Clinical trial NCT03746522
Conditions: Bardet Biedl Syndrome (BBS) Alström Syndrome (AS)
Keywords: MC4R Pathway Obesity BBS AS
Sponsor: Rhythm Pharmaceuticals, Inc.
Start date: 2018-11-23; Completion date: 2021-03-08
Enrollment: 52 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This pivotal, phase 3 study is designed to confirm the efficacy and safety of setmelanotide, a potent melanocortin receptor type 4 (MC4R) agonist, for the treatment of obesity and hyperphagia in participants with Bardet Biedl syndrome (BBS) or Alström syndrome (AS). The study's primary efficacy endpoint is to evaluate the proportion of participants (≥ 12 years of age at baseline) who lose ≥ 10% of their baseline body weight following approximately (\~) 52 weeks of treatment with setmelanotide compared to a historical control rate.

Detailed description:
Eligible participants will enter a 14-week, randomized, double-blind, placebo-controlled treatment period (Period 1) that will be followed by a 38-week open-label treatment period (Period 2) in which all participants will receive setmelanotide. Following Period 2, participants will continue receiving open-label setmelanotide for 14 weeks (Period 3), after which they could enroll into a separate treatment extension study.

Arms: arm 1: Participants received once daily SC injection of setmelanotide for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). Participants ≥16 years of age started on setmelanotide 2.0 mg with dose escalation to 3.0 mg. Participants \<16 years of age started on setmelanotide 1.0 mg with dose escalation to 3.0 mg. arm 2: Participants received once daily SC injection of placebo (matching setmelanotide) for 14 weeks in a double-blind placebo-controlled treatment period (Period 1). arm 3: After the initial 14-week double-blind treatment period, all participants immediately transitioned to open-label setmelanotide once daily SC injection for 38 weeks (Period 2) and then continued to receive setmelanotide in the 14-week open-label treatment period (Period 3).
Interventions: intervention 1: Setmelanotide intervention 2: Placebo
Intervention descriptions: intervention 1: SC injection of setmelanotide intervention 2: SC injection of placebo

Protocol documents:
Prot_000.pdf: 
A P h a s e 3 Tri al of S et m el a n oti d e ( R M- 4 9 3), a 
M el a n o c orti n- 4 R e c e pt or ( M C 4 R) A g o ni st, i n B ar d et-
Bi e dl S y n dr o m e ( B B S) a n d Al str o m S y n dr o m e ( A S) 
P ati e nt s wit h M o d er at e t o S e v er e O b e sit y
N C T: N C T 0 3 7 4 6 5 2 2
D at e: A u g u st 1 4, 2 0 1 8


C O N FI D E N TI A L  
R h yt h m  P h ar m a c e uti c als, I n c. 
C LI NI C A L  S T U D Y  P R O T O C O L  
P r ot o c ol  R M -4 9 3 -0 2 3  
A  P h as e  3 t ri al  of  S et m el a n oti d e ( R M -4 9 3),  a  M el a n o c o rti n -4  R e c e pt o r 
( M C 4 R)  A g o nist, i n  B a r d et-Bi e dl  S y n d r o m e  ( B B S) a n d  Alst r ö m s y n d r o m e  
( A S) P ati e nts  wit h  M o d e r at e t o  S e v e r e  O b esit y  
T his st u d y  will  b e  c o n d u ct e d  a c c or di n g t o t h e  pr ot o c ol  a n d i n  c o m pli a n c e  wit h  G o o d  Cli ni c al 
Pr a cti c e , t h e  et hi c al  pri n ci pl es st at e d i n t h e  D e cl ar ati o n  of  H elsi n ki, a n d  ot h er  a p pli c a bl e 
r e g ul at or y r e q uir e m e nts. 
  
St u d y  S p o ns or: 
R h yt h m  P h ar m a c e uti c als , I n c. 
5 0 0  B o ylst o n  Str e et ,  1 1t h  Fl o or 
B ost o n,  M A  0 2 1 1 6,  U S A 
T el e p h o n e:  8 5 7. 2 6 4. 4 2 8 2  
F a x:  8 5 7. 2 6 4. 4 2 9 9 
S p o ns or  Si g n at or y: 
 
D o c u m e nt  V ersi o n ( D at e):     1. 0 ( A u g ust  1 4,  2 0 1 8) 
C O N FI D E N TI A LI T Y  N O T E  
T h e i nf or m ati o n  c o nt ai n e d i n t his  d o c u m e nt is  pri vil e g e d  a n d  c o nfi d e nti al.  A n y  distri b uti o n, 
c o p yi n g,  or  dis cl os ur e is stri ctl y  pr o hi bit e d  u nl ess s u c h  dis cl os ur e is r e q uir e d  b y f e d er al 
r e g ul ati o ns  or st at e l a w.  P ers o ns t o  w h o m t h e i nf or m ati o n is  dis cl os e d  m ust  k n o w t h at it is 
c o nfi d e nti al  a n d t h at it  m a y  n ot  b e f urt h er  dis cl os e d  b y t h e m.  




Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  3 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
I N V E S TI G A T O R  S T A T E M E N T  
I  u n d erst a n d t h at  all  d o c u m e nt ati o n  pr o vi d e d t o  m e  b y  R h yt h m P h ar m a c e uti c als , I n c. ( R h yt h m) 
or its  d esi g n at e d r e pr es e nt ati v e(s)  c o n c er ni n g t his st u d y t h at  h as  n ot  b e e n  p u blis h e d  pr e vi o usl y 
will  b e  k e pt i n t h e stri ct est  c o nfi d e n c e.   T his  d o c u m e nt ati o n i n cl u d es t h e st u d y  pr ot o c ol, 
i n v esti g at or  br o c h ur e (I B),  c as e r e p ort f or ms,  a n d  ot h er s ci e ntifi c  d at a. 
T his st u d y  will  n ot  c o m m e n c e  wit h o ut t h e  pri or  writt e n  a p pr o v al  of  a  pr o p erl y  c o nstit ut e d 
I nstit uti o n al  R e vi e w  B o ar d (I R B)/ Et hi cs  C o m mitt e e ( E C).  N o  c h a n g es  will  b e  m a d e t o t h e st u d y 
pr ot o c ol  wit h o ut t h e  pri or  writt e n  a p pr o v al  of  R h yt h m  a n d t h e  I R B/E C ,  e x c e pt  w h er e  n e c ess ar y 
t o  eli mi n at e  a n i m m e di at e  h a z ar d t o t h e  p ati e nt. 
I  h a v e r e a d,  u n d erst o o d,  a n d  a gr e e t o  a bi d e  b y  all t h e  c o n diti o ns  a n d i nstr u cti o ns  c o nt ai n e d i n 
t his  pr ot o c ol. 
 
I n v esti g at or  N a m e  
  I n v esti g at or  Si g n at ur e 
  D at e  
 
 
 
 
I n v esti g ati o n al sit e  or  n a m e  of i nstit uti o n  a n d l o c ati o n ( pri nt e d) 
 
 
 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  4 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
C LI NI C A L  S T U D Y  S Y N O P SI S  
S p o ns o r   
R h yt h m  P h ar m a c e uti c als, I n c.  
I n v esti g ati o n al  D r u g  P r o d u ct  
S et m el a n oti d e ( R M -4 9 3,  M el a n o c orti n -4  R e c e pt or  A g o nist)  
P r ot o c ol  N u m b e r  
R M -4 9 3 -0 2 3  
P r ot o c ol  Titl e  
A  P h as e  3  Tri al  of  S et m el a n oti d e ( R M -4 9 3),  a  M el a n o c orti n  4  R e c e pt or ( M C 4 R)  A g o nist, i n  B ar d et -Bi e dl 
S y n dr o m e  ( B B S) a n d  Alstr ö m s y n dr o m e  ( A S) P ati e nts  wit h  M o d er at e t o  S e v er e  O b esit y  
Cli ni c al  P h as e  
Pi v ot al  P h as e  3  
T r e at m e nt I n di c ati o n  
Tr e at m e nt  of  o b esit y  a n d  h y p er p h a gi a i n  p ati e nts  wit h  B B S  or  A S  
I n v esti g at o r  St u d y  Sit es  
T his st u d y  will  b e  c o n d u ct e d  at  a p pr o xi m at el y  1 0  st u d y sit es l o c at e d i n t h e  U nit e d  St at es  a n d  E ur o p e  
O bj e cti v e(s)  
Pri m ar y  
•   T o  ass ess t h e  eff e ct  of s et m el a n oti d e  o n t h e  pr o p orti o n  of  p ati e nts  (≥ 1 2  y e ars  of  a g e  at  b as eli n e) tr e at e d 
wit h s et m el a n oti d e f or  a p pr o xi m at el y ( ~)  5 2  w e e ks  w h o  a c hi e v e  a  cli ni c all y  m e a ni n gf ul r e d u cti o n fr o m 
b as eli n e (i e,  ≥ 1 0 %) i n  b o d y  w ei g ht . 
K e y  S e c o n d ar y  
•   T o  ass ess t h e  eff e ct  of s et m el a n oti d e  o n t h e  pr o p orti o n  of  all  p ati e nts  w h o  a c hi e v e  a  ≥ 1 0 % r e d u cti o n 
fr o m  b as eli n e i n  b o d y  w ei g ht  aft er ~ 5 2  w e e ks  of tr e at m e nt  wit h s et m el a n oti d e .  
•   T o  ass ess t h e  eff e ct  of s et m el a n oti d e  o n  m e a n  p er c e nt  c h a n g e i n  b o d y  w ei g ht  (i n  p ati e nts ≥ 1 2  y e ars  of 
a g e  at  b as eli n e)  c o m p ar e d  wit h  b as eli n e  aft er  ~ 5 2  w e e ks  of tr e at m e nt  wit h s et m el a n oti d e .. 
•   T o  ass ess t h e  eff e ct  of s et m el a n oti d e  o n t h e  pr o p orti o n  of  p ati e nts  w h o  a c hi e v e  a  ≥ 2 5 % i m pr o v e m e nt i n 
t h e w e e kl y  a v er a g e  of t h e  d ail y  h u n g er s c or e  (i n  p ati e nts ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  aft er  ~ 5 2  w e e ks 
of tr e at m e nt  wit h s et m el a n oti d e . 
•   T o  ass ess t h e  eff e ct  of s et m el a n oti d e  o n t h e  m e a n  p er c e nt  c h a n g e fr o m  b as eli n e i n t h e  w e e kl y  a v er a g e 
of t h e  d ail y  h u n g er s c or e (i n  p ati e nts  ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  aft er  ~ 5 2  w e e ks  of tr e at m e nt  wit h 
s et m el a n oti d e. 
Ot h er  S e c o n d ar y  
•   T o  a ss ess t h e  eff e ct  of s et m el a n oti d e  o n t h e  m e a n  p er c e nt  c h a n g e fr o m  b as eli n e i n  b o d y  w ei g ht  (i n 
p ati e nts  ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  at t h e  W e e k  1 4  visit  c o m p ar e d  wit h  pl a c e b o .  
•   T o  a ss ess t h e  eff e ct  of s et m el a n oti d e  o n t h e  pr o p orti o n  of  p ati e nts  w h o  a c hi e v e  a  ≥ 2 5 % i m pr o v e m e nt i n 
t h e  w e e kl y  a v er a g e  of t h e  d ail y  h u n g er s c or e (i n  p ati e nts ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  at t h e  W e e k  1 4 
visit  c o m p ar e d  wit h  pl a c e b o . 
•   T o  a ss ess t h e  eff e ct  of s et m el a n oti d e  o n t h e  m e a n  p er c e nt  c h a n g e fr o m  b as eli n e i n t h e  w e e kl y  a v er a g e 
of t h e  d ail y  h u n g er s c or e  (i n  p ati e nts ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  at t h e  W e e k  1 4  visit  c o m p ar e d  wit h 
pl a c e b o . 
M et h o d ol o g y  
T his is  a  pi v ot al st u d y t o  c o nfir m t h e l o n g -t er m ( a p pr o xi m at el y  1 y e ar i n  m ost  p ati e nts)  effi c a c y  a n d s af et y  of 
s et m el a n oti d e tr e at m e nt i n  p ati e nts  w h o  h a v e  B B S  or  A S.  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  5 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
T h e st u d y  will  c o nsist  o f 3  tr e at m e nt p eri o ds  (s e e  St u d y  S c h e m ati c  b el o w).  Aft er  o bt ai ni n g i nf or m e d  c o ns e nt, 
p ot e nti al  p ati e nts  will  b e s cr e e n e d t o  d et er mi n e st u d y  eli gi bilit y.  Eli gi bl e  p ati e nts  will  e nt er  a  1 4 -w e e k, 
r a n d o mi z e d,  d o u bl e-bli n d,  pl a c e b o -c o ntr oll e d  tr e at m e nt p eri o d  ( P eri o d 1)  t h at  will  b e f oll o w e d  b y  a  3 8-w e e k 
o p e n -l a b el tr e at m e nt p eri o d  ( P eri o d 2)  i n  w hi c h  all  p ati e nts  will r e c ei v e s et m el a n oti d e.  Th e  pri m ar y  a n al ysis  will 
b e  p erf or m e d  aft er  P eri o d  2.  T o  m ai nt ai n t h e  bli n d t hr o u g h  P eri o d  2,  u p w ar d  d os e  es c al ati o n  t o a fi x e d  d os e  of 
3  m g  will  b e  p erf or m e d  d uri n g t h e first  2  w e e ks  of  b ot h t h e  d o u bl e -bli n d  ( P eri o d 1)  a n d  3 8 -w e e k  o p e n -l a b el 
( P eri o d 2)  tr e at m e nt  p eri o ds. F oll o wi n g  P eri o d   2,  p ati e nts will  c o nti n u e  t o r e c ei v e o p e n -l a b el s et m el a n oti d e f or 
1 4  w e e ks  (P eri o d   3) aft er  w hi c h t h e y  m a y  b e  e nr oll e d  i nt o  a s e p ar at e tr e at m e nt e xt e nsi o n  st u d y.  
P ati e nts  will  b e r a n d o mi z e d i n  a  1: 1 r ati o , str atifi e d  b y  a g e  gr o u p (≥ 1 2  y e ars  or  < 1 2  y e ars  of  a g e)  a n d  dis e as e 
( B B S  or  A S), t o r e c ei v e  eit h er s et m el a n oti d e Q D  or  pl a c e b o  Q D  vi a  S C i nj e cti o n f or t h e first  1 4  w e e ks.  P ati e nts 
w h o  ar e  ≥ 1 6  y e ars  of  a g e  will st art  o n s et m el a n oti d e  2  m g  or  m at c hi n g  pl a c e b o  d uri n g t h e  2 -w e e k  d os e 
es c al ati o n  a n d  will i n cr e as e t o  3  m g  or  m at c hi n g  pl a c e b o  at t h e  b e gi n ni n g  of  W e e k  3.  P ati e nts  w h o  ar e  < 1 6  y e ars 
of  a g e  w ill st art  o n  1  m g s et m el a n oti d e  or  m at c hi n g  pl a c e b o d uri n g  W e e k  1,  will i n cr e as e t o  2  m g  or  m at c hi n g 
pl a c e b o  at t h e  b e gi n ni n g  of  W e e k  2,  a n d  will i n cr e as e t o  3  m g  or  m at c hi n g  pl a c e b o  at t h e  b e gi n ni n g  of  W e e k  3. 
D uri n g t h e  1 4 -w e e k  d o u bl e -bli n d  tr e at m e nt p eri o d,  p ati e nts  will  b e  e v al u at e d  at t h e  b e gi n ni n g  of  W e e ks   2 
(t el e p h o n e  c all  o nl y,  p ati e nts  < 16  y e ars  ol d),  3 , 7 ,  11 ,  a n d  15  as  d e pi ct e d i n t h e s c h e m ati c  b el o w.    
Aft er t h e  i niti al  1 4-w e e k  d o u bl e -bli n d tr e at m e nt  p eri o d  ( P eri o d 1) ,  all  p ati e nts  will i m m e di at el y tr a nsiti o n t o 
r e c ei v e  o p e n-l a b el s et m el a n oti d e Q D  vi a  S C i nj e cti o n  f or  3 8  w e e ks ( P eri o d 2) .  T o  pr es er v e t h e  bli n d,  all  p ati e nts 
will  b e r e -titr at e d t o t h e  3 m g  cli ni c al  d os e.  T h us,  b e gi n ni n g  at  W e e k  1 5,  p ati e nts  w h o  ar e  ≥ 1 6  y e ars  of  a g e  will 
r e c ei v e  o p e n-l a b el s et m el a n oti d e  2  m g f or  2 w e e ks, f oll o w e d  b y  a  d os e i n cr e as e t o  3  m g  b e gi n ni n g  at  W e e k  1 7, 
a n d  p ati e nts  w h o  ar e  < 1 6  y e ars  of  a g e  will r e c ei v e  o p e n -l a b el s et m el a n oti d e  1 m g  d uri n g  W e e k  1 5,  2  m g  d uri n g 
W e e k  1 6,  a n d  3  m g  b e gi n ni n g  at  W e e k  1 7.  P ati e nts  will  b e  e v al u at e d  at t h e  b e gi n ni n g  of  W e e k s  1 6 (t el e p h o n e 
c all  o nl y,  p ati e nts  < 1 6  y e ars  ol d)  a n d   1 7 a n d t h e n  e v er y  6  w e e ks t h er e aft er  d uri n g  P eri o d   2. I n P eri o d   3,  pati e nts 
will  b e  e v al u at e d  e v er y  7  w e e ks.   
 
St u d y  ass ess m e nts  will  b e  p erf or m e d  at t h e ti m es s p e cifi e d i n t h e  S c h e d ul e  of  Ass ess m e nts ( S O A).  Effi c a c y 
ass ess m e nts  will i n cl u d e:  b o d y  w ei g ht;  B MI;  h u n g er ;  bo d y  c o m p ositi o n, i n cl u di n g
As r e q uir e d i n t h e  U nit e d  St at es ( U S)  b y t h e  F o o d  a n d  Dr u g  A d mi nistr ati o n ( F D A), f or  cli ni c al tri als  of  c e ntr al 
n er v o us s yst e m ( C N S) -a cti n g  o b esit y  m e di c ati o ns,
 


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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
Pri m ar y  a n d  S e c o n d ar y  E n d p oi nts  
T h e  pri m ar y  e n d p oi nt is:  
•   T h e  pr o p orti o n  of  p ati e nts  (≥ 1 2  y e ars  of  a g e  at  b as eli n e)  w h o  a c hi e v e  a    ≥1 0 % r e d u cti o n fr o m  b as eli n e  i n  b o d y 
w ei g ht  (i e,  ar e ‘r es p o n d ers’) aft er  ~ 5 2  w e e ks  of tr e at m e nt  wit h s et m el a n oti d e.  
T h e  k e y s e c o n d ar y  e n d p oi nts  ar e:  
•   T h e  pr o p orti o n  of  all  p ati e nts , r e g ar dl ess  of  a g e at  b as eli n e , w h o  a c hi e v e  a    ≥1 0 % r e d u cti o n fr o m  b as eli n e  i n 
b o d y  w ei g ht  (i e,  ar e ‘r es p o n d ers’) aft er  ~ 5 2  w e e ks  of tr e at m e nt  wit h s et m el a n oti d e . 
•   M e a n  p er c e nt  c h a n g e fr o m  b as eli n e i n  b o d y  w ei g h t (i n  p ati e nts ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  aft er  ~ 5 2  w e e ks 
of tr e at m e nt  wit h s et m el a n oti d e . 
•   T h e  pr o p orti o n  of  p ati e nts  w h o  a c hi e v e  a  ≥ 2 5 % i m pr o v e m e nt i n t h e  w e e kl y  a v er a g e  of t h e  d ail y  h u n g er s c or e 
(i n  p ati e nts ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  aft er  ~ 5 2  w e e ks  of tr e at m e nt  wit h s et m el a n oti d e . 
•   M e a n  p er c e nt  c h a n g e fr o m  b as eli n e i n  t h e  w e e kl y  a v er a g e  of t h e  d ail y  h u n g er s c or e (i n  p ati e nts ≥ 1 2  y e ars  of 
a g e  at  b as eli n e)  aft er  ~ 5 2  w e e ks  of tr e at m e nt  wit h s et m el a n oti d e . 
Ot h er  s e c o n d ar y  e n d p oi nts  ar e:  
•   M e a n  p er c e nt  c h a n g e fr o m  b as eli n e i n  b o d y  w ei g ht  (i n  p ati e nts ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  at t h e  W e e k  1 4 
visit  c o m p ar e d  wit h  pl a c e b o . 
•   T h e  pr o p orti o n  of  p ati e nts  w h o  a c hi e v e  a  ≥ 2 5 % i m pr o v e m e nt i n t h e  w e e kl y  a v er a g e  of t h e  d ail y  h u n g er s c or e  
(i n  p ati e nts ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  at t h e  W e e k  1 4  visit  c o m p ar e d  wit h  pl a c e b o . 
•   M e a n  p er c e nt  c h a n g e fr o m  b as eli n e i n t h e  w e e kl y  a v er a g e  of t h e  d ail y  h u n g er s c or e  (i n  p ati e nts ≥ 1 2  y e ars  of 
a g e  at  b as eli n e)  at t h e  W e e k  1 4  visit  c o m p ar e d  wit h  pl a c e b o . 
N u m b e r  of  P ati e nts  
It is  a nti ci p at e d t h at a p pr o xi m at el y  3 0  p ati e nt s (i n cl u di n g  at l e ast 2 0  wit h  B B S  a n d  at l e ast  6  wit h  A S ) will  b e 
e nr oll e d  a n d r a n d o mi z e d  a cr oss  a p pr o xi m at el y  1 0  c e nt ers  w orl d wi d e.    
I n cl usi o n  C rit e ri a  
A  p ati e nt  m ust  m e et  all  of t h e f oll o wi n g  crit eri a t o  b e  eli gi bl e f or t his st u d y (r ef er t o  S e cti o n  4. 1  of t h e  pr ot o c ol 
b o d y f or  p ot e nti al  e x c e pti o ns,  gi v e n t h e  ultr a -r ar e  n at ur e  of t h es e  dis e as es  a n d t h e  ass o ci at e d  c h all e n g es  wit h 
p ati e nt i d e ntifi c ati o n  a n d r e cr uit m e nt).  
1.   B B S  cli ni c al  di a g n osis  as  p er  B e al es,  1 9 9 9  (wit h  eit h er  4  pri m ar y f e at ur es  or  3  pri m ar y  a n d  2 s e c o n d ar y 
f e at ur es fr o m t a bl e  b el o w)   
B a r d et -Bi e dl  S y n d r o m e  
P ri m a r y  Di a g n osti c  C rit e ri a  
•   R o d  c o n e  d y str o p h y  
•   L e ar ni n g  dis a biliti es  
•   P ol y d a ct yl y   
•   H y p o g o n a dis m i n  m al es  
•   O b esit y  
•   R e n al  a n o m ali es   
S e c o n d a r y  Di a g n osti c  C rit e ri a  
•   S p e e c h  dis or d er/ d el a y   
•   Mil d s p asti cit y ( es p e ci all y l o w er li m bs)  
•   Str a bi sm us/ c at ar a cts/ asti g m atis m   
•   Di a b et es  m ellit us   
•   Br a c h y d a ct yl y/s y n d a ct yl y   
•   D e nt al  cr o w di n g/ h y p o d o nti a/s m all r o ots/ hi g h  ar c h e d 
p al at e  
•   D e v el o p m e nt al  d el a y   
•   L eft  v e ntri c ul ar  h y p ertr o p h y/ c o n g e nit al  h e art  d is e as e 
•   P ol y uri a/ p ol y di psi a ( n e p hr o g e ni c  di a b et es i nsi pi d us)   •   H e p ati c fi br osis  
•   At a xi a/ p o or  c o or di n ati o n  
 
S o ur c e:  B e al es  1 9 9 9  
 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  7 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
or  A S  di a g n osis  as  p er  M ars h all,  2 0 0 7  ( usi n g m aj or  a n d  mi n or  a g e  a dj ust e d  crit eri a i n t h e t a bl e  b el o w).   
Alst r ö m  S y n d r o m e  
Di a g n osti c  C rit e ri a  
Mi ni m u m 
R e q ui r e d  
M aj o r  
Mi n o r  
F o r  p ati e nt s  6 t o  ≤ 1 4  y e a rs  of  a g e  
•   M ut ati o n  of  A L M S 1  a n d/ or f a mil y  hist or y 
of  A S  
•   Visi o n ( n y st a g m us,  p h ot o p h o bi a, 
di mi nis h e d  a c uit y, if  ol d  e n o u g h f or 
t esti n g:  c o n e  d ystr o p h y  b y  E R G) 
•   O b esit y  a n d/ or i ns uli n r esist a n c e 
a n d/ or  T 2 D M  
•   Hist or y  of  D C M/ C H F  
•   H e ari n g l oss  
•   H e p ati c  d ysf u n cti o n  
•   R e n al f ail ur e  
•   A d v a n c e d  b o n e  a g e  
2  m aj or  crit eri a  
           or  
1  m aj or  a n d 
3  mi n or  crit eri a  
F o r  p ati e nts  ≥ 1 5  y e a rs  of  a g e  
•   
M ut ati o n  of  A L M S 1  a n d/ or f a mil y  hist or y 
of  A S  
•   
Visi o n ( hist or y  of  n y st a g m us i n 
i nf a n c y/ c hil d h o o d, l e g al  bli n d n ess,  c o n e 
a n d r o d  d ystr o p h y  b y  E R G)  
•   
O b esit y  a n d/ or i ns uli n r esist a n c e 
a n d/ or  T 2 D M  
•   
Hist or y  of  D C M/ C H F  
•   
H e ari n g l oss  
•   
H e p ati c  d ysf u n cti o n  
•   
R e n al f ail ur e  
•   
S h ort st at ur e  
•   
M al es:  h y p o g o n a dis m  
•   
F e m al es: irr e g ul ar  m e ns es  a n d/ or 
h y p er a n dr o g e nis m  
2  m aj or  a n d 
2  mi n or  crit eri a  
          or 
1  m aj or  a n d 
4  mi n or  crit eri a  
S o ur c e:  M ars h all  2 0 0 7  
A b br e vi ati o ns:  C H F  =  c o n g esti v e  h e art f ail ur e;  D C M  =  dil at e d  c ar di o m y o p at h y;  E R G  =  el e ctr or eti n o gr a p h y; 
T 2 D M   = T y p e  2  di a b et es  m ellit us  
 
•   N ot e :   at l e ast  9 0 %  of  p ati e nts  wit h  B B S  a n d  1 0 0 %  of  p ati e nts  wit h  A S  m ust  h a v e  g e n eti c all y 
c o nfir m e d  di a g n osis  at t h e ti m e  of  e nr oll m e nt  
o   A  g e n eti c all y  c o nfir m e d  di a g n osis  of  B B S is  d efi n e d  as  a  h o m o z y g o us  or  c o m p o u n d  h et er o z y g o us 
l oss-of -f u n cti o n  m ut ati o n i n B B S  g e n es;  p ati e nts  wit h o ut  a  g e n eti c all y  c o nfir m e d  B B S  di a g n osis 
m ust  b e r e vi e w e d  wit h t h e  S p o ns or’s  m e di c al  m o nit or  pri or  t o  e nr oll m e nt. 
o   A  g e n eti c all y  c o nfir m e d  di a g n osis  of  A S is  d efi n e d  as  a  h o m o z y g o us  or  c o m p o u n d  h et er o z y g o us 
l oss-of -f u n cti o n  m ut ati o n i n t h e A L M S 1  g e n e  
O n c e  1 0 %  of  p ati e nts  wit h o ut  a  g e n eti c all y  c o nfir m e d  B B S  di a g n osis  h a v e  b e e n  e nr oll e d i n t h e st u d y, 
sit es  will  b e  n otifi e d t h at  o nl y  g e n eti c all y  c o nfir m e d  B B S  p ati e nts  m a y  b e  e nr oll e d.  
2.   ≥ 6  y e ars  of  a g e.  
3.   O b es e,  d efi n e d  as  B MI  ≥ 3 0  k g/ m 2 f or  p ati e nts  ≥ 1 6  y e ars  of  a g e  or  w ei g ht  > 9 7t h  p er c e ntil e f or  a g e  a n d s e x 
o n  gr o wt h  c h art  ass ess m e nt f or  p ati e nts  6 t o  1 5  y e ars  of  a g e.  
4.   St u d y  p arti ci p a nt  a n d/ or  p ar e nt  or  g u ar di a n is  a bl e t o  c o m m u ni c at e  w ell  wit h t h e  I n v esti g at or, t o  u n d erst a n d 
a n d  c o m pl y  wit h t h e r e q uir e m e nts  of t h e st u d y,  a n d is  a bl e t o  u n d erst a n d  a n d si g n t h e  writt e n i nf or m e d 
c o ns e nt/ ass e nt.    
5.   F e m al e  p arti ci p a n ts  of  c hil d-b e ari n g  p ot e nti al  m ust  b e  c o nfir m e d  n o n -pr e g n a nt  a n d  a gr e e t o  us e 
c o ntr a c e pti o n  as  o utli n e d i n t h e  pr ot o c ol.  F e m al e  p arti ci p a nts  of  n o n -c hil d b e ari n g  p ot e nti al,  d efi n e d  as: 
s ur gi c all y st eril e (st at us  p ost  h yst er e ct o m y,  bil at er al  o o p h or e ct o m y,  or  bil at er al t u b al li g ati o n),  p ost -
m e n o p a us al f or  at l e ast  1 2  m o nt hs ( a n d  c o nfir m e d  wit h  a s cr e e ni n g  f olli cl e sti m ul ati n g  h or m o n e (F S H ) l e v el 
i n t h e  p ost-m e n o p a us al l a b r a n g e),  or f ail ur e t o  h a v e  pr o gr ess e d t o  T a n n er  St a g e  V  a n d/ or f ail ur e t o  h a v e 
a c hi e v e d  m e n ar c h e,  d o  n ot r e q uir e  c o ntr a c e pti o n  d uri n g t h e st u d y.   
6.   M al e  p arti ci p a nts  wit h f e m al e  p art n ers  of  c hil d b e ari n g  p ot e nti al  m ust  a gr e e t o  us e  a  d o u bl e  b arri er  m et h o d 
c o ntr a c e pti o n if t h e y  b e c o m e s e x u all y  a cti v e  d uri n g t h e st u d y  or  wit hi n  9 0  d a ys f oll o wi n g t h eir  p arti ci p ati o n 
i n t h e st u d y.  M al e  p ati e nts  m ust  als o  n ot  d o n at e s p er m  d uri n g  a n d f or  9 0  d a ys f oll o wi n g t h eir  p arti ci p ati o n 
i n t h e st u d y. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  8 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
E x cl usi o n  C rit e ri a  
A  p ati e nt  w h o  m e ets  a n y  of t h e f oll o wi n g  crit eri a  will  b e  e x cl u d e d fr o m t his st u d y (r ef er t o  S e cti o n  4. 1  of t h e 
pr ot o c ol  b o d y f or  p ot e nti al  e x c e pti o ns,  gi v e n t h e  ultr a -r ar e  n at ur e  of t h es e  dis e as es  a n d t h e  ass o ci at e d  c h all e n g es 
wit h  p ati e nt i d e ntifi c ati o n  a n d r e cr uit m e nt)  
1.   R e c e nt i nt e nsi v e ( wit hi n  2  m o nt hs)  di et  a n d/ or  e x er cis e r e gi m e n  wit h  or  wit h o ut t h e  us e  of  w ei g ht l oss 
a g e nts (i n cl u di n g  h er b al  m e di c ati o ns) t h at  h as r es ult e d i n  > 2 %  w ei g ht l oss .  T h es e  p ati e nts  m a y  b e 
r e c o nsi d er e d  a p pr o xi m at el y 1  m o nt h  aft er  c ess ati o n  of s u c h i nt e nsi v e r e gi m e ns.    
2.   C urr e nt  or  pri or ( wit hi n  pri or  2  m o nt hs)  us e  of  a n y  m e di c ati o n, i n cl u di n g t h os e  a p pr o v e d t o tr e at  o b esit y, 
t h at  c o ul d i m p a ct t h e  effi c a c y r es ults  of t his st u d y ( e g,  orlist at, l or c as eri n,  p h e nt er mi n e-t o pir a m at e, 
n altr e x o n e -b u pr o pi o n , lir a gl uti d e). P ati e nts  o n  a st a bl e  d os e  a n d r e gi m e n  (f or  at l e ast  2 m o nt hs)  of 
m e di c ati o n t o tr e at  att e nti o n  d efi cit  h y p er a cti vit y  dis or d er ( A D H D)  m a y  b e  e nr oll e d i n t h e st u d y  as l o n g  as 
t h e y  a gr e e t o r e m ai n  o n t h e s a m e  d os e  a n d r e gi m e n  d uri n g t h e st u d y. 
3.   Pri or  g astri c  b y p ass s ur g er y r es ulti n g i n  > 1 0 %  w ei g ht l oss  d ur a bl y  m ai nt ai n e d fr o m t h e  b as eli n e  pr e -
o p er ati v e  w ei g ht  wit h  n o  e vi d e n c e  of  w ei g ht r e g ai n.  S p e cifi c all y,  p ati e nts  m a y  b e  c o nsi d er e d if s ur g er y  w as 
n ot s u c c essf ul, r es ult e d i n  < 1 0 %  w ei g ht l oss  c o m p ar e d t o  pr e -o p er ati v e  b as eli n e  w ei g ht,  or t h er e is  cl e ar 
e vi d e n c e  of  w ei g ht r e g ai n  a ft er  a n i niti al r es p o ns e t o  b ari atri c s ur g er y.  All  p ati e nts  wit h  a  hist or y  of  b ari atri c 
s ur g er y  m ust  b e  dis c uss e d  wit h,  a n d r e c ei v e  a p pr o v al fr o m, t h e  S p o ns or  pri or t o  e nr oll m e nt.   
4.   Di a g n osis  of s c hi z o p hr e ni a,  bi p ol ar  dis or d er,  p ers o n alit y  dis or d er  or  ot h er  Di a g n osti c  a n d  St atisti c al  M a n u al 
of  M e nt al  Dis or d ers  fift h e diti o n ( D S M - V)  dis or d ers t h at t h e I n v esti g at or b eli e v es  will  i nt erf er e 
si g nifi c a ntl y  wit h st u d y  c o m pli a n c e.  N e ur o c o g niti v e  dis or d ers  aff e cti n g  a bilit y t o  c o ns e nt  will  n ot  b e 
dis q u alif yi n g  as l o n g  as  a n  a p pr o pri at e  g u ar di a n  a bl e t o  gi v e  c o ns e nt  h as  b e e n  a p p oi nt e d.    
5.   I n p ati e nt s  wit h  n o si g nifi c a nt  n e ur o c o g niti v e  d efi cits:  
•   A  P ati e nt  H e alt h  Q u esti o n n air e -9 ( P H Q - 9) s c or e  of  ≥ 1 5  a n d/ or  
•   A n y s ui ci d al i d e ati o n  of t y p e  4  or  5  o n t h e  C -S S R S,  a n y lif eti m e  hist or y  of  a s ui ci d e  att e m pt,  or  a n y 
s ui ci d al  b e h a vi or i n t h e l ast  m o nt h.  
6.   C urr e nt,  cli ni c all y si g nifi c a nt  p ul m o n ar y,  c ar di a c,  or  o n c ol o gi c  dis e as e  c o nsi d er e d s e v er e  e n o u g h t o 
i nt erf er e  wit h t h e st u d y  a n d/ or  c o nf o u n d t h e r es ults.  A n y  p ati e nt  wit h  a  p ot e nti all y  cli ni c all y si g nifi c a nt 
dis e as e s h o ul d  b e r e vi e w e d  wit h t h e  S p o ns or t o  d et er mi n e  eli gi bilit y.  
7.   Hist or y  of si g nifi c a nt li v er  dis e as e  or li v er i nj ur y,  or  a  c urr e nt li v er  ass ess m e nt  d u e t o  a b n or m al li v er t ests 
( as i n di c at e d  b y  a b n or m al li v er f u n cti o n t ests, al a ni n e tr a ns a mi n as e [ A L T],  as p art at e tr a ns a mi n as e [ A S T], 
al k ali n e  p h os p h at as e,  or s er u m  bilir u bi n  > 1. 5 ×  t h e  u p p er li mit  of  n or m al [ U L N] f or  a n y  of t h es e t ests) f or  a n 
eti ol o g y  ot h er t h a n  n o n -al c o h oli c f att y li v er  dis e as e ( N A F L D).  T h us,  a n y  u n d erl yi n g  eti o l o g y  b esi d es 
N A F L D, i n cl u di n g  di a g n os e d  n o n -al c o h oli c st e at o h e p atitis ( N A S H),  ot h er  c a us es  of  h e p atitis,  or  hist or y  of 
h e p ati c  cirr h osis is  e x cl usi o n ar y,  b ut t h e  pr es e n c e  of  N A F L D is  n ot  b e  e x cl usi o n ar y.    
8.   M o d er at e t o s e v er e r e n al  d ysf u n cti o n  as  d efi n e d  b y  t h e  C o c kr oft  G a ult  e q u ati o n  < 3 0  m L/ mi n. .  
9.   Hist or y  or  cl os e f a mil y  hist or y ( p ar e nts  or si bli n gs)  of s ki n  c a n c er  or  m el a n o m a  ( e x cl u di n g n o n -i n v asi v e 
b as al  or s q u a m o us  c ell l esi o n ),  or  p ati e nt  hist or y  of  o c ul ar-c ut a n e o us  al bi nis m.  
1 0.   Si g nifi c a nt  d er m at ol o gi c  fi n di n gs r el ati n g t o  m el a n o m a  or  pr e-m el a n o m a s ki n l esi o ns  ( e x cl u di n g n o n -
i n v asi v e  b as al  or s q u a m o us  c ell l esi o n),  d et er mi n e d  as  p art  of  c o m pr e h e nsi v e s ki n  e v al u ati o n  p erf or m e d  b y 
a  q u alifi e d  d er m at ol o gist  d uri n g s cr e e ni n g.  A n y  c o n c er ni n g l esi o ns i d e ntifi e d  d uri n g t h e s cr e e ni n g  p eri o d 
will  b e  bi o psi e d  a n d r es ults  m ust  b e  k n o w n t o  b e  b e ni g n  pri or t o  e nr oll m e nt. If t h e  pr e -tr e at m e nt  bi o ps y 
r es ults  ar e  of  c o n c er n, t h e  p ati e nt s h o ul d  b e  e x cl u d e d fr o m t h e st u d y.   
1 1.   P ati e nt  is, i n t h e  o pi ni o n  of t h e  St u d y I n v esti gat or,  n ot s uit a bl e t o  p arti ci p at e i n t h e  st u d y. 
1 2.   P arti ci p ati o n i n  a n y  cli ni c al st u d y  wit h  a n i n v esti g ati o n al  dr u g/ d e vi c e  wit hi n  3  m o nt hs  pri or t o t h e first  d a y 
of  d osi n g.  
1 3.   Si g nifi c a nt  h y p ers e nsiti vit y t o st u d y  dr u g.  
1 4.   I n a bilit y t o  c o m pl y  wit h t h e  Q D i nj e cti o n r e gi m e n. 




Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 0 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
T A B L E  O F  C O N T E N T S  
C LI NI C A L  S T U D Y  P R O T O C O L  ............................................................................................... 1 
A P P R O V A L  SI G N A T U R E  P A G E  .............................................................................................. 2 
I N V E S TI G A T O R  S T A T E M E N T  ................................................................................................ 3 
C LI NI C A L  S T U D Y  S Y N O P SI S  .................................................................................................. 4 
T A B L E  O F  C O N T E N T S  ............................................................................................................ 1 0 
List  of  T a bl es  ................................................................................................................................ 1 5 
List  of  Fi g u r es  ............................................................................................................................... 1 5 
LI S T  O F  A B B R E VI A TI O N S  ..................................................................................................... 1 6 
1.  
I N T R O D U C TI O N ...................................................................................................... 2 0 
1. 1.  
P ur p os e  of  St u d y .......................................................................................................... 2 0  
1. 2.  
O v er vi e w  of  B ar d et  Bi e dl  a n d  Alstr ö m  S y n dr o m es .................................................... 2 0  
 
B ar d et  Bi e dl  S y n dr o m e ................................................................................................ 2 0  
 
Alstr ö m  S y n dr o m e ....................................................................................................... 2 1  
1. 3.  
S et m el a n oti d e f or t h e  Tr e at m e nt  of  B ar d et  Bi e dl  a n d  Alstr ö m  S y n dr o m es  ................ 2 2 
1. 4.  
S et m el a n oti d e  O v er vi e w .............................................................................................. 2 3  
 
N o n cli ni c al  O v er vi e w  .................................................................................................. 2 3 
 
Cli ni c al  O v er vi e w  ........................................................................................................ 2 5 
1. 4. 2. 1.  
Cli ni c al  Effi c a c y i n  P ati e nts  wit h  B B S  a n d  A S,  T w o  F or ms  of  Cili o p at h y  O b esit y  ... 2 5 
1. 4. 2. 2.  
Cli ni c al  S af et y  .............................................................................................................. 2 6 
 
M e c h a nis m -R el at e d  A d v ers e  E x p eri e n c es  of I nt er est ................................................. 2 6  
2.  
S T U D Y  O B J E C TI V E S  .............................................................................................. 2 7 
2. 1.  
Pri m ar y  O bj e cti v e  ........................................................................................................ 2 7 
2. 2.  
S e c o n d ar y  O bj e cti v es  ................................................................................................... 2 7 
 
K e y  S e c o n d ar y  O bj e cti v es ........................................................................................... 2 7  
 
Ot h er  S e c o n d ar y  O bj e cti v es ........................................................................................ 2 7  
2. 3.  
 
3.  
I N V E S TI G A TI O N A L  P L A N  ................................................................................... 2 9 
3. 1.  
O v er all  D esi g n  a n d  Pl a n  of t h e  St u d y .......................................................................... 2 9  
3. 2.  
D os e  S el e cti o n  R ati o n al e  ............................................................................................. 3 0 
3. 3.  
St u d y  E n d p oi nts ........................................................................................................... 3 0  
 
Pri m ar y  Effi c a c y  E n d p oi nt .......................................................................................... 3 0  
 
S e c o n d ar y  E n d p oi nts ................................................................................................... 3 1  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 1 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
3. 3. 2. 1.  
K e y  S e c o n d ar y  E n d p oi nts ............................................................................................ 3 1  
3. 3. 2. 2.  
Ot h er  S e c o n d ar y  E n d p oi nts ......................................................................................... 3 1  
 
3. 4.  
J ustifi c ati o n  of t h e St u d y  D esi g n ................................................................................. 3 2  
3. 5.  
St u d y  T er mi n ati o n ....................................................................................................... 3 3  
4.  
S T U D Y  P O P U L A TI O N  ............................................................................................ 3 4 
4. 1.  
N u m b er  of  P ati e nts  ...................................................................................................... 3 4 
4. 2.  
I n cl usi o n  Crit eri a ......................................................................................................... 3 4 
4. 3.  
E x cl usi o n  Crit eri a  ........................................................................................................ 3 6 
4. 4.  
P ati e nt I d e ntifi c ati o n  a n d  R e gistr ati o n  ......................................................................... 3 7 
4. 5.  
Wit h dr a w al  of  P ati e nts  ................................................................................................. 3 7 
4. 6.  
D ur ati o n  of  P ati e nt  P arti ci p ati o n  ................................................................................. 3 8 
5.  
S T U D Y  T R E A T M E N T S  ........................................................................................... 3 9 
5. 1.  
St u d y  Dr u gs ................................................................................................................. 3 9  
5. 2.  
St u d y  Dr u g  A d mi nistr ati o n  a n d  D os e  Es c al ati o n ........................................................ 3 9  
 
A d mi nistr ati o n  ............................................................................................................. 3 9 
 
St u d y  Dr u g  D os e  Es c al ati o n  a n d  A dj ust m e nts ............................................................ 3 9  
5. 3.  
M et h o d  of  Assi g ni n g  P ati e nts t o  Tr e at m e nt ................................................................ 4 0  
5. 4.  
Bli n di n g,  P a c k a gi n g,  a n d  L a b eli n g .............................................................................. 4 0  
 
Bli n di n g  a n d  Br e a ki n g t h e  Bli n d ................................................................................. 4 0  
 
P a c k a gi n g  a n d  L a b eli n g ............................................................................................... 4 1  
5. 5.  
Pr e p ar ati o n,  H a n dli n g,  a n d  St or a g e ............................................................................. 4 1  
5. 6.  
Ass ess m e nt  of  Tr e at m e nt  C o m pli a n c e  ......................................................................... 4 1 
5. 7.  
St u d y  Dr u g  A c c o u nt a bilit y .......................................................................................... 4 1  
5. 8.  
Pri or  a n d  C o n c o mit a nt  Tr e at m e nt  ................................................................................ 4 2 
 
P er mitt e d  M e di c ati o n  ................................................................................................... 4 2 
 
Pr o hi bit e d  M e di c ati o n  a n d  S u bst a n c es  ........................................................................ 4 3 
 
C o n c o mit a nt  Pr o c e d ur es .............................................................................................. 4 3  
6.  
S T U D Y  A S S E S S M E N T S  .......................................................................................... 4 4 
6. 1.  
O v er vi e w  of  S c h e d ul e  of  Ass ess m e nts  ........................................................................ 4 4 
6. 2.  
P ati e nt  R e q uir e m e nts  ................................................................................................... 5 2 
 
C o ntr a c e pti o n ............................................................................................................... 5 2  
 
Pr ot e cti o n fr o m  S u n ..................................................................................................... 5 2  
6. 3.  
I nf or m e d  C o ns e nt/ Ass e nt  a n d  S cr e e ni n g ..................................................................... 5 2 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 2 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
 
I nf or m e d  C o ns e nt/ Ass e nt ............................................................................................ 5 2 
 
S cr e e ni n g ...................................................................................................................... 5 3 
6. 3. 2. 1.  
G e n eti c  T esti n g  ............................................................................................................ 5 3 
6. 3. 2. 2.  
D e m o gr a p hi cs  a n d  M e di c al  Hist or y ............................................................................ 5 3  
6. 4.  
Effi c a c y  M e as ur e m e nts  ................................................................................................ 5 3 
 
W ei g ht .......................................................................................................................... 5 3  
 
H ei g ht ........................................................................................................................... 5 4  
 
 
 
 
 
H u n g er/ H y p er p h a gi a  Ass ess m e nts  .............................................................................. 5 4 
6. 4. 5. 1.  
P ati e nt  Ass ess m e nts  of  H u n g er  .................................................................................... 5 4 
6. 4. 5. 2.  
6. 5.  
 
 
 
 
 
 
 
 
6. 6.  
6. 7.  
 
6. 7. 1. 1.  
S a m pl es f or  St or a g e/ Ar c hi v e  ....................................................................................... 5 9 
6. 7. 1. 2.  
6. 8.  
 
C o n c o mit a nt  M e di c ati o n  R e vi e w  ................................................................................ 5 9 
 
6. 8. 2. 1.  
6. 8. 2. 2.  
C o m pr e h e nsi v e  S ki n  E x a mi n ati o ns ............................................................................. 6 0  
 
Fit z p atri c k  S c al e  ........................................................................................................... 6 0 
 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 3 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
6. 8. 5. 1.  
6. 8. 5. 2.  
 
6. 8. 6. 1.  
 
 
 
Di et  a n d  N utriti o n al  C o u ns eli n g .................................................................................. 6 2  
 
 
6. 9.  
Or d er  of  Ass ess m e nts  .................................................................................................. 6 3 
7.  
7. 1.  
7. 2.  
7. 3.  
 
7. 4.  
7. 5.  
 
8.  
8. 1.  
 
 
8. 2.  
A n al ysis  P o p ul ati o ns .................................................................................................... 6 9  
8. 3.  
D efi niti o n  of  B as eli n e  ..................................................................................................6 9  
8. 4.  
Ti mi n g  of  A n al ys es ...................................................................................................... 7 0  
8. 5.  
Effi c a c y  A n al ys es  ........................................................................................................ 7 0 
 
Pri m ar y  Effi c a c y  A n al ysis  ........................................................................................... 7 0 
 
S e c o n d ar y  Effi c a c y  A n al ys es  ...................................................................................... 7 1 
8. 5. 2. 1.  
K e y  S e c o n d ar y  Effi c a c y  A n al ys es  ............................................................................... 7 1 
8. 5. 2. 2.  
Ot h er  S e c o n d ar y  Effi c a c y  A n al ys es  ............................................................................ 7 2 
 
8. 6.  
S af et y  A n al ys es  ............................................................................................................ 7 3 
8. 7.  
M ul ti pli cit y .................................................................................................................. 7 3 
9.  
A D MI NI S T R A TI V E  R E Q UI R E M E N T S  ................................................................ 7 4 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 4 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
9. 1.  
G o o d  Cli ni c al  Pr a cti c e  ................................................................................................. 7 4 
9. 2.  
Et hi c al  C o nsi d er ati o ns  ................................................................................................. 7 4 
9. 3.  
P ati e nt I nf or m ati o n  a n d I nf or m e d  C o ns e nt .................................................................. 7 4  
9. 4.  
P ati e nt  C o nfi d e nti alit y  ................................................................................................. 7 4 
9. 5.  
Pr ot o c ol  C o m pli a n c e .................................................................................................... 7 4  
9. 6.  
D at a  M a n a g e m e nt  ........................................................................................................ 7 5 
 
D at a  H a n dli n g .............................................................................................................. 7 5  
 
C o m p ut er  S yst e ms ....................................................................................................... 7 5  
 
D at a  E ntr y  .................................................................................................................... 7 5 
 
M e di c al I nf or m ati o n  C o di n g ........................................................................................ 7 5  
 
D at a  V ali d ati o n  ............................................................................................................ 7 5 
9. 7.  
Dir e ct  A c c ess t o  S o ur c e  D at a  ...................................................................................... 7 5 
9. 8.  
S o ur c e  D o c u m e nt/ C as e  R e p ort  F or m  C o m pl eti o n ...................................................... 7 6  
9. 9.  
R e c or d  R et e nti o n ......................................................................................................... 7 6  
9. 1 0.  
Li a bilit y I ns ur a n c e  ....................................................................................................... 7 6 
9. 1 1.  
P u bli c ati o n  of  St u d y  Fi n di n gs  a n d  Us e  of I nf or m ati o n ............................................... 7 6  
1 0.  
R E F E R E N C E S  ........................................................................................................... 7 8 
1 1.  
A P P E N DI C E S  ............................................................................................................ 8 0 
1 1. 1.  
I nj e cti o n  Sit e  E v al u ati o ns ............................................................................................ 8 0 
1 1. 2.  
Fit z p atri c k  Cl assifi c ati o n  S c al e  .................................................................................... 8 1 
1 1. 3.  
P ast  M e di c al  Hist or y  a n d  Gr o wt h  C ur v e I nf or m ati o n  ................................................. 8 2 
1 1. 4.  
G ui d a n c e f or  M o nit ori n g  P ot e nti al  Tr e at m e nt -R el at e d  D er m at ol o gi c al  C h a n g es 
a n d  S u g g est e d  Crit eri a  F or  Dis c o nti n u ati o n  of  D osi n g ............................................... 8 3  
1 1. 5.  
/ H y p er p h a gi a  Ass ess m e nts .............................................................................. 8 5 
 
P ati e nt -R e p ort e d  H u n g er  Ass ess m e nts  ........................................................................ 8 5 
 
P ar e nt/ C ar e gi v er  R e p ort e d  H u n g er  a n d  H y p er p h a gi a  Ass ess m e nts ............................ 8 6  
1 1. 6.  
Cr e ati ni n e  Cl e ar a n c e  Esti m at e  ..................................................................................... 9 0 
 
C o c k cr oft- G a ult  E q u ati o n  ............................................................................................ 9 0 
 
S c h w art z  E q u ati o n  ....................................................................................................... 9 0 
1 1. 7.  
C o nsi d er ati o ns f or r e d u ci n g  p ai n  a n d  distr ess i n t h e  p e di atri c  p o p ul ati o n .................. 9 1  
1 1. 8.  
D e cl ar ati o n  of  H elsi n ki  ................................................................................................ 9 2 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 5 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
LI S T  O F  T A B L E S  
T a bl e   1 
D os e  Es c al ati o n  S c h e d ul e  .................................................................................... 4 0 
T a bl e   2 
S c h e d ul e  of  Ass ess m e nts:   S cr e e ni n g t hr o u g h  W e e k   5 3  Visit ( E n d  of 
P eri o d   2) ............................................................................................................... 4 6 
T a bl e   3 
S c h e d ul e  of  Ass ess m e nts:   1 4 -W e e k  O p e n -L a b el  Tr e at m e nt ( P eri o d   3) 
a n d  E arl y  T er mi n ati o n  Visit  ................................................................................. 4 9 
 
LI S T  O F  FI G U R E S  
Fi g ur e  1  
L e pti n  –  M el a n o c orti n  P at h w a y ........................................................................... 2 1  
Fi g ur e  2  
S c h e m ati c  Di a gr a m  of t h e  H y p ot h al a mi c  M C 4  P at h w a y Ill ustr ati n g 
t h e  R ol e  of  S et m el a n oti d e  Tr e at m e nt t o  R e pl a c e  G e n eti c  O b esit y 
D ef e cts, i n cl u di n g  B B S  a n d  A S, t h at  ar e  U pstr e a m  of t h e  M C 4 
R e c e pt or  ............................................................................................................... 2 3 
Fi g ur e  3  
St u d y  D esi g n  S c h e m ati c ...................................................................................... 3 0  
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 6 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
LI S T  O F  A B B R E VI A TI O N S 
A b b r e vi ati o n  
D efi niti o n  
~ 
A p pr o xi m at el y 
A C T H  
A dr e n o c orti c otr o pi c  h or m o n e  
A D A  
A nti - dr u g  a nti b o d y 
A D H D  
Att e nti o n  d efi cit  h y p er a cti vit y  dis or d er  
A E (s) 
A d v ers e  e v e nt (s) 
A L T  
Al a ni n e tr a ns a mi n as e  
A S  
Alstr ö m  S y n dr o m e  
a P T T  
A cti v at e d  p arti al t hr o m b o pl asti n ti m e  
A S T  
As p art at e tr a ns a mi n as e  
A U C  
Ar e a  u n d er t h e  c o n c e ntr ati o n- ti m e c ur v e 
B B S  
B ar d et  Bi e dl  s y n dr o m e 
BI A  
Bi o el e ctri c al i m p e d a n c e  
B MI  
B o d y  m ass i n d e x 
B N D F  
Br ai n - d eri v e d  n e ur otr o p hi c f a ct or 
B P  
Bl o o d  pr ess ur e 
B U N  
Bl o o d  ur e a  nitr o g e n  
C B E R  
C e nt er f or  Bi ol o gi cs  E v al u ati o n  a n d  R es e ar c h  
C D C  
C e nt ers f or  Dis e as e  C o ntr ol  a n d  Pr e v e nti o n  
C D E R  
C e nt er f or  Dr u g  E v al u ati o n  a n d  R es e ar c h 
C GI C  
C ar e gi v er  Gl o b al I m pr essi o n  of  C h a n g e 
C GI S  
C ar e gi v er  Gl o b al I m pr essi o n  of  S e v erit y  
C m a x  
M a xi m u m  o bs er v e d  c o n c e ntr ati o n  
C N S  
C e ntr al  n er v o us s yst e m  
C O 2 
C ar b o n  di o xi d e 
C P K  
Cr e ati n e  p h os p h o ki n as e 
C R A  
Cli ni c al r es e ar c h  ass o ci at e  
C R F  
C as e r e p ort f or m  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 7 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
A b b r e vi ati o n  
D efi niti o n  
 
 
C T C A E  
C o m m o n  T er mi n ol o g y  Crit eri a f or  A d v ers e  E v e nts  
DI O  
Di et -i n d u c e d  o b es e 
D S M -III 
Di a g n osti c  a n d  St atisti c al  M a n u al  of  M e nt al  Dis or d ers 
V ersi o n III  
 
 
E C 5 0 
H alf  m a xi m al  eff e cti v e  c o n c e ntr ati o n  
 
 
e C R F  
El e ctr o ni c  c as e r e p ort f or m  
 
 
F A S  
F ull  A n al ysis  S et 
F D A  
F o o d  a n d  Dr u g  A d mi nistr ati o n 
F S H  
F olli cl e  Sti m ul ati n g  H or m o n e  
Fr e e  T 4  
Fr e e t h yr o xi n e 
G C P  
G o o d  cli ni c al  pr a cti c e  
 
  
 
 
 
 
 
 
 
 
H R  
H e art r at e  
 
 
I B 
I n v esti g at or  Br o c h ur e 
I C F 
I nf or m e d  C o ns e nt  F or m 
I C H 
I nt er n ati o n al C o u n cil  f or  H ar m o ni z ati o n 
I E C 
I n d e p e n d e nt  Et hi cs  C o m mitt e e 
 
 
 
 
 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 8 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
A b b r e vi ati o n  
D efi niti o n  
I R B 
I nstit uti o n al  R e vi e w  B o ar d 
I U D 
I ntr a ut eri n e  d e vi c e 
 
 
 
 
 
 
L E P R 
L e pti n  R e c e pt or  
L F T  
Li v er f u n cti o n t ests  
L H  
L ut ei ni zi n g  h or m o n e  
M A D  
M ulti pl e  as c e n di n g  d os e 
M C 1 R  
M el a n o c orti n  re c e pt or  t y p e  1 
M C 4 R  
M el a n o c orti n  re c e pt or  t y p e  4 
M e d D R A  
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es  
M S H  
M el a n o c yt e sti m ul ati n g  h or m o n e  
N A F L D  
N o n -al c o h oli c f att y li v er  dis e as e  
N A S H  
N o n -al c o h oli c st e at o h e p atitis  
N H L BI  
N ati o n al  H e art,  L u n g,  a n d  Bl o o d I nstit ut e 
N O A E L  
N o  o bs er v e d  a d v ers e  eff e cts l e v el  
O bs R O  
O bs er v er  R e p ort e d  O ut c o m e 
 
 
O T C  
O v er t h e  c o u nt er 
 
 
 
 
 
 
 
 
 
 
PI(s)  
Pri n ci p al I n v esti g at or(s)  
 
 
P O M C  
Pr o - o pi o m el a n o c orti n 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  1 9 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
A b b r e vi ati o n  
D efi niti o n  
P P  
P er  Pr ot o c ol  
P T  
Pr ot hr o m bi n  Ti m e  
P T T  
P arti al t hr o m b o pl asti n ti m e  
P V N  
P ar a v e ntri c ul ar  n u cl e us  
P W S  
Pr a d er -Willi  s y n dr o m e 
P W S -F P D  
Pr a d er -Willi   S y n dr o m e  F o o d  Pr o bl e m  Di ar y 
 
 
P Y Y  
P e pti d e  Y Y 
Q D  
O n c e  d ail y  
S A  
S af et y  a n al ysis  
S A E (s) 
S eri o us  a d v ers e  e v e nt (s) 
S C  
S u b c ut a n e o us  
 
 
 
 
S O A  
S c h e d ul e  of  ass ess m e nts  
 
 
T m a x  
Ti m e t o  o bs er v e d  m a xi m u m  c o n c e ntr ati o n  
T S H  
T h yr oi d sti m ul ati n g  h or m o n e 
U S  
U nit e d  St at es  
U L N  
U p p er li mit  of  n or m al 
U V  
Ultr a vi ol et  
 
 
W H O  
W orl d  H e alt h  Or g a ni z ati o n 
 
 
W M A  
W orl d  M e di c al  Ass o ci ati o n  
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  2 0 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
1.   
I N T R O D U C TI O N  
1. 1.   
P u r p os e  of  St u d y  
T his  pi v ot al,  p h as e  3 st u d y is  d es i g n e d to  c o nfir m t h e  effi c a c y  a n d s af et y  of  s et m el a n oti d e, a 
p ot e nt  m el a n o c orti n r e c e pt or t y p e  4 ( M C 4 R)  a g o nist,  f or t h e tr e at m e nt  of  o b esit y  a n d 
h y p er p h a gi a  i n  p ati e nts  wit h  B ar d et  Bi e dl s y n dr o m e ( B B S)  or  Alstr ö m s y n dr o m e ( A S). T h e 
st u d y’s  pri m ar y  effi c a c y  e n d p oi nt  will  e v al u at e t h e  pr o p orti o n  of  p ati e nts ( ≥ 1 2  y e ars  of  a g e  at 
b as eli n e)  w h o l os e  ≥ 1 0 %  of t h eir  b as eli n e  b o d y  w ei g ht  f oll o wi n g  a p pr o xi m at el y ( ~)  5 2 w e e ks  of 
tr e at m e nt  wit h s et m el a n oti d e c o m p ar e d t o  a  hist ori c al  c o ntr ol  r at e. T h e  st u d y  will  c o nsist  of 
3  tr e at m e nt p eri o ds.  Eli gi bl e  p ati e nts  will  e nt er  a  1 4 - w e e k, r a n d o mi z e d,  d o u bl e-bli n d,  pl a c e b o -
c o ntr oll e d  tr e at m e nt p eri o d  ( P eri o d 1)  t h at  will  b e f oll ow e d  b y  a  3 8- w e e k  o p e n -l a b el tr e at m e nt 
p eri o d  ( P eri o d  2) i n  w hi c h  all  p ati e nts  will r e c ei v e s et m el a n oti d e. T h e  pri m ar y  a n al ysis  will  b e 
p erf or m e d  aft er  P eri o d  2.  F oll o wi n g  P eri o d   2,  p ati e nts  will  c o nti n u e  o p e n-l a b el tr e at m e nt f or 
1 4  w e e ks ( P eri o d  3)  aft er  w hi c h t h e y  m a y  b e  e nr oll e d  i nt o  a s e p ar at e tr e at m e nt  e xt e nsi o n st u d y. 
1. 2.   
O v e r vi e w  of  B a r d et  Bi e dl  a n d  Alst r ö m  S y n d r o m e s 
Pri m ar y  cili a  ar e  e v ol uti o n aril y  c o ns er v e d  or g a n ell es  w h os e  d ysf u n cti o n l e a d t o  h u m a n  dis or d ers 
n o w  d efi n e d  as  cili o p at hi es.  H u m a n  cili o p at hi es  pr es e nt  pl ei otr o pi c  a n d  o v erl a p pi n g  p h e n ot y p es 
t h at  oft e n i n cl u d e r eti n al  d e g e n er ati o n,  c ysti c r e n al  a n o m ali es  a n d si g nifi c a nt,  e arl y-o ns et 
o b esit y. I n cr e asi n g  e vi d e n c e i m pli c at es  a n i ntri g ui n g i n v ol v e m e nt  of  cili a i n li pi d/ e n er g y 
h o m e ost asis,   a n d s u p p ort  k e y r ol es  of  cili ar y  g e n es i n t h e  d e v el o p m e nt  a n d  p at h ol o g y  of  o b esit y 
a n d  h y p er p h a gi a. 
  
B a r d et  Bi e dl  S y n d r o m e   
B B S,  o n e  of t h e  cili o p at hi es,  is  a r ar e pl ei otr o pi c  a ut os o m al r e c essi v e  dis or d er  c h ar a ct eri z e d  b y  a 
s y n dr o mi c  p h e n ot y p e  wit h  a n  o v er all  pr e v al e n c e  of  1 i n  1 2 5, 0 0 0 – 1 6 0, 0 0 0 i n  p e o pl e  of  E ur o p e a n 
d es c e nt ( F ors yt h e  2 0 1 3 ). T h e  cli ni c al  pr es e nt ati o n  of  B B S i n cl u d es  m ar k e d  o b esit y  a n d 
h y p er p h a gi a i n  a d diti o n t o s e v er al  ot h er  dis e as e f e at ur es t h at li k el y  d o  n ot ris e fr o m 
h y p ot h al a mi c i m p air m e nt.  T h es e l att er  f e at ur es i n cl u d e r o d- c o n e  d ystr o p h y,  p ost a xi al 
p ol y d a ct yl y,  c o g niti v e i m p air m e nt,  h e ari n g l oss, s p e e c h  d efi cit,  h e p ati c fi br osis,  g e nit o uri n ar y 
m alf or m ati o ns, r e n al  a b n or m aliti es , di a b et es  m ellit us,  h y p ert e nsi o n,  a n d  c o n g e nit al  h e art  dis e as e 
(B ar d et  1 9 9 5 , Bi e dl  1 9 9 5 , B e al es  1 9 9 9 , F ors yt h e  2 0 1 3 , F ors yt h e  2 0 1 5 ).  
O f  all t h es e m a nif est ati o ns ,  o b esit y  a n d  h u n g er  m a y  b e t h e m ost  dist ur bi n g  (Gr a c e  2 0 0 3 ). W hil e 
birt h   w ei g ht i n  aff e ct e d  p ati e nts is  us u all y  n or m al, si g nifi c a nt  w ei g ht  g ai n d u e t o i n cr e as e d f o o d 
i nt a k e  a n d d e cr e as e d  e n er g y  e x p e n dit ur e ( F ors yt h e  2 0 1 5 )  b e gi ns i n t h e first  y e ar  a n d is  a lif el o n g 
iss u e f or  m ost ( 7 2-9 2 %) ( F ors yt h e  2 0 1 3 ).  Rel ati v e t o  h e alt h y s u bj e cts  wit h  c o m p ar a bl e  a 
c o m p ar a bl e  b o d y  m ass i n d e x ( B MI ), p ati e nts  wit h  B B S  t e n d t o  h a v e  hi g h er  a di p osit y (Gr a c e 
2 0 0 3 ), si g nifi c a ntl y  m or e  a b d o mi n al  vis c er al f at  (F e uill a n  2 0 1 1 ),  a n d l ess l e a n  m ass (L o c k e 
2 0 0 9 ). I n  o n e  c o h ort fr o m  N e wf o u n dl a n d,  a r e gi o n  w h er e t h e  pr e v al e n c e  of  B B S is 
a p pr o xi m at el y  1 0 ti m es  m or e  c o m m o n t h a n i n t h e r est  of t h e  w orl d,  m or bi d  o b esit y 
( B MI  > 4 0 k g/ m 2) o c c urs i n  2 5 %  of s u bj e cts ( M o or e   2 0 0 5). 
B B S  is c a us e d  b y  m ut ati o ns i n  as  m a n y  as  2 1  diff er e nt  g e n es,  all  of  w hi c h  p arti ci p at e i n  cili a 
f u n cti o ni n g (S u pisti n  2 0 1 6 ),  a n d is t h er ef or e c o nsi d er e d  a  pri m ar y  cili o p at h y.  Ei g ht  of t h e  m ost 
c o ns er v e d  B B S  pr ot ei ns ( B B S 1,  B B S 2,  B B S 4,  B B S 5,  B B S 7,  B B S 8,  B B S 9  a n d  B B S 1 8 ) f or m  a 


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R h yt h m  P h ar m a c e uti c als, I n c. 
c or e  c o m pl e x,  k n o w n  as t h e  B B S o m e,  t h at  ass o ci at es  wit h t h e  cili ar y  m e m br a n e  a n d f u n cti o ns as 
a  u nit t o s ort  a n d  dir e ct  tr affi c ki n g of r e c e pt ors  a n d  ot h er  pr ot ei ns t o t h e  cili ar y  m e m br a n e  
(N a c h ur y  2 0 0 7 , L o kt e v  2 0 0 8 ).  T h e B B S 3  pr ot ei n  a p p e ars  criti c al f or  r e cr uit m e nt  of t h e  B B S o m e 
c o m pl e x  o nt o t h e  cili ar y  m e m br a n e ( L o kt e v  2 0 0 8 ),  w hil e B B S 6,  B B S 1 0  a n d  B B S 1 2  f or m  a 
c o m pl e x t h at f a cilit at es  ass e m bl y  of t h e  B B S o m e  (S e o   2 0 1 0). W hil e t h e  f u n cti o n  of t h e 
r e m ai ni n g  B B S  pr otei ns is l ess  w ell  c h ar a ct eri z e d , t h e  e xist e n c e  of t h es e f u n cti o n al  c o n n e cti o ns 
a m o n g t h e  B B S  pr ot ei ns  h el ps  e x pl ai n t h e  p h e n ot y pi c si mil ariti es  a m o n g  p ati e nts  c arr yi n g  
m ut ati o ns i n  s u c h  v ari e d B B S   g e n es (G u o  2 0 1 1 ).  
E xt e nsi v e  r es e ar c h s u g g ests t h e o b esit y   p h e n ot y p e i n  B B S is c a us e d  b y  i m p air e d tr a ns p ort  of t h e 
l e pti n r e c e pt or t o t h e  cili ar y  m em br a n e  of  pr o- o pi o m el a n o c orti n ( P O M C)  n e ur o ns  i n t h e  ar c u at e 
n u cl e us  of t h e  h y p ot h al a m us ( G u o  2 0 1 1 ).  U n d er  n or m al  c o n diti o ns, l e pti n,  a  h or m o n e 
pr e d o mi n a ntl y  m a d e  b y  a di p os e  c ells,  sti m ul at es firi n g  a n d g e n e  e x pr essi o n  i n  P O MC  n e ur o ns, 
pr o m oti n g t h e s e cr eti o n  of  al p h a- m el a n o c yt e  sti m ul ati n g  h or m o n e ( α- M S H) . T his  sti m ul at es t h e 
M C 4 R l o c at e d i n t h e s e c o n d  or d er  n e ur o ns  i n t h e  p ar a v e ntri c ul ar  n u cl e us ( P V N)  of t h e 
h y p ot h al a m us  t o  d e cr e as e h u n g er  a n d   w ei g ht a n d i n cr e as e   e n er g y  e x p e n dit ur e (Fi g ur e   1). 
I m p air e d or  a bs e n t l e pti n r e c e pt or si g n ali n g i n  P O M C  n e ur o ns  w o ul d  b e  e x p e ct e d t o r e d u c e 
M C 4 R sti m ul ati o n i n s e c o n d  or d er  n e ur o ns,  r es ulti n g i n  a n i n cr e as e i n  a p p etit e, r e d u c e d 
m et a b oli c r at e,  a n d i n cr e as e d  w ei g ht.   
Fi g u r e   1  
L e pti n  –  M el a n o c o rti n  P at h w a y   
 
T h er e is  n o  c ur e f or  B B S .  Tr e at m e nt  g e n er all y f o c us es  o n t h e s p e cifi c si g ns  a n d s y m pt o ms i n 
e a c h  i n di vi d u al.  M a n a g e m e nt  of  o b esit y i n cl u d es  e d u c ati o n,  di et,  e x er cis e,  a n d  b e h a vi or al 
t h er a pi es  b e gi n ni n g  at  a n  e arl y  a g e.  Co m pli c ati o ns  of  o b esit y , s u c h  as  a b n or m all y  hi g h 
c h ol est er ol  a n d  di a b et es  m ellit us , ar e tr e at e d  as t h e y  ar e i n t h e  g e n er al  p o p ul ati o n  (N ati o n al 
I nstit ut es  of  H e alt h  2 0 1 3). 
  
Alst r ö m  S y n d r o m e   
A S, li k e  B B S,  is a  cili o p at h y  c h ar a ct eri z e d  b y  a s y n dr o mi c  p h e n ot y p e t h at i n cl u d es  pr o gr essi v e 
c o n e-r o d  d ystr o p h y l e a di n g t o  bli n d n ess, s e ns ori n e ur al  h e ari n g l oss,  c o n g esti v e  h e art f ail ur e,  a n d 
m ar k e d  c hil d h o o d  o b esit y  ass o ci at e d  wit h  h y p eri ns uli n e mi a  a n d t y p e  2  di a b et es  m ellit us ( Gir ar d 
2 0 1 1,  D e Vri es  2 0 1 4 ).  H o w e v er, it is  c a us e d  b y bi -all eli c r e c essi v e  m ut ati o ns i n  a si n gl e  g e n e, 


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R h yt h m  P h ar m a c e uti c als, I n c. 
A L M S 1 .  W hil e t h e  e x a ct f u n cti o n  of A L M S 1   h as  n ot  y et  b e e n  el u ci d at e d, it is  k n o w n t o  pl a y a 
pi v ot al r o l e i n t h e f u n cti o n, f or m ati o n,  a n d  m ai nt e n a n c e  of  pri m ar y  cili a (K n or z  2 0 1 0 ). A L M S 1  
h as  b e e n s h o w n t o  b e i n v ol v e d i n  e n er g y  b al a n c e  a n d s ati et y r e g ul ati o n ( Al v er e z -S att a  2 0 1 5 ). 
A S  is  c o nsi d er a bl y r ar er t h a n B B S ,  wit h  ~  9 5 0  c as es  esti m at e d  w orl d wi d e (Or p h a n et  2 0 1 8 ).  
W hil e  A S  s h ar es  m a n y  of t h e s a m e  cli ni c al  f e at ur es  as  B B S, t h e  dis or d ers  c a n  us u all y  b e 
disti n g uis h e d  cli ni c all y  a n d  c o nfir m e d t hr o u g h  g e n eti cs.  W hil e t h e  d o mi n a nt  p h e n ot y p e i n  B B S 
is t y pi c all y  d e v el o p m e nt al  d ef e cts, i n  A S it is  m et a b oli c f u n cti o n.  B e gi n ni n g i n i nfa n c y,  p ati e nts 
wit h  A S  h a v e  pr o gr essi v e  m ulti or g a n  p at h ol o g y t h at t y pi c all y l e a ds t o tr u n c al  o b esit y, i ns uli n 
r esist a n c e,  h y p eri ns uli n e mi a,  h y p erl e pti n e mi a,  a n d  h y p erli pi d e mi a  b y  5  y e ars  of  a g e  a n d 
pr o gr ess es t o t y p e  2  di a b et es  m ellit us  ( T 2 D M).  T h e i n ci d e nc e  of  T 2 D M is  o n e  of  disti n g uis hi n g 
f e at ur es  b et w e e n  A S  a n d  B B S. I n  p ati e nts  wit h  A S t h e i n ci d e n c e  of  T 2 D M is  ~ 5 0-7 5 % 
c o m p ar e d  wit h  < 2 5 % i n  p ati e nts  wit h  B B S ( Gir ar d  2 0 1 1 ).  
O b esit y is  o bs er v e d  al m ost  u ni v ers all y i n  p ati e nts  wit h  A S;  e x c essi v e  w ei g ht  g ai n t y pi c all y 
b e gi ns  wit hi n t h e first  y e ar  of lif e.  H y p er p h a gi a  a n d  o bs essi o n  wit h f o o d  ar e  als o  c o m m o n i n 
p ati e nts  wit h  A S ( M ars h all  2 0 0 7 ). As  wit h  B B S, t h er e is  n o  c ur e f or  A S.  
1. 3.   
S et m el a n oti d e  f o r t h e  T r e at m e nt  of  B a r d et  Bi e dl  a n d  Alst r ö m  S y n d r o m es 
Alt h o u g h l ar g e  eff orts t o st a bili z e  b o d y  w ei g ht  wit h t h e  h el p  of  p h ysi ci a ns,  ps y c h ol o gists, 
n utriti o nists , a n d s p e ci al  e x er cis e  pr o gr a ms  ar e  oft e n  m a d e i n t h es e  p ati e nts, i n v ari a bl y t h es e 
pr o gr a ms  ar e  n o t s u c c essf ul,  a n d  aff e ct e d  p ati e nts  c o nti n u e t o  g ai n  w ei g ht st e a dil y. I n  ol d er 
p ati e nts, s h ort i nt er v als  of  w ei g ht st a bilit y ( b ut  wit h o ut  w ei g ht -l oss fr o m t h eir  b as eli n e  c o n diti o n 
of s e v er e  o b esit y)  h a v e  b e e n  p ossi bl e,  b ut  o nl y  wit h  e xtr a or di n ar y  eff orts.  T his l a c k  of r es p o ns e 
is  n ot s ur prisi n g,  as t h e  e xtr e m e  h u n g er  a n d f o o d-s e e ki n g  b e h a vi ors  u n d er pi n ni n g  o b esit y 
ass o ci at e d  wit h  d ef e cts i n t h e l e pti n - m el a n o c orti n  p at h w a y  ar e  n ot  a d dr ess e d  b y  a n y  of t h es e 
eff orts.    
S et m el a n oti d e is  a  M C 4 R  a g o nist t h at r et a i ns t h e s p e cifi cit y  a n d f u n cti o n alit y  of  n at ur all y 
o c c urri n g  α- M S H,  w hi c h is t h e  n at ur al li g a n d f or t h e  M C 4 R .  Set m el a n oti d e  h as t h e  p ot e nti al t o 
r est or e l ost  a cti vit y i n t h e  M C 4 R  p at h w a y  b y  b y p assi n g t h e  d ef e cts  u pstr e a m  of t h e  M C 4 R  a n d 
dir e ctl y  a cti v ati n g   M C 4 R  n e ur o ns i n t h e  h y p ot h al a m us  b el o w s u c h  d ef e cts (Fi g ur e  2 ). T h us, 
s et m el a n oti d e  m a y s er v e  as  a  “r e pl a c e m e nt ” t h er a p y t o r e- est a blis h  w ei g ht  a n d  a p p etit e  c o ntr ol 
i n  p ati e nts  wit h dis or d ers, s u c h  as  B B S  a n d  A S, t h at  ar e  m e di at e d  b y  hi g h er  or d er  d ef e cts.   


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R h yt h m  P h ar m a c e uti c als, I n c. 
Fi g u r e   2   
S c h e m ati c  Di a g r a m  of t h e  H y p ot h al a mi c  M C 4  P at h w a y Ill ust r ati n g t h e  R ol e 
of  S et m el a n oti d e  T r e at m e nt t o  R e pl a c e  G e n eti c  O b esit y  D ef e cts , i n cl u di n g 
B B S  a n d  A S,  t h at  a r e U pst r e a m  of t h e  M C 4  R e c e pt o r  
 
 
1. 4.   
S et m el a n oti d e  O v e r vi e w 
T h e  n o n cli n i c al  a n d  cli ni c al  d at a f or s et m el a n oti d e  ar e  bri efl y  d es cri b e d  b el o w;  m or e  d et ail e d 
i nf or m ati o n is  pr o vi d e d i n t h e I n v esti g at or’s  Br o c h ur e (I B). 
  
N o n cli ni c al  O v e r vi e w  


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R h yt h m  P h ar m a c e uti c als, I n c. 










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R h yt h m  P h ar m a c e uti c als, I n c. 
3.   
I N V E S TI G A TI O N A L  P L A N  
3. 1.   
O v e r all  D esi g n  a n d  Pl a n  of t h e  St u d y  
T his is  a  pi v ot al st u d y t o  c o nfir m t h e l o n g -t er m ( a p pr o xi m at el y  1  y e ar i n  m ost  p ati e nts)  effi c a c y 
a n d s af et y  of s et m el a n oti d e tr e at m e nt i n  p ati e nts  w h o  h a v e  B B S  or  A S.  
T h e st u d y  will  c o nsist  of  3  tr e at m e nt  p eri o ds (s e e Fi g ur e  3 ).  Aft er  o bt ai ni n g i nf or m e d  c o ns e nt, 
p ot e nti al  p ati e nts  will  b e s cr e e n e d t o  d et er mi n e st u d y  eli gi bilit y.  Eli gi bl e  p ati e nts  will  e nt er  a 
1 4- w e e k, r a n d o mi z e d,  d o u bl e- bli n d,  pl a c e b o - c o ntr oll e d tre at m e nt  p eri o d  ( P eri o d 1)  t h at  will  b e 
f oll o w e d  b y  a  3 8-w e e k  o p e n -l a b el tr e at m e nt p eri o d  ( P eri o d 2)  i n  w hi c h  all  p ati e nts  will r e c ei v e 
s et m el an oti d e.  T h e  pri m ar y  a n al ysis  will  b e  p erf or m e d  aft er  P eri o d   2.  T o  m ai nt ai n t h e  bli n d 
t hr o u g h  P eri o d  2,  d os e es c al a ti o n t o  a fi x e d  d os e  of  3 m g  will  b e  p erf or m e d  d uri n g t h e first 
2  w e e ks  i n  b ot h t h e  d o u bl e- bli n d ( P eri o d  1)  a n d 3 8 -w e e k  o p e n- l a b el ( P eri o d 2) tr e at m e nt 
p eri o ds.  F oll o wi n g  P eri o d  2,  p ati e nts  will  c o nti n u e t o r e c ei v e  o p e n -l a b el s et m el a n oti d e f or 
1 4  w e e ks ( P e ri o d 3)  aft er  w hi c h t h e y  m a y   b e  e nr olle d  i nt o  a s e p ar at e tr e at m e nt  e xt e nsi o n st u d y.   
P ati e nts  will  b e r a n d o mi z e d i n  a  1: 1 r ati o , str atifi e d  b y  a g e  gr o u p (≥ 1 2  y e ars  or  < 1 2  y e ars)  a n d 
dis e as e ( B B S  or  A S),  t o r e c ei v e  eit h er s et m el a n oti d e Q D  or  pl a c e b o  Q D  vi a  S C i nj e cti o n f or t h e 
first  1 4  w e e ks.  P ati e nts  w h o  ar e ≥ 1 6  y e ars  of  a g e  will st art  o n s et m el a n oti d e  2  m g  or  m at c hi n g 
pl a c e b o  d uri n g t h e  2- w e e k  d os e  es c al ati o n  a n d  will i n cr e as e t o  3   m g  or  m at c hi n g  pl a c e b o  at t h e 
b e gi n ni n g  of  W e e k  3.  P ati e nts  w h o  ar e  < 1 6  y e ars  of  a g e  will st art  o n s et m el a n oti d e  1  m g  or 
m at c hi n g  pl a c e b o  d uri n g  W e e k  1,  will i n cr e as e t o  2   m g  or  m at c hi n g  pl a c e b o  at t h e  b e gi n ni n g  of 
W e e k  2,  a n d  will i n cr e as e t o  3   m g  or  m at c hi n g  pl a c e b o  at t h e  b e gi n ni n g  of  W e e k  3.  D uri n g t h e 
1 4- w e e k  d o u bl e- bli n d  tr e at m e nt  p eri o d,  p ati e nts  will  b e  e v al u at e d  at t h e b e gi n ni n g  of  W e e ks   2 
(t el e p h o n e  c all  o nl y,  p ati e nts  < 1 6  y e ars  ol d),  3,  7,  11,  a n d  1 5  as  d e pi ct e d i n  Fi g ur e  3 .   
Aft er t h e  i niti al  1 4-w e e k  d o u bl e- bli n d tr e at m e nt  p eri o d  ( P eri o d  1),  all  p ati e nts  will i m m e di at el y 
tr a nsiti o n t o r e c ei v e  o p e n-l a b el s et m el a n oti d e  Q D  vi a  S C i nj e cti o n f or  3 8  w e e ks ( P eri o d  2).  T o 
pr es er v e t h e  bli n d,  all  p ati e nts  will  b e r e -es c al at e d t o t h e  3   m g  cli ni c al  d os e.  T h us,  b e gi n ni n g  at 
W e e k   1 5,  p ati e nts  w h o  ar e ≥ 1 6  y e ars  of  a g e  will r e c ei v e  o p e n -l a b el s et m el a n oti d e  2  m g f or 
2  w e e ks, f oll o w e d  b y  a  d os e i n cr e as e t o  3  m g  b e gi n ni n g  at  W e e k  1 7,  a n d  p ati e nts  w h o  ar e 
< 1 6  y e ars  of  a g e  wi ll r e c ei v e  o p e n-l a b el s et m el a n oti d e  1  m g  d uri n g  W e e k  1 5,  2  m g  d uri n g 
W e e k   1 6,  a n d  3  m g  b e gi n ni n g  at  W e e k  1 7.  P ati e nts  will  b e  e v al u at e d  at t h e  b e gi n ni n g of 
W e e k s  1 6 (t el e p h o n e  c all  o nl y,  p ati e nts  < 1 6  y e ars  ol d)  a n d  1 7  a n d t h e n  e v er y  6  w e e ks  t h er e aft er 
d uri n g t his  P eri o d   2. I n  P eri o d  3,  p ati e nts will  b e  e v al u at e d  e v er y  7  w e e ks.  
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  3 0 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
Fi g u r e   3  
St u d y  D esi g n  S c h e m ati c  
 
3. 2.   
D os e  S el e cti o n  R ati o n al e 
B as e d  o n  hist ori c al  d at a i n di c ati n g t h at  m ost  p ati e nts  at l e ast  1 6   y e ars  of  a g e  h a d  mi ni m al, if  a n y, 
a d diti o n al  gr o wt h i n  h ei g ht,  a st arti n g  d os e   of  2. 0 m g  w as s el e ct e d f or  p ati e nts  w h o  ar e  ≥ 1 6  y e ars 
of  a g e  at  e nr oll m e nt  wit h  a  pl a n n e d  d os e  es c al ati o n t o  a  cli ni c al  d os e  of  3. 0  m g  aft er  2   w e e ks.  T o 
b e  m or e  c o ns er v ati v e i n t h e  y o u n g er  p ati e nt  p o p ul ati o n,  w h er e t h e s m all est  p ati e nt is  e x p e ct e d t o 
w ei g ht  at l e ast  2 9   k g,  a st arti n g  d os e  of  1. 0 m g  w as s el e ct e d f or  p ati e nts  < 1 6  y e ars  of  a g e  at 
e nr oll m e nt.  U p w ar d  d os e  es c al ati o n  i n t h es e  p ati e nts  will  o c c ur i n  2 st e ps;  at t h e  e n d  of  W e e k   1, 
t h e  d os e  will  b e i n cr e as ed t o  2. 0  m g  a n d  at t h e  e n d  of  W e e k   2, t h e  d os e  will  b e i n cr e as e d t o 
3. 0  m g.  
3. 3.   
St u d y  E n d p oi nt s 
  
P ri m a r y  Effi c a c y  E n d p oi nt  
T h e  pri m ar y  effi c a c y  e n d p oi nt i n t his  c o nfir m ati v e,  P h as e  3 st u d y is:  
•   T h e  pr o p orti o n  of  p ati e nts ( ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  w h o  a c hi e v e  a  ≥ 1 0 % r e d u cti o n 
fr o m  b as eli n e i n  b o d y  w ei g ht (i e, ar e ‘r es p o n d ers’)  aft er  ~ 5 2  w e e ks  of tr e at m e nt  wit h 
s et m el a n oti d e. 






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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
h y p ot h al a mi c  n e ur o ns  c a us e d  b y  B B S   or A L M 1   m ut ati o ns. B e c a us e s et m el a n oti d e’s  m e c h a nis m 
of  a cti o n i n t h e  M C 4 R  p at h w a y is  d o w nstr e a m fr o m t h e l e pti n r e c e pt or , it h as t h e  p ot e nti al t o  b e 
eff e cti v e i n  b ot h  dis e as es.   
C o nfir m ati o n  of  effi c a c y  will  b e  b as e d  o n  w ei g ht l oss r es p o ns e  aft er  ~ 5 2  w e e ks ( 1   y e ar)  of 
s et m el a n oti d e tr e at m e nt  c o m p ar e d t o  a  hist ori c al  w ei g ht l oss r at e t a k e n fr o m  a l ar g e  w ell 
c h ar a ct eri z e d r e gistr y  of  B S S  p ati e nts.  T h e  1 - y e ar tr e at m e nt  d ur ati o n  w as  c h os e n t o  all o w 
s uffi ci e nt ti m e f or  p ot e nti al  w ei g ht l oss  a n d t o  e ns ur e t h at  e arl y  w ei g ht l oss is s ust ai n e d. 
H o w e v er, t h e st u d y  will  als o i n cl u d e  a  1 4- w e e k  d o u bl e- bli n d,  pl a c e b o - c o ntr oll e d  p eri o d i n  w hi c h 
5 0 %  of  p ati e nts  will r e c ei v e  m at c hi n g  pl a c e b o  a n d  5 0 %  will r e c ei v e s et m el a n oti d e.  R es ults fr o m 
t his  pl a c e b o-c o ntr oll e d  p eri o d  will  pr o vi d e  a n i nsi g ht i nt o t h e i m m e di at e  eff e ct  of s et m el a n oti d e 
c o m p ar e d  wit h  pl a c e b o  o n  e arl y  w ei g ht l oss  a n d t h e  u nr el e nti n g  h u n g er/ h y p er p h a gi a  t h at is 
c h ar a ct eristi c i n t h es e  dis e as es.  I n  p arti c ul ar, t h e  eff e ct  of s et m el a n oti d e  o n  h u n g er s c or es s h o ul d 
b e r a pi d  a n d t h e  e v al u ati o n str e n gt h e n e d  b y t his i niti al  pl a c e b o  p orti o n  of t h e st u d y.  A f ull  y e ar 
d o u bl e- bli n d , pl a c e b o - c o ntr oll e d  p eri o d w a s  n ot  c o nsi d er e d b e c a us e  t h e pr oj e ct e d  w ei g ht l oss 
r es p o n d er r at e  of t h e  u ntr e at e d  p o p ul ati o n is  w ell  u n d erst o o d fr o m t h e  C RI B B S r e gistr y. 
I m p ort a ntl y,  p ati e nt r et e nti o n  w o ul d  b e  es p e ci all y  c h all e n gi n g i n  a f ull  y e ar  pl a c e b o- c o ntr oll e d 
tri al.  
T h e r ati o n al e f or  usi n g  p ati e nts  ≥ 1 2  y e ars  of  a g e  at  b as eli n e f or t h e  pri m ar y  effi c a c y  a n al ysis is 
pr o vi d e d i n  S e cti o n  8. 5. 1 . 
3. 5.   
St u d y  T e r mi n ati o n  
T his st u d y  m a y  b e  pr e m at ur el y t er mi n at e d, if i n t h e  o pi ni o n  of t h e I n v esti g at or  ( at  a  p arti ci p ati n g 
sit e) or t h e  S p o ns or (f or t h e  w h ol e st u d y) , t h er e is s uffi ci e ntl y r e as o n a bl e  c a us e.  T h e t er mi n ati n g 
p art y  will  pr o vi d e  writt e n  n otifi c ati o n  d o c u m e nti n g t h e r e as o n f or st u d y t er mi n ati o n t o  eit h er t h e 
I n v esti g at or  or t h e  S p o ns or. 
Cir c u mst a n c es t h at  m a y  w arr a nt t er mi n ati o n i n cl u d e,  b ut  ar e  n ot li mit e d t o:  
•   D et er mi n ati o n  of  u n e x p e ct e d, si g nifi c a nt,  or  u n a c c e pt a bl e ris k t o  p ati e nts. 
•   F ail ur e t o  e nt er  p ati e nts  at  a n  a c c e pt a bl e r at e.    
•   I ns uffi ci e nt  a d h er e n c e t o  pr ot o c ol r e q uir e m e nts. 
•   I ns uffi ci e nt  c o m pl et e  a n d/ or  e v al u a bl e  d at a. 
•   Pl a ns t o  m o dif y, s us p e n d,  or  dis c o nti n u e t h e  d e v el o p m e nt  of t h e st u d y  dr u g. 
S h o ul d t h e st u d y  b e  cl os e d  pr e m at ur el y,  all st u d y  m at eri als  m ust  b e r et ur n e d t o t h e  S p o ns or  or 
d esi g n e e.  


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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
4.   
S T U D Y  P O P U L A TI O N  
4. 1.   
N u m b e r  of  P ati e nt s 
It is  a nti ci p at e d t h at a p pr o xi m at el y  3 0  p ati e nts ( at l e ast  2 0  wit h  B B S  a n d  at l e ast  6  wit h  A S ) will 
b e  e nr oll e d  a n d r a n d o mi z e d  a cr oss  a p pr o xi m at el y  1 0  c e nt ers  w orl d wi d e .  Gi v e n t h e r ar e 
i n ci d e n c e  of t h es e  dis e as es, if  a d diti o n al  p ati e nts  ar e i d e ntifi e d, t h e y  m a y  b e  e nr oll e d  as  a v ail a bl e 
t o  g ai n  a d diti o n al  e x p eri e n c e. 
T h e s p e cifi c i n cl usi o n  a n d  e x cl usi o n  crit eri a f or  e nr olli n g  p ati e nts i n t his st u d y  ar e  pr es e nt e d i n 
t h e s e cti o ns  b el o w.  As t h es e  dis e as es  ar e  ultr a-r ar e, i d e ntifi c ati o n  of  p ati e nts is  e xtr e m el y 
diffi c ult.  T h er ef or e,  a n y  crit eri a  n ot f ulfill e d  b y  a  p ati e nt  wit h  a  c o nfir m e d  B B S  or  A S  di a g n osis 
wil l  b e r e vi e w e d  wit h t h e  S p o ns or.  Ass u mi n g  n o s e v er e  h e alt h  c o n c er ns,  a j oi nt  d et er mi n ati o n 
will  b e  m a d e r e g ar di n g t h e  a c c e pt a bilit y  of  e nr olli n g  p ati e nts  n ot f ulfilli n g  all  crit eri a  o n  a  c as e 
b y  c as e  b asis.  A n y  e x c e pti o ns t o t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a  will  b e  d o c u m e nt e d i n 
writi n g  a n d  a p pr o v e d  b y  t h e  S p o ns or  pri or t o  d osi n g t h e  p ati e nt. 
4. 2.   
I n cl usi o n  C rit e ri a 
1.   B B S  cli ni c al  di a g n osis  as  p er  B e al es ,  1 9 9 9 ( wit h  eit h er  4  pri m ar y f e at ur es  or  3  pri m ar y 
a n d  2 s e c o n d ar y f e at ur es fr o m t a bl e  b el o w)   
B a r d et -Bi e dl  S y n d r o m e  
P ri m a r y  Di a g n osti c  C rit e ri a  
•   R o d  c o n e  d ystr o p h y  
•   L e ar ni n g  d is a biliti es 
•   P ol y d a ct yl y   
•   H y p o g o n a dis m i n  m al es  
•   O b esit y  
•   R e n al  a n o m ali es  
S e c o n d a r y  Di a g n osti c  C rit e ri a  
•   S p e e c h  dis or d er/ d el a y   
•   Mil d s p asti cit y ( es p e ci all y l o w er li m bs)  
•   Str a bis m us/ c at ar a cts/ asti g m atis m  
•   Di a b et es  m ellit us  
•   Br a c h y d a ct yl y/s y n d a ct yl y  
•   D e nt al  cr o w di n g/ h y p o d o nti a/s m all 
r o ots/ hi g h  ar c h e d  p al at e 
•   D e v el o p m e nt al  d el a y  
•   L eft  v e ntri c ul ar  h y p ertr o p h y/ c o n g e nit al 
h e art  d is e as e  
•   P ol y uri a/ p ol y di psi a ( n e p hr o g e ni c  di a b et es i nsi pi d us)   •   H e p ati c fi br osis  
•   At a xi a/ p o or  c o or di n ati o n  
 
S o ur c e:  B e al es  1 9 9 9  
Or  A S  di a g n osis  as  p er  M ars h all,  2 0 0 7 ( usi n g  m aj or  a n d  mi n or  a g e  a dj ust e d  crit eri a i n t h e 
t a bl e  b el o w).   


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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
Alst r ö m  S y n d r o m e  
Di a g n osti c  C rit e ri a  
Mi ni m u m  R e q ui r e d  
M aj o r  
Mi n o r  
F o r  p ati e nt s  6 t o  ≤ 1 4  y e a rs  of  a g e  
•   M ut ati o n  of  A L M S 1  a n d/ or f a mil y 
hist or y  of  A S  
•   Visi o n ( n yst a g m us,  p h ot o p h o bi a, 
di mi nis h e d  a c uit y, if  ol d  e n o u g h f or 
t esti n g:  c o n e  d ystr o p h y  b y  E R G) 
•   O b esit y  a n d/ or i ns uli n 
r esist a n c e  a n d/ or  T 2 D M 
•   Hist or y  of  D C M/ C H F  
•   H e ari n g l oss  
•   H e p ati c  d ysf u n cti o n  
•   R e n al f ail ur e  
•   A d v a n c e d  b o n e  a g e  
2  m aj or  crit eri a  
           or  
1  m aj or  a n d   
3  mi n or  crit eri a  
F o r  p ati e nt s  ≥ 1 5  y e a rs  of  a g e  
•   M ut ati o n  of  A L M S 1  a n d/ or f a mil y 
hist or y  of  A S  
•   Visi o n ( hist or y  of  n yst a g m us i n 
i nf a n c y/ c hil d h o o d, l e g al  bli n d n ess, 
c o n e  a n d r o d  d ystr o p h y  b y  E R G)  
•   O b esit y  a n d/ or i ns uli n 
r esist a n c e  a n d/ or  T 2 D M 
•   Hist or y  of  D C M/ C H F  
•   H e ari n g l oss  
•   H e p ati c  d ysf u n cti o n  
•   R e n al f ail ur e  
•   S h ort st at ur e  
•   M al es:  h y p o g o n a dis m  
•   F e m al es: irr e g ul ar  m e ns es 
a n d/ or  h y p er a n dr o g e nis m  
2  m aj or  a n d   
2  mi n or  crit eri a  
or  
1  m aj or  a n d   
4  mi n or  crit eri a  
S o ur c e:  M ars h all  2 0 0 7  
A b br e vi ati o ns :  C H F  =  c o n g esti v e  h e art f ail ur e;  D C M  =  dil at e d  c ar di o m y o p at h y;  E R G  =  el e ctr or eti n o gr a p h y; 
T 2 D M   = T y p e  2  di a b et es  m ellit us  
•   N ot e :   at l e ast  9 0 %  of  p ati e nts  wit h  B B S  a n d  1 0 0 %  of  p ati e nts  wit h  A S  m ust  h a v e  g e n eti c all y 
c o nfir m e d  di a g n osis  at t h e ti m e  of  e nr oll m e nt  
o   A  g e n eti c all y  c o nfir m e d  di a g n osis  of  B B S is  d efi n e d  as  a  h o m o z y g o us  or  c o m p o u n d  h et er o z y g o us 
l oss-of -f u n cti o n  m ut ati o n i n B B S  g e n es;  p ati e nts  wit h o ut  a  g e n eti c all y  c o nfir m e d  B B S  di a g n osis 
m ust  b e r e vi e w e d  wit h t h e  S p o ns or’s  m e di c al  m o nit or  pri or t o  e nr oll m e nt.  
o   A  g e n eti c all y  c o nfir m e d  di a g n osis  of  A S is  d efi n e d  as  a  h o m o z y g o us  or  c o m p o u n d  h et er o z y g o us 
l oss-of -f u n cti o n  m ut ati o n i n t h e A L M S 1  g e n e . 
O n c e  1 0 %  of  p ati e nts  wit h o ut  a  c o nfir m e d  B B S  di a g n osis  h a v e  b e e n  e nr oll e d i n t h e st u d y, sit es  will  b e 
n otifi e d t h at  o nl y  g e n eti c all y  c o nfir m e d  B B S  p ati e nts  m a y  b e  e nr oll e d.  
2.   ≥ 6  y e ars  of  a g e.  
3.   O b es e,  d efi n e d  as  B MI  ≥ 3 0  k g/ m 2 f or  p ati e nts  ≥ 1 6  y e ars  of  a g e  or  w ei g ht  > 9 7t h p er c e ntil e 
f or  a g e  a n d s e x  o n  gr o wt h  c h art  ass ess m e nt f or  p ati e nts  6 t o  1 5  y e ars  of  a g e. 
4.   St u d y  p arti ci p a nt  a n d/ or  p ar e nt  or  g u ar di a n is  a bl e t o  c o m m u ni c at e  w ell  wit h t h e 
I n v esti g at or, t o  u n d erst a n d  a n d  c o m pl y  wit h t h e r e q uir e m e nts  of t h e st u d y,  a n d is  a bl e t o 
u n d erst a n d  a n d si g n t h e  writt e n i nf or m e d  c o ns e nt/ ass e nt.   
5.   F e m al e  p arti ci p a nts  of  c hil d -b e ari n g  p ot e nti al  m ust  b e  c o nfir m e d  n o n- pr e g n a nt  a n d  a gr e e 
t o  us e  c o ntr a c e pti o n  as  o utli n e d i n t h e  pr ot o c ol.  F e m al e  p arti ci p a nts  of  n o n- c hil d b e ari n g 
p ot e nti al,  d efi n e d  as: s ur gi c all y st eril e (st at us  p ost  h yst er e ct o m y,  bil at er al  o o p h or e ct o m y, 
or  bil at er al t u b al li g ati o n),   p ost- m e n o p a us al f or  at l e ast  1 2  m o nt hs ( a n d  c o nfir m e d  wit h  a 
s cr e e ni n g f olli cl e sti m ul ati n g  h or m o n e (F S H ) l e v el i n t h e  p ost- m e n o p a us al l a b r a n g e),  or 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
f ail ur e t o  h a v e  pr o gr ess e d t o  T a n n er  St a g e  V  a n d/ or f ail ur e t o  h a v e  a c hi e v e d  m e n ar c h e, 
d o  n ot r e q uir e  c o ntr a c e pti o n  d uri n g t h e st u d y. 
6.   M al e  p arti ci p a nts  wit h f e m al e  p art n ers  of  c hil d b e ari n g  p ot e nti al  m ust  a gr e e t o  us e  a 
d o u bl e  b arri er  m et h o d  c o ntr a c e pti o n if t h e y  b e c o m e s e x u all y  a cti v e  d uri n g t h e st u d y  or 
wit hi n  9 0  d a ys f oll o wi n g t h eir  p arti ci p ati o n i n t h e st u d y.  M al e  p ati e nts  m ust  als o  n ot 
d o n at e s p er m  d uri n g  a n d f or  9 0  d a ys f oll o wi n g t h eir  p arti ci p ati o n i n t h e st u d y. 
4. 3.   
E x cl usi o n  C rit e ri a  
1.   R e c e nt i nt e nsi v e ( wit hi n  2  m o nt hs)  di et  a n d/ or  e x er cis e r e gi m e n  wit h  or  wit h o ut t h e  us e 
of  w ei g ht l oss  a g e nts (i n cl u di n g  h er b al  m e di c ati o ns) t h at  h as r es ult e d i n  > 2 %  w ei g ht l oss. 
T h es e  p ati e nts  m a y  b e r e c o nsi d er e d  a p pr o xi m at el y  1  m o nt h  aft er  c ess ati o n  of s u c h 
i nt e nsi v e r e gi m e ns.   
2.   C urr e nt  or  pri or ( wit hi n  pri or  2  m o nt hs)  us e  of  a n y  m e di c ati o n, i n cl u di n g t h os e  a p pr o v e d 
t o tr e at  o b esit y, t h at  c o ul d i m p a ct t h e  effi c a c y r es ults  of t his st u d y ( e g,  orlist at, l or c as eri n, 
p h e nt er mi n e-t o pir a m at e,  n altr e x o n e- b u pr o pi o n, lir a gl uti d e).  P ati e nts  o n  a st a bl e  d os e  a n d 
r e gi m e n (f or  at l e ast 2  m o nt hs)  of  m e di c ati o n t o tr e at  att e nti o n  d efi cit  h y p er a cti vit y 
dis or d er ( A D H D)  m a y  b e  e nr oll e d i n t h e st u d y  as l o n g  as t h e y  a gr e e t o r e m ai n  o n t h e 
s a m e  d os e  a n d r e gi m e n  d uri n g t h e st u d y. 
3.   Pri or  g astri c  b y p ass s ur g er y r es ulti n g i n  > 1 0 %  w ei g ht l o ss  d ur a bl y  m ai nt ai n e d fr o m t h e 
b as eli n e  pr e - o p er ati v e  w ei g ht  wit h  n o  e vi d e n c e  of  w ei g ht r e g ai n.  S p e cifi c all y,  p ati e nts 
m a y  b e  c o nsi d er e d if s ur g er y  w as  n ot s u c c essf ul, r es ult e d i n  < 1 0 %  w ei g ht l oss  c o m p ar e d 
t o  pr e-o p er ati v e  b as eli n e  w ei g ht,  or t h er e is  cl e a r  e vi d e n c e  of  w ei g ht r e g ai n  aft er  a n 
i niti al r es p o ns e t o  b ari atri c s ur g er y.  All  p ati e nts  wit h  a  hist or y  of  b ari atri c s ur g er y  m ust 
b e  dis c uss e d  wit h,  a n d r e c ei v e  a p pr o v al fr o m, t h e  S p o ns or  pri or t o  e nr oll m e nt. 
4.   Di a g n osis  of s c hi z o p hr e ni a,  bi p ol ar  dis or d er,  p ers o n alit y  dis or d er  or  ot h er  Di a g n osti c  a n d 
St atisti c al  M a n u al  of  M e nt al  Dis or d ers  fift h  e diti o n ( D S M- V)  dis or d ers t h at t h e 
I n v esti g at or b eli e v es  will i nt erf er e si g nifi c a ntl y  wit h st u d y  c o m pli a n c e.  N e ur o c o g niti v e 
dis or d ers  aff e cti n g  a bilit y t o  c o ns e nt  will   n ot  b e  dis q u alif yi n g  as l o n g  as  a n  a p pr o pri at e 
g u ar di a n  a bl e t o  gi v e  c o ns e nt  h as  b e e n  a p p oi nt e d.   
5.   I n  p ati e nts  wit h  n o si g nifi c a nt  n e ur o c o g niti v e  d efi cits:  
•   A  P H Q - 9 s c or e  of  ≥ 1 5  a n d/ or 
•   A n y s ui ci d al i d e ati o n  of t y p e  4  or  5  o n t h e  C- S S R S,  a n y lif eti m e  hist or y  of  a s ui ci d e 
att e m pt,  or  a n y s ui ci d al  b e h a vi or i n t h e l ast  m o nt h.  
6.   C urr e nt,  cli ni c all y si g nifi c a nt  p ul m o n ar y,  c ar di a c,  or  o n c ol o gi c  dis e as e  c o nsi d er e d s e v er e 
e n o u g h t o i nt erf er e  wit h t h e st u d y  a n d/ or  c o nf o u n d t h e r es ults.  A n y  p ati e nt  wit h  a 
p ot e nti all y  cli ni c all y si g nifi c a nt  dis e as e s h o ul d  b e r e vi e w e d  wit h t h e  S p o ns or t o 
d et er mi n e  eli gi bilit y.  
7.   Hist or y  of si g nifi c a nt li v er  dis e as e  or li v er i nj ur y,  or  a  c urr e nt li v er  ass ess m e nt  d u e t o 
a b n or m al li v er t ests ( as i n di c at e d  b y  a b n or m al li v er f u n cti o n t ests,  al a ni n e tr a ns a mi n as e 
[ A L T],  as p art at e tr a ns a mi n as e [ A S T],  al k ali n e  p h os p h at as e,  or s er u m  bilir u bi n  > 1. 5×  t h e 
u p p er li mit  of  n or m al [ U L N] f or  a n y  of t h es e t ests) f or  a n  eti ol o g y  ot h er t h a n  n o n-
al c o h oli c f att y li v er  dis e as e ( N A F L D).  T h us,  a n y  u n d erl yi n g  eti ol o g y  b esi d es  N A F L D, 


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R h yt h m  P h ar m a c e uti c als, I n c. 
i n cl u di n g  di a g n os e d  n o n-al c o h oli c st e at o h e p atitis ( N A S H),  ot h er  c a us es  of  h e p atitis,  or 
hist or y  of  h e p ati c  cirr h osis is  e x cl usi o n ar y,  b ut t h e  pr es e n c e  of  N A F L D is  n ot  b e 
e x cl usi o n ar y.   
8.   M o d er at e t o s e v er e r e n al  d ysf u n cti o n  d efi n e d  as   < 3 0 m L/ mi n ( A p p e n di x  1 1. 6 ). 
9.   Hist or y  or  cl os e f a mil y  hist or y ( p ar e nts  or si bli n gs)  of s ki n  c a n c er  or  m el a n o m a  
( e x cl u di n g  n o n-i n v asi v e  b as al  or s q u a m o us  c ell l esi o n), or  p ati e nt  hist or y  of  o c ul ar -
c ut a n e o us  al bi nis m.  
1 0.  Si g nifi c a nt  d er m at ol o gi c fi n di n gs r el ati n g t o  m el a n o m a  or  pr e- m el a n o m a s ki n l esi o ns 
( e x cl u di n g  n o n-i n v asi v e  b as al  or s q u a m o us  c ell l esi o n),  d et er mi n e d  as  p art  of 
c o m pr e h e nsi v e s ki n  e v al u ati o n  p erf or m e d  b y  a  q u alifi e d  d er m at ol o gist  d uri n g s cr e e ni n g. 
A n y  c o n c er ni n g l esi o ns i d e ntifi e d  d uri n g t h e s cr e e ni n g  p eri o d  will  b e  bi o psi e d  a n d r es ults 
m ust  b e  k n o w n t o  b e  b e ni g n  pri or t o  e nr oll m e nt. If t h e  pr e-tr e at m e nt  bi o ps y r es ults  ar e  of 
c o n c er n, t h e  p ati e nt s h o ul d  b e  e x cl u d e d fr o m t h e st u d y.   
1 1.  P ati e nt  is, i n t h e  o pi ni o n  of t h e  St u d y I n v esti g at or,  n ot s uit a bl e t o  p arti ci p at e i n t h e st u d y. 
1 2.  P arti ci p ati o n i n  a n y  cli ni c al st u d y  wit h  a n i n v esti g ati o n al  dr u g/ d e vi c e  wit hi n  3  m o nt hs 
pri or t o t h e first  d a y  of  d osi n g. 
1 3.  S i g nifi c a nt  h y p ers e nsiti vit y t o st u d y  dr u g. 
1 4.  I n a bilit y t o  c o m pl y wit h  Q D i nj e cti o n r e gi m e n.  
4. 4.   
P ati e nt  I d e ntifi c ati o n  a n d  R e gist r ati o n  
T h e I n v esti g at or  a n d t h e I n v esti g at or’s st u d y st aff  will i d e ntif y  p ot e nti al  p ati e nt s f or t h e st u d y. 
P ati e nts  w h o  ar e  c a n di d at es f or  e nr oll m e nt i nt o t h e st u d y  will  b e  e v al u at e d f or  eli gi bili t y  b y t h e 
I n v esti g at or t o  e ns ur e t h at t h e i n cl usi o n  a n d  e x cl usi o n  crit eri a  h a v e  b e e n s atisfi e d  a n d t h at t h e 
p ati e nt is  eli gi bl e f or  p arti ci p ati o n i n t his  cli ni c al st u d y.    
All  p ati e nts s cr e e n e d f or t h e st u d y  will  b e  ass i g n e d  a  u ni q u e s cr e e ni n g  n u m b er r e pr es e nti n g a 
c o m bi n ati o n  of t h e sit e  n u m b er  a n d  a s e q u e nti al  3- di git  n u m b er.  S cr e e ni n g  n u m b ers  will  b e 
assi g n e d  s e q u e nti all y st arti n g  at  0 0 1 (i e,  t h e first p ati e nt  s cr e e n e d  at sit e  1 0  w o ul d  b e  ass i g n e d 
s cr e e ni n g  n u m b er  1 0 0 0 1).  
4. 5.   
Wit h d r a w al  of  P ati e nts  
P ati e nts  will  b e i nf or m e d t h at t h e y  h a v e t h e ri g ht t o  wit h dr a w t h eir  c o ns e nt t o  p arti ci p at e i n  t h e 
st u d y  at  a n y ti m e f or  a n y r e as o n,  wit h o ut  pr ej u di c e t o t h eir  m e di c al  c ar e.  T h e I n v esti g at or  als o 
h as t h e ri g ht t o  wit h dr a w  p ati e nts fr o m t h e st u d y ,  aft er  disc ussi o n  wit h t h e  S p o ns or, f or  a n y  of 
t h e f oll o wi n g r e as o ns: 
•   N o n - a d h er e n c e t o st u d y  dr u g r e gi m e n  or  pr ot o c ol r e q uir e m e nts. 
•   N o n -c o m pli a n c e  wit h i nstr u cti o ns  or f ail ur e t o r et ur n f or f oll o w - u p. 
If  a  p ati e nt is  wit h dr a w n  or  dis c o nti n u e d fr o m t h e st u d y, t h e  pri m ar y r e as o n f or  wit h dr a w al fr o m 
t h e st u d y is t o  b e r e c or d e d i n t h e s o ur c e  d o c u m e nts/el e ctr o ni c  c as e r e p ort f or m ( e C R F ).   
A n y  p ati e nt t h at  dis c o nti n u es  tr e at m e nt  pri or t o  c o m pl eti n g t h e st u d y s h o ul d  b e str o n gl y 
e n c o ur a g e d t o  c o m pl et e  all r e m ai ni n g  visits  a n d  pr o c e d ur es  as  o utli n e d i n t h e  S c h e d ul e  of 
Ass ess m e nts  ( S O A) i n  S e cti o n 6 ,  e v e n if t h e y  ar e  n o l o n g er r e c ei vi n g st u d y  dr u g.   


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R h yt h m  P h ar m a c e uti c als, I n c. 
I n  c as e  of dis c o nti n u ati o n,  a ll A Es  s h o ul d  b e f oll o w e d as  d es cri b e d i n  S e cti o n  7. 4 ;  a n y s ki n A Es  
s h o ul d  c o nti n u e t o  b e f oll o w e d, if  at  all f e asi bl e, f or  ~ 6 0- 9 0  d a ys t o  c o nfir m  n e ar  or  c o m pl et e 
r es ol uti o n ( as  h as  b e e n s h o w n i n  pr e vi o us st u di es). 
T h e  S p o ns or  will  pr o vi d e  s u p p ort f or  p ati e nt  a n d  c ar e gi v er tr a v el,  will m a k e  a v ail a b l e visiti n g 
h o m e  h e alt h  c ar e  pr of essi o n als,  a n d  a n y  ot h er  n e c ess ar y l o gisti c al s u p p ort t o  e as e t h e  b ur d e n  o n 
t h e  p ati e nt t o f a cilit at e  c o m pli a n c e.   
4. 6.   
D u r ati o n  of  P ati e nt  P a rti ci p ati o n  
I n di vi d u al  p ati e nt  p arti ci p ati o n i n t his st u d y is  e x p e ct e d t o l ast f or  a p pr o xi m at el y  6 9 w e e ks 
( ~ 3 w e e k s cr e e ni n g  p eri o d   pl us  6 6 w e e ks  of tr e at m e nt  a cr oss  P eri o ds  1 t hr o u g h   3).    
T h e  e n d  of t h e tri al  will  b e  d efi n e d  as t h e l ast  p ati e nt ’s l ast  visit.  


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R h yt h m  P h ar m a c e uti c als, I n c. 
5.   
S T U D Y  T R E A T M E N T S  
5. 1.   
St u d y  D r u gs  
All st u d y  dr u gs  ar e f or i n v esti g ati o n al  us e  o nl y  a n d  ar e t o  b e  us e d  o nl y  wit hi n t h e  c o nt e xt  of t his 
pr ot o c ol.  All i n v esti g ati o n al st u d y  dr u gs (s et m el a n oti d e  a n d  pl a c e b o)  will  b e s u p pli e d  b y t h e 
S p o ns or. 
S et m el a n oti d e is t h e i n v esti g ati o n al t est  dr u g  b ei n g  e v al u at e d i n t his  cli ni c al st u d y. 
S et m el a n oti d e is  a n  8  a mi n o  a ci d,  c y cli c  p e pti d e t h at is  hi g hl y s el e cti v e  a n d  p ot e nt  a g o nist  at t h e 
h u m a n  M C 4 R.  
S et m el a n oti d e  dr u g  pr o d u ct ( s et m el a n oti d e m P E G -D S P E f or m ul ati o n)  is a s t eril e s ol uti o n f or 
i nj e cti o n. T h e  pr o d u ct  is  m a n uf a ct ur e d  at  a  c o n c e ntr ati o n  of  1 0. 0  m g/ m L.   
T h e r ef er e n c e t h er a p y f or t h e  d o u bl e- bli n d  p eri o d  of t his st u d y is  a  pl a c e b o  v e hi cl e.   
S et m el a n oti d e  a n d  pl a c e b o  ar e  cl e ar,  c ol orl ess t o sli g htl y  o p al es c e nt s ol uti o ns  ess e nti all y fr e e  of 
visi bl e  p arti c ul at es,  a n d  ar e s uit a bl e f or  a   d o u bl e- bli n d st u d y.  
5. 2.   
St u d y  D r u g  A d mi nist r ati o n  a n d  D os e  Es c al ati o n 
  
A d mi nist r ati o n  
St u d y  p ati e nts  will r e c ei v e st u d y  dr u g  b y  S C i nj e cti o n  Q D ( a d mi nist er e d i n t h e  m or ni n g).  
T h er e  will  b e  e xt e nsi v e tr ai ni n g  of  p ati e nts  i n  dr u g  a d mi nistr ati o n i n cl u di n g  e d u c ati o n al 
m at eri als.  St u d y s p e cifi c tr ai ni n g  m at eri als  will  b e  pr o vi d e d t o  b ot h t h e i n v esti g ati v e st aff  a n d 
st u d y  p arti ci p a nts  a n d  c ar e gi v ers.  T h e  S p o ns or  will  pr o vi d e  e xtr a  pl a c e b o s u p pli es f or  us e  d uri n g 
tr ai ni n g. 
T h e  g o al is f or t h e  p ati e nt  or t h eir  c ar et a k er t o s u c c essf ull y s elf - a d mi nist er t h e st u d y  dr u g  at 
h o m e.  Gi v e n t h e r arit y  of  B B S  a n d  A S,  arr a n g e m e nts  m a y  b e  m a d e f or t h os e  w h o  ar e  n ot  a bl e t o 
s u c c essf ull y s elf- a d mi nist er t h e st u d y  dr u g t o  h a v e  assist a n c e  b y  a  visiti n g  h o m e  h e alt h  c ar e 
pr a ctiti o n er.  
P ati e nts  a n d/ or t h eir  c ar et a k ers (i n cl u di n g  h o m e  h e alt h  pr a ctiti o n ers)  will  b e r es p o nsi bl e f or  all 
pr o c e d ur es  ass o ci at e d  wit h st u d y  dr u g  a d mi nistr ati o n, i e,  dr a wi n g  u p  a n d s elf- a d mi nist eri n g t h e 
st u d y  dr u g  Q D (i n cl u di n g  d uri n g t h e  pr a cti c e s essi o ns).    
T o  e ns ur e  p ati e nts  or t h eir  c ar e gi v ers  c a n s u c c essf ull y s elf - a d mi nist er st u d y  dr u g,  a tr ai ni n g 
s essi o n(s) i n t h e  cli ni c  wit h  pl a c e b o ( or s ali n e)  will  o c c ur  d uri n g s cr e e ni n g  b ef or e  e nt eri n g t h e 
r a n d o mi z e d,  d o u bl e-bli n d st u d y  p eri o d.  T his tr ai ni n g/ pr a cti c e  c a n  o c c ur  as  m a n y ti m es  as 
n e c ess ar y t hr o u g h o ut t h e st u d y t o  ass ur e  pr o p er t e c h ni q u e.  T h e tr ai ni n g/ pr a cti c e  d o es  n ot  p ert ai n 
t o t h e  h o m e  h e alt h  pr a ctiti o n ers. 
P ati e nts  will  b e r e q uir e d t o f ast  o v er ni g ht f or  all  cli ni c  visits.  W at er  will  b e  all o w e d t hr o u g h o ut 
t h e f asti n g  p eri o d.    
  
St u d y  D r u g  D os e  Es c al ati o n  a n d  A dj ust m e nts  
D os e  es c al ati o n   will  o c c ur  d uri n g t h e first  2  w e e ks  of  b ot h t h e  d o u bl e- bli n d  pl a c e b o-c o ntr oll e d 
a n d t h e  o p e n- l a b el st u d y  p eri o ds (s e e T a bl e   1).  T h e r e as o n f or r e p e ati n g t h e  d os e  es c al ati o n 


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R h yt h m  P h ar m a c e uti c als, I n c. 
pr o c e d ur e  at t h e st art  of t h e  o p e n-l a b el  p eri o d is t o  m ai nt ai n t h e  bli n d  of t h e st u d y  a n d  n ot r e v e al 
w hi c h  gr o u p  ori gi n all y st art e d  wit h  pl a c e b o/ a cti v e tr e at m e nt.  
D os es s h o ul d  n ot  b e  a dj ust e d  aft er t h e  d os e  es c al ati o n  p h as e  h as  b e e n  c o m pl et e d  u nl ess 
dis c uss e d  a n d  a p pr o v e d  b y t h e  S p o ns or.   
T a bl e   1  
D os e  Es c al ati o n  S c h e d ul e  
St u d y  W e e k  
P ati e nts  ≥ 1 6  y e a rs  of  a g e  
( D os e i n  m g) 
P ati e nts  < 1 6   y e a rs  of  a g e 
D os e ( m g) 
1  
2. 0  or  pl a c e b o  
1. 0  or  pl a c e b o  
2  
2. 0  or  pl a c e b o  
2. 0  or  pl a c e b o  
3 -1 4  
3. 0  or  pl a c e b o  
3. 0  or  pl a c e b o  
1 5  
2. 0  
1. 0  
1 6  
2. 0  
2. 0  
1 7 -7 8  
3. 0  
3. 0  
 
5. 3.   
M et h o d  of  Assi g ni n g  P ati e nts t o  T r e at m e nt  
P ati e nts  w h o  q u alif y f or t h e st u d y  will r et ur n t o t h e sit e  o n  D a y   1  of t h e  d o u bl e-bli n d  p eri o d.  
Pri or t o r a n d o mi z ati o n, t h e I n v esti g at or  will  e ns ur e t h at t h e  p ati e nt  c o nti n u es t o  m e et i n cl usi o n 
a n d  e x cl usi o n  crit eri a.  P ati e nts  w h o  c o nti n u e t o  b e  eli gi bl e t o  p arti ci p at e i n t h e st u d y  will  b e 
assi g n e d  a  u ni q u e r a n d o mi z ati o n  n u m b er  b as e d  o n  a r a n d o mi z ati o n  c o d e t h at  will  b e  g e n er at e d 
pri or t o t h e st art  of t h e st u d y.  T h e r a n d o mi z ati o n  n u m b er  c o d es t h e  p ati e nt’s i niti al tr e at m e nt 
assi g n m e nt (f or t h e  d o u bl e- bli n d  p eri o d) t o  eit h er s et m el a n oti d e  or  pl a c e b o.  T h e r a n d o mi z ati o n 
s c h e m e  will r a n d o mi z e  p ati e nts i n  a  1: 1 r ati o , str atifi e d  b y  a g e  gr o u p (≥ 1 2  y e ars   or  < 1 2 y e ars)  
a n d  dis e as e ( B B S  or  A S) , t o r e c ei v e  eit h er s et m el a n oti d e  or  pl a c e b o  d uri n g t h e first  1 4 w e e ks  of 
t h e st u d y. R a n d o mi z ati o n  n u m b ers  will  n ot  b e r e- us e d  o n c e  assi g n e d.  
5. 4.   
Bli n di n g,  P a c k a gi n g,  a n d  L a b eli n g  
  
Bli n di n g  a n d  B r e a ki n g t h e  Bli n d  
T his st u d y  will  b e  o p e n l a b el,  wit h t h e  e x c e pti o n  of  a  1 4- w e e k  d o u bl e- bli n d,  pl a c e b o- c o ntr oll e d 
p eri o d. 
T h e I n v esti g at or, st u d y sit e st aff,  cli ni c al r es e ar c h  or g a ni z ati o n st aff  pr o vi di n g sit e  m a n a g e m e nt , 
a n d  M e di c al  M o nit or  will  n ot  h a v e  a c c ess t o t h e  a ct u al tr e at m e nt  assi g n m e nt  a d mi nist er e d  d uri n g 
t h e  1 4- w e e k  d o u bl e- bli n d,  pl a c e b o- c o ntr oll e d tr e at m e nt  p eri o d ( P eri o d 1) ,  e x c e pt i n t h e  c as e  of 
a n  e m er g e n c y.  E v er y  att e m pt  will  b e  m a d e t o  m a i nt ai n t h e  bli n d t hr o u g h t h e  e n d  of t h e  3 8- w e e k, 
o p e n- l a b el tr e at m e nt  p eri o d ( P eri o d 2)  (i e,  u ntil t h e  d at a b as e s n a ps h ot  pri or t o  c o m pl eti n g t h e 
pri m ar y st atisti c al  a n al ysis).   Br e a ki n g t h e  bli n d f or  a  p ati e nt s h o ul d  b e  d o n e  o nl y i n t h e  e v e nt  of 
a  m e di c al  e m er g e n c y  w h er e t h e i d e ntit y  of st u d y  dr u g is  n e c ess ar y t o  a p pr o pri at el y tr e at t h e 
p ati e nt.  T h e r e q u est t o  br e a k t h e  bli n d s h o ul d  b e  dis c uss e d  wit h t h e  M e di c al  M o nit or  a n d t h e 
S p o ns or,  w h e n e v er  p ossi bl e. If t h e  bli n d is  br o k e n, t h e r e as o n,  w h e n  a n d  h o w t h e  bli n d  w as 
br o k e n  will  b e  d o c u m e nt e d.  


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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
  
P a c k a gi n g  a n d  L a b eli n g  
All st u d y  dr u gs, i n cl u di n g  pl a c e b o  or s ali n e  f or  pr a cti c e, will  b e s u p pli e d  b y  t h e  S p o ns or; 
pl a c e b o/s ali n e f or  pr a cti c e  S C  a d mi nistr ati o n  will  n ot  b e  bli n d e d . 
P a c k a gi n g  a n d l a b eli n g  will  b e  pr e p ar e d t o  m e et  all r e g ul at or y r e q uir e m e nts. 
T o  e ns ur e t h at t h e  p ati e nt  a n d sit e  ar e  bli n d e d  wit h r es p e ct t o  e a c h  p ati e nt’s  r a n d o mi z e d 
tr e at m e nt  assi g n m e nt,  pl a c e b o  a n d s et m el a n oti d e  ar e i d e nti c al i n  a p p e ar a n c e  a n d  ar e s u p pli e d i n 
i d e nti c al  p a c k a gi n g.  E a c h  vi al  will  c o nt ai n  a  c o d e t h at i d e ntifi es t h e  c o nt e nts  as  eit h er  pl a c e b o 
s et m el a n oti d e.  At  e a c h sit e  visit   d uri n g t h e  d o u bl e-bli n d  p eri o d ,  a n  u n bli n d e d st u d y  p h ar m a cist 
will s el e ct t h e  c orr e ct st u d y  dr u g  b as e d  o n t h e  p ati e nt’s r a n d o mi z e d tr e at m e nt  assi g n m e nt  a n d 
will  pr o vi d e t h e  bli n d e d st u d y  m e di c ati o n t o t h e  p ati e nt  or t h e  p ati e nt’s  c ar e gi v er . 
F oll o wi n g  c o m pl eti o n  of t h e  d o u bl e- bli n d  p eri o d, t h e st u d y  p h ar m a cist  will  pr o vi d e  o p e n- l a b el 
(i e,  u n bli n d e d)  vi als  of s et m el a n oti d e t o t h e  p ati e nt  or t h e  p ati e nt’s  c ar e gi v er. 
5. 5.   
P r e p a r ati o n,  H a n dli n g,  a n d  St o r a g e 
All st u d y  dr u g  m ust  b e  k e pt i n  a s e c ur e, li mit e d- a c c ess st or a g e  ar e a  at  a t e m p er at ur e  b et w e e n 
2° C t o  8° C.  B ot h  s et m el a n oti d e a n d  pl a c e b o  ar e st a bl e  at r o o m t e m p er at ur e f or  a s h ort  p eri o d 
t h at  will  all o w  p ati e nts t o tr a ns p ort st u d y  dr u g  h o m e; i c e  p a c ks  a n d  c o ol er  b a gs  will  b e  pr o vi d e d 
f or p ati e nts  a n d  c ar et a k ers  w h o  will tr a v el l o n g  dist a n c es fr o m  t h e  cli ni c. P ati e nts  will  b e 
e n c o ur a g e d t o  pr o c e e d  dir e ctl y  h o m e  aft er  cli ni c  visits i n  w hi c h st u d y  dr u g is  dis p e ns e d  t o 
mi ni mi z e t h e  a m o u nt  of ti m e t h e st u d y  dr u g is  e x p os e d t o  el e v at e d t e m p er at ur es.  
A  s e p ar at e  p h ar m a c y  m a n u al  wit h s p e cifi c i nstr u cti o ns  will  b e  pr o vi d e d t o t h e i n v esti g ati v e sit e.  
5. 6.   
Ass ess m e nt  of  T r e at m e nt  C o m pli a n c e  
T o  e v al u at e t h e  effi c a c y,
  of t h e 
st u d y  dr u g, it is  criti c al t h a t  p ati e nts re c ei v e st u d y  dr u g  as  dir e ct e d.   All  us e d st u d y  dr u g will  als o 
b e  c oll e ct e d t o  ass ess  c o m pli a n c e  wit h t h e  pr ot o c ol.  
P ati e nts  a n d/ or  c ar et a k ers  will  b e r e q uir e d t o  m ai nt ai n  a st u d y  dr u g  di ar y t o  m o nit or  c o m pli a n c e. 
I n  a d diti o n, t h e ti m e  of  d osi n g will  b e  r e c or d e d i n t h e  p ati e nt  di ar y.  T his i nf or m ati o n  will  b e 
r e c or d e d  dir e ctl y i nt o  a n  el e ctr o ni c  d at a  c a pt ur e  d e vi c e. H o m e  n urs es  will  b e  a v ail a bl e,  as 
n e e d e d, f or  a d diti o n al tr ai ni n g  a n d t o r ei nf or c e  c o m pli a n c e.   
If  a  p ati e nt  d o es  n ot r e c ei v e t h e  e ntir e  d os e  of st u d y  dr u g, t h e  a m o u nt  a d mi nist er e d  will  b e 
r e c or d e d. I n  a d diti o n, t h e r e as o n(s) is t o  b e r e c or d e d i n s o ur c e  d o c u m e nts  a n d t h e e C R F . 
A d diti o n all y,  at  all  cli ni c  visits,  a  bl o o d s a m pl e  will  b e  c oll e ct e d  pri or t o  d osi n g i n  cli ni c t o 
m e as ur e tr o u g h   c o n c e ntr ati o ns  of s et m el a n oti d e i n pl as m a .  
5. 7.   
St u d y  D r u g  A c c o u nt a bilit y  
A c c o u nt a bilit y f or t h e st u d y  dr u g  at t h e st u d y sit e is t h e r es p o nsi bilit y  of t h e I n v esti g at or.  T h e 
I n v esti g at or  will  e ns ur e t h at t h e st u d y  dr u g is  us e d  o nl y i n  a c c or d a n c e  wit h t his  pr ot o c ol. W h er e 
all o w e d, t h e I n v esti g at or  m a y  c h o os e t o  assi g n  dr u g  a c c o u nt a bilit y r es p o nsi biliti es t o  a 
p h ar m a cist  or  a n ot h er  a p pr o pri at e i n di vi d u al.  Dr u g  a c c o u nt a bilit y r e c or ds i n di c ati n g t h e  d eli v er y 
d at e t o t h e sit e, i n v e nt or y  at t h e sit e,  us e  b y  e a c h  p ati e nt, r et ur n  of  all  us e d st u d y  dr u g  t o t h e 
st u d y  c e nt er,  a n d r et ur n t o t h e  S p o ns or ( or  dis p os al  of t h e  dr u g, if  a p pr o v e d  b y t h e  S p o ns or )  will 


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R h yt h m  P h ar m a c e uti c als, I n c. 
b e  m a i nt ai n e d  b y t h e  cli ni c al sit e. T h es e r e c or ds  will  a d e q u at el y  d o c u m e nt t h at t h e  p ati e n ts  w er e 
pr o vi d e d t h e  m e di c ati o n (s et m el a n oti d e  or  pl a c e b o)  a n d  d os es  as s p e cifi e d i n t h e  r a n d o mi z ati o n 
c o d e  a n d  pr ot o c ol  a n d s h o ul d r e c o n cil e  all st u d y  dr u g r e c ei v e d fr o m t h e  S p o ns or.  R e as o ns f or 
d e p art ur e fr o m t h e  e x p e ct e d  dis p e nsi n g  r e gi m e n  m ust  als o  b e r e c or d e d.  A c c o u nt a bilit y r e c or ds 
will i n cl u d e  d at es,  q u a ntiti es,  b at c h/s eri al  n u m b ers,  e x pir ati o n  d at es (if  a p pli c a bl e),  a n d  p ati e nt 
n u m b ers.  T h e  S p o ns or  or its  d esi g n e e  will r e vi e w  dr u g  a c c o u nt a bilit y  at t h e sit e  d uri n g 
m o nit ori n g  visits.  
All  u n us e d  a n d  u s e d st u d y  dr u g  will  b e r et ur n e d  b y  p ati e nts,  a n d r et ai n e d  at t h e sit e  u ntil 
i n v e nt ori e d  b y t h e  m o nit or.  All  u n us e d,  us e d  or  e x pir e d st u d y  dr u g  will  b e r et ur n e d t o t h e 
S p o ns or  or if  a ut h ori z e d,  dis p os e d  of  at t h e st u d y sit e  a n d  d o c u m e nt e d.   
5. 8.   
P ri o r  a n d  C o n c o mit a nt  T r e at m e nt  
  
P e r mitt e d  M e di c ati o n  
F e m al e  p ati e nts  m a y  us e  h or m o n al  c o ntr a c e pti o n  as  w ell  as  h or m o n e r e pl a c e m e nt t h er a p y.  
U nl ess  c o n c o mit a nt  m e di c ati o ns  ar e li k el y t o  pr es e nt  a str o n g  p ot e nti al s af et y  c o n c er n, t h e 
g e n er al  g o al  of t his  pr ot o c ol is t o  all o w  as  m a n y  as  p ossi bl e  p ati e nts  wit h t h es e  ultr a -r ar e 
c o n diti o ns t o  p arti ci p at e i n t h e st u d y.  T h er ef or e,  p ati e nts  ar e  all o w e d  c hr o ni c  c o n c o mit a nt 
m e di c ati o ns ( e g ,  as  d es cri b e d  b el o w)  w hil e  p arti ci p ati n g i n t h e st u d y:   
•   Gr o wt h  h or m o n e 
•   C o ntr a c e pti v es  (s e e  S ecti o n  6. 2. 1  f or r e q uir e m e nts f or  c o ntr a c e pti o n) 
•   H or m o n e r e pl a c e m e nt t h er a p y  ( e g,  estr o g e n,  pr o g esti ns,  a n dr o g e ns) 
•   A nti - h y p ert e nsi v es 
•   St ati ns  a n d  ot h er li pi d -l o w eri n g t h er a pi es 
•   T h yr o xi n e  or  ot h er t h yr oi d s u p pl e m e nts 
•   Ot h er  m e di c ati o ns  c o m m o nl y  us e d i n  o b es e  p ati e nts i n cl u di n g:   e n d o cri n e t h er a pi es 
(e g ,  estr o g e ns,  bis p h os p h o n at es,  h y dr o c ortis o n e,  vit a mi n  a n d  c al ci u m s u p pl e m e nts, 
di a b eti c t h er a pi es  i n cl u di n g i ns uli n);  a n d  ot h er m e di c ati o ns ( e g ,  c ar nit ol,  C o e n z y m e 
Q 1 0,  vit a mi ns,  a nti- c o nsti p ati o n  m e di c ati o ns,  a nti- all er gi c  m e di c ati o ns).    
•   A p art fr o m  l o w t hr es h ol d  dr u gs (e g ,  a nti c o n v uls a nts,  di g o xi n, w arf ari n s o di u m ),  ot h er 
m e di c ati o ns  m a y  b e  p er mitt e d if  o n  a st a bl e  d os e (f or  at l e ast  1 - 2  m o nt hs)  u p o n 
c o ns ult ati o n  wit h t h e  S p o ns or.  
T h er e is littl e  e vi d e n c e t h at  s et m el a n oti d e will r es ult i n  dr u g i nt er a cti o ns  at  pr es e nt,  b ut  d at a  ar e 
li mit e d. P ati e nts  a n d  c ar et a k ers s h o ul d  b e  c ar ef ull y  q u esti o n e d  a b o u t  m e di c ati o n  us e t o e ns ur e 
t h at  p ot e nti al  p ati e nts  ar e  c ar ef ull y  w ar n e d  of  p ossi bl e si d e  eff e cts fr o m dr u g i nt er a cti o ns t h at 
c o ul d  o c c ur  wit h t h e s p e cifi c list  of  m e di c ati o ns t h at  a n i n di vi d u al  p ati e nt  will  b e r e c ei vi n g.    
P ati e nts  will  b e r e mi n d e d  at  e a c h  visit t h at if it  b e c o m es  n e c ess ar y f or  a  p ati e nt t o t a k e  a n y  ot h er 
m e di c ati o n  d uri n g t h e st u d y, fr o m  S cr e e ni n g  u ntil t h e  Fi n al  St u d y  Visit, t h e y  m ust i nf or m t h e 
st u d y st aff i m m e di at el y,  a n d t h e s p e cifi c  m e di c ati o n(s)  a n d i n di c ati o n(s)  m ust  b e  di s c uss e d  wit h 
t h e I n v esti g at or. All  c o n c o mit a nt  m e di c ati o ns t a k e n  d uri n g t h e st u d y  m ust  b e r e c or d e d i n t h e 
s o ur c e  d o c u m e nts  a n d  o n t h e  e C R F . 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  4 3 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
  
P r o hi bit e d  M e di c ati o n  a n d  S u bst a n c es  
M e di c ati o ns, i n cl u di n g t h os e  a p pr o v e d t o tr e at  o b esit y,  t h at  c o ul d i m p a ct t h e  effi c a c y r es ults  of 
t his st u d y  ar e  pr o hi bit e d ( e g, orlist at, l or c as eri n,  p h e nt er mi n e -t o pir a m at e,  n altr e x o n e- b u pr o pi o n, 
lir a gl uti d e). 
Sti m ul a nt  ( a n d  n o n-sti m ul a nt, if  d e cr e as e d  a p p etit e/ w ei g ht l oss is list e d si d e  eff e ct)  m e di c ati o n 
( e g, t o tr e at  att e nti o n  d efi cit  h y per a cti vit y  dis or d er  [ A D H D])  c a nn ot  b e st art e d  d uri n g t h e st u d y. 
P ati e nts  w h o  h a v e  b e e n  o n  a st a bl e  d os e  a n d r e gi m e n f or  at l e ast  2  m o nt hs  pri or t o st u d y  e ntr y 
m a y  c o nti n u e t o r e c ei v e t h e s a m e  d os e  a n d r e gi m e n  d uri n g t h e st u d y.  
A n or e cti c  a g e nts  or  dr u gs  wi t h  a n or e xi a  as  a  n o n-r ar e si d e  eff e ct  ar e  pr o hi bit e d f or t h e  d ur ati o n 
of t h e st u d y. 
  
C o n c o mit a nt  P r o c e d u r es  
C o n c o mit a nt  pr o c e d ur es  c o n d u ct e d  d uri n g t h e st u d y, i n cl u di n g t h os e  us e d t o tr e at  a d v ers e 
e v e nts,  ar e t o  b e r e p ort e d  o n t h e  e C R F . 


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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
6.   
S T U D Y  A S S E S S M E N T S  
6. 1.   
O v e r vi e w  of  S c h e d ul e  of  Ass ess m e nts  
T h e  S O A  f or tr e at m e nt  P eri o ds  1  a n d  2 is  d e pi ct e d i n T a bl e   2  a n d t h e  S O A f or t h e tr e at m e nt 
P eri o d   3 a n d t h e  e arl y t er mi n ati o n  visit (if  n e e d e d)  is  d e pi ct e d i n T a bl e   3. 
Alt h o u g h t h e st u d y  pr o c e d ur es  a n d  ass ess m e nts r e q uir e d  p er  pr ot o c ol  ar e  cl assifi e d  as  “ N o  or 
Mi ni m al  Ris k ” ( a p art fr o m  D X A  w hi c h is  cl assifi e d  as  “ Mi n or I n cr e as e  o v er  Mi ni m al  Ris k ”)  p er 
t h e  2 0 0 8  G ui d a n c e  D o c u m e nt  “ Et hi c al  C o nsi d er ati o ns f or  Cli ni c al  Tri als  o n  M e di ci n al  Pr o d u cts 
C o n d u ct e d  wit h t h e  P e di atri c  P o p ul ati o n ”,  c o nsi d er ati o ns f or r e d u ci n g  p ai n i n  distr ess i n 
p arti ci p a nts  y o u n g er t h a n  1 8  y e ars  of  a g e  ar e i n cl u d e d i n  A p p e n di x  1 1. 7 .    
U p o n  pr o vi di n g i nf or m e d  c o ns e nt,  p ati e nts  will  e nt er t h e  S cr e e ni n g  P eri o d.  D uri n g t h e  S cr e e ni n g 
P eri o d,  p ati e nts  will  b e  ass ess e d f or  eli gi bilit y  a n d i nstr u ct e d t o  c o m pl et e  a  h u n g er  q u esti o n n air e 
( A p p e n di x 1 1. 5 ) d ail y  t o  e n h a n c e t h e  u n d erst a n di n g  of  h u n g er ass o ci at e d  wit h  B B S  a n d  A S , 
pri or t o tr e at m e nt  wit h  st u d y  m e di c ati o n. D uri n g  S cr e e ni n g,  a  d et ail e d  m e di c al  hist or y  will  b e 
o bt ai n e d, i n cl u di n g  m e di c al  c h art r e vi e w  ( A p p e n di x 1 1. 3 ), t o c oll e ct i nf or m ati o n  p ert ai ni n g t o 
t h e  n at ur al  hist or y  of B B S  a n d  A S . 
Aft er  t h e  S cr e e ni n g  P eri o d i n  w hi c h  c o nfir m ati o n  of p ati e nt  eli gi bilit y  a n d  a bilit y f or  p ati e nts   or 
t h eir  c ar et a k ers t o s u c c essf ull y s elf-a d mi nist er  st u d y  dr u g is  d et er mi n e d ( or if  arr a n g e m e nts f or  a 
visiti n g  h o m e  h e alt h  c ar e  pr a ctiti o n er  ar e  n e c ess ar y) ,  p ati e nts will  b e r a n d o mi z e d t o r e c ei v e 
eit h er s et m el a n oti d e  or  pl a c e b o  a n d  will  e nt er  t h e  1 4- w e e k  d o u bl e- bli n d tr e at m e nt p eri o d 
( P eri o d 1) .  F oll o wi n g  c o m pl eti o n  of t h e  d o u bl e-bli n d tr e at m e nt  p eri o d,  all  p ati e nts  will r e c ei v e 
s et m el a n oti d e i n a  3 8- w e e k  o p e n- l a b el tr e at m e nt p eri o d  ( P eri o d 2) f o ll o w e d  b y  a  1 4- w e e k  o p e n-
l a b el tr e at m e nt  p eri o d ( P eri o d  3). 
A n y  p ati e nt  wit h dr a wi n g fr o m t h e st u d y  will  c o m pl et e t h e  E arl y  T er mi n ati o n  Visit, if  p ossi bl e, 
a n d  will  b e  e n c o ur a g e d t o  c o m pl et e  all r e m ai ni n g st u d y  visits.  F or t h os e  p ati e nts  n ot  willi n g t o 
c o m p l et e st u d y  visits  at t h e  cli ni c, h o m e  h e alt h  c ar e  pr a ctiti o n er  visits  or  t el e p h o n e f oll o w- u p 
m a y  b e  a c c e pt a bl e  t o  o bt ai n mi ni m u m  p ati e nt s elf -r e p ort e d  d at a (i e,  w ei g ht, A E s,  et c.).   
D et ail e d  d es cri pti o ns  of t h e 
 pr o c e d ur es t o  b e  c o n d u ct e d  d uri n g t his st u d y  ar e 
pr o vi d e d i n t h e f oll o wi n g s e cti o ns.   
P ati e nts  will  b e r e q uir e d t o f ast  o v er ni g ht  o n t h e  d a y  pr e c e di n g  all sit e  visits,  b e gi n ni n g  wit h t h e 
i niti al  S cr e e ni n g  Visit.  P ati e nts  will  b e  all o w e d t o t a k e t h eir  us u al  m e di c ati o ns  wit h  a si p  of 
w at er  o n t h e  m or ni n g  of  e a c h  cli ni c  visit.  
T h e  S cr e e ni n g  P eri o d  c a n  o c c ur  wit hi n  ~ 3  w e e ks  of  D a y   1,  a n d s h o ul d  b e s c h e d ul e d  wit hi n t his 
ti m efr a m e t o  all o w t est r es ults t o  b e r e c ei v e d  a n d  c o nti n u e d  eli gi bilit y  of  p ati e nts  c o nfir m e d  pri or 
t o t h e first  d os e  o n D a y   1. Ass ess m e nts  m a y  o c c ur  o v er  m ulti pl e  d a ys  d uri n g t h e  S cr e e ni n g 
P eri o d.  T o   o bt ai n s uffi ci e nt  b as eli n e  d at a  o n s y m pt o ms  of  h u n g er ( c oll e ct e d  d ail y), t h e s cr e e ni n g 
p eri o d s h o ul d  b e  a  mi ni m u m  of  2  w e e ks.    
T o   pr o vi d e fl e xi bilit y t o t h e  p ati e nt  a n d st u d y st aff, t h e  a ct u al s c h e d uli n g  of  cli ni c  visits  c a n 
o c c ur  wit hi n  a fl e xi bl e  wi n d o w  of ti m e (i d e all y  ± 3  d a ys).  H o w e v er,  as  t hes e   p ati e nt  p o p ul ati o ns 
ar e  ultr a -r ar e, all  d at a  c oll e ct e d ,  e v e n if  o utsi d e  of  visit  wi n d o ws,  will  b e i n cl u d e d i n  all  a n al ys es 
of  e n d p oi nts.  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
P a g e  4 5 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
A d diti o n all y, if t h e  p ati e nt r esi d es  a  c o nsi d er a bl e  dist a n c e fr o m t h e I n v esti g ati v e  Sit e, 
arr a n g e m e nts  m a y  b e  m a d e f or  a  h o m e  h e alt h  pr a ctiti o n er t o  c o n d u ct  a  visit  at  t h e  p ati e nt’s  h o m e 
or f or t h e  p ati e nt t o  b e s e e n  at t h eir  l o c al  p h ysi ci a n’s  offi c e, t o  o bt ain t h e  a p pli c a bl e 
d at a/s a m pl es.  T h es e  arr a n g e m e nts  m ust  b e  a p pr o v e d  b y t h e  S p o ns or i n  a d v a n c e, t o  b e s ur e t h at 
i m p ort a nt  d at a/s a m pl es  c a n b e  pr o p erl y  c oll e ct e d,  a n d  a n y s af et y  pr o c e d ur es r o b ustl y 
i m pl e m e nt e d.   
H o w e v er,  p ati e nts  m ust  b e s e e n  at t h e I n v esti g ati v e  Sit e  at  a n  a bs ol ut e  mi ni m u m  at l e ast  o n c e  f or 
S cr e e ni n g,  a n d f or  visits f or  W e e ks  1,  3,  1 5,  1 7,  2 9,  4 1,  5 3,  a n d  6 6  or  E arl y  T er mi n a ti o n visit .   


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  4 6 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
T a bl e   2  
S c h e d ul e  of  Ass ess m e nts:   S c r e e ni n g t h r o u g h  W e e k   5 3 Visit  ( E n d  of  P e ri o d  2) 
 
S cr e e ni n g  
Vi sit  
D o u bl e -Bli n d  Tr e at m e nt 
(P eri o d  1)  
3 8 -W e e k  O p e n -L a b el  Tr e at m e nt   
(P eri o d  2)  
 
S E T  or  P B O 
E s c al ati o n  
S E T  or  P B O   
S E T  E s c al ati o n  
S E T 
Vi sit ( V)  N u m b er  
V 1   
V 2   
  
V 3   
V 4   
V 5   
V 6   
  
V 7   
V 8   
V 9   
V 1 0   
V 1 1   
V 1 2   
V 1 3  
St u d y  W e e k  
-3   
1   
2   
3   
7   
1 1   
1 5   
1 5   
1 7   
2 3   
2 9   
3 5   
4 1   
4 7   
5 3  
St u d y  D a y  
( n/ a)  
1   
8   
1 5   
4 3   
7 1   
9 9   
1 0 6   
1 1 3   
1 5 5   
1 9 7   
2 3 9   
2 8 1   
3 2 3   
3 6 5  
I nf or m e d  c o n s e nt/a s s e nt  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
I n cl u si o n/e x cl u si o n r e vi e w  
X   
X   
  
  
  
  
  
  
  
  
  
  
  
  
 
M e di c al  hi st or y r e vi e w  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
G e n eti c  te sti n g 1  
X   
  
  
  
  
  
  
  
  
  
  
  
  
  
 
Ar c hi v e  s a m pl e f or  st or a g e 2  
  
X   
  
  
  
  
X †   
  
  
  
  
  
  
  
X †  
C o m pr e h e n si v e  s ki n  e x a m 3  
X   
X   
  
  
  
  
  
  
  
  
  
  
  
  
 
Fit z p atri c k  s c al e  
X   
X   
  
  
  
  
  
  
  
  
  
  
  
  
 
Pr e g n a n c y  t e st4  
X   
X †   
  
X †   
X †   
X †   
X †   
  
X †   
X †   
X †   
X †   
X †   
X †   
X †  
St u d y  dr u g  a d mi ni str ati o n/ di s p e n s e 5  
  
X   
  
X   
X   
X   
X   
  
X   
X   
X   
X   
X   
X   
X  
D ail y  h u n g er  q u e sti o n n air e 8  
X  
D ail y †  
Gl o b al  h u n g er  a s s e s s m e nt 9  
X   
  
  
X †   
  
  
X †   
  
X †   
  
X †   
  
  
  
X †  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  4 7 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
 
S cr e e ni n g  
Vi sit  
D o u bl e -Bli n d  Tr e at m e nt 
(P eri o d  1)  
3 8 -W e e k  O p e n -L a b el  Tr e at m e nt   
(P eri o d  2)  
 
S E T  or  P B O 
E s c al ati o n  
S E T  or  P B O   
S E T  E s c al ati o n  
S E T 
Vi sit ( V)  N u m b er  
V 1   
V 2   
  
V 3   
V 4   
V 5   
V 6   
  
V 7   
V 8   
V 9   
V 1 0   
V 1 1   
V 1 2   
V 1 3  
St u d y  W e e k  
-3   
1   
2   
3   
7   
1 1   
1 5   
1 5   
1 7   
2 3   
2 9   
3 5   
4 1   
4 7   
5 3  
St u d y  D a y  
( n/ a)  
1   
8   
1 5   
4 3   
7 1   
9 9   
1 0 6   
1 1 3   
1 5 5   
1 9 7   
2 3 9   
2 8 1   
3 2 3   
3 6 5  
I nj e cti o n  sit e i n s p e cti o n2 1  
  
X   
  
X   
X   
X   
X   
  
X   
X   
X   
X   
X   
X   
X  
C o n c o mit a nt  m e d i c ati o n s r e vi e w 
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
N utriti o n al  c o u n s elli n g  a n d  m o nit ori n g   
X   
X   
  
X   
X   
X   
X   
  
X   
X   
X   
X   
X   
X   
X  
†  Ass ess m e nt/s a m pl e s h o ul d  b e  p erf or m e d/ o bt ai n e d  pri or t o  a d mi nistr ati o n  of st u d y  dr u g.  
1   A  bl o o d s a m pl e  will  b e  o bt ai n e d  at  S cr e e ni n g t o  c o nfir m  a  g e n eti c  di a g n osis  of  A S  or  B B S . H o w e v er,  p ati e nts  m a y  b e  e nt er e d i nt o t h e st u d y  b as e d  o n  cli ni c al  di a g n osis  of 
B B S ( ≤ 1 0 %  of  B B S  p ati e nts)  or  pri or  g e n eti c  di a g n osis  of  B B S ( ≥ 9 0 %  of  B B S  p ati e nts)  or  A S ( 1 0 0 %  of  A S  p ati e nts) (r ef er t o  S e cti o n  4. 2 ).  This s a m pl e  m a y  als o  b e  us e d  f or 
g e n ot y pi n g  ot h er  o b esit y -r el at e d  g e n es. T h e  D N A  will  n ot  b e st u di e d  or  “t y p e d ” f or  a n y  ot h er  p ur p os e,  u nl ess  p ati e nts  ar e r e - c o ns e nt e d. 
2  E xtr a r et ai n s a m pl es  will  c o nsist  of  2 s er u m  a n d  2  pl as m a ( K 2 E D T A)  v a c ut ai n er t u b es  a n d t w o  5 ml  uri n e t u b es . 
3  A  c o m pr e h e nsi v e s ki n  e v al u ati o n  will  b e  p erf or m e d  b y  a  d er m at ol o gist.   A n y  c o n c er ni n g l esi o ns i d e ntifi e d  d uri n g t h e s cr e e ni n g  p eri o d  will  b e  bi o psi e d  a n d r es ults  k n o w n t o 
b e  b e ni g n  pri or t o first  d os e  of s et m el a n oti d e.  If t h e  pr e -tr e at m e nt  bi o ps y r es ults  ar e  of  c o n c er n, t h e  p ati e nt  will  b e  e x cl u d e d fr o m t h e st u d y.   
4  A  uri n e  pr e g n a n c y t est  m a y  b e  p erf or m e d i n  or d er t o  e x p e dit e  a v ail a bilit y  of r es ults  pri or t o  d osi n g  o n  D a y  1.  All  ot h er  pr e g n a n c y t ests  will  b e s er u m;  d osi n g  m a y  c o nti n u e 
wit h r es ults  p e n di n g. 
5  P ati e nts/ c ar et a k ers  will  dr a w  u p  a n d s elf -a d mi nist er/ a d mi nist er t h e  dr u g  o n c e  d ail y i n t h e  m or ni n g  b e gi n ni n g t h e  m or ni n g  of  D a y  1  a n d f or t h e  d ur ati o n  of  d osi n g .  O n  d a ys 
wit h  cli ni c  visits, t h e  p ati e nts/ c ar et a k ers  will  a d mi nist er t h e  dr u g i n t h e  cli ni c i n t h e  pr es e n c e  of t h e  cli ni c al st aff t o  ass ur e  pr o p er t e c h ni q u e.  P ati e nts/ c ar et a k ers  will r et ur n  all 
us e d  vi als t o t h e  cli ni c  w h e n t h e y  visit (t h e  n u m b er r e c or d e d)  a n d  b ot h  cli ni c  a d mi nist er e d st u d y  dr u g,  as  w ell  as  o ut p ati e nt  st u d y  dr u g  a d mi nistr ati o n  will  b e r e c or d e d i n  a 
st u d y  di ar y. 
8  D ail y  h u n g er  q u esti o n n air e s c or es  will  b e r e c or d e d  o n  a  d ail y  b asis,  pri or t o t h e  p ati e nt’s  m or ni n g  m e al.  If t h e  p ati e nt is  u n a bl e t o  ass ess t h eir o w n  h u n g er  d u e t o i m p air e d 
c o g niti v e f u n cti o n,  a  p ar e nt/ c ar e gi v er  ass ess m e nt  of  h y p er p h a gi a  will  b e  c o m pl et e d i nst e a d (s e e  A p p e n di x  1 1. 5. 2 ). 
9    Gl o b al  h u n g er  q u esti o ns ( A p p e n di x  1 1. 5 )  will  b e  a d mi nist er e d i n  cli ni c  as f oll o ws:  Q u esti o n  1  will  b e  as k e d  at S cr e e ni n g,  a n d  Q u esti o ns  1  a n d  2  will t h e n  b e  as k e d  as 
s p e cifi e d i n t h e  S O A  o n c e  d osi n g  h as  b e e n i niti at e d  ( D a y  1). 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  4 8 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
2 1  I nj e cti o n sit e  e v al u ati o ns  a n d s c ori n g ( b y t h e  cli ni c al st aff)  will i n cl u d e i d e ntifi c ati o n  a n d  m e as ur e m e nt  of  ar e as  of  er yt h e m a,  e d e m a, a n d i n d ur ati o n,  as  w ell  as t h e  pr es e n c e  of 
l o c ali z e d p ai n, t e n d er n ess,  a n d it c hi n g.  A d diti o n al  e v al u ati o n  d at a  c a n  b e  c oll e ct e d  at  a n y  visit  w h er e t h er e  ar e i nj e cti o n sit e r e a cti o ns  e v e n if  n ot  a ti m e p oi nt f or f or m al 
ass ess m e nt.  




Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  5 0 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
†  Ass ess m e nt/s a m pl e s h o ul d  b e  p erf or m e d/ o bt ai n e d  pri or t o  a d mi nistr ati o n  of st u d y  dr u g.  
1  E xtr a r et ai n s a m pl es  will  c o nsist  of  2 s er u m  a n d  2  pl as m a ( K 2 E D T A)  v a c ut ai n er t u b es  a n d t w o  5 ml  uri n e t u b es . 
2  A  c o m pr e h e nsi v e s ki n  e v al u ati o n  will  b e  p erf or m e d  b y  a  d er m at ol o gist.    
3  All  pr e g n a n c y t ests  will  b e s er u m;  d osi n g  m a y  c o nti n u e  wit h r es ults  p e n di n g.  
4  P ati e nts/ c ar et a k ers  will  dr a w  u p  a n d s elf -a d mi nist er/ a d mi nist er t h e  dr u g  o n c e  d ail y i n t h e  m or ni n g . O n  d a y s  wit h  cli ni c  visits, t h e  p ati e nts/ c ar et a k ers  will  a d mi nist er t h e  dr u g 
i n t h e  cli ni c i n t h e  pr es e n c e  of t h e  cli ni c al st aff t o  ass ur e  pr o p er t e c h ni q u e.  P ati e nts/ c ar et a k ers  will r et ur n  all  us e d  vi als t o t h e  cli ni c  w h e n t h e y  visit (t h e  n u m b er r e c or d e d)  a n d 
b ot h  cli ni c  a d mi nist er e d st u d y  dr u g,  as  w ell  as  o ut p ati e nt st u d y  dr u g  a d mi nistr ati o n  will  b e r e c or d e d i n  a st u d y  di ar y.  
7  D ail y  h u n g er  q u esti o n n air e s c or es  will  b e r e c or d e d  o n  a  d ail y  b asis,  pri or t o t h e  p ati e nt’s  m or ni n g  m e al.  If t h e  p ati e nt is  u n a bl e t o  ass ess t h eir  o w n  h u n g er  d u e t o im p air e d 
c o g niti v e f u n cti o n,  a  p ar e nt/ c ar e gi v er  ass ess m e nt  of  h y p er p h a gi a  will  b e  c o m pl et e d i nst e a d (s e e  A p p e n di x  1 1. 5. 2 ). 
8    Gl o b al  h u n g er  Q u esti o ns  1  a n d  2 ( A p p e n di x  1 1. 5 )  will  b e  as k e d. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  5 1 
 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  5 2 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
6. 2.   
P ati e nt  R e q ui r e m e nts  
  
C o nt r a c e pti o n 
S et m el a n oti d e  h as  n ot  b e e n  c o m pl et el y  e v al u at e d i n  n o n cli ni c al  D e v el o p m e nt al  a n d 
R e pr o d u cti v e  T o xi c ol o g y  St u di es t o  d at e ; t h er ef or e, t h e  eff e cts  of s et m el a n oti d e  o n  e m br y o-f et al 
d e v el o p m e nt  ar e  u n k n o w n  at t his ti m e.  It is i m p er ati v e  all st u d y p ati e nt s  a d h er e t o t h e 
c o ntr a c e pti o n r e q uir e m e nts  as  o utli n e d  b el o w.   
F e m al es  m ust  n ot  b e  pr e g n a nt  a n d  m us t  h a v e  a  n e g ati v e s er u m  pr e g n a n c y t est r es ult  at t h e 
S cr e e ni n g  Visit  a n d  n e g ati v e  uri n e  pr e g n a n c y t est  o n  D a y   1, wit h r es ults  k n o w n  pri or t o i niti ati n g 
d osi n g;  pr e g n a n c y t esti n g  will  b e  m o nit or e d  d uri n g t h e st u d y. 
F or f e m al e  p ati e nts  w h o  ar e  a bl e t o  b e ar  c hil dr e n,  a   hi g hl y r eli a bl e f or m  of  c o ntr a c e pti o n  m ust  b e 
us e d/ pr a cti c e d t hr o u g h o ut t h e st u d y  a n d f or  9 0 f oll o wi n g t h e st u d y.  Hi g hl y r eli a bl e  a c c e pt a bl e 
f or  of  c o ntr a c e pti o n i n cl u d e:  h or m o n al (i e,  or al, i m pl a nt a bl e,  or i nj e ct a bl e)  a n d si n gl e-b arri er 
m et h o d  (i e,  c o n d o m),  or  a n I ntr a ut eri n e  D e vi c e (I U D)  a n d si n gl e-b arri e r  m et h o d (i e,  c o n d o m)  or 
v as e ct o mi z e d  p art n er.  Tr u e  a bsti n e n c e is  a c c e pt a bl e  o nl y if it is t h e  pr ef err e d  a n d  us u al lif est yl e 
of t h e  p ati e nt. 
F e m al es  of  n o n- c hil d b e ari n g  p ot e nti al,  d efi n e d  as s ur gi c all y st eril e (st at us  p ost  h yst er e ct o m y, 
bil at er al  o o p h or e ct o m y,  or  bil at er al t u b al li g ati o n)  p ost- m e n o p a us al f or  at l e ast  1 2  m o nt hs ( a n d 
c o nfir m e d  wit h  a s cr e e ni n g  F S H l e v el i n t h e  p ost- m e n o p a us al r a n g e),  or f ail ur e t o  h a v e 
pr o gr ess e d t o  T a n n er  St a g e  V  a n d/ or f ail ur e t o  h a v e  a c hi e v e d  m e n ar c h e,  d o  n ot r e q uir e 
c o ntr a c e pti o n  d uri n g t h e st u d y.  Y o u n g er f e m al e  p ati e nt s  w h o  ar e  n ot s e x u all y  m at ur e  will  b e 
ass ess e d f or  T a n n er st a gi n g  a n d  a d vis e d   a c c or di n gl y.  
It is  n ot  k n o w n if t his tr e at m e nt  will  aff e ct s p er m at o g e n esis. T h er ef or e,  m al es  wit h f e m al e 
p art n ers  of  c hil d b e ari n g  p ot e nti al  m ust  a gr e e t o  us e  c o ntr a c e pti o n ( e g , if t h e y  h a v e  n ot  h a d  a 
v as e ct o m y t h e n s h o ul d  eit h er ( a)  a bst ai n fr o m r e pr o d u cti v e s e x u al i nt er c o urs e  or ( b)  us e  a  d o u bl e 
b arri er  m et h o d (i e,  c o n d o m  a n d  di a p hr a g m  a n d s p er mi ci d e ) if t h e y  b e c o m e s e x u all y  a cti v e 
d uri n g t h e st u d y  a n d f or  9 0  d a ys f oll o wi n g t h e st u d y.  M al e  p ati e nt s  m ust  n ot  d o n at e s p er m f or 
9 0  d a ys f oll o wi n g t h eir  p arti ci p ati o n i n t h e st u d y. 
  
P r ot e cti o n f r o m  S u n  
S ki n  h y p er pi g m e nt ati o n,  or t a n ni n g,  w as  o bs er v e d i n t h e  c y n o m ol g us  m o n k e y t o xi c ol o g y st u di es 
a n d t h e  h u m a n  P h as e  1/ 2 st u di es.  T h es e  e v e nts  w er e r e v ersi bl e   u p o n  c ess ati o n  of st u d y  dr u g. 
H o w e v er, it is still  u n c ert ai n if  e x p os ur e t o s u nli g ht  mi g ht  e x a c er b at e t h e t a n ni n g  eff e cts  of 
s et m el a n oti d e. 
It is  als o i m p ort a nt t h at  p ati e nts  d o  n ot  p arti ci p at e i n  a n y  a cti viti es t h at  will i nt e nti o nall y  c a us e 
t h eir s ki n t o t a n ( e g, visit  ultr a vi ol et ( U V ) t a n ni n g s al o ns,  us e s pr a y t a nn ers, s elf -t a n ni n g l oti o ns). 
6. 3.   
I nf o r m e d  C o ns e nt/ Ass e nt  a n d  S c r e e ni n g  
  
I nf o r m e d  C o ns e nt/ Ass e nt  
A  c o m pl et e  d es cri pti o n  of t h e st u d y is t o  b e  pr es e nt e d t o  e a c h  p ot e nti al  p ati e nt  a n d si g n e d  a n d 
d at e d i nf or m e d  c o ns e nt  a n d/ or  ass e nt is t o  b e  o bt ai n e d  b ef or e  a n y st u d y s p e cifi c  pr o c e d ur es  ar e 
p erf or m e d.   


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
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R h yt h m  P h ar m a c e uti c als, I n c. 
  
S c r e e ni n g  
Pri or t o  e nt eri n g t h e  d o u bl e - bli n d tr e at m e nt  p eri o d,  u p o n  pr o vi di n g i nf or m e d  c o ns e nt,  p ati e nts 
will  e nt er t h e  S cr e e ni n g  P eri o d.  D uri n g t h e  S cr e e ni n g  P eri o d,  p ati e nts  will  b e  ass ess e d f or 
eli gi bilit y  a n d i nstr u ct e d t o  c o m pl et e  a  h u n g er  q u esti o n n air e  d ail y t o  e n h a n c e t h e  u n d erst a n di n g 
of  h u n g er s y m pt o ms  ass o ci at e d  wit h  B B S  a n d  A S ,  pri or t o tr e at m e nt  wit h st u d y  dr u g.  As b ot h 
dis or d ers  ar e  ultr a -r ar e,  o bt ai ni n g  d ail y  h u n g er s c or es  as  w ell  as  a  v er y  d et ail e d  m e di c al  hist or y 
( m e di c al r e c or d r e vi e w)  d uri n g  S cr e e ni n g,  will  all o w f or t h e  c oll e cti o n  of i m p ort a nt  p ati e nt 
s p e cifi c  d at a (s e e  A p p e n di x  1 1. 3 ;  e g,  gr o wt h  a n d  w ei g ht  c ur v es,  ot h er  ass o ci at e d  h or m o n al  or 
m et a b oli c  a b n or m aliti es,  p e di atri c  d e v el o p m e nt al  mil est o n es  or  dist ur b a n c es,  a n d  p ossi bl e 
ort h o p e di c  or r es pir at or y  c o m pli c ati o ns  d u e t o  w ei g ht  g ai n) t h at  will  all o w f or  a  b ett er 
u n d erst a n di n g  of t h es e  r ar e f or ms  of  o b esit y.   
6. 3. 2. 1.   
G e n eti c  T esti n g  
A  bl o o d s a m pl e  will  b e  o bt ai n e d  at  S cr e e ni n g  f or g e n eti c  c o nfir m ati o n  of  B B S  or  A S .  H o w e v er, 
p ati e nts  m a y  b e  e nt er e d i nt o t h e st u d y  b as e d  o n  cli ni c al  di a g n osis  of  B B S  aft er r e vi e w  wit h t h e 
S p o ns or’s  m e di c al  m o nit or ( ≤ 1 0 %  of  B B S  p ati e nts)  or  pri or  g e n eti c  di a g n osis  of  B B S ( ≥ 9 0 %  of 
B B S  p ati e nts)  or  A S ( 1 0 0 %  of  A S  p ati e nts)  (r ef er t o  S e cti o n 4. 2 ). T his s a m pl e  m a y  als o  b e  us e d 
f or  g e n ot y pi n g  ot h er  o b esit y-r el at e d  g e n es.  A n y r e m ai ni n g s a m pl e  will  b e st or e d f or  p ossi bl e 
f ut ur e t esti n g of  o b esit y-r el at e d  g e n es  t h at  c o ul d i m p a ct  effi c a c y r es p o ns es.  T h e  D N A will   n ot  b e 
st u di e d  or  “t y p e d ” f or  a n y  ot h er  p ur p os e,  u nl ess  p ati e nts  ar e r e- c o ns e nt e d.  S a m pl es  will  b e 
l a b el e d  wit h t h e  p ati e nt i d e ntifi c ati o n  n u m b er  a n d i niti als.   
6. 3. 2. 2.   
D e m o g r a p hi cs  a n d  M e di c al  Hist o r y  
A  c o m pl et e  m e di c al  hist or y  al o n g  wit h  d e m o gr a p hi c  d at a  will  b e  o bt ai n e d f or  all  p ati e nts  d uri n g 
t h e  S cr e e ni n g  P eri o d.  D at a t o  b e r e c or d e d i n t h e s o ur c e  d o c u m e nt  a n d e C R F  i n cl u d e t h e  p ati e nt’s 
g e n d er, r a c e,  d at e  of  birt h  a n d  c o n c o mit a nt  m e di c ati o n  us e.  A d diti o n all y,  a  d et ail e d r e vi e w  of t h e 
p a ti e nt’s  m e di c al r e c or ds  will  b e  p erf or m e d t o  c oll e ct i m p ort a nt r etr os p e cti v e  d at a t o  b ett er 
u n d erst a n d t h e  n at ur al  hist or y  of  B B S  a n d  A S   p er  A p p e n di x 1 1. 3 . 
A r e c e nt  m e di c al  hist or y  will  b e  o bt ai n e d  o n  D a y   1  pri or t o first  d os e  of  dr u g t o  ass ess  c o nti n u e d 
st u d y  eli gi bilit y  a n d  a d h er e n c e t o fi n al i n cl usi o n/ e x cl usi o n  crit eri a.  T his r e c e nt  m e di c al  hist or y 
i n cl u d es  a r e vi e w f or  c h a n g es fr o m s cr e e ni n g  as w ell  as  a r e vi e w  of t h e  p ati e nt’s r e c e nt 
m e di c ati o n  us e  a n d t o  ass ess  w h et h er  a n y  c h a n g es  h a v e  o c c urr e d si n c e t h e  pr e vi o us  visit.  
6. 4.   
Effi c a c y  M e as u r e m e nts  
  
W ei g ht 
W ei g ht ( k g)  will  b e r e c or d e d  as s h o w n i n  t h e  S O A i n T a bl e   2  a n d T a bl e   3. All  m e as ur e m e nts 
will  b e  d o n e i n  tri pli c at e at  e a c h ti m e p oi nt.  W h e n e v er  p ossi bl e, t h e s a m e s c al e s h o ul d  b e  us e d 
t hr o u g h o ut t h e st u d y, i n cl u di n g t h e  S cr e e ni n g  Visit,  a n d s h o ul d  b e c ali br at e d  o n  a r e g ul ar  b asis. 
W ei g ht s h o ul d  b e  m e as ur e d  at  a p pr o xi m at el y t h e s a m e ti m e  at  e a c h  visit  a n d  aft er f asti n g f or  at 
l e ast  8  h o urs. P at i e nts s h o ul d  b e i n li g ht  cl ot hi n g  or  u n d er w e ar,  wit h  n o s h o es  a n d  h a v e  e m pti e d 
t h eir  bl a d d er.    






















Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
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R h yt h m  P h ar m a c e uti c als, I n c. 


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R h yt h m  P h ar m a c e uti c als, I n c. 


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R h yt h m  P h ar m a c e uti c als, I n c. 


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R h yt h m  P h ar m a c e uti c als, I n c. 




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R h yt h m  P h ar m a c e uti c als, I n c. 
8. 2.   
A n al ysis  P o p ul ati o ns  
T h e f oll o wi n g  a n al ysis  p o p ul ati o ns  will  b e  us e d i n t h e st atisti c al  a n al ys es. 
S c r e e ni n g  A n al ysis  S et:   is  d efi n e d  as  all s u bj e cts  w h o si g n e d t h e i nf or m e d  c o ns e nt f or m. 
S af et y  A n al ysis  S et  ( S A): is  d efi n e d  as  all  p ati e nts  w h o r e c ei v e d  at l e ast  1  d os e  of st u d y  dr u g 
( pl a c e b o  or s et m el a n oti d e).  A n al ys es  p erf or m e d  o n t h e s af et y s et  will  b e  b as e d  o n  p ati e nts 
a c c or di n g t o t h e tr e at m e nt r e c ei v e d.  
F ull  A n al ysis  S et  ( F A S): is  d efi n e d  as  all r a n d o mi z e d  p ati e nts (irr es p e cti v e  of  a g e) w h o 
r e c ei v e d  at l e ast  1  d os e  of st u d y  dr u g ( pl a c e b o  or s et m el a n oti d e)  a n d h a v e  b as eli n e  d at a. 
A n al ys es  p erf or m e d  o n t h e  F A S  will  b e  b as e d  o n s u bj e cts  as r a n d o mi z e d.  
I n  a d diti o n,  a s u bs et  of t h e  FA S  is  d efi n e d  as f oll o ws: 
•   ≥ 1 2  y e a rs  ol d  F ull  A n al ysis  S et  (≥ 1 2   y o F A S) : is  d efi n e d  as  p ati e nts i n t h e F A S  w h o  ar e 
≥ 1 2  y e ars  of  a g e  at  b as eli n e.  
I n  a d diti o n t o  a b o v e, t h e f oll o wi n g 2  a n al ysis s ets  or s u bs ets  m a y  b e  us e d f or 
s u p p orti v e/ e x pl or at or y a n al ys es  (n ot e t h at i n t h e f oll o wi n g  2  e x pl or at or y  a n al ysis s ets, if  a 
p ati e nt’s  h ei g ht  at t h e  pri m ar y  e n d p oi nt ti m e p oi nt , i e,  ~W e e k  5 3  visit,  is  n ot  a v ail a bl e, t h e n t h e 
l ast  a v ail a bl e  m e as ur e m e nt  of  h ei g ht  will  b e  us e d t o  d efi n e t h e  a n al ysis s ets). 
•   St a bl e  H ei g ht  F u ll  A n al ysis  S et: is  d efi n e d  as  p ati e nts i n t h e F A S   w h o  gr o w ≤ 2  c m i n 
h ei g ht fr o m  b as eli n e t o t h e  pri m ar y  e n d p oi nt ti m e p oi nt (i e,  ~ W e e k   5 3 visit f or  p ati e nts 
r a n d o mi z e d t o s et m el a n oti d e  or ~ W e e k   6 6  visit f or  p ati e nts r a n d o mi z e d t o  pl a c e b o)  or t o 
t h e l ast  a v ail a bl e ti m e p oi nt if it  o c c urs  pri or t o t h e  pri m ar y  e n d p oi nt. 
•   A cti v e  G r o wt h  F ull  A n al ysis  S et : is d efi n e d  as  p ati e nts i n t h e  F A S  w h o  gr o w  > 2  c m i n 
h ei g ht fr o m  b as eli n e t o t h e  pri m ar y  e n d p oi nt ti m e p oi nt (i e,  ~ W e e k   5 3 visit f or  p ati e nts 
r a n d o mi z e d t o s et m el a n oti d e  or ~ W e e k   6 6  visit f or  p ati e nts r a n d o mi z e d t o  pl a c e b o) or t o 
t h e l ast  a v ail a bl e ti m e p oi nt if it  o c c urs  pri or t o t h e  pri m ar y  e n d p oi nt. 
P e r - P r ot o c ol S et ( P P) :  all s u bj e cts i n t h e F A S   wit h o ut  a n y  m aj or  pr ot o c ol  vi ol ati o ns 
8. 3.   
D efi niti o n  of  B as eli n e  
B as eli n e f or st atisti c al  a n al ys es  of  d at a fr o m t h e  d o u bl e -bli n d  p eri o d is  d efi n e d  as t h e l ast 
a v ail a bl e  m e as ur e m e nt  pri or t o t h e r a n d o mi z ati o n (i e,  D a y  1), f or  p ati e nts r a n d o mi z e d i nt o  eit h er 
t h e s et m el a n oti d e  or  pl a c e b o  gr o u p. 


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R h yt h m  P h ar m a c e uti c als, I n c. 
B as eli n e f or st atisti c al  a n al ys es  f oll o wi n g  ~5 2  w e e ks s et m el a n oti d e tr e at m e nt is  d efi n e d  as 
f oll o ws:  
•   F or  p ati e nts i niti all y r a n d o mi z e d i nt o t h e s et m el a n oti d e  gr o u p,  b as eli n e is  d efi n e d  as t h e 
l ast  a v ail a bl e  m e as ur e m e nt  pri or t o t h e r a n d o mi z ati o n (i e,  D a y  1) 
•   F or  p ati e nts i niti all y r a n d o mi z e d i nt o t h e  pl a c e b o  gr o u p,  b as eli n e is  d efi n e d  as t h e l ast 
a v ail a bl e  m e as ur e m e nt  pri or t o t h e first  d os e  of  o p e n -l a b el s et m el a n oti d e tr e at m e nt (i e, 
W e e k  1 4  or  pr e- d os e  W e e k   1 5) 
8. 4.   
Ti mi n g  of  A n al ys es  
B y  n at ur e  of t h e st u d y  d esi g n,  a s m all  p er c e nt a g e  of  p ati e nts  w h o  ar e r a n d o mi z e d i nt o t h e 
pl a c e b o  ar m  m a y  h a v e l ess t h a n  ~ 5 2  w e e ks  of  s et m el a n oti d e tr e at m e nt  b y t h e ti mi n g  of t h e 
pri m ar y  a n al ysis ( e n d  of  P eri o d  2) ;  h e n c e,  a li n e ar  m o d el  b as e d  e xtr a p ol ati o n will  b e  us e d t o 
i m p ut e t h eir  m e as ur e m e nts aft er  ~ 5 2  w e e ks s et m el a n oti d e tr e at m e nt f or t h e  pri m ar y  a n al ysis.  I n 
g e n er al,  m issi n g  v al u es u nr el at e d t o st u d y tr e at m e nt ( e g,  d u e t o l ost t o f oll o w - u p or  miss e d  visit) 
will  als o  b e i m p ut e d  wit h t h e li n e ar  m o d el  b as e d  e xtr a p ol ati o n ,  b ut  missi n g  v al u es  d u e t o 
tr e at m e nt-r el at e d r e as o ns ( e g, l a c k  of  effi c a c y  or  A Es)  will  b e i m p ut e d  as tr e at m e nt f ail ur es. A 
d at a s n a ps h ot  will  b e t a k e n f or t h e  pri m ar y  a n al ysis.  
O n c e t h e st u d y is  c o m pl et e (i e, t h e l ast  p ati e nt  h as  c o m pl et e d  his/ h er l ast  visit), t h e  d at a b as e  will 
b e l o c k e d  a n d  a  s u p pl e m e nt al s u p p orti v e  a n al ysis   will  b e  pr o vi d e d.  
N o f or m al i nt eri m  a n al ysis is  c urr e ntl y  pl a n n e d f or t his st u d y. 
8. 5.   
Effi c a c y   A n al ys es 
  
P ri m a r y  Effi c a c y  A n al ysis 
T h e  pri m ar y  effi c a c y  e n d p oi nt is t h e  pr o p orti o n  of  p ati e nts ( ≥ 1 2  y e ars  of  a g e  at  b as eli n e)  w h o 
a c hi e v e  a  ≥ 1 0 % r e d u cti o n fr o m  b as eli n e i n  b o d y  w ei g ht (i e,  ar e ‘r es p o n d ers’)  aft er  ~ 5 2  w e e ks  of 
tr e at m e nt  wit h s et m el a n oti d e.  T h e st atisti c al  h y p ot h esis  f or t h e  pri m ar y  effi c a c y  e n d p oi nt is: 
H 0:  p t ≤   1 0 %       vs        H 1:  pt >  1 0 % 
w h er e   pt is t h e r es p o ns e r at e  aft er ~ 5 2  w e e ks  of s et m el a n oti d e tr e at m e nt (i e,  ~ W e e k  5 3  f or 
p ati e nts r a n d o mi z e d t o s et m el a n oti d e  a n d  ~ W e e k   6 6 f or  p ati e nts r a n d o mi z e d t o  pl a c e b o). 
T h e s u b gr o u p  of  p ati e nts  ≥ 1 2  y e ars  of  a g e  w as s el e ct e d f or t h e  pri m ar y  a n al ysis  b e c a us e t his is 
t h e  gr o u p  of  p ati e nts f or  w h o m t h e i nt er pr et ati o n  of  w ei g ht l oss is  m ost str ai g htf or w ar d.  N or m al 
w ei g ht  g ai n t h at  a c c o m p a ni es i n cr e as es i n  p ati e nt  h ei g ht  d uri n g  c hil d h o o d  gr o wt h  a n d 
d e v el o p m e nt  c a n  c o nf o u n d i nt er pr et ati o n  of t h e  effi c a c y  of  w ei g ht l oss  dr u gs ( K ell y   2 0 1 6). 
T h e st atisti c al  h y p ot h esis  will  b e t est e d   usi n g a n  e x a ct  bi n o mi al t est , at  a  1-si d e d  0. 0 5 
si g nifi c a n c e l e v el . T h e  1 -si d e d  0. 0 5 si g nifi c a nt l e v el  w as  c h os e n  b as e d  o n t h e s m all s a m pl e si z e 
d u e t o t h e  r arit y  of t h e  dis e as e. A  2-si d e d  9 0 %  c o nfi d e n c e i nt er v al ( CI)  will  b e  c al c ul at e d  usi n g 
t h e  e x a ct  Cl o p p er-P e ars o n  m et h o d.   T h e s u c c ess  crit eri o n f or t h e  pri m ar y  h y p ot h esis r e q uir es t h e 
r ej e cti o n  of t h e  n ull  h y p ot h esis at  t h e  1-si d e d  0. 0 5 si g nifi c a n c e l e v el.  T h e st atisti c al  crit eri o n 








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R h yt h m  P h ar m a c e uti c als, I n c. 
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 ni c al  P r a cti c e  
T h e st u d y  will  b e  c o n d u ct e d i n  a c c or d a n c e  wit h t h e I C H f or  G o o d  Cli ni c al  Pr a cti c e ( G C P)  a n d 
t h e  a p pr o pri at e r e g ul at or y r e q uir e m e nt(s). T h e I n v esti g at o r  will  b e t h or o u g hl y f a mili ar  wit h t h e 
a p pr o pri at e  us e  of t h e st u d y  dr u g  as  d es cri b e d i n t h e  pr ot o c ol  a n d  I B. Ess e nti al  cli ni c al 
d o c u m e nts  will  b e  m ai nt ai n e d t o  d e m o nstr at e t h e  v ali dit y  of t h e st u d y  a n d t h e i nt e grit y  of t h e 
d at a  c oll e ct e d.  M ast er fil es s h o ul d  b e  est a blis h e d  at t h e  b e gi n ni n g  of t h e st u d y,  m ai nt ai n e d f or 
t h e  d ur ati o n  of t h e st u d y  a n d r et ai n e d  a c c or di n g t o t h e  a p pr o pri at e r e g ul ati o ns. 
9. 2.   
Et hi c al  C o nsi d e r ati o ns  
T h e st u d y  will  b e  c o n d u ct e d i n  a c c or d a n c e  wit h  et hi c al  pri n ci pl es f o u n d e d i n t h e  D e cl ar ati o n  of 
H elsi n ki (s e e  A p p e n di x  1 1. 8 ). T h e I R B /I E C  will r e vi e w  all  a p pr o pri at e st u d y  d o c u m e nt ati o n i n 
or d er t o s af e g u ar d t h e ri g hts, s af et y,  a n d  w ell- b ei n g  of t h e  p ati e nts.  T h e st u d y  will  o nl y  b e 
c o n d u ct e d  at sit es  w h er e I R B /I E C  a p pr o v al  h as  b e e n  o bt ai n e d. T h e  pr ot o c ol,  I B, i nf or m e d 
c o ns e nt,  a d v ertis e m e nts (if  a p pli c a bl e),  writt e n i nf or m ati o n  gi v e n t o t h e  p ati e nts (i n cl u di n g  di ar y 
c ar ds), s af et y  u p d at es,  a n n u al  pr o gr ess r e p orts,  a n d  a n y r e visi o ns t o t h es e  d o c u m e nts  will  b e 
pr o vi d e d t o t h e I R B /I E C  b y t h e I n v esti g at or. 
9. 3.   
P ati e nt I nf o r m ati o n  a n d I nf o r m e d  C o ns e nt  
Aft er t h e st u d y  h as  b e e n f ull y  e x pl ai n e d,  writt e n i nf or m e d  c o ns e nt  will  b e  o bt ai n e d fr o m  eit h er 
t h e  p ati e nt  or  his/ h er  g u ar di a n  or l e g al r e pr es e nt ati v e  pri or t o st u d y  p arti ci p ati o n. T h e  m et h o d  of 
o bt ai ni n g  a n d  d o c u m e nti n g t h e i nf or m e d  c o ns e nt  a n d t h e  c o nt e nts  of t h e  c o ns e nt  will  c o m pl y 
wit h I C H -G C P  a n d  all  a p pli c a bl e r e g ul at or y r e q uir e m e nt(s).  
9. 4.   
P ati e nt  C o nfi d e nti alit y  
I n  or d er t o  m ai nt ai n  p ati e nt  pri v a c y,  all s o ur c e  d o c u m e nts/e C R F s, st u d y  dr u g  a c c o u nt a bilit y 
r e c or ds, st u d y r e p orts  a n d  c o m m u ni c ati o ns  will i d e ntif y t h e  p ati e nt  b y i niti als  a n d t h e  assi g n e d 
p ati e nt  n u m b er.  T h e  I n v esti g at or  will  gr a nt  m o nitor(s)  a n d  a u dit or(s) fr o m  t h e  S p o ns or or its 
d esi g n e e  a n d r e g ul at or y  a ut h orit y(i es)  a c c ess t o t h e  p ati e nt’s  ori gi n al  m e di c al r e c or ds f or 
v erifi c ati o n  of  d at a  g at h er e d  o n t h e s o ur c e  d o c u m e nts/ e C R F s  a n d t o  a u dit t h e  d at a  c oll e cti o n 
pr o c ess.  T h e  p ati e nt’s  c o nfi d e nti alit y  will  b e  m ai nt ai n e d  a n d  will  n ot  b e  m a d e  p u bli cl y  a v ail a bl e 
t o t h e  e xt e nt  p er mitt e d  b y t h e  a p pli c a bl e l a ws  a n d r e g ul ati o ns. 
9. 5.   
P r ot o c ol  C o m pli a n c e  
T h e  I n v esti g at or  will  c o n d u ct t h e st u d y i n  c o m pli a n c e  wit h t h e  pr ot o c ol  pr o vi d e d  b y t h e  S p o ns or, 
a n d  gi v e n  a p pr o v al/f a v or a bl e  o pi ni o n  b y t h e I R B /I E C a n d t h e  a p pr o pri at e r e g ul at or y 
a ut h orit y(i es).  M o difi c ati o ns t o t h e  pr ot o c ol s h o ul d  n ot  b e  m a d e  wit h o ut  a gr e e m e nt  of  b ot h t h e 
I n v esti g at or  a n d t h e  S p o ns or. C h a n g es t o t h e  pr ot o c ol  will r e q uir e  writt e n  I R B/I E C 
a p pr o v al/f a v or a bl e  o pi ni o n  pri or t o i m pl e m e nt ati o n,  e x c e pt  w h e n t h e  m o difi c ati o n is  n e e d e d t o 
eli mi n at e  a n i m m e di at e  h a z ar d(s) t o  p ati e nts.  T h e  I R B/I E C  m a y  pr o vi d e, if  a p pli c a bl e r e g ul at or y 
a ut h orit y(i es)  p er mit,  e x p e dit e d r e vi e w  a n d  a p pr o v al/f a v or a bl e  o pi ni o n f or  mi n or  c h a n g e(s) i n 
o n g oi n g st u di es t h at  h a v e t h e  a p pr o v al /f a v or a bl e  o pi ni o n  of t h e  I R B/I E C. T h e  S p o ns or  or 
d esi g n e e  will s u b mit  all  pr ot o c ol  m o difi c ati o ns t o t h e r e g ul at or y  a ut h orit y(i es) i n  a c c or d a n c e 
wit h t h e  g o v er ni n g r e g ul ati o ns.  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
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C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
W h e n i m m e di at e  d e vi ati o n fr o m t h e  pr ot o c ol is r e q uir e d t o  eli mi n at e  a n i m m e di at e  h a z ar d(s) t o 
p ati e nts, t h e  I n v esti g at or will  c o nt a ct  t h e  S p o ns or, if  cir c u mst a n c es  p er mit, t o  dis c uss t h e  pl a n n e d 
c o urs e  of  a cti o n.  A n y  d e p art ur es fr o m t h e  pr ot o c ol  m ust  b e f ull y  d o c u m e nt e d i n t h e s o ur c e 
d o c u m e nts/ e C R F . 
9. 6.   
D at a  M a n a g e m e nt 
  
D at a  H a n dli n g  
D at a  will  b e r e c or d e d  at t h e sit e  o n s o ur c e  d o c u m e nts  a n d r e vi e w e d  b y t h e  Cli ni c al  R es e ar c h 
Ass o ci at e ( C R A)  d uri n g  m o nit ori n g  visits.  T h e  C R A  will  v erif y  d at a r e c or d e d i n t h e  e C R F 
s yst e m wit h s o ur c e  d o c u m e nts.  All  c orr e cti o ns  or  c h a n g es  m a d e t o  a n y st u d y  d at a  m ust  b e 
a p pr o pri at el y tr a c k e d i n  a n  a u dit tr ail i n t h e  e C R F s yst e m.  El e ctr o ni c  C R Fs  will  b e  c o nsi d er e d 
c o m pl et e  w h e n  all  missi n g, i n c orr e ct,  a n d/ or i n c o nsist e nt  d at a  h a v e  b e e n  a c c o u nt e d f or.  
  
C o m p ut e r  S yst e ms  
D at a  will  b e  pr o c ess e d  usi n g  a  v ali d at e d  c o m p ut er s yst e m  c o nf or mi n g t o r e g ul at or y 
r e q uir e m e nts. 
  
D at a  E nt r y  
D at a  m ust  b e r e c or d e d  usi n g t h e  e C R F s yst e m  as t h e st u d y is i n  pr o gr ess.  All st u d y sit e 
p ers o n n el  m ust l o g i nt o t h e s yst e m  usi n g t h eir s e c ur e  us er  n a m e  a n d  p ass w or d i n  or d er t o  e nt er, 
r e vi e w,  or  c orr e ct st u d y  d at a. T h es e  pr o c e d ur es  m ust  c o m pl y  wit h  Titl e  2 1  of t h e  C o d e  of 
F e d er al  R e g ul ati o ns ( 2 1  C F R  P art  1 1).  All  p ass w or ds  will  b e stri ctl y  c o nfi d e nti al.  
  
M e di c al I nf o r m ati o n  C o d i n g 
F or  m e di c al i nf or m ati o n t h e f oll o wi n g t h es a uri  will  b e  us e d:  
M e di c al  Di cti o n ar y f or  R e g ul at or y  A cti viti es ( M e d D R A ) f or  a d v ers e  e v e nts 
W orl d  H e alt h  Or g a ni z ati o n ( W H O )  Dr u g f or  c o n c o mit a nt  m e di c ati o ns 
  
D at a  V ali d ati o n 
V ali d ati o n  c h e c ks  pr o gr a m m e d  wit hi n t h e  e C R F s yst e m,  as  w ell  as s u p pl e m e nt al  v ali d ati o n 
p erf or m e d  vi a r e vi e w  of t h e  d o w nl o a d e d  d at a,  will  b e  a p pli e d t o t h e  d at a i n  or d er t o  e ns ur e 
a c c ur at e,  c o nsist e nt,  a n d r eli a bl e  d at a.  D at a i d e ntifi e d  as  err o n e o us,  or  d at a t h at  ar e  missi n g,  will 
b e r ef err e d  t o t h e i n v esti g ati v e sit e f or r es ol uti o n t hr o u g h  d at a  q u eri es. 
El e ctr o ni c  C R Fs  m ust  b e r e vi e w e d  a n d  el e ctr o ni c all y si g n e d  b y  a n I n v esti g at or  w h o si g n e d t h e 
pr ot o c ol. 
9. 7.   
Di r e ct  A c c ess t o  S o u r c e  D at a  
M o nit ori n g  a n d  a u diti n g  pr o c e d ur es  d e v el o p e d  or r e vi e w e d  a n d  a p pr o v e d  b y t h e  S p o ns or  will  b e 
f oll o w e d, t o  c o m pl y  wit h  G C P  g ui d eli n es. 
T h e st u d y  will  b e  m o nit or e d  b y t h e  S p o ns or  or its  d esi g n e e.  M o nit ori n g  will  b e  d o n e  b y  p ers o n al 
visits fr o m  a r e pr es e nt ati v e  of t h e  S p o ns or (sit e  m o nit or)  a n d  will i n cl u d e  o n -sit e r evi e w  of t h e 
s o ur c e  d o c u m e nts/ C R Fs f or  c o m pl et e n ess  a n d  cl arit y,  cr oss - c h e c ki n g  wit h s o ur c e  d o c u m e nts, 
a n d  cl arifi c ati o n  of  a d mi nistr ati v e  m att ers  will  b e  p erf or m e d.  T h e r e vi e w  of  m e di c al r e c or ds  will 
b e  p erf or m e d i n  a  m a n n er t o  e ns ur e t h at  p ati e nt  c o nfi d e n ti alit y is  m ai nt ai n e d. 


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R h yt h m  P h ar m a c e uti c als, I n c. 
T h e sit e  m o nit or  will  e ns ur e t h at t h e i n v esti g ati o n is  c o n d u ct e d  a c c or di n g t o  pr ot o c ol  d esi g n  a n d 
r e g ul at or y r e q uir e m e nts  b y fr e q u e nt  c o m m u ni c ati o ns (l ett er, t el e p h o n e,  a n d f a x). 
All  u n us e d st u d y  dr u g  a n d  ot h er st u d y  m at eri als  ar e t o  b e r et ur n e d t o  t h e  S p o ns or aft er t h e 
cli ni c al  p h as e  of t h e st u d y  h as  b e e n  c o m pl et e d (s e e  S e cti o n  5. 7 ). 
R e g ul at or y  a ut h oriti es, t h e I R B /I E C,  a n d/ or t h e  S p o ns or’s  cli ni c al  q u alit y  ass ur a n c e  gr o u p  or 
d esi g n e e  m a y r e q u est  a c c ess t o  all s o ur c e  d o c u m e nts,  C R Fs,  a n d  ot h er st u d y  d o c u m e nt ati o n f or 
o n-sit e  a u dit  or i ns p e cti o n.  Dir e ct  a c c ess t o t h es e  d o c u m e nts  m ust  b e  g u ar a nt e e d  b y t h e 
I n v esti g at or,  w h o  m ust  pr o vi d e s u p p ort  at  all ti m es f or t h es e  a cti viti es. 
9. 8.   
S o u r c e  D o c u m e nt/ C as e  R e p o rt  F o r m  C o m pl eti o n  
S o ur c e  d o c u m e nts/ C R Fs  will  b e  c o m pl et e d f or  e a c h st u d y  p ati e nt.  It is t h e I n v esti g at or’s 
r es p o nsi bilit y t o  e ns ur e t h e  a c c ur a c y,  c o m pl et e n ess,  a n d ti m eli n ess  of t h e  d at a r e p ort e d i n t h e 
p ati e nt’s s o ur c e  d o c u m e nt/ C R F.  T h e s o ur c e  d o c u m e nt/ C R F s h o ul d i n di c at e t h e  p ati e nt’s 
p arti ci p ati o n i n t h e st u d y  a n d s h o ul d  d o c u m e nt t h e  d at es  a n d  d et ails  of st u d y  pr o c e d ur es,  a d v ers e 
e v e nts,  a n d  p ati e nt st at us.  
T h e  I n v esti g at or,  or  d esi g n at e d r e pr es e nt ati v e, s h o ul d  c o m pl et e t h e s o ur c e  d o c u m e nt/ C R F  as 
s o o n  as  p ossi bl e  aft er i nf or m ati o n is  c oll e ct e d,  pr ef er a bl y  o n t h e s a m e  d a y t h at  a st u d y  p ati e nt is 
s e e n f or  a n  e x a mi n ati o n, tr e at m e nt,  or  a n y  ot h er st u d y  pr o c e d ur e.  A n y  o utst a n di n g  e ntri es  m ust 
b e  c o m pl et e d i m m e di at el y  aft er t h e fi n al  e x a mi n ati o n.  A n  e x pl a n ati o n s h o ul d  b e  gi v e n f or  all 
missi n g  d at a. 
T h e  I n v esti g at or  m ust si g n  a n d d at e t h e I n v esti g at or’s  St at e m e nt  at t h e  e n d  of t h e s o ur c e 
d o c u m e nt/ C R F t o  e n d ors e t h e r e c or d e d  d at a.   
T h e  S p o ns or  will r et ai n t h e  ori gi n als  of  all  C R Fs.  T h e  I n v esti g at or will r et ai n  all  c o m pl et e d 
s o ur c e  d o c u m e nts/ C R Fs.  
9. 9.   
R e c o r d  R et e nti o n  
T h e  I n v esti g at or wi ll  m ai nt ai n  all st u d y r e c or ds  a c c or di n g t o I C H- G C P  a n d  a p pli c a bl e r e g ul at or y 
r e q uir e m e nt(s). R e c or ds  will  b e r et ai n e d f or  at l e ast t w o  y e ars  aft er t h e l ast  m ar k eti n g  a p pli c ati o n 
a p pr o v al  or t w o  y e ars  aft er f or m al  dis c o nti n u ati o n  of t h e  cli ni c al  d e v el o p m e nt  of t h e 
i n v esti g ati o n al  pr o d u ct  or  a c c or di n g t o  a p pli c a bl e r e g ul at or y r e q uir e m e nt(s). If t h e I n v esti g at or 
wit h dr a ws fr o m t h e r es p o nsi bilit y  of  k e e pi n g t h e st u d y r e c or ds,  c ust o d y  m ust  b e tr a nsf err e d t o  a 
p ers o n  willi n g t o  a c c e pt t h e r es p o nsi bilit y.  T h e  S p o ns or  m ust  b e  n otifi e d i n  writi n g if  a  c ust o di al 
c h a n g e  o c c urs.  
9. 1 0.   
Li a bilit y I ns u r a n c e  
T h e  S p o ns or  h as s u bs cri b e d t o  a n i ns ur a n c e  p oli c y  c o v eri n g, i n its t er ms  a n d  pr o visi o ns, its l e g al 
li a bilit y f or i nj uri es  c a us e d t o  p arti ci p ati n g  p ers o ns  a n d  arisi n g  o ut  of this r es e ar c h  p erf or m e d 
stri ctl y i n  a c c or d a n c e  wit h t h e s ci e ntifi c  pr ot o c ol  as  w ell  as  wit h  a p pli c a bl e l a w  a n d  pr of essi o n al 
st a n d ar ds. 
9. 1 1.   
P u bli c ati o n  of  St u d y  Fi n di n gs  a n d  Us e  of I nf o r m ati o n  
All i nf or m ati o n r e g ar di n g  s et m el a n oti d e s u p pli e d  b y t h e  S p o ns or t o t h e I n v esti g at or is  pri vil e g e d 
a n d  c o nfi d e nti al i nf or m ati o n.  T h e  I n v esti g at or  a gr e es t o  us e t his i nf or m ati o n t o  a c c o m plis h t h e 
st u d y  a n d  will  n ot  us e it f or  ot h er  p ur p os es  wit h o ut  c o ns e nt fr o m t h e  S p o ns or.  It is  u n d erst o o d 
t h at t h er e is  a n  o bli g ati o n t o  pr o vi d e t h e  S p o ns or  wit h  c o m pl et e  d at a  o bt ai n e d  d uri n g t h e st u d y. 


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R h yt h m  P h ar m a c e uti c als, I n c. 
T h e i nf or m ati o n  o bt ai n e d fr o m t h e  cli ni c al st u d y  will  b e  us e d t o w ar ds t h e  d e v el o p m e nt  of 
s et m el a n oti d e  a n d  m a y  b e  dis cl os e d t o r e g ul at or y  a ut horit y(i es),  ot h er i n v esti g at ors,  c or p or at e 
p art n ers,  or  c o ns ult a nts  as r e q uir e d.  
It is t h e i nt e nti o n  of t h e  S p o ns or a n d t h e  a c a d e mi c i n v esti g at ors t o  p u blis h t h e r es ults  of t his 
st u d y i n  a  p e er-r e vi e w e d j o ur n al  u p o n  c o m pl eti o n.  F or t his  p ur p os e,  a  p u bli c at i o n  c o m mitt e e  of 
t h e  k e y i n v esti g at ors  will li k el y  b e i d e ntifi e d  a n d i niti at e d d uri n g  t his tri al. 


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R h yt h m  P h ar m a c e uti c als, I n c. 
1 0.   
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Cli n  G e n et.  2 0 1 5; 8: 1 7 1 - 1 7 9.  R e vi e w. 
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1 9 9 5 J ul; 3( 4): 3 8 7- 9 9. 
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B ar d et - Bi e dl s y n dr o m e: r es ults  of  a  p o p ul ati o n s ur v e y. J  M e d  G e n et.  1 9 9 9 
J u n; 3 6( 6): 4 3 7- 4 6. 
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1 9 7 6; 1 6( 1): 3 1- 4 1. 
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P e di atr  G e n et .  2 0 1 4;3: 7 9 – 8 8. 
F e uill a n  P,  N g  D,  H a n J,  S a p p J,  W ets c h  K,  S p a ul di n g  E,  Z h e n g  Y,  C ar us o  R,  Br o o ks  B, 
J o h nst o n J,  Y a n o vs ki J,  B eis e c k er  L.  P ati e nts  wit h  B ar d et- Bi e dl s y n dr o m e  h a v e 
h y p erl e pti n e mi a s u g g esti v e  of l e pti n r esist a n c e. J  Cli n  E n d o cri n ol  M et a b.  2 0 1 1 
M ar; 9 6( 3): E 5 2 8 - E 5 3 5.  E p u b  5 J a n  2 0 1 1. 
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F ors yt h e  E,  B e al es  P L.  B ar d et - Bi e dl s y n dr o m e.  E ur J  H u m  G e n et.  2 0 1 3; 2 1: 8- 1 3.  E p u b  2 0 J u n e 
2 0 1 2.  R e vi e w.  
F ors yt h e  E,  S p ar ks  K,  H os ki ns  B,  B a g k eris  E,  M c G o w a n  B,  C arr oll  P,  H u d a  M,  M uj a hi d  S, 
P et ers  C,  B arr ett  T,  M o h a m m e d  S,  B e al es  P.  G e n eti c  pr e di ct ors  of  c ar di o v as c ul ar 
m or bi dit y i n  B ar d et - Bi e dl s y n dr o m e.  Cli n  G e n et.  2 0 1 5; 8 7: 3 4 3- 3 4 9. 
Gir ar d  D,  P etr o vs k y  N.  Alstr ö m s y n dr o m e: i nsi g hts i nt o t h e  p at h o g e n esis  of  m et a b oli c  dis or d er s. 
N at  R e v   E n d o cri n ol.  2 0 1 1  F e b; 7: 7 7 – 8 8. R e vi e w.  
G ott es di e n er  K,  C o n n ors  H,  V a n  d er  Pl o e g  L,  Fi e d or e k  F,  H yl a n  M,  L o uis  W,  L ass et er  K. 
A n al ysis  of t h e s y nt h eti c  p e pti d e  R M- 4 9 3,  a  m el a n o c orti n- 4 r e c e pt or ( M C 4 R)  a g o nist,  o n 
c ar di o v as c ul ar  p ar a m et ers i n t hr e e  P h as e 1 b/ 2 a st u di es.   P ost er  -  O b esit y  S o ci et y,  2 0 1 5. 
Gr a c e  C,  B e al es  P,  S u m m er b ell  C, J e b b  S A,  Wri g ht  A,  P ar k er  D,  K o p el m a n  P.  E n er g y 
m et a b olis m i n  B ar d et - Bi e dl s y n dr o m e. I nt J  O b es  R el at  M et a b  Dis or d.  2 0 0 3 
N o v; 2 7( 1 1): 1 3 1 9- 1 3 2 4.  
G u o  D F,  R a h m o u ni  K.  M ol e c ul ar  b asis  of t h e  o b esit y  ass o ci a t e d  wit h  B ar d et- Bi e dl s y n dr o m e. 
Tr e n ds  E n d o cri n ol  M et a b.  2 0 1 1 J ul; 2 2( 7): 2 8 6- 2 9 3.  R e vi e w.  
H aiti n a  T,  Ri n g h ol m  A,  K ell y J,  M u n d y  NI,  S c hi öt h  H B.  Hi g h  di v ersit y i n f u n cti o n al  pr o p erti es 
of  m el a n o c orti n  1 r e c e pt or ( M C 1 R) i n  di v er g e nt  pri m at e s p e ci es is  m or e str o n gl y 
ass o ci at e d  wit h  p h yl o g e n y t h a n  c o at  c ol or.  M ol  Bi ol  E v ol.  2 0 0 7  S e p; 2 4( 9): 2 0 0 1- 2 0 0 8. 
K ell y  A,  F o x  C,  R u ds er  K,  Gr oss  A,  R y d er J.  P e di atri c  o b esit y  p h ar m a c ot h er a p y:  c urr e nt st at e  of 
t h e fi el d, r e vi e w  of t h e lit er at ur e, a n d  cli ni c al tri al  c o nsi d er ati o ns.  L a n c et. 
2 0 1 6 J ul; 4 0( 7): 1 0 4 3- 1 0 5 0. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  7 9 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
K n or z  V,  S p all ut o  C,  L ess ar d  M,  P ur vis  T,  A di g u n  F,  C olli n  G,  H a nl e y  N,  Wils o n  D,  H e ar n  T. 
C e ntri ol a  ass o ci ati o n  of  A L M S 1  a n d li k el y  c e ntr os o m al f u n cti o ns  of t h e  A L M S  m otif-
c o nt ai ni n g  pr ot ei ns  C 1 0 orf 9 0  a n d  KI A A 1 7 3 1.  M ol e c ul ar  Bi ol  C ell.  2 0 1 0; 2 1: 3 6 1 7- 3 6 2 9. 
L o c k e  M,  Ti nsl e y  C,  B e ns o n  M,  Bl a k e  D.  T RI M 3 2 is  a n  E 3  u bi q uiti n li g as e f or  d ys bi n di n. 
H u m   M ol  G e n et.  2 0 0 9; 1 8( 1 3): 2 3 4 4- 2 3 5 8. 
L o kt e v  A,  Z h a n g  Q,  B e c k J,  S e ar b y  C,  S c h e et z  T,  B a z a n J,  Sl us ars ki  D,  S h effi el d  V, J a c ks o n  P , 
N a c h ur y  M.  A  B B S o m e s u b u nit li n ks  cili o g e n esis,  mi cr ot u b ul e st a bilit y,  a n d  a c et yl ati o n. 
D e v  C ell.  2 0 0 8  D e c   9; 1 5: 8 5 4- 8 6 5. 
M ars h all J ,  B e c k  S,  M aff ei  P,  N a g g ert J K.  Alstr ö m s y n dr o m e.  E ur J  H u m  G e n et. 
2 0 0 7  D e c; 1 5( 1 2): 1 1 9 3- 1 2 0 2.  E p u b  1 7  O ct  2 0 0 7.  R e vi e w.  
M o or e  S,  Gr e e n J,  F a n  Y,  B h o g al  A,  Di c ks  E,  F er n a n d e z  B,  St ef a n elll  M,  M ur p h y  C,  Cr a m er  B, 
D e a n J,  B e al es  P,  K ats a nis  N,  B ass ett  A,  D a vi ds o n  W,  P arfr e y  P.  Cli ni c al  a n d  g e n eti c 
e pi d e mi ol o g y  of  B ar d et- Bi e dl s y n dr o m e i n  N e wf o u n dl a n d:  a  2 2- y e ar  pr os p e cti v e, 
p o p ul ati o n- b as e d,  c o h ort st u d y.  A m J  M e d  G e n et.  2 0 0 5  F e b; 1 3 2 A( 4): 3 5 2- 3 6 0.  
N a c h ur y  M,  L o kt e v  A,  Z h a n g  Q,  W estl a k e  C,  P er ä n e n J,  M er d es  A,  Sl us ars ki  D,  S c h ell er  R, 
B a z a n J,  S h effi el d  V, J a c ks o n  P.  A  c or e  c o m pl e x  of  B B S  pr ot ei ns  c o o p er at es  wit h t h e 
G T P as e  R a b 8 t o  pr o m ot e  cili ar y  m e m br a n e  bi o g e n esis.  C ell.  2 0 0 7 J u n; 1 2 9: 1 2 0 1- 1 2 1 3. 
N a k a y a m a  K,  S h ot a k e  T,  T a k e n e k a  O, Is hi d a  T.  V ari ati o n  of t h e  m el a n o c orti n  1 r e c e pt or  g e n e i n 
t h e  m a c a q u es. A m J  Pri m at ol .  2 0 0 8; 7 0( 8): 7 7 8- 7 8 5. 
N H L BI.  T h e  Pr a cti c al  G ui d e I d e ntifi c ati o n,  E v al u ati o n,  a n d  Tr e at m e nt  of  O v er w ei g ht  a n d  O b es e 
i n  A d ults.  NI H  P u bli c ati o n  N o.  0 0- 4 0 8 4,  O ct o b er  2 0 0 0. 
N ati o n al I nstit ut es  of  H e alt h  [I nt er n et].  D e p art m e nt  of  H e alt h  a n d  H u m a n  S er vi c es ( U S); 
[r e vi e w e d  2 0 1 3  S e p;  cit e d  2 0 1 8 J u n  0 5].  G e n eti cs  h o m e r ef er e n c e.  Y o ur  g ui d e t o 
u n d erst a n di n g  g e n eti c  c o n diti o ns.  B ar d et- Bi e dl s y n dr o m e.  A v ail a bl e fr o m:  
htt ps:// g hr. nl m. ni h. g o v/ c o n diti o n/ b ar d et- bi e dl -s y n dr o m e. 
Or p h a n et  [I nt er n et]. Fr e n c h  N ati o n al I nstit ut e f or  H e alt h  a n d  M e di c al  R es e ar c h (I N S E R M). 
1 9 9 7 -   .  Alstr ö m  S y n dr o m e; [ cit e d  2 0 1 8  M ar  0 1].  A v ail a bl e fr o m: 
htt p:// w w w. or p h a. n et/ c o ns or/ c gi- bi n/ Dis e as e _ S e ar c h. p h p ?l n g = E N & d at a _i d = 1 3 2 8 & 
Dis e as e _ Dis e as e _ S e ar c h _ dis e as e Gr o u p = Alstr o m -s y n dr o m e & Dis e as e _ Dis e as e _ S e ar c h _ 
dis e as e T y p e = P at & Dis e as e(s)/ gr o u p  of  dis e as es = Alstr o m -s y n dr o m e &titl e = Alstr o m-
s y n dr o m e &s e ar c h = Dis e as e _ S e ar c h _ Si m pl e .  
S c h w art z  GJ,  M u ñ o z  A,  S c h n ei d er  M F,  M a k  R H,  K as k el  F,  W ar a d y  B A,  F urt h  S L.  N e w 
e q u ati o ns t o  esti m at e  G F R i n  c hil dr e n  wit h  C K D. J   A m  S o c  N e p hr ol.  2 0 0 9 
M ar; 2 0( 3): 6 2 9 - 3 7. 
S e o  S,  B a y e  L,  S c h ul z  N,  B e c k J,  Z h a n g  Q,  Sl us ars ki  D,  S h effi el d  V.  B B S 6,  B B S 1 0,  a n d  B B S 1 2 
f or m  a  c o m pl e x  wit h  C C T/ T Ri C f a mil y c h a p er o ni ns  a n d  m e di at e  B B S o m e  ass e m bl y. 
P N A S.  2 0 1 0 J a n; 1 0 7( 4): 1 4 8 8- 1 4 9 3. 
S u pisti n,  2 0 1 6  S us pisti n  E, I m y a nit o v  E.  B ar d et- Bi e dl s y n dr o m e.  M ol  S y n dr o m ol.  2 0 1 6; 7: 6 2- 7 1. 
E p u b  1 5  A pr  2 0 1 6.  R e vi e w.  




Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 1 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
1 1. 2.   
Fit z p at ri c k  Cl assifi c ati o n  S c al e  
 
S ki n 
T y p e  
S ki n  C ol o r  
C h a r a ct e risti cs  
I 
W hit e;  v er y f air; r e d  or  bl o n d  h air;  bl u e  e y es; 
fr e c kl es 
Al w a ys  b ur ns,  n e v er t a ns  
II 
W hit e; f air; r e d  or  bl o n d  h air;  bl u e,  h a z el,  or  gr e e n 
e y es  
Us u all y  b ur ns, t a ns  wit h 
diffi c ult y  
III 
Cr e a m  w hit e; f air  wit h  a n y  e y e  or  h air  c ol or;  v er y 
c o m m o n  
S o m eti m es  mil d  b ur n, 
gr a d u all y t a ns  
I V  
Br o w n; t y pi c al  M e dit err a n e a n  C a u c asi a n s ki n   
R ar el y  b ur ns, t a ns  wit h  e as e  
V   
D ar k  Br o w n;  mi d -e ast er n s ki n t y p es  
V er y r ar el y  b ur ns, t a ns  v er y 
e asil y  
VI   
Bl a c k  
N e v er  b ur ns, t a ns  v er y  e asil y  
Fit z p atri c k  1 9 7 5  
 
 
 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 2 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
1 1. 3.   
P ast  M e di c al  Hist o r y  a n d  G r o wt h  C u r v e  Inf o r m ati o n  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 3 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
1 1. 4.   
G ui d a n c e f o r  M o nit o ri n g  P ot e nti al  T r e at m e nt -R el at e d  D e r m at ol o gi c al  C h a n g es 
a n d  S u g g est e d  C rit e ri a  F o r  Dis c o nti n u ati o n  of  D osi n g  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 4 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 5 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 6 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 7 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 8 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  8 9 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  9 0 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
1 1. 6.   
C r e ati ni n e  Cl e a r a n c e  Esti m at e   
  
C o c k c r oft -G a ult  E q u ati o n   
I n  p ati e nts,  > 1 6 y e ars  of  a g e, t h e  C o c k cr oft - G a ult  e q u ati o n (C o c k cr oft  1 9 7 6 ) s h o ul d  b e  us e d  as 
f oll o ws: 
M al e  Cr e ati ni n e  Cl e ar a n c e  m L/ mi n   =  1. 0  * (( 1 4 0 - A g e) / ( S er u m  Cr e at))  * ( W ei g ht ( k g) /  7 2)  
F e m al e  Cr e ati ni n e  Cl e ar a n c e  m L/ mi n  =  0. 8 5  * (( 1 4 0 -  A g e) / ( S er u m  Cr e at))  * ( W ei g ht ( k g) /  7 2)   
W h er e :  a g e is i n  y e ars a n d s er u m  cr e ati ni n e is  i n  m g/ d L. 
  
S c h w a rt z  E q u ati o n  
I n  p ati e nts, ≤ 1 6  y e ars  of  a g e, t h e  cr e ati ni n e -c yst ati n   C  e q u ati o n (S c h w art z   2 0 0 9) s h o ul d  b e  us e d 
as f oll o ws:  
G F R = 3 9. 1[ h ei g ht/ S cr] 0. 5 1 6[ 1. 8/ c yst ati n  C]0. 2 9 4 x [ 3 0/ B U N] 0. 1 6 9[ 1. 0 9 9]m al e [ h ei g ht/ 1. 4]0. 1 8 8 
W h er e:  
G F R =  Gl o m er ul ar filtr ati o n r at e i n  c c/ mi n/ 1. 7 3 m 2 
Ht  =  H ei g ht i n  m et ers  
C yst ati n  C  =  m g/ L  
B U N  =  m g/ d L  
 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  9 1 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
1 1. 7.   
C o nsi d e r ati o ns f o r  r e d u ci n g  p ai n  a n d  dist r ess i n t h e  p e di at ri c  p o p ul ati o n  
Alt h o u g h t h e st u d y  pr o c e d ur es  a n d  ass ess m e nts r e q uir e d  p er  pr ot o c ol  ar e  cl assifi e d  as  “ N o  or 
Mi ni m al  Ris k ” ( a p art fr o m  D X A  w hi c h is  cl assifi e d  as  “ Mi n or I n cr e as e  o v er  Mi ni m al  Ris k ”)  p er 
t h e  2 0 0 8  G ui d a n c e  D o c u m e nt  “ Et hi c al  C o nsi d er ati o ns f or  Cli ni c al  Tri als  o n  M e di ci n al  Pr o d u cts 
C o n d u ct e d  wit h t h e  P e di atri c  P o p ul ati o n ”,  c o nsi d er ati o ns f or r e d u ci n g  p ai n i n  distr ess i n 
p arti ci p a nts  y o u n g er t h a n  1 8  y e ars  of  a g e  ar e s u g g est e d  b el o w.  
 
•   T h e  cli ni c al tri al  m a y  o nl y  b e  c o n d u ct e d if it s u bj e cts t h e  p ers o n  c o n c er n e d t o  as littl e 
b ur d e n  a n d  ot h er f or es e e a bl e ris ks  as  p ossi bl e;  
•   P h ysi c al  a n d  e m oti o n al  p ai n s h o ul d  b e  pr e v e nt e d  as  m u c h  as  p ossi bl e,  a n d  eff e cti v el y 
tr e at e d  w h e n  u n a v oi d a bl e. 
•   T o   mi ni mi z e  p ai n,  distr ess,  a n d f e ar, f a ciliti es s h o ul d  b e  a p pr o pri at e t o  c hil d c ar e,  a n d t h e 
p ers o n n el s h o ul d  b e tr ai n e d t o l o o k  aft er  c hil dr e n  a n d s u p er vis e d  b y  e x p eri e n c e d  h e alt h 
c ar e  pr of essi o n als.  St aff s h o ul d  b e t r ai n e d t o  c o m m u ni c at e  wit h  b ot h  p ar e nts ( or l e g al 
r e pr es e nt ati v e)  a n d  c hil dr e n. G e n er all y, t his  w o ul d  ass u m e  n o n- a d ult  p ati e nts  ar e  b ei n g 
st u di e d  at  e x p eri e n c e d  p e di atri c  c e nt ers.   
•   F or  m ost  pr o c e d ur es, t h e  c hil d s h o ul d  al w a ys  b e  a c c o m p a ni e d  b y  a tri al- r el at e d st aff 
m e m b er  w h o  c o ul d  pr o vi d e r e ass ur a n c e.  At t h e si g n  of  distr ess  a n d/ or  diss e nt t h e 
pr o c e d ur e s h o ul d  b e st o p p e d;  a s h ort  p a us e t o  all o w t h e  c hil d t o f e el i n  c o ntr ol, f urt h er 
e x pl a n ati o n  a n d  a n  ass ess m e nt  of t h e sit u ati o n  m a y  b e  n e e d e d t o r e ass ur e t h e  c hil d,  or t o 
d e ci d e t o  a b a n d o n t h e  pr o c e d ur e  at t h e  dis cr eti o n  of t h e I n v esti g at or. 
•   I n  all sit u ati o ns, i n v esti g ati o ns/i nt er v e nti o ns s h o ul d  b e li mit e d t o t h e  mi ni m u m r e q uir e d 
f or  o bt ai ni n g  v ali d  d at a  a n d  p erf or m e d  usi n g si z e-/ a g e-a p pr o pri at e  m at eri al  a n d  d e vi c es, 
i n cl u di n g li miti n g i n  a d v a n c e t h e  n u m b er  of  att e m pts f or s a m pli n g. 
•   St u d y  dr u g i nj e cti o ns s h o ul d  o nl y  b e  p erf or m e d  b y  p ar e nts ( or  h o m e  h e alt h  c ar e 
pr of essi o n als),  u nl ess t h e  c hil d is  of s uit a bl e  a g e  a n d  c o m p et e n c y,  a n d  d esir es t h e  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 c e d ur es  ar e  cl assifi e d  as l o w ris k ( e x c e pt f or  D X A  w hi c h is 
cl assifi e d  as  “ mi n or i n cr e as e  o v er  mi ni m al ris k ”), ris k s h o ul d  b e  c o nti n u o usl y  m o nit or e d 
a n d  ass ess e d  b y  a p pr o pri at e  p ers o n n el.  
•   F or  ass ess m e nts i n  w hi c h t h er e is  a  p s y c h ol o gi c al  c o m p o n e nt  m e as ur es s h o ul d  b e t a k e n 
t o  mi ni mi z e  distr ess. F or  e x a m pl e,  T a n n er  St a gi n g  ass ess m e nts  c o ul d  utili z e  a  di a gr a m 
f or t h e  c hil d t o  p oi nt t o  a n d i n di c at e  w h at st a g e t h e y  c urr e ntl y  ar e,  vs.  h a vi n g t o  h a v e  a n 
e x a m  wit h o ut  cl ot h es. 
 
A  c o m m e nt  o n  b e n efit ris k:  ris k is  v er y l o w, fr o m  pr o c e d ur es  a n d/ or  k n o w n s af et y  pr ofil e  of t h e 
dr u g ( b ot h  cli ni c all y  a n d t o xi c ol o gi c all y,  w h er e l ar g e  m ar gi ns  a n d  pr eli mi n ar y  d at a fr o m j u v e nil e 
t o xi c ol o g y st u di es  h a v e  n ot i d e ntifi e d  a n y  n e w  or  c o n c er ni n g s af et y  c o n c er ns),  a n d  b as e d  o n  o n e 
r e pr es e nt ati v e  e x a m pl e  of r ar e  g e n eti c  dis or d er  of  o b esit y i m p a cti n g t h e  M C 4  p at h w a y, t h er e is 
t h e  p ossi bilit y  of  m aj or  b e n efit. 
 
 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  9 2 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
1 1. 8.   
D e cl a r ati o n  of  H elsi n ki  
W o rl d  M e di c al  Ass o ci ati o n  D e cl a r ati o n  of  H elsi n ki:  
R e c o m m e n d ati o ns  G ui di n g  M e di c al  D o ct ors i n  Bi o m e di c al  R es e ar c h I n v ol vi n g  H u m a n  P ati e nts 
A d o pt e d  b y t h e  1 8 t h W orl d  M e di c al  Ass o ci ati o n ( W M A)  G e n er al  Ass e m bl y,  H elsi n ki,  Fi nl a n d, 
J u n e  1 9 6 4  a n d  a m e n d e d  b y t h e  2 9 t h  W M A  G e n er al  Ass e m bl y,  T o k y o, J a p a n,  O ct o b er  1 9 7 5,  3 5t h 
W M A  G e n er al  Ass e m bl y,  V e ni c e, It al y,  O ct o b er  1 9 8 3,  a n d t h e  4 1 st W M A  G e n er al  Ass e m bl y, 
H o n g  K o n g,  S e pt e m b er  1 9 8 9, t h e  4 8 t h W M A  G e n er al  Ass e m bl y,  S o m ers et  W est,  R e p u bli c  of 
S o ut h  Afri c a,  O ct o b er  1 9 9 6;  5 2 n d  W M A  G e n er al  Ass e m bl y,  E di n b ur g h,  S c otl a n d,  O ct o b er  2 0 0 0; 
5 3r d  W M A  G e n er al  Ass e m bl y,  W as hi n gt o n  2 0 0 2 ( N ot e  of  Cl arifi c ati o n  o n  p ar a gr a p h  2 9  a d d e d); 
5 5t h  W M A  G e n er al  Ass e m bl y,  T o k y o  2 0 0 4 ( N ot e  of  Cl arifi c ati o n  o n  P ar a gr a p h  3 0  a d d e d);  a n d 
5 9t h  W M A  G e n er al  Ass e m bl y,  S e o ul,  O ct o b er  2 0 0 8. 
A.   
I N T R O D U C TI O N  
1.   T h e  W orl d  M e d i c al  Ass o ci ati o n ( W M A)  h as  d e v el o p e d t h e  D e cl ar ati o n  of  H elsi n ki  as  a 
st at e m e nt  of  et hi c al  pri n ci pl es f or  m e di c al r es e ar c h i n v ol vi n g  h u m a n  p ati e nts, i n cl u di n g 
r es e ar c h  o n i d e ntifi a bl e  h u m a n  m at eri al  a n d  d at a.  
T h e  D e cl ar ati o n is i nt e n d e d t o  b e r e a d  as  a  w h ol e  a n d  e a c h  of its  c o nstit u e nt  p ar a gr a p hs 
s h o ul d  n ot  b e  a p pli e d  wit h o ut  c o nsi d er ati o n  of  all  ot h er r el e v a nt  p ar a gr a p hs.  
2.   Alt h o u g h t h e  D e cl ar ati o n is  a d dr ess e d  pri m aril y t o  p h ysi ci a ns, t h e  W M A  e n c o ur a g es  ot h er 
p arti ci p a nts i n  m e di c al r es e ar c h i n v ol vi n g  h u m a n  p ati e nts t o  a d o pt t h es e  pri n ci pl es.  
3.   It is t h e  d ut y  of t h e  p h ysi ci a n t o  pr o m ot e  a n d s af e g u ar d t h e  h e alt h  of  p ati e nts, i n cl u di n g t h os e 
w h o  ar e i n v ol v e d i n  m e di c al r es e ar c h.  T h e  p h ysi ci a n's  k n o wl e d g e  a n d  c o ns ci e n c e  ar e 
d e di c at e d t o t h e f ulfil m e nt  of t his  d ut y.  
4.   T h e  D e cl ar ati o n  of  G e n e v a  of t h e  W M A  bi n ds t h e  p h ysi ci a n  wit h t h e  w or ds,  " T h e  h e alt h  of 
m y  p ati e nt  will  b e  m y first  c o nsi d er ati o n, "  a n d t h e I nt er n ati o n al  C o d e  of  M e di c al  Et hi cs 
d e cl ar es t h at,  " A  p h ysi ci a n s h all  a ct i n t h e  p ati e nt's  b est i nt er est  w h e n  pr o vi di n g  m e di c al 
c ar e. "   
5.   M e di c al  pr o gr ess is  b as e d  o n r es e ar c h t h at  ulti m at el y  m ust i n cl u d e st u di es i n v ol vi n g  h u m a n 
p ati e nts.  P o p ul ati o ns t h at  ar e  u n d err e pr es e nt e d i n  m e di c al r es e ar c h s h o ul d  b e  pr o vi d e d 
a p pr o pri at e  a c c ess t o  p arti ci p ati o n i n r es e ar c h.   
6.   I n  m e di c al r es e ar c h i n v ol vi n g  h u m a n  p ati e nts, t h e  w ell- b ei n g  of t h e i n di vi d u al r es e ar c h 
p ati e nt  m ust t a k e  pr e c e d e n c e  o v er  all  ot h er i nt er ests.   
7.   T h e  pri m ar y  p ur p os e  of  m e di c al r es e ar c h i n v ol vi n g  h u m a n  p ati e nts is t o  u n d erst a n d t h e 
c a us es,  d e v el o p m e nt  a n d  eff e cts  of  dis e as es  a n d i m pr o v e  pr e v e nti v e,  di a g n osti c  a n d 
t h er a p e uti c i nt er v e nti o ns ( m et h o ds,  pr o c e d ur es  a n d tr e at m e nts).  E v e n t h e  b est  c urr e nt 
i nt er v e nti o ns  m ust  b e  e v al u at e d  c o nti n u all y t hr o u g h r es e ar c h f or t h eir s af et y,  eff e cti v e n ess, 
effi ci e n c y,  a c c essi bilit y  a n d  q u alit y.   
8.   I n  m e di c al  pr a cti c e  a n d i n  m e di c al r es e ar c h,  m ost i nt er v e nti o ns i n v ol v e ris ks  a n d  b ur d e ns.  
9.   M e di c al r es e ar c h is  p ati e nt t o  et hi c al st a n d ar ds t h at  pr o m ot e r es p e ct f or  all  h u m a n  p ati e nts 
a n d  pr ot e ct t h eir  h e alt h  a n d ri g hts.  S o m e r es e ar c h  p o p ul ati o ns  ar e  p arti c ul arl y  v ul n er a bl e  a n d 
n e e d s p e ci al  pr ot e cti o n.  T h es e i n cl u d e t h os e  w h o  c a n n ot  gi v e  or r ef us e  c o ns e nt f or 
t h e ms el v es  a n d th os e  w h o  m a y  b e  v ul n er a bl e t o  c o er ci o n  or  u n d u e i nfl u e n c e.  
1 0.  P h ysi ci a ns s h o ul d  c o nsi d er t h e  et hi c al, l e g al  a n d r e g ul at or y  n or ms  a n d st a n d ar ds f or r es e ar c h 
i n v ol vi n g  h u m a n  p ati e nts i n t h eir  o w n  c o u ntri es  as  w ell  as  a p pli c a bl e i nt er n ati o n al  n or ms  a n d 
st a n d ar ds.  N o  n ati o n al  or i nt er n ati o n al  et hi c al, l e g al  or r e g ul at or y r e q uir e m e nt s h o ul d r e d u c e 
or  eli mi n at e  a n y  of t h e  pr ot e cti o ns f or r es e ar c h  p ati e nts s et f ort h i n t his  D e cl ar ati o n.  


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  9 3 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
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 h e  d ut y  of  p h ysi ci a ns  w h o p arti ci p at e i n  m e di c al r es e ar c h t o  pr ot e ct t h e lif e,  h e alt h, 
di g nit y, i nt e grit y, ri g ht t o s elf - d et er mi n ati o n,  pri v a c y,  a n d  c o nfi d e nti alit y  of  p ers o n al 
i nf or m ati o n  of r es e ar c h  p ati e nts.  
1 2.  M e di c al r es e ar c h i n v ol vi n g  h u m a n  p ati e nts  m ust  c o nf or m t o  g e n er all y  a c c e pt e d s ci e ntifi c 
pri n ci pl es,  b e  b as e d  o n  a t h or o u g h  k n o wl e d g e  of t h e s ci e ntifi c lit er at ur e,  ot h er r el e v a nt 
s o ur c es  of i nf or m ati o n,  a n d  a d e q u at e l a b or at or y  a n d,  as  a p pr o pri at e,  a ni m al  e x p eri m e nt ati o n. 
T h e  w elf ar e  of  a ni m als  us e d f or r es e ar c h  m ust  b e r es p e c t e d.  
1 3.  A p pr o pri at e  c a uti o n  m ust  b e  e x er cis e d i n t h e  c o n d u ct  of  m e di c al r es e ar c h t h at  m a y  h ar m t h e 
e n vir o n m e nt.  
1 4.  T h e  d esi g n  a n d  p erf or m a n c e  of  e a c h r es e ar c h st u d y i n v ol vi n g  h u m a n  p ati e nts  m ust  b e  cl e arl y 
d es cri b e d i n  a r es e ar c h  pr ot o c ol.  T h e  pr ot o c ol s h o ul d  c o nt ai n  a st at e m e nt  of t h e  et hi c al 
c o nsi d er ati o ns i n v ol v e d  a n d s h o ul d i n di c at e  h o w t h e  pri n ci pl es i n t his  D e cl ar ati o n  h a v e  b e e n 
a d dr ess e d.  T h e  pr ot o c ol s h o ul d i n cl u d e i nf or m ati o n r e g ar di n g f u n di n g, s p o ns ors, i nstit uti o n al 
affili ati o ns,  ot h er  p ot e nti al  c o nfli cts  of i nt er est, i n c e nti v es f or  p ati e nts  a n d  pr o visi o ns f or 
tr e ati n g  a n d/ or  c o m p e ns ati n g  p ati e nts  w h o  ar e  h ar m e d  as  a  c o ns e q u e n c e  of  p arti ci p ati o n i n 
t h e r es e ar c h st u d y.  T h e  pr ot o c ol s h o ul d  d es cri b e  arr a n g e m e nts f or  p ost-st u d y  a c c ess  b y st u d y 
p ati e nts t o  i nt er v e nti o ns i d e ntifi e d  as  b e n efi ci al i n t h e st u d y  or  a c c ess t o  ot h er  a p pr o pri at e 
c ar e  or  b e n efits.   
1 5.  T h e r es e ar c h  pr ot o c ol  m ust  b e s u b mitt e d f or  c o nsi d er ati o n,  c o m m e nt,  g ui d a n c e  a n d  a p pr o v al 
t o  a r es e ar c h  et hi cs  c o m mitt e e  b ef or e t h e st u d y  b e gi ns.  T his  c o m mitt e e  m ust  b e i n d e p e n d e nt 
of t h e r es e ar c h er, t h e  S p o ns or  a n d  a n y  ot h er  u n d u e i nfl u e n c e. It  m ust t a k e i nt o  c o nsi d er ati o n 
t h e l a ws  a n d r e g ul ati o ns  of t h e  c o u ntr y  or  c o u ntri es i n  w hi c h t h e r es e ar c h is t o  b e  p erf or m e d 
as  w ell  as  a p pli c a bl e i nt er n ati o n al  n or m s  a n d st a n d ar ds  b ut t h es e  m ust  n ot  b e  all o w e d t o 
r e d u c e  or  eli mi n at e  a n y  of t h e  pr ot e cti o ns f or r es e ar c h  p ati e nts s et f ort h i n t his  D e cl ar ati o n. 
T h e  c o m mitt e e  m ust  h a v e t h e ri g ht t o  m o nit or  o n g oi n g st u di es.  T h e r es e ar c h er  m ust  pr o vi d e 
m o nit ori n g i nf or m ati o n t o t h e  c o m mitt e e,  es p e ci all y i nf or m ati o n  a b o ut  a n y s eri o us  a d v ers e 
e v e nts.  N o  c h a n g e t o t h e  pr ot o c ol  m a y  b e  m a d e  wit h o ut  c o nsi d er ati o n  a n d  a p pr o v al  b y t h e 
c o m mitt e e.   
1 6.  M e di c al r es e ar c h i n v ol vi n g  h u m a n  p ati e nts  m ust  b e  c o n d u ct e d  o nl y  b y i n di vi d u als  wit h t h e 
a p pr o pri at e s ci e ntifi c tr ai ni n g  a n d  q u alifi c ati o ns.  R es e ar c h  o n  p ati e nts  or  h e alt h y  v ol u nt e ers 
r e q uir es t h e s u p er visi o n  of  a  c o m p et e nt  a n d  a p pr o pri at el y  q u alifi e d  p h ysi ci a n  or  ot h er  h e alt h 
c ar e  pr of essi o n al.  T h e r es p o nsi bilit y f or t h e  pr ot e cti o n  of r es e a r c h  p ati e nts  m ust  al w a ys r est 
wit h t h e  p h ysi ci a n  or  ot h er  h e alt h  c ar e  pr of essi o n al  a n d  n e v er t h e r es e ar c h  p ati e nts,  e v e n 
t h o u g h t h e y  h a v e  gi v e n  c o ns e nt.  
1 7.  M e di c al r es e ar c h i n v ol vi n g  a  dis a d v a nt a g e d  or  v ul n er a bl e  p o p ul ati o n  or  c o m m u nit y is  o nl y 
j ustifi e d if t h e r es e ar c h is r es p o nsi v e t o t h e  h e alt h  n e e ds  a n d  pri oriti es  of t his  p o p ul ati o n  or 
c o m m u nit y  a n d if t h er e is  a r e as o n a bl e li k eli h o o d t h at t his  p o p ul ati o n  or  c o m m u nit y st a n ds t o 
b e n efit fr o m t h e r es ults  of t h e r es e ar c h.   
1 8.  E v er y  m e di c al r es e ar c h st u d y i n v ol v i n g  h u m a n  p ati e nts  m ust  b e  pr e c e d e d  b y  c ar ef ul 
ass ess m e nt  of  pr e di ct a bl e ris ks  a n d  b ur d e ns t o t h e i n di vi d u als  a n d  c o m m u niti es i n v ol v e d i n 
t h e r es e ar c h i n  c o m p aris o n  wit h f or es e e a bl e  b e n efits t o t h e m  a n d t o  ot h er i n di vi d u als  or 
c o m m u niti es  aff e ct e d  b y t h e  c o n diti o n  u n d er i n v esti g ati o n.  
1 9.  E v er y  cli ni c al tri al  m ust  b e r e gist er e d i n  a  p u bli cl y  a c c essi bl e  d at a b as e  b ef or e r e cr uit m e nt  of 
t h e first  p ati e nt.  
2 0.  P h ysi ci a ns  m a y  n ot  p arti ci p at e i n  a r es e ar c h st u d y i n v ol vi n g  h u m a n  p ati e nts  u nl ess t h e y  ar e 
c o nfi d e nt t h at t h e ris ks i n v ol v e d  h a v e  b e e n  a d e q u at el y  ass ess e d  a n d  c a n  b e s atisf a ct oril y 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  9 4 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
m a n a g e d.  P h ysi ci a ns  m ust i m m e di at el y st o p  a st u d y  w h e n t h e ris ks  ar e f o u n d t o  o ut w ei g h t h e 
p ot e nti al  b e n efits  or  w h e n t h er e is  c o n cl usi v e  pr o of  of  p ositi v e  a n d  b e n efi ci al r es ults.  
2 1.  M e di c al r es e ar c h i n v ol vi n g  h u m a n  p ati e nts  m a y  o nl y  b e  c o n d u ct e d if t h e i m p ort a n c e  of t h e 
o bj e cti v e  o ut w ei g hs t h e i n h er e nt ris ks  a n d  b ur d e ns t o t h e r es e ar c h  p ati e nts.  
2 2.  P arti ci p ati o n  b y  c o m p et e nt i n di vi d u als  as  p ati e nts i n  m e di c al r es e ar c h  m ust  b e  v ol u nt ar y. 
Alt h o u g h it  m a y  b e  a p pr o pri at e t o  c o ns ult f a mil y  m e m b ers  or  c o m m u nit y l e a d ers,  n o 
c o m p et e nt i n di vi d u al  m a y  b e  e nr oll e d i n  a r es e ar c h st u d y  u nl ess  h e  or s h e fr e el y  a gr e es.   
2 3.  E v er y  pr e c a uti o n  m ust  b e t a k e n t o  pr ot e ct t h e  pri v a c y  of r es e ar c h  p ati e nts  a n d t h e 
c o nfi d e nti alit y  of t h eir  p ers o n al i nf or m ati o n  a n d t o  mi ni mi z e t h e i m p a ct  of t h e st u d y  o n t h eir 
p h ysi c al,  m e nt al  a n d s o ci al i nt e grit y.  
2 4.  I n  m e di c al r es e ar c h i n v ol vi n g  c o m p et e nt  h u m a n  p ati e nts,  e a c h  p ot e nti al  p ati e nt  m ust  b e 
a d e q u at el y i nf or m e d  of t h e  ai ms,  m et h o ds, s o ur c es  of f u n di n g,  a n y  p ossi bl e  c o nfli cts  of 
i nt er est, i nstit uti o n al  affili ati o ns  of t h e r es e ar c h er, t h e  a nti ci p at e d  b e n efits  a n d  p ot e nti al ris ks 
of t h e st u d y  a n d t h e  dis c o mf ort it  m a y  e nt ail,  a n d  a n y  ot h er r el e v a nt  as p e cts  of t h e st u d y.  T h e 
p ot e nti al  p ati e nt  m ust  b e i nf or m e d  of t h e ri g ht t o r ef us e t o  p arti ci p at e i n t h e st u d y  or t o 
wit h dr a w  c o ns e nt t o  p arti ci p at e  at  a n y ti m e  wit h o ut r e pris al.  S p e ci al  att e nti o n s h o ul d  b e 
gi v e n t o t h e s p e cifi c i nf or m ati o n  n e e ds  of i n di vi d u al  p ot e nti al  p ati e nts  as  w ell  as t o t h e 
m et h o ds  us e d t o  d eli v er t h e i nf or m ati o n.  Aft er  e ns uri n g t h at t h e  p ot e nti al  p ati e nt  h as 
u n d erst o o d t h e i nf or m ati o n, t h e  p h ysi ci a n  or  a n ot h er  a p pr o pri at el y  q u alifi e d i n di vi d u al  m ust 
t h e n s e e k t h e  p ot e nti al  p ati e nt's fr e el y- gi v e n i nf or m e d  c o ns e nt,  pr ef er a bl y i n  writi n g. If t h e 
c o ns e nt  c a n n ot  b e  e x pr ess e d i n  writi n g, t h e  n o n- writt e n  c o ns e nt  m ust  b e f or m all y 
d o c u m e nt e d  a n d  wit n ess e d.  
2 5.  F or  m e di c al r es e ar c h  usi n g i d e ntifi a bl e  h u m a n  m at eri al  or  d at a,  p h ysi ci a ns  m ust  n or m all y 
s e e k  c o ns e nt f or t h e  c oll e cti o n,  a n al ysis, st or a g e  a n d/ or r e us e.  T h er e  m a y  b e sit u ati o ns  w h er e 
c o ns e nt  w o ul d  b e i m p ossi bl e  or i m pr a cti c al t o  o bt ai n f or s u c h r es e ar c h  or  w o ul d  p os e  a t hr e at 
t o t h e  v ali dit y  of t h e r es e ar c h. I n s u c h sit u ati o ns t h e r es e ar c h  m a y  b e  d o n e  o nl y  aft er 
c o nsi d er a ti o n  a n d  a p pr o v al  of  a r es e ar c h  et hi cs  c o m mitt e e.  
2 6.  W h e n s e e ki n g i nf or m e d  c o ns e nt f or  p arti ci p ati o n i n  a r es e ar c h st u d y t h e  p h ysi ci a n s h o ul d  b e 
p arti c ul arl y  c a uti o us if t h e  p ot e nti al  p ati e nt is i n  a  d e p e n d e nt r el ati o ns hi p  wit h t h e  p h ysi ci a n 
or  m a y  c o ns e nt  u n d er  d ur ess. I n s u c h sit u ati o ns t h e i nf or m e d  c o ns e nt s h o ul d  b e s o u g ht  b y  a n 
a p pr o pri at el y  q u alifi e d i n di vi d u al  w h o is  c o m pl et el y i n d e p e n d e nt  of t his r el ati o ns hi p.  
2 7.  F or  a  p ot e nti al r es e ar c h  p ati e nt  w h o is i n c o m p et e nt, t h e  p h ysi ci a n  m ust s e e k i nf or m e d 
c o ns e n t fr o m t h e l e g all y  a ut h ori z e d r e pr es e nt ati v e.  T h es e i n di vi d u als  m ust  n ot  b e i n cl u d e d i n 
a r es e ar c h st u d y t h at  h as  n o li k eli h o o d  of  b e n efit f or t h e m  u nl ess it is i nt e n d e d t o  pr o m ot e t h e 
h e alt h  of t h e  p o p ul ati o n r e pr es e nt e d  b y t h e  p ot e nti al  p ati e nt, t h e r es e ar c h  c a n n ot i nst e a d  b e 
p erf or m e d  wit h  c o m p et e nt  p ers o ns,  a n d t h e r es e ar c h  e nt ails  o nl y  mi ni m al ris k  a n d  mi ni m al 
b ur d e n.  
2 8.  W h e n  a  p ot e nti al r es e ar c h  p ati e nt  w h o is  d e e m e d i n c o m p et e nt is  a bl e t o  gi v e  ass e nt t o 
d e cisi o ns  a b o ut  p arti ci p ati o n i n r es e ar c h, t h e  p h ysi ci a n  m ust s e e k t h at  ass e nt i n  a d diti o n t o 
t h e  c o ns e nt  of t h e l e g all y  a ut h ori z e d r e pr es e nt ati v e.  T h e  p ot e nti al  p ati e nt's  diss e nt s h o ul d  b e 
r es p e ct e d.  
2 9.  R es e ar c h i n v ol vi n g  p ati e nts  w h o  ar e  p h ysi c all y  or  m e nt all y i n c a p a bl e  of  gi vi n g  c o ns e nt, f or 
e x a m pl e,  u n c o ns ci o us  p ati e nts,  m a y  b e  d o n e  o nl y if t h e  p h ysi c al  or  m e nt al  c o n diti o n t h at 
pr e v e nts  gi vi n g i nf or m e d  c o ns e nt is  a  n e c ess ar y  c h ar a ct eristi c  of t h e r es e ar c h  p o p ul ati o n. I n 
s u c h  cir c u mst a n c es t h e  p h ysi ci a n s h o ul d s e e k i nf or m e d  c o ns e nt fr o m t h e l e g all y  a ut h ori z e d 
r e pr es e nt ati v e. If  n o s u c h r e pr es e nt ati v e is  a v ail a bl e  a n d if t h e r es e ar c h  c a n n ot  b e  d el a y e d, 
t h e st u d y  m a y  pr o c e e d  wit h o ut i nf or m e d  c o ns e nt  pr o vi d e d t h at t h e s p e cifi c r e as o ns f or 


Cli ni c al  St u d y  Pr ot o c ol  R M - 4 9 3- 0 2 3  A u g ust  1 4,  2 0 1 8 
p a g e  9 5 
C O N FI D E N TI A L  
 
R h yt h m  P h ar m a c e uti c als, I n c. 
i n v ol vi n g  p ati e nts  wit h  a  c o n diti o n t h at r e n d ers t h e m  u n a bl e t o  gi v e i nf or m e d  c o ns e nt  h a v e 
b e e n st at e d i n t h e r es e ar c h  pr ot o c ol  a n d t h e st u d y  h as  b e e n  a p pr o v e d  b y  a r es e ar c h  et hi cs 
c o m mitt e e.  C o ns e nt t o r e m ai n i n t h e r es e ar c h s h o ul d  b e  o bt ai n e d  as s o o n  as  p ossi bl e fr o m t h e 
p ati e nt  or  a l e g all y  a ut h ori z e d r e pr es e nt ati v e.   
3 0.  A ut h ors,  e dit ors  a n d  p u blis h ers  all  h a v e  et hi c al  o bli g ati o ns  wit h r e g ar d t o t h e  p u bli c ati o n  of 
t h e r es ults  of r es e ar c h.  A ut h ors  h a v e  a  d ut y t o  m a k e  p u bli cl y  a v ail a bl e t h e r es ults  of t h eir 
r es e ar c h  o n  h u m a n  p ati e nts  a n d  ar e  a c c o u nt a bl e f or t h e  c o m pl et e n ess  a n d a c c ur a c y  of t h eir 
r e p orts.  T h e y s h o ul d  a d h er e t o  a c c e pt e d  g ui d eli n es f or  et hi c al r e p orti n g.  N e g ati v e  a n d 
i n c o n cl usi v e  as  w ell  as  p ositi v e r es ults s h o ul d  b e  p u blis h e d  or  ot h er wis e  m a d e  p u bli cl y 
a v ail a bl e.  S o ur c es  of f u n di n g, i nstit uti o n al  affili ati o ns  a n d  c o nfli cts  of i nt er est s h o ul d  b e 
d e cl ar e d i n t h e  p u bli c ati o n.  R e p orts  of r es e ar c h  n ot i n  a c c or d a n c e  wit h t h e  pri n ci pl es  of t his 
D e cl ar ati o n s h o ul d  n ot  b e  a c c e pt e d f or  p u bli c ati 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 h e  p h ysi ci a n  m a y  c o m bi n e  m e di c al r es e ar c h  wit h  m e di c al  c ar e  o nl y t o t h e  e xt e nt t h at t h e 
r es e ar c h is j ustifi e d  b y its  p ot e nti al  pr e v e nti v e,  di a g n osti c  or t h er a p e uti c  v al u e  a n d if t h e 
p h ysi ci a n  h as  g o o d r e as o n t o  b eli e v e t h at  p arti ci p ati o n i n t h e r es e ar c h s t u d y  will  n ot 
a d v ers el y  aff e ct t h e  h e alt h  of t h e  p ati e nts  w h o s er v e  as r es e ar c h  p ati e nts.   
3 2.  T h e  b e n efits, ris ks,  b ur d e ns  a n d  eff e cti v e n ess  of  a  n e w i nt er v e nti o n  m ust  b e t est e d  a g ai nst 
t h os e  of t h e  b est  c urr e nt  pr o v e n i nt er v e nti o n,  e x c e pt i n t h e f oll o wi n g  cir c u mst a n c es:  
•   T h e  us e  of  pl a c e b o,  or  n o tr e at m e nt, is  a c c e pt a bl e i n st u di es  w h er e  n o  c urr e nt  pr o v e n 
i nt er v e nti o n  e xists;  or  
•   W h er e f or  c o m p elli n g  a n d s ci e ntifi c all y s o u n d  m et h o d ol o gi c al r e as o ns t h e  us e  of  pl a c e b o 
is  n e c ess ar y t o  d et er mi n e t h e  effi c a c y  or saf et y  of  a n i nt er v e nti o n  a n d t h e  p ati e nts  w h o 
r e c ei v e  pl a c e b o  or  n o tr e at m e nt  will  n ot  b e  p ati e nt t o  a n y ris k  of s eri o us  or irr e v ersi bl e 
h ar m.  E xtr e m e  c ar e  m ust  b e t a k e n t o  a v oi d  a b us e  of t his  o pti o n.  
3 3.  At t h e  c o n cl usi o n  of t h e st u d y,  p ati e nts  e nt er e d i nt o t h e st u d y  ar e  e ntitl e d t o  b e i nf or m e d 
a b o ut t h e  o ut c o m e  of t h e st u d y  a n d t o s h ar e  a n y  b e n efits t h at r es ult fr o m it, f or  e x a m pl e, 
a c c ess t o i nt er v e nti o ns i d e ntifi e d  as  b e n efi ci al i n t h e st u d y  or t o  ot h er  a p pr o pri at e  c ar e  or 
b e n efits.  
3 4.  T h e  p h ysi ci a n  m ust f ul l y i nf or m t h e  p ati e nt  w hi c h  as p e cts  of t h e  c ar e  ar e r el at e d t o t h e 
r es e ar c h.  T h e r ef us al  of  a  p ati e nt t o  p arti ci p at e i n  a st u d y  or t h e  p ati e nt's  d e cisi o n t o  wit h dr a w 
fr o m t h e st u d y  m ust  n e v er i nt erf er e  wit h t h e  p ati e nt- p h ysi ci a n r el ati o ns hi p.  
I n t h e tr e atm e nt  of  a  p ati e nt,  w h er e  pr o v e n i nt er v e nti o ns  d o  n ot  e xist  or  h a v e  b e e n i n eff e cti v e, 
t h e  p h ysi ci a n,  aft er s e e ki n g  e x p ert  a d vi c e,  wit h i nf or m e d  c o ns e nt fr o m t h e  p ati e nt  or  a l e g all y 
a ut h ori z e d r e pr es e nt ati v e,  m a y  us e  a n  u n pr o v e n i nt er v e nti o n if i n t h e  p h ysi ci a n's j u d g m e nt it 
off ers  h o p e  of s a vi n g lif e, r e- est a blis hi n g  h e alt h  or  all e vi ati n g s uff eri n g.  W h er e  p ossi bl e, t his 
i nt er v e nti o n s h o ul d  b e  m a d e t h e  o bj e ct  of r es e ar c h,  d esi g n e d t o  e v al u at e its s af et y  a n d  effi c a c y. 
I n  all  c as es,  n e w i nf or m ati o n s h o ul d  b e r e c or d e d  a n d,  w h er e  a p pr o pri at e,  m a d e  p u bli cl y 
a v ail a bl e.  
 
 

SAP_001.pdf: 
Title : A Phase 3 Trial of Setmelanotide (RM-493), a 
Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-
Biedl Syndrome (BBS) and Alstrom Syndrome (AS) 
Patients with Moderate to Severe Obesity
NCT: NCT0374522
Date: October 29, 2020


STATISTICAL ANALYSIS PLAN
PROTOCOL RM-493-023
A Phase 3 trial of Setmelanotide (RM-493), a Melanocortin-4 Receptor 
(MC4R) Agonist, in Bardet-Biedl Syndrome (BBS) and Alström
syndrome (AS) Patients with Moderate to Severe Obesity
Protocol Number: 
Protocol Version and Date:
Name of Test Drug: 
Phase:
Methodology:
Sponsor:
Analysis Plan Date: 
Analysis Plan Version:
RM-493-023
Version 3.1: September 9, 2020
Version 3.0: 16 August 2020
Version 2.0: 04 February 2019
Version 1.1: 10 October 2018
Original: 14 August 2018
Setmelanotide (RM-493)
Phase 3
Randomized, 
Double-Blind, 
Placebo-Controlled 
(Period 1), Open-Label (Periods 2 and 3)
Rhythm Pharmaceuticals, Inc.
222 Berkeley Street, Suite 1200
Boston, MA 02116, USA
Tel: (857) 264-4282
Fax: (857) 264-4299
29 October 2020
Version 3.0
Confidentiality Statement
The information contained herein is confidential and the proprietary property of
Rhythm Pharmaceuticals, Inc. and any unauthorized use or disclosure of such information
without the prior written authorization of Rhythm Pharmaceuticals, Inc. is expressly prohibited.

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6
CONFIDENTIAL
Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
TABLES INCLUDED IN THE TEXT
Table 1 
Schedule of Assessments: Screening through Week 53 Visit (End of Period 2)14 
Table 2 
Schedule of Assessments: 14-Week Open-Label Treatment (Period 3) and Early 
Termination Visit................................................................................................ 17 
Table 3 
Summary of Core Analysis Elements................................................................. 42 
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7
CONFIDENTIAL
Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS
Abbreviation
Definition
AE
Adverse Event
AG
Active Growth Analysis Set
AS
Alström Syndrome
ATB
Active Treatment Baseline
BBS
Bardet-Biedl Syndrome
BMI
Body Mass Index
BOCF
Baseline Observation Carried Forward
BP
Blood Pressure
CI
Confidence Interval
CRF
Case Report Form
CRIBBS
Clinical Registry Investigating Bardet-Biedl Syndrome
Database
CS
Completers Set
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
DUS
Designated Use Set
ECG
Electrocardiogram
FAS
Full Analysis Set
HDL
High Density Lipoprotein
HR
Heart Rate
IQ
Intelligence Quotient
LOCF
Last Observation Carried Forward
MedDRA
MI
Medical Dictionary for Regulatory Activities
Multiple Imputation
NDA
New Drug Application
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8
CONFIDENTIAL
Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
Abbreviation
Definition
PCPB
Placebo-Controlled Period Baseline
PCS
~14 Week Placebo-Controlled Analysis Set
PP
Per-Protocol
PP at EOP1
Per-Protocol Set at End of Period 1
PP at EOP2
Per-Protocol Set at End of Period 2
QD
Once-Daily
SA
Safety Analysis
SAP
Statistical Analysis Plan
SC
Subcutaneous
SD
Standard Deviation
SH
Stable Height Analysis Set
SOA
Schedule of Assessments
WHO
World Health Organization
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9
CONFIDENTIAL
Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
 
1.
INFORMATION FROM THE STUDY PROTOCOL 
1.1.
Introduction and Objectives
1.1.1.
Introduction
This document presents the statistical analysis plan (SAP) for Study RM-493-023, A Phase 3 
trial of Setmelanotide (RM-493), a Melanocortin-4 Receptor (MC4R) Agonist, in Bardet-Biedl 
Syndrome (BBS) and Alström syndrome (AS) Patients with Moderate to Severe Obesity. This 
SAP is based upon protocol version dated 26 August 2020.
This SAP is designed to outline the methods to be used in the analysis of study data in order 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 study.
In addition, the SAP is intended to clarify many of the details of the more limited discussion 
in the statistical section of the protocol, therefore, the SAP will expand on and may modify 
the plans outlined in the study protocol. If changes are made to the plans outlined in the 
protocol, the SAP will supersede the relevant contents of the protocol. If, after the study has 
completed, changes are made to the SAP, then these deviations to the plan will be listed, 
along with an explanation as to why they occurred, in the Clinical Study Report for the study 
as appropriate. It should be noted that a cohort of the supplemental patients was added into 
the protocol in the midcourse of the study. However, the sponsor has specified that the
patients categorized in the pivotal cohort include all the enrolled BBS/AS patients at the time 
of the planned sixth AS patient enrollment. Based on this definition, and up to the finalization 
of the SAP, it is concluded that a total of 38 patients (the first 32 BBS patients and 6 AS 
patients) will make up the pivotal cohort. The full list of pivotal cohort patients is provided in 
Appendix I. All analyses for CSR and Submission, including demographics, disposition, 
baseline characteristics, efficacy, and safety etc., will be performed and the conclusions will be 
drawn based on the data from the pivotal cohort of patients. The purpose of the supplemental 
cohort is to gain more treatment experience. Therefore, unless stated otherwise, all analyses 
in the SAP refer to pivotal cohort only.
1.2.
Study Objectives
A brief note of initial clarification: as outlined in more detail in Sections 1.3.1 and 3.10.1, the
nature of the study design includes a randomized, double blinded and placebo-controlled 14-
week Period 1, followed directly by a ~38 weeks open label, active treatment Period 2, 
resulting in ~52 weeks on therapy. Patients then continue into another 14 weeks longer-term 
treatment. However, the primary analysis is planned after the last enrolling patient has finished 
Period 2 (i.e., at the end of ~52 weeks of overall therapy (placebo and/or active).
The approach to the primary analysis (i.e., main analysis for New Drug Application [NDA]
filing or applications in other regulatory agencies as appropriate) is outlined in Section 4.3.1.
Taking into account that enrollment has been ongoing for some time, many patients will be 
well into their second year of treatment at the time the primary analysis is planned (as the last 
patient ends ~52 weeks of overall therapy on the study). Thus, it is anticipated only a small
percentage of patients who are initially randomized into the placebo arm may have less than 
~52 weeks of setmelanotide treatment by the timing of the primary analysis (end of Period 2) 
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11
CONFIDENTIAL
Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
 
1.3.
Study Design
1.3.1.
Synopsis of Study Design
This is a pivotal study to confirm the long-term (approximately 1 year in most patients) 
efficacy and safety of setmelanotide treatment in patients who have BBS or AS. 
The study will consist of 3 treatment periods (see Figure 1). After obtaining informed consent, 
potential patients will be screened to determine study eligibility. Eligible patients will enter a 
14-week, randomized, double-blind, placebo-controlled treatment period (Period 1) that will be 
followed by a 38-week open-label treatment period (Period 2) in which all patients will receive 
setmelanotide. The primary analysis will be performed after the last patient enrolled has 
completed Period 2. To maintain the blind through Period 2, dose escalation to a fixed dose of 
3 mg will be performed during the first 2 weeks in both the double-blind (Period 1) and 38-
week open-label (Period 2) treatment periods. Following Period 2, patients will continue to 
receive open-label setmelanotide for 14 weeks (Period 3) after which they may be enrolled into 
a separate treatment extension study. 
Patients will be randomized in a 1:1 ratio, stratified by age group (≥12 years or <12 years) and 
disease (BBS or AS), to receive either setmelanotide QD or placebo QD via SC injection for 
the first 14 weeks. Patients who are ≥16 years of age will start on setmelanotide 2 mg or 
matching placebo during the 2-week dose escalation and will increase to 3 mg or matching
placebo at the beginning of Week 3. Patients who are <16 years of age will start on 
setmelanotide 1 mg or matching placebo during Week 1, will increase to 2 mg or matching 
placebo at the beginning of Week 2, and will increase to 3 mg or matching placebo at the 
beginning of Week 3. During the 14-week double-blind treatment period, patients will be 
evaluated at the beginning of Weeks 2 (telephone call only, patients <16 years old), 3, 7, 11, 
and 15 as depicted in Figure 1.
After the initial 14-week double-blind treatment period (Period 1), all patients will immediately 
transition to receive open-label setmelanotide QD via SC injection for 38 weeks (Period 2). To 
preserve the blind, all patients will be re-escalated to the 3 mg clinical dose. Thus, beginning at 
Week 15, patients who are ≥16 years of age will receive open-label setmelanotide 2 mg for 2 
weeks, followed by a dose increase to 3 mg beginning at Week 17, and patients who are <16 
years of age will receive open-label setmelanotide 1 mg during Week 15, 2 mg during Week 
16, and 3 mg beginning at Week 17. Patients will be evaluated at the beginning of Weeks 16 
(telephone call only, patients <16 years old) and 17 and then every 6 weeks thereafter during 
this Period 2. In Period 3, patients will be evaluated every 7 weeks.
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12
CONFIDENTIAL
Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
 
Figure 1
Study Design Schematic
 
1.3.2.
Randomization Methodology
This study will be open label, except for a 14-week double-blind, placebo-controlled period.
Patients who qualify for the study will return to the site on Day 1 of the double-blind period. 
Prior to randomization, the Investigator will ensure that the patient continues to meet inclusion 
and exclusion criteria. Patients who continue to be eligible to participate in the study will be 
assigned a unique randomization number based on a randomization code that will be generated 
prior to the start of the study. The randomization number codes the patient’s initial treatment 
assignment (for the double-blind period) to either setmelanotide or placebo. The randomization 
scheme will randomize patients in a 1:1 ratio, stratified by age group (≥12 years or <12 years) 
and disease (BBS or AS), to receive either setmelanotide or placebo during the first 14 weeks 
of the study. Randomization numbers will not be re-used once assigned. Please refer to the 
official randomization plan for greater details.
The Investigator, study site staff, clinical research organization staff providing site 
management, and Medical Monitor will not have access to the actual treatment assignment 
administered during the 14-week double-blind, placebo-controlled treatment period (Period 1)
except in the case of an emergency until all randomized participants have completed both the 
14-week double-blind, placebo-controlled period and the 38-week open-label portion of the 
study (Period 2).
1.3.3.
Stopping Rules and Unblinding
This study may be prematurely terminated, if in the opinion of the Investigator (at a 
participating site) or Rhythm (for the whole study), there is sufficiently reasonable cause. The 
terminating party will provide written notification documenting the reason for study 
termination to either the Investigator or Rhythm.
Circumstances that may warrant termination include, but are not limited to:
•
Determination of unexpected, significant, or unacceptable risk to subjects
•
Failure to enter subjects at an acceptable rate
•
Insufficient adherence to protocol requirements
•
Insufficient complete and/or evaluable data
•
Plans to modify, suspend, or discontinue the development of the study drug
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13
CONFIDENTIAL
Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
 
Should the study be closed prematurely, all study materials must be returned to the Sponsor or
designee.
Every attempt will be made to maintain the blind through the end of the 38-week, open-label 
treatment period (Period 2) (i.e., until the database snapshot prior to completing the primary 
analysis). Breaking the blind for a patient should be done only in the event of a medical 
emergency where the identity of study drug is necessary to appropriately treat the patient. The 
Primary Investigator will be provided with access to a system to unblind their patients, but if 
possible, the decision to break the blind should first be discussed with the Medical Monitor. If 
the blind is broken, the reason, when, and how the blind was broken will be documented.
1.3.4.
Study Procedures
The schedule of assessments (SOA), as outlined in the study protocol, is provided in Table 1 -
Table 2.
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Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
20 
CONFIDENTIAL 
 
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Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
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CONFIDENTIAL 
 
i.e., ~Week 53 visit, is not available, then the last available measurement of height will be 
used to define the analysis sets).
2.2.
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 Set. The Sponsor or designee will be
responsible for producing the final protocol violation file (formatted as a Microsoft Excel
file), in collaboration with the data monitoring group (or designee) as applicable; this file will
include a description each protocol violation and clearly identify whether or not this violation
warrants exclusion from the PP Set. This file will be finalized prior to database lock. An 
analysis performed on the PP set may be provided only if the number of patients in the PP set 
is 20% less than that in FAS/PCS set. 
All protocol violations will be presented in a data listing.
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GENERAL STATISTICAL METHODS 
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PPD


Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
24 
CONFIDENTIAL 
 
All output will be sorted and labeled according to the International Conference on
Harmonization recommendations and formatted to the appropriate page size(s).
Tabulations will be produced for appropriate demographic, baseline, efficacy, and safety
parameters. For categorical variables, summary tabulations of the number and percentage of
subjects within each category of the parameter will be presented. For continuous variables, 
the number of subjects (N), mean, 95% confidence interval of the mean, median, standard 
deviation (SD), minimum, and maximum values will be presented.
Formal statistical hypothesis testing will be performed on the primary efficacy endpoint 
with testing conducted at the 1-sided, 2.5% level of significance. Summary statistics will be 
presented, as well as confidence intervals (CIs), as described in the sections below. Trial 
success will be based on a 1-sided p-value <0.025.
3.3.
ComputingEnvironment
Unless otherwise noted, all descriptive statistical analyses will be performed using SAS®
statistical software (SAS Institute Inc., Cary, NC, USA). Medical history and AEs will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). Concomitant
medications will be coded using World Health Organization (WHO) Drug Dictionary.
3.4.
Baseline Definitions
To assess the dual nature of efficacy parameters, two efficacy baseline definitions will be used. 
•
Placebo-controlled period baseline (PCPB): is defined as the last available measurement 
prior to the first dose of setmelanotide or placebo. PCPB will be used for efficacy 
analysis based upon 14 weeks of treatment with either setmelanotide or placebo.
•
Active treatment baseline (ATB): is defined as the last available measurement prior to the
first dose of active setmelanotide. ATB will be used for efficacy analyses based upon ~52 
weeks of treatment.
For safety, including key laboratory (e.g. hematology and chemistry) parameters, the last 
measurement prior to the first dose of setmelanotide or placebo will be used as the baseline.
3.5.
Methods of Pooling Data
Data will be pooled across genetic obesity populations (BBS and AS). The primary analysis
will be performed based on pooled pivotal patients. Separate tabulations for efficacy 
parameters may be provided for the two genetic obesity populations, but no formal tests for 
differences in efficacy between groups will be carried out. BBS is a polygenic disorder; 
many participants may have “private” mutations different from all others in the study, and 
disparities in response by genotype are to be anticipated even within the BBS cohort, making 
formation of subgroups for statistical testing likely impossible.
3.6.
Adjustments for Covariates
No formal statistical analyses that adjust for possible covariate effects are planned.
3.7.
MultipleComparisons/Multiplicity
No multiplicity adjustments are required for the primary analysis as this study has only 1 
primary endpoint. This controls the overall alpha at 0.025, 1-sided.
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29 October 2020, Version 3.0
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CONFIDENTIAL 
 
There are multiple key secondary efficacy endpoints planned in the study (see Section 1.3.5.1).
However, based on the rarity of this disease, and the small number of patients to be enrolled in 
this study, the ability to use extremely rigorous statistical approaches to address multiplicity for 
these secondary endpoints is limited. Therefore, for publication, nominal-p-values will be used 
to interpret each endpoint separately in this small study. The Sponsor acknowledges that this 
approach may increase the probability of potential Type 1 error for the set of key secondary 
efficacy endpoints being analyzed. While this SAP does not envision multiplicity adjustments 
in this study, the Sponsor has pre-specified a step-down procedure (a hierarchical order of 
testing for the key secondary efficacy endpoints) to control Type-1 error, if needed for any
purpose. The key secondary endpoints are presented according to the Sponsor-specified 
hierarchical order in Section 4.3.2.
3.8.
Subgroups
3.8.1.
Subgroup Analysis by Disease Type
Subgroup analysis by disease type (e.g., BBS and AS; clinically defined or genetically defined)
on primary efficacy and key secondary efficacy endpoints will be summarized separately.
Analysis on the secondary endpoints, i.e., mean percent change of weight and hunger score at 
~14 week from baseline, will be conducted for each disease type. A 1-sided p-value and 
corresponding 95% 2-sided confidence interval will be provided. Please note that the study is 
not powered for individual subgroups, but powered based on the overall number of the pooled 
patients across disease types. Thus, the p-values for the subgroup analyses are exploratory and 
should be interpreted with caution and clinical judgement.
Please note that patients who enter the study based solely on clinical criteria (even if later they 
are confirmed by genetic testing) will define the “clinically-defined” subgroup. Therefore,
appropriate efficacy analysis by disease type subgroups will be performed based on clinically 
defined subgroup criteria.
3.8.2.
Subgroup Analysis of Pediatric Subjects
Subgroup analysis on pediatric populations will be conducted. The subgroup analysis may be 
performed based on the following age (at informed consent) categories:
•
Patients <12 years old (i.e., 6-11 years old)
•
Patients <17 years old (i.e., 6-16 years old)
Analysis of the primary efficacy and key secondary efficacy endpoints may be repeated for 
these two subsets and presented separately. Between-treatment group analysis (setmelanotide 
vs placebo) within each age category on the secondary endpoints, i.e., mean percent change of 
weight and hunger score at ~14 week from baseline, may be conducted.
The number of the 
pediatric patients in the pivotal cohort may be small, so these subgroup analyses may combine 
pediatric patients from both pivotal and supplemental cohorts as necessary.
A 1-sided p-value and corresponding 95% 2-sided confidence interval will be provided. Please 
note that the study is powered based on the overall number of the pooled patients, thus the p-
values for the subgroup analysis are exploratory and should be interpreted with caution and 
clinical judgement.
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29 October 2020, Version 3.0
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CONFIDENTIAL 
 
3.9.
Withdrawals, Dropouts, Loss to Follow-up
Patients will be informed that they have the right to withdraw their consent to participate in the 
study at any time for any reason, without prejudice to their medical care. The Investigator also 
has the right to withdraw patients from the study, after discussion with the Sponsor, for any of 
the following reasons:
•
Non-adherence to study drug regimen or protocol requirements.
•
Non-compliance with instructions or failure to return for follow-up.
If a patient is withdrawn or discontinued from the study, the primary reason for withdrawal 
from the study is to be recorded in the source documents/electronic case report form (eCRF). 
Any patient that discontinues treatment prior to completing the study should be strongly 
encouraged to complete all remaining visits and procedures as outlined in the SOA, even if 
they are no longer receiving study drug. 
In case of discontinuation, all AEs should be followed as described in Protocol Section 7.4; any 
skin AEs should continue to be followed, if at all feasible, for ~60-90 days to confirm near or 
complete resolution (as has been shown in previous studies). 
The Sponsor will provide support for patient and caregiver travel, will make available visiting 
home health care professionals, and any other necessary logistical support to ease the burden 
on the patient to facilitate compliance.
3.10.
Missing, Unused, and Spurious Data
In general, there will be no substitutions made to accommodate missing data points. All data 
recorded on the CRF will be included in data listings that will accompany the CSR.
When tabulating AE data, partial dates will be handled to more accurately determine 
whether an event was treatment-emergent.
AE start dates that are missing or incomplete will be handled as follows:
(1) Missing Day Only
•
If the month and year are the same as the month and year of the first dose 
date, the first dose date will be used.
•
If the month and year are before the month and year of the first dose date, 
the last day of the month will be assigned to the missing day.
•
If the month and year are after the month and year of the first dose date, the 
first day of the month will be assigned to the missing day.
(2) Missing Day and Month
•
If the year is the same as the year of the first dose date, the first dose date 
will be used.
•
If the year is prior to the year of the first dose date, December 31 will be 
assigned to the missing fields.
•
If the year is after the year of first dose date, January 1 will be assigned to 
the missing fields.
(3) Missing Day, Month, and Year
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CONFIDENTIAL 
 
Note, Early Termination visits will be treated as scheduled visits and may slot into any VC 
as fits criteria. Further, imputation of weight for 52 week analysis will focus on VC5 (for 
subjects initiated on active treatment) and VC7 (for subjects initiated on placebo) as these 
VCs are identified similarly, if not exactly, as the true timepoint would be identified, if it 
were not missing.
The above planned combination of the visits may be adjusted if the model cannot be fitted 
due to small sample size. Details will be defined in the ADRG. 
Once VCs are identified, they will be time aligned by treatment arm before multiple 
imputation occurs. 
That is, subjects initially randomized into the active treatment arm will have:
•
VC1
•
VC2
•
VC3
•
VC4
•
VC5 (52 Weeks on Active Treatment)
While subjects initially randomized into the placebo arm will have:
•
VC3
•
VC4
•
VC5
•
VC6
•
VC7 (52 Weeks on Active Treatment)
Monotone regression will then be used to impute the missing values, assuming proper 
missingness structure. The monotone regression method will impute 100 datasets. A seed of 
2187 has been randomly generated and will be used.
Fully conditional specification (FCS) regression may be used in the case that monotone 
regression is deemed not appropriate.
Daily hunger scores will have weekly average hunger score calculated and these weekly 
averages mapped to Visit Categories with the same algorithm as above.
3.10.2.
Approach on Missing Value Due to Other Reasons for ~52 Weeks Analysis
Every effort should be made to avoid missing values, but patients may have missing values 
due to other reasons such as lost to follow up, early dropout/discontinuation, missed visit, 
AEs etc. in addition to the administrative reason by the nature of the study design as
described above. In these cases, the same principal and MI approach will be used for 
imputation of the missing value as outlined above. However, for the primary and key 
secondary analyses, these imputed values will then be replaced with the patient’s baseline 

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CONFIDENTIAL 
 
value. This constitutes a treatment failure approach for these patients as the effective change 
and percent change from baseline will equate to 0. To assess the robustness of the analysis, a 
sensitivity analysis will also be conducted based on the imputed values themselves (no 
baseline replacement). For analyses outside of the primary and key secondary analyses, 
handling may differ based upon the analysis specified. Endpoints/analyses requiring 
imputations that are closely related to the primary or key secondary analyses will utilize the 
same handling as the primary and key secondary endpoints (baseline replacement). Other 
analyses utilizing imputation that are not closely related to the primary or key secondary 
analyses will utilize the values generated via multiple imputation and will not be replaced 
with baseline values. The specific handling for these analyses will also be outlined in the 
appropriate section below.
3.10.3.
Approach on Missing Value in ~14-Week Placebo-Controlled, Double-Blinded 
Period (Period 1)
Patients may have missing values in Period 1 for many reasons such as drop out, early 
discontinuation, missed visits, or AEs etc. Missing values in this period will be imputed with
a similar MI approach as 52 week analysis as defined in the primary imputation approach.
However, as this analysis revolves around 14 week timepoint, VC3 will be the focus of the 
imputation model. VC1, VC2, and VC3 will used in the multiple imputation model (SAS 
PROC MI) for 14 week timepoint with treatment group as a class factor. A sensitivity 
analysis may be conducted based on treatment failure approach on the missing value 
imputation for this period as appropriate.
3.11.
Visit Windows
Every effort should be made to ensure that all visits occur according to the protocol SOA,
including any dropouts. All data will be tabulated per the evaluation visit as recorded on the
CRF, even if the assessment is outside of the visit window. If the evaluation visit is missing in 
the database but there is data from an unscheduled or additional visit that is inside the visit 
window, the data from the unscheduled or additional visit will be used in data summaries.
Specific visit windows will be defined in a separate specification document. Windows around 
analysis time points will be outlined below. All available data will be listed for each subject.
3.11.1.
Analysis Window for Primary Analysis (i.e., ~52-Week Treatment) at the End of 
Period 2
The primary analysis will occur after the last enrolled patient has completed Period 2. i.e., ~52
weeks of treatment. An +/- 2 months window will be used for the primary endpoint. If a patient 
has a missing measurement at ~52 weeks of setmelanotide treatment but does have another 
non-missing measurement within 10-14 months (40-56 weeks) of active setmelanotide 
treatment, the measurement closest to 52 weeks will be used. If a patient has two non-missing 
visits within this window that are equidistant from 52 weeks, the earlier visit will be used. 
Given the fact that patients are staggered entering into the study and randomized into active 
treatment or placebo in the initial 14-week period, some patients will already have more than 1 
year (i.e., 52 weeks) of active treatment at the time of the data cut for NDA submission
(Primary Analysis). It is also likely that some other patients will have less than 1 year of active 
treatment. 
The examples below help to illustrate the approach outlined above:
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CONFIDENTIAL 
 
•
Example 1: A patient who was initially randomized to setmelanotide arm in Period 1, but
may have already had 15 months setmelanotide treatment and available data at the time 
of the primary analysis. The patient’s primary endpoint will be defined as the closest one 
to 52-weeks of active treatment within the 10-14 months window.
•
Example 2: A patient who was initially randomized to placebo in Period 1 but may have 
already been in the study for 15 months, having received 3 months of placebo then 12 
months of active setmelanotide. The patient’s primary endpoint will be defined as the 
closest one to 52-weeks of active treatment within the 10-14 month window.
•
Example 3: A patient who was initially randomized to placebo in Period 1 but may have 
been in the study for only 10 months, having received 3 months placebo then 7 months of
active setmelanotide. The patient’s primary endpoint will be defined as the patients ~12 
months active treatment measurement as generated via multiple imputation method
described above, since the patients active setmelanotide treatment duration is less than 10 
months.
•
Example 4: A patient who was initially randomized to placebo in Period 1 but may have 
been in the study for 14 months, having received 3 months placebo then 11 months of
active setmelanotide. The patient’s primary endpoint will be defined as the closest done 
to 52-weeks of active treatment within the 10-14 months window. 
There are two planned visits in Period 3 (14-week open-label treatment): Visit 14 (~Week 60)
and Visit 15 (EOS, ~Week 66). The analyses and summaries on data collected in this period 
will not be a main priority of the primary analysis for NDA submission or analyses in other 
regulatory agencies. However, an additional supportive analysis may be provided on these data 
after the approximately last patient in pivotal cohort completes the last visit at the end of period 
3.
The additional supportive analysis and summary at end of period 3 will be based on relative 
visits/days (i.e., staggered alignment) from the first dose of the setmelanotide, below examples 
illustrate the staggered alignment for analysis,
•
V2 (Week 1) of patients initially randomized in setmelanotide group (planned first dose 
visit of setmelanotide) will align with V6 (Week 15) of patients initially randomized in 
placebo group (i.e, planned first dose visit of setmelanotide).
•
V13 (Week 53) of patients initially randomized in setmelanotide group (~52 week visit 
on setmelanotide) will align with V15 (Week 66) of patients initially randomized in 
placebo group (i.e, ~52 weeks visit on setmelanotide).
•
Other visits will be aligned in a similar fashion.
3.11.2.
Analysis Window for 14 Week Analysis
A +/-1-month (4-week) window will be used for the analysis and summary of the 14-week 
endpoints.
3.12.
Interim Analyses and Timing of Planned Analyses
No formal interim analysis is currently planned for this study. However, various data cuts may 
occur in support of regulatory submissions such as a New Drug Application. The timing of 
these data cuts and the number of subjects included in each analysis will take into account 
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Rhythm Pharmaceuticals, Inc.
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29 October 2020, Version 3.0
32 
CONFIDENTIAL 
 
4.
STUDY ANALYSES 
4.1.
Subject Disposition
Subject disposition will be tabulated and include the number screened, the number
randomized, the number treated in total, the number dosed with setmelanotide, the number
dosed with placebo, the number in each subject population for analysis, and the number who
withdrew prior to completing the study and reason(s) for withdrawal.
A by-subject data listing of study completion information including the reason for premature 
study withdrawal, if applicable, will be presented. Subject disposition will include patients in 
the Screening Analysis Set.
4.2.
Demographics and Baseline Characteristics
Demographics and baseline characteristics will be summarized and presented by randomized 
treatment group and overall. Age at baseline as well as height, weight, and BMI at baseline
and initiation of active treatment will be summarized using descriptive statistics (N, mean,
95% confidence interval of the mean, SD, median, minimum, and maximum). The number 
and percentage of subjects in each sex, ethnicity, race, and clinically- or genetically-defined 
genetic deficiency categories (BBS; all AS patients were required to be genetically identified 
to enter the trial) also will be presented. The percentage of cognitively impaired subjects will 
be provided. The Fitzpatrick Classifications Scale will also be summarized. No formal 
statistical comparisons will be performed. Subject demographics will include patients in the 
Safety Analysis Set. A separate demographics summary will be created for patients ≥12 
years of age in the Full Analysis Set.
Medical history will be summarized in a table and presented in a by-patient listing.
4.3.
Efficacy Analyses
In general, efficacy analyses will be conducted using the FAS population. Additional 
supportive analysis based on the DUS, CS, and/or PP Sets etc. may be provided as appropriate.
Unless stated otherwise, all the analysis on hunger score data will be based on patients ≥12 
years of age while only descriptive summary will be provided for patients <12 years of age
(due to the different hunger score questionnaire tools). Descriptive statistics for endpoints 
analyzed at ~52 weeks will have their visits aligned by approximate relative day on 
setmelanotide (active treatment visit).
4.3.1.
Primary Efficacy Analysis
The primary efficacy analysis on the primary efficacy endpoint will be conducted in patients 
≥12 years of age (at informed consent) in the FAS population.
The primary efficacy endpoint is the proportion of patients (≥12 years of age) who achieve a 
≥10% reduction in body weight from baseline after ~52 weeks of treatment. The null
hypothesis (H0) to be tested is that the proportion of patients treated for ~52 weeks who 
achieve ≥10% reduction in body weight from baseline is less than or equal to a historical 
control rate of 10%. The alternative hypothesis (H1) is that the proportion is greater than a 
historical control rate of 10%:
H0: pt ≤ 10% vs H1: pt > 10% 
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PPD


Rhythm Pharmaceuticals, Inc.
Statistical Analysis Plan, Protocol RM-493-023
29 October 2020, Version 3.0
36 
CONFIDENTIAL 
 
This analysis will be based on a two-sample t-test for each of the 100 imputed datasets. The 
outcomes from the 100 imputed datasets will be combined using Rubin’s Rule to provide a p-
value and corresponding confidence intervals. This will be evaluated at a 1-sided, 0.025 
significance level.
Sensitivity analyses based on PP at EOP1 and CS may be provided.
Descriptive statistics for the change and percent change from baseline in body weight (kg) may
be presented for the PCS population by visit by randomized treatment.
Daily Hunger Score Percent Change from Baseline at 14 Weeks
The analysis on this secondary endpoint will be a between group comparison to investigate if 
setmelanotide-treated patients exhibit a greater improvement from baseline at ~14 weeks of 
therapy in weekly average of daily hunger scores, as compared to placebo-treated patients.
This analysis will be based on a two-sample t-test for each of the 100 imputed datasets. The 
outcomes from the 100 imputed datasets will be combined using Rubin’s Rule to provide a p-
value and corresponding confidence intervals. This will be evaluated at a 1 sided, 0.025 
significance level.
Prior to analysis, daily hunger scores for each of the 3 hunger assessments will be averaged 
separately by week, as outlined above. Sensitivity analyses based on PP at EOP1 and CS may
be provided.
Descriptive statistics for the change and percent change from baseline in weekly average of 
daily hunger scores may be presented based on the PCS population by visit by randomized 
treatment. Due to the suitability of using the hunger score tool in younger patients, this will be 
conducted in patients >=12 years of age at baseline.
4.3.4.
Sensitivity Efficacy Analyses
Non-Replacement Analysis:
In order to look at the impact of missing weight data on the proportion of patients (≥12 years of 
age) who achieve a ≥10% reduction in body weight from baseline and percent change from 
baseline after ~52 weeks of treatment, a non-replacement analysis may be done. For the 
primary analysis and key secondary analyses, patients who have missing 52 week weight data 
due to nature of study design will utilize the MI imputed 52 week values (described in the 
above Section 3.10.1) but patients who have missing 52 week data for any other reason will be 
considered treatment failures (including change and percent change from baseline set to 0). For 
this sensitivity analysis to be performed on primary and key secondary endpoints, all patients 
who have missing 52 week data, regardless of the cause, will have their MI imputed 52 week 
values used and no values will be set to baseline. Similar to the primary and key secondary 
analyses, this sensitivity analysis will generate 100 imputed datasets as appropriate and the 
outcomes from the 100 imputed datasets will be combined using Rubin’s Rule to provide a p-
value and corresponding confidence intervals. 
Active Treatment-Completer’s Analysis:
In order to look at the impact of missing weight data on the proportion of patients (≥12 years of 
age) who achieve a ≥10% reduction in body weight from baseline and percent change from 
baseline after ~52 weeks of treatment, a placebo-completer’s analysis may be done. For the 
primary analysis and key secondary analyses, patients who have missing 52 week weight data 
due to nature of study design will utilize the MI imputed 52 week values (described in the 
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Table 3
Summary of Core Analysis Elements
Endpoints
Analysis Set (1)
Primary 
(Sensitivity)
Main 
Patient 
Group
Baseline(2)
Subgroup 
Analysis
Primary
Proportion of patients who achieve a ≥10% reduction from baseline 
in body weight after ~52 weeks of treatment
FAS (SH, AG, 
PP at EOP2)
≥12 years
old
ATB
BBS, AS, <12 
yo, <17 yo
Key Secondary (after ~52 weeks of treatment)
Mean percent change from baseline in body weight 
FAS (DUS)
≥12 years
old
ATB
BBS, AS, <12 
yo, <17 yo
Mean percent change from baseline in the weekly average of the 
daily hunger score
FAS (FAS: 3/7 
daily 
responses,
DUS)
≥12 years
old
ATB
BBS, AS, <12 
yo
Proportion of patients who achieve a ≥25% improvement in the 
weekly average of the daily hunger score
FAS (FAS: 3/7 
daily 
responses)
≥12 years
old
ATB
BBS, AS
Secondary (at the Week 14 visit)
Mean percent change from baseline in body weight after treatment 
with setmelanotide as compared with placebo
PCS (PP at 
EOP1, CS)
≥12 years
old
PCPB
BBS, AS, <12 
yo, <17 yo
Mean percent change from baseline in the weekly average of the 
daily hunger score after treatment with setmelanotide as compared 
with placebo
PCS (PP at 
EOP1, CS,
PCS: 3/7 daily 
responses)
≥12 years
old
PCPB
BBS, AS, <12 
yo
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Endpoints
Analysis Set (1)
Primary 
(Sensitivity)
Main 
Patient 
Group
Baseline(2)
Subgroup 
Analysis
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Endpoints
Analysis Set (1)
Primary 
(Sensitivity)
Main 
Patient 
Group
Baseline(2)
Subgroup 
Analysis
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Endpoints
Analysis Set (1)
Primary 
(Sensitivity)
Main 
Patient 
Group
Baseline(2)
Subgroup 
Analysis
Notes: 
(1): FAS = Full Analysis Set; DUS = Designated Use Set; PCS = ~14 Week Placebo-controlled Analysis Set; CS = Completers 
Set; SH = Stable Height Analysis Set; AG = Active Growth Analysis Set; PP at EOP1 = Per-Protocol Set at End of Period 1; PP at 
EOP2 = Per-Protocol Set at End of Period 2; (see definition in Section 2.1)
(2): PCPB = Placebo-controlled period baseline; ATB = Active treatment baseline (see definition in Section 3.4)
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4.7.
Early Analyses on the ~14 Week Placebo-Controlled, Double-
Blinded, Randomized Period (Period 1) 
The study has a ~14 week placebo-controlled, double-blinded and randomized period (Period 
1). Analysis of Period 1 data at an early but appropriate time may be useful in planning 
additional clinical studies both in the same population as well as in other rare genetic disorders 
of obesity. Hence, Rhythm may consider the following approach to this data as it is expected
every pivotal patient will have completed Period 1 by approximately the end of 1Q2020.
The data on the ~14 weeks placebo-controlled period will be cleaned and finalized. Then, once 
clean and finalized, in a blinded fashion, an analysis on the Period 1 secondary efficacy 
endpoints and specified safety analysis below may be conducted by a separate independent 
statistician group otherwise unrelated to the study (e.g., by a separate team at Rhythm’s outside 
statistical designated vendor). The results of this analysis will not be released or shared with 
any Rhythm personnel, or anyone connected with the study, until the last pivotal patient 
enrolled has completed Period 2 (~52 weeks of treatment), at the time of the primary analysis. 
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If conducted, no change in the conduct of this study will be made and any conclusions will be 
used to plan and initiate additional clinical studies. In addition, all analyses will only include 
group-mean data results, with no information on any individual patient data. 
Rhythm does not expect any bias to be introduced or any impact on the type 1 error since the 
group-mean data will not be available until the study is completed through the end of Period 2.
Selected safety summaries will also be provided for this 14-week, placebo-controlled, double-
blinded, randomized period (Period 1).
The below selected summaries may be provided for this analysis:
•
Disposition and drug compliance to be summarized by group.
•
Group mean efficacy to be analyzed for the two secondary endpoints as planned in 
Section 4.3.3 (Other Secondary Endpoint Section).
•
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6.
REFERENCES 
Saris-Baglama R, Dewey C, Chisholm G, et al. (2011). QualityMetric Health Outcomes Scoring 
Software 4.5 User’s Guide. Lincoln, RI: QualityMetric Incorporated.
Vami, JW. (2017). Scaling and Scoring of the Pediatric Quality of Life Inventory PedsQL. Lyon, 
France: Mapi Research Trust.
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