Conditions: Acute Hepatic Porphyria Acute Intermittent Porphyria Porphyria, Acute Intermittent Acute Porphyria Hereditary Coproporphyria (HCP) Variegate Porphyria (VP) ALA Dehydratase Deficient Porphyria (ADP)
Keywords: Acute Intermittent Porphyria (AIP) Acute Hepatic Porphyria (AHP) Hereditary Coproporphyria (HCP) Variegate Porphyria (VP) ALA dehydratase deficient porphyria (ADP) (ALAD) RNAi therapeutic Porphyria
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 94
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the effect of subcutaneous givosiran (ALN-AS1), compared to placebo, on the rate of porphyria attacks in patients with Acute Hepatic Porphyrias (AHP).

Detailed description:

Arms:
arm 1: Givosiran 2.5 mg/kg administered subcutaneously (SC), monthly (QM), for 6 months during the 6-Month Double-blind (DB) Period, followed by givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months during the Open-label Extension (OLE) Period. arm 2: Matching placebo (normal saline \[0.9% NaCl\]) was administered SC, QM, for 6 months during the 6-Month DB Period, followed by givosiran 2.5 mg/kg or 1.25 mg/kg SC, QM for 29 months during the OLE period.

Interventions: intervention 1: Givosiran intervention 2: Placebo
Intervention descriptions: intervention 1: Givosiran by SC intervention 2: Matching placebo (normal saline \[0.9% NaCl\]) by SC

Protocol document:
Prot_002.pdf: 
 
 
Offici al Titl e:  
E N VI SI O N: A P h as e 3 R a n d o miz e d, D o u bl e -bli n d,  Pl ac e b o -C o ntr oll e d 
M ultic e nt er St u d y wit h a n  O p e n -l a b el E xt e nsi o n t o E v al u at e t h e Effic ac y 
a n d  S af et y of Gi v osir a n i n P ati e nts wit h Ac ut e H e p atic  P or p h yri as  
 
N C T N u m b er:    
N C T 0 3 3 3 8 8 1 6  
 
D oc u m e nt D at e:   
Cli nic al St u d y Pr ot oc ol , 2 9 M arc h 2 0 2 1  






Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
I N V E S TI G A T O R’ S A G R E EM E N T  
 
I h a ve rea d t he A L N-A S 1 -0 0 3 pr ot oc ol a n d a gree t o c o n d uct t he st u d y as o utli ne d.  I a gree t o 
mai ntai n t he c o nfi de ntialit y of all i nf or mati o n r ecei ve d or de v el o pe d i n c o n necti o n wit h t his 
pr ot oc ol.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pri nte d Na me of I n v esti gat or  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Si g nat ure of  I n vesti gat or 
 
 
 
 
 
 
 
 
Date  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4  
P R O T O C O L S Y N O P SI S  
P r ot oc ol Title  
E N VI SI O N: A P hase 3 Ra n d o mize d, D o u ble -bli n d, Place b o -C o ntr olle d M ultice nter St u d y wit h a n 
O pe n -la bel E xte nsi o n t o E val uate t he Efficac y a n d Safet y of Gi v osira n i n Patie nts wit h Ac ute He patic 
P or p h yrias  
P r o d uct N a me  
Gi v osira n ( A L N -A S 1)  
I n dic ati o n 
Treat me nt of ac ute he patic p or p h yrias ( A H P) i n a d ult a n d a d olesce nt patie nts  
P h ase  
P hase 3  
St u d y ce nter(s)   
T he st u d y will be c o n d ucte d at a p pr o xi matel y 5 0 st u d y ce nters w orl d wi de.  
O bjecti ves  
P ri m ar y  
•  E val uate t he effect of s u bc uta ne o us ( S C) gi v osira n ( A L N -A S 1), c o m pare d t o place b o, o n t he rate 
of p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, or i ntra ve n o us (I V) he mi n 
a d mi nistrati o n at h o me  i n patie nts wit h ac ute i nter mitte nt p orp h yria ( AI P)    
Sec o n d ar y  
•  E val uate t he effect of gi v osira n, c o m pare d t o place b o, o n uri nar y a mi n ole v uli nic aci d ( A L A) 
le vels i n patie nts wit h AI P 
•  E val uate t he effect of gi v osira n, c o m pare d t o place b o, o n uri nar y p or p h o bili n o ge n ( P B G) le vels i n 
patie nts wit h  AI P  
•  E val uate t he effect of gi v osira n, c o m pare d t o place b o, o n he mi n usa ge i n patie nts wit h AI P  
•  E val uate t he effect of gi v osira n, c o m pare d t o place b o, o n t he rate of p or p h yria attac ks re q uiri n g 
h os pitalizati o n, ur ge nt healt hcare visit, or I V he mi n a d mi nistrati o n at h o me  i n patie nts wit h a n y 
A H P  
•  E val uate t he effect of gi v osira n, c o m pare d t o place b o, i n patie nts wit h AI P o n t he s y m pt o ms of 
pai n, na usea, a n d fati g ue  
•  
E val uate t he effect of gi v osira n, c o m pare d t o place b o, i n patie nts wit h AI P o n t he P h ys ical 
C o m p o ne nt S u m mar y ( P C S) of t he 1 2 -ite m S h ort-F or m Healt h S ur ve y ( S F -1 2)  
•  E val uate t he safet y a n d t olera bilit y of gi v osira n i n patie nts wit h a n y A H P  
E x pl or at or y  
•  E val uate t he effects of gi v osira n, c o m pare d t o place b o, i n patie nts wit h AI P a n d i n patie nts wit h 
a n y A H P o ver t he 6 -m o nt h treat me nt peri o d o n:  
− 
Rate of all p or p h yria attac ks (re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, I V he mi n 
a d mi nistrati o n at h o me, or treat me nt at h o me wit h o ut I V he mi n)  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5  
− 
Uri nar y a mi n ole v uli nic aci d s y nt hase ( A L A S 1) messe n ger R N A ( m R N A) le vels  
− 
A nal gesic usa ge  
− 
A d diti o nal q ualit y of life ( Q O L) meas ures, i ncl u di n g misse d da ys of w or k/sc h o ol  
− 
Patie nt e x perie nce q uesti o n naire a n d p atie nt's i m pressi o n of healt h stat us c ha n ge  
•  Assess t he treat me nt effect of gi v osira n at e v al uate d d oses d uri n g t he o pe n -la bel e xte nsi o n ( O L E) 
peri o d i n patie nts wit h AI P a n d i n patie nts wit h a n y A H P w h o ha d pre vi o usl y bee n ra n d o mize d t o 
place b o treat me nt  
•  Assess t he l o n g -ter m treat me nt effect of gi v osira n i n patie nts wit h AI P a n d i n patie nts wit h a n y 
A H P  
•  C haracterize t he p har mac o ki netics ( P K) a n d assess t he a nti dr u g a nti b o dies ( A D A) of gi v osira n i n 
patie nts wit h a n y A H P  
E n d p oi nts  
P ri m ar y  
•  
A n n ualize d rate of p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, or I V 
he mi n a d mi nistrati o n at h o me i n patie nts wit h AI P o ver t he 6 -m o nt h treat me nt peri o d  
Sec o n d ar y  
•  
Uri nar y A L A i n patie nts wit h AI P at 3 m o nt hs  
•  
Uri nar y A L A i n patie nts wit h AI P at 6  m o nt hs  
•  
Uri nar y P B G i n patie nts wit h AI P at 6 m o nt hs  
•  
A n n ualize d rate of a d mi nistere d he mi n d oses i n patie nts wit h AI P o ver t he 6 -m o nt h treat me nt 
peri o d  
•  
A n n ualize d rate of p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, or I V 
he mi n a d m i nistrati o n at h o me i n patie nts wit h a n y A H P o ver t he 6-m o nt h treat me nt peri o d  
•  
Dail y w orst pai n sc ore as meas ure d b y Brief Pai n I n ve nt or y -S h ort F or m ( B PI -S F) n u meric 
rati n g scale ( N R S) i n patie nts wit h AI P o ver t he 6-m o nt h treat me nt peri o d  
•  
Dail y w orst na us ea sc ore as meas ure d b y N R S i n patie nts wit h AI P o ver t he 6 -m o nt h 
treat me nt peri o d 
•  
Dail y w orst fati g ue sc ore as meas ure d b y Brief Fati g ue I n ve nt or y -S h ort F or m ( B FI -S F) N R S 
i n patie nts wit h AI P o ver t he 6-m o nt h treat me nt peri o d  
•  
C ha n ge fr o m baseli ne i n t he P C S of t he S F -1 2 i n patie nts wit h AI P at 6 m o nt hs  
E x pl or at or y  
E x pl orat or y e n d p oi nts will be meas ure d i n patie nts wit h AI P a n d i n patie nts wit h a n y A H P o ver t he 6 -
m o nt h treat me nt peri o d a n d o ver t he O L E peri o d at d oses e val uate d:  
•  
Rate of p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, or I V he mi n 
a d mi nistrati o n at h o me  
•  
Rate of all p or p h yria attac ks  
•  
Rate of a d mi nistere d he mi n d oses  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6  
•  
Uri nar y A L A a n d P B G le vels  
•  
Uri nar y A L A S 1 m R N A le vels  
•  
Dail y w orst pai n, dail y w orst na usea, a n d dail y w orst fati g ue sc ore o ver 1 2 m o nt hs  
•  
P C S of t he S F -1 2  
•  
E Q -5 D -5 L i n de x sc ore  
•  
Patie nt Gl o bal I m pressi o n of C ha n ge ( P GI C)  
•  
P or p h yria Patie nt E x perie nce Q uesti o n naire ( P P E Q)  
•  
A nal gesic usa ge ( o pi oi d a n d n o n -o pi oi d)  
•  
P K pr ofile of gi v osira n  
•  
I nci de nce a n d titer of A D As 
S af et y  
•  
I nci de nce, se verit y, seri o us ness, a n d relate d ness of a d verse e ve nts d uri n g t he 6-m o nt h 
treat me nt peri o d a n d i n t he O L E peri o d 
St u d y Desi g n  
T his is a 2 -part m ultice nter, m ulti nati o nal P hase 3 st u d y desi g ne d t o e val uate t he efficac y a n d safet y 
of gi v osira n i n a d ults a n d a d olesce nts ( ≥1 2 years of a ge) wit h a d oc u me nte d dia g n osis of AI P.  T he 
efficac y a n d safet y of gi v osira n will als o be i n vesti gate d i n t he ot her A H Ps t y pes, i ncl u di n g 
Here ditar y C o pr o p or p h yria ( H C P), Varie g ate P or p h yria ( V P), a n d A L A de h y dratase deficie nt 
p or p h yria ( A D P).  
Patie nts w h o are o n he mi n pr o p h yla xis pri or t o e nr oll me nt will be eli gi ble t o partici pate if t he y meet 
t he attac k e ntr y criteria. I n t his st u d y, patie nts ma y be gi ve n he mi n f or t he treat me nt of ac ute attac ks if 
cli nicall y i n dicate d b ut ma y n ot use he mi n pr o p h ylacticall y. He mi n pr o p h yla xis is n ot per mitte d i n 
t his st u d y beca use gi v osira n is i nte n de d as m o n ot hera p y t o pre ve nt attac ks a n d t he re g ular c o-
a d mi nistrati o n of he mi n c o ul d c o nf o u n d ef ficac y a n d safet y si g nals relate d t o gi v osira n. 
I n t he first part of t he st u d y, c o nse nti n g (a n d asse nti n g, w here a p plica ble) patie nts w h o meet all 
eli gi bilit y criteria will be ra n d o mize d i n a 1: 1 rati o t o recei ve 2. 5 m g/ k g gi v osira n or place b o o nce 
m o nt hl y  f or a 6-m o nt h d o u ble -bli n d treat me nt peri o d; b ot h gi v osira n a n d place b o will be a d mi nistere d 
s u bc uta ne o usl y.  Ra n d o mizati o n i nt o treat me nt gr o u ps will be stratifie d at st u d y e ntr y b y A H P t y pe 
(AI P [ wit h m utati o n i n t he  H M B S  ge ne] vs H C P, V P, A D P, or a n y A H P wit h o ut i de ntifie d m utati o n 
i n a p or p h yria-relate d ge ne); all patie nts i n t he AI P gr o u p will be f urt her stratifie d b y eac h patie nt's 
use of he mi n pr o p h yla xis re gi me n at t he ti me of scree ni n g a n d b y eac h patie nt's hist orical a n n ualize d 
attac k rate.  Patie nts o n a he mi n pr o p h yla xis re gi me n pri or t o st u d y e ntr y will be stratifie d b y t heir 
hist orical a n n ualize d attac k rate: < 7 attac ks vs ≥7 attac ks i n t he past 1 2 m o nt hs.  Patie nts w h o were 
n ot o n a he mi n pr o p h yla xis re gi me n pri or t o st u d y e ntr y will be strat ifie d b y t heir hist orical 
a n n ualize d attac k rate: < 1 2 attac ks vs ≥1 2 attac ks i n t he past 1 2 m o nt hs.  
N o a d diti o nal stratificati o n fact ors will be c o nsi dere d f or patie nts wit h H C P, V P, A D P, or a n y A H P 
wit h o ut i de ntifie d m utati o n i n a p or p h yria -relate d ge ne. 
D uri n g t he 6 -m o nt h treat me nt peri o d, patie nts will u n der g o efficac y a n d safet y assess me nts e ver y 2 
wee ks f or t he first m o nt h a n d m o nt hl y t hereafter.  After M o nt h 6 visit pr oce d ures are c o m plete d i n t he 
treat me nt peri o d, patie nts fr o m b ot h t he gi v osira n a n d place b o ar ms will be gi n t he sec o n d part of t he 
st u d y, t he O L E peri o d d uri n g w hic h t he y will be treate d wit h gi v osira n f or u p t o 2 9 m o nt hs . Patie nts 
w h o cr osse d o ver t o t he O L E peri o d pri or t o t he i m ple me ntati o n of a me n d me nt 3 (ie, u n der 
a me n d me nt versi o n 1 or 2) a n d are recei vi n g a 2. 5  m g/ k g o nce m o nt hl y gi v osira n d ose will re mai n o n 
t hat d ose.  U p o n e ntr y t o t he O L E peri o d u n der a me n d me nt versi o n 3, patie nts will cr oss o ver t o 
recei ve a 1. 2 5 m g/ k g o nce m o nt hl y d ose of gi v osira n.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7  
After i m ple me ntati o n of a m e n d me nt  3 a n d u ntil i m ple me ntati o n of a me n d me nt  5, patie nts assi g ne d t o 
t he o nce m o nt hl y 1. 2 5-m g/ k g treat me nt gr o u p w h o e x perie nce i na de q uate disease c o ntr ol ma y be 
all o we d t o ha ve t heir m o nt hl y d ose i ncrease d t o 2. 5  m g/ k g starti n g at t he M o nt h  1 3 St u d y Vi sit ( w he n 
6  m o nt hs of o pe n -la bel gi v osira n d osi n g ha ve bee n c o m plete d at 1. 2 5 m g/ k g) base d o n disc ussi o n a n d 
a gree me nt b y t he I n vesti gat or a n d me dical m o nit or, de m o nstrati o n of t olera bilit y t o gi v osira n, a n d 
f ulfill me nt of A L A a n d cli nical acti vit y criteria. 
U p o n i m ple me ntati o n of a me n d me nt  5, all patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n o nce m o nt hl y w h o 
d o n ot ha ve o n g oi n g cli nicall y rele va nt tra nsa mi nase ele vati o ns will ha ve t heir d ose i ncrease d t o 
2. 5  m g/ k g gi v osira n o nce m o nt hl y base d o n t olera bilit y al o ne, wit h o ut a n y criteria f or A L A re d ucti o n 
or cli nical acti vit y.  See Secti o n  6. 2. 3. 4  f or f urt her i nf or mati o n o n d ose escalati o n.  
F or partic ular  st u d y visits, as s pecifie d i n t he Sc he d ule of Assess me nts, a n d w here a p plica ble c o u ntr y 
a n d l ocal re g ulati o ns a n d i nfrastr uct ure all o w, st u d y pr oce d ures, i ncl u di n g st u d y dr u g a d mi nistrati o n, 
ma y be c o n d ucte d b y a q ualifie d h o me healt hcare pr ofessi o nal. Pa tie nts m ust de m o nstrate t he a bilit y 
t o t olerate d oses of t he st u d y dr u g at t he st u d y ce nter bef ore d osi n g at a l ocati o n ot her t ha n t he st u d y 
ce nter is per mitte d.  If t he patie nt is u na ble t o c o me t o t he st u d y site, a n d a visit b y a h o me healt hcare 
pr ofessi o nal is n ot p ossi ble d ue t o circ u msta nces relate d t o t he C O VI D -1 9 pa n de mic, gi v osira n ma y 
be a d mi nistere d b y t he patie nt or t he care gi ver u n der t he o versi g ht of t he I n vesti gat or, a n d f oll o wi n g 
c o ns ultati o n wit h t he me dical m o nit or, as all o we d b y a p plica ble  c o u ntr y a n d l ocal re g ulati o ns.  
Patie nts or care gi vers will be pr o vi de d wit h a n electr o nic diar y (e Diar y) t o rec or d se verit y of dail y 
pai n, na usea, a n d fati g ue, as well as a nal gesic usa ge.  P ote ntial p or p h yria attac ks will be re p orte d b y 
patie nts a n d care g i vers t hr o u g h t he e Diar y w he n t he y occ ur; st u d y ce nters will be n otifie d w he n 
p ote ntial p or p h yria attac ks are re p orte d i n t he e Diar y.  I n i nsta nces w he n t he e Diar y is n ot use d t o 
re p ort p ote ntial p or p h yria attac ks, st u d y ce nters ma y be n otifie d b y tele p h o ne b y patie nts, care gi vers, 
or ot her healt hcare pr o vi ders.  All p ote ntial p or p h yria attac ks will be c o nfir me d b y t he I n vesti gat or.  
Patie nts ma y recei ve gi v osira n as l o n g as t he y d o n ot f ulfill a n y of t he st u d y disc o nti n uati o n criteria or 
u ntil gi v osira n is c o m merciall y a vaila ble i n t he patie nt’s territ or y or t he gi v osira n de vel o p me nt 
pr o gra m is disc o nti n ue d ( w hic he ver c o mes first).  
A n e xter nal i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C) will m o nit or safet y o ver t he c o urse of 
t he d o u ble-bli n d treat me nt peri o d  a n d u ntil all patie nts ha ve bee n i n t he O L E peri o d f or at least 
6  m o nt hs. Details f or t he c o m mittee will be pr o vi de d i n t he c o m mittee c harter.  
N u m ber of Pl a n ne d P atie nts  
T he pla n ne d t otal e nr oll me nt f or t he st u d y is a p pr o xi matel y 7 4 patie nts, i ncl u di n g a p pr o xi matel y 7 0 
AI P patie nts.   
Di a g n osis a n d M ai n Eli gi bilit y Criteri a  
T his st u d y will i ncl u de a d ults a n d a d olesce nts ( ≥1 2 years of a ge) wit h a d oc u me nte d dia g n osis of 
A H P (i ncl u di n g AI P, H C P, V P, or A D P) base d o n cli nical feat ures, d oc u me nte d e vi de nce of uri nar y 
or plas ma A L A or P B G ele vati o ns ≥4 × u p per li mit of n or mal ( U L N) wit hi n t he past year pri or t o or 
d uri n g t he Scree ni n g peri o d a n d d oc u me nte d ge netic e vi de nce of a m utati o n i n a p or p h yria -relate d 
ge ne.  If t he res ults of t he patie nt’s ge netic testi n g d o n ot i de ntif y a p or p h yria -relate d ge ne m utati o n, 
t he patie nt ma y be eli gi ble f or t he st u d y base d o n cli nical feat ures acc o m pa nie d b y s u p p orti ve 
bi oc he mical criteria.  
I n a d diti o n t o cli nical, bi oc he mical, a n d ge netic feat ures of A H P, patie nts are als o re q uire d t o ha ve 
ha d at least 2 p or p h yria attac ks i n t he last 6 m o nt hs pr i or t o scree ni n g t hat re q uire d h os pitalizati o n, 
ur ge nt healt hcare visit, or I V he mi n treat me nt at h o me.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8  
I n vesti g ati o n al Pr o d uct, D ose a n d M o de of A d mi nistr ati o n 
Gi v osira n is a s y nt hetic c he micall y m o difie d s mall i nterferi n g R N A (si R N A) tar geti n g A L A S 1 
m R N A a n d beari n g a tria nte n nar y N -acet yl galact osa mi ne li ga n d c o nj u gate d t o t he se nse stra n d.   
Patie nts ra n d o mize d t o recei ve gi v osira n will be a d mi nistere d 2. 5 m g/ k g S C m o nt hl y  d uri n g t he 
6 -m o nt h treat me nt peri o d; patie nts will recei ve 1. 2 5  m g/ k g or 2. 5 m g/ k g S C m o nt hl y d uri n g t he O L E 
peri o d  
Ref ere nce T her a p y, D ose a n d M o de of A d mi nistr ati o n  
Place b o (s o di u m c hl ori de 0. 9 % w/ v f or S C a d mi nistrati o n).   
D ur ati o n of Tre at me nt  
T he esti mate d t otal ti me o n st u d y f or eac h patie nt is u p t o 3 8 m o nt hs, i ncl u di n g u p t o 2 m o nt hs of 
scree ni n g, u p t o 3 5 m o nt hs of treat me nt ( 6-m o nt h treat me nt peri o d ( d o u ble -bli n d) + u p t o a 2 9 -m o nt h 
o pe n -la bel e xte nsi o n peri o d), a n d a 1-m o nt h f oll o w -u p peri o d.  
A patie nt will be c o nsi dere d t o ha ve c o m plete d t he pri mar y a nal ysis peri o d of t he st u d y at t he ti me of 
c o m pleti o n of t he M o nt h -6 treat me nt assess me nts.  
St atistic al Met h o ds  
T he st u d y was desi g ne d wit h t he ass u m pti o n of a mea n a n n ualize d attac k rate of 8, a sta n dar d 
de viati o n ( S D) of 5 i n t he place b o ar m, a n d a mea n a n n ualize d attac k  rate of 4. 4 wit h a n S D of 3 i n 
t he gi v osira n ar m. T his st u d y will ha ve at least 9 0 % p o wer t o detect a 4 5 % re d ucti o n i n t he 
a n n ualize d attac k rate wit h gi v osira n at a 2 -si de d 5 % si g nifica nce le vel, usi n g a ne gati ve bi n o mial 
m o del wit h 7 0 patie nts.  T his st u d y desi g n will still ha ve at least 8 0 % p o wer e ve n if t he dr o p o ut rate is 
as hi g h as 1 5 % u n der t he sa me ass u m pti o ns.   
T he o verall T y pe I err or rate will be str o n gl y c o ntr olle d at a 2-si de d 0. 0 5 si g nifica nce le vel f or t he 
pri mar y a n d sec o n dar y e n d p oi nts usi n g a n al p ha s pe n di n g f u ncti o n f or t he i nteri m a nal ysis a n d a fi xe d 
se q ue ntial testi n g pr oce d ure at t he fi nal a nal ysis. T he pri mar y e n d p oi nt will be c o m pare d bet wee n 
treat me nt ar ms at t he fi nal a nal ysis si g nifica nce le vel. If t he pri mar y a nal ysis of t he pri mar y e n d p oi nt 
is statisticall y si g nifica nt, t he n t he sec o n dar y e n d p oi nts will eac h be teste d i n t he or der s pecifie d i n t he 
Sec o n dar y E n d p oi nts secti o n.  
If a test of t he pri mar y or a sec o n dar y e n d p oi nt is n ot statisticall y si g nifica nt at t he fi nal a nal ysis 
si g nifica nce le vel, t he testi n g of re mai ni n g e n d p oi nts i n t he se q ue nce will st o p.   
T he pri mar y e n d p oi nt of t he st u d y is t he a n n ualize d rate of p or p h yria attac ks re q uiri n g h os pitalizati o n, 
ur ge nt healt hcare visit, or I V he mi n a d mi nistrati o n at h o me i n AI P patie nts o ver t he i nitial 6 -m o nt h 
treat me nt peri o d. T he a n n ualize d attac k rate will be calc ulate d as t he t otal n u m ber of pri mar y 
e n d p oi nt e ve nts, di vi de d b y t he t otal n u m ber of da ys i n t he treat me nt peri o d, a n d m ulti plie d b y t he 
n u m ber of da ys i n a year.   
T he pri mar y a nal ysis of t he pri mar y e n d p oi nt is t he c o m pa ris o n of t he mea n a n n ualize d attac k rate f or 
t he place b o a n d gi v osira n ar ms usi n g a ne gati ve bi n o mial re gressi o n m o del t hat will i ncl u de fi xe d 
effects f or t he treat me nt ar m a n d stratificati o n fact ors (stat us of he mi n pr o p h yla xis use pri or t o st u d y 
e ntr y a n d hist orical attac k rate). T he n u m ber of da ys t hat patie nts s pe n d i n t he 6 -m o nt h treat me nt 
peri o d will be i ncl u de d i n t he m o del as a n offset varia ble. T his a nal ysis will i ncl u de all ra n d o mize d 
patie nts wit h AI P ( wit h m utati o n i n t he H M B S  ge ne) w h o recei ve d  at least 1 d ose of 
gi v osira n/ place b o, gr o u pe d acc or di n g t o t heir ra n d o ml y assi g ne d treat me nt ar m (t he AI P f ull a nal ysis 
set [ F A SAI P ]). 
A n esti mate d rati o of mea n a n n ualize d attac k rates bet wee n treat me nt ar ms, wit h its c orres p o n di n g 
9 5 % c o nfi de nce i nter va l, will be esti mate d fr o m t he ne gati ve bi n o mial re gressi o n m o del. Descri pti ve 
statistics f or t he me dia n a n d i nter q uartile ra n ge of t he a n n ualize d attac k rate will als o be prese nte d f or 
eac h treat me nt ar m.   


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9  
Se nsiti vit y a nal yses will be detaile d i n t he stat istical a nal ysis pla n ( S A P). 
T he a nal ysis of t he a n n ualize d rate of p or p h yria attac ks  re q uiri n g h os pitalizati o n, ur ge nt healt hcare 
visit, or I V he mi n a d mi nistrati o n at h o me i n patie nts wit h a n y A H P w h o recei ve d at least 1 d ose of 
gi v osira n/ place b o  (t he A H P f ull a nal ysis set [ F A S]) d uri n g t he 6-m o nt h treat me nt peri o d a n d t he 
a n n ualize d rate of he mi n d oses will be c o n d ucte d usi n g t he sa me a p pr oac h as t he pri mar y a nal ysis.    
F or t he a nal ysis of uri nar y A L A -relate d e n d p oi nts, A L A le vels will be c o m pare d bet ween treat me nt 
ar ms usi n g a mi xe d -effects m o del re peate d meas ures ( M M R M) wit h baseli ne A L A as a c o nti n u o us 
c o variate, t he fi xe d effect ter ms i ncl u di n g treat me nt ar ms, stratificati o n fact ors f or AI P patie nts ( pri or 
he mi n pr o p h yla xis stat us a n d hist orical attac k rates), visit, a n d treat me nt b y visit i nteracti o n .  P B G-
relate d e n d p oi nts will als o be a nal yze d usi n g t his met h o d ol o g y.    
Dail y pai n, na usea, a n d fati g ue sc ores will be a nal yze d se paratel y usi n g t he area u n der t he c ur ve 
( A U C) a p pr oac h: t he A U C o ver 6 m ont hs i n t he res pecti ve sc ore will be calc ulate d f or eac h patie nt, 
a n d t he mea n A U C will be c o m pare d bet wee n treat me nt ar ms i n a n A N C O V A m o del.   
T he c ha n ge fr o m baseli ne i n P C S of S F -1 2 at 6 m o nt hs will be a nal yze d usi n g a n M M R M. Details o n 
t he M M R M m o del f or eac h c o nti n u o us sec o n dar y e n d p oi nt a n d t he c o variates t o be i ncl u de d will be 
descri be d i n t he S A P.  
Safet y res ults will be s u m marize d descri pti vel y.  
A n u n bli n de d i nteri m a nal ysis will be c o n d ucte d w he n a p pr o xi matel y 3 0 AI P patie nts ha ve c o m plete d 
at least 3 m o nt hs of t he treat me nt peri o d. T he e n d p oi nt f or t his i nteri m a nal ysis is t he A L A le vel at 3 
m o nt hs. T he A L A le vel at 3 m o nt hs will be c o m pare d bet wee n treat me nt ar ms usi n g a n a nal ysis of 
c o varia nce ( A N C O V A) m o del wit h t he fi xe d effect of treat me nt ar ms, stratificati o n fact ors f or AI P 
patie nts ( pri or he mi n pr o p h yla xis stat us a n d hist orical attac k rates), a n d wit h baseli ne A L A as a 
c o variate.  A n al p ha -s pe n di n g f u ncti o n will be use d t o a dj ust t he si g nifica nce le vel t o e ns ure t he 
o verall t y pe I err or rat e is n ot i nflate d; t he err or s pe n di n g f u ncti o n will be s pecifie d i n t he statistical 
a nal ysis pla n. T he si g nifica nce le vel f or t he c o m paris o n at t he i nteri m is 0. 0 0 1 ( 2 si de d).  
St o p pi n g f or efficac y or f utilit y is n ot pla n ne d i n t his st u d y.  T o e ns ure t hat  t he st u d y is a de q uatel y 
p o were d f or t he pri mar y e n d p oi nt c o m paris o n at t he fi nal a nal ysis, t he a n n ualize d attac k rates ma y 
als o be e val uate d i n a bli n de d ma n ner f or sa m ple size reassess me nt at t he ti me of t he i nteri m a nal ysis.   
Details will be descri be d i n t he S A P. 






Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me n t 7, 2 9 M arc h 2 0 2 1 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 2  
d  Me dical hist or y c ollecte d will i nc or p orate t he patie nt’s p or p h yria hist or y, i ncl u di n g t heir t y pical attac k c haracteristics, t ri g gers, a n d treat me nt, as well as 
ce ntral ve n o us access hist or y,  ir o n o verl oa d hist or y, a n d pri or li ver disease hist or y.  
e A c o m plete p h ysical e xa mi nati o n will be perf or me d at Scree ni n g, Da y 1, a n d M o nt h 6.  At all ot her visits, a tar gete d p h ysical  e xa mi nati o n will be perf or me d as 
descri be d i n Secti o n  7. 5. 3 .  T he p h ysical e xa mi nati o n will be perf or me d pri or t o d osi n g.   
f D osi n g wei g ht (i n kil o gra ms) will b e c ollecte d d uri n g t he cli nical st u d y ce nter visits. Wei g ht c ollecte d at eit her t he pre vi o us st u d y ce nter visit or c urre nt st u d y 
ce nter visit ma y be use d f or d ose calc ulati o ns. T he Scree ni n g Visit wei g ht will be use d f or d ose -calc ulati o n o n St u d y Da y 1. Hei g ht (i n ce nti meters) will be 
meas ure d a n d B MI calc ulate d at cli nic visits e ver y 6 m o nt hs ( o n Da y 1 a n d M o nt h 6).  B MI will be a ut o maticall y calc ulate d wit hi n t he data b ase.  
g Ser ol o g y i ncl u des he p atitis B s urface a nti b o d y ( H bs A b), he patitis B s urface a nti ge n ( H bs A g), a n d a nti -H C V a nti b o d y. F S H testi n g ma y be perf or me d t o 
c o nfir m s us pecte d p ost -me n o pa usal stat us.  
h  Vital si g ns i ncl u de bl o o d press ure, heart rate, b o d y te m perat ure, a n d res pirat or y rate a n d will be meas ure d w he n patie nts are i n a seate d or s u pi ne p ositi o n 
(s h o ul d be c o nsiste nt acr oss st u d y visits wit h eac h patie nt) after t he patie nt has reste d f or 1 0 mi n. O n t he Da y 1 a n d M o nt h 6 visit, vital si g ns will be c ollecte d 
pre d ose a n d 2 h o urs p ost d ose ( +  1 5  mi n utes).   O n all ot her d osi n g da ys, vital si g ns will b e c ollecte d pre d ose.  
i Si n gle 1 2 -lea d E C G will be perf or me d i n t he s u pi ne p ositi o n after t he patie nt has reste d c o mf orta bl y f or 5 mi n utes. E C Gs will be c ollecte d pri or t o a n y bl o o d 
dra ws.  
j Tri plicate 1 2 -lea d EC Gs will be perf or me d at pre d ose a n d 2 -h o urs ( +  1 5  mi n utes) p ost -d ose o n t he Da y  1, M o nt h 5, a n d M o nt h 6 visits, usi n g vali date d E C G 
ser vices e q ui p me nt fr o m a ce ntral facilit y; tri plicate meas ure me nts s h o ul d be se parate d b y a p pr o xi matel y 1 mi n ute wit h t he patie nt i n t he s u pi ne p ositi o n after 
he or s he has reste d c o mf orta bl y f or 5 mi n utes.  W he n E C G a n d bl o o d sa m ple c ollecti o n (e g, f or P K assess me nt) occ ur at t he sa me ti me,  E C G assess me nts 
s h o ul d be perf or me d bef ore bl o o d sa m ples are dra w n .  I n a pres pecified s u bset of a p pr o xi matel y 2 4 patie nts at pres pecifie d st u d y ce nters (i ncl u di n g all p atie nts 
at East Asia n st u d y ce nters [i n J a p a n, S o ut h K orea, a n d T ai wa n]), a n a d diti o nal E C G ( wit h paire d P K assess me nt) at 2 4 h o urs ( ± 2 h o urs) p ost -d ose will b e 
c ollecte d a t Da y 1 a n d M o nt h 6. 
k  Cli nical la b orat or y para meters will i ncl u de: ser u m c he mistr y i ncl u di n g L F Ts, li pase, a m ylase, he mat ol o g y, c o a g ulati o n, a n d ur i nal ysis. Bl o o d a n d uri ne 
sa m ples f or cli nical la b orat or y e val uati o ns will be c ollecte d pre d ose. Ser u m ferri ti n assess me nts will be c ollecte d at St u d y Da y 1 a n d M o nt h 6.  D-di mer 
assess me nts will be perf or me d at Scree ni n g, Da y 1, M o nt h 3, a n d M o nt h 6; as a cli nical res earc h para meter o nl y, d -di mer res ults will n ot b e c o m m u nic ate d t o 
t he st u d y ce nters.  Res ults fr o m A L T, T B L, a n d I N R tests c ollecte d wit hi n t he 1 4 da ys pri or t o d osi n g m ust b e re vie we d b y t he I n vesti gat or bef ore st u d y dr u g 
a d mi nistrati o n.  L ocall y a nal yze d res ults ma y be re vie we d t o all o w st u d y dr u g a d mi nistrati o n, b ut a d diti o nal sa m ples f or ce nt ral a nal ysis m ust als o be c ollecte d 
o n t he da y of d osi n g pri or t o d ose a d mi nistrati o n.  
l F or fe males of c hil d -beari n g p ote ntial, a ser u m pre g na nc y test will be perf or me d at Scree ni n g; t hereafter, ser u m or uri ne pre g na nc y tests will b e perf or me d 
m o nt hl y.  Res u lts m ust b e a vaila ble bef ore d osi n g.  
m  At t he M o nt h 6 visit, t he first o pe n -la bel d ose of gi v osira n i n t he e xte nsi o n st u d y will be a d mi nistere d after all sc he d ule d 6-m o nt h assess me nts (f or t he 
c o m pleti o n of t he d o u ble -bli n d peri o d) ha ve bee n perf or me d.  T he uri ne A L A a n d P B G sa m ple m ust be c ollecte d pri or t o t he first o pe n -la bel d ose of gi v osira n.  
If t he A L A a n d P B G sa m ple c ollecti o n is dela ye d d ue t o he mi n usa ge wit hi n 4 da ys of t he M o nt h 6 visit, t he o pe n -la bel d ose s h o ul d be dela ye d as well. 
n I n patients w h o were o n he mi n pr o p h yla xis pri or t o st u d y, c ollecti o n of t he Scree ni n g uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A m ust  occ ur w he n t he 
patie nt is n ot ha vi n g a n attac k, a n d ≥4 da ys after pr o p h ylacti c he mi n disc o nti n uati o n a n d after t heir last he mi n d o se T w o scree ni n g uri ne sa m ples (c ollecte d o n 
2 differe nt d a ys) s h o ul d be c ollecte d f or A L A/ P B G; o ne scre e ni n g uri ne sa m ple s h o ul d be c ollecte d f or A L A S 1 m R N A. D uri n g t he st u d y, s p ot uri ne sa m ples 
f or A L A, P B G, a n d A L A S 1 m R N A meas ure me nt s h o ul d be c ollecte d pri or t o st u d y dr u g d osi n g; h o we ver, if he mi n is us e d f or a n attac k, sc he d ule d uri nar y 
A L A, P B G a n d A L A S 1 m R N A will be c ollecte d 4 da ys ( + 4 da ys) after t he patie nt’s last he mi n d ose.  At t he M o nt h 6 visit, t he fi rst o pe n-la bel d ose of 
gi v osira n s h o ul d n ot  be a d mi nistere d u ntil t he M o nt h 6 uri ne sa m ple f or A L A, P B G ha ve bee n c ollecte d. W here a p plica ble c o u ntr y a n d l ocal re g ulati o ns a n d 
i nfrastr uct ure all o w, Scree ni n g a n d o n-st u d y uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A assess me nts ma y be c ollecte d b y a h o me healt hcare 
pr ofessi o nal, se nt t o t he st u d y ce nter b y mail, or br o u g ht t o t he st u d y ce nter at t he ne xt visit.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me n t 7, 2 9 M arc h 2 0 2 1 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 3  
o  W here all o we d per l ocal re g ul ati o ns a n d I R B/ E C a p pr o val, ser u m, plas ma, a n d uri ne sa m pl es f or e x pl orat or y bi o mar ker t esti n g, a n d meas uri n g h o m oc ystei ne 
le vels, will be c ollecte d pri or t o d osi n g.  
p  Ge netic testi n g of p or p h yria -r elate d ge nes is o nl y re q uire d i n patie nts wit h o ut pri or d oc u me nte d ge netic testi n g f or p or p h yria. See Secti o n  7. 6. 2  f or details. 
q W here all o we d per l ocal re g ul ati o ns, I R B/I E C a p pr o val, a n d patie nt c o nse nt (a n d asse nt, w here a p plica ble), a v ol u ntar y bl o o d sa m ple ma y be c ollecte d f or later 
D N A a nal ysis . See Secti o n 7. 6. 2  f or details.   
r Sa m ple t o be c ollecte d pre d ose.  
s Bl o o d sa m ples f or P K a nal ysis will be c ollecte d i n all patie nts at t he ti me p oi nts liste d i n  T a ble  8 . A n a d diti o nal 2 4 -h o ur ( ± 2 h o ur) P K assess me nt ( wit h paire d 
E C G meas ure me nt) will be perf or me d o n Da y 1 a n d M o nt h 6 i n a p pr o xi matel y 2 4 patie nts fr o m preselecte d st u d y ce nters. I n patie nts at East Asia n st u d y 
ce nters (i n J a p a n, S o ut h K orea, or T ai wa n), bl o o d sa m ples f or P K a nal ysis will be c ollecte d at t he ti me p oi nts liste d i n T a ble  9  ( w hic h i ncl u des all t h ose ti me 
p oi nts liste d i n T a ble  8 ). 
t I n patie nts at East Asia n st u d y ce nters, s p ot ( pre d ose) a n d p o ole d ( p ost d ose) uri ne sa m ples will be c ollecte d f or P K a nal ysis o n Da y 1 a n d M o nt h 6 at t he ti me 
p oi n ts liste d i n T a ble  1 0 . 
u  Q O L q uesti o n naires t o be c o m plete d i ncl u de S F -1 2, E Q -5 D -5 L, a n d da ys of misse d w or k/sc h o ol.  
v T he P GI C assesses a patie nt’s percei ve d o verall healt h stat us c ha n ge si nce t he be gi n ni n g of t he st u d y usi n g a si n gle -ite m scale. 
w  T he P P E Q is a set of q uesti o ns t o assess treat me nt e x perie nc e a n d i m pacts t o t he patie nt's life t hat are n ot c ollecte d b y t he  ot her Q O L assess me nts.  
x D ur i n g t he scree ni n g peri o d, patie nts a n d care gi vers will rec or d a mi ni m u m of 4 da ys of e Diar y e ntries f or pai n, na usea, fati g ue, a n d a nal gesic use t o pr o vi de a 
baseli ne.  T hese baseli ne e ntri es m ust b e c ollecte d o n da ys w he n t he patie nt is n ot e x perie nci n g a  p or p h yria attac k.  D uri n g t he treat me nt p eri o d t hr o u g h t he 
M o nt h 1 2 visit, e Diar y e ntries f or pai n, na usea, fati g ue a n d a nal gesic use will occ ur dail y.  P ote ntial p or p h yria attac ks wil l b e re p orte d i n t he e Diar y w h e n t he y 
occ ur t hr o u g h o ut t he d urati o n of t he st u d y (fr o m scree ni n g t hr o u g h t he E O S visit).  e Diar y trai ni n g will be c o m plete d at t he st u d y ce nter at Scree ni n g. F urt her 
details o n e Diar y trai ni n g ca n be f o u n d i n t he St u d y Ma n ual.   
y Seri o us a d verse e ve nts ( S A Es) will be c ollecte d starti n g at t he ti me t hat i nf or me d c o nse nt is si g ne d a n d t hr o u g h t he d urati o n  of t he st u d y; A Es will be c ollecte d 
starti n g at t he ti me t he first d ose of st u d y dr u g is a d mi niste re d ( St u d y Da y 1) t hr o u g h t he d urati o n of t he st u d y




Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me n t 7, 2 9 M arc h 2 0 2 1 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 5  
n or malize d rati o; L F T =li ver f u ncti o n test(s); M = m o nt h; m R N A = messe n ger ri b o n ucleic aci d; P B G = p or p h o bili n o ge n; P GI C = P atie nt Gl o bal I m pressi o n of 
C ha n ge; P K = p har mac o ki netics; P P E Q = P or p h yria P atie nt E x perie nce Q uesti o n naire; Q =e ver y; Q O L = q uali t y of life; S C =s u bc uta ne o us; T B L =t otal bilir u bi n  
N ote:  
•  
W hite b o xes re prese nt visits t o t he cli nical st u d y ce nter; gre y b o xes re prese nt st u d y visits t hat ma y be c o n d ucte d b y a h o me healt hcare pr ofessi o nal, 
w here a p plica ble c o u ntr y a n d l ocal re g ulati o ns a n d i nfrastr uct ure all o w. I n t he e ve nt t hat a patie nt is u na ble t o c o me t o t he st u d y ce nter f or a sc he d ule d 
cli nical st u d y visit or t he pr oce d ure (s) ca n n ot be c o m plete d d uri n g t he visit, vital si g n ass ess me nts, la b orat or y sa m ple c ol lecti o n, a n d/ or st u d y dr u g 
a d mi nistrati o n ma y be c o n d ucte d b y a h o me healt hcare pr ofessi o nal, w here a p plica ble c o u ntr y a n d l ocal re g ulati o ns a n d i nfrast r uct ure all o w, after 
c o ns ultati o n wit h t he me dical m o nit or  
•  
St u d y pr oce d ures, i ncl u di n g gi v osira n a d mi nistrati o n, ma y occ ur at t he p atie nt’s h o me at t he discreti o n of t he I n vesti gat or, base d o n safet y a n d 
t olera bilit y. 
a P atie nts w h o disc o nti n ue treat me nt will be as ke d t o c o m plet e t heir ne xt cli nic visit, as well as a safet y f oll o w -u p assess me nt at 3 m o nt hs ( 8 4 [ +  7] da ys) after 
t heir last d ose of gi v osira n. 
b Starti n g at M o nt h 1 3, patie nts o n t he o nce m o nt hl y 1. 2 5 m g/ k g d ose ma y ha ve t heir m o nt hl y d ose i ncrease d t o 2. 5 m g/ k g base d o n I n vesti gat or j u d ge me nt wit h 
c o nsi derati o n of t he criteria descri be d i n Secti o n  6. 2. 3. 4 .  
c A c o m plete p h ysical e xa mi nati o n will be perf or me d at t he M o nt h 1 2 a n d M o nt h 1 8 visit.  At all ot her visits, a tar gete d p h ysic al e xa mi nati o n will be perf or me d.  
T he p h ysical e xa mi nati o n will be perf or me d pri or t o d osi n g.   
d D osi n g wei g ht (i n kil o gra ms) wil l b e c ollecte d d uri n g t he cli nical st u d y ce nter visits. Wei g ht c ollecte d at eit her t he pre vi o us st u d y ce nter visit or c urre nt st u d y 
ce nter visit ma y be use d f or d ose calc ulati o ns. Hei g ht (i n ce nti meters) will be meas ure d a n d B MI will be calc ulate d at cli ni c visits e ver y 6 m o nt hs.  B MI will be 
a ut o maticall y calc ulate d wit hi n t he data b ase.  
e Vital si g ns i ncl u de bl o o d press ure, heart rate, b o d y te m perat ure, a n d res pirat or y rate a n d will be c ollecte d pre d ose. Vital s i g ns will be meas ure d w he n patie nts 
are i n a seate d or s u pi ne p ositi o n (s h o ul d be c o nsiste nt acr oss st u d y visits wit h eac h patie nt) after t he patie nt has reste d f or 1 0 mi n.   
f Tri plicate 1 2 -lea d E C Gs will be perf or me d at pre d ose a n d 2-h o urs ( +  1 5  mi n utes) p ost -d ose at t he M o nt h 1 2 visit, usi n g vali d ate d E C G ser vices e q ui p me nt 
fr o m a ce ntral facilit y; tri plicate meas ure me nts s h o ul d be se parate d b y a p pr o xi matel y 1 mi n ute, wit h t he patie nt i n t he s u pi n e p ositi o n after he or s he has reste d 
c o mf orta bl y f or 5 mi n utes. W he n E C G a n d bl o o d sa m ple c ollecti o n ( e g, f or P K assess me nt) occ ur at t he sa me ti me, E C G assess me nts s h o ul d be perf or me d 
bef ore bl o o d sa m ples are dra w n.  
g  Cli nical la b orat or y para meters will i ncl u de: ser u m c he mistr y i ncl u di n g L F Ts, li pase, a m ylase, he mat ol o g y, c o a g ulati o n, a n d ur i nal ysis. Bl oo d a n d uri ne 
sa m ples f or cli nical la b orat or y e val uati o ns will be c ollecte d pre d ose.  Ser u m ferriti n assess me nts will be c ollecte d at t he M o nt h 1 2 a n d M o nt h 1 8 visits. 
D -di mer assess me nts will be perf or me d at t he M o nt h 9 a n d M o nt h 1 2 visits; as a cli nical r esearc h para meter o nl y, d -di mer res ults will n ot b e c o m m u ni cate d t o 
t he st u d y ce nters.  Res ults fr o m A L T, T B L, a n d I N R tests c ollecte d wit hi n t he 1 4 da ys pri or t o d osi n g m ust b e re vie we d b y t he I n vesti gat or bef ore st u d y dr u g 
a d mi nistrati o n.  L ocall y a nal yz e d res ults ma y be re vie we d t o all o w st u d y dr u g a d mi nistrati o n, b ut a d diti o nal sa m ples f or ce ntral a nal ysis m ust als o be c olle cte d 
o n t he da y of d osi n g pri or t o t he d ose a d mi nistrati o n.  
h Ser u m or uri ne pre g na nc y tests will be perf or me d f or fe males of c hil d -beari n g p ote ntial.  Res ults m ust be a vaila ble bef or e d osi n g.  
i P atie nts w h o cr osse d o ver t o t he O L E peri o d pri or t o i m ple me ntati o n of a me n d me nt 3 (ie, u n der a me n d me nt versi o n 1 or 2) a n d a re recei vi n g 2. 5 m g/ k g o nce 
m o nt hl y will re mai n o n t hat d ose.  U p o n e ntr y t o t he O L E p eri o d u n der a me n d me nt versi o n 3, patie nts will cr oss o ver t o recei ve a 1. 2 5 m g/ k g o nce m o nt hl y 
d ose of gi v osira n.  
j S p ot uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A me as ure me nt d uri n g t he st u d y s h o ul d be c ollecte d pre d ose; h o we ver, if he mi n is use d f or a n attac k, 
sc he d ule d uri nar y A L A, P B G a n d A L A S 1 m R N A will be c ollecte d 4 da ys ( + 4 da ys) after t he patie nt’s last he mi n d ose. W here a p pli ca ble c o u ntr y a n d l ocal 
re g ulati o ns a n d i nfrastr uct ure all o w, uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A assess me nts ma y be c ollecte d b y a h o me healt hcare pr ofessi o nal, se nt t o 
t he st u d y ce nter b y mail, or br o u g ht t o t he st u d y ce nter at t he ne xt visit. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me n t 7, 2 9 M arc h 2 0 2 1 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 6  
k F or patie nts o n t he o nce m o nt hl y 1. 2 5 m g/ k g d ose w h o ha ve de m o nstrate d t olera bilit y t o gi v osira n, b ut ha v e i na d e q uate cli nical res p o nse, A L A meas ure me nts 
fr o m a pre vi o us visit or a l ocal la b orat or y ma y be use d b y I n vesti gat ors c o nsi deri n g d ose escalati o n t o 2. 5  m g/ k g o nce m o nt hl y.  D ose escalati o n f or patie nts o n 
t he 1. 2 5 m g/ k g m o nt hl y d ose ma y be c o nsi dere d starti n g at M o nt h 1 3.  See Secti o n 6. 2. 3. 4  f or f urt her i nf or mati o n o n d ose escalati o n criteria.   
l W here all o we d per l ocal re g ul ati o ns a n d I R B/ E C a p pr o val, ser u m, plas ma, a n d uri ne sa m pl es f or e x pl orat or y bi o mar ker t esti n g, a n d meas uri n g h o m oc ystei ne 
le vels, will be c ollecte d pri or t o d osi n g.  
m  Bl o o d sa m ples f or P K a nal ysis will be c ollecte d pre d ose a n d at t he ti me p oi nts liste d i n T a ble  8  or T a ble  9 . 
n Sa m ples will be c ollecte d pre d ose.  
o Q O L q uesti o n naires t o be c o m plete d i ncl u de S F -1 2, E Q -5 D -5 L, a n d misse d da ys of w or k/sc h o ol  
p T he P GI C assesses a patie nt’s percei ve d o verall healt h stat us c ha n ge si nce t he be gi n ni n g of t he st u d y usi n g a si n gle -ite m scale. 
q T he P P E Q is  a set of q uesti o ns t o assess treat me nt e x perie nc e a n d i m pacts t o t he patie nt's life t hat are n ot c ollecte d b y t he ot her Q O L a ssess me nts.  
r Electr o nic diar y e ntries (i ncl u di n g pai n, na usea, a n d fati g ue meas ure me nt b y N R S a n d a nal gesics q uesti o n) will be c o m plete d dail y b y patie nts a n d care gi vers 
t hr o u g h t he M o nt h 1 2 visit; p ote ntial p or p h yria attac ks will be re p orte d i n t he e Diar y w he n t he y occ ur b y patie nts a n d care givers t hr o u g h o ut t he d urati o n of t he 
st u d y (fr o m scree ni n g t hr o u g h t he E O S visit). P atie nt s/care gi vers will be trai ne d o n t he ne w a p pr oac h f or usi n g t he e diar y after M o nt h 1 2.  
 






Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me n t 7, 2 9 M arc h 2 0 2 1 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 9  
e Si n gle 1 2 -lea d E C G will be perf or me d i n t he s u pi ne p ositi o n after t he patie nt has reste d c o mf orta bl y f or 5 mi n utes. E C Gs will be c ollecte d pre d ose a n d pri or t o 
a n y bl o o d dra ws.  W he n E C G a n d bl o o d sa m p le c ollecti o n (e g, f or P K assess me nt) occ ur at t he sa me ti me, E C G assess me nts s h o ul d be perf or me d bef ore bl o o d 
sa m ples are dra w n.  U p o n i m ple me ntati o n of A me n d me nt 6, E C Gs are n o l o n ger re q uire d at t he M o nt h 2 4 a n d 3 6 visits.  
f Cli nical la b orat or y para meters will i ncl u de: ser u m c he mistr y i ncl u di n g L F Ts, li pase, a m ylase, he mat ol o g y, c o a g ulati o n, a n d uri nal ysis. Bl o o d a n d uri ne 
sa m ples f or cli nical la b orat or y e val uati o ns will be c ollecte d pre d ose.  Bl o o d a n d uri ne sa m ples f or cli nical la b orat or y asses s me nts ma y be c ollecte d offsite b y a 
h o me healt hcare pr ofessi o nal at all ti me p oi nts, w here a p pli ca ble c o u ntr y a n d l ocal re g ulati o ns a n d i nfrastr uct ure all o w.  Re s ults fr o m A L T a n d T B L tests 
c ollecte d wit hi n 6 wee ks pri or t o d osi n g m ust be re vie we d b y t he I n vesti gat or bef ore st u d y dr u g a d mi nistrati o n.  Eit her c e ntrall y or l ocall y a nal yze d A L T a n d 
T B L res ults ma y be re vie we d t o all o w st u d y dr u g a d mi nistrati o n.  I n t he e ve nt t hat gi v osira n is a d mi nistere d offsite b y t he p atie nt or care gi ver, safet y 
la b orat or y assess me nts ot her t ha n A L T a n d T B L m ust be o btai ne d fr o m a ce ntral or l ocal la b orat or y wit hi n 3 m o nt hs pri or t o d osi n g.  Ser u m ferriti n 
assess me nts will be c ollecte d at t he M o nt h 2 4, M o nt h 3 0 a n d M o nt h 3 6 visits.  
g Ser u m or uri ne pre g na nc y tests will be p erf or me d f or fe males of c hil d -beari n g p ote ntial.  Res ults m ust be a vaila ble bef or e d osi n g.  
h P atie nts w h o cr osse d o ver t o t he O L E peri o d pri or t o i m ple me ntati o n of a me n d me nt 3 (ie, u n der a me n d me nt versi o n 1 or 2) a n d a re recei vi n g 2. 5 m g/ k g o nce 
m o nt hl y w ill re mai n o n t hat d ose.  U p o n e ntr y t o t he O L E p eri o d u n der a me n d me nt versi o n 3, patie nts will cr oss o ver t o recei ve a 1. 2 5  m g/ k g o nce m o nt hl y 
d ose of gi v osira n. Starti n g at M o nt h 1 3, a d ose i ncrease t o 2. 5  m g/ k g o nce m o nt hl y ma y b e per mitte d base d o n I n v esti gat or j u d g me nt i n c o nsi derati o n of d osi n g 
criteria descri be d i n Secti o n  6. 2. 3. 4 .  U p o n i m ple me ntati o n of a me n d me nt  5, all patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n o nce m o nt hl y w h o d o n ot ha ve 
o n g oi n g cli nicall y rele va nt tra nsa mi nase ele vati o ns will ha ve t heir d ose i ncrease d t o 2. 5  m g/ k g gi v osira n o nce m o nt hl y.  See Secti o n  6. 2. 3. 4  f or f urt her 
i nf or mati o n o n d ose escalati o n. 
I S p ot uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A me as ure me nt d uri n g t he st u d y s h o ul d be c ollecte d pre d ose; h o we ver, if he mi n is use d f or a n attac k, 
sc he d ule d uri nar y A L A, P B G a n d A L A S 1 m R N A will be c ollecte d 4 da ys ( + 4 da ys) after t he patie nt’s last he mi n d ose. W here a p pli ca ble c o u ntr y a n d l ocal 
re g ulati o ns a n d i nfrastr uct ure all o w, uri ne sa m ples f or A L A, P B G, an d A L A S 1 m R N A assess me nts ma y be c ollecte d b y a h o me healt hcare pr ofessi o nal, se nt t o 
t he st u d y ce nter b y mail, or br o u g ht t o t he st u d y ce nter at t he ne xt visit.  
j W here all o we d per l ocal re g ul ati o ns a n d I R B/ E C a p pr o val, ser u m, plas ma, a n d uri ne sa m pl es f or e x pl orat or y bi o mar ker t esti n g, a n d meas uri n g h o m oc ystei ne 
le vels, will be c ollecte d pri or t o d osi n g.  
k Bl o o d sa m ples f or P K a nal ysis will be c ollecte d pri or t o d osi n g at t he ti me p oi nts liste d i n T a ble  8  or  T a ble  9 .  P K assess me nts t hat ca n n ot b e c ollecte d i n t he 
i nte n de d visit wi n d o w ma y be c o m plete d wit hi n 6 m o nt hs at t he ne xt st u d y ce nter visit.  
l Sa m ples will be c ollecte d pre d ose.  A D A assess me nts t hat ca n n ot be c ollecte d i n t he i nte n d e d visit wi n d o w ma y be c o m plete d wi t hi n 6 m o nt hs at t he ne xt 
st u d y ce nter visit. 
m  Q O L q uesti o n naires t o b e c o m plete d i ncl u de S F -1 2, E Q -5 D -5 L, a n d misse d da ys of w or k/sc h o ol.  I n sit uati o ns w here a pla n ne d st u d y visit ca n n ot b e 
c o m plete d at t he st u d y ce nter, t he patie nt will c o m plete t he Q o L q uesti o n naires at h o me.  
n T he P P E Q is a set of q uesti o ns t o assess tr eat me nt e x perie nc e a n d i m pacts t o t he patie nt's life n ot c ollecte d b y t he ot her Q O L assess me nts.  I n sit uati o ns w here 
a pla n ne d st u d y visit ca n n ot b e c o m plete d at t he st u d y ce nter, t he patie nt will c o m plete t he P P E Q q uesti o n naire at h o me.  
o  P ote ntial p or p h yria attac ks will b e re p orte d i n t he e Diar y w h e n t he y occ ur t hr o u g h o ut t he d urati o n of t he st u d y (fr o m scre e ni n g t hr o u g h t he E O S visit).  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 0  
T A B L E O F C O N T E N T S  
 
S P O N S O R P R O T O C O L A P P R O V A L  ........................................................................................... 2  
I N V E S TI G A T O R’ S A G R E EM E N T  .............................................................................................. 3  
P R O T O C O L S Y N O P SI S  ................................................................................................................ 4  
T A B L E O F C O N T E N T S  .............................................................................................................. 2 0  
LI S T O F T A B L E S  ........................................................................................................................ 2 4  
LI S T O F FI G U R E S  ....................................................................................................................... 2 4  
1.  
I N T R O D U C TI O N ...................................................................................................... 2 8  
1. 1.  
Disease O v er vie w  ....................................................................................................... 2 8  
1. 2.  
Gi v osir a n .................................................................................................................... 3 0  
1. 2. 1.  
S u m mar y of N o n cli nical Data wit h Gi v osira n  ........................................................... 3 0  
1. 2. 2.  
S u m mar y of Cli nical Dat a wit h Gi v osira n  ................................................................. 3 2  
1. 2. 2. 1.  
P hase 1 St u d y A L N -A S 1 -0 0 1  .................................................................................... 3 2  
1. 2. 2. 2.  
P hase 1/ 2 O pe n -la b el E xte nsi o n St u d y A L N-A S 1 -0 0 2  ............................................. 3 3  
1. 2. 2. 3.  
Dr u g -dr u g I nt eracti o n St u d y A L N -A S 1 -0 0 4  ............................................................. 3 4  
1. 3.  
St u d y Desi g n Rati o nale  .............................................................................................. 3 4  
1. 4.  
D ose Rati o nale  ........................................................................................................... 3 6  
1. 5.  
Be nefit -Ris k Assess me nt  ........................................................................................... 3 7  
2.  
O BJ E C TI V E S  ............................................................................................................ 3 8  
2. 1.  
Pri mar y O bj ecti ve  ...................................................................................................... 3 8  
2. 2.  
Sec o n dar y O bj ecti ves  ................................................................................................. 3 8  
2. 3.  
E x pl orat or y O bjecti ves  ............................................................................................... 3 9  
3.  
E N D P OI N T S  .............................................................................................................. 3 9  
3. 1.  
Pri mar y E n d p oi nt  ....................................................................................................... 3 9  
3. 2.  
Sec o n dar y E n d p oi nts  .................................................................................................. 3 9  
3. 3.  
E x pl orat or y E n d p oi nts  ............................................................................................... 4 0  
3. 4.  
Safet y E n d p oi nts  ........................................................................................................ 4 1  
3. 5.  
Defi niti o n of P or p h yri a Attac ks  ................................................................................. 4 1  
4.  
I N V E S TI G A TI O N A L P L A N .................................................................................... 4 2  
4. 1.  
S u m ma r y of St u d y Desi g n ......................................................................................... 4 2  
4. 2.  
D urati o n of Treat me nt  ................................................................................................ 4 4  
4. 3.  
N u m ber of Patie nts  ..................................................................................................... 4 4  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 1  
4. 4.  
Met h o d of Assi g ni n g Patie nts t o Treat me nt Gr o u ps  .................................................. 4 4  
4. 5.  
Bli n di n g  ...................................................................................................................... 4 5  
4. 6.  
Patie nt Electr o nic Diar y (e Diar y)  ............................................................................... 4 6  
4. 7.  
I n d e pe n de nt Data M o nit ori n g C o m mittee ................................................................. 4 6  
5.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  ............................................. 4 6  
5. 1.  
I n cl usi o n Criteria ........................................................................................................ 4 6  
5. 2.  
E x cl u si o n Criteria ....................................................................................................... 4 7  
5. 3.  
Disc o nti n uati o n of St u d y Dr u g a n d/ or St u d y  ............................................................. 4 8  
5. 3. 1.  
Disc o nti n uati o n of St u d y Dr u g  .................................................................................. 4 8  
5. 3. 2.  
Disc o nti n uati o n fr o m t he St u d y  ................................................................................. 4 9  
5. 3. 3.  
Wit h dra wal  of C o nse nt t o C ollect a n d Pr ocess t he Patie nt’s Pers o nal Data  .............. 5 0  
5. 3. 4.  
Re place me nt of Patie nts  ............................................................................................. 5 0  
6.  
T R E A T M E N T S  ......................................................................................................... 5 0  
6. 1.  
Treat me nts A d mi nistere d  ........................................................................................... 5 0  
6. 2.  
I n v esti gati o nal St u d y Dr u g ........................................................................................ 5 0  
6. 2. 1.  
Descri pti o n  ................................................................................................................. 5 0  
6. 2. 2.  
D ose a n d A d mi nistrati o n  ............................................................................................ 5 1  
6. 2. 2. 1.  
D uri n g t h e 6 -M o nt h Treat me nt Peri o d ( Da y 1 t o M o nt h 6)  ....................................... 5 2  
6. 2. 2. 2.  
D uri n g t h e O pe n -La bel E xte nsi o n Peri o d ( After M o nt h 6 t hr o u g h E n d of 
Treat me nt)  .................................................................................................................. 5 2  
6. 2. 3.  
D ose M o dificati o ns  .................................................................................................... 5 2  
6. 2. 3. 1.  
M o nit ori n g a n d D osi n g R ules Base d o n Li ver F u ncti o n Test Res ults  ....................... 5 3  
6. 2. 3. 2.  
M o nit ori n g a n d D osi n g R ules Base d o n Li pas e a n d A m ylas e Res ults  ...................... 5 7  
6. 2. 3. 3.  
M o nit ori n g a n d D osi n g R ules i n Patie nts wit h P ote ntial Cases of 
A na p h yl actic Reacti o n  ............................................................................................... 5 8  
6. 2. 3. 4.  
D ose Escalati o n G ui da n ce f or Gi v osira n fr o m 1. 2 5 m g/ k g O nce M o nt hl y t o 
2. 5  m g/ k g O nce M o nt hl y i n t he O pe n -La b el Peri o d  .................................................. 5 9  
6. 2. 4.  
Pre parati o n, H a n dli n g, a n d St ora ge  ........................................................................... 5 9  
6. 2. 5.  
Pac ka gi n g a n d La b eli n g  ............................................................................................. 6 0  
6. 2. 6.  
Acc o u nta bilit y  ............................................................................................................ 6 0  
6. 3.  
C o nc o mita nt Me dicati o ns  .......................................................................................... 6 0  
6. 3. 1.  
He mi n Pr o p h yla xis  ..................................................................................................... 6 1  
6. 3. 2.  
G o na d otr o pi n -Releasi n g H or m o ne A nal o g u e Treat me nt  .......................................... 6 1  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 2  
6. 3. 3.  
A nal gesic Usa ge  ......................................................................................................... 6 1  
6. 3. 4.  
Vita mi n B 6 S u p ple me ntati o n  ..................................................................................... 6 2  
6. 4.  
C o ntrace pti ve Re q uir e me nts  ...................................................................................... 6 2  
6. 5.  
Treat me nt C o m plia nce  ............................................................................................... 6 3  
7.  
S T U D Y  A S S E S S M E N T S  .......................................................................................... 6 3  
7. 1.  
Scree ni n g Assess me nts  .............................................................................................. 6 3  
7. 1. 1.  
Retesti n g  ..................................................................................................................... 6 4  
7. 1. 2.  
Rescree ni n g  ................................................................................................................ 6 4  
7. 2.  
Efficac y Assess me nts  ................................................................................................. 6 4  
7. 2. 1.  
P or p h yria Attac k Re p orti n g  ....................................................................................... 6 4  
7. 2. 2.  
Pai n a n d Pai n -Relate d Assess me nts  ........................................................................... 6 5  
7. 2. 3.  
Assess me nts of Na usea a n d Fati g ue  .......................................................................... 6 5  
7. 2. 4.  
Q ualit y of Lif e ( Q O L)  ................................................................................................ 6 5  
7. 3.  
P har mac o d y na mic Ass ess me nts  ................................................................................. 6 6  
7. 4.  
P har mac o ki netic Assess me nts  ................................................................................... 6 6  
7. 4. 1.  
P har mac o ki netic Assess me nts i n Patie nts at East Asia n St u d y Ce nters  .................... 6 7  
7. 5.  
Safet y Assess me nts  .................................................................................................... 6 7  
7. 5. 1.  
Vital Si g ns  .................................................................................................................. 6 7  
7. 5. 2.  
Wei g ht a n d Hei g ht  ..................................................................................................... 6 7  
7. 5. 3.  
P h ysical E x a mi nati o n  ................................................................................................. 6 8  
7. 5. 4.  
Electr ocar di o gra m  ...................................................................................................... 6 8  
7. 5. 5.  
C li nical La b orat or y Assess me nts ............................................................................... 6 8  
7. 5. 5. 1.  
I m m u n o ge nicit y ......................................................................................................... 7 1  
7. 5. 5. 2.  
Pre g n a nc y T esti n g  ...................................................................................................... 7 1  
7. 5. 6.  
A d verse E v e nts  ........................................................................................................... 7 1  
7. 5. 6. 1.  
Def i niti o ns .................................................................................................................. 7 1  
7. 5. 6. 2.  
Eliciti n g a n d Rec or di n g A d verse E v e nts  ................................................................... 7 3  
7. 5. 6. 3.  
Seri o us A d verse E v e nts Re q uire I m me diate Re p orti n g t o S p o ns or/ Desi g nee  ........... 7 4  
7. 5. 6. 4.  
S p o ns or Safet y Re p orti n g t o Re g ulat or y A ut h oriti es  ................................................. 7 5  
7. 5. 6. 5.  
Seri o us A d verse  E v e nt N otificati o n t o t he I nstit uti o nal Re vie w 
B oar d/I n de pe n d e nt Et hics C o m mittee  ....................................................................... 7 5  
7. 5. 6. 6.  
Pre g n a nc y Re p orti n g  .................................................................................................. 7 5  
7. 5. 6. 7.  
O ver d ose Re p orti n g  ................................................................................................... 7 5  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 3  
7. 6.  
E x pl orat or y Assess me nts  ........................................................................................... 7 5  
7. 6. 1.  
E x pl orat or y Bi o mar kers  ............................................................................................. 7 5  
7. 6. 2.  
D N A Sa m ples  ............................................................................................................. 7 6  
7. 7.  
C O VI D -1 9 D ata C ollecti o n  ........................................................................................ 7 6  
8.  
S T A TI S TI C S  .............................................................................................................. 7 6  
8. 1.  
Deter mi nati o n of Sa m ple Size  ................................................................................... 7 6  
8. 2.  
Statistical Met h o d ol o g y  ............................................................................................. 7 7  
8. 2. 1.  
P o p ulati o ns t o be A nal yz e d  ........................................................................................ 7 7  
8. 2. 2.  
E x a mi nati o n of S u b gr o u ps  ......................................................................................... 7 7  
8. 2. 3.  
Ha n dli n g of Missi n g Dat a  .......................................................................................... 7 7  
8. 2. 4.  
Baseli ne E v al uati o ns  .................................................................................................. 7 7  
8. 2. 5.  
Efficac y A nal yses  ....................................................................................................... 7 7  
8. 2. 5. 1.  
Pri mar y E n d p oi nt  ....................................................................................................... 7 8  
8. 2. 5. 2.  
Sec o n dar y E n d p oi nts  .................................................................................................. 7 8  
8. 2. 5. 3.  
E x pl orat or y E n d p oi nts  ............................................................................................... 7 9  
8. 2. 6.  
P har mac o d y na mic A n al ysis  ....................................................................................... 7 9  
8. 2. 7.  
P har mac o ki netic A n al ysis  .......................................................................................... 7 9  
8. 2. 8.  
Safet y A nal yses  .......................................................................................................... 7 9  
8. 2. 9.  
Ot h er A nal yses  ........................................................................................................... 8 0  
8. 2. 1 0.  
I nteri m A nal ysis ......................................................................................................... 8 0  
9.  
S T U D Y A D MI NI S T R A TI O N  ................................................................................... 8 1  
9. 1.  
Et hical a n d Re g ulat or y C o nsi derati o ns  ...................................................................... 8 1  
9. 1. 1.  
I nf or me d C o nse nt ....................................................................................................... 8 1  
9. 1. 2.  
Et hical Re vie w  ........................................................................................................... 8 1  
9. 1. 3.  
Seri o us Breac h of Pr ot oc ol  ......................................................................................... 8 2  
9. 1. 4.  
St u d y D oc u me ntati o n, C o nfi de ntialit y, a n d Rec or ds Rete nti o n  ................................ 8 2  
9. 1. 5.  
E n d of St u d y  ............................................................................................................... 8 3  
9. 1. 6.  
Disc o nti n uati o n of t he Cli nical St u d y  ........................................................................ 8 3  
9. 2.  
Data Q ualit y C o ntr ol a n d Q ualit y Ass ura nce  ............................................................. 8 3  
9. 2. 1.  
Data Ha n dli n g  ............................................................................................................ 8 3  
9. 2. 2.  
St u d y M o nit ori n g  ....................................................................................................... 8 3  
9. 2. 3.  
A u dits a n d I ns p ecti o ns  ............................................................................................... 8 4  
9. 3.  
P u blicati o n P olic y  ...................................................................................................... 8 4  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 4  
1 0.  
LI S T O F R E F E R E N C E S  ........................................................................................... 8 5  
1 1.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T TI M E 
P OI N T S  ...................................................................................................................... 8 7  
1 1. 1.  
Bi oc he mical Dia g n osis of A H P i n t he A bse nce of I d e ntifie d M utati o n i n a 
P or p h yria -rel ate d Ge n e .............................................................................................. 9 3  
1 1. 2.  
A na p h yl actic Reacti o ns  .............................................................................................. 9 4  
 
LI S T O F T A B L E S  
Ta ble  1:  
Sc he d ule of Assess me nts –  Scree ni n g a n d 6 -M o nt h Tr eat me nt Peri o d 
( Scree ni n g t hr o u g h M o nt h 6) ..................................................................................... 1 0  
Ta ble  2:  
Sc he d ule of Assess me nts –  O pe n -La b el E xte nsi o n Peri o d: After M o nt h 6 
t hr o u g h M o nt h 1 8  ....................................................................................................... 1 4  
Ta ble  3:  
Sc he d ule of Assess me nts f or O pe n -La bel E xte nsi o n Peri o d: M o nt h 1 9 
t hr o u g h E n d of St u d y ................................................................................................. 1 7  
Ta ble  4:  
M o nit ori n g a n d D osi n g R ules i n Patie nts wit h Ala ni ne Tra ns a mi nase ( A L T) 
Ele vati o ns  ................................................................................................................... 5 4  
Ta ble  5:  
He patic Assess me nts i n Patie nts W h o E x perie nce Ele vate d Tra nsa mi nases  ............. 5 6  
Ta ble  6:  
M o nit ori n g a n d D osi n g R ules i n Patie nts wit h Li pase or A m ylas e Ele vati o ns  ......... 5 7  
Ta ble  7:  
Cli nica l La b orat or y Assess me nts ............................................................................... 7 0  
Ta ble  8:  
P har mac o ki netic, E C G, a n d A D A Ti me P oi nts f or All Patie nts ( E x ce pt 
Patie nts at East Asia n Sites ) ....................................................................................... 8 7  
Ta ble  9:  
P har mac o ki netic, E C G, a n d A nti -Dr u g A nti b o d y Assess me nt Ti me P oi nts f or 
Patie nts at East Asia n St u d y Ce nters ( Bl o o d Sa m ples)  ............................................. 8 9  
Ta ble  1 0:  Uri ne P har ma c o ki netic/ P har mac o d y n a mic Ti me p oi nts f or Patie nts at East 
Asia n St u d y Ce nters  ................................................................................................... 9 1  
Ta ble  1 1:  Bi oc he mical Criteria i n A d diti o n t o A L A a n d P B G f or Dia g n osis of A H P i n 
t he A bse nce of a n I de ntifie d M utati o n i n a P or p hyria -rel ate d Ge n e ......................... 9 3  
Ta ble  1 2:  Sa m ps o n Criteria f or A n a p h yl actic Reacti o ns  ........................................................... 9 4  
 
LI S T O F FI G U R E S  
Fi g ure  1:  
He me Bi os y nt hetic Pat h wa y a n d E nz y m e Deficie nc y Res ulti n g i n Ac ute 
He patic P or p h yria  ....................................................................................................... 2 8  
Fi g ure  2:  St u d y Desi g n  .............................................................................................................. 4 4  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 5  
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  
A A R  
A n n ualize d attac k rate  
A E  
A d verse e ve nt  
AI P  
Ac ute i nter mitte nt p or p h yria  
A D A  
A nti -dr u g a nti b o d y  
A D P  
A L A D deficie nt p or p h yria  
A H P  
Ac ute he patic p or p h yria  
A L A  
A mi n ole v uli nic aci d  
A L A D  
A L A de h y dratase  
A L A S 1  
A mi n ole v uli nic aci d s y nt hase  
A L P  
Al kali ne p h os p hatase  
A L T  
Ala ni ne a mi n otra nsferase  
A S G P R  
Asial o gl yc o pr otei n rece pt or  
A S H E  
As y m pt o matic hi g h e xcreter  
A S T  
As partate a mi n otra nsferase  
A U C  
Area u n der t he c ur ve  
B MI  
B o d y mass i n de x  
B U N  
Bl o o d urea nitr o ge n  
C H E  
C hr o nic hi g h e xcreters  
C H M P  
C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Use  
C L/ F  
A p pare nt cleara nce  
C ma x  
Ma xi m u m plas ma c o nce ntrati o n  
C O VI D -1 9  
C or o na vir us disease 2 0 1 9  
C R O  
C o ntract researc h or ga nizati o n  
C Y P  
C yt oc hr o me P 4 5 0  
D DI  
Dr u g -dr u g i nteracti o n  
DI LI  
Dr u g -i n d uce d li ver i nj ur y 
D M C  
Data M o nit ori n g C o m mittee  
D R F  
D ose -ra n ge fi n di n g 
E C  
Et hics c o m mittee  
E C G  
Electr ocar di o gra m  
e C R F 
Electr o nic case re p ort f or m  
e G F R 
Esti mate d gl o mer ular filtrati o n rate  
E O S  
E n d of st u d y  
E Q -5 D -5 L  
E ur o Q ualit y of Life Healt h State Pr ofile Q uesti o n naire  
E U  
E ur o pea n U ni o n  
F D A  
F o o d a n d Dr u g A d mi nistrati o n  
F S H  
F ollicle -sti m ulati n g h or m o ne 
G A B A  
Ga m ma -a mi n o b ut yric aci d  
Gal N Ac  
N -acet yl galact osa mi ne  
G G T  
Ga m ma gl uta m yl tra nsferase  
G L P  
G o o d la b orat or y  practice  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 6  
G n R H  
G o na d otr o pi n -releasi n g h or m o ne 
H B M S  
H y dr o x y met h yl bila ne S y nt hase  
H bs A b  
He patitis B s urface a nti b o d y  
H bs A g  
He patitis B s urface a nti ge n  
H B V  
He patitis B vir us  
H C P  
Here ditar y C o pr o p or p h yria  
H C V  
He patitis C vir us  
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 5 0 
Half -ma xi mal i n hi bit or y c o nce ntrati o n  
I C F 
I nf or me d c o nse nt f or m 
I C H 
I nter nati o nal C o nfere nce o n Har m o nizati o n 
I E C 
I n de pe n de nt Et hics C o m mittee 
I N R (e q ui vale nt t o P T/I N R) 
I nter nati o nal n or malize d rati o (e q ui vale nt t o pr ot hr o m bi n 
ti me/i nter nati o nal n or malize d rati o) 
I R B 
I nstit uti o nal Re vie w B oar d 
I R S 
I nteracti ve res p o nse s yste m 
I S R 
I nj ecti o n site reacti o n 
I V 
I ntra ve n o us 
L F T  
Li ver f u ncti o n tests  
M A D  
M ulti ple asce n di n g d ose  
M D R D  
M o dificati o n of  diet i n re nal disease  
M M R M  
mi xe d -effects m o del re peate d meas ures  
m R N A  
Messe n ger R N A  
N O A E L  
N o o bser ve d a d verse effect le vel  
N O E L  
N o o bser ve d -effect le vel  
N R S  
N u merical rati n g scale  
N S AI Ds  
N o n -ster oi dal a nti-i nfla m mat or y dr u gs 
O L E  
O pe n -la bel e xte nsi o n 
O T C  
O ver t he c o u nter  
P B G  
P or p h o bili n o ge n  
P B G D  
P or p h o bili n o ge n Dea mi nase  
P C S  
P h ysical C o m p o ne nt S u m mar y  
P D  
P har mac o d y na mic  
P GI C  
Patie nt Gl o bal I m pressi o n of C ha n ge  
P K  
P har mac o ki netic  
P P E Q  
P or p h yria Patie nt E x perie nce Q uesti o n naire  
P T  
Pr ot hr o m bi n ti me  
Q O L  
Q ualit y of life  
R B C  
Re d bl o o d cells  
R N A  
Ri b o n ucleic aci d  
R N Ai  
R N A i nterfere nce  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 7  
S A D  
Si n gle asce n di n g d ose  
S A E  
Seri o us a d verse e ve nt  
S A P  
Statistical a nal ysis pla n  
S C  
S u bc uta ne o us  
S D  
Sta n dar d de viati o n  
S F -1 2  
1 2 -ite m S h ort-F or m Healt h S ur ve y  
Si R N A  
S mall i nterferi n g R N As  
S U S A R  
S us pecte d u ne x pecte d seri o us a d verse reacti o ns  
T B L  
T otal bilir u bi n  
T ma x  
Ti me t o ma xi m u m plas ma c o nce ntrati o n  
t ½ β 
Eli mi nati o n half -life 
U L N  
U p per li mit of n or mal  
U S  
U nite d States  
V A S  
Vis ual a nal o g scale 
V/ F  
A p pare nt v ol u me of distri b uti o n  
V P  
Varie gate p or p h yria  
W H O  
W orl d Healt h Or ga nizati o n  
 


Cli nic al St u d y Pr ot oc ol A L N- A S 1- 0 0 3
gi v osir a n ( A L N- A S 1)
A me n d me nt 7, 2 9 M arc h 2 0 2 1
Al n yl a m P h ar m ace utic als
C o nfi de nti al
2 8
1.
I N T R O D U C TI O N
1. 1.  
Dise ase O ver vie w 
T he ac ute h e patic p or p h yrias ( A H Ps) are a fa mil y of rare, seri o us a n d life-t hreate ni n g meta b olic 
dis or ders pre d o mi na ntl y ca use d b y a ge netic m utati o n i n 1 of t he 8 e nz y m es res p o nsi ble f or he m e 
s y nt hesis (Fi g ure 1 ).  T h e A H Ps i ncl u de Ac ut e I nter mitte nt P or p h yria ( AI P), Here ditar y 
C o pr o p or p h yri a ( H C P), Varie gat e P or p h yria ( V P), or A L A de h y dratas e deficie nt p or p h yria 
( A D P) ( 1); AI P is t he m ost c o m m o n A H P t y pe.  All A H P are d ue t o a ut os o mal d o mi na nt l oss- of-
f u ncti o n m utati o ns i n e nz y m es i n t he he m e bi os y nt hetic pat h wa y, wit h t he e x ce pti o n of A D P, 
w hic h is t he res ult of a ut os o mal recessi ve m utati o ns ( 2, 3).  
Fi g ure 1:  
He me Bi os y nt hetic P at h w a y a n d E nz y me Deficie nc y Res ulti n g i n Ac ute 
He p atic P o r p h yri a
Refere nce:  J a mes, et al 2 0 0 0 ( 4 )
Ac ute attac ks are tri g gere d b y str ess fact ors t hat i n d uce t he e x pressi o n of a mi n ole v uli nic aci d 
s y nt hase 1 ( A L A S 1), w hi c h is t he rate li miti n g ste p i n he me s y nt hesis.  I n w o me n, attac ks oft e n 
occ ur ar o u n d t he me nstr u al c ycle d u e t o c ha n ges i n A L A S 1 e x pressi o n fr o m h or m o nal 
fl uct uati o ns. T he i n d ucti o n of A L A S 1, u pstrea m of he me s y nt hesis e nz y m e deficie ncies, res ults i n 
i ncreas e d fl u x t hr o u g h t h e he me s y nt hesis pat h wa y a n d m ar ke d acc u m ulati o n of t he ne ur ot o xic 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2 9  
p or p h yri n prec urs ors, a mi n ole v uli nic  aci d ( A L A) a n d/ or p or p h o bili n o ge n ( P B G), t he ca usal 
fact ors dri vi n g cli nic al ma nifestati o ns of diseas e.  
Disease s y m pt o m o nset i n A H P patie nts t y picall y occ urs after p u bert y, wit h w o me n ( ~ 8 0 %) m ore 
c o m m o nl y affecte d t ha n me n (5 ).  Patie nts e x perie nci n g ac ut e attac ks pres e nt wit h hig hl y m or bi d 
a n d p ote ntiall y life -t hreate ni n g s y m pt o ms t hat relate t o wi des prea d d ysf u ncti o n acr oss t he ce ntral, 
peri p heral, a n d a ut o n o mi c ner v o us s yste m.  T he m ost de bilitati n g a n d fre q u e nt s y m pt o m d uri n g 
ac ute attac ks is diff use, s e vere n e ur o visceral p ai n , m ost ofte n i n t he a b d o me n, bac k, or li m bs.  
Ot her c o m m o n attac k si g ns a n d s y m pt o ms i ncl u de na usea a n d v o miti n g, fati g ue, h y p erte nsi o n, 
tac h ycar dia, m ot or wea k ness, h y p o n atre mia, a n d me ntal stat us c ha n ges (3 , 6 ).  T he attac k 
ma nifestati o ns a n d pai n are ofte n s o se v ere t h at t he y re q uir e h os pitalizati o n, s u p p orti ve care a n d 
t he use of hi g h-d ose i ntra ve n o us o pi oi ds (7 ).  Li m b n u m b ness, wea k ness or paresis d ue t o a 
se ns or y or m ot or ne ur o pat h y, res pecti vel y, ca n als o occ ur, wit h pr o gressi o n t o paral ysis, 
res pirat or y fail ure a n d deat h (1 , 8 , 9 ).   
Dia g n osis of A H P is ma de wit h t he c o m bi nati o n of t y pical cli nical pres e ntati o n a n d s y m pt o ms as 
descri be d a b o ve, al o n g wit h bi oc he mical testi n g f or ele vate d uri ne A L A a n d/ or P B G, a n d ge n etic 
testi n g t o i de ntif y a m utati o n i n t he res pecti ve ca usati ve ge ne ( Fi g ure  1 ). I n rare i nsta n ces, A H P 
ca n be dia g n os e d i n t he a bse nce of a n i de ntifie d m utati o n i n a p or p h yri a -rel ate d ge ne, i n w hi c h 
case a d diti o nal bi oc h e mical testi n g of plas ma a n d st o ol p or p h yri ns ca n disti n g uis h AI P fr o m t he 
ot her A H Ps ( H C P, V P, a n d A D P) (1 , 5 ). 
T here h as bee n i ncreasi n g rec o g niti o n t hat A H P patie nts ha ve si g nifica nt c hr o nic disease 
ma nifestati o ns be y o n d attac ks.  Data fr o m St u d y A L N -A S 1 -N T -0 0 1 ( E X P L O R E, a n 
o bser vati o nal nat ural hist or y st u d y), c o n d ucte d i n a se verel y affect e d A H P patie nt p o p ulati o n wit h 
rec urre nt atta c ks, deter mi ne d t hat 6 4 % of patie nts ha ve c hr o ni c s y m pt o ms, wit h al m ost 5 0 % 
e x perie nci n g s y m pt o ms o n a dail y b asis, m ost c o m m o nl y p ai n, f oll o we d b y na us ea a n d fati g ue 
(1 0 ).    
F urt her m ore, nat ur al hist or y st u dies d o n e b ot h i n t h e U S a n d i n S we de n i n AI P p atie nts 
deter mi ne d t hat 1 8 t o 2 2 % of AI P patie nts e x peri e nce c hr o nic s y m pt o ms, m ost c o m m o nl y p ai n 
(i n t he a b d o me n, bac k or li m bs) a n d fati g u e (3 , 1 1 ).   
O ver 7 5 % of ac ut e p or p h yria attac ks r e q uire ur ge nt me dical care a n d/ or h os pitalizati o n or 
i ntra ve n o us he mi n (1 0 ).  Patie nts are i nitiall y treat e d wit h s u p p orti ve care a n d i ntra ve n o us (I V) 
gl uc ose ( 1 0 % d e xtr ose), a nal gesics a n d a ntie metics, al o n g wit h t he  re m o val of k n o w n 
preci pitati n g tri g gers, s uc h as cert ai n me dicati o ns or dieti n g (1 2 ).  Pai n reli ef t y pi call y re q uir es 
o pi oi ds u ntil p or p h yri a -s pecific t hera p y ta kes effect.  I n p atie nts wit h m o derate t o se vere attac ks, 
or w h o fail t o res p o n d t o s u p p orti ve meas ures, tr eat me nt wit h I V he mi n is use d.  After 2 t o 5 d a ys 
of he mi n t reat me nt, uri nar y A L A a n d P B G le vels a p pr oac h n or malizati o n acc o m pa nie d b y 
i m pr o ve me nt i n attac k s y m pt o ms.  H o we ver, i n s o me patie nts attac ks ca n last se veral wee ks, 
re q uiri n g pr ol o n ge d he mi n use a n d h os pitalizati o n (1 3 ).  He mi n a d mi nistrati o n ca n res ult i n 
si g nifica nt ac ute si de effects s uc h as se vere hea d ac he, na usea, fl u-li ke s y m pt o ms, fati g ue a n d 
t hr o m b o p hle bitis.  
T here are n o a p pr o ve d tr eat me nts f or t he pre ve nti o n of ac ute attac ks of he patic p or p h yria, a n d 
t here is little e vi de nce p u blis he d o n h o w best t o ma na ge A H P patie nts wit h rec urre nt attac ks. 
I nitial pre ve nti o n ste ps i ncl u de a v oi da n ce of p ote ntial tri g gers i ncl u di n g har mf ul me dicati o ns, 
s m o ki n g a n d alc o h ol us e, a n d c o ns u m pti o n of a l o w-cal ori e diet (1 3 ).  T h e 3 t hera pe utic o pti o ns 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 0  
m ost c o m m o nl y e m pl o ye d t o pre ve nt attac ks are h or m o nal s u p pressi o n t hera p y, t h e off -l a bel use 
of pr o p h yl actic I V he mi n i nf usi o ns, a n d i n e xtre mel y rare cas es, li ver tra ns pla ntati o n (1 3 , 1 4 ).  
H or m o nal s u p pressi o n t h era p y usi n g a g o n a d otr o pi n -releasi n g h or m o n e ( G n R H) a nal o g ue ma y 
ha ve a b e nefici al effect i n s o me w o me n. H o we v er, t he si de effect of i n d ucti o n of me n o pa use i n a 
relati vel y y o u n g patie nt p o p ulati o n ma kes t he treat me nt diffic ult t o t olerat e (1 , 1 5 ).  S ome 
p or p h yri a s pecialists ha ve res orte d t o t he off -l a bel pr o p h ylactic use of he mi n t o pre ve nt attac ks 
des pite u nfa v ora ble c h aracteristics f or c hr o nic t h era p y.  Gi ve n t he s h ort half -life of he mi n ( 1 0. 8 
h o urs), its be neficial effect o n t he t o xic prec urs ors A L A a n d P B G is s h ort -li ve d, wit h t heir le vels 
starti n g t o rise wit hi n 4 8 h o urs of t he i nf usi o n (1 6 , 1 7 ).  I n m ost cases, p atie nts recei ve he mi n 
i nf usi o ns t hr o u g h a n i n d welli n g I V cat het er at a cli nic or i nf usi o n ce nter, o n a sc he d ule d basis.  
C hr o nic he mi n a d mi nistrati o n ca n res ult i n ve n o us da ma ge, ir o n o verl oa d a n d pr o ble ms relate d t o 
ha vi n g a n i n d welli n g I V cat heter (i nfecti o n or t hr o m b osis).  D ue t o t hese d escri be d li mitati o ns 
a n d lac k of str o n g effic ac y dat a, off -l a bel pr o p h ylactic he mi n is n ot u nif or ml y c o nsi dere d 
sta n dar d of care a m o n g p or p h yri a s peci alists f or c hr o nic treat me nt or pre v e nti o n of p or p h y ri a 
attac ks.  
I n p atie nts w h o are refract or y t o he mi n or w h o n o l o n ger ha ve a de q u ate ve n o us access, li ver 
tra ns pla ntati o n has occasi o nall y bee n perf or me d.  After li ver tra ns pla ntati o n, t he A L A a n d P B G 
le vels n or maliz e i n 2 4 h o urs a n d ac ut e attac ks cease.  I n a d diti o n, patie nt q ualit y of life h as bee n 
s h o w n t o si g nifica ntl y i m pr o ve (1 8 ).  H o we v er, gi ve n t he i n vasi ve a n d hi g h -ris k nat ure of 
tra ns pla ntati o n a n d li mite d a vaila bilit y of or ga ns, it is rarel y perf or me d (5 , 1 9 ).   
A H P is ass ociate d wit h si g nifica nt m or bi dit y a n d m ortalit y, a n d ne gati vel y affects acti vities of 
dail y li vi n g as well as t he q ualit y of life of patie nts. T here is a clear u n met n ee d f or n o v el 
t hera pe utics wit h fa v ora ble safet y pr ofiles t hat effecti vel y a n d d ura bl y decrease t he fre q ue n c y of 
de bilitati n g attac ks, di mi nis h t he c hr o nic s y m pt o ms i n bet wee n attac ks, a n d i m pr o ve patie nts’ 
q ualit y of life.  I n a d diti o n, t hera pe utics t hat d o n ot re q uire c hr o nic i n d welli n g cat heters f or 
i ntra ve n o us a d mi nistrati o n w o ul d re d uce c o m plicati o ns ass ociate d wit h a d mi nistrati o n, i ncl u di n g 
i nfecti o n, dee p v ei n t hr o m b osis a n d i n e xtre me cases t he nee d f or li ver tra ns pla ntati o n d ue t o l oss 
of ve n o us access.  
1. 2.  
Gi v osir a n  
Gi v osira n is a s y nt h etic c he micall y m o difie d s mall i nterferi n g  R N A (si R N A) tar geti n g A L A S 1 
m R N A t hat is c o vale ntl y li n ke d t o a tria nte n nar y N -acet yl  galact osa mi ne ( Gal N Ac) li ga n d ( A L N -
6 0 5 1 9) t o facilitate deli v er y t o of t he si R N A t o t he li ver ( w hic h is t he pri mar y site of A L A S 1 
s y nt hesis).  Gi v osira n acts via R N A i nt erfere nce ( R N Ai) t o i n hi bit s y nt hesis of li ver A L A S 1 a n d 
is f or m ulate d f or a d mi nistrati o n via s u bc uta ne o us ( S C) i njecti o n. 
Gi v osira n is c urre ntl y i n de vel o p me nt f or tr eat me nt of ac ute he p atic p or p h yrias ( A H Ps) i n a d ult 
a n d a d olesce nt patie nts.  
1. 2. 1.  
S u m m ar y of N o ncli nic al D at a wit h Gi v osir a n  
T he p har mac ol o g y, safet y p har mac ol o g y, dr u g m eta b olis m a n d p har mac o ki netics a n d t o xic ol o g y 
of gi v osira n were e v al uat e d i n a series of i n vitr o a n d i n vi v o n o ncli nical st u dies.  
Gi v osira n is p har mac ol o gic all y acti ve i n r o de nts,  m o n ke ys, a n d h u ma ns d u e t o c o nser vati o n 
wit hi n t he si R N A tar get s e q ue nce.  Tra nsfecti o n assa ys i n h u ma n li ver carci n o ma cell li ne -G 2 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 1  
( He p G 2) cells s h o we d d ose-de pe n d e nt i n hi biti o n of e n d o ge n o us A L A S 1 messe n ger R N A 
( m R N A) le vels wit h a half-ma xi mal i n hi bit or y c o nce ntrati o n (I C 5 0) of a p pr o xi matel y 2 6 p M 
gi v osira n.  I n m ulti ple st u dies wit h mice, rats a n d m o n ke ys, gi v osira n h as d e m o nstrate d p ote nt 
a n d d ose-de p e n de nt p har mac ol o gi c acti vit y w he n a d mi nistere d s u bc uta ne o usl y, res ulti n g i n 
c o nsiste nt re d ucti o n of A L A S 1 m R N A i n t he li ver.  After si n gle d ose a d mi nistrati o n, A L A S 1 
m R N A s u p pressi o n i n li ver is d ura ble ( 1 -4 wee ks) de pe n di n g o n t he d ose a d mi nistere d a n d 
c orrel ates wit h t he e xte nt of A L A S 1 m R N A s u p pressi o n o bser ve d i n ser u m or uri ne.  D ose 
de pe n de nt, stea d y -state A L A S 1 s u p pressi o n has als o bee n de m o nstrat e d wit h re peat-d os e 
re gi me ns.  St u dies i n r o de nt AI P m o d els ha ve c o nfir me d t hat A L A S 1 m R N A s u p pressi o n wit h 
gi v osira n tr eat me nt c orrelates wit h decreases i n A L A a n d P B G he me i nter me diates.  
A G o o d La b orat or y Practice ( G L P) -c o m plia nt safet y p har m ac ol o g y st u d y c o n d ucte d i n m o n ke ys 
s h o we d n o f u ncti o nal c ar di o vasc ular or res pirat or y effects, wit h a n o o bser ve d -effect le v el 
( N O E L) of 1 5 0 m g/ k g. N e ur ol o gi cal assess me nts were c o n d ucte d as part of a 1 3-wee k a n d a 3 9 -
wee k re peat d os e G L P t o xicit y st u d y i n m o n ke ys ( o nce wee kl y d osi n g); n o gi v osira n -relat e d 
ne ur o be ha vi oral o bser v ati o ns occ urre d i n eit her st u d y. T he N O E L f or ne ur ol o gical effects was 
1 5 0 m g/ k g a n d 1 0 0 m g/ k g i n t he 1 3 -wee k a n d 3 9 -wee k re peat -d ose G L P t o xic ol o g y st u dies, 
res pecti vel y, t he hi g h est d oses e val uate d. Ge netic t o xicit y st u dies ( bact erial re verse m utati o n, 
h u ma n peri p heral bl o o d l y m p h oc yte c hr o m os o mal a berrati o ns, a n d rat b o n e marr o w 
micr o n ucle us) ass a ys were all ne gati ve at I nter n ati o nal C o nfere nc e o n Har m o nizati o n (I C H) S 2 
( R 1) li mit d oses. 
T w o t o 4 -wee k e x pl orat or y ( n o n -G L P) d ose -ra n ge fi n di n g ( D R F) t o xic ol o g y st u dies were 
c o n d ucte d wit h gi v osira n i n mice, rats, a n d m o n ke ys.  I n all 3 s pecies, n o d ose -li miti n g t o xicit y 
( D L T) w as o bser v e d u p t o t he hi g hest d ose e val uate d ( 3 0 0 m g/ k g wee kl y S C d ose), wit h t he rat 
a p peari n g t o be t h e m ost se nsiti ve s pecies.  T he D R F st u dies were f oll o we d b y 1 3 -wee k G L P 
t o xic ol o g y st u dies i n rats a n d m o n ke ys w here gi v osira n was a d mi nistere d o nce ( 1 0 0 m g/ k g) a n d 
o nce we e kl y at d ose le v els of 0, 3, 1 0, a n d 3 0 m g/ k g i n t he rat a n d o nce wee kl y at d ose le vels of 
0, 1 5, 5 0, or 1 5 0 m g/ k g i n t he m o n ke y.  T h e n o o bser ve d a d v erse effect le vels ( N O A E Ls) were 3 0 
m g/ k g i n t he rat a n d 1 5 0 m g/ k g i n t he m o n ke y ( hi g hest d ose t este d i n e ac h s pecies).   
I n t he c hr o nic rat G L P t o xic ol o g y st u d y, gi v osira n was a d mi nistere d o nce wee kl y at d ose le v els 
of 0, 3, 1 0, a n d 3 0 m g/ k g. T he c hr o nic rat st u d y N O A E L was 1 0 m g/ k g, base d u p o n fi n di n gs at 
3 0 m g/ k g, i ncl u di n g h e pat ocell ular si n gl e cell necr os is a n d vac u olati o n i n t he li ver wit h 
c orrel ati n g cli nical pat h ol o g y c h a n ges of i ncreas e d as partate a mi n otra nsferase a n d al k ali ne 
p h os p hatase. A d diti o nall y, a n gi ectasis i n islets of La n ger ha ns (t he e n d o cri n e a n d n ot t he e x ocri ne 
re gi o ns of t he pa n creas) was o bser ve d i n a d ose -d e pe n de nt ma n n er a n d t h o u g ht t o be p ossi bl y 
sec o n dar y t o t he li ver fi n di n gs at 3 0 m g/ k g. I n t he c hr o nic m o n ke y G L P t o xic ol o g y st u d y, 
gi v osira n w as a d mi nistere d o nce w ee kl y at d ose l e vels of 0, 1 0, 3 0, a n d 1 0 0 m g/ k g.  At i nitiati o n 
of t h e treat me nt, t he m o n ke ys were 1 3 t o 1 7 m o nt hs ol d. M o n ke ys at 2 4 -3 6 m o nt hs of a ge are 
ge n erall y c o nsi d ere d t o c orres p o n d wit h t he de v el o p me nt a ge of h u ma n a d olesce nts > 1 2 years of 
a ge. T he c hr o nic m o n ke y st u d y N O A E L was 3 0 m g/ k g base d u p o n fi n di n gs at 1 0 0 m g/ k g, 
i ncl u di n g he p at ocell ular si n gle cell necr osis t hat c orrelate d wit h i ncreas e d ala ni ne 
a mi n otra nsferase, ga m m a gl uta m yl tra nsferase, as partate a mi n otra nsferase, a n d c h olester ol. 
A n gie ctasis i n t he pa ncreas was n ot o bser ve d i n t he m o n ke y st u d y.  
I n t he d efi niti ve rat fertilit y a n d e m br y ofet al de vel o p me nt st u d y, a d mi nistrati o n of gi v osira n di d 
n ot res ult i n a n y effects o n estr o us c ycli n g, mati n g, or fertilit y.  T h e mater nal N O A E L was 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 2  
deter mi ne d t o be 3 ( pri or c o ha bitati o n)/ 0. 5 ( Gestati o n Da y 6 –  1 7 [ G D 6 -1 7]) m g/ k g bas e d u p o n 
mater nal cli nical p at h ol o g y c h a n ges at ≥1 0 ( pri or c o ha bitati o n) / 1. 5 ( G D 6 –  1 7) m g/ k g.  T he 
de vel o p me ntal N O A E L was deter mi ne d t o b e 3 0 ( pri or c o ha bitati o n)/ 5 ( G D 6 -1 7) m g/ k g b ase d 
u p o n n o gi v osira n -relat e d effects o n e m br y o-fetal s ur vi val, fetal b o d y wei g hts or fetal 
malf or mati o ns.  
I n t he d efi niti ve ra b bit e m br y ofetal de v el o p me nt st u d y, t he mater nal N O A E L c o ul d n ot be 
deter mi ne d bas e d u p o n mater nal effects, w hic h i ncl u de d re d u ce d mater nal b o d y wei g ht gai ns a n d 
f o o d c o ns u m pti o n at all d oses, gr oss pat h ol o g y si g ns i n t he li ver at ≥1. 5 m g/ k g/ da y, cli nical 
pat h ol o g y c h a n ges at ≥0. 5  m g/ k g/ da y, o ne a b orti o n at 5 m g/ k g/ da y a n d 2 a b orti o ns at 2 0 m g/ k g, 
a n d i ncrease d p ost -i m pla ntati o n l oss beca use of i n creas e d earl y res or pti o ns at ≥0. 5 m g/ k g/ day.  
T he de vel o p me ntal N O A E L w as deter mi ne d t o be 0. 5 m g/ k g/ da y base d u p o n t he i ncreas e d p ost -
i m pla ntati o n l oss at ≥1. 5 m g/ k g/ da y. 
F urt her i nf or mati o n o n n o ncli nical safet y, p h ar mac ol o g y, dr u g meta b olis m, P K, a n d t o xic ol o g y of 
gi v osira n ca n be f o u n d i n t he c urre nt versi o n of t h e I n vesti gat or’s Br oc h ure.  
1. 2. 2.  
S u m m ar y of Cli nic al D at a wit h Gi v osir a n  
I n t he gi v osira n cli nical pr o gra m as of 0 5 M a y 2 0 1 7, a t otal of 4 0 u ni q ue patie nts ha ve recei ve d 
gi v osira n; d oses a d mi nistere d ra n ge d fr o m 0. 3 5  m g/ k g t o 5. 0  m g/ k g.  Data are a v aila ble fr o m 2 
c urre ntl y o n g oi n g st u dies.  
1. 2. 2. 1.  
P h ase 1 St u d y A L N -A S 1 -0 0 1  
St u d y A L N -A S 1 -0 0 1 is a P hase 1 st u d y t o e val uat e t he safet y, t olera bilit y, P K, a n d P D of 
gi v osira n i n a d ult patie nts wit h AI P.  Parts A a n d B of t his st u d y are ra n d o mize d si n gle -bli n de d 
si n gle as ce n di n g d ose ( S A D) a n d m ulti ple asce n di n g d ose ( M A D) e v al uati o ns i n AI P patie nts 
w h o are as y m pt o matic hi g h e x cret ers ( A S H E; als o k n o w n as c hr o nic hi g h e x creters [ C H E]); t hese 
are patie nts w h o d o n ot e x perie nce ac ut e p or p h yri a attac ks b ut ha v e bi oc he micall y acti ve disease 
(ie, e x crete a p pr o xi matel y 2-3 -f ol d hi g her le v els of uri nar y A L A a n d P B G, relati ve t o healt h y 
v ol u nteers).  Part C is a ra n d o mize d d o u ble -bli n d M A D desi g n; all Part C patie nts are re q uire d t o 
ha ve AI P wit h rec urre nt attac k s a n d ha v e e x perie nce d at least 2 attac ks d uri n g t he 6 m o nt hs pri or 
t o t he st u d y or t o be o n a treat me nt re gi me n of pr o p h ylactic he mi n t o pre ve nt p or p h yri a attac ks. 
Patie nts o n a pr o p h yl acti c he mi n re gi me n m ust be willi n g t o ceas e pr o p h yl actic he mi n d osi n g  
d uri n g t he r u n -i n a n d treat me nt peri o ds, alt h o u g h all patie nts o n t he st u d y are per mitte d t o recei ve 
he mi n as t hera p y f or ac ute attac ks p ost ra n d o mizati o n. T he d oses i n St u d y A L N -A S 1 -0 0 1 ra n ge d 
fr o m 0. 0 3 5 m g/ k g t o 5. 0  m g/ k g of gi v osira n.  
T he pri mar y o bje c ti ve of A L N-A S 1 -0 0 1 is t o e val uate t he safet y a n d t olera bilit y of gi v osira n 
w he n a d mi nistere d s u bc uta ne o usl y as a si n gle d os e or m ulti ple d oses t o AI P patie nts w h o are 
C H E or w h o e x perie nce rec urre nt p or p h yria attac ks.  A d diti o nal o bjecti ves i ncl u de assess me nt of 
P K, P D ( A L A a n d P B G l o weri n g), a n d cli nical acti vit y (a n n ualize d p or p h yria attac k rate, 
a n n ualize d he mi n usa ge, attac k -free i nter val, le vels of circ ulati n g A L A S 1 m R N A, a n d patie nt 
q ualit y of life) of gi v osira n.  All i nteri m preli mi nar y d ata pr o vi de d b el o w are as of 0 5 M a y 2 0 1 7.  
I n all parts ( A, B, a n d C) of t he P hase 1 st u d y ( A L N-A S 1 -0 0 1; n = 4 0 patie nts), gi v osira n h as bee n 
ge n erall y w ell t olerate d i n patie nts at d oses of u p t o 5. 0  m g/ k g.  T he m ost c o m m o n A Es 
( occ urri n g i n at least 2 patie nts) re p orte d were n as o p har y n gitis ( Parts A, B, a n d C), a b d o mi nal 
pai n ( Parts A a n d C), diarr hea, h y p o est hesia ( Part A), pr urit us, ras h ( Part B), na usea, a b d o mi nal 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 3  
diste nti o n, v o miti n g, hea dac he, p yre xia, bac k pai n, dizzi ness, mi grai ne, c o u g h, a n d or o p har y n geal 
pai n ( Part C). T here were n o d ose-de pe n d e nt A Es or cli nicall y si g nifica nt c ha n ges i n vital si g ns, 
E C G, la b orat or y val u es, or p h ysic al e x a mi nati o n fi n di n gs a n d n o dr u g -relat e d seri o us a d v erse 
e ve nts ( S A Es) or disc o nti n uati o ns d ue t o A Es were re p ort e d.  T hree pat ie nts i n Part C ha ve 
e x perie nce d a t otal of 5 S A Es, n o ne of w hic h were c o nsi dere d b y t he I n vesti gat or t o be relate d t o 
st u d y dr u g. O n e fat al S A E of pa ncreatitis occ urre d i n a patie nt wit h rec urre nt p or p h yria ( Part C) 
recei vi n g a d os e of 5 m g/ k g m o nt hl y t h a t was c o nsi dere d b y t he I n v esti gat or t o be u nrelat e d t o t he 
st u d y dr u g d ue t o t he prese nce of gall bla d der sl u d ge. 
Parts A a n d B of St u d y A L N -A S 1 -0 0 1 ( n = 2 3 p atie nts) de m o nstrate d d ose d e pe n de nt a n d d ura ble 
re d ucti o ns i n A L A S 1 m R N A a n d uri nar y A L A a n d P B G wit h si n gle a n d m ulti ple gi v osira n d oses.  
A si n gle 2. 5  m g/ k g d ose of gi v osira n res ulte d i n a 6 4 % re d ucti o n i n A L A S 1 m R N A, a n 8 6 % 
re d ucti o n i n A L A le v els, a n d a 9 5 % re d ucti o n i n P B G le vels i n C H E patie nts. I n C H E p atie nts 
w h o recei ve d 2 gi v osira n d oses of 1. 0  m g/ k g a d mi nistere d 2 8 da ys a p art, re d ucti o n i n A L A S 1 
m R N A, A L A, a n d P B G of 5 4 %, 8 4 %, a n d 8 9 %, res pecti vel y, was o bs er ve d.  
I n Part C of St u d y A L N-A S 1 -0 0 1 ( n = 1 7 patie nts), a vaila ble data de m o nstrate d mea n ma xi mal 
re d ucti o ns i n A L A S 1 m R N A relati ve t o baseli ne i n gi v osira n-tr eate d patie nts of 3 9 % i n patie nts 
treate d wit h 2. 5 m g/ k g e ver y 3 m o nt hs, 6 6 % i n patie nts treate d wit h 2. 5 m g/ k g m o nt hl y, a n d 7 0 % 
i n patie nts treate d wit h 5 m g/ k g m o nt hl y. T hes e re d ucti o ns i n A L A S 1 were acc o m pa ni e d b y 
ra pi d, d ose-de pe n de n t a n d d ura ble l o weri n g of uri ne A L A a n d P B G t o near n or mal le vels (ie, 
si milar t o t h ose see n i n healt h y v ol u nteers) after d osi n g wit h gi v osira n at eit her 2. 5 m g/ k g or 
5  m g/ k g m o nt hl y d oses f or 3 m o nt hs ( 4 d oses). M ore o ver, t h e near -n or mali zati o n of A L A a n d  
P B G le vels was acc o m pa nie d b y i m pr o ve m e nt i n attac k s y m pt o ms.  
Patie nts de m o nstrate d a 6 3 % mea n decrease i n t h eir a n n ualize d p or p h yria attac k rat e (all attac ks) 
a n d a 7 3 % me a n decrease i n t heir a n n ualize d he mi n d oses i n t he gi v osira n treat me nt peri o d 
c o m pare d t o t heir 6-m o nt h pre -treat me nt r u n-i n p h ase. I n a d diti o n, c o m pare d t o patie nts recei vi n g 
place b o d uri n g t he treat me nt peri o d, t h ose recei vi n g gi v osira n e x perie n ce d a 7 3 % re d u cti o n i n 
t heir a n n ualize d rate of attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, or I V he mi n 
a d mi nistrati o n at h o me.   
1. 2. 2. 2.  
P h ase 1/ 2 O pe n -l a bel E xte nsi o n St u d y A L N-A S 1 -0 0 2  
St u d y A L N -A S 1 -0 0 2 is a P hase 1/ 2 o pe n -la bel e xte nsi o n st u d y t o e val u ate t he l o n g-t er m safet y 
a n d cli nical acti vit y of gi v osira n i n patie nts wit h AI P a n d rec urre nt p or p h yria attac ks w h o h a ve 
c o m plete d St u d y A L N -A S 1 -0 0 1 ( Part C).   
As of 0 5 Ma y 2 0 1 7, a t ot al of 1 0 patie nts fr o m Part C of St u d y A L N -A S 1 -0 0 1 are recei vi n g 
o n g oi n g o pe n -la bel treat me nt wit h gi v osira n i n t h e P hase 1/ 2 e xte nsi o n st u d y ( A L N-A S 1 -0 0 2)  
a n d ha ve b ee n d ose d wit h gi v osira n at 2. 5 or 5. 0  m g/ k g m o nt hl y or e ver y 3 m o nt hs ; 4 patie nts are 
recei vi n g a 5 m g/ k g d ose of gi v osira n e ver y 3 m o nt hs, 2 patie nts are recei vi n g m o nt hl y d oses of 
5  m g/ k g, a n d 4 patie nts are recei vi n g m o nt hl y d os es of 2. 5  m g/ k g. Preli mi nar y res ults fr o m t he 
e xte nsi o n st u d y ( A L N -A S 1 -0 0 2) de m o nstrate c o nti n ue d safet y a n d t olera bilit y wit h l o n ger -ter m 
gi v osira n d osi n g; as of t h e 0 5  Ma y  2 0 1 7 c ut off, n o S A Es or disc o nti n uati o ns d ue t o A Es ha ve 
bee n o bser ve d. I n a d diti o n, decreases i n p or p h yri a attac k rat es a n d he mi n use s u g gest c o nti n ue d 
effic ac y wit h e xte n de d d osi n g.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 4  
After t he d ata c ut off of 0 5 Ma y 2 0 1 7, o n e patie nt i n t he 5 m g/ k g e ver y 3 m o nt hs d ose gr o u p 
e x perie nce d a n S A E of u p per e xtre mit y dee p vei n t hr o m b osis t hat was deter mi ne d b y t he 
I n v esti gat or t o be u nli kel y relate d t o st u d y dr u g d ue t o little te m p oral relati o ns hi p t o st u d y dr u g 
a d mi nistrati o n, c hr o nic v e n o us da ma ge fr o m he mi n pr o p h yl a xis, a n d t he prese nce of a n 
i n d welli n g ce ntral ve n o us cat heter.  I n a d diti o n, o ne patie nt i n t he 2. 5 m g/ k g m o nt hl y d os e gr o u p 
wit h a hist or y of ast h ma a n d m ulti ple aller gi es e x perie nce d a n S A E of a na p h ylactic reacti o n t hat 
was deter mi ne d b y t h e I n vesti gat or t o b e defi nitel y relate d t o st u d y dr u g gi ve n t he te m p oral 
relati o ns hi p of gi v osira n treat me nt t o t he o nset of t he reacti o n ( wit hi n mi n utes).  T he patie nt w as 
treate d a n d rec o vere d a n d was disc o nti n ue d fr o m t he st u d y. 
F urt her i nf or mati o n o n t he safet y, effic ac y, P K a n d P D of gi v osira n are a vaila ble i n t he 
I n v esti gat or’s Br oc h ure. 
1. 2. 2. 3.  
Dr u g -dr u g I nter acti o n St u d y A L N -A S 1 -0 0 4  
A n o pe n -la bel dr u g-dr u g i nteracti o n ( D DI) st u d y ( A L N -A S 1 -0 0 4) was c o n d ucte d i n AI P patie nts 
w h o are C H E t o e val uate t he effect of a si n gle d os e of 2. 5  m g/ k g gi v osira n a d mi nistere d S C o n 
t he p har mac o ki n etics of pr o be s u bstrates f or 5 maj or c yt o c hr o me P 4 5 0 ( C Y P) e nz y mes t hat 
acc o u nt f or t he meta b olis m of a p pr o xi matel y 8 0 % of prescri be d dr u gs (2 0 , 2 1 ).  Res ults fr o m t his 
st u d y de m o nstrate d t h at gi v osira n tr eat me nt r es ulte d i n wea k t o m o derate re d ucti o n i n t he 
meta b olic acti vit y of s o me of t he 5 C Y P e nz y mes st u die d, t here b y lea di n g t o hi g her 
c o nce ntr ati o ns of s o me s u bstrates a n d t heir met a b olites.  Trea t me nt wit h gi v osira n res ulte d i n a n 
a p pr o xi matel y 3 -f ol d i ncrease i n e x p os ure (as me as ure d b y A U C) t o caffei ne (a se nsiti ve 
s u bstrate f or C Y P 1 A 2) a n d a n a p pr o xi matel y 2-f ol d i ncrease i n e x p os ure t o de xtr o met h or p ha n (a 
se nsiti ve s u bstrate f or C Y P 2 D 6).  E x p os ure of mi daz ola m (a se nsiti ve s u bstrate f or C Y P 3 A 4) a n d 
o me praz ole (a se nsiti ve s u bstrate f or C Y P 2 C 1 9) i ncreas e d less t ha n 2 -f ol d after treat me nt wit h 
gi v osira n.  T h ere was n o effect of gi v osira n tr eat m e nt o n l osarta n (a s e nsiti ve s u bstrate f or 
C Y P 2 C 9).  
1. 3.  
S t u d y Desi g n R ati o n ale 
Data fr o m t he P has e 1 St u d y A L N -A S 1 -0 0 1 i n C H E a n d AI P patie nts has de m o nstrate d t hat 
a d mi nistrati o n of gi v osira n res ulte d i n re d u cti o n i n ser u m A L A S 1 le vels, l ea di n g t o d ose -
de pe n de nt a n d d ura ble re d ucti o ns i n uri nar y A L A a n d P B G.  F urt her m ore, i n patie nts wit h 
rec urre nt atta c ks ( Part C), t he re d ucti o n i n A L A a n d P B G was ass o ciate d wit h si g nifica nt 
re d ucti o ns i n p or p h yria disease acti vit y as i n dicat e d i n Secti o n 1. 2. 2. 1 .  P hase 1 ( A L N-A S 1 -0 0 1) 
a n d P hase 2 ( A L N -A S 1 -0 0 2) data ha v e als o de m o nstrate d e vi de nce of cli nicall y rele va nt 
re d ucti o n i n t he n u m ber a n d se verit y of p or p h yria attac ks a n d mea ni n gf ul i m pr o ve me nt i n ot her 
cli nical o utc o mes i n patie nts wit h p or p h yri a. F urt her details of St u dies A L N -A S 1 -0 0 1 a n d A L N -
A S 1 -0 0 2 are s u m mariz e d i n t he gi v osira n I n v esti gat or’s Br oc h ure.  
T he E N VI SI O N  St u d y ( A L N -A S 1 -0 0 3) is a m ultice nter, m ulti nati o nal P hase 3 st u d y d esi g ne d t o 
e val uate t he effic ac y a n d safet y of S C-a d mi nistere d gi v osira n i n patie nts wit h A H Ps ( n = 7 4); t he 
st u d y is c o m prise d of a 1: 1 ra n d o mize d, place b o-c o ntr olle d d o u ble -bli n d treat me nt peri o d of 6 
m o nt hs, f oll o we d b y a n O L E p eri o d of u p t o 3 0 m o nt hs t o e val uate t he l o n g -ter m safet y a n d 
effic ac y of gi v osira n.   
D uri n g t h e 6 -m o nt h place b o -c o ntr olle d d o u ble -bli n d treat me nt peri o d, all patie nts will recei ve S C 
d oses of 2. 5  m g/ k g gi v osira n or place b o o nce m o nt hl y.   


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 5  
Patie nts cr ossi n g o ver t o t he O L E peri o d will recei ve a d ose bas e d o n  t he pr ot oc ol versi o n u p o n 
w hic h t he y e ntere d t he O L E.  Patie nts w h o cr osse d o ver t o t he O L E peri o d pri or t o t he 
i m ple me ntati o n of a me n d me nt 3 (ie, u n der a me n d me nt versi o n 1 or 2) a n d are recei vi n g a 2. 5 
m g/ k g o nce m o nt hl y gi v osira n d ose will re mai n o n t ha t d ose.  U p o n e ntr y t o t he O L E peri o d 
u n der a me n d me nt 3, p atie nts will cr oss o ver t o recei ve t he 1. 2 5 m g/ k g o nce m o nt hl y d ose of 
gi v osira n, e na bli n g data o n t his a d diti o nal d ose of gi v osira n t o be ge nerate d.  
After i m ple me ntati o n of a me n d me nt  3 a n d u ntil i m ple me ntati o n of a me n d me nt  5, patie nts 
assi g ne d t o t he o n ce m o nt hl y 1. 2 5 -m g/ k g treat me nt gr o u p w h o e x perie nce i na de q uate disease 
c o ntr ol ma y b e all o we d t o ha ve t heir m o nt hl y d os e i ncrease d t o 2. 5  m g/ k g starti n g at t he 
M o nt h  1 3 St u d y Visit ( w he n 6  m o nt hs of  o pe n -la bel gi v osira n d osi n g ha v e bee n c o m plete d at 
1. 2 5  m g/ k g) bas e d o n disc ussi o n a n d a gree me nt b y t he I n v esti gat or a n d me dical m o nit or, 
de m o nstrati o n of t olera bilit y t o gi v osira n, a n d f ulfill me nt of A L A a n d cli nical acti vit y criteri a.  
U p o n i m ple me ntati o n of a me n d me nt  5, all patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n o nce m o nt hl y 
w h o d o n ot ha ve o n g oi n g cli nicall y rele va nt tra nsa mi nase ele vati o ns will ha ve t heir d ose 
i ncreas e d t o 2. 5 m g/ k g gi v osira n o nce m o nt hl y base d o n t olera bilit y al o ne, wit h o ut a n y crite ria 
f or A L A re d ucti o n or cli nical acti vit y t o e ns ure t h at patie nts are recei vi n g t he rec o m me n d e d d ose 
w hic h was a p pr o ve d b y t he U nite d States F o o d a n d Dr u g A d mi nistrati o n ( F D A) i n N o v e m ber 
2 0 1 9 a n d recei ve d a C o m mittee f or Me dici nal Pr o d ucts f or H u ma n Us e ( C H M P) p ositi ve o pi ni o n 
i n J a n uar y 2 0 2 0.  See Secti o n 6 . 2. 3. 4 f or f urt her i nf or mati o n o n d ose escal ati o n. 
T he pri mar y c o m p osite e n d p oi nt is t he a n n ualize d rate of p or p h yria attac ks re q uiri n g 
h os pitaliz ati o n, ur ge nt he alt hcare visits, or I V he mi n a d mi nistrati o n at h o me o ver t he 6 -m o nt h 
treat me nt peri o d.  A c ute p or p h yri a attac ks are cli nicall y mea ni n gf ul a n d p ote ntiall y 
life-t hreat e ni n g e ve nts t h at are t he m aj or c o ntri b ut ors t o disease b ur de n i n patie nts wit h A H Ps. 
T he pr o p ose d c o m p osite pri mar y e n d p oi nt of attac ks re q uiri n g h os pitalizati o ns, ur ge nt healt hcare 
visits (cli nic, e mer ge nc y de part me nt or i nf usi o n ce nter), or i ntra ve n o us he mi n a d mi nistrati o n at 
h o me are cli nical e ve nts re q uiri n g maj or s pecific i nter ve nti o n a n d ca n be o bjecti vel y meas ure d; 
base d o n res ults fr o m St u d y A L N -A S 1 -N T -0 0 1 [ E X P L O R E], a n o bser vati o nal nat ural hist or y 
st u d y (1 0 ), t h ese c h aracteristics c o m prise a p pr o xi matel y 7 6 % of all attac ks i n t he i nte n de d patie nt 
p o p ulati o n.  T he E X P L O R E st u d y p o p ulati o n c o nsiste d of a p pr o xi matel y 9 3 % patie nts wit h AI P, 
4 % wit h V P, a n d 3 % wi t h H C P; t his distri b uti o n is a p pr o xi matel y si milar t o t he p o p ulati o n 
e x pecte d f or e nr oll me nt i n t he P hase 3 st u d y ( A L N -A S 1 -0 0 3).    
Sec o n dar y e n d p oi nts i n t he P hase 3 st u d y ( A L N -A S 1 -0 0 3) i ncl u de t he uri nar y p or p h yri n 
prec urs or le vels of A L A a n d P B G at 3 m o nt hs a n d 6 m o nt hs.  T he acc u m ulati o n of t hese 
prec urs ors u pstrea m of t h e P B G D e nz y me defect is a ca usal f act or of ne ur ot o xicit y a n d cli nical 
ma nifestati o ns of disease, s uc h as p or p h yria attac ks a n d c hr o nic s y m pt o ms bet wee n attac ks; 
e vi de nce fr o m P hase 1 ( A L N-A S 1 -0 0 1) s u g gests a gra de d relati o ns hi p bet wee n re d ucti o n i n 
A L A/ P B G a n d attac k re d ucti o n. T he i m pact of gi v osira n treat me nt o n he mi n use, na usea, fati g ue 
a n d q ualit y of lif e will als o be assesse d.  
T he e n d p oi nts will be e v al uate d a gai nst a place b o c o m parat or f or t he first 6 m o nt hs of t he st u d y 
(t he d o u ble-bli n d treat me nt peri o d); after t his, all patie nts will recei ve o pe n -la bel gi v osira n f or u p 
t o a n a d diti o nal 2 9 m o nt hs i n t he e xte nsi o n p orti o n of t he st u d y. T h e place b o c o m parat or was 
selecte d bas e d on t he lac k of c o nse ns us g ui da nce o n t he sta n dar d of care f or pre ve nt ati ve 
t hera pies f or patie nts wit h rec urre nt attac ks. N o t h era pies are c urre ntl y a p pr o ve d f or t he 
pre ve nti o n of f ut ure attac ks. T he t hree o pti o ns m ost c o m m o nl y e m pl o ye d t o pre ve nt attac ks a re 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 6  
h or m o nal s u p pressi o n t hera p y, t he off -la bel use of I V he mi n as sc he d ule d or pr o p h yl actic 
i nf usi o ns, a n d i n e xtre mel y rare cases, li ver tra ns pla ntati o n (1 3 , 1 4 , 2 2 ).  T he e vi de nce s u p p orti n g 
t he safet y a n d effi cac y of eac h of t h ese o pti o ns is li mite d t o case re p orts or s mall-u nc o ntr olle d 
st u dies. T h us, t here are n o c o nse ns us g uideli nes f or t he use of a n y of t hese treat me nts as a 
pr o p h yla ctic re gi me n t o pre ve nt p or p h yri a attac ks. M ore o ver, eac h of t hese o pti o ns has 
si g nifica nt li mitati o ns.  
He mi n is t he o nl y lice ns e d me dici nal pr o d uct f or t he treat me nt of p or p h yria a n d it is o nl y 
a p pr o ve d f or use i n treati n g ac ute attac ks after t he y occ ur. Patie nts are per mitte d t o c o nti n ue t o 
recei v e sta n dar d of care treat me nt, i ncl u di n g he mi n, f or a n y ac ute attac ks t he y e x perie nce w hile 
partici pati n g i n t he P has e 3 st u d y, b ut t he y will n ot be per mitte d t o use he mi n pr o p h ylacticall y 
beca use gi v osira n is i nte n de d as m o n ot hera p y t o pre ve nt attac ks a n d t he re g ular c o -a d mi nistrati o n 
of he mi n c o ul d c o nf o u n d effic ac y a n d s afet y si g nals relate d t o gi v osira n.  
T he st u d y p o p ulati o n will be c o m prise d of a d ult s a n d a d olesce nts ( ≥1 2 years of a ge) wit h a 
d oc u me nte d dia g n osis of A H P.  
O verall, bas e d o n t he t otalit y of safet y, t olera bilit y a n d effi cac y d ata a v aila ble fr o m t he P hase 1 
place b o -c o ntr olle d st u d y ( A L N -A S 1 -0 0 1) a n d t he P hase 1/ 2 O L E st u d y ( A L N -A S 1 -0 0 2), 
gi v osira n is a n a p pr o priat e ca n di dat e t o be f urt h er st u die d i n patie nts wit hi n a P hase 3 setti n g, 
gi ve n t he hi g h u n met me dical nee d i n t his p o p ulati o n.  
1. 4.  
D ose R ati o n ale  
D ose selecti o n w as g ui de d b y t he pri nci ple of i de ntif yi n g a n o pti mal d ose t hat is b ot h we ll-
t olerate d a n d effic aci o us.  T he pr o p ose d P hase 3 gi v osira n d ose of 2. 5 m g/ k g a d mi nistere d 
m o nt hl y was selecte d bas e d o n o bser ve d d ata fr o m o n g oi n g cli nical st u dies, a n d p o p ulati o n 
p har mac o ki netic -p har m ac o d y n a mic m o deli n g. T h e ke y P D a n d cli nical para met ers use d t o 
s u p p ort t he d ose selecti o n i ncl u de decreas es i n uri nar y A L A le v els, t he m ost pr o xi mate a n d direct 
P D effect of gi v osira n, as well as re d u cti o ns i n p or p h yria attac ks, h e mi n usa ge a n d p or p h yri a 
attac k-free i nter vals. 
I n t he P h ase 1 place b o c o ntr olle d-st u d y ( St u d y A L N-A S 1 -0 0 1) a n d t h e P hase 1/ 2 O L E st u d y 
( St u d y A L N-A S 1 -0 0 2) a clear d os e res p o ns e wit h res pect t o re d ucti o n of el e vate d uri nar y A L A 
was o bser v e d, wit h m o nt hl y d osi n g yi el di n g hi g her a n d s ustai ne d re d ucti o ns c o m pare d t o d osi n g 
e ver y 3 m o n t hs. Fr o m t he d osi n g re gi me ns e val u ate d, gi v osira n d os e of 2. 5 m g/ k g a d mi nistere d 
m o nt hl y l o w ere d uri nar y A L A i n AI P p atie nts b y a b o ut 9 5 % t o le vels t hat were cl ose t o t h ose 
o bser ve d i n n or mal he alt h y v ol u nteers; t hese re d u cti o ns i n uri nar y A L A le vels were  ass ociate d 
wit h mar ke d re d u cti o ns i n p or p h yri a attac ks, he mi n usa ge a n d attac k -free i nter vals.  
I n li g ht of L F T ele v ati o ns o bser ve d i n t he st u d y, a l o wer gi v osira n d ose of 1. 2 5 m g/ k g o nce 
m o nt hl y h as bee n i ntr o d uce d as a d o w n -titrati o n d ose, as detaile d in Secti o n  6. 2. 3. 1 .   
U n der a me n d m e nt  3, patie nts e nteri n g t he O L E p eri o d will be assi g ne d t o recei ve 1. 2 5  m g/ k g 
gi v osira n o n ce m o nt hl y i n or der t o ge n erate a d diti o nal data at t his d ose le vel. W hile t he 2. 5 m g/ k g 
o nce m o nt hl y d ose h as b ee n de m o nstrat e d t o pr o vi de near -n or malizati o n of A L A le vels i n t he 
maj orit y of AI P p atie nts wit h rec urre nt attac ks i n t he c o m plete d P hase 1 A L N -A S 1 -0 0 1 st u d y 
( Part C) a nd t he o n g oi n g P hase 1/ 2 A L N -A S 1 -0 0 2 o pe n -la bel e xte nsi o n st u d y, preli mi nar y 
a nal ys es of P K a n d P D d ata s u g gest t hat a gi v osira n d ose of 1. 2 5 m g/ k g o n ce m o nt hl y w o ul d 
re d uce A L A le v els i n a s u bsta ntial n u m ber of pati e nts. T he pr o p ose d st u d y desi g n will e na bl e t he 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 7  
e val uati o n of t he P D, effi cac y, a n d safet y of t he 1. 2 5 m g/ k g m o nt hl y d ose of gi v osira n, w hile 
c o nti n ui n g t o pr o vi de dat a o n t he 2. 5 m g/ k g m o nt hl y d ose.   Bas e d o n t he first 6  m o nt hs of 
treat me nt d uri n g t he O L E peri o d i n patie nts w h o recei v e d place b o i n t he d o u ble-bli n d peri o d, a 
tre n d t o war d i ncreas e d b e nefit, as i n dicate d b y greater re d ucti o ns i n c o m p osite attac ks, he mi n use, 
a n d A L A a n d P B G le vels, was o bser v e d wit h t he 2. 5 -m g/ k g o nce m o nt hl y d ose c o m pare d t o t he 
1. 2 5 -m g/ k g o nce m o nt hl y d ose.  Gi ve n  t he tre n d t o war d i ncrease d b e nefit wit h t he 2. 5-m g/ k g 
d ose of gi v osira n c o m pare d t o t he 1. 2 5 -m g/ k g d os e a n d c o nsi deri n g t h at A H P is a disease i n 
w hic h eac h attac k is seri o us, hi g hl y m or bi d, a n d carries p ote ntial f or irre v ersi ble ne ur ol o gic 
da ma ge, i m ple me ntati o n of a me n d me nt  5 i ncreases t he d ose f or all patie nts recei vi n g 1. 2 5  m g/ k g 
gi v osira n o n ce m o nt hl y w h o d o n ot ha ve o n g oi n g cli nicall y rele va nt tra nsa mi nase ele vati o ns t o 
t he rec o m me n d e d d ose of 2. 5 m g/ k g gi v osira n S C o nce m o nt hl y, w hi c h was a p pr o ve d b y  t he 
U nite d States F D A i n N o ve m ber 2 0 1 9 a n d recei ve d a C H M P p ositi ve o pi ni o n i n J a n uar y  2 0 2 0 . 
T he c o nce ntrati o n of gi v osira n i n t he li ver is t he pri mar y dri ver f or its p har mac o d y na mic effects, 
w hic h is pri maril y affect e d b y b o d y wei g ht. P o p ulati o n p har mac o ki netic -p har mac o d y n a mic 
m o deli n g a n d si m ulati o n acr oss differe nt b o d y wei g hts s h o w si milar li ver e x p os ures of gi v osira n 
i n a d olesce nts a n d a d ults f oll o wi n g m o nt hl y d osi n g a n d c o nse q u e ntl y si milar e xte nt a n d d urati o n 
of uri nar y A L A s u p pressi o n. T heref ore, t he sa m e d oses are pr o p ose d t o be a d mi nistere d t o b ot h 
a d ults a n d a d olesce nts i n t his st u d y.  
1. 5.  
Be nefit -Ris k Assess me nt  
Base d o n t h e a vaila bl e n o ncli nical a n d cli nical data (see Secti o n  1. 2. 2 ), gi v osira n a d mi nistere d 
s u bc uta ne o usl y as a o n ce-m o nt hl y d ose re gi me n, ma y b e a ble t o offer d ose -de pe n de nt, p ote nt a n d 
s ustai ne d s u p pressi o n of A L A S 1, t here b y decreasi n g t he acc u m ulati o n of t h e ne ur ot o xic he me 
i nter me diates A L A a n d P B G.  T his ma y, i n t ur n, p ote ntiall y pre v e nt t he occ urre nce of ac ute 
p or p h yri a attac ks, as well as p ote ntiall y a m eli orate c hr o nic p or p h yri a s y m pt o ms t hat patie nts 
e x perie nce bet w ee n attac ks, i ncl u di n g pai n, na us ea, a n d fati g ue.  
T he gi v osira n n o ncli nical t o xic ol o g y pr o gra m, i ncl u di n g d ose -ra n gi n g st u dies i n t he m o use, rat, 
a n d m o n ke ys, f oll o we d b y cli nic al trial a p plicati o n -e na bli n g, as w ell as c hr o nic G L P t o xic ol o g y 
st u dies i n t he rat u p t o 2 6 wee ks a n d m o n k e y  (j u ve nile m o n ke ys  at i nitiati o n of t he st u d y) u p t o 3 9 
wee ks, de m o nstr ate d a n a de q uate s afet y mar gi n f or cli nical d osi n g of gi v osira n at 2. 5  m g/ k g p er 
m o nt h.  Gi v osira n was a d mi nistere d via S C i njecti o n i n all t o xic ol o g y st u dies, c o nsiste nt wit h t he 
i nte n de d cli nical r o ute of a d ministrati o n.  All i n vitr o a n d i n vi v o ge n etic t o xicit y st u dies were 
ne gati ve at I C H S 2 ( R 1) li mit d oses.  I n t h e rat a n d ra b bit e m br y ofet al de vel o p me ntal t o xicit y 
st u dies, gi v osira n-relate d i ncreas e d p ost-i m pla ntati o n l oss/earl y a bs or pti o n (ra b bits) a n d fetal 
s keletal variati o n (rats a n d ra b bits) were o bser ve d.   T he o bser ve d mater nal t o xicit y ma y ha v e 
ca use d or c o ntri b ute d t o t he o bser ve d e m br y ofetal effects, w hile t here was n o detecta ble le vel of 
gi v osira n via fetal tr a nsfer at a n y d ose.  T o mi ni mize a n y p ote ntial ris k of e m br y ofetal t o xicit y 
(terat o ge ni cit y), w o me n of c hil d-beari n g p ot e ntial m ust ha ve a ne gati ve pre g na n c y test, ca n n ot b e 
breastfee di n g, a n d m ust be willi n g t o use a n acce pta ble met h o d of c o ntr ace pti o n d uri n g st u dies 
wit h gi v osira n.  C o ntrac e pti o n re q uire me nts a n d g ui deli nes are pr o vi d e d i n t he cli nical st u d y 
pr ot oc ols.  
T he cli nical e x perie nce fr o m P hase 1 St u d y A L N -A S 1 -0 0 1 ( Part C) s u g gests t hat i n patie nts wit h 
AI P a n d rec urre nt attac ks, gi v osira n tr eat me nt is ass ociate d wit h s ustai ne d re d u cti o ns i n 
A L A/ P B G le vels, d ecrease d attac k fre q ue n c y (ra n gi n g fr o m 6 3 t o 7 5 %), a n d re d uce d h e mi n usa ge 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 8  
i n t he 2 4-wee k tr eat me nt peri o d, c o m pare d t o t he 1 2 -wee k r u n -i n peri o d.  I n a d diti o n, i nteri m 
safet y res ults fr o m t he o n g oi n g P hase 1 st u d y a n d P hase 1/ 2 O L E st u d y i n dicate t hat gi v osira n has 
a n acce pta ble s afet y pr ofile a n d is ge n erall y well -t olerate d. 
F urt her details o n t he n o ncli nical res ults a n d safet y res ults f or St u d y A L N -A S 1 -0 0 1 ca n be f o u n d 
i n t he gi v osira n I B. Gi v e n t he bi ol o gical tar get of gi v osira n, t he a vaila ble n o ncli nical a n d cli nical 
data, a n d t he m o de of a d mi nistrati o n, ot her p ote ntial safet y c o n cer ns i ncl u d e i njecti o n site 
reacti o ns (I S Rs), ele vati o n of li ver tra nsa mi nas es, i ncreas e d ser u m creati ni n e/ decrease d esti mate d 
gl o mer ular filtrati o n rat e (e G F R), pa ncreatitis, a n d a na p h ylactic reacti o n.  A s u m mar y of 
preli mi nar y cli nical data fr o m o n g oi n g P has e 1 a n d P hase 1/ 2 st u dies of gi v osira n ca n b e f o u n d i n 
Secti o n  1. 2. 2  a n d i n t he gi v osira n I B.  
T his cli nical pr ot oc ol i ncl u des e x cl usi o n criteria i nte n de d t o mi ni mize t he ris k of tra nsa mi nitis, 
I S R a n d pa n creatitis, a n d i nc or p orates o n g oi n g m o nit ori n g f or ele vate d tra nsa mi nases, ser u m 
li pase, a n d a na p h yl actic reacti o ns ( Secti o n  6. 2. 3 ).  S pecific r ules f or d ose wit h h ol di n g a n d 
st o p pi n g ha ve b ee n i nc or p orate d i n t he pr ot oc ol f or a b n or malities i n li ver f u ncti o n tests, a n d 
ser u m a m yl ase a n d li pas e le vels.   
Bl o o d h o m oc ystei ne le v els ma y be i ncrease d i n patie nts wit h A H P, vita mi n deficie nci es, or 
c hr o nic ki d ne y dise ase.  (2 3 -2 5 )  D uri n g treat me nt wit h gi v osira n, i ncreas es i n bl o o d 
h o m oc ystei ne l e vels ha v e bee n o bser ve d c o m pare d t o le vels bef ore treat me nt.  T he cli nical 
rele va n ce of t h e ele vati o ns i n bl o o d h o m oc ystei n e d uri n g gi v osira n treat me nt is un k n o w n.  T he 
pr ot oc ol i ncl u des m o nit ori n g f or c ha n ges i n bl o o d h o m oc ystei ne l e vels d uri n g treat me nt wit h 
gi v osira n. It is r ec o m me n de d t hat patie nts wit h i ncrease d bl o o d h o m oc ystei ne le vels recei ve a 
s u p ple me nt c o ntai ni n g vita mi n B 6 (see Secti o n 6. 3. 4 ). 
A n I n de pe n d e nt Data M o nit ori n g C o m mittee ( D M C) will m o nit or safet y o v er t he c o urse of t he 
d o u ble -bli n d treat me nt p eri o d a n d u ntil all patie nts  ha ve bee n i n t he O L E p eri o d f or at least 
6  m o nt hs ( Secti o n  4. 7 ). 
Base d o n t h e e mer gi n g efficac y a n d safet y d ata fr o m t he o n g oi n g cli nical st u dies ( A L N -A S 1 -0 0 1 
a n d A L N-A S 1 -0 0 2) a n d t he o bser ve d precli nical mar gi ns, t he b e nefit -ris k assess me nt s u p p orts 
e val uati o n of gi v osira n i n a p hase 3 St u d y i n A H P patie nts.  
2.  
O B J E C TI V E S  
2. 1.  
Pri m ar y O bjecti ve  
•  E val uate t he effect of S C gi v osira n, c o m pare d t o place b o, o n t he rate of p or p h yria 
attac ks re q uiri n g h os pitaliz ati o n, ur ge nt healt hcare visit, or I V he mi n a d mi nistrati o n at 
h o me  i n patie nts wit h AI P 
2. 2.  
Sec o n d ar y O bjecti ves  
•  E val uate t he effects of gi v osira n, c o m pare d t o place b o, o n uri nar y A L A le vels i n 
patie nts wit h AI P  
•  E val uate t he effects of gi v osira n, c o m pare d t o place b o, o n uri nar y P B G le v els i n 
patie nts wit h AI P  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3 9  
•  E val uate t he effects of gi v osira n, c o m pare d t o place b o, o n he mi n usa ge i n patie nts 
wit h AI P  
•  E val uate t he effects of gi v osira n, c o m pare d t o place b o, o n t he rate of p or p h yria attac ks 
re q uiri n g h os pitaliz ati o n, ur ge nt healt hcare visit, or I V he mi n a d mi nistrati o n at h o me 
i n patie nts wit h a n y A H P  
•  E val uate t he effects of gi v osira n c o m pare d t o place b o i n patie nts wit h AI P o n t he 
s y m pt o ms of pai n, na usea, a n d fati g ue 
•  E val uate t he effects of gi v osira n, c o m pare d t o place b o, i n patie nts wit h AI P o n t he 
P h ysical C o m p o ne nt S u m mar y ( P C S) of t he 1 2 -ite m S h ort-F or m Healt h S ur ve y 
( S F-1 2) (2 6 ) 
•   E val uate t he safet y a n d t olera bilit y of gi v osira n i n patie nts wit h a n y A H P  
2. 3.  
E x pl or at or y O bjecti ves  
•  E val uate t he effects of gi v osira n, c o m pare d t o place b o, i n patie nts wit h AI P a n d i n 
patie nts wit h a n y A H P o ver t he 6 -m o nt h treat me nt p eri o d o n: 
− Rate of all p or p h yria attac ks (re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, I V 
he mi n a d mi nistrati o n at h o me, or treat e d at h o me wit h o ut I V he mi n)  
− Uri nar y A L A S 1 m R N A l e vels  
− A nal gesic usa ge ( o pi oi d a n d n o n -o pi oi d)  
− A d diti o nal q ualit y of life ( Q O L) meas ures, i ncl u di n g misse d da ys of w or k/s c h o ol 
− Patie nt e x perie nce q uesti o n naire a n d p atie nt's i m pressi o n of healt h stat us c ha n ge  
•  Assess t he treat me nt effect of gi v osira n at e val uat e d d oses o ver t h e O L E p eri o d i n  
patie nts wit h AI P a n d i n patie nts wit h  a n y A H P w h o ha d pre vi o usl y bee n ra n d o mize d 
t o place b o treat me nt  
•  Assess t he l o n g -ter m treat me nt effect of gi v osira n i n patie nts wit h AI P a n d i n patie nts 
wit h a n y A H P  
•  C haracterize t he P K of a n d assess t he a nti dr u g a nti b o dies ( A D A) of gi v osira n i n 
patie nts wit h a n y A H P  
3.  
E N D P OI N T S  
3. 1.  
Pri m ar y E n d p oi nt  
•  A n n ualize d rate of p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, 
or I V he mi n a d mi nistrati o n at h o me i n patie nts wit h AI P o ver t he 6 -m o nt h treat me nt 
peri o d. See Secti o n  3. 5  f or t he defi niti o n of p or p h yria attac ks a n d ass ociat e d ter ms.  
3. 2.  
Sec o n d ar y E n d p oi nts  
•  Uri nar y A L A le vels i n patie nts wit h AI P at 3 m o nt hs  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 0  
•  Uri nar y A L A le vels i n patie nts wit h AI P at 6 m o nt hs  
•  Uri nar y P B G le vels i n patie nts wit h AI P at 6 m o nt hs  
•  A n n ualize d rate of a d mi nistere d he mi n d oses i n patie nts wit h AI P o ver t he 6 -m o nt h 
treat me nt peri o d 
•  A n n ualize d rate of p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare vis it, 
or I V he mi n a d mi nistrati o n at h o me i n patie nts wit h a n y A H P o ver t he 6 -m o nt h 
treat me nt peri o d ( Secti o n 3. 5 )  
•  Dail y w orst pai n sc ore as meas ure d b y Brief Pai n I n v e nt or y -S h ort F or m ( B PI -S F) 
n u meric rati n g scale ( N R S)  i n patie nts wit h AI P o ver t he 6-m o nt h treat me nt peri o d  
•  Dail y w orst na usea sc ore as meas ure d b y N R S i n patie nts wit h AI P o ver t he 6 -m o nt h 
treat me nt peri o d 
•  Dail y w orst fati g ue sc ore as meas ure d b y Brief Fati g ue I n v e nt or y -S h ort F or m ( B FI -
S F) N R S i n patie nts wit h AI P o v er t he 6-m o nt h tr eat me nt peri o d  
•  C ha n ge fr o m bas eli ne i n t he P h ysical C o m p o ne nt S u m mar y ( P C S) of t he 1 2 -ite m 
S h ort -F or m Healt h S ur ve y ( S F -1 2) (2 6 ) i n patie nts wit h AI P at 6 m o nt hs 
3. 3.  
E x pl or at or y E n d p oi nts  
E x pl orat or y e n d p oi nts will be meas ure d i n patie nts wit h AI P a n d i n p atie nts wit h a n y A H P o ver 
t he 6-m o nt h treat me nt peri o d or o ver t he O L E peri o d at d oses e val uat e d:  
•  Rate of p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt healt hcare visit, or I V 
he mi n a d mi nistrati o n at h o me ( Secti o n  3. 5 )  
•  Rate of all p or p h yria attac ks ( Secti o n  3. 5 ) 
•  Rate of a d mi nistere d h e mi n d oses  
•  Uri nar y A L A a n d P B G l e vels  
•  Uri nar y A L A S 1 m R N A l e vels  
•  Dail y w orst pai n, dail y w orst na usea, a n d dail y w orst fati g u e sc ores o ver 1 2 m o nt hs  
•  P C S of t he S F -1 2 (2 6 ) 
•  E Q -5 D -5 L i n de x sc ore (2 7 ) 
•  Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI C)  
•  P or p h yria Patie nt E x peri e nce Q uesti o n naire ( P P E Q)  
•  A nal gesic usa ge ( o pi oi d a n d n o n -o pi oi d)  
•  P K pr ofile of gi v osira n  
•  I n ci de nce a n d titer of A D As 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 1  
3. 4.  
S afet y E n d p oi nts  
•  I n ci de nce, se verit y, s eri o us ness, a n d relat e d ness of a d verse e ve nts o v er t he 6-m o nt h 
treat me nt peri o d a n d i n t he O L E peri o d i n patie nts wit h a n y A H P. Si nce p or p h yri a 
attac ks wi ll be rec or de d f or efficac y assess me nt of gi v osira n, t he y will n ot be treate d 
as A Es or S A Es as des cri be d i n Secti o n  7. 5. 6 . 
3. 5.  
Defi niti o n of P or p h yri a Att ac ks  
P or p h yria attac ks are d efi ne d as meeti n g all t he criteria bel o w:  
•  a n ac ute e pis o de of ne ur o visceral pai n i n t he a b d o me n, bac k, c h est, e xtre mities a n d/ or 
li m bs 
•  n o ot her me dicall y deter mi ne d ca use ot her t ha n a p or p h yri a attac k  
•  re q uires tr eat me nt wit h I V de xtr ose or he mi n, car b o h y drates, or a nal gesics ( o pi oi d 
[s y nt hetic a n d n o n-s y nt h etic s u bsta nces] or n o n-o pi oi d), or ot her me dicati o ns s uc h as 
a ntie metics, at a d ose or fre q ue nc y b e y o n d t he pati e nt’s us ual dail y p or p h yria 
ma na ge me nt.  
F or t he p ur p os es of t his st u d y, t he f oll o wi n g defi niti o ns will be use d t o i de ntif y eac h n o n-
o verla p pi n g s u b -t y pe of p or p h yri a attac k e ve nts: 
•  P or p h yri a att ac ks re q uiri n g h os pit aliz ati o n:  p or p h yria attac ks t hat pr o m pt a 
h os pitaliz ati o n.  H os pitaliz ati o n is defi ne d as a n a d missi o n t o a n i n patie nt u nit or a 
visit t o a n e mer ge nc y d e part me nt t hat res ults i n a n at least 2 4 -h o ur sta y ( or a c ha n ge i n 
cale n dar date if t he h os pital a d missi o n or disc har ge ti mes are n ot a vaila ble).  
•  P or p h yri a att ac ks re q uiri n g ur ge nt he alt hc are visit:  P or p h yri a attac ks t hat pr o m pt 
ur ge nt healt hcare visits.  A n ur ge nt healt hcare visit is defi ne d as a n ur ge nt, 
u nsc he d ule d office/ pr acti ce, i nf usi o n ce nt er, or a n e mer ge n c y de part me nt visit t hat 
d oes n ot meet t he criteria f or a h os pitalizati o n.  T his e n d p oi nt i nc l u des pres e ntati o n 
wit h a p or p h yria attac k o n a pr ot oc ol -sc h e d ule d cli nic visit if t he patie nt w o ul d ha ve 
s o u g ht a n ur ge nt healt hcare visit i n t he a bse nce of t he pr ot oc ol-sc he d ul e d cli nic visit.  
•  P or p h yri a att ac ks re q uiri n g I V he mi n at h o me:  P or p h yria attac ks at h o m e re q uiri n g 
I V he mi n. “ H o me” is defi ne d as a n y l ocati o n t hat d oes n ot meet t he criteria f or a 
h os pitaliz ati o n or ur ge nt healt hcare visit.  
•  P or p h yri a att ac ks at h o me n ot re q uiri n g I V he mi n:  P or p h yria attac ks at h o me t hat 
d o n ot re q ui re I V he mi n b ut are treate d wit h car b o h y drates or a n al gesics ( o pi oi d or 
n o n -o pi oi d) at a d ose or fre q ue nc y b e y o n d t he pati e nt’s us ual dail y p or p h yria 
ma na ge me nt. “ H o me” is defi ne d as a n y l ocati o n t hat d oes n ot meet t he criteria f or a 
h os pitaliz ati o n or ur g e nt healt hcare visit.  
T he start of p or p h yri a att ac ks is c haracterize d b y ac ute a n d s ustai ne d w orse ni n g of t he p atie nt’s 
p or p h yri a ma nifest ati o ns be y o n d n or mal da y -t o-d a y varia bilit y. T h e e n d of p or p h yri a attac ks is 
c haracteriz e d b y rec o ver y fr o m p or p h yria ma nifestati o ns bac k t o wit hi n a patie nt’s n or mal da y -t o-
da y v aria bilit y.  S y m pt o ms d uri n g a n attac k ma y be si milar i n nat ure i n a gi ve n patie nt, b ut n ot 
necessaril y i n de gree or s e verit y.  Si nce p or p h yri a attac ks will be rec or de d f or efficac y assess me nt 
of  gi v osira n, t he y will n ot be treate d as A Es or S A Es as descri be d i n Secti o n  7. 5. 6 . 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 2  
4.  
 I N V E S TI G A TI O N A L P L A N 
4. 1.  
S u m m ar y of St u d y Desi g n  
T his is a 2 -part m ul tice nter, m ulti nati o nal P hase 3 st u d y desi g ne d t o e val uat e t he efficac y a n d 
safet y of gi v osira n i n a d ults a n d a d olesce nts ( ≥1 2 years of a ge) wit h a d oc u me nte d dia g n osis of 
AI P.  T h e efficac y a n d safet y of gi v osira n will als o be i n vesti gat e d i n t he ot her A H Ps, i ncl u di n g 
H C P, V P, or A D P. A sc he matic of t he st u d y desi g n is s h o w n i n Fi g ure  2 .   
Patie nts w h o were o n h e mi n pr o p h yla xis pri or t o e nr oll me nt will be eli gi bl e t o partici pate if t he y 
meet t he attac k e ntr y crit eria. I n t his st u d y, p atie nts ma y be gi v e n he mi n f or t he treat me nt of ac ute 
attac ks if cli nicall y i n dicate d b ut ma y n ot use he mi n pr o p h ylacticall y.  He mi n pr o p h yla xis is n ot 
per mitte d i n t his st u d y b eca use gi v osira n is i nte n de d as m o n ot hera p y t o pr e ve nt attac ks a n d t he 
re g ular c o-a d mi nistrati o n of he mi n c o ul d c o nf o u n d efficac y a n d s afet y si g n als relate d t o 
gi v osira n.  
I n t he first part of t h e st u d y, c o ns e nti n g (a n d ass e nti n g, w here a p plica ble) patie nts w h o meet all 
eli gi bilit y criteria will be ra n d o mize d i n a 1: 1 rati o t o recei ve 2. 5  m g/ k g gi v osira n or place b o 
m o nt hl y f or a 6 -m o nt h treat me nt peri o d; b ot h gi v osira n a n d place b o will be a d mi nistere d 
s u bc uta ne o usl y. Treat me nt gr o u ps will be stratifie d at st u d y e ntr y b y A H P t y p e ( AI P [ wit h 
ge n etic e vi de n ce of m utati o n i n t he  H M B S  ge ne] vs H C P, V P, A D P, or a n y A H P wit h o ut 
i de ntifie d m utati o n i n a p or p h yri a-relate d ge ne); all patie nts wit h AI P \will be f urt her str atifie d b y 
eac h p atie nt’s use of he mi n pr o p h yla xis re gi me n at t he ti me of scree ni n g a n d b y eac h p atie nt’s  
hist orical a n n u alize d attac k rate .  AI P p atie nts o n a he mi n pr o p h yl a xis re gi me n pri or t o st u d y 
e ntr y will be stratifie d b y t heir hist orical a n n ualize d attac k rat e: < 7 attac ks vs ≥7 attac ks i n t he 
past 1 2 m o nt hs.  Patie nts w h o were n ot o n a he mi n pr o p h yla xis re gi me n pri or  t o st u d y e ntr y will 
be stratifie d b y t heir hist orical a n n ualize d attac k rate: < 1 2 attac ks vs ≥1 2 attac ks i n t he past 1 2 
m o nt hs.  
D uri n g t h e 6 -m o nt h treat me nt peri o d, patie nts will u n der g o efficac y a n d safet y assess me nts e ver y 
2 wee ks f or t he first m o nt h a n d m o nt hl y t hereafter.  F oll o wi n g t he c o m pleti o n of 6 m o nt hs of 
d o u ble -bli n de d st u d y tr eat me nt, as well as all M o nt h -6 visit assess me nts, patie nts fr o m b ot h t he 
gi v osira n a n d place b o ar ms will be gi n t he sec o n d part of t he st u d y, t he O L E peri o d i n w hic h t he y  
will be treate d wit h gi v osira n f or u p t o 2 9  m o nt hs.  Patie nts w h o cr osse d o v er t o t he O L E peri o d 
pri or t o i m ple me ntati o n of a me n d me nt 3 (ie, u n d er a me n d me nt v ersi o n 1 or 2) a n d are recei vi n g a 
2. 5  m g/ k g o nce m o nt hl y gi v osira n d os e will re mai n o n t hat d ose . U p o n e ntr y t o t he O L E p eri o d 
u n der a me n d me nt v ersi o n 3, patie nts will cr oss o ver t o recei ve a 1. 2 5 m g/ k g o nce m o nt hl y d ose 
of gi v osira n.  
After i m ple me ntati o n of a me n d me nt  3 a n d u ntil i m ple me ntati o n of a me n d me nt  5, patie nts 
assi g ne d t o t he o n ce m o nt hl y 1 . 2 5-m g/ k g treat me nt gr o u p w h o e x perie nce i na de q uate disease 
c o ntr ol ma y b e all o we d t o ha ve t heir m o nt hl y d os e i ncrease d t o 2. 5  m g/ k g starti n g at t he 
M o nt h  1 3 St u d y Visit ( w he n 6  m o nt hs of o pe n -la bel gi v osira n d osi n g ha v e bee n c o m plete d at 
1. 2 5  m g/ k g) bas e d  o n disc ussi o n a n d a gree me nt b y t he I n v esti gat or a n d me dical m o nit or, 
de m o nstrati o n of t olera bilit y t o gi v osira n, a n d f ulfill me nt of A L A a n d cli nical acti vit y criteri a.  
U p o n i m ple me ntati o n of a me n d me nt  5, all patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n o nce m o nt hl y 
w h o d o n ot ha ve o n g oi n g cli nicall y rele va nt tra nsa mi nase ele vati o ns will ha ve t heir d ose 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 3  
i ncreas e d t o 2. 5 m g/ k g gi v osira n o nce m o nt hl y base d o n t olera bilit y al o ne, wit h o ut a n y criteria 
f or A L A re d ucti o n or cli nical acti vit y.  F or f urt her details, see  Secti o n  6. 2. 3. 4 . 
Patie nts will u n der g o effi cac y a n d safet y assess me nts e ver y 2 wee ks f or t h e first m o nt h of t he 
O L E p eri o d a n d t he n m o nt hl y t hr o u g h  M o nt h 1 8, a n d e ver y 3 m o nt hs t hereafter.  
If he mi n is use d f or p or p h yria attac ks, t he s c he d ul e d uri ne sa m ple f or A L A, P B G, a n d A L A S 1 
m R N A assess me nts will be c ollecte d 4 da ys ( + 4 d a ys) after t he patie nt’s l ast he mi n d ose.  
F or partic ular visits, as s pecifie d i n t he Sc he d ul e of Assess me nts (Ta ble  2  a n d Ta ble  3 ), a n d 
w here a p plica ble c o u ntr y a n d l ocal re g ul ati o ns a n d i nfrastr uct ur e all o w, st u d y pr oce d ures ma y be 
c o n d ucte d b y a h o m e healt hcare pr ofessi o nal. St u d y dr u g a d mi nistrati o n ma y be c o n d ucte d b y a 
h o me healt hcare pr ofessi o nal f or patie nts t ha t ha ve de m o nstrate d t he a bilit y t o t olerat e t he st u d y 
dr u g at t he st u d y ce nter.  If t he patie nt is u na ble t o c o me t o t he st u d y site, a n d a visit b y a h o me 
healt hcare pr ofessi o nal is n ot p ossi ble d ue t o circ u msta nces relat e d t o t he C O VI D -1 9 p a n de mic, 
gi v osi ra n ma y b e a d mi nistere d b y t he patie nt or t h e care gi ver u n d er t he o v ersi g ht of t he 
I n v esti gat or, a n d f oll o wi n g c o ns ultati o n wit h t he me dical m o nit or, as all o we d b y a p plica bl e 
c o u ntr y a n d l ocal re g ulati o ns.  I n s uc h cases, t h e p atie nt or care gi ver m ust rece i ve a p pr o pri ate 
trai ni n g o n gi v osira n a d mi nistrati o n a n d t he use of e pi ne p hri ne (e pi pe n or e q ui vale nt) pri or t o 
d osi n g.  T his meas ur e is i nte n de d t o re mai n i n effect o nl y d uri n g peri o ds of ti me w he n t he 
C O VI D -1 9 pa n d e mic i m pe des t he a bilit y of patie nts t o  tra vel t o t he st u d y site or healt hcare 
pr ofessi o nals t o g o t o patie nts' h o mes f or d osi n g.  
Patie nts or care gi v ers will be pr o vi de d wit h a n electr o nic diar y (e Diar y) t o rec or d se verit y of dail y 
pai n, na usea, a n d fati g ue, as well as a n al gesic use. P ote ntial p or p h yria attac ks will als o be 
rec or de d i n t he e Di ar y b y patie nts a n d care gi vers w he n t he y occ ur; st u d y ce nters will be n otifie d 
w he n p ote ntial p or p h yria attac ks are re p orte d i n t h e e Diar y.  I n i nsta nces w he n t he e Diar y is n ot 
use d t o re p ort p ote ntial p or p h yri a attac ks, st u d y ce nters ma y be n otifie d b y tele p h o ne b y patie nts, 
care gi v ers, or ot her healt hcare pr o vi ders.  All p ote ntial p or p h yri a attac ks will be c o nfir me d b y t he 
I n v esti gat or. 
A n e xter nal i n de pe n de nt Data M o nit ori n g C o m mittee ( D M C; Secti o n  4. 7 ) will m o nit or safet y 
o ver t he c o urse of t he d o u ble -bli n d treat me nt peri o d a n d u ntil all patie nts ha ve bee n i n t he O L E 
peri o d f or at least 6  m o nt hs . Details f or t he c o m mittee will be pr o vi de d i n c o m mittee c harter.  
D uri n g t h e O L E Peri o d, patie nts ma y recei ve gi v osira n as l o n g as t he y d o n ot f ulfill a n y of t he 
st u d y disc o nti n uati o n crit eria (see Secti o n 5. 3 ) or u ntil gi v osira n is c o m merciall y a vaila ble i n t he 
patie nt’s territ or y or t h e gi v osira n d e vel o p me nt pr o gra m is disc o nti n ue d ( w hic he ver c o mes first).  
All patie nts are as k e d t o partici pate i n t he S afet y F oll o w -u p visit after t he y ha ve recei ve d t h eir 
last d ose of gi v osira n. 
W here re q uir e d b y l ocal re g ulati o ns, t his trial ma y be re place d wit h a p ost -mar keti n g cli nical trial 
o nce mar k eti n g a ut h orizati o n f or gi v osira n is r ecei ve d.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 4  
Fi g ure  2 :  
St u d y Desi g n   
 
A b bre viati o ns: A M ≤2 = ori gi nal pr ot oc ol ( 0 6 Se pt 2 0 1 7), pr ot oc ol a me n d me nt 1 ( 0 4 Ma y 2 0 1 8), a n d pr ot oc ol 
a me n d me nt 2. 0 ( 2 6  J ul y 2 0 1 8); A M 3 = pr ot oc ol a me n d me nt 3 ( 2 1 Se pt 2 0 1 8); A M 5 = pr ot oc ol a me n d me nt 5 
( 1 2 Fe br u ar y 2 0 2 0) 
4. 2.  
D ur ati o n of Tre at me nt  
T he esti mate d t otal ti me o n st u d y f or eac h patie nt is a p pr o xi matel y 3 8 m o nt hs, i ncl u di n g u p t o 
2  m o nt hs of scree ni n g, u p t o 3 5 m o nt hs of treat me nt ( d o u ble -bli n d treat me nt peri o d of 6 m o nt hs 
a n d u p t o 2 9 -m o nt h o pe n -la bel e xte nsi o n peri o d), a n d a 1 -m o nt h f oll o w -u p peri o d.  
T he pri mar y e n d p oi nt will be a nal yze d at t he c o m pleti o n of t he 6 -m o nt h treat me nt peri o d.  
A patie nt will be c o nsi dere d t o ha ve c o m plete d t h e pri mar y o utc o me m eas ure at t he ti me of 
c o m pleti o n of t he M o nt h -6 treat me nt ass ess me nts.  
4. 3.  
N u m ber of P atie nts  
T he pla n ne d t otal e nr oll me nt i n t he st u d y is a p pr o xi matel y 7 4 A H P patie nts, i ncl u di n g 
a p pr o xi matel y 7 0 AI P patie nts.  
4. 4.  
Met h o d of Assi g ni n g P atie nts t o Tre at me nt Gr o u ps  
Patie nts will be ra n d o mize d 1: 1 t o st u d y dr u g or pl ace b o i n a d o u bl e -bli n d ma n ner. Treat me nt 
gr o u ps will be str atifie d at st u d y e ntr y b y A H P t y p e ( AI P [ wit h ge n etic e vi d e nce of m utati o n i n 
t he H M B S  ge n e] vs H C P, V P, A D P, or a n y A H P wit h o ut i de ntifie d m utati o n i n a p or p h yria -
relate d ge n e).   
Ra n d o mizat i o n f or AI P p atie nts will be f urt her str atifie d b y eac h patie nt’s use of he mi n 
pr o p h yla xis re gi me n at t he ti me of scree ni n g  a n d b y eac h p atie nt’s  hist orical a n n ualize d attac k 
rate.  Patie nts o n a he mi n pr o p h yla xis re gi me n pri or t o st u d y e ntr y will be stratifie d b y t heir 
hist orical a n n ualize d attac k rate: < 7 attac ks vs ≥7 attac ks i n t he past 1 2 m o nt hs.  Patie nts w h o 
were n ot o n a he mi n pr o p h yla xis re gi me n pri or t o st u d y e ntr y will be str atifie d b y t h eir hist orical 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 5  
a n n ualize d attac k rate: < 1 2 attac ks vs ≥1 2 a ttac ks i n t he past 1 2 m o nt hs. T hese stratificati o n 
c ut offs are base d o n t he a vera ge a n n ualize d attac k rates o bser ve d i n t he St u d y A L N -A S 1 -N T -0 0 1 
( E X P L O R E, a n o bser vati o nal nat ural hist or y st u d y). 
As ver y fe w n o n -AI P p atie nts are a ntici pat e d t o be e nr olle d i n t he st u d y, n o a d diti o nal 
stratificati o n fact ors will be c o nsi dere d f or t hes e p atie nts.   
Eac h patie nt will be u ni q uel y i de ntifie d i n t he st u d y b y a c o m bi nati o n of t he st u d y ce nter n u m b er 
a n d patie nt i de ntificati o n n u m ber.  U p o n c o m pleti o n of t he i nf or me d c o ns e nt f or m (I C F; a n d 
asse nt, if a p plica ble) b y t he patie nt/ pare nt or g uar dia n , t he patie nt will be assi g ne d a p atie nt 
i de ntificati o n n u m ber b y t he i nteracti ve res p o nse s yste m (I R S).  T h e I n vesti gat or or his/ her 
dele gate will c o ntact t he I R S after c o nfi r mi n g t hat t he patie nt f ulfills all t he i ncl usi o n criteria a n d 
n o ne of t he e x cl usi o n criteria a n d a bli n de d treat m e nt will be assi g n e d.   
4. 5.  
Bli n di n g  
I n di vi d ual s u bject treat m e nt assi g n me nts will be mai ntai ne d b y t h e I R S. Me m bers of t he st u d y 
tea m will n ot have access t o u n bli n de d data u ntil t he 6 -m o nt h treat me nt peri o d data is u n bli n de d 
f or its fi nal a nal ysis.  A n y u n pla n n e d u n bli n di n g occ urri n g d uri n g t he st u d y peri o d will be 
d oc u me nte d a n d re p orte d i n t he cli nical st u d y re p ort.  
T he i n de pe n de nt D M C a n d a n i n de pe n de nt bi ostatistics gr o u p will ha ve access t o s u bject le vel 
treat me nt assi g n me nts. I n a d diti o n t o peri o dic safet y m o nit ori n g b y t he D M C, a n i nteri m a nal ysis 
base d o n acc u m ulati n g efficac y a n d safet y d ata ma y be p erf or me d b y a n u n bli n de d gr o u p. 
Me m bers i n t he desi g nat e d u n bli n de d gr o u p will n ot ha ve direct r oles or res p o nsi bilities i n 
c o n d ucti n g t his st u d y. Al n yla m staff me m bers w h o are i n v ol ve d i n r a n d o mizati o n a n d a nal ysis of 
P K, uri nar y A L A S 1, uri n ar y A L A, a n d P B G, a n d a nti -dr u g a nti b o d y ( A D A) ma y h a v e tr eat me nt 
assi g n me nt i nf or m ati o n b ut will n ot ha ve access t o s u bject le vel data fr o m t he cli nical trial 
data bases.   
A s u bject’s treat me nt assi g n me nt s h o ul d o nl y b e u n bli n de d w he n k n o wle d ge of t he treat me nt is 
esse ntial f or t he f urt her cli nical ma na ge me n t of t h e patie nt. T he pri n ci pal i n vesti gat or is str o n gl y 
e nc o ura ge d t o c o ntact t he me dical m o nit or bef ore u n bli n di n g a n y patie nt’s treat me nt assi g n me nt 
b ut m ust d o s o wit hi n 1 w or ki n g d a y aft er t he e v e nt.  A rec or d of w he n t h e bli n d was br o ke n, w h o 
br o ke t he bli n d, a n d w h y it was br o ke n, will be mai ntai ne d i n t he trial master file ( T M F).  
Refer t o t he I R S i nstr ucti o ns f or details o n u n bli n di n g.  
La b orat or y res ults of uri nar y A L A, P B G, ( perf or me d at a ce ntral la b orat or y) or A L A S 1 m R N A 
( perf or me d at Al n yla m) will be bli n de d fr o m after t he ti me of t he first d os e u ntil u n bli n di n g of t he 
cli nical data bas e a n d will n ot be re p orte d t o t he i n vesti gat or p ost -s cree ni n g. I n a d diti o n, 
i n vesti gat ors a n d st aff i n v ol ve d wit h t his trial a n d all me dical staff i n v ol ve d i n t he su bject’s 
me dical care s h o ul d refrai n fr o m o btai ni n g l ocal A L A or P B G meas ure m e nts u ntil at least 
1 2  wee ks after t he M o nt h 6 visit (t o a v oi d p ote ntial u n bli n di n g). If A L A or P B G is meas ure d 
d uri n g t his peri o d, all reas o na ble ste ps m ust be u n derta ke n t o a v oi d i nf or mi n g t he patie nt a n d 
st u d y pers o n n el of t he res ults.  
A list of all Al n yla m pers o n nel or pers o n nel w or ki n g o n be h alf of Al n yla m w h o are u n bli n de d t o 
st u d y data will be mai ntai ne d i n t he T M F. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 6  
4. 6.  
P atie nt Electr o nic Di ar y (e Di ar y)  
Patie nts or care gi v ers w ill be pr o vi de d wit h a n electr o nic diar y (e Diar y) at scree ni n g a n d trai ne d 
o n its use.  Dail y e ntri es i nt o t he e Diar y will i ncl u de pai n, na usea, a n d fati g ue se verit y, as well as 
a nal gesic use.  F or f urt her details, see Secti o n  7. 2. 2 . 
Patie nts or care gi v ers will re p ort p ote ntial p or p h yria attac ks i n t he e Di ar y w he n t he y occ ur fr o m 
scree ni n g t hr o u g h o ut t he d urati o n of t he st u d y.  F or a d diti o nal details, see S ecti o n 7. 2. 1 .  
C o m plete i nstr ucti o ns o n electr o nic diar y use will be pr o vi de d i n t he St u d y Ma n ual.  
4. 7.  
I n de pe n de nt D at a M o nit ori n g C o m mittee 
A n e xter nal i n de pe n de nt D M C will m o nit or safet y o ver t he c o urse of t he d o u ble -bli n d treat me nt 
peri o d a n d u ntil all patie nts ha ve bee n i n t he O L E peri o d f or at least 6  m o nt hs . A nal yses f or t he 
D M C are pr o vi de d b y a n i n de pe n de nt bi ostatistics gr o u p. Details are pr o vi de d i n t he D M C 
C harter.  
5.  
S E L E C TI O N A N D WI T H D R A W A L O F P A TI E N T S  
5. 1.  
I ncl usi o n Criteri a 
Eac h patie nt m ust meet all of t he f oll o wi n g i ncl usi o n criteria t o be eli gi ble f or e nr oll me nt i n t he 
st u d y: 
1.  A ge ≥1 2 years  
2.  D oc u me nte d dia g n osis of AI P, H C P, V P, or A D P base d o n cli nical f eat ur es (e g, ac ut e 
attac ks of a b d o mi nal, b ac k, c hest, e xtre mities, a n d/ or li m b pai n), at least o ne d oc u me nte d 
uri nar y or plas ma P B G or A L A val ue ≥4 × u p per li mit of n or mal ( U L N) wit hi n t he past 
year pri or t o or d uri n g Scree ni n g, A N D o ne of t he f oll o wi n g:  
•  D oc u me nte d ge n etic e vi d e nce of m utati o n i n a p or p h yria -rel ate d ge n e, defi ne d as 
A N Y  of t he f oll o wi n g:  
− AI P:  m utati o n i n t he h y dr o x y met h yl bila ne s y nt h ase ge ne ( H M B S ; als o    
referre d t o as t he p or p h o bili n o ge n dea mi nase [P B G D ] ge n e)  
− H C P:  m utati o n i n t he c o pr o p or p h yri n o ge n o xi dase ( C P O X ) ge n e  
− V P:  m utati o n i n t he pr ot o p or p h yri n o ge n o xi dase ( P P O X ) ge n e  
− A D P:  m utati o n i n t he a mi n ole v uli nic aci d de h y dratase ( A L A D)  h o m oz y g o us 
or c o m p o u n d heter oz y g o us ge n es  
•  O R  if t he res ults of a pati e nt’s ge netic testi n g d o n ot i de ntif y a m utati o n i n a 
p or p h yri a -relate d ge ne ( < 5 % of cas es), a p atie nt ma y b e eli gi ble f or t h e st u d y if t he y 
ha ve b ot h cli nical f eat ures a n d dia g n ostic bi oc he mical criteria c o nsiste nt wit h A H P 
(Ta ble  1 1 ) 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 7  
3.  Ha ve acti ve diseas e, wit h at least 2 p or p h yria attac ks re q uiri n g h os pitalizati o n, ur ge nt 
healt hcare visit or treat m e nt wit h I V he mi n at h o me wit hi n t he 6 m o nt hs pri or t o 
Scree ni n g  
4.  Willi n g t o disc o nti n ue a n d/ or n ot i nitiate use of pr o p h ylactic he mi n at t he ti me of 
Scree ni n g a n d f or t he d urati o n of t he st u d y  
5.  Ha ve a d e q uate v e n o us access f or st u d y sa m ple c ollecti o n as j u d ge d b y t he i n vesti gat or  
6.  Be willi n g t o c o m pl y wit h t he c o ntrace pti ve re q uire me nts d uri n g t he st u d y peri o d, as 
descri be d i n  Secti o n  6. 4 .  
7.  Be willi n g a n d a ble t o c o m pl y wit h t he st u d y r e q uire me nts a n d t o pr o vi de writte n 
i nf or me d c o nse nt per l ocal a n d nati o nal re q uire me nts.  I n t he case of patie nts u n der t he 
a ge of le gal c o nse nt, le gal g uar di a n(s) m ust pr o vi d e writte n i nf or me d c o nse nt a n d t he 
patie nt s h o ul d pr o vi de asse nt per l ocal a n d na ti o nal re q uire me nts a n d i nstit uti o nal 
sta n dar ds. 
5. 2.  
E xcl usi o n Criteri a  
Eac h patie nt m ust n ot meet a n y of t he f oll o wi n g e x cl usi o n criteria t o be eli gi ble f or e nr oll me nt i n 
t he st u d y: 
1.  A n y of t he f oll o wi n g la b orat or y para meter assess me nts at Scree ni n g:  
a. Ala ni ne a mi n otra nsf eras e ( A L T) > 2 × U L N  
b.  T otal bilir u bi n > 1. 5 × U L N. Patie nts wit h ele vate d t otal bilir u bi n t hat is sec o n dar y t o 
d oc u me nte d Gil bert’s s y n dr o me are eli gi ble if t he t otal bilir u bi n is < 2 × U L N  
c. I nter nati o nal n or malize d rati o (I N R) > 1. 5 ( patie nts on a n a ntic oa g ula nt [e g, warfari n] 
wit h a n I N R < 3. 5 will be all o we d)  
2.  Esti mate d Gl o mer ular Filtrati o n Rate (e G F R) < 3 0 m L/ mi n/ 1. 7 3 m 2 usi n g t he M o dificati o n 
of Diet i n Re nal Diseas e ( M D R D) f or m ula  
3.  O n a n acti ve li ver tra ns pl a ntati o n waiti n g list, or a ntici pate d t o u n der g o li ver 
tra ns pla ntati o n d uri n g t h e bli n de d st u d y tr eat me nt peri o d 
4.  Hist or y of m ulti ple dr u g aller gies or hist or y of aller gic reacti o n t o a n oli g o n ucle oti de or t o 
N -acet yl galact osa mi ne ( Gal N Ac)  
5.  Hist or y of i nt olera nce t o s u bc uta ne o us i njecti o n(s)  
6.  K n o w n acti ve HI V i nfecti o n; or e vi de nce of c urre nt or c hr o nic he p atitis C vir us ( H C V) or 
he patitis B vir us ( H B V) i nfecti o n  
7.  C urre ntl y e nr olle d i n a n ot her i n vesti gati o nal de vice or dr u g st u d y, or less t h a n 3 0 da ys or 
5 half -li ves ( w hic h e ver is l o n ger) si nce e n di n g a n ot her i n vesti gati o nal de vice or dr u g 
st u d y(s), or recei vi n g ot her i n vesti gati o nal a ge nt(s) 
8.  Fe males w h o are pre g n a nt, breast -fee di n g, or pla n ni n g t o bec o m e pre g n a nt d uri n g t he 
st u d y 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 8  
9.  A n y c o n diti o n (e g, me dical c o ncer n or al c o h ol or s u bsta nce a b us e),  w hic h i n t he o pi ni o n 
of t he I n vesti gat or, w o ul d ma ke t he patie nt u ns uita ble f or d osi n g or w hi c h c o ul d i nterfere 
wit h t he st u d y c o m plia nce, t he patie nt’s safet y a n d/ or t he patie nt’s partici pati o n i n t he 6 -
m o nt h treat me nt peri o d of t he st u d y.  T his i ncl u des  si g nifica nt acti ve a n d p o orl y 
c o ntr olle d ( u nsta ble) car di o vasc ular, ne ur ol o gi c, gastr oi ntesti nal, e n d ocri n e, re nal or 
ps yc hiatric dis or ders u nrelate d t o p or p h yria i d e ntifie d b y k e y la b orat or y a b n or malities or 
me dical hist or y.  
1 0.  Hist or y of rec urre nt p a ncreat itis, or ac ute pa ncreatitis wit h disease acti vit y wit hi n t he past 
1 2 m o nt hs pri or t o Scree ni n g  
1 1.  Has a maj or s ur ger y pla n ne d d uri n g t he first 6  m o nt hs of t he st u d y  
1 2.  Hist or y of s eri o us i nfecti o n wit hi n o ne m o nt h pri or t o Scree ni n g  
1 3.  Ha d a mali g na n c y wit hi n 5 yea rs pri or t o Scree ni n g, e x ce pt f or basal or s q u a m o us cell 
carci n o ma of t he s ki n, cer vical i n -sit u carci n o ma, or breast d uct al carci n o m a, t hat has bee n 
s uccessf ull y treate d 
5. 3.  
Disc o nti n u ati o n of St u d y Dr u g a n d/ or St u d y  
Patie nts or t heir le gal g uar dia ns (i n t he cas e t hat t h e patie nt is a mi n or) are free t o disc o nti n ue 
treat me nt a n d/ or st u d y or wit h dra w t heir c o ns e nt at a n y ti me a n d f or a n y reas o n, wit h o ut pe nalt y 
t o t heir c o nti n ui n g me dical care.  A n y disc o nti n uati o n of treat me nt or of t h e st u d y m ust be f ull y 
d oc u me nte d i n t he ele ctr o nic case re p ort f or m (e C R F) a n d s h o ul d be f oll o w e d u p b y t h e 
I n v esti gat or.  T he I n v esti gat or m a y wit h dra w a patie nt fr o m t he st u d y at a n y ti me if t his is 
c o nsi dere d i n t he p atie nt’s best i nterest.  
Disc o nti n uati o n of st u d y dr u g a n d wit h dra wal fr o m t he st u d y are descri be d i n Secti o n 5. 3. 1  a n d 
Secti o n  5. 3. 2  , res pecti vel y.  If a patie nt st o ps partici pati o n fr o m t he st u d y or wit h dra ws c o ns e nt 
fr o m t he st u d y, h e/s he will n ot be a ble t o re-e nr oll i n t he st u d y 
5. 3. 1.  
Disc o nti n u ati o n of St u d y Dr u g  
T he I n ves ti gat or or d esi g nee ma y disc o nti n ue d osi n g i n a patie nt if t he patie nt: 
•  Is i n si g nifica nt vi olati o n of t he pr ot oc ol 
•  E x perie nces a S A E c o nsi dere d t o be relate d t o t he st u d y dr u g or a n i nt olera ble A E  
•  Bec o m es pre g n a nt  
•  Is n o n-a d here nt t o t he treat me nt re gi me n  
T he I n vesti gat or will c o nfer wit h t he S p o ns or or me dical m o nit or bef ore disc o nti n ui n g d osi n g i n 
t he patie nt.   
Patie nts w h o are pre g na nt will be disc o nti n ue d fr o m st u d y dr u g d osi n g i m me diatel y (see 
Secti o n  7. 5. 6. 6  f or re p orti n g a n d f oll o w-u p of pre g na n c y).  A p ositi ve uri n e pre g na n c y test s h o ul d 
be c o nfir me d b y a ser u m pre g na nc y t est pri or t o disc o nti n ui n g t he st u d y dr u g.  
If a patie nt disc o nti n ues d osi n g d ue t o a s eri o us a d verse e v e nt ( S A E), t he S A E s h o ul d be f oll o we d 
as descri be d i n Secti o n  7. 5. 6 .  W he n a patie nt disc o nti n ues st u d y dr u g d osi n g, t he pri mar y reas o n 
m ust be rec or de d i n t he electr o nic case re p ort f or m (e C R F).  Patie nts w h o disc o nti n ue st u d y dr u g 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4 9  
a n d re mai n o n st u d y ma y recei v e treat me nt c o nsiste nt wit h l ocal sta n dar d practice f or t heir 
disease per I n vesti gat or j u d ge m e nt, as a p plica bl e.  
Patie nts w h o disc o nti n ue fr o m st u d y tr eat me nt d uri n g t he 6 -m o nt h treat me nt peri o d ( defi ne d as 
t he ti me t he first d ose of st u d y dr u g is a d mi nistere d o n St u d y Da y 1 t hr o u g h c o m pleti o n of t he 
M o nt h -6 assess me nts) will be e nc o ura ge d t o re m ai n o n t he st u d y a n d c o m plete assess me nts 
t hr o u g h M o nt h 6 a n d c o nti n ue t o re p ort p ote ntial p or p h yri a attac ks as t he y o cc ur; t he y will als o 
be as ke d t o c o m plete a safet y f oll o w -u p 3 m o nt hs ( 8 4 ± 1 4 da ys) after t heir l ast d ose of st u d y dr u g 
(see Ta bl e  3 ).  
Patie nts w h o disc o nti n ue st u d y treat me nt d uri n g t he O L E peri o d will be as ke d t o ret ur n f or t heir 
ne xt sc he d ule d visit t o c o m plete E O S/ E T assess me nts; t he y will als o be as ke d t o c o m plete a 
safet y f oll o w-u p visit 3 m o nt hs ( 8 4 ± 1 4 da ys) aft er t heir last d ose o f st u d y dr u g (see T a ble  3 ).  
5. 3. 2.  
Disc o nti n u ati o n fr o m t he St u d y  
A patie nt or t heir le gal g uar dia n ma y deci de t o st o p t he patie nt’s partici pati o n i n t he st u d y at a n y 
ti me.  Patie nts c o nsi deri n g st o p pi n g t he st u d y s h o ul d be i nf or me d t hat t he y ca n disc o nti n ue 
treat me nt a n d c o m plet e st u d y assess me nts i ncl u di n g f oll o w-u p, as per t h e S O A, or alter nati vel y 
ma y c o m plete a n y mi ni mal assess me nts f or w hi c h t he patie nt c o nse nts. T he I n v esti gat or ma y 
wit h dra w a patie nt at a n y ti me if t his is c o nsi dere d i n t he patie nt’s best i nterest.  
H o we ver, st u d y i nte grit y a n d i nter pret ati o n are b est mai ntai ne d if all ra n d o mize d patie nts 
c o nti n ue st u d y ass ess me nts a n d f oll o w -u p.  St o p pi n g st u d y partici pati o n c o ul d mea n:  
•  If a patie nt st o ps partici p ati o n d uri n g t he 6-m o nt h treat me nt peri o d, t he y s h o ul d be 
i nf or me d t hat t he y ca n disc o nti n ue treat me nt, b ut c o nti n ue t o c o m plete t heir st u d y 
assess me nts t hr o u g h t h e 6 -m o nt h visit, i ncl u di n g f oll o w -u p.   
•  If a patie nt st o ps partici p ati o n d uri n g t he o pe n-la bel e xte nsi o n peri o d, t he y s h o ul d 
be as ke d t o r et ur n f or a n Earl y Ter mi nati o n Visit as well as a Safet y F oll o w -U p 
Visit 3 m o nt hs after t heir last d ose of st u d y dr u g.  
•  A patie nt ca n st o p ta ki n g t he st u d y dr u g a n d st o p st u d y -relate d visits, b ut all o w t he 
i n vesti gat or a n d st u d y tea m t o re vie w t he patie nt’s me dical rec or ds, p u blic rec or ds 
or be c o nta cte d t o recei v e i nf or mati o n a b o ut t he patie nt’s healt h  
W he n a patie nt st o ps t he st u d y, t he disc o nti n uati o n a n d reas o n f or disc o nti n uati o n m ust be 
rec or de d i n t he a p pr o priate secti o n of t he el ectr o ni c case re p ort f or m (e C R F) a n d all eff orts will 
be ma de t o c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble.  If a patie nt st o ps t he 
st u d y d ue to a n a d vers e e ve nt ( A E), i ncl u di n g a n S A E, t he A E s h o ul d be f oll o we d as descri be d i n 
Secti o n  7. 5. 6 . 
If t he patie nt w a nts t o st o p partici pati o n i n t he st u d y, he/s he s h o ul d n otif y t h e st u d y d o ct or i n 
writi n g or i n a n y ot h er f or m t hat ma y b e l ocall y re q uire d. T he pers o nal data alrea d y c ollecte d 
d uri n g t he st u d y, i ncl u di n g patie nt’s bi ol o gical sa m ples, will still be use d t o get h er wit h t he data 
c ollecte d on ot her p atie nts i n t he st u d y acc or di n g t o t he i nf or me d c o nse nt a n d a p plica ble la ws.  
I n a d diti o n t o st o p pi n g partici pati o n i n t he st u d y, t he patie nt c o ul d deci de t o wit h dra w his/ her 
c o nse nt as e x plai ne d i n Secti o n  5. 3. 3    


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 0  
5. 3. 3.  
Wit h dr a w al  of C o nse nt t o C ollect a n d Pr ocess t he P atie nt’s Pers o n al D at a  
T he patie nt ma y deci de t o wit h dra w his/ her c o ns e nt i nf or mi n g t he st u d y d o ct or at a n y ti me i n 
writi n g, or i n a n y ot h er f or m t hat ma y b e l ocall y re q uire d.  T his  mea ns t hat t he patie nt wa nts t o 
st o p partici pati o n i n t he st u d y a n d a n y f urt her c oll ecti o n of his/ her pers o nal data.  
•  T he s p o ns or will c o nti n ue t o kee p a n d us e a patie nt's st u d y i nf or mati o n (i n cl u di n g 
a n y d ata res ulti n g fr o m t he a nal ysis of t he patie nt's bi ol o gical sa m ples u ntil ti me of 
wit h dra wal) acc or di n g t o a p plica ble la w.  T his is d o ne t o g u ara ntee t he vali dit y of 
t he st u d y, deter mi ne t he effects of t he st u d y treat me nt, a n d e ns ure c o m plete ness of 
st u d y d oc u me ntati o n.  
•  T he patie nt ca n als o re q u est t hat c ollecte d sa m ples be destr o ye d or ret ur n e d (t o t he 
e xte nt it is per mitte d b y a p plica ble la w) at a n y ti me.  
•  Patie nts w h o wit h dra w t heir c o nse nt t o c ollect a n d use pers o nal d ata s h o ul d 
u n dersta n d t hat p u blic r ec or ds ma y be re vie we d t o deter mi ne t he patie nt’s s ur vi val 
stat us as all o we d per l o cal a n d nati o nal re g ulati o ns.    
I n U S a n d J a pa n, ot her wise, sa m ples n ot yet a nal yze d at t he ti me of wit h dra wal ma y still be use d 
f or f urt her testi n g/ a nal ysis i n acc or da nce wit h t he ter ms of t he pr ot oc ol a n d of t he i nf or me d 
c o nse nt f or m.  
I n E U a n d rest of w orl d, i n a n y e ve nt, sa m ples n ot yet a nal yz e d at t he ti me of wit h dra wal will n ot 
be use d a n y l o n ger, u nless per mitte d b y a p plica ble la w. T he y will be st ore d or destr o ye d 
accor di n g t o a p plic a ble l e gal re q uir e me nts.  
5. 3. 4.  
Re pl ace me nt of P atie nts  
Patie nts disc o nti n ui n g fr o m st u d y dr u g or wit h dra wi n g fr o m t he st u d y will n ot be re place d.  
6.  
T R E A T M E N T S  
6. 1.  
Tre at me nts A d mi nistere d  
St u d y dr u g s u p plie d f or t his st u d y m ust n ot be use d f or a n y p ur p o s e ot her t ha n t he pres e nt st u d y 
a n d m ust n ot be a d mi nistere d t o a n y p ers o n n ot e nr olle d i n t he st u d y.  St u d y dr u g t h at has bee n 
dis pe nse d t o a patie nt a n d ret ur ne d u n us e d m ust n ot be re -dis pe ns e d t o a differe nt patie nt.  
6. 2.  
I n vesti g ati o n al St u d y Dr u g 
Detaile d i nf or mati o n des cri bi n g t he pre p arati o n, a d mi nistrati o n, a n d st ora ge of gi v osira n a n d 
place b o is pr o vi de d i n t h e P har mac y M a n ual.  
6. 2. 1.  
Descri pti o n  
T he gi v osira n dr u g pr o d u ct ( A L N -A S 1) will be s u p plie d as a sterile s ol uti o n i n water f or S C 
i njecti o n.  See t he P har m ac y Ma n ual f or f urt her details of s ol uti o n c o nce ntrati o n a n d fill v ol u me. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 1  
T he c o ntr ol dr u g f or t his st u d y will be a place b o (s o di u m c hl ori de 0. 9 % w/ v f or S C 
a d mi nistrati o n).  Place b o will be pr o vi de d b y t h e S p o ns or; it will be pac ka ge d i d e nticall y t o 
gi v osira n a n d a n i de ntic al v ol u me will be a d mi nistere d.  
6. 2. 2.  
D ose a n d A d mi nistr ati o n  
T he st u d y dr u g s h o ul d be i njecte d i nt o t he a b d o me n or u p per ar ms or t hi g hs.  Detaile d 
i nstr ucti o ns f or st u d y dr u g a d mi nistrati o n are prese nte d i n t he P har mac y M a n ual. As is c o nsiste nt 
wit h g o o d me dical practi ce f or s u b c uta ne o us dr u g a d mi nistrati o n, patie nt s will be o bser ve d f or a 
mi ni m u m of 2 0 mi n utes after eac h i njecti o n.   Treat me nt f or a n a p h yl actic reacti o ns s h o ul d be 
rea dil y a vaila bl e w here p atie nts are b ei n g d os e d, a n d f oll o w c o u ntr y a n d/ or l ocal h os pital 
treat me nt g ui deli nes (2 8 ). 
Gi v osira n will be a d mi nistere d b y a q u alifie d a n d a ut h orize d healt h care pr ofessi o nal trai ne d i n 
t he rec o g niti o n a n d ma n a ge m e nt of a na p h yl actic reacti o ns, w he n e ver p ossi ble.  St u d y dr u g 
a d mi nistrati o n ma y be c o n d ucte d at a l ocati o n ot her t ha n t he st u d y ce nter b y a h o m e healt hcare 
pr ofessi o nal, w here a p plica ble c o u ntr y a n d l ocal re g ul ati o ns a n d i nfrastr u ct ure all o w, after 
c o ns ultati o n wit h t he me dical m o nit or, d uri n g p artic ular st u d y v isits, as s p ecifie d i n t he Sc he d ul es 
of Assess me nts ( Ta ble  2  a n d Ta ble  3 ).  If t he p atie nt is u na ble t o c o me t o t he st u d y site, a n d a 
visit b y a h o me healt hcare pr ofessi o nal is n ot p ossi ble d ue t o circ u msta nces relate d t o t he 
C O VI D -1 9 pa n d e mic, gi v osira n ma y be a d mi nistere d b y t he patie nt or t he care gi v er u n der t he 
o versi g ht of t he I n vesti gat or, a n d f oll o wi n g c o ns ultati o n wit h t he me dical m o nit or, as all o we d b y 
a p plica ble c o u ntr y a n d l o cal re g ulati o ns.  I n s u c h cases, t he patie nt or care gi ver m ust recei ve 
a p pr o priate trai ni n g o n gi v osira n a d mi nistrati o n a n d t he use of e pi ne p hri ne (e pi pe n or e q ui val e nt) 
pri or t o d osi n g.  T his meas ure is i nte n de d t o r e mai n i n effect o nl y d uri n g p eri o ds of ti me w he n t he 
C O VI D -1 9 pa n d e mic i m pe des t he a bilit y of patie nts t o tra vel t o t he st u d y site or healt hcare 
pr ofessi o nals  t o g o t o patie nts' h o mes f or d osi n g.  H o we ver, st u d y dr u g a d mi nistrati o n at t he st u d y 
ce nter s h o ul d be c o nsi dere d f or patie nts w h o h a ve o n g oi n g st u d y dr u g -relat e d A Es or k n o w n ris k 
fact ors f or de vel o pi n g a n a p h yl actic reacti o ns, i ncl u di n g b ut n ot li mite d to:  pri or hist or y of a n 
a na p h ylactic reacti o n t o f o o d, me dicati o ns or d ue t o u n k n o w n eti ol o g y, w orse ni n g i njecti o n site 
reacti o ns wit h re p eat d osi n g, or a n y o ne i n t he o pi ni o n of t he i n vesti gat or t hat w o ul d be nefit fr o m 
cli nical o bser vati o n f oll o wi n g d osi n g . 
A L T a n d t otal bilir u bi n ( T B L) res ults c ollecte d wit hi n 6 wee ks of st u d y dr u g a d mi nistrati o n m ust 
be re vie we d pri or t o d osi n g.  I n t h e e ve nt t hat gi v osira n is a d mi nistere d offsite b y t he patie nt or 
care gi v er, safet y la b orat or y assess me nts ot her t ha n A L T a n d T B L m ust be o btai ne d fr o m a ce ntral 
or l ocal la b orat or y wit hi n 3 m o nt hs pri or t o d osi n g.  F or patie nts wit h ne w si g ns or s y m pt o ms, 
a p pr o priate e val uati o n, i ncl u di n g la b orat or y ass ess me nts, s h o ul d be perf or me d base d o n 
i n vesti gat or j u d g me nt pri or t o st u dy dr u g a d mi nistrati o n.  
If a patie nt d o es n ot recei ve a d ose of st u d y tr eat m e nt wit hi n t he s pecifie d d osi n g wi n d o w, t he 
I n v esti gat or s h o ul d c o ntact t he me dical m o nit or.  After s uc h c o ns ultati o n, t he d ose ma y be 
a d mi nistere d or will be c o nsi dere d misse d a n d n ot a d mi nistere d.  
Patie nts will be per mitte d t o miss o ne d ose of st u d y dr u g d uri n g t h e 6 -m o nt h treat me nt peri o d a n d 
o ne d ose wit hi n eac h 6 -m o nt h i nter val of t he O L E peri o d.  H o we v er, if a patie nt misses m ulti ple 
d oses, t he I n vesti gat or, i n c o ns ultati o n wit h t he me dical m o nit or, will disc uss w het her t he patie nt 
will be a ble t o c o nti n ue recei vi n g st u d y dr u g w hil e o n t he st u d y.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 2  
Detaile d i nstr ucti o ns f or st u d y dr u g a d mi nistrati o n are prese nte d i n t he P h ar mac y M a n ual.  I n 
a d diti o n, i nstr ucti o ns a n d pr oce d ures re l ate d t o a d mi nistrati o n of gi v osira n b y a p atie nt or 
care gi v er will be pr o vi de d i n t he Patie nt/ Care gi ver St ora ge a n d A d mi nistrati o n I nstr ucti o ns.  
6. 2. 2. 1.  
D uri n g t he 6 -M o nt h Tre at me nt Peri o d ( D a y 1 t o M o nt h 6)   
Patie nts will be a d mi nistere d gi v osira n 2. 5  m g/ k g or place b o as a n S C i njecti o n o nce a m o nt h.  
T o mai ntai n t he bli n d, t he s yri n ges are t o be mas k e d pri or t o st u d y dr u g wit h dra wal fr o m t he 
mas ke d vial.  At t he M o nt h 6 st u d y visit, f oll o wi n g t he c o m pleti o n o f all M o nt h 6 assess me nts, 
i ncl u di n g t he uri ne s a m ple f or A L A a n d P B G l e vels (t o e n d t he d o u ble-bli n d peri o d), patie nts will 
be a d mi nistere d t heir first o pe n -la bel ( u n mas k e d) d ose of gi v osira n t o be gi n t heir partici pati o n i n 
t he o pe n-la bel e xte nsi o n p orti on of t he st u d y.  
6. 2. 2. 2.  
D uri n g t he O pe n -L a bel E xte nsi o n Peri o d ( After M o nt h 6 t hr o u g h E n d of 
Tre at me nt)  
Patie nts w h o cr osse d o ver t o t he O L E peri o d pri or t o i m ple me ntati o n of a me n d me nt 3 (ie, u n der 
a me n d me nt versi o n 1 or 2) a n d are recei vi n g 2. 5  m g/ k g o nce m o nt hl y will re mai n o n t hat d ose.  
U p o n e ntr y t o t he O L E p eri o d u n der a me n d me nt versi o n 3, patie nts will cr oss o ver t o recei ve a 
1. 2 5 m g/ k g o nce m o nt hl y d ose of gi v osira n.  Aft er i m ple me ntati o n of a me n d me nt  3 a n d u ntil 
i m ple me ntati o n of a me n d me nt 5,  a d ose i ncrease t o 2. 5  m g/ k g o n ce m o nt hl y ma y be p er mitte d 
starti n g at M o nt h 1 3 f or patie nts recei vi n g 1. 2 5 m g/ k g o nce m o nt hl y (see S ecti o n  6. 2. 3. 4 ). 
U p o n i m ple m e ntati o n of a me n d me nt  5, all patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n o nce m o nt hl y 
w h o d o n ot ha ve o n g oi n g cli nicall y rele va nt tra nsa mi nase ele vati o ns will ha ve t heir d ose 
i ncreas e d t o 2. 5 m g/ k g gi v osira n o nce m o nt hl y per g ui da nce i n Secti o n  6. 2. 3. 4 . 
6. 2. 3.  
D ose M o dific ati o ns  
D uri n g t h e 6 -m o nt h d o u ble -bli n d treat me nt peri o d, n o  st u d y dr u g d ose m o dificati o ns will be 
all o we d, e x ce pt i n res p o nse t o L F T ele vati o n s as d escri be d i n Secti o n 6. 2. 3. 1 . 
D uri n g t h e o pe n -la b el e xte nsi o n peri o d, d osi n g m o dificati o ns will be all o we d u n der t he f oll o wi n g 
circ u msta nces:  
•  In res p o nse t o L F T ele v ati o ns  as descri be d i n Secti o n 6. 2. 3. 1  
•  After i m ple me ntati o n of a me n d me nt  3 a n d u ntil i m ple me ntati o n of a me n d me nt  5, 
patie nts assi g ne d t o t he o nce m o nt hl y 1. 2 5 -m g/ k g treat me nt gr o u p  w h o e x perie nce 
i na de q uate disease c o ntr ol ma y be all o we d t o ha ve t heir m o nt hl y d ose i n crease d t o 
2. 5  m g/ k g starti n g at M o nt h  1 3 ( w he n 6  m o nt hs of o pe n -la bel gi v osira n d osi n g ha ve 
bee n c o m plete d at 1. 2 5  m g/ k g) bas e d o n disc ussi o n a n d a gree me nt b y t he I n v esti gat or 
a n d me dical m o nit or, de m o nstrati o n of t olera bilit y gi v osira n, a n d f ulfill me nt of A L A 
a n d cli nical acti vit y criteria as descri be d i n Secti o n  6. 2. 3. 4 . 
•  U p o n i m ple me ntati o n of a me n d me nt  5, all patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n 
o nce m o nt hl y w h o d o n ot ha ve o n g oi n g cli nicall y rele va nt tra ns a mi nase ele vati o ns 
will ha ve t heir d ose i ncrease d t o 2. 5 m g/ k g gi v osira n o nce m o nt hl y base d o n 
t olera bilit y al o ne, wit h o ut a n y criteria f or A L A re d ucti o n or cli nical acti vit y.  See 
Secti o n  6. 2. 3. 4  for f urt her i nf or mati o n o n d ose escalati o n.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 3  
If a st u d y dr u g-relate d A E occ urs i n a p atie nt t hat t he I n v esti gat or j u d ges as prese nti n g a p ote ntial 
ris k t o t he patie nt f or f urt her d osi n g, t h e st u d y dr u g d ose m a y be hel d at t he discreti o n of t he 
I n v esti gat or an d t he me di cal m o nit or s h o ul d be c o ntacte d.  
6. 2. 3. 1.  
M o nit ori n g a n d D osi n g R ules B ase d o n Li ver F u ncti o n Test Res ults  
A L T a n d T B L res ults s h o ul d be re vie we d wit hi n 6 wee ks pri or t o d osi n g.  
F or a n y A L T ele v ati o n > 3 × U L N ( or > 3 × b aseli ne i n patie nts wit h ele vate d baseli ne) or > 3 0 0  U/ L 
( w hic he ver is l o wer), res ults s h o ul d be c o nfir me d b y t he ce ntral la b orat or y ( wit hi n 2 t o 3 da ys, 
b ut n o greater t h a n 7 da ys).  If s uc h A L T ele vati o ns are c o nfir me d, t he a d diti o nal he patic 
assess me nts  s h o w n i n Ta ble  5  s h o ul d be o btai ne d. 
S u bjects wit h a b n or mall y ele vate d h e patic la b orat or y v al ues (e g. A L T, A S T, T B L, or I N R) or 
si g ns/s y m pt o ms of he p atitis ma y meet criteria f or wit h h ol di n g st u d y dr u g.  Criteria f or 
wit h h ol di n g, m o nit ori n g a n d st o p pi n g st u d y dr u g d osi n g are detaile d i n  T a ble  4 : 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 4  
T a ble  4 : 
M o nit ori n g a n d D osi n g R ules i n P atie nts wit h Al a ni ne Tr a ns a mi n ase ( A L T) 
Ele v ati o ns  
A L T 
Tr a ns a mi n ase 
Le vel  
P ati e nts wit h N or m al B aseli ne 
A L T  
P ati e nts wit h Ele v ate d B aseli ne 
A L T a 
> 3 × t o 5 × U L N 
or B aseli ne  
•  Disc o nti n ue d osi n g w he n A L T 
is > 3 × U L N a n d p atie nt is 
s y m pt o maticb, or has T B L 
≥2 × U L N or I N R > 1. 5 (f or 
patie nts n ot o n warfari n), a n d 
t here is n o alter nati ve ca use 
•  Ot her wise, d osi n g ma y c o nti n ue 
wit h m o nit ori n g e ver y 2 wee ks 
( ± 7 da ys)c t hat i ncl u des L F Ts 
pe r Ta ble  7  a n d I N R  
•  If t he A L T ele vati o n persists f or 
≥2  m o nt hs, disc ussi o n wit h t he 
me dical m o nit or is re q uir e d 
bef ore c o nti n ui n g d osi n g.  
•  Disc o nti n ue d o si n g w he n A L T 
is > 3 × baseli ne or > 3 0 0 U/ L 
( w hic he ver is l o wer) a n d patie nt 
is s y m pt o maticb, or has T B L 
> 2 × U L N or I N R > 1. 5 (f or 
patie nts n ot o n warfari n), a n d 
t here is n o alter nati ve ca use 
•  Ot her wise, d osi n g ma y c o nti n ue 
wit h m o nit ori n g e ver y 2 wee ks 
( ± 7 da ys) d t hat i ncl u des L F Ts per 
Ta ble  7  a n d I N R.  
•  If t he A L T ele vati o n persists f or 
≥2 m o nt hs, disc ussi o n wit h t he 
me dical m o nit or is re q uir e d 
bef ore c o nt i n ui n g d osi n g. 
> 5 × t o 8 × U L N 
or B aseli ne  
•  Disc o nti n ue d osi n g w he n A L T 
> 5 × t o 8 × U L N a n d patie nt is 
s y m pt o maticb, or has T B L 
≥2 × U L N or I N R > 1. 5 (f or 
patie nts n ot o n warfari n) a n d 
t here is n o alter nati ve ca use  
•  F or patie nts w h o are 
as y m pt o matic a n d d o n ot ha ve 
I N R > 1. 5 or T B L ≥2 x U L N: 
− H ol d d osi n g if A L T > 5 × U L N, 
u ntil A L T rec o vers t o 
≤2 × U L N  
− D osi n g ca n be res u me d w he n 
A L T rec o v ers t o ≤2 x U L N 
acc or di n g t o Secti o n  6. 2. 3. 1. 1 , 
a n d f oll o wi n g disc ussi o n wit h 
t he me dical m o nit or 
•  Perf or m wee kl y ( ± 3 da ys) 
m o nit ori n g of L F Ts per  Ta ble  7  
a n d I N R u ntil A L T d ecli nes t o 
•  Disc o nti n ue d osi n g w he n A L T 
> 5 × t o 8 × bas eli ne or > 3 0 0  U/ L 
( w hic he ver is l o wer) a n d patie nt 
is s y m pt o maticb, or has T B L 
≥2 × U L N or I N R > 1. 5 (f or 
patie nts n ot o n warfari n) a n d 
t here is n o alter nati ve ca use 
•  F or patie nts w h o are 
as y m pt o matic a n d d o n ot ha ve 
I N R > 1. 5 or T B L ≥2 x U L N:  
− H ol d d osi n g if A L T 
> 5 × bas eli ne or > 3 0 0 U/ L 
( w hic he ver is l o wer), u ntil 
A L T rec o v ers t o ≤2 × b aseli ne  
− D osi n g ca n be res u me d w he n 
A L T rec o v ers t o ≤2 x baseli ne 
acc or di n g t o Secti o n  6. 2. 3. 1. 1 , 
a n d f oll o wi n g disc ussi o n wit h 
t he me dical m o nit or 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 5  
A L T 
Tr a ns a mi n ase 
Le vel  
P ati e nts wit h N or m al B aseli ne 
A L T  
P ati e nts wit h Ele v ate d B aseli ne 
A L T a 
≤3 × U L N ; t he n m o nit or e ver y 2 
wee ks ( ± 7 d a ys) u ntil A L T le vel 
reac h es 2 × U L Nc  
•  If t he A L T ele vati o n persists f or 
≥2  m o nt hs, disc ussi o n wit h t he 
me dical m o nit or is re q uir e d 
bef ore c o nti n ui n g d osi n g.  
•  Perf or m wee kl y ( ± 3 da ys) 
m o nit ori n g of L F Ts per  Ta ble  7  
a n d I N R u ntil A L T d ecli nes t o 
≤3 × baseli ne ; t he n m o nit or e ver y 
2 wee ks ( ± 7 d a ys) u ntil A L T 
le vel reac hes 2 × baseli ned 
•  If t he A L T ele vati o n persists f or 
≥2  m o nt hs, disc ussi o n wit h t he 
me dical m o nit or is re q uir e d 
bef ore c o nti n ui n g d osi n g.   
> 8 × U L N or 
B aseli ne  
Disc o nti n ue d osi n g after 
c o nfir mati o n if A L T > 8 × U L N  
Disc o nti n ue d osi n g after 
c o nfir mati o n if A L T > 8 × baseli ne or 
> 5 0 0 U/ L ( w hic he ver is l o wer)  
A b bre viati o ns:  A L T =ala ni ne a mi n otra nsferase; I N R =i nter nati o nal n or malize d rati o; L F T =li ve r f u ncti o n test(s); 
T B L =t otal bilir u bi n; U/ L = u nits per liter; U L N = u p per li mit of n or mal  
N ote:  I n a d diti o n t o t hese crit eria, ot her assess me nts or e val uati o ns ma y be perf or me d per I n vesti gat or discreti o n, as 
a p pr o priate. 
a If m ulti ple baseli ne A L T me as ure me nts are a vaila ble, baseli ne A L T will be defi ne d as t he a vera ge of t he 2 m ost 
rece nt A L T meas ure me nts pri or t o t he first d ose a d mi nistere d. 
b S y m pt o ms ma y i ncl u de na us ea, ri g ht u p per q ua dra nt pai n, j a u n dice, wit h n o k n o w n alter nati ve ca uses i de ntifie d b ut 
p ossi bl y ass ociate d wit h ( b ut n ot li mite d t o) s uc h ca uses as he pat o biliar y tract disease, viral he patitis, alc o h olic 
he p atitis, or n o n -alc o h olic steat o he p atitis ( N A S H).  A cli nical pict ure c o nsiste nt wit h dr u g -i n d uce d a ut oi m m u ne 
he p atitis, i ncl u di n g b ut n o t li mite d t o t he prese nce of ras h, fe ver, l y m p ha de n o pat h y a n d e osi n o p hilia i n a d diti o n t o 
ele vate d tra nsa mi nases ma y als o be a ca use f or c o nsi deri n g d osi n g disc o nti n uati o n.  
c T he fre q ue nc y of la b orat or y m o nit ori n g s h o ul d be decrease d fr o m e ver y 2 wee ks ( ± 7  da ys) t o m o nt hl y ( ± 7 da ys or 
d uri n g sc he d ule d st u d y visits) o nce A L T has decrease d t o ≤2 × U L N.  
d T he fre q ue nc y of la b orat or y m o nit ori n g s h o ul d be decrease d fr o m e ver y 2 wee ks ( ± 7 da ys) t o m o nt hl y ( ± 7 da ys or 
d uri n g sc he d ule d st u d y visits) o nce A L T has decrease d t o ≤2 × baseli ne.  
 
F or A L T, T B L, a n d I N R testi n g, l ocal la b orat or y res ults ma y be us e d t o i nf or m d osi n g decisi o ns; 
h o we ver, parallel sa m ples s h o ul d be c ollecte d f or a nal ysis at t he ce ntr al la b orat or y.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 6  
T a ble  5 : 
He p atic Assess me nts i n P ati e nts W h o E x perie nce Ele v ate d Tr a ns a mi n ases  
He m at ol o g y  
C B C wit h differe ntial  
 
E xte n de d He p atic P a nel  
Her pes Si m ple x Vir us 1 a n d 2 a nti b o d y I g M, I g G  
Her pes Z oster Vir us I g M, I g G  
HI V 1 a n d 2 a 
H H V -6  
C yt o me gal o vir us a nti b o dies, I g M, I g G  
H Bs A g, H Bc a nti b o d y I g M a n d I g G  
A nti -n uclear a nti b o dies  
E pstei n -Barr Vir us a nti b o dies, I g M a n d I g G  
A nti -s m o ot h m uscle a nti b o dies 
A nti -mit oc h o n drial a nti b o dies  
H C V a nti b o d y  
H A V a nti b o d y I g M  
H C V R N A P C R –  q ualitati ve a n d q ua ntitati v e 
H E V a nti b o d y I g M  
C P K  
 
I m a gi n g 
A b d o mi nal ultras o u n d wit h D o p pler fl o w ( or C T or M RI) i ncl u di n g ri g ht u p per q ua dra nt  
F oc use d Me dic al a n d Tr a vel Hist or y  
Use of a n y p ote ntiall y he pat ot o xic c o nc o mita nt 
me dicati o ns, i ncl u di n g o ver t he c o u nter me dicati o ns 
a n d her bal re me dies  
Alc o h ol c o ns u m pti o n  
Ot her p ote ntiall y he pat ot o xic a ge nts i ncl u di n g a n y 
w or k -relate d e x p os ures 
Rece nt tra vels t o areas w here he patitis A or E is 
e n de mic  
A b bre viati o ns:  A A T =al p ha -1 a ntitr y psi n; a nti -L K M =a nti -li ver-ki d ne y micr os o mal a nti b o dies; C B C =c o m plete bl o o d 
c o u nt; C P K =creati ne p h os p h o ki nase; C T =c o m p ute d t o m o gr a p h y; H A V = he patitis A vir us; H B c = he patitis B c ore; 
H Bs A g = he p atitis B vir us s urface a nti ge n; H C V = he patitis C vir us; H E V = he patitis E vir us; H H V -6 = h u ma n 
her pes vir us 6; HI V = h u ma n i m m u n o deficie nc y vir us; I g G =i m m u n o gl o b uli n G a nti b o d y; I g M =i m m u n o gl o b uli n M 
a nti b o d y; M RI = ma g netic res o na nce i ma ger y; P C R = p ol y merase c hai n reacti o n; P T = pr ot hr o m bi n ti me; 
R N A = ri b o n ucleic aci d; S L A =s ol u ble li ver a nti ge n; T S H =t h yr oi d-sti m ulati n g h or m o ne 
N ote:  
•  
All assess me nts will b e meas ure d i n ce ntral la b orat or y. T he f ull pa nel of assess me nts s h o ul d o nl y be perf or me d 
o nce; i n di vi d ual assess me nts ma y be re p eate d, as nee de d.  
•  
A d diti o nal sa m ples ma y be c ollecte d f or assess me nt of p ote ntial alter nati ve ca uses of li ver i nj ur y, w hic h ma y 
i ncl u de A A T, cer ul o plas mi n, aceta mi n o p he n/ paraceta m ol le vels, a nti-L K M a nti b o dies, t o xic ol o g y scree n, 
ferriti n, par v o vir us B 1 9, a nti-S L A a nti b o die s, ga m ma-gl o b uli ns (i ncl u di n g I g E a n d I g G l e vels), a n d tra nsferri n 
sat urati o n, as cli nicall y i n dicat e d.  
a  HI V testi n g will n ot b e perf or me d w here pr o hi bite d b y l ocal re g ulati o ns.  
6. 2. 3. 1. 1.  Criteri a f or R ec h alle n ge of Gi v osir a n After Bei n g Wit h hel d f or A L T Ele v ati o n  
F or patie nts i n w h o m gi v osira n d osi n g  is wit h hel d d ue t o ele vate d A L T, res u m pti o n of d osi n g 
ma y b e c o nsi dere d usi n g t he f oll o wi n g g ui deli nes:  
•  Patie nts w h o di d n ot meet criteria f or st u d y dr u g disc o nti n uati o n per Ta ble  4  ma y b e 
c o nsi dere d f or rec halle n ge f oll o wi n g c o ns ultati o n wit h t he me dical m o nit or a n d 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 7  
res ol uti o n of A L T t o ≤ 2 × U L N or ≤ 2 × baseli ne (f or patie nts w h o ha d ele vate d 
baseli ne A L T)  
•  T he decisi o n t o rec halle n ge t h e patie nt s h o ul d be disc usse d a n d a gree d u p o n b y t he 
patie nt, I n v esti gat or, a n d me dical m o nit or  
•  T he d ose re gi me n f or patie nts w h o meet rec halle n ge criteri a, re gar dless of t heir d ose at 
t he ti me of t he A L T ele v ati o n, is a d ose of eit her 1. 2 5 or 2. 5  m g/ k g m o nt hl y per 
I n v esti gat or j u d ge me nt a n d after disc ussi o n wit h t he me dical m o nit or: 
− L F Ts, I N R a n d T B L will be m o nit ore d e ver y 2 wee ks ( ± 7 da ys) f or t he first 
m o nt h, t he n m o nt hl y ( ± 7 da ys or d uri n g t he sc h e d ule d st u d y visits) as p er t he 
Sc he d ule of Assess me nts  
− La b orat or y m o nit ori n g a n d d osi n g r ules i n r es p o nse t o L F T ele vati o n will f oll o w 
Ta ble  4  g ui deli nes  
•  If d ose wit h h ol di n g r ules per Ta ble  4  are m et o n r ec halle n ge wit h t he 1. 2 5 -m g/ k g 
d ose, per ma n e ntl y disc o nti n ue d osi n g  
•  If a patie nt e x perie nces a sec o n d d ose h ol d d ue t o L F T ele vati o n w hile o n 2. 5  m g/ k g 
m o nt hl y:  
− F oll o w Ta ble  4  g ui deli nes f or m o nit ori n g a n d e val uati o ns  
− If A L T res ol ves t o ≤2 × U L N, re d osi n g wit h 1. 2 5 m g/ k g m o nt hl y ma y b e 
c o nsi dere d after disc ussi o n wit h t he Al n yla m me dical m o nit or.  If d osi n g is 
res u me d, f oll o w t he g ui d a nce a b o ve f or rec halle n ge re gi me n re gar di n g la b orat or y 
m o nit ori n g a n d d osi n g r ules.  N o s u bse q ue nt re -es calati o n t o 2. 5 m g/ k g m o nt hl y 
will b e all o we d.  
6. 2. 3. 2.  
M o nit ori n g a n d D osi n g R ules B ase d o n Li p ase a n d A m yl ase Res ults  
Li pas e a n d a m ylas e res ults s h o ul d be re vie we d pri or t o d osi n g.  
T he criteri a f or wit h h ol di n g, m o nit ori n g a n d st o p pi n g st u d y dr u g d osi n g base d o n li pase a n d 
a m ylas e res ults are detai l e d i n Ta ble  6 . 
T a ble  6 : 
M o nit ori n g a n d D osi n g R ules i n P atie nts wit h Li p ase or A m yl ase 
Ele v ati o ns  
H ol d F urt her 
D osi n g  
•  If a li pase or a m ylase ele vati o n > 3 × U L N ( or 3 × b aseli ne i n patie nts wit h 
ele vate d b aseli ne val ue) occ urs, wit h or wit h o ut cli nical s y m pt o ms, u ntil 
c o nfir mati o n fr o m t he ce ntral la b orat or y ( wit hi n 2 t o 3 da ys, b ut n o 
greater t ha n 7 da ys ).  
•  If t he ele v ate d li pase/a m yl ase is acc o m p a nie d b y cli nical s y m pt o ms 
c o nsiste nt wit h pa ncreatitis (e g, e pi gastric pai n, v o miti n g), d osi n g 
s h o ul d be hel d u ntil a n y a d diti o nal w or k-u p is c o m plete.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 8  
T a ble  6 : 
M o nit ori n g a n d D osi n g R ules i n P atie nts wit h Li p ase or A m yl ase 
Ele v ati o ns  
•  If t he ele v ati o n of eit her li pase or a m ylase is c o nfir me d, a n i ma gi n g 
e val uati o n s h o ul d be o btai ne d (e g, ri g ht u p p er q ua dra nt ultras o u n d 
a n d/ or ot her testi n g, base d o n I n v esti gat or j u d g m e nt).  
•  M o nit or li pase/a m ylas e e ver y 2 wee ks ( ± 7 da ys) u ntil t he ele vate d li pase 
a n d/ or a m yl ase v al ue decli nes t o < 3 × U L N.  
D osi n g M a y 
Res u me  
•  After c o ns ultati o n wit h t he me dical m o nit or a n d I n vesti gat or if t h e 
patie nt is as y m pt o matic a n d i ma gi n g st u dies d o n ot re veal he pat o biliar y 
or pa ncreatic a b n or malities.  
•  If a n alter nate eti ol o g y was i de ntifie d f or t he ele vati o ns a n d t he 
c o n diti o n has res ol ve d.  
•  M o nit or li pase/a m ylas e e ver y 2 wee ks ( ± 7 da ys) u ntil t he val ue decli nes 
t o < 3× U L N.  
Per m a ne ntl y 
Disc o nti n ue 
D osi n g  
•  If t he patie nt is dia g n ose d wit h ac ute pa n creatitis wit h n o k n o w n 
alter nate eti ol o g y (e g, ac ute gallst o nes)  
•  If t he patie nt e xperie n ces persiste nt li pase a n d a m yl ase ele vati o ns 
> 3 × U L N f or > 2 m o nt hs wit h o ut peri o ds of rec o v er y t o < 3 × U L N  
A b bre viati o ns: U L N = u p per li mit of n or mal  
F or li pase a n d a m ylase testi n g, l ocal la b orat or y res ults ma y be use d t o i nf or m d osi n g decisi o ns; 
h o we ver, parallel sa m ples s h o ul d be c ollecte d f or a nal ysis at t he ce ntr al la b orat or y.  
Li pas e a n d a m ylas e testi n g a n d i ma gi n g e val uati o ns s h o ul d als o be c o nsi d ere d at a n y p oi nt i n t he 
st u d y if a p atie nt e x perie nces u nc haracteristic si g ns a n d s y m pt o ms d uri n g p or p h yri a attac ks a n d 
t here is cli nical s us pici o n of pa ncreatitis. 
6. 2. 3. 3.  
M o nit ori n g a n d D osi n g R ules i n P atie nts wit h P ote nti al C ases of A n a p h yl actic 
Re acti o n  
A n a na p h ylactic reacti o n is a se vere, p ote ntiall y fatal, s yste mic aller gic reacti o n wit h ac ute o nset 
( mi n utes t o h o urs).  F or refere nce see Secti o n 1 1. 2  (2 8 ). 
St o p a d mi niste ri n g t he st u d y me dic ati o n i m me di atel y  if a n a na p h ylactic reacti o n t o t he st u d y 
me dicati o n is s us pecte d.  St u d y m e dicati o n m ust be per ma n e ntl y disc o nti n u e d i n patie nts f or 
w h o m a n a na p h yla ctic reacti o n is assesse d as relat e d t o t he st u d y me dicati o n.  
L a b or at or y testi n g:  O bt ai n bl o o d sa m ple f or tr y ptase, t otal I g E, a n d A D A  a nti dr u g a nti b o dies 
( A D A) i deall y wit hi n 1 5 mi n utes t o 3 h o urs after t he o nset of a s us pecte d a na p h yl actic reacti o n; 
h o we ver, u p t o 6 h o urs is acce pta ble.  A n a d diti o nal bl o o d sa m ple t o asse ss tr y ptas e, t otal I g E, 
a n d A D A s h o ul d be o btai ne d bet wee n 1 t o 2 wee ks fr o m o nset of e v e nt.  L ocal la b orat or y ma y be 
use d t o a nal yze s a m ples; h o we ver, parallel sa m ples s h o ul d be se nt t o t he ce ntral la b orat or y f or 
a nal ysis.  Sa m ple c ollecti o n a n d s hi p pi n g i nstr ucti o ns are i ncl u de d i n t he La b orat or y Ma n ual.   


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5 9  
Re p orti n g : T he PI or desi g nee m ust n otif y t he s p o ns or or desi g nee wit hi n 2 4 h o urs of t he 
occ urre nce of a s us pe cte d case of a na p h ylactic reacti o n or bei n g i nf or me d of t he c as e as re q uire d 
f or A Es of Cli nical I nterest ( A E CI) a n d S A Es, per A E re p orti n g re q uire me nts ( Secti o n  7. 5. 6. 1  
t hr o u g h Secti o n 7. 5. 6. 3 ).   
6. 2. 3. 4.  
D ose Esc al ati o n G ui d a nce f or Gi v osir a n fr o m 1. 2 5 m g/ k g O nce M o nt hl y t o 
2. 5  m g/ k g O nce M o nt hl y i n t he O pe n -L a bel Peri o d  
After i m ple me ntati o n of a me n d me nt  3 a n d u ntil i m ple me ntati o n of a me n d me nt  5, patie nts 
assi g ne d t o t he o n ce m o nt hl y 1. 2 5 -m g/ k g treat me nt gr o u p ma y b e all o we d t o ha ve t heir m o nt hl y 
d ose i ncrease d t o 2. 5  m g/ k g starti n g at t he M o nt h 1 3 St u d y Visit ( w he n 6 m o nt hs of o pe n-la bel 
gi v osira n d osi n g ha v e b ee n c o m plete d  at 1. 2 5 m g/ k g ), b ase d o n disc ussi o n a n d a gree me nt b y t he 
I n v esti gat or a n d me dical m o nit or.  D ose escalati o n ma y b e c o nsi dere d if t he f oll o wi n g criteria are 
met:  
•  T olera bilit y t o gi v osira n at 1. 2 5 m g/ k g o nce m o nt hl y has b ee n de m o nstrat e d base d  o n 
n o d ose i nterr u pti o ns d ue t o L F T ele vati o ns at t he 1. 2 5  m g/ k g o nce m o nt hl y d ose le vel 
(see Secti o n 6. 2. 3. 1 ) a n d n o si g nifica nt safet y c o n cer ns d ue t o ot her A Es t h at w o ul d 
precl u de a patie nt fr o m recei vi n g a hi g her d ose of gi v osira n as j u d ge d b y t he  
I n v esti gat or a n d S p o ns or.   
•  Uri ne A L A le v els ( m m ol/ m ol Cr) are n ot sta bl y m ai ntai ne d ≤U L N or are i n d uci ble  
•  Patie nt has i na de q uate cli nical res p o nse (e g, brea kt hr o u g h attac ks or o n g oi n g c hr o nic 
s y m pt o ms), acc or di n g t o I n v esti gat or j u d ge me nt. 
U p o n i m ple me ntati o n of a me n d me nt  5, all patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n o nce m o nt hl y 
w h o d o n ot ha ve o n g oi n g cli nicall y rele va nt tra nsa mi nase ele vati o ns wi ll ha ve t heir d ose 
i ncreas e d t o 2. 5 m g/ k g gi v osira n o nce m o nt hl y base d o n t olera bilit y al o ne, wit h o ut a n y criteria 
f or A L A re d ucti o n or cli nical acti vit y.  D ose i ncreases s h o ul d ta ke effect as of t he date t hat 
s ufficie nt st u d y dr u g mat erial ca n b e ma de a vaila ble f or t he patie nt. 
6. 2. 4.  
Pre p ar ati o n, H a n dli n g, a n d St or a ge  
St u d y dr u g will be st ore d u pri g ht a n d refri gerat e d at a p pr o xi matel y 2 t o 8° C.   
Staff at eac h cli nical st u d y ce nter, or t he h o me healt hcare pr ofessi o nal, will be res p o nsi ble f or 
pre parati o n of gi v o sira n d oses, acc or di n g t o pr oce d ures detaile d i n t he P har mac y Ma n ual.  I n 
cases w h ere gi v osira n is a d mi nistere d at h o me b y a patie nt/care gi ver, d osi n g ma y b e pre p are d a n d 
a d mi nistere d b y t he patie nt/care gi ver acc or di n g t o pr oce d ures detaile d i n t h e Patie nt / Care gi ver 
St ora ge a n d A d mi nistrati o n I nstr u cti o ns.  N o s pecial pr oce d ures f or t he s afe ha n dli n g of st u d y 
dr u g are re q uir e d.  
A S p o ns or re pres e ntati ve or desi g n ee will be p er mitte d, u p o n re q uest, t o a u dit t he s u p plies, 
st ora ge met h o ds, dis pe nsi n g pr oce d ures, a n d rec or ds. 
A d diti o nal st ora ge a n d pre parati o n det ails are pr o vi de d i n t he P har mac y Ma n ual a n d t he 
Patie nt/ Care gi v er St ora ge a n d A d mi nistrati o n I nstr ucti o ns.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 0  
6. 2. 5.  
P ac k a gi n g a n d L a beli n g  
All pac ka gi n g, la beli n g, a n d pr o d ucti o n of st u d y dr u g will be i n c o m plia nce wit h c urre nt G o o d 
Ma n ufact uri n g Practice s pecificati o ns, as w ell as a p plica ble l ocal r e g ulati o ns.  St u d y dr u g la bels 
a n d e xter nal pac k a gi n g will i ncl u de all a p pr o priate i nf or mati o n as per l o cal la beli n g re q uire me nts.  
A d diti o nal details will be a vaila b le i n t he P har mac y Ma n u al. 
6. 2. 6.  
Acc o u nt a bilit y  
T he I n vesti gat or or d esi g nee will mai ntai n acc urat e rec or ds of recei pt a n d t he c o n diti o n of t he 
st u d y dr u g s u p plie d f or t his st u d y, i n cl u di n g d ates of recei pt.  I n a d diti o n, acc urat e rec or ds will be 
ke pt of w he n a n d h o w m uc h st u d y dr u g is dis pe ns e d a n d a d mi nistere d t o eac h patie nt i n t he st u d y.  
A n y reas o ns f or de p art ure fr o m t he pr ot oc ol dis pe nsi n g re gi me n m ust als o be rec or de d.  
At t he c o m pleti o n of t he st u d y, t here will be a fi nal rec o nciliati o n of all st u d y dr u gs .  All use d, 
partiall y us e d, a n d u n use d st u d y dr u g will be ret ur ne d t o t he S p o ns or ( or desi g nee) or destr o ye d at 
t he cli nical st u d y ce nter acc or di n g t o a p plica bl e re g ulati o ns.   
F urt her i nstr u cti o ns a b o ut dr u g acc o u nta bilit y are detaile d i n t he P har mac y Ma n ual.  
6. 3.  
C o nc o mit a nt Me dic ati o ns  
Use of c o n c o mita nt me dicati o ns will be rec or de d o n t he patie nt’s electr o nic case re p ort f or m 
(e C R F) or electr o ni c diar y as i n dicate d i n t he Sc he d ules of Assess me nts (Ta ble  1 , Ta ble  2 , a n d 
Ta ble  3 ).  T his i ncl u des all prescri pti o n me dicati o ns, her bal pre parati o ns, o ver-t he-c o u nter ( O T C) 
me dicati o ns, vita mi ns, a n d mi nerals.  A n y c ha n ges i n me dicati o ns d uri n g t h e st u d y will als o be 
rec or de d o n t he e C R F. 
A n y c o nc o mita nt me dicati o n t hat is re q uire d f or t he patie nt’s welf are ma y be a d mi nistere d b y t he 
I n v esti gat or.  H o w e ver, it is t he res p o nsi bilit y of t he I n vesti gat or t o e ns ure t hat details re gar di n g 
t he me dicati o n are rec or de d o n t he e C R F.  Patie nts s h o ul d n ot start ne w me dicati o n re gi me ns 
d uri n g t he st u d y, i ncl u di n g re gi me ns of vita mi ns or her bal me di cati o ns, wit h o ut c o ns ultati o n wit h 
t he I n v esti gat or.  
P or p h yria attac ks ma y b e treate d acc or di n g t o l ocal sta n dar d of care w hic h var y b y re gi o n b ut ca n 
i ncl u de, b ut n ot li mite d t o, car b o h y drate l oa di n g, oral or I V gl u c ose, oral or I V a n al gesics, oral 
ci meti di ne, a n d I V he mi n. Use of t hese m e dicati o ns is per mi tte d at a n y p oi nt i n t he st u d y (e x ce pt 
re g ularl y sc h e d ule d he mi n f or pr o p h yla xis), base d o n cli nical j u d g me nt.  All treat me nts recei ve d 
f or p or p h yria attac ks i ncl u di n g a n y h e mi n use will be ca pt ur e d i n t he c o nc o mita nt me dicati o ns 
e C R F.   
Patie nts wit h p or p h yria c o ul d ha ve altere d he patic he me s y nt h esis, a n d treat me nt wit h gi v osira n 
c o ul d als o m o d ulate t his pat h wa y a n d s ec o n daril y i m pact C Y P e nz y m e acti vit y.  Res ults fr o m a 
D DI st u d y i n AI P p atie nts w h o are C H E are prese nte d i n Secti o n  1. 2. 2. 3 .  T he D DI st u d y 
de m o nstrate d t hat gi v osira n treat me nt r es ulte d i n wea k t o m o derate re d ucti o n i n acti vit y of s o me 
of t he C Y P e nz y mes res ulti n g i n c orres p o n di n g l o w t o m o derate i ncreas e i n t he plas ma le vels of 
dr u gs t hat are met a b olize d b y t hes e C Y P e nz y mes.  Base d o n t h e m o derat e decrease i n C Y P 2 D 6 
or C Y P 1 A 2 acti vit y, i n vesti gat ors will re vie w all c o nc o mita nt me dicati o ns t hat are pri maril y 
meta b olize d b y t hese e nz y m es a n d m o nit or t he patie nt's cli nical res p o nse t o t hese me dicati o ns 
d uri n g t he st u d y.  Me dic ati o ns meta b olize d pri maril y b y C Y P 2 D 6 a n d C Y P 1 A 2 wit h a narr o w 
t hera pe utic i n de x (ie, t hat re q uire re g ular l a b orat or y m o nit ori n g) ma y nee d t o be m o nit ore d m ore 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 1  
fre q ue ntl y t o deter mi ne if a d ose a dj ust me nt of t h e c o nc o mita nt me dicati o n is re q uire d.  F or 
patie nts w h o re q uire n e w me dicati o ns w hile o n st u d y, selecti o n of me dicati o ns t hat are n ot 
pri maril y met a b olize d b y C Y P 2 D 6 or C Y P 1 A 2 s h o ul d be c o nsi dere d.  Refer t o t he i n di vi d ual 
pr o d uct’s pres cri pti o n i nf or mati o n t o deter mi ne if t here is a nee d t o m o nit or c o nc o mita nt 
me dicati o ns f or differe n ces i n safet y or efficac y of t he me dicati o n base d o n re p orte d D DIs wit h 
C Y P 2 D 6 or C Y P 1 A 2.  F or m ore detaile d a n d u p -t o-date i nf or mati o n o n C Y P s u bstrates, see:  
htt ps:// w w w.f da. g o v/ dr u gs/ de vel o p me nt a p pr o val pr ocess/ de vel o p me ntres o urces/ dr u gi nteracti o nsl
a beli n g/ u c m 0 9 3 6 6 4. ht m.  
Sta n dar d vita mi ns (i ncl u di n g vita mi n B 6 s u p ple m e ntati o n, see Secti o n  6. 3. 4 ) a n d t o pical 
me dicati o ns are p er mitte d; h o we ver, t o pical ster oi ds m ust n ot be a p plie d a n y w h ere n ear t h e 
i njecti o n site(s) u nless me dicall y i n dicate d. 
6. 3. 1.  
He mi n Pr o p h yl a xis  
I n p atie nts w h o were on re g ul arl y sc he d ul e d he mi n pr o p h yl a xis pri or t o t he st u d y, c ollecti o n of 
uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A assess me nts d uri n g Scree ni n g m ust occ ur 
≥4  da ys after pr o p h yl acti c he mi n disc o nti n uati o n.  
Use of he mi n f or t h e treat me nt of ac ute or o n g oi n g p or p h yri a attac ks is all o we d d uri n g t he st u d y 
a n d s h o ul d be rec or de d as a c o nc o mita nt me dicati o n i n t he e C R F. If he mi n is use d f or p or p h yria 
attac ks, sc he d ul e d uri ne s a m ples f or A L A, P B G a n d A L A S 1 m R N A assess me nts will be c ollecte d 
4 da ys ( wit h a wi n d o w  of u p t o 8 da ys [ + 4 da ys]) after t he patie nt’s l ast he mi n d ose.   
W here a p plica ble c o u ntr y a n d l o cal re g ul ati o ns a n d i nfrastr uct ur e all o w, Scree ni n g a n d o n -st u d y 
uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A assess me nts ma y be c ollecte d b y a h o me 
healt hcare pr ofessi o nal, s e nt t o t he st u d y ce nter b y mail, or br o u g ht t o t he st u d y ce nter at t he ne xt 
visit.  
6. 3. 2.  
G o n a d otr o pi n -Rele asi n g H or m o n e A n al o g ue Tre at me nt  
If, at t he ti me of Scree ni n g, patie nts are recei vi n g treat me nt wit h a g o na d otr o pi n-releasi n g 
h or m o ne ( G n R H) a nal o g ue t o pre ve nt attac ks, t he y ma y e nr oll i n t he st u d y if t he y meet t he 
i ncl usi o n criteria f or p or p h yria attac ks ( Secti o n 5. 1 ) a n d a gree t o r e mai n o n G n R H treat me nt 
t hr o u g h o ut t he 6-m o nt h treat me nt peri o d.  At t he discreti o n of t he i n vesti gat or, G n R H a nal o g u es 
ma y b e disc o nti n ue d aft er patie nts ha ve c o m plete d t he 6 -m o nt h treat me nt peri o d, if cli nicall y 
i n dicate d. 
T he i nitiati o n of treat me nt wit h G n R H a nal o g u es d uri n g t he 6 -m o nt h treat me nt peri o d is 
disc o ura ge d.   
6. 3. 3.  
A n al gesic Us a ge  
A nal gesic me dicati o ns, i ncl u di n g o pi oi ds (s y nt hetic a n d n o n -s y nt hetic s u bsta nces [ narc otics]) or 
n o n -ster oi d a nti-i nfla m m at or y m e dicati o ns ( N S AI Ds) are per mitte d f or t h e ma na ge me nt of 
p or p h yri a a n d f or p or p h yria attac ks, b ase d o n cli ni cal j u d g m e nt.  All a nal gesia usa ge as ta k e n b y 
t he patie nt at h o me will be ca pt ur e d b y t he patie nt or care gi ver via t h e e Diar y usi n g dail y 
q uesti o ns o n t he t y p e, d ose, a n d fre q ue nc y of a n al gesic us e t hr o u g h M o nt h 1 2 of t he st u d y.  
A d diti o nal me dicati o ns, i ncl u di n g a n al gesics, ta ke n at a healt hcare facilit y (e g, d uri n g a n attac k) 
will be ca pt ure d i n c o n c o mita nt me dicati o ns e C R F.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 2  
After M o nt h 1 2, usa ge of a n y a nal gesic m e dicati o ns will be rec or de d i n t he c o nc o mita nt 
me dicati o ns e C R F, al o n g wit h all ot her me dicati o ns use d.  
F or patie nts bei n g tr eate d wit h re g ular o pi oi d a nal gesics b et wee n attac ks, if t he I n v esti gat or ( or a 
treati n g p ai n s peci alist) deter mi nes t hat a re d ucti o n of t he o pi oi d d ose is cli nicall y i n dicat e d, 
c o u ntr y s p ecific g ui d a nce o n o pi oi d ta peri n g s h o ul d be f oll o we d a n d c o ns ultati o n wit h a pai n 
s pecialist s h o ul d be c o nsi dere d.  A d ecrease of ≤1 0 % per wee k is c o nsiste nt wit h c urre nt 
g ui da n ce.  G ui da n ce  o n o pi oi d ta peri n g ma y b e f o u n d at: 
htt ps:// w w w.c dc. g o v/ dr u g o ver d ose/ p df/cli nical _ p oc ket _ g ui de _ta peri n g -a. p df.  
If patie nts use N S AI Ds i nter mitte ntl y or c hr o nicall y, t he y m ust be a ble t o t olerate t he m a n d ha ve 
ha d n o pre vi o us si de effects (e g, gastric dis tr ess or blee di n g).   
6. 3. 4.  
Vit a mi n B 6 S u p ple me nt ati o n  
D uri n g tr eat me nt wit h gi v osira n, bl o o d h o m oc yst ei ne le vels ma y s h o w a n i ncreas e c o m pare d t o 
le vels bef ore treat me nt.  Bl o o d h o m oc ystei ne le vels will be assesse d as i n dicate d i n t he Sc he d ul e 
of Assess me nts ( Ta ble  1 , Ta ble  2 , a n d T a ble  3) .  It is rec o m me n de d t hat p atie nts wit h i ncrease d 
bl o o d h o m oc ystei ne le v els recei ve a s u p ple me nt c o ntai ni n g vita mi n B 6 .  All vita mi n s u p ple me nts 
s h o ul d be rec or de d o n t h e c o nc o mita nt me dicati o ns e C R F. 
6. 4.  
C o ntr ace pti ve Re q uire me nts  
N o data are a v aila ble o n t he use of gi v osira n i n pr e g n a nc y; h o w e ver, t here is n o s us pici o n of 
h u ma n terat o ge nicit y bas e d o n class effects or ge n ot o xic p ote ntial.  Gi v osira n was neit her 
ge n ot o xic n or clast o ge ni c i n i n vitr o a n d i n vi v o st u dies.   
W o me n of c hil d -beari n g p ote ntial m ust be willi n g t o use acce pta ble met h o ds of c o ntrace pti o n 
fr o m 1 4 da ys bef ore t he first d ose, t hr o u g h o ut st u d y partici pati o n, i ncl u di n g t he 6-m o nt h d o u ble 
bli n d treat me nt peri o d a n d e xte nsi o n peri o d t hr o u g h t he E n d of St u d y visit or  Safet y F oll o w -u p 
visit, if t he patie nt disc o nti n ues t he st u d y pri or t o its c o m pleti o n.   
Birt h c o ntr ol met h o ds w hic h are c o nsi dere d acce pta ble i ncl u de:  
•  Place me nt of a n i ntra uteri ne de vice  
•  Bilateral t u bal occl usi o n  
•  S ur gical steriliz ati o n of male part ner ( wit h t he a p pr o priate p ost -vas ect o m y 
d oc u me ntati o n of t he a bs e nce of s per m i n t he ejac ulate; f or fe m ale patie nts o n t he 
st u d y, t he vas ect o miz e d male part ner s h o ul d be t he s ole part ner f or t hat p atie nt).  
•  Esta blis he d use of oral, i m pla nta ble, i njecta ble, tr a ns der mal h or m o nal, or i ntra uteri ne 
h or m o ne -rel easi n g s yste m as met h o ds of c o ntrace pti o n:  W o me n of c hil d-beari n g 
p ote ntial usi n g h or m o nal met h o ds of c o ntrace pti o n m ust als o use a barrier met h o d 
(c o n d o m or occl usi ve ca p [ dia p hra g m or cer vi cal/ va ult ca p] i n c o nj u ncti o n wit h 
s per mici de [e g, f oa m, gel, fil m, crea m, or s u p p osit or y]).  See Secti o n  6. 3 .  
•  If h or m o nal met h o ds of c o ntrace pti o n are me dicall y c o ntrai n dicate d d ue t o u n derl yi n g 
disease, a d o u ble -barrier met h o d (c o m bi nati o n of male c o n d o m wit h ca p, dia p hra g m, 
or s p o n ge, i n c o nj u ncti o n wit h s per mici de) is als o c o nsi dere d a n acce pta ble met h o d of 
c o ntrace pti o n.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 3  
•  Se x ual a bsti ne nce, w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yle of t he 
patie nt, is c o nsi dere d a n acce pta ble met h o d o nl y if defi ne d as refrai ni n g fr o m 
heter ose x ual i nterc o urs e d uri n g t he e ntire peri o d of ris k ass ociate d wit h t he st u d y dr u g 
( defi ne d a b o ve).  Peri o dic a bsti ne nce (e g, cale n dar, o v ulati o n, s y m pt ot her mal, p ost -
o v ulati o n met h o ds) a n d wit h dra wal are n ot c o nsi dere d se x ual a bsti ne nce a n d d o n ot 
meet criteria f or a n acce pta ble met h o d of birt h c o ntr ol.  As deter mi ne d b y t he 
i n vesti gat or, t he relia bilit y of se x ual a bsti ne nce nee ds t o be e val uat e d i n rel ati o n t o t he 
d urati o n of t he cli nical tri al a n d t he preferre d a n d us ual lifest yle of t he pati e nt.  
A bsti ne nt patie nts m ust a gree t o use 1 of t he a b o v e me nti o ne d c o ntrace pti v e met h o ds if 
t he y start a heter ose x ual relati o ns hi p d uri n g t he st u d y a n d c o nti n ue t o d o s o f or t he 
e ntire peri o d of ris k ass o ciate d wit h t he st u d y dr u g ( defi ne d a b o ve).  
•  W o me n of c hil d -beari n g p ote ntial i ncl u de a n y fe m ale patie nts w h o ha v e e x perie nce d 
me narc h e ( or b e gi n me narc he o ver t he c o urse of t h e st u d y) a n d w h o are n ot 
p ost me n o pa usal or per m a ne ntl y steriliz e d (e g, bilateral t u bal occl usi o n, h ysterect o m y, 
or bilateral sal pi n gect o m y).  A p ost me n o pa usal st ate is defi ne d as t he a bse nce of 
me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me di cal ca us e, c o nfir m e d b y a f o llicle 
sti m ulati n g h or m o ne le vel wit hi n t he p ost me n o pa usal ra n ge. 
F or male p atie nts, n o c o ntrace pti o n is re q uir e d.  
C o m plia nce wit h c o ntrace pti o n re q uire me nts will be assesse d o n a re g ul ar basis b y t he 
I n v esti gat or t hr o u g h o ut t he c o urse of t he st u d y.  
6. 5.  
Tre at me nt C o m pli a nce  
C o m plia nce wit h st u d y dr u g a d mi nistrati o n will be m o nit ore d b y st u d y staff or trai ne d h o me 
healt hcare pr ofessi o nals.  
7.  
S T U D Y A S S E S S M E N T S  
T he sc he d ule of st u d y assess me nts is pr o vi de d i n Ta ble  1  ( Scree ni n g a n d 6-M o nt h Treat me nt 
Peri o d),  Ta ble  2  ( O pe n-l a bel E xte nsi o n St u d y:  After M o nt h 6 t hr o u g h M o nt h 1 8), a n d Ta ble  3  
( O pe n-la b el E xte nsi o n St u d y:  M o nt h 1 9 t hr o u g h E O S).  
W here a p plica ble c o u ntr y a n d l o cal re g ul ati o ns a n d i nfrastr uct ur e all o w f or h o me healt hcare, 
healt hcare ma y ta k e place at a l ocati o n ot her t ha n t he cli nical trial site t o perf or m st u d y 
assess me nts i ncl u di n g tar get e d p h ysical e xa m/ b o d y s yste m assess me nt, assess me nts f or vital 
si g ns, a n d c ollecti o n of bl o o d a n d uri ne sa m ples f or safet y la b orat or y ass ess me nts, a n d P D 
assess me nts, at all ti me p oi nts as s pecifie d i n t he Sc he d ule of Ass ess me nts.  
7. 1.  
Scree ni n g Assess me nts  
A n i n f or me d c o ns e nt f or m (I C F), a n d asse nt f or m if a p plica ble, t hat has b ee n a p pr o ve d b y t h e 
a p pr o priate I nstit uti o nal Re vie w B o ar d (I R B)/I n d e pe n de nt Et hics C o m mittee (I E C) m ust be 
si g ne d b y t he p atie nt ( or le gal g u ar dia n) bef ore t h e Scree ni n g pr oce d ures are i n itiate d.  All 
patie nts ( or t heir le gal g u ar dia ns) will be gi ve n a c o p y of t h e si g n e d a n d dat e d I C F a n d/ or asse nt 
f or m. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 4  
Patie nt de m o gra p hic a n d me dical hist or y/ disease hist or y will be o btai ne d at Scree ni n g.  Patie nts 
will be scree n e d t o e ns ure t hat t he y mee t all t he i n cl usi o n criteria a n d n o n e of t he e x cl usi o n 
criteria ( Secti o n  5. 1  a n d Secti o n  5. 2 , res pecti vel y).  If re q uir e d, A L A/ P B G le vels c ollecte d d uri n g 
t he scree ni n g p eri o d f or eli gi bilit y p ur p oses s h o ul d be a nal yz e d l ocall y.  Me dical hist or y c ollecte d 
will i nc or p orate t he p atie nt’s p or p h yri a  hist or y, i ncl u di n g t heir t y pical attac k c haracteristics, 
tri g gers, a n d treat me nt, as well as ce ntr al ve n o us access hist or y, ir o n o verl oa d hist or y, a n d pri or 
li ver disease hist or y. 
A n y pre vi o us partici pati o n i n a ge ne t hera p y st u d y or ot her p or p h yri a st u d y  s h o ul d be n ote d i n t he 
e C R F.  
I n p atie nts w h o were o n he mi n pr o p h yla xis pri or t o t he st u d y, uri nar y sa m ples f or A L A, P B G, 
a n d A L A S 1 m R N A m ust be c ollecte d w he n t he patie nt is n ot ha vi n g a n attac k a n d at least 4 da ys 
after pr o p h yl actic he mi n disc o nti n uati o n a n d after t he patie nt’s last he mi n d ose.  T w o Scree ni n g 
uri ne sa m ples f or A L A a n d P B G s h o ul d be c ollect e d o n a n y 2 differe nt da ys (ca n be c o nsec uti ve 
da ys) d uri n g t he Scree ni n g peri o d; o ne Scree ni n g uri ne sa m ple s h o ul d be c ollecte d f or A L A S 1 
m R N A. W here a p plica bl e c o u ntr y a n d l ocal re g ul ati o ns a n d i nfrastr uct ure all o w, t hese sa m ples 
ma y b e c ollecte d b y a h o me healt hcare pr ofessi o n al, se nt t o t he st u d y ce nter b y mail, or br o u g ht 
t o t he st u d y ce nt er at t he ne xt visit.  Patie nts will be trai ne d o n at-h o me sa m ple c ollecti o n, 
st ora ge, a n d h a n dli n g.  
7. 1. 1.  
Retesti n g  
If, i n t he I n vesti gat or’s j u d g me nt, la b a b n or malities are li kel y t o be tra nsi e nt, la b orat or y tests ca n 
be re peate d.  I N R a n d ot her la b orat or y val ues ca n be reteste d d uri n g Scree ni n g as l o n g as t he 
patie nt ca n be e val uate d f or eli gi bilit y a n d ra n d o mize d wit hi n t he all o we d Scree ni n g p eri o d.  
7. 1. 2.  
Rescree ni n g  
A patie nt w h o d oes n ot meet all st u d y eli gi bilit y criteria d u e t o a tra nsie nt c o n diti o n o bser ve d at 
Scree ni n g (e g, pr o hi bite d me dicati o ns t hat were s u bse q ue ntl y disc o nti n ue d, varia bilit y i n A L T 
meas ure me nts) will be all o we d t o ret ur n f or res cree ni n g.  
A patie nt will be re -c o ns e nte d if res cree ni n g occ urs o utsi de of t he 6 0 -da y s cree ni n g wi n d o w. I n 
t his case, all scree ni n g pr oce d ures m ust be re peate d.  
7. 2.  
Effic ac y Ass ess me nts 
T he cli nical efficac y of gi v osira n will be assesse d b y t he fre q u e nc y a n d c haracteristics of 
p or p h yri a attac ks, as des cri be d i n Secti o ns  3. 1  a n d 3. 2 .  
7. 2. 1.  
P or p h yri a Att ac k Re p o rti n g  
P or p h yria attac ks are d efi ne d i n Secti o n  3. 5 .  Patie nts or care gi vers will re p ort p ote ntial p or p h yri a 
attac ks w he n t he y o cc ur t hr o u g h o ut t he d urati o n of t he st u d y ( Scree ni n g t hr o u g h t he E O S visit).  
If a patie nt e x perie nces a p ote ntial p or p h yri a attac k, t he patie nt or desi g nat e d care gi ver s h o ul d 
n otif y t he st u d y staff vi a t he e Diar y ( Secti o n  4. 6 ).  U n der cir c u msta nces i n w hic h t he e Diar y 
ca n n ot be use d t o rec or d a p ote ntial p or p h yria attac k, patie nts, care gi vers, or treati n g p h ysicia ns 
s h o ul d n otif y t he st u d y ce nter directl y.  I n s o me i nsta nces, t he site ma y be n otifie d of p ote ntial 
p or p h yri a attac ks b y h ealt hcare pr o vi ders n ot parti ci pati n g i n t he st u d y.   T h e st u d y ce nter will 
c o ntact t he patie nt/care gi ver or t he treati n g p h ysicia n t o deter mi ne if a p ote ntial p or p h yri a attac k 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 5  
has occ urre d; e v e nts t hat are n ot c o nfir me d as p or p h yria attac ks s h o ul d be re p orte d as A Es or 
S A Es, as defi ne d i n Secti o n  7. 5. 6 .  All rele va nt cli nical i nf or mati o n pertai ni n g t o t he e v e nt s h o ul d 
be o btai ne d, i ncl u di n g la b orat or y val ues, me di cal rec or ds, disc h ar ge s u m maries a n d m e di cal test 
res ults. 
7. 2. 2.  
P ai n a n d P ai n -Rel at e d Assess me nts  
Patie nts or care gi v ers will rec or d a nal gesic us a ge  a n d pai n -relate d ass ess me nts i n t he patie nt’s 
e Diar y dail y fr o m Scree ni n g t hr o u g h M o nt h 1 2, w hic h i ncl u des t he 6 -m o nt h treat me nt peri o d a n d 
first 6 m o nt hs of t he O L E.  D uri n g t h e scree ni n g peri o d, t here s h o ul d be a mi ni m u m of 4 e ntries 
c o m plete d o n da ys w he n t he patie nt is n ot ha vi n g a n attac k .  
Se verit y of pai n will be ca pt ure d via e Diar y usi n g q uesti o n # 3 (a n N R S) fr o m t he B PI -S F, 
w herei n t he p atie nt is as ke d t o c h o ose t he rati n g t h at descri bes t he w orst le v el of pai n e x perie nce d 
o ver t he past 2 4 h o urs.  
A nal gesic usa ge as ta ke n b y t he p atie nts at h o me will be ca pt ure d via t h e e Diar y usi n g d ail y 
q uesti o ns o n t he t y pe, d ose, a n d fre q ue nc y of a n al gesic us e t hr o u g h M o nt h 1 2 of t he st u d y. 
A d diti o nal me dicati o ns, i ncl u di n g a n al gesics, ta ke n at a healt hcare faci lit y (e g, d uri n g a n attac k) 
will be ca pt ure d i n c o n c o mita nt me dicati o ns e C R F.  
After M o nt h 1 2, usa ge of a n y a nal gesic m e dicati o ns will be rec or de d i n t he c o nc o mita nt 
me dicati o ns e C R F, al o n g wit h all ot her me dicati o ns use d.  
7. 2. 3.  
Assess me nts of N a use a a n d F ati g u e  
Patie nts or care gi v ers will rec or d t he f oll o wi n g n a usea a n d fati g u e assess m e nts i n t he patie nt’s 
e Diar y dail y fr o m St u d y Da y 1  t hr o u g h M o nt h 1 2, w hic h i ncl u des t he 6-m o nt h treat me nt peri o d 
a n d first 6  m o nt hs of t he O L E.   
Se verit y of na usea will be ca pt ure d via e Di ar y usi n g a n 1 1 -p oi nt N R S, w herei n t he patie nt is 
as ke d t o c h o ose t he rati n g t hat des cri bes t he w orst le vel of na usea e x perie n ce d o ver t h e past 2 4 
h o urs.  
Se verit y of fati g ue will b e ca pt ur e d via e Di ar y usi n g q uesti o n # 3 (a n 1 1 -p oi nt N R S) fr o m t he 
Brief Fati g ue I n ve nt or y -S h ort F or m ( B FI -S F), w h erei n t he patie nt is as k e d t o c h o ose t he rati n g 
t hat descri bes t he w orst le vel of fati g u e e x perie nce d o ver t he p ast 2 4 h o urs. 
7. 2. 4.  
Q u alit y of Life ( Q O L)  
Q O L q uesti o n naires will be use d t o e val uat e o verall heal t h stat us a n d q ualit y of life.  If Q O L 
assess me nts are o bt ai ne d d uri n g a p or p h yria attac k, it s h o ul d be d oc u me nte d i n t he patie nt’s 
e C R F. 
Q O L assess me nts i ncl u d e t he f oll o wi n g:  
•  S F -1 2: a 1 2 -q uesti o n me as ure ca pt uri n g gl o bal Q O L a n d o verall healt h stat us o ve r t he 
past 4 wee ks t hat ta k es a p pr o xi matel y 5 mi n utes t o c o m plete. (2 6 ) 
•  E Q -5 D -5 L: a 2 -pa ge scal e t hat i ncl u des q uesti o ns t hat ca pt ure h ealt h o n 5 di me nsi o ns 
( m o bilit y, s elf-care, us u al acti vities, pai n/ disc o mf ort, a n d a n xiet y/ de pressi o n) a n d a 
vis ual a nal o g s cale ( V A S) ca pt uri n g t he patie nt’s self -rat e d healt h (2 7 ).  T h e E Q-5 D -
5 L ta k es a p pr o xi matel y 5 mi n utes t o c o m plete.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 6  
•  P GI C: T he Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI C) is o ne q u esti o n a ns were d 
acc or di n g t o a 7 -p oi nt scale (ra n gi n g fr o m ver y m uc h i m pr o ve d t o ver y m u c h w orse) 
f or t he assess me nt of a p atie nt’s percei ve d o verall healt h stat us c ha n ge si nc e t he 
be gi n ni n g of t he st u d y.  T his q uesti o n naire ta k es a p pr o xi matel y 2 t o 3  mi n utes t o 
c o m plete.  
•  P P E Q: T he P or p h yria Patie nt E x perie nce Q uesti o n naire ( P P E Q) is a set of q uesti o ns t o 
assess treat me nt e x perie n ce a n d i m pacts t o t he patie nt's life n ot c ollecte d b y t he ot her 
Q O L assess me nts.  T his q uesti o n naire ta kes a p pr o xi matel y 5 mi n utes t o c o m plete.  
A d diti o nall y, da ys of misse d w or k or sc h o ol d u e t o p or p h yri a s y m pt o ms/attac ks will be assesse d.  
7. 3.  
P h ar m ac o d y n a mic Assess me nts  
Uri ne sa m ples will be c ollecte d f or assess me nt of gi v osira n P D para meters pri or t o d osi n g .  T he 
P D effect of gi v osira n will be e val uate d b y s p ot uri ne A L A a n d P B G le vels n or malize d t o s p ot 
uri ne creati ni ne le vels.  Uri ne sa m ples will be c ollecte d f or assess me nt of circ ulati n g A L A S 1 
m R N A le vels.  A nal ysis of uri ne A L A S 1 m R N A l e vels will be perf or me d at Al n yla m; all ot her 
uri ne P D a nal yses will ta ke place at a ce ntral la b orat or y.  Si nce I n v esti gat ors are bli n de d t o 
treat me nt assi g n me nts, t he y will als o be bli n de d t o A L A a n d P B G res ults a nal yze d at t he ce ntr al 
la b orat or y.  I n a d diti o n, i n vesti gat ors a n d staff i n v ol ve d wit h t his trial a n d all me dical staff 
i n v ol ve d i n t he s u bject’s me dical care s h o ul d refrai n fr o m o btai ni n g l ocal A L A or P B G 
meas ure me nts u ntil at least 1 2 wee ks aft er t he m o nt h 6 visit (t o a v oi d p ote ntial u n bli n di n g).  If 
A L A or P B G i s me as ure d d uri n g t his peri o d, all reas o na ble ste ps m ust be u n derta ke n t o a v oi d 
i nf or mi n g t he s u bject a n d st u d y pers o n nel of t he res ults.    
Uri ne A L A a nal yses ma y be c o n d ucte d at a l ocal l a b orat or y or A L A res ults fr o m pre vi o us visits 
ma y b e e val u ate d i n p atie nts o n t he 1. 2 5  m g/ k g m o nt hl y d ose i n w h o m d ose escalati o n t o 
2. 5  m g/ k g o nce m o nt hl y is bei n g c o nsi dere d d ue t o i na de q uate cli nical res p o nse a n d w h o ha v e 
de m o nstrate d t olera bilit y t o gi v osira n.  D os e escalati o n i n patie nts o n t he 1. 2 5  m g/ k g o nce 
m o nt hl y d os e ca n o cc ur starti n g at M o nt h 1 3.  See Secti o n  6. 2. 3. 4  f or f urt her i nf or mati o n o n d ose 
escalati o n.  
Details re gar di n g t h e pr ocessi n g a n d ali q u oti n g of sa m ples f or st ora ge a n d a nal ys es will be 
pr o vi de d i n t he La b orat or y M a n ual.  
7. 4.  
P h ar m ac o ki netic Asse ss me nts 
Bl o o d a n d uri ne s a m ples will be c ollecte d fr o m all patie nts f or assess me nt of t he P K of gi v osira n 
a n d its maj or meta b olite, 3'( N -1) gi v osira n, at t he ti me p oi nts i n A p pe n di x Secti o n  1 1 , Ta ble  8 , 
Ta ble  9 , a n d T a ble  1 0 .   
At selecte d st u d y visits, as n ote d i n Ta ble  8  a n d Ta ble  9 , a pre d os e sa m ple a n d a 2 h o ur p ost d ose 
sa m ple ( ± 1 5 mi n utes) will be c ollecte d i n all patie nts; t hese assess me nts will be paire d wit h 
tri plicate E C G meas ur e me nts.   
I n a d diti o n, 2 4 -h o ur ( ± 2 h o urs) p ost d ose P K sa m ples will be c ollecte d i n a s u bset of 
a p pr o xi matel y 2 4 patie nts at presele cte d st u d y ce nters (i ncl u di n g all patie nts fr o m East Asia n 
st u d y ce nt ers) (Ta ble  8  a n d Ta ble  9 ).  P o p ulati o n P K a nal ysis will be perf or me d o n t he s pars e P K 
sa m ples fr o m all patie nts. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 7  
Bl o o d m ust be ali q u ote d a n d pr ocess e d as plas ma f or P K a nal ysis.   
T he c o nce ntrati o n of gi v osira n will be deter mi ne d usi n g a v ali date d assa y.  Details re gar di n g t h e 
pr ocessi n g, s hi p pi n g, a n d a nal ysis of t he sa m ples will be pr o vi de d i n t he La b orat or y Ma n ual . 
7. 4. 1.  
P h ar m a c o ki netic Assess me nts i n P atie nts at E ast Asi a n St u d y Ce nters  
A f ull 2 4 -h o ur ( ± 2 h o urs) P K e val uati o n will be perf or me d f oll o wi n g t he first d ose ( St u d y Da y 1) 
a n d M o nt h 6 d ose fr o m all patie nts at East Asia n st u d y ce nters (J a pa n, Tai wa n, or S o ut h K orea) at 
t he ti me p oi nts s pecifie d i n Ta ble  9  ( A p pe n di x Secti o n 1 1 ).  Plas ma P K para meters s u c h as C ma x , 
tma x , t½ β , A U C, C L/ F, a n d V/ F will be assesse d f or gi v osira n a n d its maj or meta b olite, 3'( N-1) 
gi v osira n.  
A P K a nal ysis will als o be perf or me d fr o m p o ole d uri ne sa m ples c ollect e d o ver 2 4 h o urs fr o m 
patie nts at East Asia n st u d y ce nters acc or di n g t o t he sc he d ule pr o v i de d i n Ta ble  1 0  ( A p p e n di x 
Secti o n  1 1 ).  
7. 5.  
S afet y Assess me nts  
T he assess me nt of s afet y d uri n g t he st u d y will c o nsist of t he s ur veilla nce a n d rec or di n g of a d verse 
e ve nts ( A Es) i n cl u di n g s eri o us a d vers e e v e nts ( S A Es) ( Secti o n  7. 5. 6 ), rec or di n g of c o nc o mita nt 
me dicati o n a n d meas ure me nts of vital si g ns, wei g ht a n d hei g ht, p h ysic al e xa mi nati o n, a n d E C G 
fi n di n gs a n d la b orat or y t ests. 
Si nce p or p h yria attac ks ( as defi ne d i n Secti o n  3. 5 ) are rec or de d as a n efficac y assess me nt of 
gi v osira n, t hes e will n ot be treate d as A Es or S A Es.  H o we ver, if a patie nt e x perie nces a n o n -
p or p h yri a A E d uri n g a p or p h yri a attac k, it s h o ul d be re p ort e d.  
Safet y will be m o nit ore d o ver t he c o urse of t he st u d y b y a D M C, as descri be d i n Secti o n 4. 7 . 
7. 5. 1.  
Vit al Si g ns  
Vital si g ns will be meas ure d as s pe cifie d i n t he Sc he d ule of Assess me nts ( Ta ble  1 , Ta ble  2 , a n d 
Ta ble  3 ) a n d will i ncl u de bl o o d press ure, heart rate, b o d y t e m perat ure, a n d res pirat or y rate.  Vital 
si g ns will be meas ur e d i n t he seate d or s u pi ne p ositi o n (s h o ul d be c o nsiste nt t hr o u g h o ut t he st u d y 
f or eac h patie nt), after t h e patie nt has reste d c o mf orta bl y f or 1 0 mi n utes.   
Bl o o d press ure s h o ul d be ta ke n usi n g t he s a me ar m t hr o u g h o ut t he st u d y.  B o d y te m perat ure i n 
de grees Celsi us will be o btai ne d via oral, t y m pa ni c, or a xillar y met h o ds.  H eart rate will be 
c o u nte d f or a f ull mi n ute a n d rec or de d i n beats per mi n ute, a n d res pirati o n rate  will be c o u nte d f or 
a f ull mi n ute a n d rec or de d i n breat hs per mi n ute.  
F or t he safet y of t he p atie nt, a d diti o nal vital si g n assess me nts ma y be a d d e d at t he discreti o n of 
t he I n v esti gat or. 
7. 5. 2.  
Wei g ht a n d Hei g ht  
Hei g ht, b o d y w ei g ht, a n d B MI me as ure me nts will be c ollecte d as s pecifi e d i n t he Sc he d ule of 
Assess me nts ( Ta ble  1 , T a ble  2 , a n d Ta bl e  3 ). 
Hei g ht will be meas ure d i n ce nti meters a n d bo d y wei g ht will be meas ure d i n kil o gra ms.  B o d y 
mass i n de x will be calc ulate d i n t he data bas e.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 8  
B o d y wei g ht o btai ne d wit hi n 6 m o nt hs d uri n g a cli nical st u d y ce nter visit or offsite ma y be us e d 
f or d osi n g calc ulati o ns. 
7. 5. 3.  
P h ysic al E x a mi n ati o n  
C o m plete a n d tar gete d p h ysical e x a mi nati o ns will be c o n d ucte d as s pecifi e d i n t he Sc he d ule of 
Assess me nts ( Ta ble  1 , T a ble  2 , a n d Ta bl e  3 ); if a p h ysical e x a mi nati o n is sc he d ule d f or a d osi n g 
visit, it s h o ul d be c o n d ucte d pri or t o d osi n g.  
C o m plete p h ysical e x a mi nati o ns will i ncl u de t he e x a mi nati o n of t he f oll o wi n g:  ge n eral 
a p peara nce, hea d, e yes, ears, n ose a n d t hr o at, c hest/res pirat or y, heart/car di o vasc ular, 
gastr oi ntesti nal/li ver, m usc ul os keletal/e xtre mities, der mat ol o gi cal/s ki n, t h yr oi d/ nec k, l y m p h 
n o des, a n d ne ur ol o gic al/ ps yc hiatric.  
Tar gete d p h ysic al e x a mi nati o ns will i ncl u de t he e x a mi nati o n of t he f oll o wi n g:  ge n eral 
a p peara nce, c hest/res pirat or y, heart/car di o vasc ul ar, gastr oi ntesti nal/li ver, a n d 
ne ur ol o gi cal/ ps yc hiatric.  
7. 5. 4.  
Electr oc a r di o gr a m  
A si n gle sta n d ar d 1 2 -le a d E C G will be rec or de d at Scree ni n g; all ot her E C Gs will be perf or m e d 
i n tri plicate, usi n g ce ntraliz e d E C G ser vice e q ui p me nt, wit h rea di n gs a p pr o xi matel y 1 mi n ute 
a part. Tri plicat e E C Gs will be perf or me d pre d ose a n d at 2 h o urs p ost d ose i n all patie nts o n St u d y 
Da y 1 a n d at t he M o nt h 5, M o nt h 6, a n d M o nt h 1 2 visits ( Ta ble  8  a n d Ta ble  9 ); t hese assess me nts 
will be paire d wit h P K meas ure m e nts.   
I n a s u bset of a p pr o xi matel y 2 4 p atie nts fr o m pres pecifie d st u d y ce nters (i n cl u di n g all patie nts at 
East Asia n st u d y ce nters), E C Gs at 2 4 -h o urs ( ± 2 h o urs) p ost d ose s h o ul d be perf or me d i n tri plic ate 
(al o n g wit h a 2 4-h o ur P K assess me nt) o n St u d y Da y 1 a n d a t t he M o nt h 6 Visit (Ta ble  8  a n d 
Ta ble  9 ). 
Patie nts s h o ul d be s u pi ne f or at least 5 mi n utes bef ore eac h E C G is o btai ne d.  T he 
electr o p h ysi ol o gical para meters assesse d will be r h yt h m, ve ntric ular rat e, R R i nter val, P R 
i nter val, Q R S d urati o n, Q T i nter val, Bazett-c orrecte d Q T i nter val ( Q Tc B), a n d Fri d erici a 
c orrecte d Q T i nter val ( Q Tc F).  
W he n E C G a n d bl o o d sa m ple c ollecti o n (e g, f or P K assess me nt) occ ur at t h e sa me ti me, E C Gs 
s h o ul d be perf or m e d bef ore bl o o d sa m ples are dra w n.  
Si n gle sta n dar d 1 2 -E C Gs ca n be p erf or m e d o n l ocal E C G mac hi nes.  F or all tri plica te E C Gs, t he 
E C Gs m ust be ac q uire d usi n g ce ntralize d E C G ser vice e q ui p me nt a n d res ults s h o ul d be 
i nter prete d at a ce ntral la b orat or y.  T he I n vesti gat or or q ualifie d desi g n ee will re vie w all E C Gs t o 
assess w het her t he res ults ha ve c ha n ge d si nce b as eli ne a n d  t o deter mi ne t h e cli nical si g nifica nce 
of t he res ults.  A d diti o nal E C Gs ma y b e c ollecte d at t he discreti o n of t he I n vesti gat or.  
Rec or di n gs will be arc hi ve d acc or di n g t o t he St u d y Ma n u al.  
7. 5. 5.  
Cli nic al L a b or at or y Assess me nts  
Cli nical la b orat or y assess me nts are  liste d i n Ta ble  7  a n d will be e val uat e d at a ce ntral la b orat or y 
at ti me p oi nts s pecifie d i n t he Sc he d ule of Ass ess me nts ( Ta ble  1 , Ta bl e  2 , a n d Ta ble  3 ).  If a 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6 9  
cli nical la b orat or y assess me nt is sc he d ule d f or a d osi n g visit, t he bl o o d sa m ple f or t he assess me nt 
s h o ul d be c ollecte d pri or t o d osi n g.  
A L T a n d T B L c ollect e d  wit hi n 6 wee ks pri or t o d osi n g m ust be re vie we d b y t he I n v esti gat or 
bef ore st u d y dr u g a d mi nistrati o n.  I n t he e ve nt t hat gi v osira n is a d mi nistere d offsite b y patie nt or 
care gi v er, safet y la b orat or y assess me nts ot her t ha n A L T a n d T B L m ust be o btai ne d fr o m a ce ntral 
or l ocal la b orat or y wit hi n 3 m o nt hs pri or t o d osi n g.  L ocall y a nal yz e d res ults ma y be re vie we d t o 
i nf or m d osi n g decisi o ns, b ut a d diti o nal sa m ples f or ce ntr al a nal ysis m ust als o be c ollecte d o n t he 
da y of d osi n g pri or t o t he d ose a d mi nistrati o n.  
F erriti n will be assesse d at t he ce ntr al la b orat or y o n St u d y Da y 1 a n d at 6 -m o nt h i nter vals, 
t hereafter.  
D -di mer assess me nts will be perf or m e d at t he Scree ni n g, Da y 1, M o nt h 3, M o nt h 6, M o nt h 9, a n d 
M o nt h 1 2 visits o nl y; as a cli nical res earc h para m eter o n l y, d-di mer res ults will n ot be 
c o m m u nicate d t o t he st u d y ce nters.  
S pecific d osi n g a n d m o nit ori n g i nstr ucti o ns are pr o vi de d f or ele vati o ns i n A L T tra nsa mi nases 
( Secti o n 6. 2. 3. 1 ) a n d el e vati o ns i n li pase a n d/ or a m ylase ( Secti o n 6. 2. 3. 2 ).  F or a n y ot h er 
u ne x plai ne d cli nicall y rele va nt, a b n or mal la b orat or y test o cc urri n g after st u d y dr u g 
a d mi nistrati o n, t he test s h o ul d be re peate d a n d f oll o we d u p at t he discreti o n of t he I n ves ti gat or 
u ntil it has ret ur ne d t o t he n or mal ra n ge or sta bilize d, a n d/ or a dia g n osis is ma de t o a de q u atel y 
e x plai n t he a b n or malit y.  
A d diti o nal safet y la b orat or y assess me nts, i ma gi n g, a n d c o ns ultati o n ma y b e perf or me d, as 
i n dicate d b y t he cli nical sit uati o n, f or e val uati o n a n d/ or i n c o ns ultati o n wit h t he me dical m o nit or; 
res ults ma y b e c ollect e d a n d s h o ul d be i ncl u de d i n t he cli nical data bas e.     


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 0  
T a ble  7 : 
Cli nic al L a b or at or y Assess me nts  
He m at ol o g y  
C o m plete bl o o d c o u n t wit h differe ntial 
 
Ser u m C he mistr y  
S o di u m  
P otassi u m  
B U N  
P h os p hate  
Creati ni ne a n d e G F R  
Al b u mi n  
Uric aci d  
Calci u m  
T otal pr otei n  
Car b o n di o xi de  
Gl uc ose  
C hl ori de  
Li pase  
A m ylase  
Ferriti n  
Li ver F u ncti o n Tests  
 
A S T  
A L P  
A L T  
Bilir u bi n (t otal a n d direct)  
G G T  
 
Uri n al ysis  
Vis ual i ns pecti o n f or a p peara nce a n d c ol or  
Bilir u bi n  
p H ( di pstic k)  
Nitrite  
S pecific gra vit y  
R B Cs  
Ket o nes  
Ur o bili n o ge n  
Al b u mi n  
Le u k oc ytes  
Gl uc ose  
Micr osc o p y (if cli nicall y i n dicate d)  
Pr otei n  
 
C o a g ul ati o n  
 
Pr ot hr o m bi n ti me ( P T) 
Partial T hr o m b o plasti n Ti me ( P T T)  
D -di mer a 
I nter nati o nal N or malize d Rati o (I N R) 
P re g n a nc y Testi n g ( F e m ales of c hil d -be ari n g p ote nti al o nl y)  
β -h u ma n c h ori o nic g o na d otr o pi n  
 
A b bre viati o ns:  A S T =as partate tra nsa mi nase; A L P =al kali ne p h os p hatase; A L T =ala ni ne tra nsa mi nase; 
B U N = bl o o d urea nitr o ge n; e G F R =esti mate d gl o mer ular filtr ati o n rate; G G T = ga m ma -gl uta m yltra nsferase; 
I N R =i nter nati o nal n or malize d rati o; P T = pr ot hr o m bi n ti me; R B C =re d bl o o d cells. 
a   D -di mer assess me nts will be perf or me d at t he Scre e ni n g, Da y 1, M o nt h 3, M o nt h 6, M o nt h 9, a n d M o nt h 1 2 
visits o nl y; as a cli nical resear c h para meter o nl y, d -di mer res ults will n ot be c o m m u nicate d t o t he st u d y ce nters.  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 1  
7. 5. 5. 1.  
I m m u n o ge nicit y 
Bl o o d sa m ples will be c ollecte d t o e val uate t h e i nci de nce a n d titer of a nti dr u g a nti b o dies ( A D A) 
t o gi v osira n.  Bl o o d sa m ples f or A D A t esti n g m ust be c ollecte d bef ore st u d y dr u g a d mi nistrati o n 
at ti me p oi nts s pecifie d i n t he Sc he d ule of Ass ess me nts ( Ta ble  1 , Ta bl e  2 , a n d Ta ble  3 ); f or 
f urt her det ails, see Ta bl e  8  a n d Ta ble  9 .   
Sa m ple c ollecti o n f or patie nts w h o e x perie nce a p ote ntial a na p h ylactic reacti o n is disc usse d i n 
Secti o n  6. 2. 3. 3 . 
Details re gar di n g t h e pr ocessi n g, s hi p pi n g, a n d a n al ysis of t he s a m ples will be pr o vi de d i n t he 
La b orat or y M a n ual.  
7. 5. 5. 2.  
Pre g n a nc y Testi n g  
A pre g na n c y test will be perf or me d f or fe males of c hil d -beari n g p ote ntial o nl y.  A ser u m 
pr e g na nc y t est will be perf or me d at Scree ni n g a n d ser u m or uri ne pre g na n c y tests will be 
perf or me d t h ereafter per t he Sc he d ule of Ass ess me nts ( Ta ble  1 , T a ble  2 , a n d Ta ble  3 ) a n d a n y 
ti me pre g n a nc y is s us pecte d.  T he res ults of t he pre g n a nc y test m ust be k n o w n bef ore st u d y dr u g 
a d mi nistrati o n.  Patie nts w h o are pre g na nt are n ot eli gi ble f or st u d y p artici p ati o n.   
A n y w o m a n wit h a p ositi ve pre g na n c y test d uri n g t he st u d y will be disc o nti n ue d fr o m st u d y dr u g 
b ut will c o nti n ue t o be f oll o we d f or safet y.  A p ositi ve uri ne pre g n a nc y test s h o ul d be c o nfir me d 
b y a s er u m pre g na nc y test pri or t o disc o nti n ui n g t he st u d y dr u g. Patie nts det er mi ne d t o be 
pre g na nt w hile o n st u d y will be f oll o we d u ntil t he pre g na nc y o ut c o me is k n o w n (see Secti o n 
7. 5. 6. 6  f or f oll o w-u p i nstr ucti o ns).  
7. 5. 6.  
A d verse E ve nts  
7. 5. 6. 1.  
Defi niti o ns  
A d verse E ve nt  
Acc or di n g t o t he I nt er nati o nal C o nfere nce o n Har m o nizati o n (I C H) E 2 A g ui deli ne Defi niti o ns 
a n d Sta n dar ds f or E x pe dite d Re p orti n g, a n d 2 1 C F R 3 1 2. 3 2, I N D Safet y Re p orti n g, a n a d verse 
e ve nt ( A E) is a n y u nt o war d me dical oc c urre nce i n a patie nt or cli nical i n vesti gati o nal s u bject 
a d mi nistere d a me dici nal pr o d uct a n d w hic h d oes n ot necessaril y ha v e a ca usal relati o ns hi p wit h 
t his treat me nt. 
Si nce p or p h yria attac ks ( as defi ne d i n Secti o n  3. 5 ) are rec or de d as a n efficac y assess me nt of 
gi v osira n,  t hes e will n ot be treate d as A Es or S A Es. H o we ver, if a patie nt e x perie nces a n o n-
p or p h yri a A E d uri n g a p or p h yri a attac k, it s h o ul d be re p ort e d.  
Seri o us A d verse E ve nt  
A seri o us a d verse e v e nt ( S A E) is a n y u nt o w ar d m e dical occ urre nce t hat at a n y d os e:  
•  Res u lts i n deat h 
•  Is life-t hreate ni n g (a n e v e nt w hic h places t he pati e nt at i m me diate ris k of deat h fr o m 
t he e ve nt as it occ urre d.  It d oes n ot i ncl u d e a n e v e nt t hat ha d it occ urre d i n a m ore 
se vere f or m mi g ht h a ve ca use d deat h) 
•  Re q uires i n -patie nt h os pitalizati o n or pr ol o n gati o n of e xisti n g h os pitalizati o n  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 2  
•  Res ults i n persiste nt or si g nifica nt disa bilit y or i nca pacit y  
•  Is a c o n ge nital a n o mal y or birt h defect 
•  Is a n i m p orta nt me dical e ve nt t hat ma y n ot b e i m me diatel y life-t hreate ni n g or res ult i n 
deat h or h os pitalizati o n b ut ma y je o par dize t he patie nt a n d ma y re q uir e i nter ve nti o n t o 
pre ve nt o ne of t he ot her o utc o mes liste d i n t he defi niti o n a b o ve (e g, e v e nts i ncl u de 
aller gic br o n c h os pas m re q uiri n g i nte nsi ve treat me nt i n a n e mer ge n c y r o o m or at h o me, 
bl o o d d yscrasias, c o n v ulsi o ns, or t he de vel o p me nt of dr u g d e pe n d e nc y or a b use).  
P or p h yria attac ks (as defi ne d i n Secti o n 3. 5 ) will be rec or de d f or effic ac y assess me nt of gi v osira n 
a n d will n ot  be treate d as S A Es.  H o we ver, if a patie nt e x perie nces a n o n -p or p h yri a -attac k S A E 
( or S A Es) d uri n g a p or p h yria attac k t hat meets S A E criteria, t his n o n-p or p h yria -attac k S A E(s) 
s h o ul d be re p orte d.  
A d verse E ve nt Se ve rit y  
A d verse e ve nts are t o be gra de d acc or di n g t o t he cate g ories det aile d bel o w:  
Mil d:  
Mil d; as y m pt o matic or mil d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns 
o nl y; i nter ve nti o n n ot i n dicate d  
M o derate:  
M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n  i n dicate d; li miti n g a ge 
a p pr o priate i nstr u me ntal acti vities of dail y li vi n g (e g, pre pari n g meals, 
s h o p pi n g f or gr oceries or cl ot hes, usi n g t he tele p h o ne, ma na gi n g m o ne y)  
Se vere:  
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; 
h os pit alizati o n or pr ol o n gati o n of h os pitalizati o n i n dicate d; disa bli n g; li miti n g 
self-care acti vities of dail y li vi n g (ie, bat hi n g, dressi n g a n d u n dressi n g, fee di n g 
self, usi n g t he t oilet, ta ki n g me dicati o ns, a n d n ot be dri d de n); O R life -
t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d; O R deat h relate d t o 
a n a d verse e ve nt  
C ha n ges i n s e verit y s h o ul d be d oc u me nte d i n t he me dical rec or d t o all o w assess me nt of t he 
d urati o n of t he e v e nt at eac h le vel of s e verit y.  A d verse e v e nts c haract erize d as i nter mitte nt 
re q uire d o c u me ntati o n of t he start a n d st o p of eac h i nci de nce.  W he n c h a n ges i n t he se verit y of a n 
A E occ ur m ore fre q ue ntl y t ha n o n ce a d a y, t he ma xi m u m se verit y f or t he e x perie nce t hat da y 
s h o ul d be n ote d.  If t he s e verit y cat e g or y c h a n ges o ver a n u m ber of da ys, t h e n t h ose c ha n ges 
s h o ul d be rec or de d se p aratel y ( wit h disti nct o nset dates). 
A E se verit y a n d s eri o us n ess are assesse d i n de pe n de ntl y.  ‘ Se verit y’ c h aracterizes t he i nte nsit y of 
a n A E.  ‘ Seri o us’ is a re g ulat or y d efi niti o n a n d ser ves as a g ui de t o t he S p o ns or f or defi ni n g 
re g ulat or y re p orti n g o bli gati o ns (s ee defi niti o n f or S A E). 
Rel ati o ns hi p of t he A d verse E ve nt t o St u d y Tre at me nt  
T he relati o ns hi p of eac h A E t o st u d y treat me nt s h o ul d be e val uate d b y t h e I n v esti gat or usi n g t h e 
f oll o wi n g criteria:  
Defi nitel y relate d:  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, occ urri n g i n a pla usi ble 
ti me relati o ns hi p t o t he me dicati o n a d mi nistrati o n, a n d w hic h ca n n ot be 
e x plai ne d b y c o nc urre nt disease or ot her dr u gs or c he micals.  T he res p o nse t o 
wit h dra wal of t he dr u g s h o ul d be cli nicall y pla usi ble.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 3  
P ossi bl y relate d:  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h a reas o na ble ti me 
se q ue nce t o t he me dicati o n a d mi nistrati o n, b ut w hic h c o ul d als o be e x plai ne d 
b y c o nc urre nt disease or ot her dr u gs or c he micals.  I nf or mati o n o n t he dr u g 
wit h dra wal ma y be lac ki n g or u nclear.  
U nli kel y relate d:  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y, wit h little or n o 
te m p oral relati o ns hi p t o me dicati o n a d mi nistrati o n, a n d w hic h ot her dr u gs, 
c he micals, or u n derl yi n g disease pr o vi de pla usi ble e x pla nati o ns.  
N ot relate d:  
A cli nical e ve nt, i ncl u di n g la b orat or y test a b n or malit y t hat has n o te m p oral 
relati o ns hi p t o t he me dicati o n or has m ore li kel y alter nati ve eti ol o g y. 
A d verse E ve nts of Cli nic a l I nterest 
T he f oll o wi n g e ve nts are c o nsi dere d t o be A Es of cli nical i nterest:  
•  A L T ele vati o ns > 3 × U L N ( or > 3 × t h e baseli ne A L T meas ure me nt if b aseli n e is > U L N  
•  Li pas e or a m ylas e > 3 × U L N ( or > 3 × t he bas eli ne li pase or a m ylase m eas ure me nt if 
baseli ne is > U L N)   
•  Se vere or s eri o us I S Rs, I S Rs t hat are ass ociate d wit h a recall p he n o m e n o n (reacti o n at 
t he site of a pri or i njecti o n wit h s u bse q ue nt i njecti o ns) or, I S Rs t hat lea d t o te m p orar y 
d ose i nterr u pti o n or per m a ne nt disc o nti n uati o n of st u d y dr u g  
•  A na p h yl actic Reac ti o ns. A na p h yl actic reacti o n is a se vere, p ote ntiall y fatal, s yste mic 
aller gic reacti o n wit h ac ute o nset ( mi n utes t o h o urs).  S y m pt o ms of a n a n a p h ylactic 
reacti o n ma y i ncl u d e s ki n or m uc osal tiss ue (e. g. ge n eralize d hi ves, pr urit us, 
a n gi o e de ma), res pir at or y c o m pr o mise (e. g. w heezi n g, br o nc h os pas m, h y p o xia), 
re d uce d bl o o d press ur e or ass ociate d s y m pt o ms (e. g. s y nc o p e, h y p ot o nia). See 
Secti o n  1 1. 2  f or g ui dance o n dia g n osi n g a na p h ylactic reacti o ns (2 8 ).  
7. 5. 6. 2.  
Eliciti n g a n d Rec or di n g A d verse E ve nts  
Eliciti n g A d verse E ve nts  
T he patie nt s h o ul d be as k e d a b o ut me dicall y rele va nt c ha n ges i n his/ her healt h si nce t he last visit.  
T he patie nt s h o ul d als o be as ke d if h e/s he has bee n h os pitalize d, ha d a n y acci de nts, use d a n y n e w 
me dicati o ns, or c ha n ge d c o nc o mi ta nt me dicati o n r o uti nes ( b ot h prescri pti o n a n d O T C).  I n 
a d diti o n t o patie nt o bser vati o ns, A Es will be d oc u me nte d fr o m a n y cli nicall y rel e va nt la b orat or y 
fi n di n gs, p h ysical e x a mi nati o n fi n di n gs, E C G c h a n ges, or ot her fi n di n gs t h at are rele va nt t o 
patie nt safet y. 
Rec or di n g A d verse E ve nts  
T he I n vesti gat or is r es p o nsi ble f or rec or di n g n o n -seri o us A Es t hat are o bser ve d or re p orte d b y t he 
patie nt after a d mi nistrati o n of t he first d ose of st u d y dr u g re gar dless of t heir relati o ns hi p t o st u d y 
dr u g t hr o u g h t h e e n d of st u d y.  N o n -s eri o us A Es will be f oll o we d u ntil t he e n d of st u d y.  
T he I n vesti gat or is r es p o nsi ble f or rec or di n g S A Es t hat are o bser ve d or re p orte d b y t h e patie nt 
after t he ti me w h e n t he i nf or me d c o ns e nt is si g ne d re gar dl ess of t heir relati o ns hi p t o st u d y dr u g 
t hr o u g h t he e n d of st u d y.  S A Es will be f oll o we d u ntil satisfact or y res ol uti o n, u ntil baseli ne le vel 
is reac h e d, or u ntil t he S A E is c o nsi dere d b y t he I n vesti gat or t o b e c hr o nic or t he patie nt is sta ble, 
as a p pr o priat e.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 4  
All A Es m ust be rec or de d i n t he s o urce rec or ds f or t he cli nical st u d y ce nter a n d i n t he e C R F f or 
t he patie nt, w het her t h e y are c o nsi d ere d dr u g-relat e d.  Eac h A E m ust be descri be d i n detail:  o nset 
ti me a n d date, descri pti o n of e ve nt, se v erit y, relati o ns hi p t o i n vesti gati o nal dr u g, acti o n ta ke n, a n d 
o utc o me (i ncl u di n g ti me a n d date of res ol uti o n, if a p plica ble).  
F or S A Es, t he e v e nt(s) m ust be rec or de d i n t he e C R F. If t he electr o nic d ata ca pt ure ( E D C) is 
u na vaila ble, a b ac k -u p S A E f or m s h o ul d be c o m plete d.   
F or A Es t hat are c o nsi dere d A Es of cli nical i nterest, t he S p o ns or or its desi g nee s h o ul d be n otifie d 
wit hi n 2 4 h o urs usi n g a s u p ple me ntal A Es of cli ni cal i nterest ( A E CI) e C R F.  A d diti o nal cli nical 
a n d la b orat or y i nf or mati o n ma y b e c ollect e d base d u p o n t he se verit y or nat ure of t he e ve nt; see 
Secti o n  6. 2. 3   re gar di n g m o nit ori n g f or li ver or pa ncreas a b n or malities. 
Refer t o C R F c o m pleti o n g ui deli nes f or details o n re p orti n g e ve nts i n t he s u p ple me ntal A E CI 
e C R F. 
Rec or di n g a n I S R  
F or eac h I S R t hat meets A E CI criteria ( Secti o n  7. 5. 6. 1 ), t he I n vesti gat or, or dele gate, s h o ul d 
s u b mit a s u p ple me ntal I S R e C R F, rec or di n g a d diti o nal i nf or mati o n (e g, d es cri pti o ns, o nset a n d 
res ol uti o n date, se verit y, treat me nt gi ve n, a n d e ve nt o utc o me).  A n I S R is defi ne d as a l ocal 
reacti o n at or near t he site of i njecti o n.  “ At or n ear” t he i njecti o n site i ncl u des reacti o ns at t he 
i njecti o n site, a djace nt t o t he i njecti o n site, or a reacti o n w hic h ma y s hift sli g htl y a wa y fr o m t he 
i njecti o n site d ue t o gra vit y (e g, as ma y occ ur wit h s welli n g or he mat o ma).  A reacti o n wit h o nset 
a n d res ol uti o n wit hi n 4 h o urs of t he i njecti o n (e g, tra nsie nt pai n/ b ur ni n g at i njecti o n site)  d oes n ot 
meet t he st u d y d efi niti o n of a n I S R u nless i m me diate treat me nt is re q uire d.  A s yste mic reacti o n 
w hic h i ncl u des t he i njecti o n site, e g, ge n eralize d urticaria or ot h er disti nct e ntities or c o n diti o ns 
li ke l y m p ha de n o p at h y t hat ma y b e near t he i njecti o n site, is n ot c o nsi dere d a n I S R.   
7. 5. 6. 3.  
Seri o us A d verse E ve nts Re q uire I m me di ate Re p orti n g t o S p o ns or/ Desi g nee  
A n assess me nt of t he seri o us ness of eac h A E will be ma de b y t he I n v esti gat or.  A n y A E a n d 
la b orat or y a b n or malit y t h at meets t he S A E criteria i n Secti o n 7. 5. 6. 1  m ust be re p ort e d t o t he 
S p o ns or or desi g n ee wit hi n 2 4 h o urs fr o m t he ti me t hat cli nical st u d y ce nter staff first lear ns of 
t he e ve nt.  All S A Es m ust be re p orte d re gar dless of t he relati o ns hi p t o st u d y dr u g.  
T he i nitial re p ort s h o ul d i ncl u de at least t he f oll o wi n g i nf or mati o n:  
•  Patie nt’s st u d y n u m ber  
•  Descri pti o n a n d dat e of o nset of t he e ve nt  
•  Criteri o n f or seri o us  
•  Preli mi nar y assi g n me nt of relati o ns hi p t o st u d y dr u g, a n d 
•  I n v esti gat or/st u d y ce nter i nf or mati o n 
T o re p ort t he S A E, c o m plete t he S A E f or m. Wit hi n 2 4 h o urs of recei pt of f oll o w -u p i nf or mati o n, 
t he I n v esti gat or m ust u p date t he S A E f or m.  S A Es m ust be re p orte d usi n g t he c o ntact i nf or mati o n 
pr o vi de d i n t he St u d y Ma n ual.  
A p pr o priate re me dial meas ures s h o ul d be ta ke n b y t he I n v esti gat or usi n g his/ her best me dical 
j u d g me nt t o treat t he S A E.  T hese meas ures a n d t he patie nt’s res p o ns e t o t hese meas ures s h o ul d 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 5  
be rec or de d.  All S A Es, r e gar dles s of relati o ns hi p t o st u d y dr u g, will be f oll o we d b y t he 
I n v esti gat or u ntil satisfact or y res ol uti o n or t he I n v esti gat or d ee ms t he S A E t o be c hr o nic or sta bl e.  
Cli nical, la b orat or y, a n d dia g n ostic meas ures s h o ul d be e m pl o ye d b y t he I n vesti gat or as nee d e d t o 
a de q uatel y d eter mi ne t he eti ol o g y of t he e ve nt.  
7. 5. 6. 4.  
S p o ns or S afet y Re p orti n g t o Re g ul at or y A ut h orities  
T he S p o ns or or its re prese ntati ve will re p ort certai n st u d y e v e nts i n a n e x pe dite d ma n ner t o t he 
F o o d a n d Dr u g A d mi nistrati o n, t he E ur o pea n Me dici nes A ge nc y’s E u dra Vi gila nce electr o nic 
s yste m acc or di n g t o Dir ecti ve 2 0 0 1/ 2 0/ E C, a n d t o all c o u ntr y R e g ulat or y A ut h orities w here t he 
st u d y is bei n g c o n d uct e d, acc or di n g t o l ocal a p plica ble re g ulati o ns.  
7. 5. 6. 5.  
Seri o us A d verse E ve nt N otific ati o n t o t he I nstit uti o n al Re vie w 
B o ar d/I n de pe n de nt Et hics C o m mittee  
S us pecte d u ne x pecte d seri o us a d verse reacti o ns ( S U S A Rs) will be re p orte d t o t he I R B/I E C per 
t heir i nstit uti o nal p olic y b y t he I n vesti gat or or S p o ns or ( or S p o ns or desi g n ee) acc or di n g t o 
c o u ntr y re q uir e me nts.  C o pies of eac h re p ort a n d d oc u me ntati o n of I R B/I E C n otificati o n a n d 
ac k n o wle d ge me nt of recei pt will be ke pt i n t he I n vesti gat or’s st u d y file.  
7. 5. 6. 6.  
Pre g n a nc y Re p orti n g  
If a fe male patie nt b ec o m es pre g na nt d uri n g t his st u d y t hr o u g h 3 m o nt hs f oll o wi n g t he last d ose 
of st u d y  dr u g, t h e I n vesti gat or m ust re p ort t he pre g na n c y t o t he S p o ns or or desi g nee wit hi n 
2 4  h o urs of bei n g n otifie d of t he pre g n a nc y.  Details of t he pre g na nc y will be rec or de d o n t he 
pre g na nc y re p orti n g f or m.  T he patie nt s h o ul d recei ve a n y n ecessar y c o u nseli n g re gar di n g t he 
ris ks of c o nti n ui n g t he pre g n a nc y a n d t he p ossi ble effects o n t he fet us. 
T he pre g n a nc y s h o ul d be f oll o we d b y t he I n vesti gat or u ntil c o m pleti o n.  At t he c o m pleti o n of t he 
pre g na nc y, t h e I n vesti gat or will d oc u me nt t he o utc o me of t he pre g na n c y.  If t he o utc o me of t he 
pre g na nc y res ults i n a p ost part u m c o m plicati o n, s p o nta ne o us a b orti o n, still birt h, ne o natal deat h, 
or c o n ge nital a n o mal y, t h e n t he I n vesti gat or s h o ul d f oll o w t he pr oce d ures f or re p orti n g a n S A E as 
o utli ne d i n Secti o n  7. 5. 6. 3 .   
7. 5. 6. 7.  
O ver d ose Re p orti n g  
A n o ver d ose is defi ne d as a n y d os e a d mi nistere d t o or ta ke n b y a p atie nt (acci de ntall y or 
i nte nti o nall y) t hat e x cee ds t he hi ghest dail y d ose, or is at a hi g h er fre q ue n c y, t ha n i ncl u d e d i n t he 
pr ot oc ol.  It is u p t o t he I n vesti gat or t o d eci de w h et her a d os e is t o be c o nsi dere d a n o v er d ose, i n 
c o ns ultati o n wit h t he S p o ns or.  O ver d ose m ust be rec or de d i n t he e C R F.  
All re p orts of o v er d ose ( wit h or wit h o ut a n A E) m ust be re p orte d wit hi n 2 4 h o urs t o t he S p o ns or 
or desi g n ee.   
7. 6.  
E x pl or at or y Assess me nts  
7. 6. 1.  
E x pl or at or y Bi o m ar kers  
W here all o we d per l ocal re g ulati o ns a n d I R B/ E C a p pr o val a n d patie nt c o nse nt (a n d asse nt, w here 
a p plica ble), s er u m, plas ma, a n d uri ne sa m ples will be c ollecte d a n d ma y b e arc hi v e d a n d use d f or 
a nal ys es of e x pl orat or y bi o mar kers relate d t o meta b olic pr ofili n g or t he effects of gi v osira n or 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 6  
ot her pr otei ns rel ate d t o A H Ps a n d t heir c o m plicati o ns.  Sa m ples ma y als o be use d f or testi n g 
h o m oc ystei ne l e vels.  
W here l ocal r e g ulati o ns all o w, t hese bi ol o gic s a m ples f or bi o mar ker res earc h ca n b e retai n e d o n 
be half of t he S p o ns or f or a ma xi m u m of 1 5 years f oll o wi n g t he last patie nt’s last visit i n t he 
st u d y.  
Details re gar di n g t h e c o ll ecti o n, pr ocessi n g, st ora ge, a n d s hi p pi n g of sa m ples ca n be f o u n d i n t he 
La b orat or y M a n ual.  
7. 6. 2.  
D N A S a m ples  
A bl o o d or sali va sa m ple f or D N A will be c ollecte d at Scree ni n g f or ge neti c testi n g of p or p h yria -
relate d ge n es o nl y i n patie nts wit h o ut pri or d oc u me nte d ge netic testi n g f or p or p h yri a.    
I n a d diti o n, w here l o cal r e g ul ati o ns per mit a n d s u bject t o discreti o nar y a p pr o val fr o m eac h 
ce nter’s I R B/I E C as well as patie nt c o nse nt ( a n d asse nt, w here a p plica ble), a v ol u ntar y bl o o d 
sa m ple ma y b e c ollecte d as part of a l ater D N A a n al ysis, w hic h c o ul d i ncl u de a deter mi nati o n of 
t he s pectr u m of p or p h yri a m utati o ns i n patie nts wit h A H Ps a n d t he relati o ns hi p bet wee n 
p or p h yri a m utati o ns a n d t he safet y a n d effi cac y of gi v osira n.   
T he S p o ns or will a nal yze D N A se q ue n ces wit h i n ge n es rel e va nt t o t he m o de of acti o n a n d 
res p o nse t o gi v osira n.  N o a d diti o nal testi n g will be perf or me d o n t he sa m pl es c ollecte d i n t he 
st u d y.  
Details re gar di n g t h e c oll ecti o n, pr ocessi n g, st ora ge, a n d s hi p pi n g of t he sa m ples ca n be f o u n d i n 
t he La b orat or y M a n ual.  T he sa m ple c ollect e d as part of a lat er a n al ysis will be sec urel y st or e d i n 
a ce ntr al bi ore p osit or y f or u p t o 1 5 years f oll o wi n g t he c o m pleti o n of t his cli nical st u d y (ie, last 
patie nt, last visit), or as l ocal re g ulati o ns all o w.  After 1 5 y ears ha v e ela ps e d, t he sa m ples will be 
destr o ye d.  
7. 7.  
C O VI D -1 9 D at a C ollecti o n  
I nf or mati o n o n t he c or o na vir us disease 2 0 1 9 ( C O VI D-1 9) i nfecti o n stat us of t he patie nt, if 
k n o w n, a n d ot her i nf or mati o n o n t he i m pact of t he C O VI D -1 9 p a n de mic o n t he patie nt's 
parti ci pati o n i n t he st u d y will be c ollecte d.  
8.  
S T A TI S TI C S  
A detaile d Statistical A nal ysis Pla n ( S A P) will be fi nalize d bef ore a n y i nteri m a nal ysis or 
data base l oc k, w hic he v er occ urs earlier.  T h e pla n will detail t he i m ple me ntati o n of statistical 
a nal ys es i n acc or da n ce wit h t he pri nci pal feat ur es descri be d i n t he pr ot o c ol.  
8. 1.  
Deter mi n ati o n of S a m ple Size  
T he pla n ne d t otal e nr oll me nt f or t he st u d y is a p pr o xi matel y 7 4 p atie nts, i ncl u di n g a p pr o xi matel y 
7 0 AI P p atie nts.   
I n t his st u d y, 7 0 patie nts will ha ve at least 9 0% p o wer t o detect a 4 5 % re d u cti o n i n t he a n n ualize d 
attac k rat e at a 2 -si d e d 5 % si g nifica nce l e vel ass u mi n g a mea n a n n ualize d attac k rat e of 8, a 
sta n dar d de viati o n ( S D) of 5 i n t he c o ntr ol ar m, a n d a mea n a n n u alize d attac k rat e of 4. 4 wit h S D 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 7  
of 3 i n t he gi v osira n ar m, usi n g a n e gati ve bi n o mial m o del.  T his st u d y desi g n will still ha ve at 
least 8 0 % p o wer e ve n if t he dr o p o ut rate is as hi g h as 1 5 % u n der t h e sa me ass u m pti o ns.  
8. 2.  
St atistic al Met h o d ol o g y  
8. 2. 1.  
P o p ul ati o ns t o be A n al yze d  
T he p o p ulati o n a nal ysis sets f or t he 6 -m o nt h treat me nt p hase are defi n e d as f oll o ws:  
•  F ull A nal ysis Set ( F A S):  All ra n d o mize d patie nts ( A H P) w h o recei v e d at least o ne 
d ose of st u d y dr u g. Patie nts will be gr o u pe d b y t h eir ra n d o ml y assi g ne d tr eat me nt 
gr o u p (i.e. as r a n d o mize d).  
•  F ull A nal ysis Set i n AI P patie nts ( F A S AI P ): All ra n d o mize d AI P patie nts ( wit h 
m utati o n i n t he H M B S  ge ne) w h o recei v e d at least o ne d ose of st u d y dr u g. P atie nts 
will be gr o u pe d b y t heir ra n d o ml y assi g ne d tr eat m e nt gr o u p (i.e. as ra n d o mize d).  
•  Safet y A nal ysis Set:  All patie nts w h o recei ve d at l east o ne d ose of st u d y dr u g, 
gr o u pe d acc or di n g t o t he treat me nt act u all y recei ve d.  Patie nts w h o recei ve d a n y 
a m o u nt of gi v osira n will be i ncl u de d i n t he gi v osira n ar m.   
•  P K A nal ysis Set:  All patie nts w h o recei ve d a n y a m o u nt of st u d y dr u g a n d ha ve at 
least o ne p ost d ose bl o o d sa m ple f or P K para meters a n d w h o ha ve e val ua bl e P K data. 
•  P D A nal ysis Set:  All patie nts w h o recei ve d a n y a m o u nt of st u d y dr u g a n d w h o ha ve 
at least o ne p ost d ose uri n e sa m ple f or t he deter mi n ati o n of A L A or P B G will be 
i ncl u de d i n t he P D a nal yses. 
T he pri mar y p o p ulati o n use d t o e val uate efficac y will be t he F A S AI P  f or t he pri mar y e n d p oi nt a n d 
sec o n dar y e n d p oi nts i n AI P patie nts, a n d F A S f or t he sec o n dar y e n d p oi nt of a n n ualize d attac k 
rate i n A H P patie nts.  Safet y will be a nal yz e d usi n g t he Safet y A nal ysis Set. The P K a n d P D 
A nal ysis Sets will be use d t o c o n d uct P K a n d P D a nal ys es, res p ecti vel y.  
8. 2. 2.  
E x a mi n ati o n of S u b gr o u ps  
S u b gr o u p a n al ys es ma y be c o n d ucte d f or selecte d e n d p oi nts.  Detaile d met h o d ol o g y will be 
pr o vi de d i n t he S A P.  
8. 2. 3.  
H a n dli n g of Missi n g D at a  
Ha n dli n g of  missi n g data will be descri be d i n t he S A P.  
8. 2. 4.  
B aseli ne E v al u ati o ns  
De m o gra p hics a n d ot her baseli ne c haracteristics, i ncl u di n g diseas e -s pecific i nf or mati o n, will be 
s u m marize d descri pti vel y b y treat me nt ar m a n d o verall f or t he F A S a n d Safet y A nal ysis Set.   
8. 2. 5.  
E ffic ac y A n al yses 
T he a nal ysis of t he pri mar y e n d p oi nt a n d t he sec o n dar y e n d p oi nts t hat pert ai n t o t he AI P 
p o p ulati o n will be base d o n t he F A S AI P . T h e a nal ysis of t he sec o n dar y e n d p oi nts t hat pertai n t o 
t he A H P p o p ulati o n will be base d o n t he F A S. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 8  
T he o vera ll T y p e I err or rate will be str o n gl y c o ntr olle d at a 2-si de d 0. 0 5 si g nifica nce l e vel f or t h e 
pri mar y a n d sec o n dar y e n d p oi nts usi n g a n al p ha s pe n di n g f u ncti o n f or t he i nteri m a nal ysis a n d a 
fi x e d se q ue ntial testi n g pr oce d ure at t he fi n al a nal ysis.  T he primar y e n d p oi nt will be c o m pare d 
bet wee n tr eat me nt ar ms at t he fi nal a nal ysis si g nifica nce le vel.  If t he pri m ar y a nal ysis of t he 
pri mar y e n d p oi nt is statisticall y si g nifica nt, t he n t h e sec o n dar y e n d p oi nts will eac h be teste d i n 
t he or der s pecifie d i n t he Sec o n dar y E n d p oi nts secti o n ( Secti o n  3. 2 ).  
If a test of t he pri mar y or a sec o n dar y e n d p oi nt is n ot statisticall y si g nifica nt at t he fi nal a nal ysis 
sig nifica n ce, t he t esti n g of re mai ni n g e n d p oi nts i n t he se q ue nce will st o p.   
8. 2. 5. 1.  
Pri m ar y E n d p oi nt  
T he pri mar y e n d p oi nt of t he st u d y is a c o m p osite of t he a n n ualize d rate of p or p h yri a attac ks 
re q uiri n g h os pitaliz ati o n, ur ge nt healt hcare visit, or I V he mi n a d mi nistrati o n at h o me i n patie nts 
wit h AI P o ver t he 6 -m o nt h d o u ble -bli n d treat me nt peri o d ( Secti o n  3. 5 ).  T h e a n n ualize d attac k 
rate ( A A R) will be cal c ulate d as t he t otal n u m ber of p or p h yria attac ks treate d at ur ge nt healt hcare 
visit or wit h I V he mi n at h o me, di vi de d b y t he t otal n u m ber of da ys i n t he tr eat me nt peri o d, 
m ulti plie d b y t he n u m ber of da ys i n a year,  
t ot al n u m b er  of  q u alif yi n g  p or p h yri a  att ac ks  
t ot al n u m b er  of  d a ys  i n t h e tr e at m e nt p eri o d × 3 6 5 .2 5  
T he pri mar y a n al ysis is a test i n w hic h t he n ull h y p ot hesis is t hat t he rati o of t he mea n a n n u alize d 
attac k rat e f or t he gi v osira n ar m, relati ve t o t he mea n a n n ualize d attac k rate f or t he place b o ar m, 
is e q ual t o 1. 0 a n d t he alt er nati ve h y p ot hesis is t hat t he rati o is n ot e q ual t o 1. 0.  T he mea n 
a n n ualize d attac k rate f or t he place b o a n d acti ve ar ms will be c o m pare d usi n g a n e gati ve bi n o mial 
re gressi o n m odel t hat will i ncl u de fi x e d effects f or t he treat me nt ar m a n d stratificati o n fact ors 
(stat us of he mi n pr o p h yl a xis use pri or t o st u d y e ntr y a n d hist orical attac k rate).  
T he n u m ber of da ys patie nts s pe n d i n t he 6 -m o nt h d o u ble -bli n d treat me nt p eri o d will be i ncl u de d 
i n t he m o del as a n offs et varia ble. Wit h t he offset varia ble, t he n e gati ve bi n o mial re gressi o n 
m o del esse ntiall y m o dels t he a n n ualize d attac k rat e f or eac h p atie nt base d o n t he le n gt h of ti me 
t he patie nt is i n t he treat me nt peri o d, a n d he n ce, will be a ble t o acc o u nt f or t he differi n g l e n gt h of 
f oll o w-u p f or patie nts i n t he treat me nt peri o d.   
Patie nts w h o disc o nti n ue t he st u d y treat me nt earl y ( bef ore t he e n d of t he 6 -m o nt h treat me nt 
peri o d) will still be f oll o we d f or c ollecti o n of attac k data t hr o u g h t he e n d of t he 6 -m o nt h 
treat me nt peri o d a n d t heir data will be use d i n t he pri mar y a nal ysis. F or patie nts w h o disc o nti n ue 
st u d y treat me nt a n d s u bs e q ue ntl y recei ve he mi n pr o p h yla xis, t he pri mar y a nal ysis will i ncl u de 
attac k data c ollecte d u p t o t he start  of he mi n pr o p h yla xis.  
I n a d diti o n t o t he pri mar y a n al ysis p-val ue, a n esti mate d rati o of mea n a n n ualize d attac k rates 
bet wee n tr eat me nt ar ms wit h its c orres p o n di n g 9 5 % c o nfi de n ce i nter val will be esti mate d fr o m 
t he ne gati ve bi n o mial re gressi o n m o del.  Descri pti ve statistics f or t he me dia n a n d i nter q uartile 
ra n ge of t h e a n n ualize d attac k rate will als o be prese nte d f or eac h tr eat me nt ar m. 
Se nsiti vit y a n al ys es will be detaile d i n t he S A P.  
8. 2. 5. 2.  
Sec o n d ar y E n d p oi nts  
Sec o n dar y e n d p oi nts are descri be d i n Secti o n  3. 2 . 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7 9  
T he a nal ysis of t he a n n ualize d rate of p or p h yria attac ks  re q uiri n g h os pitalizati o n, ur ge nt 
healt hcare visit, or I V he mi n a d mi nistrati o n at h o me i n all A H P patie nts (t he F A S) o v er t he 6-
m o nt h d o u ble -bli n d peri o d a n d t he a n n ualize d rat e of he mi n d oses will be c o n d ucte d usi n g t he 
sa me a p pr oac h as t he pri mar y a nal ysis.    
F or t he a nal ysis of uri nar y A L A -relate d e n d p oi nts, t he A L A le vels will be c o m pare d b et wee n 
treat me nt ar ms usi n g a mi x e d-effects m o del r e peat e d meas ures ( M M R M) wit h baseli ne A L A as a 
c o nti n u o us c o variate a n d fi x e d effect ter ms i ncl u di n g treat me nt ar ms, stratificati o n fact ors f or AI P 
patie nts ( pri or he mi n pr o p h yla xis stat us a n d hist oric al attac k rates), visit a n d treat me nt b y visit 
i nteracti o n.  P B G-relat e d e n d p oi nts will als o be a nal yze d usi n g t his met h o d ol o g y.   
Dail y p ai n, na usea, a n d fati g ue s c ores will be a nal yz e d se paratel y usi n g t he area u n d er t he c ur ve 
( A U C) a p pr oac h: t he A U C o ver 6 m o nt hs i n t he res pecti ve sc ore will be cal c ulate d f or eac h 
patie nt, a n d t he mea n A U C will be c o m pare d b et wee n treat me nt ar ms i n a n A N C O V A m o del.  
T he c ha n ge fr o m bas eli ne i n P C S of S F -1 2 at 6 m o nt hs will be a nal yze d us e a n M M R M m o del.   
Details will be  descri be d i n t he S A P.  
8. 2. 5. 3.  
E x pl or at or y E n d p oi nts  
Descri pti ve statistics will be pr o vi de d f or t he e x pl orat or y e n d p oi nts ( Secti o n  3. 3 ).  Details will be 
descri be d i n t he S A P.  
8. 2. 6.  
P h ar m a c o d y n a mi c A n al ysis  
A nal ys es of A L A a n d P B G are d escri be d i n Secti o n  8. 2. 5. 2 .  I n a d diti o n, A L A a n d P B G le v els 
will be s u m mariz e d descri pti vel y at e ac h s c he d ule d visit.  
8. 2. 7.  
P h ar m a c o ki netic A n al ysis  
P o p ulati o n p har mac o ki netic a nal ysis will be perf or me d t o descri be t h e plas ma p har mac o ki n etics 
of gi v osir a n a n d its maj or meta b olite, 3'( N -1) gi v osira n. T he i m pact of rele va nt c o variat es, s uc h 
as, e g, de m o gra p hics, re n al f u ncti o n) o n plas ma P K will be e val uate d.    
I n p atie nts fr o m East Asi a n ce nters wit h 2 4-h o ur P K c ollecti o n, p har mac o ki netic a nal yses of  
plas ma a n d uri ne will be c o n d ucte d usi n g n o nc o m part me ntal met h o ds. Plas ma p har mac o ki n etic 
para meters i ncl u de b ut will n ot be li mite d t o:  ma xi m u m plas ma c o nce ntrati o n ( C ma x ), ti me t o 
ma xi m u m plas ma c o nce ntrati o n (t ma x ), eli mi nati o n half-life (t½ β ), area un der t he c o nce ntr ati o n -
ti me c ur ve ( A U C), a p pare nt cleara nce ( C L/ F), a n d a p pare nt v ol u me of distri b uti o n ( V/ F).  Ot her 
para meters ma y be calc ul ate d, if dee m e d necessar y.  
8. 2. 8.  
S afet y A n al yses  
T he pri mar y safet y para meter is t he i nci de nce of a d verse e ve nts ( A Es).   Safet y para meters als o 
i ncl u de vital si g ns, E C Gs, cli nical la b orat or y assess me nts, a n d p h ysic al e xa ms.  T he e xte nt of 
e x p os ure will be s u m mariz e d.  T he pri mar y s u m maries of t he s afet y of gi v osira n vers us place b o 
will be base d o n safet y p ara meters wit hi n t he 6-m o nt h d o u ble -bli n d treat me nt peri o d, usi n g t h e 
Safet y A nal ysis Set.  A d diti o nal safet y a nal yses will als o be perf or m e d f or t he O L E peri o d.  
A d verse e ve nts will be cl assifie d acc or di n g t o t he Me d D R A S yste m Or ga n Class a n d Preferre d 
Ter m. A Es will be c o llecte d starti n g at t he ti me t he first d ose of st u d y dr u g is a d mi nistere d ( St u d y 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 0  
Da y 1) t hr o u g h t he d urati o n of t he st u d y; S A Es will be c ollecte d starti n g at t he ti me t hat i nf or me d 
c o nse nt is si g ne d a n d t hr o u g h t he d urati o n of t he st u d y.   
T he n u m ber a n d p e rce nta ge of patie nts e x perie nci n g A Es after t h e first d os e of t he st u d y dr u g will 
be s u m marize d f or t he f oll o wi n g A E cate g ories; a d diti o nal cate g ories ma y be s pecifie d i n t he 
S A P.  
•  A n y A E  
•  A n y A E t hat is assesse d as relate d t o st u d y dr u g b y t he I n v esti gat or  
•  A n y s eri o us a d verse e v e nt ( S A E)  
•  A n y A E lea di n g t o disc o nti n uati o n of st u d y dr u g  
•  A n y A E lea di n g t o deat h  
B y -s u bject listi n gs will be pr o vi de d f or deat hs, S A Es, a n d A Es lea di n g t o st u d y disc o nti n uati o n.  
I n ci de nce of a d v erse e ve nts of cli nical i nterest will als o be s u m marize d b y treat me nt gr o u p, a n d 
b y -s u bject listi n gs will be pr o vi de d. 
Descri pti ve statistics will be pr o vi de d f or cli nical l a b orat or y d ata a n d vital si g ns data, prese nte d as 
b ot h act ual val ues a n d c h a n ges fr o m bas eli ne o ver ti me.   La b orat or y s h ift ta bles fr o m baseli ne t o 
w orst val ues will be pres e nte d.   Baseli ne will be d efi ne d as t he l ast pre d ose o bser vati o n o n or 
bef ore Da y  1.   A b n or mal p h ysical e x a mi nati o n fi n di n gs a n d 1 2 -l ea d E C G d ata will be pres e nte d 
i n a b y-p atie nt data listi n g.  
Descri pti ve statistics will be pr o vi de d f or E C G i nter val data a n d prese nte d as b ot h act ual val ues 
a n d c ha n ges fr o m bas eli ne relati ve t o eac h o n -st u d y e v al uati o n a n d t o t he last e val uati o n o n st u d y.  
Details of a n y a b n or malities will be i ncl u de d i n patie nt listi n gs. 
A nti dr u g a nti b o d y res ults, i ncl u di n g i nci de n ce a n d titer will be ta b ulate d.  A b y -patie nt data 
listi n g will als o be pr o vi de d. 
8. 2. 9.  
Ot her A n al yses  
T he l o n g -ter m efficac y a n d safet y data of gi v osira n o ver t he O L E p eri o d will be s u m marize d 
descri pti vel y. Patie nts w h o were ra n d o mize d t o place b o a n d recei ve d gi v osira n at a starti n g d ose 
of 1. 2 5 m g/ k g o nce m o nt hl y d uri n g t he O L E p eri o d ( per a m e n d me nt vers i o n 3) will be assesse d 
t o c haracteriz e t he efficac y a n d safet y f or t he l o wer d ose 1. 2 5 m g/ k g o nce m o nt hl y.    
A nal ys es f or ot her e x pl orat or y e n d p oi nts s uc h as e x pl orat or y bi o mar kers will be detaile d i n t he 
S A P.  
A d diti o nal data s u m maries t o hel p u n dersta n d  a n y i m pact of t he C O VI D -1 9 pa n de mic o n efficac y 
a n d safet y assess me nts will be perf or me d, as a p pr o priate.  
8. 2. 1 0.  
I nteri m A n al ysis 
A n u n bli n de d i nteri m a nal ysis will be c o n d u cte d w he n a p pr o xi matel y 3 0 AI P p atie nts ha ve 
c o m plete d at least 3 m o nt hs of t he treat me nt  peri o d. T he e n d p oi nt f or t his i nteri m a nal ysis is t he 
A L A le vel at 3 m o nt hs. T he A L A le v el at 3 m o nt hs will be c o m pare d b et wee n treat me nt ar ms 
usi n g a n A N C O V A m o d el wit h fi x e d effect of treat me nt ar ms, stratificati o n fact ors f or AI P 
patie nts ( pri or he mi n pr o p h yla xis stat us a n d hist orical attac k rates), a n d  wit h baseli ne A L A as a 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 1  
c o variate.  A n al p ha -s pe n di n g f u ncti o n will be use d t o a dj ust t he si g nifica n ce le vel t o e ns ure t he 
o verall t y p e I err or rate is n ot i nflate d; t he err or s pe n di n g f u ncti o n will be s p ecifie d i n t he 
statistical a nal ysis pla n.  T he si g nifica nce le vel f or t he c o m paris o n at t he i nteri m is 0. 0 0 1 
( 2-si de d).  T o assess d ura bilit y of t h e st u d y dr u g i n l o weri n g a n d mai ntai ni n g A L A le vel o ver 
ti me, t he o verall treat me nt effect fr o m M o nt h 1 t hr o ug h M o nt h 3 will be e v al uate d t hr o u g h a 
mi x e d effect m o del re p eate d meas ure m e nt ( M M R M).  
St o p pi n g f or efficac y or f utilit y is n ot pla n ne d i n t his st u d y.  T o e ns ure t hat t he st u d y is 
a de q uatel y p o w ere d f or t he pri mar y e n d p oi nt c o m paris o n at t he fi nal a nal ysi s, attac k rates ma y 
als o be e val uat e d i n a bli n de d ma n ner f or sa m ple siz e reassess me nt at t he ti me of t he i nteri m 
a nal ysis.   
T he i nteri m a nal ysis will be descri b e d i n detail i n t he S A P.  
9.  
S T U D Y A D MI NI S T R A TI O N  
9. 1.  
Et hic al a n d Re g ul at or y C o nsi der ati o ns  
T his st u d y  will be c o n d u cte d i n acc or da n ce wit h t he pr ot oc ol, all a p plica bl e re g ulat or y 
re q uire me nts, a n d t h e g ui deli nes of G o o d Cli nical Practice ( G C P).  C o m plia nce wit h G C P 
pr o vi des p u blic ass ura n ce t hat t he ri g hts, safet y, a n d well -bei n g of st u d y patie nts are pr o tecte d 
c o nsiste nt wit h t he pri nci ples t hat ha ve t heir ori gi n i n t he Declarati o n of Helsi n ki.  
9. 1. 1.  
I nf or me d C o nse nt 
T he I n vesti gat or will e ns ure t hat t he patie nt/le gal g uar dia n is gi ve n f ull a n d a de q uate oral a n d 
writte n i nf or mati o n a b o ut t he nat ure, p ur p ose, p o ssi ble ris k a n d be nefit of t he st u d y.  
Patie nts/ Le gal g u ar dia ns m ust als o be n otifie d t hat t he y are free t o disc o nti n ue fr o m t he st u d y at 
a n y ti me.  T h e patie nt/le gal g u ar dia n s h o ul d be gi ve n t he o p p ort u nit y t o as k q uesti o ns a n d 
all o we d ti me t o c o nsi der t h e i nf or mati o n pr o vi de d.  I n t he cas e of patie nts u n der t he a ge of le gal 
c o nse nt, le gal g uar dia n(s) m ust pr o vi de i nf or me d c o nse nt a n d t he patie nt s h o ul d pr o vi de asse nt 
per l ocal r e g ulati o ns a n d i nstit uti o nal sta n dar ds.  
T he patie nt’s/le gal g uar dia n’s si g n e d a n d date d i nf or me d c o nse nt (a n d ass e nt, if a p plica ble) m ust 
be o btai ne d bef ore c o n d u cti n g a n y st u d y pr oce d ures.  
T he I n vesti gat or will i nf or m t he patie nt/le gal g uar dia n if ne w i nf or mati o n bec o mes a v aila ble t hat 
ma y b e rele v a nt t o t he patie nt’s/le gal g u ar dia n’s willi n g ness t o c o nti n ue partici pati o n i n t he st u d y. 
C o m m u nicati o n of t his i nf or mati o n s h o ul d be d oc u me nte d.  
T he I n vesti gat or m ust mai ntai n t he ori gi n al, si g ne d I nf or me d C o nse nt F or m (a n d asse nt, if 
a p plica ble).  A c o p y of t h e si g ne d I nf or m e d C o nse nt F o r m (a n d asse nt, if a p plica ble) m ust be 
gi ve n t o t he p atie nt/le gal g uar dia n.  
9. 1. 2.  
Et hic al Re vie w  
T he fi nal st u d y pr ot oc ol, i ncl u di n g t he fi nal v ersi o n of t he I C F, m ust be a p pr o ve d or gi ve n a 
fa v ora bl e o pi ni o n i n writi n g b y a n I R B or I E C, as a p pr o priate.  T h e I n vesti gat or m ust s u b mit 
writte n a p pr o val b ef ore h e or s he ca n e nr oll a n y p atie nt i nt o t he st u d y.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 2  
T he I n vesti gat or is r es p o nsi ble f or i nf or mi n g t h e I R B or I E C of a n y a me n d me nt t o t he pr ot oc ol i n 
acc or da nce wit h l ocal re q uire me nts.  I n a d diti o n, t he I R B or I E C  m ust a p pr o ve all patie nt 
materials f or t he st u d y (e x ce pt t h ose t hat s u p p ort t he nee d t o r e m o ve a n a p pare nt i m me diate 
hazar d t o t he patie nt).  T he pr ot oc ol m ust be rea p pr o ve d b y t he I R B or I E C u p o n recei pt of 
a me n d me nts a n d a n n u all y, as l oc al re g ul ati o ns r e q uire.  
I nitial I R B or I E C a p pr o val of t he pr ot oc ol, a n d all materials a p pr o ve d b y t he I R B or I E C f or t his 
st u d y i ncl u di n g t h e patie nt c o nse nt f or m (a n d asse nt f or m, if a p plica ble) a n d recr uit me nt materials 
m ust be mai ntai ne d b y t h e I n vesti gat or a n d m a de a vaila ble f or i ns pecti o n.  
T he I n vesti gat or will s u b mit re p orts of S A Es as o utli ne d i n Secti o n  7. 5. 6 .  I n a d diti o n, t he 
I n v esti gat or a grees t o s u b mit pr o gress re p orts t o t he I R B or I E C per t heir l ocal re p orti n g 
re q uire me nts, or at least a n n uall y a n d at t he c o ncl usi o n of t he st u d y.  T he re p orts will be ma de 
a vaila ble t o t he S p o ns or or desi g n ee.  
A n y c o m m u nicati o ns fr o m re g ul at or y a ge ncies i n re gar d t o i ns pecti o ns, ot her st u dies t hat i m pact 
t his pr ot oc ol or t he q ualificati o ns of st u d y pers o n nel s h o ul d be pr o m ptl y re p orte d t o t he S p o ns or 
or its desi g nee.  
T he I n vesti gat or is als o r es p o nsi ble f or pr o vi di n g t he I R B or I E C wit h re p orts of a n y re p orta ble 
seri o us a d vers e dr u g reacti o ns fr o m a n y ot her st u d y c o n d u cte d wit h t he i n v esti gati o nal dr u g.  T h e 
S p o ns or or desi g n ee will pr o vi de t his i nf or mati o n t o t he I n v esti gat or.  
Maj or c ha n ges i n t his researc h acti vit y, e x ce pt t h ose t o re m o ve a n a p pare nt i m me diate hazar d t o  
t he patie nt, m ust be re vie we d a n d a p pr o ve d b y t he S p o ns or a n d t he I R B or I E C t hat a p pr o ve d t he 
st u d y.  A me n d me nts t o t he pr ot oc ol m ust be s u b mitte d i n writi n g t o t he I n vesti gat or’s I R B or I E C 
a n d t he Re g ulat or y A ut h orit y f or a p pr o val bef ore patie nts are e nr olle d u n d er t he a me n de d 
pr ot oc ol.  
9. 1. 3.  
Seri o us Bre ac h of Pr ot oc ol  
I n v esti gat ors m ust n otif y t he me dical m o nit or wit hi n 2 4 h o urs of bec o mi n g a ware of a p ot e ntial 
seri o us breac h of t he pr ot oc ol.  A seri o us breac h is a breac h t hat is li kel y t o affect t o a si g nif ica nt 
de gree t h e safet y a n d ri g hts of a st u d y p artici pa nt or t he relia bilit y a n d r o b ust ness of t he data 
ge n erat e d i n t he cli nical trial.  
9. 1. 4.  
St u d y D oc u me nt ati o n, C o nfi de nti alit y, a n d Rec or ds Rete nti o n  
All d oc u me ntati o n relati n g t o t he st u d y s h o ul d be retai ne d f or t he peri o d re q uire d b y a p plica ble 
l ocal la w.  If it bec o mes necessar y f or t he S p o ns or, t he S p o ns or’s desi g nee, a p plica ble I R B/I E C, 
or a p plica ble re g ulat or y a ut h orities t o re vie w or a u dit a n y d o c u m e ntati o n r elati n g t o t he st u d y, t he 
I n v esti gat or m ust per mit direct access t o all s o urce d oc u me nts/ data.  Rec or ds will n ot be 
destr o ye d wit h o ut i nf or mi n g t he S p o ns or i n writi n g a n d gi vi n g t he S p o ns or t he o p p ort u nit y t o 
st ore t he rec or ds f or a l o n ger peri o d at t he S p o ns or’s e x pe nse.   
T he I n vesti gat or m ust e ns ure t hat t he patie nts’ c o nfi de ntialit y will be mai ntai ne d.  O n t he C R Fs 
or ot her d oc u me nts s u b mitte d t o t he S p o ns or or desi g nees, p atie nts s h o ul d n ot be i de ntifie d b y 
t heir na mes, b ut b y t he assi g ne d patie nt n u m ber a n d i nitials.  If patie nt na m es are i n cl u de d o n 
c o pies of d oc u me nts s u b mitte d t o t he S p o ns or or desi g nees, t he na m es (e x ce pt f or i nitials) will be 
o bliterate d a n d t he assi g n e d patie nt n u m ber a d d e d t o t he d oc u me nt.  D oc u m e nts n ot f or 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 3  
s u b missi o n t o t he S p o ns or (e g, si g ne d I C Fs) s h o ul d be mai ntai ne d b y t he I n vesti gat or i n strict 
c o nfi de nce.  
T he I n vesti gat or m ust treat all i nf or mati o n relate d t o t he st u d y a n d t he c o m pile d data as 
c o nfi de ntial, w h ose use is f or c o n d ucti n g t he st u d y.  T he S p o ns or m ust a p pr o ve a n y tr a nsfer of 
i nf or mati o n n ot directl y i n v ol ve d i n t he st u d y. 
I n c o m plia nce wit h l ocal a n d/ or re gi o nal re g ulati o ns, t his cli nical st u d y m a y be re gistere d, a n d 
st u d y res ults ma y be p ost e d o n p u blic re gistries, s uc h as Cli nical Trials. g o v.  
9. 1. 5.  
E n d of St u d y  
T he E n d of St u d y is defi ne d as last patie nt, last visit.  
9. 1. 6.  
Disc o nti n u ati o n of t he Cli nic al St u d y  
T he S p o ns or reser ves t he ri g ht t o disc o nti n ue t he st u d y f or cli nical or a d mi nistrati ve reas o ns at 
a n y ti me.  If t he st u d y ce nter d oes n ot recr uit at a reas o na bl e rate, t h e st u d y ma y b e disc o nti n ue d 
at t hat site.  S h o ul d t he st u d y be t er mi nate d, a n d/ or t he st u d y ce nter cl ose d f or w hate ver reas o n, 
all d oc u me ntati o n a n d st u d y dr u g p ertai ni n g t o t he st u d y m ust be ret ur ne d t o t he S p o ns or or its 
re pres e ntati ve, a n d t he I n vesti gat ors, I E C/I R B a n d Re g ulat or y A ut h orities will be pr o m ptl y 
i nf or me d of t he ter mi nati o n a n d t he reas o n f or t he decisi o n.  T he I n vesti gat or s h o ul d pr o m ptl y 
i nf or m t he patie nts a n d ass ure a p pr o priate t hera p y a n d f oll o w-u p.  Patie nts s h o ul d t he n be 
wit h dra w n fr o m t he st u d y.   
9. 2.  
D at a Q u alit y C o ntr ol a n d Q u alit y Ass ur a nce  
9. 2. 1.  
D at a H a n dli n g  
St u d y d ata m ust be rec or de d o n case re p ort f or ms ( pa per a n d/ or electr o nic) pr o vi de d b y t he 
S p o ns or or desi g n ee o n b e half of t he S p o ns or.  Case re p ort f or ms m ust be c o m plete d o nl y b y 
pers o ns desi g nate d b y t h e I n vesti gat or.  If e C R Fs are use d, st u d y d ata m ust be e ntere d b y trai ne d 
st u d y ce nt er pers o n nel wit h access t o a v ali d a n d sec ure e C R F s yste m.  All data e ntere d i nt o t he 
e C R F m ust als o be a vaila ble i n t he s o urce d o c u me nts.  C orrecti o ns o n pa per C R Fs m ust be ma de 
s o as t o n ot o bliterate t he ori gi nal dat a a n d m ust b e i nitiale d a n d date d b y t he pers o n w h o ma de 
t he c orrecti o n. 
9. 2. 2.  
St u d y M o nit ori n g  
T he cli nical m o nit or, as a re pres e ntati ve of t he S p o ns or, has a n o bli gati o n t o cl osel y f oll o w t he 
st u d y c o n d u ct at t he st u d y ce nter.  T h e m o nit or will visit t he I n v esti gat or a n d cli nical st u d y ce nter 
peri o dicall y a n d will mai ntai n fre q ue nt tele p h o ne a n d writte n c o ntact.  T he m o nit or will mai ntai n 
c urre nt p ers o nal k n o wle d ge of t he st u d y t hr o u g h o bser vati o n, re vie w of st u d y rec or ds a n d s o urce 
d oc u me ntati o n, a n d disc ussi o n of t he c o n d uct of t he st u d y wit h t he I n v esti gat or a n d staff.  
T he m o nit or will re vie w s o urce d oc u m e nts, s yste ms a n d C R Fs t o e ns ure o verall q ualit y a n d 
c o m plete ness o f t he d ata a n d t o c o nfir m st u d y pr oce d ures are c o m plie d wit h t he re q uire m e nts i n 
t he st u d y pr ot oc ol acc uratel y. T he S p o ns or, or its desi g nee, will be all o we d t o c o n d uct st u d y 
ce nter visits t o t he i n vesti gati o n facilities f or m o nit ori n g a n y as pect of t he st u d y.  T he I n vesti gat or 
a grees t o all o w t he m o nit or t o i ns pect t he dr u g st ora ge area, st u d y dr u g st oc ks, dr u g 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 4  
acc o u nta bilit y rec or ds, p atie nt c harts a n d st u d y s o urce d oc u m e nts, a n d ot her rec or ds relati ve t o 
st u d y c o n d u ct. 
9. 2. 3.  
A u dits a n d I ns pecti o ns  
Peri o dicall y , t he S p o ns or or its a ut h orize d re pres e ntati ves a u dit cli nical i n vesti gati ve ce nters as a n 
i n de pe n de nt re vi e w of c ore trial pr ocesses a n d d o c u me nts t o deter mi ne w het her t hese acti vities 
were c o n d ucte d, a n d data were rec or de d, a n al yze d, a n d acc uratel y re p or te d acc or di n g t o t he 
pr ot oc ol, G C P g ui deli nes of t he I C H, a n d a n y a p plica ble re g ul at or y re q uire me nts.  A re g ulat or y 
a ut h orit y, a n I E C or a n I R B ma y visit t he st u d y ce nter t o perf or m a u dits or i ns pecti o ns, i ncl u di n g 
s o urce dat a verifi cati o n.  T he I n vesti gator s h o ul d c o ntact t he S p o ns or, or its desi g nee, 
i m me diatel y if c o nt acte d b y a re g ulat or y a ge n c y a b o ut a n i ns pecti o n. 
9. 3.  
P u blic ati o n P olic y  
It is i nte n de d t hat after c o m pleti o n of t he st u d y, t he data are t o be s u b mitte d f or p u blicati o n i n a 
scie ntific j o ur nal a n d/ or f or re p orti n g at a s cie ntifi c meeti n g.  A se parate p u blicati o n b y I nstit uti o n 
or I n vesti gat or ca n be s u b mitte d f or p u blicati o n after t his pri mar y ma n uscri pt is p u blis he d or 
f oll o wi n g t he peri o d of 1 8 m o nt hs after c o m pleti o n of t he st u d y at all ce nters.  A c o p y of a n y 
pr o p ose d ma n uscri pt m ust be pr o vi de d a n d c o nfir me d recei ve d at t he S p o ns or at least 3 0 da ys 
bef ore its s u b missi o n, a n d acc or di n g t o a n y a d diti o nal p u blicati o n details i n t he st u d y ce nter’s 
Cli nical Trial A gree me nt.  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 5  
1 0.  
LI S T O F R E F E R E N C E S  
1.  A n ders o n K E, Bl o o mer J R, B o n k o vs k y H L, K us h ner J P, Pierac h C A, Pi mst o ne N R, et al. 
Rec o m me n dati o ns f or t h e dia g n osis a n d treat me nt of t he ac ute p or p h yrias. A n n I nter n Me d. 
2 0 0 5; 1 4 2( 6): 4 3 9 -5 0.  
2.  P u y H, G o u ya L, De y b ac h J C. P or p h yrias. La n cet. 2 0 1 0; 3 7 5( 9 7 1 8): 9 2 4 -3 7.  
3.  B o n k o vs k y H L, Ma d d u k uri V C, Yazici C, A n ders o n K E, Bissell D M, Bl o o mer J R, et al. 
Ac ute p or p h yri as i n t he U S A: feat ures of 1 0 8 s u bjects fr o m p or p h yrias c o ns orti u m. A m J Me d. 
2 0 1 4; 1 2 7( 1 2): 1 2 3 3 -4 1.  
4.  J a mes M F, Hift RJ. P or p h yrias. Br J A naest h. 2 0 0 0; 8 5( 1): 1 4 3-5 3.  
5.  Bal wa ni M, D es nic k RJ. T he p or p h yrias: a d v a nces i n dia g n osis a n d treat me nt. Bl o o d. 
2 0 1 2; 1 2 0( 2 3): 4 4 9 6 -5 0 4.  
6.  A P F -We bcast. Patie nt F o c use d Dr u g De vel o p me nt ( P F D D) meeti n g f or t he Ac ute P or p h yrias. 
I n: F o u n dati o n A P, e dit or. U S A 2 0 1 7. p. 3: 3 3: 5 9.  
7.  Ka dis h K, S mit h K, G uilar d R. T he P or p h yri n Ha n d b o o k. Ka dis h K, S mit h K, G uilar d R, 
e dit ors 2 0 0 3.  
8.  Pisc hi k E, Ka u p pi ne n R. A n u p date of cli nical ma na ge me nt of ac ute i nter mitte nt p or p h yria. 
A p pl Cli n Ge net. 2 0 1 5; 8( 8): 2 0 1 -1 4 . 
9.  J ea ns J B, Sa vi k K, Gr oss C R, Wei mer M K, B osse n maier I C, Pierac h C A, et al. M ortalit y i n 
patie nts wit h ac ute i nter mitte nt p or p h yria re q uiri n g h os pitalizati o n: A U nite d States case series. 
A merica n J o ur nal of Me dical Ge netics. 1 9 9 6; 6 5( 4): 2 6 9 -7 3.  
1 0.  G o u ya L, Bl o o mer J R, Bal wa ni M, Bissell D M, R ees D, St olzel U, et al., e dit ors. E X P L O R E: 
A Pr os pecti ve, M ulti nati o nal, Nat ural Hist or y St u d y of Patie nts wit h Ac ut e He patic P or p h yrias 
( A H P) wit h Rec urre nt Attac ks. I nter n ati o nal C o n gress o n P or p h yri ns a n d P or p hyri as; 2 0 1 7; 
B or dea u x: I C P P.  
1 1.  A n derss o n C, I n nala E, Bac kstr o m T. Ac ute i nter mitte nt p or p h yria i n w o me n: cli nical 
e x pressi o n, use a n d e x perie nce of e x o ge n o us s e x h or m o nes. A p o p ulati o n -base d st u d y i n n ort her n 
S we de n. J I nter n M e d. 2 0 0 3; 2 5 4( 2): 1 7 6 -8 3.  
1 2 . C he m ma n ur A T, B o n k o vs k y H L. H e patic p or p h yrias: dia g n osis a n d ma na ge me nt. Cli n Li ver 
Dis. 2 0 0 4; 8( 4): 8 0 7 -3 8, viii.  
1 3.  Stei n P, Ba d mi nt o n M, Bart h J, Rees D, Ste wart M F, Britis h, et al. Best pr actice g ui deli nes o n 
cli nical ma na ge me nt of ac ute attac ks of p or p h yria a n d t heir c o m plicati o ns. A n n Cli n Bi oc he m. 
2 0 1 3; 5 0( Pt 3): 2 1 7 -2 3.  
1 4.  S o o na walla Z F, Or u g T, Ba d mi nt o n M N, El der G H, R h o des J M, Bra m hall S R, et al. Li ver 
tra ns pla ntati o n as a c ure f or ac ut e i nter mitte nt p or p h yria. T he La n cet. 2 0 0 4; 3 6 3( 9 4 1 0): 7 0 5-6.  
1 5.  A n ders o n K E. A g o n a d otr o pi n releasi n g h or m o n e a nal o g ue pre ve nts c ycli cal attac ks of 
p or p h yri a. Arc h I nter n Me d . 1 9 9 0;1 5 0 ( 7). 
1 6.  Herric k A L, Mc C oll K E, M o ore M R, C o o k A, G ol d ber g A. C o ntr olle d trial of hae m ar gi nate 
i n ac ute he p atic p or p h yri a. La ncet. 1 9 8 9; 1( 8 6 5 0): 1 2 9 5 -7.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 6  
1 7.  Hift RJ, Meiss ner P N. A n A nal ysis of 1 1 2 Ac ute P or p h yric Attac ks i n Ca p e T o w n, S o ut h 
Africa. M e dici ne. 2 0 0 5; 8 4( 1): 4 8 -6 0.  
1 8.  D o w ma n J K, G u ns o n B K, Mirza D F, Bra m hall S R, Ba d mi nt o n M N, Ne ws o me P N. Li ver 
tra ns pla ntati o n f or ac ute i nter mitte nt p or p h yria is c o m plicate d b y a hi g h rate of he patic arter y 
t hr o m b osis. Li ver Tra ns pla ntati o n. 2 0 1 2; 1 8( 2): 1 9 5-2 0 0.  
1 9.  Yas u da M, Er wi n A L, Li u L U, Bal w a ni M, C he n B, Ka dir v el S, et al. Li v er Tra ns pla ntati o n 
f or Ac ute I nter mitte nt P or p h yri a: Bi oc he mical a n d Pat h ol o gic St u dies of t he E x pla nte d Li ver. 
M ol Me d. 2 0 1 5; 2 1: 4 8 7 -9 5.  
2 0.  R y u J Y, S o n g I S, S u n w o o Y E, S h o n J H, Li u K H, C ha IJ, et al. De v el o p me nt of t he "I nj e 
c oc ktail" f or hi g h -t hr o u g h p ut e val uati o n of fi ve h u ma n c yt o c hr o me P 4 5 0 is of or ms i n vi v o. Cli n 
P har mac ol T her. 2 0 0 7; 8 2( 5): 5 3 1 -4 0.  
2 1.  Willia ms D, Ta o X, Z h u L, St o nier M, L utz J D, Mass o n E, et al. Use of a c oc ktail pr o be t o 
assess p ote ntial dr u g i nteracti o ns wit h c yt oc hr o me P 4 5 0 after a d mi nistrati o n of belatace pt, a 
c osti m ulat or y i m m u n o m o d ulat or . Br J Cli n P har mac ol. 2 0 1 7; 8 3( 2): 3 7 0-8 0.  
2 2.  Mars de n J T, G u p p y S, Stei n P, C o x T M, Ba d mi nt o n M, Gar di ner T, et al. A u dit of t he Use of 
Re g ular Hae m Ar gi nate I nf usi o ns i n Patie nts wit h Ac ute P or p h yria t o Pre v e nt Rec urre nt 
S y m pt o ms. JI M D Re p. 2 0 1 5; 2 2: 5 7 -6 5.  
2 3.  Ve nt ura P, C orra di ni E, Di Pierr o E, Marc hi ni S, Marcacci M, C u o g hi C, et al. 
H y p er h o m oc ystei ne mia i n patie nts wit h ac ute p or p h yrias: A p ot e ntiall y d a n ger o us meta b olic 
cr ossr oa d? E ur J I nter n Me d. 2 0 2 0; 7 9: 1 0 1 -7.  
2 4.  T o -Fi g ueras J, L o pez R M, De ul ofe u R , Herrer o C. Preli mi nar y re p ort: h y per h o m oc ystei ne mia 
i n patie nts wit h ac ute i nter mitte nt p or p h yri a. Met a b olis m. 2 0 1 0; 5 9( 1 2): 1 8 0 9-1 0.  
2 5.  Mar o n B A, L oscalz o J. T he treat me nt of h y p er h o m oc ystei ne mia. A n n u Re v Me d. 2 0 0 9; 6 0: 3 9 -
5 4.  
2 6.  Q ualit y Metri c. User's M a n ual f or t he S F -1 2 v 2 Healt h S ur ve y. T hir d e d. Li n c ol n, RI 2 0 1 2.  
2 7.  Her d ma n M, G u d e x C, Ll o y d A, J a nsse n M, Ki n d P, Par ki n D, et al. De vel o p me nt a n d 
preli mi nar y testi n g of t he ne w fi ve -l e vel versi o n of E Q-5 D ( E Q -5 D -5 L). Q ual Lif e Res. 
2 0 1 1; 2 0( 1 0): 1 7 2 7 -3 6.  
2 8.  Sa m ps o n H A, M u n oz -F url o n g A, Ca m p b ell R L, A d ki ns o n N F, Jr., B oc k S A, Bra n u m A, et al. 
Sec o n d s y m p osi u m o n t he defi niti o n a n d ma na ge me nt of a na p h yla xis: s u m mar y re p ort --sec o n d 
Nati o nal I nstit ute of Aller g y a n d I nfecti o us Diseas e/ F o o d Aller g y a n d A na p h yla xis Net w or k 
s y m p osi u m. A n n E mer g Me d. 2 0 0 6; 4 7( 4): 3 7 3-8 0.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 7  
1 1.  
P H A R M A C O KI N E TI C/ P H A R M A C O D Y N A MI C A S S E S S M E N T TI M E P OI N T S   
Ta ble  8  c o ntai ns a d etaile d sc he d ule f or t he c ollecti o n of E C G a n d bl o o d sa m ples f or P K a n d A D A a nal ysis. Det ails re gar di n g t he 
pr ocessi n g, s hi p pi n g, a n d a nal ysis of t he sa m ples will be pr o vi de d i n t he La b orat or y Ma n ual.  
T a ble  8 : 
P h ar m a c o ki netic, E C G, a n d A D A Ti me P oi nts f or All P atie nts ( E xce pt P ati e nts at E ast Asi a n Sites)  
St u d y P eri o d  
St u d y M o nt h/ St u d y 
D a y  
P r ot oc ol Ti me  
( h h: m m) 
P K  
Tri plic ate 
E C G  
Si n gle 1 2 -
Le a d E C G 1 
A D A  
6 -M o nt h Treat me nt 
Peri o d  
M o nt h 0  
( Da y 1)  
Pre d ose  
X  
X  
 
X  
0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
2 4: 0 0 ( ± 2 h o urs)  
X 2 
X 2 
 
 
M o nt h 1  
( Da y 2 9 ± 7  da ys)  
Pre d ose  
X  
 
 
X  
M o nt h 3  
( Da y 8 5 ± 7  da ys)  
Pre d ose  
X  
 
 
X  
M o nt h 5  
( Da y 1 4 1 ± 7  da ys)  
Pre d ose  
X  
X  
 
 
 0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
M o nt h 6  
( Da y 1 6 9 ± 7  da ys)  
Pre d ose  
X  
X  
 
X  
0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
0 4: 0 0 ( ± 1 5 mi n)  3 
X  
 
 
 
2 4: 0 0 ( ± 2 h o urs)  
X 2 
X 2 
 
 
O pe n -La bel 
E xte nsi o n Peri o d  
M o nt h 7  
( Da y 1 9 7 ± 7  da ys)  
Pre d ose  
X  
 
 
X  
Pre d ose  
X  
X  
 
X  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 8  
St u d y P eri o d  
St u d y M o nt h/ St u d y 
D a y  
P r ot oc ol Ti me  
( h h: m m) 
P K  
Tri plic ate 
E C G  
Si n gle 1 2 -
Le a d E C G 1 
A D A  
M o nt h 1 2  
( Da y 3 3 7 ± 7  da ys)  
0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
0 4: 0 0 ( ± 1 5 mi n) 3  
X  
 
 
 
M o nt h 1 8  
( Da y 5 0 5 ± 7  da ys)  
Pre d ose  
X  
 
 
X  
M o nt h 2 4  
( Da y 6 7 3 ± 1 4 da ys)4 
Pre d ose  
X  
  
 
X  
M o nt h 3 6  
( Da y 1 0 0 9 ± 1 4 
da ys)/ E O S 4 
A n y ti me  
 
 
 
X  
A b bre viati o ns:  A D A =a nti -dr u g a nti b o dies; E C G =electr ocar di o gra m; E O S =e n d of st u d y; h h = h o urs; m m = mi n utes  
1 Si n gle 1 2 -lea d E C Gs s h o ul d als o be perf or me d at Scree ni n g. F or f urt her details, see Secti o n 7. 5. 4 . Wit h t he i m ple me ntati o n of A me n d me nt 6, si n gle 12 -lea d 
E C Gs are n o l o n ger re q uire d at t he M o nt h 2 4 a n d 3 6 visits.  
2 I n a pres pecifie d s u bset of a p pr o xi matel y 2 4 patie nts at pres pecifie d st u d y ce nters (i ncl u di n g all patie nts at East Asia n st u d y ce nters), a n a d diti o nal 2 4 -h o ur ( ± 2 
h o urs) P K a n d tri plicate  E C G sa m ple (see Secti o n  7. 5. 4 ) will be c ollecte d o n Da y 1 a n d M o nt h 6.  
3 F or patie nts recei vi n g 1. 2 5  m g/ k g gi v osira n m o nt hl y ( patie nts w h o recei ve d t heir first d ose i n t he o pe n-la bel e xte nsi o n peri o d u n der pr ot oc ol a me n d me nt 
versi o n 3), a d diti o nal bl o o d sa m ples f or P K will be c ollecte d 4 h o urs p ost -d ose at t he M o nt h 6 a n d M o nt h 1 2 visits.  
4 P har mac o ki netic a n d A D A assess me nts t hat ca n n ot be c ollecte d i n t he i nte n de d visit wi n d o w ma y be c o m plete d wit hi n 6 m o nt hs at t he ne xt st u d y ce nter visit.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8 9  
Ta ble  9  pr o vi des a s c he d ule f or t he c ollecti o n of E C G a n d bl o o d sa m ples f or P K a n d A D A a nal ysis i n all patie nts at East Asia n st u d y 
ce nters (i n J a pa n, Tai w a n, a n d S o ut h K orea).  Details re gar di n g t he pr o cess i n g, s hi p pi n g, a n d a n al ysis of t he sa m ples will be pr o vi de d 
i n t he La b orat or y M a n ual. 
T a ble  9 : 
P h ar m a c o ki netic, E C G, a n d A nti -Dr u g A nti b o d y Assess me nt Ti me P oi nts f or P atie nts at E ast Asi a n St u d y 
Ce nters ( Bl o o d S a m ples)  
St u d y P eri o d  
St u d y M o nt h ( St u d y 
D a y)  
S a m pli n g Ti me  
( h h: m m) 
P K  
Tri plic ate 
E C G  
Si n gle 
1 2 -Le a d E C G 1 
A D A  
6 -M o nt h 
Treat me nt Peri o d  
M o nt h 0 ( Da y 1)  
Pre d ose  
X  
X  
 
X  
0 0: 1 5 ( ± 5 mi n)  
X  
 
 
 
0 0: 3 0 ( ± 5 mi n)  
X  
 
 
 
0 1: 0 0 ( ± 1 0 mi n)  
X  
 
 
 
0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
0 4: 0 0 ( ± 1 5 mi n)  
X  
 
 
 
0 6: 0 0 ( ± 1 5 mi n)  
X  
 
 
 
0 8: 0 0 ( ± 1 5 mi n)  
X  
 
 
 
2 4: 0 0 ( ± 2 h o urs)  
X  
X  
 
 
M o nt h 1 ( Da y  2 9 ± 7  da ys)  Pre d ose  
X  
 
 
X  
M o nt h 3  
( Da y 8 5 ± 7 da ys)  
Pre d ose  
X  
 
 
X  
M o nt h 5 
( Da y 1 4 1 ± 7  da ys)  
Pre d ose  
X  
X  
 
 
0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
M o nt h 6 
( Da y 1 6 9 ± 7  da ys)  
Pre d ose  
X  
X  
 
X  
0 0: 1 5 ( ± 5 mi n)  
X  
 
 
 
0 0: 3 0 ( ± 5 mi n)  
X  
 
 
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9 0  
St u d y P eri o d  
St u d y M o nt h ( St u d y 
D a y)  
S a m pli n g Ti me  
( h h: m m) 
P K  
Tri plic ate 
E C G  
Si n gle 
1 2 -Le a d E C G 1 
A D A  
0 1: 0 0 ( ± 1 0 mi n)  
X  
 
 
 
0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
0 4: 0 0 ( ± 1 5 mi n)  
X  
 
 
 
0 6: 0 0 ( ± 1 5 mi n)  
X  
 
 
 
0 8: 0 0 ( ± 1 5 mi n)  
X  
 
 
 
2 4: 0 0 ( ± 2 h o urs)  
X  
X  
 
 
O pe n -La bel 
E xte nsi o n  Peri o d  
M o nt h 7  
( Da y 1 9 7 ± 7  da ys)  
Pre d ose  
X  
 
 
X  
M o nt h 1 2 
( Da y 3 3 7 ± 7  da ys)  
Pre d ose  
X  
X  
 
X  
0 2: 0 0 ( ± 1 5 mi n)  
X  
X  
 
 
M o nt h 1 8 
( Da y 5 0 5 ± 7  da ys)  
Pre d ose  
X  
 
 
X  
M o nt h 2 4 ( Da y 
6 7 3 ± 1 4  da ys) 2 
Pre d ose  
X  
 
 
X  
M o nt h 3 6  
( Da y 1 0 0 9 ± 1 4 da ys)/ 
E O S 2 
A n y ti me  
 
 
 
X  
A b bre viati o ns: A D A =a nti -dr u g a nti b o dies; E C G =electr ocar di o gra m; E O S =e n d of st u d y; h h = h o urs; m m = mi n utes  
1 Si n gle 1 2 -lea d E C Gs s h o ul d als o be perf or me d at Scree ni n g. F or f urt her details, see Secti o n 7. 5. 4 .  Wit h t he i m ple me nt ati o n of A me n d me nt 6, si n gle 1 2-lea d 
E C Gs are n o l o n ger re q uire d at t he M o nt h 2 4 a n d 3 6 visits.  
2  P har mac o ki netic a n d A D A assess me nts t hat ca n n ot be c ollecte d i n t he i nte n de d visit  wi n d o w ma y be c o m plete d wit hi n 6 m o nt hs at t he ne xt st u d y ce nter visit.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9 1  
Ta ble  1 0  pr o vi des a s c he d ule f or t he c ollecti o n of s p ot ( pre d ose) a n d p o ole d uri ne sa m ples f or a nal ysis of P K, P D, a n d A D A i n 
patie nts at East Asia n st u d y ce nters. V ol u me m ust be rec or de d.  
T a ble  1 0 : 
Uri ne P h a r m ac o ki netic/ P h ar m a c o d y n a mic Ti me p oi nts f or P atie nts at E ast Asi a n St u d y Ce nters  
St u d y P eri o d  
St u d y M o nt h  
( St u d y D a y) 
S a m pli n g Ti me  
( h h: m m) 
P K  
A L A a n d P B G  
6 -M o nt h 
Treat me nt Peri o d  
M o nt h 0  
( Da y 1) 
Pre d ose  
X  
X b 
0 -6 h o urs ( ± 3 0 mi n) a 
X  
X b 
6 -1 2 h o urs ( ± 3 0 mi n) a 
X  
X b 
1 2 -2 4 h o urs ( ± 2 h o urs) a 
X  
 
M o nt h 0  
( Da y 1 5 ± 2 da ys)  
 A n y ti me  
 
X c 
M o nt h 1  
( Da y 2 9 ± 7 da ys)  
Pre d ose  
 
X c 
M o nt h 2  
( Da y 5 7 ± 7 da ys)  
Pre d ose  
 
X c 
M o nt h 3  
( Da y 8 5 ± 7 da ys)  
Pre d ose  
 
X c 
M o nt h 4  
( Da y 1 1 3 ± 7 da ys)  
Pre d ose  
 
X c 
M o nt h 5  
( Da y 1 4 1 ± 7 da ys)  
Pre d ose  
 
X c 
M o nt h 6  
( Da y 1 6 9 ± 7 da ys)  
Pre d ose  
X  
X b 
0 -6 h o urs ( ± 3 0 mi n) a 
X  
X b 
6 -1 2 h o urs ( ± 3 0 mi n) a 
X  
X b 
1 2 -2 4 h o urs ( ± 2 h o urs) a 
X  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9 2  
St u d y P eri o d  
St u d y M o nt h  
( St u d y D a y) 
S a m pli n g Ti me  
( h h: m m) 
P K  
A L A a n d P B G  
A b bre viati o ns: A L A =a mi n ole v uli nic aci d; h h = h o urs; m m = mi n utes; P B G = p or p h o bili n o ge n; P K = p har mac o ki netics  
a O n Da y 1 a n d M o nt h 6, all p ost d ose uri ne sa m ples c ollecte d wit hi n a c ollecti o n i nter val will be p o ole d  
b At ti me p oi nts w here P K sa m pli n g is perf or me d, uri ne sa m ples f or A L A a n d P B G meas ure me nt will be ali q u ote d fr o m 
i n di vi d ual ti me p oi nt ( n o n-p o ole d) uri ne sa m ples o btai ne d f or P K assess me nts  
c S p ot uri ne sa m ples f or A L A, P B G, a n d A L A S 1 m R N A me as ure me nt d uri n g t he st u d y s h o ul d be c ollecte d pre d ose; h o we ver, 
if he mi n is use d f or a n attac k, sc he dule d uri nar y A L A, P B G a n d A L A S 1 m R N A will be c ollecte d 4 da ys ( + 4 da ys) after t he 
patie nt’s last he mi n d ose. W here a p plica ble c o u ntr y a n d l ocal re g ulati o ns a n d i nfrastr uct ure all o w, uri ne sa m ples f or A L A, 
P B G, a n d A L A S 1 m R N A ass ess me nts ma y be c ollecte d b y  a h o me healt hcare pr ofessi o nal, se nt t o t he st u d y ce nter b y mail, 
or br o u g ht t o t he st u d y ce nter at t he ne xt visit.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9 3  
1 1. 1.  
Bi oc he mic al Di a g n osis of A H P i n t he A bse nce of I de ntifie d M ut ati o n i n a P or p h yri a -rel ate d Ge ne 
T a ble  1 1 : 
Bi oc he mic al C riteri a i n A d diti o n t o A L A a n d P B G f or Di a g n osis of A H P i n t he A bse nce of a n I de ntifie d 
M ut ati o n i n a P or p h yri a -rel at e d Ge ne  
 
AI P wit h o ut i de ntifie d 
ge ne m ut ati o n  
H C P wit h o ut i de ntifie d 
ge ne m ut ati o n  
V P wit h o ut i de ntifie d 
ge ne m ut ati o n  
A D P wit h o ut i de ntifie d 
ge ne m ut ati o n  
Plas ma 
P or p h yri ns  
•  < 4. 5 μ g/ d L, or < 5 -f ol d 
i ncrease (relati ve t o 
U L N of 0. 9 μ g/ d L)  
•  Fl u oresce nce sca n ni n g at 
ne utral p H s h o ws n o 
pea k or a s mall pea k at 
~ 6 2 0 n m.  
N ote : AI P patie nts wit h 
se vere re nal disease are a n 
e xce pti o n a n d ma y ha ve 
s u bsta ntial i ncreases i n 
plas ma p or p h yri ns.  
•  < 5 μ g/ d L, or < 5 -f ol d 
i ncrease (relati ve t o 
U L N of 0. 9 μ g/ d L)  
•  Fl u oresce nce sca n ni n g 
at ne utral p H s h o ws n o 
pea k or a s mall pea k at 
~ 6 2 0 n m.  
N ote: t his criteri o n 
a p plies t o H C P patie nts 
wit h o ut s ki n lesi o ns. S ki n 
lesi o ns are rare i n t his 
disease, b ut if prese nt are 
ofte n acc o m pa nie d b y 
s u bsta ntial i ncreases i n 
plas ma p or p h yri ns. A n 
e xce pti o n will be ma de 
f or t his criteri o n i n s uc h 
cases. 
•  > 2. 7 μ g/ d L, or > 3 -f ol d 
i ncrease (relati ve t o 
U L N of 0. 9 μ g/ d L)  
•  Fl u oresce nce sca n ni n g at 
ne utral p H s h o wi n g a 
pea k at ~ 6 2 6 n m.  
•  Plas ma: sa me as AI P  
•  Er yt hr oc ytes: mar ke d 
i ncrease i n zi nc 
pr ot o p or p h yri n I X 
( > 4 0 0 μ g/ d L)  
T otal Fecal 
P or p h yri ns  
•  W N L ( < 4 0 0 μ g/ g dr y 
wei g ht or < 2 -f ol d 
i ncrease (relati ve t o 
U L N of 2 0 0  μ g/ g dr y 
wei g ht)  
•  > 4 0 0 μ g/ g dr y wei g ht 
or > 2 -f ol d i ncrease 
(relati ve t o U L N of 
2 0 0  μ g/ g dr y wei g ht)  
•  Pre d o mi na nce of 
c o pr o p or p h yri n III a n d 
a c o pr o p or p h yri n III/I 
rati o > 1. 5 
•  > 4 0 0 μ g/ g dr y wei g ht or 
> 2 -f ol d i ncrease (relati ve 
t o U L N of 2 0 0 μ g/ g dr y 
wei g ht)  
•  Pre d o mi na nce of 
c o pr o p or p h yri n III a n d 
pr ot o p or p h yri n I X  
•  W N L or m o dest i ncrease 
( < 5 0 0 μ g/ g dr y wei g ht or 
< 2. 5 -f ol d i ncrease 
(relati ve t o U L N of 
2 0 0  μ g/ g dr y wei g ht)  
A b bre v iati o ns: A D P = A L A D deficie nt p or p h yria; A H P =ac ute he patic p or p h yria; AI P =ac ute i nter mitte nt p or p h yria; A L A D = A L A de h y dratase; 
H C P = here ditar y c o pr o p or p h yria; U L N = u p per li mit of n or mal; V P = varie gate p or p h yria; W N L = wit hi n n or mal li mits  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7, 2 9 M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9 4  
1 1. 2.  
A n a p h yl actic Re acti o ns  
T a ble  1 2 : 
S a m ps o n Criteri a f or A n a p h yl actic Re acti o ns  
 
A da pte d fr o m Sa m ps o n et al. 2 0 0 6 (2 8 )   
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7 S u m m ar y of C h a n ges, 2 9  M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1  
A L N -A S 1 -0 0 3 P R O T O C O L  A M E N D M E N T 7  
S U M M A R Y O F C H A N G E S D A T E D 2 9  M A R C H 2 0 2 1  
E N VI SI O N: A P h ase 3 R a n d o mize d, D o u ble -bli n d, Pl ace b o -C o ntr olle d M ultice nter St u d y 
wit h a n O pe n -l a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of Gi v osir a n i n P atie nts 
wit h Ac ute He p atic P o r p h yri as  
1.  
R A TI O N A L E F O R P R O T O C O L A M E N D M E N T  
T he p ur p ose of t his pr ot o c ol a me n d me nt is t o rec o m me n d testi n g of bl o o d h o m oc ystei ne l e vels.  
I n a d diti o n, it is rec o m me n de d t hat p atie nts wit h i ncreas e d bl o o d h o m oc ystei ne le vels r ecei ve a 
s u p ple me nt c o ntai ni n g vita mi n B 6. 
 
T hese rec o m me n dati o ns are bei n g ma d e beca use d uri n g gi v osira n  tr eat me nt, i ncreases i n bl o o d 
h o m oc ystei ne l e vels ha v e bee n o bser ve d c o m pare d t o le vels bef ore  gi v os ir a n treat me nt.  T h us, 
m o nit ori n g f or c h a n ges i n bl o o d h o m oc ystei ne  le vels d uri n g tr eat me nt wit h gi v osira n h as bee n 
i nc or p orate d i nt o t he pr ot oc ol.  Bl o o d h o m oc ystei ne le vels ma y als o be i n crease d i n p atie nts wit h 
ac ute he p atic p or p h yri a ( A H P), vita mi n def icie nci es, or c hr o nic ki d ne y disease.  T h e cli nical 
rele va n ce of t h e ele vati o ns i n bl o o d h o m oc ystei n e d uri n g gi v osira n treat me nt is u n k n o w n.  
D etaile d reas o ns f or eac h c ha n ge are pr o vi de d i n Secti o n  2 .  C orrecti o ns t o t y p o gra p hical err ors, 
p u nct uati o n, gra m mar, a b bre viati o ns, a n d f or m atti n g, as w ell as a d mi nistrati ve c ha n ges are n ot 
detaile d.  
 
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7 S u m m ar y of C h a n ges, 2 9  M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2  
2.  
P R O T O C O L A M E N D M E N T 7  D E T AI L E D S U M M A R Y O F  C H A N G E S  
T he pri mar y secti o n(s) of t he pr ot oc ol affecte d b y t he c ha n ges i n Pr ot oc ol A me n d me nt 7 are  i n dicat e d.  T he c orres p o n di n g te xt has 
bee n re vis e d t hr o u g h o ut t he pr ot oc ol.  Delet e d te xt is i n dicate d b y stri ke o ut a n d a d de d te xt is i n dicate d b y b ol d  f o nt, rele va nt t o eac h 
p ur p ose descri be d.  
 
P ur p ose:  A d d me as uri n g bl o o d h o m ocystei ne levels as p art o f t he ex pl or at ory bi o m arker assess me nt. 
T he pri mar y c h a n ge o cc urs i n Secti o n 7. 6. 1 E x pl orat or y Bi o mar kers  
Re vise d te xt:  ( o nl y first para gra p h wit h re visi o n is s h o w n)  
W here all o we d per l ocal re g ulati o ns a n d I R B/ E C a p pr o val a n d patie nt c o nse nt (a n d asse nt, w here a p plica ble), ser u m, plas m a, a n d 
uri ne sa m ples will be c ollecte d a n d ma y b e arc hi v e d a n d use d f or a n al ys es of e x pl orat or y bi o mar kers relate d t o meta b olic pr of ili ng or 
t he effects of gi v osira n or ot her pr otei ns relate d t o A H Ps a n d t heir c o m plicati o ns.  S a m ples m a y als o be use d f or testi n g 
h o m oc ystei ne le vels.  
Secti o ns als o reflecti n g t his c ha n ge:  
•  Ta ble 1, Sc he d ule of Ass ess me nts –  Scree ni n g a n d 6 -M o nt h Treat me nt Pe ri o d ( Scree ni n g t hr o u g h M o nt h 6) (f o ot n ote o) 
•  Ta ble 2, Sc he d ule of Ass ess me nts –  O pe n -La bel E xte nsi o n Peri o d: After M o nt h 6 t hr o u g h M o nt h 1 8 (f o ot n ote l)  
•  Ta ble 3, Sc he d ule of Ass ess me nts f or O pe n -La b el E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y (f o ot n ote j)  
P ur p ose:  T o a d d i ncre as es i n bl o o d h o m ocystei ne levels t o t he be nefit -risk assess me nt, n oti n g t he u nk n o w n cli nic al relev a nce, a n d t o 
i nf or m t he I nvesti g at or a b o ut t he p ossi bility t o s u p ple me nt wit h vit a mi n B 6 s h o ul d i ncre ases i n h o m ocystei ne levels occ ur.  
T he pri mar y c h a n ge o cc urs i n Secti o n 1. 5 Be nefit -Ris k Assess me nt  
A d de d te xt:  ( 3 r d t o last para gra p h) 
Bl o o d h o m oc ystei ne le v els m a y be i ncre ase d i n p atie nts wit h A H P, vit a mi n deficie ncies, or c hr o nic ki d ne y dise ase .( 2 3-2 5)   
D uri n g tre at me nt wit h gi v osir a n, i ncre ases i n bl o o d h o m oc ystei ne le vels h a ve bee n o bser ve d c o m p are d t o le vels bef ore 
tre at me nt.  T he cli nic al rele v a nce of t he el e v ati o ns i n bl o o d h o m oc ystei ne d uri n g gi v osir a n tre at me nt is u n k n o w n.  T he 
pr ot oc ol i ncl u des m o nit ori n g f or c h a n ges i n bl o o d h o m oc ystei ne le vels d uri n g tre at me nt wit h gi v osir a n.  It is rec o m me n de d 
t h at p atie nts wit h i ncre ase d bl o o d h o m oc ystei ne le vels recei ve a s u p ple me nt c o nt ai ni n g vit a mi n B 6  (see Secti o n 6. 3. 4). 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 7 S u m m ar y of C h a n ges, 2 9  M arc h 2 0 2 1  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
P ur p ose:  T o a d d t h at vit a mi n B 6 s u p ple me nt ati o n is a n acce pte d p ote nti al c o nc o mit a nt me dic ati o n if i ncre ases i n bl o o d h o m ocystei ne 
levels occ ur. 
T he c ha n ges i ncl u de t he a d diti o n of Secti o n 6. 3. 4 Vita mi n B 6 S u p ple me ntati o n  
A d de d te xt: ( Secti o n 6. 3. 4)  
Secti o n 6. 3. 4 Vit a mi n B 6 S u p ple me nt ati o n  
D uri n g tre at me nt wit h gi v osir a n, bl o o d h o m oc ystei ne le vels m a y s h o w a n i ncre ase c o m p are d t o le vels bef ore tre at me nt.  Bl o o d 
h o m oc ystei ne le vels will be assesse d as i n dic ate d i n t he Sc he d ule of Assess me nts ( T a ble 1, T a ble 2, a n d T a ble 3).  It is 
rec o m me n de d t h at p atie nts wit h i ncre ase d bl o o d h o m oc ystei ne le vels recei ve a s u p ple me nt c o nt ai ni n g vit a mi n B 6 .  All vit a mi n 
s u p ple me nts s h o ul d be rec o r de d o n t he c o nc o mit a nt me dic ati o ns e C R F.  
Secti o n als o reflecti n g t his c ha n ge:  
•  Secti o n 6, C o nc o mita nt Me dicati o ns ( fi nal se nte n ce a d d e d a cr oss-li n k t o t he vita mi n B 6 s u p ple me ntati o n secti o n)  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1  
A L N -A S 1 -0 0 3 P R O T O C O L  A M E N D M E N T 6  
S U M M A R Y O F C H A N G E S D A T E D 2 3  A P RI L 2 0 2 0  
E N VI SI O N: A P h ase 3 R a n d o mize d, D o u ble -bli n d, Pl ace b o -C o ntr olle d M ultice nter St u d y 
wit h a n O pe n -l a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of Gi v osir a n i n P atie nts 
wit h Ac ute He p atic P o r p h yri as  
1.  
R A TI O N A L E F O R P R O T O C O L A M E N D M E N T  
T he p ur p ose of t his pr ot o c ol a me n d me nt is t o i nc or p orate Ur ge nt Safet y M eas ures ( U S Ms) t hat 
were c o m m u nicate d t o i n vesti gat ors i n a Dear I n v esti gat or Letter t o ass ur e t he safet y of st u d y 
partici pa nts w hile mi ni mizi n g ris ks t o st u d y i nte grit y a mi d t he C O VI D -1 9 pa n de mic. T hes e 
c ha n ges are i n li ne wit h g ui da n ce fr o m b ot h t he E ur o pea n Me di ci nes A ge n c y a n d t he U nite d 
States F o o d a n d Dr u g  A d mi nistrati o n  o n t he c o n d uct of cli nical trials d uri n g t he C O VI D -1 9 
pa n de mic .[E M A 2 0 2 0; F D A 2 0 2 0 ] 
T he U S M m o dificati o ns a n d ne w pr o ce d ures are o utli ne d bel o w, a n d a det aile d s u m mar y of t h e 
pr ot oc ol c ha n ges is pr o vi de d i n Secti on  2 . T hese c ha n ges s h o ul d be a d o pte d i m me diatel y per t he 
Dear I n vesti gat or Letter  date d 0 7 A pril 2 0 2 0 . 
•  Gi v osir a n D osi n g O utsi de t he St u d y Ce nter b y P a ti e nt or C are gi ver 
F oll o wi n g a p pr o priat e trai ni n g o n gi v osira n a d mi nistrati o n a n d t he use of e pi ne p hri ne 
(e pi pe n or e q ui vale nt), dosi n g will be per mitte d at a l ocati o n ot her t ha n t he st u d y 
ce nter (e g, at h o me) b y t he patie nt or care gi ver at all ti me p oi nt s u n der t he o versi g ht 
of t he  I n vesti gat or a n d f oll o wi n g c o ns ultati o n wit h t he m e dical m o nit or .  T his 
meas ure  is i nte n de d t o r e mai n i n effect o nl y d uri n g peri o ds of ti me w he n t he 
C O VI D -1 9 pa n d e mic i m pe des t he a bilit y of patie nts t o tra vel t o t he st u d y site or 
healt hcare pr ofessi o nals t o g o t o patie nts' h o mes f or d osi n g.  
•  St u d y Visit Wi n d o w  
E x ce pt f or assess me nts wit h ot her s pecifie d ti mi n g re q uire me nts (as n ote d bel o w), 
st u d y assess me nts a n d d osi n g are t o be perf or me d wit hi n a visit wi n d o w of ± 1 4 da ys 
( pre vi ousl y ± 7 da ys). St u d y dr u g d os es m ust be a d mi nistere d at least 1 4 da ys a part , 
a n d t his is e x pecte d t o be t olerate d bas e d o n safet y data fr o m t he P hase 1 st u d y 
(A L N -A S 1 -0 0 1 ), w hic h e val uate d d osi n g at 5. 0 m g/ k g m o nt hl y (t wice t h e t hera p e utic 
d ose of 2. 5◦m g/ k g m o nt hl y).  
•  Assess me nts of A d verse E ve nts, C o nc o mit a nt Me dic ati o ns (i ncl u di n g he mi n use), 
H os pit aliz ati o ns/ Pr oce d ures, a n d P or p h yri a Att ac ks  
In sit uati o ns w here a st u d y visit ca n n ot be c o m plete d at t he st u d y ce nter or offsite b y 
a healt hcare pr ofessi o nal v isit, t he st u d y I n v esti gat or ( or dele gate) m a y ver ball y 
c o ntact t he patie nt wit hi n t he st u d y visit wi n d o w t o assess f or a n y a d verse e ve nts, 
c o nc o mita nt me dicati o ns (i ncl u di n g he mi n use), h os pitalizati o ns/ pr oce d ures, a n d 
p or p h yri a attac ks.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2  
•  Li ver F u ncti o n Te sts 
Ala ni ne a mi n otra nsf eras e ( A L T) a n d t otal bilir u bi n  res ults m ust be o btai ne d fr o m a 
ce ntral or l o cal la b orat or y a n d re vie we d wit hi n 6 wee ks  ( pre vi o usl y 1 4 d a ys) pri or t o 
eac h gi v osira n d os e.  
I n cli nical st u dies t o date, tra nsa mi nase el e vati o ns ha ve pri m aril y occ urre d bet wee n  3  
a n d 5 m o nt hs f oll o wi n g i nitiati o n of gi v osira n treat me nt.  Si nce all patie nts i n St u d y 
A L N -A S 1 -0 0 3 ha v e recei ve d at least 1 8  m o nt hs of d osi n g wit h gi v osira n, t he 
re q uire me nt t o re vie w t h e res ults of li ver f u ncti o n tests o btai ne d wi t hi n 6 wee ks of 
d osi n g is c o nsi dere d j ustifie d.  T his is als o ali g ne d wit h t he U S a n d E U pres cri bi n g 
i nf or mati o n t hat state t hat t he li ver f u ncti o n tests s h o ul d be re peate d m o nt hl y d uri n g 
t he first 6 m o nt hs of treat me nt, a n d as cli nicall y i n dicate d t hereaf ter. 
•  Ti me Peri o d t o O bt ai n Wei g ht f or D ose Deter mi n ati o n  
D ose will be base d o n w ei g ht o btai ne d wit hi n 6 m o nt hs  ( pre vi o usl y at t he c urre nt or 
pri or st u d y visit) pri or t o d osi n g.  D osi n g wei g ht ma y b e c ollecte d d uri n g cli nical 
st u d y ce nt er visits or offsite. 
Gi ve n t he e x pa n de d use of offsite a d mi nistrati o n, use of a pri or wei g ht per mits 
acc urate det er mi nati o n of d ose a n d v ol u me wit h o ut ma n ual calc ulati o ns or ver bal 
or ders.   All patie nts are a d ult ; t heref ore, s u bsta ntial fl uct uati o ns i n b o d y wei g ht o ver a 
6 -m o nt h  peri o d are n ot e x pecte d.   Pri or a nal ys es of t he st u d y d ata ha v e s h o w n mea n 
b o d y w ei g ht t o be sta bl e o ver ti me.  
•  Q u alit y of Life ( Q O L) a n d P or p h yri a P atie nt E x perie nce Q uesti o n n aire ( P P E Q) 
Assess me nts  
I n sit uati o ns w here a pl a n ne d st u d y visit ca n n ot b e c o m plete d at t he st u d y ce nter, t he 
patie nt will c o m plete t he Q O L a n d P P E Q q uesti o n naires at h o me.  
•  Assess me nt of E C G  
F urt her assess me nt of E C G is n o l o n ger warra nte d, beca use n o cli nicall y si g nifica nt 
E C G fi n di n gs, i ncl u di n g Q T i nter val pr ol o n gati o n, ha v e bee n o bser ve d f oll o wi n g 
c o m pre he nsi ve a nal yses acr oss t he A L N -A S 1 -0 0 3 St u d y a n d t he P hase 1/ 2 o pe n -la bel 
e xte nsi o n st u d y ( A L N -A S 1 -0 0 2) t o date.  T o mi ni mize e x p os ure t o C O VI D -1 9, 
decrease t he b ur de n o n p atie nts a n d trial sites, a n d ali g n wit h t he U S a n d E U 
prescri bi n g i nf or mati o n, w hic h d o n ot re q uire E C G assess me nt f or d osi n g, E C Gs are 
n o l o n ger re q uir e d  i n t his st u d y.  F or f urt her i nf or mati o n, refer t o t he gi v osira n ( A L N-
A S 1) I n v esti gat or’s Br oc h ure.  
•  Assess me nts Re q uire d t o be Perf or me d at St u d y Ce nter Visits  
W here a p plica ble c o u ntr y a n d l o cal re g ul ati o ns a n d i nfrastr uct ur e all o w f or h o me 
healt hcare, healt hcare ma y ta ke place at a l ocati o n ot her t ha n t he cli nical tri al site t o 
perf or m st u d y assess me nts i ncl u di n g tar get e d p h ysical e xa m/ b o d y s yst e m assess m e nt, 
assess me nts f or vital si g ns, a n d c ollecti o n of bl o o d a n d uri ne sa m ples f or safet y 
la b orat or y ass ess me nts, a n d p har mac o d y n a mic ( P D)  assess me nts, at all ti me p oi nts as 
s pecifie d i n t he Sc he d ul e of Assess me nts. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
I n t he e ve nt t hat gi v osira n is a d mi nistere d offsite b y t he patie nt or care gi ver, safet y 
la b orat or y ass ess me nts ( ot her t ha n li ver f u ncti o n tests) m ust be o btai ne d fr o m a 
ce ntral or l o cal la b orat or y wit hi n 3 m o nt hs pri or t o d osi n g ( pre vi o usl y at t he cli nical 
st u d y ce nt er visit).  T his sa me fre q u e nc y for la b orat or y assess me nts was  i m ple me nte d 
i n t he P hase 1/ 2, o pe n-la bel, e xte nsi o n St u d y A L N-A S 1 -0 0 2 aft er 1 8 m o nt hs ( t o date 
all patie nts treate d f or ≥3 0 m o nt hs ) a n d t his has bee n acce pta ble f or safet y 
m o nit ori n g.  
•  P h ar m a c o ki netic a n d A nti -dr u g A nti b o d y Assess me nts Re q uire d t o be 
Perf or me d at St u d y Ce nter Visits  
Gi ve n  t he e x pa n de d use of offsite d osi n g, phar mac o ki netic ( P K) a n d a nti -dr u g 
a nti b o d y ( A D A) assess me nts ma y b e c o m plete d wit hi n 6 m o nt hs at t he ne xt st u d y 
ce nter visit  ( pre vi o usl y at t he cli nical st u d y ce nter visit). 
All patie nts ha ve c o m plete d 1 8 m o nt hs of treat me nt i n St u d y A L N -A S 1 -0 0 3 .  The P K 
of gi v osira n ha ve b ee n  w ell c haracterize d  bas e d o n t he a vaila ble st u d y data .  Res ults 
s h o w t hat e x p os ure t o gi v osira n a n d its meta b olites is c o nsiste nt acr oss st u d y visits.  
Data fr o m st u d y visits aft er M o nt h 1 8 are n ot e x pecte d t o si g nifica ntl y alter t he 
c urre nt u n d ersta n di n g of gi v osira n P K.  
T he i nci de nce of A D As d ue t o gi v osira n h as bee n ver y l o w i n t he c urre nt st u d y, as 
well as i n ot her cli nical st u dies  of gi v osira n.  I n t he c urre nt st u d y, t here h as bee n o nl y 
1 case of treat me nt -e mer ge nt A D As d ue t o gi v osira n.  T he a nti b o d y titer was l o w a n d 
tra nsie nt, wit h t he patie nt s u bse q ue ntl y testi n g ne gati ve.  Bas e d o n t he c ollecti ve 
e vi de nce t o d ate, gi v osira n is  c o nsi dere d t o ha ve a ver y l o w ris k of eliciti n g a n 
i m m u ne res p o nse. 
•  C ollecti o n of Inf or m ati o n R el ate d t o C O VI D -1 9  
I nf or mati o n rel ate d t o t he i m pact of t he C O VI D-1 9 pa n de mic o n patie nt partici pati o n 
i n t he st u d y will be c ollecte d f or eac h p atie nt.  A d diti onal i nf or mati o n re gar di n g 
c ollecti o n of t his i nf or mati o n, i ncl u di n g c o m pleti o n of a ne w case re p ort f or m 
s pecific t o C O VI D-1 9, will be pr o vi de d se paratel y.  
T his c ha n ge is i m ple me nte d t o e na ble a n al ysis of t he i m pact of t he C O VI D -1 9 gl o bal 
pa n de mic o n cli ni cal trial data.  
•  U p d ates t o St u d y A d mi nistr ati o n  
Te xt was u p date d t o pr o vi de clarificati o n o n I n vesti gat or res p o nsi bilities re gar di n g 
c o m m u nicati o n of ne w st u d y i nf or m ati o n t o patie nts a n d I nstit uti o nal Re vie w B oar ds 
(I R B)/I n d e pe n d e nt Et hics C o m mittees (I E Cs). 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4  
Refere n ces:  
F D A G ui da n ce o n C o n d uct of Cli nical Trials of Me dical Pr o d ucts d uri n g C O VI D -1 9 Pa n de mic: 
G ui da nce f or I n d ustr y, I n vesti gat ors, a n d I nstit uti o nal Re vie w B o ar ds. 
htt ps:// w w w.f da. g o v/r e g ulat or y -i nf or mati o n/searc h-f da-g ui da nce -d oc u me nts/f da -g ui d a nce -
c o n d uct -cli nical-trials-m e dical -pr o d ucts -d uri n g -c o vi d -1 9 -pa n de mic  
G ui da nce o n t he M a na ge me nt of Cli nical Trials d uri n g t he C O VI D -1 9 ( C or o na vir us) Pa n de mic, 
Versi o n 1. 0 ( 2 0/ 0 3/ 2 0 2 0). htt ps:// w w w.e ma.e ur o pa.e u/e n/ ne ws/ g ui da nce -s p o ns ors-h o w -ma n a ge -
cli nical-trials-d uri n g -c o vi d -1 9 -pa n de mic  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5  
2.  
P R O T O C O L A M E N D M E N T 6  D E T AI L E D S U M M A R Y O F  C H A N G E S  
T he pri mar y secti o n(s) of t he pr ot oc ol affecte d b y t he c ha n ges i n Pr ot oc ol A me n d me nt 6 are i n dicat e d.  T he c orres p o n di n g te xt  has 
bee n re vis e d t hr o u g h o ut t he pr ot oc ol.  Delet e d te xt is i n dicate d b y stri ke o ut a n d a d de d te xt is i n dicate d b y b ol d  f o nt, rele va nt t o eac h 
p ur p ose descri be d.  
 
P ur p ose:  T o e x p a n d t he use of offsite a d mi nistr ati o n t o i ncl u de giv osir a n d osi n g by t he p atie nt or c are giver.  
T he pri mar y c h a n ge s o cc ur i n Secti o n 6. 2. 2, D ose a n d A d mi nistrati o n,  
Re vise d te xt:   
1 st para gra p h:  
Gi v osira n will be a d mi nistere d b y a q u alifie d a n d a ut h orize d healt h care pr ofessi o nal trai ne d i n t he rec o g niti o n a n d ma na ge me nt of 
a na p h ylactic reacti o ns.   T he st u d y dr u g s h o ul d be i njecte d i nt o t he a b d o me n or u p per ar ms or t hi g hs.  Detaile d i nstr ucti o ns f or st u d y 
dr u g a d mi nistrati o n are prese nte d i n t he P har m ac y Ma n ual. As is c o nsiste nt wit h g o o d me dical practi ce f or s u b c uta ne o us dr u g 
a d mi nistrati o n, patie nts will be o bser ve d f or a mi ni m u m of 2 0 mi n utes after eac h i njecti o n.   Treat me nt f or a na p h yl actic re acti o ns 
s h o ul d be rea dil y a v aila ble w here p atie nts are bei n g d ose d a n d f oll o w c o u ntr y a n d/ or l ocal h os pital treat me nt g ui deli nes ( 2 5) . 
2 n d para gra p h:   
Gi v osir a n will be a d mi nistere d b y a q u alifie d a n d a ut h orize d he alt h c are pr ofessi o n al tr ai ne d i n t he rec o g niti o n a n d 
m a n a ge me nt of a n a p h yl actic re a cti o ns, w he ne ver p ossi ble.   St u d y dr u g a d mi nistrati o n ma y be c o n d ucte d at a l ocati o n ot her t ha n 
t he st u d y ce nter b y a h o me healt hcare pr ofessi o n al, w here a p plica ble c o u ntr y a n d l o cal r e g ulati o ns a n d i nfrastr u ct ure all o w, after 
c o ns ultati o n wit h t he me dical m o nit or, d uri n g p artic ular st u d y visits, as s p ecifie d i n t he Sc he d ul es of Assess me nts ( Ta ble 2 a n d 
Ta ble  3).  If t he p atie nt is u n a ble t o c o me t o t he st u d y site, a n d a visit b y a h o me he alt hc a re pr of essi o n al is n ot p ossi ble d ue t o 
circ u mst a nces rel at e d t o t he C O VI D -1 9 p a n de mic, gi v osir a n m a y be a d mi nistere d b y t he p atie nt or t he c a re gi ver u n der t he 
o versi g ht of t he I n vesti g at or, a n d f oll o wi n g c o ns ult ati o n wit h t he me dic al m o nit or, as all o w e d b y a p plic a ble c o u ntr y a n d l oc al 
re g ul ati o ns.  I n s uc h c ases, t he p atie nt or c a re gi ver m ust recei ve a p pr o pri ate tr ai ni n g o n gi v osir a n a d mi nistr ati o n a n d t he u se 
of e pi ne p hri ne (e pi pe n or e q ui v ale nt) pri or t o d osi n g.   T his me as ure is i nte n de d t o re m ai n i n effect o nl y d uri n g peri o ds of ti me 
w he n t he C O VI D -1 9 p a n de mic i m pe des t he a bilit y of p atie nts t o tr a vel t o t he st u d y site or he alt hc are pr ofessi o n als t o g o t o 
p atie nts' h o mes f or d osi n g.   H o we ver, st u d y dr u g a d mi nistrati o n at t he st u d y ce nter s h o ul d be c o nsi dere d f or patie nts w h o ha ve 
o n g oi n g st u d y dr u g -relat e d A Es or k n o w n ris k fact ors f or de vel o pi n g a n a p h ylactic reacti o ns, i ncl u di n g b ut n ot li mite d t o: pri or hist or y 
of a n a na p h yl actic reacti o n t o f o o d, me dicati o ns or d ue t o u n k n o w n eti ol o g y, w orse ni n g i njecti o n site reacti o ns w it h re peat d osi n g, or 
a n y o n e i n t he o pi ni o n of t he i n vesti gat or t h at w o ul d be nefit fr o m cli nical o bser vati o n f oll o wi n g d osi n g.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6  
Last p ara gra p h:  
Detaile d i nstr ucti o ns f or st u d y dr u g a d mi nistrati o n are prese nte d i n t he P h ar mac y M a n ual.  I n a d diti o n, i nstr ucti o ns a n d pr oce d ures 
rel ate d t o a d mi nistr ati o n of gi v osir a n  b y a p atie nt or c are gi ver will be pr o vi de d i n t he P atie nt/ C are gi ver St or a ge a n d 
A d mi nistr ati o n I nstr ucti o ns.  
Secti o n(s) als o reflecti n g t his c ha n ge:  
•  S y n o psis  
•  Secti o n 4. 1  
•  Secti o n 6. 2. 4  
P ur p ose:  T o e x p a n d t he st u dy visit wi n d o w.  
T he pri mar y c h a n ge o cc urs i n Ta ble 3, Sc he d ule of Assess me nts f or O pe n -La b el E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y.  
Re vise d te xt:  I n T a ble 3, t he visit wi n d o w was c h a n ge d t o ± 1 4  d a ys  ( pre vi o usl y ± 7 da ys) f or all visits. 
Secti o n(s) als o reflecti n g t his c ha n ge:   
•  Secti o n 5. 3. 1  
P ur p ose:  T o a ll o w t he st u dy I nvesti g at or ( or dele g ate) t o ver b ally c o nt a ct t he p atie nt wit hi n t he st u dy visit wi n d o w t o assess f or a ny 
a dverse eve nts, c o n c o mit a nt me dic ati o ns (i n cl u di n g he mi n use), h os pit aliz ati o ns/ pr oce d ures, a n d p or p hyri a att acks.  
T he c ha n ges occ ur i n t he sec o n d b ullet p oi nt f oll o wi n g Ta bl e 3 , Sc he d ule of Assess me nts f or O pe n -La b el E xte nsi o n Peri o d: M o nt h 1 9 
t hr o u g h E n d of St u d y. 
Re vise d te xt:  
•  St u d y pr oce d ures, i ncl u di n g gi v osira n a d mi nistrati o n, ma y occ ur at t he p atie nt’s h o me at t he discreti o n of t he I n vesti gat or, 
base d o n safet y a n d t olera bilit y.  I n sit u ati o ns w here a st u d y visit c a n n ot be c o m plete d at t he st u d y ce nter or offsite b y 
a h o me he al t hc a re pr of essi o n al visit, t he st u d y I n vesti g at or ( or del e g ate) m a y ver b all y c o nt act t he p atie nt wit hi n t he 
st u d y visit wi n d o w t o assess f or a n y a d verse e ve nts, c o nc o mit a nt me dic ati o ns (i ncl u di n g he mi n use), 
h os pit aliz ati o ns/ pr oce d ures, a n d p or p h yri a att ac ks.  
P ur p ose:  T o e x p a n d t he wi n d o w f or A L T a n d t ot al bilir u bi n tests f or decisi o ns o n giv osir a n d osi n g.  
T he pri mar y c h a n ge o cc urs i n Secti o n 6. 2. 2., D ose a n d A d mi nistrati o n, 3 r d para gra p h  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7  
Re vise d te xt: A L T a n d t otal bilir u bi n ( T B L) res ults c ollecte d wit hi n 6 wee ks  1 4 da ys of st u d y dr u g a d mi nistrati o n m ust be re vie we d 
pri or t o d osi n g.  I n t he e v e nt t hat gi v osira n is a d mi nistere d offsite b y t he patie nt or care gi ver, s afet y l a b orat or y assess me nts ot her t ha n  
A L T a n d T B L m ust be o btai ne d fr o m a ce ntral or l ocal la b orat or y wit hi n 3 m o nt hs pri or t o d osi n g.  F or patie nts wit h ne w si g ns  or 
s y m pt o ms, a p pr o priat e e val uati o n, i ncl u di n g la b orat or y assess me nts, s h o ul d be perf or me d bas e d o n i n vesti gat or j u d g me nt pri or to 
st u d y dr u g a d mi nistrati o n. 
Secti o n(s) als o reflecti n g t his c ha n ge:   
•  Ta ble 3, f o ot n ote f  
•  Secti o n 6. 2. 3. 1  
•  Secti o n 7. 5. 5  
P ur p ose: T o i ncre ase t he wi n d o w f or o bt ai ni n g b o dy wei g ht f or d ose deter mi n ati o n.  
T he pri mar y c h a n ge o cc urs i n Secti o n 7. 5. 2, Wei g ht a n d Hei g ht , 3r d para gra p h  
Re vise d te xt:  B o d y wei g ht o bt ai ne d wit hi n 6 m o nt hs d uri n g a cli nic al st u d y ce nter visit or offsite  eit her at t he pre vi o us st u d y 
ce nter visit or c urre nt st u d y ce nter visit  ma y be us e d f or d osi n g calc ulati o ns.  
Secti o n(s) als o reflecti n g t his c ha n ge: 
•  Ta ble 3, f o ot n ote c  
P ur p ose: T o a ll o w f or re m ote c o nt act a n d c o m pl eti o n of QO L a n d P P E Q q uesti o n n aires.  
T he c ha n ges occ ur i n Ta ble 3, Sc he d ule of Ass ess me nts f or O pe n -La bel E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y  
Re vise d te x t: 
F o ot n ote m  
m  Q O L q u esti o n naires t o be c o m plete d i ncl u de S F -1 2, E Q -5 D -5 L, a n d misse d da ys of w or k/sc h o ol.  I n sit u ati o ns w here a pl a n ne d 
st u d y visit c a n n ot be c o m plete d at t he st u d y ce nter, t he p atie nt will c o m plete t he Q o L q uesti o n n aires at h o me . 
F o ot n o te n 
n T he P P E Q is a set of q uesti o ns t o assess treat me nt e x perie nce a n d i m pacts t o t he patie nt's life n ot c ollecte d b y t he ot her Q O L 
assess me nts.  I n sit u ati o ns w here a pl a n ne d st u d y visit c a n n ot be c o m plete d at t he st u d y ce nter, t he p atie nt will c o m plete  t he 
P P E Q q uesti o n n aire at h o me.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8  
P ur p ose: T o re m ove re q uire me nts f or E C Gs.  
T he pri mar y c h a n ge o cc urs i n Secti o n 7. 5. 4, Electr ocar di o gra m, 1 st para gra p h  
Re vise d te xt: A si n gle sta n dar d 1 2 -le a d E C G will be rec or de d at Scree ni n g, M o nt h 2 4, a n d at t he E n d of Treat me nt ( E O S) Visit ; all 
ot her E C Gs will be perf or me d i n tri plicate, usi n g ce ntralize d E C G ser vice e q ui p me nt, wit h rea di n gs a p pr o xi matel y 1 mi n ute a pa rt. 
Tri plicate E C Gs will be perf or me d pre d os e a n d at 2 h o urs p ost d ose i n all patie nts o n St u d y Da y 1 a n d  at t he M o nt h 5, M o nt h 6, a n d 
M o nt h 1 2 visits ( Ta ble 8 a n d Ta ble 9); t hes e assess me nts will be paire d wit h P K meas ure me nts.  
Secti o n(s) als o reflecti n g t his c ha n ge:  
•  Ta ble 3, 7 t h r o w a n d f o ot n ote e 
•  Ta ble 8  
•  Ta ble 9  
P ur p ose: T o a ll o w cert ai n st u dy visit assess me nts t o be perf or me d offsite a n d pr ovi de a wi n d o w f or s afety l a b or at ory res ults pri or t o 
d osi n g by t he p atie nt or c are give r. 
T he c ha n ge occ ur s i n Secti o n 7 , St u d y Assess me nts. 
Re vise d te xt:   T he sc he d ule of st u d y assess me nts is p r o vi de d i n Ta ble 1 ( S cree ni n g a n d 6-M o nt h Treat me nt Peri o d), Ta bl e 2 ( O pe n -
la bel E xte nsi o n St u d y:  After M o nt h 6 t hr o u g h M o nt h 1 8), a n d Ta ble 3 ( O pe n-la bel E xte nsi o n St u d y:  M o nt h 1 9 t hr o u g h E O S). 
W here a p plic a ble c o u ntr y a n d l oc al re g ul ati o ns a n d i nfr astr uct ure all o w f or h o me he alt hc are, he alt hc are m a y t a ke pl ace at a 
l oc ati o n ot her t h a n t he cli nic al tri al site t o perf or m st u d y assess me nts i ncl u di n g t ar gete d p h ysic al e x a m/ b o d y s yste m 
assess me nt, assess me nts f or vit al si g ns, a n d c ollecti o n of bl o o d a n d uri n e s a m ples f or s afet y l a b or at or y assess me nts, a n d P D 
assess me nts, at all ti me p oi nts as s pecifie d i n t he Sc he d ule of Assess me nts . 
A d diti o nall y, Secti o n 6. 2. 2 , D ose a n d A d mi nistrati o n, 3r d para gra p h, is affecte d b y t hese c h a n ges. 
Re vise d te xt:   
A L T a n d t otal  bilir u bi n ( T B L) res ults c ollecte d wit hi n 6 wee ks of st u d y dr u g a d mi nistrati o n m ust be re vie we d pri or t o d osi n g.  I n t he 
e ve nt t h at gi v osir a n is a d mi nistere d offsite b y t he p atie nt or c are gi ver, s afet y l a b or at or y assess me nts ot her t h a n A L T a n d T B L 
m ust be o bt ai ne d fr o m a ce ntr al or l oc al l a b or at or y wit hi n 3 m o nt hs pri or t o d osi n g.   F or patie nts wit h ne w si g ns or s y m pt o ms, 
a p pr o priate e val uati o n, i ncl u di n g la b orat or y ass ess me nts, s h o ul d be perf or me d base d o n i n vesti gat or j u d g me nt pri or t o st u d y d r u g 
a d mi nist rati o n. 
Ot her s ecti o n(s) als o reflecti n g t h ese c h a n ges: 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9  
•  Ta ble 3,  f o ot n otes b, c, d, a n d f  
•  Secti o n 7. 5. 2  
•  Secti o n 7. 5. 5  
P ur p ose: T o b r o a de n t he wi n d o w f or P K a n d A D A assess me nts re q uire d t o be perf or me d at st u dy ce nter visits.  
T he pri mar y c h a n ges o cc ur i n Ta ble 3 , Sc he d ule of Assess me nts f or O pe n-La b el E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y . 
Re vise d te xt:  
F o ot n ote  k  
k Bl o o d sa m ples f or P K a nal ysis will be c ollecte d pri or t o d osi n g at t he ti m e p oi nts liste d i n Ta ble 8 or Ta ble 9.  P K assess me nts m a y  
be c o m plete d wit hi n 6 m o nt hs, at t he ne xt st u d y ce nter visit.  
F o ot n ote  l 
l Sa m ples will be c ollecte d pre d ose.  A D A assess me nts m a y be c o m plete d wit hi n 6 m o nt hs, at t he ne xt st u d y ce nter visit . 
Secti o n(s) als o reflecti n g t hese c ha n ges:  
•  Ta ble 8  
•  Ta ble 9  
P ur p ose: C ollect i nf or m ati o n rel ate d t o t he i m p act of t he C O VI D -1 9 p a n de mic o n p atie nt p artici p ati o n i n t he st u dy, t o e n a ble a n alysis 
of t he i m p act of t he C O VI D -1 9 gl o b al p a n de mic o n cli nic al tri al d at a.  
T he pri mar y c h a n ge o cc urs i n a ne wl y a d d e d Secti o n 7 . 7, C O VI D-1 9 Data C ollecti o n.  
A d de d te xt:  
Secti o n 7. 7  
C O VI D -1 9 D at a C ollecti o n  
I nf or m ati o n will be c ollecte d o n t he c o r o n a vir us dise ase 2 0 1 9 ( C O VI D -1 9) i nfecti o n st at us of t he p atie nt, if k n o w n, a n d ot her 
i nf or m ati o n o n t he i m p act of t he C O VI D-1 9 p a n de mic o n t he p atie nt's p artici p ati o n i n t he st u d y.  
Secti o n(s) als o reflecti n g t his c ha n ge:  
•  Secti o n 8. 2. 9  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1)  
A me n d me nt 6 S u m m ar y of C h a n ges, 2 3  A pril 2 0 2 0  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 0  
P ur p ose: T o pr ovi de cl arific ati o n o n I nvesti g at or res p o nsi bilities re g ar di n g c o m m u nic ati o n of ne w st u dy i nf or m ati o n t o p atie nts a n d 
I R B/I E Cs. 
T he se c h a n ges o cc ur i n Secti o n 9. 1. 1, I nf or me d C o nse nt, a n d Secti o n 9. 1. 2, Et hical Re vie w . 
A d de d te xt:  
Secti o n 9. 1. 1 , 3r d para gra p h  
T he I n vesti g at or will i nf or m t he p atie nt/le g al g u ar di a n if ne w i nf or m ati o n bec o mes a v ail a ble t h at m a y be rele v a nt t o t he 
p atie nt’s/le g al g u ar di a n’s willi n g ness t o c o nti n ue p artici p ati o n i n t he st u d y.  C o m m u nic ati o n of t his i nf or m ati o n s h o ul d be 
d oc u me nte d.  
Secti o n 9. 1. 2, 2 n d para gra p h  
T he I n vesti gat or is r es p o nsi ble f or i nf or mi n g t h e I R B or I E C of a n y a me n d me nt t o t he pr ot oc ol i n acc or da n ce wit h l ocal re q uir e me nts.  
I n a d diti o n, t he I R B or I E C m ust a p pr o ve all patie nt materials f or t h e st u d y (e xce pt t h ose th at s u p p ort t he nee d t o re m o ve a n 
a p p are nt i m me di ate h az ar d t o t he p atie nt) .  T h e pr ot oc ol m ust be rea p pr o ve d b y t h e I R B or I E C u p o n recei pt of a me n d me nts a n d 
a n n uall y, as l ocal r e g ulati o ns re q uire.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1 ) 
A me n d me nt 5  S u m m ar y of C h a n ges , 1 2  Fe br u ar y 2 0 2 0  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1  
A L N -A S 1 -0 0 3  P R O T O C O L A M E N D M E N T 5  
S U M M A R Y O F C H A N G E S D A T E D  1 2  F E B R U A R Y 2 0 2 0  
E N VI SI O N: A P h ase 3 R a n d o mize d, D o u ble -bli n d, Pl ace b o -C o ntr olle d M ultice nter St u d y 
wit h a n O pe n -l a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of Gi v osir a n i n P atie nts 
wit h Ac ute He p atic P o r p h yri as  
 
R ati o n ale f or Pr ot oc ol A me n d me nt  
T he pri mar y p ur p os e f or t his pr ot oc ol a me n d me nt is t o i ncrease t he d os e of gi v osira n f or patie nts 
recei vi n g 1. 2 5  m g/ k g gi v osira n s u bc uta ne o usl y ( S C) o nce m o nt hl y t o t he rec o m me n de d d ose of 
2. 5  m g/ k g gi v osira n S C o nce m o nt hl y , w hi c h was a p pr o ve d b y t he U nite d States F o o d a n d Dr u g 
A d mi nistrati o n ( F D A)  i n N o ve m ber 2 0 1 9 a n d recei ve d a C o m mittee f or M e dici nal Pr o d ucts f or 
H u ma n Use ( C H M P) p ositi ve o pi ni o n i n J a n uar y  2 0 2 0 .  D ata fr o m t he 6 -m o nt h ra n d o mize d, 
place b o -c o ntr olle d, d o u ble -bli n d ( D B ) peri o d a n d o pe n -la bel e xte nsi o n (O L E ) peri o d t hr o u g h t he 
M o nt h  1 2 data -c ut ha v e de m o nstrate d  t hat treat me nt at 2. 5  m g/ k g gi v osira n S C o nce  m o nt hl y 
res ulte d i n s ustai ne d l o w eri n g of t he diseas e ca usal fact ors a mi n ole v uli nic aci d ( A L A ) a n d 
p or p h o bili n o ge n ( P B G ) a n d is  ass ociate d wit h s u bsta ntial be nefits i ncl u di n g re d uci n g de bilitati n g 
ne ur o visceral attac ks a n d i m pr o vi n g c hr o ni c disease as pect s s uc h as he mi n use, dail y p ai n, 
a nal gesic use, p h ysic al f u ncti o ni n g, a n d q u alit y of life.  T hese be n eficial effects were 
acc o m pa ni e d b y a n acce pta ble a n d ma na gea ble s afet y pr ofile t hr o u g h t he M o nt h  1 2 data -c ut, 
w hic h s u p p orts a fa v ora ble be nefit -ris k pr ofile f or gi v osira n at t he 2. 5-m g/ k g S C o nce m o nt hl y 
d ose .  A tre n d t o war d i ncrease d b e nefit as i n dicate d b y greater re d u cti o n i n c o m p osite attac ks, 
he mi n use, a n d A L A a n d P B G le vels was o bs er ve d d uri n g t he first 6  m o nt hs of treat me nt i n  t he 
O L E wit h t he 2. 5 -m g/ k g S C o nce m o nt hl y  d os e c o m pare d t o t he 1. 2 5 -m g/ k g S C o nce m o nt hl y  
d ose i n patie nts w h o recei ve d place b o d uri n g t he D B peri o d.  F urt h er m ore, I n v esti gat ors 
re q ueste d t o i ncreas e t he d ose t o 2. 5 m g/ k g  gi v osira n S C o nce m o nt h l y f or 1 4  of t he 3 7  patie nts 
(3 8 %) recei vi n g 1. 2 5  m g/ k g gi v osira n S C o nce m o nt hl y  i n t he O L E beca us e of i na de q u ate 
cli nical res p o nse  as per mitte d i n Secti o n 6. 2. 3. 4 of t he pr ot oc ol.  Gi ve n t he tre n d t o war d 
i ncreas e d be nefit wit h t he 2. 5-m g/ k g S C o nce m o nt hl y  d ose of gi v osira n c o m pare d t o t he 
1. 2 5 -m g/ k g S C o nce m o nt hl y  d ose a n d c o nsi deri n g t hat ac ute he p atic  p or p h yria ( A H P ) is a 
disease i n w hic h eac h attac k is seri o us, hi g hl y m or bi d, a n d carries p ote ntial f or irre v ersi ble 
ne ur ol o gi c da ma ge, all p atie nt s, i n t he a bse nce of o n g oi n g  cli nicall y rele va nt tra nsa mi nase 
ele vati o ns , will be  treate d wit h t he rec o m me n de d d ose of 2. 5  m g/ k g gi v osira n S C o nce m o nt hl y.  
T he f oll o wi n g  a d diti o nal c ha n ges are als o bei n g i m ple me nte d : 
•  All o w p atie nts w h o de vel o p a tra nsa mi nase ele vati o n t hat meets a pr ot oc ol-defi ne d 
d ose h ol di n g r ule w hile recei vi n g 2. 5  m g/ k g gi v osira n S C o nce m o nt hl y t o res u me 
d osi n g at eit her t he 1. 2 5 - or 2. 5 -m g/ k g gi v osira n S C o nce m o nt hl y d ose after 
res ol uti o n of ala ni ne a mi n otra nsferase ( A L T ) t o ≤2 ×u p per li mit of n or mal ( U L N ; or 
≤2 × baseli ne f or patie nts w h o ha d ele vate d baseli n e A L T) per t he I n v esti gat or’s 
j u d ge me nt a n d after disc ussi o n wit h t he me dical m o nit or .  T his c ha n ge will e na ble t he 
c ollecti o n of r o b ust safet y dat a at t he c o m merical  d ose after a d ose i nterr u pti o n f or 
A L T ele vati o n i n a cli nical trial setti n g.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1 ) 
A me n d me nt 5  S u m m ar y of C h a n ges , 1 2  Fe br u ar y 2 0 2 0  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2  
•  Disc o nti n uati o n of m o nit ori n g b y t he D ata M o nit ori n g C o m mittee ( D M C):  I n 
Oct o ber  2 0 1 9 , t he D M C f or St u d y  A L N -A S 1 -0 0 3  met a n d re vie we d all a v aila ble 
data , w hic h i ncl u de d at leas t 1 2 m o nt hs of data f or all patie nts o n t he st u d y  ( 6 m o nt hs 
d uri n g t he D B p eri o d a n d 6  m o nt hs d uri n g t he O L E  peri o d) .  T he D M C deter mi ne d 
t hat t he safet y pr ofile f or gi v osira n c o nti n ue d t o be acce pta ble a n d a gree d wit h t he 
S p o ns or’ s rec o m me n d ati o n t o ter minate t he D M C f or t he re m ai n der of t h e O L E 
p eri o d of t he st u d y .  Base d o n t he fa v ora ble safet y pr ofile f or gi v osira n, a p pr o val of 
gi v osira n b y t he F D A i n N o v e m ber 2 0 1 9 , a n d C H M P p ositi ve o pi ni o n i n 
J a n uar y 2 0 2 0 , t he D M C c harter is bei n g a me n de d i n parallel wit h t his a me n d me nt t o 
per mit disc o nti n uati o n of t he D M C .  Patie nt safet y will c o nti n ue t o be m o nit ore d o n a 
re g ular b asis b y t he S p o ns or acc or di n g t o sta n d ar d o perati n g pr oce d ures . 
•  Re m o v al of t he re q uir e m e nt t o test a n d re vie w t h e res ults f or i nter nati o nal n or malize d 
rati o (I N R) wit hi n 1 4  da ys pri or t o d osi n g :  Base d o n data fr o m t he gi v osira n 
de vel o p me nt pr o gra m, testi n g of I N R pri or t o d osi n g has n ot e n ha nced  t he detecti o n 
of ac ute h e patic i nj ur y be y o n d t he pre d ose assess me nt of A L T a n d t otal bilir u bi n 
( T B L).  A d diti o nall y, n o cli nicall y si g nifica nt c ha n ges i n c oa g ulati o n para meters ha ve 
bee n see n i n p atie nts wit h A L T ele vati o ns > 3 × U L N.  M ore o ver, testi n g of I N R o n 
eac h p atie nt  pri or t o d osi n g re q uires c ollecti o n of a d diti o nal a n d u n necess ar y bl o o d 
sa m ples.  I n all patie nts wit h A L T ele vati o n > 3 × U L N, I N R testi n g will still be  
re q uire d t o pr o vi de f urt h er i nf or mati o n o n t he se v erit y of he patic i nj ur y (see 
Secti o n  6. 2. 3. 1).  E val uati o n of A L T a n d T B L wit hi n 1 4  da ys pri or t o d osi n g  a n d 
testi n g of I N R wit h r e g ular cli nical la b orat ories as s pecifie d i n t he Sc he d ul e of 
Assess me nts  will c o nti n ue . 
•  U p date p ote ntial safet y c o ncer ns t o be c o nsiste nt wit h e mer gi n g d ata a n d t o ali g n 
wit h t he I n v esti gat ors Br oc h ure.  
A detaile d s u m mar y of c ha n g es is pr o vi de d i n  Ta ble  1 .  C orrecti o ns t o t y p o gra p hical err ors, 
p u nct uati o n, gra m mar, a b bre viati o ns, a n d f or m atti n g  (i ncl u di n g a d mi nistrati ve c ha n ges bet w ee n 
pr ot oc ol a me n d me nt s 4  a n d 5 ) are n ot d etaile d.  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1 ) 
A me n d me nt 5  S u m m ar y of C h a n ges , 1 2  Fe br u ar y 2 0 2 0  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
T a ble  1 : 
Pr ot oc ol A me n d me nt 5 Det aile d S u m m a r y of C h a n ges  
T he pri mar y secti o n(s) of t he pr ot oc ol affecte d b y t he c ha n ges i n Pr ot oc ol A me n d me nt 5  are i n dicat e d.  T he c orres p o n di n g te xt has 
bee n re vis e d t hr o u g h o ut t he pr ot oc ol.   Delet e d te xt is i n dicate d b y stri ke o ut; a d de d te xt is i n dicate d b y b ol d  f o nt. 
P ur p ose:  T o i ncre ase t he d ose of giv osir a n f or p atie nts receivi n g 1. 2 5  m g/k g giv osir a n S C o nce m o nt hly t o t he rec o m me n de d d ose of 2. 5  m g/k g 
giv osir a n S C o nce m o nt hly.  
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3. 4,  D ose Escalati o n G ui da nce f or Gi v osira n fr o m 1. 2 5  m g/ k g O nc e M o nt hl y t o 2. 5  m g/ k g O n ce 
M o nt hl y i n t he O pe n -La bel Peri o d  
N o w rea ds:  
6. 2. 3. 4  
D ose Esc al ati o n G ui d a nce f or Gi v osir a n fr o m 1. 2 5 m g/ k g O nce M o nt hl y t o  2. 5  m g/ k g O nce 
M o nt hl y i n t he O pe n -L a bel Peri o d  
After i m ple me nt ati o n of a me n d me nt  3 a n d u ntil i m ple me nt ati o n of a me n d me nt  5, p atie nts assi g ne d t o 
t he o nce m o nt hl y 1. 2 5-m g/ k g tre at me nt gr o u p m a y be  all o we d t o h a ve t heir m o nt hl y d ose i ncre ase d t o 
2. 5  m g/ k g S starti n g at t he M o nt h  1 3 St u d y Visit ( w he n 6 m o nt hs of o pe n -l a bel gi v osira n d osi n g h a ve  bee n 
c o m plete d at 1. 2 5  m g/ k g ), b ase d o n disc ussi o n a n d a gree me nt b y t he I n vesti g at or a n d me dic al m o nit or.  
D ose esc al ati o n m a y be  c o nsi dere d patie nts recei vi n g o pe n la bel gi v osira n at S C d oses of 1. 2 5  m g/ k g m o nt hl y 
ma y b e per mitte d t o i ncrease t heir m o nt hl y d ose t o 2. 5 m g/ k g base d o n I n v esti gat or j u d ge me nt.  I n v esti gat ors 
ma y c o nsi der d ose escal ati o n  if t he f oll o wi n g criteria are met:  
•  T olera bilit y t o gi v osira n at 1. 2 5 m g/ k g o nce m o nt hl y has b ee n de m o nstrat e d base d o n n o d ose 
i nterr u pti o ns d ue t o L F T ele vati o ns at t he 1. 2 5 m g/ k g o nce m o nt hl y d ose le vel (see Secti o n  6. 2. 3. 1) 
a n d n o si g nifica nt safet y c o ncer ns d ue t o ot her A Es t hat w o ul d precl u de a p atie nt fr o m recei vi n g a  
hi g her d ose of gi v osira n as j u d ge d b y t he  I n vesti gat or a n d S p o ns or.   
•  Uri ne A L A le v els ( m m ol/ m ol Cr) are n ot sta bl y m ai ntai ne d ≤U L N or are i n d uci ble  
•  Patie nt has i na de q uate cli nical res p o nse (e g, brea kt hr o u g h attac ks or o n g oi n g c hr o nic s y m pt o ms), 
acc or di n g t o I n v esti gat or j u d ge me nt.  
U p o n i m ple me nt ati o n of a me n d me nt  5, all p atie nts recei vi n g 1. 2 5  m g/ k g gi v osir a n o nce m o nt hl y w h o d o 
n ot h a ve o n g oi n g cli nic all y rele v a nt tr a ns a mi n ase ele v ati o ns will h a ve t heir d ose i ncre ase d t o 2. 5  m g/ k g 
gi v osir a n o nce m o nt hl y  b ase d o n t oler a bilit y al o ne, wit h o ut a n y criteri a f or A L A re d ucti o n or cli nic al 
acti vit y .  D ose i ncre ases s h o ul d t a ke effect as of t he d ate t h at s ufficie nt st u d y dr u g m ateri al c a n be m a de 
a v ail a ble f or t he p atie nt.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1 ) 
A me n d me nt 5  S u m m ar y of C h a n ges , 1 2  Fe br u ar y 2 0 2 0  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4  
Uri ne A L A a nal yses ma y be c o n d ucte d at a  l ocal l a b orat or y or A L A res ults fr o m pre vi o us visits ma y be 
e val uate d i n patie nts o n t he 1. 2 5 m g/ k g m o nt hl y d ose i n w h o m d ose escalati o n t o 2. 5  m g/ k g o n ce m o nt hl y is 
bei n g c o nsi dere d  
T he decisi o n t o i ncrease t he gi v osira n d ose fr o m 1. 2 5 m g/ k g m o nt hl y t o 2. 5  m g/ k g m o nt hl y will be disc usse d 
a n d a gree d u p o n b y t he I n vesti gat or a n d me dical m o nit or pri or t o i nitiati o n of t he ne xt d ose.  
U p o n i ncreas e of t he gi v osira n d ose t o 2. 5 m g/ k g m o nt hl y:  
•  L F Ts, I N R, a n d T B L will be m o nit ore d e ver y 2 wee ks ( ± 7 da ys) f or t he  first m o nt h f oll o wi n g t he 
d ose i ncrease t o 2. 5 m g/ k g, t he n m o nt hl y ( ± 7 da ys or d uri n g t h e sc he d ule d st u d y visits) as per t he 
Sc he d ule of Assess me nts  
•  La b orat or y m o nit ori n g a n d d osi n g r ules i n r es p o nse t o L F T ele vati o n will f oll o w Ta ble  4  g ui d eli nes  
•  F or pat ie nts i n w h o m gi v osira n d osi n g is wit h hel d d ue t o ele vate d A L T, res u m pti o n of d osi n g ma y 
be c o nsi dere d base d o n t he g ui d a nce i n Secti o n  6. 2. 3. 1. 1 . 
 
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  
•  
S y n o psis , St u d y Desi g n 
•  
T a ble 3, f o ot n otes h a n d j  
•  
Secti o n 1. 3, St u d y Desi g n Rati o nale  
•  
Secti o n 1. 4, D ose Rati o nale  
•  
Secti o n 4. 1, S u m mar y of St u d y Desi g n  
•  
Fi g ure 2, St u d y Desi g n  
•  
Secti o n 6. 2. 2. 2, D uri n g t he O pe n -La bel E xte nsi o n Peri o d ( A fter M o nt h 6 t hr o u g h E n d of Treat me nt) 
•  
Secti o n 6. 2. 3, D ose M o dificati o ns  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1 ) 
A me n d me nt 5  S u m m ar y of C h a n ges , 1 2  Fe br u ar y 2 0 2 0  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5  
P ur p ose:  All o w p atie nts w h o devel o p a tr a ns a mi n ase elev ati o n t h at meets a pr ot oc ol defi ne d d ose h ol di n g r ule w hile receivi n g 2. 5  m g/k g 
giv osir a n S C o nce m o nt hly t o res u me d osi n g at eit her t he 1. 2 5 - or 2. 5 -m g/k g giv osir a n S C o nce m o nt hly d ose after res ol uti o n of A L T  t o ≤2 × U L N 
( or ≤2 × b aseli ne f or p atie nts w h o h a d elev ate d b aseli ne A L T) per t he I nvesti g at or’s j u d ge me nt a n d after disc ussi o n wit h t he medic al m o nit o r. 
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3. 1. 1 , Criteria f or Rec halle n ge of Gi v osira n After Bei n g Wit h he l d f or A L T Ele vati o n 
N o w rea ds:  
6. 2. 3. 1. 1  Criteri a f or Rec h alle n ge of Gi v osir a n After Bei n g Wit h hel d f or A L T Ele v ati o n  
F or patie nts i n w h o m gi v osira n d osi n g  is wit h hel d d ue t o ele vate d A L T, res u m pti o n of d osi n g ma y b e 
c o nsi dere d usi n g t he f oll o wi n g g ui deli nes:  
•  Patie nts w h o di d n ot meet criteria f or st u d y dr u g disc o nti n uati o n per Ta ble 4  ma y b e c o nsi dere d f or 
rec halle n ge f oll o wi n g c o ns ultati o n wit h t he me dical m o nit or a n d res ol uti o n of A L T t o ≤ 2 × U L N or 
≤ 2 × baseli ne (f or patie nts w h o ha d ele vate d ba seli ne A L T) 
•  T he decisi o n t o rec halle n ge t h e patie nt s h o ul d be disc usse d a n d a gree d u p o n b y t he patie nt, 
I n v esti gat or, a n d me dical m o nit or 
•  T he d ose re gi me n f or patie nts w h o meet rec halle n ge criteri a, re gar dless of t heir d ose at t he ti me of 
t he A L T ele vati o n, is a d ose of eit her 1. 2 5 or 2. 5  m g/ k g m o nt hl y  per I n vesti gt or j u d ge me nt  a n d 
after disc ussi o n wit h t he me dic al m o nit or : 
− L F Ts, I N R a n d T B L will be m o nit ore d e ver y 2 wee ks ( ± 7 da ys) f or t he first m o nt h, t he n 
m o nt hl y ( ± 7 da ys or d uri n g t he sc he d ule d st u d y vi sits) as per t he Sc he d ule of Assess me nts 
− La b orat or y m o nit ori n g a n d d osi n g r ules i n r es p o nse t o L F T ele vati o n will f oll o w Ta ble 4  
g ui deli nes  
•  If d ose wit h h ol di n g r ules per Ta ble 4  are m et o n t hisrec h alle n ge wit h  t he 1. 2 5-m g/ k g  d ose, 
per ma ne ntl y disc o nti n ue d osi n g  
•  F or patie nts treate d wit h 2. 5 m g/ k g m o nt hl y gi v osira n at t he ti me of t he A L T ele vati o n, d ose re
escalati o n t o 2. 5 m g/ k g m o nt hl y m a y be c o nsi dere d if t he f oll o wi n g criteria are m et:  
 A p pr o val b y t he me dical m o nit or afte r at least 3 d oses of 1. 2 5 m g/ k g m o nt hl y f or p atie nts w h o 
meet b ot h criteria b el o w:  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1 ) 
A me n d me nt 5  S u m m ar y of C h a n ges , 1 2  Fe br u ar y 2 0 2 0  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6  
o  Patie nt has n ot met d ose wit h h ol di n g or disc o nti n uati o n r ules per T a ble 4  d uri n g tr eat me nt 
wit h 1. 2 5 m g/ k g m o nt hl y  
o  Patie nt has i na de q uate c o ntr ol of p or p h yria s y m pt o ms o n t he 1. 2 5 m g/ k g m o nt hl y re gi me n, 
per i n vesti gat or’s ass ess me nt  
 L F Ts, I N R, a n d T B L will be m o nit ore d e ver y 2 wee ks ( ± 7 da ys) f or t he first m o nt h after d ose 
re es calati o n, a n d t he n m o nt hl y as per t he Sc he d ul e of Assess me nts  
•  If a patie nt e x perie nces a sec o n d d ose h ol d d ue t o L F T ele vati o n w hile o n 2. 5 m g/ k g m o nt hl y:  
− F oll o w Ta ble 4  g ui deli nes f or m o nit ori n g a n d e val uati o ns  
− If A L T res ol ves t o ≤2 × U L N, re d osi n g wit h 1. 2 5 m g/ k g m o nt hl y ma y b e c o nsi dere d if t his d ose 
was pre vi o usl y t olerat e d a n d t here is a p pr o val b y after disc ussi o n wit h  t he Al n yla m me dical 
m o nit or.  If d osi n g is res u me d, f oll o w t he g ui d a nce a b o ve f or rec halle n ge re gi me n re gar di n g 
la b orat or y m o nit ori n g a n d d osi n g r ules.  N o s u bs e q ue nt re-escal ati o n t o 2. 5 m g/ k g m o nt hl y will 
be all o we d  
o  L F Ts, I N R, a n d T B L will be m o nit ore d e ver y 2 wee ks ( ± 7 da ys) f or t he first m o nt h after 
d ose res u mi n g 1. 2 5 m g/ k g, a n d t h e n m o nt hl y as p er t he Sc he d ule of Assess me nts  
 
P ur p ose:  Disc o nti n u ati o n of m o nit ori n g by t he D at a M o nit ori n g C o m mittee ( D M C)  
T he pri mar y c ha n ge occ urs i n Secti o n 4. 7, I n de pe n de nt Data M o nit ori n g C o m mittee  
N o w rea ds:  
4. 7  
I n de pe n de nt D at a M o nit ori n g C o m mittee 
A n e xter nal i n de pe n de nt D M C will m o nit or safet y o ver t he c o urse of t he d o u ble -bli n d tre at me nt peri o d a n d 
u ntil all p atie nts h a ve bee n i n t he O L E peri o d f or at le ast 6  m o nt hs st u d y. A nal ys es f or t he D M C are 
pr o vi de d b y a n i n de pe n d e nt bi ostatistics gr o u p. Details are pr o vi d e d i n t he D M C C harter . 
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  
•  
S y n o psis , St u d y Desi g n 
•  
Secti o n 1. 5, Be nefit -Ris k Assess me nt  
•  
Secti o n 4. 1, S u m mar y of St u d y Desi g n  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
gi v osir a n ( A L N -A S 1 ) 
A me n d me nt 5  S u m m ar y of C h a n ges , 1 2  Fe br u ar y 2 0 2 0  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7  
•  
Fi g ure 2, St u d y Desi g n  
•  
Secti o n 6. 2. 2. 2, D uri n g t he O pe n -La bel E xte nsi o n Peri o d ( After M o nt h 6 t hr o u g h E n d of Treat me nt)  
•  
Secti o n 6. 2. 3, D ose M o dificati o ns  
P ur p ose:  Re m ov al of t he re q uire me nt t o test a n d revie w t he res ults f or i nter n ati o n al n or m alize d r ati o (I N R) wit hi n 1 4  d ays pri or t o d osi n g  
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 2, D ose a n d A d mi nistrati o n  
N o w rea ds:  
A L T  a n d , t otal bilir u bi n ( T B L) a n d I N R res ults c ollecte d wit hi n 1 4 da ys of st u d y dr u g a d mi nistrati o n m ust be re vie we d 
pri or t o d osi n g.   
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  
•  
T a ble 3, f o ot n ote f  
•  
Secti o n 6. 2. 3. 1, M o nit ori n g a n d D osi n g R ules Base d o n Li ver F u ncti o n T est Res ults  
•  
Secti o n 7. 5. 5,  Cli nical La b orat or y Assess me nts  
P ur p ose:  U p d ate p ote nti al s afety c o ncer ns t o be c o nsiste nt wit h e mer gi n g d at a a n d t o ali g n wit h t he I nvesti g at ors Br oc h ure . 
T he pri mar y c ha n ge occ urs i n Secti o n 1. 5, Be nefit -Ris k Assess me nt  
N o w rea ds:  
Gi ve n t he bi ol o gical tar get of gi v osira n, t he a vaila ble n o ncli nical a n d cli nical data, a n d t he m o de of a d mi nistrati o n, ot her 
i m p orta nt p ote ntial ris kss afet y c o ncer ns i ncl u de i njecti o n site reacti o ns (I S Rs), ele v ati o n of li ver tra nsa mi nases 
a b n or malities , incre ase d ser u m cre ati ni ne / decre ase d esti m ate d gl o mer ul ar filtr ati o n r ate (e G F R), pa ncreatitis , a n d 
a na p h ylactic reacti o n s. 
P ur p ose:  C orrect ty p o gr a p hic al err ors, p u nct u ati o n, gr a m m ar, a b brevi ati o ns, a n d f or m atti n g [, i ncl u di n g a d mi nistr ative c h a n ges, if ap pr o pri ate]  
T hese c ha n ges are n ot liste d i n di vi d uall y.  
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
g i v osir a n (A L N -A S 1 ) 
A me n d me nt 4 S u m m ar y of C h a n ges , 2 8 M a y  2 0 1 9  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1  
A L N -A S 1 -0 0 3 P R O T O C O L  A M E N D M E N T 4  
S U M M A R Y O F C H A N G E S D A T E D 2 8 M A Y  2 0 1 9  
E N VI SI O N: A P h ase 3 R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d M ultice nter St u d y 
wit h a n O pe n -l a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of Gi v osir a n i n P atie nts 
wit h Ac ute He p atic P o r p h yri as  
R ati o n ale f or Pr ot oc ol A me n d me nt  
T he pri mar y p ur p os e f or t his pr ot oc ol a me n d me nt is t o pr o vi de u p date d i nf or mati o n fr o m a 
rece ntl y c o m plet e d dr u g-dr u g i nteracti o n st u d y  ( A L N-A S 1 -0 0 4) perf or m e d i n AI P patie nts w h o 
are as y m pt o matic hi g h e x creters (als o r eferre d t o as c hr o nic hi g h e x cret ers [ C H E]) i n t he 
c o nc o mita nt me dicati o ns secti o n ( Secti o n  6. 3).  T he res ults of t he st u d y i n dicate d t hat gi v osira n 
treat me nt res ulte d i n mo derate re d ucti o n i n C Y P 1 A 2 a n d C Y P 2 D 6 acti vit y, wea k re d ucti o n i n 
C Y P 3 A 4 a n d C Y P 2 C 1 9 acti vit y, a n d n o c ha n ge i n t he acti vit y of C Y P 2 C 9.  
A d diti o nal u p dates are b ei n g i m ple me nte d as n ote d bel o w:   clarificati o n t hat patie nts ma y 
c o nti n ue t o recei ve gi v osira n  u ntil it is c o m merciall y a vaila ble i n t he patie nt’s territ or y, u p date t o 
clarif y t hat staff d o n ot nee d t o wait u ntil t he e n d of t he st u d y b ef ore o btai ni n g l ocal A L A or 
P B G meas ur e me nt s, u p d ates t o be c o nsiste nt wit h c ha n ges ma d e i n a me n d me nt 3, a d diti o n of 
g ui da n ce f or seri o us breac hes of pr ot oc ol, u p date d  P K, E C G a n d A D A ti me p oi nts, a n d deleti o n 
of Secti o n  1 1. 2 , List of S e nsiti ve C Y P 3 A s u bstrates a n d t h ose wit h a Narr o w T hera p e utic Ra n ge. 
A detaile d s u m mar y of c ha n ges is pr o vi de d i n  Ta ble  1 .  Correcti o ns t o t y p o gra p hical err ors, 
p u nct uati o n, gra m mar, a b bre viati o ns, a n d f or m atti n g (i ncl u di n g a d mi nistrati ve c ha n ges bet w ee n 
pr ot oc ol a me n d me nts  3 a n d  4) a re n ot d etaile d. 
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
g i v osir a n (A L N -A S 1 ) 
A me n d me nt 4 S u m m ar y of C h a n ges , 2 8 M a y  2 0 1 9  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2  
T a ble  1 : 
Pr ot oc ol A me n d me nt  4 Det aile d S u m m a r y of C h a n ges  
T he pri mar y secti o n(s) of t he pr ot oc ol affecte d b y t he c ha n ges i n Pr ot oc ol A me n d me nt  4 are i n dicat e d.  T he c orres p o n di n g te xt has 
bee n re vis e d t hr o u g h o ut t he pr ot oc ol.  Delet e d te xt is i n dicate d b y stri ke o ut; a d de d te xt is i ndicate d b y b ol d  f o nt. 
P ur p ose:  U p d ate d Secti o n 1. 2. 2, S u m m ary of Cli nic al D at a wit h Giv osir a n, wit h res ults of t he o pe n -l a bel dr u g-dr u g i nter acti o n st u dy ( A L N -A S 1 -
0 0 4) t o s u p p ort c h a n ges i n Secti o n 6. 3, C o nc o mit a nt Me dic ati o ns.  
T he pri mar y c ha n ge is t he a d diti o n of Secti o n  1. 2. 2. 3, Dr u g -dr u g I nteracti o n St u d y A L N -A S 1 -0 0 4  
A d de d te xt : 
1. 2. 2. 3  
Dr u g -dr u g I nter acti o n St u d y A L N -A S 1 -0 0 4  
A n o pe n-l a bel dr u g- dr u g i nter acti o n ( DDI) st u d y ( A L N- A S 1- 0 0 4) w as c o n d ucte d i n AI P p atie nts w h o are 
C H E t o e v al u ate t he effect of a si n gle d ose of 2. 5 m g/ k g gi v osir a n a d mi nistere d S C o n t he p h ar m a c o ki netics 
of pr o be s u bstr ates f or 5 m aj or c yt oc hr o me P 4 5 0 ( C Y P) e nz y mes t h at acc o u nt f or t he met a b olis m of 
a p pr o xi m atel y 8 0 % of prescri be d dr u gs ( 2 4, 2 5).  Res ults fr o m t his st u d y de m o nstr ate d t h at gi v osir a n 
tre at me nt res ulte d i n we a k t o m o der ate re d ucti o n i n t he met a b olic acti vit y of s o me of t he 5 C Y P enz y mes 
st u die d, t here b y le a di n g t o hi g her co nce ntr ati o ns of s o me s ubstr ates a n d t heir m et a b olites.  Tre at me nt wit h 
gi v osir a n res ulte d i n a n a p pr o xi m atel y 3-f ol d incre ase i n ex p os ure ( as me as ure d b y A U C) t o c affei ne ( a 
se nsiti ve s u bstr ate for C Y P 1 A 2) a n d a n a p pr o xi m atel y 2-f ol d i ncre ase i n ex p os ure t o de xtr o met h or p h a n ( a 
se nsiti ve s u bstr ate for C Y P 2 D 6).  E x p os ure of m i d az ol a m ( a se nsiti ve s u bstr ate for C Y P 3 A 4) a n d 
o me pr az ole ( a se nsiti ve s u bstr ate for C Y P 2 C 1 9) i ncre ase d less t h a n 2 -f ol d af ter tre at me nt wit h gi v os ir a n.  
T here w as n o effect of gi v os ir a n tre at me nt o n l os art a n ( a se nsiti ve s u bstr ate for C Y P 2 C 9). 
P ur p ose:   Cl arify t h at s u bjects m ay c o nti n ue u ntil giv osir a n is c o m merci ally av ail a ble or t he giv osir a n devel o p me nt pr o gr a m is disc o nti n ue d.  
T he pri mar y c ha n ge is t he a d diti o n of 2  se nte nces t o Secti o n 4. 1, S u m mar y of St u d y Desi g n.  
A d de d te xt : 
D uri n g t he O L E Peri o d, p atie nts m a y recei ve gi v osir a n as l o n g as t he y d o n ot f ulfill a n y of t he st u d y disc o nti n u ati o n 
criteri a (see Secti o n  5. 3 ) or u ntil gi v osir a n is c o m merci all y a v ail a ble i n t he p atie nt’s territ or y or t he gi v osir a n
de vel o p me nt pr o gr a m is disc o nti n ue d ( w hic he ver c o mes first).  
All p atie nts are as ke d t o p artici p ate i n t he S afet y F oll o w -u p visit after t he y h a ve recei ve d t heir l ast d ose of gi v osir a n.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
g i v osir a n (A L N -A S 1 ) 
A me n d me nt 4 S u m m ar y of C h a n ges , 2 8 M a y  2 0 1 9  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  

Sy n o psis, St u dy Desi g n
P ur p ose:  U p d ate d c o nc o mit a nt me dic ati o ns t o i n dic ate t h at giv osir a n tre at me nt c o ul d affect dr u gs t h at are met a b olize d pri m arily by C Y P 2 D 6 
a n d C Y P 1 A 2.  
T he pri mar y c ha n ge occ urs i n Secti o n  6. 3, C o nc o mita nt Me dicati o ns  
F or merl y rea d:  
Patie nts wit h p or p h yria c o ul d ha ve altere d he me s y nt hesis a n d tr eat me nt wit h gi v osira n c o ul d als o m o d ulate t his 
pat h wa y an d ca n sec o n daril y i mpact c yt o c hr o me p 4 5 0 ( C Y P) e nz y me acti vit y. St u dies i n m o n ke ys c o ul d n ot 
e x cl u de t he p ote ntial f or gi v osira n t o alter t he cleara nce o f dr u gs meta b olize d b y t he C Y P 3 A e nz y m es.  
I n v esti gat ors will revie w all me dic ati o ns at t he st u dy start a n d m o nit or t he res p o nse t o t hese me dic ati o ns d uri n g t he 
st u d y.  Me dic ati o ns wit h a na rr o w t hera p e utic i n dex t hat re q uire reg ular m o nit ori n g ma y ne e d t o be m o nit ore d 
m ore fre q u e ntl y i n t he i nitial sta ges of t h e st u dy t o deter mi ne w he t h er a d os e adj ust me nt of t he c o n c o mita nt 
me dicati o n is re q uire d.  A list of c o m m o n me dicati o ns t hat are se nsiti ve C Y P 3 A s u bstrates or C Y P 3 A s u bstrates 
wit h a narr o w t hera pe utic ra n ge ca n be f o u n d i n Secti o n 1 1. 2. F or m ore detaile d a n d u p-t o - date i nf or mati o n o n 
C Y P 3 A s u bstrates, see: 
htt ps:// w w w.f da. g o v/ dr u gs/ de vel o p me nta p pr o val pr ocess/ de vel o p me ntres o urces/ dr u gi nteracti o nsla beli n g/ uc m 0 9 3 6
6 4 .ht m.
N o w rea ds:  
Patie nts wit h p or p h yria c o ul d ha ve altered he p atic  he me s y nt hesis, a n d tr eat me nt wit h gi v osiran c o ul d als o 
m o d ulate t his pa t h wa y an d ca n sec o n d aril y i mpa ct c yt oc hr o me p 4 5 0 ( C Y P) e nz yme acti vit y .  St u dies Res u lts fr o m 
a D DI st u d y  i n m o n ke ys c o ul d n ot e xcl u de t he p ote ntial f or AI P p atie nts w h o are C H E are prese nte d i n Secti o n 
1. 2. 2. 3.  T he D DI st u d y de m o nstr ate d t h at gi v osira n t o altert he cleara nce tre at me nt res ulte d i n we a k t o 
m o der ate re d ucti o n i n ac ti vit y of s o me of t he CY P enz y mes res ulti n g i n corres p o n di n g l o w t o m o der ate 
i ncre ase i n t he pl as m a l e ve ls of dr u g s t h at are meta b olize d b y t hese C Y P e nz y mes.  B ase d o n t he m o der ate 
decre ase i n b y the C Y P 3 A e nz y mes.  C Y P 2 D 6 or C Y P 1 A 2 acti vit y,.   Iin v esti ga t ors will revie w all c o nc o mit a nt 
me dicati o ns t h at are p ri ma ril y met a b olize d b y t hese enz y mes at t he st u d y start a n d m o ni t or t he p atie nt’ s cli nical 
res p o nse t o t hese me di cati o ns d uri n g t he st u d y.  Me dicati o ns met a b olize d p ri m aril y b y C Y P 2 D 6 a n d C Y P 1 A 2  
wit h a narr o w t h era p e utic i n de x (ie, t hat re q uire re g ul ar l a b or at ory m o nit ori n g ) m a y ne e d t o b e m o nit ore d m ore 
fre q ue ntl y i n t he i nitial stages of t he st u dy t o deter mi ne w het her if a d ose adj ust me nt of t he c o nc o mita nt me dicati o n 
is re q uire d.  A list of c o m m o n me dicati o ns t hat are sensiti ve C Y P 3 A s u bstrates or C Y P 3 A s u bstra tesF or p ati e nts 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
g i v osir a n (A L N -A S 1 ) 
A me n d me nt 4 S u m m ar y of C h a n ges , 2 8 M a y  2 0 1 9  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4  
w h o re q uire ne w  me dic ati o ns w hile o n st u d y, selecti o n of me dic ati o ns t h at are n ot pri m aril y met a b olize d b y 
C Y P 2 D 6 or C Y P 1 A 2 s h o ul d be c o nsi dere d.  Refer t o t he i n di vi d u al pr o d uct’s prescri pti o n i nf or m ati o n t o 
deter mi ne if t here is a n ee d t o m o nit or c o nc o mit a nt me dic ati o ns f or differe nces i n s afet y or effic ac y of t he 
me dic ati o n b ase d o n re p orte d D DIs  wit h a narr o w t hera pe utic ra n ge ca n be f o u n d i n Secti o n  1 1. 2 .C Y P 2 D 6 or 
C Y P 1 A 2.  F or m ore detaile d a n d u p-t o - date i nf or mati o n o n C Y P 3 A s u bstrates, see: 
htt ps:// w w w.f da. g o v/ dr u gs/ de vel o p me nta p pr o val pr ocess/ de vel o p me ntres o urces/ dr u gi nteracti o nsla beli n g/ uc m 0 9 3 6
6 4. ht m.
P ur p ose:  C orrect a n err or i n Secti o n  7. 3 s o t h at st aff d o n ot nee d t o w ait u ntil t he e n d of t he st u dy bef ore o bt ai ni n g a l oc al A L A or P B G 
me as ure me nt.  
T he pri mar y c ha n ge occ urs i n Secti o n  7. 3, P har mac o d y na mic Assess me nts  
F or merl y  rea d: 
Uri ne sa m ples wi ll be c ollecte d f or assess me nt of gi v osira n P D para meters pri or t o d osi n g.  T he P D effect of 
gi v osira n will be e val uat e d b y s p ot uri n e A L A a n d P B G le vels n or malize d t o s p ot uri ne creati ni ne l e vels.  Uri ne 
sa m ples will be c ollecte d f or assess me nt of circ ulati n g A L A S 1 m R N A le vels.  A nal ysis of uri n e A L A S 1 m R N A 
le vels will be perf or me d at Al n yla m; all ot her uri ne P D a nal yses will ta ke place at a ce ntr al la b orat or y.  Si nce 
I n v esti gat ors are bli n de d t o treat me nt assi g n m e nts, t he y will als o be bli n de d t o A L A a n d P B G res ults a nal yze d at 
t he ce ntral la b orat or y.  I n a d diti o n, i n vesti gat ors a n d staff i n v ol ve d wit h t his trial a n d all me dical staff i n v ol ve d i n 
t he s u bject’s me dical care s h o ul d refrai n fr o m o bt ai ni n g l ocal A L A or P B G meas ure m e nts u ntil at least 1 2 wee ks 
after t he m o nt h 6 visit or u ntil t he s u bject e n ds t he st u d y, w hic h e ver is later (t o a v oi d p ote ntial u n bli n di n g).  If A L A 
or P B G is meas ur e d d uri n g t his peri o d, all reas o n a ble ste ps m ust be u n dert a ke n t o a v oi d i nf or mi n g t he s u bject a n d 
st u d y pers o n n el of t he res ults. 
N o w rea ds:  
Uri ne sa m ples will be c ollecte d f or assess me nt of gi v osira n P D para meters pri or t o d osi n g.  T he P D effect of 
gi v osira n will be e val uat e d b y s p ot uri n e A L A a n d P B G le vels n or malize d t o s p ot uri ne creati ni ne l e vels.  Uri ne 
sa m ples will be c ollecte d f or assess me nt of circ ulati n g A L A S 1 m R N A le vels.  A nal ysis of uri n e A L A S 1 m R N A 
le vels will be perf or me d at Al n yla m; all ot her uri ne P D a nal yses will ta ke place at a ce ntr al la b orat or y.  Si nce 
I n v esti gat ors are bli n de d t o treat me nt assi g n m e nts, t he y will als o be blin de d t o A L A a n d P B G res ults a nal yze d at 
t he ce ntral la b orat or y.  I n a d diti o n, i n vesti gat ors a n d staff i n v ol ve d wit h t his trial a n d all me dical staff i n v ol ve d i n 
t he s u bject’s me dical care s h o ul d refrai n fr o m o bt ai ni n g l ocal A L A or P B G meas ure m e nts u ntil at least 1 2 wee ks
after t he m o nt h 6 visit or u ntil t he s u bject e n ds t he st u d y, w hic h e ver is later (t o a v oi d p ote ntial u n bli n di n g).  If A L A 
or P B G is meas ur e d d uri n g t his peri o d, all reas o n a ble ste ps m ust be u n dert a ke n t o a v oi d i nf or mi n g t he s u bject a n d 
st u d y pers o n n el of t he res ults.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
g i v osir a n (A L N -A S 1 ) 
A me n d me nt 4 S u m m ar y of C h a n ges , 2 8 M a y  2 0 1 9  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5  
P ur p ose:  U p d ate d wi n d o w f or vit al si g ns, tri plic ate 1 2 -le a d E C Gs, a n d P K s a m ples at t he 2 h o ur ti me p oi nts  at t he D ay  1 a n d M o nt h  5, 6, a n d 
1 2  visits fr o m 1 0  t o 1 5  mi n utes t o be c o nsiste nt wit h c h a n ges i m ple me nte d i n A me n d me nt  3.  
T he pri mar y c ha n ge occ urs i n S y n o psis, T a ble  1, F o ot n otes h a n d j  
F or merl y  rea d: 
h Vital si g ns i ncl u de bl o o d press ure, heart rate, b o d y te m perat ure, a n d res pirat or y rate a n d will b e meas ure d w he n patie nts are  i n a seate d 
or s u pi ne p ositi o n (s h o ul d be  c o nsiste nt acr oss st u d y visits wit h eac h patie nt) after t he patie nt has reste d f or 1 0 mi n. O n t he Da y 1 a n d 
M o nt h 6 visit, vital si g ns will be c ollecte d pre d ose a n d 2 h o urs p ost d ose ( +  1 0 mi n utes).  O n all ot her d osi n g da ys, vital si g ns will be 
c ollecte d pre d ose.
i Si n gle 1 2 -lea d E C G will be perf or me d i n t he s u pi ne p ositi o n after t he patie nt has reste d c o mf orta bl y f or 5 mi n utes. E C Gs will be 
c ollecte d pri or t o a n y bl o o d dra ws.  
j Tri plicate 1 2 -lea d E C Gs will be perf or me d at pre d ose a n d 2-h o urs ( +  1 0 mi n utes ) p ost-d ose o n t he Da y  1, M o nt h 5, a n d M o nt h 6 visits, 
usi n g vali date d E C G ser vices e q ui p me nt fr o m a ce ntral facilit y; tri plicate meas ure me nts s h o ul d be se p arate d b y a p pr o xi matel y 1 mi n ute 
wit h t he patie nt i n t he s u pi ne p ositi o n after he or s he has reste d c o mf orta bl y f or 5 mi n utes.  W he n E C G a n d bl o o d sa m pl e c ollecti o n (e g, 
f or P K assess me nt) occ ur at t he sa me ti me, E C G assess me nts s h o ul d be perf or me d bef ore bl o o d sa m ples are dra w n .  I n a pres pecifie d 
s u bset of a p pr o xi matel y 2 4 patie nts at pres pecifie d st u d y ce nters (i ncl u di n g all patie nts at East Asia n st u d y ce nters [i n J a pa n, S o ut h 
K orea, a n d T ai wa n]), a n a d diti o nal E C G ( wit h paire d P K assess me nt) at 2 4 h o urs ( ± 2 h o urs) p ost -d ose will be c ollecte d at Da y 1 a n d 
M o nt h 6.  
N o w rea ds:  
h Vital si g ns i ncl u de bl o o d press ure, heart rate, b o d y te m perat ure, a n d res pirat or y rate a n d will b e meas ure d w he n patie nts are i n a seate d 
or s u pi ne p ositi o n (s h o ul d be c o nsiste nt acr oss st u d y visits wit h eac h patie nt) after t he patie nt has reste d f or 1 0 mi n. O n t he Da y 1 a n d 
M o nt h 6 visit, vital si g ns will be c ollecte d pre d ose a n d 2 h o urs p ost d ose ( +  1 0 1 5  mi n utes).  O n all ot her d osi n g da ys, vital si g ns will be 
c ollecte d pre d ose.
i Si n gle 1 2 -lea d E C G will be perf or me d i n t he s u pi ne p ositi o n after t he patie nt has reste d c o mf orta bl y f or 5 mi n utes. E C Gs will be 
c ollecte d pri or t o a n y bl o o d dra ws.  
j Tri plicate 1 2 -lea d E C Gs will be perf or me d at pre d ose a n d 2-h o urs ( +  1 0 1 5  mi n utes) p ost -d ose o n t he Da y  1, M o nt h 5, a n d M o nt h 6 
visits, usi n g vali date d E C G ser vices e q ui p me nt fr o m a ce ntr al facilit y; tri plicate meas ure me nts s h o ul d be se p arate d b y a p pr o xi matel y 1 
mi n ute wit h t he patie nt i n t he s u pi ne p ositi o n after he or s he has reste d c o mf orta bl y f or 5 mi n utes.  W he n E C G a n d bl o o d sa m ple 
c ollecti o n (e g, f or P K assess me nt) occ ur at t he s a me ti me,  E C G assess me nts s h o ul d be perf or me d bef ore bl o o d sa m ples are dra w n .  I n a 
pres pecifie d s u bset of a p pr o xi matel y 2 4 patie nts at pres pecifie d st u d y ce nters (i ncl u di n g all p atie nts at East Asia n st u d y c e nters [i n J a p a n, 
S o ut h K orea, a n d T ai wa n]), a n a d diti o nal E C G ( wit h paire d P K assess me nt) at 2 4 h o urs ( ± 2 h o urs) p ost -d ose will be c ollecte d at Da y 1 
a n d M o nt h 6. 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
g i v osir a n (A L N -A S 1 ) 
A me n d me nt 4 S u m m ar y of C h a n ges , 2 8 M a y  2 0 1 9  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6  
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  

Sy n o psis, T a ble 2, F o ot n ote f

Secti o n 7. 4, P h ar m ac oki netic Assess me nts
P ur p ose:  Secti o n 9. 1. 3, Seri o us Bre ac h of Pr ot oc ol , w as a d de d t o ali g n wit h t he pr ocess f or t he re p orti n g p ote nti al seri o us bre ac hes of pr ot oc ol . 
T he pri mar y c ha n ge is t he a d diti o n of Secti o n  9. 1. 3 , Seri o us Bre ac h of Pr ot oc ol 
A d de d te xt : 
9. 1. 3.  Seri o us Bre ac h of P r ot oc ol  
I n vesti g at ors m ust n otif y t he Me dic al M o nit or wit hi n 2 4 h o urs of bec o mi n g a w are of a p ote nti al seri o us bre ac h of t he 
pr ot oc ol.  A seri o us bre ac h is a bre ac h t h at is li kel y t o affect t o a si g nific a nt de gree t he s afet y a n d ri g hts of a st u d y 
p artici p a nt or t h e reli a bilit y a n d r o b ust ness of t he d at a ge ner ate d i n t he cli nic al tri al.  
P ur p ose:  U p d ate d T a ble 8, P h ar m ac oki netic, E C G, a n d A D A Ti me P oi nts f or All P atie nts ( Exce pt P atie nts at E ast Asi a n Sites), t o i n dic ate t h at 
E C G assess me nt as are n ot re q uire d at 4  h o urs p ost d ose at t he M o nt h 6 or M o nt h 1 2 visits . 
T he pri mar y c ha n ge occ urs i n Secti o n  1 1, P h ar m ac oki netic/ P h ar m ac o dy n a mic Assess me nt Ti me P oi nts  
Re vise d te xt:  
Re m o ve d Xs i n Tri plicate E C G c ol u m n at t he 4 -h o ur p ost d ose ti me p oi nts at t he M o nt h  6 a n d M o nt h  1 2 visits.  
P ur p ose:  Bec a use d at a fr o m t he h u m a n dr u g -dr u g i nter acti o n st u dy s h o we d t h at giv osir a n tre at me nt res ulte d i n a m o der ate ( > 2 -f ol d) re d ucti o n 
of C Y P 2 D 6 a n d C Y P 1 A 2 met a b olic activity, t he g ui d a nce f or i nvesti g at ors i n Secti o n  6. 3 w as u p d ate d t o rec o m me n d t h at me dic ati o ns met a b olize d 
pri m arily by C Y P 2 D 6 a n d C Y P 1 A 2 wit h a n arr o w t her a pe utic i n dex m ay nee d t o be m o nit ore d m ore fre q ue ntly t o deter mi ne if a d os e a dj ust me nt 
of t he c o nc o mit a nt me dic ati o n is re q uire d.  I n t he a bse nce of c o m pre he nsive lists of pr o d ucts met a b olize d by C Y P 2 D 6 a n d C Y P 1 A 2, Secti o n 6. 3 
n o w directs t he I nvesti g at or t o t he pr o d uct i nf or m ati o n of a ny c o nc o mit a nt me dic ati o n re q uire d a n d t o t he T a ble of S u bstr ates  f or C Y P e nzy mes o n 
t he F D A We bsite t o deter mi ne if c o nc o mit a nt me dic ati o ns met a b olize d pri m arily by C Y P 2 D 6 a n d C Y P 1 A 2 nee d t o be m o nit ore d m ore fre q ue ntly.   
Secti o n 1 1. 2, List of Se nsitive C Y P 3 A S u bstr ates a n d T h ose wit h a N arr o w T her a pe utic R a n ge, w as delete d bec a use , b ase d o n t he res ults fr o m t he 
h u m a n dr u g -dr u g i nte r acti o n st u dy, giv osir a n tre at me nt res ults i n o nly a we ak ( < 2-f ol d) re d ucti o n of C Y P 3 A 4 met a b olic activity, a n d t he 
rec o m me n d ati o n t o m o nit or t he dr u g res p o nse i n p atie nts o n me dic ati o ns pri m arily met a b olize d by C Y P 3 A 4 w as n ot c o nsi dere d nec ess ary. 
T he pri mar y c ha n ge occ urs i n Secti o n  1 1. 2, List of Se nsiti ve C Y P 3 A S u bstrates a n d T h ose wit h a Narr o w T hera pe utic Ra n ge . 
Secti o n 1 1. 2  was delete d.  
P ur p ose:  C orrect ty p o gr a p hic al err ors, p u nct u ati o n, gr a m m ar, a b brevi ati o ns, a n d f or m atti n g  
T hese c ha n ges are n ot liste d i n di vi d uall y.  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A L N -A S 1  (gi v osir a n ) 
A me n d me nt 3  S u m m ar y of C h a n ges , 2 1 Se pte m ber 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1  
A L N -A S 1 -0 0 3  P R O T O C O L A M E N D M E N T 3   
S U M M A R Y O F C H A N G E S D A T E D  2 1 Se pte m ber 2 0 1 8  
E N VI SI O N: A P h ase 3 R a n d o mize d, D o u ble -Bli n d, Pl ace b o -C o ntr olle d M ultice nter St u d y 
wit h a n O pe n -l a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of Gi v osir a n i n P atie nts 
wit h Ac ute He p atic P o r p h yri as  
R ati o n ale f or Pr ot oc ol A me n d me nt  
I n li g ht of li ver tra nsa mi nase ele v ati o ns o bser ve d i n t he st u d y, a l o wer gi v osira n d ose  of 
1. 2 5  m g/ k g o nce m o nt hl y w as  i ntr o d uce d i n A me n d me nt 2  as a rec halle n ge d ose f or p atie nts 
w h o res u me d osi n g aft er res ol uti o n of li ver tra nsa mi nase ele vati o ns.  I n or der t o ge nerate 
a d diti o nal data at t his d ose le vel, e v al uati o n of t he 1. 2 5  m g/ k g o nce m o nt hl y d ose is pr o p os e d f or 
patie nts cr ossi n g o v er t o t he o pe n -la bel e xte nsi o n [O L E ] peri o d u n der t his a me n d me nt , after t heir 
c o m pleti o n of t he 6 m o nt h d o u ble -bli n d place b o -c o ntr olle d peri o d . W hile t he 2. 5 m g/ k g o nce 
m o nt hl y d os e has bee n d e m o nstrate d t o pr o vi de near -n or malizati o n of  A L A le vels i n t he 
maj orit y of AI P p atie nts wit h rec urre nt attac ks i n t he c o m plete d P hase 1 A L N-A S 1 -0 0 1 st u d y 
( Part C) a n d t he o n g oi n g P hase 1/ 2 A L N-A S 1 -0 0 2 o pe n -la bel e xte nsi o n st u d y, preli mi nar y  
a nal ys es of P K a n d P D d ata s u g gest t hat a gi v osira n d ose of 1. 2 5 m g/ k g o n ce m o nt hl y w o ul d 
re d uce A L A le v els i n a s u bsta ntial n u m ber of pati e nts .  T his st u d y desi g n will e na ble t he 
e val uati o n of t he P D, effi cac y, a n d safet y of t he 1. 2 5  m g/ k g o nce m o nt hl y d ose of gi v osira n  i n 
t he O L E peri o d, w hile c o nti n ui n g t o pr o vi de data o n t he 2. 5 m g/ k g o nce m o nt hl y d ose.     
T he pri mar y p ur p os e f or t his pr ot oc ol a me n d me nt is t o:  
 I m ple me nt t he i n cl usi o n of a n a d diti o nal, l o wer d ose of gi v osira n ( 1. 2 5 m g/ k g o nce 
m o nt hl y) d uri n g t he o pe n -la bel e xte nsi o n peri o d 
 Pr o vi de s pecif ic g ui da n ce f or i ncreasi n g d ose fr o m 1. 2 5 m g/ k g o n ce m o nt hl y t o 
2. 5  m g/ k g o nce m o nt hl y i n patie nts w h o t olerate  1. 2 5  m g/ k g o nce m o nt hl y d ose b ut 
w h o are e x perie nc i n g i na de q uate diseas e c o ntr ol. 
 A d d s tatistical a nal ys es t o e val uate t he d ura bilit y of t he treat me nt effect.  
A detaile d s u m mar y of c ha n ges is pr o vi de d i n  Ta ble  1 .  Correcti o ns t o t y p o gra p hical err ors, 
p u nct uati o n, gra m mar, a b bre viati o ns, a n d f or m atti n g (i ncl u di n g a d mi nistrati ve c ha n ges bet w ee n 
pr ot oc ol a me n d me nt s 2  a n d 3 ) are n ot d etaile d.  
 
 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A L N -A S 1  (gi v osir a n ) 
A me n d me nt 3  S u m m ar y of C h a n ges , 2 1 Se pte m ber 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2  
T a ble  1 : 
Pr ot oc ol A me n d me nt 3  Det aile d S u m m a r y of C h a n ges   
T he pri mar y secti o n(s) of t he pr ot oc ol affecte d b y t he c ha n ges i n Pr ot oc ol A me n d me nt 3  are i n dicat e d.  T he c orres p o n di n g te xt has 
bee n re vis e d t hr o u g h o ut t he pr ot oc ol.  Delet e d te xt is i n dicate d b y stri ke o ut; a d de d te xt is i n dicate d b y b ol d  f o nt. 
P ur p ose:  U p d ate  t he d ose r ati o n ale t o i ncl u de t he  a d diti o n of t he 1. 2 5 m g/k g o nce m o nt hly d os e 
T he pri mar y c ha n ge occ urs i n Secti o n 1. 4 D ose Rati o nale . 
A d de d te xt : 
I n li g ht of L F T ele v ati o ns o bser ve d i n t he st u d y, a l o wer gi v osir a n d ose of 1. 2 5 m g/ k g o nce m o nt hl y h as bee n 
i ntr o d uce d as a d o w n-titr ati o n d ose, as det aile d i n Secti o n 6. 2. 3. 1.  I n or der t o ge ner ate a d diti o n al d at a at t his d ose 
le vel, e v al u ati o n of t he 1. 2 5 m g/ k g o nce m o nt hl y d ose is pr o p ose d f or p atie nts cr ossi n g o ver t o t he O L E peri o d 
u n der a me n d me nt 3. W hile t he 2. 5 m g/ k g o nce m o nt hl y d ose h as bee n de m o nstr ate d t o pr o vi de ne ar -
n or m aliz ati o n of A L A le vels i n t he m aj orit y of AI P p atie nts wit h rec urre nt att ac ks i n t he c o m plete d P h ase 1 A L N -
A S 1 -0 0 1 st u d y ( P art C) a n d t he o n g oi n g P h ase 1/ 2 A L N -A S 1 -0 0 2 o pe n -l a bel e xte nsi o n st u d y, preli mi n ar y a n al yses 
of P K a n d P D d at a s u g gest t h at a gi v os ir a n d ose of 1. 2 5 m g/ k g o nce m o nt hl y w o ul d re d uce A L A le vels i n a 
s u bst a nti al n u m ber of p atie nts. T he pr o p ose d st u d y desi g n will e n a ble t he e v al u ati o n of t he P D, effic ac y, a n d s afet y 
of t he 1. 2 5 m g/ k g m o nt hl y d ose of gi v osir a n, w hile c o nti n ui n g t o pr o vi de d at a o n t he 2. 5 m g/ k g m o nt hl y d ose.  
T he c o nce ntrati o n of gi v osira n i n t he li ver is t he pri mar y dri ver f or its p har mac o d y na mic effects, w hic h is pri maril y 
affecte d b y b o d y wei g ht. P o p ulati o n p har mac o ki netic -p har mac o d y na mic m o deli n g a n d si m ulati o n acr oss differe nt b o d y 
wei g hts s h o w si milar li v er e x p os ures of gi v osira n i n a d olesce nts a n d a d ults f oll o wi n g 2. 5 m g/ k g  m o nt hl y d osi n g a n d 
c o nse q ue ntl y si milar e xte nt a n d d urati o n of uri nar y A L A s u p pressi o n i n a d olesce nts a n d a d ults.  As a res ult, t he 2. 5 
m g/ k g m o nt hl y d ose re gi me n was selecte d f or t he pr o p ose d P hase 3 pi v otal st u d y i n . T heref ore, t he s a me d oses are 
pr o p ose d t o be a d mi nistere d t o b ot h  a d ults a n d a d olesce nts . i n t his st u d y. 
Secti o ns c o ntai ni n g relate d c ha n ges :   
 
Secti o n 1. 3 St u d y Desi g n Rati o nale  
 
Secti o n 8. 2. 9 Ot her A nal yses  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A L N -A S 1  (gi v osir a n ) 
A me n d me nt 3  S u m m ar y of C h a n ges , 2 1 Se pte m ber 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
P ur p ose:  R evise t he ex pl or at ory o bjective a n d e n d p oi nt t o i n dic ate t h at m ulti ple d oses will be assesse d d uri n g t he O L E peri o d 
T he pri mar y c ha n ge occ urs i n Secti o n 2. 3 E x pl orat or y O bjecti ves  
Re vise d te xt : 
 Assess t he wit hi n patie nt treat me nt effect of gi v osira n at e v al u ate d d oses  o ver t he O L E p eri o d i n  p atie nts 
wit h AI P a n d i n p atie nts wit h a n y A H P w h o ha d pre vi o usl y b ee n ra n d o mize d t o place b o tr eat me nt  
Secti o ns als o c o ntai ni n g t his c ha n ge:  
 
S y n o psis  
 
Secti o n 3. 3 E x pl orat or y E n d p oi nts  
P ur p os e:  U p d ate  st u dy desi g n text a n d ass oci ate d st u dy desi g n fi g ure  t o i ncl u de t he cr oss over str ate gy f or  ev al u ati o n of a sec o n d  d ose 
( 1. 2 5 m g/k g o nce m o nt hly) d uri n g t he O L E peri o d . 
T he pri mar y c ha n ge occ urs i n Secti o n 4. 1 S u m mar y of St u d y Desi g n  
A d de d te xt:  
P ati e nts  e nteri n g t he O L E peri o d w h o cr osse d o ver t o t he O L E peri o d pri or t o i m ple me nt ati o n of a me n d me nt 3 
(ie, u n der a me n d me nt versi o n 1 or 2) a n d are recei vi n g a 2. 5  m g/ k g o nce m o nt hl y  gi v osir a n d ose  will re m ai n o n 
t h at d ose. U p o n e ntr y t o t he O L E peri o d u n der a me n d me nt versi o n 3, p atie nts will cr oss o ver t o recei ve a 1. 2 5 
m g/ k g o nce m o nt hl y d ose of gi v osir a n. St arti n g at t he M o nt h 1 3 Visit ( w he n 6 m o nt hs of o pe n-l a bel gi v osir a n 
d osi n g h a ve bee n c o m pl ete d) , p atie nts i n t he 1. 2 5 m g/ k g m o nt hl y tre at me nt gr o u p w h o e x perie nce i n a de q u ate 
dise ase c o ntr ol m a y  h a ve t heir m o nt hl y d ose i ncre ase d t o 2. 5  m g/ k g gi v osir a n u p o n disc ussi o n a n d a gree me nt b y 
t he I n vesti g at or a n d m e dic al m o nit or  a n d de m o nstr ati o n of t ole r a bilit y t o gi v osir a n a n d if A L A criteri a are met .  
F or f urt her det ails, see Secti o n 6. 2. 3. 4 . 
P ati e nts  will u n der g o efficac y a n d s afet y assess me nts e ver y 2 wee ks f or t h e first m o nt h of t he O L E peri o d a n d 
t he n m o nt hl y t hr o u g h M o nt h 1 8, a n d e ver y 3 m o nt hs t hereafter.  
Secti o ns c o ntai ni n g relate d c ha n ges : 
 
S y n o psis  
 
T a ble 1: Sc he d ule of Assess me nts  –  Scree ni n g a n d 6 -M o nt h Treat me nt Peri o d ( Scree ni n g t hr o u g h M o nt h 6) ; ne w f o ot n ote a d de d  
 
T a ble 2: Sc he d ule of Assess me nts –  O pe n -La bel E xte nsi o n Peri o d: After M o nt h 6  t hr o u g h M o nt h 1 8; ne w f o ot n ote a d de d  
 
T a ble 3: Sc he d ule of Assess me nts f or O pe n -La bel E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y; ne w f o ot n ote a d de d  
 
Fi g ure 2: St u d y Desi g n ; revise d fi g ure t o s h o w 1. 2 5 m g/k g d ose 
 
Secti o n 1. 3 St u d y Desi g n Rati o nale  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A L N -A S 1  (gi v osir a n ) 
A me n d me nt 3  S u m m ar y of C h a n ges , 2 1 Se pte m ber 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4  
 
Secti o n 1. 4 D ose Rati o nale  
 
Secti o n 6. 2. 2. 2  D uri n g t he O pe n -La bel E xte nsi o n Peri o d ( After M o nt h 6 t hr o u g h E n d of Treat me nt)  
 
Secti o n 6. 2. 3  D ose M o dificati o ns  
 
Sec tio n 6. 2. 3. 4  D ose Escalati o n G ui da nce f or Gi v osira n fr o m 1. 2 5 m g/ k g O nce M o nt hl y t o 2. 5 m g/ k g O nce M o nt hl y i n t he O pe n -La bel 
Peri o d  
 
Secti o n 8. 2. 9 Ot her A nal yses  
 
 
P ur p ose:   A d d  ne w secti o n o n  d ose esc al ati o n g ui d a nce f or p atie nts receivi n g t he 1. 2 5 m g/k g o nce m o nt hly d ose . 
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3. 4 D ose Escalati o n G ui da nce f or Gi v osira n fr o m 1. 2 5 m g/ k g O nce M o nt hl y t o 2. 5 m g/ k g O nce 
M o nt hl y i n t he O pe n -La bel Peri o d  
A d de d te xt:  
St arti n g at t he M o nt h 1 3 St u d y Visit ( w he n 6 m o nt hs of o pe n-l a bel gi v osir a n d osi n g h a ve bee n 
c o m plete d) , p atie nts recei vi n g o pe n-l a bel gi v osir a n at S C d oses of 1. 2 5 m g/ k g m o nt hl y m a y be per mitte d 
t o i ncre ase t h eir m o nt hl y d ose t o 2. 5 m g/ k g b ase d o n I n vesti g at or j u d ge me nt.  I n vesti g at o rs m a y c o nsi der 
d ose esc al ati o n if t he f oll o wi n g criteri a are met:  
 T oler a bilit y t o gi v osir a n at 1. 2 5 m g/ k g o nce m o nt hl y h as bee n de m o nstr ate d b ase d o n n o d ose 
i nterr u pti o ns d ue t o L F T ele v ati o ns at t he 1. 2 5 m g/ k g o nce m o nt hl y d ose le vel (see Secti o n 
6. 2. 3. 1 ) a n d n o si g nific a nt s afet y c o ncer ns d ue t o ot her A Es t h at w o ul d precl u d e a p atie nt fr o m 
recei vi n g a hi g her d ose of gi v osir a n as j u d ge d b y t he  I n vesti g at or a n d S p o ns or.   
 Uri ne A L A le vels ( m m ol/ m ol Cr) are n ot st a bl y m ai nt ai ne d ≤U L N or a re i n d uci ble .  
 P ati e nt h as i n a de q u ate cli nic al res p o nse (e g, bre a kt hr o u g h att ac ks or o n g oi n g c hr o nic 
s y m pt o ms), acc o r di n g t o I n vesti g at or j u d ge me nt. 
Uri ne A L A a n al yses m a y be c o n d ucte d at a l oc al l a b or at or y or A L A res ults fr o m pre vi o us visits m a y be 
e v al u ate d i n p atie nts o n t he 1. 2 5 m g/ k g m o nt hl y d ose i n w h o m d ose es c al ati o n t o 2. 5  m g/ k g o nce m o nt hl y 
is bei n g c o nsi dere d.  
T he decisi o n t o i ncre ase t he gi v osir a n d ose fr o m 1. 2 5 m g/ k g m o nt hl y t o 2. 5  m g/ k g m o nt hl y will be 
disc usse d a n d a gree d u p o n b y t he I n vesti g at or a n d me dic al m o nit or pri or t o i niti ati o n of t he ne xt d ose.  
U p o n i ncre ase of t he gi v o sir a n d ose t o 2. 5 m g/ k g m o nt hl y: 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A L N -A S 1  (gi v osir a n ) 
A me n d me nt 3  S u m m ar y of C h a n ges , 2 1 Se pte m ber 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5  
 L F Ts, I N R, a n d T B L will be m o nit ore d e v er y 2 wee ks ( ± 7 d a ys) f or t he first m o nt h f oll o wi n g 
t he d ose i ncre ase t o 2. 5 m g/ k g, t he n m o nt hl y ( ± 7 d a ys or d uri n g t he sc he d ule d st u d y visits) as 
per t he Sc he d ule of Assess me nts . 
 L a b o r at or y m o nit ori n g a n d d osi n g r ules i n res p o nse t o L F T ele v ati o n will f oll o w T a ble 4 
g ui deli nes . 
 F or p ati e nts i n w h o m gi v osir a n d osi n g is wit h hel d d ue t o ele v ate d A L T, res u m pti o n of d osi n g 
m a y be c o nsi dere d b ase d o n t he g ui d a nce i n Secti o n 6. 2. 3. 1. 1.  
Secti o ns  c o ntai ni n g relate d c ha n ges : 
 
S y n o psis  
 
T a ble 2: Sc he d ule of Assess me nts –  O pe n -La bel E xte nsi o n Peri o d: After M o nt h 6 t hr o u g h M o nt h 1 8;  ne w f o ot n ote a d de d  
 
T a ble 3: Sc he d ule of Assess me nts f or O pe n -La bel E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y; ne w  f o ot n ote a d de d 
 
Secti o n 4. 1  S u m mar y of St u d y Desi g n  
 
Secti o n 6. 2. 2. 2  D uri n g t he O pe n -La bel E xte nsi o n Peri o d ( After M o nt h 6 t hr o u g h E n d of Treat me nt)  
 
Secti o n 6. 2. 3  D ose M o dificati o ns  
 
 
P ur p ose:   A d d  g ui d a nce o n ev al u ati o n of  uri ne A L A i n t he c o ntext of d ose esc al ati o n fr o m t he 1. 2 5 m g/k g o nce m o nt hly d ose t o t he 2. 5 m g/k g o nce 
m o nt hly d ose . 
T he pri mar y c ha n ge occ urs i n Secti o n 7. 3 P har mac o d y na mic Assess me nts  
A d de d te xt:  
Uri ne A L A a n al yses m a y be c o n d ucte d at a l oc al l a b or at or y or A L A res ults fr o m pre vi o us v isits m a y be 
e v al u ate d i n p atie nts o n t he 1. 2 5 m g/ k g m o nt hl y d ose i n w h o m d ose es c al ati o n t o 2. 5 m g/ k g o nce m o nt hl y 
is bei n g c o nsi dere d d ue t o i n a de q u ate cli nic al res p o nse a n d w h o h a ve de m o nstr ate d t oler a bilit y t o 
gi v osir a n.  D ose esc al ati o n i n p atie nts o n  t he 1. 2 5 m g/ k g o nce m o nt hl y d ose c a n occ ur st arti n g at M o nt h 
1 3.  See Secti o n 6. 2. 3. 4  f or f urt her i nf or m ati o n o n d ose esc al ati o n. 
Secti o ns  c o ntai ni n g relate d c ha n ges : 
 
Secti o n 6. 2. 3. 4 D ose Escalati o n G ui da nce f or Gi v osira n fr o m 1. 2 5 m g/ k g O nce M o nt hl y t o 2. 5 m g/ k g O nce M o nt hl y i n t he O pe n -La bel 
Peri o d  
 
T a ble 8: P har mac o ki netic, E C G, a n d A D A Ti me P oi nts f or All Patie nts ( E xce pt Patie nts at East Asia n Sites)  


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A L N -A S 1  (gi v osir a n ) 
A me n d me nt 3  S u m m ar y of C h a n ges , 2 1 Se pte m ber 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6  
P ur p ose:   R e m ove se nsitivity a n alysis det ails a n d e m p h asize  t he st atistic al a n alysis pl a n f or t hese det ails . 
T he pri mar y c ha n ge occ urs i n Secti o n 8. 2. 5. 1  Pri mar y E n d p oi nt  
Delete d  te xt: 
A se nsiti vit y a nal ysis of t he a n n ualize d e ve nt r ates, wit h o ut a dj ust me nt f or t he le n gt h of ti me i n t he treat me nt 
peri o d, will als o be c o n d ucte d. A d diti o nal se nsiti vit y S e nsiti vit y a nal yses will be detaile d i n t he S A P . 
Secti o n als o c o ntai ni n g t his c ha n ge:  
 
S y n o psis  
P ur p ose:   U p d ate  a n alysis  met h o d fr o m a n alysis of c ov ari a nce ( A N C O V A ) t o mixe d effect m o del re pe ate d me as ure me nt ( M M R M ) f or f ull d o u ble-
bli n d a n alysis of A L A a n d c h a n ge fr o m b aseli ne i n p hysic al c o m p o ne nt s u m m ary ( P C S ) of S F -1 2  
T he pri mar y c ha n ge occ urs i n Secti o n 8. 2. 5. 2  Sec o n dar y E n d p oi nts  
Re vise d  te xt: 
F or t he a nal ysis of uri nar y A L A -relate d e n d p oi nts, t he A L A le vels will be c o m pare d b et wee n treat me nt ar ms 
usi n g a n a nal ysis of c o varia nce ( A N C O V A) m o del wit h a mi xe d -effects m o del re pe ate d me as ures ( M M R M) 
wit h b aseli ne A L A as a c o nti n u o us c o v ari ate a n d fi x e d effect of ter ms i n cl u di n g treat me nt ar ms, 
stratificati o n fact ors f or AI P p atie nts ( pri or he mi n pr o p h yl a x is stat us a n d hist orical attac k rates), a n d wit h t he 
baseli ne A L A as a c o v ari ate visit a n d tre at me nt b y visit i nter acti o n .  P B G-relate d e n d p oi nts will als o be 
a nal yze d usi n g t his met h o d ol o g y.   
Dail y p ai n, na usea, a n d fati g ue s c ores will be a nal yz e d se parat el y usi n g t he area u n d er t he c ur ve ( A U C) 
a p pr oac h: t he A U C o ver 6 m o nt hs i n t he res pecti ve sc ore will be calc ulat e d f or eac h patie nt, a n d t h e mea n A U C 
will be c o m pare d b et wee n treat me nt ar ms i n a n A N C O V A m o del.  T he c h a n ge fr o m b aseli ne i n P C S of S F -1 2 
at 6 m o nt hs will  als o be a nal yze d use a n  A N C O V A M M R M  m o del.   Details o n t he A N C O V A m o d el f or eac h 
c o nti n u o us sec o n dar y e n d p oi nt a n d t he c o variat es t o be i ncl u de d  will be descri be d  i n t he S A P. 
Secti o ns  c o ntai ni n g relate d c ha n ges : 
 
S y n o psis  
 
Secti o n 8. 2. 1 0 I nteri m A nal ysis 


Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A L N -A S 1  (gi v osir a n ) 
A me n d me nt 3  S u m m ar y of C h a n ges , 2 1 Se pte m ber 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7  
P ur p ose:   C h a n ge a n alysis met h o d o n  d ur a bility of effect  f or i nteri m a n alysis fr o m A N C O V A t o M M R M . 
T he pri mar y c ha n ge occ urs i n Secti o n 8. 2. 1 0 I nteri m A nal ysis  
Re vise d te xt:  
T o assess d ura bilit y of t he st u d y dr u g i n l o weri n g a n d mai ntai ni n g A L A le vel o ver ti me, t he A L A l e vels at 1 
a n d 2 m o nt hs of t h ose patie nts w h o are i ncl u de d i n t he i nteri m a nal ysis will als o be a nal yz e d usi n g t he 
A N C O V A m o del descri b e d a b o ve. o v er all tre at me nt effect fr o m M o nt h 1 t hr o u g h M o nt h 3 will be 
e v al u ate d t hr o u g h a mi xe d effect m o del re pe ate d me as ure me nt ( M M R M) . 
Secti o ns als o c o ntai ni n g relate d c ha n ges : 
 
S y n o psis  
 
Secti o n 8. 2. 5. 2 Sec o n dar y E n d p oi nts  
P ur p ose:   I n T a ble 8, i ncre ase t he s a m ple c ollecti o n ti me wi n d o ws, a n d f or t he ne w 1. 2 5 m g/k g o nce m o nt hly d ose, a d d 4 -h o urs p ost d ose 
assess me nts of P K a n d Tri plic ate E C G f or M o nt h s 6  a n d 1 2.  
T he pri mar y c ha n ge occ urs i n T a ble 8: P har mac o ki netic, E C G, a n d A D A Ti me P oi nts f or All Patie nts ( E xce pt Patie nts at East Asia n Sites)  
Re vise d  : 
I n ta bl e, f or m o nt hs 0, 5, 6, a n d 1 2, c orrecte d t h e ti me p oi nt 0 2: 0 0 ( ± 1 0 mi n)  t o bec o me: 0 2: 0 0 ( ±1 5 mi n)  
     0 2: 0 0 ( ± 1 0 1 5  mi n)  
F or m o nt hs 6 a n d 1 2, als o a d de d t he ti me p oi nt 0 4: 0 0 ( ±1 5 mi n)  i n P K a n d Tri plicate E C G c ol u m n cells a n d 
ne w f o ot n ote s pecific t o t his ti me p oi nt.  
     0 4: 0 0 ( ± 1 5 mi n) 3 
F o ot n ote:  
     3F or  p atie nts recei vi n g 1. 2 5 m g/ k g gi v osir a n m o nt hl y ( p atie nts w h o recei ve d t heir first d ose i n t he 
o pe n -l a bel e xte nsi o n peri o d u n der pr ot oc ol a me n d me nt versi o n 3), a d diti o n al bl o o d s a m ples f or P K 
will be c ollecte d 4 h o urs p ost -d ose at t he M o nt h 6 a n d M o nt h 1 2 visits.  
Secti o ns c o ntai ni n g relate d c ha n ges:   
 
T a ble 9: P har mac o ki netic, E C G, a n d A nti -Dr u g A nti b o d y Assess me nt Ti me P oi nts f or Patie nts at East Asia n St u d y Ce nters ( Bl o o d 
Sa m ples)  
P ur p ose:  C orrect ty p o gr a p hic al err ors, p u nct u ati o n, gr a m m ar, a b brevi ati o ns, a n d f or m atti n g, a n d a p ply a d mi nistr ative c h a n ges .   
T hese c ha n ges are n ot liste d i n di vi d uall y.  
 


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2  S u m m ar y of C h a n ges , _2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1  
A L N -A S 1 -0 0 3 P R O T O C O L A M E N D M E N T 2  
S U M M A R Y O F C H A N G E S D A T E D 2 6 J U L Y 2 0 1 8  
 
E N VI SI O N: A P h ase 3 R a n d o mize d, D o u ble -bli n d, Pl ace b o -C o ntr olle d M ultice nter St u d y 
wit h a n O pe n -l a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of Gi v osir a n i n P atie nts 
wit h Ac ute He p atic P o r p h yri as  
 
R ati o n ale f or Pr ot oc ol A me n d me nt  
D ue t o rece nt cas e re p orts of a n i ncrease i n li ver tr a nsa mi nases, t he pri mar y p ur p ose f or t his 
pr ot oc ol a me n d me nt is t o : 
• 
Re q uire i n vesti gat or s t o r e vie w pred os e li ver f u n cti o n tests pri or t o st u d y dr u g 
a d mi nistrati o n  
• 
I m ple me nt a sta n dar d he patic assess me nt pa n el if patie nts de vel o p si g nifi ca nt A L T 
ele vati o n  
• 
P r o vi de s pecific g ui da n ce f or rec halle n ge usi n g a l o wer d ose i n patie nts w h ose A L T 
res ol ves aft er st u d y dr u g d osi n g has bee n wit h hel d d ue t o A L T ele vati o n 
• 
E x pa n d t he me dical hist or y c ollecti o n t o i ncl u de a s pecific i n q uir y i nt o ir o n o verl oa d a n d 
ot her li ver diseas e  
A detaile d s u m mar y of c ha n ges is pr o vi de d i n  Ta ble  1 .  Correcti o ns t o t y p o gra p hical err ors, 
p u nct uati o n, gra m mar, a b bre viati o ns, a n d f or m atti n g ( i ncl u di n g a d mi nistrati ve c ha n ges bet w ee n 
t he a me n d me nt 1 a n d a me n d me nt 2 ) are n ot detail e d.  
 


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2 S u m m ar y of C h a n ges, _ 2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2  
T a ble  1 : 
Pr ot oc ol A me n d me nt 2  Det aile d S u m m a r y of C h a n ges  
T he pri mar y secti o n(s) of t he pr ot oc ol affecte d b y t he c ha n ges i n Pr ot oc ol A me n d me nt 2  are i n dicat e d.  T he c orres p o n di n g te xt has 
bee n re vis e d t hr o u g h o ut t he pr ot oc o l.  Delet e d te xt is i n dicate d b y stri ke o ut; a d de d te xt is i n dicate d b y b ol d  f o nt. 
 
P ur p ose:  A d d cli nic al l a b or at ory assess me nts s o t h at assess me nts occ us at e ac h st u dy  visit i n t he o pe n -l a bel exte nsi o n peri o d 
T he pri mar y c ha n ge occ urs i n T a ble 3, Sc he d u le of Assess me nts f or O pe n-La bel E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y  
Re vise d te xt:  
A d de d “ Xs” i n r o w “ Cli nical La b orat or y Assess me nts” at M o nt h 1 9/ 2 0, M o nt h 2 2/ 2 3, M o nt h 2 5/ 2 6, M o nt h 2 8/ 2 9, 
M o nt h 3 1/ 3 2, a n d M o nt h 3 4/ 3 5.  
P ur p ose: A d d t h at d ose  m o dific ati o n  is all o we d i n res p o nse t o elev ate d  L F Ts . 
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3, D ose M o dificati o ns  
A d de d te xt:  
N o st u d y dr u g d ose m o dificati o ns will be all o we d , e xce pt i n res p o nse t o L F T ele v ati o ns as descri be d i n Secti o n 
6. 2. 3. 1.  
P ur p ose: S pecify  a d diti o n al he p atic assess me nts f or p atie nts w h o devel o p si g nific a nt A L T elev ati o n; si m plify text (first se nte nce). 
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3. 1 , M o nit ori n g a n d D osi n g R ules Base d o n Li ver F u ncti o n T est Res ults  
Re vise d te xt: 
L F T  A L T, T B L, a n d I N R  res ults fr o m t he pre vi o us visit s h o ul d be re vie we d wit hi n 1 4 d a ys  pri or t o d osi n g.  
F or a n y A L T ele vati o n > 3 ×  U L N ( or > 3 ×  baseli ne i n patie nts wit h ele vate d baseli ne) or > 3 0 0  U/ L ( w hic he ver is l o wer), 
res ults s h o ul d be c o nfir me d b y t he ce ntral la b orat or y ( wit hi n 2 t o 3 da ys, b ut n o greater t ha n 7 da ys).   If s uc h A L T 
ele v ati o ns are c o nfir me d, t he a d diti o n al he p atic assess me nts s h o w n i n T a ble  s h o ul d be o bt ai ne d. 
S u bj ects wit h a b n or mall y ele vate d he patic la b orat or y val ues (e g. A L T, A S T, t otal bilir u bi n [T B L ], or i n ter nati o nal 
n or malize d rati o I N R) or si g ns/s y m pt o ms of he patitis ma y meet criteria f or wit h h ol di n g st u d y dr u g. Criteria f or 
wit h h ol di n g, m o nit ori n g a n d st o p pi n g st u d y dr u g d osi n g are detaile d i n T a ble 4.  
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  
 
Secti o n 1. 5, Be nefit -Ris k Assess me nt  
 
 


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2 S u m m ar y of C h a n ges, _ 2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
P ur p ose:  U p d ate m o nit ori n g a n d d osi n g  r ules f or p atie nts w h o devel o p si g nific a nt A L T elev ati o n; re m ove re d u n d a ncy (f o ot n ote e) 
T he pri mar y c ha n ge occ urs i n  T a ble 4 : M o nit ori n g a n d D osi n g R ules i n Patie nts wit h Ala ni ne Tra nsa mi nase ( A L T) Ele vati o ns  
Re vise d te xt:  
 
A L T Tr a ns a mi n ase 
Le vel  
P atie nts wit h N or m al B aseli ne A L T  
P atie nts wit h Ele v ate d B aseli ne A L T a 
> 3 × t o 5 × U L N or 
B aseli ne  
 Disc o nti n ue d osi n g w he n A L T is > 3 × U L N a n d 
patie nt is s y m pt o matic b wit h  or h as  T B L ≥2 × U L N 
or I N R > 1. 5 (f or patie nts n ot o n warfari n) , a n d 
t here is n o alter n ati ve c a use 
 Ot her wise, d osi n g ma y c o nti n ue wit h m o nit ori n g 
e ver y 2 wee ks ( ± 7 da ys) c t hat i ncl u des he mat ol o g y, 
bi oc he mistr y, L F T, a n d c oa g ulati o n 
assess me nts L F Ts  per T a ble 6  7  a n d I N R  
 If t he A L T ele vati o n persists f or ≥2 m o nt hs, 
disc ussi o n wit h t he me dical m o nit or is re q uire d 
bef ore c o nti n ui n g d osi n g.  
 Disc o nti n ue d osi n g w he n A L T is > 3 × ba seli ne or 
> 3 0 0 U/ L ( w hic he ver is l o wer) a n d patie nt is 
s y m pt o matic b, wit h  or h as  T B L > 2 × U L N or I N R 
> 1. 5 (f or patie nts n ot o n warfari n) , a n d t here is n o 
alter n ati ve c a use  
 Ot her wise, d osi n g ma y c o nti n ue wit h m o nit ori n g 
e ver y 2 wee ks ( ± 7 da ys) d t hat i ncl u des he mat ol o g y, 
bi oc he mistr y, L F T, a n d c oa g ulati o n assess me nts L F Ts  
per T a ble 6  7 a n d I N R  
 If t he A L T ele vati o n persists f or ≥2 m o nt hs, 
disc ussi o n wit h t he me dical m o nit or is re q uire d bef ore 
c o nti n ui n g d osi n g 
> 5 × t o 8 × U L N or 
B aseli ne  
 Disc o nti n ue d osi n g w he n A L T > 5 × t o 8 × U L N a n d 
patie nt is s y m pt o matic b wit h  or h as  T B L ≥2 × U L N 
or I N R > 1. 5 (f or p atie nts n ot o n w arf ari n) a n d 
t here is n o alter n ati ve c a use  
 F or  patie nts n ot o n warfari n) w h o are as y m pt o m atic 
a n d d o n ot h a ve I N R > 1. 5 or T B L ≥2 x  U L N:  
 H ol de H ol d  d osi n g if A L T > 5 × U L N , u ntil A L T 
rec o vers t o ≤2 × U L N 
 Disc o nti n ue d osi n g w he n A L T > 5 × t o 8 × baseli ne or 
> 3 0 0  U/ L ( w hic he ver is l o wer) a n d patie nt is 
s y m pt o matic b wit h  or h as  T B L ≥2 × U L N or I N R 
> 1. 5 (f or patie nts n ot o n warfari n) a n d t here is n o 
alter n ati ve c a use  
 F or p atie nts w h o are as y m pt o m atic a n d d o n ot 
h a ve I N R > 1. 5 or T B L ≥2 x U L N:  
 H ol de H ol d  d osi n g if A L T > 5 × baseli ne or > 3 0 0 U/ L 
( w hic he ver is l o wer), u ntil A L T rec o vers t o 
≤2 × baseli ne  


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2 S u m m ar y of C h a n ges, _ 2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4  
 D osi n g c a n be res u me d w he n A L T rec o vers t o 
≤2 x U L N acc or di n g t o Secti o n  6. 2. 3. 1. 1 , a n d 
f oll o wi n g disc ussi o n wit h t he me dic al m o nit or 
 Perf or m wee kl y ( ± 3 da ys) m o nit ori n g , i ncl u di n g 
he mat ol o g y, bi oc he mistr y, a n d c oa g ulati o n  of L F Ts  
per T a ble 6  7 a n d I N R  u ntil A L T decli nes t o 
≤3 × U L N ; t he n m o nit or e ver y 2 wee ks ( ± 7 da ys) 
u ntil A L T le vel reac hes 2 × U L N c  
  If t he A L T ele vati o n persists f or ≥2 m o nt hs, 
disc ussi o n wit h t he me dical m o nit or is re q uire d  
bef ore c o nti n ui n g d osi n g.  
 D osi n g c a n be res u me d w he n A L T rec o vers t o 
≤2 x b aseli ne acc or di n g t o Secti o n  6. 2. 3. 1. 1 , a n d 
f oll o wi n g disc ussi o n wit h t he me dic al m o nit or 
 Perf or m wee kl y ( ± 3 da ys) m o nit ori n g , i ncl u di n g 
he mat ol o g y, bi oc he mistr y, a n d c oa g ulati o n  of L F Ts  
per T a ble 6  7 a n d I N R  u ntil A L T decli nes t o 
≤3 × baseli ne ; t he n m o nit or e ver y 2 wee ks ( ± 7 da ys) 
u ntil A L T le vel rea c hes 2 × baseli ne d 
 If t he A L T ele vati o n persists f or ≥2 m o nt hs, 
disc ussi o n wit h t he me dical m o nit or is re q uire d 
bef ore c o nti n ui n g d osi n g.   
 e After d osi n g is hel d, o nce A L T has decrease d t o ≤2 × U L N or ≤2 × baseli ne ( w hic he ver is hi g her), re d osi n g ma y be c o nsi dere d. I n 
patie nts wit h n or mal baseli ne A L T, per ma ne ntl y disc o nti n ue d osi n g if A L T i ncreases t o > 5 × U L N f oll o wi n g re peat d osi n g.  I n pat ie nts 
wit h ele vate d baseli ne A L T, per ma ne ntl y disc o nti n ue d osi n g if A L T i ncreases t o > 5 × baseli ne or > 3 0 0 U/ L ( w hic he ver c o mes first) 
f oll o wi n g re peat d osi n g. 
 
P ur p ose: Cl arify t h at s a m ples are c ollecte d f or a n alyses at t he ce ntr al l a b or at ory.  
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3. 1, M o nit ori n g a n d D osi n g R ules Base d o n Li ver F u ncti o n T est Res ults  
Re vise d te xt:  
F or A L T, A S T, P T/I N R T B L , a n d T B L I N R testi n g, l ocal la b orat or y res ults ma y be use d t o i nf or m d osi n g decisi o ns; 
h o we ver, parallel sa m ples s h o ul d be c o nfir me d c ollecte d f or a n al ysis at t he ce ntral la b orat or y.  
. 


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2 S u m m ar y of C h a n ges, _ 2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5  
P ur p ose:  A d d a st a n d ar d he p atic assess me nt p a n el f or p atie nts w h o devel o p si g nific a nt A L T elev ati o n  
T he pri mar y c ha n ge occ urs i n ( ne w) T a ble 5: He patic Assess me nts i n Patie nts W h o E x perie nce Ele vate d Tra nsa mi nases  
A d de d te xt:  
T a ble 5: He p atic Assess me nts i n P atie nts W h o E x perie nce Ele v ate d Tr a ns a mi n ases  
He m at ol o g y  
C B C wit h differe nti al  
 
E xte n de d He p atic P a nel  
Her pes Si m ple x Vir us 1 a n d 2 a nti b o d y I g M, I g G  
Her pes Z oster Vir us I g M, I g G  
HI V 1 a n d 2 a 
H H V -6  
C yt o me g al o vir us a nti b o dies, I g M, I g G  
H Bs A g, H Bc a nti b o d y I g M a n d I g G  
A nti -n ucle ar a nti b o dies  
E pstei n -B arr Vir us a nti b o dies, I g M a n d I g G  
A nti -s m o ot h m uscle a nti b o dies 
A nti -mit oc h o n dri al a nti b o dies  
H C V a nti b o d y  
H A V a nti b o d y I g M  
H C V R N A P C R –  q u alit ati ve a n d q u a ntit ati ve  
H E V a nti b o d y I g M  
C P K  
 
 
 
I m a gi n g 
A b d o mi n al ultr as o u n d wit h D o p pler fl o w ( or C T or M RI) i ncl u di n g ri g ht u p per q u a dr a nt  
F oc use d Me dic al a n d Tr a vel Hist or y  
Use of a n y p ote nti all y he p at ot o xic c o nc o mit a nt 
me dic ati o ns, i ncl u di n g o ver t he c o u nter me dic ati o ns a n d 
her b al re me dies  
Alc o h ol c o ns u m pti o n  
Ot her p ote nti all y he p at ot o xic a ge nts i ncl u di n g a n y w or k -
rel ate d e x p os ures  
Rece nt tr a vels t o are as w here he p atitis A or E is 
e n de mic 
 
 
A b bre vi ati o ns:  A A T = al p h a -1 a ntitr y psi n; a nti -L K M = a nti -li ver-ki d ne y micr os o m al a nti b o dies; C B C =c o m plete bl o o d c o u nt; 
C P K =cre ati ne p h os p h o ki n as e; C T =c o m p ute d t o m o gr a p h y; H A V = he p atitis A vir us; H B c = he p atitis B c o re; H Bs A g = he p atitis B 
vir us s urf ace a nti ge n; H C V = he p atitis C vir us; H E V = he p atitis E vir us; H H V -6 = h u m a n her pes vir us 6; HI V = h u m a n 
i m m u n o deficie nc y vir us; I g G =i m m u n o gl o b uli n G a nti b o d y; I g M =i m m u n o gl o b uli n M a nti b o d y; M RI = m a g netic res o n a nce 
i m a ger y; P C R = p ol y mer ase c h ai n re acti o n; P T = pr ot hr o m bi n ti me; R N A =ri b o n uclei c aci d; S L A =s ol u ble li ver a nti ge n; 
T S H =t h yr oi d -sti m ul ati n g h o r m o ne 
N ote:  
 
All assess me nts will be me as ure d i n ce ntr al l a b or at or y. T he f ull p a nel of assess me nts s h o ul d o nl y be perf or me d o nce; 
i n di vi d u al assess me nts m a y be re pe ate d, as nee de d. 
 
A d diti o n al s a m ples m a y be c ollecte d f or assess me nt of p ote nti al alter n ati ve c a uses of li ver i nj ur y, w hic h m a y i ncl u de 
A A T, cer ul o pl as mi n, acet a mi n o p he n/ p ar acet a m ol le vels, a nti -L K M a nti b o dies, t o xic ol o g y scree n, ferriti n, p ar v o vir us 
B 1 9, a nti -S L A a nti b o dies, g a m m a -gl o b uli ns (i ncl u di n g I g E a n d I g G le vels), a n d tr a nsferri n s at ur ati o n, as cli nic all y 
i n dic ate d.  
a  HI V testi n g will n ot be per f or me d w here pr o hi bite d b y l oc al re g ul ati o ns. 


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2 S u m m ar y of C h a n ges, _ 2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6  
P ur p ose:  A d d  s pecific g ui d a nce f or rec h alle n ge i n p atie nts w h o meet criteri a after d ose i nterr u pti o n  
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3. 1. 1 , Criteria f or Rec halle n ge of Gi v osira n After Bei n g Wit h hel d  f or A L T Ele vati o n 
A d de d te xt:  
F or p atie nts i n w h o m gi v osir a n d osi n g is wit h hel d d ue t o ele v ate d A L T, res u m pti o n of d osi n g m a y be c o nsi dere d 
usi n g t he f oll o wi n g g ui deli nes:  
 
P atie nts w h o di d n ot meet criteri a f or st u d y dr u g disc o nti n u ati o n per  T a ble 4  m a y be c o nsi dere d f or 
rec h alle n ge f oll o wi n g c o ns ult ati o n wit h t he me dic al m o nit or a n d res ol uti o n of A L T t o ≤ 2 x U L N or ≤ 2 x 
b aseli ne (f or p atie nts w h o h a d ele v ate d b aseli ne A L T)  
 
T he decisi o n t o rec h alle n ge t he p atie nt s h o ul d be disc usse d a n d a gree d u p o n b y t he p atie nt, 
I n vesti g at or, a n d me dic al m o nit or 
 
T he rec h alle n ge re gi me n is a re d uce d d ose of 1. 2 5 m g/ k g m o nt hl y:  
 L F Ts a n d I N R will be m o nit ore d e ver y 2 wee ks ( ± 7 d a ys) f or t he first m o nt h, t he n m o nt hl y ( ± 7 
d a ys or d uri n g t he sc he d ule d st u d y visits) as per  t he Sc he d ule of Assess me nts 
 L a b or at or y m o nit ori n g a n d d osi n g r ules i n res p o nse t o L F T ele v ati o n will f oll o w  T a ble 4  g ui deli nes  
 If d ose wit h h ol di n g r ules per T a ble 4 are met o n t his d ose, per m a ne ntl y disc o nti n ue d osi n g  
 
D ose re -esc al ati o n t o 2. 5 m g/ k g m o nt h l y m a y be c o nsi dere d if t he f oll o wi n g criteri a are met:  
 A p pr o v al b y t he me dic al m o nit or after at le ast 3 d oses of 1. 2 5 m g/ k g m o nt hl y f or p atie nts w h o meet 
b ot h criteri a bel o w:  
o  P atie nt h as n ot met d ose wit h h ol di n g or disc o nti n u ati o n r ules per T a ble 4 d uri n g tre at me nt 
wit h 1. 2 5 m g/ k g m o nt hl y  
o  P atie nt h as i n a de q u ate c o ntr ol of p or p h yri a s y m pt o ms o n t he 1. 2 5 m g/ k g m o nt hl y re gi me n, per 
i n vesti g at or’s assess me nt  


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2 S u m m ar y of C h a n ges, _ 2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7  
A d de d te xt  
(c o nti n ue d): 
 L F Ts a n d I N R will be m o nit ore d e ver y 2 wee ks ( ± 7 d a ys) f or t he first m o nt h after d ose re-
esc al ati o n, a n d t he n m o nt hl y as per t he Sc he d ule of Assess me nts  
 If a p atie nt e x perie nces a sec o n d d ose h ol d d ue t o L F T ele v ati o n w hile o n 2. 5  m g/ k g m o nt hl y:  
o  F oll o w T a ble 4 g ui deli nes f or m o nit ori n g a n d e v al u ati o ns  
o  If A L T res olves t o ≤2 x U L N, re d osi n g wit h 1. 2 5 m g/ k g m o nt hl y m a y be c o nsi dere d if t his d ose 
w as pre vi o usl y t oler ate d a n d t here is a p pr o v al b y t he Al n yl a m me dic al m o nit or.  If d osi n g is 
res u me d, f oll o w t he g ui d a nce a b o ve f or rec h alle n ge re gi me n re g ar di n g l a b or at or y m o n it ori n g 
a n d d osi n g r ules.  N o s u bse q ue nt esc al ati o n t o 2. 5 m g/ k g m o nt hl y will be all o we d  
o  L F Ts a n d I N R will be m o nit ore d e ver y 2 wee ks ( ± 7 d a ys) f or t he first m o nt h after d ose 
res u mi n g 1. 2 5 m g/ k g, a n d t he n m o nt hl y as per t he Sc he d ule of Assess me nt  
P ur p ose:   A d d t h at l oc al l a b or at ory res ults m ay be use d t o i nf or m d osi n g decisi o ns a n d cl arify t h at s a m ples are als o t o be c ollecte d f o r a n alyses 
at t he ce ntr al l a b or at ory.  
T he pri mar y c ha n ge occ urs i n Secti o n 6. 2. 3. 2, M o nit ori n g a n d D osi n g R ules Base d o n Li pase a n d A m ylase Res ults  
Re vise d te xt  
Li pase a n d a m ylase res ults fr o m t he pre vi o us visit s h o ul d be re vie we d pri or t o d osi n g.  
...F or li pase a n d a m ylase testi n g, l ocal la b orat or y res ults ma y be use d t o i nf or m d osi n g decisi o ns; h o we ver, parallel 
sa m ples s h o ul d be c o nfi me d  c ollecte d f or a n al ysis  at t he ce ntral la b orat or y.  
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  
 
Secti o n 1. 5, Be nefit -Ri s k Assess me nt 
P ur p ose:  Pr ovi de det ails t h at i nf or m ati o n o n ir o n overl o a d a n d ot her liver dise ases are i ncl u de d i n t he c ollecti o n of me dic al hist ory. 
T he pri mar y c ha n ge occ urs i n Secti o n 7. 1, Scree ni n g Assess me nts  
A d de d te xt:  
Me dical hist or y c ollecte d will i nc or p orate t he patie nt’s p or p h yria hist or y, i ncl u di n g t heir t y pical attac k c haracteristics, 
tri g gers, a n d treat me nt, as well as ce ntral ve n o us access hist or y, ir o n o verl o a d hist or y, a n d pri or li ver dise ase hist or y. 
Secti o n(s) als o c o ntai ni n g t his c h a n ge: 
 
T a ble 1, Sc he d ule of Assess me nts –  Scree ni n g a n d 6 -M o nt h Treat me nt Peri o d ( Scree ni n g t hr o u g h M o nt h 6); f o ot n ote c  


A L N -A S 1 ( gi v osir a n)  
 
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
 
A me n d me nt 2 S u m m ar y of C h a n ges, _ 2 6 J ul y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8  
P ur p ose:  A d d t h at i nvesti g at ors m ust revie w pre d ose liver f u ncti o n tests wit hi n 1 4 d ays pri or t o st u dy dr u g a d mi nistr ati o n, w hic h c a n be fr o m a 
l oc al l a b or at ory.  Cl arify t h at a d diti o n al s a m ples are als o c ollecte d f or ce ntr al l a b or at ory a n alysis 
T he pri mar y c ha n ge occ urs i n Secti o n 7. 5. 5, Cli nical La b orat or y Assess me nts  
A d de d te xt:  
A L T, T B L, a n d I N R c ollecte d wit hi n 1 4  d a ys pri or t o d o si n g m ust be re vie we d b y t he I n vesti g at or bef ore st u d y 
dr u g a d mi nistr ati o n.  L oc all y a n al yze d res ults m a y be re vie we d t o i nf or m d osi n g decisi o ns, b ut a d diti o n al s a m ples 
f or ce ntr al a n al ysis m ust als o be c ollecte d o n t he d a y of d osi n g pri or t o t he d ose a d ministr ati o n . 
Secti o n(s) als o c o ntai ni n g t his c ha n ge:  
 
T a ble 1, Sc he d ule of Assess me nts –  Scree ni n g a n d 6 -M o nt h Treat me nt Peri o d ( Scree ni n g t hr o u g h M o nt h 6); f o ot n ote j  
 
T a ble 2, Sc he d ule of Assess me nts –  O pe n -La bel E xte nsi o n Peri o d: After M o nt h 6 t hr o u g h M o nt h 1 8; f o ot n ote f  
 
T a ble 3, Sc he d ule of Assess me nts f or O pe n -La bel E xte nsi o n Peri o d: M o nt h 1 9 t hr o u g h E n d of St u d y ( E O S), f o ot n ote f  
 
Secti o n 6. 2. 2, D ose a n d A d mi nistrati o n  
P ur p ose:  C orrecte d p u nct u ati o n, gr a m m ar, a n d f or m atti n g.  
T hese c ha n ges are n ot liste d i n di vi d uall y. 
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of C h a n ges _ 0 4  M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1  
A L N -A S 1 -0 0 3 Pr ot oc ol A me n d me nt 1  
S u m m ar y of C h a n ges ( d ate d 0 4  M a y  2 0 1 8 )  
c o m p are d t o Ori gi n al Pr ot oc ol  ( 0 6 Se pte m ber 2 0 1 7 ) 
E N VI SI O N: A P h ase 3 R a n d o mize d, D o u ble -bli n d, Pl ace b o -C o ntr olle d M ultice nter St u d y 
wit h a n O pe n -l a bel E xte nsi o n t o E v al u ate t he Effic ac y a n d S afet y of Gi v osir a n i n P atie nts 
wit h Ac ute He p atic P o r p h yri as  
R ati o n ale f or Pr ot oc ol A me n d me nt  
T he p ur p ose of t h e a me n d me nt is t o:  
 I n cl u de cli nical d ata o n a si ngle case of a na p h ylactic reacti o n, i nf or m ati o n re gar di n g t he 
p ote ntial ris k f or a na p h yl actic reacti o n s, a n d pr o vi de u p date d g ui da nce  f or d osi n g a n d 
m o nit ori n g  f or a n a p h ylactic reacti o ns.  T he e ve nt of a na p h ylactic reacti o n was pre vi o usl y 
re p orte d t o a p plic a ble re g ulat or y a ut h orities a n d I nstit uti o nal Re vie w B oar ds/ Et hics 
C o m mittees.  
 A d d t w o q ualit y of lif e meas ures:  
o  Patie nt Gl o bal I m pr essi o n  of C ha n ge ( P GI C) at M o nt hs 6 a n d 1 2  
o  P or p h yria Patie nt E x peri e nce Q uesti o n naire ( P P E Q)  at M o nt hs 6, 1 2, 1 8, a n d 2 4 .   
 U p date g ui da nce a n d pr o ce d ures  o n p atie nt wit h dra wal fr o m st u d y.  
 Clarif y t hat A L A/ P B G le vels meas ure d d ur i n g s cree ni n g are acce pta bl e f or use as e ntr y 
criteria  
 p r o vi de t he f oll o wi n g a d diti o nal clarificati o ns :  
o  pre d ose sa m ples  ( n ot restricte d t o 6 0 mi n utes bef ore d osi n g), 
o  i nteri m a nal ysis f or sa m ple size reassess me nt  is bli n de d 
o  defi niti o n of se x ual a bsti ne nce  
o  co ntrace pti o n wit h a n i ntra uteri ne h or m o ne -releasi n g s yste m als o re q uir es use of a 
barrier m et h o d    
A detaile d s u m mar y of t h e c ha n ges is pr o vi de d i n  Ta ble  1 .  Correcti o ns t o t y p o gra p hical err ors 
f or matti n g, a n d ali g ni n g t e xt bet wee n secti o ns , a n d ot her mi n or u p dates are n ot o utli ne d i n t he 
ta ble. 
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
2  
T a ble  1 : 
Pr ot oc ol A me n d me nt  1 Det aile d S u m m a r y of C h a n ges  
T he pri mar y secti o n(s) of t he pr ot oc ol affecte d b y t he c ha n ges i n t he pr ot oc ol a me n d me nt are i n d icat e d.  T he c orres p o n di n g te xt has 
bee n re vis e d t hr o u g h o ut t he pr ot oc ol.  Delet e d te xt is i n dicate d b y stri ke o ut; a d de d te xt is i n dicate d b y b ol d  f o nt. 
 
P ur p ose: Pr ovi de d et ails of  a n a n a p hyl actic re acti o n re p orte d i n St u dy A L N -A S 1 -0 0 2  
T he pri mar y c h a n ge o cc urs i n Secti o n 1. 2. 2. 2 - P hase 1/ 2 O pe n -l a bel E xte nsi o n St u d y A L N-A S 1 -0 0 2  
A d de d te xt:  
I n a d diti o n, o ne patie nt i n t he 2. 5 m g/ k g m o nt hl y d ose gr o u p wit h a hist or y of ast h ma a n d m ulti ple aller gies 
e x perie nce d a n S A E of  a na p h yl actic reacti o n t hat was deter mi ne d b y t h e I n vesti gat or t o b e defi nitel y relate d t o 
st u d y dr u g gi ve n t he t e m p oral relati o ns hi p of gi v osira n treat me nt t o t he o ns et of t he reacti o n ( wit hi n mi n utes).  
T he patie nt was tr eate d a n d rec o vere d a n d was dis c o nti n ue d fr o m t he st u d y.  
Secti o n(s) als o c o ntai ni n g t his c ha n ge  
 Secti o n 1. 5  Be nefit -Ris k Assess me nt  
 
P ur p ose: C orrect t h at p atie nts will receive o pe n -l a bel giv osir a n f or u p t o 2 9 m o nt hs r at her t h a n  u p t o  3 0 m o nt hs.  T he fi n al m o nt h is a 
p ost -d ose o bserv ati o n peri o d.  T his is n ot a c h a n ge t o t he Sc he d ule of Assess me nts.  
T he pri mar y c h a n ge o cc urs i n Secti o n 1. 3 -  St u d y Desi g n Rati o nal e  
N o w rea ds:  
T he e n d p oi nts will be e v al uate d a gai nst a place b o c o m para t or f or t he first 6 m o nt hs of t he st u d y (t h e d o u ble-
bli n d treat me nt peri o d); after t his, all patie nts will recei v e o pe n -l a bel gi v osira n f or u p t o a n a d diti o nal 3 0  2 9 
m o nt hs i n t he e xte nsi o n p orti o n of t he st u d y.  
Secti o n(s) als o c o ntai ni n g t his c ha n ge  
 S y n o psis:  St u d y Desi g n  
 Secti o n 4. 1:  S u m mar y of St u d y Desi g n   
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
3  
P ur p ose:  A d d a n a p hyl actic re acti o n t o giv osir a n p ote nti al risks  
T he pri mar y c h a n ge o cc urs i n Secti o n 1. 5 -  Be n efit -Ris k Assess me nt  
N o w rea ds:  
F urt her details o n t he n o ncli nical res ults  a n d safet y res ults f or St u d y A L N -A S 1 -0 0 1 ca n be f o u n d i n t he 
gi v osira n I B. Gi v e n t he bi ol o gical tar get of gi v osira n, t he a vaila ble n o ncli nical a n d cli nical d ata, a n d t he m o de 
of a d mi nistrati o n, ot her p ote ntial  i m p ort a nt t he oretical ris ks i ncl u de t he ris k of se vere or seri o us  i njecti o n site 
reacti o ns (I S Rs), li ver tr a nsa mi nase a b n or malities, pa ncreatitis, a n d a n a p h yl actic re a cti o n.  A s u m mar y of 
preli mi nar y cli nical data fr o m o n g oi n g P has e 1 a n d P hase 1/ 2 st u dies of gi v osira n ca n b e f o u n d i n Secti o n  1. 2. 2  
a n d i n t he gi v osira n I B.   
T his cli nical pr ot oc ol i ncl u des e x cl usi o n criteria i nte n de d t o mi ni mize t he ris k of tra nsa mi nitis, I S R a n d 
pa ncreatitis, a n d als o i nc or p orates o n g oi n g m o nit ori n g f or ele vate d tra ns a mi nases, ser u m li pase, a n d  
a n a p h yl actic re acti o n  ( Secti o n 6. 2. 3 ). 
 
P ur p ose: Cl arify t h at ot her me dic ati o ns m ay b e c o nsi dere d i n t he defi niti o n of  p or p hyri a att ack  
T he pri mar y c h a n ge o cc urs i n Secti o n 3. 5 Defi niti o n of P or p h yri a Attac ks  
A d de d te xt:  
re q uires tr eat me nt wit h I V de xtr ose or he mi n, car b o h y drates, or a nal gesics ( o pi oi d [s y nt hetic a n d n o n -s y nt hetic 
s u bsta nces] or n o n-o pi oi d ), or ot her me dic ati o ns s uc h as a ntie metics, at d ose or fre q ue nc y b e y o n d t he 
patie nt’s us ual dail y p or p h yria m a na ge m e nt  
 
 
 
P ur p ose: Cl arify t h at t his st u dy m ay be  re pl a ce d wit h a p ost-m arketi n g st u dy i n re gi o ns t h at receive m arketi n g a ut h oriz ati o n f or 
giv osir a n  
T he pri mar y c h a n ge o cc urs i n Secti o n 4. 1 S u m mar y of St u d y Desi g n  
A d de d te xt:  
W here re q uire d b y l oc al re g ul ati o ns, t his tri al m a y be re pl ace d wit h a p ost -m a r keti n g cli nic al tri al o nce 
m a r keti n g a ut h oriz ati o n f or gi v osir a n is recei ve d.  
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
4  
P ur p ose: Cl arify t h at d oc u me nte d P B G or A L A elev ati o ns  me as ure d d uri n g scree ni n g are a cce pt a ble f or use as e ntry criteri a   
T he pri mar y c h a n ge o cc urs i n Secti o n 5. 1 
 I n cl usi o n Criteria # 2 
A d de d Te xt  
at least o ne d oc u me nt e d uri nar y or plas ma P B G or A L A val ue ≥4 × u p per li mit of n or mal ( U L N) wit hi n t he past 
year pri or t o or d uri n g Scree ni n g . 
 
P ur p ose: U p d ate i ncl usi o n re g ar di n g i nf or me d c o nse nt t o cl arify h a n dli n g of c o nse nt f or p atie nts u n der le g al a ge t o c o nse nt   
T he pri mar y c h a n ge o cc urs i n Se cti o n 5. 1  I n cl usi o n Criteria # 7 
N o w rea ds:  
Be willi n g a n d a ble t o c o m pl y wit h t he st u d y re q uire me nts a n d t o pr o vi de writte n i nf or me d c o ns e nt per l ocal 
a n d asse nt n ati o n al re q uire me nts .  I n t h e cas e of patie nts u n der t he a ge of le gal c o nse nt, per l ocal a n d nati o nal 
re q uire me nts le g al g u ar di a n(s) m ust pr o vi de writte n i nf or me d c o nse nt a n d t he p atie nt sh o ul d pr o vi de 
asse nt per l oc al re g ul ati o ns a n d i nstit uti o n al st a n d ar ds.  
 
 
P ur p ose:  C h a n ge d ti mi n g f or pl a n ne d s ur gery excl usi o n s o it w as n ot t o o restrictive f or t he t ar get p atie nt p o p ul ati o n  
T he pri mar y c h a n ge o cc urs i n Secti o n 5. 2 
 E x cl usi o n Criteria # 1 1  
N o w rea ds:  
Has pla n ne d el ecti ve  a  maj or s ur ger y s c he d ule d t o occ ur pl a n ne d  d uri n g t he st u d y first 6  m o nt hs of t he 
st u d y. 
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
5  
P ur p ose:  U p d ate d  secti o n title a n d w or di n g t o reflect c urre nt C o m p a ny l a n g u a ge  
T he pri mar y c h a n ge o cc urs i n Secti o n  5. 3  Disc o nti n uati o n of St u d y Dr u g a n d/ or St u d y  ( ne w title) 
N o w rea ds:  
Patie nts or t heir le gal g uar dia ns (i n t he cas e t hat t h e patie nt is a mi n or) are free t o disc o nti n ue st u d y dr u g 
treat me nt a n d/ or st u d y  or wit h dra w fr o m t he st u d y  t heir c o nse nt at a n y ti me a n d f or a n y reas o n, wit h o ut 
pe nalt y t o t heir c o nti n ui n g me dical care.  A n y disc o nti n uati o n of treat me nt or wit h dra wal fr o m  of  t he st u d y 
m ust be f ull y d oc u me nt e d i n t he electr o nic case re p ort f or m (e C R F), a n d s h o ul d be f oll o we d u p b y t he 
I n v esti gat or.  T he I n v esti gat or m a y wit h dra w a patie nt fr o m t he st u d y at a n y ti me if t his is c o nsi dere d t o be i n 
t he patie nt’s best i nterest. 
Pr oce d ures f or t he disc o nti n uati o n Disc o nti n u ati o n  of st u d y dr u g a n d wit h dra wal fr o m t he st u d y are descri b e d 
i n Secti o n 5 . 3. 1 a n d Secti o n  5. 3. 2  res pecti vel y. , res pecti vel y.  If a p atie nt st o ps p artici p ati o n fr o m t he 
st u d y or wit h dr a ws c o nse nt fr o m t he st u d y, he/s he will n ot be a ble t o re -e nr oll i n t he st u d y  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
6  
P ur p ose:  U p d ate d t o cl arify o pti o ns f or p atie nts w h o pre m at urely disc o nti n ue st u dy dr u g a n d t o ali g n pr ot oc ol text wit h s a m ple 
I nf or me d C o nse nt F or m.    
T he pri mar y c h a n ge o cc urs i n Secti o n 5. 3. 2 
 Disc o nti n uati o n fr o m t he St u d y  
N o w rea ds:  
A patie nt ma y wit h dra w fr o m t he st u d y at a n y ti me.  A p atie nt or t hei r le g al g u ar di a n m a y deci de t o st o p t he 
p atie nt’s p artici p ati o n i n t he st u d y at a n y ti me.  P ati e nts c o nsi deri n g t o st o p t he st u d y s h o ul d be 
i nf or me d t h at t he y c a n disc o nti n ue tre at me nt a n d c o m plete st u d y assess me nts i ncl u di n g f oll o w-u p, as per 
t he S O A, or alter n ati vel y m a y c o m plete a n y mi ni m al assess me nts f or w hic h t he p atie nt c o nse nts. T he 
I n vesti g at or m a y wit h dr a w a p atie nt at a n y ti me if t his is c o nsi dere d t o be i n t he p atie nt’s best i nterest.  
H o we ver, st u d y i nte grit y  a n d i nter pret ati o n is best mai ntai ne d if all ra n d o mi ze d patie nts c o nti n ue st u d y 
assess me nts a n d f oll o w -u p.   Patie nts c o nsi deri n g wit h dra wi n g fr o m t he st u d y s h o ul d be i nf or me d t hat t he y ca n 
disc o nti n ue treat me nt a n d c o m plete t heir st u d y assess me nts t hr o u g h t he 6 m o nt h visit, i ncl u di n g f oll o w
u p.  If a 
patie nt still c h o oses t o wit h dra w fr o m t he st u d y pri or t o t he c o m pleti o n of t he 6 m o nt h treat me nt peri o d, e ver y 
eff ort s h o ul d be ma d e t o c o n d uct earl y t h e assess me nts sc he d ule d t o be perf or me d at t he 6 m o nt h visit (see ).  
St o p pi n g st u d y p artici p ati o n c o ul d me a n:  
 If a p atie nt st o ps p artici p ati o n d uri n g t he 6-m o nt h tre at me nt peri o d, t he y s h o ul d be 
i nf or me d t h at t he y c a n disc o nti n ue tre at me nt, b ut c o nti n ue t o c o m plete t heir st u d y 
assess me nts t hr o u g h t he 6 -m o nt h visit, i ncl u di n g f oll o w -u p.   
 If a p atie nt st o ps p artici p ati o n d uri n g t he o pe n-l a bel e xte nsi o n peri o d, t he y s h o ul d be 
as ke d t o ret ur n f or a n E arl y Ter mi n ati o n Visit as well as a S afet y F oll o w -U p Visit 3 
m o nt hs after t hei r l ast d ose of st u d y dr u g.  
 A p atie nt  c a n st o p t a ki n g t he st u d y dr u g a n d st o p st u d y -rel ate d visits, b ut all o w t he 
i n vesti g at or a n d st u d y te a m t o re vie w t he p atie nt’s me dic al rec or ds, p u blic rec or ds or be 
c o nt acte d i n or der t o recei ve i nf or m ati o n a b o ut t he p atie nt’s he alt h  
W he n a patie nt wit h d ra ws fr o mst o ps t he st u d y, t h e pri mar y disc o nti n u ati o n a n d  reas o n f or disc o nti n uati o n 
m ust be rec or de d i n t he a p pr o priate secti o n of t he electr o nic case re p ort f or m (e C R F) a n d all eff orts will be 
ma de t o c o m plete a n d re p ort t he o bser vati o ns as t h or o u g hl y as p ossi ble.  If a patie nt wit h dra ws st o ps t he st u d y 
d ue t o a n a d verse e v e nt ( A E), i ncl u di n g a n S A E, t he A E s h o ul d be f oll o we d as descri be d i n Secti o n  7. 5. 6.  
If t he p atie nt w a nts t o st o p p artici p ati o n i n t he st u d y, he/s he s h o ul d n otif y t he st u d y d oct or i n writi n g or 
i n a n y ot her f or m t h at m a y be l o c all y re q uire d. T he pers o n al d at a alre a d y c ollecte d d uri n g t he st u d y, 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
7  
i ncl u di n g p atie nt’s bi ol o gic al s a m ples, will still be use d t o get her wit h t he d at a c ollecte d o n ot h er p atie nts 
i n t he st u d y acc or di n g t o t he i nf or me d c o nse nt a n d a p plic a ble l a ws. 
I n a d diti o n t o st o p pi n g p artici p ati o n i n t he st u d y, t he p atie nt c o ul d deci de t o wit h dr a w his/ her c o nse nt as 
e x pl ai ne d i n Se cti o n 5. 3. 3.  
 
P ur p ose: Ne w secti o n a d de d t o disc uss wit h dr a w al of c o nse nt     
T he pri mar y c h a n ge o cc urs i n Secti o n 5. 3. 3 ( ne w s ecti o n)
 Wit h dra wal  of C o nse nt t o C ollect a n d Pr ocess t he Patie nt’s Pers o nal Data  
Ne w te xt:  
T he patie nt ma y deci de t o wit h dra w his/ her c o ns e nt i nf or mi n g t he st u d y d o ct or at a n y ti me i n writi n g, or i n a n y 
ot her f or m t hat ma y be l o call y re q uir e d.  T his  mea ns t hat t he patie nt wa nts t o st o p partici pati o n i n t he st u d y a n d 
a n y f urt her c ollecti o n of his / her pers o nal dat a.  
 T he s p o ns or will c o nti n ue t o kee p a n d us e a patie nt's st u d y i nf or mati o n (i n cl u di n g a n y d ata 
res ulti n g fr o m t he a nal ysis of t he patie nt's bi ol o gi cal sa m ples u ntil ti me of wit h dra wal) acc or di n g 
t o a p plica ble la w.  T his is d o ne t o g u ara ntee t he vali dit y of t he st u d y, deter mi ne t he effects of t he 
st u d y treat me nt, a n d e ns ure c o m plete ness of st u d y d oc u me ntati o n. 
 T he patie nt ca n als o re q u est t hat c ollecte d sa m ples be destr o ye d or ret ur n e d (t o t he e xte nt it is 
per mitte d b y a p plica ble l a w) at a n y ti me.  
 Patie nts w h o wit h dra w t heir c o nse nt t o c ollect a n d use p ers o nal d ata s h o ul d u n dersta n d t hat 
p u blic rec or ds ma y b e re vie we d t o deter mi ne t h e patie nt’s s ur vi val stat us as all o we d per l ocal 
a n d nati o nal re g ulati o ns.    
I n U S a n d J a pa n, ot her wise, sa m ples n ot yet a nal yze d at t he ti me of wit h dra wal ma y still be use d f or f urt her 
testi n g/a nal ysis i n acc or da nce wit h t he ter ms of t he pr ot oc ol a n d of t h e i nf or me d c o nse nt f or m. 
I n E U a n d rest of w orl d, i n a n y e ve nt, sa m ples n ot yet a nal yz e d at t he ti me of wit h dra wal will n ot be use d a n y 
l o n ger, u nless per mitte d b y a p plica ble la w. T he y will be st ore d or destr o ye d acc or di n g t o a p plica ble le gal 
re q uire me nts. 
 
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
8  
P ur p ose: Pr ovi de g ui d a n ce o n m o nit ori n g a n d m a n a ge me nt of p ote nti al a n a p hyl actic re acti o n s d ue t o st u dy dr u g  
( N ote: n o c h a n ges t o t he sc he d ule of assess me nts re g ar di n g visits c o n d ucte d at t he st u dy ce nter vs. ot her l oc ati o ns were m a de i n t he 
a me n d me nt)  
T he pri mar y c h a n ge o cc urs i n Secti o n 6. 2. 2 
 D ose a n d A d mi nistrati o n  
Re vise d  te xt: 
Gi v osira n will be a d mi nistere d b y a q u alifie d a n d a ut h orize d staff at t he st u d y ce nter.  I n t he e v e nt t hat a patie nt 
is u na ble t o c o me t o t he st u d y ce nter f or a sc h e d ul e d cli nical st u d y visit, he alt h c are pr ofessi o n al tr ai ne d i n 
t he rec o g niti o n a n d m a n a ge me nt of an a p h yl actic re acti o ns.  T he st u d y dr u g s h o ul d be i njecte d i nt o t he 
a b d o me n or u p per ar ms or t hi g hs.  Det aile d i nstr ucti o ns f or st u d y dr u g a d mi nistr ati o n are prese nte d i n 
t he P h ar m ac y M a n u al. As is c o nsiste nt wit h g o o d me dic al pr actice f or s u bc ut a ne o us dr u g 
a d mi nistr ati o n, p atie nts will be o bser ve d f or a mi ni m u m of 2 0 mi n utes after e ac h i njecti o n.  Tre at me nt 
f or a n a p h yl actic re acti o n s s h o ul d be re a dil y a v ail a ble w here p atie nts are bei n g d ose d , a n d f oll o w c o u ntr y 
a n d/ or  l oc al h os pit al tre at me nt g ui deli nes. [2 5 ] 
St u d y dr u g a d mi nistrati o n ma y b e c o n d uct e d at a l ocati o n ot her t ha n t he st u d y ce nter b y a h o me healt hcare 
pr ofessi o nal, w here a p plica ble c o u ntr y a n d l ocal re g ul ati o ns a n d i nfrastr u ct ure all o w, after c o ns ultati o n wit h t he 
me dical m o nit or .  F or, d uri n g par tic ular st u d y visits, as s pecifie d i n t he Sc he d ules of Ass ess me nts ( Ta ble 2  a n d 
), d osi n g ma y als o be perf or me d Ta ble 3 ).  H o w e ver, s t u d y dr u g a d mi nistr ati o n at a l ocati o n ot her t ha n t he 
st u d y ce nt er s h o ul d be b y a q ualifie d h o me healt hcare pr ofessi o nal w here a p plica ble  c o u ntr y a n d l o cal 
re g ulati o ns a n d i nfrastr uct ure all o w. T he st u d y dr u g s h o ul d be i nject e d i nt oc o nsi dere d f or p atie nts w h o h a ve 
o n g oi n g st u d y dr u g -rel ate d A Es or k n o w n ris k f act ors f or de vel o pi n g a n a p h yl actic re acti o n s, i ncl u di n g 
b ut n ot li mite d t o: a pri or hist or y of a n a n a p h yl actic re a cti o n t o f o o d, me dic ati o ns or u n k n o w n eti ol o g y, 
w orse ni n g i njecti o n site re acti o ns wit h re pe at d osi n g, or a n y o ne i n t he a b d o me n or u p per ar ms or t hi g hs.  
Patie nts m ust de m o nstrate t hat t he y ca n t olerate d ose o pi ni o n of t he i n vesti g at or t h at w o ul d be nefit fr o m 
cli nic al o bser v ati o n f oll o wi n g d osi n g. at a l ocati o n ot her t ha n t he st u d y ce nter is per mitte d . 
Secti o n(s) als o c o ntai ni n g si milar or relate d c ha n ges  
 Secti o n 6. 2. 3 . 3 ( ne w secti o n)  M o nit ori n g a n d D osi n g R ules i n Patie nts wit h P ote ntial A na p h ylacti c Reacti o n s 
 
P ur p ose:  cl arify t h at M o nt h 6 A L A a n d P B G assess me nts ( at t he e n d of t he d o u ble -bli n d peri o d) m ust be c o m plete d pri or t o 
a d mi nistr ati o n of t he first o pe n -l a bel d ose of giv osir a n 
T he pri mar y c h a n ge  o cc urs i n Secti o n 6. 2. 2. 1   D uri n g t he 6 -M o nt h Treat m e nt Peri o d ( Da y 1 t o M o nt h 6)  


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
9  
A d de d te xt:  
At t he M o nt h 6 st u d y visit, f oll o wi n g t he c o m pleti o n of all M o nt h 6 assess me nts , i ncl u di n g t he uri ne s a m ple 
f or A L A a n d P B G le vels (t o e n d t he d o u ble-bli n d peri o d), patie nts will be a d mi nistere d t heir first o pe n -la bel 
( u n mas ke d) d ose of gi v osira n t o be gi n t heir partici pati o n i n t he o pe n-la bel e xte nsi o n p orti o n of t he st u d y. 
 
P ur p ose:  A d d g ui d a nce a n d pr oce d ures f or m a n a ge me nt of p ote nti al c ases of a n a p hyl actic re acti o n  
A d de d te xt:  
A n a na p h yla ctic reacti o n is a se vere, p ote ntiall y fatal, s yste mic aller gic reacti o n wit h ac ute o nset ( mi n utes t o 
h o urs).  F or refere nce s ee Secti o n 1 1. 3.   
 
St o p a d mi nisteri n g t he st u d y me dic ati o n i m me di atel y  if a n a na p h ylactic reacti o n t o t he st u d y m e dicati o n is 
s us pecte d.  St u d y me di cati o n m ust be per ma ne ntl y disc o nti n ue d i n patie nts f or w h o m a n a n a p h ylacti c reacti o n 
is assesse d as r elate d t o t he st u d y me dicati o n. 
 
L a b or at or y testi n g:  O bt ai n bl o o d sa m pl e f or tr y ptase , t otal I g E, a n d A D A  a nti dr u g a nti b o dies ( A D A), i deall y 
wit hi n 1 5 mi n utes t o 3 h o urs after t h e o nset of a s us pecte d a n a p h yl actic reacti o n; h o we ver, u p t o 6 h o urs is 
acce pta ble.  A n a d diti o nal bl o o d sa m ple t o assess tr y ptas e, t otal I g E, a n d A D A s h o ul d be o btai ne d b et wee n 1 to 
2 wee ks  fr o m o nset of e v e nt.  L o cal la b orat or y ma y be us e d t o a nal yz e sa m ples; h o we ver, parallel sa m ples 
s h o ul d be se nt t o t he ce ntral la b orat or y f or a n al ysis.  Sa m ple c ollecti o n a n d s hi p pi n g i nstr ucti o ns are i ncl u de d 
i n the La b orat or y M a n ual.  
  
Re p orti n g : T he PI or desi g nee m ust n otif y t he s p o ns or or desi g nee wit hi n 2 4 h o urs of t he occ urre nce of a 
s us pecte d case of a na p h ylactic reacti o n or bei n g i nf or me d of the case as re q uire d f or A Es of C li nical I nterest 
( A E CI) a n d S A Es, p er A E re p orti n g re q uir e me nts  ( Secti o ns 7. 5. 6. 1  t hr o u g h Secti o n 7. 5. 6. 3 ). 
Secti o n(s) als o c o ntai ni n g si milar or relate d c ha n ges  
 Secti o n  7. 5. 5. 1  I m m u n o ge ni cit y 
 Secti o n 7. 5. 6. 1 Defi niti o ns, A d verse E v e nts of Cli nical I nt erest  
 Secti o n 1 0  List of Re fere nces 
 Secti o n 1 1. 3  A na p h yl actic Reacti o ns  
 
 
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 0  
P ur p ose:  Revis e d defi niti o n of sex u al a bsti ne nce t o ali g n wit h c urre nt st a n d ar ds  a n d cl arifie d t h at i ntr a uteri ne h or m o ne rele asi n g 
syste m is a met h o d re q uiri n g a b arrier met h o d 
T he pri mar y c h a n ge o cc urs i n Secti o n 6. 4  C o ntrace pti ve Re q uire m e nts  
N o w rea ds  
Se x ual a bsti ne nce , w he n t his is i n li ne wit h t he preferre d a n d us u al lifest yl e of t he patie nt, is c o nsi dere d a n 
acce pt a ble met h o d o nl y if defi ne d as refr ai ni n g fr o m heter ose x u al i nterc o urse d uri n g t he e nti re peri o d of 
ris k ass oci ate d wit h t he st u d y dr u g ( defi ne d a b o ve).   Peri o dic a bsti ne n ce (e g, cal e n dar, o v ul ati o n, 
s y m pt ot her mal, p ost-o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n.  
c o nsi dere d se x u al a bsti ne nce a n d d o n ot meet criteri a f or a n acce pt a ble met h o d of birt h c o ntr ol.  As 
deter mi ne d b y t he i n vesti g at or, t he reli a bilit y of se x u al a bsti ne nce nee ds t o be e v al u ate d i n rel ati o n t o t he 
d ur ati o n of t he cli nic al tri al a n d t he preferre d a n d us u al lifest yle of t he p atie nt .  A bsti ne nt patie nts m ust 
a gree t o us e 1 of t he a b o ve me nti o ne d c o ntrace pti ve met h o ds if t he y start s e x ual relati o ns hi ps a heter ose x u al 
rel ati o ns hi p  d uri n g t he st u d y a n d c o nti n ue t o d o s o f or 3 m o nt hs after t heir last d ose a d mi nistrati o n. t he e ntire 
peri o d of  ris k ass oci ate d wit h t he st u d y dr u g ( defi ne d a b o ve).  
N o w rea ds  
Esta blis he d use of oral, i m pla nta ble, i njecta ble, or  tra ns der mal h or m o n al, or i ntr a uteri ne h or m o ne-rele asi n g 
s yste m as met h o ds of c o ntrace pti o n:  W o me n of c hil d -beari n g p ote ntial usi n g h or m o n al met h o ds of 
c o ntrace pti o n m ust als o use a barrier met h o d ( c o n d o m or occl usi ve ca p [ dia p hra g m or cer vical/ va ult ca p] i n 
c o nj u ncti o n wit h s per mici de [e g, f oa m, gel, fil m, crea m, or s u p p osit or y]).  See Secti o n  6. 3 a n d Secti o n 1 1. 2 . 
 
P ur p ose: Cl arify re q uire me nts P B G or A L A elev ati o ns d uri n g Scree ni n g  
T he pri m ary c h a n ge occ urs i n Secti o n 7. 1 Scree ni n g Assess me nts  
A d de d te xt:  
If re q uir e d, A L A/ P B G le vels c ollecte d d uri n g t he scree ni n g p eri o d f or eli gi bilit y p ur p os es s h o ul d be a nal yze d 
l ocall y.   
 
P ur p ose: Cl arify e Di ary c o m pleti o n re q uire me nts d uri n g Scree ni n g  
T he pri m ary c h a n ge occ urs i n Secti o n 7. 2. 2 P ai n a n d P ai n -Rel ate d Assess me nts  
A d de d te xt:  
D uri n g t h e scree ni n g peri o d, t here s h o ul d be a mi ni m u m of 4 e ntries c o m plete d o n da ys w h e n t he patie nt is n ot 
ha vi n g a n attac k.  
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 1  
P ur p ose: I ncl u d e d a n a d diti o n al Q u ality of Life assess me nt s 
T he pri mar y c h a n ge o cc urs i n Secti o n 7. 2. 4  Q ualit y of Life ( Q O L)  
A d de d te xt:  
 P GI C: T he Patie nt Gl o bal I m pr essi o n of C ha n ge ( P GI C) is o ne q u esti o n a ns were d acc or di n g t o a 7 -p oi nt 
scale (ra n gi n g fr o m ver y m uc h i m pr o ve d t o ver y m uc h w orse) f or t he assess me nt of a patie nt’s percei ve d 
o verall healt h stat us c h a n ge si nc e t he be gi n ni n g of t he st u d y.  T his q uesti o n naire ta kes a p pr o xi matel y 2 t o 
3  mi n utes t o c o m plete.  
 P P E Q: T he P or p h yria Patie nt E x perie nce Q uesti o n naire ( P P E Q)  is a set of q uesti o ns t o assess treat me nt 
e x perie nce a n d i m pacts t o t he patie nt's life n ot c ollec te d b y t he ot her Q O L assess me nts.  
Secti o n(s) als o c o ntai ni n g si milar or relate d c ha n ges  
 Ta ble 1 a n d F o ot n ote s t o Ta ble 1: Sc he d ule of Assess me nts 
 Ta ble 2 a n d F o ot n ote s t o Table 2: Sc he d ule of Assess me nts  
 Ta ble 3 a n d F o ot n otes t o Ta ble 3: Sc he d ule of Assess me nts  
 Secti o n 2. 3:  E x pl orat or y O bjecti ves  
 Secti o n 3. 3:  E x pl orat or y E n d p oi nts  
 
P ur p ose: t o u p d ate t he g ui d a nce o n wei g ht c ollecti o n f or d osi n g c alc ul ati o ns  
T he pri mar y c h a n ge o cc urs i n Secti o n 7. 5. 2 - Wei g ht a n d Hei g ht  
A d de d te xt:  
B o d y wei g ht eit her at t h e pre vi o us st u d y ce nter visit w here wei g ht is c ollecte d will  or c urre nt st u d y ce nter 
visit m a y  b e use d f or d osi n g calc ulati o ns.  
Secti o n(s) als o c o ntai ni n g si milar or relate d c ha n ges  
 F o ot n otes t o Ta ble 1: Sc he d ule of Assess me nts  
 F o ot n otes t o Ta ble 2:  Sc he d ule of Assess me nts  
 F o ot n otes t o Ta ble 3: Sc he d ule of Assess me nts  
 


A L N -A S 1  
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 2  
P ur p ose: A d de d a n a p h yl actic re acti o ns t o list of A dverse Eve nts of Cli nic al I nterest  
T he pri mar y c h a n ge o cc urs i n Secti o n 7. 5. 6. 1 
 Defi niti o ns
A d de d te xt:  
A na p h yl actic Reacti o ns. A n a na p h ylactic reacti o n is a se vere, p ote ntiall y fatal, s yste mic aller gic reacti o n wit h 
ac ute o nset ( mi n utes t o h o urs).  S y m pt o ms of a n a na p h yl actic reacti o n  ma y i ncl u de s ki n or m uc osal tiss ue (e. g. 
ge n eralize d hi ves, pr urit us, a n gi oe de ma), res pirat or y c o m pr o mise (e. g. w heezi n g, br o nc h os p as m, h y p o xia), 
re d uce d bl o o d press ur e or ass ociate d s y m pt o ms (e. g. s y nc o p e, h y p ot o nia). See Secti o n 1 1. 3 f or g ui d a nce o n 
dia g n osi n g a n a p h yl actic reacti o ns.  [2 6 ]   
P ur p ose: U p d ate d det ails of st atistic al a n alyses f or bi o m arkers   
T he pri mar y c h a n ge o cc urs i n Secti o n 8. 2. 5. 2 
 Sec o n dar y E n d p oi nt
N o w rea ds: 
F or t he a nal ysis of uri nar y A L A -relate d e n d p oi nts, t he A L A le vels will be c o m pare d b et wee n treat me nt ar ms 
usi n g a n a nal ysis of c o varia nce ( A N C O V A) m o del wit h  fi xe d effect of tre at me nt ar ms, str atific ati o n f act ors 
f or AI P p atie nts ( pri or he mi n pr o p h yl a xis st at us a n d hist oric al att ac k r ates), a n d wit h t he baseli ne A L A as 
a c o vari ate.  P B G -rel ate d e n d p oi nts will als o be a nal yze d usi n g t his met h o d ol o g y.   
Secti o n(s) als o c o ntai ni n g si milar or relate d c ha n ges  

Secti o n 8. 2. 1 0: I nteri m A nal ysis


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 3  
P ur p ose: re m o ve d t he pr es pecifie d wi n d o w f or pre d ose s a m pli n g ti me f or all uri ne P K, P D a n d A D A assess me nts  
T he pri mar y c h a n ge o cc urs i n Secti o n 1 1 P har mac o ki netic/ P har mac o d y na mic Assess me nt Ti me P oi nts 
 Ta ble 7 ( P har mac o ki netic, 
E C G, a n d A D A Ti me P oi nts f or All Patie nts [ E x ce pt Patie nts at East Asia n Sites]) ,  
N o w rea ds:  
Pre d ose ( wit hi n 6 0 mi n utes bef ore d osi n g) 
Secti o n(s) als o c o ntai ni n g si milar or relate d c ha n ges  
 Ta ble 8 ( P har mac o ki neti c, E C G, a n d A nti -Dr u g A nti b o d y ( A D A) Ass ess me nt Ti me P oi nts f or Patie nts at East Asia n St u d y 
Ce nters [ Bl o o d Sa m ples])  
 Ta ble 9 ( Uri n e P har mac o ki netic/ P har mac o d y na mi c Ti me p oi nts f or Patie nts at East Asia n St u d y Ce nters)  
 


A L N -A S 1   
Cli nic al St u d y Pr ot oc ol A L N -A S 1 -0 0 3  
 
A me n d me nt 1 S u m m ar y of  C h a n ges _ 0 4 M a y 2 0 1 8  
 
Al n yl a m P h ar m ace utic als  
C o nfi de nti al  
1 4  
P ur p ose: A d d  g ui d a nce f or di a g n osi n g a n a p hyl actic re acti o ns  
T he pri mar y c h a n ge o cc urs  i n Secti o n 1 1. 3 ( ne w s ecti o n)  A na p h ylactic R eacti o n s 
A d de d te xt:  
T a ble  2  
S a m ps o n  Criteri a  f or A n a p h yl actic Re acti o ns  
 
A da pte d fr o m Sa m ps o n et al. 2 0 0 6 [ 2 6 ] 
 
 

SAP_003.pdf: 
 
 
Official Title:  
ENVISION: A Phase 3 Randomized, Double-blind, Placebo-Controlled 
Multicenter Study with an Open-label Extension to Evaluate the Efficacy 
and Safety of Givosiran in Patients with Acute Hepatic Porphyrias 
 
NCT Number:   
NCT03338816 
 
Document Date:   
Statistical Analysis Plan, 13 Feb 2019 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
1 
STATISTICAL ANALYSIS PLAN 
 
ENVISION: A Phase 3 Randomized, Double-blind, Placebo-Controlled 
Multicenter Study with an Open-label Extension to Evaluate the Efficacy 
and Safety of Givosiran in Patients with Acute Hepatic Porphyrias 
 
Protocol Number: 
Protocol Version and Date: 
ALN-AS1-003 
Protocol Amendment 3: 21 September 2018 
Original Protocol: 06 September 2017  
Investigational Drug: 
ALN-AS1 (Givosiran) 
Phase: 
Phase 3 
Sponsor: 
Alnylam Pharmaceuticals, Inc. 
300 Third Street 
Cambridge, MA  02142 USA 
 
 
 
 
Sponsor Representative: 
 
 
 
Analysis Plan Version and 
Date: 
SAP Amendment 2: 13 February 2019 
SAP Amendment 1: 11 September 2018 
Original SAP: 05 December 2017 
 
Confidentiality Statement 
The concepts and information contained in this document or generated during the study are 
considered proprietary and may not be disclosed in whole or in part without expressed written 
authorization of Alnylam Pharmaceuticals, Inc. 
 
PI
PI


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
2 
APPROVAL SIGNATURE PAGE 
ENVISION: A Phase 3 Randomized, Double-blind, Placebo-Controlled 
Multicenter Study with an Open-label Extension to Evaluate the Efficacy 
and Safety of Givosiran in Patients with Acute Hepatic Porphyrias 
 
Protocol Number: 
ALN-AS1-003  
Analysis Plan Version and Date: 
Amendment 2: 13 February 2019 
 
This document has been approved and signed electronically on the final page by the following: 
 
 
 
  
  
Alnylam Pharmaceuticals, Inc. 
 
 
 
Alnylam Pharmaceuticals, Inc 
 
PI
PI


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
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TABLE OF CONTENTS 
APPROVAL SIGNATURE PAGE .................................................................................................2 
TABLE OF CONTENTS .................................................................................................................3 
LIST OF TABLES ...........................................................................................................................5 
LIST OF FIGURES .........................................................................................................................5 
LIST OF ABBREVIATIONS ..........................................................................................................6 
1. 
INTRODUCTION ........................................................................................................8 
2. 
STUDY OVERVIEW ...................................................................................................8 
2.1. 
Synopsis of Study Design .............................................................................................8 
2.2. 
Randomization Methodology .......................................................................................9 
2.3. 
Blinding ........................................................................................................................9 
2.4. 
Study Procedures ........................................................................................................10 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................10 
3.1. 
Objectives ...................................................................................................................10 
3.1.1. 
Primary Objective .......................................................................................................10 
3.1.2. 
Secondary Objectives .................................................................................................10 
3.1.3. 
Exploratory Objectives ...............................................................................................11 
3.2. 
Endpoints ....................................................................................................................11 
3.2.1. 
Primary Endpoint ........................................................................................................11 
3.2.2. 
Secondary Endpoints ..................................................................................................11 
3.2.3. 
Exploratory Endpoints ................................................................................................12 
3.2.4. 
Safety Endpoints .........................................................................................................12 
4. 
PATIENT POPULATION ..........................................................................................13 
5. 
GENERAL STATISTICAL METHODS ...................................................................14 
5.1. 
Determination of Sample Size ....................................................................................14 
5.2. 
General Considerations ...............................................................................................14 
5.3. 
Computing Environment ............................................................................................15 
5.4. 
Baseline Definitions ....................................................................................................15 
5.5. 
Randomization Stratification Factors .........................................................................16 
5.6. 
Visit Windows ............................................................................................................16 
5.7. 
Multiple Comparisons/Multiplicity ............................................................................17 
5.8. 
Analysis Cutoff and Database Lock ...........................................................................17 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
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5.9. 
Interim Analyses .........................................................................................................18 
5.10. 
Analyses for the Entire Study .....................................................................................18 
6. 
STATISTICAL ANALYSIS ......................................................................................21 
6.1. 
Patient Disposition ......................................................................................................21 
6.2. 
Demographics and Baseline Characteristics ...............................................................21 
6.3. 
Protocol Deviations ....................................................................................................21 
6.4. 
Drug Exposure ............................................................................................................22 
6.5. 
Efficacy Analysis ........................................................................................................22 
6.5.1. 
Primary Endpoint ........................................................................................................23 
6.5.1.1. 
Primary Analysis using Negative Binomial Regression Model .................................23 
6.5.1.2. 
Component Analysis ...................................................................................................24 
6.5.1.3. 
Analysis in the Per Protocol Set .................................................................................24 
6.5.1.4. 
Sensitivity Analysis ....................................................................................................24 
6.5.2. 
Secondary Endpoints ..................................................................................................25 
6.5.3. 
Exploratory Endpoints ................................................................................................26 
6.5.4. 
Subgroup Analysis ......................................................................................................27 
6.6. 
Pharmacodynamic Analysis........................................................................................28 
6.7. 
Pharmacokinetic Analysis ..........................................................................................28 
6.8. 
Safety Analysis ...........................................................................................................28 
6.8.1. 
Adverse Events ...........................................................................................................29 
6.8.2. 
Laboratory Data ..........................................................................................................30 
6.8.3. 
Vital Signs and Physical Examination ........................................................................31 
6.8.4. 
Electrocardiogram .......................................................................................................31 
6.8.5. 
Prior and Concomitant Medications ...........................................................................32 
6.9. 
Anti-Drug Antibody ....................................................................................................32 
7. 
CHANGES FROM PREVIOUS VERSION(S) .........................................................33 
7.1. 
Changes in SAP Amendment 1 ..................................................................................33 
7.2. 
Changes in SAP Amendment 2 ..................................................................................34 
8. 
REFERENCES ...........................................................................................................35 
9. 
APPENDICES ............................................................................................................36 
9.1. 
Details of Interim Analysis .........................................................................................36 
9.1.1. 
Interim Analysis Population .......................................................................................36 
9.1.2. 
Rationale for Month 3 ALA Endpoint ........................................................................36 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
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9.1.3. 
Analysis of ALA Endpoint .........................................................................................37 
9.1.3.1. 
Primary Analysis Using ANCOVA/Multiple Imputation ..........................................37 
9.1.3.2. 
Additional Analysis ....................................................................................................38 
9.1.3.3. 
Durability of ALA Lowering ......................................................................................38 
9.2. 
Sample SAS Code for Interim Analysis of ALA Data ...............................................38 
9.3. 
Details of the Pattern Mixture Model for ALA ..........................................................40 
9.4. 
Details of the Pattern Mixture Model for Attack Data ...............................................41 
9.5. 
Analgesic medications ................................................................................................43 
 
LIST OF TABLES 
Table 1: 
Derived Analysis Visit Windows ...............................................................................16 
LIST OF FIGURES 
Figure 1: 
Study Design .................................................................................................................9 
Figure 2: 
ALA Levels over Time (in Days) for Individual AIP Patients in the Givosiran 
Phase 1 Study (Cohort C) ...........................................................................................37 
 
 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
6m-DB 
6-month double-blind placebo-controlled 
AAR 
Annualized attack rate  
ADP 
ALA dehydratase deficient porphyria 
AE 
Adverse event 
ALA 
Aminolevulinic acid 
ALAS1 
Aminolevulinic acid synthase 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Class 
AUC 
Area under curve 
BMI 
Body mass index 
CI 
Confidence interval 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DB 
Double-blind 
DMC 
Data monitoring committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report form 
HBMS  
Hydroxymethylbilane Synthase 
HCP 
Hereditary Coproporphyria 
HLT 
High Level Term 
HRQOL 
Health-related quality of life 
IA 
Interim analysis 
ICH 
International Council for Harmonisation 
IRS 
Interactive response system 
ISR 
Injection site reaction 
LLN 
Lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Multiple imputation 
MMRM 
Mixed effect model repeated measurement 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
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Abbreviation 
Definition 
mRNA 
messenger RNA 
NCI 
National Cancer Institute 
OLE 
Open label extension 
PBG 
Porphobilinogen 
PD 
Pharmacodynamics 
PGIC 
Patient Global Impression of Change 
PK 
Pharmacokinetics 
PMM 
Pattern Mixture Model 
PPS 
Per Protocol Set 
PT 
Preferred Term 
Q1 
First quartile 
Q3 
Third quartile 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous 
SD 
Standard deviation 
SEM 
Standard error of mean 
SMQ 
Standardized MedDRA Query 
SOC 
System organ class 
SSR 
Sample size reassessment 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
ULN 
Upper Limit of Normal 
VP 
Variegate porphyria 
WHO 
World Health Organization 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
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1. 
INTRODUCTION 
Acute hepatic porphyrias (AHPs) are a family of rare, serious and life-threatening disorders 
characterized by acute and severe neurovisceral attacks, often requiring hospitalization or urgent 
healthcare visit, as well as by chronic debilitating symptoms. Patients are treated with intravenous 
hemin during acute attacks, but there is a high unmet need for safe and efficacious therapies to 
prevent attacks and decrease the chronic symptoms in between attacks. Givosiran is an 
investigational RNA interference (RNAi) agent in development for the treatment of AHPs in adult 
and adolescent patients. It acts to inhibit synthesis of liver aminolevulinic acid synthase (ALAS1) 
messenger RNA (mRNA) with consequent reductions in aminolevulinic acid (ALA) and 
porphobilinogen (PBG) levels, the neurotoxic intermediates that are causal in this disease. 
Givosiran is formulated for administration via subcutaneous (SC) injection.  
The ENVISION Study (ALN-AS1-003) is a Phase 3 study designed to evaluate the efficacy and 
safety of SC-administered givosiran in patients with AHPs. This statistical analysis plan (SAP) 
outlines the methods to be used in the analysis of study data in order to address the study 
objectives of Study ALN-AS1-003. Any change to the data analysis methods described in the 
protocol, as well as the justification for the change, will be described in the SAP and clinical 
study report (CSR). 
An original version of the SAP was signed off on Dec 05, 2017. The SAP amendment 1 provided 
updated plan for analysis of the data and was signed off on Sep 11, 2018, prior to the interim 
analysis. This SAP amendment 2 provides detailed planned analyses for data in the OLE periods 
and will be finalized and signed off before the final analysis of the 6-month double-blind (6m-
DB) data and the unblinding of treatment assignments. The changes in these SAP amendments are 
documented in Section 7 . 
2. 
STUDY OVERVIEW 
2.1. 
Synopsis of Study Design 
The ENVISION Study (ALN-AS1-003) is a multicenter, multinational Phase 3 study designed to 
evaluate the efficacy and safety of givosiran in approximately 74 patients with AHPs; the study is 
comprised of a 1:1 randomized, double-blind, placebo-controlled period of 6 months, followed by 
an open-label extension (OLE) period of up to 30 months to evaluate the long-term safety and 
efficacy of givosiran.  
Patients who crossed over to the OLE period prior to the implementation of the protocol 
amendment 3 (i.e., under amendment version 1 or 2) and are receiving a 2.5 mg/kg once monthly 
givosiran dose will remain on that dose. Upon entry to the OLE period under amendment version 
3, patients will cross over to receive a 1.25 mg/kg once monthly dose of givosiran. Starting at 
Month 13 (when 6 months of open-label givosiran dosing have been completed), patients in the 
once monthly 1.25 mg/kg treatment group who experience inadequate disease control may have 
their monthly dose increased to 2.5 mg/kg, upon discussion and agreement by the Investigator and 
medical monitor and demonstration of tolerability to givosiran and if ALA criteria are met (urine 
ALA levels (mmol/mol Cr) are not stably maintained ≤ULN or are inducible). 
The study design schema is presented in Figure 1.  


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
9 
Figure 1: 
Study Design 
  
 
2.2. 
Randomization Methodology 
Patients will be randomized 1:1 to the givosiran treatment arm and the placebo arm in a double-
blinded manner. Treatment will be stratified at randomization by AHP type (acute intermittent 
porphyria (AIP) [with genetic evidence of mutation in the hydroxymethylbilane synthase 
(HMBS) gene] vs hereditary coproporphyria (HCP), variegate porphyria (VP), ALA dehydratase 
deficient porphyria (ADP), or any AHP without identified mutation in a porphyria-related gene).  
Randomization for AIP patients will be further stratified by each patient’s use of hemin 
prophylaxis regimen at the time of screening and by each patient’s historical annualized attack 
rate prior to randomization.  Patients on a hemin prophylaxis regimen prior to study entry will be 
stratified by their historical annualized attack rate: <7 attacks vs ≥7 attacks.  Patients who were 
not on a hemin prophylaxis regimen prior to study entry will be stratified by their historical 
annualized attack rate: <12 attacks vs ≥12 attacks. 
2.3. 
Blinding 
Treatment assignments will be maintained by the Interactive Response System (IRS) which has 
controlled access limited to supply chain team members. Any unplanned unblinding occurring 
during the 6-month double-blind placebo-controlled treatment period (referred to as the 6m-DB 
period hereafter) will be documented and reported in the CSR. 
The independent (external) data monitoring committee (DMC) and an independent (external) 
biostatistics group supporting the DMC will have access to subject level treatment assignments 
throughout the study. 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
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An unblinded interim analysis (IA) will be conducted when approximately 40 AIP patients have 
completed at least 3 months of the double-blind treatment period. This IA will be based on 
creatinine normalized urinary ALA (referred to as ALA hereafter) data at 3 months for regulatory 
filing, and the analysis will be performed by the ALA IA independent statistician and 
programmer. The IA Filing Decision Committee at Alnylam will review data provided by the 
ALA IA independent statistician and programmer and decide whether to proceed to filing based 
on the IA results. If the committee makes an affirmative filing decision based on the IA, an 
Alnylam unblinded IA filing team will be formed and will have access to treatment assignment 
information in patients included for IA. They will not have access to post-IA patient-level study 
data until the 6m-DB period data are locked and unblinded, except for access to unblinded 
Suspected Unexpected Serious Adverse Reaction (SUSAR) safety data as shared with the agency 
via regular pharmacovigilance (PV) process, and safety data on the approximately 40 AIP patients 
included in the IA needed to prepare the 90-day safety update.  
A blinded study conduct team will be in place throughout the 6m-DB period of the study 
regardless of the ALA interim analysis results. The blinded study conduct team will not have 
access to treatment assignment or any information that could reveal treatment assignment (e.g. 
PK, ALA, PBG, and ALAS1) until the study is unblinded for the primary efficacy analysis at 
Month 6.  
Details about the specifics of the blinding aspects for the whole, including before, during, and 
after the IA are outlined in the Blinding Plan. Details about the measures taken for the unblinded 
IA, including concepts and plans for how the IA will be conducted and maintenance of data 
integrity are outlined in the Data Integrity Plan (Amendment 3, 07Sep2018). 
 
2.4. 
Study Procedures 
The schedule of assessments is described in the study protocol (Table 1, Table 2, and Table 3). 
3. 
OBJECTIVES AND ENDPOINTS 
3.1. 
Objectives 
3.1.1. 
Primary Objective 
 Evaluate the effect of givosiran, compared to placebo, on the rate of porphyria attacks 
requiring hospitalization, urgent healthcare visit, or IV hemin administration at home 
in patients with AIP 
3.1.2. 
Secondary Objectives 
 Evaluate the effects of givosiran, compared to placebo, on urinary ALA levels in 
patients with AIP 
 Evaluate the effects of givosiran, compared to placebo, on urinary PBG levels in 
patients with AIP 


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 Evaluate the effects of givosiran, compared to placebo, on hemin usage in patients 
with AIP 
 Evaluate the effects of givosiran, compared to placebo, on the rate of porphyria attacks 
requiring hospitalization, urgent healthcare visit, or IV hemin administration at home 
in patients with any AHP  
 Evaluate the effects of givosiran compared to placebo in patients with AIP on the 
symptoms of pain, nausea, and fatigue 
 Evaluate the effects of givosiran, compared to placebo, in patients with AIP on the 
Physical Component Summary (PCS) of the 12-item Short-Form Health Survey 
(SF-12)  
  Evaluate the safety and tolerability of givosiran in patients with any AHP 
3.1.3. 
Exploratory Objectives 
 Evaluate the effects of givosiran, compared to placebo, in patients with AIP and in 
patients with any AHP over the 6m-DB period on: 
 Rate of all porphyria attacks (requiring hospitalization, urgent healthcare visit, IV 
hemin administration at home, or treated at home without IV hemin) 
 Urinary ALAS1 mRNA levels 
 Analgesic usage (opioid and non-opioid) 
 Additional quality of life (QOL) measures, including missed days of work/school 
 Assess the treatment effect of givosiran at evaluated doses over the OLE period in 
patients with AIP and in patients with any AHP who had previously been randomized 
to placebo treatment  
 Assess the long-term treatment effect of givosiran in patients with AIP and in patients 
with any AHP 
 Characterize the PK of and assess the antidrug antibodies (ADA) of givosiran in 
patients with any AHP 
3.2. 
Endpoints 
3.2.1. 
Primary Endpoint 
Annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV 
hemin administration at home in patients with AIP over the 6m-DB period. 
3.2.2. 
Secondary Endpoints 
 Urinary ALA levels in patients with AIP at 3 months 
 Urinary ALA levels in patients with AIP at 6 months  
 Urinary PBG levels in patients with AIP at 6 months  


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 Annualized rate of administered hemin doses (evaluated by annualized days of hemin 
use, see Section 6.5.2 for details) in patients with AIP over the 6m-DB period 
 Annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit, 
or IV hemin administration at home in patients with any AHP over the 6m-DB period  
 Daily worst pain score as measured by Brief Pain Inventory-Short Form (BPI-SF) 
numeric rating scale (NRS) in patients with AIP over the 6m-DB period 
 Daily worst fatigue score as measured by Brief Fatigue Inventory-Short Form (BFI-
SF) NRS in patients with AIP over the 6m-DB period 
 Daily worst nausea score as measured by NRS in patients with AIP over the 6m-DB 
period 
 Change from baseline in the Physical Component Summary (PCS) of the 12-item 
Short-Form Health Survey (SF-12) in patients with AIP at 6 months 
3.2.3. 
Exploratory Endpoints 
Exploratory endpoints will be measured in patients with AIP and in patients with any AHP over 
the 6m-DB period or over the OLE period:  
 Rate of porphyria attacks requiring hospitalization, urgent healthcare visit, or IV 
hemin administration at home 
 Rate of all porphyria attacks 
 Rate of administered hemin doses (evaluated by annualized days of hemin use, see 
Section 6.5.2 for details) 
 Urinary ALA and PBG levels 
 Urinary ALAS1 mRNA levels  
 Daily worst pain, daily worst fatigue, and daily worst nausea scores over 12 months 
 PCS of the SF-12 
 EQ-5D-5L index score 
 Patient Global Impression of Change (PGIC) 
 Porphyria Patient Experience Questionnaire (PPEQ) 
 Analgesic usage (opioid and non-opioid) 
 Plasma PK parameters of givosiran 
 Incidence and titer of ADAs 
3.2.4. 
Safety Endpoints 
The primary safety parameter is the adverse events (AEs) that occurred on or after the time of the 
first dose of study drug is administered. Safety parameters also include vital signs, ECGs, clinical 
laboratory assessments, and physical exams. The primary summaries of the safety of givosiran 
versus placebo will be based on safety parameters assessed during the 6m-DB period. The 


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frequency of AEs will also be evaluated over the entire study including the 6m-DB and OLE 
periods. Since porphyria attacks will be recorded for efficacy assessment of the study drug, they 
will not be treated as AEs or SAEs.  
4. 
PATIENT POPULATION 
The populations (analysis sets) are defined as follows:  
 Full Analysis Set (FAS):  All randomized patients who received at least one dose of 
study drug. Patients will be grouped by their randomly assigned treatment group (i.e. 
as randomized).  
 AIP patients in the Full Analysis Set (FASAIP): All randomized AIP patients (with 
identified mutation in the HMBS gene) who received at least one dose of study drug. 
Patients will be grouped by their randomly assigned treatment group (i.e. as 
randomized).  
 Per Protocol Analysis Set (PPS): All randomized AIP patients (with identified 
mutation in the HMBS gene) who received at least 4 doses (>60%) of study drug 
during the 6-month double-blind period, were followed for collection of attack data 
through 6 months (≥162 days) and did not experience major protocol deviations that 
may impact the primary efficacy results (e.g., not meeting the key inclusion/exclusion 
criteria). Patients will be analyzed according to their randomly assigned treatment 
group. 
 Safety Analysis Set (SAS): All patients who received at least one dose of study drug, 
grouped according to the treatment actually received.  
 PK Analysis Set: All patients who received at least one dose of study drug and have 
evaluable PK data contributing to the estimation of PK parameter. 
 PD Analysis Set: All patients who received at least one dose of study drug and who 
have baseline and at least one post-dose urine sample for the determination of ALA or 
PBG. 
 All Givosiran Treated Set: All patients who received at least one dose of givosiran, 
including patients who took givosiran during the 6m-DB period and patients who first 
took placebo during the 6m-DB period and switched to givosiran during the OLE 
period. 
Both FAS and FASAIP will be used to evaluate efficacy endpoints. The primary endpoint will also 
be analyzed using the Per Protocol Set. Safety during the 6m-DB period will be analyzed using 
the Safety Analysis Set. The PK and PD Analysis Sets will be used to conduct PK and PD 
analyses, respectively. The All Givosiran Treated Set will be used to summarize long-term 
efficacy and safety data during givosiran treatment. See Section 5.10 for details. Number of 
patients included in all analysis sets will be provided.  


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5. 
GENERAL STATISTICAL METHODS 
5.1. 
Determination of Sample Size 
The planned total enrollment for the study is approximately 74 patients, including approximately 
70 AIP patients. 
Seventy patients will yield at least 90% power to detect a 45% reduction in the annualized attack 
rate at a 2-sided 5% significance level assuming a mean annualized attack rate of 8, a standard 
deviation (SD) of 5 in the placebo arm (mean/SD of 4/2.9 for 6 months to preserve the over-
dispersion of 3.8), and a mean annualized attack rate of 4.4 with SD of 3 in the givosiran arm 
(mean/SD of 2.2/1.8 for 6 months to preserve the over-dispersion of 4.2), using a negative 
binomial model.  This study design will still have at least 80% power even if the dropout rate is as 
high as 15% under the same assumptions.  
5.2. 
General Considerations 
Categorical variables will be summarized using counts and percentages.  
Continuous variables will be summarized using the following descriptive summary statistics: 
number of patients (n), mean, SD, median, interquartile range (Q1, Q3), minimum value (min), 
and maximum value (max). The precision of the measurement for each continuous variable will 
be used to determine the number of decimal places to present in tables, figures and derived 
listings. Minimum and maximum values will be reported with the same precision as the units of 
measure. The mean, median, SD, Q1 and Q3 will be reported to one greater decimal place. Any 
values that require transformation to standard units (metric or SI) will be converted with the 
appropriate corresponding precision.  
The day of the first dose of study drug administered is defined as Day 1. Study Day is defined as 
the number of days between the day of the first dose of study drug (Day 1) and the specific time 
point. The Study Day of a time point of interest is calculated as follows.   
If after Day 1,  
Study Day = date of interest  date of the first dose of study drug + 1 
If prior to Day 1,  Study Day = date of interest  date of the first dose of study drug 
Study days are negative when the time point of interest is prior to Day 1, positive when time of 
interest is after Day 1. There is no Day 0. For example, the day before the first study drug dose is 
defined as Day -1. 
For ALA, PBG and urinary creatinine, the assessments collected and recorded as lower than the 
lower limit of quantification/detection will be replaced by half of the lower limit of 
quantification/detection. For other safety laboratory parameters, the assessments collected and 
recorded as lower than the lower limit of quantification/detection will be replaced by the lower 
limit of quantification/ detection. Any assessment collected and recorded as greater than the upper 
limit of quantification will be replaced by the upper limit of quantification. 
For all analysis sets except for the All Givosiran Treated Set, summaries will be presented by 
treatment arm (givosiran and placebo).  
For the All Givosiran Treated Set, summaries will be presented by the following groups: 


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 Givosiran/Givosiran: all patients who received givosiran during the 6m-DB including 
patients who continued to receive givosiran during the OLE period and patients who 
discontinued treatment during the 6m-DB period; 
 Placebo/Givosiran: all patients who received placebo during the 6m-DB period and 
switched to givosiran in the OLE period;  
 All Givosiran: all patients who received at least one dose of givosiran during either 
6m-DB or OLE period.   
5.3. 
Computing Environment 
All statistical analyses will be performed using validated SAS statistical software Version 9.4 (or 
later), unless otherwise noted. Figures may be generated using R version 3.4 (or later). 
5.4. 
Baseline Definitions 
For ALA, PBG, and ALAS1 mRNA, collection of the screening urine samples must occur when 
the patient is not having an attack, and ≥4 days after prophylactic hemin discontinuation and after 
their last hemin dose. Two screening urine samples (collected on 2 different days) should be 
collected for ALA/PBG; one screening urine sample should be collected for ALAS1 mRNA. On 
Day 1 visit, before the first dose of study drug is administered, the third urine sample for 
ALA/PBG is scheduled to be collected. If a patient is having an attack or it has been less than 4 
days after the last hemin dose on Day 1, the third urine sample will not be collected on Day 1 and 
will be postponed until at least 4 days after the last hemin dose. The baseline creatinine 
normalized ALA/PBG/ALAS1 values will be defined as the median of measurements taken on or 
prior to Day 1. Any samples taken during an attack or within 3 days after receiving hemin on or 
prior to Day 1 will be excluded from the baseline calculation. For a patient, if all available 
samples on or prior to Day 1 meet the exclusion criteria, the last non-missing value on or prior to 
Day 1 will be used as the baseline value for the patient.  
Daily worst scores in pain, nausea and fatigue, as well as analgesic medication use at home, are 
collected using an electronic diary (eDiary) by patients or caregivers. During the Screening 
period, the eDiary variables are collected when patients are not experiencing a porphyria attack. 
For each eDiary variable collected in the Screening period, the average of a minimum of 4 days 
and a maximum of 7 days (consecutive days not required) is defined as the baseline value. If there 
are more than 7 days collected for any variable, the measurements closest to Day 1 will be used. 
All measurements used for the baseline value must be taken when a patient is not experiencing a 
porphyria attack. If a patient has less than 4 days of measurements on non-attack days prior to 
Day 1, the average of the available non-attack days will be used for the baseline value.  
For all other measures, baseline will be defined as the last non-missing value available on or prior 
to the first dose of study drug, unless otherwise specified. 
For the All Givosiran Treated Set, baseline for patients who switched from placebo to givosiran 
will be redefined as the values prior to the first dose of Givosiran. For ALA, PBG, and ALAS1 
mRNA, the redefined baseline will be calculated as the median of all values after the first dose in 
the 6m-DB period and prior to the first dose in the OLE period, excluding samples during an 
attack or within 3 days after receiving hemin. For all the other endpoints, the redefined baseline 
will be derived in the similar way as described above for the baseline for the 6m-DB period.  


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5.5. 
Randomization Stratification Factors 
Randomization for this study is first stratified by AHP type: AIP [with genetic evidence of a 
mutation in the HMBS gene] vs non-AIP [HCP, VP, ADP, or any AHP without an identified 
mutation in a porphyria-related gene].  
The AIP patient stratum is further stratified by the use of hemin prophylaxis or not immediately 
prior to Screening, and on the historical AAR. Patients who had been on hemin prophylaxis will 
be stratified by their historical AAR of <7 vs ≥7.  Patients who had not been on a hemin 
prophylaxis will be stratified by their historical AAR: <12 vs ≥12. This historical AAR is 
calculated based on the medical record reviewed for inclusion criterion of at least 2 attacks 
requiring hospitalization, urgent healthcare visit or IV hemin administration at home within the 6 
months prior to randomization.  
Since only a few patients in the non-AIP stratum of HCP, VP, ADP, or any AHP without 
identified mutation in a porphyria-related gene are anticipated to be enrolled in the study, there is 
no further stratification within the stratum. 
The historical AAR prior to randomization will be classified into high versus low when used as a 
categorical covariate. For patients on a hemin prophylaxis regimen at the time of screening, high 
attack rate is defined as AAR ≥7. For patients not on a hemin prophylaxis regimen at screening, 
AAR ≥12 is considered as high attack rates. 
Stratification factors are recorded in both the IRS and the clinical database. In statistical analyses 
that use randomization stratification factors as covariates, the stratum assignment will reflect the 
values as recorded in the clinical database. In the presence of stratification errors, the stratification 
used in analysis may not match that in the IRS. In addition, for non-AIP patients, the two AIP-
specific stratification factors hemin prophylaxis regimen and historical AAR are collected in the 
clinical database and will be used as covariates in the analysis of AHP population.   
5.6. 
Visit Windows   
For PD and clinical laboratory parameters, analysis visits will be derived for the 6m-DB period 
based on the study day and visit windows. Target days and the acceptable range of study days for 
each visit are defined in Table 1  below. If more than one visit falls within a visit window, the 
visit occurring closest to the target day will be selected. If there are multiple visits with the same 
distance from the scheduled visit day, the later visit will be selected. The derived visits will be 
used for all analyses. 
Table 1: 
Derived Analysis Visit Windows 
Study Visit 
Target Day 
Window 
Screening 
Day -60 to -1 
≤ -1 
Day 1 
1 
1 
Week 2 
15 
2 – 22 
Month 1 
29 
23 – 43 
Month 2 
57 
44 – 71 


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Study Visit 
Target Day 
Window 
Month 3 
85 
72 – 106 
Month 4 
113 
107 – 127 
Month 5 
141 
128 – 155 
Month 6 
169 
156 - the earlier of (Day 183, and the 
day of the first dose of OLE) 
For PD and laboratory parameters assessed during the OLE period and for vital signs and ECG 
measurements during the entire study, no windowing rules will be implemented, and the reported 
clinical visits will be used for analysis. 
For QOL assessments including SF-12, EQ-5D-5L and missed days of work/school, data are 
collected every 3 months up to 12 months, then every 6 months afterwards. If the scheduled visits 
are not performed, any unscheduled and/or discontinuation visits will be mapped to the 
corresponding scheduled visits if the visit dates fall into below windows. The midpoint of two 
visits will be included in the time window of the preceding visit. 
Scheduled visits (Month 3, 6, 9, 12) ± 6 weeks 
Scheduled visits (Month 18, 24, 30, 36) ± 12 weeks 
For patients who switched from placebo to givosiran, study visits will be mapped based on the 
redefined baseline.  
The derived visits will be used for analyses. 
5.7. 
Multiple Comparisons/Multiplicity 
At the time of the unblinded interim analysis, only the first secondary efficacy endpoint ALA 
levels at Month 3 will be assessed. A significance level of 0.001 will be used when comparing the 
ALA levels between the two treatment arms using an ANCOVA model.  
For the final analyses of the 6m-DB primary treatment period, a significance level of 0.049 will 
be used to test the efficacy endpoints, reflecting a penalty of 0.001 for the unblinded interim 
analysis. A fixed-sequence testing strategy for the primary and secondary endpoints will be 
implemented to control the overall type I error rate. The primary endpoint will be compared 
between treatment arms at the significance level of 0.049. If the test is statistically significant, 
then the secondary endpoints will each be tested at the same significance level of 0.049 in the 
order specified in the efficacy endpoint section (Section 3.2 ). If the test of an endpoint in the 
sequence is not statistically significant, the testing of remaining endpoints in the sequence will 
stop and the null hypotheses for the subsequent tests will not be rejected. 
There will be no multiplicity adjustment for exploratory endpoints.  
5.8. 
Analysis Cutoff and Database Lock 
For the interim analysis and the final 6m-DB analysis, as this study will be ongoing, the study 
database will be soft-locked with all data up to a prespecified cutoff date quality controlled, i.e. 
data in EDC will be frozen and external data such as laboratory data will be QA’d and cleaned. 


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The soft lock is an interim database lock. Additional details regarding the soft lock process are 
located in the study Data Management Plan. 
The interim and the final 6m-DB analysis will include data on or prior to this prespecified cutoff 
date. For assessments with starting/ending dates (e.g., AEs, medications, medical history), the 
starting date will be compared with the pre-specified cutoff date.  
After the study is completed, i.e., all patients completed the OLE period and the safety follow-up 
visits, the database will be hard locked and all data collected will be used for analysis. 
5.9. 
Interim Analyses 
An unblinded interim analysis will be conducted when approximately 40 AIP patients have 
completed the Month 3 visit. The data for these ~40 patients will be soft-locked for an interim 
database lock and transferred in support of the interim analysis. A cutoff analysis approach will 
be implemented in the analysis datasets as specified in Section 5.8 . The details of the interim 
analyses are discussed in Appendix 9.1  
5.10. 
Analyses for the Entire Study 
The study design includes a 6m-DB period and an OLE period. The primary objective is to 
evaluate the efficacy and safety of givosiran compared with placebo during the 6m-DB period. In 
addition, the long-term efficacy and safety of givosiran during the entire givosiran treatment 
period (beyond 6m-DB) will be characterized for the All Givosiran Treated Set. For patients who 
received placebo in the 6m-DB period and givosiran in the OLE period, the intra-patient 
comparison of the two treatment periods will be conducted to assess the trajectory changes for 
selected efficacy parameters. 
The detailed definitions for different treatment periods are as the following. 
 6m-DB Period 
The treatment comparison of givosiran versus placebo will focus on the 6m-DB period, 
defined as below:  
1) For patients who received at least one dose of givosiran during the OLE period, all 
assessments collected prior to the first dose of givosiran in the OLE period will be 
included in the 6m-DB period. All data will be included in the summary tables and 
figures. 
2) For patients who discontinued treatment and did not receive any givosiran dose in the 
OLE period, all assessments will be included in the 6m-DB period. Assessments 
collected within given time windows (details listed in below table) will be included in 
summary tables/figures and those outside the time windows will be listed only unless 
specified otherwise (e.g., AEs in Section 6.8 ).   
Endpoint 
Windowing rule for patients who did not enter OLE 
Safety and PD endpoints Assessments with onset date within 28 days of the last dose [1] 
Attacks and hemin use 
related endpoints 
Data collected on or before the earlier of 1) Day 162 which is the 
start day of Month 6 visit window; and 2) end of study (EOS) 
date.  


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Endpoint 
Windowing rule for patients who did not enter OLE 
Other clinical efficacy 
endpoints 
Assessments collected on or before Day 183. 
[1] In a rare situation that a patient did not discontinue 6m-DB and did not enter OLE, all data will be 
included in summary. For AE summary, related AEs will be considered as TEAE and included in summary 
tables regardless of time window.  
 OLE Period 
The start day of the OLE period is defined as the day when the first dose of the OLE 
period is administered. The assessments collected or AEs with onset after the 
administration of the first dose of the OLE period will be included in the OLE period. 
When assessments or AE onset dates are exactly the first OLE dose date with time 
missing, the records will be included in the OLE period.  
 During Givosiran Treatment 
For all patients who received at least one dose of givosiran, data will be summarized for 
the “during givosiran treatment” period, defined as below. 
1) For patients who received givosiran in the 6m-DB period, all assessments collected 
after the first dose of givosiran during the entire study including both the 6m-DB and 
OLE periods (if available) will be included in the “during givosiran treatment”. 
2) For patients who received placebo in the 6m-DB period and switched to givosiran in 
the OLE period, all assessments collected after the first dose of givosiran in the OLE 
period will be included in the “during givosiran treatment”. 
3) For patients who discontinued givosiran treatment during the 6m-DB period, the data 
handling will follow the same rules as discussed above for “6m-DB period”. For 
discontinuation in the OLE period, assessments within 28 days of the last dose of 
givosiran will be included in summaries. For ongoing patients, all data are included. 
Selected efficacy parameters will be summarized over the entire study including the 6m-DB and 
OLE periods for all patients to show the trajectory changes comparing the placebo experience 
versus the givosiran experience, for example, summary of creatinine normalized urinary ALA by 
visit. In these summaries, the treatment groups are “Givosiran” or “Placebo” based on 
randomization during the 6m-DB period.  
Intra-patient comparison for ALA, AAR and annualized days of hemin use 
For patients who received placebo during the 6m-DB period and crossed over to receive givosiran 
during the OLE period, intra-patient comparisons for ALA, AAR and annualized days of hemin 
use will be performed to evaluate the efficacy of givosiran versus placebo.  
For AAR and annualized days of hemin use, a negative binomial regression model with period as 
a main effect and patient as a random effect (PROC GENMOD with the REPEATED statement) 
will be fitted to compare the mean rate during the 6m-DB period while on placebo and that of the 
OLE period while on Givosiran treatment. In addition, individual patient’s AAR and annualized 
days of hemin use during the 6m-DB and the OLE periods will be calculated separately and 
compared graphically. To avoid an unstable estimation due to limited duration of follow-up, the 


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AAR and annualized days of hemin use will only be calculated for patients who have at least 85 
days of follow-up during the OLE period. 
For creatinine normalized ALA, Wilcoxon signed rank test will be used to make intra-patient 
comparisons on the medians over the 6m-DB period versus the OLE period, Month 3 vs. Month 
9, and Month 6 vs. Month 12, when sufficient data are collected during the OLE period. 
Treatment sequence 
Patients are assigned to receive either 2.5 mg/kg or 1.25 mg/kg once monthly dose of givosiran 
upon entry to the OLE period through the end of Month 12 (At Month 13, patients on 1.25 mg/kg 
once monthly dose may receive a dose adjustment). After sufficient data are collected during the 
OLE period, summaries for the All Givosiran Treated Set will be provided by the following 
subgroups: 
 Givosiran/Givosiran:  
 Givosiran 2.5 mg/kg/Givosiran 2.5 mg/kg: all patients who received givosiran 2.5 
mg/kg in 6m-DB and OLE periods. 
 Givosiran 2.5 mg/kg/ Givosiran 1.25 mg/kg: all patients who received givosiran 
2.5 mg/kg in the 6m-DB period and givosiran 1.25 mg/kg in the OLE period; 
 Overall: all patients who received givosiran at any dose level in the 6m-DB, 
including patients who discontinued during 6m-DB and did not receive dose in 
OLE. 
 Placebo/Givosiran:  
 Placebo/Givosiran 2.5 mg/kg: all patients who received placebo in the 6m-DB 
period and givosiran 2.5 mg/kg in the OLE period;  
 Placebo/ Givosiran 1.25 mg/kg: all patients who received placebo in the 6m-DB 
period and givosiran 1.25 mg/kg in the OLE period.  
 Overall: all patients who received placebo during the 6m-DB period and switched 
to givosiran at either dose level in the OLE period;  
 Givosiran 2.5 mg/kg: all patients who received givosiran 2.5 mg/kg in either 6m-DB 
or OLE periods; 
 All Givosiran: all patients who received any dose of givosiran during either 6m-DB or 
OLE period.   
To assess the effect of givosiran 2.5 mg/kg and 1.25 mg/kg on ALA reduction separately, for the 
two subgroups Placebo/Givosiran 2.5 mg/kg and Placebo/Givosiran 1.25 mg/kg, Wilcoxon signed 
rank test will be conducted for intra-patient comparison on the medians over the 6m-DB period 
versus the OLE period, Month 3 vs. Month 9, and Month 6 vs. Month 12, when sufficient data are 
collected during the OLE period. 


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6. 
STATISTICAL ANALYSIS 
6.1. 
Patient Disposition 
Number and percentage of patients in the following categories will be summarized by treatment 
arm and overall as appropriate:  
 Randomized 
 Treated 
 Completed the Months 3 and 6 visits 
 Discontinued treatment and primary reasons for treatment discontinuation  
 Withdrew from the study and primary reasons for withdrawal 
 Entered the OLE period. 
The number and percentage of patients enrolled by country and site will be summarized by 
randomized treatment arm and overall. The number and percentage of patients in each level of 
each randomization stratification factor recorded in IRS, and a comparison of the number and 
percentage of patients in each randomization stratification factor in IRS versus the clinical 
database will be summarized by randomized treatment arm and overall.  
6.2. 
Demographics and Baseline Characteristics 
Demographic, background (e.g. medical history) and baseline disease characteristics will be 
summarized by treatment arm and overall.  
Age, height, weight, and body mass index (BMI) will be summarized by descriptive statistics.  
Age group, sex, race, ethnicity, and region will be summarized by presenting the numbers and 
percentages of patients in each category.   
The following baseline disease characteristics will also be summarized: age at diagnosis, time 
from diagnosis to randomization, prior hemin prophylaxis status (Y/N) at screening, number of 
attacks requiring hospitalization, urgent healthcare visits or IV hemin administration at home in 
the last 6 months prior to the study, prior chronic symptoms when not having attacks (Y/N) and 
prior chronic opioid medication usage when not having attacks (Y/N).  
6.3. 
Protocol Deviations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the clinical protocol. Protocol deviations will be classified by medical review prior to 
primary analysis and major protocol deviations will be identified. A major protocol deviation is a 
deviation that may significantly impact the completeness, accuracy, and/or reliability of the trial 
data; that may significantly affect a subject's rights, safety, or well-being. (ICH. E3 R1 Structure 
and Contents of Clinical Study Reports Guidance for Industry. 2013)  All major deviations related 
to trial inclusion or exclusion criteria, conduct of the trial, patient management or patient 
assessment will be described in the clinical study report.  
The Sponsor or designee will be responsible for producing the final protocol deviation file 
(formatted as a Microsoft Excel file). This file will include a description of each protocol 


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deviation and whether or not this deviation is classified as a major protocol deviation. In addition, 
each major deviation will be clearly identified as to whether or not it warrants exclusion from the 
Per Protocol Set, based on the potential impact on the primary efficacy results according to the 
judgment of the Sponsor. This file will be finalized prior to study unblinding. 
6.4. 
Drug Exposure  
Exposure to study medication in days and the number of study drug SC administrations received 
will be summarized by treatment arm.  
The last date of exposure to study drug is defined as the earliest day of the following dates:  
 Last dose date + 27 days 
 Analysis cutoff date  
 The date of EOS 
Duration of exposure is defined as the last date of exposure to study drug  date of the first dose 
+1. The exposure during the 6m-DB period is right censored by the date of the first OLE dose, i.e. 
the last exposure day in the 6m-DB period is no later than the day before the first OLE dose. 
Similarly, the exposure during the OLE is left censored by the date of the first OLE dose, i.e. the 
Day 1 of the OLE is the day of the first OLE dose.  
Dose interruptions and compliance are not taken into account for duration of exposure.  
6.5. 
Efficacy Analysis 
All efficacy endpoints will be analyzed in both AIP and AHP patients. Model-based analysis for 
AIP and AHP patients will adjust for the two stratification factors, i.e. use of hemin prophylaxis at 
screening (Y/N) and historical AAR prior to randomization (High/Low), unless otherwise 
specified. For analysis of AHP patients, AHP type (AIP versus non-AIP) will not be included in 
the model due to the small number of non-AIP patients.  
Porphyria Attacks  
Porphyria patients experiencing acute attacks present with highly morbid and potentially life-
threatening symptoms relating to dysfunction across the central, peripheral, and autonomic 
nervous system. The most commonly seen signs and symptoms of a porphyria attack include 
diffuse, severe neurovisceral pain mostly in the abdomen, back, or limbs, nausea and vomiting, 
fatigue, hypertension, tachycardia, motor weakness.  
Attacks can be reported by patients through eDiary or communicated with investigators. Protocol 
defined criteria for porphyria attacks include investigator-confirmed attacks requiring 
hospitalization, urgent healthcare visit, IV hemin administration at home, or treated at home not 
requiring hemin use. For data collection, each attack is reported with one associated outcome in 
the hierarchical order, e.g., if an attack requires both hospitalization and urgent healthcare, the 
attack will be reported as requiring hospitalization only. The porphyria attacks in the primary 
endpoint include those attacks requiring hospitalization, urgent healthcare visits or IV hemin 
administration at home. 
The start time of a porphyria attack is defined as the time at which acute and sustained worsening 
of the patient’s porphyria manifestations beyond normal day-to-day variability. The end of 


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porphyria attacks is characterized by recovery back to within a patient’s normal day-to-day 
variability. Attacks that occur on the same calendar day of the last treated attack will be 
considered a part of the original attack and will count as one attack in the calculation of the AAR. 
Any attacks that begin on the next day from the last treated attack ends will constitute a new 
attack.   
6.5.1. 
Primary Endpoint 
The primary endpoint of the study is the annualized rate of porphyria attacks requiring 
hospitalization, urgent healthcare visit, or IV hemin administration at home in patients with AIP 
over the initial 6m-DB period. The primary analysis set for the primary endpoint is FASAIP 
(defined in Section 4 ).  
The number of qualifying porphyria attacks is annualized for each patient using below formula:   
Annualized attack rate (AAR) =
total number of porphyria attacks
total number of days in the treatment period × 365.25. 
Let λG represent the mean AAR for givosiran arm and λO represent the mean AAR for the placebo 
arm.  The hypotheses of the primary analysis are:  
Ho: λG
λO
= 1                      HA: λG
λO
≠1 
The statistical significance level for the primary analysis of the primary endpoint is 2-sided 0.049. 
An estimated AAR ratio :
λG
λO < 1 and 2-sided p-value < 0.049 will lead to rejection of Ho.  
6.5.1.1. 
Primary Analysis using Negative Binomial Regression Model  
The primary analysis will be performed using a negative binomial regression model that include 
fixed effects of the treatment arms, the stratification factors for the AIP patients, which include 
the hemin prophylaxis regimen prior to the study (yes vs no) and historical AAR (high vs low). 
The logarithm of the amount of time (in the units of year) that each patient spends in the 6m-DB 
period will be included in the model as an offset variable. With the offset variable, the negative 
binomial regression model essentially models the AAR for each patient based on the length of 
time in the treatment period, and hence will be able to account for the different lengths of follow-
up time. 
For patients who discontinue the study treatment early (before the end of the 6m-DB period), best 
efforts will be made to continue the collection of attack and hemin use data. The primary efficacy 
analysis will be based on all qualified attacks occurring in the 6m-DB period, including those that 
occur after treatment discontinuation. No imputation of attack data is planned for the primary 
analysis.  
In addition to p-value, an estimated ratio of mean AARs between the two treatment arms with the 
corresponding 95% confidence interval will be estimated from the negative binomial regression 
model.  Descriptive statistics for the median and interquartile range of the annualized attack rate 
will also be presented by treatment arm. 


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6.5.1.2. 
Component Analysis  
The annualized rate of porphyria attacks is a composite endpoint including three components: 1) 
attacks requiring hospitalization; 2) attacks requiring urgent healthcare visit; or 3) attacks 
requiring IV hemin administration at home. The AAR of each of the three components will be 
analyzed using the same negative binomial regression model and the estimated ratio of mean 
AARs between treatment arms with corresponding 95% confidence interval will be provided. 
Zero-inflated negative binomial regression model will also be used to analyze each component to 
address the potential issue of an “excessive” number of patients with zero attack. When there are 
less than 10 patients experiencing attacks in a component, model-based analysis will not be 
conducted for that component.  
6.5.1.3. 
Analysis in the Per Protocol Set 
The analysis of the primary endpoint using negative binomial regression model will also be 
conducted for the Per Protocol Set (PPS) (defined in Section 4 ). 
6.5.1.4. 
Sensitivity Analysis  
The attack data collection is on calendar days, i.e. start and stop times by hours are not collected. 
To evaluate the impact of potential under- or over-counting of attacks due to the 1-day window, 
the following two sensitivity analyses will be performed for attacks meeting the primary endpoint 
definition:  
 Count all discrete attacks even if they overlap during a day.  
 Extend the attack counting windows to a 2-day window, i.e. attacks that occurs on the 
same calendar day, or are separated by one calendar day will be counted as one attack.  
An Andersen-Gill model using the same fixed effects as the primary model will be performed 
treating the attacks as recurrent events.  
If the number of zero attacks are high, a zero inflated negative binomial model will be performed 
to provide further assurance of the results. 
Attack data could be missing if a patient stops attack data collection before the end of the 6m-DB 
period, e.g. due to study discontinuation. The missing data period is defined as the time (days) 
between the end of attack data collection and Day 162 which is the earliest expected end of the 
6m-DB period of a patient, inclusive. For patients who provide attack data through the end of 6m-
DB period, no missing data imputation will be performed. If ≥ 5% patients on givosiran arm have 
missing attack data, a pattern mixture model (PMM) with MI will be performed to assess the 
robustness of primary analysis results to the possible violation of the MAR missingness 
assumption. The details of the PMM approach for attack data is described in Section 9.4 . 
In addition, AAR based on the following revised definitions will also be analyzed using the 
primary analysis method:  
 All investigator-confirmed attacks: all attacks meeting the protocol defined criteria, 
including attacks requiring hospitalization, urgent healthcare visit, IV hemin 
administration at home, or treated at home not requiring hemin use. 


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 Potential attacks: in addition to the investigator-confirmed attacks, attacks not 
confirmed by investigator but were deemed as potential attacks will also be included. 
Attacks that were reported due to entry errors will be excluded. An Alnylam medical 
monitor reviewed the reasons that investigators decided a reported attack was not a 
protocol-defined attack to determine which could be considered potential attacks (e.g., 
exclusion of unique potential attacks due to duplicate or accidental entry). This was 
done in a blinded manner prior to the 6m-DB period interim database lock and 
unblinding.  
For these analyses, attacks with duplicated or overlapping dates will be counted as one attack. 
6.5.2. 
Secondary Endpoints 
The annualized-event-rate type of endpoints include the annualized rate of hemin administration 
in AIP patients (FASAIP) and the AAR requiring hospitalization, urgent care visits or IV hemin 
treatment at home in AHP patients (FAS) over the 6m-DB period. The number of events for each 
patient is annualized in the same way as AAR defined for the primary endpoint, divided by 
treatment period (in days) and multiplied by a year (365.25 days). These endpoints will be 
analyzed using a negative binomial regression model similar as the one used for the primary 
endpoint. Since hemin is administered as a one dose per day regimen, the annualized rate of 
hemin administration will be evaluated by the annualized days of hemin use.  
The biomarker endpoints include the ALA levels in AIP patients (FASAIP) at 3 months and 6 
months, the urinary PBG levels in AIP patients (FASAIP) at 6 months. Any postbaseline 
ALA/PBG values measured within 3 days after hemin use during the 6m-DB period will be 
treated as missing and excluded from analysis. For each biomarker secondary endpoint, the 
biomarker levels at the specified time point will be estimated and compared between two 
treatment arms using an MMRM model. The model will include baseline of the corresponding 
biomarker level as a continuous covariate, stratification factors (prior hemin prophylaxis status 
and historical attack rates), visit, treatment, and visit by treatment as fixed effects, and patient as a 
random effect. An unstructured covariance matrix will be used to model the within-subject error. 
If the fit of the unstructured covariance structure fails to converge, a compound symmetry 
covariance structure will be used. The least squares (LS) means and the corresponding SEM and 
95% CIs for each treatment arm, along with the LS mean difference between two treatment arms 
at each post-baseline visit will be presented. The p-value for the treatment difference for each 
endpoint (ALA at Month 3 and Month 6; PBG at Month 6) will be presented. In addition, the 
overall p values measuring the average treatment effect on ALA and PBG during the entire 6m-
DB period will also be reported to assess the durability of the treatment effect. If normal 
assumptions are violated, a non-parametric Wilcoxon rank sum test will be performed. For ALA 
at Month 3 and Month 6, if the drop-out rate during the 6m-DB period is ≥ 5% on the givosiran 
arm, sensitivity analyses will be performed using a PMM approach as described in Section 9.3.  
Daily worst scores for pain measured by BPI-SF in Numeric Rating Scale (NRS), fatigue 
measured by BFI-SF in NRS, and nausea measured by NRS are collected through eDiary.  For 
each of the symptoms (pain, fatigue and nausea), daily eDiary entries will be averaged into a 
weekly (i.e. 7 day) score. The change from baseline in weekly mean scores is defined as the post-
baseline weekly mean score minus the baseline score. The AUC of change from baseline over 6 
months in the respective measure will be calculated for each patient based on change from 


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baseline in weekly mean scores. For each of the measures, the AUC of change from baseline will 
be compared between two treatment arms using ANCOVA model with fixed effects of treatment 
arms and two stratification factors. In addition, the average weekly score change from baseline 
over 6 months will also be calculated and analyzed using ANCOVA.  
Symptoms are expected to be elevated during porphyria attacks. This AUC approach encapsulates 
the peaks of these symptoms during attacks as well as lingering chronicity of these symptoms 
throughout the entire treatment period. AUC approaches have been used in other episodic 
conditions to compare both the severity and duration of pain across groups.  
The weekly mean score will be calculated using the following algorithm: 
1. A completed week will be defined as a week where a patient completes 4 or more daily 
entries in a week, which is consistent with other diary-based PRO research. The available 
eDiary entries for a completed week will be averaged to determine the weekly symptom 
score. 
2. A missing week will be defined as a week where a patient is missing 4 or more daily 
entries. In a missing week, if there is one or more recorded attack days during the week, 
the mean score will be derived based on the following rules:  
 If there are 1 or more completed attack day diary entries, the mean weekly score will 
be computed as an average of the daily entries for that week. 
 If there is no completed attack day diary entry, the weekly mean score will be imputed 
using the average of all non-missing attack-week weekly mean scores within the same 
treatment period for the patient. If there’s no non-missing attack week score, the 
weekly mean score will be imputed by the worst weekly mean scores within the same 
treatment period for the patient.   
Patients are expected to have elevated symptom scores during porphyria attacks, which 
can span over multiple days. This algorithm intends to preserve any completed eDiary 
entries collected during days associated with attacks.  
3. In a missing week without any attack days, the weekly mean score will be imputed by the 
last observed non-missing week without any attack days. If there is no last observed non-
missing week without any attack days, the imputation will be based on baseline 
observation carried forward (BOCF).  
The SF-12 scores are obtained using the Optum (PRO CoRE 1.3 Smart Measurement® System) 
software with the 2009 U.S. general population t-scores applied. For the Physical Component 
Summary (PCS) of SF-12 score, change from baseline at Month 6 in AIP patients (FASAIP) will 
be analyzed using an MMRM model with baseline score as a continuous covariate, fixed effect 
terms including treatment arms, stratification factors, visit (Month 3 or Month 6), and visit by 
treatment interaction.  
All secondary endpoints defined for the AIP patients will also be analyzed for the AHP patients 
using similar methods.  
6.5.3. 
Exploratory Endpoints 
The continuous exploratory endpoints in AIP patients for the 6m-DB period including EQ-5D-5L 
index score will be analyzed using an MMRM model similar to the one employed for the 
secondary endpoint PCS SF-12. 


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Patient Global Impression of Change (PGIC) at Month 6 and Month 12 will be summarized 
descriptively with number and proportion of patients in each category, as well as the two 
combined categories of “Improved” and “No Change or Worsening”. The category of “Improved” 
includes minimally improved, much improved, and very much improved. The category of no 
change or worsening includes no change, very much worse, much worse, and minimally worse. 
Mantel Haenszel chi-square test will be used to compare the proportion of “Improved” between 
the two treatment arms. Odds ratio will be estimated.  
Missed days of work/school in the past 4 weeks at Month 6 will be summarized descriptively. 
Porphyria Patient Experience Questionnaire (PPEQ) will be summarized descriptively.  
For endpoints assessed in patients with any AHP (FAS) over the 6m-DB period, the analyses will 
be conducted using methods similar as those employed for the AIP patients (FASAIP). 
For EQ-5D-5L, a categorical summary of the numbers and percentages of patients reporting each 
ordinal response within each EQ-5D domain will also be presented. 
Analgesic medication use during the 6-month DB period will be summarized as follows: 
 Number (%) of patients who took at least one analgesic medication by category 
(opioid, non-opioid, either opioid or non-opioid) and PT during periods of screening, 
Month 1 to 3, Month 4 to the end of 6m-DB period, and during the 6m-DB period. 
 Descriptive summary on proportion of days with analgesic use during the 6m-DB 
period by category (opioid, non-opioid, either opioid or non-opioid).   
Refer to Appendix 9.5 for the detailed rules in categorizing analgesic medication and opioid/non-
opioid. 
Data collected during the OLE period will be summarized descriptively. For daily worst 
pain/nausea/ fatigue scores collected during the OLE period, change from baseline in weekly 
mean scores will be summarized descriptively. 
6.5.4. 
Subgroup Analysis 
For the primary endpoint, subgroup analyses will be conducted to assess the consistency of 
treatment effect for the AIP and AHP patients during the 6m-DB period. A negative binomial 
regression model will be fit to estimate the treatment effect within each subgroup. The model 
includes treatment arms as a fixed effect and each patient’s time on study as an offset variable. An 
estimated ratio of mean AARs between the two treatment arms with the corresponding 95% CI 
will be estimated for each subgroup. If the number of patients in either treatment arm of a 
subgroup is less than 10, only descriptive statistics will be presented.  
 Age at Screening (< or ≥ median age in the overall population)  
 Race (White or Non-white) 
 Sex (Female or Male) 
 Region group 1: North America (including US and Canada) or Other (outside North 
America) 
 Region group 2: Europe or Other (outside Europe) 


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 Baseline BMI (<25 or ≥25) 
 Prior hemin prophylaxis status (Yes or No) 
 Historical attack rates prior to randomization based on the hemin prophylaxis status 
prior to the study (high or low) 
 For patients on a hemin prophylaxis regimen at the time of screening, if AAR ≥7, the 
patient is considered having high attack rates prior to the study.  For patients who were 
not on a hemin prophylaxis regimen at screening, AAR ≥12 is considered with high 
attack rates. 
 Prior chronic opioid use when not having attacks (Yes or No) 
 Prior chronic symptoms when not having attacks (Yes or No) 
Other subgroups may be examined, if deemed appropriate.  
The subgroup analyses may also be performed for other secondary endpoints. 
The number of non-AIP patients is anticipated to be only a few. Descriptive statistics on the 
primary and secondary endpoints will be provided by treatment arm for non-AIP patients.  
6.6. 
Pharmacodynamic Analysis  
Analyses of secondary endpoints relating to ALA and PBG levels are described in Section 6.5.2.  
In addition, ALA, PBG, and ALAS1 levels will be summarized descriptively at each scheduled 
visit.  
Population PK/PD analyses will be described in a separate population PK/PD analysis plan.  
6.7. 
Pharmacokinetic Analysis 
Plasma concentrations of givosiran and its major metabolite, AS(N-1)3’ givosiran, will be 
summarized by nominal sampling time.  
In patients at East Asian study centers with intense PK sampling, plasma and urine PK parameters 
of givosiran and AS(N-1)3’ givosiran will be determined using non-compartmental methods. PK 
parameters include maximum plasma concentration (Cmax), time to maximum plasma 
concentration (tmax), elimination half-life (t½β), and area under the concentration-time curve 
(AUC). Other parameters may be calculated, if deemed necessary. PK parameters will be 
described using summary statistics. 
Population PK analysis will be used to describe plasma PK of givosiran and AS(N-1)3’ givosiran 
across all patients. The population PK analysis will be described in a separate modeling and 
simulation analysis plan. 
6.8. 
Safety Analysis 
An adverse event (AE) is any untoward medical event associated with the use of a study drug, 
whether or not it is considered related to the study drug. The primary safety parameter is the AEs 
that first occurs or worsens after the first dose of study drug. Safety parameters also include vital 


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signs, ECGs, clinical laboratory assessments, and physical exams. Analyses for safety parameters 
will be conducted using the Safety Analysis Set.  
Time windows for safety data to be analyzed for the 6m-DB period and the entire study including 
both 6m-DB and OLE periods as well as safety follow-up are described in Section 5.10 . All 
safety data regardless of time windows will be listed and summarized for selected endpoints, i.e. 
AEs by system organ class (SOC) and preferred term (PT), SAEs by SOC and PT, and selected 
laboratory parameters.  
Subgroup analysis for safety variables may be conducted if deemed appropriate and necessary.  
No inferential safety analysis is planned.   
6.8.1. 
Adverse Events  
AEs will be classified by the MedDRA coding system (version 21.0 or later) and displayed in 
tables and data listings using SOC and PT.  
AEs will be summarized by the numbers and percentages of patients reporting at least one AE, 
having at least one AE by primary SOC and PT. A patient with multiple occurrences of an AE 
will be counted only once in the respective AE category. Patients who report multiple occurrences 
of the same AE (PT) will be classified according to the most related or most severe occurrence, 
respectively. 
Injection site reaction (ISR) events will be thoroughly summarized. The numbers and percentages 
of patients reporting at least one ISR event and the numbers and percentages of patients with 
different ISR symptoms will be summarized. Note that multiple symptoms of a single ISR will 
not be counted as multiple ISRs. In addition, ISRs will be characterized by injection. The 
incidence rate of ISR, defined as the number of ISRs divided by total number of injections will 
also be summarized. If there are multiple ISRs that occur between two consecutive injections, 
these events are considered caused by the earlier injection and counted as one ISR.  
An overall summary of AEs will include the number and percentage of patients with any AE, any 
AE assessed by the Investigator as related to treatment (possibly related or definitely related), any 
severe AE, any severe AE related to treatment, any serious AE (SAE), any SAE related to 
treatment, any AE/SAE of clinical interest; any AE/SAE leading to treatment discontinuation, any 
study drug related AE/SAE leading to treatment discontinuation, any AE/SAE leading to study 
withdrawal, any study drug related AE/SAE leading to study withdrawal, and any deaths. 
Tabulations by SOC and PT may be produced for the following. The SOC and PT within each 
SOC will be presented alphabetically.  
 All AEs;  
 AEs by severity;  
 All SAEs;  
 AEs related to treatment;  
 SAEs related to treatment;  
 AEs leading to temporary treatment interruption;  


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 AEs leading to treatment discontinuation;  
 SAEs leading to treatment discontinuation;  
 AEs leading to study withdrawal;  
 SAEs leading to study withdrawal.  
Tabulations by PT in decreasing order in frequency in the givosiran arm will be produced for the 
following.  
 All AEs;  
 All SAEs;  
 AEs related to treatment; 
 SAEs related to treatment; 
AEs and SAEs will also be summarized by maximum relationship to study drug and by maximum 
severity.  
AEs mapping to the MedDRA high level term (HLT) of injection site reaction will be 
summarized by preferred term. AEs mapping to the standard MedDRA query (SMQ) Drug 
Related Hepatic Disorder will be summarized by SOC and preferred term. Adverse event 
mapping to a customized Acute Pancreatitis SMQ will be summarized by SOC and preferred term 
(PT). AEs mapping to the Acute Renal Failure SMQ will be summarized by SOC and PT. AEs 
mapping to the Anaphylactic Reaction SMQ will be summarized by PT. AEs mapping to the 
SMQ Malignant or Unspecified Tumors will be summarized by high level term and preferred 
term. Other SMQs or AE groupings may be evaluated.  
AEs mapping to a modified Acute Pancreatitis SMQ were summarized by SOC and PT. This 
custom SMQ strategy was developed in such a way as to capture more possible pancreatitis cases 
than the standard MedDRA SMQ. This SMQ included all AEs from the acute pancreatitis SMQ 
(narrow terms) plus the PTs for lipase increased, lipase abnormal, amylase increased, amylase 
abnormal, hyperlipasaemia, hyperamylasaemia, pancreatic enzyme abnormality, pancreatic 
enzymes abnormal, pancreatic enzymes increased.    
All AEs collected will be listed along with the information collected on those AEs, e.g. AE 
relationship to study drug, AE outcome etc. By-patient listings will also be provided for the 
following:  all deaths, all SAEs, and all AEs leading to treatment discontinuation or study 
withdrawal, all AEs leading to death. 
A listing of ISRs will be presented including descriptions, onset and resolution date, severity, 
treatment given, and event outcome. 
6.8.2. 
Laboratory Data 
Knowledge of several clinical laboratory tests, including ALA, PBG, and ALAS1, has the 
potential to unblind the reviewer. Procedures to protect the blind, including permissions to view 
these lab values, are described in the Data Integrity Plan (Amendment 3, 07Sep2018). 
Clinical laboratory values will be expressed in Standard International (SI) units. Missing 
laboratory data will not be imputed.  


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Summary data for each laboratory parameter will be presented for each continuous clinical 
laboratory parameter (including hematology, serum chemistry, liver function tests and 
coagulation studies).  Descriptive statistics will be presented for the actual values, change from 
baseline, and percent change from baseline by visit. 
Shift tables will be employed to summarize the baseline category versus the “worst” post-baseline 
category for selected parameters.   
A listing will be produced for amylase and lipase in all patient with amylase/lipase observations 
above 3×ULN flagged.  A listing for all patients with abnormal liver function tests defined as an 
ALT >3×ULN, AST >3×ULN, or total bilirubin >2×ULN at any time point will also be provided.   
A table will be produced to summarize the number and percentage of patients in each of below 
category at any post-baseline time point.  
 ALT >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
 AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
 ALT or AST >1 & ≤3, >3 & ≤5, >5 & ≤10, >10 & ≤20, >20×ULN, 
 ALP > 1.5×ULN, 
 Total Bilirubin >1.5 & ≤2, >2 & ≤3, >3 & ≤5 and >5×ULN, 
 Total Bilirubin > 1.5×ULN concurrent with ALT or AST > 3×ULN, 
 Total Bilirubin > 2×ULN concurrent with ALT or AST > 3×ULN 
EDISH plots for ALT, AST, and total bilirubin will also be provided.   
For hematology and blood chemistry, summary tables of potentially clinically significant 
abnormalities will be provided. The results may also be graded according to the NCI CTCAE 
Version 4.0 or above. A shift summary of baseline to maximum post-baseline CTCAE grade may 
be presented, as appropriate.  
All laboratory data will be provided in data listings.  Out-of-range laboratory results will be 
identified in the listings. 
6.8.3. 
Vital Signs and Physical Examination 
Descriptive statistics by visit and treatment arm will be provided for each variable.  
Vital sign measurements will be presented for each patient in a data listing, with abnormal vital 
signs flagged. 
6.8.4. 
Electrocardiogram   
Electrocardiogram (ECG) findings will include rhythm, ventricular rate, PR interval, QRS 
duration, QT interval, and QTc interval. For post-baseline assessments where ECG is performed 
in triplicate, the average of the 3 (or all available) readings will be used for analysis.    
Corrected QT interval (QTc), if not collected, will be calculated using both Fridericia’s and 
Bazett's correction formula.  


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Bazett’s square-root corrected QT: QTcB (ms) = QT (ms)  
60
)
(bpm
HR
 
 
Fridericia’s cube-root corrected QT: QTcF (ms) = QT (ms)  3
60
)
(bpm
HR
. 
PR, QRS, QT, QTc (ie, QTcB and QTcF) and RR intervals and their change from pre-dose 
baseline will be summarized for each treatment group by scheduled visit.  Subjects will be 
categorized into ≤ 450, > 450 - 480, > 480 - 500, or > 500 ms per their maximum post-baseline 
absolute QTc interval and ≤ 30, > 30 - 60, or > 60 ms per their maximum change from baseline 
QTc interval. The number and percentage of subjects in each category will be summarized for 
each treatment group.  
All ECG data for each patient will be provided in a data listing. 
6.8.5. 
Prior and Concomitant Medications 
Prior medications are those medications taken prior to the first dose of study drug. If the 
medication end date is before the date of first dose of study drug, the medication will be 
summarized as prior medication regardless of whether the start date is missing or not. 
Concomitant medications are medications, other than study drug, taken at or after the first dose of 
study drug, as well as medications with a start date prior to first dose of study drug and are 
ongoing after first dose of study drug. If medication start date is on or after date of first dose of 
study drug, the medication will be summarized as concomitant medication regardless of whether 
the medication end date is missing or not. If the end date of a medication is missing or incomplete 
such that it cannot be determined whether it is before first study drug dose, it will be counted as a 
concomitant medication.   
Prior and concomitant medications will be coded using the WHO Drug Dictionary (March 2018). 
Results will be tabulated by anatomical therapeutic class (ATC) and preferred term. 
6.9. 
Anti-Drug Antibody  
The number and percentage of patients with confirmed positive ADA assay results at any time 
during study as well as at each scheduled visit will be summarized. The titer results for patients 
with confirmed positive ADA results will also be summarized using descriptive statistics. 
ADA data and patients with confirmed positive ADA results will be presented in data listings. 


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7. 
CHANGES FROM PREVIOUS VERSION(S) 
7.1. 
Changes in SAP Amendment 1 
The SAP Amendment 1 includes more details previously not discussed in the original SAP. Some 
changes to analysis methods are made following regulatory feedback and further assessments.  
Amendment 1 was signed off before the interim analysis. The details of changes and rationales 
are listed in below table. 
Summary of Changes 
Rationale 
In the protocol and original SAP, an interim 
sample size reassessment (SSR) was planned 
but was not conducted during study. 
An SSR was originally planned to be performed 
at the time of the interim analysis to potentially 
increase the number of AIP patients in the study 
from approximately 70 to 90. Due to fast 
enrollment of the study leading to greater than 
expected numbers of patients randomized, an 
interim analysis for SSR was therefore no 
longer necessary. 
For the interim analysis of ALA at Month 3, 
the missing data imputation was mLOCF in the 
original SAP; in this amendment, the 
imputation will be based on MI. Additional 
sensitivity analyses are added including a 
PMM and a non-parametric method. 
Updates made following regulatory feedback. 
For the analysis of ALA/PBG at the end of 6m-
DB period, the primary analysis was based on 
ANCOVA/mLOCF in the original SAP; in this 
amendment, the primary analysis for 
ALA/PBG will be based on MMRM and a 
sensitivity analysis using PMM is added for 
ALA.  
Both MMRM and MI/ANCOVA are based on MAR 
assumption and MMRM is often considered a more 
simple and powerful method. PMM is added to 
assess the robustness of the results when 
missingness mechanism is MNAR. 
For the analysis of primary endpoint attack 
rate, PMM is added to address potential 
missing attack data and other sensitivity 
analyses are added (Section 6.5.1.3). 
These sensitivity analyses are added to assess the 
robustness of the primary analysis results. 
The median instead of the mean of valid pre-
dose values is used to derive baseline 
ALA/PBG. 
Due to the variability with PD measures, the median 
is less affected by extreme values than the mean.  
For the secondary endpoint PCS SF-12, the 
primary analysis method is changed from 
ANCOVA to MMRM. 
This endpoint is measured at Month 3 and Month 6. 
MMRM implicitly imputes missing data using data 
from both time points while ANCOVA does not 
address missing data.  
For the secondary endpoints daily worst score 
of pain, nausea, and fatigue, the AUC over 6 
months will be derived by first calculating the 
weekly mean scores (Section 6.5.2).   
Updated to address regulatory feedback on missing 
data handling and justification of AUC method. 


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7.2. 
Changes in SAP Amendment 2 
In the SAP Amendment 2, detailed analyses for the entire study including OLE period are added. 
Amendment 2 will be signed off before the final analysis of the 6-month double-blind (6m-DB) 
data and the unblinding of treatment assignments.  
In this version, a new analysis population All Givosiran Treated Set is added, additional 
subgroups of the All Givosiran Treated Set were defined to accommodate analysis of the different 
givosiran doses allowed in the OLE period with Protocol Amendment 3, and different treatment 
periods are defined to allow for the analysis of data in the overall study. In addition, Per Protocol 
Set is defined to allow for an evaluation of the primary endpoint in the subset of patients who 
fulfill the protocol in terms of the eligibility requirements, adherence to the study drug and 
outcome assessments. A few minor updates are made to the analysis of the 6m-DB period, e.g., 
zero-inflated negative binomial regression model is added to analyze components of attacks. For 
the analysis of worst scores of pain, fatigue, and nausea, the following updates are made: 
 The AUC of weekly scores is updated as the AUC of change from baseline in weekly 
scores. Note that with an ANCOVA analysis adjusted for baseline, using the actual 
score or change from baseline as a response variable will yield the same estimate of 
treatment difference and p value. This update is made to allow for a direct estimate of 
the LS mean change from baseline in each treatment arm. 
 The mean weekly score change from baseline over 6 months is defined for analysis, 
which is mathematically similar to the AUC of change from baseline in weekly score 
but is clinically meaningful and interpretable.  
 The testing order of daily worst scores of fatigue and nausea are switched because the 
mean nausea scores at baseline are low therefore less likely to show improvement with 
treatment.  


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8. 
REFERENCES 
Keene ON, Roger JH, Hartley BF, Kenward MG. Missing data sensitivity analysis for recurrent 
event data using controlled imputation. Pharm Stat. 2014;13(4):258-264. doi:10.1002/pst.1624 
Rubin, D.B. (1987), Multiple Imputation for Nonresponse in Surveys, New York: John Wiley & 
Sons, Inc.  
Rubin, D.B. (1996), “Multiple Imputation After 18+ Years,” Journal of the American Statistical 
Association, 91, 473 489. 
Siddiqui, O. (2011). MMRM versus MI in Dealing with Missing Data  A Comparison Based on 
25 NDA Data Sets, Journal of Biopharmaceutical Statistics, 21: 423 436, 2011. 
 


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9. 
APPENDICES 
9.1. 
Details of Interim Analysis 
At the interim, the only efficacy endpoint to be assessed is the Month 3 ALA level in AIP 
patients. The other efficacy endpoints will not be analyzed. ALA data beyond 3 months will be 
summarized descriptively by treatment arm for each scheduled visit during the 6m-DB period. 
Patient disposition, demographic and baseline characteristics, drug exposure, safety, PK, and PD 
will be summarized as described in Section 6 .  
9.1.1. 
Interim Analysis Population  
The analysis sets for the interim analysis are defined as follows:  
 Interim Full Analysis Set (IFAS): a randomized patient will be included in the IFAS if  
1) the patient was randomized more than 92 days before the cutoff date; OR, 
2) the patient was randomized between 78 and 92 days before the cutoff date and both 
criteria below are met 
a. the patient has finished the Month 3 visit on or before the cutoff date 
b. all patients who have a randomization date before this patient are included  
Patients will be grouped by their randomly assigned treatment group (i.e. as randomized) 
for the efficacy analyses.  
 AIP patients in the Interim Full Analysis Set (IFASAIP) 
 Interim Safety Analysis Set (ISAS): includes the same cohort of patients as in the 
IFAS but grouped according to the treatment actually received.   
The primary efficacy analysis set for the ALA data is IFASAIP. The ALA data of the non-AIP 
patients who have finished the Month 3 visit in the IFAS will be presented in a listing. The safety 
analyses will be based on the ISAS and will also be performed for the AIP and non-AIP patients 
separately. PK analysis at interim will be include patients who have evaluable PK data 
contributing to the estimation of PK parameters.  
9.1.2. 
Rationale for Month 3 ALA Endpoint 
Three months of treatment is considered an appropriate time point for assessment of the efficacy 
of givosiran based on ALA levels observed in the givosiran Phase 1 study. In the Phase 1 study, 
there were 40 individual patients including 17 AIP patients with recurrent attacks, the patient 
population of the ENVISION study and 23 asymptomatic high excreters (ASHE, or chronic high 
excreters CHE). Among the 17 AIP patients with recurrent attacks, 3 patients were treated with 
givosiran at the Phase 3 dose (2.5mg/kg monthly) for three months and 4 patients were treated 
with placebo. The ALA levels for both treatment (N=3) and placebo (N=4) patients were plotted 
over time (in days) in Figure 2 below. All three patients receiving givosiran experienced a rapid 
and robust decrease in ALA levels starting at Day 7 after the first dose, with plateau in ALA 
levels at Day 21 that was maintained throughout the entire dosing period (3 months).  


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  Figure 2: 
ALA Levels over Time (in Days) for Individual AIP Patients in the Givosiran 
Phase 1 Study (Cohort C) 
 
 
The planned sample size for the interim analysis is based on the following power considerations. 
Assuming the mean ALA levels (SD) at 3 months in the placebo and givosiran arms are 20.0 
(11.1) and 2.3 (1.1) mmol/mol (based on Phase 1 study data), 40 AIP patients will yield more than 
90% power in the ALA comparison at α level of 0.001.   
9.1.3. 
Analysis of ALA Endpoint 
9.1.3.1. 
Primary Analysis Using ANCOVA/Multiple Imputation 
The primary analysis to evaluate the treatment effect in ALA at Month 3 is an ANCOVA model, 
with multiple imputation (MI) assuming missing at random (MAR) in case of missing data at 
Month 3. The ANCOVA model includes baseline ALA as a continuous covariate and fixed effect 
terms including treatment arm and stratification factors for AIP patients (prior hemin prophylaxis 
status and historical attack rates). The significance level for the comparison at the interim is 0.001 
(2-sided). Any ALA values measured within 3 days after hemin use will be excluded from the 
ALA analysis and will be treated as missing. The Least Square (LS) means, SEMs and 95% 
confidence intervals (CIs) for the LS means, difference in LS Means, and corresponding 95% CIs 
and p-value will be presented.  
Missing data at Month 3 will be multiply imputed separately for each treatment arm using the 
Markov Chain Monte Carlo (MCMC) method following the MAR assumption. Treatment arm, 
the stratification factors, ALA measurements at baseline, Week 2, Month 1 and Month 2 will be 
included in the imputation model. One hundred imputed datasets will be generated using the SAS 
PROC MI procedure. Each of the imputed datasets will then be analyzed via the primary 
ANCOVA model. The LS means and standard errors will be combined using SAS PROC 
MIANALZYE to produce inferences including treatment difference in LS means, 95% CI for the 
treatment difference, and the p-value. Point estimates (LS means and treatment difference) will be 
calculated as the average of the 100 complete-data estimates. A total variance estimate will be 
calculated as a weighted sum of within-imputation variance, which is the average of the complete-


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data variance estimates, and a between-imputation variance term. The sample code for performing 
the primary analysis is provide in Section 9.1. 
9.1.3.2. 
Additional Analysis 
When there is missing data at Month 3, the following sensitivity analyses will be conducted to 
assess the robustness of the primary analysis. 
 Pattern mixture model (PMM) approach which accommodates situations where the 
missingness mechanism is missing not at random (MNAR). The details are described 
in Section 9.2  .  
 Completer analysis: the primary ANCOVA model will be applied to analyze the 
subset of IFASAIP patients with non-missing Month 3 ALA value. 
The upper limit normal (ULN) of the ALA level observed in the healthy volunteers is 1.5 
mmol/mol Cr. The proportions of patients with Month 3 ALA levels below the thresholds of 1.5, 
2, 3, and 4 times of the ULN in each treatment arm will be calculated. The difference between the 
proportions and the 95% exact confidence interval for the difference will be calculated. Patients 
with missing Month 3 ALA values will be included in the denominator.  
Q-Q plot of the residual of the ANCOVA completer analysis will be provided for a visual 
examination of the normality assumption.  
A non-parametric Wilcoxon rank sum test will be performed as a sensitivity analysis of the 
primary model.   
9.1.3.3. 
Durability of ALA Lowering 
The primary ANCOVA model (without missing data imputation) will be applied to evaluate the 
treatment effect at Week 2, Month 1 and Month 2. The LS mean ALA levels over time will be 
plotted for each treatment arm to assess the longitudinal treatment effect of Givosiran on ALA 
lowering. Spaghetti plots for individual patient will also be provided. 
In the givosiran-treated arm, it is expected that there will be substantial ALA knockdown starting 
at Month 1 and maintained throughout the treatment duration. To assess the durability of 
treatment effect in ALA knockdown, the overall treatment effect over 3 post-baseline visits 
Month 1, Month 2 and Month 3 will be evaluated through a mixed effect model repeated 
measurement (MMRM). The MMRM model includes baseline ALA level as a continuous fixed 
covariate, stratification factors (prior hemin prophylaxis status and historical attack rates), visit 
and treatment as fixed factors, and patient as a random factor. An unstructured covariance matrix 
will be used to model the within-subject error. If the fit of the unstructured covariance structure 
fails to converge, a compound symmetry covariance structure will be used. The overall LS mean 
treatment difference measuring the average treatment effect on ALA from Month 1 to 3 and 
associated p value will be estimated. 
9.2. 
Sample SAS Code for Interim Analysis of ALA Data  
At the interim analysis, ANCOVA/MI is specified as the primary analysis of ALA data. The 
analysis is performed in 3 steps with sample SAS code provided below. 
Step 1. 100 datasets will be imputed. Negative imputed values will be replaced by 0.10. 


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PROC MI data=&dsin. seed=1234 nimpute=100 out=&method._out; 
   
by treatment; 
   
em maxiter=300 converge=1e-4 itprint outem=outem; 
   
var &cov. &base. &varlist. &resp.;   
   
mcmc chain=multiple initial=em; 
run; 
*Apply truncations to negative imputed values; 
data &method._out; 
   
set &method._out; 
  
if m3 < 0 then m3 = 0.10; 
  
if m2 < 0 then m2 = 0.10; 
   
if m1 < 0 then m1 = 0.10; 
   
if m0_5 < 0 then m0_5 = 0.10; 
if m0 < 0 then m0 = 0.10; 
run; 
Notes: 
dsin=alydsv: an input dataset with treatment group, subject id, covariates (2 stratification 
factors in 0/1 format), creatinine normalized ALA at baseline (m0), week 2(m0_5), Month 
1 (m1), Month 2 (m2), and Month 3 (m3). 
resp: m3 
base: m0 
trt: trt01p 
cov: 2 stratification factors in 0/1 format 
varlist: values at week 2, month 1 and 2 (m0_5, m1, m2) 
Step 2. The imputed datasets will be analyzed using ANCOVA model. 
PROC MIXED data=&method._out method=reml; 
  
by _Imputation_; 
class &trt. (ref='Placebo') &cov.;  
   
model &resp.= &trt. &base. &cov. /ddfm=kr; 
    
lsmeans &trt. / pdiff=control('Placebo') cl diff; 
    
ods output lsmeans = &method._lsm; 
    
ods output diffs = &method._diff; 
run; 
Step 3. Combine the analysis results using Rubin’s formula through PROC MIANALYZE. 
PROC MIANALYZE data=&method. lsm; 
   
by &trt.; 
   
modeleffects estimate; 
   
stderr; 
   
ods output ParameterEstimates=&method._LSest; 
run; 


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9.3. 
Details of the Pattern Mixture Model for ALA  
For the IA analysis of ALA level at Month 3, if there are missing data at Month 3, the PMM 
sensitivity analysis will be performed. Patients with missing data at Month 3 will be categorized 
into 3 mutually exclusive patterns as described below: 
1. Placebo patients: the missing Month 3 ALA value is considered MAR and will be imputed 
using MI estimated from placebo patients.  
2. Givosiran patients who have taken at least one dose within 56 days of Month 3: due to the 
long PD effect observed in the AS1-001 study, treatment effect of givosiran is assumed to 
maintain for up to 56 days. Therefore, the missing Month 3 ALA value will be imputed 
using the distribution of observed givosiran data assuming MAR.  
3. Givosiran patients who have not taken any dose within 56 days of Month 3: a conservative 
approach will be taken to assume the givosiran treatment effect is similar to that of 
placebo at Month 3. Therefore, the missing Month 3 ALA value will be imputed using the 
distribution of observed placebo data using copy reference (CR) approach.  
Missing values will be imputed 100 times to generate 100 complete datasets. The same ANCOVA 
model applied to the ALA data at the interim analysis will be fit to each complete dataset for the 
ALA level at Month 3 (Section 9.1.3.1 ). The resulting estimates from the 100 analyses will be 
combined using Rubin’s formulae.  
The detailed steps of implementation are provided below with sample SAS code. 
Step 0. Assign a missing pattern to each patient whose ALA at Month 3 is missing. 
Step 1. One hundred datasets will be imputed. MCMC method will be used to impute missing 
data for Patterns 1 and 2 with MAR. FCS method will be applied to Pattern 3 with MNAR.  
Step 1.1 For Patterns 1 and 2, MI with MAR assumption will be performed. 
PROC MI data=DATAIN seed=1234 nimpute=100 out=DATA_STEP1_1; 
   
by treatment; 
   
em maxiter=300 converge=1e-4 itprint outem=outem; 
   
var &cov. &base. &varlist. &resp.;  
   
mcmc chain=multiple initial=em; 
run; 
Step 1.2 For Pattern 3 patients, replace the ALA in DATA_STEP1_1 with data from 
DATAIN and denote the updated data DATA_STEP1_2. Impute missing values for 
Pattern 3 using the copy reference (CR) method. 
proc mi data=DATA_STEP1_2 seed=&seed. nimpute=1 out=DATA_STEP2; 
   
by _imputation_; 
   
class treatment &cov.; 
   
fcs nbiter=30 reg (&resp. = &cov. &base. &varlist.); 
   
mnar model (&resp. / modelobs= (treatment='Placebo')); 
   
var &cov. &base. &varlist. &resp.; 
run; 
Negative imputed values will be replaced by 0.10 following Section 9.1 . 


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Steps 2 and 3. Follow Section 9.1 . 
At the final analysis, if the drop-out rate during the 6m-DB period is > 5%, the PMM will also be 
performed as a sensitivity analysis to evaluate the treatment effect in ALA at Month 3 and Month 
6, respectively. The implementation steps of PMM are similar as those described above. 
9.4. 
Details of the Pattern Mixture Model for Attack Data 
Patients with missing attack data will be categorized into one of the following missing patterns. 
MI approach for each missing pattern is described as below (Keene, 2014). 
1. Patients treated with placebo during the 6m-DB period.  
The missing data are considered MAR and will be imputed based on the attack rate of the 
placebo arm. 
2. Early withdrawals treated with givosiran during the 6m-DB period. 
Givosiran patients who withdraw on or before 56 days after the first dose of givosiran are 
considered as not having obtained positive treatment effect. Therefore, missing data will 
be imputed based on the attack rate of the placebo arm using copy reference (CR) 
approach.  
3. Non-early withdrawals treated with givosiran during the 6m-DB period. 
Givosiran patients who withdraw more than 56 days after the first dose of givosiran are 
considered as having achieved some treatment effect during the on-treatment period (on 
or before 56 days after the last dose of givosiran), and the effect will be lost during the 
off-treatment period (more than 56 days after the last dose of givosiran). Missing data 
during the on-treatment period are considered MAR and will be imputed based on the 
attack rate of the givosiran arm. Missing data during the off-treatment period will be 
imputed based on the attack rate of the placebo arm using unconditional reference (UR) 
approach assuming this period represents a new episode for the patient.  
The analysis model is the same as the primary negative binomial regression model. The primary 
model will be fitted to each complete dataset with imputed values. Rubin’s rules will be applied to 
combine the estimates. 
This sensitivity analysis can be implemented in the following steps. 
Step 0. Assign a missing pattern to each patient whose duration of follow-up period (observed 
period before withdrawal) is less than 162 days and calculate the duration of missing period. For 
non-early withdrawals treated with givosiran (missing pattern 3), there are 2 missing periods, i.e. 
the on-treatment period and the off-treatment period. Duration of each missing period needs to be 
derived. 
Let 𝑑𝑢𝑟 be the duration of the follow-up period. The duration of missing period for missing 
patterns 1 and 2 is 162 days-𝑑𝑢𝑟. The duration of missing periods for missing pattern 3 also 
depends on the last day of on-treatment period (denoted as 𝑥), which is the last dosing day+55 
days (56 days from administration of the last dose).  


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Scenarios 
Duration of missing 
period on-treatment 
(days) 
Duration of missing 
period off-treatment 
(days) 
Total duration of 
missing period 
(days) 
𝑥≤𝑑𝑢𝑟 
0 
162 −𝑑𝑢𝑟 
162 −𝑑𝑢𝑟 
𝑑𝑢𝑟< 𝑥≤162 
𝑥−𝑑𝑢𝑟 
162 −𝑥 
162 −𝑑𝑢𝑟 
𝑥> 162 
162 −𝑑𝑢𝑟 
0 
162 −𝑑𝑢𝑟 
 
Step 1. Fit the imputation model, derive and sample from the posterior distribution for each 
coefficient and the over-dispersion parameter. The following example SAS code will be applied 
to generate 100 posterior draws. 
PROC GENMOD data=data_attack; 
class treatment strat_1 strat_2;  
model attack_observed=treatment strat_1 strat_2 / link=log dist=negbin 
offset=logfollowup_observed; 
bayes outpost=data_out thinning=20 nmc=2000 nbi=1000; 
run; 
 
Step 2. For each draw (after thinning) the expected number of events is calculated for the follow-
up period and the missing period(s) after withdrawal for each patient, based on the duration of the 
follow-up period and the missing period(s). The design matrices for an individual patient are 
modified to assign the withdrawal to the desired treatment arm for the follow-up and the missing 
period(s) depending on the imputation method, i.e. MAR, CR, and UR. The number of attacks 
from missing period(s) can be sampled based on the conditional/marginal distribution of the 
number attacks from missing period(s) given that from the follow-up period. The total number of 
numbers of attacks is the sum of the observed and the imputed number of attacks. (Keene, 2014) 
 
Missing 
Pattern 
Number of attacks 
observed during the 
follow-up period 
Number of attacks 
imputed during the 
missing period(s) 
Imputation 
method 
Total number of 
attacks 
1 
𝑦1 
𝑦2
̂ 
MAR 
𝑦1 + 𝑦2
̂ 
2 
𝑦1 
𝑦2
̂ 
CR 
𝑦1 + 𝑦2
̂ 
3 
𝑦1 
𝑦21
̂  
MAR 
𝑦1 + 𝑦21
̂ + 𝑦22
̂  
 
 
𝑦22
̂  
UR 
 
 
Step 3. Fit the total number of attacks using the primary analysis model and 162 days being the 
total duration of the follow-up period for all patients with missing attack data. Derived parameters 
from the model will be combined across 100 imputation datasets using Rubin’s formula as 


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implemented in the MIANALYZE procedure. The estimated treatment difference and their 
confidence intervals will be transformed to the original scale. 
 
PROC GENMOD data=data_attack; 
 
by _Imputation_; 
class treatment strat_1 strat_2;  
model attack_total=treatment strat_1 strat_2 / link=log dist=negbin 
offset=logfollowup_total; 
run; 
9.5. 
Analgesic medications 
Analgesic medications, including opioids (synthetic and non-synthetic substances [narcotics]) or 
non-steroid anti-inflammatory medications (NSAIDs) are permitted for the management of 
porphyria and for porphyria attacks. All analgesia usage as taken by the patient at home will be 
captured by the patient or caregiver via the eDiary through Month 12 of the study. Additional 
medications, including analgesics, taken at a healthcare facility (eg, during an attack) will be 
captured in concomitant medications eCRF. After Month 12, usage of any analgesic medications 
will be recorded in the concomitant medications eCRF, along with all other medications used. 
In supporting analgesic usage (opioid and non-opioid) analysis, the following criteria (based on 
ATC codes and indication as appropriate) will be used in categorization of analgesic medication 
and opioid/non-opioid.  
  Opioid: 
 ATC3CD: N02A 
 ATC4CD: N01AH 
 ATC4CD: N01AX where CMINDC “PAIN” or “PORPHYRIA ACUTE ATTACK”  
 ATC4CD: R05DA where CMINDC “PAIN” or “PORPHYRIA ACUTE ATTACK” 
  Non-opioid: 
 ATC4CD: M01AB, M01AE, M02AA, N02BA, N02BE, N02BG, N02CC 
 ATC4CD: N02CX where CMINDC “PAIN” or “PORPHYRIA ACUTE 
ATTACK” or “MIGRAINES” 
 ATC4CD: N03AX where CMINDC “PAIN” or “PORPHYRIA ACUTE ATTACK” 
 ATC4CD: N06AX where CMINDC “PAIN” or “PORPHYRIA ACUTE ATTACK” 
 


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7. 
CHANGES FROM PREVIOUS VERSION(S) 
7.1. 
Changes in SAP Amendment 1 
The SAP Amendment 1 includes more details previously not discussed in the original SAP. Some 
changes to analysis methods are made following regulatory feedback and further assessments.  
Amendment 1 was signed off before the interim analysis. The details of changes and rationales 
are listed in below table. 
Summary of Changes 
Rationale 
In the protocol and original SAP, an interim 
sample size reassessment (SSR) was planned 
but was not conducted during study. 
An SSR was originally planned to be performed 
at the time of the interim analysis to potentially 
increase the number of AIP patients in the study 
from approximately 70 to 90. Due to fast 
enrollment of the study leading to greater than 
expected numbers of patients randomized, an 
interim analysis for SSR was therefore no 
longer necessary. 
For the interim analysis of ALA at Month 3, 
the missing data imputation was mLOCF in the 
original SAP; in this amendment, the 
imputation will be based on MI. Additional 
sensitivity analyses are added including a 
PMM and a non-parametric method. 
Updates made following regulatory feedback. 
For the analysis of ALA/PBG at the end of 6m-
DB period, the primary analysis was based on 
ANCOVA/mLOCF in the original SAP; in this 
amendment, the primary analysis for 
ALA/PBG will be based on MMRM and a 
sensitivity analysis using PMM is added for 
ALA.  
Both MMRM and MI/ANCOVA are based on MAR 
assumption and MMRM is often considered a more 
simple and powerful method. PMM is added to 
assess the robustness of the results when 
missingness mechanism is MNAR. 
For the analysis of primary endpoint attack 
rate, PMM is added to address potential 
missing attack data and other sensitivity 
analyses are added (Section 6.5.1.3). 
These sensitivity analyses are added to assess the 
robustness of the primary analysis results. 
The median instead of the mean of valid pre-
dose values is used to derive baseline 
ALA/PBG. 
Due to the variability with PD measures, the median 
is less affected by extreme values than the mean.  
For the secondary endpoint PCS SF-12, the 
primary analysis method is changed from 
ANCOVA to MMRM. 
This endpoint is measured at Month 3 and Month 6. 
MMRM implicitly imputes missing data using data 
from both time points while ANCOVA does not 
address missing data.  
For the secondary endpoints daily worst score 
of pain, nausea, and fatigue, the AUC over 6 
months will be derived by first calculating the 
weekly mean scores (Section 6.5.2).   
Updated to address regulatory feedback on missing 
data handling and justification of AUC method. 


Statistical Analysis Plan, Protocol ALN-AS1-003 
 ALN-AS1 (Givosiran) 
SAP Amendment 2 
Alnylam Pharmaceuticals 
Confidential 
34 
7.2. 
Changes in SAP Amendment 2 
In the SAP Amendment 2, detailed analyses for the entire study including OLE period are added. 
Amendment 2 will be signed off before the final analysis of the 6-month double-blind (6m-DB) 
data and the unblinding of treatment assignments.  
In this version, a new analysis population All Givosiran Treated Set is added, additional 
subgroups of the All Givosiran Treated Set were defined to accommodate analysis of the different 
givosiran doses allowed in the OLE period with Protocol Amendment 3, and different treatment 
periods are defined to allow for the analysis of data in the overall study. In addition, Per Protocol 
Set is defined to allow for an evaluation of the primary endpoint in the subset of patients who 
fulfill the protocol in terms of the eligibility requirements, adherence to the study drug and 
outcome assessments. A few minor updates are made to the analysis of the 6m-DB period, e.g., 
zero-inflated negative binomial regression model is added to analyze components of attacks. For 
the analysis of worst scores of pain, fatigue, and nausea, the following updates are made: 
 The AUC of weekly scores is updated as the AUC of change from baseline in weekly 
scores. Note that with an ANCOVA analysis adjusted for baseline, using the actual 
score or change from baseline as a response variable will yield the same estimate of 
treatment difference and p value. This update is made to allow for a direct estimate of 
the LS mean change from baseline in each treatment arm. 
 The mean weekly score change from baseline over 6 months is defined for analysis, 
which is mathematically similar to the AUC of change from baseline in weekly score 
but is clinically meaningful and interpretable.  
 The testing order of daily worst scores of fatigue and nausea are switched because the 
mean nausea scores at baseline are low therefore less likely to show improvement with 
treatment.  


ALN-AS1 (Givosiran) 
Statistical Analysis Plan, Protocol ALN-AS1-003 
 
SAP Amendment 1 
Alnylam Pharmaceuticals 
Confidential 
33 
7 CHANGES FROM PREVIOUS VERSION(S) 
The SAP Amendment 1 includes more details previously not discussed in the original SAP. Some 
changes to analysis methods are made following regulatory feedback and further assessments. 
The Amendment is signed off before the study is unblinded. The details of changes and rationales 
are listed in below table.  
Summary of Changes 
Rationale 
In the protocol and original SAP, an 
interim sample size reassessment (SSR) 
was planned but was not conducted during 
study. 
An SSR was originally planned to be performed 
at the time of the interim analysis to potentially 
increase the number of AIP patients in the study 
from approximately 70 to 90. Due to fast 
enrollment of the study leading to greater than 
expected numbers of patients randomized, an 
interim analysis for SSR was therefore no 
longer necessary. 
For the interim analysis of ALA at Month 
3, the missing data imputation was 
mLOCF in the original SAP; in this 
amendment, the imputation will be based 
on MI. Additional sensitivity analyses are 
added including a PMM and a non-
parametric method. 
Updates made following regulatory feedback. 
For the analysis of ALA/PBG at the end of 
6m-DB period, the primary analysis was 
based on ANCOVA/mLOCF in the 
original SAP; in this amendment, the 
primary analysis for ALA/PBG will be 
based on MMRM and a sensitivity analysis 
using PMM is added for ALA.  
Both MMRM and MI/ANCOVA are based on 
MAR assumption and MMRM is often 
considered a more simple and powerful method. 
PMM is added to assess the robustness of the 
results when missingness mechanism is MNAR. 
For the analysis of primary endpoint attack 
rate, PMM is added to address potential 
missing attack data and other sensitivity 
analyses are added (Section 6.5.1.3). 
These sensitivity analyses are added to assess 
the robustness of the primary analysis results. 
The median instead of the mean of valid 
pre-dose values is used to derive baseline 
ALA/PBG. 
Due to the variability with PD measures, the 
median is less affected by extreme values than 
the mean.  
For the secondary endpoint PCS SF-12, the 
primary analysis method is changed from 
ANCOVA to MMRM. 
This endpoint is measured at Month 3 and 
Month 6. MMRM implicitly imputes missing 
data using data from both time points while 
ANCOVA does not address missing data.  


ALN-AS1 (Givosiran) 
Statistical Analysis Plan, Protocol ALN-AS1-003 
 
SAP Amendment 1 
Alnylam Pharmaceuticals 
Confidential 
34 
For the secondary endpoints daily worst 
score of pain, nausea, and fatigue, the AUC 
over 6 months will be derived by first 
calculating the weekly mean scores 
(Section 6.5.2).   
Updated to address regulatory feedback on 
missing data handling and justification of AUC 
method.