Conditions: Acromegaly
Keywords: Octreotide Capsules Acromegaly somatostatin receptor ligands (SRLs) Mpowered OOC-ACM-302
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 146
Healthy volunteers: no

Brief summary:
Octreotide capsule is a novel, orally-administered formulation of the commercially-available injectable drug octreotide. In a recent phase 3 trial (OPTMAL; NCT03252353), oral octreotide capsules demonstrated sustained biochemical response up to 13 months in patients with acromegaly previously managed with somatostatin analog injections (ref).

The objective of this study was to compare the efficacy, safety, and patient reported outcomes (PROs) between oral octreotide capsules and injectable somatostatin receptor ligands (SRLs).

Detailed description:
This was phase 3, randomized, open-label, active controlled, multicenter study to evaluate the maintenance of response, safety and patient reported outcomes (PROs) in acromegaly patients treated with octreotide capsules and in patients treated with standard of care parenteral somatostatin receptor ligands (SRLs), who previously tolerated and demonstrated biochemical control on both treatments.

The core study consisted of three phases: a Screening phase, Run-in phase and a Randomized Controlled Treatment (RCT) phase.

Eligible patients who were biochemically controlled on parenteral SRLs were switched to octreotide capsules for a 26-week period Run-in phase. During this phase the effective dose for each patient was determined through dose titration.

Patients whose acromegaly has been controlled biochemically on octreotide capsules at the end of the Run-in phase entered a 36-week open-label RCT phase, where they randomized to continue on octreotide capsules or switch back to their injectable SRL treatment (as received prior to Screening).

Following the completion of the core study (Screening, Run-in and RCT phases), eligible patients were offered to enter the Study Extension phase and receive octreotide capsules until product marketing or study termination.

A Sub-study, performed in selected non-European sites, allowed patients with inadequate biochemical control on octreotide capsules during the Run-in phase to enter a Combination phase and receive co-administration of octreotide capsules with cabergoline tablets for a total of 36 weeks.

Arms:
arm 1: Oral octreotide capsules arm 2: Oral octreotide capsules arm 3: Injectable somatostatin analogs (octreotide or lanreotide) arm 4: Octreotide capsules plus cabergoline

Interventions: intervention 1: Octreotide capsules
Intervention descriptions: intervention 1: None

Protocol document:
Prot_000.pdf: 






 
 
    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. 






 
 
 
 
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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  




 
 
 
 
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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  
 


 
 
 
 
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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  


 
 
 
 
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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  


 
 
 
 
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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  


 
 
 
 
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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 


 
 
 
 
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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 








 
 
 
 
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Pa ge 7 5  of 1 4 2  
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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:  


 
 
 
 
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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 .  


 
 
 
 
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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 


 
 
 
 
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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. 


 
 
 
 
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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 








 
 
 
 
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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 


 
 
 
 
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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. 


 
 
 
 
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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. 


 
 
 
 
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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 






 
 
 
 
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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, 


 
 
 
 
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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) 


 
 
 
 
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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 %). 


 
 
 
 
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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. 


 
 
 
 
 
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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.  


 
 
 
 
 
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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 


 
 
 
 
 
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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 


 
 
 
 
 
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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 =   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
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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  
 
 
 
 
 
 


 
 
 
 
 
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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. 


 
 
 
 
 
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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.  


 
 
 
 
 
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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 


 
 
 
 
 
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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.  

SAP_001.pdf: 








C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 5  of 4 4  
 
 
 
LI S T O F A B B R E VI A TI O N S  
%  
Perce nt  
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 v e nt  
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 ns a mi nase  
A N C O V A  
A nal ysis of C o varia nce  
A S T  
As partate A mi n otra nsferase  
A T C  
A U C  
A nat o mical T hera pe utic C he mical  
Area U n der t he C ur v e  
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)  
CI  
C o nfi de nce I nter val  
C P K  
Creati ne P h os p h o ki nase  
C R  
C o m plete Res p o n der  
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  
E M A  
E ur o pea n Me dici nes A ge nc y  
E O T  
E n d -of -Tr eat me nt  
E Q -5 D -5 L  
E ur o Q ol –  5 Di me nsi o ns –  5 Le v els Q ualit y of Life q uesti o n naire  
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 U  
F oll o w -u p  
g  
Gra m  
G G T  
Ga m ma -Gl uta m yl Tra nsferase  
G H  
Gr o wt h H or m o ne  
GI  
Gastr oi ntesti nal  
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 partat e a mi n otra nsferase)  
G P T ( A L T)  
H b   
Gl uta mic P yr u vic Tra nsa mi nase (ala ni ne tra nsa mi nase)  
He m o gl o bi n 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 6  of 4 4  
 
 
 
H b A 1c  
Htc  
Gl yc os yl ate d He m o gl o bi n  
H e mat ocrit  
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I D M C  
I n d e pe n de nt Data M o nit ori n g C o m mittee  
I G F-1  
I ns uli n-li ke Gr o wt h Fact or 1  
I M P  
I n v esti gati o nal Me dici nal Pr o d uct  
k g  
Kil o gra m  
L  
Liter  
L A R  
L D H  
L o n g -acti n g Releas e  
L actate d e h y dr o ge n ase  
L O C F  
ls mea ns 
M C M C  
Last O bs er vati o n Carrie d F or w ar d  
L east s q uar e mea ns  
Mar k o v C hai n M o nte Carl o 
Me d D R A  
Me dical Dicti o nar y f or R e g ul at or y Acti vities  
m g  
Milli gra m  
MI D  
Mi ni mal I m p orta nt Differe nce  
m L  
Milliliter  
n g  
Na n o gra m  
NI  
N o n -i nferi orit y  
N R  
N o n -Res p o n der  
O A S  
Octre oti de A n al ysis Set  
P R  
Partial Res p o n der  
P R O  
Patie nt Re p orte d O utc o m e  
P T  
Preferre d Ter m  
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 v e nt  
S A P  
Statistical A nal ysis Pla n  
S A S  
Safet y A nal ysis Set  
S C  
Steeri n g C o m mittee  
S D  
Sta n dar d De viati o n  
S O C (treat me nt)  
Sta n dar d of Care  
S O C (safet y)  
S yste m Or ga n Class  
S O P  
Sta n dar d O perati o n Pr oce d ures  
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 S eri o us A d vers e Reacti o n  
T E A E  
Treat me nt E mer ge nt A E  
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  


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 7  of 4 4  
 
 
 
U L N  
U p per Li mit of N or mal  
W P AI: S H P  
W or k Pr o d ucti vit y a n d A cti vit y I m pair me nt Q uesti o n naire S pecific Healt h 
Pr o ble m V 2. 0  
W H O  
W orl d Healt h Or ga nizati o n  
W H O Dr u g  
W orl d Healt h Or ga nizati o n Dr u g Dicti o nar y  
 
 
 
 
 








C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 1 1  of 4 4  
 
 
 
criteria f or r a n d o mizati o n i nt o t he R C T p hase or C o m bi nati o n p hase s u b- st u d y will re v ert t o t heir 
pri or i njecta ble S R L treat me nt ( pri or t o Scree ni n g) or ot her treat me nt as deter mi ne d b y t heir 
p h ysicia n, a n d be f oll o w e d f or 1 2 w e e ks after last d ose.  
Patie nts w h o earl y ter mi n ate t he R u n -i n p hase f or a n y reas o n i n sites w h o d o n ot partici pate i n t he 
C o m bi nati o n  p hase  s u b -st u d y  will  re vert  bac k  t o  t heir  i njecta ble  S R L  treat me nt  ( pri or  t o  
Scree ni n g) 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 u p f or 1 2 
wee ks after last d ose of st u d y me dicati o n.  
D at a b ase  l ock  f or  t he  C ore st u dy  a n d  t he  C o m bi n ati o n  p h ase  s u b-st u dy  will  occ ur  at  t he  
c o m pleti o n of b ot h t he R C T p h ase/ E n d of Tre at me nt ( E O T ) (l ast p atie nt c o m pletes week 6 2) a n d 
t he C o m bi n ati o n p h ase s u b-st u dy (l ast p atie nt c o m pletes week 3 6), a n d will n ot i ncl u de t he F oll o w-
u p p h ase, 
or St u dy Exte nsi o n tre at me nt p h ase. I nteri m a n alyses of t he Exte nsi o n 
P h ase will be c o n d ucte d peri o dic ally, after c o m pl eti o n of t he R C T p h ase. D at a c ollecte d p ost R C T, 
p h ase or C o m bi n ati o n p h ase s u b -st u dy will be i ncl u de d i n t he St u dy Exte nsi o n d at a b ase. Det ails 
of t hese a n alyses will be o utli ne d i n a se p ar ate S A P.  
 
Fi g ure 2. 2- 1 St u d y O ver vie w 
 
 
 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 1 2  of 4 4  
 
 
 
F or St u d y Decisi o n Tr ee, please  r efer t o A p pe n di x A i n t he St u d y pr ot oc ol. 
C ore st u d y d ur ati o n will be 6 6 wee ks, c o m prise d of: 
P h ase  
D ur ati o n  
Visit wi n d o w  
Scree ni n g p has e:  
u p t o f o ur wee ks 
 
R u n- i n  p hase  ( octre oti de  
ca ps ules):  
2 6 wee ks  
± 3 da ys *  
Ra n d o mize d
 C o ntr olle d
 
Treat me nt  ( R C T)  p hase  
( octre oti de  ca ps ules  vs.  
Pare nter al S R Ls):  
3 6 wee ks  
± 3 da ys  
 
         * At we e k 2 6, t h e visit wi n d o w will b e – 3 d a ys t o 1 0 d a ys  
D urati o n of ot her st u d y p hases will be as f oll o ws:  
C o m bi n ati o n p h ase s u b -st u d y (i n selecte d sites): A d mi nistrati o n of o ctre oti de ca ps ules 8 0 m g 
(eac h ca ps ule str e n gt h is 2 0 m g ) wit h  
 
.  H o we v er, i f t he pati e nt is bi oc he micall y c o ntr olle d  (defi ne d as I G F -
1 <  1. 3 ×  U L N ) at t he w ee k 4 assess me nt  of t h e C o m bi nati o n p hase s u b -st u d y, bas e d o n cli nical 
j u d ge me nt, t he ca ber g oli ne d ose ca n be mai ntai n e d (i.e. n o f urt her d ose escalati o n is re q uire d ). 
T he  st u d y p h ase  is 3 6 wee ks (i n parallel t o t he c ore st u d y d urati o ns). Visit wi n d o w ± 3 da ys.  










C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 1 7  of 4 4  
 
 
 
4 h o urs  acc or di n g t o 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 D gi ve n i n t he 
pr ot oc ol. 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 n ce ntrati o n or t he dat a p oi nt will be c o nsi dere d 
missi n g.  
 
At eac h visit t hat b ot h I G F -1 a n d G H are c ollecte d, patie nts will be classifie d i nt o 1 of 3 gr o u ps 
base d o n t heir I G F- 1 a n d mea n G H val u es as f oll o ws:  
 
•  C o m plete Res p o n der ( C R): I G F- 1 ≤ 1 x U L N a n d G H < 2. 5 n g/ m L 
•  Partial  Res p o n der ( PR): 1 x U L N < I G F- 1 < 1. 3 x U L N a n d G H < 2. 5 n g/ m L 
•  N o n - Res p o n der ( NR): I G F - 1 ≥ 1. 3 x U L N or  G H ≥ 2. 5 n g/ m L 
4. 5. 2  I G F- 1 Ti me Wei g hte d A ver a ge ( T W A) 
T he T W A res p o nse, o ver t he treat me nt p hase re prese nts a n i nte grate d meas ure of efficac y acr oss 
ti me. It is deri v e d as t he area u n der t h e c ur v e (A U C ) di vi de d b y t h e t otal a m o u nt of ti me u n der 
o bser vati o n bet wee n t he first a n d last I G F - 1 val ue. 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. T W A will be deri ve d as  f oll o ws: 
 
1)  At eac h p ost bas eli ne ti me p oi nt calc ulate  [( Yt + Y t- 1) * Δ  ti me (i n da ys)]/ 2 
2)  S u m u p t he val ues t o o btai n o verall A U C  
3)  Di vi de b y t he t otal ti me u n der o bser vati o n (i n D a ys) bet wee n t he first a n d l ast I G F -
1 val ues, 
 
w here  Yt a n d Y t-1 are t he I G F-1 val ues  at t h e ti me p oi nt a n d t he pre vi o us ti me p oi nt, a n d Δ  ti me is 
t he ti me bet wee n t he t w o ti me p oi nts i n da ys. T h e first ti me p oi nt s h o ul d be t he wee k 2 6 ( b aseli ne 
f or t he R C T p hase) val u e.  T h e last ti me p oi nt s h o ul d be t he wee k 6 2/ E O T val ue.  A n y val ues 
c ollecte d > 1 d a y aft er t h e date of last d ose will n ot be use d i n t he deri vati o n.  
4. 5. 3  AI S 
T he acr o me gal y i n de x of se verit y ( 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  D  i n  pr ot oc ol).  At  eac h  visit  t he  
f oll o wi n g s y m pt o ms will be assesse d: Hea d ac h e, S welli n g of e xtre mities, J oi nt pai n, S weati n g a n d 
Fat i g ue. Eac h s y m pt o m will be gr a de d b y its hi g hest se verit y d uri n g t he last f o ur wee ks, fr o m n o 
s y m pt o ms (sc or e 0), t o mil d s y m pt o ms ( 1), m o d erate ( 2) or s e vere s y m pt o ms ( 3). 
T he o ver all AI S s c ore is t he s u m of se verit y sc ores f or eac h of t he 5 acr o m e gal y s ym pt o ms. T he 
ra n ge will be 0 t o 1 5, wit h 0 re pres e nti n g n o s y m pt o ms a n d 1 5 re pres e nti n g se vere s y m pt o ms. 
 
A patie nt will be c o nsi dere d t o be cli nicall y c o ntr olle d if t heir o verall AI S sc ore at w ee k 6 2/ E O T, 
as c o m par e d t o wee k 2 6 (start of R C T) , is t he sa m e or better (i.e., re d uce d). 
 
S y m pt o ms are c o nsi dere d t o be acti ve if t he s c ore is greater t ha n 0. 
4. 5. 4  Acr o -T S Q  
 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 1 8  of 4 4  
 
 
 
T he ne w v ersi o n of t he Acr o -T S Q i ncl u d es si x scales: S y m pt o m I nterfere nce c o ntai ns f o ur ite ms 
relate d t o i nterfer e nce wit h s y m pt o ms; Treat me nt C o n ve nie nce c o ntai ns si x ite ms relate d t o t he 
c o n ve nie nce/i nc o n ve nie n ce a n d eas e of a d mi nistrati o n; I njecti o n Site I nterfere nce c o ntai ns t w o 
ite ms relate d t o i njecti o n site reacti o ns; GI I nterfere n ce c o nt ai ns t hree ite ms relate d t o GI si de 
effects;  Treat me nt  Sat isfacti o n  c o ntai ns  t hree  ite ms  relate d  t o  treat me nt  satisfacti o n;  a n d  
E m oti o nal Reacti o n i ncl u des t hree ite ms relate d t o e m oti o nal reacti o ns t o treat me nt.  
 
Eac h s cale sc or e ca n ra n ge fr o m 0 t o 1 0 0, wit h 0 re pres e nti n g t he l o w est a n d 1 0 0 re pres e nti n g t he 
b est p ossi ble sc ore f or eac h of t he si x scales. Acr o -T S Q scale s c ores are calc ulate d if res p o nses 
fr o m at least 5 0 % of t h e ite ms wit hi n t hat scale are pr o vi de d.  
 
4. 5. 5  E Q- 5 D- 5 L   
E Q - 5 D-5 L (fi ve s e verit y le vels E Q - 5 D), de vel o p e 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 h e p atie nt f or use as a m eas 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 et al., 2 0 1 1).  
 
It c o m 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 dert a ke us ual 
acti vities, pai n a n d disc o mf ort, a n d a n xiet y a n d d e 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 di me nsi o n : ‘ n o pr o ble ms’ (assi g ne d a val ue of 1), ‘sli g ht pr o ble ms’ 
(assi g n e d a val u e of 2), ‘ m o derate pr o ble ms’ (assi g ne d a val ue of 3), ‘se vere pr o ble ms’ (assi g n e d 
a val ue of 4) a n d ‘ u na ble t o/e xtre me pr o ble ms’  (assi g ne d a val ue of 5) (refere nce A p pe n di x G  i n 
pr ot oc ol ). T he 1- di git le vel val ues  f or t h e 5 di me nsi o ns ca n be c o m bi ne d i n a 5 -di git n u m ber 
descri bi n g t he res p o n d e nt’s healt h state .   
 
It s h o ul d b e n ote d t hat t h e n u merals 1-5 ha v e  n o a rit h metic pr o perties a n d s h o ul d n ot be use d as 
a car di nal sc or e; h o we v er, t he r es p o nses t o all fi v e di me nsi o ns, ca n b e c o n verte d  fr o m a 5-di git 
n u m ber t o a si n gle s u m m ar y i n de x usi n g t he E Q-5 D -5 L Cr oss w al k Val u e S ets a vaila ble o nli ne at 
htt p:// w w w.e ur o q ol. or g/ a b o ut- e q- 5 d/ val uati o n- of-e q- 5 d/e q- 5 d- 5l- val ue-s ets. ht ml.
 T he
 i n de x
 
val ues ra n ge fr o m 0  t o 1 w here hi g h er i n de x val ues re pres e nt better h ealt h states. O nl y sites l ocate d 
i n t he f oll o wi n g c o u ntries will ha ve a n i n de x sc ore gi ve n: Fra n ce,  Ger ma n y, Net herl a n ds, S pai n, 
U K a n d  U S . If t her e are a n y missi n g le vel val u es f or a n y of t h e 5 di me nsi o ns, t he n t he i n de x sc ore 
will be missi n g.  
 
T he E Q -V A S r ec or ds t he patie nt’s self -rate d healt h o n a 2 0- c m vertical, vis ual a nal o g ue scale wit h 
e n d p oi nts la belle d ‘t he b est healt h y o u ca n i ma gi ne’  ( v al ue of 1 0 0) a n d ‘t he w orst healt h y o u ca n 
i ma gi ne’ ( val ue 0).  
 
4. 5. 6  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 pecifi c  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 dat e d t o ol t o meas ure healt h o utc o mes i n cli nical tri al 
setti n gs ( Reill y et al., 1 9 9 3).  


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 1 9  of 4 4  
 
 
 
 
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 vera ll healt h a n d s y m pt o ms, relati ve t o meas ures of ge n eral h ealt h 
perce pti o ns, r ole ( p h ysical), r ole ( 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 nterfer e nce wit h re g ul ar acti vit y ( A p p e n di x H). 
 
T he W P AI yiel ds f o ur t y pes of sc or es:   
1.  A bse nteeis m ( w or k ti me misse d) 
2.  Prese nteeis m (i m pair me nt at w or k / re d u ce d o n -t he-j o b effecti ve n ess) 
3.  W or k pr o d ucti vit y l oss ( o verall w or k i m pair m e nt / a bse nteeis m pl us prese nteeis m) 
4.  Acti vit y I m pair m e nt 
 
Eac h of t he 4 W P AI o ut c o mes ar e e x pres se d as i m pair me nt perce nta ges, wit h hi g her n u m bers 
i n dicati n g gr eater i m pair me nt a n d less pr o d ucti vit y, i.e., w orse o utc o mes, as f oll o ws:  
 
T he W P AI - S H P c o nsists of t he f oll o wi n g 6 Q uesti o ns: 
•  Q 1 = c urre ntl y e m pl o ye d  
•  Q 2 = h o urs misse d d ue t o s pecifie d pr o ble m 
•  Q 3 = h o urs misse d ot her reas o ns 
•  Q 4 = h o urs act uall y w or k e d 
•  Q 5 = de gr ee pr o bl e m aff ecte d pr o d u cti vit y w hile w or ki n g 
•  Q 6 = de gr ee pr o bl e m aff ecte d r e g ular acti vities  
 
Eac h of t he 4 W P AI sc or es are d eri ve d as f oll o ws:  
•  Perce nt w or k ti me misse d  d ue t o pr o ble m: Q 2/( Q 2 + Q 4) * 1 0 0 
•  Perce nt i m pair me nt w hil e w or ki n g d ue t o pr o ble m: Q 5/ 1 0 * 1 0 0 
•  Perce nt o verall w or k i m p air me nt d ue t o pr o ble m: 
•  Q 2/( Q 2 + Q 4) +[( 1 -( Q 2/( Q 2 + Q 4))) x( Q 5/ 1 0)] * 1 0 0 
•  Perce nt acti vit y i m pair m e nt d ue t o pr o ble m: Q 6/ 1 0  * 1 0 0 
 
 
 
5  
G E N E R A L A N A L Y SI S D E FI NI TI O N  
5. 1  
Ge ner al C o nsi der ati o ns  
F or  cate g orical  par a met ers,  t he  n u m ber  a n d  perce nta ge  of  patie nts  i n  eac h  cat e g or y will  be  
prese nte d.  T h e  p o p ulati o n  c o u nt  of  eac h  ta ble  will  ge nerall y  be  t he  de n o mi nat or  use d  f or  
perce nt a ge calc ul ati o ns  or will be base d o n t he n u m ber of patie nts a p pr o pri ate f or t he p ur p ose of 
a nal ysis . T he c o u nts of missi n g val ues will be prese nte d i n s u m mar y ta bles al o n g wit h perce nta ges, 
if re q uire d. F or c o nti n u o us para meters, descri pti ve statistics will ge nerall y i ncl u de n u m ber of 
patie nts ( n), mea n, sta n d ar d de viati o n ( S D), me dia n, 2 5 t h perce ntile, 7 5 t h perce ntile, mi ni m u m, a n d 
ma xi m u m.  
U nless ot her wise s pecifi e d, Bas eli ne f or t he R u n -i n p hase will be defi n e d as t he last val ue rec or de d 
pri or t o or e q ual t o t he d ate of t he first d ose of o ctre oti de ca ps ules (i. e., t he date of ass ess me nt will 
be ≤ date of first d ose) , a n yti me d uri n g scree ni n g or Baseli ne visit. T he wee k 2 6 val ue will be use d 
as t he b aseli ne v al ue f or t he R C T p hase.  I n case of missi n g v al ues at wee k 2 6, t he l ast availa bl e 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 0  of 4 4  
 
 
 
val ue o n st u d y dr u g, pri or t o wee k 2 6 a n d n ot earlier t ha n wee k 2 0 will be use d as t he Baseli ne 
val ue f or t he R C T  p has e.  Baseli ne f or t h e c o m bi nati o n p hase will b e t he last val ue rec or d e d d uri n g 
t he r u n-i n p hase, a n d bef ore t he i nitiati o n of treat me nt wit h ca ber g oli ne.     
All data will be p o ole d acr oss all sites f or re p orti n g p ur p oses, gi ve n t he lar ge n u m ber of sites i n 
relati o n t o t he t otal sa m ple size. 
T he ge n er al r ule of prese nti n g t he deci mal places are m i ni m u m a n d ma xi m u m val ues will be 
prese nte d wit h t he sa me n u m ber of deci mals as c ollecte d f or t he data, mea ns a n d me dia ns will 
dis pla y 1 a d diti o nal deci mal, S D a n d sta n dar d err ors will be dis pla ye d wit h 2 a d diti o nal deci mals.  
If t he dat a has hi g her precisi o n wit h 3 or m ore deci mal places (f or e x a m ple La b orat or y d ata) t h e n 
t he data will be deter mi ne d o n a b y -para meter basis. Perce nta ges will be dis pla ye d wit h 1 deci mal  
places, if t he perce nta ge is zer o o r 1 0 0 t he n t he y will be dis pla ye d as “ 0 % ” a n d 1 0 0 % res pecti vel y. 
All p- val ues will be prese nte d t o 3 deci mals , if p- val ues are less t ha n 0. 0 0 1 t he y will be dis pla ye d 
as “ < 0. 0 0 1 ”.  
T he desi g n of t he st u d y all o ws f or p atie nt s t o ha ve var yi n g n u m b ers of visits d uri n g t he R u n- i n 
a n d R C T P hase of t he st u d y. T he d ur ati o n of e x p os ure t o eac h d ose will als o var y. F or a nal ysis 
p ur p oses data will be pr ese nte d se par atel y f or eac h p hase of t he st u d y as f oll o ws : 
1.  S u m maries i n t he R u n -i n P hase will be prese nte d o verall a n d w he n a p plica bl e als o b y  fi nal 
tar get d ose le v el ( 4 0, 6 0 or 8 0). 
2.  S u m maries i n t he R C T P hase will be prese nte d b y O ctre oti de ca ps ules , S R L i njecti o ns 
(Octre oti de  L A R or La nre oti de)  a n d f or all patie nt s re gar dless of treat me nt assi g n me nt. 
Octre oti de ca ps ules i n t hese s u m maries will i m pl y t he fi nal tar get d ose le vel ac hie v e d 
d uri n g t h e R u n- i n p has e. W he n a p plica ble O ctre oti de ca ps ules  will be pres e nte d b y tar ge t 
d ose le vel ( 4 0, 6 0 or 8 0) a n d S R L i njecti o ns will be prese nt e d b y d ose le vel as f oll o ws:  
S R L I njecti o n D ose  
D ose Le vel C ate g or y  
A n y octre oti de d ose < 2 0 m g t otal/ m o nt h or 
la nre oti de < 9 0 m g t otal/ m o nt h 
L o w  
A n y octre oti de d ose < 3 0 m g t otal/ m o nt h o r 
la nre oti de < 1 2 0 m g t otal/ m o nt h 
Mi d dle 
A n y octr e oti de d ose ≥ 3 0 m g t otal/ m o nt h or 
la nre oti de ≥ 1 2 0 m g t otal/ m o nt h 
Hi g h  
3.  S u m maries i n t he C o m bi nati o n P hase will be prese nte d f or all a p plica ble patie nt s, a n d 
w he n a p plica bl e b y Car b er g oli ne d ose.  
5. 2  
S u b gr o u ps  
T he f oll o wi n g s u b gr o u ps will be s u m marize d f or s pecific ta bles, a nal yses a n d p hases:  
•  Ge n der: Mal e, Fe male  
•  Re gi o n : (East er n  E ur o p e, Wester n E ur o pe, N. A m erica) 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 1  of 4 4  
 
 
 
•  A ge : < 6 5 years ol d, ≥6 5 years ol d  
•  Tar get D ose of Or al Octr e oti de: 4 0 m g,  6 0 m g,  8 0 m g  
•  Pri or D ose of S R L  I nject a bles: L o w, Mi ddle, Hi g h ( See Secti o n 4. 1) 
•  R u n-i n Baseli ne I G F - 1: ≤1 U L N, [ >1 , <1. 3 U L N], ≥1. 3 U L N  
•  R u n- i n Baseli ne Res p o nse: C o m plete Res p o nse ( C R), Partial Res p o nse ( P R), N o Res p o nse 
( N R) 
•  R C T Baseli ne  ( w ee k 2 6)- I G F- 1: ≤1 U L N , [ >1, < 1. 3 U L N], ≥1. 3 U L N  
•  R C T  Baseli ne ( wee k 2 6) Res p o nse: C o m plete Res p o nse ( C R), Partial Res p o nse ( P R), N o 
Res p o nse ( N R) 
5. 3  
D at a  H a n dli n g C o n ve nti o ns  
5. 3. 1  Missi n g D at a 
Pri mar y E n d p oi nt Base d o n E M A A d vice 
S h o ul d a patie nt  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 o ac 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 dl ess of t heir T W A.  
A d diti o nal l y, a se nsiti vit y a n al ysis will  be c o n d u cte d t o e x a mi ne t he i m pact of missi n g data  b y 
i m p uti n g missi n g I G F-1  val ues  usi n g   the  Mar k o v  C hai n  M o nte  Carl o  ( M C M C)  met h o d  f or 
m ulti ple i m p utati o n.  It is t he e x pectati o n t hat t he missi n g ness p atter n will be i nter mitte nt or 
n o n m o n ot o ne. 
M ulti ple i m p utati o n a n d t he s u bse q ue nt a nal ysis will i n v ol ve t he tas ks descri be d bel o w: 
1.  Create a data s et, o ne f or eac h treat me nt gr o u p, of s u bjects wit h o bser ve d val ues a n d t h ose 
nee di n g esti mati o n b y m ulti ple i m p utati o n. T he missi n g I G F -1 v al ues i n eac h data s et will 
be fille d i n usi n g t he M C M C met h o d wit h a t otal of 5 0 sets of i m p utati o ns bei n g perf or me d. 
T he pr oce d ur e will se q u e ntiall y esti mate a n i m p utati o n m o del f or I G F -1 val ues at eac h 
p ost- Bas eli ne visit ( u p t o Wee k 6 2), wit h baseli ne d ose a n d baseli ne I G F -1 as pre dict ors. 
N ote t hat I G F -1 val ues at earlier visits will als o be use d as pre dict ors f or t he m o del of I G F -
1 at later visits. T he r es ulti n g data sets f or eac h treat me nt ar m will be c o m bi n e d i nt o o ne 
c o m plete data set b ase d o n eac h of t h e 5 0 i m p utati o ns.  
2.  N ote: T he i m p utati o n m o del base d o n t he M C M C met h o d will o nl y all o w c o nti n u o us 
varia bles as pre dict ors. T heref ore, baseli ne d ose (f or eac h treat me nt gr o u p) will be re -
c o de d wit h i n dicat or vari a bles. T he n u m ber of i n dicat or v aria bles will be o ne less t h a n t he 
t otal n u m ber of baseli ne d ose cate g ories (i.e., 2). 
3.  F or eac h c o m plete i m p ute d data set, t he dic h ot o m o us T W A res p o n der rate base d o n t he 
I G F-1 val ues will be c o m p ute d. Eac h c o m plete i m p ut e d data set will t he n be a n al yze d 
base d o n t he details i n Secti o n 8. 1. 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 2  of 4 4  
 
 
 
4.  T he r es ults fr o m t h e a nal ysis of eac h of t h e 5 0 i m p ute d data sets will b e c o m bi ne d i nt o a 
si n gle i nfere nce usi n g S A S P R O C MI A N A L Y Z E. 
Pri mar y E n d p oi nt 
 
F or t he 2 c o -pri mar y des cri pti ve  
 e n d p oi nts, a patie nt will be classifie d as a res p o n der base d 
o n t he a ver a ge of t w o val ues, wee k 2 4 & 2 6 f or t h e e n d of t he r u n -i n p has e a n d wee k 5 8 & 6 2, f or 
t he e n d of t h e R C T p hase.  If a patie nt o nl y has a si n gle v alue, b ut a n u nsc he d ule d assess me nt w as 
c o n d ucte d i n t he s a me ti me fr a me (i.e., b et wee n wee k 2 4 & 2 6, +/ - 3 da ys, or b et wee n wee k 5 8 & 
6 3, +/ - 3 da ys), t h e n t he u nsc he d ule d ass ess me nt will be use d.  If t here  is o nl y a si n gle v al ue a n d 
n o u nsc he d ule d assess m e nt, t he si n gle val u e will be use d.  If a p atie nt c o m pletes t he res pecti ve 
p hase of t he st u d y, b ut is missi n g b ot h val ues, t he w orst o bser v ati o n ( hi g hest val u e) o bser ve d 
d uri n g t he res pecti ve p hase will be use d t o deter mi ne t heir res p o nse.  If a p atie nt disc o nti n ues t he 
p hase earl y, t he y will be classifie d as a n o n -res p o n der. 
Ot her E n d p oi nts 
Details f or i m p utati o n r ules f or sec o n dar y a n d e x pl orat or y e n d p oi nts are pr o vi de d i n secti o ns 8. 2 
a n d 8. 3, res pecti vel y. 
Missi n g Dates  
F or start dat es of me dicati o ns /a d verse e ve nts, if o nl y t h e year is s pecifi e d, J a n uar y 1 will be 
i m p ute d f or a nal ysis p ur p oses.  If t he m o nt h a n d year o nl y are pr o vi de d, t he 1st of t he s pecifie d 
m o nt h will be i m p ute d.   
F or st o p dates of me dicati o ns /a d verse e ve nts, if o nl y t he year is s pecifie d, Dece m ber 3 1  will be 
i m p ute d f or a nal ysis p ur p oses.  If t h e m o nt h a n d year o nl y are pr o vi de d, t he e n d of t he s pecifie d 
m o nt h will be i m p ute d.   
If f urt her i m p utati o ns are dee me d necessar y t o facilitate re p orti n g, t he n t he c o n ve nti o ns use d will 
be eit her a d d e d i nt o t he S A P a n d/ or d oc u me nte d s pecificall y i n t he st u d y re p ort. 
6  
S T U D Y P A TI E N T S 
6. 1  
A n al ysis P o p ul ati o ns   
6. 1. 1  F ull A n al ysis Set ( F A S)  
F A S is defi ne d as all ra n d o mize d patie nts t o t he R C T p hase w h o recei ve at least o ne d ose of st u d y 
me dicati o n a n d ha ve o ne p ost ra n d o mizati o n meas ure me nt of I G F -1. T his p o p ulati o n will ser ve as 
t he pri mar y efficac y a nal ysis p o p ulati o n f or t h e R C T p hase of t he c ore st u d y. Patie nts will be 
i ncl u de d i n t he gr o u p t o w hic h t he y were ra n d o mize d.  
6. 1. 2  Per - Pr ot oc ol A n al ysis Set ( P P)  
Per -Pr ot oc ol A nal ysis Set ( P P) is defi ne d as all patie nts i n t he F A S wit h o ut a maj or pr ot oc ol 
vi olati o n.  
6. 1. 3  S af et y A n al ysis Set ( S A S)  
S A S is defi ne d as all ra n d o mize d patie nts w h o recei ve at least o ne d ose of st u d y me dic ati o n d uri n g 
t he R C T p hase. T his p o p ulati o n will ser ve as t he pri mar y s afet y a nal ysis p o p ulati o n f or t he R C T 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 3  of 4 4  
 
 
 
p hase of t he c ore st u d y. Patie nts will be i ncl u de d i n t he gr o u p acc or di n g t o w hic h me dicati o n t he y 
act uall y recei ve d. If a p atie nt  recei v e d b ot h medicati o ns, t he y will be c o u nt e d i n b ot h gr o u ps. 
6. 1. 4  E nr olle d A n al ysis Set ( E A S)  
E A S is defi ne d as all pati e nts w h o ar e e nr olle d i nt o t he R u n -i n p hase of t he c ore st u d y a n d recei ve 
at least o ne d ose of st u d y m e dicati o n. T his p o p ul ati o n will be use d f or t h e a na l ysis of s afet y a n d 
efficac y dat a d uri n g t he R u n -i n p hase of t he c ore st u d y.  
6. 1. 5  Octre oti de A n al ysis Set ( O A S)  
O A S is defi ne d as all patie nts w h o recei v e at least o ne d ose of octre oti de ca ps ules d uri n g t h e r u n-
i n a n d at least o n e d ose of octre oti de ca ps ul es d uri n g t h e R C T p has e .  T his p o p ulati o n will be use d 
t o s u m marize efficac y a n d safet y data acr oss t he r u n-i n a n d R C T p hases of t he st u d y. 
6. 1. 6  C o m bi n ati o n A n al ysis Set ( C A S)  
C A S is defi ne d as all pati e nts w h o are e nr olle d i nt o C o m bi nati o n p hase s u b -st u d y. T his p o p ul ati o n 
will be use d f or t he a n al ysis of safet y a n d efficac y data c ollecte d i n t he c o m bi nati o n ar m.  
6. 1. 7  All R a n d o mize d P atie nt s 
All Ra n d o mize d Patie nt s are all patie nts t hat were ra n d o mize d t o st u d y me dicati o n f or t he R C T 
p hase. T his p o p ulati o n will be use d f or t he a n al ysis of dis p ositi o n.  
6. 1. 8  All Scree ne d P atie nts  
All Scree ne d Patie nts are all patie nts wit h a n i nf or me d c o nse nt date .  
6. 1. 9  R u n -i n P h ase C o m pleters 
R u n- i n P hase C o m pleters are all patie nts t hat di d n ot disc o nti n ue t he R u n -i n P hase earl y. T hes e 
patie nts c o m plete d t he R u n-i n P hase as re p orte d o n t he P hase C o m pleti o n e C R F.  
6. 1. 1 0  R C T  P h ase C o m pleters  
R C T  P hase C o m pleters are all patie nts t hat di d n ot disc o nti n ue t he R C T  P hase earl y. T hese p atie nts 
c o m plete d t he R C T  P hase as re p orte d  o n t he P has e C o m pleti o n e C R F.  
6. 1. 1 1  C o m bi n ati o n P h ase C o m plet ers  
C o m bi nati o n P hase C o m pleters ar e all patie nts t hat di d n ot disc o nti n ue t he C o m bi nati o n P hase 
earl y. T hese patie nts c o m plete d t he C o m bi nati o n  P hase as re p orte d o n t he P hase C o m pleti o n 
e C R F.  
6. 2  
Pr ot oc ol D e vi ati o ns 
All pr ot oc ol de vi ati o ns will be r e vie we d a n d classifie d as maj or or mi n or bef ore data b ase l oc k. 
Maj or p r ot oc ol de viati o ns are c o m plia nce iss ues t hat i m pact patie nt  safet y or t he scie ntific i nte grit y 
of t he st u d y d ata. T he y i n cl u de, b ut are n ot li mite d t o : 
•  Vi olati o ns of i ncl usi o n a n d e x cl usi o n criteria ( R u n-I n, R C T a n d/ or C o m bi nati o n P hases). 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 4  of 4 4  
 
 
 
•  Recei vi n g t he wr o n g st u d y me dicati o n , or recei vi n g st u d y me dicati o n at i nc orrect d osi n g 
or fre q u e nc y  
•  N o n- c o m plia nce wit h st u d y me dicati o n.  A patie n t is defi ne d as n o n-c o m plia nt if t he patie nt  
t o o k < 7 5 % of t he st u d y me dicati o n assi g n e d t o eac h s pecific p hase.   
•  Ta ki n g a pr o hi bite d pri or me dicati o n or recei vi n g a pr o hi bite d pri or t hera p y as liste d i n 
Pr ot oc ol Secti o n 6. 1 0. 2 
•  Ta ki n g a pr o hi bite d c o nc o mi ta nt me dicati o n as liste d i n Pr ot oc ol Secti o n 6. 1 0. 4 Fail ure t o 
a d here t o st u d y ter mi nati o n r ules i n t he r u n-i n peri o d 
•  Fail ure t o a d h er e t o st u d y ter mi nati o n r ules i n t he r u n -i n peri o d 
T he fi nal maj or pr ot oc ol de viati o ns defi niti o ns will be deter mi ne d pri or t o data base l oc k. Maj or 
pr ot oc ol de viati o ns will be s u m marize d f or All Ra n d o mize d S u bjects, E A S a n d C A S p o p ulati o ns.  
6. 3  
Dis p ositi o n of P atie nt s 
Dis p ositi o n will be s u m marize d f or t he r u n-i n p has e, R C T p hase a n d c o m bi nati o n p hase s e paratel y 
usi n g t he E A S, All Ra n d o mize d Patie nt s a n d t he C A S , res pecti vel y.  
Dis p ositi o n f or t he R u n-i n P hase 
F or t he r u n -i n p has e a s e parat e s u m mar y pres e nti n g t he overa ll n u m ber of patie nt s scree n e d as 
well as t he n u m ber of patie nt s classifie d as scree n fail ures, a n d ass ociate d reas o ns  will be pr o vi de d .  
T he f oll o wi n g p atie nt  dat a will be s u m marize d f or t he E A S: 
•  O verall n u m ber of patie nt s e nr olle d as well as  t he n u m ber of patie nt s t hat disc o nti n ue d 
d uri n g t he R u n -i n P hase a n d ass ociate d reas o ns. T h e n u m ber of patie nt s t hat were treat me nt 
fail ures  i n  t he  R u n-i n  P hase  a n d  e nr olle d  i n  t he  C o m bi nati o n  P hase  will  als o  be  
s u m marize d. 
•  O verall  n u m ber of p atie nt s t hat c o m plete d  R u n-i n P hase. O ut of w hi c h t he n u m ber of 
patie nts t hat c o nti n ue d i nt o t he R C T, c o nti n ue d i nt o t he c o m bi nati o n p hase or c o m plete d 
t he r u n-i n b ut n ot c o nti n ue d treat me nt ( n ot eli gi ble f or R C T or n ot eli gi ble f or c o m bi nati o n 
or eli gi ble f or R C T yet d eci de d t o disc o nti n ue)  
•  O verall n u m ber of patie nts t hat c o m plete d f oll o w u p per pr ot oc ol (i n p o p ulati o ns t hat 
re q uire f oll o w u p)  
T he s u m mar y ta ble will prese nt data  f or all patie nt s a n d b y tar get oral d os e.  
 
Dis p ositi o n f or t he R C T P hase 
F or t he R C T  p hase a s u m mar y will be pr o vi de d ta b ulati n g t he n u m ber a n d perce nt a ge of patie nts; 
ra n d o mize d,  disc o nti n ue d,  i ncl u di n g  reas o n  f or  disc o nti n uati o n,  c o m plete d,   o ut  of  w hic h  
c o nti n ue d i nt o t he  E xte nsi o n p hase,  or c o m plete d t he R C T b ut n ot c o nti n ue d treat me nt ( n ot eli gi ble 
f or E xte nsi o n or eli gi bl e f or E xte nsi o n yet d ecli ne d t o e nter)   a n d c o m plete d  f oll o w- u p (i n 
p o p ulati o ns t hat re q uire f oll o w u p  per pr ot o c ol ), usi n g t he All Ra n d o mi ze d Set.  Data will be 
s u m marize d o verall, a n d b y treat me nt gr o u p. 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 5  of 4 4  
 
 
 
T he  treat me nt  gr o u p  c ol u m ns  f or  t he  s u m mar y  ta ble  will  i ncl u de  oral  octre oti de  t otal;  oral  
octre oti de tar get d oses of 4 0, 6 0, or 8 0 m g; i njecti o n S R Ls (t otal); a n d i njecti o n S R Ls (l o w, mi d dle 
or hi g h d oses). 
 
Dis p ositi o n f or t he C o m bi nati o n S u b st u d y 
F or t h e c o m bi nati o n s u b st u d y a s u m mar y will be pr o vi de d ta b ulati n g t h e n u m ber a n d perce nta ge 
of patie nts; e nr olle d, disc o nti n ue d, i ncl u di n g reas o n f or disc o nti n uati o n, c o m plete d, o ut of w hic h 
c o m pete d a n d c o nti n ue d i nt o t he E xte nsi o n or c o m plete d t he R C T b ut n ot c o nti n ue d i nt o t he 
e xte nsi o n ( n ot eli gi ble f or E xte nsi o n or eli gi ble f or E xte nsi o n yet decli ne d t o e nter), a n d n u m ber 
of patie nts  t hat c o m plete d  f oll o w-u p (i n p o p ulati o ns t hat re q uire f oll o w u p per pr ot oc ol)  usi n g t he 
C A S.  
Data will be pres e nte d o v erall (i.e., ca ber g oli ne t otal ).  
7  
 D E M O G R A P HI C S A N D B A S E LI N E DI S E A S E C H A R A C T E RI S TI C S  
7. 1  
De m o gr a p hics a n d b aseli ne dise ase c h ar acteristics  
D e m o gra p hic a n d baseli ne disease c h aracteristics d ata will be s u m marize d f or t he r u n-i n p hase, 
R C T p hase, a n d c o m bi nati o n p hase usi n g t he E A S, F A S a n d C A S p o p ulati o ns, res pecti vel y.  F or 
t he R C T p hase, if t he F A S a n d S A S p o p ulati o ns are differe nt , t h e n t he S A S will als o be us e d t o 
s u m marize data f or t he R C T p hase.   F or t he E A S  t he s u m mar y ta ble will prese nt data  f or all 
patie nt s a n d b y tar get d ose ( 4 0, 6 0, 8 0) . F or t he F A S a n d S A S p o p ulati o n s, t he s u m mar y ta ble will 
prese nt d ata o v erall a n d b y treat me nt gr o u p ( oral vs. S R Ls ). If t he F A S a n d S A S p o p ulati o ns are 
t he sa me, o nl y t he F A S will be pr o vi de d. F or t he C A S p o p ulati o n t he s u m mar y t a ble will pres e nt  
data f or all patie nts   
T he f oll o wi n g c o nti n u o us de m o gr a p hics data will be s u m marize d:  
•  A ge at scr ee ni n g i n years. A ge will be deri ve d fr o m t he year of birt h ( year of St u d y Da y 0 
– year of birt h).  
•  Wei g ht at  scr ee ni n g i n k g 
•  H ei g ht at scree ni n g i n c m  
•  B MI at scree ni n g i n k g/ m 2. B MI is calc ulate d as wei g ht / hei g ht i n meters s q uare d.  
 
T he f oll o wi n g cate g orical de m o gr a p hics data will be s u m marize d:  
•  A ge: < 6 5 years ol d, ≥6 5 years ol d; < 7 5 years ol d, ≥7 5 years ol d  
•  Ge n der: Mal e, Fe male  
•  Et h nicit y: His pa nic or Lati n o, N ot His pa nic or Lati n o, N ot Re p orte d, U n k n o w n 
•  Race: Asia n, A merica n I n dia n or Alas ka n Nati v e, Blac k Africa n or Afri ca n/ A merica n, 
Nati ve Ha waiia n or Pacific Isla n d er, W hite/ Ca ucasia n, Ot her. If m ore t ha n o ne race ca n is 
selecte d t he p atie nt will be prese nt e d i n eac h racial cate g or y i n t he s u m mar y ta ble(s).  
 
T he f oll o wi n g c o nti n u o us baseli ne disease c ha ract eristics data will be s u m marize d: 
•  Ti me fr o m Last S ur ger y (if a p plica ble)  
•  Ti me fr o m Last Ra diati o n (if a p plica ble)  
•  AI S Sc or e at Baseli ne  


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 6  of 4 4  
 
 
 
•  I G F-1 l e vels i n U L N val ues ( Baseli ne , Wee k 2 6  a n d C o m bi nati o n P hase Baseli ne) 
•  G H le vels i n n g / m L ( Baseli ne, Wee k 2 6 a n d C o m bi nati o n P hase Baseli ne) 
 
T he f oll o wi n g c ate g orical baseli ne disease c haract eristics  data will be s u m marize d:  
•  D urati o n of Acr o m e gal y : < 1 0 years, 1 0-< 2 0 years, ≥2 0 years, u n k n o w n. D urati o n will be 
calc ulate d as t he diff er e n ce i n years fr o m t he dat e of dia g n osis t o date of i nf or me d c o nse nt.  
•  Pit uitar y T u m or C haracteristics: Micr oa de n o ma, Macr oa d e n o ma , Ot her 
•  Pre vi o us Treat me nts f or Acr o me gal y a n y Ti me i n t he Past :  
S ur ger y o nl y ( Yes/ N o)  
Ra di ot hera p y o nl y ( Yes/ N o)  
S ur ger y a n d r a di ot hera p y ( Yes/ N o) 
Neit her S ur ger y n or r a di ot hera p y ( Y es/ N o) 
•  Resi d ual T u m or Size: N o re m na nts, < 5 m m, 5- 1 0 m m, > 1 0 m m 
•  Acr o me gal y  S y m pt o ms  A n yti me  i n  t he  Past  ( Base d  o n  Scree ni n g)  a n d  at  Baseli ne,  
se parat el y:  J oi nt  Pai n,  Pers pirati o n  ( S weati n g),  S welli n g  of  E xtre mities,  Fati g ue,  
Hea dac he, S n ori n g, Slee p a p nea, Car pal T u n nel S y n dr o me, Ot her 
•  At Least O ne or m ore A cti ve S y m pt o ms at Baseli ne: At least 1, At Least 2, at Least 3, …  
•  I G F-1 at Baseli ne:  ≤1 U L N , > 1- 1. 3 U L N, ≥1. 3 U L N f or t he E A S o nl y 
•  I G F-1 at Baseli ne a n d W ee k 2 6: ≤1 U L N , > 1- 1. 3 U L N, ≥1. 3 U L N  f or t he F A S o nl y 
•  I G F-1 at Baseli ne a n d C o m bi nati o n P hase Baseli ne: ≤1 U L N , > 1- 1. 3 U L N, ≥1. 3 U L N, ≥ 
2 U L N  f or t he C A S o nl y 
•  Re s p o nse at Baseli ne a n d wee k 2 6: ( C R, P R, N R) f or t he F A S o nl y 
•  Res p o nse at Baseli ne: ( C R, P R, N R) f or t he E A S a n d C A S o nl y 
•  G H at Baseli ne:  < 1 n g / m L, 1- 2. 5 n g / m L, ≥2. 5 n g / m L f or t h e E A S a n d C A S 
•  G H at Baseli ne a n d Wee k 2 6: < 1 n g / m L, 1- 2. 5 n g / m L, ≥2. 5 n g / m L f or t he F A S 
•  Me dical Treat me nt  o n ra n d o mizati o n : Octre oti de ca ps ules vs. S R Ls ( O ctre oti de L A R (l o w, 
mi d dle a n d hi g h d oses) a n d La nre oti de (l o w, mi d dle a n d hi g h d os es) 
•  Tar get D ose o n Oral O ctr e oti de f or t he F A S o nl y 
•  Pri or I nj ecta ble Treat me nt  Octre oti de L A R (l o w, mi d dle a n d hi g h d oses) a n d La nre oti de 
(l o w, mi d dle a n d hi g h d oses) 
Baseli ne disease c har acteristics will be s u m marize d  f or select s u b gr o u ps liste d i n Secti o n 5. 3. 
7. 2  
Me dic al hist or y  
Me dical hist or y will be c o de d wit h Me dical Di cti o nar y f or Re g ulat or y Acti vities ( Me d D R A) 
versi o n 1 8. 1 or later a n d s u m marize d b y S yste m Or ga n Class ( S O C)  a n d Preferre d Ter m  ( P T) wit h 
c o u nts  a n d  perce nt a ges . A patie nt  will  o nl y  be  c o u nte d  o nce  i n  a n  S O C  a n d  a n  S O C/ P T 
c o m bi nati o n.  
Me dical hist or y wi ll be s u m marize d f or t he r u n-i n p hase, R C T p hase a n d e xte nsi o n p hase usi n g 
t he E A S, F A S a n d C A S, res pecti vel y.  F or t he R C T p hase, if t he F A S a n d S A S p o p ulati o ns are 
differe nt , t he n t he S A S will als o be use d t o s u m marize data f or t he R C T p hase.  F or t h e E A S t he 
s u m mar y t a ble will pr ese nt data  f or all patie nt s a n d b y t ar get d ose ( 4 0, 6 0, 8 0) . F or t he F A S a n d 
S A S p o p ulati o ns, t he s u m mar y ta bl e will prese nt data o verall a n d b y treat me nt gr o u p ( oral vs. 
S R Ls). F or t he C A S p o p ulati o n t he s u m mar y ta bl e will prese nt data f or all patie nts  


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 7  of 4 4  
 
 
 
7. 3  
Pri o r  Me dic ati o ns, C o nc o mit a nt M e dic ati o ns  a n d C o nc o mit a nt Pr oce d ures  
All me dicati o ns ta ke n wit hi n 1 2 wee ks of  t h e i nitial Scree ni n g visit (wit hi n  1 year f or acr o m e gal y 
treat me nts), t hr o u g h t he e n d of t he st u d y will be rec or de d o n t he pri or a n d c o nc o mita nt me dicati o ns 
e C R F. All c o nc o mita nt pr oce d ur es will be rec or de d o n t he c o nc o mita nt pr o ce d ures e C R F. 
T he W orl d Healt h Or ga nizati o n ( W H O) Dr u g Dicti o nar y ( Se pte m b er 2 0 1 5 ) will be use d t o ma p 
eac h re p orte d me dicati o n t o a s pecific a nat o mic t hera pe utic class ( A T C) Le v el 4 a n d preferre d 
ter m ( P T).  Me d D R A 1 8. 1  or later  will be use d t o ma p eac h re p ort e d t hera p y/ pr o ce d ure t o a 
s pecific A T C Le v el 4 a n d P T. 
C o nc o mita nt me dicati o ns a n d pr o ce d ures will be s u m marize d  f or t he r u n-i n p hase, R C T p hase a n d 
e xte nsi o n p hase usi n g t h e E A S, F A S a n d C A S, res pecti vel y.  F or t he R C T p hase, if t he F A S a n d 
S A S p o p ulati o ns are differe nt , t he n t he S A S will als o be use d t o s u m marize data f or t he R C T 
p hase.  F or t he E A S t he s u m mar y ta ble will prese nt data  f or all patie nt s a n d b y tar get d ose ( 4 0, 6 0, 
8 0). F or t he F A S a n d S A S p o p ulati o ns, t he s u m m ar y ta ble will prese nt data o verall a n d b y 
treat me nt gr o u p ( oral vs. S R Ls). F or t he C A S p o p ulati o n t he s u m mar y t a ble will prese nt dat a f or 
all patie nts  
F or t he R u n-i n P hase 
F or t he p ur p ose of a nal yses, c o nc o mita nt me dicati o ns  are defi ne d as all me dicati o ns  (e x cl u di n g 
st u d y dr u g) ta ke n o n or after t he d a y of t h e first d os e of o ctre oti de ca ps ules d uri n g t h e R u n -i n u ntil 
t he e n d of t he R u n-i n P h ase or c o nti n ui n g d uri n g t he r u n -i n p hase.   C o nc o mita nt pr oce d ures are 
defi ne d as all pr oce d ures perf or me d o n or after t he da y of t he first d ose of octre oti de ca ps ules 
d uri n g t he R u n -i n u ntil t he e n d of t he R u n-i n P hase.  Pri or c o nc o mita nt me dicati o ns are defi ne d as 
all me dicati o ns ta ke n pri or t o t he first d os e of o ctre oti de ca ps ules a n d t hat are n ot c o nti n ui n g (i.e., 
the st o p date is pri or t o t he start date of octre oti de ca ps ules).  Pri or c o n c o mita nt pr oce d ures are 
defi ne d as all pr oce d ures perf or me d  pri or t o t he first d ose of octre oti de ca ps ules. 
F or t he R C T P hase 
F or t he p ur p ose of a nal yses, c o nc o mita nt me dicati o ns  are defi ne d as all me dicati o ns (e x cl u di n g 
st u d y dr u g) ta ke n o n or after t he da y of t he first ra n d o mize d d ose of st u d y dr u g d uri n g t he R C T 
P hase u ntil t he e n d of t h e R C T P hase or me dicati o ns w hic h are c o nti n ui n g at t he start of t he R C T 
P hase .   C o nc o mita nt pr oce d ures are defi ne d as all pr oce d ures perf or me d o n or after t he da y of t he 
first ra n d o mize d d ose of st u d y dr u g d uri n g t he R C T P hase u ntil t he e n d of t he R C T P hase.  Pri or 
c o nc o mita nt me dicati o ns are d efi ne d as all me dicati o ns ta ke n pri or t o t he first ra n d o mize d d ose of 
st u d y dr u g a n d t hat are n ot c o nti n ui n g.  Pri or c o nc o mita nt pr oce d ures are d efi ne d as all pr oce d ures 
perf or me d  pri or t o t he first ra n d o mize d d ose of st u d y dr u g. 
F or t he C o m bi nati o n S u b st u d y 
F or t he p ur p ose of a nal yses, c o nc o mita nt me dicati o ns are defi ne d as all me dicati o ns (e x cl u di n g 
st u d y dr u g) ta ke n o n or after t he da y of t he first d ose of st u d y dr u g d uri n g t he c o m bi nati o n p hase 
u ntil t he e n d of t he c o m bi nati o n P hase or c o nti n ui n g d uri n g t he c o m bi nati o n p hase.   C o n c o mita nt 
pr oce d ur es are defi n e d as all pr o ce d ur es perf or m e d o n or aft er t h e first d os e of st u d y dr u g d uri n g 
t he c o m bi nati o n p hase u ntil t he e n d of t he c o m bi nati o n P hase.  Pri or c o nc o mita nt me dicati o ns are 
defi ne d as all me dicati o n s ta ke n pri or t o t he first d ose of st u d y dr u g i n t he c o m bi nati o n p hase a n d 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 8  of 4 4  
 
 
 
t hat are n ot c o nti n ui n g.  Pri or c o nc o mita nt pr oce d ures are defi ne d as all pr oce d ures perf or me d  
pri or t o t he first d ose of st u d y dr u g i n t he c o m bi nati o n p hase. 
 
8  
T R E A T M E N T E X P O S U R E A N D C O M P LI A N C E  
8. 1  
E xte nt of E x p os ure a n d C o m pli a nce: Octre oti de  C a ps ules  
Octre oti de ca ps ules  (eac h ca ps ule is 2 0 m g stre n gt h) will  be a d mi nistere d t wice dail y ( A M a n d 
P M). Octre oti de ca ps ule  e x p os ure a n d c o m plia nce will be s u m marize d f or patie nt s i n t he R u n-i n 
p hase usi n g t he E A S, f or patie nt s i n t he R C T p hase usi n g b ot h t he S A S a n d F A S, a n d f or patie nt s 
i n t he C o m bi nati o n p hase usi n g t he C A S.  If t he F A S a n d S A S p o p ulati o ns are t he s a me, o nl y t he 
S A S will be pr o vi de d f or t he R C T p hase.  A d diti o nall y, a s u m mar y of e x p os ure will be pres e nte d 
acr oss t he R u n -I n a n d R C T p hases c o m bi ne d usi n g t he O A S.   
 
Octre oti de C a ps ules T a ke n d uri n g  R u n -i n p h ase 
O ctre oti de ca ps ules ca n b e  u p-titrate d d uri n g t he i nitial R u n-i n p hase fr o m 4 0 m g/ da y t o 6 0 m g/ da y 
a n d 6 0 m g/ da y t o 8 0 m g/ da y, b ase d o n cli nical a n d bi oc he mical res p o ns e.  
I n t he R u n-i n p hase, t he d urati o n of st u d y dr u g e x p os ure (i n wee ks) will be s u m marize d b y t he 
d ose le vel  a n d o verall, usi n g sta n dar d descri pti ve statistics.   
 
Descri pti ve st atistics f or t he ti me t o t he first d os e escalati o n fr o m 4 0 m g t o 6 0 m g a n d ti me t o t he 
sec o n d d ose escalati o n fr o m 6 0 m g t o 8 0 m g will be prese nte d. A fi g ure de picti n g t he ti me t o eac h 
d ose escal ati o n f or eac h p atie nt will be prese nte d.  
 
T he n u m ber a n d pr o p orti o n of patie nt s at eac h d ose le vel  (4 0, 6 0 a n d 8 0 m g/ da y ) b y visit, will als o 
be prese nt e d.  
 
C o m plia nce t o eac h d ose le vel of  octre oti de ca ps ules fr o m first dose i n t he R u n-i n p hase t hr o u g h 
t he last visit of R u n- i n p hase will b e calc ulate d a n d s u m marize d f or t he E A S patie nt s f or eac h 
tar get d ose le v el a n d o verall. 
 
F or t he p ur p ose of a nal ysis, c o m plia nce t o  eac h d ose le vel of  octre oti de ca ps ules d uri n g t he R u n -
i n p hase will be calc ul ate d as 1 0 0× ( t otal n u m ber of ca ps ules act uall y ta ke n / t otal n u m b er of 
ca ps ules e x pecte d t o be ta ke n). T his calc ulati o n will be use d f or eac h d ose le vel t he patie nt  
recei v e d d uri n g t he R u n -i n p hase a n d o verall . T he n u m bers a n d perce nt a ges of patie nt s <7 5 % 
c o m plia nt, 7 5- 1 0 0 % c o m plia nt, 1 0 0- 1 2 0 c o m plia nt a n d > 1 2 0 % c o m plia nt will be ta b ulate d.   
T he  n u m ber of act ual ca ps ules ta ke n f or eac h d ose le vel will be t he t otal n u m ber of ca ps ules 
dis pe nse d – t otal n u m ber of ca ps ules ret ur ne d d uri n g t he ti me t he patie nt  was o n t hat partic ular 
d ose.  
 
T he n u m ber of e x pecte d ca ps ules ta ke n f or t he tar get d ose l e vel will be deri ve d as f oll o ws: 
 
D ose Le vel  
E x pecte d N u m ber of C a ps ules T a ke n  
4 0 m g  
2 ca ps ules × ( first da y of t he p hase –  last da y of t h e p hase) 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 2 9  of 4 4  
 
 
 
6 0 m g  
3 ca ps ules × ( first da y of t he p hase –  last da y of t h e p hase) 
8 0 m g  
4 ca ps ules × ( first da y of t he p hase –  last da y of t h e p hase) 
O verall  
S u m of e x pecte d n u m ber of ca ps ules ta k e n o ver all of t he d ose  le v els assi g n e d 
F or t he r u n-i n p hase, t h e s u m mar y ta bl e will prese nt c ol u m ns f or octre oti de  ca ps ules o verall  a n d 
b y  fi nal tar get octr e oti de ca ps ule d oses of 4 0, 6 0, or 8 0 m g.  
Octre oti de C a ps ules T a ke n d uri n g  R C T  p h ase   
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 d e ca ps ules treat me nt (tar get d ose le vel 4 0, 6 0 or 8 0 m g) or re vert t o t heir 
S O C i njecta ble S R L d uri n g t he R C T p has e.  T he S R L i njecti o ns c o m plia nce a n d e xte nt of e x p os ure 
is detaile d i n Secti o n 7. 2 bel o w. 
 
T he f oll o wi n g p ara met ers will be calc ulate d f or t he R C T P hase si milarl y t o t he al g orit h ms  a n d 
l o gic use d f or t he R u n-i n P hase: 
•  D urati o n of e x p os ure i n wee ks 
•  C o m plia nce 
S u m maries  will i ncl u de  c ol u m ns f or octre oti de ca ps ules  o verall  a n d octre oti de ca ps ule tar get d oses 
of 4 0, 6 0, or 8 0 m g.  
 
Octre oti de C a ps ules T a ke n D uri n g C o m bi n ati o n P h ase  
Patie nts e nteri n g t he C o m bi nati o n p hase s u b -st u d y will recei v e c o-a d mi nistrati o n of octre oti de 
ca ps ules at 8 0 m g wit h ca ber g oli ne 
. Ca b er g oli ne 
c o m plia nce a n d e xte nt of e x p os ure is detaile d i n Secti o n 7. 3 bel o w.  
 
T he f oll o wi n g p ara met ers will be calc ulate d f or t h e C o m bi nati o n P hase si milarl y t o t he al g orit h ms  
a n d l o gic us e d f or t he R u n- i n P hase: 
•  D urati o n of e x p os ure i n wee ks 
•  C o m plia nce 
 
S u m maries  will be prese nte d f or all patie nt s, as all patie nts will be o n 8 0 m g. 
8. 2  
E xte nt of E x p os ure a n d C o m pli a nce: S R L I njecti o ns  ( Octre oti de a n d L a nre oti de) 
 
I n t he R C T p hase, f or patie nts ra n d o mize d t o t he acti ve c o ntrol ar m, S R Ls will be i njecte d 
s u bc uta ne o usl y at site visits at t he sa me d ose a n d a d mi nistrati o n fre q ue n c y as  recei ve d pri or t o 
st u d y e ntr y. F or t his st u d y, t he d ose ra n ges all o we d f or O ctre oti de or La nre oti de are a n y d os e use d 
o n t he mar ket ( Octr e oti de 1 0, 2 0 a n d 3 0 m g a n d La nre oti de 6 0, 9 0 a n d 1 2 0 m g) as l o n g as t he 
d osi n g i nter val d oes n ot e x cee d o nce e v er y 8 wee ks (e. g. d osi n g i nter vals of e ver y 4, 5, 6, 7 or 8 
wee ks are all o we d). D osi n g e v er y 2 w ee ks is n ot all o we d u nless t he p atie nt was sta bilize d f or 4 
m o nt hs o n a m o nt hl y d osi n g re gi me n.  
 
F or t he F A S a n d S A S p o p ulati o ns t he s u m mar y ta ble will prese nt all patie n ts ra n d o mize d t o S R Ls 
i njecti o ns, a n d b y pri or d ose of S R L  I njecta bl es: L o w, Mi ddle, Hi g h .  If t he F A S a n d S A S 
p o p ulati o ns are t he sa me, o nl y t he S A S will be pr o vi de d. 








C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 3 3  of 4 4  
 
 
 
t o ha ve w orse n e d.  If a patie nt has n ot disc o nti n ue d, b ut is missi n g t heir wee k 6 2/ E O T AI S 
assess me nt,  t he n  t he  L O C F  a p pr oac h  will  be  use d  t o  i m p ute t heir  AI S  score,  pri or  t o  
deter mi nati o n of res p o ns e stat us.  A d diti o nall y, a n ot her a nal ysis will be perf or me d t h at will 
i m p ute all missi n g AI S s c ores usi n g t he L O C F a p pr oac h. 
 
F or t he e n d p oi nt of “ Pr o p orti o n of patie nts of t h ose c o m pleti n g t h e R C T p hase (at a ti me octr e oti de 
ca ps ules wer e n ot c o m merciall y a vaila ble at t he s pecific c o u ntr y), w h o e nt er t he St u d y E xte nsi o n 
p hase”, a s u m mar y of t h e n u m ber a n d pr o p orti o n of patie nts  will be pr o vi de d, i ncl u di n g t he 9 5 % 
c o nfi de nce i nter val s base d o n t he Cl o p per- Pears o n  A p pr oac h, o verall a n d b y eac h treat me nt gr o u p 
( octre oti de a n d S R L).  N o i nfere ntial testi n g a n d or esti mati o n bet wee n gr o u ps will be c o n d ucte d. 
T he de n o mi nat or will be deter mi ne d at t he ti me of t he c o m pleti o n of t he R C T p hase base d o n 
c o m mercial a vaila bilit y of octre oti de.  If octre oti de is n ot c o m merciall y a vaila ble i n a n y of t he 
c o u ntries i ncl u de d i n t his st u d y, t he de n o mi nat or will be t hat of t he F A S c o m pleters . 
 
E n d p o i nts t hat are C ha n ges fr o m Baseli ne 
A nal ys es of t he c h a n ge fr o m t he start of R C T p hase ( wee k 2 6) t hr o u g h t he e n d of t he R C T p hase 
( wee k 6 2/ E O T) f or IG F- 1 a n d t he c ha n ge fr o m t he start ( wee k 2 6) t o t he e n d of t he R C T p hase 
( wee k  6 2/ E O T)  i n  mea n  i nte gr ate d  G H  will  be  c o n d ucte d  usi n g  a n  a nal ysis  of  c o vari a nce  
(A N C O V A ) t o a dj ust f or baseli ne (IG F- 1 a n d G H, res pecti vel y). T he a dj uste d mea n rati o (i. e., 
relati ve c ha n ge), a n d ass ociate d 9 5 % CIs  will be re p orte d. D ata will be a n al yze d o n t he l o g s cale 
a n d bac k tr a n sf or me d f or re p orti n g. T he c h a n ge t hr o u g h t he e n d of t he R C T p hase f or I G F-1 will 
be deri ve d as a ti me w ei g hte d a vera ge c h a n ge ( See Secti o n 3. 6. 2), starti n g wit h t he first o bs er ve d 
val ue f oll o wi n g ra n d o mi zati o n (i.e., wee k 2 6), a n d usi n g t he w ee k 2 6 val u e as t he b aseli ne val u e 
t o calc ulate t he c ha n ge at eac h visit. 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 h e d ule d” visits. 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 ng val ue will be i m p ute d  f or I G F- 1.  F or G H, if a patie nt is 
missi n g t he wee k 6 2/ E O T val ue, it will be i m p ute d usi n g t he L O C F a p pr oac h.  I n a d diti o n, a n 
a nal ysi s of t he c ha n ge fr o m baseli ne fr o m  wee k 2 6 t o e n d of  t he R C T p hase ( wee k 6 2 /E O T ) will 
als o be c o n d uct e d  f or I G F- 1. If a p atie nt is missi n g t heir w ee k 6 2/ E O T I G F- 1 v al ue,  it will be 
i m p ute d usi n g t he L O C F a p pr oac h. 
 
S hifts fr o m wee k 2 6 ( R C T Baseli ne) t o  w ee k 6 2/ E O T, i n I G F-1 a n d G H , f or t he R C T p hase will 
als o be prese nte d  b y treat me nt gr o u p . S hift ta bles will be pr o d uce d f or I G F-1 usi n g t he f oll o wi n g 
cate g ories (I G F - 1 ≤1 x U L N L , I G F-1 bet w ee n > 1 x U L N  a n d < 1. 3 x U L N , I G F-1 ≥ 1. 3  x U L N , 
earl y ter mi nate d, missi n g ). A s hift ta ble s u m marizi n g G H ( < 1. 0 n g/ ml , 1. 0 – 2. 5 n g/ ml , > 2. 5 n g/ ml , 
earl y ter mi nate d, missi n g ) fr o m R C T baseli ne ( wee k 2 6) t o t he t o w ee k 6 2/ E O T of t he R C T p has e  
will als o be prese nte d.   
 
A C R O -T S Q  
T he S A P will be a me n de d wit h f urt her det ails o n t he a nal yses of A C R O- T S Q as state d i n Secti o n 
1. T he q uesti o n naire w as 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 p atie 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 h e 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 nal 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 w ere e val uate d a n d f o u n d t o be acce pta ble. It e ms relate d t o 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 3 4  of 4 4  
 
 
 
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 h er 
wit 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 h e c urre nt st u d y.  
 
A nal ysis of t he Acr o -T S Q d uri n g t he R C T P hase will be c o n d ucte d usi n g t he F ull A nal ysis Set 
( F A S). A nal yses will be base d u p o n all a vaila ble data, a n d missi n g scal e d ata will n ot b e i m p ute d. 
O nl y data fr o m t he ne w v ersi o ns of t he Acr o -T S Q will be a nal yz e d, a n d we will o nl y i ncl u de dat a 
fr o m s u bjects t hat ha ve c o m plete d t he Wee k 2 6 a n d at least o ne a d diti o nal ti me p oi nt d uri n g t he 
R C T P hase.   Descri pti ve statistics will be re p orte d f or all Acr o -T S Q scale sc ores at We e ks 2 6, 3 8, 
5 0 a n d 6 2, i ncl u di n g sa m ple size, mea n, me dia n, sta n dar d de viati o n, mi ni m u m, ma xi m u m, a n d 
9 5 % c o nfi d e nce i nter val. Descri pti ve statistics will be re p orte d s e paratel y b y treat me nt ar m a n d 
als o b y treat me nt ar m a n d bi oc he mical c o ntr ol stat us d uri n g t he R C T, defi ne d as a n I G F -1 Ti me 
Wei g hte d A vera ge ( T W A) d uri n g t he R C T P hase of < 1. 3 × U L N (s ee defi niti o n of Pri mar y 
E n d p oi nt a b o ve ) a n d t he e n d of treat me nt ( E O T) I G F-1 val ue b ase d o n t he a vera ge fr o m Wee ks 
5 8 a n d 6 2.  
 
Descri pti ve statistics will a ls o be re p orte d f or c h a n ge fr o m Wee k 2 6 i n Acr o-T S Q scale sc ores at 
Wee ks  3 8,  5 0  a n d  6 2,  i ncl u di n g  s a m ple  size,  mea n,  me dia n,  sta n dar d  de viati o n,  mi ni m u m,  
ma xi m u m, a n d 9 5 % c o nfi de nce i nter v al. Descri pti ve statistics f or c ha n ge s c ores will be re p orte d 
b y tr eat me nt ar m a n d als o b y treat me nt ar m a n d bi oc he mical c o ntr ol stat us d uri n g t he R C T , defi ne d 
as a n I G F-1 Ti me Wei g ht e d A ver a ge ( T W A) d uri n g t he R C T P hase of < 1. 3 × U L N (s ee defi niti o n 
of Pri mar y E n d p oi nt a b o ve) a n d t he e n d of treat me nt ( E O T) I G F-1 val ue base d o n t he a vera ge 
fr o m Wee ks 5 8 a n d 6 2.  A c o m paris o n of t he treat me nt gr o u ps will be ma de f or eac h scale 
se parat el y usi n g a r e peate d meas ures mi x e d m o del, wit h t he c ha n ge fr o m Baseli ne (i.e., Wee k 2 6 
of t he R u n -I n P hase) as t he de pe n de nt v aria ble, b aseli ne (i.e., Wee k 2 6 of t he R u n-I n P has e) as a 
c o variate a n d fi x e d eff ects f or treat me nt gr o u p, ti me p oi nt a n d t he treat me nt gr o u p b y ti me p oi nt 
i nteracti o n. S u bject will be treate d as a ra n d o m effect, usi n g a n u nstr uct ure d c o varia n ce.   
 
If t h e m o del fails t o c o n ver ge, alter nati ve c o varia n ce str uct ures will be c o nsi dere d (e. g., C S, A R( 1), 
etc..), a n d t he o ne w hic h pr o vi des t he l o west AI C will be c h ose n.  T he least s q uare mea ns (ls mea ns) 
treat me nt diff ere n ce f or eac h ti me p oi nt a n d t he 9 5 % CI will be re p orte d. F or t he t hree A cr o -T S Q 
scales  wit h  esta blis he d  MI D  esti mates  ( S y m pt o m  I nterfere nce:  MI D  =  1 1;  Treat me nt  
C o n ve nie nce: MI D = 1 0; GI I nterfer e nce: MI D = 9), s u bjects will be classifi e d as I m pr o v e d (scale 
sc ores i ncr ease b y MI D val ue or gr eater fr o m Wee k 2 6 t o Wee k 6 2), U nc h a n ge d (scale sc ores d o 
n ot i ncreas e or d ecr ease b y MI D val u e fr o m Wee k 2 6 t o Wee k 6 2) or W orse ne d (scale sc ores 
decrease b y MI D val ue or gr eater fr o m Wee k 2 6 t o Wee k 6 2).  I n a d diti o n, f or all si x Acr o -T S Q 
scales, s u bjects will be cl assifie d as I m pr o v e d (s cale sc ores i ncreas e b y > 0. 5 S D or greater fr o m 
Wee k 2 6 t o Wee k 6 2), U nc ha n ge d (scal e sc ores d o n ot i ncrease or decreas e b y 0. 5 S D fr o m Wee k 
2 6 t o Wee k 6 2) or W orse ne d (scale sc ores decreas e b y < 0. 5 S D or greater fr o m Wee k 2 6 t o Wee k 
6 2). 
 
9. 4  
E x pl or at or y Effic ac y A n al yses  
R C T P hase  






C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 3 7  of 4 4  
 
 
 
 
T he E Q - 5 D-5 L will be s u m marize d at baseli ne a n d t he e n d of t he r u n-i n as f oll o ws: 
•  A s u m mar y of t he fre q ue nc y a n d pr o p orti o n of re p orte d pr o ble ms f or eac h le v el a n d 
di me nsi o n, 
•  A descri pti ve s u m mar y of t he V A S,  
•  A descri pti ve s u m mar y of t he i n de x val ue. 
N o i nfere ntial statistics will be re p orte d. 
 
Eac h of t he 4 W P AI sc ores will be s u m marize d at baseli ne a n d t he e n d of t he r u n -i n usi n g 
descri pti ve statistics.  N o i nfere ntial statistics will be re p ort e d.  
 
A nal ysis of t h e Acr o -T S Q d uri n g t h e R u n -i n P hase will be c o n d ucte d usi n g t he enr olle d a n al ysis 
set  ( E A S)  f or  t h ose  s u bjects  t hat  ha ve  c o m plete d  b ot h  Baseli ne  a n d  Wee k  2 6  assess me nts.  
A nal ys es will be base d u p o n all a vaila ble data, a n d missi n g scale d ata will n ot be i m p ute d. We 
will i ncl u de data fr o m s u bjects t hat ha ve c o m plet e d t he ne w versi o ns of t he Acr o -T S Q, a n d will 
e x pl ore t he p ossi bilit y of i ncl u di n g data fr o m s u bjects usi n g t h e ol d versi o n w here c o m m o n 
ite ms/scales are utilize d.  Descri pti ve statistics will be re p orte d f or all Acr o -T S Q scale s c ores at 
Scree ni n g,  Baseli ne a n d  W ee k 2 6, i ncl u di n g sa m ple size, mea n, me dia n, sta n dar d de viati o n, 
mi ni m u m, ma xi m u m, a n d 9 5 % c o nfi de n ce i nter v al.  
 
Descri pti ve statistics will be re p orte d f or t he E A S w h o c o m plete d t he u p date d versi o n of t he 
q uesti o n naire at least o n Scree ni n g/ B L a n d Wee k 2 6, as well as se paratel y f or t h ose ra n d o mize d 
vers us n ot ra n d o mize d t o t he R C T p hase. Descri pti ve statistics will als o be re p ort e d f or c ha n ge 
fr o m  Baseli ne i n  Acr o-T S Q  scale sc ores  at  Wee k  2 6,  i ncl u di n g sa m ple size,  mea n,  me dia n,  
sta n dar d de viati o n, mi ni m u m, ma xi m u m, a n d 9 5 % c o nfi de n ce i nter val. As a b o ve, descri pti ve 
statistics f or c h a n ge s c or es will be re p ort e d o verall , as well as se p arat el y f or t h ose e nt eri n g v ers us 
n ot e nteri n g t h e R C T P hase.  
 
F or t he t hree A cr o -T S Q s cales wit h esta blis he d MI D esti mates ( S y m pt o m I nterfere nce: MI D = 1 1; 
Treat me nt  C o n ve nie n ce:  MI D = 1 0;  GI  I nterfere nce:  MI D = 9),  s u bjects  will  be  classifie d  as  
I m pr o v e d (s cale sc ores i ncreas e b y MI D val ue or greater fr o m Bas eli ne t o Wee k 2 6), U nc h a n ge d 
(scale sc or es d o n ot i ncrease or decr ease b y MI D val ue fr o m Bas eli ne t o Wee k 2 6), or W orse ne d 
(scale sc ores decrease b y MI D v al ue or greater fr o m Baseli ne t o Wee k 2 6). I n a d diti o n, f or all si x 
Acr o -T S Q scal es, s u bjects will be classifie d as I m pr o ve d (scale sc ores i ncreas e b y > 0. 5 S D or 
g r eater fr o m Bas eli ne t o Wee k 2 6), U n c ha n ge d (s cale sc ores d o n ot i ncrease or decrease b y 0. 5 
S D fr o m Bas eli ne t o Wee k 2 6), or W orse n e d (scale sc ores decrease b y < 0. 5 S D or greater fr o m 
Baseli ne t o Wee k 2 6).  
 
I n or der t o i de ntif y c har acteristics of p atie nts o n S R L treat me nts t hat w o ul d be pre dicti ve f or a 
s uccessf ul s witc h t o oral treat me nt, if s uc h e xist, e x pl orat or y a n al yses will be c o n d u cte d usi n g all 
patie nts e nr olle d i nt o t he r u n-i n p hase. U ni variate a n d m ulti variate l o gistic re gressi o n m o dels will 
be e x pl ore d t o i de ntif y b aseli ne c har acteristics  i.e., baseli ne I G F -1 le vel, G H 1, d ose of S R L i njecti o n, 
d urati o n of disease, AI S sc ore, ge n der, a ge, a n d B MI, ass ociate d  wit h bi oc he mical res p o nse at t he 
e n d of t he d os e titrati o n p hase. A patie nt will be c o nsi dere d a res p o n der ( i.e., ha d a s u ccessf ul 
s witc h) if at t he e n d of t he R u n -i n p hase t heir I G F- 1 is < 1. 3 ×  U L N a n d mea n i nte grate d G H  is 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 3 8  of 4 4  
 
 
 
< 2. 5 n g/ m L .  E ac h of t he a b o ve baseli ne c haracteristics will be i ncl u de d i n u ni variate m o dels.  All 
baseli ne c har ac teristics w hic h are f o u n d t o be statisticall y si g nifica nt ( p < 0. 0 5) will be i ncl u de d i n 
a m ulti variate l o gistic re gr essi o n m o del t o deter mi ne t he fi nal set of c haract eristics w hic h are 
pre dicti ve of res p o nse b ase d o n ste p wise a p pr oac h usi n g a 1 0 % si g nifica n ce le vel.   I n a d diti o n, 
all baseli ne c har acteristics of t h ose p atie nts eli gi ble t o e nter t he R C T p h ase a n d t h ose patie nts w h o 
were  n ot, will be prese nte d usi n g descri pti ve statistics.   C o m paris o ns bet wee n t he t w o gr o u ps 
(eli gi ble vs n ot) will be ma de usi n g t w o -sa m ple t-tests a n d C hi-s q uare tests, as a p pr o priat e.  If a n y 
c haracteristics  are f o u n d t o be si g nifica nt, w hic h are n ot liste d a b o ve, t he y will als o be i ncl u de d i n 
u ni variate a n d m ulti variate l o gistic re gressi o n m o dels as descri b e d  a b o ve. 
 
R u n- i n + R C T P hase  
A nal ysis of t he e x pl orat or y e n d p oi nt (s) b ase d o n t he R u n- i n a n d R C T p has e will be s u m marize d 
usi n g t he O A S  p o p ulati o n c o m bi ne d.  T he  pr o p orti o n of patie nts w h o mai ntai n or i m pr o ve t heir 
o verall AI S sc ore at t he e n d of t he R C T p hase (i m pr o ve me nt defi ne d as a re d ucti o n of at least o ne 
p oi nt i n t he AI S sc ore), c o m pare d t o Bas eli ne (i. e., pri or t o t he R u n -i n p hase) will be a nal yze d  
usi n g t he sa me a p pr oac h as t he pri mar y e n d p oi nt. 
 
S hifts fr o m r u n -i n baseli ne t o wee k 6 2/ E O T, i n I G F-1 a n d G H , f or t he R u n-I n a n d R C T p hase 
c o m bi ne d, will be prese nte d usi n g t he O A S. S hift ta bles will be pr o d uce d f or I G F-1 usi n g t he 
f oll o wi n g cate g ori es (I G F- 1 ≤1, I G F -1 bet w ee n > 1 a n d < 1. 3, I G F -1  ≥  1. 3 , earl y ter mi nate d, 
missi n g ). S hift ta bles f or  G H will use t he f oll o wi n g cate g ories ( < 1. 0, 1. 0 – 2. 5, > 2. 5 ,  earl y 
ter mi nate d, missi n g).  
 
S hift ta bles s h o wi n g t he p r o p orti o n of patie nts w h o w orse n e d,  mai ntai n e d or i m pr o v e d t heir 
o verall AI S sc ore at t he e n d of t he R C T p hase (i m pr o ve me nt defi ne d as a re d ucti o n of at least o ne 
p oi nt i n t he AI S sc or e , w orse ne d defi n e d as a n i ncrease of at least 1 p oi nts a n d mai ntai ne d defi ne d 
as n o c ha n ge ), c o m pare d t o Baseli ne (i. e., pri or t o t he R u n-i n p hase) will be pr o vi de d.  If a p atie nt 
ter mi nates earl y, t h eir last assess me nt will be use d. 
 
9. 5  
C o m bi n ati o n P h ase S u b -st u d y (i n selecte d sites)  
 
A nal ysis of t he c o m bi nati o n p hase e n d p oi nts will use t he C A S p o p ulati o n. T he pr o p orti o n a n d 
t w o-si de d 9 5 % CI of t h e pr o p orti o n ( b ase d o n t he Cl o p per Pears o n met h o d) will be re p orte d f o r 
eac h bi n o mial e n d p oi nt. If a p atie nt  earl y ter mi nates, t he y will be c o nsi dere d a n o n -res p o n der.  F or 
all  ot her  patie nts ,  t he L O C F  a p pr oac h  will  be  use d  t o  i m p ute  a n y  missi n g  val ues,  pri or  t o  
deter mi ni n g t he p atie nts’ res p o nse stat us.  
 
S hifts fr o m t he c o m bi nati o n baseli ne t o t he e n d of t he c o m bi nati o n p has e, i n I G F -1 a n d G H, f or 
t he c o m bi nati o n p has e, will be pr ese nte d usi n g t he C A S.  Shift ta bl es will be pr o d u ce d f or I G F-1 
us i n g t he  f oll o wi n g  cat e g ories  (I G F- 1 ≤1,  I G F -1  bet wee n  > 1  a n d  < 1. 3,  I G F -1  ≥  1. 3 ,  earl y  
ter mi nate d, missi n g). S hift ta bles f or G H will use t he f oll o wi n g cate g ori es  ( < 1. 0, 1. 0 – 2. 5, > 2. 5 , 
earl y ter mi nate d, missi n g ).  
 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 3 9  of 4 4  
 
 
 
A d diti o nall y, t he rate of c ha n ge f or I G F -1 will be esti mate d usi n g a re p eate d meas ures mi x e d 
effects m o del ( wit h o ut i m p utati o n of missi n g data). T he m o del will c o ntai n fi x e d effects f or 
baseli ne I G F - 1, visit a n d t he i nteracti o n bet wee n b aseli ne I G F-1 a n d visit.  S u bject will be treate d 
as ra n d o m  wit h a n d u nstr uct ure d c o varia n ce matri x.  If t he m o del will n ot c o n ver ge, alter n ati ve 
c o varia n ce str uct ures will be e val uate d wit h t he best fit deter mi ne d b y t he AI C a n d S B C criteria.  
 
1 0  S A F E T Y A N A L Y S E S  
All  safet y  e n d p oi nts  will  be  s u m marize d  acr oss  eac h  p has e  of  t he  st u d y  se p arat el y  usi n g  
descri pti ve  statistics.  Safet y  e n d p oi nts  will  be  als o  prese nte d  f or  all  p atie nts  ra n d o mize d  t o  
octre oti de ca ps ules t hr o u g h o ut t he r u n-i n a n d R C T p hase c o m bi ne d usi n g t he O A S. 
F or t he R u n- i n p hase, safet y e n d p oi nts will be s u m marize d f or t he E A S w here ta ble s u m maries 
will i ncl u de treat me nt gr o u p c ol u m ns f or oral o ctre oti de tar get d oses of 4 0, 6 0, or 8 0 m g a n d a 
t otal c ol u m n. F or t he R C T p hase, safet y e n dp oi nts will be s u m marize d f or t he S A S  w here ta ble 
s u m maries will i ncl u de treat me nt gr o u p c ol u m ns f or oral octre oti de t otal; oral octre oti de tar get 
d oses of 4 0, 6 0, or 8 0 m g; i njecti o n S R Ls (t otal); a n d i njecti o n S R Ls (l o w, mi d dle or hi g h d oses).  
F or  t he  C o m bi nati o n  p hase,  saf et y  e n d p oi nts  will  be  s u m marize d  f or  t he  C A S  w here  ta ble  
s u m maries will i ncl u de treat me nt gr o u p c ol u m ns f or t he hi g h est d ose of ca ber g oli ne a n d o verall.  
F or s u m maries of t he R u n -I n + R C T p hases c o m bi ne d, usi n g t he O A S, treat me nt gr o u p c ol u m ns 
f or oral octre oti de tar get d oses of 4 0, 6 0, or 8 0 m g a n d a t otal c ol u m n will be prese nt e d. 
1 0. 1  A d verse E ve nt  
A d verse e v e nts ( A Es) ar e  assesse d at all st u d y visits fr o m i nf or me d c o nse nt si g ni n g , h o we ver o nl y 
treat me nt e mer ge nt a d v erse e ve nts ( T E A Es) wi ll be pr o vi de d i n s u m mar y ta bles.  All a d vers e 
e ve nts will be pr o vi de d i n listi n gs . A treat me nt e mer ge nt  a d verse e v e nt is defi ne d as a n A E wit h 
a n o nset o n or after  st u d y dr u g i nitiati o n at R u n-i n (Da y  0) or a n A E t hat h as w orse n e d  i n se v erit y 
after t he first d ose of st u d y dr u g  a n d pri or t o t he last d ose of st u d y dr u g . A d verse e ve nts will be 
c o de d usi n g t he Me d D R A Dicti o nar y V ersi o n 1 8. 1 or later .  
 
All  re p orte d  A Es  will  be  s u m marize d  b y  s yste m  or ga n  cl ass  ( S O C)  a n d  preferre d  ter m.  
A d diti o nall y, A Es will be s u m marize d b y preferre d ter m  i n desce n di n g or der of fre q u e nc y base d 
o n t he t otal c ol u m n of eac h ta ble, a n d t he n al p ha beticall y .  If s e verit y is missi n g, t he ma xi m u m 
se verit y will be i m p ute d.  F or a nal ys es b y relati o ns hi p , all A Es defi ne d as “ p ossi bl y relate d” or 
“relate d ” t o st u d y dr u g will be c o nsi dere d as rel ate d. If relati o ns hi p is missi n g, t he A E will b e 
c o nsi dere d r elate d.  
 
F or eac h st u d y p has e t he f oll o wi n g A E s u m mari es will be pr o vi de d: 
•  O verall A E s u m mar y  
•  All A Es b y S O C a n d P T  
•  All A Es b y S O C, P T a n d Se verit y  
•  All A Es b y S O C, P T a n d Relati o ns hi p  
•  All A Es res ulti n g i n Disc o nti n uati o n b y S O C, P T a n d Relati o ns hi p 
•  All S A Es b y S O C a n d P T  


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 4 0  of 4 4  
 
 
 
•  All S A Es b y S O C, P T a n d Relati o ns hi p. 
 
All A Es will be assi g ne d t o a st u d y p has e bas e d o n t he start date  of t he A E i n rel ati o n t o t he start 
a n d st o p dates of eac h st u d y p h ase.  If t he A E starte d i n t he r u n -i n p h ase, it will be assi g ne d t o t he 
r u n-i n p hase, if it starte d i n t he R C T p hase it will be assi g ne d t o t he R C T p hase, if it starte d i n t he 
C o m bi nati o n p hase it will be assi g n e d t o t he c o m bi nati o n p hase.   S u m maries of t he R u n -I n + R C T 
p hase will i ncl u de A Es w hic h starte d i n eit her p h ase.  
 
1 0. 2  Cli nic al L a b or at or y Tests  
All cli nical la b orat or y ass ess me nts will be perf or me d b y a ce ntral la b orat or y.  C o nti n u o us data will 
be s u m marize d at eac h ti me p oi nt usi n g descri pti ve statistics.  B ot h a bs ol ute a n d c ha n ge fr o m 
baseli ne will be pr o vi de d f or eac h c o nti n u o us la b para meter.  
 
Baseli ne v al ues f or eac h p hase ar e defi ne d i n Secti o n 4. 1. T hese s u m mar y t a ble s will als o prese nt 
t he nu m ber a n d p erce nt a ge of patie nt s wit h la b orat or y v al ues t hat fall o utsi de t he la b orat or y 
refere nce ra n ges.  All cate g ori cal la b val ues will be s u m marize d b y prese nti n g t he n u m ber a n d 
perce nt a ge of p atie nts b y cate g or y.   
 
A d diti o nal ta ble s u m maries will prese nt s hifts fr o m baseli ne t o eac h p ost baseli ne visit, f or eac h 
st u d y p h ase se paratel y. S hifts will be defi ne d acc or di n g t o la b orat or y refere nce ra n ge s, wit h val ues 
bel o w t he l o wer li mit of n or mal, wit hi n t he n or mal refere nce ra n ge  a n d a b o v e u p per li mit of n or mal 
re p orte d. Cat e g orical la b data will n ot ha ve s hifts prese nte d.  A lis ti n g  of patie nt s wit h n ota ble 
a b n or malities at a n y visit occ urri n g after treat me nt will be pr o vi de d b y p h as e .   
 
T he f oll o wi n g l a b data t h at will be s u m marize d as c o nti n u o us data:   
• 
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 hit e bl o o d cell 
( W B C) c o u nt a n d diff ere ntial, platelets 
• 
Ser u m bi oc he mistr y: gl u c 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 nsfer ase ( G G T), lact ate de h y dr o ge n ase ( 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 r efer t o Pr ot oc ol Secti o n 6. 2. 4
(
 
• 
T S H, free T 4  
• 
H b A 1c  
• 
Li 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, p H 
 
T he f oll o wi n g l a b data t h at will be s u m marize d as cate g orical data:   
• 
U ri nal ysis: ket o nes, 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 n c y test, if a p plica ble 
• 
Uri ne pre g n a nc y test, if a p plica ble  
• 
F P G; f or dia betic p atie nts o nl y at Scree ni n g  


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 4 1  of 4 4  
 
 
 
1 0. 3  Vit al Si g ns  
Vital si g ns will b e s u m marize d at eac h ti me p oi nt usi n g descri pti ve statistics.  B ot h a bs ol ute a n d 
c ha n ge fr o m b aseli ne will be pr o vi de d f or eac h c o nti n u o us la b para meter.  Baseli ne val ues f or eac h 
p hase ar e defi n e d i n Secti o n 4. 1.  
1 0. 4  E C G  
All 1 2 -Lea d E C Gs will be rea d  b y a ce ntral la b. 1 2 -Lea d E C G p ara met ers will be s u m marize d at 
eac h ti me p oi nt usi n g d es cri pti ve statistics.  B ot h a bs ol ute a n d c ha n ge fr o m baseli ne will be 
pr o vi de d f or eac h c o nti n u o us 1 2- Lea d E C G p ara meter. Baseli ne val u es f or eac h p h ase are 
defi ne d i n Secti o n 4. 1.  
 
A d diti o nall y, t he n u m b ers a n d perce nt a ges of pati e nt s wit h E C G a b n or malities (as d eter mi ne d b y 
t he ce ntr al la b or at or y) at eac h visit  will be pres e nte d .  T he para meters a n d a b n or malit y criteria are 
s pecifie d i n t he ta ble b el o w: 
  
  
  
 
Para meter   
  
 
A b n or malit y Criteri o n  
P R i nter val   
  
  
< 1 1 0 ms 
  
  
  
  
> 3 0 0 ms  
 
Q R S i nter val     
 
≥1 2 0 ms 
 
Q Tc F     
  
  
< 3 5 0 ms 
  
  
  
  
Male > 4 5 0 ms or Fe male > 4 7 0 ms  
  
  
  
  
> 5 0 0 ms  
 
Heart r ate   
  
  
< 5 0 b p m 
  
  
  
  
> 1 1 0 b p m 
 
S hift ta bles will be use d t o s h o w t he c ha n ges fr o m baseli ne  t o eac h p ost baseli ne ti me p oi nt base d 
o n t he a b o ve a b n or malit y criteria.  
 
A lis ti n g of patie nt s wit h n ota ble a b n or malities at a n y visit occ urri n g after treat me nt will be 
pr o vi de d b y p hase 
1 0. 5  Ec h oc ar di o gr a m   
I n sel ecte d sites partici p ati n g i n t he C o m bi nati o n p hase, car diac E C H O is perf or me d t o ass ess 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 o r val ve leaflet 
t hic ke ni n g). It s h o ul d be d o ne as s pecifie d i n t he Pr ot oc ol’s Sc he d ule of Assess me nts ( A p pe n di x 
B t hr o u g h A p p e n d i x D) 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.  All E C H O  data will be liste d  o nl y. 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 4 2  of 4 4  
 
 
 
1 0. 6  A b d o mi n al ( G all bl a d der) Ult r as o u n d   
A b d o mi nal ultras o u n d is 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 p eci fie d 
i n t he Pr ot oc ol’s Sc he d ule of Assess me nts ( A p p e n di x B t hr o u g h A p pe n di x D). T he f oll o wi n g 
i nf or mati o n was c ollect e d a n d will be s u m marize d at eac h baseli ne a n d e n d of p h ase visit  usi n g 
sta n dar d des cri pti ve statistics (i.e., n u m bers a n d perce nt a ges f or cate g ori es of n or mal/a b n or mal 
res ults). 
• 
Ultras o u n d N or malit y ( N or mal = Yes  re p orte d o n e C R F; A b n or mal = N o)  
• 
Biliar y Sl u d ge (N o r m al = N o re p orte d o n e C R F; A b n or mal = Yes) 
• 
Wall T hic ke ni n g ( N or mal = N o re p ort e d o n e C R F; A b n or mal = Y es ) 
• 
Dilati o n of C o m m o n Bile D uct ( N or mal = N o re p orte d o n e C R F; A b n or mal = Yes ) 
 
S hifts  fr o m  cate g ories  of  C h olelit hiasis  ( Si n gle  St o ne,  M ulti ple  St o nes,  N o ne,  N u m ber  N ot  
Re p orte d) will als o be s u m marize d.  
1 0. 7  P h ysic al E x a mi n ati o n 
C o m plete p h ysical  e x a m i nati o n  data are c ollecte d as s pecifi e d i n  t he Pr ot oc ol’s 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 D i n pr ot oc ol).  
Acr o me gal y dir ecte d a n d treat me nt direct e d p h ysical e x a mi nati o n  i n t he R C T p hase, will be 
c o n d ucte d as s pecifie d i n t he Pr ot oc ol’s 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 
D i n pr ot oc ol).  
All p h ysical e x a m data  a n d acr o me gal y directe d,  a n d treat me nt directe d e x a m data  will be liste d.   
1 1  I N T E RI M A N A L Y SI S   
N o i nteri m a nal ysis is pla n ne d, f or t he R C T p has e a n d t he C o m bi nati o n p hase s u b -st u d y; h o w e ver, 
data will be re vie we d i n p hases b y t he I D M C f or safet y p ur p oses.  At t he c o m pleti o n of t he R C T 
a n d C o m bi nati o n p hase s u b -st u d y t he data base will be clea n e d a n d l oc ke d a n d res ults of t he st u d y 
re p orte d. A n i nteri m a n al ysis of t he S t 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 his a nal ysis 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 ol lecti o n, n o a dj ust me nts f or m ulti plicit y will be re q uire d.  
 
1 2  S O F T W A R E A N D P R O G R A M MI N G S P E CI FI C A TI O N S   
1 2. 1  St atistic al S oft w are  
All a nal ys es will be perf or me d usi n g S A S 9. 4, or hi g her, i n acc or da n ce wit h P har m -Ola m S O P 
0 0 9- 2 0- S A S Pr o gr a m D e vel o p me nt a n d C ha n ge C o ntr ol.  
1 2. 2  Ge ner al Pr o gr a m mi n g S pecific ati o ns  
All ta bles will i ncl u de t he s p o ns or na me, pr ot oc ol I D, “ Pa ge x of y” a n d “ Draft” or “ Fi nal” i n t he 
hea der.  
T he last 2- f o oter li nes will be:  
1.  Data S o urce: (a dat a set f or listi n gs, a listi n g refere nce f or ta bles ) l eft j ustifie d 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 4 3  of 4 4  
 
 
 
2.  “Pr o gra m L ocati o n: P: \9 2 9 C hias ma \Stats \Pr o gra ms \x x x.sas ” left j ustifie d a n d “Date -Ti me: 
D D M M M Y Y Y Y: H H: M M ”  ri g ht j ustifie d 
 
 


C hias ma, I n c.  
Versi o n 3. 0, 1 5  Ma y 2 0 1 9  
Trial I D: M P O W E R E D  
Pr ot oc ol: O O C -A C M -3 0 2 Versi o n 4. 0 , A me n d me nt 3. 0  
 
 
 
Pa ge 4 4  of 4 4  
 
 
 
1 3  R E F E R E N C E LI S T  
Car o n, P., Bec k ers, A., 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 hieff o, C., C o o k, D., et al. ( 2 0 1 3). " Efficac y a n d safet y of a n o ctre 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. 
 
S u da, K., I n os hita, N., et al. ( 2 0 1 3). " Effi cac y of c o m bi ne d octre oti de a n d ca ber g oli n e 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 h e literat ure." E n d ocri ne 
j o ur nal 6 0( 4): 5 0 7- 5 1 5. 
 
Ya n, X. a n d S u, X. G. ( 2 0 1 0). " Stratifie d Wils o n a n d Ne wc o m be c o nfi de n ce 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. 
  
Ye o n hee Ki m, Gilea d S cie nces, Se u n g h y u n W o n  ( 2 0 1 3).  “ A dj uste d pr o p orti o n differe nce a n d 
c o nfi de nce i nter val i n str atifie d ra n d o mize d trials .”  P har ma S U G 2 0 1 3 - Pa per S P 0 4 . 
 
I nter nati o nal  C o nfere nce  o n  Har m o nizati o n.  Statistical  Pri nci ples  f or  Cli nical  Trials  ( E 9),  5  
Fe br u ar y 1 9 9 8. 
 
1 4  A P P E N DI CI E S  
1 4. 1  C h a n ges t o t he Pr ot o c ol S pecifie d a n al yses   
If differe nt fr o m statistical secti o n of pr ot oc ol, list here .