A Randomised, Double Blind, Placebo Controlled Study to Evaluate the Micro-macroscopic Effects on Muscles, the Safety and Tolerability, and the Efficacy of Givinostat in Patients With Becker Muscular Dystrophy (BMD)
Phase: PHASE2
Conditions: Becker Muscular Dystrophy
Sponsor: Italfarmaco

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1  of 1 1 0  
 
 
I T A L F A R M A C O 
 
FI N A L  C LI NI C A L S T U D Y  P R O T O C O L  
Pr ot oc ol N u m ber : D S C/ 1 5/ 2 3 5 7/ 5 3  
Pr ot oc ol Title : A r a n d o mise d, d o u ble -bli n d, pl ace b o -c o ntr olle d st u d y t o 
e v al u ate t he micr o -m acr osc o pic effects o n m uscles, t he s afet y a n d 
t oler a bilit y, a n d t he effic ac y of gi vi n ost at i n p atie nts wit h Bec ker M usc ul ar 
D ystr o p h y  
 
I N D N u m ber:  
N A  
E u dr a C T N u m ber:  
2 0 1 7 -0 0 1 6 2 9 -4 1  
N a me of Pr o d uct:  
Gi vi n ostat  
P h ase of De vel o p me nt:  
2  
I n dic ati o n: 
Bec ker  M usc ul ar D ystr o p h y  ( BM D)  
S p o ns or:  
Pa ol o Bettica, M D, P h D  
Direct or of Cli nical Res earc h a n d 
De vel o p me nt  
I T A L F A R M A C O S. p. A.  
V ia dei la v orat ori 5 4  
2 0 0 9 2 Ci nisell o Balsa m o, Ital y  
Tel:  
+ 3 9 0 2 6 4 4 3 2 5 1 1  
Fa x:   + 3 9 0 2 6 4 4 3 4 6  
A me n de d Pr ot oc ol Versi o n:  
5 . 0 
Pr ot oc ol D ate:  
A me n d me nt N o. 1 D ate : 
A me n d me nt N o. 2 D ate : 
A me n d me nt N o. 3 D ate:  
A me n d me nt N o. 4 D ate:  
 
2 0  J u ne 2 0 1 7  
2 4 Ja n uar y 2 0 1 8  
3 1  J ul y 2 0 1 8 
1 3  Dece m b er 2 0 1 9  
1 7  J u ne 2 0 2 0  
-C O N FI D E N TI A L - 
T his d oc u me nt a n d its c o nte nts are t he pr o p ert y of a n d c o nfi de ntial t o 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
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Italfar mac o S. p. A .  A n y u na ut h orize d c o p yi n g or use of t his d oc u me nt is 
pr o hi bite d.  
 
S P O N S O R A P P R O V A L P A G E  
 
 
Date:  
 
Pa ol o Bettica, M D, P h D  
Direct or of Cli nical Res earc h a n d 
De vel o p me nt  
 
 
 
 
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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I N V E S TI G A T O R P R O T O C O L A G R E E M E N T P A G E 
 
I a gree: 
•  
T o ass u me res p o nsi bilit y f or t he pr o per c o n d u ct of t he st u d y at t his site.  
•  
T o c o n d uct t he st u d y i n c o m plia nce wit h t his pr ot oc ol, a n y f ut ure a m e n d me nts, a n d 
wit h a n y ot her st u d y c o n d uct pr oce d ures pr o vi de d b y Italfar mac o S. p. A . 
•  
N ot t o i m ple me nt a n y c ha n ges t o t h e pr ot oc ol wit h o ut writte n a gree me nt fr o m 
Italfar mac o S. p. A  a n d pri or  re vie w a n d writte n a p pr o val fr o m t he I nstit uti o nal Re vie w 
B oar d /I n de pe n de nt Et hi cs C o m mittee, e xce pt 
w here necessar y t o eli mi nate a n 
i m me diate hazar d t o s u bjects.  
•  
T hat I a m t h or o u g hl y fa miliar wit h t he a p pr o priate use of t he st u d y dr u g, as descri be d 
i n this pr ot oc ol a n d a n y ot her i nf or mati o n pr o vi de d b y Italfar mac o S. p. A i ncl u di n g, 
b ut n ot li mite d t o, t he I n v esti gat or’s Br oc h ure (I B).  
•  
T hat I a m a w are of, a n d will c o m pl y wit h, G C P a n d all a p plica ble re g ulat or y 
re q uire me nts. 
•  
T o e ns ure t hat all pers o ns assi sti n g me wit h t he st u d y are a de q uatel y i nf or me d a b o ut 
t he Italfar mac o S. p. A st u d y dr u g a n d of t heir st u d y-relate d d uties a n d f u ncti o ns as 
descri be d i n t he pr ot o c ol.  
 
Si g nat ure:  
 
 
Date:  
 
 
Na me 
( pri nt): 
 
 
 
 
Site 
N u m ber:  
Pri nci pal I n v esti gat or  
 
_ _ _ _ _ _ _ _ _ _ _  
 
 
 
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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1  
S Y N O P SI S  
Title of St u d y:  
A ra n d o mise d, d o u ble -bli n d, place b o -c o ntr olle d st u d y t o e val u ate t h e 
micr o -macr osc o pic effects o n m uscles, t he safet y a n d t olera bilit y, 
a n d t he efficac y of gi vi n ostat i n patie nts wit h Bec ker 
M usc ular 
D ystr o p h y  
Pr ot oc ol N u m ber : 
D S C/ 1 5/ 2 3 5 7/ 5 3  
St u d y Desi g n:  
T his is a p h ase 2, ra n d o mise d, d o u ble -bli n d, place b o -c ontr olle d 
st u d y. A p pr o xi matel y 4 8 eli gi ble patie nts will  be ra n d o mize d i n a 2: 1 
rati o t o be treate d wit h gi vi n ostat or place b o f or a peri o d of 1 2 
m o nt hs.  
I n vesti g at ors/ St u d y 
Sites:  
T he st u d y will be c o n d ucte d at 1 -2 i n vesti gati o nal site(s). 
P h ase of 
De vel o p me nt:  
P hase 2  
O bjecti ves:  
T he pri mar y o bjecti ve is t o esta blis h t he hist ol o gical effects of 
gi vi n ostat vers us place b o a d mi nistere d o ver 1 2 m o nt hs.  
T he sec o n d ar y o bjecti ves of t his st u d y are t he f oll o wi n g:  
•  T o esta b lis h t he 
macr osc o pic 
m uscle effects of gi vi n ostat 
vers us place b o a d mi nistere d c hr o nicall y o ver 1 2 
m o nt hs 
assesse d b y M RI/ M R S.  
•  T o esta blis h t he ot her hist ol o gical effects of gi vi n ostat vers us 
place b o a d mi nistere d o ver 1 2 m o nt hs.  
•  T o esta blis h t he efficac y 
of 
gi vi n ostat 
vers us 
place b o 
a d mi nistere d c hr o nicall y o ver 1 2 m o nt hs i n sl o wi n g disease 
pr o gressi o n.  
•  T o assess t h e safet y a n d t olera bilit y of gi vi n ostat vers us 
place b o a d mi nistere d c hr o nicall y.  
•  T o e val uate t he p h ar m ac o ki netic ( P K)  pr ofile of gi vi n ostat 
a d mi nistere d c hr o nicall y i n t he tar get p o p ulati o n.  
•  T o 
e val uate t he i m p act 
of 
gi vi n ostat 
vers us 
place b o 
a d mi nistere d c hr o nicall y o n q ualit y of life a n d acti vities of 
dail y li vi n g.  
T he e x pl orat or y o bj ecti v es are t h e f oll o wi n g: 
•  T o e val u ate t he c orrelati o n bet wee n t he P K pr ofile of gi vi n ostat 
a n d p har mac o d y na mics ( P D) data.  
•  T o e val uate a p ossi ble disease -relate d bi o mar ker.  
•  T o e x pl ore a d diti o nal dis ease -relate d M RI bi o mar kers. 
St u d y P o p ul ati o n : 
T he st u d y 
will e nr oll a d ult 
male patie nts 
wit h a n esta blis he d 
m olec ular dia g n osis of B ec ker M us c ular D ystr o p h y ( B M D ). 
Selecti o n of 
S u bjects : 
Patie nts m ust meet all of t he f oll o wi n g criteria i n or der t o be i ncl u d e d 
i n t he st u d y: 
1.  A m b ula nt 
male patie nts a ge d ≥1 8 years t o ≤ 6 5 years at 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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ra n d o mizati o n 
wit h B M D dia g n osis c o nfir me d b y ge neti c 
testi n g.  
2.  A ble a n d willi n g t o gi ve i nf or me d c o nse nt i n writi n g.  
3.  A ble t o perf or m 6 M W T at scree ni n g wit h a mi ni m u m dista nce 
of 2 0 0 m a n d ma xi m u m dist a nce of 4 5 0 m.  
4.  If i n treat me nt 
wit h s yste mic c ortic oster oi ds a n d/ or 
A C E 
i n hi bit or, a n d/ or β or α a dre ner gic rece pt or bl oc ker, n o 
si g nifica nt c ha n ge i n d osa ge or d osi n g re gi me n (e xcl u di n g 
c ha n ges relate d t o b o d y wei g ht c ha n g e) f or a mi ni m u m of 6 
m o nt hs i m me diatel y pri or t o start of st u d y treat me nt.  
5.  Patie nts 
m ust be 
willi n g t o use a de q uate c o ntrace pti o n. 
C o ntrace pti ve 
met h o ds 
m ust be use d fr o m Ra n d o mizati o n 
t hr o u g h 3 m o nt hs after t h e last d ose of st u d y treat me nt. 
Patie nts 
meeti n g a n y of t he f oll o wi n g criteria  are i neli gi ble t o 
partici pate i n t his st u d y:  
1.  E x p os ure t o a n ot her i n vesti gati o nal dr u g wit hi n 3 m o nt hs pri or 
t o t he start of st u d y treat me nt. 
2.  Use of a n y p h ar mac ol o gic treat me nt, ot her t ha n c ortic oster oi ds, 
t hat mi g ht ha ve a n effect o n m uscle stre n gt h or f uncti o n wit hi n 
3 m o nt hs pri or t o t he start of st u d y treat me nt (e. g., gr o wt h 
h or m o ne). Vita mi n D, calci u m, a n d a n y ot h er s u p ple me nts will 
be all o we d.  
3.  S ur ger y t hat mi g ht affect  m uscle stre n gt h or f u ncti o n wit hi n 3 
m o nt hs bef ore st u d y e ntr y or pl a n ne d s ur ger y at a n y ti m e 
d uri n g t he st u d y.  
4.  Prese nce of ot her cli ni call y si g nifica nt diseas e t hat i n t he 
I n v esti gat or’s o pi ni o n c o ul d a d versel y affect t he safet y of t h e 
patie nt, ma ki n g it  u nli kel y t hat t he c o urse of treat me nt or 
f oll o w-u p is c o m plete d, or c o ul d i m pair t he assess me nt of 
st u d y res ults. 
5.  A dia g n osis of ot h er u nc o ntr olle d ne ur ol o gical diseases or 
prese nce of rel e va nt s o matic dis or ders n ot relate d t o B M D t hat 
ma y i nterfere wit h t he a bilit y t o perf or m t he m uscle f u ncti o n 
tests a n d/ or t o c o m pl y wit h t he st u d y pr ot oc ol pr oce d ures. 
6.  Platelet  c o u nt, 
W B C  c o u nt a n d he m o gl o bi n at scree ni n g < 
L o wer Li mit of N or mal ( L L N). If la b orat or y scree ni n g res ults 
are < L L N, platelet c o u nt, W B C c o u nt a n d he m o gl o bi n are t o 
be re peate d o nce, a n d if a gai n < L L N bec o me e x cl usi o nar y.  
7.  S y m pt o matic car di o m y o pat h y or heart fail ure ( Ne w Y or k Heart 
Ass ociati o n Class III or I V) or left ve ntric ul ar ej ecti o n fracti o n 
< 5 0 % at scree ni n g or wit h heart tra ns pla nt.  
8.  C ur re nt li ver disease or i m pair me nt, i ncl u di n g b ut n ot li mite d 
t o ele vate d t otal bilir u bi n ( > 1. 5 x U L N), u nl ess sec o n dar y t o 
Gil bert’s disease or patter n c o nsiste nt wit h Gil bert's disease.  
9.  I n a de q uat e re n al f u ncti o n, as defi ne d b y s er u m C ystati n C > 2 x 
t he up per li mit of n or m al ( U L N). If t he v al ue is > 2 x U L N, 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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ser u m C ystati n C will be re peat e d o nce, a n d if a g ai n > 2 x U L N 
bec o mes e x cl usi o nar y.  
1 0.  P ositi ve test f or he patitis 
B s urface a nti ge n, he patitis 
C 
a nti b o d y, or h u ma n i m m u n o deficie nc y vir us at scree ni n g.  
1 1.  Baseli ne c orrecte d Q T i nter val, Fr idericia’s c orrecti o n ( Q Tc F) 
> 4 5 0 msec, (as t he mea n of 3 c o nsec uti ve rea di n gs 5 mi n utes 
a part) or hist or y of a d diti o nal ris k fact ors f or t orsa des de 
p oi ntes (e. g., heart fail ure, h y p o k ale mia, or fa mil y hist or y of 
l o n g Q T s y n dr o me). 
1 2.  C urre nt p s yc hiatri c ill ness/s ocial sit uati o ns re n deri n g t h e 
p ote ntial patie nt u na ble t o u n dersta n d a n d c o m pl y wit h t he 
m uscle f u ncti o n tests 
a n d/ or 
wit h t he st u d y 
pr ot oc ol 
pr oce d ures.  
1 3.  H y perse nsiti vit y t o t he c o m p o ne nts of st u d y me dicati o n.  
1 4.  S or b it ol i nt olera nce or s or bit ol mala bs or pti o n, or t he here ditar y 
f or m of fr uct ose i nt olera nce. 
1 5.  C o ntrai n dicati o ns t o m uscle bi o ps y.  
1 6.  C o ntrai n dicati o ns t o 
M RI/ M R S (e. g., cla ustr o p h o bia, 
metal 
i m pla nts, or seiz ure dis or der). 
1 7.  H y pertri gl yceri de mia ( ˃ 1. 5 x u p per li mit of n or mal [U L N ])*  
 
* At scree ni n g, patie nts wit h h y pertri gl yceri de mi a ca n be e nr olle d if 
i n sta ble treat me nt a n d wit h c o ntr olle d le vels of tri gl yceri des (i.e. 
wit hi n n or mal ra n ge) f or at least si x m o nt hs.  
Pl a n ne d S a m ple 
Size:  
A p pr o xi matel y 4 8  patie nts are t o be ra n d o mize d . 
Str atific ati o n : 
T he ra n d o mizati o n pr ocess will be stratifie d b y t he c o nc o mita nt 
ster oi ds use at baseli ne ( yes vs. n o). 
R a n d o m izati o n 
r ati o:  
T he gi vi n ostat or place b o ra n d o mizati o n rati o is 2: 1.  
St u d y d ur ati o n f or 
p artici p a nts : 
T he st u d y is ma de u p of a 4 -wee k scree ni n g peri o d , a 1 2-m o nt h 
treat me nt peri o d a n d a 4-wee k f oll o w -u p peri o d.  T he t otal st u d y 
peri o d f or eac h p atie nt is t heref ore of 1 4 m o nt hs. 
Refere nce  
T her a p y:  
Gi vi n ostat or place b o oral s us pe nsi o n ( 1 0 m g/ m L) t wice dail y ( bi d) 
(i n a fe d state) as des cri b e d bel o w: 
Wei g ht ( k g)  
≥3 0 a n d 
< 4 0  
≥4 0 a n d 
< 5 0  
≥5 0 a n d 
< 6 0  
≥6 0 a n d 
< 7 0  
≥7 0  
D ose ( m g) bi d  
2 6. 7  
3 3. 3  
3 6. 7  
4 0  
4 6. 7  
Or al s us pe nsi o n 
( m L) bi d 
2. 7  
3. 3  
3. 7  
4. 0  
4. 7  
 
Criteri a f or 
E v al u ati o n:  
T he pri mar y efficac y assess me nt is T otal fi br osis  ( %) assesse d 
t hr o u g h hist ol o gical e xa mi nati o n of m uscle bi o psies. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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T he sec o n d ar y efficac y assess me nts are t he f oll o wi n g:  
•  Fat fracti o n of v ast us lateralis a n d s ole us e val u ate d b y M R S  
tec h ni q ue 
•  Fat fracti o n of pel vic gir dle a n d l o wer li m b m uscles e val uate d 
b y Di x o n M RI tec h ni q ue  
•  C S A  of  pel vic gir dle a n d l o wer li m b m uscles b y mea ns of 
Di x o n M RI tec h ni q ue  
•  Ot her bi o ps y hist ol o gical para m eters ( Cr oss -Secti o nal Area 
( C S A), M uscle Fi ber 
Area  Fracti o n [ M F A F ], re ge n erati v e 
fi bers) 
•  M ot or F u ncti o n Meas ure me nt ( M F M)  
•  Ti me F u ncti o n Tests ( T F T)  
o  Ti me t o rise fr o m fl o or  
o  R u n/ wal k 1 0 m  
o  Ti me t o cli m b 4 sta n dar d ste ps  
•  Si x Mi n ute Wal k Test ( 6 M W T)  
•  M uscle stre n gt h e v al uat e d b y k nee e xte nsi o n, el b o w fle xi o n 
as meas ure d b y Ha n d -Hel d M y o metr y ( H H M)  
•  Q ualit y of life (assess e d b y S F 3 6)  
Safet y a n d t olera bilit y will be e val uate d b y m o nit ori n g he mat ol o g y 
a n d bl o o d c he mistr y, c oa g ulati o n, uri nal ysis, vital si g ns, p h ysical 
e xa mi nati o ns, wei g ht, hei g ht, ec h ocar d i o gr a m, E C G a n d res pirat or y 
f u ncti o n e val uati o n. 
A bl o o d sa m ple will be c ollecte d d uri n g t he st u d y f or L T B P 4 a n d 
Oste o p o nti n ge n ot y pi n g. Patie nts w h o ha ve alrea d y c o ncl u de d t he 
st u d y ma y be as ke d t o ret ur n t o t he ce nter f or a bl o o d sa m ple 
c ollecti o n  
B l o o d sa m ple c ollecti o n f or ser u m circ ulati n g pr otei ns ( b y a n E LI S A 
base d s yste m)  at ra n d o mizati o n, 6 
m o nt hs a n d at t he e n d of 
treat me nt. 
Bl o o d sa m ples will be o btai ne d f or P K a nal ysis of gi vi n ostat a n d its 
meta b olites.  
St u d y E n d p oi nts:  
Pri mar y e n d p oi nt: Mea n c ha n ge i n t otal fi br osis ( %) c o m p ari n g t he 
hist ol o g y of m uscle bi o psies bef ore a n d after 1 2 m o nt hs of treat me nt 
wit h gi vi n ostat vers us place b o.  
Sec o n dar y e n d p oi nts:  
•  Mea n c h a n ge i n fat fracti o n of vast us lateralis 
a n d s ole us 
c o m pari n g  Ma g n etic Res o na nce S pectr osc o p y ( M R S) bef ore 
a n d after 1 2 
m o nt hs of treat me nt wit h gi vi n ostat vers us 
place b o.  
•  Mea n c h a n ge i n fat fracti o n of pel vic gir dle a n d l o wer li m b 
m uscles c o m pari n g 
Ma g netic Res o na n ce I ma gi n g ( M RI) 
bef ore a n d after 1 2 m o nt hs of trea t me nt wit h gi vi n ostat vers us 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 8  of 1 1 0  
place b o.  
•  Mea n 
C S A of 
pel vic gir dle a n d l o wer li m b m uscles 
c o m pari n g M RI b ef ore a n d after 1 2 m o nt hs of treat me nt wit h 
gi vi n ostat vers us place b o.  
•  Mea n c ha n g e i n ot her hist ol o g y para meters (e. g. 
Cr oss -
Secti o nal 
Area ( C S A) , M F A F ,  re g e nerati ve fi bers) 
c o m pari n g t he hist ol o g y bi o psies bef ore a n d aft er 1 2 m o nt hs 
of treat me nt wit h gi vi n ostat.  
•  Mea n c h a n ge i n M ot or F u ncti o n Meas ure me nt ( M F M) bef ore 
a n d after 1 2 
m o nt hs of treat me nt wit h gi vi n ostat vers us 
place b o.  
•  Mea n c h a n ge i n Ti me F u nc ti o n Tests (ti me t o cli m b f o ur 
sta n dar d ste ps, ti me t o rise fr o m fl o or a n d ti me t o wal k/r u n 1 0 
m) bef ore a n d after 1 2 m o nt hs of treat me nt wit h gi vi n ostat 
vers us place b o  
•  Mea n c ha n g e i n 6 Mi n ute Wal ki n g Test ( 6 M W T) bef ore a n d 
after 1 2 m o nt hs of treat me nt wit h gi vi n ostat vers us place b o.  
•  Pr o p orti o n of patie nts wit h < 1 0 % w orse ni n g i n 6 M W T at t he 
e n d of st u d y.  
•  Pr o p orti o n of patie nts w h o l ose t he a bilit y t o rise fr o m fl o or 
( Baseli ne t hr o u g h e n d of st u d y). 
•  Pr o p orti o n of patie nts w h o l ose a m b ulati o n d uri n g t he st u d y.  
•  Mea n c h a n ge i n m uscl e stre n gt h e val uat e d b y k nee e xte nsi o n, 
el b o w fle xi o n as meas ure d b y Ha n d Hel d M y o m etr y ( H H M), 
bef ore a n d after 1 2 m o nt hs of treat me nt wit h gi vi n ostat vers us 
place b o.  
•  Mea n c h a n ges i n q ualit y of life (ass esse d b y t he 3 6 -ite m S h ort 
F or m s ur ve y [ S F 3 6]) bef ore a n d after 1 2 m o nt hs of treat me nt 
wit h gi vi n ostat as c o m pare d t o place b o.  
Safet y e n d p oi nts:  
•  N u m ber of patie nts e x p erie nci n g treat me nt -e mer g e nt a d verse 
e ve nts ( T E A Es) a n d seri o us a d verse e v e nts ( S A Es) fr o m 
Baseli ne t hr o u g h e n d of st u d y ( E O S).  
•  T y pe, i nci de nce, a n d s e v erit y of T E A Es a n d S A Es ( Baseli ne 
t hr o u g h E O S). 
•  C ha n ges fr o m bas eli ne t o e n d of st u d y of:  
o  Vital si g ns a n d cli nical la b orat or y t ests ( bl o o d c he mistr y 
a n d hemat ol o g y).  
o  P h ysical e xa mi nati o n.  
o  P ul m o nar y  f u ncti o n e v al uate d b y F orce d Vital Ca pacit y 
( F V C), F orce d E x pirat or y V ol u me at 1 sec o n d ( F E V 1), 
F V C/ F E V 1, Pea k E x pirat or y Fl o w ( P E F).  
o  Car diac f u ncti o n e val uat e d b y E C G a n d E C H O.  
o  Wei g ht, hei g ht, a n d b o d y mass i n de x  ( B MI). 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 9  of 1 1 0  
P har mac o ki netic e n d p oi nts  
•  Descri pti o n of t he P K of gi vi n ostat a n d its maj or meta b olites: 
I T F 2 3 7 4 a n d I T F 2 3 7 5. 
E x pl orat or y e n d p oi nts:  
•  P K -P D a nal yses of t h e relati o ns hi p bet wee n 
metrics of 
e x p os ure a n d t h e efficac y/safet y e n d p oi nts of gi vi n ostat.  
•  A nal yses t o e x pl ore w het her t he effects of gi vi n ostat vers us 
place b o a d mi nistere d c hr o nicall y ma y be relate d t o t he t y pe 
of L T B P 4 or o ste o p o nti n ge n ot y pe.  
•  E val uati o n of s er u m cir c ulati n g pr otei ns , b y a n E LI S A  base d 
s yste m, as p ote ntial bi o mar kers f or B M D.  
•  A d diti o nal e val uati o ns of ot her 
m uscle i ma ge para meters 
assesse d b y 
M RI ( details will be pr o vi de d i n a s pecific 
i ma gi n g pr ot oc ol). 
R ules f or cess ati o n  
of r a n d o mise d 
tre at me nt i n a n 
i n di vi d u al 
p artici p a nt : 
T he St u d y treat me nt s h o ul d be per ma ne ntl y disc o nti n ue d if a n y of 
t he f oll o wi n g e ve nts occ ur: 
•  Se vere dr u g -rel ate d diarr hea (i ncreas e of ≥ 7 st o ols per da y)  
•  A n y dr u g -relate d S A E 
•  Q Tc F  > 5 0 0 msec  
•  Platelet c o u nt ≤ 5 0 x 1 0 9/ L (see pr ot o c ol f or det ails)   
•  W hite bl o o d cell c o u nt ≤ 2. 0 x 1 0
9/ L (see pr ot oc ol f or details) 
•  He m o gl o bi n ≤ 8. 0 g/ d L (see pr ot oc ol f or details)  
R ules f or 
te m p or ar y 
i nterr u pti o n of 
r a n d o mise d 
tre at me nt i n a n 
i n di vi d u al 
p artici p a nt  a n d 
d ose m o dific ati o n  
T he St u d y treat me nt s h o ul d be te m p oraril y i nterr u pte d if a n y of t he 
f oll o wi n g e ve nts occ ur, see pr ot oc ol f or details: 
•  M o derate 
or s e vere 
diarr hea 
(i ncrease 
m ore t ha n 
4 
st o ols/da y).  
•  Platelet c o u nt < 7 5 x 1 0 9/ L b ut > 5 0 x 1 0 9/ L. 
•  W hite bl o o d cell < 3. 0 x 1 0
9/ L b ut > 2. 0 x 1 09/ L. 
•  He m o gl o bi n < 1 0. 0 g/ d L b ut > 8. 0 g/ d L  
•  Tri gl yceri des > 3 0 0  m g/ d L *  
 
St u d y treat me nt ca n be res u me d at a le vel 2 0 %  s maller t ha n t he d ose 
at w hic h a n A E lea di n g t o a te m p orar y st o p occ urre d, o n ce plate lets 
a n d/ or w hite bl o o d cell a n d/ or he m o gl o bi n a n d/ or tri gl yceri d es are 
n or malize d or w h e n diarr hea is mil d . 
* Treat me nt f or  hi g h tri gl yceri des ca n be prescri be d b y t he 
i n vesti gat or if val ues are a b o ve UL N . 
S a m ple size 
c alc ul ati o n : 
T he pri mar y h y p ot hesis t o be test e d i n t his st u d y is t hat  t otal fi br osis 
( %) will i ncreas e less i n t he gi vi n ostat gr o u p t ha n i n t he place b o  
gr o u p . T he pri mar y e n d p oi nt of t he st u d y is t he mea n c ha n g e fr o m 
baseli ne t o 
1 2 
m o nt hs i n 
t otal fi br osis (ass u mi n g 
n or mal 
distri b uti o n).  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 0  of 1 1 0  
A sa m ple size of 4 8 patie nts wit h e val ua ble baseli ne bi o psies ( i n a 
2: 1 rati o, 3 2  a n d 16  res p ecti vel y) will pr o vi de 8 0 % p o wer t o test t he 
n ull h y p ot hesis of n o treat me nt effect ( gi vi n ostat –  place b o) o n t otal 
fi br osis vs t he alter nati ve h y p ot hesis t hat t he treat me nt effect is ≥ 9 %  
usi n g  a t w o-si de d t-test wit h al p ha le vel of 5 % a n d ass u mi n g  a 
c o m m o n S D of 1 0 % ( wit h t he S D bei n g base d u p o n bli n de d i nteri m 
data fr o m first 2 0 patie nts  wit h vali d bi o psies ).  
All o wi n g f or a n a p pr o xi mate 5 %  of patie nts wit h n ot e val ua ble 
bi o psies , t he t otal n u m ber of patie nts t o be ra n d o mize d is 5 1  (i.e. 3 4  
i n gi vi n ostat ar m a n d 1 7  i n place b o ar m). 
I nteri m a n al ysis: 
N o f or mal i nteri m efficac y a nal ysis is pla n ne d. After t he first 2 0 
baseli ne bi o psies were 
c ollecte d, a des cri pti ve bli n de d i nteri m 
a nal ysis w as perf or m e d ai me d at c h ec ki n g t he real varia bilit y of t he 
pri mar y e n d p oi nt u n der o bser vati o n i n t he pre vi o us  pr ot oc ol st u d y .  
T he hist o pat h ol o gical feat ures o bser ve d i n t h is bli n de d i nteri m 
a nal ysis s h o we d t hat t h e mea n C S A of t he bice ps fi bers i n B M D 
( mea n: 4 8 7 1. 6 8 μ m2; mi n 1 9 3 3. 4 9 μ m2; a n d ma x 9 4 4 6. 3 4 μ m 2; a n d 
S. D.: 1 9 0 4. 8 6 μ m 2) is si milar t o t he a ge-mat c he d C S A i n male a d ult 
healt h y i n di vi d uals , alt h o u g h wit h a lar ger de gree of fi ber siz e 
varia bilit y  d ue t o  a s u bsta ntial n u m ber of b ot h h y pertr o p hic a n d 
h y p otr o p hic  fi bers. As a c o nse q ue nce, t he li keli h o o d t hat gi vi n ostat  
ca n i ncrease t h e C S A of fi ber s f urt h er is l o w a n d als o it is d o u btf ul 
t hat a f urt her i ncrease i n fi ber C S A w o ul d be be nefi ci al. T he 
hist o pat h ol o gical feat ur e s o bser ve d i n t hes e preli mi nar y bi o psies 
s h o we d als o si g nifica nt fi br o-a di p ose re place m e nt,  w hic h  ca n be 
c o nsi dere d t he hall mar k of t he disease . The c ha n g e of t otal fi br osis is 
c o nsi dere d a m ore i n dicati ve o utc o me meas ure  of t he p ossi ble effect  
of gi vi n ostat  rel ati ve t o t he assess me nt of C S A a n d, he nce, it is t o be 
e val uate d as t he pri mar y e n d p oi nt f or t he trial . 
After st u d y e nr oll me nt is c o m plete d a n d baseli n e data are c ollect e d 
f or all s u bjects, a sec o n d bli n de d i nteri m a nal ysis will be perf or me d 
t o 
o btai n 
a 
preli mi nar y 
o ver vi e w 
of t he 
baseli ne patie nt 
c haracteristics .  
St atistic al Met h o ds 
a n d Pl a n ne d 
A n al yses:  
A n al ysis of Pri m ar y Effic ac y E n d p oi nt  
T he efficac y a nal ysis will be perf or me d o n t he i nt e nt t o treat a n al ysis 
set as pri mar y a n al ysis a n d o n t he per pr ot oc ol set as s u p p orti ve.  
T he pri mar y efficac y v aria ble, t h e a bs ol ute c h a n ge i n mea n t otal 
fi br osis fr o m bas eli ne t o e n d p oi nt after 1 2 m o nt hs of t hera p y, as 
assesse d b y bi o ps y, will be a n al yze d o n t he ori gi nal scale b y mea ns 
of a n a nal ysis of c o vari a nce ( A N C O V A) m o del wit h baseli ne t otal 
fi br osis val ue as c o vari ate a n d treat me nt a n d c o n c o mita nt ster oi d use 
at baseli ne as i n de pe n d e nt class v aria bles. M ea n esti mates will be 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 1  of 1 1 0  
pr o vi de d t o get her 
wit h t heir 
c orres p o n di n g t w o -si de d 
9 5 %  
c o nfi de nce i nter vals. P ossi ble nee d f or l o g tr a nsf or mati o n of t his 
varia ble will be ass esse d b y c hec k of A N C O V A m o del resi d uals.  
T he a n al ysis f or t he pri mar y varia bles d escri be d a b o v e will b e 
perf or me d usi n g m ulti ple i m p utati o ns t o acc o u nt f or missi n g val ues .   
A n al ysis of Sec o n d ar y Effic ac y E n d p oi nts  
All sec o n dar y effi cac y a nal yses will be perf or me d base d o n t he I T T 
a n d will be re p orte d b y pla n ne d treat me nt gr o u p.  T he f oll o wi n g 
e n d p oi nts will be a nal yze d usi n g a n A N C O V A m o del si milar t o t he 
o ne descri b e d f or t he pri mar y e n d p oi nt:  
•  C ha n ge i n fat fracti o n of vast us lat eralis a n d s ol e us aft er 1 2 
m o nt hs of t hera p y  
•  C ha n ge i n f at fracti o n of pel vic gir dle a n d l o wer li m b m uscles 
after 1 2 m o nt hs of t hera p y  
•  C ha n ge i n Cr oss Secti o nal Area ( C S A) of  pel vic gir dle a n d 
l o wer li m b m uscles after 1 2 m o nt hs of t hera p y  
•  C ha n ge i n ot her hist ol o g y para meters ( e.g . C S A, M F A F , , 
re ge nerati ve fi b ers) after 1 2 m o nt hs of t hera p y 
•  C ha n ge i n M F M t otal sc ore aft er 1 2 m o nt hs of t hera p y  
•  C ha n ge i n Ti me d F u ncti o n Tests ( T F Ts) (i.e. ti me t o cli m b 
f o ur sta n d ar d ste ps, ti me t o rise fr o m fl o or a n d ti me t o wal k 
1 0 m) after 1 2 m o nt hs of t hera p y  
•  C ha n ge i n 6 M W T sc ore after 1 2 m o nt hs of t hera p y  
•  C ha n ge i n m uscle stre n gt h e val uate d b y k nee e xte nsi o n a n d 
el b o w fle xi o n aft er 1 2 m o nt hs of t hera p y  
T he f oll o wi n g e n d p oi nts will als o be a nal yze d:  
•  T he p r o p orti o n of patie nts wit h < 1 0 % w ors e ni n g i n 6 M W T 
sc ore after 1 2 m o nt hs of t hera p y, t he pr o p orti o n of patie nts 
w h o l ose t he a bilit y t o rise fr o m fl o or d uri n g t he st u d y, a n d 
t he pr o p orti on of patie nts w h o l ose a m b ulati o n d uri n g t he 
st u d y will be c o m pare d bet wee n ar ms usi n g a stratifie d 
C oc hra n Ma ntel -Hae ns zel ( C M H) c hi s q uare test wit h a t w o -
si de d α = 0. 0 5 le vel. 
As f or t he pri mar y e n d p oi nt, t he 
stratificati o n fact or is c o nc o mita nt ster oi d use at baseli ne. T he 
pr o p orti o n, al o n g wit h its e xact t w o -si de d 9 5 % CI, will be 
c o m p ute d wit hi n eac h treat me nt gr o u p. A t w o -si de d 9 5 % CI 
f or differe nce of pr o p orti o n bet wee n t he treat me nt gr o u ps will 
als o be c o m p ute d . 
•  C ha n ge i n q ualit y of life after 1 2 m o nt hs of t hera p y  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 2  of 1 1 0  
S u m mar y descri pti ve statistics will be pr o vi de d at eac h ti me p oi nt f or 
t he q ualit y of life s c ores/ d o mai ns as assess e d b y t he S F-3 6 
q uesti o n naire.  
 
Pr ot oc ol D ate:  
A me n d me nt N o. 1 
D ate:  
A me n d me nt N o. 2 
D ate  
A me n d me nt N o 3 
D ate  
A me n d me nt N o  4  
D ate  
2 0 J u ne 2 0 1 7  
 
2 4 Ja n uar y 2 0 1 8  
 
3 1  J ul y 2 0 1 8 
 
Fi nal 1 3  Dece m ber 2 0 1 9  
 
1 2  M a y 2 0 2 0  
 
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 3  of 1 1 0  
2  
T A B L E O F C O N T E N T S  
 
1  
S Y N O P SI S  ............................................................................................................. 4  
2  
T A B L E O F C O N T E N T S  ................................................................................... 1 3  
3  
LI S T O F A B B R E VI A TI O N S  ............................................................................ 1 8  
A M E N D M E N T N o. 1  ..................................................................................................... 2 1  
A M E N D M E N T N o. 2  ..................................................................................................... 2 2  
A M E N D M E N T N o. 3  ..................................................................................................... 2 5  
A M E N D M E N T N o. 4  ..................................................................................................... 2 6  
4  
I N T R O D U C TI O N .............................................................................................. 2 8  
4. 1  
Bac k gr o u n d o n Bec k er M usc ular D ystr o p h y  ....................................................... 2 8  
4. 2  
Bac k gr o u n d o n Gi vi n ostat (I T F 2 3 5 7)  .................................................................. 2 9  
4. 2. 1  
N o ncli nical St u dies  ........................................................................... 3 1  
4. 2. 2  
Cl i nical E x perie nce wit h Gi vi n ostat I ncl u di n g Ris ks a n d Be nefits .. 3 5  
4. 2. 3  
Rati o nale of t he st u d y  ....................................................................... 3 8  
5  
S T U D Y O B J E C TI V E S A N D E N D P OI N T S  .................................................... 4 0  
5. 1  
St u d y O bjecti ves  ................................................................................................... 4 0  
5. 1. 1  
Pri mar y O bjecti ve  ............................................................................. 4 0  
5. 1. 2  
Sec o n dar y O bj ecti ves  ........................................................................ 4 0  
5. 1. 3  
Sec o n dar y E x pl or at or y O bjecti ves  .................................................... 4 0  
5. 2  
St u d y E n d p oi nts  .................................................................................................... 4 1  
5. 2. 1  
Pri mar y E n d p oi nt  .............................................................................. 4 1  
5. 2. 2  
Sec o n dar y E n d p oi nts ......................................................................... 4 1  
5. 2. 3  
Safet y E n d p oi nts  ............................................................................... 4 2  
5. 2. 4  
P har mac o ki netic E n d p oi nts ............................................................... 4 2  
5. 2. 5  
E x pl orat or y E n d p oi nts  ...................................................................... 4 2  
6  
I N V E S TI G A TI O N A L P L A N ............................................................................ 4 3  
6. 1  
Descri pti o n of O v erall St u d y Desi g n a n d Pla n  ..................................................... 4 3  
6. 2  
Disc ussi o n of St u d y Desi g n  .................................................................................. 4 4  
7  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  ................................... 4 4  
7. 1  
I n cl usi o n Criteria .................................................................................................. 4 4  
7. 2  
E xcl us i o n Criteria ................................................................................................. 4 5  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 4  of 1 1 0  
7. 3  
Wit h dra wal a n d R e m o val of Patie nts  ................................................................... 4 6  
7. 3. 1  
Safet y St o p pi n g R ules  ....................................................................... 4 8  
8  
T R E A T M E N T S  .................................................................................................. 5 0  
8. 1  
Details of St u d y  Treat me nts  ................................................................................. 5 0  
8. 2  
D osa ge  .................................................................................................................. 5 1  
8. 2. 1  
Rati o nal f or D ose Selecti o n  .............................................................. 5 1  
8. 2. 2  
D osa ge Sc he d ul e  ............................................................................... 5 3  
8. 3  
St u d y Treat me nt Assi g n me nt  ............................................................................... 5 4  
8. 4  
Bli n di n g  ................................................................................................................ 5 5  
8. 5  
Dr u g S u p pl y  .......................................................................................................... 5 6  
8. 5. 1  
Pac ka gi n g  .......................................................................................... 5 6  
8. 5. 2  
La belli n g  ........................................................................................... 5 6  
8. 5. 3  
St ora ge  .............................................................................................. 5 7  
8. 6  
Treat me nt A cc o u nta bilit y a n d C o m plia nce  .......................................................... 5 7  
8. 7  
Pri or a n d C o nc o mita nt Ill nesses a n d Me dicati o ns  ............................................... 5 8  
8. 7. 1  
Pri or a n d C o nc o mita nt Ill nesses  ....................................................... 5 8  
8. 7. 2  
Pri or a n d C o nc o mita nt Me dicati o ns  ................................................. 5 8  
8. 8  
Treat me nt f or h y pertri gl y ceri de mia  ..................................................................... 5 9  
9  
S T U D Y P R O C E D U R E S  .................................................................................... 5 9  
9. 1  
Pr oce d ures b y St u d y Visit  .................................................................................... 6 3  
9. 1. 1  
Visit 1 a n d Visit 2 - Scree ni n g ( Wee k -4 + 2 wee ks)  ....................... 6 3  
9. 1. 2  
Visit 3 - Ra n d o mizati o n ( Wee k 0)  .................................................... 6 4  
9. 1. 3  
Visit 4 ( Wee k 2 ± 3 da ys)  ................................................................. 6 4  
9. 1. 4  
Visits 5 ( Wee k 4 ± 3 da ys)  ................................................................ 6 5  
9. 1. 5  
Visit 6 ( Wee k 6 ± 3 da ys)  ................................................................. 6 5  
9. 1. 6  
Visit 7 ( Wee k 8 ± 3 da ys)  ................................................................. 6 5  
9. 1. 7  
Visit 8 ( Wee k 1 2 ± 7 da ys)  ............................................................... 6 6  
9. 1. 8  
Visit 9 ( Wee k 2 4 ± 7 da ys)  ............................................................... 6 6  
9. 1. 9  
Visit 1 0 ( Wee k 3 6 ± 7 da ys)  ............................................................. 6 7  
9. 1. 1 0  Visit 1 1: E n d of St u d y Visit ( E O S, 
Wee k 4 8 ± 7 da ys) a n d earl y 
wit h dra wal visit  ................................................................................. 6 8  
9. 1. 1 1  F oll o w -u p Visit ( Wee k 5 2) ( ± 7 da ys)  .............................................. 6 9  
9. 1. 1 2  U nsc he d ule d Visits  ........................................................................... 6 9  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 5  of 1 1 0  
9. 2  
St u d y C o ncl usi o n  .................................................................................................. 6 9  
1 0  
E F FI C A C Y A S S E S S M E N T S  ............................................................................ 7 0  
1 0. 1  Pri mar y Efficac y Assess me nt  ............................................................................... 7 0  
1 0. 2  Sec o n dar y Efficac y Assess me nts  ......................................................................... 7 0  
1 1  
P H A R M A C O KI N E TI C S A N D BI O M A R K E R S  ............................................ 7 1  
1 1. 1  P har mac o ki netic Sa m pli n g  ................................................................................... 7 1  
1 1. 1. 1  Bl o o d Sa m ples  .................................................................................. 7 1  
1 1. 2  P har mac o ki netic A n al ytical Met h o d ol o g y  ........................................................... 7 2  
1 1. 3  Bi o mar kers  ........................................................................................................... 7 2  
1 2  
S A F E T Y A S S E S S M E N T S  ................................................................................. 7 3  
1 2. 1  Vital Si g ns, wei g ht a n d hei g ht  .............................................................................. 7 3  
1 2. 2  P h ysical E xa mi nati o n  ........................................................................................... 7 3  
1 2. 3  Electr ocar di o gra m  ................................................................................................ 7 4  
1 2. 4  Ec h ocar di o gra m  .................................................................................................... 7 4  
1 2. 5  P ul m o nar y F u ncti o n Test  ..................................................................................... 7 4  
1 2. 6  La b orat or y Ass ess me nts  ....................................................................................... 7 5  
1 2. 7  A d verse E v e nts  ..................................................................................................... 7 7  
1 2. 7. 1  Defi niti o ns  ......................................................................................... 7 7  
1 2. 7. 2  A d verse E v e nt Re p orti n g  .................................................................. 7 9  
1 2. 7. 3  Seri o us A d verse E v e nt Re p orti n g  ..................................................... 8 1  
1 2. 7. 4  O ver d ose  ........................................................................................... 8 3  
1 2. 7. 5  Pre g na nc y re p orti n g  .......................................................................... 8 4  
1 3  
S T A TI S TI C A L A N A L Y SI S  .............................................................................. 8 4  
1 3. 1  Deter mi nati o n of Sa m ple Size  .............................................................................. 8 5  
1 3. 2  A nal ysis P o p ulati o ns  ............................................................................................ 8 5  
1 3. 2. 1  Inte nt -T o -Treat A n al ysis Set  ............................................................. 8 5  
1 3. 2. 2  Per Pr ot oc ol Set  ................................................................................. 8 6  
1 3. 2. 3  Safet y Set  .......................................................................................... 8 6  
1 3. 2. 4  P har mac o ki netic Set  .......................................................................... 8 6  
1 3. 3  De m o gra p hic a n d Baseli ne C haracteristics  .......................................................... 8 6  
1 3. 4  I n v esti gati o nal Me dici nal Pr o d ucts  ..................................................................... 8 7  
1 3. 5  Pri or a n d C o nc o mita nt T hera p y  ........................................................................... 8 7  
1 3. 6  Efficac y A nal ysis  .................................................................................................. 8 7  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 6  of 1 1 0  
1 3. 6. 1  A nal ysis of Pri mar y Effi cac y E n d p oi nt  ............................................ 8 7  
1 3. 6. 2  A nal ysis of Sec o n dar y Efficac y E n d p oi nts  ....................................... 8 8  
1 3. 7  P har mac o ki netic A n al ysis  .................................................................................... 9 1  
1 3. 8  Safet y A nal ysis  ..................................................................................................... 9 1  
1 3. 9  E x pl orat or y A nal ysis  ............................................................................................ 9 2  
1 3. 1 0  I nteri m A nal yses .................................................................................................. 9 3  
1 4  
S T U D Y M A N A G E M E N T  ................................................................................. 9 3  
1 4. 1  A p pr o val a n d C o nse nt  .......................................................................................... 9 3  
1 4. 1. 1  Re g ulat or y G ui deli nes ....................................................................... 9 3  
1 4. 1. 2  I n d e pe n de nt Et hics C o m mittees........................................................ 9 4  
1 4. 1. 3  Patie nt I nf or me d C o nse nt .................................................................. 9 4  
1 4. 1. 4  Disc o nti n uati o n of t he st u d y b y t he S p o ns or  .................................... 9 5  
1 4. 1. 5  Data Ha n dli n g  ................................................................................... 9 6  
1 4. 2  S o urce D oc u m e nts  ................................................................................................ 9 6  
1 4. 3  Rec or d Rete nti o n  .................................................................................................. 9 6  
1 4. 4  M o nit ori n g  ............................................................................................................ 9 7  
1 4. 5  Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ............................................................... 9 8  
1 4. 6  Pr ot oc ol A me n d me nt a n d Pr ot oc ol De viati o n  ...................................................... 9 8  
1 4. 6. 1  Pr ot oc ol A me n d me nt  ........................................................................ 9 8  
1 4. 6. 2  Pr ot oc ol De viati o ns  ........................................................................... 9 9  
1 4. 7  E t hical C o nsi derati o ns .......................................................................................... 9 9  
1 4. 8  Fi na nci n g a n d I ns ura n ce  ....................................................................................... 9 9  
1 4. 9  P u blicati o n P olic y/ Discl os ure of Data a n d C o nfi d e ntialit y  ................................ 1 0 0  
1 5  
R E F E R E N C E S  ................................................................................................. 1 0 1  
1 6  
A P P E N DI C E S  ................................................................................................... 1 0 4  
1 6. 1  C o m bi ne d list of dr u gs t hat pr ol o n g Q T a n d/ or ca use t ors a des d e P oi ntes ( T D P)
 ........................................................................................................................... 1 0 4  
1 6. 2  Dr u gs k n o w n t o be a s u bstrate of O C T 2 tra ns p orter  .......................................... 1 0 7  
1 6. 3  Dr u gs k n o w n t o be P -gl y c o pr otei n i n hi bit ors  .................................................... 1 0 8  
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 7  of 1 1 0  
I N-T E X T T A B L E S  
Ta ble 1:  E x p os ure mar gi ns f or C m a x  a n d A U C:  rat vs. D M D s u bjects a n d m o n ke y vs. D M D 
s u bjects ................................................................................................................... 3 3  
Ta ble 2:  I n v esti gati o nal Me dici nal Pr o d ucts ........................................................................ 5 1  
Ta ble 3:  Gi vi n ostat -Place b o Starti n g D ose  .......................................................................... 5 3  
Ta ble 4:  Gi vi n ostat -Place b o D ose M o dificati o n  .................................................................. 5 4  
Ta ble 5:  Sc he d ule of Assess me nts  ....................................................................................... 6 0  
Ta ble 6:  La b orat or y Ass ess me nt Sa m ples  ............................................................................ 7 6  
 
I N-T E X T FI G U R E S  
Fi g ure 1:  St u d y Desi g n  .......................................................................................................... 4 3  
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 8  of 1 1 0  
3  
LI S T O F A B B R E VI A TI O N S  
A b bre vi ati o n  
Defi niti o n  
4 S C  
4 -Stairs C li m b 
6 M W T  
Si x -Mi n ute Wal ki n g T est 
A D R  
A d verse Dr u g R eacti o n 
A E  
A d verse E v e nt  
A L P  
Al kali ne P h os p hatase  
A L T  
Ala ni ne A mi n otra nsferas e  
A N C O V A  
A nal ysis of C o varia nce  
a P T T 
Acti vate d Partial T hr o m b o plasti n T i me 
A S T  
As partate A mi n otra nsferase  
A T C  
A nat o mical T hera pe utic C he mical  
A U C  
Area U n der t he C ur ve  
bi d  
t wice dail y 
B M D  
Bec ker M usc ul ar D ystr o p h y  
B MI  
B o d y M ass In d e x  
B U N  
Bl o o d Urea N itr o ge n 
C K  
Creati ni ne P h os p h o ki nase  
C M H  
C oc hra n Ma ntel -Hae ns zel  
C M V  
C yt o me gal o vir us  
C R A  
Cli nical Researc h A ss o ciate  
C R P  
C -Reacti ve Pr otei n  
C S A  
Cr oss Secti o nal A rea  
C S R  
Cli nical St u d y R e p ort 
D A P C  
D ystr o p hi n -Ass ociate d Pr otei n C o m ple x  
D C M  
Dilate d Car di o m y o pat h y  
D M D  
D uc he n ne M us c ular D ystr o p h y  
E C G  
Electr ocar di o gra m  
E C H O  
Ec h ocar di o gra m  
e C R F 
electr o nic Cas e Re p ort F or m  
E D C  
Electr o nic Data Ca pt ure  
E O S  
E n d Of S t u d y 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 9  of 1 1 0  
F E V 1  
F orce d E x pirat or y V ol u me at 1 sec o n d  
F V C  
F orce d Vital Ca pacit y  
Ft 3  
Free T 3  
F U V  
F oll o w -U p Visit  
G C P  
G o o d Cli nical Practice  
G G T  
Ga m ma -Gl uta m yl T ra ns pe pti dase 
H Bs A g  
He patitis B s urface A nti ge n  
H C V  
He patitis C Vir us  
H D A C  
Hist o ne D eacet ylase  
H D A Ci  
Hist o ne Deacet ylase I n hi bit ors  
H D L  
Hi g h -De nsit y Li p o pr otei n  
H H M  
Ha n d -H el d M y o metr y  
I B 
I n v esti gat or’s Br oc h ure 
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 nizati o n 
I E C 
I n d e pe n de nt Et hics C o m mittee 
I L-1 β  
I nterle u ki n-1 bet a  
I T T 
I nte nti o n-t o-Treat  
I V R S 
I nteracti ve V oice Res p o nse S yste m 
I W R S 
I nteracti ve We b Res p o ns e S yste m 
L D H  
Lactate D e h y dr o g e nase  
L D L  
L o w -De nsit y Li p o pr otei n  
I F N-γ  
I nterfer o n ga m ma 
I L-6  
I nterle u ki n-1 2  
I L-1 2  
I nterle u ki n-6  
L L N  
L o wer Li mit N or mal  
L O C F  
Last O bser vati o n Carrie d F or war d  
M C H  
Mea n C or p usc ular H e m o gl o bi n  
M C H C  
Mea n C or p usc ular He m o gl o bi n C o nce ntrati o n  
M C V  
Mea n C or p usc ular V ol u me  
Me d D R A  
Me dical Dicti o nar y f or C o m pete nt Acti vities  
M F A F  
M uscle Fi bers Area Fracti o n  
M F F  
M uscle Fat F racti o n 
M F M  
M ot or F u ncti o n Meas ure me nt  
M RI  
Ma g netic Res o na nce I ma gi n g  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 0  of 1 1 0  
M R S  
Ma g netic Res o na nce S pectr osc o p y  
N O  
Nitric O xi de  
P E F  
Pea k E x pirat or y Fl o w  
PI  
Pri nci pal I n v esti gat or  
P K  
P har mac o ki netic  
P P S  
Per Pr ot oc ol Set  
P T  
Pr ot hr o m bi n T i me 
P T  
Preferre d Ter m  
Q T  
Q T i nter val  
Q Tc  
C orrecte d Q T i nter val  
Q Tc F  
Q T i nter val, Fri derici a’s c orrecti o n  
R O M  
Ra n ge o f Moti o n  
S A E  
Seri o us  A d verse E v e nt  
S A P  
Statistical A nal ysis Pla n  
S D  
Sta n dar d D e viati o n  
S F 3 6  
S h ort F or m 3 6  
S O C  
S yste m Or ga n Class  
T E A E  
Treat me nt -E mer ge nt A d verse E ve nt  
T F T  
Ti me d F u ncti o n T est  
T N F -α  
T u m or Necr osis F act or-al p ha 
U L N  
U p per Li mit N or mal  
W B C  
W hite Bl o o d C ell 
W H O -D R L  
W H O -Dr u g Refere n ce List  
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 1  of 1 1 0  
A M E N D M E N T N o.  1  
T he mai n p ur p ose s of t his pr ot oc ol a me n d me nt are:  
1.  T o s pecif y t hat t he fat fracti o n a n d cr oss s ecti o n e val uati o ns b y mea ns of Di x o n M RI 
will i n v ol ve m uscles of t he l o wer l e g, as w ell as t h ose of t he t hi g h a n d p el vic gir dle as 
ori gi nall y pla n ne d.  
2.  T o m o dif y t he a ge li mit state d i n I ncl usi o n Criteri o n 1 . A ge h as bee n raise d fr o m 6 0 
t o 6 5 years after I n v esti gat ors a d vise d of t he prese nce of p ote ntial p atie nts o ver t he 
a ge of 6 0 w h o ot h er wise meet all eli gi bilit y criteria . 
3.  T o delete t he re p etiti o n of t he f u ncti o nal t ests (i.e. ti me t o cli m b 4 sta n dar d ste ps, ti me 
t o rise fr o m fl o or, ti me t o wal k 1 0 m eters, m ot or f u ncti o n meas ure a n d m uscle 
stre n gt h) at t he ra n d o mi zati o n visit , si nce n ote w ort h y c ha n ges are n ot e x pecte d i n 
t hese patie nts wit hi n 1 m o nt h of scree ni n g. O nl y 6 M WT will be perf or me d a n d t he 
a vera g e of t he s c ores at scree ni n g a n d ra n d o mizati o n will be use d as baseli ne val ue.  
4.  T o c orrect t he i nf or mati o n relate d t o t he e v al uati o n of ser u m circ ulati n g pr otei ns as 
p ote ntial bi o mar kers f or B M D . T h ese a nal yses will n ot be carrie d o ut t hr o u g h 
S o ma Sca n ® tec h ni q ue beca use t he ce ntral la b orat or y ori gi nall y c h ose n f or t his st u d y 
n o l o n ger pr o vi des t his ser vice.  Bi o mar ker e v al uati o n will be perf or me d  b y a 
differe nt pr o vi der usi n g a n E LI S A -base d s yste m . 
5.  T o i ncrease  t h e fre q ue n c y of t h yr oi d f u ncti o n m o nit ori n g t o e ns ure p atie nt safet y. 
M o nit ori n g will n o w be carri e d o ut m o nt hl y u n til t he t hir d m o nt h a n d t h e n e v er y 3 
m o nt hs u n til t he e n d of t he st u d y. 
6.  T o i ncl u de  i nf or mati o n o n t he bac k u p s yste m f or ra n d o mizati o n a n d treat me nt 
assi g n m e nt. T he I nteracti ve V oice Res p o nse S yste m (I V R S)  will  be use d i n t he 
u nli kel y case of We b Res p o nse S yste m (I W R S) u na vaila bilit y.  
7.  T o c orrect t he i nf or mati o n o n t he uri ne a nal ysis, w hic h  will be d o ne b y di pstic k o n  
site a n d n ot b y t he ce ntr al la b. 
8.  T o i ncl u de mi n or c ha n g es t o i ncrease clarit y a n d c orrect t y p o gra p hic err ors.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 2  of 1 1 0  
T he c ha n g es i n t he pr ot oc ol affect I nf or me d C o nse nt a n d t heref ore  a re vise d I nf or me d 
C o nse nt t hat c o nsi ders  t he c ha n g es d escri be d i n t his  a me n d ment will be pr o vi de d a n d 
s u b mitte d f or a p pr o val.  
A M E N D M E N T N o. 2  
1.  T he 
mai n 
p ur p os e 
of 
A me n d me nt 
2 is t o a d dress safet y iss ue , na mel y 
t hr o m b oc yt o pe nia arisi n g f oll o wi n g  t he treat me nt of t he first 2 1 patie nts e nr olle d i n 
t he prese nt st u d y.  
T hr o m b oc yt o pe nia is a well -d oc u me nte d si de effect of treat me nt wit h gi vi n ostat  a n d 
miti gati o n meas ures  c o nsisti n g of treat me nt i nterr u pti o n a n d / or d ose re d ucti o n  were f ull y 
i nc or p orate d i nt o t he ori gi nal pr ot oc ol. As state d i n Secti o ns 7. 3. 1 a n d 8. 2. 2, pat ie nts wit h a 
platelet c o u nt < 7 5 x 1 0 9/ L b ut > 5 0 x 1 09/ L were t o te m p oraril y i nterr u pt treat me nt a n d t he n 
res u me it at a d ose le vel 1/ 3 s maller t ha n t he ori gi nal d ose ( 2 6. 7-4 6. 7 m g b.i. d acc or di n g t o 
b o d y wei g ht i nstea d of 4 0-7 0 m g b.i. d)  o n ce pl atelets a n d/ or ot her l a b orat or y p ara met ers 
were n or malize d . I n a d diti o n, in case of t w o c o nsec uti ve platelet c o u nts ≤ 1 5 0 x 1 0 9/ L 
patie nts were  t o r e d uce d osa ge as i n dicat e d a b o ve. 
D uri n g st u d y c o n d uct, t he S p o ns or n otice d a hi g h i nci de nce of p a tients re q uiri n g d os e 
re d ucti o n d ue t o t hr o m b oc yt o pe nia ( 11 / 2 1 patie nts , wit h  t hree re q uiri n g te m p orar y 
i nterr u pti o n). Si nce t he st u d y is still bli n de d, t he S p o ns or d oes n ot k n o w t he e xact n u m ber of 
patie nts w h o are o n gi vi n ostat. H o we ver, as treat me nt assi g n me nt is ra n d o mize d (rati o 2: 1), 
t he S p o ns or ca n ass u me t hat 2/ 3 of t he patie nts are ta ki n g gi vi n ostat, t heref ore 1 4/ 2 1 s h o ul d 
be i n t he gi vi n ostat gr o u p  a n d it is esti mate d t hat a p pr o xi matel y 8 0 % of patie nts i n t he 
gi vi n ostat gr o u p ( 1 1/ 1 4) re q uire d a d ose re d ucti o n. I n a d diti o n, 3 patie nts e x perie nce d a 
platelet c o u nt decreas e a n d are at ris k of d os e re d ucti o n, w hic h w o ul d bri n g t he  perce nta ge  of 
patie nts i n t he gi vi n ostat  gr o u p w h o re q uir e d or will li kel y re q uire a d os e re d ucti o n t o 1 0 0 % 
( 1 4/ 1 4). 
T hese preli mi nar y bli n d e d res ults t heref ore s u g gest t hat t he starti n g d ose of t he c urre nt 
pr ot oc ol w o ul d be diffic ult t o ma na ge o utsi de of a cli nical trial e n vir o n m e nt, a n d si nce t he 
c urre nt d ose re d ucti o n r ule is a de q uate i n kee pi n g a n acce pta ble le vel of platelets, a ne w 
starti n g d ose c orres p o n di n g t o t he re d uce d d ose of t he ori gi nal pr ot oc ol (i.e. 2 6. 7 -4 6. 7 m g 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 3  of 1 1 0  
b.i. d acc or di n g t o b o d y wei g ht) is n o w pr o p ose d b y t he S p o ns or a n d I n v esti gat or. T his ne w 
starti n g d ose e ns ures a mea n A U C 0 -2 4 si milar t o t hat ac hie ve d wit h 2 5 m g/ bi d base d o n t h e 
data fr o m st u d y D S C/ 1 1/ 2 3 5 7/ 4 3 i n D M D patie nts (i.e., a p pr o xi matel y 6 7 4 n g * h/ m L), w hic h 
s h o we d a n acce pta ble safet y pr ofile al o n g 
wit h de m o nstrati o n of si g nifica nt be nefits 
acc or di n g t o hist ol o gical e xa mi nati o n  (see m or e d etails i n secti o n 8. 2. 1 ). 
I n a d diti o n, ne w safet y r ules will be a p plie d, all o wi n g t he st u d y dr u g t o b e re d u ce d b y 2 0 % 
fr o m t he ne w starti n g d ose if t he patie nt meets st o p pi n g criteria (see secti o n 7. 3. 1 ). 
2.  A si g nifica nt i ncrease i n plas ma tri gl yceri de s has s o far bee n re p orte d i n f o ur patie nts 
u n der treat me nt alt h o u g h f or t w o of t he m t he i ncrease d le vels were alrea d y prese nt at 
baseli ne. U nli ke t hr o m b oc yt o pe nia, gi vi n ostat -relate d h y pertri gl yceri de mia has n ot 
bee n re p orte d i n pre vi o us st u dies lea di n g t o belie ve t hat s uc h c o n diti o n ma y be a 
s pecific feat ure of patie nts wit h Bec ker m usc ular d ystr o p h y. T he relati o ns hi p bet wee n 
h y pertri gl yceri d e mia, Bec ker m usc ul ar d ystr o p h y a n d treat me nt wit h gi vi n ostat is 
c urre ntl y u n d er st u d y. I n t he mea nti me, a n d t o saf e g u ar d p atie nt safet y, a ne w 
e xcl usi o n criteri o n h as bee n a d de d t o t he pr ot oc ol e xcl u di n g patie nts 
wit h 
h y pertri gl yceri d e mia , i.e. e xcl usi o n criteri o n n. 1 7 “ H y pertri gl yceri d e mia ( ˃ 1. 5 x 
u p per 
li mit 
of 
n or mal 
[ U L N]) . 
M ore o v er, 
f or 
patie nts 
w h o 
de vel o p 
h y p ertri gl yceri d e mia d uri n g t he st u d y treat me nt, a s afet y r ule was a d de d (e. g. t he 
St u d y treat me nt s h o ul d be te m p oraril y i nterr u pte d if Tri gl yceri d es > 3 0 0 m g/ d L; see 
secti o n 7. 3. 1 ), a n d t he I n v esti gat or will be all o we d t o prescri b e a n y a vaila ble 
treat me nt f or t his c o n diti o n (see secti o n 8. 8 ).  
F urt her m ore, t o pr o vi de t he hi g hest de gree of safet y, t he st u d y pr ot oc ol has bee n a me n de d t o 
i nte nsif y patie nt m o nit ori n g as f oll o ws:  
3.  A d diti o nal u nsc he d ule d visits wit h a car di ol o gist ma y be re q uir e d at t he discreti o n of 
st u d y cli nicia ns if pati e nts prese nt cli nical or i nstr u me ntal s us pici o n of car diac 
a b n or malities s uc h as si g ns a n d s y m pt o ms of h eart fail ure or n e w alterati o ns o n 
r o uti ne E C G (see T a ble 5  a n d secti o n 1 2 ).  
4.  A d diti o nal safet y assess me nts ( bl o o d tests) ma y be re q uire d at t he discreti o n of  st u d y 
cli nicia ns. T o 
mi ni mize i nc o n ve ni e nce t o patie nts, t hese ass ess me nts 
will be 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 4  of 1 1 0  
perf or me d at t he p atie nt’s h o me b y a l o cal q u alifie d n urse trai n e d in t he st u d y 
pr ot oc ol  (see T a ble 5  a n d secti o n 1 2 ). 
Ot her mi n or c ha n g es ha v e bee n ma de t o t he pr ot o c ol as f oll o ws:  
5.  Patie nts will be gi ve n a diar y t o assess c o m plia nce wit h st u d y t reat me nts (see 
a d diti o nal r o ws i n t he Ta ble 5 : “ Patie nt diar y dis pe nsati o n” at visit 3 a n d “ Patie nt 
c o m plia nce t hr o u g h diar y” at visit 8, 9, 1 0 a n d 1 1  a n d t he relate d visits descri pti o n i n 
secti o n 9. 1 ). 
6.  At t he discreti o n of t he I n vesti gat or, patie nts n ot meeti n g i ncl usi o n/e xcl usi o n cr iteria 
ma y be re -scree ne d t wice wit h a n i nter val of at least 3 0 da ys bet wee n assess me nts  
(see secti o n 7 ). 
7.  Eli gi bilit y criteria 
will be e val uate d at scree ni n g o nl y (a n d n ot als o at t he 
ra n d o mizati o n visit, see visit descri pti o n at secti o n 9. 1. 2  “ Re vi e w of eli gi bilit y 
criteria usi n g t he ass ess me nts d o ne at scree ni n g” ). 
8.  Clarificati o n of t w o e xcl usi o n  criteria, i.e. e xcl usi o n criteria n. 5 “ A dia g n osis of 
ot her u nc o ntr olle d ne ur ol o gical diseases or prese n ce of rele va nt s o matic dis or ders n ot 
relate d t o B M D t hat ma y i nterfere wit h t he a bilit y t o perf or m t he m uscle f u ncti o n 
tests a n d/ or t o c o m pl y wit h t he st u d y pr ot oc ol pr oce d ures” a n d n. 1 2 “ C urre nt 
ps yc hiatric ill ness/s ocial sit uati o ns re n deri n g t he p ote ntial patie nt u na ble t o 
u n dersta n d a n d c o m pl y wit h t he m uscle f u ncti o n tests a n d/ or wit h t he st u d y pr ot oc ol 
pr oce d ures” . 
9.  I n t he f o ot n ote n.3  of t he Ta ble 5  a n d secti o n 1 2. 3  was s pecifie d t he le vel of Q Tc F f or 
w hic h t he site has t o perf or me d t he 1 2 -lea d E C G i n tri plicate (e. g. 1 2-lea d E C G is t o 
be d o ne i n tri plicate at t he scree ni n g visit a n d d uri n g t he ot her visits if a n E C G 
de m o nstrates a pr ol o n ge d Q Tc F i nter val ˃ 4 5 0 msec o btai ne d o n 2 m ore E C Gs o ver a 
bri ef peri o d . If t he a vera ge d Q Tc F val ue meets t he st o p pi n g criteria ( > 5 0 0 ms), t he 
patie nt has t o i nterr u pt t he st u d y treat me nt ). 
1 0.  A descri pti o n of t h e m uscle bi o ps y ra n d o mizati o n pr oce d ure use d t o all ocate t he 
patie nt t o o ne of t he 2 m uscle bi o ps y se q ue nces b y t he s yste m: V 2: Ri g ht Ar m - V 1 1: 
Left Ar m or  V 2: L eft Ar m - V 1 1: Ri g ht Ar m , was a d de d (see secti o n 9. 1 ). 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 5  of 1 1 0  
1 1.  C ha n ges ha v e bee n ma d e t o i ncrease clarit y a n d c orrect t y p o gr a p hic err ors  (e. g. fat 
fracti o n ass ess me nt of t he s ole us m uscle b y M R S  see secti o n 5. 2. 2 , 1 0. 2  a n d 1 3. 6. 2 ).  
T he c ha n g es i n t he pr ot oc ol will be reflecte d i n a n a me n de d  I nf or me d C o nse nt t hat will be 
s u b mitte d f or a p pr o val. C ha n ges t o t he pr ot o c ol a n d c orres p o n di n g para gra p hs of t he 
s y n o psis are s h o w n i n t he trac k c ha n g es versi o n of t he pr ot oc ol usi n g stri ke t hr o u g h re d f o nt 
f or deleti o ns a n d re d u n d erli ne d f or a d diti o ns. 
A M E N D M E N T N o. 3  
T he mai n p ur p ose s of a me n d me nt 3 are as f oll o ws : 
1.  T he pr ot oc ol h as bee n i nte grate d wit h perti ne nt i nf or mati o n a d de d t o t he latest 
versi o n of t he I n v esti gat or’s Br oc h ure ( Versi o n 2 0 . 0).  
Secti o n 4. 2. 2 –  Cli nic al Ex perie nce wit h Givi n ost at I ncl u di n g Risks a n d Be nefits  –  
has bee n u p dat e d wit h ne w i nf or mati o n c o ncer ni n g  he m orr ha gic dr u g -relat e d A Es .  
Secti o n 8. 7. 2 –  Pri or a n d c o nc o mit a nt me dic ati o ns  –  n o w i ncl u des P -gl yc o pr otei ns 
( P-g p) as me di cati o ns w h ose use re q uires ca uti o n . T he st u d y dr u g is a P -gl yc o pr otei n 
a n d breast ca ncer resista nce pr otei n  ( B C R P) s u bstrate a n d t heref ore c o -a d mi nist rati o n 
of P -g p i n hi bit ors 
ma y res ult i n i ncrease d plas ma c o nce ntr ati o ns of gi vi n ostat. 
I n crease d oral a bs or pti o n is us uall y of li mite d cli nical c o ncer n e xce pt f or dr u gs t hat 
ha ve a  n arr o w t h era p e utic i n de x , w hic h is n ot t he case of gi vi n ostat. Ne vert heless , P-
g p i n hi bit ors s h o ul d be pr o perl y ma na ge d i n cli nical st u dies  a n d a ne w a p pe n di x 
( A p pe n di x 1 6. 3) listi n g P -g p i n hi bit ors has bee n a d de d t o t he pr ot oc ol.  
2.  Secti o n 9. 1. 1 0 –  E n d of St u dy Visit  –  a n d Ta ble 5 –  Sc he d ule of Assess me nts  –  n o w 
i n dicate t hat M RI/ M R S a n d bi o ps y e val u ati o ns sc he d ule d f or t he e n d of st u d y visit 
ma y be perf or me d o n differe nt da ys a n d t h at treat me nt is t o c o nti n ue u p t o t he last 
assess me nt.  
3.  Secti o n 1 3. 1 0 - I nt eri m A n alyses –  besi d es t he i nteri m a nal ysis f oresee n t o  c hec k  t he 
sa m ple size ass u m pti o n, it was deci d e d t o pla n a n a d diti o nal i nteri m a nal ysis t o o btai n 
a preli mi nar y o ver vie w of t he b aseli ne patie nt c haracteristics after st u d y e nr oll me nt is 
c o m plete d.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 6  of 1 1 0  
4.  T he I nteri m a n alysis secti o n of t he sy n o psis  ha s bee n  u p date d acc or di n g t o t he 
pr ot oc ol c ha n ges d escri b e d i n ite m 3.  
A M E N D M E N T N o. 4  
1.  T he mai n p ur p ose s of a me n d me nt  4 is t o a me n d t he pri mar y e nd p oi nt.  
T he c h oice of t he pri mar y e n d p oi nt was base d o n  t he hist ol o gical fi n di n gs c ollecte d 
after 
1 
year 
of tr eat me n t 
wit h 
gi vi n ostat i n t he 
p hase II cli nical trial 
( D S C/ 1 1/ 2 3 5 7/ 4 3) i n D M D (Bettic a et al. 2 0 1 6 ). I n t hat st u d y gi vi n ostat was a ble t o 
c o u nteract t he p at h o ge nesis of D M D b y i ncreasi n g fi ber C S A a n d M us cle Fi b er  Area 
Fracti o n ( M F A F %) a n d b y re d uci n g n ecr osis, fi br osis a n d fatt y re place m e nt. I n t he 
a bse nce of hist o m or p h o metrical data of m uscle bi o psies i n B M D a n d si nce fi br o -
a di p o ge nic m uscle re pla ce me nt is c o nsi dere d less pr o mi ne nt i n B M D vers us D M D, 
t he S p o ns or c o nsi dere d C S A t he para meter t hat c o ul d be b etter tra nslate d fr o m D M D 
t o B M D t o e val uate t he hist ol o gical effects of gi vi n ostat. The hist o pat h ol o gical 
feat ur es o bser ve d i n t he a nal ysis d o ne o n t he preli mi nar y 2 0 baseli ne bi o psies s h o we d 
t hat t he mea n C S A of t he bice ps fi bers i n B M D ( mea n: 4 8 7 1. 6 8 μ m2; mi n 1 9 3 3. 4 9 
μ m 2 ;a n d ma x 9 4 4 6. 3 4 μ m 2; a n d S. D.: 1 9 0 4. 8 6 μ m 2) is si milar t o t he a ge-matc he d 
C S A i n male a d ult healt h y i n di vi d uals  (i.e. fi ber t y pe 1 mea n 4 5 2 4. 6 2 ± 1 6 3 0. 4 3 μ m 2, 
fi ber t y pe 2 a 5 2 5 5. 9 3 ±  2 2 4 5. 1 4  μ m 2  a n d fi ber t y pe 2 b mea n  4 0 7 7. 8 1 ± 1 6 3 9 μ m 2) 
(Pereir a  et al. 2 0 1 4 ), alt h o u g h wit h a lar g er d e gree of fi b er siz e v aria bilit y  d ue t o  a 
s u bsta ntial n u m ber of b ot h h y pertr o p hic a n d h y p otr o p hic  fi bers. As a c o nse q ue nce, 
t he li keli h o o d t hat gi vi n ostat  ca n i ncrease t he C S A of fi ber s f urt her is l o w a n d als o it 
is d o u btf ul t hat a f urt her i ncreas e i n fi ber C S A 
w o ul d be be neficial. 
T he 
hist o pat h ol o gical feat ur e s o bser ve d i n t hes e preli mi nar y bi o psies c o nfir me d a 
si g nifica nt fi br o-a di p ose re place m e nt . C o nsi deri n g t hat t he hist ol o gic al res ults after 
1 2 m o nt hs of treat me nt wit h gi vi n ostat i n D M D c hil dre n s h o we d t hat gi vi n ostat 
si g nifica ntl y re d uce d t he a m o u nt of fi br otic a n d fat re place me nt (Bettic a et al. 2 0 1 6 ), 
a n d t hat t he  fi br o-a di p os e re place me nt ca n b e c o nsi dere d t he h all mar k of t he disease , 
t he c ha n g e of t otal fi br osis is c o nsi dere d a m ore i n dicati ve o utc o me m eas ure of t h e 
p ossi ble effect  of gi vi n ostat   relati ve t o t he assess me nt of C S A  a n d, he nce, it is t o be 
e val uate d as t he pri mar y e n d p oi nt f or t he trial . 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 7  of 1 1 0  
2.  Secti o ns “Sa m ple size  deter mi nati o n ” (1 3. 1 ) a n d “S tatistical A nal ysis ” (1 3 ) were 
re vise d a cc or di n g t o t he c ha n ge o f t he pri mar y e n d p oi nt  descri be d  a b o ve. A sa m ple 
size of 4 8 patie nts wit h e val ua ble baseli ne bi o psies (i n a 2: 1 rati o, 3 2 a n d 1 6 
res pecti vel y) will pr o vi d e 8 0 % p o wer t o test t he n ull h y p ot hesis of n o treat me nt effect 
( gi vi n ostat –  place b o) o n t otal fi br osis vs t h e alter nati ve h y p ot hesis t hat t h e treat me nt 
effect is ≥ 9 % usi n g a t w o -si de d t-t est wit h al p ha le vel of 5 % a n d ass umi n g a 
c o m m o n S D of 1 0 % ( wit h t he S D bei n g base d u p o n bli n de d i nteri m data fr o m first 2 0 
patie nts  wit h vali d pre a n d p ost -treat me nt bi o psi es ). Wit h a reas o na ble all o wa nce of 
5 % of  patie nts   wit h u n e val ua ble bi o psies at t he e n d of st u d y , t he t otal n u m ber of 
patie nts t o be ra n d o mize d is 5 1 .  
M ore o ver, i n t he c o nte xt of t he ne w pri mar y e n d p oi nt (it is e x pecte d t hat t otal fi br osis 
( %) will i ncrease less i n t he gi vi n ostat gr o u p t ha n i n t he place b o  gr o u p ) a L O C F  
a nal ysis is c o nsi dere d n ot a p pr o priate beca us e a n y missi n g f oll o w -u p val ue will be  
re place d b y t hat s u bject’s pre vi o usl y o bser ve d val ue (i.e. t he baseli ne val u e) a n d t his 
a p pr oac h ca n be q uesti o na ble a n d n ot c o nser vati ve , f or t his reas o n a m ulti ple 
i m p utati o n met h o d  will be use d t o ha n dle missi n g data .  
3.  Secti o n s “St u d y Desi g n ” (6. 1  a n d 6. 2 ) a n d “I nteri m A nal ysis” (1 3 ) w ere u p date d 
i ncl u di n g a descri pti o n of c o ncl usi o ns  o n t he first bli n de d i nteri m a nal ysis perf or me d 
o n t he first 2 0 baseli ne bi o psies  w hic h le d t he pr ot oc ol a me n d me nt n.  4. as descri be d 
a b o ve. T h e d etails a b o ut met h o d ol o g y a n d t he res ults are re p ort e d i n t h e s p ecific S A P 
a n d Statistical Re p ort a vaila ble as sta n d -al o ne d oc u me nts.  
4.  Secti o n  “ Bi o mar ker” ( 1 1. 3 ) was m o difie d t o i n dicate t hat p atie nts w h o h a ve alr ea d y 
c o ncl u de d t he st u d y ma y be as ke d t o r et ur n t o t he ce nter f or a bl o o d s a m ple c ollecti o n  
necessar y f or L T B P 4 a n d Oste o p o nti n ge n ot y pi n g  if t he sa m ple was n ot alrea d y 
collecte d .  
 
 
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 8  of 1 1 0  
4  
I N T R O D U C TI O N 
4. 1  
B ac k gr o u n d  o n Bec ker  M usc ul ar D ystr o p h y  
D ystr o p hi n o pat hies i ncl u de a s pectr u m of m uscle disease s ca use d b y pat h o ge nic varia nts i n 
t he D M D  ge ne, w hic h e n c o des t he pr otei n d ystr o p hi n. T he mil d e n d of t he s pectr u m i ncl u des 
t he p he n ot y pes of as y m pt o matic i ncreas e i n t he ser u m c o nce ntr ati o n of creati ne 
p h os p h o ki nase ( C K) a n d m uscle cra m ps wit h m y o gl o bi n uria . T he s e v ere e n d i n cl u des 
pr o gressi ve m uscle diseases t hat are classifie d as D uc he n ne/ Bec k er m usc ular d ystr o p h y 
w he n s keletal m uscle is pri maril y affecte d a n d as D M D -ass ociate d dilate d car di o m y o pat h y 
( D C M) w he n t he h eart is pri maril y affecte d (D arr as  et al. 2 0 0 0 ). T h e B M D p he n ot y pe 
occ urs w he n s o me d ystr o p hi n is pr o d uce d d ue t o  deleti o ns or d u plicati o ns t hat j u xta p ose i n -
fra me e x o ns, s o me s plici n g varia nts, a n d m ost n o n-tr u ncati n g si n gle-bas e c ha n ges t hat res ult 
i n tra nslati o n of a pr otei n pr o d uct wit h i ntact N a n d C ter mi ni. T he s h orter-t ha n-n o r mal 
d ystr o p hi n pr otei n m olec ule, w hic h retai ns partial f u ncti o n, pr o d uces t he mil der Bec ker  
p he n ot y pe ( D e b ur gr ave et al. 2 0 0 7 ). 
Bec ker 
m usc ular d ystr o p h y ( B M D) occ urs i n 
a p pr o xi matel y 1 i n 3 0, 0 0 0 male birt hs ( He d ge et al. 2 0 0 8 ). 
S y m pt o ms of Bec ker m usc ula r d ystr o p h y us uall y be gi n i n t he tee ns or late t we nties. I nitial 
s y m pt o ms ma y i ncl u de cra m pi n g a n d re d u ce d e n d ura nce d uri n g e xercise. M uscle gra d uall y 
deteri orat es i n t he hi ps, pel vis, t hi g hs a n d s h o ul ders lea di n g t o wal ki n g o n t oes wit h t he 
st o mac h f or ward. S h orte ni n g of m uscl e fi bers ca n res ult i n t he i na bilit y t o m o ve certai n 
m uscles (c o ntract ures). T he pr o gressi o n of B M D is sl o wer a n d m ore varia ble t ha n D uc he n ne 
M usc ular D ystr o p h y  ( D M D) b ut us uall y res ults i n t he nee d f or a w heelc hair.  
S u bcli nical or c li nical car diac i n v ol ve me nt is prese nt i n a p pr o xi matel y 9 0 % of i n di vi d uals 
wit h B M D a n d is c haract erize d b y re place me nt of m y ocar di u m wit h  c o n necti ve tiss ue or fat. 
T he left ve ntric ular w alls are m ost e xte nsi vel y affect e d, s pari n g t he ri g ht ve ntricle a n d t he 
atri u m. T y pical i nitial ma nifestati o ns of car diac i n v ol ve me nt are si n us tac h ycar dia, tall R 1 i n 
V 1, pr o mi ne nt Q i n I, a V L, V 6 or i n II, III, a n d a V F, i ncrease d Q T dis persi o n a n d p ossi bl y 
a ut o n o mic d ysf u ncti o n. I nitiall y, ec h ocar di o gra p h y is n or mal or s h o ws re gi o nal wall m oti o n 
a b n or malities i n areas of fi br osis. Wit h s prea di n g of fi br osis, left ve ntric ul ar d ysf u ncti o n a n d 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 2 9  of 1 1 0  
ve ntric ular arr h yt h mias a d diti o nall y occ ur. Heart fail ure a n d s u d de n d eat h ma y occ ur i n t he 
fi nal sta ges of t he disease  (Fi nsterer a n d  St oll ber ger 2 0 0 3 ).  
T he dia g n osis of Bec ker m usc ular d ystr o p h y is base d o n p h ysical s y m pt o ms, fa mil y hist or y, 
a n ele vate d c o nce ntrati o n of creati ne ki nase ( C K) i n t he bl o o d i n dicati n g destr ucti o n of 
m uscle, a n d m olec ular g e netic testi n g. D M D is t he o nl y g e ne t h at has bee n ass o ciate d wit h 
Bec ker m usc ular d ystr o p h y a n d ma n y differe nt t y pes of D M D ge ne m utati o ns ha ve bee n 
i de ntifie d i n i n di vi d uals wit h t his c o n diti o n. I d e ntificati o n of a D M D g e ne m utati o n fr o m 
m olec ular g e netic testi n g c o nfir ms t he dia g n osis.  If m olec ular g e netic testi n g is perf or me d 
a n d a D M D ge ne m utati o n is n ot f o u n d, a s keletal m uscle bi o ps y is rec o m me n de d t o e xa mi ne 
t he prese n ce of t he d ystr o p hi n pr otei n.  
N o s pecific treat me nt is a vaila ble f or Bec ker m usc ular d ystr o p h y b ut q ualit y of life  a n d 
lifes pa n ca n b e i m pr o ve d wit h a p pr o priat e care. P h ysical a n d occ u p ati o nal t hera p y ca n 
re d uce or d ela y j oi nt c o ntract ures. S ur ger y is s o meti mes rec o m me n d e d t o treat c o ntract ures 
or sc oli osis. 
Wei g ht c o ntr ol ca n hel p t o re d uce stress o n t he heart a n d 
m u scles. 
C ortic oster oi ds are oft e n prescri be d t o h el p sl o w d o w n t he l oss of m uscle f u ncti o n. R o uti ne 
m o nit ori n g b y a car di ol o gist is rec o m me n de d.  O nl y fe w d r u gs are u n der i n vesti gati o n 
i ncl u di n g Atal ure n, a n orall y s mall-m olec ule c o m p o u n d t hat i nteracts wit h t he ri b os o me, t o 
e na ble t he ri b os o me t o rea d t hr o u g h pre mat ure n o nse nse st o p si g nals o n m R N A a n d all o w 
t he cell t o pr o d uce a s h ort-le n gt h, f u ncti o nal d ystr o p hi n; a n d gra n ul oc yte  c ol o n y -sti m ulati n g 
fact or ( G-C S F) , w hic h w as re p orte d t o e x ert t he pr oliferat i o n of satellite cells, t he re g ulati o n 
of m y o blast pr oliferati o n, a n d t he differe ntiati o n a n d pr o m oti o n of m uscl e  re g e nerati o n a n d 
re pair ( htt ps://cli nicaltrials. g o v). 
4. 2  
B ac k gr o u n d o n  Gi vi n ost at  (I T F 2 3 5 7) 
Zi nc de pe n de nt hist o ne deacet ylases  ( H D A Cs) are a class of 1 1 is oe nz y mes ass ociate d wit h 
n u mer o us n uclear re press or c o m ple xes t hat, o nce recr uite d t o s pecific sites of e uc hr o m ati n, 
mai ntai n n ucle os o me hist o nes i n a state of deacet ylati o n s o t hat 
d e o x yri b o n ucleic aci d 
(D N A ) re mai ns ti g htl y bo u n d a n d i naccessi ble t o tra nscri pti o n fact ors f or g e ne e x pressi o n. I n 
c o ntrast, i n hi biti o n of H D A C res ults i n h y peracet ylati o n of t hese hist o nes a n d all o ws t he 
u nra veli n g of D N A s ufficie nt f or t h e bi n di n g of tra nscri pti o n fact ors a n d t he s y nt hesis of 
mess e n ger ri b o n u cleic aci d (m R N A ). 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 0  of 1 1 0  
Gi vi n ostat  is a n orall y acti ve h y dr o xamic aci d deri vati ve wit h  p ote nt H D A C ( C lass I a n d II) 
i n hi bit or y acti vit y. C o nse q ue ntl y , g i vi n ostat s hares t he a nti-t u m or pr o perties of t he hist o ne 
deacet ylase i n hi bit or ( H D A C i)- class. In t he cli nic, t he H D A C i d oses re q uire d t o ac hie ve 
effic ac y i n ca ncer patie nts are ge n erall y p o orl y t olerate d ( G u h a 2 0 1 5), h o we ver while 
reacti vati o n of e pi ge n eticall y sile nce d t u m or s u p press ors a p p are ntl y re q uires hi g h 
c o nce ntr ati o ns of H D A C i, s o me ge n e pro m oters ma y be affecte d at m uc h l o w er a n d b etter 
t olerate d d oses. It has bee n s u g geste d t h at re g ul at ors of cell fate  i n ste m or pr o ge nit or cells 
are u n d er t he c o ntr ol of pr o m oters t hat are i n a p oise d, “ bi vale nt” st ate, c haract erize d b y t he 
si m ulta ne o us prese nce of b ot h c hr o mati n  acti vati o n a n d sile nci n g mar ks  wit hi n t he sa me 
re g ulat or y re gi o n ( Az u ar a et al. 2 0 0 6 , B er nstei n et al. 2 0 0 6 ). E x p os ure t o l o w d os es of 
H D A C i ma y, i n t hese cas es, ti p t he bala nce a n d re dir ect differe ntiati o n pr o gra ms.  
D ystr o p hi n i nteracts wit h a gr o u p of peri p heral me m bra ne a n d tra ns me m bra ne pr otei n s t o 
f or m t he d ystr o p hi n-ass o ciate d pr otei n c o m ple x ( D A P C), w hic h pr o vi des t he m olec ular li n k 
bet wee n t he c yt os kelet o n a n d t he e xtracell ul ar m atri x of s keletal m y ofi bers  t hat is disr u pte d 
i n d ystr o p hic m uscle (Erv asti 2 0 0 7 ). As s uc h, D A P C s u p p orts sarc ole m mal i nte grit y d uri n g 
m uscle c o ntracti o n. Ne ur o nal nitric o xi de s y nt has e ( n N O S) is a n i m p orta nt c o m p o ne nt of t h e 
D A P C. Nitric o xi de ( N O) pr o d uce d b y n N O S was s h o w n t o s pecificall y i nacti vate H D A C 2 
via S -nitr os ylati o n of a c ys tei ne resi d ue (C ol ussi  et al. 2 0 0 8 ). T his 
mec ha nis m is 
d ysf u ncti o nal i n d ystr o p hic m uscle, lea di n g t o a berra n tl y u pre g ul ate d H D A C acti vit y. T here 
are at least t w o disti nct mec ha nis ms b y w hic h t his u pre g ulati o n i m pi n ges pat h ol o gicall y o n 
cell fate d ecisi o ns d uri n g m uscle re ge n erati o n ( C o ns alvi  et al. 2 01 1 ):  
1.  Resi de nt m uscle i nterstitial  fi br o-a di p o ge nic pr o ge nit ors ( F A Ps) ret ai n t he a bilit y t o t ur n 
i nt o fi br oa di p oc ytes i n res p o nse t o si g nals release d b y de ge nerati n g m uscl es. T hese cells 
affect differe ntiati o n of m uscle satellite cells i nt o m uscle fi bers t hr o u g h secreti o n of 
f ollistati n, t he e n d o ge n o us a nta g o nist of t he m ost p ote nt i n hi bit or of skelet al m y o ge nesis, 
m y ostati n. 
Direct i n hi biti o n of 
m y ostati n or deli ver y of f ollistati n e xerte d si milar  
be neficial effects i n m d x mice, t he m o use m o del of D M D. T he f ollistati n ge ne pr o m oter 
is c o ntr olle d b y H D A C 2 i n m uscle cells ( Mi netti et al. 2 0 0 6 ) a n d dir ect i n hi biti o n of 
H D A C 2 b y  H D A Ci, or i nacti vati o n b y eit her 
N O  d o n ors or b y rec o nstit uti o n of  
d ystr o p hi n -N O si g nali n g lea ds t o dere press i o n of f ollistati n, w hic h me diates t he a bilit y of 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 1  of 1 1 0  
H D A Ci a n d N O si g nali n g t o sti m ulate 
m y o ge nesis 
i n vitr o a n d c o u nters 
m uscle 
de ge nerati o n i n m d x mice.  
2.  Hist o ne deacet ylas e i n hi bit ors  ma y directl y sti m ulate t he m y o ge nic differe ntiati o n of 
F A Ps . T he  H D A C i n hi biti o n i n d uces t w o c ore c o m p o ne nts of t he 
m y o ge nic 
tra nscri pti o nal mac hi ner y, 
M y o D a n d B A F 6 0 C, a n d u p-re g ulates t he m y o ge nic mi Rs 
( m y o mi Rs) ( mi R-1. 2, mi R -1 3 3, a n d mi R -2 0 6), w hic h t ar get t h e alter nati ve B A F 6 0 
varia nts B A F 6 0 A a n d B A F 6 0 B, ulti matel y pr o m oti n g pr o m y o ge nic differe ntiati o n w hile 
s u p pressi n g t he fi br o-a di p o genic p he n ot y pe ( S acc o ne  et al. 2 0 1 4 ). H ist o ne deacet ylase 
i n hi bit ors, t heref ore, see m t o dere press a ‘‘late nt’’ m y o ge nic pr o gra m i n F A Ps fr o m 
d ystr o p hic m uscles, at least at earl y sta ges of disease.  
B y i n hi biti n g se veral pr o -i nfla m mat or y c yt o ki nes (e. g., t u m or necr osis fact or-al p ha [T N F -α ], 
i nterle u ki n -1 bet a [ I L-1 β ], i nterfer o n ga m ma [I F N-γ], I nterle u ki n-6 [ I L-6 ], a n d I nterle u ki n 1 2 
[I L-1 2 ]), g i vi n ostat als o re d uces t h e pr o d ucti o n a n d acti vit y of pr o -i nfla m mat or y c yt o ki nes 
(Le o ni  et al. 2 0 0 5, J o oste n et al. 2 0 1 1 ), w hic h ha ve bee n s h o w n t o i n hi bit m uscle satellite 
cell differe ntiati o n i nt o  m uscle fi bers  (B ol dri n et al . 2 0 1 5 , Tier ney et al. 2 0 1 4 , D oles a n d 
Ol wi n  2 0 1 4 ).  
N o n -cli nical data i n a c or neal fi br osis ra b bit m o del a n d i n a m o use m o d el of li ver fi br osis  
s u g gest als o a nti-fi br otic pr o perties of gi vi n ostat (Li m et al, 2 0 1 6; W a n g et al, 2 0 1 5 ). 
E x peri me ntall y, t he precli nical effecti ve n ess of gi vi n ostat was de m o nstrate d i n 
m o use 
m o dels wit h  m usc ular d ystr o p h y, s uc h as t he m d x mice . Gi vi n ostat  pr o d uce d be n eficial 
f u ncti o nal a n d m or p h ol o gical effects, s uc h as i n creas e d cr oss-s ecti o nal area of m y ofi bers, 
decrease d  i nfl a m mat or y i nfiltrate, a n d pre ve nti o n of fi br otic scars, w hic h c o ntri b ute t o 
c o u nter t he m uscle l oss a n d t he f u ncti o nal decli ne t hat  are t y pi call y o bser ve d i n m d x mice . 
4. 2. 1  N o ncli nic al St u dies   
A sta n dar d n o ncli nical pr o gra m c o m p os e d of s afet y p har mac ol o g y, p har mac o ki netics, si n gle 
a n d re peat d ose t o xicit y, 
m uta ge nicit y/ ge n ot o xicit y, re pr ot o xicit y a n d j u ve nile t o xicit y 
st u dies has alrea d y bee n carri e d o ut t o s u p p ort t he oral a d mi nistrati o n of gi vi n ostat t o a d ult 
a n d p e diatri c s u bjects. Details of eac h st u d y are a v aila ble i n t he c urre nt I n vesti gat or’s 
Br oc h ure  (I B). 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 2  of 1 1 0  
I n s u m mar y, i n rats t he pre d o mi na nt t o xicities at t he hi g hest d oses were he mat ol o gic, wit h 
lar ger d ecreases i n w hite bl o o d cells ( W B C) a n d s maller effects o n re d bl o o d cells  ( R B C) 
a n d platelets. This t o xicit y patter n is differe nt fr o m t he o ne o bser ve d  i n h u ma ns, w here 
t hr o m b oc yt o pe nia a n d n ot le u k o pe nia is d ose-li miti n g. 
N o n -he mat ol o gic t o xicit y i n rats i ncl u de d c ha n ges i n bl o o d c he mistr y: decrease i n t otal 
pr otei ns, al kali ne p h os p hatase ( A L P), ala ni ne a mi n otra nsferase ( A L T) a n d i ncrease i n 
as partate a mi n otra nsferas e ( A S T), bilir u bi n, urea , creati ni ne a n d tri gl yceri d es. T hese c h a n g es 
were m o dest (e q u al t o or less t ha n 5 0 %), t heir e xte nt o verla p pe d wit h t hat of c o ntr ol a ni mals 
a n d t he y w ere n ot c o nsi d ere d  of t o xic ol o gical si g nifica nce.  L o wer wei g ht of li ver, s ple e n a n d 
a dre nals was als o o bser ve d . The u n derl yi n g hist o pat h ol o gical c ha n g es were mi ni mal  i n all 
cases a n d all pat h ol o gic effects tre n de d t o war d re v ersi bilit y f oll o wi n g t he rec o ver y peri o d.   
In t he 3 9 -wee k st u d y i n m o n ke ys, he mat ol o gic t o xicities were of mi n or si g nifica nce, wit h a 
mi ni mal decreas e i n R B C c o u nts see n d uri n g a n d at t he e n d of t h e treat me nt  peri o d at t h e 
hi g h d ose o nl y. A d ose -relate d decrease i n wei g ht of t he t h y m us was o bser ve d i n b ot h se xes 
at all d oses. Hist ol o gicall y, a n i ncreas e d i nci d e nce of mi ni mal i n v ol uti o n/atr o p h y was 
o bs er ve d i n h i g h-d ose a ni mals. T he d ose of 1 2  m g/ k g / da y was defi ne d as t he N o -A d verse 
Effect Le v el ( N O A E L) u n der t he c o n diti o ns use d i n t his  st u d y, e v e n if t he c o m p o u n d was 
well t olerate d als o a t t he hi g hest d ose of 3 0 m g/ k g. A d diti o nal fi n di n gs i ncl u de d mi ni mal 
effect s o n h e patic e nz y mes ( A L T, A S T), tri gl y ceri des, a n d bilir u bi n. S o me of t hes e effects 
were o bser ve d at i nter me diate e xa mi nati o n ( Wee k 2 0) a n d partiall y rec o vere d at t h e e n d of 
t he treat me nt peri o d. Treat me nt -relate d effects were o bser ve d at t he hi g h d ose als o i n t he 
b o n e marr o w a n d li ver. T he b o ne marr o w s h o we d sli g htl y re d uce d cell ularit y i n t w o a ni mals 
gi ve n 3 0  m g/ k g/ da y . T he li ver s h o we d mi ni mal bile d uct h y per plasia i n t w o male a ni mals o ut 
of f o ur  recei vi n g 3 0 m g/ k g/ da y. 
Gi vi n ostat is eli mi nate d f or a p pr o xi matel y 5 0 % i n feces after I V a d mi nistrati o n t o rats, 
hi g hli g hti n g t h e q ua ntitati ve i m p orta nce of biliar y e xcreti o n.  I n a d diti o n, a m ore i nte nsi v e 
bi otra nsf or mati o n occ urs i n a ni mal s pecies wit h res pect t o h u ma ns as s h o w n i n i n vitr o 
meta b olic sta bilit y t ests 
wit h he pat oc ytes of differe nt s pecies (I ntri nsic 
Cleara nce 
( µ L/ mi n * 1 0 6 cells: h u ma ns = 4. 0; m o n ke y = 2 5. 4; d o g = 3 2. 4; rat= 3 3. 8; m o use = 4 2. 0). B ile d uct 
h y per plasia is t h us li kel y t o be t he res ult of a pr o n o u nce d met a b olis m a n d e x creti o n of 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 3  of 1 1 0  
gi vi n ostat i n t he  precli nical s pecies, w hic h is als o ass ociate d wit h i nc rease d plas ma bilir u bi n 
le vels. T heref ore, t his fi n di n g ca n  b e easil y m o nit ore d i n h u ma ns.  Of n ote, n o i ncrease of 
he patic e n z y me or bilir u bi n has bee n rec or de d i n  s u bjects treate d s o far; bilir u bi n le vels are 
als o m o nit ore d cli nic all y i n D M D s u bjects  wit h, s o far, n o e vi de nce of  si g nifica nt alterati o ns, 
pr o vi di n g n o c o nfir mati o n of  t he occ urre n ce of a n al o g o us t o xicities i n h u ma ns. 
T he ma xi m u m o bser ve d c o nce ntr ati o n  (C ma x ) a n d area u n der t he c ur ve ( A U C ) safet y m ar gi ns 
were calc ulat e d usi n g t he N O A E L of 1 0 m g/ k g / da y o btai ne d i n rats after 6 m o nt hs of 
a d mi nistrati o n, t he N O A E L of 1 2 m g/ k g / da y o btai ne d after e x p osi n g m o n ke ys f or 3 9 
c o nsec uti ve wee ks , a n d t he act ual h u ma n data o btai ne d i n t he cli nical st u d y i n D M D s u bjects  
(S t u d y D SC/ 1 1/ 2 3 5 7/ 4 3) after 1 2 m o nt hs  a d mi nistrati o n of 3 7. 5 m g t wice dail y (bi d ) (i.e., 
C ma x  a p pr o xi matel y 1 0 4 n g/ m L a n d  A U C a p pr o xi mate l y 1 1 4 4 n g * h/ m L). T he h u ma n 
e x p os ure ac hie v e d at t his d ose le vel is t h e e x p os ure t o b e use d i n t his st u d y 
( D S C/ 1 5/ 2 3 5 7/ 5 3). 
Safet y rati os calc ulate d usi n g data fr o m b ot h t he a ni mal s pecies use d i n t o xic ol o g y st u dies 
differe d q uit e mar k e dl y o ne fr o m t he ot her. T he rat t o h u ma n e x p os ure mar gi ns ( Ta ble 1 ) 
were 0. 1 6 ( C ma x ) a n d 0. 0 4 ( A U C) at t he h u ma n e x p os ure c o nsi dere d (i.e., C ma x  a p pr o xi matel y 
1 0 0 n g/ m L a n d A U C a p pr o xi matel y 1 1 5 0 n g * h/ m L), w hil e t he e x p os ure mar gi ns C ma x  a n d 
A U C were lar ger f or m o n ke ys t ha n t h ose see n i n rats.  T he C ma x  rati o was a b o ut 2. 4 f ol d an d 
t he mea n A U C rati o was 0. 3 4. A m ore i nte nsi ve bi otra nsf or mati o n is o bser ve d i n rats a n d 
m o n ke ys as e vi de nce d b y t he lar ger i ntri nsic cleara nce a n d t he s h orter half -life of gi vi n ostat 
i n rats a n d m o n ke ys c o m pare d t o h u ma ns.  
Ta ble 1 : E x p os ure mar gi ns f or C ma x  a n d A U C:  rat vs. D M D s u bjects a n d m o n ke y vs. D M D 
s u bjects 
R ati os N O A E L r ats/ p ae di at ric D M D e x p os ure  
R ati os N O A E L m o n ke y/ p ae di atric D M D e x p os ure  
 
C m a x  
A U C 0 -t 
 
C m a x  
A U C 0 -t 
Wee k 2 6  
0. 1 6  
0. 0 4  
Wee k 3 9  
2. 4 0  
0. 3 4  
N O A E L =  n o -o bser ve d -a d verse -effect -le vel; D M D =  D uc he n ne m usc ular d ystr o p h y; C ma x =  ma xi m u m o bser ve d 
c o nce ntrati o n; A U C 0 -4 =  area u n der t he c ur ve (o ver t he first 4 h o urs)  
E ve n t h o u g h t he safet y mar gi n s bet wee n N O A E L i n n o n -cli nical st u dies/ p e diatric D M D 
e x p os ure are < 1 (e xce pt f or Cma x m o n ke y), t he mai n fi n di n gs o bser ve d i n n o n -cli nical 
t o xic ol o g y st u dies (e. g., re d ucti o n i n w hite bl o o d cells, cell ularit y re d ucti o n i n b o ne marr o w, 
re d uce d t h y m us wei g ht, a n d bile d uct h y per plasi a) were o bser ve d at hi g h d oses of gi vi n ostat 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 4  of 1 1 0  
(e. g., rats, 9 0-1 6 0 -2 5 0 m g/ k g/ da y de pe n di n g o n t he treat me nt d urati o n; d o gs, 5 0 m g/ k g/ da y; 
a nd m o n ke ys, 3 0 -9 0 m g/ k g/ da y);  all of t he m, as descri be d a b o v e, ca n a n d will be caref ull y 
m o nit ore d d uri n g t his cli nical st u d y. 
C o ncer ni n g safet y p har mac ol o g y, gi vi n ostat has a fa v ora ble pr ofile. T he I C 5 0 of gi vi n ostat 
i n t he i n vitr o h E R G assa y was 1. 4 µ M. At 3 a n d 1 0 µ M, gi vi n ostat i ncreas e d t he acti o n 
p ote ntial d urati o n at 5 0 % a n d 9 0 % re p olarizati o n d uri n g bra d ycar dia , alt h o u g h n ot i n a 
statisticall y si g nifica nt ma n ner. Gi vi n ostat di d n ot i n d uce a n y mar ke d c ha n ges i n heart rate, 
electr ocar di o gra m ( E C G ) i nter vals, or wa vef or m at a n y d ose i n i n viv o i n a car di o vas c ular 
st u d y i n d o gs.  T he c o m bi ne d e vi de nce fr o m t hese i n vitr o a n d i n viv o st u dies pl us t he lac k of 
acc u m ulati o n of dr u g i n t he heart as see n i n tiss ue distri b uti o n st u dies, s u g gest t hat t he dr u g 
is u nli kel y t o e xert a n y car di o vasc ul ar si de effect at t hera pe utic d os es. T he 
ma xi mal 
circ ulati n g c o n ce ntrati o ns see n i n b ot h a d ult  a n d p e diatric s u bjects recei vi n g t he hi g hest 
d oses of gi vi n ostat were ge nerall y bel o w 1 0 0 -1 5 0 n g/ m L ( 2 0 0 -3 0 0 n M) of t otal gi vi n ostat, 
c orres p o n di n g t o 5 -7. 5 n g/ m L ( 1 0 -1 5 n M) of free gi vi n ostat, a p pr o xi matel y 9 0 -1 4 0 f ol d less 
t ha n t he I C 5 0 o n h E R G. 
Fi nall y, gi vi n ostat was p os iti ve f or fra mes hift m utati o ns i n t he bact erial m uta ge nesis ass a y ( 2 
o ut of 5 strai ns), ne g ati ve i n t w o i n vitr o ma m malia n cell assa ys a n d i n t w o i n viv o 
ge n ot o xicit y st u dies i n rats res ulti n g n ot ge n ot o xic t o ma m malia n or ga nis ms .  
N o ncli nical e vi de n ce s u p p orts a p ote ntial t hera p e utic r ole of g i vi n ostat i n D M D. A  d ose -
fi n di n g st u d y usi n g d oses of g i vi n ostat ra n gi n g fr o m 1 t o 1 0 m g/ k g/ da y orall y deli vere d dail y 
f or 3 m o nt hs t o m d x (i.e., m uri ne m o del of D M D) mice ( 2 m o nt h s ol d at t h e be gi n ni n g of t he 
treat me nt) was c o n d u cte d ( C o ns alvi et al. 2 0 1 1 ). T he effect of t hese d oses was c o m pare d t o 
t hat of ve hi cle al o n e ( oral deli vere d) or t he H D A Ci T S A ( 0. 6 m g/ k g, i. p.) a n d assesse d b y 
m o nit ori n g t otal b o d y wei g ht d uri n g t he ti me o f e x p os ure, t he wei g ht of si n gle m uscles at t he 
e n d of t he tr eat me nt, a n d b y meas uri n g m uscle f u ncti o n ( wit h trea d mill test at s pecific ti me 
p oi nts d uri n g t he treat me nt) a n d Cr oss Secti o nal Area ( C S A ) at t he e n d of t he treat me nt. T he 
res ults s h o we d a n i ncrease of t he wei g ht of a si n gle m uscle a nal ys e d , a d ose-de pe n d e nt 
re d ucti o n of i ntra m usc ular fi br osis a n d i nfla m mat or y i nfiltrate (b y m yel o per o xi dase acti vit y) 
a n d a d ose -rel ate d i ncrease of m uscl e mass a n d fi ber C S A.  All t hese hist ol o gical effects 
tra nslate d i nt o a n i m pr o ve me nt i n f u ncti o n as assesse d b y m o nit ori n g t he perf or ma nce of 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 5  of 1 1 0  
m d x mice o n a tr ea d mill test at defi ne d ti m e p oi nts d uri n g t he tr eat me nt. T o f urt her el uci d ate 
t he relati o ns hi p bet wee n g i vi n ostat e x p os ure a n d effects o n 
m uscle tiss ue a n d o n 
perf or ma n ce, a p har mac o ki netic / p har mac o d y n a mic ( P K/ P D) a nal ysis was c o n d ucte d, w hic h 
s h o we d t hat at le ast a bl o o d A U C 0 -2 4 of 6 0 0 n m ol * h/ L ( i.e., c orres p o n di n g t o  3 0 0 n g * h/ m L) 
was esti mate d t o be nee d e d t o e xert t he b enefici al hist ol o gical a n d f u ncti o nal effects i n  mice . 
4. 2. 2  Cli nic al E x perie nce wit h G ivi n ost at Incl u di n g R is ks a n d B e nefits 
C o m plete a n d u p date d d ata t hat des cri be t h e cli nical e x perie nce wit h gi vi n ostat are re p ort e d 
i n Secti o n 6 “ Effects i n H u ma ns” of t he c urre nt I n v esti gat or Br oc h ure D ossier relat e d t o  
I T F 2 3 5 7. 
Gi vi n ostat has bee n teste d i n a n u m ber of cli nical st u dies i n a d ults a n d pae diatric 
p o p ulati o ns.   
T hree maj or i n dicati o ns ha ve bee n e x pl ore d wit h Gi vi n ostat : c hr o nic i nfla m mat or y diseases, 
ne ur o m usc ular dis or der s a n d o nc ol o g y. T he ma xi m u m a d mi nistere d d ose was a si n gle d ose 
of 6 0 0 m g i n healt h y v ol u nteers a n d u p t o 4 0 0 m g o nce per wee k i n s u bjects wit h m ulti ple 
m yel o ma . D oses u p t o a p pr o xi matel y 1 0 0 m g bi d  wer e ge nerall y well t ol erate d i n a d ults . I n 
s u bjects wit h D M D e nr olle d i n st u d y D S C/ 1 1/ 2 3 5 7/ 4 3  (i.e., s u bjects bet w ee n 7 a n d 1 0 y ears 
of a ge  at st u d y start ), t he ma xi m u m d ose a d mi nistere d i n t h e d ose escalati o n p hase was 5 0 
m g bi d  f or u p t o 2 wee ks, w hile t he  ma xi m u m d ose a d mi nistere d f or u p t o 1 y ear i n t he 
sec o n d part of t h e st u d y was 3 7. 5 m g bi d . Si nce cleara nce i ncre ases wit h i ncreas e d wei g ht, 
d oses were  i n crease d i n t he e xte nsi o n p hase of st u d y D S C/ 1 1/ 2 3 5 7/ 4 3 d ue t o t he i ncreas e i n 
wei g ht of t he e nr olle d c hil dre n; as a res ult , t he ma xi m u m d ose a d mi nistere d was 6 0 m g  bi d .  
I n p atie nts s ufferi n g fr o m c hr o nic i nfla m mat or y diseases, or D M D or h ealt h y v ol u nteers, t he 
m ost c o m m o nl y occ urri n g a d verse e ve nts were mil d -t o-m o derate, d ose -rel ate d platelet c o u nt 
re d ucti o ns, a n d n o n -s pecific gastr oi ntesti nal s y m pt o ms i ncl u di n g na usea, vo miti n g , 
a b d o mi nal pai n a n d diarr hea. Patie nts wit h c hr o nic i nfla m mat or y diseases re p orte d als o mil d 
u p per res pirat or y tract i nfecti o ns. W orse ni n g of disease u n d er st u d y (e. g. ps oriasis or Cr o h n’s 
disease) w as als o re p orte d i n patie nts. T he effects o n plat elets i n Cr o h n’s disease a n d 
ps oriasis patie nts were mai nl y o bser ve d at t h e 1 0 0 m g b.i. d. d ose, w hic h d ue t o t he 
u nfa v ora bl e ris k -b e nefit rati o was disc o nti n ue d pre mat urel y i n t h e st u d y a n d has ne v er bee n 
a p plie d a gai n i n f urt her st u dies i n c hr o nic i nfla m m at or y c o n diti o ns; c o n versel y, at d oses s uc h 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 6  of 1 1 0  
as 5 0 m g o. d. or 5 0 m g b.i. d. t he decreases i n pl atelet c o u nts were well c o nfi ne d wit hi n t he 
ra n ge of n or m alit y. T he maj orit y of re d ucti o ns i n platelets were mil d a n d occ urre d us uall y 
wit hi n t he first wee k after treat me nt i nitiati o n a n d reac h e d a na dir p oi nt after 2 t o 3 wee ks of 
treat me nt a n d t he n a ‘ platea u.” All occ urre nces res ol ve d f ull y wit hi n 2 t o 3 wee ks f oll o wi n g 
disc o nti n uati o n of t hera p y, s u g gesti n g a ra pi dl y re versi ble effect.  T he 
maj orit y of 
t hr o m b oc yto pe nic e v e nts were mil d i n se verit y wit h fe wer t h a n 1 0 % of s u bjects de vel o pi n g 
platelets c o u nt b el o w 7 5 x 1 0 9/ L. I n or der t o pre ve nt a n y se vere t hr o m b oc yt o pe nia, cl ose 
m o nit ori n g of he mat ol o g y val ues  will be i m ple me nte d d uri n g t he st u d y.  
O verall, si xtee n h e m orr ha gic dr u g -relate d A Es were re p orte d b y 1 4 patie nts i n t he c o m plete d 
cli nical trials wit h g i vi n ostat. H o we ver, o nl y i n se ve n of t hese cas es were t he  he m orr ha gic 
dr u g -relat e d A Es i n p atie nts wit h c o nc o mita nt t hr o m b oc yt o pe nia; t hese were all o nc ol o g y 
pa tie nts a n d, i n s o me t hr o m b oc yt o pe nia, u p t o gra de 4 was alrea d y prese nt bef ore gi vi n ostat 
treat me nt starte d. I n all t he re m ai ni n g cas es ( ni ne he m orr ha gi c dr u g-relat e d A Es occ urri n g i n 
se ve n s u bjects), platelet c o u nts at t he ti me of t he he m orr ha gic A E were eit her wit hi n n or mal 
ra n ge or a b o v e t he u p per li mit of n or mal. N o ne of t he dr u g-relate d he m orr ha gic e pis o des 
were o bs er ve d i n D M D s u bjects .  
M ost pre mat ure disc o nti n uati o ns see n i n c o m plete d  or disc o nti n ue d st u dies were  ass oci ate d 
wit h a decrease i n platel et c o u nts. Disc o nti n uati o ns d ue t o t his reas o n were mai nl y c o nfi ne d 
t o t he 1 0 0 m g b.i. d. d ose. Ot her ca uses of pre mat ure disc o nti n uati o ns were m ostl y relate d t o 
w orse ni n g of diseas e u n d er st u d y.  
Cases of mil d u p per res pirat or y tract i nf ecti o ns were re p orte d i n s u bjects treate d wit h 
I T F 2 3 5 7. Fi ve patie nts wit h m ulti ple m yel o ma e x perie nce d se vere s yste mi c i nfecti o ns. 
O verall, tr eat me nt wit h I T F 2 3 5 7 of b ot h h ealt h y v ol u nteers a n d patie nts di d n ot s h o w 
cli nicall y mea ni n gf ul c ha n ges f or a n y of t he meas ure d c he mistr y para meters, wit h t he 
e xce pti o n of a tra nsie nt a n d sli g ht i ncrease i n ser u m creati ni ne le vels o bser ve d i n o n l y o ne 
st u d y i n Cr o h n’s disease patie nts. 
T here was n o e vi d e nce of ge n eral s yste mic t o xicit y refl ecte d b y c h a n ges i n vital si g ns i n t he 
st u die d p o p ulati o ns. Fi nall y, alt h o u g h s o me e pis o des of Q Tc pr ol o n gati o n were re p orte d 
( 9 0 % of t h ose re p orte d i n o nc ol o gical st u dies), n o e ve nts of cli nical c o ncer n or d ose relate d 
tre n d were see n. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 7  of 1 1 0  
I n c o n cl usi o n, I T F 2 3 5 7 a p peare d t o be reas o n a bl y well t olerate d at t he teste d d oses i n 
healt h y v ol u nteers or patie nts , w here d ose -relate d platelets c o u nt re d u cti o n s a n d diarr hea 
were t he m ost fre q ue ntl y re p orte d A Es.  
C o ncer ni n g t he cli nical e x perie nce i n d ystr o p hi n o pat hies , a p hase II cli nical trial 
( D S C/ 1 1/ 2 3 5 7/ 4 3) has b ee n c o n d ucte d t o e val u ate t he s afet y a n d t he p ote ntial of I T F 2 3 5 7 as 
a treat me nt f or D M D  (B ettic a et al.  2 0 1 6 ). D S C/ 1 1/ 2 3 5 7/ 4 3 was a n o pe n la bel 2 -part, P hase 
II st u d y i n a m b ulat or y c hil dre n a ge d ≥ 7 t o 1 0. P art 1 was a d ose escalati o n st u d y t o i de ntif y 
t he Ma xi m u m T olerate d D ose ( M T D) a n d rec o m me n d t he d ose f or Part II ( 1 2 m o nt hs). T he 
pri mar y o bjecti ve of t he st u d y was t o c o nfir m i n h u ma ns t hat I T F 2 3 5 7 ca n c o u nteract t he 
hist ol o gical si g ns of t he disease b y e val uati n g t he dr u g’s effects  c o m pari n g baseli ne a n d e n d 
of treat me nt m uscle bi o psies ( brac hial bice ps). T he pri mar y e n d p oi nt was t he c ha n g e of 
M uscle Fi b er Ar ea Fracti o n ( M F A F) after 1 2 m o nt hs of treat me nt. A d diti o nal hist ol o gical 
para meters asses se d as sec o n dar y e n d p oi nts were cr oss-secti o nal area ( C S A), necr osis, 
h y perc o ntr acte d fi bers, fatt y r e place me nt a n d fi br osis . Sec o n dar y e n d p oi nts were c ha n g e i n 
m usc ul ar f u ncti o n aft er 1 2 m o nt hs of treat me nt base d o n t he 6 
Mi n ute 
Wal ki n g Test 
( 6 M W T), N ort h Star A m b ulat or y Assess me nt ( N S A A) a n d Perf or man ce U p per Li m b ( P U L).  
M F A F i ncreas e d i n all c hil dre n wit h a 
mea n relati ve i ncreas e of 2 9. 1 % ( p < 0. 0 0 0 1). 
E n d o m ysial a n d p eri m ysial fi br osis decreas e d i n all c hil dre n wit h a mea n relati ve decrease i n 
t otal fi br osis of 2 7. 4 % ( p < 0. 0 0 0 1). 
M ore o ver, si g nifica nt i m pr o ve me nts of hist ol o gical 
feat ur es were o bser ve d wit h re d ucti o n of necr otic a n d h y perc o ntr acte d fi ber n u m ber, as well 
as decrease of fat tiss ue re place me nt. M F A F i ncrease d d ue t o a h o m o ge ne o us i ncre me nt of 
t he C S A val ue of all fi b ers wit h a mea n c ha n g e of 8 6 5. 2 7 ± 5 5 5. 3 5 μ m2. C ha n ge i n 6 M W T 
dista nce, N S A A t otal s c ore, ti me t o sta n d fr o m fl o or a n d P U L were -2 4. 6 ± 3 6. 1 1 meter s 
( mea n ± S D), -2. 5 ± 2. 8 5 p oi nts, 0. 7 2 ± 1. 3 6 sec o n ds a n d -0. 2 ± 2. 6 9, res p ecti vel y.   
T he st u d y pr ot oc ol was a me n de d a n d a n e xte nsi o n p hase is o n g oi n g. T he e xte nsi o n will 
all o w t he e val uati o n of t he safet y a n d t olera bilit y of l o n g -ter m a d mi nistrati o n of I T F 2 3 5 7 
(f or u p t o 4 ye ars of tr eat me nt) a n d t o e val uat e t he effect of treat me nt o n m uscle f u ncti o n. 
T he ris k/ be nefit rati o of t he pr o p ose d st u d y is p ost ulate d t o be fa v ora ble f or b ot h t he res ults 
of t he cli nical safet y a n d pre -cli nical t o xic ol o g y st u dies a n d f or t he efficac y res ults i n t he 
pre vi o us P hase 2 D M D st u d y.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 8  of 1 1 0  
4. 2. 3  R ati o n ale  of t he st u dy 
T he c o nce pt of dise ase m o dificati o n i n D M D/ B M D is c haracterize d b y sl o wi n g d o w n or 
st o p pi n g t he acc u m ulati o n a n d t he pr o gressi o n of disa bilit y. T his i ncl u des t he dela y of 
s y m pt o ms of wea k ness, or l oss of f u ncti o n, i n certai n m uscle gr o u ps, t h e dela y of ge n eral 
l oss of e ner g y, as well as t he dela y i n ti me t o milest o ne e ve nts (e. g. ti me t o w heelc hair, ti me 
t o l oss of u p per li m b use, ti me t o assiste d ve ntilati o n). 
N o ncli nical st u dies  ha ve s h o w n t hat g i vi n ostat has a p ote nt a nti -i nfla m mat or y effect (see 
(c urre nt  I B) a n d t hat H D A Ci re g ulate t he tra nscri pti o n of ke y fact ors i n m uscle re ge n erati o n  
s uc h as f ollistati n. I T F 2 3 5 7 si g nifica ntl y c o u nteracts hist ol o gical dise ase pr o gressi o n i n 
c hil dre n wit h D uc he n ne M uscle d ystr o p h y a ge d 7 t o 1 0 years, i ncreasi n g m uscle fi bers, 
re d uci n g 
necr osis, fatt y re place me nt a n d fi br osis a n d decreasi n g t he n u m ber of 
h y perc o ntr acte d fi b ers. Alt h o u g h u n der p o were d, t he f u n cti o n tests ( 6 M W T, N S A A a n d P U L) 
a n d t he p ul m o nar y f u ncti o n tests s h o w a n o verall sta bilit y.  
T hese res ults i n dicate t h at t he i n d ucti o n of a n acti ve re g e nerati o n pr o gra m, t he re d ucti o n of 
a di p ose re place me nt a n d t he e nlar g e me nt of pre-e xisti n g m uscle fi bers are all ke y ele me nts 
of gi vi n ostat ’s mec h a nis m of acti o n  ( M o A), s u p p orti n g t he p ote ntial t hera pe utic r ole of 
g i vi n ostat i n c o u nteracti n g m uscle tiss ue de ge nerati o n.  
O n t he basis of its p utati ve M o A as descri be d a b o ve, g i vi n ostat is e x pecte d t o act at all sta ges 
of t he diseas e a n d t o c o u nter t he dise ase p at h o ge netic e ve nts i n all m usc ular districts. As t he 
p ath o ge netic mec ha nis m of B M D is si milar t o D M D  (i.e. sa me ge ne m utate d, b ut differe nt 
m utati o n) , gi vi n ostat is e x pecte d t o c o u nter t he disease pat h o g e netic e v ents als o i n B M D .  
T he rati o nal of t his st u d y was  t o re plicate t he hist ol o gic fi n di n gs c ollecte d d uri n g t he p hase II 
cli nical trial ( D S C/ 1 1/ 2 3 5 7/ 4 3) i n D M D ( Bettic a et al. 2 0 1 6 ). T he pri mar y e n d p oi nt was 
selecte d o n t he b asis of t he res ults of st u d y D S C/ 1 1/ 2 3 5 7/ 4 3 , w here fi ber C S A e nlar g eme nt  
a p peare d ke y i n gi vi n ostat’s p har mac ol o gical effect.  H o we ver, as d escri be d i n t he  secti o n 
“a me n d me nt  4 ”, the hist o pat h ol o gical feat ur es o bser ve d i n t he  a nal ysis d o ne o n t he 
preli mi nar y 2 0 bas eli ne bi o psies s h o we d a si milar a ge-matc h e d 
m ale a d ult healt h y 
i n di vi d uals mea n C S A of t he bi ce ps fi ber, wit h a ver y lar ge  de gree of fi b er siz e varia bilit y  
bei n g acc o u nte d f or a s u bsta ntial n u m ber of h y pertr o p hic a n d als o b y h y p otr o p hic  fi bers. As 
a c o nse q ue n ce, t he li keli h o o d t hat gi vi n ostat  ca n i ncrease t he C S A of fi b er s f urt her is l o w 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 3 9  of 1 1 0  
a n d als o it is d o u btf ul t hat a f urt her  i ncrease i n fi ber C S A w o ul d be be neficial. T he 
hist o pat h ol o gical feat ure s o bser ve d i n t hese preli mi nar y bi o p sies s h o we d als o si g nifica nt 
fi br o-a di p ose re pl ace m e nt, pr o ba bl y d ue t o t he c hr o nicit y of t he disease . C o nsi deri n g t hat t he 
hist ol o gic res ults after 1 2 m o nt hs of treat me nt wit h gi vi n ostat i n D M D c hil dre n s h o we d t hat 
gi vi n ostat si g nifica ntl y re d uce d t h e a m o u nt of fi br otic tiss ue a n d fat re pl ace me nt ( Bettic a et 
al. 2 0 1 6 ), a n d t hat t he  fi br o-a di p ose re place me nt ca n b e c o nsi d ere d t he hall mar k of t h e 
disease , t he c ha n g e of t otal fi br osis is c o nsi dere d a m ore i n dicati ve o utc o me meas ure of t he 
p ossi ble effect  of gi vi n ostat   rel ati ve t o t he assess me nt of C S A a n d, he nce, it is t o be 
e val uate d as t he pri mar y e n d p oi nt  f or t he trial. C o nsi deri n g t he rece nt rec o m me n dati o ns 
o utli ne d i n t he E M A “ G ui deli ne o n t he cli nical i n vesti gati o n of me dici nal pr o d ucts f or t he 
treat me nt of D u c he n ne a n d Bec ker m usc ul ar d ystr o p h y” ( Dece m b er 2 0 1 5) a n d i n t he Fe deral 
Dr u g A d mi nistrati o n ( F D A) draft g ui da nce f or i n d ustr y “ D uc he n ne M us c ular D ystr o p h y a n d 
relate d d ystr o p hi n o pat hi es: de vel o pi n g dr u gs f or treat me nt” (J u ne 2 0 1 5), s o me f u ncti o nal 
tests ha ve b ee n c h ose n t o e val uat e t he effi cac y of gi vi n ostat i n sl o wi n g d o w n disease 
pr o gressi o n.  U nli ke D M D, t here is scarce data i n B M D a b o ut sta n dar dize d f u ncti o nal 
meas ures s u c h as t he Si x 
Mi n ute 
Wal k Test ( 6 M W T), t he 
N ort h Star 
A m b ulat or y 
Assess me nt ( N S A A), a n d Ti me d F u ncti o n Tests ( T F Ts: r u n/ wal k 1 0 m, rise fr o m t he fl o or, 
cli m b f o ur sta n d ar d ste ps), t heref ore t he f u ncti o n al e n d p oi nts were selecte d o n t he basis of 
fe w literat ure d ata (Bell o et al, 2 0 1 6 ; Me n d ell et al, 2 0 1 5; Fisc her et al, 2 0 1 6 ) a n d cli nical 
practice.  
T he f u ncti o nal s ec o n dar y e n d p oi nts i ncl u de d i n t his trial are M F M, 6 M W T, a n d T F Ts ; as 
descri be d b y Fis her ( Fis c her et al, 2 0 1 6), t he y are relia ble tests t o assess disa bilit y i n a n 
a m b ula nt B M D p o p ulati o n , s h o wi n g a hi g h i nter-correl ati o n .  
E ve n if n o data are a vaila ble o n m uscle stre n gt h i n B M D patie nts, it h as bee n i ncl u de d as 
sec o n dar y e n d p oi nt i n li g ht of gi vi n ostat’s M o A (e. g., i ncreas e fi b ers C S A) a n d  is e x p ecte d 
t o be a p pr o priat e f or e val uat i n g t he efficac y of gi vi n ostat. 
C o ncer ni n g t he i ma gi n g e n d p oi nts, p re vi o us st u dies ha ve s h o w n t hat 
M RI ca n vis ualize 
str uct ural alterati o ns of m uscle i n m usc ular d ystr o p hies (T asc a et al, 2 0 1 2, Willc ocks  et al, 
2 0 1 6, Tri plett et al, 2 0 1 4,  B o n ati et al, 2 0 1 5 ) a n d t hat fat fracti o n meas ure d b y M RI or 
ma g netic res o n a nce s p ectr osc o p y ( M R S) hi g hl y c orrel at es 
wit h l o wer li m b f u ncti o n. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 4 0  of 1 1 0  
Alt h o u g h l o n git u di nal data o n M RI/ M R S partic ularl y fr o m ra n d o mise d cli nical trials are still 
li mite d, fatt y de ge neratio n of t he m uscl e, i n partic ular  M uscle Fat Fracti o n ( M F F) e val uate d 
b y M RI Di x o n tec h ni q u e of t he t hi g h m uscles s h o we d e x celle nt c orrel ati o n wit h cli nical 
f u ncti o n i n B M D patie nts (Fisc her et al, 2 0 1 6 ), assesse d b y M F M, 6 M W T a n d T F Ts a n d 
mi g ht be a pr o misi n g s urr o gate o u t c o me mar ker  i n cli nical trials. F or t he reas o n descri be d 
a b o ve, 
M F F e v al uate d b y 
M RI wit h Di x o n tec h ni q ue as well as 
M R S are s ec o n dar y 
e n d p oi nts of t he st u d y.  
Fi nall y , safet y a n d t olera bilit y a n d p har mac o ki netics will be als o assesse d i n t he st u d y f or a 
p r o per ris k-b e nefit e v al u ati o n of gi vi n ostat . 
5  
S T U D Y  O B J E C TI V E S  A N D E N D P OI N T S  
5. 1  
St u d y O bjecti ves  
5. 1. 1  Pri m ary O bjective  
T he pri mar y o bjecti ve of t he prese nt st u d y is t o esta blis h t he hist ol o gical effects  of gi vi n ostat 
vers us place b o a d mi nistere d o ver 1 2 m o nt hs.  
5. 1. 2  Sec o n d ary O bjectives  
T he sec o n d ar y o bjecti ves of t his st u d y are  t he f oll o wi n g: 
•  T o esta blis h t he macr osc o pic m uscle effects of gi vi n ostat vers us place b o a d mi nistere d 
c hr o nicall y o ver 1 2 m o nt hs assesse d b y M RI/ M R S.  
•  T o esta blis h t he ot her hist ol o gical effects of gi vi n ostat vers us place b o a d mi nistere d 
o ver 1 2 m o nt hs.  
•  T o esta blis h t he effic ac y of gi vi n os tat vers us place b o a d mi nistere d c hr o nicall y o ver 1 2 
m o nt hs i n sl o wi n g disease pr o gressi o n.  
•  T o assess t h e safet y a n d t olera bilit y of gi vi n ostat vers us pl ace b o a d mi nistere d 
c hr o nicall y.  
•  T o e val uate t he p h ar mac o ki netic ( P K) pr ofile of gi vi n ostat a d mi nistere d c hr o nicall y i n 
t he tar get p o p ulati o n.  
•  T o e val uate t he i m pact of gi vi n ostat vers us place b o a d mi nistere d c hr o nicall y o n q ualit y 
of  life a n d acti vi ties of dail y li vi n g .  
5. 1. 3  Sec o n d ary E x pl or at ory O bjectives  
•  T o 
e val uat e t he 
c orrelati o n 
bet w ee n 
t h e P K  pr ofile 
of 
g i vi n ostat a n d 
p har mac o d y n a mics  ( P D) data. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 4 1  of 1 1 0  
•  T o e val uate a p ossi ble disease -relate d bi o mar ker.  
•  T o e x pl ore a d diti o nal dis ease -relate d M RI bi o mar kers. 
5. 2  
St u d y E n d p oi nts  
5. 2. 1  Pri m ary E n d p oi nt  
T he pri mar y e n d p oi nt of t his st u d y is t he mea n c ha n ge i n mea n  t otal fi br osis ( %) c o m pari n g 
t he hist ol o g y of m uscle bi o psies bef ore a n d aft er 1 2 m o nt hs of tr eat m e nt wit h gi vi n ostat  
vers us place b o . 
5. 2. 2  Sec o n d ary E n d p oi nts  
T he sec o n d ar y e n d p oi nts f or t his st u d y are as f oll o ws:  
•  Mea n c ha n ge i n fat fracti o n of vast us lateralis 
a n d s ole us  c o m pari n g 
Ma g netic 
Res o na nce S pectr osc o p y ( M R S) bef ore a n d after 1 2 
m o nt hs of tr eat me nt 
wit h 
gi vi n ostat vers us place b o.  
•  Mea n c ha n g e i n fat fracti o n of 
pel vic gir dle a n d l o wer li m b m uscles c o m pari n g  
Ma g netic Res o na n ce I m a gi n g ( M RI) b ef ore a n d after 1 2 m o nt hs of treat me nt wit h 
gi vi n ostat vers us place b o.  
•  Mea n c h a n ge i n Cr oss Secti o nal Area ( C S A) of pel vic gir dle a n d l o wer li m b m uscles 
c o m pari n g 
M RI bef ore a n d after 1 2 m o nt hs of treat me nt wit h  gi vi n osta t vers us 
place b o.  
•  Mea n c h a n ge i n ot her hist ol o g y para meters (e. g. 
C S A , M F A F , re ge n erati ve fi bers) 
c o m pari n g t he hist ol o g y bi o psies bef ore a n d after 1 2 
m o nt hs of tr eat me nt wit h 
gi vi n ostat.  
•  Mea n c ha n g e i n M ot or  F u ncti o n Meas ure me nt  (M F M ) bef ore a n d after 1 2 m o nt hs of 
treat me nt wit h gi vi n ostat vers us place b o .  
•  Mea n c ha n g e i n Ti me F u ncti o n Tests (ti me t o cli m b f o ur sta n dar d ste ps, ti me t o rise 
fr o m fl o or a n d ti me t o wal k/r u n 1 0 m) b ef ore a n d after 1 2 m o nt hs of tr eat me nt wit h 
gi vi n ostat vers us place b o  
•  Mea n c ha n g e i n 
6 
Mi n ute 
Wal ki n g Test ( 6 M W T ) bef ore a n d  after 1 2 m o nt hs of 
treat me nt wit h gi vi n ostat vers us place b o. 
•  Pr o p orti o n of patie nt s wit h < 1 0 % w orse ni n g i n 6 M W T at t he e n d of st u d y.  
•  Pr o p orti o n of patie nt s w h o l ose t he a bilit y t o rise fr o m fl o or ( Baseli ne t hr o u g h e n d of 
st u d y). 
•  Pr o p orti o n of patie nt s w h o l ose a m b ulati o n d uri n g t he st u d y.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 4 2  of 1 1 0  
•  Mea n c h a n ge i n m us cle stre n gt h e val uate d b y k nee e xte nsi o n, el b o w fle xi o n  as 
meas ure d b y Ha n d Hel d M y o metr y ( H H M ), bef ore a n d aft er 1 2 m o nt hs of treat me nt 
wit h gi vi n ostat vers us place b o.  
•  Mea n c ha n g es i n q ualit y of life (assesse d b y t he 3 6 -ite m S h ort F or m s ur ve y [ S F 3 6]) 
b ef ore a n d aft er 1 2 m o n t hs of treat me nt wit h gi vi n ostat as c o m pare d t o place b o.   
5. 2. 3  S afety E n d p oi nts  
T he safet y e n d p oi nts of t his st u d y are  as f oll o ws : 
•  N u m ber of patie nt s e x perie nci n g treat me nt-e m er ge nt a d verse e ve nts ( T E A Es) a n d 
seri o us a d vers e e v e nts ( S A Es) fr o m Baseli ne t hr o u g h e n d of st u d y ( E O S).  
•  T y pe, i nci de nce, a n d se v erit y of T E A E s a n d S A Es ( Baseli ne t hr o u g h E O S). 
•  C ha n ges fr o m bas eli ne t o e n d of st u d y of:  
o  Vital si g ns a n d cli nical la b orat or y tests ( bl o o d c he mistr y a n d he mat ol o g y).  
o  P h ysical e xa mi nati o n . 
o  P ul m o nar y  f u ncti o n e val uate d b y F orce d Vital C a pacit y ( F V C), F orce d E x pirat or y 
V ol u me at 1 sec o n d ( F E V 1), F V C/ F E V 1, Pea k E x pirat or y Fl o w ( P E F).  
o  Car diac f u ncti o n e val uat e d b y E C G a n d E C H O . 
o  Wei g ht, hei g ht, a n d b o d y mass i n de x ( B MI).  
5. 2. 4  P h ar m ac o ki netic E n d p oi nts  
T he P K e n d p oi nts of t his st u d y are as f oll o ws:  
•  Descri pti o n of t he P K of gi vi n ostat a n d its maj or meta b olites: I T F 2 3 7 4 a n d I T F 2 3 7 5 . 
5. 2. 5  
E x pl or at ory E n d p oi nts  
T he e x pl orat or y e n d p oi nt s of t his st u d y  are t he f oll o wi n g:  
•   P K -P D a nal yses of t he relati o ns hi p  bet wee n 
metrics of e x p os ure a n d t he 
effic ac y/safet y e n d p oi nts of gi vi n ostat.  
•  A nal yses t o e x pl ore w h et her t he effects of gi vi n ostat vers us place b o a d mi nistere d 
c hr o nicall y ma y be relate d t o t he t y pe of L T B P 4  or  Oste o p o nti n ge n ot y pe.  
•  E val uati o n of s er u m cir c ulati n g pr otei n s, b y a n E LI S A bas e d s yste m, as p ote ntial 
bi o mar kers f or  B M D.  
•  A d diti o nal e val uati o ns of ot her m uscle i ma g e para meters assesse d b y  M RI ( details 
will be pr o vi de d  i n a s pecific i ma gi n g pr ot oc ol). 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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6  
I N V E S TI G A TI O N A L P L A N 
6. 1  
Descri pti o n of O ver all  St u d y Desi g n  a n d Pl a n  
T his is a P hase  2 , ra n d o mise d, d o u ble-bli n d, pl ace b o -c o ntrolle d  st u d y. A m b ula nt  patie nt s 
w h o ha ve pr o vi de d writte n i nf or me d c o ns e nt will u n der g o a 4 -wee k scree ni n g peri o d t o 
deter mi ne eli gi bilit y f or t he st u d y. A p pr o xi matel y 
4 8  eli gi ble patie nts wil l t he n be 
ra n d o mize d i n a 2: 1 rati o t o be tr eate d wit h gi vi n ostat or place b o f or a p eri o d of 1 2 m o nt hs . 
T he ra n d o mizati o n pr ocess will be stratifie d b y t h e fact or relate d t o c o n c o mita nt ster oi d use 
at baseli ne ( yes vs. n o). Patie nts  w h o c o m plete t he st u d y (i.e. 1 2 m o nt hs of treat me nt) will be 
as ke d t o ret ur n  f or a f oll ow -u p visit  4 wee ks aft er t he e n d of tr eat me nt.  
A n o ver vie w of t he st u d y is pr o vi de d i n Fi g ure 1 . 
Fi g ure 1 : St u d y Desi g n  
 
A t otal of 1 2  visits  will ta ke place d uri n g t he st u d y: Scree ni n g  ( V 1, V 2), Ra n d o miz ati o n 
( V 3), Treat me nt ( V 4-V 1 0 ), E n d of St u d y ( V 11 ) a n d F oll o w-u p ( V 1 2 ). Visits d uri n g t he 
treat me nt peri o d will ta k e place e ver y 1 2 wee ks e xce pt f or t he first 2  m o nt hs, w he n t h e y will 
occ ur e ver y 2 wee ks t o all o w cl ose m o nit ori n g of he mat ol o gical safet y p ara meters. Patie nts  
ma y be e val uate d m ore ofte n if necessar y , f or safet y reas o ns. Patie nt s w h o disc o nti n ue t he 
st u d y treat me nt earl y will be as ke d  t o c o me i n f or a n Earl y Wit h dra wal Visit wit hi n 4 wee ks 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
- 
D o u bl e -bli n d Tr e at m e n t 
P eri o d  
  
R a n d o mi z ati o n  
  
S cr e e ni n g  
P eri o d  
- 
 
  
  
  
1 m o nt h  
  
Place b o  
  
1 2 m o nt hs  
  
Gi vi n ostat  
  
  
  
  
F oll o w -u p  
1 m o nt h  

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after t he last d ose of st u d y treat me nt. Patie nt s w h o ha ve o n g oi n g A Es at disc o nti n uati o n will 
be f oll o we d u ntil res ol uti o n or sta bilizati o n.  
6. 2  
Disc ussi o n of  St u d y  Desi g n  
T his st u d y has bee n desi g ne d a s a c o n ve nti o nal parallel -gr o u p desi g n . Si nce t he st u d y will be 
c o n d ucte d i n a  p o p ulati o n 
wit h a seri o us a n d life -t hreate ni n g dise ase, t he un e q ual 
ra n d o mizati o n rati o ( 2: 1  g i vi n ostat vs.  p lace b o) will be a p plie d t o re d uce t he e x p os ure t o 
place b o . A 2: 1 ra n d o mizati o n als o pr o vi d es f or a n i ncreas e d n u m ber of patie nt s w h o are 
e x p ose d t o g i vi n ostat. T he ra n d o mizati o n pr ocess will be stratifie d b y t h e fact or relate d t o 
c o nc o mita nt ster oi d use at  baseli ne ( yes vs. n o).  
C o nsi deri n g a 5 % of u n e val ua ble bas eli ne bi o psies , 5 1  patie nt s will b e ra n d o mize d  i n t he 
st u d y t o ha ve 4 8  f ull y e v al ua ble patie nt s.  
After t he first 2 0 baseli ne m uscle bi o psies were  c ollecte d, a bli n de d i nteri m a nal ysis was 
pla n ne d, ai me d at c h ec ki n g t he varia bilit y of t he ori gi nal pri mar y e n d p oi nt (i.e. C S A) . T h e 
o bser ve d vari a bilit y of t he ori gi nal pri mar y e n d p oi nt was ver y lar ge, lea di n g t o a re visi o n of 
t he pri mar y e n d p oi nt t o % t otal fi br osis. Th e sa m ple size was  a me n de d acc or di n gl y t o re q uire 
a t otal of 5 1 patie nt t o be ra n d o mize d o n a 2: 1 b asis.   
7  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
T he st u d y will e nr oll a d ult male patie nts  wit h a n esta blis he d m olec ular dia g n osis of B M D . 
S pecific e ntr y criteria ar e detaile d i n Secti o n 7. 1  a n d i n Secti o n 7. 2 . 
At t he discreti o n of t he I n vesti gat or, patie nts n ot meeti n g i ncl usi o n/e xcl usi o n criteria ma y be 
re-scree n e d t wice wit h a n i nter val of at least 3 0 d a ys bet wee n assess me nts.  
Patie nt s dr o p pi n g o ut bef ore t he e n d of treat me nt will n ot be re place d.  
7. 1  
I ncl usi o n Criteri a 
Patie nt s m ust meet all of t he f oll o wi n g criteria i n or der t o be i ncl u d e d i n t he st u d y : 
1.  
A m b ula nt male patie nt s a ge d ≥1 8 years t o ≤ 6 5 years at ra n d o mizati o n wit h B M D 
dia g n osis c o nfir me d b y g e netic testi n g.  
2.  
A ble a n d willi n g t o gi ve i nf or me d c o nse nt i n writi n g. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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3.  
A ble t o perf or m 6 M W T at scree ni n g wit h a mi ni m u m  dista nce of 2 0 0 m  a n d 
ma xi m u m  dista nce of 4 5 0 m.  
4.  
If i n tr eat me nt wit h s yste mic c ortic oster oi ds a n d/ or A C E i n hi bit or, a n d/ or β or α 
a dre ner gic rece pt or bl o c ker, n o si g nifica nt c h a n ge i n d osa ge or d osi n g re gi me n 
(e xcl u di n g c ha n g es relate d t o b o d y wei g ht c ha n ge) f or a mi ni m u m of 6 m o nt hs 
i m me diatel y pri or t o start of st u d y treat me nt. 
5.  
Patie nt s m ust be willi n g t o use a de q u ate c o ntrace pti o n. C o ntrace pti ve met h o ds m ust 
be use d fr o m Ra n d o mizati o n t hr o u g h 3 m o nt hs after t he last d ose of st u d y treat me nt, 
a n d i ncl u de t he f oll o wi n g:  
•  Tr ue a bsti ne nce (a bse n ce of a n y se x ual i nterc o urse), w h e n i n li ne wit h t he 
preferre d a n d us ual lifest yle of t he patie nt . Peri o dic a bsti ne nce (e. g. cale n dar 
o v ulati o n, s y m pt ot her mal, p ost  o v ulati o n 
met h o ds) a n d 
wit h dr a wal are n ot 
acce pta ble met h o ds of c o ntrace pti o n.  
•  C o n d o m wit h s per mici de a n d t he fe mal e part n er  m ust use a n acce pt a ble met h o d 
of c o ntr ace pti o n, s u c h as a n oral, tr a ns der mal, i njecta ble or i m pla nte d ster oi d -
base d c o ntrace pti ve, or a dia p hra g m or a barrier met h o d of c o ntrace pti o n i n 
c o nj u ncti o n 
wit h s per mici dal jell y s uc h as f or e x a m ple cer vical ca p 
w it h 
s per mici de jell y. 
7. 2  
E xcl usi o n Criteri a  
Patie nt s meeti n g a n y of t he f oll o wi n g criteria are i neli gi ble t o partici pate i n t his st u d y: 
1.  
E x p os ure t o a n ot her i n v esti gati o nal dr u g wit hi n 3 m o nt hs pri or t o t he start of st u d y 
treat me nt. 
2.  
Use of a n y p har mac ol o gic tr eat me nt, ot her t ha n c ort ic oster oi ds, t hat mi g ht ha ve a n 
effect o n m uscl e stre n gt h or f u ncti o n wit hi n 3 m o nt hs pri or t o t he start of st u d y 
treat me nt (e. g., gr o wt h h or m o ne). Vita mi n D, calci u m, a n d a n y ot her s u p ple me nts 
will be all o we d.  
3.  
S ur ger y t hat mi g ht ha ve a n effect o n m uscle str e n gt h or f u ncti o n wit hi n 3 m o nt hs 
bef ore st u d y e ntr y or pla n ne d s ur ger y at a n y ti me d uri n g t he st u d y.  
4.  
Prese nce of ot her cli nic all y si g nifica nt disease t hat i n t he I n v esti gat or’s o pi ni o n c o ul d 
a d versel y affect t he s afet y of t he pat ie nt, ma ki n g it u nli kel y t hat t he c o urse of 
treat me nt or f oll o w-u p is c o m plete d, or c o ul d i m pair t he assess me nt of st u d y res ults.  
5.  
A  dia g n osis of ot her u nc o ntr olle d ne ur ol o gical diseases or prese n ce of rele va nt 
s o matic dis or ders n ot relate d t o B M D t hat ma y i nterfere wit h t he a bilit y t o perf or m 
t he m uscle f u ncti o n tests a n d/ or t o c o m pl y wit h t he st u d y pr ot oc ol pr oce d ures. 

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6.  
Platelet  c o u nt, White Bl o o d Cell ( W B C) c o u nt a n d h e m o gl o bi n at scree ni n g <  L o wer 
Li mit of N or mal ( L L N). If la b orat or y scree ni n g res ults are <  L L N,  p latelet c o u nt, 
W B C c o u nt a n d he m o gl o bi n are t o b e re peat e d o nce , a n d if a g ai n <  L L N  bec o me 
e xcl usi o nar y.   
7.  
S y m pt o matic car di o m y o pat h y or heart fail ure ( Ne w Y or k Heart Ass ociati o n Clas s III 
or I V) or l eft ve ntric ul ar ejecti o n fracti o n <  5 0 % at scr ee ni n g or wit h heart tra ns pla nt.  
8.  
C urre nt li ver diseas e or i m pair me nt,  i ncl u di n g b ut n ot li mite d t o el e vate d t otal 
bilir u bi n (> 1. 5 x U L N), u nless sec o n dar y t o Gil bert’s disease or patter n c o nsi ste nt 
wit h Gil bert's  disease.  
9.  
In a de q uat e re nal f u ncti o n, as defi ne d b y ser u m C ystati n C >  2 x t he u p per li mit of 
n or mal ( U L N ). If t he val ue is > 2 x U L N,  ser u m C ystati n C will be re peate d o n ce, 
a n d if a gai n  >  2 x U L N  b ec o mes e x cl usi o nar y .  
1 0.  
P ositi ve test f o r he patitis B s urface a nti ge n, he patitis C a nti b o d y, or h u ma n 
i m m un o deficie nc y vir us at scree ni n g.  
1 1.  
B aseli ne c orrecte d Q T i nter val, Fre derici a’s  c orrecti o n ( Q Tc F ) > 4 5 0 msec , (as t he 
mea n of 3 c o nsec uti ve rea di n gs 5 mi n utes a part) or hist or y of a d diti o nal ris k fact ors 
f or t orsa des d e p oi ntes (e. g., heart fail ure, h y p o kal e mia, or fa mil y hist or y of l o n g Q T 
s y n dr o me). 
1 2.  
C urre nt p s yc hiatri c ill ness/s ocial sit uati o ns re n deri n g t he pote ntial patie nt  u na ble t o 
u n dersta n d a n d c o m pl y wit h t he m uscle f u ncti o n tests a n d/ or wit h t he st u d y pr ot oc ol 
pr oce d ures.  
1 3.  
H y perse nsiti vit y t o t he  c o m p o ne nts of st u d y me dicati o n.  
1 4.  
S or bit ol i nt olera nce or  s or bit ol mala bs or pti o n, or t he here ditar y f or m of fr uct ose 
i nt olera nce. 
1 5.  
C o ntrai n dicati o ns t o m uscle bi o ps y . 
1 6.  
C o ntrai n dicati o ns t o 
M RI / M R S (e. g., cla ustr o p h o bia, 
metal i m pla nts, or seiz ure 
dis or der).  
1 7.  
H y pertri gl yceri de mia ( ˃ 1. 5 x u p per li mit of n or mal [U L N ]) * 
* At scree ni n g, patie nts wit h h y pertri gl yceri de mia ca n b e e nr olle d if i n sta ble 
treat me nt a n d wit h c o ntr olle d le vels of tri gl yceri des (i.e. wit hi n n or mal ra n ge) f or at 
least si x m o nt hs. 
7. 3  
Wit h dr a w al  a n d Re m o v al  of P atie nt s  
Wit h dra wal fr o m st u d y partici pati o n  a n d st u d y me dicati o n ma y occ ur u n der t he f oll o wi n g 
circ u msta nces:  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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•  Wit h dra wal of c o ns e nt:  T he patie nt  d esire s t o wit h dra w fr o m f urt her partici pati o n i n 
t he st u d y i n t he a bse nce of t he I n vesti gat or det er mi n i n g a me dical  nee d t o wit h dra w.  
If t he patie nt  g i v es a reas o n f or wit h dra wi n g, it s h o ul d be rec or de d i n t he electr o nic 
Case Re p ort F or m ( e C R F). 
•  Pr ot oc ol Vi olati o n : T he patie nt ’s fi n di n gs or c o n d uct fails t o m eet t he pr ot oc ol e ntr y 
criteria  
•  L ost t o F oll o w -U p : T he patie nt  st o p pe d c o mi n g f or visits, a n d st u d y pers o n nel were 
u na ble t o c o ntact t he p atie nt  (at least 3 c o nt act atte m pts s h o ul d be d oc u me nte d). 
•  Ot her reas o n : T he p atie nt  was disc o nti n ue d  f or a reas o n ot her t ha n t h ose liste d a b o ve, 
s uc h as at t h e discreti o n of t he I n v esti gat or ( i. e., a n y ot her c o n diti o n t hat, i n t he 
o pi ni o n of t he I n vesti gat or, ma y je o par dize t he st u d y c o n d uct acc or di n g t o t he 
pr ot oc ol, or w he n t he I n vesti gat or feels t hat it is i n t he best i nterest of t he patie nt  t o 
disc o nti n ue)  or ter mi nati o n of st u d y b y t he S p o ns or . 
 
 
Wit h dra wal fr o m st u d y me dicati o n ma y occ ur u n der t he f oll o wi n g cir c u msta nce:  
•  A d verse e ve nt : Cli nical or la b orat or y e ve nts occ ur t hat, i n t he me dical j u d g me nt of 
t he I n v esti gat or f or t he best i nterest of t he patie nt , are gr o u n ds f or disc o nti n uati o n. 
M ore o ver, if t he p atie nt  meets o ne of t h e safet y st o p pi n g criteria des cri be d i n Secti o n 
7. 3. 1 , he will be wit h dra w n fr o m t he st u d y me dicati o n . I n cas e of wit h dr a wal d u e t o 
A Es/ S A Es, t he I n vesti gat or will f oll o w u p t he p atie nt  u ntil res ol uti o n or a cce pta ble 
sta bilizati o n of t he e ve nt a n d d oc u me nt all t he rele va nt i nf or mati o n, as a p plica ble.  
Bef ore wit h dr a wi n g a s u bject, e ac h c ase c a n be disc usse d wit h t he st u d y 
me dic al 
m o nit or, b ut t he fi n al decisi o n re m ai ns wit h t he I n vesti g at or o nl y or a ut h orize d 
desi g nee.  If t he s afet y of t he s u bject c a n be re as o n a bl y ass ure d, t he s u bject will n ot be 
disc o nti n ue d.  
I n case of wit h dr a wal fr o m st u d y partici p ati o n a n d /or st u d y me di cati o n, t he f oll o wi n g 
ge neral r ules a p pl y:  
•  If a patie nt  is disc o nti n ue d fr o m st u d y me dicati o n  a n d is wit h dra w n fr o m t he st u d y 
f or a n y reas o n, t he st u d y site m ust i m me diatel y n otif y t he me dical m o nit or. 
•  W he n a patie nt  wit h dr a ws fr o m t he st u d y, t he d ate a n d reas o ns f or wit h dra wal s h all 
be rec or d e d b y t he I n vesti gat or o n t he patie nt’s me dic al file a n d o n t he rele va nt pa ge 
of t he eC R F.  I n cas e of m ulti ple reas o ns, A Es  s h o ul d be i n dicate d as t he pri mar y 
reas o n w he ne v er a p plica ble. All rele va nt i nf or mati o n relate d t o t he reas o n f or 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 4 8  of 1 1 0  
treat me nt disc o nti n uati o n i ncl u di n g c o ntri b ut or y fact ors m ust be i ncl u de d o n t he 
e C R F. 
•  A ll patie nt s pre mat urel y disc o nti n ui n g t he st u d y m ust be see n f or a fi nal e val uati o n  
perf or me d wit hi n  4 wee ks after t he last dr u g i nta ke . Fi nal e val u ati o n is defi ne d as 
c o m pleti o n of t he assess me nts sc he d ule d f or t he Earl y Wit h dra wa l Visit (as detaile d 
i n S ecti o n 9. 1. 1 0 ). Data c ollecte d d uri n g t he fi nal e val uati o n are cr ucial t o t he 
i nte grit y of t he fi nal st u d y a nal ysis beca use earl y wit h dra wal m a y be rel ate d t o t h e 
safet y pr ofile of t he st u d y dr u g. T he I n vesti gat or will ma ke e v er y eff ort t o see patie nt s 
w h o fai l t o ret ur n f or a fi nal visit. 
•  If a p atie nt  is disc o nti n ue d pre mat urel y fr o m t he st u d y d ue t o a treat me nt-relat e d 
T E A E or seri o us T E A E, t he T E A E or seri o us T E A E will be f oll o we d u ntil it 
res ol ves (ret ur ns t o n or mal or bas eli ne val ues) or sta bilizes, or u ntil it is j u d ge d b y 
t he I n v esti gat or t o be n o l o n ger cli nicall y si g nifica nt. 
O nce a p atie nt  is wit h dra w n fr o m t he st u d y, he ma y n ot re-e nter it. 
 
7. 3. 1  S afety St o p pi n g R ules    
T he st u d y treat me nt s h o ul d be per m a ne ntl y  disc o nti n ue d  if a n y of t he f oll o wi n g e ve nts 
occ ur:  
•  S e vere dr u g -rel ate d diarr hea (i ncreas e of ≥ 7 st o ols per da y).  
•  A n y dr u g -relate d S A E. 
•  Q Tc F  >  5 0 0 msec * . 
•  Platelet  c o u nt ≤ 5 0 x 1 0 9/ L. T o a v oi d la b orat or y err ors a n d a n o mal o us val ues, a 
platelet c o u nt ≤ 5 0 x 1 0 9/ L m ust be c o nfir me d wit h a re peate d test perf or me d o n t he 
ne xt w or ki n g da y . Treat me nt s h o ul d be st o p pe d u ntil t he retest res ult bec o mes 
a vaila ble. If t h e re peate d platelet c o u nt is still ≤ 5 0 x 1 0 9/ L, st u d y treat me nt m us t be 
per ma ne ntl y disc o nti n ue d. If t he re peate d test is acce pt a ble, t he patie nt  ca n res u me 
treat me nt.   
•  W hite bl o o d cell c o u nt  ≤ 2. 0 x 1 0 9/ L. To a v oi d la b orat or y err ors a n d a n o mal o us 
val ues, w hite bl o o d cells  ≤ 2. 0 x 1 0 9/ L m ust be c o nfir m e d wit h a re peate d test 
perf or me d  o n t he ne xt w or ki n g da y. T reat me nt s h o ul d be st o p pe d u ntil t he retest 
res ult bec o mes a v aila ble. If t he re p eate d w hite bl o o d cells c o u nt is still ≤ 2. 0 x 1 0 9/ L, 
st u d y treat me nt m u st be per ma ne ntl y disc o nti n ue d. If t he re p eate d test is acce pta ble, 
t he patie nt  ca n res u me tr eat me nt.    
•  H e m o gl o bi n ≤ 8. 0 g/ d L. T o a v oi d la b orat or y err ors a n d a n o mal o us val ues, 
he m o gl o bi n  ≤ 8. 0 g/ d L m ust be c o nfir m e d wit h a re p eate d test perf or me d o n t he n e xt 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 4 9  of 1 1 0  
w or ki n g da y. T h e treat me nt s h o ul d be st o p pe d u ntil t he retest res ult bec o mes 
a vaila ble. If t he re peate d he m o gl o bi n is still ≤ 8. 0 g/ d L, st u d y treat me nt m u st be 
per ma ne ntl y disc o nti n ue d.  If t he re peate d test is acce pt a ble, t he patie nt  ca n res u me 
treat me nt.  
T he I n vesti gat or will f oll o w u p  u ntil res ol uti o n or acce pta ble st a bilizati o n of t he e ve nt a n d 
d oc u me nt all t he rele v a nt i nf or mati o n, as a p plica ble . After t he res ol uti o n/sta bilizati o n of t he 
e ve nt, t he patie nt  will be wit h dra w n fr o m t he st u d y a n d t he E O S  Visit (see Secti o n 9. 1. 1 0 ) 
will be perf or me d.  
*  B ase d o n a v era g e Q Tc val ue of tri plicate E C Gs . F or e xa m ple, if a n E C G de m o nstrates a pr ol o n ge d Q T 
i nter val, 2 m ore E C Gs s h o ul d be o btai ne d o ver a brief peri o d, a n d t he n t he a vera ge d Q Tc F  val ues of t he 3 
E C Gs s h o ul d be use d t o deter mi ne w het her t he patie nt  s h o ul d be disc o nti n ue d fr o m t he st u d y. If t he mea n Q TcF  
val ue of t he 3 re plicates still meets t he st o p pi n g criteria , t he patie nt  has t o i nterr u pt t he st u d y treat me nt, t he 
me dical m o nit or has t o be i nf or me d a n d  t he val ue m ust be c o nfir me d b y ce ntral rea di n g bef ore wit h dra wi n g t he 
patie nt  fr o m t he st u d y. T he Q Tc has t o be calc ulate d wit h t he Fri dericia f or m ula Q Tc = Q T/ R R 1/ 3. 
T he S t ud y treat me nt s h o ul d be te m p or aril y i nterr u pte d if a n y of t he f oll o wi n g e ve nts occ ur:  
•  M o derate or s e vere diarr h ea (i ncreas e m ore t ha n 4 st o ols per da y).  
•  Platelet  c o u nt <  7 5 x 1 0 9/ L b ut > 5 0 x 1 0 9/ L (treat me nt s h o ul d be te m p oraril y 
st o p pe d, a n d t h e platel et  c o u nt re p eated wit hi n  1 wee k a n d r eteste d u ntil platelets are 
n or mal ). 
•  W hite bl o o d cell  <  3. 0 x 1 0 9/ L b ut > 2. 0 x 1 0 9/ L (treat me nt s h o ul d be te m p oraril y 
st o p pe d, a n d w hite bl o o d cells  re-m eas ure d wit hi n  1 wee k a n d re teste d u ntil w hite 
bl o o d cells are n or m al ). 
•  H e m o gl o bi n <  1 0. 0 g/ d L b ut > 8. 0 g/ d L  (treat me nt s h o ul d be te m p oraril y st o p pe d, 
a n d he m o gl o bi n  re-me as ure d  wit hi n  1 wee k a n d re teste d u ntil he m o gl o bi n  is n or mal). 
•  Tri gl yceri des ˃ 3 0 0 m g/ d L  (see als o secti o n 8. 8 ) 
 
T he s t u d y treat me nt ca n be re d uce d b y 2 0 %  of t he c urre nt d ose at w hic h t he A E lea di n g t o 
te m p orar y i nterr u pti o n o cc urre d , o nce plat elets  a n d/ or w hite bl o o d c ell a n d/ or he m o gl o bi n  
a n d/ or tri gl yceri des are n or malize d , or diarr h ea is mil d. See Secti o n 8. 2. 2 f or m ore details.  
T he patie nt  ma y ha v e u nsc he d ule d visits  if nee de d u ntil t he A E res ol v es, a n d will t he n 
c o nti n ue t he  st u d y as per sc he d ule d visits. F urt her pr oce d ures  ( bl o o d sa m ple c ollecti o n) ma y 
als o be perf or me d b y a q ualifie d trai ne d n urs e at t he patie nt’s h o me.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 0  of 1 1 0  
I n a d diti o n, if a patie nt  has  a c o nsiste nt ( at least t w o c o nsec uti ve e val uati o n s) platelet c o u nt ≤ 
1 5 0 x 1 0 9/ L t hat d oes n ot meet st o p pi n g criteria f or platelets, t he I n vesti gat or will ha ve t o 
re d uce t h e d ose b y 2 0 %  of t he c urre nt d ose . See S ecti o n 8. 2. 2 f or m ore d et ails.  
He mat ol o g y para meters will be e val uat e d e v er y 2 wee k s d uri n g t he first 2 m o nt h s of 
treat me nt ( Visits 4-7) t o cl osel y m o nit or t hese safet y para met ers. 
A n y decisi o n c o ncer ni n g d ose a dj ust me nt a n d/ or m o dificati o n of sc he d ule of assess me nts 
ca n b e disc usse d wit h t he 
Me dical 
M o nit or, b ut t he fi nal decisi o n re mai ns wit h t h e 
I n v esti gat or o nl y or a ut h orize d desi g ne e. 
If a patie nt  has a me dical e ve nt n ot necessaril y dr u g relate d t hat re q uires i nterr u pti o n of st u d y 
treat me nt d osi n g f or >  4 wee ks, t he I n v esti gat or  ca n disc uss t he case wit h t he me dical 
m o nit or t o deci de w het her t he p atie nt  ma y re s u me st u d y treat me nt, h o we ver t h e fi nal 
decisi o n re mai ns wit h t he I n vesti gat or  o nl y  or a ut h orize d desi g ne e .  
8  
T R E A T M E N T S  
8. 1  
Det ails of St u d y Tre at me nts  
T he i n vesti gati o nal st u d y dr u g t o b e use d i n t his st u d y is g i vi n ostat (I T F 2 3 5 7) a n d a place b o. 
F or t he d urati o n of t he st u d y, g i vi n ostat a n d place b o w ill be s u p plie d b y Italfar mac o S. p. A . 
T he c haract eristics of t he st u d y treat me nt are liste d i n t he Ta ble bel o w:  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 1  of 1 1 0  
Ta ble 2 : I n v esti gati o nal Me dici nal Pr o d ucts 
 
I n vesti g ati o n al Me dici n al  Dr u g  
 
Test tre at me nt  
C o m p ar at or  
Pr o d uct n a m e:  
I T F 2 3 5 7/g i vi n ostat*  
Place b o  
D os a ge f or m:  
Oral s us pe nsi o n  
Oral s us pe nsi o n  
U nit d ose 
stre n gt h: 
B ottle c o ntai ni n g  1 4 0 m L of 
g i vi n ostat 1 0 m g/ m L  
B ottle c o ntai ni n g  1 4 0 m L of p lace b o, a 
c o m bi nati o n of 0. 1 % w/ v Tita ni u m 
( o pacifier, t o rese m ble s us pe nsi o n 
a p peara nce) a n d 0. 1 % w/ v of a n 
a d diti o nal fla v ori n g a ge nt (t o rese m ble 
t he sli g htl y bitteris h  aftertaste t y pical 
of t he dr u g s u bsta nce)  
R o ute of  
A d mi nistr ati o n  
Oral a d mi nistrati o n u n der fe d 
c o n diti o ns  
Oral a d mi nistrati o n u n der fe d 
c o n diti o ns  
D osi n g 
i nstr ucti o ns: 
See Ta ble 3 : Gi vi n ostat -
P lace b o Starti n g D ose 
See Ta ble 3 : Gi vi n ostat -P lace b o 
Starti n g D ose . 
P h ysic al 
descri pti o n:  
W hite t o off -w hite or fai ntl y 
pi n k, h o m o ge n o us s us pe nsi o n 
w he n mi xe d  
W hite t o off -w hite or fai ntl y pi n k, 
h o m o ge n o us s us pe nsi o n w he n mi xe d  
De vic e i ncl u de d 
i n t he 
p ac k a gi n g : 
T w o g ra d uat e d d osi n g 
s yri n ges f or oral use: 
O ne 5 m L s yri n ge a n d  
O ne 1 m L s yri n ge  
T w o g ra d uat e d d osi n g s yri n ges f or 
oral use : 
O ne 5 m L s yri n ge a n d  
O ne 1 m L s yri n ge  
* Gi vi n ostat  is use d t o i n dicate t he w h ole st u d y dr u g na me g i vi n ostat h y dr oc hl ori de m o n o h y drate . T he 
d osa g es /c o nce ntrati o ns of t he st u d y dr u g are e x presse d as g i vi n ostat h y dr oc hl ori de m o n o h y drate . 
8. 2  
D os a ge  
8. 2. 1  R ati o n al f or D ose S electi o n 
T he d ose f or t his st u d y h as bee n selecte d b ase d o n  t he d ose ra n gi n g e val u ati o n perf or me d  i n 
t he m d x m o use m o del,  t he res ults of t he P hase 2 st u d y i n p e diatric patie nt s wit h D uc he n ne 
M usc ular D ystr o p h y ( D M D ) ( D S C/ 1 1/ 2 3 5 7/ 4 3), a n d t he e v al uati o n of P K a n d efficac y 
res ults o btai ne d i n ot her i nfla m mat or y diseases. 
T he P K/ P D a nal ysis d o n e wit h t he d ata c ollect e d d uri n g t he n o n -cli nical st u d ies i n t he m d x 
m o del  s h o we d t hat a bl o o d A U C 0 -2 4 of at least 3 0 0 n g * h/ m L was esti mate d t o be nee de d t o 
e xert t he be neficial hist ol o gical  a n d f u ncti o nal effects i n mice  a n d t h us was c o nsi dere d t h e 
tar get e x p os ure f or t he e x pl orat or y P hase 2 st u d y i n t he D M D p o p ulati o n .  
S t u d y D S C/ 1 1/ 2 3 5 7/ 4 3 was desi g ne d t o first verif y t hat d oses of g i vi n ostat lea di n g t o a n 
A U C 0 -2 4 of at leas t 3 0 0 n g * h/ m L i n m ost D M D patie nt s were t olerate d a n d t he n t o verif y t hat 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 2  of 1 1 0  
s uc h e x p os ur es w o ul d tr a nslate i nt o a sig nifica nt hist ol o gical be nefit.  Res ults  c o nfir me d t hat 
d oses of 2 5/ 3 7. 5  m g bi d  are t olerate d , res ult i n a n A U C 0 -2 4 of at least 3 0 0 n g * h/ m L i n t he 
maj orit y of treate d D M D patie nt s a n d l ead t o  a si g nifica nt hist ol o gical be nefit.  I n st u d y 
D S C/ 1 1/ 2 3 5 7/ 4 3, t he effects of gi vi n ostat o n t he 
M uscle Fi b er Area Fracti o n ( pri mar y 
e n d p oi nt of t he st u d y) a n d o n t he ot her k e y hist ol o gical para m eters ( T ot al Fi br osis, T otal 
Necr osis, Fa tt y Re place me nt) were c o m para ble w he n patie nts w h o mai ntai ne d t he 3 7. 5 m g 
b.i. d. d ose t hr o u g h o ut t he st u d y ( n = 7) were c o m p are d t o t h ose w h o re d u ce d t he d ose t o 2 5 m g 
b.i. d. ( n = 1 2). I n a p ost-h oc a nal ysis, t he Cr oss Secti o nal Area ( C S A) of t he m uscle fi bers i n 
patie nts w h o mai ntai ne d t he 3 7. 5 m g b.i. d. d ose t hr o u g h o ut t he st u d y ( n = 7) was lar ger t ha n 
t hat i n patie nts w h o re d uce d t he d ose t o 2 5 m g b.i. d. ( n = 1 2); h o we ver a hi g hl y si g nifica nt 
i ncreas e i n C S A was see n i n b ot h d ose gr o u ps. 
O n t he ot her ha n d,  cli nical e x perie nce i n c hr o nic i nfla m mat or y diseases i n a d ult a n d p e diatric 
p o p ulati o ns (i.e., Cr o h n’s Disease, Ps oriasis, S yste mic O nset J u ve nile I di o pat hic Art hritis 
a n d P ol yartic ular C o urse J u ve nile I di o pat hic Art hritis ) ha ve s h o w n t hat g i vi n ostat was 
o verall n ot eff ecti ve i n c o ntr olli n g s y m pt o ms a n d bi ol o gical feat ures of t hese dise ases at 
e x p os ures ( A U C 0 -2 4) c o m para ble or l o wer  t o t h ose o btai ne d i n st u d y D S C/ 1 1/ 2 3 5 7/ 4 3.   
Base d o n t hese c o nsi derati o ns, t he S p o ns or belie ves t hat d oses lea di n g t o dail y e x p os ures 
l o wer t ha n t h ose o btai ne d i n st u d y D S C/ 1 1/ 2 3 5 7/ 4 3 are ver y u nli kel y t o be eff ecti ve a n d 
t heref ore c h ose a n i nitial st u d y d ose t o e ns ure a mea n A U C0 -2 4 si milar t o t hat ac hie ve d wit h 
3 7. 5 m g/ bi d  d uri n g t he D S C/ 1 1/ 2 3 5 7/ 4 3 st u d y i n D M D patie nt s (i.e., a p pr o xi matel y 1 1 5 0  
n g * h / m L).  
U nf ort u natel y, t h e maj orit y of t he patie nts tr eat e d wit h t he starti n g d os e use d i n pr ot oc ol 
versi o n 2. 0 (i.e. d ose l ea di n g t o d ail y e x p os ures o btai ne d wit h 3 7. 5 m g/ bi d i n st u d y 
D S C/ 1 1/ 2 3 5 7/ 4 3) e x perie nce d a platel et c o u nt d ecreas e t hat re q uire d d os e re d ucti o n. E ve n if 
a strict re gi me n of platel et c o u nt m o nit ori n g a n d t he i m ple me ntati o n of a set of safet y r ules 
were a d e q uate t o e ns ure patie nt safet y, t h ese preli mi nar y bli n de d res ults s u g gest t hat t h e 
starti n g d ose i n dicate d in pr ot oc ol versi o n 2. 0 w o ul d be diffic ult t o ma na ge o utsi de of a 
cli nical trial e n vir o n me nt. As a c o nse q ue nce, a ne w starti n g d ose c orres p o n di n g t o t he 
re d uce d d ose of pr ot o c ol versi o n 2. 0 (i.e. 2 6. 7-4 6. 7 m g b.i. d acc or di n g t o b o d y wei g ht) is 
pr o p ose d b y t he S p o ns or i n pr ot oc ol versi o n 3. 0. T his ne w starti n g d ose e ns ures a mea n 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 3  of 1 1 0  
A U C 0 -2 4 si milar t o t hat ac hie ve d wit h 2 5 m g/ bi d d uri n g t he D S C/ 1 1/ 2 3 5 7/ 4 3 st u d y i n D M D 
patie nts (i.e., a p pr o xi m atel y 6 7 4 n g * h/ m L), 
w hic h 
was safe a n d s h o we d si g nifica nt 
hist ol o gical be nefit . 
Lastl y, si nce  wei g ht was s h o w n t o si g nifica ntl y affect g i vi n ostat cleara n ce, the i nitial d ose 
will be  a dj uste d t o t he b o d y wei g ht of t he patie nt  (see Secti o n 8. 2. 2 ).  
8. 2. 2  D os a ge Sc he d ule  
Gi vi n ostat  oral s us pe nsi o n ( 1 0 m g/m L ) a n d place b o oral s us pe nsi o n is t o be a d mi nistere d 
orall y as 2 oral d oses dail y i n a fe d c o n diti o n (e. g. i n t he m or ni n g after brea kfast a n d i n t he 
e ve ni n g aft er di n ner) . B ef ore its use , t he s us pe nsi o n m ust be s ha ke n f or at least 3 0 seco n ds 
b y r otati n g t he b ottle 1 8 0°. T h e s us p e nsi o n is  a d mi nistere d b y mea ns of a gra d u ate d d osi n g 
s yri n ge. T he d osa g e t o be a d mi nistere d is base d o n patie nt  wei g ht as  descri be d  bel o w:  
Ta ble 3 : Gi vi n ostat -P lace b o Starti n g D ose 
Wei g ht ( k g)  
≥3 0 a n d < 4 0  
≥4 0 a n d < 5 0  
≥5 0 a n d < 6 0  
≥6 0 a n d < 7 0  
≥7 0  
D ose ( m g) bi d  
2 6. 7  
3 3. 3  
3 6. 7  
4 0  
4 6. 7  
Or al s us pe nsi o n ( m L) 
bi d  
2. 7  
3. 3  
3. 7  
4  
4. 7  
 
D ose M o dificati o ns : 
After ra n d o mizati o n, p atie nt s will be as ke d t o ha v e  he mat ol o g y  assess me nt s e ver y t w o wee ks  
d uri n g t he first t w o m o nt h s of treat me nt  t o cl osel y m o nit or t hese para meter s f or s afet y 
p ur p oses . 
St u d y treat me nt d ose a dj ust me nt i ncl u di n g safet y r ules f or per ma n e ntl y or te m p orari ly 
st o p pi n g st u d y treat me nt are des cri be d i n Secti o n  7. 3. 1 . 
As me nti o ne d i n Secti o n 7. 3. 1 , if a patie nt  has  c o nsiste nt ( at least 2 c o nsec uti ve e val uati o n s) 
platelet c o u nt s ≤ 1 5 0 x 1 0 9/ L b ut d oes n ot meet t he st o p pi n g criteria d u e t o platelet  re d ucti o n, 
t he I n v esti gat or will ha ve t o re d uce t he d os e b y  2 0 %  of t he c urre nt  d ose  ( See Ta ble 4). 
St u d y treat me nt ca n be res u me d at a le vel 2 0 %  s maller t ha n t he d ose  at w hic h a n  A E lea di n g 
t o a te m p orar y st o p occ urre d, o nce platelets a n d/ or w hite bl o o d cell a n d/ or he m o gl o bi n  
a n d/ or tri gl yceri des  are n or malize d or w he n diarr h ea is mil d ( See Ta ble 4). 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 4  of 1 1 0  
Ta ble 4 : Gi vi n ostat -Place b o  D ose M o dificati o n  
 
St a rti n g D ose ( m g) bi d  
2 6. 7  
3 3. 3  
3 6. 7  
4 0  
4 6. 7  
Or al s us pe nsi o n ( m L) bi d  
2. 7  
3. 3  
3. 7  
4  
4. 7  
Re d uce d D ose ( m g) bi d 
2 1. 4  
2 6. 6  
2 9. 4  
3 2  
3 7. 4  
Or al s us pe nsi o n ( m L) bi d  
2. 1  
2. 7  
2. 9  
3. 2  
3. 7  
 
8. 3  
St u d y Tre at me nt Assi g n me nt  
Patie nt s will be dis pe nse d  t he st u d y treat me nt o n a n o ut patie nt basis.  All st u d y treat me nt 
s u p plies are t o be use d o nl y f or t his pr ot oc ol a n d f or n o ot her p ur p os e.  
Patie nts will be assi g ne d t o o ne of t he t w o treat me nt ar ms (gi vi n ostat vs. place b o ) i n a 2: 1 
rati o. T he ra n d o mizati o n pr ocess will be stratifie d b y  t he fact or relate d t o c o nc o mita nt ster oi d 
use at baseli ne ( yes vs. n o) . 
T he ra n d o mizati o n n u m bers will be ge n erat e d usi n g pr oce d ures t hat e ns ure t hat treat me nt 
assi g n me nt is u n biase d. A patie nt ra n d o mizati o n list will be pr o d uce d usi n g a vali date d 
s yste m t hat a ut o mates t he ra n d o m assi g n me nt of patie nt n u m bers t o ra n d o mizati o n n u m bers. 
At Visit 3, all p atie nt s w h o f ulfill all i ncl usi o n criteria a n d n o ne of t h e e xcl usi o n criteria will 
be ra n d o mize d vi a a n I nteracti ve 
We b Res p o ns e S yste m (I W R S) t o o n e of t he tr eat me nt 
ar ms. T he i n vesti gat or or his/ her dele gate will l o g o n t o t he I W R S , c o nfir m t hat t he patie nt  
f ulfills all t he i ncl usi o n/e xcl usi o n criteria a n d e nter i nf or mati o n rele va nt t o t he stratificati o n 
fact or. T h e I W R S will assi g n a ra n d o mizati o n n u m ber t o t he patie nt  w hi c h will be use d t o 
li n k t he patie nt  t o a treat me nt ar m .  
D uri n g t he st u d y, t he I n vesti gat or will s u p pl y the patie nt  wit h t he a p pr o priate n u m ber of 
s us pe nsi o n b ottles s ufficie nt t o c o ver t he p eri o d bet wee n t w o visits (3 m o nt hs of treat me nt).    
T he I n vesti gat or is t o use t he I W R S at eac h dis pe nsi n g visit t o o btai n t he pac ka gi n g n u m ber 
of t he st u d y treat me nt t o be dis pe nse d t o t he p atie nt . St u d y treat m e nt s h o ul d be dis pe nse d  b y 
a ut h orize d pers o n nel o nl y.  
T he I n v esti gat or will pr o vi de  t he patie nt  wit h  writte n i nstr ucti o n s o n t he d osa ge a n d 
c orres p o n di n g v ol u me i n milliliters of s us pe nsi o n t o be ta k e n at eac h a d mi nistrati o n . 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 5  of 1 1 0  
I n t h e u nli kel y cas e of s yste m u na vaila bilit y, t he I nteracti ve V oice Res p o nse S yste m (I V R S) 
will be use d as bac k u p f or ra n d o mizati o n a n d tr eat me nt assi g n me nt.  
8. 4  
Bli n di n g  
T his is a d o u ble -bli n d, place b o -c o ntr olle d st u d y, s o patie nt s recei vi n g gi vi n ostat or place b o 
will recei ve me dicati o n i n disti n g uis ha ble i n a p peara n ce.  Pers o n nel i n v ol ve d i n t he st u d y 
(I n vesti gat ors, n urses, all ot her site pers o n nel, cli nical researc h ass o ciat e [ C R A], Me dical 
M o nit ors, Pr oject Ma na g ers, Data M a na g ers a n d Stati sticia ns) will re mai n bli n d at all ti mes, 
u nless k n o wle d ge of t he st u d y treat me nt is rele va nt t o t he safet y of t he pa tie nt. If t he 
I n v esti gat or or a ut h orize d desi g nee deci des t o brea k t he c o de of a patie nt , it is s u g geste d t hat 
t he M o nit ori n g Tea m ( M e dical M o nit or or C R A) be c o ns ulte d if p ossi ble b ef ore brea ki n g t he 
c o de, h o we ver t his is n ot ma n dat or y  si nce t he decisi o n of t he I n vesti gat or ca n n ot be 
i nfl ue nce d n or d o es it re q uire t he a p pr o val of t he  M o nit ori n g Tea m .  
C o de brea ki n g ca n be p erf or me d b y t he I n v esti gat or or a ut h ori ze d d esi g nee at a n y ti me b y 
us i n g t he pr o per m o d ul e of t he I W R S. I n t he u nli kel y case of s yste m u na vaila bilit y, t he 
I nteracti ve V oice Res p o nse S yste m (I V R S) will be use d as bac ku p f or c o d e brea ki n g . 
If t he c o de is br o ke n t he I n v esti gat or m ust rec or d t he date, ti me, a n d reas o n f or brea ki n g t h e 
c o de i n t he eC R F, a n d m ust n otif y t he M o nit o ri n g Tea m as s o o n as p ossi bl e. 
Bef ore wit h dr a wi n g a p atie nt,  e ac h c ase c a n be disc usse d wit h t he st u d y 
me dic al 
m o nit or, b ut t he fi n al decisi o n re m ai ns wit h t he I n vesti g at or o nl y or a ut h orize d 
desi g nee. If t he s afet y of t he s u bject c a n be re as o n a bl y ass ure d , t he s u bject will n ot be 
disc o nti n ue d.  
As platelet c o u nt re d ucti o ns are o bser ve d after treat me nt wit h gi vi n osta t, st u d y site pers o n nel 
w h o  perf or m t he hist ol o g y a nal ysis, t he f u ncti o n al tests a n d t he M RI / M R S a nal ysis m ust be 
diffe re nt fr o m t he pers o n nel wh o  re vie w safet y res ults a n d t hese  m ust n ot be s hare d wit h t he 
pers o n nel res p o nsi ble f or t he f u ncti o nal tests , hist ol o g y a n d M RI/ M R S a nal yses .  
Re gar di n g t he P K  res ults, all t he pers o n nel i n v ol ve d i n t he st u d y will re mai n bli n d at all 
ti mes a n d S p o ns or ma y re vie w t he P K  res ults o nl y i n scram ble d f or m at.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 6  of 1 1 0  
8. 5  
Dr u g S u p pl y  
T he i n vesti gati o nal site will be s u p plie d wit h  a n u m ber of s us p e nsi o n b ottles s ufficie nt t o 
treat the patie nt s e nr olle d i n t he st u d y.  
8. 5. 1  P ac k a gi n g  
P ri mar y pac ka gi n g will c o nsist of a n a m ber plastic b ottle c o ntai ni n g t he s us pe nsi o n. 
Gi vi n ostat/ p lace b o oral s us pe nsi o n is s u p plie d i n a 1 5 0 m L ca pacit y a m ber P E T b ottle cl ose d 
b y mea ns of a re d -w hite H D P E c hil d -pr o of scre w ca p wit h a L D P E s h utter/s yri n ge -a d a pter.  
Eac h b ottle c o ntai ns 1 4 0 m L of gi vi n ostat 1 0 m g/ m L or place b o . T he sec o n dar y pac k a gi n g 
will be a cart o n b o x c o ntai ni n g o ne  a m ber b ottle a n d  t w o s yri n ges as d osi n g s yste m s f or 
dis pe nsi n g t he s us pe nsi o n . 
8. 5. 2  L a belli n g  
T he pri mar y a n d sec o n d ar y la bels will s h o w all t he i nf or mati o n re q ueste d i n acc or da nce wit h 
A n ne x 1 3 of  G o o d  Ma n ufact uri n g Practice a n d l o cal le gislati o n .  
Me dicati o n la bels will be i n t he l ocal la n g ua ge . 
T he la bels  will i ncl u de at least:  
•  Na me of t he me di ci nal pr o d uct  
•  P har mace utical d osa ge f or m  
•  R o ute of a d mi nistrati o n  
•  Q ua ntit y of d osa ge u nits  
•  Stre n gt h / p ote nc y 
•  Batc h n u m ber/ Pac ka gi n g n u m ber  
•  S p o ns or’s st u d y c o de ( *)  
•  E u dra C T n u m ber ( *)  
•  I n v esti gat or na me ( *) 
•  Site a n d patie nt  n u m ber ( *)  
•  Treat me nt/ Ra n d o mizati o n n u m ber ( *)  
•  Na me, a d dress, a n d tel e p h o ne n u m ber of t h e mai n c o ntact (t he s p o ns or or t he 
c o ntract r esearc h or g a niz ati o n or t he i n vesti gat or) ( *) ( * *)  
•  Peri o d of use ( *)  
•  St ora ge c o n diti o ns ( *)  
•  Directi o ns f or  us e ( *) ( * *)  
•  F or cli nical tri al use o nl y ( *)  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 7  of 1 1 0  
•  Kee p o ut of reac h of c hil dre n ( *)  
N otes:  
( *) Acc or di n g t o A n ne x 1 3 a n d E U la w i n f orce, w he n usi n g a ce ntr alize d electr o nic 
ra n d o mizati o n s yste m, s o me of t he liste d i nf or mati o n ma y be o mitte d fr o m t he la bel.  
( * *) Acc or di n g t o A n n e x 1 3, s uc h i nf or m ati o n mi g ht n ot nee d t o a p pear o n t he la bel if 
se parat el y pr o vi de d i n a l eaflet or car d.  
8. 5. 3  St or a ge  
T he i n vesti gati o nal site will st ore t he st u d y treat me nt u n der t he c o n diti o ns s pecifie d here 
bel o w, e ns uri n g t hat it is n ot accessi ble t o u na ut h orize d pers o ns u ntil it is dis pe nse d t o t he 
patie nt . 
G i vi n ostat/p lace b o s us pe nsi o n is t o be st ore d i n a refri g erat or at 5° C  ±  3° C. O nce t he 
c o ntai ner is  o pe n e d, t he s us pe nsi o n ca n be a d mi nistere d f or a ma xi m u m of 3 0  da ys.  
8. 6  
Tre at me nt Acc o u nt a bilit y a n d C o m pli a nce  
T he st u d y treat me nt pac ka gi n g  will be pr o vi de d wit h tear -off la bels; bef ore treat me nt 
dis pe nsati o n t he tear-off la bel s h o ul d be re m o ve d fr o m t he patie nt ’s pac k b y t he I n v esti gat or 
a n d st uc k o n t he a p pr o priate dr u g acc o u nta bilit y f or m.  
At eac h dis pe nsi n g visit, t he patie nt  will ret ur n  all b ottles pre vi o usl y recei ve d ( use d, p artiall y 
use d a n d u n use d) a n d recei ve a ne w s u p pl y  of t he st u d y treat me nt.  
Patie nt  c o m plia nce will be e val uate d t hr o u g h a patie nt diar y i n dicati n g h o w ma n y d oses were 
effecti vel y a d mi nistere d b y t he patie nt .  
Dr u g acc o u nta bilit y  will be c hec ke d b y It alfar mac o S. p. A. or its desi g nee bas e d o n a n 
acc o u nta bilit y l o g  c o m plete d b y site staff a n d m o nit ore d b y It alfar mac o S. p. A. or its 
desi g nee.  
T he use d, p artiall y use d , a n d u n use d b ottles will be c ollecte d a n d se nt b ac k t o It alfar m ac o  
S. p. A. or t heir desi g nee p eri o dicall y or at t he e n d of t he st u d y.   

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 8  of 1 1 0  
8. 7  
Pri or a n d C o nc o mit a nt Ill nesses a n d Me dic ati o ns  
8. 7. 1  Pri or a n d C o nc o mit a nt Ill nesses  
I n v esti gat ors s h o ul d d oc u me nt all si g nifica nt pri or ill nesses t hat t he patie nt  has e x perie nce d 
wit hi n 6 m o nt hs of  scree ni n g. A d diti o nal ill nesses prese nt at t he ti me w he n i nf or me d c o nse nt 
is gi ve n a n d u p t o t he ti me of first d osi n g are t o be re ga r de d as c o n c o mita nt ill nesses.  
Ill nesses first occ urri n g or detecte d d uri n g t he st u d y a n d/ or w orse ni n g of a c o n c omita nt 
ill ness d uri n g t he st u d y are t o be d oc u me nt e d as A Es o n t he eC R F.  
8. 7. 2  Pri or a n d C o nc o mit a nt Me dic ati o ns  
All me dicati o ns a n d ot her treat me nts ta ke n b y t he patie nt  d uri n g t he st u d y, i ncl u di n g t h ose 
treat me nts i nitiate d wit hi n 6 m o nt hs pri or t o t he start o f t he st u d y, m ust be rec or de d o n t he 
eC R F.  
C o nc o mita nt treat me nts are defi ne d as tr eat me nts ta ke n after st u d y  treat m e nt a d mi nistrati o n. 
A n y me dicati o n or t hera p y t hat is ta ke n b y or a d mi nistere d t o t he p atie nt  d uri n g t he st u d y 
m ust be rec or de d i n t he eC R F.  T he e ntr y m ust i ncl u de  d ose, re gi me n, r o ute, i n dicati o n, a n d 
dates of use.  
After t he 
Scree ni n g  visit, 
me dicati o n t o treat 
mi n or treat me nt -e mer ge nt ill nesses are 
ge nerall y p er mitte d; s u p porti ve treat me nts s u c h as a ntie metics, a nti diarr heals , a nti p yretics, 
a nti-aller gics, a n al gesics a n d a nti bi otics are all o we d.   
Use of Vita mi n D, cal ci u m a n d a n y ot her s u p ple me nts if cli nicall y i n dicate d bef ore 
e nr ollme nt a n d f or t he d urati o n of t he st u d y is all o we d  
T he f oll o wi n g t hera pies are e x pressl y pr o hi bite d  t hr o u g h o ut t he st u d y:  
•  A n y o t her i n vesti gati o nal dr u g  w hile o n t his st u d y .  
•  A n y d ystr o p hi n rest orati o n pr o d uct .  
•  A n y p har mac ol o gic treat me nt, ot her t ha n c ortic oster oi ds, t hat mi g ht ha ve a n effect o n 
m uscle st re n gt h or f u ncti o n (e. g., gr o wt h h or m o n e) . 
T he f oll o wi n g are c o nc o mita nt t hera p y re q uiri n g c a uti o n  t hr o u g h o ut t he st u d y: 
•  Dr u gs k n o w n t o i n crease t he Q T i nter val (see A p pe n di x 1 6. 1  f or a list of s uc h 
c o m p o u n ds) .  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 5 9  of 1 1 0  
•  L i ve or li ve atte n u ate d v acci nes: th e p atie nt  m ust be caref ull y m o nit ore d. W hile t h e 
decisi o n of t he I n vesti g at or ca n n ot be i nfl ue n ce d, rejecte d  n or a p pr o ve d b y t he 
Me dical M o nit or, it is a d vise d b ut n ot ma n dat or y t hat t he I n v esti gat or disc uss t he cas e 
wit h t he Me dical M o nit or bef ore usi n g t hese vacci nes.  
•  Dr u gs k n o w n  t o b e a s u bstrate of Or ga ni c Cati o n Tra ns p ort er 2  (see A p pe n di x 1 6. 2  
f or a list of s uch  c o m p o u n ds).  
•  A nti platelet, t hr o m b ol ytic or a ntic oa g ul a nt dr u gs m ust be caref ull y m o nit ore d.  
•  Dr u gs k n o w n t o be P -gl yc o pr otei n i n hi bit ors (see A p pe n di x 1 6. 3 f or a list of s uc h 
c o m p o u n ds).  
 
8. 8  
Tre at me nt f or h y pertri gl yceri de mi a  
If a s u bject e x peri e nces a n i ncreas e of tri gl yceri d es > U L N duri n g t he st u d y, t he i n vesti gat or 
is all o we d t o prescri be a de q uate treat me nt i ncl u di n g dietar y s u p ple me nts . T hese treat me nts 
will be rei m b urse d b y t he S p o ns or.  
9  
S T U D Y P R O C E D U R E S  
Ta ble 5  o utli nes t he ti mi n g of pr oce d ures a n d assess me nts t o be perf or m e d t hr o u g h o ut t he 
st u d y. 
See  
Secti o n  
9. 1  
f or  
a d diti o nal  
details  
of  
st u d y  
pr oce d ures.

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 0  of 1 1 0  
 
Ta ble 5 : 
Sc he d ule of Assess me nts  
M o nt h  
-1  
0  
1  
2  
3  
6  
9  
1 2  
1 3  
Wee k  
-4  
0  
2  
4  
6  
8  
1 2  
2 4  
3 6  
4 8  
5 2  
Visit wi n d o w  
+ 2 wee ks  
0  
± 3 
da ys  
± 3 
da ys  
± 3 
da ys  
± 3 
da ys  
± 7 
da ys  
± 7 
da ys  
± 7 da ys  
± 7 da ys  
± 7 da ys  
Visit *  
V 1  
V 2  
V 3  
V 4  
 
 
 
V 5  
 
 
 
V 6  
 
 
 
V 7  
 
 
 
V 8  
 
 
 
V 9  
 
 
 
V 1 0  
 
 
 
V 1 1  
V 1 2  
Scree ni n g  
R a n d  
E O S/ E arl y 
Wit h dr a w al
1 
F U V 2 
I nf or me d c o nse nt 
X  
 
 
 
 
 
 
 
 
 
 
 
Eli gi bilit y criteria  
X  
 
 
 
 
 
 
 
 
 
 
 
Me dical hist or y a n d 
de m o gra p hic data  
X  
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d c o nc o mita nt 
me dicati o ns  
X  
 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
P h ysica l e xa mi nati o n  
X  
 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
Vital Si g ns  
X  
 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
Wei g ht  
X  
 
X  
X  
X  
 
X  
X  
X  
X  
X  
 
Hei g ht  
X  
 
 
 
 
 
 
 
 
 
X  
 
E C G Test 3 
X  
 
X  
X  
X  
 
X  
X  
X  
X  
X  
X  
E C H O  
X  
 
 
 
 
 
 
 
 
 
X  
 
P ul m o nar y f u ncti o n tests 4 
X  
 
 
 
 
 
 
 
 
 
X  
 
Ser ol o g y 5  
X  
 
 
 
 
 
 
 
 
 
 
 
He m a t ol o g y6 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Bl o o d c he mistr y 7 
X  
 
 
 
 
 
X  
X  
X  
X  
X  
X  
T h yr oi d  f u ncti o n tests ( T S H, f T 3, 
f T 4) 
X  
 
 
 
X  
 
X  
X  
X  
X  
X  
X  
C oa g ula ti o n tests ( P T a n d a P T T) 
X  
 
 
 
 
 
X  
X  
X  
X  
X  
X  
Uri ne a n al ysis 8 
X  
 
 
 
 
 
X  
X  
X  
X  
X  
X  
S F -3 6   
X  
 
 
 
 
 
 
 
 
 
X  
 
Ti me f u ncti o n tests  (ti me t o 
cli m b 4 sta n dar d ste ps, ti me t o 
rise fr o m fl o or, ti me t o wal k 1 0 
m)  
X  
 
 
 
 
 
 
X  
X  
X  
X  
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 1  of 1 1 0  
 
M o nt h  
-1  
0  
1  
2  
3  
6  
9  
1 2  
1 3  
Wee k  
-4  
0  
2  
4  
6  
8  
1 2  
2 4  
3 6  
4 8  
5 2  
Visit wi n d o w  
+ 2 wee ks  
0  
± 3 
da ys  
± 3 
da ys  
± 3 
da ys  
± 3 
da ys  
± 7 
da ys  
± 7 
da ys  
± 7 da ys  
± 7 da ys  
± 7 da ys  
Visit *  
V 1  
V 2  
V 3  
V 4  
 
 
 
V 5  
 
 
 
V 6  
 
 
 
V 7  
 
 
 
V 8  
 
 
 
V 9  
 
 
 
V 1 0  
 
 
 
V 1 1  
V 1 2  
Scree ni n g  
R a n d  
E O S/ E arl y 
Wit h dr a w al
1 
F U V 2 
6 M W T  
X  
 
X  
 
 
 
 
X  
X  
X  
X  
 
M F M  
X  
 
 
 
 
 
 
X  
X  
X  
X  
 
M uscle stre n gt h
9 
X  
 
 
 
 
 
 
X  
X  
X  
X  
 
P K bl o o d sa m ple c ollecti o n 1 0 
 
 
 
 
X  
 
 
X  
X  
 
X  
 
Bi o mar k ers bl o o d c ollecti o n 1 2 
 
 
X  
 
 
 
 
 
X  
 
X  
 
St u d y treat me nt dis pe nsati o n a n d 
acc o u nta bilit y  
 
 
X  
 
 
 
 
X  
X  
X  
 
 
Patie nt diar y dis pe nsati o n  
 
 
X  
 
 
 
 
 
 
 
 
 
Patie nt c o m plia nce  t hr o u g h diar y 
 
 
 
 
 
 
 
X  
X  
X  
X  
 
A E assess me nt  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
M R
 + M usc ular bi o ps y  
 
X 1 1 
 
 
 
 
 
 
 
 
 X 1 3  
 
6 M W T = 6 -mi n ute wal ki n g test; A E =a d verse e ve nt; M F M =  M ot or F u ncti o n meas ure;  S F 3 6 =  S h ort F or m ( 3 6) Healt h S ur ve y; P T = Pr ot hr o m bi n ti me; a P P T =  
acti vate d partial t hr o m b o plasti n ti me; E C G =  electr ocar di o gra m; E C H O =  ec h ocar di o gra m; P K = p har mac o ki netics;  M RI =  ma g netic res o na nce i ma gi n g; F E V 1 = 
f orce d e x pirat or y v ol u me at 1 sec o n d; F V C =f orce d vital ca pacit y; P E F = pea k e x pirat or y fl o w; R B C -re d bl o o d cell; 
W B C = w hite bl o o d cell; A L T =ala ni ne 
a mi n otra nsferase; A S T =as partate a mi n otra nsferase; L D H =  lactate de h y dr o ge nase; C R P = C-reacti ve pr otei n; G G T = g a m ma-gl uta m yl tra ns pe pti dase; B U N = bl o o d 
urea nitr o ge n; f T 3 =  free T 3 (t he acti ve part of trii o d ot h yr o ni ne); f T 4 = Free T 4 (t he acti ve part of t h yr o xi ne); T S H =t h yr oi d -sti m ulati n g h or m o ne; e G F R =esti mat e 
Gl o mer ular Filtrati o n Rate;  H H M = h a n d -hel d m y o metr y; M M T = ma n ual m uscle testi n g  
*  
U nsc h e d ule d visits ma y ta ke place at t he discreti o n of t he I n vesti gat or s uc h as a d diti o nal car di ol o g y visits at t he st u d y ce n ter or visits at t he patie nt’s 
h o me b y a q ualifie d trai ne d n urse  f or bl o o d sa mple c ollecti o n . 
1.  
If t he patie nt  is disc o nti n ue d fr o m t he st u d y treat me nt, t he patie nt  will be as ke d t o ret ur n f or t he earl y wit h dra wal visit t o be perf or me d wit hi n 4 wee ks 
of t he last d ose of st u d y treat me nt.  I n t his case, t he S F -3 6  e val uati o n a n d M RI ma y n ot be perf or me d.  
2.  
T he patie nt s w h o c o m plete t he st u d y (i.e. 1 2 m o nt hs of treat me nt) will be as ke d t o ret ur n t o t he ce ntre f or t he F oll o w -u p visit t o be perf or me d after 4 
wee ks fr o m t he last d ose of st u d y treat me nt (i.e. 4 wee ks ± 1). 
3.  
A 1 2 -lea d E C G is t o be d o ne i n tri plicate at t he scree ni n g visit a n d d uri n g t he ot her visits if a n E C G de m o nstrates a pr ol o n ge d Q T c F i nter val ˃ 4 5 0  msec  
o btai n e d  o n 2 m ore E C Gs o ver a brief peri o d . T he a vera ge d Q Tc F val ues of t he 3 E C Gs is t o be use d t o deter mi ne w het her t he pat ie nts s h o ul d be 
disc o nti n ue d fr o m t he st u d y.  
4.  
P ul m o nar y f u ncti o n tests : F E V 1 , F V C a n d P E F.  
5.  
Ser ol o g y C M V I g M , H Bs A g/ H C V/ HI V , E B V I g G.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 2  of 1 1 0  
 
6.  
He m at ol o g y test: R B C, W B C (i ncl u di n g differe ntial c o u nt), he m o gl o bi n, M C H, M C H C, M C V, he mat ocrit, a n d plat elets. Test will be d o ne acc or di n g t o 
t he sc h e d ule (i.e., e v er y t w o wee ks  t he first 2  m o nt h s of treat me nt) a n d are t o be perf or me d m ore fre q ue ntl y if cli nicall y i n dicate d.  N ote: Re p eat visits 
f or t he platelets c o u nt will be perf or me d  at t he re q uest of t he I n vest i gat or. 
7.  
Ser u m bl o o d c he mistr y : t otal bilir u bi n, direct bilir u bi n, al kali ne p h os p hatase, a m ylase, A L T, A S T, L D H, c ystati n C, C R P, G G T, creati ne ki nase, t otal 
pr otei n, al b u mi n, uric aci d, tri gl yceri des, p h os p h or us, t otal c h olester ol, L D L, H D L, s o di u m, p otass i u m, c hl ori de, calci u m, gl uc ose, creati ni ne, B U N, 
bicar b o nate) , N T -pr o B N P .  
8.  
Uri nal ysis: a p peara n ce, p H, s pecific gra vit y, pr otei n, gl uc ose, ket o ne b o dies, bl o o d a n d W B Cs, a n d ur o bili n o ge n.  
9.  
M uscle stre n gt h tests: k nee e xte nsi o n, el b o w fle xi o n b y H H M.  
1 0.  
P har m ac o ki netic sa m ple c ollecti o n: sa m pli n g ( 2 pre -d ose d uri n g t he treat me nt a n d 4 p ost -d ose) will be c ollecte d as des cri be d i n t he pr ot oc ol d uri n g t he 
f oll o wi n g visits: 5 ( 4 wee ks), 8 ( 1 2 wee ks), 9 ( 2 4 wee ks), a n d 1 1  ( Wee k 4 8). At t hese visits, t he patie nt  wil l b e as ke d t o ta k e t he m or ni n g d ose at site. 
1 1.  
T he first M RI ( b y  Di x o n  tech ni q ue ), M R S tests a n d m usc ular bi o ps y ha ve t o be perf or me d w he n all i ncl usi o n/e xcl usi o n criteria ha v e bee n alrea d y 
e v al uate d a n d t he patie nt  is eli gi ble. M RI/ M R S a n d m usc ular bi o ps y ca n be perf or me d i n differe nt da ys.   
1 2  
L T B P 4 a n d oste o p o nti n ge n ot y pe a fter ra n d o mizati o n a n d bl o o d sa m ple c ollecti o n f or ser u m circ ulati n g pr otei ns  (b y a n E LI S A base d s yste m)  at 
ra n d o mizati o n, 6 m o nt hs a n d at t he e n d of treat me nt. 
1 3  
M RI / M R S a n d bi o ps y ma y be perf or me d o n differe nt da ys. Treat me nt is t o c o nti n ue u p t o t he last assess me nt.  
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 3  of 1 1 0  
9. 1  
P r oce d ures b y St u d y Visit  
T wel ve  (1 2 ) st u d y visits, i ncl u di n g t he Scree ni n g a n d Ra n d o miz ati o n Visits , are pla n ne d. 
Assess me nts will  be p erf or me d as o utli ne d i n t he f oll o wi n g b y-visit s u bsecti o ns.  As platelet 
c o u nt re d u cti o ns are o bser ve d after tr eat me nt wit h gi vi n osta t, st u d y site pers o n nel w h o 
perf or m f u ncti o nal tests a n d M RI / M R S m ust be diffe re nt fr o m t he pers o n nel w h o re vie w 
safet y res ults relat e d t o la b orat or y tests, a n d t hese m ust n ot be s har e d wit h t he pers o n nel 
res p o nsi ble f or t he f u ncti o nal tests a n d M RI/ M R S. 
9. 1. 1  Visit 1 a n d Visit 2  - Scree ni n g  ( Wee k -4  +  2 wee ks ) 
T he S cree ni n g visit s ( Visit 1 a n d Visit 2 ) will occ ur wit hi n 4 wee ks  ( ± 2 wee ks) pri or t o t he 
Ra n d o miz ati o n Visit . T he f oll o wi n g assess me nts will be perf or me d  at Visit 1:  
•  W ritte n I nf or m e d C o nse nt  
•  Eli gi bilit y criteria : re vie w of i ncl usi o n a n d e xcl usi o n criteria 
•  M e dical h ist or y a n d de m o gra p hic data 
•  P ri or me dicati o ns (ta ke n i n t he past 6 m o nt hs) 
•  P h ysical exa mi nati o n  
•  V ital si g ns (bl o o d press ure, heart r ate a n d b o d y te m perat ure ) 
•  W ei g ht  a n d h ei g ht  
•  1 2 -lea d E C G  (i n tri plicat e)  
•  Ec h ocar di o gra m  
•  P ul m o nar y f u ncti o n tests : F E V 1, F V C, F E V 1/ F V C, a n d P E F 
•  Bl o o d c ollecti o n  f or:  
o  
ser ol o g y  
o  
h e mat ol o g y  
o  
bl o o d che mistr y  
o  
c oa g ulati o n tests ( pr ot hr o m bi n ti me [ P T] a n d acti vate d partial t hr o m b o plasti n 
ti me [a P T T]) 
o  
t h yr oi d f u ncti o n tests ( T S H, f T 3, f T 4) 
•  U ri ne a nal ysis 
•  Q ualit y of Life test (S F -3 6 ) 
•  6 M W T  + M F M  
•  M uscle stre n gt h test  ( k nee e xte nsi o n a n d el b o w fle xi o n b y H H M) 
•  T i me f u ncti o n tests 
•  A E  assess me nts  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 4  of 1 1 0  
If all i ncl usi o n a n d e xcl usi o n criteria ha ve b ee n m et a n d t he patie nt  is eli gi ble, a n M RI, M R S 
a n d m uscle bi o ps y are t o be p erf or me d b ef ore t he first I M P d ose. At t h e discreti o n of t h e 
I n v esti gat or, patie nts n ot meeti n g i ncl usi o n/e xcl usi o n criteria ma y be re-scree n e d t wice wit h 
a n i nter val of at least 3 0 da ys bet wee n assess me nts.  
At Visit 1, after ha vi n g fille d i n t he “ Eli gi bilit y criteria” s ecti o n of t he e C R F, eli gi ble p atie nts 
will be ra n d o mize d t o o n e of t he t w o f oll o wi n g m u scle bi o ps y se q ue nces b y t he s yste m:  
V 2: Ri g ht Ar m - V 1 1: Left Ar m  
V 2: Left Ar m - V 1 1: Ri g ht Ar m  
T he site will recei v e t he m uscle bi o ps y se q ue nce b y e mail.  
Ra n d o mizati o n will be bala nce d i n a rati o of 1: 1 a n d will n ot be stratifie d.  
If nee d e d f or l o gistic reas o ns, Visit 2 ca n be c o m plete d o n  t w o differe nt d a ys i ncl u de d i n t he 
wi n d o w peri o d bet w ee n Visit 1 a n d Visit 3 . Patie nt s will be i nstr ucte d t o a v oi d p h ysical 
acti vit y t hat w o ul d e xcee d t heir n or mal acti vit y f or 3 da ys bef ore eac h visit.  
9. 1. 2  Visit 3 - R a n d o miz ati o n  ( Wee k 0) 
Data c ollecte d at Visit 3 will re prese nt  bas eli ne val ues f or st u d y e n d p oi nts.  
At Visit 3, t he  f oll o wi n g assess me nts will be perf or me d: 
•  Re vie w of eli gi bilit y criteria usi n g t he assess me nts d o ne at scree ni n g. 
•  P ri or a n d c o nc o mita nt  m e dicati o ns  
•  P h ysical e xa mi nati o n   
•  V ital si g ns ( bl o o d press ure, heart r ate a n d b o d y te m perat ure)  
•  Wei g ht  
•  1 2 -lea d E C G  
•  B l o o d c ollecti o n f or  he m at ol o g y  a n d bi o mar ker e val uati o n  
•  6 M W T  
•  Ra n d o mizati o n a n d dis pe nsati o n of  st u d y treat me nt 
•  A E  assess me nt s 
•  Patie nt diar y dis pe nsati o n  
9. 1. 3  Visit  4  ( Wee k 2  ±  3  d ays ) 
T he f oll o wi n g assess me nts will be perf or me d a t Visit 4 , after 2  wee k s ( ± 3  da ys) of 
treat me nt: 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 5  of 1 1 0  
•  C o nc o mita nt me dicati o ns  
•  P h ysical e xa mi nati o n   
•  V ital si g ns ( bl o o d press ure, heart r ate a n d b o d y te m perat ure)  
•  Wei g ht  
•  1 2 -lea d E C G  
•  B l o o d c ollecti o n f or  h e m at ol o g y   
•  A Es assess me nts  
9. 1. 4  Visit s 5  ( Wee k 4 ±  3 d ays)  
T he f oll o wi n g assess me nts will be perf or me d at Visit 5, after 4 wee ks ( ± 3 da ys) of 
treat me nt. Patie nt s will be i nstr ucte d t o ta ke t he m or ni n g d ose at t he site i n case of pre-d ose 
P K a nal ysis . 
•  C o nc o mita nt me dicati o ns  
•  P h ysical e xa mi nati o n  
•  Vital si g ns ( bl o o d press ure, heart r ate a n d b o d y te m perat ure)  
•  Wei g ht  
•  1 2 -lea d E C G  
•  Bl o o d c ollecti o n f or he m at ol o g y , th yr oi d f u ncti o n tests ( T S H, f T 3, f T 4)  a n d P K 
a nal ysis  
A Es assess me nts  
9. 1. 5   Visit 6  ( Wee k 6  ±  3  d ays ) 
Visit 6 is re q uire d if t h e platelet v al ues at a n y visit d uri n g t he first m o nt h of treat me nt 
decrease d  m or e t ha n 1 0 % fr o m t he P L T val ue m eas ure d at t he Ra n d o mizati o n Visit (i.e . Visit 
3 -wee k 0) or at t he discreti o n of t he I n v esti gat or.  
Visits 6  will be perf or m e d  6 wee ks aft er t he R a n d o mizat i o n Visit ( ± 3  da ys)  esse ntiall y f or 
safet y p ur p oses, a n d t he f oll o wi n g assess me nts will be perf or m e d:  
•  B l o o d c ollecti o n  f or he m at ol o g y  
•  A E assess me nts . 
9. 1. 6  Visit 7  (Wee k 8  ±  3  d ays ) 
At Visit 7 , after 2  m o nt h s of treat me nt  ( ± 3  da ys) , t he assess me nts liste d bel o w will be 
perf or me d . 
•  C o nc o mita nt me dicati o ns  
•  P h ysical e xa mi nati o n  
•  V ital si g ns ( bl o o d press ure, heart r ate a n d b o d y te m perat ure)  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 6  of 1 1 0  
•  Wei g ht  
•  1 2 -lea d E C G  
•  B l o o d c ollecti o n f or : 
o  
he mat ol o g y  
o  
bl o o d c he mistr y  
o  
c oa g ulati o n tests ( pr ot hr o m bi n ti me [ P T] a n d acti vate d partial t hr o m b o plasti n 
ti me [a P T T]) 
o  
th yr oi d f u ncti o n tests ( T S H, f T 3, f T 4)  
•  Uri ne a nal ysis  
•  A E assess me nts  
9. 1. 7  Visit 8  ( Wee k 1 2  ±  7  d ays )  
T he f oll o wi n g assess me nts will be perf or me d a t Visit 8  ( ± 3 da ys), after 3  m o nt hs of 
treat me nt . Patie nt s will be i nstr ucte d t o ta ke t he m or ni n g d ose at t he site i n case of pre-d ose 
P K a nal ysis . 
•  C o nc o mita nt me dicati o ns  
•  P h ysical e xa mi nati o n  
•  V ital si g ns ( bl o o d press ure, heart rate a n d b o d y te m perat ure)  
•  W ei g ht  
•  1 2 -lea d E C G  
•  B l o o d c ollecti o n  f or:  
o  he mat ol o g y  
o  bl o o d c he mistr y  
o  c oa g ulati o n tests ( P T a n d a P T T) 
o  th yr oi d f u ncti o n tests ( T S H, f T 3, f T 4)  
o  P K a nal ysis  
•  U ri ne a nal ysis 
•  6 M W T + M F M  
•  M uscle stre n gt h test ( k nee e xte nsi o n a n d el b o w fle xi o n b y H H M)  
•  Ti me f u ncti o n tests  
•  Dis pe nsati o n  a n d acco u nt a bilit y of st u d y treat me nt  
•  Diar y ret ur n a n d p atie nt c o m plia nce  
•  A E  assess me nts  
9. 1. 8  Visit 9  ( Wee k 2 4  ± 7 d ays )  
Visits 9 will ta ke place 2 4  wee ks after t he Ra n d o mizati o n  visit , wit h a wi n d o w of ± 7 d a ys. 
S u bjects will be i nstr ucte d t o ta ke t h e m or ni n g d ose at t h e site  i n cas e of pre-d os e P K 
a nal ysis . 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 7  of 1 1 0  
T he f oll o wi n g asse ss me nts will be perf or me d: 
•  C o nc o mita nt me dicati o ns  
•  P h ysical e xa mi nati o n   
•  V ital si g ns ( bl o o d press ure, heart rate a n d b o d y te m perat ure)  
•  W ei g ht  
•  1 2 -lea d E C G  
•  B l o o d c ollecti o n  f or:  
o  he mat ol o g y  
o  bl o o d c he mistr y  
o  c oa g ulati o n tests ( P T a n d a P T T)  
o  th yr oi d f u ncti o n tests ( T S H, f T 3, f T 4)  
o  P K a nal ysis  
o  Bi o mar ker e val u ati o n  
•  U ri ne a nal ysis 
•  6 M W T + M F M  
•  M uscle stre n gt h test ( k nee e xte nsi o n a n d el b o w fle xi o n b y H H M)  
•  Ti me f u ncti o n tests 
•  Dis pe nsati o n  a n d acc o u nt a bilit y of st u d y treat me nt  
•  A E  assess me nts  
•  Diar y ret ur n a n d p atie nt c o m plia nce  
9. 1. 9  Visit 1 0 ( Wee k 3 6 ± 7 d ays)  
Visits 1 0 will ta ke place 3 6 wee ks after t he Ra n d o mizati o n visit, wit h a wi n d o w of ± 7 da ys.  
T he f oll o wi n g ass ess me nts will be perf or me d : 
•  C o nc o mita nt me dicati o ns  
•  P h ysical e xa mi nati o n  
•  Vital si g ns ( bl o o d press ure , heart rate a n d b o d y te m perat ure)  
•  Wei g h  
•  1 2 -lea d E C G 
•  Bl o o d c ollecti o n f or:  
o  he mat ol o g y  
o  bl o o d c he mistr y  
o  c oa g ulati o n tests ( P T a n d a P T T)  
o   th yr oi d f u ncti o n tests ( T S H, f T 3, f T 4) 
•  Uri ne a nal ysis  
•  6 M W T + M F M  
•  M uscle stre n gt h test ( k nee e xte nsi o n a n d el b o w fle xi o n b y H H M)  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 8  of 1 1 0  
•  Ti me d f u ncti o n tests  
•  Dis pe nsati o n a n d acc o u nta bilit y of st u d y treat me nt  
•  A E assess me nts  
•  Diar y ret ur n a n d p atie nt c o m plia nce  
9. 1. 1 0  Visit 1 1 : E n d of St u dy Visit (E O S , Wee k 4 8  ± 7 d ays) a n d e arly wit h dr a w al visit  
T he E O S ( Visit 1 1 ) will be sc he d ule d at t he e n d of treat me nt (i.e., 4 8  wee ks after t he 
Ra n d o mizati o n Visit, ± 7 da ys ). Patie nt s will be i nstr ucte d t o ta ke t he m or ni n g d ose at t he 
site i n case of pre-d ose P K a nal ysis . 
Patie nt s w h o pre mat urel y wit h dra w fr o m t he st u d y f or a n y reas o n  will u n der g o  a n Earl y 
Wit h dra wal Visit wit hi n 
f o ur wee ks after t he last d ose of st u d y treat me nt. T he Earl y 
Wit h dra wal Visit 
re q uir e me nts are t he sa me as t h ose of t he E O S Visit descri be d i n t his 
secti o n. 
T he f oll o wi n g assess me nts will be perf or me d  d uri n g t his visit : 
•  C o nc o mita nt me dicati o ns  
•  P h ysical e xa mi nati o n   
•  V ital si g ns ( bl oo d press ure, heart rate a n d b o d y te m perat ure) 
•  Wei g ht  
•  Hei g ht  
•  1 2 -lea d E C G  
•  Ec h ocar di o gra m  
•  P ul m o nar y f u ncti o n test s: F E V 1, F V C, F E V 1/ F V C, a n d P E F 
•  B l o o d c ollecti o n  f or 
o  he mat ol o g y  
o  bl o o d c he mistr y  
o  c oa g ulati o n te sts ( P T a n d a P T T) 
o   t h yr oi d f u ncti o n tests ( T S H, f T 3, f T 4) 
o  P K a nal ysis  
o  Bi o mar ker a nal ysis  
•  U ri ne a nal ysis; 
•  6 M W T + M F M  
•  M uscle stre n gt h test ( k nee e xte nsi o n a n d el b o w fle xi o n b y H H M)  
•  Ti me d f u ncti o n tests  
•  Q ualit y of Life test (ass esse d b y S F -3 6 ) 
•  A E assess me nts  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 6 9  of 1 1 0  
•  Diar y ret ur n a n d p atie nt c o m plia nce  
•  M RI / M R S a n d m uscle bi o ps y e val uati o ns, w hic h ma y be perf or me d o n differe nt da ys 
(i n case of earl y wit h dra w al visit t he M RI / M R S a n d Q ualit y of Life test d o  n ot ha ve 
t o be perf or m e d ). Treat m e nt is t o c o nti n ue u p t o t he last assess me nt . 
9. 1. 1 1  F oll o w -u p Visit  (W ee k 5 2 ) ( ± 7 d ays) 
T he f oll o w -u p visit will be perf or me d 4 wee ks after t he last d ose is a d mi nistere d ( ± 7 da ys) .  
T he f oll o wi n g assess me nts will be perf or me d:  
•  C o nc o mita nt me dicati o ns  
•  P h ysical exa mi nati o n   
•  V ital si g ns (bl o o d press ur e, heart r ate a n d b o d y te m perat ure ) 
•  1 2 -lea d E C G  
•  B l o o d c ollecti o n f or   
o  he mat ol o g y   
o  bl o o d c he mistr y   
o  coa g ulati o n tests ( P T a n d a P T T) 
o  t h yr oi d f u ncti o n tests ( T S H, f T 3, f T 4) 
•  U ri ne a nal ysis 
•  A E  assess me nts  
9. 1. 1 2  U nsc he d ule d Visits  
T he I n v esti gat or ma y , at his/ her discreti o n , arra n ge f or a p atie nt  t o h a v e a n u nsc he d ule d 
assess m e nt, es peci all y i n  case of A Es  or a b n or mal car diac/ bl o o d test res ults  t hat re q uire 
f oll o w-u p or a n A E c o nsi dere d b y t h e I n v esti gat or t o be p ossi bl y relate d t o t he use of t he 
st u d y treat me nt. A d diti o nal bl o o d dra ws  f or safet y ma y als o be perf or me d  b y a st u d y n urse at 
t he patie nt’s h o me. T he u nsc he d ule d visit pa ge i n t he e C R F m ust be c o m plete d  i n t hese 
cases.   
9. 2  
St u d y C o ncl usi o n  
T he e n d of t he trial is d efi ne d as t he date of t he last visit of t he last p atie nt  u n der g oi n g t he 
trial. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 7 0  of 1 1 0  
1 0  E F FI C A C Y A S S E S S M E N T S  
1 0. 1  Pri m ar y E ffic ac y A ssess me nt 
T he pri mar y efficac y assess me nt f or t his st u d y is t he t otal fi br osis ( %) assesse d t hr o u g h 
hist ol o gical e xa mi nati o n  of m uscle bi o psies.  
1 0. 2  Sec o n d ar y E ffic ac y A ss ess m e nts  
T he sec o n d ar y efficac y assess me nts  are t he f oll o wi n g: 
•  Fat fracti o n of vast us lateralis a n d s ole us e val u ate d b y M R S tec h ni q ue  
•  Fat fracti o n of pel vic gir dle a n d l o wer li m b m uscles e val uate d b y Di x o n M RI 
tec h ni q ue 
•  Cr oss Secti o nal Area ( C S A) of pel vic gir dle a n d l o wer li m b m uscles b y mea ns of 
Di x o n M RI te c h ni q ue.  
•  Ot her bi o ps y hist ol o gical para meters ( C S A , M F A F, re g e nerati ve fi bers ). 
•  M ot or F u ncti o n Meas ure me nt ( M F M)  
T he M ot or F u ncti o n Meas ure ( M F M) is a t o ol d esi g ne d f or ne ur o m usc ul ar dise ases a n d is 
a p plica ble t o all de grees of disease se v erit y. It was vali date d i n ter ms of re pr o d uci bilit y, 
c o nstr uct vali dit y, a n d c o nc urre nt vali dit y.  T he M F M c o nsists of 3 2 ite ms (tas ks) classifie d 
i nt o t he f oll o wi n g t hree di me nsi o ns: D 1, sta n di n g a n d tra nsfers; D 2, a xial a n d pr o xi mal 
m ot or ca pac it y; a n d D 3, distal m ot or ca pacit y. Eac h ite m is sc ore d o n a f o ur-p oi nt Li kert 
scale. T he g e neri c gra di n g is meas ure d as f oll o ws: 0, ca n n ot i nitiate t he tas k or ca n n ot 
mai ntai n t he starti n g p ositi o n; 1, partiall y perf or ms t he tas k; 2, perf or ms t he tas k wit h 
c o m pe nsat or y m o ve me nts ( p ositi o n mai ntai ne d f or a n i ns ufficie nt peri o d of ti me, sl o w ness, 
u nc o ntr olle d m o ve me nts, etc.); a n d 3, p erf or ms t h e tas k f ull y a n d ‘ n or mall y’, t he m o ve me nt 
bei n g c o ntr olle d, mastere d, directe d, a n d p erf or me d at a c o nsta nt s pe e d  (v uiller ot et al. 2 0 1 0 ). 
•  Ti me F u ncti o n Tests ( T F T)  
o  Ti me t o rise fr o m fl o or  
o  R u n/ wal k 1 0 m  
o  Ti me t o cli m b 4 sta n dar d ste ps  
T he T F Ts will be p erf or me d i n a sta n dar dize d ma n ner descri be d i n a s pecific site ma n ual.  
•  Si x Mi n ute Wal k Test ( 6 M W T)  
T he 6 M W T will be perf or me d i n a sta n dar di ze d m a n ner des cri be d i n a s p ecific site ma n ual.  
•  M uscle stre n gt h e val uat e d b y k nee e xt e nsi o n, el b o w fle xi o n as meas ure d b y  Ha n d -
Hel d M y o metr y  (H H M ). 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 7 1  of 1 1 0  
Usi n g H H M, t he m uscle stre n gt h of t he k nee e xte ns or a n d el b o w fle x or will be meas ure d 
f oll o wi n g sta n dar dize d pr oce d ures; bilateral ass ess me nts will be d o ne, a n d 3 meas ure me nts 
will be rec or de d fr o m eac h m uscle gr o u p o n eac h si de.   
•  Q ualit y of life (assess e d b y  S F 3 6 ) 
T he S F -3 6 is a set of g e neric, c o here nt, a n d easil y a d mi nistere d q ualit y -of -life meas ures. 
T hese me as ures rel y u p o n patie nt self -re p orti n g a n d are n o w wi del y utilize d b y ma na g e d care 
or ga nizati o ns  f or r o uti ne m o nit ori n g a n d assess me nt of care o utc o mes i n a d ult patie nts. 
A ll t he f u ncti o nal a n d stre n gt h assess me nts will be e val u ate d b y q ualifie d f u ncti o nal 
e val uat ors (i .e., p h ysi ot hera pists) w h o will be differe nt fr o m t he site p ers o n nel w h o re vie w 
safet y res ults. T he s afet y res ults m ust n ot be s hare d wit h p h ysi ot hera pists.   
T he M RI/ M R S pers o n nel i n v ol ve d will be differe nt fr o m t he site pers o n nel. T he y will n ot 
re vie w safet y res ults; safet y res ults m ust n ot be s hare d wit h t he m. T he e xa ms will be 
perf or me d i n a sta n dar di ze d ma n ner descri be d i n a s pecific site ma n ual.  
1 1  P H A R M A C O KI N E TI C S  A N D BI O M A R K E R S  
1 1. 1  P h ar m ac o ki netic S a m pli n g  
1 1. 1. 1  Bl o o d S a m ples  
Bl o o d sa m ples f or P K a n al ysis of gi vi n ostat a n d its meta b olites will be c ollecte d as i n dicate d 
i n t he Sc he d ule of Assess me nts ( Ta ble 5 ). T he re are 4 visits w here t he P K sa m ples ca n be 
ta ke n: Visits 5  ( Wee k 4), 8  ( Wee k 1 2), 9  ( Wee k 2 4) a n d 1 1  ( Wee k 4 8).  
All patie nt s will ha ve a t otal of 6 P K bl o o d s peci me ns dra w n d uri n g t he st u d y: 
•  T w o sa m ples dra w n pre -d ose, t hese 2 s peci me ns m ust be dra w n at 2 differe nt visits;  
•  O ne sa m ple dra w n bet w ee n 0 a n d 2 h o urs p ost -d ose;  
•  O ne sa m ple dra w n bet w ee n 2 a n d 4 h o urs p ost -d ose;  
•  O ne sa m ple dra w n bet w ee n 4 a n d 6 h o urs p ost -d ose;  
•  O ne sa m ple dra w n bet w ee n 6 a n d 1 0 h o urs p ost -d ose.  
D uri n g Visits 5 ( wee k 4), 8 ( wee k 1 2), 9 ( wee k 2 4) a n d 1 1 ( wee k 4 8), at least o ne P K  sa m ple 
is c ollecte d f or eac h pati e nt . After ra n d o mizati o n, site pers o n nel will be i nf or me d at w hic h 
ti me t he P K sa m ples will be dra w n d uri n g t hese visits.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 7 2  of 1 1 0  
O n t he da y w he n t he pre -d ose P K bl o o d is dra w n, patie nt s s h o ul d be i nstr ucte d t o ta ke t he 
m or ni n g d ose at t he site  a n d pr o vi de t he d ate a n d ti me of t h e last e ve ni n g d ose fr o m t he d a y 
bef ore t he visit, w hic h will be rec or de d i n t he s o urce d oc u m e nts a n d e C R F t o get her wit h t he 
date a n d ti me of t he bl o o d dra ws pri or t o t he m or ni n g i nta ke of t he c o m p o u n d.  
O n t he da ys  t hat p ost-d os e P K sa m ples are o btai ne d, t he m or ni n g d ose ma y be ta ke n at h o me , 
b ut patie nt s s h o ul d be re mi n de d t o re me m ber t he ti me t he d ose was ta ke n. F or t he p ost -d ose 
bl o o d dra ws,  date a n d ti me of t he d ose pri or t o t he bl o o d dra ws a n d t he date a n d ti me of 
bl o o d dra ws will be rec or de d i n t he s o urce d oc u me nts a n d e C R F. T he date a n d ti me of t he 
first d ose will be rec or de d i n t he s o urce d oc u m e nts a n d e C R F f or eac h patie nt . 
If t he patie nt  is wit h dra w n fr o m t he st u d y pre mat urel y, if n ot all P K sa m ples were o btai ne d 
pri or t o earl y wit h dra w al, t he re mai ni n g P K sa m ples ma y be dra w n d uri n g t he Earl y 
Wit h dra wal  Visit  t o o btai n all re q uire d P K sa m ples. 
S pecific details re gar di n g c ollecti o n, ha n dli n g, pr ocessi n g, st ora ge, a n d s hi p me nt of P K 
sa m ples ca n be f o u n d i n a se p arate la b orat or y m a n ual (f o u n d i n t he rele va nt secti o n of t he 
I n v esti gat or’s F ol der). 
1 1. 2  P h ar m ac o ki netic  A n al ytic al Met h o d ol o g y  
T he c o nce ntra ti o n of g i vi n ostat a n d its mai n meta b olites will be deter mi ne d fr o m t he plas ma 
sa m ples usi n g a v ali date d a nal ytical met h o d. Details of t he met h o d v ali dati o n a n d sa m pl e 
a nal ysis will be i ncl u de d i n  t he fi nal C li nical St u d y R e p ort ( C S R).  
1 1. 3  Bi o m ar kers  
A bl o o d sa m ple will be c ollecte d d uri n g t he st u d y f or L T B P 4 a n d Oste o p o nti n ge n ot y pi n g. 
Patie nts w h o ha ve alr ea d y c o ncl u de d t he st u d y ma y be as ke d t o ret ur n t o t he ce nt er f or a 
bl o o d sa m ple c ollecti o n  
B l o o d sa m ple c ollecti o n f or ser u m circ ulati n g pr otei ns ( b y a n ELI S A base d s yste m)  will be 
c ollecte d at r a n d o mizati o n, 6 m o nt hs a n d at t he e n d of treat me nt.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 7 3  of 1 1 0  
1 2  S A F E T Y A S S E S S M E N T S  
S afet y a n d t olera bilit y will be e val uate d b y m o nit ori n g he mat ol o g y a n d bl o o d c he mistr y, 
c oa g ulati o n, uri nal ysis,  vital si g ns, p h ysical e xa mi nati o ns,  wei g ht, hei g ht,  ec h ocar di o gra m , 
E C G  a n d res pirat or y f u ncti o n e val uati o n t o be perf or me d at pr ot oc ol-s pecifie d visits, as 
s pecifie d i n t he Sc he d ule of Assess me nts, Ta ble 5 , a n d b y rec or di n g A Es occ urri n g 
t hr o u g h o ut t he st u d y. 
A d diti o nal u nsc he d ule d visits wit h a car di ol o gist  ma y be re q uire d at t he discreti o n of st u d y 
cli nicia ns  f or p atie nts prese nti n g c li nical or i nstr u me ntal s us pici o n of car diac a b n or malities 
s uc h as si g ns a n d s y m pt o ms of heart fail ure or n e w alterati o ns o n r o uti ne E C G . M ore o ver, 
a d diti o nal safet y assess me nts ( bl o o d tests) ma y be re q uire d at t he discreti o n of st u d y 
cli nicia ns a n d will b e perf or me d at t he patie nt’s h o me b y a q ualifie d n urse trai ne d o n t he 
st u d y pr ot oc ol. 
1 2. 1  Vit al Si g ns , wei g ht a n d hei g ht 
Vital si g ns ( b o d y te m perat ure, heart rate, s yst olic a n d diast olic bl o o d press ure meas ure me nts, 
will be meas ure d after t he patie nt  has bee n resti n g i n a sitti n g p ositi o n f or at least 5  mi n utes.  
Bl o o d press ure meas ur e me nts are t o be ta ke n i n t he sa me ar m f or t he d urati o n of t he st u d y.  
B o d y wei g ht ( wit h o ut s h oes) a n d hei g ht ( wit h o ut s h oes) will be rec or de d at t he visits 
i n dicate d i n t he Sc he d ule of Assess me nts, Ta ble 5 . 
Vital si g n meas ure me nts will be re peate d if cli nicall y si g nifica nt or m ac hi ne/e q ui p me nt 
err ors occ ur. O ut -of -ra n g e bl o o d press ure  or heart rate  meas ure me nts will be re peate d at t he 
In v esti gat or’s discreti o n. A n y c o nfir me d, cli nicall y si g nifica nt vital si g n meas ure m e nts m ust 
be rec or de d as a n A E . 
1 2. 2  P h ysic al E x a mi n ati o n  
A c o m plete p h ysical e xa mi n ati o n (hea d, e yes, ears, n ose, a n d t hr oat, heart, l u n gs, a b d o me n, 
s ki n, l y m p h n o des, e xtre mities a n d ner v o us s yste m ) will be perf or me d at Scree ni n g (Visit 1 ) 
b y a p h ysicia n.  I n a d diti o n, me dical hist ory will be rec or de d at scree ni n g . 
A li mite d p h ysical e x a m i nati o n t o verif y c o nti n ue d patie nt  eli gi bilit y a n d t o f oll o w u p o n a n y 
c ha n ge i n me dical hist or y will be perf or me d at t he visits i n dicate d i n t he Sc he d ule of 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
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Assess me nts , Ta ble 5 . All c ha n ges n ot prese nt at b aseli ne or descri be d i n t he  me dical hist or y 
a n d i de ntifie d as cli nicall y n ote w ort h y m ust be rec or de d as A E s. 
1 2. 3  Electr oc a r di o gr a m  
A 1 2 -lea d resti n g E C G 
will be o btai ne d at t he visits i n dicate d i n t he Sc he d ule of 
Assess me nts , Ta ble 5 .  
At t he S cree ni n g  Visit , t he I n v esti gat or will  e x a mi ne t he 3 E C G traces f or si g ns of car diac 
disease t hat c o ul d e x cl u d e t he patie nt  fr o m t he st u d y.  
A n assess me nt of n or mal or a b n or mal will be rec or de d.  If t he E C G is c o nsi dere d a b n or mal, 
t he a b n or malit y will be d oc u me nte d o n t h e eC R F.  If a n E C G de m o nstr ates a pr ol o n ge d Q TcF  
in ter val ( ≥4 5 0 ms), t he I n vesti gat or will o btai n 2 m ore E C Gs o ver a bri ef peri o d ( 5 mi n utes 
bet wee n rec or di n gs), a n d t he n use t he a vera ge d Q Tc F  val ue of t he 3 E C Gs. If t h e a v era g e d 
Q Tc F  v al ue meets t he st o p pi n g criteria  ( > 5 0 0 ms), t he patie nt  has t o i nterr u pt t he st u d y 
treat me nt, t he Me dical 
M o nit or  m ust  be i nf or me d a n d t h e mea n Q Tc F  v al ue m ust b e 
c o nfir me d b y ce ntral r ea di n g .  
T he Q Tc h as t o be cal c ulate d wit h t he Fri d ericia f or m ula  Q Tc = Q T/ R R 1/ 3. 
Electr ocar di o gra ms will be re p eate d if cli nicall y si g nifica nt a b n or malities are o bser ve d or 
artifacts are prese nt.  
1 2. 4  Ec h oc ar di o gr a m  
Sta n dar d Ec h ocar di o gra ms  will be c o n d ucte d at t he visits i n dicate d i n t he Sc he d ule of 
Assess me nts, Ta ble 5 , a n d m ore ofte n if cli nicall y i n dicate d.  
1 2. 5  P ul m o n ar y F u ncti o n T est 
F orce d e x pirat or y v ol u m e at 1 sec o n d ( F E V 1), F V C , F E V1/ F V C, a n d P E F , will be c ollect e d 
as per t he site’s sta n dar d pr ocess at the visits i n dicate d i n t he Sc he d ule of Assess me nts, Ta ble 
5  a n d m ore ofte n if cli nic all y i n dicate d.   
At eac h ass ess me nt, t hree atte m pts  wit h ma xi mal ef f ort will be e v al uate d f or  eac h patie nt , 
a n d a n e x perie n ce d te c h nicia n perf o r mi n g t he testi n g 
will deter mi ne if t he eff ort is 
acce pta ble. All t he st u d y res ults will be rec or de d i n t he e C R F.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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1 2. 6  L a b or at or y Assess m e nts  
La b orat or y assess me nt s a m ples,  Ta ble 6 , will  be o btai ne d at desi g nate d visits as detaile d i n 
t he Sc he d ule of Ass ess me nts, Ta ble 5 . 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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Ta ble 6 : La b orat or y Ass ess me nt Sa m ples  
 
He m at ol o g y  
Ser u m c he mistr y  
Uri ne a n al ysis 
( di pstic k) 
C o a g ul ati o n  
Ser ol o g y  
•  He m at ocrit 
( Hct) 
•  He m o gl o bi n 
( H b) 
•  Mea n 
c or p usc ular 
he m o gl o bi n 
( M C H) 
•  Mea n 
c or p usc ular 
he m o gl o bi n 
c o nce ntrati o n 
( M C H C) 
•  Mea n 
c or p usc ular 
v ol u me ( M C V)  
•  Platelet c o u nt  
•  Re d bl o o d cell 
( R B C) c o u nt  
•  W hite bl o o d 
cell ( W B C) 
c o u nt  
 wit h differe ntial  
 
•  Al b u mi n  
•  Ala ni ne 
a mi n otra nsferase ( A L T)  
•  Al kali ne p h os p hatase 
( A L P) 
•  A m ylase  
•  As partate 
a mi n otra nsferase ( A S T)  
•  Bicar b o nate  
•  Bl o o d Urea Nitr o ge n 
( B U N)  
•  Calci u m  
•  C hl ori de  
•  C ystati n C  
•  Creati ni ne  
•  Creati ne ki nase  
•  C -reacti ve pr otei n ( C R P) 
•  Ga m ma -gl uta m yl 
tra ns pe pti dase ( G G T) 
•  Gl uc ose  
•  Lactate de h y dr o ge nase 
( L D H) 
•  N T -pr o B N P   
•  P otassi u m  
•  P h os p h or us  
•  S o di u m  
•  T otal bilir u bi n  
•  Direct bilir u bi n  
•  T otal pr otei n  
•  T h yr oi d -sti m ulati n g 
h or m o ne ( T S H)  
•  Tr igl y ceri des 
•  T otal c h olester ol  
•  L o w -De nsit y 
Li p o pr otei n ( L D L)  
•  Hi g h -De nsit y 
Li p o pr otei n ( H D L)  
•  f T 3 (free T 3 –  t he acti ve 
part of 
trii o d ot hyr o ni ne)  
•  f T 4 (free T 4 –  t he acti ve 
part of t h yr o xi ne)  
•  Uric aci d  
•  A p peara nce  
•  p H  
•  Pr otei n  
•  Gl uc ose  
•  Ket o ne b o dies  
•  I n dicat ors of 
bl o o d a n d 
W B Cs  
•  S pecific 
gra vit y  
•  Ur o bili n o ge n  
 
•  Pr ot hr o m bi n 
ti me ( P T) 
•  Acti vate d 
partial 
t hr o m b o plast
i n ti me 
( P T T) 
•  C M V I g M  
•  H Bs A g  
•  H C V  
•  HI V  
•  E B V I g G  
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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Bl o o d sa m ples will be a nal yz e d i n a ce ntral la b orat or y , uri nal ysis b y di pstic k will be 
e val uate d at site . All la b orat or y re p orts 
m ust be re vie we d, si g ne d a n d date d b y t he 
I n v esti gat or. A le gi ble c o p y of all re p orts m ust be file d wit h t he me dical rec or d (s o urce 
d oc u me nt) f or t hat visit. A n y la b orat or y test res ult c o nsi dere d b y t he I n vesti gat or t o be 
cli nicall y si g nificant s h o ul d be c o nsi dere d a n A E. Cli nicall y si g nifica nt a b n or mal val ues 
occ urri n g d uri n g t he st u d y will be f oll o we d u ntil r e peat test r es ults ret ur n t o n or mal, sta bilize, 
or are n o l o n g er cli nicall y si g nifica nt.   
1 2. 7  A d verse E ve nt s 
1 2. 7. 1  D efi niti o n s 
A d verse E v e nts :  
A n A E is “a n y u nt o war d me dical o cc urre nce i n a s u bject or cli nical i n vesti gati o n s u bject 
a d mi nistere d a p har mace utical pr o d uct a n d w hic h d oes n ot necessaril y ha ve a ca us al 
relati o ns hi p wit h t his treat me nt (I nter nati o nal C o nfere n ce o n Har m o nisati o n [I C H] E 2 A).”  
St u d y treat me nt i ncl u des b ot h t he i n vesti gati o nal dr u g u n der e val uati o n a n d  pl ace b o. Me dical 
c o n diti o ns t hat were pres e nt bef ore starti n g st u d y treat me nt are o nl y c o nsi dere d A Es if t he y 
w orse n after t he s u bje ct has starte d t he st u d y treat me nt. A b n or mal la b orat or y val ues or test 
res ults c o nstit ute A Es o nl y if t he y i n d uce cli nical si g ns or s y m pt o ms, are c o nsi dere d 
cli nicall y si g nifica nt, or re q uir e tr eat me nt. All me dical a n d ps yc hiatri c c o n diti o ns (e x ce pt 
t h ose relate d t o t he i n di cati o n u n der st u d y) pres e nt at scree ni n g will be d oc u me nt e d i n t he 
me dical hist or y eC R F. C ha n ges i n t hese c o n diti o ns a n d ne w s y m pt o ms, p h ysical si g ns, 
s y n dr o mes, or diseas es s h o ul d be n ote d o n t he A E eC R F pa g e d uri n g t he rest of t he st u d y. 
Cli nicall y si g nifica nt la b orat or y a b n or malities sh o ul d als o be rec or de d as A Es. S ur gical 
pr oce d ures t hat were pla n ne d bef ore t he s u bject e nr olle d i n t he st u d y are n ot c o nsi dere d A Es 
if t he c o n diti o ns w ere k n o w n bef ore st u d y i ncl usi o n; t he me dical c o n diti o n s h o ul d be 
re p orte d i n t he s u bject’s me dical hist or y. 
A d verse Dr u g Reacti o n : 
I n t he pre-a p pr o val cli nical e x perie n ce wit h a ne w me dici nal pr o d uct: “all n o xi o us a n d 
u ni nte n de d res p o nses t o a me dici nal pr o d uct rel ate d t o a n y d ose s h o ul d be c o nsi dere d a n 
A d verse Dr u g Reacti o n  ( A D R).”  T he p hras e “res p o nse s t o a me dical pr o d uct” mea ns t hat a 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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ca usal relati o ns hi p bet wee n a me dical pr o d uct a n d a n A E  is at least a reas o na ble p ossi bilit y, 
i.e., t he relati o ns ca n n ot be r ule d o ut. 
Re gar di n g mar kete d m e dici nal pr o d ucts, a well -acce pte d d efi ni ti o n of a n a d v erse dr u g 
reacti o n i n t he p ost-m ar keti n g setti n g is f o u n d i n W H O Tec h nical Re p ort 4 9 8 [ 1 9 7 2] a n d  
rea ds as f oll o ws: “A res p o nse t o a dr u g w hic h is n o xi o us a n d u ni nte n de d a n d w hic h occ urs at 
d oses n or mall y use d i n 
ma n f or pr o p h yla xis, dia g n osis , or t hera p y of disease or f or 
m o dificati o n of p h ysi ol o gical f u ncti o n. ”  
U ne x pect e d A d vers e Dr u g Reacti o n  - A n u ne x pecte d A D R is a n A D R , t he nat ure or se verit y 
of w hic h is n ot c o nsiste nt wit h t he a p plica ble pr o d uct i nf or mati o n ( i.e., Secti o ns 7 a n d 8 of 
t he curre nt I B f or I T F 2 3 5 7 Gi vi n ostat  H y dr oc hl ori de M o n o h y drate).  
Seri o us A d verse E v e nt : 
A n  S A E  (e x perie nce) or reacti o n is a n y u nt o w ar d me dical occ urre n ce t hat at a n y d ose: 
•  is fatal (res ults i n t he o ut c o me deat h) 
•  is life-t hreate ni n g * 
•  re q uires i n-p atie nt h os pitaliz ati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n 
•  res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y 
•  is a c o n ge nital a n o mal y/ birt h defect 
•  is me dicall y si g nifica nt or re q uires i nter ve nti o n t o pre ve nt o ne or ot her of t h e o utc o mes 
liste d a b o ve 
* T he ter m “life -t hreate ni n g” refers t o a n e ve nt i n w hic h t he s u bject is at ris k of deat h at t he ti me of t he e ve nt; it 
d oes n ot refer t o a n e v e nt t hat h y p ot heticall y ma y ca use deat h if it is m ore se vere.  
I n a d diti o n, a n y s us pect of tra ns missio n of i nfecti ve a ge nts t hr o u g h st u d y dr u g m ust be 
re p orte d t o t he S p o ns or as a S A E as me dicall y si g nifica nt e ve nt. 
Ot her i m p orta nt me dical e ve nts t hat ma y n ot be i m me diatel y life -t hreat e ni n g or res ult i n 
deat h or h os pitali zati o n, base d u p o n a p pr o priate me d ical j u d g me nt, are c o nsi dere d S A Es if 
t he y are t h o u g ht t o je o par dize t he s u bject a n d/ or re q uire me dical or s ur gical i nter ve nti o n t o 
pre ve nt o ne of t he o utc o mes defi ni n g a S A E.   
T he e ve nt d oes n ot q u alif y as a n S A E if t he h os pitalizati o n:  
•  was f or r o uti ne t reat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass o ciate d wit h a n y 
deteri orati o n i n c o n diti o n e. g. seiz ure m o nit ori n g  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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•  i n v ol ve d treat me nt, w hi c h was el ecti ve or pre-pla n ne d, f or a pre -e xisti n g c o n diti o n t hat is 
u nrelate d t o t he i n dicati o n u n der st u d y  a n d di d n ot w orse n  
•  was f or g e neral care, n ot ass ociate d wit h a n y d eteri orati o n i n c o n diti o n  
•  i n v ol ve d o nl y treat me nt o n a n e mer g e nc y, o ut p atie nt basis f or a n e ve nt n ot f ulfilli n g a n y 
of t he ot her defi niti o ns of seri o us a n d n ot res ulti n g i n h os pital a d missi o n.  
A S us pecte d U ne x pecte d  Seri o us A d verse Reac ti o n ( S U S A R) is referre d t o a n A D R t hat 
c o m pl ies wit h b ot h t he defi niti o ns of “seri o us” a n d “ u ne x pecte d .” 
1 2. 7. 2  A dverse Eve nt Re p orti n g  
T he I n vesti gat ors or t heir desi g nees are re q u este d t o c ollect a n d asses s a n y s p o nta ne o us A E 
re p orte d b y t he patie nt  a n d t o q uesti o n t he patie nt  a b o ut A Es a n d u n der  c urre nt ill nesses at 
eac h visit d uri n g t he tr eat me nt peri o d a n d a n y f oll o w -u p visit perf or m e d t o m o nit or a n y dr u g -
relate d A E t hat is still o n g oi n g be y o n d t he l ast sc he d uled visit u ntil rec o ver y. T h e 
q uesti o ni n g of t he patie nt  re gar di n g A Es is ge neralize d s uc h as : “H o w h ave y o u bee n feeli n g 
si nce y o ur l ast visit ?”  
A n y A E occ urri n g fr o m t he I nf or me d C o nse nt si g nat ure u p t o t he first st u d y dr u g i nta ke will 
be rec or de d o n t he me di cal hist or y secti o n of t he eC R F as baseli ne c o n diti o n, w hile a n y A E 
occ urri n g aft er a patie nt  has ta ke n t he first st u d y treat me nt u p t o t he foll o w -u p st u d y visit, 
w het her v ol u nteere d b y t he 
patie nt , disc o vere d d uri n g ge n eral q u esti o ni n g b y t he 
I n v esti gat ors or dete cte d t hr o u g h p h ysical e xa mi n ati o n, la b orat or y test or ot her mea ns will be 
rec or de d o n t he s pecific s ecti o n of t he eC R F.  
Eac h A E wil l be d escri be d b y:  
•  seri o us ness 
•  d urati o n (start a n d e n d dates)  
•  se verit y 
•  relati o ns hi p wit h t he st u d y dr u g 
•  acti o n ta ke n  
T he se verit y of a n A E s h o ul d be assesse d a n d gra de d acc or di n g t o t he m ost rece ntl y 
p u blis he d Nati o nal Ca ncer I nstit ute C o m m o n Ter mi n ol o g y Criteria f or A E ( C T C A E v. 4. 0 3, 
1 4  J u ne 2 0 1 0).  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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T he relati o ns hi p wit h t he st u d y dr u g s h o ul d be assesse d as: 
•  relate d t o st u d y dr u g; 
•  n ot re late d t o st u d y dr u g; 
•  u n k n o w n.  
T he assess me nt of t he relati o ns hi p of a n a d verse e ve nt wit h t he a d mi nistrati o n of st u d y dr u g 
is a cli nic al decisi o n bas e d o n all a vaila bl e i nf or mati o n at t he ti me of t h e c o m pleti o n of t he 
eC R F.  
A n assess me nt of “ Rel ate d ” i n di cates t hat t here is a reas o na ble s us pici o n t hat t he A E is 
ass ociate d wit h t he use of t he st u d y dr u g.  
A n assess me nt of “ N ot rel ate d ” 
w o ul d i ncl u de t he e xiste nce of a clear alter nati ve 
e x pla nati o n, or n o n -pla usi bilit y.  
A n assess me nt “ U nk n o w n ” i n dicates t here  is n ot a reas o na ble s us pici o n t hat t he A E  is 
ass ociate d wit h t he use of t he st u d y dr u g a n d at t he sa me ti me t here is n ot t he e xiste nce of a 
clear alter nati ve e x pl a nati o n or n o n -pla usi bilit y . I n t his cas e, t he I n vesti g at or has t o c ollect 
all p ossi ble i nf or mati o n i n or der t o assess t he relati o ns hi p wit h t he st u d y dr u g, partic ularl y i n 
case of S A E s. 
Fact ors t o b e c o nsi dere d i n assessi n g t he relati o ns hi p of t he A E  t o st u d y dr u g i ncl u de: 
•  te m p oral se q ue n ce fr o m st u d y dr u g a d mi nistrati o n  
•  rec o ver y o n disc o nti n uati o n a n d rec urre n ce o n r ei ntr o d ucti o n  
•  c o nc o mita nt diseases  
•  ev ol uti o n of t he treate d disease  
•  c o nc o mita nt me dicati o n  
•  p har mac ol o g y a n d P K  of t he st u d y dr u g 
•  prese nc e of a n alter nati ve e x pla nati o n  
 
A b n or mal L a b orat or y F i n di n gs a n d O t her O bjecti ve M eas ure me nts: 
A b n or mal la b orat or y fi n di n gs a n d ot her o bjecti ve meas ure m e nts s h o ul d n ot be r o uti nel y 
ca pt ure d a n d re p orte d as A Es as t he y will be c ollecte d a n d a nal y z e d se paratel y i n t he eC R F.  
H o we ver, a b n or mal la b orat or y fi n di n gs a n d ot her o bjecti ve meas ure m e nts t hat meet t he 
criteria f or a n S A E, res ult i n disc o nti n uati o n of t he st u d y dr u g or re q uir e 
me di cal 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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i nter ve nti o n, or are j u d ge d b y t he I n vesti gat or t o be cli nicall y si g nifica nt c ha n ges fr o m 
baseli nes val ues s h o ul d b e ca pt ur e d a n d re p orte d o n t he A E pa ges  of t he eC R F.  
W he n re p orti n g a n a b n or mal la b orat or y fi n di n g o n t he A E pa ges of t he 
eC R F, a cli nical 
dia g n osis s h o ul d be rec or de d i n a d diti o n t o t he a b n or mal val ue itself, if t hi s is a vaila ble (f or 
e xa m ple “a ne mia” i n a d diti o n t o “ h e m o gl o bi n = 1 0. 5 g/ dl”).  
Baseli ne Me dical C o n diti o n : 
Me dical c o n diti o ns prese nt at t he scree ni n g visit t hat d o n ot w ors e n i n s e v erit y or fre q u e nc y 
d uri n g t he st u d y are d efi ne d as b aseli ne m e di cal c o n diti o ns a n d are n ot A Es.  T hese m e dical 
c o n diti o ns s h o ul d be a de q uatel y d oc u me nte d o n t he a p pr o priat e pa ge of t he e C R F, i.e., t he 
me dical hist or y pa ge. H o we ver, me dical c o n diti o ns prese nt at t he i nitial st u d y visit s t hat 
w orse n i n se verit y or fre q ue nc y d uri n g t he st u d y s h o ul d be rec or de d a n d re p orte d as A Es.  
1 2. 7. 3  Seri o us A dverse Eve nt Re p orti n g  
A n y S A E, i ncl u di n g deat h fr o m a n y ca us e 1t t hat occ urs after patie nt /pare nt/le gal g uar dia n 
ha ve si g ne d t he I nf or me d C o nse nt a n d u p t o t he f oll o w -u p visit (re g ar dless of relati o ns hi p t o 
st u d y dr u g/c o m parat or) m ust be re p orte d b y t h e I n vesti gat ors t o t he S p o ns or wit hi n 2 4 h o urs 
of lear ni n g of its occ urre nce.  
Seri o us a d verse e ve nt  re p orts m ust be m a de w het her or n ot t h e I n v esti gat or c onsi ders t he 
e ve nt t o be rel ate d t o t he i n vesti gati o nal dr u g.  
Relate d  S A Es m ust  be c ollecte d a n d re p orte d re gar dless of t he ti me ela pse d fr o m t he last 
st u d y dr u g a d mi nistrati o n, e ve n if t he st u d y has b ee n cl ose d.  
As s o o n as a n A E  bec o mes seri o us , it will be rec or de d i n t he A E secti o n of t he e C R F a n d t he 
electr o nic S A E t o ol will se n d t he I n v esti gat or a war ni n g t o access t h e t o ol, w hic h will se n d 
a n e mail c o ntai ni n g a n S A E f or m i n attac h me nt . T he I n vesti gat or is t o c o m plete t he f or m a n d 
se n d it t o t he P har maco vi gila nce U nit of t he C R O via e mail usi n g t he c o ntact details 
pr o vi de d bel o w.  A p a per S A E F or m will be als o a vaila ble as bac k u p  a n d m a y be se nt b y f a x . 
 
 
1 Deat h is a n o utc o me a n d s h o ul d n ot be a n e ve nt u nless t he deat h is s u d de n a n d ca n n ot be clearl y attri b ute d t o 
a n y ca use. T he ca use of a fatal S A E s h o ul d be t he c o n diti o n t hat le d t o t he s u bject’s deat h.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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I nitial c o m pleti o n a n d f oll o w-u p re p orti n g u p dates of t he S A E are t o be carrie d o ut b y 
se n di n g t he S A E re p ort directl y t o t he C R O P H V via e mail.  
S ufficie nt details m ust be pr o vi de d t o all o w f or a c o m plete me dical assess m e nt of t he A E a n d 
i n de pe n de nt det er mi nati o n of p ossi ble ca usalit y. T he I n vesti gat ors are o bli ge d t o p urs ue a n d 
pr o vi de a d diti o nal i nf or mati o n as re q u este d b y 
 
 of t he st u d y or Cli nical Researc h a n d 
De vel o p me nt Direct or, or his desi g nee.   
T he I n vesti gat or m ust n otif y t he C R O P har mac o vi gila nce of t he S A E b y c o m pleti n g t he S A E 
re p orti n g f or m wit hi n 2 4 h o urs of a S A E; t he n, o nl y i n case of S A E n otificati o n b y fa x 
( bac k u p s yste m) t h e I n vesti gat or m ust c o nfir m a n y S A E n otificati o ns b y maili n g t o t he mail 
a d dress or p h o ni n g t o t he p h o ne n u m ber s pecifie d bel o w:  
  
 
  
 
 
 
If n otificati o n ca n n ot be ma de via t hes e mea ns d ue t o tec h nical deli ver y pr o ble ms, i nitial 
n otificati o n ma y be ma de b y tele p h o n e, usi n g t he S A E 
 
 
T he sa me pr oce d ure m ust be a p plie d t o t he S A E f oll o w -u p i nf or mati o n.  Preli mi nar y re p orts 
of S A Es 
m ust be f oll o we d b y detaile d descri pti o ns, i ncl u di n g clear a n d a n o n y mize d 
p h ot oc o pies of h os pital case re p orts, c o ns ulta nt re p orts, a ut o ps y re p orts, a n d ot her d oc u me nts 
w he n re q u este d a n d a p plica ble.   
A p pr o priat e re me di al me as ures s h o ul d b e ta ke n t o treat t he S A E a n d t he res p o nse s h o ul d be 
rec or de d. Cli nical, la b orat or y a n d dia g n ostic m eas ures s h o ul d be e m pl o ye d as nee de d  t o 
deter mi n e t he eti ol o g y of t he pr o ble m. All S A Es will be f oll o we d u ntil t he I n vesti gat or a n d 
S p o ns or a gree t h e e ve nt is satisfact oril y res ol ve d.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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A n y S A E t hat is n ot res ol ve d b y t he e n d of t he st u d y or u p o n disc o nti n uati o n of t he patie nt ’s 
partici pati o n i n t he st u d y is t o be f oll o we d u ntil it eit her res ol ves, sta bilizes, ret ur ns t o 
baseli ne val u es (if a baseli ne val ue is a vaila ble), or is s h o w n t o n ot be attri b uta ble t o t he 
st u d y dr u g or pr oce d ures. 
All seri o us a n d u ne x pect e d A E s t hat are ass ociate d wit h t he use of t he st u d y dr u g ( S U S A Rs) 
will be n otifie d b y  t he 
 P har mac o vi gila nce U nit  t o t he Et hic C o m mittees or I nstit uti o nal 
Re vie w B oar d  a n d c o m pete nt a ut h orit y wit hi n t he re q uir e d ti me a n d f oll o wi n g pr oce d ures 
re q uire d b y a p plica ble la ws. It is i m perati ve t hat t he S p o ns or be i nf or me d as s o o n as 
p ossi ble, s o t hat re p orti n g ca n be d o n e wit hi n t he re q uire d ti me fra me.  
1 2. 7. 4  Over d ose  
I n ge n eral, a dr u g o ver d ose i n a cli nical st u d y is defi ne d as t he acci de nt al or i nte nti o nal use 
of a dr u g or me dici ne i n a n a m o u nt e xcee di n g t he pr ot oc ol defi ne d d os e. T he I n vesti gat or 
m ust i m me diatel y n otif y t he S p o ns or of a n y o cc urre nce of o ver d ose wit h st u d y dr u g.  I n t his 
st u d y, if a n A E is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of g i vi n ostat/p lace b o, t he A E 
is re p orte d as a S A E, e ve n if n o ot her criteria f or s eri o us ness are met. 
If a d ose of g i vi n ostat/p lace b o meeti n g t he pr ot oc ol defi niti o n of o ver d ose is ta ke n wit h o ut 
a n y ass ociate d cli nica l s y m pt o ms or a b n or mal la b orat or y res ults, t he o ver d ose is re p orte d as 
a n o n-seri o us E ve nt of Cli nical I nterest, usi n g t he ter mi n ol o g y “acci de ntal or i nte nti o nal 
o ver d ose wit h o ut a d verse effect.”  
A n y i nsta nce of o ver d ose (s us pecte d or c o nfir me d, wit h a n d w it h o ut a n A E) m ust be re p orte d 
t o t he S p o ns or wit hi n 2 4 h o urs a n d, o nl y i n case of A Es,  m us t be f ull y d oc u me nte d as a S A E. 
Details of a n y si g ns or s y m pt o ms a n d t heir ma na ge me nt s h o ul d be rec or de d i n t he S A E F or m 
i ncl u di n g details of a n y a nti d ote or s yste matic treat me nt a d mi nistere d. A n y si g ns or 
s y m pt o ms of o ver-d osa g e will be treate d s y m pt o maticall y.  
A n y ot her sit uati o ns p utti n g t he patie nt  at ris k of a n a d v erse reacti o n, s uc h as mis use a n d 
a b use, me dicati o n err ors, s us pect of tra ns missi o n of i nfecti ve a g e nts m ust be re p ort e d t o t he 
S p o ns or wit hi n 2 4 h o urs a n d be f ull y d oc u me nte d as a S A E.  
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 8 4  of 1 1 0  
1 2. 7. 5  Pre g n a ncy re p orti n g  
Si nce it is p ossi ble t o ra n d o mize fertile trial m ale patie nt s i n t his tri al, t he patie nt  m ust b e 
i nf or me d b y t he i n vesti gat or t hat if it is s us pecte d t hat his part ner bec o mes pre g na nt d uri n g 
t he st u d y treat me nt or wit hi n 3 m o nt hs after t he st u d y treat me nt, he s h o ul d i nf or m t he site 
pers o n nel i m me diatel y of t his pre g na nc y.  
If t he I n vesti gat or is m a d e a w are t hat t he p art ner of a p atie nt  w h o is p artici p ati n g i n  t he st u d y 
bec o me s pre g na nt, h e/s he is re q uir e d t o re p ort wit hi n 2 4 h o urs t he pre g na nc y, usi n g t he 
Pre g na nc y 
N otificati o n  F or m a vaila ble i n t he I n vesti gat or 
St u d y 
File, 
t o C R O  
P har mac o vi gila nce  b y m aili n g t o t he mail a d dress or fa xi n g n u m bers s p ecifie d bel o w:  
  
 
  
 
 
 
If n otificati o n can n ot be ma de via t hes e mea ns d ue t o tec h nical deli ver y pr o ble ms, i nitial 
n otificati o n ma y be ma de b y tele p h o n e, usi n g t he 
 
 
W he ne v er p ossi ble, s uc h pre g na n c y s h o ul d be f oll o we d u ntil ter mi nat i o n, a n y pre mat ure 
ter mi nati o n s h o ul d be re p orte d, a n d t he stat us of t he m ot her a n d c hil d s h o ul d be re p orte d t o 
t he s p o ns or after deli ver y. 
1 3  S T A TI S TI C A L A N A L Y SI S  
A S tatistical A nal ysis P la n ( S A P) will be pre p are d pri or t o t h e pla n ne d i nteri m a nal ysis t o 
pr o vi de f ull details o n t he met h o ds descri be d h ere a n d pr o vi de a c o m plet e descri pti o n of t he 
data prese nt ati o ns re q uir e d f or t his st u d y.  C ha n ges t o t he statistical a nal ysis pla n ne d i n t his 
pr ot oc ol will be descri be d i n t he S A P al o n g wit h t he rati o nale f or t he c h a n g es.  
Data c ollecte d i n t his st u d y will be liste d a n d s u m marize d as d escri b e d bel o w.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 8 5  of 1 1 0  
C o nti n u o us data will be s u m marize d b y mea n, sta n dar d de viati o n ( S D), me dia n, first a n d 
t hir d q uartiles, mi ni m u m a n d ma xi m u m. Cate g orical data will be prese nte d b y a bs ol ute a n d 
relati ve fre q ue n cies ( n a n d %) or c o nti n ge n c y ta bl es. 
All statistical ta bles, listi n gs, fi g ures a n d a nal ys es will be perf or me d b y mea ns of S A S ®  
releas e 9. 4 or later ( S A S I nstit ute, I nc., C ar y, N C, U S A). 
T w o -si ded al p ha le vel 0. 0 5 will be c o nsi dere d. N o al p ha le vel a dj ust me nt will be carrie d o ut 
f or pri mar y a n d sec o n d ar y o utc o me varia bles. 
 
1 3. 1  Deter mi n ati o n  of S a m ple S ize 
T he h y p ot hesis t o be teste d i n t his st u d y is as f oll o ws:  
𝐻0 :𝜇𝐺−𝜇𝑃= 0      𝑣𝑠   𝐻1 :𝜇𝐺−𝜇𝑃≠0       
w here 𝜇𝐺 a n d 𝜇𝑃    t he mea n c ha n ge fr o m baseli ne t o 1 2 m o nt hs i n t otal fi br osis ( %) f or t h e 
gi vi n ostat a n d place b o gr o u ps res pecti vel y.  
A sa m ple siz e of 4 8 p atie nts wit h e val ua ble baseli ne bi o psies ( i n a 2: 1 rati o, 3 2  a n d 16  
res pecti vel y) will pr o vi de 8 0 % p o wer t o test t he n ull h y p ot hesis of n o treat me nt effect 
( gi vi n ostat –  place b o) o n t otal fi br osis vs t he alter nati ve h y p ot hesis t hat t he treat me nt effect 
is ≥ 9 % usi n g a t w o-si de d t-test wit h al p ha le vel of 5 % a n d assu mi n g a c o m m o n S D of 1 0 % 
( wit h t he S D bei n g b ase d u p o n bli n de d i nteri m d ata fr o m first 2 0 p atie nts wit h vali d pre a n d 
p ost -treat me nt bi o psies). 
All o wi n g f or a n a p pr o xi mate 5 % of patie nts wit h u ne val ua ble  bi o psies, t he t otal n u m ber of 
patie nts t o be ra n d o mize d is 5 1 (i.e. 3 4 i n gi vi n ostat ar m a n d 1 7 i n place b o ar m).  
 
 
 
1 3. 2  A n al ysis P o p ul ati o ns  
1 3. 2. 1  I nte nt-T o -Tre at A n alysis Set  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 8 6  of 1 1 0  
T he I nte nt -t o-Treat (I T T) A nal ysis Set c o m prises all patie nt s t o w h o m st u d y treat me nt has 
bee n assi g ne d b y ra n d o mizati o n a n d w h o recei ve d at least o ne d os e of st u d y me dicati o n. 
Acc or di n g t o t he i nte nt t o treat pri nci ple, patie nt s will be a nal yze d acc or di n g t o t he treat me nt 
t he y ha ve bee n assi g ne d t o d uri n g t he ra n d o mizati o n pr oce d ure. T h e I T T set will ser ve as t he 
basis f or t he a n al ysis of efficac y . 
1 3. 2. 2  Per Pr ot oc ol Set  
T he Per -Pr ot oc ol Set ( P P S) c o nsists of a s u bset of patie nts i n t he I T T w h o ha d n o maj or 
pr ot oc ol de viati o n. Pr ot oc ol de viati o ns lea di n g t o e xcl usi o n fr o m t he P P S will be defi ne d i n a 
se parat e d oc u me nt. T he P PS  will ser ve as s u p p orti ve a nal ysis of t he pri mar y e n d p oi nt.  
1 3. 2. 3  S afety Set  
T he Safet y A nal ysis Set c o nsists of all patie nt s w h o recei v e d at least o ne d ose of st u d y 
me dicati o n. Patie nt s w h o ha ve bee n ra n d o mize d a n d di d n ot ta ke at least o ne d ose of st u d y 
me dicati o n will n ot be i ncl u de d i n t he safet y set. Patie nt s will be a nal yze d acc or di n g t o t he 
st u d y treat me nt t he y act uall y recei v e d. T his a nal ysis set will be use d f or t he a nal ysis of 
safet y. 
1 3. 2. 4  P h ar m ac o ki netic Set  
P har mac o ki netic a nal y ses will be perf or me d o n t he P har mac o ki n etic Set ( P K), defi ne d as all 
ra n d o mize d patie nts w h o ha ve recei ve d at least o n e d ose of st u d y treat me nt a n d ha ve at least 
p ost -baseli ne P K sa m ple.  
 
1 3. 3  De m o gr a p hic a n d B aseli ne C h ar acteristics  
Patie nt de m o gra p hics a n d baseli ne c haract eristics will be s u m marize d o n t he I T T, o verall a n d 
b y treat me nt gr o u p, b y m ea ns of s u m mar y descri pti ve statistics.  
A c o m plete d escri pti o n of patie nt  dis p ositi o n will be pr o vi de d, o v erall a n d b y tr eat me nt 
gr o u p s pecif yi n g t he n u m ber of ra n d o mize d pati e nt s, n u m ber of patie nt s at eac h visit, a n d 
c o m plete d a n d disc o nti n ue d patie nt s a n d t he reas o n f or t he disc o nti n uati o n. 
T he a nal ysis p o p ulati o ns will be descri be d a n d t h e reas o ns f or e xcl u di n g t h e patie nt  fr o m a n y 
a nal ysis set w ill be pr o vi de d wit h t he n u m ber of pr ot oc ol vi olat ors per eac h criteri o n.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 8 7  of 1 1 0  
Me dical hist or y data will be prese nt e d b y Me d D R A S yste m Or ga n Class a n d Preferre d Ter m.  
 
1 3. 4  I n vesti g ati o n al Me dici n al Pr o d uct s 
D urati o n of e x p os ur e t o st u d y treat me nt, d efi ne d as t he ti me el a pse d fr o m t he date of t h e first 
treat me nt i nta ke t o t he date of t he last treat me nt i nta ke, a n d dail y d os a ge ( m g) will be 
s u m marize d. T h e n u m ber of patie nts wit h d os e c ha n ges/te m p orar y i nterr u pti o ns/ per ma ne nt 
disc o nti n uati o n 
will 
be 
prese nte d 
al o n g 
wit h 
t he 
reas o ns 
f or 
t he 
d ose 
c ha n ge/i nterr u pti o ns/ disc o nti n uati o n. A nal ysis will be base d o n t he safet y s et.  
 
1 3. 5  Pri or a n d C o nc o mit a nt T her a p y  
Pri or treat me nts, defi ne d as t h ose ta ke n wit hi n 6 m o nt hs pri or t o scree ni n g, s h o ul d be 
rec or de d i n t he s o urce do c u me nts as pri or me dicati o ns.  
C o nc o mita nt treat me nts are defi ne d as tr eat me nts ta ke n after st u d y dr u g a d mi nistrati o n.  
Pri or a n d c o nc o mita nt me dicati o ns will be classifie d usi n g t he W H O -D R L dr u g dicti o nar y 
( usi n g t he most rece nt v ersi o n) a n d s u m marize d o verall  b y W H O A nat o mical T hera p e utic 
C he mical / A T C) Class a n d Preferre d T er m . All a nal yses will be base d o n t he safet y 
p o p ulati o n.  
 
1 3. 6  Effic ac y A n al ysis  
1 3. 6. 1  A n alysis of Pri m ary Effic acy E n d p oi nt  
T he pri mar y efficac y a n al ysis will be perf or me d o n t he I T T set as pr i mar y a nal ysis a n d o n 
t he P P S as s u p p orti ve a nal ysis a n d will be re p orte d b y pla n ne d treat me nt gr o u p. 
T he pri mar y efficac y varia ble, t he a bs ol ute c ha n g e i n  mea n t otal fi br osis ( %) fr o m bas eli ne 
t o e n d p oi nt aft er 1 2 m o nt hs of t hera p y, as ass esse d b y bi o ps y,  will b e a n al yze d  o n t he 
ori gi nal scale  b y mea ns of a n a nal ysis of c o v aria nce ( A N C O V A) m o del wit h baseli ne  t otal 
fi br osis ( %) val u e as c o variate a n d treat me nt a n d c o nc o mita nt ster oi d use at baseli ne as 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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i n de pe n de nt class varia bles. Mea n esti mates 
will be pr o vi de d  t o get her 
wit h t heir 
c orres p o n di n g t w o-si de d 9 5 % c o nfi de n ce i nter vals. P ossi ble nee d f or l o g tra nsf or mati o n of 
t his varia ble will be assesse d b y c hec k of A N C O V A m o del resi d uals. 
M ulti ple i m p utati o n met h o ds will be  a p plie d f or ha n dli n g missi n g data.  F urt her det ails will 
be pr o vi de d i n t he Statistical A nal ysis Pla n ( S A P).  
1 3. 6. 2  A n alysis of Sec o n d ary Effic acy E n d p oi nts  
All sec o n dar y efficac y a nal yses will be perf or me d base d o n t he I T T set a n d will be re p orte d 
b y pla n ne d tre at me nt gr o u p.  
•  C ha n ge i n fat fracti o n of vast us lateralis a n d s ole us after 1 2 m o nt hs of t hera p y  
T he a bs ol ute c ha n g e i n fat fracti o n of v ast us lateralis a n d s ole us after 1 2 m o nt hs of t hera p y, 
as assesse d b y 
M a g netic Res o na nce S pectr osc o p y ( M R S), will be a nal yze d usi n g a n 
A N C O V A m o del si milar t o t h e o ne descri be d f or t he pri mar y e n d p oi nt.  P ossi ble nee d f or l o g 
tra nsf or mati o n of t his varia ble will be assesse d b y c hec k of A N C O V A m o d el resi d uals 
•  C ha n ge i n fat fracti o n of pel vic gir dle a n d l o w er li m b m uscles after  1 2 m o nt hs of 
t hera p y 
T he a bs ol ute c ha n ge i n fat fracti o n of p el vic gir dle a n d l o w er li m b m uscl es after 1 2 m o nt hs 
of t hera p y, as assesse d b y Ma g netic Res o na nce I ma gi n g ( M RI ), will be a nal yze d usi n g a n 
A N C O V A m o del si milar t o t h e o ne descri be d f or t he pri mar y e n d p oi nt.  P ossi ble nee d f or l o g 
tra nsf or mati o n of t hese v aria ble will be ass esse d b y c hec k of A N C O V A m o del resi d uals  
•  C ha n ge i n Cr oss Secti o nal Area ( C S A) of p el vic gir dle a n d l o wer li m b m uscle s after 
1 2 m o nt hs of t hera p y  
T he a bs o l ute c ha n ge i n C S A of pel vic gir dle a n d l o wer li m b m uscles after 1 2 m o nt hs of 
t hera p y, as assesse d b y M RI, will be a nal yze d usi n g a n A N C O V A m o del si milar t o t he o ne 
descri be d f or t he pri mar y e n d p oi nt.  P ossi ble nee d f or l o g tra nsf or m ati o n of t his varia ble w ill 
be assesse d b y c hec k of A N C O V A m o del resi d u als  
•  C ha n ge i n ot her hist ol o g y para meters (i.e. Cr oss -Secti o nal Area ( C S A) , M F A F , 
re ge nerati ve fi b ers) after 1 2 m o nt hs of t hera p y 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 8 9  of 1 1 0  
T he a bs ol ute c ha n g e i n ot her hist ol o g y para meters after 1 2 m o nt hs of t hera p y, as assesse d b y 
bi o ps y, will be a n al yze d usi n g a n A N C O V A m o del si milar t o t h e o n e descri be d f or t h e 
pri mar y e n d p oi nt. P ossi ble nee d f or l o g tra nsf or m ati o n of t hese v aria ble s will be assesse d b y 
c hec k of A N C O V A m o d el resi d uals.  
•  C ha n ge i n M F M t otal s c ore aft er 1 2 m o nt hs of t hera p y  
T he a bs ol ute c h a n ge i n M F M t otal sc ore aft er 1 2 m o nt hs of t hera p y will b e a nal yze d usi n g a n 
A N C O V A m o del si milar t o t h e o ne descri be d f or t he pri mar y e n d p oi nt. P ossi ble nee d f or l o g 
tra nsf or mati o n of t his varia ble will be assesse d b y c hec k of A N C O V A m o d el resi d uals. 
•  C ha n ge i n Ti me d F u ncti o n Tests ( T F Ts) (i.e. ti me t o cli m b f o ur sta n dar d ste ps, ti me 
t o rise fr o m fl o or a n d ti m e t o wal k 1 0 m) aft er 1 2 m o nt hs of t hera p y 
T he a bs ol ute c ha n g e i n f u ncti o nal para meters after 1 2 m o nt hs of t h era p y, as assess e d b y 
Ti me d F u ncti o n Tests ( T F Ts), will be a nal yze d usi n g a n A N C O V A m o del si milar t o t h e o ne 
descri be d f or t he pri mar y e n d p oi nt. P ossi ble nee d f or l o g tra nsf or mati o n of t hese varia bles 
will be assesse d b y c h ec k of A N C O V A m o del r esi d ual s. 
•  C ha n ge i n 6 M W T sc ore after 1 2 m o nt hs of t hera p y  
T he a bs ol ute c ha n ge i n 6 M W T sc ore after 1 2 m o nt hs of t hera p y will be a nal yze d usi n g a n 
A N C O V A m o del si milar t o t h e o ne descri be d f or t he pri mar y e n d p oi nt. P ossi ble nee d f or l o g 
tra nsf or mati o n of t his variable will be assesse d b y c hec k of A N C O V A m o d el resi d uals.  
•  Pr o p orti o n of patie nt s wit h < 1 0 % w orse ni n g i n 6 M W T sc ore after 1 2 m o nt hs of 
t hera p y 
W orse ni n g is d efi ne d as a re d u cti o n i n 6 M W T sc o re after 1 2 m o nt hs of t h era p y c o m pare d t o 
baseli ne sc ore. T he a v era g e of t he sc ores at scree ni n g a n d ra n d o mizati o n will be use d as 
baseli ne sc ore. T h e pr o p orti o n of patie nt s wit h < 1 0 % w orse ni n g i n 6 M W T after 1 2 m o nt hs 
of t hera p y will be c o m pare d bet w ee n ar ms usi n g a stratifie d C oc hra n 
Ma ntel -Hae ns zel 
( C M H) c hi s q uare test wit h a t w o-si de d α = 0. 0 5 le vel. As f or t he pri mar y e n d p oi nt, t he 
stratificati o n fact or is c o nc o mita nt ster oi d use at baseli ne. T he pr o p orti o n, al o n g wit h its 
e xact t w o -si de d 9 5 % CI, will be c o m p ute d wit hi n eac h treat me nt gr o u p. A t w o -si de d 9 5 % CI 
f or differe n ce of pr o p orti o n bet wee n t he treat me n t gr o u ps will als o be c o m p ute d. I n cas e of 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 9 0  of 1 1 0  
patie nts wit h n o 6 M W T assess me nt at 1 2 m o nt hs/ E O S, t he last a vaila ble sc ore will be us e d 
f or t he a n al ysis. 
•  Pr o p orti o n of patie nt s w h o l ose a bilit y t o rise fr o m fl o or d uri n g the st u d y  
T he pr o p orti o n of patie nt s w h o l ose a bilit y t o rise fr o m fl o or d uri n g t he st u d y, as assesse d b y 
T F T , will be c o m pare d bet wee n ar ms usi n g a stratifie d C oc hra n Ma ntel-Hae nszel ( C M H) c hi 
s q uare test wit h a t w o-si de d α = 0. 0 5 le vel. As f or t he pri mar y en d p oi nt, t he stratificati o n 
fact or is c o nc o mita nt ster oi d use at baseli ne. T he pr o p orti o n, al o n g wit h its e xact t w o -si de d 
9 5 % CI, will be c o m p ut e d wit hi n eac h tr eat me nt gr o u p. A t w o -si de d 9 5 % CI f or differe n ce 
of pr o p orti o n bet wee n t he treat me nt gr o u ps will als o be c o m p ute d . I n case of patie nts wit h n o 
6 M W T assess me nt at 1 2 m o nt hs/ E O S, t he last a vaila ble sc ore will be use d f or t he a n al ysis  
•  Pr o p orti o n of patie nts w h o l ose a m b ulati o n d uri n g t he st u d y  
T h e pr o p orti o n of patie nt s w h o l ose a m b ulati o n d uri n g t he st u d y, as assesse d b y 6 M W T, will 
be c o m pare d bet w ee n ar ms usi n g a stratifie d C oc hra n M a ntel -Hae nszel ( C M H) c hi s q uare 
test wit h a t w o-si de d α = 0. 0 5 le vel. As f or t he pri mar y e n d p oi nt, t he stratificati o n fact or is 
c o nc o mita nt ster oi d use at baseli ne . T he pr o p orti o n, al o n g wit h its e xact t w o-si de d 9 5 % CI, 
will be c o m p ute d wit hi n eac h tr eat me nt gr o u p. A t w o -si de d 9 5 % CI f or differe n ce of 
pr o p orti o n bet wee n t he treat me nt gr o u ps will als o be c o m p ute d.  I n case of patie nts wit h n o 
6 M W T assess me nt at 1 2 m o n t hs/ E O S, t he last a vaila ble sc ore will be use d f or t he a n al ysis 
•  C ha n ge i n m uscle stre n gt h e val uate d b y k nee e xte nsi o n a n d el b o w fle xi o n after 1 2 
m o nt hs of t hera p y  
T he a bs ol ute c ha n ge i n m uscle stre n gt h e val uate d b y k nee e xte nsi o n a n d el b o w fle xi o n after 
1 2  m o nt hs of t hera p y, as assesse d b y H H M, will be a nal yze d usi n g a n A N C O V A m o del 
si milar t o t he o ne descri b e d f or t he pri mar y e n d p oi nt. P ossi ble nee d f or l o g tra nsf or mati o n of 
t his varia ble will be assesse d b y c hec k of A N C O V A m o del resi d uals. 
•  C ha n ge i n q uali t y of life after 1 2 m o nt hs of t hera p y 
S u m mar y descri pti ve statistics will be pr o vi de d at eac h ti me p oi nt f or t he q ualit y of life 
sc ores/ d o mai ns as ass esse d b y t he S F-3 6 q u esti o n naire.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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1 3. 7  P h ar m ac o ki netic A n al ysis  
P K a nal yses will be perf or me d  o n t he P har mac o ki netic Set  t o: 
•  descri be t he p har mac o ki netics of gi vi n ostat a n d its maj or meta b olites: I T F 2 3 7 4 a n d 
I T F 2 3 7 5 i n t he patie nt  p o p ulati o n;  
•  e x pl ore t he relati o ns hi ps bet wee n m etrics of e x p os ure a n d efficac y/safet y e n d p oi nts 
of gi vi n ostat.  
F urt her det ails o n t he e x pl orat or y a nal yses will be pr o vi de d i n t he p har mac o ki netic a nal ysis 
pla n.  
1 3. 8  S afet y A n al ysis  
Safet y a nal yses will be c o n d ucte d o n t he Safet y Set a n d will be re p o rte d b y act ual treat me nt 
gr o u p. N o met h o d ol o g y f or missi n g data ha n dli n g will be a p plie d f or saf et y para meters.  
•  A d verse e ve nts  
Acc or di n g t o t he o nset d ate of t he e v e nt, A Es will be defi ne d as f oll o ws:  
o  T reat me nt-e mer ge nt A Es, t h ose e v e nts wit h a n o nset dat e o n or after treat me nt 
i nitiati o n. 
o  N o n -treat me nt-e mer g e nt A Es, t h ose e ve nts wit h a n o nset date b et w ee n i nf or me d 
c o nse nt a n d treat me nt i nitiati o n.  
N o n -treat me nt-e mer g e nt A Es will  o nl y be  liste d f or all scree ne d patie nts. 
T he i nci de nce of treat me nt -e mer ge nt A Es will be ta b ulate d b y Me d D R A S yste m Or ga n Class 
( S O C) a n d Preferre d Ter m ( P T). T he i nci de nce of T E A Es will als o be s u m marize d b y s yste m 
or ga n class, preferre d t er m a n d se verit y ( bas e d o n i n vesti gat or’s j u d g me nt).  
T he a n al ysis b y S O C a n d P T will be re peate d f or S A Es re g ar dless of dr u g relati o ns hi p, f or 
dr u g -relat e d S A Es, A Es 
wit h a n o utc o me of deat h a n d 
A Es lea di n g t o 
per ma ne nt 
disc o nti n uati o n of treat me nt.  A Es f or w hic h relati o ns hi p t o st u d y dr u g is n ot s pecifie d will be 
c o nsi dere d tr eat me nt  relate d. 

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Deat hs , ot her S A Es a n d A Es lea di n g t o per ma ne nt treat me nt disc o nti n uati on will als o be 
liste d. 
•  La b orat or y p ara m eters  
T he a bs ol ute val ue a n d t he c ha n ge fr o m baseli ne will be a nal yze d f or eac h la b orat or y 
para meter (s e paratel y f or he mat ol o g y a n d bl o o d c he mistr y) b y 
mea ns of s u m mar y 
descri pti ve statistics at eac h ti me p oi nt. I n a d diti o n, s hift ta bles usi n g t he l o w/ n or mal/ hi g h 
classificati o n t o c o m pare baseli ne t o t he w orst o n -treat me nt val ue will be pr o vi de d. 
Listi n gs of all la b orat or y data wit h val ues fla g ge d t o s h o w t he classificati o ns relati ve t o t he 
la b orat or y n or mal ra n ges will als o be ge nerate d. 
•  Ot her safet y para meters  
S u m mar y descri pti ve statistics 
will be pr o vi de d f or vital si g ns, p ul m o nar y  f u ncti o n 
(i ncl u di n g F V C, F E V 1, F V C/ F E V 1, P E F), car di ac para meters e val uat e d b y E C G a n d E C H O, 
p h ysical e xa mi nati o n (i n cl u di n g wei g ht a n d B MI).  
1 3. 9  E x pl or at or y A n al ysis  
Bi o m ar kers  
T he ge n ot y pe of L T B P 4 a n d oste o p o nti n a n d t he ser u m circ ulati n g pr otei ns , usi n g a n E LI S A 
base d s yste m,  will be assesse d as p ote ntial bi o mar kers f or B M D.  A nal yses t o e x pl ore 
w het her t he effects of gi vi n ostat vers us plac e b o a d mi nistere d c hr o nicall y ma y b e relate d t o 
t he t y pe of L T B P 4 or Oste o p o nti n ge n ot y pe will be d o ne. A d diti o nal details will be pr o vi de d 
i n t he S A P. 
M RI  bi o m ar ker  
I n or der t o e x pl ore dise ase-relat e d M RI bi o mar kers, e val uati o ns of a d diti o nal m uscle i ma ges 
para meters, as assesse d b y M RI, will be perf or me d. F urt h er det ails will be pr o vi de d i n a 
s pecific i ma gi n g pr ot oc ol. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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1 3. 1 0  I nteri m A n al yses  
A bli n de d i nteri m o n t he first 2 0 patie nts wit h vali d bi o psies was pla n ne d, wit h t he g oal t o 
assess t he varia bilit y ass u me d i n t he ori gi nal p o wer cal c ulati o n. N o f or mal i nteri m efficac y 
a nal ysis was ( or is) pl a n n e d  i n t his st u d y. 
As pla n ne d, a fter t he first 2 0 baseli ne bi o psies were  c ollect e d, a descri pti ve bli n de d i nteri m 
a nal ysis was  perf or me d t o assess t he varia bilit y of t he ori gi nal pri mar y e n d p oi nt , i.e. C S A. 
T he i nteri m data s h o w e d t hat t he 
mea n a n d varia bilit y of t he Cr oss Secti o nal Area  
( C S A)( mea n: 4 8 7 1. 6 8 μ m2; mi n 1 9 3 3. 4 9 μ m2 ; ma x 9 4 4 6. 3 4 μ m 2; a n d S. D.: 1 9 0 4. 8 6 μ m 2) 
were a p pr o xi matel y 4 f ol d  ( 3 0 0 %) hi g h er t ha n t he D uc he n n e data t hat was use d i n t he 
ori gi nal  calc ulati o n of t he sa m ple size  ( mea n: 1 1 9 1. 0 9  μ m 2, S. D.: 4 0 0. 9 8 μ m 2 i n 
D S C/ 1 1/ 2 3 5 7/ 4 3 st u d y). As c o nse q ue n ce of t his i nteri m a nal ysis t he pr ot o c ol was a me n de d 
(A M E N D M E N T N o. 4 ) wit h % t otal fi br osis re placi n g C S A as t he pri mar y e n d p oi nt. T he 
sa m ple size was a dj uste d acc or di n gl y t o e ns ure a d e q uate p o wer f or t he ne w pri mar y e n d p oi nt 
p r o p ose d. 
A d diti o nal details a b o ut met h o d ol o g y a n d t he res ults are re p orte d i n t he s pecific S A P a n d 
Statistical Re p ort a vaila ble as sta n d - al o ne d oc u m e nts.  
M ore o ver, aft er st u d y e nr oll me nt is c o m plete d a n d baseli ne data are c ollect e d f or all s u bjects, 
a seco n d bli n de d i nteri m a nal ysis will be perf or m e d t o o btai n a preli mi nar y o ver vie w of t he 
baseli ne patie nt c haracteristics.  T he res ults of t his a nal ysis will n ot be use d t o c ha n g e t he 
sa m ple size a n d/ or a n y e n d p oi nts. 
 
 
1 4  S T U D Y M A N A G E M E N T  
1 4. 1  A p pr o v al a n d C o nse nt  
1 4. 1. 1  Re g ul at ory G ui deli nes  

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T he In v esti gat or will e ns ure t hat t his st u d y is c o n d ucte d i n f ull c o nf or mit y wit h t he pri nci ples 
of t he “ Declarati o n of Helsi n ki” or wit h t he la ws a n d re g ulati o ns of t he c o u ntr y i n w hic h t he 
researc h is c o n d u cte d, w hic he ver aff or ds greater pr otecti o n t o t he i n di vi d ual.  
T he st u d y m ust f ull y a d here t o t he pri nci ples o utli ne d i n “ G ui deli ne f or G o o d Cli nical 
Practice” I C H Tri partite G ui deli ne or wit h l ocal la w if it aff or ds greater pr otecti o n t o t he 
s u bject.  
T his st u d y will be perf or me d i n acc or da nce wit h E U a n d c o u ntr y re g ulati o n i n f orce.  
T his st u d y will als o be carrie d o ut i n acc or da nce wit h S O Ps of Italfar mac o S. p. A. a n d/or its 
desi g nee . 
T he I n v esti gat or a grees, w he n si g ni n g t he pr ot oc ol, t o a d here t o t he i nstr ucti o ns a n d 
pr oce d ures descri be d t herei n a n d t here b y t o a d here t o t he pri nci ples of G C P t o w hic h it 
c o nf or ms.  
1 4. 1. 2  I n de pe n de nt Et hics C o m mittees 
T he pr ot oc ol, i n f or me d c o nse nt f or m, recr uit me nt materials, a n d all partici p a nt materials will 
be s u b mitte d t o t he I n de p e n de nt Et h ics C o m mittee (I E C) f or re vi e w a n d a p pr o val. T his st u d y 
will be u n derta k e n o nl y after a p pr o val of t he pr ot oc ol , i nf or me d c o nse nt f or m a n d all ot her 
materi als descri be d a b o ve has bee n o btai ne d fr o m t he a p pr o priate I E C  a n d a c o p y of t he 
si g ne d a n d date d a p pro v al has bee n recei v e d b y Italfar mac o S. p. A . T he na me a n d occ u p ati o n 
of t he c hai r ma n a n d t he me m bers of t he I E C m ust be s u p plie d t o It alfar mac o S. p. A. or its 
desi g nee . T h e I E C m ust be i nf or me d of all s u bse q ue nt pr ot oc ol a m e n d me nts a n d s h o ul d be 
as ke d w het h er a re-e val u ati o n of t he et hical as p ects of t he st u d y is necessar y.  
If a p plica ble, i nteri m re p orts o n t he st u d y a n d re vie ws of its pr o gress will be s u b mitte d t o t he 
I E C b y t he I n vesti gat or at i nter vals sti p ulate d i n t heir g ui deli nes . At t he c o m pleti o n or 
ter mi nati o n of t he st u d y, t he I n v esti gat or m ust s u b mit a cl ose-o ut letter t o t he I E C a n d t o 
Italfar mac o S. p. A. 
1 4. 1. 3  P atie nt  I nf or me d C o nse nt   
Pri or t o t he be gi n ni n g of t he st u d y, t he Pri nci pal I n v e sti gat or ( PI) m ust ha ve I E C writte n 
a p pr o val/fa v o ra ble o pi ni o n of t he writte n I nf or me d C o nse nt F or m a n d a n y ot her writte n 
i nf or mati o n t o be pr o vi de d t o t he p atie nt . T he a p pr o ve d patie nt  i nf or mati o n letter/I nf or m e d 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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C o nse nt  F or m m ust be file d i n t he st u d y files ( cli nical T rial 
Master File [T M F ] a n d 
In v esti gat or F ile [I F]). F or eac h st u d y p atie nt , a writte n Inf or me d C o nse nt F or m will be 
o btai ne d pri or t o a n y pr ot oc ol relate d acti vities. I nf or me d c o nse nt  ma y be o btai ne d fr o m 
patie nt s w h o  are ca p a ble of pr o vi di n g c o nse nt . As part of t his pr oce d ure, t he PI or a 
desi g nate d re prese nt ati ve m ust e x plai n orall y a n d i n writi n g t he nat ure, d urati o n, a n d p ur p ose 
of t he st u d y, a n d t he acti o n of t he dr u g i n s uc h a ma n ner t hat t he p atie nt  is a ware of t he 
p ote ntial ris ks, i nc o n ve nie nces, or a d verse effects  t hat ma y occ ur. Patie nt s s h o ul d be gi ve n 
a m ple ti me a n d o p p ort u nit y t o i n q uire a b o ut t he details of t he st u d y pri or t o deci di n g w het h er 
t o partici pate i n t he st u d y. It is t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat all 
q uesti o ns a b o ut t he st u d y are a ns were d t o t he satisfacti o n of t he p atie nt s.  
Patie nt s s h o ul d be i nf or me d t hat t he y ma y wit h dra w fr o m t he st u d y at a n y ti me.  T he y will 
recei v e all i nf or mati o n t hat is re q uire d b y l ocal re g ulati o ns a n d I C H g ui d eli nes. T he PI  or a 
desi g nate d re prese nt ati ve will pr o vi de t he s p o ns or or its re prese ntati ve wit h a c o p y of t he 
I E C a p pr o ve d I C F pri or t o t he start of t he st u d y.  
T he I C F s h o ul d be si g ne d a n d date d b y t he patie nt  a n d t he I n vesti gat or o n t he sa me da y.  If 
t he patie nt  is n ot a ble t o rea d, a n i m partial wit ness s h o ul d be prese nt d uri n g t he i nf or me d 
c o nse nt disc ussi o n, a n d t he wit ness m ust c o -si g n a n d date t he i nf or me d c o nse nt f or m. T he 
patie nt  m ust  recei ve a c o p y of t he si g ne d d oc u me nts.  
1 4. 1. 4  Disc o nti n u ati o n of t he st u dy by t he S p o ns or  
T he S p o ns or has t he ri g ht t o ter mi na te t his st u d y at a n y ti me. Reas o ns f or ter mi nati n g t he 
st u d y ma y i ncl u de t he f oll o wi n g: 
•  u nsatisfact or y patie nt  e nr ol me nt  
•  i nacc urate or i nc o m plete q ualit y or q ua ntit y of data rec or di n g  
•  i nci de nce or s e verit y of a d verse dr u g reacti o ns i n t his or ot her st u dies wit h st u d y dr u g 
i n dicati n g a p ote ntial healt h hazar d t o patie nt s 
•  p o or a d here nce t o pr ot o c ol a n d re g ulat or y re q uire me nts  
•  pla ns t o m o dif y or disc o nti n ue t h e de vel o p me nt of t he st u d y dr u g  

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1 4. 1. 5  D at a H a n dli n g   
 
Data o n patie nt s c ollecte d o n e C R Fs d uri n g t he trial will be d oc u me nte d i n a n a n o n y m o us 
fas hi o n a n d t he patie nt  will o nl y be i de ntifie d b y t he patie nt  n u m ber. All t he i nf or mati o n 
re q uire d b y t he pr ot o c ol s h o ul d be pr o vi de d a n d a n y o missi ons re q uir e e x pla nati o n. All 
e C R Fs m ust be c o m plete d e x pe diti o usl y after t he patie nt ’s visit. 
T he In v esti gat or m ust mai ntai n s o urce d oc u me nts f or eac h s u bject i n t he st u d y . Data re p orte d 
o n t he eC R F t hat are deri ve d fr o m s o urce d oc u me nts s h o ul d be c o nsiste n t wit h t he s o urce 
d oc u me nts, or t he discre pa ncies m ust be e x plai n e d.  
Cli nical data will be e ntere d o n eC R F s, a 2 1 C R F Part 1 1 c o m plia nt, f or tr a ns missi o n t o t he 
S p o ns or.  Data o n eC R Fs  tra ns mitte d via t he we b-base d data s yste m m ust c orres p o n d t o a n d 
be s u p p orte d b y s o urce d oc u me ntati o n mai ntai ne d at t he st u d y site. All st u d y f or ms a n d 
rec or ds tra ns mitte d t o t he S p o ns or m ust carr y o nl y c o de d i de ntifiers s uc h t hat pers o nall y 
i de ntif yi n g inf or mati o n is n ot tra ns mitte d.  T he pri mar y met h o d of data tra ns mittal is via t he 
sec ure, i nter net-bas e d E D C  s yste m. Access t o t he E D C s yste m is a vaila ble t o a ut h orize d 
users via t he st u d y’s I nter net we b site, w here a n assi g ne d user na me a n d pass w or d are 
re quire d f or access.  
Case Re p ort F or ms  will be c o nsi dere d c o m plete w he n all missi n g a n d/ or i nc orrect data ha ve 
bee n res ol v e d.   
1 4. 2  S o urce D oc u me nts  
S o urce d oc u m e nts c o ntai n  all i nf or mati o n i n ori gi nal rec or ds a n d certifie d c o pi es of ori gi nal 
rec or ds of cli nical fi n di n gs, o bser vati o ns, data or ot her acti vities i n a cli nical st u d y necessar y 
f or t he rec o nstr ucti o n a n d e val uati o n of t he st u d y. All s o urce d oc u me nts s h o ul d be c o m plete d 
i n a neat, le gi ble ma n ner t o e ns ure acc urate i nter pretati o n of data.  
1 4. 3  Rec or d R ete nti o n  
T he I n vesti gat or m ust arra n ge f or rete nti o n  of st u d y rec or ds at t he site. T he nat ur e of t h e 
rec or ds a n d t he d urati o n of t he rete nti o n peri o d m ust meet t he re q uire me nts of re g ulat or y 
a ut h orities.   

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T he S p o ns or a n d t he I n v esti gat or s hall arc hi ve t h e c o nte nt of t he cli nical trial master file f or 
at least 2 5 y ears aft er t h e e n d of t he cli nical st u d y. H o we v er, t he me dical files of patie nt s 
s hall be arc hi v e d i n acc or da nce wit h nati o nal la w. 
T he c o nt e nt of t he cli nical trial master file s hall be arc hi ve d i n a wa y t hat e ns ures t hat it is 
rea dil y a vaila bl e a n d accessi ble, u p o n re q uest, t o t he c o m pete nt a ut h orities. 
A n y tra nsfer of o w n ers hi p of t he c o nte nt of t he cli nical trial master file s h all be d oc u me nte d.  
A n y alterati o n t o t he c o nte nt of t he I n v esti gat or file s hall be tracea ble a n d t he I n v esti gat or 
s h o ul d ta ke meas ures t o pre ve nt a cci de ntal or pre mat ure destr ucti o n of t h ese d oc u me nts .  
1 4. 4  M o nit ori n g  
T he st u d y will be m o nit ore d t o e ns ure t hat it is c o n d ucte d a n d d oc u me nte d pr o perl y 
acc or di n g t o t he pr ot oc ol, G C P, a n d all a p plica ble re g ulat or y re q uire me nts.  
A site visit will be hel d pri or t o i nitiati o n of pati e nt  e nr ol me nt . T h e pr ot o c ol, e C R Fs, st u d y 
dr u g s u p plies a n d rele va nt pr oce d ures will be e x plai ne d t o t he I n vesti gat ors a n d his/ her staff 
i n detail at t he site visit . O n -site m o nit ori n g visits will be ma de at a p pr o priate ti mes d uri n g 
t he st u d y. 
Cli nical 
m o nit ors 
m ust ha ve direct access 
t o s o urce d oc u m e ntati o n t o c hec k t he 
c o m plete ness , clarit y, c o nsiste nc y of t he d ata rec or de d i n t he e C R Fs  f or eac h patie nt  a n d t he 
a d here n ce t o t he pr ot oc ol a n d t o G C P . T he cli nical m o nit ors will als o c hec k t he pr o gress of  
e nr ol me nt a n d t he h a n dli n g of st u d y me dicati o n t o e ns ure t hat st u d y me dicati o n is bei n g 
st ore d, dis pe nse d, a n d acc o u nte d f or acc or di n g t o s pecificati o ns.  
T he I nvesti gat or  will ma ke a vaila ble t o t he cli nical m o nit or s o urce d oc u me nts a n d me dical 
rec or ds n ecess ar y t o c hec k t he e C R Fs.  N o i nf or mati o n i n t hese rec or ds a b o ut t he i de ntit y of 
t he patie nt s will lea ve t he st u d y ce nter. I n a d diti o n, t he I n vesti gat or a n d ke y trial pers o n nel 
will w or k cl osel y wit h t he cli nical m o nit or a n d, as nee de d, pr o vi d e t he m a p pr o pri ate 
e vi de nce t hat t he c o n d uct of t h e st u d y is b ei n g d o ne i n acc or da n ce wit h a p plica ble 
re g ulati o ns a n d G C P g ui deli nes.  
M o nit ori n g sta n dar d pr oce d ures re q uire f ull v erificati o n f or t he prese nce of i nf or me d 
c o nse nt, a d here nce t o t he i ncl usi o n/e xcl usi o n criteria, d oc u me nt ati o n of S A Es a n d t he 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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rec or di n g of pri mar y efficac y a n d safet y varia bles. T he In v esti gat or is res p o nsi ble f or 
c o m pleti n g t he eC R Fs e x pe diti o usl y t o ca pt ure all t he rele va nt i nf or mati o n, w hile t he 
m o nit or is res p o nsi ble f or re vie wi n g t he m a n d clarif yi n g a n y data q ueries . 
1 4. 5  Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce  
T he S p o ns or or its desi g nee will perf or m t he q ualit y ass ura nce a n d q ualit y c o ntr ol acti vities 
of t his st u d y; h o we ver, res p o nsi bilit y f or t he acc urac y, c o m plet e ness, a n d relia bilit y of t he 
st u d y data prese nte d t o t h e S p o ns or lies wit h t he I n vesti gat or ge nerati n g t he data.  
T he S p o ns or will arra n ge a u dits as part of t he i m ple me ntati o n of q ualit y ass ura nce t o e ns ure 
t hat t he st u d y is bei n g c o n d ucte d i n c o m plia nce wit h t he pr ot oc ol, Sta n dar d O perati n g 
Pr oce d ures, G C P, a n d all a p pli ca ble re g ulat or y re q uire me nts. A u dits will be i n de pe n de nt of 
a n d se parate fr o m t h e  r o uti ne m o nit ori n g a n d q ualit y c o ntr ol f u ncti o ns. Q ualit y ass ur a nce 
pr oce d ures will be p erf or me d at st u d y sites a n d d uri n g data ma na ge me nt t o ass ure t hat s afet y 
a n d effi cac y d ata are a d e q uate a n d well d oc u me nt e d.  
A Re g ulat or y A ut h orit y ma y als o wis h t o c o n d u ct a n i ns pecti o n ( d uri n g t he st u d y or e ve n 
after its c o m pleti o n) . If a n i ns pecti o n is re q u este d b y a Re g ulat or y A ut h orit y, t he I n vesti gat or 
m ust i nf or m Italfar mac o S. p. A. i m me diatel y t hat t his re q uest has bee n ma de.  
F or la b orat ories ha n dli n g cli nical l a b orat or y sa m ples, t he accre ditati o n certificate a n d 
la b orat or y n or m al u nits a n d ra n ges m ust be pr o vi d e d t o t he S p o ns or a n d/ or C R O a n d m ust be 
u p date d as nee de d b y eac h trial ce ntre.  
1 4. 6  P r ot oc ol A me n d me nt a n d P r ot oc ol D e vi ati o n   
1 4. 6. 1  Pr ot oc ol A me n d me nt  
A n y c ha n ge or a d diti o n t o t his pr ot oc ol re q uires a writte n pr ot oc ol a me n d me nt t hat m ust be  
a p pr o ve d b y It alfar m ac o S. p. A.  
A me n d me nts ca n be classifie d as s u bsta ntial w he n t he y i m pact o ne of t he f oll o wi n g criteria:  
•  T he safet y or p h ysical or me ntal i nte grit y of t he pa tie nt 
•  T h e scie ntific val u e of t h e st u d y  
•  T he c o n d uct or m a na ge m e nt  of t he st u d y  
•  T he q ualit y or safe t y of a n y I M P use d i n t he st u d y 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 9 9  of 1 1 0  
S u bsta ntial a me n d me nts re q uir e t he a ut h orizati o n t o t he C o m pete nt A ut h orit y a n d t he 
p osit i ve o pi ni o n of t he rele va nt I E C bef ore i m ple me ntati o n.  
I n cas e of ur ge nt safet y meas ures t o pr ot ect t he patie nt  a gai nst a n y i m m e diate hazar d , t h ese 
meas ures 
m a y 
be ta ke n wit h o ut pri or a ut h ori zati o n fr o m t he C o m pete nt A ut h orit y or 
fa v ora bl e o pi ni o n of t h e I E C. I n t his cas e, t he C o m pete nt A ut h orit y a n d I E C will be i nf or m e d 
as s o o n as p ossi ble usi n g t he fastest mea ns of c o m m u nicati o n f oll o we d b y a writte n re p ort.  
A me n d me nts classifie d as n o n -s u bsta ntial re q uire o nl y n otificati o n t o t he I E C i n v ol ve d. 
1 4. 6. 2  Pr ot oc ol Devi ati o ns  
S h o ul d a pr ot oc ol de viati o n occ ur, t he S p o ns or m ust be i nf or me d as s o o n  as p ossi ble. 
Pr ot oc ol de viati o ns a n d/ or vi olati o ns a n d t he reas o ns t he y occ urre d will be i ncl u de d i n t he 
C S R . Re p orti n g of pr ot oc ol de viati o ns t o t he I E C a n d i n acc or da nce wit h a p plica ble 
Re g ulat or y A ut h orit y ma n dates is a n  I n vesti gat or res p o nsi bilit y. 
1 4. 7  E t hic al C o nsi der ati o ns  
T his st u d y will be c o n d ucte d i n acc or da n ce wit h t he acce pte d versi o n of t he Declarati o n of 
Helsi n ki a n d/ or all rele v a nt fe deral r e g ulati o ns, as set f ort h i n Parts 5 0, 5 6, 3 1 2, S u b par t D, of 
Title 2 1 of t he C F R, i n acc or da nce wit h E ur o pea n a n d c o u ntr y re g ulati o ns i n f orce a n d i n 
c o m plia nce wit h G C P g ui deli nes.  
T he I E C will re vie w a n d a p pr o ve t his pr ot oc ol , t he i nf or me d c o nse nt f or m , t he recr uit me nt 
materials, a n d all partici pa nt materi als.    
1 4. 8  F i n a nci n g a n d Ins ur a nce  
Pri or t o t he st u d y c o m me nci n g, t he S p o ns or ( or its desi g ne e) a n d t he In vesti gat or ( or t he 
i nstit uti o n, as a p plica ble) will a gree o n c osts necessar y t o perf or m t he st u d y.  T his a gree me nt 
will be d oc u me nte d i n a fi na ncial a gree me nt t hat will be si g ne d b y t he In vesti gat or ( or t he 
i nstit uti o n si g nat or y) a n d t he S p o ns or ( or its desi g nee).  
T he I n vesti gat or is re q uire d t o ha ve a de q uat e c urre nt i ns ura nce t o c o ver clai ms f or 
ne gli ge nce a n d/ or mal practice.  T he S p o ns or will pr o vi de i ns ura nce c o vera ge f or t he cli nical 
st u d y as re q uire d b y n ati o nal re g ulati o ns. 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 0 0  of 1 1 0  
1 4. 9  P u blic ati o n P olic y / Discl os ure of D at a  a n d C o nfi de nti alit y   
T he I n v esti gat or m ust ass ure t hat p atie nt s’ a n o n y mit y will be mai ntai ne d a n d t h at t heir 
i de ntities will be pr otecte d fr o m u na ut h orize d parties . O n e C R Fs or ot her d oc u me nts 
s u b mitte d t o t he S p o ns or, patie nt s s h o ul d n ot be i de ntifie d b y t heir na mes, b ut b y an 
i de ntificati o n c o de. T h e I n v esti gat or s h o ul d kee p a n e nr ol me nt l o g s h o wi n g c o des, na mes 
a n d a d dress es.  
B y si g ni n g t he pr ot oc ol, t he I n vesti gat or a grees t o kee p all i nf or mati o n pr o vi de d b y 
Italfar mac o S. p. A. i n stri ct c o nfi de nce a n d t o re q u est si milar c o nfi d e ntialit y fr o m his/ her staff 
a n d t he I E C.  St u d y d oc u me nts pr o vi de d b y Italfar mac o S. p. A. ( pr ot oc ols, I Bs, e C R Fs, a n d 
ot her materi al) will be st ore d a p pr o priatel y t o e ns ure t heir c o nfi de ntialit y . T he i nf or mati o n 
pr o vi de d b y It alfar mac o S. p. A. t o t he I n v e sti gat or ma y n ot be discl ose d t o ot hers wit h o ut 
direct writte n a ut h orizati o n fr o m It alfar m ac o S. p. A., e xce pt t o t he e xte nt necessar y t o o btai n 
i nf or me d c o nse nt fr o m patie nt s w h o wis h t o partici pate i n t he st u d y.  
B ot h t he use of data a n d t he p u blicati o n p o lic y are detaile d wit hin t he cli nical st u d y 
a gree m e nt.  Intellect ual pr o pert y ri g hts (a n d relat e d matters) ge nerate d b y t he I n v esti gat or a n d 
ot hers perf or mi n g t he cli nical st u d y will be s u bject t o t he ter ms of a cli nical st u d y a gree me nt 
t hat will be a gree d u p o n bet wee n t he I nstit uti o n a n d t he S p o ns or or t heir desi g nee.  Wit h 
res pect t o s uc h ri g hts, t h e S p o ns or or its desi g nee will s olel y o w n  all ri g hts a n d i nterest s i n 
a n y materials, d ata , a n d i ntellect ual pr o pert y ri g hts de vel o pe d b y I n v esti gat ors a n d ot hers 
perf or mi n g t he cli nic al st u d y descri be d i n t his pr ot oc ol, s u bject t o t he ter ms of a n y s uc h 
a gree m e nt.  I n or der t o facilitate s uc h o w ners hi p, I n vesti gat ors will be re q uire d t o assi g n all 
s uc h i n ve nti o ns eit her t o t heir I nstit uti o n or directl y t o t he S p o ns or or its desi g nee, as will be 
set f ort h i n t he cli nical st u d y a gree m e nt. 
Italfar mac o S. p. A ass ures t hat t he ke y desi g n ite ms of t he Pr otoc ol will be p u blis he d i n a 
p u blicl y accessi ble data b ase s uc h as “ Cli nicaltrials. g o v .” M o re o ver, u p o n c o m pleti o n of t he 
st u d y a n d fi nalizati o n of t he st u d y re p ort, t he res ults of t h is st u d y will be s u b mitte d f or 
p u blicati o n or p oste d i n a p u blicl y accessi b le data base.   
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 0 1  of 1 1 0  
1 5  R E F E R E N C E S  
Az uara V, Perr y B , Sa uer S et al. ( 2 0 0 6). C hr o mati n si g nat ures of pl uri p ote nt cell li nes. Nat 
Cell Bi ol. 2 0 0 6; 8( 5): 5 3 2 -5 3 8.  
B ell o L, Ca m pa dell o P, Bar p A et al. F u ncti o n al c ha n ges i n Bec ker m usc ular d ystr o p h y: 
i m plicati o ns f or cli nical trials i n d ystr o p hi n o pat hies. Sci Re p. 2 0 1 6 Se p 1; 6: 3 2 4 3 9 
Ber nstei n B E.,  Mi k kelse n  T S, Xie X , et al. ( 2 0 0 6). A bi vale nt c hr o mati n str uct ure mar ks ke y 
de vel o p me ntal ge n e s i n e m br y o nic ste m cells. Cell.  1 2 5( 2): 3 1 5 -3 2 6.  
Bettica P, Petri ni S, D' Oria V et al . ( 2 0 1 6). Hist ol o gical effects of gi vi n ostat i n b o ys wit h 
D uc he n ne m us c ular d ystr o p h y. Ne ur o m usc ul Dis or d.  2 6( 1 0):  6 4 3 -6 4 9 . 
B ol dri n L, Za m mit P S, 
M or ga n J E. ( 2 0 1 5) Satellite cells fr o m d ystr o p hic m uscle retai n 
re ge nerati ve ca pacit y. Ste m cell res earc h. 1 4( 1): 2 0 -9.  
B o nati U, Haf ner P, Sc ha deli n S et al.  Q ua ntitati ve m uscle 
M RI: A p o werf ul s urr o gate 
o utc o me 
meas ur e i n 
D uc he n ne 
m usc ular d ystr o p h y. Ne ur o m usc ular dis or ders: 
N M D. 
2 0 1 5; 2 5( 9): 6 7 9 -8 5.  
C ol ussi C , M ozzetta C, G urt ner A et al. ( 2 0 0 8). H D A C 2 bl oc ka de b y nitric o xi de a n d hist o ne 
deacet ylase i n hi bit ors re veals a c o m m o n tar g et i n D uc he n ne m usc ul ar d ystr o p h y treat me nt. 
Pr oc Natl Aca d Sci U S A . 1 0 5( 4 9): 1 9 1 8 3 -1 9 1 8 7.  
C o nsal vi S , Sacc o ne V, Gi or da ni L et al. ( 2 0 1 1). Hist o ne deacet ylas e i n hi bit ors i n t he 
treat me nt of m usc ular d ystr o p hies: e pi ge netic dr u gs f or ge netic dise ases. M ol Me d . 1 7( 5 -6): 
4 5 7 -4 6 5.  
Darras B T, Miller D T, Uri o n D K. D ystr o p hi n o pat hies. 2 0 0 0 Se p 5 [ u p date d 2 0 1 4  
N o v  2 6]. I n: Pa g o n R A, A da m M P, Ar di n ger H H, Wallace S E, A me mi ya A, Bea n LJ H,  
Bir d T D, Le d better N, M eff or d H C, S mit h RJ H, Ste p he ns K, e dit ors. Ge ne Re vie ws ®  
[I nter net]. Seattle ( W A): U ni versit y of Was hi n gt o n, Seattle; 1 9 9 3-2 0 1 7  
De b ur gra ve N, Da o u d F, Lle nse S  et al. ( 2 0 0 7). Pr otei n - a n d m R N A-base d p he n ot y pe -
ge n ot y pe c orrelati o ns i n D M D/ B M D wit h p oi nt m utati o ns a n d m olec ular basis f or B M D wit h 
n o nse nse a n d fra mes hift m utati o ns i n t he D M D ge ne.  H u m M utat.  2 8( 2): 1 8 3 -9 5.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 0 2  of 1 1 0  
D oles J D, Ol wi n B B. ( 2 0 1 4). T he i m pact of J A K-S T A T si g nali n g o n m uscle re ge n erati o n. 
Nat ure me dici n e. 2 0( 1 0): 1 0 9 4 -5.  
Er vasti, J. M. ( 2 0 0 7). D ystr o p hi n, its i nteracti o ns wit h ot her pr otei ns, a n d i m plicati o ns f or 
m usc ular d ystr o p h y. Bi oc hi m Bi o p h ys Acta . 1 7 7 2( 2): 1 0 8 -1 1 7.  
Fisc her D, Haf ner P, R u bi n o D et al.  T he 6 -mi n ute wal k test, m ot or f u ncti o n meas ure a n d 
q ua ntitati ve t hi g h m uscle 
M RI i n Bec ker m us c ular d ystr o p h y: A cr oss -secti o nal st u d y. 
Ne ur o m usc ul Dis or d. 2 0 1 6 J ul; 2 6( 7): 4 1 4 -2 2.  
Fi nsterer J, St oll ber ger C. ( 2 0 0 3). T he heart i n h u ma n d ystr o p hi n o patlies. Car di ol o g y.  9 9( 1): 
1 -1 9.  
G u ha  M. ( 2 0 1 5). H D A C i n hi bit ors still nee d a h o me r u n, des pite rece nt a p pr o val. Nat Re v 
Dr u g Disc o v. 1 4( 4): 2 2 5 -2 2 6.  
He d ge M R, C hi n E L H, M ulle J G et al. ( 2 0 0 8). Micr oarra y -bas e d m utati o n i n t he d ystr o p hi n 
ge ne. H u m M utat. 2 9( 9): 1 0 9 1 -1 0 9 9.  
Her ma ns M C, Pi nt o Y M, Mer kies I S et al. ( 2 0 1 0) Here ditar y m usc ular d ystr o p hies a n d t he 
heart. Ne ur o m usc ul Dis or d.  2 0( 8): 4 7 9 -9 2.  
J o oste n, L. A., F. Le o ni, et al. ( 2 0 1 1). I n hi biti o n of H D A C acti vit y b y I T F 2 3 5 7 a meli orat es 
j oi nt i nfla m mati o n a n d pre ve nts cartila ge a n d b o n e destr ucti o n i n e x peri me ntal art hritis. M ol 
Me d . 1 7( 5-6): 3 9 1 -3 9 6 ). 
Le o ni  F, F ossati G, Le wis E  et al. (2 0 0 5 ). T he hist o ne deacet ylas e i n hi bit or I T F 2 3 5 7 re d uces 
p r o d ucti o n of pr o-i nfla m mat or y c yt o ki nes i n vitr o a n d s yste mic i nfla m mati o n i n viv o. M ol 
Me d . 1 1: 1 -1 5.  
Li m R R, Ta n A, Li u Y C et al.  I T F 2 3 5 7 tra nsacti vates I d 3 a n d re g ulat e T G F beta/ B M P 7 
si g nali n g pat h wa ys t o atte n uate c or neal fi br osis. Sci Re p. 2 0 1 6 ; 6: 2 0 8 4 1.  
Me n dell J R, Sa he n k Z, Mali k V et al. F ollistati n ge ne t hera p y trial f or bec k er m usc ul ar 
d ystr o p h y. M ol T her. 2 0 1 5 Ja n; 2 3( 1): 1 9 2 -2 0 1.  
Mi netti G C , et al. ( 2 0 0 6). F u ncti o nal a n d m or p h ol o gical rec o v er y of d ystr o p hic m uscles i n 
mice treat e d wit h deacet ylase i n hi bit ors.  Nat Me d 1 2( 1 0): 1 1 4 7 -1 1 5 0.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                    A me n de d Pr ot o c ol Versi o n 5. 0 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 1 0 3  of 1 1 0  
Pereira 
M C, Is a ya ma 
R N, Sea bra J C, 
Ca m p os 
G E, Pasc h oal I A. Distri b uti o n a n d  
m or p h o metr y of s k eletal m uscle fi bers i n pati e nts wit h c hr o nic o bstr ucti ve  p ul m o nar y 
disease a n d c hr o nic h y p o xe mia. M uscle Ner ve.  2 0 0 4 Dec; 3 0( 6): 7 9 6 -8 . 
Sacc o ne V , et al. ( 2 0 1 4). H D A C -re g ulat e d m y o mi Rs c o ntr ol B A F 6 0 varia nt e xc ha n g e a n d 
direct t he f u ncti o nal p he n ot y pe of fi br o -a di p o ge nic pr o ge nit ors i n d ystr o p hic m uscles.  Ge nes 
De v . 2 8( 8): 8 4 1 -8 5 7.  
Tasca G, Ia n nacc o ne E, 
M o nf orte 
M  et al. M uscle 
M RI i n Bec ker m usc ular d ystr o p h y. 
Ne ur o m usc ular dis or ders: N M D. 2 0 1 2; 2 2 S u p pl 2: S 1 0 0 -6.  
Tier n e y 
M T, A y d o g d u T, Sala D,  et al. ( 2 0 1 4) S T A T 3 si g nali n g c o ntr ols satellite cell 
e x pa nsi o n a n d s kelet al m uscle re p air. Nat ur e me di ci ne. 2 0 1 4; 2 0( 1 0): 1 1 8 2 -6.  
Tri plett W T, Bali ga n d C, F or bes S C et al.  C he mical s hift -base d M RI t o meas ure fat fracti o ns 
i n d ystr o p hic s keletal m uscle. Ma g netic res o na nce in me dici ne : official j o ur nal of t he S ociet y 
of 
Ma g netic Res o na nce i n 
Me dici ne / S ociet y of 
Ma g netic Res o na nce i n 
Me dici ne. 
2 0 1 4; 7 2( 1): 8 -1 9.  
V uiller ot C, Girar d ot F, Pa ya n C et al. M o nit ori n g c ha n ges a n d pre dicti n g l oss of a m b ulati o n 
i n D uc he n ne m usc ul ar d ystr o p h y wit h t he m ot or f u ncti o n meas ure. De v Me d C hil d Ne ur ol. 
2 0 1 0 Ja n; 5 2( 1): 6 0 -5  
Wa n g Y G, X u L, Wa n g T et al.  Gi vi n ostat i n hi biti o n of he patic stellate cell pr oliferati o n a n d 
pr otei n acet ylati o n. W orl d J Gastr oe nter ol. 2 0 1 5; 2 1( 2 7): 8 3 2 6 -3 9.  
Willc o c ks RJ, R o o ne y W D, Tri plett W T et al.  M ultice nter pr os pecti ve l o n git u di nal st u d y of 
ma g netic res o na n ce bi o m ar kers i n a lar g e d uc h e n ne m usc ular d ystr o p h y c o h ort. A n nals of 
ne ur ol o g y. 2 0 1 6.  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                     A me n de d Pr ot o c ol Versi o n 5. 0 
 
1 7  J u ne 2 0 2 0                                                                                                                                                                                                                                 Pa ge 1 0 4  of 1 1 0  
1 6  A P P E N DI C E S  
1 6. 1  C o m bi ne d list of dr u gs t h at pr ol o n g Q T a n d/ or c a use t ors a des de P oi ntes ( T D P)  
S o urce:  Ariz o n a Ce nter f or E d ucati o n a n d Researc h o n T h era p e utics.  Li n k: htt p:// w w w.cre di ble me ds. or g/e ver y o n e/c o m p osite -list-
all-qt dr u gs/.  List last re vise d: 1 4 Marc h  2 0 1 7.  Accesse d 2 7 Marc h  2 0 1 7.  
Cre di ble Me ds ®  has re vi e we d a v aila ble e vi de nce f or t he dr u gs o n t he f oll o wi n g list a n d place d  t he m i n o ne of t hree d esi g nate d 
cate g ories: K n o w n Ris k of T d P ( K R), P ossi ble Ris k of T d P ( P R) or C o n diti o nal Ris k of T d P ( C R). T he f ull descri pti o n of t hese 
cate g ories ca n b e f o u n d o n t he Cre di ble Me ds. or g we bsite . 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                     A me n de d Pr ot o c ol Versi o n 5. 0 
 
1 7  J u ne 2 0 2 0                                                                                                                                                                                                                                 Pa ge 1 0 5  of 1 1 0  
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                     A me n de d Pr ot o c ol Versi o n 5. 0 
 
1 7  J u ne 2 0 2 0                                                                                                                                                                                                                                 Pa ge 1 0 6  of 1 1 0  
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                     A me n de d Pr ot o c ol Versi o n 5. 0 
 
1 7  J u ne 2 0 2 0                                                                                                                                                                                                                  
Pa ge 1 0 7  of 1 1 0  
 
1 6. 2  Dr u gs k n o w n  t o be a s u bstr ate of O C T 2 tr a ns p orter  
O C T 2 tra ns p orter = Or g a nic Cati o n Tra ns p orter 2  
S o urce: htt p:// w w w.strai g ht healt hcare.c o m/ or ga ni c -cati o n-tr a ns p orter-2. ht ml  
Access e d Marc h 2 7t h, 2 0 1 7.  
Ge neric N a me  
Br a n d 
N a mes 
( P arti al 
List)  
O C T 2 i nter acti o n 
A ma nta di ne  
 
S u bstrate  
A mil ori de  
Mi da m or
®  
S u bstrate  
Ci meti di ne  
Ta ga met ®  
S u bstrate  
Creati ni ne  
 
S u bstrate  
D ofetili de  
Ti k os y n ®  
S u bstrate  
D o pa mi ne  
 
S u bstrate  
Fa m oti di ne  
Pe pci d ®  
S u bstrate  
Me ma nti ne  
Na me n da ®  
S u bstrate  
Metf or mi n  
Gl uc o p ha ge ®  
S u bstrate  
O xali plati n  
El o xati n ®  
S u bstrate  
Pi n d ol ol  
Vis ke n ®  
S u bstrate  
Pr ocai na mi de  
 
S u bstrate  
Ra niti di ne  
Za ntac ®  
S u bstrate  
Tri met h o pri m  
Bactri m ®  
S u bstrate  
Vare nicli ne  
C ha nti x ®  
S u bstrate  
 
 
 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                     A me n de d Pr ot o c ol Versi o n 5. 0 
 
1 7  J u ne 2 0 2 0                                                                                                                                                                                                                  
Pa ge 1 0 8  of 1 1 0  
1 6. 3  Dr u gs k n o w n t o be P -gl yc o pr otei n i n hi bit ors  
S o urce: htt ps:// w w w.strai g ht healt hcare.c o m/ p -gl yc o pr otei n. ht ml  
Access e d J ul y 2 6t h, 2 0 1 9.  
Ge neric n a m e  
Br a n d n a mes ( p arti al list)  
A mi o dar o ne  
C or dar o ne ®  
At or vastati n  
Li pit or ®  
Azit hr o m yci n  
Zit hr o ma x ®  
B oce pre vir  
Victrelis ®  
Br o m ocri pti ne  
C ycl oset ® , Parl o del® , etc. 
Ca pt o pril  
Ca p ote n ®  
Car ve dil ol  
C ore g ®  
Clarit hr o m yci n  
Bia xi n ®  
C o bicistat  
part of Stri bil d ®  
C o ni va pta n  
Va pris ol ®  
C ycl os p ori ne  
Ne oral ® , Ge n graf® , Sa n di m m u ne®  
Daclatas vir  
Da kli nza ™ 
Diltiaze m  
Car dize m ® , Cartia ® , Dilac or® , Diltia®  
D o xaz osi n  
Car d ura ®  
Dr o ne dar o ne  
M ulta q
®  
Er yt hr o m yci n  
E. E. S ® , Er y-ta b®  
Fel o di pi ne  
Ple n dil ®  
Fl u vastati n  
Lesc ol ®  
Gleca pre vir  
Ma v yret ™ 
I n di na vir 
Cri xi va n ®  

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                     A me n de d Pr ot o c ol Versi o n 5. 0 
 
1 7  J u ne 2 0 2 0                                                                                                                                                                                                                  
Pa ge 1 0 9  of 1 1 0  
Itrac o naz ole 
S p ora n o x ®  
Ket oc o naz ole  
Niz oral ®  
Le di pas vir  
Har v o ni  
Li na gli pti n  
Tra dje nta ®  
L o pi na vir a n d rit o na vir  
Kaletra ®  
L o vastati n  
Me vac or
®  
Me peri di ne  
De mer ol ®  
Met ha d o ne  
 
Nelfi na vir  
Virace pt ®  
Nicar di pi ne  
Car de ne ®  
Parita pre vir  
Vie kira Pa k ™, Tec h ni vie ™ 
Pe ntaz oci ne  
Tal wi n ®  
Pi bre ntas vir  
Ma v yret ™ 
Pr o gester o ne  
 
Q uerceti n  
s u p ple me nt 
Q ui ni di ne  
 
Ra n olazi ne  
Ra ne xa ®  
Reser pi ne  
 
Rit o na vir  
N or vir ®  
Sa q ui na vir  
I n virase®  
Sarec ycli ne  
Se ysara ™ 
Si me pre vir  
Ol ysi o ®  
Si m vastati n  
Z oc or ®  
S u v ore xa nt  
Bels o mra ® - i n vitr o data 

Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
Gi vi n ostat                                                                                                                                     A me n de d Pr ot o c ol Versi o n 5. 0 
 
1 7  J u ne 2 0 2 0                                                                                                                                                                                                                  
Pa ge 1 1 0  of 1 1 0  
Tacr oli m us  
Pr o graf ®  
Ta m o xife n