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
Phase: PHASE3
Conditions: Acute Hepatic Porphyria, Acute Intermittent Porphyria, Porphyria, Acute Intermittent, Acute Porphyria, Hereditary Coproporphyria (HCP), Variegate Porphyria (VP), ALA Dehydratase Deficient Porphyria (ADP)
Sponsor: Alnylam Pharmaceuticals

 
 
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 ]