A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 111 in Children With Achondroplasia
Phase: PHASE2
Conditions: Achondroplasia
Sponsor: BioMarin Pharmaceutical

 
 
 
 
    
 
 
 
 
 
 
Offici al Title : A P hase 2, O pe n -la bel, Se q u e ntial C o h ort D ose-escalati o n St u d y of B M N 
  
    
1 1 1 i n C hil dre n wit h Ac h o n dr o plasia 
 
N C T N u m ber : N C T 0 2 0 5 5 1 5 7 
 
A p plic a nt/ M A H:  Bi o Mari n  P har mace utical I nc.  
 
Versi o n D ate : 2 2 A u g ust 2 0 1 6   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Pr o prietar y a n d C o nfi de ntial
1 6
A P P E N DI C E S
1 6. 1
St u d y I nf or m ati o n
1 6. 1. 1
Pr ot oc ol a n d Pr ot oc ol A me n d me nt s
Pr ot oc ol 1 1 1 -2 0 2 A 4 FI N A L  2 2 A U G 2 0 1 6
Pr ot oc ol 1 1 1 -2 0 2 A 3 FI N A L  2 6 O C T 2 0 1 5
Pr ot oc ol 1 1 1 -2 0 2 A 2 FI N A L  0 8 M A Y 2 0 1 5
Pr ot oc ol 1 1 1 -2 0 2 A 1 FI N A L  0 3J U N 2 0 1 4
Pr ot oc ol 1 1 1 -2 0 2 FI N A L 2 5 O C T 2 0 1 3
Pr ot oc ol 1 1 1 -2 0 2 FI N A L Fre nc h Re v -0 3 3 0 O C T 2 0 1 5
Pr ot oc ol 1 1 1 -2 0 2 FI N A L Fre nc h Re v -0 1 0 9 S E P 1 4
1 6. 1. 1 G ui deli nes
A nt hr o p o metric Meas ure me nt Pr oce d ures V 2 . 0 7J U L2 0 1 5
El b o w Ra n ge of M oti o n G ui deli nes 0 5J U N 2 0 1 5
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Pa ge 1
                            1 1 1- 2 0 2 C S R

 
 
C LI NI C A L S T U D Y P R O T O C O L  
St u d y Title:  
A P hase 2, O pe n -la bel, Se q ue ntial C o h ort D ose-escalati o n St u d y of B M N 
1 1 1 i n C hil dre n wit h Ac h o n dr o plasia  
Pr ot oc ol N u m ber:  
1 1 1 -2 0 2  
I n vesti g ati o n al Pr o d uct: 
B M N 1 1 1 ( m o difie d r h C N P)  
I N D N u m ber: 
1 1 1 2 9 9  
E ur o pe a n U ni o n Dr u g 
Re g ul ati n g A ut h orities 
Cli nic al Tri als ( E u dr a C T) 
N u m ber:  
2 0 1 3 -0 0 4 1 3 7 -3 2  
I n dic ati o n: 
Ac h o n dr o plasia  
S p o ns or:  
Bi o Mari n P har mace utical I nc.  
1 0 5 Di gital Dri ve  
N o vat o, C A 9 4 9 4 9  
De vel o p me nt P h ase:  
P hase 2  
S p o ns or's Res p o nsi ble 
M e dic al M o nit or:  
, M D, P h D 
Me dical Direct or  
Tre at me nt D ur ati o n:  
U p t o 2 4  m o nt hs  
St u d y D ur ati o n:  
2 5  m o nt hs  
D ose  I niti al P h ase : 
 
 
 
 
D ose O pti o n al, O pe n -l a bel 
E xte nsi o n P h ase:  
C o h ort 1: dail y m or ni n g d ose of 2. 5  µ g/ k g  
C o h ort 2: dail y m or ni n g d ose of u p t o 7. 5  µ g/ k g  
C o h o rt 3: dail y m or ni n g d ose of u p t o 1 5. 0 µ g/ k g  
C o h ort 4: dail y m or ni n g d ose of 3 0  µg/ k g  
 
 
D oses f or s u bj ects i n C o h orts 1 - 4 ma y i ncrease u p t o 3 0 µ g/ k g   
 
 
D ate of Ori gi n al Pr ot oc ol:  
2 5 Oct o ber 2 0 1 3  
D ate of A me n d me nt 1  
0 3 J u ne  2 0 1 4  
D ate of A me n d me nt 2  
0 8  M a y 2 0 1 5  
D ate of A me n d me nt 3  
2 6  Oct o ber 2 0 1 5  
D ate of A me n d me nt 4  
2 2  A u g ust  2 0 1 6  
 
Pr o pert y of Bi o Mari n 
C O N FI D E N TI A L  
Ma y n ot be di v ul ge d, p u blis he d, or ot her wise discl ose d t o ot hers wit h o ut pri or writte n a p pr o val fr o m 
Bi o Mari n. 
T his st u d y will be c o n d ucte d acc or di n g t o t he pri nci ples of G o o d Cli nical Practice as descri be d i n t he 
U. S. C o de of Fe deral Re g ulati o ns a n d t he I nter nati o nal C o nfere nce o n Har m o nisati o n G ui deli nes, 
i ncl u di n g t he arc hi vi n g of esse ntial d oc u me nts. 
Bi o Mari n is a re gistere d tra d e mar k of Bi o Mari n P h ar mac e utical I nc.  
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pr ot oc ol. p df
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
C LI NI C A L S T U D Y P R O T O C O L A M E N D M E N T S U M M A R Y  
A me n d me nt: 4 
D ate: 2 2 A u g ust  2 0 1 6 
 
R A TI O N A L E A N D S U M M A R Y O F M A J O R C H A N G E S  
T his pr ot oc ol is bei n g r e vise d t o ma ke t he f oll o wi n g c h a n ges: 
1.  C o h ort 5 will n ot be i nitiate d a n d has b ee n wit h dra w n fr o m t he pr ot oc ol.  
Rati o nale:  A me n d me nt 2 of St u d y 1 1 1- 2 0 2 i nc or p orate d t he o pti o n t o a d d t w o 
a d diti o nal c o h orts at d oses of 3 0 μ g/ k g ( C o h ort 4) a n d u p t o 6 0 μ g/ k g ( C o h ort 5). 
T hese d oses w ere pr o p os e d t o ac hie v e e x p os ures e x pecte d t o res ult i n f urt her 
i ncreas es i n a n n ualize d gr o wt h vel ocit y ( A G V) wit h a n acce pta ble safet y pr ofile i n 
c hil dre n wit h A C H. Preli mi nar y res ults fr o m C o h ort 4 ( 3 0 µ g/ k g) s h o w a greater t ha n 
d ose- pr o p orti o nal i ncr eas e i n B M N 1 1 1 e x p os ure, wit h  a mar gi nal i m pr o ve me nt i n 
b ot h a bs ol ute A G V a n d c ha n ge fr o m b aseli ne A G V after 6 m o nt hs of B M N 1 1 1 
treat me nt w he n c o m par e d wit h C o h ort 3 ( 1 5 µ g/ k g). T h us, C o h ort 5 ( wit h d osi n g u p 
t o 6 0 µ g/ k g) will n ot be p urs ue d. 
2.  A d mi nistrati ve c ha n ges a n d mi n or e dits f or clarit y a n d c o n siste nc y ha v e bee n 
i nc or p orate d:  
a. St u d y R ati o nale has bee n re vise d t o ma ke t he c o nt e nt m ore c o ncis e [ § 7. 3]. 
b.  Safet y R ati o nale has bee n re vise d t o ma ke t he c o nte nt m ore c o ncise; pleas e refer 
t o t he I n v esti gat ors Br oc h ure f or d etaile d safet y i nf or mati o n [ § 7. 4. 2. 2]. 
c. Beca use C o h ort 5 has b ee n wit h dra w n, t he n u m ber of s u bjects has b ee n re d uce d 
fr o m a p pr o xi matel y 4 6 t o a p pr o xi matel y 3 6 s u bjects [ § 9. 1; § 1 3. 5]. 
d.  I nf or mati o n re gar di n g bl o o d press ure assess me nt s has bee n cl arifie d  [ Sc he d ule of 
E ve nts; § 9. 1 0. 4. 4. 1]. 
 
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 3 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
2  
S Y N O P SI S  
N A M E O F C O M P A N Y  
Bi o Mari n P har mace utical I nc.  
1 0 5 Di gital Dri ve  
N o vat o, C A 9 4 9 4 9 
 
N A M E O F FI NI S H E D 
P R O D U C T:  
B M N 1 1 1 
 
N A M E O F I N V E S TI G A TI O N A L 
P R O D U C T: m o difie d r h C N P  
S U M M A R Y T A B L E  
Referri n g t o Part of t he D ossier:  
 
V ol u me:  
 
Pa ge:  
 
Refere nce:  
F O R N A TI O N A L 
A U T H O RI T Y U S E O N L Y:  
TI T L E O F S T U D Y : A P hase 2, O pe n-la bel, Se q ue ntial C o h ort D ose-escalati o n St u d y of B M N 1 11 i n 
C hil dre n wit h Ac h o n dr o plasia 
P R O T O C O L N U M B E R : 1 1 1-2 0 2  
S T U D Y SI T E S : A p pr o xi matel y 1 0  sites 
P H A S E O F D E V E L O P M E N T : P hase 2 
S T U D Y R A TI O N A L E:  
Ac h o n dr o plasia ( A C H), t he m ost c o m m o n f or m of dis pr o p orti o nate s h ort stat ure or d warfis m, is a n 
a ut os o mal d o mi na nt ge netic s keletal dis or der ca use d b y a gai n - of-f u ncti o n m utati o n i n t he fi br o blast 
gr o wt h fact or rece pt or - 3 ge ne (F G F R 3 ), a ne gati ve re g ulat or of e n d oc h o n dral b o ne f or mati o n. C-t y pe 
natri uretic pe pti de ( C N P) a n d its rece pt or, N P R -B, are ke y re g ulat ors of s keletal gr o wt h. Alterati o n i n 
C N P/ N P R -B si g nali n g lea ds t o s keletal -relate d p he n ot y pes. Re d uce d or a bse nt C N P e x pressi o n i n 
mice res ults i n se vere d warfis m as a c o nse q ue nce of i m paire d e n d oc h o n dral ossificati o n 
( C h us h o, 2 0 0 1, Pr oc Natl. Aca d Sci U. S. A). I n di vi d uals w h o ha ve a m utati o n i n N P R-B t hat i n hi bits its 
f u ncti o n, ha ve a c o n diti o n k n o w n as acr o mes o melic d ys plasia t y pe Mar otea u x, c haracterize d b y 
i m paire d s keletal gr o wt h, a b n or mal gr o wt h plates, a n d s h ort miss ha pe n b o nes i n t he e xtre mities 
( Bartels, 2 0 0 4, A m.J. H u m. Ge net.).  C o n versel y, o vere x pressi o n of C N P res ults i n o ver gr o wt h i n mice 
a n d h u ma ns ( B occiar di, 2 0 0 7, H u m. M utat.). 
I n mice wit h a F G F R 3  gai n - of-f u ncti o n m utati o n, c o nti n u o us C N P i nf usi o n (Yas o da, 2 0 0 9, 
E n d ocri n ol o g y ) le d t o n or malizati o n of t he d warfis m p he n ot y pe, i n dicati n g t hat C N P/ N P R-B 
acti vati o n re d uce d F G F R 3 d o w nstrea m si g nali n g.  T his w or k pr o vi de d t he pre- cli nical pr o of of 
c o nce pt t hat C N P mi g ht be a t hera p y f or A C H. H o we ver, s u bc uta ne o us ( S C) a d mi nistrati o ns of C N P, 
a preferre d cli nical r o ute, faile d t o i n d uce s keletal gr o wt h, pres u ma bl y beca use of its ra pi d eli mi nati o n 
me diate d b y N P R- C, a cleara nce rece pt or, a n d b y ne utral e n d o pe pti dase ( N E P) pr ote ol ysis.  C N P 
half- life is less t ha n 2 mi n utes after I V a d mi nistrati o n.   
B M N 1 1 1 is a rec o m bi na nt C N P a nal o g ue t hat has bee n e n gi neere d t o c o nfer N E P resista nce. 
B M N  1 1 1 has a l o n ger half-life, a p pr o xi matel y 4 5 mi n utes i n h u ma ns. 
T he p har mac ol o gical acti vit y of B M N 1 1 1 was e x pl ore d i n mice ( wil d-t y pe mice a n d t w o m o use 
m o dels of A C H, a se vere, F gfr 3 Y 3 6 7 C/ +  m o del, a n d a mil d F gfr 3 G 3 8 0 R/ +  [ Ac h] m o del) a n d i n 
n or mal rats a n d m o n ke ys.  Partial t ha nat o p h oric d ys plasia [ T D] ( L or get, 2 0 1 2, A m.J H u m. Ge net) or 
c o m plete [ Ac h] re versi o n of t he A C H p he n ot y pe was o bser ve d i n t hese m o use m o dels after B M N 1 1 1 
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pr ot oc ol. p df
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
a d mi nistrati o n.  A d diti o nall y, i n wil d -t y pe mice rats, a n d n or mal m o n ke ys, B M N 1 1 1 a d mi nistrati o n 
res ulte d i n gr o wt h plate e x pa nsi o n a n d d ose-de pe n de nt s keletal gr o wt h at he m o d y n a micall y t olerate d 
d ose le vels.   
I n St u d y 1 1 1- 1 0 1, t he safet y a n d t olera bilit y of B M N 1 1 1 were assesse d i n a d ult male v ol u nteers 
wit h o ut A C H.   T his P hase I st u d y was a t w o - part, d o u ble- bli n d, place b o-c o ntr olle d st u d y.  Part 1 
e xa mi ne d a series of si n gle s u bc uta ne o us d oses ( 5 µ g/ k g, 1 0 µ g/ k g a n d 1 5 µ g/ k g), a n d Part 2 i ncl u de d 
1 0 da ys  of eit her fi xe d d osi n g or d ose escalati o n ( 0. 5 µ g/ k g t o 8 µ g/ k g).  B M N 1 1 1 was ge nerall y well 
t olerate d at all d oses.  As e x pecte d, mil d, tra nsie nt, self-li mite d h y p ote nsi o n was re p orte d  (refer t o 
c urre nt I n vesti gat ors Br oc h ure f or a d diti o nal i nf or mati o n) . B M N 1 1 1 de m o nstrate d d ose-relate d li near 
i ncreases i n e x p os ure b y ma xi m u m o bser ve d plas ma c o nce ntrati o n ( Cma x ) (fr o m 2. 5 µ g/ k g t o 
1 5 µ g/ k g) i n healt h y v ol u nteers; plas ma mea n half -life ra n ge d fr o m 4 0 t o 5 5 mi n utes. 
St u d y 1 1 1- 2 0 2 is desi g ne d as a pr o of- of-c o nce pt st u d y f or B M N 1 1 1 i n c hil dre n wit h A C H. T he i nitial 
p hase of t his st u d y is 6 m o nt hs a n d will all o w f or assess me nt of t he effect of dail y B M N 1 1 1 
a d mi nistrati o n o n safet y, t olera bilit y, gr o wt h vel ocit y, a bs ol ute gr o wt h, a n d b o d y pr o p orti o ns at d ose s 
ra n gi n g fr o m 2. 5- 3 0 μ g/ k g gi ve n s u bc uta ne o usl y dail y. A cli nicall y rele va nt i ncrease i n a n n ualize d 
gr o wt h vel ocit y is c o nsi dere d t o be i n t he ra n ge of 2 5 %- 5 0 % c ha n ge fr o m baseli ne, alt h o u g h t he 
tar gete d i ncrease ma y be refi ne d base d o n o n g oi n g c o m pre he nsi ve safet y a n d efficac y re vie w of 
B M N  1 1 1. A d diti o nal e x pl orat or y e n d p oi nts t hat reflect t he me dical c o m plicati o ns of A C H will als o 
be e val uate d.  
After c o m pleti n g t he i nitial p hase of t he st u d y lasti n g 6 m o nt hs, s u bjects ma y e nr oll i n a n o pti o nal, 
o pe n- label e xte nsi o n peri o d of a p pr o xi matel y 1 8 m o nt hs t o c o m me nce at t he e n d of t he i nitial p hase of 
t he st u d y, ma ki n g a t otal st u d y d urati o n of a p pr o xi matel y 2 5 m o nt hs, i ncl u di n g a 1- m o nt h safet y 
f oll o w- u p visit.  T he rati o nale f or t he e xte nsi o n p hase is t o assess t he l o n g -ter m safet y a n d t olera bilit y 
of B M N  1 1 1 i n c hil dre n wit h A C H; a n d t o assess l o n ger-ter m effects of B M N 1 1 1 o n gr o wt h i n t hese 
c hil dre n. 
Safet y data i n m o n ke ys s u p p ort d osi n g A C H c hil dre n at t he pr o p ose d d oses of 3 0 µ g/ k g dail y wit h 
caref ul m o n it ori n g a n d ma na ge me nt of he m o d y na mic a n d s keletal c ha n ges.  T o date, cli nical data i n 
St u d y 1 1 1- 2 0 2 de m o nstrate d t hat B M N 1 1 1 was ge nerall y well t olerate d at d oses u p t o 3 0 µ g/ k g 
wit h o ut e vi de nce of a b n or mal gr o wt h or si g nifica nt car di o vasc ular effects.  
O B J E C TI V E S:  
T he pri mar y o bjec ti ve of t he i nitial 6- m o nt h p hase is:  
•  
T o e val uate t he safet y a n d t olera bilit y of dail y S C i nj ecti o ns of B M N  1 1 1 a d mi nistere d f or 
6 m o nt hs  
T he pri mar y o bjecti ve of t he st u d y e xte nsi o n is:  
•  
T o e val uate t he safet y a n d t olera bilit y  of dail y S C i nj ecti o ns of B M N  1 1 1 a d mi nistere d f or u p 
t o 2 4 m o nt hs   
T he sec o n dar y o bj ecti ves of t he st u d y are:  
•  
T o e val uate c ha n ge fr o m baseli ne i n a n n ualize d gr o wt h vel ocit y f oll o wi n g dail y S C i nj ecti o ns 
of B M N  1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 24 m o nt hs  
•  
T o e val uate c ha n ges fr o m baseli ne i n gr o wt h para meters f oll o wi n g dail y S C i nj ecti o ns of 
B M N  1 1 1 a d mi nistere d f or 6  m o nt hs, a n d u p t o 2 4 m o nt hs  
•  
T o e val uate c ha n ges fr o m baseli ne i n b o d y pr o p orti o ns ( u p per ar m t o f orear m le n gt h, u p per 
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
le g t o l o wer le g le n gt h, a n d u p per t o l o wer b o d y se g me nt rati os) f oll o wi n g dail y S C i nj ecti o ns 
of B M N  1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  
T o e val uate d ose -e x p os ure a n d P K pr ofiles of B M N 1 1 1 i n c hil dre n wit h A C H f oll o wi n g dail y 
S C i nj ecti o ns of B M N 1 1 1 at eac h d ose le vel a n d o ver m ulti ple da ys   
T he e x pl orat or y o bj ecti ves of t he st u d y are:  
•  
T o e val uate c ha n ge fr o m baseli ne i n Q C T b o ne mi neral de nsit y ( B M D) f oll o wi n g dail y 
S C  i nj ecti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs 
•  
T o e val uate c ha n ges fr o m baseli ne i n gr o wt h plate m or p h ol o g y f oll o wi n g dail y S C i njecti o ns 
of B M N  1 1 1 f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  
T o e val uate c ha n ges fr o m baseli ne i n l o n g - b o ne gr o wt h, a n d m or p h ol o g y of t he s pi ne 
f oll o wi n g dail y S C i njecti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  
T o e val uate c ha n ges fr o m baseli ne i n slee p a p nea f oll o wi n g dail y S C i njecti o ns a d mi nistere d 
f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  
T o e val uate c ha n ges fr o m baseli ne i n el b o w j oi nt ra n ge of m oti o n b y g o ni o metr y, f oll o wi n g 
dail y S C i nj ecti o ns a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs 
•  
T o e val uate c ha n ges fr o m baseli ne i n B M N  1 1 1 acti vit y bi o mar kers a n d b o ne/c olla ge n 
bi o mar kers f oll o wi n g dail y S C i nj ec ti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 
2 4 m o nt hs  
•  
T o  e val uate i m m u n o ge nicit y fr o m baseli ne a n d assess i m pact o n safet y, P K, a n d efficac y 
meas ures f oll o wi n g dail y S C i nj ecti o ns of B M N 1 1 1 d uri n g t he 6 m o nt hs, a n d u p t o 
2 4 m o nt hs  
S T U D Y D E SI G N A N D P L A N:  
T he pri mar y o bjecti ve of t his st u d y is t o assess t he safe t y a n d t olera bilit y of dail y B M N 1 1 1 
a d mi nistere d t o c hil dre n wit h A C H.  D ose re gi me ns will be assesse d wit h f o ur d osi n g c o h orts.  
A p pr o xi matel y 3 6 s u bjects w h o are 5 t o 1 4 years ol d (i ncl usi ve) will be e nr olle d.  A ma xi m u m of fi ve 
c hil dre n fr o m o ne ge n der ma y be e nr olle d i n eac h c o h ort if t he t otal size of t he c o h ort is ei g ht or ni ne 
s u bj ects; a ma xi m u m of si x c hil dre n fr o m o ne ge n der ca n be e nr olle d i n eac h c o h ort if t he size of t he 
c o h ort is 1 0 s u bjects. 
C o m pre he nsi ve o ut patie nt safet y m o nit ori n g will be  c o n d ucte d f or all s u bjects after t he first d ose of 
st u d y dr u g is recei ve d o ver t he c o urse of t he first 1 0 da ys, f oll o we d b y cl ose m o nit ori n g t hr o u g h o ut 
t he d urati o n of t he st u d y.  T he c o m pre he nsi ve safet y m o nit ori n g i ncl u des a mi ni m u m of 8 h o urs p ost 
d ose o bser vati o n o n t he first t w o da ys of d osi n g a n d at least 4 h o urs p ost d ose o bser vati o n o n st u d y 
da ys 3 a n d 4.  S u bjects ma y be o bser ve d f or a l o n ger d urati o n a n d/ or a d diti o nal visits ma y be a d de d 
f or f urt her safet y assess me nt o n Da ys 5-9 at t he discreti o n  of t he I n vesti gat or i n c o ns ultati o n wit h t he 
Bi o Mari n Me dical M o nit or.  A visit o n Da y 1 0 c o ncl u des t he c o m pre he nsi ve o ut patie nt 
safet y- m o nit ori n g peri o d.  Vital si g ns will be m o nit ore d fre q ue ntl y d uri n g t he i nitial peri o d of 
Da ys  1- 1 0, i ncl u di n g a p pr o xi matel y e ver y 1 0 - 2 0 mi n utes f or t he first 2 h o urs p ost d ose o n visit da ys.   
A d diti o nal safet y assess me nts d uri n g t his peri o d are electr ocar di o gra m ( E C G), p h ysical e xa ms, A E 
assess me nt, a n d cli nical la bs ( T a ble  9. 1 . 1).  
B M N 1 1 1 will be a d mi nistere d as a m or ni n g d ose i n o ne of t he f oll o wi n g dail y d osi n g re gi me ns: 
•  
C o h ort 1: t he first ei g ht s u bjects w ill recei ve 2. 5 µ g/ k g B M N 1 1 1.  
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pr ot oc ol. p df
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  
C o h ort 2: t he sec o n d ei g ht s u bj ects will re cei ve u p t o 7. 5 µ g/ k g B M N 1 1 1.  
•  
C o h ort 3: t he t hir d ei g ht  t o te n s u bjects will recei ve u p t o 1 5. 0 µ g/ k g B M N 1 1 1. 
•  
C o h ort 4:  t he f o urt h ei g ht t o te n s u bjects will recei ve 3 0. 0 µ g/ k g B M N 1 1 1. 
If s u bjects are t olerati n g t he dr u g well, care gi vers ma y be a ble t o a d mi nister st u d y dr u g at h o me if 
a p pr o ve d b y t he I n vesti gat or, a n d a de q uate trai ni n g is de m o nstrate d.  Ot her wise, h o me d osi n g m ust be 
perf or me d b y a h o me healt h pr ofessi o nal.  H o me healt h care is n ot re q uire d at a n y p oi nt.  I n t he i nitial 
p hase, o n wee ks w he n care gi vers/s u bjects will n ot see eit her a h o me healt hcare pr ofessi o nal or a st u d y 
staff me m ber, a p h o ne call b y t he st u d y staff me m ber t o t he care gi ver/s u bj ect will be re q uire d.  D uri n g 
t he call, st u d y staff will as k t he care gi ver a b o ut c orrect a d mi nistrati o n pr oce d ures, assess a d verse 
e ve nts ( A Es), rec or d c o nc o mita nt me dicati o ns, a n d a ns wer q uesti o ns.  D uri n g t he o pti o nal, o pe n-la bel 
e xte nsi o n p hase, t he call fre q ue nc y will c ha n ge t o e ver y t w o wee ks  f or t he first 6 m o nt hs of t he 
e xte nsi o n p hase a n d m o nt hl y t hereafter.  
D ose Esc al ati o n Pl a n D uri n g t he I niti al 6 M o n t hs of t he St u d y 
F or eac h c o h ort, t w o se nti nel s u bj ects will be e nr olle d a n d m o nit ore d. A D M C re vie w will occ ur after 
b ot h se nti nel s u bjects reac h Da y 1 0; if st o p pi n g criteria are n ot met, a n d after re vie w a n d a p pr o val b y 
t he D M C, t he re mai n der of t he c o h ort ma y t he n be e nr olle d.  
S u bj ects will re mai n o n a dail y fi xe d d ose t hr o u g h o ut t he i nitial 6- m o nt h treat me nt peri o d.  S u bjects i n 
eac h c o h ort c o nti n ue t o recei ve dail y d osi n g ( C o h ort 1, 2. 5 µ g/ k g; C o h ort 2, u p t o 7. 5 µ g/ k g, C o h ort 3, 
u p t o 1 5 µ g/ k g, a n d C o h ort 4, 3 0 µ g/ k g) f or 6 m o nt hs u nless st o p pi n g criteria are met. W he n cli nical 
safet y is esta blis he d a n d st o p pi n g criteria are n ot met after all 8- 1 0 s u bj ects ha ve c o m plete d at 
mi ni m u m t heir first 1 0  da ys of c o h ort d osi n g, a n d after D M C re vie w a n d a p pr o val, t he s u bse q ue nt 
c o h ort ma y be o pe n t o e nr oll me nt.  
D at a M o nit ori n g C o m mittee  
I n a d diti o n t o safet y m o nit ori n g b y Bi o Mari n pers o n nel, a n i n de pe n de nt D M C will act as a n a d vis or y 
b o d y t o Bi o Mari n a n d will m o nit or t he safet y a n d P K ( w he n a vaila ble) of s u bj e cts i n t he st u d y.  T he 
D M C will i ncl u de i n de pe n de nt e x perts a n d ke y o pi ni o n lea ders i n fiel ds t hat ma y i ncl u de, b ut n ot 
li mite d t o: A C H, natri uretic pe pti des, b o ne gr o wt h, car di ol o g y, ra di ol o g y, cli nical p har mac ol o g y, a n d 
bi ostatistics.  T he  D M C will ma ke rec o m me n dati o ns f or st o p pi n g or c o nti n ui n g t he st u d y o n a s u bject 
le vel a n d/ or o n a c o h ort le vel per t he pre-s pecifie d st o p pi n g criteria.  T he D M C ma y als o pr o vi de 
rec o m me n dati o ns f or d ose m o dificati o ns as nee de d f or eac h c o h ort.   
I n di vi d u al S u bject St o p pi n g Criteri a 
F or i n di vi d ual s u bjects, te m p orar y d osi n g s us pe nsi o n, per ma ne nt disc o nti n uati o n of d osi n g, or , i n 
e xce pti o nal circ u msta nces,  d ose re d ucti o n  will be c o nsi dere d a n d D M C will be i nf or me d (at a 
mi ni m u m) if a n y of t he f oll o wi n g occ ur: 
•  
A n y treat me nt -e mer ge nt a d verse e ve nt ( T E A E) at least Gra de 3 assesse d b y t he I n vesti gat or 
a n d/ or S p o ns or Me dical M o nit or  
•  
A n y t w o T E A Es Gra de 2 e x perie nce d b y t he sa me s u bject wit hi n 1 wee k,  i ncl u di n g t w o 
s y m pt o matic h y p ote nsi o n e ve nts wit hi n 1 wee k ( n o n- ur ge nt me dical i nter ve nti o n i n dicate d) or 
a n y Gra de 3 h y p ote nsi ve e ve nt ( ur ge nt me dical i nter ve nti o n or h os pitalizati o n i n dicate d) 
assesse d b y t he I n vesti gat or a n d/ or S p o ns or’s Me dical M o nit or  
•  
Pr ol o n gati o n of Q T c -F  i nter val t o m ore t ha n 5 0 0 mil lisec o n d ( msec), ve ntric ular tac h ycar dia 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
greater t ha n fi ve beats  
•  
A n y cli nicall y si g nifica nt w orse ni n g of e xisti n g dis pr o p orti o nate gr o wt h, as deter mi ne d b y 
p h ysical meas ure me nt rati os a n d/ or I n vesti gat or assess me nts base d o n i ma gi n g, meas ure me nt 
or cli nical o bser vati o n fi n di n gs 
o  U p pe r ar m t o f orear m le n gt h rati o 
o  U p per le g t o l o wer le g le n gt h rati o 
o  U p per t o l o wer b o d y se g me nt rati o 
•  
Cli nicall y si g nifica nt w orse ni n g of b o ne m or p h ol o g y as e vi de nce d b y de vel o p me nt of ti bial 
b o wi n g, or w orse ni n g of e xisti n g ti bial b o wi n g as o bser ve d via cli nical or ra di o gra p hic 
assess me nt  
•  
Cli nicall y si g nifica nt w orse ni n g of el b o w j oi nt ra n ge of m oti o n base d o n cli nical assess me nt 
a n d o n g o ni o metr y meas ure me nts of fle xi o n-e xte nsi o n 
•  
Fi n di n gs o n cli nical hi p e xa m or hi p i ma gi n g assess me nts t hat are deter mi ne d t o be cli nicall y 
si g nifica nt as deci de d b y pri nci pal i n vesti gat or a n d i n c o ns ultati o n wit h s p o ns or me dical 
m o nit or a n d ort h o pe dic s pecialist (if nee de d). 
If t he s u bject meets a n y st o p pi n g criteria, after I n vesti gat or c o ns ultati o n wit h t he Bi o Mari n Me dical 
M o nit or a n d D M C, t he s u bject ma y  be re- c halle n ge d at t he sa me d ose .  If t he s u bject meets st o p pi n g 
criteria o n re -c halle n ge or if re-c halle n ge at sa me d ose is n ot cli nicall y i n dicate d, ot her o pti o ns t hat 
ma y be c o nsi dere d i ncl u de:  
•  
Re -c halle n ge at l o wer d ose wit h c o nsi derati o n gi ve n t o u p war d titrati o n t o t olerate d 
d ose/c o h ort d ose  
•  
Per ma ne nt treat me nt disc o nti n uati o n ( wit h a n o pti o n of o n g oi n g assess me nt i n t he st u d y)  
C o h ort St o p pi n g Criteri a  
F or a n y o pe n c o h ort a n d all hi g her d ose c o h orts, te m p orar y d osi n g s us pe nsi o n or d ose re d ucti o n will 
be c o nsi dere d a n d D M C re vie w will be c o n d ucte d (at a mi ni m u m) if a n y of t he f oll o wi n g occ ur: 
•  
A n y t w o s u bj ects wit hi n a c o h ort ha ve treat me nt- e mer ge nt A E at least Gra de 3; a n y t w o 
s u bj ects ha ve t w o s y m pt o matic h y p ote nsi o n e ve nts wit hi n 1 wee k eac h Gra de 2 ( n o n- ur ge nt 
me dical i nter ve nti o n i n dicate d); or a n y t w o s u bjects ha ve a Gra de 3 h y p ote nsi o n e ve nt ( ur ge nt 
me dical i nter ve nti o n or h os pitalizati o n i n dicate d) as assesse d b y t he I n vesti gat or a n d/ or 
S p o ns or Me dical M o nit or  
•  
A n y  o ne s u bj ect wit h a n y treat me nt -e mer ge nt A E Gra de 4 or 5 assesse d b y t he I n vesti gat or 
a n d/ or S p o ns or Me dical M o nit or  
•  
A n y t w o s u bj ects wit hi n a c o h ort ha ve p r ol o n gati o n of Q T c- F i nter val t o m ore t ha n 5 0 0 msec, 
ve ntric ular tac h ycar dia greater t ha n fi ve  beats  
•  
A n y t w o s u bj ects wit hi n a c o h ort ha ve cli nicall y si g nifica nt w orse ni n g of e xisti n g 
dis pr o p orti o nate gr o wt h, as deter mi ne d b y p h ysical meas ure me nt rati os a n d/ or I n vesti gat or 
assess me nts base d o n i ma gi n g, meas ure me nt or cli nical o bser vati o n fi n di n gs:  
o  U p per ar m t o f orear m le n gt h rati o 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
o  U p per le g t o l o wer le g le n gt h rati o  
o  U p per t o l o wer b o d y se g me nt rati o 
•  
A n y t w o s u bj ects wit hi n a c o h ort e x hi bit cli nicall y si g nifica nt w orse ni n g of b o ne m or p h ol o g y 
as e vi de nce d b y de vel o p me nt of ti bial b o wi n g, or w orse ni n g of e x isti n g ti bial b o wi n g as 
o bser ve d via cli nical or ra di o gra p hic assess me nt  
•  
A n y t w o s u bj ects e x hi bit cli nicall y si g nifica nt w orse ni n g of el b o w j oi nt ra n ge of m oti o n base d 
o n cli nical assess me nt a n d o n g o ni o metr y meas ure me nts of fle xi o n -e xte nsi o n  
•  
A n y t w o s u bj ects e x hi bit fi n di n gs o n cli nical hi p e xa m or hi p i ma gi n g assess me nts t hat are 
deter mi ne d t o be cli nicall y si g nifica nt as deci de d b y pri nci pal i n vesti gat or a n d, if nee de d, i n 
c o ns ultati o n wit h s p o ns or me dical m o nit or a n d ort h o pe dic s pecialist (if nee de d). 
•  
A n y ot her reas o n D M C a d vises te m p orar y disc o nti n uati o n of c o h ort d osi n g u ntil f urt her 
re vie w of safet y data is c o n d ucte d 
Sites  ha ve 1 b usi ness da y t o re p ort t o Bi o Mari n a n e ve nt t hat meets i n di vi d ual or c o h ort st o p pi n g 
criteria.  D M C ca n as k f or a d diti o nal  a vaila ble data w hile re vie wi n g s u bject(s) w h o met i n di vi d ual 
st o p pi n g criteria, or s u bjects wit h a n y ot her ne w safet y fi n di n g. I n or der t o assess si g nifica nce of t he 
fi n di n gs, D M C ca n re q uest t o re vie w a d diti o nal data f or ot her s u bjects i n t he c o h ort, or a n y ot her 
s u bj ects i n t he st u d y. T hese a d diti o nal data i ncl u de, b ut are n ot li mite d t o, p h ysical e xa m, vital si g ns, 
a nt hr o p o metric meas ures, E C G, E C H O, a n d la b res ults.  T he D M C will re vie w a vaila ble, rele va nt 
safet y data wit hi n 5-7 da ys after Bi o Mari n is a p prise d of a n e ve nt.  Bi o Mari n will kee p all sites 
i nf or me d of e nr oll me nt pa uses, t o e ns ure t hat n o s u bjects i n t he c o h ort (a n d all hi g her c o h orts) t hat are 
affecte d b y st o p pi n g criteria are treate d, a n d n o ne w s u bj ects are e nr olle d, u ntil t he assess me nt is 
c o m plete.  Base d o n its re vie w, t he D M C ma y ma ke a n y of t he f oll o wi n g rec o m me n dati o ns: 
•  
C o nti n ue c o h ort a n d se q ue ntial d osi n g of c o h orts as pla n ne d wit h a d diti o nal safet y m o nit ori n g 
a n d/ or safet y re vie ws as i n dicate d  
•  
C o nti n ue c urre nt c o h ort, b ut hi g her d ose c o h orts will recei ve l o wer d oses t ha n pla n ne d  
•  
Decrease c o h ort d ose a n d decrease d oses of s u bse q ue nt c o h orts  
•  
E xte n d te m p orar y treat me nt disc o nti n uati o n u ntil a d diti o nal data are a vaila ble a n d/ or f urt her 
re vie w/c o ns ultati o n occ urs  
•  
Per ma ne ntl y disc o nti n ue treat me nt f or all c o h orts  
•  
D ose a d diti o nal s u bjects of t he c o h ort at t he sa me d ose  
C o h ort d oses ma y be c ha n ge d, base d o n D M C re vie w of safet y a n d efficac y data, t o a n y d ose bet wee n 
0. 5 µ g/ k g a n d 3 0 µ g/ k g. A n y s u bject w h o disc o nti n ues fr o m st u d y dr u g will be e nc o ura ge d t o 
c o m plete assess me nts as a p pr o priate f or t he d urati o n of t he st u d y ( Secti o n 9. 3. 3 ). 
O pti o n al, O pe n -l a bel E xte nsi o n P h ase of t he St u d y  
I n t he o pe n-la bel, o pti o nal e xte nsi o n p hase, t he l o n g-ter m safet y, t olera bilit y, a n d effects of B M N  1 1 1 
o n gr o wt h will be e val uate d i n c hil dre n wit h A C H w h o ha ve c o m plete d a n i nitial 6 m o nt hs of 
treat me nt wit h B M N 1 1 1. At t he Da y 1 8 3/ 6-m o nt h visit, s u bjects w h o elect t o c o nti n ue partici pati n g 
i n t he o pti o nal o pe n-l a bel e xte nsi o n p hase will be c o nse nte d  f or t he e xte nsi o n p hase.  T hese s u bjects 
will recei ve st u d y dr u g o n Da y 1 8 4 of t he i nitial p hase , w hic h als o mar k s t he be gi n ni n g of t he 
e xte nsi o n p hase.  Dr u g treat me nt will c o nti n ue wit h o ut i nterr u pti o n.  S u bjects w h o decli ne t o 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
partici pate i n  t he e xte nsi o n p hase will ret ur n at Da y 2 0 8  f or t he S afet y F oll o w -U p visit a n d e xit t he 
st u d y. 
I n t he 1 8- m o nt h o pti o nal, o pe n-la bel e xte nsi o n p hase , su bj ects wit hi n eac h c o h ort will eit her re mai n 
o n t he sa me sta ble d ose t hat t he y  ha ve bee n recei vi n g d uri n g t he i nitial 6 m o nt hs of treat me nt, or t he 
d ose f or all s u bjects i n t he c o h ort (e xce pt c o h ort 4) ma y be i ncrease d base d o n t he f oll o wi n g r ules: 
( 1) I nitial d ose was deter mi ne d t o e x hi bit s u b o pti mal efficac y o n t he basis of gr o wt h meas ure me nts 
after at least 6 m o nt hs of treat me nt base d o n t he re vie w of t he data f or all s u bjects i n t he c o h ort.  
( 2) I nitial d ose, a n d ot her d oses hi g her t ha n t he i nitial d ose, b ut l o wer t ha n t he d ose t o w hic h t he 
c o h ort is bei n g i ncrease d were ge nerall y well t olerate d f or at least 6 m o nt h s base d o n re vie w of data 
f or all s u bjects i n t he c o h ort. 
( 3) T he d ose t o w hic h t he s u bj ects i n t he c o h ort are bei n g escalate d has bee n pre vi o usl y s h o w n t o be 
well t olerate d f or at least  1 0 da ys of c o m pre he nsi ve o ut patie nt safet y m o nit ori n g as descri be d i n  
Secti o n 9. 1  base d o n D M C re vie w of t he data f or all s u bj ects i n t he c o h ort pre vi o usl y assi g ne d t o t he 
c o nsi dere d d ose.  
D uri n g t he o pti o nal, o pe n- la bel e xte nsi o n p hase , visits will ta ke place at 2- t o 3- m o nt h i nter vals.  T he 
site will call t he care gi ver/s u bj ect bet wee n visits e ver y t w o wee ks f or t he first 6 m o nt hs a n d e ver y 
m o nt h f or t he re mai n der of t he st u d y .  
T he ti mi n g of d ose a dj ust me nts a n d f oll o w- u p visits after a dj ust me nt is c o nti n ge nt u p o n t he ti me at 
w hic h t he d ose a dj ust me nt was rec o m me n de d.  If t he rec o m me n dati o n t o a dj ust t he d ose is 
c o m m u nicate d t o t he sites w he n t he ne xt sc he d ule d visit is ≤ 4 wee ks a wa y, d ose a dj ust me nt will be 
d o ne at t he ne xt sc he d ule d visit.  If t he rec o m me n dati o n t o a dj ust t he d ose is c o m m u nicate d t o t he 
sites w he n t he ne xt sc he d ule d visit is > 4 wee ks a wa y, a n u nsc he d ule d d ose a dj ust me nt visit will be 
d o ne wit hi n 4 wee ks.  I n b ot h cases, a f oll o w -u p visit 4 wee ks ( ± 2  wee ks)  is re q uire d after t he d ose 
a dj ust me nt. T he d ose a dj ust me nt f oll o w -u p visit will be s c he d ule d 4 wee ks after t he d ose a dj ust me nt 
visit U N L E S S a re g ularl y sc he d ule d visit occ urs wit hi n t he ± 2 -wee k  visit wi n d o w , i n w hic h case a 
se parate f oll o w- u p visit will n ot be re q uire d.  
D M C data re vie w will occ ur a p pr o xi matel y e ver y 4 m o nt hs d uri n g t he o pti o nal, o pe n- la bel e xte nsi o n 
p hase.  
S u bj ects w h o partici pate i n t he o pe n-la bel e xte nsi o n p hase of st u d y 1 1 1- 2 0 2 will ha ve t he o pti o n t o 
e nr oll i n t he l o n g-ter m e xte nsi o n st u d y 1 1 1- 2 0 5 at t he M o nt h 2 4/ St u d y C o m pleti o n Visit.  M o nt h 2 4 
assess me nts will ser ve as Baseli ne/scree ni n g assess me nts f or e ntr y t o st u d y 1 1 1 - 2 0 5. 
N U M B E R O F S U B J E C T S P L A N N E D:  
A p pr o xi matel y 3 6 c hil dre n wit h A C H, as d oc u me nte d b y cli nical gr o u n ds a n d ge netic testi n g  
DI A G N O SI S A N D A L L  C RI T E RI A F O R I N C L U SI O N A N D E X C L U SI O N:  
I ncl usi o n Criteri a: 
I n di vi d uals m ust meet t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble t o partici pate i n t his st u d y:  
1.  Pare nt(s) or g uar dia n(s) are willi n g a n d a ble t o pr o vi de writte n, si g ne d i nf or me d c o nse nt after 
t he nat ure of t he st u d y has bee n e x plai ne d a n d pri or t o perf or ma nce of a n y researc h-relate d 
pr oce d ure. Als o, s u bjects u n der t he a ge of 1 8 are willi n g a n d a ble t o pr o vi de writte n asse nt 
(if re q uire d b y l ocal re g ulati o ns or t he I R B/ E C) after t he nat ure of t h e st u d y has bee n 
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e x plai ne d a n d pri or t o perf or ma nce of a n y researc h -relate d pr oce d ure. 
2.  5 t o 1 4 years ol d, i ncl usi ve at st u d y e ntr y 
3.  Ha ve A C H, d oc u me nte d b y cli nical gr o u n ds a n d c o nfir me d b y ge netic testi n g 
4.  Ha ve at least a 6 - m o nt h peri o d of pretreat me nt gr o wt h assess me nt i n St u d y 1 1 1- 9 0 1 
i m me diatel y bef ore st u d y e ntr y, a n d ha ve  o ne d oc u me nte d sta n di n g hei g ht at least 6 m o nt hs 
( +/- 1 0 da ys) pri or t o t he scree ni n g visit f or 1 1 1- 2 0 2 
5.  Fe males  ≥ 1 0 years ol d or w h o ha ve be g u n me nses m ust ha ve a ne gati ve pre g na nc y t est at t he 
Scree ni n g Visit a n d be willi n g t o ha ve a d diti o nal pre g na nc y tests d uri n g t he st u d y   
6.  If se x uall y acti ve, willi n g t o use a hi g hl y effecti ve met h o d of c o ntrace pti o n w hile partici pati n g 
i n t he st u d y 
7.  Are a m b ulat or y a n d a ble t o sta n d wit h o ut assista nce  
8.  Are willi n g a n d a ble t o perf or m all st u d y pr oce d ures as p h ysicall y p ossi ble 
9.  Pare nts or care gi vers are willi n g t o a d mi nister dail y i njecti o ns t o t he s u bjects  a n d c o m plete t he 
re q uire d trai ni n g 
A d diti o n al I ncl usi o n Criteria f or O pti o n al, O pe n -l a bel E xte n si o n P h ase: 
1.  A p pr o priate writte n i nf or me d c o nse nt (a n d asse nt, if a p plica ble) 
E xcl usi o n Criteri a:  
I n di vi d uals w h o meet a n y of t he f oll o wi n g e xcl usi o n criteria are n ot eli gi ble t o partici pate i n t he st u d y:  
1.  Ha ve h y p oc h o n dr o plasia or s h ort stat ure c o n diti o n ot her t ha n A C H (e. g., tris o m y 2 1, 
pse u d oac h o n dr o plasia) 
2.  Ha ve a n y of t he f oll o wi n g:  
a. H y p ot h yr oi dis m or h y pert h yr oi dis m 
b.  I ns uli n-re q uiri n g dia betes mellit us  
c. A ut oi m m u ne i nfla m mat or y disease (i ncl u di n g celiac disease , l u p us ( S L E), j u ve nile 
der mat o m y ositis , scler o der ma, a n d ot hers) 
d.  I nfla m mat or y b o wel disease  
e. A ut o n o mic ne ur o pat h y 
f. Rece nt ac ute ill ness ass ociate d wit h v ol u me de pleti o n (e. g., na usea, v o miti n g, diarr hea) 
t hat has n ot c o m pletel y res ol ve d pri or t o t he first d ose of t he st u d y dr u g 
3.  Ha ve a n u nsta ble c o n diti o n li kel y t o re q uire s ur gical i nter ve nti o n d uri n g t he st u d y (i ncl u di n g 
pr o gressi ve cer vical me d ullar y c o m pressi o n)  
4.  Gr o w t h plates ha ve f use d 
5.  Ha ve a hist or y of a n y of t he f oll o wi n g: 
a. Re nal i ns ufficie nc y defi ne d as ser u m creati ni ne > 2 m g/ dl  
b.  A ne mia  
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c. Baseli ne s yst olic bl o o d press ure ( B P) < 7 5 milli meters of merc ur y ( m m H g) or rec urre nt 
s y m pt o matic h y p ote nsi o n ( defi ne d as e pis o des of l o w B P ge nerall y acc o m pa nie d b y 
s y m pt o ms i.e., dizzi ness, fai nti n g) or rec urre nt s y m pt o matic ort h ostatic h y p ote nsi o n 
d.  Car diac or vasc ular disease, i ncl u di n g t he f oll o wi n g:  
i. 
Car diac d ysf u ncti o n (a b n or mal ec h ocar di o gra m [ E C H O] i ncl u di n g a b n or mal left 
ve nt ricle [ L V] mass) at Scree ni n g Visit  
ii. 
H y pertr o p hic car di o m y o pat h y  
iii. 
P ul m o nar y h y perte nsi o n 
i v. 
C o n ge nital heart disease wit h o n g oi n g car diac d ysf u ncti o n  
v.  
Cere br o vasc ular disease  
vi.  
A ortic i ns ufficie nc y  
vii.  
Cli nicall y si g nifica nt atrial or ve ntric ular arr h yt h mias  
6.  Ha ve t h e f oll o wi n g c o nfir me d E C G fi n di n gs: 
a. Ri g ht or left atrial e nlar ge me nt or ve ntric ular h y pertr o p h y  
b.  P R i nter val >  2 0 0 msec  
c. Q R S i nter val >  1 1 0 msec 
d.  C orrecte d Q Tc - F  > 4 5 0 ms ec  
e. Sec o n d- or t hir d -de gree atri o ve ntric ular bl oc k  
7.  D oc u me nte d V ita mi n D deficie nc y (i.e., c o nce ntrati o n of 2 5- h y dr o x y- vita mi n D i n t he bl o o d 
ser u m occ urs at 1 2 n g/ m L or less)  
8.  Re q uire a n y i n vesti gati o nal a ge nt pri or t o c o m pleti o n of st u d y peri o d 
9.  Ha ve recei ve d a n ot her i n vesti gati o nal pr o d uct or i n vesti gati o nal me dical de vice wit hi n 
3 0 da ys bef ore t he Scree ni n g Visit  
1 0.  Ha ve use d a n y ot her i n vesti gati o nal pr o d uct or i n vesti gati o nal me dical de vice f or t he 
treat me nt of A C H or s h ort stat ure at a n y ti me 
1 1.  C urre nt c hr o nic t hera p y wit h a nti h y perte nsi ve me dicati o ns, a n gi ote nsi n-c o n verti n g e nz y me 
( A C E) i n hibit ors, a n gi ote nsi n II rece pt or bl oc kers, di uretics, beta -bl oc kers, calci u m -c ha n nel 
bl oc kers, car diac gl yc osi des, s yste mic a ntic h oli ner gic a ge nts, a n y me dicati o n t hat ma y i m pair 
or e n ha nce c o m pe nsat or y tac h ycar dia,  di uretics, or ot her dr u gs k n o w n t o alter re nal or t u b ular 
f u ncti o n 
1 2.  Ha ve bee n treate d wit h gr o wt h h or m o ne, i ns uli n-li ke gr o wt h fact or 1 (I G F- 1), or a na b olic 
ster oi ds i n t he pre vi o us 6 m o nt hs or l o n g-ter m treat me nt ( > 3 m o nt hs) at a n y ti me  
1 3.  Ha ve ha d re g ular l o n g- ter m treat me nt ( > 1 m o nt h) wit h oral c ortic oster oi ds (l o w- d ose o n g oi n g 
i n hale d ster oi d f or ast h ma, or i ntra nasal ster oi ds, are acce pta ble) 
1 4.  C o nc o mita nt me dicati o n t hat pr ol o n gs t he Q T/ Q Tc- F i nter val wit hi n 1 4 da ys or 5 half- li ves, 
w hic he ver is l o n ger, bef ore t he Scree ni n g Visit 
1 5.  Pre g na nt or bre astfee di n g at t he Scree ni n g Visit or pla n ni n g t o bec o me pre g na nt (self or 
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part ner) at a n y ti me d uri n g t he st u d y  
1 6.  Ha ve ha d li m b -le n gt he ni n g or b o ne-relate d s ur ger y or e x pecte d t o ha ve li m b-le n gt he ni n g or 
b o ne-relate d s ur ger y d uri n g t he st u d y peri o d.  S u bjec ts wit h pre vi o us li m b-le n gt he ni n g or 
b o ne- relate d s ur ger y ma y e nr oll if s ur ger y occ urre d at least 1 8 m o nt hs pri or t o t he st u d y a n d 
heali n g is c o m plete wit h o ut se q uelae 
1 7.  Ha ve ha d a fract ure of t he l o n g b o nes or s pi ne wit hi n 6 m o nt hs pri or t o scree ni n g (e xce p t f or 
fract ure of di gits or t oes) 
1 8.  Ha ve as partate a mi n otra nsferase ( A S T) or ala ni ne a mi n otra nsferase ( A L T) at least 3 x u p per 
li mit of n or mal ( U L N) or t otal bilir u bi n at least 2 x U L N (e xce pt f or s u bjects wit h k n o w n 
hist or y of Gil bert’s disease) 
1 9.  E vi de nce of se vere slee p a p nea re q uiri n g s ur ger y or ne w i nitiati o n of C P A P ( base d o n t he 
scree ni n g slee p st u d y)  
2 0.  Ha ve c urre nt mali g na nc y, hist or y of mali g na nc y, or c urre ntl y u n der w or k- u p f or s us pecte d 
mali g na nc y  
2 1.  Ha ve k n o w n h y perse nsiti vit y t o B M N 1 1 1 or its e xci pie nts 
2 2.  Ha ve a c o n diti o n or circ u msta nce t hat, i n t he vie w of t he I n vesti gat or, places t he s u bj ect at 
hi g h ris k f or p o or treat me nt c o m plia nce or f or n ot c o m pleti n g t he st u d y 
2 3.  C o nc urre nt disease or c o n diti o n t hat, i n t he vie w of t he I n vesti gat or, w o ul d i nterfere wit h 
st u d y partici pati o n or safet y e val uati o ns, or w o ul d pre dis p ose t he s u bject t o h y p ote nsi o n (s uc h 
as rece nt gastr oe nteritis or de h y drati o n f or a n y reas o n)  
2 4.  Ha ve a b n or mal fi n di n gs o n baseli ne cli nical hi p e xa m or i ma gi n g assess me nts t hat are 
deter mi ne d t o be cli nicall y si g nifica nt as deter mi ne d b y t he PI  
2 5.  Ha ve a hist or y of hi p s ur ger y or se vere hi p d ys plasia 
2 6.  Ha ve a hist or y of cli nicall y si g nifica nt hi p i nj ur y i n t he 3 0  da ys pri or t o scree ni n g 
2 7.  Hist or y of sli p pe d ca pital fe m oral e pi p h ysis or a vasc ular necr osis  of t he fe m oral hea d  
2 8.  Are u na ble t o lie flat w he n i n pr o ne p ositi o n ( nee de d f or hi p m o nit ori n g e xa m) 
A d diti o n al E xcl usi o n Criteri a f or O pti o n al, O pe n -l a bel E xte nsi o n P h ase : 
1.  Use of restricte d t hera pies d uri n g t he i nitial 6 m o nt hs of t he st u d y (see a b o ve) 
2.  Pe r ma ne ntl y disc o nti n ue d B M N 1 1 1 d uri n g t he i nitial 6 m o nt hs of t he st u d y 
I N V E S TI G A TI O N A L P R O D U C T, D O S E, R O U T E, A N D R E GI M E N:  
T he cli nical dr u g pr o d uct will be s u p plie d i n sterile, si n gle- d ose, T y pe I glass vials wit h c oate d st o p per 
a n d fli p- off al u mi n u m ca p. B M N 1 1 1 dr u g pr o d uct is s u p plie d as 0. 8 m g, 2  m g, or 1 0 m g l y o p hilize d, 
preser vati ve -free, w hite t o yell o w p o w der f or rec o nstit uti o n wit h sterile water f or i njecti o n ( W FI). T he 
rec o nstit ute d s ol uti o n is c ol orless t o yell o w a n d c o ntai ns 0. 2 m g/ m L t o 1 0 m g/ ml of B M N 1 1 1, as well 
as citric aci d, s o di u m citrate, tre hal ose, ma n nit ol, met hi o ni ne, p ol ys or bate 8 0, a n d sterile W FI. T he 
tar get p H of t he rec o nstit ute d s ol uti o n is 5. 5.  Sterile water f or i njecti o n will be c o m merciall y s o urce d. 
All rec o nstit uti o n a n d  d ose pre parati o n ste ps will be perf or me d as i n dicate d i n t he B M N 1 1 1 I nj ecti o n 
G ui de a n d I nj ecti o n D V D. 
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Pr o prietar y a n d C o nfi de ntial 
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B M N 1 1 1 will be a d mi nistere d i n t he m or ni n g as a si n gle S C i njecti o n at t he f oll o wi n g d oses: 
2. 5 µ g/ k g, u p t o 7. 5 µ g/ k g, u p t o 1 5. 0 µ g/ k g, a n d 3 0 µ g/ k g . 
R E F E R E N C E T H E R A P Y, D O S E, R O U T E, A N D R E GI M E N:  
N A  
D U R A TI O N O F T R E A T M E N T:  
Si x m o nt hs f or t he i nitial p hase a n d 1 8 m o nt hs f or t he o pti o nal, o pe n- la bel e xte nsi o n p hase, f or a t otal 
of u p t o 2 4 m o nt hs.  
C RI T E RI A F O R E V A L U A TI O N:  
Safet y: Safet y will be e val uate d b y t he i nci de nce of A Es, seri o us a d verse e ve nts ( S A Es), la b orat or y 
test res ults ( uri nal ysis, c he mistr y, he mat ol o g y), c ha n ges i n vital si g ns, p h ysical e xa mi nati o n, E C G a n d 
E C H O res ults, i ma gi n g, cli nical hi p assess me nt , a n d a nti - B M N 1 1 1 i m m u n o ge nicit y assess me nts.  
Efficac y: Efficac y will be assesse d b y c ha n ge fr o m baseli ne i n hei g ht gr o wt h vel ocit y (a n n ualize d t o 
c m/ yr), gr o wt h para meters, a n d i n b o d y pr o p orti o ns .  T hese will be assesse d b y a nt hr o p o metric 
meas ure me nts a n d meas ure me nt rati os.   A nt hr o p ometric meas ure me nts ma y i ncl u de b ut are n ot 
li mite d t o sta n di n g hei g ht, sitti n g hei g ht, wei g ht, hea d circ u mfere nce, u p per a n d l o wer ar m a n d le g, 
ha n d a n d f o ot.  U p per ar m t o f orear m  le n gt h rati o, u p per le g t o l o wer le g le n gt h rati o, a n d u p per t o 
l o wer b o d y se g me nt rati o will be calc ulate d. 
P h ar m ac o ki netics  
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be esti mate d b y n o n- c o m part me ntal a nal ysis:  
•  
Area u n der t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y ( A U C 0-∞)  
•  
Area u n der t he plas ma c o nce ntrati o n- ti me c ur ve fr o m 0 t o t he ti me of last meas ura ble 
c o nce ntrati o n ( A U C 0 -t) 
•  
C ma x  
•  
Ti me t o reac h C ma x  ( Tma x ) 
•  
Eli mi nati o n half -life (t1/ 2) 
•  
A p pare nt cleara nce of dr u g ( C L/ F)  
•  
A p pare nt v ol u me of distri b uti o n base d u p o n t he ter mi nal p hase ( V z/ F) 
T he i m pact o f a nti b o dies o n P K will be e val uate d. 
D ose pr o p orti o nalit y a n d dr u g acc u m ulati o n after re peat- d ose a d mi nistrati o n will als o be e val uate d. 
P K para meters at Da y 1 8 3 will be c o m pare d t o Da ys 1, 1 0, 2 9, a n d 8 5. 
E x pl or at or y: 
Bi o mar kers will be e val uate d b y c ha n ge fr o m baseli ne a n d ma y i ncl u de assess me nt f or cartila ge 
t ur n o ver ( C-ter mi nal cr oss-li n ke d tel o pe pti de of t y pe II c olla ge n [ C T X-II]), c h o n dr oc yte a n d 
oste o blast acti vit y ( b o ne -s pecific al kali ne p h os p hatase [ B S A P]), b o ne f or mati o n ( pr o-c olla ge n T y pe  1 
N- ter mi nal pr o pe pti de [ P 1 N P]), oste ocalci n; a n d mar kers of B M N 1 1 1 acti vit y (c yclic g ua n osi ne 
m o n o p h os p hate [c G M P], N-ter mi nal pr o pe pti de of C- t y pe natri uretic pe pti de [ N T- pr o C N P], a n d atrial 
natri uretic pe pti de [ A N P]) as well as a d diti o nal e x pl orat or y bi o mar kers.  
E x pl orat or y i ma gi n g assess me nt data t o be e val uate d i ncl u de meas ure me nts of t he s pi ne, l o n g b o nes 
a n d e xtre mities, as well as meas ures of gr o wt h plate, b o ne a ge, a n d b o ne mi neral de nsit y.   
Slee p st u d y  (c o n d ucte d at a certifie d slee p ce nter): A slee p-testi n g de vice will be use d t o assess t he 
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Pr o prietar y a n d C o nfi de ntial 
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prese nce a n d se verit y of slee p -dis or dere d breat hi n g b y meas ure me nt of bl o o d o x y ge n sat urati o n, p ulse 
rate, a n d airfl o w d uri n g o ver ni g ht m o nit ori n g at Scree ni n g a n d o n Da ys 8 5 a n d 1 8 3 of t he i nitial 
p hase, a n d M o nt h s 1 2 a n d 2 4 of t he o pti o nal, o pe n- la bel e xte nsi o n p hase.  Assess me nt of slee p a p nea 
will i ncl u de, b ut ma y n ot be li mite d t o , deter mi ni n g t he n u m ber of e pis o des of a p nea a n d h y p o p nea 
per h o ur ( A p nea/ H y p o p nea I n de x, A HI).   
F le xi o n-e xte nsi o n meas ure s of el b o w j oi nt ra n ge of m oti o n will be meas ure d wit h a g o ni o meter.  
S T A TI S TI C A L M E T H O D S:  
S a m ple  Size Deter mi n ati o n : A p pr o xi matel y 3 6 pe diatric s u bjects wit h A C H will partici pate i n t his 
st u d y. N o f or mal sa m ple size calc ulati o ns were perf or me d.  
Data a nal ysis wil l be carrie d o ut f or t he i nitial 6- m o nt h peri o d a n d t he e xte nsi o n peri o d, res pecti vel y. 
S af et y A n al ysis:  
F or eac h of t he t w o peri o ds, all s u bjects w h o recei ve at least o ne d ose of st u d y treat me nt i n t his st u d y 
a n d ha ve a n y p ost treat me nt safet y i nf or mati o n i n t he c orres p o n di n g peri o d will be i ncl u de d i n t he 
safet y a nal ysis.  T he safet y a nal ysis will be descri pti ve a n d will be s u m marize d b y d ose c o h ort a n d all 
c o h orts c o m bi ne d.  
All A Es will be c o de d usi n g t he m ost c urre nt versi o n of Me dical Dicti o nar y f or Re g ulat or y Acti vities 
( Me d D R A) t o assi g n s yste m or ga n class a n d preferre d ter m classificati o n t o e ve nt a n d disease, base d 
o n t he ori gi nal ter ms e ntere d o n t he C R F. T he i nci de nce of A Es will be s u m marize d b y s yste m or ga n 
class, preferre d ter m, relati o ns hi p t o  st u d y treat me nt, a n d se verit y. All A Es, i ncl u di n g S A Es a n d A Es 
t hat lea d t o per ma ne nt disc o nti n uati o n fr o m t he st u d y a n d fr o m t he st u d y treat me nt, will be liste d. 
All  ot her safet y meas ures i ncl u di n g la b orat or y tests, vital si g ns, E C G a n d c o nc o mita nt me dic ati o n data 
will als o be s u m marize d descri pti vel y.  La b orat or y tests will als o be s u m marize d b y a bs ol ute a n d 
perce nt c ha n ge fr o m baseli ne a n d liste d f or eac h d ose c o h ort a n d f or all c o h orts c o m bi ne d.  Vital 
si g ns, E C G a n d E C H O res ults will als o be liste d.   
Effic ac y A n al ysis:  
Efficac y a nal ysis will be carrie d o ut f or t he i nitial 6 - m o nt h peri o d a n d t he e xte nsi o n peri o d. F or eac h 
of t he t w o peri o ds, data  fr o m all s u bjects w h o recei ve at least o ne d ose of st u d y treat me nt a n d w h o 
ha ve p ost treat me nt data f or a n y efficac y e n d p oi nt i n t he c orres p o n di n g peri o d will be i ncl u de d i n t he 
efficac y a nal ysis f or t hat e n d p oi nt.   
A n n ualize d gr o wt h vel ocit y, base d o n sta n di n g hei g ht meas ures at e ver y 6- m o nt h ti me p oi nt, will be 
s u m marize d usi n g descri pti ve statistics ( mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m). T he test of 
h y p ot hesis of n o c ha n ge fr o m t he baseli ne i n gr o wt h vel ocit y will be c o n d ucte d via paire d t- test f or t he 
i nitial 6- m o nt h peri o d a n d p- val ue will be c o nsi dere d descri pti ve. C ha n ges i n b o d y pr o p orti o n rati os 
( up per ar m t o f orear m le n gt h rati o, u p per le g t o l o wer le g le n gt h rati o, a n d u p per t o l o wer b o d y 
se g me nt rati o) fr o m baseli ne t o eac h sc he d ule d ti me p oi nt will be si milarl y s u m marize d a n d teste d at 
t he i nitial 6- m o nt h ti me p oi nt. T he meas ure me nt of sta n di n g hei g ht will be c o n verte d t o a ge- a n d se x-
a p pr o priate sta n dar d sc ore ( S D S), als o referre d t o as Z -sc ore, b y c o m paris o n wit h n or mal refere nce 
sta n dar ds ( n ot A C H). T he Z-sc ore will be s u m marize d si milarl y t o gr o wt h vel ocit y. Res ults will be 
s u m marize d b y d ose c o h ort a n d f or all c o h orts c o m bi ne d. 
Ot her a nt hr o p o metric meas ures (sitti n g hei g ht, wei g ht, hea d circ u mfere nce, u p per a n d l o wer ar m a n d 
le g, ha n d a n d f o ot, etc.) will be s u m marize d at eac h ti me p oi nt a n d will be e val uate d f or c ha n ges fr o m 
baseli ne.  
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3  
T A B L E  O F C O N T E N T S  
1 
TI T L E P A G E  ....................................................................................................................... 1 
2  S Y N O P SI S  ...........................................................................................................................3  
3  T A B L E O F C O N T E N T S  ...................................................................................................1 5  
4  LI S T O F A B B R E V A TI O N S  A N D D E FI NI TI O N S O F T E R M S  .....................................2 1  
5  E T HI C S ..............................................................................................................................2 4  
5. 1  I nstit uti o nal Re vie w B oar d or I n de p e n de nt Et hics C o m mittee ................................2 4  
5. 2  Et hical C o n d uct of St u d y .......................................................................................... 2 4  
5. 3  S u bject I nf or mati o n a n d I nf or me d C o nse nt .............................................................. 2 5  
6  I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E ........................2 6  
7  I N T R O D U C TI O N .............................................................................................................2 7  
7. 1  N o ncli nical St u dies  ...................................................................................................2 8  
7. 2  Pre vi o us Cli nical St u dies  ..........................................................................................2 9  
7. 3  St u d y R ati o na le .........................................................................................................3 0  
7. 4  S u m mar y of O v er all Ris ks a n d Be n efits  ...................................................................3 1  
7. 4. 1  
S u m mar y of Ris ks fr o m N o ncli nical St u dies  ..............................................3 1  
7. 4. 2  
S u m mar y of Ris ks fr o m Cli nical St u dies  ....................................................3 1  
7. 4. 2. 1  
1 1 1- 1 0 1 ........................................................................................ 3 1  
7. 4. 2. 2  
1 1 1- 2 0 2 ........................................................................................ 3 1  
7. 4. 3  
S u m mar y of P ote ntial Be nefits fr o m Cli nical St u dies  ................................3 2  
8  S T U D Y O BJ E C TI V E S  ......................................................................................................3 3  
9  I N V E S TI G A TI O N A L P L A N ............................................................................................3 5  
9. 1  O verall St u d y Desi g n a n d Pla n  .................................................................................3 5  
9. 1. 1  
D ose M o dificati o ns f or S afet y .................................................................... 4 8  
9. 1. 1. 1  
St o p pi n g Criteria  ..........................................................................4 8  
9. 1. 2  
D ose M o dificati o ns f or Efficac y ................................................................. 5 0  
9. 2  Disc ussi o n of St u d y Desi g n, I n cl u di n g C h oice of C o ntr ol Gr o u p ............................ 5 0  
9. 3  Selecti o n of St u d y P o p ulati o n ................................................................................... 5 1  
9. 3. 1  
I n cl usi o n Criteria .........................................................................................5 1  
9. 3. 2  
E x cl usi o n Criteria  ........................................................................................5 2  
-
pr ot oc ol. p df
Pa ge 1 6

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 6 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
9. 3. 3  
Re m o val of S u bjects fr o m Treat me nt or Assess m e nt  .................................5 4  
9. 3. 4  
S u bject I d e ntificati o n a n d Re place me nt of S u bjects  ...................................5 6  
9. 4  Treat me nts  .................................................................................................................5 7  
9. 4. 1  
Treat me nts A d mi nistere d  ............................................................................5 7  
9. 4. 1. 1  
B M N 1 1 1 ..................................................................................... 5 7  
9. 4. 2  
I d e ntit y of I n vesti gati o nal Pr o d uct ..............................................................5 7  
9. 4. 2. 1  
Pr o d uct C haracteristics a n d La b eli n g  ..........................................5 8  
9. 4. 3  
St ora ge  .........................................................................................................5 8  
9. 4. 4  
Directi o ns f or A d mi nistrati o n  .....................................................................5 8  
9. 4. 5  
Met h o d of Assi g ni n g S u bjects t o Treat me nt Gr o u ps .................................. 6 0  
9. 4. 6  
Selecti o n of D oses Use d i n t he St u d y ......................................................... 6 0  
9. 4. 7  
Bli n di n g ....................................................................................................... 6 1  
9. 4. 8  
Selecti o n of Ti mi n g of D ose f or Eac h S u bject ............................................ 6 1  
9. 4. 8. 1  
Pri or a n d C o nc o mita nt Me dicati o ns  ............................................6 1  
9. 4. 9  
Treat me nt C o m plia nce  ................................................................................6 2  
9. 5  I n v esti gati o nal Pr o d uct Acc o u nta bilit y .....................................................................6 2  
9. 5. 1  
Ret ur n a n d Dis p ositi o n of Cli nical S u p plies ............................................... 6 2  
9. 6  Dietar y or Ot h er Pr ot oc ol Restricti o ns ......................................................................6 3  
9. 7  De m o gra p hic Data a n d Me dical Hist or y  ..................................................................6 3  
9. 8  Bi ol o gical Pare nt Sta n di n g H ei g ht ............................................................................ 6 3  
9. 9  P h ysical E x a mi nati o n Fi n di n gs ................................................................................. 6 3  
9. 1 0  Efficac y a n d Saf et y Vari a bles  ...................................................................................6 3  
9. 1 0. 1  Efficac y a n d Saf et y Meas ure me nts Assesse d  .............................................6 3  
9. 1 0. 2  Efficac y Varia bles  .......................................................................................6 4  
9. 1 0. 2. 1  
P har mac o ki netic V aria bl es  ..........................................................6 4  
9. 1 0. 3  E x pl orat or y Effi cac y Varia bles  ...................................................................6 6  
9. 1 0. 3. 1  
P har mac o d y na mic V aria bles  .......................................................6 6  
9. 1 0. 3. 1. 1  
Bi o mar ker Researc h Sa m ple A nal yses  ........................6 6  
9. 1 0. 3. 2  
Slee p A p nea  .................................................................................6 6  
9. 1 0. 3. 3  
I ma gi n g Assess me nt Pr oce d ures ( per Sc h e d ule of E ve nts) .........6 7  
-
pr ot oc ol. p df
Pa ge 1 7

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
9. 1 0. 4  Safet y Vari a bles  ..........................................................................................6 8  
9. 1 0. 4. 1  
A d verse E v e nts  ............................................................................6 8  
9. 1 0. 4. 2  
Cli nical La b orat or y Assess me nts  .................................................6 8  
9. 1 0. 4. 3  
Ot her La b orat or y Assess me nts  ....................................................7 0  
9. 1 0. 4. 4  
Vital Si g ns, P h ysical E x a mi nati o ns a n d Ot her 
O bser vati o ns Relate d t o S afet y ....................................................7 0  
9. 1 0. 4. 4. 1  
Vital Si g ns  ....................................................................7 0  
9. 1 0. 4. 4. 2  
Miti gati n g t he Ris k of P ote ntial H y p ote nsi o n  .............7 1  
9. 1 0. 4. 4. 3  
Hi p M o nit ori n g ............................................................ 7 2  
9. 1 0. 4. 4. 4  
E C Gs  ............................................................................7 2  
9. 1 0. 4. 4. 5  
E C H O  ...........................................................................7 2  
9. 1 0. 4. 4. 6  
A nti - B M N 1 1 1 I m m u n o ge ni cit y Ass ess me nts 
a n d I g E Testi n g ............................................................ 7 2  
9. 1 0. 4. 4. 6. 1  
Sc he d ule d I m m u n o ge nicit y Assess me nts ........ 7 2  
9. 1 0. 4. 4. 6. 2  
A d H oc Safet y Assess me nts  ............................7 3  
9. 1 0. 4. 5  
Pre g n a nc y T esti n g  ........................................................................7 3  
9. 1 1  Pe diatric Bl o o d V ol u me ............................................................................................ 7 4  
1 0  R E P O R TI N G A D V E R S E E V E N T S  .................................................................................7 5  
1 0. 1  Safet y Para met ers a n d D efi niti o ns  ............................................................................7 5  
1 0. 1. 1  A d verse E v e nts  ............................................................................................7 5  
1 0. 1. 2  Seri o us A d verse E v e nts ............................................................................... 7 5  
1 0. 2  Met h o ds a n d Ti mi n g f or Ca pt uri n g a n d Assessi n g Safe t y Para met ers .....................7 6  
1 0. 2. 1  A d verse E v e nt Re p orti n g Peri o d ................................................................. 7 6  
1 0. 2. 2  Eliciti n g A d vers e E ve nts  .............................................................................7 6  
1 0. 2. 3  Assess me nt of Seri o us ness, Se verit y, a n d Ca usalit y ................................... 7 6  
1 0. 2. 3. 1  
Seri o us ness ................................................................................... 7 6  
1 0. 2. 3. 2  
Se verit y  ........................................................................................7 7  
1 0. 2. 3. 3  
Ca usalit y  ......................................................................................7 7  
1 0. 3  Pr oce d ures f or Rec or di n g A d v erse E v e nts  ...............................................................7 9  
1 0. 3. 1  Rec or di n g A d verse E ve nts o n a n e C R F ...................................................... 7 9  
1 0. 3. 1. 1  
Dia g n osis vers us Si g ns a n d S y m pt o ms........................................ 7 9  
-
pr ot oc ol. p df
Pa ge 1 8

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 8 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 0. 3. 1. 2  
A d verse E v e nts Occ urri n g Sec o n d ar y t o Ot her E v e nts  ...............7 9  
1 0. 3. 1. 3  
Per siste nt or Rec urre nt A d verse E ve nts .......................................7 9  
1 0. 3. 1. 4  
A b n or mal La b orat or y Val ues ...................................................... 8 0  
1 0. 3. 1. 5  
Pre -e xisti n g C o n diti o ns ................................................................8 0  
1 0. 3. 1. 6  
Ge ner al P h ysical E x a mi nati o n Fi n di n gs  ......................................8 1  
1 0. 3. 1. 7  
H os pitalizati o n, Pr ol o n ge d H os pitalizati o n, or S ur ger y .............. 8 1  
1 0. 3. 1. 8  
Deat hs  ..........................................................................................8 1  
1 0. 3. 1. 9  
Pre g n a nc y  .....................................................................................8 1  
1 0. 4  Re p orti n g Re q uir e me nts ........................................................................................... 8 2  
1 0. 4. 1  E x pe dite d Re p orti n g Re q uire me nts ............................................................. 8 2  
1 0. 4. 2  I R B Re p orti n g Re q uire m e nts ......................................................................8 2  
1 0. 5  F oll o w- u p of Patie nts aft er A d verse E ve nts ............................................................. 8 2  
1 0. 6  P ost- St u d y A d v erse E v e nts ....................................................................................... 8 3  
1 0. 7  Ur ge nt Safet y M eas ur es  ............................................................................................8 3  
1 0. 8  Bi o Mari n P har mac o vi gila nce C o ntact I nf or mati o n .................................................. 8 5  
1 1  S T U D Y P R O D C E D U R E S  ................................................................................................8 6  
1 1. 1  Scree ni n g Visit ( Da y - 3 0 t o Da y - 1) .........................................................................8 6  
1 1. 2  Treat me nt Visits  ........................................................................................................8 7  
1 1. 2. 1  Da y 1 ( n o visit wi n d o w) .............................................................................. 8 7  
1 1. 2. 2  Da ys 2 a n d 3, ( n o visit wi n d o w) .................................................................. 8 7  
1 1. 2. 3  Da y 4 ( n o visit wi n d o w) .............................................................................. 8 8  
1 1. 2. 4  Da y 1 0 ( ± 1 Da y)  ........................................................................................8 8  
1 1. 2. 5  Da y 1 5 ( ± 1 Da y)  ........................................................................................8 8  
1 1. 2. 6  Da y 2 2 ( ± 1 Da y)  ........................................................................................8 9  
1 1. 2. 7  Da y 2 9 ( ± 1 Da y)  ........................................................................................8 9  
1 1. 2. 8  Da y 4 3 ( ± 7 Da ys)  ......................................................................................9 0  
1 1. 2. 9  Da y 8 5 ( ± 7 Da ys)  ......................................................................................9 0  
1 1. 2. 9. 1  
Da y 1 2 7 ( ± 7 Da ys)  .....................................................................9 1  
1 1. 2. 9. 2  
Da y 1 8 3 M o nt h 6 ( ± 7 D a ys)  ......................................................9 1  
1 1. 3  Safet y F oll o w -U p Visits ............................................................................................9 3  
-
pr ot oc ol. p df
Pa ge 1 9

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 9 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 1. 3. 1  Da y 2 0 8 ( ± 7 Da ys)  .....................................................................................9 3  
1 1. 3. 2  Earl y Ter mi nati o n ( 6 - M o nt h I nitial P hase) .................................................9 3  
1 1. 4  O pti o nal, O pe n- la bel E xte nsi o n Visits......................................................................9 4  
1 1. 4. 1  M o nt h 8 ( ± 7 da ys) ..................................................................................... 9 4  
1 1. 4. 2  M o nt hs 1 0 ( ± 7 da ys), 1 5 ( ± 1 4 da ys), a n d 2 1 ( ± 1 4 da ys) ...................... 9 5  
1 1. 4. 3  M o nt h 1 2 ( ± 7 da ys) ................................................................................... 9 5  
1 1. 4. 4  M o nt h 1 8 ( ± 1 4 da ys) ................................................................................. 9 6  
1 1. 4. 5  M o nt h 2 4/ St u d y C o m pleti o n Visit ( ± 1 4 da ys) .......................................... 9 7  
1 1. 5  Safet y F oll o w -U p Visits ............................................................................................9 8  
1 1. 5. 1  M o nt h 2 5 ( ± 7 da ys) ................................................................................... 9 8  
1 1. 5. 2  Earl y Ter mi nati o n ( O pti o nal, O pe n- La bel E xte nsi o n P hase) ..................... 9 8  
1 1. 6  D ose A dj ust me nt Visits  ............................................................................................9 9  
1 1. 6. 1  If t he Ne xt Sc he d ule d Visit is ≤ 4 Wee ks A wa y, D ose A dj ust me nt 
Ta kes Place at t he Ne xt Sc he d ule d Visit ...................................................1 0 0  
1 1. 6. 2  If t he Ne xt Sc he d ule d Visit is  > 4 Wee ks A wa y, D ose A dj ust me nt 
Ta kes Place at a n U nsc h e d ule d Visit Wit hi n 4 Wee ks Fr o m D M C 
Decisi o n T o D ose A dj ust .......................................................................... 1 0 0  
1 1. 7  7- 1 0 Da y P ost- d ose A dj ust me nt ............................................................................. 1 0 1  
1 1. 8  4 Wee ks P ost D ose A dj ust me nt F oll o w- u p Visit Assess me nts (  ± 2 wee ks)  .........1 0 1  
1 2  D A T A Q U A LI T Y A S S U R A N C E  ...................................................................................1 0 2  
1 3  S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F  S A M P L E SI Z E  ................1 0 3  
1 3. 1  Statistical a n d A nal ytical Pla ns  ...............................................................................1 0 3  
1 3. 1. 1  I nteri m A nal yses ........................................................................................1 0 3  
1 3. 1. 2  Pr oce d u res f or A cc o u nti n g f or Missi n g, U n us e d a n d S p uri o us Data ........1 0 3  
1 3. 2  Efficac y A nal ysis  ....................................................................................................1 0 3  
1 3. 3  P har mac o ki netic A n al ys es  ......................................................................................1 0 4  
1 3. 3. 1  E x pl orat or y A nal yses ................................................................................ 1 0 4  
1 3. 3. 1. 1  
Bi o mar ker A nal ysis ................................................................... 1 0 4  
1 3. 3. 1. 2  
Slee p A p nea A n al ysis  ................................................................1 0 4  
1 3. 3. 1. 3  
I ma gi n g Assess me nt A nal ysis ...................................................1 0 4  
1 3. 3. 1. 4  
I m m u n o ge nicit y A n al ysis ..........................................................1 0 4  
-
pr ot oc ol. p df
Pa ge 2 0

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 0 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 3. 3. 1. 5  
El b o w J oi nt Ra n ge of M oti o n .................................................... 1 0 5  
1 3. 4  Safet y A nal ysis  .......................................................................................................1 0 5  
1 3. 5  Deter mi nati o n of Sa m ple Size  ................................................................................1 0 5  
1 3. 6  A nal ysis P o p ulati o ns ............................................................................................... 1 0 5  
1 3. 7  C ha n ges i n t he C o n d uct of t he St u d y or Pla n ne d A nal ys es .................................... 1 0 6  
1 4  D A T A M O NI T O RI N G C O M M I T T E E ...........................................................................1 0 7  
1 5  C O M P E N S A TI O N, I N S U R A N C E A N D I N D E M NI T Y  ................................................1 0 8  
1 6  C A S E R E P O R T F O R M S A N D S O U R C E D O C U M E N T S  ............................................1 0 9  
1 7  S T U D Y M O NI T O RI N G A N D  A U DI TI N G  ...................................................................1 1 1  
1 8  R E T E N TI O N O F R E C O R D S  .........................................................................................1 1 2  
1 9  U S E O F I N F O R M A TI O N A N D P U B LI C A TI O N  .........................................................1 1 3  
2 0  R E F E R E N C E S  ................................................................................................................1 1 4  
2 1  I N V E S TI G A T O R R E S P O N SI BI LI T E S .........................................................................1 1 6  
2 1. 1  C o n d uct of St u d y a n d Pr otecti o n of H u ma n Patie nts ............................................. 1 1 6  
2 2  SI G N A T U R E P A G E  .......................................................................................................1 1 7  
2 3  P R O T O C O L A M E N D M E N T T E X T R E VI SI O N S  ........................................................1 1 8  
LI S T O F T A B L E S  
Ta ble  9. 1. 1:  Sc he d ule of E ve nts f or 6- M o nt h I nitial P hase of t he St u d y ............................... 3 9 
Ta ble  9. 1. 2:  O pti o nal, O pe n-la bel E xte nsi o n P hase of t he St u d y ........................................... 4 2 
Ta ble  9. 1. 3:  Criteria f or D ose A dj ust me nt Visits  ................................................................... 4 7 
Ta ble  9. 1 0. 2. 1. 1:  P K Sa m ple Sc he d ule................................................................................... 6 5 
Ta ble  9. 1 0. 4. 2. 1:  Cli nical La b orat or y T ests ........................................................................... 6 9 
Ta ble  9. 1 0. 4. 4. 1. 1:  Vital Si g n Assess me nt Fre q ue nc y ........................................................... 7 1 
Ta ble  1 0. 2. 3. 2. 1:  A d vers e E ve nt Gra di n g ( Se verit y) Scale .................................................... 7 7 
Ta ble  1 0. 2. 3. 3. 1:  Ca u salit y Attri b uti o n G ui da nce .................................................................. 7 8 
 
LI S T O F FI G U R E S  
Fi g ure  9. 1. 1:  1 1 1- 2 0 2 St u d y D esi g n ....................................................................................... 3 8 
 
-
pr ot oc ol. p df
Pa ge 2 1

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 1 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
4  
LI S T O F A B B R E V A TI O N S  A N D D E FI NI TI O N S O F T E R M S  
µ g/ k g  
micr o gra m/ kil o gra m  
A C E  
a n gi ote nsi n-c o n verti n g e nz y me  
Ac h  
F gfr 3 G 3 8 0 R  ac h o n dr o plasia m o use m o del  
A C H  
ac h o n dr o plasia 
A E  
a d verse e ve nt 
A HI  
a p nea h y p o p nea i n de x 
A L T  
ala ni ne a mi n otra nsa mi nase 
A N P  
atrial natri uretic pe pti de 
A P  
a nteri or -p osteri or  
A S T 
as partate a mi n otra nsferase  
A U C  
area u n der t he plas ma c o nce ntrati o n -ti me c ur ve  
B M D  
b o ne mi neral de nsit y 
B MI  
b o d y mass i n de x  
B N P  
B -t y pe Natri uretic Pe pti de 
B P  
bl o o d press ure 
B S A P  
b o ne -s pecific al kali ne p h os p hatase 
° C 
de gree Celsi us  
C F R  
C o de of Fe d eral Re g ulati o ns  
c G M P 
c yclic g ua n osi ne m o n o p h os p hate  
C ma x  
ma xi m u m o bser ve d plas ma c o nce ntrati o n  
C N P  
C-t y pe natri uretic pe pti de 
C N P 5 3  
C -t y pe natri uretic pe pti de ( 5 3 a mi n o aci ds i n le n gt h) 
C R A  
cli nical researc h ass ociate 
C R F  
case re p ort f or m 
C T  
X -ra y c o m p ute d t o m o gra p h y  
C T C A E  
C o m m o n T er mi n ol o g y Criteria f or A d verse E ve nts  
C T X -II 
C- ter mi nal cr oss-li n ke d tel o pe pti de of t y pe II c olla ge n 
C V  
car di o vasc ular 
D M C  
data m o nit ori n g c o m mittee  
E C  
et hics c o m mittee 
E C G  
electr ocar di o gra m 
E C H O  
ec h ocar di o gra m 
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F G F  
fi br o blast gr o wt h fact or 
-
pr ot oc ol. p df
Pa ge 2 2

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 2 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
G 3 8 0 R  
s u bstit uti o n i n t he tra ns me m bra ne d o mai n of t he F G F R 3 rece pt or at p ositi o n 3 8 0 
H R  
heart rate  
I C F 
i nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n 
I g E 
i m m u n o gl o b uli n E 
I P 
i n vesti gati o nal pr o d uct 
I R B 
i nstit uti o nal re vie w b oar d 
k Da  
kil o dalt o n 
L V  
left ve ntric ular 
M A P K  
mit o ge n -acti vate d pr otei n ki nase 
m g  
milli gra m  
m L  
milliliter  
m m H g  
milli meters of merc ur y  
msec  
millisec o n d  
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
N A b  
ne utralizi n g a nti b o dies 
N E P  
ne utral e n d o pe pti dase  
N O A E L  
n o o bser ve d a d verse effect le vel  
N P  
natri uretic pe pti de  
N P R -B  
natri uretic pe pti de rece pt or t y pe B  
N T -pr o C N P  
N -ter mi nal pr o pe pti de of C-t y pe natri uretic pe pti de  
P 1 N P  
pr o- c olla ge n T y pe 1 N-ter mi nal pr o pe pti de  
P A  
p osteri or -a nteri or 
P D  
p har mac o d y na mics  
PI  
P ri nci pal In vesti gat or  
P K  
p har mac o ki netics  
P R  
a meas ure of ti me bet wee n t he start of t he P wa ve t o t he start of t he Q R S c o m ple x  
Q C T  
q ua ntitati ve c o m p ute d t o m o gra p h y 
Q R S  
de flecti o n o bser ve d o n a n E C G t hat c orres p o n ds t o t he de p olarizati o n of t he ri g ht 
a n d left ve ntricles 
Q T  
a meas ure of t he ti me bet wee n t he start of t he Q wa ve  a n d t he e n d of t he T wa ve   
Q T c -F  
Fri dericia’s c orrecte d Q T i nter val  
r H C N P  
rec o m bi na nt C-t y pe natri uretic pe pti de 
S A Es  
seri o us a d verse e ve nts 
S C  
s u bc uta ne o us 
S C F E  
sli p pe d ca pital fe m oral e pi p h ysis 
-
pr ot oc ol. p df
Pa ge 2 3

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 3 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
S D  
sta n dar d de viati o n 
t1/ 2 
eli mi nati o n half -life 
T A b  
t otal a nti b o d y 
T D  
t ha nat o p h oric d ys plasia 
T E A E  
treat me nt-e mer ge nt a d verse e ve nt  (a n A E w hic h occ urs p ost-d ose or w hic h is 
prese nt pre -d ose a n d bec o mes m ore se vere p ost - d ose)    
T ma x  
ti me t o reac h Cma x  
U L N  
u p per li mit of n or mal 
W FI  
water f or i njecti o n  
-
pr ot oc ol. p df
Pa ge 2 4

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 4 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
5  
E T HI C S  
Bi o Mari n P har mace utical I nc. ( her eafter referre d t o as Bi o Mari n or t he S p o ns or) c o n d ucts its 
st u dies acc or di n g t o t he hi g hest et hical a n d scie ntific sta n dar ds. T he f oll o wi n g secti o ns 
artic ulate sta n dar ds t o w hic h I n v esti gat ors will be hel d acc o u nt a ble, as w ell as matters of 
c o m plia nce t o d oc u me nt a d here n ce t o s uc h sta n d ar ds. 
5. 1  
I nstit uti o n al Re vie w B o ar d or I n de pe n de nt Et hics C o m mittee  
I n v esti gat ors ar e e x pecte d t o i nteract wit h Et hics C o m mittees ( E Cs) pr o m ptl y, as re q uire d, 
d uri n g t he c o urse of t he st u d y. T his i ncl u des b ut is n ot li mite d t o, pr o vi di n g a p pr o priate 
d oc u me ntati o n t o s u p p ort st u d y i nitiati o n a n d mai ntai ni n g a p pr o priate fl o w of safet y a n d 
ot her i nf or mati o n d uri n g t he c o urse of t h e st u d y a n d f or st u d y cl ose- o ut acti vities. Bi o Mari n 
( or desi g nee) will assist I n vesti gat ors wit h access t o ti mel y a n d acc urate i nf or mati o n a n d 
wit h ass uri n g pr o m pt r es ol uti o n of a n y q ueries. 
Pri or t o i nitiati n g t he st u d y, t he I n vesti gat or will o btai n writte n c o nfir mati o n t hat t he 
i nstit uti o nal re vie w b oar d (I R B) or i n de pe n d e nt et hics c o m mittee (E C) is pr o perl y 
c o nstit ute d a n d c o m plia nt wit h I nter n ati o nal C o nfere nce o n Har m o nisati o n of Tec h nical 
Re q uire me nts f or Re gistr ati o n of P har mace uticals f or H u ma n Us e (I C H) a n d G o o d Cli nical 
Practice ( G C P) re q uire m e nts, a p plica ble la ws a n d l ocal re g ulati o ns. A c o p y of t he 
c o nfir mati o n fr o m t he I R B/ E C will be pr o vi de d t o Bi o Mari n or its desi g nee. T he I n vesti gat or 
will pr o vi de t he I R B/ E C wit h all a p pr o priate material, i ncl u di n g t he pr ot oc ol, I n vesti gat or’s 
Br oc h ure (I B), t he I nf or me d C o nse nt F or m (I C F) i ncl u di n g c o m pe ns ati o n pr oce d ures, a n d 
a n y ot h er writte n i nf or mati o n or e d ucati o nal mat erials pr o vi de d t o t he s u bjects, i ncl u di n g all 
I C Fs tra nslate d t o a l a n g ua ge ot her t ha n t h e nati v e la n g ua ge of t he cli nical site. T he st u d y 
will n ot be i nitiate d a n d I n vesti gati o nal Pr o d uct (I P) s u p plies will n ot be s hi p pe d t o t he site 
u ntil a p pr o priate d oc u me nts fr o m t he I R B/ E C c o nfir mi n g u nc o n diti o nal a p pr o val of t he 
pr ot oc ol, t he I C F a n d all s u bject recr uit me nt materials are o btai ne d i n writi n g b y t he 
I n v esti gat or a n d c o pi es are recei ve d at Bi o Mari n or its desi g nee. T he a p pr o val d oc u me nt 
s h o ul d refer t o t he st u d y b y pr ot oc ol title a n d Bi o Mari n pr ot oc ol n u m ber (if p ossi ble), 
i de ntif y t he d o c u me nts re vie we d, a n d i ncl u d e t he date of t he re vie w a n d a p pr o val. Bi o Mari n 
will e ns ure t hat t he a p pr o priate re p orts o n t he pr o gress of t he st u d y are ma d e t o t he I R B/ E C 
a n d Bi o Mari n b y t he I n v esti gat or i n acc or da nce wit h a p plica ble g ui da nce d oc u me nts a n d 
g o ver n me ntal r e g ulati o ns. 
5. 2  
Et hic al C o n d uct of St u d y  
It is e x pecte d t hat I n v esti gat ors u n d ersta n d a n d c o m pl y wit h t he pr ot oc ol. T his i ncl u des b ut is 
n ot li mite d t o esta blis hi n g a n d m eeti n g e nr oll me nt c o m mit me nts, i ncl u di n g pr o vi di n g 
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pr ot oc ol. p df
Pa ge 2 5

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 5 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
eli gi ble s u bjects f or st u d y e nr oll me nt; a d heri n g t o dia g n ostic or ot h er pr o ce d ures as s pecifie d 
i n t he pr ot oc ol; a n d ass uri n g a p pr o priate c o m plia nce wit h st u d y treat me nt a d mi nistratio n a n d 
acc o u nta bilit y.  
T his st u d y will be c o n d u cte d i n acc or da n ce wit h t he f oll o wi n g: 
•  U S C o de of Fe d eral Re g ulati o ns ( C F R) secti o ns t hat a d dress cli nical researc h st u dies, 
a n d/ or ot her nati o nal a n d l ocal re g ulati o ns, as a p plica ble 
•  I C H H ar m o nise d Tri p artite G ui deli ne: G ui deli ne f or G o o d Cli nical Practice E 6 
(I C H E 6)  
•  T he et hical pri nci ples esta blis he d b y t he Decl arati o n of Helsi n ki  
S pecificall y, t his st u d y is base d o n a de q uatel y perf or me d la b orat or y a n d a ni mal 
e x peri me ntati o n , a n d a h u ma n cli nical trial i n he alt h y v ol u nteers . T h e st u d y will be 
c o n d ucte d u n der a pr ot o c ol re vie we d a n d a p pr o v e d b y a n I R B/ E C a n d will be c o n d ucte d b y 
scie ntificall y a n d me dicall y q ualifie d pers o ns. T he be nefits of t he st u d y are i n pr o p orti o n t o 
t he ris ks. T he ri g hts a n d welfar e of the s u bjects will be res pecte d a n d t he I n vesti gat ors 
c o n d ucti n g t h e st u d y d o n ot fi n d t he hazar ds t o o ut wei g h t he p ot e ntial be nefits. Eac h s u bject, 
or his/ her le gall y a ut h ori ze d re prese nt ati ve will pr o vi de writte n, i nf or me d c o nse nt bef ore a n y 
st u d y-r elate d tests or e val uati o ns are perf or me d. 
5. 3  
S u bject I nf or m ati o n a n d I nf or me d C o nse nt  
A pr o perl y writte n a n d e x ec ute d I C F, i n c o m plia n ce wit h t he Declarati o n of Helsi n ki, 
I C H E 6 ( Secti o n 4. 8), U nite d States ( U S) C o de of Fe deral Re g ulati o ns ( C F R) 2 1 C F R § 5 0 
a n d ot her a p plica ble l ocal re g ul ati o ns, will be o btai ne d f or eac h s u bject pri or t o e nteri n g t he 
s u bject i nt o t he st u d y. T h e I n vesti gat or will pre p are t he I C F a n d pr o vi de t he d oc u me nts t o 
Bi o Mari n f or a p pr o v al pri or t o s u b missi o n t o t he I R B/ E C a p pr o val. Bi o Mari n a n d t he 
I R B/ E C m ust a p pr o ve t h e d oc u me nts bef ore t he y are i m ple me nte d. A c o p y of t he a p pr o v e d 
I C F ( mi n or asse nt f or m a n d pare ntal I C F f or st u di es i n v ol vi n g mi n ors), a n d if a p plica ble, a 
c o p y of t he a p pr o ve d s u bject i nf or mati o n s heet a n d all I C Fs tra nslate d to a la n g u a ge ot her 
t ha n t he nati ve la n g ua ge of t he cli nical site m ust als o be recei ve d b y Bi o M ari n or desi g nee 
pri or t o a n y st u d y- s pecifi c pr oce d ures bei n g p erf or me d. 
S u bjects u n der t he a ge of 1 8 years will pr o vi de writte n asse nt (if re q uire d b y l ocal 
re g ulati o ns or t he I R B/ E C), a n d his/ her le gall y a ut h orize d re prese nt ati ve ( p are nt or le gal 
g uar dia n) will pr o vi de writte n i nf or me d c o nse nt f or s uc h s u bjects. T he I n v esti gat or will 
pr o vi de c o pies of t he si g ne d I C F t o eac h s u bject ( or t he le gall y a ut h orize d re pres e ntati ve of 
t he s u bjects) a n d will mai ntai n t he ori gi nal i n t he rec or d file of t he s u bject. 
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pr ot oc ol. p df
Pa ge 2 6

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 6 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
6  
I N V E S TI G A T O R S A N D S T U D Y A D MI NI S T R A TI V E S T R U C T U R E  
D uri n g a d mi nistrati o n of i nf or me d c o nse nt, e x pect ati o ns re gar di n g partici pati o n i n t he st u d y 
s h o ul d be ma de clear t o s u bjects. S u bjects  w h o are n ot willi n g a n d/ or are n ot a ble t o c o m pl y 
wit h all as pects of t he st u d y s h o ul d n ot be e n c o ura ge d t o p artici pate. 
Pri or t o be gi n ni n g t he st u d y, t he I n vesti gat or at eac h site m ust pr o vi de t o Bi o Mari n or 
desi g nee, a f ull y e x ec u te d a n d si g n e d U S F o o d a n d Dr u g A d mi nistrati o n ( F D A) F or m 
F D A  1 5 7 2 a n d a Fi n a nci al Discl os ure F or m. All s u b-I n vesti gat ors m ust be liste d o n 
F or m  F D A 1 5 7 2. Fi n a nci al Discl os ure F or ms m ust als o be c o mplete d f or all 
S u b-I n v esti gat ors liste d o n t he F or m F D A 1 5 7 2 w h o will be directl y i n v ol v e d i n t he 
treat me nt or e v al uati o n of s u bjects i n t his st u d y. 
T he st u d y will be a d mi nistere d b y a n d m o nit ore d b y e m pl o yees or re pres e ntati ves of 
Bi o Mari n. Cli nical res ear c h ass ociates ( C R As) or trai ne d desi g nees will m o nit or ea c h site o n 
a peri o dic basis a n d p erf or m verificati o n of s o urce d oc u me ntati o n f or eac h s u bject as well as 
ot her re q ui r e d re vi e w pr o cesses. Bi o Mari n Re g ulat or y Affairs De part me nt ( or desi g nee) will 
be res p o nsi ble f or t he ti mel y r e p orti n g of S A Es t o a p pr o pria te re g ulat or y a ut h orities as 
re q uire d. 
A C o or di nati n g I n v esti gat or will be i de ntifie d w h o will be res p o nsi ble f or st u d y o ver vie w. 
T he C o or di nati n g I n vesti gat or will rea d t he cli nical st u d y re p ort ( C S R) a n d c o nfir m t hat it 
acc ur atel y des cri bes t he c o n d uct a n d res ults of t he st u d y, t o t he best of his or her k n o wle d ge. 
T he C o or di nati n g I n vesti gat or will be c h ose n o n t he basis of acti ve p artici p ati o n i n t he st u d y, 
a bilit y t o i nter pret dat a, a n d willi n g ness t o re vie w a n d si g n t he re p ort i n a s pecifie d 
ti mefra me. T he i d e ntit y of t he C o or di nati n g I n vesti gat or a n d a list of all I n v esti gat ors 
partici pati n g i n t he st u d y will be pr o vi de d i n t he C S R. 
La b orat or y e val uati o ns will be perf or me d at ce ntral la b orat ories u nless use of a l ocal 
la b orat or y is cli nicall y i n dicate d i n or der t o ha ve e x pe dite d res ults.  See La b orat or y Ma n u al 
f or detaile d r e q uire me nts. 
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pr ot oc ol. p df
Pa ge 2 7

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
7  
I N T R O D U C TI O N 
B M N 1 1 1 is a pr o p os e d t hera pe utic o pti o n f or AC H , t he m ost c o m m o n f or m of d warfis m. 
A C H is a rar e disease wit h a pre val e nce of 1/ 2 5 0 0 0 i n t he U S ( W y n n, 2 0 0 7, A m J Me d 
Ge net  A).  It is a c h o n dr o d ys plasia c haracterize d b y r hiz o melic s h ort li m bs a n d s h ort stat ure. 
T he  a d ult hei g ht is j ust o ver 4 feet. C haracteristic feat ures i ncl u de l o n g a n d narr o w tr u n k, a 
lar ge hea d wit h fr o ntal b ossi n g, h y p o plasia of t he mi d-face, b o we d le gs a n d ste n osis of t he 
f ora me n a n d s pi nal ca n als t hat ca n be life-t hreat e ni n g. F ora me n ma g n u m st e n osis ca n lea d t o 
cer vic o me d ullar y c o m pr essi o n i n i nfa nts wit h c o m plicati o ns i ncl u di n g h y dr oce p hal us, 
h y p ot o nia, r es pirat or y i ns ufficie nc y, a p nea, c ya n otic e pis o des, fee di n g pr o ble ms, 
q ua dri par esis, a n d s u d de n deat h.  
T here are n o a p pr o ve d p har mac ol o gic i nter ve nti o ns f or A C H .  H u ma n Gr o wt h H or m o ne 
( Ge n otr o pi n ®, H u m otr o pe ®, a n d N utr o pi n ®) is n ot a p pr o ve d f or A C H  as n o l o n g-ter m 
effects o n gr o wt h were d e m o nstrate d i n t he A C H  p o p ulati o n.  C urre nt treat me nts are f o c use d 
o n ne ur os ur gical i nter ve nti o ns f or f ora me n ma g n u m ste n osis or l u m bar ste n osis, 
t h orac ol u m bar br aces t o hel p a meli orate t he k y p h osis, or li m b le n gt he ni n g re q uiri n g m ulti ple 
o perati o ns o ver 2 t o 3 years ( S hirle y, 2 0 0 9, J A m Acad Ort h o p. S ur g.) ; (H ort o n, 2 0 0 7, 
La n cet ).  
A C H  is ca use d b y a gai n- of-f u n cti o n m utati o n i n F G F R 3, a ne gati ve re g u l at or of 
c h o n dr oc yte pr olifer ati o n a n d differe ntiati o n.  T he m ost c o m m o n m utati o n ( 9 8 %) i n A C H  
patie nts is a G 3 8 0 R s u bstit uti o n i n t he tra ns me m bra ne d o mai n of F G F R 3.  T he maj orit y of 
ne w cas es ( 8 0 %) ori gi nat e fr o m pare nts wit h n or mal stat ure.  Ot her s k eletal 
c h o n dr o d ys plasia are ca use d b y gai n- of-f u ncti o n m utati o n i n F G F R 3.  T heir p he n ot y p es are 
si milar t o AC H  b ut t heir se verities var y fr o m mil d ( h y p o c h o n dr o plasia) t o let hal (T D ), 
de pe n di n g o n t he ge n etic  m utati o n.  
T he e xtracell ular si g nal -r e g ul ate d ki nase ( E R K) mit o ge n-acti vate d pr otei n ki nase ( M A P K) 
pat h wa y me diates p art of F G F R 3  i n hi biti o n of c h o n dr oc yt e pr oliferati o n a n d differe ntiati o n 
( F ol d y n o va-Tra ntir k o va, 2 0 1 2, H u m. M utat.) .  T he E R K M A P K pat h wa y is m o d ulate d b y 
C N P, a p ositi ve re g ulat or of c h o n dr oc yt e pr oliferati o n a n d differe ntiati o n.  Bi n di n g of C N P 
t o t he Natri uretic Pe pti de-Rece pt or  B ( N P R - B) a nta g o nizes F G F R 3 d o w nstrea m si g n ali n g b y 
i n hi biti n g t he M A P K ( E R K 1/ 2) pat h wa y at t he le vel of R A F- 1 ( Krejci, 2 0 0 5, J. Cell Sci.); 
( Yas o da, 2 0 0 4, N a t. Me d.); (Yas o da, 2 0 0 9, E n d o cri n ol o g y ); ( Pejc h al o va, 2 0 0 7, 
M ol. Ge net. Meta b ).  T his cr osstal k was de m o nstrate d i n a m o use m o del of F G F R 3-relate d 
c h o n dr o d ys plasia ( Y as o d a, 2 0 0 4, Nat. Me d. ); ( Yas o da, 2 0 0 9, E n d ocri n ol o g y).  T h e d warfis m 
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pr ot oc ol. p df
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 2 8 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
p he n ot y p e of mice h ar b ori n g t he F G F R 3 G 3 8 0 R  m utati o n was resc ue d b y e x pressi o n of C N P i n 
cartila ge or b y t he c o nti n u o us a d mi nistrati o n of C N P (i nf usi o n). 
C N P is a me m ber of t he natri uretic pe pti de ( N P) fa mil y t hat i ncl u des Atrial Natri uretic 
Pe pti de ( A N P) a n d B-t y p e Natri ur etic Pe pti de  ( B N P). T hese pe pti des are str uct urall y relat e d 
b ut are disti nct paracri ne/ a ut ocri ne ( C N P) or e n d o cri ne ( A N P a n d B N P) fact ors t hat re g ulate 
t he car di o vas c ular ( C V), s keletal, ner v o us, re pr o d ucti ve a n d ot her s yste ms. S y nt hetic a n al o gs 
of A N P (a nariti de a n d car periti de) a n d B N P ( n esiriti de) ha ve bee n i n ves ti gate d as p ote ntial 
t hera pies f or t he treat me nt of dec o m pe nsat e d heart fail ure a n d car di o vasc ular-rel ate d 
diseases.  
B M N 1 1 1 is a 3 9- a mi n o aci d C N P a nal o g ue har b ori n g t he 3 7 a mi n o aci ds of t he h u ma n 
C N P 5 3 C-ter mi nal se q ue nce a n d m o difie d b y t he a d diti o n of t w o a mi n o aci ds ( Pr o- Gl y) o n 
t he N-ter mi n us.  It is a r ec o m bi na nt h u ma n pe pti de f use d t o h u ma n tra ns cri pti o n fact or 
( T A F) a n d e x presse d as a n i ncl usi o n b o d y i n E.c oli .  B M N 1 1 1 is li berate d a n d s ol u bilize d 
fr o m t he T A F-f usi o n pr otei n b y f or mic aci d clea v age, a n d p urifie d b y c ol u m n 
c hr o mat o gra p h y (L o n g, 2 0 1 2, J Bi otec h n ol).  B M N 1 1 1 was desi g ne d t o 1) mi mic C N P 
acti vities i n ter ms of rece pt or b i n di n g a n d p har mac ol o gical acti vit y a n d 2) be resista nt t o 
N E P di gesti o n i n or der t o ha ve a n e xte n de d half-life i n c o m paris o n t o C N P t hat is pres u me d 
t o i ncrease e x p os ure t o t he tar get gr o wt h plate ( We n dt, 2 0 1 5, J. P har mac ol. E x p. T her.).  
A c o m pre he nsi v e re vie w of B M N 1 1 1 is c o ntai n e d i n t he c urre nt v ersi o n of t he I n vesti gat or’s 
Br oc h ure s u p plie d b y Bi o Mari n.  I n vesti gat ors are t o re vie w t he I n vesti gat or’s Br oc h ure 
pri or t o i nitiati n g t his st u d y.  
7. 1  
N o ncli nic al St u dies  
T he n o ncli nical st u dies c haract erize d t he pri mar y p har mac o d y n a mic acti vit y of B M N 1 1 1 i n 
n or mal mice, rats a n d c y n o m ol g us m o n ke ys a n d i n t w o m o use m o dels of A C H ( T D [se vere] 
a n d Ac h [ mil d]). Res pirat or y a n d C N S safet y p har mac ol o g y were e val u ate d i n rats a n d 
C V  safet y p har m ac ol o g y i n tele meterize d m o n ke ys. R e peat- d ose t o xicit y a n d T K G L P 
st u dies were c o m plete d i ncl u di n g t w o 2 8- d a y st u dies: o ne i n t he y o u n g a d ult rat a n d o ne i n 
t he j u ve nile m o n ke y, t hree 2 6- wee k st u dies: o ne i n t he j u ve nile rat, o ne i n t he a d ult rat a n d 
o ne i n t he j u ve nile m o n ke y, a n d o ne 4 4- wee k st u d y i n se x uall y mat ure c y n o m ol g us m o n k e ys 
( wit h o pe n gr o wt h plates).  
O verall, B M N 1 1 1-r elate d fi n di n gs were li mite d t o t he k n o w n mec ha nis m of acti o n of C N P 
o n t he gr o wt h plate a n d v asc ulat ure, res ulti n g i n t h e pr o m oti o n of l o n git u di nal b o ne gr o wt h 
at he m o d y n a micall y t oler ate d d ose le vels. A d d iti o nall y, re versi ble s u b c uta ne o us i njecti o n 
site reacti o ns were r e p ort e d, i ncl u di n g i njecti o n site disc ol orati o n a n d micr osc o pic fi n di n gs 
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pr ot oc ol. p df
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Pa ge 2 9 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
of peri vasc ul ar m o n o n ucl ear cell i nfiltrates t hat were see n wit h sli g htl y hi g h er i nci de nce a n d 
se verit y i n B M N 1 1 1-treate d rats a n d m o n ke ys c o m pare d t o t he ve hicl e c o ntr ol.  T here w ere 
n o B M N 1 1 1-r elate d eff ects o n res pirat or y, C N S, or se x ual de vel o p me nt a n d re pr o d ucti ve 
perf or ma n ce. A d v erse s k eletal c ha n ges ass ociat e d wit h e x a g gerate d gr o wt h were s ee n i n all 
n or mal n o ncli nical s peci es wit h o pe n gr o wt h plat es, a n d were d ose-, e x p os ure- a n d ti me-
de pe n de nt. T hes e effects i ncl u de d a b n or mall y s ha pe d fe m oral hea d, aceta b ular gr o wt h 
ce nter/ plate d ys pl asia a n d c o nc o mita nt artic ular cartila ge de ge nerati o n wit h cli nical 
ma nifestati o ns of restrict e d use of hi ps. 
 
 
 
 
 
 
 
 
 
 
 
7. 2  
Pre vi o us Cli nic al St u dies  
St u d y 1 1 1- 2 0 2 is t he sec o n d st ud y of B M N 1 1 1 i n h u ma ns.  St u d y 1 1 1- 1 0 1 ( A P hase 1, 
2- Part, D o u ble- bli n d, Place b o-c o ntr olle d St u d y t o E val uate t he Safet y, T olera bilit y, a n d 
P har mac o ki netics of Si n gle a n d M ulti ple S u bc uta ne o us D oses of B M N 1 1 1 A d mi nistere d t o 
Healt h y A d ult V ol u nteers) was  t he first-i n- h u m a n st u d y of B M N 1 1 1.   
Res ults fr o m St u d y 1 1 1- 1 0 1 i nitiall y i nf or me d St u d y 1 1 1- 2 0 2.  
 
 
 
 
 
 
 
 
 
 
 
 
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Pr o prietar y a n d C o nfi de ntial 
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7. 3  
St u d y R ati o n ale 
St u d y 1 1 1- 2 0 2 is desi g ne d as a pr o of- of-c o nce pt st u d y f or B M N 1 1 1 i n c hil dre n wit h A C H. 
T he i nitial p hase of t his st u d y is 6 m o nt hs a n d will all o w f or assess me nt of t he effect of d ail y 
B M N  1 1 1 a d mi nistrati o n o n safet y, t olera bilit y, gr o wt h vel ocit y, a bs ol ute gr o wt h, a n d b o d y 
pr o p orti o ns at d oses ra n gi n g fr o m 2. 5- 3 0 µ g/ k g gi ve n s u bc uta ne o usl y dail y. A cli nicall y 
rele va nt i ncreas e i n a n n u alize d gr o wt h vel o cit y is c o nsi dere d t o be i n t he ra n ge of 2 5 %-5 0 % 
c ha n ge fr o m baseli ne, alt h o u g h t he tar gete d i ncrease ma y b e refi ne d bas e d o n o n g oi n g 
c o m pre he nsi ve s afet y a n d efficac y re vie w of B M N 1 1 1. A d diti o nal e x pl orat or y e n d p oi nts 
t hat reflect t he me dical c o m plicati o ns of A C H will als o be e val uate d.  
B M N 1 1 1 dr u g e x p os ure, B M N 1 1 1 p har mac o d y n a mics ( P D; i.e., bi o mar kers), a n d t he 
relati o ns hi p of B M N 1 1 1 a n d i m m u n o ge nicit y will be e x pl ore d, as will c ha n ges i n B MI, 
gr o wt h plate m or p h ol o g y, l o n g- b o n e gr o wt h, l u m bar s pi ne m or p h ol o g y, a n d slee p a p nea. 
A fter c o m pleti n g t he i nitial p hase of t he st u d y lasti n g 6 m o nt hs, s u bjects ma y e nr oll i n a n 
o pti o nal, o pe n-la bel e xte nsi o n peri o d of a p pr o xi matel y 1 8 m o nt hs t o c o m m e nce at t he e n d of 
t he i nitial p hase of t he st u d y, ma ki n g a t otal st u d y d urati o n of a p pr o xi matel y 2 5 m o nt hs, 
i ncl u di n g a 1- m o nt h safet y f oll o w- u p visit.  T he rati o nale f or t he e xte nsi o n p hase is t o assess 
t he l o n g-ter m saf et y a n d t olera bilit y of B M N 1 1 1 i n c hil dre n wit h A C H; a n d t o assess 
l o n ger-ter m effects of B M N 1 1 1 o n gr o wt h i n t hese c hil dre n. 
St u d y d urati o ns of 2 years a n d l o n ger ha v e bee n pre vi o usl y re p orte d i n st u dies of gr o wt h 
h or m o ne i n c hil dre n wit h A C H  ( Sta m o ya n n o u, 1 9 9 7, A m J Me d Ge net ), ( T a na ka, 1 9 9 8, E ur 
J E n d ocri n ol.). 
T he C o h ort 4 d ose of 3 0 µ g/ k g was  selecte d wit h t he i nte nt t o ac hie ve e x p os ures e x pecte d t o 
res ult i n f urt her i ncreas es i n gr o wt h v el ocit y i n c hil dre n wit h A C H wit h a n acce pta ble safet y 
pr ofile.  
P K data fr o m  St u d y 1 1 1- 2 0 2 i n dicate t hat e x p os ures ac hie v e d i n A C H c hil dre n gi ve n 
1 5 µ g/ k g ar e c o m par a ble t o a mi ni mall y bi ol o gicall y acti ve e x p os ure ra n ge b ut less t ha n 
t h ose re q uire d f or si g nifica nt gr o wt h i n m o n ke ys. P K data s u p p ort e val uati o n of d oses of 
3 0 µ g/ k g t o f urt her c har acterize d ose-res p o nse relati o ns hi ps a n d p ote ntiall y ac hie ve 
e x p os ures res ulti n g i n f urt her gr o wt h.  
Safet y d ata i n m o n ke ys s u p p ort d osi n g A C H c hil dre n at t he pr o p os e d d oses of 3 0 µ g/ k g 
dail y , wit h caref ul m o nit ori n g a n d ma na ge m e nt of he m o d y n a mic a n d s k eletal c ha n ges.  
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Pr o prietar y a n d C o nfi de ntial 
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T o date, cli nical  dat a i n St u d y 1 1 1- 2 0 2 d e m o nstrate d t hat B M N 1 1 1 w as ge nerall y well 
t olerate d at d oses u p t o 3 0 µ g/ k g wit h o ut e vi de nce of a b n or mal gr o wt h or si g nifica nt 
car di o vas c ular effects.   
7. 4  
S u m m ar y of O ver all Ris ks a n d Be nefits  
7. 4. 1  S u m m ar y of R is ks f r o m N o ncli nic al S t u dies 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 4. 2  S u m m ar y of Ris ks f r o m Cli nic al St u dies  
7. 4. 2. 1  
1 1 1- 1 0 1 
Base d o n re vie w of t he first-i n- h u ma n P hase 1 st u d y of B M N 1 1 1 i n healt h y a d ult v ol u nteers, 
St u d y 1 1 1- 1 0 1, B M N 1 1 1 a d mi nistere d S C dail y was well t olerat e d wit h d oses ra n gi n g fr o m 
0. 5 µ g/ k g t o 1 5 µ g/ k g.  All A Es  were of mil d se verit y , a n d n o S A Es w ere re p orte d.  T he 
m ost c o m m o n A E was  mil d, tra nsie nt, self -li mite d ort h ostatic h y p ote nsi o n, of w hic h t he 
maj orit y of cases w ere as y m pt o matic a n d o bser ve d o nl y u p o n ass u m pti o n of a n u pri g ht 
p ost ure f oll o wi n g rec u m be nce.  N o d os e- li miti n g t o xicities were i de ntifie d o utsi de of t hese 
C V fi n di n gs. 
7. 4. 2. 2  
1 1 1- 2 0 2 
Base d o n re vie w of t his o n g oi n g p hase 2 cli nical trial, i njecti o n site reacti o ns ha ve bee n 
i de ntifie d as ris ks ass ociate d wit h B M N 1 1 1 i njecti o ns. H y p ote nsi o n a n d h y perse nsiti vit y 
reacti o ns are p ote ntial ris ks ass ociate d wit h B M N 1 1 1 i njecti o ns. F or a detaile d s u m mar y of 
ris ks, please refer t o t he c urre nt I B. 
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Pr o prietar y a n d C o nfi de ntial 
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I n t he p h ase 2 st u d y B M N 1 1 1- 2 0 2, i njecti o n site reacti o ns w ere t he m ost c o m m o n A Es 
re p orte d a n d ar e c o nsi der e d as a n i de ntifie d ris k ass ociate d wit h B M N 1 1 1 i njecti o ns.  
T he  m ost c o m m o n i njecti o n site reacti o ns acr oss all c o h orts i ncl u de d: i njecti o n site 
er yt h e ma, i njecti o n site s welli n g, a n d i njecti o n site urticari a .  Of n ote, all i njecti o n site 
reacti o ns ha v e bee n re p orte d as n o n-seri o us a n d gra de 1 i n se v erit y, a n d n o s u bjects have 
disc o nti n ue d fr o m t he st u d y or p er ma n e ntl y disc o nti n ue d st u d y treat me nt as a res ult of t he 
e ve nts.  
T he m ost i m p orta nt p ote ntial ris ks i de ntifie d t o date i ncl u de h y p ote nsi o n (a n d c o m plicati o ns 
relate d t o h y p ote nsi o n a n d/ or tac h ycar dia) a n d t he de vel o p me nt of a nti- B M N 1 1 1 a nti b o dies.  
A nti -B M N  1 1 1 a nti b o dies ha ve t he p ote ntial t o me diate aller gi c reacti o ns, re d uce effi cac y, 
a n d/ or cr oss-react wit h e n d o ge n o us C N P or ot her u n defi ne d a ge nts.  A nti- B M N  1 1 1 
a nti b o dies c o nti n ue t o be m o nit ore d i n t he st u d y. N o gra de 2 or hi g h er or s eri o us 
h y perse nsiti vit y r eacti o ns ha ve bee n re p ort e d t o date.  Re p orte d a d vers e e v e nts of 
h y p ote nsi o n ha v e bee n mil d, n o n-seri o us, a n d ha v e res ol ve d wit h o ut me dical i nter ve nti o n.   
B ot h t hese p ote ntial ris ks  will c o nti n ue t o be cl osel y m o nit ore d. 
7. 4. 3  S u m m ar y of P ote nti al Be nefits  fr o m Cli nic al St u dies 
F or c hil dr e n w h o r ecei ve B M N 1 1 1 as p art of t his st u d y, p ote ntial be nefits ma y i ncl u d e 
i m pr o ve me nt of a n n ualize d gr o wt h vel ocit y rates; a n d i m pr o ve me nt of t he dis pr o p orti o nate 
gr o wt h wit h p ote ntial be nefits o n se veral of t he m e dical c o m plicati o ns of A C H (l u m bar s pi ne 
a n g ul ati o n, ti bial b o wi n g, a n d slee p a p n ea). 
 
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Pr o prietar y a n d C o nfi de ntial 
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8  
S T U D Y O B J E C TI V E S  
T he pri mar y o bjec ti ve of t he i nitial 6- m o nt h p hase is:  
•  
T o e val uate t he s afet y a n d t olera bilit y of d ail y S C i njecti o n s of B M N 1 1 1 
a d mi nistere d f or 6 m o nt hs   
T he pri mar y o bjecti ve of t he st u d y e xte nsi o n is: 
•  T o e val uate t he s afet y a n d t olera bilit y of d ail y S C i njecti o ns of B M N  1 1 1 
a d mi nistere d f or u p t o 2 4 m o nt hs   
T he sec o n d ar y o bjecti ves of t he st u d y are:  
•  T o e val uate c h a n ge fr o m baseli ne i n a n n ualize d gr o wt h vel ocit y f oll o wi n g dail y S C 
i njecti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  T o e val uate c ha n ges fr o m baseli ne i n gr o wt h para meters f oll o wi n g dail y S C 
i njecti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  T o e val uate c ha n ges fr o m baseli ne i n b o d y pr o p orti o ns ( u p per ar m t o f orear m le n gt h, 
u p per le g t o l o wer l e g le n gt h, a n d u p p er t o l o wer b o d y se g m e nt rati os) f oll o wi n g 
dail y S C i njecti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  T o e val uate t he e x p os ure a n d P K pr ofiles of B M N 1 1 1 i n c hil dre n wit h A C H 
f oll o wi n g dail y S C i njecti o ns of B M N 1 1 1 at eac h d ose le vel  a n d o ver m ulti ple da ys 
T he e x pl orat or y o bj ecti v es of t he st u d y are:  
•  T o e val uate c ha n ge fr o m baseli ne i n Q C T b o ne mi neral de nsit y ( B M D) f oll o wi n g 
dail y S C i njecti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs 
•  T o e val uate c ha n ges fr o m baseli ne i n gr o wt h plat e m or p h ol o g y f oll o wi n g dail y S C 
i njecti o ns of B M N 1 1 1 f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  T o e val uate c ha n ges fr o m baseli ne i n l o n g - b o n e gr o wt h, a n d m or p h ol o g y of t he s pi ne 
f oll o wi n g dail y S C i njecti o ns of B M N 1 1 1 a d mi nistere d f or 6 m o nt hs, a n d u p t o 
2 4 m o nt hs  
•  T o e val uate c ha n ges fr o m baseli ne i n slee p a p n ea f oll o wi n g dail y S C i njecti o ns 
a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  T o e val uate c ha n ges fr o m baseli ne i n el b o w j oi nt ra n ge of m oti o n b y g o ni o metr y, 
f oll o wi n g dail y S C i njecti o ns a d mi nistere d f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
•  T o e val uate c ha n ges fr o m baseli ne i n B M N  1 1 1 acti vit y bi o mark ers a n d 
b o ne/c olla ge n bi o mar k ers f oll o wi n g dail y S C i njecti o ns of B M N 1 1 1 a d mi nistere d 
f or 6 m o nt hs, a n d u p t o 2 4 m o nt hs  
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•  T o e val uate i m m u n o ge ni cit y fr o m baseli ne a n d assess i m pact o n safet y, P K , a n d 
efficac y meas ures f oll o wi n g dail y S C i njecti o ns of B M N 1 1 1 d uri n g t he 6 m o nt hs, 
a n d u p t o 2 4 m o nt hs  
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9  
I N V E S TI G A TI O N A L P L A N 
9. 1  
O ver all St u d y Desi g n a n d Pl a n  
St u d y 1 1 1- 2 0 2 is a pe diatric, P hase 2, o pe n- la bel d ose-escalati o n st u d y of a p pr o xi matel y 
3 6 s u bjects wit h a cli nical dia g n osis of A C H.  S u bjects w h o are 5 t o 1 4 years ol d i ncl usi ve, 
wit h d oc u me nte d A C H c o nfir me d b y ge netic t esti n g, ha v e at least a 6 - m o nt h peri o d of 
pretreat me nt gr o wt h assess me nt i n St u d y 1 1 1- 9 0 1 i m me diatel y bef ore st u d y e ntr y, a n d w h o 
meet t he st u d y eli gi bilit y criteria will partici p ate.  B M N  1 1 1 will be a d mi nistere d dail y f or 
6 m o nt hs, pr o vi de d n o ne of t he pr ot oc ol- defi ne d st o p pi n g or safet y criteria, defi ne d bel o w, 
are met.  O n  d a ys of sc h e d ule d cli nic visits, B M N 1 1 1 a d mi nistrati o n will be perf or me d i n 
t he cli nic relati ve t o t he s c he d ule d ass ess me nts a n d pr oce d ures defi n e d i n t he 1 1 1- 2 0 2 
Sc he d ule of E ve nts ( T a bl e  9. 1. 1).  
C o m pre he nsi ve o ut patie nt safet y m o nit ori n g will be c o n d u cte d f or all s u bj ects o ver t he 
c o urse of t he first 1 0 da ys  after t he first d o se of st u d y dr u g is recei ve d, f oll o we d b y cl ose 
m o nit ori n g t hr o u g h o ut t he d urati o n of t he st u d y.  T he c o m pre h e nsi ve safet y m o nit ori n g 
i ncl u des a mi ni m u m of 8 h o urs p ost- d ose o bser v ati o n o n t he first t w o da ys of d osi n g a n d at 
least 4 h o urs p ost d ose o bser vati o n o n st u d y Da ys 3 a n d 4.  S u bjects ma y b e o bser ve d f or a 
l o n ger d urati o n a n d/ or a d diti o nal visits ma y be a d de d f or f urt her safet y ass ess me nt o n 
Da y s 5- 9 at t he discreti o n of t he I n vesti gat or i n c o ns ultati o n wit h t he Bi o Mari n Me dical 
M o nit or.  A visit o n Da y  1 0 c o ncl u des t he c o m pre he nsi ve o ut patie nt safet y- m o nit ori n g 
peri o d.  Vital si g ns will b e m o nit ore d fre q u e ntl y d uri n g t he i nitial peri o d of Da ys 1 - 1 0, 
i ncl u di n g a p pr o xi matel y e ver y 1 0- 2 0 mi n utes f or t he first 2 h o urs p ost d ose o n visit da ys.  
A d diti o na l safet y assess me nts d uri n g t his peri o d are E C G, p h ysical e x a ms, A E assess me nt, 
a n d cli nical la bs ( T a ble  9. 1. 1).  
A ma xi m u m of fi ve c hil dre n fr o m o ne ge n der ma y be e nr olle d i n eac h c o h ort if t he t otal size 
of t he c o h ort is ei g ht or ni ne s u bjects; a ma xi m u m of si x c hil dre n fr o m o ne ge n d er ca n be 
e nr olle d i n eac h c o h ort if t he size of t he c o h ort is 1 0 s u bjects. 
B M N 1 1 1 will be a d mi nistere d as a m or ni n g d os e i n o ne of t he f oll o wi n g d ail y d osi n g 
re gi me ns: 
•  C o h ort 1 ( n = 8): dail y m or ni n g d ose of 2. 5 µ g/ k g B M N 1 1 1 
•  C o h ort 2 ( n = 8): dail y m or ni n g d ose of u p t o 7. 5 µ g/ k g B M N 1 1 1 
•  C o h ort 3 ( n = 8- 1 0): dail y m or ni n g d ose of u p t o 1 5. 0 µ g/ k g B M N 1 1 1 
•  C o h ort 4 ( n = 8- 1 0): dail y m or ni n g d ose of 3 0. 0 µ g/ k g B M N 1 1 1 
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It is ge n erall y e x pecte d t hat after s u bjects are t olerati n g t he dr u g well a n d s pecifie d criteria 
ha ve bee n met, care gi vers will be gi n a d mi nisteri n g st u d y dr u g.  I n t h e i nitial p hase, o n w ee ks 
w he n care gi vers/s u bjects will n ot see eit her a h o m e healt hcare pr ofessi o nal or a st u d y st aff 
me m ber, a p h o ne call b y t he st u d y staff me m ber t o t he care gi ver/s u bject will be re q uire d.  
D uri n g t h e call, st u d y staff will as k t he care gi ver a b o ut c orrect a d mi nistrati o n pr oce d ures, 
assess a d verse e v e nts ( A Es), rec or d c o nc o mita nt me dicati o ns, a n d a ns w er q uesti o ns.  D uri n g 
t he o pti o nal, o pe n-la bel e xte nsi o n p hase, t he call fre q ue nc y will c ha n ge t o e ver y 2 w ee ks 
( ± 3 da ys) f or t h e first 6 m o nt hs of t he e xte nsi o n p hase a n d m o nt hl y ( ± 5 d a ys)  t hereafter.  
A f oll o w- u p p h o ne call will ta ke place 7- 1 0 d a ys after d ose a dj ust m e nt visits. 
D ose Esc al ati o n Pl a n d uri n g t he I niti al 6 M o nt hs of t he St u d y  
F or eac h c o h ort, t w o se nti nel s u bjects will be e nr olle d a n d m o nit ore d. A D M C re vie w will 
occ ur after b ot h se nti nel s u bjects reac h Da y 1 0; if st o p pi n g criteri a are n ot met, a n d after 
re vie w a n d a p pr o v al b y t he D M C, t he re mai n der of t he c o h ort ma y t he n b e e nr olle d.  
S u bjects will re mai n o n a fi x e d dail y d os e t hr o u g h o ut t he i nitial 6 - m o nt h treat me nt peri o d.  
S u bjects i n eac h c o h ort c o nti n ue t o recei ve d ail y d osi n g ( C o h ort 1, 2. 5 µ g/ k g; C o h ort 2, u p t o 
7. 5 µ g/ k g, C o h ort 3, u p t o 1 5 µ g/ k g, a n d C o h ort 4, 3 0. 0 µ g/ k g) f or 6 m o nt hs u nless st o p pi n g 
criteria are met. If st o p pi n g criteria are n ot met after all 8- 1 0 s u bjects i n a c o h ort ha ve 
c o m plete d t heir first 1 0 d a ys of c o h ort d osi n g, a n d after D M C re vie w a n d a p pr o val, t he 
s u bse q ue nt c o h ort ma y  b e o pe n t o e nr oll me nt. 
O pti o n al, O pe n- l a bel E xte nsi o n P h ase of t he St u d y  
I n t he o p e n-la b el, o pti o nal e xte nsi o n p hase, t he l o n g-ter m safet y, t olera bilit y, a n d effects of 
B M N 1 1 1 o n gr o wt h will be e val uat e d i n c hil dre n wit h A C H w h o ha ve c o m plete d a n i nitial 
6 m o nt hs of treat me nt wit h B M N 1 1 1. At t he Da y 1 8 3/ 6- m o nt h visit, s u bjects w h o elect t o 
c o nti n ue partici pati n g i n t he o pti o nal o pe n-la bel e xte nsi o n p hase will be c o nse nte d f or t he 
e xte nsi o n p hase.  T hese s u bjects will recei v e st u d y dr u g o n Da y 1 8 4 of t he i nitial p hase, 
w hic h als o mar ks t he be gi n ni n g of t he e xte nsi o n p hase.  Dr u g treat me nt will c o nti n ue 
wit h o ut i nterr u pti o n.  S u bjects w h o decli ne t o partici pate i n t he e xte nsi o n p hase will ret ur n at 
Da y 2 0 8 f or t he Safet y F oll o w- U p visit a n d e xit t he st u d y. 
I n t he 1 8- m o nt h o pti o nal, o pe n-la bel e xte nsi o n p hase, s u bjects wit hi n eac h c o h ort will eit her 
re mai n o n t he sa me sta bl e d ose t hat t he y ha v e bee n recei vi n g d uri n g t he i nitial 6 m o nt hs of 
treat me nt, or t he d ose f or all s u bjects i n t he c o h ort (e x ce pt c o h ort 4 ) ma y b e i ncrease d bas e d 
o n t he f oll o wi n g r ul es: 
-
pr ot oc ol. p df
Pa ge 3 7

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 3 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
( 1) I nitial d ose was d eter mi ne d t o e x hi bit s u b o pti mal efficac y o n t he basis of gr o wt h 
meas ure me nts after at least 6 m o nt hs of treat me nt base d o n t he re vie w  of t h e data f or all 
s u bjects i n t he c o h ort.  
( 2) I nitial d ose, a n d ot her d oses hi g her t ha n t he i nitial d ose, b ut l o wer t ha n t he d ose t o w hic h 
t he c o h ort is bei n g i ncrease d wer e ge nerall y well t olerate d f or at least 6 m o nt h base d o n 
re vie w of d ata f or all s u bjects i n t he c o h ort. 
( 3) T he d ose t o w hi c h t he s u bjects i n t he c o h ort are bei n g es calate d h as bee n pre vi o usl y 
s h o w n t o be well t olerate d f or at least 1 0 da ys of c o m pre he nsi ve o ut patie nt safet y m o nit ori n g 
as descri be d i n Secti o n 9. 1 , base d o n D M C re vie w of t he data f or all s u bjects i n t he c o h ort 
pre vi o usl y assi g n e d t o t he c o nsi der e d d ose.  
D uri n g t h e o pti o nal, o pe n- la bel e xte nsi o n p hase, visits will ta ke place at 2- t o 3- m o nt h 
i nter vals.  T he site will call t he car e gi ver/s u bje ct bet wee n t he visits e ver y t w o wee ks f or t he 
first 6 m o nt hs a n d e ver y m o nt h f or t he re mai n der of t he st u d y.  
D M C data re vie w will occ ur a p pr o xi matel y e ver y 4 m o nt hs d uri n g t he o pti o nal, o pe n- la bel 
e xte nsi o n p hase.   
S u bjects w h o partici pate i n t he o pe n- label e xte nsi o n p hase of st u d y 1 1 1- 2 0 2 will ha ve t he 
o pti o n t o e nr oll i n t he l o n g-ter m e xte nsi o n st u d y 1 1 1- 2 0 5 at t he Mo nt h 2 4 / St u d y C o m pleti o n 
Visit .  M o nt h 2 4 assess me nts will ser ve as Baseli n e/scree ni n g assess me nts f or e ntr y t o st u d y 
1 1 1- 2 0 5.  
Criteri a f o r D ose A dj ust me nt Visits  
T he ti mi n g of d ose a dj ust me nts a n d f oll o w- u p visits after a dj ust me nt is c o nti n ge nt u p o n t he 
ti me at w hic h t he d ose a dj ust me nt was rec o m me n d e d.  O ne of t w o s ce nari os will a p pl y: 
•  Sce nari o 1:  Rec o m me n d ati o n t o a dj ust t he d ose is ma de w he n t he n e xt sc he d ule d 
visit is  ≤ 4 wee ks  a wa y fr o m t he date t hat t he d ose c ha n ge is c o m m u nicat e d t o sites . 
D ose a dj ust me nt will be d o ne at t he ne xt sc he d ule d visit.  
•  Sce nari o 2:  Rec o m me n d ati o n t o a dj ust t he d ose is ma de w he n t he n e xt sc he d ule d 
visit is  >  4 wee ks a wa y  fr o m t he date t hat t he d ose c ha n ge is c o m m u nicat e d t o sites .  
A n u nsc he d ule d d ose a dj ust me nt visit will  be d o ne wit hi n 4 wee ks.   
I n b ot h cases, a f oll o w- u p visit 4 wee ks ( ± 2 wee ks)  is re q uire d after t he d ose a dj ust me nt. 
T he d ose a dj ust me nt f oll o w- u p visit will be sc he d ul e d 4 wee ks after t he d ose a dj ust me nt visit 
U N L E S S a re g ularl y s c h e d ule d visit occ urs wit hi n t he ± 2 -wee k  visit wi n d o w, i n w hic h cas e 
a se par ate f oll o w - u p visit will n ot be re q uire d.  
-
pr ot oc ol. p df
Pa ge 3 8

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 3 8 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
Please ref er t o  Ta bl e  9. 1. 3 f or a list of assess me nts ass ociate d wit h D ose A dj ust me nt a n d 
F oll o w- u p Visits.  
Assess me nts  
F or a disc ussi o n of effi ca c y assess me nts, see Se cti o n 9. 1 0. 2 ; e x pl orat or y efficac y 
assess me nts, Secti o n 9. 1 0. 3 ; safet y assess me nts, Secti o n 9. 1 0. 4 ; a nd P K/ P D varia bles, 
Secti o n s 9. 1 0. 2. 1  a n d 9. 1 0. 3. 1 .  T he 1 1 1- 2 0 2 st u d y desi g n is prese nte d i n Fi g ure  9. 1. 1. 
Fi g ure  9. 1. 1:  1 1 1- 2 0 2 St u d y Desi g n 
 
A s u m mar y of e v e nts a n d asse ss me nts are pr o vi d e d b y visit i n Ta ble  9. 1. 1. 
 
-
pr ot oc ol. p df
Pa ge 3 9

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 3 9 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
T a ble 9. 1. 1 :  Sc he d ule of E ve nts f or 6 -M o nt h I niti al P h ase of t he St u d y  
Pr oce d ure a 
Scree ni n g  
D a y -3 0 t o 
D a y -1  
D a y 
1  
D a y 
2  
D a y 
3  
D a y 
4  
D a y 1 0  
±  1 D a y  
D a y 1 5  
± 1 D a y  
D a y 2 2  
± 1 D a y  
D a y 2 9  
± 1 D a y  
D a y 4 3  
± 7 D a ys  
D a y 
8 5  ± 7 
D a ys  
D a y 
1 2 7  
± 7 
D a ys  
D a y 
1 8 3 ± 7 
D a ys  
M 6  
S afet y 
F oll o w -
u p   D a y 
2 0 8  
± 7 D a ys  
E arl y 
Ter m  
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Me dical hist or y
b 
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P are ntal hei g ht c 
X c 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ge netic testi n g  
(if nee de d)d 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
P h ysical 
e xa mi nati o n e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T a n ner Sta ge of 
P u bertal 
De vel o p me nt  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Pre g na nc y test e 
X  
 
 
 
 
 
 
 
 
X  
X  
X  
X  
X  
X  
Vital si g ns f 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A nt hr o p o metric 
meas ure me nts g 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
 
X g 
W ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
El b o w j oi nt ra n ge of 
m oti o n h 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
B aseli ne hi p 
assess me nt, i ncl u di n g 
A P x -ra y of pel visi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hi p m o nit ori n g  
(refer t o g ui da nce)j 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Slee p a p nea 
assess me nts k 
X 
 
 
 
 
 
 
 
 
 
X 
 
X 
 
X 
E C G  
X  
 
 
 
 
X  
 
 
X  
 
X  
 
X  
X  
X  
E C H O  
X  
 
 
 
 
 
 
 
 
 
 
 
X  
 
 
Cli nical la bs 
X  
X  
 
 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
X  
-
pr ot oc ol. p df
Pa ge 4 0

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 0 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
Pr oce d ure a 
Scree ni n g  
D a y -3 0 t o 
D a y -1  
D a y 
1  
D a y 
2  
D a y 
3  
D a y 
4  
D a y 1 0  
±  1 D a y  
D a y 1 5  
± 1 D a y  
D a y 2 2  
± 1 D a y  
D a y 2 9  
± 1 D a y  
D a y 4 3  
± 7 D a ys  
D a y 
8 5  ± 7 
D a ys  
D a y 
1 2 7  
± 7 
D a ys  
D a y 
1 8 3 ± 7 
D a ys  
M 6  
S afet y 
F oll o w -
u p   D a y 
2 0 8  
± 7 D a ys  
E arl y 
Ter m  
( he mat ol o g y, 
c he mistr y, a n d 
uri nal ysis) l 
Uri ne c he mistr y m  
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T h yr oi d f u ncti o n tests  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Ser u m gl uc ose le vels  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Vita mi n D  
X  
 
 
 
 
 
 
 
 
 
 
 
X  
 
X  
A nti -B M N 1 1 1 
i m m u n o ge nicit yn 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
X 
X 
X 
P D B M N  1 1 1 acti vit y 
bi o mar kers o 
X 
X 
 
 
 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
N T pr o C N P 
( plas ma) 
X 
 
 
 
 
 
 
 
X 
X 
 
X 
X 
 
X 
A N P ( plas ma)  
 
X  
 
 
 
X  
 
 
X  
 
 
X  
 
 
 
c G M P ( uri ne)  
 
X  
 
 
 
X  
X  
 
X  
X  
X  
X  
X  
 
 
P D b o ne a n d c olla ge n 
bi o mar kers p 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
B S A P (ser u m)  
X  
X  
 
 
 
X  
X  
 
X  
X  
X  
X  
X  
 
X  
P 1 N P (ser u m)  
X  
X  
 
 
 
 
X  
 
X  
X  
X  
X  
X  
 
X  
C T X -II ( uri ne) 
X  
X  
 
 
 
 
X  
X  
X  
X  
X  
X  
X  
 
X  
Oste ocalci n 
(ser u m) 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
P K q  
 
X  
 
 
 
X  
 
 
X  
 
X  
 
X  
 
 
Q ua ntitati ve 
c o m p ute d  
t o m o gra p h y ( Q C T) of 
f orear m a n d ti bia s, v 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
-
pr ot oc ol. p df
Pa ge 4 1

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 1 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
Pr oce d ure a 
Scree ni n g  
D a y -3 0 t o 
D a y -1  
D a y 
1  
D a y 
2  
D a y 
3  
D a y 
4  
D a y 1 0  
±  1 D a y  
D a y 1 5  
± 1 D a y  
D a y 2 2  
± 1 D a y  
D a y 2 9  
± 1 D a y  
D a y 4 3  
± 7 D a ys  
D a y 
8 5  ± 7 
D a ys  
D a y 
1 2 7  
± 7 
D a ys  
D a y 
1 8 3 ± 7 
D a ys  
M 6  
S afet y 
F oll o w -
u p   D a y 
2 0 8  
± 7 D a ys  
E arl y 
Ter m  
B o ne a ge x -ra y ( P A 
of ha n d a n d wrist) t, v  
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X q 
A P l o wer e xtre mit y 
x -ra yu, v 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Lateral l u m bar s pi ne 
x -ra yw 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
A P x -ra y of s pi nex  
X  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o nc o mita nt 
me dicati o ns y 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
St u d y dr u g 
a d mi nistrati o n  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
St u d y dr u g 
acc o u nta bilit y  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
A d verse e ve nts a a 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
W ee kl y p h o ne calls 
or h o me healt h 
visits b b 
O nl y re q uire d o n wee ks w he n t here are n o st u d y visits.    
 
-
pr ot oc ol. p df
Pa ge 4 2

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 2 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
T a ble 9. 1. 2 :  O pti o n al, O pe n -l a bel E xte nsi o n P h ase of t he St u d y  
Pr oce d ure a 
M 8  
± 7 D a ys  
M 1 0   
± 7 D a ys  
M 1 2  
± 7 D a ys  
M 1 5   
± 1 4 D a ys  
M 1 8  
 ± 1 4 D a ys  
M 2 1  
± 1 4 D a ys  
M 2 4 / St u d y 
C o m pleti o n 
Visit z 
± 1 4 D a ys  
S afet y 
F oll o w -u p a a 
M 2 5  
± 7 D a ys  
E arl y 
Ter m  
P h ysical e xa mi nati o n e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T a n ner Sta ge of P u bertal 
De vel o p me nt  
 
 
X 
 
X 
 
X 
 
X 
Pre g na nc y test e 
X  
X  
X  
X  
X  
X  
X  
X  
X  
Vital si g ns f 
X 
X 
X 
X 
X 
X 
X 
X 
X 
A nt hr o p o metric meas ure me nts g 
X 
X 
X 
X 
X 
X 
X 
X 
X 
W ei g ht  
X  
X  
X  
X  
X  
X  
X  
X  
X  
El b o w j oi nt ra n ge of m oti o n h 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hi p m o nit ori n g (refer t o g ui da nce) j 
 
 
X 
 
X 
 
X 
 
X 
Slee p a p nea assess me nts k 
 
 
X  
 
 
 
X  
 
X k 
E C G  
X  
X  
X  
X  
X  
X  
X  
 
X  
E C H O  
 
 
X 
 
X 
 
X 
 
X 
Cli nical la bs ( he mat ol o g y, c he mistr y, 
a n d uri nal ysis) l 
X 
X 
X 
X 
X 
X 
X 
X 
X 
T h yr oi d f u ncti o n test s 
 
 
 
 
 
 
X 
 
 
Uri ne c he mistr y m  
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vita mi n D  
 
 
 
 
 
 
X 
 
X 
A nti -B M N 1 1 1 i m m u n o ge nicit y n 
X 
X 
X 
X 
X 
X 
X 
X 
X 
P D B M N  1 1 1 acti vit y bi o mar kers o 
 
 
X 
 
X 
 
X 
 
X 
N T pr o C N P ( plas ma)  
 
 
X 
 
 
 
X 
 
X 
A N P ( plas ma)  
 
 
X 
 
 
 
X 
 
 
-
pr ot oc ol. p df
Pa ge 4 3

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 3 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
Pr oce d ure a 
M 8  
± 7 D a ys  
M 1 0   
± 7 D a ys  
M 1 2  
± 7 D a ys  
M 1 5   
± 1 4 D a ys  
M 1 8  
 ± 1 4 D a ys  
M 2 1  
± 1 4 D a ys  
M 2 4 / St u d y 
C o m pleti o n 
Visit z 
± 1 4 D a ys  
S afet y 
F oll o w -u p a a 
M 2 5  
± 7 D a ys  
E arl y 
Ter m  
c G M P ( uri ne)  
 
 
X  
 
X  
 
X  
 
 
P D b o ne a n d c olla ge n bi o mar kers p 
X  
X  
X  
X  
X  
X  
X  
 
X  
B S A P (ser u m)  
X  
X  
X  
X  
X  
X  
X  
 
X  
P 1 N P (ser u m)  
X  
X  
X  
X  
X  
X  
X  
 
X  
C T X -II ( uri ne) 
X  
X  
X  
X  
X  
X  
X  
 
X  
Oste ocalci n (ser u m)  
 
 
X  
 
 
 
X  
 
X  
P K q,r 
X  
X  
X  
X  
X  
X  
X  
 
 
Q ua ntitati ve c o m p ute d t o m o gr a p h y 
( Q C T) of f orear m a n d ti bias, v  
 
 
X 
 
 
 
X 
 
X 
B o ne a ge x -ra y ( P A of ha n d a n d 
wrist) t, v  
 
 
X 
 
X 
 
X 
 
X 
A P l o wer e xtre mit y xra y u, v 
 
 
X  
 
 
 
X  
 
X  
Lateral l u m bar s pi ne x -ra yw   
 
 
 
 
 
 
X  
 
X  
A P x -ra y of s pi nex 
 
 
 
 
 
 
X  
 
X x 
C o nc o m ita nt me dicati o nsy 
X  
X  
X  
X  
X  
X  
X  
X  
X  
St u d y dr u g a d mi nistrati o n  
X  
X  
X  
X  
X  
X  
X  
 
 
St u d y dr u g acc o u nta bilit y  
X  
X  
X  
X  
X  
X  
X  
 
X  
A d verse e ve nts a a 
X  
X  
X  
X  
X  
X  
X  
X  
X  
P h o ne calls b b 
E ver y t w o wee ks ( ±  3 da ys) f or t he first 6 m o nt hs a n d e ver y m o nt h ( ±  5 da ys) f or t he re mai n der of t he st u d y. 
 
N O T E: A L L A S S E S S M E N T S P R E -D O S E E X C E P T W H E N S P E CI FI E D.  
a Da y 1 0 -2 9 visits ha ve a ± 1- d a y wi n d o w; Da ys 4 3 -1 8 3  visits ha ve a ± 7 Da y wi n d o w; t here is n o Da y 0.  M o nt hs 8 -1 2  ha ve a ± 7- da y  wi n d o w.   M o nt hs 1 5 -2 4 ha ve 
a ±  1 4 -da y wi n d o w .  Meas ure me nt a n d i ma gi n g assess me nts ca n be c o n d ucte d eit her pre -d ose or p ost -d ose.  
-
pr ot oc ol. p df
Pa ge 4 4

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 4 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
b Me dical hist or y , i ncl u di n g gr o wt h hist or y a n d A C H-relate d hist or y, s h o ul d elicit all maj or ill nesses, dia g n oses, a n d s ur geries t hat t he s u bj ect has e ver ha d ; a n y 
pri or or  e xisti n g me dical c o n diti o ns t hat mi g ht i nterfere wit h st u d y partici pati o n or safet y . 
c S ta n di n g hei g ht of t he partici p a nt’s bi ol o gical pare nts will b e assesse d.  Pri or t o t he meas ure me nt bei n g ta ke n, eac h pare nt is re q uire d t o c o m plete a n I C F s pecific 
t o pare nt hei g ht assess me nt.  T he I C F will be si g ne d pri or t o t he assess me nt, w hic h ca n b e d o ne at a n y p oi nt i n t he st u d y.  If bi ol o gical pare nt is n ot a vaila ble 
d uri n g t he c o urse of t he st u d y t o ta ke t heir sta n di n g hei g ht , if c o nse nte d, ca n pr o vi de t heir stated hei g ht . 
d If s u bj ects ha d pre vi o us ge neti c testi n g, s u bj ects m ust ha ve eit her a writte n letter b y t he p h ysicia n c o nfir mi n g ge netic testi n g, i ncl u di n g t he s pecific m utati o n 
re q uire d f or t he 1 1 1-2 0 2 st u d y i ncl u de t he i de ntificati o n of F G F R 3 m utati o n ( G 3 4 6 E, G 3 7 5 C, G 3 8 0 R, or “ ot her”) O R a la b certificati o n wit h t he st u d y s pecific 
m utati o n d oc u me nte d.  
e C o m plete p h ysical e xa m i ncl u des all maj or b o d y s yste ms, i ncl u di n g assess me nt of ge neral a p peara nce; C V; der mat ol o gic; hea d, e yes, ears, n ose, a n d t hr oat; 
l y m p hatic; res pirat or y; gastr oi ntesti nal ( GI ); m usc ul os keletal; a n d ne ur ol o gical/ ps yc h ol o gi cal a n d ge nit o uri nar y.  Pre g na nc y test will be c o n d ucte d at eac h 
i n dicate d visit f or fe male s u bj ects w h o ha ve be g u n me nses or are 1 0  years of a ge a n d ol der.  Eit her uri ne or  ser u m test ma y be use d t o c o nfir m pre g na nc y. 
f All treat me nt visits ha ve pre -d ose vital si g n assess me nts .  Vital si g ns at pre-d ose  i ncl u de: b o d y te m perat ure i n de grees Celsi us (° C), heart rate, B P, a n d res pirat or y 
rate.  Post -d ose meas ure me nts i ncl u de heart  rate a n d B P. 
Vit al Si g n Assess me nt Fre q u e nc y  
Scree ni n g  
After at least 5  mi n of rest, s u bj ect’s B P is ta ke n i n sitti n g p ositi o n.  
T he n t he s u bj ect will sta n d a n d B P will be ta ke n a gai n at a p pr o xi matel y 1  a n d 3 mi n utes after sta n di n g.   
 
Assess me nt Fre q ue nc y  
D osi n g Visits  
0 -1 hr p ost -d ose  
0 -2 hr p ost -d ose  
2 -4 hr p ost d ose  
4 -8 hr p ost -d ose  
Da ys 1, 2  
 
q 1 5 mi n ( ± 5 mi n)  
q 3 0 mi n ( ± 5 mi n)  
q 6 0 mi n ( ± 1 0 mi n)  
Da ys 3, 4 a n d d ose a dj ust me nt  visit i n 
o pti o nal, o pe n -la bel e xte nsi o n p hase 
 
q 1 5 mi n ( ± 5 mi n)  
q 3 0 mi n ( ± 5 mi n)  
 
All ot her d osi n g visits  
q 1 5 mi n ( ± 5 mi n);  
fi nal assess me nt pri or t o e n d of visit 
(if l o n ger t ha n 1 hr) 
 
 
 
1.  
Vital si g n meas ure me nts are ta k e n o n ce p er ti me p oi nt i n a sitti n g p ositi o n after at least 5 mi n utes of rest.   
2.  
Left brac hial ar m  s h o ul d b e t h e first met h o d of assess me nt c o nsi d ere d, a n d t h e sa me site s h o ul d b e use d f or meas ure me nt of B P i n eac h s u bject t hr o u g h o ut t he st u d y.  
3.  
Heart rate s h o ul d b e ta ke n at eac h ti me p oi nt t h at B P is meas ure d.   
4.  
W he n bl o o d sa m ples a n d B P assess me nts are  sc h e d ule d at t h e sa me ti me or wit hi n t h e sa me ti me wi n d o w, B P s h o ul d be meas ure d bef ore bl o o d sa m ples are dra w n.   
5.  
If a B P meas ure me nt m ust b e ta k e n after a bl o o d dra w, e ns ure a d e q u ate a n al gesia f or t h e bl o o d dra w a n d wait se veral mi n utes b ef ore meas uri n g B P.   
6.  
Vital si g ns ma y b e m o nit ore d m ore fre q u e ntl y or f or l o n ger d urati o n p ost -d ose as cli nicall y i n dicate d.  
7.  
If a s u bject h as a h y p ote nsi ve e ve nt ( or s y m pt o ms p ote ntiall y c o nsiste nt wit h h y p ote nsi o n) or a d ecrease i n s yst olic B P of 2 0 m m H g or m ore fr o m p re-d ose s yst olic 
B P, bl o o d press ure a n d h eart rate ( B P/ H R) s h o ul d b e meas ure d a n d rec or d e d a p pr o xi matel y e ver y 1 5 mi n utes f or t he first h o ur a n d e ver y 3 0 mi n utes t hereaft er u ntil 
t he s yst olic B P ret ur ns t o pre-d ose s yst olic B P ( or wit hi n t h e n or mal ra n ge f or t his p atie nt as d efi n e d b y PI) a n d s y m pt o ms (if prese nt)  res ol ve.  
-
pr ot oc ol. p df
Pa ge 4 5

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 5 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
g G r o wt h meas ures ma y be c ollecte d a p pr o xi matel y t he sa me ti me eac h da y (± 2 hr  ar o u n d t he ti me w he n t he first meas ur e me nt assess me nt was ta ke n at Scree ni n g).  
Meas ure me nts ma y i ncl u de b u t are n ot li mite d t o sta n di n g hei g ht, sitti n g hei g ht, wei g ht, he a d circ u mfere nce, u p per a n d l o wer ar m a n d le g, ha n d a n d f o ot.  
Meas ure me nts n ot ta ke n i n t he mi dsa gittal pla ne s h o ul d be ta ke n o n t he ri g ht si de of t he b o d y w he n p ossi ble. T a ke a nt hr o p o metric meas ure me nts at  earl y 
ter mi nati o n visit o nl y if s u bj ect disc o nti n ues after Da y 4 3.  
h T he sa me el b o w will be use d eac h ti me t he meas ure me nt is ta ke n.  
i If s u bj ect is alrea d y e nr olle d, baseli ne hi p assess me nt, i ncl u di n g x-ra y of pel vis, will be c o n d ucte d at ne xt  sc he d ule d visit.  If t his visit o verla ps wit h a sc he d ule d 
hi p -m o nit ori n g visit, t he hi p assess me nt will be c o n d ucte d . 
j Hi p m o nit ori n g: t his assess me nt will i ncl u de me dical hist or y  of t he hi p  a n d p h ysical e xa m t o deter mi ne c ha n ges i n hi p f u ncti o n or pai n wit h hi p ra n ge of m oti o n. 
C ha n ges fr o m baseli ne will tri g ger f urt her e val uati o n.  
k If slee p a p nea rea di n g is n ot a cc urate, s u bj ect ma y nee d t o re peat assess me nt.  Slee p a p ne a assess me nt at earl y ter mi nati o n visit  o nl y if s u bj ect disc o nti n ues after 
1 8  m o nt hs . 
l Cli nical la bs ( he mat ol o g y, c he mistr y, a n d uri nal ysis) are all pre -d ose dra ws  (sa m ples ca n b e dra w n a n yti me d uri n g t he visit if t here is n o dr u g a d mi nistrati o n) .  
m  First v oi d u p o n arri val at t he cli nic .  Scree ni n g, D a ys 1, 1 0, 1 5, 2 2, 2 9, 4 3, 8 5, 1 2 7, 1 8 3, M 8, M 1 0, M 1 2, M 1 5, M 1 8 , M 2 1, M 2 4, f oll o w-u p 4 w k p ost -escalati o n 
d ose , safet y f oll o w-u p, a n d earl y ter mi nati o n .  O ne hr , 2 hr, a n d 4 hr p ost -d ose c ollecte d Da ys 1, 1 0, 1 5, 2 9, 4 3, 8 5, 1 2 7, 1 8 3, M 1 2, M 1 8, M 2 4  ( ±  20 mi n utes f or 
all uri ne sa m ple ti me p oi nts ).   
n A nti b o dies: T otal a n d ne utrali zi n g a nti -B M N  1 1 1 i m m u n o ge nicit y sa m ples (ser u m) will be dra w n pre -d ose at eac h ti me p oi nt liste d  o n t he S O E . T otal 
i m m u n o gl o b uli n E (I g E) a n d dr u g-s pecific I g E will be dra w n o n Da y 1 a n d i n t he e ve nt of si g nifica nt h y per se nsiti vit y a d verse e ve nt (as defi ne d i n 
S ecti o n 9. 1 0. 4. 4. 6. 2 ), or at In vesti gat or or S p o ns or discreti o n. T he dr u g -s pecific I g E sa m pl e s h o ul d be dra w n at least 8 hr  after t he e ve nt start ti me a n d bef ore t he 
ne xt d ose. A sa m ple f or t otal I g E a n d ser u m tr y ptase s h o ul d be dra w n wit hi n a n h o ur of t he start of t he e ve nt w he n p ossi ble or d uri n g t he u nsc he dule d safet y visit.  
o N T pr o C N P: Scree ni n g; at d osi n g visits, plas ma pre -d ose a n d 4 hr p ost -d ose (  ± 3 0  mi n utes); A N P: plas ma pre -d ose,  1 5 mi n p ost -d ose (  ± 5 mi n utes), a n d 2 hr  
p ost -d ose (  ± 1 5 mi n utes); c G M P: uri ne pre -d ose, 1 hr p ost -d ose, 2 hr p ost -d ose, a n d 4 hr p ost -d ose (  ± 2 0 mi n utes f or all uri ne sa m ple ti me p oi nts).  
p All b o ne a n d c olla ge n bi o mar kers  are dra w n pre -d ose  (sa m ples ca n be dra w n a n yti me d uri n g t he visit if t here is n o dr u g  a d mi nistrati o n). 
q F or s u bj ects i n t he 6 -m o nt h i nitial p hase, o n Da ys 1, 1 0, 2 9, 8 5, a n d 1 8 3, P K sa m ples are c ollecte d pre -d ose a n d at 5 ( ± 2 mi n), 1 5 ( ± 2 mi n), 3 0 ( ± 5 mi n), 
6 0  ( ± 5 mi n), 9 0 ( ± 5 mi n ), 1 2 0 ( ± 5 mi n), a n d 1 8 0 ( ± 5 mi n) mi n utes p ost d ose.  F or s u bj ects o n a fi xe d d ose i n t he  o pti o nal, o pe n -la bel e xte nsi o n p has e, f ull P K 
sa m ples will be ta ke n at M o nt hs 1 2 a n d 2 4. P artial P K sa m ples will be ta ke n at f o ur ti me p oi nts ( pre -d ose, 1 5, 3 0, a n d  6 0 mi n utes p ost d ose) t o esti mat e e x p os ure 
a n d t o c orres p o n d wit h i m m u n o ge nicit y assess me nts. T hese partial P K dra ws will ta ke pla ce at M o nt hs 8, 1 0, 1 5, 1 8, a n d 2 1 wit h i m m u n o ge nicit y ass ess me nts 
(sa m ples ca n be dra w n a n yti me d uri n g t he visit if t here is n o dr u g a d mi nistrati o n).  
r F or s u bj ects w h ose d oses are a dj uste d u p war d i n t he o pti o nal, o pe n -la bel e xte nsi o n p hase, f ull P K sa m ples will be dra w n o n Da y 1 of d ose a dj ust me nt a n d at 
s u bse q ue nt visits per c ollecti o n sc he d ule i n T a ble  9. 1 0. 2. 1 . 1. P artial P K sa m ples will als o be dra w n at s u bse q ue nt visits per c ollecti o n sc he d ule i n  T a ble  9. 1 0. 2. 1 . 1. 
-
pr ot oc ol. p df
Pa ge 4 6

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 6 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
s F or meas ure me nt of gr o wt h pl ate, B M D, b o ne le n gt h. T his s ca n will be ac q uire d wit h a sta n dar d C T sca n ner, cali br ati o n p ha nt o m, a n d desi g nate d s oft ware, usi n g 
a pre deter mi ne d l o w ra diati o n d ose pr ot oc ol, w hic h a v oi ds direct ra diati o n t o t he hea d a n d t ors o.  
t B o ne a ge x -ra y a n d A P l o wer e xtre mit y (i n t he i nitial p hase of t he st u d y) are o btai ne d at t he earl y ter mi nati o n visit o nl y if s u bj ect disc o nti n ues after Da y 6 0  (t o 
re d uce u n necessar y ra diati o n e x p os ure ). 
u F or A P l o wer e xtre mit y x- ra y, assess t he sa me si de of t he b o d y t hr o u g h o ut t he st u d y. 
v Q C T, b o ne a ge, a n d l o wer e xtre mit y (i n t he o pti o nal, o pe n -l a bel e xte nsi o n p hase  of t he st u d y) are o btai ne d at t he earl y ter mi nati o n visit o nl y if t he pre vi o us 
assess me nt was d o ne m ore t ha n 6 0 da ys pri or t o earl y ter mi nati o n ( u nless a d diti o nal st u d y is rec o m me n de d b y In vesti gat or, Bi o Mari n, or D M C) . 
w  Lateral l u m ber s pi ne x -ra y at earl y ter mi nati o n visit o nl y if s u bj ect disc o nti n ues after 1 8 m o nt hs. 
x A P x -ra y of s pi ne at earl y ter mi nati o n visit o nl y if s u bj ect disc o nti n ues after 1 8 m o nt hs. 
y All me dicati o ns ( prescri pti o n, o ver -t he-c o u nter a n d her bal) a n d n utriti o nal s u p ple me nts ta ke n 3 0 da ys pri or t o Scree ni n g a n d t hr o u g h o ut t he st u d y s h o ul d be 
d oc u me nte d.  
z S u bj ects w h o partici pate i n t he o pe n -la bel e xte nsi o n p hase of st u d y 1 1 1-2 0 2 will ha ve t he o pti o n t o e nr oll i n t he l o n g -ter m e xte nsi o n st u d y 1 1 1-2 0 5 at t he 
M 2 4/ St u d y C o m pleti o n Visit.   M o nt h 2 4 assess me nts will ser ve as B aseli ne/scree ni n g assess me nts f or e ntr y t o st u d y 1 1 1 -2 0 5.    
aa After writte n i nf or me d c o nse nt b ut bef ore st u d y treat me nt i nitiati o n, o nl y S A Es ass ociate d wit h pr ot oc ol -i m p ose d i nter ve nti o ns will be rec or de d. After st u d y dr u g 
i nitiati o n, all A Es a n d S A Es will be rec or de d u ntil 4 wee ks after eit her t he last a d mi nistrati o n of st u d y dr u g or t he Earl y T er mi nati o n visit. If a s u bj ect is 
disc o nti n ue d fr o m t he st u d y pre mat urel y, A Es a n d S A E s will be rec or de d at t he Earl y T er mi nati o n vis it.  T he Da y 2 0 8 Safet y F oll o w -u p visit is n ot re q uire d if a 
s u bj ect e nr olls i n t he o pti o nal, o pe n -la bel e xte nsi o n st u d y at t he Da y 1 8 3/ M o nt h 6 visit . T he M o nt h 2 5 Safet y F oll o w -u p visit will be wai ve d if a s u bj ect e nr olls i n 
t he 1 1 1-2 0 5 e xte nsi o n st u d y at  t he M o nt h 2 4/ St u d y C o m pleti o n visit.  
b b I n t he i nitial p hase of t he st u d y, on wee ks w he n care gi vers/s u bj ects will n ot see eit her a h o me healt hcare pr ofessi o nal or a st u d y staff me m ber,  a p h o ne call b y t he 
st u d y staff me m ber t o t he care gi ver/s u bj ect will be re q uire d.  D uri n g t he call st u d y staff will as k t he care gi ver a b o ut c orrect a d mi nistrati o n pr oce d ures, assess 
a d verse e ve nts ( A Es), rec or d c o nc o mita nt me dicati o ns, a n d a ns wer q uesti o ns.  D uri n g t he o pti o nal, o pe n -la bel e xte nsi o n p hase, t he call fre q ue nc y wi ll c ha n ge t o 
e ver y 2 wee ks  ( ± 3 da ys) f or t he first 6 m o nt hs of t he e xte nsi o n phase  a n d m o nt hl y ( ± 5 da ys) t hereafter. 
 
 
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pr ot oc ol. p df
Pa ge 4 7

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
T a ble 9. 1. 3 :  Criteri a f or D ose A dj ust me nt Visits  
D ose A dj ust me nt 
Rec o m me n d ati o n *  
D ose A dj ust me nt 
M a de  
D ose A dj ust me nt Visit 
Pr oce d ures  
F oll o w -u p P h o ne c all  
4- w ee k  
F oll o w -u p Visit  
(± 2 w ee k s) 
Pr oce d ures D o ne at F oll o w -u p 
Visit  
N e xt sc he d ule d visit 
is  ≤ 4 wee ks  a wa y  
A t ne xt sc he d ule d 
visit  
T he pr oce d ures bel o w are d o ne 
at d ose a dj ust me nt visits.  If t he 
d ose a dj ust me nt visit ha p pe ns 
at a re g ularl y sc he d ule d visit, 
c o n d uct t he re mai ni n g 
sc he d ule d visit pr oce d ures as 
well.  
7 -1 0 da ys p ost d ose 
a dj ust me nt  
Sc he d ule 4 wee ks 
after t he d ose 
a dj ust me nt visit if 
a re g ularl y 
sc he d ule d visit 
d oes n ot occ ur  
wit hi n t he visit 
wi n d o w  
T he pr oce d ures  bel o w  are d o ne 
at a dj ust me nt f oll o w-u p visits.  
If t he a dj ust me nt f oll o w-u p  visit 
ha p pe ns at a re g ularl y sc he d ul e d 
visit, c o n d uct t he re mai ni n g 
sc he d ule d visit pr oce d ures as 
well.  
N e xt sc he d ule d visit 
is  >  4 wee ks  a wa y  
U nsc he d ule d d ose 
a dj ust me nt visit  t o 
be d o ne wit hi n 4 
wee ks fr o m D M C 
decisi o n t o d ose 
a dj ust 
•  
P h ysical e xa m  
•  
Vital si g ns   
•  
W ei g ht  
•  
A nt hr o p o metr y  
•  
E C G 
•  
C li nical la bs 
•  
U ri ne c he mistr y 
•  
F ull P K  
•  
C o nc o m ita nt me d icati o ns 
•  
D r u g a d mi nistrati o n 
•  
D r u g acc o u nta bilit y 
•  
A Es  
•  
P h ysical e xa m  
•  
Vital si g ns   
•  
W ei g ht  
•  
C li nical la bs 
•  
E C G 
•  
C o nc o m ita nt me d icati o ns 
•  
D r u g a d mi nistrati o n 
•  
D r u g acc o u nta bilit y 
•  
A Es  
* If a d ose is de-escalate d, st u d y sta ff will re q u est t h at t h e s u bject c o me i n as s o o n as p ossi ble. F oll o w-u p o cc urs 4 wee ks later.  
 
 
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pr ot oc ol. p df
Pa ge 4 8

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 8 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
9. 1. 1  D ose M o dific ati o ns f or S afet y 
9. 1. 1. 1  
St o p pi n g Criteri a  
I n di vi d u al S u bject St o p pi n g Criteri a  
F or i n di vi d ual s u bjects, te m p orar y d osi n g s us pe nsi o n, per ma ne nt disc o nti n uati o n of d osi n g, 
or, i n e x ce pti o nal circ u msta nces, d ose re d ucti o n will be c o nsi dere d a n d D M C will be 
i nf or me d (at a mi ni m u m) if a n y of t he f oll o wi n g o cc ur: 
•  A n y T E A E  at least Gra d e 3 assesse d  b y t he I n vesti gat or a n d/ or S p o ns or Me dical 
M o nit or 
•  A n y t w o T E A Es  Gr a de 2 e x perie nce d b y t he s a me s u bject wit hi n 1 wee k i ncl u di n g 
t w o s y m pt o matic h y p ote nsi o n e ve nts wit hi n 1 wee k ( n o n- ur ge nt me dical i nter ve nti o n 
i n dicate d) or a n y Gra d e 3 h y p ote nsi ve e ve nt ( ur ge nt me dical i nter ve nti o n or 
h os pitalizati o n i n dicate d) assesse d b y t he I n v esti gat or a n d/ or S p o ns or’s Me dical 
M o nit or 
•  Pr ol o n gati o n of Q T c- F i nter val t o m ore t ha n 5 0 0 msec, ve ntric ular tac h ycar dia 
gr eater t ha n fi ve b eats  
•  A n y cli nicall y  si g nifica nt w orse ni n g of e xisti n g dis pr o p orti o nate gr o wt h, as 
deter mi ne d b y p h ysica l meas ure me nt rati os a n d/ or I n vesti gat or ass ess me nt base d o n 
i ma gi n g, meas ure me nt or cli nical o bser vati o n fi n di n gs  
o  U p per ar m  t o f orear m le n gt h rati o 
o  U p per le g t o l o wer le g le n gt h rati o  
o  U p per t o l o wer b o d y s e g me nt rati o 
•  Cli nicall y si g nifica nt w orse ni n g of b o n e m or p h ol o g y as e vi de nce d b y de vel o p me nt of 
ti bial b o wi n g, or w ors e ni n g of e xisti n g ti bial b o wi n g as o bs er ve d vi a cli nical or 
ra di o gra p hic assess me nt  
•  Cli nicall y si g nifica nt w orse ni n g of el b o w j oi nt ra n ge of m oti o n base d o n cli nical 
assess me nt a n d o n g o n i o metr y meas ure m e nts of fle xi o n-e xte nsi o n 
•  Fi n di n gs o n cli nical hi p e x a m or hi p i ma gi n g ass ess me nts t hat are deter mi ne d t o be 
cli nicall y si g nifica nt as d eci de d b y pri nci p al i n vesti gat or a n d  i n c o ns ultati o n wit h 
s p o ns or me dical m o nit or a n d ort h o pe dic s pecialist (if nee de d) 
If t he s u bject meets a n y st o p pi n g criteria, aft er I n v esti gat or c o ns ultati o n wit h t he Bi o Mari n 
Me dical M o nit or a n d D M C (if warra nte d), t he s u bject ma y  be re -c h alle n ge d at t he sa me 
d ose.  If t he s u bject meets st o p pi n g criteri a o n re-c halle n ge or if re -c halle n ge at sa me d ose is 
n ot cli nicall y i n dicate d, ot her o pti o ns t hat ma y b e c o nsi dere d i ncl u d e: 
-
pr ot oc ol. p df
Pa ge 4 9

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 4 9 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  Re -c halle n ge at l o wer d ose wit h c o nsi derati o n gi v e n t o u p war d titrati o n t o t olerate d 
d ose/c o h ort d ose 
•  Per ma ne nt treat me nt disc o nti n uati o n ( wit h  a n d o pti o n of o n g oi n g ass ess me nt i n t he 
st u d y) 
C o h ort St o p pi n g Criteri a  
F or a n o p e n c o h ort a n d all hi g her d ose c o h orts, te m p orar y d osi n g s us pe nsi o n or d ose 
re d ucti o n will be c o nsi dere d a n d D M C re vie w will be c o n d ucte d (at a mi ni m u m) if a n y of t he 
f oll o wi n g occur:  
•  A n y t w o s u bjects wit hi n a c o h ort ha v e T E A E at least Gra de 3; a n y t w o s u bjects ha ve  
t w o s y m pt o matic h y p ote nsi o n e ve nts wit hi n 1 wee k eac h  Gra d e 2  ( n o n- ur ge nt 
me dical i nter ve nti o n i n dicate d);  or a n y  t w o s u bjects ha ve a Gra de 3 h y p ote nsi o n 
e ve nt (ur ge nt me dical i nt er ve nti o n or h os pitalizati o n i n dicate d) assess e d b y t he 
I n v esti gat or a n d/ or S p o ns or Me dical M o nit or 
•  A n y o n e s u bject wit h a n y T E A Es Gra d e 4 or 5 ass esse d  b y t he I n v esti gat or a n d / or 
S p o ns or Me dical M o nit or 
•  A n y t w o s u bjects wit hi n a c o h ort ha v e p r olo n gati o n of Q Tc- F i nter v al t o m ore t ha n 
5 0 0 msec, ve ntric ular tac h ycar dia great er t ha n fi v e beats   
•  A n y t w o s u bjects wit hi n a c o h ort ha v e cli nicall y si g nifica nt w orse ni n g of e xisti n g 
dis pr o p orti o nate gr o wt h, as deter mi ne d b y p h ysical meas ure me nt rati os a n d/ or 
I n v esti gat or assess me nt b ase d o n i ma gi n g, m eas ure me nt or cli nical o bser vati o n 
fi n di n gs  
o  U p per ar m t o f orear m le n gt h rati o 
o  U p per le g t o l o wer le g le n gt h rati o  
o  U p per t o l o wer b o d y s e g me nt rati o 
•  A n y t w o s u bjects wit hi n a c o h ort e x hi bit cli nicall y si g nificant w orse ni n g of b o ne 
m or p h ol o g y as e vi de nce d b y de v el o p me nt of ti bial b o wi n g, or w orse ni n g of e xisti n g 
ti bial b o wi n g as o bser v e d via cli nical or ra di o gra p hic assess me nt 
•  A n y t w o s u bjects e x hi bit cli nicall y si g nifica nt w orse ni n g of el b o w j oi nt ra n ge of 
m oti o n base d o n cli nical assess me nt a n d o n g o n i o metr y meas ure m e nts of 
fle xi o n-e xte nsi o n  
•  A n y t w o s u bjects e x hi bit fi n di n gs o n cli nical hi p e x a m or hi p i ma gi n g ass ess me nts 
t hat are det er mi ne d t o be cli nicall y si g nifica nt as d eci de d b y pri nci p al i n vesti gat or 
a n d, if nee d e d, i n c o ns ultati o n wit h s p o ns or me dical m o nit or a n d ort h o pe di c s pecialist 
(if nee de d) 
•  A n y ot her reas o n D M C a d vises te m p orar y disc o nti n uati o n of c o h ort d osi n g u ntil 
f urt her r e vie w of s afet y d ata is c o n d ucte d 
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Pa ge 5 0 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
Sites ha ve 1 b usi ness da y t o re p ort t o Bi o Mari n a n e ve nt t hat meets i n di vi d ual or c o h ort 
st o p pi n g criteri a.  D M C ca n as k f or a d diti o nal a v aila ble data w hile re vie wi n g  s u bject(s) w h o 
met i n di vi d ual st o p pi n g criteria, or s u bjects wit h a n y ot her ne w safet y fi n di n g. I n or der t o 
assess si g nifica nce of  t he fi n di n gs, D M C ca n re q u est t o re vie w a d diti o nal d ata f or ot her 
s u bjects i n t he c o h ort, or a n y ot h er s u bjects i n t he st u d y. T hes e a d diti o nal data i ncl u de, b ut 
are n ot li mite d t o, p h ysical e x a m, vital si g ns, a nt h r o p o metric meas ures, E C G, E C H O, a n d la b 
res ults.  T he D M C will re vie w a v aila ble, rel e va nt safet y data wit hi n 5 - 7 da ys after Bi o Mari n 
is a p prise d of a n e ve nt.  Bi o Mari n will kee p all sites i nf or me d of e nr oll me nt pa uses, t o e ns ure 
t hat n o s u bjects i n t he c o h ort (a n d all hi g her c o h orts) t hat are affecte d b y st o p pi n g criteria are 
treate d, a n d n o n e w s u bjects are e nr olle d, u ntil t he assess me nt is c o m plete.  Base d o n its 
re vie w, t he D M C ma y m a ke a n y of t h e f oll o wi n g rec o m me n dati o ns: 
•  C o nti n ue c o h ort a n d se q ue ntial d osi n g of c o h orts as pla n ne d wit h a d diti o nal safet y 
m o nit ori n g a n d/ or safet y re vie ws as i n dicate d  
•  C o nti n ue c urre nt c o h ort, b ut hi g her d os e c o h orts will recei ve l o w er d oses t ha n 
pla n ne d  
•  Decr ease c o h ort d ose a n d decrease d oses of s u bse q ue nt c o h orts  
•  E xte n d te m p orar y tr eat m e nt disc o nti n uati o n u ntil a d diti o nal data are a vaila ble a n d/ or 
f urt her r e vie w/c o ns ultati o n occ urs  
•  Per ma ne ntl y dis c o nti n ue treat me nt f or all c o h orts 
•  D ose a d diti o nal s u bjects of t he c o h ort at t he s a me d ose  
C o h ort d oses ma y b e c ha n ge d, b ase d o n D M C re vie w of safet y a n d efficac y dat a, t o a n y d ose 
bet wee n 0. 5 µ g/ k g a n d 3 0 µ g/ k g.  A n y s u bject w h o disc o nti n ues fr o m st u d y dr u g will be 
e nc o ura ge d t o c o m plete assess me nts f or t he d urati o n of t he st u d y. 
9. 1. 2  D ose M o dific ati o ns f or Effic ac y  
D ose m o dificati o ns f or efficac y ar e disc usse d i n Secti o n 9. 1  (s u bsecti o n O pti o n al, 
O pe n -l a bel Ext e nsi o n P h ase of t he St u dy).  
9. 2  
Disc ussi o n of St u d y Desi g n, I ncl u di n g C h oice of C o ntr ol Gr o u p  
T he i nte nt a n d desi g n of t his P hase 2 st u d y is t o assess B M N 1 1 1  as a t hera pe utic o pti o n f or 
t he treat me nt of c hil dre n wit h A C H.  C hil dre n 5- 1 4 years ol d  wit h A C H were c h ose n b eca use 
su bjects wit h A C H ha ve a n F G F R - 3 gai n of f u ncti o n m utati o n a n d beca use preli mi nar y 
efficac y e v al uati o n, deter mi ne d b y c h a n ge i n a n n u alize d gr o wt h vel o cit y, re q uires treat me nt 
of su bjects pri or t o e pi p h ys eal gr o wt h plate cl os ure, w hic h occ urs i n late a d olesce nce.  
Gr o wt h vel ocit y i n c hil dr e n wit h A C H re mai ns relati vel y sta ble fr o m a p pr o xi matel y 3 years 
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ol d t o gr o wt h plate cl os ure ( H o o v er- F o n g, 2 0 0 8, A m.J Cli n N utr. ).  C hil dre n y o u n ger t ha n 
5 years ol d will n ot be e nr olle d i n or der t o esta blis h a safet y pr ofile i n  a n ol der p o p ulati o n 
first, as well as t o mi ni mize t he c o nf o u n di n g effects of n o nli near gr o wt h rat es a n d 
i nacc ur acies i n here nt i n meas ure me nt of rec u mbe nt le n gt h i n y o u n g c hil dre n.  As c hil dre n 
wit h A C H d o n ot e x perie nce t he n or mal p h ysi ol o gical gr o wt h accelerati o n ass ociate d wit h 
p u bert y ( H o o ver- F o n g, 2 0 0 8, A m.J Cli n N utr.) t hat c o ul d c o nf o u n d t he d ata, t he p o p ulati o n 
is n ot li mite d t o pre - p u besce nt c hil dre n.  A m a xi m u m of fi ve c hil dre n fr o m o ne ge n der m a y 
be e nr olle d i n eac h c o h ort if t he t otal size of t he c o h ort is ei g ht or ni ne s u bjects; a ma xi m u m 
of si x c hil dre n fr o m o ne ge n d er ca n be e nr olle d i n eac h c o h ort if t he size of t he c o h ort is 
1 0 s u bjects. 
9. 3  
Selecti o n of St u d y P o p ul ati o n 
S u bjects 5 - 1 4 years ol d (i ncl usi ve) w h o ha v e d oc u me nte d A C H, as d oc u me nte d b y cli nical 
gr o u n ds a n d c o nfir m e d b y ge n etic testi n g, were selecte d t o partici pat e i n t his st u d y.  
A d diti o nal criteria f or partici pati o n i n t he st u d y are pr o vi de d i n Secti o ns 9. 3. 1  a n d 9. 3. 2 . 
9. 3. 1  I ncl usi o n Criteri a 
I n di vi d uals m ust meet t h e f oll o wi n g i ncl usi o n criteria t o be eli gi ble t o parti ci pate i n this 
st u d y: 
1.  Pare nt(s) or g u ar dia n(s) are willi n g a n d a ble t o pr o vi de writte n, si g n e d i nf or me d 
c o nse nt after t he nat ur e of t he st u d y h as bee n e x plai ne d a n d pri or t o p erf or ma nce of 
a n y researc h -rel ate d pr o ce d ure. Als o, s u bjects u n der t he a ge of 1 8 are willi n g  a n d 
a ble t o pr o vi de writte n asse nt ( if re q uire d b y l ocal re g ulati o ns or t he I R B/ E C) after 
t he nat ure of t h e st u d y h as bee n e x plai ne d a n d pri or t o perf or m a nce of a n y researc h-
relate d pr o ce d ur e. 
2.  Are 5 t o 1 4 years ol d, i ncl usi ve, at st u d y e ntr y 
3.  Ha ve A C H, d o c u me nte d b y cli nical gr o u n ds a n d c o nfir me d b y ge netic t esti n g 
4.  Ha ve at least a 6 - m o nt h peri o d of pretreat me nt gr o wt h assess me nt i n St u dy 1 1 1 - 9 0 1 
i m me diatel y bef ore st u d y e ntr y, a n d ha v e  o ne d oc u me nte d sta n di n g h ei g ht at least 
6 m o nt hs ( +/- 1 0 da ys) pri or t o t he scree ni n g visit f or 1 1 1- 2 0 2  
5.  Fe males  ≥ 1 0 years ol d or w h o ha ve be g u n m e nses m ust ha ve a ne gati ve pre g na n c y 
test at t he Scree ni n g Visit a n d be willi n g t o ha v e a d diti o nal pre g n a nc y tests d uri n g t he 
st u d y. 
6.  If se x uall y acti ve, willi n g t o use a hi g hl y effe cti ve met h o d of c o ntrace pti o n w hile 
partici pati n g i n t he st u d y  
7.  Are a m b ulat or y a n d a ble t o sta n d wit h o ut assista nce  
8.  Are willi n g a n d a ble t o p erf or m all st u d y pr oce d ures as p h ysicall y p ossi ble 
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9.  Pare nts or care gi vers ar e willi n g t o a d mi nister dail y i njecti o ns  t o t he s u bjects 
A d diti o n al I ncl usi o n Criteria O pti o n al, O pe n -l a bel E xte nsi o n P h ase: 
1.  A p pr o priate writte n i nf or me d c o nse nt (a n d asse nt, if a p plica ble) 
9. 3. 2  E xcl usi o n Criteri a  
I n di vi d uals w h o meet a n y of t he f oll o wi n g e x cl usi o n criteria are n ot eli gi ble t o partici pate i n 
t he st u d y: 
1.  Ha ve h y p oc h o n dr o plasia or s h ort stat ure c o n diti o n ot her t ha n A C H (e g, tris o m y 2 1, 
pse u d oac h o n dr o pl asia) 
2.  Ha ve a n y of t he f oll o wi n g:  
a. H y p ot h yr oi dis m or h y pert h yr oi dis m 
b.  I ns uli n-r e q uiri n g dia betes mellit us  
c. A ut oi m m u ne i nfla m mat or y disease (in cl u di n g celi ac diseas e, l u p us ( S L E), 
j u ve nile der mat o m y ositis, scler o der m a, a n d ot hers) 
d.  I nfla m mat or y b o wel disease  
e. A ut o n o mic ne ur o pat h y 
f. Rece nt a c ut e ill ness ass ociate d wit h v ol u me de pleti o n (e. g., n a usea, v o miti n g, 
diarr hea ) t hat has n ot c o m pletel y res olve d pri or t o t he first d ose of t he st u d y dr u g 
3.  Ha ve a n u nsta ble c o n diti o n li kel y t o re q uire s ur gi cal i nter ve nti o n d uri n g t h e st u d y 
(i ncl u di n g pr o gressi ve cer vical me d ullar y c o m pressi o n) 
4.  Gr o wt h plates ha v e f use d  
5.  Ha ve a hist or y of a n y of t he f oll o wi n g:  
a. Re nal  i ns ufficie nc y, d efi ne d as creati ni ne > 2 m g/ dl 
b.  A ne mia  
c. Baseli ne s yst olic B P <  7 5 m m H g or rec urre nt s y m pt o matic h y p ote nsi o n ( defi ne d 
as e pis o des of l o w B P  ge nerall y acc o m pa nie d b y s y m pt o ms i.e., dizzi ness, 
fai nti n g) or rec urr e nt s y m pt o matic ort h ostatic h y pote nsi o n 
d.  Car diac or v asc ular dis ease, i ncl u di n g t he f oll o wi n g: 
i. 
Car diac d ysf u n cti o n (a b n or mal E C H O i ncl u di n g a b n or mal L V  mass)  at 
Scree ni n g Visit  
ii. 
H y p ertr o p hic car di o m y o pat h y  
iii. 
P ul m o nar y h y perte nsi o n 
i v. 
C o n ge nital heart diseas e  wit h o n g oi n g car diac d ysf u ncti o n 
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v.  
C ere br o vas c ular disease  
vi.  
A ortic i ns ufficie n c y  
vii.  
Cli nicall y si g nifica nt atri al or ve ntric ular arr h yt h mias  
6.  Ha ve t he f oll o wi n g c o nfir me d E C G fi n di n gs: 
a. Ri g ht or left atri al e nlar ge me nt or ve ntric ul ar h y p ertr o p h y  
b.  P R i nter val >  2 0 0 msec  
c. Q R S i nter val >  1 1 0 msec 
d.  C orr ecte d Q Tc- F > 4 50 msec  
e. Sec o n d - or t hir d - d e gree atri o ve ntric ular bl oc k 
7.  D oc u me nte d Vita mi n D deficie nc y (i.e., c o n ce ntrati o n of 2 5- h y dr o x y- vita mi n D i n 
t he bl o o d ser u m occ urs at 1 2 n g/ m L or less) 
8.  Re q uire a n y i n vesti gati o nal a ge nt pri or t o c o m pleti o n of st u d y peri o d 
9.  Ha ve r ecei v e d a n ot her i n vesti gati o nal pr o d u ct or i n vesti ga ti o nal me dical de vice 
wit hi n 3 0 da ys bef ore t he Scree ni n g visit  
1 0.  Ha ve use d a n y ot her i n vesti gati o nal pr o d uct or i n v esti gati o nal me dical de vi ce f or t h e 
treat me nt of A C H or s h ort stat ure at a n y ti me 
1 1.  C urre nt c hr o nic t h era p y wit h a nti h y pert e nsi ve me dicati o ns, A C E i n hi bit ors, 
a n gi ote nsi n II rece pt or bl oc kers, di uretics, b eta- bl oc kers, calci u m- c h a n nel bl oc kers, 
car diac gl yc osi des, s yste mic a ntic h oli ner gic a ge nts, a n y me dicati o n t hat ma y i m pair 
or e n ha nce c o m pe ns at or y tac h ycar dia, di uretics, or ot her dr u gs k n o w n t o alt er re n al or 
t u b ular f u ncti o n 
1 2.  Ha ve bee n treate d wit h gr o wt h h or m o ne, I G F- 1, or a na b olic ster oi ds i n t he pre vi o us 
6 m o nt hs or l o n g- ter m tr eat me nt ( > 3 m o nt hs) at a n y ti me 
1 3.  Ha ve ha d re g ular l o n g- ter m treat me nt ( > 1 m o nt h) wit h oral c ortic oster oi ds (l o w- d ose 
o n g oi n g i n hale d  ster oi d f or ast h ma, or i ntra n asal ster oi ds, are acce pta ble)  
1 4.  C o nc o mita nt me dicati o n t hat pr ol o n gs t he Q T/ Q T c- F i nter val wit hi n 1 4 da ys or 
5 half -li ves, w hic he v er is l o n ger, b ef ore t he Scree ni n g visit  
1 5.  Pre g n a nt or br eastfee di n g at t he Scree ni n g Visit or pla n ni n g t o bec o me pre g na nt (s elf 
or part ner) at a n y ti me d uri n g t he st u d y.  
1 6.  Ha ve ha d li m b-le n gt he ni n g or b o n e-relate d s ur ger y or e x pecte d t o ha ve li m b-
le n gt he ni n g or b o n e-r elat e d s ur ger y d uri n g t h e st u d y peri o d.  S u bjects wit h pre vi o us 
li m b-le n gt he ni n g or b o n e-relate d s ur ger y ma y e nr oll if s ur ger y occ urre d at least 
1 8 m o nt hs pri or t o t he st u d y a n d h eali n g is c o m plete wit h o ut se q uelae. 
1 7.  Ha ve ha d a fr act ur e of t h e l o n g b o n es or s pi ne wit hi n 6 m o nt hs pri or t o scree ni n g 
(e x ce pt f or fr act ur e of di gits or t oes) 
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1 8.  Ha ve A S T  or A L T  at least 3 x U L N  or t otal bilir u bi n at least 2 x U L N (e x ce pt f or 
s u bjects wit h k n o w n hist or y of Gil bert’s disease) 
1 9.  E vi de nce of s e ver e slee p a p nea re q uiri n g s ur ger y or ne w i nitiati o n of C P A P ( base d o n 
t he scree ni n g slee p st u d y)  
2 0.  Ha ve c urre nt mali g na n c y, hist or y of mali g na n c y, or c urre ntl y u n d er w or k- u p f or 
s us pecte d mali g na nc y 
2 1.  Ha ve k n o w n h y p erse nsiti vit y t o B M N 1 1 1 or its e x ci pie nts 
2 2.  Has a c o n diti o n or cir c u msta nce t hat, i n t he vie w of t he I n vesti gat or, places t he 
s u bject at hi g h ris k f or p o or treat me nt c o m plia nce or f or n ot c o m pleti n g t he st u d y 
2 3.  C o nc urre nt diseas e or c o n diti o n t hat, i n t he vie w of t he I n vesti gat or, w o ul d i nterfere 
wit h st u d y partici pati o n or safet y e v a l uati o ns, or w o ul d pre dis p ose t he s u bject t o 
h y p ote nsi o n (s u c h as r ece nt gastr oe nteritis or de h y drati o n f or a n y reas o n) 
2 4.  Ha ve a b n or mal fi n di n gs o n baseli ne cli nical hi p e x a m or i ma gi n g assess me nts t hat are 
deter mi ne d t o be cli nicall y si g nifica nt as deter mi n e d b y t h e PI 
2 5.  Ha ve a hist or y of hi p s ur ger y or se v ere hi p d ys plasia 
2 6.  Ha ve a hist or y of cli nicall y si g nifica nt hi p i nj ur y i n t he 3 0 da ys pri or t o scree ni n g 
2 7.  Hist or y of sli p pe d ca pital fe m oral e pi p h ysis or a v asc ular necr osis of t he fe m oral hea d  
2 8.  Are u na ble t o lie flat w he n i n pr o ne p ositi o n ( nee d e d f or hi p m o nit ori n g e x a m) 
A d diti o n al E xcl usi o n Criteri a f or O pti o n al, O pe n -l a bel E xte nsi o n P h ase: 
1.  Use of r estricte d  t her a pies d uri n g t he i nitial 6 m o nt hs of t he st u d y 
2.  Per ma ne ntl y dis c o nti n ue d B M N 1 1 1 d uri n g t he i nitial 6 m o nt hs of t he st u d y 
9. 3. 3  Re m o v al of S u bjects  f r o m Tre at me nt or Ass ess me nt 
S u bjects  ( or t heir le gall y a ut h orize d re pres e ntati ve) ha ve t he ri g ht t o wit h dra w t heir c o ns e nt 
t o partici pate i n t he st u d y at a n y ti me wit h o ut prej u dice. T he I n v esti gat or m ust wit h dra w 
fr o m t he st u d y a n y s u bject w h o re q uests t o be wit h dra w n. A s u bject’s parti ci pati o n i n t he 
st u d y ma y be disc o nti n ue d at a n y ti me at t he discreti o n of t he I n vesti gat or a n d i n acc or da nce 
wit h his/ her cli nical j u d g me nt. W he n p ossi ble, t he tests a n d e val uati o n s liste d f or t he 
ter mi nati o n visit s h o ul d be carrie d o ut.   
I n v esti gat ors or s u bjects ma y s us pe n d or disc o nti n ue a d mi nistrati o n of t he i n vesti gati o nal 
pr o d uct. T he c o m plet e ness of t he st u d y dat a ma y affect t he i nte grit y a n d acc urac y of t he 
st u d y res ults.  T heref ore, s u bjects w h o disc o nti n ue st u d y treat me nt s h o ul d be e nc o ura ge d t o 
c o nti n ue t o u n der g o as m a n y of t he pr ot oc ol- s p ecifie d pr oce d ures a n d assess me nts as 
p ossi ble f or t he re mai n d er of t he st u d y, as l o n g as s uc h c o nti n ue d partici p ati o n d oes n ot 
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detri m e ntall y aff ect t he h ealt h, safet y, or welfare of t he s u bject.  F or s u bjects w h o 
disc o nti n ue st u d y dr u g b ut re mai n i n t he st u d y, P K assess me nts will be wai ve d c o m pletel y; 
vital si g ns a n d cli nical la bs/ bi o mar kers will be o btai ne d o nl y o n ce at eac h visit s u bs e q ue nt t o 
dr u g disc o nti n uati o n.  Pr e-a n d p ost- d ose d esi g nati o ns will n ot a p pl y as t he s u bject has 
disc o nti n ue d d osi n g a n d vital si g n a n d cli nical la b/ bi o mar kers assess me nts pre vi o usl y 
desi g nat e d as “ p ost -d os e” will be wai ve d.  All ot h er assess me nts at eac h  visit s h o ul d be 
c o m plete d if p ossi ble a n d t he s u bject is willi n g.  Data fr o m t he st u d y pr o ce d ures a n d 
assess me nts ma y be use d t o f urt her c h aracterize t h e nat ural pr o gressi o n of A C H.  
T he I n vesti gat or ( or desi g nee) m ust c o ntact t he Bi o Mari n Me dical M o nit or bef ore a s u bject 
is disc o nti n ue d b y t he Pri nci pal I n vesti gat or (PI ) fr o m eit her t he st u d y or fr o m f urt her st u d y 
treat me nt. Bi o Mari n res er ves t he ri g ht t o disc o nti n ue t he st u d y at a n y ti me f or eit her cli nical 
or a d mi nistrati ve reas o ns a n d t o disc o nti n ue partici pati o n of a n i n di vi d ual I n vesti gat or or 
st u d y site f or p o or e nr oll me nt or n o nc o m plia nce wit h t he pr ot oc ol or re g ul at or y 
re q uire me nts. 
Reas o ns f or w hic h a s u bject ma y be wit h dra w n fr o m t he st u d y or fr o m st u d y treat me nt b y 
eit her t he I n v esti gat or or Bi o Mari n i ncl u de b ut are n ot li mite d t o t he f oll o wi n g:  
•  Gr o wt h plates ha ve cl ose d  
•  S u bject  e x perie nces a s eri o us or i nt olera ble A E  
•  S u bject de vel o ps a cli nicall y si g nifica nt la b orat or y a b n or malit y  
•  S u bject re q uires me dicati o n or me dical pr o ce d ure pr o hi bite d b y t he pr ot oc ol  
•  S u bject d oes n ot a d her e t o st u d y re q uire me nts s pecifie d i n t he pr ot oc ol 
•  S u bject was err o ne o usl y a d mitte d i nt o t he st u d y or d oes n ot meet e ntr y crit eria 
•  S u bject is l ost t o f oll o w- u p 
•  S u bject bec o mes pr e g na nt (refer t o Secti o n  1 0. 3. 1. 9  f or details o n t he re p orti n g 
pr oce d ur es t o f oll o w i n t he e ve nt of pre g na n c y)  
If a s u bject fails t o ret ur n f or sc he d ule d visits, d oc u me nte d eff ort m ust be ma de t o deter mi ne 
t he reas o n. If t he s u bject ca n n ot be reac h e d b y tele p h o ne, a certifie d letter s h o ul d be se nt t o 
t he s u bject ( or t he s u bject’s le gall y a ut h orize d re prese ntati ve, if a p pr o priat e) re q u esti n g t hat 
he or s he c o nt act t he I n v esti gat or. A c o p y of t his l etter a n d a n y res p o nse s h o ul d be ke pt i n t he 
s u bject st u d y r ec or ds. If t he s u bject ca n n ot b e c o nt acte d or d o es n ot res p o n d, t he s u bject will 
be c o nsi der e d l ost t o f oll o w- u p. 
T he I n vesti gat or ( or desi g nee) m ust e x plai n t o eac h s u bject bef ore e nr oll me nt i nt o t he st u d y 
t hat t he s u bject’s pr otecte d healt h i nf or mati o n, o btai ne d d uri n g t h e st u d y, ma y b e s hare d wit h 
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Pa ge 5 6 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
Bi o Mari n, r e g ulat or y a ge ncies, a n d t he I R B or E C; hereafter c ollecti vel y referre d  t o as t he 
et hics c o m mittee (E C ). It is t he I n v esti gat or’s ( or desi g nee’s) res p o nsi bilit y t o o btai n writte n 
per missi o n t o use pr otect e d healt h i nf or mati o n per c o u ntr y-s pecific re g ul ati o ns, s uc h as t he 
Healt h I ns ura nce P orta bilit y a n d A cc o u nta bilit y A ct ( HI P A A) i n t he U nite d States of 
A merica ( U S A), fr o m eac h s u bject ( or t he s u bj ect’s le gall y a ut h orize d re prese ntati ve). 
If per missi o n t o use pr otecte d healt h i nf or m ati o n is wit h dra w n b y t he s u bject, it is t he 
res p o nsi bilit y of t he I n v esti gat or t o o btai n a writte n re q uest fr o m t he s u bject t o e ns ure t hat n o 
f urt her dat a will be c ollecte d fr o m t he s u bject. T h e s u bject will t he n be re m o ve d fr o m t he 
st u d y. 
9. 3. 4  S u bject  I de ntific ati o n a n d Re pl ace me nt of S u bjects  
Eac h s u bject  will be assi g ne d a u ni q ue s u bject i de ntifier. T his u ni q ue i de ntifier will be o n all 
C R F pa ges.  
S u bjects w h o disc o nti n ue d t he st u d y pri or t o D a y 1 0 ma y b e re place d u p o n disc ussi o n wit h 
t he D M C. S u bject s w h o  disc o nti n ue d t he st u d y after Da y 1 0 of t h e i nitial p hase will n ot be 
re place d. 
D ur ati o n of S u bject  P a rtici p ati o n  
T he pla n ne d s u bject parti ci pati o n i n t his st u d y is 7 m o nt hs f or t h ose s u bjects w h o d o n ot 
c o nti n ue i n t he o pti o nal, o pe n- la bel e xte nsi o n p hase, a n d 2 5 m o nt hs f or s u bjects w h o 
c o nti n ue. S u bjects will recei ve st u d y treat me nt dail y f or 6 m o nt hs i n t he i nitial p hase, a n d 
1 8 m o nt hs i n t he o pti o nal, o pe n- la bel e xte nsi o n p hase f or a t otal of u p t o 2 4 m o nt hs. 
F oll o wi n g c o m pleti o n of 6 m o nt hs, s u bjects w h o decli ne t o partici pat e i n t he e xte nsi o n p hase 
will be f oll o we d f or safet y f or a n a d diti o nal 1 m o nt h. T he safet y f oll o w -u p assess me nt will 
be a tele p h o n e call ma de wee kl y t o t he s u bject’s le gal g u ar dia n t o assess f or a n y A Es t hat 
ma y h a ve occ urr e d f oll o wi n g c o m pleti o n of d osi n g. T hes e s u bjects will ret ur n at Da y 2 0 8 f or 
t he Safet y F oll o w-U p visit a n d e xit t he st u d y.   F or s u bjects w h o partici pate i n t he o pti o nal, 
o pe n- la bel e xte nsi o n p hase, f oll o wi n g c o m pleti o n of M o nt h 2 4, s u bjects will be f oll o we d f or 
safet y f or a n a d diti o nal m o nt h t o M o nt h 2 5. S u bjects w h o partici p ate i n t he o pe n-la b el 
e xte nsi o n p hase of st u d y 1 1 1- 2 0 2 will ha ve t he o pti o n t o e nr oll i n t he l o n g- ter m e xte nsi o n 
st u d y 1 1 1- 2 0 5 at t he M o nt h 2 4/ St u d y C o m pleti o n Visit.  T he M o nt h 2 5 Safet y F oll o w u p 
visit will be wai ve d if a s u bject e nr olls i n t he 1 1 1- 2 0 5 e xte nsi o n st u d y at t h e Mo nt h 2 4/ St u d y 
C o m pleti o n Visit .   
F oll o w- u p assess me nts a n d pr oce d ures s h o ul d be perf or me d as o utli ne d i n t he 1 1 1- 2 0 2 
Sc he d ule of E ve nts ( T a bl e  9. 1. 1).  
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
S u bjects w h o disc o nti n ue fr o m st u d y treat me nt pri or t o M o nt h 6 will be as ke d t o c o m plete 
st u d y assess me nts a n d pr oce d ures f or t he re mai n d er of t he i nitial p hase of t he st u d y. S u bjects 
w h o disc o nti n ue fr o m st u d y treat me nt pri or t o M o nt h 2 4 will be as ke d t o c o m plete st u d y 
assess me nts a n d pr oce d ures f or t he re mai n der of t he o pti o nal, o pe n- la bel p hase of t he st u d y. 
If s u bjects disc o nti n ue fr o m st u d y treat me nt a n d d ecli ne t o partici pat e f or t he re mai n der of 
t he st u d y, t he y will be as ke d t o ret ur n f or a fi nal f oll o w-u p visit 4 wee ks after t heir last st u d y 
visit.  
S u bjects  will partici pate i n t he st u d y u ntil c o m pleti o n or u ntil o ne of t he f oll o wi n g occ urs: 
t he s u bject wit h dra ws c o nse nt a n d disc o nti n ues fr o m t he st u d y, t he s u bject is disc o nti n ue d 
fr o m t he st u d y at t he discreti o n of t he I n vesti gat or or Bi o Mari n, or t he st u d y is ter mi nate d. 
9. 4  
Tre at me nts  
9. 4. 1  Tre at me nts A d mi nistere d  
S u bjects will be a d mi nistere d B M N 1 1 1 d uri n g t h e st u d y.  T h e n or mal d osi n g sc h e d ule is 
7 da ys a wee k.  
9. 4. 1. 1  
B M N 1 1 1 
D uri n g t h e st u d y, s u bject assi g ne d t o recei ve B M N 1 1 1 will be a d mi nistere d o ne of t he 
f oll o wi n g dail y d osi n g re gi me ns: 
•  C o h ort 1: dail y m or ni n g d ose of 2. 5 µ g/ k g B M N 1 1 1 
•  C o h ort 2: dail y m or ni n g d ose u p t o 7. 5 µ g/ k g B M N 1 1 1 
•  C o h ort 3: dail y m or ni n g d ose u p t o 1 5. 0 µ g/ k g B M N 1 1 1 
•  C o h ort 4: dail y m or ni n g d ose 3 0. 0 µ g/ k g B M N 1 1 1 
T he i njecti o n sites s h o ul d be alter nat e d bet wee n d oses. D oses ma y be a d mi nistere d i n a n y of 
t he c o m m o n S C areas ( u p per ar m, t hi g h, a b d o me n, b utt oc ks [refer t o I njecti o n G ui de f or 
details]) . F oll o wi n g a d mi nistrati o n of eac h d os e, s u bjects will be o bser ve d f or a mi ni m u m of 
3 0 mi n utes (l o n ger if cli nicall y i n dicat e d) eit her i n t he cli nic or at t he s u bject’s h o me ( b y 
h o me healt h n urse or p ar e nt or g u ar dia n ). I nstr ucti o ns f or h o me a d mi nistrati o n of st u d y dr u g 
f or s u bjects w h o q ualif y f or par e nt or g uar dia n a d mi nistrati o n are pr o vi de d i n t he B M N 1 1 1 
I njecti o n G ui de a n d I njecti o n D V D . 
9. 4. 2  I de ntit y of I n vesti g ati o n al Pr o d uct 
B M N 1 1 1 is cl o ne d i nt o t he pJ e x press 4 0 1 vect or, e x presse d i n E. c oli  a n d t he n p urifie d. 
T he  dr u g s u bsta nce is a m o difie d C N P pe pti de t hat retai ns wil d -t y pe acti vit y a n d s p ecificit y. 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
T he m o difie d C N P se q ue nce is 
P G Q E H P N A R K Y K G A N K K G L S K G C F G L K L D RI G S M S G L G C.  
T he a mi n o aci d se q u e nce is a n a nal o g ue of t h e nat urall y o cc urri n g tiss ue e x presse d f or m of 
C- t y pe n atri uretic p e pti de ( C N P 5 3). B M N 1 1 1 is a rec o m bi na nt 3 9 a mi n o aci d pe pti de t hat 
i ncl u des t he 3 7 C-ter mi n al a mi n o aci ds of t he h u ma n C N P 5 3 se q ue nce, a n d m o difie d b y t he 
a d diti o n of t he 2 a mi n o aci ds ( Pr o- Gl y) o n t he N- ter mi n us. It is a c yclic p e pti de f or med b y a n 
i ntra m olec ular dis ulfi de b o n d. T he m olec ular wei g ht of t he p urifie d pr o d u ct is 4. 1 k Da.  
9. 4. 2. 1  
Pr o d uct C h ar act eristics a n d L a beli n g  
T he cli nical dr u g pr o d u ct will be s u p plie d i n sterile, si n gle - d ose, T y pe I glass vials wit h 
c oate d st o p per a n d fli p- off al u mi n u m ca p. B M N 1 1 1 dr u g pr o d uct is s u p plie d as 0. 8 m g, 
2 m g , or 1 0 m g l y o p hilize d, preser vati ve-free, w hite t o yell o w p o w d er f or rec o nstit uti o n wit h 
sterile water f or i njecti o n ( W FI). T he rec o nstit ute d s ol uti o n is c ol orless t o yell o w a n d 
c o ntai ns 0. 2 m g/ m L t o 1 0 m g/ ml of B M N 1 1 1, as well as citric aci d, s o di u m citrate, 
tre hal ose, ma n nit ol, met hi o ni ne, p ol ys or bat e 8 0, a n d sterile W FI. T he tar get p H of t he 
rec o nstit ute d s ol uti o n is 5. 5.  Sterile water f or i njecti o n will be c o m merci all y s o urce d. All 
rec o nstituti o n a n d d ose pre par ati o n ste ps will be perf or me d as i n dicate d i n t he B M N 1 1 1 
I njecti o n G ui de a n d I njecti o n D V D . 
T he B M N 1 1 1 kit la bel i ncl u des t he f oll o wi n g i nf or mati o n: t he l ot n u m ber, t he re q uire d 
st ora ge c o n diti o ns, a pr eca uti o nar y state me nt, t he e x pir y d ate, t he st u d y n u m ber, a n d 
Bi o Mari n P har mace utical na me a n d l ocati o n. 
9. 4. 3  St or a ge 
At t he st u d y site, all st u d y treat me nt m ust be st ore d u n der t he c o n diti o ns s pecifie d i n t he 
I n v esti gat or’s Br oc h ure i n a sec ur e area accessi ble o nl y t o t he desi g nate d p har macists a n d 
cli nical site pers o n nel. All st u d y treat me nt m ust be st ore d a n d i n ve nt orie d a n d t he i n ve nt ories 
m ust be caref ull y a n d acc uratel y d oc u me nte d acc or di n g t o a p plica ble state, fe deral a n d l ocal 
re g ulati o ns, I C H G C P, a n d st u d y pr oce d ures.  
S pecific i nf o r mati o n f or st ora ge a n d ret ur n of st u d y dr u g is pr o vi d e d i n t he P har mac y 
Ma n ual.  
9. 4. 4  Directi o ns f or A d mi nistr ati o n  
Refer t o t he I nj ecti o n G ui de f or c o m plete st u d y treat me nt pre p arati o n i nstr ucti o ns. T he date, 
ti me, v ol u me, a n d c o nce ntrati o n of eac h d ose of st ud y treat me nt a d mi nistere d t o eac h s u bject 
m ust be rec or d e d o n t he a p pr o priate C R F, a n d ( mi n us c o nce ntrati o n) i n t he s u bject's st u d y 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
w or k b o o k (if i njecti o n pr o vi de d b y p are nt/ g uar dia n) or n ursi n g visit re p ort (if i njecti o n is 
pr o vi de d b y H o me H ealt h Care N u rs e [ H HR N ]). 
B M N 1 1 1 will be a d mi nistere d i n t he m or ni n g as a si n gle S C i njecti o n at t he f oll o wi n g 
d oses: 2. 5 µ g/ k g, u p t o 7. 5 µ g/ k g, u p t o 1 5. 0 µ g/ k g, a n d 3 0. 0 µ g/ k g. C hil dre n s h o ul d ha ve a n 
a de q uate brea kfast . I n t h e h o ur pri or t o i njecti o n, all s u bjects s h o ul d ha ve atte m pte d t o dri n k 
8 o u nces ( ~ 2 5 0 ml ) of fl ui d (e. g. water, mil k, j uice, etc.), a n d t he o ut c o me m ust be 
d oc u me nte d b y t he site o n cli nic visit da ys . 
Care gi vers ma y a d mi nister st u d y dr u g at h o me if a p pr o ve d b y t he I n vesti gat or a n d if 
a de q uate t r ai ni n g is d e m o nstrate d.  A pare nt/ g u ar dia n ma y b e eli gi ble t o a d mi nister st u d y 
dr u g if h e or s he m eets all of t he f oll o wi n g criteria: 
•  T he s u bject has bee n o n a sta ble d osi n g re gi me n f or a mi ni m u m of 4 da ys   
•  PI has a p pr o ve d a d mi nistrati o n of st u d y dr u g b y t he pare nt or g uar dia n  
•  T he par e nt or g uar di a n h as c o m plete d t he A d mi nistrati o n Trai ni n g c o n d uct e d b y 
q ualifie d st u d y site pers o n nel a n d has bee n o bser v e d b y t h e st u d y site p ers o n nel t o be 
a ble t o a de q u atel y pre p ar e t he pr o per d ose a n d p erf or m t he i njecti o ns safel y  
F or d osi n g bet wee n pla n ne d cli nic visits pri or t o pare nt/ g uar di a n a p pr o v al, a h o me healt h 
n urse ma y a d mi nister st u d y dr u g or s u bjects ma y be a d mi nistere d dr u g i n t he cli nic b y st u d y 
staff.   
If a s u bject h as e x perie nce d a C T C A E Gra de 3 or hi g her A E  t hat is c o nsi dere d p ossi bl y or 
pr o ba bl y dr u g -r elate d, a n d/ or a h y p erse nsiti vit y reacti o n d uri n g t h e st u d y, t he s u bject’s 
s uita bilit y f or at- h o me dr u g a d mi nistrati o n will be e val uate d b y t he I n vesti gat or a n d t he 
S p o ns or’s Me dical M o nit or.  
I n t he i nitial p has e, on w ee ks w he n care gi vers/s u bjects will n ot see eit her a h o me healt hcare 
pr ofessi o nal or a st u d y st aff me m ber, a p h o ne call b y t he st u d y staff me m ber t o t he 
care gi v er/s u bject will be re q uire d.  D uri n g t he call st u d y staff will as k t he care gi ver a b o ut 
c orrect a d mi nistrati o n pr oce d ures, assess a d v erse e ve nts ( A Es), rec or d c o n c o mita nt 
me dicati o ns, a n d a ns w er q uesti o ns.  D uri n g t he o pti o nal, o pe n- la bel e xte nsi o n p hase, t he call 
fre q ue n c y will c ha n ge t o e ver y t w o w ee ks f or t he first 6 m o nt hs of t he e xte nsi o n p hase a n d 
m o nt hl y t h ereafter.  
S u bjects  w h o are eli gi ble f or at - h o me dr u g a d mi nistrati o n will be pr o vi de d wit h 
H o me -A d mi nistrati o n Tr ai ni n g Materials t o s u p ple me nt t he i n - pers o n trai ni n g pr o vi de d b y 
t he q ualifie d st u d y site p ers o n nel. T he H o me -A d mi nistrati o n Trai ni n g Materials will i ncl u de 
ste p-b y -ste p i nstr ucti o n o n t he f oll o wi n g:  
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•  H o w t o i de ntif y if t h e st u d y dr u g is u ns uita ble f or i njecti o n a n d h o w t o re p ort t o t he 
st u d y site 
•  H o w t o deter mi ne w h e n t o perf or m t he i njecti o ns a n d w hat is re q uire d i m me di atel y 
bef ore p erf or mi n g t he i nj ecti o ns 
•  H o w t o safel y pr e par e a n d perf or m t he i njecti o ns of st u d y dr u g  
•  H o w t o ma ke s ure t h e s u bject is a de q uatel y h y drate d  
•  H o w t o recei ve, tra ns p ort, trac k, st ore, pre pare, a n d ret ur n b ot h use d a n d u n use d st u d y 
dr u g kits 
•  H o w  t o safel y use a n d dis p ose of s yri n ges use d f or i njecti o ns of st u d y dr u g  
•  H o w t o use a ne w s yri n ge a n d vial e v er y ti me dr u g is a d mi nistere d  
•  H o w t o car e f or s u bject’s i njecti o n site after a n i nj ecti o n of st u d y dr u g 
•  H o w t o i de ntif y a n a d verse reacti o n a n d h o w t o re p ort t his reacti o n t o t he st u d y site 
a n d d oc u me nt it i n t he st u d y pr o vi d e d s u bject w or k b o o k  
•  W h o t o c o ntact at t he st u d y site i n cas e of a n e mer ge n c y or c o n cer n/ q uesti o n  
•  H o w t o deter mi ne i n w hi c h i nsta nces t o c o ntact t he l ocal e mer ge nc y t ele p h o ne li ne 
T he I n vesti gat or or t h e S p o ns or’s Me dical M o nit or ma y re q u est t hat dr u g a d mi nistrati o n b y 
t he pare nt be h alte d at a n y ti me a n d t hat t he i njecti o ns be perf or me d b y t he st u d y site 
pers o n nel or h o me h ealt h care n urse.  
9. 4. 5  Met h o d of Assi g ni n g S u bjects  t o Tre at ment Gr o u ps  
N o  ra n d o mizati o n sc he d ule will be ge nerate d. All eli gi ble s u bjects will recei ve B M N 1 1 1. 
9. 4. 6  Selecti o n of D oses Use d i n t he St u d y  
T he pr ot oc ol will utilize dail y, s u bc uta n e o usl y a d mi nistere d, wei g ht base d, 
fi x e d-wit hi n -c o h ort d osi n g.  
 
 
 
 
 
 
 
 
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2 2 A u g ust 2 0 1 6 
 
    
 
 
 
 
 
 
 
  
 
  
T o date, cli nical  dat a i n St u d y 1 1 1- 2 0 2 d e m o nstrate d t hat B M N 1 1 1 w as ge nerall y well 
t olerate d at d oses u p t o 3 0 µ g/ k g wit h o ut e vi de nce of a b n or mal gr o wt h.  
9. 4. 7  Bli n di n g  
St u d y 1 1 1- 2 0 2 is a n o pe n-la bel st u d y.  N o bli n di n g will be perf or me d. 
9. 4. 8  Selecti o n of Ti mi n g of D ose f or E ac h S u bject  
9. 4. 8. 1  
Pri o r a n d C o nc o mit a nt Me dic ati o ns  
All me dicati o ns ( prescri pti o n, o ver-t he-c o u nt er [ O T C] a n d her bal), a n d n utriti o nal 
s u p ple me nts 3 0 da ys pri or  t o scree ni n g a n d t hr o u g h o ut t he st u d y will be rec or de d o n t he 
desi g nat e d C R F.  T he I n vesti gat or m a y pres cri be a d diti o nal me dicati o ns d uri n g t he st u d y, as 
l o n g as t he prescri be d me dicati o n is n ot pr o hi bite d b y t he pr ot oc ol. I n t he e ve nt of a n 
e mer ge n c y, a n y nee de d me dicati o ns ma y b e prescri be d w it h o ut pri or a p pr o val, b ut t he 
M e dical M o nit or m ust be n otifie d of t he use of a n y c o ntrai n dicate d m e dicati o ns i m me diatel y 
t hereafter.  A n y c o nc o mita nt me dicati o ns a d de d or disc o nti n ue d d uri n g t h e st u d y s h o ul d be 
rec or d e d o n t he C R F. C o nc o mita nt me dicati o n i nf or mati o n will be c ollecte d at t he ti me 
p oi nts i n dicate d i n t he Sc he d ule of E ve nts ( T a ble  9. 1. 1). 
T he f oll o wi n g m e dicati o ns are e x cl u de d d uri n g t h e scree ni n g peri o d t hr o u g h c o m pleti o n of 
t he st u d y: 
•  Gr o wt h h or m o ne, i ns uli n-li ke gr o wt h fact or 1 (I G F- 1), or a na b olic ster oi ds 
•  A C E  i n hi bit ors, car diac gl yc osi des, calci u m c h a n n el bl oc kers, bet a bl oc kers, or 
a nti h y perte nsi ve me dicati o ns  
-
pr ot oc ol. p df
Pa ge 6 2

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 2 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  Di uretics  
•  Pr o be neci d, or ot her dr u gs k n o w n t o alter re n al or t u b ular f u ncti o n  
•  C o nc o mita nt me dicati o n t hat pr ol o n gs t he Q T/ Q T c- F i nter val 
•  A n y ot her i n vesti gati o nal pr o d uct f or t he treat me nt of A C H or s h ort stat ure 
9. 4. 9  Tre at me nt C o m pli a nce  
T he date, ti me, v ol u me, a n d c o nce ntrati o n of eac h d ose of st u d y dr u g a d mi nistere d t o eac h 
s u bject m ust be rec or de d.  T hese data will be use d t o assess treat me nt c o m plia nce.   
9. 5  
I n vesti g ati o n al Pr o d uct Acc o u nt a bilit y 
T he I n vesti gat or or d esi g nee is res p o nsi ble f or mai ntai ni n g acc urat e rec or ds (i ncl u di n g dat es 
a n d q ua ntities) of I P(s) recei ve d, s u bjects t o w h o m I P is dis pe nse d (s u bject- b y -s u bject d ose 
s pecific acc o u nti n g), a n d I P l ost or acci de ntall y or deli beratel y destr o ye d, or t here w as a 
te m perat ur e e x c ursi o n a n d t he I P is n ot usa ble. T h e I n vesti gat or or d esi g n ee m ust retai n all 
use d, u n use d, or e x pire d I P u ntil t he st u d y m o nit or ( o n -site C R A) has c o nfir me d t he 
acc o u nta bilit y data. Ret ur ne d a ncillar y s u p plies will be destr o ye d per site S O P.   
I n v esti gati o nal Pr o d uct acc o u nta bilit y s h o ul d be c o m plete d per t he Sc he d ul e of E ve nts, 
Ta ble  9. 1. 1. 
9. 5. 1  Ret ur n a n d Dis p ositi o n of Cli nic al S u p plies  
Use d a n d u n use d st u d y i n vesti gati o nal pr o d u ct m ust be ke pt i n a sec ure l o cati o n f or 
acc o u nta bilit y a n d r ec o n ciliati o n b y t he st u d y m o nit or. T he I n vesti gat or or desi g nee m ust 
pr o vi de writte n e x pla nati o n f or a n y destr o ye d or missi n g st u d y i n vesti gati o nal pr o d uct or 
st u d y materi als.  
Use d a n d u n use d st u d y i n vesti gati o nal pr o d u ct ma y b e destr o ye d o n site, per t he site’s 
sta n dar d o per ati n g pr oce d ures, b ut o nl y after Bi o Mari n has gra nt e d a p pr o val f or dr u g 
destr ucti o n. T he st u d y m o nit or m ust acc o u nt f or all st u d y i n vesti gati o nal pr o d uct i n a f or mal 
rec o nciliati o n pr o cess pri or t o st u d y i n vesti gati o nal pr o d uct destr ucti o n. U n use d I P ma y o nl y 
be destr o ye d if t he st u d y site ca n als o pr o vi de a certificate of d estr ucti o n or a recei pt f or 
destr ucti o n w he ne v er u n use d I P is destr o ye d.  All st u d y i n vesti gati o nal pr o d uct destr o ye d o n 
site m ust be d oc u me nte d. D oc u me ntati o n m ust be pr o vi de d t o Bi o Mari n a n d retai ne d i n t he 
I n v esti gat or st u d y files. If a site is u na ble t o destr o y st u d y i n vesti gati o nal pr o d uct 
a p pr o priatel y, t he site m ust ret ur n u n use d a n d us e d st u d y i n vesti gati o nal pr o d uct t o Bi o Mari n 
dr u g distri b uti o n ce nter u p o n re q uest. T he ret ur n of st u d y treat me nt or st u d y treat me nt 
materials m ust be acc o u nte d f or o n a St u d y Dr u g Ret ur n F or m l ocat e d i n t he P har mac y 
Ma n ual.   All st u d y i n vesti gati o nal pr o d u ct a n d relate d materials s h o ul d be st ore d, 
-
pr ot oc ol. p df
Pa ge 6 3

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 3 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
i n ve nt orie d, rec o ncile d, a n d destr o ye d or ret ur ne d acc or di n g t o a p plica ble state a n d fe d eral 
re g ulati o ns a n d st ud y pr o ce d ures.  
Pare nts or g uar di a ns of s u bjects w h o q ualif y f or h o me a d mi nistrati o n of st u d y i n vesti gati o nal 
pr o d uct will be pr o vi de d wit h i nstr ucti o ns f or ret ur ni n g use d a n d u n use d st u d y 
i n vesti gati o nal pr o d u ct a n d t he pr o per dis p osal of a n y st u d y dr u g m aterials (refer t o t he 
H o me A d mi nistrati o n Trai ni n g/ Patie nt Materials s ecti o n i n t he St u d y Refere nce Ma n u al).  
9. 6  
Diet ar y or Ot her Pr ot o c ol Restri cti o ns  
B M N 1 1 1 will be a d mi nistere d i n t he m or ni n g as a si n gle S C i njecti o n.  C hil dre n s h o ul d 
ha ve a n a de q uat e brea kfast.   I n t he h o ur pri or t o i njecti o n, all s u bjects s h o ul d ha ve atte m pte d 
t o dri n k 8 o u nces ( ~ 2 5 0 ml ) of fl ui d (e. g. wat er, mil k, j uice, etc.), a n d t he o utc o me m ust be 
d oc u me nte d b y t he site o n cli nic visit da ys.   
9. 7  
De m o gr a p hic D at a a n d Me dic al Hist or y  
De m o gra p hic d ata a n d a detaile d me dical hist or y will be o btai ne d at Scree ni n g. T his me dical 
hist or y s h o ul d elicit all maj or ill nesses, dia g n oses, a n d s ur geries t h at t he s u bject has e ver ha d ; 
a n y pri or or e xisti n g me dical c o n diti o ns t hat mi g ht i nterfere wit h st u d y p artici pati o n or 
safet y; a n d e v al uati o n f or k nee, t hi g h, hi p or gr oi n pai n, or c ha n ge i n gait/acti vit y.   
9. 8  
Bi ol o gic al P are nt St a n di n g Hei g ht 
T he sta n di n g h ei g ht of t he partici pa nt’s bi ol o gical pare nts will be assess e d if t he y a gree t o 
partici pate.  Pri or t o t he meas ure me nt, eac h p are nt is re q uire d t o c o m plete a n I C F s pecific t o 
t his o pti onal pare nt hei g ht assess me nt.  
9. 9  
P h ysic al E x a mi n ati o n Fi n di n gs 
P h ysical e x a mi nati o n will i ncl u de assess me nt of ge neral a p peara n ce; C V; der mat ol o gi c; 
hea d, e yes, ears, n o se, a n d t hr oat; l y m p hatic; res pirat or y; GI; m usc ul os kelet al; a n d 
ne ur ol o gi cal/ ps yc h ol o gical a n d ge nit o uri nar y. T a n ner sta ge of P u b ertal De v el o p me nt will 
als o be assesse d.  T h e r ef ere nce t o t he Ta n n er sta ge assess me nt d oc u me nt is i ncl u de d i n t he 
St u d y R efer e nce Ma n ual.  Ot her b o d y s yste ms ma y be e x a mi ne d. Da y 1 res ults will be t he 
baseli ne val ues a n d cli nicall y si g nifica nt c ha n ges fr o m baseli ne will be rec or de d as a n A E or 
S A E as a p pr o priat e.  
9. 1 0  
Effic ac y a n d S af et y V ari a bles 
9. 1 0. 1  Effic ac y a n d S af et y Me as ure me nts Assess e d  
T he Sc he d ule of E v e nts i n Secti o n  9. 1  descri bes t he ti mi n g of re q uire d e v al uati o ns. 
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pr ot oc ol. p df
Pa ge 6 4

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 4 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
9. 1 0. 2  Effic ac y V ari a bles  
Efficac y will be assesse d b y c h a n ge fr o m baseli ne i n hei g ht gr o wt h vel o cit y (a n n ualiz e d t o 
c m/ year),  gr o wt h par a meters, a n d i n b o d y pr o p orti o ns. T hese c h a n ges will be assesse d b y 
a nt hr o p o metric meas ure me nts a n d meas ure m e nt rati os.  A nt hr o p o metric meas ure me nts ma y 
i ncl u de b ut are n ot li mite d t o sta n di n g hei g ht, sitti n g hei g ht, w ei g ht, h ea d circ u mfere nce, 
u p per a n d l o w er ar m a n d le g, h a n d a n d f o ot.  U p p er ar m t o f o rear m le n gt h rati o, u p per le g t o 
l o wer le g le n gt h r ati o, a n d u p per t o l o wer b o d y s e g me nt rati o will be calc ul ate d. 
T he f oll o wi n g gr o wt h meas ures ma y  b e c ollecte d a p pr o xi matel y t he sa me ti me eac h d a y  
( ± 2 h o urs ar o un d t he ti me of first meas ure me nt assess me nt, i ncl u di n g Scree ni n g 
meas ure me nt assess me nt ) b y a st u d y st aff me m ber , prefera bl y t he s a me pers o n t hr o u g h o ut 
t he st u d y, w h o h as bee n trai ne d b y a Bi o Mari n re prese ntati ve .  Meas ure m e nts n ot ta ke n i n 
t he mi dsa gittal pla ne s h o ul d be ta ke n o n t he ri g ht si de of t he b o d y w he n p ossi ble.  
Meas ure me nts ma y  i n cl u de b ut are n ot li mite d t o sta n di n g hei g ht, sitti n g hei g ht, hea d 
circ u mfere nce, u p per a n d l o wer ar m a n d le g, ha n d a n d f o ot. Sta n dar dize d meas uri n g 
e q ui p me nt a n d detai le d meas ure me nt tec h ni q ues are det aile d i n t he A nt hr o p o metric 
G ui deli nes.   
T he f oll o wi n g rati os will be calc ul ate d:  
•  U p per ar m t o f orear m le n gt h rati o  
•  U p per le g t o l o wer le g le n gt h rati o  
•  U p per t o l o wer b o d y s e g me nt rati o 
A d diti o nal rati os ma y b e calc ulate d . 
Wei g ht will be meas ur e d at Scree ni n g a n d at eac h i n -cli nic d osi n g visit.  
9. 1 0. 2. 1  
P h ar m a c o ki netic V ari a bles  
I n t he i nitial p has e of t he st u d y, o n Da ys 1, 1 0, 2 9, 8 5, a n d 1 8 3, P K plas ma sa m ples are 
c ollecte d pr e- d ose a n d at 5 ( ± 2 mi n), 1 5 ( ± 2 mi n), 3 0 ( ± 5 mi n),  6 0 ( ± 5 mi n), 9 0 ( ±  5 mi n), 
1 2 0 ( ±  5 mi n) mi n, a n d 1 8 0  ( ± 5 mi n) mi n p ost- d ose as i n dicate d i n Ta bl e  9. 1. 1 a n d are 
c o nsi dere d t o r e pres e nt f ull P K sa m pli n g. 
W he ne ver p ossi ble, t he f oll o wi n g P K para meters will be esti mate d b y n o n-c o m part me ntal 
a nal ysis f or Da ys 1, 1 0, 2 9, 8 5, a n d 1 8 3: 
•  Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m ti me 0 t o i nfi nit y ( A U C0- ∞) 
•  Area u n d er t he plas ma c o nce ntrati o n -ti me c ur ve fr o m 0 t o t he ti me of last meas ura ble 
c o nce ntr ati o n ( A U C 0-t) 
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pr ot oc ol. p df
Pa ge 6 5

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 5 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  C ma x  
•  T ma x  
•  Eli mi nati o n half -life (t1/ 2) 
•  A p pare nt cl ear a nce of dr u g ( C L/ F)  
•  A p pare nt v ol u me of distri b uti o n base d u p o n t he ter mi nal p hase ( V z/ F) 
D ose pr o p orti o nalit y a n d dr u g acc u m ulati o n after re peat d os e a d mi nistrati o n will als o be 
e val uate d. P K para meters  at Da y 1 8 3 will be c o m pare d t o Da ys 1, 1 0, 2 9, a n d 8 5 t o 
deter mi ne if ti me rel ate d c ha n ges i n e x p os ure a n d cleara nce o cc ur . 
F or s u bjects w h os e d ose d oes n ot c ha n ge i n t he o pti o nal, o pe n-la bel e xte nsi o n p hase, f ull P K 
sa m ples will be ta ke n at M o nt hs 1 2 a n d 2 4. Partial P K sa m ples will be ta ke n at f o ur ti me 
p oi nts ( pre- d ose, 1 5, 3 0, a n d 6 0 mi n utes p ost d ose) t o esti mate e x p os ure a n d t o c orres p o n d 
wi t h i m m u n o ge nicit y ass ess me nts. T hese partial P K dra ws will ta ke place at M o nt hs 8, 1 0, 
1 5, 1 8, a n d 2 1 wit h i m m u n o ge ni cit y assess me nts.   
F or s u bjects w h os e d oses are a dj uste d i n t he o pti o nal, o pe n-la bel e xte nsi o n p hase, f ull P K 
sa m ples will be dra wn at t he d ose a dj ust me nt visit , e ve n if t he d ose a dj ust me nt visit falls o n a 
re g ularl y sc h e d ule d visit w here a partial P K is ot her wise i n dicat e d . At s u bse q ue nt visits, f ull 
or partial P K will be dra w n  per c ollecti o n sc he d ule i n Ta ble  9. 1 0. 2. 1. 1.  N ote: P K sa m ple 
sc he d ule d oes n ot c h a n ge f oll o wi n g d ose a dj ust me nt. 
T a ble 9. 1 0. 2. 1. 1 :  P K S a m ple Sc he d ule   
I niti al P h ase 
D a y  
1 
1 0  
2 9  
8 5  
1 8 3  
F ull a 
F ull  
F ull  
F ull  
F ull  
 
 
 
 
 
O pti o n al , O pe n-l a bel E xte nsi o n P h ase  
M o nt h  
8 
1 0  
1 2  
1 5  
1 8  
2 1  
2 4  
P artial b 
P artial  
F ull  
P artial  
P artial  
P artial  
F ull  
 
 
 
 
 
 
 
a F ull P K  plas ma sa m ples are c ollecte d pre -d ose a n d at 5 ( ±  2 mi n), 1 5 ( ±  2 mi n), 3 0  ( ± 5 mi n), 6 0  ( ± 5 mi n), 
9 0  ( ± 5 mi n), 1 2 0 ( ±  5 mi n), a n d 1 8 0 ( ±  5 mi n) mi n utes  p ost -d ose.  
b P arti al P K  sa m ples are c ollecte d at f o ur ti me p oi nts: pre -d ose, 1 5  ( ± 2 mi n) , 3 0 ( ± 5 mi n) , a n d 6 0 ( ± 5 mi n)  
mi n utes p ost -d ose.  
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pr ot oc ol. p df
Pa ge 6 6

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 6 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
Refer t o t he L a b orat or y Ma n ual f or a d diti o nal i nstr ucti o ns re gar di n g o btai ni n g a n d s hi p pi n g 
sa m ples. Bi o Mari n will p erf or m sa m ple a nal ysis, a n d sa m ples ma y als o be use d f or ass a y 
de vel o p me nt.  
9. 1 0. 3  E x pl or at or y Effic ac y V ari a bles 
Fle xi o n -e xte nsi o n meas ures of el b o w j oi nt ra n ge of m oti o n will be meas ure d wit h a 
g o ni o meter.  R efer t o t he i nstr ucti o nal g u i deli nes f or el b o w j oi nt ra n ge of m oti o n, l ocate d i n 
St u d y R efere nce Ma n ual.  
9. 1 0. 3. 1  
P h ar m a c o d y n a mi c V ari a bles 
Bi o mar kers will be e val u ate d b y c ha n ge fr o m b aseli ne a n d ma y i ncl u de b ut are n ot li mite d t o 
assess me nt f or cartila ge t ur n o ver ( C T X -II), c h o n dr oc yt e a n d oste o bl ast acti vit y 
( b o ne-s pecific al k ali ne p h os p hatase), b o n e f or mati o n ( P 1 N P), b o ne t ur n o ver ( oste ocalci n); 
a n d mar kers of B M N 1 1 1 bi oacti vit y (c G M P, N T- pr o C N P, a n d A N P) as w ell as a d diti o nal 
e x pl orat or y bi o mar k ers . Bi o Mari n or d esi g n ee will perf or m a nal ysis, a n d s a m ples ma y als o 
be use d f or assa y de v el o p me nt. 
Sa m ples f or bl o o d a n d uri ne bi oc he mical mar k ers of c olla ge n a n d b o n e t ur n o ver, a n d f or 
mar kers of B M N  1 1 1 acti vit y, will be c ollecte d at t he ti me p oi nts prese nte d i n  Ta ble  9. 1. 1. 
Refer t o t he La b orat or y Ma n ual f or i nstr ucti o ns re gar di n g o btai ni n g a n d s hi p pi n g sa m ples. 
T he testi n g f acilit y a n d s a m ple t y p e will als o be i ncl u de d i n t he La b orat or y Ma n u al.  
9. 1 0. 3. 1. 1  Bi o m ar ker Res e arc h S a m ple A n al yses  
All bi o mar ker sa m ples c ollecte d i n t his st u d y ma y be us e d f or e x pl orat or y bi o mar ker 
researc h i ncl u di n g e v al uati o n of a d diti o nal bi o mar kers n ot s pecificall y liste d i n 
Secti o n  9. 1 0. 3. 1 . I n a d diti o n, sa m ples c ollecte d f or ot her p ur p oses m a y be use d f or 
e x pl orat or y use o n ce t he pri mar y use has b ee n c o m plete d.  
9. 1 0. 3. 2  
Slee p A p ne a  
U ntreate d slee p a p n ea i n c hil d h o o d has bee n re peate dl y ass o ciate d wit h p o or f u ncti o nal a n d 
healt h o utc o mes, i ncl u di n g ne gati ve i m pacts o n certai n as pects of c hil d de vel o p me nt s uc h as 
be ha vi or a n d lear ni n g.  C o g niti ve defi cits re p orte d t o be ass ociate d wit h slee p a p nea i n 
c hil dre n i ncl u de lear ni n g, me m or y, a n d vis ual-s patial s kills; la n g ua ge, ver b al fl ue nc y, sc h o ol 
perf or ma n ce a n d e x ec uti ve f u ncti o ns. I n a d diti o n, pe diatric slee p- dis or dere d breat hi n g has 
bee n ass oci ate d wit h gr o wt h a b n or malities; alterati o ns i n car diac h ealt h, i ncl u di n g b ot h 
s yst olic a n d diast olic bl o o d press ure, a ut o n o mic re g ul ati o n, brai n o x y ge nati o n, a n d cere bral 
bl o o d fl o w, s u g gesti n g t h at c hil d h o o d o bstr ucti ve slee p a p nea s y n dr o me m a y j e o par dize 
l o n g-ter m car di o v asc ular healt h; a n d s yst e mic mar kers of i nfla m mati o n 
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pr ot oc ol. p df
Pa ge 6 7

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
 ( Marc us, 2 0 1 2, Pe diatrics ). Gi ve n t hat slee p a p n ea is a fi n di n g i n c hil dre n wit h A C H  
( Waters, 1 9 9 3, Arc h. Dis. C hil d), a n d its i m plicati o ns o n f u ncti o nal a n d healt h o utc o mes, a 
slee p-testi n g d e vice (slee p testi n g is c o n d ucte d at a certifi e d slee p ce nter) will be use d t o 
assess t he pres e nce a n d s e verit y of slee p - dis or dere d breat hi n g b y meas ure m e nt of bl o o d 
o x y ge n s at urati o n, p ulse rate, a n d airfl o w d uri n g o ver ni g ht m o nit ori n g at S cree ni n g a n d o n 
Da ys 8 5 a n d 1 8 3 of t he i nitial p hase, a n d M o nt hs 1 2 a n d 2 4 of t he o pti o nal, o pe n- la bel 
e xte nsi o n p hase, a n d at E arl y Ter mi nati o n if s u bject disc o nti n ues after 1 8 m o nt hs.  
Assess me nt of e pis o des of slee p a p n ea will i ncl u de, b ut ma y n ot b e li mite d t o, t he n u m ber of 
e pis o des of a p n ea a n d h y p o p nea per h o ur ( A p n ea/ H y p o p n ea I n d e x, A HI).  If slee p a p n ea 
rea di n g is n ot acc urate, s u bject ma y nee d t o re peat assess me nt t he ne xt da y.  
9. 1 0. 3. 3  
I m a gi n g Assess me nt Pr oce d ures ( per Sc he d ule of E ve nts) 
I ma gi n g assess me nt pr oce d ures f or all visits m ust be perf or me d usi n g t he s a me i nstr u me nts. 
•  A P x -ra y of p el vis f or baseli ne hi p assess me nt.  
•  P osteri or- a nteri or ( P A) r a di o gra p hs of t he left ha n d a n d wrist t o assess b o n e a ge  
( Gre ulic h, 1 9 7 1, Sta nf or d U ni versit y Press.); ( Ta n ner, 1 9 7 5, Aca de mic Press.), 
gr o wt h plates, ha n d le n gt h, a n d c ortical t hic k n ess.  
•  A nteri or- p oste ri or (A P ) l o wer e xtre mit y ra di o gra p h t o assess gr o wt h plates, ti bial 
le n gt h, c ortical t hic k ness, a n d b o wi n g. 
•   A P ra di o gra p hs of l u m b ar s pi ne t o assess tra ns verse i nter pe dic ul ar dista nce.  A n A P 
x- ra y of s pi ne will als o be assesse d at scree ni n g f or t he p ur pose of l a n d mar ki n g. 
•  Lat eral r a di o gra p hs of l u m bar s pi ne t o assess, t h orac ol u m bar l or d osis a n gl e, verte bral 
m or p h ol o g y, as w ell as ot her p ote ntial c ha n ges rel ate d t o s pi nal ste n osis.   
•  Q C T sca n of f orear m a n d ti bia t o assess b o ne mi neral de nsit y, gr o wt h pla te 
m or p h ol o g y, a n d b o n e le n gt h.  T his sca n will be ac q uire d wit h a sta n d ar d C T sca n ner, 
cali brati o n p ha nt o m, a n d desi g nat e d s oft ware, usi n g a pre det er mi ne d l o w ra diati o n 
d ose pr ot oc ol, w hic h a v oi ds direct ra diati o n t o t he hea d a n d t ors o.  
S h o ul d s u bjects’ i ma gi n g assess me nt  yi el d a n y c o ncer ns, a d diti o nal i ma gi n g ma y b e 
c o n d ucte d ; t his will be deter mi ne d b y t he Pri nci p al I n v esti gat or i n c o nj u ncti o n wit h t he 
Bi o Mari n Me dical M o nit or a n d t he D M C if i n dicate d.  I m a gi n g assess me nts will be c ollecte d 
a n d i nter pret e d b y a ce ntr al rea d er , e x ce pt f or A P X -ra y of t he pel vis, w hic h will be re vie we d 
b y a l o cal ra di ol o gist a n d t he PI t o deter mi ne cli nical si g nifi ca nce .  Refer t o t he I m a gi n g 
G ui deli nes ( Bi ocli nica a n d eR T) f or det aile d i ma gi n g ass ess me nt re q uire me nts a n d 
pr oce d ur es. 
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pr ot oc ol. p df
Pa ge 6 8

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 8 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
9. 1 0. 4  S af et y V ari a bles 
Safet y will be e val uat e d b y t he i nci d e nce of A Es, S A Es, a n d cli nicall y si g nifica nt c ha n ges  i n 
vital si g ns, p h ysical e x a mi nati o n, E C G a n d E C H O res ults, i ma gi n g, a nti- B M N 1 1 1 
i m m u n o ge nicit y assess m e nts , a n d la b orat or y t est res ults ( uri nal ysis, c h e mistr y, he m at ol o g y).  
A d diti o nall y, i ma gi n g, hi p m o nit ori n g, bi o mar ker, a n d p h ysi cal meas ure me nt data , i ncl u di n g 
el b o w j oi nt ra n ge of m oti o n meas ure d wit h g o ni o meter , will be utilize d f or safet y -relate d 
re vie ws a n d a nal ysis.  
9. 1 0. 4. 1  
A d verse E ve n ts 
T he occ urre n ce of A Es will be assesse d c o nti n u o usl y fr o m t he ti me t he s u bject si g ns t he I C F. 
T he deter mi nati o n, e v al uati o n a n d re p orti n g of A Es will be perf or me d as o utli ne d i n 
Secti o n  1 0 . Assess me nts of A Es will occ ur at t he ti me p oi nts s h o w n i n Ta ble  9. 1. 1.  
A d diti o nall y, site staff will c o ntact st u d y s u bjects b y tele p h o n e at mi ni m u m o nce a w ee k 
d uri n g t he i nitial p hase of t he st u d y t o ass ess A Es, a n d o nce e ver y 2- 4 wee ks d uri n g t he 
o pti o nal, o pe n- la bel e xte nsi o n p hase.   
9. 1 0. 4. 2  
Cli nic al L a b or at or y Assess me nts 
S pecific visits f or o btai ni n g cli nical la b orat or y ass ess me nt sa m ples are pr o vi de d i n 
Ta ble  9. 1. 1.  T he sc h e d ul e d cli nical la b orat or y tests are liste d i n  Ta ble  9. 1. 1. Refer t o t he 
La b orat or y M a n ual f or i nstr ucti o ns o n o btai ni n g a n d s hi p pi n g sa m ples. 
A n y a b n or mal test res ults deter mi ne d t o be cli nicall y si g nifica nt b y t he I n vesti gat or s h o ul d 
be re peate d ( at t he I n vesti gat or’s discreti o n) u ntil t he ca use of t he a b n or malit y is deter mi ne d, 
t he val ue ret ur ns t o baseli ne or t o wit hi n n or mal li mits, or t he I n vesti gat or deter mi nes t hat t he 
a b n or mal val ue is n o l o n ger cli nicall y si g nifica nt.   
All cli nical la b orat or y r es ult pa ges a n d A P pel vis X- ra y re p orts s h o ul d be i nitiale d a n d date d 
b y a n I n vesti gat or or acce pta ble desi g nee , al o n g wit h a c o m me nt re gar di n g w h et her or n ot a n 
a b n or mal res ult is cli nicall y si g nifi ca nt. Eac h cli nicall y si g nifica nt la b orat or y res ult s h o ul d be 
rec or d e d as a n A E i n t he C R F. 
T he dia g n osis, if k n o w n, ass ociate d wit h a b n or m alities i n cli nical la b orat or y tests t hat are 
c o nsi dere d cli nicall y si g nifica nt b y t h e I n vesti gat or will be rec or de d o n t he A E C R F  
( Secti o n 1 0. 3. 1. 4 ). 
 
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pr ot oc ol. p df
Pa ge 6 9

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 6 9 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
T a ble 9. 1 0. 4. 2. 1 :  Cli nic al L a b or at or y Tests 
Bl o o d C he mistr y  
He m at ol o g y  
Uri n al ysis  
Al b u mi n  
He m o gl o bi n  
A p peara nce  
Al kali ne p h os p hatase, t otal  
He mat ocrit  
C ol or  
A L T ( S G P T)  
W B C c o u nt  
p H  
A S T ( S G O T)  
R B C c o u nt  
S pecif ic gra vit y 
Direct bilir u bi n  
Platelet c o u nt  
Ket o nes  
T otal bilir u bi n  
Differe ntial cell c o u nt  
Pr otei n  
B U N  
 
Gl uc ose  
Calci u m  
 
Bilir u bi n  
C hl ori de  
 
Nitrite  
P otassi u m  
 
Ur o bili n o ge n  
S o di u m  
 
He m o gl o bi n  
T otal c h olester ol  
 
 
Uric aci d  
 
 
Gl uc ose  
 
 
G G T  
 
Bi o m ar kers  
L D H  
 
B M N  1 1 1 acti vit y bi o mar kers  
P h os p h or us  
 
B o ne a n d c olla ge n bi o mar kers  
T otal pr otei n  
 
Uri ne C he mistr y  
Vita mi n D  
 
S o di u m  
 Creati ni ne  
 
P otassi u m  
Al kali ne p h os p hatase, b o ne -s p ecific 
T h yr oi d f u ncti o n   
( T S H, T 3, free T 4) 
 
Creati ni ne  
 
 
 
Bl o o d S p eci al C he mistr y  
 
 
B M N 1 1 1 acti vit y bi o mar kers  
 
 
B o ne a n d c olla ge n bi o mar kers  
 
 
A nti -B M N 1 1 1 a nti b o dies  
 
 
A L T, ala ni ne a mi n otra nsferas e;  A S T, as partate a mi n otra nsferase; B U N, bl o o d urea nitr o ge n; G G T, ga m ma -
gl uta m yltra nsferase; L D H, lactate de h y dr o ge nase; R B C, re d bl o o d cell; S G O T, ser u m gl ut a mic -o xal oacetic 
tra nsa mi nase; S G P T, ser u m gl uta mic-p yr u vic tra nsa mi nase; W B C, w hite bl o o d cell.  
 
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pr ot oc ol. p df
Pa ge 7 0

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 7 0 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
9. 1 0. 4. 3  
Ot her L a b or at or y Assess me nts  
S u bjects  will be as ke d t o pr o vi de ser u m a n d uri ne at t he ti mes i n dicate d i n t he Sc he d ule of 
E ve nts ( Ta ble  9. 1. 1). 
F or s u bjects w h o h a ve n ot ha d ge netic testi n g c o nfir mi n g dia g n osis of A C H, m olec ular 
ge n etic dia g n osis t o i de ntif y t he F G F R 3 m utati o n ( G 3 4 6 E, G 3 7 5 C, G 3 8 0 R, or “ ot her”) will 
be perf or me d.  If s u bj ects ha d p re vi o us ge n etic testi n g, s u bjects m ust ha ve eit her a writte n 
letter b y t h e p h ysicia n c o nfir mi n g ge n etic testi n g, i ncl u di n g t he s pecific m utati o n, or a la b 
certificati o n wit h t he st u d y s pecific m utati o n d oc u me nte d.  
9. 1 0. 4. 4  
Vit al Si g ns, P h ysic al E x a mi n ati o ns a n d Ot h er O bser v ati o ns Rel ate d t o S afet y  
9. 1 0. 4. 4. 1  Vit al Si g ns  
Vital si g ns will i ncl u de seate d s yst olic bl o o d press ure ( S B P) a n d diast olic bl o o d press ure 
( D B P) meas ure d i n m m H g, h eart rate i n beats per mi n ute, res pirati o n rat e i n breat hs per 
mi n ute, a n d te m perat ur e i n de g r ees Celsi us (° C).  All treat me nt visits ha ve pre- d ose vital si g n 
assess me nts.  P ost- d ose assess me nts i ncl u de heart rate a n d B P.  O n visit Da ys 1, 2, 3, a n d 4, 
mi ni m u m assess me nt fre q ue nc y is e ver y 1 5  mi n ( ±  5 mi n) f or 2 h o urs p ost d ose; a n d 
assess me nt is ta ke n e ver y 3 0 mi n ( ±  5 mi n) fr o m 2 t o 4 h o urs p ost d ose.  O n visit Da ys 1 a n d 
2, 4 t o 8 h o urs p ost- d ose meas ure me nts are ta k e n e ver y 6 0 mi n ( ±  1 0 mi n).   F or all ot her 
d osi n g visits, assess me nt is e ver y 1 5 mi n ( ±  5 mi n) f or t he first h o ur p ost d ose a n d a fi n al 
assess me nt pri or t o t he e n d of t he visit (if l o n ger t ha n 1 h o ur).  Vital si g n assess me nt 
fre q ue n c y is prese nte d i n Ta ble  9. 1 0. 4. 4. 1. 1. 
At Scree ni n g, after at least 5 mi n utes  of rest, s u bject’s B P  is ta ke n i n sitti n g p ositi o n.  T he n 
t he s u bject will sta n d a n d B P will be ta ke n a gai n at a p pr o xi matel y 1 a n d 3 mi n utes after 
sta n di n g.  At ot her visits, vital si g n meas ure me nts are ta k e n o nce p er ti me p oi nt i n a sitti n g 
p ositi o n after at least 5  mi n utes of rest.  Heart rat e s h o ul d be ta ke n at eac h ti me p oi nt t hat B P  
is meas ure d.  W he n bl o o d sa m ples a n d B P  ass ess me nts are sc h e d ule d at t h e sa me ti me or 
wit hi n t he sa me ti me wi n d o w, B P  s h o ul d be meas ure d bef ore bl o o d sa m ples are dra w n.  If a 
B P  meas ur e me nt m ust be ta ke n after a bl o o d dra w, e ns ure a d e q uate a nal gesi a f or t he bl o o d 
dra w a n d wait se veral mi n utes bef ore m eas uri n g B P .  Vital si g ns ma y b e m o nit ore d m ore 
fre q ue ntl y or f or l o n ger d urati o n p ost-d ose as cli ni call y i n dicate d  (T a ble  9. 1. 1).  
 
 
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pr ot oc ol. p df
Pa ge 7 1

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 7 1 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
T a ble  9. 1 0. 4. 4. 1. 1:  Vit al Si g n Assess me nt Fre q ue nc y   
Vit al Si g n Assess me nt Fre q u e nc y  
Scree ni n g  
After at least 5  mi n of rest, s u bj ect’s B P is ta ke n i n sitti n g p ositi o n.  
T he n t he s u bj ect will sta n d a n d B P will be ta ke n a gai n at a p pr o xi matel y 1  a n d 
3 mi n utes a fter sta n di n g.  
 
Assess me nt Fre q ue nc y  
D osi n g Visits  
0- 1 hr p ost -d ose  
0- 2 hr p ost -d ose  
2- 4 hr p ost d ose  
4- 8 hr p ost -d ose  
Da ys 1, 2  
 
q 1 5 mi n  
( ± 5 mi n) 
q 3 0 mi n  
( ± 5 mi n) 
q 6 0 mi n  
 ( ± 1 0 mi n) 
Da ys 3, 4  a n d d ose 
a dj ust me nt visit i n 
o pti o nal, o pe n -la bel 
e xte nsi o n p hase  
 
q 1 5 mi n  
( ± 5 mi n) 
q 3 0 mi n  
( ± 5 mi n) 
 
All ot her d osi n g visits  
q 1 5 mi n ( ± 5 mi n);  
fi nal assess me nt pri or 
t o e n d of visit (if l o n ger 
t ha n 1 hr).  I ncl u des 
d ose a dj ust me nt a n d 
f oll o w u p visits. 
 
 
 
1.  Vital si g n meas ure me nts are t a ke n o nce per ti me p oi nt i n a sitti n g p ositi o n after at least 5 mi n utes of 
rest.   
2.  Left brac hial ar m s h o ul d be t he first met h o d of assess me nt c o nsi dere d, a n d t he sa me site s h o ul d be 
use d f or meas ure me nt  of B P i n eac h s u bj ect t hr o u g h o ut t he st u d y.  
3.  Heart rate s h o ul d be ta ke n at e ac h ti me p oi nt t hat B P is meas ure d.   
4.  W he n bl o o d sa m ples a n d B P assess me nts are sc he d ule d at t he sa me ti me or wit hi n t he sa me ti me 
wi n d o w, B P s h o ul d be meas ur e d bef ore bl o o d sa m ples  are dra w n.   
5.  If a B P meas ure me nt m ust be ta ke n after a bl o o d dra w, e ns ure a de q uate a nal gesia f or t he bl o o d dra w 
a n d wait se veral mi n utes bef or e meas uri n g B P.   
6.  Vital si g ns ma y be m o nit ore d m ore fre q ue ntl y or f or l o n ger d urati o n p ost -d ose as cli nicall y i n d icate d. 
7.  If a s u bj ect has a h y p ote nsi ve e ve nt ( or s y m pt o ms p ote ntiall y c o nsiste nt wit h h y p ote nsi o n) or a 
decrease i n s yst olic B P of 2 0 m m H g or m ore fr o m pre -d ose s yst olic B P, bl o o d press ure a n d heart rate 
( B P/ H R) s h o ul d be meas ure d a n d rec or de d a p pr o xi matel y e ver y 1 5 mi n utes f or t he first h o ur a n d 
e ver y 3 0 mi n utes t hereafter u ntil t he s yst olic B P ret ur ns t o pre -d ose s yst olic B P ( or wit hi n t he n or mal 
ra n ge f or t his s u bj ect as defi ne d b y PI) a n d s y m pt o ms (if prese nt) res ol ve.  
 
9. 1 0. 4. 4. 2  Miti g ati n g t he Ris k of P ote nti a l H y p ote nsi o n  
St u d y p ers o n nel a n d care gi vers s h o ul d b e a w are of t he p ote ntial ris k of h y p ote nsi o n wit h 
B M N 1 1 1 a d mi nistrati o n.  S u bjects m ust be well  h y drate d a n d h a ve eate n brea kfast pri or t o 
a d mi nistrati o n of B M N 1 1 1 .  I n t h e h o ur pri or t o i njecti o n, all s u bjects s h o ul d ha ve atte m pte d 
t o dri n k 8 o u nces ( ~ 2 5 0 ml) of fl ui d (e. g. wat er, mil k, j uice, etc.), a n d t he o utc o me m ust be 
d oc u me nte d b y t he site o n cli nic visit da ys.  Care gi vers s h o ul d be trai ne d t o o bser ve a n d 
rec o g nize t he s y m pt o ms of de h y drati o n (e. g. fr o m fe ver, v o miti n g, diarr h ea, etc.) a n d c o ntact 
t he I n v esti gat or pri or t o st u d y dr u g a d mi nistrati o n if de h y drati o n is s us pecte d.  Site pers o n nel 
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pr ot oc ol. p df
Pa ge 7 2

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 7 2 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
a n d car e gi vers s h o ul d be trai ne d t o i de ntif y t he s y m pt o ms of h y p ote nsi o n a n d, if t he y o cc ur, 
s h o ul d i m ple me nt first -ai d strate gies at t he discreti o n of t he i n vesti gat or s uc h as ha vi n g t he 
s u bject lie d o w n s u pi ne, ele vati n g t he l o wer e xtre mities, a n d a d mi nisteri n g fl ui ds.  F or 
g ui deli nes o n h o w t o r e p ort a d verse e ve nts ass o ciate d wit h h y p ot e nsi o n, refer t o Secti o n 1 0 . 
9. 1 0. 4. 4. 3  Hi p M o nit ori n g  
Baseli ne hi p assess me nts will be c o n d ucte d f or all c o h orts, a n d will i ncl u de me dical hist or y, 
p h ysical e x a m, a n d A P x -ra y of t he p el vis.  S u bse q ue nt hi p m o nit ori n g ass ess me nts will be 
c o n d ucte d at r e g ul ar 6 - m o nt h i nter vals.  Me dical hist or y will be o btai ne d t o e val uate f or hi p, 
t hi g h, or k nee pai n, or c h a n ge i n gait.  T he p h ysical e x a m will i ncl u de s u pi ne a n d pr o ne 
assess me nt t o deter mi ne pai n or li mitati o n wit h hi p ra n ge of m oti o n a n d i nt er nal/e xter nal 
r otati o n of hi p j oi nt.  C ha n ges fr o m baseli ne will tri g ger f urt her e val u ati o n, w hic h ma y 
i ncl u de a d diti o nal hi p i ma gi n g, a n d/ or ort h o pe dic c o ns ultati o n.  D M C will be n otifie d of 
a b n or mal res ults fr o m hi p m o nit ori n g assess me nts t o deter mi ne if/ w he n B M N 1 1 1 treat me nt 
s h o ul d be te m p oraril y or per ma ne ntl y disc o nti n ue d, or d ose re d u ce d.  
9. 1 0. 4. 4. 4   E C Gs  
A sta n dar d 1 2-l ea d E C G will i ncl u de heart rate, r h yt h m, i nter vals, a xis, c o n d ucti o n defects, 
a n d a nat o mic a b n or malities. If cli nicall y si g nifica nt a b n or malities are n ote d,  t he I n v esti gat or 
or desi g n ee is r e q uire d t o assess w het her it is a p pr o priate f or t he s u bj ect t o c o nti n ue i n t he 
st u d y. E C Gs will be perf or me d at t he ti me p oi nts i n dicate d i n t he Sc he d ule of E ve nts 
(Ta ble  9. 1. 1). 
9. 1 0. 4. 4. 5  E C H O  
Car diac a n at o m y a n d f u n cti o n will be e val uate d b y a sta n d ar d 2- di me nsi o nal D o p pler E C H O. 
T he data r ec or d e d is t o i ncl u de ve ntric ular ca vit y size, val ve c haracterizati o n ( prese n ce or 
a bse nce of val ve ste n osis or re g ur gitati o n a n d cli nical si g nifi ca nce), ve ntri c ular wal l 
t hic k ness, re gi o nal wall m oti o n, L V mass cal c ulati o n, a n d pericar di al c haracterizati o n. 
E C H Os will be perf or m e d at t he ti me p oi nts i n dicate d i n t he Sc he d ule of E ve nts 
(Ta ble  9. 1. 1).  
9. 1 0. 4. 4. 6  A nti - B M N 1 1 1 I m m u n o ge nicit y Assess me nts a n d I g E Testi n g 
9. 1 0. 4. 4. 6. 1  
Sc he d ule d I m m u n o ge nicit y Assess me nts  
Bl o o d ser u m sa m pli n g f or i m m u n o ge nicit y assess me nts will be perf or me d at t he ti me p oi nts 
i n dicate d i n t he Sc he d ule of E ve nts (Ta ble  9. 1. 1 a n d Ta ble  9. 1. 2). 
Sc he d ule d sa m ples will be teste d i n o ne or m ore of t he f oll o wi n g ass ess me nts: 
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pr ot oc ol. p df
Pa ge 7 3

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 7 3 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  A nti - B M N 1 1 1 t otal a nti b o d y ( T A b) 
•  E n d o ge n o us C N P, A N P, a n d B N P cr oss- reacti vit y 
•  A nti - B M N 1 1 1 ne utr alizi n g a nti b o d y ( N A b) 
Testi n g f or t he pres e nce of cr oss -r eacti ve a nti b o dies t hat bi n d t o e n d o ge n o us C N P, A N P, or 
B N P a n d f or t he pres e nce of B M N 1 1 1- N A bs will be perf or m e d o n baseli n e sa m ples a n d 
a nti- B M N 1 1 1 T A b -p ositi ve sa m ples.   
9. 1 0. 4. 4. 6. 2  
A d H oc S af et y Assess me nts  
Sa m ples f or t otal I g E a n d dr u g- s pecifi c I g E testi n g will be dr a w n pre- d ose o n Da y 1.  If a 
si g nifica nt h y p erse nsiti vit y a d v erse e ve nt ( defi ne d as gra de 3 or hi g her, or re q uiri n g 
te m p orar y or p er ma n e nt cessati o n of B M N 1 1 1, or at t he discreti o n of I n vesti gat or a n d/ or 
Bi o M ari n, e x cl u di n g reacti o ns t hat are s olel y a l o c alize d i njecti o n site reacti o n) occ urs , a n 
u nsc he d ule d safet y visit s h o ul d occ ur wit hi n 4 8 h o urs of t he start of t he reacti o n, i ncl u di n g 
i ns pecti o n of t he i njecti o n site a n d cli nical la b orat or y tests. Bl o o d ser u m sa m ples s h o ul d be 
c ollecte d a n d test e d i n o ne or m ore of t h e f oll o wi n g ass ess me nts: 
•  A nti -B M N 1 1 1 I g E ( dr u g -s p ecific I g E) 
•  T otal I g E  
•  Ser u m tr y ptas e 
If feasi ble, a sa m ple f or dr u g-s pecifi c I g E s h o ul d b e dra w n at least 8 h o urs after t he e v e nt 
start ti me a n d bef or e t he ne xt d ose . A sa m ple f or t otal I g E a n d ser u m tr y ptase s h o ul d als o be 
dra w n wit hi n a n h o ur of t he start of t he e v e nt w he n p ossi ble or d uri n g t he u nsc he d ule d safet y 
visit.  
A l ocalize d i njecti o n site reacti o n is defi n e d as s ki n si g ns or s y m pt o ms restricte d t o o ne 
affecte d pri mar y l ocati o n, i. e., hi ves, w heals, or s welli n g or a n area of er yt he ma, re d n ess, 
i n d urati o n, pai n, or itc hi n g at or n ear t he site of i nj ecti o n. Ma na ge m e nt of s uc h l ocalize d 
reacti o ns s h o ul d be det er mi ne d b y t he I n v esti gat or’s cli nical j u d g me nt i n c o ns ultati o n wit h 
t he S p o ns or’s Me dical M o nit or (if warra nte d). 
9. 1 0. 4. 5  
Pre g n a nc y Testi n g  
Fe male s u bjects w h o ha v e be g u n me nses or are  ≥ 1 0 years ol d will ha ve a uri ne  or ser u m  
pre g na nc y t est at t he ti me p oi nts s pecifie d i n t he Sc he d ule of E ve nts ( T a bl e  9. 1. 1).  Fe male 
s u bjects wit h a p ositi ve pre g na nc y t est at Scree ni n g d o n ot meet eli gi bilit y criteria f or 
e nr oll me nt ( Secti o n  9. 3. 2 ). 
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2 2 A u g ust 2 0 1 6 
Ser u m pre g na n c y tests will be perf or me d i n t he e v e nt t hat uri ne pre g n a nc y t est res ults are 
p ositi ve or e q ui v oc al. 
Refer t o Secti o n  1 0. 3. 1. 9  f or details o n t he re p orti n g pr o ce d ures t o f oll o w i n t he e ve nt of 
pre g na nc y. 
9. 1 1  
Pe di at ric Bl o o d V ol u me 
Cli nical la bs a n d i m m u n o ge ni cit y sa m ples are rel e va nt t o safet y assess me nt i n t his st u d y.   
T he o bjecti ve of t h e P K assess me nts is t o u n dersta n d t he relati o ns hi p bet w ee n e x p os ure a n d 
bi ol o gic acti vit y.  T he o bjecti ves of e x pl ori n g p har mac o d y na mic acti vit y bi o mar kers are t o 
de m o nstrate bi ol o gi c acti vit y of B M N 1 1 1 a n d t o u n dersta n d b ot h t he i m pa ct of i m m u ne 
res p o nses o n dr u g acti vit y a n d t h e mec h a nis ms of C V c ha n ges d uri n g d osi n g; a n d f or b o ne 
a n d c olla ge n bi o mar k ers, t o de m o nstrate acti vit y at t he gr o wt h plate (c h o n dr oc yt e) a n d b o ne 
( oste o blast) le vels. 
T o mi ni mize bl o o d c ollecti o n v ol u mes, assa y t ec h n ol o gies w ere c h ose n t hat are ca pa ble of 
se nsiti vel y detecti n g a nal yt es usi n g t he l o west p ossi ble v ol u me of bl o o d f or a nal ysis.  
A d diti o nall y, assa ys ca pa ble of detecti n g a n al yt es i n uri ne rat her t h a n bl o o d ha ve bee n 
selecte d w h ere p ossi ble. 
 
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1 0  
R E P O R TI N G A D V E R S E E V E N T S  
1 0. 1  
S af et y P ar a meters a n d Defi niti o ns  
Safet y assess me nts will c o nsist of m o nit ori n g a n d rec or di n g pr ot o c ol- defi n e d A Es a n d S A Es; 
meas ure me nt of pr ot oc ol- s pecifie d h e mat ol o g y, cli nical c he mistr y, a n d uri n al ysis vari a bles; 
meas ure me nt of pr ot oc ol-s pecifie d vital si g ns; a n d ot her pr ot oc ol- defi ne d e ve nts of s peci al 
i nterest t hat are d ee me d critical t o t he safet y e v al u ati o n of t he st u d y dr u g. 
1 0. 1. 1  A d verse E ve nts  
F or t his pr ot oc ol, a r e p orta ble A E  is a n y u nt o war d me dical occ urre n ce (e g, si g n, s y m pt o m, 
ill ness, disease or i nj ur y) i n a s u bject a d mi nistere d t he st u d y- dr u g or ot her pr ot oc ol-i m p ose d 
i nter ve nti o n, re gar dless of attri b uti o n. T his i ncl u des t he f oll o wi n g: 
•  A Es n ot pre vi o usl y o bs er ve d i n t he s u bject t hat e mer ge d uri n g t he c o urse of t he 
st u d y. 
•  Pre -e x isti n g me dical c o n diti o ns j u d ge d b y t h e I n v esti gat or t o h a ve w ors e ne d i n 
se verit y or fr e q ue n c y or c ha n ge d i n c h aracter d uri n g t he st u d y. 
•  C o m plicati o ns t hat occ ur as a res ult of n o n- dr u g pr ot oc ol-i m p ose d i nter ve nti o ns 
(e. g., A Es r elate d t o scr ee ni n g pr o ce d u res, me dicati o n was h o ut, or n o-treat me nt 
r u n-i n). 
A n a d vers e dr u g r eacti o n is a n y A E f or w hic h t h ere is a reas o na ble p ossi bilit y t hat t he st u d y 
dr u g ca use d t h e A E. “ Reas o na ble p ossi bilit y” mea ns t here is e vi de n ce t o s u g gest a ca us al 
relati o ns hi p bet wee n t he st u d y- dr u g a n d t he A E. 
W he ne ver p ossi ble, it is prefera ble t o rec or d a dia g n osis as t he A E t er m rat her t ha n a s eries 
of ter ms relati n g t o a dia g n osis.  
1 0. 1. 2  Seri o us A d v erse E ve nts  
A seri o us a d verse e v e nt ( S A E) is a n y u nt o w ar d m e dical occ urre nce t hat at a n y d os e meets 
o ne or m ore of t he f oll o wi n g criteria:  
•  Is fatal 
•  Is life t hreat e ni n g  
N ote: Life -t hre ate ni n g refers t o a n eve nt t h at pl aces t he p atie nt at i m me di ate risk of 
de at h. T his defi niti o n d oes n ot i ncl u de a re acti o n t h at, h a d it occ urre d i n a m ore 
severe f or m, mi g ht h ave c a use d de at h. 
•  Re q uires or pr ol o n gs i n p atie nt h os pitalizati o n.  H os pitalizati o n f or less t ha n 2 4 h o urs 
will n ot be c o nsi dere d t o be a n S A E.  
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y  
•  Is a c o n ge nital a n o mal y or birt h defect i n t he c hil d or fet us of a p atie nt e x p ose d t o I P 
pri or t o c o nce pti o n or d uri n g pre g na n c y 
•  
Is a n i m p orta nt me dical e ve nt or reacti o n t hat, bas e d o n me dical j u d g me nt, ma y 
je o par dize t he patie nt or re q uire i nter v e nti o n t o pre ve nt o ne of t he a b o ve 
c o nse q ue nces (e. g., a na p h yla xis) 
All a d verse e ve nts t hat d o n ot meet a n y of t he criteria f or S A Es s h o ul d be re gar de d as n o n-
seri o us A Es. 
1 0. 2  
Met h o ds a n d Ti mi n g f or C a pt uri n g a n d Assessi n g S afet y P a r a meters  
1 0. 2. 1  A d verse E ve nt R e p orti n g Peri o d  
T he st u d y A E re p orti n g p eri o d is as f oll o ws: after i nf or me d c o ns e nt b ut pri or t o i nitiati o n of 
st u d y treat me nt, o nl y S A Es ass ociate d wit h a n y pr ot oc ol-i m p ose d i nter ve nti o ns will be 
re p orte d.  After i nf or me d c o nse nt is o btai ne d a n d t he first a d mi nistrati o n of st u d y dr u g, all 
n o n- seri o us A Es a n d S A Es re p orti n g peri o d be gi ns a n d c o nti n ues u ntil 4 wee ks  f oll o wi n g 
eit her t he last a d mi nistrati o n of st u d y dr u g or t h e earl y t er mi nati o n visit, w hic he ver is l o n ger. 
T he M o nt h 2 5 Safet y F oll o w- u p Visit will be wai ve d if a s u bject e nr olls i n t he 1 1 1- 2 0 5 
e xte nsi o n st u d y at t he M o nt h 2 4/ St u d y C o m pleti o n Visit . T he criteria f or d e ter mi ni n g, a n d 
t he re p orti n g of S A Es are  pr o vi de d i n Secti o n  1 0. 1. 2 .  
1 0. 2. 2  Eliciti n g A d verse E ve nts  
I n v esti gat ors will see k i nf or mati o n o n A Es a n d S A Es at eac h patie nt c o ntact b y s pecific 
q uesti o ni n g a n d, as a p pr o priate, b y e x a mi nati o n.  I nf or mati o n o n all A Es a n d S A Es s h o ul d 
be rec or de d i n t he p atie nt’s me dical rec or d a n d o n t he A E Case Re p ort F or m ( C R F). 
1 0. 2. 3  Assess me nt of Seri o us ness, Se verit y, a n d C a us alit y 
T he  I n vesti gat or r es p o nsi ble f or t he care of t he patie nt or me dicall y q ualifie d desi g nee will 
assess A Es f or s e verit y, r elati o ns hi p t o st u d y dr u g, a n d seri o us ness ( refer t o Secti o n 1 0. 1. 2  
f or S A E defi niti o ns).  T h ese assess me nts s h o ul d b e ma de b y a st u d y cli nici a n wit h t he 
trai ni n g a n d a ut h orit y t o ma ke a dia g n osis (e g, M D/ D O, p h ysi cia n’s assist a nt, n urse 
practiti o ner, or D D S). 
1 0. 2. 3. 1  
Seri o us ness  
T he i n vesti gat or will assess if a n A E s h o ul d be classifie d as “seri o us” bas e d o n t he 
seri o us ness criteria e n u m erate d i n Secti o n 1 0. 1. 2 .  Seri o us ness ser ves as a g ui de f or defi ni n g 
re g ulat or y r e p orti n g o bli gati o ns. 
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1 0. 2. 3. 2  
Se verit y  
Se verit y (as i n mil d, m o derate , or se vere hea dac he) is n ot e q ui vale nt t o seri o us ness, w hic h is 
ba se d o n patie nt/e ve nt o utc o me or acti o n criteria us uall y ass o ciate d wit h e v e nts t hat p ose a 
t hreat t o a patie nt’s life or f u ncti o ni n g.  T h e se v erit y of eac h will be assesse d usi n g t he 
defi ne d cate g ories i n T a ble  1 0. 2. 3. 2. 1. 
T he I n v esti gat or will det er mi ne t he se v erit y of eac h A E a n d S A E usi n g t h e N CI C T C A E v 4. 
A d verse e ve nts t hat d o n ot ha ve a c orres p o n di n g C T C A E ter m will be assesse d acc or di n g t o 
t he ge ner al g ui d eli nes f or gr a di n g use d i n t he C T C A E v 4 as state d bel o w. 
T a ble 1 0. 2. 3. 2. 1:  A d verse E ve nt  Gr a di n g  ( Se verit y) Sc ale 
Gr a de  
Descri pti o n  
1 
Mil d: as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n osti c o bser vati o ns o nl y; i nter ve nti o n 
n ot i n dicate d  
2 
M o derate: mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge-a p pr o priate 
i nstr u me ntal A D L a 
3 
Se vere  or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g: h os pitalizati o n or 
pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g self care A D L b 
4 
Life t hreate ni n g or de bilitati n g: c o nse q ue nces; ur ge nt i nter ve nti o n 
i n dicate d 
Gra de 4 a n d 5 A Es s h o ul d 
al wa ys be re p orte d as 
S A Es   
5 
Deat h relate d t o a n A E  
a I nstr u me ntal A D L refer t o t he f oll o wi n g e xa m ples: pre pari n g meals, s h o p pi n g f or gr oceri es or cl ot hes, usi n g 
t he tele p h o ne, ma na gi n g m o ne y. 
b Self care A D L refer t o t he f oll o wi n g e xa m ples: bat hi n g, dressi n g a n d u n dressi n g, fee di n g o neself, usi n g t he 
t oilet, ta ki n g me dicati o ns, n ot be dri d de n. 
 
1 0. 2. 3. 3  
C a us alit y 
T he I n vesti gat or will det er mi ne t he relati o ns hi p of a n A E t o t he st u d y dr u g a n d will rec or d it 
o n t he s o urce d o c u me nts a n d A E C R F.  T o e ns ure c o nsiste nc y of ca usalit y assess me nts, 
I n v esti gat ors s h o ul d a p pl y t he g ui da n ce i n Ta bl e  1 0. 2. 3. 3. 1. 
 
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T a ble 1 0. 2. 3. 3. 1 :  C a us alit y Attri b uti o n G ui d a nce  
Rel ati o ns hi p  
Descri pti o n  
N ot Relate d  
•  
E x p os ure t o t he I P has n ot occ urre d  
O R  
•  
T he a d mi nistrati o n of t he I P a n d t he occ urre nce of t he A E ar e n ot 
reas o na bl y relate d i n ti me  
O R  
•  
T he A E is c o nsi dere d li kel y t o be relate d t o a n eti ol o g y ot her t ha n t he use 
of t he I P; t hat is, t here are n o facts, e vi de nce, or ar g u me nts t o s u g gest a 
ca usal relati o ns hi p t o t he I P.  
Relate d  
•  
T he a d mi nistrati o n of t he I P a n d t he occ urre nce of t he A E ar e rea s o na bl y 
relate d i n ti me 
A N D  
•  
T he A E c o ul d p ossi bl y be e x plai ne d  b y fact ors or ca uses ot her t ha n 
e x p os ure t o t he I P  
O R  
 
•  
T he a d mi nistrati o n of I P a n d t he occ urre nce of t he A E are reas o na bl y 
relate d i n ti me  
A N D  
•  
T he A E is m ore li kel y e x plai ne d b y e x p os ure t o  t he I P t ha n b y ot her 
fact ors or ca uses. 
 
Fact ors s u g gesti ve of a ca usal relati o ns hi p c o ul d i ncl u de ( b ut are n ot li mite d t o): 
•  Pla usi ble te m p oral relati o ns hi p  
•  A bse nce of alter n ati ve e x pla nati o ns  
•  Rarit y of e ve nt i n a gi ve n patie nt or disease stat e  
•  A bse nce o f e ve nt pri or t o st u d y dr u g e x p os ure 
•  C o nsiste nc y wit h st u d y pr o d uct p har mac ol o g y 
•  K n o w n relati o ns hi p t o u n derl yi n g mec ha nis m of st u d y dr u g acti o n 
•  Si milarit y t o a d v erse reacti o ns see n wit h relate d dr u g pr o d ucts  
•  A bate me nt of A E wit h disc o nti n uati o n of st u d y dr u g, a n d/ or rec urre nce of A E wit h 
rei ntr o d ucti o n of st u d y dr u g 
T he i n vesti gat or’s assess me nt of ca usalit y f or i n di vi d ual A E re p orts is part of t he st u d y 
d oc u me ntati o n pr ocess.  Re gar dless of t he I n vesti gat or’s assess me nt of ca usalit y f or 
i n di vi d ual A E re p orts, t he S p o ns or will pr o m ptl y e val uate all re p orte d S A Es a gai nst 
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c u m ulati ve pr o d uct e x perie nce t o i de ntif y a n d e x pe diti o usl y c o m m u nicate p ossi ble ne w 
safet y fi n di n gs t o i n vesti gat ors a n d a p plica ble re g ulat or y a ut h orities. 
1 0. 3  
Pr o ce d ures f or R ec or di n g A d verse E ve nts  
1 0. 3. 1  Rec or di n g A d verse E ve nts o n a n e C R F  
I n v esti gat ors s h o ul d use precise me di cal ter mi n ol o g y w h e n rec or di n g A Es or S A Es o n a n 
e C R F.  A v oi d c oll o q uialis ms a n d a b bre viati o ns. 
Rec or d o nl y o ne dia g n osis, si g n, or s y m pt o m per e ve nt fiel d o n t he A E e C R F (e g, na us ea a n d 
v o miti n g s h o ul d n ot be rec or de d i n t he s a me e ntr y, b ut as 2 se p arate e ntries). 
I n or der t o cl assif y A Es a n d diseases, preferre d ter ms will be assi g ne d b y t h e S p o ns or t o t he 
ori gi nal ter ms e nter e d o n t he e C R F, usi n g M e d D R A ( Me dical Di cti o nar y f or Re g ul at or y 
Acti vities) ter mi n ol o g y . 
1 0. 3. 1. 1  
Di a g n osis v ers us Si g ns a n d S y m pt o ms  
Usi n g acce pt e d me dical t er mi n ol o g y, e nt er t he dia g n osis (if k n o w n).  If n ot k n o w n, e nter t he 
m ost me dicall y si g nifica nt si g n or s y m pt o m.  If a dia g n osis s u bse q ue ntl y b ec o mes a v aila ble, 
t he n t his dia g n osis s h o ul d be e nter e d o n t he A E f or m, re placi n g t he ori gi n al e ntries w here 
a p pr o priate. 
1 0. 3. 1. 2  
A d verse E ve nts Occ urri n g Sec o n d ar y t o Ot her E ve nts  
I n ge ner al, A Es occ urri n g sec o n dar y t o ot her e ve nts (e g, casca de e ve nts) s h o ul d be i de ntifie d 
b y t h eir pri mar y ca use.  F or e x a m ple, if se vere di arr hea is k n o w n t o ha ve res ulte d i n 
de h y drati o n, it is s ufficie nt t o rec or d o nl y diarr hea as a n A E or S A E o n t he e C R F.  H o we v er, 
me dicall y i m p orta nt e ve nts t hat ma y be li n ke d a n d/ or se parat e d i n ti me s h o ul d be r ec or de d as 
i n de pe n de nt e v e nts o n t he e C R F.  F or e x a m ple, if se vere h e m orr h a ge lea ds t o re nal fail ure, 
b ot h e ve nts s h o ul d be rec or de d se paratel y o n t he e C R F. 
1 0. 3. 1. 3  
Persiste nt or Rec u rre nt A d verse E ve nts  
A persiste nt A E is o ne t h at e xte n ds c o nti n u o usl y, wit h o ut res ol uti o n, bet wee n patie nt 
e val uati o n ti me p oi nts.  S uc h a n e v e nt s h o ul d be rec or de d o nl y o nce o n t he e C R F u nless its 
se verit y i ncreases or d ecr eases (i n w hic h cas e it s h o ul d be rec or de d a gai n o n t he A E e C R F).  
A rec urre nt A E is o n e t hat occ urs a n d res ol ves b et wee n patie nt e v al uati o n ti me p oi nts, b ut 
t he n s u bse q ue ntl y rec urs.  All rec urre nces of t he A E are c o nsi dere d s e parate e ve nts a n d 
s h o ul d be rec or de d as s u c h o n t he A E e C R F. 
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1 0. 3. 1. 4  
A b n or m al L a b or at or y V al ues 
La b orat or y test r es ults will be rec or d e d o n t he la b ora t or y res ults pa ges of t h e e C R F, or 
a p pear o n electr o nicall y pr o d uce d la b orat or y re p orts s u b mitte d directl y fr o m t he ce ntral  
la b orat or y, if a p plica ble. 
A n y la b orat or y res ult a b n or malit y f ulfilli n g t h e criteria f or a S A E s h o ul d b e re p ort e d as  s uc h, 
i n a d diti o n t o bei n g rec or de d as a n A E i n t he e C R F. 
A cli nical la b orat or y a b n or malit y s h o ul d be d oc u me nte d as A E if a n y o n e or m ore of t he 
f oll o wi n g c o n diti o ns is met: 
•  Acc o m pa nie d b y cli nical s y m pt o ms  
•  Lea di n g t o a c h a n ge i n st u d y me dicati o n (e. g. d os e m o dificati o n, i nterr u pti o n or 
per ma ne nt disc o nti n uati o n)  
•  Re q uiri n g a c ha n ge i n c o nc o mita nt t hera p y (e. g. a d diti o n of, i nterr u pti o n of, 
disc o nti n uati o n of, or a n y ot her c ha n ge i n a c o n c o mita nt me dicati o n, t hera p y or 
treat me nt). 
•  T he la b orat or y a b n or malit y persists u p o n re peat c o nfir mat or y testi n g.  
•  T he a b n or malit y s u g gests a disease a n d/ or or ga n t o xicit y  
•  T he a b n or malit y is of a d e gree t h at re q uires acti ve ma na ge me nt (e g, c ha n ge of d ose, 
disc o nti n uati o n of st u d y dr u g, m ore fre q ue nt f oll o w- u p assess me nts, f urt h er 
dia g n ostic i n vesti gati o n, etc.) 
T his a p plies t o  a n y pr ot oc ol a n d n o n-pr ot oc ol s p ecifie d safet y a n d efficac y la b orat or y  res ult 
fr o m tests perf or me d aft er t he first d ose of st u d y me dicati o n t hat falls o utsi de t he la b orat or y 
refere nce r a n ge a n d m eets t he cli nical si g nifica nce criteria. 
T his d oes n ot a p pl y t o  a n y a b n or mal la b orat or y res ult t hat falls o utsi de t he la b orat or y  
refere nce r a n ge b ut t hat d oes n ot meet t he cli nical si g nifica n ce criteria (t hes e will be 
a nal yze d a n d re p orte d as la b orat or y a b n or malities), t h ose t hat are c o nsi dere d A Es of t he t y pe 
e x plicitl y e x e m pte d b y t h e pr ot oc ol, or t h ose w hic h are a res ult of a n A E t hat has alrea d y 
bee n re p orte d.   
1 0. 3. 1. 5  
Pre - e xisti n g C o n diti o ns 
A pre - e xisti n g c o n diti o n is o ne t hat is prese nt at t h e start of t he st u d y.  S uc h c o n diti o ns 
s h o ul d be rec or de d as me dical hist or y o n t he a p pr o priate e C R F. 
A pre - e xisti n g c o n diti o n s h o ul d be rec or de d as a n A E or S A E d uri n g t he st u d y o nl y  if t he 
fre q ue n c y, i nte nsit y, or c haract er of t he c o n diti o n w orse ns d uri n g t he st u d y peri o d.  It is 
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pr ot oc ol. p df
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 8 1 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
i m p orta nt to c o n ve y t h e c o nce pt t hat a pre-e xisti n g c o n diti o n has c ha n ge d b y i ncl u di n g 
a p plica ble la n g ua ge i n t he ver bati m des cri pti o n of t he e ve nt (e. g., w orse ni n g bac k pai n ). 
1 0. 3. 1. 6  
Ge ner al P h ysic al E x a mi n ati o n Fi n di n gs 
At scree ni n g, a n y cli nicall y si g nifica nt a b n or malit y  s h o ul d be rec or de d as a pre-e xisti n g 
c o n diti o n (refer t o Secti o n 1 0. 3. 1. 5 ).  D uri n g t he st u d y, a n y n e w cli nicall y si g nifica nt 
fi n di n gs a n d/ or a b n or malities disc o vere d o n p h ysi cal e x a mi nati o n t hat meet t he defi niti o n of 
a n A E (or a n S A E) m ust be rec or de d a n d d oc u me nt as a n A E or S A E o n t h e A E e C R F. 
1 0. 3. 1. 7  
H os pit aliz ati o n, Pr ol o n ge d H os pit aliz ati o n, or S ur ger y 
A n y A E t hat res ults i n h os pitalizati o n or pr ol o n ge d h os pitalizati o n s h o ul d be d oc u me nte d 
a n d re p ort e d as a n S A E u nless s pecifica ll y i nstr uct e d ot her wise i n t his pr ot o c ol (refer t o 
Secti o n 1 0. 1. 2 ). 
T here are s o me h os pitali zati o n sce nari os t hat d o n ot re q uire re p orti n g as a n S A E w he n t here 
is n o occ urre n ce of a n A E.  T hese sce nari os i ncl u de pla n ne d h os pitalizati o ns or pr ol o n ge d 
h os pitalizati o ns t o:  
•  Perf or m a pr ot o c ol -ma n d ate d efficac y meas ure me nt  
•  U n der g o a dia g n ostic or electi ve s ur gical pr oce d ure f or a pre- e xisti n g me dical 
c o n diti o n t hat has n ot c ha n ge d 
•  Recei ve sc h e d ule d t her a p y (st u d y dr u g or ot her wis e) f or t he st u d y i n dicati o n 
1 0. 3. 1. 8  
De at hs  
All deat hs t hat occ ur d uri n g t he A E re p orti n g peri o d (refer t o Secti o n 1 0. 2. 1 ), re gar dless of 
attri b uti o n, will be rec or d e d o n t he A E e C R F a n d e x pe diti o usl y re p ort e d t o t he S p o ns or as a n 
S A E.  
W he n rec or di n g a d eat h, t he e ve nt or c o n diti o n t hat ca use d or c o ntri b ute d t o t he fatal 
o utc o me s h o ul d be rec or de d as t he si n gl e me dical c o nce pt o n t he e C R F.  
1 0. 3. 1. 9  
Pre g n a nc y  
Alt h o u g h n ot a n A E p er se, pre g na n c y i n eit her a patie nt or t he part n er of a patie nt ta ki n g 
trial me dicati o n s h o ul d be re p ort e d as a n S A E t o facilitate o utc o me m o nit ori n g b y t he 
S p o ns or. 
Pre g n a nc y i n a p atie nt  or part ner s h o ul d be re p ort e d wit hi n 2 4 h o urs of t he site bec o mi n g 
a war e of t he pr e g na n c y b y f a xi n g t he Pre g na n c y F or m i n t he st u d y refer e nce materials t o 
B P V.  T he pr e g na n c y re p orti n g peri o d be gi ns f oll o wi n g first d ose of st u d y dr u g a n d 4 wee ks 
after last d ose of st u d y dr u g. I n a d diti o n, pre g na n c y i n a p atie nt  is als o re p orte d o n t he E n d of 
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 8 2 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
St u d y e C R F. T he I n vesti gat or m ust ma k e e ver y eff ort t o f oll o w t he patie nt  t hr o u g h res ol uti o n 
of t he pre g n a nc y ( d eli ver y or ter mi nati o n) a n d t o re p ort t he res ol uti o n o n t he Pre g na nc y 
F oll o w- u p F or m i n t he st u d y r efere nce materials. I n t he e ve nt of pre g na n c y i n t he part ner of a 
st u d y patie nt , t he I n v esti gat or s h o ul d ma k e e v er y reas o na bl e atte m pt t o o btai n t he w o ma n’s 
c o nse nt f or r eleas e of pr otecte d healt h i nf or mati o n. 
A b orti o n, w het her t hera p e utic or s p o nta ne o us, s h o ul d al wa ys be classifi e d as a n S A E (as t he 
S p o ns or c o nsi ders t hese t o be me dicall y si g nifica nt), rec or d e d o n t he e C R F, a n d 
e x pe diti o usl y r e p orte d t o t he S p o ns or as a n S A E. 
1 0. 4  
Re p orti n g Re q uire me nts  
1 0. 4. 1  E x pe dite d Re p orti n g Re q uire me nts  
All S A Es  t hat occ ur d uri n g t he c o urse of t he A E Re p orti n g Peri o d (refer t o Secti o n  1 0. 2. 1 ), 
w het her or n ot c o nsi dere d relate d t o st u d y dr u g, m ust be re p orte d b y fa xi n g t he st u d y-
s pecific S A E Re p ort F or m t o Bi o Mari n P har mac o vi gila nce ( B P V) wit hi n 2 4 h o urs of t he site 
bec o mi n g a ware of t h e e ve nt.  Eac h S A E m ust als o be re p ort e d o n t he a p pr o priate e C R F .  
I n v esti gat ors s h o ul d n ot wait t o c ollect i nf or mati o n t hat f ull y d oc u me nts t h e e ve nt bef ore 
n otif yi n g B P V of a n S A E.   Bi o Mari n ma y b e re q uire d t o re p ort certai n S A Es t o re g ulat or y 
a ut h orities wit hi n 7 cale n dar da ys of b ei n g n otifie d a b o ut t he e ve nt; t heref ore, it is i m p orta nt 
t hat I n v esti gat ors s u b mit a n y i nf or mati o n re q u este d b y Bi o Mari n as s o o n as it bec o mes 
a vaila ble. 
T he st u d y S A E r e p orti n g peri o d is as f oll o ws: after i nf or me d c o ns e nt b ut pri or t o i nitiati o n of 
st u d y treat me nt, o nl y S A Es ass ociate d wit h a n y pr ot oc ol-i m p ose d i nter ve nti o ns will be 
re p orte d.  After i nf or me d c o nse nt is o btai ne d a n d t he first a d mi nistrati o n of st u d y dr u g, all 
S A Es m ust be re p orte d t hr o u g h 4 wee ks f oll o wi n g eit her t he last a d mi nistrati o n of st u d y dr u g 
or t he earl y t er mi nati o n visit, w hic he ver is l o n ger.  
1 0. 4. 2  I R B Re p orti n g Re q uire me nts 
Re p orti n g of S A Es t o t he I R B will be d o ne i n c o m plia nce wit h t he sta n dar d o perati n g 
pr oce d ur es a n d p olicies of t he I R B a n d wit h a p plica ble re g ulat or y re q uire m e nts. A de q uate 
d oc u me ntati o n m ust be o btai ne d b y Bi o Mari n s h o wi n g t hat t he I R B was pr o perl y a n d 
pr o m ptl y n otifie d as r e q uire d. 
1 0. 5  
F oll o w- u p of P atie nts after A d verse E ve nts  
T he I n vesti gat or s h o ul d f oll o w all u nres ol ve d A Es/ S A Es u ntil t he e ve nts are res ol ve d or ha ve 
sta bilize d, t he patie nt is lost t o f oll o w- u p, or it has bee n deter mi ne d t hat t he st u d y treat me nt 
or partici pati o n is n ot t he ca use of t h e A E/ S A E.   O utc o me of A Es a n d  res ol uti o n of SA Es 
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pr ot oc ol. p df
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Pa ge 8 3 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
( wit h dates) s h o ul d be d o c u me nte d o n t he A E e C R F a n d i n t he patie nt’s m e dical rec or d t o 
facilitate s o urce data v erificati o n. 
F or s o me S A Es, t he S p o ns or ma y f oll o w u p b y tele p h o ne, fa x, electr o ni c mail, a n d/ or a 
m o nit ori n g visit t o o btai n a d diti o nal case det ails (e . g., h os pital disc har ge s u m mar y, 
c o ns ulta nt re p ort, or a ut o ps y r e p ort) dee me d necessar y t o a p pr o pri atel y e val uate t he S A E 
re p ort. 
1 0. 6  
P ost -St u d y A d verse E ve nts  
At t he last sc he d ule d visit, t he I n v esti gat or s h o ul d i nstr uct eac h p atie nt  t o re p ort, t o t he 
I n v esti gat or a n d/ or t o B P V directl y, a n y s u bse q u e nt S A Es t hat t he patie nt ’s pers o nal 
p h ysicia n(s) belie v es mi g ht be relate d t o pri or st u d y treat me nt.  
T he I n vesti gat or s h o ul d n otif y t he st u d y S p o ns or of a n y deat h or S A E occ urri n g at a n y ti me 
after a patie nt  has disc o nti n ue d or ter mi nate d st u d y partici pati o n, if t he I n v esti gat or b elie ves 
t hat t he deat h or S A E ma y ha v e bee n relat e d t o pri or st u d y treat me nt. T he S p o ns or s h o ul d 
als o be n otifie d if t he I n v esti gat or s h o ul d bec o me a ware of t he d e vel o p me nt of ca ncer or of a 
c o n ge nital a n o mal y i n a s u bse q ue ntl y c o ncei v e d offs pri n g of a patie nt  t hat p artici pate d in t his 
st u d y.  
1 0. 7  
Ur ge nt S af et y Me as ures  
T he re g ulati o ns g o ver ni n g cli nical trials state t hat t he s p o ns or a n d I n vesti gat or are re q uire d t o 
ta ke a p pr o priate ur ge nt safet y meas ures t o pr otect patie nts a gai nst a n y i m me diate hazar ds 
t hat ma y aff ect t he saf et y of patie nts, a n d t hat t he a p pr o priate re g ulat or y b o dies s h o ul d be 
n otifie d acc or di n g t o t heir res pecti ve re g ul ati o ns. Acc or di n g t o t he E ur o p ea n U ni o n ( E U) 
Cli nical Trial Directi ve 2 0 0 1/ 2 0/ E C, “ …i n t he li g ht of t he circ u msta nces, n ota bl y t he 
occ urr e nce of a n y n e w e ve nt relati n g t o t he c o n d u ct of t he trial or t he d e vel o p me nt of t he 
i n vesti gati o nal me dici nal pr o d uct w here t hat ne w e ve nt is li kel y t o affect t he safet y of t h e 
patie nt s, t he s p o ns or a n d t he I n v esti gat or s hall ta k e a p pr o pri ate ur ge nt s afet y meas ures t o 
pr otect t he patie nt s a gai nst a n y i m me diate h azar d. T he s p o ns or s hall f ort h wit h i nf or m t he 
c o m pete nt a ut h orities of t h ose ne w e ve nts a n d t he meas ures ta k e n a n d s hall e ns ure t hat t he 
I R B/ E C/ R E B is n otifie d at t he sa me ti me.”  
T he re p orti n g peri o d f or t hese e ve nts w hi c h ma y re q uire t he i m ple me ntati o n of ur ge nt safet y 
meas ures is t he peri o d fr o m t he ti me of si g ni n g of t he I C F t hr o u g h t he c o m pleti o n of t he last 
st u d y visit or at t he Earl y Ter mi nati o n Visit ( E T V ). I n vesti gat ors are re q uire d t o re p ort a n y 
e ve nts w hic h ma y r e q uir e t he i m ple me ntati o n of ur ge nt safet y meas ures t o Bi o Mari n wit hi n  
2 4 h o urs. 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
E x a m ples of sit uati o ns t hat ma y re q uire ur ge nt safet y meas ures i ncl u d e disc o ver y of t h e 
f oll o wi n g: 
•  I m me diat e nee d t o re vise t he I P a d mi nistrati o n (e g, m o difie d d ose a m o u nt or 
fre q ue n c y n ot defi ne d i n pr ot oc ol) 
•  Lac k of st u d y scie ntific v al ue, or detri me nt al st u d y c o n d uct or ma na ge me nt 
•  Disc o ver y t hat t he q u alit y or s afet y of t h e I P d oes n ot meet esta blis he d safet y 
re q uire me nts 
 
 
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pr ot oc ol. p df
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Pa ge 8 5 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 0. 8  
Bi o M ari n P h ar m ac o vi gil a nce C o nt act I nf o r m ati o n  
C o ntact i nf or mati o n f or Bi o Mari n P har mac o vi gila nce is as f oll o ws: 
Bi o Mari n P har mace utical I nc.  
A d dress:  
1 0 5 Di gital Dri ve  
N o vat o, C A 9 4 9 4 9 U S A  
P h o ne:  
( 4 1 5) 5 0 6-6 1 7 9  
Fa x:  
( 4 1 5) 5 3 2-3 1 4 4  
E -mail:  
dr u gs afet y @ b mr n. c o m  
T he I n vesti gat or is e n c o ura ge d  t o disc uss wit h t he Me dical M o nit or a n y A Es f or w hic h t he 
iss ue of seri o us ness is u n clear or q uesti o ne d. C o ntact i nf or mati o n f or t h e Me dical M o nit or is 
as f oll o ws: 
Na me:  
, M D, P h D 
A d dress:  
Bi o Mari n 
P har mace utical I nc.  
1 0 5 Di gital Dri ve  
N o vat o, C A 9 4 9 4 9 U S A 
P h o ne:  
 
Fa x:  
 
E -mail:  
 
 
 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 1  
S T U D Y P R O D C E D U R E S  
1 1. 1  
Scree ni n g Visit  ( D a y -3 0  t o D a y - 1) 
Writte n i nf or me d c o nse nt a n d asse nt, as a p pr o priate, after t h e nat ure of t he st u d y has bee n 
e x plai ne d m ust b e o btai ne d pri or t o a n y researc h -relate d pr oce d ures. Scree ni n g Visit 
pr oce d ur es a n d ass ess me nts t hat s h o ul d be perf or me d are n ote d b el o w. 
•  O pti o nal pare ntal hei g ht assess me nt ( N O T E: ca n be d o ne at a n y p oi nt i n t h e st u d y) 
•  Me dical hist or y, i n cl u di n g gr o wt h hist or y a n d A C H- relat e d hist or y 
•  Ge netic testi n g (if nee de d)  
•  P h ysical e x a mi nati o n  
•  Ta n ner Sta ge of P u bertal De vel o p me nt  
•  Wei g ht  
•  Vital s i g ns ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  El b o w j oi nt ra n ge of m oti o n 
•  Baseli ne hi p assess me nt , i ncl u di n g A P x-ra y of pel vis 
•  Slee p a p nea assess me nts  
•  E C G  
•  E C H O  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  T h yr oi d f u ncti o n tests 
•  Ser u m gl uc os e le vels  
•  Vita mi n D  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  P D B M N 1 1 1 acti vit y bi o mar kers ( N T pr o C N P o nl y [ plas ma]) 
•  P D B o ne a n d c olla ge n bi o mar kers (all) 
•  Q C T of f orear m a n d ti bia 
•  B o ne a ge x- ra y (P A  of h a n d a n d wrist)  
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pr ot oc ol. p df
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Pa ge 8 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  A P l o wer e xtre mit y ra di o gr a p h  
•  Lat eral l u m bar s pi n e x -ra y 
•  A P x-ra y of s pi ne 
•  C o nc o mita nt me dicati o ns  
•  A d verse e ve nts  
1 1. 2  
Tre at me nt Visits  
1 1. 2. 1  D a y 1 ( n o visit wi n d o w) 
•  P h ysical e x a mi nati o n  
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  Wei g ht  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mis tr y 
•  P D B M N  1 1 1 acti vit y bi o mar kers  (all e x ce pt N T pr o C N P ) 
•  P D B o ne a n d c olla ge n bi o mar kers (all e x ce pt oste ocalci n ) 
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nts 
•  P K  (f ull) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 2  D a ys 2 a n d 3, ( n o visit wi n d o w)  
•  P h ysical e x a mi nati o n  
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  Wei g ht  
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
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Pa ge 8 8 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 1. 2. 3  D a y 4 ( n o visit wi n d o w) 
•  P h ysical e x a mi nat i o n 
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate)  
•  Wei g ht  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 4  D a y 1 0 (
 ±  1 D a y) 
•  P h ysical e x a mi nat i o n 
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate)  
•  Wei g ht  
•  E C G  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  P D B M N  1 1 1 acti vit y bi o mar kers (c G M P a n d A N P) 
•  P D B o ne a n d c olla ge n bi o mar ker ( B S A P o nl y) 
•  A nti - B M N 1 1 1 i m m un o ge nicit y assess me nts  
•  P K  (f ull) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 5  D a y 1 5 (
 ±  1 D a y ) 
•  P h ysical e x a mi nati o n  
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  Wei g ht  
•  Cli nical la bs ( he mat o l o g y, c h e mistr y, a n d uri nal ysis)  
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pr ot oc ol. p df
Pa ge 8 9

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 8 9 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  Uri ne c he mistr y  
•  P D B M N  1 1 1 acti vit y bi o mar kers (c G M P o nl y) 
•  P D B o ne a n d c olla ge n bi o mar kers ( all e x ce pt oste ocalci n ) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 6  D a y 2 2 (
 ±  1 D a y) 
•  P h ysical e x a mi nati o n  
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  Wei g ht  
•  Uri ne c he mistr y  
•  P D B o ne a n d c olla ge n bi o mar ker ( C T X-II uri ne  o nl y) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 7  D a y 2 9 (
 ±  1 D a y ) 
•  P h ysical e x a mi nati o n  
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  Wei g ht  
•  E C G  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  P D B M N  1 1 1 acti vit y bi o mar kers  (all) 
•  P D B o ne a n d c olla ge n bi o mar kers ( all e x ce pt oste ocalci n ) 
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nt(s) 
•  P K  (f ull) 
•  C o nc o mita nt me dicati o ns  
-
pr ot oc ol. p df
Pa ge 9 0

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 0 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 8  D a y 4 3 (
 ±  7 D a y s) 
•  P h ysical e x a mi nati o n  
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d   
•  El b o w j oi nt ra n ge of m oti o n 
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  P D B M N  1 1 1 acti vit y bi o mar ker ( c G M P  a n d N T pr o C N P o nl y) 
•  P D B o ne a n d c olla ge n bi o mar kers ( all e x ce pt oste ocalci n ) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 9  D a y 8 5 (
 ±  7 D a y s) 
•  P h ysical e x a mi nati o n  
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  El b o w j oi nt ra n ge of m oti o n 
•  Slee p a p nea assess me nts  
•  E C G  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
-
pr ot oc ol. p df
Pa ge 9 1

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 1 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  Uri ne c he mistr y  
•  P D B M N  1 1 1 acti vit y bi o mar kers ( c G M P o nl y) 
•  P D B o ne a n d c olla ge n bi o mar kers ( all e x ce pt oste ocalci n ) 
•  A nti - B M N 1 1 1 i mm u n o ge nicit y assess me nt(s)  
•  P K  (f ull) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 9. 1  
D a y 1 2 7 (
 ±  7 D a y s) 
•  P h ysical e x a mi nati o n  
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  El b o w j oi nt ra n ge of m oti o n 
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  P D B M N  1 1 1 acti vit y bi o mar kers  (all) 
•  P D B o ne a n d c olla ge n bi o mar kers ( all e x ce pt oste ocalci n ) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 2. 9. 2  
D a y 1 8 3 M o nt h 6  ( ±  7 D a y s) 
•  I nf or me d c o ns e nt f or o pti o nal, o pe n-la bel e xte nsi o n p hase 
•  P h ysical e x a mi nati o n  
•  Ta n ner Sta ge of P u bertal De vel o p me nt  
-
pr ot oc ol. p df
Pa ge 9 2

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 2 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital s i g ns ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  Hi p m o nit ori n g 
•  Slee p a p nea assess me nts  
•  E C G  
•  E C H O  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mi str y 
•  T h yr oi d f u ncti o n tests 
•  Ser u m gl uc os e le vels  
•  Vita mi n D  
•  P D B M N  1 1 1 acti vit y bi o mar kers  (all e x ce pt A N P ) 
•  P D B o ne a n d c olla ge n bi o mar kers (all) 
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nt(s) 
•  P K  (f ull) 
•  Q C T of f orear m a n d ti bia 
•  B o ne a ge x- ra y (P A  of h a n d a n d wrist) 
•  A P l o wer e xtre mit y ra di o gr a p h   
•  Lat eral l u m bar s pi n e x -ra y 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
-
pr ot oc ol. p df
Pa ge 9 3

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 3 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 1. 3  
S af et y F oll o w- U p Visits  
1 1. 3. 1  D a y 2 0 8 ( ±
 7 D a ys) 
•  P h ysical e x a mi nati o n  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe m ale s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P , res pirat or y rate) 
•  El b o w j oi nt ra n ge of m oti o n 
•  E C G  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nts  
•  C o nc o mita nt me dicati o ns  
•  A d verse e ve nts  
1 1. 3. 2  E arl y Ter mi n ati o n ( 6-M o nt h I niti al P h ase)  
•  P h ysical e x a mi nati o n  
•  Ta n ner Sta ge  of P u bertal De vel o p me nt 
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts ( o nl y if t he s u bject disc o nti n ues after D a y 4 3) 
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  Hi p m o nit ori n g 
•  Slee p a p nea assess me nts   
•  E C G  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri na l ysis) 
•  Uri ne c he mistr y  
•  Vita mi n D  
•  P D B M N  1 1 1 acti vit y bi o mar kers ( N T pr o C N P o nl y) 
-
pr ot oc ol. p df
Pa ge 9 4

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 4 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  P D B o ne a n d c olla ge n bi o mar kers ( all) 
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nts 
•  B o ne a ge x-ra y ( P A of h a n d a n d wrist) ( o bt ai ne d o nl y if t he s u bject disc o nti n ues after 
Da y 6 0) 
•  A P l o wer e xtre mit y ra di o gra p h ( o btai ne d o nl y if t h e s u bject disc o nti n ues aft er 
Da y  6 0) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 4  
O pti o n al, O pe n- l a bel E xte nsi o n Visits 
T he o pti o nal, o pe n- la b el e xtensi o n p hase of t he st u d y will r u n t hr o u g h M o nt h 2 5.  H o we ver, 
t he M o nt h 2 5 Safet y visit will be wai ve d if a s u bject e nr olls i n t he 1 1 1- 2 0 5 e xte nsi o n st u d y at 
t he M o nt h 2 4/ St u d y C o m pleti o n Visit. 
1 1. 4. 1  M o nt h 8  ( ±  7 d a ys) 
•  P h ysical e x a mi nati o n  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  E C G  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nts  
•  P D b o ne a n d c olla ge n bi o mar kers (all e x ce pt oste ocalci n)  
•  P K  ( partial) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
-
pr ot oc ol. p df
Pa ge 9 5

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 5 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  A d verse e ve nts  
1 1. 4. 2  M o nt h s 1 0 (  ±  7 d a ys), 1 5  ( ±  1 4 d a ys), a n d 2 1 (  ±  1 4 d a ys) 
•  P h ysical e x a mi nati o n  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  E C G  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nt(s)  
•  P D b o ne a n d c olla ge n bi o mar kers ( all e x ce pt oste ocalci n ) 
•  P K  ( partial) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 4. 3  M o nt h 1 2 (
 ±  7 d a ys) 
•  P h ysical e x a mi nati o n  
•  Ta n ner Sta ge  of P u bertal De vel o p me nt 
•  Pre g n a nc y tes t ( uri ne or s er u m) f or fe male s u bj ects w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  Hi p m o nit ori n g 
•  Slee p a p nea assess me nts  
-
pr ot oc ol. p df
Pa ge 9 6

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 6 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  E C G  
•  E C H O  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mi str y 
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nt (s) 
•  P D B M N 1 1 1 acti vit y bi o mar kers (all ) 
•  P D b o ne a n d c olla ge n bi o mar kers ( all) 
•  P K  (f ull) 
•  Q C T of f orear m a n d ti bia 
•  B o ne a ge x- ra y (P A  of h a n d a n d wrist)  
•  A P l o wer e xtre mit y ra di o gr a p h  
•  C o nc o mita nt me dicati o ns  
•  St u d y d r u g a d mi nistrati o n 
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 4. 4  M o nt h 1 8 (
 ±  1 4 d a ys) 
•  P h ysical e x a mi nati o n  
•  Ta n ner Sta ge  of P u bertal De vel o p me nt 
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d  
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  Hi p m o nit ori n g 
•  E C G  
•  E C H O  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
-
pr ot oc ol. p df
Pa ge 9 7

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nt(s)  
•  P D B M N 1 1 1 acti vit y bi o mar kers (c G M P o nl y) 
•  P D b o ne a n d c olla ge n bi o mar kers (all e x ce pt oste ocalci n)  
•  P K  ( partial) 
•  B o ne a ge x- ra y (P A  of h a n d a n d wrist)  
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d ver se e ve nts 
1 1. 4. 5  M o nt h 2 4 / St u d y C o m pleti o n Visit ( ±  1 4 d a ys) 
•  P h ysical e x a mi nati o n  
•  Ta n ner Sta ge  of P u bertal De vel o p me nt 
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  Hi p m o nit ori n g 
•  Slee p a p nea assess me nts  
•  E C G  
•  E C H O  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mi str y 
•  T h yr oi d f u ncti o n tests 
•  Vita mi n D  
•  A nti - B M N 1 1 1 i m m u n o ge nicit y 
•  P D B M N 1 1 1 acti vit y bi o mar kers ( all) 
•  P D b o ne a n d c olla ge n bi o mar kers (all) 
-
pr ot oc ol. p df
Pa ge 9 8

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 8 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  P K  (f ull) 
•  Q C T of f orear m a n d ti bia 
•  B o ne a ge x- ra y (P A  of h a n d a n d wrist) 
•  A P l o wer e xtre mit y ra di o gr a p h  
•  Lat eral l u m bar s pi n e x -ra y  
•  A P  x-ra y of s pi ne 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g a d mi nistrati o n  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 5  
S af et y F oll o w- U p Visits  
1 1. 5. 1  M o nt h 2 5 (
 ±  7 d a ys) 
•  P h ysical e x a mi nati o n  
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d 
•  Vital si g ns  ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate) 
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis)  
•  Uri ne c he mistr y  
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nt(s)  
•  C o nc o mita nt me dicati o ns  
•  A d verse e ve nts  
1 1. 5. 2  E arl y Ter mi n ati o n ( O pti o n al, O pe n-L a bel E xte nsi o n P h ase)  
•  P h ysical e x a mi nati o n  
•  Ta n ner Sta ge  of P u bertal De vel o p me nt 
•  Pre g n a nc y test ( uri ne or s er u m) f or fe male s u bj ects  w h o ha ve be g u n m e nses or 
are  ≥ 1 0 years ol d  
-
pr ot oc ol. p df
Pa ge 9 9

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 9 9 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate)  
•  A nt hr o p o metric meas ure me nts  
•  Wei g ht  
•  El b o w j oi nt ra n ge of m oti o n 
•  Hi p m o nit ori n g 
•  Slee p a p nea assess me nts ( o nl y if s u bject disc o nti n ues after 1 8 m o nt hs) 
•  E C G  
•  E C H O  
•  Cli nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis) 
•  Uri ne c he mistr y  
•  Vita mi n D  
•  A nti - B M N 1 1 1 i m m u n o ge nicit y assess me nt(s) 
•  P D B M N 1 1 1 acti vit y bi o mar kers ( N T pr o C N P o nl y) 
•  P D b o ne a n d c olla ge n bi o mar kers (all) 
•  Q C T of f orear m a n d ti bia ( o nl y if t he pre vi o us ass ess me nt was d o ne m ore t ha n 
6 0 da ys pri or t o earl y t er mi nati o n) 
•  B o ne a ge x-ra y ( P A of h a n d a n d wrist) ( o nl y if t h e pre vi o us assess me nt w as d o ne 
m ore t ha n 6 0 da ys pri or t o earl y ter mi nati o n) 
•  A P l o wer e xtre mit y ra di o gr a p h ( o nl y if t he pre vi o us assess me nt was d o ne m ore t ha n 
6 0 da y s pri or t o earl y t er mi nati o n) 
•  Lat eral l u m bar s pi n e x -ra y ( o nl y if t he s u bject disc o nti n ues after 1 8 m o nt hs) 
•  A P x -ra y of s pi ne ( o nl y if t he s u bject disc o nti n ues after 1 8 m o nt hs) 
•  C o nc o mita nt me dicati o ns  
•  St u d y dr u g acc o u nta bilit y  
•  A d verse e ve nts  
1 1. 6  
D ose A dj ust me n t Visits  
See  Ta ble  9. 1 0. 2. 1. 1.  F ull P K is t o be c o n d ucte d o n t he Da y 1 tra nsiti o n t o ne xt hi g her d ose 
per Ta ble  9. 1 0. 2. 1. 1. 
-
pr ot oc ol. p df
Pa ge 1 0 0

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 0 0 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
1 1. 6. 1  If t he Ne xt Sc he d ule d Visit  is ≤ 4 Wee ks A w a y, D ose A dj ust me nt T a kes Pl ace at 
t he Ne xt Sc he d ule d Visit  
T he pr oce d ures b el o w ar e d o ne at a dj ust me nt visits.  If t he a dj ust me nt visit ha p pe ns at a 
re g ularl y sc h e d ule d visit, c o n d uct t he re m ai ni n g s c he d ule d visit pr oce d ures as well. 
•  P h ysical e x a m  
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate)  
•  W ei g ht 
•  A nt hr o p o metr y 
•  E C G 
•  C li nical la bs 
•  U ri ne c he mistr y 
•  F ull P K  
•  C o nc o m ita nt me ds  
•  D r u g a d mi nistrati o n 
•  Dr u g acc o u nta bilit y 
•  A d verse e ve nts  
1 1. 6. 2  If t he Ne xt Sc he d ule d Visit is  >  4 Wee ks A w a y, D ose A dj ust me nt T a kes Pl ace at 
a n U nsc he d ule d Visit Wit hi n 4 Wee ks F r o m D M C Decisi o n T o D ose A dj ust  
•  P h ysical e x a m  
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate)  
•  A nt hr o p o metr y 
•  W ei g ht 
•  E C G 
•  C li nical la bs ( he mat ol o g y, c h e mistr y, a n d uri nal ysis) 
•  U ri ne c he mistr y 
•  P K (f ull) 
•  C o nc o m ita nt me ds  
•  D r u g a d mi nistrati o n 
•  Dr u g acc o u nta bilit y 
-
pr ot oc ol. p df
Pa ge 1 0 1

 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 0 1 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  A d verse e ve nt s 
1 1. 7  
7- 1 0 D a y P ost- d ose A dj ust me nt  
• 
P h o ne call  
1 1. 8  
4 Wee ks P ost D ose A dj ust me nt F oll o w -u p Visit Assess me nts  ( ±  2 w ee ks)  
If a r e g ular or u ns c he d ul e d visit occ urs wit hi n t he ± 2-wee k visit wi n d o w, f oll o w- u p visit ca n 
be wai ve d.   T h e pr oce d ur es bel o w are d o ne at a dj ust me nt f oll o w- u p visits.  If t he a dj ust me nt 
f oll o w- u p visit ha p pe ns at a re g ularl y sc h e d ule d visit, c o n d uct t he re mai ni n g sc h e d ule d visit 
pr oce d ur es as w ell.  
•  P h ysical e x a m  
•  Vital si g ns ( b o d y te m per at ure, heart rat e, B P, res pirat or y rate)   
•  W ei g ht 
•  Cli nical la bs  
•  E C G 
•  C o nc o m ita nt me ds  
•  D r u g a d mi nistrati o n 
•  Dr u g acc o u nta bilit y 
•  A d verse e ve nts  
 
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1 2  
D A T A Q U A LI T Y A S S U R A N C E  
Bi o Mari n pers o n nel or d esi g nees will visit t he st u d y site pri or t o i nitiati o n of t he st u d y t o 
re vie w wit h t he site pers o n nel i nf or mati o n a b o ut t he I P, pr ot oc ol a n d ot her re g ulat or y 
d oc u me nt re q uir e me nts, a n y a p plica ble ra n d o mizati o n pr oce d ures, s o urce d oc u me nt 
re q uire me nts, C R Fs, m o nit ori n g re q uire me nts, a n d pr oce d ures f or re p orti n g A Es, i ncl u di n g 
S A Es.  
At visits d uri n g a n d aft er t he st u d y, a C R A will m o nit or t he site f or c o m plia nce wit h 
re g ulat or y d oc u m e ntati o n, wit h a f oc us o n acc urate a n d c o m plete rec or di n g of d ata o n C R Fs 
fr o m s o urce d o c u me nts, a d here n ce t o pr ot o c ol, ra n d o mizati o n (if a p plica ble), S A E re p orti n g 
a n d dr u g acc o u nta bilit y r ec or ds.  
Data q ualit y c o ntr ol a n d a nal ysis will be p erf or m e d b y Bi o Mari n or a desi g nee, base d o n a 
pre defi n e d a nal ysis pla n.  
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1 3  
S T A TI S TI C A L M E T H O D S A N D D E T E R MI N A TI O N O F  S A M P L E SI Z E  
1 3. 1  
St atistic al a n d A n al ytic al Pl a ns  
T he statistical a nal ysis pla n ( S A P) will pr o vi de a d diti o nal details o n t he pla n ne d statistical 
a nal ysis. U nl ess ot her wis e state d, all a nal ys es will be perf or me d usi n g S A S.  
1 3. 1. 1  I nteri m A n al yses 
N o f or mal  i nteri m a nal ys es f or efficac y are pla n n e d f or t his st u d y.  H o w e ver, efficac y d ata 
fr o m t he first t hree c o h orts ma y  be e val uate d t o i nf or m i nter nal decisi o n-ma ki n g re gar d i n g 
C o h ort 4.  E fficac y d ata ma y  als o be use d t o i nf or m t he decisi o n t o i ncreas e a c o h ort d os e if 
t he initial d ose e x hi bit s s u b o pti mal efficac y.  T o a d dress o bjecti ves of t he st u d y, f or m al 
a nal ys es will be perf or m e d w he n all s u bjects h a ve c o m plete d t he i nitial 6- m o nt h p hase a n d 
w he n all a vaila ble s u bjects ha ve c o m plete d t he e xte nsi o n p hase. A d diti o nal e x pl orat or y 
a nal ys es ma y be p erf or me d i n t he e xte nsi o n p hase. 
1 3. 1. 2  Pr o ce d ures f or A cc o u nti n g f or Missi n g, U n use d a n d S p uri o us D at a  
N o i m p utati o n of missi n g dat a is pla n ne d f or t his st u d y.   
1 3. 2  
Effic ac y A n al ysis 
Efficac y a nal ysis will be carri e d o ut f or t he i nitial 6 - m o nt h peri o d a n d t he e xte nsi o n peri o d. 
F or eac h of t h e t w o peri o ds, all s u bjects w h o recei ve at least o ne d os e of st u d y treat me nt a n d 
w h o ha ve p ost- tr eat me nt data i n t he c orres p o n di n g peri o d f or a n y effi cac y e n d p oi nt will be 
i ncl u de d i n t he effi cac y a nal ysis f or t h at e n d p oi nt.  T he baseli ne of t h e gr o wt h vel ocit y is 
esta blis he d i n t he nat ural hist or y st u d y of B M N 1 1 1- 9 0 1, base d o n t he sta n di n g hei g ht 
meas ure me nts i n t he last 6 m o nt hs pri or t o e nr oll me nt t o B M N  1 1 1- 2 0 2. T he baseli ne f or 
ot her effi cac y e n d p oi nts is defi ne d as t he last n o n- missi n g assess me nt pri or t o t he first d ose. 
A n n ualize d g r o wt h vel ocit y, base d o n sta n di n g h ei g ht meas ures at e v er y 6- m o nt h ti me p oi nt, 
will be s u m marize d usi n g des cri pti ve statistics ( mea n, S D, me dia n, mi ni m u m, a n d 
ma xi m u m). T he test of h y p ot hesis of n o c ha n ge fr o m t he baseli ne i n a n n ualize d gr o wt h 
vel ocit y will be c o n d ucte d via paire d t- test f or t he i nitial 6- m o nt h peri o d a n d p-val ue will be 
c o nsi dere d d escri pti ve.  C ha n ge i n b o d y pr o p orti o n rati os ( u p per ar m t o f orear m le n gt h rati o, 
u p per le g t o l o wer l e g le n gt h rati o, a n d u p p er t o l o wer b o d y se g me nt rati o ) fr o m baseli ne t o 
eac h sc h e d ule d ti me p oi nt will be si milarl y s u m marize d a n d teste d  at t he i nitial 6-m o nt h ti me 
p oi nt.  T he meas ure me nt of hei g ht will be c o n vert e d t o a ge- a n d se x -a p pr o priate sta n dar d 
sc ore ( SD S) , als o r ef err e d t o as Z-s c ore, b y c o m p aris o n wit h n or mal refere nce sta n dar ds ( n ot 
A C H). T he Z -s c ore will be s u m marize d si milarl y t o gr o wt h v el ocit y.  Res ults will be 
s u m marize d b y d ose c o h ort a n d f or all c o h orts c o m bi ne d. 
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Ot her a nt hr o p o metri c meas ures (sitti n g h ei g ht, w ei g ht, hea d circ u mfere n ce, u p per a n d l o w er 
ar m a n d le g, ha n d a n d f o ot, etc. ) will be s u m marize d at eac h ti me p oi nt a n d will be e val uate d 
f or c ha n ges fr o m b aseli ne.   
1 3. 3  
P h ar m a c o ki netic A n al yses  
P K para meters will be s u m marize d usi n g descri pti ve statistics. Res ults will be s u m marize d 
b y d ose c o h ort. 
1 3. 3. 1  E x pl or at or y A n al yses 
E x pl orat or y a nal ys es will be carrie d o ut f or t h e i nitial 6 - m o nt h peri o d a n d t h e e xte nsi o n 
peri o d, res pecti vel y. 
1 3. 3. 1. 1  
Bi o m ar ker A n al ysis 
Bi o mar kers i ncl u de, b ut are n ot li mite d t o, as sess me nt f or cartila ge t ur n o v er ( C T X-II), 
c h o n dr oc yte a n d oste o blast acti vit y ( B S A P), b o ne f or mati o n ( P 1 N P), oste o calci n; a n d 
mar kers of B M N  1 1 1 bi o acti vit y (c G M P, N T- pr o C N P, a n d A N P).  T hese bi o mar ker 
meas ures will be s u m marize d b y c ha n ge fr o m b aseli ne b y  st u d y ti me p oi nt.  Res ults will be 
s u m marize d b y d ose c o h ort.  A d diti o nall y, t he bi o mar kers ma y b e assess e d f or t he 
c orrel ati o ns wit h cli nical o utc o mes.  
1 3. 3. 1. 2  
Slee p A p ne a A n al ysis  
T he n u merical varia bles of slee p a p n ea a n al ysis will be s u m marize d usi n g descri pti ve 
statistics ( mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m) a n d t he cate g orical varia bles will be 
s u m marize d b y n u m ber a n d perce nt a ge of s u bjects. 
1 3. 3. 1. 3  
I m a gi n g Assess me nt A n al ysis 
C ha n ges fr o m bas eli ne t o e n d of st u d y i n meas ures of verte bral hei g ht i ma gi n g ass ess m e nt of 
t he l u m bar s pi ne, Q C T of t he f orear m a n d ti bia will be s u m marize d usi n g descri pti ve 
statistics ( mea n, S D, me dia n, mi ni m u m, a n d ma xi m u m) a n d will be teste d via paire d t-test.  
T he p - val ue will be c o nsi dere d des cri pti ve.  C ha n ges fr o m baseli ne i n b o n e de nsit y a n d b o n e 
q ualit y will be si milarl y s u m marize d a n d teste d. Res ults will be s u m marize d b y d ose c o h ort .   
1 3. 3. 1. 4  
I m m u n o ge nicit y A n al ysis 
I m m u n o ge nicit y will be s u m marize d b y c h a n ge fr o m baseli ne as well as b y st u d y ti me p oi nt. 
Res ults will be s u m marize d b y d os e c o h ort a n d f or all c o h orts c o m bi ne d. A d diti o nall y, 
i m m u n o ge nicit y ma y be assesse d f or c orrelati o ns wit h meas ures of s afet y , P K, a n d efficac y.  
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1 3. 3. 1. 5  
El b o w J oi nt R a n ge of M oti o n 
T he val ue a n d c ha n ge fr o m baseli ne i n t he el b o w j oi nt ra n ge of m oti o n t o eac h sc he d ul e d 
ti me p oi nt will be s u m marize d usi n g descri pti ve statistics ( mea n, S D, me dia n, mi ni m u m, a n d 
ma xi m u m). Res ults will be s u m marize d b y d ose c o h ort.  
1 3. 4  
S af et y A n al ysis 
Safet y a nal ysis will be carrie d o ut f or t he i nitial 6 m o nt hs peri o d a n d t he e xte nsi o n peri o d, 
res pecti vel y. F or eac h of t he t w o peri o ds, all s u bjects w h o recei ve at least o ne d ose of st u d y 
treat me nt i n t his st u d y a n d ha ve a n y p ost-treat me nt safet y i nf or mati o n i n t he c orres p o n di n g 
peri o d will be i ncl u de d i n t he safet y a n al ysis.  T h e safet y a nal y sis will be descri pti ve a n d will 
be s u m marize d b y d ose c o h ort a n d all c o h orts c o m bi ne d. 
All A Es will be c o de d usi n g t he c urre nt v ersi o n of Me d D R A t o assi g n s yste m or ga n class 
a n d preferr e d ter m cl assificati o n t o e ve nt a n d disease, base d o n t h e ori gi nal ter ms e ntere d o n 
t he C R F.  T he i nci de nce of A Es will be s u m marize d b y s yste m or ga n class, preferre d t er m, 
relati o ns hi p t o st u d y treat me nt, a n d se verit y. All A Es, i ncl u di n g S A Es a n d A Es t hat lea d t o 
per ma ne nt disc o nti n uati o n fr o m t he st u d y a n d fr o m t he st u d y t reat me nt, will be liste d. 
All ot her safet y meas ures i ncl u di n g la b orat or y tests, vital si g ns,  E C G , a n d c o nc o mita nt 
me dicati o n data will als o be s u m marize d descri pti vel y. La b orat or y t ests will als o be 
s u m marize d b y a bs ol ute a n d perce nt c ha n ge fr o m baseli ne a n d liste d f or eac h d ose c o h ort 
a n d f or all c o h orts c o m bi ne d.  Vital si g ns, E C G a n d E C H O res ults will als o be liste d.   T he 
baseli ne f or la b orat or y tests a n d E C G is defi ne d as t he last n o n- missi n g ass ess me nt pri or t o 
t he first d ose. 
1 3. 5  
Deter mi n ati o n of S a m ple S ize 
A p pr o xi matel y 3 6 p e diatric s u bjects  wit h A C H will partici pate i n t his st u d y.  N o f or mal 
sa m ple size calc ulati o ns were p erf or me d.  
1 3. 6  
A n al ysis P o p ul ati o ns 
T he f oll o wi n g p o p ul ati o ns will be defi ne d f or t h e i nitial 6- m o nt h peri o d a n d t he e xte nsi o n 
peri o d, re s pecti vel y. 
S af et y A n al ysis:  F or eac h of i nitial 6- m o nt h peri o d a n d t he e xte nsi o n peri o d, all s u bjects 
w h o recei ve at least o ne d ose of st u d y treat me nt i n t his st u d y a n d ha ve a n y p ost treat me nt 
safet y i nf or mati o n i n t he c orres p o n di n g peri o d will be i ncl u d e d i n t he safet y a nal ysis.   
Effic ac y A n al ysis:  F or eac h of i nitial 6- m o nt h peri o d a n d t he e xte nsi o n peri o d, all s u bjects 
w h o recei ve at least o ne d ose of st u d y treat me nt a n d w h o ha ve p ost treat me nt data f or a n y 
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efficac y e n d p oi nt i n t he c orres p o n di n g peri o d will be i ncl u de d i n t he efficac y a n al ysis f or t hat 
e n d p oi nt. 
P K A n al ysis:  F or eac h of i nitial 6 - m o nt h peri o d a n d t he e xte nsi o n peri o d, all s u bjects w h o 
recei v e at least o ne d os e of st u d y treat me nt i n t his st u d y a n d h a ve a n y p ost-treat me nt P K 
i nf or mati on i n t he c orr es p o n di n g peri o d will be i ncl u de d i n t he a nal ysis. 
I m a gi n g Assess me nt A n al ysis:  F or eac h of i nitial 6 - m o nt h peri o d a n d t he e xte nsi o n peri o d, 
all s u bjects w h o recei ve at least o ne d ose of st u d y treat me nt a n d w h o h a ve p ost- treat me nt 
data f or a n y i ma gi n g assess me nt e n d p oi nt i n t he c orres p o n di n g peri o d will b e i ncl u de d i n t he 
a nal ysis f or t hat e n d p oi nt. 
Bi o m ar ker A n al ysis:  F or eac h of i nitial 6 - m o nt h peri o d a n d t he e xte nsi o n peri o d, all 
s u bjects w h o recei ve at l east o ne d ose of st u d y treat me nt i n t his st u d y a n d ha ve a n y p ost-
treat me nt bi o mar ker assess me nt i n t he c orres p o n di n g peri o d will be i ncl u de d i n t he a nal ysis. 
1 3. 7  
C h a n ges i n t he C o n d uct of t he St u d y or Pl a n ne d A n al yses  
O nl y Bi o Mari n ma y m o dif y t he pr ot oc ol.  A n y c h a n ge i n st u d y c o n d uct c o nsi dere d necessar y 
b y t he I n vesti gat or will be ma de o nl y aft er c o ns ult ati o n wit h Bi o Mari n, w h o will t he n iss ue a 
f or mal pr ot oc ol a me n d m e nt t o i m ple me nt t he c ha n ge.  T h e o nl y e x ce pti o n is w he n a n 
I n v esti gat or c o nsi ders t h at a s u bject’s safet y is c o m pr o mise d wit h o ut i m me diate acti o n. I n 
t hese circ u msta n ces, i m me diate a p pr o v al of t he c hair ma n of t he I R B/ E C m ust be s o u g ht, a n d 
t he I n v esti gat or s h o ul d i nf or m Bi o Mari n a n d t he f ull I R B/ E C wit hi n 2 w or ki n g da ys after t he 
e mer ge n c y occ urs.   
Wit h t he e x ce pti o n of mi n or a d mi nistrati ve or t y p o gra p hical c h a n ges, t he I R B/ E C m ust 
re vie w a n d a p pr o v e all pr ot oc ol a me n d me nts. Pr ot oc ol a me n d me nts t hat ha ve a n i m pact o n 
s u bject ris k or t he st u d y o bjecti ves, or re q uire re visi o n of t he I C F, m ust recei ve a p pr o v al 
fr o m t he I R B/ E C pri or t o t heir i m ple me ntati o n. 
W he n a pr ot oc ol a me n d me nt s u bsta ntiall y alters t he st u d y desi g n or t he p ote ntial ris ks or 
b ur de n t o s u bjects, t he I C F will be a me n de d a n d a p pr o ve d b y Bi o Mari n a n d t he I R B/ E C, a n d 
all acti ve s u bjects  m ust a gai n pr o vi d e i nf or me d c o nse nt. 
N ote: If discr e pa nci es e xist bet wee n t he te xt of t he statistical a nal ysis as pla n ne d i n t he 
pr ot oc ol, a n d t he fi nal S A P, a pr ot oc ol a me n d me nt will n ot be iss ue d a n d t he S A P will 
pre vail.  
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1 4  
D A T A M O NI T O RI N G C O M M I T T E E 
I n a d diti o n t o safet y m o nit ori n g b y Bi o Mari n pers o n nel, a n i n de pe n d e nt D M C will act as a n 
a d vis or y b o d y t o Bi o Mari n a n d will m o nit or t he safet y a n d P K of s u bj ects i n t he st u d y.  
T he  D M C will i ncl u de i n de pe n de nt e x perts a n d k e y o pi ni o n lea d ers i n fiel ds, w hic h ma y 
i ncl u de, b ut n ot li mite d t o: A C H , natri uretic pe pti des, b o ne gr o wt h, car di ol o g y, ra di ol o g y, 
cli nical p har mac ol o g y, a n d bi ostatistics.   T he D M C will ma ke rec o m me n d ati o ns f or st o p pi n g 
or c o nti n ui n g t he st u d y o n a s u bject le vel a n d/ or o n a c o h ort le vel p er t he pre- s pecifie d 
st o p pi n g criteri a.  T he D M C ma y als o pr o vi de rec o m me n dati o ns f or d ose m o dificati o ns as 
nee de d f or eac h c o h ort.   
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1 5  
C O M P E N S A TI O N, I N S U R A N C E A N D I N D E M NI T Y  
T here will be n o m o net ar y c o m p e nsati o n pr o vi de d t o s u bjects f or t heir partici pati o n i n t his 
st u d y.  Bi o M ari n is res p o nsi ble f or all st u d y p artici pati o n e x pe nses, i ncl u di n g tests, 
pr oce d ur es, a n d tr eat me nts. I n a d diti o n, Bi o M ari n ma y rei m b urse t he c ost of tra vel f or 
st u d y-r elate d visits after E C a p pr o val. Bi o Mari n will n ot pa y f or a n y h os pitalizati o ns, tests, 
or treat me nts f o r m e dical pr o ble ms t hat are n ot part of t his pr ot oc ol re gar dless of t heir 
relati o ns hi p t o t he s u bject’s disease. C osts ass ociate d wit h h os pitalizati o ns, tests, a n d 
treat me nts s h o ul d be bille d a n d c ollecte d i n t he w a y t h at s uc h c osts w o ul d be c ust o maril y 
bi lle d a n d c ollecte d. 
T he I n vesti gat or s h o ul d c o ntact Bi o Mari n i m me di atel y u p o n n otificati o n t hat a st u d y s u bject 
has a n i nj ur y relat e d t o t he st u d y tr eat me nt or t o t h e pr oce d ures or assess me nts perf or me d as 
part of t he st u d y. A n y s u bject w h o e x perie nces a s t u d y-relate d i nj ur y s h o ul d be i nstr ucte d b y 
t he I n v esti gat or t o see k me dical treat me nt at a pre-s pecifi e d me dical i nstit uti o n (if p ossi ble) 
or at t he cl osest me dical treat me nt facilit y (if n ecessar y). T he s u bject s h o ul d be gi v e n t he 
c o ntact i nf or mati o n if t he y r e q uire f urt her i nf or mati o n a b o ut or assista nce wit h treat me nt f or 
st u d y-r elate d i nj uries. T h e treati n g p h ysicia n s h o ul d bill t he s u bject’s healt h i ns ura nce 
c o m pa n y or ot her t hir d p art y p a yer f or t he c ost of t his me dical treat me nt. If t he s u bject has 
f oll o we d t he I n vesti gat or’s i nstr ucti o ns, Bi o Mari n will pa y f or reas o na ble a n d necessar y 
me dical ser vices t o treat t he i nj uries ca use d b y t h e st u d y treat me nt or st u d y assess me nts or 
pr oce d ur es if t hese c osts are n ot c o v ere d b y h ealt h i ns ura nce or a n ot her t hir d part y t h at 
c ust o maril y w o ul d p a y t hese c osts. I n s o me j uris di cti o ns, Bi o Mari n is o bli gate d b y la w t o 
pa y f or st u d y- r elate d i nj uries wit h o ut pri or rec o urs e t o t hir d part y pa yer billi n g. If t his is t he 
case, Bi o Mari n will c o m pl y.  
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1 6  
C A S E R E P O R T F O R M S A N D S O U R C E D O C U M E N T S  
Electr o nic C R Fs will be pr o vi de d f or eac h s u bject. T he I n vesti gat or m ust re vie w a n d 
electr o nicall y si g n t he c o m plete d C R F case b o o k t o verif y its acc urac y.  
C R Fs m ust be c o m plete d usi n g a w e b – base d a p plicati o n t hat has bee n d e vel o pe d f or t he 
st u d y a n d h as bee n v ali date d. St u d y site pers o n nel or desi g n ee will be trai n e d o n t he 
a p plicati o n a n d will e nter t he cli nical data fr o m s o urce d oc u m e ntati o n. U nless e x plicitl y 
all o we d i n t he C R F i nstr ucti o ns, bla n k data fiel ds are n ot acce pt a ble.  
I n t he e ve nt of a n e ntr y err or or if n e w i nf or m ati o n bec o mes a v aila ble, t he val ue will be 
c orrecte d b y des electi n g t he err o n e o us res p o nse a n d t he n selecti n g or e nt eri n g t he fact ual 
res p o nse. I n c o m plia nce wit h 2 1 C F R Part 1 1, t he s yste m will re q uire t he p ers o n nel ma ki n g 
t he c orr ecti o n t o e nter a r eas o n f or c ha n gi n g t he v al ue. T he d oc u m e nte d a u dit trail will 
i ncl u de t he reas o n f or t he c ha n ge, t he ori gi n al val u e, t he ne w v al ue, t he ti me of t he 
c orrecti o n, a n d t he i de ntit y of t he o p erat or. 
Bi o Mari n P har mace utical p olic y is t hat st u d y d ata o n t he C R Fs m ust be verifia ble t o t he 
s o urce dat a, w hic h necessitates access t o all ori gi n al rec or di n gs, la b orat or y re p orts, a n d 
s u bject rec or ds. I n a d diti o n, all s o urce dat a s h o ul d be attri b uta ble (si g ne d a n d date d). T he 
I n v esti gat or m ust t heref ore a gr ee t o all o w direct access t o all s o urce data. S u bjects ( or t heir 
le gall y a ut h orize d re pr es e ntati ve) m ust als o all o w access t o t heir me dical rec or ds, a n d 
s u bjects will be i nf or me d of t his a n d will c o nfir m t heir a gree me nt w h e n gi vi n g i nf orm e d 
c o nse nt.  
A C R A desi g nat e d b y Bi o Mari n will c o m pare t he C R Fs wit h t he ori gi nal s o urce d oc u m e nts 
at t he st u d y site a n d will e val uate t he m f or c o m plete ness a n d acc urac y bef ore desi g nati n g 
t he m as “ S o urce Data V erifie d” ( S D V). If a n err or is disc o vere d at a n y ti me or a clarificati o n 
is nee de d, t he C R A ( or d esi g nee) will create a n el ectr o nic q uer y o n t he ass ociate d fiel d. Site 
pers o n nel will t he n a ns w er t he q uer y b y eit her c orrecti n g t he data or res p o n di n g t o t he q uer y. 
T he C R A will t he n re vie w t he res p o nse a n d deter mi ne eit her t o cl ose t he q uer y or re – q uer y 
t he site if t he res p o nse d o es n ot f ull y a d dress t he q uesti o n. T his pr ocess is re peate d u ntil all 
o pe n q ueries h a ve bee n a ns were d a n d cl ose d.  
Bef ore a C R F cas e b o o k ca n be l oc ke d, d ata fiel ds m ust be s o ur ce data v erifie d a n d q ueries 
cl ose d. Refer t o t he St u d y M o nit ori n g Pla n f or det ails o n w hic h fiel ds m ust be s o urce d ata 
verifie d.  T he I n vesti gat or will t he n electr o nicall y si g n t he case b o o k, s pecif yi n g t hat t he 
i nf or mati o n o n t he C R Fs is acc ur ate a n d c o m plete. T he Data M a na ger ( or d esi g nee) will t he n 
set t he stat us of t he f or ms, visits, a n d t he e ntire case b o o k t o L o c ke d. U p o n c o m pleti o n of t he 
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Pr o prietar y a n d C o nfi de ntial 
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C S R, a n electr o nic c o p y of eac h site’s cas e b o o ks will be c o pie d t o a c o m p act dis k ( C D) a n d 
will be se nt t o eac h si te f or rete nti o n wit h ot her st u d y d oc u m e nts. 
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Pr o prietar y a n d C o nfi de ntial 
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1 7  
S T U D Y M O NI T O RI N G A N D  A U DI TI N G  
Q ualifie d i n di vi d uals desi g nate d b y Bi o Mari n will m o nit or all as pects of t h e st u d y acc or di n g 
t o G C P a n d sta n dar d o perati n g pr oce d ures f or c o m plia nce wit h a p plica ble g o ver n me nt 
re g ulati o ns. T he I n v esti gat or a gr ees t o all o w t hese m o nit ors direct access t o t he cli nical 
s u p plies, dis pe nsi n g, a n d st ora ge areas a n d t o t he cli nical files, i ncl u di n g ori gi nal me dical 
rec or ds, of t he st u d y s u bjects, a n d, if re q ueste d, a grees t o assist t he m o nit ors. T he 
I n v esti gat or a n d staff ar e res p o nsi ble f or b ei n g prese nt or a vaila ble f or c o ns ultati o n d uri n g 
r o uti nel y sc h e d ule d site visits c o n d ucte d b y Bi o Mari n or its desi g n ees. 
Me m bers of Bi o Mari n P har mace utical  G C P C o m plia nce De p art me nt or d esi g nees m a y 
c on d uct a n a u dit of a cli nical site at a n y ti me bef ore, d uri n g, or after c o m pleti o n of t he st u d y. 
T he I n vesti gat or will be i nf or me d if a n a u dit is t o ta ke place a n d a d vise d as t o t he sc o pe of 
t he a u dit. Re prese ntati ves of t he F D A or ot her Re g ulat or y A ge ncies m a y als o c o n d uct a n 
a u dit of t he st u d y. If i nf or me d of s uc h a n i ns pecti o n, t he I n vesti gat or s h o ul d n otif y Bi o Mari n 
i m me diatel y. T he I n vesti gat or will e ns ure t hat t he a u dit ors ha ve access t o t he cli nical 
s u p plies, st u d y site facilities, ori gi nal s o urce d o c u me ntati o n, a n d all st u d y files. 
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1 8  
R E T E N TI O N O F R E C O R D S  
T he I n vesti gat or m ust ret ai n all st u d y rec or ds re q uire d b y Bi o Mari n a n d b y t he a p plica ble 
re g ulati o ns i n a sec ure a n d safe f acilit y. T h e I n vesti gat or m ust c o ns ult a Bi o Mari n 
re pres e ntati ve bef ore dis p osal of a n y st u d y rec or ds, a n d m ust n otif y Bi o M ari n of a n y c h a n ge 
i n t he l ocati o n, dis p ositi o n or c ust o d y of t he st u d y files. T he I n vesti gat or /i nstit uti o n m ust 
ta ke meas ur es t o pre v e nt acci de nt al or pre mat ure d estr ucti o n of esse ntial d o c u me nts, t hat is, 
d oc u me nts t hat i n di vi d uall y a n d c ollecti vel y p er mit e val uati o n of t he c o n d u ct of a st u d y a n d 
t he q ualit y of t he d ata pr o d uce d, i ncl u di n g pa per c o pies of st u d y rec or ds (e. g., s u bj ect c harts) 
as well as a n y ori gi nal s o urce d oc u m e nts t hat are electr o nic as re q uire d b y a p plica ble 
re g ulat or y r e q uire me nts.  
All st u d y rec or ds m ust be retai ne d f or at least 2 years after t he l ast a p pr o v al of a mar k eti n g 
a p plicati o n i n t he U S or a n I C H re gi o n a n d u ntil ( 1) t here are n o p e n di n g or c o nte m plate d 
mar keti n g a p plicati o ns i n t he U. S. or a n I C H re gi o n or ( 2) at least 2 years h a ve ela ps e d si nce 
t he f or mal disc o nti n uati o n of cli nical de vel o p me nt of t he I P. T he I n v esti gat or /i nstit uti o n 
s h o ul d retai n s u bject i de ntifiers f or at least 1 5 years after t h e c o m pleti o n or disc o nti n uati o n 
of t he st u d y. S u bject  files a n d ot her s o urce data m ust be ke pt f or t he ma xi m u m peri o d of ti me 
per mitte d b y t he h os pital, i nstit uti o n or pri vate practice, b ut n ot less t ha n 1 5 years. T hes e 
d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d, h o we ver, if re q uir e d b y t he a p plica ble 
re g ulat or y r e q uire me nts or b y a Bi o M ari n a gree m e nt. Bi o Mari n m ust be n otifie d a n d will 
assist wit h rete nti o n s h o ul d I n vesti gat or /i nstit uti o n be u na ble t o c o nti n ue mai nte na nce of 
s u bject files f or t he f ull 1 5 years. It is t he res p o nsi bilit y of Bi o Mari n t o i nf or m t he 
I n v esti gat or /i nstit uti o n as t o w he n t hese d oc u me nts n o l o n ger n ee d t o be retai ne d. 
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Pr o prietar y a n d C o nfi de ntial 
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1 9  
U S E O F I N F O R M A TI O N A N D P U B LI C A TI O N  
Bi o Mari n r ec o g nizes t he i m p orta nce of c o m m u nicati n g me dical st u d y d ata a n d t heref ore 
e nc o ura ges t heir p u blicati o n i n re p uta ble scie ntific j o ur nals a n d at se mi nars or c o nfere nces. 
T he details of t he pr o cess es of pr o d uci n g a n d re vie wi n g re p orts, ma n uscri pts, a n d 
prese ntati o ns base d o n t h e data fr o m t his st u d y will be descri be d i n t he Cli nical Trial 
A gree me nt b e t wee n Bi o Mari n a n d t he i nstit uti o n of t he I n vesti gat or. 
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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
2 0  
R E F E R E N C E S  
Bart els, C F, B u k ul mez, H, Pa da yatti, P, R hee, D K et. al. M utati o ns i n t he tra ns me m bra ne 
natri uretic pe pti de rece pt or N P R -B i m pair s kelet al gr o wt h a n d ca use acr o m es o melic 
d ys plasia, t y pe M ar otea u x. A m J H u m Ge net 7 5[ 1], 2 7- 3 4. 2 0 0 4. 
B occi ar di, R, Gi or da, R, B utt gereit, J, Gi melli, S et. al. O vere x pressi o n of t he C- t y p e 
natri uretic pe pti de ( C N P) is ass ociate d wit h o ver gr o wt h a n d b o ne a n o malies i n a n i n di vi d ual 
wit h bala nce d t( 2; 7) tr a nsl ocati o n. H u m M utat 2 8[ 7], 7 2 4- 7 3 1. 2 0 0 7. 
C h us h o, H, Ta m ura, N, O ga wa, Y, Yas o da, A et. al. D warfis m a n d earl y d eat h i n mice 
lac ki n g C-t y p e natri ur etic pe pti de. Pr oc N atl Aca d Sci U S A 9 8[ 7], 4 0 1 6- 4 0 2 1. 2 0 0 1. 
F ol d y n o v a- Tra ntir k o va, S, Wilc o x, W R, Krejci, P. Si xtee n years a n d c o u nti n g: t he c urre nt 
u n dersta n di n g of fi br o blast gr o wt h fact or rece pt or 3 ( F G F R 3) si g n ali n g i n s keletal 
d ys plasias. H u m M utat 3 3[ 1], 2 9- 4 1. 2 0 1 2. 
Gre ulic h W, P yle S. Ra di o gr a p hic Atlas of S kelet al De vel o p me nt of t he H a n d a n d Wrist. 2 n d 
e d. Sta nf or d: Sta nf or d U ni versit y Press, 1 9 7 1. [ T his p u blic ati o n is a b o ok a n d t heref ore is 
n ot i ncl u de d i n t he s u b missi o n.]. 
H o o ver- F o n g, J E, Sc h ulze, KJ, Mc Grea d y, J, Bar n es, H et. al. A ge-a p pr o pri ate b o d y mass 
i n de x i n c hil dre n wit h ac h o n dr o plasia: i nter pret ati o n i n relati o n t o i n de x es of hei g ht. A m J 
Cli n N utr 8 8[ 2], 3 6 4- 3 7 1. 2 0 0 8. 
H ort o n, W A, Hall, J G, Hec ht, J T. Ac h o n dr o plasia. La n cet 3 7 0[ 9 5 8 2], 1 6 2- 1 7 2. 2 0 0 7. 
Krejci, P, Masri, B, F o nt ai ne, V, Me ki kia n, P B et. al. I nt eracti o n of fi b r o bl ast gr o wt h fact or 
a n d C- natri uretic p e pti de si g nali n g i n re g ulati o n of c h o n dr oc yt e pr oliferati o n a n d 
e xtracell ular matri x h o me ostasis. J Cell Sci 1 1 8[ Pt 2 1], 5 0 8 9- 5 1 0 0. 2 0 0 5. 
L o n g, S, We n dt, D, Bell, S. A n o vel met h o d f or t he lar ge-scale pr o d ucti o n of P G - C N P 3 7, a 
C-t y pe n atri uretic p e pti de a nal o g ue. J Bi otec h n ol 1 6 2[ 2], 1 9 6- 2 0 1. 2 0 1 2. 
L or get, F, K aci, N, Pe n g, J, oist- Lasseli n, C et. al. E val uati o n of t he t hera pe utic p ote ntial of a 
C N P a nal o g i n a F gfr 3 m o use m o del reca pit ulati n g ac h o n dr o plasia. A m J H u m Ge net 9 1[ 6], 
1 1 0 8- 1 1 1 4. 2 0 1 2. 
Marc us, C L, Br o o ks, LJ, Dra per, K A, G ozal, D et. al. Dia g n osis a n d ma na ge me nt of 
c hil d h o o d o bstr ucti ve slee p a p nea s y n dr o me. Pe di atrics 1 3 0[ 3], e 7 1 4-e 7 5 5. 2 0 1 2. 
Pejc hal o va, K, Krejci, P, Wilc o x, W R. C- natri uretic pe pti de: a n  i m p orta nt re g ul at or of 
cartila ge. M ol G e net Met a b 9 2[ 3], 2 1 0- 2 1 5. 2 0 0 7. 
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pr ot oc ol. p df
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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 1 5 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
S hirle y, E D, Ai n, M C. A c h o n dr o plasia: ma nifest ati o ns a n d treat me nt. J A m Aca d Ort h o p 
S ur g 1 7[ 4], 2 3 1- 2 4 1. 2 0 0 9. 
Sta m o ya n n o u, L, K arac h ali o u, F, Ne o u, P, Pa pata xiarc h o u, K et. al. Gr o wt h a n d gr o wt h 
h or m o ne t hera p y i n c hil dre n wit h ac h o n dr o plasia: a t w o- year e x perie nce. A m J Me d Ge net 
7 2[ 1], 7 1- 7 6. 1 9 9 7. 
Ta na ka, H, K u b o, T, Ya mate, T, O n o, T et. al. Effect of gr o wt h h or m o ne t hera p y i n c hil dre n 
wit h ac h o n dr o plasia: gr o wt h patter n, h y p ot ha la mi c- pit uitar y f u ncti o n, a n d ge n ot y p e. E ur J 
E n d ocri n ol 1 3 8[ 3], 2 7 5- 2 8 0. 1 9 9 8. 
Ta n ner J, W hite h o use R. Assess me nt of s keletal m at urit y a n d pre dicti o n of a d ult hei g ht 
( T W 2 met h o d). 2 n d e d. L o n d o n: A ca de mic Press, 1 9 7 5. [ T his p u blic ati o n is a b o ok a n d 
t heref ore is n ot i ncl u de d i n t he s u b missi o n.]. 
Waters, K A, E ver ett, F, Sille nce, D, Fa ga n, E et. al. Breat hi n g a b n or maliti es i n slee p i n 
ac h o n dr o plasia. Arc h Dis C hil d 6 9[ 2], 1 9 1- 1 9 6. 1 9 9 3. 
We n dt, DJ, D v ora k- E well, M, B ulle ns, S, L or get, F et. al. N e utral e n d o p e pti dase-resista nt C-
t y pe n atri uretic pe pti de varia nt re prese nts a n e w t h era pe utic a p pr o ac h f or treat me nt of 
fi br o blast gr o wt h fact or r ece pt or 3-relat e d d warfis m. J P har mac ol E x p T her 3 5 3[ 1], 1 3 2- 1 4 9. 
2 0 1 5. 
W y n n, J, Ki n g, T M, Ga m bell o, MJ, Waller, D K et. al. M ortalit y i n ac h o n dr o plasia st u d y: a 
4 2- year f oll o w - u p. A m J Me d Ge net A 1 4 3 A[ 2 1], 2 5 0 2- 2 5 1 1. 2 0 0 7. 
Yas o da, A, Kita m ur a, H, F ujii, T, K o n d o, E et. al. S yste mic a d mi nistrati o n of C- t y pe 
natri uretic pe pti de as a n o vel t hera pe utic strate g y f or s keletal d ys plasias. E n d ocri n ol o g y . 
2 0 0 9. 
Yas o da, A, K o m ats u, Y, C h us h o, H, Mi yaza wa, T et. al. O vere x pressi o n of C N P i n 
c h o n dr oc ytes resc u es ac h o n dr o plasia t hr o u g h a M A P K- de pe n d e nt pat h wa y. Nat Me d 1 0[ 1], 
8 0- 8 6. 2 0 0 4. 
 
 
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2 1  
I N V E S TI G A T O R R E S P O N SI BI LI T E S 
2 1. 1  
C o n d uct of St u d y  a n d Pr otecti o n of H u m a n P atie nts  
I n acc or da n ce wit h F D A F or m 1 5 7 2, t he I n v esti gat or will e ns ure t hat: 
•  He or s he will c o n d u ct t he st u d y i n acc or d a nce wit h t he rele va nt, c urre nt pr ot oc ol a n d 
will o nl y m a ke c h a n ges i n a pr ot oc ol aft er n otif yi n g t he S p o ns or, e x ce pt w he n 
necessar y t o pr otect t he s afet y, ri g hts, or w elfare of patie nts.  
•  He or s he will pers o nall y c o n d uct or s u per vise t he st u d y. 
•  He or s he will i nf or m a n y p ote ntial patie nts, or a n y pers o ns use d as c o ntr ols, t hat t he 
dr u gs are b ei n g use d f or i n vesti gati o nal p ur p os es a n d he or s he will e ns ure t hat t he 
re q uire me nts r elati n g t o o btai ni n g i nf or me d c o nse nt i n 2 1 C F R Part 5 0 a n d I R B 
re vie w a n d a p pr o v al i n 2 1 C F R Part 5 6 are met.  
•  He or s he will r e p ort t o t he S p o ns or a d vers e e x perie nces t hat o cc ur i n t he c o urse of 
t he i n vesti gati o n i n acc or da nce wit h 2 1 C F R 3 1 2. 6 4. 
•  He or s he h as rea d a n d u n dersta n ds t he i nf or mati o n i n t he I n v esti gat or’s Br oc h ure, 
i ncl u di n g p ote ntial ris ks a n d si de effects of t he dr u g. 
•  His or her staff a n d all pers o ns w h o assist i n t he c o n d uct of t he st u d y are i nf or me d 
a b o ut t heir o bli gati o ns i n meeti n g t he a b o ve c o m mit me nts  
•  He or s he will e ns ur e t hat a de q uate a n d acc urat e rec or ds i n acc or d a nce wit h 2 1  C F R 
3 1 2. 6 2 a n d t o ma ke t h ose rec or d s a vaila bl e f or i ns pecti o n i n acc or da nce wit h 2 1 C F R 
3 1 2. 6 8. 
•  He or s he will e ns ur e t hat t he I R B/ E C c o m plies wit h t he re q uire me nts of 2 1 C F R Part 
5 6, a n d ot her a p plica ble r e g ul ati o ns, a n d c o n d ucts i nitial a n d o n g oi n g re vie ws a n d 
a p pr o vals of t he st u d y. H e o r s he will als o e ns ure t hat a n y c ha n ge i n res earc h acti vit y 
a n d all pr o ble ms i n v ol vi n g ris ks t o h u ma n patie nts or ot hers are re p orte d t o t he 
I R B/ E C. A d diti o nall y, he or s he will n ot ma ke a n y c ha n ges i n t he researc h wit h o ut 
I R B/ E C a p pr o val, e x ce pt w here n ecess ar y t o eli mi nate a p pare nt i m me diate hazar ds t o 
h u ma n patie nts. 
•  He or s he a grees t o c o m pl y wit h all ot her re q uire m e nts re gar di n g t he o bli gati o ns of 
cli nical I n vesti gat ors a n d all ot her perti ne nt re q uire me nts i n 2 1 C F R Part 3 1 2. 
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2 2  
SI G N A T U R E P A G E  
Pr ot oc ol Ti tle: A P has e 2, O pe n-la bel, Se q u e ntial C o h ort D ose- escalati o n St u d y of 
B M N  1 1 1 i n C hil dre n wit h Ac h o n dr o plasia 
Pr ot oc ol N u m ber: 1 1 1- 2 0 2 
I h a ve r ea d t he f or g oi n g pr ot oc ol a n d a gree t o c o n d uct t his st u d y as o utli ne d. I a gree t o 
c o n d uct t he st u d y i n c o m plia nce wit h all a p plica bl e re g ulati o ns a n d g ui deli nes, i ncl u di n g E 6 
I C H, as state d i n t he pr ot oc ol, a n d ot her i nf or m ati o n s u p plie d t o me. 
 
 
 
 
 
I n v esti gat or Si g nat ure 
 
Date  
 
Pri nte d Na me:  
 
 
 
Acce pt e d f or t he S p o ns or: 
 
 
S
 
Date  
 
 
Pri nte d Na me:  
 M D P h D 
 
 
 
D o c u Si g n E n v el o p e I D: E 4 E 6 8 E 8 A- 5 7 C 1- 4 4 A 3- A E 7 8- 0 C 6 4 D 2 C B 4 5 F 6
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pr ot oc ol. p df
Pa ge 1 1 8