Conditions: Becker Muscular Dystrophy
Keywords: Givinostat Becker Dystrophy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 51
Healthy volunteers: no

Brief summary:
Objectives:

Primary objective: to establish the histological effects of Givinostat versus placebo administered over 12 months.

Secondary Objectives:

* To establish the macroscopic muscle effects of Givinostat versus placebo administered over 12 months assessed by Magnetic Resonance Imaging (MRI)/Magnetic Resonance Spectroscopy (MRS).
* To determine the other histological effects of Givinostat versus placebo administered over 12 months.
* To establish the efficacy of Givinostat versus placebo administered chronically over 12 months in slowing disease progression.
* To assess the safety and tolerability of Givinostat versus placebo administered chronically.
* To evaluate the pharmacokinetic (PK) profile of Givinostat administered chronically in the target population.
* To evaluate the impact of Givinostat versus placebo administered chronically on quality of life and activities of daily living.

Detailed description:
This was a phase 2, randomised, double-blind, placebo-controlled study. Eligible patients were randomized in a 2:1 ratio to receive Givinostat or placebo for 12 months. Randomization was stratified by concomitant steroid use at baseline (yes or no). The study comprised twelve (12) visits: screening (V1, V2), randomization (V3), treatment (V4-V10), end of study (V11) and follow-up (V12). Visits during treatment took place every 12 weeks, except for the first 2 months, when they occurred every 2 weeks to allow closer monitoring of safety.

Givinostat (ITF2357) oral suspension (10 mg/mL) was initially administered as 2 daily doses of 40-70 mg according to body weight after a meal (high dose). With amendment 2 of the protocol, a lower starting dose was implemented to address cases of thrombocytopenia reported following the treatment of the first 21 patients and corresponded to the reduced dose of the original protocol (i.e., 26.7-46.7 mg b.i.d according to body weight, i.e., low dose).

51 patients were to be enrolled to provide a sample size of 48 patients with evaluable baseline biopsies. Seventy patients provided written informed consent, 51 (72.86%) completed screening successfully and were randomized; 34 patients (66.67%) to the Givinostat group and 17 (33.33%) to the placebo group.

Arms:
arm 1: Givinostat oral suspension (10 mg/mL) twice daily in a fed state arm 2: Placebo oral suspension (10 mg/mL) twice daily in a fed state

Interventions: intervention 1: Givinostat intervention 2: Placebo
Intervention descriptions: intervention 1: suspension of Givinostat (10 mg/mL) intervention 2: suspension manufactured to mimic Givinostat

Protocol document:
Prot_000.pdf: 
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  
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  of 1 1 0  
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  
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  of 1 1 0  
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  
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  of 1 1 0  
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  
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  of 1 1 0  
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  
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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  
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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  
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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  
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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  
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•  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 
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•  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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1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 4 3  of 1 1 0  
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  


Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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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. 


Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 4 6  of 1 1 0  
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 
1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 7 4  of 1 1 0  
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  
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 5  of 1 1 0  
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  
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 6  of 1 1 0  
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  
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 7  of 1 1 0  
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  
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 8  of 1 1 0  
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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1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 7 9  of 1 1 0  
•  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  
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 0  of 1 1 0  
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  
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 3  of 1 1 0  
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  
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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  
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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  
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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  
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 1  of 1 1 0  
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. 


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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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 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 9 3  of 1 1 0  
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  


Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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1 7  J u ne 2 0 2 0                                                                                                                                      Pa ge 9 4  of 1 1 0  
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  
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 5  of 1 1 0  
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  


Italfar mac o S. p. A.                                                                                                                                              D S C/ 1 5/ 2 3 5 7/ 5 3  
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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.   


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 7  of 1 1 0  
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  
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 8  of 1 1 0  
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  
 
 
 

SAP_001.pdf: 


Statistical Analysis Plan 
Sponsor: ITALFARMACO 
Protocol: DSC/15/2357/53 
 
  
                    Ver.04 25Jun2020 
Page 2 of 43 
Document History 
Status and 
Version 
Release Date 
Change Description 
Reason/Comment 
Draft 
Version 0.1 
18/02/2019 
N.A. 
N.A. 
Draft 
Version 0.2 
20/02/2019 
Internal review 
Internal review 
Draft 
Version 0.3 
08/02/2021 
Adaptation to new template. 
Analyses updated according to 
latest protocol (version 5.0 
amendment 4, dated June 17, 
2020). 
Internal review and 
Sponsor’s review 
Draft 
Version 0.4 
19/02/2021 
The following sections have been 
modified: Section 2 (endpoints 
better specified) and Section 6 
(6.3.2.1 inverted with 6.3.2.2, 
exploratory analyses of section 
6.3.3 have been reported in 
Section 6.5, analyses added in 
section 6.4.1, 6.4.3 better 
specified, analyses added in 
section 6.4.4) 
Sponsor’s review 
Draft 
Version 0.5 
06/04/2021 
The following sections have been 
modified: Section 6.3.1 and 
Section 6.3.2.2 (Primary analysis 
based on observed and log 
transformed data. Multiple 
imputation performed as 
sensitivity analysis) 
Section 6.3.2.3 (Analysis added for 
fiber size variability) 
Section 6.3.2.4-6.3.2.7 (Analysis 
based on MMRM model instead 
of ANCOVA) 
Section 6.3.3 (Analysis added to 
aid interpretation of TFT velocity) 
Sponsor’s review 


Statistical Analysis Plan 
Sponsor: ITALFARMACO 
Protocol: DSC/15/2357/53 
 
  
                    Ver.04 25Jun2020 
Page 3 of 43 
Status and 
Version 
Release Date 
Change Description 
Reason/Comment 
Draft 
Version 0.6 
20/04/2021 
The following sections have been 
modified: Section 4.4.3 (Better 
specified), Sections 6.3.1, 6.3.2.2 
and 6.3.2.3 (Mixed Model added 
in order to evaluate the effect of 
biopsy sites), Section 6.3.2.3 
(Sensitivity analyses added), 
Section 6.3.2.8 (data handling 
rules added). 
Sponsor’s review 
Final version 
1.0 
27/04/2021 
First Final Version release 
Sponsor’s approval