A Phase 3, Randomized, Active Controlled Study to Evaluate Maintenance of Response, Safety and Patient Reported Outcomes in Acromegaly Patients Treated With Octreotide Capsules vs. Parenteral Somatostatin Receptor Ligands
Phase: PHASE3
Conditions: Acromegaly
Sponsor: Chiasma, Inc.



 
 
    P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 4 of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
P R O T O C O L S Y N O P SI S  
St u d y Title  
A p hase 3, ra n d o mize d, o pe n -la bel, acti ve c o ntr olle d, m ultice nter st u d y t o 
e val uate mai nte na nce of res p o nse, safet y a n d patie nt re p orte d o utc o mes i n 
acr o me gal y patie nts treate d wit h octre oti de ca ps ules, a n d i n patie nts treate d wit h 
sta n dar d of care pare nteral s o mat ostati n rece pt or li ga n ds w h o pre vi o usl y t olerate d 
a n d de m o nstrate d a bi oc he mical c o ntr ol o n b ot h treat me nts .  
Pr ot oc ol N o.  
O O C -A C M -3 0 2  
Cli nic al Sites  
Gl o bal, M ultice nter St u d y  
St u d y P h ase  
3  
I n vesti g ati o n al 
Pr o d ucts  
Octre oti de C a ps ules 
Octre oti de ca ps ule is a n o vel, orall y -a d mi nistere d f or m ulati o n of t he well -
c haracterize d a n d c o m merciall y -a vaila ble pare nteral dr u g octre oti de. It is a 
ca ps ule fille d wit h a n oil y s us pe nsi o n of octre oti de f or m ulate d wit h pr o prietar y 
Tr a nsie nt Per mea bilit y E n ha ncer ( T P E ® ) e xci pie nts. T he T P E facilitates 
paracell ular tra nsit acr oss t he i ntesti nal wall, pri maril y via tra nsie nt a n d re versi ble 
o pe ni n g of t he ti g ht j u ncti o ns bet wee n cells, e na bli n g i ntact octre oti de t o be 
a bs or be d. T he ca ps ule is e nteric c oate d a n d desi g ne d t o pass i ntact t hr o u g h t he 
st o mac h a n d diss ol ve i n t he s mall i ntesti ne. 
Octre oti de ca ps ules (eac h ca ps ule stre n gt h is 2 0  m g) s h o ul d be a d mi nistere d 
t wice dail y o n a n e m pt y st o mac h, i.e. at least 1 h o ur pri or t o a meal or at least t w o 
h o urs after a meal . 
Octre oti de ca ps ules will be a d mi nistere d t o all eli gi ble patie nts d uri n g t he R u n -i n 
p hase, a n d will be u p titrate d (fr o m 4 0  m g t o 6 0  m g a n d 8 0  m g/ da y), base d o n 
cli nical a n d bi oc he mical res p o nse. Patie nts w h o are bi oc he micall y c o ntr olle d at 
t he e n d of t he R u n-i n p hase will be ra n d o mize d t o eit her c o nti n ue octre oti de 
ca ps ules treat me nt or re vert t o t heir sta n dar d of care ( S O C) i njecta ble 
s o mat ostati n rece pt or li ga n d ( S R L), d uri n g t he ra n d o mize d c o ntrolle d treat me nt 
( R C T) p hase . 
Patie nts e nteri n g t he St u d y E xte nsi o n p hase will c o nti n ue octre oti de ca ps ules f or 
5 y ear s or u ntil pr o d uct mar keti n g or ter mi nati o n of st u d y b y S p o ns or  (t he earliest 
of w hic h ). F oll o wi n g t he c o m pleti o n of t he 5- y ear E xte nsi o n p hase, t he S p o ns or 
will  eit her e xte n d  t he E xte nsi o n p hase  (via pr ot oc ol a me n d me nt s, f or a n 
a d diti o nal y ear or u ntil pr o d uct mar k eti n g or st u d y ter mi nati o n , t he earliest of 
w hic h ), or c o nsi der c o m p assi o nate use (if re q ueste d b y t he pri nci pal In vesti gat or 
u n der c o m passi o nate use pr ot oc ol) ; s u bse q ue ntl y a c o m p assi o nate use pr ot oc ol 
will be pre pare d a n d s u b mitte d f or re g ulat or y a p pr o val.  
I nject a ble S o m at ost ati n Rece pt or Li g a n ds -- S R Ls ( Octre oti de L A R or 
L a nre oti de)  
Patie nts ra n d o mize d t o t he acti ve c o ntr ol ar m i n t he R C T p hase, will recei ve t heir 
S O C  i njecta ble S R L ( octre oti de L A R or la nre oti de), acc or di n g t o t he i n di vi d ual 
patie nt use p ri or t o e nr oll me nt i n t he st u d y. 
C a ber g oli ne (f or C o m bi n ati o n p h ase s u b -st u dy i n selecte d sites) 
Ca ber g oli ne is a l o n g -acti n g d o pa mi ne rece pt or a g o nist wit h a hi g h affi nit y f or 
D 2  rece pt ors. It is c o m m o nl y use d f or t he treat me nt of acr o me gal y as 
m o n ot hera p y or i n c o m bi nati o n wit h ot her a ge nts.  
P atie nts w h o fail t o res p o n d t o octre oti de ca ps ules 8 0  m g f or at least t w o wee ks 
t hera p y d uri n g t he c o urse of t he R u n-i n, or patie nts i neli gi ble t o e nter t he R C T o n 

 
 
    P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 9 of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
will be ra n d o mize d at wee k 2 6 i n a 3 :2  rati o t o o ne of t w o treat me nt ar ms: 
c o nti n ue treat me nt wit h octre oti de ca ps ules (treat me nt ar m 1) or s witc h t o t heir 
pri or pare nteral S R L treat me nt ( treat me nt ar m 2) f or a n a d diti o nal 3 6  wee ks  
(starti n g o n wee k 2 6 t hr o u g h wee k 6 2). 
T he st u d y will utilize ce ntralize d stratifie d ra n d o mizati o n base d o n t he f oll o wi n g 
varia bles o n wee k 2 4  of t he R u n -i n p hase: 
•  
I G F-1 ≤1 ×  U L N vs. I G F -1 > 1 ×  U L N t o  < 1. 3 ×  U L N at wee k 2 4  
•  
Octre oti de ca ps ules treat me nt d ose  at wee k 2 4  ( 4 0 m g vs. 6 0 m g or 
8 0  m g)  
Cli nic visits d uri n g t he R C T p hase will be sc he d ule d t o occ ur e ver y f o ur wee ks  
( wee k 2 6 2, 3 0, 3 4, 3 8, 4 2, 4 6, 5 0, 5 4, 5 8 a n d 6 2). Patie nts ra n d o mize d t o recei ve 
pare nteral S R Ls will recei v e t heir i njecti o ns at t he site at t he sa me fre q ue nc y  a n d 
d ose  as recei ve d pri or t o scree ni n g. Patie nts, w h o recei ve d pare nteral S R Ls e ver y 
f o ur ( or fi ve) wee ks, will recei ve t heir i njecti o ns e ver y f o ur wee ks at wee ks 2 6, 
3 0, 3 4, 3 8, 4 2 , 4 6 , 5 0, 5 4 a n d 5 8. Patie nts w h o recei ve d pare nteral S R Ls at a n 
i nter val of o nce e ver y ei g ht wee ks will be assesse d e ver y f o ur wee ks  y et will 
recei ve t heir i njecti o n e ver y ei g ht wee ks ( wee ks 2 6, 3 4,4 2 , 5 0 a n d 5 8). Patie nts 
w h o recei ve d t heir pare nte ral S R Ls i njecti o ns e ver y si x ( or se ve n) wee ks will 
atte n d visit wee k 3 2 i nstea d of visits wee ks 3 0 a n d 3 4 , visit wee k 4 4 i nstea d of 
visit wee ks 4 2 a n d 4 6  a n d visit wee k 5 6 i nstea d of wee ks 5 4 a n d 5 8. T hese 
patie nts  will recei ve t heir i njecti o n o n wee ks 2 6, 3 2, 3 8, 4 4, 5 0 a n d 5 6 . Visit 
wi n d o w will be ± 3 da ys.  
I G F-1 will be assesse d o n all sc he d ule d visits  d uri n g t he R C T p hase , G H will be 
assesse d at wee k 2 6 ( E n d of R u n -i n/ be gi n ni n g of R C T) a n d wee k 6 2 / E n d of 
treat me nt. Acr o me gal y s y m pt o ms will be c ollecte d at eac h visit. Ot her 
pr oce d ures will be c o n d ucte d as s pecifie d i n t he  Sc he d ule of Acti vities. 
U nsc he d ule d visits will be all o we d t hr o u g h o ut t he st u d y f or safet y or 
ma na ge me nt of acti ve disease, per t he In vesti gat or discreti o n, t hr o u g h o ut t he 
R C T p h ase. 
All eff orts s h o ul d be ma de t o mai ntai n patie nts o n t heir ra n d o mize d treat me nt 
t hr o u g h o ut t he R C T p hase u p t o c o m pleti o n of t he c ore st u d y.  
Eli gi ble patie nts w h o ha ve c o m plete d t he R C T p hase will be offere d t o c o nti n ue 
i nt o a v ol u ntar y St u d y E xte nsi o n p hase  a n d recei ve octre oti de ca ps ules . 
Patie nts c o m pleti n g t he R C T p hase w h o are i neli gi ble t o e nter t he St u d y 
E xte nsi o n p hase  (see eli gi bilit y criteria), d ue t o i na de q uate c o ntr ol, patie nts w h o 
d o n ot o pt t o e nter t he St u d y E xte nsi o n p hase or patie nts w h o disc o nti n ue 
treat me nt earl y d uri n g R C T, will re vert bac k t o t heir pri or i njecta ble S R L ( pri or 
t o Scree ni n g, n o n -I M P), or ot her treat me nt as deter mi ne d b y t heir p h ysicia n ; 
t hese patie nts will u n der g o t hree F oll o w -u p visit s wit hi n 1 2  wee ks  ( + 4, + 8 a n d 
+ 1 2 wee ks)  after t heir last st u d y me dicati o n d ose . 
C o m bi n ati o n p h ase s u b-st u d y (i n selecte d sites) 
Patie nts w h o fail t o res p o n d  t o octre oti de ca ps ules 8 0  m g f or at least t w o wee ks 
t hera p y d uri n g t he c o urse of t he R u n-i n p hase , or patie nts i neli gi ble t o e nter t he 
R C T o n octre oti de ca ps ules 8 0  m g, d ue t o i n -a de q uate bi oc he mical c o ntr ol, wit h 
I G F- 1 ≥ 1. 3  ×  U L N t o I G F - 1 < 2 ×  U L N , or I G F -1 < 1. 3 ×  U L N a n d G H ≥ 2. 5 
n g/ m L , will e nter t he C o m bi nati o n p hase  s u b-st u d y a n d recei ve c o -a d mi nistrati o n 
of octre oti de ca ps ules 8 0  m g wit h ca ber g oli ne 
 f or 3 6  wee ks . 
2 Visit wi n d o w f or wee k 2 6 will be -3 t o + 1 0 da ys  

 
 
    P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
E xcl usi o n 
Criteri a  
A n y of t he f oll o wi n g will e xcl u de a patie nt fr o m partici pati n g i n t he st u d y: 
1.  Patie nts ta ki n g i njecti o ns of l o n g -acti n g S R Ls less fre q ue ntl y t ha n o nce 
e ver y ei g ht wee ks  ( d osi n g i nter val > 8 wee ks). 
2.  Patie nts w h o pre vi o usl y partici pate d i n C H -A C M -0 1.  
3.  S y m pt o matic c h olelit hiasis . 
4.  Recei ve d pit uitar y ra di ot hera p y wit hi n fi ve y ears pri or t o scree ni n g 
(i ncl u di n g t otal b o d y, hea d a n d nec k or stere otactic ra di ot hera p y). 
5.  U n der g o ne pit uitar y s ur ger y wit hi n si x m o nt hs pri or t o scree ni n g  or ha ve 
electe d s ur ger y pla n ne d wit hi n  t he c o urse of the c ore st u d y . 
6.  Hi g h -ris k patter n4 of pit uitar y t u m or l ocati o n o n pit uitar y ma g netic 
res o na nce i ma gi n g (M RI) / C o m p ute d t o m o gra p h y ( C T) as per me dical 
hist or y or  m ost rece nt  M RI/ C T. 
7.  Hist or y of u nsta ble a n gi na or ac ute m y ocar dial i nfarcti o n wit hi n t he 1 2 
wee ks  prece di n g t he scree ni n g visit or ot her cli nicall y si g nifica nt car diac 
disease at t he ti me of scree ni n g as j u d ge d b y t he Pri nci pal I n vesti gat or . 
8.  A n y cli nicall y si g nifica nt u nc o ntr olle d ner v o us s yste m, gastr oi ntesti nal 
( GI), re nal, p ul m o nar y, or he patic c o nc o mita nt disease t hat i n t he 
I n vesti gat or’s o pi ni o n w o ul d precl u de patie nt partici pati o n. 
9.  E vi de nce of acti ve mali g na nt disease or  mali g na ncies dia g n ose d wit hi n 
t he pre vi o us y ear  (e xce pt f or basal cell carci n o ma a n d u nc o m plicate d – 
u p t o sta ge 1 s q ua m o us cell carci n o ma  t hat has bee n e xcise d a n d c ure d). 
1 0.  K n o w n aller g y or h y perse nsiti vit y t o a n y of t he test c o m p o u n ds or 
materials . 
1 1.  K n o w n u nc o ntr olle d dia betes defi ne d as ha vi n g a fasti n g gl uc ose 
>  1 5 0  m g/ d L ( 8. 3  m m ol/ L) or gl y c os ylate d he m o gl o bi n ( H b A 1c) ≥ 8 % 
( patie nts ca n be rescree ne d after dia betes is br o u g ht u n der a de q uate 
c o ntr ol, or i n case H b A 1c < 8%) . 
1 2.  K n o w n defects i n vis ual fiel ds d ue t o o ptic c hias mal c o m pressi o n or 
ot her ne ur ol o gical si g ns, relate d t o t he pit uitar y t u m or mass. Patie nts wit h 
l o n g-sta n di n g ( > 1 2 m o nt hs), fi xe d, mi n or defects ma y be c o nsi dere d o n a 
case-b y -case basis after c o ns ultati o n wit h t he me dical m o nit or . 
1 3.  Fe male patie nts w h o are pre g na nt or lactati n g or i nte n di n g t o bec o me 
pre g na nt d uri n g  t he st u d y. 
1 4.  K n o w n hist or y of i m m u n o deficie nc y (e. g., HI V  p ositi ve ). 
1 5.  A L T, A S T  or  A L P > 3  ×  U L N  or T otal  Bilir u bi n  > 1. 5 ×  U L N . 
1 6.  U n der g o ne maj or s ur ger y/s ur gical t hera p y f or a n y ca use wit hi n 
f o ur wee ks pri or t o e nr oll me nt or pla n ne d pr oce d ure d uri n g t he st u d y. 
1 7.  K n o w n h y p ot h yr oi dis m or h y p oc ortis olis m n ot a de q uatel y treate d wit h a 
sta ble d ose of t h yr oi d or ster oi d h or m o ne re place me nt t hera p y f or ≥ 1 2 
wee ks . 
4 Hi g h ris k t u m or b ur de n is defi ne d b y t he prese nce of a n y of t he f oll o wi n g:  
•  
T u m or rec urre nce or gr o wt h of resi d ual t u m or wit hi n o ne  ye ar after s ur ger y or ra diati o n ( wit h t he 
e xce pti o n of t u m or re gr o wt h occ urri n g if S R Ls ha ve bee n st o p pe d i n t he past)  
•  
T u m or c o m pressi o n of t he o ptic c hias m a n d i n vasi o n  of a djace nt brai n str uct ures ( wit h t he e xce pti o n of 
s p he n oi d si n us a n d ca ver n o us si n us) 
•  
A ntici pate d nee d f or s ur ger y or ra diati o n d uri n g t he c o urse of t he st u d y peri o d base d o n t u m or gr o wt h 
o n serial M RIs  
•  
Metastatic pit uitar y carci n o ma or pri or c he m ot hera p y f or pit uitar y carci n o ma  

 
 
    P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 5  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
1 8.  A n y c o n diti o n t hat ma y je o par dize st u d y partici pati o n (e. g., cli nicall y 
si g nifica nt a b n or mal scree ni n g cli nical or la b orat or y fi n di n g d uri n g 
scree ni n g), t he i nter pretati o n of st u d y res ults or ma y i m p e de t he a bilit y t o 
o btai n i nf or me d c o nse nt (e. g., me ntal c o n diti o n) . 
1 9.  Hist or y of illicit dr u g or alc o h ol a b use  wit hi n fi ve y ears . 
2 0.  I nta ke of a n i n vesti gati o nal dr u g wit hi n 3 0  da ys pri or t o i nitiati o n of 
st u d y treat me nt. 
2 1.  Treat me nt wit h pe g vis o ma nt wit hi n 1 2 wee ks  bef ore t he scree ni n g visit . 
2 2.  Treat me nt wit h d o pa mi ne a g o nists wit hi n 6 wee ks bef ore t he scree ni n g 
visit . 
2 3.  Treat me nt wit h pasire oti de wit hi n 1 2 wee ks  bef ore t he scree ni n g visit. 
Eli gi bilit y 
criteri a t o R C T 
P h ase  
1.  Patie nts w h o c o m plete d t he f ull d urati o n of t he R u n -i n p hase a n d t heir 
acr o me gal y is bi oc he micall y c o ntr olle d ( base d o n  I G F-1 a n d G H le vels at  
wee k 2 4), wit h I G F -1 < 1. 3 ×  U L N a n d mea n i nte grate d G H < 2. 5  n g/ m L . 
2.  I n vesti gat or assess me nt t hat t he patie nt ’s acr o me gal y is a de q uatel y 
c o ntr olle d  (acr o me gal y relate d cli nical s y m pt o ms are mai ntai ne d wit h n o 
mea ni n gf ul e xacer bati o n c o m pare d t o Baseli ne).   
Eli gi bilit y 
Criteri a t o 
C o m bi n ati o n 
p h ase s u b -st u d y 
(i n selecte d 
sites): 
Patie nts c o m pl yi n g wit h all  of t he f oll o wi n g criteria:  
1.  Patie nts w h o fail  t o res p o n d t o octre oti de  ca ps ules 8 0  m g  f or at least t w o 
wee ks d uri n g t he c o urse of t he R u n -i n p hase or patie nts i neli gi ble t o e nter 
t he R C T p hase  o n octre oti de ca ps ules 8 0  m g d ue t o i n -a de q uate c o ntr ol 
of acr o me gal y at wee k 2 4 (as e vi de nt o n wee k 2 6) wit h  (a) I G F-1 le vels 
bet wee n 1. 3  ×  U L N  t o 2 ×  U L N  or ( b) I G F-1 < 1. 3  ×  U L N a n d 
G H  ≥2. 5  n g/ m L  
2.  Patie nt is willi n g a n d a ble t o c o m pl y wit h t he pr ot oc ol re q uire me nts f or 
t he d urati o n of t he C o m bi nati o n p hase s u b-st u d y. 
E xcl usi o n criteri a f or C o m bi n ati o n p h ase  s u b-st u d y (i n selecte d sites): 
A patie nt ca n n ot e nter t he C o m bi nati o n p hase  s u b-st u d y if t he y meet o ne of t he 
f oll o wi n g criteria:  
1.  Patie nt  is c urre ntl y ha vi n g st u d y me dicati o n wit h hel d f or a st u d y 
me dicati o n -relate d A E. 
2.  Patie nt has  a cli nicall y si g nifica nt or u nsta ble me dical or s ur gical 
c o n diti o n detecte d or w orse n s d uri n g t he st u d y, w hic h w o ul d precl u de 
safe partici pati o n a n d c o m pleti o n of t he st u d y. 
3.  Patie nt has k n o w n h y perse nsiti vit y t o er g ot deri vati ves.  
4.  Patie nt has u nc o ntr olle d  h y perte nsi o n  ( ≥ 1 6 0 m m H g s yst olic O R ≥ 1 0 0 
m m H g diast olic bl o o d press ure) . 
5.  Patie nt has h ist or y of cli nicall y si g nifica nt car diac val ve dis or der or st u d y 
ec h ocar di o gra m ( E C H O) val ve dis or der fi n di n g  d uri n g t he R u n -i n p hase 
or  at e ntr y i nt o t he C o m bi nati o n p hase  s u b-st u d y ( val ve leaflet 
t hic ke ni n g, val ve restricti o n, or mi xe d val ve restricti o n-ste n osis). 
6.  Patie nt has h ist or y of p ul m o nar y, pericar dial, or retr o perit o neal fi br otic 
dis or ders . 
7.  Patie nt recei v es p he n ot hiazi nes, b ut yr o p he n o nes, t hi o xa nt he nes, or 
met ocl o pra mi de.  

 
 
    P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 2 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
At t he c o m pleti o n of t he R C T p hase, data will be a nal y ze d a n d re p orte d. Patie nts 
c o nti n ui n g i nt o St u d y E xte nsi o n p hase will be a nal yze d se paratel y.  
S u b -st u d y A n al yses f or C o m bi n ati o n p h ase (i n selecte d sites) 
Patie nts c o nti n ui n g i nt o t he C o m bi nati o n p hase s u b -st u d y will be a nal y ze d 
se paratel y usi n g t he C A S  p o p ulati o n  a nal ysis. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 2 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
6. 9  A C C O U N T A BI LI T Y A N D C O M P LI A N C E O F S T U D Y M E DI C A TI O N  ................................... 8 4  
6. 1 0  P RI O R A N D C O N C O MI T A N T T H E R A P Y  .......................................................................... 8 4  
6. 1 0. 1  Ge neral G ui d eli nes  .......................................................................................... 8 4  
6. 1 0. 2  Pr o hi bite d Pri or Me dicati o n or T hera pies  ....................................................... 8 5  
6. 1 0. 3  All o we d Me dicati o ns  ...................................................................................... 8 5  
6. 1 0. 4  Pr o hi bite d C o nc o mita nt Me dicati o n  ............................................................... 8 5  
7  
S A F E T Y A N D P H A R M A C O V I GI L A N C E ..................................................................... 8 6  
7. 1  A D V E R S E E V E N T  .......................................................................................................... 8 6  
7. 2  S E RI O U S A D V E R S E E V E N T S  ......................................................................................... 8 8  
7. 3  D E FI NI TI O N O F A N U N E X P E C T E D A D V E R S E E V E N T  ..................................................... 8 9  
7. 4  N O TI FI C A TI O N O F S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E E V E N T  .................... 8 9  
7. 5  A N TI CI P A T E D A D V E R S E E V E N T S  ................................................................................. 9 1  
7. 6  O C T R E O TI D E S A F E T Y G UI D A N C E  ................................................................................. 9 1  
8  
S T A TI S TI C A L A N A L Y SI S  P L A N  ................................................................................... 9 3  
8. 1  S A M P L E S I Z E C O N SI D E R A TI O N  .................................................................................... 9 4  
8. 2  A N A L Y Z E D P O P U L A TI O N S  ............................................................................................ 9 4  
8. 2. 2  
Per -Pr ot oc ol A nal ysis Set ( P P)  ....................................................................... 9 5  
8. 2. 3  
Safet y A nal ysis Set ( S A S)  .............................................................................. 9 5  
8. 2. 4  
E nr olle d A nal ysis Set ( E A S)  ........................................................................... 9 5  
8. 2. 5  
C o m bi nati o n A nal ysis Set ( C A S)  ................................................................... 9 5  
8. 2. 6  
E xte nsi o n A nal ysis Set ( E X T -A S)  .................................................................. 9 5  
 
 
8. 3  E N D P OI N T S  ................................................................................................................... 9 5  
8. 4  S T A TI S TI C A L A N A L Y SI S  ............................................................................................... 9 5  
8. 4. 1  
Ge neral C o nsi der ati o ns ................................................................................... 9 5  
8. 4 . 2 
De m o gra p hics a n d Baseli n e  ............................................................................ 9 6  
8. 4. 3  
Pri mar y Efficac y A nal ysis 
 ............................................................... 9 6  
8. 4. 4  
A d diti o nal Pri mar y Efficac y A nal ysis 
 .............................................. 9 6  
8. 4. 5  
Sec o n dar y Efficac y A nal ysis  .......................................................................... 9 7  
8. 4. 6  
E x pl orat or y Efficac y A nal ysis  ........................................................................ 9 8  
 
 
8. 4. 8  
C o m bi nati o n P hase S u b -st u d y (i n selecte d sites) ............................................ 9 8  
8. 4. 9  
St u d y E xte nsi o n P hase  .................................................................................... 9 9  
8. 4. 1 0  Healt h Ec o n o mics A nal yses  ............................................................................ 9 9  
8. 4. 1 1  Safet y A nal ysis  ............................................................................................... 9 9  
8. 4. 1 2  I nteri m A nal yses ............................................................................................. 9 9  
9  
E T HI C S .............................................................................................................................. 1 0 0  
9. 1  IN S TI T U TI O N A L R E VI E W B O A R D O R IN D E P E N D E N T E T HI C S C O M MI T T E E  ................. 1 0 0  
9. 2  E T HI C A L C O N D U C T O F T H E S T U D Y  ............................................................................ 1 0 0  
9. 3  P A TI E N T IN F O R M A TI O N A N D C O N S E N T  ..................................................................... 1 0 0  
9. 4  P A TI E N T IN S U R A N C E  .................................................................................................. 1 0 1  
9. 5  P E R S O N A L D A T A P R O T E C TI O N  .................................................................................. 1 0 1  
9. 6  S T U D Y C O M MI T T E E S ..................................................................................................1 0 1
9. 6. 1  
Steeri n g C o m mittee  ....................................................................................... 1 0 1  
9. 6. 2  
I n de pe n de nt Data M o nit ori n g C o m mittee ..................................................... 1 0 1  
9. 7  P R O T O C O L E X C E P TI O N S A N D D E VI A TI O N S  ................................................................ 1 0 2  
9. 8  P R O T O C O L A M E N D M E N T S  ......................................................................................... 1 0 2  
1 0  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  .............................................. 1 0 2  
1 0. 1  A U DI T S A N D IN S P E C TI O N S  ......................................................................................... 1 0 2  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 2 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
L I S T O F T A B L E S  
Ta ble 1  
Defi niti o n of A d verse E ve nts Se verit y ............................................................ 8 7  
Ta ble 2  
Defi niti o n of A d verse E ve nts Ca usalit y  .......................................................... 8 8  
Ta ble 3  
St u d y  P o wer  i n  relati o n  t o  Res p o nse  Rate  t o  S R L  a n d  Octre oti de  
ca ps ules  ........................................................................................................... 9 4  
 
L I S T O F F I G U R E S 
Fi g ure 1  
Me dical Ma n a ge me nt of Patie nts wit h Acr o me gal y  ....................................... 4 1  
Fi g ure  2 
I n di vi d ual I G F-1 le vels, e x presse d as a perce nta ge of t he a ge -a dj uste d 
U L N ra n ge d uri n g treat me nt wit h S R Ls (s o mat ostati n a nal o g ue) al o ne 
(bl ack  s q u ares )  a n d  after  ca ber g oli ne  a dj u ncti o n  (o pe n  circles )  i n  
patie nts wit h acr o me gal y  ................................................................................. 4 2  
Fi g ure 3  
St u d y O ver vie w  .............................................................................................. 5 0  
 
 
Fi g ure 5  
Decisi o n Tree f or A b n or mal Li ver F u ncti o n Tests  ......................................... 9 3  
 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 2 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
G L O S S A R Y
S u bject a n d patie nt will be use d i nterc ha n gea bl y t hr o u g h o ut t his d oc u me nt.  
A b bre vi ati o n/ Ter m  
Defi niti o n  
%  
Perce nt  
A A C E  
A merica n Ass ociati o n of Cli nical E n d ocri n ol o gists  
A C R O -T S Q  
Acr o me gal y Treat me nt Satisfacti o n Q uesti o n naire  
A E  
A d verse E ve nt  
A E SI  
A d vere E ve nt of S pecial I nterest  
AI S  
Acr o me gal y I n de x of Se verit y  
A L P  
Al kali ne P h os p hatase  
A L T  
Ala ni ne Tra nsa mi nase  
A N C O V A  
A nal ysis of C o varia nce
A PI  
Acti ve P har mace utical I n gre die nt  
A S T  
As partate A mi n otra nsferase  
A U C  
Area U n der t he C ur ve  
BI D  
T wice Dail y; bis i n die  
B L  
Baseli ne  
C A S  
C o m bi nati o n A nal ysis Set (s u b-st u d y i n selecte d sites) 
C B C  
C o m plete Bl o o d C o u nt  
C F R  
C o de of Fe deral Re g ulati o ns  
CI  
C o nfi de nce I nter val  
C P K  
Creati ne P h os p h o ki nase  
C R O  
C o ntract Researc h Or ga nizati o n  
d  
Da y  
d L  
Deciliter  
E A S  
E nr olle d A nal ysis Set  
E C G  
Electr ocar di o gra m  
E C H O  
Ec h ocar di o gra m  
e C R F  
Electr o nic Case Re p ort F or m ; a n y refere nce t o rec or di n g data i n t o t he e C R F 
refers t o t he pr ocess of i nitiall y rec or di n g data  i n t he patie nt’s me dical files 
or  st u d y -s pecific  s o urce  d oc u me nts, b y  t he  rele va nt  st u d y  pers o n nel , 
f oll o we d b y u pl oa d i nt o t he e C R F, as detaile d i n t he St u d y M o nit ori n g Pla n. 
E M A  
E ur o pea n Me dici nes A ge nc y  
E N D O  
E n d ocri ne S ociet y  
E O T  
E n d -of -Treat me nt  
E Q -5 D -5 L
E ur o Q ol – 5 Di me nsi o ns – 5 Le vels Q ualit y of Life q uesti o n naire
E S R D  
E n d Sta ge Re nal Disease  
E X T -A S  
E xte nsi o n A nal ysis Set  
F A S  
F ull A nal ysis Set  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F P G  
Fasti n g Plas ma Gl uc ose  
F U  
F oll o w -u p  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 2 8  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A b bre vi ati o n/ Ter m  
Defi niti o n  
g  
Gra m  
G C P  
G o o d Cli nical Practice
G G T  
Ga m ma -Gl uta m yl Tra nsferase  
G H  
Gr o wt h H or m o ne  
G H R H
Gr o wt h H or m o ne -Releasi n g H or m o ne
GI  
Gastr oi ntesti nal  
G L P  
G o o d La b orat or y Practice  
G M P  
G o o d Ma n ufact uri n g Practice  
G O T ( A S T)  
Gl uta mic O x al oacetic Tra nsa mi nase (as partate a mi n otra nsferase) 
G P T ( A L T)  
Gl uta mic P yr u vic Tra nsa mi nase (ala ni ne tra nsa mi nase)  
H b A 1c  
Gl y c os ylate d He m o gl o bi n  
HI V  
H u ma n I m m u n o deficie nc y Vir us  
I B 
I n vesti gat or’s Br oc h ure 
I C F 
I nf or me d C o nse nt F or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nisati o n  
I D M C 
I n de pe n de nt Data M o nit ori n g C o m mittee 
I E C 
I n de pe n de nt Et hics C o m mittee 
I G F-1  
I ns uli n-li ke Gr o wt h Fact or 1 
i m 
I ntra m usc ular 
I M P 
I n vesti gati o nal Me dici nal Pr o d uct 
I N R 
I nter nati o nal N or malize d Rati o (f or bl o o d c oa g ulati o n tests) 
I R B 
I nstit uti o nal Re vie w B oar d 
I V 
I ntra ve n o us 
I W R S/I V R S 
I nteracti ve W e b / V oice Res p o nse S yste m  
k D A  
Kil o Dalt o n  
k g  
Kil o gra m  
L  
Liter  
L A R  
L o n g -acti n g Release  
L F T  
Li ver F u ncti o n Test  
L O C F  
Last O bser vati o n Carrie d F or war d
Me d D R A  
Me dical Dicti o nar y f or Re g ulat or y Acti vities  
m g  
Milli gra m  
MI D  
Mi ni mal I m p orta nt Differe nce  
mi n  
Mi n ute  
m L  
Milliliter  
m m ol  
Milli m ole  
M RI  
Ma g netic Res o na nce I ma gi n g  
 
N D A  
Ne w Dr u g A p plicati o n  
n g  
Na n o gra m  
NI  
N o n -i nferi orit y  
O G T T  
Oral Gl uc ose T olera nce Test  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 2 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A b bre vi ati o n/ Ter m  
Defi niti o n  
P D  
P har mac o d y na mic  
PI  
Pri nci pal I n vesti gat or  
P K  
P har mac o ki netic  
P PI  
Pr ot o n P u m p I n hi bit or  
P R O
Patie nt Re p orte d O utc o me
P T  
Preferre d Ter m  
Q A  
Q ualit y Ass ura nce  
R A  
Re g ulat or y A ut h orit y  
R B C  
Re d Bl o o d Cell  
R C T  
Ra n d o mize d C o ntr olle d Treat me nt P hase  
S A E  
Seri o us A d verse E ve nt  
S A P  
Statistical A n al ysis Pla n  
S A S  
Safet y A nal ysis Set  
S C  
Steeri n g C o m mittee  
sc (i njecti o n) 
S u bc uta ne o us  
S D  
Sta n dar d De viati o n
S E R M  
Selecti ve Estr o ge n Rece pt or M o d ulat or  
S O C (safet y)  
S yste m Or ga n Class  
S O C (treat me nt)  
Sta n dar d of Care  
S O P  
Sta n dar d O perati o n Pr oce d ures  
S P A  
S pecial Pr ot oc ol Asses me nt  
S R L  
S o mat ostati n Rece pt or Li ga n ds  
S U S A R  
S us pecte d U ne x pecte d Seri o us A d verse Reacti o n  
T E A E  
Treat me nt E mer ge nt A d verse E ve nts  
T P E  
Tra nsie nt Per mea bilit y E n ha ncer  
T S H  
T h yr oi d Sti m ulati n g H or m o ne  
T W A  
Ti me Wei g hte d A vera ge  
U L N  
U p per Li mit of N or mal  
U S  
U nite d States  
 
 
W B C  
W hite Bl o o d Cell  
W H O  
W orl d Healt h Or ga nizati o n  
W k  
Wee k  
W O C F  
W orst o bser vati o n carrie d f or war d  
W P AI: S H P  
W or k Pr o d ucti vit y a n d Acti vit y I m pair me nt Q uesti o n naire S pecific Healt h 
Pr o ble m V 2. 0  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 3 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
1
I N T R O D U C TI O N 
1. 1  
T H E R A P E U TI C IN DI C A TI O N S  
Acr o me gal y is a rare dis or der of dis pr o p orti o nate s keletal, tiss ue, a n d or ga n gr o wt h arisi n g fr o m 
h y persecreti o n of gr o wt h h or m o ne ( G H) a n d i ns uli n -li ke gr o wt h fact or 1 (I G F-1). T he ele vate d 
G H a n d I G F -1 le vels lea d als o t o a wi de ra n ge of car di o vasc ular, res pirat or y, e n d ocri ne, a n d 
meta b olic c o -m or bi dities. I n o ver 9 5 % of cases t he eti ol o g y is attri b ute d t o G H - pr o d uci n g 
be ni g n pit uitar y a de n o ma (Be n -S hl o m o a n d Mel me d 2 0 0 8 ; Mel me d 2 0 0 9 ; Mel me d, C ola o et 
al. 2 0 0 9). 
T he a n n ual i nci de nce of acr o me gal y is 3 t o 5 cases per o ne milli o n i n di vi d uals, a n d esti mate d 
pre vale nce is 4 0  t o 7 0 cases per milli o n wit h me n a n d w o me n e q uall y affecte d (H ol da wa y a n d 
Rajas o or ya 1 9 9 9 ). O wi n g t o its i nsi di o us o nset it is ofte n dia g n ose d late ( 4 t o m ore t ha n 1 0 
years after o nset), at a n a vera ge a ge of a b o ut 4 0 years. At dia g n osis, patie nts ge nerall y e x hi bit 
c oarse ne d facial feat ures, e xa g gerate d gr o wt h of ha n ds a n d feet, a n d s oft tiss ue h y pertr o p h y. 
T he  dia g n osis  of  acr o me gal y  re q uires  de m o nstrati o n  of  d ysre g ulate d  a n d  e n ha nce d  G H  
secreti o n or  ele vate d I G F -1 le vels, reflecti ve of peri p heral tiss ue e x p os ure t o t o nicall y ele vate d 
G H c o nce ntrati o ns  (C ha ns o n a n d Sale na ve 2 0 0 8 ; Mel me d 2 0 0 9 ). 
1. 2
C U R R E N T T H E R A P Y  
Treat me nt  o pti o ns  f or  acr o me gal y  i ncl u de  s ur gical  resecti o n  of  t he  pit uitar y  a de n o ma,  
ra di ot hera p y, a n d dr u g t hera p y t o re d uce G H a n d I G F-1 le vels t o n or mal val ues. C urre ntl y, t here 
are t hree dr u g classes a vaila ble f or t he treat me nt of acr o me gal y: s o mat ost ati n rece pt or li ga n ds 
( S R Ls) or s o mat ostati n a nal o gs ( octre oti de, la nre oti de a n d pasire oti de ), d o pa mi ne a g o nists 
( br o m ocri pti ne a n d ca ber g oli ne), a n d a G H rece pt or a nta g o nist ( pe g vis o ma nt) (Mel me d, C ola o 
et al. 2 0 0 9; Mel me d, Klei n ber g et al. 2 0 1 4 ).  
S R Ls  are, at prese nt, t he m ost wi del y use d dr u gs t o c o ntr ol acr o me gal y. Octre oti de is a n 
octa pe pti de, dis pla yi n g a hi g h affi nit y f or s o mat ostati n rece pt or s u bt y pes 2 a n d 5, effecti vel y 
s u p pressi n g G H h y persecreti o n i n u p t o  ~ 6 0 % of patie nts wit h acr o me gal y (C ola o, Fer o ne et al. 
2 0 0 4 ; C ha ns o n a n d Sale na ve 2 0 0 8 ; Mel me d 2 0 0 9 ; Fleseri u 2 0 1 4 ; Mel me d, Klei n ber g et al. 
2 0 1 4 ). 
Octre oti de has bee n a p pr o ve d as a n i m me diate -release (I R) i njecta ble s ol uti o n b y t he F D A si nce 
1 9 8 8  a n d  i n  U K  i n  1 9 8 9.  Octre oti de  I R  f or m ulati o n  is  a vaila ble  u n der  t he  bra n d  na me  
Sa n d ostati n  b y  N o vartis  or  as  a  ge neric  f or m  s ol d  b y  se veral  differe nt  s u p pliers.  It  is  
a d mi nistere d as a t hree ti mes a da y s u bc uta ne o us (sc) i njecti o n. A l o n g -acti n g de p ot f or m ulati o n 
of octre oti de has bee n i nitiall y a p pr o ve d i n Fra nce i n 1 9 9 5 a n d i n 1 9 9 8 i n t he U S,  f or t he 
treat me nt of acr o me gal y. Octre oti de l o n g-acti n g f or m ulati o n is mar kete d u n der t he bra n d na me 
Sa n d ostati n L A R b y N o vartis. It is a d mi nistere d as m o nt hl y dee p i ntra gl uteal i ntra m usc ular (i m) 
i njecti o n. La nre oti de l o n g-acti n g f or m ulati o n is mar kete d u n der t he bra n d na me S o mat uli ne 
A ut o gel b y I pse n. It is a d mi nistere d e ver y f o ur wee ks ( or si x t o ei g ht  wee ks at t he hi g her d ose). 
Treat me nt wit h S R Ls is r o uti nel y d o ne b y d ose titrati o n, base d o n i n di vi d ual bi oc he mical 
disease c o ntr ol.  
1. 3  
IN V E S TI G A TI O N A L T H E R A P Y  
C hias ma  has de vel o pe d o ctre oti de ca ps ules, a ne w f or m ulati o n of octre oti de f or oral deli ver y. 
It is a n e nteric c oate d ca ps ule fille d wit h a n oil y s us pe nsi o n of u n m o difie d octre oti de  f or m ulate d 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 3 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
wit h tra nsie nt per mea bilit y e n ha ncer ( T P E ® )1 e xci pie nts. T he e nteric c oati n g all o ws t he i ntact 
ca ps ule t o pass t hr o u g h t he st o mac h a n d disi nte grate w he n it reac hes t he hi g her p H of t he s mall 
i ntesti ne t o disc har ge octre oti de ca ps ules  s us pe nsi o n. 
T he T P E platf or m facilitates i ntesti nal a bs or ba nce of dr u g m olec ules wit h li mite d i ntesti nal 
bi oa vaila bilit y. T he T P E f or m ulati o n pr otects t he dr u g m olec ule fr o m i nacti vati o n b y t he h ostile 
gastr oi ntesti nal ( GI) e n vir o n me nt a n d at t he sa me ti me acts o n t he  GI wall t o i n d uce l ocal, 
tra nsie nt a n d re versi ble o pe ni n g of t he paracell ular r o ute all o wi n g per meati o n of t he dr u g 
m olec ules t hr o u g h t he ti g ht j u ncti o ns. T hese t w o attri b utes e ns ure t hat w he n deli vere d i n T P E 
f or m ulati o n, t he dr u g reac hes t he bl o o dstrea m effecti vel y i n its nati ve acti ve f or m . 
T he T P E is a c o m bi nati o n of e xci pie nts asse m ble d i n a pr ocess lea di n g t o a n oil y s us pe nsi o n of 
h y dr o p hilic particles c o ntai ni n g me di u m -c hai n fatt y aci d salts a n d t he acti ve p har mace utical 
i n gre die nt ( A PI) s us pe n de d i n a li p o p hilic me di u m. All of t he T P E f or m ulati o n i n gre die nts are 
p har mace utical gra de a n d are safe f or p har mace utical use.  
1. 3. 1  
N o n cli nic al St u dies 
T he n o ncli nical st u dies c o n d ucte d wit h octre oti de ca ps ules  i ncl u de: ( 1) p har mac ol o g y st u dies 
c haracterizi n g t he T P E tec h n ol o g y, ( 2) p har mac o ki netics ( P K) i n rats, pi gs a n d m o n ke ys a n d 
( 3)  t he  t o xic ol o g y  of  re peat  d oses  of  octre oti de ca ps ules  i n  m o n ke ys.  O verall, octre oti de 
ca ps ules ha ve  bee n s h o w n t o ha ve bi oa vaila bilit y i n a ni mals of u p t o 1 0 % i n rats a n d pi gs usi n g 
jej u nal  i nt u bati o n  a n d  u p  t o  2. 4 %  i n  m o n ke ys  usi n g  oral  a d mi nistrati o n  of  e nteric-c oate d 
ca ps ules. T o xic ol o g y st u dies u p t o 9 m o nt hs i n d urati o n i n c y n o m ol g us m o n ke ys s h o we d a lac k 
of a n y si g ns of t o xicit y at dail y d oses of u p t o 2 0 m g of octre oti de w hic h is e q ui vale nt t o a 
h u ma n d ose of a p pr o xi matel y 1 1 3 m g base d o n b o d y s urface area c o n versi o n fact ors bet wee n 
s pecies a n d a n a vera ge h u ma n b o d y wei g ht of 7 0 k g. T he n o ncli nical st u dies wit h octre oti de 
ca ps ules ha ve de m o nstrate d t hat t he  GI per mea bilit y f oll o wi n g T P E a d mi nistrati o n was li mite d 
t o m olec ules s maller t ha n 7 0 k Da i n size a n d t o 6 0 t o 9 0 mi n utes i n d urati o n. T hese data i n dicate 
t hat use of t he T P E tec h n ol o g y will n ot per mit a bs or pti o n of i ntesti nal pat h o ge ns t hat are lar ger 
t ha n 7 0 k Da i n size (e. g., bacteria, vir uses, t o xi ns). T he GI per mea bilit y was s h o w n t o be a 
tra nsie nt a n d re versi ble pr ocess. 
M ore detaile d i nf or mati o n is a vaila ble i n t he octre oti de ca ps ules  I n vesti gat or's Br oc h ure (I B). 
1. 3. 2  
Cli nic al St u dies  
Octre oti de ca ps ules  ha ve  bee n e val uate d i n a n e xte nsi ve cli nical pr o gra m  i n w hic h t he P K, 
p har mac o d y na mics ( P D), safet y a n d t olera bilit y ha ve bee n assesse d u n der vari o us c o n diti o ns.  
I n  a d diti o n,  t he  l o n g-ter m  efficac y,  safet y  a n d  t olera bilit y  of  octre oti de  ca ps ules  were  
i n vesti gate d i n a P hase 3 st u d y i n patie nt s wit h acr o me gal y ( C H-A C M - 0 1). 
O verall, 2 1 4 s u bjects were e x p ose d i n 1 1 P hase 1 p har mac ol o g y st u dies ( 1 8 4 healt h y v ol u nteers, 
1 8 patie nts wit h he patic i m pair me nt, 6 patie nts wit h se vere re nal i m pair me nt, a n d 6 patie nts 
wit h E S R D o n dial ysis). Dr u g e x p os ure i n t he p har mac ol o g y st u dies wa s t y picall y 1 da y a n d 
n ot m ore t ha n 6 da ys. 
O verall, 3 4 9 acr o me gal y patie nts were e x p ose d t o octre oti de ca ps ules  i n t hree P hase 3 st u dies 
( 2 0 3 patie nts i n st u dies C H -A C M -0 1 a n d O O C -A C M - 3 0 3 i ncl u di n g O O C -A C M - 3 0 3 E xte nsi o n 
p hase a n d 14 6 patie nts i n t he c urrent o n g oi n g St u d y O O C -A C M - 3 0 2. I n C H-A C M -0 1 a n d 
O O C -A C M - 3 0 3 st u dies 9 2 patie nts  were e x p ose d t o octre oti de ca ps ules f or at least 1 2 m o nt hs.  
 
1 T P E is a pr o prietar y e xci pie nt mi xt ure t hat per mits oral a d mi nistrati o n.  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 3 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
1. 3. 2. 2  
P h ase 3 St u d y C H -A C M -0 1 i n Acr o me g al y P atie nts  
St u d y C H -A C M -0 1 was a P hase 3, o pe n -la bel, d ose-titrati o n, mai nte na nce of res p o nse, baseli ne 
c o ntr olle d, wit h dra wal st u d y c o n d ucte d t o e val uate t he efficac y a n d safet y of octre oti de ca ps ules  
i n patie nts wit h acr o me gal y w h o res p o n de d t o a n d t olerate d treat me nt wit h pare nteral S R Ls . 
T he st u d y c o nsiste d of a c ore t reat me nt peri o d of at least 7 m o nt hs a n d a n o pti o nal e xte nsi o n 
treat me nt peri o d of 6 m o nt hs. T he c ore T reat me nt peri o d c o nsiste d of a D ose E scalati o n P hase 
of 2 t o 5  m o nt hs t o i de ntif y t he t hera pe utic d ose ( 2 0  +  2 0 m g, 4 0  +  2 0 m g, or 4 0  +  4 0  m g) f or 
eac h p atie nt o n t he basis of meas ure me nts of I G F -1 a n d a Fi xe d D ose P hase of 2 t o 5  m o nt hs, 
d uri n g w hic h t he t hera pe utic d ose was mai ntai ne d.  Octre oti de ca ps ules  were  a d mi nistere d t wice 
dail y  ( BI D) as m or ni n g a n d e ve ni n g d oses ≥ 1 h o ur pri or t o or ≥ 2 h o urs after a meal.  Efficac y 
was assesse d as t he pr o p orti o n of patie nts w h o mai ntai ne d t heir baseli ne bi oc he mical ( G H a n d 
I G F-1)  res p o nse  t o  pare nteral  S R Ls  f oll o wi n g  a  s witc h  t o  octre oti de  ca ps u les  f or  u p  t o  
1 3 m o nt hs. Octre oti de ca ps ules safet y pr ofile was assesse d f or ne w si g nals, p ossi bl y relate d t o 
t he ne w f or m ulati o n or r o ute of a d mi nistrati o n, i n c o m paris o n wit h  t he k n o w n safet y pr ofile of 
octre oti de . 
E fficac y a nal yses de m o nstrate d t hat oct re oti de ca ps ules are effecti ve as a mai nte na nce t hera p y 
i n m ost patie nts f or w h o m treat me nt wit h S R L  i njecti o ns has bee n s h o w n t o be effecti ve a n d 
t olerate d. T he  res p o nse  t o  octre oti de  treat me nt  was  mai ntai ne d  i n  a  cli nicall y  rele va nt  
pr o p orti o n of patie nt s after s witc hi n g fr o m pare nteral S R L treat me nt t o octre oti de ca ps ules, 
6 5 % ( 9 8/ 1 5 1) at 7 m o nt h s a n d 6 2 % ( 9 3/ 1 5 1) at 1 3 m o nt hs - c o m pare d t o 8 9 % o n pare nteral 
S R L  at baseli ne. Patie nt s i nitiall y res p o n di n g t o octre oti de ca ps ules mai ntai ne d t his res p o nse 
t hr o u g h 1 3 m o nt hs, wit h a res p o nse rate si milar t o t hat k n o w n fr o m t he literat ure wit h pare nteral 
S R Ls  (C hieff o, C o o k et al. 2 0 1 3 ). F urt her m ore, acr o me gal y s y m pt o ms i m pr o ve d si g nifica ntl y 
u n der octre oti de ca ps ules c o m pare d t o pare n teral S R L t hera p y. 
T he P K  of octre oti de ca ps ules was st u die d i n 4 6 patie nts. T here was a d ose -relate d i ncrease i n 
t he mea n plas ma octre oti de c o nce ntrati o ns after c hr o nic a d mi nistrati o n of 4 0 m g ( 2 0 m g BI D), 
6 0 m g ( 4 0 m g i n t he m or ni n g / 2 0 m g i n t he e ve ni n g/ ni g ht), a n d 8 0 m g BI D. Si milar tre n ds i n 
octre oti de P K bet wee n healt h y s u bjects a n d patie nts wit h acr o me gal y were see n f oll o wi n g oral 
a d mi nistrati o n, c o m pare d t o i njecti o ns, wit h e xce pti o n of l o n ger half -life i n acr o me gal y patie nts 
treate d wit h octre oti de ca ps ules. 
T he  safet y  pr ofile  of  octre oti de  ca p s ules was  c o nsiste nt  wit h  t he  k n o w n  safet y  pr ofile  of  
octre oti de a n d t he disease b ur de n of acr o me gal y.  N o ne w or u ne x pecte d safet y si g nals were 
detecte d d uri n g t he st u d y. T he m ost c o m m o nl y re p orte d a d verse e ve nts  ( A Es) were si milar t o 
t h ose re p orte d wit h p are nteral S R Ls b ut wit h n o i njecti o n site reacti o ns, reflecti n g t he p ote ntial 
be nefit of t he oral a p plicati o n of octre oti de o ver t he pare nteral S R Ls.   
1. 3. 2. 3  
P h ase 3 St u d y O O C -A C M -3 0 3 st u d y  i n Acr o me g al y P atie nts 
St u d y O O C -A C M -3 0 3, c o n d ucte d u n der a U S A F D A  S pecial Pr ot oc ol Assess me nt a gree me nt  
(S P A ), was a 9-m o nt h, ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d st u d y i n 5 6 acr o me gal y 
patie nts. Eli gi ble patie nts were re q uire d t o be res p o n ders t o i njecta ble S R Ls, defi ne d as ha vi n g 
a n a vera ge I G F -1 ≤ 1 ti mes U L N base d o n t he t w o  scree ni n g assess me nts. T he pri mar y efficac y 
e n d p oi nt a n d all sec o n dar y efficac y e n d p oi nts f or t his st u d y were met. 
Pri mar y e n d p oi nt: 
•  5 8 % of t he patie nts o n octre oti de  ca ps ules mai ntai ne d t heir I G F -1 res p o nse c o m pare d t o 
1 9 % of t he patie nts o n place b o ( p = 0. 0 0 7 9). 8 1 % of patie nts ra n d o mize d t o place b o l ost 
I G F-1 c o ntr ol w hile o n place b o. T h us, t he place b o wit h dra wal treat me nt res ulte d i n m ost 
patie nts  l osi n g  bi oc he mical  disease  c o ntr ol,  w hic h  c o nfir me d  t hat  patie nts  ha d  acti ve  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 3 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
disease. Efficac y of octre oti de ca ps ules was de m o nstrate d b y t he o bser vati o n t hat 5 8 % of 
patie nts ra n d o mize d t o acti ve t hera p y retai ne d bi oc he mical disease c o ntr ol.  
Sec o n dar y efficac y e n d p oi nts: 
•  7 8 % of pati e nts treate d wit h octre oti de ca ps ules mai ntai ne d t heir gr o wt h h or m o ne ( G H) 
le vels bel o w 2. 5 n g/ m L at t he e n d of t he c ore st u d y vs 3 0 % of patie nts treate d wit h place b o 
( p = 0. 0 0 0 7). 
•  T he ti me t o l oss of res p o nse  ( defi ne d as I G F-1 > 1. 0 ti mes U L N o n t w o c o nsec uti ve visits)  
was si g nifica ntl y greater i n t he octre oti de  ca ps ules gr o u p c o m pare d t o t he place b o gr o u p 
( p < 0. 0 0 0 1). T he me dia n a n d 7 5t h perce ntile ti me s t o l oss of res p o nse i n t he place b o gr o u p 
w ere 1 6. 0 a n d  1 6. 6 wee ks, res pecti vel y, w hile t he me dia n a n d 7 5 t h perce ntile ti me s t o l oss 
of res p o nse i n t he octre oti de  ca ps ules gr o u p w ere n ot reac he d (i.e., > 3 6 wee ks).  T we nt y -
si x of 2 8 patie nts ( 9 3 %) i n t he place b o gr o u p met t his l oss of res p o nse criteria b y t he e n d 
of t he st u d y (i.e., wee k 3 6) vs 1 3 of 2 8 patie nts ( 4 6 %) i n t he octre oti de  ca ps ules gr o u p. 
•  T he ti me t o l oss of res p o nse  ( defi ne d as I G F-1 ≥ 1. 3 ti mes U L N o n t w o c o nsec uti ve visits)  
was si g nifica ntl y greater i n t he octre oti de  ca ps ules gr o u p c o m pare d t o t h e place b o gr o u p 
( p < 0. 0 0 0 1). T he me dia n a n d 7 5t h perce ntile ti me s t o l oss of res p o nse i n t he place b o gr o u p 
were 1 6. 2 wee ks a n d 2 9. 3 wee ks, res pecti vel y, w hile t he me dia n a n d 7 5 t h perce ntile ti mes 
t o l oss of res p o nse i n t he octre oti de  ca ps ules gr o u p were n ot reac he d (i.e., > 3 6 wee ks). 
T we nt y -t w o of 2 8 patie nts ( 7 9 %) i n t he place b o gr o u p met t his l oss of res p o nse criteria b y 
t he e n d of t he st u d y (i.e., wee k 3 6) vs 9 of 2 8 patie nts ( 3 2 %) i n t he octre oti de ca ps ules 
gr o u p. 
•  7 5 % of patie nts treate d w it h octre oti de ca ps ules di d n ot re q uire resc ue me dicati o n wit h 
i njecta ble S R Ls ( octre oti de L A R or la nre oti de de p ot) a n yti me t hr o u g h o ut t he c ore st u d y vs 
3 2 % of patie nts treate d wit h place b o ( p = 0. 0 0 2 9). 
9 0 % of patie nts c o m pleti n g t hera p y o n octre oti de ca p s ules o pte d t o g o i nt o t he o pe n la bel 
e xte nsi o n ( O L E ).T he safet y pr ofile of octre oti de ca ps ules was c o nsiste nt wit h t he k n o w n safet y 
pr ofile of octre oti de a n d t he disease b ur de n of acr o me gal y. N o ne w or u ne x pecte d safet y 
si g nals were detecte d d uri n g t he st u d y. T he m ost c o m m o nl y re p orte d A Es were si milar t o t h ose 
re p orte d wit h l o n g-acti n g s o mat ostati n a nal o gs b ut wit h n o i njecti o n site reacti o ns.  
M ore detaile d i nf or mati o n, i ncl u di n g O verall Be nefit t o Ris k Assess me nt , is a vaila ble i n t he 
octre oti de ca ps ules  I B. 
1. 4  
O V E R A L L B E N E FI T T O R I S K A S S E S S M E N T  
1. 4. 1. 1  
Be nefits 
I n  healt h y  v ol u nteers,  2 0  m g  octre oti de  ca ps ules  yiel de d  s yste mic  dr u g  e x p os ure  ( A U C ) 
c o m para ble  t o  a  0. 1 -m g  sc  d ose  of  octre oti de  ( T u via et  al,  2 0 1 2 ). O ctre oti de ca psules  
si g nifica ntl y i n hi bite d b ot h basal G H secreti o n a n d G H R H-i n d uce d G H secreti o n. I n hi biti o n 
of G H was rec or de d i n all healt h y v ol u nteer s u bjects recei vi n g octre oti de  ca ps ules .  
T he  n o vel octre oti de  ca ps ules T P E tec h n ol o g y safel y a n d s uccessf ull y all o we d oral deli ver y of 
a t hera pe utic pe pti de t o ac hie ve s yste mic e n d ocri ne effects. T wice - dail y octre oti de ca ps ules 
a p pears t o offer a safe o pti o n f or acr o me gal y m o n ot hera p y.  
St u d y O O C -A C M -3 0 3, c o n d ucte d u n der a  S P A -a gree d pr ot oc ol, met its  pri mar y efficac y 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 3 5  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
e n d p oi nt a n d all its sec o n dar y hierarc hical efficac y e n d p oi nts. 5 8 % of t he patie nts o n octre oti de  
ca ps ules  mai ntai ne d t heir I G F -1 res p o nse c o m pare d t o 1 9 % of t he patie nts o n place b o ( p = 
0. 0 0 7 9). 7 5 % of patie nts treate d wit h octre oti de  caps ules di d n ot re q uire resc ue me dicati o ns 
wit h i njecta ble S R Ls  a n d 7 5 % c o m plete d t he st u d y o n st u d y dr u g . 9 3 % of place b o p atie nts l ost 
t heir res p o nse at s o me ti me t hr o u g h o ut t he st u d y. 8 1 % of patie nts ra n d o mize d t o place b o faile d 
t o mai ntai n t heir res p o nse at t he e n d of t he st u d y. T h us , t he place b o wit h dra wal treat me nt 
res ulte d i n m ost patie nts l osi n g bi oc he mical c o ntr ol of t heir disease, t h us c o nfir mi n g t hat t his 
patie nt  p o p ulati o n i n dee d ha d acti ve disease.  
I n  St u d y  C H-A C M - 0 1 6 5 %  of  octre oti de  ca ps ules patie nts  met  t he  pri mar y  e n d p oi nt  of  
res p o nse at t he 7-m o nt h e n d of c ore treat me nt ( b y last o bser vati o n carrie d f or war d [ L O C F] 
i m p utati o n f or n o n-c o m pleters), a n d 5 3 % met t he pri mar y e n d p oi nt of res p o nse at e n d of 
treat me nt b y w orst o bser vati o n ca rrie d f or war d (W O C F ).  
Patie nts o n octre oti de  ca ps ules t hera p y e x hi bite d mai nte na nce or re d ucti o n of acr o me gal y 
s y m pt o ms. I n St u d y O O C-A C M -3 0 3, 1 5 patie nts ( 5 3. 6 %) i n t he octre oti de  ca ps ules gr o u p a n d 
2 6 patie nts ( 9 2. 9 %) i n t he place b o gr o u p e x perie nce d A E s of s pecial i nterest (A E SIs ). I n St u d y 
C H -A C M -0 1 , t he o verall AI S s y m pt o m sc ore s h o we d a statisticall y si g nifica nt re d ucti o n ( p  = 
0. 0 2 7 5) fr o m Baseli ne t o E n d of C ore Treat me nt i n t he mI T T p o p ulati o n. T he i n di vi d ual 
s y m pt o m sc ores f or s welli n g of e xtre mities a n d j oi nt pai n als o s h o we d a statisticall y si g nifica nt 
re d ucti o n bet wee n Baseli ne t o E n d of C ore Treat me nt ( p  = 0. 0 1 6 5, p = 0. 0 3 8 2, res pecti vel y).    
1. 4. 1. 2  
Ris ks  
T he safet y pr ofile of octre oti de  ca ps ules was c o nsiste nt wit h t he k n o w n safet y pr ofile of 
octre oti de a n d t he disease b ur de n of acr o me gal y. N o ne w or u ne x pecte d safet y si g nals were 
detecte d d uri n g t he octre oti de ca ps ules n o ncli nical a n d cli nical pr o gra m ( St u dies C H -A C M -
0 1, O O C -A C M - 3 0 3). T he m ost c om m o nl y re p orte d T E A Es were si milar t o t h ose re p orte d wit h 
s o mat ostati n a nal o gs b ut wit h n o i njecti o n site reacti o ns. 
Octre oti de ca ps ules war ni n g a n d preca uti o ns are si milar t o Sa n d ostati n la bel 
•  C h olelit hiasis a n d Gall bla d der Sl u d ge: S o mat ostati n a nal o gs ha ve bee n s h o w n t o i n hi bit 
gall bla d der  c o ntractilit y  a n d  decrease  bile  secreti o n,  w hic h  ma y  lea d  t o  ec h o ge nic  
gall bla d der a b n or malities or sl u d ge.  
•  Gall bla d der -relate d A Es ha ve bee n re p orte d i n cli nical trials i n patie nts recei vi n g octre oti de 
ca ps ules . S y m pt omatic patie nts s h o ul d be m o nit ore d peri o dicall y . 
•  H y per gl yce mia a n d H y p o gl yce mia: S o mat ostati n a nal o gs ha ve bee n s h o w n t o alter t he 
bala nce bet wee n t he c o u nter -re g ulat or y h or m o nes (i ns uli n, gl uca g o n, a n d G H) w hic h ma y 
res ult  i n  h y p o gl yce mia  or  h y per gl yce mia.  Bl o o d  gl uc ose  le vels  s h o ul d  t heref ore  be  
m o nit ore d w he n s o mat ostati n a nal o g treat me nt is i nitiate d, or w he n t he d ose is altere d. 
A nti dia betic treat me nt s h o ul d be a dj uste d acc or di n gl y. 
•  T h yr oi d F u ncti o n A b n or malities:  S o mat ostati n a nal o gs ha ve bee n s h o w n t o s u p press t he 
secreti o n of t h yr oi d-sti m ulati n g h or m o ne ( T S H), w hic h ma y res ult i n h y p ot h yr oi dis m. 
Baseli ne  a n d  peri o dic  assess me nt  of  t h yr oi d  f u ncti o n  ( T S H,  t otal,  a n d/ or  free  T 4)  is  
rec o m me n de d d uri n g c hr o nic octre oti de t hera p y. 
•  Car diac F u ncti o n A b n or mal ities: I n acr o me gal y patie nts, bra d ycar dia, arr h yt h mias, a n d 
c o n d ucti o n a b n or malities ha ve bee n re p orte d d uri n g t hera p y wit h s o mat ostati n a nal o gs. 
T he relati o ns hi p of t hese e ve nts t o s o mat ostati n a nal o gs is n ot esta blis he d beca use ma n y of 
t hese  patie nts  have  u n derl yi n g  car diac  disease.  Ot her  E C G  c ha n ges  s uc h  as  Q T  
pr ol o n gati o n, a xis s hifts, earl y re p olarizati o n, l o w v olta ge, R/ S tra nsiti o n, earl y R wa ve 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 3 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
pr o gressi o n, a n d  n o ns pecific  S T -T wa ve  c ha n ges  ha ve bee n  re p orte d i n  patie nts w h o  
recei ve d s o mat ostati n anal o gs. T hese E C G c ha n ges are n ot u nc o m m o n i n patie nts wit h 
acr o me gal y.  D ose a dj ust me nts i n dr u gs s uc h as beta -bl oc kers t hat ha ve bra d ycar dia effects 
ma y be necessar y.  
•  N utriti o n: De presse d vita mi n B 1 2 le vels a n d a b n or mal Sc hilli n g tests ha ve bee n o bser ve d 
i n s o me patie nts recei vi n g t hera p y wit h s o mat ostati n a nal o gs. M o nit ori n g of vita mi n B 1 2 
le vels is rec o m me n de d d uri n g t hera p y wit h s o mat ostati n a nal o gs. 
Patie nts c o ul d be prescri be d wit h o ctre oti de  ca ps ules , a n d t h ose w h o  nee d t o re vert t o i njecta ble 
S R Ls c o ul d d o s o wit h o ut l o n g -ter m deteri orati o n i n I G F- 1. I n St u d y O O C-A C M -3 0 3 t he 
maj orit y  of  patie nts  w h o  were  resc ue d  f oll o wi n g  a  s h ort  trial  of  t hera p y  wit h  octre oti de 
ca ps ules ret ur ne d t o t heir baseli ne val ues f oll o wi n g o ne S R L i njecti o n . A d diti o nall y, treat me nt 
i nterr u pti o n is a r o uti ne practice i n t he treat me nt of acr o me gal y, f or t h ose wit hi n 1 0 years of 
ra di ot hera p y—t o deter mi ne o n g oi n g nee d f or t hera p y —a n d i n pre g na nc y.  
A d mi nistrati o n of octre oti de  ca ps ules wit h f o o d  decrease d t he e xte nt of e x p os ure b y 8 2 % t o 
9 2 % w he n 2 0 m g octre oti de  ca ps ules was a d mi nistere d 1 or 2 h o urs after a f ull meal or 1 h o ur 
pri or t o a f ull meal. T here is a p ote ntial ris k f or n ot c o m pl yi n g wit h f o o d restricti o ns. H o we ver, 
as n o n-c o m plia nce tr a nslates t o a n i m me diate i ncrease i n cli nical s y m pt o ms, patie nts will li kel y 
kee p  wit hi n  t hese  restricti o ns,  a n d  t heref ore  it  s h o ul d  n ot  be  re gar de d  as  a n act ual ris k. 
Acr o me gal y patie nts w or k har d t o re d uce acr o me gal y s y m pt o ms d ue t o t heir ver y ne gati ve 
im pact o n q ualit y of life. A d diti o nall y , t hese patie nts are r o uti nel y m o nit ore d bi oc he micall y 
f or t heir disease stat us, a n d t heref ore l oss of c o ntr ol w o ul d be rea dil y detecta ble.  
1. 4. 1. 3  
Ris k/ Be n efit  Asses me nt  
O verall, t he res ults o bser ve d i n t he t w o pi v otal P hase 3 st u dies, O O C -A C M -3 0 3 a n d C H -A C M -
0 1, c o nfir m t he efficac y of octre oti de ca ps ules a n d t he d ura bilit y of its effect.    
Octre oti de, t he acti ve i n gre die nt i n octre oti de  ca ps ules, is a well - u n derst o o d acti ve i n gre die nt. 
It is t he sa me acti ve i n gre die nt i n b ot h Sa n d ostati n a n d Sa n d ostati n L A R, eac h a p pr o ve d f or 
t he treat me nt of acr o me gal y, t he sa me p o p ulati o n st u die d i n t he octre oti de  ca ps ules cli nical 
de vel o p me nt pr o gra m.  
St u d y  O O C -A C M -3 0 3  was  c o n d ucte d  u n der  a  S P A;  t he  st u d y  met  t he  pri mar y  efficac y  
e n d p oi nt a n d all sec o n dar y hierarc hical efficac y e n d p oi nts. 
B ot h P hase 3 trials were mai nte na nce - of-res p o nse trials, w here t he defi niti o n of res p o nse was 
i de ntical t o t he i ncl usi o n criterio n f or bi oc he mical c o ntr ol at scree ni n g .  
T he octre oti de ca ps ules cli nical  pr o gra m  de m o nstrate d  a n  acce pta ble  safet y  pr ofile  f or  
octre oti de  ca ps ules  wit h n o ne w safet y si g nals a n d a n a bse nce of i njecti o n site reacti o ns. T he 
disc o nti n uati o n rate f or St u d y O O C -A C M - 3 0 3 was l o wer t ha n f or St u d y C H -A C M -0 1 , li kel y 
reflecti n g  a  better  u n dersta n di n g  t hat  A Es  occ urri n g  o n  i nitiati o n  of  octre oti de  ca ps ules 
treat me nt ge nerall y res ol ve d o n c o nti n ue d treat me nt as ha d bee n o bser ve d i n St u d y C H -A C M -
0 1. T here was n o d ose res p o nse i n t he re p orte d T E A Es.  
C urre nt i njecta ble t hera pies f or acr o me gal y are s u b o pti mal f or patie nts f or se veral reas o ns. 
T he  i njecti o ns are p o orl y t olerate d d ue t o si g nifica nt persiste nt pai n lasti n g f or da ys, n o d ules, 
he m orr ha ge, i nfla m mati o n, a n d scarri n g. 
I n a d diti o n t o t his p h ysical i m pact of i njecti o ns t here is als o a n e m oti o nal i m pact of fr ustrati o n, 
a n xiet y, a n d l oss of i n de pe n de nce. W or k ti me is l ost d ue t o sc he d uli n g a n d tra vel f or i njecti o ns, 
A Es  ass ociate d wit h i njecti o ns, a n d e xacer bati o n of s y m pt o ms near  t he e n d of t he i njecti o n 
i nter val.  Direct  a n d  i n direct  c osts  of  m o nt hl y  i njecti o ns  f or  b ot h  patie nts  a n d H C P s  are  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 3 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
si g nifica nt.  T hese  i njecti o n  b ur de ns  are  s u p p orte d  b y  e x pert  treati n g  p h ysicia ns,  patie nt  
testi m o nials, t he literat ure, t he F D A a n d W H O p ost-mar keti n g A E  data base, t he C hias ma P R O 
st u d y c o n d ucte d i n t he E U, a n d a P R O st u d y c o n d ucte d i n t he U S.  
T he e xacer bati o n of s y m pt o ms near  t he e n d of t he i njecti o n i nter val deser ves f urt her me nti o n 
beca use it w o ul d n ot be a ntici pate d f or dail y treat me nt wit h octre oti de  ca ps ules . St u dies ha ve 
s h o w n t hat lo n g- acti n g s o mat ostati n a nal o gs ofte n d o  n ot pr o vi de a f ull m o nt h of a de q uate 
s y m pt o matic c o ntr ol, wit h > 5 0 % of patie nts re p ort i n g a wear -off effect a n d rec urre nce or 
w orse ni n g o f s y m pt o ms near  t he e n d of t he d osi n g i nter val (Stras b ur ger et al, 2 0 1 6 ; Geer et al, 
2 0 1 9 ). S y m pt o m  rec urre nce  s o meti mes  necessitates  s u p ple me ntal  patie nt  i njecti o ns.  
A d diti o nall y, l o gistical c halle n ges a n d tec h nical diffic ulties ca n als o affect pr o per i nj ecti o n 
pre parati o n a n d a d mi nistrati o n, w hic h, i n t ur n, ca n i m pair effecti ve dr u g deli ver y  a n d s y m pt o m 
c o ntr ol. 
Octre oti de  ca ps ules ha ve  a s h ort a n d eas y titrati o n sc he d ule, wit h a si n gle u p or d o w n d ose 
titrati o n. P atie nts ca n be prescri be d wit h octre oti de ca ps ules, a n d t h ose w h o  nee d t o re vert t o 
i njecta ble S R Ls ca n d o s o wit h o ut l o n g-ter m deteri orati o n i n I G F-1 c o ntr ol . Si milar te m p orar y 
treat me nt i nterr u pti o n is alrea d y r o uti ne practice i n acr o me gal y patie nts , s uc h as d uri n g t he first 
1 0  years  after  pit uitar y  irra diati o n  t o  assess  t he nee d  f or  c o nti n ue d  t hera p y  a n d  d uri n g  
pre g na nc y.  
1. 4. 1. 4  
C o ncl usi o n  
I n c o ncl usi o n, t w o a de q uate a n d well-c o ntr olle d P hase 3 st u dies de m o nstrate d t hat octre oti de 
ca ps ules  are effecti ve  as  a  mai nte na nce  t hera p y  i n  m ost  acr o me gal y patie nts  f or  w h o m  
treat me nt wit h s o mat ostati n a nal o g i njecti o ns has bee n s h o w n t o be effecti ve a n d t olerate d. 
•  O ctre oti de  ca ps ules  are effecti ve mai nte na nce t hera p y f or patie nts pre vi o usl y mai ntai ne d 
o n i njecta ble s o mat ostati n rece pt or li ga n ds.  
•  Efficac y is d ura ble:  
o  I n St u d y O O C-A C M -3 0 3, 9 2 % of t he patie nts i nitiall y res p o n di n g t o octre oti de  ca ps ules  
ha d a s ustai ne d or d ura ble res p o nse t o e n d of treat me nt at 9 m o nt hs. 
o  I n  St u d y  C H-A C M -0 1,  8 6 %  of  t he  patie nts  w h o  e ntere d  t he  Fi xe d -D ose  p hase  as  
res p o n ders  mai ntai ne d  t his  res p o nse  at  t he  E n d  of  C ore  Treat me nt.  T he  o bser ve d  
mai nte na nce - of-res p o nse rate f or patie nts i n b ot h trials w h o were a ble t o be c o ntr olle d 
o n octre oti de  ca ps ules was c o nsiste nt wit h t hat k n o w n fr o m t he literat ure f or pare nteral 
s o mat ostati n rece pt or li ga n ds ( Sa n d ostati n L A R PI 2 0 1 9; La ncra nja n 1 9 9 9). 
o  I n St u d y C H-A C M -0 1, patie nts o n octre oti de ca ps ules t hera p y e x hi bite d a re d uce d 
pre vale nce of acr o me gal y s y m pt o ms at e n d of st u d y a n d i n St u d y O O C -A C M - 3 0 3 
patie nts o n octre oti de  ca ps ules t hera p y e x perie nce d fe wer A E SIs c o m pare d wit h patie nts 
o n place b o.  
o  Patie nts were satisfie d wit h octre oti de  ca ps ules treat me nt: I n St u d y O O C-A C M - 3 0 3, 
9 0 % of patie nts ( 2 1/ 2 4) c o m pleti n g t he trial o n octre oti de  ca ps ules c o nti n ue d i nt o t he 
O L E a n d, i n St u d y C H -A C M -0 1, 8 6 % of t he patie nts ( 8 8/ 1 0 2 patie nts) w h o c o m plete d 
t he C ore Treat me nt Peri o d electe d t o c o nti n ue t o t he 6-m o nt h E xte nsi o n Treat me nt 
Peri o d a n d n ot re vert t o i njecti o ns. 
o  T he res ults n ote d are statisticall y si g nifica nt a n d cli nicall y mea ni n gf ul.  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 4 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
2. 2. 4
S afet y O utc o mes  
•  Fre q ue nc y a n d se verit y of A Es  a n d seri o us a d verse e ve nts  ( S A Es) 
•  Cli nicall y si g nifica nt la b orat or y a b n or malities  
2. 2. 5  
C o m bi n ati o n P h ase S u b -St u d y  En d p oi nts  
T he f oll o wi n g e x pl orat or y e n d p oi nts will be defi ne d f or t he C o m bi nati o n p hase  s u b-st u d y (i n 
selecte d sites) of t he st u d y: 
•  Pr o p orti o n of patie nts wit h t he f oll o wi n g I G F -1 a n d mea n i nte grate d G H val ues 
at t he e n d of t he C o m bi nati o n p hase s u b- st u d y c o m pare d t o Baseli ne  
- 
I G F- 1 < 1. 3 ×  U L N a n d mea n i nte grate d G H  <  2. 5. n g/ m L 
- 
I G F- 1 <  1. 0 ×  U L N a n d mea n i nte grate d G H <  1. 0 n g/ m L 
- 
I G F- 1 <  1. 3 ×  U L N  
- 
I G F- 1 ≤ 1. 0 ×  U L N  
- 
Mea n i nte grate d G H  <  2. 5 n g/ m L 
- 
Mea n i nte grate d G H  <  1. 0 n g/ m L 
•  Rate of c ha n ge i n I G F- 1 (i.e., sl o pe)  
•  Pr o p orti o n of patie nts w h o re d uce d t he o verall n u m ber of acti ve acr o me gal y 
s y m pt o ms, at t he e n d of t he C o m bi nati o n p hase s u b-st u d y, c o m pare d t o baseli ne  
•  Pr o p orti o n  of  patie nts  w h o  i m pr o ve d  t heir  AI S  sc ore  at  t he  e n d  of  t he  
C o m bi nati o n p hase s u b-st u d y c o m pare d t o baseli ne 
3  
S T U D Y D E SI G N  
T his will be a P hase 3, ra n d o mize d, o pe n -la bel, acti ve-c o ntr olle d, m ultice nter st u d y t o e val uate 
mai nte na nce of res p o nse, safet y a n d patie nt re p orte d o utc o mes  ( P R Os) i n acr o me gal y patie nts 
treate d  wit h  octre oti de  ca ps ules  a n d  i n  patie nts  treate d  wit h  S O C  pare nteral  S R Ls,  w h o  
pre vi o usl y t olerate d a n d de m o nstrate d bi oc he mical c o ntr ol o n b ot h treat me nts. 
T he C ore st u d y will c o nsist of 3 p hases: a Scree ni n g p hase,  a R u n -in p hase a n d a R C T p hase  
(Fi g ure 3 ). 
A Steeri n g C o m mittee ( S C) will act i n a n a d vis or y ca pacit y t o t he S p o ns or t o pr o vi de o versi g ht 
t o t he trial c o n d uct a n d t o s u p p ort its s uccessf ul c o m pleti o n. 
A n I D M C will act i n a n a d vis or y ca pacit y t o t he S p o ns or t o m o nit or patie nt s’ safet y d uri n g t he 
st u d y. 
After  u p t o 4 wee k s Scree ni n g p hase, eli gi ble patie nts w h ose acr o me gal y has bee n c o ntr olle d 
bi oc he micall y  ( defi ne d  as  I G F -1  <  1. 3  ×  U L N  a n d  mea n  i nte grate d  G H  < 2. 5  n g/ m L)  o n  
pare nteral S R Ls will be s witc he d t o octre oti de ca ps ules f or a 2 6-wee k R u n -i n p hase. D uri n g 
t his p hase t he effecti ve d ose f or eac h patie nt will be deter mi ne d t hr o u g h d ose titrati o n (see 
Secti o n  6. 2 ).  
Patie nts w h ose acr o me gal y has bee n c o ntr olle d bi oc he micall y o n octre oti de ca ps ules at t he e n d 
of t he R u n -i n P hase will e nter a 3 6- wee k o pe n -la bel R C T p hase w here t he y will be ra n d o mize d 
t o c o nti n ue o n octre oti de ca ps ules or s witc h bac k t o t heir S O C i njecta ble S R L (as recei ve d pri or 
t o Scree ni n g). 
F oll o wi n g t he c o m pleti o n of t he C ore st u d y ( Scree ni n g, R u n-i n a n d R C T p hases), eli gi ble 
patie nts will be offere d  t o e nter t he St u d y E xte nsi o n p hase a n d recei ve octre oti de ca ps ules  f or 
5 year s or u ntil pr o d uct mar keti n g or st u d y ter mi nati o n  (t he earliest of w hic h). Be y o n d 5- year s 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 5 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
 
 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 5 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
4
S T U D Y P O P U L A TI O N  
Patie nts  dia g n ose d  wit h  acr o me gal y,  w h o  are  treate d  wit h  S R L  i njecti o ns  ( octre oti de  or  
la nre oti de) f or at least 6 m o nt hs, wit h sta ble d ose f or at least 4 m o nt hs a n d are bi oc he micall y 
c o ntr olle d (IG F -1 < 1. 3  ×  U L N a n d mea n i nte grate d G H < 2. 5 n g/ m L ) as e vi de nt at scree ni n g  
are eli gi ble t o partici pate i n t he st u d y . 
4. 1  
IN C L U SI O N C RI T E RI A  
Patie nts m ust meet a ll i ncl usi o n criteria t o be eli gi ble f or t he st u d y. 
1.  A d ult s u bjects, a ge d 1 8 t o 7 5 years  ol d, i ncl usi ve, at t he Scree ni n g visit . 
2.  Patie nts wit h acr o me gal y, defi ne d as d oc u me nte d e vi de nce of G H -secreti n g 
pit uitar y t u m or t hat is a b n or mall y res p o nsi ve t o a n oral gl uc ose t olera nce test or 
a b n or mal I G F- 1 le vels 
  
 w h o are c urre ntl y 
recei vi n g pare nteral S R Ls ( octre oti de or la nre oti de b ut n ot pasire oti de) f or at 
least 6 m o nt hs wit h a sta ble d ose f or at least t he last f o ur m o nt hs. 
3.  D oc u me nte d bi oc he mical c o ntr ol of t heir acr o me gal y o n t he c urre nt d ose of S R L 
(I G F- 1 <  1. 3 ×  U L N a n d mea n i nte grate d G H <  2. 5 n g/ m L o ver t w o h o urs), 
base d o n Scree ni n g assess me nt . 
4.  Patie nts a ble a n d willi n g t o c o m pl y wit h t he re q uire me nts of t he pr ot oc ol at t he 
ti me of S cree ni n g . 
5.  W o me n w h o are of c hil d beari n g p ote ntial s h o ul d use a n acce pta ble met h o d f or 
birt h c o ntr ol. Acce pta ble met h o ds i ncl u de h or m o nal c o ntrace pti o n ( oral 
c o ntrace pti ves  – as l o n g as o n sta ble d ose, patc h, i m pla nt, a n d i njecti o n), 
i ntra uteri ne de vices, or d o u ble barrier met h o ds (e. g., va gi nal dia p hra g m, va gi nal 
s p o n ge pl us c o n d o m or c o n d o m pl us s per mici dal jell y), se x ual a bsti ne nce 1  or a 
vasect o mize d part ner. W o me n ma y be s ur gicall y sterile or at least 1 year p ost -
last me nstr ual peri o d. W o me n ta ki n g oral c o ntrace pti o n c o ntai ni n g 
le v o n or gestrel s h o ul d eit her c ha n ge treat me nt (at least o ne m o nt h pri or t o first 
st u d y me dicati o n d ose) or use a mec ha nical barrier met h o d . 
6.
Patie nts a ble t o u n dersta n d a n d si g n writte n i nf or me d c o nse nt t o partici pate i n 
t he st u d y. 
4. 2
E X C L U SI O N C RI T E RI A  
A n y of t he f oll o wi n g will e xcl u de a patie nt fr o m partici pati n g i n t he st u d y:  
1.
Patie nts ta ki n g i njecti o ns of l o n g -acti n g S R Ls less fre q ue ntl y  t ha n o nce e ver y 
ei g ht wee ks  ( d osi n g i nter val > 8 wee ks). 
2.  Patie nts w h o pre vi o usl y partici pate d i n C H -A C M - 0 1. 
3.  S y m pt o matic c h olelit hiasis . 
4.  Recei ve d pit uitar y ra di ot hera p y wit hi n fi ve years pri or t o scree ni n g (i ncl u di n g 
t otal b o d y, hea d a n d nec k or stere otactic ra di ot hera p y). 
5.  U n der g o ne pit uitar y s ur ger y wit hi n si x m o nt hs pri or t o scree ni n g or ha ve electe d 
s ur ger y pla n ne d wit hi n t he c o urse of t he c ore st u d y. 
1 A bsti ne nce is defi ne d as refrai ni n g fr o m heter ose x ual i nterc o urse d uri n g t he scree ni n g, t reat me nt p hase a n d at 
least 2 wee ks f oll o wi n g treat me nt disc o nti n uati o n 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 5 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
6.
Hi g h -ris k patter n1 of pit uitar y t u m or l ocati o n o n pit uitar y M RI / C o m p ute d 
t o m ogra p h y ( C T) as per me dical hist or y or m ost rece nt M RI / C T. 
7.  Hist or y of u nsta ble a n gi na or ac ute m y ocar dial i nfarcti o n wit hi n t he 1 2 wee ks  
prece di n g t he scree ni n g visit or ot her cli nicall y si g nifica nt car diac disease at t he 
ti me of scree ni n g as j u d ge d b y t he Pri nci pal I n vesti gat or. 
8.  A n y cli nicall y si g nifica nt u nc o ntr olle d ner v o us s yste m, gastr oi ntesti nal ( GI), 
re nal, p ul m o nar y, or he patic c o nc o mita nt disease t hat i n t he I n vesti gat or’s 
o pi ni o n w o ul d precl u de patie nt partici pati o n. 
9.  E vi de nce of acti ve mali g na nt disease or  mali g na ncies dia g n ose d wit hi n t he 
pre vi o us  year ( e xce pt f or basal cell carci n o ma  a n d u nc o m plicate d --u p t o sta ge 
1 s q ua m o us c ell carci n o ma  t hat has bee n e xcise d a n d c ure d).  
1 0.  K n o w n aller g y or h y perse nsiti vit y t o a n y of t he test c o m p o u n ds or materials. 
1 1.  K n o w n u nc o ntr olle d dia betes defi ne d as ha vi n g a fasti n g gl uc ose >  1 5 0 m g/ d L 
( 8. 3 m m ol/ L) or gl yc os ylate d he m o gl o bi n ( H b A 1c) ≥ 8 % ( patie nts ca n be 
rescree ne d after dia betes is br o u g ht u n der a de q uate c o ntr ol, or i n case 
H b A 1c  < 8 %). 
1 2.  K n o w n defects i n vis ual fiel ds d ue t o o ptic c hias mal c o m pressi o n or ot her 
ne ur ol o gical si g ns, relate d t o t he pit uitar y t u m or mass. Patie nts wit h l o n g -
sta n di n g ( > 1 2 m o nt hs), fi xe d, mi n or defects ma y be c o nsi dere d o n a case- b y-
case basis after c o ns ultati o n wit h t he me dical m o nit or.  
1 3.  Fe male patie nts w h o are pre g na nt or lactati n g or i nte n di n g t o bec o me pre g na nt 
d uri n g t he st u d y. 
1 4.  K n o w n hist or y of i m m u n o deficie nc y (e. g., HI V p ositi ve ) 
1 5.  A L T, A S T, or A L P > 3  ×  U L N  or T otal Bilir u bi n > 1. 5 ×  U L N . 
1 6.  U n der g o ne maj or s ur ger y/s ur gical t hera p y f or a n y ca use wit hi n f o ur wee ks pri or 
t o e nr oll me nt or pla n ne d pr oce d ure d uri n g t he st u d y. 
1 7.  K n o w n h y p ot h yr oi dis m or h y p oc ortis olis m n ot a de q uatel y treate d wit h a sta ble 
d ose of t h yr oi d or ster oi d h or m o ne re place me nt t hera p y f or ≥ 1 2 wee ks. 
1 8.  A n y c o n diti o n t hat ma y je o par dize st u d y partici pati o n (e. g., cli nicall y si g nifica nt 
a b n or mal scree ni n g cli nical or la b orat or y fi n di n g d uri n g scree ni n g), t he 
i nter pretati o n of st u d y res ults or ma y i m pe de t he a bilit y t o o btai n i nf or me d 
c o nse nt (e. g., me ntal c o n diti o n). 
1 9.  Hist or y of illicit dr u g or alc o h ol a b use  wit hi n fi ve years . 
2 0.  I nta ke of a n i n vesti gati o nal dr u g wit hi n 3 0 da ys pri or t o i nitiati o n of st u d y 
treat me nt. 
2 1.  Treat me nt wit h pe g vis o ma nt wit hi n 1 2 wee ks bef ore t he scree ni n g visit. 
2 2.  Treat me nt wit h d o pa mi ne a g o nists wit hi n 6 wee ks bef ore t he scree ni n g visit . 
1 Hi g h ris k t u m or b ur de n is defi ne d b y t he prese nce of a n y of t he f oll o wi n g:  
•  
T u m or rec urre nce or gr o wt h of resi d ual t u m or wit hi n o ne  ye ar after s ur ger y or ra diati o n ( wit h t he 
e xce pti o n  of t u m or re gr o wt h occ urri n g if S R Ls ha ve bee n st o p pe d i n t he past)  
•  
T u m or c o m pressi o n of t he o ptic c hias m a n d i n vasi o n  of a djace nt brai n str uct ures ( wit h t he e xce pti o n of 
s p he n oi d si n us a n d ca ver n o us si n us) 
•  
A ntici pate d nee d f or s ur ger y or ra diati o n d uri n g t he c o urse of t he st u d y peri o d base d o n t u m or gr o wt h 
o n serial M RIs  
•  
Metastatic pit uitar y carci n o ma or pri or c he m ot hera p y f or pit uitar y carci n o ma  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 6 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
a p plica ble (f or w o me n wit h c hil d beari n g p ote ntial) 
•  I G F- 1 
•  G H: Fi ve sa m ples e ver y 3 0 ±  5 mi n utes o ver t w o h o urs fr o m ti me 0 t o 2 h o urs  
•  C o m plete p h ysical e xa mi nati o n 1 
•  Acr o me gal y directe d p h ysical e xa mi nati o n 
•  AI S  
•  A b d o mi nal ( g all bla d der) ultras o u n d 
5. 2
R U N -I N P H A S E  ( 2 6 W E E K S ) 
At  t he  R u n -i n  p hase,  all  eli gi ble  patie nts  will  recei ve  octre oti de  ca ps ules  f or  2 6  wee ks . 
O ctre oti de  ca ps ules  d ose  s h o ul d  be  escalate d  per  I n vesti gat or’s  discreti o n i n  t he  case  of  
si g nifica ntl y i ncrease d I G F-1 le vels c o m pare d t o baseli ne, w orse ni n g of acr o me gal y s y m pt o ms 
or b ot h (f or d ose-escalati o n r ules refer t o Secti o n  6. 2 ). T he d ose escalati o n will be d o ne i n a 
ste p wise ma n ner fr o m 4 0 m g/ da y ( 2 0 m g BI D) t o 6 0 m g/ da y ( 4 0 m g i n t he m or ni n g a n d 2 0 m g 
i n t he e ve ni n g/ni g ht) t o 8 0  m g/ da y ( 4 0 m g  BI D).  
Deter mi nati o n of eli gi bilit y t o c o nti n ue i nt o t he R C T p hase will be d o ne at wee k 2 6, base d o n 
bi oc he mical res ults at wee k 2 4. 
5. 2. 1  
B aseli ne Visit  
T he f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d at Baseli ne ( B L) Visit 2: 
•  A C R O -T S Q  
•  E Q - 5 D- 5 L 
•  W P AI  
•  I ncl usi o n a n d e xcl usi o n criteria re vie w a n d c o nfir mati o n 
•  Vital si g ns  
•  1 2- Lea d E C G  
•  Wei g ht  
•  Safet y l a b orat or y tests: he mat ol o g y, bi oc he mistr y, uri nal ysis, T S H, free T 4, a n d 
li pi d pr ofile (t otal c h olester ol, tri gl yceri des, hi g h-de nsit y li p o pr otei n, a n d l o w -
de nsit y li p o pr otei n)  
•  Uri ne  pre g na nc y  test  f or  w o me n  of  c hil d beari n g  p ote ntial,  P ositi ve  uri ne  
pre g na nc y test will be f oll o we d b y a c o nfir mat or y ser u m pre g na nc y test. I n case 
of p ositi ve uri ne pre g na nc y test s u bjects c o ul d n ot be d ose d, u ntil t he res ults of 
t he ser u m pre g na nc y test will be a vaila ble. P ositi ve ser u m pre g na nc y test will 
res ult i n a s u bject bei n g a scree ni n g fail ure. 
•  I G F- 1 a n d G H3  
•  Acr o me gal y  directe d p h ysical  e xa mi nati o n  (i ncl u di n g s ki n  reacti ve  lesi o ns, 
1 Acr o me gal y relate d si g ns a n d s y m pt o ms s h o ul d be ca pt ure d u n der t he acr o me gal y s y m pt o ms assess me nt. Ot her 
si g ns a n d s y m pt o ms n ot ca pt ure d i n t he acr o me gal y s y m pt o ms assess me nt s h o ul d be ca pt ure d i n t he me dical 
c o n diti o n f or m. 
2 Ti me fr o m last d ose s h o ul d n o t e xcee d i njecti o n i nter val + 3 da ys 
3 G H: At Baseli ne, fi ve  sa m ples will be c ollecte d e ver y 3 0  ±  5 mi n utes f or t w o h o urs, fr o m 0- 2 h o urs , bef ore 
octre oti de ca ps ules  a d mi nistrati o n  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 6 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
p ote ntiall y ass ociate d wit h i njecti o ns) 
•  AI S   
•  A Es a n d c o nc o mita nt me dicati o ns rec or di n g 
•  Dis pe nse st u d y me dicati o n (call I V R S/I W R S) 
•  Octre oti de ca ps ules  a d mi nistrati o n at t he site  
•  Dr u g a d mi nistrati o n i nstr ucti o ns : a p pl y f o o d ha bits q uesti o n naire, a n d a dj ust 
octre oti de ca ps ules a d mi nistrati o n a n d ti mi n g t o t he patie nt ha bits.  I nstr uct t he 
patie nt  h o w  he /s he s h o ul d  ta ke  his/ her ot her  c o nc o mita nt  dr u gs  (t h yr oi d  
h or m o nes, a nti- dia betic me dicati o ns, P PIs or H 2 bl oc kers) . 
•  I nstr uct  t he  patie nt t hat  octre oti de ca ps ules  s h o ul d  be  ta ke n  o n  a n  e m pt y  
st o mac h at least o ne h o ur pri or t o a meal or at least t w o h o urs after. O pti o nal 
dr u g a d mi nistrati o n ti mi n g  f or patie nts: 
M or ni n g D ose 
- 
Ta ke t he m or ni n g d ose first t hi n g i n t he m or ni n g wit h a glass of water a n d ha ve y o ur 
brea kfast at least o ne h o ur later, or 
- 
Ha ve brea kfast a n d ta ke y o ur m or ni n g d ose at least t w o h o urs later a n d at least o ne 
h o ur pri or t o l u nc h  
E ve ni n g D ose. 
- 
Ta ke y o ur e ve ni n g d ose bef ore g oi n g t o be d, at least t w o h o urs after d i n ner or a n y 
ot her s nac k or 
- 
Ta ke y o ur e ve ni n g d ose at least 1 h o ur pri or t o di n ner a n d at least t w o h o urs f oll o wi n g 
a n earlier s nac k/ meal . 
O nl y  at selecte d sites partici pati n g i n t he C o m bi nati o n p hase s u b-st u d y, a n E C H O  s h o ul d be 
perf or me d f or all patie nts e nr olli n g i nt o t he C o m bi nati o n s u b-st u d y.  F or t h ose sites w h o ca n n ot 
perf or m a n E C H O  fr o m t he ti me fra me bet wee n wee k 2 5 (a vaila bilit y of wee k 24 I G F -1 a n d 
G H res ults) a n d wee k 2 6 (e nr oll me nt i nt o t he C o m bi nati o n s u b -st u d y p hase), t he E C H O ma y 
be perf or me d, wit hi n t he i nitial 1 2 wee ks of t he R u n -i n p hase, s o t hat res ults are a vaila ble pri or 
t o st u d y e ntr y i nt o t he Co m bi nati o n p hase  s u b-st u d y.  
Tel e p h o ne C all  at Wee k 1 a n d Wee k 2  
T he f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d o n t he pre -Sc he d ule d tele p h o ne 
calls at Wee k 1 a n d 2 ( ± 3 da ys): 
•  A Es  rec or di n g 
•  AI S   
•  C o m plia nce assess me nt  a n d dr u g a d mi nistrati o n i nstr ucti o ns 
•  A d dress a n y p ote ntial q uesti o ns t he patie nt  ma y ha ve wit h t he ne w treat me nt  
5. 2. 2  
R u n -I n Tre at me nt Visits ( Wee k 4, Wee k 8, Wee k 1 2, Wee k 1 6, Wee k 2 0 a n d 
Wee k 2 4) 
D uri n g t he R u n -i n p hase, patie nts will ret ur n t o t he cli nic f or a site visit e ver y 4 wee ks (±  3 
da ys) t hr o u g h wee k 2 4 a n d will atte n d a n e n d of t he R u n-i n visit  at wee k 2 6.  
T he f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d e ver y f o ur wee ks ( wee k 4, wee k 
8, wee k 1 2, wee k 1 6, wee k 2 0 a n d wee k 2 4): 
•  Octre oti de ca ps ules a d mi nistrati o n at t he site – w ee ks 2 4 o nl y 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 6 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
T he st u d y will util ize ce ntralize d stratifie d ra n d o mizati o n base d o n t he f oll o wi n g varia bles o n 
wee k 2 4 of t he R u n-i n p hase: 
•  I G F-1 ≤1  ×  U L N vs. I G F - 1 > 1  ×  U L N t o < 1. 3 ×  U L N  
•  Octre oti de ca ps ules treat me nt d ose  at wee k 2 4  ( 4 0 m g vs. 6 0 m g or 8 0 m g) 
5. 2. 4  
E n d of R u n -i n Visit ( Wee k 26)  
T he visit wi n d o w f or wee k 2 6 is -3 t o + 1 0 da ys t o all o w s ufficie nt ti me t o s u p pl y t he st u d y 
dr u g f oll o wi n g wee k 2 5 pre-ra n d o mizati o n. 
T he f oll o wi n g assess me nts a n d pr oce d ures will be perf or me d at wee k 2 6/ E n d of R u n- I n:  
•  A C R O -T S Q
•  E Q - 5 D- 5 L 
•  W P AI  
•  Safet y l ab orat or y tests: he mat ol o g y, bi oc he mistr y, uri nal ysis, T S H, free T 4, 
li pi d pr ofile (t otal c h olester ol, tri gl yceri des, hi g h-de nsit y li p o pr otei n, a n d l o w -
de nsit y li p o pr otei n), H b A 1c , a n d ser u m pre g na nc y test, if a p plica ble f or w o me n 
of c hil d beari n g p ote ntial 
•  Wei g ht  
•  Vital si g ns  
•  1 2- lea d E C G  
•  Acr o me gal y directe d p h ysical e xa mi nati o n  
•  AI S  
•  A E s a n d c o nc o mita nt me dicati o ns rec or di n g 
•  A b d o mi nal ( g all bla d der) ultras o u n d  
•  I G F- 1 a n d G H1  
•  Verif y a vaila bilit y of rece nt car diac E C H O  wit hi n t he last si x m o nt hs  
•  I ncl usi o n  a n d  e xcl usi o n  criteria  re vie w  f or  eli gi bilit y  i nt o  R C T  p hase  or  
C o m bi nati o n p hase s u b-st u d y  
•  Dis pe nse st u d y me dicati o n (call I V R S/I W R S) 
•  St u d y me dicati o n a d mi nistrati o n  a n d i nstr ucti o ns 
- 
i n R C T p hase, octre oti de ca ps ules f or t h ose ra n d o mize d t o oral ar m a n d S R L 
i njecti o ns t o t h ose ra n d o mize d t o t he i njecta ble ar m – sa me d ose as a d mi nistere d pri or 
t o scree ni n g. 
- 
i n C o m bi nati o n p hase s u b-st u d y, octre oti de ca ps ules + ca ber g ol i ne 
•  C o m plia nce assess me nt  
•  St u d y me dicati o n acc o u nta bilit y 
•  C o m plete treat me nt p hase c o m pleti o n f or m  
1 G H: fi ve sa m ples will be c ollecte d e ver y 3 0  ±  5 mi n utes o ver t w o h o urs, 2 t o 4 h o urs after octre oti de ca ps ules 
a d mi nistrati o n  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 6 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
5. 3
R A N D O MI Z E D C O N T R O L L E D T R E A T M E N T ( R C T) P H A S E   
Cli nic visits d uri n g t he R C T p hase will be sc he d ule d t o occ ur e ver y f o ur wee ks  (wee ks 2 6, 3 0, 
3 4, 3 8, 4 2, 4 6, 5 0 , 5 4, 5 8 a n d 6 2/ E O T). Patie nts w h o recei ve d pare nteral S R Ls e ver y 6 wee ks 
will atte n d visits o n wee ks 2 6, 3 2, 3 8, 4 4 , 5 0 a n d 5 6 ( wee k 6 2 st u d y pr oce d ures are descri be d 
i n Secti o n  5. 3. 1 ). Visit wi n d o w  fr o m wee k 3 0 o n war d will be ± 3 da ys. 
T he wee k 2 6 pr oce d ures ( R C T baseli ne) will be t he sa me as  perf or me d at t he e n d of t he R u n -i n 
(see Secti o n  5. 2. 4 ). 
All eff orts s h o ul d be ma de t o mai ntai n patie nts o n t heir ra n d o mize d treat me nt t hr o u g h o ut t he 
R C T p hase u p t o c o m pleti o n of t he c ore st u d y. 
T he f oll o wi n g pr oce d ures a n d assess me nts will be c o n d ucte d d uri n g R C T p hase visits: 
•  A C R O -T S Q  ( wee ks 3 8 a n d 5 0 o nl y) 
•  E Q - 5 D- 5 L ( wee ks 3 8 a n d 5 0 o nl y) 
•  W P AI  
•  Wei g ht  
•  Vital si g ns  
•  Safet y l a b orat or y tests: he mat ol o g y  a n d bi oc he mistr y  
•  I G F- 1  
•  Acr o me gal y  directe d p h ysical  e xa mi nati o n  (i ncl u di n g s ki n  reacti ve lesi o ns, 
p ote ntiall y ass ociate d wit h i njecti o ns)  
•  AI S  
•  A E s i ncl u di n g GI a n d i njecti o n site reacti o ns  
•  C o nc o mita nt me dicati o ns rec or di n g  
•  Dis pe nse st u d y me dicati o n (call I V R S/I W R S) 
•  St u d y me dic ati o n a d mi nistrati o n per ra n d o mizati o n assi g n me nt1  
•  Dr u g a d mi nistrati o n i nstr ucti o ns ( wee k s 3 8 a n d 5 0 o nl y) 
•  St u d y me dicati o n acc o u nta bilit y 
•  C o m plia nce assess me nt  ( wee ks 3 8 a n d 5 0 o nl y) 
5. 3. 1  
R C T: E n d of Tre at me nt V isit ( Wee k 6 2) 
T he f oll o wi n g pr oce d ures will be d o ne at wee k 6 2 /E O T 2  visit  of R C T p hase: 
•  A C R O -T S Q
•  E Q - 5 D- 5 L 
•  W P AI  
1 Patie nts ra n d o mize d t o recei ve pare nteral S R Ls will recei ve t heir i njecti o ns at t he site at t he sa me fre q ue nc y  a n d 
d ose  as recei ve d pri or t o S cree ni n g. Patie nts, w h o recei ve d pare nteral S R Ls e ver y f o ur or fi ve wee ks , will recei ve 
t heir i njecti o ns e ver y f o ur wee ks at wee ks 2 6, 3 0, 3 4, 3 8, 4 2 ,4 6 , 5 0, 5 4 a n d 5 8. Patie nts w ho recei ve d  pare nteral 
S R Ls  at a n i nter val of o nce e ver y ei g ht wee ks will be assesse d e ver y f o ur wee ks  yet will recei ve t heir i njecti o n 
e ver y ei g ht wee ks ( wee ks 2 6, 3 4,4 2 , 5 0 a n d 5 8). Patie nts w h o recei ve d S R L  i njecti o ns e ver y si x or se ve n wee ks 
will atte n d  visit wee k 3 2 i nstea d of visit wee ks 3 0 a n d 3 4 , visit wee k 4 4 i nstea d of visit wee ks 4 2 a n d 4 6  a n d 
visit 5 6 i nstea d of visit wee ks 5 4 a n d 5 8; t hese patie nts  will recei ve t heir i njecti o n o n wee ks 2 6, 3 2, 3 8, 4 4 , 5 0 
a n d 6 0 . 
2 E O T pr oce d ures will als o be perf or me d i n a n y case of earl y treat me nt disc o nti n uati o n  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 6 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
•  Acr o me gal y directe d p h ysical e xa mi nati o n  
•  AI S  
•  A E s a n d c o nc o mita nt me dicati o ns rec or di n g  
•  Dis pe nse st u d y me dicati o n (call I V R S/I W R S) 
•  St u d y me dicati o n acc o u nta bilit y 
T he  f oll o wi n g  pr oce d ures  will  be  d o ne  at  C o m bi nati o n p hase s u b-st u d y  wee k 3 6 /E n d  of  
c o m bi nati o n treat me nt 1 visit:  
•  Octre oti de ca ps ules a d mi nistrati o n at t he site  
•  A C R O -T S Q  
•  E Q - 5 D- 5 L 
•  W P AI  
•  Safet y l a b orat or y tests: he mat ol o g y, bi oc he mistr y, uri nal ysis, T S H, free T 4, a n d 
li pi d pr ofile (t otal c h olester ol, tri gl yceri des, hi g h-de nsit y li p o pr otei n, a n d l o w -
de nsit y li p o pr otei n), H b A 1c a n d ser u m pre g na nc y test, if a p plica ble  
•  Wei g ht 
•  Vital si g ns  
•  1 2- lea d E C G  
•  C ar diac E C H O  
•  Acr o me gal y directe d p h ysical e xa mi nati o n  
•  AI S  
•  A E s a n d c o nc o mita nt me dicati o ns rec or di n g  
•  A b d o mi nal ( gall bla d der) ultras o u n d  
•  St u d y me dicati o n acc o u nta bilit y 
•  I G F- 1 a n d G H2  
•  Assess eli gi bilit y t o c o nti n ue i nt o St u d y E xte nsi o n p hase (see Secti o n  4. 5 ) a n d 
if eli gi ble o btai n i nf or me d c o nse nt si g nat ure a n d dis pe nse st u d y m e dicati o n 
(call I V R S/I W R S) 
•  C o m plete treat me nt p hase c o m pleti o n f or m  
At t he e n d of t he C o m bi nati o n p hase  s u b-st u d y eli gi ble patie nts will be offere d t o e nter t he 
St u d y E xte nsi o n p hase o n t he sa me c o m bi nati o n treat me nt re gi me n . 
Patie nts w h o earl y disc o nti n ue treat me nt d uri n g t he C o m bi nati o n p hase  s u b-st u d y will re ve rt t o 
t heir  pri or  i njecta ble  S R L  treat me nt ( pri or  t o  Scree ni n g,  n o n- I M P) or  ot her  treat me nt  as  
deter mi ne d b y t heir p h ysicia n a n d will be f oll o we d f or  1 2 wee ks  p ost last d ose. Refer t o 
Se cti o n 4. 9. 3  f or Earl y Ter mi nati o n criteria fr o m C o m bi nati o n p hase s u b-st u d y. 
Patie nts w h o c o m plete t he C o m bi nati o n p hase  s u b-st u d y a n d are i neli gi ble t o e nter t he St u d y 
E xte nsi o n p hase (see eli gi bilit y criteria  i n Secti o n  4. 5 ) or patie nts w h o o pt n ot t o e nter t he St u d y 
E xte nsi o n p hase , will re vert t o t heir pri or S O C i njecta ble S R L treat me nt ( pri or t o S cree ni n g, 
1 E O T pr oce d ures will als o be perf or me d i n a n y case of earl y treat me nt disc o nti n uati o n  
2 G H: Fi ve  sa m ples will be c ollecte d e ver y 3 0  ±  5 mi n utes o ver t w o h o urs, 2 t o 4 h o urs after octre oti de ca ps ules 
a d mi nistrati o n  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 7 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
•  
 
 
 
I n vesti g at or’s decisi o n t o t er mi n ate t he st u d y : 
•  Vital si g ns  
•  I G F- 1  
•  Acr o me gal y directe d p h ysical e xa mi nati o n  
•  AI S  
•  A Es a n d c o nc o mita nt me dicati o ns rec or di n g 
•  
   
I n vesti g at or’s decisi o n t h at t he p atie nt will recei ve octre oti de c a ps ules as p art of t he St u d y 
E xte nsi o n p h ase:
•  Re - verif y patie nt c o nse nt f or St u d y E xte nsi o n p hase   
•  Vital si g ns  
•  I G F- 1  
•  Acr o me gal y directe d p h ysical e xa mi nati o n  
•  AI S  
•  A Es a n d c o nc o mita nt me dicati o ns rec or di n g 
•  Dis pe nse st u d y me dicati o n ( octre oti de ca ps ules) (call I V R S/I W R S) 
•  Dr u g a d mi nistrati o n i nstr ucti o ns 
•  
 
5. 6
S T U D Y E X T E N SI O N P H A S E  
Patie nts w h o c o m plete d t he R C T p hase  a n d ha d a de q uatel y c o ntr olle d I G F- 1 (see eli gi bilit y 
criteria  t o  t he  St u d y  E xte nsi o n  p hase , Secti o n 4. 5 ),  or  w h o  be nefite d  si g nifica ntl y  fr o m  
octre oti de ca ps ules  treat me nt (as deter mi ne d b y t he st u d y In vesti gat or, a n d a gree d b y t he st u d y 
me dical m o nit or), ma y e nter t he St u d y E xte nsi o n p hase. E li gi ble patie nts, pre vi o usl y treate d 
wit h octre oti de ca ps ules  d uri n g t he R C T p hase, will c o nti n ue t o recei ve octre oti de ca ps ules 
re gi me n, w hile patie nts treate d wit h l o n g acti n g S R Ls i njecti o ns d uri n g t he R C T p hase will 
s witc h t o t he octre oti de ca ps ules  d ose t he y were c o ntr olle d o n at t he e n d of t he R u n -i n p hase. 
Patie nts  m ust  si g n  a  St u d y  E xte nsi o n  i nf or me d  c o nse nt  pri or  t o  e nr olli n g  i nt o  t he  St u d y  
E xte nsi o n p hase. T he St u d y E xte nsi o n p hase will c o nti n ue f or 5 year s or u ntil t he date w he n t he 
st u d y me dicati o n ( octre oti de ca ps ules) bec o mes c o m merciall y a vaila ble i n t he a p plica ble re gi o n 
or c o u ntr y or w he n t he S p o ns or deci des t o ter mi nate t he st u d y.  F oll o wi n g t he c o m pleti o n of t he 
5- year St u d y E xte nsi o n p hase, t he S p o ns or will  eit her e xte n d t he St u d y  E xte nsi o n p hase (via 
pr ot oc ol a men d me nt s, f or a n a d diti o nal year or u ntil pr o d uct mar keti n g or st u d y ter mi nati o n ) or 
c o nsi der c o m passi o nate use (if re q ueste d b y t he pri nci pal In vesti gat or u n der c o m passi o nate use 
pr ot oc ol) ;  s u bse q ue ntl y  a  c o m passi o nate  use  pr ot oc ol  will  be  pre pare d  a n d  s u bmitte d  f or  
re g ulat or y a p pr o val. 
I n  a d diti o n,  patie nts  a de q uatel y  c o ntr olle d  o n  t he  c o m bi nati o n  of  octre oti de  ca ps ules  a n d  
ca ber g oli ne at t he e n d of t he 3 6- wee k C o m bi nati o n p hase  s u b-st u d y (see eli gi bilit y criteria, 
Secti o n  4. 5 ) or patie nts si g nifica ntl y be nefiti n g fr o m t he c o m bi nati o n treat me nt (as deter mi ne d 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 7 5  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
T he f oll o wi n g assess me nts are ma n dat or y d uri n g a n u nsc he d ule d visit: 
•  A Es a n d c o nc o mita nt me dicati o ns rec or di n g 
•  Vital si g ns  
T he  f oll o wi n g  assess me nts  are  re q uire d  o n  a n y  u nsc he d ule d  visit  d ue  t o  i na de q u ate 
bi oc he mical or cli nical c o ntr ol of acr o me gal y (as deter mi ne d b y t he In vesti gat or),  i n a d diti o n 
t o t he meas ures liste d a b o ve: 
•  I G F-1 assess me nt  
•  Acr o me gal y directe d p h ysical e xa mi nati o n 
•  AI S  
•  C o m plia nce assess me nt a n d dr u g a d mi nistrati o n i nstr ucti o ns 
•  D ose t itrati o n – d uri n g R u n- i n p hase, d ose a dj ust me nt d uri n g t he C o m bi nati o n 
p hase s u b-st u d y 
•  Ot her as dee me d necessar y b y t he st u d y I n vesti gat or 
5. 1 0  
E F FI C A C Y A S S E S S M E N T S  
5. 1 0. 1  
I G F-1 a n d G H  
I G F- 1 a n d G H le vels will be assesse d b y a ce ntral la b orat or y.  
I G F-1 c o nce ntrati o n i n t he  bl o o d will  be assesse d at all st u d y visits  (si n gle sa m ple). G H 
c o nce ntrati o n i n t he bl o o d will be assesse d at selecte d st u d y visits  (as s pecifie d i n Sc he d ule of 
Assess me nts  A p pe n di x B  t hr o u g h A p pe n di x E ). Bl o o d sa m ples f or G H will be c ollecte d e ver y 
3 0 ± 5  mi n utes o ver t w o  h o urs (t otal fi ve sa m ples), at scree ni n g fr o m ti me 0-2 h o urs, at Baseli ne 
bef ore octre oti de ca ps ules  a d mi nistrati o n fr o m 0 -2 h o urs, at all ot her visits  ( visit wee k 2 4, visit 
wee k 2 6/ E O T, visit wee k 6 2 / E O T, a n n uall y d uri n g t he St u d y E xte nsi o n p hase  a n d at t he e n d of 
St u d y E xte nsi o n ), 2-4 h o urs after octre oti de ca ps ules  a d mi nistrati o n; f or patie nts ra n d o mize d t o 
t he S R L i njecti o n ar m, G H at wee k 6 2 / E O T will be assess base d o n bl o o d sa m ples  c ollecte d 
e ver y 3 0  ±  5 mi n utes f or t w o h o urs, pri or t o t he a d mi nistrati o n of t he ne xt ( n o n -I M P) i njecti o n. 
T he mea n i nte grate d c o nce ntrati o n will be calc ulate d. A mi ni m u m of t hree G H sa m ples are 
nee de d t o calc ulate t he mea n i nte grate d c o nce ntrati o n or t he data p oi nt  will be c o nsi dere d 
missi n g . G H sa m ples s h o ul d be  c ollecte d after at least 4 h o urs fast; t he fast s h o ul d be mai ntai ne d 
d uri n g t he 2 h o urs sa m pli n g. 
5. 1 0. 2  
Or al Gl uc ose T oler a nce Test ( O G T T)  
O G T T is t he g ol d sta n dar d f or dia g n osis of acr o me gal y a n d c o nfir mati o n of disease acti vit y. At 
ti me zer o bl o o d sa m ple is dra w n a n d t he patie nt is t he n gi ve n 7 5 gr a m of gl uc ose s ol uti o n t o 
dri n k wit hi n a 5 -mi n ute ti me fra me.  Bl o o d is dra w n at 3 0 mi n utes i nter vals f or meas ure me nt of 
gl uc ose a n d G H le vels ( 3 0, 6 0, 9 0 a n d 1 2 0 mi n utes p ost gl uc ose l oa d). Fail ure t o s u p press na dir 
G H  le vels  bel o w  1  n g/ ml  ( Katz nels o n,  La ws  et  al.  2 0 1 4 ), is  c o nsi dere d  a  p ositi ve  test, 
c o nfir mi n g disease acti vit y i n acr o me gal y. O G T T will be c o n d ucte d as s pecifie d i n A p pe n di x 
E  
Pre parati o n:  
•  U nrestricte d car b o h y drate diet f or 3 da ys pri or t o t he test; 
•  O ver ni g ht fast (at least 8 h o urs) – (e. g. fast fr o m 2 4: 0 0 h o urs t he pre vi o us ni g ht), 
water is all o we d  
Patie nt as pects of test:  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 7 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
•  Patie nt s h o ul d atte n d t he i n-cli nic visit o n m or ni n g ti me, a n d pr oce d ure is e x plai ne d 
•  Patie nt s h o ul d be seate d t hr o u g h o ut test – s m o ki n g is n ot per mitte d; 
•  Disc o nti n ue test if a n y gl uc ose is l ost b y v o miti n g; 
•  B rea kfast is gi ve n w he n test has bee n c o m plete d; 
Tec h nical details of test:  
•  place I V ca n n ula f or sa m ple c ollecti o n  
•  ti me 0 - ta ke bl o o d f or gr o wt h h or m o ne, I G F- 1, gl uc ose a n d a n y ot her safet y la bs; 
•  patie nt t he n c o ns u mes  7 5  gra m of gl uc ose s ol uti o n t o dri n k wit hi n a 5-mi n ute ti me 
fra me  
•  ti mes + 3 0 + 6 0 + 9 0 + 1 2 0 mi n utes – ta ke bl o o d f or gr o wt h h or m o ne a n d gl uc ose; 
•  sa m ples i ncl u di n g baseli ne bl o o ds are se nt t o ce ntral la borat or y  o n c o m pleti o n of test. 
If O G T T is c o ntrai n dicate d (e. g. i n a patie nt wit h se vere u nc o ntr olle d dia betes as deter mi ne d 
b y t he st u d y i n v esti gat or), 7 G H sa m ples, ta ke n wit hi n 3 h o urs (ti me zer o, 3 0, 6 0, 9 0, 1 2 0, 1 5 0, 
1 8 0 mi n utes), will be d o ne i nstea d.  A vera ge G H le vels ≥ 2. 5  n g/ ml will c o nfir m e vi de nce of 
acti ve disease.   
5. 1 0. 3  
Acr o me g al y S y m pt o ms Assess me nt – I n de x of Se verit y ( AI S) 
Acr o me gal y s y m pt o ms are r o uti nel y assesse d i n cli nical trials (La ncra nja n a n d At ki ns o n 1 9 9 9 ; 
Trai ner, Dra ke et al. 2 0 0 0 ; Car o n, Bec kers et al. 2 0 0 2 ; C ha ns o n a n d Sale na ve 2 0 0 8 ; Peterse n n, 
Sc h o p o hl et al. 2 0 1 0 ; C hieff o, C o o k et al. 2 0 1 3 ; C ola o, Br o nstei n et al. 2 0 1 4 ; Peterse n n, Farrall 
et al. 2 0 1 4). Alt h o u g h s o me varia bilit y e xists bet wee n st u dies i n t he se verit y sc ori n g s yste m ( 0-
3, 0- 4, 0- 8), si milar s y m pt o ms are r o uti nel y assesse d i n all st u dies. Acc or di n g t o t he c o nse ns us 
g ui deli nes, acr o me gal y s y m pt o ms are c o nsi dere d a c ore cli nical o utc o me (Gi usti na, C ha ns o n et 
al.  2 0 1 4) t hat  s h o ul d  be  i nc or p orate d  i nt o  pr os pecti ve  cli nical  trials  f or  e val uati n g  ne w  
treat me nts. 
AI S will be assesse d t hr o u g h o ut t he st u d y as s pecifie d i n Sc he d ule of Assess me nts ( A p pe n di x  
B  t hr o u g h A p pe n di x E ). At eac h visit t he f oll o wi n g s y m pt o ms will be assesse d: Hea dac he, 
S welli n g of e xtre mities, J oi nt pai n, S weati n g a n d Fati g ue. Eac h s y m pt o m will be gra de d fr o m 
n o s y m pt o ms (sc ore 0), t o mil d s y m pt o ms ( 1), m o derate ( 2) or se vere s y m pt o ms ( 3)  (A p pe n di x 
J). 
5. 1 1  
P A TI E N T R E P O R T E D O U T C O M E A N D H E A L T H E C O N O MI C S Q U E S TI O N N AI R E S  
5. 1 1. 1  
Acr o me g al y Tre at me nt S atisf acti o n Q uesti o n n aire ( A C R O-T S Q)  
A treat me nt  satisfacti o n  q uesti o n naire  f or  a d ult  patie nts  wit h  acr o me gal y,  de vel o pe d  b y  
C hias ma, will be use d i n t his st u d y a n d is i nte n de d t o be c o m plete d b y t he patie nt (i.e. P R O).  
T he q uesti o n naire was de vel o pe d acc or di n g t o best practices f or P R O de vel o p me nt. It was 
vali date d  i n a sta n d-al o ne st u d y usi n g data fr o m 7 9 acr o me gal y patie nts e nr olle d fr o m 1 4 
cli nical practices i n t he U S a n d E ur o pe a n d t he Acr o me gal y C o m m u nit y . Its meas ure me nt 
pr o perties, i ncl u di n g i nter n al c o nsiste nc y relia bilit y, test -retest relia bilit y, c o nstr uct vali dit y 
a n d k n o w n  gr o u ps  vali dit y  were  e val uate d a n d  f o u n d  t o  be  acce pta ble.  I te ms  relate d  t o  
E m oti o nal I m pact a n d i njecti o n site reacti o ns were re vise d base d o n t hese res ults, a n d, t o get her 
w it h res p o nsi ve ness t o c ha n ge a n d mi ni mal i m p orta nt differe nce ( MI D)  f or all scales, will be 
e val uate d usi n g data fr o m t he r u n-i n p hase of t he c urre nt st u d y. 
T he q uesti o n naire has se veral versi o ns a vaila ble f or use at differe nt ti me p oi nts t hr o u g h o ut t he 
stu d y, eac h wit h mi n or m o dificati o ns (s pecificall y t he recall peri o d of i nterest). Wee k 6 2/e n d 
of treat me nt versi o n of t he A C R O -T S Q , is attac he d i n A p pe n di x G .  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 7 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
T his  q uesti o n naire  is  e x pecte d  t o  ge nerate  bala nce d  i nf or mati o n  o n  t he  a d va nta ges  a n d  
disa d va nta ges of b ot h treat me nt o pti o ns f or acr o me gal y ( octre oti de ca ps ules a n d pare nteral 
S R Ls). T he r es ults of t he A C R O -T S Q  will pr o vi de a c o m pre he nsi ve assess me nt pertai ni n g t o 
treat me nt satisfacti o n, i ncl u di n g treat me nt prefere nce, relate d t o m o de of a d mi nistrati o n. 
T he A C R O -T S Q  is f oc use d o n t he f oll o wi n g as pects: 
•  Acr o me gal y S y m pt o ms   
•  Treat me nt -relate d Gastr oi ntesti nal si de effects    
•  I njecti o n Site Reacti o ns   
•  Treat me nt A d mi nistrati o n B ot her  
•  Treat me nt C o n ve nie nce  
•  E m oti o nal I m pact 
•  Treat me nt Satisfacti o n  
•   
T he q uesti o n naire will be assesse d as s pecifie d i n t he Sc he d ule of Assess me nts ( A p pe n di x B  
t hr o u g h A p pe n di x E ). 
5. 1 1. 2  
E ur o Q ol – 5 Di me nsi o ns – 5 Le ve ls ( E Q- 5 D-5 L)   
E Q - 5 D- 5 L (fi ve  se verit y  le vels  E Q-5 D) ,  de vel o pe d  b y  t he  E ur o Q o L,  is  a  sta n dar dize d  
i nstr u me nt t o be c o m plete d b y t he patie nt f or use as a meas ure of healt h o utc o me a p plica ble t o 
a wi de ra n ge of healt h c o n diti o ns (Her d ma n, G u de x et al. 2 0 1 1 ). It c om prises fi ve di me nsi o ns 
of healt h: m o bilit y, a bilit y t o self -care, a bilit y t o u n derta ke us ual acti vities, pai n a n d disc o mf ort, 
a n d a n xiet y a n d de pressi o n. Base d o n q ualitati ve a n d q ua ntitati ve st u dies c o n d ucte d b y t he 
E ur o Q ol Gr o u p, t here are fi ve o pti o ns (le vels) u n der eac h d o mai n: ‘n o pr o ble ms ’, ‘sli g ht 
pr o ble ms’,  ‘ m o derate  pr o ble ms ’,  ‘se vere  pr o ble ms’  a n d  ‘u na ble  t o/e xtre me  pr o ble ms ’ 
(A p pe n di x H ). T he res p o nses t o all fi ve di me nsi o ns , ca n be c o n verte d t o a si n gle s u m mar y 
i n de x, utilit y (ra n ge: 0-1), b y usi n g val ue sets. Hi g her i n de x val ues re prese nt better healt h states . 
5. 1 1. 3
W or k Pr o d uct i vit y a n d Acti vit y I m p air me nt Q uesti o n n aire S pecific He alt h 
Pr o ble m V 2. 0 ( W P AI: S H P)  
W or k 
Pr o d ucti vit y a n d Acti vit y  I m pair me nt Q uesti o n naire  S pecific  Healt h  Pr o ble m  V 2. 0  
( W P AI: S H P) is a sta n dar dize d a n d vali date d  t o ol t o meas ure healt h o utc o mes i n cli nical trial 
setti n gs (Reill y, Z br oze k et al. 1 9 9 3 ). S pecificall y, t his self-a d mi nistere d t o ol meas ures ti me 
misse d  fr o m  w or k,  i m pair me nt  of  w or k  a n d  re g ular  acti vities  d ue  t o  o verall  healt h  a n d  
s y m pt o ms, r elati ve t o meas ures of ge neral healt h perce pti o ns, r ole ( p h ysical), role (e m oti o nal), 
pai n, s y m pt o m se verit y a n d gl o bal meas ures of w or k a n d i nterfere nce wit h re g ular acti vit y 
(A p pe n di x I ). 
5. 1 2  
S A F E T Y A S S E S S M E N T S  
Safet y ass ess me nts i ncl u de A Es (eit her re p orte d b y t he patie nt  or o bser ve d b y t he I n vesti gat or ), 
c o nc o mita nt me dicati o n use, vital si g ns, E C G, p h ysical e xa mi nati o n, a b d o mi nal ( gall bla d der ) 
ultras o u n d, car diac E C H O , a n d la b orat or y assess me nts; t hese assess me nts will be c o n d ucte d as 
s pecifie d i n Sc he d ule of Assess me nts (A p pe n di x B  t hr o u g h A p pe n di x E ). 
5. 1 2. 1  
A d verse E ve nts  
A d verse e ve nts ( A Es) will be assesse d at all st u d y visits t hr o u g h o ut t he st u d y fr o m i nf or me d 
c o nse nt si g ni n g. A n y A Es t hat occ ur t hr o u g h o ut t he st u d y  (i ncl u di n g t he f oll o w u p peri o ds) will 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 7 8  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
be rec or de d  ( Refer t o Secti o n  7 ). A n y ne w A E  or e xacer bati o n of e xisti n g c o n diti o n  (i ncl u di n g 
acr o me gal y s y m pt o ms , see S ecti o n 7. 1 f or details) t hat occ ur bet wee n sc he d ule d visits s h o ul d 
be br o u g ht t o t he atte nti o n of t he I n vesti gat or a n d rec or de d  as a n A E o n t he a p pr o priate e C R F 
pa ge, as well as  i n t he patie nt ’s me dical file. 
F or list of c o m m o n A Es ass ociate d wit h octre oti de ca ps ules, please refer t o t he c orres p o n di n g 
I n vesti gat or’s Br oc h ure. 
5. 1 2. 2  
Me dic al Hist or y a n d C o nc o mit a nt Me dic ati o ns  
A n y diseases t hat are o n g oi n g at scree ni n g a n d bef ore t he baseli ne will be d oc u me nte d i n t he 
me dical hist or y a n d c o nc o mita nt disease secti o n of t he e C R F. T he dia g n osis of c o nc o mita nt 
disease res ulti n g fr o m assess me nt at t he scree ni n g m ust be als o d oc u me nte d i n t he me dical 
hist or y.  
Use of c o nc o mita nt me dicati o n will be rec or de d o nt o t he e C R F fr o m t he patie nt’s me dical file 
at eac h st u d y visit t hr o u g h o ut t he st u d y. T his will i ncl u de  tra de na me ( ge neric na me), stre ngt h, 
u nit, r o ute of a d mi nistrati o n, d osa ge f or m, fre q ue nc y, i n dicati o n, start  a n d st o p date(s) of 
a d mi nistrati o n . Refer t o Secti o n  6. 1 0  f or pr o hi bite d a n d all o we d me dicati o ns. 
5. 1 2. 3
Vit al Si g ns  
Vital si g ns will be meas ure d at all st u d y visits a n d will i ncl u de bl o o d press ure  a n d heart rate, at 
rest as per sta n dar d practice at t he i nvesti gati o nal site.  Si g nifica nt fi n di n gs n otice d after t he start 
of st u d y me dicati o n w hic h meet t he defi niti o n of a n A E m ust be rec or de d o n t he A E e C R F. 
5. 1 2. 4  
E C G Assess me nt  
T wel ve -lea d E C G will be d o ne as s pecifie d i n Sc he d ule of Assess me nts ( A p pe n di x B  t hr o u g h 
A p pe n di x E ). A n y E C G a b n or malit y deter mi ne d b y t he I n vesti gat or t o be cli nicall y si g nifica nt 
w ill be n ote d as a n A E o n t he a p pr o priate e C R F pa ge(s). S uc h a b n or malities will cl osel y be 
m o nit ore d u p t o t heir res ol uti o n. 
5. 1 2. 5  
P h ysic al E x a mi n ati o n  
C o m plete p h ysical e xa mi nati o n  will be c o n d ucte d o n as s pecifie d i n Sc he d ule of Assess me nts 
(A p pe n di x B  t hr o u g h A p pe n di x E ). 
Acr o me gal y directe d p h ysical e xa mi nati o n, will be c o n d ucte d as s pecifie d i n Sc he d ule of 
Assess me nts ( A p pe n di x B  t hr o u g h A p pe n di x E ). It will i ncl u de assess me nt of p h ysical si g ns 
relate d t o acr o me gal y (s welli n g of e xtre mities, facial feat ures, si g ns a n d s y m pt o ms p ote ntiall y 
ass ociate d  wit h  car pal  t u n nel  s y n dr o me,  ot he r  s yste ms  -- e. g.  car di o vasc ular,  ne ur ol o g y,  
a b d o me n -- as necessar y, per t he In vesti gat or’s j u d g me nt ) a n d treat me nt relate d si g ns a n d 
s y m pt o ms  (prese nce  of  i njecti o n  site  reacti o ns  e. g.  er yt he ma, n o d ules,  he mat o ma,  
i nfla m mati o n, atr o p h y, or  ot her). 
Si g nifica nt fi n di n gs ma de after t he start of st u d y me dicati o n w hic h meet t he defi niti o n of a n A E 
m ust be rec or de d o n t he A E e C R F. 
Hei g ht will be rec or de d at Scree ni n g a n d wei g ht meas ure me nts will be rec or de d as s pecifie d 
i n Sc he d ule of Assess me nts (A p pe n di x B  t hr o u g h A p pe n di x E ).  
P ositi ve acr o me gal y relate d si g ns t hat are als o ca pt ure d o n t he AI S s h o ul d be ca pt ure d o n t he 
c orres p o n di n g AI S e C R F a n d n ot re p orte d as a n A E. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 7 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
5. 1 2. 6
A b d o mi n al  Ultr as o u n d  
A b d o mi nal ultras o u n d wi ll be c o n d ucte d t o m o nit or gall  bla d der a n d biliar y tract disease as 
s pecifie d  i n  Sc he d ule  of  Assess me nts  (A p pe n di x  B  t hr o u g h  A p pe n di x  E ). A b d o mi nal  
ultras o u n d  ma y  be  re peate d  d uri n g  t he  treat me nt p eri o d  t o  c o m pl y  wit h  l ocal  g ui deli nes.  
E vi de nce of c h olelit hiasis, biliar y sl u d ge, a n d bile d uct dilatati o n will be d oc u me nte d. 
5. 1 2. 7  
Ec h oc ar di o gr a m 
I n selecte d sites partici pati n g i n t he C o m bi nati o n p hase s u b-st u d y, car diac E C H O  will be 
perf or me d t o assess t he p ote ntial prese nce of val v ular disease ( val v ular re g ur gitati o n, val v ular 
restricti o n or val ve leaflet t hic ke ni n g). It will be d o ne as s pecifie d i n Sc he d ule of Assess me nts 
(A p pe n di x B  t hr o u g h A p pe n di x E ) i n all patie nts recei vi n g c o m bi nati o n treat me nt of octre oti de 
ca ps ules + ca ber g oli ne . 
5. 1 2. 8  
S afet y L a b or at or y Assess me nts  
All cli nical la b orat or y assess me nts will be perf or me d b y a ce ntral la b orat or y (e xce pt f or uri ne 
pre g na nc y test) . Bl o o d sa m pli n g will be d o ne u n der fasti n g c o n diti o ns (at least ei g ht h o urs). 
Fasti n g  c o n diti o ns  ma y  be  altere d  o n  a  case-b y -case  basis,  per  t he  I n vesti gat or’s cli nical 
discreti o n, a n d a d oc u me nte d rati o nale, at visits w he n G H assess me nt f oll o wi n g octre oti de 
ca ps ules a d mi nistrati o n is assesse d at t he cli nical site as s pecifie d i n Sc he d ule of Assess me nts 
(A p pe n di x B  t hr o u g h A p pe n di x E ). La b orat or y tests ( he mat ol o g y a n d ser u m c he mistr y) will be 
d o ne u n der o ver ni g ht fasti n g c o n diti o ns at all cli nic visits e xce pt wee k 2 4/ 2 6, e n d of R C T  ( wee k 
6 2)/ e n d of C o m bi nati o n p hase  ( wee k 3 6); these are visits w here G H is c ollecte d a n d o nl y a 
4- h o ur fa st is re q uire d. 
T he la b orat or y e val uati o ns will i ncl u de, b ut n ot li mite d t o:  
•  He mat ol o g y: re d bl o o d cell c o u nt, he m o gl o bi n ( H b ), he mat ocrit ( Htc), w hite 
bl o o d cell ( W B C) c o u nt a n d differe ntial , platelets 
•  Ser u m bi oc he mistr y: g l uc ose, t otal bilir u bi n (i n case t hat it is f o u n d ele vate d 
direct a n d i n direct bilir u bi n) , al b u mi n, s o di u m, p otassi u m, calci u m, creati ni ne, 
B U N, p h os p h or o us, uric aci d, G O T  ( A S T), G P T ( A L T), al kali ne p h os p hatase 
(A L P ),  ga m ma- gl uta m yl tra nsferase ( G G T), lactate  de h y dr o ge nase  (L D H ), 
creati ne p h os p h o ki nase ( C P K ), t otal pr otei n (f or a d diti o nal assess me nts i n case 
of a b n or mal li ver f u ncti o ns please refer t o Secti o n  7. 6 ).  
•  T S H, free T 4  
•  H b A 1c. 
•  F P G ; f or dia betic patie nts o nl y at Scree ni n g 
•  L i pi d pr ofile (t otal c h olester ol, tri gl yceri des, H D L, L D L)  
•  Uri nal ysis : gl uc ose,  ket o nes,  p H,  pr otei n,  s pecific  gra vit y ,  a n d  r o uti ne  
micr osc o p y o bser vati o ns 
•  Ser u m pre g na nc y test, if a p plica ble 
•  Uri ne pre g na nc y test, if a p plica ble 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 8 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
M ar kete d l o n g acti n g octre oti de a n d la nre oti de i njecti o ns as well as ca ber g oli ne ta b lets 0. 5 m g 
will be pr oc ure d b y t he S p o ns or, re -la bele d a n d distri b ute d t o partici pati n g sites. Details will be 
pr o vi de d i n t he St u d y P har mac y ma n ual.  
6. 6  
P A C K A GI N G A N D L A B E LI N G  O F S T U D Y M
E DI C A TI O N  
Octre oti de ca ps ules will a p pear as e nteric -c oate d ca ps ules pr o vi de d b y t he S p o ns or i n wallets 
c o ntai ni n g 2 8 ca ps ules. T he wallets will be pac ka ge d a n d la bele d i n c o m plia nce wit h t he E U 
G M P, A n ne x  1 3 of dr u gs use d i n cli nical trials a n d wit h F D A 2 1  C F R Part 3 1 2. 6 L a beli n g of 
a n i nvesti g ati o n al ne w dr u g . 
All st u d y me dicati o ns ( octre oti de ca ps ules, c o m parat or S R Ls a n d ca ber g oli ne 1) will be la bele d 
as s pecifie d i n t he St u d y P har mac y Ma n ual a n d ma y i ncl u de at mi ni m u m:  
•  Pr o d uct na me 
•  D ose  
•  L ot / batc h n u m ber 
•  Date of ma n ufact ure  
•  Retest date  
•  E x pirati o n date 
•  Pr ot oc ol n u m ber 
•  S p o ns or’s na me  
•  I nstr ucti o ns f or use a n d st ora ge 
•  “I n vesti gati o nal Use O nl y” state me nt  
6. 7  
D I S T RI B U TI O N A N D R E C EI P T  O F S T U D Y M
E DI C A TI O N  
F or detaile d i nf or mati o n  o n t he distri b uti o n a n d recei pt of st u d y me dicati o n  please refer t o t he 
St u d y P har mac y Ma n ual. 
T he  st u d y  me dicati o ns 
will  be  s hi p pe d  u n der  a p pr o priate  c o n diti o ns  wit h  te m perat ure  
m o nit ori n g de vice f or s u p plies t hat nee d t o be s hi p pe d u n der refri gerate d c o n diti o ns. U p o n 
arri val at t he cli nical i n vesti gati o n site, t he st u d y p har macist or desi g nate d tea m me m ber s h o ul d 
e xa mi ne  t he  st u d y me dicati o n  s u p plies a n d re p ort  a n y discre pa ncies  i n a m o u nts  recei ve d,  
da ma ge d s u p plies or te m perat ure e xc ursi o n i m me diatel y as o utli ne d i n t he P har mac y Ma n ual  
Eac h s hi p me nt of st u d y me dicati o n  s u p plies f or t he st u d y will be acc o m pa nie d b y a s hi p me nt 
f or m descri bi n g t he c o nte nts of t he s hi p me nt, ac k n o wle d ge me nt of recei pt a n d ot her a p pr o priate 
d oc u me ntati o n. T he st u d y staff will c o nfir m t he recei pt of cli nical s u p pl y a n d will ret ur n si g ne d 
dr u g acc o u nta bilit y l o gs as i nstr ucte d i n t he St u d y P har mac y Ma n ual.  
All st u d y s u p plies s h o ul d arri ve at t he P har mac y/I n vesti gati o nal site i n s ufficie nt q ua ntit y a n d 
i n  ti me  t o  e na ble  d osi n g  as  sc he d ule d.  Sites  m ust  c o m m u nicate  i n di vi d ual  patie nt  stat us  
f oll o wi n g eac h st u d y visit t o tri g ger s hi p me nts of st u d y me dicati o n i n ti me f or t he s u bse q ue nt 
visit.  
1 F or C o m bi nati o n p hase s u b -st u d y i n selecte d sites 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 8 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
6. 8
S T O R A G E O F S T U D Y  M
E DI C A TI O N  
T he p har macist ( or ot her a ut h orize d desi g nee) is res p o nsi ble f or e ns uri n g t hat t he a p pr o priate 
st ora ge  c o n diti o ns  f or  t he  i n vesti gati o nal  pr o d ucts are  mai ntai ne d  i n  acc or da nce  wit h  t he  
re q uire me nts i n t he St u d y P har mac y Ma n ual.  
Wallets  c o ntai n i n g e nteric-c oate d octre oti de  ca ps ules  s h o ul d  be  st ore d  at  5 ±  3 °C.  Dail y 
te m perat ure m o nit ori n g s h o ul d be mai ntai ne d b y t he site staff a n d re vie we d o n a re g ular basis 
b y t he st u d y m o nit or. A n y si g nifica nt or e xte n de d te m perat ure e xc ursi o ns nee d t o be re p orte d 
i m me diatel y as o utli ne d i n t he St u d y P har mac y Ma n ual. Mi n or te m perat ure e xc ursi o ns t hat ma y 
occ ur fr o m o pe ni n g t he d o or of t he refri gerat or will be rec or de d b ut are n ot a ca use of c o ncer n 
a n d d o n ot nee d t o be re p orte d. 
T he  st u d y  staff  a n d  m o nit ors  s h o ul d  als o  c hec k  t he  st u d y  me dicati o n  s u p plies  t o  e ns ure  
s ufficie nt a m o u nt of st u d y me dicati o n is o n ha n d f or acti ve patie nts a n d t hat t he s u p plies are n ot 
e x pire d.  
All st u d y me dicati o ns m ust be ke pt i n a l oc ke d area wit h access t o t he st u d y me dicati o n li mite d 
t o desi g nate d st u d y pers o n nel. O nl y pers o n nel u n der t he s u per visi o n of eit her t he I n vesti gat or 
or t he l ocal p har macist are a ut h orize d t o dis pe nse st u d y me dicati o n. 
F urt her details a n d i nstr ucti o ns will be pr o vi de d i n t he St u d y P har mac y Ma n ual. 
6. 9
A C C O U N T A BI LI T Y A N D C O M P LI A N C E O F S T U D Y M
E DI C A TI O N  
T he I n vesti gat or or p har macist/ desi g nee ma y dis pe nse st u d y me dicati o n(s) o nl y t o patie nts 
e nr olle d i n t he st u d y.  I n di vi d ual patie nt acc o u nta bilit y rec or ds m ust be ke pt b y t he site staff.  
T he patie nt n u m ber, t he date, batc h n u m ber/ wallet n u m ber, a n d q ua ntit y of st u d y me dicati o n 
use d or ret ur ne d b y t he patie nt will be rec or de d o n t he a p pr o priate acc o u nta bilit y f or ms b y t he 
site staff. T hese rec or ds a n d t he i n ve nt or y of st u d y me dicati o n  o n site will be verifie d b y t he 
st u d y m o nit or f or acc urac y a n d c o m plete ness o n a n o n g oi n g basis t hr o u g h o ut t he st u d y. U n use d 
dr u g s u p plies will be dis p ose d of as i nstr ucte d i n t he St u d y P har mac y Ma n ual.  
Treat me nt  c o m plia nce  will  be  assesse d  at  all  visits  d uri n g  t he  st u d y.  It  will  be  base d  o n  
acc o u nta bilit y rec or ds a n d a n i n ve nt or y of use d/ u n use d s u p plies. St u d y me dicati o ns c o m plia nce 
ma y be e n ha nce d wit h re g ular tele p h o ne calls a n d ot her re mi n ders.  
At t he e n d of t he st u d y, t he m o nit or will c o n d uct a fi nal  dr u g rec o nciliati o n f or all patie nts a n d 
t he st u d y site o verall. All rec or ds of st u d y me dicati o n  recei pt, acc o u nta bilit y rec or ds a n d dr u g 
dis p ositi o n rec or ds will be e xa mi ne d a n d rec o ncile d b y t he st u d y m o nit or.  F urt her details will 
be pr o vi de d i n t he St u d y P har mac y Ma n ual.  
6. 1 0  
P RI O R A N D C O N C O MI T A N T T H E R A P Y  
6. 1 0. 1  
Ge ner al G ui deli nes  
All pri or treat me nts recei ve d b y t he patie nt  wit hi n 3 0 da ys of t he i nitial Scree ni n g visit will be 
rec or de d o n t he patie nt ’s e C R F i ncl u di n g t he treat me nt's na me, i n dicati o n a n d t he start a n d st o p 
dates . 
A n y me dicati o ns (i ncl u di n g prescri pti o n, o ver -t he-c o u nter, her bal s u p ple me nts a n d healt h st ore 
pr o d ucts) t o be ta ke n d uri n g t he st u d y m ust be a p pr o ve d b y t he I n vesti gat or a n d rec or de d  o n t he 
c o nc o mita nt me dicati o n e C R F pa ge . 
All c o nc o mita nt me dicati o ns ta ke n b y t he patie nt  m ust be rec or de d o n t he e C R F, al o n g wit h t he 
i n dicati o n a n d start a n d st o p dates as well as dail y d ose. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 8 5  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
6. 1 0. 2
Pr o hi bite d Pri or Me dic ati o n  or T her a pies  
•  Treat me nt wit h pe g vis o ma nt wit hi n 1 2 wee ks bef ore t he scree ni n g visit 
•  Treat me nt wit h d o pa mi ne a g o nists wit hi n 6 wee ks bef ore t he scree ni n g visit  
•  Treat me nt wit h pasire oti de wit hi n 1 2 wee ks bef ore t he scree ni n g visit  
•  Treat me nt wit h l o n g -acti n g S R Ls at a d osi n g fre q ue nc y differe nt t ha n o nce 
m o nt hl y e xce pt f or la nre oti de 1 2 0 m g e ver y si x or ei g ht wee ks  
•  Pit uitar y ra di ot hera p y wit hi n fi ve years pri or t o scree ni n g  
•  Ne w treat me nt wit h estr o ge ns a n d / or selecti ve estr o ge n rece pt or m o d ulat ors 
(S E R M s); sta ble re gi me n of estr o ge ns a n d/ or S E R Ms will be per mitte d . W o me n 
w h o are treate d wit h  oral c o ntrace pti ves f or 2 1 da ys or w h o are treate d wit h 
acti ve ( h or m o ne c o ntai ni n g) pills f or 2 1 da ys a n d wit h n o n -acti ve pills ( n o n -
h or m o ne c o ntai ni n g), d uri n g t he m o nt h ly peri o d s h o ul d ma ke all eff orts t o 
sc he d ule all t heir cli nical visits a n d s pecificall y Scree ni n g, Baseli ne, w ee k 2 4, 
w ee k 2 6 a n d wee k 6 2, a n d e n d of treat me nt p hase, d uri n g  t he 2 1 da ys w he n 
acti ve h or m o nal c o ntrace pti o n is a d mi nistere d a n d prefera bl y o n t he sa me wee k 
pre/ p ost t he m o nt hl y peri o d. 
6. 1 0. 3
All o we d Me dic ati o ns  
Ot her t ha n t he i n vesti gati o nal me di cinal dr u gs, c o nc o mita nt me dicati o ns all o we d t o be use d i n 
t his st u d y are t h ose use d at scree ni n g t o c o ntr ol e xisti n g me dical c o n diti o n a n d/ or t h ose ta ke n 
d uri n g t he st u d y t o treat p ossi ble A Es .  
C o nc o mita nt a d mi nistrati o n of octre oti de ca ps ules  a n d t h yr oi d h or m o ne re place me nt t hera p y 
( H R T) is per mitte d o n a n e m pt y st o mac h after a n o ver ni g ht fast or t w o h o urs after brea kfast . 
P PIs  a n d H2 bl oc kers are a d vise d t o be ta ke n at least 3 0-6 0 mi n utes pri or  t o meals a n d at least 
1 h o ur after octre oti de ca ps ule a d mi nistrati o n. A nti -aci d is a d vise d t o be ta ke n wit h f o o d or 
j ust  pri or  t o  meals.  Ti mi n g  of  octre oti de  ca ps ules  i nta ke  i n  patie nts  ta ki n g  a nti- dia betic 
me dicati o ns s h o ul d be disc usse d wit h t he st u d y I n vesti gat or/st u d y n urse. 
L o pera mi de is all o we d t o treat GI s y m pt o ms . 
Ac ute ster oi d use s h o ul d be d oc u me nte d o n t he a p pr o priate e C R F pa ge. 
All c o nc o mita nt me dicati o ns use d t o treat A Es  will be rec or de d i n t he patie nt ’s me dical file 
a n d o n t he a p pr o priate e C R F pa ge. 
If i nta ke of a ne w s yste mic prescri pti o n dr u g s h o ul d bec o me necessar y f or a n y reas o n d uri n g 
t he c o urse of t he st u d y, t he patie nt is re q uire d t o i nf or m t he I n vesti gat or i m me diatel y, w h o will 
rec or d t he dr u g, t he d ose a n d t he ti me of a d mi nistrati o n i n t he patie nt ’s e C R F. 
6. 1 0. 4  
Pr o hi bite d C o nc o mit a nt M e dic ati o n 
W o me n ta ki n g oral c o ntrace pti o n c o ntai ni n g le v o n or gestrel are a d vise d t o s witc h t o a n ot her 
oral c o ntrace pti ve or barrier met h o d . 
P are nteral S R Ls  or d o pa mi ne a g o nists ot her t ha n t he i n vesti gati o nal me dical pr o d uct s all o we d 
d uri n g t he st u d y, G H a nta g o nists, or a n y ot her i n vesti gati o nal t hera p y f or t he treat me nt of 
acr o me gal y  are pr o hi bite d d uri n g t he c o urse of t he st u d y. 
P he n ot hiazi nes,  b ut yr o p he n o nes,  t hi o xa nt he nes,  or  met ocl o pra mi de  are  pr o hi bite d  i n  t he  
C o m bi nati o n P hase s u b-st u d y. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 8 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
7
S A F E T Y A N D P H A R M A C O VI GI L A N C E  
7. 1
A D V E R S E E V E N T  
T he F D A defi nes a n A E as “ A d verse e ve nt mea ns a n y u nt o war d me dical occ urre nce ass ociate d 
wit h t he use of a dr u g i n h u ma ns, w het her or n ot c o nsi dere d dr u g relate d”  (U S De part me nt of 
Healt h a n d H u ma n Ser vices F o o d a n d Dr u g A d mi nistrati o n Dece m ber 2 0 1 2 ). 
A n  A E  (als o  referre d  t o  as  a n  a d verse  e x perie nce)  ca n  t heref ore  be  a n y  u nfa v ora ble  a n d 
u ni nte n de d  si g n  (e. 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  te m p orall y  
ass ociate d wit h t he use of a dr u g, wit h o ut a n y j u d g me nt a b o ut ca usalit y or seri o us ness. A n A E  
ca n arise fr o m a n y u se of t he dr u g (e. g., off-la bel use, use i n c o m bi nati o n wit h a n ot her dr u g) 
a n d fr o m a n y r o ute of a d mi nistrati o n, f or m ulati o n, or d ose, i ncl u di n g a n o ver d ose. 
A n a b n or mal res ult of dia g n ostic pr oce d ures i ncl u di n g a b n or mal la b orat or y fi n di n gs will be 
c o nsi de re d a n A E if it f ulfills o ne or m ore of t he f oll o wi n g:  
•  Res ults i n patie nt 's wit h dra wal b y t he I n vesti gat or 
•  Is ass ociate d wit h cli nical si g ns or s y m pt o ms 
•  Res ults i n c ha n ge i n st u d y me dicati o n sc he d ule or i n c o nc o mita nt me dicati o n 
•  Is c o nsi dere d b y t he I n vesti gat or t o be of cli nical si g nifica nce (a la b orat or y 
a b n or malit y t hat is n ot cli nicall y si g nifica nt will n ot be c o nsi dere d a n A E)  
A ne w c o n diti o n or t he w orse ni n g of a pre-e xisti n g c o n diti o n will be c o nsi dere d a n A E. 
A n a d verse reacti o n mea ns a n y A E  ca use d b y a dr u g. A d verse reacti o ns are a s u bset of all 
s us pecte d a d verse reacti o ns f or w hic h t here is reas o n t o c o ncl u de t hat t he dr u g ca use d t he e ve nt.  
S us pecte d a d verse reacti o n is “a n y A E  f or w hic h t here is a reas o na ble p ossi bilit y t hat t he dr u g 
ca use d t he a d verse e ve nt.”  
A Es d o n ot i ncl u de t he f oll o wi n g : 
•  Sta ble or i nter mitte nt c hr o nic c o n diti o ns (s uc h as m y o pia re q uiri n g e ye glasses) 
t hat are prese nt pri or t o st u d y e ntr y a n d d o n ot w orse n d uri n g t he st u d y 
•  Me dical  or  s ur gical  pr oce d ures  (e. g.,  s ur ger y,  e n d osc o p y,  t o ot h  e xtracti o n,  
tra nsf usi o n). T he c o n diti o n t hat lea ds t o t he pr oce d ure is a n A E if n ot prese nt at 
baseli ne . 
•  O ver d ose of eit her st u d y me dicati o n or c o nc o mita nt me dicati o n wit h o ut a n y 
si g ns or s y m pt o ms u nless t he patie nt  is h os pitalize d f or o bser vati o n 
•  H os pitalizati o n f or electi ve s ur ger y pla n ne d pri or t o st u d y (sit uati o n w here a n 
u nt o war d me dical occ urre nce has n ot occ urre d) 
•  Pre g na nc y will n ot be c o nsi dere d a n A E, b ut if occ urs, will be re p orte d o n 
pre g na nc y f or m. 
A Es will be assesse d at all st u d y visits t hr o u g h o ut t he st u d y fr o m i nf or me d c o nse nt si g ni n g. 
A Es re p orte d pri or t o d osi n g o n Baseli ne Da y will be ca pt ure d a n d c o nsi dere d n o n -treat me nt 
e mer ge nt A Es. Treat me nt E mer ge nt A Es ( T E A Es) will be c o nsi dere d al l A Es t hat occ urre d 
fr o m Baseli ne (f oll o wi n g st u d y me dicati o n a d mi nistrati o n) t o e n d of c ore st u d y  (i.e. e n d of R C T 
p hase) . A Es re p orte d after ter mi nati o n/c o m pleti o n of t he c ore st u d y, d uri n g t he F oll o w- u p 
p hase, as well as A Es  t hat occ urre d wit hi n t he C o m bi nati o n p hase s u b-st u d y will be re p orte d 
se paratel y. A Es  re p orte d d uri n g t he St u d y E xte nsi o n p hase will be re p orte d se paratel y a n d 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 8 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
•  I m p orta nt me dical e ve nts t hat ma y n ot res ult i n deat h, be life -t hreate ni n g, or 
re q uire h os pitalizati o n ma y be seri o us w he n, base d u p o n a p pr o priate me dical 
j u d g me nt, t he y ma y je o par dize t he patie nt  a n d ma y re q uire me dical or s ur gical 
i nter ve nti o n t o pre ve nt o ne of the o utc o mes liste d a b o ve.  
I n p atie nt h os pit aliz ati o n or pr ol o n g ati o n of e xisti n g h os pit aliz ati o n mea ns t hat h os pital 
i n patie nt a d missi o n a n d/ or pr ol o n gati o n of h os pital sta y were re q uire d f or treat me nt of A E, or 
t hat t he y occ urre d as a c o nse q ue nce of t he e ve nt. 
H os pitalizati o n f or electi ve treat me nt of a pre -st u d y c o n diti o n t hat di d n ot w orse n w hile o n 
st u d y a n d o pti o nal h os pitalizati o ns n ot ass ociate d wit h a cli nical A E  (e. g., electi ve c os metic 
s ur ger y) are n ot c o nsi dere d S A Es. 
I m p ort a nt me dic al e ve nts  are t h ose w hic h ma y n ot be i m me diatel y life-t hreate ni n g, b ut ma y 
je o par dize t he patie nt  a n d ma y re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her seri o us o utc o mes 
liste d a b o ve. E xa m ples of s uc h e ve nts are i nte nsi ve treat me nt i n a n e mer ge nc y r o o m or at h o me 
f or aller gic br o nc h os pas m; bl o o d d yscrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n; 
res ulti n g i n a n A E  will n or mall y be c o nsi dere d seri o us b y t his criteri o n.  
A life-t hre ate ni n g a d verse dr u g e x perie nce is a n y A E  t hat places t he patie nt , i n t he vie w of 
t he I n vesti gat or, at i m me diate ris k of deat h fr o m t he reacti o n as it occ urre d, i.e., it d oes n ot 
i ncl u de a reacti o n t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h. 
7. 3  
D E FI NI TI O N O F A N U N E X P E C T E D A D V E R S E E V E N T  
A n u ne x pecte d  a d verse e ve nt is a n y A E , t he s pecificit y or se verit y of w hic h is n ot c o nsiste nt 
wit h i nf or mati o n i n t he cli nical pr ot oc ol or c urre nt I n vesti gat or’s Br oc h ure f or a n u na p pr o ve d 
st u d y me dicati o n or pac ka ge i nsert/s u m mar y of pr o d uct c haracteristics f or a n a p pr o ve d p r o d uct 
( pac ka ge i nserts are a vaila ble se paratel y at t he partici pati n g ce nter). E val uati o n will be assesse d 
se paratel y f or eac h of t he I M Ps i n t he st u d y.  
Seri o us U ne x pecte d S us pecte d A d verse Re acti o n ( S U S A R)  is a seri o us a d verse reacti o n 
assesse d as u ne x pe cte d b y t he S p o ns or a n d t hat is j u d ge d b y eit her t he re p orti n g In vesti gat or 
or t he S p o ns or t o ha ve a reas o na ble ca usal relati o ns hi p t o a me dical pr o d uct. 
7. 4  
N O TI FI C A TI O N O F S E RI O U S U N E X P E C T E D S U S P E C T E D A D V E R S E E V E N T  
T he I n vesti gat or is res p o nsi ble f or i de ntif yi n g, d oc u me nti n g, e val uati n g a n d re p orti n g S A Es i n 
acc or da nce  wit h  t he  pr ot oc ol,  2 1 C F R 3 1 2. 3 2,  2 1 C F R 3 1 2. 6 4,  I nter nati o nal  C o nfere nce  o n  
Har m o nisati o n  (I C H) g ui deli nes, a n d all ot her a p plica ble re g ulati o ns. 
I niti al N otific ati o n  
U p o n i de ntificati o n, all S A Es will be re p orte d b y t he site wit hi n 2 4 h o urs usi n g t he a p pr o priate 
e C R F. If e C R Fs are n ot a vaila ble, S A Es s h o ul d be re p orte d t o t he c o ntract researc h or ga nizati o n 
( C R O), P har m - Ola m wit hi n 2 4 h o urs usi n g t he c o ntact i nf or mati o n pr o vi de d bel o w.  I n case of 
e mer ge nc y, a 2 4- h o ur c o u ntr y- s pecific T oll -Free  n u m ber is a vaila ble i n t he St u d y Bi n der. 
 
 
T hese preli mi nar y re p orts will be f oll o we d wit hi n 2 4 h o urs b y m ore detaile d descri pti o ns t hat 
will i ncl u de a c o m plete d S A E f or m, c o pies of h os pital case re p orts (i.e., h os pital pr o gress n otes, 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 9 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, A me n d me nt 5  
res ults of a p plica ble dia g n ostic tests, la b res ults a n d bi o ps y res ults), a ut o ps y re p orts, a n d ot her 
d oc u me nts, w he n re q ueste d a n d a p plica ble. 
F or re g ulat or y p ur p oses, t he i nitial S A E re p orts s h o ul d i ncl u de: 
a) 
a s us pecte d i n vesti gati o nal me dici nal pr o d uct  
b)  
a n i de ntifia ble patie nt (e. g., st u d y patie nt c o de n u m ber) 
c)  a n
 A E  wit h seri o us ness  reas o n a n d t he I n vesti gat or’s assess me nt of t he relati o ns hi p t o 
st u d y me dicati o n 
d)   
a n i de ntifia ble re p orti n g s o urce (I n vesti gat or c o ntact details)  
O nce re p orte d, t he S A E f or m a n d acc o m pa n yi n g d oc u me ntati o n s h o ul d be place d i n t he S A E 
secti o n of t he I n vesti gat or’s site file. 
I n a d diti o n, all A Es / S A Es / S U S A Rs will be re p orte d b y t he S p o ns or t o  t he I D M C, I R B/I E C 
a n d re g ulat or y a ut h orities as re q uire d b y l ocal re g ulati o ns a n d I C H- G C P g ui deli nes. 
F oll o w- u p of S A Es / S U S A Rs  
F oll o w- u p of S A Es / S U S A Rs t hat occ ur d uri n g t he st u d y will c o nti n ue u ntil t heir satisfact or y 
res ol uti o n or sta bilizati o n. I n o utsta n di n g cases, it ma y be defi ne d as “ o n g oi n g wit h o ut f urt her 
f oll o w- u p” b y t he I n vesti gat or a n d S p o ns or’s decisi o n. 
W he n  s u p ple me nt ar y  i nf or mati o n  is  a vaila ble,  a  f oll o w -u p  S A E  Re p ort  F or m  m ust  be  
c o m plete d b y t he site ( mar ke d as “f oll o w -u p re p ort”).  T he c o ntact re p ort i nf or mati o n f or f oll o w -
u p S A E re p orti n g is t he sa me as f or i nitial S A E re p orts (see a b o ve secti o n) . 
If s u p ple me ntar y i nf or mati o n o n a S A E has t o be se nt, t he S A E f or m has t o be use d mar ke d as 
“f oll o w- u p re p ort” a n d s h o ul d be place d i n t he S A E secti o n of t he I n vesti gat or’s site file 
I nf or m ati o n t o Incl u de o n S A E F or m  
T he f oll o wi n g i nf or mati o n s h o ul d be pr o vi de d i n t he S A E f or m t o acc uratel y a n d c o m pletel y 
rec or d t he e ve nt: 
•  I n vesti gat or na me a n d site n u m ber (if a p plica ble), site  a d dress 
•  Patie nt  st u d y i de ntificati o n n u m ber 
•  Patie nt ’s i nitials (if a p plica ble) 
•  Patie nt’s  de m o gra p hics ( ge n der ; date of birt h or a ge , as a p pr o priate;  wei g ht; 
hei g ht) 
•  Cli nical E ve nt:  
- 
Descri pti o n  
- 
Date a n d ti me of o nset, st o p date, or d urati o n  
- 
Se verit y  
- 
Treat me nt (i ncl u di n g h os pitalizati o n)  
- 
Relati o ns hi p t o st u d y me dicati o n (ca usalit y) 
- 
Acti o n ta ke n re gar di n g st u d y me dicati o n 
- 
I nf or mati o n o n rec o ver y a n d a n y se q uelae 
- 
If t he A E res ulte d i n deat h 
- 
Ca use of deat h ( w het her or n ot t he deat h was relate d t o st u d y me dicati o n) 
- 
A ut o ps y fi n di n gs (if a vaila ble) 
- 
Me dical Hist or y case re p ort f or m (c o p y)  
- 
C o nc o mita nt Me dicati o n case re p ort f or m ( c o p y) 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 9 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, A me n d me nt 5  
- 
A n y rele va nt re p orts (la b orat or y, disc har ge, etc.) 
F or m ore details, refer t o P har m -Ola m Safet y Pla n.  
Acc o m pa n yi n g d oc u me ntati o n, s uc h as c o pies of h os pital case re p orts, a ut o ps y re p ort, a n d ot her 
d oc u me nts w he n a p plica ble, s h o ul d be se nt as s o o n as t he y are a vaila ble. 
S u bse q ue nt  a d diti o nal  i nf or mati o n  (f oll o w -u p)  a b o ut  a n y  S A E  u na vaila ble  at  t he  i nitial  
re p orti n g s h o ul d be f or war de d b y t he site t o t he S p o ns or re prese ntati ve a n d st u d y m o nit or wit hi n 
2 4 h o urs of t he i nf or mati o n bec o mi n g a vaila ble. 
S A Es  s h o ul d als o be re p orte d t o t he I R B/I E C acc or di n g t o l ocal re g ulati o ns. 
Patie nt s w h o ha ve ha d a n S A E d uri n g t he treat me nt peri o d m ust be f oll o we d cli nicall y u ntil all 
para meters (i ncl u di n g la b orat or y) ha ve eit her ret ur ne d t o n or mal or ha ve sta bilize d or ar e 
ot her wise e x plai ne d . 
A n y ne wl y e mer ge nt S A Es after treat me nt is disc o nti n ue d or t he patie nt has c o m plete d t he st u d y 
t hat is c o nsi dere d t o be relate d t o t he st u d y me dicati o n or st u d y partici pati o n s h o ul d be rec or de d 
a n d re p orte d  i m me diatel y t o 
 
. 
T he In vesti gat or will f ill o ut t he A E  eC R F pa ge a n d if rele va nt, t he C o nc o mita nt Me dicati o ns 
Rec or d i n t he eC R F. A partic ular atte nti o n will be ma de t o e ns ure n o discre pa ncies bet wee n t he 
A E a n d t he S A E f or m (i.e., o utc o me, se verit y, relati o ns hi p m ust be c o nsiste nt). 
F oll o w- u p Re p orts f or N o n- S eri o us A Es  
All A Es, t hat d o n ot meet a n y of t he criteria f or seri o us, s h o ul d be re gar de d as n o n -S A Es a n d 
will be rec or de d o n t he A E  Rec or d i n t he e C R F a n d if rele va nt, t he C o nc o mita nt Me dicati o ns 
Rec or d i n t he e C R F. Se verit y a n d relati o ns hi p t o st u d y me dicati o n  will be assi g ne d b y t he 
I n vesti gat or as descri be d i n t he secti o n a b o ve. F oll o w- u p of A Es t hat occ ur d uri n g t he st u d y 
will c o nti n ue u ntil t heir satisfact or y res ol uti o n or sta bilizati o n. I n o utsta n di n g cases, it ma y be 
defi ne d as “ o n g oi n g wit h o ut f urt her f oll o w- u p” b y t he I n vesti gat or a n d S p o ns or’s decisi o n. 
7. 5
A N TI CI P A T E D A D V E R S E E V E N T S  
Pre vi o us h u ma n e x perie nce a n d k n o w n A Es  of octre oti de  are detaile d i n t he c orres p o n di n g I B. 
7. 6
O C T R E O TI D E S A F E T Y G UI D A N C E  
Bel o w are t he S p o ns or’s safet y g ui da nce f or usi n g octre oti de i n case of c o m m o n GI  a d verse 
e ve nts, ele vate d li ver f u ncti o n tests ( L F Ts) a n d/ or bl o o d s u gar dis or der . T hese g ui deli nes 
s h o ul d be use d t o g ui de treat me nt, h o we ver, i n a n y case, s h o ul d n ot re place cli nical j u d g me nt.  
C o m m o n G astr oi ntesti n al A dverse Eve nts  
I n t he pre vi o us P hase 3 St u d y ( C H-A C M - 0 1), GI s y m pt o ms were a m o n g t he m ost c o m m o nl y 
re p orte d A Es. T hese A Es were ge nerall y tra nsie nt a n d decli ne d wit h ti me ( me dia n d urati o n 
was  1 3 da ys ). M ost were mil d t o m o derate  i n i nte nsit y, a n d occ urre d d uri n g t he first t w o 
m o nt hs. T here was n o d ose relati o ns hi p a n d m ost res ol ve d wit h treat me nt c o nti n uati o n.  
I n patie nts w h o de vel o p a b d o mi nal s y m pt o ms (e. g., na usea, v o miti n g, a b d o mi nal pai n or 
diarr hea), c o m m o n  GI ill nesses  s h o ul d be e xcl u de d (e. g., gastr oe nteritis, c h olestasis, etc.), a n d 
treate d acc or di n gl y. If s y m pt o ms are mil d t o m o derate i n i nte nsit y a n d patie nt is a ble t o t olerate 
oral me dicati o ns, c o nsi derati o n s h o ul d be gi ve n t o treati n g t he patie nt s y m pt o maticall y wit h 
a nti-e metics or a nti-diarr heals  t o deter mi ne if patie nt’s GI s y m pt o ms will res ol ve o n t hera p y . 
Patie nts w h o ha ve se vere or persiste nt s y m pt o ms or w h o ca n n ot t olerate f o o d/fl ui ds s h o ul d be 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 9 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
disc o nti n ue d  
Of  n ote,  a  p hase  1  st u d y  s h o we d  n o  i nteracti o n  bet wee n  l o pera mi de  a n d  oral  octre oti de  
ca ps ules. F or patie nts w h o are e nr olle d i n t he C o m bi nati o n p hase  s u b-st u d y ( partici pati n g sites 
o nl y), as  n ote d  i n  Secti o n 6. 1 0. 4 ,  D 2-a nta g o nists  (e. g.,  p he n ot hiazi nes,  b ut yr o p he n o nes,  
thi o xa nt he nes, or met ocl o pra mi de)  s h o ul d n ot be a d mi nistere d c o nc urre ntl y wit h ca ber g oli ne 
f or t he treat me nt of GI s y m pt o ms or a n y ot her A E.  
Liver Dysf u ncti o n  
S o mat ostati n  a nal o gs  i ncl u di n g  octre oti de  ha ve  bee n  ass ociate d  wit h  li ver  f u ncti o n  
a b n or malities, as well as s p ora dic p ost -mar keti n g re p orts of ac ute he patitis wit h or wit h o ut 
c h olestasis, ja u n dice a n d c h olestatic ja u n dice.  
Octre oti d e  i n hi bits  secreti o n  of  c h olec yst o ki ni n,  res ulti n g  i n  re d uce d  c o ntractilit y  of  t he  
gall bla d der a n d a n i ncrease d ris k of sl u d ge a n d st o ne f or mati o n.  Biliar y disease is t he m ost 
c o m m o n reas o ns f or li ver d ysf u ncti o n i n acr o me gal y patie nts. 
Li ver f u ncti o n tes ts ( A L T, A S T a n d Bilir u bi n), will be m o nit ore d r o uti nel y at all sc he d ule d 
visits  d uri n g  all  p hases  of  t he  st u d y.  Li ver  f u ncti o n  tests  c o ul d  als o  be  assesse d  at  a n y  
u nsc he d ule d st u d y visit, as cli nicall y i n dicate d. 
Patie nts w h o de vel o p li ver f u ncti o n a b n or m alities (ele vate d tra nsa mi nases t o > 3  ×  U L N) d uri n g 
t he st u d y s h o ul d be e val uate d f or c o m m o n ca uses of he patitis s uc h as c h olestasis, alc o h olic li ver 
disease, n o n -alc o h olic steat o he patitis, e n vir o n me ntal e x p os ures, ot her dr u g/ her bal s u p ple me nt 
e x p os ures, viral or a ut oi m m u ne he patitis.  T he dia g n ostic w or k u p of li ver d ysf u ncti o n s h o ul d 
be  g ui de d  b y  t he  patie nt’s  me dical  hist or y  a n d  p h ysical  e xa m,  a n d  l ocal  practice,  at  t he  
I n vesti gat or’s discreti o n.  
Patie nts wit h as y m pt o matic li ver d ysf u ncti o n (i.e., A L T or A S T > 3  ×  U L N a n d < 5  ×  U L N a n d 
t otal bilir u bi n < 2 ×  U L N), ma y c o nti n ue t o recei ve st u d y dr u g  (Fi g ure 5 ). Li ver f u ncti o n tests 
m ust be re peate d i n 7 da ys. I n case of c o nti n ue d tra nsa mi nase ele vati o n, peri o dical  f oll o w u p 
visits s h o ul d be c o nsi dere d, per t he I n vesti gat or’s discreti o n u p t o res ol uti o n/ret ur n t o baseli ne. 
F oll o w u p s h o ul d i ncl u de m o nit ori n g of s y m pt o ms p ote ntiall y ass ociate d wit h ac ute he patitis 
( ne w a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt pai n or te n der ness, fe ver, 
ras h, a n d/ or e osi n o p hilia), or wit h c o m plicati o ns of c h olestasis (e. g. c h ola n gitis). I n case of 
s y m pt o ms s u g gesti ve of c h olestasis, a f oll o w u p a b d o mi nal ultras o u n d s h o ul d be c o nsi dere d. 
L ocal assess me nt of I N R c o ul d be a d de d t o t he li ver f u ncti o n tests, base d o n t he I n vesti gat or’s 
discreti o n.  
All p atie nts w h o de vel o p si g nifica nt li ver d ysf u ncti o n ( A L T or A S T ≥ 5  ×  U L N) s h o ul d ha ve 
st u d y  dr u g  hel d  a n d  be  f oll o we d  u p  wit hi n  3  da ys  a n d  e ver y  3-4  da ys  t hereafter  u p  t o  
res ol uti o n/ret ur n t o baseli ne. I n case A L T/ A S T re mai ns a b o ve 5 ×  U L N, st u d y dr u g s h o ul d be 
disc o nti n ue d. If A L T/ A S T has falle n t o > 3  ×  U L N a n d < 5  ×  U L N, patie nts s h o ul d be ma na ge d 
as descri be d i n t he pre vi o us para gra p h. 
If li ver f u ncti o n tests n or malize or ret ur n t o baseli ne, w hile st u d y dr u g has bee n hel d, t he 
decisi o n t o res u me st u d y dr u g m ust be disc usse d wit h t he st u d y me dical m o nit or. 
If n o alter nati ve eti ol o g y e xists st u d y dr u g s h o ul d be disc o nti n ue d i n t he f oll o wi n g sce nari os: 
•  A L T or A S T > 5  ×  U L N  f or at least 2 wee ks  
•  A L T or A S T > 3  ×  U L N a n d ( T B L > 2  ×  U L N or I N R > 1. 5  ×  U L N ) 
•  A L T or A S T > 3  ×  U L N wit h ne w a p peara nce of fati g ue, na usea, v o miti n g, ri g ht 
u p per q ua dra nt pai n or te n der ness, fe ver, ras h, a n d/ or e osi n o p hilia ( > 5 %). 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 9 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Fi g ure 5 
Decisi o n Tree f or A b n or m al Li ver F u ncti o n Tests
Gl uc ose M et a b olis m  
Beca use of its i n hi bit or y acti o n o n gr o wt h h or m o ne, gl uca g o n, a n d i ns uli n, octre oti de ma y 
affect  gl uc ose  re g ulati o n.  P ost -pra n dial  gl uc ose  t olera nce  ma y  be  i m paire d  a n d,  i n  s o me  
i nsta nces, persiste nt h y per gl yce mia ma y be i n d uce d as a res ult of c hr o nic a d mi nistrati o n. 
H y p o gl yce mia has als o bee n re p orte d.  
I ns uli n re q uire me nts of patie nts wit h t y pe I dia betes mellit us t hera p y ma y be re d uce d b y 
a d mi nistrati o n of octre oti de. I n n o n -dia betics a n d t y pe II dia betics wit h partiall y i ntact i ns uli n 
reser ves, octre otide a d mi nistrati o n ca n res ult i n p ost -pra n dial i ncreases i n gl ycae mia. He nce, 
ser u m gl uc ose will be m o nit ore d d uri n g all sc he d ule d st u d y visits, a n d as cli nicall y i n dicate d 
at  u nsc he d ule d  visits.  Dia betic  patie nts  s h o ul d  be  a d vise d  t o  re p ort  a n y  si g nifica nt  
i ncreases/ decreases i n t heir bl o o d gl uc ose le vels, or i ns uli n re q uire me nts. 
T he ma na ge me nt of i m paire d gl uc ose meta b olis m ass ociate d wit h  octre oti de ca ps ules s h o ul d 
be si milar t o ot her s o mat ostati n a nal o gs (i.e. octre oti de or la nre oti de), i n c o nj u ncti o n wit h 
cli nical j u d g me nt. As wit h octre oti de or la nre oti de, d ose a dj ust me nts of i ns uli n a n d a nti dia betic 
me dici nal pr o d ucts ma y be re q uire d wit h octre oti de  ca ps ules . 
I n patie nts i n w h o m s o mat ostati n a nal o gs t hera p y w orse ns gl uc ose c o ntr ol, re d ucti o n of t he 
so mat ostati n a nal o gs d ose, or dia betes ma na ge me nt wit h gl uc ose -l o weri n g a ge nts s h o ul d be 
c o nsi dere d. 
A c o m plete descri pti o n of t he o pti o ns f or ma na gi n g i m paire d gl uc ose t olera nce is be y o n d t he 
sc o pe of t he pr ot oc ol. Patie nts w h o de vel o p refract or y or la bile gl uc ose meta b olis m s h o ul d be 
c o nsi dere d f or disc o nti n uati o n fr o m t he st u d y. 
8
S T A TI S TI C A L A N A L Y SI S  P L A N  
A descri pti o n of statistical met h o ds f oll o ws a n d will be descri be d i n m ore detail i n t he Statistical 
A nal ysis Pla n ( S A P), w hic h will be fi nalize d pri or t o t he first patie nt ra n d o mize d. As t he st u d y 
is o pe n-la bel, earl y fi nalizati o n will pre ve nt t he i ntr o d ucti o n of bias. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 9 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
statistics will ge nerall y i ncl u de n u m ber of patie nt s ( n), mea n, sta n dar d de viati o n ( S D), me dia n, 
mi ni m u m, a n d ma xi m u m. 
Baseli ne f or t he R u n-i n p hase will be defi ne d as t he last val ue pri or t o t he R u n -i n p hase. T he 
wee k 2 6 val ue will be use d as t he baseli ne val ue f or t he R C T p hase . 
Gi ve n t he s mall n u m ber of patie nt s, data will be p o ole d acr oss all sites f or re p orti n g p ur p oses. 
8. 4. 2  
De m o gr a p hics a n d B aseli ne  
De m o gra p hic data, baseli ne c haracteristics, me dical hist or y a n d c o nc o mita nt me dicati o ns will 
be s u m marize d usi n g descri pti ve statistics.  Data will be prese nte d b y treat me nt gr o u p, a n d 
o verall, f or t he F A S a n d S A S, a n d o verall f or t he E A S a n d C A S. 
8. 4. 3  
Pri m ar y Effic ac y A n al ysis  
 
T he pri mar y efficac y a nal ysis will esti mate t he pr o p orti o n of patie nts bi oc he micall y c o ntr olle d 
t hr o u g h o ut t he  R C T  p hase  wit hi n  eac h  treat me nt  ar m. A  patie nt  will  be  c o nsi dere d  
bi oc he micall y c o ntr olle d if his/ her T W A, d uri n g t he R C T p hase, f or I G F- 1 is < 1. 3 x U L N. T he 
use of T W A res p o nse o ver ti me is a si m ple l o n git u di nal data a nal ysis a p pr oac h i nte n de d t o 
mi ni mize t he n u m ber of missi n g patie nts fr o m  a pri mar y effecti ve ness a nal ysis a n d t o acc o u nt 
f or nat ural variati o n a m o n g t he meas ure of i nterest t hat ma y be o bser ve d o ver t he ti me peri o d 
of m o nit ori n g. T he T W A  res p o nse, o ver t he treat me nt peri o d re prese nts a n i nte grate d meas ure 
of efficac y acr oss ti me. It is deri ve d as t he area u n der t he c ur ve ( A U C ) di vi de d b y t he t otal 
a m o u nt of ti me u n der o bser vati o n. All meas ure me nts will be use d, i ncl u di n g data c ollecte d at 
“ Disc o nti n uati o n” visits a n d “ U nsc he d ule d” visits.  E ver y eff ort will be ma de t o f oll o w patie nts 
t o c o m pleti o n of t he R C T p hase. T he dr o p o ut rate is e x pecte d t o be mi ni mal, b ut s h o ul d patie nt’s  
dr o p o ut, all data c ollecte d u p  t o t hat p oi nt a n d i ncl u di n g t he ti me of disc o nti n uati o n will be 
i ncl u de d i n t he pri mar y a nal ysis. Gi ve n t his a p pr oac h f or calc ulati n g t he T W A  res p o nse f or a n 
e n d p oi nt, n o missi n g val ue will be i m p ute d.  H o we ver, if a patie nt disc o nti n ues d uri n g t he R C T 
p hase f or lac k of efficac y, he/s he will be c o nsi dere d t o be N O T bi oc he micall y c o ntr olle d, 
re gar dless of t heir T W A. T he  u na dj uste d differe nce bet wee n ar ms a n d t he a dj uste d differ e nce 
bet wee n ar ms will be re p orte d . T he a dj uste d differe nce will be o btai ne d b y calc ulati n g t he 
wei g hte d a vera ge of t he strat u m s pecific differe nces ( w here t he strat u m are defi ne d i n t he 
ra n d o mizati o n pr ocess) usi n g t he i n verse of t he varia nce wei g hti n g st rate g y (Ya n a n d S u 2 0 1 0 ). 
A n assess me nt  of n o n -i nferi orit y will be ma de usi n g a n NI mar gi n of -2 0 %. T he differe nce 
( octre oti de ca ps ules – I njecta ble S R Ls) i n res p o nse rate a n d t w o-si de d 9 5 % CI f or t he differe nce 
will be calc ulate d.  If t he l o wer b o u n d of t he CI is greater t ha n t he NI mar gi n of -2 0 %, octre oti de 
ca ps ules  will  be  declare d  n o n -i nferi or  t o  i njecta ble  S R Ls.  T he  F A S  will  be  t he  pri mar y  
p o p ulati o n use d f or t his a nal ysis, wit h a P P p o p ulati o n use d as a se nsiti vit y a nal ysis.  A d diti o nal 
se nsiti vit y a nal yses ma y be c o n d ucte d t o e xa mi ne t he i m pact of missi n g data. F urt her details 
will be pr o vi de d i n t he S A P. 
8. 4. 4  
A d diti o n al Pri m ar y Effic ac y A n al ysis  
 
Pri mar y efficac y a nal yses  
 will be c o n d ucte d f or b ot h t he R u n -i n p hase a n d f or t he 
R C T p hase as f oll o ws:  
•  R u n -i n p hase - Pr o p orti o n of patie nts bi oc he micall y c o ntr olle d at t he e n d of t he 
R u n -i n p hase defi ne d as I G F-1 < 1. 3  ×  U L N ( base d o n t he a vera ge of wee k 2 4 
a n d wee k 2 6)  
•  R C T  p hase  - Pr o p orti o n  of  patie nts  o n  octre oti de  ca ps ules  w h o  are  
bi oc he micall y  c o ntr olle d  at  t he  e n d  of  t he  R C T  p ha se,  defi ne d  as  I G F-1 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 9 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
meas ures  mi xe d  effects  m o del  ( wit h o ut  i m p utati o n  of  missi n g  data ). P R O  a n d  healt h  
ec o n o mics o utc o mes  c ollecte d i n t he C o m bi nati o n p hase s u b-st u d y will be s u m marize d o ver 
ti me. F urt her d etails of t he a nal ysis met h o d ol o g y f or t he C o m bi nati o n p hase s u b -st u d y will be 
pr o vi de d i n t he S A P. 
8. 4. 9  
St u d y E xte nsi o n P h ase  
Data c ollecte d i n t he St u d y E xte nsi o n p hase will be s u m marize d b y ti me p oi nt  usi n g descri pti ve 
statistics. A n al yses will be base d o n t he E X T-A S.  Missi n g data will be mai ntai ne d as missi n g.  
F urt her details of t he a nal ysis met h o d ol o g y f or t he St u d y E xte nsi o n p hase will be pr o vi de d i n 
t he S A P. 
8. 4. 1 0  
He alt h Ec o n o mics A n al yses  
A sta n d -al o ne a nal ysis pla n will be de vel o pe d f or t he e x pl orat or y healt h ec o n o mic a nal yses. 
T hese a nal yses will be c o n d ucte d o u tsi de of t he mai n cli nical st u d y a nal ysis i n s u p p ort of 
rei m b urse me nt s u b missi o ns i n vari o us c o u ntries. 
8. 4. 1 1  
S afet y  A n al ysis 
All  safet y  e n d p oi nts  will  be  s u m marize d  acr oss  eac h  p hase  of  t he  st u d y  se paratel y  usi n g  
descri pti ve statistics. F or t he R u n -i n p hase, t he E A S will be use d, f or t he R C T p hase, t he S A S 
will be use d, f or t he C o m bi nati o n p hase  s u b-st u d y, t he C A S will be use d a n d f or t he St u d y 
E xte nsi o n p hase t he E X T -A S will be use d. Data i n t he R u n- i n p hase a n d C o m bi nati o n p hase  
s u b-st u d y will be s u m marize d o verall. Data i n t he R C T p hase will be s u m marize d b y treat me nt 
ar m a n d o verall.  Data i n t he St u d y E xte nsi o n p hase will be s u m marize d o verall a n d b y gr o u p; 
( 1) t h ose o n octre oti de ca ps ules a n d, ( 2) t h ose o n b ot h octre oti de  ca ps ules a n d ca ber g oli ne 
( C o m bi nati o n p hase s u b-st u d y i n selecte d sites). 
8. 4. 1 1. 1  A d verse E ve nts  
A Es  will be c o de d usi n g Me dical Dicti o nar y f or Re g ulat or y Acti vities ( Me d D R A).  
T he n u m ber a n d perce nta ge of patie nt s re p orti n g T E A Es, S A Es,  T E A Es c o nsi dere d relate d t o 
st u d y me dicati o n a n d T E A Es lea di n g t o disc o nti n uati o n fr o m st u d y me dicati o n  will be re p orte d 
b y S yste m Or ga n Class ( S O C) a n d preferre d ter m ( P T).  T he T E A Es b y ma xi m u m se verit y will 
als o be re p orte d b y S O C a n d P T. 
8. 4. 1 1. 2  L a b or at or y Assess me nts  
Descri pti ve statistics will be use d t o s u m marize t he o bser ve d val ues a n d c ha n ges fr o m baseli ne 
at eac h sc he d ule d visit. A s hift ta ble (a b n or mal l o w, n or mal, a b n or mal hi g h) will be pr o vi de d 
f or selecte d la b orat or y tests, t o s h o w c ha n ges fr o m baseli ne. 
8. 4. 1 1. 3  Vit al Si g ns  
Descri pti ve statistics will be use d t o s u m marize t he o bser ve d val ues a n d c ha n ges fr o m baseli ne 
at eac h sc he d ule d visit.  
8. 4. 1 1. 4  E C G , E C H O , Ultr as o u n d a n d P h ysic al E x a mi n ati o n 
Descri pti ve statistics will be use d t o s u m marize data at eac h sc he d ule d visit. S hift ta bles will 
be use d t o s h o w c ha n ges fr o m baseli ne. 
8. 4. 1 2
I nteri m A n al yses 
N o i nteri m a nal ysis is pla n ne d , f or t he R C T p hase a n d t he C o mb i nati o n p hase s u b-st u d y; 
h o we ver, data will be peri o dicall y re vie we d b y t he I D M C f or safet y p ur p oses . Interi m a nal yses 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
of t he St u d y E xte nsi o n p hase ma y be c o n d ucte d f or re g ulat or y re p orti n g p ur p oses.  T h ese 
a nal yse s will be c o n d ucte d b y t he S p o ns or, or its desi g nee. As t he St u d y E xte nsi o n p hase is a n 
o pe n la bel, si n gle treat me nt p hase of t he st u d y, t o all o w l o n g -ter m safet y data c ollecti o n, n o 
a dj ust me nts f or m ulti plicit y will be re q uire d . See Secti o n 9. 6. 2  
9  
E T HI C S  
9. 1  
IN S TI T U TI O N A L R E VI E W B O A R D O R IN D E P E N D E N T E T HI C S C O M MI T T E E  
Pri or t o i nitiati o n of t he st u d y, t he I n vesti gat or will s u b mit t he st u d y pr ot oc ol a n d a me n d me nts, 
sa m ple I C F, a n d a n y ot her d oc u me nts t hat ma y be re q ueste d t o t he I R B/I E C f or re vie w a n d 
a p pr o val. T he I n vesti gat or will re q uest t ha t t he I R B/I E C pr o vi de writte n a p pr o val of t he st u d y 
a n d  will  kee p  o n  file  rec or ds  of  a p pr o val  of  all  d oc u me nts  pertai ni n g  t o  t his  st u d y.  T he  
I n vesti gat or will n ot be gi n t he st u d y u ntil t he pr ot oc ol a n d I C F ha ve bee n a p pr o ve d b y t he 
I R B/I E C. T he I n vesti gat or m ust a gree t o ma ke a n y re q uire d pr o gress re p orts t o t he I R B/I E C, as 
well as re p orts of S A Es, life -t hreate ni n g c o n diti o ns, or deat h. 
9. 2
E T HI C A L C O N D U C T O F T H E S T U D Y  
All cli nical w or k c o n d ucte d u n der t his pr ot oc ol is s u bject t o G C P g ui deli nes. T his i ncl u des a n 
i ns pecti o n b y S p o ns or or its desi g nee, healt h a ut h orit y or I R B/I E C re prese ntati ves at a n y ti me. 
T he I n vesti gat or m ust a gree t o t he i ns pecti o n of st u d y -relate d rec or ds b y healt h a ut h orit y 
re prese ntati ves a n d/ or S p o ns or or its desi g nee. 
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he f oll o wi n g g ui deli nes: 
•  G C P: C o ns oli date d G ui deli ne (I nter nati o nal C o nfere nce o n Har m o nisati o n of 
Tec h nical Re q uire me nts f or t he Re gistrati o n of P har mace uticals f or H u ma n 
Use, Ma y 1 9 9 6). 
•  Declarati o n of Helsi n ki: Brazil , 2 0 1 3 (A p pe n di x K ) 
•  U S C o de of Fe deral Re g ulati o ns ( Title 2 1, C F R Part 1 1, 5 0, 5 4, 5 6 a n d 3 1 2) 
a n d/ or E U Directi ves; a n d/ or l ocal c o u ntr y re g ulati o ns a n d g ui d eli nes. 
9. 3  
P A TI E N T  IN F O R M A TI O N A N D C O N S E N T  
Pri or t o scree ni n g f or t he st u d y, eac h patie nt  will be i nf or me d i n detail a b o ut t he st u d y 
me dicati o n s t o be a d mi nistere d a n d t he nat ure of t he cli nical i n vesti gati o n wit h its ris ks a n d 
disc o mf orts t o be e x pecte d. T he basic ele me nts of i nf or me d c o nse nt as s pecifie d b y t he F D A 
( 2 1 C F R  5 0. 2 5) a n d I C H-G C P will be f oll o we d.  T he patie nt s will als o be i nstr ucte d t hat t he y 
are free t o wit h dra w t heir c o nse nt a n d disc o nti n ue t heir partici pati o n i n t he st u d y at a n y ti me 
wit h o ut prej u dice. Writte n c o nse nt will be o btai ne d fr o m eac h patie nt t o be i n v ol ve d i n t he 
cli nical trial b y usi n g t he I R B/I E C -a p pr o ve d I C F pri or t o t he c o n d uct of a n y st u d y-relate d 
acti vit y. Eac h patie nt  will be gi ve n a c o p y of t he writte n I C F, a n d eac h patie nt ’s c hart will 
i ncl u de t he si g ne d I C F f or st u d y partici pati o n. T he ori gi nal patie nt  si g ne d a n d date d I C Fs will 
be mai ntai ne d b y t he site f or as l o n g as s pecifie d i n I C H G C P 1. 
1 Esse ntial d oc u me nts s h o ul d be retai ne d u ntil at least 2 y ears after t he last a p pr o val of a mar keti n g 
a p plicati o n i n a n I C H re gi o n a n d u ntil t here are n o pe n di n g or c o nte m plate d mar keti n g a p plicati o ns 
i n  a n  I C H  re gi o n  or  at  least  2  y ears  ha ve  ela pse d  si nce  t he  f or mal  disc o nti n uati o n  of  cli nical  
de vel o p me nt of t he i n vesti gati o nal pr o d uct. T hese d oc u me nts s h o ul d be retai ne d f or a l o n ger peri o d 
h o we ver if re q uire d b y t he a p plica ble re g ulat or y re q uire me nts or b y a n a gree me nt wit h t he s p o ns or. 
It is t he res p o nsi bilit y of t he s p o ns or t o i nf or m t he i n vesti gat or/i nstit uti o n as t o w he n t hese d oc u me nts 
n o l o n ger nee d t o be retai ne d.  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Patie nt s will be re q uire d t o si g n a n a d diti o nal I C F t o partici pate i n t he St u d y E xte nsi o n p hase. 
9. 4
P A TI E N T  IN S U R A N C E  
A pr o d uct lia bilit y i ns ura nce p olic y t o c o ver a gai nst  a n y i nj ur y a n d da ma ges arisi n g fr o m t he 
use of pr o d ucts i n t his pr oject is pr o vi de d b y C hias ma f or t he t otal d urati o n of t he st u d y c o veri n g 
t he patie nts a n d I n vesti gat ors i n res pect of t he ris ks i n v ol ve d i n c o n d ucti n g t his st u d y acc or di n g 
t o t his pr ot oc ol. T he i ns ura nce p olic y will be file d i n t he I n vesti gat or’s site file or ca n be ma de 
a vaila ble t o t he I n vesti gat o r a n d t o t he I R B/I E C u p o n re q uest. 
W here a p plica ble, patie nt s will be i ns ure d t hr o u g h c o ntract bet wee n a n i ns ura nce c o m pa n y a n d 
t he S p o ns or. 
9. 5  
P E R S O N A L D A T A P R O T E C TI O N  
T he st u d y will be c o n d ucte d i n acc or da nce wit h t he data pr otecti o n la ws t hat a p pl y i n a partic ular 
c o u ntr y a n d j uris dicti o n.   
C hias ma c o m plies wit h t he pri nci ple of patie nt ’s ri g ht t o pr otecti o n a gai nst i n vasi o n of pri vac y. 
T hr o u g h o ut t his trial, all patie nt  data will be i de ntifie d o nl y b y a patie nt  i de ntificati o n n u m ber. 
T he pers o nal data wi ll be bli n de d i n all data a nal yses. T he patie nt m ust be i nf or me d a n d c o nse nt 
as re q uire d t hat a ut h orize d pers o n nel of C hias ma s uc h as st u d y m o nit or, a u dit or etc. a n d rele va nt 
healt h re g ulat or y a ge nc y will ha ve direct access t o pers o nal me dical data t o ass u re a hi g h q ualit y 
sta n dar d of t he st u d y. 
At t he patie nt 's re q uest, me dical i nf or mati o n ma y be gi ve n t o his or her pers o nal p h ysicia n or 
ot her a p pr o priate me dical pers o n nel res p o nsi ble f or his or her welfare.  Pers o nal p h ysicia n will 
be n otifie d b y site pers o n nel of patie nt  partici pati o n i n t he st u d y. 
9. 6  
S T U D Y C O M MI T T E E S  
9. 6. 1
Steeri n g C o m mittee  
A Steeri n g C o m mittee ( S C) will act i n a n a d vis or y ca pacit y t o t he S p o ns or t o pr o vi de o versi g ht 
t o t he trial c o n d uct a n d t o s u p p ort its s uccessf ul c o m pleti o n. T he S C will als o e ns ure tra ns pare nt 
ma na ge me nt of t he st u d y acc or di n g t o t he pr ot oc ol t hr o u g h rec o m me n di n g a n d a p pr o vi n g 
m o dificati o ns  as  circ u msta nces  re q uire.  T he  S C  will  re vie w  pr ot oc ol  a me n d me nts  as  
a p pr o priate. T o get her wit h t he cli nical trial tea m, t he S C will a ls o de vel o p rec o m me n dati o ns 
f or p u blicati o ns of st u d y res ults i ncl u di n g a ut h ors hi p r ules. 
9. 6. 2
I n de pe n de nt D at a M o nit ori n g C o m mittee 
A n I D M C will be assi g ne d b y t he S p o ns or pri or t o t he be gi n ni n g of t he st u d y.  T he I D M C will 
act i n a n a d vis or y ca pacit y t o t he S p o ns or t o m o nit or patie nt safet y of octre oti de ca ps ules i n 
acr o me gal y patie nt s w h o partici pate i n t he st u d y. T he I D M C res p o nsi bilities are t o:  
•  Re vie w t he pla ns f or data safet y a n d m o nit ori n g 
•  E val uate  t he  p r o gress  of  t he  trial,  st u d y  data  q ualit y,  ti meli ness,  patie nt  
recr uit me nt,  accr ual  a n d  rete nti o n,  patie nt s’  ris k  vers us  be nefit,  a n d  ot her  
fact ors t hat c o ul d affect t he st u d y o utc o me  
•  Perf or m i nteri m re vie ws of ke y safet y  data at re g ular i nter vals d uri n g t he c o urse 
of t he st u d y  
•  I D M C will re vie w t he data fr o m t he C o m bi nati o n p hase s u b-st u d y (i n selecte d 
sites) at re g ular i nter vals t o e ns ure t he safet y of partici pati n g s u bjects  
•  I D M C will re vie w t he data fr o m t he St u d y E xte nsi o n p hase at re g ular i nter vals 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
t o e ns ure t he safet y of partici pati n g s u bjects  
•  C o nsi der rele va nt i nf or mati o n t hat ma y ha ve a n i m pact o n t he safet y of t he 
partici pa nts or t he et hics of t he st u d y  
•  Pr otect t he safet y of t he st u d y partici pa nts 
•  Ma ke rec o m me n dati o ns t o t he S p o ns or c o ncer ni n g c o n ti n uati o n, ter mi nati o n or 
ot her m o dificati o ns of t he st u d y base d o n t heir o bser vati o ns of t he safet y of t he 
st u d y 
F or eac h I D M C meeti n g, pre -s pecifie d re p orts will be pr o vi de d b y t he data ma na ge me nt gr o u p. 
I n a d diti o n, t he I D M C C hair will be pr o vi de d wit h or ha ve access t o peri o dical safet y  re p orts 
as s pecifie d i n t he I D M C c harter. T he I D M C C hair ma y s hare t hese re p orts wit h t he I D M C or 
c o n ve ne a d diti o nal meeti n gs of t he I D M C at his/ her discreti o n. T he I D M C C hair ma y re q uest 
a d diti o nal data base d o n t he re vie w of st u d y data. 
F urt her details re gar di n g data safet y m o nit ori n g g ui deli nes will be i ncl u de d i n t he  I D M C 
C harter, w hic h is t he g o ver ni n g d oc u me nt t hat s u perse des t his secti o n of t he pr ot oc ol.  
9. 7  
P R O T O C O L E X C E P TI O N S A N D D E VI A TI O N S  
N o pr ot oc ol de viati o ns are a ntici pate d as it is e x pecte d t hat patie nt s will meet all eli gi bilit y 
criteria. De part ures fr o m t he pr ot oc ol s h o ul d be a v oi de d, u nless re q ui re d f or t he safet y of t he 
patie nt . Pr ot oc ol de viati o ns, a n d if p ossi ble t he reas o n f or occ urre nce, will be d oc u me nte d b y 
t he  st u d y m o nit or. S h o ul d a n y pr ot oc ol  de viati o ns occ ur, t he I n vesti gat or  m ust  re p ort  t he 
de viati o n t o t he S p o ns or , a n d if re q uire d, t o  t he I R B/I E C, i n acc or da nce wit h l ocal re g ulati o ns, 
wit hi n reas o na ble ti me.  
9. 8  
P R O T O C O L A M E N D M E N T S  
C ha n ges t o t he pr ot oc ol ma y be ma de o nl y b y t he S p o ns or ( wit h or wit h o ut c o ns ultati o n wit h 
t he  I n vesti gat or).  All  pr ot oc ol  m o dificati o ns  m ust  be  s u b mitte d  t o  t he  site  I R B/I E C  i n  
acc or da nce wit h l ocal re q uire me nts a n d, if re q uire d, t o t he Re g ulat or y A ut h orit y, eit her as a n 
a me n d me nt or a n otificati o n. A p pr o val f or a me n d me nts m ust be a waite d bef ore a n y c ha n ges 
ca n be i m ple me nte d, e xce pt f or c ha n ges necessar y t o eli mi nate a n i m me diate hazar d t o st u d y 
patie nt s, or w he n t he c ha n ges i n v ol ve o nl y l o gistical or a d mi nistrati ve as pects of t he trial. N o 
a p pr o val is re q uire d f or n otificati o ns.  
1 0  
Q U A LI T Y C O N T R O L A N D Q U A LI T Y A S S U R A N C E  
T he st u d y will be c o n d ucte d acc or di n g t o G C P as o utli ne d b y I C H T o pic E 6 ste p  5 g ui deli nes. 
T he S p o ns or  a n d/ or desi g nate d C R O  mai ntai ns a q ualit y ass ura nce s yste m wit h writte n sta n dar d 
o perati n g pr oce d ures ( S O Ps ) t o e ns ure t hat cli nical trials are c o n d ucte d a n d data are ge nerate d, 
d o c u me nte d a n d re p orte d i n c o m plia nce wit h t he pr ot oc ol, G C P a n d a p plica ble re g ulat or y 
re q uire me nts. 
1 0. 1  
A U DI T S A N D IN S P E C TI O N S  
T he  st u d y  ma y  be  a u dite d  acc or di n g  t o  t he  S p o ns or's  q ualit y  ass ura nce  ( Q A )  i ns pecti o n  
pr o gra m. T he p ur p ose of t he a u dit is t o deter mi ne w het her or n ot t he st u d y is bei n g c o n d ucte d 
a n d m o nit ore d i n c o m plia nce wit h st u d y pr ot oc ol a n d I C H G C P g ui deli ne. A u dit visit(s) will be 
arra n ge d i n a d va nce wit h site pers o n nel at a m ut uall y acce pta ble ti me.  
T he I n vesti gat or s h o ul d u n dersta n d t hat s o urce d oc u me nts f or t his trial s h o ul d be ma de a vaila ble 
t o a p pr o priatel y q ualifie d pers o n nel fr o m t he S p o ns or q ualit y ass ura nce or its desi g nees or t o 
re g ulat or y a ut h orit y i ns pect ors after a p pr o priate n otificati o n. T he verificati o n of t he e C R F data 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
m ust be b y direct i ns pecti o n of s o urce d oc u me nts. T hese a u dits or i ns pecti o ns ma y ta ke place 
at a n y ti me, d uri n g or after t he st u d y, a n d are base d o n t he nati o nal re g ulati o ns, as well as I C H 
g ui deli nes. 
1 0. 2
S T U D Y M
O NI T O RI N G  
M o nit ori n g of t he st u d y is t he res p o nsi bilit y of t he S p o ns or a n d ma y be dele gate d t o a C R O or 
a c o ntract m o nit or. T he st u d y m o nit or will a d vise t he I n vesti gat or re gar di n g t he practical 
c o n d uct of t he st u d y a n d mai ntai ni n g c o m plia nce wit h t he pr ot oc ol, G C P a n d all a p plica ble 
re g ulat or y re q uire me nts. 
Bef ore  st u d y  i nitiati o n,  at  a  site  i nitiati o n  visit  or  at  a n  I n vesti gat or’s  meeti n g,  a  C R O  
re prese ntati ve will re vie w t he pr ot oc ol a n d e C R Fs wit h t he I n vesti gat or a n d his staff. 
T hr o u g h o ut t he c o urse  of t he st u d y, t he st u d y m o nit or will o versee t he c o n d uct a n d t he pr o gress 
of t he st u d y b y fre q ue nt c o ntacts wit h t he I n vesti gat or.  T his will i ncl u de tele p h o ne calls a n d o n -
site  visits. D uri n g  t he  o n -site  visits,  t he  e C R F  will  be  re vie we d  f or  c o m plete ness  wit h 
c orres p o n di n g s o urce d oc u me nts.  As part of t he data a u dit, s o urce d oc u me nts will be ma de 
a vaila ble  f or  re vie w  b y  t he  st u d y  m o nit or.  T he  st u d y  m o nit or  will  als o  perf or m  dr u g  
acc o u nta bilit y c hec ks a n d will peri o dicall y re q uest re vie w of t he I n vesti gat or  st u d y file t o e ns ure 
c o m plete ness of d oc u me ntati o n i n all res pects of cli nical st u d y c o n d uct. 
Peri o dicall y, s o me or all of t he facilities use d i n t he st u d y (e. g., l ocal la b orat or y, p har mac y) ma y 
be re vie we d. M o nit ori n g visits will be arra n ge d i n a d va nce w it h site pers o n nel at a m ut uall y 
acce pta ble ti me. S ufficie nt ti me m ust be all o we d b y t he site pers o n nel f or t he m o nit or t o re vie w 
e C R Fs a n d r ele va nt s o urce d oc u me nts. T he I n vesti gat or s h o ul d be a vaila ble t o a ns wer q uesti o ns 
or res ol ve data clarificati o ns. T he I n vesti gat or or a p p oi nte d dele gate will recei ve t he st u d y 
m o nit or d uri n g t hese o n -site visits, c o o perate i n pr o vi di n g t he d oc u me nts f or i ns pecti o n, a n d 
res p o n d t o i n q uiries. 
T he I n vesti gat or will e ns ure t hat t he st u d y partici pa nts are a ware of a n d c o ns e nt t hat pers o nal 
i nf or mati o n ma y be scr uti nize d d uri n g t he data verificati o n pr ocess as part of st u d y-relate d 
m o nit ori n g a n d a u diti n g b y pr o perl y a ut h orize d pers o ns ass ociate d wit h C hias ma or i ns pecti o n 
b y  d o mestic  a n d/ or  f orei g n  re g ulat or y  a ut h orit y(ies).  H o we ver,  partici pati o n  a n d  pers o nal  
i nf or mati o n s h o ul d be treate d as strictl y c o nfi de ntial t o t he e xte nt t hat t he a p plica ble la w per mits 
a n d n ot be p u blicl y a vaila ble. 
U p o n c o m pl eti o n of t he st u d y, t he st u d y m o nit or will arra n ge f or a fi nal re vie w of t he  st u d y 
files after w hic h t he files s h o ul d be sec ure d f or t he a p pr o priate ti me peri o d. 
1 0. 3  
Q U A LI T Y L A B O R A T O R Y S T A N D A R D S  
La b orat or y tests or e val uati o ns descri be d i n t his pr ot oc ol will be c o n d ucte d i n acc or da nce wit h 
q ualit y la b orat or y sta n dar ds as descri be d i n t he S O Ps of t he l ocal i nstit uti o n la b orat or y a n d 
ce ntral la b orat ories.  
Bef ore t he st u d y be gi ns, t he la b orat ories t o be use d i n t he st u d y will pr o vi de a list of t he 
refere nce ra n ges f or all la b orat or y tests t o be u n derta ke n a n d details of t he met h o d use d f or 
q ualit y c o ntr ol. T hese will be hel d i n t he I n vesti gat or file a n d t he trial master file. T he met h o ds 
e m pl o ye d f or eac h assa y s h o ul d be a vaila ble o n re q uest. A n y c ha n ge i n t he la b orat or y, its 
pr oce d ures, refere nces, val ues, etc. d uri n g t he st u d y m ust be n otifie d pr o m ptl y t o t he S p o ns or. 
1 0. 4
S T U D Y D O C U M E N T A TI O N  
St u d y d oc u me nts will i ncl u de t he f oll o wi n g: 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, A me n d me nt 5  
•  Si g ne d I C Fs 
•  S o urce d oc u me nts (e. g., patie nt  files, me dical n otes, st u d y w or ks heets) 
•  I n vesti gat or c o pies of t he e C R Fs a n d S A E re p orts 
•  I n vesti gat or site file + c onte nts 
•  St u d y Ma n ual s (i ncl u di n g la b orat or y ma n ual, p har mac y ma n ual a n d refere nce 
ma n ual) 
•  I n vesti gat or meeti n g bi n der a n d or ot her trai ni n g materials 
U p o n c o m pl eti o n of t he st u d y, t he st u d y m o nit or will arra n ge f or a fi nal re vie w of t he st u d y 
files after w hic h t he files s h o ul d be sec ure d f or t he a p pr o priate ti me peri o d. 
1 0. 4. 1
S o urce D oc u me nt  
T he I n vesti gat or will per mit st u d y -relate d m o nit ori n g, a u dits b y or o n be half of t he S p o ns or, 
I R B/I E C re vie w a n d re g ulat or y i ns pecti o ns pr o vi di n g direct access t o s o urce data d oc u me nts. 
S o urce d oc u me nts are ori gi nal rec or ds i n w hic h ra w data are first rec or de d.  T hese ma y be 
office/cli nic/ h os pital rec or ds, c harts, diaries, ultras o u n d i ma ges, a n d la b orat or y res ults, E C G 
pri nt o uts, p har mac y rec or ds, care rec or ds, c o m plete d scales f or eac h st u d y partici pa nt a n d/ or 
w or ks heets pr o vi de d b y t he S p o ns or. S o urce d oc u me nts s h o ul d be ke pt i n a sec ure a n d li mite d 
access area. All s o urce d oc u me nts s h o ul d be acc urate, clear, u na m bi g u o us, per ma ne nt a n d 
ca pa ble of bei n g a u dite d. T he y  s h o ul d be ma de usi n g a per ma ne nt f or m of rec or di n g (i n k, 
t y pi n g, pri nti n g, o ptical disc, etc.). T he y s h o ul d n ot be o bsc ure d b y c orrecti n g fl ui d or ha ve 
te m p orar y  attac h me nts  (s uc h  as  re m o va ble  self-stic k  n otes).  S o urce  d oc u me nts  t hat  are  
c o m p uter  ge nerate d  a n d  st ore d  electr o nicall y  m ust  be  pri nte d,  si g ne d  a n d  date d  b y  t he  
I n vesti gat or. 
S o urce  data  f or  patie nt s  re gistere d  t o  t he  st u d y  s h o ul d  i n dicate  date  I C F  was  si g ne d,  
partici pati o n  i n  cli nical  pr ot oc ol  n u m ber  a n d  title,  treat me nt  n u m ber,  e vi de nce  t hat  
i ncl usi o n/e xcl usi o n criteria ha ve bee n met.  
1 0. 4. 2
Rec or di n g of D at a o n Electr o nic C ase Re p ort F or m (e C R F)  
N o data will be directl y e ntere d i nt o t he e C R F wit h o ut s o urce d oc u me ntati o n. 
T he st u d y w or ks heets pr o vi de d b y t he S p o ns or ma y be  use d t o ca pt ure all st u d y dat a n ot 
rec or de d i n t he patie nt ’s me dical rec or d. Alter nati vel y, t he site ma y create a n d use t heir o w n 
st u d y w or ks heets. O nl y a patie nt  i de ntificati o n n u m ber will be use d t o i de ntif y t he patie nt . T he 
In vesti gat or m ust kee p a se parate l o g of patie nt na mes a n d  me dical rec or d n u m bers ( or ot her 
pers o nal i de ntifiers).  
T he pr ot oc ol will use a n I nter net -Base d Re m ote Data E ntr y S yste m, pri maril y t o c ollect cli nical 
trial data at t he i n vesti gati o nal sites. T he s yste m will be use d t o e nter, m o dif y, mai ntai n, arc hi ve, 
retrie ve, a n d tra ns mit data. T he s yste m was c o nfi g ure d base d o n re q uire me nts fr o m t he S p o ns or. 
Pa per s o urce d oc u me nts are t o be retai ne d t o e na ble a rec o nstr ucti o n a n d e val uati o n of t he st u d y. 
N o  ori gi nal  o bser vati o ns  will  be  e ntere d  directl y  i nt o  t he  c o m p u terize d  s yste m. S o urce  
d oc u me nts i ncl u de t he cli nic or h os pital patie nt files a n d st u d y w or ks heets pr o vi de d b y t he 
S p o ns or. Data will be rec or de d i n t he st u d y w or ks heets as a p pr o priate t o c o m plete a n d/ or clarif y 
s o urce data. 
T he desi g n of a c o m p ut erize d s yste m c o m plies wit h all a p plica ble re g ulat or y re q uire me nts f or 
rec or d kee pi n g a n d rec or d rete nti o n i n cli nical trials ( 2 1 C F R Part 1 1 a n d I C H E 6 G o o d Cli nical 
Practice)  t o  t he  sa me  de gree  of  c o nfi de nce  as  is  pr o vi de d  wit h  pa per  s yste ms.  Cli ni cal 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 5  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
In vesti gat ors m ust retai n eit her t he ori gi nal or a c o p y of all s o urce d oc u me nts se nt t o a S p o ns or 
or C R O , i ncl u di n g q uer y res ol uti o n c orres p o n de nce. T he s yste m is desi g ne d s o t hat c ha n ges t o 
a n y rec or d d o n ot o bsc ure t he ori gi nal i nf or mati o n.  T he a u dit  rec or d clearl y i n dicates t hat a 
c ha n ge was ma de a n d cl earl y pr o vi des a mea ns t o l ocate a n d rea d t he pri or i nf or mati o n. All 
c ha n ges  t o  t he  data  ha ve  a n  electr o nic  a u dit  trail,  i n  ac c or da nce  wit h  2 1  C F R  1 1. 1 0(e).  
Electr o nic si g nat ures will be use d i n c o nf or ma nce wit h 2 1 C F R Part 1 1.  
1 0. 4. 3  
I n vesti g at or Site File 
All d oc u me nts re q uire d f or t he c o n d uct of t he st u d y as s pecifie d i n t he I C H -G C P g ui deli nes 
will be mai ntai ne d b y t he I n vesti gat or i n a n or derl y ma n ner a n d ma de a vaila ble f or m o nit ori n g 
a n d/ or a u diti n g b y t he S p o ns or a n d re g ulat or y a ge ncies. 
1 0. 5  
C LI NI C A L T RI A L S U P P LI E S  
T he S p o ns or or its ve n d ors will be res p o nsi ble f or pr o vi di n g st u d y s u p plies a n d f or e ns uri n g 
t hat t he y are use d, ma na ge d a n d acc o u nte d f or pr o perl y.  Acc urate a n d ti mel y rec or ds of t he 
dis p ositi o n a n d acc o u nta bilit y of all st u d y dr u gs m ust be mai ntai ne d b y t he site a n d re vie we d 
b y t he S p o ns or re prese ntati ve m o nit or .   T he s u p plies a n d i n ve nt or y rec or d m ust be ma de 
a vaila ble  f or  i ns pecti o n  u p o n  re q uest.  U p o n  c o m pleti o n  or  ter mi nati o n  of  t he  st u d y,  t h e 
I n vesti gat or will kee p t he re mai ni n g cli nical s u p plies al o n g wit h a c o p y of t he i n ve nt or y rec or d 
a n d a rec or d of t he cli nical s u p plies ret ur ne d. U n der n o circ u mst a nces will t he I n vesti g at or 
all o w t he st u d y me dic ati o n s t o be use d ot her t h a n as directe d b y t his pr ot oc ol. 
U p o n  c o m pleti o n  or  ter mi nati o n  of  t he  st u d y,  all  st u d y  s u p plies  will  be  dis p ose d  of  per  
i nstr ucti o ns fr o m t he S p o ns or a n d/ or its ve n d ors ( C R O).   
Cli nical trial s u p plies i ncl u de, h o we ver, n ot li mite d t o: e C R F, st u d y w or ks heets, la b s u p plies 
a n d st u d y me dicati o n s. 
1 0. 6  
D A T A M
A N A G E M E N T  
Data Ma na ge me nt ser vices will be pr o vi de d b y t he C R O.  After t he data ha ve bee n e ntere d a n d 
verifie d,  vari o us  e dit  c hec ks  will  be  perf or me d  f or  t he  p ur p ose  of  e ns uri n g  t he  acc urac y, 
i nte grit y, a n d vali dit y of t he data base. T hese e dit c hec ks ma y i ncl u de:  
•  Missi n g val ue c hec ks  
•  Ra n ge c hec ks 
•  C o nsiste nc y c hec ks  
•  Se q ue nce c hec ks  
•  Pr o ba bilistic c hec ks 
•  Pr ot oc ol a d here nce c hec ks  
Q ueries ge nerate d fr o m t hese c hec ks will be se nt t o t he i n vesti gati o nal site f or res ol uti o n, a n d 
t he data base will be u p date d t o reflect q uer y res ol uti o ns as a p pr o priate. 
F or details o n data ma na ge me nt  pr ocesses, please refer t o t he St u d y Data Ma na ge me nt Pl a n. 
1 1  
S T U D Y A D MI NI S T R A TI O N  
1 1. 1  
P A R TI CI P A TI N G C E N T E R S
T his will be a m ultice nter, w orl d wi de st u d y . 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, A me n d me nt 5  
1 1. 2
R E Q UI R E D D O C U M E N T S P RI O R T O S T U D Y INI TI A TI O N  
Pri or t o t he release of st u d y me dicati o n t o a site, all esse ntial st u d y d oc u me nts m ust be c ollecte d, 
re vie we d a n d a p pr o ve d. T hese ma y i ncl u de:  
•  A p pr o priate l ocal healt h a ut h orit y d oc u me ntati o n pr o perl y si g ne d a n d date d b y 
t he re q uire d I n vesti gat or (i.e., t he s u b missi o n pac ka ge) 
•  Si g ne d c o p y ( ori gi nal) of t he a p pr o ve d pr ot oc ol 
•  C o m plete d a n d si g ne d state me nt of I n vesti gat or 
•  A si g ne d Cli nical Trial A gree me nt  
•  C urric ul u m vitae f or t he I n vesti gat or a n d s u b -I n vesti gat or (ca n be c ollecte d at 
site i nitiati o n visit) 
•  I R B/I E C  na me  a n d  a d dress;  a n d  me m bers hi p  list  (ca n  be  c ollecte d  at  site  
i nitiati o n visit) 
•  Letter of a p pr o val fr o m t he I R B/I E C f or b ot h pr ot oc ol (i de ntifie d b y pr ot oc ol 
title a n d n u m ber) a n d I C F (i de ntifie d b y pr ot oc ol title a n d n u m ber) 
•  C o p y of t he I R B/I E C -a p pr o ve d writte n I C F t o be use d i n t he st u d y (t hat has als o 
bee n a p pr o ve d b y t he S p o ns or) 
•  Pr o visi o ns f or direct access t o s o urce/ data d oc u me nts if necessar y f or trial -
relate d m o nit ori n g, a u dits, I R B/I E C re vie w, a n d re g ulat or y i ns pecti o n 
•  Na me a n d l ocati o n of t he la b orat or y utilize d f or la b orat or y assa ys, a n d ot her 
facilities c o n d ucti n g tests, as well as a c o p y of t he la b orat or y certificate a n d list 
of n or mal la b orat or y val ues  (ca n be c ollecte d at site i nitiati o n visit) 
I n case a la b orat or y certificati o n is n ot a vaila ble, a writte n state me nt as t o h o w t he la b orat or y 
c o m plies wit h q ualit y ass ura nce s h o ul d be pr o vi de d. 
U p o n satisfact or y recei pt of all re q uire d re g ulat or y d oc u me nts, S p o ns or will arra n ge t hat st u d y 
me dicati o n s be deli vere d t o t he st u d y site. S u p pl y of all ot her st u d y materials will be t he 
res p o nsi bilit y of C hias ma a n d/ or desi g nee. Patie nt  e ntr y s h o ul d n ot be gi n u ntil after t he re q uire d 
re g ulat or y d oc u me nts are c o nfir me d as recei ve d a n d t he I n vesti gat or Meeti n g/I nitiati o n visit 
has occ urre d. All pers o n nel e x pecte d t o be i n v ol ve d i n t he c o n d uct of t he st u d y will u n der g o 
orie ntati o n t o i ncl u de re vie w of st u d y pr ot oc ol, i nstr ucti o ns f or e C R F c o m pleti o n, A E re p orti n g, 
a n d o verall res p o nsi bilities i ncl u di n g t h ose f or dr u g acc o u nta bilit y a n d st u d y file mai nte na nce. 
T he I n v esti gat or a n d/ or desi g nee (st u d y m o nit or) will pre pare a n I n vesti gat or's site file.  T his 
file s h o ul d be use d f or all trial relate d d oc u me nts. T he I n vesti gat or will be res p o nsi ble f or 
kee pi n g t he I n vesti gat or's site file u p date d a n d e ns uri n g t hat all re q uire d d oc u me nts are file d. 
T he file will be i ns pecte d d uri n g m o nit ori n g visits. 
1 1. 3  
S T U D Y C O M P L E TI O N  
T his st u d y is e x pecte d t o e n d w he n all re q uire d patie nt s ha ve bee n e nr olle d a n d t he last patie nt  
has c o m plete d t he st u d y a n d q uer y res ol uti o n has bee n c o m plete d. 
Data  a n d  materials  t hat  are  re q uire d  bef ore  t he  st u d y  ca n  be  c o nsi dere d  c o m plete  a n d/ or  
ter mi nate d are: 
•  La b orat or y fi n di n gs, cli nical data, a n d all s pecial test res ults fr o m scree ni n g 
t hr o u g h t he e n d of t he f oll o w- u p peri o d 
•  e C R F (i ncl u di n g c orrecti o n f or ms) pr o perl y c o m plete d b y a p pr o priate st u d y 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
pers o n nel a n d electr o nicall y si g ne d b y t he I n vesti gat or 
•  C o m plete d Dr u g Acc o u nta bilit y Rec or ds 
•  State me nt of o utc o me f or eac h S A E re p orte d  
•  C o pies  of  pr ot oc ol  a me n d me nts  a n d  I R B/I E C  as  well  as  rele va nt  healt h  
a ut h orit y a p pr o val/ n otificati o n (if a p plica ble)  
1 1. 4
C LI NI C A L S T U D Y R E P O R T  
A cli nical st u d y re p ort will be de vel o pe d b y t he S p o ns or at c o m pleti o n of data a nal ysis. T his 
re p ort will be a cli nical a n d statistical i nte grate d re p ort, acc or di n g t o t he I C H E 3 g ui deli nes. 
1 1. 5
R E T E N TI O N O F S T U D Y R E C O R D S  
T he I n vesti gat or will retai n c o pies of t he a p pr o ve d pr ot oc ol, c o m plete d e C R F, I C Fs, rele va nt 
s o urce d oc u me nts, a n d all ot her s u p p orti n g d oc u me ntati o n relate d t o t he pr oject f or as l o n g as 
s pecifie d i n I C H G C P 1. i n a sec ure a n d safe facilit y wit h li mite d access If t he I n vesti gat or is 
u na ble t o retai n t he st u d y d oc u me nts f or t he re q uire d a m o u nt of ti me, S p o ns or or desi g nee m ust 
be i nf or me d of t he i n di vi d ual w h o will be ass u mi n g t his res p o nsi bilit y. 
F urt her rete nti o n, if re q uire d, will be ne g otiate d at t he e n d of t his peri o d. I n t hat case, C hias ma 
will n otif y, i n writi n g, t he I n vesti gat or w he n t he cli nical st u d y data ma y be discar de d. T he 
I n vesti gat or  will  ta ke  meas ures  t o  pre ve nt  acci de ntal  or  pre mat ure  destr ucti o n  of  t hese 
d oc u me nts. 
T hese  files  m ust  be  ma de  a vaila ble  f or  i ns pecti o n  u p o n  reas o na ble  re q uest  b y  a ut h orize d  
re prese ntati ves of S p o ns or a n d / or t he rele va nt re g ulat or y a ge ncies. 
1 1. 6
C O N FI D E N TI A LI T Y A N D P U B LI C A TI O N O F S T U D Y D A T A  
All  i nf or mati o n  s u p plie d  b y  C hias ma  i n  ass ociati o n  wit h  t his  st u d y  a n d  n ot  pre vi o usl y  
p u blis he d, is c o nsi dere d c o nfi de ntial i nf or mati o n. T his i nf or mati o n i ncl u des, b ut is n ot li mite d 
t o,  t he  I n vesti gat or’s  Br oc h ure,  t he  pr ot oc ol,  e C R Fs,  a n d  ot her  scie ntific  data.  A n y  data  
c ollecte d d uri n g t he st u d y are als o c o nsi dere d c o nfi de ntial. T his c o nfi de ntial i nf or mati o n s hall 
re mai n s ole pr o pert y of C hias ma, s hall n ot be discl ose d t o ot hers wit h o ut t he writte n c o nse nt of 
C hias ma, a n d s hall n ot be use d e xce pt i n t he perf or ma nce of t his st u d y . 
D ata ca n n ot be use d f or p u blicati o n or re p orti n g o utsi de of t his st u d y u ntil t he st u d y is c o m plete d 
or disc o nti n ue d b y C hias ma.  T his is necessar y si nce disse mi nati o n of preli mi nar y i nf or mati o n 
ma y  i na p pr o priatel y  affect  t he  o bjecti vit y  of  t his  st u d y.  F or  t h is  reas o n,  C hias ma,  st u d y  
In vesti gat ors or ot her parties will n ot be all o we d t o perf or m s u bset a nal yses at a n y p oi nt bef ore 
t he c o ncl usi o n of t his st u d y. Vi olati o n of t his will res ult i n a ut o matic e x p ulsi o n fr o m t his st u d y.  
C hias ma rec o g nizes t he i m p orta nc e of ti mel y c o m m u nicati o n of me dical researc h a n d scie ntific 
data a n d its o bli gati o ns t o patie nt s e nr olle d i n t he st u d y. T he o bject of t he st u d y will be t o p u blis h 
1 E s s e nti al d oc u m e nt s s h o ul d b e r et ai n e d u ntil at l e a st 2 y e ar s aft er t h e l a st a p pr o v al of 
a m ar k eti n g a p plic ati o n i n a n I C H r e gi o n a n d u ntil t h er e ar e n o p e n di n g or c o nt e m pl at e d 
m ar k eti n g a p plic ati o n s i n a n I C H r e gi o n or at l e a st 2 y e ar s h a v e el a p s e d si nc e t h e f or m al 
di sc o nti n u ati o n of cli nic al d e v el o p m e nt of t h e i n v e sti g ati o n al pr o d uct. T h e s e d oc u m e nt s 
s h o ul d b e r et ai n e d f or a l o n g er p eri o d h o w e v er if r e q uir e d b y t h e a p plic a bl e r e g ul at or y 
r e q uir e m e nt s or b y a n a gr e e m e nt wit h t h e s p o n s or. It i s t h e r e s p o n si bilit y of t h e s p o n s or 
t o i nf or m t h e i n v e sti g at or/i n stit uti o n a s t o w h e n t h e s e d oc u m e nt s n o l o n g er n e e d t o b e 
r et ai n e d.  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 8  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
t he res ults of t he c o m plete st u d y i n a n a p pr o priate peer-re vie we d j o ur nal after t he c o ncl usio n. 
A f or mal p u blicati o n of data c ollecte d as a res ult of t he st u d y is pla n ne d a n d will be c o nsi dere d 
a j oi nt p u blicati o n b y t he In vesti gat ors a n d t he a p pr o priate C hias ma pers o n nel.  A ut h ors hi p will 
be deter mi ne d b y m ut ual a gree me nt.  I n ge neral, t he I n vestigat ors w h o ha ve ma de t he m ost 
s u bsta ntial c o ntri b uti o ns t o t he st u d y will be c o nsi dere d lea d a n d/ or se ni or a ut h ors. Re vie w a n d 
c o m me nt  b y  C hias ma  o n  draft  a bstracts  a n d  ma n uscri pts  is  re q uire d  pri or  t o  p u blicati o n.  
A ut h ors s h o ul d s u b mit draft p u blicati o ns t o C hias ma n o fe wer t ha n si xt y ( 6 0) da ys pri or t o 
s u b missi o n  t o  a n y  j o ur nal,  p u blis her  a n d/ or  t hir d  part y.  T his  re q uire me nt  s h o ul d  n ot  be  
c o nstr ue d as a mea ns of restricti n g p u blicati o n, b ut is i nte n de d s olel y (a) t o e ns ure c o nc urre nce 
re gar di n g data, e val uati o ns, a n d c o ncl usi o ns, ( b) t o pr o vi de a n o p p ort u nit y t o s hare wit h t he 
In vesti gat or a n y ne w or u n p u blis he d i nf or mati o n of w hic h he or s he ma y be u na ware a n d (c) t o 
e ns ure t hat n o C hias ma c o nfi de ntial i nf or mati o n has bee n i ncl u de d.  If t he S p o ns or belie ve s t hat 
s uc h p u blicati o n or discl os ure c o ntai ns c o nfi de ntial i nf or mati o n, t he I n vesti gat or/a ut h or a grees 
t o re m o ve s uc h c o nfi de ntial i nf or mati o n fr o m t he pr o p ose d p u blicati o n or discl os ure. 
T he i nf or mati o n de vel o pe d d uri n g t he c o n d uct of t his st u d y is als o c o nsi dere d c o nfi de ntial, a n d 
will use d b y C hias ma. T his i nf or mati o n ma y be discl ose d as dee me d necessar y b y C hias ma. T o 
all o w t he use of t his i nf or mati o n deri ve d fr o m t his st u d y, t he I n vesti gat or is o bli ge d t o pr o vi de 
C hias ma wit h c o m plete test res ults a n d  all data c ollecte d a n d de vel o pe d i n t his st u d y. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
1 2  
R E F E R E N C E S  
A bs, R., J. Ver helst, et al. ( 1 9 9 8). " Ca ber g oli ne i n t he treat me nt of acr o me gal y: a st u d y i n 6 4 
patie nts." T he J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m 8 3 ( 2): 3 7 4- 3 7 8. 
Be n -S hl o m o, A. a n d S. Mel me d ( 2 0 0 8). " Acr o me gal y." E n d ocri n ol Meta b Cli n N ort h A m 
3 7 ( 1): 1 0 1- 1 2 2, viii. 
B urt, M. G. a n d K. K. H o ( 2 0 0 6). " Ne wer o pti o ns i n t he ma na ge me nt of acr o me gal y." I nter nal 
me dici ne j o ur nal 3 6 ( 7): 4 3 7- 4 4 4. 
Car o n, P., A. Bec kers, et al. ( 2 0 0 2). " Efficac y of t he ne w l o n g -acti n g f or m ulati o n of la nre oti de 
(la nre oti de A ut o gel)  i n  t he  ma na ge me nt  of  acr o me gal y."  T he  J o ur nal  of  cli nical  
e n d ocri n ol o g y a n d meta b olis m 8 7 ( 1): 9 9- 1 0 4. 
C ha ns o n, P. a n d S. Sale na ve ( 2 0 0 8). " Acr o me gal y." Or p ha net J Rare Dis  3 : 1 7. 
C hieff o, C., D. C o o k, et al. ( 2 0 1 3). " Efficac y a n d safet y of a n octre oti de i m pla nt i n t he 
treat me nt of patie nts wit h acr o me gal y." T he J o ur nal of cli nical e n d ocri n ol o g y a n d 
meta b olis m  9 8 ( 1 0): 4 0 4 7- 4 0 5 4. 
C ola o, A., M. D. Br o nstei n, et al. ( 2 0 1 4). " Pasire oti d e vers us octre oti de i n acr o me gal y: a hea d -
t o-hea d  s u peri orit y  st u d y."  T he  J o ur nal  of  cli nical  e n d ocri n ol o g y  a n d  meta b olis m  
9 9 ( 3): 7 9 1- 7 9 9. 
C ola o, A., A. Di Sar n o, et al. ( 2 0 0 0). " Ne w me dical a p pr oac hes i n pit uitar y a de n o mas."  
H or m o ne researc h  5 3 S u p pl 3 : 76- 8 7.  
C ola o, A., D. Fer o ne, et al. ( 2 0 0 4). " S yste mic C o m plicati o ns of Acr o me gal y: E pi de mi ol o g y, 
Pat h o ge nesis, a n d Ma na ge me nt." E n d ocr Re v 2 5 ( 1): 1 0 2- 1 5 2. 
C ozzi, R., R. Atta nasi o, et al. ( 1 9 9 8). " Ca ber g oli ne i n acr o me gal y: a re ne we d r ole f or d o pa mi ne 
a g o nist  treat me nt?"  E ur o pea n  j o ur nal  of  e n d ocri n ol o g y  /  E ur o pea n  Fe derati o n  of  
E n d ocri ne S ocieties 1 3 9 ( 5): 5 1 6- 5 2 1. 
C ozzi, R., R. Atta nasi o, et al. ( 2 0 0 4). " Ca ber g oli ne a d diti o n t o de p ot s o mat ostati n a nal o g ues 
i n resista nt acr o me galic patie nts: efficac y a n d lac k of pre dicti ve val ue of pr olacti n 
stat us." Cli nical e n d ocri n ol o g y  6 1 ( 2): 2 0 9- 2 1 5. 
C ue vas- Ra m os, D. a n d M. Fleseri u ( 2 0 1 4). " S o mat ostati n rece pt or li ga n ds a n d resista nce t o 
treat me nt i n pit uitar y a de n o mas." J o ur nal of m olec ular e n d ocri n ol o g y 5 2 ( 3): R 2 2 3- 2 4 0. 
Del D ott o, P., A. C olzi, et al. ( 1 9 9 7). " Cli nical a n d p har mac o ki netic e val uati o n of L -d o pa a n d 
ca ber g oli ne c otreat me nt i n Par ki ns o n's disease." Cli nical ne ur o p har mac ol o g y  2 0 ( 5): 
4 5 5- 4 6 5. 
E ur o pea n Me dici nes A ge nc y ( 2 0 1 4). Cer del ga (eli gl ustat) Assess me nt re p ort f or a n i nitial 
mar keti n g a ut h orisati o n a p plicati o n. Pr oce d ure n o. E M E A/ H/ C/ 0 0 3 3 7 2 4. C o m mittee 
f or
 Me dici nal
 Pr o d ucts
 f or
 H u ma n
 Use
 ( C H M P).
 L o n d o n: 
1- 7 5 
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n  G B/ d oc u me nt li brar y/ E P A R -
_ P u blic _assess me nt _re p ort/ h u ma n/ 0 0 3 7 2 4/ W C 5 0 0 1 8 2 3 8 9. p df . 
Ezzat, S. ( 2 0 0 4). " P har mac ol o gical a p pr oac h t o t he treat me nt of acr o me gal y." Ne ur os ur gical 
f oc us 1 6 ( 4): E 3. 
Fleseri u, M. ( 2 0 1 3). " T he r ole of c o m bi nati o n me dical t hera p y i n acr o me gal y: h o pe f or t he 
n o nres p o nsi ve patie nt." C urre nt o pi ni o n i n e n d ocri n ol o g y, dia betes, a n d o besit y 2 0 ( 4): 
3 2 1- 3 2 9. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 0 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
1 2
R E F E R E N C E S  
A bs, R., J. Ver helst, et al. ( 1 9 9 8). " Ca ber g oli ne i n t he treat me nt of acr o me gal y: a st u d y i n 6 4 
patie nts." T he J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m 8 3 ( 2): 3 7 4- 3 7 8. 
Be n -S hl o m o, A. a n d S. Mel me d ( 2 0 0 8). " Acr o me gal y." E n d ocri n ol Meta b Cli n N ort h A m 
3 7 ( 1): 1 0 1- 1 2 2, viii. 
B urt, M. G. a n d K. K. H o ( 2 0 0 6). " Ne wer o pti o ns i n t he ma na ge me nt of acr o me gal y." I nter nal 
me dici ne j o ur nal 3 6 ( 7): 4 3 7- 4 4 4. 
Car o n, P., A. Bec kers, et al. ( 2 0 0 2). " Efficac y of t he ne w l o n g -acti n g f or m ulati o n of la nre oti de 
(la nre oti de A ut o gel)  i n  t he  ma na ge me nt  of  acr o me gal y."  T he  J o ur nal  of  cli nical  
e n d ocri n ol o g y a n d meta b olis m 8 7 ( 1): 9 9- 1 0 4. 
C ha ns o n, P. a n d S. Sale na ve ( 2 0 0 8). " Acr o me gal y." Or p ha net J Rare Dis  3 : 1 7. 
C hieff o, C., D. C o o k, et al. ( 2 0 1 3). " Efficac y a n d safet y of a n octre oti de i m pla nt i n t he 
treat me nt of patie nts wit h acr o me gal y." T he J o ur nal of cli nical e n d ocri n ol o g y a n d 
meta b olis m  9 8 ( 1 0): 4 0 4 7- 4 0 5 4. 
C ola o, A., M. D. Br o nstei n, et al. ( 2 0 1 4). " Pasire oti d e vers us octre oti de i n acr o me gal y: a hea d -
t o-hea d  s u peri orit y  st u d y."  T he  J o ur nal  of  cli nical  e n d ocri n ol o g y  a n d  meta b olis m  
9 9 ( 3): 7 9 1- 7 9 9. 
C ola o, A., A. Di Sar n o, et al. ( 2 0 0 0). " Ne w me dical a p pr oac hes i n pit uitar y a de n o mas."  
H or m o ne researc h  5 3 S u p pl 3 : 76- 8 7.  
C ola o, A., D. Fer o ne, et al. ( 2 0 0 4). " S yste mic C o m plicati o ns of Acr o me gal y: E pi de mi ol o g y, 
Pat h o ge nesis, a n d Ma na ge me nt." E n d ocr Re v 2 5 ( 1): 1 0 2- 1 5 2. 
C ozzi, R., R. Atta nasi o, et al. ( 1 9 9 8). " Ca ber g oli ne i n acr o me gal y: a re ne we d r ole f or d o pa mi ne 
a g o nist  treat me nt?"  E ur o pea n  j o ur nal  of  e n d ocri n ol o g y  /  E ur o pea n  Fe derati o n  of  
E n d ocri ne S ocieties 1 3 9 ( 5): 5 1 6- 5 2 1. 
C ozzi, R., R. Atta nasi o, et al. ( 2 0 0 4). " Ca ber g oli ne a d diti o n t o de p ot s o mat ostati n a nal o g ues 
i n resista nt acr o me galic patie nts: efficac y a n d lac k of pre dicti ve val ue of pr olacti n 
stat us." Cli nical e n d ocri n ol o g y  6 1 ( 2): 2 0 9- 2 1 5. 
C ue vas- Ra m os, D. a n d M. Fleseri u ( 2 0 1 4). " S o mat ostati n rece pt or li ga n ds a n d resista nce t o 
treat me nt i n pit uitar y a de n o mas." J o ur nal of m olec ular e n d ocri n ol o g y 5 2 ( 3): R 2 2 3- 2 4 0. 
Del D ott o, P., A. C olzi, et al. ( 1 9 9 7). " Cli nical a n d p har mac o ki netic e val uati o n of L -d o pa a n d 
ca ber g oli ne c otreat me nt i n Par ki ns o n's disease." Cli nical ne ur o p har mac ol o g y  2 0 ( 5): 
4 5 5- 4 6 5. 
E ur o pea n Me dici nes A ge nc y ( 2 0 1 4). Cer del ga (eli gl ustat) Assess me nt re p ort f or a n i nitial 
mar keti n g a ut h orisati o n a p plicati o n. Pr oce d ure n o. E M E A/ H/ C/ 0 0 3 3 7 2 4. C o m mittee 
f or
 Me dici nal
 Pr o d ucts
 f or
 H u ma n
 Use
 ( C H M P).
 L o n d o n: 
1- 7 5 
htt p:// w w w.e ma.e ur o pa.e u/ d ocs/e n  G B/ d oc u me nt li brar y/ E P A R -
_ P u blic _assess me nt _re p ort/ h u ma n/ 0 0 3 7 2 4/ W C 5 0 0 1 8 2 3 8 9. p df . 
Ezzat, S. ( 2 0 0 4). " P har mac ol o gical a p pr oac h t o t he treat me nt of acr o me gal y." Ne ur os ur gical 
f oc us 1 6 ( 4): E 3. 
Fleseri u, M. ( 2 0 1 3). " T he r ole of c o m bi nati o n me dical t hera p y i n acr o me gal y: h o pe f or t he 
n o nres p o nsi ve patie nt." C urre nt o pi ni o n i n e n d ocri n ol o g y, dia betes, a n d o besit y 2 0 ( 4): 
3 2 1- 3 2 9. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Fleseri u,  M.  ( 2 0 1 4).  " A d va nces  i n  t he  p har mac ot hera p y  of  patie nts  wit h  acr o me gal y."  
Disc o ver y me dici ne  1 7 ( 9 6): 3 2 9- 3 3 8. 
Geer E .B, Sisc o J, A del ma n D .T, et al. ( 2 0 1 9). " O bser ve d disc or da nce bet wee n o utc o mes 
re p orte d b y acr o me gal y patie nts a n d t heir treati n g e n d ocri n ol o g y me dical pr o vi der. " 
Pit uitar y . 2 0 1 9. d oi: 1 0. 1 0 0 7/s 1 1 1 0 2- 0 1 9- 0 1 0 1 3- 2. [ E p u b a hea d of pri nt] 
Gi usti na, A., P. C ha ns o n, et al. ( 2 0 1 4). " E x pert c o nse ns us d oc u me nt: A c o nse ns us o n t he 
me dical treat me nt of acr o me gal y." Nat ure re vie ws. E n d ocri n ol o g y 1 0 ( 4): 2 4 3- 2 4 8. 
Her d ma n, M., C. G u de x, et al. ( 2 0 1 1). " De vel o p me nt a n d preli mi nar y testi n g of t he ne w fi ve -
le vel versi o n of E Q-5 D ( E Q - 5 D- 5 L)." Q ualit y of life researc h : a n i nter nati o nal j o ur nal 
of q ualit y of life as pects of treat me nt, care a n d re ha bilit ati o n 2 0 ( 1 0): 1 7 2 7- 1 7 3 6. 
H ol da wa y, I. M. a n d C. Rajas o or ya ( 1 9 9 9). " E pi de mi ol o g y of acr o me gal y." Pit uitar y  2 ( 1): 2 9-
4 1. 
Jac ks o n, S. N., J. F o wler, et al. ( 1 9 9 7). " Ca ber g oli ne treat me nt of acr o me gal y: a preli mi nar y 
d ose fi n di n g st u d y." Cli nical e n d ocri n ol o g y  4 6 ( 6): 7 4 5- 7 4 9. 
Jaffe, C. A. a n d A. L. Bar ka n ( 1 9 9 2). " Treat me nt of acr o me gal y wit h d o pa mi ne a g o nists." 
E n d ocri n ol o g y a n d meta b olis m cli nics of N ort h A merica  2 1 ( 3): 7 1 3- 7 3 5. 
Jalla d,  R.  S.  a n d  M.  D.  Br o nstei n  ( 2 0 0 9).  " O pti mizi n g  me dical  t hera p y  of  acr o me gal y:  
be neficial  effects  of  ca ber g oli ne  i n  patie nts  u nc o ntr olle d  wit h  l o n g -acti n g  release  
octre oti de." Ne ur oe n d ocri n ol o g y 9 0 ( 1): 8 2- 9 2. 
Katz nels o n,  L.,  J.  L.  At ki ns o n,  et  al.  ( 2 0 1 1).  " A merica n  Ass ociati o n  of  Cli nical  
E n d ocri n ol o gists me dical g ui deli nes f or cli nical practice f or t he dia g n osis a n d treat me nt 
of acr o me gal y --2 0 1 1 u p date." E n d ocri ne practice : official j o ur nal of t he A merica n 
C olle ge of E n d ocri n ol o g y a n d t he A merica n Ass ociati o n of Cli nical E n d ocri n ol o gists  
1 7 S u p pl 4 : 1- 4 4. 
Katz nels o n, L., E. R. La ws, Jr., et al. ( 2 0 1 4). " Acr o me gal y: a n e n d ocri ne s ociet y cli nical 
practice g ui deli ne." T he J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m  9 9 ( 1 1): 
3 9 3 3- 3 9 5 1. 
La ncra nja n, I. a n d A. B. At ki ns o n ( 1 9 9 9). " Res ults of a E ur o pea n m ultice ntre st u d y wit h 
Sa n d ostati n L A R i n acr o me galic patie nts. Sa n d ostati n L A R Gr o u p." Pit uitar y  1 ( 2): 
1 0 5- 1 1 4. 
Mai o ne, L., C. Garcia, et al. ( 2 0 1 2) . " N o e vi de nce of a detri me ntal effect of ca ber g oli ne t hera p y 
o n car diac val ves i n patie nts wit h acr o me gal y." T he J o ur nal of cli nical e n d ocri n ol o g y 
a n d meta b olis m 9 7 ( 9): E 1 7 1 4- 1 7 1 9. 
Ma njila, S., O. C. W u, et al. ( 2 0 1 0). " P har mac ol o gical ma na ge me nt of acr o m e gal y: a c urre nt 
pers pecti ve." Ne ur os ur gical f oc us 2 9 ( 4): E 1 4. 
Maraz uela, M., A. Ra m os -Le vi, et al. ( 2 0 1 4). " Ca ber g oli ne treat me nt i n acr o me gal y: pr os." 
E n d ocri ne 4 6 ( 2): 2 1 5- 2 1 9. 
Mattar, P., M. R. Al ves Marti ns, et al. ( 2 0 1 0). " S h ort - a n d l o n g-ter m efficacy of c o m bi ne d 
ca ber g oli ne  a n d  octre oti de  treat me nt  i n  c o ntr olli n g  i gf -I  le vels  i n  acr o me gal y."  
Ne ur oe n d ocri n ol o g y 9 2 ( 2): 1 2 0- 1 2 7. 
Mel me d, S. ( 2 0 0 9). " Acr o me gal y pat h o ge nesis a n d treat me nt." J Cli n I n vest 1 1 9 ( 1 1): 3 1 8 9-
3 2 0 2. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Mel me d, S., A. C ola o, et al. ( 2 0 0 9). " G ui deli nes f or acr o me gal y ma na ge me nt: a n u p date." J 
Cli n E n d ocri n ol Meta b 9 4 ( 5): 1 5 0 9- 1 5 1 7. 
Mel me d, S., D. L. Klei n ber g, et al. ( 2 0 1 4). " Acr o me gal y: assessi n g t he dis or der a n d na vi gati n g 
t hera pe utic o pti o ns f or treat me nt." E n d ocri ne practice : official j o ur nal of t he A merica n 
C olle ge of E n d ocri n ol o g y a n d t he A merica n Ass ociati o n of Cli nical E n d ocri n ol o gists  
2 0 S u p pl 1 : 7- 1 7; q uiz 1 8- 2 0. 
Mi n niti, G., M. L. Jaffrai n -Rea, et al. ( 1 9 9 7). " Ac ute effects of octre oti de, ca ber g oli ne a n d a 
c o m bi nati o n  of  b ot h  dr u gs  o n  G H  secreti o n  i n  acr o me galic  patie nts."  La  Cli nica  
tera pe utica 1 4 8 ( 1 2): 6 0 1- 6 0 7. 
M o yes, V. J., K. A. Metcalfe, et al. ( 2 0 0 8). " Cli nical use of ca ber g oli ne as pri mar y a n d 
a dj u ncti ve treat me nt f or acr o me gal y." E ur o pea n j o ur nal of e n d ocri n ol o g y / E ur o pea n 
Fe derati o n of E n d ocri ne S ocieties 1 5 9 ( 5): 5 4 1- 5 4 5. 
Nie ma n, L. K. ( 2 0 1 5). Patie nt testi m o nial. 
N o vartis ( 2 0 1 2). Sa n d ostati n ( octre oti de acetate) f or I njecti o n – U S Prescri bi n g I nf or mati o n. 
N o vartis  ( 2 0 1 4).  Sa n d ostati n ®  L A R ®  De p ot  ( octre oti de  acetate  f or  i njecta ble  s us pe nsi o n)  
Prescri bi n g I nf or mati o n. Basel, N o vartis A G. 
Peterse n n, S., A. J. Farrall, et al. ( 2 0 1 4). " L o n g -ter m efficac y a n d safet y of s u bc uta ne o us 
pasire oti de i n acr o me gal y: res ults fr o m a n o pe n -e n de d, m ultice nter, P hase II e xte nsi o n 
st u d y." Pit uitar y  1 7 ( 2): 1 3 2- 1 4 0. 
Peterse n n, S., J. Sc h o p o hl, et al. ( 2 0 1 0). " Pasire oti de ( S O M 2 3 0) de m o nstrates efficac y a n d 
safet y i n patie nts wit h acr o me gal y: a ra n d o mize d, m ultice nter, p hase II trial." T he 
J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m 9 5 ( 6): 2 7 8 1- 2 7 8 9. 
Reill y,  M.  C.,  A.  S.  Z br oze k,  et  al.  ( 1 9 9 3).  " T he  vali dit y  a n d  re pr o d uci bilit y  of  a  w or k  
pr o d ucti vit y a n d acti vit y i m pair me nt i nstr u me nt." P har mac o Ec o n o mics 4 ( 5): 3 5 3- 3 6 5. 
Sa n dret, L., P. Mais o n, et al. ( 2 0 1 1). " Pl ace of ca ber g oli ne i n acr o me gal y: a meta -a nal ysis." 
T he J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m 9 6 ( 5): 1 3 2 7- 1 3 3 5. 
Sel varaja h, D., J. We bst er, et al. ( 2 0 0 5). " Effecti ve ness of a d di n g d o pa mi ne a g o nist t hera p y t o 
l o n g-acti n g  s o mat ostati n  a nal o g ues  i n  t he  ma na ge me nt  of  acr o me gal y."  E ur o pea n 
j o ur nal of e n d ocri n ol o g y / E ur o pea n Fe derati o n of E n d ocri ne S ocieties 1 5 2 ( 4): 5 6 9-
5 7 4. 
Sisc o, J. ( 2 0 1 5). Patie nt testi m o nial. 
Stei n bec k,  K.  a n d  J.  R.  T urtle  ( 1 9 7 9).  " Treat me nt  of  acr o me gal y  wit h  br o m ocr y pti ne."  
A ust ralia n a n d Ne w Zeala n d j o ur nal of me dici ne 9 ( 3): 2 1 7- 2 2 4. 
Stras b ur ger  C .J,  Kara vita ki  N,  St ör ma n n  S,  et  al.  ( 2 0 1 6)."Patie nt -re p orte d  o utc o mes  of  
pare nteral s o mat ostati n a nal o g ue i njecti o ns i n 1 9 5 patie nts wit h acr o me gal y ". E ur J 
E n d ocri n ol. 1 7 4 ( 3): 3 5 5- 3 6 2.  
S u da, K., N. I n os hita, et al. ( 2 0 1 3). " Efficac y of c o m bi ne d octre oti de a n d ca ber g oli ne treat me nt 
i n patie nts wit h acr o me gal y: a retr os pecti ve cli nical st u d y a n d re vie w of t he literat ure." 
E n d ocri ne j o ur nal  6 0 ( 4): 5 0 7- 5 1 5. 
Trai ner, P. J., W. M. Dra ke, et al. ( 2 0 0 0). " Treat me nt of acr o me gal y wit h t he gr o wt h h or m o ne -
rece pt or a nta g o nist pe g vis o ma nt." T he Ne w E n gla n d j o ur nal of me dici ne  3 4 2 ( 1 6): 
1 1 7 1- 1 1 7 7. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
T u via S, Ats m o n J, Teic h ma n S . L, et al ( 2 0 1 2) . "Oral octre oti de a bs or pti o n i n h u ma n s u bjects: 
c o m para ble p har mac o ki netics t o pare nteral octre oti de a n d effecti ve gr o wt h h or m o ne 
s u p pressi o n." J Cli n E n d ocri n ol Meta b. 9 7 ( 7): 2 3 6 2- 2 3 6 9.  
U S De part me nt of Healt h a n d H u ma n Ser vices F o o d a n d Dr u g A d mi nistrati o n ( Dece m ber 
2 0 1 2). Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R). G ui da nce f or I n d ustr y a n d 
I n vesti gat ors:  Safet y  Re p orti n g  Re q uire me nts  f or  I N Ds  a n d  B A/ B E  St u dies  ( draft  
g ui da nce) Dr u g Safet y. 
Valassi, E., A. Kli ba ns ki, et al. ( 2 0 1 0). " Cli nical Re vie w #: P ote ntial car diac val ve effects of 
d o pa mi ne a g o nists i n h y per pr olacti ne mia." T he J o ur nal of cli nical e n d ocri n ol o g y a n d 
meta b olis m  9 5 ( 3): 1 0 2 5- 1 0 3 3. 
Vilar, L., M. F. Aze ve d o, et al. ( 2 0 1 1). " R ole of t he a d diti o n of ca ber g oli ne t o t he ma na ge me nt 
of acr o me galic patie nts resista nt t o l o n gter m treat me nt wit h octre oti de L A R." Pit uitar y  
1 4 ( 2): 1 4 8- 1 5 6. 
Ya n, X. a n d X. G. S u ( 2 0 1 0). " Stratifie d Wils o n a n d Ne wc o m be c o nfi de nce i nter vals f or 
m ulti ple bi n o mial pr o p orti o ns ." Statistics i n Bi o p har mace utical Researc h  2 ( 3): 3 2 9-
3 3 5. 
 
 
 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, A me n d me nt 5  
A p pe n di x A 
St u d y Decisi o n Tree  
 
 
 
 

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 5  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x B 
Sc he d ule of Acti vities  - C ore St u d y – Scree ni n g a n d R u n -i n P h ase 
P ar a meter  
Scree ni n g  
R u n -i n P h ase wit h octre oti de c a ps ules  
St u d y Wee k/ M o nt h  
≥-2 8 da y s 
Baseli ne 1 
W k 1 

 
W k 2 
 
W k 
4 
W k 8  
W k 1 2  
W k 1 6  
W k 2 0  
W k 2 4
2 
W k 
2 5 
W k 
2 6/ E n d 
of R u n -
I n 
Visit Wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
-3 t o 
+ 1 0  
Si g ne d i nf or me d c o nse nt  
X  
  
 
 
  
  
  
  
  
  
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
 
 
  
  
  
  
  
 
 
 X  
Ma g netic Res o na nce I ma gi n g ( M RI)
 3 
X  
 
 
 
 
 
 
 
 
 
 
 
Acr o me gal y Treat me nt Satisfacti o n Q uesti o n naire ( A C R O -T S Q)  
X  
X  
 
 
  
  
  
 
 
  
 
X  
E ur o Q ol –  5 Di me nsi o ns –  5 Le vels  ( E Q-5 D -5 L)  
X  
X  
 
 
  
  
  
  
  
  
 
X  
W or k pr o d ucti vit y q uesti o n naire ( W P AI)  
X  
X  
 
 
 
 
 
 
 
 
 
X  
Me dical hist or y/ de m o gra p hics a n d hei g ht  
X  
  
 
 
  
  
  
  
  
  
 
  
Wei g ht  
X  
X   
 
 
 X  
 X  
 X  
 X  
 X  
 X  
 
X  
He mat ol o g y 4 a n d c he mistr y 5 
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
Fasti n g Plas ma Gl uc ose ( F P G) 6 
X  
 
 
 
 
 
 
 
 
 
 
 
He m o gl o bi n A 1c ( H b A1c)  
X  
  
 
 
  
  
  
  
  
  
 
X  
T h yr oi d -sti m ulati n g h or m o ne ( T S H), free T 4 
  
X  
 
 
  
  
  
  
  
  
 
X  
Li pi d pr ofile 7  
  
X  
 
 
  
  
  
  
  
  
 
X  
Uri nal ysis  
X  
X  
 
 
 
 
 
  
  
 
 
X  
Ser u m pre g na nc y f or w o me n wit h c hil d beari n g p ote ntial  
X  
X 8 
 
 
 
 
 
 
 
 
 
X  
Uri ne pre g na nc y test f or w o me n wit h c hil d beari n g p ote ntial  
 
X  
 
 
 
 
 
 
 
 
 
 
Gr o wt h H or m o n e ( G H, mea n i nte grate d) 9 
X  
X  
 
 
 
 
 
 
 
X  
 
X  
I ns uli n-li ke gr o wt h fact or 1 (I G F-1)  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
A b d o mi nal ( Gall bla d der ) ultras o u n d  
X  
  
 
 
  
  
  
  
  
  
 
X  
C o m plete p h ysical e xa mi nati o n  
X  
  
 
 
  
  
 
  
 
  
 
 
Acr o me gal y directe d p h ysical e xa mi nati o n  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
Acr o me gal y s y m pt o ms - I n de x of Se verit y ( AI S) 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
                                                 
1 Ti me fr o m last d ose s h o ul d n ot e xcee d i njecti o n i nter val + 3 da ys  
2 Wee k 2 4 bi oc he mical res p o nse (I G F -1 a n d G H), will be use d t o deter mi ne res p o nse a n d i ncl usi o n i nt o Ra n d o mize d C o ntr olle d Treat me nt  
3 M RI a vaila ble wit hi n 1 2 m o nt hs pri or t o scree ni n g is acce pta ble . If re m na nts are n ot visi ble or less t ha n 5  m m at last M RI , M RI d o ne wi t hi n 2 years is als o acce pta ble. A C T ca n be d o ne i n place of a n 
M RI if t he M RI is c o ntrai n dicate d . 
4 He mat ol o g y: R B C, H b, Htc, platelets, W B C a n d differe ntial c o u nt  
5 C he mistr y: gl uc ose, t otal bilir u bi n (i n case ele vate d direct a n d i n direct bilir u bi n), al b u mi n, Na, K, Ca, creati ni ne, B U N, p h os p h or us, uric aci d, G O T, G P T, A L P, G G T , L D H , C P K, t otal pr otei n; f or 
a d diti o nal safet y assess me nt i n case of a b n or mal li ver f u ncti o n, see Secti o n 7. 6 . Bl o o d sa m pli n g will be d o ne u n der o ver ni g ht fasti n g c o n diti o ns at all visits e xce pt wee k 2 4/ 2 6, w here o nl y a f o ur - h o ur 
fast is re q uire d. 
6 F or dia betic patie nts o nl y m ust be c ollecte d u n der fasti n g c o n diti o ns.  
7 Li pi d pr ofile = t otal c h olester ol, tri gl y ceri des, H D L a n d L D L  
8 Ser u m pre g na nc y is o nl y a p plica ble f or w o me n patie nts wit h p ositi ve uri ne pre g na nc y test at Baseli ne.  
9 G H: Fi ve sa m ples c ollecte d e ver y 3 0  ±  5 mi n utes o ver t w o h o urs. At scree ni n g fr o m ti me 0 -2 h o urs ( pri or t o S O C S R L a d mi nistrati o n, if pla n ne d), at Baseli ne bef ore octre oti de ca ps ules a d mi nistrat i o n 
fr o m 0-2 h o urs, at all ot her visits 2 -4 h o urs after octr e oti de ca ps ules a d mi nistrati o n. G H assess me nt s h o ul d be d o ne u n der fasti n g c o n diti o ns  (patie nts t o fast 4 h o urs pri or t o a n d t he 2 h o urs after G H 
sa m pli n g) 

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
P ar a meter  
Scree ni n g  
R u n -i n P h ase wit h octre oti de c a ps ules  
St u d y Wee k/ M o nt h  
≥-2 8 da y s 
Baseli ne 1 
W k 1 

 
W k 2 
 
W k 
4 
W k 8  
W k 1 2  
W k 1 6  
W k 2 0  
W k 2 4
2 
W k 
2 5 
W k 
2 6/ E n d 
of R u n -
I n 
Visit Wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
-3 t o 
+ 1 0  
Vital si g ns  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
1 2 -lea d electr ocar di o gra m ( E C G)  
X  
X  
 
 
 
 
 
 
 
 
 
X  
Ec h ocar di o gra m  ( E C H O) - Verif y a vaila bilit y wit hi n t he last 6  
m o nt hs  
 
X 1 0 
 
 
 
X 1 1 
C o nc o mita nt me dicati o n  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
A d verse e ve nts  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
Pre -ra n d o mizati o n  ( n ot a site visit b y patie nt)  
 
 
 
 
 
 
 
 
 
 
X  
 
Ra n d o mi zati o n (call I V R S/I W R S)  
 
 
 
 
 
 
 
 
 
 
 
X  
Dis pe nse st u d y me dicati o n (call I V R S/I W R S) 
 
X  
 
 
X  
X  
X  
X  
X  
X  
 
X 1 2 
St u d y me dicati o n  a d mi nistrati o n at t he site  
 
X  
 
 
 
 
 
 
 
X  
 
X  
D ose titrati o n 1 3 
  
 
 
 
X  
X  
X  
X  
X  
X  
 
 
Dr u g a d mi nistrati o n i nstr ucti o ns  
 
X  
 
 
X  
 
X  
 
 
 
 
X  
C o m plia nce assess me nt  
 
 
X  
X  
X  
 
X  
 
 
 
 
X  
St u d y me dicati o n  acc o u nta bilit y  
  
  
 
 
X  
X  
X  
X  
X  
X  
 
X  
Treat me nt P hase C o m pleti o n  f or m 
 
 
 
 
 
 
 
 
 
 
 
X 
( R u n-
i n) 
                                                 
1 0 O nl y at selecte d sites partici pati n g i n t he C o m bi nati o n p hase s u b -st u d y, a n E C H O s h o ul d be perf or me d f or all patie nts e nr olli n g i nt o t he C o m bi nati o n s u b-st u d y.  F or t h ose sites w h o ca n n ot 
perf or m a n E C H O fr o m t he ti me fra me bet wee n wee k 2 5 (a vaila bilit y of wee k 2 4 I G F -1 a n d G H res ults) a n d wee k 2 6 (e nr oll me nt i nt o t he C o m bi nati o n s u b -st u d y p hase), t he E C H O ma y be 
perf or me d, wit hi n t he i nitial 1 2 wee ks of t he R u n -i n p hase, s o t hat res ults are a vaila ble pri or t o st u d y e ntr y i nt o t he C o m bi nati o n p hase s u b-st u d y  
1 1 Verif y a vaila bilit y of Ec h ocar di o gra m wit hi n t he last si x m o nt hs f or patie nts c o nti n ui n g t o C o m bi nati o n p hase s u b -st u d y (i n selecte d sites).  
1 2 If patie nts are eli gi ble t o e nter R C T p hase, de pe n di n g o n ra n d o mizati o n sc he me, t he y ca n eit her recei ve octre oti de ca ps ules or S R L i njecti o ns; if patie nts eli gi ble t o e nter C o m bi nati o n p hase 
s u b-st u d y (i n selecte d sites), t he y will recei ve octre oti de ca psules + ca ber g oli ne  
1 3 Assess t he nee d t o escalate d ose case d o n pre -defi ne d criteria of bi oc he mical res p o nse a n d s y m pt o matic c o ntr ol   

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x D 
Sc he d ule of Acti vities – C o m bi n ati o n P h ase s u b -st u d y (i n selecte d sites) 
P ar a meter  
 
C o m bi n ati o n P h ase  s u b-st u d y (i n selecte d sites) 1 
St u d y Wee k/ M o nt h  
Da y 0 2 
W k 2 

  
W k 
4  
W k 6 

  
W k 
8  
W k 
1 2  
W k 
1 6  
W k  
2 0  
W k 
2 4  
W k 
2 8  
W k 
3 2  
W k 3 6 / E O T3  
Site visit wi n d o w ( d a ys)  
 
 
± 3  
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
 
 
 
 
 
 
 
X  
Si g ne d i nf or me d c o nse nt f or St u d y E xte nsi o n  
 
 
 
 
 
 
 
 
 
 
 
X  
A C R O -T S Q  
X  
 
 
 
 
 
 
 
 
 
 
X  
E Q -5 D -5 L  
X  
 
 
 
 
 
 
 
 
 
 
X  
W P AI  
X  
 
 
 
 
 
 
 
 
 
 
X  
Wei g ht  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
He mat ol o g y 4 a n d c he mistr y 5 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
He m o gl o bi n A 1c 
X  
 
 
 
 
 
 
 
 
 
 
X  
T S H, free  T 4  
X  
 
 
 
 
 
 
 
 
 
 
X  
Li pi d pr ofile 6  
X  
 
 
 
 
 
 
 
 
 
 
X  
Uri nal ysis  
X  
 
 
 
 
 
 
 
 
 
 
X  
Ser u m pre g na nc y (if a p plica ble) 
X  
 
 
 
 
 
 
 
 
 
 
X  
G H ( mea n i nte grate d) 7 
X  
 
 
 
 
 
 
 
 
 
 
X  
I G F-1  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
Ec h ocar di o gra m  ( E C H O) 
X  
 
 
 
 
X  
 
 
X  
 
 
X  
A b d o mi nal ( Gall bla d der) ultras o u n d  
X  
 
 
 
 
 
 
 
 
 
 
X  
Vital si g ns  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
Acr o me gal y directe d p h ysical e xa mi nati o n  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
AI S  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -lea d electr ocar di o gra m ( E C G) 
X  
 
 
 
 
 
 
 
 
 
 
X  
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Dis pe nse st u d y me dicati o n  (call 
I V R S/I W R S) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Ca ber g oli ne d ose titrati o n i nstr ucti o ns 8  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
                                                 
1 I n selecte d sites w here t he C o m bi nati o n p hase s u b-st u d y is c o n d ucte d, patie nts w h o fail t o res p o n d t o octre oti de ca ps ules 8 0 m g f or at least t w o wee ks t hera p y d uri n g t he c o urse of t he R u n -i n 
p hase, or patie nts i neli gi ble t o e nter t he R C T p hase o n octre oti de ca ps ules 8 0  m g, d ue t o i n -a de q uate bi oc he mical c o ntr ol, wit h I G F - 1 ≥ 1. 3 ×  U L N) will be eli gi ble t o e nter t he C o m bi nati o n 
p hase s u b -st u d y. T hese patie nts will  recei ve c o-a d mi nistrati o n of octre oti de ca ps ules  8 0 m g wit h ca ber g oli ne 
 f or 3 6 wee ks. T he 3 6 wee ks will parallel R C T d urati o n.  
2 T his visit is eit her wee k 2 6 f or s u bjects  n ot eli gi ble t o e nter t he R C T a n d eli gi ble f or C o m bi nati o n p hase s u b -st u d y ( base d o n wee k 2 4 bi oc he mical res p o nse) or a n y earlier visit f or s u bjects w h o 
disc o nti n ue d treat me nt i n t he R u n -i n p hase d ue t o treat me nt fail ure as defi ne d i n t he pr ot oc ol. Visit wi n d o w will be -3 t o + 1 0 da ys.  
3 E O T pr oce d ures will als o be perf or me d f or patie nts w h o earl y disc o nti n ue treat me nt.  
4 He mat ol o g y: R B C, H b, Htc,  platelets  a n d differe ntial c o u nt . 
5 C he mistr y  gl uc ose, t otal bilir u bi n  (i n case ele vate d direct a n d i n direct bilir u bi n), al b u mi n, Na, K, Ca, creati ni ne B U N, p h os p h or us, uric aci d, G O T, G P T, A L P, G G T , L D H , C P K, t otal pr otei n; 
f or a d diti o nal safet y assess me nt i n case of a b n or mal li ver f u ncti o n, see Secti o n 7. 6 . Bl o o d sa m pli n g will be d o ne u n der o ver ni g ht fasti n g c o n diti o ns at all visits e xce pt wee k 3 6. 
6 Li pi d pr ofile = t otal c h olester ol, tri gl y ceri des, H D L a n d L D L . 
7 G H: Fi ve  sa m ples c ollecte d e ver y 3 0 ±  5 mi n utes o ver t w o  h o urs. 2  t o 4 h o urs after octre oti de ca ps ules  a d mi nistrati o n. G H assess me nt s h o ul d be d o ne u n der fasti n g c o n diti o ns ( patie nts t o fast 
4 h o urs pri or t o a n d d uri n g t he 2 h o urs sa m pli n g) 
8 Ca ber g oli ne s h o ul d be ta ke n at di n ner; d ose escalati o n e ver y t w o wee ks  per pr ot oc ol . 

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
P ar a meter  
 
C o m bi n ati o n P h ase  s u b-st u d y (i n selecte d sites) 1 
St u d y Wee k/ M o nt h  
Da y 0 2 
W k 2 

  
W k 
4  
W k 6 

  
W k 
8  
W k 
1 2  
W k 
1 6  
W k  
2 0  
W k 
2 4  
W k 
2 8  
W k 
3 2  
W k 3 6 / E O T3  
Site visit wi n d o w ( d a ys)  
 
 
± 3  
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
Octre oti de ca ps ules at t he site  
X  
 
 
 
 
 
 
 
 
 
 
X  
St u d y me dicati o n acc o u nta bilit y  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
C o m plia nce assess me nt  
 
X  
 
X  
 
 
 
 
 
 
 
 
Acr o me gal y s y m pt o ms b y p h o ne  
 
 
 
 
 
 
 
 
 
 
 
 
Treat me nt P hase C o m pleti o n f or m  
 
 
 
 
 
 
 
 
 
 
 
X 
( C o m bi nati o n) 
A C R O- T S Q = Acr o me gal y Treat me nt Satisfacti o n Q uesti o n naire; AI S = acr o me gal y s y m pt o ms - i n de x of se verit y; E Q- 5 D-5 L = E ur o Q ol – 5 Di me nsi o ns – 5 Le vels; E O T = e n d of treat me nt; 
G H  =  gr o wt h h or m o ne; I G F- 1 =  i ns uli n-li ke gr o wt h fact or 1; I V R S/I W R S – I nteractive v oice/ we b res p o nse s yste m ; T S H  =  t h yr oi d-sti m ulati n g h or m o ne; W k = wee k ; W P AI = W or k 
pr o d ucti vit y q uesti o n naire 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x E 
Sc he d ule of Acti vities – 
 St u d y E xte nsi o n a n d F oll o w-u p P h ases  
 
P ar a meter  
 
St u d y E xte nsi o n P h ase 2 
F U 
P h ase 3 
St u d y Wee k/ M o nt h  
W k 0/ R C T 
Wee k 6 2
4  
W k 1 

6 
 
 
Visit wi n d o w ( da ys)  
 
 
( ± 1 0) 
( ±3 ) 
 
X  
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
Si g ne d i nf or me d c o nse nt  
X  
 
 
 
A C R O -T S Q  
 
 
M o nt hs 3, 6 , 1 2 &  
e ver y 1 2 M  
M o nt h 3 
o nl y 8 
E Q -5 D -5 L  
 
 
W P AI  
 
 
Wei g ht  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
 
He mat ol o g y 9 a n d c he mistr y 1 0 
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
 
He m o gl o bi n A 1c 
 
 
M o nt hs 6, 1 2, & 
e ver y 1 2 M 
 
T S H, free  T 4  
 
 
 
Li pi d pr ofile 1 1  
 
 
 
                                                 
1 A p plica ble f or patie nts w h o c o m plete d t he R C T p hase o n octre oti de ca ps ules wit h I G F- 1 < 1. 3  U L N at t heir last assess me nt (e. g. wee k 5 8 or a n u nsc he d ule d visit)  or are i n t he E xte ns i o n P hase 
wit h I G F - 1 < 1. 3   U L N at t heir last assess me nt .  
2 D uri n g t he first y ear of t he St u d y E xte nsi o n p hase, cli nic visits will be sc he d ule d t o occ ur e ver y 1 2 wee ks ( ± 1 0 da ys). T here after, i n-cli nic visits will occ ur e ver y 2 4 wee ks ( ± 1 0 da ys), wit h 
dis pe nsi n g visits e ver y 1 2 wee ks ( ± 1 0 da ys).  . 
3 F oll o w-u p - f or patie nts w h o pre mat urel y disc o nti n ue d t he st u d y  (a n y p hase), or patie nt i neli gi ble t o e nter R C T p hase or C o m bi nati o n p hase s u b-st u d y or patie nt i neli gi ble or n ot o pti n g i nt o t he 
 st u d y E xte nsi o n p hase  will be d o ne at + 4, + 8 a n d + 1 2 wee ks p ost last d ose of st u d y me dicati o n; patie nts w h o pre mat ure disc o nti n ue fr o m R C T p hase or St u d y 
E xte nsi o n p hase will u n der g o a F oll o w -u p visit 1 2 wee ks after last d os e of st u d y me dicati o n. 
 
 
6 Patie nts w h o s witc he d fr o m S R Ls d uri n g R C T p h ase t o octre oti de ca ps ules  will be c o ntacte d b y p h o ne a wee k after first d ose.  
7 If c o nti n ue t o St u d y E xte nsti o n 
8 A p plica ble o nl y f or patie nts disc o nti n ui n g t he st u d y d uri n g t he R u n -i n or d o n ot c o nti n ue i nt o t he R C T p hase. 
9 He mat ol o g y: R B C, H b, Htc,  pla telets a n d differe ntial c o u nt . 
1 0 C he mistr y gl uc ose, t otal bilir u bi n  (i n case ele vate d direct a n d i n direct bilir u bi n), al b u mi n, Na, K, Ca, creati ni ne  B U N, p h os p h or us, uric aci d, G O T, G P T, A L P, G G T , L D H , C P K, t otal pr otei n; 
f or a d diti o nal safet y assess me nt i n case of a b n or mal li ver f u ncti o n, see Secti o n 7. 6 . Bl o o d sa m pli n g will be d o ne u n der o ver ni g ht fasti n g c o n dit i o ns at all visits. 
1 1 Li pi d pr ofile = t otal c h olester ol, tri gl y ceri des, H D L a n d L D L . 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
P ar a meter  
 
St u d y E xte nsi o n P h ase 2 
F U 
P h ase 3 
St u d y Wee k/ M o nt h  
W k 0/ R C T 
Wee k 6 2
4  
W k 1 

6 
 
 
Visit wi n d o w ( da ys)  
 
 
( ± 1 0) 
( ±3 ) 
Uri nal ysis  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
 
Ser u m pre g na nc y (if a p plica ble) 
 
 
e ver y 6 M 
 
G H ( mea n i nte grate d) 1 2 
 
 
e ver y 1 2 M & last 
visit   
M o nt h 3 
o nl y 
I G F-1  
 
 
M o nt h s 3, 6  
a n d e ver y 6 M  
Oral gl uc ose t olera nce test ( O G T T) 1 3 
 
 
 
 
C o nfir mati o n of disease acti vit y  
 
 
 
 
Ec h ocar di o gra m  ( E C H O) 
 
 
M o nt hs 6, 1 2 a n d 
e ver y 1 2 M 1 4 
 
Vital si g ns  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
Acr o me gal y directe d p h ysical e xa mi nati o n 
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
AI S  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
1 2 -lea d electr ocar di o gra m ( E C G) 
 
 
M o nt hs 6 a n d 1 2  
X  
C o nc o mita nt me dicati o n  
 
X 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
A d verse e ve nts  
 
X 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
Dis pe nse st u d y me dicati o n  (call I V R S/I W R S) 
 
 
E ver y  3 M 
 
Octre oti de ca ps ules at t he site   
 
 
E ver y 1 2 M  
 
Dr u g a d mi nistrati o n i nstr ucti o n  
 
 
M o nt hs 3, 6, 9, 1 2 
 
                                                 
1 2 G H: Fi ve  sa m ples c ollecte d e ver y 3 0 ±  5 mi n utes o ver t w o  h o urs. 2  t o 4 h o urs after octre oti de ca ps ules  a d mi nistrati o n. G H assess me nt s h o ul d be d o ne u n der fasti n g c o n diti o ns ( patie nts t o fast 
4 h o urs pri or t o a n d d uri n g t he 2 h o urs sa m pli n g). 
1 3 Bl o o d sa m pli n g f or O G T T will be d o ne u n der fasti n g c o n diti o ns (at least ei g ht h o urs). Fi ve  sa m ples e ver y 3 0 mi n utes ( 0, 3 0, 6 0, 9 0 a n d 1 2 0 mi n utes)  will be c ollecte d  t o assess gl uc ose a n d 
G H le vels, f oll o wi n g 7 5 g gl uc ose l oa d. If O G T T is c o ntrai n dicate d, a vera ge G H of 7 sa m ples will be ta ke n wit hi n 3 h o urs ≥ 2. 5 n g/ m L.  
1 4 Car diac E C H O will be d o ne at M o nt h 6 a n d 1 2 a n d e ver y 1 2 m o nt hs  o nl y f or patie nts o n c o m bi nati o n of octre oti de ca ps ules a n d ca ber g oli ne ( C o m bi nati o n p hase s u b-st u d y i n selecte d sites). 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x F 
L a beli n g  I nf or m ati o n  f or  S o m at ost ati n  Rece pt or  Li g a n ds  a n d 
C a ber g oli ne 
La bels / pac ka ge i nserts f or o ctre oti de  f or injecti o n (sc a n d L A R) , la nre oti de f or i njecti o n 
( A ut o gel or De pot) , a n d Ca ber g oli ne will be attac he d se paratel y.  
 
Octre oti de f or I njecti o n  
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 0/ 0 1 9 6 6 7s 0 5 8, 0 2 1 0 0 8s 0 2 3l bl. p df   
 
La nre oti de f or I njecti o n ( A ut o gel or De p ot) 
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 1/ 0 2 2 0 7 4s 0 0 3l bl. p df   
 
Ca ber g oli ne  
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 1/ 0 2 0 6 6 4s 0 1 1l bl. p df   
 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x H  
E ur o Q ol – 5 Di me nsi o ns – 5 Le vels He alt h O utc o me q uesti o n n aire ( E Q -
5 D- 5 L) 
U n der eac h hea di n g, please tic k t he O N E b o x t hat best descri bes y o ur healt h T O D A Y. 
M O BI LI T Y  
I ha ve n o pr o ble ms i n wal ki n g a b o ut  
 
I ha ve sli g ht pr o ble ms i n wal ki n g a b o ut  
 
I ha ve m o derate pr o ble ms i n wal ki n g a b o ut  
 
I ha ve se vere pr o ble ms i n wal ki n g a b o ut  
 
I a m u na ble t o wal k a b o ut  
 
 
S E L F -C A R E  
I ha ve n o pr o ble ms was hi n g or dressi n g m yself  
 
I ha ve sli g ht pr o ble ms was hi n g or dressi n g m yself  
 
I ha ve m o derate pr o ble ms was hi n g or dressi n g m yself  
 
I ha ve se vere pr o ble ms was hi n g or dressi n g m yself  
 
I a m u na ble t o was h or dress m yself  
 
 
U S U A L A C TI VI TI E S (e. g. w ork, st u dy, h o use w ork, f a mily or leis ure activities) 
I ha ve n o pr o ble ms d oi n g m y us ual acti vities  
 
I ha ve sli g ht pr o ble ms d oi n g m y us ual acti vities  
 
I ha ve m o derate pr o ble ms d oi n g m y us ual acti vities  
 
I ha ve se vere pr o ble ms d oi n g m y us ual acti vities  
 
I a m u na ble t o d o m y us ual acti vities  
 
 
P AI N / DI S C O M F O R T  
I ha ve n o pai n or disc o mf ort  
 
I ha ve sli g ht pai n or disc o mf ort  
 
I ha ve m o derate pai n or disc o mf ort  
 
I ha ve se vere pai n or disc o mf ort  
 
I ha ve e xtre me pai n or disc o mf ort � 
 
 
A N XI E T Y / D E P R E S SI O N  
I a m n ot a n xi o us or de presse d  
 
I a m sli g htl y a n xi o us or de presse d 
 
I a m m o deratel y a n xi o us or de presse d  
 
I a m se verel y a n xi o us or de presse d  
 
I a m e xtre mel y a n xi o us or de presse d  
 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
U K ( E n glis h) v 2. 0 © 2 0 0 9 E ur o Q o L Gr o u p E Q -5 D ™ is a tr a de m ark of t he E ur o Q o L 
Gr o u p  
 
 
We w o ul d li ke t o k n o w h o w g o o d or b a d y o ur he alt h is T O D A Y.  
T his sc ale is n u m bere d fr o m 0 t o 1 0 0.  
1 0 0
 me a ns
 t he
 best  
he alt h
 y o u
 c a n
 i m a gi ne.  
0 me a ns t he w orst  he alt h y o u c a n i m a gi ne. 
M ar k a n X o n t he sc ale t o i n dic ate h o w y o ur he alt h is T O D A Y.  
N o w, ple ase write t he n u m ber y o u m ar ke d o n t he sc ale i n t he b o x 
bel o w.  
 
 
Y O U R H E A L T H T O D A Y =   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x J  
Acr o me g al y S y m pt o ms - I n de x of Se verit y  
 
Acr o me g al y s y m pt o m 
Se verit y I n de x  
0 
1 
2 
3 
N o S y m pt o ms 
Mil d  M o der ate  Se vere  
He a d ac he  
 
 
 
 
S welli n g of e xtre mities   
 
 
 
J oi nt p ai n 
 
 
 
 
S we ati n g  
 
 
 
 
F ati g ue  
 
 
 
 
 
 
 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 8  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x K  
Decl ar ati o n of Helsi n ki ( 2 0 1 3) 
 
A d o pte d b y t he 1 8t h W M A Ge neral Asse m bl y, Helsi n ki, Fi nla n d, J u ne 1 9 6 4  
a n d a me n de d b y t he:  
2 9t h W M A Ge neral Asse m bl y, T o k y o, Ja pa n, Oct o ber 1 9 7 5  
3 5t h W M A Ge neral Asse m bl y, Ve nice, Ital y, Oct o ber 1 9 8 3 
4 1st W M A Ge neral Asse m bl y, H o n g K o n g, Se pte m ber 1 9 8 9  
4 8t h W M A Ge neral Asse m bl y, S o merset West, Re p u blic of S o ut h Africa, Oct o ber 1 9 9 6  
5 2 n d W M A Ge neral Asse m bl y, E di n b ur g h, Sc otla n d, Oct o ber 2 0 0 0  
5 3r d W M A Ge neral Asse m bl y, W as hi n gt o n D C , U S A, Oct o ber 2 0 0 2 ( N ote of Clarificati o n a d de d) 
5 5t h W M A Ge neral Asse m bl y, T o k y o, Ja pa n, Oct o ber 2 0 0 4 ( N ote of Clarificati o n a d de d)  
5 9t h W M A Ge neral Asse m bl y, Se o ul, Re p u blic of K orea, Oct o ber 2 0 0 8  
6 4t h W M A Ge neral Asse m bl y, F ortaleza, Brazil, Oct o ber 2 0 1 3  
Pre a m ble  
1.  
T he W orl d Me dical Ass ociati o n ( W M A) has de vel o pe d t he Declarati o n of Helsi n ki as a 
state me nt of et hical pri nci ples f or me dical researc h i n v ol vi n g h u ma n s u bjects, i ncl u di n g 
researc h o n i de ntifia ble h u ma n material a n d data. 
T he Declarati o n is i nte n de d t o be rea d as a w h ole a n d eac h of its c o nstit ue nt para gra p hs 
s h o ul d be a p plie d wit h c o nsi derati o n of all ot her rele va nt para gra p hs. 
2.  
C o nsiste nt wit h t he ma n date of t he W M A, t he Declarati o n is a d dresse d pri maril y t o 
p h ysicia ns. T h e W M A e nc o ura ges ot hers w h o are i n v ol ve d i n me dical researc h i n v ol vi n g 
h u ma n s u bjects t o a d o pt t hese pri nci ples. 
Ge ner al Pri nci ples  
3.  
T he Declarati o n of Ge ne va of t he W M A bi n ds t he p h ysicia n wit h t he w or ds, “ T he healt h 
of m y patie nt will be m y first c o ns i derati o n,” a n d t he I nter nati o nal C o de of Me dical 
Et hics declares t hat, “ A p h ysicia n s hall act i n t he patie nt's best i nterest w he n pr o vi di n g 
me dical care.”  
4.   
It is t he d ut y of t he p h ysicia n t o pr o m ote a n d safe g uar d t he healt h, well- bei n g a n d ri g hts 
of  patie nts,  i ncl u di n g  t h ose  w h o  are  i n v ol ve d  i n  me dical  researc h.  T he  p h ysicia n's  
k n o wle d ge a n d c o nscie nce are de dicate d t o t he f ulfil me nt of t his d ut y. 
5.  
Me dical pr o gress is base d o n researc h t hat ulti matel y m ust i ncl u de st u dies i n v ol vi n g 
h u ma n s u bjects. 
6. 
T he pri mar y p ur p ose of me dical researc h i n v ol vi n g h u ma n s u bjects is t o u n dersta n d t he 
ca uses, de vel o p me nt a n d effects of diseases a n d i m pr o ve pre ve nti ve, dia g n ostic a n d 
t hera pe utic i nter ve nti o ns ( met h o ds, pr oce d ures a n d treat me nts). E ve n t he best pr o ve n 
inter ve nti o ns  m ust  be  e val uate d  c o nti n uall y  t hr o u g h  researc h  f or  t heir  safet y,  
effecti ve ness, efficie nc y, accessi bilit y a n d q ualit y.  
7.  
Me dical researc h is s u bject t o et hical sta n dar ds t hat pr o m ote a n d e ns ure res pect f or all 
h u ma n s u bjects a n d pr otect t heir healt h a n d ri g hts. 
8.  
W hile t he pri mar y p ur p ose of me dical researc h is t o ge nerate ne w k n o wle d ge, t his g oal 
ca n ne ver ta ke prece de nce o ver t he ri g hts a n d i nterests of i n di vi d ual researc h s u bjects.  
9. 
It is t he d ut y of p h ysicia ns w h o are i n v ol ve d i n me dical researc h t o pr otect t he life, healt h, 
di g nit y, i nte grit y, ri g ht t o self -deter mi nati o n, pri vac y, a n d c o nfi de ntialit y of pers o nal 
i nf or mati o n of researc h s u bjects. T he res p o nsi bilit y f or t he pr otecti o n of researc h s u bjects 
m ust al wa ys rest wit h t he p h ysi cia n or ot her healt h care pr ofessi o nals a n d ne ver wit h t he 
researc h s u bjects, e ve n t h o u g h t he y ha ve gi ve n c o nse nt. 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
1 0.  
P h ysicia ns  m ust  c o nsi der  t he  et hical,  le gal  a n d  re g ulat or y  n or ms  a n d  sta n dar ds  f or  
researc h  i n v ol vi n g  h u ma n  s u bjects  i n  t heir  o w n  c o u ntries  as  well  as  a p plica ble  
i nter nati o nal n or ms a n d sta n dar ds. N o nati o nal or i nter nati o nal et hical, le gal or re g ulat or y 
re q uire me nt s h o ul d re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h s u bjects set 
f ort h i n t his Declarati o n. 
1 1.  
Me dical researc h s h o ul d be c o n d ucte d i n a ma n ner t hat mi ni mises p ossi ble har m t o t he 
e n vir o n me nt. 
1 2.  
Me dical researc h i n v ol vi n g h u ma n s u bjects m ust be c o n d ucte d o nl y b y i n di vi d uals wit h 
t he a p pr o priate et hics a n d scie ntific e d ucati o n, trai ni n g a n d q ualificati o ns. Research o n 
patie nts or healt h y v ol u nteers re q uires t he s u per visi o n of a c o m pete nt a n d a p pr o priatel y 
q ualifie d p h ysicia n or ot her healt h care pr ofessi o nal. 
1 3.  
Gr o u ps t hat are u n derre prese nte d i n me dical researc h s h o ul d be pr o vi de d a p pr o priate 
access t o partici pati o n i n researc h.  
1 4.  
P h ysicia ns w h o c o m bi ne me dical researc h wit h me dical care s h o ul d i n v ol ve t heir patie nts 
i n researc h o nl y t o t he e xte nt t hat t his is j ustifie d b y its p ote ntial pre ve nti ve, dia g n ostic 
or t hera pe utic val ue a n d if t he p h ysicia n has g o o d  reas o n t o belie ve t hat partici pati o n i n 
t he researc h st u d y will n ot a d versel y affect t he healt h of t he patie nts w h o ser ve as 
researc h s u bjects. 
1 5.  
A p pr o priate c o m pe nsati o n a n d treat me nt f or s u bjects w h o are har me d as a res ult of 
partici pati n g i n researc h m ust be e ns ure d. 
Ris ks, B ur de ns a n d Be nefits  
1 6.  
I n  me dical  practice  a n d  i n  me dical  researc h,  m ost  i nter ve nti o ns  i n v ol ve  ris ks  a n d  
b ur de ns. 
Me dical researc h i n v ol vi n g h u ma n s u bjects ma y o nl y be c o n d ucte d if t he i m p orta nce of 
t he o bjecti ve o ut wei g hs t he ris ks a n d b ur de ns t o t he researc h s u bjects. 
1 7.  
All me dical researc h i n v ol vi n g h u ma n s u bjects m ust be prece de d b y caref ul assess me nt 
of pre dicta ble ris ks a n d b ur de ns t o t he i n di vi d uals a n d gr o u ps i n v ol ve d i n t he researc h i n 
c o m paris o n wit h f oreseea ble be nefits t o t he m a n d t o ot her i n di vi d uals or gr o u ps affecte d 
b y t he c o n diti o n u n der i n vesti gati o n. 
Meas ures t o mi ni mise t he ris ks m ust be i m ple me nte d. T he ris ks m ust be c o nti n u o usl y 
m o nit ore d, assesse d a n d d oc u me nte d b y t he researc her. 
1 8.  
P h ysicia ns ma y n o t be i n v ol ve d i n a researc h st u d y i n v ol vi n g h u ma n s u bjects u nless t he y 
are c o nfi de nt t hat t he ris ks ha ve bee n a de q uatel y assesse d a n d ca n be satisfact oril y 
ma na ge d. 
W he n t he ris ks are f o u n d t o o ut wei g h t he p ote ntial be nefits or w he n t here is c o ncl usi ve 
pr o of of defi niti ve o utc o mes, p h ysicia ns m ust assess w het her t o c o nti n ue, m o dif y or 
i m me diatel y st o p t he st u d y. 
V ul ner a ble Gr o u ps a n d I n di vi d u als  
1 9.  
S o me gr o u ps a n d i n di vi d uals are partic ularl y v ul nera ble a n d ma y ha ve a n i ncrease d 
li keli h o o d of bei n g wr o n ge d or of i nc urri n g a d diti o nal har m. 
All v ul nera ble gr o u ps a n d i n di vi d uals s h o ul d recei ve s pecificall y c o nsi dere d pr otecti o n.  
2 0.  
Me dical researc h wit h a v ul nera ble gr o u p is o nl y j ustifie d if t he researc h is res p o nsi ve 
t o t he healt h nee ds or pri orities of t his gr o u p a n d t he researc h ca n n ot be carrie d o ut i n 
a  n o n-v ul nera ble  gr o u p.  I n  a d diti o n,  t his  gr o u p  s h o ul d  sta n d  t o  be nefit  fr o m  t he  
k n o wle d ge, practices or i nter ve nti o ns t hat res ult fr o m t he researc h.  

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 4 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Scie ntific Re q uire me nts a n d Rese arc h Pr ot oc ols  
2 1.  
Me dical  researc h  i n v ol vi n g  h u ma n  s u bjects  m ust  c o nf or m  t o  ge nerall y  acce pte d  
scie ntific pri nci ples, be base d o n a t h or o u g h k n o wle d ge of t he scie ntific literat ure, ot her 
rele va nt s o urces of i nf or mati o n, a n d a de q uate la b orat or y a n d, as a p pr o priate, a ni mal 
e x peri me ntati o n. T he welfare of a ni mals use d f or researc h m ust be res pecte d.  
2 2.  
T he desi g n a n d perf or ma nce of eac h researc h st u d y i n v ol vi n g h u ma n s u bjects m ust be 
clearl y descri be d a n d j ustifie d i n a researc h pr ot oc ol.  
T he pr ot oc ol s h o ul d c o ntai n a state me nt of t he et hical c o nsi derati o ns i n v ol ve d a n d 
s h o ul d  i n dicate  h o w  t he  pri nci ples  i n  t his  Declarati o n  ha ve  bee n  a d dresse d.  T he  
pr ot oc ol  s h o ul d  i ncl u de  i nf or mati o n  re gar di n g  f u n di n g,  s p o ns ors,  i nstit uti o nal  
affiliati o ns,  p ote ntial  c o nflicts  of  i nterest,  i nce nti ves  f or  s u bjects  a n d  i nf or mati o n  
re gar di n g pr o visi o ns f or treati n g a n d/ or c o m pe nsati n g s u bjects w h o are har me d as a 
c o nse q ue nce of partici pati o n i n t he researc h st u d y. 
I n cli nical trials, t he pr ot oc ol m ust als o descri be a p pr o priate arra n ge me nts f or p ost-trial 
pr o visi o ns. 
Rese arc h Et hics C o m mittees  
2 3.  
T he researc h pr ot oc ol m ust be s u b mitte d f or c o nsi derati o n, c o m me nt, g ui da nce a n d 
a p pr o val t o t he c o ncer ne d researc h et hics c o m mittee bef ore t he st u d y be gi ns. T his 
c o m mittee m ust be tra ns pare nt  i n its f u ncti o ni n g, m ust be i n de pe n de nt of t he researc her, 
t he s p o ns or a n d a n y ot her u n d ue i nfl ue nce a n d m ust be d ul y q ualifie d. It m ust ta ke i nt o 
c o nsi derati o n t he la ws a n d re g ulati o ns of t he c o u ntr y or c o u ntries i n w hic h t he researc h 
is t o be perf or me d as well as a p plica ble i nter nati o nal n or ms a n d sta n dar ds b ut t hese 
m ust n ot be all o we d t o re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h s u bjects 
set f ort h i n t his Declarati o n. 
T he c o m mittee m ust ha ve t he ri g ht t o m o nit or o n g oi n g st u dies. T he resea rc her m ust 
pr o vi de m o nit ori n g i nf or mati o n t o t he c o m mittee, es peciall y i nf or mati o n a b o ut a n y 
seri o us  a d verse  e ve nts.  N o  a me n d me nt  t o  t he  pr ot oc ol  ma y  be  ma de  wit h o ut  
c o nsi derati o n a n d a p pr o val b y t he c o m mittee. After t he e n d of t he st u d y, t he researc hers 
m ust s u b mit a fi nal re p ort t o t he c o m mittee c o ntai ni n g a s u m mar y of t he st u d y’s 
fi n di n gs a n d c o ncl usi o ns. 
Pri v ac y a n d C o nfi de nti alit y  
2 4.  
E ver y preca uti o n m ust be ta ke n t o pr otect t he pri vac y of researc h s u bjects a n d t he 
c o nfi de ntialit y of t heir pers o nal i nf or mati o n. 
I nf or me d C o nse nt  
2 5.  
Partici pati o n b y i n di vi d uals ca pa ble of gi vi n g i nf or me d c o nse nt as s u bjects i n me dical 
researc h m ust be v ol u ntar y. Alt h o u g h it ma y be a p pr o priate t o c o ns ult fa mil y me m bers 
or  c o m m u nit y  lea ders,  n o  i n di vi d ual  ca pa ble  of  gi vi n g  i nf or me d  c o nse nt  ma y  be  
e nr olle d i n a researc h st u d y u nless he or s he freel y a grees.  
2 6.  
I n me dical researc h i n v ol vi n g h u ma n s u bjects ca pa ble of gi vi n g i nf or me d c o nse nt, eac h 
p ote ntial s u bject m ust be a de q uatel y i nf or me d of t he ai ms, met h o ds, s o urces of f u n di n g, 
a n y  p ossi ble  c o nflicts  of  i nterest,  i nstit uti o nal  affiliati o ns  of  t he  researc her,  t he  
a ntici pate d be nefits a n d p ote ntial ris ks of t he st u d y a n d t he disc o mf ort it ma y e ntail, 
p ost- st u d y pr o visi o ns a n d a n y ot her rele va nt as pects of t he st u d y. T he p ote ntial s u bject 
m ust be i nf or me d of t he ri g ht t o ref use t o partici pate i n t he st u d y or t o wit h dra w c o nse nt 
t o partici pate at a n y ti me wit h o ut re prisal. S pecial atte nti o n s h o ul d be gi ve n t o t he 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 4 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
s pecific i nf or mati o n nee ds of i n di vi d ual p ote ntial s u bjects as well as t o t he met h o ds 
use d t o deli ver t he i nf or mati o n. 
After e ns uri n g t hat t he p ote ntial s u bject has u n derst o o d t he i nf or mati o n, t he p h ysicia n 
or a n ot her a p pr o priatel y q ualifie d i n di vi d ual m ust t he n see k t he p ote ntial s u bject’s 
freel y-gi ve n i nf or me d c o nse nt, prefera bl y i n writi n g. If t he c o nse nt ca n n ot be e x presse d 
i n writi n g, t he n o n- writte n c o nse nt m ust be f or mall y d oc u me nte d a n d wit nesse d. 
All me dical researc h s u bjects s h o ul d be gi ve n t he o pti o n of bei n g i nf or me d a b o ut t he 
ge neral o utc o me a n d res ults of t he st u d y. 
2 7.  
W he n see ki n g i nf or me d c o nse nt f or partici pati o n i n a researc h st u d y t he p h ysicia n m ust 
be partic ularl y ca uti o us if t he p ote ntial s u bject is i n a de pe n de nt relati o ns hi p wit h t he 
p h ysicia n or ma y c o nse nt u n der d uress. I n s uc h sit uati o ns t he i nf or me d c o nse nt m ust 
be s o u g ht b y a n a p pr o priatel y q ualifie d i n di vi d ual w h o is c o m pletel y i n de pe n de nt of 
t his relati o ns hi p. 
2 8.  
F or a p ote ntial researc h s u bject w h o is i nca pa ble of gi vi n g i nf or me d c o nse nt, t he 
p h ysicia n m ust see k i nf or me d c o nse nt fr o m t he le gall y a ut h orise d re prese ntati ve. T hese 
i n di vi d uals m ust n ot be i ncl u de d i n a researc h st u d y t hat has n o li keli h o o d of be nefit 
f or t he m u nless it is i nte n de d t o pr o m ote t he healt h of t he gr o u p re prese nte d b y t he 
p ote ntial s u bject, t he res earc h ca n n ot i nstea d be perf or me d wit h pers o ns ca pa ble of 
pr o vi di n g i nf or me d c o nse nt, a n d t he researc h e ntails o nl y mi ni mal ris k a n d mi ni mal 
b ur de n. 
2 9.  
W he n a p ote ntial researc h s u bject w h o is dee me d i nca pa ble of gi vi n g i nf or me d c o nse nt 
is a ble t o gi ve asse nt t o decisi o ns a b o ut partici pati o n i n researc h, t he p h ysicia n m ust 
see k t hat asse nt i n a d diti o n t o t he c o nse nt of t he le gall y a ut h orise d re prese ntati ve. T he 
p ote ntial s u bject’s disse nt s h o ul d be res pecte d. 
3 0.  
Researc h  i n v ol vi n g  s u bjects  w h o  are  p h ysicall y  or  me ntall y  i nca pa ble  of  gi vi n g  
c o nse nt, f or e xa m ple, u nc o nsci o us patie nts, ma y be d o ne o nl y if t he p h ysical or me ntal 
c o n diti o n t hat pre ve nts gi vi n g i nf or me d c o nse nt is a necessar y c haracteristic of t he 
researc h gr o u p. I n s uc h circ u msta nces t he p h ysicia n m ust see k i nf or me d c o nse nt fr o m 
t he le gall y a ut h orise d re prese ntati ve. If n o s uc h re prese ntati ve is a vaila ble a n d if t he 
researc h ca n n ot be dela ye d, t he st u d y ma y pr ocee d wit h o ut i nf or me d c o nse nt pr o vi de d 
t hat t he s pecific reas o ns f or i n v ol vi n g s u bjects wit h a c o n diti o n t hat re n ders t he m u na ble 
t o gi ve i nf or me d c o nse nt ha ve bee n state d i n t he researc h pr ot oc ol a n d t he st u d y has 
bee n a p pr o ve d b y a researc h et hics c o m mittee. C o nse nt t o re mai n i n t he researc h m ust 
be o btai ne d as s o o n as p ossi ble fr o m t he s u bject or a le gall y a ut h orise d re prese ntati ve. 
3 1.  
T he p h ysicia n m ust f ull y i nf or m t he patie nt w hic h as pects of t heir care are relate d t o 
t he researc h. T he ref usal of a patie nt t o partici pate i n a st u d y or t he patie nt’s decisi o n 
t o  wit h dra w  fr o m  t he  st ud y  m ust  ne ver  a d versel y  affect  t he  patie nt - p h ysicia n 
relati o ns hi p. 
3 2.  
F or me dical researc h usi n g i de ntifia ble h u ma n material or data, s uc h as researc h o n 
material or data c o ntai ne d i n bi o ba n ks or si milar re p osit ories, p h ysicia ns m ust see k 
i nf or me d c o nse nt f or its c ollecti o n, st ora ge a n d/ or re use. T here ma y be e xce pti o nal 
sit uati o ns  w here  c o nse nt  w o ul d  be  i m p ossi ble  or  i m practica ble  t o o btai n  f or  s uc h 
researc h. I n s uc h sit uati o ns t he researc h ma y be d o ne o nl y after c o nsi derati o n a n d 
a p pr o val of a researc h et hics c o m mittee.  
Use of Pl ace b o  
3 3.  
T he be nefits, ris ks, b ur de ns a n d effecti ve ness of a ne w i nter ve nti o n m ust be teste d 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
 
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 4 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
a gai nst t h ose of t he best pr o ve n i nter ve nti o n(s), e xce pt i n t he f oll o wi n g circ u msta nces:  
W here  n o  pr o ve n  i nter ve nti o n  e xists,  t he  use  of  place b o,  or  n o  i nter ve nti o n,  is  
acce pta ble; or  
W here f or c o m pelli n g a n d scie ntificall y s o u n d met h o d ol o gical reas o ns t he use of a n y 
i nter ve nti o n  less  effecti ve  t ha n  t he  best  pr o ve n  o ne,  t he  use  of  place b o,  or  n o  
i nter ve nti o n is necessar y t o deter mi ne t he efficac y or safet y of a n i nter ve nti o n  
a n d t he patie nts w h o recei ve a n y i nter ve nti o n less effecti ve t ha n t he best pr o ve n o ne, 
place b o,  or  n o  i nter ve nti o n  will  n ot  be  s u bject  t o  a d diti o nal  ris ks  of  seri o us  or  
irre versi ble har m as a res ult of n ot recei vi n g t he best pr o ve n i nter ve nti o n. 
E xtre me care m ust be ta ke n t o a v oi d a b use of t his o pti o n. 
P ost -Tri al Pr o visi o ns  
3 4.  
I n a d va nce of a cli nical trial, s p o ns ors, researc hers a n d h ost c o u ntr y g o ver n me nts 
s h o ul d  ma ke  pr o visi o ns  f or  p ost-trial  access  f or  all  partici pa nts  w h o  still  nee d  a n  
i nter ve nti o n i de ntifie d as be neficial i n t he trial. T his i nf or mati o n m ust als o be discl ose d 
t o partici pa nts d uri n g t he i nf or me d c o nse nt pr ocess. 
Rese arc h Re gistr ati o n a n d P u blic ati o n a n d Disse mi n ati o n of Res ults  
3 5. 
E ver y  researc h  st u d y  i n v ol vi n g  h u ma n  s u bjects  m ust  be  re gistere d  i n  a  p u blicl y  
accessi ble data base bef ore recr uit me nt of t he first s u bject.  
3 6.  
Researc hers, a ut h ors, s p o ns ors, e dit ors a n d p u blis hers all ha ve et hical o bli gati o ns wit h 
re gar d t o t he p u blicati o n a n d disse mi nati o n of t he res ults of researc h. Researc hers ha ve 
a d ut y t o ma ke p u blicl y a vaila ble t he res ults of t heir researc h o n h u ma n s u bjects a n d 
are acc o u nta ble f or t he c o m plete ness a n d acc urac y of t heir re p orts. All parties s h o ul d 
a d here t o acce pte d g ui deli nes f or et hical re p orti n g. Ne gati ve a n d i nc o ncl usi ve as well 
as p ositi ve res ults m ust be p u blis he d or ot her wise ma de p u blicl y a vaila ble. S o urces of 
f u n di n g,  i nstit uti o nal  affiliati o ns  a n d  c o nflicts  of  i nterest  m ust  be  declare d  i n  t he  
p u blicati o n.  Re p orts  of  researc h  n ot  i n  acc or da nce  wit h  t he  pri nci ples  of  t his  
Declarati o n s h o ul d n ot be acce pte d f or p u blicati o n. 
U n pr o ve n I nter ve nti o ns i n Cli nic al Pr actice  
3 7.  
I n t he treat me nt of a n i n di vi d ual patie nt, w here pr o ve n i nter ve nti o ns d o n ot e xist or 
ot her k n o w n i nter ve nti o ns ha ve bee n i neffecti ve, t he p h ysicia n, after see ki n g e x pert 
a d vice, wit h i nf or me d c o nse nt fr o m t he patie nt or a le gall y a ut h orise d re prese ntati ve, 
ma y use a n u n pr o ve n i nter ve nti o n if i n t he p h ysicia n's j u d ge me nt it offers h o pe of 
sa vi n g life, re-esta blis hi n g healt h or alle viati n g s ufferi n g. T his i nter ve nti o n s h o ul d 
s u bse q ue ntl y  be  ma de  t he  o bject  of  researc h,  desi g ne d  t o  e val uate  its  safet y  a n d  
efficac y. I n all cases, ne w i nf or mati o n m ust be rec or de d a n d, w here a p pr o priate, ma de 
p u blicl y a vaila ble.  
© W orl d Me dical Ass ociati o n, I nc. – All Ri g hts reser ve d.  

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Fleseri u,  M.  ( 2 0 1 4).  " A d va nces  i n  t he  p har mac ot hera p y  of  patie nts  wit h  acr o me gal y."  
Disc o ver y me dici ne  1 7 ( 9 6): 3 2 9- 3 3 8. 
Geer E .B, Sisc o J, A del ma n D .T, et al. ( 2 0 1 9). " O bser ve d disc or da nce bet wee n o utc o mes 
re p orte d b y acr o me gal y patie nts a n d t heir treati n g e n d ocri n ol o g y me dical pr o vi der. " 
Pit uitar y . 2 0 1 9. d oi: 1 0. 1 0 0 7/s 1 1 1 0 2- 0 1 9- 0 1 0 1 3- 2. [ E p u b a hea d of pri nt] 
Gi usti na, A., P. C ha ns o n, et al. ( 2 0 1 4). " E x pert c o nse ns us d oc u me nt: A c o nse ns us o n t he 
me dical treat me nt of acr o me gal y." Nat ure re vie ws. E n d ocri n ol o g y 1 0 ( 4): 2 4 3- 2 4 8. 
Her d ma n, M., C. G u de x, et al. ( 2 0 1 1). " De vel o p me nt a n d preli mi nar y testi n g of t he ne w fi ve -
le vel versi o n of E Q-5 D ( E Q - 5 D- 5 L)." Q ualit y of life researc h : a n i nter nati o nal j o ur nal 
of q ualit y of life as pects of treat me nt, care a n d re ha bilit ati o n 2 0 ( 1 0): 1 7 2 7- 1 7 3 6. 
H ol da wa y, I. M. a n d C. Rajas o or ya ( 1 9 9 9). " E pi de mi ol o g y of acr o me gal y." Pit uitar y  2 ( 1): 2 9-
4 1. 
Jac ks o n, S. N., J. F o wler, et al. ( 1 9 9 7). " Ca ber g oli ne treat me nt of acr o me gal y: a preli mi nar y 
d ose fi n di n g st u d y." Cli nical e n d ocri n ol o g y  4 6 ( 6): 7 4 5- 7 4 9. 
Jaffe, C. A. a n d A. L. Bar ka n ( 1 9 9 2). " Treat me nt of acr o me gal y wit h d o pa mi ne a g o nists." 
E n d ocri n ol o g y a n d meta b olis m cli nics of N ort h A merica  2 1 ( 3): 7 1 3- 7 3 5. 
Jalla d,  R.  S.  a n d  M.  D.  Br o nstei n  ( 2 0 0 9).  " O pti mizi n g  me dical  t hera p y  of  acr o me gal y:  
be neficial  effects  of  ca ber g oli ne  i n  patie nts  u nc o ntr olle d  wit h  l o n g -acti n g  release  
octre oti de." Ne ur oe n d ocri n ol o g y 9 0 ( 1): 8 2- 9 2. 
Katz nels o n,  L.,  J.  L.  At ki ns o n,  et  al.  ( 2 0 1 1).  " A merica n  Ass ociati o n  of  Cli nical  
E n d ocri n ol o gists me dical g ui deli nes f or cli nical practice f or t he dia g n osis a n d treat me nt 
of acr o me gal y --2 0 1 1 u p date." E n d ocri ne practice : official j o ur nal of t he A merica n 
C olle ge of E n d ocri n ol o g y a n d t he A merica n Ass ociati o n of Cli nical E n d ocri n ol o gists  
1 7 S u p pl 4 : 1- 4 4. 
Katz nels o n, L., E. R. La ws, Jr., et al. ( 2 0 1 4). " Acr o me gal y: a n e n d ocri ne s ociet y cli nical 
practice g ui deli ne." T he J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m  9 9 ( 1 1): 
3 9 3 3- 3 9 5 1. 
La ncra nja n, I. a n d A. B. At ki ns o n ( 1 9 9 9). " Res ults of a E ur o pea n m ultice ntre st u d y wit h 
Sa n d ostati n L A R i n acr o me galic patie nts. Sa n d ostati n L A R Gr o u p." Pit uitar y  1 ( 2): 
1 0 5- 1 1 4. 
Mai o ne, L., C. Garcia, et al. ( 2 0 1 2) . " N o e vi de nce of a detri me ntal effect of ca ber g oli ne t hera p y 
o n car diac val ves i n patie nts wit h acr o me gal y." T he J o ur nal of cli nical e n d ocri n ol o g y 
a n d meta b olis m 9 7 ( 9): E 1 7 1 4- 1 7 1 9. 
Ma njila, S., O. C. W u, et al. ( 2 0 1 0). " P har mac ol o gical ma na ge me nt of acr o m e gal y: a c urre nt 
pers pecti ve." Ne ur os ur gical f oc us 2 9 ( 4): E 1 4. 
Maraz uela, M., A. Ra m os -Le vi, et al. ( 2 0 1 4). " Ca ber g oli ne treat me nt i n acr o me gal y: pr os." 
E n d ocri ne 4 6 ( 2): 2 1 5- 2 1 9. 
Mattar, P., M. R. Al ves Marti ns, et al. ( 2 0 1 0). " S h ort - a n d l o n g-ter m efficacy of c o m bi ne d 
ca ber g oli ne  a n d  octre oti de  treat me nt  i n  c o ntr olli n g  i gf -I  le vels  i n  acr o me gal y."  
Ne ur oe n d ocri n ol o g y 9 2 ( 2): 1 2 0- 1 2 7. 
Mel me d, S. ( 2 0 0 9). " Acr o me gal y pat h o ge nesis a n d treat me nt." J Cli n I n vest 1 1 9 ( 1 1): 3 1 8 9-
3 2 0 2. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Mel me d, S., A. C ola o, et al. ( 2 0 0 9). " G ui deli nes f or acr o me gal y ma na ge me nt: a n u p date." J 
Cli n E n d ocri n ol Meta b 9 4 ( 5): 1 5 0 9- 1 5 1 7. 
Mel me d, S., D. L. Klei n ber g, et al. ( 2 0 1 4). " Acr o me gal y: assessi n g t he dis or der a n d na vi gati n g 
t hera pe utic o pti o ns f or treat me nt." E n d ocri ne practice : official j o ur nal of t he A merica n 
C olle ge of E n d ocri n ol o g y a n d t he A merica n Ass ociati o n of Cli nical E n d ocri n ol o gists  
2 0 S u p pl 1 : 7- 1 7; q uiz 1 8- 2 0. 
Mi n niti, G., M. L. Jaffrai n -Rea, et al. ( 1 9 9 7). " Ac ute effects of octre oti de, ca ber g oli ne a n d a 
c o m bi nati o n  of  b ot h  dr u gs  o n  G H  secreti o n  i n  acr o me galic  patie nts."  La  Cli nica  
tera pe utica 1 4 8 ( 1 2): 6 0 1- 6 0 7. 
M o yes, V. J., K. A. Metcalfe, et al. ( 2 0 0 8). " Cli nical use of ca ber g oli ne as pri mar y a n d 
a dj u ncti ve treat me nt f or acr o me gal y." E ur o pea n j o ur nal of e n d ocri n ol o g y / E ur o pea n 
Fe derati o n of E n d ocri ne S ocieties 1 5 9 ( 5): 5 4 1- 5 4 5. 
Nie ma n, L. K. ( 2 0 1 5). Patie nt testi m o nial. 
N o vartis ( 2 0 1 2). Sa n d ostati n ( octre oti de acetate) f or I njecti o n – U S Prescri bi n g I nf or mati o n. 
N o vartis  ( 2 0 1 4).  Sa n d ostati n ®  L A R ®  De p ot  ( octre oti de  acetate  f or  i njecta ble  s us pe nsi o n)  
Prescri bi n g I nf or mati o n. Basel, N o vartis A G. 
Peterse n n, S., A. J. Farrall, et al. ( 2 0 1 4). " L o n g -ter m efficac y a n d safet y of s u bc uta ne o us 
pasire oti de i n acr o me gal y: res ults fr o m a n o pe n -e n de d, m ultice nter, P hase II e xte nsi o n 
st u d y." Pit uitar y  1 7 ( 2): 1 3 2- 1 4 0. 
Peterse n n, S., J. Sc h o p o hl, et al. ( 2 0 1 0). " Pasire oti de ( S O M 2 3 0) de m o nstrates efficac y a n d 
safet y i n patie nts wit h acr o me gal y: a ra n d o mize d, m ultice nter, p hase II trial." T he 
J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m 9 5 ( 6): 2 7 8 1- 2 7 8 9. 
Reill y,  M.  C.,  A.  S.  Z br oze k,  et  al.  ( 1 9 9 3).  " T he  vali dit y  a n d  re pr o d uci bilit y  of  a  w or k  
pr o d ucti vit y a n d acti vit y i m pair me nt i nstr u me nt." P har mac o Ec o n o mics 4 ( 5): 3 5 3- 3 6 5. 
Sa n dret, L., P. Mais o n, et al. ( 2 0 1 1). " Pl ace of ca ber g oli ne i n acr o me gal y: a meta -a nal ysis." 
T he J o ur nal of cli nical e n d ocri n ol o g y a n d meta b olis m 9 6 ( 5): 1 3 2 7- 1 3 3 5. 
Sel varaja h, D., J. We bst er, et al. ( 2 0 0 5). " Effecti ve ness of a d di n g d o pa mi ne a g o nist t hera p y t o 
l o n g-acti n g  s o mat ostati n  a nal o g ues  i n  t he  ma na ge me nt  of  acr o me gal y."  E ur o pea n 
j o ur nal of e n d ocri n ol o g y / E ur o pea n Fe derati o n of E n d ocri ne S ocieties 1 5 2 ( 4): 5 6 9-
5 7 4. 
Sisc o, J. ( 2 0 1 5). Patie nt testi m o nial. 
Stei n bec k,  K.  a n d  J.  R.  T urtle  ( 1 9 7 9).  " Treat me nt  of  acr o me gal y  wit h  br o m ocr y pti ne."  
A ust ralia n a n d Ne w Zeala n d j o ur nal of me dici ne 9 ( 3): 2 1 7- 2 2 4. 
Stras b ur ger  C .J,  Kara vita ki  N,  St ör ma n n  S,  et  al.  ( 2 0 1 6)."Patie nt -re p orte d  o utc o mes  of  
pare nteral s o mat ostati n a nal o g ue i njecti o ns i n 1 9 5 patie nts wit h acr o me gal y ". E ur J 
E n d ocri n ol. 1 7 4 ( 3): 3 5 5- 3 6 2.  
S u da, K., N. I n os hita, et al. ( 2 0 1 3). " Efficac y of c o m bi ne d octre oti de a n d ca ber g oli ne treat me nt 
i n patie nts wit h acr o me gal y: a retr os pecti ve cli nical st u d y a n d re vie w of t he literat ure." 
E n d ocri ne j o ur nal  6 0 ( 4): 5 0 7- 5 1 5. 
Trai ner, P. J., W. M. Dra ke, et al. ( 2 0 0 0). " Treat me nt of acr o me gal y wit h t he gr o wt h h or m o ne -
rece pt or a nta g o nist pe g vis o ma nt." T he Ne w E n gla n d j o ur nal of me dici ne  3 4 2 ( 1 6): 
1 1 7 1- 1 1 7 7. 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
T u via S, Ats m o n J, Teic h ma n S . L, et al ( 2 0 1 2) . "Oral octre oti de a bs or pti o n i n h u ma n s u bjects: 
c o m para ble p har mac o ki netics t o pare nteral octre oti de a n d effecti ve gr o wt h h or m o ne 
s u p pressi o n." J Cli n E n d ocri n ol Meta b. 9 7 ( 7): 2 3 6 2- 2 3 6 9.  
U S De part me nt of Healt h a n d H u ma n Ser vices F o o d a n d Dr u g A d mi nistrati o n ( Dece m ber 
2 0 1 2). Ce nter f or Dr u g E val uati o n a n d Researc h ( C D E R). G ui da nce f or I n d ustr y a n d 
I n vesti gat ors:  Safet y  Re p orti n g  Re q uire me nts  f or  I N Ds  a n d  B A/ B E  St u dies  ( draft  
g ui da nce) Dr u g Safet y. 
Valassi, E., A. Kli ba ns ki, et al. ( 2 0 1 0). " Cli nical Re vie w #: P ote ntial car diac val ve effects of 
d o pa mi ne a g o nists i n h y per pr olacti ne mia." T he J o ur nal of cli nical e n d ocri n ol o g y a n d 
meta b olis m  9 5 ( 3): 1 0 2 5- 1 0 3 3. 
Vilar, L., M. F. Aze ve d o, et al. ( 2 0 1 1). " R ole of t he a d diti o n of ca ber g oli ne t o t he ma na ge me nt 
of acr o me galic patie nts resista nt t o l o n gter m treat me nt wit h octre oti de L A R." Pit uitar y  
1 4 ( 2): 1 4 8- 1 5 6. 
Ya n, X. a n d X. G. S u ( 2 0 1 0). " Stratifie d Wils o n a n d Ne wc o m be c o nfi de nce i nter vals f or 
m ulti ple bi n o mial pr o p orti o ns ." Statistics i n Bi o p har mace utical Researc h  2 ( 3): 3 2 9-
3 3 5. 
 

 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, A me n d me nt 5  
A p pe n di x A 
St u d y Decisi o n Tree  
 

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 5  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x B 
Sc he d ule of Acti vities  - C ore St u d y – Scree ni n g a n d R u n -i n P h ase 
P ar a meter  
Scree ni n g  
R u n -i n P h ase wit h octre oti de c a ps ules  
St u d y Wee k/ M o nt h  
≥-2 8 da y s 
Baseli ne 1 
W k 1 

 
W k 2 
 
W k 
4 
W k 8  
W k 1 2  
W k 1 6  
W k 2 0  
W k 2 4
2 
W k 
2 5 
W k 
2 6/ E n d 
of R u n -
I n 
Visit Wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
-3 t o 
+ 1 0  
Si g ne d i nf or me d c o nse nt  
X  
  
 
 
  
  
 
  
  
  
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
X  
 
 
  
  
 
  
  
 
 X  
Ma g netic Res o na nce I ma gi n g ( M RI)
 3 
X  
 
 
 
 
 
 
 
 
 
 
Acr o me gal y Treat me nt Satisfacti o n Q uesti o n naire ( A C R O -T S Q)  
X  
X  
 
 
  
  
 
 
 
  
 
X  
E ur o Q ol –  5 Di me nsi o ns –  5 Le vels  ( E Q-5 D -5 L)  
X  
X  
 
 
  
  
 
  
  
  
 
X  
W or k pr o d ucti vit y q uesti o n naire ( W P AI)  
X  
X  
 
 
 
 
 
 
 
 
X  
Me dical hist or y/ de m o gra p hics a n d hei g ht  
X  
  
 
 
  
  
 
  
  
  
 
  
Wei g ht  
X  
X   
 
 
 X  
 X  
 X  
 X  
 X  
 X  
 
X  
He mat ol o g y 4 a n d c he mistr y 5 
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
Fasti n g Plas ma Gl uc ose ( F P G) 6 
X  
 
 
 
 
 
 
 
 
 
 
He m o gl o bi n A 1c ( H b A1c)  
X  
  
 
 
  
  
 
  
  
  
 
X  
T h yr oi d -sti m ulati n g h or m o ne ( T S H), free T 4 
  
X  
 
 
  
  
 
  
  
  
 
X  
Li pi d pr ofile 7  
  
X  
 
 
  
  
 
  
  
  
 
X  
Uri nal ysis  
X  
X  
 
 
 
 
 
  
  
 
X  
Ser u m pre g na nc y f or w o me n wit h c hil d beari n g p ote ntial
X
X 8
 
 
 
 
 
X
Uri ne pre g na nc y test f or w o me n wit h c hil d beari n g p ote ntial  
 
X  
 
 
 
 
 
 
 
 
 
Gr o wt h H or m o n e ( G H, mea n i nte grate d) 9 
X  
X  
 
 
 
 
 
 
 
X  
 
X  
I ns uli n-li ke gr o wt h fact or 1 (I G F-1)  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
A b d o mi nal ( Gall bla d der ) ultras o u n d  
X  
  
 
 
  
  
  
  
  
  
 
X  
C o m plete p h ysical e xa mi nati o n  
X  
  
 
 
  
  
 
  
 
  
 
 
Acr o me gal y directe d p h ysical e xa mi nati o n  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
Acr o me gal y s y m pt o ms - I n de x of Se verit y ( AI S) 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
1 Ti me fr o m last d ose s h o ul d n ot e xcee d i njecti o n i nter val + 3 da ys  
2 Wee k 2 4 bi oc he mical res p o nse (I G F -1 a n d G H), will be use d t o deter mi ne res p o nse a n d i ncl usi o n i nt o Ra n d o mize d C o ntr olle d Treat me nt  
3 M RI a vaila ble wit hi n 1 2 m o nt hs pri or t o scree ni n g is acce pta ble . If re m na nts are n ot visi ble or less t ha n 5  m m at last M RI , M RI d o ne wi t hi n 2 years is als o acce pta ble. A C T ca n be d o ne i n place of a n 
M RI if t he M RI is c o ntrai n dicate d . 
4 He mat ol o g y: R B C, H b, Htc, platelets, W B C a n d differe ntial c o u nt  
5 C he mistr y: gl uc ose, t otal bilir u bi n (i n case ele vate d direct a n d i n direct bilir u bi n), al b u mi n, Na, K, Ca, creati ni ne, B U N, p h os p h or us, uric aci d, G O T, G P T, A L P, G G T , L D H , C P K, t otal pr otei n; f or 
a d diti o nal safet y assess me nt i n case of a b n or mal li ver f u ncti o n, see Secti o n 7. 6 . Bl o o d sa m pli n g will be d o ne u n der o ver ni g ht fasti n g c o n diti o ns at all visits e xce pt wee k 2 4/ 2 6, w here o nl y a f o ur - h o ur 
fast is re q uire d. 
6 F or dia betic patie nts o nl y m ust be c ollecte d u n der fasti n g c o n diti o ns.  
7 Li pi d pr ofile = t otal c h olester ol, tri gl y ceri des, H D L a n d L D L  
8 Ser u m pre g na nc y is o nl y a p plica ble f or w o me n patie nts wit h p ositi ve uri ne pre g na nc y test at Baseli ne.  
9 G H: Fi ve sa m ples c ollecte d e ver y 3 0  ±  5 mi n utes o ver t w o h o urs. At scree ni n g fr o m ti me 0 -2 h o urs ( pri or t o S O C S R L a d mi nistrati o n, if pla n ne d), at Baseli ne bef ore octre oti de ca ps ules a d mi nistrat i o n 
fr o m 0-2 h o urs, at all ot her visits 2 -4 h o urs after octr e oti de ca ps ules a d mi nistrati o n. G H assess me nt s h o ul d be d o ne u n der fasti n g c o n diti o ns  (patie nts t o fast 4 h o urs pri or t o a n d t he 2 h o urs after G H 
sa m pli n g) 

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 6  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
P ar a meter  
Scree ni n g  
R u n -i n P h ase wit h octre oti de c a ps ules  
St u d y Wee k/ M o nt h  
≥-2 8 da y s 
Baseli ne 1 
W k 1 

 
W k 2 
 
W k 
4 
W k 8  
W k 1 2  
W k 1 6  
W k 2 0  
W k 2 4
2 
W k 
2 5 
W k 
2 6/ E n d 
of R u n -
I n 
Visit Wi n d o w ( d a ys)  
 
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
-3 t o 
+ 1 0  
Vital si g ns  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
1 2 -lea d electr ocar di o gra m ( E C G)  
X  
X  
 
 
 
 
 
 
 
 
X  
Ec h ocar di o gra m ( E C H O) - Verif y a vaila bilit y wit hi n t he last 6
m o nt hs  
 
X 1 0
 
X 1 1
C o nc o mita nt me dicati o n  
X  
X  
 
 
X  
X  
X  
X  
X  
X  
 
X  
A d verse e ve nts  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
X  
Pre -ra n d o mizati o n  ( n ot a site visit b y patie nt)  
 
 
 
 
 
 
 
 
 
X  
 
Ra n d o mi zati o n (call I V R S/I W R S)  
 
 
 
 
 
 
 
 
 
 
X  
Dis pe nse st u d y me dicati o n (call I V R S/I W R S) 
 
X  
 
 
X  
X  
X  
X  
X  
X  
 
X 1 2 
St u d y me dicati o n  a d mi nistrati o n at t he site  
 
X  
 
 
 
 
 
 
 
X  
 
X  
D ose titrati o n 1 3 
  
 
 
 
X  
X  
X  
X  
X  
X  
 
 
Dr u g a d mi nistrati o n i nstr ucti o ns  
 
X  
 
 
X  
 
X  
 
 
 
X  
C o m plia nce assess me nt
X
X
X
X
X
St u d y me dicati o n  acc o u nta bilit y  
  
  
 
 
X  
X  
X  
X  
X  
X  
 
X  
Treat me nt P hase C o m pleti o n  f or m 
 
 
 
 
 
 
 
 
 
 
X 
( R u n-
i n) 
1 0 O nl y at selecte d sites partici pati n g i n t he C o m bi nati o n p hase s u b -st u d y, a n E C H O s h o ul d be perf or me d f or all patie nts e nr olli n g i nt o t he C o m bi nati o n s u b-st u d y.  F or t h ose sites w h o ca n n ot 
perf or m a n E C H O fr o m t he ti me fra me bet wee n wee k 2 5 (a vaila bilit y of wee k 2 4 I G F -1 a n d G H res ults) a n d wee k 2 6 (e nr oll me nt i nt o t he C o m bi nati o n s u b -st u d y p hase), t he E C H O ma y be 
perf or me d, wit hi n t he i nitial 1 2 wee ks of t he R u n -i n p hase, s o t hat res ults are a vaila ble pri or t o st u d y e ntr y i nt o t he C o m bi nati o n p hase s u b-st u d y  
1 1 Verif y a vaila bilit y of Ec h ocar di o gra m wit hi n t he last si x m o nt hs f or patie nts c o nti n ui n g t o C o m bi nati o n p hase s u b -st u d y (i n selecte d sites).  
1 2 If patie nts are eli gi ble t o e nter R C T p hase, de pe n di n g o n ra n d o mizati o n sc he me, t he y ca n eit her recei ve octre oti de ca ps ules or S R L i njecti o ns; if patie nts eli gi ble t o e nter C o m bi nati o n p hase 
s u b-st u d y (i n selecte d sites), t he y will recei ve octre oti de ca psules + ca ber g oli ne  
1 3 Assess t he nee d t o escalate d ose case d o n pre -defi ne d criteria of bi oc he mical res p o nse a n d s y m pt o matic c o ntr ol   

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 1 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x D 
Sc he d ule of Acti vities – C o m bi n ati o n P h ase s u b -st u d y (i n selecte d sites) 
P ar a meter  
 
C o m bi n ati o n P h ase  s u b-st u d y (i n selecte d sites) 1 
St u d y Wee k/ M o nt h  
Da y 0 2 
W k 2 

  
W k 
4  
W k 6 

  
W k 
8  
W k 
1 2  
W k 
1 6  
W k
2 0  
W k 
2 4  
W k 
2 8  
W k 
3 2  
W k 3 6 / E O T3  
Site visit wi n d o w ( d a ys)  
 
 
± 3  
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
 
 
 
 
 
 
 
X  
Si g ne d i nf or me d c o nse nt f or St u d y E xte nsi o n  
 
 
 
 
 
 
 
 
 
 
 
X  
A C R O -T S Q  
X  
 
 
 
 
 
 
 
 
 
 
X  
E Q -5 D -5 L  
X  
 
 
 
 
 
 
 
 
 
 
X  
W P AI  
X  
 
 
 
 
 
 
 
 
 
 
X  
Wei g ht  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
He mat ol o g y 4 a n d c he mistr y 5 
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
He m o gl o bi n A 1c 
X  
 
 
 
 
 
 
 
 
 
 
X  
T S H, free  T 4  
X  
 
 
 
 
 
 
 
 
 
 
X  
Li pi d pr ofile 6  
X  
 
 
 
 
 
 
 
 
 
 
X  
Uri nal ysis  
X  
 
 
 
 
 
 
 
 
 
 
X  
Ser u m pre g na nc y (if a p plica ble) 
X  
 
 
 
 
 
 
 
 
 
 
X  
G H ( mea n i nte grate d) 7 
X  
 
 
 
 
 
 
 
 
 
 
X  
I G F-1  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
Ec h ocar di o gra m  ( E C H O) 
X  
 
 
 
 
X  
 
 
X  
 
 
X  
A b d o mi nal ( Gall bla d der) ultras o u n d  
X  
 
 
 
 
 
 
 
 
 
 
X  
Vital si g ns  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
Acr o me gal y directe d p h ysical e xa mi nati o n  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
AI S  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
1 2 -lea d electr ocar di o gra m ( E C G) 
X  
 
 
 
 
 
 
 
 
 
 
X  
C o nc o mita nt me dicati o n  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
A d verse e ve nts  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
Dis pe nse st u d y me dicati o n  (call 
I V R S/I W R S) 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
Ca ber g oli ne d ose titrati o n i nstr ucti o ns 8  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
1 I n selecte d sites w here t he C o m bi nati o n p hase s u b-st u d y is c o n d ucte d, patie nts w h o fail t o res p o n d t o octre oti de ca ps ules 8 0 m g f or at least t w o wee ks t hera p y d uri n g t he c o urse of t he R u n -i n 
p hase, or patie nts i neli gi ble t o e nter t he R C T p hase o n octre oti de ca ps ules 8 0  m g, d ue t o i n -a de q uate bi oc he mical c o ntr ol, wit h I G F - 1 ≥ 1. 3 ×  U L N) will be eli gi ble t o e nter t he C o m bi nati o n 
p hase s u b -st u d y. T hese patie nts will  recei ve c o-a d mi nistrati o n of octre oti de ca ps ules  8 0 m g wit h ca ber g oli ne 
 f or 3 6 wee ks. T he 3 6 wee ks will parallel R C T d urati o n.  
2 T his visit is eit her wee k 2 6 f or s u bjects  n ot eli gi ble t o e nter t he R C T a n d eli gi ble f or C o m bi nati o n p hase s u b -st u d y ( base d o n wee k 2 4 bi oc he mical res p o nse) or a n y earlier visit f or s u bjects w h o 
disc o nti n ue d treat me nt i n t he R u n -i n p hase d ue t o treat me nt fail ure as defi ne d i n t he pr ot oc ol. Visit wi n d o w will be -3 t o + 1 0 da ys.  
3 E O T pr oce d ures will als o be perf or me d f or patie nts w h o earl y disc o nti n ue treat me nt.  
4 He mat ol o g y: R B C, H b, Htc,  platelets  a n d differe ntial c o u nt . 
5 C he mistr y  gl uc ose, t otal bilir u bi n  (i n case ele vate d direct a n d i n direct bilir u bi n), al b u mi n, Na, K, Ca, creati ni ne B U N, p h os p h or us, uric aci d, G O T, G P T, A L P, G G T , L D H , C P K, t otal pr otei n; 
f or a d diti o nal safet y assess me nt i n case of a b n or mal li ver f u ncti o n, see Secti o n 7. 6 . Bl o o d sa m pli n g will be d o ne u n der o ver ni g ht fasti n g c o n diti o ns at all visits e xce pt wee k 3 6. 
6 Li pi d pr ofile = t otal c h olester ol, tri gl y ceri des, H D L a n d L D L . 
7 G H: Fi ve  sa m ples c ollecte d e ver y 3 0 ±  5 mi n utes o ver t w o  h o urs. 2  t o 4 h o urs after octre oti de ca ps ules  a d mi nistrati o n. G H assess me nt s h o ul d be d o ne u n der fasti n g c o n diti o ns ( patie nts t o fast 
4 h o urs pri or t o a n d d uri n g t he 2 h o urs sa m pli n g) 
8 Ca ber g oli ne s h o ul d be ta ke n at di n ner; d ose escalati o n e ver y t w o wee ks  per pr ot oc ol . 

 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
P ar a meter  
 
C o m bi n ati o n P h ase  s u b-st u d y (i n selecte d sites) 1 
St u d y Wee k/ M o nt h  
Da y 0 2 
W k 2 

  
W k 
4  
W k 6 

  
W k 
8  
W k 
1 2  
W k 
1 6  
W k
2 0  
W k 
2 4  
W k 
2 8  
W k 
3 2  
W k 3 6 / E O T3  
Site visit wi n d o w ( d a ys)  
 
 
± 3  
 
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
± 3  
 
Octre oti de ca ps ules at t he site  
X  
 
 
 
 
 
 
 
 
 
 
X  
St u d y me dicati o n acc o u nta bilit y  
X  
 
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
C o m plia nce assess me nt  
 
X  
 
X  
 
 
 
 
 
 
 
 
Acr o me gal y s y m pt o ms b y p h o ne  
 
 
 
 
 
 
 
 
 
 
 
 
Treat me nt P hase C o m pleti o n f or m  
 
 
 
 
 
 
 
 
 
 
 
X 
( C o m bi nati o n) 
A C R O- T S Q = Acr o me gal y Treat me nt Satisfacti o n Q uesti o n naire; AI S = acr o me gal y s y m pt o ms - i n de x of se verit y; E Q- 5 D-5 L = E ur o Q ol – 5 Di me nsi o ns – 5 Le vels; E O T = e n d of treat me nt; 
G H  =  gr o wt h h or m o ne; I G F- 1 =  i ns uli n-li ke gr o wt h fact or 1; I V R S/I W R S – I nteractive v oice/ we b res p o nse s yste m ; T S H  =  t h yr oi d-sti m ulati n g h or m o ne; W k = wee k ; W P AI = W or k 
pr o d ucti vit y q uesti o n naire 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x E 
Sc he d ule of Acti vities – 
 St u d y E xte nsi o n a n d F oll o w-u p P h ases  
P ar a meter  
 
St u d y E xte nsi o n P h ase 2 
F U 
P h ase 3 
St u d y Wee k/ M o nt h  
W k 0/ R C T 
Wee k 6 2
4  
W k 1 

6 
 
 
Visit wi n d o w ( da ys)  
 
 
( ± 1 0) 
( ±3 ) 
 
X  
 
 
 
I ncl usi o n/e xcl usi o n criteria 
X  
 
 
 
Si g ne d i nf or me d c o nse nt  
X  
 
 
 
A C R O -T S Q  
 
 
M o nt hs 3, 6 , 1 2 &  
e ver y 1 2 M  
M o nt h 3 
o nl y 8 
E Q -5 D -5 L
W P AI  
 
 
Wei g ht  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
 
He mat ol o g y 9 a n d c he mistr y 1 0 
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
 
He m o gl o bi n A 1c 
 
 
M o nt hs 6, 1 2, & 
e ver y 1 2 M 
 
T S H, free  T 4  
 
 
 
Li pi d pr ofile 1 1  
 
 
 
1 A p plica ble f or patie nts w h o c o m plete d t he R C T p hase o n octre oti de ca ps ules wit h I G F- 1 < 1. 3  U L N at t heir last assess me nt (e. g. wee k 5 8 or a n u nsc he d ule d visit)  or are i n t he E xte ns i o n P hase 
wit h I G F - 1 < 1. 3   U L N at t heir last assess me nt .  
2 D uri n g t he first y ear of t he St u d y E xte nsi o n p hase, cli nic visits will be sc he d ule d t o occ ur e ver y 1 2 wee ks ( ± 1 0 da ys). T here after, i n-cli nic visits will occ ur e ver y 2 4 wee ks ( ± 1 0 da ys), wit h 
dis pe nsi n g visits e ver y 1 2 wee ks ( ± 1 0 da ys).  . 
3 F oll o w-u p - f or patie nts w h o pre mat urel y disc o nti n ue d t he st u d y  (a n y p hase), or patie nt i neli gi ble t o e nter R C T p hase or C o m bi nati o n p hase s u b-st u d y or patie nt i neli gi ble or n ot o pti n g i nt o t he 
 st u d y E xte nsi o n p hase  will be d o ne at + 4, + 8 a n d + 1 2 wee ks p ost last d ose of st u d y me dicati o n; patie nts w h o pre mat ure disc o nti n ue fr o m R C T p hase or St u d y 
E xte nsi o n p hase will u n der g o a F oll o w -u p visit 1 2 wee ks after last d os e of st u d y me dicati o n. 
 
 
6 Patie nts w h o s witc he d fr o m S R Ls d uri n g R C T p h ase t o octre oti de ca ps ules  will be c o ntacte d b y p h o ne a wee k after first d ose.  
7 If c o nti n ue t o St u d y E xte nsti o n 
8 A p plica ble o nl y f or patie nts disc o nti n ui n g t he st u d y d uri n g t he R u n -i n or d o n ot c o nti n ue i nt o t he R C T p hase. 
9 He mat ol o g y: R B C, H b, Htc, pla telets a n d differe ntial c o u nt . 
1 0 C he mistr y gl uc ose, t otal bilir u bi n  (i n case ele vate d direct a n d i n direct bilir u bi n), al b u mi n, Na, K, Ca, creati ni ne  B U N, p h os p h or us, uric aci d, G O T, G P T, A L P, G G T , L D H , C P K, t otal pr otei n; 
f or a d diti o nal safet y assess me nt i n case of a b n or mal li ver f u ncti o n, see Secti o n 7. 6 . Bl o o d sa m pli n g will be d o ne u n der o ver ni g ht fasti n g c o n dit i o ns at all visits. 
1 1 Li pi d pr ofile = t otal c h olester ol, tri gl y ceri des, H D L a n d L D L . 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
P ar a meter  
 
St u d y E xte nsi o n P h ase 2 
F U 
P h ase 3 
St u d y Wee k/ M o nt h  
W k 0/ R C T 
Wee k 6 2
4  
W k 1 

6 
 
 
Visit wi n d o w ( da ys)  
 
 
( ± 1 0) 
( ±3 ) 
Uri nal ysis  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
 
Ser u m pre g na nc y (if a p plica ble)
e ver y 6 M
G H ( mea n i nte grate d) 1 2 
 
 
e ver y 1 2 M & last 
visit   
M o nt h 3 
o nl y 
I G F-1  
 
 
M o nt h s 3, 6  
a n d e ver y 6 M  
Oral gl uc ose t olera nce test ( O G T T) 1 3 
 
 
 
 
C o nfir mati o n of disease acti vit y  
 
 
 
 
Ec h ocar di o gra m  ( E C H O) 
 
 
M o nt hs 6, 1 2 a n d 
e ver y 1 2 M 1 4 
 
Vital si g ns  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
Acr o me gal y directe d p h ysical e xa mi nati o n 
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
AI S  
 
 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
1 2 -lea d electr ocar di o gra m ( E C G) 
 
 
M o nt hs 6 a n d 1 2  
X  
C o nc o mita nt me dicati o n  
 
X 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
A d verse e ve nts  
 
X 
M o nt hs 3, 6, 9, 1 2 
a n d e ver y 6 M  
X 
Dis pe nse st u d y me dicati o n  (call I V R S/I W R S) 
 
 
E ver y  3 M 
 
Octre oti de ca ps ules at t he site   
 
 
E ver y 1 2 M  
 
Dr u g a d mi nistrati o n i nstr ucti o n  
 
 
M o nt hs 3, 6, 9, 1 2 
 
1 2 G H: Fi ve  sa m ples c ollecte d e ver y 3 0 ±  5 mi n utes o ver t w o  h o urs. 2  t o 4 h o urs after octre oti de ca ps ules  a d mi nistrati o n. G H assess me nt s h o ul d be d o ne u n der fasti n g c o n diti o ns ( patie nts t o fast 
4 h o urs pri or t o a n d d uri n g t he 2 h o urs sa m pli n g). 
1 3 Bl o o d sa m pli n g f or O G T T will be d o ne u n der fasti n g c o n diti o ns (at least ei g ht h o urs). Fi ve  sa m ples e ver y 3 0 mi n utes ( 0, 3 0, 6 0, 9 0 a n d 1 2 0 mi n utes)  will be c ollecte d  t o assess gl uc ose a n d 
G H le vels, f oll o wi n g 7 5 g gl uc ose l oa d. If O G T T is c o ntrai n dicate d, a vera ge G H of 7 sa m ples will be ta ke n wit hi n 3 h o urs ≥ 2. 5 n g/ m L.  
1 4 Car diac E C H O will be d o ne at M o nt h 6 a n d 1 2 a n d e ver y 1 2 m o nt hs  o nl y f or patie nts o n c o m bi nati o n of octre oti de ca ps ules a n d ca ber g oli ne ( C o m bi nati o n p hase s u b-st u d y i n selecte d sites). 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 2 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x F 
L a beli n g  I nf or m ati o n  f or  S o m at ost ati n  Rece pt or  Li g a n ds  a n d 
C a ber g oli ne 
La bels / pac ka ge i nserts f or o ctre oti de  f or injecti o n (sc a n d L A R) , la nre oti de f or i njecti o n 
( A ut o gel or De pot) , a n d Ca ber g oli ne will be attac he d se paratel y.  
 
Octre oti de f or I njecti o n  
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 0/ 0 1 9 6 6 7s 0 5 8, 0 2 1 0 0 8s 0 2 3l bl. p df   
La nre oti de f or I njecti o n ( A ut o gel or De p ot) 
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 1/ 0 2 2 0 7 4s 0 0 3l bl. p df   
Ca ber g oli ne  
htt p:// w w w.access data.f da. g o v/ dr u gsatf da _ d ocs/la bel/ 2 0 1 1/ 0 2 0 6 6 4s 0 1 1l bl. p df   

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 3  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x H  
E ur o Q ol – 5 Di me nsi o ns – 5 Le vels He alt h O utc o me q uesti o n n aire ( E Q -
5 D- 5 L) 
U n der eac h hea di n g, please tic k t he O N E b o x t hat best descri bes y o ur healt h T O D A Y. 
M O BI LI T Y  
I ha ve n o pr o ble ms i n wal ki n g a b o ut  
 
I ha ve sli g ht pr o ble ms i n wal ki n g a b o ut  
 
I ha ve m o derate pr o ble ms i n wal ki n g a b o ut  
 
I ha ve se vere pr o ble ms i n wal ki n g a b o ut  
 
I a m u na ble t o wal k a b o ut  
 
 
S E L F -C A R E  
I ha ve n o pr o ble ms was hi n g or dressi n g m yself  
 
I ha ve sli g ht pr o ble ms was hi n g or dressi n g m yself  
 
I ha ve m o derate pr o ble ms was hi n g or dressi n g m yself  
 
I ha ve se vere pr o ble ms was hi n g or dressi n g m yself  
 
I a m u na ble t o was h or dress m yself  
 
 
U S U A L A C TI VI TI E S (e. g. w ork, st u dy, h o use w ork, f a mily or leis ure activities) 
I ha ve n o pr o ble ms d oi n g m y us ual acti vities  
 
I ha ve sli g ht pr o ble ms d oi n g m y us ual acti vities  
 
I ha ve m o derate pr o ble ms d oi n g m y us ual acti vities  
 
I ha ve se vere pr o ble ms d oi n g m y us ual acti vities  
 
I a m u na ble t o d o m y us ual acti vities  
 
 
P AI N / DI S C O M F O R T  
I ha ve n o pai n or disc o mf ort  
 
I ha ve sli g ht pai n or disc o mf ort  
 
I ha ve m o derate pai n or disc o mf ort  
 
I ha ve se vere pai n or disc o mf ort  
 
I ha ve e xtre me pai n or disc o mf ort � 
 
 
A N XI E T Y / D E P R E S SI O N  
I a m n ot a n xi o us or de presse d  
 
I a m sli g htl y a n xi o us or de presse d 
 
I a m m o deratel y a n xi o us or de presse d  
 
I a m se verel y a n xi o us or de presse d  
 
I a m e xtre mel y a n xi o us or de presse d  
 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 4  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
U K ( E n glis h) v 2. 0 © 2 0 0 9 E ur o Q o L Gr o u p E Q -5 D ™ is a tr a de m ark of t he E ur o Q o L 
Gr o u p  
 
 
We w o ul d li ke t o k n o w h o w g o o d or b a d y o ur he alt h is T O D A Y.  
T his sc ale is n u m bere d fr o m 0 t o 1 0 0.  
1 0 0
 me a ns
 t he
 best  
he alt h
 y o u
 c a n
 i m a gi ne.  
0 me a ns t he w orst  he alt h y o u c a n i m a gi ne. 
M ar k a n X o n t he sc ale t o i n dic ate h o w y o ur he alt h is T O D A Y.  
N o w, ple ase write t he n u m ber y o u m ar ke d o n t he sc ale i n t he b o x 
bel o w.
Y O U R H E A L T H T O D A Y =   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 7  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x J
 Acr o me g al y
 
S y m pt o ms - I n de x of Se verit y  
Acr o me g al y s y m pt o m 
Se verit y I n de x  
0 
1 
2 
3 
N o S y m pt o ms 
Mil d  M o der ate  Se vere  
He a d ac he  
 
 
 
 
S welli n g of e xtre mities   
 
 
 
J oi nt p ai n 
 
 
 
 
S we ati n g  
 
 
 
 
F ati g ue  
 
 
 
 
 
 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 8  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
A p pe n di x K  
Decl ar ati o n of Helsi n ki ( 2 0 1 3) 
A d o pte d b y t he 1 8t h W M A Ge neral Asse m bl y, Helsi n ki, Fi nla n d, J u ne 1 9 6 4  
a n d a me n de d b y t he:  
2 9t h W M A Ge neral Asse m bl y, T o k y o, Ja pa n, Oct o ber 1 9 7 5  
3 5t h W M A Ge neral Asse m bl y, Ve nice, Ital y, Oct o ber 1 9 8 3 
4 1st W M A Ge neral Asse m bl y, H o n g K o n g, Se pte m ber 1 9 8 9  
4 8t h W M A Ge neral Asse m bl y, S o merset West, Re p u blic of S o ut h Africa, Oct o ber 1 9 9 6  
5 2 n d W M A Ge neral Asse m bl y, E di n b ur g h, Sc otla n d, Oct o ber 2 0 0 0  
5 3r d W M A Ge neral Asse m bl y, W as hi n gt o n D C , U S A, Oct o ber 2 0 0 2 ( N ote of Clarificati o n a d de d) 
5 5t h W M A Ge neral Asse m bl y, T o k y o, Ja pa n, Oct o ber 2 0 0 4 ( N ote of Clarificati o n a d de d)  
5 9t h W M A Ge neral Asse m bl y, Se o ul, Re p u blic of K orea, Oct o ber 2 0 0 8  
6 4t h W M A Ge neral Asse m bl y, F ortaleza, Brazil, Oct o ber 2 0 1 3  
Pre a m ble  
1.  
T he W orl d Me dical Ass ociati o n ( W M A) has de vel o pe d t he Declarati o n of Helsi n ki as a 
state me nt of et hical pri nci ples f or me dical researc h i n v ol vi n g h u ma n s u bjects, i ncl u di n g 
researc h o n i de ntifia ble h u ma n material a n d data. 
T he Declarati o n is i nte n de d t o be rea d as a w h ole a n d eac h of its c o nstit ue nt para gra p hs 
s h o ul d be a p plie d wit h c o nsi derati o n of all ot her rele va nt para gra p hs. 
2.  
C o nsiste nt wit h t he ma n date of t he W M A, t he Declarati o n is a d dresse d pri maril y t o 
p h ysicia ns. T h e W M A e nc o ura ges ot hers w h o are i n v ol ve d i n me dical researc h i n v ol vi n g 
h u ma n s u bjects t o a d o pt t hese pri nci ples. 
Ge ner al Pri nci ples  
3.  
T he Declarati o n of Ge ne va of t he W M A bi n ds t he p h ysicia n wit h t he w or ds, “ T he healt h 
of m y patie nt will be m y first c o ns i derati o n,” a n d t he I nter nati o nal C o de of Me dical 
Et hics declares t hat, “ A p h ysicia n s hall act i n t he patie nt's best i nterest w he n pr o vi di n g 
me dical care.”  
4.   
It is t he d ut y of t he p h ysicia n t o pr o m ote a n d safe g uar d t he healt h, well- bei n g a n d ri g hts 
of  patie nts,  i ncl u di n g  t h ose  w h o  are  i n v ol ve d  i n  me dical  researc h.  T he  p h ysicia n's  
k n o wle d ge a n d c o nscie nce are de dicate d t o t he f ulfil me nt of t his d ut y. 
5.  
Me dical pr o gress is base d o n researc h t hat ulti matel y m ust i ncl u de st u dies i n v ol vi n g 
h u ma n s u bjects. 
6. 
T he pri mar y p ur p ose of me dical researc h i n v ol vi n g h u ma n s u bjects is t o u n dersta n d t he 
ca uses, de vel o p me nt a n d effects of diseases a n d i m pr o ve pre ve nti ve, dia g n ostic a n d 
t hera pe utic i nter ve nti o ns ( met h o ds, pr oce d ures a n d treat me nts). E ve n t he best pr o ve n 
inter ve nti o ns  m ust  be  e val uate d  c o nti n uall y  t hr o u g h  researc h  f or  t heir  safet y,  
effecti ve ness, efficie nc y, accessi bilit y a n d q ualit y.  
7.  
Me dical researc h is s u bject t o et hical sta n dar ds t hat pr o m ote a n d e ns ure res pect f or all 
h u ma n s u bjects a n d pr otect t heir healt h a n d ri g hts. 
8.  
W hile t he pri mar y p ur p ose of me dical researc h is t o ge nerate ne w k n o wle d ge, t his g oal 
ca n ne ver ta ke prece de nce o ver t he ri g hts a n d i nterests of i n di vi d ual researc h s u bjects.  
9. 
It is t he d ut y of p h ysicia ns w h o are i n v ol ve d i n me dical researc h t o pr otect t he life, healt h, 
di g nit y, i nte grit y, ri g ht t o self -deter mi nati o n, pri vac y, a n d c o nfi de ntialit y of pers o nal 
i nf or mati o n of researc h s u bjects. T he res p o nsi bilit y f or t he pr otecti o n of researc h s u bjects 
m ust al wa ys rest wit h t he p h ysi cia n or ot her healt h care pr ofessi o nals a n d ne ver wit h t he 
researc h s u bjects, e ve n t h o u g h t he y ha ve gi ve n c o nse nt. 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 3 9  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
1 0.  
P h ysicia ns  m ust  c o nsi der  t he  et hical,  le gal  a n d  re g ulat or y  n or ms  a n d  sta n dar ds  f or  
researc h  i n v ol vi n g  h u ma n  s u bjects  i n  t heir  o w n  c o u ntries  as  well  as  a p plica ble  
i nter nati o nal n or ms a n d sta n dar ds. N o nati o nal or i nter nati o nal et hical, le gal or re g ulat or y 
re q uire me nt s h o ul d re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h s u bjects set 
f ort h i n t his Declarati o n. 
1 1.  
Me dical researc h s h o ul d be c o n d ucte d i n a ma n ner t hat mi ni mises p ossi ble har m t o t he 
e n vir o n me nt. 
1 2.  
Me dical researc h i n v ol vi n g h u ma n s u bjects m ust be c o n d ucte d o nl y b y i n di vi d uals wit h 
t he a p pr o priate et hics a n d scie ntific e d ucati o n, trai ni n g a n d q ualificati o ns. Research o n 
patie nts or healt h y v ol u nteers re q uires t he s u per visi o n of a c o m pete nt a n d a p pr o priatel y 
q ualifie d p h ysicia n or ot her healt h care pr ofessi o nal. 
1 3.  
Gr o u ps t hat are u n derre prese nte d i n me dical researc h s h o ul d be pr o vi de d a p pr o priate 
access t o partici pati o n i n researc h.  
1 4.  
P h ysicia ns w h o c o m bi ne me dical researc h wit h me dical care s h o ul d i n v ol ve t heir patie nts 
i n researc h o nl y t o t he e xte nt t hat t his is j ustifie d b y its p ote ntial pre ve nti ve, dia g n ostic 
or t hera pe utic val ue a n d if t he p h ysicia n has g o o d  reas o n t o belie ve t hat partici pati o n i n 
t he researc h st u d y will n ot a d versel y affect t he healt h of t he patie nts w h o ser ve as 
researc h s u bjects. 
1 5.  
A p pr o priate c o m pe nsati o n a n d treat me nt f or s u bjects w h o are har me d as a res ult of 
partici pati n g i n researc h m ust be e ns ure d. 
Ris ks, B ur de ns a n d Be nefits  
1 6.  
I n  me dical  practice  a n d  i n  me dical  researc h,  m ost  i nter ve nti o ns  i n v ol ve  ris ks  a n d  
b ur de ns. 
Me dical researc h i n v ol vi n g h u ma n s u bjects ma y o nl y be c o n d ucte d if t he i m p orta nce of 
t he o bjecti ve o ut wei g hs t he ris ks a n d b ur de ns t o t he researc h s u bjects. 
1 7.  
All me dical researc h i n v ol vi n g h u ma n s u bjects m ust be prece de d b y caref ul assess me nt 
of pre dicta ble ris ks a n d b ur de ns t o t he i n di vi d uals a n d gr o u ps i n v ol ve d i n t he researc h i n 
c o m paris o n wit h f oreseea ble be nefits t o t he m a n d t o ot her i n di vi d uals or gr o u ps affecte d 
b y t he c o n diti o n u n der i n vesti gati o n. 
Meas ures t o mi ni mise t he ris ks m ust be i m ple me nte d. T he ris ks m ust be c o nti n u o usl y 
m o nit ore d, assesse d a n d d oc u me nte d b y t he researc her. 
1 8.  
P h ysicia ns ma y n o t be i n v ol ve d i n a researc h st u d y i n v ol vi n g h u ma n s u bjects u nless t he y 
are c o nfi de nt t hat t he ris ks ha ve bee n a de q uatel y assesse d a n d ca n be satisfact oril y 
ma na ge d. 
W he n t he ris ks are f o u n d t o o ut wei g h t he p ote ntial be nefits or w he n t here is c o ncl usi ve 
pr o of of defi niti ve o utc o mes, p h ysicia ns m ust assess w het her t o c o nti n ue, m o dif y or 
i m me diatel y st o p t he st u d y. 
V ul ner a ble Gr o u ps a n d I n di vi d u als  
1 9.  
S o me gr o u ps a n d i n di vi d uals are partic ularl y v ul nera ble a n d ma y ha ve a n i ncrease d 
li keli h o o d of bei n g wr o n ge d or of i nc urri n g a d diti o nal har m. 
All v ul nera ble gr o u ps a n d i n di vi d uals s h o ul d recei ve s pecificall y c o nsi dere d pr otecti o n.  
2 0.  
Me dical researc h wit h a v ul nera ble gr o u p is o nl y j ustifie d if t he researc h is res p o nsi ve 
t o t he healt h nee ds or pri orities of t his gr o u p a n d t he researc h ca n n ot be carrie d o ut i n 
a  n o n-v ul nera ble  gr o u p.  I n  a d diti o n,  t his  gr o u p  s h o ul d  sta n d  t o  be nefit  fr o m  t he  
k n o wle d ge, practices or i nter ve nti o ns t hat res ult fr o m t he researc h.  

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 4 0  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
Scie ntific Re q uire me nts a n d Rese arc h Pr ot oc ols  
2 1.  
Me dical  researc h  i n v ol vi n g  h u ma n  s u bjects  m ust  c o nf or m  t o  ge nerall y  acce pte d  
scie ntific pri nci ples, be base d o n a t h or o u g h k n o wle d ge of t he scie ntific literat ure, ot her 
rele va nt s o urces of i nf or mati o n, a n d a de q uate la b orat or y a n d, as a p pr o priate, a ni mal 
e x peri me ntati o n. T he welfare of a ni mals use d f or researc h m ust be res pecte d.  
2 2.  
T he desi g n a n d perf or ma nce of eac h researc h st u d y i n v ol vi n g h u ma n s u bjects m ust be 
clearl y descri be d a n d j ustifie d i n a researc h pr ot oc ol.  
T he pr ot oc ol s h o ul d c o ntai n a state me nt of t he et hical c o nsi derati o ns i n v ol ve d a n d 
s h o ul d  i n dicate  h o w  t he  pri nci ples  i n  t his  Declarati o n  ha ve  bee n  a d dresse d.  T he  
pr ot oc ol  s h o ul d  i ncl u de  i nf or mati o n  re gar di n g  f u n di n g,  s p o ns ors,  i nstit uti o nal  
affiliati o ns,  p ote ntial  c o nflicts  of  i nterest,  i nce nti ves  f or  s u bjects  a n d  i nf or mati o n  
re gar di n g pr o visi o ns f or treati n g a n d/ or c o m pe nsati n g s u bjects w h o are har me d as a 
c o nse q ue nce of partici pati o n i n t he researc h st u d y. 
I n cli nical trials, t he pr ot oc ol m ust als o descri be a p pr o priate arra n ge me nts f or p ost-trial 
pr o visi o ns. 
Rese arc h Et hics C o m mittees  
2 3.  
T he researc h pr ot oc ol m ust be s u b mitte d f or c o nsi derati o n, c o m me nt, g ui da nce a n d 
a p pr o val t o t he c o ncer ne d researc h et hics c o m mittee bef ore t he st u d y be gi ns. T his 
c o m mittee m ust be tra ns pare nt  i n its f u ncti o ni n g, m ust be i n de pe n de nt of t he researc her, 
t he s p o ns or a n d a n y ot her u n d ue i nfl ue nce a n d m ust be d ul y q ualifie d. It m ust ta ke i nt o 
c o nsi derati o n t he la ws a n d re g ulati o ns of t he c o u ntr y or c o u ntries i n w hic h t he researc h 
is t o be perf or me d as well as a p plica ble i nter nati o nal n or ms a n d sta n dar ds b ut t hese 
m ust n ot be all o we d t o re d uce or eli mi nate a n y of t he pr otecti o ns f or researc h s u bjects 
set f ort h i n t his Declarati o n. 
T he c o m mittee m ust ha ve t he ri g ht t o m o nit or o n g oi n g st u dies. T he resea rc her m ust 
pr o vi de m o nit ori n g i nf or mati o n t o t he c o m mittee, es peciall y i nf or mati o n a b o ut a n y 
seri o us  a d verse  e ve nts.  N o  a me n d me nt  t o  t he  pr ot oc ol  ma y  be  ma de  wit h o ut  
c o nsi derati o n a n d a p pr o val b y t he c o m mittee. After t he e n d of t he st u d y, t he researc hers 
m ust s u b mit a fi nal re p ort t o t he c o m mittee c o ntai ni n g a s u m mar y of t he st u d y’s 
fi n di n gs a n d c o ncl usi o ns. 
Pri v ac y a n d C o nfi de nti alit y  
2 4.  
E ver y preca uti o n m ust be ta ke n t o pr otect t he pri vac y of researc h s u bjects a n d t he 
c o nfi de ntialit y of t heir pers o nal i nf or mati o n. 
I nf or me d C o nse nt  
2 5.  
Partici pati o n b y i n di vi d uals ca pa ble of gi vi n g i nf or me d c o nse nt as s u bjects i n me dical 
researc h m ust be v ol u ntar y. Alt h o u g h it ma y be a p pr o priate t o c o ns ult fa mil y me m bers 
or  c o m m u nit y  lea ders,  n o  i n di vi d ual  ca pa ble  of  gi vi n g  i nf or me d  c o nse nt  ma y  be  
e nr olle d i n a researc h st u d y u nless he or s he freel y a grees.  
2 6.  
I n me dical researc h i n v ol vi n g h u ma n s u bjects ca pa ble of gi vi n g i nf or me d c o nse nt, eac h 
p ote ntial s u bject m ust be a de q uatel y i nf or me d of t he ai ms, met h o ds, s o urces of f u n di n g, 
a n y  p ossi ble  c o nflicts  of  i nterest,  i nstit uti o nal  affiliati o ns  of  t he  researc her,  t he  
a ntici pate d be nefits a n d p ote ntial ris ks of t he st u d y a n d t he disc o mf ort it ma y e ntail, 
p ost- st u d y pr o visi o ns a n d a n y ot her rele va nt as pects of t he st u d y. T he p ote ntial s u bject 
m ust be i nf or me d of t he ri g ht t o ref use t o partici pate i n t he st u d y or t o wit h dra w c o nse nt 
t o partici pate at a n y ti me wit h o ut re prisal. S pecial atte nti o n s h o ul d be gi ve n t o t he 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 4 1  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
s pecific i nf or mati o n nee ds of i n di vi d ual p ote ntial s u bjects as well as t o t he met h o ds 
use d t o deli ver t he i nf or mati o n. 
After e ns uri n g t hat t he p ote ntial s u bject has u n derst o o d t he i nf or mati o n, t he p h ysicia n 
or a n ot her a p pr o priatel y q ualifie d i n di vi d ual m ust t he n see k t he p ote ntial s u bject’s 
freel y-gi ve n i nf or me d c o nse nt, prefera bl y i n writi n g. If t he c o nse nt ca n n ot be e x presse d 
i n writi n g, t he n o n- writte n c o nse nt m ust be f or mall y d oc u me nte d a n d wit nesse d. 
All me dical researc h s u bjects s h o ul d be gi ve n t he o pti o n of bei n g i nf or me d a b o ut t he 
ge neral o utc o me a n d res ults of t he st u d y. 
2 7.  
W he n see ki n g i nf or me d c o nse nt f or partici pati o n i n a researc h st u d y t he p h ysicia n m ust 
be partic ularl y ca uti o us if t he p ote ntial s u bject is i n a de pe n de nt relati o ns hi p wit h t he 
p h ysicia n or ma y c o nse nt u n der d uress. I n s uc h sit uati o ns t he i nf or me d c o nse nt m ust 
be s o u g ht b y a n a p pr o priatel y q ualifie d i n di vi d ual w h o is c o m pletel y i n de pe n de nt of 
t his relati o ns hi p. 
2 8.  
F or a p ote ntial researc h s u bject w h o is i nca pa ble of gi vi n g i nf or me d c o nse nt, t he 
p h ysicia n m ust see k i nf or me d c o nse nt fr o m t he le gall y a ut h orise d re prese ntati ve. T hese 
i n di vi d uals m ust n ot be i ncl u de d i n a researc h st u d y t hat has n o li keli h o o d of be nefit 
f or t he m u nless it is i nte n de d t o pr o m ote t he healt h of t he gr o u p re prese nte d b y t he 
p ote ntial s u bject, t he res earc h ca n n ot i nstea d be perf or me d wit h pers o ns ca pa ble of 
pr o vi di n g i nf or me d c o nse nt, a n d t he researc h e ntails o nl y mi ni mal ris k a n d mi ni mal 
b ur de n. 
2 9.  
W he n a p ote ntial researc h s u bject w h o is dee me d i nca pa ble of gi vi n g i nf or me d c o nse nt 
is a ble t o gi ve asse nt t o decisi o ns a b o ut partici pati o n i n researc h, t he p h ysicia n m ust 
see k t hat asse nt i n a d diti o n t o t he c o nse nt of t he le gall y a ut h orise d re prese ntati ve. T he 
p ote ntial s u bject’s disse nt s h o ul d be res pecte d. 
3 0.  
Researc h  i n v ol vi n g  s u bjects  w h o  are  p h ysicall y  or  me ntall y  i nca pa ble  of  gi vi n g  
c o nse nt, f or e xa m ple, u nc o nsci o us patie nts, ma y be d o ne o nl y if t he p h ysical or me ntal 
c o n diti o n t hat pre ve nts gi vi n g i nf or me d c o nse nt is a necessar y c haracteristic of t he 
researc h gr o u p. I n s uc h circ u msta nces t he p h ysicia n m ust see k i nf or me d c o nse nt fr o m 
t he le gall y a ut h orise d re prese ntati ve. If n o s uc h re prese ntati ve is a vaila ble a n d if t he 
researc h ca n n ot be dela ye d, t he st u d y ma y pr ocee d wit h o ut i nf or me d c o nse nt pr o vi de d 
t hat t he s pecific reas o ns f or i n v ol vi n g s u bjects wit h a c o n diti o n t hat re n ders t he m u na ble 
t o gi ve i nf or me d c o nse nt ha ve bee n state d i n t he researc h pr ot oc ol a n d t he st u d y has 
bee n a p pr o ve d b y a researc h et hics c o m mittee. C o nse nt t o re mai n i n t he researc h m ust 
be o btai ne d as s o o n as p ossi ble fr o m t he s u bject or a le gall y a ut h orise d re prese ntati ve. 
3 1.  
T he p h ysicia n m ust f ull y i nf or m t he patie nt w hic h as pects of t heir care are relate d t o 
t he researc h. T he ref usal of a patie nt t o partici pate i n a st u d y or t he patie nt’s decisi o n 
t o  wit h dra w  fr o m  t he  st ud y  m ust  ne ver  a d versel y  affect  t he  patie nt - p h ysicia n 
relati o ns hi p. 
3 2.  
F or me dical researc h usi n g i de ntifia ble h u ma n material or data, s uc h as researc h o n 
material or data c o ntai ne d i n bi o ba n ks or si milar re p osit ories, p h ysicia ns m ust see k 
i nf or me d c o nse nt f or its c ollecti o n, st ora ge a n d/ or re use. T here ma y be e xce pti o nal 
sit uati o ns  w here  c o nse nt  w o ul d  be  i m p ossi ble  or  i m practica ble  t o o btai n  f or  s uc h 
researc h. I n s uc h sit uati o ns t he researc h ma y be d o ne o nl y after c o nsi derati o n a n d 
a p pr o val of a researc h et hics c o m mittee.  
Use of Pl ace b o  
3 3.  
T he be nefits, ris ks, b ur de ns a n d effecti ve ness of a ne w i nter ve nti o n m ust be teste d 

 
 
 
 
 
P RI VI L E G E D & C O N FI D E N TI A L  
Pr ot oc ol O O C -A C M -3 0 2  
Pa ge 1 4 2  of 1 4 2  
Ja n uar y 1 6, 2 0 2 0 
Versi o n 6, 
 
a gai nst t h ose of t he best pr o ve n i nter ve nti o n(s), e xce pt i n t he f oll o wi n g circ u msta nces:  
W here  n o  pr o ve n  i nter ve nti o n  e xists,  t he  use  of  place b o,  or  n o  i nter ve nti o n,  is  
acce pta ble; or  
W here f or c o m pelli n g a n d scie ntificall y s o u n d met h o d ol o gical reas o ns t he use of a n y 
i nter ve nti o n  less  effecti ve  t ha n  t he  best  pr o ve n  o ne,  t he  use  of  place b o,  or  n o  
i nter ve nti o n is necessar y t o deter mi ne t he efficac y or safet y of a n i nter ve nti o n  
a n d t he patie nts w h o recei ve a n y i nter ve nti o n less effecti ve t ha n t he best pr o ve n o ne, 
place b o,  or  n o  i nter ve nti o n  will  n ot  be  s u bject  t o  a d diti o nal  ris ks  of  seri o us  or  
irre versi ble har m as a res ult of n ot recei vi n g t he best pr o ve n i nter ve nti o n. 
E xtre me care m ust be ta ke n t o a v oi d a b use of t his o pti o n. 
P ost -Tri al Pr o visi o ns  
3 4.  
I n a d va nce of a cli nical trial, s p o ns ors, researc hers a n d h ost c o u ntr y g o ver n me nts 
s h o ul d  ma ke  pr o visi o ns  f or  p ost-trial  access  f or  all  partici pa nts  w h o  still  nee d  a n  
i nter ve nti o n i de ntifie d as be neficial i n t he trial. T his i nf or mati o n m ust als o be discl ose d 
t o partici pa nts d uri n g t he i nf or me d c o nse nt pr ocess. 
Rese arc h Re gistr ati o n a n d P u blic ati o n a n d Disse mi n ati o n of Res ults  
3 5. 
E ver y  researc h  st u d y  i n v ol vi n g  h u ma n  s u bjects  m ust  be  re gistere d  i n  a  p u blicl y  
accessi ble data base bef ore recr uit me nt of t he first s u bject.  
3 6.  
Researc hers, a ut h ors, s p o ns ors, e dit ors a n d p u blis hers all ha ve et hical o bli gati o ns wit h 
re gar d t o t he p u blicati o n a n d disse mi nati o n of t he res ults of researc h. Researc hers ha ve 
a d ut y t o ma ke p u blicl y a vaila ble t he res ults of t heir researc h o n h u ma n s u bjects a n d 
are acc o u nta ble f or t he c o m plete ness a n d acc urac y of t heir re p orts. All parties s h o ul d 
a d here t o acce pte d g ui deli nes f or et hical re p orti n g. Ne gati ve a n d i nc o ncl usi ve as well 
as p ositi ve res ults m ust be p u blis he d or ot her wise ma de p u blicl y a vaila ble. S o urces of 
f u n di n g,  i nstit uti o nal  affiliati o ns  a n d  c o nflicts  of  i nterest  m ust  be  declare d  i n  t he  
p u blicati o n.  Re p orts  of  researc h  n ot  i n  acc or da nce  wit h  t he  pri nci ples  of  t his  
Declarati o n s h o ul d n ot be acce pte d f or p u blicati o n. 
U n pr o ve n I nter ve nti o ns i n Cli nic al Pr actice  
3 7.  
I n t he treat me nt of a n i n di vi d ual patie nt, w here pr o ve n i nter ve nti o ns d o n ot e xist or 
ot her k n o w n i nter ve nti o ns ha ve bee n i neffecti ve, t he p h ysicia n, after see ki n g e x pert 
a d vice, wit h i nf or me d c o nse nt fr o m t he patie nt or a le gall y a ut h orise d re prese ntati ve, 
ma y use a n u n pr o ve n i nter ve nti o n if i n t he p h ysicia n's j u d ge me nt it offers h o pe of 
sa vi n g life, re-esta blis hi n g healt h or alle viati n g s ufferi n g. T his i nter ve nti o n s h o ul d 
s u bse q ue ntl y  be  ma de  t he  o bject  of  researc h,  desi g ne d  t o  e val uate  its  safet y  a n d  
efficac y. I n all cases, ne w i nf or mati o n m ust be rec or de d a n d, w here a p pr o priate, ma de 
p u blicl y a vaila ble.  
© W orl d Me dical Ass ociati o n, I nc. – All Ri g hts reser ve d.