i nta ke a n d e n er g y 
e x pe n dit ure. As de picte d i n  F i g ure 1 , t he peri p heral h or m o ne g hreli n sti m ulates h y p ot h ala mic 
ne ur o pe pti de Y ( N P Y) a n d A g o uti- Relat e d Pe pti de ( A g R P) - pr o d u ci n g n e ur o ns, w hic h eac h i ncrease 
a p petite a n d r e d uce m eta b olic rate. T hes e t w o ne ur o pe pti des ( N P Y a n d A G R P) are “ d o w nstrea m” 
fr o m peri p heral g hreli n a n d pr o vi de p o werf ul ore xi ge nic (i.e., a p p etite-sti m ulati n g) si g nals t hat ca n 
eac h b e c o u nter e d b y mel a n oc orti n a g o nists t hr o u g h acti vati o n of t he mela n oc orti n 4 rece pt or 
( M C 4 R). U n der n or mal c o n diti o ns, t he nat ural li ga n ds f or t he M C 4 R i n t he h y p ot hala m us are d eri ve d 
fr o m p r o- o pi o mela n o c orti n (P O M C ) ne ur o ns. P O M C ne ur o ns e x press le pti n rece pt ors ( L E P Rs ) o n 
t heir cell s urf ace, w hic h ca n be acti vate d b y t he a n ore xi ge nic, fat - deri ve d h or m o ne, le pti n. 
 
Fi g ure 1 :  Sc he m atic o utli ne of h y p ot h al a mic f o o d i nt a ke c o ntr ol 
T he i m p orta nce of t his pat h wa y i n h u n ger a n d wei g ht re d u cti o n is s u p p orte d b y str o n g cli nical 
ge n etic vali dati o n.  Ge n etic defects f or m ost of t he ste ps i n t he L E P R -P O M C - M C 4 R pat h wa y (f or 
si m plicit y r eferre d t o as t he M C 4 pat h wa y hereafter)  ha v e res ulte d i n t he e x pecte d  e xtre me o besit y 
p he n ot y p e:  f or e x a m ple, defects al o n g t h e M C 4  pat h wa y ha v e ca us e d  earl y o nset, se v ere o besit y a n d 
h y per p ha gia, a n d set mela n oti de is h y p ot hesize d t o be “re pl ace m e nt t hera p y” f or t hese ge n etic defects 
t hat res ult i n pr of o u n d o b esit y a n d h y p er p ha gi a.   
T his pr ot oc ol will e val uate t he eff ect of s et mela n oti de i n o ne ultra- rare ge n etic dis or der of o b esit y 
t hat is ca use d b y m utati o ns i n t he LE P R u pstrea m of t he M C 4 R (as s h o w n i n Fi g ure 2, i n t he c o nte xt 

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R hyt h m P h ar m ace utic als, I nc. 
Metre le pti n treat me nt, s o t he f oc us f or t his pr ot oc ol will be o n t h ose patie nts wit h L E P R  h o m oz y g o us 
( or c o m bi ne d het er oz y g o us) m utati o ns.  As  f or P O M C  a n d P C S K 1  ge ne d eficie nci es, t he l oss of 
acti vati o n t hr o u g h t h e ke y M C 4  pat h wa y is h y p ot hesize d t o be rest ore d b y M C 4 R a g o nist acti vati o n 
b y set mela n oti de.  L E P R deficie nc y m a y occ ur i n a p pr o xi matel y 1- 5 % of s u bjects wit h se vere, earl y 
o nset o besit y ass o ciate d wit h se vere h y p er p ha gia ( Far o o qi 2 0 0 7) a n d s o m a y b e sli g htl y m ore 
pre vale nt t ha n P O M C deficie nc y o besit y .  Affecte d s u bjects ma nifest i nte nse h y p er p ha gi a, se vere 
o besit y, alterati o ns i n i m m u ne f u ncti o n, a n d dela ye d p u bert y, al l i n t he a bs e nce of d e vel o p me ntal 
dela y ( Cle me nt 1 9 9 8, Far o o qi 2 0 0 7).   
As me nti o ne d a b o ve, o besit y a n d h y per p ha gia d e v el o p d ue t o t he missi n g acti vati o n of P O M C 
ne ur o ns, w hic h i n t ur n lea ds t o t he occ urre nce of M S H deficie nc y a n d i m paire d re g ulati o n of satiet y 
a n d e ner g y e x pe n dit ure.  T his occ urs beca use P O M C ne ur o ns are n ot acti vate d base d o n t he m issi n g 
le pti n si g nal. Patie nts wit h P O M C a nd L E P R ge ne m utati o ns e x hi bit a cli nical o nset ver y earl y i n 
life, ofte n be gi n ni n g i n i nfa nc y, wit h r a pi d wei g ht gai n t hat is ass oci ate d wit h v oraci o us, o veracti ve 
a p petite a n d pr o n o u n ce d h y per p ha gic fee di n g b e h a vi ors.  Re mar ka bl e wei g ht i n creases o v er ma n y 
sta n dar d de viati o ns fr o m t he n or mal wei g ht gr o wt h c ur ves are t y pical i n t h ese patie nts.   
1. 2.  R ati o n ale a n d J ustific ati o n f or t he Pr o p os al t o T re at L E P R deficie nt p atie nts wit h a n 
M C 4 R a g o nist 
Set mela n oti de is a M C 4 R a g o nist t hat retai ns t he s pecificit y a n d f u n cti o nalit y of t he nat urall y 
occ urri n g P O M C -deri ve d ne ur o pe pti de, α - M S H, w hic h is t he nat ural li ga n d f or M C 4 R.  
T he mela n oc orti ns ( M C s) are a fa mil y of p e pti de h or m o nes (i ncl u di n g A C T H, α-M S H, β - M S H, a n d 
γ-M S H) t hat ar e all deri v e d fr o m t he c o m m o n prec urs or, P O M C . T he M Cs re g ulate e n er g y 
h o me ostasis a n d b o d y w ei g ht ( Wi k ber g 2 0 0 8, F oster 2 0 0 3, Mar ks 2 0 0 1 ).  M C 4 Rs are e x presse d 
t hr o u g h o ut t he ce ntral n er v o us s yste m a n d are i n v ol ve d i n t he re g ulati o n of be ha vi or a n d met a b olic 
pr ocesses ass ociate d wit h e ner g y h o me ostasis (s atiet y , e ner g y e x pe n dit ure).  M C 4 R has bee n 
i de ntifie d as t he d o mi na nt M C rece pt or i n v ol ve d i n b o d y w ei g ht re g ulati o n.  T heref ore, set mel a n oti de 
has t he p ote ntial t o rest or e l ost acti vit y i n t he M C 4 R pat h wa y b y b y passi n g t he defects u pstrea m of 
M C 4 R a n d directl y acti v ati n g M C 4 R ne ur o ns i n t he h y p ot h ala m us bel o w s uc h defects.  T h us, 
set mela n oti de ma y ser v e as a n ot her f or m of “re place me nt” t hera p y t o re-est a blis h wei g ht a n d a p petit e 
c o ntr ol i n patie nts wit h t hese m o n o ge nic dis or ders.   
O besit y ma y als o occ ur if t he P O M C ne ur o ns are n ot acti vate d base d o n t h e missi n g le pti n si g nal, 
d ue t o a le pti n rece pt or m utati o n.  T his ma y be d ue t o a le pti n deficie n c y ( l oss- of-f u ncti o n m utati o n 
i n t he le pti n ge n e), w here treat me nt wit h le pti n has bee n de m o nstrat e d t o res ult i n sig nifica nt wei g ht 
l oss [3 ].  H o we v er, patie nts wit h a m utati o n i n t he L E P R  ge n e ca n n ot b e nefit fr o m treat me nt wit h 
metrele pti n.   O besit y persists i n patie nts wit h L E P R deficie nc y b eca us e of t he fail ure of t he L E P R  t o 
acti vate P O M C ne ur o ns, w hic h i n t ur n res ults i n a lac k of t he pr o d u cti o n of M S H. F or t his reas o n, 
set mela n oti de treat me nt is li kel y t o lea d t o acti vati o n of t he M C 4 R i n t hese cases, a n d t h ere b y t o a 
re d ucti o n i n h y p er p h a gia a n d i ncrease d b o d y w ei g ht.  I n b ot h t he P O M C a n d LE P R defici e nt patie nt 
p o p ulati o ns, u n der-e x pressi o n of t he P O M C ge ne pr o d uct d ue t o t hese ge netic defects res ults i n a 
partial M S H deficie n c y, w hic h ca n b e o verc o me wit h set mela n oti de treat me nt.  
T he use of set mel a n oti de f or t he treat me nt of L E P R deficie nc y  o b esit y s pecificall y, a n d as a pr o of of 
c o nce pt t hat set mela n oti d e ca n act as “re place me nt t hera p y” f or defects i n t he br oa der M C 4 pat h wa y 
(s uc h as P O M C deficie n c y o b esit y), is s u p p orte d b y t w o sets of cli nical data:  res ults i n t w o P O M C 
ge n e defi cie nc y p atie nts a n d i nitial res ults i n t he t hree LE P R defici e nc y patie nt s. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
   
 I niti al Cli nic al D at a i n T hree  LE P R D eficie nc y O besit y P atie nt s 

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R hyt h m P h ar m ace utic als, I nc. 
 Cli nic al S af et y  i n P O M C a n d L E P R Deficie nc y 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
P O M C a n d L E P R deficie nc y o b esit y p atie nts recei vi n g o pe n- la bel set mela n oti de i n R M- 4 9 3- 0 1 1 
ha ve re p orte d i nter mitte nt mil d a d verse e ve nts a n d ha ve t olerat e d a n d  mai nt ai ne d l o n g-ter m 
set mela n oti de i njecti o ns.  Mil d pai n a n d i n d urati o n at i njecti o n sites were re p orte d pri maril y earl y i n 
treat me nt, a n d ha v e bee n less fre q ue nt wit h i njecti o n site r otati o n o ver ti me.  S ki n a n d pri or s ki n ne vi 
dar ke ne d o v er ti me, wit h hair c ha n ge fr o m re d t o br o w n als o n ote d. Fati g u e, dr y m o ut h, a n d feeli n gs 
of e m pti ness or sa d ness wit h wa ni n g of h u n ger w ere i nter mitte ntl y re p ort e d b y i n di vi d ual patie nts.  
 
I nitial d osi n g a n d d ose es calati o n of set mela n oti de di d n ot de m o nstrate B P or H R i ncreas es as 
m o nit ore d d uri n g f ull da y cli nic visits at eac h titrati o n ste p.  T hereafter, s yst olic a n d diast olic B P  a n d 
H R de m o nstrate d cli nicall y mea ni n gf ul re d ucti o ns o ver ti me i n ass ociati o n wit h wei g ht  
re d ucti o n (K ü h n e n, 2 0 1 6 ). 
 
O ne patie nt e x perie nce d a n S A E of i nfl ue nza i m m u nizati o n reacti o n d uri n g t he st u d y, w hic h 
re q uire d o v er ni g ht o bser vati o n i n h os pital d ue t o decrease d B P a n d aller gic s y m pt o ms.  T his  
patie nt ha d e x perie nce d a si milar se vere i nfl ue nza i m m u nizati o n reacti o n i n t he past, pri or t o  
starti n g set mela n oti de; t h eref ore, t his S A E was c o nsi dere d u nrel ate d t o st u d y dr u g.  T h ere ha ve  
bee n n o disc o nti n uati o ns d ue t o treat me nt e mer ge nt A Es. 
 Pr o of- of- C o nce pt S u m m a r y  
T hese P hase 2 cli nical data de m o nstrate t he c o m pelli n g efficac y of set mela n oti de i n t w o a d ult 
patie nts wit h P O M C deficie nc y o besit y a n d t he i nitial t hree patie nts wit h L E P R deficie nc y o besit y.  
T he eff ect of tr eat me nt w as ver y s u bsta ntial a n d o b vi o us, e ve n i n t he setti n g of a n o pe n- l a bel trial.  
T he eff ect of tr eat me nt w as als o clearl y re v erse d u p o n wit h dra wal of t he dr u g i n t he first P O M C 
patie nt, b ut re- i nitiati o n of t hera p y a gai n de m o nstrate d t he be n eficial effects of set mela n oti de.  S uc h 
dra matic wei g ht a n d fee di n g be h a vi or c ha n ges are q uite c o n vi nci n g, e ve n if o bser ve d i n a n o p e n-
la bel, s mall n setti n g (i n t w o ge netic dis or ders of o besit y), b eca us e t hese p atie nts ha d pre vi o usl y 
de m o nstrate d l o n g- ter m r efract ori ness t o atte m pte d wei g ht l oss or h u n ger a meli orati o n i n me dical 
care pr o vi de d b y t heir Berli n , Paris  or U K  p h ysi ci a ns f or o ver 2 deca des.   
I n s u m mar y, set mela n oti de ma y pr o vi de f or t he rest orati o n of m ore n or mal h u n ger / a p petite wit h 
i ntact satiet y r es p o nses a n d acti ve re g ul ati o n of e n er g y e x pe n dit ure, ser vi n g as a f or m of re place me nt 
t hera p y t hat ulti matel y ca n lea d t o mar ke dl y i m pr o ve d wei g ht re g ulati o n wit h pr of o u n d b o d y wei g ht 
a n d fat mass l oss o ver ti me i n a variet y of M S H - deficie nt s y n dr o mes, i ncl u di n g LE P R deficie nt 
patie nts.  T hese “ precisi o n me dici ne” t hera pe utic effects of set mela n oti de are e vi d e nt  i n a p pr o priat el y 
i de ntifie d patie nts wit h m o n o ge nic l oss-of -f u n cti o n m utati o ns i n t he L E P R  ge n e; t his trial will als o be 
testi n g f or si milar t hera p e utic res p o nses i n a d diti o nal L E P R  defi cie nc y o b esit y p atie nts fr o m ot her 
gl o bal a n d U S cli nical sites .   
1. 3.  Set mel a n oti de Pr o perties a n d A d diti o n al Cli nic al E x perie nce  
Set mela n oti de is  a n 8-a mi n o aci d, c yclic pe pti de t hat bi n ds wit h  hi g h  affi nit y (i n hi bit or y c o nsta nt 
[ Ki] = 2. 1 n M) t o t he h u ma n  M C 4 R a n d is efficie nt  i n acti vati n g M C 4 R ( 5 0 % effecti ve c o n ce ntrati o n 
[ E C5 0] = 0. 2 7 n M).  
 N o nc li nic al Ex perie nce  
T he set mela n oti de pe pti d e was  i nitiall y sel ecte d f or cli nical de vel o p me nt b ase d  o n its acce pt a ble 
circ ulati n g half -lif e ( 2. 8 - 3. 5 h o urs i n n o n- h u ma n pri mates) a n d t he a bilit y t o decrease  b o d y w ei g ht  

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
gai n  a n d s u p press f o o d i nta ke i n n or mal rats.  S u bs e q ue nt st u dies de m o nstrate d t he effi cac y of  
set mela n oti de i n s u p pressi n g f o o d i nta ke a n d b o d y w ei g ht  gai n  i n diet -i n d uce d o bese ( DI O) mice,  
rats, d o gs, a n d m o n ke ys, as well  as i n ge netic  m o d els  of o besit y, i ncl u di n g l e pti n-deficie nt  o b/ o b  
mice  a n d le pti n rece pt or deficie nt o bes e Z uc ker f a/f a rats.  Lat er  st u dies i n o bese m o n ke ys s h o we d 
t hat set mela n oti de di d n ot i ncrease bl o o d press ure ( B P) or h eart  rate ( H R), a p ote ntial c o ncer n 
o bser ve d wit h ot her M C 4 R a g o nist c o m p o u n ds. 
  Fi nall y,  c hr o nic t o xic ol o g y, re pr o d u cti ve, a n d j u ve nile 
t o xic ol o g y st u dies usi n g t he R M- 4 9 3-m P E G/ D S P E f or m ulati o n ha ve all c o m plete d t heir i n -life 
p orti o ns, wit h n o ne w t o xic ol o gical fi n di n gs re p orte d, a n d re p orts are bei n g pre pare d.   
  Mec h a nis m - Rel at e d A d verse E x perie nces of I nterest  
T he  m ost si g nifica nt p ote ntial safet y iss ue f or M C 4 R a g o nist c o m p o u n ds is t he c o ncer n a b o ut 
p ote ntial mec ha nis m -bas e d  i ncreases i n H R  a n d B P.   A n  M C 4 R a g o nist, L Y 2 1 1 2 6 8 8 ( Eli Lill y  a n d 
C o m pa n y), h a d bee n  st u die d i n t he cli nic a n d ca us e d H R  a n d B P  i ncreas es at all d oses (e. g., u p t o a 
mea n  9. 4 m m  H g  i n creas e i n s yst olic bl o o d press ure  [ S B P] at t he hi g hest d ose). (Gree nfiel d 2 0 0 9 , 
Kie vit  et al 2 0 1 3) W hile  t he i ncreas es were  n ot a n  i m me diate safet y c o n cer n f or t he healt h y  
v ol u nteers i n t he Lill y  st u d y, si milar b ut c hr o nic i ncreas es i n a n o bes e pati e nt  p o p ulati o n w o ul d ha ve 
bee n  pr o ble matic.  
Set mela n oti de was  de vel o pe d i n n o ncli nical st u dies t o a nal yze a n d o b viate t hese car di o vasc ular (C V ) 
effects.  Ma n y  n o ncli nical st u dies were  perf or me d  t o de m o nstrate t hat set mela n oti de di d n ot ca use 
si milar C V  effects  as L Y 2 1 1 2 6 8 8, w hile  still deli veri n g  e q ual or great er  effi cac y i n a ni mal m o dels.  
T he  u n derl yi n g pre mise of t he de vel o p me nt pr o gra m was  t hat set mela n oti d e i n h u ma ns w o ul d deli ver  
efficac y o n w ei g ht  l oss wit h o ut u nacce pta ble C V  effects.  
T he cli nical effects of set mela n oti de were rece ntl y re vie we d, a n d t here was little, if a n y e vi de n ce of 
B P or H R c ha n ge fr o m b aseli ne vs place b o  i n a n y st u d y, n or e vi d e nce of a P K/ P D relati o ns hi p 
( G ottes die ner 2 0 1 5).   
Ot her  p ote ntial saf et y a n d/ or t olera bilit y iss ues t h at ha ve bee n  re p orte d fr o m p u blis he d literat ure f or 
s o me M C 4 R a g o nists i n cli nical a n d a ni mal st u dies ha ve i ncl u de d n a usea  a n d v o miti n g,  male pe nil e 
erecti o ns,  i ncr eas es i n fe male se x ual ar o usal, a n d off -tar get acti vit y at t he cl osel y relate d M C 1 R 
( w hic h me diates  mel a ni n  de p ositi o n i n t he s ki n, pr o d uci n g ta n ni n g).  I n a d diti o n t o caref ul  C V  
m o nit ori n g, t he set mela n oti de pr o gra m was  d esi g ne d  t o i ncl u de caref ul  m o nit ori n g  f or t hes e p ote nti al 
mec ha nis m -base d  eff ects  i n t he i nitial cli nical st u dies. 

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R hyt h m P h ar m ace utic als, I nc. 
 Set mel a n oti de Cli nic al S af et y a n d T oler a bilit y S u m m ar y  
Set mela n oti de has bee n e val uate d i n P hase 1 a n d P hase 2 cli nical st u dies i n healt h y o b ese v ol u nteers.  
As of N o ve m ber 2 0 1 5, a p pr o xi matel y 2 0 0 h ealt h y o bes e s u bjects e x p ose d t o set mela n oti de at d oses 
ra n gi n g fr o m 0. 0 0 2 5 t o 2. 0 m g/ k g/ 2 4 h o urs ( 0. 1 2 – 9. 1 2 m g t otal dail y d ose).  Of t hes e 2 0 0 s u bjects, 
t he maj orit y w ere h ealt h y o bes e ( b o d y mass i n de x [ B MI] ≥3 0 m2) v ol u nteers, of w h o m ~ 4 0 recei ve d a 
si n gle set mela noti de d os e a n d ~ 1 6 0 r ecei v e d re p eate d d oses f or 3, 1 4, 2 8 or 9 0 da ys.  I n a d diti o n, 
set mela n oti de has bee n st u die d i n ~ 4 0 patie nts wit h rare ge netic dis or d ers of o besit y (i ncl u di n g 
P O M C deficie nc y o besit y, L E P R defici e nc y o besit y a n d Pra der -Willi s y n dr o me), wit h a ver y s mall 
n u m ber of patie nts ha vi n g c o m plet e d m ore t ha n o ne- year of treat me nt.  
Set mela n oti de has bee n e val uate d i n 6 c o m plete d cli nical st u dies a n d 3 o n g oi n g cli nical st u dies, a n d 
is ge nerall y well t oler ate d.  T he data fr o m t hese st u dies c o nti n ue t o s u p p ort t he h y p ot hesis t hat 
set mela n oti de d oes n ot ca use i ncr eases i n H R a n d B P. 
A d verse e ve nt ( A E) t hat ha ve bee n n u mericall y greater wit h set mela n oti de treat me nt as c o m p are d t o 
place b o ( w h et her rate d as “ dr u g -r elate d” or n ot b y i n vesti gat ors) m a y i ncl u de:  fati g u e, diarr hea, 
na usea, v o miti n g, d ar ke ni n g of s ki n lesi o ns, s ki n disc ol orati o n/ h y per pi g m e ntati o n, decrease d 
a p petite, pe nile erecti o ns, hea dac he, bac k pai n, a n d i njecti o n site pr urit us.   
O verall st u d y disc o nti n uati o ns were r are, as were Seri o us A d verse E v e nts ( S A Es).  T here h as bee n 
o nl y o ne S A E t hat w as c o nsi dere d p ossi bl y dr u g relate d (at y pical c hest pai n i n a patie nt a d mi nistere d 
set mela n oti de; car diac a n d p ul m o nar y ca uses were caref ull y e val uate d a n d e x cl u de d).  F o ur ot her 
S A Es re p orte d w ere c o nsi dere d n ot dr u g-relate d: 1) se vere gr oi n strai n, 2) s e vere a b d o mi nal pai n, 
(res p o n de d ra pi dl y t o treat me nt i n t he h os pital), 3) biliar y d ys ki nesi a i n a p atie nt a d mi nistere d 
place b o, a n d 4) n u m b ness i n t he ar m f oll o wi n g e x cessi ve alc o h ol c o ns u m pti o n ( w hic h res ol ve d i n 2 
da ys).  
F or a c o m plete s u m mar y of all pre -cli nical a n d cli nical data, pleas e refer t o t he c urre nt Set mela n oti de 
I n v esti gat or’s Br oc h ure (I B). 

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R hyt h m P h ar m ace utic als, I nc. 
2.  S T U D Y O B J E C TI V E S A N D E N D P OI N T S  
2. 1.  St u d y O bjecti ves  
L E P R  defici e nc y o besit y is a n ultra-rare ge n etic c o n diti o n c haracterize d b y se vere  earl y o ns et o besit y 
a n d pr of o u n d h y per p ha gi a (c haracterize d b y patie nts as i ncreas e d a p petite a n d h u n ger wit h i m paire d 
satiet y) wit h n u mer o us c o m or bi dities, a n d li kel y earl y m ortalit y.  To o ur k n o wle d ge t hr o u g h patie nt 
i de ntificati o n eff orts, there ha ve b ee n less t ha n 5 0 cases c urre ntl y des cri be d i n t he literat ure, wit h 
m ost cases dia g n ose d as c hil dre n.  T heref ore, we a ntici pate patie nt i de ntifi cati o n t o be c halle n gi n g 
a n d are t ar geti n g e nr olli n g at least 1 0 i n di vi d uals ( pe diatric, a d oles ce nts a n d/ or a d ults), m ostl y fr o m 
a m o n g alrea d y i d e ntifie d patie nts,  t o assess t he safet y a n d efficac y of set mela n oti de i n patie nts wit h 
L E P R defici e nc y  o besit y.  Gi ve n t he rarit y a n d u n met nee d of L E P R defici e nc y a n d t he i nitial 
c o m pelli n g r es ults i n t he first LE P R patie nt s a n d t he t w o P O M C deficie nc y o besit y  patie nts treate d, a 
c o n ve nti o nal place b o c o ntr olle d trial is n ot li kel y t o be feasi ble. D ue t o t he ultra-rare pre vale n ce of 
L E P R defici e nc y o besit y, if a d diti o nal patie nts are i de ntifie d be y o n d t he tar get e nr oll me nt of 1 0, t he y 
ma y b e e nr olle d.   
T he o bjecti ve of t his st u d y is t w of ol d; first, t o assess safet y a n d efficac y of set mela n oti de after 1 year 
of c hr o nic tr eat me nt . Sec o n dl y, si nce t here are s o fe w patie nts wit h L E P R deficie nc y a vaila ble, a n d 
t his st u d y is a n o p e n la bel desi g n, e vi de n ce of dr u g effect will be s o u g ht wit hi n eac h patie nt’s c o urse 
of treat me nt.   Theref ore, eac h p atie nt will partici pate i n a s h ort, d o u ble- bli n d place b o -c o ntr olle d 
wit h dra wal peri o d t hat will all o w patie nts t o ser ve as t heir o w n c o ntr ol t o assess a n y re v ersal effects 
o n wei g ht a n d h u n ger t o c o nfir m a n y dr u g effects .  
 Pri m ar y  O bjecti ve:  
•  T o de m o nstrate statisticall y si g nifi ca nt a n d cli nicall y mea ni n gf ul effe cts of set mela n oti de o n 
perce nt b o d y wei g ht c ha n ge i n p atie nts wit h L E P R  deficie nc y o b esit y d ue t o rare bi- allelic or 
l oss- of f u ncti o n m utati o ns at t he e n d of 1 year of treat me nt. 
 Sec o n d ar y O bjecti ves:  
T o assess t he effect of set mela n oti de , o ver o ne ye ar, o n: 
•  S afet y a n d t oler a bilit y of set mela n oti de (i ncl u di n g B P a n d H R). 
•  H u n ger f or patie nts ≥1 2 years ol d. 
•  P erce nt c h a n ge i n b o d y f at mass.  
•  Gl uc ose par a meters:  f asti n g gl uc ose, gl ycate d he m o gl o bi n ( H b A 1 c ), oral gl uc ose t olera n ce 
test (O G T T ) wit h f o c us o n para meters of i ns uli n se nsiti vit y.  
•  Waist circ u mfere n ce.  
•  D uri n g wit h dra wal fr o m dr u g: re vers al of w ei g ht a n d h u n ger re d ucti o n d uri n g t he d o u ble-
bli n d place b o-c o ntr olle d wit h dra wal peri o d.   

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R hyt h m P h ar m ace utic als, I nc. 
B o d y c o m p ositi o n assess me nts i ncl u di n g t otal b o d y w ei g ht l oss, fat l oss, a n d 
 
meas ure d i n  k g as well as perce nt c ha n ge fr o m baseli ne at t he e n d of 1 year of treat me nt.  
Gl uc ose par a meters as meas ure d b y fasti n g gl uc os e, H b A 1c a n d O G T T wit h f oc us o n para meters of 
i ns uli n se nsiti vit y o v er ti me will be assesse d .  O G T T will n ot be perf or me d f or s u bjects wit h a 
dia g n osis of T y p e 1 or T y p e 2 di a betes. 
Waist circ u mfere n ce will be meas ur e d per  U S N ati o nal H eart L u n g a n d Bl o o d I nstit ute criteria [ 2 0 0 0 
N H L B I] o ver ti me . 
T o e ns ure i m pr o ve m e nts i n wei g ht a n d h u n ger are dr u g relate d i n t his ultra-rare p atie nt p o p ulati o n, a 
var yi n g d o u ble- bli n d place b o wit h dra wal peri o d will be i m ple me nte d t hat will all o w eac h patie nt t o 
ser ve as t heir o w n c o ntr ol.  Wei g ht a n d h u n ger will be meas ure d d uri n g t his peri o d t o assess t he 
efficac y of st o p pi n g a n d restarti n g set mela n oti de treat me nt. 
P ote ntial i m pr o ve me nts i n 
 
will be a ssesse d o v er ti me.   
C ha n ges  i n gr o wt h a n d d e vel o p me nt i n patie nts < 1 8 years of a ge will be assesse d wit h re g ular hei g ht, 
wei g ht a n d B MI deter mi nati o ns (i ncl u di n g Z sc ore calc ul ati o ns) f or e v e nt u al c o m paris o n t o a ge- a n d 
ge n d er - m atc he d p o p ulati o ns.  
Gi ve n t he  s mall n u m ber of patie nts e x pecte d t o partici pate i n t he vari o us s u b-st u dies (
, it is n ot a ntici pate d t hat a n y 
c o ncl usi o ns will be ma de a b o ut eff ects of set mela n oti de o n t hese para meter, h o we ver, tre n ds o ver 
ti me will be e x pl ore d. 

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R hyt h m P h ar m ace utic als, I nc. 
A d diti o na ll y, as r e q uire d b y t he Fo o d a n d Dr u g A d mi nistrati o n ( F D A ) f or all C N S-acti ve o besit y 
me dicati o ns ,
  G ui da nce is pr o vi de d f or a n y w orse ni n g of d e pressi o n or s uici dalit y d uri n g t he st u d y.  I n 
a d diti o n, s pecific g ui deli nes f or der mat ol o gi cal e v e nts, li ver f u ncti o n a b n or malities, a n d pe nile 
erecti o ns are pr o vi d e d i n t he A p pe n di ces.  At all ti mes, t h ese g ui da nces are s u bject t o t he cli nical 
j u d g me nt of t he I n vesti gat or a n d st u d y c o ns ulta nts (if a p plica ble). 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
3.  I N V E S TI G A TI O N A L P L A N 
3. 1.  O ver all Desi g n a n d Pl a n of t he St u d y  
T his is a pi v otal P hase 3  st u d y t o assess l o n g-ter m ( 1 year) efficac y of set m ela n oti de i n L E P R  
deficie nc y o b esit y.   
After pr o vi di n g i nf or me d c o nse nt, patie nts will e nter t he Scree ni n g Peri o d .  D uri n g t h e Scree ni n g 
Peri o d, p atie nts will be assesse d f or eli gi bilit y a n d i nstr ucte d t o c o m plete a h u n ger q uesti o n naire 
dail y f or a mi ni m u m of o ne wee k  a n d i deall y t w o wee ks  t o esta blis h a bas eli ne a n d t o e n ha nce t he 
u n dersta n di n g of h u n ger s y m pt o ms ass ociate d wit h L E P R defici e nc y o besit y pri or t o treat me nt wit h 
set mela n oti de. As L E P R deficie nc y  is ultra-rare, o btai ni n g dail y h u n ger s c ores as w ell as a ver y 
detaile d me dical hist or y ( me dical rec or d re vie w)  d uri n g Scree ni n g will all o w f or t he c ollecti o n of 
i m p orta nt patie nt s pecific data (see A p pe n di x 1 1. 3 ; e. g., gr o wt h a n d w ei g ht c ur ves, ot her ass ociate d 
 a b n or malities, pe diatric de vel o p me ntal milest o nes or dist ur ba nces, a n d 
p ossi ble ort h o pe dic or res pirat or y c o m plicati o ns d ue t o wei g ht gai n) t hat will all o w f or a better 
u n dersta n di n g of t his rar e m o n o ge nic f or m of o b esit y.   
After t he Scr ee ni n g P eri o d, t here are f o ur treat me nt p hases t o t he st u d y:  
O pe n La bel D ose T itrati o n P hase  ( 2 – 1 2 wee ks) 
I n t his p has e of t he st u d y, a patie nt’s i n di vi d ual t hera pe utic d os e will be est a blis he d. T he starti n g 
d ose is 1. 0 m g f or a d ult patie nts a n d 0. 5 m g f or a d ol esce nt a n d 0. 2 5 m g f or pe diatric patie nts.  
Patie nts will ret ur n t o t he cli nic e ver y t w o w ee ks t o assess t heir wei g ht l oss a n d h u n ger sc ores a n d 
d osi n g will i ncrease e v er y t w o w ee ks i n 0. 5 m g i ncre me nts u ntil a patie nt’s i n di vi d ual t hera pe utic 
d ose is esta blis he d per t h e g ui d eli nes i n A p pe n di x 1 1. 8.   
As t his is a gl o bal st u d y, t he ma xi m u m all o wa ble d ose differs ac r oss c o u ntries base d o n fee d b ac k 
fr o m c o m pete nt a ut h oriti es.  T he U S, U K a n d t h e Net herla n ds h a ve a p pr o v e d a ma xi m u m d ose of 3. 0 
m g, w hile G er ma n y a n d Fra n ce ha v e a p pr o ve d a ma xi m u m d ose of 2. 5 m g.  T heref ore, t he d urati o n 
of t he d ose titrati o n sta ge will ra n ge fr o m 2 t o 1 2 wee ks, de p e n di n g o n t he n u m ber of escalati o ns 
re q uire d t o defi ne t he t hera pe utic d ose a n d t he a p pr o ve d ma xi m u m d ose i n t he c o u ntr y of t he 
partici pati n g site.   
O pe n La bel P has e  ( 1 0 w ee ks) 
After esta blis hi n g a p atie nt’s i n di vi d ual t hera pe utic d ose, t he patie nt will c o nti n ue d osi n g f or a n 
a d diti o nal 1 0 wee ks, r es ulti n g i n 1 2 t otal wee ks of treat me nt at t heir t hera pe utic d ose (i ncl u di n g t h e 
last 2 wee ks at t he t hera p e utic d ose i n t he d ose titrati o n p hase).  T o c o nti n u e treat me nt a fter 1 2 w eeks 
o f treat me nt at t heir t h era pe utic d ose, patie nts m ust ac hie ve a wei g ht l oss of 5 k g or great er  fr o m 
baseli ne if t heir bas eli ne wei g ht w as greater t ha n 1 0 0 k g or a wei g ht l oss of > 5 % fr o m baseli ne if 
t heir baseli ne w ei g ht w as < 1 0 0 k g.  Patie nts w h o  d o n ot ac hie ve d t hes e wei g ht l oss criteria will be 
disc o nti n ue d fr o m treat m e nt, b ut s h o ul d c o nti n ue wit h ot her st u d y pr o ce d ures t hr o u g h st u d y e n d. 
P lace b o- C o ntr olle d, D o u ble- Bli n de d Wit hdra wal P hase  ( 8 wee ks) 
Patie n ts t hat ac hie ve a 5 k g or 5 %  wei g ht l oss after 1 2 wee ks of treat me nt at t heir t hera pe utic d os e 
will recei ve  eit her place b o or acti ve f or f o ur wee ks a n d t he n cr oss- o v er t o t he o p p osite treat me nt f or 
f o ur wee ks.  T he tr eat me nt assi g n me nt d uri n g t he first f o ur- w ee k peri o d will be d o u ble- bli n de d s o 
t hat t he sites a n d patie nts d o n ot k n o w if t heir first f o ur-w ee k bl oc k of treat me nt is  place b o or acti ve. 
O pe n La bel Treat me nt P hase ( 3 2 w ee ks)  

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R hyt h m P h ar m ace utic als, I nc. 
After c o m pleti n g t he place b o -c o ntr olle d, d o u ble- bli n de d wit h dra wal p has e, patie nts will c o nti n ue 
d osi n g at t heir i n di vi d ual t hera pe utic d os e f or a n a d diti o nal 3 2 wee ks.  At t he e n d of t he 3 2 wee ks, 
patie nts ca n e nr oll i n a se parate  l o n g-t er m e xte nsi o n st u d y t o c o nti n ue recei vi n g set mela n oti de ( St u d y 
R M - 4 9 3- 0 2 2) or t he y ca n c o m plete treat me nt wit h a fi nal visit a p pr o xi matel y 3 0 d a ys after t heir last 
d ose. 
Fi g ure 7 : St u d y Sc he m a  
 
It is a ntici pate d t hat at least 1 0 patie nts will be e nr olle d  i n t his st u d y.  H o w e ver, d ue t o t he ultra-rare 
pre vale n ce of t his p o p ulati o n, if m ore patie nts are i de ntifie d d uri n g t h e c o n d uct of t he st u d y, t h e y 
ma y  als o be e nr olle d.   
I n a d diti o n, f or patie nts at sites w here feasi ble, a n d w h o a gree t o partici pat e, 
3. 2.  R ati o n ale f or t he D oses 
A rece nt i n vesti gat or- i nitiate d trial ( R M- 4 9 3- 0 1 1) of set mela n oti de i n t his p o p ulati o n of m o n o ge nic 
o besit y patie nts use d a si milar d ose titrati o n sc he me t hat de m o nstrate d mi ni mal i nitial wei g ht l oss at 
d oses of 0. 2 5 – 0. 5 m g Q D, yet m ea ni n gf ul a n d pr o gressi ve wei g ht l oss wit h Q D d oses of 1. 0 m g a n d 
a b o ve.  I n a d diti o n, t her e was n o e vi de n ce of i ncrease d se nsiti vit y or n e w safet y iss ues arisi n g i n t his 
se nti nel patie nt trial at a n y d ose of set mela n oti de t o date.   
T his ra n ge of d os es is als o s u p p orte d b y d ata i n t h e ge neral o bese p o p ul ati o n: ( 1) d oses assesse d i n 
t he M ulti ple Asce n di n g D ose ( M A D) P hase 1 b st u d y, w hic h c o nsiste ntl y res ulte d i n cli nicall y 
i m p orta nt, statisticall y si g nifica nt, t hera p e utic effects i n healt h y o bese i n di vi d uals; ( 2) d oses t hat 
pr o vi de t he P K pr ofile of t he o nce dail y S C i njecta ble f or m ulati o n of set m ela n oti de t o ac hie v e a 
tr o u g h as cl ose as p ossi bl e t o a ntici pate d tar get of ~ 3- 5 n g/ m L.  
H o we ver, beca use t he n u m ber of m o n o ge nic P O M C/ L E P R  o besit y patie nts e x p ose d t o M C 4 R 
a g o nists s uc h as set mela n oti de t o date is ver y s mall, t he d ose of set mela n oti de will be caref ull y 
titrate d u p war ds f or eac h patie nt o n a n i n di vi d ual basis t o i de ntif y o ne’s safe a n d effi caci o us d ose.  
T he i nitial d ose of set mela n oti de t o be a d mi nistere d t o a d ults will be a dail y d ose of 1. 0 m g Q D b y 
S C i njecti o n, wit h i ncre me ntal i ncreas es of 0. 5 m g o n e v er y 2-w ee k  b asis u p t o a ma xi m u m t otal 

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R hyt h m P h ar m ace utic als, I nc. 
dail y d ose of 3. 0 m g  or 2. 5 m g de p e n di n g o n t h e ma xi m u m a p pr o ve d d ose i n t he partici pati n g 
c o u ntr y. 
D osi n g i n a d oles ce nt a n d pe diatric patie nts will f oll o w t he sa me deli berate d os e titrati o n a p pr oac h 
e m pl o ye d f or a d ult s u bjects, e x ce pt t hat t he starti n g d ose will be 0. 5 m g per da y f or a d ol esce nt 
patie nts a n d 0. 2 5 m g f or pe diatric patie n ts as o p p ose d t o 1. 0 m g, i.e. set mel a n oti de d os e titrati o n 
i ncreas es will be ste p wise, risi n g b y 0. 5 m g at eac h 2-wee k titrati o n ste p.  F or all pe diatric patie nts , 
t he ma xi m u m all o wa ble  d ose will be 2. 5 m g/ da y.  T he t o p d ose f or a d olesce nt patie nts will be 2. 5 or 
3. 0 m g de p e n di n g o n t h e ma xi m u m a p pr o ve d d ose i n t he partici pati n g c o u ntr y. 
 
D uri n g t h e d ose titrati o n p hase, 
 t he d ose is 
i ncre me ntall y i ncr ease d t o e x pl ore t he e x p os ure-res p o nse c ur ves f or safety a n d effi cac y. O nce a 
patie nt f ulfills t he d ose titrati o n wei g ht l oss a n d / or h u n ger sc ore tar gets ( A p pe n di x 1 1. 8 ), t he 
i n di vi d ual patie nt’s t hera pe utic d ose will ha ve bee n ac hie ve d, n o f urt her d ose titrati o n will occ ur, a n d 
patie nts will pr ocee d i nt o t he 1 0 -wee k O pe n La bel Acti ve Treat me nt P hase.   
T he hi g h est p ote ntial d ose all o we d i n t he d ose titrati o n sta ge f or a d ol esce nts a n d a d ults is eit her 3. 0 
m g or 2. 5 m g  ( d e pe n di n g o n t he ma xi m u m a p pr o ve d d ose i n t he partici p ati n g c o u ntr y) a n d 2. 5 m g f or 
all pe diatric patie nts ( a ge d 6 – 1 1 years ol d).  T o xic ol o g y st u dies i n rats a n d m o n ke ys pr o vi d e 
e xtre mel y lar ge mar gi ns ( > 1 5 0 -f ol d) t o h u ma n cli nical e x p os ures at t he 2. 5 a n d 3. 0 m g/ da y d os es (i n 
m g/ m 2 c o m paris o ns; gr eater mar gi ns were ac hie ve d o n a m g/ k g basis).  D oses u p t o 1 0 m g ha v e bee n 
gi ve n i n si n gle d oses t o ge neral o b ese patie nts, a n d t he li miti n g t o xicit y was na usea (a n d i n s o me 
cases v o mit i n g).  Ot her wise d oses u p t o 2. 0 m g / da y ha v e bee n a d mi nistere d f or u p t o 1 2 wee ks i n 
healt h y o b ese v ol u nteers a n d d oses of u p t o 2. 5 m g/ da y a d mi nistere d f or u p t o 1 0 wee ks re prese nts 
t he hi g hest d ose st u die d i n patie nts wit h Pra der-Willi S y n dr o me wit h n o n e w safet y iss ues arisi n g 
w hile t his trial has bee n i n pr o gress ( as o utli ne d i n t he R M- 4 9 3 I n v esti gat or Br oc h ure). T he m ost 
c o m m o n a d verse e ve nt w as l ocal i njecti o n site reacti o ns ( w hic h ca n b e easil y m o nit ore d).  W hile t he 
e x perie nce t o date (fr o m t he t w o i nitial patie nts wit h P O M C  deficie nc y o besit y) s u g gests t hat t he 
li kel y titrate d d ose (e ver y 2 w ee ks) ma y b e 1. 5 m g/ da y, t his pr ot oc ol all o ws t he c ha nce t o d ose u p t o 
2. 5 or 3. 0 m g t o de m o nstrate r o b ust efficac y o n w ei g ht l oss a n d h u n ger re d ucti o n.  T he t o p d ose of 
2. 5 or 3. 0 m g is s u p p orte d b y t he e x celle nt safet y pr ofile o bser v e d i n P O M C a n d L E P R patie nts aft er 
pr ol o n ge d d osi n g at 1. 5 a n d 2. 0 m g. 
3. 3.  J ustific ati o n of t he St u d y Desi g n 
Set mela n oti de is bei n g e val uate d as a p ot e ntial treat me nt f or rare, ge netical l y defi n e d o bese 
p o p ulati o ns.  A n i n vesti gat or- i nitiate d P hase 2a pr o of of c o nce pt st u d y i n P O M C an d L E P R  defi cie nt 
patie nts  ( RM- 4 9 3- 0 1 1) is c urre ntl y o n g oi n g a n d t hat st u d y f or ms t he basis f or t he c urre nt pr ot oc ol, as 
n ote d i n Secti o n 1. 2 .     
Perce nt c h a n ge i n b o d y wei g ht will be t he pri mar y  e n d p oi nt f or t his re gistrati o n pr ot oc ol, wit h l o n g-
ter m efficac y t o be e val u ate d after 1 year of st u d y.   T here is n o pla n ne d c o m paris o n t o a ra n d o mize d 
place b o  gr o u p gi ve n t h e r arit y of m o n o ge nic L E P R  deficie nc y o b esit y .  T o pr o vi de s u p p ort i n 
assessi n g s et mela n oti de treat me nt i n t his  o pe n-la b el si n gle-ar m trial desi g n , i n di vi d ual patie nt s will 
als o be e val uat e d d uri n g a d o u ble- bli n d place b o -c o ntr olle d wit h dra wal  p hase i n w hic h patie nts ca n 
ser ve as t heir o w n c o ntr ol t o assess a n y re v ersal effects o n wei g ht a n d re p orte d h u n ger sc ores. I n 
a d diti o n, t he hist or y of u n- re mitti n g h u n ger a n d w ei g ht gai n re p orte d i n t hese patie nts will be 
caref ull y d o c u me nte d (s ee A p pe n di x 1 1. 3 ) t o s u bsta ntiate t hat t he wei g ht l oss a ntici pate d i n t his 
st u d y is dr u g-r elate d.    

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T h e pr o p osal f or t he d o u ble- bli n d place b o -c o ntr olle d wit h dra wal  peri o d is base d o n:  ( 1) t he 
c o m pelli n g r es p o nse t o s et mela n oti de de m o nstrat e d b y t h e se nti nel patie nt s e nr olle d i n t he o pe n-la b el 
i n vesti gat or-i nitiate d st u d y; ( 2) cha n ge fr o m bas eli ne a n d/ or s h ort- ter m re versi bilit y e val u ati o ns off 
treat me nt ma y esta blis h t he i m pact a n d re pr o d uci bilit y of acti ve dr u g effects, es peciall y i n L E P R  
deficie nc y o b esit y p atie nts, w h o are e x pecte d t o h a ve l o n g, nat ural hist or y e val uati ve data f or mar ke d 
wei g ht gai n pri or t o treat me nt a vaila ble f or c o m paris o ns; a n d ( 3) place b o c o m paris o ns wit h s o fe w 
L E P R ge n etic  m utati o n  patie nts e xisti n g, all of w h o m are e x pecte d t o de m o nstrate a ver y hi g h n ee d 
f or t hera p y, w o ul d n ot be feasi ble or pr o ba bl y et hi call y acce pta ble.     
3. 4.  St u d y Ter mi n ati o n  
T his st u d y ma y be pr e mat urel y ter mi nate d, if i n t h e o pi ni o n of t he I n vesti gat or (at a partici pati n g site) 
or R h yt h m (f or t he w h ole st u d y), t here is s ufficie ntl y reas o na ble ca use.  T he ter mi nati n g part y will 
pr o vi de writte n n otificati o n d oc u me nti n g t he reas o n f or st u d y t er mi nati o n t o eit her t he I n v esti gat or or 
R h yt h m.  
Circ u msta nces t hat ma y warr a nt ter mi nati o n i ncl u de, b ut are n ot li mite d t o:  
•  Deter mi nati o n of u ne x pecte d, si g nifi ca nt, or u nacce pta ble ris k t o patie nts. 
•  Fail ure t o e nt er patie nts at a n acce pta ble rate.   T his is partic ularl y i m p orta nt, as t he n u m ber of 
patie nts h o pe d t o e nr oll i n t his st u d y re prese nts a s u bsta ntial p orti o n of all alrea d y i de ntifie d 
patie nts w orl d wi de.  
•  I ns ufficie nt a d h ere n ce t o pr ot oc ol re q uire m e nts. 
•  I ns ufficie nt c o m plet e a n d/ or e val ua ble d ata. 
•  Pla ns t o m o dif y, s us p e n d or disc o nti n ue t he de vel o p me nt of t he st u d y dr u g. 
S h o ul d t he st u d y b e cl ose d pre mat urel y, all st u d y materials m ust be ret ur n e d t o R h yt h m or d esi g nee 
a n d R h yt h m will n otif y t he a p plica ble c o m pete nt a ut h orities a n d et hics c o m mittees as per I C H E 6 R 2 
a n d t he E U Cli nical Trials Directi ve ( 2 0 0 1/ 2 0/ E C). 
I n a d diti o n, it is still u nclear h o w ma n y patie nts will be re q uire d i n a pi v otal st u d y t o assess t he safet y 
a n d effi cac y of set mela n oti de i n L E P R  deficie n c y patie nts, a n ultra -rare c o n diti o n.  T heref ore, t his 
st u d y ma y be ter mi nate d w he n R h yt h m, i n c o ns ult ati o n wit h re g ul at or y a ut h orities, deter mi nes t hat 
t here is s ufficie nt p atie nt data t o s u p p ort t he p ote ntial a p plicati o n f or re gistrati o n of t his dr u g f or a n 
i n dicati o n i n L E P R  deficie nc y o besit y.   

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R hyt h m P h ar m ace utic als, I nc. 
4.  S T U D Y P O P U L A TI O N  
4. 1.  N u m ber of P atie nt s 
It is c urre ntl y a ntici pate d t hat at least 1 0 patie nt s will be treate d f or ~ 1 year wit h set mela n oti de.   
Gi ve n  t he ultra-r ar e i nci d e nce of t h e disease, if a d diti o nal patie nts are i de ntifie d, t he y m a y be 
e nr olle d as a v aila ble t o gai n a d diti o nal e x perie nce.   T he st u d y p o p ulati o n will i ncl u de o bese males 
a n d fe males t h at are at least 6 years ol d wit h c o nfir me d dia g n o sis of bi-allelic or l oss- of-f u n cti o n 
L E P R  l oss of f u ncti o n ge ne m utati o n. 
Gi ve n t his st u d y i n v ol ves partici pa nts < 1 8 years of a ge, meas ures s h o ul d be ta ke n t o re d uce pai n a n d 
distress i n t his y o u n ger p o p ulati o n.  C o nsi derati o ns f or t he st u d y st aff are i n cl u de d i n A p pe n di x 
1 1. 1 1.  
T he s pecific i n cl usi o n a n d e x cl usi o n criteria f or e nr olli n g patie nts i n t his st u d y are prese nte d i n t he 
secti o n bel o w.  As t hese patie nt s are ultra -rare, a n y criteria n ot f ulfille d will be re vie w e d wit h 
R h yt h m .  Ass u mi n g n o s e vere h ealt h c o n cer ns, a j oi nt deter mi nati o n will be ma de re gar di n g t he 
acce pta bilit y of e nr olli n g patie nt s n ot f ulfilli n g all criteria o n a cas e b y cas e basis.  A n y e x ce pti o ns t o 
t he i ncl usi o n a n d ex cl usi o n criteria will be d o c u me nte d i n writi n g a n d a p pr o ve d b y R h yt h m pri or t o 
d osi n g t he patie nt. 
4. 2.  I ncl usi o n Criteri a: 
1.  Bi -allelic, h o m oz y g o us or c o m p o u n d heter oz y g o us (a differe nt ge n e m utati o n o n eac h allele) 
ge n etic stat us f or t he L E P R  ge ne, wit h t he l oss- of-f u ncti o n ( L O F) v aria nt f or eac h allele 
c o nferri n g a se v ere o b esit y p he n ot y pe.        
2.  A ge 6 years a n d a b o v e.    
3.  If a d ult a ge ≥1 8 years , o b esit y wit h B MI ≥ 3 0 k g/ m 2; if c hil d or a d olesce nt, o besit y wit h B M I 
≥ 9 5t h  perce ntile f or a ge o n gr o wt h c hart assess me nt.  
4.  St u d y p artici pa nt a n d/ or pare nt or g u ar dia n is a ble t o c o m m u nicate well wit h t he i n vesti gat or, 
t o u n dersta n d a n d c o m pl y wit h t he re q uire me nts of t he st u d y, a n d is a ble t o u n dersta n d a n d 
sig n t he writte n i nf or me d c o nse nt/asse nt, aft er bei n g i nf or m e d a b o ut t he st u d y.   
5.  F e male p artici pa nt s of c hil d- beari n g p ote ntial m ust a gree t o use c o ntrace pti o n as o utli ne d i n 
t he pr ot oc ol.  Fe m ale partici pa nts of n o n-c hil d beari n g p ote ntial, defi ne d as s ur gicall y sterile 
(stat us p ost h yster ect o m y, bilateral o o p h orect o m y, or bilateral t u bal li gati o n) p ost-me n o pa usal 
f or at least 1 2 m o nt hs (a n d c o nfir me d wit h a scree ni n g F S H le v el i n t he p ost- me n o pa usal la b 
ra n ge), or ha ve d ela ye d p u bertal de vel o p me nt a n d fail ure t o ha v e ac hie v e d me narc h e, d o n ot 
re q uire c o ntrace pti o n d uri n g t he st u d y.  
6.  Male  partici pa nt s wit h f emale part ners of c hil d beari n g p ote ntial m ust a gree t o a d o u ble barri er 
met h o d if t he y b ec o me s e x uall y acti v e d uri n g t he st u d y. Male p atie nt s m ust n ot d o nate s per m 
d uri n g a n d f or 9 0 d a ys f oll o wi n g t heir partici pati o n i n t he st u d y. 
4. 3.  E xcl usi o n Criteri a  
1.  Rece nt i nte nsi ve ( wit hi n 2 m o nt hs) diet a n d/ or e xercise re gi me n wit h or wit h o ut t he use of 
wei g ht l oss a ge nts i ncl u di n g her b al me dicati o ns, t hat has res ulte d i n wei g ht l oss or wei g ht 
sta bilizati o n.  Patie nts ma y b e rec o nsi dere d a p pr o xi matel y 1 m o nt h after cessati o n of s uc h 
i nte nsi ve re gi me ns.   
2.  Pri or gastri c b y pass s ur ger y  res ulti n g i n >1 0 % w ei g ht l oss d ura bl y mai ntai ne d fr o m t he 
baseli ne pre -o per ati ve w ei g ht  wit h n o e vi de n ce of wei g ht re gai n.  S pecificall y, patie nt s ma y 

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R hyt h m P h ar m ace utic als, I nc. 
be c o nsi der e d if s ur ger y was n ot s uccessf ul , or res ulte d i n < 1 0 % wei g ht l oss c o m pare d t o pre-
o perati ve bas eli ne wei g ht  or clear e vi de n ce of w ei g ht re gai n aft er a n i nitial res p o nse t o 
bariatric s ur ger y .  All patie nts wit h a hist or y of b ariatric s ur ger y m ust be disc usse d wit h, a n d 
recei v e a p pr o v al fro m R h yt h m pri or t o e nr oll me nt .  
3.  Dia g n osis of s c hiz o p hre nia, bi p olar dis or der, p ers o nalit y dis or der or ot her Dia g n ostic a n d 
Statistical Ma n ual of Me ntal Dis or ders ( D S M -III) dis or ders t hat t he i n vesti gat or b elie ves will 
i nterfer e si g nifi ca ntl y wit h st u d y c o m plia nce. 
4.  A Patie nt Healt h Q uesti o n naire - 9 (P H Q - 9) sc ore of ≥ 1 5. 
5.  A n y s uici d al i deati o n of t y p e 4 or 5 o n t he C ol u m bia S uici de Se verit y R ati n g Scal e ( C- S S R S ).  
A n y lifeti me hist or y of a s uici de atte m pt, or a n y s uici dal be ha vi or i n t he last m o nt h. 
6.  C urre nt, se ver e sta ble r estricti ve or o bstr ucti ve l u n g diseas e arisi n g beca use of e xtre me 
o besit y, e vi de n ce of si g nifica nt heart fail ure ( N Y H A Class 3 or great er) , or o nc ol o gic disease , 
if t hese wer e se v ere e n o u g h t o i nterfere wit h t he st u d y a n d/ or w o ul d c o nf o u n d t he res ults. 
A n y s u c h patie nts s h o ul d be disc usse d wit h t he s p o ns or pri or t o i ncl usi o n. 
7.  Hist or y of si g nifica nt li ver disease or li ver i nj ur y, or c urre nt li ver assess me nt f or a ca use of 
a b nor mal li ver tests  [as i n dicate d b y a b n or m al li ver f u ncti o n tests, ala ni n e tra nsa mi nase 
(A L T ), as p artate tr a nsa mi nase ( A S T ), al k ali ne p h os p hatase, or ser u m bilir u bi n ( > 2. 0 x u p per 
li mit of n or mal (U L N ) f or a n y of t hese t ests)] f or a n eti ol o g y ot her t ha n n o n-alc o h olic fatt y 
li ver disease ( N A F L D).  T h us, a n y u n d erl yi n g eti ol o g y besi des N A F L D, i ncl u di n g dia g n ose d 
n o n- alc o h olic steat o h e patitis ( N A S H), ot her ca us es of he patitis,  or hist or y of he patic cirr h osis 
will be e x cl usi o nar y, b ut t he prese n ce of N A F L D w o ul d n ot be e x cl usi o nar y .   
8.  Hist or y or prese n ce of i m paire d re nal f u ncti o n as i n dicate d b y cli nicall y si g nifica nt a b n or mal 
creati ni ne, bl o o d ur ea nitr o ge n ( B U N ), or uri nar y c o nstit ue nts (e. g., al b u mi n uria) or m o derate 
t o se vere r e nal d ysf u n cti o n as defi ne d b y t he C oc kcr oft Ga ult e q u ati o n < 3 0 m L/ mi n  
( A p pe n di x 1 1. 1 0 ).  
9.  Hist or y or cl ose f a mil y hist or y ( par e nts or si bli n gs) of s ki n ca ncer or mela n o ma, or patie nt 
hist or y of o c ular - c uta ne o us al bi nis m. 
1 0.  Si g nifica nt der mat ol o gic fi n di n gs  relati n g t o mela n o ma or pre- m ela n o ma s ki n lesi o ns, 
deter mi ne d  as p art of a s cree ni n g c o m pre h e nsi ve s ki n e val uati o n perf or me d b y a q u alifie d 
der mat ol o gist.  A n y c o ncer ni n g l esi o ns i de ntifie d d uri n g t he s cree ni n g p eri o d will be bi o psie d 
a n d res ults k n o w n t o be be ni g n pri or t o e nr oll me nt .  If t h e pre-treat me nt bi o ps y res ults are of 
c o ncer n, t h e patie nt ma y nee d t o be e x cl u de d fr o m t he st u d y.   
1 1.  V ol u nteer is, i n t he o pi ni o n of t he St u d y I n v esti gat or, n ot s uita ble t o partici pate i n t he st u d y. 
1 2.  Partici pati o n i n a n y cli nical st u d y wit h a n i n vesti gati o nal dr u g/ d e vice wit hi n 3 m o nt hs pri or t o 
t he first da y of d osi n g. 
1 3.  Pre vi o us hist or y of s i g nifica nt h y p erse nsiti vit y t o e x o ge n o usl y i njecte d pe pti des (e. g. 
urticaria, s h ort n ess of breat h, or m ore se v ere res p o nses i ncl u di n g a n a p h ylact oi d reacti o ns or 
a na p h yla xis).  
1 4.  I n a bilit y t o c o m pl y wit h Q D i njecti o n re gi me n. 
1 5.  Patie nts w h o ha ve bee n place d i n a n i nstit uti o n t hr o u g h a n official or c o urt or der, as well as 
t hose w h o are d e pe n d e nt o n t he s p o ns or, I n vesti gat or or st u d y site. 
4. 4.  P ati e nt  I de ntific ati o n a n d Re gistr ati o n 
T he I n vesti gat or a n d t he I n v esti gat or’s st u d y staff will i de ntif y p ote ntial patie nt s f or t he st u d y.  
Patie nts w h o are ca n di dates f or e nr oll me nt i nt o t he st u d y will be e v al uate d f or eli gi bilit y b y t he 

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R hyt h m P h ar m ace utic als, I nc. 
I n v esti gat or t o e ns ure t h at t he i ncl usi o n a n d e x cl usi o n criteria ha v e bee n s atisfie d a n d t hat t he patie nt 
is eli gi ble f or p artici pati o n i n t his cli nical st u d y.   
All patie nts scree n e d f or t he st u d y will be assi g ne d a u ni q ue scree ni n g n u m ber re prese nti n g a 
c o m bi nati o n of t he site n u m ber a n d a s e q ue ntial 3- di git n u m ber, w hi c h will be use d t o i de ntif y 
patie nts t hr o u g h o ut t heir partici pati o n i n t he st u d y.  Scree ni n g n u m bers will be assi g n e d se q u e ntiall y 
starti n g at 0 0 1 (i. e.; t he first patie nt  scree ne d at sit e 1 0 w o ul d be assi g ne d s cree ni n g n u m ber 1 0 0 0 1).  
O nce a p atie nt n u m ber h as bee n assi g n e d, it ca n n ot be re use d.  
4. 5.  Wit h dr a w al of P atie nts  
Patie nts will be i nf or me d t hat t he y h a ve t he ri g ht t o wit h dra w fr o m t he st u d y at a n y ti me f or a n y 
reas o n, wit h o ut prej u dice t o t heir me dical care.  T he I n vesti gat or als o h as t he ri g ht t o wit h dra w 
patie nts fr o m t he st u d y , after disc ussi o n wit h t he s p o ns or, f or a n y of t he f oll o wi n g reas o ns: 
•  A E s, w hic h j ustif y ceasi n g treat me nt.  Specific pre defi ne d e v e nts  f or disc o nti n uati o n, as 
well as a d diti o nal g ui d eli nes f or safet y m o nit ori n g, are i ncl u de d i n A p p e n di ces 1 1. 4 – 
1 1. 7. 
•  N o n -a d here nce t o st u d y dr u g re gi me n or pr ot oc ol re q uire me nts. 
•  N o n -c o m plia nce wit h i nstr ucti o ns or fail ure t o ret ur n f or f oll o w- u p. 
•  Fail ure t o de m o nstr ate 5 k g of wei g ht l oss ( or 5 % if baseli ne b o d y wei g ht is < 1 0 0 k g) at 
t he e n d of t he 1 0-wee k o pe n la bel treat me nt p hase.  
If a patie nt is wit h dra w n fr o m treat me nt or disc o nti n ue d fr o m t he st u d y, t h e pri mar y reas o n is t o be 
rec or d e d i n t he s o urce d o c u me nts/case re p ort f or m ( C R F ).   
All patie nts w h o are n o l o n ger recei vi n g acti ve treat me nt pri or t o c o m pleti n g t he ~ 1 year treat me nt 
peri o d s h o ul d be str o n gl y e nc o ura ge d t o c o m plete all re mai ni n g visits a n d pr oce d ures as o utli ne d i n 
t he Sc he d ule of Ass ess me nts i n Secti o n 6 . 
I n case of wit h dra w al fr o m t he st u d y (i.e. wit h dra wi n g c o ns e nt), all a d v ers e e ve nts s h o ul d be 
f oll o we d as des cri be d i n Secti o n  7. 4 ; a n y s ki n a d v erse e x perie n ces s h o ul d c o nti n ue t o be f oll o we d, if 
at all feasi ble, f or ~ 6 0- 9 0 da ys t o c o nfir m near, or c o m plete res ol uti o n (as h as bee n s h o w n i n 
pre vi o us st u dies).      
R h yt h m will pr o vi de s u p p ort f or patie nt a n d care gi ver tra vel, will ma ke a vaila b le visiti n g h o me 
healt h car e pr of essi o nals, a n d a n y ot her n ecess ar y l o gistical s u p p ort  t o eas e t he b ur de n o n t he patie nt 
t o facilitate c o m plia nce.   
 

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R hyt h m P h ar m ace utic als, I nc. 
5.  S T U D Y T R E A T M E N T S  
5. 1.  St u d y Dr u gs  
All s t u d y dr u gs ar e f or i n vesti gati o nal use o nl y a n d are t o be us e d o nl y wit hi n t he c o nte xt of t his 
pr ot oc ol .  All i n vesti gati o nal st u d y dr u gs (s et mela n oti de a n d place b o) will be s u p plie d b y R h yt h m. 
Set mela n oti de dr u g pr o d uct ( R M- 4 9 3-m P E G/ D S P E f or m ulati o n) is  a sterile s ol uti o n f or i njecti o n.  
T he pr o d uct is ma n uf act ure d at a c o nce ntrati o n of 1 0. 0 m g/ m L.   
Place b o will be ve hicle.   
Set mela n oti de  a n d place b o are cl ear, c ol orless t o sli g htl y o pal esce nt s ol uti o ns esse ntiall y free of 
visi ble partic ulates, a n d are s uita ble f or a d o u ble- bli n d st u d y.  Set mela n oti d e a n d place b o will be 
a d mi nistere d as S C  i njecti o n o nce dail y .  
All st u d y dr u g m ust be k e pt i n a sec ur e, li mite d -access st ora ge area at a te m perat ure b et wee n 2° C t o 
8° C.  B ot h set mela n oti de a n d place b o are st a ble at r o o m te m perat ure f or a s h ort peri o d t hat will all o w 
patie nts t o tra ns p ort st u d y dr u g h o m e ; ice pac ks a n d c o oler ba gs will be pr o vi de d f or patie nt s a n d 
caret a kers w h o will tra vel l o n g dista nces fr o m t he cli nic.   Patie nts will be e nc o ura ge d t o pr ocee d 
directl y h o m e after cli nic visits i n w hic h st u d y dr u g is dis pe nse d t o mi ni mize t he a m o u nt of ti me t he 
st u d y dr u g is e x p ose d t o ele vate d te m perat ures.   
A se par ate p har m ac y ma n ual wit h s pecific i nstr ucti o ns will be pr o vi de d t o t he i n vesti gati ve site.  
T h ere will be e xte nsi ve trai ni n g of p atie nts i n dr u g a d mi nistrati o n i ncl u di n g e d ucati o nal materials.  
St u d y s p ecific tr ai ni n g m aterials will be pr o vi de d t o b ot h t he i n vesti gati ve staff a n d st u d y partici pa nts 
a n d car e gi vers .  R h yt h m will pr o vi de e xtra place b o s u p plies f or use d uri n g trai ni n g. 
5. 2.  St u d y Dr u g D ose a n d A d mi nistr ati o n  
St u d y p atie nts will recei ve st u d y dr u g b y S C i njecti o n o nce dail y (a d mi nistere d i n t he m or ni n g). T he 
d ose titrati o n p hase will c o nsist of a d ose titrati o n  p hase of u p t o 1 0 wee ks.  O nce t he p atie nt’s  
t hera pe utic d os e is deter mi ne d, t he sa me d ose/ v ol u me will be a d mi nistere d t hr o u g h o ut t he re mai n der 
of t he st u d y. 
T he g o al  is f or t he p atie nt or t heir car eta ker t o s uccessf ull y s elf-a d mi nister t he st u d y dr u g t he msel v es 
at h o me.  Gi ve n t he r arit y of LE P R patie nts, arra n ge m e nts ma y b e ma de f or t h ose w h o are n ot a ble t o 
s uccessf ull y self-a d mi nister t he st u d y dr u g t o ha ve assista nce b y a visiti n g h o me healt h care 
practiti o ner.  
Patie nts a n d/ or t heir careta kers (i ncl u di n g h o me h ealt h practiti o ners) will be res p o nsi ble f or all 
pr oce d ur es ass oci ate d wit h  st u d y dr u g a d mi nistrati o n , i.e., dra wi n g u p, a n d self-a d mi nisteri n g t he 
st u d y dr u g o nce dail y (i n cl u di n g d uri n g t he practi ce peri o ds).    
T o  e ns ure patie nts or t h eir car e gi vers ca n s uccessf ull y self -a d mi nister st u d y dr u g, a trai ni n g peri o d i n 
t he cli nic wit h place b o  ( or sali ne) d uri n g scree ni n g will occ ur bef ore e nt eri n g  t he o p e n la bel d ose 
titrati o n p hase.  T his trai ni n g/ practice peri o d ca n occ ur as m a n y ti mes as n ecessar y  t hr o u g h o ut t he 
st u d y t o ass ure pr o per t ec h ni q ue.  T he trai ni n g/ practice peri o d d o es n ot pert ai n t o t he h o me healt h 
practiti o ners.     
Patie nts will be re q uire d t o fast o ver ni g ht f or all cli nic visits.  Water will be all o we d thr o u g h o ut t he 
fasti n g p eri o d.    

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R hyt h m P h ar m ace utic als, I nc. 
 D ose Titr ati o n a n d A dj us t me nts 
E x perie nce i n t he first t w o P O M C patie nts a n d t he 3 L E P R  defici e nt patie nt s e nr olle d i n t he 
i n vesti gat or-i nitiate d trial ( R M- 4 9 3- 0 1 1), as n ote d a b o ve, has s h o w n mar ke d re d ucti o ns i n h u n ger 
a n d wei g ht wit h o ut re veali n g a n y ne w or u na ntici p ate d A E s t o date.  T h e efficaci o us d ose i n t hes e 
patie nts has ra n ge d fr o m t otal dail y d oses of 1- 2 m g of s et mela n oti de .  H o w e ver, d ue t o t he s m all 
n u m ber of P O M C/ L E P R  deficie nt patie nts e x p ose d t o set mela n oti de t o date, caref ul i ncreas es i n d ose 
titrati o ns will be c o n d ucte d. 
T he first d ose of s et mela n oti de will be a d mi nistere d at t he start of  t he D ose Titrati o n P hase be gi n ni n g 
wit h  wee k 1.  Patie nts will ret ur n t o t he cli nic e ver y 2 w ee ks  t o assess f or efficac y a n d if i n di vi d ual 
patie nt d oses are t o b e titrate d u p war ds ( per Ta ble 1  a n d A p pe n di x 1 1. 8 ).  D uri n g t h e D ose T itrati o n 
P hase, t he patie nt’s t her a pe utic d ose will be i de ntifie d.  D oses s h o ul d n ot be i ncrease d b y m ore t h a n 
0. 5 m g.  D oses s h o ul d n ot be a dj uste d after t he d ose titrati o n p hase has bee n c o m plete d u nless 
disc usse d a n d a p pr o v e d b y t he S p o ns or.   
T a ble 1 : D ose Titr ati o n Sc he d ule  
D ose Titrati o n 
Wee k  
A d ult  
D ose ( m g)  
A d olesce nt  
D ose ( m g)  
Pe diatric  
D ose ( m g)  
1 -2  
1. 0  
0. 5  
0. 2 5  
3 -4  
1. 5  
1. 0  
0. 5  
5 -6  
2. 0  
1. 5  
1. 0  
7 -8  
2. 5  
2. 0  
1. 5  
9 -1 0  
3. 0 *  
2. 5  
2. 0  
1 1 -1 2  
N A  
3. 0 *  
2. 5  
* Ca n o nl y escalate t o 3. 0 m g if a p pr o ve d b y t he partici pati n g c o u ntr y’s c o m pete nt a ut h orit y, ot her wise t he 
ma xi m u m all o wa ble d ose is 2. 5 m g.   
F or patie nts w h o ma y h a ve reac he d t he m a xi m u m d ose b ut ha ve n ot l ost t he tar get w ei g ht as 
descri be d i n A p p e n di x 1 1. 8 , patie nts will be all o we d t o c o nti n ue i nt o t he 1 0- wee k o p e n la bel acti ve 
treat me nt p hase t o all o w t he patie nt t he o p p ort u nit y t o res p o n d.  
Alt h o u g h L E P R deficie nt patie nts ha ve n ot bee n treate d l o n g ter m wit h set mela n oti de, t here is li mite d 
l o n g ter m dat a i n t he t w o P O M C deficie nt patie nts.  T his data de m o nstrates t hat e ve n w he n B MI’s 
near n or m alizati o n, d ose re d ucti o ns ha ve pr o m pte d i ncreas es i n h u n ger sc ores u ntil t he res u m pti o n of 
t he i n di vi d ual patie nts i nitiall y deter mi ne d t h era p e utic d ose.  H o we v er, as e x perie nce is li mite d, 
d uri n g t he 3 2- wee k O pe n La b el Treat me nt P hase, if patie nts’ b o d y wei g ht n or malizes t o a n 
a p pr o priate l e vel (i.e. B MI < 2 7 f or a d ults or a n a ge a n d ge n d er val ue e q ui vale nt t o < 9 5 t h perce ntile f or 
pe diatrics or a d ol esce nts), a d ose re d u cti o n ma y be c o nsi dere d u p o n c o ns ultati o n wit h t he s p o ns or.    
5. 3.  Met h o d of Assi g ni n g P atie nts t o Tre at me nt 
Patie nts w h o q ualif y f or t he st u d y will ret ur n t o t h e site o n Da y  1 of t he d os e titrati o n p hase.  Pri or t o 
i nitiati n g o pe n la bel d ose titrati o n, t he I n v esti gat or will e ns ure t hat t he patie nt c o nti n ues t o meet 
i ncl usi o n a n d e x cl usi o n criteria, a n d p erf or m all pre- d ose pr o ce d ures.   
O nce t he pr e- d ose pr oce d ures ar e c o m plete d, t he patie nt dee me d eli gi ble f or t he st u d y, t he first d ose 
of set mela n oti de  will be a d mi nistere d  i n t he pres e nce of t he I n vesti gat or or t he I n v esti gat or’s researc h 
staff. 

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R hyt h m P h ar m ace utic als, I nc. 
Si nce t his is a n o pe n la bel st u d y, e x ce pt f or t he d o u ble- bli n d wit h dra wal peri o d, all patie nts will be 
assi g ne d t o acti ve treat me nt e x ce pt f or d uri n g t he d o u ble- bli n d wit h dra wal p hase.  
 
 

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R hyt h m P h ar m ace utic als, I nc. 
5. 4.  Bli n di n g, P ac k a gi n g, a n d L a beli n g 
 Bli n di n g  a n d Bre a ki n g t he Bli n d  
T his st u d y will be o pe n l a bel, e x ce pt f or t he 8- wee k d o u ble- bli n d, place b o c o ntr olle d varia bl y ti me d 
wit h dra wal peri o d.  Bli n di n g will be acc o m plis he d s o t hat all patie nts a n d st u d y- relate d staff re m ai n 
bli n de d t o st u d y dr u g a n d patie nt assi g n ati o n.   
T he I n vesti gat or, st u d y site staff, cli nical researc h or ga nizati o n staff pr o vi di n g site ma na ge me nt a n d 
Me dical M o nit or will n ot ha ve access t o t he act ual treat me nt se q ue n ce bei n g a d mi nistere d  d uri n g t he 
8- wee k d o u bl e- bli n d place b o c o ntr olle d p has e, e x ce pt i n t he case of a n e m er ge n c y.  Brea ki n g t h e 
bli n d f or a patie nt s h o ul d be d o ne o nl y i n t he e ve nt of a me dical e m er ge n c y w here t he i d e ntit y of 
st u d y dr u g is necessar y t o a p pr o priatel y treat t he patie nt.  T he re q u est t o brea k t he bli n d s h o ul d be 
disc usse d wit h t he Me dical M o nit or a n d R h yt h m, w he ne ver p ossi ble.  If t h e bli n d is br o ke n, t he 
reas o n, w h e n a n d h o w t h e bli n d was br o ke n will b e d oc u me nte d.  E v er y att e m pt will be ma de t o 
mai ntai n t he bli n d t hr o u g h o ut t he st u d y. 
 P ac k a gi n g a n d L a beli n g 
All st u d y dr u gs, i ncl u di n g place b o f or practice, will be s u p plie d b y R h yt h m. 
Pac ka gi n g a n d la b eli n g will be pre par e d t o meet all re g ulat or y re q uire me nts.  
5. 5.  D ur ati o n of P atie nt P artici p ati o n 
I n di vi d ual patie nt p artici pati o n i n t his st u d y ( Scree ni n g peri o d [ 2- 4 wee ks ], o pe n label d ose titrati o n 
peri o d [ 1 2 wee ks  ma xi m u m d urati o n ], o pe n la bel acti ve treat me nt [ 1 0 wee ks], d o u ble- bli n d place b o-
c o ntr olle d wit h dra w al peri o d [ 8 wee ks ], a n d o pe n la bel treat me nt  [ 3 2 wee k s]) will ra n ge b et wee n a 
mi ni m u m of a p pr o xi matel y 5 4 wee ks a n d a ma xi m u m of a p pr o xi matel y 6 6 wee ks, as c urre ntl y 
pla n ne d.    
Patie nts w h o ha ve ha d a p ositi ve res p o nse t o set mela n oti de after 1 year of treat me nt will ha ve t he 
o p p ort u nit y t o e nr oll i n a f ut ure, se para te, e xte nsi o n pr ot oc ol t o all o w f or c o nti n ue d treat me nt.  T his 
f ut ure e xte nsi o n pr ot oc ol will be s u b mitte d a n d a p pr o ve d b y a p plica bl e re g ulat or y a ut h orities pri or t o 
patie nts d osi n g be y o n d t his pr ot oc ol’s st u d y d urati o n.  
T he e n d of t he tri al will be defi n e d as t he last patie nt last visit.  
5. 6.  Assess me nt of Tre at me nt C o m pli a nce  
T o  e val uate t he s afet y, t olera bilit y, 
a n d p har mac o d y na mics of t he st u d y dr u g, it is 
critical t hat patie nts recei ve st u d y dr u g as directe d.  All use d st u d y dr u g will be  c ollecte d t o ass ess 
c o m plia nce wit h t he pr ot oc ol. 
Patie nts a n d/ or car eta kers will be re q uire d t o mai ntai n a st u d y dr u g di ar y t o m o nit or c o m plia nce.  I n 
a d diti o n, t he ti me of d osi n g will be r ec or d e d i n t he patie nt diar y.   
If a patie nt d o es n ot recei ve t he e ntire d os e of st u d y dr u g, t h e a m o u nt a d mi nistere d will be rec or de d.  
I n a d diti o n, t he reas o n(s) is t o be rec or d e d i n s o urce d oc u me nts a n d t h e C R F. 
A d diti o nall y, at all cli nic visits, a bl o o d sa m ple will be c ollecte d pri or t o d osi n g i n cli nic t o meas ure 
tr o u g h c o nce ntr ati o ns of set mela n oti de i n plas ma.   

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R hyt h m P h ar m ace utic als, I nc. 
5. 7.  St u d y Dr u g Acc o u nt a bilit y  
Acc o u nta bilit y f or t he st u d y dr u g at t he st u d y site is t he res p o nsi bilit y of t he I n vesti gat or.  T h e 
I n v esti gat or will e ns ure t hat t he st u d y dr u g is use d o nl y i n acc or da n ce wit h t his pr ot oc ol.  W here 
all o we d, t he I n vesti gat or ma y c h o ose t o assi g n dr u g acc o u nta bilit y res p o nsi bilities t o a p har macist or 
a not her a p pr o priate i n di vi d ual.  Dr u g acc o u nta bilit y rec or ds i n dicati n g t he d eli ver y date t o t he site, 
i n ve nt or y at t he site, use b y eac h p atie nt, ret ur n of all use d st u d y dr u g t o t h e st u d y ce nter, a n d ret ur n 
t o R h yt h m ( or dis p osal of t he dr u g, if a p pr o ve d b y R h yt h m) will be mai ntai ne d b y t h e cli nical site.  
T hese rec or ds will a de q u atel y d o c u me nt t hat t he p atie nts were pr o vi de d t he d oses as s pecifi e d i n t he 
pr ot oc ol a n d s h o ul d rec o ncile all st u d y dr u g recei ve d fr o m R h yt h m.  Reas o ns f or de part ure fr o m t he 
e x pecte d dis pe nsi n g r e gi me n m ust als o be rec or de d.  Acc o u nta bilit y rec or ds will i ncl u de dates, 
q ua ntities, batc h/serial n u m bers, e x pirati o n dates (if a p plica ble), a n d patie nt n u m bers.  T he S p o ns or 
or its desi g nee will re vie w dr u g acc o u nta bilit y at t he site d uri n g m o nit ori n g visits.  
All u n use d a n d use d st u d y dr u g will be ret ur ne d b y patie nts, a n d retai n e d at t he site u ntil i n ve nt orie d 
b y t h e m o nit or.  All u n us e d, use d or e x pire d st u d y dr u g will be ret ur ne d t o R h yt h m or if a ut h orize d, 
dis p ose d of at t he st u d y site a n d d oc u me nte d.   
5. 8.  Pri o r a n d C o nc o mit a nt Tre at me nt  
 Per mitte d Me dic ati o n  
Fe male p atie nts ma y use h or m o nal c o ntrace pti o n as well as h or m o ne re place me nt t hera p y.  
U nless c o nc o mita nt me di cati o ns are li kel y t o prese nt a str o n g p ote ntial safet y c o n cer n, t h e ge neral 
g oal of t his pr ot oc ol is t o all o w as ma n y as p ossi ble patie nts wit h t his ultra -rare c o n diti o n t o 
partici pate i n t he st u d y.  T her ef ore, p atie nts are all o we d c hr o nic c o nc o mita nt me dicati o ns (e. g., as 
descri be d b el o w) w hile p artici pati n g i n t he st u d y:    
a. Gr o wt h h or m o ne; 
b.  C o ntrace pti ves;  
c. H or m o ne re pl ace m e nt t hera p y;  
d.  A nti -h y p erte nsi ves;  
e. Stati ns  a n d ot her li pi d-l o weri n g t hera pies; 
f. T h yr o xi n e or ot her t h yr oi d s u p ple me nts; 
g.  Ot her me dicati o ns c o m m o nl y use d i n o bes e patie nts i ncl u di n g:  e n d ocri n e t hera pies 
(e. g., estr o ge ns, F osa m a x, h y dr o c ortis o ne, vita mi n a n d calci u m s u p ple me nts, dia betic 
t hera pies i ncl u di n g i ns uli n); a n d ot her me dicati o ns (e. g. , car nit ol, C oe nz y m e Q 1 0, 
vita mi ns, a nti -c o nsti pati o n me dicati o ns, a nti-aller gic me dicati o ns).   
h.  A part fr o m  l o w t hr es h ol d dr u gs (i.e.: a ntic o n v ulsa nts, di g o xi n, C o u ma di n, etc.), ot her 
me dicati o ns ma y b e per mitte d if o n a sta ble d ose u p o n c o ns ultati o n wit h t he S p o ns or.  
T here is little e vi de nce t hat set mela n oti de  will res ult i n dr u g i nteracti o ns at prese nt, b ut data is 
li mite d.  Patie nts a n d careta kers s h o ul d be caref ull y assess e d t o deter mi ne t hat p ote ntial patie nts are 
s pecificall y scree n e d t o d eter mi ne if sta ble d os es are e x pecte d d uri n g t he st u d y, a n d caref ull y war ne d 
of p ossi ble si de eff ects of dr u g i nteracti o ns t hat c o ul d occ ur wit h t he s pecific list of me dicati o ns t hat 
a n i n di vi d ual patie nt will be recei vi n g.   
Patie nts will be re mi n de d at eac h visit t hat if it bec o mes necessar y f or a pati e nt t o ta ke a n y ot her 
me dicati o n d uri n g t h e st u d y, fr o m Scree ni n g u ntil t he Fi nal St u d y Visit, t he y m ust i nf or m t he st u d y 

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R hyt h m P h ar m ace utic als, I nc. 
staff i m me diatel y, a n d t h e s pecific m e dicati o n(s) a n d i n dicati o n(s) m ust be disc usse d wit h t he 
I n v esti gat or.  All c o nc o mita nt me dicati o ns ta ke n d uri n g t he st u d y m ust be rec or de d i n t he s o urce 
d oc u me nts a n d o n t he C R F. 
 Pr o hi bite d Me dic ati o n a n d S u bst a nces  
Me dicati o ns t hat c o ul d i m pact t he efficac y assess me nts d uri n g t he st u d y are pr o hi bite d. 
A n orectic  a ge nts or dr u gs wit h a n ore xia as a n o n-rare si de effect are pr o hi bite d f or t he d urati o n of t he 
st u d y. 
 C o nc o mit a nt Pr oce d ures  
C o nc o mita nt pr oce d ures c o n d ucte d d uri n g t he st u d y, i ncl u di n g t h ose use d t o treat a d verse e v e nts, are 
t o be re p orte d o n t h e C R F. 

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R hyt h m P h ar m ace utic als, I nc. 
6.  S T U D Y A S S E S S M E N T S  
6. 1.  O ver vie w of Sc he d ule of Assess me nts  
T he Sc he d ule of Assess me nts ( S O A) t o be c o n d u cte d d uri n g t he st u d y are de picte d i n Ta ble s 6- 1A, 
6- 1 B a n d 6- 1 C .  
Alt h o u g h t he st u d y pr oce d ures a n d ass ess me nts re q uire d per pr ot o c ol a re cl assifie d as “ N o or 
Mi ni mal Ris k” ( a part fr o m  D E X A w hic h is classifie d as “ Mi n or I n crease o ver Mi ni mal Ris k”) per  
t he 2 0 0 8 G ui dance D oc u me nt “ Et hical C o nsi derati o ns f or Cli nical Trials o n Me dici nal Pr o d ucts 
C o n d ucte d wit h t he Pe diatric P o p ulati o n”, c o nsi d erati o ns f or re d uci n g pai n i n distress i n partici pa nts 
y o u n ger t ha n 1 8 years of a ge ar e i ncl u de d i n A p p e n di x 1 1. 1 1 .    
U p o n pr o vi di n g i nf or me d c o nse nt, patie nts will e nter t he Scree ni n g Peri o d.  D uri n g t h e Scree ni n g 
Peri o d, p atie nts will be assesse d f or  eli gi bilit y a n d i nstr ucte d t o c o m plete a h u n ger q uesti o n naire 
( A p pe n di x 1 1. 9 ) dail y  t o e n ha nce t he u n derst a n di n g of h u n ger ass o ciate d wit h L E P R deficie n c y, 
pri or t o treat me nt wit h set mela n oti de.  D uri n g S cree ni n g, a det aile d me dical hist or y will be o btai ne d, 
i ncl u di n g me dical c hart r e vie w ( A p p e n di x 1 1. 3 ), t o c ollect i nf or mat i o n pert ai ni n g t o t he nat ural 
hist or y of L E P R defici e n c y. 
After  t he Scr ee ni n g Peri o d i n w hic h c o nfir mati o n of patie nt eli gi bilit y a n d a bilit y f or p atie nts  or t heir 
caret a kers t o s uccessf ull y self -a d mi nister place b o  is deter mi ne d ( or if arra n ge me nts f or a visiti n g 
h o me healt h care pr actiti o ner ar e necessar y) , patie nts will e nter t he o pe n-la bel d ose titrati o n p hase.  
I n t his p has e, t he first d ose of set mela n oti de will be a d mi nistere d at t he start of D ose Titrati o n 
be gi n ni n g at w ee k  1.  Patie nts will ret ur n t o t he cli nic e ver y 2 w ee ks  f or t heir d oses t o be titrate d 
u p war ds ( p er  Secti o n 5. 2. 1  a n d A p pe n di x 1 1. 8 ).  D uri n g t h e dose titrati o n  p hase,  t he patie nt’s o pti mal 
d ose will be i de ntifie d , a n d d ose escal ati o n will st o p.   
O nce a p atie nt ’s t her a pe utic d ose is deter mi ne d, t h e patie nt will e nter a 1 0- wee k  o pe n l a bel acti ve 
treat me nt p hase.   
F oll o wi n g t he 1 0- wee k  o pe n la bel acti ve treat me nt p hase, patie nts will be gi n  t he 8- wee k d o u ble- bli n d 
place b o - c o ntr olle d wit h dra wal  peri o d w here patie nts will be assi g ne d t o  t h e 4- wee k se q ue n ce i n 
w hic h t he y recei ve place b o i n a d o u ble- bli n de d se q ue nce. T h e ke y o bjecti ve of t his p hase is t o 
i m ple me nt t he o nl y d o u ble- bli n d, place b o- c o ntr olle d peri o d f or t his st u d y t hat will i nf or m patie nt’s 
s y m pt o matic h u n ger a n d wei g ht c ha n ge res p o nses t o st o p pi n g a n d t he n restarti n g act i ve t hera p y wit h 
set mela n oti de wit h o ut a ware n ess of t he ti mi n g o f t he wit h dra wal.  Gi ve n t his s h ort, ma xi m u m 4-
wee k i nter v al, it is e x pecte d t hat all s u bjects will be a ble t o t olerat e a n d re p ort o n s y m pt o ms a n d 
wei g ht c ha n ges d uri n g t his d o u ble- bli n d, plac e b o-c o ntr olle d p hase.  If patie nts are n ot a ble t o t olerate 
t he a ntici pate d wei g ht gai n a n d ret ur n of s y m pt o ms of h u n ger, patie nts ma y be all o we d t o res u m e 
o pe n la bel acti ve treat me nt u p o n disc ussi o n a n d a gree me nt fr o m R h yt h m. A n y s u c h a gree me nt will 
be d oc u me nte d i n writi n g a n d a p pr o ve d b y R h yt h m pri or t o res u mi n g t he p atie nt o n acti ve treat me nt. 
T hereafter p atie nts will res u me o pe n la bel acti ve treat me nt f or a n a d diti o nal ~ 3 2 wee ks, f or a t otal of 
~ 5 2 wee ks of tr eat me nt at t he i n di vi d ual patie nt’s t hera pe utic d os e (i ncl usi ve of t he 4- w ee k place b o 
wit h dra wal).  
F oll o wi n g t he d os e titrati o n a n d 1 0- wee k o pe n la b el acti ve treat me nt p hases, o nl y patie nts w h o l ose 
at least 5 k g of wei g ht fr o m baseli ne  ( or 5 % if b aseli ne wei g ht < 1 0 0 k g), a n d w h o c o nti n ue t o s h ow 
t olera bilit y t o set mela n oti de, will c o nti n ue i nt o t he rest of t he st u d y. Patie nts w h o d o n ot e x hi bit t he 
re q uire d w ei g ht l oss will be wit h dra w n fr o m t he st u d y, a n d c o m plete t he E arl y T er mi nati o n Visit.   

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R hyt h m P h ar m ace utic als, I nc. 
F or patie nts w h o c o m plete t he st u d y b ut d o n ot wis h t o e nr oll i nt o t he f ut ure l o n g- t er m e xte nsi o n 
st u d y (as n ot e d i n Secti o n 5. 5), patie nts will be re q uire d t o ret ur n f or a Fi nal Visit ~ 3 0 da ys after t h e 
last d ose of set mela n oti d e, f or a fi nal f oll o w- u p safet y assess me nt.  A n y o n g oi n g A Es re p orte d at t his 
visit s h o ul d be m o nit ore d as o utli ne d i n Secti o n 7. 4.  F or patie nts w h o e nr oll i n t he f ut ure l o n g- t er m 
e xte nsi o n pr ot oc ol, t his visit is n ot re q uire d.   
A n y p atie nt wit h dra wi n g fr o m t he st u d y will c o m plete t he Earl y T er mi nati o n Visit, if p ossi ble, a n d 
wil l be e nc o ura ge d t o c o m plete all re mai ni n g st u d y visits .  F or t h ose p atie nts n ot willi n g t o c o m plete 
st u d y visits at t he cli nic, h o me healt h care practiti o ner visits or tele p h o ne f oll o w- u p ma y b e 
acce pta ble t o o btai n mi ni m u m patie nt self -re p ort e d data (i.e.: wei g ht, A E s, etc.).   
Detaile d descri pti o ns of t he safet y, P D  a n d  
 pr o ce d ures t o b e c o n d uct e d d uri n g t his st u d y are 
pr o vi de d i n t he secti o ns bel o w.  T he a m o u nt of bl o o d v ol u me t o be dra w n f or t hese pr o ce d ures is 
wit hi n t he acce pta ble li mits f or eac h vi sit a n d o ver t he d urati o n of t he st u d y ( A p pe n di x 1 1. 1 2).  
H o we ver, bl o o d dra ws m a y b e c h alle n gi n g i n t his p o p ulati o n of e xtre mel y o bese patie nts d ue t o p o or 
access t o t heir vei ns.  I n t hese i nsta nces, t he PI s h o ul d c o ntact t he Me dical M o nit or t o pri oritize 
sa m pli n g, wit h sa m ples b ei n g c ollecte d f or safet y t he hi g h est pri orit y.    
Patie nts will be re q uire d t o fast o ver ni g ht o n t he d a y prece di n g all visits, be gi n ni n g wit h t he i nitial 
Scree ni n g Visit.  Patie nts will be all o we d t o ta ke t heir us ual me dicati o ns wit h a si p of water o n t he 
m or ni n g of eac h cli nic visit.  
T he Scree ni n g Peri o d ca n occ ur wit hi n ~ 4 wee ks of Da y 1  a n d s h o ul d be s c he d ule d wit hi n t his 
ti mefra me t o all o w test r es ults t o be recei v e d a n d c o nti n ue d eli gi bilit y of p atie nts c o nfir me d pri or t o 
t he first d ose o n Da y 1. Assess me nts ma y o cc ur o ver m ulti ple da ys d uri n g t he Scree ni n g Peri o d.  All 
scree ni n g bl o o d w or k s h o ul d be c ollecte d b et wee n St u d y Da y -2 8 a n d - 1 4 i n or der t o e ns ure t he W H O 
ma xi m u m c u m ulati ve bl o o d v ol u mes are n ot e x cee de d o ver t h e c o urs e of t he st u d y. T o  o btai n 
s ufficie nt baseli ne d ata o n s y m pt o ms of h u n ger (c ollecte d dail y), t he scree ni n g peri o d s h o ul d be a 
mi ni m u m of t w o wee ks  a n d u p t o f o ur wee ks.   
T o  pr o vi de fle xi bilit y t o t he patie nt a n d st u d y staff f or t he n u m ber of cli nic visits, t he act ual 
sc he d uli n g of cli nic visits ca n all o w fle xi bilit y i n ti mi n g of visits.  D uri n g t he D ose Titrati o n p has e, 
t he g o al will be f or visits t o occ ur wit hi n +/ - 3 da ys.  B ut as t his patie nt p o p ulati o n is ultra-rare, all 
data c ollecte d , e ve n if o utsi de of visit wi n d o ws, will be i ncl u de d i n all a nal ys es of e n d p oi nts.  
A d diti o nall y, if t he patie nt resi des a c o nsi dera ble dista nce fr o m t he I n vesti gati ve Site, arra n ge me nts 
ma y b e ma de f or a h o me healt h practiti o ner t o c o n d uct a visit t o t he patie nt’s h o me or f or t he p atie nt 
t o be see n at t heir l o cal p h ysicia n’s office, t o o btai n t he a p plica ble d ata/sa m ples.  T hese arra n ge me nts 
m ust be a p pr o ve d b y t he S p o ns or i n a d va nce, t o b e s ure t hat i m p orta nt data/sa m ples ca n be pr o p erl y 
c ollecte d, a n d a n y saf et y pr oce d ur es r o b ustl y i m ple me nte d.   
H o we ver, patie nts m ust be see n at t he I n vesti gati v e Site at a n a bs ol ute mi ni m u m at least o nce f or 
Scree ni n g, f or a n y d ose titrati o n, start, mi d dle a n d e n d of t he d o u ble- bli n d place b o c o ntr olle d 
wit h dra wal peri o d, a n d at t he 6- m o nt h, 9- m o nt h a n d e n d of 1 year of treat m e nt ( pri mar y efficac y 
e n d p oi nt), a n d Earl y T er mi nati o n visits  (i.e.; Visits V 1, a n y V 2, V 3, V 5, V 6, V 7, V 8, V 1 0, V 1 1, a n d 
V 1 3 ).   
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
T a ble 6- 1 A: 
Sc he d ule of Assess me nts : Scree ni n g a n d D ose Titr ati o n #  

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
St u d y Peri o d  
Sc ree ni n g * *  
O pe n L a bel  
D ose Titr ati o n 6 
Pr oce d ure                      Visit N u m be r  ( V) 
V 1  
V 2 a 6 
St art of D os e Titr ati o n Wee k  
( D ose Titr ati o n St u d y D a y ± 3  d a ys)  
-4 t o 0  
(-2 8 t o -1)  
1  
( 1) 
 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
 
T a ble 6- 1 B: 
Sc he d ule of Assess me nts : 1 0 Wee k Acti ve Tre at me nt a n d 8 Wee k D o u ble -Bli n d 
Pl ace b o C o ntr olle d Wit h dr a w al  
 
St u d y Peri o d  
O pe n L a bel  
D o u ble Bli n d  
Acti ve Tre at me nt 7 
Pl ace b o -C o nt r olle d 
Wit h dr a w al
7 
Pr oce d ure                    Visit N u m ber ( V)  
St art of Wee k  
( St u d y D a y) 
V 3  
3 
( 1 5) 
V 4 *  
5 
( 2 9) 
V 5  
9 
( 5 7) 
V 6  
1 3  
( 8 5) 
V 7  
1 7  
( 1 1 3) 
P re g na n c y test  
X 4, 5 
X 4 , 5 
X 4 , 5 
X 4 , 5 
X 4 , 5 
P h ysical e xa mi n ati o n 1 
 
 
 
X 
 
Hei g ht 1 
 
 
 
X  
 
C o m pre h e nsi ve s ki n e xa m 2 
 
 
 
 
 
Wei g ht/ waist circ u mfere n c e
1 1  
X 5 
X 5 
X 5 
X 5 
X 5 
Arc hi ve sa m ple f or st ora ge 1 2  
 
 
 
X 5 
 
T hera pe utic D ose Esta blis h e d  
X 
 
 
 
 
St u d y treat me nt a d mi nistrati o n 1 3 
X 
X 
X 
X 
X 
I njecti o n site i ns p ecti o n1 4  
X  
X  
X  
X  
X  
Vital si g ns 1 5  
X 5 
X 5 
X 5 
X 5 
X 5 
E C G ( 1 2 -lea d)1 7  
 
 
 
X 5 
 
Safet y la b orat or y tests 1 8  
 
X 5 
 
X 5 
 
O G T T 2 8 
 
 
 
X 5 
 
Dail y H u n ger  Q u esti o n n aire 2 0 
X 5 
X 5 
X 5 
X 5 
X 5 
Gl o bal H u n ger Q u esti o ns 3 3 
 
 
 
X 5 
X 5 
B o d y C o m p ositi o n 2 3 
 
 
 
X 
 
A nti -R M -4 9 3 a nti b o d y sa m ples  
 
X 5 , 2 6 
 
X 5 , 2 6 
 
A d verse E ve nt assess me nt 2 5 
X  
X  
X  
X  
X  
C o nc o mita nt me ds re vie w  
X 
X 
X 
X 
X 
N utriti o n al c o u nseli n g a n d M o nit ori n g 3 6 
 
X 
X 
 
 
Tele p h o n e c o ntact  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O pti o n al S u b -St u di es  
 
 
 
 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
T a ble 6- 1 C: 
Sc he d ule of Assess me nts : A d diti o n al 3 2 Wee k O pe n L a bel Tre at me nt  
St u d y Peri o d  
O pe n L a bel  
E arl y 
Ter mi n ati o n/ Fi n al 
Visit 9 
Acti ve Tre at me nt 8  
Pr oce d ure                Visit N u m be r 
( V) 
St art of Wee k  
( St u d y D a y) 
V 8  
2 1  
( 1 4 1) 
V 9  
2 7  
( 1 8 3) 
V 1 0 *  
3 3  
( 2 2 5) 
V 1 1  
3 9  
( 2 6 7) 
V 1 2 *  
4 5  
( 3 0 9) 
V 1 3  
5 3  
( 3 6 5) 
 
P re g na n c y test  
X 4, 5 
X 4 , 5 
X 4 , 5 
X 4, 5 
X 4 , 5 
X 4, 5 
X 
P h ysical e xa mi n ati o n 1 
 
X  
 
 
 
X  
X  
Hei g ht 1 
 
X  
 
X  
 
X  
 
C o m pre h e nsi ve s ki n e xa m 2 
 
 
 
X 
 
X 
X 
Wei g ht/ waist circ u mfere n c e
1 1  
X 5 , 3 5 
X 5 , 3 5 
X 5 , 3 5 
X 5 , 3 5 
X 5 , 3 5 
X 5 , 3 5 
X  
Arc hi ve sa m ple f or st ora ge 1 2  
 
 
 
 
 
X 5 
 
St u d y treat me nt a d mi nistrati o n 1 3 
X 
X 
X 
X 
X 
X 
 
I njecti o n site i ns p ecti o n1 4  
X  
X  
X  
X  
X  
X  
 
Vital si g ns 1 5  
X 5 
X 5 
X 5 
X 5 
X 5 
X 5 
X  
E C G ( 1 2 -lea d)1 7  
 
X 5 
 
 
 
X 5 
 
Safet y la b orat or y tests 1 8  
 
X 5 
 
X 5 
 
X 5 
X  
O G T T 2 8 
 
 
 
 
 
X 5 
 
Dail y H u n ger Q u esti o n n aire 2 0 
X 5 
X 5 
X 5 
X 5 
X 5 
X 5 
X  
Gl o bal H u n ger Q u esti o ns 3 3 
X 5 
X 5 
 
 
 
X 5 
X 
B o d y C o m p ositi o n 2 3 
 
 
 
 
 
X 
 
A nti -R M -4 9 3 a nti b o d y sa m ples  
 
X 5 , 2 6 
 
X 5 , 2 6 
 
X 5 , 2 6 
X 5 , 2 6 
A d verse E ve nt assess me nt 2 5 
X 
X 
X 
X 
X 
X 
X 
C o nc o mita nt me ds re vie w  
X  
X  
X  
X  
X  
X  
X  
N utriti o n al c o u nseli n g a n d 
M o nit ori n g
3 6 
X 
X 
X 
X 
X 
X 
 
Tele p h o n e c o ntact  
X  
X  
X  
X  
X  
X  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
O pti o n al S u b -St u di es  
 
 
 
 
 
 
 
 

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R hyt h m P h ar m ace utic als, I nc. 
 
T a ble 6- 1: 
Sc he d ule of Ass ess me nts  F o ot n otes     
1  
A c o m plete p h ysical e xa mi nati o n will be c o n d ucte d at scree ni n g a n d at t he e n d of st u d y.  A b bre viate d 
p h ysical e xa ms will be c o n d ucte d o n i nter ve ni n g visits ( V 6 a n d V 9).  As part of t he c o m plete p h ysical 
e xa ms at scree ni n g a n d e n d of st u d y,
 Me narc he a n d me nstr ual 
hist or y will be o btai ne d i n all fe males.  A dre narc he sta gi n g will be perf or me d.  T estic ular v ol u mes will be 
d oc u me nte d b y t he Pra der met h o d ol o g y f or males, a n d breast de vel o p me nt will be d oc u me nte d f or 
fe males.  Hei g ht will be meas ure d d uri n g t he Scree ni n g Peri o d o nl y  f or t h ose patie nts ≥1 8 years of a ge.  
He i g ht will be meas ure d per  t he S O A  f or t h ose patie nts < 1 8 years of a ge. Hei g ht (c m) will be meas ure d, 
wit h o ut s h oes, s oc ks or hats acc or di n g t o t he S O A usi n g a wall- m o u nte d sta di o meter.  All meas ure me nts 
will be d o ne i n tri plicat e at eac h ti me p oi nt a n d rec or de d t o t he nearest 1 0 t h of a deci mal place.  T he 
sta di o meter s h o ul d be cali brate d at t he ti me of use or wit hi n t he pre vi o us f o ur h o urs.    
2  
A c o m pre he nsi ve s ki n e val uati o n will be perf or me d b y a der mat ol o gist.  A n y c o ncer ni n g lesi o ns 
i de ntifie d d uri n g t he scree ni n g peri o d will be bi o psie d a n d res ults k n o w n t o be be ni g n pri or t o first d ose 
of set mela n oti de.  If t he pre -treat me nt bi o ps y res ults are of c o ncer n, t he patie nt will be e xcl u de d fr o m t he 
st u d y.   
3  
O pti o nal s u b -st u dies f or I n vesti gati ve Sites t hat ca n perf or m t hese assess me nts a n d ha ve patie nts willi n g 
a n d a ble t o partici pate.  I n t he e ve nt a site ca n perf or m m ulti ple s u b-st u dies, care nee ds t o be ta ke n i n 
or der t o n ot o ver b ur de n wit h m ulti ple a d diti o nal assess me nts/ visits.    
4  
Uri ne pre g na nc y test ma y be perf or me d t o e x pe dite a vaila bilit y of res ults pri or t o d osi n g o n D ose 
Titrati o n Da y 1.  All ot her pre g na nc y tests will be ser u m ; d osi n g ma y c o nti n ue wit h res ults pe n di n g. 
5  
Pri or t o st u d y dr u g a d mi nistrati o n.    
6  
T he D ose Titrati o n p hase will be a varia ble sc he d ule lasti n g a mi ni m u m of 2 wee ks a n d a ma xi m u m of 1 0 
wee ks , i n w hic h patie nts will ret ur n t o t he cli nic a p pr o xi matel y e ver y 2 wee ks t o esta blis h t he i n di vi d ual 
pa tie nt’s t hera pe utic d ose per  A p pe n di x 1 1. 8 .  Gi ve n t he varia ble n u m ber of d ose titrati o n ste ps i n t he 
D ose Titrati o n P hase, eac h D ose Titrati o n Visit  N u m ber ( V) will re mai n V 2 wit h a n al p ha betize d s uffi x 
a d de d t o eac h titrati o n visit (i.e.; first d ose titrati o n at start of Wee k 1 = V 2a, sec o n d d ose titrati o n at start 
of Wee k 3 = V 2 b, etc.) .  T his will all o w f or t he Visits t o be  a p pr o priatel y trac ke d.  Ad diti o nall y, eac h 
d ose titrati o n visit will ha ve t he sa me pre- a n d p ost- d ose assess me nts as o utli ne d i n t he S O A  (e xce pt f or 
A nti - R M- 4 9 3 a nti b o dies a n d 
       
7  
O nce t he patie nt’s i n di vi d ual t hera pe utic d ose is esta blis he d t he patie nt will e nter t he O pe n La bel Acti ve 
Treat me nt p hase f or 1 0 a d diti o nal wee ks, f or a c o m bi ne d t otal of 1 2 wee ks of d osi n g at t he t hera pe utic 
d ose.  D uri n g t his ti me, t he st u d y cale n dar will be reset, starti n g w he n t he t hera pe utic d ose was i nitiate d 
(i.e. t he last 2 wee ks of d ose titrati o n w he n t he t hera pe utic d ose was esta blis he d).  T heref ore, t he O pe n 
La bel Acti ve Treat me nt p hase starts at t he be gi n ni n g of W ee k 3 ( V3). Patie nts l osi n g 5 k g of wei g ht ( or 
5 % if baseli ne wei g ht < 1 0 0 k g) at t he e n d of t he O pe n La bel Treat me nt p hase will e nter t he D o u ble-
Bli n d Place b o C o ntr olle d Wit h dra wal p hase lasti n g 8 wee ks.   
8  
U p o n c o m pleti o n of t he D o u ble- Bli n d  Place b o C o ntr olle d Wit h dra wal p hase, patie nts will res u me O pe n 
La bel Acti ve Treat me nt f or a n a d diti o nal ~ 3 2 wee ks.   
9  
Earl y T er mi nati o n : F or t h ose patie nts w h o wit h dra w c o nse nt or are wit h dra w n a n d n ot willi n g t o 
c o m plete t he re mai ni n g st u d y visits, t he earl y ter mi nati o n visit assess me nts s h o ul d be perf or me d, w he n 
p ossi ble.  A d diti o nall y, patie nts w h o wit h dra w a n d are n ot willi n g t o ret ur n f or t he re mai ni n g cli nic visits 
ca n be c o ntacte d via p h o ne, if a me na ble, t o c ollect self -re p orte d patie nt data (i.e.: wei g ht, h u n ger, A Es, 
etc.). Fi nal Visit : F or patie nts w h o c o m plete t he st u d y b ut d o n ot wis h t o e nr oll i nt o t he f ut ure l o n g- ter m 
e xte nsi o n st u d y (as n ote d i n Secti o n 5. 5), patie nts will be re q uire d t o ret ur n f or a Fi nal Visit ~ 3 0 da ys 
after t he last d ose  of set mela n oti de, f or a final f oll o w- u p safet y assess me nt.  A n y o n g oi n g A Es re p orte d at 

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t his visit s h o ul d be m o nit ore d as o utli ne d i n Secti o n 7. 4. F or patie nts w h o e nr oll i nt o t he l o n g -ter m 
e xte nsi o n st u d y, t his visit is n ot re q uire d.   
1 0  
1 1  Wei g ht is t o be meas ure d at t he cli nic usi n g t he sa me scale after patie nts ha ve e m ptie d t heir bla d der a n d 
w hile fasti n g.  Patie nts are t o wear li g ht cl ot hi n g or u n der wear, n o s h oes, a n d will be wei g he d at 
a p pr o xi matel y t he sa me ti me of da y.  Wei g ht meas ure me nts are t o be d o ne i n tri plicate; waist 
circ u mfere nce will be si n gle meas ures.  
1 2  E xtra retai n sa m ples will c o nsist of 2 ser u m a n d 2 plas ma ( K 2 E D T A) vac utai ner t u bes.  
1 3  St u d y dr u g is a d mi nistere d b y patie nts/careta kers be gi n ni n g t he m or ni n g of Da y 1 a n d f or t he d urati o n of 
d osi n g.  Patie nts/careta kers will dra w u p a n d self -a d mi nister/a d mi nister t he dr u g o nce dail y  i n t he 
m or ni n g. O n da ys wit h cli nic visits, t he patie nts/careta kers will a d mi nister t he dr u g i n t he cli nic i n t he 
prese nce of t he cli nical staff t o ass ure pr o per tec h ni q ue.  Patie nts/careta kers will ret ur n all use d vials t o 
t he cli nic w he n t he y visit (t he n u m ber rec or de d) a n d b ot h cli nic a d mi nistere d st u d y dr u g, as well as 
o ut patie nt st u d y dr u g a d mi nistrati o n will be rec or de d i n a st u d y diar y.   
1 4  I nj ecti o n site e val uati o ns a n d sc ori n g ( b y t he cli nical staff) will i ncl u de i de ntificati o n a n d meas ure me nt of 
areas of er yt he ma, e de ma a n d i n d urati o n, as well as t he prese nce of l ocalize d pai n, te n der ness a n d itc hi n g.  
A d diti o nal e val uati o n data ca n be c ollecte d at a n y visit w here t here are i njecti o n site reacti o ns e ve n if n ot 
a ti me p oi nt f or f or mal assess me nt.   
1 5  All B P a n d H R meas ure me nts are t o be o btai ne d i n t he sitti n g p ositi o n f oll o wi n g at least 5 mi n utes of 
rest.  All meas ure me nts will be ta ke n i n tri plicate, a p pr o xi matel y 2 mi n utes a part.  W he n p ossi ble, B P 
s h o ul d be ta ke n i n t he n o n- d o mi na nt ar m t hr o u g h o ut t he st u d y, usi n g t he sa me met h o d ol o g y (a ut o mate d 
or ma n ual) p er A p pe n di x 1 1. 7 .  B o d y te m perat ure (° C) a n d res pirati o n rate ( breat hs/ mi n ute) will be 
o btai ne d i n t he sitti n g p ositi o n f oll o wi n g at least 5 mi n utes of rest.   
1 6  D uri n g Da y 1  a n d f or a n y d ose titrati o n , vitals will be c ollecte d pri or t o d osi n g a n d t he n a p pr o xi matel y 
h o url y p ost- d ose f or u p t o 8 h o urs .     
1 7  A si n gle 1 2-lea d E C G will be perf or me d i n t he s u pi ne p ositi o n f oll o wi n g a peri o d of at least 1 0 mi n utes 
of rest. O n  da ys i n w hic h d ose titrati o n occ urs, meas ures will be o btai ne d pri or t o d osi n g a n d 
a p pr o xi matel y 8 h o urs p ost- d ose.  E C Gs will be c ollecte d el ectr o nicall y, i n tri plicate, at eac h 
ti me p oi nt, per  i nstr ucti o ns i n Secti o n 6. 4. 7 .  E C Gs will be i n a f or mat w here t he electr o nic c o p y 
ca n be pr o vi d e d f or ce ntr al rea di n g, if n ee de d  
1 8  Safet y la b orat ories will i ncl u de: C B C wit h platelet c o u nt a n d sta n dar d i n dices, c he mistr y pa nel  (i ncl u des 
s o di u m, p otassi u m, c hl ori de, C O 2, al b u mi n, t otal pr otei n, gl uc ose, B U N, creati ni ne, uric aci d, A S T, A L T, 
G G T, C P K, al kali ne p h os p hatase, t otal bilir u bi n, direct bilir u bi n, L D H, calci u m, p h os p h or us), uri nal ysis 
wit h micr osc o pic a nal ysis if p ositi ve fi n di n gs o n di pstic ks warra nt f urt her e xa mi nati o n.  Safet y 
la b orat ories s hall als o i ncl u de a c oa g ulati o n pr ofile ( pr ot hr o m bi n ti me [ P T] or i nter nati o nal n or malize d 
rati o [I N R], a n d partial t hr o m b o plasti n ti me [ P T T], als o referre d t o as acti vate d partial  t hr o m b o plasti n 
ti me [a P T T].  Fasti n g sa m ples ( 8 h o urs mi ni m u m) are re q uire d at all ti me p oi nts w here feasi ble.  
 a n d H b A 1c  will als o be i ncl u de d.  
1 9  

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2 0  Dail y  h u n ger q uest i o n naire sc ores will be assesse d b y as ki n g t he patie nt t o sc ore t hei r h u n ger
 Dai l y h u n ger 
q uesti o n nair e sc ores will be rec or de d dail y, pri or t o t he patie nt’s m or ni n g meal. 
2 1  
2 2  
2 3  B o d y c o m p ositi o n ma y be perf or me d usi n g a n a p pr o priate met h o d a vaila ble at sites (e. g. BI A, D X A, etc.)  
Refer  to S ecti o n 6. 3. 3  re gar din g a p pr o priate met h o d ol o g y f or assessi n g t his patie nt p o p ulati o n.  
2 4  O nce all t he pre -d ose assess me nts ha ve bee n perf or me d, t he decisi o n t o d ose titrate per A p pe n di x 1 1. 8  
will be ma de.  If t he pat ie nt’s t hera pe utic d ose has bee n esta blis he d, t he patie nt will tra nsiti o n i nt o t he 1 0-
wee k O pe n La bel Acti ve Treat me nt P hase, recei ve t heir t hera pe utic d ose, a n d c o m plete t he V 3 p ost - d ose 
assess me nts  as defi ne d i n t he S O A .  If t he patie nt’s t hera pe utic d ose has n ot bee n esta blis he d per  
A p pe n di x 1 1. 8 , t he patie nt will be a d mi nistere d st u d y dr u g, c o m plete t he d ose titrati o n p ost- d ose 
assess me nts  as defi ne d i n t he V 2 S O A , a n d ret ur n t o t he cli nic i n ~ 2 wee ks  f or t he ne xt se q ue ntial Visit 2 
(i.e.; V 2 b, V 2c, etc.). 
2 5  A d verse e ve nts will be rec or de d fr o m t he ti me a patie nt pr o vi des i nf or me d c o nse nt.  A E s re p orte d after 
d osi n g o n Da y 1 will be c o nsi dere d treat me nt-e mer ge nt A E s. 
2 6  A n y patie nts wit h p ositi ve a nti - dr u g a nti b o dies will be f oll o we d ~e ver y 3 m o nt hs u ntil titers res ol ve or 
ret ur n t o baseli ne. 
2 7  T ele p h o ne c o ntact b y site m o nt hl y, or m ore fre q ue ntl y, if nee de d.  
2 8  F oll o wi n g c ollecti o n of pre- meal (ti me 0) bl o o d sa m ples, patie nts will be gi ve n a sta n dar d oral gl uc ose 
t olera nce test. T he f oll o wi n g bl o o d sa m ples will be o btai ne d d uri n g eac h O G T T:  Bl o o d gl uc ose a n d 
i ns uli n at a p pr o xi matel y 3 0, 6 0 9 0 a n d 1 2 0 mi n utes after meal start.   O G T T will n ot be perf or me d f or 
s u bj ects wit h a dia g n osis of T y pe 1 or T y pe 2 dia betes. 
2 9  ~ 8 h o urs p ost- d ose o n Da y 1 o nl y. 
3 0  ~ 8 h o urs p ost- d ose.   
3 1  T o be c ollecte d  at St u d y Da y 1 5  a n d Da y 2 9 d uri n g t he d ose titrati o n p hase  (i.e. V 2 b a n d V 2c or V 2 b a n d 
V 3  if t he patie nt’s t hera pe utic d ose is esta blis he d at t he first d ose le vel)  
3 2  A bl o o d sa m ple will be o btai ne d at Scree ni n g f or ge n ot y pi n g f or mec ha nis ms c o nsi dere d t o be p ossi bl y 
relate d t o t he safet y or efficac y res p o nse t o t he st u d y me dicati o n (e. g., ot her o besit y relate d ge nes).   
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3 4  
3 5  F or  pe diatric patie nts, wei g ht will be meas ure d e ver y 2 - 3 wee ks bet wee n visits d uri n g t he a d diti o nal 3 2- 
wee k o pe n la bel treat me nt p hase, at t he patie nt’s h o me b y a pare nt or c are gi ver.   
3 6  F or pe diatric patie nts o nl y, N utriti o nal C o u nseli n g a n d M o nit ori n g will be perf or me d b y a n a p pr o priate 
dieticia n or n utriti o nist ( or e q ui vale nt) t o e ns ure t hat pe diatric patie nts ha ve a de q uate n utriti o nal/ dietar y 
i nta ke t o mai ntai n pr o per gr o wt h a n d de vel o p me nt.  A d diti o nal la b orat or y assess me nts i n dicati ve of 
n utriti o nal stat us ma y be m o nit ore d, as a p pr o priate (e. g. al b u mi n, vita mi n D, t otal l y m p h oc ytes a n d 
I G F 1). 
3 7  C ollect bet wee n 8 a n d 1 0 a m 
3 8  
  
# 
O nce a patie nt’s t hera pe utic d ose has bee n esta blis he d acc or di n g t o A p pe n di x 1 1. 8 , n o f urt her d ose 
titrati o ns will occ ur, a n d patie nts will tra nsiti o n directl y i nt o t he 1 0 wee k O pe n La bel Acti ve Treat me nt 
p hase.  T heref ore , t he D ose Titrati o n p hase will be a mi ni m u m of 2 wee ks a n d a ma xi m u m of 1 0 wee ks.  
* 
F or patie nts t hat resi de a c o nsi dera ble dista nce  fr o m t he cli nic, t hese visits are o pti o nal cli nic visits , a n d 
ma y be perf or me d b y t he patie nt’s l ocal p h ysicia n or h o me healt h care pr ofessi o nals.  
+ 
If t he visit is perf or me d b y a h o me healt h care pr ofessi o nal, assess me nt ma y be perf or me d at t he ne xt 
sc he d ule i n cli nic visit. 
^  
F or patie nts e nr olle d i n Fra nce, t he 
are 
c o m p uls or y, a n d n ot o pti o nal. 
†  
T est n ot c o n d ucte d at t his visit f or patie nts 6 t o 1 1 years.  
* *   All scree ni n g bl o o d w or k s h o ul d be c ollecte d bet wee n St u d y Da y - 2 8 a n d - 1 4 i n or der t o e ns ure t he W H O 
ma xi m u m c u m ulati ve bl o o d v ol u mes are n ot e xcee de d o ver t he c o urse of t he st u d y.  
 

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R hyt h m P h ar m ace utic als, I nc. 
6. 2.  P ati e nt Re q uire me nts  
 C o ntr ace pti o n  
Set mela n oti de  has n ot bee n c o m pletel y e val u ate d i n n o n cli nical De vel o p m e ntal a n d 
Re pr o d ucti ve T o xic ol o g y St u dies t o date; t heref ore, t he effects of set mela n oti de o n e m br y o-fet al 
de vel o p me nt ar e u n k n o w n at t his ti me.  It is i m perati ve all st u d y patie nts a d here t o t he 
c o ntrace pti o n re q uire m e nts as o utli ne d bel o w.   
Fe males m ust n ot be pr e g na nt a n d m ust ha ve a n e gati ve s er u m pre g n a nc y t est res ult at t he 
Scree ni n g Visit a n d ne gati ve uri ne pre g n a nc y test o n Da y 1 , wit h res ults k n o w n pri or t o i nitiati n g 
d osi n g; pre g n a nc y testi n g will be m o nit ore d d uri n g t he st u d y.  
F or f e male s w h o are a ble t o bear c hil dre n, a hi g hl y relia ble f or m of c o ntrace pti o n m ust be 
use d/ practice d t hr o u g h o ut t he st u d y a n d f or 9 0 da ys f oll o wi n g t he st u d y.  Hi g hl y relia bl e 
acce pta ble f or ms  of c o ntr ace pti o n i ncl u de: h or m o n al (i.e., oral, i m pla nta ble, or i njecta ble) w he n 
use d t o get h er wit h a si n gle- barri er met h o d (i.e. c o n d o m), or an I ntra uteri ne De vice (I U D) w he n 
use d t o get h er wit h a si n gle-barri e r met h o d (i.e. c o n d o m) or vasect o mize d part ner.   Tr ue 
a bsti ne nce is acce pta bl e o nl y if it is t he preferre d a n d us ual lifest yl e of t he patie nt . 
Fe males of n o n -c hil d beari n g p ote ntial, defi n e d as s ur gicall y sterile (stat us p ost h ysterect o m y, 
bilateral o o p h orect o m y, or bi lateral t u bal li gati o n) p ost- me n o pa usal f or at least 1 2 m o nt hs (a n d 
c o nfir me d wit h a scree ni n g F S H le vel i n t he p ost- me n o pa usal ra n ge), or d ela ye d p u bertal 
de vel o p me nt a n d f ail ure t o ha ve ac hi e ve d me narc he, d o n ot re q uire c o ntrace pti o n d uri n g t h e 
st u d y.  Yo u n ger fe m ale p atie nt s w h o are n ot se x uall y mat ure will be assesse d f or Ta n ner sta gi n g 
a n d a d vise d acc or di n gl y.   
It is n ot k n o w n if t his treat me nt will affect s p er mat o ge n esis.  T heref ore, m ales wit h fe male 
part ners of c hil d beari n g p ote ntial m ust a gree t o us e c o ntrace pti o n (e. g., if t he y h a ve n ot ha d a 
vasect o m y t he n s h o ul d eit her (a) a bstai n fr o m re pr o d ucti ve se x ual i nterc o urse or ( b) us e a d o u ble 
barrier m et h o d (i.e., c o n d o m a n d dia p hra g m a n d s per mici de ) if t he y b ec o m e se x uall y acti ve 
d uri n g t he st u d y a n d f or 9 0 da ys f oll o wi n g t he st u d y. Male patie nt s m ust n ot d o nate s per m f or 9 0 
da ys f oll o wi n g t heir p arti ci pati o n i n t he st u d y.  
 Pr otecti o n f r o m S u n  
S ki n h y p er pi g me ntati o n, or ta n ni n g, was o bser v e d i n t he c y n o m ol g us m o n k e y t o xic ol o g y 
st u dies, a n d t he h u ma n P hase 1  a n d P hase 2 st u dies.  T hese e ve nts w ere re v ersi ble u p o n 
cessati o n of st u d y dr u g.  H o we ver, it is still u ncertai n if e x p os ure t o s u nli g ht mi g ht e x acer bat e 
t he ta n ni n g eff ects of set mela n oti de. 
It is als o i m p orta nt t hat p atie nts d o n ot partici pate i n a n y acti vities t hat will i nte nti o nall y ca us e 
t heir s ki n t o ta n (e. g.; visit ultra vi olet (U V ) ta n ni n g sal o ns, use s pra y ta n n ers, self-ta n ni n g 
l oti o ns, etc.). 
6. 3.  Effic ac y Me as ure me nts  
 Wei g ht 
Wei g ht ( k g) will be r ec or de d as s h o w n i n t he S O A , a n d ge nerall y will be assesse d a n d rec or d e d 
e ver y t w o w ee ks d uri n g t he earlier p hases of t he st u d y .  All meas ure me nts will be d o ne i n 
tri plicate at eac h ti me p oi nt.  W he ne ver p ossi ble, t he sa me scale s h o ul d be use d t hr o u g h o ut t he 

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R hyt h m P h ar m ace utic als, I nc. 
st u d y, i ncl u di n g t h e Scree ni n g Visit, a n d s h o ul d b e cali brat e d o n a re g ular basis.  Wei g ht s h o ul d 
be meas ur e d w he n p atie nts are fasti n g a n d at a p pr o xi matel y t he sa m e ti me at eac h visit.  Patie nts 
s h o ul d be i n li g ht cl ot hi n g or u n d er w ear , wit h n o s h oes a n d ha ve e m ptie d t heir bla d der.    
F or pe diatric patie nts, wei g ht will be meas ure d m ore fre q ue ntl y d uri n g t he A d diti o nal 3 2- wee k 
O pe n La bel Treat me nt P hase as s h o w n i n t he S O A, at t he patie nt’s h o me.  F or t hese h o m e 
meas ure me nts, t he p are nt or car e gi ver s h o ul d be i nstr ucte d t o f oll o w t he sa me pr oce d ures n ote d 
a b o ve 
 W aist Circ u mf ere nce  
Waist circ u mfere n ce ( c m) will be meas ure d acc or di n g t o t he Nati o nal H eart, L u n g, a n d Bl o o d 
I nstit ute (N H L BI ) criteri a [N H L BI 2 0 0 0 ] d uri n g t he st u d y as s h o w n i n t he S O A .  All 
meas ure me nts will be si n gle meas ures.  W he ne v er p ossi ble, t he sa me st u d y staff me m ber s h o ul d 
perf or m t he meas ure m e nt f or a gi ve n patie nt t o mi ni mize varia bilit y.  Waist circ u mfere nce 
s h o ul d be meas ure d w he n patie nts are fasti n g a n d at a p pr o xi matel y t he sa me ti me at eac h visit.  
Patie nts s h o ul d be i n li g ht cl ot hi n g a n d ha v e e m ptie d t heir bla d der. 
 B o d y C o m p ositi o n   
Partici pa nts will ha ve b o d y c o m p ositi o n meas ure me nts perf or me d usi n g a n a p pr o priate 
met h o d ol o g y t hat is a vail a ble at t he site (e. g.: D X A sca ns, bi oelectrical i m pe da nce ( BI A), etc.) 
o ve r t he c o urse of t he st u d y.   
F or D X A  met h o d ol o g y, w hic h  uses l o w d ose x-ra ys t o n o n-i n vasi vel y ass ess s keletal a n d s oft 
tiss ue de nsit y, half- b o d y sca ns ma y be p erf or me d f or patie nt s t hat e xte n d be y o n d t h e sca n ni n g 
area. T he ris k ass o ciate d wit h e x p os ure t o i o nizi n g ra diati o n is mi ni mal a n d f urt her mi ni mize d 
t hr o u g h t he e x cl usi o n of pre g na nt w o me n.  If pati e nts are se v erel y o b ese a n d ca n n ot be meas ure d 
i n t he D X A sca n n er a v aila ble d ue t o practical li mitati o ns (size of D X A mac hi ne), t he n ot her 
met h o d ol o gies s h o ul d be c o nsi dere d (i. e., BI A ).  If D X A is a vaila bl e b ut patie nts are t o o lar ge t o 
e nter at Scr ee ni n g, D X A s h o ul d be a d de d at a ti me w he n patie nts ma y ha v e l ost e n o u g h w ei g ht 
t o d o a de q uate D X A meas ure me nts (as D X A ma y pr o vi de a d diti o nal i nf or mati o n a b o ve BI A, f or 
e x a m ple) i n a d diti o n t o t he met h o d ol o g y use d at Scree ni n g.   
If b o d y c o m p ositi o n i nstr u me nts are n ot a v aila ble at a s pecifi c site, a n d arra n ge m e nts ca n n ot be 
ma de t o o btai n t hese meas ure me nts, t he s p o ns or m a y wai ve t he re q uire me nt f or b o d y 
c o m p ositi o n meas ure me nts at t hat site.   
6. 4.  Cli nic al Pr oce d ures a n d S af et y Assess me nts  
 I nf or me d C o nse nt/ Asse nt 
A c o m plete descri pti o n of t he st u d y is t o be prese nte d t o eac h p ote ntial pati e nt a n d si g n e d a n d 
date d i nf or me d c o nse nt a n d/ or Asse nt is t o be o btai ne d bef ore a n y st u d y s pecific pr oce d ures are 
perf or me d.   
 De m o gr a p hics a n d Me dic al Hist or y  
A c o m plete me dical  hist or y al o n g wit h de m o gra p hic data will be o btai ne d f or all patie nts d uri n g 
t he Scree ni n g Peri o d.  D ata t o be rec or d e d i n t he s o urce d oc u m e nt a n d C R F i ncl u de t he p atie nt’s 
ge n d er, r ace, date of birt h a n d c o nc o mita nt me dicati o n use. A d diti o nall y, a detaile d re vie w of t he 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
patie nt’s me dical r ec or ds will be perf or me d t o c ollect i m p orta nt retr os p ecti ve data t o better 
u n dersta n d t he nat ur al hist or y of L E P R deficie nc y  per  A p pe n di x 1 1. 3 . 
A rece nt me dical hist or y will be o btai ne d o n Da y 1 pri or t o first d ose of dr u g t o assess c o nti n ue d 
st u d y eli gi bilit y a n d a d h ere nce t o fi nal i ncl usi o n/e x cl usi o n criteria.  T his rece nt me dical hist or y 
i ncl u des a re vi e w f or c ha n ges fr o m scree ni n g as w ell as a re vi e w of t he p atie nt’s rece nt 
me dicati o n use a n d t o ass ess w het her  a n y c h a n ges ha ve occ urre d si nce t he pre vi o us visit.  
 P h ysic al E x a mi n ati o n, C o m pre he nsi ve S ki n E x a mi n ati o n, a n d Hei g ht 
P hysic al Ex a mi n ati o ns 
A c o m plete p h ysical e x a mi nati o n will i ncl u de re vie w of peri p h eral l y m p h n o des, hea d, e yes 
(i ncl u di n g c o nj u n cti va), ears, n ose, m o ut h a n d or o p har y n x, nec k, heart, l u n gs, a b d o m e n, 
m usc ul os keletal i ncl u di n g bac k, e xtre mities a n d n e ur ol o gi c assess me nts .  
All p h ysical e x a mi nati o ns are t o be c o n d ucte d i n a de q uate li g ht.   
C ha n ges  fr o m bas eli ne i n a n y p h ysi cal e x a mi nati o n fi n di n gs i de ntifie d b y t he I n vesti gat or as 
cli nicall y si g nifica nt m ust be rec or de d as a n A E o n t he a p pr o priat e C R F.  
C o m pre he nsive S ki n Ex a mi n ati o ns 
C o m pre he nsi ve s ki n e x a mi nati o ns will be perf or me d b y a Der m at ol o gist.   
T he I n vesti gat or will i de ntif y a D er mat ol o gist t o ser ve as a c o ns ulta nt f or t he I n vesti gati ve Site.  
Eac h patie nt will recei ve a c o m plete, c o m pre he nsi ve s ki n e x a m as part of Scree ni n g, pri or t o a n y 
set mela n oti de treat me nt.  A n y at y pi cal lesi o ns s h o ul d be c o nsi dere d f or bi o ps y pri or t o st u d y 
start.  T he der m at ol o gist will c o nti n ue t o m o nit or eac h p atie nt, perf or mi n g c o m pre he nsi ve s ki n 
e x a mi nati o ns as o utli ne d i n t he Sc he d ule of Assess me nts.   
I n t he e ve nt a p atie nt e x perie nces c ha n ges t o s ki n or s ki n lesi o ns t hat are u nres ol ve d ( or h a ve n ot 
si gnifica ntl y i m pr o ve d or are cl os e t o res ol uti o n) at t he e n d of st u d y , t h e patie nt ma y b e as ke d t o 
ret ur n f or a d diti o nal f oll o w u p assess me nts t o d oc u me nt pr o gress t o war ds res ol uti o n. 
Hei g ht 
Hei g ht ( c m) will be meas ure d, wit h o ut s h oes, s oc ks or hats per  t he S O A  usi n g a wall- m o u nte d 
sta di o meter.  All meas ur e me nts will be d o ne i n tri plicate  at eac h ti me p oi nt  a n d rec or de d t o t he 
nearest 1 0 t h of a deci mal place .  T he st a di o meter s h o ul d be cali brate d at t he ti me of use or wit hi n 
t he pre vi o us f o ur h o urs. 

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R hyt h m P h ar m ace utic als, I nc. 
 Fit z p atric k Sc ale  
Eac h patie nt is t o be cate g orize d f or s ki n t y pe acc or di n g t o t he Fitz patric k scale [ Fitz patric k ].  
T he Fitz patric k Scale is d e picte d i n A p pe n di x 1 1. 2 . 
 C o nc o mit a nt Me dic ati o n Re vie w  
A re vie w of c o nc o mita nt me dicati o ns will be c o n d ucte d d uri n g t he Scree ni n g Peri o d a n d at e ver y 
st u d y visit.  A n y me di cati o ns ta ke n b y st u d y patie nts will be recor de d i n s o urce d oc u m e nts a n d 
o n t he a p pr o priat e C R F. 
 Vit al Si g ns  
Vital si g ns will be o btai n e d i n t he sitti n g p ositi o n f oll o wi n g at least 5 mi n utes of rest eac h ti me 
t he y are meas ure d p er  t h e S O A .   
Bl o o d press ure a n d he art r ate 
Bl o o d press ur e ( B P; m m H g) a n d heart rat e ( H R; b p m) will be perf or m e d usi n g t he sa me 
met h o d ol o g y t hr o u g h o ut t he st u d y ( ma n u al or a ut o mate d) as o utli ne d i n A p pe n di x 1 1. 7 .  S pecial 
atte nti o n s h o ul d be pai d t o e ns ure t he a p pr o priat e c uff size i n t his patie nt p o p ulati o n, as n ote d i n 
t he A p pe n di x . 
Re peat meas ur es a n d m ore fr e q ue nt m o nit ori n g ca n be i m ple me nte d f or si g nifica nt i ncreases i n 
B P or H R.   
T o all o w f or a tr o u g h bl o o d press ure rea di n g, t he patie nt s h o ul d be i nstr ucte d n ot t o ta ke t he 
st u d y me dicati o n o n st u d y da ys w he n vital si g ns are t o be meas ure d  i n t he cli nic. 
B o dy te m per at ure a n d r es pir ati o n r ate 
B o d y te m per at ure (° C) a n d res pirati o n rat e ( breat hs/ mi n ute) will be o btai ne d i n t he sitti n g 
p ositi o n f oll o wi n g at least 5 mi n utes of rest.  
 1 2- Le a d Electr oc a r di o gr a m  
Si n gle 1 2- lea d electr ocar di o gra ms will be p erf or m e d f oll o wi n g a peri o d of at least 1 0 mi n utes of 
rest i n t he s u pi ne p ositi o n.  O n da ys w he n d oses are titrate d, E C Gs will be o btai ne d pri or t o 
d osi n g, a n d at ~ 8 h o urs p ost- d ose. 
E C G Pr oce d ures  
All E C Gs s h o ul d be perf or me d i n tri plicate per  t h e Sc he d ule of Assess me nts wit h t he f oll o wi n g 
g ui deli nes: 
•  E C G tec h nicia ns s h o ul d be t h or o u g hl y trai ne d i n t he a d mi nistrati o n of a 1 2- Lea d E C G, 
t he i nstit uti o n’s s pecific pr ot oc ols a n d pr oce d ures f or E C G tests a n d t he re q uire me nts of 
t he st u d y pr ot oc ol.   
•  E C G e q ui p me nt s h o ul d be m o der n e q ui p me nt wit h t he ca pacit y f or di gital si g nal 
pr ocessi n g t o all o w f or ce ntral rea di n g.  T he sa m e ma ke a n d m o del of E C G mac hi ne wit h 
t he sa me st yl e of lea ds s h o ul d be use d f or all patie nts.  S uc h e q ui p me nt s h o ul d be 

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R hyt h m P h ar m ace utic als, I nc. 
rece ntl y ser vice d a n d cali brate d. Mac hi ne cali brati o n rec or ds a n d perf or ma nce data 
s h o ul d be mai ntai ne d o n file.   
•  Patie nts s h o ul d be i n a s u pi ne p ositi o n a n d ha ve reste d f or 1 0 mi n utes. 
•  E C Gs at eac h pr ot oc ol ti me p oi nt s h o ul d be rec or d e d i n tri plic ate, wit h at least 1 mi n ute 
bet wee n r ec or di n gs.  
Re a di n g E C Gs 
Site m o nit ori n g:  
Sites s h o ul d rea d E C Gs f or st u d y m o nit ori n g a n d C R Fs per t heir us ual pr o ce d ures. 
Ce ntral Rea di n g:  
R h yt h m ma y elect, if n ee de d f or r e g ulat or y reas o ns, t o c ollect E C Gs f or ce ntral rea di n g.  If s o, 
t he i nte nti o n will be t hat a si n gle Ce ntral rea der will rea d all E C Gs.  T heref ore, all E C Gs m ust be 
a vaila ble a n d st or e d electr o nicall y f or t his p ur p ose.  W he n se nt f or Ce ntral rea di n g, t he E C Gs 
m ust be pre par e d t o be r ea d i n a bli n de d fas hi o n.  Ce ntral r ea d ers of E C Gs s h o ul d be bli n de d t o 
ti me, treat me nt a n d s u bject i de ntifier.  
 Cli nic al L a b or at or y Tests 
All scree ni n g bl o o d w or k s h o ul d be c ollecte d bet w ee n St u d y D a y - 2 8 a n d - 1 4 i n or der t o e ns ure 
t he W H O ma xi m u m c u m ulati ve bl o o d v ol u mes are n ot e x cee de d o v er t he c o urse of t he st u d y. 
Cli nical safet y l a b orat or y tests are t o be perf or m e d b y t he l ocal la b orat or y a n d patie nts are t o be 
fasti n g f or 8 h o urs.  La bs are t o be dra w n pri or t o d osi n g.  
All cli nicall y si g nifica nt la b orat or y a b n or malities will be f oll o we d - u p b y re peat testi n g a n d 
f urt her i n vesti gate d p er  t he j u d g me nt of t h e I n vesti gat or.   
Li ver f u ncti o n test a b n or malities will be e val uate d i n acc or d a nce wit h F D A G ui da nce ( 2 0 0 9 ) as 
descri be d i n t he A p p e n di x 1 1. 6 .   
S pecific tests ar e descri be d bel o w.  
6. 4. 9. 1.  He m at ol o gy, Cli nic al  C he mistry a n d Uri n alysis  
He mat ol o g y a n d cli nical c he mistr y s a m ples will be c ollecte d i n t he faste d state.  
He m at ol o gy: 
C o m plete bl o o d c o u nt wit h platelet c o u nt a n d sta n dar d i n dices will be o btai ne d. 
C he mistry:  
S o di u m, p otassi u m, c hl ori de, C O 2, al b u mi n, t otal pr otei n, gl uc os e, bl o o d urea nitr o ge n ( B U N), 
creati ni ne, uric aci d, as partate a mi n otra nsferas e ( A S T), ala ni ne a mi n otra nsferase ( A L T), ga m ma -
gl uta m yltra ns pe pti das e ( G G T), creati ne p h os p h o ki nase ( C P K), al kali ne p h os p hatase, t otal 
bilir u bi n, direct bilir u bi n, lactate de h y dr o ge nas e ( L D H), calci u m a n d p h os p h or us. 
C o a g ul ati o n pr ofile:    
Pr ot hr o m bi n ti me ( P T)  or i nter nati o nal n or malize d rati o (I N R), a n d partial t hr o m b o plasti n ti me 
( P T T), als o referr e d t o as acti vate d partial t hr o m b o plasti n ti me (a P T T). 

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R hyt h m P h ar m ace utic als, I nc. 
Uri n alysis:  
p H, gl uc os e, pr otei n, ket o nes, bilir u bi n, bl o o d, ur o bili n o ge n, s pecific gra vit y, nitrite, a n d 
le u k oc yt es b y di pstic k a n al ysis or mac hi ne uri nal ysis.  Uri ne micr osc o pic e x a mi nati o n will be 
perf or me d if p ositi ve fi n di n gs o n di pstic ks warra nt f urt her e x a mi nati o n. 
6. 4. 9. 2.  
 a n d H b A 1 c: 
  Bl o o d sa m ples will nee d t o be c ollecte d w he n t h e 
patie nt is i n  t he faste d state. 
H b A 1 c le vels will be meas ure d as o utli ne d i n t he S O A . 
 Or al Gl uc ose T oler a nce Test ( O G T T)  
O G T T will be perf or me d t o e val uate st u d y dr u g effects o n p ost pra n dial gl u c ose a n d i ns uli n.  A 
baseli ne O G T T will be perf or me d a n d a f oll o w- u p O G T T will be c o n d u ct e d per t he S O A.  A n 
o ver ni g ht fast of at least 8 h o urs i n d urati o n is re q uire d pri or t o a d mi nistrati o n of t he O G T T.  
F oll o wi n g c ollecti o n of pre- meal (ti me 0) bl o o d sa m ples, patie nt s will be gi ve n a sta n dar d O G T T 
meal. O G T T will n ot be perf or me d f or s u bjects wit h a dia g n osis of T y p e 1 or T y p e 2 dia bet es.  
T he f oll o wi n g bl o o d sa m ples will be o btai ne d d uri n g eac h M T T: 
•  Bl o o d gl uc ose:  Ti me 0 ( pre- meal) a n d a p pr o xi matel y 3 0, 6 0, 9 0 a n d 1 2 0 mi n utes after meal 
start. 
•  Bl o o d i ns uli n:  Ti me 0 ( pre- meal) a n d a p pr o xi matel y 3 0, 6 0, 9 0 a n d 1 2 0 mi n utes after meal 
start. 
H o me ostasis M o del of Assess me nt – I ns uli n Resista nce ( H O M A-I R) will be calc ul ate d usi n g t h e 
fasti n g gl uc os e a n d i ns uli n le vels o btai ne d as part of t he M T T. 

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R hyt h m P h ar m ace utic als, I nc. 
6. 4. 1 2. 1.  
S a m pl es f or St or a ge / Arc hive 
E xtra re tai n sa m ples will be use d i n t he e ve nt t hat u nsc he d ule d dia g n ostic t ests are re q uire d f or 
safet y reas o ns, or f or a d diti o nal
 t hat are c urre ntl y n ot d efi ne d b ut are directl y relate d 
t o t he ai ms of t his st u d y.  T hese sa m ples will be retai ne d u ntil t he st u d y has bee n c o m plete d, a n d 
u ntil t he S p o ns or has n otifie d t he st u d y site i n writi n g t hat t he sa m ples ca n be discar d e d. 
 I njecti o n Site E v al u ati o n a n d Sc ori n g 
I njecti o n sites will be car ef ull y i ns pecte d, e v al uate d a n d sc ore d d uri n g t he st u d y peri o d. T h e 
i njecti o n site e val uati o n will i ncl u de i de ntificati o n a n d meas ure me nt of areas of er yt h e ma, e d e ma 
a n d i n d urati o n, as well as t he prese n ce of l ocalize d pai n, te n der ness a n d itc hi n g.  A sa m ple 
i njecti o n site e val uati o n f or m is i ncl u de d i n A p pe n di x  1 1. 1 . 
I n a d diti o n, u nsc he d ule d e val uati o ns ma y als o be rec or de d as warra nt e d b y cli nical c o n diti o ns. 
 A nti -R M - 4 9 3 A nti b o d y ( A D A) Me as ure me nts  
Bl o o d sa m ples f or meas ure me nt of a nti- R M -4 9 3 a nti b o dies  will be c ollecte d pri or t o d osi n g, a n d 
t he n at t he ti me- p oi nts i de ntifie d i n t he S O A.  A n y patie nt wit h a  p ositi ve titer will be f oll o we d 
u ntil res ol uti o n.   
 P ati e nt Q uesti o n n aires  
T he patie nt q uesti o n naires will be a ns were d b y t he patie nt a n d/ or careta k e r after caref ul trai ni n g. 
H u n ger Sc ores 
H u n ger will be ass esse d usi n g a d ail y q uesti o n naire as w ell as a set of t w o gl o bal q uesti o ns per 
t he S O A. 
Gl o b al H u n ger Q uesti o ns:  T w o gl o bal q uesti o ns will be as ke d at certai n st u d y visits per t he 
Sc he d ule o f Assess me nts.  F or patie nts ≥1 2 years of a ge, t he p atie nt will a ns wer t he q uesti o ns 
t he msel ves. 

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R hyt h m P h ar m ace utic als, I nc. 
D aily H u n ger Q uesti o n n aire :  H u n ger will be ass esse d dail y i n all patie nts. 
F or patie nts ≥1 2 years of a ge , a set of three q u esti o ns will be as ke d  usi n g 
 
 
T he dai l y h u n ger q u esti o n naire will be c o m plete d dail y, pri or t o d osi n g i n t he m or ni n g.  Patie nts 
will rec or d t heir h u n ger s c ores pri or t o t he m or ni n g meal (faste d). 
T he Gl o bal H u n ger Q uesti o ns a n d Dail y H u n ger Q uesti o n naire is i n A p pe n di x 1 1. 9 . 

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R hyt h m P h ar m ace utic als, I nc. 
 Diet a n d N utriti o n al C o u nseli n g  
F or a d oles ce nts a n d a d ult patie nts, n o s pecial dietar y c o u nseli n g will be part of t his trial, b ut 
patie nts w ill be c o u nsele d t o c o nti n ue t heir us ual diet at h o me. 

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R hyt h m P h ar m ace utic als, I nc. 
F or pe diatric patie nts, n utriti o nal c o u nseli n g a n d m o nit ori n g will be perf or me d b y a n a p pr o priate 
dieticia n or n utriti o nist ( or e q ui vale nt) acc or di n g t o t he S O A, t o e ns ure t hat pe diatric patie nts 
ha ve a d e q uate n utriti o nal/ dietar y i nta k e t o mai ntai n pr o per gr o wt h a n d de v el o p me nt.  A d diti o nal 
la b orat or y ass ess me nts i n dicati ve of n utriti o nal stat us ma y be m o nit ore d as a p pr o priate (e. g. 
al b u mi n, vita mi n D, t otal l y m p h oc ytes a n d I G F 1).      
 A d verse E ve nts  
Eac h patie nt m ust be car ef ull y m o nit ore d f or t he de vel o p me nt of a n y A E s t hr o u g h o ut t he st u d y 
fr o m Scree ni n g t hr o u g h t he Fi nal St u d y Visit.  T his i nf or mati o n s h o ul d be o btai ne d i n t he f or m 
of n o n-lea di n g q uesti o ns (e. g., “ H o w are y o u feeli n g? ”), a n d fr o m si g ns a n d s y m pt o ms detecte d 
d uri n g eac h e x a mi nati o n, fr o m la b orat or y e val uati o n, o bser vati o ns of st u d y pers o n nel, a n d 
s p o nta ne o us re p orts fr o m patie nts. 
All A Es, i ncl u di n g i njecti o n site reacti o ns a n d p ot e ntial s yste mic reacti o ns will be gra de d usi n g 
t he Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A d v erse E ve nts ( C T C A E) 
gr a di n g s yst e m.   
C o m plete details o n A E  m o nit ori n g are pr o vi de d i n Secti o n 7 . 
 O pti o n al S u b -St u dies  

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R hyt h m P h ar m ace utic als, I nc. 
 Or der of Assess me nts  
W he n sc he d ule d at t he sa me ti me p oi nt, t he or der of pr oce d ures s h o ul d be as f oll o ws: o btai n 
vital si g ns, perf or m 1 2-lea d E C G, f oll o we d b y bl o o d dra ws (at t he s pecifie d ti me p oi nt, if 
a p plica ble).  A dj ust me nts ma y be m a de de p e n di n g u p o n s pecific circ u msta nces. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 

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R hyt h m P h ar m ace utic als, I nc. 
7.  A D V E R S E E V E N T S  
M o nit ori n g of a d v erse e v e nts will be c o n d ucte d t hr o u g h o ut t he st u d y.  A d v erse e v e nts will be 
rec or d e d i n t he C R Fs fr o m Scree ni n g t hr o u g h t he Fi nal St u d y Visit.  A d verse e ve nts t hat occ ur 
after t he start of st u d y dr u g a d mi nistrati o n will be c o nsi dere d treat me nt e m er ge nt a d v erse e ve nts 
( T E A Es).  S A Es will be r ec or de d t hr o u g h t he Fi n al St u d y Visit.  All a d vers e e ve nts s h o ul d be 
m o nit ore d u ntil t he y ar e r es ol ve d or ar e clearl y det er mi ne d t o be d ue t o a p ati e nt’s sta ble or 
c hr o nic c o n diti o n or i nter c urre nt ill ness(es). 
7. 1.  Defi niti o ns, D oc u me nt ati o n, a n d Re p orti n g  
A n a d verse e v e nt ( A E)  is a n y u nt o w ar d me dical occ urre nce ass ociat e d wit h t he use of a dr u g i n 
h u ma ns, w het her or n ot c o nsi dere d dr u g relate d.  A n a d ver s e e ve nt (als o referre d t o as a n a d vers e 
e x perie nce) ca n b e a n y u nfa v ora bl e a n d u ni nte n de d si g n (e. g., a n a b n or mal la b orat or y fi n di n g), 
s y m pt o m, or disease t e m p orall y ass ociate d wit h t he use of a dr u g, wit h o ut a n y j u d g me nt a b o ut 
ca usalit y.  A n A E  ca n arise fr o m a n y use of t he dr u g (e. g., off-la bel use, us e i n c o m bi nati o n wit h 
a n ot her dr u g) a n d fr o m a n y r o ute of a d mi nistrati o n, f or m ulati o n, or d ose, i ncl u di n g a n o v er d ose. 
A n A E  or s us pect e d a d verse reacti o n is c o nsi dere d seri o us (S A E ) if, i n t he vie w of eit her t h e 
i n vesti gat or or s p o ns or, it res ults i n a n y of t he f oll o wi n g o utc o mes: 
•  Deat h.  
•  Lif e -t hreate ni n g.  Life-t hreate ni n g mea ns t hat t he patie nt was at i m me diate ris k of deat h 
fr o m t he reacti o n as it occ urre d, i. e., it d oes n ot i ncl u de a reacti o n whic h h y p ot heticall y 
mi g ht ha ve ca use d d eat h ha d it occ urre d i n a m ore se vere f or m.  
•  I n- patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n.  H os pitalizati o n 
a d missi o ns a n d/ or s ur gical o perati o ns sc he d ul e d t o occ ur d uri n g t he st u d y peri o d, b u t 
pla n ne d pri or t o st u d y e ntr y are n ot c o nsi dere d A Es if t he ill ness or diseas e e xiste d bef ore 
t he patie nt was e nr olle d i n t he st u d y, pr o vi de d t h at it di d n ot deteri orate i n a n u ne x pecte d 
ma n ner d uri n g t he st u d y (e. g., s ur ger y perf or me d earlier t h a n pla n ne d).  
•  A persiste nt or si g nifica nt i nca pacit y or s u bsta ntial disr u pti o n of t he a bilit y t o c o n d uct 
n or mal life f u ncti o ns. 
•  C o n ge nital a n o mal y/ birt h defect. 
•  I m p ort a nt me dical e v e nt.  A n i m p orta nt me dical e ve nt is a n e ve 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 pitalizati o n b ut ma y be c o nsi dere d a n S A E w he n, 
base d u p o n a p pr o priate me dical j u d g m e nt, it ma y je o par dize t he patie nt or patie nt a n d 
ma y r e q uire m e dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o ut c o mes liste d i n t he 
defi niti o ns f or S A Es.  E xa m ples of s uc h me dical e ve nts i ncl u de aller gic br o nc h os pas m 
re q uiri n g 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, bl o o d d ys crasias or 
c o n v ulsi o ns t hat d o n ot res ult i n i n- patie nt h os pitalizati o n, or t he de vel o p me nt of dr u g 
de pe n de n c y or dr u g a b us e. 
7. 2.  Pr o ce d ures f or A E a n d S A E Re p orti n g  
Eac h patie nt m ust be car ef ull y m o nit ore d f or t he de vel o p me nt of a n y A E s.  T his i nf or mati o n 
s h o ul d be o btai ne d i n t he f or m of n o n-lea di n g q u esti o ns (e. g., “ H o w are y o u feeli n g? ”) a n d fr o m 
si g ns a n d s y m pt o ms detecte d d uri n g eac h e x a mi nati o n, o bser vati o ns of st u d y pers o n nel, a n d 
s p o nta ne o us re p orts fr o m patie nts. 

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R hyt h m P h ar m ace utic als, I nc. 
All A E s (seri o us a n d n o n-seri o us) s p o nta ne o usl y re p orte d b y t he patie nt a n d/ or i n res p o nse t o a n 
o pe n q uesti o n fr o m st u d y pers o n nel or re veale d b y o bser vati o n, p h ysical e x a mi nati o n or ot her 
dia g n ostic pr o ce d ur es will be rec or d e d o n t he a p pr o priate C R F.  A n y cli nicall y rele va nt 
deteri orati o n i n la b or at or y ass ess me nts or ot her cli nical fi n di n gs is c o nsi dere d a n A E  a n d m ust 
be rec or de d o n t he a p pr o priate C R F.  W he n p ossi ble, si g ns a n d s y m pt o ms i n dicati n g a c o m m o n 
u n derl yi n g p at h ol o g y s h o ul d be n ote d as o ne c o m pre he nsi ve e ve nt. 
All S A Es t hat occ ur d uri n g t he st u d y m ust be re p orte d b y t h e i n vesti gat or t o t he Me dical 
M o nit or wit hi n 2 4 h o urs  fr o m t he poi nt i n ti me w he n t he i n vesti gat or bec o mes a ware of t he 
S A E.   All S A Es m ust be re p orte d w h et her or n ot c o nsi dere d ca usall y relat e d t o t he st u d y 
dr u g.  S A E f or ms will be c o m plete d a n d t he i nf or mati o n c ollecte d will i ncl u de patie nt n u m ber, 
a narr ati ve descri pti o n of t he e ve nt a n d a n assess me nt b y t he i n vesti gat or as t o t he se verit y of 
t he e ve nt a n d r elate d n ess t o st u d y dr u g.  F oll o w- u p i nf or mati o n o n t he S A E ma y b e re q u este d 
b y R h yt h m or its desi g n ee.  
 
All S A E c orres p o n de n ce s h o ul d be a d dresse d t o 
 f or trac ki n g a n d 
d oc u me ntati o n p ur p oses.  
If t here ar e seri o us, u ne x pecte d a d v erse dr u g reacti o ns ass ociate d wit h t he use of t he st u d y dr u g, 
R h yt h m or desi g nee will n otif y t he a p pr o priate re g ulat or y a ge nc y(ies) , Et hi c C o m mittees ( E Cs) 
a n d all partici pati n g i n vesti gat ors o n a n e x pe dite d basis.  It is t he res p o nsi bilit y of t he 
i n vesti gat or t o pr o m ptl y n otif y t he I nstit uti o nal Re vie w B o ar d (I R B)/I n de p e n de nt Et hics 
C o m mittee (I E C) w h ere re q uire d of t h e I R B/I E C of all u ne x pecte d seri o us a d verse dr u g 
reacti o ns i n v ol vi n g ris k t o h u ma n patie nts.  A n u ne x pecte d e ve nt is o ne t hat is n ot re p orte d i n t he 
I B. 
F or b ot h seri o us a n d n o n-seri o us A E s, t he I n v esti gat or m ust det er mi ne b ot h t he i nte nsit y of t he 
e ve nt a n d t he r elati o ns hi p of t he e ve nt t o st u d y dr u g a d mi nistrati o n.  O nl y t h ose i njecti o n site 
reacti o ns c o nsi dere d cli nicall y si g nifica nt b y t he I n vesti gat or will be rec or de d as A Es. 
I nte nsit y of all A Es i ncl u di n g cli nicall y si g nifica nt treat me nt-e mer ge nt la b orat or y a b n or m alities, 
i njecti o n site reacti o ns a n d p ote ntial s yste mic reacti o ns will be gra d e d per  t h e C T C A E Versi o n 
4. 0 3.  T he C T C A E gra de refers t o t he se verit y of t he A E a n d ra n ges fr o m Gra de 1 ( mil d A E), 
Gra de 2 ( m o derat e A E), Gra de 3 (se vere A E) a n d Gra de 4 (life -t hreate ni n g or disa bli n g A E) t o 
Gra de 5 ( deat h r elate d t o A E).  
A d verse e ve nts n ot liste d b y t he C T C A E will be gra de d as f oll o ws: 

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R hyt h m P h ar m ace utic als, I nc. 
Mil d : disc o mf ort n otice d b ut n o disr u pti o n of n or mal dail y acti vit y. 
M o der ate:  disc o mf ort s ufficie nt t o re d u ce or affect dail y acti vit y.  
Se vere:  i n a bilit y t o w or k or perf or m n or mal dail y acti vit y. 
Lif e t hre ate ni n g :  re pres e nts a n i m me diate t hreat t o life. 
Rel ati o ns hi p  t o st u d y dr u g a d mi nistrati o n will be deter mi ne d b y t he i n vesti gat or acc or di n g t o 
t he f oll o wi n g criteria. 
N o ne:  N o rel ati o ns hi p bet wee n t he e ve nt a n d t h e a d mi nistrati o n of st u d y dr u g.  T h e e v e nt is 
relate d t o ot her eti ol o gies, s uc h as c o nc o mita nt me dicati o ns or patie nt’s cli nical state. 
U nli kel y:  T he c urre nt st ate of k n o wle d ge i n dicat es t hat a rel ati o ns hi p t o st u d y dr u g is u nli kel y 
or t he te m p oral r elati o ns hi p is s uc h t hat st u d y dr u g w o ul d n ot ha v e ha d a n y reas o na bl e 
ass ociati o n wit h t he o bser ve d e ve nt.  
P ossi ble:  A r eacti o n t hat f oll o ws a pla usi ble te m p oral se q ue n ce fr o m a d mi nistrati o n of t he st u d y 
dr u g a n d f oll o ws a k n o w n res p o nse patter n t o t he s us pecte d st u d y dr u g.  T he reacti o n mi g ht ha v e 
bee n pr o d uce d b y t he patie nt’s cli nical state or ot h er m o des of t hera p y a d mi nistere d t o t he 
patie nt.  
Pr o b a ble:  A reacti o n t hat f oll o ws a pla usi ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he 
st u d y dr u g a n d f oll o ws a k n o w n res p o nse p atter n t o t he s us pecte d st u d y dr u g.  T he reacti o n 
ca n n ot be r eas o na bl y e x plai ne d b y t h e k n o w n c h aracteristics of t he p atie nt’s cli nical state or 
ot her m o des of t her a p y a d mi nistere d t o t he patie nt. 
F or t he p ur p os e of safet y a n al ys es, all A Es t hat are classifie d as p ossi ble or pr o ba ble will be 
c o nsi dere d tr eat me nt -r elate d e ve nts. 
7. 3.  A d verse E ve nts a n d Ris ks  
O verall, set mela n oti de h as bee n ge n er all y w ell -t olerate d i n pre vi o us st u dies. Dr u g-Relate d 
T E A Es (f or w hic h t he a d verse e v e nt was ass esse d as p ossi bl y or pr o b a bl y relate d t o st u d y dr u g 
b y t he i n vesti gat or) were re p orte d . Beca use v er y fe w st u dies ha ve bee n d o ne usi n g 
set mela n oti de, t here ma y be ot her u n k n o w n si de effects. T h e PIs ( or a c o veri n g cli nicia n) will be 
a vaila ble at all ti mes t o st u d y partici pa nts i n t he e v e nt of a cli nical e mer ge n c y; b ot h t his 
a vaila bilit y a n d h o w t o reac h t he i n vesti gat ors i n a n e mer ge n c y will be clearl y c o m m u nicate d 
orall y a n d i n writi n g t o st u d y partici pa nts. All st u d y i nter v e nti o ns will be pr o vi de d free of c ost.  
 
Please ref er  t o t he c urr e nt I n vesti gat or’s Br oc h ure f or a c o m pre he nsi ve s u m mar y of t he A Es 
re p orte d t o dat e.   
 Me dic al m o nit ori n g  
T he me dical m o nit ori n g f or t he st u d y ma y  be del e gat e d  t o a me dical m o nit or s u p plie d b y t he 
C R O ma na gi n g t he  o p erati o nal c o n d uct of t his st u d y.  T he PI has o veral l res p o nsi bilit y f or t h e 
i nte grit y of t he st u d y a n d partici pa nt safet y. T his i nf or mati o n, as well as a n y ot her u na ntici pate d 
pr o ble ms i n v ol vi n g ris ks t o patie nt s or ot hers, will als o be re p ort e d t o t he F D A.  
T his st u d y will als o be m o nit ore d b y a safet y m o nit ori n g c o m mittee, w h o will be res p o nsi ble f or 
caref ul saf et y e val uati o ns of  patie nts, w hile treat m e nt c o nti n ues i n t his st u d y.  

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R hyt h m P h ar m ace utic als, I nc. 
D uri n g t h e c o n d uct of st u d y, r es p o nsi bilities of t he S M B will be t o re vie w p eri o dicall y t he st u d y 
data b y perf or mi n g a q ualitati ve a n d q ua ntitati ve safet y assess m e nt. I n a d diti o n, t he S M B s h o ul d 
deter mi ne w het h er t he b asic st u d y ass u m pti o ns re mai n vali d, a n d e val uate w het her t he o v erall 
i nte grit y, scie ntific m erit a n d c o n d uct of t he st u d y are still acce pta ble. T h e S M B will ma ke 
decisi o ns re gar di n g c o nti n uati o n or ter mi nati o n of t he st u d y or s u g gest c ha n ges i n t he d esi g n of 
t he st u d y or its pr oce d ures or b ot h.  
T he S M B me m bers will be c o m prise d of b ot h i nter nal R h yt h m e m pl o yees ( i.e. R h yt h m’s C M O) 
a n d pers o ns i n de p e n de nt of R h yt h m.  T he S M B will meet q uarterl y t hr o u g h o ut t he d urati o n of 
t he trial. 
7. 4.  M o nit ori n g of A d verse E ve nts a n d Peri o d of O bser v ati o n 
A E s will be rec or de d o n t he C R Fs starti n g fr o m Scree ni n g u p t o a n d i n cl u di n g t he Fi nal St u d y 
Visit.  S A E s a n d deat hs will be rec or d e d o n t he C R Fs starti n g fr o m t he ti me t he I C F is si g ne d 
a n d c o nti n ui n g t hr o u g h t he Fi nal St u d y Visit.  All A Es s h o ul d be m o nit ore d u ntil t he y are 
res ol ve d or are clearl y d eter mi ne d t o be d ue t o a p atie nt’s sta ble or c hr o nic c o n diti o n or 
i nterc urr e nt ill ness(es). 
A n y S A E t hat o cc urs at a n y ti me aft er c o m pleti o n  of t he st u d y, w hi c h t he i n vesti gat or c o nsi ders 
t o be relate d t o st u d y dr u g, m ust be r e p orte d t o R h yt h m or desi g nee. 
7. 5.  G ui deli nes  f or A d diti o n al M o nit ori n g a n d S us pe nsi o n of D osi n g f or a P atie nt 
Patie nts will be m o nit ore d caref ull y d uri n g t h e treat me nt peri o d d uri n g o n site cli nic visits as 
well as peri o dic tel e p h o n e calls ma de t o t he p atie nts b y t he st u d y staff.  I n t he e ve nt a p atie nt is 
wit h dra w n fr o m tr eat me nt d ue t o a n A E, t he patie nt s h o ul d be e nc o ura ge d t o c o m plete t he fi nal 
st u d y/earl y t er mi nati o n visit t o m o nit or t he e ve nt t o res ol uti o n a n d o btai n a d diti o nal pr ot oc ol 
defi ne d saf et y assess me nts.  
S pecific g ui deli nes f or d er mat ol o gi cal e v e nts, ele vate d li ver f u n cti o n tests (L F Ts ), a n d pe nile 
erecti o ns are pr o vi d e d i n t he A p pe n di ces.  At all ti mes, t his g ui da nce is s u bject t o t he cli nical 
j u d g me nt of t he I n vesti gat or a n d st u d y c o ns ulta nts (if a p plica ble).   
T he I n vesti gat or s hall n otif y t he Me di cal M o nit or i n t he e ve nt a n y st u d y partici pa nt f ulf ills a n y 
of t he criteri a defi ne d i n t he a p pe n dices n ote d a b o ve, or u n der g o es a d diti o nal m o nit ori n g f or a n y 
of t he e ve nts defi ne d her ei n. 
 De pressi o n or S uici d alit y  
A patie nt s h o ul d be ref erre d t o a M H P if he/s he h as: 
• A 
. 
• A n y s uici d al be ha vi or. 
• A n y 
. 
A ref err al t o a M H P s h o ul d als o be ma de if i n t he o pi ni o n of t he I n v esti gat or it is necessar y f or 
t he safet y of t he p atie nt.  If a patie nt’s ps yc hiatric dis or der ca n b e a d e q uatel y treate d wit h 
ps yc h o - a n d/ or p h ar mac ot hera p y, t he n t he p atie nt, at t he discreti o n of t he M H P, s h o ul d be 
c o nti n ue d i n t he trial. 

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R hyt h m P h ar m ace utic als, I nc. 
8.  S T A TI S TI C A L P R O C E D U R E S  
 
T his secti o n descri bes t h e pla ns f or a n al ysis. Details o n t he statistical pla n will be pr o vi de d i n a 
c o m plete Statistical A nal ysis Pla n  ( S A P).  A n y a d diti o nal a nal yses a n d s pecific c o n ve nti o ns f or 
a nal ysis will be d escri be d i n t he S A P  a n d Cli nical St u d y R e p ort ( C S R). 
8. 1.  S a m ple Size Esti m ati o n  a n d Pri m ar y P o w er St ate me nt  
T he pri mar y e n d p oi nt is pr o p orti o n of patie nts i n t he F A S w h o de m o nstrate at least 1 0 % wei g ht 
at 1 year ( 1 0 - 1 4 m o nt hs p ost baseli ne) c o m pare d t o baseli ne.  Patie nts wit h missi n g data aft er 1 0 
m o nt hs fr o m baseli ne will be c o u nte d as n ot ha vi n g 1 0 % wei g ht l oss at 1 year.  T h e pri mar y 
researc h h y p ot hesis is t hat t his pr o p orti o n is at least 5 %.  T he n ull h y p ot hesis is t hat t his 
pr o p orti o n is at m ost 5 %.  Rati o nale f or t he 5 % hist orical c o ntr ol val ue f or t his c o m paris o n is as 
f oll o ws. 
 
T he a vaila ble d ata s u g gests t hat 0 % of L E P R  defi cie nc y patie nts w o ul d de m onstrate at least 1 0 % 
wei g ht l oss i n a si n gle year, e ve n wit h e xtra or di nar y meas ures.  T he e x ce pti o n mi g ht be after 
bariatric s ur ger y, as s o m e patie nts ha ve h a d ver y s h ort-ter m i m pr o ve me nts, t h o u g h o ver ti me 
t heir o ver w h el mi n g h u n ger lea ds t o w ei g ht re gai n.  I n t he a bse n ce of s u c h meas ures i n o ur 
cli nical trial (e x cl usi o ns fr o m t he trial), a n d t he ge neral c o ntrai n dicati o n of bariatric s ur ger y i n 
t his p o p ulati o n, it is defe nsi ble t o c o nsi der t hat n o ( 0 %) patie nts w o ul d meet t hese criteria a n d 
t he statistical c o m paris o n f or t his e n d p oi nt s h o ul d be a c o m paris o n t o a 0 % pr o p orti o n.  Des pite 
t his str o n g rati o nale b ase d o n t he nat ural hist or y of t hese patie nts, si nce t h e data are li mite d a n d 
t he n u m ber of patie nts i n t he trial is s mall, it is pr o ba bl y m ore a p pr o priate t o g o be y o n d t his ver y 
c o nser vati ve esti mate of 0 % res p o n ders, t o d o o ur hist orical c o ntr ol c o m paris o ns ass u mi n g t hat a 
s mall pr o p orti o n of t he p o p ulati o n (i.e. 5 %, or a n ull of 0. 0 5) mi g ht  s h o w a 1 0 % wei g ht l oss i n 
a n y gi v e n cal e n dar year; he nce w e pr o p ose a cate g orical c o m paris o n t o a 5 % res p o n der esti mate 
i n u ntreate d hist orical patie nts.  
 
T he f oll o wi n g p o wer ta bl e s h o ws t he p o wer t o det ect vari o us pr o p orti o ns w h o a c hie ve 1 0 % 
wei g ht l oss at 1 year f or L E P R patie nts, ass u mi n g a n ull h y p ot hesis val ue of 5 % res p o n d ers f or 
al p ha = 0. 0 5, 1-si de d: 
 
 
 
 
 
 
 
 
 
 
 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
Plas ma c o nce ntr ati o ns will be s u m marize d.   Plas ma c o nce ntrati o ns ma y be c o m pare d t o P D 
e n d p oi nts. 
8. 3.  Ti mi n g of A n al yses 
It is pla n ne d t h at an a n al ysis ma y  be c o m plete d o nce all pla n ne d p atie nts ha ve c o m plete d ~ 1 year 
of treat me nt, data has bee n clea n e d a n d fi n alize d, a n d t he data b ase is l oc ke d f or assess me nts 
(i ncl u di n g t he d o u ble- bli n d place b o- c o ntr olle d wit h dra wal p has e, t he o nl y part of t he st u d y 
w hic h is n ot o pe n la bel).    
8. 4.  L o n g- T er m E xt e nsi o ns a n d P o oli n g of P atie nts fr o m ot her S t u dies 
It is e x pecte d t hat L E P R deficie nc y p atie nts w h o c o nti n ue t o t olerate set mel a n oti de after 1 year 
of treat me nt, a n d w h o s h o w cli nicall y i m p orta nt wei g ht l oss, will be c o nti n ue d i n l o n g- ter m 
e xte nsi o ns (t o be f ull y o utli ne d i n a f ut ure e xte nsi o n pr ot oc ol, as n ote d i n Secti o n 5. 5 ), o n a year 
b y year basis.   A d diti o nal a nal ys es will s u m marize t he l o n g -ter m e x perie n ce as a p pr o priate. 
It is als o e x pecte d t hat s o me patie nts ma y n ot e nter t his st u d y (f or l o gistical reas o ns) b ut will be 
partici pati n g i n a n esse ntiall y i de ntical pr ot o c ol ( St u d y R M- 4 9 3- 0 1 1) wit h a l o n g-t er m e xte nsi o n 
p hase.   After assessi n g t h at st u d y c o n d u ct a n d u p o n deter mi ni n g esse ntiall y i de ntical treat me nt 
pr oce d ur es t o t hi s st u d y, t hese patie nts will als o be caref ull y i de ntifie d i n t he Cli nical St u d y 
Re p ort.  T heir data will als o be s u m marize d a n d p o ole d wit h data fr o m pati e nts w h o e ntere d t his 
pi v otal st u d y i n a s u p ple me ntal a nal ysis. 
8. 5.  St atistic al A n al ysis Pl a n  
T he f ull Statistical A nal ysis Pla n f or t his st u d y will pr o vi de m ore detaile d st atistical pr oce d ures 
pri or t o a n y pla n ne d a nal ysis. 

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R hyt h m P h ar m ace utic als, I nc. 
9.  A D MI NI S T R A TI V E R E Q UI R E M E N T S  
9. 1.  G o o d Cli nic al Pr a ctice  
T he st u d y will be c o n d ucte d i n acc or d a nce wit h t he I nter n ati o nal C o u ncil o n Har m o nizati o n 
(I C H) f or G o o d Cli nical Practice ( G C P) a n d t he a p pr o priate re g ulat or y re q uire me nt(s).  T he 
I n v esti gat or will be t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he st u d y dr u g as descri be d i n 
t he pr ot oc ol a n d I B.  Ess e ntial cli nical d oc u me nts will be mai ntai ne d t o de m o nstrate t he vali dit y 
of t he st u d y a n d t he i nte grit y of t he d ata c ollecte d.  Master files s h o ul d be esta blis he d at t he 
be gi n ni n g of t he st u d y, mai ntai ne d f or t he d urati o n of t he st u d y a n d retai n e d acc or di n g t o t he 
a p pr o priate re g ulati o ns.  
9. 2.  Et hic al C o nsi der ati o ns 
T he st u d y will be c o n d ucte d i n acc or d a nce wit h et hical pri nci ples f o u n de d i n t he Declarati o n of 
Helsi n ki (see A p p e n di x 1 1. 7 ).  T he I R B /I E C will re vie w all a p pr o priate st u d y d oc u m e ntati o n i n 
or der t o saf e g uar d t he ri g hts, safet y, a n d w ell- bei n g of t he p atie nts.  T he st u d y will o nl y b e 
c o n d ucte d at sites w h ere I R B /I E C a p pr o v al has bee n o btai ne d.  T he pr ot oc ol, I B, i nf or me d 
c o nse nt, a d vertise me nts (if a p plica ble), writte n i nf or mati o n gi ve n t o t he p atie nts (i ncl u di n g diar y 
car ds), s afet y u p d ates, a n n ual pr o gress re p orts, a n d a n y re visi o ns t o t hese d oc u me nts will be 
pr o vi de d t o t he I R B /I E C b y t he I n vesti gat or. 
9. 3.  P ati e nt I nf or m ati o n a n d I nf or me d C o ns e nt 
After t he st u d y has b ee n f ull y e x plai ne d, writte n i nf or me d c o ns e nt will be o btai ne d fr o m eit her 
t he patie nt or his/ her g uar dia n or le gal re prese ntati ve pri or t o st u d y partici p ati o n.  T he met h o d of 
o btai ni n g a n d d o c u me nti n g t he i nf or me d c o nse nt a n d t he c o nte nts of t he c o nse nt will c o m pl y 
wit h I C H -G C P a n d all a p plica ble re g ulat or y re q uire me nt(s).  
9. 4.  P ati e nt C o nfi de nti alit y  
I n or der t o mai ntai n patie nt pri vac y, all s o urce d oc u me nts/ C R Fs, st u d y dr u g acc o u nta bilit y 
rec or ds, st u d y r e p orts a n d c o m m u nicati o ns will i de ntif y t he p atie nt b y i nitials a n d t he assi g ne d 
patie nt n u m ber.  T he i n v esti gat or will gra nt m o nit or(s) a n d a u dit or(s) fr o m R h yt h m or its 
desi g nee a n d re g ulat or y a ut h orit y(i es) access t o t he patie nt’s ori gi nal me dical rec or ds f or 
verificati o n of d ata ga t here d o n t he s o urce d oc u m e nts/ C R Fs a n d t o a u dit t he data c ollecti o n 
pr ocess.  T he p atie nt’s c o nfi de ntialit y will be mai ntai ne d a n d will n ot be ma de p u blicl y a vaila ble 
t o t he e xte nt per mitte d b y t he a p plica ble la ws a n d re g ulati o ns. 
9. 5.  Pr ot oc ol C o m pli a nce  
T he i n vesti gat or will c o n d uct t he st u d y i n c o m plia nce wit h t he pr ot oc ol pr o vi de d b y R h yt h m, 
a n d gi v e n a p pr o v al/fa v or a ble o pi ni o n b y t he I R B /I E C a n d t he a p pr o pri ate re g ul at or y 
a ut h orit y(i es).  M o dificati o ns t o t he pr ot oc ol s h o ul d n ot be ma de wit h o ut a gree me nt of b ot h t he 
I n v esti gat or a n d R h yt h m.  C ha n ges t o t he pr ot oc ol will re q uire writte n I R B/I E C 
a p pr o val/fa v ora ble o pi ni o n pri or t o i m ple me ntati o n, e x ce pt w he n t he m o dificati o n is nee de d t o 
eli mi nate a n i m me diate h azar d(s) t o patie nts.  T he I R B/I E C ma y pr o vi de, if a p plica ble re g ulat or y 
a ut h orit y(i es) per mit, e x pe dite d re vie w a n d a p pr o v al/fa v ora bl e o pi ni o n f or mi n or c ha n ge(s) i n 
o n g oi n g st u dies t hat ha ve t he a p pr o val /fa v ora ble o pi ni o n of t he I R B/I E C.  R h yt h m or desi g nee 
will s u b mit all pr ot oc ol m o dificati o ns t o t he re g ulat or y a ut h orit y(i es) i n acc or da nce wit h t he 
g o ver ni n g re g ulati o ns.  

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R hyt h m P h ar m ace utic als, I nc. 
W he n i m me diate de viati o n fr o m t he pr ot oc ol is re q uire d t o eli mi nate a n i m me diate hazar d(s) t o 
patie nts, t he i n vesti gat or will c o ntact R h yt h m, if circ u msta nces per mit, t o disc uss t h e pla n ne d 
c o urse of acti o n.  A n y de part ures fr o m t he pr ot oc ol m ust be f ull y d oc u me nt e d i n t he s o urce 
d oc u me nts/ C R F. 
9. 6.  D at a M a n a ge me nt 
 D at a H a n dli n g 
Data will be rec or d e d at t he site o n s o urce d o c u me nts a n d re vie w e d b y t he Cli nical Researc h 
Ass ociate ( C R A) d u ri n g m o nit ori n g visits.  T he C R A will verif y d ata rec or de d i n t he e C R F 
s yste m wit h s o urce d oc u me nts.  All c orrecti o ns or c ha n ges ma d e t o a n y st u d y dat a m ust be 
a p pr o priatel y tr ac ke d i n a n a u dit trail i n t he e C R F s yste m.  Electr o nic C R Fs will be c o nsi dere d 
c o m plete w he n all missi n g, i nc orrect, a n d/ or i nc o nsiste nt data ha ve bee n acc o u nte d f or. 
 C o m p uter S yste ms  
Data will be pr ocesse d usi n g a v ali date d c o m p uter s yste m c o nf or mi n g t o re g ulat or y 
re q uire me nts. 
 D at a E ntr y  
Data m ust be rec or de d usi n g t he e C R F s yste m as t he st u d y is i n pr o gress.  All st u d y site 
pers o n nel m ust l o g i nt o t he s yste m usi n g t heir sec ure user n a me a n d p ass w or d i n or der t o e nter, 
re vie w, or c orr ect st u d y data.  T hese pr oce d ures m ust c o m pl y wit h Title 2 1 of t he C o de of 
Fe deral Re g ulati o ns ( 2 1 C F R Part 1 1).  All pass w or ds will be strictl y c o nfi de ntial.  
 Me dic al I nf or m ati o n C o di n g 
F or me dical i nf or mati o n t he f oll o wi n g t hes a uri will be use d: 
Me d D R A f or a d v erse e v e nts  
W H O Dr u g f or c o n c o mita nt me dicati o ns 
 D at a V ali d ati o n 
Vali dati o n c hec ks pr o gra m me d wit hi n t he e C R F s yste m, as w ell as s u p ple me ntal vali dati o n 
perf or me d vi a re vi e w of t he d o w nl oa de d d ata, will be a p plie d t o t he data i n or der t o e ns ure 
acc ur ate, c o nsiste nt, a n d relia ble data.  Data i de ntifie d as err o ne o us, or d ata t hat are missi n g, will 
be ref err e d t o t he i n vesti gati ve site f or res ol uti o n t hr o u g h d ata q ueri es. 
Electr o nic C R Fs m ust be re vie we d a n d electr o nicall y si g ne d b y a n I n vesti gat or w h o si g n e d t he 
pr ot oc ol. 
9. 7.  Direct Access t o S o urce D at a  
M o nit ori n g a n d a u diti n g pr oce d ur es de vel o p e d or re vie we d a n d a p pr o ve d b y R h yt h m will be 
f oll o we d, t o c o m pl y wit h G C P g ui deli nes.  
T he st u d y will be m o nit ore d b y R h yt h m or its desi g nee.  M o nit ori n g will be d o ne b y p ers o nal 
visits fr o m a re pres e ntati ve of t he s p o ns or (site m o nit or) a n d will i ncl u de o n- site revie w of t he 
s o urce d oc u m e nts/ C R Fs f or c o m plete n ess a n d clarit y, cr oss-c hec ki n g wit h s o urce d oc u m e nts, 
a n d clarifi cati o n of a d mi nistrati ve matters will be perf or me d.  T he re vie w of me dical rec or ds will 
be perf or me d i n a ma n n er t o e ns ure t hat patie nt c o nfi de ntialit y is mai ntai ne d.  

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R hyt h m P h ar m ace utic als, I nc. 
T he site m o nit or will e ns ure t hat t he i n vesti gati o n is c o n d ucte d acc or di n g t o pr ot oc ol desi g n a n d 
re g ulat or y r e q uire me nts b y fre q ue nt c o m m u nicati o ns (letter, tele p h o ne, a n d fa x). 
All u n use d st u d y dr u g a n d ot her st u d y mat erials are t o be ret ur n e d t o R h yt h m after t he cli nical 
p hase of t he st u d y has b ee n c o m plete d (s ee Secti o n 5. 7 ). 
Re g ulat or y a ut h orities, t he I R B /I E C, a n d/ or R h yt h m’s cli nical qualit y ass ura nce gr o u p or 
desi g nee ma y r e q uest access t o all s o urce d oc u m e nts, C R Fs, a n d ot her st u d y d oc u m e ntati o n f or 
o n- site a u dit or i ns pecti o n.  Direct access t o t hes e d oc u me nts m ust be g u ara ntee d b y t he 
i n vesti gat or, w h o m ust pr o vi de s u p p ort at all times f or t hese acti vities.  
9. 8.  S o urce D oc u me nt/ C as e Re p ort F or m C o m pleti o n  
S o urce d oc u me nts/ C R Fs will be c o m plete d f or eac h st u d y patie nt.  It is t he I n vesti gat or’s 
res p o nsi bilit y t o e ns ure t he acc urac y, c o m plete n ess, a n d ti meli ness of t he data re p orte d i n t he 
patie nt’s s o urce d o c u me nt/ C R F.  T he s o urce d oc u me nt/ C R F s h o ul d i n dicate t he patie nt’s 
partici pati o n i n t he st u d y a n d s h o ul d d oc u me nt t he dates a n d details of st u d y pr o ce d ures, a d v erse 
e ve nts, a n d patie nt stat us. 
T he i n vesti gat or, or desi g nate d re prese ntati ve, s h o ul d c o m plete t he s o urce d oc u me nt/ C R F as 
s o o n as p ossi ble after i nf or mati o n is c ollecte d, prefera bl y o n t he s a me da y t hat a st u d y p atie nt is 
see n f or a n e x a mi nati o n, treat me nt, or a n y ot h er st u d y pr o ce d ure.  A n y o utsta n di n g e ntri es m ust 
be c o m plete d i m me diatel y after t he fi nal e x a mi nati o n.  A n e x pla nati o n s h o ul d be gi ve n f or all 
missi n g data.  
T he i n vesti gat or m ust si g n a n d date t he I n v esti gat or’s State me nt at t he e n d of t he s o urce 
d oc u me nt/ C R F t o e n d ors e t he rec or de d d ata.   
R h yt h m will retai n t he ori gi nals of all C R Fs.  T he i n vesti gat or will ret ai n all c o m plete d s o urce 
d oc u me nts/ C R Fs. 
9. 9.  Rec or d R ete nti o n  
T he i n vesti gat or will mai ntai n all st u d y rec or ds acc or di n g t o I C H -G C P a n d a p plica ble re g ulat or y 
re q uire me nt(s).  Rec or ds will be retai ne d f or at least t w o years aft er t he last mar keti n g 
a p plicati o n a p pr o val or t w o years after f or mal dis c o nti n uati o n of t he cli nical de vel o p me nt of t he 
i n vesti gati o nal pr o d u ct or acc or di n g t o a p plica ble re g ulat or y re q uire me nt(s).  If t he i n vesti gat or 
wit h dra ws fr o m t he res p o nsi bilit y of k ee pi n g t he st u d y rec or ds, c ust o d y m ust be tra nsferre d t o a 
pers o n willi n g t o acce pt t he res p o nsi bilit y.  R h yt h m m ust be n otifie d i n writi n g if a c ust o dial 
c ha n ge o cc urs.  
9. 1 0.  Li a bilit y I ns ur a nce  
R h yt h m has s u bscri be d t o a n i ns ura nce p olic y c o v eri n g, i n its ter ms a n d pr o visi o ns, its le gal 
lia bilit y f or i nj uries ca us e d t o partici pati n g pers o ns a n d arisi n g o ut of t his researc h perf or me d 
strictl y i n acc or da n ce wit h t he scie ntific pr ot oc ol as well as wit h a p plica ble la w a n d pr ofessi o nal 
sta n dar ds. 
9. 1 1.  P u blic ati o n of St u d y Fi n di n gs a n d Use of I nf or m ati o n  
All i nf or mati o n re gar di n g set mela n oti de  s u p plie d b y R h yt h m t o t he i n vesti gat or is pri vile ge d a n d 
c o nfi de ntial i nf or mati o n.  T he i n vesti gat or a grees t o use t his i nf or mati o n t o acc o m plis h t he st u d y 
a n d will n ot use it f or ot her p ur p oses wit h o ut c o ns e nt fr o m R h yt h m.  It is u n derst o o d t hat t here is 
a n o bli gati o n t o pr o vi de R h yt h m wit h c o m plete d ata o btai ne d d uri n g t he st u d y.  T he i nf or mati o n 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
o btai ne d fr o m t he cli nical st u d y will be use d t o war ds t he de vel o p me nt of s et mela n oti de a n d ma y 
be discl ose d t o re g ulat or y a ut h orit y(i es), ot her i n v esti gat ors, c or p orate part ners, or c o ns ulta nts as 
re q uire d. 
It is t he i nte nti o n of R h yt h m a n d t he aca de mic i n v esti gat ors t o p u blis h t he res ults of t his st u d y i n 
a peer -re vi e wed j o ur n al u p o n c o m pleti o n.  F or t his p ur p ose, a p u blicati o n c o m mittee of t he ke y 
i n vesti gat ors will li kel y b e i de ntifie d a n d i nitiate d d uri n g t his trial. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
1 0.  R E F E R E N C E S  
Cle me nt K, D u ber n B, M e ncar elli M, et al. U ne x pecte d e n d o cri ne feat ures a n d n or mal 
pi g me ntati o n i n a y o u n g a d ult patie nt carr yi n g a n o vel h o m oz y g o us m utati o n i n t he P O M C  ge ne. 
J Cli n E n d ocri n ol Met a b. 2 0 0 8; 9 3( 1 2): 4 9 5 5- 4 9 6 2. 
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni ne cleara nce fr o m s er u m creati ni ne.  Ne p hr o n. 
1 9 7 6; 1 6( 1): 3 1- 4 1. 
C oll A P, Far o o qi I S, C hallis B G, Ye o G S, O' Ra hill y S. Pr o o pi o mela n oc orti n a n d e ner g y 
bala nce: i nsi g hts fr o m h u ma n a n d m uri ne ge n etics. J Cli n E n d ocri n ol Met a b. 2 0 0 4; 8 9( 6): 2 5 5 7-
2 5 6 2. 
Far o o qi I S, V ol ders K, Sta n h o pe R, et al. H y per p h a gi a a n d earl y- o nset o b esit y d ue t o a n o v el 
h o m oz y g o us misse nse m utati o n i n pr o h or m o ne c o n vertase 1/ 3. J Cli n E n d o cri n ol Met a b. 
2 0 0 7; 9 2( 9): 3 3 6 9- 3 3 7 3. 
Far o o qi, I. S., et al., Cli nical a n d m olec ular ge n etic s pectr u m of c o n ge nital deficie nc y of t he  
le pti n rece pt or. N E n gl J Me d , 2 0 0 7. 3 5 6( 3): p. 2 3 7- 4 7. 
 
Fitz patric k T B: S oleil et pea u. J Me d Est het 1 9 7 5; 2: 3 3 0 3 4. 
 
F oster A C, J o p pa M, Mar kis o n S, et al. B o d y wei g ht re g ul ati o n b y s electi v e M C 4 rece pt or 
a g o nists an d a nta g o nists. A n n N Y Ac a d Sci. 2 0 0 3; 9 9 4: 1 0 3- 1 1 0. 
G ottes die ner K, C o n n ors H, Va n der Pl oe g L, Fie d ore k F, H yl a n M, L o uis W, Lasseter K. 
A nal ysis of t h e s y nt h etic pe pti de R M - 4 9 3, a mela n oc orti n- 4 rece pt or ( M C 4 R) a g o nist, o n 
car di o vas c ular para meters i n t hree P hase 1 b/ 2a st u dies .  P oster - O besit y S ociet y, 2 0 1 5. 
Gree nfiel d, J. R., J. W. Miller, J. M. Ke o g h, E. He n ni n g, J. H. Satter w hit e, G. S. Ca mer o n, B. 
Astr uc, J. P. Ma yer, S. Bra ge, T. C. See, D. J. L o mas, S. O' Ra hill y, a n d I. S. Far o o qi. 2 0 0 9. 
' M o d ulati o n of bl o o d pr ess ure b y ce ntral mela n oc orti ner gic pat h w a ys', N E n gl J Me d, 3 6 0: 4 4-
5 2. 
J ac ks o n R S, Cree mers J W, Far o o qi I S, et al. S mall-i ntesti nal d ysf u ncti o n acc o m pa nies t he 
c o m ple x e n d ocri n o pat h y of h u ma n pr o pr otei n c o n vertase 1 d eficie n c y. J Cli n I nvest . 
2 0 0 3; 1 1 2( 1 0): 1 5 5 0- 1 5 6 0. 
J ac ks o n R S, Cree mers J W, O ha gi S, et al. O besit y a n d i m paire d pr o h or m o ne pr ocessi n g 
ass ociate d wit h m utati o ns i n t he h u ma n pr o h or m o ne c o n vert ase 1 ge n e. Nat Ge net. 
1 9 9 7; 1 6( 3): 3 0 3- 3 0 6. 
Kie vet P, Hale m H, Mar ks D L, et al. C hr o nic tr eat me nt wit h a mela n oc orti n - 4 rece pt or a g o nist 
ca uses w ei g ht l oss, r e d uces i ns uli n resista nce, a n d i m pr o ves car di o vas c ular f u ncti o n i n diet-
i n d uce d o bese r hes us maca q ues. Dia b etes 2 0 1 3; 6 2: 4 9 0- 4 9 7. 
Kr u de H, Bie ber ma n n H, L uc k W, H or n R, Bra ba nt G, Gr uters A. Se v ere earl y - o nset o besit y, 
a dre nal i ns ufficie nc y a n d re d hair pi g me ntati o n ca use d b y P O M C  m utati o ns i n h u ma ns. Nat 
Ge net. 1 9 9 8; 1 9( 2): 1 5 5- 1 5 7. 
K ü h ne n P., Cle me nt K., Wie ga n d S., Bla n k e nstei n O., G ottes die ner K., M arti ni L. L., M ai K. 
Bl u me - Pe yta vi U., Gr üters A., Kr u de H. Pr o o pi o mela n oc orti n Deficie nc y Treate d wit h a 
Mela n oc orti n - 4 Rece pt or A g o nist. N E n gl J Me d 2 0 1 6. 3 7 5( 3): 2 4 0- 2 4 6. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
Mar ks D L, C o ne R D. Ce ntral mela n oc orti ns a n d t he re g ulati o n of w ei g ht d uri n g ac ute a n d 
c hr o nic diseas e. Rece nt Pr o g H or m Res. 2 0 0 1; 5 6: 3 5 9- 3 7 5. 
Marti n M G, Li n d b er g I, S ol orza n o - Var gas R S, et al. C o n ge nital pr o pr otei n c o n vertas e 1/ 3 
deficie nc y ca us es mala bs or pti ve diarr hea a n d ot her e n d ocri n o p at hies i n a p e diatric c o h ort. 
G astr oe nter ol o gy. 2 0 1 3; 1 4 5( 1): 1 3 8- 1 4 8. 
N H L BI. T he Prac tical G ui de I d e ntificati o n, E val u ati o n, a n d Treat me nt of O ver w ei g ht a n d O bese 
i n A d ults. NI H P u blicati o n N o. 0 0- 4 0 8 4, Oct o ber 2 0 0 0. 
Pa g o n R A, A d a m M P, Ar di n ger H H, et al., e dit ors. Ge ne Re vie ws ® [I nter n et]. Seattle ( W A): 
U ni versit y of Was hi n gt o n, Seattle, 2 0 1 3; 1 9 9 3- 2 0 1 5. 
Ra mac ha n dr a p pa S, Far o o qi I S. Ge n etic a p pr o ac h es t o u n dersta n di n g h u ma n o besit y. J Cli n 
I nvest. 2 0 1 1; 1 2 1( 6): 2 0 8 0- 2 0 8 6. 
Sei da h N G, Prat A. T he bi ol o g y a n d t hera pe utic t ar geti n g of t he pr o pr otei n c o n vertas es. N at Rev 
Dr u g Disc ov. 2 0 1 2; 1 1( 5): 3 6 7- 3 8 3. 
U S De part me nt of H ealt h a n d H u ma n Ser vices, F o o d a n d Dr u g A d mi nistrati o n, Ce nter f or Dr u g 
E val uati o n a n d Researc h ( C D E R) Ce nter f or Bi ol o gics E v al uati o n a n d Researc h ( C B E R). 
G ui da nce f or I n d ustr y Dr u g- I n d uce d Li v er I nj ur y: Pre mar keti n g Cli nical E val uati o n. Sil ver 
S pri n g, M D. J ul y 2 0 0 9 
va n der Klaa u w A A, Far o o qi I S. T he h u n ger ge n es: pat h wa ys t o o b esit y. C ell. 2 0 1 5; 1 6 1( 1): 1 1 9-
1 3 2. 
Wi k ber g J E, M ut ulis F. Tar geti n g mela n o c orti n rece pt ors: a n a p pr oac h t o treat wei g ht dis or ders 
a n d se x ual d ysf u n cti o n. Nat Re v Dr u g Disc o v. 2 0 0 8; 7( 4): 3 0 7- 3 2 3. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
1 1. 2.  Fit z p atric k Cl assific ati o n Sc ale  
 
S ki n 
T y pe  
S ki n C ol or  
C h ar acteristics  
I 
W hite; ver y f air; re d or bl o n d hair; bl ue e yes; 
frec kl es 
Al wa ys b ur ns, ne v er ta ns  
II 
W hite; fair; re d or bl o n d hair; bl ue, hazel, or gree n 
e yes  
Us uall y b ur ns, t a ns wit h 
diffic ult y  
III 
Crea m w hite; fair wit h a n y e ye or hair c ol or; ver y 
c o m m o n 
S o meti mes mil d b ur n, 
gra d uall y ta ns  
I V 
Br o w n; t y pical Me diterra nea n Ca ucasia n s ki n  
Rarel y b ur n s, ta ns wit h ease 
V  
Dar k Br o w n; mi d -easter n s ki n t y pes  
Ver y rarel y b ur ns, t a ns ver y 
easil y 
VI  
Blac k  
Ne ver b ur ns, ta ns ver y easil y  
Fitz patric k T B: S oleil et pea u. J Me d Est het 1 9 7 5; 2: 3 3 0 3 4. 
 
 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
t he P hase 1/ 2 st u dies de m o nstrates t he c ha n ges i n lesi o ns re vers e u p o n cessati o n of st u d y dr u g, 
s o if a lesi o n c o nti n ues t o dar ke n or c ha n ge after st u d y treat me nt has bee n c o m plete d, caref ul 
c o nsi derati o n s h o ul d be gi ve n f or f urt h er der mat ol o gical e val uati o n or bi o ps y.  If dr u g is 
disc o nti n ue d, all p atie nts wit h cli nicall y i n dicate d l esi o ns are t o be f oll o we d b y t he 
Der mat ol o gist u ntil  pr o gr ess t o war ds res ol uti o n of t he e ve nt ( u p t o ~ 6 0- 9 0 d a ys after l ast d osi n g, 
if nee de d). 
 
 

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R hyt h m P h ar m ace utic als, I nc. 
1 1. 5.  G ui d a nce f or M o nit ori n g P ote nti al Tre at me nt -Rel ate d Pe nile Erecti o ns a n d 
S u g geste d Criteri a f or Disc o nti n u ati o n of D osi n g 
T he I n vesti gat or will i de ntif y a Ur ol o gist t o ser ve as a c o ns ulta nt f or t h e I n vesti gati ve Site i n t he 
e ve nt a patie nt r e p orts a cli nicall y si g nifica nt erecti o n.  Male patie nts will be i nstr ucte d t o 
i m me diatel y r e p ort a n y n o n-er otic erecti o ns lasti n g f or m ore t ha n 3 0 mi n ut es, or a pai nf ul 
erecti on of a n y d urati o n, t o t he I n v esti gat or. 
As pre vi o usl y m e nti o ne d, pe nile erecti o ns i n males are effects ass ociate d wit h M C 4 R a g o nis m, 
a n d ha ve b ee n see n i n set mela n oti de P hase 1  a n d 2 st u dies.  H o we ver, o cc urre nce of t hese e ve nts 
d oes n ot a p pear t o c orr el ate wit h d ose a n d d urati o n of d osi n g, as t h e n u m ber of e v e nts di d n ot 
i ncreas e wit h d ose or d ur ati o n of d osi n g.  T hes e e ve nts ha ve bee n i nter mitte nt us uall y lasti n g less 
t ha n 2 0 mi n utes, pai nless, a n d res ol ve d wit h o ut i nter ve nti o n.  S o me patie nts ha ve ha d a series of 
s uc h erecti o ns o ver a m ulti-h o ur i nter val, wit h i nter mitte nt flacci dit y.  If a p atie nt re p orts a 
pai nless, n o n- er otic c o nti n u o us erecti o n of m ore t ha n o ne- h o ur d urati o n, b ase d o n I n vesti gat or 
j u d g me nt, st u d y dr u g i njecti o n is t o be i m me diatel y disc o nti n ue d.  If after st u d y dr u g 
disc o nti n uati o n t he e ve nt d oes n ot res ol ve, f urt her treat me nt ma y be pr o vi de d as cli nicall y 
i n dicate d. 
Erecti o ns lasti n g m or e t h a n f o ur h o urs or pai nf ul erecti o ns of s h orter d urati o n are of s eri o us 
c o ncer n, es peciall y si nce  t he prese n ce of p ai n ma y c o n n ote l ocalize d pe nile isc he mia.  N o 
pai nf ul or pr ol o n ge d erecti o ns ha ve bee n re p orte d i n P hase 1 or 2 st u dies, h o we ver, i n t he e ve nt 
o ne is re p orte d, st u d y dr u g i njecti o n is t o be st o p p e d i m me diatel y a n d a n e x a mi nati o n of t he 
p atie nt perf or m e d b y t he I n v esti gat or.  T he Ur ol o g y C o ns ulta nt is t o be n otifie d i m me diatel y a n d 
is t o pr o vi de e mer ge nt i nstr ucti o ns re gar di n g f urt her e val u ati o n a n d treat me nt.   
 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
1 1. 6.  E v al u ati o n of A b n or m al Li ver F u ncti o n Tests ( L F Ts) 
W hile t here has bee n n o si g nal of ele vate d L F Ts d uri n g t he P has e 1/ 2 st u dies of R M- 4 9 3, n or 
a n y si g nal i de ntifi e d i n t he t o xic ol o gical st u dies, t he f oll o wi n g is g ui da n ce f or e val uati o n of a n y 
L F T a b n or malities i de ntifie d d uri n g t he c o urs e of t his st u d y  
 
1.  If A L T or A S T > 3 U L N, re peat i n 4 8- 7 2 hrs. 
2.  If re p eat A L T or A S T ar e still > 3 U L N, re peat L F Ts (i ncl u di n g tra nsa mi nase, al kali ne 
p h os p hatase a n d bilir u bi n le vels) e ver y 4 8- 7 2 hrs.  I n a d diti o n, t he f oll o wi n g s h o ul d be 
perf or me d:  
O btai n a detaile d hist or y of s y m pt o ms, pri or a n d c o nc urre nt diseases, c o n c o mita nt dr u g 
use (i ncl u di n g O T C, her b al a n d dietar y s u p ple m e nts), alc o h ol a n d recreati o nal dr u g 
use a n d s peci al diets  
O btai n hist or y of e x p os ure t o e n vir o n me ntal c he mical a ge nts 
C o nsi der e val uati o n f or ac ute viral he p atitis t y p es A, B, C, D a n d E, a ut oi m m u ne or 
alc o h olic he patitis, n o nal c o h olic steat o he patitis ( N A S H), biliar y tract disease a n d 
isc he mic li ver i nj ur y 
C o nsi der a d diti o nal tests t o e val uate he p atic f u ncti o n, as a p pr o pri ate, s uc h as I N R. 
C o nsi der he pat ol o g y c o ns ultati o n 
Fre q u e nc y of re peat testi n g ca n be r e d uce d if L F T a b n or malities sta bilize or if t he patie nt is 
as y m pt o matic a n d st u d y dr u g is disc o nti n ue d. 
3.  Disc o nti n ue st u d y dr u g a d mi nistrati o n if:  
A L T or A S T > 8 x U L N o n a n y s i n gle d eter mi nati o n 
A L T or A S T > 5 x U L N f or m ore t ha n 2 w ee ks 
A L T or A S T > 3 x U L N wit h t otal bilir u bi n > 2 x U L N or I N R > 1. 5 
A L T or A S T > 3 x U L N wit h t he a p peara nce of fati g ue, fe ver, ras h, a n d/ or e osi n o p hilia 
( > 5 %) or na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der n ess t hat is m ore 
fre q ue nt a n d/ or m ore se v ere t ha n p atie nt’s baseli n e D G s y m pt o ms 
4.  F oll o w- u p t o Res ol uti o n:  All st u d y patie nts wit h cli nicall y si g nifica nt treat me nt -e mer ge nt 
L F T a b n or malities s h o ul d be f oll o we d u ntil val ues ret ur n t o n or mal or bas el i ne le vels 
A da pte d fr o m: U S De p art me nt of Healt h a n d H u m a n Ser vices, F o o d a n d Dr u g A d mi nistrati o n, 
Ce nter f or Dr u g E val uati o n a n d Resear c h ( C D E R) Ce nter f or Bi ol o gi cs E val uati o n a n d Researc h 
( C B E R). G ui da n ce f or I n d ustr y Dr u g-I n d u ce d Li v er I nj ur y: Pre mar keti n g Cli nical E val uati o n. 
Sil ver S pri n g, M D. J ul y 2 0 0 9. 
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
1 1. 7.  St a n d ar diz ati o n of Bl o o d Press ure Me as ure me nt  
F or B P meas ure m e nts, t he patie nt will re mai n i n t he sitti n g p ositi o n f or at le ast 5 mi n utes 
bef ore a n y B P r ea di n gs are rec or de d. S yst olic a n d diast olic bl o o d press ures will be deter mi ne d 
b y a v era gi n g t hr ee (3) c o nsec uti ve meas ure me nts o btai ne d 2 mi n utes a part. N o ne of t he 3 
c o nsec uti ve r ea di n gs ca n be > 5 m m H g fr o m t he calc ulate d a v era ge of t he 3 rea di n gs .  If t his 
occ urs, o btai n a d diti o nal rea di n gs, 2 mi n utes a part, u ntil 3 c o nsec uti ve sta ble meas ure me nts are 
o btai ne d.  Rec or d o nl y t h e 3 sta ble rea di n gs, i n a d diti o n t o t he mea n, t he i nitial ti me of t he 
meas ure me nt a n d t he ar m use d f or t he meas ure m e nt i n t he case re p ort f or ms  (as o utli ne d bel o w). 
T he f oll o wi n g i nstr u cti o ns will be f oll o we d f or b ot h ma n ual a n d a ut o matic bl o o d press ure 
meas ure me nts ( wit h ste ps s pecific t o ma n ual i de ntifie d b y “[ M A N U A L] ” ). 
Please pa y s pecial  atte nti o n t o selecti n g t he a p pr o priate c uff size f or t his patie nt p o p ulati o n, as 
n ote d bel o w. 
T he acc urac y a n d r elia bilit y of bl o o d press ure rea di n gs will i ncrease b y f oll o wi n g t hes e 
sta n dar dize d ste ps: 
a. Sit uate t he i n di vi d ual i n a q uiet e n vir o n me nt wit h t he ar m resti n g at heart l e vel. 
b.  [ M A N U A L] F or m a n ual meas ure me nts, place t he ma n o meter at e ye le vel, s ufficie ntl y 
cl ose t o rea d t h e cali br ati o n mar ki n gs o n t he ga u ge or c ol u m n. 
c. Select t he a p pr o priatel y size d c uff. T he pr o p er c uff size s h o ul d be use d o n t he n o n-
d o mi n a nt ar m t hr o u g h o ut t he st u d y. Bla d der wi dt h s h o ul d be at least 4 0 % of ar m 
circ u mfere nce; bla d der s h o ul d be at least 8 0 % of ar m circ u mfere nce.  
d.  [ M A N U A L] L ocat e t he brac hial arter y al o n g t h e i n ner u p per ar m b y pal pati o n. 
e. Wra p t he c uff s m o ot hl y a n d s n u gl y ar o u n d t h e ar m, ce nt eri n g t he bla d d er o v er t he 
brac hial arter y. T h e l o wer mar gi n s h o ul d be 2. 5 c m a b o ve t he a ntec u bital s pace. ( D o n ot 
rel y o n c uff m ar ki n g; fi n d t he ce nter b y f ol di n g t h e bla d der i n half.) 
f. F or ma n u al meas ure m e nts:  
i. 
Deter mi ne t he le v el f or ma xi mal i nflati o n b y  o bs er vi n g t h e press ure at w hic h t he 
ra dial p ulse is n o l o n ger pal pa ble as t he c uff is ra pi dl y i nflate d ( p al pate d s yst olic) 
a n d b y a d di n g 3 0 m m H g. 
ii. 
Ra pi dl y a n d stea dil y d efl ate t he c uff. T he n w ait 1 5 t o 3 0 sec o n ds bef ore re-
i nflati n g. 
iii. 
F or ma n u al meas ure m e n ts, p ositi o n t he stet h osc o pe o ver t he p al pate d brac hial 
arter y b el o w t he c uff at t he a ntec u bital f oss a. Ear pieces s h o ul d p oi nt f or w ar d. 
T he bell hea d of t he stet h osc o pe s h o ul d be a p plie d wit h li g ht press ure, e ns uri n g 
s ki n c o ntact at all p oi nts. Hea v y press ure ma y dist ort s o u n ds. 
i v. 
Ra pi dl y a n d stea dil y i nfl ate t he c uff t o t he ma xi mal i nflati o n le vel as deter mi ne d 
i n Ste p f. 
v.  
Release t he air i n t he c uff s o t hat t he press ure falls at a rate of 2 t o 3 m m per 
sec o n d. 
vi.  
N ote t he s yst olic pr ess ure at t he o nset of at least t w o c o nsec uti ve b eats ( P h ase 1 
K or ot k off s o u n ds). Bl o o d press ure le v els s h o ul d al wa ys be rec or d e d i n e v e n 
n u m bers a n d r ea d t o t he nearest 2 m m H g mar k o n t he ma n o meter. 
vii.  
Rec or d t he diast olic pr ess ure at t he cessati o n of t h e K or ot k off s o u n ds ( P has e V). 
Liste n f or 1 0 t o 2 0 m m H g bel o w t h e last s o u n d hear d t o c o nfir m disa p p eara nce, 
a n d t he n deflat e t he c uff ra pi dl y a n d c o m pletel y.  

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R hyt h m P h ar m ace utic als, I nc. 
g.  F or a ut o matic meas ure m e nt:  
i. 
Ta ke a ut o matic meas ure me nts a n d rec or d.  
h.  Rec or d t he patie nt’s p ositi o n a n d t he ar m use d f or t he meas ure m e nt.  
i. Wait 2 mi n utes bef ore re peati n g t h e press ure meas ure me nt i n t he sa me ar m t o per mit t he 
releas e of bl o o d tra p p e d i n t he ar m vei ns. 
j. N ote t hat all t hree rea di n gs at eac h ti me p oi nt s h o ul d be ca pt ure d o n t h e cas e re p ort f or m, 
as well as t he a v era ge .  
k.  F or eac h patie nt, t he m et h o d use d f or B P deter mi nati o ns ( ma n ual or a ut o matic) s h o ul d be 
use d t hr o u g h o ut t he st u d y.  I n a d diti o n, t he sa me size c uff s h o ul d be use d t hr o u g h o ut.  
Care s h o ul d be ta ke n t o ma ke all meas ure me nts i n t he sa me p ositi o n (sitti n g) f or all 
meas ure me nts.  
 
R o u n di n g R ules f or Bl o o d Press ure Me as ure me nts  
Bl o o d press ur e rea di n gs will be rec or d e d t o t he nearest e v e n m m H g. D o n ot r o u n d off t o t he 
ne arest 5 or 1 0 m m H g B P re a di n g. T heref ore, a 1 4 2/ 9 4 rea di n g s h o ul d n ot be re p orte d as 
1 4 0/ 9 5, b ut s h o ul d be re p orte d as 1 4 2/ 9 4. 
W he n calc ulati n g t h e me a ns (a vera ge) of t h e rea di n gs, t he f oll o wi n g r ules s h o ul d be use d: 
If t he val ue is X X. 1 t o X X. 4, it s h o ul d be r o u n de d d o w n (e x a m ple: A diast olic mea n of 9 7. 2 
w o ul d be rec or de d as 9 7, as w o ul d a mea n of 9 7. 4). 
If t he val ue is X X. 5 or gr eater it s h o ul d be r o u n d e d u p (e x a m ple: A diast olic mea n of 9 7. 5 w o ul d 
be rec or de d as 9 8, as w o ul d a mea n of 9 7. 9). 
T he me a n of t he rea di n gs ma y be a n o d d n u m ber. 
 
S peci al Pitf alls a n d Pr o ble ms  
T he A usc ultat or y G a p  
[ M A N U A L] I n s o me s u bjects, partic ularl y i n patie nts wit h h y perte nsi o n, t h e s o u n ds hear d o v er 
t he brac hial arter y w he n t he c uff press ure is hi g h disa p pear as t he press ure is re d uce d a n d t he n 
rea p pear at s o me l o wer l e vel. T his earl y, te m p orar y disa p p eara nce of s o u n d is calle d t he 
a usc ultat or y ga p a n d occ urs d uri n g t h e latter part of P hase I a n d P has e II. Beca use t his ga p ma y 
e xte n d o ver a ra n ge as gr eat as 4 0 m m H g, o ne ma y seri o usl y u n d eresti mate t he s yst olic press ure 
or o veresti mate t he di ast olic press ure, u nless its prese nce is e x cl u de d b y first pal pati n g f or 
disa p pear a nce of t he r a dial p ulse as t he c uff press ure is raise d.  
Effect of Ar m P ositi o n  
T he press ur e i n t he ar m i ncreas es as t he ar m is l o were d fr o m t he le vel of t he ( p hle b ostatic a xis); 
c o n versel y, r aisi n g t h e ar m a b o ve t his p ositi o n l o wers t he press ure meas ure me nt. T he effect is 
lar gel y e x plai ne d b y h y dr ostatic press ure or b y t h e effect of gra vit y o n t he c ol u m n of bl o o d. 
T heref ore, w h e n meas uri n g i n direct bl o o d press ure, t he patie nts ar m s h o ul d be p ositi o ne d s o t hat 
t he l ocati o n of t he stet h osc o pe hea d ( prefera bl y t he bell or its e q ui vale nt) is at t he le vel of t he 
heart. T his l ocati o n of t h e heart is ar bitraril y ta ke n t o be at t he j u ncti o n of t he f o urt h i nterc ostal 
s pace a n d t h e l o wer l eft ster nal b order. W he n t he p atie nt is se ate d, pl aci n g t he ar m o n a 
ne ar b y t a blet o p a little a b o ve w aist le vel will res ult i n a s atisf act or y p ositi o n.   

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R hyt h m P h ar m ace utic als, I nc. 
Lar ge Ar m Size  
Falsel y ele v ate d i n direct press ure meas ure m e nts ma y b e o btai ne d i n patie nts wit h i ncrease d ar m 
girt h i f t he sta n d ar d-size d bla d der a n d tec h ni q ue are use d. T his is ca use d b y t he use of bla d ders 
t hat are t o o s mall, wit h s u bse q ue nt e x cessi ve l oss of c uff press ure t hr o u g h t he t hic k, 
c o m pressi ble s oft tiss ues of t he lar ge ar ms. T his pr o ble m ma y b e mi ni mize d b y usi n g a bla d d er 
wi dt h t hat is 4 0 t o 5 0 % of meas ure d ar m circ u mfere nce. I n i n di vi d uals wit h m o deratel y lar ge 
ar m size, a lar ge a d ult c uff ( 3 2 t o 4 2 c m wi de) will us uall y be a d e q uate, b ut a lar ger c uff ( 3 8- 5 0 
c m) s h o ul d be a vaila bl e, if necessar y. 
 
 

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R hyt h m P h ar m ace utic als, I nc. 

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R hyt h m P h ar m ace utic als, I nc. 

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R hyt h m P h ar m ace utic als, I nc. 

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R hyt h m P h ar m ace utic als, I nc. 

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R hyt h m P h ar m ace utic als, I nc. 

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R hyt h m P h ar m ace utic als, I nc. 

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R hyt h m P h ar m ace utic als, I nc. 
1 1. 1 0.  Cre ati ni ne Cle ar a nce Esti m ate b y C oc kcr oft -G a ult E q u ati o n  
 
Male Creati ni ne Cleara n ce m L/ mi n  = 1. 0 * (( 1 4 0 - A ge) / ( Ser u m  Creat)) * ( Wei g ht ( k g) / 7 2)  
 
Fe male  Cr eati ni ne Clear a nce m L/ mi n = 0. 8 5 * (( 1 4 0 - A ge) / ( Ser u m  Creat)) * ( Wei g ht ( k g) /  7 2)  
  
 
A ge i n years  
Ser u m creati ni ne i n m g/ d L  
 
 
C oc kcr oft D W, Ga ult M H. Pre dicti o n of creati ni n e cleara n ce fr o m ser u m cr eati ni n e.  Ne p hr o n . 1 9 7 6; 1 6( 1): 3 1-4 1.  
 
 
 

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R hyt h m P h ar m ace utic als, I nc. 
1 1. 1 1.  C o nsi der ati o ns f or re d uci n g p ai n a n d distress i n t he pe di atric p o p ul ati o n  
Alt h o u g h t he st u d y pr oce d ures a n d ass ess me nts re q uire d per pr ot o c ol are cl assifie d as “ N o or 
Mi ni mal Ris k” ( a part fr o m  D E X A w hic h is classifie d as “ Mi n or I n crease o ver Mi ni mal Ris k”) 
per  t he 2 0 0 8 G uida n ce D oc u me nt “ Et hical C o nsi derati o ns f or Cli nical Trials o n Me dici na l 
Pr o d ucts C o n d ucte d wit h t he Pe diatric P o p ulati o n”, c o nsi derati o ns f or re d u ci n g p ai n i n distress 
i n partici pa nts y o u n ger t ha n 1 8 years of a ge are s u g geste d bel o w. 
 
•  T he cli nic al trial ma y o nl y be c o n d ucte d if it s u bjects t he pers o n c o n cer n e d t o as little 
b ur de n a n d ot her f or eseea ble ris ks as p ossi ble; 
•  P h ysical a n d e m oti o nal pai n s h o ul d be pre ve nt e d as m uc h as p ossi ble, a n d effecti vel y 
treate d w h e n u na v oi da bl e. 
•  T o  mi ni mize pai n, distress, a n d fear, facilities s h o ul d be a p pr o priat e t o c hil dcare, a n d t he 
pers o n nel s h o ul d be trai n e d t o l o o k after c hil dre n a n d s u per vise d b y e x perie nce d h ealt h 
care pr ofessi o nals. Staff s h o ul d be trai ne d t o c o m m u nicate wit h b ot h pare nts ( or le gal 
re pres e ntati ve) a n d c hil dr e n.  Ge nerall y, t his w o ul d ass u me n o n-a d ult patie nts are bei n g 
st udie d at e x perie nce d p e diatric ce nters .  
•  F or m ost pr oce d ures, t he c hil d s h o ul d al wa ys b e acc o m pa nie d b y a trial- relate d staff 
me m ber w h o c o ul d pr o vi de reass ura nce. At t he si g n of distress a n d/ or disse nt t he 
pr oce d ur e s h o ul d be st o p pe d; a s h ort pa use t o all o w t he c hil d t o feel i n c o ntr ol, f urt her 
e x pla nati o n a n d a n assess me nt of t he sit uati o n ma y be n ee d e d t o reass ure t he c hil d, or t o 
deci de t o a b a n d o n t he pr oce d ure at t he discreti o n of t he I n vesti gat or. 
•  I n all sit uati o ns, i n vesti gati o ns/i nter ve nti o ns s h o ul d be li mite d t o t he mi ni m u m re q uire d 
f or o btai ni n g v ali d data a n d perf or me d usi n g size-/a ge-a p pr o priate mat erial a n d de vices, 
i ncl u di n g li miti n g i n a d v a nce t he n u m b er of atte m pts f or sa m pli n g. 
•  St u d y dr u g i njecti o ns s h o ul d o nl y be perf or me d b y pare nts ( or h o m e healt h care 
pr ofessi o nals), u nless t he c hil d is of s uita ble a ge a n d c o m pete nc y, a n d desires t he a bilit y 
t o d o s o. 
•  Alt h o u g h al m ost all st u d y pr o ce d ures are classifie d as l o w ris k ( e x ce pt for  D E X A w hic h 
is classifie d as “ mi n or i n creas e o ver mi ni mal ris k ”), ris k s h o ul d be c o nti n u o usl y 
m o nit ore d a n d assesse d b y a p pr o priate p ers o n nel .  
•  F or ass ess me nts i n w hic h t here is a ps yc h ol o gical c o m p o ne nt meas ures s h o ul d be ta ke n 
t o mi ni mize distress.  F or e x a m ple, Ta n ner Sta gi n g ass ess me nts c o ul d utilize a dia gra m 
f or the c hil d t o p oi nt t o a n d i n dicate w hat sta ge t h e y c urre ntl y are, vs. h a vi n g t o ha v e a n 
e x a m wit h o ut cl ot hes. 
 
A c o m me nt o n be nefit ris k:  ris k is ver y l o w, fr o m pr oce d ures a n d/ or k n o w n safet y pr ofile of t he 
dr u g ( b ot h cli nicall y a n d t o xic ol o gicall y, w h ere lar ge mar gi ns a n d preli mi nar y data fr o m j u ve nile 
t o xic ol o g y st u dies ha ve n ot i de ntifie d a n y n e w or c o ncer ni n g s afet y c o n cer ns), a n d base d o n o n e 
re pres e ntati ve e x a m ple of rar e ge netic dis or d er of o besit y i m pacti n g t he M C 4 pat h wa y, t here is 
t he p ossi bilit y of maj or b e nefit. 
 
 

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R hyt h m P h ar m ace utic als, I nc. 
1 1. 1 2.  Bl o o d V ol u mes f or St u d y Tests 
T he bl o o d v ol u mes f or st u d y ass ess me nts are liste d i n Ta bles 1 a n d 2 bel o w.   
 
 

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
 
1 1. 1 3.  Decl ar ati o n of Helsi n ki  
W orl d Me dic al Ass oci ati o n Decl ar ati o n of Helsi n ki:  
Rec o m me n dati o ns G ui di n g Me dical D oct ors i n Bi o me dical Researc h I n v ol vi n g H u ma n Patie nts 
A d o pte d b y t h e 1 8 t h W orl d Me dical Ass ociati o n ( W M A) Ge neral Asse m bl y, H elsi n ki, Fi nla n d, 
J u ne 1 9 6 4 a n d a me n de d b y t he 2 9 t h W M A Ge neral Asse m bl y, T o k y o, J a pa n, Oct o ber 1 9 7 5, 3 5t h 
W M A Ge neral Asse m bl y, Ve nice, It a l y, Oct o ber 1 9 8 3, a n d t he 4 1st W M A Ge neral Asse m bl y, 
H o n g K o n g, Se pt e m ber 1 9 8 9, t he 4 8 t h W M A Ge neral Asse m bl y, S o merset West, Re p u blic of 
S o ut h Africa, Oct o b er 1 9 9 6; 5 2 n d W M A Ge neral Asse m bl y, E di n b ur g h, Sc otla n d, Oct o ber 2 0 0 0; 
5 3r d W M A Ge ner al Asse m bl y, Was hi n gt o n 2 0 0 2 ( N ote of Clarificati o n o n para gra p h 2 9 a d d e d); 
5 5t h W M A Ge neral Asse m bl y, T o k y o 2 0 0 4 ( N ote of Clarificati o n o n Para gra p h 3 0 a d de d); a n d 
5 9t h W M A Ge neral Asse m bl y, Se o ul, Oct o ber 2 0 0 8. 
A.  
I N T R O D U C TI O N  
1.  T he W orl d Me dical Ass o ciati o n ( W M A) has de vel o pe d t he Declarati o n of Helsi n ki as a 
state me nt of et hical pri n ci ples f or me dical researc h i n v ol vi n g h u ma n patie nts, i ncl u di n g 
researc h o n i de ntifia bl e h u ma n material a n d d ata.  
T he Decl arati o n is i nte n d e d t o be rea d as a w h ole a n d eac h of its c o nstit ue nt para gra p hs 
s h o ul d n ot be a p plie d wit h o ut c o nsi derati o n of all ot her rele v a nt para gra p hs.  
2.  Alt h o u g h t he D eclar ati o n is a d dresse d pri maril y t o p h ysicia ns, t he W M A e n c o ura ges ot h er 
partici pa nts i n me dical r esearc h i n v ol vi n g h u ma n patie nts t o a d o pt t hese pri nci ples.  
3.  It is t he d ut y of t he p h ysi cia n t o pr o m ote a n d safe g uar d t he healt h of patie nts, i ncl u di n g t h ose 
w h o are i n v ol ve d i n me di cal res ear c h. T he p h ysici a n's k n o wle d ge a n d c o ns cie nce are 
de dicate d t o t he f ulfil me nt of t his d ut y.  
4.  T he Decl arati o n of G e ne va of t he W M A bi n ds t he p h ysicia n wit h t he w or ds, " T he h ealt h of 
m y patie nt will be m y first c o nsi derati o n," a n d t he I nter nati o nal C o de of M e dical Et hics 
declar es t hat, " A p h ysicia n s hall act i n t he patie nt's best i nterest w he n pr o vi di n g me dical 
care."  
5.  Me dical pr o gr ess is base d o n researc h t hat ulti matel y m ust i ncl u de st u dies i n v ol vi n g h u ma n 
patie nts. P o p ulati o ns t hat are u n derre prese nt e d i n me dical res earc h s h o ul d be pr o vi de d 
a p pr o priate access t o partici pati o n i n researc h.  
6.  I n me di cal r esearc h i n v ol vi n g h u ma n patie nts, t he well- bei n g of t he i n di vi d ual researc h 
patie nt m ust ta ke prece de nce o ver all ot her i nterests.  
7.  T he pri mar y p ur p os e of me dical res earc h i n v ol vi n g h u ma n p atie nts is t o u n dersta n d t he 
ca uses, de v el o p me nt a n d effects o f diseas es a n d i m pr o ve pre v e nti ve, dia g n ostic a n d 
t hera pe utic i nter v e nti o ns ( met h o ds, pr oce d ures a n d treat me nts). E ve n t h e b est c urre nt 
i nter ve nti o ns m ust be e val uate d c o nti n uall y t hr o u g h researc h f or t heir safet y, effecti ve ness, 
efficie n c y, accessi bilit y a n d q ualit y.  
8.  I n me di cal pr actice a n d i n me dical res earc h, m ost i nter ve nti o ns i n v ol ve ris ks a n d b ur de ns.  
9.  Me dical res ear c h is patie nt t o et hical sta n dar ds t hat pr o m ote res pect f or all h u ma n patie nts 
a n d pr otect t heir h ealt h a n d ri g hts. S o me res earc h p o p ulati o ns are partic ul arl y v ul nera ble a n d 
nee d s peci al pr otecti o n. T hese i ncl u de t h ose w h o ca n n ot gi ve or ref use c o nse nt f or 
t he msel ves a n d t h ose w h o ma y b e v ul nera bl e t o c oerci o n or u n d u e i nfl ue n ce.  
1 0.  P h ysicia ns s h o ul d c o nsi d er t he et hical, le gal a n d re g ul at or y n or ms a n d sta n dar ds f or researc h 
i n v ol vi n g h u ma n patie nts i n t heir o w n c o u ntries as well as a p plica ble i nter n ati o nal n or ms a n d 

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R hyt h m P h ar m ace utic als, I nc. 
sta n dar ds. N o nati o nal or i nter nati o nal et hical, le gal or re g ulat or y re q uire me nt s h o ul d re d uce 
or eli mi nate a n y of t he pr otecti o ns f or res earc h patie nts set f ort h i n t his Declarati o n.  
B.  
B A SI C P RI N CI P L E S F O R A L L M E DI C A L R E S E A R C H  
1 1.  It is t he d ut y of p h ysicia ns w h o partici pate i n me di cal res earc h t o pr otect t h e life, healt h, 
di g nit y, i nte grit y, ri g ht t o self - deter mi nati o n, pri vac y, a n d c o nfi d e ntialit y of pers o nal 
i nf or mati o n of resear c h p atie nts.  
1 2.  Me dical res ear c h i n v ol vi n g h u ma n p atie nts m ust c o nf or m t o ge nerall y acce pte d scie ntific 
pri nci ples, be base d o n a t h or o u g h k n o wl e d ge of t he scie ntific literat ure, ot her rel e va nt 
s o urces of i nf or mati o n, a n d a de q uate l a b orat or y a n d, as a p pr o pri ate, a ni mal e x peri me ntati o n. 
T he welf are of a ni mals use d f or r esearc h m ust be res pect e d.  
1 3.  A p pr o priate ca uti o n m ust be e x ercise d i n t he c o n d uct of me dical researc h t hat ma y h ar m t he 
e n vir o n me nt.  
1 4.  T he desi g n a n d perf or ma nce of eac h researc h st u d y i n v ol vi n g h u m a n patie nts m ust be clearl y 
descri be d i n a researc h pr ot oc ol. T he pr ot oc ol s h o ul d c o ntai n a state me nt of t he et hical 
c o nsi derati o ns i n v ol ve d a n d s h o ul d i n dicate h o w t he pri nci ples i n t his Decl arati o n h a ve b ee n 
a d dresse d. T h e pr ot oc ol s h o ul d i ncl u de i nf or mati o n re gar di n g f u n di n g, s p o ns ors, i nstit uti o nal 
affiliati o ns, ot her p ote ntial c o nflicts of i nterest, i nce nti ves f or p atie nts a n d pr o visi o ns f or 
treati n g a n d/ or c o m p e nsati n g patie nts w h o are har me d as a c o ns e q ue nce of partici pati o n i n 
t he researc h st u d y. T he pr ot oc ol s h o ul d descri be arra n ge m e nts f or p ost-st u d y access b y st u d y 
patie nts t o i nter ve nti o ns i de ntifie d as be n eficial i n t he st u d y or access t o ot her a p pr o priate 
care or be n efits.  
1 5.  T he resear c h pr o t oc ol m ust be s u b mitte d f or c o nsi derati o n, c o m me nt, g ui da nce a n d a p pr o v al 
t o a researc h et hics c o m mittee bef ore t he st u d y b e gi ns. T his c o m mittee m ust be i n de pe n de nt 
of t he resear c her, t he s p o ns or a n d a n y ot her u n d ue i nfl ue nce. It m ust ta ke i nt o c o nsi derati o n 
t he la ws a n d r e g ulati o ns of t he c o u ntr y or c o u ntries i n w hic h t he researc h is t o be perf or m e d 
as well as a p plica ble i nter nati o nal n or ms a n d sta n dar ds b ut t hese m ust n ot be all o we d t o 
re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h patie nts set fort h i n t his Declarati o n. 
T he c o m mittee m ust ha ve t he ri g ht t o m o nit or o n g oi n g st u dies. T he researc her m ust pr o vi de 
m o nit ori n g i nf or mati o n t o t he c o m mittee, es peci all y i nf or mati o n a b o ut a n y seri o us a d vers e 
e ve nts. N o c h a n ge t o t he pr ot oc ol ma y b e ma de wit h o ut c o nsi derati o n a n d a p pr o val b y t he 
c o m mittee.  
1 6.  Me dical res ear c h i n v ol vi n g h u ma n p atie nts m ust be c o n d ucte d o nl y b y i n di vi d uals wit h t he 
a p pr o priate s cie ntific trai ni n g a n d q u alificati o ns. Researc h o n p atie nts or h ealt h y v ol u nteers 
re q uires t he s u p er visi o n of a c o m pete nt a n d a p pr o priatel y q u alifie d p h ysici a n or ot her h ealt h 
care pr ofessi o nal. T h e res p o nsi bilit y f or t h e pr otecti o n of researc h p atie nts m ust al wa ys rest 
wit h t he p h ysicia n or ot her healt h care pr ofessi o nal a n d ne ver t he researc h patie nts, e ve n 
t h o u g h t he y ha v e gi ve n c o nse nt.  
1 7.  Me dical res ear c h i n v ol vi n g a disa d va nta ge d or v ul nera ble p o p ulati o n or c o m m u nit y is o nl y 
j ustifie d if t he researc h is res p o nsi ve t o t he healt h nee ds a n d pri orities of t his p o p ulati o n or 
c o m m u nit y a n d if t here is a reas o n a ble li keli h o o d t hat t his p o p ulati o n or c o m m u nit y sta n ds t o 
be nefit fr o m t he res ults of t he researc h.  
1 8.  E ver y me dical researc h st u d y i n v ol vi n g h u ma n p atie nts m ust be prece de d b y caref ul 
assess me nt of pre di cta ble ris ks a n d b ur de ns t o t he i n di vi d uals a n d c o m m u nities i n v ol ve d i n 
t he researc h i n c o m p aris o n wit h f oreseea ble be n efits t o t he m a n d t o ot her i n di vi d uals or 
c o m m u nities affect e d b y t he c o n diti o n u n der i n vesti gati o n.  
1 9.  E ver y cli nical trial m ust be re gister e d i n a p u blicl y accessi ble data bas e bef ore recr uit me nt of 
t he first patie nt.  

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C O N FI D E N TI A L  
 
R hyt h m P h ar m ace utic als, I nc. 
2 0.  P h ysicia ns ma y n ot parti ci pate i n a researc h st u d y i n v ol vi n g h u ma n patie nts u nless t he y are 
c o nfi de nt t hat t he ris ks i n v ol ve d ha ve bee n a d e q uatel y ass esse d a n d ca n be satisfact oril y 
ma na ge d. P h ysicia ns m ust i m me diatel y st o p a st u d y w h e n t he ris ks are f o u n d t o o ut wei g h t he 
p ote ntial be nefits or w he n t here is c o ncl usi ve pr o of of p ositi ve a n d be neficial res ults.  
2 1.  Me dical res ear c h i n v ol vi n g h u ma n p atie nts ma y o nl y be c o n d ucte d if t he i m p orta nce of t h e 
o bjecti ve o ut wei g hs t he i n here nt ris ks a n d b ur de ns t o t he researc h patie nts.  
2 2.  Partici pati o n b y c o m p ete nt i n di vi d uals as patie nts i n me dical researc h m ust be v ol u ntar y. 
Alt h o u g h it ma y be a p pr o priate t o c o ns ult fa mil y me m bers or c o m m u nit y l ea ders, n o 
c o m pete nt i n di vi d ual ma y be e nr olle d i n a researc h st u d y u nless he or s h e freel y a grees.  
2 3.  E ver y preca uti o n m ust be ta ke n t o pr otect t he pri vac y of researc h p atie nts a n d t he 
c o nfi de ntialit y of t heir pers o nal i nf or mati o n a n d t o mi ni mize t he i m pact of t he st u d y o n t heir 
p h ysical, me nt al a n d s oci a l i nte grit y.  
2 4.  I n me di cal r esearc h i n v ol vi n g c o m pet e nt h u ma n p atie nts, eac h p ote ntial p atie nt m ust be 
a de q uatel y i nf or me d of t he ai ms, met h o ds, s o urces of f u n di n g, a n y p ossi ble c o nflicts of 
i nterest, i nstit uti o nal affiliati o ns of t he researc h er, t he a ntici pate d be n efits a n d p ote ntial ris ks 
of t he st u d y a n d t he disc o mf ort it ma y e nt ail, a n d a n y ot h er rele va nt as p ects of t he st u d y. T h e 
p ote ntial patie nt m ust be i nf or me d of t he ri g ht t o ref use t o partici p ate i n t he st u d y or t o 
wit h dra w c o nse nt t o partici pate at a n y ti me wit h o ut re prisal. S pecial atte nti o n s h o ul d be 
gi ve n t o t he s pecific i nf or mati o n nee ds of i n di vi d ual p ote ntial patie nts as well as t o t he 
met h o ds use d t o deli ver t he i nf or mati o n. After e ns uri n g t hat t he p ote ntial p atie nt has 
u n derst o o d t he i nf or mati o n, t he p h ysicia n or a n ot her a p pr o priatel y q ualifie d i n di vi d ual m ust 
t he n see k t he p ote ntial patie nt's fr eel y- gi ve n i nf or me d c o nse nt, prefera bl y i n writi n g. If t he 
c o nse nt ca n n ot be e x presse d i n writi n g, t he n o n- writte n c o nse nt m ust be f or mall y 
d oc u me nte d a n d wit ness e d.  
2 5.  F or me dical resear c h usi n g i de ntifia ble h u m a n material or d ata, p h ysicia ns m ust n or mall y 
see k c o nse nt f or t he c ollecti o n, a nal ysis, st ora ge a n d/ or re use. T h ere ma y b e sit uati o ns w here 
c o nse nt w o ul d be i m p ossi ble or i m practical t o o bt ai n f or s uc h researc h or w o ul d p ose a t hreat 
t o t he vali dit y of t he r esearc h. I n s u c h sit uati o ns t he researc h m a y be d o ne o nl y aft er 
c o nsi derati o n a n d a p pr o v al of a r esearc h et hics c o m mittee.  
2 6.  W he n see ki n g i nf or me d c o nse nt f or partici pati o n i n a researc h st u d y t he p h ysicia n s h o ul d be 
partic ularl y ca uti o us if t he p ote ntial patie nt is i n a de pe n de nt relati o ns hi p wit h t he p h ysicia n 
or ma y c o nse nt u n der d ur ess. I n s uc h sit uati o ns t he i nf or me d c o nse nt s h o ul d be s o u g ht b y a n 
a p pr o priatel y q u alifie d i n di vi d ual w h o is c o m pletel y i n de pe n d e nt of t his rel ati o ns hi p.  
2 7.  F or a p ot e ntial researc h p atie nt w h o is i nc o m pete nt, t he p h ysicia n m ust see k i nf or me d 
c o nse nt fr o m t he le gall y a ut h orize d re pres e ntati ve. T hese i n di vi d uals m ust n ot be i ncl u de d i n 
a researc h st u d y t hat h as n o li keli h o o d of be nefit f or t he m u nless it is i nte n de d t o pr o m ote t he 
healt h of t he p o p ulati o n r e prese nt e d b y t he p ote nti al patie nt, t he researc h ca n n ot i nstea d be 
perf or me d wit h c o m pete nt pers o ns, a n d t he researc h e ntails o nl y mi ni mal ris k a n d mi ni mal 
b ur de n.  
2 8.  W he n a p ote ntial researc h patie nt w h o is dee me d i nc o m pete nt is a ble t o gi ve asse nt t o 
decisi o ns a b o ut partici pati o n i n researc h, t he p h ysi cia n m ust see k t hat asse nt i n a d diti o n t o 
t he c o nse nt of t he le gall y a ut h orize d re pres e ntati v e. T he p ote ntial patie nt's disse nt s h o ul d be 
res pect e d.  
2 9.  Researc h i n v ol vi n g patie nts w h o are p h ysicall y or me ntall y i nca pa ble of gi vi n g c o ns e nt, f or 
e x a m ple, u nc o nsci o us patie nts, ma y be d o n e o nl y if t he p h ysical or me ntal c o n diti o n t hat 
pre ve nts gi vi n g i nf or me d c o nse nt is a necessar y c haract eristic of t he resea rc h p o p ulati o n. I n 
s uc h circ u msta nces t he p h ysicia n s h o ul d see k i nf or me d c o nse nt fr o m t he le gall y a ut h orize d 

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R hyt h m P h ar m ace utic als, I nc. 
re pres e ntati ve. If n o s u c h re pres e ntati ve is a vaila bl e a n d if t he researc h ca n n ot be dela ye d, 
t he st u d y ma y pr o cee d wit h o ut i nf or me d c o nse nt pr o vi de d t hat t he s pecifi c reas o ns f or 
i n v ol vi n g patie nts wit h a c o n diti o n t hat re n ders t he m u na ble t o gi ve i nf or me d c o nse nt ha ve 
bee n state d i n t he r esearc h pr ot oc ol a n d t he st u d y has bee n a p pr o ve d b y a researc h et hics 
c o m mittee. C o nse nt t o re mai n i n t he resear c h s h o ul d be o btai ne d as s o o n as p ossi ble fr o m t he 
patie nt or a le gall y a ut h orize d re pres e ntati ve.  
3 0.  A ut h ors, e dit ors a n d p u blis hers all ha ve et hical o bli gati o ns wit h re gar d t o t he p u blicati o n of 
t he res ults of res ear c h. A ut h ors ha ve a d ut y t o ma ke p u blicl y a vaila ble t he res ults of t heir 
researc h o n h u ma n p atie nts a n d are acc o u nt a ble f or t he c o m plete ness a n d acc urac y of t heir 
re p orts. T he y s h o ul d a d h ere t o acce pt e d g ui deli nes f or et hical re p orti n g. N e gati ve a n d 
i nc o ncl usi ve as well as p ositi ve res ults s h o ul d be p u blis he d or ot her wise m a de p u blicl y 
a vaila ble. S o urces of f u n di n g, i nstit uti o nal affiliati o ns a n d c o nflicts of i nterest s h o ul d be 
declar e d i n t he p u blicati o n. Re p orts of researc h n ot i n acc or da n ce wit h t he pri nci ples of t his 
Declar ati o n s h o ul d n ot be acce pte d f or p u blicati o n.  
C 
A D DI TI O N A L P RI N CI P L E S F O R M E DI C A L R E S E A R C H C O M BI N E D WI T H 
M E DI C A L C A R E  
3 1.  T he p h ysi cia n ma y c o m bi ne me dical res earc h wit h me dical care o nl y t o t he e xte nt t hat t he 
researc h is j ustifie d b y its p ote ntial pre ve nti ve, dia g n ostic or t hera pe utic v al ue a n d if t he 
p h ysicia n h as g o o d reas o n t o belie ve t hat partici pati o n i n t he researc h st u d y will n ot 
a d versel y aff ect t he healt h of t he patie nts w h o ser ve as res earc h patie nts.  
3 2.  T he be nefits, ris ks, b ur de ns a n d eff ecti ve ness of a ne w i nter ve nt i o n m ust be teste d a gai nst 
t h ose of t he best c urre nt pr o ve n i nter ve nti o n, e x ce pt i n t he f oll o wi n g circ u msta nces:  
•  T he use of place b o, or n o treat me nt, is acce pta ble i n st u dies w here n o c urre nt pr o ve n 
i nter ve nti o n e xists; or  
•  W here f or c o m p elli n g a n d scie nt ificall y s o u n d met h o d ol o gical reas o ns t he use of place b o 
is necessar y t o d eter mi ne t he efficac y or s afet y of a n i nter ve nti o n a n d t he p atie nts w h o 
recei v e place b o or n o treat me nt will n ot be patie nt t o a n y ris k of seri o us or irre versi ble 
har m. E xtre me car e m ust be ta ke n t o a v oi d a b us e of t his o pti o n.  
3 3.  At t he c o ncl usi o n of t he st u d y, patie nts e ntere d i nt o t he st u d y are e ntitle d t o be i nf or me d 
a b o ut t he o utc o me of t he st u d y a n d t o s hare a n y b e nefits t hat res ult fr o m it, f or e x a m ple, 
access t o i nter ve nti o ns i de ntifie d as be n eficial i n t he st u d y or t o ot her a p pr o priate care or 
be nefits.  
3 4.  T he p h ysi cia n m ust f ull y i nf or m t he patie nt w hic h as pects of t he care are relate d t o t he 
researc h. T h e ref usal of a patie nt t o partici pate i n a st u d y or t he p atie nt's d ecisi o n t o wit h dra w 
fr o m t he st u d y m ust ne v er i nterfere wit h t he patie nt-p h ysicia n relati o ns hi p.  
I n t he treat me nt of a pati e nt, w here pr o ve n i nter v e nti o ns d o n ot e xist or ha ve bee n i neffecti ve, 
t he p h ysicia n, after see ki n g e x pert a d vice, wit h i nf or me d c o nse nt fr o m t he patie nt or a le gall y 
a ut h orize d re pres e ntati ve, ma y use a n u n pr o v e n i nter ve nti o n if i n t he p h ysi cia n's j u d g me nt it 
offers h o p e of sa vi n g life, re -esta blis hi n g healt h or alle viati n g s ufferi n g. W here p ossi ble, t his 
i nter ve nti o n s h o ul d be ma de t he o bject of res earc h, desi g ne d t o e val uate its safet y a n d efficac y. 
I n all cases, n e w i nf or mati o n s h o ul d be rec or de d a n d, w here a p pr o pri ate, ma de p u blicl y 
a vaila ble.