Conditions: Achondroplasia
Keywords: Achondroplasia Dwarfism Bone Diseases, Developmental Bone Diseases
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 35
Healthy volunteers: no

Brief summary:
This is a Phase 2, open-label, sequential cohort dose-escalation study of BMN 111 in children with achondroplasia. The primary objective is to assess the safety and tolerability of daily BMN 111 administered to children with achondroplasia.

Detailed description:

Arms:
arm 1: Cohort 1: 2.5 ug/kg arm 2: Cohort 2: 7.5 ug/kg, arm 3: Cohort 3: 15 ug/Kg arm 4: Cohort 4: 30 ug/kg

Interventions: intervention 1: BMN 111
Intervention descriptions: intervention 1: BMN 111 will be administered daily for 24 months in an open-label sequential dose adjustment fashion.

Protocol document:
Prot_000.pdf: 
 
 
 
 
    
 
 
 
 
 
 
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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pr ot oc ol. p df
Pa ge 1
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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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 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 
Pa ge 5 
 
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 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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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  
-
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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 
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  
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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 
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  
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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 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  
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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. 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  
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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 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 
 
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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 
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 
-
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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 
-
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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 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  
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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 
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 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 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 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 o prietar y a n d C o nfi de ntial 
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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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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 
2 2 A u g ust 2 0 1 6 
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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Pa ge 3 1 
 
Pr o prietar y a n d C o nfi de ntial 
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 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 
2 2 A u g ust 2 0 1 6 
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 
2 2 A u g ust 2 0 1 6 
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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B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 3 4 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
•  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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Pa ge 3 5 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
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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Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
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. 
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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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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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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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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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2 2 A u g ust 2 0 1 6 
•  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  
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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 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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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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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
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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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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. 
-
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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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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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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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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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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•  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 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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Pr o prietar y a n d C o nfi de ntial 
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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 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 
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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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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 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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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 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 
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pr ot oc ol. p df
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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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Pr o prietar y a n d C o nfi de ntial 
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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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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 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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Pr o prietar y a n d C o nfi de ntial 
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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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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 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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pr ot oc ol. p df
Pa ge 1 1 7


 
B M N 1 1 1- 2 0 2 A me n d me nt 4 
Pa ge 1 1 7 
 
Pr o prietar y a n d C o nfi de ntial 
2 2 A u g ust 2 0 1 6 
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
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SAP_001.pdf: 
 
 
 
 
    
 
 
 
 
 
 
Official Title: A Phase 2, Open-label, Sequential Cohort Dose-escalation Study of BMN 
 
  
111 in Children with Achondroplasia 
 
 
NCT Number: NCT02055157 
 
Applicant/MAH: BioMarin Pharmaceutical Inc. 
 
Version Date: 11 June 2018  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Proprietary and Confidential
16.1.9 Documentation of Statistical Methods
16.1.9.1
Statistical Analysis Plan
Statistical Analysis Plan (SAP) (11JUN2018)
Statistical Analysis Plan Signature Pages
111-202 Clinical Pharmacology Analysis Plan (CPAP) (08JUN2018)
16.1.9.2
Data Monitoring Committee (DMC) Materials
DMC Charter
BMN 111-202 DMC Charter V1 (25OCT2013)
BMN 111-202 DMC Charter V2 (05SEP2014)
BMN 111-202 DMC Charter V3 (15MAY2015)
BMN 111-202_205 DMC Charter V4 (01FEB2016)
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Statistical Analysis Plan 
Phase 2 Clinical Study Report 
 
Study 111-202 
 
A Phase 2, Open-label, Sequential Cohort Dose-
escalation Study of BMN 111 in Children with 
Achondroplasia 
 
Final  
June 11th, 2018 
 
The information in this document is considered privileged and confidential by BioMarin Pharmaceutical 
Inc., and may not be disclosed to others except to the extent necessary to obtain Institutional Review 
Board approval and informed consent, or as required by Federal and State Laws.  Persons to whom this 
information is disclosed must be informed that this information is privileged and confidential and that it 
should not be further disclosed. 
 
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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS .......................................................................................................... 4 
2 
INTRODUCTION ............................................................................................................................ 6 
2.1 
Objectives of Study ................................................................................................................ 6 
2.2 
Study Design........................................................................................................................... 7 
2.3 
Study Population ..................................................................................................................... 8 
2.4 
Sample Size Determination .................................................................................................... 9 
2.5 
Blinding and Randomization Methods ................................................................................... 9 
2.5.1 
Blinding Method ...................................................................................................... 9 
2.5.2 
Interim Analysis ....................................................................................................... 9 
3 
GENERAL ANALYSIS CONSIDERATION ............................................................................... 10 
3.1 
Analysis Populations ............................................................................................................ 10 
3.1.1 
Enrolled Population ............................................................................................... 10 
3.1.2 
Efficacy Analysis Population ................................................................................. 10 
3.1.3 
Safety Analysis Population .................................................................................... 10 
3.2 
Data and Cohort Presentation ............................................................................................... 10 
3.3 
Study Day Derivation ........................................................................................................... 10 
3.4 
Visit Windows for Analysis ................................................................................................. 11 
3.5 
Handling of Dropouts and Missing Data .............................................................................. 13 
4 
SUBJECT DISPOSITION ............................................................................................................. 14 
5 
DISCONTINUATION AND COMPLETION ............................................................................... 15 
6 
PROTOCOL EXEMPTIONS AND DEVIATIONS ...................................................................... 16 
7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ..................................................... 17 
8 
MEDICAL HISTORY ................................................................................................................... 18 
9 
PRIOR AND CONCOMITANT MEDICATIONS/PROCEDURES............................................. 19 
10 COMPLIANCE .............................................................................................................................. 20 
11 EXTENT OF EXPOSURE TO STUDY DRUG ............................................................................ 21 
12 EFFICACY EVALUATIONS ....................................................................................................... 22 
12.1 Primary Efficacy Endpoint ................................................................................................... 23 
12.2 Secondary Efficacy Endpoints .............................................................................................. 23 
12.2.1 Annualized Growth Velocity ................................................................................. 23 
12.2.2 Key Growth Measures ........................................................................................... 24 
12.2.3 Height and Weight Z-Scores .................................................................................. 24 
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12.2.4 Body Proportions ................................................................................................... 24 
12.2.5 Other Growth Measures ......................................................................................... 25 
13 EXPLORATORY ANALYSIS ...................................................................................................... 26 
13.1 Biomarker Analysis .............................................................................................................. 26 
13.2 Sleep Apnea Analysis ........................................................................................................... 26 
13.3 Imaging Assessment Analysis .............................................................................................. 26 
13.4 Elbow Joint Range of Motion ............................................................................................... 27 
14 SAFETY EVALUATIONS ............................................................................................................ 28 
14.1 Adverse Events ..................................................................................................................... 28 
14.1.1 All Adverse Events ................................................................................................ 29 
14.2 Clinical Laboratory Tests ..................................................................................................... 31 
14.3 Vital Signs ............................................................................................................................ 32 
14.4 Electrocardiogram and Echocardiogram .............................................................................. 32 
14.5 Hip Monitoring ..................................................................................................................... 32 
14.6 Tanner Stage ......................................................................................................................... 32 
14.7 Immunogenicity Analysis ..................................................................................................... 32 
14.8 Pregnancy Testing ................................................................................................................ 33 
15 PHARMACOKINETICS ANALYSIS .......................................................................................... 34 
16 REFERENCES ............................................................................................................................... 35 
17 SUMMARY OF KEY CHANGES TO STUDY SAP ................................................................... 36 
18 APPENDIX .................................................................................................................................... 37 
 
 
 
 
 
 
 
 
 
 
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1 
LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACH 
Achondroplasia 
ADA 
Anti-drug antibody 
AE 
Adverse event 
ANP 
Atrial natriuretic peptide 
ATC 
Anatomical Therapeutic Chemical 
BMI 
Body Mass Index 
BMN 
BioMarin 
BSAP 
Bone-specific alkaline phosphatase 
BNP 
Brain natriuretic peptide 
cGMP 
Cyclic guanosine monophosphate 
CNP 
C-type natriuretic peptide 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events (v4.0) 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic case report form 
ISR 
Injection site reaction 
MedDRA 
Medical Dictionary for Regulatory Activities 
NAb 
Neutralizing antibody 
PK 
Pharmacokinetic 
PT 
Preferred term 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SC 
subcutaneous 
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SMQ 
Standardized MedDRA Queries 
SOC 
System organ class 
TAb 
Total antibody 
TEAE 
Treatment-emergent adverse event 
WHO 
World Health Organization 
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2 
INTRODUCTION 
Study 111-202 (protocol dated on 25 October 2013) is a phase 2, open-label, sequential cohort dose-
escalation study designed as a proof of concept study for BMN 111 in children with Achondroplasia (ACH). 
This 6-month study will allow for assessment of the effect of daily BMN 111 administration on safety, 
tolerability, growth velocity, absolute growth, and body proportions. A clinically relevant increase in 
annualized growth velocity is considered to be in the range of 25%-50% change from baseline, although the 
targeted increase may be refined based on ongoing comprehensive safety and efficacy review of BMN 111. 
Additional exploratory endpoints that reflect the medical complications of ACH will also be evaluated.  
Amendment 1 (dated on 03 June 2014) of this study establishes an optional, open-label extension period of 
approximately 18 months to commence at the end of the initial phase of the study, making a total study 
duration of approximately 25 months, including a 1-month safety follow-up visit. The rationale for extending 
this Phase 2 study is to assess the long-term safety and tolerability of BMN 111 in children with ACH; and to 
assess longer-term effects of BMN 111 on growth in these children.  
Amendment 2 (dated on 08 May 2015) establishes higher doses in two additional cohorts. Cohort 4 and 5 
doses of 30 µg/kg and up to 60 µg/kg respectively were selected with the intent to achieve exposures 
expected to result in further increases in growth velocity in children with ACH with an acceptable safety 
profile. 
Amendment 3 (dated 26 Oct 2015) added thyroid function test to Month 24 of the open-label extension 
phase of the study to assess any changes in thyroid function over the course of the open-label extension 
phase. 
Amendment 4 (dated 22 Aug 2016) removed Cohort 5 based on preliminary data from Cohort 4. 
The purpose of this Statistical Analysis Plan (SAP) is to provide a comprehensive description of 
methods of the data analyses included in the Phase 2 clinical study report. 
2.1 
Objectives of Study 
The primary objective of the initial 6-month period is: 
 
To evaluate the safety and tolerability of daily SC injections of BMN 111 administered for 6 months  
The primary objective of the study extension is: 
 
To evaluate the safety and tolerability of daily SC injections of BMN 111 administered for up to 24 
months   
The secondary objectives of the study are:  
 
To evaluate change from baseline in annualized growth velocity following daily SC injections of 
BMN 111 administered for 6 months, and up to 24 months  
 
To evaluate changes from baseline in growth parameters following daily SC injections of BMN 111 
administered for 6 months, and up to 24 months  
 
To evaluate changes from baseline in body proportions (upper arm to forearm length, upper leg to 
lower leg length, and upper to lower body segment ratios) following daily SC injections of 
BMN 111 administered for 6 months, and up to 24 months  
 
To evaluate dose-exposure and PK profiles of BMN 111 in children with ACH following daily SC 
injections of BMN 111 at each dose level and over multiple days  
The exploratory objectives of the study are: 
 
 
To evaluate change from baseline in QCT bone mineral density (BMD) following daily SC 
injections of BMN 111 administered for 6 months, and up to 24 months  
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 
To evaluate changes from baseline in growth plate morphology following daily SC injections of 
BMN 111 for 6 months, and up to 24 months  
 
To evaluate changes from baseline in long-bone growth, and morphology of the spine following 
daily SC injections of BMN 111 administered for 6 months, and up to 24 months   
 
To evaluate changes from baseline in sleep apnea following daily SC injections administered for 6 
months, and up to 24 months   
 
To evaluate changes from baseline in elbow joint range of motion by goniometry, following daily 
SC injections administered for 6 months, and up to 24 months  
 
To evaluate changes from baseline in BMN 111 activity biomarkers and bone/collagen biomarkers 
following daily SC injections of BMN 111 administered for 6 months, and up to 24 months   
 
To evaluate immunogenicity from baseline and assess impact on safety, PK, and efficacy measures 
following daily SC injections of BMN 111 during the 6 months, and up to 24 months   
 
2.2 
Study Design 
The primary objective of this study is to assess the safety and tolerability of daily BMN 111 administered to 
children with ACH.  Dose regimens will be assessed with four dosing cohorts.  The study design is presented 
in Figure 2.2.1.  Approximately 36 subjects who are 5 to 14 years old (inclusive) will be enrolled.  A 
maximum of five children from one gender may be enrolled in each cohort if the total size of the cohort is 
eight or nine subjects; a maximum of six children from one gender can be enrolled in each cohort if the size 
of the cohort is 10 subjects. 
Comprehensive outpatient safety monitoring will be conducted for all subjects after the first dose of study 
drug is received over the course of the first 10 days, followed by close monitoring throughout the duration of 
the study.  The comprehensive safety monitoring includes a minimum of 8 hours post dose observation on 
the first two days of dosing and at least 4 hours post dose observation on study days 3 and 4.  Subjects may 
be observed for a longer duration and/or additional visits may be added for further safety assessment on 
Days 5-9 at the discretion of the Investigator in consultation with the BioMarin Medical Monitor.  A visit on 
Day 10 concludes the comprehensive outpatient safety-monitoring period.  Vital signs will be monitored 
frequently during the initial period of Days 1-10, including approximately every 10-20 minutes for the first 2 
hours post dose on visit days.   
Additional safety assessments during this period are electrocardiogram (ECG), physical exams, AE 
assessment, and clinical labs.  
BMN 111 will be administered as a morning dose in one of the following daily dosing regimens: 
 
Cohort 1: the first eight subjects will receive 2.5 µg/kg BMN 111.  
 
Cohort 2: the second eight subjects will receive up to 7.5 µg/kg BMN 111. 
 
Cohort 3: the third eight to ten subjects will receive up to 15.0 µg/kg BMN 111. 
 
Cohort 4:  the fourth eight to ten subjects will receive 30.0 µg/kg BMN 111. 
For each cohort, two sentinel subjects will be enrolled and monitored. A DMC review will occur after both 
sentinel subjects reach Day 10; if stopping criteria are not met, and after review and approval by the DMC, 
the remainder of the cohort may then be enrolled.  
Subjects will remain on a daily fixed dose throughout the initial 6-month treatment period.  Subjects in each 
cohort continue to receive daily dosing (Cohort 1, 2.5 µg/kg; Cohort 2, up to 7.5 µg/kg, Cohort 3, up to 15 
µg/kg, and Cohort 4, 30 µg/kg) for 6 months unless stopping criteria are met. When clinical safety is 
established and stopping criteria are not met after all 8-10 subjects have completed at minimum their first 
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10 days of cohort dosing, and after DMC review and approval, the subsequent cohort may be open to 
enrollment.  
In the 18-month optional, open-label extension period, eligible Cohorts 1 and 2 subjects were dose escalated 
to the 15µg/kg dose while Cohort 3 and Cohort 4 subjects continued at their respective starting doses of 
15µg/kg and 30µg/kg, respectively, based on the pre-specified dose adjustment criteria described in the 
protocol and amendments. 
Figure 2.2.1:   Study Design 
 
2.3 
Study Population 
Children 5-14 years old with ACH were chosen because subjects with ACH have an FGFR-3 gain of 
function mutation and because preliminary efficacy evaluation, determined by change in annualized 
growth velocity, requires treatment of subjects prior to epiphyseal growth plate closure, which occurs in 
late adolescence. Growth velocity in children with ACH remains relatively stable from approximately 3 
years old to growth plate closure (Hoover-Fong, 2008, Am.JClinNutr.). Children younger than 5 years 
old will not be enrolled in order to establish a safety profile in an older population first, as well as to 
minimize the confounding effects of nonlinear growth rates and inaccuracies inherent in measurement 
of recumbent length in young children.  
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2.4 
Sample Size Determination 
Approximately 8-10 subjects will be enrolled in each cohort to evaluate the safety and tolerability of 
BMN 111 in this population. No formal sample size calculations were performed. 
2.5 
Blinding and Randomization Methods 
2.5.1 
Blinding Method 
No blinding or randomization was performed in this study. 
2.5.2 
Interim Analysis 
No formal interim analyses for efficacy are planned for this study. However, efficacy data from the first 
three cohorts will be evaluated to inform decision-making regarding higher doses and summarized in the end 
of phase 2 report. Efficacy data will also inform the decision to increase a cohort dose if the initial dose 
exhibits suboptimal efficacy.  
To address objectives of the study, analyses will be performed when all subjects have completed the initial 6-
month period and when all available subjects have completed the extension period.  
Additional exploratory analyses may be performed in the extension period. 
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3 
GENERAL ANALYSIS CONSIDERATION 
3.1 
Analysis Populations 
The following populations are defined for the initial 6-month period and the extension period, respectively.  
The number of subjects in each population will be summarized by cohort in the initial 6-month period and by 
dose level in the extension period. 
3.1.1 
Enrolled Population 
All subjects who consented and were screened and eligible will be included in Enrolled population.  
3.1.2 
Efficacy Analysis Population 
For each of initial 6-month period and the extension period, all subjects who receive at least one dose of 
study treatment and who have post treatment data for any efficacy endpoint in the corresponding period 
will be included in the Efficacy Analysis and Extension Efficacy Analysis population, respectively. 
3.1.3 
Safety Analysis Population 
Safety Analysis Population consists of all subjects who receive at least one dose of study treatment and 
will be used for safety analysis in the initial 6-month period and entire study period. 
Extension Safety Analysis Population consists of all subjects who receive at least one dose of study 
treatment in the extension period and will be used for safety analysis in the extension period.  
3.2 
Data and Cohort Presentation 
All available data for study BMN111-202 will be used for the final analysis. Efficacy data collected in study 
BMN111-901 that is 12 months prior to screening in BMN111-202 for subjects who subsequently enrolled 
in study BMN11-202, and are included in the corresponding analysis population, will be summarized in 
efficacy tables and figures. 
For the initial 6-month period, unless otherwise specified, all data will be presented for each cohort and all 
cohorts combined. 
In the extension period, efficacy and imaging assessment data will be summarized for Cohorts 1 and 2 
subjects who switched to 15µg/kg by cohort, and Cohort 1 and 2 combined. 
In the entire study period, efficacy and imaging assessment data will be summarized for Cohort 3 and Cohort 
4 separately, and Cohort 3 and 4 combined. 
In the extension period, all other data will be summarized by dose level and all cohorts combined. For the 
entire study period, unless otherwise specified, safety data are summarized by dose level, and by cohort, and 
all cohorts combined. Subjects in Cohorts 1 and 2 may be represented at multiple dose levels and are 
accounted once for each dose level they receive. 
3.3 
Study Day Derivation 
A study day will be obtained by subtracting the initial study drug start date from a visit date plus 1, if the 
visit date occurs after the initial study drug start date.  Otherwise, the study day will be the visit date minus 
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the initial study drug start date.  Therefore, Study Day 1 will be the same date as the initial study drug start 
date. 
3.4 
Visit Windows for Analysis 
An assessment for a subject will be classified according to the study day of the assessment where it falls 
within a window.  The analysis windows are designated for each scheduled visit and centered on a target 
day. If there are two or more assessments within a designated window, the assessment that is closest to the 
target day will be used for analyses.  If the two closest assessments to the target day are equidistant from the 
target day, the assessments taken on a scheduled visit per CRF page will be used.  
Data in BMN111-901 for subjects who enrolled in BMN111-202 study and are included in the 
corresponding analysis population will be used in efficacy summary tables and figures. The analysis visits 
and windows for assessments in BMN111-901 are defined below in Table 3.4.1. The analysis windows for 
assessments in BMN111-202 are defined below in Table 3.4.2 for the initial 6-month period and the 
extension period. Unless otherwise specified, all analysis are based on derived visits. 
 
Table 3.4.1:  Visit Time Windows for Observed Assessments in BMN111-901 
Derived Visit 
Target Daya 
Windowa 
-6M 
-183 
-228 
-138 
-12M 
-364 
-409 
-319 
aTarget days and window are relative to the Screening date from the Anthropometric CRF form in BMN111-
202 
 
 
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Table 3.4.2: Visit Time Windows for Observed Assessments in BMN111-202 
Derived Visit 
Target Daya 
Window 
Initial 6-Month Period 
Baseline 
 
The last assessment on or prior to the first 
dose unless otherwise specified. 
Day 1 
Day 1 
Day 1 
Day 2 
Day 2 
Day 2 
Day 3 
Day 3 
Day 3 
Day 4 
Day 4 
Day 4 – Day 7 
Day 10 
Day 10 
Day 8 – Day 12 
Day 15 
Day 15 
Day 13 – Day 18 
Day 22 
Day 22 
Day 19 – Day 25 
Day 29 
Day 29 
Day 26 – Day 36 
Day 43 
Day 43 
Day 37 – Day 64 
Day 85 
Day 85 
Day 65 – Day 106 
Day 127 
Day 127 
Day 107 – Day 155 
Day 183 
Day 183 
Day 156 – The last date of the Day 183 visit 
or Day 190 for subjects not entering the 
extension period 
Extension Period (For subjects who enter extension) 
Month 8 
Day 243 
Day 183 Visit Date + 1 – Day 273 
Month 10 
Day 303 
Day 274 – Day 333 
Month 12 
Day 364 
Day 334 – Day 410 
Month 15 
Day 456 
Day 411 – Day 501 
Month 18 
Day 547 
Day 502 – Day 592 
Month 21 
Day 638 
Day 593 – Day 684 
Month 24 
Day 730 
Day 685 – the actual date of the nominal 
month 24 visit regardless of the analysis day 
a  Target days are relative to the first dosing day.  
For two 
 subjects, 
 and 
, the Month 24 visit in study 111-202 occurred 
on 
2016 and 
2016 respectively, and subjects were unable to complete all assessments, 
so returned to complete the Month 24 visit assessments within the allowed protocol window for this 
visit, on 
2016 and 
2016 respectively. The data from both these two visits are 
considered in the Month 24 assessments. 
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3.5 
Handling of Dropouts and Missing Data 
Subjects who discontinued prematurely after Day 10 will not be replaced. Missing dates or partially 
missing dates will be imputed conservatively for concomitant medications and AEs to ensure that 
an AE is considered treatment emergent and has the longest possible duration. 
   
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4 
SUBJECT DISPOSITION 
Subject disposition will be summarized separately for two periods; the initial 6 month period, and 
the entire study. 
The number of subjects enrolled, the number of subjects treated, the number of subjects who 
completed/continuing/discontinued treatment, and the number of subjects who 
completed/continuing/discontinued from the period will be summarized by cohort and across all 
cohorts. 
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5 
DISCONTINUATION AND COMPLETION  
Of the number of subjects enrolled, for subjects who prematurely discontinued the study, the primary reason 
for study discontinuation will be summarized by cohort in the initial 6-month period, and by dose level in the 
extension period.  
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6 
PROTOCOL EXEMPTIONS AND DEVIATIONS 
Protocol deviations, as recorded in the eCRF, will be summarized by cohort and overall.  Subjects with any 
deviation, any major deviation, and any minor deviation will be summarized, along with the type of 
deviation.  Summaries will be based on the Safety Population. 
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7 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
Subject demographic information will be summarized for all subjects in the safety population. The 
demographics including age at enrollment, age group, sex, race, ethnicity, and Tanner stage at baseline will 
be summarized using descriptive statistics. 
Age groups are defined based on the age at screening as follows: 
 
≥ 5 and < 8 years of age 
 
≥ 8 and < 10 years of age 
 
≥ 10 and ≤ 14 years of age 
Baseline subject characteristics, including height, weight, and BMI, will be provided for efficacy analysis 
population in the growth measures tables. 
Tanner stage will be recorded at each visit and the number and percent of subjects at each stage will be 
summarised by cohort and overall. 
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8 
MEDICAL HISTORY 
Subject’s chronic diseases, disorders, allergies, and surgeries in the past will be collected as general medical 
history. Medial history will be coded in accordance with MedDRA 19.1. General medical history will be 
summarized by system organ class (SOC) and by preferred term (PT) for the safety population. 
 
 
  
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9 
PRIOR AND CONCOMITANT MEDICATIONS/PROCEDURES 
Prior and concomitant medications will be summarized for the safety population.  For analysis purposes, the 
following definitions will be used to determine prior and concomitant medications for the overall study 
period: 
 
Prior medications: Any medications taken and ended prior to the initial study drug administration 
date will be considered prior medications. 
 
Concomitant medications: Any medications taken on or after the initial study drug administration 
date up to 30 days after discontinuation of study treatment will be considered concomitant 
medications. This also includes medications initially taken prior to the initial study drug 
administration date but continued or ended on or after the initial study drug administration date. 
Concomitant medications will be summarized for overall study period. In the event the start date of a 
medication is partial, the following imputation rules will be applied: 
 
If only day is missing, then the start date will be imputed as the first day of the month. If month and 
year are the same as the month and year of first dose of study drug then the start date will be imputed 
as the first dose date.  
 
If only year is non-missing, then the start date will be imputed as the first day of the year. If year is 
the same as the year of first dose of study drug then the start date will be imputed as the first dose 
date. 
In the event the stop date of a medication is partial, the following imputation rules will be applied: 
 
If only day is missing, then the end date will be imputed as the last day of the month.  
 
If only year is non-missing, then the end date will be imputed as the last day of the year. If the 
imputed date is beyond the study completed or discontinued date, the imputed date will be replaced 
with the study completed or discontinued date. 
All medications will be coded using the current version of the World Health Organization Drug (WHO 
Drug) dictionary (Version September 2015).  Prior and concomitant medication use will be separately 
summarized by Anatomical Therapeutic Chemical (ATC) medication class (Level 4) and preferred name 
(i.e., generic medication name). If a medication doesn’t have ATC level 4, they are grouped as ATC Level 4 
classification unavailable.  A subject reporting the same medication more than once will be counted once 
when calculating the number and percentage of subjects who received that medication.  
 
 
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10 COMPLIANCE 
Treatment compliance will be calculated based on the drug exposure records captured in eCRF and 
summarized for the safety analysis population.  
The total amount of study drug taken will be calculated from the data collected on the drug dispensation CRF 
during the study. The total planned study drug intake (planned dose) will be calculated as the doses planned 
in corresponding treatment duration. 
Percentage compliance will be derived from the total amount of study drug intake divided by the planned 
study drug intake, and multiplied by 100%: 
 
 
 
Treatment Compliance = 
dose
Planned
Total
aken
TotalDrugT

100
 
, where planned dose is the protocol-specified dose which changes when subjects change/switch dose, and 
total drug taken takes into account any units left in the syringe. 
Treatment compliance will be calculated and summarized by cohort and overall in the initial 6-month period. 
In the extension period, it will be calculated for each dose level a patient has ever taken and summarized by 
dose level for all cohorts combined. In the entire study period, it will be summarized by dose level for all 
cohorts combined, and by cohort and overall. 
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11 EXTENT OF EXPOSURE TO STUDY DRUG 
For each of the initial 6-month, the extension period, and entire study period, total duration of study drug 
exposure, mean daily dose received (µg/kg), number of subjects who missed at least one dose, and number 
of days subjects missed at least one dose (for subjects who missed at least one dose) will be presented using 
descriptive statistics such as n, mean, SD, median, minimum, and maximum.   
The number and percentage of subjects who permanently discontinue study drug during the initial 6-month 
period, the extension period, and entire study period will be provided along with the reason for study drug 
discontinuation. 
The summaries will be presented for each cohort and overall in the initial 6-month period by dose level in for 
the extension period, and by dose level, by cohort, and all cohorts combined.  
 
 
 
 
 
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12 EFFICACY EVALUATIONS 
Efficacy analysis will be carried out for the initial 6-month period and the entire study period. Figures are 
reported on the efficacy populations. Summary tables and figures include assessments at 12 months and 6 
months prior to screening (-12M and -6M Visits in Study 111-901). 
 
  
Some growth parameters were only optional to collect. These parameters are not included in the figures due 
to the sparse data. They are indicated in the tables 
 
The mean (or the non-missing measurement in case one of the two measurements is missing) of the two 
measurements recorded on the anthropometric measurements in the eCRF at each scheduled visit based on 
analysis windows will be used for the outputs/figures 
 
All assessments collected during the study are included in the outputs even if they occur following treatment 
discontinuation 
The baseline annualized growth velocity (AGV) is established in the natural history study of Study 111-901, 
based on the standing height measurements in the 6 months prior to the screening visit of Study 111-202. For 
all other efficacy endpoints, the Baseline is defined as the last non-missing assessment prior to the first dose 
of study drug. Unless otherwise specified, efficacy analyses will be performed using available data at derived 
visits.  
In the initial 6-month period, efficacy data will be summarized (absolute measures and change from 
baseline) by cohort and overall. With the exception of AGV, summaries include measurements from all 
scheduled assessments. Separate tables with testing are provided just for Day 183 including baseline just for 
those with assessment at Day 183. 
In the entire study period, efficacy data will be summarized for Cohort 3 and Cohort 4 by cohort and Cohort 
3 and 4 combined. Summaries include assessments from 12 months prior to screening (-12M Visit in Study 
111-901) to up to the Month 24 Visit in study 111-202. 
For Cohort 1 and 2 subjects who were switched to 15µg/kg dose level, the endpoints will be summarized by 
descriptive statistics at -12M, -6M, Baseline, Day 183, the first visit a patient was switched to 15µg/kg as 
well as the first visit with at least 6 months, and 12 months on 15µg/kg per cohort, and Cohort 1 and 2 
combined. Absolute measures and changes from baseline, or change from first visit a patient was switched to 
15µg/kg (as applicable), are provided. It is important to note that since the time when the subjects switched 
doses differs the interpretation of the summaries of data for subjects who switch should be considered with 
caution. 
For all parameters, figures by cohort summarizing the means and SDs are provided for the visits included in 
the summary tables. 
Exploratory testing 
P-values and 95% confidence intervals for the change between baseline and the post-treatment assessment 
(i.e. calculated as post-treatment-baseline) will be provided for the endpoints AGV, height Z-score and body 
proportions at the Month 6, Month 12, Month 18 and Month 24 visits. No testing is performed for the cohort 
1 and 2 switcher assessments. 
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All p-values will be considered descriptive and no adjustment for multiplicity will be made. 
The p-values are derived from the two-sided paired t-test on the following pair of hypotheses:  
 
H0: Change from baseline = 0 
 
H1: Change from baseline ≠ 0 
 
12.1 Primary Efficacy Endpoint 
No primary efficacy endpoint is planned for this study. 
12.2 Secondary Efficacy Endpoints 
 
12.2.1 Annualized Growth Velocity 
Annualized growth velocity (AGV) is defined as follows: 
AGV (cm/yr.)  = 
Height at the End of the Interval (cm)− Height at the Beginning of the Interval (cm)
Interval Length in Days
× 365.25 
Where the interval length in days is calculated as interval end date – interval start date.  
The interval for the calculation of the baseline AGV starts on the day of the visit in Study 111-901 that is 6 
months prior to the date of the screening visit in study 111-202 and ends on the date of the screening visit in 
Study 111-202. A sensitivity analysis is included that considers baseline AGV derived over the 12 months 
prior to screening. 
The AGV based on the interval between baseline and the current visit will be summarized at each 6 months 
(absolute and change from baseline) using descriptive statistics (mean, SD, median, 25th and 75th percentiles, 
minimum, and maximum).  
In addition, the AGV based on the 6-month intervals will be summarized whereby AGV at each post-
baseline visit is derived over the previous 6 month interval. 
 
E.g. AGV at (Day 183 to Month 12) = ((Height at Month 12 Visit – Height at Day 183 Visit)/ (Date of 
Month 12 Visit – Date at Day 183 Visit)) x 365.25. 
  
For Cohort 1 and 2 switchers the assessments do not include AGV 1st visit on 15 µg/kg. 
Figures by cohort, summarizing the means and SDs, are provided for the visits included in the tables. 
In addition, figures include by cohort scatter plots at each 6 month visit by age, sex and Tanner stage at the 
visit (genital for males/breasts for females), dot plots for baseline versus post-baseline assessment and 
individual spaghetti plots.  
Cohort 3 and 4 AGV plots over the entire study period, (AGV from baseline and 6-month intervals). For 
Cohort 1 and 2 switchers, the mean (+/- SD) AGV at baseline, the 1st visit with at least 6 months, and 12 
months on 15µg/kg will be plotted by cohort. 
 
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12.2.2 Key Growth Measures 
Key growth measures include: 
 
Standing Height (cm) 
 
Sitting Height (cm) 
 
Lower Body Length (cm) – calculated as [Standing Height – Sitting Height] 
 
Upper Arm Length (cm) 
 
Lower Arm (Forearm) Length (cm) 
 
Upper Leg Length (Thigh ) (cm) 
 
Tibial Length (cm) 
 
Knee to Heel Length (cm) 
Summary tables and figures are provided as described above in Section 12. 
A further figure of individual subject data is included: Spaghetti Plot of Standing Height with Age-Specific 
Non-ACH and ACH References by Cohort and Sex (in initial 6 month period, and entire study period). 
 
12.2.3 Height and Weight Z-Scores  
Height and weight will be converted to age-and sex-appropriate standard score (SDS), also referred to as Z-
score, by comparison with normal reference standards (non-ACH) from the Centers for Disease Control and 
Prevention (CDC) database. 
Summary tables and figures are provided as described above in Section 12. 
Further figures of individual subject data are also included: 
 
Height Z-Scores Using Non-ACH References over Age Prior to Treatment (BMN111-901) and in 
Entire Study Period – Cohort 3 and 4 
 
Change from Baseline in Height Z-Scores Using Non-ACH References over Age by Subject and 
Cohort – Cohort 3 and 4 
 
Change from Baseline in Height Z-Scores Using Non-ACH References over Age by Subject and 
Cohort – Cohort 1 and 2 switchers 
 
12.2.4 Body Proportions 
The following body proportion ratios are assessed (* optional): 
 
Upper to Lower Body ratio: Sitting Height / (Standing Height – Sitting Height) 
 
Upper Arm Length to Lower Arm (Forearm) Length ratio: Upper Arm Length / Lower Arm 
(Forearm) Length 
 
Upper to Lower Leg ratio: 
• 
Upper Leg Length (Thigh) / Knee to Heel Length 
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• 
Upper Leg Length (Thigh)/ Tibial Leg Length 
 
Arm Span* to Height ratio: Arm Span / Standing Height 
 
Summary tables and figures are provided as described above in Section 12. 
 
12.2.5 Other Growth Measures 
Some other growth measures are also summarized (* are optional): 
 
Arm span (cm) * 
 
Weight (kg) 
 
BMI (kg/m2) 
 
Head Circumference (cm) 
 
Head Length (cm) * 
 
Foot: Length and Width (cm) 
 
Waist Circumference (cm) * 
 
Hand: Palm Length, Middle Finger Length, and Palm Width (cm) 
 
Chest: Mid-expiration, Maximum Inspiration, and Maximum Expiration (cm) * 
 
Summary tables and figures are provided as described above in Section 12. 
In addition to the summaries and figures described above, the further figure is included: 
 
Spaghetti Plot of Weight with Age-Specific Non-ACH References by Cohort, Sex in initial 6 month 
period, and entire study period. 
 
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13 EXPLORATORY ANALYSIS 
13.1 Biomarker Analysis 
Biomarkers assessed are (C-terminal cross-linked telopeptide of type II collagen [CTX-II]), chondrocyte and 
osteoblast activity (bone-specific alkaline phosphatase [BSAP]), bone formation (pro-collagen Type 1 N-
terminal propeptide [P1NP]), osteocalcin; and markers of BMN 111 activity (cyclic guanosine 
monophosphate [cGMP], N-terminal propeptide of C-type natriuretic peptide [NT-proCNP], and atrial 
natriuretic peptide [ANP]). 
CTXII, BSAP, PINP and Osteoblast will be evaluated by value and change from baseline to each scheduled 
visit. and cGMP, NT-proCNP, and ANP are assessed at the pre-dose and post dose assessment.   
Tables will be summarized on the safety population by cohort and all cohorts combined in the initial 6-
month period by dose level in the extension period, and by dose level, by cohort, and all cohorts combined in 
the entire study period.  Figures will be summarized by cohort in the initial 6-month period, by dose level in 
the extension period, and by dose, by cohort, and all cohorts combined in the entire study period. 
For CTX-II, BSAP, P1NP, and osteocalcin, post-baseline assessments on the day of escalation will be 
summarized under the previous dose.  
For cGMP, NT-proCNP, and ANP, post-baseline assessments on the day of escalation will be summarized 
under the new dose.  
13.2 Sleep Apnea Analysis 
A sleep-testing device will be used to assess the presence and severity of sleep-disordered breathing by 
measurement of blood oxygen saturation, pulse rate, and airflow during overnight monitoring at Screening 
and on Days 85 and 183 of the initial phase, and Months 12 and 24 of the optional, open-label extension 
phase. Assessment of sleep apnea will include, but may not be limited to, determining the number of 
episodes of apnea and hypopnea per hour (Apnea/Hypopnea Index, AHI). Other exploratory analysis of sleep 
apnea may be performed.   
The full list of variables to be summarised will be described in more detail in a separate appendix. 
13.3 Imaging Assessment Analysis 
 Exploratory imaging assessment data to be evaluated include measurements of lumbar spine, lower 
extremity, bone age, QCT and will be summarised for the absolute measures change from baseline and 
percent change from baseline using the efficacy population. Difference between estimated skeletal bone age 
and chronological age will be calculated and reported in a summary table. In the initial 6-month period, 
imaging assessment data will be summarized by cohort and overall. In the entire period, the data will be 
summarized by descriptive statistics at each available derived visit for Cohort 3 and 4 and Cohort 3 and 4 
combined. For Cohorts 1 and 2 subjects who were switched to 15µg/kg dose level, the data will be 
summarized with descriptive statistics at the first visit a patient was switched to 15 µg/kg as well as the first 
visit with at least 6 months and 12 months on 15µg/kg by cohort and Cohort 1 and 2 combined.  
Mean value of QCT, x-ray lumbar spine, lower extremity, bone age at each time point will be plotted by 
cohort for Cohort 3 and 4 in the entire study period. For Cohort 1 and 2 switchers, the mean value of the 
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same imaging assessment data at baseline, 1st visit with at least 6 months and 12 months on 15ug/kg will also 
be plotted by cohort. 
13.4 Elbow Joint Range of Motion 
The value and change from baseline in the elbow joint range of motion to each scheduled time point will be 
summarized using descriptive statistics (mean, SD, median, 25th/75th percentile, minimum, and maximum). 
Results will be summarized for the efficacy population by cohort and overall in the initial 6-month period by 
dose level in the extension period, and by dose level, by cohort, and all cohorts combined in the entire study 
period.  The value of the elbow joint range of motion at each time point for each individual will be plotted by 
cohort for the entire study period. 
 
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14 SAFETY EVALUATIONS 
Safety analysis will be carried out for the initial 6-month period, the extension period, and the entire study 
period, respectively. For each of the periods, all subjects who receive at least one dose of study treatment in 
the corresponding period and have any post-treatment safety information will be included in the safety 
analysis. Safety will be assessed by examining the incidence, severity grade, and relationship to study drug 
of all treatment-emergent adverse events (TEAEs) reported during the study period In addition, all other 
safety measures including clinical laboratory results, vital signs, electrocardiogram (ECG) and 
Echocardiogram (ECHO) values will be assessed. Unless otherwise specified, the baseline for safety 
endpoints is defined as the last non-missing assessment prior to the first dose. Numeric parameters will be 
summarized by descriptive statistics including n, mean, SD, median, minimum, and maximum. Adverse 
events will be summarized by number and percentage. Change from baseline will be calculated when both 
baseline and post-baseline results are non-missing numeric values. 
For the initial 6-month period, unless otherwise specified, safety data will be presented for each cohort and 
all cohorts combined.  
For the extension period, unless otherwise specified, safety data are summarized by dose level and all 
cohorts combined.  
For the entire study period, unless otherwise specified, safety data are summarized by dose level and by 
cohort and all cohorts combined.  
Subjects in Cohorts 1 and 2 may be represented at multiple dose levels and accounted once for each dose 
level they receive. Note the following rules are applied to associate the safety measure to a specific dose: 
 
AEs are associated to the dose taken on the start date of the AE. 
 
For mean summaries of safety parameters at visits over the course of the study the assessments on 
the day of escalation will be summarized under the previous dose. 
 
For mean summaries assessing pre and post dose measure on a specific day the assessments on the 
day of escalation will be summarized under the new dose. 
For all summary tables for patients who discontinue treatment, all safety assessments within 30 days from 
the treatment discontinuation date will be included in summary tables.  
 
 
 
14.1 Adverse Events 
Adverse events will be coded in accordance with MedDRA version 19.1. A TEAE is defined as any AE that 
newly appeared or worsened in severity following initiation of study drug administration during the AE 
reporting period. After informed consent is obtained and the first administration of study drug, all non-
serious AEs and SAEs reporting period begins and continues until 4 weeks following either the last 
administration of study drug or the early termination visit, whichever is longer. If the onset date or end date 
of an adverse event is partial, the same imputation rules described in Section 9 will be applied. 
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AEs are summarized by incidence rates and for specific tables also by exposure adjusted incidence rates: 
 
Incidence rates calculated as number of subjects with the event divided by the number of subjects in 
the population being assessed 
 
Exposure-adjusted incidence rates (EAIR) are calculated by dividing the total number of events by 
the total treatment exposure in the period under assessment for the subjects in the population being 
assessed. The exposure time for each subject is derived as the time from the date of first dose, to the 
date of the last dose in the period under assessment. 
 
14.1.1 All Adverse Events 
The following summaries will be provided for each period:  
 
Overall Summary of AEs 
 
TEAEs by System Organ Class (SOC), Preferred Term (PT), and severity 
 
TEAEs assessed by investigators as related to study drug by SOC, PT and severity 
 
TEAEs by PT 
 
TEAEs by SOC 
 
Serious AEs (SAEs) by SOC and PT 
 
TEAEs leading to discontinuation by PT 
 
Incidence and exposure-adjusted event rates of TEAEs by SOC and PT 
AEs of Special Interest 
 
Injection site reactions by SOC, PT, and severity 
 
Frequency and duration of ISRs  
 
ISR symptom by SOC, PT and severity 
 
Incidence and exposure-adjusted event rates of Hypotension TEAEs by SOC and PT 
 
Incidence and exposure-adjusted event rates of Heart Rate Change TEAEs by SOC and PT 
 
Incidence and exposure-adjusted event rates of events suggestive of Hypotension TEAEs by SOC 
and PT 
 
Incidence and exposure-adjusted event rates of Hypersensitivity TEAEs (SMQ) by SOC and PT 
 
Incidence and exposure-adjusted event rates of Hypersensitivity TEAEs (excluding ISRs) by SOC 
and PT 
 
Incidence and exposure-adjusted event rates of ISRs TEAEs by SOC and PT 
 
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Search criteria for the ADR/SMQ search criteria: 
 
Injection Site Reaction (ISR) 
o TEAEs are identified using having high level terms of MedDRA of ‘Injection Site Reaction’ 
o ISR Symptom page, which captures additional symptoms associated with a specific ISR AE 
 
Hypotension  
o TEAEs are identified as PT: Blood pressure ambulatory decreased, Blood pressure 
decreased, Blood pressure diastolic decreased, Blood pressure orthostatic decreased, Blood 
pressure systolic decreased, Blood pressure systolic inspiratory decreased, Diastolic 
hypotension, Hypotension, Orthostatic hypotension 
o TEAEs suggestive of Hypotension are identified as PT: Fatigue, Nausea, Loss of 
consciousness, Vision blurred, Cold sweat, Dizziness, Syncope, Presyncope.  
 
Heart Rate Change 
o TEAEs of Heart Rate Change are identified as PT: Atrial tachycardia, Postural orthostatic 
tachycardia syndrome, Rebound tachycardia, Sinus tachycardia, Supraventricular 
tachycardia, Tachycardia, Tachycardia paroxysmal, Ventricular tachycardia, Bradycardia.  
 
Hypersensitivity – refer to BioMarin pharmacovigilance standard search terms 
o TEAEs – Broad Hypersensitivity SMQ (421 narrow and broad search term PTs) 
o 
 
  
 
A figure is provided for Mean Frequency of Injection Site Reactions by Month in Entire Study Period for all 
Cohorts by Dose 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.2 Clinical Laboratory Tests 
Summaries are provided for the 6 month period by cohort, the extension period by dose, and the entire study 
period by dose and by cohort. Descriptive statistics for clinical laboratory tests and change from baseline at 
each scheduled visit based on analysis windows will be presented.  
Shift table from baseline to most extreme post-baseline value (including scheduled and unscheduled visits) 
based on the CTC grading (Grade 0 - 4 where available) will also be generated for each parameter as 
appropriate.  Percentages are based on the number of subjects with each Baseline CTCAE grade. 
All non-missing numeric results will be used to determine CTC grade based on CTCAE v4.0.  Summary 
tables consider all lab assessments from baseline up to 30 days post treatment discontinuation.  
 
 
Lab parameters assessed 
Hematology: (counts for differentials) 
Blood Chemistry  
Urine: Chemistry 
Urinalysis 
Other labs 
For the initial 6-month period, clinical laboratory tests will be presented for each cohort and all cohorts 
combined. For the extension period, clinical laboratory tests are summarized by dose level. For the entire 
study period, clinical laboratory tests are summarized by dose level, by cohort, and all cohorts combined.  
Figures are provided for each of the lab parameters summarized in the tables (1) by cohort for the first 6 
months (2) by dose for the extension (3) for the entire study period by cohort. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14.3 Vital Signs 
Descriptive statistics for pre-dose vital signs (including systolic and diastolic blood pressure, heart rate, 
respiratory rate, and temperatures available) at each scheduled visit based on analysis windows will be 
presented.  
Except for respiratory rate and temperature, change from pre-dose to multiple post-dose time points at 
specific time points will also be summarized.  
For the initial 6-month period, mean vital signs will be summarized for each cohort and all cohorts 
combined. 
For the extension period, vital signs are summarized by dose level and summaries.  
For the entire study period, vital signs are summarized by dose level, by cohort, and all cohorts combined.  
Figures will be summarized for each study period for pre and post dose assessments. 
Dot Plot of Change from Pre-dose at Each Time Point for Systolic Blood Pressure/Heart Rate on Day 1 and 
Day 2 are also provided 
 
14.4 Electrocardiogram and Echocardiogram 
Descriptive statistics for pre-dose Electrocardiogram (ECG) results at each scheduled visit based on analysis 
windows will be presented. For the initial 6-month period, ECG data will be presented for each cohort and 
all cohorts combined. For the extension period, ECG data are summarized by dose level. For the entire study 
period, ECG data are summarized by dose level, by cohort, and all cohorts combined. 
Both ECG and Echocardiogram (ECHO) results will be listed by subject.  
14.5 Hip Monitoring 
All hip monitoring assessments will be listed by subject.  
14.6 Tanner Stage 
All tanner stage assessments will be listed by subject. 
14.7 Immunogenicity Analysis 
Anti-drug antibody (ADA) tests will be performed using validated immunogenicity assays. Serum samples 
for ADA tests will be collected at each scheduled visit described in the protocol and amendments. ADA tests 
will include anti-BMN 111 total antibody (TAb); TAb cross-reactive with endogenous CNP, BNP or ANP; 
and anti-BMN 111 neutralizing antibody (NAb). NAb testing will not be performed if the TAb is negative.  
. Immunogenicity will be summarized for the entire study period, 
by cohort, and all cohorts combined.  Additionally, immunogenicity will be assessed for correlations with 
measures of safety and efficacy by analyzing ADA positive and negative subjects. 
Specifically, change in growth velocity from baseline by ADA status (ADA negative and ADA positive) will 
be presented using box plots. Incidence of hypersensitivity adverse events (including/excluding ISRs) in 
ADA negative and positive subjects will be summarized using box plots.  
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The data conversion rules for immunogenicity analysis are listed in section 18.0.  
14.8 Pregnancy Testing 
Female subjects who have begun menses or are ≥ 10 years old will have a urine or serum pregnancy test at 
the time points specified in the Schedule of Events.  Female subjects with a positive pregnancy test at 
Screening do not meet eligibility criteria for enrollment. Serum pregnancy tests will be performed in the 
event that urine pregnancy test results are positive or equivocal.  
 
 
 
 
 
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15 PHARMACOKINETICS ANALYSIS 
The pharmacokinetics analysis plan will be documented in a separate document.  
 
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16 REFERENCES 
Hoover-Fong, JE, Schulze, KJ, McGready, J, Barnes, H et. al. Age-appropriate body mass index in children 
with achondroplasia: interpretation in relation to indexes of height. Am J ClinNutr 88[2], 364-371. 2008. 
 
 
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17 SUMMARY OF KEY CHANGES TO STUDY SAP 
Version 
Affected 
Section(s) 
Summary of Revisions 
Number 
Date 
Draft SAP 
July 2015 
Efficacy 
Inclusion of -12M and -6 M data from 901 study  
Draft SAP 
July 2015 
Exploratory 
Removal of the exploratory population definition 
Draft SAP 
July 2015 
Safety 
Addition of Tanner stage table 
Draft SAP 
July 2015 
Safety 
Update safety population definition 
Draft SAP 
July 2015 
Safety 
Creation of separate appendix for sleep apnea 
Draft SAP 
July 2015 
Efficacy 
Clarification on windowing for two 
 subjects 
 and 
. 
Draft SAP 
July 2015 
Safety 
Addition of protocol deviation table 
Draft SAP 
July 2015 
Efficacy 
Non confirmatory testing on the endpoints AGV, height Z score and 
the upper lower body ratios at D183 M12, M18 and M24 
Draft SAP 
July 2015 
Efficacy 
Use of ACH references for subject spaghetti plot references 
 
 
 
 
 
 
 
 
 
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18 APPENDIX 
Operational Data Conversion Table for Immunogenicity Analysis 
Assay 
Result
Type 
Result = “Concentration 
(Titer Units)” 
Pos/Neg for
Incidence Table 
Numerical Value 
for Display 
Numerical Value 
for Calculation 
Anti-
BMN111
TAb 
Numeric
Titer 
Negative Screen 
Negative 
1 
0 
Negative Immunodepletion 
Negative 
1 
0 
Negative Titer (<10) 
Negative 
1 
0 
* Value * (e.g. 20, 30, …)
Positive 
e.g. 20, 30, … 
e.g. 20, 30, … 
Imputed values - none 
MRD of assay: 10 
Anti-
BMN111
NAb 
Numeric
Titer 
Negative Screen 
Negative 
1 
0 
Negative Immunodepletion 
Negative 
1 
0 
Negative Titer (<5) 
Negative 
1 
0 
* Value * (e.g. 10, 20, …)
Positive 
e.g. 10, 20, … 
e.g. 10, 20, … 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
MRD of Assay: 5 
ANP
Reactivity 
Binary 
Negative Screen 
Negative 
Negative Immunodepletion 
Negative 
Positive Immunodepletion 
Positive 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
BNP 
Reactivity 
Binary 
Negative Screen 
Negative 
Negative Immunodepletion 
Negative 
Positive Immunodepletion 
Positive 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
CNP-22
Reactivity 
Binary 
Negative Screen 
Negative 
Negative Immunodepletion 
Negative 
Positive Immunodepletion 
Positive 
Imputed values – if TAb negative then impute result as ‘Negative’ for same study visit 
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SART Document Approval Form 
                              
CFT-116863- ITEM Rev. 00 
 
Pg. 1 of 1 
Study name:  
Overview 
Purpose (Check only 1): 
Final draft SAP
 
Revision(s) to the final draft SAP  
Final SAP
 
Amendment(s) to the final SAP
 
The TOC of TLGs defined by the SAP
 
 
TLG mockups and specifications defined by a SAP
Revision(s) to the TLG mockups and specifications 
document after its approval, determined by the 
Biostatistican to require SART approval
 
Request(s) for major changes to mockups and 
specifications after review of TLG outputs 
produced for the Dry Run  
Other: 
 
 
Comments 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Approval 
_
___________________    __ /___ /____ 
dd    MON    yyyy 
 
 
____
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dd    MON    yyyy 
 
 
___
___ /____ 
dd    MON    yyyy 
 
 
 
 
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dd    MON    yyyy 
 
 
A
    __ /___ /____ 
dd    MON    yyyy 
A
    __ /___ /____ 
dd    MON    yyyy 
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105 Digital Drive 
Novato, CA 94949 
 
Clinical Pharmacology Analysis Plan (CPAP) 
 
A Phase 2, Open-label, Sequential Cohort Dose-escalation Study 
of BMN 111 in Children with Achondroplasia  
 
 
 
 
Protocol Number: 111-202 
June 8, 2018 
 
 
 
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B j QM AR I N• Clinical Pharmacology Analysis Plan for 111-202 
APPROVALS 
Lead Clinical Pharmacology Scientist: 
, Ph.D. 
Scientist I, Clinical Pharmacology 
BioMarin Pharmaceutical Inc. 
Approver: 
, Ph.D. 
, Clinical Pharmacology 
BioMarin Pharmaceutical Inc. 
Proprietary and Confidential 
Date 
Date 
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TABLE OF CONTENTS 
 
1 INTRODUCTION ...............................................................................................................5 
2 STUDY OBJECTIVES ........................................................................................................6 
3  STUDY DESIGN.................................................................................................................7 
4 NUMBER OF SUBJECTS PLANNED...............................................................................9 
5 DATA HANDLING ............................................................................................................9 
5.1 Data Source and Archival ...........................................................................................9 
5.2 Missing Values ............................................................................................................9 
5.3 Measurements below the Lower Limit of Quantification ...........................................9 
5.4 Outlier Handling .......................................................................................................10 
5.5 Representation of Mean Concentrations ...................................................................10 
5.6 Sample Reprocessing ................................................................................................10 
6 SCHEDULE OF INTENDED ANALYSIS AND DEPENDENCIES ..............................11 
7 PHARMACOKINETIC PARAMETER ANALYSIS METHODS ..................................11 
7.1 Software ....................................................................................................................11 
7.2 Population(s) to be Analyzed ....................................................................................11 
7.3 Pharmacokinetic Parameter Analysis Methods.........................................................11 
7.4  Requirements for PK Parameter Reporting: ............................................................12 
7.4.1 
Cmax and Tmax ...............................................................................................12 
7.4.2 
Lambda Z derived Parameters (AUC0-∞, t1/2, λz, Vz/F, CL/F) .....................12 
7.5  Statistical Analysis Methods ....................................................................................13 
7.6 Suggested Tables and Figures ...................................................................................13 
7.6.1 
Tables ..........................................................................................................13 
7.6.2 
Figures .........................................................................................................14 
8 PHARMACOKINETIC / PHARMACODYNAMIC ANALYSIS ...................................14 
8.1 Software ....................................................................................................................14 
8.2 Population(s) to be Analyzed ....................................................................................14 
8.3 Analysis Methods ......................................................................................................14 
8.4 Summary Methods ....................................................................................................15 
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8.5 Suggested Tables and Figures ...................................................................................15 
8.5.1 
Tables ..........................................................................................................15 
8.5.2 
Figures .........................................................................................................15 
9 QUALITY CONTROL ......................................................................................................15 
10 REFERENCE .....................................................................................................................16 
 
 
 
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1 
INTRODUCTION 
This clinical pharmacology analysis plan was developed after review of protocol 111-202.  
This plan describes the core set of planned analyses of the clinical pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. Descriptions of the planned data preparation, 
analysis methods to be used and tables and figures to be presented in the clinical 
pharmacology report are provided in this document. The final methods of analysis 
implemented and results generated will be reported in the clinical pharmacology report and 
included as an appendix in the clinical study report. The bioanalytical method will be 
described in a separate report and referenced in the clinical pharmacology report. Any 
deviation from this plan will be documented in the appropriate section of the clinical 
pharmacology report.  
 
 
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2 
STUDY OBJECTIVES 
The primary objective of the initial 6-month period was to evaluate the safety and tolerability 
of daily subcutaneous (SC) injections of BMN 111 administered for 6 months.  
The primary objective of the open-label extension phase was to evaluate the safety and 
tolerability of daily SC injections of BMN 111 administered for up to 24 months.   
The secondary objectives of the study were:  
• To evaluate change from baseline in annualized growth velocity following daily SC 
injections of BMN 111 administered for 6 months, and up to 24 months.  
• To evaluate changes from baseline in growth parameters following daily SC 
injections of BMN 111 administered for 6 months, and up to 24 months.  
• To evaluate changes from baseline in body proportions (upper arm to forearm length, 
upper leg to lower leg length, and upper to lower body segment ratios) following 
daily SC injections of BMN 111 administered for 6 months, and up to 24 months.  
• To evaluate the exposure and PK profiles of BMN 111 in children with ACH 
following daily SC injections of BMN 111 at each dose level and over multiple days. 
The exploratory objectives of the study were: 
• To evaluate change from baseline in quantitative computed tomography (QCT) bone 
mineral density (BMD) following daily SC injections of BMN 111 administered for 6 
months, and up to 24 months. 
• To evaluate changes from baseline in growth plate morphology following daily SC 
injections of BMN 111 for 6 months, and up to 24 months.  
• To evaluate changes from baseline in long-bone growth, and morphology of the spine 
following daily SC injections of BMN 111 administered for 6 months, and up to 
24 months.  
• To evaluate changes from baseline in sleep apnea following daily SC injections 
administered for 6 months, and up to 24 months.  
• To evaluate changes from baseline in elbow joint range of motion by goniometry, 
following daily SC injections administered for 6 months, and up to 24 months.  
• To evaluate changes from baseline in BMN 111 activity biomarkers and 
bone/collagen biomarkers following daily SC injections of BMN 111 administered 
for 6 months, and up to 24 months.  
• To evaluate immunogenicity from baseline and assess impact on safety, PK, and 
efficacy measures following daily SC injections of BMN 111 during the 6 months, 
and up to 24 months.  
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 3  
STUDY DESIGN 
Study 111-202 was a pediatric, Phase 2, open-label dose-escalation study to assess the safety 
and tolerability of daily BMN 111 administered to up to 35 subjects with a clinical diagnosis 
of ACH. Subjects who were 5 to 14 years old inclusive, with documented ACH confirmed by 
genetic testing, had at least a 6-month period of pretreatment growth assessment in Study 
111-901 immediately before study entry, and who met the study eligibility criteria were to be 
eligible to participate in this study. The Study 111-202 design is presented in Figure 3.1. 
A maximum of 5 children from 1 gender were to be enrolled in each cohort if the total size of 
the cohort was 8 or 9 subjects; a maximum of 6 children from 1 gender could be enrolled in 
each cohort if the size of the cohort was 10 subjects. 
Subjects remained on a fixed daily dose throughout the initial 6-month treatment period. 
Subjects in each cohort receive daily BMN 111 SC dosing (Cohort 1, N=8, 2.5 µg/kg; Cohort 
2, N=8, up to 7.5 µg/kg, Cohort 3, N=8-10, up to 15 µg/kg, Cohort 4, N=8-10, 30.0 µg/kg) 
for 6 months unless stopping criteria were met. This was immediately followed by an 
optional, open-label extension period of approximately 18 months to commence at the end of 
the initial phase of the study, making a total study duration of approximately 25 months, 
including a 1-month safety follow-up visit. The rationale for extending this Phase 2 study 
was to assess the long-term safety and tolerability of BMN 111 in children with ACH; and to 
assess longer-term effects of BMN 111 on growth in these children. 
In the 18-month optional, open-label extension period, subjects within each cohort either 
remained on the same dose that they received during the initial 6 months of treatment, or the 
dose for all subjects in the cohort was increased based on the following rules: 
1. Initial dose was determined to exhibit suboptimal efficacy based on growth 
measurements after at least 6 months of treatment based on the review of the data for all 
subjects in the cohort.  
2. Initial dose, and other doses higher than the initial dose, but lower than the dose to which 
the cohort was being increased were generally well tolerated for at least 6 months based 
on review of data for all subjects in the cohort. 
3. The dose to which the subjects in the cohort were being escalated had been previously 
shown to be well tolerated for at least 10 days of comprehensive outpatient safety 
monitoring, based on a review of the data for all subjects in the cohort previously 
assigned to the considered dose.  
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Figure 3.1:  BMN 111-202 Study Design 
 
 
 
 
  
 
 
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4 
NUMBER OF SUBJECTS PLANNED 
A total of up to 35 subjects were to be enrolled in the study (N=8 subjects for Cohort 1, N=8 
subjects for Cohort 2, N=8-10 subjects for Cohort 3 and N=8-10 subjects for Cohort 4). 
5 
DATA HANDLING 
5.1 
Data Source and Archival 
Plasma BMN 111 concentration-time data and the other required data such as 
demographics and dose records will be transferred from BioMarin’s Biometrics 
Department in an appropriate SAS dataset format. 
Source and analysis datasets will be stored in the appropriate Livelink folder in  
accordance with SOP-104400 Preparing a Clinical Pharmacology Report. 
5.2 
Missing Values 
Missing concentration values will be ignored in graphic presentations, descriptive 
statistics, and the computation of PK parameters. No imputation of missing 
concentration values will occur.  
Concentration records without the associated sampling or dosing time data will be 
also be ignored in graphic presentations, descriptive statistics, and the computation of 
PK parameters. Nominal time will not be imputed. 
5.3 
Measurements below the Lower Limit of Quantification 
For PK analyses, concentration values below the lower limit of quantification 
(LLOQ) of the analytical method that are associated with time points prior to Tmax 
will be replaced by zero.  Concentration records below the LLOQ that are associated 
with time points occurring after Tmax will be treated as missing. Concentration values 
below the LLOQ that are embedded between two quantifiable concentrations 
(quantifiable concentration immediately prior and immediately following) will be 
treated as missing.  
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5.4 
Outlier Handling 
On a case by case basis, it may be necessary to exclude anomalous or erroneous 
individual PK concentration values from the calculation of derived PK parameters.  It 
is up to the scientific judgement of the clinical pharmacology (CP) scientist to 
exclude such cases. Reasons may include dose administration error or major protocol 
violations with an impact on PK. Exclusion of data along with reasons should be 
reported in the appropriate section of the CP report. 
5.5 
Representation of Mean Concentrations 
The central tendency of PK profiles will be graphically depicted as mean 
concentration-time profiles constructed using nominal sampling times.  Mean 
concentration values will be calculated and reported only if three non-missing values 
are present for the nominal time point.  Concentration values below the LLOQ will be 
treated as zero in the mean concentration calculations.  If the mean concentration 
value is less than the LLOQ, the mean concentration value will be set to below the 
LLOQ in tables. 
5.6 
Sample Reprocessing 
Samples may be reanalyzed in accordance with the standard operating procedure at 
the bioanalytical laboratory. If an observed concentration value represents an 
unexplained, significant deviation from the temporal consistency with the prior and 
following samples in the affected subject’s concentration-time profile, the CP 
scientist may issue a request for sample reprocessing. Sample reprocessing will only 
be done if sufficient sample volume exists and if the stability of the sample is 
adequate. 
 
 
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6 
SCHEDULE OF INTENDED ANALYSIS AND DEPENDENCIES 
Final data analyses will be performed after the clinical database has been locked, the 
bioanalytical data has been quality assured, and the data has be transferred to BioMarin 
Clinical Pharmacology.  
7 
PHARMACOKINETIC PARAMETER ANALYSIS METHODS 
7.1 
Software 
PK Parameter estimation and statistical analyses will be done using the current 
validated instance of Phoenix WinNonlin (version 6.4, Certara L.P., St. Louis, MO). 
Additional software may be used for data processing and graphing including R 
(version 3.4.1 or later), The R Foundation for Statistical Computing, Vienna, Austria) 
with R Studio version (1.1.423, or later, R Studio, Inc., Boston, MA). 
7.2 
Population(s) to be Analyzed 
All subjects who receive a dose of BMN 111 and have measurable concentration 
values, for whom the primary PK data are considered to be sufficient and 
interpretable, will be included in the PK analysis.   
7.3 
Pharmacokinetic Parameter Analysis Methods 
Estimates of the following PK parameters will be obtained and additional PK 
parameters may be estimated as deemed appropriate by the analyst. 
Tmax 
Time to reach maximum observed post-dose concentration 
Cmax 
Maximum observed post-dose concentration 
AUC0- t 
Area under the plasma concentration-time curve from 0 to the 
time of last measurable concentration 
AUC0-∞ 
Area under the plasma concentration-time curve from time 0 to 
infinity, calculated as AUC0-∞ = AUC0-t + Ct/λz, where Ct is the 
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last measurable concentration and λz is the terminal elimination 
rate constant 
t1/2 
Terminal half-life 
CL/F 
Apparent clearance, calculated as Dose/AUC0-∞ where F is 
absolute bioavailability 
Vz/F 
Volume or apparent volume of distribution, calculated as 
(CL/F)/λz 
AUC0-t will be calculated using the linear trapezoidal rule for increasing 
concentrations and the logarithmic trapezoidal rule for decreasing concentrations. 
Linear Trapezoidal Rule                                 Logarithmic Trapezoidal Rule  
 
where is t is (t2-t1) and t is time and C is concentration. 
 
7.4 
 Requirements for PK Parameter Reporting: 
 
 
7.4.1 Cmax and Tmax 
• If two peak concentrations of equal magnitude occur, the first peak and its 
corresponding timepoint will be reported as Cmax and Tmax respectively. 
7.4.2 Lambda Z derived Parameters (AUC0-∞, t1/2, λz, Vz/F, CL/F) 
• The terminal elimination rate constant λz will initially be estimated using 
the best fit default method in Phoenix WinNonlin. The plots can then be 
analyzed by visual inspection to assess the quality of the estimation. If any 
of the conditions below are met then any parameter dependent on λz for 
computation (e.g., t1/2, AUC0-∞) and λz should not be included in 
descriptive statistics and statistical testing procedures: 
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o If the coefficient of determination (R-squared) is less than 0.800 
o If AUC extrapolation >20 %  
o If less than 3 quantifiable concentrations-time values included in the 
regression of the terminal phase. Cmax should not be used in the 
determination of λz. 
7.5 
 Statistical Analysis Methods 
All evaluable PK concentrations that were sampled within the protocol specified time 
windows and were not excluded or deemed and outlier, will be included in the 
summary statistics. PK concentrations will be summarized using nominal time. For 
descriptive statistics of concentration data, BLQ values will be treated as zero. 
Statistics presented will include sample size (n), mean, standard deviation (SD), 
minimum, median, maximum, and coefficient of variation (%CV).  Mean, median, 
SD and CV% will not be reported when n is < 3. 
All PK parameters that were not excluded or flagged as unreliably calculated will be 
included in the summary statistics. PK concentrations that were excluded from 
summary statistics will be documented in an exclusion table.  
7.6 
Suggested Tables and Figures  
7.6.1 Tables 
• 
Individual PK parameters  
• 
Summary statistics of concentrations by nominal time for each analyte 
and treatment 
• 
Summary statistics of PK parameters by treatment  
• 
PK concentration-time data that was excluded from NCA 
Additional tables may be generated as deemed appropriate. 
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7.6.2 Figures 
• 
Individual plasma concentration vs. time profiles by treatment and analyte 
• 
Mean plasma concentration (Mean + SD) versus nominal time profiles 
by treatment 
Additional figures may be generated as deemed appropriate by the analyst. 
8 
PHARMACOKINETIC / PHARMACODYNAMIC ANALYSIS 
If supported by the data, the exposure-response relationship between BMN 111 exposure and 
immunogenicity, efficacy, biomarker, and safety PD endpoints of interest will be explored. 
The PD endpoints examined may include changes in annualized growth velocity (AGV), 
urine cGMP and serum BSAP biomarkers, heart rate (HR), blood pressure (BP), and 
incidences of injection site reactions (ISRs) and hypotension. Additional PD endpoints may 
be evaluated if deemed appropriate by the analyst. 
8.1 
Software 
Data processing, graphics, and statistical modeling will be done using R (version 
3.4.1 or later), The R Foundation for Statistical Computing, Vienna, Austria) with R 
Studio version (1.1.423, or later, R Studio, Inc., Boston, MA) 
8.2 
Population(s) to be Analyzed 
All subjects who were administered a dose of BMN 111 and provided evaluable and 
interpretable PK and PD assessments with be included in the PK/PD analysis dataset. 
8.3 
Analysis Methods 
Potential Correlations between BMN 111 and PD endpoints of interest will be 
explored graphically. Statistical modeling may then be used to further explore 
exposure-response correlations identified with the graphical analysis.  
 
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8.4 
Summary Methods 
Descriptive statistics of BMN 111 exposure by PD endpoint may be calculated and 
will include sample size (n), mean, standard deviation (SD), minimum, median, 
maximum, and coefficient of variation (%CV). 
8.5 
Suggested Tables and Figures 
8.5.1 Tables 
• 
PD endpoints used in PK/PD analyses by individual subject 
• 
Summary statistics of BMN 111 exposure by PD endpoint for 
categorical endpoints 
• 
Summary tables for any statistical models used 
8.5.2 Figures 
• 
Distribution plots of BMN 111 exposure by PD endpoints for 
categorical endpoints 
• 
Scatter plots of BMN 111 exposure by PD endpoint for continuous 
endpoints 
• 
Summary figures for any statistical models used 
Additional tables and figures may be generated as deemed appropriate by the 
analyst. 
9 
QUALITY CONTROL 
Quality control review of the PK analysis and report will be performed according to WI-
114791 Guidelines for Conducting Noncompartmental Analysis. 
 
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10 
REFERENCE 
1. 
SOP-103648 Phoenix WinNonlin Data Processing Through the Phoenix Platform 
2. 
SOP-104400 Preparing a Clinical Pharmacology report 
 
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