Clinical trial NCT03287960
Conditions: Leptin Receptor Deficiency Obesity
Keywords: LEPR deficiency obesity setmelanotide RM-493 Leptin receptor Obesity Melanocortin 4 receptor
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2018-01-30; Completion date: 2020-09-25
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To demonstrate statistically significant and clinically meaningful effects of setmelanotide on percent body weight change in participants with LEPR deficiency obesity due to rare bi-allelic or loss-of function mutations at the end of 1 year of treatment.

Detailed description:

Arms: arm 1: Participants received titrated doses of setmelanotide once daily, by SC injection during titration period for 2 - 12 weeks. Thereafter, participants continued setmelanotide at their specific therapeutic dose for an additional 10 weeks during the open label treatment period. Participants who achieved at least a 5 kg weight loss (or at least 5% weight loss if baseline body weight was \<100 kg) at the end of the open label treatment period, continued into the 8-week double-blind withdrawal period and received 4 weeks setmelanotide and 4 weeks placebo. Following the withdrawal period, participants entered open label treatment period and received setmelanotide to complete approximately 52 weeks (\~1 year) of treatment at a therapeutic dose.
Interventions: intervention 1: Setmelanotide intervention 2: Placebo
Intervention descriptions: intervention 1: Once daily subcutaneous injection intervention 2: Once daily subcutaneous injection

Protocol documents:
Prot_000.pdf: 
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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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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  
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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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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R hyt h m P h ar m ace utic als, I nc. 
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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C O N FI D E N TI A L  
 
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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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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R hyt h m P h ar m ace utic als, I nc. 
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).   
3 3  


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R hyt h m P h ar m ace utic als, I nc. 
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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C O N FI D E N TI A L  
 
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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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, 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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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C O N FI D E N TI A L  
 
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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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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pa ge 8 9 
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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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. 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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C O N FI D E N TI A L  
 
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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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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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.  
 
 

SAP_001.pdf: 
Confidentiality 
This document is confidential and proprietary property of Rhythm Pharmaceuticals, Inc. and to be used only as 
authorized by Rhythm Pharmaceuticals, Inc..  No part is to be reproduced, disclosed to others, or quoted without 
prior written authorization from Rhythm Pharmaceuticals, Inc. 
STATISTICAL ANALYSIS PLAN 
Protocol RM-493-015 
 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 
Protocol Number: 
(Version Date) 
RM-493-015 
(10 APR 2018, Version 1.1, Amendment 3) 
Name of Test Drug: 
Setmelanotide (RM-493, Melanocortin-4 Receptor Agonist) 
Phase: 
3 
Methodology: 
Pivotal, 1 year open-label active treatment with a double-
blind, placebo-controlled withdrawal period 
Sponsor: 
Rhythm Pharmaceuticals, Inc. 
500 Boylston Street, 11th Floor 
Boston, MA 02116, USA 
Sponsor Representative: 
 
Document Date: 
16 April 2019 
Document Version: 
Version 2.0 




Rhythm Pharmaceuticals, Inc. 
Protocol RM-493-015 
 
16 Apr 2019 
 
CONFIDENTIAL 
 
3 
TABLE OF CONTENTS 
Section 
Page 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS ............................................ 7 
1.1. 
Introduction .......................................................................................................... 7 
1.2. 
Objectives of Statistical Analysis ........................................................................ 8 
2. 
STUDY DESIGN .............................................................................................................. 9 
2.1. 
Synopsis of Study Design ..................................................................................... 9 
2.2. 
Randomization Methodology ............................................................................ 11 
2.3. 
Blinding During the 8-Week Double-Blind Withdrawal ................................ 11 
2.4. 
Data Handling to Ensure Study Integrity ........................................................ 11 
2.5. 
Planned Trial Conduct Assessment and Safety Monitoring .......................... 13 
2.6. 
Study Procedures ............................................................................................... 13 
2.7. 
Efficacy, Pharmacokinetic, and Safety Variables ........................................... 13 
2.7.1. 
Efficacy Variables ................................................................................. 13 
2.7.2. 
Pharmacokinetic Variables ................................................................... 16 
2.7.3. 
Safety Variables .................................................................................... 16 
3. 
SUBJECT POPULATIONS .......................................................................................... 17 
3.1. 
Population Definitions ....................................................................................... 17 
3.1.1. 
Key Populations: ................................................................................... 17 
3.2. 
Rationale for the DUS Population as Population of Interest for 
Percent Change in Weight and Hunger over 1-year (Key 
Secondary Endpoints) ........................................................................................ 18 
3.4. 
Protocol Violations ............................................................................................. 21 
4. 
STATISTICAL METHODS ......................................................................................... 23 
4.1. 
Sample Size Justification ................................................................................... 23 
4.2. 
General Statistical Methods and Data Handling ............................................ 23 
4.2.1. 
General Methods ................................................................................... 23 
4.2.2. 
Definition of Baselines, Study Periods, and Reporting ........................ 24 
4.2.3. 
Computing Environment ....................................................................... 25 
4.2.4. 
Methods of Pooling Data between Different Protocols for 
Supplemental Exploratory Analyses ..................................................... 25 
4.2.5. 
Adjustments for Covariates ................................................................... 26 
4.2.6. 
Multiple Comparisons/Multiplicity ...................................................... 26 


Rhythm Pharmaceuticals, Inc. 
Protocol RM-493-015 
 
16 Apr 2019 
 
CONFIDENTIAL 
 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2.7. 
Subpopulations ...................................................................................... 27 
4.2.8. 
Withdrawals, Dropouts, Loss to Follow-up .......................................... 27 
4.2.9. 
Missing, Unused, and Spurious Data .................................................... 27 
4.2.10. 
Visit Windows ...................................................................................... 29 
4.3. 
Data Verification Procedures during Screening and the Titration 
Period .................................................................................................................. 29 
4.4. 
Subject Disposition ............................................................................................. 30 
4.5. 
Demographic and Baseline Characteristics ..................................................... 30 
4.6. 
Efficacy Evaluations .......................................................................................... 30 
4.6.1. 
Primary Efficacy Evaluation ................................................................. 31 
4.6.2. 
Key Secondary Efficacy Endpoints ...................................................... 31 
4.6.3. 
Secondary Efficacy Endpoints .............................................................. 34 
4.7. 
Rationale for Key Elements of the SAP ........................................................... 39 
4.7.1. 
Definitions of Success for Clinical Benefit in the 
Assessment of Efficacy for the Primary and Secondary 
Endpoints .............................................................................................. 39 
4.8. 
Pharmacokinetic Evaluations ........................................................................... 46 
4.9. 
Safety Analyses ................................................................................................... 46 
4.9.1. 
Adverse Events ..................................................................................... 46 
4.9.2. 
Laboratory Data .................................................................................... 47 
4.9.3. 
Vital Signs and Physical Examinations ................................................ 47 
4.9.4. 
Electrocardiogram ................................................................................. 48 
4.9.5. 
Concomitant Medications ..................................................................... 48 
5. 
CHANGES TO PLANNED ANALYSES .................................................................... 49 
6. 
References ....................................................................................................................... 50 
7. 
CLINICAL STUDY REPORT APPENDICES ........................................................... 51 
Appendix 1: Schedule of Assessments .......................................................................... 51 
Appendix 2: Supplemental Statistical Analyses supporting the primary 
and key endpoints. .............................................................................................. 59 
 
 


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Protocol RM-493-015 
 
16 Apr 2019 
 
CONFIDENTIAL 
 
5 
ABBREVIATIONS 
Abbreviation 
Definition 
ACTH 
Adrenocorticotropic hormone 
AE 
Adverse event 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
ATC 
Anatomic Therapeutic Class 
AUC 
Area under the curve 
BIA 
Bio-electrical impedance analysis 
BMI 
Body mass index 
BP 
Blood pressure 
BPM 
Beats per minute 
BTD 
Breakthrough Therapy Designation 
BQL 
Below the limit of quantification  
BUN 
Blood urea nitrogen 
CGIC 
Caregiver Global Impression of Change 
CGIS 
Caregiver Global Impression of Severity 
CI 
Confidence Interval 
CLIA 
Clinical Laboratory Improvement Amendments 
CM 
Centimeters 
CO2 
Carbon dioxide 
CPK 
Creatine phosphokinase 
CRF 
Case report form 
CS 
Completer Set 
CSR 
Clinical study report 
DEXA 
Dual-energy x-ray absorptiometry 
DUS 
Designated Use Set 
ECG 
Electrocardiogram 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration  
FSH 
Follicle Stimulating Hormone 
GGT 
Gamma-glutamyltranspeptidase  
HbA1c 
Hemoglobin A1c 
HOMA 
Homeostatic model assessment 
HR 
Heart rate 
ICH 
International Conference for Harmonization 
INR 
International normalized ratio 
KG 
Kilograms 
LDH 
Lactate dehydrogenase 
LepR 
Leptin Receptor 


Rhythm Pharmaceuticals, Inc. 
Protocol RM-493-015 
 
16 Apr 2019 
 
CONFIDENTIAL 
 
6 
LOCF 
Last observation carried forward 
LOF 
Loss of function 
MC4R 
Melanocortin Receptor type 4 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCE 
New Chemical Entity 
NRS 
Numeric rating scale 
OGTT 
Oral glucose tolerance test 
ORO 
Observer-Related Outcomes 
PD 
Pharmacodynamic 
PGIC 
Patient Global Impression of Change  
PGIS 
Patient Global Impression of Severity  
PI 
Primary Investigator 
 
 
POC 
Proof-of-concept 
POMC 
Pro-opiomelanocortin 
PP 
Per Protocol 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RS1 
Responder’s set 1 
RS2 
Responder’s set 2 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan  
SAS 
Statistical Analysis Software 
SD 
Standard deviation 
SMB 
Safety Monitoring Board 
SOA 
Schedule of assessments 
SOC 
System/Organ/Class 
USPI 
US Package Insert 
WHO 
World Health Organization 


Rhythm Pharmaceuticals, Inc. 
Protocol RM-493-015 
 
16 Apr 2019 
 
CONFIDENTIAL 
 
7 
1. 
INTRODUCTION AND OBJECTIVES OF ANALYSIS 
1.1. 
Introduction 
This document presents the statistical analysis plan (SAP) for Rhythm Pharmaceuticals, Inc. 
(Rhythm), Protocol No.  RM-493-015: 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.  It contains the details and methods to be used to perform the 
proposed efficacy and safety analyses, including planned summary tables and by-patient 
listings.  
Study RM-493-015 is a pivotal Phase 3 study designed to demonstrate statistically significant 
and clinically meaningful effects of setmelanotide on percent body weight change in patients 
with LEPR deficiency obesity due to rare bi-allele or loss-of-function mutations at the end of 1 
year of treatment.  Effects on hunger score suppression will also be evaluated over the course of 
treatment.   
The extreme rarity of LEPR deficiency obesity has led to the small target number of LEPR 
deficiency patients to be enrolled and evaluated in this open-label clinical study of 
setmelanotide.  We have found that patients are difficult to identify and recruit.  In many ways, 
the set of patients under study will constitute a collection of detailed clinical case reports with a 
comprehensive baseline and past medical history assessment and complete clinical efficacy, 
safety and laboratory evaluations conducted for each patient.  Patient numbers may be increased 
or decreased to satisfy regulatory requirements for registration, depending upon the number of 
affected patients identified.   
It is planned that approximately ten treated pivotal patients will receive approximately one-year 
of setmelanotide at daily doses that will be individually titrated for each patient during their 
initial dose titration, with additional supplementary patients who will receive less than one-year 
of treatment at the time of filing; the primary analyses will only include the pivotal patients, and 
the primary analyses will later be repeated with the supplemental patients as supportive 
analyses.  In addition, personalized therapeutic response assessments of weight reduction and 
hunger score changes after 12 weeks, and at approximately one year of dosing will also be 
assessed.  Thus, many analyses will involve descriptive summary statistics derived from 
absolute and percentage responses for each patient over differing periods of time.   
There will also be an 8-week double-blind, placebo-controlled withdrawal period consisting of 4 
weeks of active therapy and 4 weeks of masked placebo substitution conducted in each patient 
serving as their own control.  Assessments of each patient during this period will involve 
defined comparisons to weight and hunger scores just before and just after this sequence, which 
will be the only closed (blinded) design element of this study.   
After this withdrawal period is completed, long-term efficacy and safety analyses will evaluate 
responses for total treatment periods extending for approximately 1 year.  Overall, data will be 
tabulated and depicted to highlight individual patient responses as well as key group mean 
results to fully characterize key study data from this set of LEPR deficiency obesity patients. 
The protocol includes elements to assess the expected robust treatment effects of setmelanotide 
despite the open-label design and small patient numbers.  All these elements -- including prior 
patient histories documenting unsuccessful control of weight and hunger, other key medical and 


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natural history elements, potential responses (or the lack thereof, as in the Phase 2 study) during 
individualized dose titration from sub-therapeutic to personalized target efficacy doses, data 
from the double-blind, placebo-controlled withdrawal period, and the anticipated extremely 
robust weight and hunger responses during long term open-label treatment – are expected to 
help demonstrate and substantiate the effects of setmelanotide in this rare genetic form of 
obesity. 
Access to efficacy data from this study will be restricted as defined in this SAP (further details 
in Section 2.4), in order to insure integrity of this Phase 3 study. 
This SAP was based on Amendment 3 to the final protocol dated 10 April 2018.  [Note that this 
amendment, which includes approval for enrollment of POMC deficiency obesity patients age 6 
years and older, has not been approved at all clinical trial sites.  Nonetheless, the sponsor 
Rhythm has included analyses pertaining to the evaluation of this younger age group in this SAP 
to prospectively identify these planned analyses, which will be conducted on younger age 
ranges of patients only if they are approved for enrollment in the trial.]  
The reader of this SAP is encouraged to read the clinical protocol, and other relevant documents 
for details on the planned conduct of this study.  The objectives listed below (primary, 
secondary and exploratory) are found in the protocol.  Other than the schedule of study 
procedures, which is provided in Appendix 1, operational aspects related to collection and 
timing of planned clinical assessments are not repeated in this SAP unless relevant to the 
planned analyses. 
1.2. 
Objectives of Statistical Analysis 
This SAP is designed to outline the methods to be used in the analysis of study data to answer 
the study objectives.  Populations for analysis, data handling rules, statistical methods, and 
formats for data presentation are provided.  The statistical analyses and summary tabulations 
described in this SAP will provide the basis for the results sections of the clinical study report 
(CSR) for this trial. 
This SAP also will outline any differences in the currently planned analytical objectives relative 
to those planned in the study protocol. 


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2. 
STUDY DESIGN 
2.1. 
Synopsis of Study Design 
This is a multicenter, open-label, pivotal Phase 3 trial, with a double-blind placebo-controlled 
withdrawal period, evaluating the efficacy and safety of setmelanotide on percent body weight 
change at approximately the end of 1 year of treatment in patients at least 6 years old.  The 
study includes a comprehensive screening period to evaluate potential participants with LEPR 
deficiency obesity.  Given the rarity of such patients, a thorough understanding of the genetics 
and disease history for each patient dating to as early in childhood as possible is critical to 
understand the natural history of patients with this early-onset, extreme genetic obesity. The 
sponsor medical monitor will be in close contact with Site Primary Investigators (PIs) for the 
initial screening and assessment of potential candidate patients.  Details to be jointly reviewed 
and verified by PIs with the medical monitor include body weight history (to be as 
comprehensive as feasible in these patients to help understand a complete weight and body mass 
index (BMI) trajectory prior to setmelanotide initiation), review of key disease features and 
other past medical history elements, and pertinent inclusion and exclusion criteria details for 
each participant in this pivotal trial.  In addition, DNA sequence details for each LEPR 
deficiency obesity patient will be reviewed to ensure that appropriate bi-allelic mutations that 
define the specific LEPR gene variants have been identified for the LEPR deficiency patients 
enrolled in this clinical trial.  These mutations will be subsequently verified using Clinical 
Laboratory Improvement Amendments (CLIA)-approved DNA sequencing of a genomic DNA 
sample collected from each patient.   
The treatment phase of the study will begin with an initial period of dose titration in 0.5 mg 
increments and lasting between 2 and 12 weeks (ranging from as brief as a single dose step at 
either 1.0 mg for adults or 0.5 mg for pediatric (ages 6 – 11 years) and adolescent (ages 12 – 18 
years) subjects, to as many as 6 dose steps to reach 3.0 mg QD starting from the 0.5 mg starting 
dose in pediatric and adolescent subjects). Thus, each subject will have his/her dose 
individualized depending on the number of dosing increments administered, where each 
individual patient’s therapeutic dose will be established by upwards dose titration in 2 week 
intervals (refer to Appendix 11.8 of the protocol). Thereafter, patients will continue on active 
treatment at their optimal therapeutic dose for an additional 10 weeks, for a total combined 
dosing duration of 12 weeks at the individual patient’s established therapeutic dose [i.e., the last 
2 weeks during dose titration plus 10 weeks of open label treatment]. Patients who demonstrate 
at least 5 kg weight loss (or 5% weight loss change from baseline if baseline body weight is < 
100 kg) at the end of this 12-week Open Label Treatment Period will continue onto the double-
blind, placebo-controlled, withdrawal period lasting 8 weeks, including a 4-week period of 
placebo treatment. Patients who do not demonstrate at least 5 kg weight loss (or 5% weight loss 
change from baseline if baseline body weight is < 100 kg) will continue in the study but will be 
withdrawn from treatment. Following the withdrawal period, all patients will complete 
approximately 1 year of total therapeutic dosing. It is planned that the individual patient’s 
therapeutic dose, established during the initial period of dose titration, will continue throughout 
the study. Please refer to the protocol for more detailed information.  
It is anticipated that ~10 pivotal patients will be enrolled in this study (with approximately 1-
year of treatment), due to the ultra-rare incidence of this population of patients. The pivotal 
patient set will be the first ~10 patients enrolled (in order of enrollment), and once determined, 


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will be clearly documented.  Enrollment will be kept open after the first ~10 pivotal patients 
begin, for the purpose of collecting additional supporting data. 
Patients as young as 6 years of age will be enrolled at clinical sites where Amendment 3 is 
approved.  Note that Amendment 3, which proposes enrollment of patients 6 years and older, 
remains under regulatory review with some European Union (EU) health authorities; this SAP 
has included elements that proactively address proposed specific assessments in this younger 
age cohort, assuming it will eventually be approved in most locations.   
In addition, for patients at sites where feasible, and who agree to participate, there are optional 
sub-studies to evaluate robust 
, and blood pressure/heart rate (BP/HR) by 
data. It is anticipated that only a modest number of patients and 
sites will participate in each sub-study, and care should be taken not to overburden individual 
patients. 
Thus, patients will progress sequentially through the study as depicted in Figure 1 below. 
Figure 1 - Study Schema 
 
 
 


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2.2. 
Randomization Methodology 
There will be no randomization in this trial.  
2.3. 
Blinding During the 8-Week Double-Blind Withdrawal 
The only double-blind study period in Study RM-493-015 is timed to occur immediately 
following the 12-week initial therapeutic test period after individualized up titration to a 
therapeutic dose.  A more detailed description of the analysis of this important period follows in 
Section 4.6.3 
This 8-week placebo-controlled withdrawal period is blinded to patients and site staff; thus, all 
site and investigator staff and study participants will be blinded and unaware of the sequence 
each participant is receiving.  In contrast, sponsor personnel are aware of the sequence, with the 
4-week active therapy preceding the 4-week placebo withdrawal period for all patients during 
this 8-week study interval, but will have no access to efficacy data from this period until the 
study is complete and the database locked.  The rationale for this fixed sequencing with 
continuing active treatment preceding withdrawal to masked placebo in all subjects is to allow 
each participant to experience a total of 16 weeks of continuous active treatment at an 
individualized therapeutic dose established for each patient prior to the introduction of the 
placebo.   
Breaking the blind of the 8-week double-blind placebo controlled phase for the clinical site staff 
will only be done in the event of a medical emergency where the identity of study drug is 
necessary to appropriately treat the patient.  The request to break the blind will be discussed 
with the medical monitor and Rhythm, whenever possible.  All details of when and how the 
blind was broken will be documented in the CSR.  
2.4. 
Data Handling to Ensure Study Integrity 
The open-label design of this pivotal clinical trial makes it important for the sponsor to be 
blinded to key efficacy data, to ensure bias is not introduced into this study by data reviews.   
To this end, efficacy and safety data from this study will be carefully controlled both within the 
sponsor and outside: 
• No combined or integrated patient data will be tabulated by the sponsor, shared with any 
investigator, investigator site staff, or outside personnel until the study is complete and 
the database for 1-year data is locked and finalized.   
• Safety information will be shared with the Safety Monitoring Board (SMB), and any 
blinded safety data (i.e., from the double-blind, placebo-controlled withdrawal period) 
will not be unblinded until the study is complete and the database for 1-year data is 
locked and finalized.  The exception can be if the outside member(s) of the SMB 
requires unblinded data to fully evaluate a safety concern, in which case the process, 
details and reason for unblinding will be carefully outlined in the CSR, and such data 
will only be available to the outside (independent) member of the SMB.   
• The sponsor medical monitor and study clinical operations lead will have access to all 
safety and efficacy clinical data only during open-label dose titration phase.  This close 
engagement by two key Rhythm study personnel in early periods of the RM-493-015 


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study for every patient is necessary to advise clinical site investigators or study staff on 
appropriate dose titration decisions.  No other Rhythm personnel or any other individuals 
will have access to, or be allowed to obtain any access to this information in any form.  
Recall that the period covering the last 2 weeks of titration also is identical to the first 2 
weeks of individualized therapeutic dosing, followed by 10 additional weeks to complete 
the entire 12-week dosing period at each participant’s personalized therapeutic dose.     
• Thereafter, all accruing study weight and hunger response data, during the 10 additional 
weeks of the initial 12-week dosing period, will no longer be available for the Rhythm 
medical monitor or study clinical operations lead, and will remain unavailable in any 
form for any other individuals (i.e., no Rhythm personnel will have access to the weight 
and hunger data).  Specifically, from the time each study participant establishes their 
individualized therapeutic dose (with consensus between each Principal Investigator and 
the sponsor medical monitor), and at the beginning of 10 additional weeks at this 
therapeutic dose level, all clinical data files for primary and secondary efficacy endpoint 
parameters that are maintained by the data management vendor (MedSource) will no 
longer be accessible to Rhythm personnel or other blinded individuals. 
• All weight and daily hunger data past the dose-titration phase will not be accessible to 
the lead or consulting biostatistician.  
• Similarly, all accruing study weight and hunger response data will continue to remain 
unavailable to the Rhythm medical monitor or study clinical operations lead during the 
8-week double-blind withdrawal period, and during the subsequent period of continued 
open label treatment until the full 1-year efficacy treatment period is completed at the 
end of the trial.  As noted above, clinical data files for these primary and secondary 
efficacy endpoint parameters that are maintained by the data management vendor 
(MedSource) will not be accessible.  These data will also remain unavailable in any form 
for any other individuals (i.e., no Rhythm personnel will have access to the weight and 
hunger data).   
• In addition, no data will be unblinded from the 8-week double-blind placebo controlled 
withdrawal period for any reason (except for safety reasons outlined below) until the 
study is complete, all data has been cleaned, and the database is locked.  
• The Rhythm study monitor and study operations lead will continue to monitor patient 
safety and laboratory data with the PI and during clinical site interactions in these 
subsequent phases of the study, but they will not inquire or communicate anything 
regarding ongoing efficacy, in particular weight and hunger responses with clinical site 
personnel.  All site personnel will be instructed not to provide any insight, information 
or indications about any efficacy data during the course of the study except during the 
open-label titration phase.  
• In the event an Investigator judges that a dose adjustment may be necessary, 
Investigators will be instructed to contact the Independent SMB member for 
consultation, who can then engage the Rhythm Medical Monitor once all efficacy and 
potential unblinding data, including patient identity, have been redacted.  Any dose 
adjustments will be documented in the SMB minutes in an anonymized manner.  It is 
anticipated that this type of clinical review request would be a rare event; if such cases 


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occur, the process, details and reason for a dose adjustment discussion will be carefully 
documented, and all data shared would be included in a note to file on such discussions.   
• A clinical operational specialist(s) will be informed by the investigator at each site if a 
patient achieves the ≥ 5 kg weight loss threshold at the end of the 12-week initial 
treatment period and will be continuing on active treatment.  This information will be 
used to arrange drug supply for patients who continue on treatment in the study (note 
that all patients will be encouraged to continue study visits, even if not on treatment, but 
those who do not achieve the ≥5 kg weight loss threshold will not receive any further 
active or placebo treatment.) 
2.5. 
Planned Trial Conduct Assessment and Safety Monitoring  
The open-label design of this pivotal clinical trial for all but 8 weeks of the double-blind, 
placebo-controlled withdrawal period and the very small number of investigative clinical sites 
involved in evaluating these extremely rare LEPR deficiency patients should enable the timely 
and thorough review of accruing clinical safety data.  A SMB for the RM-493-015 study has 
been set up and details on SMB operation and analysis support will be documented in a separate 
SMB charter.  
2.6. 
Study Procedures 
The schedule of assessments (SOA), as outlined in the study protocol, is provided in Appendix 
1.  Table 1 illustrates the schedule for screening and dose titration, Table 2 illustrates the 10-
week active treatment and 8-week double-blind placebo controlled withdrawal period, and 
Table 3 illustrates the additional ~32-week open label treatment period. All footnotes can be 
found following Table 3. 
2.7. 
Efficacy, Pharmacokinetic, and Safety Variables 
2.7.1. 
Efficacy Variables 
The primary objective of this study is to demonstrate the efficacy of setmelanotide. The primary 
endpoint is the proportion of patients in the full analysis set (FAS) population who meet the 
≥10% weight loss threshold (responders) after approximately 1 year of treatment (pivotal patient 
set), compared to the proportion from historical data (at most 5% responders in the null 
population).  
If this analysis reaches statistical significance (1-sided test, alpha=0.05), then the proportion of 
patients in the FAS population who show ≥10% weight loss after approximately 1 year of 
treatment will be numerically compared (point estimate) to the 35% proportion of responders as 
defined in the “Success Criteria” (description and rationale are provided in Section 4.7.1). 
Key Secondary Endpoints (with analysis to be performed at approximately 1 year) are as 
follows: 
• The first key secondary endpoint is the mean percent change from baseline in body 
weight (kg) at the end of approximately 1 year of treatment in the Designated Use Set 
(DUS) population (see Sections 3.1 and 3.2 for a description and rationale for the 
primary population).  
If this analysis reaches statistical significance (P<0.05 compared to the null hypothesis 
of 0% weight loss; 1-sided test, alpha=0.05), then the mean percent change from 


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baseline at the end of approximately 1 year of treatment in the DUS population will be 
numerically compared (point estimate) to the ≥10% mean reduction from baseline in 
body weight “Success Criteria” for this study (description and rationale are provided in 
Section 4.7.1).  
• The second key secondary endpoint is the mean percent change in weekly average 
hunger (using “most hunger over the last 24-hours” daily response) from baseline at the 
end of approximately 1 year of treatment.  Hunger assessments will be determined on the 
weekly mean of daily responses, evaluated in patients aged 12 years and older in the 
DUS population.   
If this analysis reaches statistical significance (P<0.05 compared to the null hypothesis 
of 0% weight loss; 1-sided test, alpha=0.05), then the mean percent change in weekly 
average hunger at the end of approximately 1-year of treatment in the DUS population 
will be numerically compared (point estimate) to the 25% reduction from baseline 
“Success Criteria” (a description and rationale is provided in Section 4.7.1).  
• The third key secondary endpoint is a categorical analysis of the proportion of patients in 
the FAS population who meet the ≥25% improvement in hunger threshold (responders) 
at the end of approximately 1 year of treatment, compared to the proportion from 
historical data (at most 5% responders in the null population). 
If this analysis reaches statistical significance, then the proportion of patients in the FAS 
population who show ≥25% improvement in hunger at the end of approximately 1 year 
of treatment will be numerically compared (point estimate) to the to the 35% proportion 
of responders as defined in the “Success Criteria” (a description and rationale is 
provided in Section 4.7.1). 
Secondary endpoints (with analyses to be performed at approximately 1 year, except for the 
withdrawal analysis) are as follows: 
• The proportion of patients who meet categorical thresholds of 5%, 15%, 20%, 25%, 
30%, 35% and 40% weight loss from baseline.  
• Global hunger as assessed by the Patient Global Impression of Severity (PGIS) and the 
Patient Global Impression of Change (PGIC) in patients ≥ 12 years of age.  
• 
• Global hunger as assessed by the Caregiver Global Impression of Severity (CGIS) and 
the Caregiver Global Impression of Change (CGIC) in patients 6 years old up to < 12 
years of age. 
• During withdrawal from drug: reversal of weight gain and hunger reduction during the 
double- blind placebo-controlled withdrawal period. 
• Percent change in body fat and body mass as measured by either dual-energy x-ray 
absorptiometry (DEXA) or bio-electrical impedance analysis (BIA), site-specific.  
• Percent change in BMI.  
• Change in glucose parameters: fasting glucose, glycated hemoglobin (HbA1c), oral 


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glucose tolerance test (OGTT) with concomitant insulin measurements to focus on 
parameters of insulin sensitivity. 
• Change in waist circumference (cm). 
• Safety and tolerability of setmelanotide (including BP and HR) via proportions of 
patients with AE's and shift from normal range status in lab parameters. 
 
  
 


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2.7.2. 
 
2.7.3. 
Safety Variables 
Safety and tolerability of setmelanotide will be assessed by frequency and severity of AEs as 
well as changes in physical examinations, electrocardiograms (ECGs), vital signs (including 
resting BP and HR), clinical laboratory evaluations, monitoring for changes in neurocognition 
and pubertal development, including bone age progression in patients ≤16 years of age and 
injection site reactions.  


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3. 
SUBJECT POPULATIONS 
3.1. 
Population Definitions 
There are 4 important populations from the RM-493-015 pivotal clinical trial that Rhythm 
intends to evaluate for efficacy and safety.  One key population of this trial, which is the 
population that will be indicated for use of setmelanotide, is the one that includes a pre-defined 
weight loss at 12 weeks of treatment.  The rationale for this population is outlined below.  
Because this population will be the designated population indicated for setmelanotide treatment, 
it is referred to as the Designated Use Set (DUS) Population.  
Other key populations, defined below, include a comprehensive safety analysis set (SAS), the 
full analysis set (FAS), and a completer’s set (CS) who will have completed the full 1-year 
clinical trial period.   
3.1.1. 
Key Populations:  
Full Analysis Set (FAS): all subjects who received at least 1 dose of study medication and had 
a baseline assessment.  This population includes patients who do and do not demonstrate at least 
5 kg weight loss over the 12-week Open-Label Treatment Period and proceed into the double-
blind, placebo controlled withdrawal period.  It also includes all patients who do not provide a 
week 12 observation. 
• The FAS population, (or modified intent-to-treat population) will provide information 
on the effect of setmelanotide on all patients who initiate treatment and have at least a 
baseline assessment, regardless of whether the patient meets the threshold for continuing 
into the longer-term study following individualized dose titration and the 12-week 
therapeutic response period on the personalized therapeutic dose determined for each 
patient.  This population will include patients who do not complete the study for any 
reasons (due to AEs, stop treatment due to failure to achieve the necessary ≥5 kg weight 
loss from baseline after 12 weeks of therapeutic treatment, etc.).  Every effort will be 
made to continue following all patients (on treatment or not) through the full year of this 
pivotal trial to obtain the (approximately) 1-year observations. 
Designated Use Set (DUS):  The DUS is intended to define the population of patients who 
demonstrate at least 5 kg weight loss (or at least 5% if baseline body weight, especially in 
pediatric subjects, is < 100 kg) over the 12-week Open-Label Treatment Period and 
subsequently proceed into the double-blind, placebo controlled withdrawal period, regardless of 
later disposition. 
• Thus, the DUS population includes only patients who achieve a qualifying response 
necessary for continued treatment after the initial therapeutic trial at each patient’s 
individualized therapeutic dose (i.e., ≥ 5 kg weight loss, or ≥ 5% weight loss if baseline 
weight is < 100 kg, after the open-label run-in).  This population will provide the most 
accurate efficacy evaluation data according to the intended use of setmelanotide in 
LEPR deficiency obesity (see larger rationale below).   
Safety Analysis Set (SAS): all subjects who received at least 1 dose of study medication. 
• The SAS Population will be the trial population defined by those who receive at least 
one dose of setmelanotide, and will be used for all evaluations of safety parameters.  


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Ultimately, this population may be identical to the FAS population depending on final 
patient experience in this trial.  The SAS is the primary population for the analysis of 
 
 and safety endpoints.     
Completers Set (CS): all subjects in the DUS who both demonstrate at least 5 kg weight loss 
over the 12-week Open-Label Treatment Period and continue in the trial on active treatment to 
complete a full year (approximately) of treatment. 
• The CS population includes participants who complete the entire treatment period for 
this trial and remain on treatment at the last (approximately 1-year) treatment visit.  The 
rationale for this population is that scientifically it best represents the effect of 
setmelanotide on weight loss and hunger in the LEPR deficiency patient population who 
demonstrate at least a 5 kg weight loss (or 5% if baseline weight is < 100 kg) by 12 
weeks and receive an approximately full year treatment course for evaluation of the 
primary weight endpoint.  Hence, the CS population provides an estimate of what would 
be expected from one year of treatment in any patient who demonstrates at target 
therapeutic response for weight loss by 12 weeks and is able to continue long-term 
setmelanotide therapy for approximately one year of treatment.    
3.2. 
Rationale for the DUS Population as Population of Interest for 
Percent Change in Weight and Hunger over 1-year (Key Secondary 
Endpoints) 
The DUS population will be the primary population for the analysis of key secondary efficacy 
parameters that evaluate mean change in both body weight and hunger from baseline.  This 
population will also be applicable for the evaluation of these parameters in the assessment of 
success of this study (see Section 4.7.1).   
The FAS population will be used for the primary efficacy analysis, as well as the analysis of all 
categorical efficacy endpoints for body weight and hunger score assessments (i.e., responder 
analyses).  
All key parameters will also be evaluated for the FAS and CS populations.  
Rhythm proposes that the DUS population represents the most accurate and scientifically 
compelling population to evaluate for the proposed indication and to characterize the 
quantitative magnitude of full efficacy data in the final US Package Insert (USPI).  According to 
the clinical protocol, this population best defines the target population for labeling according to 
the intended use of setmelanotide.  Therefore, this population will address the key scientific and 


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clinical question: “What is the expected effect of setmelanotide on body weight reduction and 
hunger suppression in the designated population when used as indicated in the label?”  Hence, 
this cohort will be a vital analysis population for the SAP.   
In contrast, the FAS population is not as suitable as an efficacy population for mean weight loss, 
for evaluations of mean change from baseline, for many important reasons: 
• Most importantly, the FAS population may include patients who do not meet the 12-
week rule for continuing treatment based on a ≥ 5 kg weight loss response OR who drop 
out early in the study.  As a result, the FAS population would include a mixture of 
patients, both with and without actual treatment experience, because the FAS population 
includes all patients who enter the study through approximately one year (including 
subjects who drop out for any reason, or who do not pass the stipulated weight reduction 
response rule, or who do not proceed with active treatment past the 12-week Open Label 
Treatment Period).  The resulting distribution of percent change in body weight is likely 
to be bi-modal, and provides significant loss of power for this endpoint with N=10 
patients (the feasible limit for recruitment that is the current target of this protocol in 
such an ultra-rare indication). Table 6 and Table 7 of Appendix 5 provide estimated 1-
sided confidence limits for a DUS and a simulated bi-modal FAS population, 
respectively.  These tables show the large increase in the confidence interval (CI) half-
width when a bi-modal distribution is simulated (as may occur in the FAS population).   
• In addition, the use of FAS population for assessing mean efficacy changes from 
baseline may inadvertently bias against the intended effect of setmelanotide treatment.  
Based on prior case descriptions and limited natural history data for rare LEPR 
deficiency patients, LEPR deficiency patients do not necessarily remain stable but often 
actively gain weight without therapy.  For example, ongoing weight gains of 5 to 10 kg 
per year are commonplace in fully characterized cases (described fully in the Rhythm 
Breakthrough Therapy Designation (BTD) application, submission 0041, November 2, 
2015).  Because the main weight endpoint after approximately 1 year of treatment in this 
pivotal trial is not placebo-compared, the inclusion in the FAS population of 
prospectively defined yet untreated patients (because they did not achieve this initial 
response threshold) would add subjects with highly divergent weight trajectories in the 
final efficacy evaluations.  As a consequence, the analysis of this FAS population could 
be confounded and inappropriately underestimate the effects of setmelanotide treatment 
in the intended treatment population.  The DUS population of patients who are intended 
to continue for long term treatment may also include subjects who discontinue for AEs 
or other reasons, but at least this population would not include subjects who were never 
intended to use setmelanotide long-term in the first place based on the failure to achieve 
5 kg or more weight loss during an initial therapeutic dose test.     
• The natural history of this disorder, with ongoing weight gains of +5 to +10 kg per year 
(with both a mean and  median yearly weight gain of +7 kg; based on analysis of weight 
curves since birth for existing patients in our trials) in the absence of setmelanotide 
treatment, also clearly supports that the FAS population likely will be bimodal if any 
patients are discontinued early due to lack of early weight loss.  This will likely result in 
non-normal distributions and the potential for some confusion of the treatment effect in 
the label.   


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• While Rhythm is proposing that several key analyses for percent reduction in weight 
(first key secondary endpoint) and hunger (key secondary endpoint) will be assessed in 
the DUS population, for each of these endpoints we will also provide a sensitivity 
analysis to be performed in the FAS population, using a non-parametric rank analysis as 
described below, which should mitigate the issues raised by the occurrence of a bimodal 
distribution.  We propose that this analysis be accompanied with a tabulation of the 
percent of patients who do not meet the ≥5 kg threshold (i.e., those who do not achieve 
the threshold for long-term dosing after the first 12-weeks of therapeutic dosing), to 
provide useful information needed in the label.  
Thus, similar mean change from baseline analyses, albeit via non-parametric rank tests 
(specifically, Wilcoxon 1-sample signed rank tests comparing the mean weight percent change 
from baseline against 0%), will be conducted for the FAS population, as for the primary DUS 
population, along with disposition tables of subjects who did not meet the criteria for inclusion 
in either the DUS or the CS populations and the reasons why (e.g., unable to pass the ≥ 5 kg 
(5% in subjects with baseline body weight < 100 kg) stopping rule to be included in DUS, other 
lack of efficacy, withdrawal due to AEs, etc.).  These factors will likely be the most informative 
data gathered from the FAS and CS populations, as it will provide information on patients who 
either do not respond to treatment or have issues with tolerating the study drug.  
The following exploratory subject population will also be evaluated and used for presentation 
and analysis of the data: 
Exploratory Population: 
Per Protocol Set (PP): all subjects in the FAS without any major protocol violations (see 
Section 3.3). 


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3.4. 
Protocol Violations 
At the discretion of the sponsor, major protocol violations as determined by a review of the data 
prior to unblinding of the study results and the conduct of statistical analyses may result in the 
removal of a subject’s data from the PP Population.  In this open-label study with only limited 
double-blind treatment data, decisions on protocol violators may be subject to bias, and hence 
only major deviations will be considered.  The sponsor, or designee, will be responsible for 
producing the final protocol violation file (formatted as a Microsoft Excel file), in collaboration 
with Cytel and the data monitoring group as applicable; this file will include a description of the 
protocol violation, and clearly identify whether a violation warrants exclusion from the PP 
Population.  This file will be finalized prior to hard database lock. 
Major protocol violations may include, among others: 
1. Violation of key inclusion/exclusion criteria, as reviewed by study clinician. 


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2. Violation of legal documents including, but may not be limited to informed consent  
and patient privacy. 
 
All protocol violations will be presented in the data listings. 


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4. 
STATISTICAL METHODS 
This SAP may not describe all analyses that will be performed for this study.  It is expected that 
additional exploratory analyses may be requested by the Sponsor and performed to supplement 
the results outlined in this SAP, because the purpose will be to explore all possible data from the 
limited number of subjects.  
4.1. 
Sample Size Justification 
The primary endpoint is proportion of patients who demonstrate at least 10% weight loss at ~1 
year from baseline.  The primary research hypothesis is that this proportion is at least 5%.  The 
null hypothesis is that this proportion is at most 5%.  Rationale for the 5% historical control 
value for this comparison is as follows. 
The available data suggests that 0% of LEPR deficiency patients would demonstrate at least 
10% weight loss in a single year, even with extraordinary measures.  The exception might be 
after bariatric surgery, as some patients have had very short-term improvements, though over 
time their overwhelming hunger leads to weight regain.  In the absence of such measures in our 
clinical trial (exclusions from the trial), and the general contraindication of bariatric surgery in 
this population, it is defensible to consider that no (0%) patients would meet these criteria and 
the statistical comparison for this endpoint should be a comparison to a 0% proportion.  Despite 
this strong rationale based on the natural history of these patients, since the data are limited and 
the number of patients in the trial is small, it is probably more appropriate to go beyond this 
very conservative estimate of 0% responders, to do the historical control comparisons assuming 
that a small proportion of the population (i.e. 5%, or a null of 0.05) might show a 10% weight 
loss in any given calendar year; hence it is assumed a categorical comparison to a 5% responder 
estimate in untreated historical patients.  
Assuming LEPR deficiency patients will be a total sample size of ~10 patients in the one year 
study, all power statements will assume n=10 patients in the study.  The actual numbers for this 
ultra-rare disease may be larger or smaller.    
It is expected that treatment with RM-493 for 1 year is associated with a TRUE underlying 
probability of at least 10% weight loss at 1 year of at least 50%.  That assumption yields at least 
94% power to yield a statistically significant (alpha=0.051-sided) difference from the null 
hypothesis 5% value for N=10 patients.  If the TRUE probability of at least 10% weight loss at 1 
year is 40%, then power is ~83%.   
4.2. 
General Statistical Methods and Data Handling 
4.2.1. 
General Methods 
All output will be incorporated into Microsoft Word files, sorted and labeled according to the 
International Conference on Harmonisation (ICH) recommendations, and formatted to the 
appropriate page size(s). 
Tabulations will be produced for appropriate demographic, baseline, efficacy, pharmacokinetic 
and safety parameters.  For categorical variables, summary tabulations of the number and 
percentage within each category (with a category for missing data) of the parameter will be 
presented.  For continuous variables, the mean, median, standard deviation, minimum and 


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maximum values will be presented.  Formal statistical hypothesis testing will be performed on 
the primary and secondary efficacy endpoints with all tests conducted at the 1-sided, 0.05 level 
of significance, for a comparison of change from baseline.  Note that no comparator population 
is included in this study.   
However, the endpoint pertaining to the 8-week placebo withdrawal period will be analyzed and 
presented differently, as each patient will serve as their own control and data will be examined 
relative to both the preceding and the ensuing active treatment periods. Summary statistics will 
be presented, as well as confidence intervals on selected parameters, as described in the sections 
below.   
  
4.2.2. 
Definition of Baselines, Study Periods, and Reporting 
The last value (of weight, last week of mean hunger scores, etc.) obtained prior to the first dose 
of any active treatment in the open-label dose titration phase will be considered the baseline 
value for statistical analysis for the primary analyses for one-year data. Note that if the weekly 
average hunger score prior to the first administration of study drug is missing, the daily hunger 
score collected on Day 1 (first day of active dose) will be used as “Baseline.” 
For the specific analysis of the withdrawal period for the key primary weight analysis, the 
baseline will be the weight loss (kg) over the first 4-weeks of the double-blind, placebo-
controlled withdrawal period (i.e., the weight change (loss) that that occurs over the last 4 weeks 
of active treatment), which will be compared to the weight change (gain) during the 4-weeks of 
placebo-controlled withdrawal.  
For the specific analysis of the withdrawal period for key secondary supporting hunger analysis, 
baseline hunger (“most hunger over past 24-hours”) will be considered the last evaluable week 
of hunger data obtained just prior to the beginning of the off-treatment 4-week placebo-
controlled interval for each patient.  
For other interval analyses (for example, the exploratory analysis of weight loss over the initial 
12-week therapeutic dose treatment), the last value prior to the beginning of that interval will be 
considered the baseline.  
Visit 13 will be considered the end of ~1 year of treatment. Therefore, the approximate one year 
of treatment includes the final 2 weeks of the dose titration period (Visit 2a, 2b, etc.), the 10 
weeks of the open label treatment period (Visit 3 – Visit 5), the 8 weeks of the placebo-
controlled withdrawal period (Visit 6 – Visit 7) and the final ~32 weeks of open label treatment 
(Visit 8 – Visit 13). The actual total time on treatment will be ~48 weeks, due to the 4 weeks of 
placebo withdrawal.  The pre-specified visit window for Visit 13 will be 10-14 months of 
treatment.  
Reporting of measurements in summary tables will be performed with all individual therapeutic 
doses combined due to small sample sizes. The primary focus for analysis will be on the impact 
at the end one year of treatment (i.e., at the end of all treatment intervals (titration, 12-week 
open label, 8-week double blind and 32-week open label) to complete the approximate one-year 
treatment period.  Additional analyses will focus on the specific intervals separately (screening, 
titration, initial 12-open label treatment period, the 8-week double blind period, and the 32-week 
open label treatment period).   


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Supplemental exploratory analyses will be examined for data collected during the screening 
period, as well as the dose titration period to better understand baseline variability of LEPR 
deficiency subjects in a clinical trial, and to understand the therapeutic dose response during 
titration. Specifically, hunger and weight variability/stability or loss/gain, as well as patient 
medical history will be examined from before study entry (patient history from birth, if 
available), during the 4 weeks of screening and the 2-12 weeks of titration. 
4.2.3. 
Computing Environment 
All descriptive statistical analyses will be performed using SAS statistical software (Version 9.4 
or higher), unless otherwise noted.  Medical History and AEs will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 20.0.  Concomitant medications will be 
coded using World Health Organization (WHO) Drug version March 2016.  
4.2.4. 
Methods of Pooling Data between Different Protocols for Supplemental 
Exploratory Analyses 
It is expected that patients who continue to tolerate setmelanotide after approximately 1 year of 
treatment, and who show clinically important weight loss, will continue on long-term extensions 
(to be fully outlined in a future extension protocol, as noted in Section 5.5 of the protocol), on a 
year by year basis.  Additional analyses will summarize the long-term experience as appropriate. 
It is also expected that some LEPR deficiency obesity patients will be participating in a 
separate, essentially identical proof-of-concept protocol (Study RM-493-011) with a long-term 
extension phase, and possibly in other studies.  After assessing study conduct of subjects in the 
RM-493-011 study and upon determining essentially identical treatment procedures to this 
current pivotal study, these sentinel patients from Study RM-493-011 will also be identified and 
included in a pooled supplemental analysis.  Clinical data from these 3 patients in the RM-493-
011 study will be summarized and pooled (based on treatment duration) with data from the RM-
493-015 study patients in a supplemental analysis. 
In addition, if any other LEPR deficiency patients are treated in any other Rhythm study, their 
data will be summarized and may be included as well in this supplemental analysis.  
Appropriate statistical methods will be employed in order to take into account study differences 
in the pooled analysis. The following pooled analyses will be done: 
1. Percent change from baseline in body weight (kg) and hunger score at the end of 
approximately 1 year of treatment: Although the placebo withdrawal period does not 
occur in the same design between the two studies, the data collected during this period 
will be included in the pooled analysis. It is expected that weight loss will taper toward 
the end of approximately 1 year on treatment, and both weight fluctuations from dose 
changes or 4 weeks on placebo will be negligible in the examination of body weight at 
this time point. Only morning hunger will be examined in the pooled analysis as global 
hunger (PGIS/CGIS, PGIC/CGIC)
Both hunger 
and body weight will be analyzed as described in Section 4.6.2. The pooled analyses will 
be performed in two ways. RM-493-011 does not have a nominal Visit 13; for both 
analyses, approximately 1 year in this study will be derived by relative day (study day in 
relation to first administration of study drug). However, there will be two approaches in 
pooling with the RM-493-015 study data: 1) using the nominal Visit 13 (or, for diary 


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daily hunger scores, the closest week to the nominal Visit 13) and 2) by relative day, 
where 1 year (Week 52) will be derived programmatically based on the date of first 
dose, and the closest nominal visit to this Week 52 derivation based on actual time spend 
on drug will be considered the 1 year timepoint. 
2. Body weight (kg) and morning hunger score at the end of the titration period: As length 
of time spent during the titration period will differ between participants, rate of weight 
loss per week and its 95% CI will be calculated for this phase of the study.  If more 
appropriate, this can be summarized in a figure rather than performing inferential 
statistical analysis.  Change from baseline in hunger score will be analyzed as described 
in Section 4.6.2, with the inclusion of an adjustment for number of weeks in titration.  
3. Descriptive statistics for all participants: Mean, standard deviation, median, Q1, Q3, 
minimum and maximum for weight, BMI and daily hunger will be examined for all 
patients across both studies. Participant plots will also be output for these 3 endpoints to 
examine trends across the course of approximately 1 year (and beyond) for both studies. 
4.2.5. 
Adjustments for Covariates 
For continuous endpoints, the only covariate considered will be the baseline measurement of the 
endpoint of interest. Additionally, as a sensitivity analysis, age and BMI, provided the sample 
size is adequate, may be considered as covariates in a sensitivity analysis for continuous 
endpoints. If the sample size does not support this, these characteristics may be examined in a 
subgroup analysis.   
4.2.6. 
Multiple Comparisons/Multiplicity 
Multiplicity for the primary analysis is not of concern as there is a single primary efficacy 
analysis as outlined in Section 4.6.1.   
This study will consist of ~10 pivotal patients, and in many ways, the set of patients under study 
will constitute a collection of detailed clinical case reports with a comprehensive baseline and 
past medical history assessment and complete clinical efficacy, safety and laboratory 
evaluations conducted for each patient.  Based on the ultra-rare prevalence of this disease, and 
the small number of patients to be enrolled in this study (representing a large proportion of the 
known, published patients with this disorder), the ability to use extremely rigorous statistical 
approaches to address multiplicity for many endpoints is limited. Therefore, for publication, 
nominal-p-values will be used to interpret each endpoint separately in this small study where 
sample size is limited by feasibility.   
Rhythm acknowledges that this approach may increase the probability of potential Type 1 error 
for the set of endpoints being analyzed.  This may be a regulatory concern, so we have pre-
specified a step-down procedure to control Type-1 error, if needed for this purpose.   
For the endpoints below, for regulatory evaluations, we control for multiplicity, by stepping 
down in the following order, if statistical significance is achieved in the primary endpoint:   
1. The first key secondary endpoint is change from baseline in body weight at 
approximately 1-year in the DUS population.   
2. The second key secondary endpoint is change from baseline in weekly “most hunger in 
the last 24 hours” hunger scores over approximately 1-year of treatment in the DUS 


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population.   
3. The third key secondary endpoint is the categorical percent of responders analysis of 
hunger (using the 25% improvement in hunger threshold) in the FAS population at 
approximately 1-year.   
Another key set of analyses is from the double-blind, placebo controlled withdrawal period, 
which serves as an internal control for the weight loss/hunger improvements in this study. 
Rhythm believes the analyses outlined for this withdrawal period are underpowered, and hence 
will be more supportive and descriptive, and therefore will not be adjusted for multiplicity.   
No interim analysis is currently planned for this protocol, so no adjustment for multiplicity is 
needed for any interim look.   
4.2.7. 
Subpopulations 
The following subgroups will be examined, provided the sample size is adequate in each group: 
• Age (6 – 12, 12 – 18 and 18+ years of age) 
• Sex (male, female) 
• Race (white, non-white) 
• Site (US, Europe) 
• Met stopping rule (< 5 kg weight loss, ≥ 5 kg weight loss; or 5% for subjects with 
baseline weight < 100 kg) – differences with respect to demographics and baseline 
characteristics 
• BMI (< 50; ≥ 50 at baseline) 
Subgroup analyses will be explored for the combined pivotal and supplemental cohort, these are 
described in Section 3.3. 
4.2.8. 
Withdrawals, Dropouts, Loss to Follow-up 
Subjects who withdraw from the study will not be replaced.  However, due to the small sample 
size, every possible effort will be made to follow any subjects who may withdraw and 
discontinue treatment for the remainder of the study in order to examine both safety and efficacy 
measures.  Similarly, for any patient who meets the stopping rule and withdraws from active 
therapy, every possible effort will be made to follow these subjects through the approximate1-
year timepoint.  These follow-up assessments will include all study visits and procedures, 
including weight and hunger assessments.   
4.2.9. 
Missing, Unused, and Spurious Data 
As visit windows are very flexible, we do not anticipate a significant amount of missing data. 
However, missing data for the primary and key secondary endpoints will be handled in the 
following ways:  
• The primary method for handling missing primary/key secondary endpoint data at 
approximately 1 year will first examine the reason for missingness. If unrelated to 
treatment (e.g.: patient moved), the endpoint will either be extrapolated using a linear 
model (y=a+b*study week) based on existing data points or imputed using the 


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longitudinal mixed model for analysis. If the reason for missingness is directly related to 
treatment (lack of efficacy or an AE), weight change at approximately 1 year will be 
conservatively imputed as 0 kg. Likewise, hunger change at approximately 1 year will be 
imputed as 0. If less than 3 months of  data are available for the supplemental patients at 
the time of first analysis of the combined cohorts, these patients will not be imputed and 
will be left out of the analysis until more data is available.    
o Example 1: A patient drops out of the trial after 6 months after experiencing an 
AE deemed related to treatment; their 1 year body weight change from baseline 
will be imputed as 0 kg and hunger change will be imputed as 0, as the reason for 
missingness is related to treatment (treatment-related AE).  
o Example 2: A patient drops out of the trial after 9 months due to moving out of 
the area; their 1 year body weight and hunger changes from baseline will be 
imputed using a linear model to extrapolate based on data up through their 9 
months in the trial as the reason for missingness is not related to treatment 
(patient moved). 
o Example 3: A supplemental patient has 2 months of data available at the time of 
the first analysis of the combined cohorts (pivotal and supplemental); their 1 year 
body weight and hunger changes from baseline will not be imputed at that time. 
Data will be displayed in summary tables and listings, but this patient will not be 
included in a formal analysis of the primary and secondary endpoints.   
• As sensitivity analyses, the following methods will also be examined, regardless of the 
reason for missingness of data:  
o Weight loss/hunger trends will be extrapolated to determine the weight at 1 year; 
a linear model will be fit to the individual patient’s observed data. 
o For categorical endpoints, all patients not ongoing on test treatment and missing 
their data at 1 year will be considered ‘failures,’ for example: for the primary 
analysis, it will be assumed those missing 1 year data did not achieve at least a 
10% weight loss from baseline.  Ongoing patients will have weight/hunger 
imputed as described above. 
o Last observation available will be carried forward and considered as the 
weight/hunger at approximately 1 year. 
For non-primary or key secondary endpoint analyses utilizing a longitudinal mixed model, if a 
visit it missed, an assumption is made that data will be missing at random, consistent with 
longitudinal analyses.  The first key secondary analysis of the DUS population employs a 
longitudinal mixed model, and all available data will be included. However, because assuming 
all missing data is missing at random is too liberal, missing 1 year outcome data will be first 
imputed as described in the first bullet above (the reason for missingness will first be discerned). 
As a sensitivity analysis, the model will also be run with observed data; no manual or model-
based imputation will be performed.    
AE dates that are missing or incomplete are derived as follows: 
• If the start date of an AE is partially or completely missing, the date will be compared as 
far as possible with the date of the start of administration of study drug. The AE will be 


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assumed to be treatment-emergent if it cannot be definitively shown that the AE did not 
occur or worsen during the treatment-emergent period (worst case approach).  
The following general rules will be used: 
• If the start date is complete, an AE will only be excluded as being treatment-emergent if 
the start date is before the date of study drug administration or if the stop date is before 
study drug administration.  
• If the start day is missing but the start month and year are complete, an AE will only be 
excluded as being treatment-emergent if the start month/year is before the month/year of 
study drug administration or if the stop date is before study drug administration.  
• If the start day and month are missing but the start year is complete, an AE will only be 
excluded as being treatment-emergent if start year is before the year of study drug 
administration or if the stop date is before study drug administration.  
• If the start date is completely missing, an AE will be considered treatment-emergent 
unless the stop date is before study drug administration.  
4.2.10. 
Visit Windows 
As this patient population is very rare, visit windows will not be employed in the analysis, i.e., 
data will not be excluded from the analysis based on whether the data fell outside of visit 
windows. However, the goal will be for visits to occur within +/- 3 days during the Dose 
Titration phase, and within +/- 4 weeks during the 32-week Open Label Treatment Period. For 
the one year timepoint, the 1-year visit data will be included in the primary and key secondary 
endpoints if it occurs between 10 and 14 months after the start of the study. Throughout this 
SAP, ‘approximately 1 year’ refers to this 1-year timepoint data collection, which can occur 
during months 10 – 14.   
4.3. 
Data Verification Procedures during Screening and the Titration 
Period  
It is important to verify data handling for proper handling and compliance.  Therefore, an early 
look of the screening and initial clinical data (only during the initial titration period) in raw form 
(including individual patient listings but not summarized in tables) will be taken based on 
enrollment and planning.  Data from the screening period will be examined when 2-3 
participants have completed this stage of the study as discussed in Section 4.2.2 to examine 
missing data percentages, completeness of past weight and growth data, including pediatric 
weight curves, past medical history, associated disorders, and pre-existing concomitant 
hormonal therapies and other medications.  Additionally, vital signs, medical history, hunger 
and weight data will be examined once 2-3 patients finish their initial titration.  Special attention 
will be devoted to the completeness of dosing titration and therapeutic level decision making at 
the end of this titration period based on early weight and hunger change data and BP or HR data 
recorded during titration clinic visits.  Combined or exploratory results will not be allowed to be 
viewed by clinical site staff or other individuals who have clinical influence in reporting the 
study results.   


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No further efficacy data reviews will be conducted from the time each patient is decided to have 
attained a therapeutic dose and starts the 10 weeks of personalized therapeutic level dosing 
followed by the double-blind, placebo-controlled withdrawal period.   
4.4. 
Subject Disposition 
A tabulation of subject disposition will be tabulated, including the number screened, the number 
dosed with setmelanotide, the number in each subject population for analysis, the number that 
withdrew prior to completing the study, and reasons for withdrawal.   
A by-subject listing of study completion information, including the reason for premature study 
withdrawal, if applicable, will be presented. 
4.5. 
Demographic and Baseline Characteristics 
Baseline, demographic and medical history information will be summarized for the DUS, CS 
and FAS populations using descriptive statistics.  No formal statistical comparisons will be 
performed.  
Demographic and baseline data will be provided in data listings. 
4.6. 
Efficacy Evaluations 
Efficacy analyses will be conducted primarily in the FAS and DUS populations as specified 
below; analyses in the CS population will also be performed for key endpoints (if it differs from 
the DUS), but analyses in the PP Population will be performed only if the need is indicated by 
the number of protocol violations; specifically, only if the number of subjects in the PP 
population differs from the FAS by more than 15% on the primary endpoint, then the primary 
endpoint and key secondary endpoints will be analyzed in the PP population as well. All 
efficacy analyses will be performed in both pivotal cohort, supplemental cohort, and combined 
pivotal and supplemental cohorts (refer to Section 3.3 for more information on the supplemental 
cohort). Note that the primary and key secondary endpoints will be conducted in the FAS, DUS, 
and CS populations. 
For each binary endpoint, a tabular summary will be provided; this will include number and 
proportion of subjects who meet the categorical criteria and binomial test results (p-values and 
two-sided 90% CIs).  
For each continuous endpoint, a tabular summary will be provided; this will include summary 
statistics (N, mean, SD, median, minimum and maximum) and model results (p-values and two-
sided 90% CIs).  
Efficacy endpoints being examined as percent change from approximately 1 year will primarily 
be defined using the nominal Visit 13. For diary data (daily hunger scores), the closest week to 
the nominal Visit 13 will be determined and used as the approximate 1 year timepoint. As a 
sensitivity analysis, all primary and key secondary endpoints will also be analyzed by relative 
day (study day in relation to first administration of study drug). Specifically, Week 52 will be 
derived programmatically based on the date of first dose, and the closest nominal visit to this 
Week 52 derivation based on actual time spend on drug will be considered the 1 year timepoint. 
Refer to Section 4.2.10 regarding visit windows.  
All efficacy endpoints will also be displayed in by-patient listings.  


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Weight and daily hunger data will be graphed in both overall and by-patient plots; by-patient 
plots will include historical data prior to the start of study. Cumulative proportion of responder 
plots will also be shown for a range of thresholds/cutoffs that encompass all patients' values.   
4.6.1. 
Primary Efficacy Evaluation 
The primary endpoint is the proportion of patients in the FAS population who achieve at least a 
10% weight loss from baseline at approximately 1 year threshold compared to the null 
hypothesis that 5% of patients will achieve this threshold. This will be analyzed via the exact 
binomial test which will test whether the percentage of patients who reach at least 10% weight 
loss is greater than 5%. Two-sided, 90% CIs will be calculated using the exact Clopper-Pearson 
method.  
Once the primary endpoint analysis is complete, and if it reaches statistical significance, the 
proportion of patients in the FAS population who show ≥10% weight loss at approximately 1 
year will be numerically compared (point estimate) to the 35% proportion of responders as 
defined in the “Success Criteria;” no formal statistical analysis will be performed. 
Rationale for 1-sided alpha=0.05:  This study will consist of ~10 pivotal patients, and in many 
ways, the set of patients under study will constitute a collection of detailed clinical case reports 
with a comprehensive baseline and past medical history assessment and complete clinical 
efficacy, safety and laboratory evaluations conducted for each patient.  Based on the ultra-rare 
prevalence of this disease, and the small number of patients to be enrolled in this study 
(representing a large proportion of the known, published patients with this disorder), the power 
for extremely rigorous statistical approaches is limited.  Based on the marked weight loss 
previously demonstrated in this population, Rhythm has chosen 1-sided, alpha=0.05 as the 
scientific approach, which we identify as the primary analysis.  However, as this may not meet 
regulatory standards for approval, a 1-sided, alpha=0.025 comparison may also be required.  
By-patient data listings and plots of weight across the course of the study will also be presented. 
4.6.2. 
Key Secondary Efficacy Endpoints 
Key secondary efficacy endpoints will be analyzed in the DUS population (percent change from 
baseline in body weight, “most hunger in the past 24-hours”), and in the FAS population 
(categorical analysis for a threshold of ≥25% improvement in hunger scores).  Each of these will 
be separately numerically compared (point estimate) to the “Success Criteria” for this these 
endpoints (a description and rationale is provided in Section 4.7.1).   
All key secondary efficacy endpoints will assess the effect the effect of setmelanotide over the 
course of approximately 1-year. 
These analyses will be supported by the pre-specified similar analyses in all populations (DUS, 
FAS, and CS populations), and for hunger, by the additional hunger assessments (morning 
hunger, average hunger).   
Specifically, daily hunger will be assessed on individual patients ages 12 and above, with 
support from their parent/caregiver, using a hunger questionnaire 


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Prior to analysis, daily hunger scores for each of the 3 hunger assessments will be averaged 
separately by week.  For a week of hunger scores to be considered evaluable, scores need to be 
recorded and available for analysis on at least 1 of 7 days to provide sufficient data to determine 
mean values. In order to look at impact of missing hunger data, a sensitivity analysis will be 
done to examine if there are any differences in conclusions drawn by data available; primary 
and key secondary analysis for daily hunger scores will be repeated for patients with at least 3 of 
7 days of data present, 4 of 7 days of data present, 5 of 7 days of data present, 6 of 7 days of 
data present, and 7 of 7 days of data present.      
Percent change from baseline in body weight (kg) at the end of approximately 1 year of 
treatment in the DUS population will be assessed as the first secondary efficacy evaluation.   If 
statistical significance is achieved for this endpoint, the mean percent change from baseline at 
the end of approximately 1-year of treatment in the DUS population will be numerically 
compared (point estimate) to the ≥10% mean change from baseline in body weight “Success 
Criteria” for this study (a description and rationale is provided in Section 4.7.1). 
The protocol specifies that the weight measurement at any given visit will be measured at the 
clinic in triplicate, and averaged of the 3 measurements taken as the visit weight.  
A linear mixed model repeated measures analysis of variance with a fixed term for time and 
baseline weight and a random effect for subjects will be used to assess the primary efficacy 
endpoint at approximately 1-yeart.  All weight measurements obtained during the study will be 
included in the model and missing data will be handled as described in Section 4.2.9.  An 
unstructured covariance matrix will be used to model the expected different variances among 
the participants. In the event the mixed model does not converge with an unstructured 
covariance matrix; a compound-symmetric then Toeplitz covariance matrix will be employed 
instead. Additionally, a paired t-test will be derived from the model and compared to no change 
(0% mean percent weight change from baseline) and will use Satterthwaite's degrees of freedom 
estimates (1-sided, compared to alpha of 0.05 for the primary success of this endpoint; a 
comparison to an alpha of 0.025 will also be provided).  
The assumption of normality will be visually assessed via a visual diagnostic of closeness to 
normality, not as a conditional test associated with efficacy endpoint analyses. Graphical 
assessments of residuals from the model fit may be examined. If a substantial departure from 
normality is observed, a transformation such as log (post/pre) or rank or other non-parametric 
test (such as 1-sample Wilcoxon signed rank test versus a 0% change from baseline) may be 
used to analyze the data as a sensitivity analysis for continuous endpoints; however, the analysis 
on the original scale of observation will be reported. 
Once this analysis is complete, and if it is statistically significant, the mean percent change from 
baseline at the end of 1-year of treatment in the DUS population will be numerically compared 
(point estimate) to the ≥10% mean change from baseline in body weight; no formal statistical 
analysis will be performed.   
Results from the linear mixed model repeated measures analysis of variance will be presented in 
a table. 


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Rhythm is proposing that this first secondary endpoint also be performed in the FAS population, 
using a non-parametric 1-sample Wilcoxon signed rank approach (comparing the mean weight 
percent change from baseline against 0%), which should mitigate the issues raised by the 
occurrence of a bimodal distribution.  We propose that this analysis be applied as a sensitivity 
analysis, along with a tabulation of the percent of patients who do not meet the ≥5 kg threshold, 
to provide useful information needed in the label. 
The second key secondary endpoint is the mean percent change from baseline in weekly average 
hunger (using “most hunger over the last 24 hours” daily response) in the DUS population (for 
patients 12 years of age and older). This endpoint will be measured as described above and will 
be analyzed in a similar manner as the key secondary endpoint. Specifically, it will be analyzed 
using a linear mixed model for repeated measures analysis of covariance with weekly average 
hunger percent change from baseline as the outcome and fixed terms for time and baseline 
hunger and a random effect for subject. “Hunger in the morning” and “average hunger over a 
24-hour period” will be analyzed in the same manner as additional secondary endpoints.  
Once the second key secondary analysis is complete, and if it is statistically significant, the 
mean percent change in hunger from baseline at the end of approximately 1-year of treatment in 
the DUS population will be numerically compared (point estimate) to a 25% mean change from 
baseline in hunger; no formal statistical analysis will be performed.   
As a sensitivity analysis, the second key secondary endpoint will also be analyzed for the FAS 
population, using a non-parametric 1-sample Wilcoxon signed rank approach (specifically, 
Wilcoxon 1-sample signed rank tests comparing the mean weight percent change from baseline 
against 0%), which should mitigate the issues raised by the occurrence of a bimodal distribution. 
The third key secondary endpoint is the proportion of patients in the FAS population who 
achieve at least a 25% hunger improvement from baseline threshold compared to the null 
hypothesis that 5% of patients will achieve this threshold at the end of approximately 1-year of 
treatment. This will be analyzed via the exact binomial test which will test whether the 
percentage of patients who reach at least 25% hunger improvement is greater than 5%.  
Once the third key secondary analysis is complete, and if it reaches statistical significance, the 
proportion of patients in the FAS population who show ≥25% hunger improvement will be 
numerically compared (point estimate) to the 35% proportion of responders at the end of 
approximately 1-year of treatment as defined in the “Success Criteria;” no formal statistical 
analysis will be performed.   
   
 
 


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4.6.3. 
Secondary Efficacy Endpoints 
Secondary efficacy endpoints will be analyzed first for the DUS population, to be supported by 
the pre-specified similar analyses in the FAS and CS populations; other populations will be 
analyzed as indicated.    
Secondary objectives are to assess the effect of setmelanotide over the course of approximately 
1 year on the following: 
• The proportion of patients who meet categorical thresholds of 5%, 15%, 20%, 25%, 
30%, 35% and 40% weight loss from baseline.  
• Global hunger as assessed by the Patient Global Impression of Severity (PGIS) and the 
Patient Global Impression of Change (PGIC) in patients ≥ 12 years of age.  
• Hunger and/or hyperphagia assessments in patients 6 years old up to < 12 years of age 
(to be enrolled when Amendment 6, the pediatric age amendment, is implemented). 
• Global hunger as assessed by the Caregiver Global Impression of Severity (CGIS) and 
the Caregiver Global Impression of Change (CGIC) in patients 6 years old up to < 12 
years of age. 
• Percent change in body fat and body mass as measured by either DEXA or BIA (site- or 
sub-study specific).  
• Percent change in BMI.  
• Change in glucose parameters: fasting glucose, HbA1c, OGTT with focus on parameters 
of insulin sensitivity. 
• Change in waist circumference (cm). 
• Safety and tolerability of setmelanotide (including BP and HR). 
Secondary objectives are to assess the effect of setmelanotide during the double-blind, placebo-
controlled withdrawal period as follows: 
• During withdrawal from drug: reversal of weight and hunger reduction during the 
double-blind placebo-controlled withdrawal period. 
Safety and Tolerability 
Frequencies of AEs and injection site reactions, as well as percentage of abnormal ECGs, vital 
signs, laboratory evaluations, glucose parameters and 
 in patients ≤16 years of 
age will be examined in order to assess safety and tolerability of the treatment. Additionally, 
shifts between each study visit where the above is collected and the baseline measurement will 
be tabulated. Please see Section 4.9 for more detail regarding summary of safety measurements.  


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Data plots and displays will be aligned by week according to the timing of when the therapeutic 
dose for each individual participant was achieved; thus, each patient graphic display should 
include a total of 12 weeks of open-label therapeutic dosing following a variable number of 
titration steps for each patient.  Thereafter, the 8-week double-blind placebo or active periods 
will be depicted, followed by the remaining open-label treatment period on active therapeutic 
level dosing.   
Patient Global Impression of Severity (PGIS) and Change (PGIC) 
Additionally, two global hunger questions will also be administered to patients ≥ 12 years of age 
to assess static and current states of hunger, PGIS and PGIC, at screening (question 1 only), 
Visits 6 and 7 during the placebo withdrawal period, Visit 8, 9 and 13 during the second open 
label treatment period and the final visit. These categorical measurements identify level of 
hunger at the time the question is asked (question 1) as well as in comparison with prior to study 
start (question 2). PGIS (question 1) data will be transformed into a numeric index ranging from 
0-3, with higher scores being more severe. For the raw categorical data, shift tables between 
each study visit where PGIS is collected and the baseline measurement will be tabulated. As 
there is no baseline comparator for PGIC and the question itself asks to compare hunger prior to 
study start, this data will be displayed in a table of frequencies for each visit and no formal 
statistical inference will be done. Numeric data for PGIS will be analyzed in the same manner as 
the key secondary endpoint, described in Section 4.6.2, in order to examine change from 
baseline at approximately 1 year.  
Two global hunger questions, the Caregiver Global Impression of Severity (CGIS) and the 
Caregiver Global Impression of Change (CGIC), will also be administered to the parent or 
caregiver of patients 6-11 years of age to assess their perceptions of the child’s hunger or feed-
seeking behavior (both current status and change from baseline).  These data will be examined 
in the same manner described above for the PGIS and PGIC. 
Body Fat, Body Mass, BMI and Waist Circumference 
Body fat and body mass will be measured by either DEXA or BIA, based on what is available at 
each study site, at screening, Visit 6 and Visit 13.  BMI will be calculated for each individual 
based on their weight at each time point and the last height measurement available.  Analyses 
for body fat, body mass, BMI and waist circumference will employ similar methods as the key 
secondary efficacy analysis as described in Section 4.6.2, with change from baseline at 
approximately 1 year including both absolute kg change from baseline and percent change from 
baseline. 
Glucose Parameters 
Glucose parameters include fasting glucose, HbA1c and an OGTT with focus on parameters of 
insulin sensitivity derived from insulin assay measurements. Glucose and HbA1c are collected 
at screening, Visits 2a, 4, 6, 9, 11, 13 and the final visit. An OGTT with concurrent insulin 
levels at all time points will be done at screening, Visit 6 and Visit 13. The main analysis will be 
on the area-under-the-curve (AUC) of insulin and glucose, compared to baseline.  In addition, 
the glucose and insulin data will be presented in tables illustrating shifts between each study 


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visit starting from the baseline measurement, and tabulations of abnormal measurements will be 
shown.  These data will also be displayed in a figure (glucose and HbA1c plots over time versus 
study week, plus OGTT plots with glucose and insulin levels over time during the OGTT).  
Additional analyses such as HOMA (homeostatic model assessment) measures of insulin 
sensitivity may be included as additional descriptive statistics. 
Analysis of Reversal of Weight and Hunger Reduction during the Double-Blind Placebo-
Controlled Withdrawal Period 
This study includes a single, double-blind, placebo-controlled period lasting 8 weeks in duration 
as described in Section 2.1 and shown in Figure 1.  The sequence of this double-blind 8-week 
period is masked to patients and clinic site personnel, but follows the same sequence in all 
patients: continued active therapy for 4 weeks (weeks 13-16), followed by the 4-week placebo 
withdrawal (weeks 17-20), then re-treatment at the therapeutic dose, which for this analysis 
includes just the first four weeks after restarting open-label setmelanotide (weeks 21-24).  
Retreatment at the therapeutic dose continues long term for the remainder of the study to ~ 1 
year.  The focused analysis of this on-off-on treatment period is to be comprehensive and assess 
weight and hunger changes preceding, during, and following the double-blind withdrawal 
period, and therefore weight and hunger changes will also be assessed for this analysis for the 
first 4 weeks of open-label re-treatment following the placebo withdrawal in every patient.   
The key endpoint for weight during this period will be the absolute difference between change 
in weight (kg) over the last 4-weeks of active treatment (i.e., nominally the weight loss during 
weeks 13-16) and the change in weight during the 4-week placebo-controlled withdrawal period 
(i.e., nominally weeks 17-20). This will be examined using summary statistics (N, mean, 
median, min-max) for the absolute change in weight during this period.  If the withdrawal 
period is <4 weeks, the data will be normalized to a 4-week period.  
Supplemental analyses for weight will include summary statistics for the weight change in each 
of the three periods described above:  the last 4-weeks of active treatment before placebo 
withdrawal, the 4-week placebo-controlled withdrawal period, and the first four weeks of active 
re-treatment.   
The key endpoint for hunger during this period will be the absolute difference (in score) from 
the last active treatment measurement prior to the withdrawal phase and the last hunger 
assessment measurement at end of the withdrawal phase.  Specifically, this will be the absolute 
change in mean weekly “most hunger in the last 24 hours” hunger score for the last evaluable 
week prior to the withdrawal of active treatment (nominally the data from the full week 16), 
compared to the mean weekly hunger score for the last week of the 4-week withdrawal period 
(nominally the data from the full week 20). Similar supporting analyses will be performed for 
the other hunger assessments (e.g., daily morning hunger score).  This will be examined using 
summary statistics (N, mean, median, min-max) for the absolute change in weight during this 
period. If the withdrawal period is <4 weeks, the last hunger value off of treatment in this period 
will be considered the end value for the withdrawal period (e.g., if the withdrawal period last 3 
weeks, the last weight value on placebo withdrawal will be used in this analysis).  
We do not have good estimates for the magnitude or variability of effects of a withdrawal 
period, such as included in this protocol, as such procedures have not been included in previous 
protocols.  The only guiding information was an open label withdrawal for the first patient in the 
Phase 2 study, where the one patient gained 4.8 kg over the first ~2-3 weeks of the withdrawal 


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period, and her hunger scores increased from 0-1 to 7 points.  The magnitude of effects on 
weight are limited by the length of the withdrawal period (i.e., 4 weeks) and therefore, the 
change in weight is likely to be small in additional patients.  For hunger, the magnitude of effect 
might be larger, as shown by changes in hunger over short periods of time (i.e., weeks) for the 
patients in Study RM-493-011.  However, as shown in Appendix 5, the variability of hunger 
scores is quite large. As a result, any statistical test is likely to be underpowered relative to the 
overall variability of weight and hunger change in this study.  Therefore, the key weight and 
hunger data will be the summary statistics as outlined above; a paired t-test will also be 
employed to determine if weight and hunger differences (between the two periods described 
above) are different from zero. All comparisons using the t-test will be within-patient 
comparisons.  
Weight and weekly hunger scores (actual values and change for each individual will be 
tabulated, presented in listings and displayed in a figure across time for this 12-week period.  A 
plot of weights (by week) and hunger scores (by mean weekly scores) will also be presented 
with each of the three 4-week periods labelled.  Changes pre- and post-withdrawal will be 
examined to evaluate possible hysteresis of weight and hunger changes during these transitions 
off and on therapy in each patient.  Additional exploratory analyses may be examined, including 
calculation of the rate of weight gain and hunger reversal during the 4 weeks on placebo to 
illustrate how quickly weight is gained and hunger reappears once treatment is halted.  In 
addition, changes in PGIC and PGIS will be summarized.  
Other Secondary Analyses 
Evaluations by interval will also be performed for key weight and hunger parameters.  Changes 
from baseline during screening, dose titration, open-label treatment periods (initial 12-week; 
later 32 week) and the withdrawal phase will all be looked at individually. The model described 
in Section 4.6.2 will be implemented, for each phase of the study separately, so the following 
will be likely examined: change in weight between baseline and end of dose titration, baseline 
and first open-label treatment period, baseline and double-blind withdrawal period and finally, 
baseline and second open-label treatment period. 
By-patient data listings of other secondary endpoints will also be presented.  


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4.7. 
Rationale for Key Elements of the SAP 
4.7.1. 
Definitions of Success for Clinical Benefit in the Assessment of Efficacy for the 
Primary and Secondary Endpoints 
This section defines what results would need to be seen in this study for it to be regarded as a 
success.  The first key step in the definition of success is to reach statistical significance on the 
primary and key secondary endpoints.  However, statistical significance is  necessary but not 
sufficient, and it is important to consider whether the data are clinically meaningful in the 
context of this indication.  This section provides a guide for a threshold for clinical 
meaningfulness for this indication, for the primary and key secondary endpoints. 
Due to several contributing factors -- a) the small size of this study, b) the potential for wide 
confidence limits (especially in some populations of interest, such as the FAS, which may be a 
bi-modal population), c) the lack of experience in this ultra-rare orphan population, and d) 
limited data on the natural history of this disease (to determine good baselines in historical data) 
-- a rigorous statistical approach to clinically meaningful bounds is not proposed.  Specifically, 
for the thresholds proposed below, once statistical significance is achieved, a numerical 
comparison of the results (point estimate) of the key endpoints will define overall success in this 
study. 
Most importantly, the SAP provides trial success criteria for the primary endpoint, which will 
determine the success of this study.  All data and rationales provided for key secondary 
endpoints are to provide context only.  
Context for the Assessment and Definition of Trial Success 
For an open-label pivotal clinical trial in a limited number of rare patients, Rhythm understands 
and agrees with the FDA perspective that designating a prospective definition of trial success is 


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critical.  Rhythm considers three components to be crucial to understand in order to provide 
context for setting this prospective success target.     
First, it is clearly important to consider the FDA guidance for general obesity products that has 
guided development of current obesity medications is also informative.  Key points from the 
FDA guidance and relevant general obesity clinical trial data are briefly provided in the next 
section to highlight this perspective. 
Second, to help gauge what is observed in clinical trials that led to FDA approvals, it is also 
important to consider the magnitude of weight changes demonstrated in pivotal clinical trials 
that led to the approval of current general obesity products.  Relevant general obesity clinical 
trial data are also briefly described to highlight this perspective, including how relatively small 
in magnitude such differences between active therapy compared to placebo have been, and how 
difficult it is for general obese patients to maintain any long-term weight reduction from 
baseline over time.  The modest long-term efficacy of current obesity therapies has been one of 
their major limitations.   
Finally, it is useful to emphasize the relentless progression and refractoriness of the early-onset, 
extreme obesity that develops in LEPR deficiency obesity (often +5% to +10% body weight 
gain during each year of life, estimates based on limited weight curves from infancy in LEPR 
patients; see figure below).  These aspects were described comprehensively in the BTD 
application and are described only briefly here.  Given the therapeutic challenges in the general 
obesity population, it is not at all surprising that diet plus exercise is almost uniformly futile in 
LEPR deficiency or other monogenic obesity disorders characterized by stronger major gene 
effects than seen in general polygenic human obesity.    
FDA Draft Guidance on Developing Products for Weight Management:  Mean Differences 
and Categorical Responses for Weight Change from Baseline   
The FDA Draft Guidance from 2007 cites a 5% efficacy benchmark as the target minimum 
percent decrease for weight loss agents seeking approval for broad use in general common 
obesity, noting that “in general, a product can be considered effective for weight management if 
after 1 year of treatment the following occurs:   The difference in mean weight loss between the 
active-product and placebo-treated groups is at least 5 percentage points and the difference is 
statistically significant.”   In addition to setting this target value for mean difference in weight 
loss, categorical weight responses are also cited as important to consider for approving weight 
loss therapies.  The following goals for categorical weight reduction response are noted, namely 
that “the proportion of subjects who lose greater than or equal to 5 percent of baseline body 
weight in the active-product group is at least 35 percent, is approximately double the proportion 
in the placebo-treated group, and the difference between groups is statistically significant.” 
Rhythm considers these two interrelated weight reduction targets -- the first based on a 5% 
mean reduction vs. placebo after approximately 1 year of treatment and the second based on 
categorical 5% weight reduction responses from baseline among the treated population, again 
over approximately 1 year – as the appropriate paradigms (in approach, if not in magnitude) to 
set targets for determining success of setmelanotide in treating LEPR deficiency obesity in the 
pivotal RM-493-015 clinical trial.   
Clinical Data Over Long-Term Dosing / Reference Points from General Obesity Clinical 
Trials for Setting Success Criteria:    


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The magnitude of mean weight reduction achieved in general obesity clinical trials is also 
informative for setting an appropriate success target for setmelanotide in LEPR deficiency.  Five 
New Chemical Entities (NCEs) or combination products are currently approved by FDA for 
chronic weight management.  These agents and their weight reduction impact vs. placebo after 
approximately 1 year of chronic dosing consist of orlistat (2.9 – 3.4 kg; 2.9 – 3.4%), lorcaserin 
(3.6 kg, 3.6%), phentermine / topiramate fixed-combination (6.6 - 8.6 kg; 6.6 – 8.6%), 
naltrexone / buproprion (4.8%) and liraglutide injection (5.8 kg).  These medicines were 
approved by FDA between 1999 through 2014 (Apovian, 2015).  Overall, the weight change 
demonstrated by these therapies above diet and lifestyle alone after approximately 1 year on 
active treatment ranges from 2.9% to 8.6% weight reductions.   [The specific kg values and/or 
% ranges for these agents are included adjacent to the individual products noted above; note that 
in nearly all trial populations the mean baseline weights for the general obese adult populations 
studied were approximately 100 kg, leading to similar kg and percent weight reductions 
(Apovian, 2015)].  These clinical data provide a framework of the magnitude of mean weight 
loss changes achieved by current obesity medication approved for use in general human obesity.  
As such, they also inform Rhythm’s proposal to define a success target for weight loss with 
setmelanotide over a similar time course for chronic treatment of approximately one year in 
LEPR deficiency obesity.      
LEPR Deficiency:  Major Gene Effects Conferring Early-Onset Extreme Obesity  
Overall, the size of the LEPR deficiency obesity patient population to be enrolled and evaluated 
in this study is very small (N ~ 10 pivotal patients).  LEPR deficiency is one of several 
monogenic forms of obesity impacting the leptin – melanocortin pathway that causes extreme, 
early-onset obesity, often beginning in infancy and progressing in severity throughout childhood 
and into adolescence and adulthood without any abatement; detailed clinical and genetic 
features of LEPR deficiency obesity have been previously submitted to FDA as part of the prior 
BTD application (submission Sequence 0071, March 27, 2017).   
The pivotal study represents a small, open-label trial employing a “personalized medicine” type 
of dosing and treatment approach, with every patient is part of the DUS population needing to 
qualify for long-term treatment by demonstrating ≥ 5 kg weight reduction from baseline (or ≥ 
5% weight reduction if baseline weight was < 100 kg) during an initial individualized 
therapeutic dosing and test period.  The expected clinical results for these rare genetic obesity 
patients was considered by the FDA and the Sponsor to represent a set of informative case 
reports grouped in this nature because large clinically significant treatment effect sizes are 
expected for both weight reduction and hunger score improvements.     
Success for the Primary and Key Secondary Endpoint:  Interrelated Weight Reduction 
Goals Equal to Twice the FDA Guidance Targets 
• 10% OBSERVED Percent Mean Weight Loss from Baseline in the DUS Population 
• 35% of Patients Achieve a 10% Weight Reduction from Baseline in the FAS Population 
Rhythm’s general approach to defining success was to use the paradigm from the FDA guidance 
(defining a percent mean weight loss target and/or a percent of patients achieving a clinically 
important threshold) but including a greater magnitude of effect of setmelanotide in this rare 
disease population.  
Rationale for ≥10% mean weight loss from baseline in the DUS population. 




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Ten percent mean weight loss from baseline is also designated as a target success threshold 
because this magnitude of mean weight loss (either as a mean change vs. placebo) represents a 
clinically meaningful threshold, and a level of response not previously attained among 
therapeutic weight loss clinical trials of either oral or injectable approved weight loss medicines 
in a general obesity population (Apovian, 2015).  Thus, the achievement of a ≥ 10% weight 
reduction from baseline in LEPR deficiency obesity would be expected to be both statistically 
significant and clinically significant, especially in this severe, early-onset obesity patient 
population suffering from unremitting hunger.  In fact, the relentless progression of extreme 
weight gain amounting to 5 – 10 kg per year beginning early in childhood in the majority of 
genetically identified cases makes this goal highly impactful in such patients.  There are very 
few, if any, cases where conventional diet and exercise management and/or non-specific weight 
loss therapies can provide lasting weight reduction.  Thus, the impact of 10% weight loss can be 
significant on co-morbidities and quality of life in general common obesity and it is likely to be 
as or possibly more impactful in this early-onset, extreme form of genetic obesity. 
Thus, the efficacy threshold Rhythm has designated for setmelanotide in LEPR deficiency 
obesity is approximately > 2 times higher than the efficacy goal cited by FDA for general 
obesity (with caveats).  Rhythm proposes that this ≥10% response from baseline weight 
threshold is rigorous and appropriate for the genetically defined and extreme LEPR deficiency 
obesity population, especially in the absence of any alternative therapies or interventions for this 
rare genetic form of extreme obesity.  
Rationale for at least 35% of patient attain a ≥10% mean weight loss from baseline in the FAS 
population. 
The paragraphs above help to establish the “≥10% weight loss” vs. baseline as a clinically 
meaningful threshold for this indication, and this rationale also applies to a categorical analysis.  
For this analysis, it is more appropriate to consider the FAS population to understand the full 
efficacy of setmelanotide in this categorical approach. 
Therefore, analogous with FDA guidance but with greater percent weight loss as a threshold, 
and understanding the desire for “intention to treat” analyses, we also propose that an analogous 
categorical response criterion could also be set for success of RM-493-015, namely, that at least 
35% of patients from the FAS population demonstrate ≥10% weight reduction from baseline 
after approximately 1-year on treatment.   
Here, the complex issue is how to compare vs. historical controls.  The available data suggests 
that 0% of LEPR deficiency patients would demonstrate at least 10% weight loss in a single 
year, even with extraordinary measures.  The exception might be after bariatric surgery, as some 
patients have had very short term improvements, though over time their overwhelming hunger 
leads to weight regain.  In the absence of such measures in our clinical trial (exclusions from the 
trial), and the general contraindication of bariatric surgery in this population, it is defensible to 
consider that no (0%) patients would meet these criteria and the statistical comparison for this 
endpoint should be a comparison to a 0% proportion.  Despite this strong rationale based on the 
natural history of these patients, since the data are limited and the number of patients in the trial 
is small, it is probably more appropriate to go beyond this very conservative estimate of 0% 
responders, to do our historical control comparisons assuming that a small proportion of the 
population (i.e. 5%, or a null of 0.05) might show a 10% weight loss in any given calendar year; 


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hence we propose a categorical comparison to a 5% responder estimate in untreated historical 
patients.  
Statistical tables to support the categorical weight analysis (Table 4 and Table 5 of Appendix 5) 
show the p-values to reject the null hypothesis for a given observed number of successes, and 
the power for this endpoint, respectively.   
Success for Secondary Efficacy Endpoints – Hunger Score Change from Baseline 
Besides extreme weight gain, pronounced and unrelenting hunger / hyperphagic feeding 
behaviors represent the most debilitating symptoms that plague patients with early-onset 
extreme obesity caused by LEPR deficiency.  Hunger and increased appetite symptoms can be 
even more challenging when patients and parents are not able to convince pediatricians and 
other health professionals of their impact, especially as hunger is a normal daily experience in 
nearly everyone that has converted to a pathological extreme, almost addictive, symptom in 
LEPR deficiency patients.  Therefore, adult and pediatric age range efficacy assessments relying 
on self-reported hunger scores and/or parent/caregiver observer-related outcome (ORO) 
assessments represent important secondary endpoints for the RM-493-015 pivotal trial (and 
exploratory endpoints for patients age 6 through age 11 years given challenges in ORO 
assessments of this symptom). 
Nonetheless, in recognition of their importance for daily symptoms and health impact in LEPR 
deficiency patients, Rhythm proposes that mean reduction in “most hunger in the last 24 hours” 
hunger scores from baseline ≥ 25% over approximately 1-year would define a prospective 
percent reduction that would represent a clinically meaningful response on incessant and 
debilitating hunger symptoms in LEPR deficiency obesity patients.   
While not a criterion for success, robust supporting data from the initial 12 weeks of therapeutic 
treatment, as well as a robust magnitude of change upon double-blind, placebo-controlled 
withdrawal would provide additional corroboration.  
For this endpoint, it is especially important to emphasize that success is a numerical comparison 
of the mean changes in hunger assessments.  At present, we have almost no variability data to 
support a power analysis for this endpoint, and only limited data to estimate a magnitude.  As 
such, this endpoint might be under powered.  Using all current data, an updated estimate of the 
1-sided confidence limits for hunger percent change from baseline is included in Table 6 of 
Appendix 5.  This table shows that the half-width of the confidence interval for hunger change 
from baseline might exceed 70 percentage points, and Table 9 (power table, Appendix 5) 
supports that for this study, a true underlying mean percent change from baseline of -32.5% 
achieves 80% power (alpha=0.05) to yield an OBSERVED difference that achieves statistical 
significance (-38% for an alpha=0.025).   




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4.8. 
 
4.9. 
Safety Analyses 
Safety analyses will be conducted using the SAF Population and data will be collected as 
described in Appendix 1. 
4.9.1. 
Adverse Events 
AEs will be coded using MedDRA and displayed in tables and listings using 
System/Organ/Class (SOC) and Preferred Term. 
Analyses of AEs will be performed for those events that are considered treatment emergent, 
where treatment emergent is defined as any AE with onset after the administration of study 
medication through the end of the study, specifically, 30 days after the last dose of 
setmelanotide, or any event that was present at baseline but worsened in intensity or was 
subsequently considered drug-related by the investigator through the end of the study.   
AEs are summarized by subject incidence rates, therefore, in any tabulation, a subject 
contributes only once to the count for a given AE (SOC or preferred term). 
The number and percentage of subjects with any treatment-emergent AE, with any treatment-
emergent AEs assessed by the Investigator as related to treatment (definite, probable, or possible 
relationship), and with any SAE will be summarized by treatment group and overall.  In these 
tabulations, each subject will contribute only once (i.e., the most related occurrence or the most 


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intense occurrence) to each of the incidence rates in the descriptive analysis, regardless of the 
number of episodes. 
No formal hypothesis-testing analysis of AE incidence rates will be performed.   
All AEs occurring during the study will be listed in subject data listings. 
By-subject listings also will be provided for the following: subject deaths; SAEs; and AEs 
leading to withdrawal.  
An additional listing will include onset and resolution dates, verbatim term, preferred term, 
treatment, severity, relationship to treatment, action taken, and outcome will be provided. 
Summary tables and figures (by-patient) illustrating frequency of AEs of special interest will 
also be examined. 
4.9.2. 
Laboratory Data 
Clinical laboratory values will be expressed using SI units. 
Safety laboratory data will include CBC with platelet count and standard indices, a chemistry 
panel (includes sodium, potassium, chloride, CO2, albumin, total protein, glucose, BUN, 
creatinine, uric acid, AST, ALT, GGT, CPK, alkaline phosphatase, total bilirubin, direct 
bilirubin, LDH, calcium, phosphorus), urinalysis if positive findings on dipsticks warrant further 
examination, a coagulation profile (prothrombin time [PT] or international normalized ratio 
[INR], and partial thromboplastin time [PTT]), fasting samples where feasible, 
and HbA1c. These will be collected at screening, visits 2a, 4, 6, 9, 11, 13 and the final 
visit. 
The actual value and change from baseline (as defined by the last measurement obtained prior to 
the first dose of the active treatment during the open-label dose titration phase) to each on study 
evaluation will be summarized for each clinical laboratory parameter, including hematology and 
clinical chemistry.  In the event of repeat values, the last non-missing value per study day/time 
will be used.  Screening values will also be included in these tables and figures.  
A shift from baseline table will be presented (N and %) for the following categories, where each 
patient is counted in one cell only. Missing data will not be imputed. There will be no inferential 
analysis. 
• Hematology 
• Chemistry 
All laboratory data will be provided in both data listings, as well as figures, which will illustrate 
all measurements taken in both the pre-dose (screening) period and treatment period. 
A subset listing will be presented for all clinically significant and abnormal laboratory values. 
4.9.3. 
Vital Signs and Physical Examinations 
Vital sign data will include BP, HR, body temperature, respiration rate and will be collected at 
all visits.  
The actual value and change from baseline (as defined by the last measurement obtained prior to 
the first dose of the active treatment during the open-label dose titration phase) to each on study 
evaluation will be summarized for vital signs.   


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Repeat measures or more frequent monitoring can be implemented for significant increases in 
BP or HR. 
By-subject listings of vital sign measurements will be presented in data listings. 
Physical examination results at each time point will be summarized; shifts from baseline in 
physical examination findings to each on study visit will also be presented.  All physical 
examination findings will be presented in a data listing. 
If greater than 4 patients participate in the 24-hour 
sub-study, the data will be 
summarized; otherwise, individual data will be presented.  
4.9.4. 
Electrocardiogram 
ECG data will be collected at screening, visits 2a, 6, 9, 13, and the final visit.  
Results will be summarized descriptively, including the number and percent of subjects with 
normal, abnormal and clinically significant abnormal results at baseline and each study visit.  In 
particular, analysis of QTc intervals will be computed both for mean changes from baseline, as 
well as categorical analyses.  
All ECG data for each subject will be provided in data listings. 
4.9.5. 
Concomitant Medications 
A review of concomitant medications will be conducted during the screening period and at 
every study visit. Any medications taken by study patients will be recorded in source documents 
and on the appropriate CRF.  
Concomitant medications will be coded using the WHO Drug dictionary. Results will be 
tabulated by Anatomic Therapeutic Class (ATC) and preferred term. 
The use of concomitant medications will be included in by-subject data listing. 


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6. 
REFERENCES 
 
Apovian CM, Aronne LJ, Bessesen DH, McDonnell ME, Murad MH, Pagotto U, Ryan D, Still 
C. Pharmacological Management of Obesity: An Endocrine Society Clinical Practice Guideline. 
J Clin Endocrinol Metab. 2015, 100(2): 342-362. 
Kuehnen P, Clement K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, Mai K, 
Blume-Peytavi U, Gruters A, Krude H. Proopiomelanocortin Deficiency Treated with a 
Melanocortin-4 Receptor Agonist. NEJM 2016; 375: 240-246. 
 
 
 
 
 


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7. 
CLINICAL STUDY REPORT APPENDICES 
Appendix 1: Schedule of Assessments 
Table 1 - Screening and Dose Titration# 
Study Period 
Screening 
Open Label Dose 
Titration6 
Procedure 
Visit Number (V) 
V1 
V2a6 
Start of Dose Titration Week (Dose 
Titration Study Day ± 3 days) 
-4 to 0 
(-28 to -1) 
1 
(1) 
Informed consent/Assent 
X 
Inclusion/Exclusion review 
X 
X5 
Medical history review 
X 
X5 
Pregnancy test 
X 
X4, 5 
Physical examination1 
X 
Height1 
X 
Comprehensive skin exam2 
X 
Fitzpatrick scale 
X 
Open label placebo practice 
X 
Dose Titration Decision24 
X5 
Weight/waist circumference11 
X 
X5 
Archive sample for storage12 
X 
Study treatment administration13 
X 
Injection site inspection14 
X 
Vital signs15 
X 
X5,16 
ECG (12-lead)17 
X 
X5, 17 
Safety laboratory tests18 
X 
X5 
OGTT28 
X 
Daily Hunger Questionnaire20 
X 
X5 
Global Hunger Questions33 
X 
Body Composition23 
X 
Anti-RM-493 antibody samples 
X 
X5, 26, 31 
Adverse Event assessment25 
X 
X 
Concomitant meds review 
X 
X 
Telephone contact 
X 
 
 
 


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Optional Sub-Studies 
 
 
 


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Table 2 - 10 Week Active Treatment and 8 Week Double-Blind Placebo Controlled Withdrawal 
Study Period 
Open Label 
Double Blind 
Active Treatment7 
Placebo-Controlled 
Withdrawal7 
Procedure 
Visit Number (V) 
Start of Week (Study Day) 
V3 3 
(15) 
V4* 5 
(29) 
V5 9 
(57) 
V6 13 
(85) 
V7 17 
(113) 
Pregnancy test 
X4,5 
X4,5 
X4,5 
X4,5 
X4,5 
Physical examination1 
X 
Height1 
X 
Comprehensive skin exam2 
Weight/waist circumference11 
X5 
X5 
X5 
X5 
X5 
Archive sample for storage12 
X5 
Therapeutic Dose Established 
X 
Study treatment administration13 
X 
X 
X 
X 
X 
Injection site inspection14 
X 
X 
X 
X 
X 
Vital signs15 
X5 
X5 
X5 
X5 
X5 
ECG (12-lead)17 
X5 
Safety laboratory tests18 
X5 
X5 
OGTT28 
X5 
Daily Hunger Questionnaire20 
X5 
X5 
X5 
X5 
X5 
Global Hunger Questions33 
X5 
X5 
Body Composition23 
X 
Anti-RM-493 antibody samples 
X5, 26 
X5, 26 
Adverse Event assessment25 
X 
X 
X 
X 
X 
Concomitant meds review 
X 
X 
X 
X 
X 
Telephone contact 
X 
X 
X 
X 
X 
 
Optional Sub-Studies 
 
 
 
 


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Table 3 - Additional 32 Week Open Label Treatment 
 
Optional Sub-Studies 
Study Period 
Open Label 
Early 
Termination 
/ Final 
Visit9 
Active Treatment8 
Procedure 
Visit Number (V) 
Start of Week (Study Day) 
V8 21 
(141) 
V9 27 
(183) 
V10* 33 
(225) 
V11 39 
(267) 
V12* 45 
(309) 
V13 53 
(365) 
Pregnancy test 
X4, 5 
X4,5 
X4,5 
X4, 5 
X4,5 
X4, 5 
X 
Physical examination1 
X 
X 
X 
Height1 
X 
X 
X 
Comprehensive skin exam2 
X 
X 
X 
Weight/waist circumference11 
X5 
X5 
X5 
X5 
X5 
X5 
X 
Archive sample for storage12 
X5 
Study treatment administration13 
X 
X 
X 
X 
X 
X 
Injection site inspection14 
X 
X 
X 
X 
X 
X 
Vital signs15 
X5 
X5 
X5 
X5 
X5 
X5 
X 
ECG (12-lead)17 
X5 
X5 
Safety laboratory tests18 
X5 
X5 
X5 
X 
OGTT28 
X5 
Daily Hunger Questionnaire20 
X5 
X5 
X5 
X5 
X5 
X5 
X 
Global Hunger Questions33 
X5 
X5 
X5 
X 
Body Composition23 
X 
Anti-RM-493 antibody samples 
X5, 26 
X5, 26 
X5, 26 
X5, 26 
Adverse Event assessment25 
X 
X 
X 
X 
X 
X 
X 
Concomitant meds review 
X 
X 
X 
X 
X 
X 
X 
Telephone contact 
X 
X 
X 
X 
X 
X 
X 






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22 
23 Body composition may be performed using an appropriate method available at sites (e.g. BIA, DXA, etc.) 
Refer to Section 6.3.3 regarding appropriate methodology for assessing this patient population. 
24 Once all the pre-dose assessments have been performed, the decision to dose titrate according to Appendix 
11.8 will be made. If the patient’s therapeutic dose has been established, the patient will transition into the 
10-week Open Label Active Treatment Phase, receive their therapeutic dose, and complete the V3 post-
dose assessments as defined in the SOA. If the patient’s therapeutic dose has not been established 
according to Appendix 11.8, the patient will be administered study drug, complete the dose titration post-
dose assessments as defined in the V2 SOA, and return to the clinic in ~2 weeks for the next sequential 
Visit 2 (i.e.; V2b, V2c, etc.). 
25 Adverse events will be recorded from the time a patient provides informed consent. AEs reported after 
dosing on Day 1 will be considered treatment-emergent AEs. 
26 Any patients with positive anti-drug antibodies will be followed ~every 3 months until titers resolve or 
return to baseline. 
27 Telephone contact by site on a monthly basis, or more frequently, if needed. 
28 Following collection of pre-meal (time 0) blood samples, patients will be given a standard oral glucose 
tolerance test. The following blood samples will be obtained during each OGTT: Blood glucose and insulin 
at approximately 30, 60 90 and 120 minutes after meal start. 
29 ~8 hours post-dose on Day 1 only. 
30 ~8 hours post-dose. 
31 To be collected on the first two, two-week dose titration visits (V2a and V2b [or V3, if the patient’s 
therapeutic dose has been established]). 
32 A blood sample will be obtained at Screening for genotyping for mechanisms considered to be possibly 
related to the safety or efficacy response to the study medication (e.g., other obesity related genes). 
33 
34 


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be measured only if BP increases are noted). 
# 
Once a patient’s therapeutic dose has been established according to Appendix 11.8, no further dose 
titrations will occur, and patients will transition directly into the 10 week Open Label Active Treatment phase.  
Therefore, the Dose Titration phase will be a minimum of 2 weeks and a maximum of 10 weeks. 
* 
For patients that reside a considerable distance from the clinic, these visits are optional clinic visits, and 
may be performed by the patient’s local physician or home health care professionals. 
+ 
If the visit is performed by a home health care professional, assessment may be performed at the next 
schedule in clinic visit. 
§  
For patients previously enrolled, the assessment should be performed at the patient’s next scheduled visit. 
 
 


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Appendix 2: Supplemental Statistical Analyses supporting the primary and key 
endpoints.  
Table 4 - Calculating p-values for the categorical (binary endpoint) proportion of patients with (i) 
weight loss from baseline of ≥10% at 1-year, or (ii) proportion of patients with 
≥25% improvement in hunger score at 1-year 
In each case comparing to null hypothesis value that assumes 5% (0.05) of untreated patients with 
weight loss from baseline of ≥10% (≥25% improvement in hunger score) at approximately 1-year (for 
N=10 patients total) 
For total sample size N=10 (i.e., the FAS population), the table below shows p-values to reject the null 
hypothesis in favor of the alternative that proportion exceeds 0.05 for a given observed number of 
successes using a 1-sided exact binomial test: 
No. of patients who achieve weight loss ≥ 10% OR 
25% improvement in hunger score 
P-value 
1 
0.401 
2 
0.086 
3 
0.012 
4 
0.001 
5 
0.00006 
6 
0.000003 
7 
<0.000001 
8 
<0.000001 
9 
<0.000001 
10 
<0.000001 
 
 
 


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Table 5 - Power for 1-sample unconditional exact binomial test of % responders versus null 
hypothesis value 5% (weight and hunger) for alpha=0.05 and 0.025, 1-sided 
For total sample size N=10, the table below shows the power for variety of TRUE underlying 
proportions (0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9) for test versus 0.05.  
TRUE underlying 
proportion 
Table entries are power to reject indicated null hypothesis 
and conclude TRUE proportion is higher 
null hypothesis rate=0.05 
alpha=0.05 1-sided* 
alpha=0.025 1-sided* 
0.2 
0.322 
0.322 
0.3 
0.617 
0.617 
0.4 
0.833 
0.833 
0.5 
0.945 
0.945 
0.6 
0.988 
0.988 
0.7 
0.998 
0.998 
0.8 
>0.999 
>0.999 
0.9 
>0.999 
>0.999 
*Note that alpha = 0.05 and 0.025 yield the same power because of the discrete nature of the response. 


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Table 6 - Calculating 1-sided upper confidence limits for mean weight percent change from 
baseline 
Using all prior data of all possible patients (2 POMC, 3 LepR, 5 Bardet-Biedl) from Studies RM-
493-011 and -014 (i.e., using N=10 patient’s data for variability estimates). 
The purpose of this analysis is to use all data available, including patients with other upstream MC4 
pathway disorders, to estimate variability and to provide the most realistic evaluation of the half-width 
of the confidence interval for percent change in weight from baseline at approximately 1-year.  Note that 
this data includes these patients, all of whom show important weight loss, and assumes all will complete 
approximately 1 year of treatment.  Please compare with Table 7, which assumes a more realistic FAS-
type of population, where a small proportion of patients will not be responders or will not complete 
approximately 1-year of treatment.  
Prior assumptions to calculate SD: Total sample size N=10, with various follow-up times. Using a linear 
mixed effects model with week as a fixed effect and patient as a random effect, we can extrapolate to 44 
weeks of weight loss (exclude 8 weeks of placebo controlled phase). The estimated percent change is -
21.53% from baseline and the conservative estimate of standard deviation is 8.79%. 1-sided confidence 
limit uses all data available. SD of 8.79 implies an observed range of 4x8.79=35.2 for the 10 weight 
change values.  The actual observed range is equal to 34 so this seems to be a reasonable approximation. 
Sample size 
T-statistic for 
95% CI 
T-statistic for 
97.5% CI 
95% 1-sided upper 
confidence limit 
using SD =8.79 
97.5% 1-sided 
upper confidence 
limit using  
SD = 8.79 
5 
2.13 
2.78 
18.72 
24.44 
6 
2.02 
2.57 
17.76 
22.59 
7 
1.94 
2.45 
17.05 
21.54 
8 
1.89 
2.36 
16.61 
20.74 
9 
1.86 
2.31 
16.35 
20.30 
10 
1.83 
2.26 
16.09 
19.87 
 
 
 


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Table 7 - Calculating 1-sided upper confidence limits for mean weight percent change from 
baseline 
Using prior data of several patients (2 POMC, 3 LepR, 5 Bardet-Biedl) from Studies RM-493-011 
and -014 (i.e., using N=7 patient’s data for variability estimates), then including fabricated data 
from N=3 participants who gain at least 5% of weight from baseline. This represents what is likely 
to be seen for the FAS population. 
Like Table 6, the purpose of this analysis is to use all data available, including patients with other 
upstream MC4 pathway disorders, to estimate variability and to provide the most realistic evaluation of 
the half-width of the confidence interval for percent change in weight from baseline at approximately 1-
year.  However, unlike Table 6, this analysis models a more realistic FAS-type population that includes 
N=7 treated patients who respond and complete approximately 1-year of treatment, along with N=3 
patients who demonstrate at least 5% weight gain from baseline at approximately 1-year (either because 
they are non-responders at 12 weeks and are discontinued from treatment, or because of early drop-out 
for other reasons).  This results in a bi-modal distribution, and markedly larger estimates of the half-
width of the CI.   
Prior assumptions to calculate SD: Total sample size N=10, with various follow-up times. Using a linear 
mixed effects model with week as a fixed effect and patient as a random effect, we can extrapolate to 44 
weeks of weight loss (exclude 8 weeks of placebo controlled phase). The estimated percent change is -
12.55% from baseline and the conservative estimate of standard deviation is 16.46%. 1-sided confidence 
limit uses 7 true patient’s data, 3 patients fabricated data. SD of 16.46 implies an observed range of 
4x16.46=65.8 for the 10 weight change values.  The actual observed range is equal to 42.9 so there is no 
need for a conservative estimate. Note that a pooled analysis of 3 non-responders and 7 responders is 
likely a bi-modal distribution; hence, analysis via the usual normal distribution may not be 
appropriate.  Hence, the precision indicated in the table below may be overly conservative since use of a 
rank transformation or an analysis of proportion of responders may be more appropriate and more 
precise. 
Sample size 
T-statistic for 
95% CI 
T-statistic for 
97.5% CI 
95% 1-sided 
upper confidence 
limit using SD = 
16.46 
97.5% 1-sided 
upper 
confidence limit 
using SD = 16.46 
5 
2.13 
2.78 
35.06 
45.76 
6 
2.02 
2.57 
33.25 
42.30 
7 
1.94 
2.45 
31.93 
40.33 
8 
1.89 
2.36 
31.11 
38.85 
9 
1.86 
2.31 
30.62 
38.02 
10 
1.83 
2.26 
30.12 
37.20 
*Note that the 3 fabricated had assumed % change from baseline of 5.88%, 7.41% and 10%.  
 


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Table 8 - Calculating 1-sided upper confidence limits for mean hunger percent change from 
baseline 
Using prior data of some patients (2 POMC, 3 LepR, 3 Bardet-Biedl) from Studies RM-493-011 
and -014 (i.e., using N=8 patient’s data used for variability estimates). 
The purpose of this analysis is to use all data available, including patients with other upstream MC4 
pathway disorders, to estimate variability and to provide the most realistic evaluation of the half-width 
of the confidence interval for percent change in hunger at approximately 1-year.  Note that this data 
includes patients all of whom show important improvements in hunger, and assumes all will complete 
approximately 1 year of treatment.   
Prior assumptions to calculate SD: Total sample size N=8, with various follow-up times. Using a linear 
mixed effects model with week as a fixed effect and patient as a random effect, we can extrapolate to 44 
weeks of hunger (exclude 8 weeks of placebo controlled phase). The estimated percent change is -
70.52% from baseline and the conservative estimate of standard deviation is 38.11%. 1-sided confidence 
limit uses all data available. SD of 38.11 implies an observed range of 4x38.11=152.4 for the 8 hunger 
change values.  The actual observed range is equal to 50 so there is no need for a conservative estimate. 
Sample size 
T-statistic for 
95% CI 
T-statistic for 
97.5% CI 
95% 1-sided 
upper 
confidence limit 
using SD = 38.11 
97.5% 1-sided 
upper 
confidence 
limit using SD = 
38.11 
5 
2.13 
2.78 
81.17 
105.95 
6 
2.02 
2.57 
76.98 
97.94 
7 
1.94 
2.45 
73.93 
93.37 
8 
1.89 
2.36 
72.03 
89.94 
9 
1.86 
2.31 
70.88 
88.03 
10 
1.83 
2.26 
69.74 
86.13 
 
 
 


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Table 9 - Power for 1-sample mean percent change from baseline versus null hypothesis value 0% 
(weight/hunger percent change from baseline) for alpha=0.05 and 0.025, 1-sided 
For total sample size N=10, the table below shows the power for variety of TRUE underlying mean 
percent change from baseline of -2% through -12% for test versus 0% (i.e., focused on weight percent 
change from baseline; similar information about hunger percent change from baseline is included in the 
footnote).  
 
TRUE 
underlying 
mean percent 
change from 
baseline 
Table entries are power to reject indicated null hypothesis 
null hypothesis percent mean 
percent change from baseline in 
weight=0, assuming SD=8.79 
null hypothesis mean percent 
change from baseline in hunger=0, 
assuming SD=38.11 
alpha=0.05 1-
sided 
alpha=0.025 1-
sided 
alpha=0.05 1-
sided 
alpha=0.025 1-
sided 
-2 
0.164 
0.094 
0.068 
0.035 
-3 
0.259 
0.161 
0.079 
0.041 
-4 
0.377 
0.251 
0.091 
0.048 
-5 
0.507 
0.363 
0.104 
0.056 
-6 
0.636 
0.487 
0.118 
0.065 
-7 
0.751 
0.612 
0.134 
0.075 
-8 
0.843 
0.727 
0.152 
0.086 
-9 
0.909 
0.821 
0.170 
0.099 
-10 
0.952 
0.892 
0.190 
0.112 
-11 
0.977 
0.939 
0.212 
0.127 
-12 
0.990 
0.969 
0.235 
0.143 
Note about power for hunger scores: For hunger, alpha=0.05, the minimal OBSERVED difference to achieve 
statistical significance is -21.5 mean percent change from baseline. The TRUE underlying mean percent change 
from baseline of -32.5% achieves 80% power to yield an OBSERVED difference that achieves statistical 
significance. -38.5% achieves 90% power. For hunger, alpha=0.025, the minimal OBSERVED difference to 
achieve statistical significance 50% power is -26.5 mean percent change from baseline, -38% TRUE underlying 
difference achieves 80% power, and -44% achieves 90% power.