Open-label, Long-term, Extension Treatment Using Intra-Erythrocyte Dexamethasone Sodium Phosphate (EryDex System) in Patients With Ataxia Telangiectasia Who Participated in the ATTeST-IEDAT-02-2015 Study
Phase: PHASE3
Conditions: Ataxia Telangiectasia, Genetic Syndrome
Sponsor: Quince Therapeutics S.p.A.

 
 
 
 
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  
I E D A T-0 3 -2 0 1 8  
St u d y Titl e  
O pe n -l a bel, L o n g -t er m, E xt e nsi o n  T r eat m e nt usi n g 
Intr a -E r yt hr oc yt e D e xa m et has o ne S o di u m P h os p hat e i n  
Pati e nts wit h A t a xi a T el a n gi ect asi a W h o P arti ci pat e d i n 
t he I E D A T-0 2 -2 0 1 5 S t u d y 
S h ort St u d y Titl e - Acr o n y m  
O L E -I E DA T  
P h as e  
P has e III  
E u dr a C T N u m ber  
2 0 1 8 -0 0 0 3 3 8 -3 6  
I N D N u m ber 
1 1 5 9 2 9  
D at e of Pr ot oc ol  
Versi o n 1. 0: 2 5 Ja n u ar y 2 0 1 8, Fi n al  
Versi o n 2. 0: 2 9 Mar c h  2 0 1 8, Fi n al  
Versi o n 3. 0 : 3 0 A pril 2 0 1 8, Fi n al  
Versi o n 4. 0 : 1 9 Marc h 2 0 1 9 , Fi n al 
Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al  
Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al  
Versi o n 7. 0: 0 1 Dece m ber  2 0 2 0, F i n al 
A ut h or  
  
S p o ns or  
Er y Del S. p. A.  
Vi a M e ucci, 3  
2 0 0 9 1 Br ess o ( MI), It al y  

: + 3 9 0 2 3 6 5 0 4 4 7 0  
: + 3 9 0 2 3 6 5 0 4 4 7 4 
Tri al Pr ot oc ol Versi o n  
Versi o n 7 . 0: 0 1 Dece m ber  2 0 2 0, Fi n al  
 
G C P St at e me nt  
T his st u d y will b e p erf or me d i n c o m pli a nce wit h G o o d Cli nic al Pr a ctic e ( G C P),  
t h e De cl ar ati o n of Helsi n ki ( wit h a me n d me nts) a n d l o c al l e g al a n d r e g ul at or y r e q uir e me nts. 
 
C O N FI D E N TI A LI T Y  
T h e i nf or m ati o n c o nt ai n e d h erei n is t h e pr o pert y of Er y Del S. p. A. a n d  m a y n ot be re pr o d u ce d, p u blis h e d 
or discl ose d t o ot h ers wit h o ut writt e n a ut h orisati o n of Er y Del S. p. A  
 
 
 
Er y Del S. p. A., Vi a Me uc ci 3 , 2 0 0 9 1 Br ess o ( MI) (It al y) 
P P D

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2  of 1 3 2  
 
 
1  
S Y N O P SI S  
Titl e of t he St u d y  
O p e n -l a bel,  
L o n g-t er m,  
E xt e nsi o n  
Tr e at me nt  
usi n g Intr a -E r yt hr oc yte 
D e x a met has o ne S o di u m P h os p hat e i n  Pati e nts wit h A t a xi a T el a n gi e ctasi a Wh o 
P arti ci p at e d i n t h e I E D A T-0 2 -2 0 1 5 S t u d y.  
Pr ot o c ol N u m be r   
I E D A T-0 3 -2 0 1 8  
P h as e of De v el o p me nt   
III 
Ce nt e r(s)/ C o u nt r y(i es)   
2 0 -2 5 c e nt ers i n N ort h A meri ca, E ur o pe, Afri c a, Asi a a n d A ustrali a  
Pl a n ne d Tri al Pe ri o d  
(fi rst s u bj e ct e nr oll e d - 
l ast s u bj e ct o ut) 
First S u bj e ct I n ( F SI): 1 2 J u n e  2 0 1 8  
Last S u bj e ct I n ( L SI):  3 r d Q u art er 2 0 2 1  
St u d y O bj e cti v es  
Pri m a r y  O bj e cti ve:  
•  
T o m o nit or a n d e v al uat e t h e l o n g-t er m s af et y a n d t ol er abilit y of E D S -E P 
i n A T p ati e nts. 
E x pl o r at or y O bj e cti ve : 
•  
T o e v al u ate t h e l o n g t er m eff e ct of E D S -E P i n tr e ati n g C N S s y m pt o ms as 
me as ur e d b y t h e  “ M o difi e d” I nt er nati o nal C o oper ati ve At a xi a Rati n g Scale  
( mI C A R S), a n d Cli ni c al Gl o b al I m pr essi o n of s e v erit y a n d c h a n ge ( C GI-
S/ C).  
Se c o n d a r y  O bj e cti ve :  
•  
T o e v al u at e t h e l o n g -t er m effe ct of E D S-E P o n h e alt h r el at e d Q u alit y of 
Lif e ( Q o L; E Q -5 D -5 L s c al e).  
St u d y Desi g n  
 
T his is a n i nt er nati o n al ( N ort h A meri c a, E ur o p e, Afri c a, Asi a a n d A ustr alia), 
m ulti -c e nter, pr os p ecti ve, o p e n -l a b el tr e at me nt st u d y, d esi g n e d t o c o nti n u e t o  
pr o vi de t h e st u d y me di c ati o n t o all p ati e nts w h o c o m pl et e d  t h e f ull tr e at me nt 
p eri o d  (i n cl u di n g t hos e tr e at e d wit h pl a c e b o) i n t h e I E D A T-0 2 -2 0 1 5 tri al, 
c o m pl et ed  t h e st u d y ass ess me nts, d o n ot pr es e nt s af et y c o ntr ai n di cati o n t o 
c o nti n uati o n of tr e at me nt , a n d pr o vi ded  i nf or me d c o ns e nt. T h e st u d y ai ms t o 
c oll e ct i nf or mati o n o n t h e l o n g -t er m s af et y a n d eff i c ac y of t h e tri al tr e at me nt. 
M or e o v er, p ati e nts w h o wer e  dis c o nti n ue d  fr o m t h e A T Te S T st u d y d uri n g t he 
C O VI D -1 9 p a n d e mic w ill b e eli gi bl e t o r e c ei v e t h e Er y De x tr e at me nt i n t he 
c o nt e xt of t h e O L E-I E D A T st u d y, i n t h e a bs e n c e of s afet y c o ntrai n di cati o ns t o 
c o nti n uati o n of t h e tr e at me nt, a n d s u bj e ct t o t h e pr o vi si o ns of t h e i nf or me d 
c o ns e nt . 
P ati e nts me eti n g all s el e cti o n crit eria will r e c ei v e m o nt hl y i nf usi o ns of E D S -E P 
). If t his d os e of E D S-E P is n o t t ol erate d, 
t h e p ati e nt s h o ul d b e dis c o nti n ue d fr o m t h e st u d y.  
D uri n g t h e 
st u d y, l o n g-t er m effi c a c y ass ess me nts 
will b e p erf or me d  
a p pr o xi mat el y e v er y 6 m o nt hs , w hil e s af et y p ar a met ers will b e ass esse d at eac h 
m o nt hl y visit.  
T h e I C A R S , E Q-5 D -5 L a n d t h e C GI -C/ S  will b e a d mi nistere d b y a sit e r ater .   
As a r es ult of t h e C O VI D -1 9 p a n d e mi c, t e m p orar y c h a n ges t o t h e pr ot o c ol ha ve 
b e e n i m pl e me nt e d. T h ese c h a n ges ar e d escri be d i n A p p e n di x 1 3 . 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3  of 1 3 2  
 
Pl a n ne d N u m be r of 
P ati e nts  
All p ati e nts e nr oll e d i n t his st u d y will h a v e p arti ci pate d i n St u d y I E D A T -0 2 -
2 0 1 5, a n d t h er e will b e n o d e n o v o  e nr oll me nt of n e w p ati e nts.  It is esti mate d t hat 
a ma xi m u m of 1 5 0  p atie nts fr o m t h e pri or st u d y will e nt er t his st u d y.   
I ncl usi o n a n d E x cl usi o n 
Crit e ri a  
I ncl usi o n Crit e ri a 
1.  Pati e nt c o m pl ete d t h e d o u ble -bli n d p eri o d i n t h e I E D A T -0 2 -2 0 1 5 trial a n d  
m ust h a v e c o m pl et e d t h e fi n al ( Visit 1 5/ M o nt h 1 2) effi c ac y ass ess me nts of 
I E D A T-0 2 -2 0 1 5  or dis c o nti n u e d t h e st u d y d uri n g t h e C O VI D -1 9 p a n de mic. 
2.  Pati e nt t ol er ate d t h e st u d y me di c ati o n,  wit h o ut a n y e vi d e nc e of ster oi d 
a d v erse e v e nts, or tr e at me nt -r el at e d s e vere/ s eri o us a d v erse e ve nts. 
3.  B o d y wei g ht > 1 5 k g.  
4.  T h e p ati e nt a n d his/ h er p ar e nt/ care gi ver (if b el o w t h e a ge of c o ns e nt), or a 
l e gal r e pr ese nt ati v e, h as pr o vi d e d writte n i nf or me d c o nse nt t o p arti ci pate. If 
c o ns e nt is pr o vi de d s ol el y b y t h e c ar e gi v er i n a c c or da n ce wit h l ocal 
r e g ul ati o ns, t h e p ati e nt m ust pr o vi de asse nt t o p arti ci pat e i n t h e st u d y.  
5.  Pati e nt d o es n ot pr es e nt s afet y c o ntr ai n dic ati o n f or c o nti n uati o n of tr e at me nt , 
as d et er mi n e d b y t h e Pri nci p al I n v esti gat or ( PI) a c c or di n g t o t h e pr o ce d ures 
d es cri be d b el o w.  
 
Pr o c e d ur e f o r s el e cti n g p ati e nts f o r f urt her t r e at me nt  i n I E D A T-0 3 -2 0 1 8  
•  
T h e  Pri n ci p al  I n v esti gat or will as k all p ati e nts w h o 
me et t h e a b o ve 
r e q uir e me nts, a n d d et er mi ne th eir i nt er est i n c o nti n ui n g t o r e c ei v e tr e at me nt 
wit h t h e st u d y me di cati o n i n a n e w pr ot oc ol. T h e Pri n ci p al I n v esti gat or will 
t h e n d et er mi ne t h e eli gi bilit y of t h e p ati e nts o n t h e b asis of his/ h er cli nical 
j u d ge me nt of p ati e nts’ st at us a n d t h eir s af et y. 
E x cl usi o n Crit e ri a 
Ge n er al  
1.  Fe mal es t h at ar e  
a. pr e g n a nt, or ar e br east -f ee di n g (f or E U c o u ntries o nl y);  
b.  of c hil d b eari n g p ot e nti al, pr e g n a nt, or ar e br e ast -f ee di n g (f or U S 
a n d Rest of W orl d c o u ntri es).  
Fe m al es of c hil d be ari n g p ot e nti al usi n g a d e q u ate birt h c o ntr ol, as 
d et er mi ne d b y t h eir He alt h C ar e Pr o vi der, will b e eli gi bl e.  
2.  A dis a bilit y t h at ma y pr e v e nt t h e p ati e nt fr o m c o m pl eti n g all st u d y 
r e q uir e me nts. 
3.  C urr e nt p arti ci pati o n i n a cli ni cal st u d y wit h  a n ot her i n v esti gati o n al dr u g.  
Me di c al Hist ory a n d C urre nt St at us  
4.  C D 4 + l y m p h o c yt es c o u nt < 4 0 0/ m m 3 (f or p ati e nts 6 y e ars of a ge) or 
< 1 5 0/ m m 3 (f or p ati e nts > 6 y e ars). I n pr es e n ce of or al i nf e cti o ns, li k e oral 
c a n di di asis, d o c u me nte d at t h e s cr ee ni n g or r e c urr e nt as p er me di cal hist or y 
d o c u me nt ati o n, t h e li mit i n cre as es t o  < 2 0 0/ m m 3 (f or p atie nts > 6 y e ars).  
5.  C urr e nt n e o pl astic dise ase.  
6.  S e v er e i m p air me nt of t h e i m m u n ol o gic al s yst e m.  
7.  Se v er e or u nsta bl e p ul mo nar y disease.  
8.  U n c o ntr olle d di a b et es.  
P ati e nts wit h di a betes t h at h as b ee n st a bilize d (i.e. n o h y p o gl yce mic or 
h y p er gl yc e mi c e pis o d es i n t h e p ast 3 m o nt hs) will b e eli gi ble.   
9.  A n y ot h er s e v er e, u nst a bl e, or s eri o us dise as e or c o n diti o n t h at i n t he 
I n v esti gat or’s o pi ni o n w o ul d p ut t h e p ati e nt at ris k f or i m mi n e nt lif e-
t hr e at e ni n g m or bi dit y, n e e d f or h os pit ali zati o n, or m ort alit y.  
1 0. Eli gi bilit y of p ati e nts wit h a b n or mal l a b or at or y t est v al ues will b e d et er mi ne d 
b y t h e I n v esti gat or.  
1 1. C o nfir me d h e m o gl o bi n o pat hi es, e. g. h e m o gl o bi n C dis e as e, si c kl e c ell 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4  of 1 3 2  
 
a n e mi a, or t h alass e mi a.  
1 2. M o d er ate or s e vere r e nal a n d/ or h e pati c i m p air me nt.   
1 3. Pati e nts w h o e x peri e n ce d m o derate/ s e v er e st er oi d si d e e ff ects, or m o derate/ 
s e v er e a d v ers e e v e nts ass o ci at e d wit h  t h e st u d y me di c ati o n a d mi nist ere d i n 
t h e I E D A T-0 2 st u d y.  
Pri or/ C o n c o mit a nt Me dic ati o n  
1 4. Re q uir es tr e at me nt wit h a n oral or p are nteral st er oi d. Tr e at me nt wit h i n h ale d 
or i ntr a n as al st er oi ds f or ast h m a or all er gi es, as well as us e of t o pic al 
st er oi ds will b e p er mitt e d.  
1 5. Re q uir es a n y  ot her  c o nc o mit a nt me di cati o n pr o hi bite d b y t h e pr ot oc ol.  
1 6. Us e of a n y dr u g t h at is a str o n g i n d uc er/i n hi bit or of C Y P 3 A 4.  
 
Sc he d ul e of Visits a n d 
Ass ess me nts: B as eli ne  
visit  (Visit 1 ) 
Fi n al e v al u ati o ns f or I E D A T -0 2 -2 0 1 5 st u d y ( Visit 1 5/ M o nt h 1 2) will s er ve as 
b as eli ne e val u ati o ns f or p atie nts c o nti n ui n g i n I E D A T -0 3 -2 0 1 8 st u d y.  
Pati e nts pr o vi di n g i nf or me d c o nse nt or ass e nt a n d  me eti n g t h e eli gi bilit y criteria 
will r e c ei v e st u d y tr eat me nt pr e pare d a n d a d mi nist er e d as f oll o ws: 
•  
Vit al si g ns  
•  
(s e e Se cti o n 1 1. 5 ),  
 
. 
•  
 
  
•  
A d diti o n of t h e assi g n e d st u d y me di cati o n ( D S P) t o t h e E D S pr o c ess 
•  
 
 
 
 
  
 
 
 
  
 
 
  
 
 
 
 
  
 
 
 
 
C CI
C CI
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5  of 1 3 2  
 
 
 
Bef or e t h e E D S -E P i nf usi o n, p ati e nts ( w o me n of c hil d be ari n g p ot e nti al) must 
u n d er g o a uri n e pr e g n a nc y t est. All p ati e nts s h o ul d u n d er g o ass ess me nt of pri or 
a n d c o n c o mita nt me di cati o n a n d A Es.  
Aft er c o m pl eti o n of t h e I V i nf usi o n of t h e st u d y tr e at me nt , t h e f oll o wi n g 
ass ess me nts will b e p erf or me d o n Da y 1:  
•  
Vit al si g ns  
•  
P h ysi c al e xa mi n ati o n  
•  
Ass ess me nt of A Es  
• 
Ass ess me nt of c o nc o mit a nt me di cati o ns  
A p pli c a bl e o nl y f or p ati e nts w h i c h will b e e nr oll e d wit h o ut c o m pl eti n g t he 
A T Te S T tri al (i.e. w h o dis c o nti n u e d t h e St u d y I E D A T -0 2 -2 0 1 5 d uri n g t he 
C O VI D -1 9 p a n d e mi c ) a n d w hi c h ma y  n ot h a ve fi nal e v al u ati o ns f or I E D A T -0 2 -
2 0 1 5 st u d y ( Visit 1 5/ M o nt h 1 2)  
Aft er pr o vi di n g  t h e i nf or me d c o ns e nt or ass e nt, as a p plic a bl e, p ati e nts will e nter 
t h e s cr e e ni n g p h ase. T h e s cr e e ni n g p h ase will l ast at ma xi m u m 3 0 d a ys f or t h ose 
p ati e nts w h o ar e i n tr e at me nts wit h ot h er c orti c oster oi d c o m p o u n ds ( was h o ut 
fr o m pr e vi o us tr eat me nt), w hil e f or ot h er p ati e nts t he s cr e e ni n g p h as e will 
c oi n ci de wit h t h e s cr e e ni n g visit ( 1 d a y l o n g , pr o vi d e d t h at all t h e r e q uire d 
l a b or at or y r e p orts ar e a v aila ble a n d r e vi e wed b ef or e t h e eli gi bilit y c o nfir mati o n 
at t h e b as eli n e). As s o o n as t h e eli gi bilit y is c o nfir me d, t h e p ati e nts c a n u n der go 
t h e b as eli n e visit as d escri be d at t h e b e gi n ni n g of t his s e cti o n. 
T h e f oll o wi n g s cre e ni n g e v al uati o ns will b e c o n d u ct e d:  
•  
Me di c al hist or y a n d d e m o gr a p hi cs  
•  
P h ysi c al e xa mi n ati o n  
•  
Vit al si g ns (i n cl u di n g h ei g ht a n d wei g ht i n tri pli cat e)  
•  
Ne ur ol o gi cal e x a mi nati o n  
•  
Ta n n er st a gi n g of t h e br e asts i n pr e -me narc h al f e mal es a n d of t he 
s cr ot u m i n mal es w h o h a v e n ot c o m pl et e d p u b ert y. P ost -me narc hal 
f e mal es a n d mal es w h o h a v e c o m pl et e d p u b ert y will b e e x cl u de d fr o m 
t his gr o wt h a n al ysis. 
•  
I C A R S ( a d mi nistere d b y t h e q u alifi e d site-s pe cifi c r at er).  
•  
C GI -S  
•  
1 2 -l e a d st a n dar d El e ctr o car di o gr a m ( E C G)  
•  
R o uti n e l a b orat or y t ests , o n t h e di v erte d bl o o d s a m pl e (s ee Se cti o n 1 1.5 ) 
•  
S p e ci al l a b orat or y t ests: H b A 1 c, C D 4 + l y m p h o c yt es c o u nt,  a n d  C R P ,, 
o n t h e di v erte d bl o o d s a m pl e (s ee Se cti o n 1 1. 5 ) 
•  
Ser u m pr e g n a n c y t est ( w o me n of c hil d be ari n g p ot e nti al) , o n t h e di verte d 
bl o o d s a m pl e (s e e Se cti o n 1 1. 5 ) 
•  
B M D  
•  
C S S R S  
•  
E Q -5 D -5 L   
•  
Bl o o d c oll ecte d t o ass ess R B C os m oti c r esist a n ce (i n s el ect e d c e nt ers)  
•  
Pl as ma c ortis ol –  s a m pl e t o b e c oll e cte d b ef or e 8: 0 0 A M. If t h e b asal 
c ortis ol l e v el is wit hi n t h e r ef er e nce n or mal r a n ge, t h e p ati e nt c a n be 
e nr oll e d i n t h e st u d y. If t h e 8: 0 0 A M c ortis ol l e v el  is b el o w 3 -5  µ g/ d L 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6  of 1 3 2  
 
( d e p e n di n g o n ass a y) r e gar dl ess of s y m pt o ms, or t h e p ati e nt e x hi bits 
si g ns or s y m pt o ms of a dr e nal i ns uffi ci e nc y (s e e A p p e n di x 1 2 ) a n d has a 
c ortis ol < 1 0 µ g/ d L, t h e p ati e nt will r e c ei v e a hi g h d os e A C T H 
sti m ul ati o n t est, r e gar dl ess of wei g ht, wit hi n 2 4 h o urs. If t h e A C T H 
sti m ul ati o n t est is n or mal, t h e p atie nt c a n b e e nr oll e d after t h e effects of 
t h e A C T H h a v e dissi pat e d ( e. g., 3 0 da ys aft er A C T H a d mi nistere d).  If 
t h e p ati e nt f ails t h e A C T H sti m ul ati o n t est t h e y will b e e x cl u d e d fr o m 
t h e st u d y a n d r ef err e d t o a p e di atric e n d o cri n ol o gist, 
wit h a 
r e c o m me n d ati o n t o pr escri be str ess d os e st er oi ds.  
•  
A ss ess me nt of pri or a n d c o n c o mit a nt me dic ati o ns  
•  
Ass ess me nt of A Es  
If a n y a b n or mal l a b or at or y t est r es ults, vit al si g n me as ure me nts, or E C G fi n di n gs 
of cli ni c al si g nifi ca nc e ar e n ot e d at t h e s cr e e ni n g visit, t h es e m ust b e r e p eate d 
d uri n g t h e 3 0 -da y s cree ni n g p eri o d a n d t h e r es ults ma de a v ail a b l e pri or t o ma ki n g 
t h e fi n al d e cisi o n o n a p ati e nt’s eli gi bilit y f or t h e st u d y at Bas eli n e. A d v erse 
e v e nts, r e p ort e d b y t h e p ati e nt or o bs er ve d b y t h e i n v esti gat or, a n d t h e us e of 
c o n c o mit a nt me dic ati o n will b e r e c or de d fr o m t h e ti me of si g ni n g of i nf or me d  
c o ns e nt t hr o u g h t h e e n d of t h e st u d y.  
Sc he d ul e of Visits a n d 
Ass ess me nts: M o nt hs 1 -5  
a n d 7 - 1 1  
At M o nt hs 1 - 5  a n d 7 - 1 1 , t h e f oll o wi n g ass ess me nts will b e p erf or me d:  
•  
Vit al si g ns  
•  
La b or at or y t ests: s er u m cr e ati ni ne, o n t h e di v ert e d bl o o d s a m pl e (see 
Se cti o n 1 1. 5 ) 
•  
R o uti n e l a b orat or y t ests , o n t h e di v erte d bl o o d s a m pl e (s ee Se cti o n 1 1.5 ) 
•  
Uri n e pr e g n a nc y t est will b e p erf or me d b ef or e e v er y i nf usi o n (f or 
w o me n of c hil d beari n g p ot e nti al)  
•  
C -S S R S  
•  
Ass ess me nt of pri or a n d c o n c o mit a nt me dic ati o n  
•  
Ass ess me nt of A Es  
•  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
.  
•  
St u d y t r e at me nt a d mi nist r ati o n b y I V i nf usi o n, wit hi n 3 0 mi n after 
t he E D S pr o c ess h as be e n c o m pl et e d.  
•  
 
 
 
  
 
 
 
 
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7  of 1 3 2  
 
 
 
•  
Aft er c o m pl eti o n of t h e I V i nf usi o n of t h e st u d y tr e at me nt t h e f oll o wi n g 
ass ess me nts will b e p erf or me d : 
o  
P h ysi c al e x a mi nati o n a n d vital si g ns 1 -2 hr aft er t h e e n d of 
i nf usi o n; 
o  
Ass ess me nt of A Es a n d c o nc o mit a nt me di cati o ns . 
Sc he d ul e of Visits a n d 
Ass ess me nts: M o nt hs 6  
a n d 1 2  
At M o nt hs 6  a n d 1 2 t h e f oll o wi n g ass ess me nts will b e p erf or me d b ef or e tr eat me nt 
a d mi nistr ati o n ( u nless s p ecifie d ot her wise):  
•  
P h ysi c al e xa mi n ati o n 
•  
Vit al si g ns  
•  
Ne ur ol o gi cal e x a mi nati o ns  
•  
I C A R S  
•  
C GI -S a n d C GI -C  
•  
E Q -5 D -5 L   
•  
C -S S R S  
•  
B M D  
•  
1 2 -l e a d st a n dar d E C G 
•  
R o uti n e l a b orat or y t ests , o n t h e di v erte d bl o o d s a m pl e (s ee Se cti o n 1 1.5 ) 
•  
S p e ci al l a b orat or y t ests: H b A 1 c, C D 4 + l y m p h o c yt es c o u nt,  a n d  C R P ,, 
o n t h e di v erte d bl o o d s a m pl e (s ee Se cti o n 1 1. 5 ) 
•  
Ser u m pr e g n a n c y t est ( w o me n of c hil d be ari n g p ot e nti al) , o n t h e di verte d 
bl o o d s a m pl e (s e e Se cti o n 1 1. 5 ) 
•  
Uri n e pr e g n a nc y t est will b e p erf or m e d b ef ore e v er y i nf usi o n f or w o me n 
of c hil d b eari n g p ot e nti al.  
•  
Ass ess me nt of p h ysic al d e v el o p me nt, s e x ual mat ur ati o n, a n d t h e effect 
of tr e at me nt wit h d e xa met has o n e o n t h es e as p ects. Ta n n er st a gi n g of t he 
br e asts i n pr e -me narc hal f e males a n d of t h e s cr ot u m i n mal es w h o ha ve 
n ot c o m pl ete d p u b ert y, will b e p erf or me d at M o nt hs 6 a n d 1 2. P ost -
me n ar c hal f e mal es a n d mal es w h o h a v e c o m pl et e d p u b ert y will be 
e x cl u de d fr o m t his gr o wt h a n al ysis.   
•  
Ass ess me nt of c o nc o mit a nt me di cati o ns  
•  
Ass ess me nt of A Es  
•  
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
•  
St u d y t r e at me nt a d mi nist r ati o n b y I V i nf usi o n, wit hi n 3 0 mi n after 
t he E D S pr o c ess h as be e n c o m pl et e d.  
•  
 
 
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 8  of 1 3 2  
 
 
  
 
 
 
 
 
 
•  
Aft er c o m pl eti o n of t h e I V i nf usi o n of t h e st u d y tr e at me nt t h e f oll o wi n g 
ass ess me nts will b e p erf or me d:  
o  
P h ysi c al e xa mi n ati o n a n d vit al si g ns 1 -2 hr aft er i nf usi o n ; 
o  
A ss ess me nt of c o nc o mit a nt me di cati o ns ; 
o  
Ass ess me nt of A Es . 
T h e s c h e d ule of visits  a n d  ass ess me nts f or t h e first 1 2 m o nt hs - as d es cri be d 
a b o v e -  will b e r e pli c ate d f or t h e s e c o n d y e ar o n war ds , if p ati e nts c o nti n ue 
tr e at me nt f or m ore t h a n 1 2 m o nt hs. 
S af et y F o ll o w-u p Visit  
All p ati e nts w h o dis c o nti n ue will b e r e q uire d t o r et ur n f or a Saf et y F oll o w -u p 
Visit a p pr o xi mat el y 6 0 d a ys  ( ± 7 d a ys) aft er t h eir l ast i nf usi o n. At t his visit,  
pl as ma c ortis ol, pr e g n a nc y st at us (f or w o me n of c hil d be ari n g p ot e nti al ), vital 
si g ns will b e ass ess e d, as well as  t h e o c c urre nc e of a n y A Es or Seri o us A Es 
( S A Es) r e p orte d b y t h e p ati e nt/ care gi ver or o bs er ve d b y t h e I n v esti gat or si nc e t he 
pr e vi o us visit .  
I n v esti g ati o n al Me di ci n al 
Pr o d uct(s): d os e, m o de of 
a d mi nist r ati o n, a n d  
d osi n g s c he d ul e  
T h e st u d y tr e at me nt c o nsists of a  
 d e x a met has o ne 
s o di u m p h os p h at e ( D S P) a d mi nist er e d vi a e x vi v o e nc a ps ul ati o n i nt o a ut ol o go us 
er yt hr oc ytes ( E D S) t h at ar e i nf us e d i nt o t h e p atie nt wit h A T .  T h e d os e  of E D S -
E P  h as b e e n s el e ct e d t o  all o w c oll ect i o n of l o n g-ter m s af e y d at a o n a hi g h d ose . 
H o we v er , if t his d os e is ass ociate d wit h si g nific a nt  t ol er a bilit y iss ues t hat d o n ot 
r es ol v e, t h e n t h e p ati e nt s h o ul d b e disc o nti n ue d fr o m t h e st u d y.  
A ut ol o g o us w h o l e bl o o d  
 t o b e us e d f or t h e E D S pr o c ess will be 
c oll e cte d a c c or di n g t o t h e i nstr ucti o ns pr o vi de d  i n Se cti o n 1 1. 5 . Det ails of t hese 
pr o c e d ures ar e d es cri be d i n a s e p ar ate d o c u me nt e ntitle d “ St u d y Pr o c e d ures o n 
St erilit y Testi n g  for St u d y I E D A T-0 3 -2 0 1 8 ( O L E -I E D A T)”, w hi c h will be 
pr o vi de d t o e a c h sit e ( s e e A p p e n di x 9 ). T h e st u d y me di c ati o n will b e pr e pare d 
wit h a
 
 
 
St u d y tr e at me nt will b e a d mi nistere d b y m o nt hl y I V i nf usi o n. 
 
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 9  of 1 3 2  
 
Pl a n ne d Tr e at me nt 
D ur ati o n pe r P ati e nt  
T h e o p e n -la bel tr e at me nt p eri o d is pl a n n e d f or 1 2 m o nt hs, b ut ma y b e e xt e n de d 
f urt h er a n d c o nti n u e u ntil p ati e nts e v e nt u all y wit h dra w c o nse nt or t h e I n v esti gat or 
d e ci d es t o dis c o nti n u e tr e at me nt b ase d o n a ris k/ b e n efit assess me nt.  
St atisti c al Met h o ds   
Des cri pti ve st atistics ( n, me a n, st a n dar d d e viati o n [ S D], me di a n, mi ni mu m, a n d 
ma xi m u m) will b e pr o vi d e d f or all c o nti n u o us effic ac y me as ures f or a ct u al 
v al u es a n d c h a n ges fr o m b as eli n e of St u d y I E D A T -0 3 -2 0 1 8  at e a c h ti me -p oi nt.  
F or c at e g ori cal v aria bl es,  t h e n u m ber a n d p erce nt a ge of p ati e nts i n e a c h 
c at e g or y will b e pr ese nt e d at e a c h ti me -p oi nt.  T h e a n al ysis of l o n g -t er m efficac y 
of E D S -E P is a n e x pl orat or y o bj ecti ve of t his e xt e nsi o n st u d y, a n d will b e b ase d 
o n t h e r es ults f or t h e “ M o difi e d ” I nt er nati o na l C o o perati ve At a xi a Rati n g Sc al e 
( mI C A R S), a n d t h e Cli ni c al Gl o bal I m pr essi o n of s e verit y a n d c h a n ge ( C GI-
S/ C) . T h e me a n ( S D) c h a n ge fr o m b as eli ne at e a c h ti me-p oi nt will b e e v al uat e d 
f or t h e mI C A R S a n d t h e C GI-S.  F or t h e C GI -C h a n ge, t h e pr o p orti o n [ n( %) ] of 
p ati e nts r at e d as i m pr o v e d, as well as t h ose s h o wi n g n o c h a n ge or w orse ni n g, at 
e a c h ti me -p oi nt will b e c al c ul at e d.  A d diti o nal a nal yses will b e p erf or me d t o 
d et er mi ne t h e c h a n ge i n e a c h of t h e effi c ac y me as ur es c o m par e d t o t h e b as eli n e 
of t h e I E D A T -0 2 -2 0 1 5 st u d y, c o m pari n g p ati e nts w h o wer e tr e at e d wit h E D S -
E P t hr o u g h o ut t h e d o u ble -bli n d a n d o p e n -la bel tr e at me nt p eri o ds vs. t h os e w h o 
r e c ei v e d pl ace b o f or v ar yi n g p eri o ds i n St u d y I E D A T-0 2 -2 0 1 5, b ef ore b ei n g 
s wit c h e d t o t h e a cti ve tr e at me nt. As a s e c o n d ar y o bje cti v e, si mil ar d escri pti v e 
a n al ys es will b e p erf or me d t o e v al uate t h e l o n g-ter m eff ects of E D S-E P o n 
h e alt h -r el at e d Q u alit y of Lif e ( Q o L), as ass ess e d b y t h e E Q-5 D -5 L s c al e.  
Des cri pti ve  st atisti cal a n al ys es  of c ha n ge s fr o m b aseli ne will b e p erf or m e d f or all 
s af et y p ar a met ers. A b n or mal a n d cli ni call y n ot a ble v al ues will b e i d e ntifi e d a n d 
list e d f or e a c h p ar a meter, as a p pr o pri at e. 
A n al ysis P o p ul ati o ns   
T h e f oll o wi n g a n al ysis s ets will b e us e d:   
 
1) Effi c a c y P o p ul ati o n ( E P) : All p ati e nts w h o e nt er st u d y I E D A T-0 3, h a ve a 
b as eli ne effi cac y ass ess me nt i n st u d y I E D A T -0 3, a n d w h o r e c ei v e d at l e ast o ne 
d os e of st u d y me di c ati o n a n d h a d at l e ast o n e p ost -b aseli ne effi ca c y ass ess me nt 
of t h e pri mar y effi cac y v aria bl e i n t his e xt e nsi o n  st u d y.   
2) S af et y P o p ul ati o n ( S P) : All s u bj e cts w h o r e c ei v e a d os e of st u d y me di cati o n, 
a n d h a v e at l e ast o n e p ost -d ose s af et y ass ess me nt will b e i n cl u de d i n t h e s afet y 
a n al ys es. 
 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 
A pril 2 0 1 9, Fi n al;  Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 0  of 1 3 2  
 
 
Sc he d ule of Visits a n d Assess me nts : 1st ye ar of o pe n -l a bel e xte nsi o n tre at me nt (Visit 1 t o Visit 1 3 t o be re plic ate d f or t he sec o n d ye ar 
o n w ar ds)  
 
Visit ( V )  Sc r e e ni n g 
P h ase *  
B aseli ne/
V 1 ( &)  
 
V 2   
V 3   
V 4   
V 5   
V 6   
V 7   
V 8   
V 9   
V 1 0   
V 1 1   
V 1 2   
V 1 3  
S af et y 
f oll o w u p 
visits (e) 
St u d y D a y o r M o nt h ( D/ M) ( i)  D -3 0 t o -1  
D 0  
M o nt h  
1  
M o nt h  
2  
M o nt h  
3  
M o nt h  
4  
M o nt h  
5  
M o nt h  
6  
M o nt h  
7  
M o nt h  
8  
M o nt h  
9  
M o nt h  
1 0  
M o nt h  
1 1  
M o nt h  
1 2  (l) 
~ 6 0  d a ys 
afte r l ast 
i nf usi o n 
Pr o c e d ur e  ( §) 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
I nf or m e d C o nse nt Si g n at ure 
X   
X ( pre)   
  
  
  
  
  
  
  
  
  
  
  
 
 
I n cl usi o n/ E x cl usi o n Crit eria  
X   
X ( pre)   
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
E D S -E P I nf usi o n ( h)  
 
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
1 2   
1 3   
 
C ult ure -b a se d st erilit y t est ( j) 
  
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
 
Ne ur ol o gic al E x a mi n ati o n  
X  
  
  
  
  
  
  
X ( pre)  
  
  
  
  
  
X ( pre)   
 
P h ysic al E x a mi n ati o n ( k ) 
X  
X ( p ost)   
X( p ost)   
X( p ost)   
X( p ost)   
X ( p ost)   
X( p ost)  
X ( pre; 
p ost)  
X( p ost)   
X( p ost)   
X( p ost)  
X( p ost)   
X( p ost)   
X ( pre; 
p ost)  
 
Ta n n er Sc ale  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
Vit al Si g ns ( h)  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
E C G  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
R o uti n e La b orat or y Tests (a)  
X  
  
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
 
Ser u m cre ati ni n e ( g)  
 
  
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
  
X ( pre)   
X ( pre)  
X ( pre)   
X ( pre)   
X ( pre)   
 
 
B o n e Mi n eral De nsit y  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
Ser u m( $)/ Uri n e( *) Pre g n a n c y Test 
( d) 
X  ( $, *; pre) 
X( *, pre)   
X( *; pre)   
X( *; pre)   
X( *; pre)   
X( *; pre)   
X( *; pre)   X( $, *; pre)   X( *; pre)   
X( *; pre)   
X( *; pre)  
X( *; pre)   
X( *; pre)   
X( $, *; pre)   
X( $)  
I C A R S  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
C GI -C  
 
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
C GI -S  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
Q u alit y of Lif e ( E Q -5 D -5 L)  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
C -S S R S  
X  
  
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)  
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X  
H e m ol ysis p a n el ( m ) 
  
X ( pre)   
  
  
  
X ( pre)   
  
  
  
X ( pre)   
  
  
  
  
X ( pre)  
S p e cial La b orat or y Tests ( b; c)  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
E D S e n d pr o d u ct sa m ple (f)  
  
X ( p ost)   
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Pri or/ C o n c o mit a nt Tre at m e nts  
T hr o u g h o ut t h e d urati o n of t h e st u d y  
A d v erse E v e nts  
T hr o u g h o ut t h e d urati o n of t h e st u d y  
 
 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 
A pril 2 0 1 9, Fi n al;  Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 1  of 1 3 2  
 
*      A p plic a ble o nl y f or p atie nts w h o will b e e nr olle d wit h o ut c o m pleti n g t h e A T Te S T trial (i. e. w hic h w ere  dis c o nti n u e d fr o m t h e St u d y I E D A T-0 2 -2 0 1 5 d uri n g t h e C O VI D -
1 9 p a n d e mic ) a n d w hic h m a y  n ot h a v e fi n al e v al u ati o ns f or I E D A T -0 2 -2 0 1 5 st u d y ( Visit 1 5/ M o nt h 1 2) . Patie nts si g ni n g t h e i nf or m e d c o nse nt f or m or ass e nt, as a p plic a ble, 
at t his visit, d o n ot n e e d t o re c o ns e nt at b as eli n e visit.  
&)  T h e f oll o wi n g “ b as eli n e ” ass ess m e nts f or  I E D A T-0 3 -2 0 1 8  will b e d o n e as p art of t h e fi n al M o nt h 1 2 e v al u ati o n i n St u d y I E D A T -0 2 -2 0 1 5: p h ysic al/ n e ur ol o gical 
e x a mi n ati o n ; 1 2 -le a d sta n d ar d E C G; la b orat or y e v al uati o ns  [i n cl u di n g h e mat ol o g y , cli nic al c he mistr y, uri n al ysis , s er u m pre g n a nc y test ( w o m e n of c hil d be ari n g p ote ntial); 
sp e cial la b orat or y tests: H b A 1 c, C D 4 + l y m p h oc ytes c o u nt  a n d C R P ]; Ta n n er  s c ale; I C A R S; C GI-S; C GI -C ; E Q -5 D -5 L ; C-S S R S; B M D; Re vie w of A Es a n d c o n c o mita nt 
m e dic ati o ns.  
 
a) 
R o uti n e la b orat or y ass ess m e nts t o i n cl u d e c o m plete h e m at ol o g y, bi o c he mistr y, a n d uri nal ysis.  
b) 
S p e cial la b orat or y tests i n cl u d e H b A 1c, C D 4 + l y m p h o c ytes c o u nt  a n d  C R P .   
c) 
Bl o o d s a m ple t o b e c olle cte d b ef ore 8: 0 0 A M f or m e as ure m e nt of plas ma c ortis ol at t h e f oll o wi n g ti m es: ( 1 ) w h e n p atie nts are s y m pt o matic, a n d (2 ) w h e n p atie nts are at 
m ost ris k f or a dre n al i ns ufficie nc y a n d a dre n al crisis, s u c h as f oll o wi n g dis c o nti n u ati o n or i nterr u pti o ns of d e x a m et h as o n e d osi n g (i. e., l o a di n g f ail ures a n d f oll o win g 
dis c o nti n u ati o n of t h e st u d y dr u g) .   
d) 
F or w o m e n of c hil d b e ari n g p ote ntial o nl y.  T h e test res ults m ust b e n e gati v e at b as eli n e ( uri n e) f or t h e p atie nt t o b e eli gi ble f or t h e st u d y. Uri n e pre g n a n c y test will be 
p erf or m e d b ef ore e v er y i nf usi o n , w hile s er u m pre g n a n c y test will b e p erf or me d at M o nt h 6, 12 a n d s afet y f oll o w u p visit .  
e) 
A Saf et y F oll o w -u p ass ess m e nt will b e p erf or m e d a p pr o xi m atel y 6 0 d a ys ( ± 7 d a ys) after  t h e fi n al i nf usi o n; at t his visit, plas m a c ortis ol, pre g n a n c y stat us (f or w o m e n of 
c hil d b e ari n g p ote ntial), vital si g ns will b e ass ess e d, a s w ell as t h e o c c urre nc e of a n y A Es or Seri o us A Es si n c e t h e fi n al e v al u ati o n will b e re p orte d.   
f)  U p o n c o m pleti o n of t h e E D S pr o c ess , t h e re m ai ni n g s a m ple i n t h e s atellite s a m ple b a gor, if t his is n ot a v aila ble, a s a m ple c olle cte d fr o m a n ot h er E D S -E P s a m pl i n g p oi nt, 
will b e us e d f or d eter mi n ati o n of D S P c o nte nt a n d C B C .  
g)  
Bl o o d s a m ple f or s er u m cre ati ni n e m e as ure m e nt t o b e ta k e n b ef ore i nf usi o n.  
h) 
Vital si g ns  t o b e p erf or m e d at e a c h visit pre a n d p ost i nf usi o n (at s af et y f oll o w u p visit, o nl y o n c e). Vital si g n s t o i n cl u d e h ei g ht a n d w ei g ht m e as ure m e nts i n tri plic ate at 
s cre e ni n g, b as eli n e, M o nt h 6 a n d 1 2 .  
i)  
T h e m o nt hl y i nf usi o ns s h o ul d b e p erf or me d e v er y 2 1 -2 8 d a ys. A wi n d o w of + 1 0 d a ys will b e p er mitte d o n e a c h of t h e s c h e d ule d m o nt hl y visits. T h eref ore, n o E D S -E P 
i nf usi o n s h o ul d b e p erf or m e d less t h a n 2 1 d a ys or m ore t h a n 3 8 d a ys after t h e pre vi o us i nf usi o n. T h e wi n d o w b et w ee n a n i nf usi o n a n d t h e s u bs e q u e nt o n e s h o ul d b e ke pt 
as re g ular as p ossi ble t hr o u g h o ut t h e st u d y, a v oi di n g fl u ct uati o ns i n a d mi nistrati o n wi n d o ws. T h e d ate of a n i nf usi o n is n ot b o u n d t o t h e d ate of t h e i nitial tre at m e nt b ut to 
t h e d ate of t h e pre vi o us I M P a d mi nistrati o n.  
j)  
1 m L bl o o d c olle cte d, after bl o o d di v ersi o n, f or a er o bic c ult ure, b ef ore E D S pr o c ess (s e e  “ St u d y Pr o c e d ures o n Sterilit y Testi n g  f or St u d y I E D A T-0 3 -2 0 1 8 ( O L E -I E D A T)”; 
A p p e n di x 9 ). M ore o v er, a s a m ple of t h e E D S-E P (a p pr o xi m atel y 1 ml p er i n o c ul u m f or a t otal of 2 m L) will b e c olle cte d fr o m s atellite s a m ple b a g , t o p erf or m a c ult ure-
b as e d sterili t y test. A 1 m L sterile s a m ple of t h e E D S -E P will b est ore d u n d er refri gerati o n as a “ Rete nti o n Sa m ple ”.  
k) 
At M o nt h 1 -5 a n d 7 -1 1 visits, p h ysic al e x a mi nati o n a n d vital si g ns 1 -2 hr after t h e e n d of i nf usi o n. At M o nt h 6 a n d 1 2 visits, t h e p h ysic al e x a mi n ati o n will b e p erf or me d 
pre -d os e as w ell.  
l)  
M o nt h 1 2 i nf usi o n, a n d all of t h e ass ociate d pr o c e d ures, w o ul d o nl y b e d o ne i n p atie nts w h o are c o nti n ui n g o p e n la b el tre at m e nt p ast o n e y e ar  
m)  H e m ol ysis p a n el , i n cl u di n g uri n al ysis  
 
( §)   As a res ults of t h e C O VI D -1 9 p a n de mic, te m p orar y a d diti o nal s afet y ass ess m e nts m a y b e re q u este d at s o m e visits. T h es e c h a n ges are d es cri b e d i n A p p e n di x 1 3 . 
 
( pre) Pre E D S-E P i nf usi o n pr o c e d ure  
( p ost) P ost E D S-E P i nf usi o n pr o ce d ure  

P P D
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Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 3  of 1 3 2  
 
Si g n at ure P a ges  ( c o nt’ d) 
 
 
I nvesti g at or 
 
Ce nt er N o. _ _ _ _ _ _ _ _ _ _ _ _  
 
I a gree t o c o n d u ct t h e cli nical trial i n acc or da n ce wit h t his Pr ot oc ol a n d i n c o m plia n ce wit h G o o d Cli nical 
Practice a n d all a p plica ble re g ulat or y re q uire m e nts.  
 
 
 
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I nvesti g at or’s N a me ( Pri nte d) 
Title  
 
 
 
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Si g n at ure  
D ate of Si g n at ure  ( d d / m m / yyyy) 
 
 
 
Cli nic al Rese arc h Or g a niz ati o n  
 
It al y 
 
T h e S p o ns or h as tra nsferre d all res p o nsi bilities f or t h e c o n d u ct of t h e trial t o t h e C R O  or ot h er desi g n at e d 
ve n d ors f or s pecific ser vices .  
 
 
 
P P D

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 4  of 1 3 2  
 
3  
T A B L E O F C O N T E N T S  
 
1   
S Y N O P SI S ................................................................................................................................ 2  
2   
SI G N A T U R E P A G E  ................................................................................................................ 1 2  
3   
T A B L E O F C O N T E N T S .......................................................................................................... 1 4  
4   
A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  .............................................................. 1 7  
5   
TI T L E O F S T U D Y  .................................................................................................................. 2 0  
6   
P R O T O C O L N U M B E R  ........................................................................................................... 2 0  
7   
B A C K G R O U N D A N D S T U D Y R A TI O N A L E  ......................................................................... 2 0  
7. 1   
Bac k gr o u n d Inf or m ati o n  .................................................................................................... 2 0  
7. 1. 1  
) ............................................................................................. 2 0  
7. 1. 2  
N o n -Cli ni c al Tri als wit h E D S  ............................................................................................................. 2 0  
7. 1. 3  
S u m m a r y of H u m a n Cli nic al Tri als wit h E D S ................................................................................. 2 1  
7. 2  
 ..................................................................................... 3 2  
7. 3   
St u d y Rati on ale  ................................................................................................................. 3 3  
8   
S T U D Y O BJ E C TI V E S  ............................................................................................................ 3 9  
9   
I N V E S TI G A TI O N A L P L A N ................................................................................................... 3 9  
9. 1   
St u d y Desi g n ..................................................................................................................... 3 9  
9. 2   
St u d y P o p ulati o n  ............................................................................................................... 3 9  
9. 2. 1  
I ncl usi o n Criteri a .................................................................................................................................. 3 9  
9. 2. 2  
E x cl usi o n Crit eri a  ................................................................................................................................. 4 0  
9. 3   
Pre m at ure Disc o ntin u ati on  ................................................................................................. 4 1  
9. 4   
Rec or d of St u d y Partici pa nts an d Scree nin g Failures ............................................................ 4 1  
1 0  
S T U D Y M E DI C A TI O N ........................................................................................................... 4 2  
1 0. 1  
 .................................................................................. 4 2  
1 0. 1. 1  
 .................................................................................................................. 4 2  
1 0. 1. 2  
 ............................................................................................................................................... 4 2  
1 0. 1. 3  
 .................................................................................................................................................. 4 2  
1 0. 2  
................................................................................................... 4 3  
1 0. 3   
 ............................................................................................................................. 4 4  
1 0. 4  
Acc o u nt a bilit y ................................................................................................................... 4 4  
1 0. 5  
O ver d ose  .......................................................................................................................... 4 4  
1 0. 6  
Occ u pati on al Safet y ........................................................................................................... 4 5  
1 1  
E val u ati ons  an d Pr oce d ures  ...................................................................................................... 4 6  
1 1. 1  
Writt en Inf or m e d C o nsent  .................................................................................................. 4 6  
1 1. 2  
St u d y C o n du ct ................................................................................................................... 4 6  
1 1. 3  
Sc h e d ule of Vis its an d Assess m ents.................................................................................... 4 9  
1 1. 4  
Visit Sc h e dule an d Assess m ents  ......................................................................................... 5 2  
1 1. 4. 1  
B aseli ne visit ( Visit 1/ D a y 0)  ............................................................................................................... 5 2  
1 1. 4. 2  
M o nt hs 1 -5 ( Visits 2 -6) a n d 7 - 1 1 ( Visits 8 -1 2)  ................................................................................. 5 4  
1 1. 4. 3  
M o nt hs 6 ( Visit 7) a n d 1 2 ( Visit 1 3) .................................................................................................... 5 5  
1 1. 4. 4  
S af et y F oll o w -u p Visit ( Visit 1 6)  ......................................................................................................... 5 6  
1 1. 4. 5  
Visit Wi n d o ws  ........................................................................................................................................ 5 6  
1 1. 5  
La b orat or y Sa m ple C ollecti o n  ............................................................................................ 5 6  
1 1. 6  
Meas ure m e nt of De xa m et h as o n e S o di u m P h os p h at e a n d Ot h er A n al yt es i n I nf usi o n Ba g Sa m ple
  
5 7  
1 1. 7  
C o n c o mit a nt Me dicati o ns  .................................................................................................. 5 8  
1 2  
E F FI C A C Y E V A L U A TI O N S ................................................................................................... 6 0  
1 2. 1  
I C A R S.............................................................................................................................. 6 0  
1 2. 1. 1  
Desc ri pti o n of t he I C A R S  .................................................................................................................... 6 0  
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 5  of 1 3 2  
 
1 2. 1. 2  
V ali dit y of I C A R S i n A T P atie nt P o p ul ati o n  ................................................................................... 6 0  
1 2. 1. 3  
St a n d ar di z ati o n of Rati ngs  .................................................................................................................. 6 1  
1 2. 2  
Cli nical Gl o bal I m pressi o n ( C GI -C a n d C GI -S) ................................................................... 6 1  
1 2. 3  
Q u alit y of Life Scale .......................................................................................................... 6 2  
1 2. 4  
Rat er Re q uire m ents an d Traini n g  ....................................................................................... 6 2  
1 2. 5  
Or der of Test Perf or m a n ce  ................................................................................................. 6 3  
1 3  
S A F E T Y E V A L U A TI O N S  ...................................................................................................... 6 4  
1 3. 1  
P h ysical a n d Neur ol o gical E xa mi n ati o ns ............................................................................. 6 4  
1 3. 2  
Vit al Si g ns  ........................................................................................................................ 6 4  
1 3. 3  
Electr ocar di o gra m ( E C G)  .................................................................................................. 6 5  
1 3. 4  
St a n dar d La b orat or y E valu ati ons an d Scree nin g Tests .......................................................... 6 5  
1 3. 5  
S pecial La b orat or y E val u ati o ns  .......................................................................................... 6 7  
1 3. 6  
St erilit y Testin g of E D S -E P  ............................................................................................... 6 7  
1 3. 7  
C ol u m bia Suici de Se verit y Ratin g Scale ( C -S S R S)  .............................................................. 6 8  
1 3. 8  
B o n e Mi n eral Densit y ( B M D)  ............................................................................................ 6 8  
1 3. 9  
Ta n n er St a gin g  .................................................................................................................. 6 8  
1 4  
R E P O R TI N G S A F E T Y I N F O R M A TI O N  ................................................................................. 6 9  
1 4. 1  
A d verse E ve nts  ................................................................................................................. 6 9  
1 4. 1. 1  
Gl oss a r y  .................................................................................................................................................. 6 9  
1 4. 1. 2  
D at a C olle cti o n  ...................................................................................................................................... 7 0  
1 4. 1. 3  
S u bj e ct Foll o w -u p  ................................................................................................................................. 7 2  
1 4. 1. 4  
Re p orti ng Seri o us A d ve rs e Ev e nts ( S A Es)  ....................................................................................... 7 2  
1 4. 2  
Safet y Re p orti n g t o In vesti gat ors, I R Bs/I E Cs, a n d Re gulat or y Aut h orities  ............................ 7 3  
1 4. 3  
Re p orti n g O ver d ose  ........................................................................................................... 7 3  
1 4. 4  
Pre g n a n c y  ......................................................................................................................... 7 3  
1 4. 5  
I n de pe n dent Dat a Safet y M onit orin g B oar d......................................................................... 7 4  
1 5  
S U BJ E C T C O M P L E TI O N A N D DI S C O N TI N U A TI O N  ........................................................... 7 4  
1 5. 1  
Defi niti ons  ........................................................................................................................ 7 4  
1 5. 2  
Pr oce d ures f or Ha n dli n g Wit h dra wals  ................................................................................. 7 4  
1 6  
S T A TI S TI C A L M E T H O D S  ..................................................................................................... 7 6  
1 6. 1  
A n al ysis of Efficac y  .......................................................................................................... 7 6  
1 6. 2  
St atistical Met h o ds  ............................................................................................................ 7 6  
1 6. 2. 1  
S a m pl e Siz e  ............................................................................................................................................ 7 6  
1 6. 2. 2  
B a c k g r o u n d a n d De m o g r a p hic C h a r acte ristics  ............................................................................... 7 6  
1 6. 2. 3  
St u d y Me dic ati o n  .................................................................................................................................. 7 6  
1 6. 2. 4  
C o nc o mit a nt Me dic ati o ns a n d T he r a p y  ............................................................................................ 7 6  
1 6. 2. 5  
S af et y E v al u ati o ns ................................................................................................................................. 7 7  
1 6. 2. 6  
Effic ac y A n al yses ................................................................................................................................... 7 7  
1 7  
E T HI C S  .................................................................................................................................. 7 9  
1 7. 1  
Et hical C o nsi derati ons  ....................................................................................................... 7 9  
1 7. 2  
I E C/IR B A p pr o val ............................................................................................................. 7 9  
1 8  
A D MI NI S T R A TI V E C O N SI D E R A TI O N S  ............................................................................... 8 0  
1 8. 1  
Re g ulat or y Re q uire m e nts: S p o ns or/I n vesti gat or O bli gati ons  ................................................ 8 0  
1 8. 2  
C urric ulu m Vit ae ............................................................................................................... 8 0  
1 8. 3  
I n vesti gat or an d St u d y A d ministrati ve Str u ct ure .................................................................. 8 0  
1 8. 4  
I n vesti gat or’s St at e m e nt..................................................................................................... 8 0  
1 8. 5  
M o nit orin g Pr oce d ures ....................................................................................................... 8 0  
1 8. 5. 1  
St u d y M o nit ori ng  .................................................................................................................................. 8 0  
1 8. 5. 2  
C ase Re po rt F or ms ( C R Fs)  ................................................................................................................. 8 1  
1 8. 5. 3  
A u diti n g/I ns pe cti n g  .............................................................................................................................. 8 1  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 6  of 1 3 2  
 
1 8. 6  
Arc hi vi n g of Rec or ds ......................................................................................................... 8 1  
1 8. 7  
Fi n al Cli nical St u d y Re p ort  ................................................................................................ 8 1  
1 8. 8  
St u d y D oc u m e nt ati on an d Pu blicati on of Res ults  ................................................................. 8 1  
1 8. 9  
Fi n a n cial A gree m ent .......................................................................................................... 8 2  
1 8. 1 0  Ter mi n ati o n of St u d y  ......................................................................................................... 8 2  
1 8. 1 0. 1  St u d y Disc o nti n u ati o n b y t he S p o ns or ............................................................................................... 8 3  
1 8. 1 0. 2  St u d y Disc o nti n u ati o n b y t he I nv esti g at or ........................................................................................ 8 3  
1 8. 1 1  I ns uran ce P olic y ................................................................................................................ 8 3  
1 8. 1 2  Fi n a n cial Discl os ure  .......................................................................................................... 8 3  
1 9  
R E F E R E N C E S  ........................................................................................................................ 8 4  
A P P E N DI C E S  ................................................................................................................................. 8 8  
A p pe n di x 1: Decl ar ati o n of Helsi n ki ........................................................................................... 8 8  
A p pe n di x 2: I C H G C P - I n vesti g at or’s Res p o nsi biliti es  ............................................................. 9 4  
A p pe n di x 3: I n vesti g at or St ate me nt  ..........................................................................................1 0 0  
A p pe n di x 4: Cli nic all y N ot a ble V al ues  ......................................................................................1 0 2  
A p pe n di x 5: Desc ri pti o n of t he Er y De x S yste m ( E D S)  ..............................................................1 0 6  
A p pe n di x 6: S a m ple St u d y S ol uti o n a n d Me di c ati o n L a b els  .....................................................1 1 3  
A p pe n di x 7: E nc a ps ul ati o n Pr oce d ure C hec klist .......................................................................1 1 8  
A p pe n di x 8: Met h o d f or Me as uri n g De x a met h as o ne S o di u m P h os p h ate i n S a m ples T a ke n fr o m 
S atellite S a m ple B a g or a n y ot her E D S -E P S a m pli n g P oi nt .......................................................1 2 4  
A p pe n di x 9: Ase ptic pr oce d ures f or pre ve nti o n of c o nt a mi n ati o n of E D S -E P sterilit y s a m ples  .1 2 5  
A p pe n di x 1 0: 1 4 -d a y sterilit y test usi n g a c ult ure -b ase d met h o d –  S a m pli n g pr oce d ure ............1 2 6  
A p pe n di x 1 1: Acti o n Pl a n i n C ase of P ositi ve P ost -Rel e ase Sterilit y Test Res ults  ......................1 2 8  
A p pe n di x 1 2: Si g ns a n d S y m pt o m ps of A dre n al I ns uffici e nc y ...................................................1 3 0  
A p pe n di x 1 3: Te m p or ar y c h a n ges t o t he Pr ot oc ol i m ple me nte d/t o be i m ple me nte d as a res ult of 
C O VI D -1 9 p a n de mic … … … … … … … … … … … … … … … … … … … … … … … … … .… … … … …. .1 3 2  
 
 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 7  of 1 3 2  
 
4  
A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
 
A C T H  
A dre n oc ortic otr o pic h or m o n e  
A Es  
A d verse E ve nts  
A L T ( S G P T)  
Ala ni n e -a mi n otra nsferase  
A N O V A  
A n al ysis of Varia n ce  
A N C O V A  
A n al ysis of C o varia n ce  
A S T ( S G O T)  
As partic -a mi n otra nsferase  
A T  
At a xia Tel a n giect asia  
A T M  
At a xia Tela n giect asia M ut at e d  
A T P  
A de n osi n e tri p h os p h at e  
A U C  
Area u n der t h e plas m a  dr u g  c o n ce ntrati o n vs. ti m e  c ur ve  
B A R S  
Brief At a xia Rati n g Scale  
B M D  
B o n e mi n eral de nsit y  
B MI  
B o d y Mass I n de x  
B P  
Bl o o d Press ure  
b p m  
Beats per mi n ut e  
B U N  
Bl o o d Urea Nitr o ge n  
C B C  
C o m plet e bl o o d c o u nt  
C D 4 + l y m p h oc yt es   
Cl ust er differe ntial 4 p ositi ve l y m p h oc yt es  
C GI -S / C GI -C  
Cli nical Gl o bal I m pressi o n of Se verit y / C h a n ge 
C F  
C ystic fi br osis  
C ma x  
Ma xi m u m plas m a  dr u g  c o n ce ntrati o n aft er d osi n g  
C N S  
Ce ntral Ner v o us S yst e m  
C O P D  
C hr o nic o bstr u cti ve p ul m o n ar y disease  
C P K  
Creati n e p h os p h o ki n ase  
5 1Cr  
C hr o mi u m -5 1  
C R A  
Cli nical Researc h Ass ociat e  
C R F  
Case Re p ort F or m  
C R O  
C o ntract Researc h Or ga ni zati o n  
C R P  
C -Reacti ve Pr ot ei n  
C -S S R S  
C ol u m bia -S uici de Se verit y Rati n g Scale  
C S R  
Cli nical St u d y  Re p ort  
C V  
C oefficie nt of variati o n  
C Y P 3 A 4  
C yt oc hr o m e P 4 5 0 3 A 4  
D  
Da y  
2, 3 -D P G  
2, 3 -Di p h os p h o gl yceric aci d  
D S P  
De xa m et h as o n e s o di u m p h os p h at e  
E C G  
Electr ocar di o gra m  
E D S  
Er y De x  S yst e m  
E D S -E P  
Er y De x S yst e m e n d pr o d u ct  
EI A  
E n z y m e i m m u n oassa y  
E P  
E val u a ble P o p ulati o n  
E Q -5 D -3 L  
E ur o Q ol 5 D T hree -le vel versi o n 
E Q -5 D -5 L  
E ur o Q ol 5 D Fi v e-le vel versi o n  
E SI -M S  
Electr os pra y m ass s pectr o m etr y  
F A S  
F ull A n al ysis Set  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 8  of 1 3 2  
 
F S I 
First S u bject  I n 
F W E R  
Fa mil y -wise err or rat e  
G 6 P D  
Gl u c ose -6 -p h os p h at e de h y dr o ge n ase  
G C P  
G o o d Cli nical Practice  
G M P  
G o o d Ma n ufact uri n g Practice  
S G O T ( A S T) 
Ser u m Gl ut a mic -O xal o acetic Tra nsa mi n ase  
S G P T ( A L T)  
Ser u m Gl ut a mic -P y r u vic Tra nsa mi n ase 
H b A 1c  
Bl o o d gl yc os ylat e d h ae m o gl o bi n  
Hct  
He m at ocrit  
H D L  
Hi g h de nsit y li p o pr ot ei n  
H b  
He m o gl o bi n  
H b A 1c  
Bl o o d gl yc os ylat e d h e m o gl o bi n  
HI V  
H u m a n I m m u n o deficie n c y Vir us 
H P L C  
Hi g h Perf or m a n ce Li q ui d C hr o m at o gra p h y  
h r 
H o ur  
I B D 
I nfla m m at or y b o wel disease 
I C A R S 
I nt er n ati o nal C o o perati ve At ax ia Rati n g Scale 
I C F 
I nf or m e d C o nse nt F or m 
I C H 
I nt er n ati o nal C o nfere n ce o n Har m o nizati o n  
I C S H 
I nt er n ati o nal C o m mittee f or St a n dar dizati o n i n He m at ol o g y 
I E C 
I n de pe n de nt Et hics C o m mitt ee 
I M P 
I n vesti gati o n Me dici n al Pr o d u ct 
I R B 
I nstit uti o nal Re vie w B oar d 
I S F 
I n vesti gat or Sit e File 
I T T 
I nt e nti o n-t o-Treat  
I V R S 
I nt eracti ve V oice Res p o nse S yst e m  
I W R S 
I nt eracti ve We b Res p o nse S yst e m 
I U 
I nt er n ati o nal U nit 
L D H  
Lact at e de h y dr o ge n ase  
L D L  
L o w de nsit y li p o pr ot ei n  
L O C F  
Last o bser vati o n carrie d f or war d  
L S I 
Last S u bject  I n 
L S L V  
Last S u bject  Last Visit  
M  
M o nt h  
M A O  
M o n oa mi n e o xi dase  
M A R  
Missi n g at ra n d o m  
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 h e m o gl o bi n c o n ce ntrati o n  
M C V  
Mea n c or p usc ular v ol u m e  
µ Ci  
Micr oc uries  
m Ci  
Millic uries  
mi n  
Mi n ut e  
m m H g  
Milli m et ers of m erc ur y ( bl o o d press ure)  
M M R M  
Mi xe d M o del Re peat e d Meas ures  
mI C A R S  
M o difie d versi o n of t h e I nt er n ati o n al C o o perati ve At a xia Rati n g 
Scale e xcl u di n g oc ul o m ot or it e ms ( 1 7 -1 9) a n d it e ms 8 -1 2  
N S AI D  
N o n -st er oi dal a nti-i nfla m m at or y dr u g 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 1 9  of 1 3 2  
 
 
 
 
 
O C  
O bser ve d cases  
O T C  
O ver -t h e-c o u nt er  
p B A R  
Pr o ba bilistic baseli n e ra n d o mizati o n  
P K  
P h ar m ac o ki n etic(s)  
R B Cs  
Re d Bl o o d Cells  
R C L  
Re d Cell L oa der  
R D W  
Re d bl o o d cell distri b uti o n wi dt h  
R M A N O V A  
Re peat e d Meas ures A n al ysis of Varia n ce  
R T  
R o o m Te m perat ure  
S A Es  
Seri o us A d verse E ve nts  
S A R A  
Scale f or Assess m e nt of Rati n g of At a xia  
S D  
St a n dar d De viati o n  
S N RI  
Ser ot o ni n -n ore pi n e p hri ne re u pt a ke i n hi bit or  
S O Ps  
St a n dar d O perati n g Pr oce d ures  
S P  
Safet y P o p ulati o n  
S S RI  
Selecti ve ser ot o ni n re u pt a ke i n hi bit or  
t1/ 2 
Half -life 
T 5 0  
Ti m e t o disa p peara n ce of 5 0 % of t h e la belle d re d bl o o d cells fr o m 
t h e circ ulati o n 
9 9 mTc  
Tec h n eti u m -9 9 m  
T C A  
Tric yclic a nti de pressa nt  
T E A Es  
Treat m e nt E m er ge nt A d verse E ve nts  
tma x  
Ti m e t o m a xi m u m plas m a c o n ce ntrati o n aft er d osi n g  
U L N  
U p per li mit of n or m al  
W B C  
W hit e Bl o o d Cells  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 0  of 1 3 2  
 
5  
TI T L E O F S T U D Y  
O pe n -la bel, L o n g -t er m, E xt e nsi o n  Treat m e nt usi n g Intra -E r yt hr oc yte D e xa m et h as o n e S o di u m P h o s p h at e 
i n Patie nts wit h A t a xia T ela n giect asia W h o Partici pat e d i n t h e I E D A T -0 2 -2 0 1 5 St u d y . 
 
6  
P R O T O C O L N U M B E R  
T his st u d y is bei n g c o n d u ct e d u n der P r ot oc ol N o. I E D A T-0 3 -2 0 1 8 . 
 
7  
B A C K G R O U N D A N D S T U D Y R A TI O N A L E  
7. 1   
B ac k gr o u n d I nf or m ati o n  
7. 1. 1  
Overvie w of t he  
 Syste m ( E D S)   
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7. 1. 2  
N o n -Cli nic al Tri als wit h E D S  
P h ar m ac o ki n etics is t h e o nl y c h aract eristic of t h e dr u g pr o d u ct  ( de xa m et h as o n e s o di u m p h os p h at e; D S P) 
p h ar m ac ol o g y t h at differs fr o m t h at o bt ai n e d wit h t h e or di n ar y r o ut es of a d mi nistrati o n ( oral, i ntra ve n o us, 
i ntra m usc ular, et c.) d u e t o t h e n o vel m et h o d of a d mi nistrati o n b y ex viv o  e n ca ps ulati o n of t h e dr u g i nt o 
h u m a n a ut ol o g o us re d bl o o d cells w hic h are t h e n i nf use d.  T h e p h ar m ac o ki n etics of t h e dr u g pr o d u ct i n 
h u m a ns was e val u at e d i n  cli nical trials.  It is n ot p ossi ble t o st u d y t h e  p h ar m ac o ki n etics i n a ni m al m o dels 
beca use t h e de p h os p h or ylati o n rat e of t h e pr o -dr u g, D S P, t o t h e diff usi ble acti ve dr u g, de xa m et h as o n e, in 
h u m a n R B Cs is ver y differe nt fr o m R B C de p h os p h or ylati o n rat es i n ot h er s pecies (Z occ hi et al, 1 9 9 1 ).   
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 1  of 1 3 2  
 
 
7. 1. 3  
S u m m ary of H u m a n Cli nic al Tri als wit h E D S   
A t ot al of 2 0 9  s u bjects h a ve recei ve d at least o n e d ose of E D S-E P . Of t h ese, 1 1 5 partici pat e d i n I n vesti gat or-
i nitiat e d a n d 8 9 i n S p o ns or-i nitiat e d st u dies. A t ot al of 1 8 27  E D S -E P  i nf usi o ns h a ve bee n a d mi nist ere d; 
3 6 6 of t h ese i nf usi o ns were perf or m e d i n t h e 8 9 patie nts e nr olle d i n S p o ns or -i nitiat e d st u dies. T we nt y-t wo 
patie nts wit h A T were a d mi nist ere d 3 4 4 E D S -E P  i nf usi o ns i n a p h ase II st u d y (I E D A T-0 1 -2 0 1 0) a n d i n 
s u bse q u e nt c o m passi o n at e use.   
T a ble 1 bel o w lis ts t h e trials perf or m e d t o dat e, t h e i n dicati o n, t h e n u m ber of s u bjects, t h e d oses 
a d mi nist ere d,  t h e treat m e nt d urati o n, a n d ke y safet y fi n di n gs. 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
Pa ge 2 2  of 1 3 2  
 
P P D
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
Pa ge 2 3  of 1 3 2  
 
A t ot al of 1 8 2 7  E D S -E P i nf usi o ns of E D S -E P  h a ve bee n a d mi nist ere d t o t h e s u bjects i n t h e c o m plet e d  
st u dies, a n d n o t o xicit y relat e d t o R B Cs pr ocesse d f or de xa m et h as o n e d osi n g h as bee n o bser ve d.  T h ese 
i n cl u de 5 1  pe diatric patie nts ( < 1 8 years) s ufferi n g fr o m c ystic fi br osis ( n = 1 1 ), Cr o h n’s disease ( n = 1 9) or 
A T ( n = 2 2 , o n e patie nt was 1 9 years of a ge  at i n cl usi o n ); s o m e of t h ese patie nts h a ve bee n e x p ose d t o E D S 
f or u p 3 6 m o nt hs. T h ere was n o c o nsist e nt patt er n of de xa m et h as o n e -relat e d a d verse fi n di n gs re p ort e d i n 
t h ese pe diatric p o p ulati o n s.  
A d diti o n al det aile d i nf or m ati o n o n pre -cli nical a n d cli nical st u dies e val u ati n g t h e E D S  ca n be f o u n d i n t he 
c urre nt versi o n of t h e I n vesti gat or’s Br oc h ure. 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 4  of 1 3 2  
 
7. 1. 3. 1  
Cli nic al St u dy I E D A T -E R Y 0 1 -2 0 1 0: Pil ot Pr o of of C o nce pt P h ase II Tri al i n P atie nts wit h At axi a 
Tel a n giect asi a [C hess a et al, 2 0 1 4 ] 
Title:  E val u ati o n of Effects of Intra -E r yt hr oc yt e D e xa m et h as o n e S o di u m P h os p h at e o n Ne ur ol o gical 
S y m pt o ms i n A t a xia-T ela n giect asia Patie nts   
St u d y Desi g n a n d Patie nt P o p ulati o n  
T his was a si n gle -ar m, o pe n -la bel, 6 -m o nt h, P h ase II st u d y t o assess t h e effect of  t h e Er y De x S yst e m e n d 
pr o d u ct ( E D S -E P; de xa m et h as o n e s o di u m p h os p h at e [ D S P] e n ca ps ulat e d i n a ut ol o g o us er yt hr oc yt es b y t he 
E D S pr ocess)  o n n e ur ol o gical s y m pt o ms of patie nts wit h At a xia Tela n giect asia ( A T) e nr olle d i n t w o ce nt ers 
i n It al y. Males a n d fe m ales, > 3 years of a ge, wit h n e ur ol o gical si g ns of A T ( u n-c o or di n ati o n of t h e h ea d 
a n d e yes i n lat eral gaze deflecti o n, gait at a xia ass ociat e d wit h a n i n a p pr o priat el y n arr o w base), a n 
a ut o n o m o us gait ( or h el pe d b y s u p p ort), a n d a ge n etic dia g n osis of A T (at least o n e A T M m ut ati o n) a n d/ or 
A T M pr ot ei n deficie n c y b y West er n bl ot, were i n cl u de d. Patie nts wit h l o w C D 4 + l y m p h oc yt es c o u nts, 
c urre nt/ pre vi o us n e o plastic disease, hist or y of se vere i m pair m e nt of t h e i m m u n ol o gical s yst e m, c hr o nic 
c o n diti o ns re prese nti n g a c o ntrai n dicati o n t o t h e use of st er oi d dr u gs, or a n y ot h er si g nifica nt disease t hat 
c o ul d h a ve p ut t h e patie nt at ris k were e xcl u de d. Fe m ales of c hil d beari n g p ot e ntial t h at were pre g n a nt, 
breastfee di n g or n ot  usi n g a de q u at e c o ntrace pti o n were als o e xcl u de d. Eli gi ble patie nts c o ul d n ot h a ve 
partici pat e d i n a trial wit h a n ot h er i n vesti gati o n al a ge nt wit hi n 3 0 da ys of t h e st art of t h e Scree ni n g Peri o d, 
a n d m ust h a ve disc o nti n u e d pri or st er oi d m e dicati o n at least 3 0 da ys bef ore t h e first d ose of E D S -E P .  
O bjecti ves  
T h e pri m ar y o bjecti ve of t h e trial was t o e val u at e t h e effect of E D S -E P  i n i m pr o vi n g n e ur ol o gical s y m pt o ms 
of A T patie nts o ver a 6 -m o nt h treat me nt peri o d, assesse d b y m ea ns of t h e I C A R S ( Tr o uillas et al. , 1 9 9 7). 
T h e I C A R S is a 1 0 0 -p oi nt se mi -q u a ntit ati ve scale offeri n g a c o m part m e ntalize d q u a ntificati o n of t he 
f oll o wi n g 4 s u b-sc ores: P ost ure a n d gait dist ur ba n ces, ki n etic f u n cti o ns, s peec h dis or ders, a n d oc ul o m ot or 
dis or ders. T h e I C A R S rati n g was perf or m e d b y a trai n e d n e ur ol o gist at baseli n e ( bef ore t h e first d ose) a n d 
at 1, 3 a n d 6 m o nt hs aft er t h e first E D S -E P  a d mi nistrati o n; a n al ysis of t h e c h a n ge fr o m baseli n e at eac h visit 
was perf or m e d o n t h e I T T p o p ulati o n usi n g Re peat e d Meas ures A n al ysis of Varia n ce ( R M A N O V A). 
Sec o n dar y o bjecti ves of t h e trial were t o e val u at e t h e safet y pr ofile of E D S -E P  t hr o u g h t he assess m e nt of 
T E A Es, i n cl u di n g st er oi d -de pe n de nt a d verse reacti o ns, S A Es, st a n dar d la b orat or y para m et ers, p h ysical 
e xa mi n ati o n, vit al si g ns, E C Gs a n d c o n c o mit a nt m e dicati o ns a n d pr oce d ures.  A d diti o n all y, t h e effects of 
E D S -E P  were  assesse d o n t h e patie nts ’ gl o bal h ealt h st at us (I G A), oc ular m otilit y,  a n d a da pti ve be h a vi o ur 
( V A B S). T h e effect of E D S-E P o n s pecial la b orat or y para m et ers, i. e. t ot al c h oles t er ol, H D L, L D L, bl o o d 
gl yc os ylat e d h e m o gl o bi n ( H b A 1c), C D 4 +  l y m p h oc yt es c o u nts , α -fet o pr ot ei n, uri n ar y c ortis ol a n d plas m a 
c ortis ol , was als o m eas ure d.  
Met h o ds  
Patie nts pr o vi di n g  i nf or m e d c o nse nt  (al o n g wit h  c o nse nt  of  t h eir pare nts  or  le gal g u ar dia n,  as re q uire d) 
e nt ere d  a 3 0 -da y  scree ni n g peri o d,  d uri n g  w hic h  a n y pri or  c ortic ost er oi d  treat m e nt was  wit h dra wn.  
Me dical  hist or y  a n d de m o gra p hic  i nf or m ati o n was  c ollect e d,  a n d p h ysical  a n d n e ur ol o gical  
e xa mi n ati o ns,  vit al  si g ns, E C G  a n d st a n dar d la b orat or y t ests were  perf or m e d.  Patie nts m eeti n g  all  
selecti o n  crit eria  were  e nr olle d  i n t h e treat m e nt peri o d  a n d 
 
 
 
 
 
  
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 5  of 1 3 2  
 
A  p h ysical  e xa mi n ati o n,  vit al  si g ns a n d r o uti n e la b orat or y t ests were  perf or m e d at eac h m o nt hl y visit.  
T h e  pri m ar y  efficac y  m eas ure (I C A R S) was  assesse d  at  o n e  m o nt h,  a n d at  t h e 3 -m o nt h  visit,  all efficac y  
assess m e nts  were  d o n e,  al o n g wit h  t h e s pecial la b orat or y t ests ( bef ore dr u g  i nf usi o n). A  fi n al e val u ati on  
was  perf or m e d  at  6  m o nt hs  aft er  t h e i nitial i nf usi o n ( o n e m o nt h  aft er t h e last d ose),  d uri n g  w hic h  all  
efficac y  a n d safet y assess m e nts  were  perf or m e d.  T h e  occ urre n ce  of  a n y A Es  a n d t h e use  of  c o n c o mitant  
m e dicati o n  were  rec or de d fr o m t h e ti m e of  si g ni n g of  t h e c o nse nt  f or m u ntil  t h e e n d of  t h e st u d y. 
Bl o o d  sa m ples f or t h e P K a n al ysis  were  c ollect e d  fr o m select e d patie nts pri or  t o d osi n g ( 0  hr),  a n d at  4 
h o urs a n d 1 5 a n d 3 0 da ys  p ost -d ose  f or t h e first a n d f o urt h i nf usi o ns.  
Dis p ositi o n  
A t ot al of 2 6 patie nts wit h A T were scree n e d a n d 2 2 were e nr olle d i n t h e st u d y, re prese nti n g t h e I T T 
p o p ulati o n.  F o ur s u bjects disc o nti n u e d pre m at urel y; o n e wit h dre w c o nse nt, a n ot h er patie nt was dr o p pe d 
d u e t o a pr ot oc ol vi olati o n ( C D + 4 l y m p h oc yt es bel o w c ut -off at baseli n e), a n d 2 patie nts e x perie n ce d 
la b orat or y a b n or m alities ( decrease i n C D 4 + ly m p h oc yt es c o u nt) t h at le d t o t h eir wit h dra wal.    
De m o gra p hics a n d Disease C h aract eristics  
T h e m ea n ( S D) a ge of t h e A T patie nts was 1 1. 2 ( 3. 5) years, wit h 1 1 ( 5 0 %) patie nts bei n g m ales. All patie nts 
were Ca u casia n wit h a m ea n wei g ht of 2 9. 1 ( 9. 5) k g a n d B MI of 1 5. 6 ( 2. 6). T h e a vera ge a ge of dia g n osis 
of A T was 6 0. 0 ( 3 5. 2) m o nt hs, wit h a m ea n a ge  of s y m pt o m o nset of 2 5. 9 ( 1 7. 5) m o nt hs. T h e m ea n baseline 
sc ores f or t h e I C A R S a n d V A B S were 5 0. 6 ( 1 2. 8) a n d 5. 5 ( 2. 0), res pecti vel y. Mea n baseli n e sc ores o n t he 
s u b-scales of t h e I C A R S were as f oll o ws: p ost ure/ gait dist ur ba n ce –  2 0. 9 ( 7. 1); ki n etic f u n ct i o n –  2 3. 1 ( 6. 2); 
s peec h dis or ders –  3. 5 ( 1. 4); a n d oc ul o m ot or dis or ders –  3. 2 ( 1. 0). T w o patie nts were o n i n h alati o nal 
st er oi ds at scree ni n g, a n d t h ese m e dicati o ns were disc o nti n u e d.  
Efficac y Res ults  
Si xt ee n patie nts ( 7 2. 7 %) recei ve d all 6 i nf usi o ns of E D S -E P , as pla n n e d. Res ults f or t h e pri m ar y efficac y 
m eas ure (c h a n ge fr o m t ot al baseli n e I C A R S sc ore) f or t h e I T T p o p ulati o n ( n = 2 2) i n dicat e d a n o verall 
st atisticall y si g nifica nt ( p = 0. 0 2, 
R M A N O V A) i m pr o ve m e nt 
wit h E D S -E P treat m e nt. Si g nifica nt 
i m pr o ve m e nt was o bser ve d aft er 3 a n d 6 m o nt hs of treat m e nt wit h E D S -E P f or t h e ki n etic s u b -sc ore of t he 
I C A R S, t h e cli nicia n rat e d t h e I n vesti gat or Gl o bal Assess m e nt (I G A), a da pti ve be h a vi or (as assesse d b y t he 
V A B S) a n d oc ular m otilit y.  
 
 
 
 
 
 
 
  
Safet y Res ults  
T h e safet y p o p ulati o n i n cl u de d all 2 2 patie nts. O verall, 1 5 ( 6 8. 2 %) of patie nts e x perie n ce d at t ot al of 2 9 
T E A Es, m ost of w hic h were rat e d as mil d ( ~ 6 0 % of s u bjects) a n d n ot relat e d t o t h e st u d y m e dicati o n ( > 
9 0 % of patie nts), wit h t he e xce pti o n of 1 patie nt wit h a mil d h y perc h olest er ole mia. T w o S A Es were re p ort e d 
d uri n g t h e st u d y, i n cl u di n g o n e case of se vere p n e u m o nia  a n d a sec o n d patie nt wit h br o n c h o p n e u m o nia, 
a n d br o n c hiect asis a n d blee di n g; b ot h patie nts re q uire d h os p it alisati o n. B ot h cases were c o nsi dere d 
u nrelat e d t o st u d y m e dicati o n a n d res ol ve d wit h treat m e nt.  
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 6  of 1 3 2  
 
T w o patie nts h a d a > 2 0 % decrease i n C D 4 + l y m p h oc yt es c o u nt d uri n g t h e st u d y peri o d w hic h res ult e d i n 
pre m at ure disc o nti n u ati o n, a n d were c o nsi dere d relat e d t o st u d y m e dicati o n. 
T h ere were n o cli nicall y m ea ni n gf ul c h a n ges i n m ea n val u es f or r o uti n e la b orat or y para m et ers wit h E D S -
E P  treat m e nt, e xce pt f or ser u m ir o n, w hic h s h o we d a > 2 0 % m ea n decrease fr o m baseli n e val u e, wit h 8 
patie nts h a vi n g n e wl y occ urri n g a b n or m al (l o w) val u es at t h e fi n al visit ( o n e re p ort e d as a T E A E). F or t he 
s pecial la b orat or y para m et ers, n o cli nicall y m ea ni n gf ul c h a n ges were o bser ve d, e xce pt f or uri n ar y c ortis ol, 
w hic h s h o we d a n a p pr o xi m at el y 3 0 % decrease fr o m baseli n e t o t h e fi n al visi t (st atisticall y si g nifica nt, 
p = 0. 0 1 6). Alt h o u g h t his c o ul d i n dicat e a n effect of E D S -E P o n t h e h y p ot h ala m o -pit uitar y -a dre n al a xis, a 
c o m paris o n of bl o o d a n d uri n ar y c ortis ol le vels vers us d ose di d n ot i n dicat e a n y relati o ns hi p. N o cli nicall y 
si g nifica nt ch a n ges wit h E D S -E P  treat m e nt were o bser ve d f or vit al si g ns, E C Gs, or p h ysical e xa mi n ation 
fi n di n gs. 
C o n cl usi o ns  
I n t his o pe n-la bel st u d y i n A T patie nts > 3 years of a ge, E D S-E P  treat m e nt f or 6 m o nt hs le d t o a st atistically 
si g nifica nt i m pr o ve m e nt i n t h e pri m ar y efficac y m eas ure, t h e I C A R S, w hic h assesses ke y s y m pt o ms of t he 
disease. A d diti o n al st atisticall y si g nifica nt be n efits of E D S treat m e nt were n ot e d i n t h e Ki n etic F u n ction 
s u b-scale of t h e I C A R S, I G A, a da pti ve be h a vi or ( V A B S), a n d oc ular m otilit y (a d h oc scale). E D S -E P  was 
ge n erall y well t olerat e d i n t his s u bject p o p ulati o n, wit h o nl y t w o patie nts disc o nti n ui n g pre m at urel y d u e t o 
a d verse e ve nts. T w o patie nts e x perie n ce d seri o us a d verse e ve nts relat e d t o p ul m o n ar y i nfecti o ns; m ost A Es 
were mil d i n i nt e n sit y a n d c o nsi dere d u nrelat e d t o st u d y m e dicati o n.  
La b orat or y fi n di n gs i n dicat e d a l o w ser u m ir o n le vels i n a p pr o xi m at el y o n e t hir d of patie nts a n d a m ean 
re d u cti o n i n uri n ar y c ortis ol, w hic h di d n ot a p pear t o be relat e d t o t h e d ose a d mi nist ere d.  
 
 
 
 
 
Pil ot o bser vati o n t h at hi g h er D S P l oa d a p pear s t o be ass ociat e d wit h i m pr o ve d res p o nse of t h e I C A R S h as 
le d t h e S p o ns or t o t ar get hi g h er D S P d oses i n f ut ure efficac y st u dies. 
7. 1. 3. 2  
Cli nic al St u dy I E D -P K 0 1 -2 0 1 3  
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 7  of 1 3 2  
 
 
  
  
 
 
 
  
 
 
 
 
 
P h ar m ac o ki n etic Res ults  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Safet y Res ults  
A dverse eve nts.  T h ere were n o S A Es, or disc o nti n u ati o ns d u e t o A Es i n eit h er gr o u p. Fi ve of 9 ( 5 5. 6 %) 
s u bjects i n Gr o u p 1 re p ort e d a t ot al of 5 T E A Es, all of mil d i nt e nsit y. I n Gr o u p 2, 5 s u bjects ( 5 5. 6 %) 
re p ort e d a t ot al of 6 T E A Es, 4 of mil d a n d 3 of m o derat e i nt e nsit y. T w o s u bjects h a d T E A Es t h at re q uire d 
dr u g treat m e nt, o n e wit h a b d o mi n al disc o mf ort (treat e d wit h a n a nt aci d) a n d t h e ot h er wit h gastr oi nt estinal 
pai n (treat e d  wit h a nti -gas a ge nt) a n d gi n gi val pai n (treat e d wit h a n al gesics). All of t h e T E A Es res ol ve d 
wit h o ut a n y se q u elae. N o Gr o u p 1 s u bjects recei ve d a c o n c o mit a nt m e dicati o n d uri n g t h e st u d y a n d o nl y 
t w o Gr o u p 2 s u bjects recei ve d o n e or 
m ore c o n c o mit a nt m e dicat i o ns f or t h eir T E A Es (a b d o mi n al 
disc o mf ort, gi n gi val pai n, a n d gastr oi nt esti n al pai n).  
St a n d ar d l a b or at ory  tests. A n u m ber of s m all b ut st atisticall y si g nifica nt tra nsie nt c h a n ges i n h e m at ol o gical 
(a bs ol ut e e osi n o p hils, h e m at ocrit, h e m o gl o bi n, l y m p h oc yt es, m o n oc yt es, R B C c o u nt, M C H, n e utr o p hils, 
plat elet, a n d 
W B C c o u nt) a n d bi oc h e mical ( A S T, creati n e p h os p h o ki n ase, C O 2, creati ni n e, gl u c ose, 
c h olest er ol, p ot assi u m, s o di u m, L D H, H D L a n d B U N) para m et ers ass ociat e d wit h D S P a d mi nistrati o n were 
o bser ve d. S p ora di c a b n or m al val u es ( hi g h/l o w) were n ot e d f or s o m e of t h e la b orat or y h e m at ol o g y a n d 
bi oc h e mistr y para m et ers at Da y 2 a n d/ or t h e fi n al visit ( Da y 4 2); h o we ver, n o n e of t h ese were c o nsi dere d 
t o be cli nicall y si g nifica nt. N o m ea ni n gf ul c h a n ges fr o m baseli n e were o bser ve d i n a n y uri n al ysis para m et er 
t hr o u g h o ut t h e st u d y. B ot h i n creases a n d decreases c o m pare d t o baseli n e were o bser ve d f or la b orat or y 
a n al yt es i n Gr o u ps 1 a n d 2, wit h o ut a n y c o nsist e nt patt er n of c h a n ge.   
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 8  of 1 3 2  
 
Ot her l a b or at ory tests . Ser u m c ortis ol le vels were si g nifica ntl y re d u ce d u p t o t h e 4 8 -h o ur ti m e p oi nt i n 
Gr o u p 1, w hile i n Gr o u p 2 a si g nifica nt decrease i n ser u m c ortis ol le vels was o bser ve d t hr o u g h t he 7 -da y 
ti m e p oi nt a n d at Da y 4 2, b ut n ot at Da y 1 4. Uri n ar y c ortis ol s h o we d n o si g nifica nt re d u ct i o n at a n y ti me 
p oi nt.  
All 9 patie nts i n eac h of t h e treat m e nt gr o u ps h a d n or m al R B C os m otic resist a n ce val u es at Na Cl 
c o n ce ntrati o ns fr o m 0. 5 5 % u p t o 0. 8 5 % o n Da y 1 bef ore t h e E D S pr ocess. T h e m aj orit y of t h e patie nts h ad 
n or m al R B C os m otic resist a n ce val u es at Na Cl c o n ce ntrati o ns bet wee n 0. 3 0 % a n d 0. 5 0 %; h o we ver, 4 
patie nts ( 2 i n Gr o u p I a n d 2 i n Gr o u p II) s h o we d a patt er n of decrease d l ysis w hile o n e s u bject h a d a patt ern 
of b or derli n e i n crease. Res ults f or R B C os m otic resist a n ce f or t h e sa m ple t a ke n fr o m t h e i nf usi o n ba g, 
f oll o wi n g t h e E D S pr ocess, c o nfir m e d a patt er n of decrease d l ysis at t h e 0. 4 0 % -0. 5 0 % c o n ce ntrati o n ra n ge 
i n 3 ( 1 i n Gr o u p I a n d 2 i n Gr o u p II) o ut of 4 patie nts t h at h a d t his patt er n bef ore t h e pr oce d ure. All ot h er 
patie nts e x hi bit e d R B C os m otic fra gilit y wit hi n t h e n or m al ra n ge.  
Free h e m o gl o bi n val u es were a b o ve n or m al ( hi g h) o n Da y 1 ( pri or t o i nf usi o n) i n 4 of 9 patie nts i n Gr o u p 
1 a n d i n 6 of 9 patie nts i n Gr o u p 2. T h e m ea n val u e f or free h e m o gl o bi n bef ore i nf usi o n i n t h e 9 patie nts  in 
Gr o u p 1 was 6. 7 9 m g/ d L ( m e dia n 5. 3 0 m g/ d L) wit h a m a xi m u m s u bject val u e of 1 2. 6 0  m g/ d L, a n d t he 
m ea n val u e f or t h e 9 patie nts i n Gr o u p 2 was 2 3. 6 2 m g/ d L ( m e dia n 1 6. 2 0 m g/ d L) wit h a m a xi m u m s u bject 
val u e of 7 6. 0 0 m g/ d L. Free h e m o gl o bi n was det ect e d s p or a dicall y als o aft er i nf usi o n d uri n g t his trial.  
A n al ysis of plas m a sa m ples (t a ke n f or P K det er mi n ati o n) i n dicat e d t h e prese n ce of free h e m o gl o bi n i n 
sa m ples at baseli n e pri or t o t h e E D S e n d pr o d u ct i nf usi o n. T h e prese n ce of free plas m a h e m o gl o bi n m a y 
h a ve  res ult e d fr o m t h e bl o o d dra wi n g t ec h ni q u e use d t o c ollect t h e sa m ples (e. g., use of I V cat h et er wit h a 
2 2 -ga u ge n ee dle). A n al ysis of uri n e sa m ples f or h e m o gl o bi n, bilir u bi n, ur o bili n o ge n, uri n e clarit y a n d c ol or 
di d n ot det ect a n y patt er n s u g gesti ve of h e m o gl o bi n uria or ass ociat e d fi n di n gs i n a n y s u bject.  
Ot her s afety p ar a meters . A b n or m alities i n vit al si g ns t h at were re p ort e d as T E A Es i n cl u de d a mil d i n crease 
i n diast olic bl o o d press ure ( D B P) o n t h e da y of st u d y dr u g i nf usi o n, t w o re p orts of mil d ‘ ort h ost atic 
t ac h ycar dia’ o n t h e da y of d osi n g, a n d mil dl y ra pi d h eart beat/ pal pit ati o ns; all res ol ve d wit h o ut se q u elae. 
S m all st atisticall y si g nifica nt m ea n c h a n ges ( p < 0. 0 5) were o bser ve d f or s yst olic bl o o d press ure, diast olic 
bl o o d press ure a n d p ulse rat e, pri m a ril y at earl y ti m e-p oi nts ( Da ys 2 a n d 3), i n b ot h gr o u ps, b ut di d n ot 
i n dicat e a n y patt er n of a d verse c h a n ge.  N o st atisticall y si g nifica nt m ea n c h a n ges fr o m Baseli n e were 
o bser ve d at a n y ti m e p oi nt f or s u pi n e res pirat or y rat e, b o d y t e m perat ure m eas ures or  b o d y wei g ht.  
T h e o verall i nt er pret ati o n of t h e E C G di d n ot i n dicat e a n y a d verse car diac effects of E D S -E P treat m e nt, as 
n o n e wl y occ urri n g a b n or m alities were o bser ve d p ost -baseli n e.  I n a d diti o n, n o st atisticall y si g nifica nt 
c h a n ges i n a n y E C G para m et er w ere n ot e d at Da y 4 2.  O n e p h ysical e xa mi n ati o n fi n di n g was re p ort e d ( Da y 
4 2) as a T E A E ( mil d se verit y ri g ht e ye u p per li d i nfla m m ati o n t h at was n ot c o nsi dere d t o be cli nicall y 
si g nifica nt b y t h e I n vesti gat or), a n d o n e s u bject h a d a n e w a b n or m alit y i n refle xes re p ort e d o n t he 
n e ur ol o gical e xa mi n ati o n ( Da y 4 2).  
7. 1. 3. 3  
Cli nic al St u dy Ery 5 1 Cr -0 1 -2 0 1 4   
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 2 9  of 1 3 2  
 
 
 
 
 
 
 
   
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  
  
Res ults   
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
S u m m ary of S afety D at a  
N o c o nsist e nt patt er n of c h a n ges of a m a g nit u de t h at le d t o val u es t h at were a b n or m al, or were dee m e d 
cli nicall y n ot a ble, was det ect e d i n s u bjects recei vi n g E D S -pr ocesse d er yt hr oc yt es c o nt ai ni n g D S P or sali n e 
f or m eas ures e val u ati n g a pre-s pecifie d h e m ol ysis pa n el of t ests, or ot h er r o uti n e la b orat or y h e m at ol o g y, 
bi oc h e mistr y, a n d uri n al ysis para m et ers. Si milarl y, t h ere was n o e vi de n ce of a s yst e m atic effect o n vit al 
si g ns, wei g ht, or E C Gs, a n d n o patt er n of a d verse e ve nts was det ect e d wit h t h e trial treat m e nts.  T h ere were 
n o disc o nti n u ati o ns d u e t o A Es, seri o us a d verse e ve nts ( S A E), o r A Es rat e d se vere or u n e x pect e d.  
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 0  of 1 3 2  
 
7. 1. 3. 4  
Cli nic al St u dy I E D A T-0 2 -2 0 1 5  
T his is a n i nt er n ati o n al ( N ort h A m erica, E ur o pe, Africa, Asia a n d A ustralia), m ulti -ce nt er, o n e -year, 
ra n d o mize d, pr os pecti ve, d o u ble-bli n d, place b o -c o ntr olle d, p h ase III st u d y, desi g n e d t o as sess t h e effect of 
t w o n o n-o verla p pi n g d ose ra n ges of E D S E P, a d mi nist ere d b y I V i nf usi o n o n ce per m o nt h, o n n e ur ol o gical 
s y m pt o ms of patie nts wit h A T. All patie nts w h o c o m plet e t h e assess m e nts as desi g n e d o ver t h e i nitial 
treat m e nt peri o d of t h e trial will be eli gi ble t o c o nti n u e i n a n a d diti o n al d o u ble-bli n d, place b o -c o ntr olle d 
e xt e nsi o n treat m e nt peri o d desi g n e d t o c ollect i nf or m ati o n o n t h e l o n g -t er m safet y a n d efficac y of t h e trial 
treat m e nts.  
T h e i nitial treat m e nt peri o d will be c o nsi dere d c o m plet e w h e n t h e e n d p oi nt assess m e nt (at Visit 9 or at earl y 
disc o nti n u ati o n) h as bee n perf or m e d f or all patie nts.  Patie nts w h o are n ot e x perie n ci n g se vere si de -effects, 
a n d h a ve  n ot  det eri orat e d si g nifica ntl y w hile o n t h e treat me nt , a n d pr o vi de i nf or m e d c o nse nt will be eli gi ble 
t o c o nti n u e treat m e nt f or a n a d diti o n al 6 m o nt hs i n a d o u ble-bli n d, place b o -c o ntr olle d e xt e nsi o n treat ment 
peri o d. Patie nts m eeti n g all e ntr y crit eria will be treat e d as f oll o ws:  
• 
Patie nts ori gi n all y ra n d o mize d t o E D S -E P treat m e nt gr o u ps ( Gr o u p 1 o r Gr o u p 2) will c o nti n ue on 
t h e sa m e treat m e nt; 
• 
Patie nts ori gi n all y ra n d o mize d t o t h e Place b o gr o u p ( Gr o u p 3) will be re -ra n d o mize d i n e q u al 
pr o p orti o ns ( 1: 1) t o recei ve eit h er t h e 
 D S P/i nf usi o n or ~ 
 D S P/i nf usi o n, 
as f oll o ws:  
o  F oll o wi n g t h e i nitial (a p pr o xi m at el y) 6 m o nt hs of treat m e nt, o n e t hir d of t h e ori gi n all y 
ra n d o mize d place b o patie nts will be re-ra n d o mize d t o treat m e nt wit h E D S-E P, as descri be d 
a b o ve; 
o  Aft er (a p pr o xi m at el y) 9 m o nt hs of treat m e nt, o n e t hir d of t h e ori gi n all y ra n d o mize d 
place b o patie nts will be re -ra n d o mize d t o treat m e nt wit h E D S-E P, as descri be d a b o ve;  
o  At (a p pr o xi m at el y) 1 2 m o nt hs, all re m ai ni n g place b o patie nts w h o c o nti n u e o pe n -la bel 
treat m e nt will recei ve treat m e nt wit h E D S-E P, as descri be d a b o ve.  
A mi ni m u m of 1 8 0 patie nts m eeti n g all selecti o n crit eria will be e nr olle d a n d ra n d o mize d t o o n e of t h e 3 
treat m e nt gr o u ps (a p pr o xi m at el y 6 0 patie nts per gr o u p). 
T h e o bjecti ves of t h e St u d y are t h e f oll o wi n g:  
I niti al Tre at me nt Peri o d  
Pri m ar y Efficac y O bject i ve: 
• 
T o e val u at e t h e effect of t w o
 e n d 
pr o d u ct [ E D S -E P; t h e E D S is a c o m bi n ati o n pr o d u ct t h at is use d t o l oa d de xa m et h as o n e s o di u m 
p h os p h at e ( D S P) i nt o a ut ol o g o us er yt hr oc yt es, creati n g t h e E D S e n d pr o d u ct, w hic h is i nf use d i nt o t he 
patie nt], c o m pare d t o place b o, o n ce ntral n er v o us s yst e m ( C N S) s y m pt o ms m eas ure d b y t h e ‘ M o difie d’ 
I nt er n ati o nal C o o perati ve At a xia Rati n g Scale ( mI C A R S) i n patie nts wit h at a xia t ela n giect asia ( A T).  
Ke y Sec o n dar y Ef ficac y O bjecti ve: 
• 
T o e val u at e t h e effect of E D S -E P, c o m pare d t o place b o, i n t his p o p ulati o n o n t h e Cli nical Gl o bal 
I m pressi o n of C h a n ge fr o m baseli n e ( C GI-C).  
Safet y O bjecti ve :  
C CI
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 1  of 1 3 2  
 
• 
T o e val u at e t h e safet y a n d t olera bilit y of E D S -E P c o m pare d t o place b o i n A T pa tie nts, base d o n t he 
occ urre n ce of 
Treat m e nt -E mer ge nt 
A d verse 
E ve nts ( T E A Es), i n cl u di n g Seri o us 
A Es a n d 
disc o nti n u ati o ns d u e t o A Es, a n d c h a n ges i n vit al si g ns, la b orat or y para m et ers, E C Gs a n d 
p h ysical/ n e ur ol o gical e xa mi n ati o n fi n di n gs.  
Sec o n dar y Efficac y O bjecti ves :  
• 
T o e val u at e t h e effect of E D S -E P, c o m pare d t o place b o, i n t his p o p ulati o n o n t h e f oll o wi n g efficac y 
m eas ures:  
o  Cli nical Gl o bal I m pressi o n of Se verit y ( C GI -S) of n e ur ol o gical s y m pt o ms of A T;  
o  A da pti ve be h a vi or m eas ure d b y t h e Vi n ela n d A da pti ve Be h a vi or Scales ( V A B S);  
Tertiar y O bjecti ves :  
• 
T o e val u at e t h e effect of E D S -E P o n h ealt h -relat e d Q u alit y of Life ( Q o L) usi n g t h e E Q-5 D -5 L scale;  
• 
T o assess t h e p h ar m ac o ki n etic a n d p h ar m ac o d y n a mic relati o ns hi ps bet wee n de xa m et h as one 
a d mi nist ere d t hr o u g h E D S -E P a n d safet y, t olera bilit y, a n d de m o gra p hic varia bles.  
• 
T o e val u at e t h e p h ar m ac o ki n etic ( P K) pr ofile of de xa m et h as o n e a d mi nist ere d t hr o u g h E D S -E P at t w o 
d ose le vels base d o n p o ole d dat a fr o m all patie nts i n eac h treat m e nt gr o u p.  
A det er mi n ati o n of i n di vi d u al P K para m et ers will be perf or m e d f or patie nts wit h a n a de q u at e n u m ber of 
P K bl o o d sa m ples aft er t h e i nitial i nf usi o n.  
E x pl orat or y O bjecti ve : 
• 
T o c ollect dat a o n t h e use of t h e A -T N E S T c o n c urre nt wit h t h e I C A R S, C GI -S a n d C GI -C, as well as 
its use i n la n g u a ges ot h er t h a n E n glis h, a n d t o c o m pare it wit h t h e dat a fr o m t h e scales refere n ce d t o 
assess t h e ps yc h o m etric pr o perties of t h e A -T N E S T.  
Ex te nsi o n Tre at me nt Peri o d  
Pri m ar y O bjecti ve : 
• 
T o e val u at e t h e efficac y of t w o d ose ra n ges 
 c o m pare d 
t o place b o i n treati n g C N S s y m pt o ms i n A T patie nts d uri n g l o n g-t er m treat m e nt ( u p t o 1 2 m o nt hs), as 
m eas ure d b y t h e ‘ M o difie d’ I C A R S.  
Sec o n dar y O bjecti ves : 
• 
T o e val u at e t h e l o n g -t er m ( u p t o 1 2 m o nt hs) safet y a n d t olera bilit y of E D S-E P i n A T patie nts;  
• 
T o c o m pare t h e effects of t h e t w o d ose ra n ges of E D S -E P o n t h e cli nicia n’s gl o bal i m pressi o n ( C GI -C 
a n d C GI -S), a da pti ve be h a vi or ( V A B S), a n d Q o L ( E Q -5 D -5 L scale).  
Res ults  
T h e st u d y is o n g oi n g at t h e ti m e of t h e fi n alizati o n of t h e I E D A T-0 3 -2 0 1 8 St u d y Pr ot oc ol, s o n o dat a are 
c urre ntl y a vaila ble.  At t h e ti m e of t h e fi n alizati o n of t h e I E D A T -0 3 -2 0 1 8 St u d y Pr ot oc ol  Versi o n 1. 0 , 1 3 1 
a d verse e ve nts occ urre d i n 5 5 ra n d o mize d patie nts , a n d 3 of t h ese h a ve bee n re p ort e d as  S A Es.  At t h e ti me 
of t h e fi n alizati o n of t h e I E D A T -0 3 -2 0 1 8 St u d y Pr ot oc ol  Versi o n 1. 0 , t h e Dat a Safet y M o nit ori n g B oar d 
di d n’t e x press a n y c o n cer n a n d t h e o ut c o m e of t h e D S M B re vie w of t h e o n g oi n g dat a was t o c o nti n u e t he 
trial wit h o ut m o dificati o n. 
 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 2  of 1 3 2  
 
7. 2   
Dr u g Pr o d uct  a n d Deli ver y S yste m   
Ge neric N a me  
Dr u g :  De xa m et h as o n e s o di u m p h os p h at e s ol uti o n (  
), referre d t o as D S P S ol uti o n  
Pr ocess S ol ut i o ns:  H y pert o nic/ h y p ot o nic st erile s ol uti o ns  
Devices :  Bl o o d pr ocessi n g e q ui p m e nt  a n d kit of si n gle use st erile dis p osa ble de vice access ories  
Pr o priet ar y N a me  
Dr u g :  N ot det er mi n e d (a pr o priet ar y n a m e f or de xa m et h as o n e s o di u m p h os p h at e s ol uti o n, 
 h as 
n ot yet bee n pr o p ose d)  
Pr ocess S ol uti o ns :  PI G P A H y pert o nic S ol uti o n, H y p ot o nic S ol uti o n 1, a n d H y p ot o nic S ol uti o n 2 
Devices :  Re d Cell L oa der a n d Er y Kit_ 0 1  
T he  
 S yste m ( E D S)  
T h e   
 S yst e m ( E D S) is use d t o l oa d de xa m et h as o n e s o di u m p h os p h at e ( D S P), a m ar ket e d dr u g, i nt o 
a ut ol o g o us er yt hr oc yt es, creati n g t h e E D S e n d pr o d u ct  ( E D S-E P) , w hic h is i nf use d o n ce per m o nt h i nt o t he 
patie nt.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
C CI
C CI
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 3  of 1 3 2  
 
 
 
 
 
 
 
 
 
  
 
7. 3   
St u d y R ati o n ale  
T his is a n i nt er n ati o n al ( N ort h A m erica, E ur o pe, Africa, Asia a n d A ustralia), m ulti -ce nter, pr os pecti ve, 
o pe n -la bel treat m e nt st u d y, desi g n e d t o c o nti n u e t o pr o vi de t h e st u d y m e dicati o n t o all patie nts w h o 
c o m plet e d t h e f ull treat m e nt peri o d (i n cl u di n g t h ose treat e d wit h place b o) i n t h e I E D A T-0 2 -2 0 1 5 trial, 
c o m plet e d t h e st u d y assess m e nts, d o n ot prese nt safet y c o ntrai n dicati o n t o c o nti n uati o n of treat m e nt , an d 
pr o vi de d  i nf or m e d c o nse nt. T h e st u d y ai ms at c ollecti n g i nf or m ati o n o n t h e l o n g-t er m safet y a n d efficac y 
of t h e trial treat m e nt.  
T h e st u d y ai ms t o c ollect i nf or m ati o n o n t h e l o n g -t er m safet y a n d efficac y of E D S -E P  treat m e nt i n patients 
w h o h a ve c o m plet e d t h e f ull treat m e nt peri o d i n t h e I E D A T-0 2 -2 0 1 5 st u d y.  
R ati o n ale f or Usi n g t he E D S  i n Tre ati n g  A T P atie nts   
A T is c o nsi dere d a r are dise ase b y t h e Office of Rare Diseases of t h e Nati o n al I nstit utes of Healt h ( U S), as 
well as b y Or p h a net , t h e c o ns orti u m of E ur o pea n part n ers. T h ere is n o m ar ket e d dr u g a p pr o ve d t o treat A T, 
a n d t h ere is n o treat m e nt a vaila ble t h at s l o ws d o w n or st o ps t h e pr o gressi o n of A T patie nts t o earl y 
de bilit ati n g disa bilit y a n d m ort alit y. S y m pt o m atic, pre ve nti ve , a n d s u p p orti ve m a n a ge m e nt of t h e ke y 
disa bilities a n d s y m pt o ms of t h e disease h as pr o vi de d li mit e d be n efit. I m m u n e def icie n cies are m a n a ge d b y 
a d mi nistrati o n of i m m u n o gl o b uli ns, a n d i nfecti o ns are m a n a ge d b y b ot h pre ve nti ve a n d s y m pt o m atic use 
of a nti bi otics. De vel o p m e nt al deficie n cies are m a n a ge d b y p h ysical t h era pies, e d u cati o n, or t ar get ed 
treat m e nts (H oc h e et al, 2 0 1 2 ). 
Ne ur ol o gical de ge n erati o n is t h e m aj or c o ntri b ut or t o t h e se vere o ut c o m e of t h e disease. T h e pr o gressi o n 
of t h e n e ur ol o gic pr o ble ms is c urre ntl y u nst o p pa ble. A nti -p ar ki ns o n a n d a ntie pile ptic dr u gs pr o vi de li mit ed 
be n efit i n t h e m a n a ge m e nt of e xtra p yra mi dal s y m pt o ms. T h e sere n di pit o us disc o ver y of t h e be n efit of s h ort -
t er m bet am et h as o ne i n a patie nt wit h A T ( B u o ni et al, 2 0 0 6 ), a n d f urt h er pil ot, u n c o ntr olle d, s h ort– ter m 
treat m e nt trials i n s m all n u m bers of patie nts h a ve s u g gest e d t h at bet a m et has o n e at d oses of 0. 0 3 m g/ k g, b ut 
n ot 0. 0 1  m g/ k g, gi ve n f or a s h ort peri o d h as be n eficial effects o n t h e n e ur ol o g ical i m pair m e nt of A T patie nts 
(R uss o et al, 2 0 0 9; Br occ oletti et al, 2 0 0 8 ). Treat m e nt disc o nti n uati o n i n t h ese st u dies was acc o m pa nie d b y 
t h e rea p peara n ce of s y m pt o ms, s u g gesti n g t h at l o n g -t er m a d mi nistrati o n m a y be re q uire d t o preser ve t he 
be n efit.  
T h ese earl y fi n di n gs wit h a d mi nistrati o n of bet a m et h as o n e pr o m pt e d t h e searc h f or st er oi ds t h at c o ul d be 
gi ve n at l o w plas m a c o n ce ntrati o ns f or a n e xt e n de d pe ri o d of ti m e wit h o ut t h e ass ociat e d st er oi d-li ke 
effects. T h e E D S , c o nsisti n g of de xa m et h as o n e s o di u m p h os p h at e ( D S P)  e n ca ps ulat e d i n a ut ol o g o us 
er yt hr oc yt es,  all o ws t h e a d mi nistrati o n of de xa m et h as o n e at l o w plas m a c o n ce ntrati o ns t h at are ass ociat e d 
wit h a p pr o xi m at el y 8 0 -8 5 % occ u pati o n of t h e gl u c oc ortic oi d rece pt or ( G R), si milar t o t h e G R occ u pa n c y 
t h at occ urs wit h t h e bet a m et h as o n e plas m a c o n ce ntrati o ns re p ort e d b y Br occ oletti et al, 2 0 1 1.  T h e E D S 
pr o vi des t h e be n efit of l o w a n d c o nst a nt plas m a deli ver y of de xa m et h as o n e wit h o ut t h e ass ociat e d st er oi d 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 4  of 1 3 2  
 
si de effects, des pit e l o n g-t er m use i n t h e pe diatric p o p ulati o n (R ossi et al, 2 0 0 1; L u ci di et al, 2 0 0 6; A n n ese 
et al, 2 0 0 5; B ossa et al, 2 0 0 8; Castr o et al, 2 0 0 7 ).  
T h e m ec h a nis m of acti o n of gl u c oc ortic oi ds i n pr o d u ci n g t h e be n efits o bser ve d i n A -T patie nts was 
p ost ulat e d t o occ ur t hr o u g h re g ulati o n of e x pressi o n of c ortic ost er oi d -res p o nsi ve ge n es, s u p pressi o n of 
i nfla m m at or y c yt o ki n es, or its effect as a n a nti o xi da nt (R uss o L. et al., 2 0 0 9 ). Rece ntl y, a n effect of 
de xa m et h as o n e o n A T M  ( At a xia Tela n giect asia M ut at e d) ge n e s plici n g i n a n A T l y m p h o blast oi d cell li n e, 
lea di n g t o pr o d u cti o n of a n e w acti ve A T M pr ot ei n varia nt, h as bee n de m o nstrat e d ( Me n ott a M. et al., 
2 0 1 2 ). T his m a y e x plai n i n part t h e be n eficial effect of treat m e nt wit h gl u c oc ortic oi d a n al o g u es i n A T 
patie nts. T h e res ults s h o w, f or t h e first ti m e i n m a m m alia n cells, a s h ort direct re peat -m e diat e d n o n -
ca n o nical s plici n g e ve nt i n d u ce d  b y de xa m et h as o n e t h at lea ds t o t h e s ki p pi n g of m ut ati o ns u pstrea m of 
n u cle oti de resi d u e 8 4 5 0 of A T M  C o di n g D N A Se q u e n ce ( C D S).  
A pil ot,  o pe n -la bel, 6-m o nt h  st u d y was  perf or m e d  wit h E D S -E P  i n A T patie nts (C h essa et al, 2 0 1 4 ). I n t his 
st u d y, st atisticall y si g nifica nt ( p = 0. 0 2; R M A N O V A) i m pr o ve m e nt (re d u cti o n) i n t h e I C A R S sc ore fr o m 
baseli n e t o e n d p oi nt ( ~ 4 p oi nts; I T T p o p ulati o n; n = 2 2) was o bser ve d . T h e decisi o n t o i nitiat e t h e o n g oi n g 
I E D A T-0 2 -2 0 1 5 d o u ble -bli n d, place b o -c o ntr olle d  st u d y i n A T patie nts  was base d o n t h e res ults fr o m t h e 
a b o ve  m e nti o n e d pil ot  st u d y, as well as t h e ot h er e vi de n ces of t h e be n efit of st er oi ds i n treati n g t h e disease, 
as descri be d a b o ve.   
R ati o n ale f or t he P atie nt P o p ul ati o n  
O nl y patie nts w h o partici pat e d i n t h e I E D A T-0 2 -2 0 1 5 trial  a n d m eet t h e f oll o wi n g  selecti o n crit eria will be 
eli gi ble f or t his  trial: c o m plet e d t h e f ull treat m e nt peri o d i n t h e I E D A T-0 2 -2 0 1 5 trial, c o m plet e d t h e st u dy 
assess m e nts, d o n ot prese nt safet y c o nt rai n dicati o ns t o c o nti n u ati o n of treat m e nt, a n d pr o vi de d  i nf or m e d 
c o nse nt. D uri n g t h e C O VI D -1 9 pa n de mic, s o m e patie nts h a d t o be disc o nti n u e d fr o m t h e I E D A T -0 2 -2 0 1 5 
trial; f or t his reas o n, t h e eili gi bilit y of t h e I E D A T-0 3 -2 0 1 8 ( O L E -I E D A T) trial h as bee n a me n de d t o all o w 
patie nts  w hic h were disc o nti n u e d  fr o m t h e A T Te S T st u d y, t o recei ve t h e Er y De x treat m e nt i n t he c o ntext 
of t h e O L E -I E D A T st u d y. Eli gi bilit y is s u bject t o t h e a bse n ce of safet y c o ntrai n dicati o n t o c o nti n u ati o n of 
treat m e nt, a n d pr o visi o n of  i nf or m e d c o nse nt. 
Pr oce d ure f or selecti n g p atie nts f or f urt her tre at me n t 
T h e  Pri n ci pal  I n vesti gat or will as k all patie nts w h o m eet t h e a b o ve re q uire m e nts, a n d det er mi n e t h eir 
i nt erest i n c o nti n ui n g t o recei ve treat m e nt wit h t h e st u d y m e dicati o n i n a n e w pr ot oc ol.  
T h e Pri n ci pal I n vesti gat or will t h e n det er mi n e t h e eli gi bilit y  of t h e patie nt s o n t h e basis of his/ h er cli nical 
j u d ge m e nt of patie nts’ st at us a n d t h eir safet y.  
A brief descri pti o n of t h e i m p ort a nt feat ures of A T is pr o vi de d pri or t o disc ussi n g t h e selecti o n crit eria.  
A t a xia tela n giect asia ( A T) is a rare i n h erit e d a u t os o m al recessi ve, m ultis yst e m dis or der, c h aract erize d b y 
t h e f oll o wi n g: pr o gressi ve n e ur ol o gic disease, i n cl u di n g cere bellar at a xia a n d oc ul o m ot or a pra xia; 
c ut a n e o us a n d oc ular t ela n giect asia ( 9 0 %); i n crease d al p h a -feto -pr ot ei n le vels ( 9 5 %); re d u ce d or a b se nt 
I g A le vels ( 7 0 %) a n d A T M pr ot ei n ( 9 8 %); i n crease d s usce pti bilit y t o c hr o nic n asal a n d p ul m o n ary 
i nfecti o ns ( 7 0 %); dela ye d or ga n m at urati o n; a n d i n crease d s usce pti bilit y t o X-ra ys a n d m ali g n a n cies 
(H oc h e et al, 2 0 1 2 ). I n c o u ntries w h ere m arria ge bet ween c o usi ns is u n c o m m o n, s u c h as i n t h e U. S., t he 
i n ci de n ce of A T is a b o ut 1 i n 4 0, 0 0 0 li ve birt hs. H o we ver, a m o n g et h nic gr o u ps w h ere c o usi n -c o usin 
m arria ges are c o m m o n, t h e i n ci de n ce i n creases si g nifica ntl y. T h e carrier fre q u e n c y is a p pr o xi m at el y 1 i n 
1 0 0 pers o ns (htt ps:// w w w. at a xia. or g/ p df/ At a xia % 2 0 Tela n giect asia. p df ). T h e esti m at e d pre vale n ce i n 
E ur o pe is 1 i n 1 0 0 ,0 0 0 p o p ulati o n ( Or p h a n et. 2 0 1 4 ). At a xia t ela n giect asia  is d u e t o m ut ati o ns i n t h e A T M 
ge n e l ocat e d o n h u m a n c hr o m os o m e 1 1 ( 1 1 q 2 2. 3). T h ese defects i n t h e A T M ge n e re d u ce or eli mi n at e t he 
f u n cti o n of t h e A T M pr ot ei n t h at c o ntr ols cell di visi o n a n d is i n v ol ve d i n d o u ble -stra n d D N A re pair  (Lee 
a n d Mc Ki n n o n, 2 0 0 0 ; B oe hrs et al, 2 0 0 7), t h us lea di n g t o re peat e d i nfecti o ns a n d m ali g n a n cies.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 5  of 1 3 2  
 
T h e o nset of s y m pt o ms bec o m es e vi de nt i n earl y c hil d h o o d w h e n c hil dre n de m o nstrat e u nstea di n ess w hile 
wal ki n g, or s wa yi n g w h e n st a n di n g still or sitti n g. M ost c hil dre n wit h A T h a ve st a ble n e ur ol o gic s y m pt o ms 
f or t h e first 4 t o 5 years of life, b ut be gi n t o s h o w i n creasi n g pr o ble ms i n earl y sc h o ol years. Oc ul o m ot or 
a pra xia, sl urre d s peec h, a n d diffic ulties i n s wall o wi n g a p pear i n lat e pre -sc h o ol a n d earl y sc h o ol a ge 
c hil dre n. A T pa tie nts are u n a ble t o c o ntr ol t h eir m uscles b y t h e ti m e t h e y are 1 0 t o 1 2 years of a ge, a n d t his 
m a y lea d t o pr o ble ms wit h fi n e  m ot or f u n cti o ns ( writi n g, c ol o ri n g, a n d usi n g ut e nsils t o eat), a n d sl urri n g 
of s peec h ( d ysart hria) t h at us u all y st o p pr o gressi n g  aft er t h e a ge of a b o ut 1 2 t o 1 5 years. M ost A T patie nts 
are restrict e d t o w h eelc h air use f or a m b ulati o n ar o u n d t his a ge. I n v ol u nt ar y m o ve m e nts s u c h as tre m ors, 
m y ocl o nic jer ks, d yst o nia, c h orea, at h et osis, et c., are varia ble i n t h e a ge of o nset a n d rat e o f pr o gressi o n. 
(B o der, 1 9 8 5; Perl m a n et al, 2 0 0 3; C h u n a n d Gatti, 2 0 0 4 ) T h e i m m u n e s yst e m bec o m es pr o gressi vel y 
wea ker, a n d rec urre nt res pirat or y i nfecti o ns a n d bl o o d ca n cers are n ot e d i n lat e -st a ge patie nts. T h ere is hi gh 
varia bilit y i n life -e x pect a n c y; h o we ver, m ost patie nts die ar o u n d t h e a ge of 2 5 years, lar gel y d u e t o c hr o nic 
l u n g disease or m ali g n a n cies. (P o u par d, 2 0 0 3; Cra wf or d et al, 2 0 0 6 ) 
T h e e xcl usi o n crit eria f or t h e st u d y are desi g n e d t o e xcl u de patie nts w h o w o ul d be at i n crease d ris k f or a n 
a d verse o ut c o m e relat e d t o treat m e nt wit h E D S -E P  or t h eir partici pati o n i n t h e trial d u e t o t h eir m e dical 
hist or y/c urre nt st at us or use of c o n c o mit a nt m e dicati o n. De xa m et h as o n e h as t erat o ge nic p ot e ntial i n 
r o de nts; t h eref ore, fe m ales of c hil d beari n g p ot e ntial will be i n cl u de d o nl y if t h e y are practici n g a de q u at e 
c o ntrace pti o n , as descri be d at S ecti o n 9. 2. 2 . P re g n a nt w o m e n will be  e xcl u de d. De xa m et h as o n e is e xcret e d 
i n breast mil k; t h eref ore, patie nts w h o are breast-fee di n g are als o e xcl u de d. Patie nts wit h A T are at i n crease d 
ris k of n e o plastic a n d i m m u n ol o gical diseases d u e t o t h e decrease d a bilit y of t h e A T M ge n e t o re pair D N A; 
t h eref ore, patie nts wit h t h ese c o n diti o ns are e xcl u de d.  
R ati o n ale f or t he St u dy Desi g n  
O pe n -l a bel Desi g n  
T h e o pe n -la bel desi g n all o ws patie nts w h o c o m plet e d t h e  f ull treat m e nt peri o d i n t h e I E D A T-0 2 -2 0 1 5 a n d 
all its assess m e nts  (or  were disc o nti n u e d  fr o m t h e St u d y I E D A T-0 2 -2 0 1 5 d uri n g t h e C O VI D -1 9 pa n de mic ), 
t o c o nti n u e treat me nt as l o n g as t h eir p h ysicia n det er mi n es t h e y are n ot e x perie n ci n g a n y a d verse effects 
t h at w o ul d n ecessit at e disc o nti n u ati o n of treat m e nt a n d d o n ot prese nt safet y c o ntrai n dicati o ns t o 
c o nti n u ati o n of treat m e nt .  T his st u d y als o gi ves patie nts w h o were rece i vi n g place b o treat m e nt i n t h e pri or 
st u d y t h e o p p ort u nit y t o st art treat m e nt wit h E D S-E P.  
Pri m ary E n d p oi nt  
T h e  pri m ar y o bjecti ve  is t o m o nit or a n d e val u at e t h e l o n g -t er m safet y a n d t olera bilit y of E D S-E P i n A T 
patie nts . T his will be d o n e base d o n t h e oc c urre n ce of Treat m e nt -E mer ge nt A d verse E ve nts ( T E A Es), 
i n cl u di n g Seri o us A Es a n d disc o nti n u ati o ns d u e t o A Es, a n d c h a n ges i n vit al si g ns, la b orat or y para m et ers, 
E C Gs a n d p h ysical/ n e ur ol o gical e xa mi n ati o n fi n di n gs . 
Ex pl or at ory E n d p oi nt  
T h e e x pl orat or y o bjec ti ve is to e val u at e t h e l o n g -t er m effect of E D S-E P i n treati n g C N S s y m pt o ms as 
m eas ure d b y t h e I nt er n ati o n al C o o perati ve At a xia Rati n g Scale (I C A R S), Cli nical Gl o bal I m pressi o n  of 
se verit y a n d c h a n ge ( C GI-S/ C) .  T his will all o w assess m e nt of w h et h er t h e be n efits o bser ve d i n t h e pri or 
st u d y (I E D A T-0 2) persist d uri n g l o n g -t er m treat m e nt.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 6  of 1 3 2  
 
Sec o n d ary  E n d p oi nt  
T h e sec o n dar y o bjecti ve is to e val u at e t h e l o n g -t er m effect of E D S-E P o n h ealt h relat e d Q u alit y of Life 
( Qo L; E Q -5 D -5 L scale).    
R ati o n ale f or E D S  D ose  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
   
 
  
 
 
e 
 
a 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 7  of 1 3 2  
 
 
   
R ati o n ale f or E ffic acy Me as ures  
T h e t h e l o n g t er m efficac y m eas ures  f or t his trial were select e d base d o n fee d bac k fr o m R e g ulat or y 
A ut h orities  a n d o n t h e pre vi o us st u d y I E D A T -0 2 -2 0 1 5 . T h e efficac y  m eas ures t o be use d i n t h e st u d y are 
descri be d bel o w.  
I nter n ati o n al C o o per ative At axi a R ati n g Sc ale ( I C A R S) 
T h e I C A R S will be use d t o m eas ure efficac y i n t h e st u d y. T h e i nt er n al c o nsist e n c y, crit eri o n -relat e d 
vali dit y, a n d i nt er n al c o nstr u ct vali dit y of t h e I C A R S h a ve bee n est a blis h e d i n patie nts wit h f ocal cere bellar 
lesi o ns (Sc h oc h B et al, 2 0 0 7 ). T h e i nt er-rat er relia bilit y, t est-ret est relia bilit y a n d i nt er n al c o nsist e n c y h a ve 
als o bee n vali dat e d i n patie nts wit h s pi n ocere bellar at a xia ( We yer et al, 2 0 0 7, Sc h mit z-H u bsc h et al , 
2 0 0 6a ). T h e I C A R S t ot al sc ore satisfie d all ps yc h o m etric crit eria i n a vali dati o n st u d y i n patie nts wit h 
Frie dric h’s At a xia  ( Ca n o et al, 2 0 0 5; Met z et al 2 0 1 3) T h e I C A R S h as bee n use d as a n  o ut c o m e m eas ure in 
i nt er ve nti o n al st u dies i n patie nts wit h at a xia, b ut t h ere are n o cli nical dat a t o s u g gest t h e m a g nit u de of 
c h a n ge o n t h e I C A R S t h at w o ul d c orres p o n d t o a cli nicall y rele va nt i m pr o ve m e nt, d u e t o t h e a bse n ce of 
a n y dr u g pr o d u ci n g s u c h a b e n efit. T h e I C A R S h as bee n use d i n se veral st u dies i n patie nts wit h Frie dreic h’s 
At a xia o ver t h e a ge of 8 years, i n p h ase 3 p ot e ntiall y pi v ot al trials ( L y n c h et al, 2 0 1 0 ), as well as i n o pe n-
la bel l o n g-t er m st u dies (Meier et al, 2 0 1 2 ).  
T h e I C A R S was use d als o i n t w o i nt er ve nti o nal st u dies i n c hil dre n wit h A T.   Za n olli et al, 2 0 1 2 s h o we d a 
st atisticall y si g nifica nt decrease i n t h e I C A R S t ot al sc ore i n a place b o -c o ntr olle d cr oss o ver st u d y i n 1 3 
c hil dre n wit h A T treat e d wit h oral bet a m et h as o n e ( Za n n olli et al , 2 0 1 2). Nisse n k or n et al, usi n g I C A R S as 
a sec o n dar y e n d p oi nt, s h o we d i m pr o ve m e nt i n t h e st atic a n d ki n etic s u bscales i n a s h ort -t er m o pe n-la bel 
st u d y i n 1 7 c hil dre n (fr o m 4 years of a ge) treat e d wit h a m a nt a di n e ( Nisse n k or n et al, 2 0 1 3 ).  
I n c o or di n ati o n of e ye m o ve m e nts, n yst a g m us a n d l oss i n sacca dic e ye m o ve m e nt c o ntr ol is o bser ve d earl y 
i n t h e A T disease pr ocess (H oc h e et al, 2 0 1 2 ). T h e I C A R S it e ms relati n g t o oc ular m otilit y d o n ot pr o vi de 
a c o m pre h e nsi ve assess m e nt of t his d o m ai n.  Als o, n o scale h as bee n vali dat e d f or t h e m eas ure m e nt of 
oc ular m otilit y  i n A T patie nts. T h e i n vesti gat or will be as ke d t o assess t h e oc ular m otilit y it e m base d o n t he 
sit e’s cli nical para di g m  a n d t h e i nstr u cti o ns f or rati n g t h e I C A R S .  
As A T is a se vere, rel e ntlessl y pr o gressi ve dis or der t h at lea ds t o l oss of i n de pe n de nt m o ve m e nt i n m ost 
patie nts b y t h e a ge of 1 0  t o1 6 years, a n y st atisticall y si g nifica nt differe n ce fr o m place b o o ver a 6 -m o nt h 
peri o d s h o ul d be c o nsi dere d as a treat m e nt s u ccess.  
M ost of t h e de vel o p m e nt al a n d vali dati o n st u dies of t h e I C A R S were perf or m e d i n patie nts w h o were 1 0 
years of a ge o r ol der. An i nt er n ati o nal st u d y h as bee n c o m plet e d ( Cli nical Trials. g o v : N C T 0 1 9 4 2 8 5 0 ) t o 
e xt e n d its vali dit y t o patie nts i n t h e a ge -ra n ge of 5 t o 10 years. Dat a c ollect e d fr o m t his  vali dati o n st u d y i n 
select e d ce nt ers [ Dat a o n file, Er y Del S. p. A] i n dicat e d t h at t h e distri b uti o n of sc ores f or t h e I C A R S f or 
patie nts wit h A T  u n der 1 0 years  of a ge  was si milar t o t h e sc ores f or t h ese patie nts o n ot h er vali dat e d scales 
s u c h as t h e S A R A (Sc h mit z -H u bsc h et al, 2 0 0 6 b ) a n d t h e B A R S ( Sc h m a h m a n n et al, 2 0 0 9 ). Dat a c ollect e d 
fr o m t h e vali dati o n st u d y i n select e d ce nt ers c o nfir m e d t h at t he se verit y of A T i n crease d wit h a ge  i n patie nts 
u n der t h e a ge of 1 0 years , as de m o nstrat e d b y a si g nifica nt c orrelati o n of t h e t ot al sc ores o n t h e I C A R S, 
S A R A, a n d t h e B A R S, b ut n ot f or patie nts a b o ve 1 0 years.   O verall, t h e distri b uti o n of sc ores f or t h e I C A R S 
f or 5 t o 1 0 year-ol d patie nts wit h A T was si milar t o t h e sc ores f or ot h er vali dat e d scales s u c h as t h e S A R A,  
B A R S , C GI -S a n d C GI u nstr uct ure d.   
T h ese l ocal rat er rati n gs will be use d i n t h e a n al ysis of t h e e x pl orat or y  e n d p oi nt.  
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 8  of 1 3 2  
 
Alt h o u g h t h e I C A R S will  be rat e d i n its e ntiret y, t h e  pri m ar y a n al yses will be li mit e d t o t h e ‘ M o difie d’ 
I C A R S; t his versi o n e xcl u des It e ms 8-1 2  relat e d t o k i n etic f u n cti o n a n d It e ms 1 7-1 9 relat e d t o  o c ul o m ot or 
f u n cti o ns t h at are re q uire d f or vis u al c o ntr ol, as t h ese it e ms are not directl y pre dicti ve of c h a n ge i n 
f u n cti o ni n g.  
C GI -C a n d C GI -S  
T h e Cli nical Gl o bal I m pressi o n ( C GI) c o nsist s of t w o 7 -p oi nt, cli nicia n -rat e d, Li kert-t y pe scales assessi n g 
c h a n ge fr o m baseli n e ( C GI -C) a n d se verit y of ill n ess ( C GI -S)  (G u y, 1 9 7 6 ). I n t h e c urre nt st u d y, a n o verall 
assess m e nt of t h e c h a n ge i n t h e patie nt’s n e ur ol o gical s y m pt o ms of A T, c o m pare d t o t h e  st at us at baseli n e, 
will be perf or m e d at eac h visit a n d use d as t h e ke y sec o n dar y efficac y m eas ure . T o e ns ure i n de pe n de n ce of 
t his rati n g fr o m t h e rati n g of t h e I C A R S (t h e pri m ar y efficac y m eas ure), a differe nt rat er will perf or m t he 
C GI -C.   
I n a d diti o n, t h e se verit y of ill n ess at baseli n e a n d at eac h s u bse q u e nt ti m e p oi nt will be assesse d usi n g t he 
C GI -S. N o versi o n of t h e  C GI -S  e xist s w hic h  h as  bee n s pecificall y a da pt e d f or use i n A T patie nts ; t h eref ore, 
a 5-p oi nt  str u ct ure d versi o n was de vel o pe d w hic h t a kes i nt o acc o u nt t he se verit y of t h e f oll o wi n g s y m pt o ms 
of A T: at a xia ( wal ki n g), d ysart hria, d ys m etria, e xtra p yra mi dal s y m pt o ms (c h orea, m y ocl o n us, d yst o nia, 
a n d tre m or), a n d e ye m o ve m e nts.  Rati n gs of n o n e, mil d, m o derat e, se vere , a n d ver y se vere are sel ect e d 
base d o n t h e le vel of s y m pt o m at ol o g y. A  pil ot vali dati o n st u d y h as bee n perf or m e d i n A T patie nts usi n g 
t h e C GI -S scale, a n d t h e res ults i n dicat e  t h at t h e C GI– S a de q u at el y discri mi n at e d patie nts wit h mil d, 
m o derat e , or se vere disease [ Dat a o n file, Er y Del S. p. A.] . T h e distri b uti o n of patie nts t o differe nt sc ores o n 
t h e C GI-S of A T was si milar usi n g t h e I C A R S, B A R S , a n d S A R A i n 6  t o 9 year -ol ds. T h e C GI -S f or 
patie nts ≥1 0 years of a ge was great er t h a n i n 6  t o 9 year -ol d patie nts; h o we ver, t h e distri b uti o n of sc ores o n 
t h e I C A R S, B A R S, a n d S A R A was si milar acr oss se verit y cat e g ories.  
Q o L Sc ale ( E Q -5 D -5 L ) 
I m pr o ve m e nts i n q u alit y of life ( Q o L) are a n i m p ort a nt g oal f or treat m e nt of patie nts wit h A T.  T h eref ore, 
t h e E Q -5 D -5 L  scale assessi n g Q o L h as bee n i n cl u de d as a sec o n dar y efficac y m eas ure.  T h e E Q -5 D is a 
st a n dar dize d i nstr u m e nt f or assessi n g h ealt h -relate d Q o L i n a variet y of h ealt h c o n diti o ns  (Ra bi n a n d de 
C h arr o, 2 0 0 1 ). T h e E Q -5 D -5 L  is a n e wer versi o n of t h e scale, w hic h i n cl u des fi ve le vels of se verit y f or 
eac h of t h e fi ve E Q -5 D di m e nsi o ns ( Her d m a n et al, 2 0 1 1), a n d h as bee n vali dat e d i n a di verse pati ent 
p o p ulati o n i n 6 c o u n tries, i n cl u di n g 8 patie nt gr o u ps wit h c hr o nic c o n diti o ns a n d a st u de nt c o h ort (Ja nssen 
et al, 2 0 1 3) . F or c hil dre n a n d a d olesce nts, t h e E Q-5 D -5 L a d mi nistrat ors will be trai n e d t o h el p t h e y o u n ger 
p o p ulati o n i n t h e st u d y c o m plet e t h e  scale.  Assess m e nt of t h e E Q -5 D -5 L  will be perf or m e d b y t h e  patie nt , 
or  t h e patie nt’s pare nt/care gi ver , at re g ular i nt er vals t hr o u g h o ut t h e st u d y.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 3 9  of 1 3 2  
 
8  
S T U D Y O B J E C TI V E S  
 
Pri m ar y O bjecti ve : 
• 
T o m o nit or a n d e val u at e t h e l o n g -t er m safet y a n d t olera bilit y of E D S-E P i n A T patie nts  
E x pl or at or y  O bjecti ve:  
• 
T o e val u at e t h e l o n g t er m effect of E D S -E P i n treati n g C N S s y m pt o ms as m eas ure d b y t h e “ M o difie d” 
I nt er n ati o nal C o o perati ve At a xia Rati n g Scale (m I C A R S), a n d Cli nical Gl o bal I m pressi o n of se verit y 
a n d c h a n ge ( C GI -S/ C)  
Sec o n d ar y  O bjecti ve:  
• 
T o e val u at e t h e l o n g -t er m effect of E D S-E P o n h ealt h relat e d Q u alit y of Life ( Q o L; E Q -5 D -5 L scale).  
 
9  
I N V E S TI G A TI O N A L P L A N   
9. 1   
St u d y Desi g n  
T his is a n i nt er n ati o n al ( N ort h A m erica, E ur o pe, Africa, Asia a n d A ustralia), m ulti -ce nter, pr os pecti ve, 
o pe n -la bel treat m e nt st u d y, desi g n e d t o c o nti n u e t o  pr o vi de t h e st u d y m e dicati o n t o all patie nts w h o 
c o m plet e d t h e f ull treat m e nt peri o d (i n cl u di n g t hose treat e d wit h place b o ) i n t h e I E D A T-0 2 -2 0 1 5 trial, 
c o m plet e d t h e st u d y assess m e nts, d o n ot prese nt safet y c o ntrai n dicati o ns t o c o nti n uati o n of treat m e nt an d 
pr o vi de d  i nf or m e d c o nse nt. D uri n g t h e C O VI D -1 9 pa n de mic, s o m e patie nts h a d t o be disc o nti n u e d fr o m 
t h e I E D A T-0 2 -2 0 1 5 trial; f or t his reas o n, t h e eili gi bilit y of t h e I E D A T -0 3 -2 0 1 8 ( O L E -I E D A T) trial h as 
bee n a m e n de d t o all o w patie nts w hic h were disc o nti n u e d fr o m t h e A T Te S T st u d y, t o recei ve t h e Er y De x 
treat m e nt i n t h e c o nt e xt of t h e O L E-I E D A T st u d y. Eli gi bilit y is s u bject t o t h e a bse n ce of safet y 
c o ntrai n dicati o n s t o c o nti n u ati o n of treat m e nt, a n d pr o visi o n of t h e i nf or m e d c o nse nt. 
T h e st u d y ai ms at c ollecti n g i nf or m ati o n o n t h e l o n g -t er m safet y a n d efficac y of t h e trial treat m e nt.  
Patie nts m eeti n g all selecti o n crit eria will recei ve m o nt hl y i nf usi o ns of E D S -E P (
 
). D uri n g t h e St u d y, l o n g t er m effi cac y assess m e nts will be e val u at e d e ver y 6 m o nt hs , w hile 
t h e safet y para m et ers will be assesse d at eac h m o nt hl y visit.  
T h e I C A R S, E Q -5 D -5 L a n d t h e C GI -C/ S will be a d mi nist ere d b y a sit e rat er.  
Listi n gs of t h e st u d y pr oce d ures t o be perf or m e d at eac h visi t are pr o vi de d  i n Secti o n 1 1. 0 .   
 
9. 2   
St u d y P o p ul ati o n   
9. 2. 1  
I ncl usi o n Criteri a  
T o be eli gi ble, t h e patie nt  m ust m eet all of t h e f oll o wi n g crit eria:  
1.  Patie nts c o m plet e d t h e d o u ble -bli n d peri o d i n t h e I E D A T -0 2 -2 0 1 5 trial a n d h a ve c o m plet e d t h e fi n al 
( Visit 1 5/ M o nt h 1 2) efficac y assess m e nts of I E D A T-0 2 -2 0 1 5  or disc o nti n u e d t h e st u d y d uri n g t he 
C O VI D -1 9 pa n de mic  
2.  Patie nts t olerat e d t h e st u d y m e dicati o n wit h o ut a n y e vi de n ce of st er oi d a d verse e ve nts, or treat m e nt -
relat e d se vere/ seri o us a d verse e ve nts. 
3.  B o d y wei g ht > 1 5 k g.  
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 0  of 1 3 2  
 
4.  T h e patie nt a n d his/ h er pare nt/care gi ver (if bel o w t h e a ge of c o nse nt), or a le gal re prese nt ati ve, h as 
pr o vi de d writt e n i nf or m e d c o nse nt t o partici pat e. If c o nse nt is pr o vi de d s olel y b y t h e care gi ver i n 
acc or da n ce wit h l ocal re g ulati o ns, t h e patie nt m ust pr o vi de asse nt t o partici pat e i n t h e st u d y.   
5.  Patie nt d oes n ot prese nt safet y c o ntrai n dicati o ns f or c o nti n u ati o n of treat m e nt , as det er mi ne d b y t h e 
Pri n ci pal I n vesti gat or ( PI) acc or di n g t o t h e pr oce d ures descri be d bel o w.  
Pr oce d ure f or selecti n g p atie nts f or f urt her tre at me nt  
T h e  Pri n ci pal  I n vesti gat or will as k all patie nts w h o m eet t h e a b o ve re q uire m e nts, a n d det er mi n e t h eir 
i nt erest i n c o nti n ui n g t o recei ve treat m e nt wit h t h e st u d y m e dicati o n i n a n e w pr ot oc ol. T h e Pri n ci pal 
I n vesti gat or will t h e n det er mi n e t h e eli gi bilit y of t h e patie nts o n t h e basis of his/ h er cli nical j u d ge m ent 
of patie nts’ st at us  a n d t h eir safet y.  
9. 2. 2  
E xcl usi o n Criteri a   
T o be eli gi ble, t h e patie nt  m ust n ot m eet a n y of t h e f oll o wi n g crit eria:  
Ge ner al  
1.  Fe m ales t h at are  
a.  pre g n a nt, or are breast -fee di n g (f or E U c o u ntries o nl y);  
b.  of c hil d beari n g p ot e ntial, pre g n a nt , or are breast -fee di n g (f or U S a n d Rest of W orl d c o u ntries).  
Fe m ales of c hil d be ari n g p ote nti al usi n g a de q u ate birt h c o ntr ol, as  deter mi ne d by t heir He alt h C are 
Pr ovi der, will be eli gi ble . 
2.  A disa bilit y t h at m a y pre ve nt t h e patie nt fr o m c o m pleti n g all st u d y re q uire m e nts.  
3.  C urre nt partici pati o n i n a n ot h er cli nical st u d y  wit h a n ot h er i n vesti gati o n al dr u g .  
Me dic al Hist ory a n d C urre nt St at us  
4.  C D 4 + l y m p h oc yt es c o u nt < 4 0 0/ m m 3 (f or patie nts 6 years of a ge) or < 1 5 0/ m m 3 (f or patie nts > 6 years). 
I n prese n ce of oral i nfecti o ns, li ke oral ca n di diasis, d oc u m e nt e d at t h e scree ni n g or rec urre nt as per 
m e dical hist or y d oc u m e nt ati o n, t he li mit i n creases t o < 2 0 0/ m m 3 (f or patie nts > 6 years).  
5.  C urre nt n e o plastic d isease. 
6.  Se vere i m pair m e nt of t h e i m m u n ol o gical s yst e m.  
7.  Se vere or u nst a ble p ul m o n ar y disease.  
8.  U n c o ntr olle d dia bet es.  
P atie nts wit h di a betes t h at h as bee n st a bilize d (i. e. n o hy p o glyce mic or hy per glyce mic e pis o des i n t he 
p ast 3 m o nt hs) will be eli gi ble.  
9.  A n y ot h er se vere, u nst a ble, or seri o us disease or c o n diti o n t h at i n t h e I n vesti gat or’s o pi ni o n w o ul d p ut 
t h e patie nt at ris k f or i m mi n e nt life-t hreat e ni n g m or bi dit y, n ee d f or h os pit alizati o n, or m ort alit y.  
1 0.  Eli gi bilit y of patie nts wit h a b n or m al la b orat or y t est val u es will be det er mi n e d b y t h e I n vesti gat or.  
1 1.  C o nfir m e d h e m o gl o bi n o pat hies, e. g. h e m o gl o bi n C disease, sic kle cel l a n e mia, or t h alasse mia.  
1 2.  M o derat e or se vere re n al a n d/ or h e patic i m pair m e nt.   
1 3.  Patie nts w h o e x perie n ce d m o derat e/ se vere st er oi d si de effects, or m o derat e/ se vere a d verse e ve nts 
ass ociat e d wit h t h e st u d y m e dicati o n a d mi nist ere d i n t h e I E D A T -0 2 st u d y. 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 1  of 1 3 2  
 
Pri or/ C o nc o mit a nt Me dic ati o n  
1 4.  Re q uires treat m e nt wit h a n oral or pare nt eral st er oi d. Tre at me nt wit h i n h ale d or i ntr a n as al ster oi ds 
f or ast h m a or aller gies, as well as use of t o pic al ster oi ds will be per mitte d.  
1 5.  Re q uires a n y ot h er c o n c o mit a nt m e dicati o n pr o hi bit e d b y t h e pr ot oc ol.  
1 6.  Use of a n y dr u g t h at is a str o n g i n d u cer/i n hi bit or of C Y P 3 A 4.  
 
9. 3   
Pre m at ure Disc o nti n u ati o n  
Patie nt s w h o disc o nti n u e fr o m t h e st u d y pre m at urel y m ust h a ve t h eir reas o n f or disc o nti n u ati o n e nt ere d in 
t h e Case Re p ort F or ms ( C R F s). Patie nt s w h o disc o nti n u e fr o m t h e st u d y aft er h a vi n g recei ve d a d ose of 
st u d y m e dicati o n will n ot be re place d.   
All patie nts  w h o disc o nti n u e pre m at urel y  will be as ke d t o ret ur n  f or t h e Safet y f oll o w u p visit.  
9. 4   
Rec or d of St u d y P artici p a nts a n d Scree ni n g F ail ures  
T h e i n vesti gat or will be re q uire d t o m ai nt ai n a c o nfi de ntial rec or d of all st u d y partici pa nts, i n cl u di n g all 
patie nt s w h o were scree n e d f or t h e st u d y, b ut were n ot e nr olle d  t o treat m e nt. T h e c o nfi de ntial rec or d m ust 
i n cl u de s ufficie nt i nf or m ati o n s o t h at it w o ul d be p ossi ble t o c o nt act t h e st u d y patie nt . I nf or m ati o n o n 
patie nt s w h o h a ve si g n e d I C Fs, b ut h a ve faile d scree ni n g, s h o ul d be e nt ere d o n t h e Scree n Fail ure C R F.  
T h e pri m ar y reas o n f or scree n fail ure will be rec or de d usi n g t h e f oll o wi n g cat e g ories: 
• 
Di d n ot m eet e ntr y crit eria  
• 
Maj or pr ot oc ol de viati o n  
• 
Pre -treat m e nt E ve nt/ A d verse E ve nt 
• 
L ost t o f oll o w -u p  
• 
V ol u nt ar y wit h dra wal (s pecif y reas o n)  
• 
St u d y t er mi n ati o n  
• 
Ot h er (s pecif y reas o n) . 
Patie nts will kee p t h e sa m e scree ni n g n u m ber assi g n e d d uri n g t h e I E D A T -0 2 -2 0 1 5 St u d y .   
 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 2  of 1 3 2  
 
1 0  S T U D Y M E DI C A TI O N  
1 0. 1  
  
 
 
.   
1 0. 1. 2   
 
 
 
 
  
1 0. 1. 3   
  
 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
   
 
  
  
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 3  of 1 3 2  
 
 
 
 
1 0. 2  
  
A descri pti o n of t h e E D S a n d det ails of t h e pr oce d ure f or t h e e n ca ps ulati o n pr ocess are pr o vi de d i n 
A p pe n di x 5 . 
C CI
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 4  of 1 3 2  
 
 
 
   
 
  
 
 
 
 
 
 
  
 
 
   
  
 
 
 
 
 
 
 
 
  
1 0. 4  Acc o u nt a bilit y  
D uri n g t h e c o urse of t h e st u d y, t h e st u d y p h ar m acist or  sit e pers o n n el desi g n at e d b y t h e I n vesti gat or t o 
m a n a ge t h e st u d y m e dicati o n  m us t rec or d t h e st u d y dr u g dis p ositi o n a n d kee p t h e acc o u nt a bilit y f or ms 
u p dat e d. T h e st u d y dr u g acc o u nt a bilit y f or ms will be cr oss -c h ec ke d wit h t h e E n ca ps ulati o n Pr oce d ure 
C h ec k -List ( A p pe n di x 7 ). A c o p y of t h e acc o u nt a bilit y f or ms m ust be ke pt i n t h e st u d y files at t h e sit e, a n d 
t h e ot h er c o p y will be wit h dra w n b y t h e C R O st aff res p o nsi ble f or m o nit ori n g t h e st u d y m e dicati o n . The 
use d a n d u n use d de xa m et h as o n e  vials,  as well as t h e E n ca ps ulati o n Pr oce d ure C h ec k -List , will be ke pt at 
t h e sit e f or acc o u nti n g a n d rec o n ciliati o n b y t h e C R A vs. t h e st u d y d oc u m e nt ati o n. T h e use d i nf usi o n ba gs 
c o nt ai ni n g a n y re m ai ni n g er yt hr oc yt es ( wit h D S P e n ca ps ulat e d) will be dis p ose d of at t h e sit e, wit h 
a p pr o priat e d oc u m e nt ati o n.  
1 0. 5  O ver d ose  
Eac h i nf usi o n s h o ul d c o nt ai n  a 
 e n ca ps ulat e d i n a ut ol o g o us R B Cs.  
H o we ver, b ase d u p o n  res ults of pri or st u dies, s o m e i nt er-i n di vi d u al varia bilit y i n l oa de d d ose is e x pect e d; 
t h eref ore, a d mi nist ere d  d oses of  D S P  great er  
 will be c o nsi dere d a n o ver d ose. Treat m e nt f or a n 
o ver d ose s h o ul d be t h e sa m e as  t h e cli nical m a n a ge m e nt f or a n o ver d ose of de xa m et h as o n e .  
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 5  of 1 3 2  
 
1 0. 6  Occ u p ati o n al S afet y  
T h ere are n o ris ks a ntici pat e d  relat e d t o t h e st u d y m e dicati o n f or t h e st aff i n v ol ve d i n a d mi nist eri n g E D S  
t o t h e patie nt s i n t his st u d y. St a n dar d pr oce d ures a n d preca uti o ns f or h a n dli n g n ee dles a n d bi ol o gical 
sa m ples s h o ul d be f oll o we d.   
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 6  of 1 3 2  
 
1 1  E V A L U A TI O N S A N D P R O C E D U R E S   
1 1. 1  Writte n I nf or me d C o nse nt   
Writt e n I nf or m e d C o nse n t m ust be o bt ai n e d fr o m t h e  patie nt a n d his/ h er pare nt/care gi ver (if bel o w t h e a ge 
of c o nse nt), or le gal re prese nt ati ve (if n ecessar y), at baseli n e  pri or t o i nitiati n g a n y st u d y pr oce d ures 
re q uire d b y t h e pr ot oc ol, acc or di n g t o t h e pr oce d ure descri be d i n S ecti o n 1 7 .  
T his pr ocess s h o ul d be perf or m e d at scree ni n g o nl y f or patie nts w h ic h will be e nr olle d wit h o ut c o m pletin g 
t h e A T Te S T trial (i. e. w h o were  disc o nti n u e d  fr o m t h e St u d y I E D A T-0 2 -2 0 1 5 d uri n g t h e C O VI D -1 9 
pa n de mic ), a n d w h o m a y  n ot h a ve fi n al e val u ati o ns f or I E D A T -0 2 -2 0 1 5 st u d y ( Visit 1 5/ M o nt h 1 2) ; t h ese 
patie nts will h a ve t o u n der g o a scree ni n g p h ase bef ore t h e baseli n e visit, t h eref ore c o nse nti n g s h o ul d be 
perf or m e d bef ore a n y scree ni n g relat e d pr oce d ure t a kes place.  
If c o nse nt is pr o vi de d s olel y b y t h e care gi ver i n acc or da n ce wit h l ocal re g ulati o ns, t h e patie nt m ust pr o vi de 
asse nt t o partici pat e i n t h e st u d y.  T h e det ails of t h e st u d y s h o ul d be disc usse d wit h t h e patie nt  a n d 
pare nt/care gi ver or le gal re prese nt ati ve (if n ecessa r y) pri or t o o bt ai ni n g i nf or m e d c o nse nt , a n d the I nf or med 
C o nse nt F or m  (I C F) m ust be si g n e d a n d dat e d b y t h e patie nt, pare nt/care gi ver/ le gal re prese nt ati ve (if 
n ecessar y),  a n d b y t h e I n vesti gat or or his/ h er desi g n ee. A c o p y of t h e si g n e d I C F will be pr o vi de d t o t he 
patie nt , a n d t h e ori gi n al will be ret ai n e d wit h t h e s o urce d oc u m e nts.  
1 1. 2  St u d y C o n d uct   
T h e str u ct ure of t his st u d y  o pe n -la bel e xt e nsi o n  treat m e nt st u d y, as well as a det aile d listi n g of t he 
assess m e nts a n d pr oce d ures t o be perf or m e d at eac h visit is pr o vi de d i n Secti o n 1 1. 4 . T h e sa m e sc h e m e a n d 
assess m e nts will be re plicat e d f or t h e sec o n d year o n war ds . 
As a res ults of t h e C O VI D -1 9 pa n de mic, t e m p orar y c h a n ges t o t h e p r ot oc ol h a ve bee n i m plem e n t e d. T h ese 
c h a n ges are descri be d i n A p pe n di x 1 3 . 
Scree ni n g p h ase  
A p plica ble o nl y f or patie nts w h ic h will be e nr olle d wit h o ut c o m pleti n g t h e A T Te S T trial . 
Aft er pr o vi di n g c o nse nt/asse nt, as descri be d i n Secti o n 1 1. 1 , patie nts will e nt er t h e scree ni n g p h ase. T h e 
scree ni n g p h ase will last at m a xi m u m 3 0 da ys .  A n y pre vi o us treat m e nts wit h  c ortic ost er oi d c o m p o u n ds 
will be wit h dra w n ( was h o ut fr o m pre vi o us treat m e nt), w hile f or ot h er patie nts t h e scree ni n g p h ase m a y  
c oi n ci de wit h t h e scree ni n g visit ( 1 da y l o n g , pr o vi de d t h at all t h e re q uire d la b orat or y re p orts are a vaila ble 
a n d re vie we d bef ore t h e eli gi bilit y c o nfir m ati o n at t h e basel i n e). 
As s o o n as all scree ni n g 
assess m e nts/ pr oce d ures h a ve bee n perf or m e d a n d  eli gi bilit y is c o nfir m e d, t h e patie nts ca n u n der g o t he 
baseli n e visit.  
T h e scree ni n g e val u ati o n descri be d i n Secti o n 1 1. 4  will be perf or m e d.  
If a n y a b n or m al la b orat or y t est res ults, vit al si g n m eas ure m e nts, or E C G fi n di n gs of cli nical si g nifica n ce 
are n ot e d at t h e scree ni n g visit, t h ese m ust be re peat e d d uri n g t h e 3 0 -da y scree ni n g peri o d a n d t h e res ults 
m a de a vaila ble pri or t o m a ki n g t h e fi n al decisi o n o n a patie nt’s eli gi bilit y f or t h e st u d y at Baseli n e. A d verse 
e ve nts, re p ort e d b y t h e patie nt or o bser ve d b y t h e i n vesti gat or, a n d t h e use of c o n c o mit a nt m e dicati o n will 
be rec or de d fr o m t h e ti m e of si g ni n g t h e i nf or m e d c o nse nt t hr o u g h t he e n d of t h e st u d y. 
B aseli ne  
Fi n a l e val u ati o ns f or  t h e I E D A T-0 2 -2 0 1 5  trial will ser ve as baseli n e e val u ati o ns f or patie nts c o nti n ui n g i n 
t h e I E D A T-0 3 -2 0 1 8  st u d y. T h e f oll o wi n g “ baseli n e” assess m e nts f or I E D A T -0 3 -2 0 1 8 will be d o n e as 
part of t h e fi n al Vist 1 5  e val u ati o n i n St u d y I E D A T -0 2 -2 0 1 5: p h ysical/ n e ur ol o gical exa mi n ati o n; 1 2 -lea d 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 7  of 1 3 2  
 
st a n dar d E C G; la b orat or y e val u ati o ns [i n cl u di n g h e m at ol o g y, cli nical c h e mistr y, uri n al ysis, ser u m 
pre g n a n c y t est ( w o m e n of c hil d beari n g p ot e ntial); s pecial la b orat or y t ests: H b A 1c, C D 4 + l y m p h oc yt es 
c o u nt  a n d C R P ]; assess m e nt of p h ysical de vel o p m e nt, se x u al  m at urati o n, a n d t h e effect of treat m e nt wit h 
de xa m et h as o n e o n t h ese as pects ( Ta n n er scale);  I C A R S; C GI-S; C GI -S; V A B S: E Q -5 D -5 L; C -S S R S; 
B M D; re vie w of A Es a n d c o n c o mit a nt m e dicati o ns.  
Aft er pr o vi di n g c o nse nt /asse nt, as descri be d i n Secti o n 1 1. 1 , eac h patie nt will u n der g o e val u ati o n of t he 
eli gi bilit y crit eria  at t h e baseli n e visit,  a n d if eli gi ble , will pr ocee d wit h t h e E D S -E P i nf usi o n .  De m o gr a p hic 
i nf or m ati o n will be r olle d o ver fr o m t h e I E D A T-0 2 -2 0 1 5 e C R F a n d rec h ec ke d b y t h e I n vesti gat ors f or 
c o nsist e n c y, as well as m e dical hist or y.  
Bef ore t h e E D S -E P i nf usi o n, all patie nts will u n der g o vit al si g ns e val u ati o n , h e m ol ysis pa n el ( o n t he 
di vert e d bl o o d sa m ple , see Secti o n 1 1. 5 ) a n d assess m e nt of pri or a n d c o n c o mit a nt m e dicati o n a n d A Es . 
W o m e n of c hil d beari n g p ot e ntial m ust u n der g o a uri n e pre g n a n c y t est. . 
 
 
 
 
 
 
 
 
  
St u d y treat m e nt a d mi nistrati o n b y I V i nf usi o n will be perf or m e d wit hi n 3 0 mi n aft er t h e E D S pr ocess h as 
bee n c o m plet e d.  
 
 
 
 
  
Aft er c o m pleti o n of t h e I V i nf usi o n of  t h e st u d y treat m e nt t h e f oll o wi n g assessm e nts will be perf or m e d o n 
Da y 0 ( B aseli n e/ Visit  1) : Vit al si g ns ,  p h ysical e xa mi n ati o n ( 1-2 hr aft er i nf usi o n) , assess m e nt of A Es, a n d 
assess m e nt of c o n c o mit a nt m e dicati o ns.  
M o nt hs 1 -5 a n d 7 - 1 1  
Bef ore t h e E D S -E P i nf usi o n, patie nts m ust u n der g o t o l a b orat or y t ests: t h e di vert ed bl o o d sa m ple (see 
Secti o n 1 1. 5 ) will be c ollect e d f or m eas ure m e nt of ser u m creati ni n e a n d r o uti n e t ests. 
W o m e n of 
c hil d beari n g p ot e ntial m ust u n der g o a pre g n a n c y uri n e t est.  
A  C -S S R S assess m e nt, will be perf or m e d at eac h of t h ese visits , as well as  a vit al si g ns assess m e nt . I n 
a d diti o n,  a h e m ol ysis pa n el o n di vert e d bl o o d sa m ple  (see Secti o n 1 1. 5 ) will be d o n e at t h e M o nt h 4 a n d 
M o nt h 8 visits .  
All patie nts s h o ul d u n der g o assess m e nt of pri or a n d c o n c o mit a nt m e dicati o n a n d A Es.  
 
 
 
 
 
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 8  of 1 3 2  
 
 
 
 
  
St u d y treat m e nt a d mi nistrati o n b y I V i nf usi o n, will be perf or m e d wit hi n 3 0 mi n aft er t h e E D S pr ocess h as 
bee n c o m plet e d.  
T h e sat ellit e sa m ple ba g will be  det ac h e d a n d  use d f or st erilit y c ult ure t ests: a sa m ple of t h e E D S -E P 
(a p pr o xi m at el y 1 ml per i n oc ul u m f or a t ot al of 2 m L) will be c ollect e d t o perf or m a st erilit y t est usi n g a 
c ult ure -base d m et h o d as prese nt e d i n  A p pe n di x 1 0 . A 1 -m L st erile sa m ple of t h e E D S -E P will be st ore d 
u n der refri gerati o n as a " Ret e nti o n Sa m ple".  I n case of p ositi ve/c o nt a mi n ate d post -release st erilit y res ults, 
a n acti o n pla n h as bee n est a blis h e d as prese nt e d i n Secti o n 1 3. 6 a n d i n A p pe n di x 1 1 .  
Aft er c o m pleti o n of t h e I V i nf usi o n of t h e st u d y treat m e nt t h e f oll o wi n g assess m e nts will be perf or m e d : 
Vit al si g ns , p h ysical e xa mi n ati o n (1 -2 hr aft er i nf usi o n) , assess m e nt of A Es, a n d assess m e nt of c o n c o mitant 
m e dicati o ns  
M o nt hs 6 a n d 1 2  
At M o nt hs 6 a n d 1 2 t h e f oll o wi n g assess m e nts will be perf or m e d bef ore treat m e nt a d mi nistrati o n : all 
assess m e nts o f efficac y (I C A R S, C GI-C, C GI -S  a n d E Q -5 D -5 L ) a n d safet y ( vit al si g ns, E C G, r o utine 
la b orat or y t ests o n t h e di vert e d bl o o d sa m ples  (see Secti o n 1 1. 5 ), p h ysical a n d n e ur ol o gical e xa mi n ati o ns, 
C -S S R S, B M D a n d assess m e nts of A Es a n d c o n c o mit a nt m e dicati o n use), as well as s pecial la b orat or y t es ts 
(H b A 1c, C D 4 + l y m p h oc yt es c o u nt  a n d C R P ), o n t h e di vert e d bl o o d sa m ples (see Secti o n 1 1. 5 ). A ser u m 
( o n t h e di vert e d bl o o d sa m ples, see Secti o n 1 1. 5 ) a n d uri n e pre g n a n c y t est will be perf or m e d f or w o m e n of 
c hil d beari n g p ot e ntial.  P h ysical de vel o p m e nt, se x u al 
m at urati o n, a n d t h e effect of treat m e nt wit h 
de xa m et h as o n e o n t h ese as pects  will be assesse d ( Ta n n er scale) . Ta n n er st a gi n g of t h e breasts i n pre-
m e n arc h al fe m ales a n d of t h e scr ot u m i n m ales w h o h a ve n ot c o m plet e d p u bert y, will be perf or m e d at 
M o nt hs 6 a n d 1 2. P ost -m e n arc h al fe m ales a n d m ales w h o h a ve c o m plet e d p u bert y will be e xcl u de d fr o m 
t his gr o wt h a n al ysis. 
 
 
 
 
 
 
 
 
  
St u d y treat m e nt a d mi nistrati o n b y I V i nf usi o n, will be perf or m e d wit hi n 3 0 mi n aft er t h e E D S pr ocess h as 
bee n c o m plet e d.  
 
 
 
 
  
Aft er c o m pleti o n of t h e I V i nf usi o n of t h e st u d y treat m e nt, a p h ysical e xa mi n ati o n a n d vit al si g ns will be 
perf or m e d ( 1 -2 hr aft er i nf usi o n), as well as assess m e nts of A Es a n d c o n c o mit a nt m e dicati o n use . 
C CI
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 4 9  of 1 3 2  
 
A M o nt h 1 2 i nf usi o n, a n d all of t h e ass ociat e d pr oce d ures, w o ul d o nl y be d o n e i n patie nts w h o are 
c o nti n ui n g o pe n la bel treat m e nt past o n e year . T h e sc h e d ule of visits a n d assess m e nts  f or t h e first 1 2 m o nt hs 
- as descri be d a b o ve - will be re plicat e d f or t h e sec o n d year o n war ds .  
S afety F oll o w -u p Visit  
All patie nts w h o disc o nti n u e will be re q uire d t o ret ur n f or a Safet y F oll o w -u p Visit a p pr o xi m at el y  6 0 da ys 
( ± 7 da ys) aft er t h eir last i n f usi o n. At t his visit, plas m a c ortis ol, h e m ol ysis pa n el, pre g n a n c y st at us (f or 
w o m e n of c hil d beari n g p ot e ntial), C -S S R S, a n d vit al si g ns will be assesse d, as well as  t h e occ urre n ce of 
a n y A Es or Seri o us A Es ( S A Es) re p ort e d b y t h e patie nt/care gi ver or o bse r ve d b y t h e I n vesti gat or si n ce t he 
pre vi o us visit . 
Ev al u ati o n a n d I nf usi o n Sc he d ule  
T h e m o nt hl y i nf usi o ns s h o ul d be perf or m e d e ver y 2 1 -2 8 da ys. A wi n d o w of + 1 0 da ys will be peri mitt ed 
o n eac h of t h e sc h e d ule d m o nt hl y visits. T h eref ore, n o E D S -E P i nf usi o n s h o ul d be perf or m e d less t h a n 2 1 
da ys or m ore t h a n 3 8 da ys aft er t h e pre vi o us i nf usi o n. T h e wi n d o w bet wee n a n i nf usi o n a n d t h e s u bse q u ent 
o n e s h o ul d be ke pt as re g ular as p ossi ble t hr o u g h o ut t h e st u d y, a v oi di n g fl u ct u ati o ns i n a d mi nistration 
wi n d o ws. T h e dat e of a n i nf usi o n is n ot b o u n d t o t h e dat e of t h e i nitial treat m e nt b ut t o t h e dat e of t he 
pre vi o us I M P a d mi nistrati o n I nf usi o ns s h o ul d n ot be s ki p pe d; t h eref ore, if n ecessar y, t h e i nf usi o n sc h e d ule 
ca n be m o difie d t o c o nf or m t o t h e a b o ve g ui deli n es.  
1 1. 3  Sc he d ule of Visits a n d Assess me nts   
A n o ver vie w of t h e sc h e d ule of e val u ati o ns f or t h e st u d y is prese nt e d i n Ta ble  2  f or t h e first 1 2 m o nt hs will 
be re plicat e d f or t h e sec o n d year o n war ds . 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 
A pril 2 0 1 9, Fi n al;  Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 0  of 1 3 2  
 
T a ble 2 . Sc he d ule of Visits a n d Assess me nts: 1 st ye ar of o pe n-l a bel e xte nsi o n tre at me nt (t o be re plic ate d f or t he sec o n d ye ar o n w ar ds) 
Visit ( V)  Sc r e e ni n g 
P h ase *  
B aseli ne/
V 1 ( &)  
 
V 2   
V 3   
V 4   
V 5   
V 6   
V 7   
V 8   
V 9   
V 1 0   
V 1 1   
V 1 2   
V 1 3  
S af et y 
f oll o w u p 
visits (e)  
St u d y D a y o r M o nt h ( D/ M) (i)   D -3 0 t o -1  
D 0  
M o nt h  
1  
M o nt h  
2  
M o nt h  
3  
M o nt h  
4  
M o nt h  
5  
M o nt h  
6  
M o nt h  
7  
M o nt h  
8  
M o nt h  
9  
M o nt h  
1 0  
M o nt h  
1 1  
M o nt h  
1 2 (l)  
~ 6 0 d a ys 
afte r l ast 
i nf usi o n 
Pr o c e d ur e ( §)  
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
I nf or m e d C o nse nt Si g n at ure 
X   
X ( pre)   
  
  
  
  
  
  
  
  
  
  
  
 
 
I n cl usi o n/ E x cl usi o n Crit eria  
X   
X ( pre)   
  
  
  
  
  
  
  
  
  
  
  
 
 
 
 
  
  
  
  
  
  
  
  
  
  
  
  
 
 
E D S -E P I nf usi o n ( h)  
 
1   
2   
3   
4   
5   
6   
7   
8   
9   
1 0   
1 1   
1 2   
1 3   
 
C ult ure -b a se d st erilit y t est (j)  
  
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)   
X ( p ost)  
X ( p ost)   
X ( p ost)   
 
Ne ur ol o gic al E x a mi n ati o n  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
P h ysic al E x a mi n ati o n ( k)  
X  
X ( p ost)   
X( p ost)   
X( p ost)   
X( p ost)   
X ( p ost)   
X( p ost)  
X ( pre; 
p ost)  
X( p ost)   
X( p ost)   
X( p ost)  
X( p ost)   
X( p ost)   
X ( pre; 
p ost)  
 
Ta n n er Sc ale  
X  
  
  
  
  
  
  
X ( pre)  
  
  
  
  
  
X ( pre)   
 
Vit al Si g ns ( h)  
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X   
X  
E C G  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
R o uti n e La b orat or y Tests (a)  
X  
  
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
 
Ser u m cre ati ni n e ( g) 
 
  
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
  
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
X ( pre)   
 
 
B o n e Mi n eral De nsit y  
X  
  
  
  
  
  
  
X ( pre)   
  
  
  
  
  
X ( pre)   
 
Ser u m( $)/ Uri n e( *) Pre g n a n c y Test 
( d) 
X ( $, *; pre) 
X( *, pre)   
X( *; pre)   
X( *; pre)   
X( *; pre)   
X( *; pre)   
X( *; pre)   X( $, *; pre)   X( *; pre)   
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I C A R S  
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C GI -C  
 
  
  
  
  
  
  
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C GI -S  
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Q u alit y of Lif e ( E Q -5 D -5 L)  
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C -S S R S  
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H e m ol ysis p a n el ( m)  
  
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S p e cial La b orat or y Tests ( b; c)  
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E D S e n d pr o d u ct sa m ple (f)  
  
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Pri or/ C o n c o mit a nt Tre at m e nts  
T hr o u g h o ut t h e d urati o n of t h e st u d y  
A d v erse E v e nts  
T hr o u g h o ut t h e d urati o n of t h e st u d y 
 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 
A pril 2 0 1 9, Fi n al;  Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 1  of 1 3 2  
 
*      A p plic a ble o nl y f or p atie nts w h ic h will b e e nr olle d wit h o ut c o m pleti n g t h e A T Te S T trial (i. e. w h o w ere  dis c o nti n u e d fr o m t h e St u d y I E D A T-0 2 -2 0 1 5 d uri n g t h e C O VI D -
1 9 p a n d e mic ), a n d w h ic h m a y  n ot h a v e fi nal e v al u ati o ns f or I E D A T -0 2 -2 0 1 5 st u d y ( Visit 1 5/ M o nt h 1 2). Patie nts si g ni n g t h e i nf or m e d c o ns e nt f or m or ass e nt, as a p plic a ble, 
at t his visit d o n ot n e e d t o re c o ns e nt at b as eli n e visit.  
&)  T h e f oll o wi n g “ b as eli n e ” ass ess m e nts f or  I E D A T-0 3 -2 0 1 8  will b e d o n e as p art of t h e fi n al M o nt h 1 2 e v al u ati o n i n St u d y I E D A T -0 2 -2 0 1 5: p h ysic al/ n e ur ol o gical 
e x a mi n ati o n ; 1 2 -le a d sta n d ar d E C G; la b orat or y e v al uati o ns  [i n cl u di n g h e mat ol o g y , cli nic al c he mistr y, uri n al ysis , s er u m pre g n a nc y test ( w o m e n of c hil d be ari n g p ote ntial) ; 
sp e cial la b orat or y tests: H b A 1 c, C D 4 + l y m p h o c ytes c o u nt  a n d C R P]; Ta n n er  s c ale; I C A R S; C GI-S; C GI -C; V A B S: E Q -5 D -5 L ; C-S S R S; B M D; Re vie w of A Es a n d 
c o n c o mita nt m e dicati o ns.  
 
a) 
R o uti n e la b orat or y ass ess m e nts t o i n cl u d e c o m plete h e m at ol o g y, bi o c he mistr y, a n d uri nal ysis. 
b) 
S p e cial la b orat or y tests i n cl u d e H b A 1c, C D 4 + l y m p h o c ytes c o u nt  a n d  C R P .   
c) 
Bl o o d s a m ple t o b e c olle cte d b ef ore 8: 0 0 A M f or m e as ure m e nt of plas ma c ortis ol at t h e f oll o wi n g ti m es: ( 1 ) w h e n p atie nts are s y m pt o matic, a n d (2 ) w h e n p atie nts are at 
m ost ris k f or a dre n al i ns ufficie nc y a n d a dre n al crisis, s u c h as f oll o wi n g dis c o nti n u ati o n or i nterr u pti o ns of d e x a m et h as o n e d osi n g (i. e., l o a di n g f ail ures a n d f oll o win g 
dis c o nti n u ati o n of t h e st u d y dr u g) .   
d) 
F or w o m e n of c hil d b e ari n g p ote ntial o nl y.  T h e test res ults m ust b e n e gati v e at b as eli n e ( uri n e) f or t h e p atie nt t o b e eli gi ble f or t h e st u d y. Uri n e pre g n a n c y test will be 
p erf or m e d b ef ore e v er y i nf usi o n , w hile s er u m pre g n a n c y test will b e p erf or me d at M o nt h 6,  1 2  a n d s afet y f oll o w u p visit .  
e) 
A Saf et y F oll o w -u p ass ess m e nt will b e p erf or m e d a p pr o xi m atel y 6 0 d a ys ( ± 7 d a ys) after  t h e fi n al i nf usi o n; at t his visit, plas m a c ortis ol, pre g n a n c y stat us (f or w o m e n of 
c hil d b e ari n g p ote ntial), vital si g ns will b e ass ess e d, a s w ell as t h e o c c urre nc e of a n y A Es or Seri o us A Es si n c e t h e fi n al e v al u ati o n will b e re p orte d.   
f)  U p o n c o m pleti o n of t h e E D S pr o c ess , t h e re m ai ni n g s a m ple i n t h e s atellite s a m ple b a g or, if t his is n ot a v aila ble, a s a m ple c olle cte d fr o m a n ot h er E D S -E P s a m p li n g p oint, 
will b e us e d f or d eter mi n ati o n of D S P c o nte nt a n d C B C .  
g)  
Bl o o d s a m ple f or s er u m cre ati ni n e m e as ure m e nt t o b e ta k e n b ef ore i nf usi o n.  
h) 
Vital si g ns  t o b e p erf or m e d at e a c h visit pre a n d p ost i nf usi o n (at s af et y f oll o w u p visit, o nl y o n c e). Vital si g ns t o i n cl u d e h ei g ht a n d w ei g ht m e as ure m e nts i n tri plic ate at 
s cre e ni n g, b as eli n e, M o nt h 6 a n d 1 2 .  
i)  
T h e m o nt hl y i nf usi o ns s h o ul d b e p erf or me d e v er y 2 1 -2 8 d a ys. A wi n d o w of + 1 0 d a ys  will b e p er mitte d  o n e a c h of t h e s c h e d ule d m o nt hl y visits. T h eref ore, n o E D S -E P 
i nf usi o n s h o ul d b e p erf or m e d less t h a n 2 1 d a ys or m ore t h a n 3 8 d a ys after t h e pre vi o us i nf usi o n. T h e wi n d o w b et w ee n a n i nf usi o n a n d t h e s u bs e q u e nt o n e s h o ul d b e ke pt 
as re g ular as p ossi ble t hr o u g h o ut t h e st u d y, a v oi di n g fl u ct uati o ns i n a d mi nistrati o n wi n d o ws. T h e d ate of a n i nf usi o n is n ot b o u n d t o t h e d ate of t h e i nitial tre at m e nt b ut to 
t h e d ate of t h e pre vi o us I M P a d mi nistrati o n.. 
j)  
1 m L bl o o d c olle c te d, after bl o o d di v ersi o n, f or a er o bic c ult ure, b ef ore E D S pr o c ess (s e e “ St u d y Pr o c e d ures o n Sterilit y Testi n g  f or St u d y I E D A T-0 3 -2 0 1 8 ( O L E -I E D A T)”; 
A p p e n di x 9 ). M ore o v er, a s a m ple of t h e E D S-E P (a p pr o xi m atel y 1 ml p er i n o c ul u m f or a t otal of 2 m L) will b e c olle cte d fr o m s atellite s a m ple b a g, t o p erf or m a c ult ure-
b as e d sterilit y test. A 1 m L sterilit y s a m ple of t h e E D S -E P will b e st ore d u n d er refri gerati o n as a “ Rete nti o n Sa m p le ”. 
k) 
At M o nt h 1 -5 a n d 7 -1 1 visits, p h ysic al e x a mi nati o n a n d vital si g ns 1 -2 hr after t h e e n d of i nf usi o n. At M o nt h 6 a n d 1 2 visits, t h e p h ysic al e x a mi n ati o n will b e p erf or me d 
pre -d os e as w ell.  
l)  
M o nt h 1 2 i nf usi o n, a n d all of t h e ass ociate d pr o c e d ures, w o ul d o nl y b e d o ne i n p atie nts w h o are c o nti n ui n g o p e n la b el tre at m e nt p ast o n e y e ar  
m)  H e m ol ysis p a n el , i n cl u di n g uri n al ysis  
 
( §)   As a res ults of t h e C O VI D -1 9 p a n de mic, te m p orar y a d diti o nal s afet y ass ess m e nts m a y b e re q u este d at s o m e visits. T h es e c h a n ges are d es cri b e d i n A p p e n di x 1 3 . 
( pre) Pre E D S-E P i nf usi o n pr o c e d ure  
( p ost) P ost E D S-E P i nf usi o n pr o ce d ure

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 2  of 1 3 2  
 
1 1. 4  Visit Sc he d ule a n d Assess me nts   
1 1. 4. 1  Scree ni n g p h ase ( D -3 0 t o -1 ) 
A p plica ble o nl y f or patie nts w h ic h will be e nr olle d wit h o ut c o m pleti n g t he A T Te S T trial . 
 
After pr o vi di n g c o nse nt/asse nt, as descri be d i n Secti o n 1 1. 1 , patie nts will e nter t he scree ni ng p hase. T he 
scree ni n g p hase will last at ma xi m u m 3 0 da ys.  A n y pre vi o us treat me nts wit h c ortic oster oi d c o m p o u n ds 
will be wit h dra w n ( was h o ut fr o m pre vi o us treat me nt), w hile f or ot her patie nts t he scree ni n g p hase ma y 
c oi nci de wit h t he scree ni n g visit ( 1 da y  l o n g, pr o vi de d t hat all t he re q uire d la b orat or y re p orts are 
a vaila ble a n d re vie we d bef ore t he eli gi bilit y c o nfir mati o n at t he baseli ne ). As s o o n as all scree ni n g 
assess me nts/ pr oce d ures ha ve bee n perf or me d a n d eli gi bilit y is c o nfir me d, t he patie nts ca n u n d er g o t he 
baseli ne visit.  
T he f oll o wi n g scree ni n g e val uati o ns will be c o n d ucte d:  
a) Me dical hist or y a n d de m o gra p hics  
b)  P h ysical e xa mi nati o n  
c) Vital si g ns (i ncl u di n g hei g ht a n d wei g ht i n tri plicate)  
d)  Ne ur ol o gical e xa mi nati o n  
e) Ta n ner sta gi n g of t he breasts i n pre -me narc hal fe males a n d of t he scr ot u m i n males w h o ha ve n ot 
c o m plete d p u bert y. P ost -me narc hal fe males a n d males w h o ha ve c o m plete d p u bert y will be 
e xcl u de d fr o m t his gr o wt h a nal ysis.  
f) I C A R S (a d mi nistere d b y t he q ualifie d site-s pecific rater).  
g)  C GI -S  
h) 1 2 -lea d sta n dar d Electr ocar di o gra m ( E C G)  
i) R o uti ne la b orat or y tests, o n t he di verte d bl o o d sa m ple (see Secti o n 1 1. 5 ) 
j) S pecial la b orat or y tests: H b A 1c, C D 4 + l y m p h oc ytes c o u nt,  a n d C R P,, o n t he di verte d bl o o d 
sa m ple (see Secti o n 1 1. 5 ) 
k)  Ser u m pre g na nc y test ( w o me n o f c hil d beari n g p ote ntial), o n t he di verte d bl o o d sa m ple (see 
Secti o n 1 1. 5 ) 
l) B M D  
m)  C S S R S  
n) E Q -5 D -5 L  
o)  Bl o o d c ollecte d t o assess R B C os m otic resista nce (i n selecte d ce nters)  
p)  Plas ma c ortis ol –  sa m ple t o be c ollecte d bef ore 8: 0 0 A M. If t he basal c ortis ol le vel is wit hi n t he 
refere nce n or mal ra n ge, t he patie nt ca n be e nr olle d i n t he st u d y. If t he 8: 0 0 A M c ortis ol le vel is 
bel o w 3 -5 µ g/ d L ( de pe n di n g o n assa y) re gar dless of s y m pt o m s, or t he patie nt e x hi bits si g ns or 
s y m pt o ms of a dre nal i ns ufficie nc y (see A p pe n di x 1 2) a n d has a c ortis ol < 1 0 µ g/ d L, t he patie nt 
will recei ve a hi g h d ose A C T H sti m ulati o n test, re gar dless of wei g ht, wit hi n 2 4 h o urs. If t he 
A C T H sti m ulati o n test is n or mal,  t he patie nt ca n be e nr olle d after t he effects of t he A C T H ha ve 
dissi pate d (e. g., 3 0 da ys after A C T H a d mi nistere d).  If t he patie nt fails t he A C T H sti m ulati o n test 
t he y will be e xcl u de d fr o m t he st u d y a n d referre d t o a pe diatric e n d ocri n ol o gist, wit h a 
reco m me n dati o n t o prescri be stress d ose ster oi ds  
q)  Assess me nt of pri or a n d c o nc o mita nt me dicati o ns  
r) Assess me nt of A Es  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 3  of 1 3 2  
 
If a n y a b n or m al la b orat or y t est res ults, vit al si g n m eas ure m e nts, or E C G fi n di n gs of cli nical si g nifica n ce 
are n ot e d at t h e scree ni n g visit, t h ese m ust be re peat e d d uri n g t h e 3 0 -da y scree ni n g peri o d a n d t h e res ults 
m a de a vaila ble pri or t o m a ki n g t h e fi n al decisi o n o n a patie nt’s eli gi bilit y f or t h e st u d y at Baseli n e. B M D 
a b n or m alities at scree ni n g visit s h o ul d be re p ort e d i n t h e Me dical Hist or y,  as it w o ul d u n derli n e a pre -
e xisti n g c o n diti o n.  
A d verse e ve nts, re p ort e d b y t h e patie nt or o bser ve d b y t h e i n vesti gat or, a n d t h e use of c o n c o mit a nt 
m e dicati o n s, will be rec or de d fr o m t h e ti m e of si g ni n g of i nf or m e d c o nse nt t hr o u g h t h e e n d of t h e st u d y.  
1 1. 4. 2  B a seli ne visit ( Visit 1/ D ay 0) 
Fi nal e val uati o ns f or I E D A T -0 2 -2 0 1 5 st u d y ( Visit 1 5/ M o nt h 1 2) will ser ve as baseli ne e val uati o ns f or 
patie nts c o nti n ui n g i n I E D A T-0 3 -2 0 1 8 st u d y. T he f oll o wi n g “ baseli ne” assess me nts f or I E D A T -0 3 -2 0 1 8 
will be d o ne as part of t h e fi nal Visit 1 5  e val uati o n i n St u d y I E D A T-0 2 -2 0 1 5: p h ysical/ ne ur ol o gic al 
exa mi nati o n; 1 2 -lea d sta n dar d E C G; la b orat or y e val uati o ns [i ncl u di n g he mat ol o g y, cli nical c he mistr y, 
uri nal ysis, ser u m pre g na nc y test ( w o me n of c hil d beari n g p ote ntial); s pecial la b orat or y tests: H b A 1c, C D 4 + 
l y m p h oc ytes c o u nt a n d C R P ]; assess me nt of p h ysical de vel o p me nt, se x ual mat urati o n, a n d t he effect of 
treat me nt wit h de xa met has o ne o n t hese as pects ( Ta n ner scale); I C A R S; C GI-S; C GI -S; E Q -5 D -5 L; C -
S S R S; B M D; re vie w of A Es a n d c o nc o mita nt me dicati o ns.   
a) O btai ni n g writte n i nf or me d c o nse nt ( bef ore a n y st u d y pr oce d ures)  
b)  C hec k of t he de m o gra p hic i nf or mati o n, me dical hist or y, pre vi o us a n d c o nc o mita nt me dicati o ns, 
o n g oi n g a d verse e ve nts a n d n o n -dr u g t hera pies a n d pr oce d ures ( dem o gra p hic i nf or mati o n, 
me dical hist or y   r olle d o ver fr o m I E D A T-0 2 -2 0 1 5 e C R F ) 
c) Vital si g ns [i ncl u di n g hei g ht a n d wei g ht meas ure me nts i n tri plicate at baseli ne ; calc ulati o n of 
B MI, te m perat ure ( oral or t y m pa nic, acc or di n g t o t he s pecific me dical practice of t he Ce nter), 
p ulse, s yst olic a n d diast olic B P, a n d res pirat or y rate].  
d)  He m ol ysis pa nel ( i ncl u di n g uri nal ysis) , o n t he di verte d bl o o d sa m ples (see Secti o n 1 1. 5 ) 
Patie nts pr o vi di n g i nf or me d c o nse nt or asse nt a n d meeti n g t he eli gi bilit y criteria will recei ve st u d y 
treat me nt pre pare d a n d a d mi nistere d as f oll o ws: 
e) 1 m L bl o o d c ollecte d, after bl o o d di versi o n  (see Secti o n 1 1. 5 ), f or aer o bic c ult ure 
f) A ut ol o g o us bl o o d c ollecti o n f or E D S pr ocessi n g  
g)  A d diti o n of t he assi g ne d st u d y me dicati o n ( D S P) t o t he E D S pr oces s 
h) U p o n c o m pleti o n of t he E D S pr ocess, fill t he satellite sa m ple ba g 
 
 if n o ot her sa m ples b ut t he o nes f or sterilit y c ult ure test 
will be c ollecte d).  
i) St u d y treat me nt a d mi nistrati o n b y I V i nf usi o n, wit hi n 3 0 mi n after t he E D S pr ocess has bee n 
c o m plete d.  
j) 
 
 
 
 
 
 
  
Bef ore t he E D S -E P i nf usi o n, patie nts ( w o me n of c hil d beari n g p ote ntial) m ust u n der g o a pre g na nc y uri ne 
test. All patie nts s h o ul d u n der g o assess me nt of pri or a n d c o nc o mita nt me dicati o n a n d A Es. 
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 4  of 1 3 2  
 
After c o m pleti o n of t he I V i nf usi o n of t he st u d y treat me nt t he f oll o wi n g assess me nts will be perf or me d o n 
Da y 0 : 
k)  Vital si g ns - b o d y wei g ht a n d hei g ht i n tri plicate, calc ulati o n of B MI, te m perat ure  (oral  or t y m pa nic, 
acc or di n g t o t he s pecific me dical practice of t he Ce nter) , p ulse, s yst olic a n d diast olic B P, a n d 
res pirat or y rate 
l) P h ysical e xa mi nati o n  
m)  Assess me nt of A Es occ urri n g after gi vi n g i nf or me d c o nse nt  –  re p orte d b y t he patie nt or o bser ve d 
b y t he I n vesti gat or  
n) Assess me nt of c o nc o mita nt me dicati o ns  
1 1. 4. 3  M o nt hs 1 -5 ( Visits 2 -6) a n d 7 - 1 1 ( Visits 8 -1 2)  
At M o nt hs 1 - 5 a n d 7 - 1 1, t h e f oll o wi n g assess m e nts will be perf or m e d:  
a) La b orat or y tests , o n t he di verte d bl o o d sa m ple (see Secti o n 1 1. 5 ): ser u m creati ni ne 
b)  R o uti ne la b orat or y tests , o n t he di verte d bl o o d sa m ple (see Secti o n 1 1. 5 ): 
• 
h e m at ol o g y  
• 
cli nical c h e mistr y  
• 
uri n al ysis  
c) He m ol ysis pa nel ( i ncl u di n g uri nal ysis) , o n t he di verte d bl o o d sa m ple (see Secti o n 1 1. 5 ): o nl y at 
M o nt h 4 a n d 8  
d)  Uri ne pre g na nc y test will be perf or me d bef ore e ver y i nf usi o n (f or w o me n of c hil d beari n g 
p ote ntial)  
e) C -S S R S  
f) Assess me nt of pri or a n d c o nc o mita nt me dicati o n  
g)  Assess me nt of A Es  - re p orte d b y t he patie nt or o bser ve d b y t he I n vesti gat or 
h) 1 m L bl o o d c ollecte d, after bl o o d di versi o n  (see Secti o n 1 1. 5 ), f or aer o bic c ult ure  
i) A ut ol o g o us bl o o d c ollecti o n f or E D S pr ocessi n g  
j) A d diti o n of t he assi g ne d st u d y me dicati o n ( D S P) t o t he E D S pr ocess  
k)  U p o n c o m pleti o n of t he E D S pr ocess, fill t he satellite sa m ple ba g wit h 
 
 if n o ot her sa m ples b ut t he o nes f or sterilit y c ult ure test 
will be c ollecte d).  
l) St u d y treat me nt a d mi nistrati o n b y I V i nf usi o n, wit hi n 3 0 mi n after t he E D S pr ocess has bee n 
c o m plete d.  
m)  
 
 
 
 
 
 
  
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 5  of 1 3 2  
 
Aft e r c o m pleti o n of t h e I V i nf usi o n of t h e st u d y treat m e nt t h e f oll o wi n g assess m e nts will be perf or m e d : 
n) P h ysical e xa mi nati o n a n d vital si g ns  (b o d y wei g ht a n d h ei g ht, calc ulati o n of B MI, t e m perat ure  - 
oral  or t y m pa nic, acc or di n g t o t h e s pecific m e dical practice of t h e Ce nt er  - p ulse, s yst olic a n d 
diast olic B P, a n d res pirat or y rat e ) 1 -2 hr after t he e n d of i nf usi o n  
o)  Assess me nt of A Es a n d c o nc o mita nt me dicati o ns  
1 1. 4. 4  M o nt hs 6  ( Visit 7 ) a n d 1 2  ( Visit 1 3 ) 
At M o nt hs 6  a n d 1 2 t h e f oll o wi n g assess m e nts will be perf or m e d bef ore treat m e nt a d mi nistrati o n ( u nless 
s pecifie d ot h er wise):  
a) P h ysical e xa mi nati o n  
b)  Vital si g ns (b o d y wei g ht a n d h ei g ht i n tri plicat e, calc ulati o n of B MI, t e m perat ure  - oral  or 
t y m pa nic, acc or di n g t o t h e s pecific m e dical practice of t h e Ce nt er - p ulse, s yst olic a n d diast olic 
B P, a n d res pirat or y rat e ) 
c) Ne ur ol o gical e xa mi nati o ns  
d)  I C A R S  
e) C GI -S a n d C GI -C  
f) E Q -5 D -5 L  
g)  C -S S R S  
h) B M D  
i) 1 2 -lea d sta n dar d E C G  
j) R o uti ne la b orat or y tests , o n t he diverte d bl o o d sa m ple  (see Secti o n 1 1. 5 ) 
k)  S pecial la b orat or y tests , o n t he di verte d bl o o d sa m ple (see Secti o n 1 1. 5 ): H b A 1c, C D 4 + 
l y m p h oc ytes c o u nt a n d C R P.  
l) Ser u m pre g na nc y test ( w o me n of c hil d beari n g p ote ntial) , o n t he di verte d bl o o d sa m ple (see 
Secti o n 1 1. 5 ). 
m)  Uri ne pre g na nc y test will be perf or me d bef ore e ver y i nf usi o n f or w o me n of c hil d beari n g 
p ote ntial.  
n) Assess me nt of p h ysical de vel o p me nt, se x ual mat urati o n, a n d t he effect of treat me nt wit h 
de xa met has o ne o n t hese as pects. Ta n ner sta gi n g of t he breasts i n pre -me narc hal fe males a n d of 
t he scr ot u m i n males w h o ha ve n ot c o m plete d p u bert y. P ost-me narc hal fe male s a n d males w h o 
ha ve c o m plete d p u bert y will be e xcl u de d fr o m t his gr o wt h a nal ysis.   
o)  Assess me nt of c o nc o mita nt me dicati o ns  
p)  Assess me nt of A Es - re p orte d b y t he patie nt or o bser ve d b y t he I n vesti gat or 
q)  1 m L bl o o d c ollecte d, after bl o o d di versi o n  (see Secti o n 1 1. 5 ), f or aer o bic c ult ure  
r) A ut ol o g o us bl o o d c ollecti o n f or E D S pr ocessi n g  
s) A d diti o n of t he assi g ne d st u d y me dicati o n ( D S P) t o t he E D S pr ocess .  
t) U p o n c o m pleti o n of t he E D S pr ocess, fill t he satellite sa m ple ba g wit h a p pr o xi matel y   
 
if n o ot her sa m ples b ut t he o nes f or sterilit y c ult ure test 
will be c ollecte d).  
u) St u d y treat me nt a d mi nistrati o n b y I V i nf usi o n, wit hi n 3 0 mi n after t he E D S pr ocess has bee n 
c o m plete d.  
v)  
 
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 6  of 1 3 2  
 
 
 
 
 
 
  
 
After c o m pleti o n of t he I V i nf usi o n of t he st u d y treat me nt t he f o ll o wi n g assess me nts will be perf or me d: 
w)  P h ysical e xa mi nati o n a n d vital si g ns 1 -2 hr after i nf usi o n  
x)  Assess me nt of c o nc o mita nt me dicati o ns  
y)  Assess me nt of A Es - re p orte d b y t he patie nt or o bser ve d b y t he I n vesti gat or 
1 1. 4. 5  S afety F oll o w -u p Visit ( Visit 1 6)  
All patie n ts w h o disc o nti n u e will be re q uire d t o ret ur n f or a Safet y F oll o w-u p Visit a p pr o xi m at el y 6 0 da ys 
( ± 7 da ys) aft er t h eir last i nf usi o n. At t his visit, plas m a c ortis ol, h e m ol ysis pa n el, pre g n a n c y st at us (f or 
w o m e n of c hil d beari n g p ot e ntial), C -S S R S, a n d vit a l si g ns will be assesse d, as well as t h e occ urre n ce of 
a n y A Es or Seri o us A Es ( S A Es) re p ort e d b y t h e patie nt/care gi ver or o bser ve d b y t h e I n vesti gat or si n ce t he 
pre vi o us visit . 
1 1. 4. 6  Visit Wi n d o ws  
A wi n d o w of + 1 0 da ys will be per mitt e d o n eac h of t h e sc h e d ule d m o nt hl y visits. T h eref ore, n o E D S-E P 
i nf usi o n s h o ul d be perf or m e d less t h a n 2 1 da ys or m ore t h a n 3 8 da ys aft er t h e pre vi o us i nf usi o n. T h e 
wi n d o w bet wee n a n i nf usi o n a n d t h e s u bse q u e nt o n e s h o ul d be ke pt as re g ular as p ossi ble t hr o u g h out t he 
st u d y, a v oi di n g fl u ct u ati o ns i n a d mi nistrati o n wi n d o ws..  
1 1. 5  L a b or at or y S a m ple C ollecti o n   
S t u dy pr oce d ures t o e ns ure sterility of t he E D S-E P  
A se ptic pr oce d ures s h o ul d be i m ple m e nt e d t o e ns ure st erilit y d uri n g bl o o d c ollecti o n f or t h e E D S 
pr ocess, t h e vari o us st e ps of t h e E D S pr ocess, sa m ple c ollecti o n f or r o uti n e la b orat or y t ests, sa m ple 
c ollecti o n fr o m t h e E D S -E P f or st erilit y t esti n g, a n d a d mi nistrati o n of t h e E D S -E P t o  t h e patie nt. Det ails 
of t h ese pr oce d ures are descri be d i n a se parat e d oc u m e nt e ntitle d “ St u d y Pr oce d ures o n St erilit y Testi n g  
f or St u d y I E D A T-0 3 -2 0 1 8 ( O L E -I E D A T)”, w hic h will be pr o vi de d t o eac h sit e (see A p pe n di x 9 ). T h ese 
n e w pr oce d ures i n cl u de t h e f oll o wi n g m eas ures t h at m ust be perf or m e d t o e ns ure st erilit y:  
• 
Bl o o d sa m pli n g u n der st erile c o n diti o ns.  
• 
Caref ul h a n d was hi n g a n d use of fres h ( n o n -st erile) gl o ves f or eac h patie nt, disi nfect e d fre q u e ntl y 
usi n g a bact erici dal r u b.  
• 
Fre q u e nt a n d re peat e d use o f a bact erici dal s ol uti o n, i n cl u di n g t h e m a n dat or y use of 2 % 
c hl or h e xi di n e i n 7 0 % is o pr o p yl alc o h ol f or disi nfecti o n of t h e s ki n at t h e ve ni p u n ct ure sit e, or 
d uri n g h a n dli n g of t h e ve n o us cat h et er (if use d), a n d f or disi nfecti n g p orts, c o n n ect ors a n d 
w or ki n g s urfaces/e n vir o n m e nts.  
• 
 
 
 
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 7  of 1 3 2  
 
 
  
 
 
 
  
Bl o o d s a m pli n g   
Ve n o us bl o o d sa m ples will be dra w n f or r o uti n e safet y e val u ati o ns t o be perf or m e d at l ocal le vel, acc or di n g 
t o Sit es’ cli nical practice a n d l ocal re g ulati o ns.  
T h e t ot al a m o u nt of bl o o d  t o be dra w n o n a n y si n gle da y  or wit hi n a n y 8 -wee k peri o d  m ust c o nf or m  t o t he 
g ui deli n es s pecifie d  f or pe diatric patie nts b y t h e W orl d Healt h Or ga nizati o n ( H o wie, 2 0 1 1 ).  
Uri ne c ollecti o n  
U ri n e n ee de d f or t h e uri n al ysis will be c ollect e d at Baseli n e visit, M o nt h 4, M o nt h 8, Safet y f oll o w u p visits 
-as part of h e m ol ysis pa n el  a n d acc or di n g t o  l ocal la b orat or y g ui deli n es.  
P re g n a ncy test 
All fe m ale patie nt s of c hil d beari n g p ot e ntial  will h a ve a bl o o d sa m ple dra w n at M o nt h 6  a n d M o nt h 1 2  f or 
a ser u m pre g n a n c y t est. “N o n -ch il d beari n g p ot e ntial” is defi n e d as f oll o ws:  
• 
s ur gical st erilizati o n ( h yst erect o m y, bilat eral o o p h orect o m y, or bilat eral t u bal li gati o n), or  
• 
patie nt is pre -p u bert al, wit h c o nfir m ati o n t h at m e nstr uati o n h as n ot st art e d.   
Res ults of t h e  ser u m pre g n a n c y  t est m ust be n e gati ve at t h e I E D A T-0 2 -2 0 1 5  st u d y fi n al visit f or t h e patient  
t o be i n cl u de d i n t h e I E D A T-0 3 -2 0 1 8 st u d y. 
A u ri n e pre g n a n c y t est will be perf or m e d m o ntl y bef ore e ver y i nf usi o n , st arti n g fr o m baseli n e visit. Res ults 
of t h e uri n e  pre g n a n c y t es t m ust be n e gati ve at Baseli n e ( Da y 0) f or t h e patie nt t o be eli gi ble . 
All bl o o d a n d uri n e sa m ples f or safet y ( h e m at ol o g y/ cli nical c h e mistr y / uri n al ysis)  a n d s pecial la b orat or y  
e val u ati o ns will be a n al yze d b y t h e l ocal la b orat or y.  
1 1. 6  Me as ure me nt of De x a met h as o ne  S o di u m P h os p h ate  a n d Ot her A n al ytes  i n I nf usi o n B a g 
S a m ple   
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
C CI
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 8  of 1 3 2  
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
  
1 1. 7  C o nc o mit a nt Me dic ati o ns  
All patie nts t o be i n cl u de d i n t h e st u d y m ust n ot h a ve recei ve d oral or pare nt eral st er oi d t h era p y wit hi n 4 
wee ks pri or t o t h e a d mi nistrati o n of E D S . T reat m e nt wit h i n h ale d or i ntra n asal st er oi ds f or ast h m a or 
aller gies, as well as t h e use of t o pical st er oi ds, will be per mitt e d.  I n a d diti o n, patie nt s wit h a hist or y of use 
or c urre ntl y usi n g  a n y of t h e f oll o wi n g  m e dicati o ns  will be e xcl u de d fr o m partici pati o n , acc or di n g t o t he 
g ui deli n es s pecifie d :  
• 
Narc otic a n al gesics  –  use wit hi n 4 wee ks pri or t o baseli n e , u nless t h e i nt a ke is st a ble si n ce I E D A T-
0 2 -2 0 1 5 st u d y ;  
• 
A nti ps y c h otics  - u nless  use d at a l o w, st a ble d ose si n ce I E D A T-0 2 -2 0 1 5 st u d y , i n w hic h case t h ey 
will be per mitt e d ;  
• 
Dr u gs t h at are s tr o n g i n d u cers (e. g. car ba m aze pi n e, St. J o h n’s w ort) or i n hi bit ors (e. g. 
clarit hr o m yci n, gra pefr uit j uice)  of C Y P 3 A 4  wit hi n 4 wee k s pri or t o baseli n e; 
Dr u gs t h at are i n d ucers or i n hi bit ors of Cyt oc hr o me P 4 5 0 3 A 4 ( C Y P 3 A 4) m ay alter  t he pl as m a 
levels of dex a met h as o ne, w hic h is met a b olize d by t his e nzy me.  T heref ore, i n t he c urre nt st u dy, a ny 
dr u g t h at is a str o n g i n d ucer  or i n hi bit or  o f C Y P 3 A 4 will be pr o hi bite d fr o m use d uri n g t he tri al.  
P atie nts w h o are t aki n g t hese dr u gs u p o n e ntry i nt o t he scree ni n g peri o d s h o ul d h ave t he 
me dic ati o n disc o nti n ue d , if p ossi ble, or be s witc he d t o a n ot her si mil ar me dic ati o n t h at d oes n ot 
h ave t his pr o p erty.  A  li nk t o a we bsite wit h a list of dr u gs t h at are str o n g i n d ucers or i n hi bit ors of 
C Y P 3 A 4  will be pr ovi de d t o t he I nvesti g at or as a refere nce.  
• 
A m p h ot erici n -B  –  c o m bi n ati o n wit h c ortic ost er oi ds or c ortic otr o pi n ( A C T H) 
m a y i n d u ce 
h y p o p ot asse mia;  
• 
T h e use of li ve or att e n uat e d vacci n es is pr o hi bit e d. H o we ver, t h e use of a vacci n e t h at c o nt ains 
kille d vir uses is left t o t h e cli nical j u d ge m e nt of t h e Pri n ci pal I n vesti gat or, a n d t h e st a n dar d of care 
at t h e sit e . Th e re q uire m e nts f or t h e  vacci n ati o n will be base d o n t h e l ocal/sit e cli nical st a n dar d of 
care practices, S P C ( S u m m ar y of Pr o d u ct C h aract eristics) of t h e gi ve n pr o d u ct/ vacci n e a n d ge n eral 
c o nsi derati o ns relati n g t o t h e ti mi n g ga p t h e  i nf usi o n a n d t h e vacci n ati o n. T his decisi o n i s u p t o 
t h e I n vesti gat or`s m e dical j u d g m e nt a n d discreti o n. 
Patie nt s o n st a ble d oses of ot h er dr u gs, s u c h as a nti h y pert e nsi ves, be n z o diaze pi n es,  a nti hist a mines  
( hist a mi n e rece pt or bl oc kers), birt h c o ntr ol, pr ot o n -p u m p i n hi bit ors, vit a mi ns/ m ulti -vita mi ns,  anti -dia betics 
a ge nts  a n d li pi d -l o weri n g a ge nts (e. g. st ati ns), will be eli gi ble f or t h e st u d y. T h e use of o t h er c o nc o mitant 
m e dicati o ns  wit h C N S effects s h o ul d be disc uss e d wit h a n d  a p pr o ve d b y t h e Me dical M o nit or  at t h e C R O  
bef ore prescri bi n g t o t h e patie nt d uri n g t he st u d y . U se of i m m u n o gl o b uli ns eit her a d mi nist ere d b y I V or I M 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 5 9  of 1 3 2  
 
r o ut e is per mitt e d; t h e I n vesti gat or s h o ul d det er mi n e t he o pti m al ti mi n g of t h e d ose wit h res pect t o t h e E D S 
i nf usi o n.   
D uri n g t h e e ntire peri o d of t h e st u d y, st arti n g wit h t he si g ni n g of t h e I C F, a n y n e w treat m e nt t hat is i nitiated 
m ust be re p ort e d i n t h e C R F usi n g t h e p h ar m ac ol o gical n a m e ( n ot t h e tra de n a m e, wit h t h e e xce pti o n of 
m e dici n es i n fi xe d c o m bi n ati o n), s pecif yi n g dail y d ose, r o ut e, d urati o n of treat m e nt , reas o n f or use. Aft er 
scree ni n g, patie nt s s h o ul d be i nstr u ct e d t o c o nt act t h e I n vesti gat or bef o re st arti n g a n y O T C or prescri pti o n 
m e dicati o n  o n t h eir o w n or as prescri be d b y t h eir p h ysicia n . T h e Me dical M o nit or  at t h e C R O  s h o ul d be  
i nf or m e d of a n y n e w m edicati o n t h at m a y be  a pr o hi bit e d m e dicati o n a n d is st art e d d uri n g t h e st u d y, a n d 
will m a ke a  decisi o n w h et h er or n ot it  is acce pt a ble f or t h e patie nt  t o c o nti n u e i n t h e trial.  
T h e c urre nt partici pati o n i n a cli nical trial wit h a n ot h er i n vesti gati o n al dr u g is a n e xcl usi o n crit eri o n.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 0  of 1 3 2  
 
1 2  E F FI C A C Y E V A L U A TI O N S  
1 2. 1  I C A R S 
1 2. 1. 1  Descri pti o n of t he I C A R S  
T h e pri m ar y efficac y e n d p oi nt i n t h e A T st u d y will be t h e m ea n c h a n ge fr o m baseli n e  t o e n d p oi nt (M o nt h 
6  or earl y disc o nti n u ati o n)  i n t h e t ot al sc ore o n t h e ‘ M o difie d’ I nt er n ati o nal C o o perati ve At a xia Rati n g 
Scale (I C A R S).  
T h e I C A R S (Tr o uillas et al, 1 9 9 7 ), t h e m ost fre q u e ntl y use d cli nicia n-( n e ur ol o gist) rat e d m eas ure i n 
patie nts wit h at a xias, was de vel o pe d b y a C o m mitt ee of t h e W orl d Fe derati o n of Ne ur ol o g y t o h el p 
st an dar dize c o m m o n m a nifest ati o ns of s y n dr o m es t h at lea d t o cere bellar d ysf u n cti o n. T h e I C A R S is a 1 0 0 -
p oi nt, se mi -q u a ntit ati ve scale offeri n g a c o m part m e nt alize d q u a ntificati o n of t h e f oll o wi n g 4 s u b -sc ores: 
P ost ure a n d Gait Dist ur ba n ces ( 3 4 p oi nts), Ki n etic  F u n cti o ns ( 5 2 p oi nts), S peec h Dis or ders ( 8 p oi nts), a n d 
Oc ul o m ot or Dis or ders ( 6 p oi nts).  
T h e c o m plet e I C A R S will be rat e d i n t h e c urre nt st u d y; h o we ver, f or t h e pri m ar y efficac y e n d p oi nt, t he 
‘ M o difie d’ I C A R S will use d .  T h e ‘ M o difie d’  I C A R S e xcl u des all of t h e O c ul o m ot or  D is or ders it e ms 
(it e ms 1 7-1 9) a n d it e ms  8 -1 2  i n t h e Ki n etic F u n cti o ns d o m ai n, as t h ese it e ms d o n ot directl y c o ntri b ut e t o 
f u n cti o ni n g.  
1 2. 1. 2  V ali dity of I C A R S i n A T P a tie nt Po p ul ati o n  
T h e i nt er n al c o nsist e n c y, crit eri o n -relat e d vali dit y, a n d i nt er n al c o nstr u ct vali dit y of t h e I C A R S h a ve bee n 
est a blis h e d i n patie nts wit h f ocal cere bellar lesi o ns (Sc h oc h B et al, 2 0 0 7 ). T h e i nt er-rat er relia bilit y, t est-
ret est relia bilit y a n d i nt er n al c o nsist e n c y h a ve als o bee n vali dat e d i n patie nts wit h s pi n ocere bellar at a xia 
( We yer et al, 2 0 0 7, Sc h mit z-H u bsc h et al , 2 0 0 6a ). T h e I C A R S t ot al sc ore satisfie d all ps yc h o m etric crit eria 
i n a vali dati o n st u d y i n patie nts wit h Frie dric h’s At a xia ( Ca n o et al, 2 0 0 5; Met z et al 2 0 1 3) T h e I C A R S h as 
bee n use d as a n  o ut c o m e m eas ure i n i nt er ve nti o nal st u dies i n patie nts wit h at a xia, b ut t h ere are n o cli nical 
dat a t o s u g gest t h e m a g nit u de of c h a n ge o n t h e I C A R S t h at w o ul d c orres p o n d t o a cli nicall y rele va nt 
i m pr o ve m e nt, d u e t o t h e a bse n ce of a n y dr u g pr o d u ci n g s u c h a be n efit. T h e I C A R S h as bee n use d i n se veral 
st u dies i n patie nts wit h Frie dreic h’s At a xia o ver t h e a ge of 8 years, i n p h ase III p ot e ntiall y pi v ot al trials 
(L y n c h et al, 2 0 1 0 ), as well as i n o pe n-la bel l o n g-t er m st u dies ( Meier et al, 2 0 1 2).  
T h e I C A R S was use d als o i n t w o i nt er ve nti o n al st u dies i n c hil dre n wit h A T. Za n olli et al, 2 0 1 2 s h o we d a 
st atisticall y si g nifica nt decrease i n t h e I C A R S t ot al sc ore i n a place b o -c o ntr olle d cr oss o ver st u d y i n 1 3 
c hil dre n wit h A T treat e d wit h oral bet a m et h as o n e ( Za n n olli et a l, 2 0 1 2). Nisse n k or n et al, usi n g I C A R S as 
a sec o n dar y e n d p oi nt, s h o we d i m pr o ve m e nt i n t h e st atic a n d ki n etic s u bscales i n a s h ort -t er m o pe n-la bel 
st u d y i n 1 7 c hil dre n (fr o m 4 years of a ge) treat e d wit h a m a nt a di n e ( Nisse n k or n et al, 2 0 1 3 ). As A T is a 
se vere, rele ntlessl y pr o gressi ve dis or der t h at lea ds t o l oss of i n de pe n de nt m o ve m e nt i n m ost patie nts b y t he 
a ge of 1 0  t o 1 6 years, a n y st atisticall y si g nifica nt differe n ce fr o m place b o o ver a 6 -m o nt h peri o d s h o ul d be 
c o nsi dere d as a treat m e nt s u ccess.  
M ost of t h e de vel o p m e nt al a n d vali dati o n st u dies of t h e I C A R S were perf or m e d i n patie nts w h o were 1 0 
years of a ge or ol der; a n i nt er n ati o nal st u d y h as bee n c o m plet e d  (Cli nical Trials. g o v: N C T 0 1 9 4 2 8 5 0 ) t o 
e xt e n d its vali dit y t o patie nts i n t h e a ge -ra n ge of 5  t o1 0 years.  Dat a c ollect e d fr o m t h e vali dati o n st u d y i n 
select e d ce nt ers [ Dat a o n file, Er y Del S. p. A] i n dicat e d t h at t h e distri b uti o n of sc ores f or t h e I C A R S f or 
patie nts wit h A T  u n der 1 0 years of a ge was si milar t o t h e sc ores f or t h ese patie nts o n ot h er vali dat e d scales 
s u c h as t h e S A R A ( Sc h mit z -H u bsc h et al, 2 0 0 6 b ) a n d t h e B A R S ( Sc h m a h m a n n et al, 2 0 0 9 ). Dat a c ollect e d 
fr o m t h e vali dati o n st u d y i n select e d ce nt ers c o nfir m e d t h at t he se verit y of A T i n creased  wit h a ge  i n patie nts 
u n der t h e a ge of 1 0 years , as de m o nstrat e d b y a si g nifica nt c orrelati o n of t h e t ot al sc ores o n t h e I C A R S, 
S A R A , a n d t h e B A R S , b ut n ot f or patie nts a b o ve 1 0 years.  O verall, t h e distri b uti o n of sc ores f or t h e I C A R S 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 1  of 1 3 2  
 
f or 5 t o 1 0 year -ol d patie nts wit h A T was si milar t o t h e sc ores f or ot h er vali dat e d scales s u c h as t h e S A R A, 
B A R S, C GI -S (str u ct ured  a n d u nstr u ct ure d  versi o ns) .  
1 2. 1. 3  St a n d ar diz ati o n of R ati n gs  
T o m a xi mize t h e c o nsist e n c y of t h e dat a o bt ai n e d fr o m t h e I C A R S, t h e sa m e sit e’s n e ur ol o gist, q u alifie d , 
trai n e d, a n d certifie d i n t h e use of t h e I C A R S a n d wit h e x pertise i n t h e fiel d of A T dis or ders, will e val u ate 
t h e sa m e patie nt at a p pr o xi m at el y t h e sa m e ti m e t hr o u g h o ut t h e st ud y. I C A R S rati n gs s h o ul d be c o m plet e d 
wit h o ut  c o nsulti n g sc ores fr o m t h e pre vi o us visit.  
T h e I C A R S will be perf or m e d at M o nt h 6 a n d M o nt h 1 2 .   
1 2. 2  Cli nic al Gl o b al I m pressi o n {C GI -C a n d C GI -S  (str uct ure d)} 
T h e C GI ( G u y, 1 9 7 6) is t h e ge n eral n a m e f or t w o scales, t h e C GI  - C h a n ge scale ( C GI -C) a n d C GI - Se verit y 
scale ( C GI-S).  T h e C GI -C scale  assesse s t h e c h a n ge i n t h e patie nt’s cli nical st at us fr o m baseli n e  usi n g a 
7 -p oi nt scale, ra n gi n g fr o m 1 ( ver y m u c h i m pr o ve d) t o 7 ( ver y m u c h w orse), wit h a sc ore of 4 i n dicati n g 
n o c h a n ge. I n t h e c urre nt st u d y, t he c h a n ge fr o m t h e patie nt’s baseli n e c o n diti o n will be assesse d at all p ost -
baseli n e visits, a n d t h e m ea n rati n g of c h a n ge at E n d p oi nt ( M o nt h 6  or earl y disc o nti n u ati o n) will be t he 
ke y sec o n dar y  efficac y m eas ure  T h e rat er per f or mi n g t h e C GI-C will be differe nt fr o m t h e rat er perf or mi n g 
t h e I C A R S rati n g, a n d will assess t h e patie nt wit h o ut access t o t h e I C A R S rati n gs or safet y dat a.  A 
g ui deli n e f or perf or mi n g t h e rati n g of c h a n ge usi n g t h e C GI-C is pr o vi de d bel o w.  
F or t h e C GI -C rati n g, cli nicia ns will be re q uire d t o c o n d u ct a f ull cli nical i nt er vie w a n d e xa mi n ati o n of t he 
patie nt, if n ecessar y wit h t h e care gi ver prese nt.  T h e i nt er vie w a n d e xa mi n ati o n s h o ul d assess vari o us 
as pects of t h e patie nt’s a p peara n ce ( gr o o mi n g, e vi de n ce  of falls, et c.), at a xia, c o g niti o n ( orie nt ation, 
calc ulati o n a bilit y, la n g u a ge, a bilit y t o f oll o w c o m m a n ds, 
m e m or y, et c.), a pra xia, d ysart hria, 
e xtra p yra mi dal m ot or s y m pt o ms, acti vities of dail y li vi n g a n d m o o d.  T h e C GI -C rati n g s h o ul d be base d 
o n a h oli stic assess m e nt of t h e patie nt, a n d s h o ul d n ot be a n c h ore d t o s pecific c h a n ge or c ut -off sc ores of 
perf or m a n ce -base d m eas ures.  It is n ot n ecessar y f or t h e rat er t o use s pecific scales or be g ui de d b y t h eir 
sc ores f or se verit y; h o we ver, t h e rat er m a y re vie w fi n di n gs o n ot h er m eas ures t h at are assesse d i n t h e trial, 
e. g. V A B S, q u alit y of life scale ( E Q -5 D -5 L ), t o g ui de t h eir assess m e nts. T h e rat ers m a y als o use a d diti o n al 
scales or m eas ures t o assess s pecific d o m ai ns; h o we ver, it is i m p ort a nt t h at t he rat ers  use t h e sa m e m et h ods 
at baseli n e a n d at all s u bse q u e nt visits.   
T h e C GI -S scale m eas ures gl o bal se verit y of ill n ess at a gi ve n p oi nt i n ti m e , a n d is us u all y rat e d o n a 
7 -p oi nt, Li kert -t y pe scale ra n gi n g fr o m 1 ( n or m al, n ot ill at all) t o 7 (a m o n g t h e m ost e xtre m el y ill patie nts).  
H o we ver, n o versi o n of t h e C GI -S e xists w hic h h as bee n s pecificall y a da pt e d f or use i n A T patie nts; 
t h eref ore, a 5-p oi nt versi o n was de vel o pe d t h at t a kes i nt o acc o u nt t h e se verit y of t h e f oll o wi n g s y m pt o ms 
of A T: at a xia ( wal ki n g) , d ysart hria, d ys m etria, e xtra p yra mi dal s y m pt o ms (c h orea, m y ocl o n us, d yst o nia, 
a n d tre m or), a n d e ye m o ve m e nts.  Rati n gs of n o n e ( 0), mil d ( 1), m o derat e ( 2), se vere ( 3) a n d ver y se vere 
( 4) are select e d base d o n t h e le vel of s y m pt o m at ol o g y.  T w o i n de pe n de nt versi o ns of t h e C GI -S scale were 
de vel o pe d, a str u ct ure d scale, base d o n t h e 5 disease -relat e d a n c h ors a n d a n u nstr u ct ure d scale base d o n t he 
cli nical j u d g m e nt of a n e x perie n ce d p h ysicia n. B ot h t h e str u ct ure d a n d u n str u ct ure d versi o ns were fiel d-
t est e d.  Th e fi n al  str u ct ure d C GI -S sc ore is base d o n t h e se verit y of t h e s y m pt o ms i n eac h d o m ai n, as 
i n dicat e d bel o w: 
• 
A rati n g of 0 ( n ot ill/as y m pt o m atic) c a n  be m a de o nl y if t h ere are n o s y m pt o ms, or a rati n g of mil d 
o n o nl y o n e s y m pt o m d o m ai n;  
• 
A rati n g of 1 ( mil d) ca n be m a de o nl y if t h ere are n ot m ore t h a n 2 d o m ai ns rat e d great er t h a n mil d;  
• 
A rati n g of 2 ( m o derat e) ca n  be m a de o nl y if t h ere are n ot m ore t h a n 2 d o m ai ns rat e d great er t han 
m o derat e;  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 2  of 1 3 2  
 
• 
A rati n g of 3 (se vere) ca n be m a de o nl y if t h ere are n ot m ore t h a n 2 d o m ai ns rat e d great er t han 
se vere; 
• 
A rati n g of 4 ( ver y se vere) ca n  be m a de o nl y if t h ere are at least 2 d o m ai ns rat e d as se vere a n d at 
least 2 rat e d as ver y se vere. 
A pil ot vali dati o n st u d y h as bee n perf or m e d i n A T patie nts usi n g t h e C GI -S scale, a n d t h e res ults i n dicate  
t h at t h e C GI-S a de q u at el y discri mi n at e d  patie nts wit h mil d, m o derat e , or se vere disease  [ Dat a o n file, 
Er y Del S. p. A.] . T h e distri b uti o n of patie nts t o differ e nt sc ores o n t h e C GI -S  of A T was si milar usi n g t he 
I C A R S, B A R S, a n d S A R A i n 6  t o 9 year ol ds. T h e C GI -S  f or patie nts 1 0 years of a ge or ol der  was great er 
t h a n i n 6 t o 9 year ol d patie nts; h o we ver, t h e distri b uti o n of sc ores o n t h e I C A R S, B A R S , a n d S A R A wa s 
si milar acr oss se verit y cat e g ories.   
1 2. 3  Q u alit y o f L ife Sc ale  
A patie nt /care gi ver-rat e d assess m e nt of q u alit y of life ( Q o L) will be perf or m e d usi n g t h e E Q -5 D -5 L  scale. 
T h e E Q -5 D is a st a n dar dize d i nstr u m e nt f or assessi n g h ealt h -relat e d Q o L, w hic h pr o vi des a si m ple 
descri pti ve pr ofile a n d a si n gle i n de x val u e f or h ealt h st at us i n a variet y of h ealt h c o n diti o ns ( Ra bi n a n d de 
C h arr o, 2 0 0 1 ). T h e scale was ori gi n all y desi g n e d f or use i n a d ult p o p ulati o ns, 1 8 years of a ge a n d ol der . 
T h e E Q -5 D i n cl u des si n gle it e m m eas ures of fi ve h ealt h di m e nsi o ns: m o bilit y, self -care, us u al acti vities, 
pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n. Eac h it e m h as t hree p ossi ble res p o nse o pti o ns t h at all o w t he 
s u bject t o rat e ( n o pr o ble ms/s o m e or m o derat e pr o ble ms/e xtre m e pr o ble ms) t h eir c urre nt st at e wit h res pect 
t o eac h of t h e 5 d o m ai ns. I n a d diti o n, E Q-5 D i n cl u des a gl o bal rati n g of c urre nt h ealt h usi n g a vis u al 
a n al o g u e scale ( V A S) ra n gi n g fr o m 0 ( w orst i m a gi n a ble) t o 1 0 0 ( best i m a gi n a ble). T h e E Q -5 D is 
c o g niti vel y si m ple, a n d pr o vi des a sc ore t h at ca n be c o m pare d acr oss differe nt c o n diti o ns 
(htt p:// w w w. e ur o q ol. or g/ ).  
T h e E Q -5 D -5 L  t h at will be use d i n t his st u d y is a n e wer versi o n of t h e scale, w hic h i n cl u des fi ve le vels of 
se verit y (i.e., n o pr o ble ms, sli g ht pr o ble ms, m o derat e pr o ble ms, se vere pr o ble ms, a n d e xtre m e pr o ble ms) 
f or eac h of t h e fi ve E Q-5 D di m e nsi o ns  ( Her d m a n et al, 2 0 1 1); rat h er t h a n t h e t hree le vels i n cl u de d i n t he 
pre vi o us versi o n ( E Q -5 D -3 L). T h e E Q -5 D -5 L h as bee n vali dat e d i n a di vers e patie nt p o p ulati o n i n 6 
c o utries, i n cl u di n g 8 patie nt gr o u ps wit h c hr o nic c o n diti o ns (e. g. car di o vasc ular disease, res pirat or y disease, 
de pressi o n, dia bet es, li ver disease, pers o n alit y dis or ders, art hritis, str o ke) a n d a st u de nt c o h ort (Ja n sse n et 
al, 2 0 1 3 ).  
F or c hil dre n a n d a d olesce nts, t h e E Q-5 D -5 L a d mi nistrat ors will be trai n e d t o h el p t h e y o u n ger p o p ulati on 
i n t h e st u d y c o m plet e t h e scale. T h e E Q-5 D -5 L a d mi nistrat or will e x plai n i n det ail t h e scale t o t h e y o u n ger 
patie nts a n d will c o nfir m t h at t h e y u n derst a n d h o w t h e scale s h o ul d be c o m plet e d. T h e y will e x plai n w h at 
eac h d o m ai n m eas ures i n a c hil d frie n dl y m a n n er a n d will c o nfir m t h at t h e res p o n de nt u n derst a n ds h o w t o 
c o m plet e t h e scale. Wit h re gar ds t o t h e us u al acti vities d o m ai n, t h e a d mi nistrat or will e x plai n t h at t his 
d o m ai n m eas ures if a s u bject h as diffic ulties g oi n g t o sc h o ol, or wit h h o b bies, s p orts, pla yi n g a n d d oi n g 
t hi n gs wit h fa mil y or frie n ds. T h e a d mi nistrat or will be prese nt d uri n g t h e c o m pleti o n a n d will be a vaila ble 
t o h el p t h e c hil d if h e/s h e d oes n ot u n derst a n d a q u esti o n or h e/s h e h as q u esti o ns relat e d t o scale c o m pleti on. 
If t h e patie nt is u n a ble t o c o m plet e t h e scale, it will be c o m plet e d b y t h e patie nt’s pare nt/car gi ver.  
1 2. 4  R ater  Re q uire me nts a n d  Tr ai ni n g  
Pr o perl y  q u alifie d rat ers will n ee d t o be i de ntifie d at eac h sit e t o perf or m t h e rati n gs o n t h e efficac y 
m eas ures. T h e I C A R S rat er m ust re m ai n bli n de d t o ot h er assess m e nts  a n d will n ot h a ve access t o t h e safet y 
dat a . T h e C GI rat er will n ot h a ve access t o t h e I C A R S  rati n gs or safet y dat a, b ut m a y refer t o ot h er scales 
i n sc ori n g t h e C GI.  Trai ni n g a n d certificati o n o n t h e I C A R S a n d C GI will t a ke place at t h e I n vesti gat or’s 
m eeti n g  a n d a d diti o n al trai ni n g a n d  a n i ntra -rat er relia bilit y (t est-ret est) assess m e nt will be perf or m e d 
d uri n g t h e st u d y .  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 3  of 1 3 2  
 
1 2. 5  Or der of Test Perf or m a nce  
T h e I C A R S s h o ul d be t h e first scale a d mi nist ere d.  T h e se q u e n ce of perf or m a n ce f or t h e ot h er efficac y 
assess m e nts is n ot fi xe d acr oss t h e st u d y; h o we ver, t h e or der i n w hic h t h ese t ests are perf or m e d f or a n 
i n di vi d u al patie nt  s h o ul d be ke pt c o nst a nt t hr o u g ho ut t h e trial.   

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 4  of 1 3 2  
 
1 3  S A F E T Y E V A L U A TI O N S  
T h e assess m e nt of safet y a n d t olera bilit y will be base d o n t h e f oll o wi n g:  
a) V it al si g ns (b o d y wei g ht, t e m perat ure  [ oral or t y m pa nic], p ulse, s yst olic a n d diast olic bl o o d 
press ure, a n d res pirat or y rat e  
b)  S t a n dar d la b orat or y t ests (cli nical c h e mistr y , h e m at ol o g y, a n d uri n al ysis)  
c) 1 2 -lea d st a n dar d E C G  
d)  P h ysical  a n d  n e ur ol o gical  e xa mi n ati o ns  
e) S pecial la b orat or y para m et ers  
f) C -S S R S  
g)  B M D  
h) C ult ure -base d st erilit y t est o n E D S -E P  
i) Ta n n er st a gi n g  
j) S u bjecti ve re p orti n g of a n y A E b y t h e patie nt  
k)  O bjecti ve o bser vati o n of a n y A E b y t h e I n vesti gat or  
l) T h e i n vesti gat or will be as ke d t o c o m m e nt o n a n y cli nicall y si g nifica nt a b n or m al t est res ults.  
T h e fre q u e n c y of i n vesti gati o ns t h at i n v ol ve bl o o d dra ws h a ve bee n verifie d  t o e ns ure t h at t h e v ol u m e of 
bl o o d t a ke n fr o m patie nts c o nf or ms t o t h e  g ui deli n es s pecifie d f or pe diatric patie nts b y t h e W orl d Healt h 
Or ga nizati o n ( H o wie, 2 0 1 1 ).  
1 3. 1  P h ysic al  a n d Ne ur ol o gic al  E x a mi n ati o n s  
P h ysical  a n d n e ur ol o gical  e xa mi n ati o n s will be perf or m e d as s pecifie d o n t h e Sc h e d ule of Visits a n d 
Assess m e nts.  T h e p h ysical e xa mi n ati o n will i n cl u de a n e xa mi n ati o n of ge n eral a p peara n ce, s ki n, n ec k 
(i n cl u di n g t h yr oi d), e yes a n d ears, n ose, m o ut h, t hr oat, l u n gs, h eart, a b d o m e n, bac k, l y m p h n o des, 
e xtre mities a n d n er v o us s yst e m.  Ge nit al, uri n ar y tract a n d rect al e xa mi n ati o n s are n ot re q uire d .  T he 
fi n di n gs will be e nt ere d o n t h e P h ysical E xa mi n ati o n secti o n of t h e C R F . 
1 3. 2  Vit al Si g ns  
Vit al si g ns assess m e nts will be perf or m e d as s pecifie d o n t h e Sc h e d ule of Visits a n d Assess m e nts a n d will 
i n cl u de b o d y wei g ht, t e m perat ure (oral  or t y m pa nic, acc or di n g t o t h e s pecific m e dical practice of t he 
Ce nt er ) , p ulse, s yst olic a n d diast olic bl o o d press ure, a n d res pirat or y rat e. Hei g ht will be m eas ure d  b y a 
st a di o m et er i n tri plicat e at eac h re q uire d  visit,  a n d use d al o n g wit h b o d y wei g ht  (als o m eas ure d i n tri plicate 
at eac h re q uire d visit ) t o calc ulat e B o d y Mass I n de x ( B MI). P ulse a n d bl o o d press ure w ill be m eas ure d aft er 
t h e patie nt  h as bee n i n t h e s u pi n e p ositi o n f or at least 5 mi n ut es.    
If a c h a n ge of cli nic al relev a nce fr o m pre-d ose t o p ost -d ose is o bser ve d, t h e vit al si g ns assess m e nt s h o uld 
be re peat e d as oft e n as n ee de d, at t h e discreti o n of t h e  I n vesti gat or. G ui deli n es f or cli nicall y n ot a ble vit al 
si g ns val u es are pr o vi de d i n A p pe n di x 4 . Fi n di n gs s h o ul d be d oc u m e nt e d o n t h e Vit al Si g ns secti o n of t he 
Case Re p ort F or m.   

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 5  of 1 3 2  
 
1 3. 3  Electr oc ar di o gr a m ( E C G)  
All patie nt s will h a ve a st a n dar d 1 2-lea d E C G perf or m e d l ocall y, as s pecifie d o n t h e Sc h e d ule of Visits a n d 
Assess m e nts . T h e E C G will be d o n e at M o nt h 6 a n d 1 2  i n tri plicat e, at least 1 0 mi n a part , a n d t h e val u es 
will be a vera ge d  t o o bt ai n t h e baseli n e val u es . 
T h e re vie w a n d i nt er pret ati o n of t h e 1 2 -lea d E C Gs will be perf or m e d b y a car di ol o gist or q u alifie d 
p h ysicia n at t h e i n vesti gati o n al sit e. T h e re p ort fr o m t h e l ocal E C G ser vice m ust be re vie we d b y t he 
In vesti gat or, i nitiale d a n d dat e d, a n d c o pies i nsert e d i n t h e patie nt ’s rec or ds a n d att ac h e d t o t h e C R F. If 
cli nicall y si g nifica nt a b n or m alities are f o u n d, t h e patie nt’s E C G s h o ul d be re peat e d at re g ular i nt er vals u ntil 
it ret ur ns t o n or m al.   
Eac h E C G traci n g m ust h a ve t h e f oll o wi n g i nf or m ati o n e nt ere d o n it:  
• 
St u d y n u m ber,   
• 
Sit e n u m ber ,  
• 
S u bject’s n u m ber a n d i nitials,   
• 
Dat e a n d ti m e E C G o bt ai n e d.  
If cli nicall y si g nifica nt a b n or m alities are f o u n d, t h e patie nt ’s E C G s h o ul d be re peat e d at re g ular i nt er vals 
u ntil it ret ur ns t o n or m al. T h e car di ol o gist or q u alifie d p h ysicia n re vie wi n g t h e E C Gs s h o ul d use t he 
f oll o wi n g g ui deli n es i n det er mi ni n g t h e cli nical si g nifica n ce of a n y a b n or m al fi n di n gs:   
• 
P R i nt er val: < 1 0 0 msec or >  2 1 0 msec  
• 
Q R S i nt er val: < 5 0 msec or > 1 2 0 msec  
• 
Q Tc i nt er val: > 4 5 0 msec  
• 
Heart rat e : < 5 0 b p m (si n us bra d ycar dia) or > 1 2 0 b p m ( si n us t ac h ycar dia) 
• 
M or p h ol o g y: prese n ce of T -wa ve i n vers i o n, a b n or m al R-wa ves, 
pat h ol o gical 
Q -wa ves, or 
si g nifica nt S T ele vati o n or de pressi o n.  
1 3. 4  St a n d ar d L a b or at or y E v al u ati o ns  a n d Scree ni n g Tests  
Bl o o d a n d uri n e sa m ples f or m eas ure m e nt of st a n dar d la b orat or y para m et ers will be as s pecifie d o n t he 
Sc h e d ule of V isits a n d Assess m e nts.  
E val u ati o ns of t h e h e m at ol o g y, cli nical c h e mistr y a n d uri nal ysis a n al yt es list e d i n Ta ble 3  will be perf or m e d 
at eac h of t h e visits list e d a b o ve. I n a d diti o n, a ser u m pre g n a n c y t est will be perf or m e d f or w o m e n  of 
c hil d beari n g p ot e nt ial at  M o nt h 6  a n d M o nt h 1 2 . F or w o m e n of c hil d beari n g p ot e ntial als o a m o nt hl y urine  
pre g n a n c y t est will be perf or m e d bef ore e ver y i nf usi o n t hr o u g h o ut t h e st u d y. F or det ails o n t h e ase ptic 
pr oce d ure f or bl o o d wit h dra wal a n d o n bl o o d di versi o n see “ St u d y Pr oce d ures o n St erilit y Testi n g  f or St u dy 
I E D A T-0 3 -2 0 1 8 ( O L E -I E D A T)” (A p pe n di x 9 ) 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 6  of 1 3 2  
 
 
T a ble 3 . S u m m ar y of st a n d ar d l a b or at or y a n al ytes  
L A B O R A T O R Y A N A L Y T E S  
He m at ol o g y  o r C B C   
Cli ni c al C he mist r y  
Uri n al ysis  ( a ut o m ate d) 
He mat o crit  
S o di u m   
Al k ali n e p h os p h at as e  
C ol or  
He m o gl o bi n  
P ot assi u m   
L D H  
p H  
R B C c o u nt  
C hl ori d e   
C P K  
S p e cifi c gr a vit y 
W B C c o u nt  
Cal ci u m   
Tri gl y c eri des   
Pr ot ei n  
Diff er e nti al W B C c o u nt  P h os p h or us   
T ot al c h ol est er ol    
Gl u c os e  
•  
Ne utr o p hils  
Ser u m ir o n   
H D L c h ol est er ol   
Ket o n es  
•  
L y m p h o c yt es  
Bi c ar b o nat e   
L D L c h ol est er ol   
R B C, W B C, c asts  *  
•  
M o n o c ytes  
Gl u c os e   
 
Nitrit es  
•  
E osi n o p hils  
B U N  
 
Bilir u bi n  
•  
Bas o p hils  
Cr e ati ni ne   
 
He m o gl o bi n  
Pl at el ets  
T ot al  bilir u bi n   
 
Ur o bili n o ge n   
M C V  
Al b u mi n   
 
*  Refle x micr os c o pic 
a n al ysis t o b e p erf or m e d  
o nl y  if ot h er a n al ytes are 
a b n or m al o n a ut o m ate d 
testi n g 
M C H  
T ot al pr ot ei n   
 
M C H C  
A S T ( S G O T)   
 
R D W  
A L T ( S G P T)   
 
S p e ci al Di a g n osti c Tests:  
S er u m pr e g n a ncy t est  (t o b e p erf or me d at M o nt h 6, M o nt h 1 2 a n d s af et y f oll o w u p visit f or w o me n 
of c hil d b eari n g p ot e ntial) . F or w o me n of c hil d beari n g p ot e ntial als o a m o nt hl y uri ne  pr e g n a nc y t est 
will b e p erf or me d b ef or e e v er y i n f usi o n t hr o u g h o ut t h e st u d y. 
 
T h e I n vesti gat or m ust re vie w t h e fi n al I E D A T-0 2 -2 0 1 5 val u es,  pri or t o t h e first a d mi nistrati o n of t h e st u dy 
dr u g i n I E D A T-0 3 -2 0 1 8 , t o e ns ure t h at t h e patie nt m eets t h e pr ot oc ol’s  i n cl usi o n/e xcl usi o n crit eria. T h e 
I n vesti gat or m ust re vie w la b orat or y val u es fr o m eac h s u bse q u e nt e val u ati o n  wit hi n 2 4 h o urs of rec ei pt of 
t h e la b orat or y re p ort. Aft er t h e re vie w is c o m plet e d, t h e I n vesti gat or m ust si g n a n d dat e eac h la b orat or y 
re p ort.  
T h e l ocal la b orat or y s h o ul d pr o vi de q u alit y certificati o ns/accre dit ati o ns  a n d n or m al refere n ce ra n ges f or 
t h e la b orat or y t ests o n t h e la b orat or y res ults re p ort. A val u e is  c o nsi dere d  n or m al  w h e n it falls o n or wit hin 
t h e u p per a n d l o wer li mits of t h e referen ce ra n ge  f or t h e la b orat or y. A val u e is  c o nsi dere d  a b n or m al w h en 
it e xcee ds t h e u p per or l o wer li mit of t h e refere n ce ra n ge. T h e l ocal la b orat or y s h o ul d verif y t h at a b n or m al 
res ults are n ot d u e t o pre -a n al ytical pr o ble ms (e. g., sa m ple t a ke n i m pr o perl y, sa m ple st ore d i n c orrectl y , 
sa m ple la bele d i n c orrectl y) or t o a n al ytical pr o ble ms (e. g., m ac hi n e n ot acc urat el y cali brat e d, t ec h nical 
pr o ble ms wit h e q ui p m e nt or rea ge nts, or det eri orati o n of a n al yt e).  If t h ere are a n y c o nflicts bet wee n 
refere n ce ra n ges i n A p p e n di x 4  a n d t h e refere n ce ra n ges f or t h e l ocal la b orat or y, t h e l ocal la b orat or y 
refere n ce ra n ges will h a ve prece de n ce i n t h e det er mi n ati o n of A Es.  
T h e I n vesti gat or m ust e val u at e a n y c h a n ge of cli nic al relev a nce i n a la b orat or y t est as t o w h et h er it m eets 
t h e defi niti o n of a n a d verse e ve nt, a n d re peat, if n ee de d, a n y cli nicall y si g nifica nt a b n or m al la b orat or y t est. 
A n y la b orat or y a b n or m alities m eeti n g t h e defi niti o n of a n a d verse e ve nt s h o ul d be rec or de d o n t h e A d verse 
E ve nts C R F.  
Refer t o Secti o n 1 4 , “ Re p orti n g Safet y I nf or m ati o n ” f or f urt h er directi o ns.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 7  of 1 3 2  
 
1 3. 5  S peci al L a b or at or y E v al u ati o ns  
Meas ure m e nt of select e d “s pecial” la b orat or y para m et ers h as bee n i n cl u de d i n t h e st u d y t o e val u ate 
p ot e ntial effec ts of de xa m et h as o n e (E D S -E P ) treat m e nt (f or det ails o n ase ptic pr oce d ure f or bl o o d 
wit h dra wal a n d o n bl o o d di versi o n see “ St u d y Pr oce d ures o n St erilit y Testi n g  f or St u d y I E D A T-0 3 -2 0 1 8 
( O L E-I E D A T)”; A p pe n di x 9 ). T h e  f oll o wi n g s pecial la b orat or y para m et ers will be assesse d i n t h e st u d y:   
• 
Bl o o d gl yc os ylat e d h e m o gl o bi n ( H b A 1c, %) , C D 4 + l y m p h oc yt es a n d C -reacti ve pr ot ei n ( C R P)–  t o be 
perf or m e d at M o nt hs 6 a n d 1 2 .  
• 
Scree ni n g f or a dre n al i ns ufficie n c y will be perf or m e d i n all patie nts, re gar dless of wei g ht, via earl y  
m or ni n g ( bef ore 8: 0 0 A M) plas m a c ortis ol t esti n g at t h e f oll o wi n g ti m es: ( 1) w h e n patie nts are 
s y m pt o m atic, a n d ( 2) w h e n patie nts are at m ost ris k f or a dre n al i ns ufficie n c y a n d a dre n al crisis, s u ch 
as f oll o wi n g disc o nti n u ati o n or i nt err u pti o ns of  de xa m et h a s o n e d osi n g (i. e., l oa di n g fail ures a n d 
f oll o wi n g disc o nti n u ati o n of t h e st u d y dr u g). If t h e 8: 0 0 A M c ortis ol le vel is bel o w 3 -5 μ g/ d L 
( de pe n di n g o n assa y) re gar dless of s y m pt o ms, or t h e patie nt e x hi bits si g ns or s y m pt o ms of a dre n al 
i ns ufficie n c y (A p pe n di x  1 2 ) a n d h as a c ortis ol < 1 0 μ g/ d L, t h e patie nt will recei ve a hi g h d ose A C T H 
sti m ulati o n t est, re gar dless of wei g ht, wit hi n 2 4  h o urs. If t h e A C T H sti m ulati o n t est is n or m al, t he 
patie nt ca n c o nti n u e d osi n g wit h  E D S -E P, aft er t h e effects of t h e A C T H h a ve di ssi pat e d (e. g., 3 0 da ys 
aft er A C T H a d mi nist ere d). If  t h e patie nt fails t h e A C T H sti m ulati o n t est t he y will be disc o nti n u e d fro m 
t h e st u d y a n d referre d t o a pe diatric e n d ocri n ol o gist, wit h a rec o m m e n dati o n t o prescri be stress d ose 
st er oi ds. 
• 
Hi g h d ose A C T H s ti m ulati o n t est –  I n t h e e ve nt t h at patie nts s h o w si g ns or s y m pt o ms of a dre n al 
i ns ufficie n c y (A p pe n di x 1 2 ) d uri n g t h e st u d y, es peciall y f oll o wi n g i nt err u pti o n of t h e st u d y dr u g 
(i n cl u di n g l oa di n g fail ures), t h e y will be t est e d f or a dre n al i ns ufficie n c y usi n g a hi g h d ose A C T H 
sti m ulati o n t est ( 2 5 0 μ g gi ve n i. v. or i. m.), re gar dless of wei g ht. If A C T H t esti n g c o nfir ms a dre n al  
i ns ufficie n c y, t h e patie nt will be referre d f or e val u ati o n a n d treat m e nt. Bl o o d sa m ples ( 2. 0 m L) f or 
m eas ure m e nt of pl as m a c ortis ol will be c ollect e d pri or t o A C T H a d mi nistrati o n ( 0 mi n), a n d at 3 0 a n d  
6 0 mi n p ost -d ose. A rise i n plas m a c ortis ol le vel t o great er t h a n 1 8 μ g/ d L wit hi n 6 0 mi n de m o nstrates  
a n or m al res ult. A rise i n c ortis ol t o less t h a n 1 8 μ g/ d L wit hi n 6 0 mi n de m o nstrat es a n a b n or m al  
res p o nse. 
 
1 3. 6  Sterilit y Testi n g of E D S -E P  
 
 
  
 
 
 
 
 
 
 
  
 
C CI

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 8  of 1 3 2  
 
1 3. 7  C ol u m bi a S uici de Se verit y R ati n g Sc ale ( C -S S R S)  
T h e C -S S R S ( P os n er et al, 2 0 0 7 ; P os n er et al, 2 0 1 1) is a st a n dar dize d s uici dal rati n g s yst e m t h at h as 
pr o vi de d dat a f or t h e pe diatric s uici dal ris k a n al ysis of a nti de pressa nts c o n d u ct e d b y t h e F o o d a n d Dr u g 
A d mi nistrati o n ( F D A).  T h e  pe diatric  versi o n of t h e scale will  be use d f or patie nts w h o are less t h a n 1 2 
years of a ge  at t h e baseli n e  visit (a n d will be use d t hr o u g h o ut t h e s t u d y, e ve n if a patie nt t ur ns 1 2 d uri n g 
t h e c o urse of t h e st u d y). T h e t est assess m e nts will be perf or m e d usi n g t h e “Si n ce Last Visit ” versi o n of t he 
C -S S R S.  S u bjects wit h s uici dal i deati o n will be e xcl u de d fr o m partici pati n g i n t h e trial.  
 
1 3. 8  B o ne Mi ner al De nsit y  ( B M D) 
Meas ure m e nts of B M D  will be perf or m e d f or all patie nts at at 6  a n d 1 2 m o nt hs t o assess p ot e ntial st er oi d-
relat e d c h a n ges.  B o n e m ass will be m eas ure d i n t h e s pi n e a n d t ot al b o d y (less t h e h ea d ), f oll o wi n g t he 
g ui deli n es pr o vi de d i n t h e 2 0 1 3 I nt er n ati o nal S ociet y f or Cli nical De nsit o m etr y O fficial P e diatric P ositi on  
(G or d o n  et al, 2 0 1 4 ).  T h e s u g gest e d m et h o d  f or assessi n g  B M D i n t h e st u d y is d u al e n er g y x-ra y 
a bs or pti o m etr y ( D X A). T h e a n al ysis will  be perf or m e d  wit h Z -sc ores f oll o wi n g t h e a b o ve g ui deli n es . T h e 
sa m e m et h o d of assess m e nt will  be use d f or eac h patie nt t hr o u g h o ut t h e st u d y.  
 
1 3. 9  Ta n ner S t a gi n g 
Assess m e nt of p h ysical de vel o p m e nt, se x u al m at urati o n, a n d t h e effect of treat m e nt wit h de xa m et h asone 
o n t h ese as pects will be e val u at e d usi n g t h e Ta n n er scale ( Mars h all a n d Ta n n er 1 9 6 9, 1 9 7 0 ) at 6 a n d 1 2 
m o nt hs . T h e scale defi n es p h ysical m eas ure m e nts of de vel o p m e nt i n c hil dre n, a d olesce nts a n d a d ults base d 
o n e xt er n al pri m ar y a n d sec o n dar y se x c h aract eristics, s u c h as t h e size of t h e breast, ge nit als, t estic ular 
v ol u m e a n d de vel o p m e nt of p u bic h air. D u e t o n at ural variati o n, i n di vi d u als pass t hr o u g h t he Ta n n er st a ges 
at differe nt rat es, de pe n di n g i n partic ular o n t h e ti mi n g of p u bert y. Ta n n e r st a gi n g of t h e breasts i n pre-
m e n arc h al fe m ales a n d of t h e scr ot u m i n m ales w h o h a ve n ot c o m plet e d p u bert y, will be perf or m e d. P ost -
m e n arc h al fe m ales a n d m ales w h o h a ve c o m plet e d p u bert y will be e xcl u de d fr o m t his gr o wt h a n al ysis.   

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 6 9  of 1 3 2  
 
1 4  R E P O R TI N G S A F E T Y I N F O R M A TI O N  
1 4. 1  A d verse E ve nts  
Assess me nt of A d verse E ve nts ( A Es) will be perf or me d t hr o u g h o ut t he st u d y, fr o m t he ti me of si g n i n g of 
t he I C F at baseli ne  t hr o u g h t he fi nal st u d y visit ( M o nt h 1 2  or earl y disc o nti n uati o n ). All A d verse E ve nts 
will be rec or de d i n t he C R F.  I n a d diti o n, all s u bjects will be f oll o we d u p t hr o u g h 3 0 da ys after t he fi nal 
visit ( M o nt h 1 2  or earl y disc o nti n uati o n) or at least 6 0 da ys after t he fi nal i nf usi o n, w hic he ver is l o n ger, f or 
t he occ urre nce  of a n y  A Es or  S A E s.   
1 4. 1. 1  Gl oss ary  
A dverse Dr u g Re acti o n ( A D R)  
I n t h e pre-a p pr o val cli nical e x perie n ce wit h a n e w m e dici n al pr o d u ct or its n e w usa ges, partic ularl y as t he 
t h era pe utic d ose(s) m a y n ot be est a blis h e d, all n o xi o us a n d u ni nt e n de d res p o nses t o a m edici n al pr o d u ct 
relat e d t o a n y d ose s h o ul d be c o nsi dere d a d verse dr u g reacti o ns. T h e p hrase “res p o nse t o a m e dici n al 
pr o d u ct ” m ea ns t h at a ca usal relati o ns hi p bet wee n a m e dici n al pr o d u ct a n d a n a d verse e ve nt is at last a 
reas o n a ble p ossi bilit y, i. e., t h e relati o ns hi p ca n n ot be r ule d o ut.  
A dverse Eve nt ( A E)  
A n A E is a n y u nt o war d m e dical occ urre n ce i n a patie nt or cli nical i n vesti gati o n s u bject a d mi nist ere d a 
p h ar m ace utical pr o d u ct a n d t h at d oes n ot n ecessaril y h a ve a ca usal relati o ns hi p wit h t his treat m e nt. A n A E 
ca n t h eref ore be a n y u nfa v ora ble a n d u ni nt e n de d si g n (i n cl u di n g a n a b n or mal la b orat or y fi n di n g), s y m pt o m, 
or disease t e m p orall y ass ociat e d wit h t h e use of a m e dici n al (i n vesti gati o n al) pr o d u ct, w h et her or n ot related 
t o t h e m e dici n al (i n vesti gati o n al) pr o d u ct. 
Seri o us A dverse Eve nt ( S A E) or Seri o us A dverse Dr u g Re acti o n ( Seri o us A D R)  
A n y u nt o war d m e dical occ urre n ce t h at at a n y d ose:  
• 
Res ults i n deat h,  
• 
Is life-t hreat e ni n g, i. e., a n e ve nt w hic h, i n t h e vie w of t h e I n vesti gat or, places t h e s u bject at 
i m m ediat e ris k of deat h fr o m t h e e ve nt as it occ urre d (it d oes n ot i n cl u de a n e ve nt w hich 
h y p ot h eticall y mi g ht h a ve ca use d deat h if it were m ore se vere)  
• 
Re q uires i n patie nt h os pit alizati o n or pr ol o n gati o n of e xisti n g h os pit alizati o n,  
• 
Res ults i n persist e nt or si g nifica nt disa bilit y/i n ca pacit y,  
• 
Is a c o n ge nit al a n o m al y/ birt h defect (if e x p os ure t o pr o d u ct j ust bef ore c o n ce pti o n or d uri n g 
pre g n a n c y res ult e d i n a n a d verse o ut c o m e i n t h e c hil d), or  
• 
Is a n i m p ort a nt m e dical e ve nt t h at m a y je o par dize t h e s u bject or m a y re q uire m e dical i nt er ve ntion 
t o pre ve nt o n e of t h e o ut c o m es list e d a b o ve.  
S y m pt o ms or m e dicall y si g nifica nt la b orat or y or i nstr u m e ntal (e. g., electr ocar di o gra p hic) a b n or m alities of 
a pre-e xisti n g disease, s u c h as ca n cer or ot h er disease, s h o ul d n ot be c o nsi dere d a n a d verse e ve nt.  H o we ver, 
t h e occ urre n ce of n e w s y m pt o ms , or la b orat or y or i nstr u m e ntal a b n or m alities, as well as w orse ni n g of pre -
e xisti n g s y m pt o ms, are c o nsi dere d a d verse e ve nts.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 0  of 1 3 2  
 
U nex pecte d A dverse Dr u g Re acti o n  
A n U n e x pect e d A d verse Dr u g Reacti o n is a n a d verse e ve nt, t h e n at ure or se verit y of w hic h is n ot c o nsistent 
wit h t h e a p plica ble pr o d u ct i nf or m ati o n (e. g., I n vesti gat or’s Br oc h ure f or a n u n a p pr o ve d i n vesti gati o nal 
pr o d u ct or Pac ka ge I nsert/ S u m m ar y of Pr o d u ct C h aract eristics f or a n a p pr o ve d pr o d u ct).  
N o n -Seri o us A dverse Eve nt  
A n o n -seri o us a d verse e ve nt is a n y a d verse e ve nt t h at d oes n ot m eet t h e crit eria list e d a b o ve f or a seri o us 
a d verse e ve nt.  
1 4. 1. 2  D at a C ollecti o n  
F or eac h e ve nt, rec or d t h e f oll o wi n g i nf or m ati o n o n t h e A d verse E ve nt secti o n of t h e Case Re p ort F or m:  
• Cl assific ati o n of t he E ve nt:  Classif y t h e e ve nt as eit h er seri o us or n o n -seri o us  
• Descri pti o n of Si g ns or S y m pt o ms:  W h e n e ver p ossi ble, rec or d a s pecific dia g n osis f or t h e e ve nt.  If a 
dia g n osis ca n n ot be m a de, t h e n rec or d eac h si g n or s y m pt o m se parat el y, e. g., rec or d n a usea a n d 
v o miti n g as t w o e ve nts.  If m ulti ple e pis o des of a n e ve nt occ ur, se parat e d b y a n a p pr o priat e ti m e i nt er val 
t o j ustif y c o nsi deri n g t h e s u bse q u e nt e pis o des as a re peat occ urre n ce, rec or d eac h e pis o de se parat el y o n 
t h e Case Re p ort F or m. 
• O nset D ate a n d Ti me:  Rec or d t h e dat e a n d ti m e t h e e ve nt st art e d.  If a c h a n ge fr o m baseli n e/ pre vi o us 
e val u ati o n i n a la b orat or y t est is re p ort e d as a n a d verse e ve nt, rec or d t h e st art dat e as t h e dat e of 
c ollecti o n of t h e first la b sa m ple t h at s h o ws t h e c h a n ge.  
• St o p D ate a n d Ti me:  Rec or d t h e dat e a n d ti m e t h e e ve nt res ol ve d.  If a c h a n ge fr o m baseli n e/ pre vi o us 
e val u ati o n i n a la b orat or y t est is re p ort e d as a n a d verse e ve nt, rec or d t h e st o p dat e as t h e dat e of 
c ollecti o n of t h e first sa m ple t h at s h o ws a ret ur n t o t h e pre vi o us le vel.  
• I nte nsit y:  
1.  M il d: E ve nt n ot res ulti n g i n disa bilit y/i n ca pacit y, w hic h res ol ves wit h o ut treat me nt.  
2.  M o der ate: E ve nt  n ot res ulti n g i n disa bilit y/i n ca pacit y, w hic h re q uires treat m e nt.  
3.  Se vere: E ve nt res ulti n g i n t e m p orar y a n d 
mil d disa bilit y/i n ca pacit y, w hic h re q uires 
treat m e nt. 
• Rel ati o ns hi p t o t he St u d y A ge nt:  E ver y eff ort s h o ul d be m a de t o det er mi n e t h e ca use of eac h a d verse 
e ve nt.  T h e c orrelati o n bet wee n t h e st u d y a ge nt a n d t h e a d verse e ve nt s h o ul d be classifie d as f oll o ws:  
 
1.  Pr o b a ble    
a) T h e e ve nt f oll o ws a reas o n a ble t e m p oral se q u e n ce fr o m a d mi nistrati o n of t he 
st u d y a ge nt;  
b) T h e e ve nt f oll o ws a k n o w n res p o nse patt er n t o t h e st u d y a ge nt;  
c) T h e e ve nt ca n n ot be  reas o n a bl y e x plai n e d b y:  
• 
t h e k n o w n c h aract eristics of s u bject’s cli nical st at e, or  
• 
b y ot h er t h era p y a d mi nist ere d, or  
• 
b y t h e dia g n ostic/i nt er ve nti o n al pr oce d ure;  
d) T h ere is e vi de n ce of partial or c o m plet e disa p peara n ce of t h e e ve nt aft er 
wit h dra wal of t h e pr o d u ct ( p ositi ve de -c h alle n ge)  
 
  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 1  of 1 3 2  
 
2.  P ossi ble    
a) T h e e ve nt f oll o ws a reas o n a ble t e m p oral se q u e n ce fr o m a d mi nistrati o n of t he 
st u d y a ge nt; 
b) Ca usati o n of t h e e ve nt b y t h e st u d y a ge nt ca n n ot be e xcl u de d;  
c) T h e e ve nt f oll o ws a k n o w n res p o nse patt er n t o t h e st u d y a ge nt b ut t he e ve nt c o uld 
h a ve bee n  pr o d u ce d b y:  
• 
t h e s u bject’s cli nical st at e, or   
• 
ot h er t h era p y a d mi nist ere d, or  
• 
a dia g n ostic/i n t er ve nti o n al pr oce d ure. 
 
 
3.  U nli kel y  
 
a) T h e a d verse e ve nt f oll o ws a reas o n a ble t e m p oral se q u e n ce fr o m a d mi nistration 
of t h e st u d y a ge nt;  
b) Ot h er reas o ns are m ore li kel y t o be t h e ca use of t h e a d verse e ve nt, base d o n t he 
prese nt k n o wle d ge of t h e  
• 
disease u n der treat m e nt, or  
• 
ot h er t h era p y a d mi nist ere d, or  
• 
st u d y dr u g; 
c) A ca usal relati o ns hi p bet wee n t h e a d ver se e ve nt a n d t h e st u d y dr u g ca n n ot be 
r ule d o ut wit h cert ai nt y. 
 
 
4.  N ot Rel ate d   T h e e ve nt is eit h er a pre -d ose e ve nt or is defi nit el y d u e t o ca uses se parat e fr o m t he 
a d mi nistrati o n of t h e st u d y a ge nt, i. e.,  
• 
d oc u m e nt e d pre -e xisti n g c o n diti o n  
• 
t ec h nical a n d/ or m a n u al pr oce d ural pr o ble ms  
• 
c o n c o mit a nt m e dicati o n  
• 
s u bject’s cli nical st at e. 
 
• Acti o n T a ke n , i n rel ati o n t o tre at me nt of t he A E:   
0.  N o ne  
1.  Dr u g tre at me nt re q uire d  (a m e dicati o n was prescri be d or c h a n ge d; rec or d o n t he 
C o n c o mit a nt Me dicati o n secti o n of t h e Case Re p ort F or m)  
2.  N o n -dr u g tre at me nt re q uire d  (a n o n-dr u g treat m e nt was prescri be d or c h a n ge d, 
rec or d u n der “ C o m m e nts” i n t h e A d verse E ve nt secti o n of t h e Case Re p ort F or m)  
3.  H os pit aliz ati o n or pr ol o n ge d h os pit aliz ati o n  (fill o ut a n  S A E re p ort)   
4.  Di a g n ostic or cli nic al test(s) c o n d ucte d  (att ac h a c o p y of t h e res ults t o t h e Case 
Re p ort F or m)  
5.  S u bject disc o nti n ue d fr o m t he st u d y  
 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 2  of 1 3 2  
 
• Acti o n t a ke n wit h st u d y tre at me nt  
0.  D ose n ot c h a n ge d  
1.  Dr u g i nterr u pte d  
2.  Dr u g wit h dr a w n  
3.  N ot a p plic a ble  
 
• S u bject O utc o me:   
1.  Rec o vere d wit h o ut se q uel ae  
2.  Rec o vere d wit h se q uel ae ( descri be t h e se q u elae u n der “ C o m m e nts” i n t h e A d verse 
E ve nt secti o n of t h e Case Re p ort F or m)  
3.  N ot Rec o vere d, e ve nt o n -g oi n g  (f oll o w t h e s u bject u ntil a defi nit e o ut c o m e ca n be 
det er mi n e d.  W h e n f oll o w -u p dat a are c ollect e d, re p ort f oll o w -u p i nf or m ati o n u n der 
“ C o m m e nts” i n t h e A d verse E ve nt secti o n of t h e Case Re p ort F or m; if e ve nt is seri o us, 
fill i n a f oll o w-u p Seri o us A d verse E ve nt Re p ort)  
4.  Die d  (list pri m ar y ca use of deat h u n der “ E ve nt Descri pti o n ” of t h e A d verse E ve nt 
secti o n of t h e Case Re p ort F or m; if a vaila ble, att ac h a c o p y of t h e a ut o ps y re p ort t o t he 
Case Re p ort F or m a n d se n d a c o p y t o t h e S p o ns or)  
• C o m me nts:  
Pr o vi de ot h er perti n e nt cli nical i nf or m ati o n a n d o bser vati o ns u n der “ C o m m e nts” i n t h e A d verse 
E ve nt secti o n of t h e Case Re p ort F or m.  F or e xa m ple, rec or d pre dis p osi n g or c o ntri b utin g 
c o n diti o ns, s u c h as pre vi o us hist or y, c o n c o mit a nt diseases or m e dicati o ns, a n d/ or pr oce d ural 
ris ks. 
1 4. 1. 3  S u bject F oll o w -u p  
E ver y att e m pt s h o ul d be m a de t o f oll o w t h e s u bject u ntil t h e a d verse e ve nt h as res ol ve d or u ntil t he 
I n vesti gat or det er mi n es t h e s u bject h as ret ur n e d t o a n acce pt a ble st at e of h ealt h.  
1 4. 1. 4  Re p orti n g Seri o us A dverse Eve nts ( S A Es)   
T h e I n vesti gat or m ust re p ort all seri o us a d verse e ve nts wit hi n 2 4 h o urs , irres pecti ve of t h e relati o ns hip 
t o st u d y m e dicati o n, t o t h e C R O, b y fa x or b y e -m ail ( as bac k -u p o pti o n) , c o m pleti n g t h e a p pr o priat e 
re p orti n g f or m.  T h e C R O will t h e n f or war d t his i nf or m ati o n t o Er y Del  wit hi n o n e b usi n ess da y of recei pt.  
T h e n a m es of t h e C R O c o nt act will be c o m m u nicat e d t o t h e i n vesti gat ors b y t h e C R O pri or t o t h e st art of 
s u bject e nr oll m e nt.  
T h e mi ni m u m i nf or m ati o n re q uire d f or a n i nitial re p ort of a Seri o us A E is as f oll o ws:  
• 
Se n der of re p ort ( n a m e, a d dress of I n vesti gat or, sit e n u m ber),  
• 
S u bject i de ntificati o n (scree ni n g n u m ber),  
• 
Pr ot oc ol n u m ber,  
• 
Re p ort a ble e ve nt.  
 
All S A E re p orts a n d a n y case of o ver d ose lea di n g t o a n A E or S A E m ust be fa xe d usi n g t h e a p pr o priat e 
re p orti n g f or m t o t h e f oll o wi n g n u m ber wit hin 2 4 h o urs:  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 3  of 1 3 2  
 
 
M ateri o v i gil a nce a n d P h ar m ac o vi gil a nce U nit  
 
I n case of fa x fail ure, all sit es ca n use t h e f oll o wi n g e m ail a d dress as bac k-u p o pti o n:  
E m ail: 
I n case of deat h, a c o m pre h e nsi ve n arrati ve re p ort of t h e case s h o ul d be pre pare d b y t h e I n vesti gat or a n d 
se nt t o t h e C R O b y m ail t o get h er wit h t h e Seri o us A E F or m, ret ai ni n g a c o p y o n-sit e. If a n a ut o ps y is 
perf or m e d, a c o p y of t h e a ut o ps y re p ort s h o ul d be acti vel y s o u g ht b y t h e I n vesti gat or a n d se nt t o t h e C R O 
as s o o n as a vaila ble. A c o p y of t h e a ut o ps y re p ort will be ret ai n e d o n -sit e. 
A f oll o w -u p Seri o us A d verse E ve nt Re p ort will be c o m plet e d b y t h e I n vesti gat or if i m p ort a nt f oll o w -u p 
i nf or m ati o n (i. e., dia g n osis, o ut c o m e, ca usalit y assess m e nt, res ults of s pecific i n vesti gati o ns) are m a de 
a vaila ble aft er s u b missi o n of t h e i nitia l f or m. T h e f oll o w -u p f or m will be se nt t o t h e C R O as descri be d 
a b o ve.  
If t h e I n vesti gat or bec o m es a ware of a n y deat hs or Seri o us A d verse E ve nts aft er t h e e n d of t h e 6 0 -da y 
f oll o w-u p wi n d o w est a blis h e d i n t h e pr ot oc ol f oll o wi n g i n vesti gati o n al pr o d u ct a d m i nistrati o n, t h e y will 
be re p ort e d t o t h e C R O as descri be d a b o ve.  
1 4. 2  S afet y Re p orti n g t o I n vesti g at ors, I R Bs/I E Cs, a n d Re g ul at or y A ut h orities  
T h e S p o ns or or t h eir desi g n ee will be res p o nsi ble f or re p orti n g all S A Es t o re g ulat or y a ut h orities, 
i n vesti gat ors, a nd I n de pe n de nt Et hics C o m mitt ees / I nstit uti o nal Re vie w B oar ds (I R Bs/I E Cs), as 
a p plica ble, i n acc or da n ce wit h n ati o n al re g ulati o ns f or t h e U nit e d St ates.  F or all acti ve i n vesti gat ors l ocat ed 
i n t h e U nit e d St at es, t h e Sp o ns or or t h eir desi g n ee will pre pare a n e x pe dit e d re p ort f or all S A Es t h at are 
u n e x pect e d a n d p ot e ntiall y relat e d t o t h e st u d y dr u g, a n d c o pies will be distri b ut e d acc or di n g t o all 
a p plica ble la ws a n d re g ulati o ns.  T h e i n vesti gati o n al sit e als o will f or war d a c o p y of all e x pe dit e d re p orts 
t o t h eir I R B/I E C.  
1 4. 3  Re p orti n g O ver d ose  
If t h e i n vesti gati o n al sit e st aff a d mi nist eri n g t h e st u d y m e dicati o n re p orts t h at a s u bject was gi ve n  m ore 
t h a n t h e s pecifie d d ose of st u d y m e dicati o n , t his will be c o nsi dere d a n o ver d ose a n d m ust be re p ort e d 
i mm e diat el y t o t h e I n vesti gat or. A n y i nst a n ce of o ver d ose, w h et h er s y m pt o m atic or n ot, m ust be 
c o m m u nicat e d t o t h e C R O wit hi n 2 4 h o urs a n d be f ull y d oc u m e nt e d as a Seri o us A d verse E ve nt.  Det ails 
of a n y si g ns or s y m pt o ms a n d t h eir m a n a ge m e nt s h o ul d be rec or d e d i n cl u di n g det ails of a n y a nti d ot e(s) 
a d mi nist ere d.  
1 4. 4  Pre g n a nc y   
T his st u d y will e xcl u de  pre g n a nt  a n d breast -fee di n g patie nts, a n d fe m ales of c hil d beari n g p ot e ntial, u nless 
t h e y are practici n g a de q u at e c o ntrace pti o n , as det er mi n e d b y t h eir Healt h Care Pr o vi der.  As a f urt her 
preca uti o n, a  ser u m pre g n a n c y t est will be perf or m e d at M o nt hs 6 , 1 2  a n d safet y f oll o w u p visits f or all 
y o u n g w o m e n w h o h a ve h a d a m e nstr u al peri o d wit hi n t h e past year.  Res ults of t h e  pre g n a n c y  t ests at 
I E D A T-0 2 -2 0 1 5 fi n al visit  m ust be n e gati ve f or t h e patie nt t o be ra n d o mize d t o treat m e nt.    
P P D
P P D

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 4  of 1 3 2  
 
If a patie nt bec o m es pre g n a nt d uri n g t h e st u d y, s h e will be disc o nti n u e d fr o m t h e st u d y i m m e diat ely. 
Patie nts  a n d t h eir pare nts/care gi vers  s h o ul d be i nstr u ct e d t o n otif y t h e I n vesti gat or if it is  det er mi n e d t hat, 
aft er c o m pleti o n of t h e st u d y t h e y h a ve bec o m e pre g n a nt, eit h er d uri n g t h e treat m e nt p h ase of t h e st u d y or 
wit hi n 3 0 da ys of c o m pleti n g t h e st u d y. W h e n e ver p ossi ble a pre g n a n c y s h o ul d be f oll o we d t o t er m, a n y 
pre m at ure t er mi n ati o ns re p ort e d, a n d t h e st at us of t h e m ot h er a n d c hil d s h o ul d be re p ort e d t o t h e C R O or 
Er y Del aft er deli ver y.  
Base d o n t h e esti m at e d h alf -life of de xa m et h as o n e gi ve n wit h t h e E D S, i. e. less t h a n 4 da ys, a peri o d of o n e 
m o nt h of c o nti n u e d c o ntrace pti o n s h o ul d f oll ow aft er st u d y c o n cl usi o n or earl y t er mi n ati o n d u e t o a n y 
reas o n. 
1 4. 5  I n de pe n de nt D at a S afet y M o nit ori n g B o ar d  
A n in de pe n de nt Dat a Safet y M o nit ori n g B oar d  ( D S M B) will be est a blis h e d b y Er y D el t o re vie w t h e safet y 
of all patie nts e nr olle d i n t h is trial, o n a n o n g oi n g basis. N o  Er y D el e m pl o yee or i n vesti gat or i n v ol ve d i n 
t h e E D S  cli nical st u dies will be a v oti n g m e m ber of t his b oar d. T h e D S M B will re g ularl y re vie w t h e safet y 
dat a  as it  accr u e s. 
T h e B oar d will be re g ularl y n otifie d of t h e occ urre n ce of a n y fat al or life t hreat e ni n g e ve nts i m m e diately 
( wit hi n 7 cale n dar da ys) a n d a n y ot h er seri o us a d verse e ve nts wit hi n 1 5 cale n dar da ys. T h e B oar d will als o 
recei ve u p dat es o n a n y a d verse dr o p o uts o n a re g ular basis ( o n ce per m o nt h).  T h e B oar d will h a ve access  
t o t h e safet y dat a i n cl u di n g seri o us A Es a n d a d verse dr o p o uts, as well as cli nicall y si g nifica nt a b n or m al 
la b orat or y t ests, vit al si g ns a n d E C Gs at peri o dic i nt er vals.  
T h e D S M B will  re vie w all of t h e safet y dat a o n a n o n g oi n g basis, wit h s pecial e m p h asis o n t h e i n ci de n ce 
a n d se verit y of st er oi d relat e d e ve nts, n e w i nfecti o ns, a n d seri o us A Es a n d deat hs, i n a d diti o n t o t he st a n dard 
safet y para m et ers. Aft er re vie wi n g t h e e m er gi n g safet y pr ofile f or E D S -E P , t h e B oar d will m a ke a 
rec o m m e n dati o n t o Er y D el t o (a) a m e n d t h e o n g oi n g  st u dy  (e. g., i n crease safet y m o nit ori n g, m o dif y 
d osi n g ), ( b) t er mi n at e t h e E D S pr o gra m (e. g., t h e E D S -E P  safet y pr ofile is u n acce pt a ble),  (c) c o nti n u e t he 
cli nical pr o gra m as desi g n e d . T h e c urre nt st u d y  pr ot oc ol  will n ot be a m e n de d or c h a n ge d (t his i n cl u des t he 
st u d y desi g n a n d e ntr y crit eria) u nless m a n dat e d b y t h e e m er gi n gsafet y pr ofile of E D S -E P .  
Det ails of t h e D S M B c h art er  (se parat e d oc u m e nt) will be s u b mitt e d t o re g ulat or y a ut h orities, a n d will be  
a vaila ble  t o I E Cs/I R Bs u p o n re q u est.  
 
1 5  S U B J E C T C O M P L E TI O N A N D DI S C O N TI N U A TI O N  
1 5. 1  Defi niti o ns  
 ‘ Disc o nti n u ati o n’ will refer t o a n y s u bject w h o d oes n ot c o m plet e t h e f ull 1 2 m o nt hs ( ±3 0 da ys) of t his  
e xt e nsi o n.  
1 5. 2  Pr oce d ures f or H a n dli n g Wit h dr a w als  
I n t h e a bse n ce of a m e dical c o ntrai n dicati o n or si g nifica nt pr ot oc ol vi olati o n, e ver y eff ort s h o ul d be m a de 
b y t h e In vesti gat or t o kee p t h e patie nt i n t h e st u d y. A ll eff orts s h o ul d be m a de t o re p ort t h e o bser vati o ns as 
t h or o u g hl y as p ossi ble at t h e ti m e of t h e patie nt’s wit h dra wal, wit h a n e x pla n ati o n of w h y t h e s u bject is 
wit h dra wi n g fr o m t h e st u d y.  
T h e crit eria f or disc h ar gi n g a patie nt  fr o m t h e st u d y are list e d bel o w.  T h e I n vesti gat or m ust i n dicat e t he 
pri m ar y reas o n ( o nl y o n e ca n be re p ort e d) f or disc o nti n u ati o n, as well as t h e dat e  w h e n t h e decisi o n was 
m a de; t h ese  will be s pecifie d o n t h e ‘ E n d of St u d y ’ f or m. 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 5  of 1 3 2  
 
A patie nt m a y be wit h dra w n fr o m st u d y partici pati o n if:  
• 
A n y h y perse n siti vit y or aller gic reacti o n, clearl y li n ke d t o t h e st u d y m e dicati o n, h as occ urre d;  
• 
t h e patie nt e x perie n ces a n A E s ufficie ntl y se vere, i n t h e o pi ni o n of t h e i n vesti gat or, t h at it 
c o ntrai n dicat es  t h e patie nt c o nti n ui n g i n t h e st u d y;  
If t he p atie nt ex perie nces a syste mic ill ness c o nsi dere d u nrel ate d t o t he st u dy me dic ati o n , it still m ust 
be re p orte d as a n A E.  
• 
t h e patie nt/care gi ver wit h dra w s c o nse nt  (e. g. s u bject ref uses t o h a ve a n y m ore bl o o d sa m ples t a ke n  
f or t h e E D S pr ocess; i n t his i nst a n ce a s pecific reas o n m ust be rec or de d b y t h e i n vesti gat or); 
• 
a m aj or pr ot oc ol de viati o n t h at je o par dizes t h e c o nti n u e d well-bei n g of t h e patie nt or p oses a n ris k t o 
t h e patie nt’s h ealt h; 
If t he p atie nt is a ble t o a bst ai n i n t he f ut ure fr o m activities/ be h avi ors t h at c o nstit ute d a m aj or 
pr ot oc ol vi ol ati o n, t he p atie nt s h o ul d be all o we d t o c o nti n ue.   
• 
t h e patie nt is l ost t o f oll o w-u p, i. e., t h e s u bject di d n ot ret ur n t o t h e cli nic, a n d att e m pts t o c o nt act t he 
s u bject were u ns u ccessf ul.  Atte m pts t o c o nt act t h e s u bject m ust be d oc u m e nt e d ; 
• 
th e S p o ns or, IE C/ I R B, or re g ulat or y a ge n c y t er mi n at es t h e st u d y. 
Dr o p o uts will n ot be re place d.   
T h e In vesti gat or m a y t er mi n at e a patie nt’s st u d y partici pati o n at a n y ti m e d uri n g t he st u d y if a patie nt m eets 
t h e st u d y t er mi n ati o n crit eria descri be d a b o ve. I n a d diti o n, a patie nt or his/ h er  pare nt/ g u ar dia n m a y 
disc o nti n u e t h e patie nt’s partici pati o n wit h o ut gi vi n g a reas o n at a n y ti m e d uri n g t h e st u d y. S h o ul d a 
patie nt’s partici pati o n be disc o nti n u e d, t h e pri m ar y reas o n f or  t er mi n ati o n m ust be rec or de d. F or patie nts 
w h o  disc o nti n u e pri or t o M o nt h 1 2 , an att e m pt s h o ul d be m a de t o perf or m t h e safet y f oll o w u p visit o n t he 
patie nt , a n d t o f oll o w u p o n a n y safet y iss u es u ntil res ol uti o n.  
Patie nts w h o disc o nti n u e pre m at urel y s h o ul d be f oll o we d u p  f or 6 0  da ys  aft er t h eir fi n al i nf usi o n  re gar di n g 
t h e occ urre n ce of a n y Seri o us A d verse E ve nts.  
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 6  of 1 3 2  
 
1 6  S T A TI S TI C A L M E T H O D S  
1 6. 1  A n al ysi s of Effic ac y   
Pri m ary E n d p oi nt  
T o m o nit or a n d e val u at e t h e l o n g -t er m safet y a n d t olera bilit y of E D S-E P i n A T patie nts.  
E x pl or at ory E n d p oi nt  
T o e val u at e t h e l o n g t er m effect of E D S -E P i n treati n g C N S s y m pt o ms as m eas ure d b y t h e “ M o difie d ”  
I nt er n ati o nal C o o perati ve At a xia Rati n g Scale (m I C A R S), Cli nical Gl o bal I m pressi o n  of se verit y a n d 
c h a n ge ( C GI -S/ C)   
Sec o n d ary E n d p oi nt  
T o e val u at e t h e l o n g -t er m effect of E D S-E P o n h ealt h relat e d Q u alit y of Life ( Q o L; E Q -5 D -5 L scale).  
1 6. 2  St atistic al Met h o ds   
1 6. 2. 1  S a m ple Size   
T h ere is n o f or m al sa m ple size calc ulati o n, as t h e sa m ple size is de pe n de nt o n t h e n u m ber of patie nts w h o 
c o m plet e t h e d o u ble -bli n d e xt e nsi o n st u d y ( Pr ot oc ol I E D A T -0 2 -2 0 1 5), e x press t h e desire t o c o nti n u e 
treat m e nt wit h t h e i n vesti gati o n al dr u g, a n d m eet th e selecti o n crit eria defi n e d i n Secti o n 9. 2  of t h e St u d y 
I E D A T-0 3 pr ot oc ol. It is e x pect e d t h at a m a xi m u m of 1 5 0  patie nts will e nt er t his o pe n -la bel e xt e nsi o n. 
 
T h e f oll o wi n g a n al ysis sets will be use d:  
1 ) Effic acy P o p ul ati o n  ( E P): All patie nts w h o e nt er st u d y I E D A T-0 3, h a ve a baseli n e efficac y assess m e nt 
i n st u d y I E D A T-0 3, a n d w h o recei ve d at least o n e d ose of st u d y m e dicati o n a n d h a d at least o n e p ost -
baseli n e efficac y assess m e nt of t h e pri m ar y efficac y varia ble i n t his e xt e nsi o n st u d y.    
2 ) S afety P o p ul ati o n ( S P) : All s u bjects w h o recei ve a d ose of st u d y m e dicati o n, a n d h a ve at least o n e 
p ost -d ose safet y assess m e nt wi ll be i n cl u de d i n t h e safet y a n al yses.  
1 6. 2. 2  B ac k gr o u n d a n d De m o gr a p hic C h ar acteristics   
T h e bac k gr o u n d a n d de m o gra p hic c h aract eristics will c o nsist of a ge, se x, h ei g ht, b o d y wei g ht,  B MI,  past 
a n d c urre nt m e dical c o n diti o ns, a n d hist or y of disease. C o nti n u o us varia bles will be s u m m arize d b y m ea n, 
st a n dar d de viati o n, m e dia n, a n d ra n ge ( mi ni m u m, m a xi m u m), a n d discret e varia bl es will be s u m m arized 
usi n g fre q u e n cies a n d perce nt a ges.   
1 6. 2. 3  St u dy Me dic ati o n  
T h e n u m ber of patie nts recei vi n g a d ose of st u d y treat m e nt will be re p ort e d, a n d t h e a vera ge d ose of E D S -
E P  ( R B C-e n ca ps ulat e d D S P ) a d mi nist ere d  t o eac h  patie nt a n d acr oss all patie nts , base d o n m eas ure m ents 
of sa m ples t a ke n fr o m t h e i nf usi o n ba gs pri or t o d o si n g, will be s u m m arize d b y m ea n, st a n dar d de viati o n, 
m e dia n, a n d ra n ge ( mi ni m u m, m a xi m u m).  
1 6. 2. 4  C o nc o mit a nt Me dic ati o ns a n d T her a py   
A listi n g of c o n c o mit a nt m e dicati o ns a d mi nis tere d fr o m t h e ti m e of d osi n g of t h e st u d y m e dicati o n t hrou gh 
c o m pleti o n of t h e fi n al e val u ati o n ( M o nt h 1 2  or earl y disc o nti n u ati o n) will be pr o vi de d.    

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 7  of 1 3 2  
 
1 6. 2. 5  S afety Ev al u ati o n s  
All patie nts i n t h e Safet y P o p ulati o n will be i n cl u de d i n t h e safet y a n al yses. All a d verse e ve nts will be list e d 
a n d s u m m arize d b y b o d y s yst e m a n d preferre d t er m.  T h e i n ci de n ce of A Es ( %) a n d t h eir  i nt e nsit y a n d 
relat e d n ess t o t h e st u d y dr u g, as assesse d b y t h e I n vesti gat or, will be re p ort e d.  Seri o us a d verse e ve nts  
( S A Es) a n d e ve nts w h ic h are n e wl y occ urri n g or w orse ni n g aft er a d mi nistrati o n of t h e st u d y m e dicati on 
will be s u m m arize d. I n a d diti o n, a d verse e ve nts t h at res ult i n deat h or disc o nti n u ati o n ( A D O) of t h e st u dy 
m e dicati o n will be list e d se parat el y.  
Ot h er safet y para m et ers s u c h as vit al si g ns, st a n dar d la b orat or y para m et ers, E C Gs, p h ysical/ n e ur ol o gical 
e xa mi n ati o n fi n di n gs, a n d s pecial la b orat or y para m et ers will be list e d a n d s u m m arize d acc or di n gl y. 
A b n or m al a n d cli nicall y n ot a ble val u es will be i de ntifie d a n d list e d f or eac h par a m et er , as a p pr o priat e.  
1 6. 2. 5. 1  I nteri m S afety Revie w  
T h e  i n de pe n de nt Dat a Safet y M o nit ori n g B oar d ( D S M B) t h at was est a blis h e d b y Er y Del t o re vie w t he 
safet y of all patie nts e nr olle d i n  t h e I E D A T-0 2 st u d y, will c o nti n u e t o m o nit or t h e safet y of all patie nts 
c o nti n ui n g i n  t his trial, o n a n o n g oi n g basis. N o Er y Del e m pl o yee or i n vesti gat or i n v ol ve d i n t h e E D S-E P 
cli nical st u dies will be a m e m ber of t his b oar d.  T h e D S M B will m eet re g ularl y  t o assess t h e safet y fr o m 
t h e e m er gi n g dat a. T h e ti m e bet wee n s u ccessi ve m eeti n gs s h o ul d n ot be m ore t h a n t hree m o nt hs. 
Aft er re vie wi n g t h e e m er gi n g safet y pr ofile f or E D S -E P, t h e D S M B will m a ke a rec o m m e n dati o n t o Er y Del 
t o (a) a m e n d t h e o n g oi n g E D S-E P s t u d y, ( b) t er mi n at e t h e E D S-E P, or (c) c o nti n u e t h e cli nical pr o gra m as 
desi g n e d. T h e c urre nt st u d y will n ot be a m e n de d or c h a n ge d (t his i n cl u des t h e st u d y desi g n a n d e ntry 
crit eria) u nless m a n dat e d b y t h e e m er gi n g safet y pr ofile of E D S -E P.  
A se parat e D S M B St atistical A n al ysis Pla n will be de vel o pe d f or s pecif yi n g t h e a n al yses, t a bles, listi n gs 
a n d fi g ures t o be pre pare d f or D S M B m eeti n gs.  
T h e D S M B will be re g ularl y n otifie d of t h e occ urre n ce of a n y fat al or life t hreat e ni n g e ve nts i m m e diat ely 
( wit hi n 7 cale n dar da ys) a n d a n y ot h er seri o us a d verse e ve nts wit hi n 1 5 cale n dar da ys. T h e D S M B will als o 
recei ve u p dat es o n a n y a d verse dr o p o uts o n a re g ular basis ( o n ce per m o nt h).  T h e D S M B will h a ve access 
t o t h e safet y dat a i n cl u di n g seri o us A Es a n d a d verse dr o po uts, as well as cli nicall y si g nifica nt a b n or m al 
la b orat or y t ests, vit al si g ns a n d E C Gs at peri o dic i nt er vals..  
Det ails of t h e D S M B c h art er (se parat e d oc u m e nt) will be s u b mitt e d t o re g ulat or y a ut h orities, a n d will be 
a vaila ble t o Et hics C o m mitt ees/I R Bs u p o n re q u est.   
1 6. 2. 6  Effic acy A n alyses  
Descri pti ve st atistics ( n, m ea n, st a n dar d de viati o n [ S D], m e dia n, mi ni m u m, a n d m a xi m u m) will be pr o vi de d 
f or all c o nti n u o us efficac y m eas ures f or act u al val u es a n d c h a n ges fr o m baseli n e of St u d y I E D A T -0 3  at 
eac h ti m e -p oi nt.  F or cat e g orical varia bles, t h e n u m ber a n d perce nt a ge of patie nts i n eac h cat e g or y will be 
prese nt e d at eac h ti m e -p oi nt.  
T h e a n al ysis of l o n g -t er m efficac y of E D S -E P  is a n e x pl orat or y o bjecti ve of t his e xt e nsi o n st u d y , a n d will 
be base d o n t h e res ults f or t h e “ M o difie d” I nt er n ati o nal C o o perati ve At a xia Rati n g Scale (m I C A R S), a n d 
t h e Cli nical Gl o bal I m pressi o n of se verit y a n d c h a n ge ( C GI -S/ C) .  Descri pti ve st atistics will be perf or m e d 
t o det er mi n e t h e pr o p orti o n of patie nts w h o i m pr o ve, m ai nt ai n t h eir c urre nt st at e, or w orse n aft er o n e year  
of treat m e nt wit h E D S-E P  i n t his o pe n -la bel e xt e nsi o n st u d y, c o m pare d t o t h e ir baseli n e  st at us at e ntr y i nt o 
t h e I E D A T-0 3 -2 0 1 8  trial.  T h e m ea n  ( S D) c h a n ge fr o m baseli n e at eac h ti m e -p oi nt will be e val u at e d f or 
t h e mI C A R S a n d t h e  C GI -S.  F or t h e C GI -C h a n ge, t h e pr o p orti o n  [ n( %)] of patie nts rat e d as i m pr o ve d, as 
well as t h ose s h o wi n g n o c h a n ge or w orse ni n g,  at eac h ti m e -p oi nt  will be calc ulat e d .   

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 7 8  of 1 3 2  
 
A d diti o n al a n al ys es will be perf or m e d t o det er mi n e t h e c h a n ge i n  eac h of t h e  efficac y m eas ures  c o m pare d 
t o t h e baseli n e of t h e I E D A T-0 2 -2 0 1 5  st u d y, c o m pari n g patie nts w h o were treat e d wit h E D S-E P t hr o u g h out 
t h e d o u ble-bli n d a n d o pe n -la bel treat m e nt peri o ds vs. t h ose w h o recei ve d place b o f or var yi n g peri o ds  i n 
St u d y I E D A T -0 2 -2 0 1 5 , bef ore bei n g s wit c h e d t o t h e acti ve treat m e nt . As a sec o n dar y o bjecti ve, si milar 
descri pti ve a n al yses will be perf or m e d t o e val u at e t h e l o n g-t er m effects of E D S-E P o n h ealt h -related 
Q u alit y of Life ( Q o L ), as assesse d b y t h e E Q -5 D -5 L s cale.  
T h e det ails of t h e st atistical a n al yses will be prese nt e d i n a se parat e St atistical A n al ysis Pla n.  
H a n dli n g of Dr o p o uts a n d Missi n g D at a  
Patie nts w h o disc o nti n u e treat m e nt pre m at urel y , i. e. pri or t o t h e M o nt h 1 2 visit, are defi n e d as dr o p o uts. 
All fi n al M o nt h 1 2 ( Visit 1 3) e va ulati o ns s h o ul d be perf or m e d at t h e ti m e of disc o nti n u ati o n.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
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1 7  E T HI C S  
1 7. 1  Et hic al C o nsi der ati o ns  
T h e st u d y will be carrie d o ut i n acc or da n ce wit h t h e Declarati o n of Helsi n ki, as a m e n de d b y t h e 6 4 t h Ge n eral 
Asse m bl y of t h e W orl d Me dical Ass ociati o n,  F ort aleza, Brazil, Oct o ber 2 0 1 3  (A p pe n di x 1 ).  
S u bject I nf or m ati o n a n d Inform ed C o nse nt  
T h e I nf or m e d C o n se nt F or m, as well as t h e S u bject I nf or m ati o n S h eet , m ust be a p pr o ve d b y t h e  I R B/I E C 
t o get h er wit h t h e St u d y Pr ot oc ol, bef ore t h e st art of t h e st u d y.  
All s u bjects , or if n ecessar y t h eir pare nt/care gi ver or le gal re prese nt ati ve ( wit h asse nt b y t h e s u bject), m ust 
si g n a n d pers o n all y dat e a n a p pr o ve d I nf or m e d C o nse nt F or m aft er recei vi n g det aile d writt e n a n d ver bal 
i nf or m ati o n a b o ut t h e reas o n, t h e n at ure, t h e re q uire d pr oce d ures, t h e i nt e n de d d urati o n a n d t h e p ossi ble 
ris ks a n d be n efits a n d a n y disc o mf ort ass ociat e d wit h t h e st u d y. Eac h s u bject s h o ul d be i nf or m e d t hat 
his/ h er partici pati o n i n t h e st u d y is v ol u nt ar y a n d t h at h e/s h e m a y ref use t o partici pat e or wit h dra w fr o m 
t h e trial, at a n y ti m e, wit h o ut pe n alt y or l oss of be n efits t o w hic h t h e s u bject is ot her wise e ntitle d.  
T h e la n g u a ge use d i n t h e oral a n d writt e n i nf or m ati o n a b o ut t h e trial, i n cl u di n g t h e writt e n I nf or m ed 
C o nse nt F or m s h o ul d be as n o n -t ec h nical as practical a n d s h o ul d be u n derst a n da ble t o t h e s u bject. T h e 
s u bject m ust be gi ve n a m ple ti m e t o rea d a n d t o u n derst a n d t h e S u bject I nf or m ati o n S h eet a n d o p p ort u nit y 
t o i n q uire a n d as k a n y clarificati o n a b o ut t h e trial bef ore si g ni n g t h e I nf or m e d C o nse nt F or m. 
N o st u d y pr oce d ure c a n be perf or me d (i ncl u di n g t he b aseli ne  visit) bef ore t he i nf or me d c o nse nt f or m 
h as bee n si g ne d. T h e i nf or m e d c o nse nt pr oce d ure m ust be d o n e acc or di n g t o t h e g ui deli n es pr o vi de d i n 
t h e Declarati o n of Helsi n ki a n d t h e I C H E 6 G ui deli n e f or G o o d Cli nical Practice.  
T h e s u bject m ust be m a de a ware a n d a gree t h at pers o n al i nf or m ati o n m a y be scr uti nize d d uri n g a u dit / 
i ns pecti o n b y c o m pet e nt a ut h orities a n d pr o perl y a ut h orize d pers o ns.  H o we ver, pers o n al i nf or m ati o n will 
be treat e d as strictl y c o nfi de ntial a n d will n ot be p u blicl y a vaila ble.  
B y si g ni n g t h e I n vesti gat or St at e m e nt (A p pe n di x 3 ), t h e I n vesti gat or ass ures Er y Del P h ar m ace utic als  t hat 
I nf or m e d C o nse nt will be o bt ai n e d.  
Ori gi n al si g n e d I nf or m e d C o nse nt F or ms will be file d wit h t h e I n vesti gat or’s File.  
1 7. 2  I E C/I R B A p pr o v al  
T h e pr ot oc ol, I n vesti gat o r’s Br oc h ure, S u bject I nf or m ati o n S h eet, I nf or m e d C o nse nt F or m a n d a n y 
a d vertise m e nt f or t h e recr uit m e nt of s u bjects m ust be re vie we d a n d a p pr o ve d b y a n a p pr o priat el y 
c o nstit ute d I E C/I R B, as re q uire d i n C h a pt er 3 of t h e I C H E 6 G ui deli n e. A c o p y of t h e C o m m itt ee’s dat e d 
a p pr o val a n d a list of t h e m e m bers of t h e I E C/I R B will be gi ve n t o t h e S p o ns or f or t h e S p o ns or's files. A 
c o p y will be als o i n cl u de d i n t h e Fi n al Re p ort. Writt e n I E C/I R B a p pr o val m ust be o bt ai n e d b y t h e S p o ns or 
pri or t o s hi p m e nt of st u d y a ge n t or s u bject e nr oll m e nt.  A n y a m e n d m e nts t o t h e pr ot oc ol, I nf or m e d C o nsent 
F or m  (I C F) or S u bject I nf or m ati o n S h eet, ot h er t h a n a d mi nistrati ve o n es, m ust be a p pr o ve d b y t his 
c o m mitt ee.   
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
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1 8  A D MI NI S T R A TI V E C O N SI D E R A TI O N S  
1 8. 1  Re g ul at or y Re q uire me nts: S p o ns or/I n vest i g at or O bli g ati o ns 
T his st u d y will be c o n d u ct e d i n acc or da n ce wit h t h e Declarati o n of Helsi n ki a n d t h e I C H E 6 G ui deli n e 
( G o o d Cli nical Practice, see A p pe n di x 2 ).  T o e ns ure c o m plia n ce t h e I n vesti gat or a grees, b y writt e n c o nsent 
t o t his pr ot oc ol, t o f ull y co o perat e wit h c o m plia n ce c h ec ks b y all o wi n g access t o all d oc u m e nt ati on, 
i n cl u di n g s u bjects’ h os pit al files (t h e s o urce d oc u m e nts), b y a ut h orize d i n di vi d u als. 
1 8. 2  C urric ul u m Vit ae  
T h e I n vesti gat or a n d a n y c o -I n vesti gat or(s) m ust pr o vi de t h e S p o ns or wit h c urre n t c o pies of t h eir o w n 
c urric ul u m vit ae.  
1 8. 3  I n vesti g at or a n d St u d y A d mi nistr ati ve Str uct ure 
T h e a d mi nistrati ve str u ct ure of t h e st u d y (e. g., I n vesti gat ors, m o nit ori n g a n d e val u ati o n pers o n n el, 
la b orat or y facilities, cli nical trial s u p pl y m a n a ge m e nt) is prese nte d i n t h e Trial Mast er File.  
T he listi n g s h o ul d i ncl u de:  
a)  
T he I n vesti gat or(s);  
b)   
A n y ot her pers o n carr yi n g o ut o bser vati o ns of pri mar y or ot her maj or efficac y or safet y 
varia bles, s uc h as a n urse, p h ysicia n's assista nt, cli nical ps yc h ol o gist, cli nical p har macist or 
h o use staff p h ysicia n.   
1 8. 4  I n vesti g at or’s St ate me nt 
T his d oc u m e nt, si g n e d  a n d dat e d b y t h e Pri n ci pal I n vesti gat or, descri bes t h e I n vesti gat or’s o bli gati o ns. T he 
st a n dar d t e xt is a p pe n de d t o t h e pr ot oc ol (A p pe n di x 3 ). 
1 8. 5  M o nit ori n g Pr oce d ures  
1 8. 5. 1  St u dy M o nit ori n g  
A C R O will be select e d b y t h e S p o ns or t o o versee t h e c o n d u ct of t h e trial .  A n a p pr o priat e re prese nt ati ve 
of t h e C R O ( St u d y M o nit or) will m ai nt ai n c o nt act wit h t h e I n vesti gat or a n d will visit t h e st u d y sit e f or t he 
p ur p ose of disc ussi n g a n d/ or retrie vi n g dat a. A n i nitiati o n ( pre -st u d y) visit will be m a de b y t h e St u dy 
M o nit or t o  disc uss wit h t h e I n vesti gat or t h e pr ot oc ol a n d t h e o bli gati o ns of b ot h t h e S p o ns or a n d t he 
I n vesti gat or.  T h e I n vesti gat or m ust all o w t h e St u d y M o nit or t o perf or m peri o dic, i nt eri m m o nit ori n g visits.  
T h e p ur p oses of t h ese visits are:  
• T o verif y t h at writt e n I nf or m e d C o nse nt was o bt ai n e d pri or t o eac h s u bject’s partici pati o n i n t h e trial.  
• T o assess t h e pr o gress of t h e st u d y.  
• T o re vie w t h e c o m plia n ce wit h t h e st u d y pr ot oc ol.  
• T o det er mi n e w h et h er all a d verse e ve nts were a p pr o priat el y re p ort e d.  
• T o det er mi n e w h et h er t h e I n vesti gat or is m ai nt ai ni n g t h e esse ntial d oc u m e nts.  
• T o disc uss a n y e m er ge nt pr o ble m.  
• T o c h ec k t h e Case Re p ort F or ms ( C R Fs) f or le gi bilit y, acc urac y a n d c o m plet e n ess.  
• T o vali dat e t h e c o nt e nts of t h e C R Fs a gai nst s o urce d oc u m e nts.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
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• T o c ollect c o m pl et e d C R Fs.  
• T o assess t h e st at us of dr u g st ora ge, dis pe nsi n g a n d retrie val.  
T h e I n vesti gat or will m a ke a vaila ble t h e s o urce d oc u m e nts f or i ns pecti o n.  T his i nf or m ati o n will be 
c o nsi dere d as c o nfi de ntial. Vi ol ati o ns of a n d devi ati o ns fr o m t he pr ot oc ol m ust b e n otifie d t o t he St u dy 
M o nit or as s o o n as p ossi ble.  
T h e St u d y M o nit or will perf or m a cl ose o ut visit at t h e ti m e w h e n all C R Fs h a ve bee n retrie ve d a n d all 
q u eries h a ve bee n a ns were d.  
1 8. 5. 2  C ase Re p ort F or ms ( C R Fs)  
Electr o nic Case Re p ort F or ms  (eC R Fs ) will be pr o vi de d  f or eac h s u bject. T h e st u d y M o nit or will re vie w 
t h e f or ms at eac h sit e visit.  
Case Re p ort F or ms m ust be c o m plet e d f or all s u bjects w h o si g n I nf or m e d C o nse nt, e ve n if t h e s u bject fails 
t o c o m plet e t h e st u d y. N o secti o n of t h e C R Fs is t o be left bla n k wit h o ut a n a p pr o priat e e x pla n ati o n b y t he 
I n vesti gat or, si n ce t h e lac k of s u c h e x pla n ati o n m a y n ecessit at e discar di n g a n ot h er wise usa ble o bser vati o n.  
If re q u est e d, c o pies of t h e C R Fs are t o be m a de a vaila ble t o t h e a p pr o priat e re g ulat or y a ge n cies.  
1 8. 5. 3  A u diti n g/I ns pecti n g  
T h e I n vest i gat or will m a ke all perti n e nt rec or ds a vaila ble, i n cl u di n g s o urce d oc u m e nt ati o n, f or i ns pecti on 
b y re g ulat or y a ut h orities a n d f or a u diti n g b y t h e S p o ns or.  T his i nf or m ati o n will be c o nsi dere d as 
c o nfi de ntial. A u dits/I ns pecti o ns m a y occ ur a n y ti m e fr o m st a rt t o aft er c o n cl usi o n of t h e st u d y. W h e n a n 
I n vesti gat or si g ns t h e pr ot oc ol, h e/s h e a grees t o all o w re g ulat or y a ut h orities a n d Er y Del  a u dit ors t o i ns pect 
his/ h er st u d y rec or ds.  
1 8. 6  Arc hi vi n g of Rec or ds  
C o pies of t h e pr ot oc ol, s u bject i de ntificati o n c o des, eC R Fs, s o urce dat a, I nf or m e d C o nse nt F or ms a n d ot h er 
d oc u m e nts pert ai ni n g t o t h e st u d y c o n d u ct m ust be ke pt f or t h e m a xi m u m peri o d of ti m e as re q uire d b y t he 
stu d y ce nt er. T his ti m e peri o d m ust be at least t w o years aft er t h e last a p pr o val of t h e m ar keti n g a p plicati on 
of t h e st u d y a ge nt i n a n I C H re gi o n a n d u ntil t h ere are n o pe n di n g or c o nt e m plat e d m ar keti n g a p plicati o ns 
i n a n I C H re gi o n, or at least t w o years h a ve ela pse d si n ce t h e f or m al disc o nti n u ati o n of cli nical de vel o p m ent 
of t h e st u d y a ge nt.  
N o st u d y d oc u m e nt s h o ul d be destr o ye d wit h o ut pri or writt e n a gree m e nt bet wee n t h e S p o ns or a n d t he 
I n vesti gat or. Ori gi n als of all d oc u m e nt ati o n a n d c o pies of o ut g oi n g c orres p o n de n ce c o n cer ni n g t h e st u dy 
will be st ore d a n d ret ai n e d b y t h e S p o ns or i n a safe area i n t h e  Trial Mast er File f or t h e lifeti m e of t he 
pr o d u ct. I n partic ular, t h e fi n al re p ort  se nt b y t h e I n vesti gat or t o t h e I R B/I E C m ust be ret ai n e d b y t he 
S p o ns or, or t h e s u bse q u e nt o w n er, f or fi ve years be y o n d t h e lifeti m e of t h e st u d y a ge nt.  
1 8. 7  Fi n al Cli nic al St u d y Re p ort  
T h e Fi n al Cli nical St u d y Re p ort ( C S R) will be writt e n b y t h e C R O, acc or di n g t o s pecificati o ns t o be defi n e d 
b y Er y Del .  
1 8. 8  St u d y D oc u me n t ati o n a n d P u blic ati o n of Res ults 
St u dy D oc u me nt ati o n  
All u n p u blis h e d d oc u m e nt ati o n (i n cl u di n g t h e pr ot oc ol, C R Fs a n d I n vesti gat or's Br oc h ure) gi ve n t o t he 
I n vesti gat or is strictl y c o nfi de ntial.  All reci pie nts m ust a gree n ot t o discl ose t h e i nf or m ati o n h erein 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
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c o nt ai n e d t o a n y pers o n n ot c o n n ect e d wit h t h e st u d y wit h o ut t h e pri or writt e n a ut h orizati o n of Er y Del  
S. p. A .  T h e s u b missi o n of t h ese d oc u m e nts t o t h e I R B/I E C is e x pressl y per mitt e d.  T h e i n v ol ve d parties 
a gree t h at t he res ults of t his st u d y will be use d i n t h eir ori gi n al f or m a n d/ or i n a gl o bal re p ort f or s u b missi on 
t o g o ver n m e nt al a n d re g ulat or y a ut h orities of a n y c o u ntr y.  
All i nf or m ati o n c o m m u nicate d t o t h e i n vesti gat or(s) b y Er y Del  is t h e e xcl usi ve pr o pert y of Er y Del S. p. A . 
T h e Pri n ci pal I n vesti gat or will e ns ure t his i nf or m ati o n s h all be ke pt strictl y c o nfi de ntial b y hi m/ h er or a n y 
ot h er pers o n c o n n ect e d wit h  t h e st u d y a n d s h all n ot be discl ose d t o a n y t hir d part y wit h o ut t h e pri or written 
c o nse nt of Er y Del . 
P u blic ati o n of Res ults   
A n y f or m al prese nt ati o n or p u blicati o n of t h e dat a fr o m t his trial will be c o nsi dere d as a j oi nt p u blicati on 
b y t h e I n vesti gat or(s) a n d Er y Del.  A ut h ors hi p will be det er mi n e d b y a P u blicati o n C o m mitt ee c o nsistin g 
of t h e lea d i n vesti gat or(s) fr o m t h e trial,  re prese nt ati ves fr o m Er y Del , a n d a n e xt er n al c o ns ult a nt wit h 
e x pertise i n t h e fiel d. F or m ulti -ce nter st u dies, it is m a n dat or y t h at t h e first p u blicati o n is base d o n dat a 
fr o m all ce nt ers, a n al yze d as sti p ulat e d i n t h e pr ot oc ol b y a st atisticia n desi g n at ed b y Er y Del.  I n vesti gat ors 
partici pati n g i n t his st u d y a gree n ot t o prese nt or p u blis h dat a gat h ere d fr o m a si n gle ce nt er or s u b -gr o u p of 
ce nt ers bef ore t h e f ull i nitial p u blicati o n, u nless a gree d t o b y all ot h er i n vesti gat ors a n d Er y Del.  A ut h ors hip 
of a n y p u blicati o n res ulti n g fr o m t his trial will i n cl u de m e m bers of eac h of t h e c o ntri b uti n g ce nt ers  a n d ke y 
c o ntri b ut ors t o t h e desi g n a n d e xec uti o n of t h e st u d y, i n cl u di n g  Er y Del pers o n n el.  
Er y Del will f or m a st u d y p u blicati o n c o m mitt ee t o c o or di n at e a n d de vel o p a p u blicati o n p olic y a n d h el p i n 
its i m ple m e nt ati o n.  T h e p u blicati o n c o m mittee will be c o m prise d of t h e Pri n ci pal I n vesti gat ors fr o m eac h 
of t h e c o u ntries (t o be det er mi n e d b y Er y Del ), base d o n t h eir c o ntri b uti o ns t o st u d y c o n d u ct a n d t h eir stat us 
i n t h e fiel d.  T h e ot h er m e m bers of t h e p u blicati o n c o m mitt ee will i n cl u de a re prese nt ati ve of Er y Del a n d 
a n e xt er n al c o ns ult a nt.  Me m bers of t h e p u blicati o n c o m mitt ee ca n n ot ser ve as first a ut h ors of m ore t han 
o n e pri m ar y p u blicati o n.  
T h e a ut h ors hi p of t h e first m ultice nt er pa per will be c o m prise d of m e m bers of t h e p u blicati o n c o m mittee, 
Pri n ci pal I n vesti gat ors of t h e t hree sit es wit h t h e hi g h est n u m bers of vali d patie nts, a n d Er y Del 
re prese nt ati ves w h o h a ve m a de si g nifica nt c o ntri b uti o ns t o t h e desi g n, c o n d u ct a n d a n al ysis of t h e res ults. 
T h e Pri n ci pal I n vesti gat ors of all c o ntri b uti n g ce nt ers will be ac k n o wle d ge d i n t h e p u blicati o n.  T h e 
P u blicati o n C o m mitt ee will deci de o n t h e c o nt e nt, j o ur n al, a n d se q u e n ce o f p u blicati o ns / prese nt ati o ns. 
A n y p u blicati o n, a bstract, or pa per of a n y i nf or m ati o n or m at erial relati n g t o or arisi n g o ut of t h e prese nt 
cli nical st u d y s h all be se nt t o Er y Del f or re vie w at least si xt y ( 6 0) da ys bef ore prese nt ati o n at a n y c o n gress, 
or p u blicati o n of t h e fi n al f or m(s) b y a n y j o ur n al. Er y Del will i nf or m t h e I n vesti gat or of a n y c h a n ges or 
deleti o ns n ecessar y t o preser ve Er y Del’s c o nfi de ntial a n d pr o priet ar y t ec h nical i nf or m ati o n. All ri g hts a n d 
i nt erests w orl d wi de i n a ny i n ve nti o ns, k n o w -h o w or ot h er i nt ellect u al or i n d ustrial pr o pert y ri g hts, w hich 
arise d uri n g t h e c o urse a n d/ or as a res ult of t h e prese nt cli nical st u d y or w hic h arise fr o m t h e i nf or m ation 
or m at erials s u p plie d u n der t his A gree m e nt, s h all be assi g n e d t o,  vest i n a n d re m ai n t h e pr o pert y of Er y Del 
S. p. A.    
1 8. 9  Fi n a nci al A gree me nt  
A fi n a n cial a gree m e nt (se parat e fr o m t h e pr ot oc ol) will be m a de a n d si g n e d b y Er y Del S. p. A.  or t h eir 
desi g n ee a n d b y a re prese nt ati ve  of t h e I nstit uti o n w h ere t h e st u d y will be c o n d u ct e d.  
1 8. 1 0  Ter mi n ati o n of St u d y  
I n t h e e ve nt t h at t h e I n vesti gat or is u n a ble t o c o nti n u e t h e st u d y, a n ot h er s uit a ble s u b -I n vesti gat or at t he 
sit e will be desi g n at e d t o ser ve as t h e I n vesti gat or i n t h e i nt eri m, u ntil a n e w I n vesti gat or ca n be i de ntifie d. 
T his i nt eri m I n vesti gat or, if a p pr o ve d b y t h e sit e I R B/I E C will carr y o ut t h e res p o nsi bilities of t he 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 8 3  of 1 3 2  
 
I n vesti gat or. D oc u m e nt ati o n t estif yi n g t o t his will be s u b mitt e d t o t h e St u d y M o nit or wit hi n 1 0 da ys of t he 
c h a n ge. Wit hi n 6 m o nt hs of t h e a p p oi nt m e nt of t h e i nt e ri m I n vesti gat or, t h e n e w Pri n ci pal I n vesti gat or 
m ust be i de ntifie d a n d a p pr o ve d b y b ot h Er y Del S. p. A.  a n d t h e I R B/I E C f or t h e st u d y t o c o nti n u e at t he 
sit e.  
If t h e S p o ns or a n d/ or t h e I n vesti gat or s h o ul d disc o ver c o n diti o ns arisi n g d uri n g t h e st u d y t h at i n dicat e it 
s h o ul d be t er mi n at e d, a n a p pr o priat e sc h e d ule f or t er mi n ati o n will be i nstit ute d.  If t h e I n vesti gat or 
t er mi n at es t h e st u d y, a n e x pla n at or y lett er will be pr o vi de d t o Er y Del . S h o ul d t h e st u d y be disc o nti n ued 
d u e t o a decisi o n b y Er y Del , t h e I n vesti gat or will be rei m b urse d f or reas o n a ble e x pe nses i n c urre d a n d f or 
t h e s u bjects act u all y treat e d acc or di n g t o t h e st u d y pr ot oc ol. 
1 8. 1 0. 1  St u dy Disc o nti n u ati o n by t he S p o ns or  
T h e S p o ns or m a y t er mi n at e t h e e ntire st u d y, or t h e st u d y at a n i n di vi d u al sit e, at a n y ti m e, f or a n y of t he 
f oll o wi n g reas o ns: 
• 
fail ure t o e nr oll s u bjects; 
• 
pr ot oc ol vi olati o ns or de viati o ns;  
• 
i n acc urat e or i n c o m plet e dat a; 
• 
n o n G C P c o m plia n ce;  
• 
c o m pleti o n of e nr ol m e nt;  
• 
a d mi nistrati ve reas o ns . 
1 8. 1 0. 2  St u dy Disc o nti n u ati o n by t he I nvesti g at or  
T h e I n vesti gat or m a y t er mi n at e his/ h er partici pati o n i n t h e st u d y i n c o ns ult ati o n wit h t h e S p o ns or d u e t o 
t h e occ urre n ce of si g nifica nt a d verse e ve nts a n d/ or a d verse dr u g reacti o ns e n da n geri n g t h e h ealt h of 
s u bjects, w hic h m a ke it et hicall y u n acce pt a ble t o c o n ti n u e. 
1 8. 1 1  I ns ur a nce P olic y 
Er y Del S. p. A.,  or its desi g n ee, will pr o vi de i ns ura n ce c o vera ge f or da m a ges e m er gi n g fr o m t h e trial a n d 
i n v ol vi n g t h e s u bjects treat e d wit h t h e t est c o m p o u n d, pr o vi de d t h at t h e I n vesti gat or(s) h a ve a d h ere d t o t he 
t er ms a n d pr o visi o ns of t h e pr ot oc ol. T h e pri n ci pal I n vesti gat or will be s u p plie d wit h all dat a c o n cer ni n g 
t h e i ns ura n ce c o m pa n y a n d p olic y n u m ber f or a m a xi m u m s u m i ns ura ble. 
1 8. 1 2  Fi n a nci al Discl os ure  
T h e Pri n ci pal I n vesti gat or a n d s u b -I n vesti gat ors will pr o vi de t h e S p o ns or wit h a de q u at e a n d acc urate 
fi n a n cial i nf or m ati o n ( P D 3 5) t o e ns ure t h at t h e S p o ns or ca n m a ke c o m plet e a n d acc urat e fi n a n cial 
certificati o n of discl os ure st at e m e nts t o c o n cer n e d re g ulat or y a ut h orities.  It is t h e d ut y of t h e I n vesti gat or 
t o pr o m ptl y u p dat e pre vio us i nf or m ati o n pr o vi de d t o t h e S p o ns or if t h ere are salie nt c h a n ges t h at occ ur 
d uri n g t h e c o urse of t h e st u d y, a n d f or a peri o d of o n e year f oll o wi n g its c o m pleti o n (last patie nt last visit) .  
T h e st u d y will be perf or m e d u n der a U S I N D; t h eref ore, all I n v esti gat ors/s u b -I n vesti gat ors, c o ntract ors, 
et c., are e x pect e d t o c o m pl y wit h t h e o bli gati o ns as s pecifie d i n t h e C F R ( 2 1 C F R part 5 4) b y t h e U S F D A, 
i n cl u di n g re q uire m e nts f or f ull Fi n a n cial Discl os ure (G ui da n ce f or Cli nical I n vesti gat ors, I n d ustr y a n d F D A  
St aff: Fi n a n cial Discl os ure b y Cli nical I n vesti gat ors, Fe br u ar y 2 0 1 3 ). 
 
 

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 8 4  of 1 3 2  
 
1 9  R E F E R E N C E S  
 
1.  A n n ese V, Latia n o A, R ossi L, et al. Er yt hr oc yt es -m e diat e d deli ver y of De xa m et h as o n e i n st er oi d -
de pe n de nt I B D patie nts –  A pil ot u n c o ntr olle d st u d y. A m J Gastr oe nt er ol 2 0 0 5; 1 0 0: 3 7 0 -1 3 7 5.  
2.  A wa d M, Al -S h a mra n y M, L oc ker D, Alle n F, Fei n e J. Effect of re d u ci n g t h e n u m ber of it e ms of 
t h e Oral Healt h I m pact Pr ofile o n res p o nsi ve n ess, vali dit y a n d relia bilit y i n e de nt ul o us p o p ulati ons. 
C o m m u nit y De nt Oral E pi de mi ol 2 0 0 8 ; 3 6( 1): 1 2-2 0 .  
3.  B o der E. At a xia -t ela n giect asia: a n o ver vie w. I n: Gatti R A, S wift M, e ds. At a xia-t ela n giect asia: 
Ge n etics, Ne ur o pat h ol o g y, a n d I m m u n ol o g y of a De ge n erati ve Disease of C hil d h o o d. Kr oc 
C o nfere n ce Series. V ol. 1 9. Ne w Y or k: Ala n R. Liss I n c 1 9 8 5: 1 -6 3.  
4.  B oe hrs J K , He J , Hala b y  
MJ , Ya n g 
D Q . 
C o nstit uti ve e x pressi o n 
a n d c yt o plas mic 
c o m part m e nt alizati o n of A T M pr ot ei n i n differe ntiat e d h u m a n n e ur o n -li ke S H-S Y 5 Y cells. J 
Ne ur oc h e m  2 0 0 7; 1 0 0( 2): 3 3 7 -3 4 5.  
5.  B ossa F, Latia n o A, R ossi L,  et al. Er yt hr oc yt e -m e diat e d deli ver y of de xa m et h as o n e i n patie nts 
wit h mil d -t o-m o derat e ulcerati ve c olit is, refract or y t o m esala mi n e: a ra n d o mize d, c o ntr olle d st u d y. 
A m J Gastr oe nt er ol 2 0 0 8; 1 0 3: 1 -8.  
6.  B ossa F, A n n ese V, Val va n o M R,  et al. Er yt hr oc yt e -m e diat e d deli ver y of De xa m et h as o n e 2 1 -
p h os p h at e i n st er oi d -de pe n de nt Ulcerati ve C olitis: a ra n d o mize d, d o u ble -b li n d, s h a m-c o ntr olled 
st u d y. I nfla m m B o wel Dis 2 0 1 3; 1 9: 1 8 7 2-7 9.  
7.  Br occ oletti T, Del Gi u dice E, A m or osi S, et al.  St er oi d -i n d u ce d i m pr o ve m e nt of n e ur ol o gical si g ns 
i n at a xia-t ela n giect asia patie nts. E ur J Ne ur ol 2 0 0 8; 1 5( 3): 2 2 3-8.  
8.  Br occ oletti T, Del Gi u dice E , Cirill o E, et al. Efficac y of ver y -l o w-d ose bet a m et h as o n e o n 
n e ur ol o gical s y m pt o ms i n at a xia -t ela n giect asia. E ur J Ne ur ol 2 0 1 1; 1 8( 4): 5 6 4-7 0.  E p u b 2 0 1 0 Se p 
1 4.  
9.  B u o ni S, Za n n olli R, S orre nti n o L, F ois A. Bet a m et h as o n e a n d i m pr o ve m e nt of n e ur ol o gical 
s y m pt oms i n at a xia t ela n giect asia. Arc h Ne ur ol 2 0 0 6; 6 3: 1 4 6 9 -1 4 8 2.  
1 0.  Ca n o SJ,  H o bart J C, Hart P E,  et al. I nt er n ati o n al C o o perati ve At a xia Rati n g Scale (I C A R S): 
a p pr o priat e f or st u dies of Frie dreic h's at a xia? M o v Dis or d 2 0 0 5; 2 0( 1 2): 1 5 8 5 -9 1.  
1 1.  Castr o M, K n afelz D, R ossi L, et al. Peri o dic treat m e nt wit h a ut ol o g o us er yt hr oc yt es l oa de d wit h 
de xa m et h as o n e 2 1 -p h os p h at e f or fist ulizi n g pe diatric Cr o h n’s disease: Case re p ort. J Pe diatric 
Gastr oe nt er ol N utr 2 0 0 6; 4 2: 3 1 3 -3 1 5.   
1 2.  Castr o M, R ossi L, Pa pa dat o u B,  et al. L o n g -t er m treat m e nt wit h a ut ol o g o us re d bl o o d cells l oa de d 
wit h de xa m et h as o n e 2 1 – p h os p h at e i n pe diatric patie nts affect e d b y st er oi d -de pe n de nt Cr o h n 
disease . J Pe diatric Gastr oe nt er ol N utr 2 0 0 7; 4 4: 4 2 3-4 2 6.  
1 3.  C h essa L, Le u zzi V, Ple ba ni A, et al. I ntra-er yt hr oc yt e i nf usi o n of  de xa m et h as o n e re d u ces 
n e ur ol o gical s y m pt o ms i n At a xia Tela n giect asia patie nts: Res ults of a P h ase 2 trial.  Or p h a n et J 
Rare Dis 2 0 1 4; 9: 5 .  
1 4.  C h u n H H, Gatti R A. At a xia -t ela n giect asia, a n e v ol vi n g p h e n ot y pe. D N A Re pair 2 0 0 4; 3: 1 1 8 7-
1 1 9 6.  
1 5.  Cra wf or d T O, Ma n dir A S, Left o n -Greif M A,  et al. Q u a ntit ati ve n e ur ol o gic assess m e nt of at a xia-
t ela n giect asia. Ne ur ol o g y 2 0 0 0; 5 4: 1 5 0 5-1 5 0 9.  
1 6.  Cra wf or d T O, S k olas k y R L, Fer n a n dez R, et al. S ur vi val pr o ba bilit y i n at a xia t ela n giect asia. Arc h 
Dis C hil d 2 0 0 6 ; 9 1( 7): 6 1 0-1 1.  
1 7.  Cri n elli R, A nt o n elli A, Bia n c hi M, Ge ntili ni L, Scara m u cci S, Ma g n a ni M. Selecti ve i n hi biti o n of 
N F -k B acti vati o n a n d T N F -α pr o d u cti o n i n m acr o p h a ges b y re d bl o o d cell -m e diat e d deli ver y of 
de xa m et h as o n e. Bl o o d Cells M ol Dis 2 0 0 0; 2 6( 3): 2 1 1 -2 2 2.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 8 5  of 1 3 2  
 
1 8.  D’ Asce n z o 
M, A nt o n elli A, C hiara nti ni L, 
Ma n ci ni U, 
Ma g n a ni 
M. Re d bl o o d cells as a 
gl u c oc ortic oi ds deli ver y s yst e m. I n: Er yt hr oc yt es as dr u g carriers i n m e dici n e. S pra n del U, Wa y J L 
(e ds), Ple n u m Press, Ne w Y or k 1 9 9 7, 8 1-8 8.  
1 9.  D mitrie n k o A, D’ A g osti n o R.  Tra diti o n al m ulti plicit y a dj ust m e nt m et h o ds i n cli nical trials. St atist 
Me d 2 0 1 3; 3 2 5 1 7 2 – 5 2 1 8.  
2 0.  D u m o nt LJ, A u B u c h o n J P. E val u ati o n of pr o p ose d F D A crit eria f or t h e e val u ati o n of ra di ola belle d 
re d cell rec o ver y trials. Tra nsf usi o n 2 0 0 8; 4 8: 1 0 5 3-6 0  
2 1.  Er y De x  S yst e m  ( E D S) I n vesti gat or’s Br oc h ure, E diti o n N o. 7 , A pril 2 0 , 2 0 2 0 . 
2 2.  G or d o n C M et al ., 2 0 1 3 Pe diatric P ositi o n De vel o p m e nt C o nfere n ce: E xec uti ve S u m m ar y a n d 
Reflecti o ns. J o ur n al of Cli nical De nsit o m etr y: Assess m e nt a n d Ma n a ge m e nt of M usc ol os kelet al 
Healt h , 2 0 1 4;  1 7, (2 ): 2 1 9 -2 2 4 . 
2 3.  G u y  W. Cli nical Gl o bal I m pressi o ns.  1 9 7 6. Nati o n al I nstit ut e of 
Me nt al Healt h. E C D E U 
Assess m e nt Ma n u al f or Ps yc h ot h era p y.  
2 4.  Her d m a n M, G u de x C, Ll o y d A, et al. De vel o p m e nt a n d preli mi n ar y t esti n g of t h e n e w fi ve -le vel 
versi o n of t h e E Q-5 D ( E Q -5 D -5 L). Q u al Life Res 2 0 1 1; 2 0( 1 0): 1 7 2 7 -3 6.  
2 5.  H oc h e F, Sei del K, T h eis M, et al. Ne ur o de ge n erati o n i n At a xia Tela n giect asia. W h at is Ne w? 
W h at is E vi de nt ? Ne ur o pe diatrics 2 0 1 2; 4 3( 3): 1 1 9 -2 9. E p u b 2 0 1 2 Ma y 2 1.  
2 6.  H o wie S R. Bl o o d sa m ple v ol u m es i n c hil d h ealt h researc h: re vie w of safe li mits. B ull W orl d Healt h 
Or ga n 2 0 1 1; 8 9: 4 6 -5 3.  
2 7.  htt ps:// w w w. at a xia. or g/ p df/ At a xia % 2 0 Tela n giect asia. p df .  
2 8.  Ja nsse n M, Pic kar d A S, G olic ki D, et al. Meas ure m e nt of pr o perties of t h e E Q -5 D -5 L c o m pare d t o 
t h e E Q-5 D -3 L acr oss ei g ht patie nt gr o u ps: a m ulti -c o u ntr y st u d y. Q u al Life Res 2 0 1 3; 2 2( 7): 1 7 1 7 -
2 7.  
2 9.  Lee Y , Mc Ki n n o n PJ. A T M de pe n de nt a p o pt osis i n t h e n er v o us s yst e m.  A p o pt osis 2 0 0 0; 5( 6): 5 2 3 -
5 2 9.  
3 0.  L u ci di V, T ozzi A E, Bella S, T urc h ett a A. A pil ot trial o n safet y a n d efficac y of er yt hr oc yt e -
m e diat e d st er oi d treat m e nt i n C F patie nts. B M C Pe diatrics 2 0 0 6, 6: 1 7.  
3 1.  L y n c h D R, Perl m a n S L, Meier T. A p h ase 3, d o u ble -bli n d, place b o -c o ntr olle d trial of i de be n o n e i n 
Frie dreic h at a xia. Arc h Ne ur ol 2 0 1 0; 6 7( 8): 9 4 1 -7.  
3 2.  Ma g n a ni M, R ossi L, D’ Asce n z o M,  et al. Er yt hr oc yt e  e n gi n eeri n g f or dr u g deli ver y a n d t ar geti n g. 
Bi ot ec h n ol A p pl Bi oc h e m 1 9 9 8; 2 8: 1 -6.   
3 3.  Mars h all W A, Ta n n er J M (J u n e 1 9 6 9). Variati o ns i n patt er n of p u bert al c h a n ges i n girls . Arc h. Dis. 
C hil d. 4 4 ( 2 3 5): 2 9 1 – 3 0 3.   
3 4.  Mars h all W A, Ta n n er J M ( Fe br u ar y 1 9 7 0). Variati o ns i n t h e patt er n of p u bert al c h a n ges i n b o ys . 
Arc h. Dis. C hil d. 4 5 ( 2 3 9): 1 3 – 2 3.   
3 5.  Mc H or n e y C A. Ge n eral h ealt h m eas ure m e nt: Past acc o m plis h m e nts a n d a m eas ure m e nt para di g m 
f or t h e 2 1st ce nt ur y. A n n I nt Me d 1 9 9 7; 1 2 7: 7 4 3 -5 0 .  
3 6.  Mc H or n e y C A, Ware J, R o g ers W, et al. T h e Vali dit y a n d Relati ve Precisi o n of M O S S h ort - a n d 
L o n g -F or m Healt h St at us Scales a n d Dart m o ut h C O O P C h arts: Res ults fr o m t h e 
Me dical 
O ut c o m es St u d y.  Me dical Care 1 9 9 2; 3 0 : M S 2 5 3.  
3 7.  Meier T,  Perl m a n S L, R u m m e y C,  et al. Assess m e nt of n e ur ol o gical efficac y of i de be n o n e i n 
pe diatric patie nts wit h Frie dreic h's at a xia: dat a fr o m a 6 -m o nt h c o ntr olle d st u d y f oll o we d b y a 1 2 -
m o nt h o pe n -la bel e xt e nsi o n st u d y. J Ne ur ol 2 0 1 2; 2 5 9( 2): 2 8 4-9 1.  
3 8.  Me n ott a M, Bia gi otti S, Bia n c hi M,  et al. De xa m et h as o n e partiall y resc u es at a xia t ela n giect asia -
m ut at e d ( A T M) deficie n c y i n at a xia t ela n giect asia b y pr o m oti n g a s h ort e n e d pr ot ei n varia nt 
ret ai ni n g ki n ase acti vit y. J Bi ol C h e m 2 0 1 2; 2 8 7( 4 9): 4 1 3 5 2-6 3.  

Cli ni c al St u d y Pr ot o c ol I E D A T -0 3 -2 0 1 8    
  
  
E D S i n At a xi a Tel a n gi ect asi a P ati e nts  
Versi o n 1. 0, Fi n al, 2 5 J a n uar y 2 0 1 8; Versi o n 2. 0, Fi n al, 2 9 Mar c h 2 0 1 8; Versi o n 3. 0, Fi n al, 3 0 A pril 2 0 1 8; Versi o n 
4. 0: 1 9 Mar c h 2 0 1 9, Fi n al ; Versi o n 5. 0: 2 9 A pril 2 0 1 9, Fi n al; Versi o n 6. 0: 2 2 Ma y 2 0 2 0, Fi n al ; Versi o n 7. 0: 0 1 
Dece m ber  2 0 2 0, Fi n al  
 
Pa ge 8 6  of 1 3 2  
 
3 9.  Met z G,  C o p par d N, C o o per J M,  et al. Rati n g disease pr o gressi o n of Frie dreic h's at a xia b y t he 
I nt er n ati o nal C o o perati ve 
At a xia Rati n g Scale: a n al ysis of a 6 0 3-patie nt dat a base. Brai n 
2 0 1 3; 1 3 6( Pt 1): 2 5 9 -6 8.  
4 0.  Mit c h ell C D, Ric h ar ds S M, Ki nse y S E,  et al. ; Me dical Researc h C o u n cil C hil d h o o d Le u kae mia 
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