Multicenter, Randomized, Double-blind, Double Dummy, Parallel Group, Active-controlled 8-week Study and 8-week Open Label Extension to Evaluate the Effect of Initiation of Sacubitril/Valsartan on Objective Measures of Waking Activity and Sleep, as Health-related Quality of Life Functions in Subjects With Heart Failure and Reduced Ejection Fraction (AWAKE-HF).
Phase: PHASE4
Conditions: Heart Failure, Reduced Ejection Fraction
Sponsor: Novartis Pharmaceuticals

U S Cli ni c al D e v el o p m e nt a n d M e di c al Aff air s - N o v arti s P h ar m a c e uti c al
L C Z 6 9 6  s a c u bitril/ v al s art a n 
Cli ni c al Tri al Pr ot o c ol  C L C Z 6 9 6 B U S 1 4  / N C T 0 2 9 7 0 6 6 9
M ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, d o u bl e  d u m m y , p ar all el 
gr o u p, a cti v e -c o ntr oll e d 8 -w e e k st u d y a n d 8 -w e e k o p e n l a b el 
e xt e n si o n t o e v al u at e t h e eff e ct of i niti ati o n of 
s a c u bitril/ v al s art a n o n o bj e cti v e  m e a s ur e s of w a k i n g a cti vit y  
a n d sl e e p, a s h e alt h -r el at e d q u alit y of lif e f u n cti o n s i n s u bj e ct s 
w it h h e art fail ur e a n d r e d u c e d  ej e cti o n fr a cti o n : ( A W A K E-H F)
D o c u m e nt t y p e:  
A m e n d e d Pr ot o c ol V er si o n
V er si o n n u m b er: 
V 0 2 Cl e a n
Cli ni c al tri al p h a s e: 
I V
R el e a s e d at e:
1 3 -M ar -2 0 1 8
Pr o p ert y of N o v arti s
C o nfi d e nti al
M a y n ot b e u s e d, di v ul g e d, p u bli s h e d, or ot h er wi s e di s cl o s e d
wit h o ut t h e c o n s e nt of N o v arti s
Cli ni c al Tri al Pr ot o c ol T e m pl at e V er si o n 3. 2 ( J ul y 2 0 1 6 )

N o v arti s
C o nfi d e nti al
P a g e 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T a bl e of c o nt e nt s
Ta ble of c o nte nts .................................................................................................................2
List of ta bles ........................................................................................................................5
List of fi g ures ......................................................................................................................5
List of a b bre viati o ns ............................................................................................................6
Gl ossar y  of ter ms.................................................................................................................8
Pr ot oc ol s u m mar y ..............................................................................................................1 1
1 
I ntr o d ucti o n .......................................................................................................................1 5
1. 1 
Bac k gr o u n d ............................................................................................................1 5
1. 2 
P ur p ose ..................................................................................................................1 8
2 
St u d y  o bjecti ves a n d e n d p oi nts.........................................................................................1 8
2. 1 
O bjecti ves a n d relate d e n d p oi nts ...........................................................................1 9
3 
I n vesti gati o nal pla n ...........................................................................................................2 2
3. 1 
St u d y  desi g n...........................................................................................................2 2
3. 2 
Rati o nale f or st u d y desi g n .....................................................................................2 3
2 4
3. 4 
Rati o nale f or c h oice of c o m parat or .......................................................................2 4
3. 5 
P ur p ose a n d ti mi n g of i nteri m a nal ys es/ desi g n a da ptati o ns ..................................2 5
3. 6 
Ris ks a n d be nefits ..................................................................................................2 5
4 
P o p ulati o n ..........................................................................................................................2 5
4. 1 
I ncl usi o n criteria ....................................................................................................2 5
4. 2 
E xcl usi o n criteria ...................................................................................................2 6
5 
Treat me nt ...........................................................................................................................2 8
5. 1 
St u d y  treat me nt......................................................................................................2 8
5. 1. 1 
I n vesti gati o nal a n d c o ntr ol dr u gs ..........................................................2 8
5. 1. 2 
A d diti o nal treat me nt ..............................................................................3 0
5. 2 
Treat me nt ar ms ......................................................................................................3 0
5. 3 
Treat me nt assi g n me nt a n d ra n d o mizati o n............................................................. 3 1
5. 4 
Treat me nt bli n di n g .................................................................................................3 1
5. 5 
Treati n g t he patie nt ................................................................................................3 1
5. 5. 1 
S u bject N u m beri n g ................................................................................3 1
5. 5. 2 
Dis pe nsi n g t he st u d y dr u g .....................................................................3 2
5. 5. 3 
Ha n dli n g of st u d y  a n d a d diti o nal treat me nt..........................................3 2
5. 5. 4 
I nstr ucti o ns f or prescri bi n g a n d ta ki n g st u dy treat me nt ........................3 3
5. 5. 5 
Per mitte d d ose a dj ust me nts a n d i nterr u pti o ns of st u d y  treat me nt ........3 6
5. 5. 6 
Resc ue me dicati o n f or w orse ni n g heart fail ure .....................................3 8

N o v arti s
C o nfi d e nti al
P a g e 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
5. 5. 7  
C o nc o mita nt me dicati o n....................................................................... 3 9
5. 5. 8 
Pr o hi bite d me dicati o n........................................................................... 3 9
5. 5. 9 
E mer ge nc y  brea ki n g of assi g ne d treat me nt c o de..................................4 0
5. 6 
St u d y  c o m pleti o n a n d disc o nti n uati o n...................................................................4 1
5. 6. 1 
St u d y  c o m pleti o n a n d p ost-st u d y treat me nt..........................................4 1
5. 6. 2 
Disc o nti n uati o n of st u d y  treat me nt.......................................................4 1
5. 6. 3 
Wit h dra wal of i nf or me d c o nse nt ...........................................................4 2
5. 6. 4 
L oss t o f oll o w - u p ..................................................................................4 3
5. 6. 5 
Earl y st u d y ter mi nati o n b y t he s p o ns or .................................................4 3
6 
Visit sc he d ule a n d assess me nts......................................................................................... 4 3
6. 1 
I nf or mati o n t o be c ollecte d o n scree ni n g fail ures..................................................4 8
6. 2 
Patie nt de m o gra p hics/ ot her baseli ne c haracteristics .............................................4 8
6. 3 
Treat me nt e x p os ure a n d c o m plia nce .....................................................................4 8
6. 4 
Efficac y ..................................................................................................................4 8
6. 4. 1 
Efficac y  assess me nt ..............................................................................4 8
6. 4. 2 
A p pr o priate ness of efficac y  assess me nts..............................................4 9
6. 5 
Safet y .....................................................................................................................5 0
6. 5. 1 
P h y sical e xa mi nati o n ............................................................................5 0
6. 5. 2 
Vital si g ns ..............................................................................................5 1
6. 5. 3 
Hei g ht a n d wei g ht .................................................................................5 1
6. 5. 4 
A n gi oe de ma ..........................................................................................5 1
6. 5. 5 
La b orat or y  e val uati o ns..........................................................................5 1
6. 5. 6 
Pre g na nc y  a n d assess me nts of fertilit y .................................................5 2
6. 5. 7 
A p pr o priate ness of safet y  meas ure me nts..............................................5 2
6. 6 
Ot her assess me nts ..................................................................................................5 2
5 2
5 3
5 3
6. 6. 4 
Se ns or Meas ure me nts ............................................................................5 3
6. 6. 5 
Res o urce utilizati o n ...............................................................................5 5
7 
Safet y  m o nit ori n g..............................................................................................................5 5
7. 1 
A d verse e ve nts .......................................................................................................5 5
7. 2 
Seri o us a d verse e ve nts ...........................................................................................5 7
7. 2. 1 
Defi niti o n of S A E .................................................................................5 7
7. 2. 2 
S A E re p orti n g ........................................................................................5 7
7. 3 
Re p orti n g of st u d y treat me nt err ors i ncl u di n g mis use/a b use ................................5 8

N o v arti s
C o nfi d e nti al
P a g e 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
7. 4 
Pre g na nc y  re p orti n g...............................................................................................5 9
8 
Data re vie w a n d data base ma na ge me nt .............................................................................5 9
8. 1 
Site m o nit ori n g ......................................................................................................5 9
8. 2 
Data c ollecti o n....................................................................................................... 6 0
8. 3 
Data base ma na ge me nt a n d q ualit y  c o ntr ol............................................................6 0
8. 4 
Data M o nit ori n g C o m mittee ..................................................................................6 1
8. 5 
A n gi oe de ma A dj u dicati o n C o m mittee ..................................................................6 1
9 
Data a nal y sis......................................................................................................................6 2
9. 1 
A nal y sis sets ..........................................................................................................6 2
9. 2
S u bject de m o gra p hics a n d ot her baseli ne c haracteristics...................................... 6 2
9. 3 
Treat me nts .............................................................................................................6 3
9. 4 
A nal y sis of t he pri mar y varia ble(s) .......................................................................6 3
9. 4. 1 
Pri mar y  Varia ble(s)...............................................................................6 3
9. 4. 2 
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis ..........................6 3
9. 4. 3 
Ha n dli n g of missi n g val ues/ce ns ori n g/ disc o nti n uati o ns .......................6 4
9. 4. 4 
Se nsiti vit y  a nal yses ...............................................................................6 4
9. 5 
A nal y sis of sec o n dar y varia bles ............................................................................6 4
9. 5. 1 
Efficac y  varia bles..................................................................................6 4
9. 5. 2 
Safet y  varia bles.....................................................................................6 5
9. 5. 3 
Res o urce utilizati o n ...............................................................................6 5
9. 5. 4 
P har mac o ki netics ..................................................................................6 5
9. 5. 5 
D N A ......................................................................................................6 5
9. 5. 6 
Bi o mar kers ............................................................................................6 5
9. 5. 7 
P K/ P D ...................................................................................................6 5
6 5
9. 7 
I nteri m a nalys es .....................................................................................................6 7
9. 8 
Sa m ple size calc ulati o n.......................................................................................... 6 7
1 0
Et hical c o nsi derati o ns ........................................................................................................6 8
1 0. 1 
Re g ulat or y  a n d et hical c o m plia nce........................................................................6 8
1 0. 2 
I nf or me d c o nse nt pr oce d ures.................................................................................6 8
1 0. 3 
Res p o nsi bilities of t he i n vesti gat or a n d I R B/ I E C..................................................6 8
1 0. 4 
P u blicati o n of st u d y  pr ot oc ol a n d res ults...............................................................6 9
1 0. 5 
Q ualit y  C o ntr ol a n d Q ualit y Ass ura nce.................................................................6 9
1 1
Pr ot oc ol a d here nce ............................................................................................................6 9
1 1. 1 
Pr ot oc ol a me n d me nts .............................................................................................6 9
1 2
Refere nces .........................................................................................................................7 0

N o v arti s
C o nfi d e nti al
P a g e 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 3
A p pe n di x 1: Cli nicall y  n ota ble la b orat or y val ues a n d vital si g ns.....................................7 3
1 4
A p pe n di x 2: L i ver e ve nt a n d La b orat or y tri g ger Defi niti o ns a n d F oll o w- u p 
Re q uire me nts .....................................................................................................................7 4
1 5
A p pe n di x 3: S pecific Re nal Alert Criteria a n d Acti o ns ....................................................7 7
1 6
A p pe n di x 4: G ui deli ne f or t he ma na ge me nt of re nal d y sf u ncti o n ....................................7 8
1 7
A p pe n di x 5 : G ui deli nes f or t he ma na ge me nt of bl o o d press ure .......................................7 9
8 0
8 4
9 0
2 1
A p pe n di x 9: Pr o hi bite d Me dicati o ns: Prescri pti o n a n d n o n -prescri pti o n me dicati o ns 
ta ke n f or i ns o m nia or t o i n d uce slee p................................................................................9 1
Li st of t a bl e s
Ta ble 2 - 1
O bjecti ves a n d relate d e n d p oi nts ..........................................................1 9
Ta ble 5 - 1
I n vesti gati o nal a n d c o m parat or treat me nt d uri n g t he d o u ble-bli n d 
e p oc h .....................................................................................................2 8
Ta ble 5 - 2
Treat me nt d ose le vels d uri n g t he d o u ble -bli n d e p oc h ..........................2 8
Ta ble 5 - 3
I n vesti gati o nal treat me nt d uri n g t he o pe n la bel e p oc h .........................2 9
Ta ble 5 - 4
Treat me nt D ose Le vels d uri n g t he o pe n -la bel e p oc h............................3 0
Ta ble 5 - 5
St u d y  dr u g dis pe nse d d uri n g d o u ble- bli n d treat me nt e p oc h.................3 4
Ta ble 5 - 6
St u d y  dr u g dis pe nse d d uri n g o pe n-la bel treat me nt e p oc h ....................3 5
Ta ble 5 - 7
Safet y  a n d t olera bilit y g ui da nce f or d ose a dj ust me nts..........................3 6
Ta ble 5 - 8
Pr o hi bite d me dicati o n ( Please als o see A p pe n di x 9)............................ 4 0
Ta ble 6 - 1
Assess me nt sc he d ule .............................................................................4 4
Ta ble 7 - 1
G ui da nce f or ca pt uri n g t he st u d y treat me nt err ors i ncl u di n g mis use ...5 9
Ta ble 1 4 - 1 
Li ver E ve nt a n d La b orat or y  Tri g ger Defi niti o ns ..................................7 4
Ta ble 1 4 - 2 
F oll o w U p Re q uire me nts f or L i ver E ve nts a n d La b orat or y Tri g gers...7 5
Ta ble 1 5 - 1 
S pecific Re nal Alert Criteria a n d Acti o ns .............................................7 7
Li st of fi g ur e s
Fi g ure 3 - 1 
St u d y  desi g n..........................................................................................2 3

N o v arti s
C o nfi d e nti al
P a g e 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
Li st of a b br e vi ati o n s
A A S M
A m eri c a n A c a d e m y of Sl e e p M e di ci n e
A C C
A n gi o e d e m a A dj u di c ati o n C o m mitt e e
A C Ei
A n gi ot e n si n C o n v erti n g E n z y m e  i n hi bit or
A E
A d v er s e E v e nt
A R B
A n gi ot e n si n R e c e pt or Bl o c k er
b.i. d.
t wi c e a d a y
B MI
B o d y M a s s I n d e x
C F R
U S C o d e of F e d er al R e g ul ati o n s
C D S
C or e D at a S h e et (f or m ar k eti n g dr u g s)
C H F
C o n g e sti v e H e art F ail ur e
C O P D
C hr o ni c O b str u cti v e P ul m o n ar y Di s e a s e
C R F
C a s e R e p ort/ R e c or d F or m ( p a p er or el e ctr o ni c)
C P A P
C o nti n u o u s P o siti v e Air w a y Pr e s s ur e
C P O
C o u ntr y P h ar m a Or g a ni z ati o n
C R O
C o ntr a ct R e s e ar c h Or g a ni z ati o n
C- S S R S
C ol u m bi a S ui ci d e S e v erit y R ati n g S c al e
C T C
C o m m o n T er mi n ol o g y Crit eri a
C T R D
Cli ni c al Tri al R e s ult s D at a b a s e
C V
C ar di o v a s c ul ar
D S & E
Dr u g S af et y & E pi d e mi ol o g y
E C G
El e ctr o c ar di o gr a m
E D C
El e ctr o ni c D at a C a pt ur e
e S o ur c e
El e ctr o ni c S o ur c e
G C P
G o o d Cli ni c al Pr a cti c e
h C G
H u m a n C h ori o ni c G o n a d otr o pi n
H D P E
Hi g h D e n sit y P ol y et h yl e n e
H F
H e art F ail ur e
H Fr E F
H e art f ail ur e wit h r e d u c e d ej e cti o n fr a cti o n
H R -Q o L
H e alt h R el at e d Q u alit y of Lif e
H S T
H o m e Sl e e p T e st
I C D
I m pl a nt e d C ar di o v ert er d efi brill at or s
I C H
I nt er n ati o n al C o nf er e n c e o n H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or 
R e gi str ati o n of P h ar m a c e uti c al s f or H u m a n U s e
I E C
I n d e p e n d e nt Et hi c s C o m mitt e e
i. v.
i ntr a v e n o u s
I R B
I n stit uti o n al R e vi e w B o ar d
I R T
I nt er a cti v e R e s p o n s e T e c h n ol o g y
I U D
I ntr a ut eri n e D e vi c e
I U S
I ntr a ut eri n e S y st e m
K C C Q
K a n s a s Cit y  C ar di o my o p at h y Q u e sti o n n air e

N o v arti s
C o nfi d e nti al
P a g e 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
L F T
Li v er f u n cti o n t e st
L V E F
L eft V e ntri c ul ar Ej e cti o n Fr a cti o n
M e d D R A 
M e di c al di cti o n ar y f or r e g ul at or y a cti viti e s
M W T
Mi n ut e W al k  T e st
N E P
N e utr al E n d o p e pti d a s e
N Y H A
N e w Y or k H e art A s s o ci ati o n
o. d.
o n c e a d a y
O T C
O v er t h e C o u nt er
p. o.
Or al(l y)
P R O
P ati e nt R e p ort e d O ut c o m e
P S G
P ol y s o m n o gr a p h y
R A A S
R e ni n A n gi ot e n si n Al d o st er o n e S y st e m
S A E
S eri o u s A d v er s e E v e nt
S P P B
S h ort P h y si c al P erf or m a n c e B att er y
S U S A R
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n s
S T D
St u d y T r e at m e nt Di s c o nti n u ati o n 
U S PI
U nit e d St at e s P a c k a g e I n s ert
W H O
W o rl d H e alt h Or g a ni z ati o n
W o C
Wi t h dr a w al of C o n s e nt

N o v arti s
C o nfi d e nti al
P a g e 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
Gl o s s ar y  of t er m s
C o h ort 
A s p e cifi c gr o u p of p ati e nt s/ s u bj e ct s f ulfilli n g c ert ai n crit eri a
C o ntr ol dr u g
Dr u g s( s) u s e d a s a c o m p ar at or t o r e d u c e a s s e s s m e nt bi a s, pr e s er v e 
bli n di n g of i n v e sti g ati o n al dr u g, a s s e s s i nt er n al st u d y v ali dit y, a n d/ or 
e v al u at e c o m p ar ati v e eff e ct s of t h e i n v e sti g ati o n al dr u g
D o s a g e
D o s e of t h e st u d y tr e at m e nt gi v e n t o t h e p ati e nt i n a ti m e u nit ( e. g. 1 0 0 
m g  o n c e a d a y, 7 5 m g t wi c e a d a y)
El e ctr o ni c D at a C a pt ur e 
( E D C)
El e ctr o ni c d at a c a pt ur e ( E D C) i s t h e el e ctr o ni c a c q ui siti o n of cli ni c al 
st u d y d at a u si n g d at a c oll e cti o n s y s t e m s, s u c h a s W e b- b a s e d 
a p pli c ati o n s, i nt er a ct i v e v oi c e r e s p o n s e sy s t e m s a n d cli ni c al l a b or at or y 
i nt erf a c e s.
E D C i n cl u d e s t h e u s e of El e ctr o ni c C a s e R e p ort F or m s ( e C R F s) w hi c h 
ar e u s e d t o c a pt ur e d at a tr a n s cri b e d fr o m p a p er s o ur c e f or m s u s e d at 
t h e p oi nt of c ar e.
e S o ur c e
e S o ur c e Dir e ct D at a E ntr y ( D D E) r ef er s t o t h e c a pt ur e of cli ni c al st u d y 
d at a el e ctr o ni c all y, at t h e p oi nt of c ar e. e S o ur c e Pl atf or m/ A p pli c ati o n s 
r e d u c e t h e u s e of p a p er c a pt ur e s o ur c e d at a d uri n g cli ni c al vi sit s. 
e S o ur c e c o m bi n e s s o ur c e d o c u m e nt s a n d c a s e r e p ort f or m s ( e C R F s) 
i nt o o n e a p pli c ati o n, all o wi n g f or t h e r e al ti m e c oll e cti o n of cli ni c al tri al 
i nf or m ati o n t o s p o n s or s a n d ot h er o v er si g ht a ut h oriti e s, a s a p pr o pri at e.
E nr oll m e nt
P oi nt/ti m e of p ati e nt e ntr y i nt o t h e st u d y at w hi c h i nf or m e d c o n s e nt m u st 
b e o bt ai n e d ( e. g. pri or t o st arti n g a n y of t h e pr o c e d ur e s d e s cri b e d i n t h e 
pr ot o c ol)
E p o c h
A p orti o n of t h e st u d y w hi c h s er v e s a s p e cifi c p ur p o s e. T y p i c al e p o c h s 
ar e: s cr e e ni n g/r e cr uit m e nt, w a s h -o ut, tr e at m e nt, a n d f oll o w -u p
I n v e sti g ati o n al dr u g
T h e dr u g w h o s e pr o p erti e s ar e b ei n g t e st e d i n t h e st u d y; t hi s d efi niti o n 
i s c o n si st e nt wit h U S C F R 2 1 S e cti o n 3 1 2. 3 a n d i s sy n o n y m o u s wit h 
“i n v e sti g ati o n al n e w dr u g” or “i n v e sti g ati o n al m e di ci n al pr o d u ct.”
M e di c ati o n p a c k n u m b er 
A u ni q u e i d e ntifi er o n t h e l a b el of e a c h i n v e sti g ati o n al dr u g p a c k a g e
P art 
A si n gl e c o m p o n e nt of a st u d y w hi c h c o nt ai n s diff er e nt o bj e cti v e s or 
p o p ul ati o n s wit hi n t h at si n gl e st u d y. C o m m o n p art s wit hi n a st u d y ar e: a 
si n gl e d o s e p art a n d a m ulti pl e d o s e p art, or a p art i n p ati e nt s/ s u bj e ct s 
wit h e st a bli s h e d di s e a s e a n d i n t h o s e wit h n e wl y -di a g n o s e d di s e a s e.
P ati e nt/ s u bj e ct I D 
A u ni q u e n u m b er a s si g n e d t o e a c h p ati e nt u p o n si g ni n g t h e i nf or m e d 
c o n s e nt 
R a n d o mi z ati o n n u m b er
A u ni q u e i d e ntifi er a s si g n e d t o e a c h r a n d o mi z e d p ati e nt, c orr e s p o n di n g 
t o a s p e cifi c tr e at m e nt ar m a s si g n m e nt
R e d u c e d Ej e cti o n 
Fr a cti o n 
L eft v e ntri c ul ar ej e cti o n fr a cti o n ≤ 4 0 %

N o v arti s
C o nfi d e nti al
P a g e 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
S o ur c e D at a/ D o c u m e nt
S o ur c e d at a r ef er s t o t h e i niti al r e c or d, d o c u m e nt, or pri m ar y  l o c ati o n 
fr o m w h er e d at a c o m e s. T h e d at a s o ur c e c a n b e a d at a b a s e, a d at a s et, 
a s pr e a d s h e et or e v e n h ar d -c o d e d d at a, s u c h a s p a p er or e S o ur c e.
St u d y dr u g/ tr e at m e nt
A n y si n gl e dr u g or c o m bi n ati o n of dr u g s a d mi ni st er e d t o t h e p ati e nt a s 
p art of t h e r e q uir e d st u d y pr o c e d ur e s; i n cl u d e s i n v e sti g ati o n al dr u g ( s), 
pl a c e b o/ c o m p ar at or a cti v e dr u g r u n -i n s or b a c k gr o u n d t h er a p y
St u d y T r e at m e nt 
Di s c o nti n u ati o n ( T D)
W h e n t h e p ati e nt p er m a n e ntl y st o p s t a ki n g st u d y tr e at m e nt pri or t o t h e 
d efi n e d st u d y tr e at m e nt c o m pl eti o n d at e 
V ari a bl e
A m e a s ur e d v al u e or a s s e s s e d r e s p o n s e t h at i s d et er mi n e d i n s p e cifi c 
a s s e s s m e nt s a n d u s e d i n d at a a n al y si s t o e v al u at e t h e dr u g b ei n g 
t e st e d i n t h e st u d y
Wi t h dr a w al of c o n s e nt 
( Wo C)
Wi t h dr a w al of c o n s e nt fr o m t h e st u d y i s d efi n e d a s w h e n a p ati e nt d o e s 
n ot w a nt t o p arti ci p at e i n t h e st u d y a n y l o n g er, a n d d o e s n ot w a nt a n y 
f urt h er vi sit s or a s s e s s m e nt s, a n d d o e s n ot w a nt a n y f urt h er st u d y 
r el at e d c o nt a ct, a n d d o e s n ot all o w a n al y si s of alr e a d y o bt ai n e d bi ol o gi c 
m a t eri al
A m e n d m e nt v 0 2 r ati o n al e
T he pri mar y  p ur p ose of t his a me n d me nt is t o a d d statistical met h o d ol o g y to acc o u nt f or t he 
p ossi bilit y  that t he pri mar y  en d p oi nt is n ot n or mall y  distri b ute d. I n the e ve nt t hat t he pri mar y 
e n d p oi nt is n ot n or mall y distri b ute d a n d t he l o g n or mal distri b uti o n is a better fit, a l o g 
tra nsf or mati o n will be use d i n t he a nalys is of t he pri mar y e n d p oi nt.
C h a n g e s t o t h e pr ot o c ol

Pr ot oc ol S u m mar y  – Data A nal ys is secti o n u p date d base d o n a me n d me nt u p dates

Secti o n 9. 4. 2 Statistical m o del, h y p ot hesis, a n d met h o d of a nal ys is: a d diti onal statistical 
met h o d ol o g y  i ncl u de d

Secti o n 9. 4. 4 Se nsiti vit y  anal ys es: re m o ve d te xt f or c o nsiste nc y wit h statistical 
met h o d ol o g y  u p dates

Secti o n 9. 8 Sa m ple size calc ulati o n: a d de d te xt c o nsiste nt wit h statistical met h o d ol o g y 
u p dates 
C ha n ges t o s pecific secti o ns of t he pr ot oc ol are s h o w n i n t he trac k c ha n ges versi o n of t he 
pr ot oc ol usi n g stri ke t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne d f or i nserti o ns.
A 
c o p y of t his a me n de d pr ot oc ol
will 
be se nt t o t he I nstit uti o nal Re vie w 
B oar d 
(IR B s)/I n de pe n de nt Et hics C o m mittee (I ECs) a n d Healt h A ut h orities .

N o v arti s
C o nfi d e nti al
P a g e 1 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I RB/I E C
a p pr o val pri or t o 
i m ple me ntati o n. 
T he c ha n ges herei n d o N O T affect t he trial s pecific m o del I C F. 
S u m m ar y  of pr e vi o u s a m e n d m e nt s
A m e n d m e nt v 0 1 ( 2 6 J ul 2 0 1 7)
A m e n d m e nt r ati o n al e
 A d diti o nal clarificati o n is a d de d t o i ncl usi o n criteri o n 3 .  T hese 
m o dificati o ns are base d o n fee d bac k recei ve d fr o m i n vesti gat ors d uri n g site i nitiati o n visits.   
T he trial o bjecti ves a n d relate d e n d p oi nts are si m plifie d base d o n t he re p orti n g a n d a nal ys is 
pla n.  
C h a n g e s t o t h e pr ot o c ol

Ta ble  2 -1: O bjecti ves a n d Relate d E n d p oi nts – clarifie d e n d p oi nts f or eac h o bjecti ve 
base d o n re p orti n g a n d a nal ysis pla n

I ncl usi o n criteri o n # 3: a d de d defi niti o n of re d uce d ejecti o n fracti o n


C ha n ges t o s pecific secti o ns of t he pr ot oc ol are s h o w n i n t he trac k c ha n ges versi o n of t he 
pr ot oc ol usi n g stri ke t hr o u g h re d f o nt f or deleti o ns a n d re d u n derli ne d f or i nserti o ns.
A 
c o p y of t his a me n de d pr ot oc ol
will 
be se nt t o t he I nstit uti o nal Re vie w 
B oar d 
(IR B s)/I n de pe n de nt Et hics C o m mittee (I ECs) a n d Healt h A ut h orities .
T he c ha n ges descri be d i n t his a me n de d pr ot oc ol re q uire I RB/I E C
a p pr o val pri or t o 
i m ple me ntati o n. 
T he c ha n ges herei n affect t he I nf or me d C o nse nt. Sites are req uire d t o u p date a n d s u b mit f or 
a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his 
pr ot oc ol a me n d me nt.

N o v arti s
C o nfi d e nti al
P a g e 1 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
Pr ot o c ol s u m m ar y
Pr ot o c ol n u m b er
C L C Z 6 9 6 B U S 1 4
F ull Titl e
M ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, d o u bl e d u m m y, p ar all el gr o u p, 
a cti v e -c o ntr oll e d 8 -w e e k st u d y a n d 8 -w e e k o p e n l a b el e xt e n si o n t o 
e v al u at e t h e eff e ct of i niti ati o n of s a c u bitril/ v al s art a n o n o bj e cti v e 
m e a s ur e s of w a k i n g a cti vit y a n d sl e e p, a s h e alt h -rel at e d q u alit y of lif e 
f u n cti o n s i n s u bj e ct s wit h h e art f ail ur e a n d r e d u c e d ej e cti o n fr a cti o n
( AW A K E -H F) .
Bri ef titl e
St u d y o n t h e eff e ct s of S a c u bitril/ V al s art a n o n p h y si c al a cti vit y a n d sl e e p 
i n h e art f ail ur e wit h r e d u c e d ej e cti o n fr a cti o n p ati e nt s.
S p o n s or a n d Cli ni c al 
P h a s e
N o v arti s P h ar m a c e uti c al s: P h a s e I V
I n v e sti g ati o n t y p e
I nt er v e nti o n al
St u d y t y p e
M ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, d o u bl e d u m m y, p ar all el gr o u p, 
a cti v e -c o ntr oll e d
P ur p o s e a n d r ati o n al e 
T h e p ur p o s e of t hi s st u d y i s t o i n v e s ti g at e t h e eff e ct s of i niti ati o n of 
s a c u bitril/ v al s art a n v s e n al a pril tr e at m e nt o n o bj e cti v e m e a s ur e s of b ot h 
w a ki n g a cti vit y a n d sl e e p i n s u bj e ct s wit h h e art f ail ur e wit h r e d u c e d 
ej e cti o n fr a cti o n.
Pri m ar y O bj e cti v e( s)  
T h e pri m ar y  o bj e cti v e i s t o e v al u at e t h e eff e ct of i niti ati o n of 
s a c u bitril/ v al s art a n tr e at m e nt v er s u s e n al a pril o n p h y si c al a cti vit y d uri n g 
t h e w a ki n g h o ur s a s a n o bj e cti v e m e a s ur e of p h y si c al f u n cti o n.
T h e pri m ar y  e n d p oi nt i s t h e c h a n g e i n m e a n a cti vit y c o u nt s c oll e ct e d 
d uri n g t h e m o st a cti v e 3 0 mi n ut e s of t h e s u bj e ct’ s d a y b et w e e n b a s eli n e 
p h a s e ( m e a n of e n d p oi nt d at a c oll e ct e d e a c h d a y d uri n g w e e k - 1) a n d 
t h e fi n al r a n d o mi z e d tr e at m e nt p h a s e m e a s ur e m e nt ( m e a n of e n d p oi nt 
d at a c oll e ct e d e a c h d a y d uri n g w e e k 8 ), a s m e a s ur e d b y wri st-w or n 
a c c el er o m et er c oll e ct e d a cti gr a p h y (t ot al c o u nt s p er 3 0 mi n p eri o d 
c oll e ct e d d uri n g t h e m o st a cti v e 3 0 mi n ut e s of e a c h d a y).
S e c o n d ar y O bj e cti v e s 
T h e s e c o n d ar y o bj e cti v e i s t o e v al u at e t h e eff e ct of i niti ati o n of 
s a c u bitril/ v al s art a n tr e at m e nt v er s u s e n al a pril o n s u bj e ct s’ sl e e p a s a n 
o bj e cti v e m e a s ur e of p h y si c al f u n cti o n .
T h e s e c o n d ar y e n d p oi nt s i n cl u d e:
 
C h a n g e i n m e a n a cti vit y ( c o u nt s p er mi n ut e) d uri n g sl e e p 
b et w e e n b a s eli n e p h a s e ( m e a n of d at a c oll e ct e d d uri n g w e e k - 1) 
a n d t h e fi n al r a n d o mi z e d tr e at m e nt p h a s e m e a s ur e m e nt ( m e a n 
of d at a c oll e ct e d d uri n g w e e k 8 ), a s m e a s ur e d b y a cti gr a p h y 
( a cti vit y c o u nt s p er mi n ut e d uri n g d ail y sl e e p p eri o d, wri st-w or n 
a c c el er o m et er).
 
T h e c h a n g e i n m e a n a cti vit y d uri n g sl e e p b et w e e n b a s eli n e 
p h a s e ( m e a n of d at a c oll e ct e d d uri n g t h e ni g ht s of w e e k - 1) a n d 
e a c h r a n d o mi z e d tr e at m e nt a n d o p e n l a b el p h a s e
m e a s ur e m e nt , a s m e a s ur e d b y a cti gr a p h y (W e e k  1, 9 , a n d 1 6) 
( a cti vit y c o u nt s p er mi n ut e d uri n g d ail y sl e e p p eri o d, wri st -w or n 
a c c el er o m et er).
 
T h e c h a n g e i n m e a n a cti vit y c o u nt s c oll e ct e d d uri n g t h e m o st 
a cti v e 3 0 mi n ut e s of t h e s u bj e ct’ s d a y b et w e e n b a s eli n e p h a s e 
( me a n of d at a c oll e ct e d e a c h d a y d uri n g w e e k - 1) a n d e a c h 
r a n d o mi z e d tr e at m e nt a n d o p e n l a b el p h a s e m e a s ur e m e nt

N o v arti s
C o nfi d e nti al
P a g e 1 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
(W e e k s 1 , 9 , a n d 1 6),  a s m e a s ur e d b y wri st w or n a c c el er o m et er 
c oll e ct e d a cti gr a p h y.
St u d y d e si g n
A m ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, d o u bl e d u m m y, p ar all el gr o u p, 
a cti v e -c o ntr oll e d 8 -w e e k st u d y wit h o p e n l a b el e xt e n si o n u si n g m e di c al 
d e vi c e -gr a d e s u bj e ct w or n s e n s or s t o m e a s ur e w a ki n g a n d sl e e pi n g 
p h y si c al a cti vit y i n t h e a m b ul at or y o ut p ati e nt s e tti n g.  T h e 1 8 w e e k st u d y 
d ur ati o n will c o n si st of a 2 -w e e k b a s eli n e o b s er v ati o n p h a s e ( wit h 
s u bj e ct s c o nti n ui n g t h eir c urr e nt h e art f ail ur e dr u g t h er a p y), f oll o w e d b y 
a n 8 w e e k bli n d e d tr e at m e nt p h a s e d uri n g w hi c h s u bj e ct s ar e 
r a n d o mi z e d ( 1: 1) t o eit h er initi ati o n of s a c u bitril/ v al s art a n tr e at m e nt or 
e n al a pril c o m p ar at or, a n d fi n all y a n 8 w e e k o p e n l a b el e xt e n si o n p h a s e 
d uri n g w hi c h all s u bj e ct s ar e tr e at e d wit h s a c u bitril/ v al s art a n.  E a c h 
s u bj e ct will u n d er g o a 3 6 h o ur w a s h o ut p eri o d [d uri n g w hi c h A C Ei 
( An gi ot e n si n c o n v erti n g e n z y m e  i n hi bit or), or st u d y dr u g will b e wit h h el d]
b ef or e t h e st art of t h e r a n d o mi z e d, bli n d e d tr e at m e nt p h a s e, a n d a g ai n 
b ef or e b e gi n ni n g t h e o p e n l a b el e xt e n si o n p h a s e. T h e st u d y will i n cl u d e 8 
offi c e vi sit s a n d 5 t el e -vi sit s.
P o p ul ati o n
T h e st u d y p o p ul ati o n will c o n si st of o ut p ati e nt m al e a n d f e m al e s u bj e ct s, 
b et w e e n 1 8 - 8 0 y e ar s of a g e, wit h H Fr E F N Y H A cl a s s II or III.  T h e g o al 
i s t o h a v e a t ot al of a p pr o xi m at el y 1 3 6 s u bj e ct s r a n d o mi z e d, i n 
a p pr o xi m at el y 2 5 -3 0 c e nt er s i n t h e U nit e d St at e s. S u bj e ct s will h a v e m et 
all ot h er i n cl u si o n a n d n o n e of t h e e x cl u si o n crit eri a.
K e y I n cl u si o n crit eri a 
S u bj e ct s eli gi bl e f or i n cl u si o n i n t hi s st u d y m u st f ulfill all of t h e f oll o wi n g 
crit eri a:
 
Wr itt e n i nf or m e d c o n s e nt m u st b e o bt ai n e d b ef or e a n y 
a s s e s s m e nt i s p erf or m e d. 
 
M e n a n d w o m e n b et w e e n 1 8 a n d 8 0 y e ar s of a g e
 
S u bj e ct s di a g n o s e d wit h N Y H A cl a s s II or III h e art f ail ur e a n d 
wit h r e d u c e d ej e cti o n ( H Fr E F) .  ( R e d u c e d ej e cti o n i s d efi n e d a s 
l eft v e ntri c ul ar E F ≤ 4 0 %.  L V E F ≤4 0 % m a y  b e d et er mi n e d vi a 
a n y l o c al m e a s ur e m e nt wit hi n t h e p a st 6 m o nt h s pri or t o si g ni n g 
c o n s e nt, u si n g e c h o c ar di o gr a p h y, m ulti g at e d a c q ui siti o n s c a n 
( M U G A), C T s c a n ni n g, M RI or v e ntri c ul ar a n gi o gr a p h y pr o vi d e d 
n o s u b s e q u e nt st u d y d o c u m e nti n g a n E F of > 4 0 %.   If t h e E F 
m e a s ur e m e nt i s e x pr e s s e d a s a v al u e r a n g e, t h e a v er a g e of t h e 
r a n g e e n d p oi nt v al u e s s h o ul d b e u s e d a s t h e E F).
 
S u bj e ct s m u st b e a c a n di d at e f or tr e at m e nt wit h 
s a c u bitril/ v al s art a n a s p er U nit e d St at e s P a c k a g e I n s ert ( U S PI) 
 
S u bj e ct s m u st b e li v i n g i n a tr a diti o n al r e si d e n c e, a p art m e nt, or 
n o n -c o m m u n al a d ult h o m e w h er e t h e y c a n m o v e a b o ut fr e el y 
a n d fr e q u e ntl y a n d ar e pri m aril y r e s p o n si bl e f or s c h e d uli n g t h eir 
sl e e p a n d d ail y a cti viti e s
K e y E x cl u si o n crit eri a 
S u bj e ct s f ulfilli n g a n y of t h e f oll o wi n g crit eri a ar e n ot eli gi bl e f or i n cl u si o n 
i n t hi s st u d y. N o a d diti o n al e x cl u si o n s m a y b e a p pli e d b y t h e i n v e sti g at or, 
i n or d er t o e n s ur e t h at t h e st u d y p o p ul ati o n will b e r e pr e s e nt ati v e of all 
eli gi bl e s u bj e ct s.
 
S u bj e ct s wit h a hi st or y of h y p er s e n s iti vit y t o a n y of t h e st u d y 
dr u g s, i n cl u di n g hi st or y of h y p er s e n siti vit y t o dr u g s of si mil ar 
c h e mi c al cl a s s e s, or all er g y t o A C EI s, A R B s, or N E P i n hi bit or s 
a s w ell a s k n o w n or s u s p e ct e d c o ntr ai n di c ati o n s t o t h e st u d y 
dr u g s.
 
S u bj e ct s wit h a hi st or y of a n gi o e d e m a dr u g r el at e d or ot h er wi s e

N o v arti s
C o nfi d e nti al
P a g e 1 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
 
S u bj e ct s wit h s y m pt o m ati c h y p ot e n si o n or s y st oli c bl o o d 
pr e s s ur e < 1 0 0 m m H g at s cr e e ni n g or < 9 5 m m H g at 
r a n d o mi z ati o n
 
S u bj e ct s wit h a n y c o n diti o n s i n s ki n or u p p er e xtr e miti e s w hi c h 
w o ul d li mit t h e a bilit y t o t ol er at e a wri st -w or n a cti gr a p h y d e vi c e
o n t h e n o n -d o m i n a nt ar m f or 2 4 h o ur s/ d a y f or t h e d ur ati o n of t h e 
st u d y .
 
S u bj e ct s w h o ar e n o n a m b ul at or y or u s e m o bilit y a s si sti v e 
d e vi c e s s u c h a s m ot ori z e d d e vi c e s, w h e el c h air s, or w al k er s. 
T h e u s e of c a n e s f or st a bilit y w hil e a m b ul ati n g i s a c c e pt a bl e.
 
S u bj e ct s wit h p h y si c al a cti vit y i m p air m e nt pri m aril y d u e t o 
c o n diti o n s ot h er t h a n h e art f ail ur e s u c h a s:
 
E x erti o n al a n gi n a
 
i nfl a m m at or y or d e g e n er ati v e j oi nt di s e a s e
 
g o ut
 
p eri p h er al v a s c ul ar di s e a s e
 
n e ur ol o gi c di s e a s e aff e cti n g a cti vit y or m o bilit y
St u d y tr e at m e nt 
All eli gi bl e s u bj e ct s will b e r a n d o mi z e d t o r e c ei v e eit h er 
s a c u bitril/ v al s art a n or e n al a pril. B ot h s a c u bitril/ v al s art a n a n d e n al a pril 
a n d t h eir m at c hi n g pl a c e b o s will b e p a c k a g e d a n d l a b el e d b y t h e s p o n s or 
i n a c c or d a n ce wit h t h e U S C o d e of F e d er al R e g ul ati o n s g o v er ni n g 
h a n dli n g of i n v e sti g ati o n al tr e at m e nt s, a n d will b e di s p e n s e d b y t h e st u d y 
p h y si ci a n.
S a c u bitril/ v al s art a n a n d e n al a pril will b e p a c k a g e d s e p ar at el y t o li mit t h e 
n u m b er of p a c k t y p e s w hi c h will all o w m or e fl e xi bilit y i n t h e dr u g s u p pl y 
pr o c e s s t o c o v er all t h e diff er e nt tr e at m e nt p o s si biliti e s (tr e at m e nt ar m 
a n d m e di c ati o n d o s e l e v el), s e e T a bl e 5 - 2 a n d T a bl e 5 - 4.
Effi c a c y a s s e s s m e nt s 
Wi ll c o n si st of m e a s ur e m e nt s b a s e d o n:
 
A cti gr a p h y

K e y s af et y 
a s s e s s m e nt s
S af et y a s s e s s m e nt s will c o n si st of m o nit ori n g a n d r e c or di n g of all 
a d v er s e e v e nt s a n d s eri o u s a d v er s e e v e nt s, e v al u ati o n of h e m at ol o g y, 
bl o o d c h e mi str y a n d uri n e v al u e s, r e g ul ar m e a s ur e m e nt of vit al si g n s a n d 
t h e p erf or m a n c e of p h y si c al e x a mi n ati o n s.



D at a a n al y si s
T h e pri m ar y  e n d p oi nt i s t h e c h a n g e i n m e a n a cti vit y c o u nt s c oll e ct e d 
d uri n g t h e m o st a cti v e 3 0 mi n ut e s of t h e s u bj e ct’ s d a y b et w e e n b a s eli n e 
p h a s e ( m e a n of d at a c oll e ct e d e a c h d a y d uri n g w e e k - 1) a n d t h e fi n al 
r a n d o mi z e d tr e at m e nt p h a s e m e a s ur e m e nt ( m e a n of e n d p oi nt d at a 
c oll e ct e d e a c h d a y d uri n g w e e k 8 ), a s m e a s ur e d b y wri st-w or n 
a c c el er o m et er c oll e ct e d a cti gr a p h y (t ot al c o u nt s p er 3 0 mi n p eri o d 
c oll e ct e d d uri n g t h e m o st a cti v e 3 0 mi n ut e s of e a c h d a y).
T h e pri m ar y  effi c a c y v ari a bl e will b e a n al y z e d b y a n an al y si s of 
c o v ari a n c e ( A N C O V A) m o d el wit h tr e at m e nt a n d b a s eli n e a cti vit y a s 
e x pl a n at or y v ari a bl e s. T h e l e a st s q u ar e s m e a n s of t h e t w o tr e at m e nt 
gr o u p s, l e a st s q u ar e s m e a n diff er e n c e of t h e tr e at m e nt gr o u p s, 9 5 % 
c o nfi d e n c e i nt er v al f or t h e diff er e n c e i n t h e t w o tr e at m e nt gr o u p s, a n d p -
v al u e b a s e d o n t h e fitt e d li n e ar m o d el will b e r e p ort e d.

N o v arti s
C o nfi d e nti al
P a g e 1 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
B ef or e p erf or mi n g t h e a b o v e a n al y si s, t e st s of n or m alit y of t h e v ari a bl e 
a n d it s l o g tr a n sf or m ati o n (l o g ( w e e k 8 v al u e) – l o g ( b a s eli n e v al u e)) will 
b e p erf or m e d. I n t h e e v e nt t h e v ari a bl e i s n ot n or m all y di stri b ut e d ( b a s e d 
o n S h a pir o -Wi l k t e st p-v al u e < 0. 0 5) b ut t h e l o g n or m al di stri b uti o n fit s 
b ett er, t h e a b o v e a n al y si s will b e p erf or m e d u si n g t h e l o g tr a n sf or m e d 
d at a. A nti -l o g of t h e l e a st s q u ar e s m e a n diff er e n c e of t h e tr e at m e nt 
gr o u p s will b e u s e d t o r e p ort t h e r ati o of t h e tr e at m e nt diff er e n c e i n t h e 
ori gi n al s c al e.
T h e s e c o n d ar y effi c a c y  v ari a bl e s ar e t h e f oll o wi n g:
 
C h a n g e i n m e a n a cti vit y ( c o u nt s p er mi n ut e) d uri n g sl e e p 
b et w e e n b a s eli n e p h a s e a n d w e e k 8 ( R a n d o mi z e d tr e at m e nt 
p h a s e)
 
C h a n g e i n m e a n a cti vit y d uri n g sl e e p b et w e e n b a s eli n e p h a s e 
a n d w e e k 1 ( R a n d o mi z e d tr e at m e nt p h a s e)
 
C h a n g e i n m e a n a cti vit y d uri n g sl e e p b et w e e n b a s eli n e p h a s e 
a n d w e e k 9 a n d 1 6 ( O p e n l a b el e xt e n si o n p h a s e )
 
C h a n g e i n m e a n a cti vit y c o u nt s d uri n g t h e m o st a cti v e 3 0 
mi n ut e s of t h e s u bj e ct’ s d a y b et w e e n b a s eli n e p h a s e a n d w e e k 
1 ( R a n d o mi z e d tr e at m e nt p h a s e )
 
C h a n g e i n m e a n a cti vit y c o u nt s d uri n g t h e m o st a cti v e 3 0 
mi n ut e s of t h e s u bj e ct’ s d a y b et w e e n b a s eli n e p h a s e a n d w e e k 9 
a n d 1 6 ( O p e n l a b el e xt e n si o n p h a s e )
D uri n g t h e r a n d o mi z e d tr e at m e nt p h a s e , m e a n c h a n g e fr o m b a s eli n e f or 
e a c h c o nti n u o u s v ari a bl e will b e a n al y z e d at e a c h ti m e p oi nt u si n g t h e 
s a m e A N C O V A m o d el a s f or t h e pri m ar y  effi c a c y v ari a bl e, a n d mi s si n g 
d at a will b e i mp ut e d u si n g t h e L O C F m et h o d.
D uri n g t h e o p e n l a b el e xt e n si o n p h a s e , c h a n g e fr o m b a s eli n e ( m e a n of 
w e e k - 1) f or e a c h c o nti n u o u s v ari a bl e will b e a n al y z e d at e a c h ti m e p oi nt 
u si n g p air e d t -t est s f or t h e gr o u p r a n d o mi z e d t o s a c u bitril/ v al s art a n . T h e 
a n al y s e s will b e r e p e at e d u si n g t h e w e e k 8 m e a s ur e m e nt a s b a s eli n e f or 
t h e gr o u p r a n d o mi z e d t o E n al a pril.
A s s u mi n g a si g nifi c a n c e l e v el of 0. 0 5, a t ot al s a m pl e si z e of 1 3 6 s u bj e ct s 
w o ul d pr o vi d e 9 0 % p o w er t o d et e ct a diff er e n c e of 5 0 0 0 i n t h e c h a n g e 
fr o m b a s eli n e i n me a n a cti vit y c o u nt s c oll e ct e d d uri n g t h e m o st a cti v e 3 0 
mi n ut e s b et w e e n t h e s a c u bitril/ v al s art a n tr e at m e nt gr o u p a n d t h e 
e n al a pril gr o u p d uri n g W e e k 8 , a s s u mi n g a c o m m o n st a n d ar d d e vi ati o n 
of 7 4 0 0 ( M a ur er 2 0 0 9 ) a n d a 2 0 % dr o p -o ut r at e a n d a 1 0 % r at e of 
s u bj e ct s wit h n o n -e v al u a bl e d at a.
A s s u mi n g a si g nifi c a n c e l e v el of 0. 0 5, a s a m pl e si z e of 1 3 6 s u bj e ct s 
w o ul d pr o vi d e 9 3 % p o w er t o d et e ct a 3. 5 p oi nt diff er e n c e i n t h e c h a n g e 
fr o m b a s eli n e i n m e a n a cti vit y v al u e d uri n g t h e sl e e p ( e x pr e s s e d a s 
c o u nt s p er mi n ut e) b et w e e n t h e s a c u bitril/ v al s art a n tr e at m e nt gr o u p a n d 
t h e e n al a pril gr o u p d uri n g W e e k  8, a s s u mi n g a c o m m o n st a n d ar d 
d e vi ati o n of 4. 9 a n d a 2 0 % dr o p -o ut r at e a n d a 1 0 % r at e of s u bj e ct s wit h 
n o n -e v al u a bl e d at a ( P et er s o n 2 0 1 2 )
K e y w or d s
H e art f ail ur e, H R e E F, P h y si c al A cti vit y, A cti gr a p h y,
w a k e

N o v arti s
C o nfi d e nti al
P a g e 1 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 
I ntr o d u cti o n
1. 1 
B a c k gr o u n d 
Fati g ue is t he car di nal s y m pt o m of heart fail ure ( H F); t he de gree t o w hic h H F i m pacts patie nts’ 
ca pacit y for p h y sical acti vit y an d restf ul slee p is t he pri mar y  effect or of healt h -relate d q ualit y 
of life ( H R-Q o L) f or t hese patie nts ( Re de ker 2 0 0 5 , Ma urer 2 0 0 9 ). Earl y real-w orl d cli nical 
e x perie nce wit h sac u bitril/ valsarta n has bee n ass ociate d wit h a nec d otal re p orts of cli nicall y-
mea ni n gf ul i m pr o ve me nts i n H R -Q o L f or s u bjects wit h heart fail ure a n d re d uce d ejecti o n 
fracti o n as earl y as s h ortl y after i nitiati o n of sac u bitril/ valsarta n t hera py ( d uri n g titrati o n t o 
tar get d ose). Alt h o u g h 
assess me nt of H R -Q o L 
i n P A R A DI G M -H F 
b y  questi o n naire 
de m o nstrate d t hat treat me nt wit h sac u bitril/ valsarta n sl o we d deteri orati o n of H R -Q o L i n 
c o m paris o n t o e nala pril, t he data di d n ot s h o w a statisticall y mea ni n gf ul i m pr o ve me nt i n H R -
Q o L , n or was t here a n y assess me nt of t he s h ort-ter m i m pact of treat me nt o n H R -Q o L  (J h u n d 
2 0 1 5 ).  More o ver, assess me nt of c ha n ges i n s h ort-ter m H R -Q o L i n H F s u bjects is si m pl y not 
feasi ble wit h c urre nt tra diti o nal q uesti o n naire -base d assess me nts d ue t o t he lac k of vali date d 
q uesti o n naires desi g ne d f or a s h ort-ter m recall peri o d a n d li mitati o ns i n se nsiti vit y ca use d b y  
t he i n here nt varia bilit y ass ociate d wit h t he s u bjecti ve nat ure of t hese i nstr u me nts. 
T o o bjecti vel y assess t he i m pact of i nitiati o n of sac u bitril/ valsarta n treat me nt vs e nala pril o n 
earl y H R -Q o L, we pr o p ose t his cli nical st u d y usi n g di gital se ns or tec h n ol o g y to assess p h y sical 
acti vit y d uri n g a wa ke a n d slee p, a n d s h ort-ter m recall s ym pt o m assess me nt i n o ut patie nt 
a m b ulat or y H F patie nts i n t heir h o me e n vir o n me nt. 
C h all e n g e s i n t h e a s s e s s m e nt of H R -Q o L
Vari o us o bjecti ve a n d s u bjecti ve p h y sical acti vit y assess me nt met h o ds ha ve bee n de vel o pe d. 
S u bjecti ve me t h o ds s uc h as q uesti o n naires, s ur ve ys a n d diaries are i ne x pe nsi ve t o ols t hat assess 
t he le vel of p h y sical acti vit y in a s u bjects’ e ver y da y life o utsi de of a cli nic, b ut ofte n rel y on 
i n di vi d ual o bser vati o ns a n d are s u bject t o patie nt recall (Wa n g 2 0 1 1 ) a n d re p orti n g bias (Sallis 
2 0 0 0 ). I nteresti n gly, t he be nc h mar k i nstr u me nts f or p h y sical assess me nt use s u bjecti ve 
j u d g me nts t o detect c ha n ges i n w hat is act uall y a  patter n of n o n- s u bjecti ve e ve nts. F or e xa m ple, 
t he Ka nsas Cit y  Car di o m yo pat h y Q uesti o n naire ( K C C Q) is a self-a d mi nistere d, 2 3- ite m 
q uesti o n naire t hat q ua ntifies p h y sical li mitati o ns, s ym pt o ms, self-efficac y, s ocial i nterfere nce 
a n d q ualit y  of life. T he p h y sical li mitati o n d o mai n of t his i nstr u me nt was desi g ne d t o detect 
cli nicall y si gnifica nt c ha n ges i n ca pacit y f or p h y sical acti vit y, a n d was vali date d a gai nst t he 6 
Mi n ute Wal k Test ( M W T) a n d p h y sical li mitati o n d o mai ns i n ot her acce pte d q uesti o n naire -
base i nstr u me nts ( G u yatt 1 9 8 5 ). 
I n c o m paris o n t o s u bjecti ve assess me nts, o bjecti ve tec h ni q ues li ke t he 6 M W T are i n here ntl y 
m ore se nsiti ve a n d re pr o d uci ble; h o we ver, t he y  tra diti o nall y d o n ot pr o vi de a n y mec ha nis m t o 
assess s u bjects’ p h y sical li mitati o n i n t he c o nte xt of t heir e ver yd a y  life. T he artificial cli nical 
setti n g i n w hic h tra diti o nal o bjecti ve assess me nts ta ke place li mits t he a bilit y of t hese 
i nstr u me nts t o detect p h ysical li mitati o n as e x perie nce d i n s u bjects’ e ver yda y  life. F urt her m ore, 
o bjecti ve tec h ni q ues s uc h as t he 6 M W T 
or S h ort P h y sical Perf or ma nce Batter y  (S P P B) 
(Vas u nilas h or n 2 0 0 9 ) ofte n i m p ose a b ur de n o n t he ti me a n d res o urces of cli nics perf or mi n g 

N o v arti s
C o nfi d e nti al
P a g e 1 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
t he m. T he e mer ge nce of t he use of weara ble di gital m o ve me nt se ns ors s uc h as acceler o meters 
f or meas uri n g p hys ical acti vit y all o ws f or t he ca pt ure of data t hat is b ot h o bjecti vel y meas ure d 
a n d ca pt ure d i n t he c o nte xt of s u bjects’ e ver yd a y  life. 
A c ti gr a p h y: a n e w a p pr o a c h t o a s se s s m e nt of p h y si c al a cti vit y
Acceler o meters are di gital se ns ors w hic h ca n be w or n o n t he wrist, t hi g h, tr u n k, or a n kles a n d 
meas ure t he accelerati o ns of t he de vice i n m oti o n al o n g refere nce a xes. Accelerati o n is 
pr o p orti o nal t o e xter nal f orce a n d t heref ore ca n reflect i nte nsit y a n d fre q ue nc y of h u ma n 
p h y sical acti vit y. T he meas ure me nt of acti vit y wit h a weara ble acceler o meter is k n o w n as 
acti gra p h y. Acti gra p hic assess me nt data fr o m a n acceler o meter t y picall y i n v ol ves i nte grati o n 
of accelerati o n data (c ollec te d i n u nits of ms- 1s- 1) wit h res pect t o ti me (C he n 2 0 0 5 ). 
Acceler o meters t y picall y sa m ple accelerati o n at a rate of 3 2 -1 0 0 Hz (c y cles per sec o n d). 
Accelerati o n data is c o n de nse d a n d st ore d i n t he de vice i n fi xe d ‘e p oc hs’ of ti me. 
Rece ntl y , acti gra p h y has bee n s uccessf ully 
use d i n pr os pecti ve i nter ve nti o nal st u dies t o 
assess t he i m pact of p har mac ol o gical 
treat me nt o n t he p hys ical acti vit y of s u bjects 
d uri n g b ot h slee p a n d wa ki n g peri o ds. A st u d y 
of at o pi c der matitis patie nts re p orte d t he use 
of acti gra p h y t o e val uate treat me nt i n d uce d 
re d ucti o n of itc h-relate d slee p disr u pti o n 
(Ne m ot o 2 0 1 6 ). N ota bly i n t his st u d y, t he 
assess me nt of t he i m pact of itc h o n slee p 
efficie nc y wit h acti gra p h y pr o ve d resista nt t o 
place b o effect w hic h is t y picall y o bser ve d 
w he n usi n g tra diti o nal i nstr u me nts t o assess itc h.   Acti gra p h y was als o s uccessf ull y use d t o 
assess t he i m pact of treat me nt wit h celec o xi b o n t he da yti me s ym pt o ms of pati e nts wit h 
oste oart hritis ( Tr u dea u 2 0 1 5 ).  I nteresti n gly, q uesti o n naire -base d assess me nt of pai n was 
s u bject t o a hi g h place b o res p o nse rate a n d di d n ot meet statistical si g nifica nce w hile 
acti gra p hic assess me nt of i ncrease i n s u bjects’ acti vit y  le vels de m o nstrate d a si g nifica nt 
treat me nt effect.  
Fi g ure 1 Tr a nsiti o n al c h a n ge ( me a n ± S E) i n acti gr a p hic all y
assesse d slee p efficie nc y. 

N o v arti s
C o nfi d e nti al
P a g e 1 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T h e i m p ort a n c e of p h y si c al a cti vit y i n H F
T he i na bilit y to perf or m e xercise or p h y sical acti vit y wit h o ut disc o mf ort ma y  be o ne of t he first 
s ym pt o ms e x perie nce d b y  patie nt s wit h H F a n d is a pri nci pal reas o n f or see ki n g me dical care. 
Heart fail ure is a maj or healt h pr o ble m, wit h a n i ncreasi n g i nci de nce a n d a gl o o m y pr o g n osis 
t hat is t ypicall y  acc o m pa nie d b y  an i ncreasi n g li mite d ca pacit y f or p h y sical acti vit y an d 
w orse ni n g o verall H R -Q o L  (Wiele n ga 1 9 9 7 ). 
P h y sical i nacti vit y al o ne is a seri o us pr o ble m a n d 
has bee n i de ntifie d as t he f o urt h lea di n g ris k fact or 
f or gl o bal m ortalit y  ca usi n g a n esti mate d 3. 2 milli o n 
deat hs w orl d wi de ( Cas perse n 1 9 8 5 , Steele 2 0 0 0).  
I n multi ple st u dies of H F patie nts, a re d ucti o n i n 
p h y sical act i vit y as meas ure d b y  acti gra p h y has 
bee n de m o nstrate d t o be str o n gl y pre dicti ve of b ot h 
m ortalit y  an d h os pitalizati o n (H o well 2 0 1 0 ). A 
st u d y of acti gra p h y data c ollecte d fr o m o n b oar d 
acceler o meters  
i n  
i m pla nte d  
car d i o verter 
defi brillat ors (I C Ds) f o u n d p h y sical acti vit y to be a 
str o n g pre dict or of o utc o me i n a lar ge c o h ort of H F 
patie nts (C o nraa ds 2 0 1 4 ). I n a d diti o n, a rece nt st u d y 
of 6 0 Ne w Y or k Heart Ass ociati o n ( N Y H A) III H F patie nts i de ntifie d t he s pecific acti vit y 
patter n feat ures of s ke w ness (a meas ure of t he s y m metr y of t he distri b uti o n c ur ve) a n d k urt osis
(a meas ure of t he s har p ness of t he pea k of t he distri b uti o n c ur ve) t o be i n de pe n de ntl y pre dicti ve 
of all-ca use m ortalit y (Meli n 2 0 1 6 ).  On t he ot her ha n d, a n i ncrease i n ca pacit y for p h y sical 
acti vit y has bee n s h o w n t o be be neficial f or H F patie nts. E xerc ise i n d uce d i m pr o ve me nt i n 
ca pacit y for acti vit y res ults i n a si g nifica nt i m pr o ve me nt i n all para meters of q ualit y  of life 
i ncl u di n g p hys ical, psyc h ol o gical, s ocial a n d e n vir o n me ntal d o mai ns ( B ocali ni 2 0 0 8 ). 
A c ti gr a p h y t o a s s e s s i m p a ct of H F m a n a g e m e nt o n p h ysi c al a cti vit y
T o date, o nl y  o ne st u d y has use d acti gra p h y t o assess treat me nt effects i n H F patie nts. A st u d y 
of t he effect of is os or bi de m o n o nitrate o n t he acti vit y le vels of H F patie nts wit h preser ve d 
ejectio n fracti o n use d acti gra p h y t o assess effects o n s u bjects’ m o ve me nt le vels o ver 6 wee ks 
(Re dfiel d 2 0 1 5 ). W hile t here was n o si g nifica nt bet wee n -gr o u p differe nce i n 6 M W T, or Q o L 
q uesti o n naire res ults ( K C C Q, Mi n nes ot a li vi n g wit h heart fail ure), acti gra p h y data re veale d a 
d ose -de pe n de nt tre n d t o war d l o wer acti vit y le vels a n d a statisticall y si g nifica nt decrease i n 
acti ve ti me per da y  in s u bjects i n t he hi g hest d ose treat me nt ar m.  Alt h o u g h t he re d ucti o n of 
acti vit y levels i n t he treat me nt gr o u p was u ne x pecte d, t his st u d y furt her de m o nstrate d t he 
se nsiti vit y of o bjecti ve assess me nts i n c o m paris o n t o tra diti o nal q uesti o n naire -base d 
a p pr oac hes.  It is n ote w ort h y t hat t here were si g nifica nt tec h nical li mitati o ns i n t he de v ice use d 
i n t his st u d y that ma y  ha ve c o ntri b ute d t o t he see mi n gly p ara d o xical res ults. T he acti vit y se ns or 
use d i n t his st u d y co m pile d a n d st ore d data i n 1 5 mi n ute e p oc hs; w hile t his has n o i m pact o n 
t he meas ure me nt of o verall acti vit y , gr o u pi n g acti vit y data i nt o e p oc hs t his le n gt h re d uce d t he 
Fi g ure 2 K a pl a n – Meier esti m ates f or t he i nci de nce of de at h or 
h os pit aliz ati o n. 8 3 4 p atie nts str atifie d i n 4 gr o u ps b ase d o n t he 
c o m bi n ati o n of p h ysic al acti vit y a n d t he C H A R M ris k sc ore. F or b ot h 
p ar a meters, t he me di a n v al ue ( 1 8 8 mi n/ d a n d 4. 8 p oi nts, res pecti vel y) is 
use d t o gr o u p p atie nts i n t he l o w or hi g h c ate g or y. ( C o nr a a ds 2 0 1 4)

N o v arti s
C o nfi d e nti al
P a g e 1 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
res ol uti o n of t he acti vit y data, a n d li mits o p p ort u nities f or t he assess me nt of acti vit y patter ns. 
Ot her acti gra p h y st u dies of patie nts wit h c hr o nic ill ness ha ve de m o nstrate d t hat m ore 
s ym pt o matic patie nts ha ve ge ner all y b ot h a re d ucti o n i n acti vit y whe n acti ve a n d are less still 
w he n resti n g, c o m pare d t o healt hier patie nts ( Ma urer 2 0 0 9 ).  If H F patie nts s pe n d m ost of t heir 
ti me at rest, treat me nt relate d i ncreases i n p h y sical acti vit y whe n acti ve ma y  be offset b y  a 
c o nc o mita nt re d ucti o n i n m o ve me nt w he n at rest. As a res ult, t his ca n a p pear as a si m ple 
decrease i n o verall acti vit y if acceler o metr y data is c o m pile d a n d a vera ge d o ver lar ge peri o ds 
of ti me ( w he n l o n g meas ure me nt e p oc hs are use d). 
Sl e e p a n d H F
Slee p is t he c o m pa ni o n H R -Q O L f u ncti o n t o p h ysical acti vit y, a n d is e q uall y im p orta nt as it 
fills t he p orti o n of t he da y  not a vaila ble f or p h y sical acti vit y. M ulti ple 
st u dies of slee p 
d y sf u ncti o n i n heart fail ure patie nts ha v e de m o nstrate d a n i ne xtrica ble ass ociati o n bet wee n 
slee p f u ncti o n, m ortalit y, a n d slee p- dis or dere d breat hi n g (Pe nzel 2 0 1 5 ).  Ot her st u dies als o 
s u g gest t hat slee p a p nea ma y  lea d t o t he pr o gressi o n of car diac d y sf u ncti o n i n H F patie nts 
(Ber ma n 1 9 9 1 ). T he a d verse effect o n car diac f u ncti o n pr o ba bl y arises fr o m re petiti ve a p neas 
ca usi n g e xcessi ve sti m ulati o n of t he s ym pat hetic ner v o us s yste m, arterial o x y he m o gl o bi n 
desat urati o n an d i ncreases i n s y ste mic bl o o d press ure (Bra dle y  1 9 9 6). T he i nci de nce of slee p -
dis or dere d breat hi n g, s pecifically ce ntral slee p a p nea, is hi g her i n t he c o n gesti ve heart fail ure 
( C H F) p o p ulati o n w here it has bee n de m o nstrate d t o be a n i n de pe n de nt pre dict or of m ortalit y 
(Kasai 2 0 1 2, La nfra nc hi 1 9 9 9 ). T here is als o e vi de nce of a c o m ple x ass ociati o n bet wee n 
ve ntric ular arr h yt h mias a n d slee p-dis or dere d breat hi n g (Si n 1 9 9 9 ) a n d data t hat s u g gests t he 
o bser ve d i ncrease i n m ortalit y  is t he res ult of i ncrease d i nci de nce of s u d de n deat h (Y u mi n o 
2 0 0 9, Kasai 2 0 1 2 ). I n a d diti o n, t he disc o nti n uit y of slee p by f re q ue nt ar o usals ma y als o lea d t o 
t he de vel o p me nt of e xcessi ve d a y ti me slee pi ness a n d fati g ue i n C H F patie nts wit h slee p a p neas 
(Ha nl y 1 9 9 5 ). I n HF patie nts, p o or slee p q ualit y  an d c o nti n uit y was c orrelate d wit h re d uce d 
da y ti me acti vit y, self-re p orte d p h ysical f u ncti o n, a n d me ntal healt h (Re de ker 2 0 0 5 ).   
1. 2 
P ur p o s e 
T he p ur p ose of this st u d y is t o i n vesti gate t he effects of i nitiati o n of sac u bitril/ valsarta n vs 
e nala pril treat me nt o n o bjecti ve meas ures of b ot h wa ki n g acti vit y an d slee p i n s u bjects wit h 
heart fail ure wit h re d uce d ejecti o n fracti o n. 
2 
St u d y  o bj e cti v e s a n d e n d p oi nt s
Meas ure me nts will be d o ne at wee ks - 1, 1, 8, 9 , a n d 1 6. Wee k 8
is c o nsi dere d t he pri mar y ti me 
p oi nt (e n d of d o u ble bli n d peri o d). 

N o v arti s
C o nfi d e nti al
P a g e 1 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
2. 1 
O bj e cti v e s a n d r el at e d e n d p oi nt s
T a bl e 2 - 1 
O bj e cti v e s a n d r el at e d e n d p oi nt s
O bjecti ve(s)
E n d p oi nt(s)
Pri m ar y O bjecti ve(s)

T he pri mar y  o bjecti ve is t o e val uate t he 
effect of i nitiati o n of sac u bitril/ valsarta n 
treat me nt vers us e nala pril o n p h ysical 
acti vit y d uri n g t he wa ki n g h o urs as a n 
o bjecti ve meas ure of p h ysical f u ncti o n .
E n d p oi nt(s) f or pri m ar y o bjecti ve(s) 

T he pri mar y  e n d p oi nt is t he c ha n ge i n 
mea n acti vit y c o u nts c ollecte d d uri n g 
t he m ost acti ve 3 0 mi n utes of t he 
s u bject’s da y bet wee n baseli ne p hase 
( mea n of data c ollecte d eac h da y d uri n g 
wee k - 1) a n d t he fi nal ra n d o mize d 
treat me nt p hase meas ure me nt ( mea n of 
e n d p oi nt data c ollecte d eac h da y  d uri n g 
wee k 8 ), as meas ure d b y wrist-w or n 
acceler o meter c ollecte d acti gra p h y 
(t otal c o u nts per 3 0 mi n peri o d 
c ollecte d d uri n g t he m ost acti ve 3 0 
mi n utes of eac h da y ).
Sec o n d ar y O bjecti ve(s)

T he sec o n dar y  o bjecti ve is t o e val uate 
t he effect of i nitiati o n of 
sac u bitril/ valsarta n treat me nt vers us 
e nala pril o n s u bjects’ slee p as a n 
o bjecti ve meas ure of p h ysical f u ncti o n .
E n d p oi nt(s) f or sec o n d ar y o bjecti ve(s)
T he sec o n d ar y e n d p oi nts i ncl u de:

C ha n ge i n mea n acti vit y  (c o u nts per 
mi n ute) d uri n g slee p bet wee n baseli ne 
p hase ( mea n of data c ollecte d d uri n g 
wee k - 1) a n d t he fi nal ra n d o mize d 
treat me nt p hase meas ure me nt ( mea n of 
data c ollecte d d uri n g wee k 8 ), as 
meas ure d b y acti gra p h y (acti vity c o u nts 
per mi n ute d uri n g dail y slee p peri o d, 
wrist -w or n acceler o meter).

T he c ha n ge i n mea n acti vit y  d uri n g 
slee p bet wee n baseli ne p hase ( mea n of 
data c ollecte d d uri n g t he ni g hts of wee k 
- 1) a n d eac h ra n d o mize d treat me nt a n d 
o pe n la bel p hase meas ure me nt , as 
meas ure d b y acti gra p h y (Wee k 1 , 9, 
a n d 1 6) (acti vit y  c o u nts per mi n ute 
d uri n g dail y slee p peri o d, wrist -w or n 
acceler o meter).

T he c ha n ge i n mea n acti vit y  c o u nts 
c ollecte d d uri n g t he m ost acti ve 3 0 
mi n utes of t he s u bject’s da y  bet wee n 

N o v arti s
C o nfi d e nti al
P a g e 2 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
O bjecti ve(s)
E n d p oi nt(s)
baseli ne p hase ( mea n of data c ollecte d 
eac h da y d uri n g wee k - 1 ) a n d eac h 
ra n d o mize d treat me nt a n d o pe n la bel 
p hase meas ure me nt (Wee k 1 , 9, a n d 
1 6),  as meas ure d b y wrist w or n 
acceler o meter c ollecte d acti gra p h y.

N o v arti s
C o nfi d e nti al
P a g e 2 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 2 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
3 
I n v e sti g ati o n al pl a n
3. 1 
St u d y d e si g n
T his st u d y is a m ultice nter, ra n d o mize d, d o u ble -bli n d, d o u ble d u m m y , parallel gr o u p, acti ve-
c o ntr olle d 8- wee k st u d y wit h o pe n la bel e xte nsi o n usi n g me dical de vice -gra de s u bject w or n 
se ns ors t o meas ure wa ki n g a n d slee pi n g p h y sical acti vit y i n t he a m b ulat or y o ut patie nt setti n g.  
T he 1 8 wee k st u d y  d urati o n will c o nsist of a 2-wee k baseli ne o bser vati o n p hase ( wit h s u bjects 
c o nti n ui n g t heir c urre nt heart fail ure dr u g t hera p y), f oll o we d b y  an 8 wee k bli n de d treat me nt 
p hase d uri n g w hic h s u bjects are ra n d o mize d ( 1: 1) t o eit her i nitiati o n of sac u bitril/ valsarta n 
treat me nt or e nala pril c o m parat or, a n d fi nally a n 8 wee k o pe n la bel e xte nsi o n p hase d uri n g 
w hic h all s u bjects are treate d wit h sac u bitril/ valsarta n.  Eac h s u bject will u n der g o a 3 6 h o ur 
was h o ut peri o d [d uri n g w hic h A C Ei ( A n gi ote nsi n c o n verti n g e nz y m e i n hi bit or), or st u d y dr u g 
will be wit h hel d ] bef ore t he start of t he ra n d o mize d, bli n de d treat me nt p hase, a n d a gai n bef ore 
be gi n ni n g t he o pe n la bel e xte nsi o n p hase. T he st u d y will i ncl u de 8 office visits a n d 5 tele-visits.
S u bjects will wear a wrist -w or n acti gra p h y de vi ce c o nti n u o usl y f or t he 1 8 wee k d urati o n of t he 
st u d y, fr o m t he ti me of e nr oll me nt (t he start of t he 2 wee k baseli ne p hase) t o t he e n d of t he 
o pe n -la bel e xte nsi o n p hase (e n d of treat me nt wee k 1 6).  Du ri n g t his 1 8 wee k i nter val, t he 
de vices will be e xc ha n ge d fi ve ti mes d uri n g fi ve st u d y visits, t o g uar d a gai nst data l oss a n d 
e ns ure a de q uate batter y  life. Data will be c ollecte d c o nti n u o usl y duri n g t he trial a n d alt h o u g h 
o nl y  data c ollecte d d uri n g assess m e nt peri o ds will c o ntri b ute t o pr os pecti vel y  defi ne d e n d p oi nts, 
ot her data m a y  be assesse d i n f ut ure a nal ys is of patter ns o bser ve d d uri n g t he st u d y. A d diti o nall y , 
c o nti n u o us wear re d uces o p p ort u nities f or la pses i n c o m plia nce w hile a d di n g ver y  mi ni mal 
assess me nt b ur de n f or s u bjects.  
Eac h assess me nt peri o d is se ve n c o nti g u o us da y s.  This will all o w f or c o nti n u o us acti gra p h y 
rec or di n g o ver t he se ve n da y peri o d,
 
 
 

N o v arti s
C o nfi d e nti al
P a g e 2 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
 
Fi g ur e 3- 1 
St u d y  d e si g n
3. 2 
R ati o n al e f or st u d y  d e si g n
T he desi g n of t he st u d y facilitates t he assess me nt of c ha n ge i n se q ue ntial dail y  ph y sical acti vit y, 
 H F s ym pt o ms a n d healt h -relate d q ualit y  of life; bet wee n baseli ne t o select ti me 
p oi nt 
assess me nt peri o ds 
after ra n d o mize d, bli n de d assi g n m e nt t o treat me nt wit h 
sac u bitril/ valsarta n vers us t he acti ve c o m parat or e nala pril. Assess me nt of t he pri mar y e n d p oi nt 
at 8 wee ks ca pt ures t he earl y i m pact of i nitiati o n of sac u bitril/ valsarta n vers us e nala pril, w hic h 
is t he f oc us of t he st u dy.
Wa ki n g acti vit y will be t he pri mar y  en d p oi nt, a n d slee p acti vit y (a meas ure of slee p dist ur ba nce) 
is t he sec o n dar y e n d p oi nt. Acti gra p h y, w hic h has bee n well c haracterize d f or t he meas ure me nt 
of b ot h da y ti me a n d slee p p h y sical acti vit y varia bles, will be use d t o i nf or m t he pri mar y  an d 
sec o n dar y e n d p oi nts. 
Pri or t o ra n d o mizati o n, t here will be a 2 wee k p hase w here de vice fa miliarizati o n a n d baseli ne 
assess me nt will be c o m plete d. T he i nitial baseli ne wee k will pr o vi de a n o p p ort u nit y  for t he 
s u bjects t o bec o me fa miliar a n d accli mate d t o t he testi n g de vices a n d assess me nt r o uti nes, pri or 
t o e nteri n g t he baseli ne p hase of t he st u d y. Data fr o m t he sec o n d wee k of t his p hase, t he 
‘ baseli ne p hase ’ (Wee k 
-1 ) will be c o nsi dere d as t he baseli ne val ue f or c o m paris o n t o 
s u bse q ue nt peri o ds. Data c ollecte d o utsi de of t he defi ne d meas ure me nt peri o ds will be e xcl u de d 
fr o m a nalys is f or t he defi ne d st u d y e n d p oi nts.
T he 3 6- h o ur was h -o ut i nter val after ra n d o mizati o n a n d bef ore e nteri n g t he o pe n -la bel e xte nsi o n 
is re q uire d per t he F D A a p pr o ve d U S PI la bel because t here is a p ote ntial f or i ncrease d ris k f or 
a n gi oe de ma i n s u bjects w h o 
recei ve b ot h a n A C E 
i n hi bit or a n d t he c o m bi nati o n of 
sac u bitril/ valsarta n. 
T he ra n d o mize d c o m paris o n p hase of 8 wee ks pr o vi des t he direct assess me nt of t he i nitial a n d 
earl y c ha n ges ass ociate d wit h sac u bitril/ valsarta n treat me nt t o treat me nt wit h t he acti ve 
c o m parat or e nala pril.

N o v arti s
C o nfi d e nti al
P a g e 2 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T he o pe n la bel p hase of 8 wee ks pr o vi des t he o p p ort u nit y  for e ver y su bject t o recei ve sac u bitril 
/ valsarta n.  T his res ults i n o ne gr o u p of s u bjects t hat will recei ve sac u bitril/ valsarta n f or a t otal 
of 1 6 wee ks, pr o vi di n g i nf or mati o n o n t he e n d p oi nts after t his d urati o n of c o nti n u o us t hera p y . 
It als o pr o vi des t he o p p ort u nit y  to e val uate c ha n ges after i nitiati n g sac u bitril/ valsarta n i n a 
gr o u p of s u bje cts w h o all ha d bee n pre vi o usl y  recei vi n g e nala pril treat me nt f or 8 wee ks.
T he s u bject p o p ulati o n will be descri be d i n m ore detail i n t he Secti o n 4 bel o w.
3. 4 
R ati o n al e f or c h oi c e of c o m p ar at or
Treat me nt wit h A C Ei has bee n well esta blis he d as t he sta n dar d of care f or re ni n–a n gi ote nsi n –
al d oster o ne s yste m ( R A A S) bl oc ka de a n d is rec o m me n de d b y  treat me nt g ui deli nes as a 1 A 
rec o m me n dati o n f or all s u bjects wit h C H F a n d re d uce d left ve ntric ular ejecti o n fracti o n  
( L V E F), u nless A C Ei- i nt olera nt. A d diti o nall y , A C Ei ma y  re d uce a ortic stiff ness b y  op p osi n g 
vas oc o nstricti ve, h y pertr o p hic, a n d pr ofi br otic effects of a n gi ote n si n II o n t he vessel wall.

N o v arti s
C o nfi d e nti al
P a g e 2 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
3. 5 
P ur p o s e a n d ti mi n g of i nt eri m a n al y s e s/ d e si g n a d a pt ati o n s
N ot a p plica ble.
3. 6 
Ri s k s a n d b e n efit s 
T he ris k t o s u bjects i n t his trial will be mi ni mize d b y  co m plia nce wit h t he eli gi bilit y criteria 
a n d st u d y pr oce d ures, cl ose cli nical m o nit ori n g, a n d t he pr o visi o n of resc ue o pti o ns.
E x perie nce i n t he P A R A DI G M -H F trial; b ot h i n t he r u n-i n p hase as well as t he d o u ble -bli n d 
ra n d o mizati o n p hase
i n dicate d t hat t he maj or 
ris ks ass ociate d wit h 
t he treat me nt of 
sac u bitril/ valsarta n are re nal d y sf u ncti o n, h y per kale mia, a n d h y p ote nsi o n. Res ults fr o m t he 
TI T R A TI O N st u d y in dicate d t hat s u bjects w h o m are A C Ei or A R B naï ve are at a n i ncrease d 
ris k of e x perie nci n g t hese a d verse e ve nts.
I n t his st u d y, t he ris k of e x perie nci n g re nal d y sf u ncti o n, h y per kal e mia, a n d h y p ote nsi o n are 
miti gate d i n t his st u d y  b y ap pr o priate u p- titrati o n of t he dr u g at wee ks 2, 4, 8, 1 0, a n d 1 2 . T he 
ris ks are f urt her miti gate d b y  ap pr o priate i ncl usi o n a n d e xcl usi o n criteria. S u bjects are e xcl u de d 
if t he y ha ve a p otassi u m > 5. 2 m m ol/l at scree ni n g.
Sac u bitril/ valsarta n ma y als o ca use a n gi oe de ma. T he ris k of de vel o pi n g a n gi oe de ma is 
i ncrease d if s u bjects ta ke b ot h a n A C Ei a n d sac u bitril/ valsarta n. T o decrease t his ris k, all 
s u bjects will u n der g o a 3 6 h o ur was h o ut peri o d bef ore e nteri n g t he ra n d o mize d p hase e p oc h 
a n d bef ore c o nti n ui n g i nt o t he o pe n -la bel treat me nt e p oc h t o mi ni mize t he i nteracti o n bet wee n 
a n A C Ei a n d sac u bitril/ valsarta n i n p ote ntiati n g t he de vel o p me nt of a n gi oe de ma.
All s u bjects will be all o we d t o c o nti n ue recei vin g t he rest of t heir bac k gr o u n d car di o vasc ular 
( C V) me dicati o ns t hr o u g h o ut t he st u d y. S u bjects will be ra n d o mize d t o st u d y treat me nt o nl y 
after t he i n vesti gat or has c o nfir me d t he s u bject is o n sta ble treat me nt wit h g ui deli ne -directe d 
t hera py f or heart failure wit h re d uce d ejecti o n fracti o n ( H Fr E F), ot her t ha n A C Eis a n d A R Bs, 
w hic h will e ns ure t hat s u bjects are recei vi n g a p pr o priate treat me nt f or t heir heart fail ure. 
I n t he P A R A DI G M -H F st u d y, sac u bitril/ valsarta n re d uce d t he ris k of car di o vasc ular ( C V) 
deat h, H F h os pitalizati o n a n d d ue t o t hese si g nifica nt res ults, sac u bitril/ valsarta n is n o w 
i n dicate d t o re d uce t hese ris ks i n s u bjects wit h c hr o nic heart fail ure ( N Y H A class II-I V) a n d 
re d uce d ejecti o n fracti o n.
4 
P o p ul ati o n
T he st u d y p o p ulati o n will c o nsist o f o ut patie nt male a n d fe male s u bjects, bet wee n 1 8 - 8 0 years 
of a ge, wit h H Fr E F N Y H A class II or III.  The g oal is t o ha ve a t otal of a p pr o xi matel y 13 6 
s u bjects ra n d o mize d, i n a p pr o xi matel y 2 5- 3 0 ce nters i n t he U nite d States. S u bjects m ust met 
all i ncl usi o n a n d n o ne of t he e xcl usi o n criteria.
4. 1 
I n cl u si o n crit eri a
S u bjects eli gi ble f or i ncl usi o n i n t his st u d y  m ust f ulfill all of t he f oll o wi n g criteria:

N o v arti s
C o nfi d e nti al
P a g e 2 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1.
Writte n i nf or me d c o nse nt m ust be o btai ne d bef ore a n y  assess me nt is perf or me d. 
2.
Me n a n d w o me n bet wee n 1 8 a n d 8 0 y ears of a ge
3.
S u bjects dia g n ose d wit h N Y H A class II or III heart fail ure a n d wit h re d uce d ejecti o n 
( H Fr E F) ( Re d uce d ejecti o n is defi ne d as left ve ntric ular E F ≤ 4 0 %.  L V E F ≤4 0 % ma y  be 
deter mi ne d via a n y l ocal meas ure me nt wit hi n t he past 6 m o nt hs pri or t o si g ni n g c o nse nt,
usi n g ec h ocar di o gra p h y, m ulti gate d ac q uisiti o n sca n ( M U G A), C T sca n ni n g, M RI or 
ve ntric ular a n gi o gra p h y pr o vi de d n o s u bse q ue nt st u d y  d oc u me nti n g a n E F of > 4 0 %.  If 
t he E F meas ure me nt is e x presse d as a val ue ra n ge, t he a vera ge of t he ra n ge e n d p oi nt 
val ues s h o ul d be use d as t he E F ).
4.
S u bjects m ust be a ca n di date f or treat me nt wit h sac u bitril/ valsarta n as per U S PI  
5.
S u bjects m ust be li vi n g i n a tra diti o nal resi de nce, a part me nt, or n o n -c o m m u nal a d ult h o me 
w here t he y  ca n m o ve a b o ut freely a n d fr e q ue ntl y a n d are pri maril y res p o nsi ble f or 
sc he d uli n g t heir slee p a n d dail y acti vities
4. 2 
E x cl u si o n crit eri a
S u bjects f ulfilli n g a n y of t he f oll o wi n g criteria are n ot eli gi ble f or i ncl usi o n i n t his st u d y. N o 
a d diti o nal e xcl usi o ns ma y  be a p plie d b y  the i n vesti gat or, i n or der t o e ns ure t hat t he st u d y 
p o p ulati o n will be re prese ntati ve of all eli gi ble s u bjects.
1.
S u bjects wit h a hist or y  of h yperse nsiti vit y  t o a ny of t he st u d y dr u gs, i ncl u di n g hist or y of 
h y perse nsiti vit y  t o dr u gs of si milar c he mical classes, or aller g y t o A C EIs, A R Bs, or N E P 
i n hi bit ors as well as k n o w n or s us pecte d c o ntrai n dicati o ns t o t he st u d y dr u gs.
2.
S u bjects wit h a hist or y  of a n gi oe de ma dr u g relate d or ot her wise
3.
S u bjects wit h s y m pt o matic h y p ote nsi o n or s ys t olic bl o o d press ure < 1 0 0 m m H g at 
scree ni ng or < 9 5 m m H g at ra n d o mizati o n.
4.
S u bjects wit h a n y  c o n diti o ns i n s ki n or u p per e xtre mities w hic h w o ul d li mit t he a bilit y t o 
t olerate a wrist-w or n acti gra p h y de vice o n t he n o n d o mi na nt ar m f or 2 4 h o urs/ da y f or t he 
d urati o n of t he st u d y .
5.
S u bjects u n willi n g or u na ble t o wear a n d o perate t he st u d y  meas ure me nt de vices f or t he 
p hases re q uire d.
6.
S u bjects w h o are c urre ntl y h os pitalize d, or were disc har ge d fr o m t he h os pital wit hi n 4 
wee ks pri or t o e nr oll me nt.
7.
S u bjects w h o are alrea d y ta ki n g sac u bitril/ valsarta n 
8.
S u bjec ts w h o are n o na m b ulat or y or use m o bilit y assisti ve de vices s uc h as m ot orize d 
de vices, w heelc hairs, or wal kers. T he use of ca nes f or sta bilit y  w hile a m b ulati n g is 
acce pta ble.
9.
S u bjects wit h p h y sical acti vit y i m pair me nt pri maril y  d ue t o c o n diti o ns ot her t ha n heart 
fail ure s uc h as:

E xerti o nal a n gi na

i nfla m mat or y or de ge nerati ve j oi nt disease

g o ut

peri p heral vasc ular disease

N o v arti s
C o nfi d e nti al
P a g e 2 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

ne ur ol o gic diseases affecti n g acti vit y or m o bilit y
1 0. S u bjects wit h n o nt y pical circa dia n be ha vi oral patter ns (f or e xa m ple: s hift w or kers acti vel y 
r otati n g s hifts, s u bjects wit h n o n- 2 4-h o ur slee p wa ke dis or der as res ult of bli n d ness)
1 1. S u bjects wit h tre m or, ri g or or m o bilit y  li mitati o ns affecti n g t he n o n d o mi na nt ar m (e. g. d ue 
t o Par ki ns o n’s disease, j oi nt c o ntract ures, paralys is, i nj ur y etc.)
1 2. S u bjects wit h c hr o nic o bstr ucti ve p ul m o nar y  disease ( C O P D) w h o re q uire s u p ple me ntal 
o x y ge n. 
1 3. S u bjects usi n g a c o nti n u o us p ositi ve air wa y  press ure ( C P A P) de vices or si milar 
tec h n ol o g y f or treat me nt of slee p dis or ders
1 4. S u bjects u n willi n g or u na ble t o refrai n fr o m t he use of prescri pti o n a n d/ or o ver t he c o u nter 
( O T C) slee p ai ds f or t he d urati o n of t he st u d y 
1 5. S u bjects wit h b o d y  mass i n de x ( B MI)  > 3 5
1 6. S u bjects wit h c hr o nic persiste nt atrial fi brillati o n.  
1 7. S u bjects wit h dia betes w h o are ta ki n g alis kire n.
1 8. S u bjects recei vi n g nesiriti de 
1 9. S u bjects ta ki n g bile aci d se q uesteri n g a ge nts s uc h as c h olest yra mi ne or c olesti p ol (t o 
a v oi d i nterfere nce wit h st u d y  dr u g a bs or pti o n).
2 0. S u bjects w h o are e nr olle d or partici pati n g as a s u bject i n a n y ot her cli nical trial i n v ol vi n g 
a n y i n vesti gati o nal a ge nt or i n vesti gati o nal de vice wit hi n 3 0 da ys bef ore scree ni n g.
2 1. S u bjects wit h a p otassi u m > 5. 2 m E q/ L  at scree ni n g. 
2 2. S u bject wit h a hist or y  of mali g na nc y of a ny or ga n s y ste m w h o ha ve a life e x pecta nc y of 
less t ha n 1 year.
2 3. Pre g na nt or n ursi n g (lactati n g) w o me n, w here pre g na nc y  is defi ne d as t he state of a fe male 
after c o nce pti o n a n d u ntil t he ter mi nati o n of gestati o n, c o nfir me d b y  a p ositi ve h u ma n 
c h ori o nic g o na d otr o pi n ( h C G) la b orat or y  test.
2 4. W o me n of c hil d - beari n g p ote ntial, defi ne d as all w o me n p h y si ol o gically ca pa ble of 
bec o mi n g pre g na nt, u nless t he y  are usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n 
d uri n g d osi n g a n d f or 7 da y s after st o p pi n g of st u d y me dicati o n. Hi g hly effecti ve 
c o ntrace pti o n met h o ds i ncl u de:
a.
T otal 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 lifestyl e of t he 
s u bject). Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s ym 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
b.
Fe male sterilizati o n ( ha ve ha d s ur gical bi lateral o o p h orect o m y wit h or wit h o ut 
h y sterect o my) t otal h ys terect o my or t u bal li gati o n at least si x wee ks bef ore ta ki n g 
i n vesti gati o nal dr u g. I n case of o o p h orect o my al o ne, o nl y w he n t he re pr o d ucti ve 
stat us of t he w o ma n has bee n c o nfir me d by f oll o w u p h or m o ne le vel assess me nt
c.
Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe male s u bjects o n t he 
st u d y, t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat s u bject
d.
Use of oral, (estr o ge n a n d pr o gester o ne), i njecte d or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n or place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s y ste m 
(I U S) or ot her f or ms of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y (fail ure 
rate < 1 %), f or e xa m ple h or m o ne va gi nal ri n g or tra ns der mal h or m o ne c o ntrace pti o n.

N o v arti s
C o nfi d e nti al
P a g e 2 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
I n case of use of oral c o ntrace pti o n w o me n s h o ul d ha ve bee n sta ble o n t he sa me pill f or a 
mi ni m u m of 3 m o nt hs bef ore ta ki n g i n vesti gati o nal dr u g.
W o me n are c o nsi dere d p ost -me n o pa usal a n d n ot of c hil d beari n g p ote ntial if t he y  ha ve ha d 1 2 
m o nt hs of nat ural (s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical pr ofile (e. g. a ge 
a p pr o priate, hist or y  of vas o m ot or s ym pt o ms) or ha ve ha d s ur gical bilateral o o p h orect o m y ( wit h 
or wit h o ut h y sterect o my) , t otal h y sterect o my o r t u bal li gati o n at least si x wee ks a g o. I n t he case 
of o o p h orect o m y al o ne, o nl y  whe n t he re pr o d ucti ve stat us of t he w o ma n has bee n c o nfir me d 
b y  f oll o w u p h or m o ne le vel assess me nt is s he c o nsi dere d n ot of c hil d beari n g p ote ntial.
5 
Tr e at m e nt
5. 1 
St u d y tr e at m e nt
5. 1. 1 
I n v e sti g ati o n al a n d c o ntr ol dr u g s
All eli gi ble s u bjects will be ra n d o mize d t o recei ve eit her sac u bitril/ valsarta n or e nala pril. T he 
f oll o wi n g st u dy treat me nt will be pr o vi de d:
T a bl e 5- 1 
I n v e sti g ati o n al a n d c o m p ar at or tr e at m e nt d uri n g t h e d o u bl e -bli n d 
e p o c h
Tr e at m e nt Ar m
N u m b er of 
S u bj e ct s
Mi ni m u m
d o s e
M a xi m u m 
d o s e
Fr e q u e n c y 
F or m ul ati o n
A d mi ni str ati o n 
R o ut e
s a c u bitril/ v al s art a n* 
6 8 
2 4/ 2 6 m g 
9 7/ 1 0 3 m g 
BI D
T a bl et
Or al
s a c u bitril/ v al s art a n
m at c hi n g pl a c e b o
Or al
e n al a pril
6 8 
2. 5 m g 
1 0 m g 
BI D
T a bl et
Or al
e n al a pril m at c hi n g 
pl a c e b o
Or al
*I n v e sti g ati o n al pr o d u ct l a b eli n g f or s a c u bitril/ v al s art a n d o s e l e v el s i s b a s e d o n t h e t ot al c o ntri b uti o n of b ot h c o m p o n e nt s of 
s a c u bitril/ v al s art a n a n d r e a d s, 5 0 m g, 1 0 0 m g a n d 2 0 0 m g. T hi s i s e q ui v al e nt t o t h e s a c u bitril/ v al s art a n d o s e l e v el s 2 4/ 2 6 m g, 
4 9/ 5 1 m g a n d 9 7/ 1 0 3 m g, r e s p e cti v el y.
T a bl e 5- 2 
Tr e at m e nt d o s e l e v el s d uri n g t h e d o u bl e -bli n d e p o c h
D o s e L e v el
S a c u bitril/ v al s art a n*
E n al a pril
1
2 4/ 2 6 m g or m at c hi n g pl a c e b o BI D
2. 5 m g or m at c hi n g pl a c e b o BI D
2
4 9/ 5 1 m g or m at c hi n g pl a c e b o BI D
5 m g or m at c hi n g pl a c e b o BI D
3
9 7/ 1 0 3 m g or m at c hi n g pl a c e b o BI D 
1 0 m g or m at c hi n g pl a c e b o BI D

N o v arti s
C o nfi d e nti al
P a g e 2 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
D o s e L e v el
S a c u bitril/ v al s art a n*
E n al a pril
*I n v e sti g ati o n al pr o d u ct l a b eli n g f or s a c u bitril/ v al s art a n d o s e l e v el s i s b a s e d o n t h e t ot al c o ntri b uti o n of b ot h c o m p o n e nt s of 
s a c u bitril/ v al s art a n a n d r e a d s, 5 0 m g, 1 0 0 m g a n d 2 0 0 m g. T hi s i s e q ui v al e nt t o t h e s a c u bitril/ v al s art a n d o s e l e v el s 2 4/ 2 6 m g , 
4 9/ 5 1 m g a n d 9 7/ 1 0 3 m g, r e s p e cti v el y.
B ot h sac u bitril/ valsarta n a n d e nala pril a n d t heir matc hi n g place b os will be pac ka ge d a n d 
la bele d b y  the s p o ns or i n acc or da nce wit h t he U S C o de of Fe deral Re g ulati o ns g o ver ni n g 
ha n dli n g of i n vesti gati o nal treat me nts, a n d will be dis pe nse d b y  t he st u d y p h ysicia n.
Sac u bitril/ valsarta n a n d e nala pril will be pac ka ge d se paratel y t o li mit t he n u m ber of pac k t y p es 
w hic h will all o w m ore fle xi bilit y  i n t he dr u g s u p pl y pr ocess t o c o ver all t he differe nt treat me nt 
p ossi bilities (treat me nt ar m a n d me dicati o n d ose le vel), see Ta ble 5 -2 a n d Ta ble 5 - 4. 
Pac ka gi n g t y pe is descri be d bel o w:

sac u bitril/ valsarta n a n d its matc hi n g place b o will be pr o vi de d i n hi g h-de nsit y  
p ol y et h yl e ne ( H D P E) b ottles.

e nala pril 2. 5 m g a n d its matc hi n g place b o will be pr o vi de d i n H D P E b ottles.

e nala pril 5 m g a n d 1 0 m g a n d its matc hi n g place b os will be pr o vi de d i n blister pac ks .
Eac h partici pati n g site will be pr o vi de d wit h a n i n vesti gati o nal dr u g s u p pl y co ntai ni n g D ose 
Le vels 1, 2, 3 a n d t heir matc hi n g place b os. B ottles a n d blister pac ks will be n u m bere d a n d 
assi g ne d via a n i nteracti ve res p o nse tec h n ol o g y  (I R T). Treat me nt f or t he da y of ra n d o mizati o n 
a n d all visits f or war d will be assi g ne d via I R T. 
All s u bjects will be gi n t he st u d y on D o se Le vel 1. At eac h s u bse q ue nt st u d y visit d uri n g t he 
d o u ble -bli n d e p oc h, t he st u d y  p h ysicia n will se q ue ntiall y u p-titrate t he st u d y dr u g d ose ( base d 
o n cli nical t olera nce a n d t he U S PI ) t o ac hie ve t he desire d d ose of D ose Le vel 3 ( 9 7/ 1 0 3 m g 
sac u bitril/ valsarta n BI D or 1 0 m g e nala pril BI D).
S u bjects n ot t olerati n g escalati o n fr o m D ose Le vel 1 t o D ose Le vel 2 ( or D ose Le vel 2 t o D ose 
Le vel 3) ca n be titrate d d o w n t o t he ne xt l o wer D ose Le vel (i ncl u di n g acti ve me dicati o n a n d 
matc hi n g 
place b os), if, i n t he i n vesti gat or’s j u d ge me nt, t he a dj ust me nt/eli mi nati o n of 
c o nc o mita nt me dicati o ns is n ot p ossi ble or d oes n ot alle viate t he si de effects of c o ncer n. S e e 
Secti o n 5. 5. 5 .
T his st u d y is desi g ne d as a d o u ble -bli n d, d o u ble -d u m m y  trial t o e ns ure bli n di n g d uri n g t he 
e ntire c o urse of t he st u d y. T o mai ntai n t he bli n di n g, s u bjects will be re q uire d t o ta ke t heir 
assi g ne d acti ve treat me nt ta blet al o n g wit h place b o matc hi n g t he o p p osite treat me nt t wice dail y .
T a bl e 5- 3 
I n v e sti g ati o n al tr e at m e nt d uri n g t h e o p e n l a b el e p o c h
Tr e at m e nt 
N u m b er of
s u bj e ct s
Mi ni m u m 
d o s e *
M a xi m u m 
d o s e
Fr e q u e n c y 
F or m ul ati o n 
R o ut e
O p e n -l a b el 
( s a c u bitril/
v al s art a n)
1 3 6 
2 4/ 2 6 m g 
9 7/ 1 0 3 m g 
BI D 
T a bl et 
Or al
* s a c u bitril/ v al s art a n 2 4/ 2 6 m g BI D ( D o s e L e v el 1) will b e gi v e n t o s u bj e ct s w h o c o m pl et e d t h e d o u bl e-bli n d tr e at m e nt e p o c h 
o n D o s e L e v el 1 a n d i s al s o a v ail a bl e if d o w n -titr ati o n i s r e q uir e d.

N o v arti s
C o nfi d e nti al
P a g e 3 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T a bl e 5- 4 
Tr e at m e nt D o s e L e v el s d uri n g t h e o p e n -l a b el e p o c h
D o s e L e v el *
S a c u bitril/ v al s art a n
1
2 4/ 2 6 m g BI D
2
4 9/ 5 1 m g BI D
3
9 7/ 1 0 3 m g BI D
* s a c u bitril/ v al s art a n 2 4/ 2 6 m g BI D ( D o s e L e v el 1) will b e gi v e n t o s u bj e ct s w h o c o m pl et e d t h e d o u bl e -bli n d 
tr e at m e nt e p o c h o n D o s e L e v el 1 a n d i s al s o a v ail a bl e if d o w n-titr ati o n i s r e q uir e d.
O pe n -la bel sac u bitril/ valsarta n will be pac ka ge d a n d la bele d by t he s p o ns or i n acc or da nce wit h 
t he U S C o de of Fe deral Re g ulati o n g o ver ni n g ha n dli n g of i n vesti gati o nal treat me nts, a n d will 
be dis pe nse d b y t he st u d y p h ys icia n.  O pe n-la bel treat me nt will be pr o vi de d f or 8 wee ks.
All s u bjects e nteri n g t he o pe n la bel-treat me nt e p oc h will be gi ve n sac u bitril/ valsarta n 4 9/ 5 1 m g 
BI D ( D ose Le vel 2) u nless t he y  co m plete d t he d o u ble -bli n d treat me nt e p oc h o n D ose Le vel 1. 
I nstea d, t hese s u bjects will e nter t he o pe n -la bel e p oc h o n sac u bitril/ valsarta n 2 4/ 2 6 m g BI D 
d ose ( D ose Le vel 1). At eac h s u bse q ue nt st u d y visit d uri n g t he o pe n -la bel e p oc h, t he st u d y 
p h y sicia n will se q ue ntiall y up- titrate t he st u d y dr u g d ose ( base d o n cli nical t olera nce a n d t he 
U S PI ) t o ac hie ve t he tar gete d desire d d ose of 9 7/ 1 0 3 m g sac u bitril/ valsarta n BI D ( D ose Le vel 
3). 
D uri n g t he o pe n la bel p hase , patie nts n ot t olerati n g t he escalati o n fr o m D ose Le vel 1 t o D ose 
Le vel 2 ( or D ose Le vel 2 t o D ose Le vel 3) ca n be titrate d d o w n t o t he ne xt l o wer D ose Le vel, 
if, i n t he i n vesti gat or’s j u d ge me nt, t he a dj ust me nt/eli mi nati o n of c o nc o mita nt me dicati o ns is 
n ot p ossi ble or d oes n ot alle viate t he si de effects of c o ncer n.  See Secti o n 5. 5. 5 .
5. 1. 2 
A d diti o n al tr e at m e nt
T he pr ot oc ol re q uire s s u bjects t o c o nti n ue t heir c urre nt heart fail ure dr u g t hera py, d uri n g t he 2 -
wee k baseli ne p hase.   
5. 2 
Tr e at m e nt ar m s
S u bjects will be assi g ne d at Da y  1 t o o ne of t he f oll o wi n g t w o treat me nt ar ms i n a 1: 1 rati o:

sac u bitril/ valsarta n; or,

e nala pril
S u bject s will be assi g ne d at Wee k 8 t o o pe n la bel e xte nsi o n p hase d uri n g w hic h all s u bjects 
will recei ve:

sac u bitril/ valsarta n

N o v arti s
C o nfi d e nti al
P a g e 3 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
5. 3 
Tr e at m e nt a s si g n m e nt a n d r a n d o mi z ati o n
At visit 3 all eli gi ble s u bjects/s u bjects will be ra n d o mize d via I nteracti ve Res p o nse Tec h n ol o g y 
(IR T) t o o ne of t he treat me nt ar ms. T he i n vesti gat or or his/ her dele gate will c o ntact t he I RT 
after c o nfir mi n g t hat t he s u bject f ulfills all t he i ncl usi o n/e xcl usi o n criteria. T he I R T will assi g n 
a ra n d o mizati o n n u m ber t o t he s u bject, w hic h will be use d t o li n k t he s u bject t o a treat me nt ar m 
a n d will s pecif y a uni q ue me dicati o n n u m ber f or t he first pac ka ge of st u d y dr u g t o be dis pe nse d 
t o t he s u bject. 
T he ra n d o mizati o n n u m bers will be ge nerate d usi n g t he f oll o wi n g pr oce d ure t o e ns ure t hat 
treat me nt assi g n me nt is u n biase d a n d c o nceale d fr o m s u bject a n d i n vesti gat or staff. A s u bject 
ra n d o mizati o n list will be pr o d uce d b y  the I RT pr o vi der usi n g a vali date d s yste m t hat a ut o mates 
t he ra n d o m assi g n me nt of s u bject n u m bers t o ra n d o mizati o n n u m bers. T hese ra n d o mizati o n 
n u m bers are li n ke d t o t he differe nt treat me nt ar ms, w hic h i n t ur n are li n ke d t o me dicati o n 
n u m bers. A se parate me dicati o n list will be pr o d uce d b y or u n der t he res p o nsi bilit y of N o vartis 
Dr u g S u p pl y  Ma na ge me nt usi n g a vali date d s yste m t hat a ut o mates t he ra n d o m assi g n me nt of 
me dicati o n n u m bers t o pac ks c o ntai ni n g t he i n vesti gati o nal dr u g(s).
T he ra n d o mizati o n sc he me f or s u bjects will be re vie we d a n d a p pr o ve d b y a me m ber of 
Bi o metrics U S C D M A.  
5. 4 
Tr e at m e nt bli n di n g 
S u bjects, i n vesti gat or staff, pers o ns perf or mi n g t he assess me nts, data a nal ysts a n d t he Cli nical 
Trial Tea m ( C T T) will re mai n bli n d t o t he i de ntit y of t he treat me nt fr o m t he ti me of 
ra n d o mizati o n u ntil data base l oc k, usi n g t he f oll o wi n g met h o ds: ( 1) Ra n d o mizati o n data are 
ke pt strictl y  c o nfi de ntial u ntil t he ti me of u n bli n di n g, a n d will n ot be accessi ble b y a ny o ne else 
i n v ol ve d i n t he st u d y wit h t he e xce pti o n of t he I RT pr o vi der ge nerati n g t he ra n d o mizati o n c o de. 
( 2) T he i de ntit y of t he treat me nts will be c o nceale d b y t he use of i n vesti gati o nal treat me nts t hat 
are i de ntical i n pac ka gi n g, la beli n g, a n d sc he d ule of a d mi nistrati o n, a p peara nce, taste a n d o d or.
A d o u ble -d u m m y desi g n is use d beca use t he i de ntit y of t he st u d y dr u g ca n n ot be dis g uise d, as 
t he dr u g pr o d ucts are visi bl y  differe nt. T o mai ntai n t he bli n di n g, s u bjects will be re q uire d t o 
ta ke t heir assi g ne d acti ve treat me nt ta blet al o n g wit h place b o matc hi n g t he o p p osite treat me nt 
t wice daily.
U n bli n d i n g will o nl y occ ur i n t he case of s u bject e mer ge ncies (see Secti o n 5. 6 ) a n d at t he 
c o ncl usi o n of t he st u d y.
5. 5 
Tr e ati n g t h e p ati e nt 
S p o ns or q ualifie d me dical pers o n nel will be rea dil y a vaila ble t o a d vise o n trial relate d me dical 
q uesti o ns or pr o ble ms.
5. 5. 1 
S u bj e ct N u m b eri n g
Eac h s u bject is 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 his/ her ce nter n u m ber a n d 
s u bject n u m ber. T he ce nter n u m ber is assi g ne d b y  No vartis t o t he i n vesti gati ve site. U p o n 
si g ni n g t he i nf or me d c o nse nt f or m, t he s u bject is assi g ne d a s u bject n u m ber b y t he i n vesti gat or. 
At eac h site, t he first s u bject is assi g ne d s u bject n u m ber 1, a n d s u bse q ue nt s u bjects are assi g ne d 

N o v arti s
C o nfi d e nti al
P a g e 3 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
c o nsec uti ve n u m bers (e. g. t he sec o n d s u bject is assi g ne d s u bject n u m ber 2, t he t hir d s u bject is 
assi g ne d s u bject n u m ber 3). T he i n vesti gat or or his/ her staff will c o ntact t he I RT a n d pr o vi de 
t he re q ueste d i de ntif yi n g i nf or mati o n f or t he s u bject t o re gister t he m i nt o t he I R T. O nl y t he 
assi g ne d s u bject n u m ber m ust be e nt ere d i n t he fiel d la bele d “ S u bject I D” o n t he E D C data 
e ntr y scree n (e. g. e nter ‘ 1’, ‘ 2’, etc.). O nce assi g ne d t o a s u bject, t he s u bject n u m ber will n ot be 
re use d. If t he s u bject fails t o be ra n d o mize d f or a n y reas o n, t he I R T m ust be n otifie d wit hi n 2 
da y s t hat t he s u bject was n ot ra n d o mize d. 
5. 5. 2 
Di s p e n si n g t h e st u d y dr u g 
Eac h st u d y site will be s u p plie d wit h st u d y  dr u g i n pac ka gi n g of i de ntical a p peara nce.
N o vartis will s u p pl y eac h st u d y site wit h t he ra n d o mize d a n d o pe n-la bel treat me nt i n cli nical 
trial pac ka gi n g. T he st u d y dr u g pac ka gi n g has a 2- part la bel. A u ni q ue ra n d o mizati o n n u m ber 
is pri nte d o n eac h part of t his la bel w hic h c orres p o n ds t o o ne of t he “ n” treat me nt ar ms a n d a 
[s pecific visit or d ose/ d ose le vel]. I n vesti gat or staff will i de ntif y the st u dy dr u g pac ka ge(s) t o 
dis pe nse t o t he s u bject b y  co ntacti n g t he I R T a n d o btai ni n g t he me dicati o n n u m ber(s). 
I m me diatel y bef ore dis pe nsi n g t he pac ka ge t o t he patie nt, i n vesti gat or staff will detac h t he o uter 
part of t he la bel fr o m t he pac ka gi n g a n d affi x it t o t he s o urce d oc u me nt ( Dr u g La bel F or m) f or 
t hat s u bject’s u ni q ue s u bject n u m ber.
5. 5. 3 
H a n dli n g of st u d y  a n d a d diti o n al tr e at m e nt
N o a d diti o nal treat me nt is pr o vi de d as part of t he st u d y
5. 5. 3. 1 
H a n dli n g of st u d y  tr e at m e nt
St u d y  treat me nt m ust be recei ve d b y  a desi g nate d pers o n at t he st u d y site, ha n dle d a n d st ore d 
safely a n d pr o perl y, a n d ke pt i n a sec ure d l ocati o n t o w hic h o nl y t he i n vesti gat or a n d desi g nees 
ha ve access. U p o n recei pt, all st u d y treat me nt m ust be st ore d accor di n g t o t he i nstr ucti o ns 
s pecifie d o n t he la bels. Cli nical s u p plies are t o be dis pe nse d o nl y i n acc or da nce wit h t he 
pr ot oc ol. Tec h nical c o m plai nts are t o be re p orte d t o t he res pecti ve N o vartis C P O Q ualit y 
Ass ura nce. Me dicati o n la bels will i ncl u de st ora ge c o n diti o ns b ut n o i nf or mati o n a b o ut t he 
s u bject e xce pt f or t he me dicati o n n u m ber. 
T he i n vesti gat or m ust mai ntai n a n acc urate rec or d of t he s hi p me nt a n d dis pe nsi n g of st u d y 
treat me nt i n a dr u g acc o u nta bilit y l o g. M o nit ori n g of dr u g acc o u nta bilit y will be perf or me d b y 
m o nit ors d uri n g site visits or re m otel y a n d at t he c o m pleti o n of t he trial. S u bjects will be as ke d 
t o ret ur n all u n use d st u d y treat me nt a n d pac ka gi n g at t he e n d of t he st u d y or at t he ti me of 
disc o nti n uati o n of st u d y  treat me nt. 
At t he c o ncl usi o n of t he st u d y, a n d as a p pr o priate d uri n g t he c o urse of t he st u d y, t he i n vesti gat or 
will ret ur n all u n use d st u d y treat me nt, pac ka gi n g, dr u g la bels, a n d a c o p y o f t he c o m plete d dr u g 
acc o u nta bilit y lo g t o t he N o vartis m o nit or or t o t he N o vartis a d dress pr o vi de d i n t he i n vesti gat or 
f ol der at eac h site.
5. 5. 3. 2 
H a n dli n g of a d diti o n al tr e at m e nt
N ot a p plica ble.

N o v arti s
C o nfi d e nti al
P a g e 3 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
5. 5. 4 
I n str u cti o n s f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt
N o vartis will s u p pl y the i n vesti gat ors wit h all me dicati o ns s ufficie nt f or t he c o urse of t he st u d y. 
S u bjects will be pr o vi de d wit h me dicati o n pac ks c o ntai ni n g st u d y dr u g c orres p o n di n g t o t heir 
assi g ne d treat me nt ar m a n d d ose le vel, s ufficie nt t o last u ntil t he ne xt sc he d ule d visit. St u d y  
me dicati o n s h o ul d be ta ke n wit h a gl ass of water wit h or wit h o ut f oo d. If t he patie nt misses 
ta ki n g a ny st u d y dr u g d ose, he/s he s h o ul d ta ke it as s o o n as p ossi ble, u nless it is wit hi n 4 h o urs 
f or t he f oll o wi n g sc he d ule d d ose. I n this case, t he patie nt s h o ul d s ki p t he misse d d ose a n d ret ur n 
bac k t o his/ her re g ular st u d y  dru g a d mi nistrati o n sc he d ule.
I n or der t o a de q uatel y bli n d t he st u d y, patie nts will be re q uire d t o ta ke t heir assi g ne d acti ve 
treat me nt ta blet al o n g wit h place b o matc hi n g t he o p p osite treat me nt t wice dail y . S u bjects will 
be i nstr ucte d t o ta ke a t otal of t w o ta blets b y m o ut h t wice a da y f or t he d urati o n of t he d o u ble-
bli n d treat me nt e p oc h, as f oll o ws:

O ne ta blet fr o m t he sac u bitril/ valsarta n – sac u bitril/ valsarta n matc hi n g place b o pac k, a n d;

O ne ta blet fr o m t he e nala pril - e nala pril matc hi n g place b o pac k
Ta ble 5- 5 s u m marizes t he st u d y dr u g t hat will be ta ke n d uri n g t he d o u ble -bli n d treat me nt e p oc h 
b y  visit a n d Ta ble 5 - 6 s u m marizes t he st u d y dr u g t hat will be ta ke n d uri n g t he o pe n -la bel 
treat me nt e p oc h.

N o v arti s
C o nfi d e nti al
P a g e 3 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
F orce d -titrati o n will pr ocee d acc or di n g t o t he f oll o wi n g ta ble:
T a bl e 5- 5 
St u d y  dr u g di s p e n s e d d uri n g d o u bl e-bli n d tr e at m e nt e p o c h
Vi sit
D o s e 
L e v el
S a c u bitril/ v al s art a n **
E n al a pril
R o ut e 
Ti mi n g
R a n d o/ Vi sit 3 
1 a, b
2 4/ 2 6 m g or 
m a t c hi n g pl a c e b o BI D
2. 5 m g or 
m a t c hi n g pl a c e b o BI D
Or al 
A M & P M
W e e k  2/ Vi sit 5  
2 c/ 3d
4 9/ 5 1 m g / 9 7/ 1 0 3 m g 
or 
m a t c hi n g pl a c e b o BI D
5 m g or 
m a t c hi n g pl a c e b o BI D
Or al 
A M & P M
W e e k  4/Vi sit 6  
2 c/ 3d
4 9/ 5 1 m g / 9 7/ 1 0 3 m g 
or m at c hi n g pl a c e b o 
BI D
1 0 m g or 
m a t c hi n g pl a c e b o BI D
Or al 
A M & P M
**I n v e sti g ati o n al pr o d u ct l a b eli n g f or s a c u bitril/ v al s art a n d o s e l e v el s i s b a s e d o n t h e t ot al c o ntri b uti o n of b ot h 
c o m p o n e nt s of s a c u bitril/ v al s art a n a n d r e a d s, 5 0 m g, 1 0 0 m g a n d 2 0 0 m g. T hi s i s e q ui v al e nt t o t h e 
s a c u bitril/ v al s art a n d o s e l e v el s 2 4/ 2 6 m g, 4 9/ 5 1 m g a n d 9 7/ 1 0 3 m g, r e s p e cti v el y.
a. I niti al st arti n g d o s e ( L e v el 1) Eli gi bl e p ati e nt s will b e r a n d o mi z e d vi a I R T t o eit h er s a c u bitril/ v al s art a n or 
e n al a pril, D o s e L e v el 1.
b. A v ail a bl e aft er R a n d o/ Vi sit 3 t o e n d of d o u bl e - bli n d tr e at m e nt e p o c h o nl y if D o s e L e v el s 2 a n d 3 ar e n ot 
t ol er at e d d e s pit e m o difi c ati o n of ot h er n o n-di s e a s e -m o dif yi n g H F m e di c ati o n s a n d r e -c h all e n g e.
c. O nl y if D o s e L e v el 3 i s n ot t ol er at e d d e s pit e m o difi c ati o n of ot h er n o n -di s e a s e - m o dif yi n g H F m e di c ati o n s a n d 
r e-c h all e n g e.
d. T hi s t ar g et D o s e L e v el m u st b e m ai nt ai n e d f or a s l o n g a d ur ati o n a s p o s si bl e. If d o w n -titr ati o n i s n e c e s s ar y 
d u e t o si d e eff e ct s, t h e p ati e nt s h o ul d b e r e -c h all e n g e d a s s o o n a s m e di c all y p o s si bl e p er t h e i n v e sti g at or’ s 
j u d g m e nt.

At Ra n d o mizati o n o n Da y  1 ( Visit 3, e nr olle d s u bjects will be ra n d o mize d via IR T t o 
eit her sac u bitril/ valsarta n or e nala pril. All s u bjects will start at D ose Le vel 1 ( 2. 5 m g 
e nala pril or 2 4/ 2 6 m g sac u bitril/ valsarta n, BI D).

At Wee k 1 ( Visit 4), s u bjects will ha ve a tele p h o ne visit.  

At Wee k 2 ( Visit 5), s u bjects will be f orce -titrate d t o t he ne xt d ose, D ose Le vel 2 ( 5 m g 
e nala pril or 4 9/ 5 1 m g sac u bitril/ valsarta n, BI D) or D ose Le vel 3 ( 1 0 m g e nala pril or 
9 7/ 1 0 3 m g sac u bitril/ valsarta n, BI D) a n d re mai n o n t his d ose t hr o u g h t he e ve ni n g d ose 
pri or t o Wee k 4 ( Visit 6).

At Wee k 4 ( Visit 6), s u bjects will be f orce -titrate d t o t he ne xt d ose, D ose Le vel 2 ( 5 m g 
e nala pril or 4 9/ 5 1 m g sac u bitril/ valsarta n, BI D) or D ose Le vel 3 ( 1 0 m g e nala pril or 
9 7/ 1 0 3 m g sac u bitril/ valsarta n, BI D) a n d re mai n o n t his d ose t hr o u g h t he e ve ni n g d ose 
pri or t o Wee k 8 ( Visit 8).

At Wee k 6 ( Visit 7), s u bjects will ha ve a tele p h o ne visit.

All s u bjects t hat c o m plete t he 8 wee k d o u ble -bli n d treat me nt e p oc h will pr ocee d i nt o t he 
8- wee k o pe n -la bel e p oc h o n sac u bitril/ valsarta n.

At Wee k 8 ( Visit 8 ), Dr u g acc o u nta bility will be perf or me d a n d all d o u ble -bi n d treat me nt 
me dicati o n will be re t ur ne d t o t he site.

N o v arti s
C o nfi d e nti al
P a g e 3 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

O pe n -la bel sac u bitril/ valsarta n will be dis pe nse d at Wee k 8 ( Visit 8 ) wit h s u bject’s 
i nstr ucti o ns N O T t o start t heir o pe n la bel-treat me nt u ntil after c o m pleti n g a 3 6-h o ur was h 
o ut. All patie nts will ha ve t he was h o ut i n or der t o mai ntai n t he bli n di n g of t he c ore st u d y. 
All d ose le vels will be a vaila ble t hr o u g h o ut t he st u d y. D ose a dj ust me nts t o l o wer d ose le vels 
ma y  b e ma de at a n y ti me at b ot h sc he d ule d a n d u nsc he d ule d visits o nl y  if in dicate d f or bl o o d 
press ure c o ntr ol/t olera bilit y  reaso ns.
All st u d y  treat me nt assi g ne d b y t he I R T will be rec or de d/ data base d i n t he I R T.
All d osa ges prescri be d a n d dis pe nse d t o t he s u bject a n d all d ose c ha n ges d uri n g t he st u d y m ust 
be rec or de d i n t he I R T a n d o n t he D osa ge A d mi nistrati o n Rec or d e C R F.
St u d y  medicati o n s h o ul d be ta ke n t wice dail y wit h a glass of water wit h or wit h o ut f o o d. 
If t he s u bject misses ta ki n g a n y st u d y dru g d ose, he/s he s h o ul d ta ke it as s o o n as p ossi ble a n d 
wit hi n 4 h o urs of t he sc he d ule d d ose ti me. If t he patie nt is u na ble t o ta ke t he misse d d ose wit hi n 
4 h o urs of t he sc he d ule d d ose ti me, he/s he s h o ul d s ki p t he misse d d ose a n d ret ur n bac k t o his/ her 
re g ular st u dy dr u g a d mi nistrati o n sc he d ule.
T he i n vesti gat or m ust pr o m ote c o m plia nce b y  instr ucti n g t he s u bject t o ta ke t he st u d y treat ment 
e xactl y as prescri be d a n d b y  stati n g t hat c o m plia nce is necessar y  for t he s u bject’s safety a n d 
t he vali dit y  of t he st u d y. T he s u bject m ust als o be i nstr ucte d t o c o ntact t he i n vesti gat or if he/s he 
is u na ble f or a ny reas o n t o ta ke t he st u d y treat me nt as prescri be d.
T a bl e 5- 6 
St u d y  dr u g di s p e n s e d d uri n g o p e n-l a b el tr e at m e nt e p o c h
Vi sit
D o s e L e v el
S a c u bitril/ 
v al s art a n**
R o ut e
Ti mi n g
W e e k  8/ Vi sit 8
W e e k s 1 0 -1 6
1
2 4/ 2 6 m g
Or al
A M & P M
2
4 9/ 5 1 m g
Or al
A M & P M
3
9 7/ 1 0 3 m g
Or al
A M & P M
**I n v e sti g ati o n al pr o d u ct l a b eli n g f or s a c u bitril/ v al s art a n d o s e l e v el s i s b a s e d o n t h e t ot al c o ntri b uti o n of b ot h 
c o m p o n e nt s of s a c u bitril/ v al s art a n a n d r e a d s, 5 0 m g, 1 0 0 m g a n d 2 0 0 m g. T hi s i s e q ui v al e nt t o t h e 
s a c u bitril/ v al s art a n d o s e l e v el s 2 4/ 2 6 m g, 4 9/ 5 1 m g a n d 9 7/ 1 0 3 m g, r e s p e cti v el y.

All s u bjects e nteri n g t he o pe n-la bel treat me nt e p oc h will start o pe n-la bel treat me nt o n 
sac u bitril/ valsarta n 4 9/ 5 1 m g BI D ( D ose Le vel 2) u nless t he y c o m plete d t he d o u ble-bli n d 
treat me nt e p oc h o n D ose Le vel 1. I nstea d, t hese s u bjects will e nter t he o pe n-la bel e p oc h 
o n sac u bitril/ valsarta n 2 4/ 2 6 m g BI D d ose ( D ose Le vel 1).

St u d y  treat me nt will be f orce-titrate d e ver y 2 wee ks t o reac h t he tar get d ose of sac u bitril 
/ valsarta n 9 7/ 1 0 3 m g BI D ( D ose Le vel 3).

N o v arti s
C o nfi d e nti al
P a g e 3 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
Sc he d ule a n d d ose a dj ust me nts will o nl y  be all o we d if, i n t he i n vesti gat or’s j u d ge me nt, t he 
a dj ust me nt/eli mi nati o n of c o nc o mita nt me dicati o ns is n ot p ossi ble or d oes n ot alle viate t he si de 
effects of c o ncer n. See Secti o n 5. 5. 5 .
5. 5. 5 
P er mitt e d d o s e a dj u st m e nt s a n d i nt err u pti o n s of st u d y  tr e at m e nt 
E ver y  atte m pt s h o ul d be ma de t o mai ntai n s u bjects o n t he tar get st u d y dr u g d ose le vel f or as 
l o n g as p ossi ble t hr o u g h o ut t he st u d y.  If, h o we ver, i n t he o pi ni o n of t he i n vesti gat or, a s u bject 
is u na ble t o t olerate t he pr ot oc ol -s pecifie d tar get d ose, t he i n vesti gat or s h o ul d c o nsi der w het her 
d ose a dj ust me nts of c o nc o mita nt me dicati o ns ma y rectif y the sit uati o n bef or e re d uci n g t he d ose 
of st u d y treat me nt. If a dj ust me nt of t he c o nc o mita nt me dicati o ns is n ot p ossi ble or d oes n ot 
alle viate t he si de effects of c o ncer n, t he i n vesti gat or m a y  do w n -titrate t he d ose of t he st u d y dr u g 
t o t he pre vi o us d ose le vel. If nee de d, t he st u d y dr u g ma y be st o p pe d c o m pletel y, if t his occ urs, 
the s u bject s h o ul d ret ur n t o t he cli nic as s o o n as p ossi ble, after disc o nti n uati o n of st u d y dr u g, 
f or a n e n d of st u d y visit.  S u bjects ma y  restart t heir c urre nt d ose of st u d y dr u g f oll o wi n g a n 
i nterr u pti o n of treat me nt, base d o n i n vesti gat or j u d g me nt.  
St u d y  dr u g d ose le vel a dj ust me nts s h o ul d be mai nl y  base d o n o verall safet y an d t olera bilit y 
wit h s pecial f oc us o n:

H y per kale mia

S y m pt o matic h y p ote nsi o n

Cli nicall y  si g nifica nt decrease i n e G F R/i ncrease i n ser u m creati ni ne ( defi ne d as a 
ser u m creati ni ne of ≥0. 5 m g/ dl wit h at least a 2 5 % decrease i n e G F R).
T hese c ha n ges m ust be rec or de d o n t he D osa ge A d mi nistrati o n Rec or d C R F.
A dj ust me nt of st u d y dr u g d ose le vel
T a bl e 5- 7  
S af et y  a n d t ol er a bilit y g ui d a n c e f or d o s e a dj u st m e nt s
P ar a m et er
Crit eri a
P ot a s si u m l e v el
K > 5. 3 m E q/ L
Ki d n e y f u n cti o n

e G F R re d ucti o n ≥ 3 5 % c o m pare d t o baseli ne; 
O R,
ser u m creati ni ne of ≥0. 5 m g/ dl wit h at least a 2 5 % 
decrease i n e G F R
Bl o o d pr e s s ur e

N o s y m pt o matic h y p ote nsi o n or S B P ˂ 9 0 m m H g
A d v er s e e v e nt s ( A E s) or c o n diti o n s

N o p ost ural s y m pt o ms or a n y  c o n diti o ns t hat 
precl u de c o nti n uati o n acc or di n g t o t he 
i n vesti gat or’s j u d g me nt

N o v arti s
C o nfi d e nti al
P a g e 3 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
E ver y  atte m pt s h o ul d be ma de t o mai ntai n s u bjects o n tar get st u d y dr u g D ose Le vel 3 f or as 
l o n g as p ossi ble t hr o u g h o ut t he st u d y . If, h o we ver, i n t he o pi ni o n of t he i n vesti gat or, a patie nt 
is u na ble t o t olerate t he pr ot oc ol -s pecifie d tar get d ose, t he i n vesti gat or will ma na ge t he patie nt’s 
treat me nt acc or di n g t o t he bel o w g ui deli nes:
Ste ps:
1.
A dj ust C o nc o mit a nt Me dic ati o ns

D ose a dj ust me nts/eli mi nati o n of c o nc o mita nt me dicati o ns ma y  re me d y t he sit uati o n 
bef ore re d uci n g t he d ose of st u d y treat me nt. If a dj ust me nt of t he c o nc o mita nt 
me dicati o ns is n ot p ossi ble or d oes n ot alle viate t he si de effects of c o ncer n, T H E N;
2.
A dj ust St u d y Tre at me nt D ose Le vel

D o w n -titrate st u d y treat me nt t o t he pre vi o us d ose le vel. T he s u bject ma y c o nti n ue 
recei vi n g t he l o wer d ose le vel f or a rec o m me n de d peri o d of 1 t o a ma xi m u m of 4 
wee ks.

A re -c halle n ge t o titrate bac k u p t o t he tar get d ose le vel s h o ul d be atte m pte d at 2 
wee ks, or w he n s u bject is dee me d sta ble. T H E N:
3.
F urt her A dj ust St u d y Tre at me n t D ose Le vel

If t olera bilit y iss ues are n ot alle viate d des pite d o w n-titrati o n b y o ne d ose le vel, t he 
i n vesti gat or ma y d o w n-titrate f urt her t o t he ne xt l o wer st u d y treat me nt d ose le vel. T he 
s u bject ma y c o nti n ue recei vi n g t he l o wer d ose le vel f or a rec o m me n de d peri o d of 1 t o 
a ma xi m u m of 4 wee ks. See Ste p 5.

A gai n, o nce sta ble, t he s u bject s h o ul d be re-c halle n ge d wit h u p- titrati o n t o t he ne xt 
hi g her d ose le vel i n a n atte m pt t o gra d uall y  bri n g t he s u bject bac k t o t he tar get st u d y 
treat me nt d ose le vel ( D ose Le vel 3 ).

T he i n vesti gat or ma y  c h o ose t he ne xt d ose le vel f or d o w n- or u p -titrati o n acc or di n g t o 
his or her cli nical j u d g me nt.
4.
St o p pi n g St u d y Tre at me nt
If nee de d, t he st u dy treat me nt ma y be st o p pe d c o m pletel y, h o we ver, e ver y eff ort m ust be 
ma de t o c o m plete a n e n d of st u d y  visit a n d o btai n f oll o w u p healt h stat us i nf or mati o n f or 
a n y s u bject t hat wit h dra ws fr o m t he st u d y. See Secti o n 5. 6. 2
5.
St u d y dr u g rest art after te m p or ar y tre at me nt i nterr u pti o n

O nce t he i n v esti gat or c o nsi ders t he s u bject’s c o n diti o n a p pr o priate f or recei vi n g t he 
st u d y dr u g, t he i n vesti gat or s h o ul d re-start t he s u bject o n st u d y treat me nt at t he m ost 
a p pr o priate a n d all o wa ble d ose le vel per his/ her me dical j u d g me nt.

If t olerate d, t he s u bject sh o ul d be titrate d u p t o t he ne xt d ose le vel e ver y  1 t o 4 wee ks, 
as per t he i n vesti gat or’s j u d g me nt.

N o v arti s
C o nfi d e nti al
P a g e 3 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

I n s o me i nsta nces, D ose Le vel 1 or 2 c o ul d be mai ntai ne d if t he i n vesti gat or c o nsi ders 
t hat t he s u bject’s c o n diti o n w o ul d n ot all o w a n y f urt her u p-titrati o n t o t he tar get d ose 
of st u d y  me dicati o n ( D ose Le vel 3). I n t his case, it w o ul d be acce pta ble t o mai ntai n 
t he s u bject at D ose Le vel 1 or 2, w hic he ver is t he hi g her a n d t olerate d d ose le vel b y 
t he s u bject, b ut reas o ns f or n ot getti n g t o D ose Le vel 3 nee d t o be ca pt ure d i n t he 
e C R F.

S h o ul d t he s u bject n ot t olerate t he re -start st u d y dr u g d ose le vel, he/s he ma y be d o w n-
titrate d a gai n (if a p pr o priate) or disc o nti n ue d fr o m st u d y treat me nt.
S u bjects re-starte d o n t he st u d y dr u g will retai n t heir ori gi nal ra n d o mizati o n a n d st u d y 
i de ntificati o n n u m bers.
T he I RT m ust be c o ntacte d t o re gister a n y  cha n ges i n t he s u bject’s st u d y  treat me nt d ose le vel, 
i ncl u di n g i n cases of te m p orar y a n d per ma ne nt wit h dra wal or re-start of t he st u d y dr u g, a n d t o 
o btai n t he me dicati o n n u m be rs of t he st u d y dr u g s u p plies re q uire d f or t he ne w st u d y treat me nt 
d ose le vel. All d ose c ha n ges a n d i nterr u pti o ns m ust 
als o be rec or de d o n t he D osa ge 
A d mi nistrati o n Rec or d e C R F.
St u d y  visits s h o ul d occ ur as cl ose as p ossi ble t o t he pre -defi ne d visit a n d time sc he d ule 
descri be d i n Ta ble 6- 1 . T he ti mefra me bet wee n t he re g ular visits s h o ul d be mai ntai ne d as 
sc he d ule d, irres pecti ve of t he n u m ber of u nsc he d ule d visits t hat ma y be perf or me d i n bet wee n, 
or d ose i nterr u pti o ns t hat ma y occ ur.
I n case of pre g na nc y  disc o vere d d uri n g t he st u d y, t he patie nt s h o ul d be i nstr ucte d t o st o p ta ki n g 
t he st u d y dr u g i m me diatel y. ( See Secti o ns 6. 5. 6 a n d Secti o n 7. 4 )
5. 5. 6 
R e s c u e m e di c ati o n f or wor s e ni n g h e art f ail ur e
At a n y ti me d uri n g t he 8 wee k ra n d o mize d, d o u ble -bli n d treat me nt e p oc h, i n vesti gat ors ha ve 
t he o pti o n t o wit h dra w s u bjects fr o m st u d y treat me nt if t he y de vel o p si g ns a n d s ym pt o ms of 
w orse ni n g heart fail ure f or w hic h t he i n vesti gat or w o ul d li ke t o a d mi nister a p pr o priate t hera p y.

A p pr o priate a dj ust me nts, i nte nsificati o ns, or a d diti o ns t o c o nc o mita nt me dicati o ns 
s h o ul d be c o nsi dere d bef ore deci di n g t o wit h dra w t he s u bject fr o m st u dy treat me nt.

S u bjects C A N N O T recei ve A C E is a n d/ or A R Bs d uri n g t he st u d y. T hese 
me dic ati o ns c a n O N L Y be a d mi nistere d if t he i n vesti g at or belie ves t h at t he 
s u bject nee ds t o be wit h dr a w n fr o m st u d y tre at me nt s o t h at t he y m a y be tre ate d 
wit h t hese t her a pies d ue t o si g ns a n d s y m pt o ms of w orse ni n g he art f ail ure.

A 3 6 h o ur w as h -o ut peri o d is re q uire d if t he i n vesti g at or c h o oses t o wit h dr a w t he 
s u bject  fr o m d o u ble-bli n d tre at me nt a n d s witc h t o s ac u bitril/ v als art a n or A C Ei 
d ue t o s y m pt o ms of w orse ni n g he art f ail ure.

Use of resc ue me dicati o n m ust be rec or de d o n t he a p pr o priate C o nc o mita nt
Me dicati o ns e C R F.
I n vesti gat ors will use cli nical j u d ge me nt t o deter mi ne if s u bject’s c o n diti o n re q uires cl oser 
m o nit ori n g. U nsc he d ule d visits are per mitte d as nee de d.

N o v arti s
C o nfi d e nti al
P a g e 3 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
5. 5. 7 
C o n c o mit a nt m e di c ati o n
T he i n vesti gat or m ust i nstr uct t he patie nt t o n otif y t he st u d y site a b o ut a n y ne w me dicati o ns 
he/s he ta kes after t he patie nt was e nr olle d i nt o t he st u d y. All me dicati o ns, pr oce d ures a n d 
si g nifica nt n o n- dr u g t hera pies (i ncl u di n g p h y sical t hera py a n d bl o o d tra nsf usi o ns) a d mi nistere d 
after t he patie nt was e nr olle d i nt o t he st u d y m ust be rec or de d i n t he C o nc o mita nt Me dicati o ns 
or S ur gical a n d M e dical P r oce d ures e C R F as a p pr o priate .
Eac h c o nc o mita nt dr u g m ust be i n di vi d uall y assesse d a gai nst all e xcl usi o n criteria/ pr o hi bite d 
me dicati o n. If i n d o u bt t he i n vesti gat or s h o ul d c o ntact t he N o vartis me dical m o nit or bef ore 
ra n d o mizi n g a patie nt or all o wi n g a ne w me dicati o n t o be starte d.
A C Ei a n d A R Bs:
T he c o nc o mita nt use of o pe n -la bel A C EI or A R B is strictly pr o hi bite d w hile t he s u bject is 
recei vi n g st u d y me dicati o n. If t he i n vesti gat or belie ves t hat a d diti o n of a n A C EI or A R B is 
necessar y , t he n st u dy d r u g m ust be disc o nti n ue d. St u d y me dicati o n s h o ul d be st o p pe d 3 6 h o urs 
pri or t o a d diti o n of o pe n -label A C EI.
Ot her he art f ail ure a n d c ar di o v asc ul ar me dic ati o n
If a s u bject’s c o n diti o n warra nts a n y c ha n ge i n c o nc o mita nt heart fail ure or car di o vasc ular 
me dicati o ns, c ha n ges ma y  be ma de at t he i n vesti gat or’s discreti o n. Oral di uretics ma y be use d 
a n d ma y be a dj uste d t hr o u g h o ut t he st u d y d urati o n at t he discreti o n of t he i n vesti gat or.
Me dic ati o ns a n d s u bst a nces k n o w n t o r aise p ot assi u m le vels
P otassi u m s pari n g di uretics, p otassi u m s u p ple me nts, al d oster o ne a nta g o nists, a n d a n y ot her 
me dicati o ns k n o w n t o raise p otassi u m le vels s h o ul d be use d wit h ca uti o n w hile t he s u bject is 
recei vi n g st u d y me dicati o n d ue t o t he i ncrease d p ossi bilit y of occ urre nce of h y per kale mia. Salt 
s u bstit utes c o ntai ni n g p otassi u m c hl ori de are als o t o be a v oi de d w he n p ossi ble.  Potassi u m 
le vels s h o ul d be m o nit ore d re g ularl y  es peciall y i n t h ose w h o are recei vi n g t hese me dicati o ns.
C o nc o mita nt a d mi nistrati o n of re ni n i n hi bit ors, s uc h as alis kire n, is pr o hi bite d i n patie nts wit h 
dia betes mellit us.
P h os p h o diester ase -5 ( P D E -5) i n hi bit ors
P D E - 5 i n hi bit ors s h o ul d be use d wit h ca uti o n w hile t he s u bject is recei vi n g st u d y me dicati o n 
d ue t o t he i ncrease d p ossi bilit y  of occ urre nce of h yp ote nsi o n.
Nesiriti de a n d i ntr a ve n o us nitr ates
T he c o nc o mita nt a d missi o n of sac u bitril/ valsarta n wit h nesiriti de or i ntra ve n o us nitrates has n ot 
bee n st u die d. Gi ve n bi ol o gical i nteracti o n bet wee n sac u bitril a n d B N P, c o nc o mita nt use of 
nesiriti de (rec o m bi na nt B N P) is pr o hi bite d. Intra ve n o us nitrates are als o pr o hi bite d .
5. 5. 8 
Pr o hi bit e d m e di c ati o n
Use of t he treat me nts dis pla y e d i n t he ta ble bel o w a n d A p pe n di x 9 is N O T all o we d after t he 
baseli ne p hase . Please n ote t he list of pr o hi bite d me dicati o n is n ot e x ha ustive. If y o u ha ve a n y 
q uesti o ns, t he me dical m o nit or s h o ul d be c o ntacte d. 

N o v arti s
C o nfi d e nti al
P a g e 4 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T a bl e 5- 8 
Pr o hi bit e d m e di c ati o n ( Pl e a s e al s o s e e A p p e n di x 9)
5. 5. 9 
E m er g e n c y  br e a ki n g of a s si g n e d tr e at m e nt c o d e
E mer ge nc y  co de brea ks m ust o nl y  be u n derta ke n w he n it is re q uire d t o i n or der t o treat t he 
patie nt safely. M ost ofte n, st u d y treat me nt disc o nti n uati o n a n d k n o wle d ge of t he p ossi ble 
treat me nt assi g n me nts are s ufficie nt t o treat a st u d y patie nt w h o prese nts wit h a n e mer ge nc y 
c o n diti o n. E mer ge nc y  treat me nt c o de brea ks are perf or me d usi n g t he I R T. W he n 
t he 
i n vesti gat or c o ntacts t he s yste m t o brea k a treat me nt c o de f or a patie nt, he/s he m ust pr o vi de t he 
re q ueste d patie nt i de ntif yi n g i nf or mati o n a n d c o nfir m t he necessity t o brea k t he treat me nt c o de 
f or t he patie nt. T he i n vesti gat or will t he n recei ve details of t he i n vesti gati o nal dr u g treat me nt 
f or t he s pecifie d patie nt a n d a fa x o r e mail c o nfir mi n g t his i nf or mati o n. T he s yste m will 
a ut o maticall y inf or m t he N o vartis m o nit or f or t he site a n d t he St u d y  Tea m t hat t he c o de has 
bee n br o ke n.
M e di c ati o n
Pr o hi biti o n p eri o d
A cti o n t a k e n
A C EI s I n hi bit or s: 
b e n a z e pril, e n al a pril, 
Li si n o pril, c a pt o pril, 
R a mi pril, F o si n o pril, 
M o e xi pril Q ui n a pril, 
Tr a n d ol a pril
D ur ati o n of st u d y
Di s c o nti n u e st u d y tr e at m e nt
Ali s kir e n ( o nl y s u bj e ct s wit h 
c o n c urr e nt di a b et e s)
D ur ati o n of st u d y
Di s c o nti n u e st u d y tr e at m e nt
Bil e a ci d s e q u e st eri n g 
a g e nt s ( s u c h a s 
c h ol e st y r a mi n e or 
c ol e sti p ol)
D ur ati o n of st u d y
S wit c h t o alt er n at e a g e nt t o a v oi d 
i nt erf er e n c e wit h st u d y dr u g a b s or pti o n. 
If u s e of alt er n at e a g e nt i s n ot 
a p pr o pri at e, d o n ot r a n d o mi z e or 
di s c o nti n u e st u d y  dr u g tr e at m e nt.
N e siriti d e a n d i ntr a v e n o u s 
nitr at e s
D ur ati o n of st u d y
D o n ot r a n d o mi z e. If h o s pit ali z e d, eit h er 
i nt err u pt or di s c o nti n u e st u d y tr e at m e nt. 
N e siriti d e a n d i ntr a v e n o u s nitr at e s h a v e 
n ot b e e n st u di e d. Or al, t o pi c al a n d 
s u bli n g u al nitr at e s ar e p er mi s si bl e.
Pr e s cri pti o n a n d n o n -
pr e s cri pti o n m e di c ati o n s 
t a k e n f or i n s o m ni a or t o 
i n d u c e sl e e p ( S e e A p p e n di x 
9 f or d et ail s a n d e x a m pl e s)
D ur ati o n of st u d y
Di s c o nti n u e st u d y tr e at m e nt

N o v arti s
C o nfi d e nti al
P a g e 4 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
It is t he i n vesti gat or’s res p o nsi bilit y to e ns ure t hat t here is a de pe n da ble pr oce d ure i n place to 
all o w access t o t he I RT/c o de brea k car ds at a n y ti me i n case of e mer ge nc y. T he i n vesti gat or 
will pr o vi de:

pr ot oc ol n u m ber

st u d y dr u g na me (if a vaila ble)

patie nt n u m ber
I n a d diti o n, oral a n d writte n i nf or mati o n t o t he s u bject m ust be pr o vi de d o n h o w t o c ontact 
his/ her bac k u p i n cases of e mer ge nc y, or w he n he/s he is u na vaila ble, t o e ns ure t hat u n -bli n di n g 
ca n be perf or me d at a n y t i me. 
5. 6 
St u d y c o m pl eti o n a n d d i s c o nti n u ati o n 
5. 6. 1 
St u d y c o m pl eti o n a n d p o st- st u d y tr e at m e nt
A s u bject will be c o nsi dere d t o ha ve c o m plete d t he st u d y whe n t he s u bject has c o m plete d t he 
last visit pla n ne d i n t he pr ot oc ol ( Visit 1 3). At t he e n d of st u d y visit, s u bjects will be as ke d t o 
ret ur n all re mai ni n g st u d y dr u g.  The i n vesti gat or m ust pr o vi de f oll o w- u p me dical care f or all 
s u bjects w h o are pre mat urel y  wit h dra w n fr o m t he st u d y, or m ust refer t he m f or a p pr o priate 
o n g oi n g care.
5. 6. 2 
Di s c o nti n u ati o n of st u d y t r e at m e nt
S u bjects ma y  v ol u ntarily disc o nti n ue t he st u d y dr u g f or a n y reas o n at a n y ti me. 
St u d y  dr u g m ust be disc o nti n ue d u n der t he f oll o wi n g circ u msta nces: 

Wit h dra wal of c o nse nt

Pre g na nc y

Use of pr o hi bite d c o nc o mita nt me dicati o n

A n y  pr ot oc ol de viati o n t hat c o nstit utes a ris k t o t he s u bject

I n vesti gat or belie ves t hat c o nti n uati o n of st u d y dr u g ma y be detri me ntal t o t he s u bject’s 
well -bei n g

St u d y  me dicati o n ma y be disc o nti n ue d at t he i n vesti gat or’s discreti o n if a n y of t he 
f oll o wi n g occ ur:

A n y  se vere s us pecte d dr u g relate d A E

S us pecte d occ urre nce of a n gi oe de ma. A s u bject wit h a n y  si g ns or sy m pt o ms of cli nicall y  
si g nifica nt a n gi oe de ma s ho ul d be t h or o u g hl y e val uate d b y t he i n vesti gat or t o deter mi ne if 
it c o nstit utes a reas o n f or disc o nti n uati o n of st u d y me dicati o n.
De pe n di n g o n t he ser u m p otassi u m, bl o o d press ure, or e G F R, s u bjects ma y nee d t o ha ve t heir 
st u d y dr u g d ose or t he d ose of a n other c o nc o mita nt me dicati o n re d uce d or disc o nti n ue d; or, if 
a p pr o priate, ha ve p ote ntiall y  co ntri b uti n g a ge nts a dj uste d. Refer t o a p pe n dices f or treat me nt 
g ui deli nes f or h y per kale mia, h y p ote nsi o n or re nal d ysf u ncti o n, res pecti vel y.
I n t he case of st u d y dr u g disc o nti n uati o n, e ver y eff ort m ust be ma de t o c o m plete a n e n d of st u d y 
visit a n d o btai n f oll o w u p healt h stat us i nf or mati o n f or a n y su bjects t hat wit h dra w fr o m t he 

N o v arti s
C o nfi d e nti al
P a g e 4 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
st u d y. If t he s u bject ref uses, he/s he s h o ul d be c o ntacte d b y  tele p h o ne i n place of pr ot oc ol -
s pecifie d visits u nless t he s u bject e x pressl y ref uses s uc h c o ntacts. 
T he i n vesti gat or m ust n otif y  t he s p o ns or of a n y st u d y dr u g disc o nti n uati o n a n d rec or d it o n t he 
D osa ge A d mi nistrati o n Rec or d e C R F.
If disc o nti n uati o n of st u d y treat me nt occ urs, t he s u bject s h o ul d N O T be c o nsi dere d wit h dra w n 
fr o m t he st u d y. T he s u bject s h o ul d ret ur n t o t he cli nic as s o o n as p ossi ble, after disc o nti n uati o n 
of st u d y dr u g, f or a n e n d of st u d y visit.  All assess me nts fr o m t he fi nal visit ( Visit 1 3 ) i n t he 
visit sc he d ule of assess me nts (Ta ble 6- 1 ) m ust be c o m plete d a n d rec or de d i n t he e C R F.  The 
St u d y  Co m pleti o n e C R F will als o nee d t o be c o m plete d. T he i n vesti gat or m ust deter mi ne t he 
pri mar y  reas o n f or t he s u bject’s pre mat ure d isc o nti n uati o n of st u d y treat me nt a n d rec or d t his 
i nf or mati o n i n t he e C R F. 
If t he s u bject ca n n ot or is u n willi n g t o atte n d a n y visit(s), t he site staff s h o ul d mai ntai n re g ular 
tele p h o ne c o ntact wit h t he s u bject, or wit h a pers o n pre -desi g nate d b y  the s u bject. T his 
tele p h o ne c o ntact s h o ul d prefera bly be d o ne acc or di n g t o t he st u d y visit sc he d ule. 
T he i n vesti gat or m ust als o c o ntact t he s p o ns or t o re gister t he s u bject’s disc o nti n uati o n fr o m 
st u d y treat me nt.
5. 6. 3 
Wit h dr a w al of i nf or m e d c o n s e nt
S u bjects ma y  vol u nta ril y wit h dra w c o nse nt t o partici pate i n t he st u d y for a n y reas o n at a n y ti me. 
Wit h dra wal of c o nse nt fr o m t he st u d y  is defi ne d as w he n a s u bject:

D oes n ot wa nt t o partici pate i n t he st u d y  a n ym ore
a n d

D oes n ot wa nt a n y f urt her visits or assess me nts
a n d

D oes n ot wa nt a n y f urt her st u d y relate d c o ntacts
a n d

D oes n ot all o w a nal ys is of alrea d y o btai ne d bi ol o gic material 
I n this sit uati o n, t he i n vesti gat or m ust ma ke e ver y eff ort (e. g. tele p h o ne, e-mail, letter) t o 
deter mi ne t he pri mar y  reas o n f or t he s u bject’s decisi o n t o wit h dra w his/ her c o nse nt a n d rec or d 
t his i nf or mati o n. 
St u d y  treat me nt m ust be disc o nti n ue d a n d n o f urt her assess me nts c o n d ucte d, a n d t he data t hat 
w o ul d ha ve bee n c ollecte d at s u bse q ue nt visits will be c o nsi dere d missi n g. 
F urt her atte m pts t o c o ntact t he patie nt are n ot all o we d u nless safet y fi n di n gs re q uire 
c o m m u nicati n g or f oll o w - u p.
All eff orts s h o ul d be ma de t o c o m plete t he assess me nts pri or t o st u d y wit h dra wal. A fi nal 
e val uati o n at t he ti me of t he patie nt’s st u d y wit h dra wal s h o ul d be ma de as detaile d i n t he 
assess me nt ta ble bel o w.

N o v arti s
C o nfi d e nti al
P a g e 4 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
5. 6. 4 
L o s s t o f oll o w -u p
F or s u bjects w h ose stat us is u nclear beca use t he y  fail t o a p pear f or st u d y visits wit h o ut stati n g 
a n i nte nti o n t o disc o nti n ue or wit h dra w, t he i n vesti gat or s h o ul d s h o w " d ue dili ge nce" b y  
d oc u me nt i n g i n t he s o urce d oc u me nts ste ps ta ke n t o c o ntact t he s u bject, e. g. dates of tele p h o ne 
calls, re gistere d letters, etc. A s u bject ca n n ot be c o nsi dere d as l ost t o f oll o w- u p u ntil t he ti me 
p oi nt of his/ her sc he d ule d e n d of st u d y  visit has passe d.
5. 6. 5 
E arl y  st u d y t er mi n ati o n b y t h e s p o n s or 
T he st u d y  ca n be ter mi nate d b y N o vartis at a n y ti me f or a n y reas o n. T his ma y i ncl u de reas o ns 
relate d t o t he be nefit ris k assess me nt of partici pati n g i n t he st u d y, practical reas o ns, or f or 
re g ulat or y or me dical reas o ns (i ncl u din g sl o w e nr ol me nt). S h o ul d t his be necessar y , t he s u bject 
m ust be see n as s o o n as p ossi ble a n d treate d as a pre mat urel y  wit h dra w n s u bject. T he 
i n vesti gat or m a y  be i nf or me d of a d diti o nal pr oce d ures t o be f oll o we d i n or der t o e ns ure t hat 
a de q uate c o nsi derati o n is gi ve n t o t he pr otecti o n of t he s u bject’s i nterests. T he i n vesti gat or will 
be res p o nsi ble f or i nf or mi n g t he I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee 
(IR Bs/I E Cs) of t he earl y  ter mi nati o n of t he trial.
6 
Vi sit s c h e d ul e a n d a s s e s s m e nt s
All assess me nts are liste d i n Ta ble 6- 1 . Assess me nts t hat are t o be re p orte d i n t he cli nical 
data base are mar ke d wit h a n ‘ X’. Assess me nts t hat will o nl y  be re p orte d i n t he s o urce 
d oc u me ntati o n are mar ke d wit h a n ‘ S ’.  S u bjects s h o ul d be see n f or all visits o n t he desi g nate d 
da y  or as cl ose t o it as p ossi ble, wit h a n all o we d visit wi n d o w of ± 3 da ys f or visits 1, 3, 5, 6, 8, 
1 0, 1 1, a n d 1 3.. St u d y  staff s h o ul d call s u bjects f or all tele-visits o n t he desi g n ate d da y  or as 
cl ose t o it as p ossi ble, wit h a n all o we d visit wi n d o w of ± 3 da y  f or visits 2, 4, 7, 9 a n d 1 2. 
Eli gi ble s u bjects m a y  start st u d y treat me nt o nce it is c o nfir me d t hat t he y meet all i ncl usi o n 
criteria a n d n o ne of t he e xcl usi o n criteria. 
S u bj ects ma y be c o ntacte d f or safet y e val uati o ns f or 3 0 da ys after t he last d ose. D oc u me ntati o n 
of atte m pts t o c o ntact t he s u bject s h o ul d be rec or de d i n t he s o urce d oc u me ntati o n.  Unsc he d ule d 
visits f or safet y/ me dicati o n e val uati o n/ u nsc he d ule d assess me nts are per mitte d at a n y ti me 
d uri n g t he st u d y.

N o v arti s
C o nfi d e nti al
P a g e 4 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T a bl e 6- 1 
A s s e s s m e nt s c h e d ul e
P h ase
Scree ni n g/ B aseli ne
R a n d o mize d Tre at me nt
O pe n L a bel E xte nsi o n
U nsc he d ule d ◊
Visit N u m ber
1
2
3
4  
5  
6  
7  
8  
9 
1 0  
1 1  
1 2  
1 3 / E O S
D a ys
- D a y 1 4
- D a y 7 t o - D a y 
1
D a y 1   
D a y 7 
D a y 1 4   
D a y 2 8   
D a y 4 2   
D a y 5 6
D a y 
6 3 
D a y 7 0   
D a y 8 4   
D a y 9 8 
D a y 1 1 2 
U N S C H E D
Ti m e of Visit 
Wee k   - 2 
Wee k   - 1
D a y 1 
Wee k  1 
Wee k  2 
Wee k  4 
Wee k  6 
Wee k  8
Wee k  
9
Wee k  
1 0
Wee k  
1 2
Wee k  
1 4
Wee k  
1 6 
U N S C H E D
Visit t y pe 
Office 
Tele -visit
Office
(ra n d o mizati o n)
Tele -visit 
Office   
Office
Tele -
visit 
Office
Tele -
visit 
Office   
Office
Tele -
visit 
Office   
Office
I ncl usi o n/  E xcl usi o n 
X
X
I nf or me d c o nse nt * *
X
De m o gr a p hics
X
Me dic al Hist or y
X
H F Si g n a n d 
s y mpt o m s/ N Y H A
Cl assific ati o n ( H F Si g n 
a n d s y m pt o ms)
X
X
X   
X
X
X   
X
X
X
C o m plete P h ysic al 
e x a mi n ati o n
S
S
S
S
Li m ite d C ar di o v asc ul ar 
P h ysic al E x a mi n ati o n
S
S
S
Hei g ht 1
X
Wei g ht
2
X
X
X   
X
X
X   
X
X
X
Vit al Si g ns
X
X
X   
X
X
X   
X
X
X
Dis pe nse st u d y 
me dic ati o n
X
X   
X
X
X   
X
Bli n d titr ati o n
X   
X

N o v arti s
C o nfi d e nti al
P a g e 4 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
P h ase
Scree ni n g/ B aseli ne
R a n d o mize d Tre at me nt
O pe n L a bel E xte nsi o n
U nsc he d ule d ◊
Visit N u m ber
1
2
3
4  
5  
6  
7  
8  
9 
1 0  
1 1  
1 2  
1 3 / E O S
D a ys
- D a y 1 4
- D a y 7 t o - D a y 
1
D a y 1   
D a y 7 
D a y 1 4   
D a y 2 8   
D a y 4 2   
D a y 5 6
D a y 
6 3 
D a y 7 0   
D a y 8 4   
D a y 9 8 
D a y 1 1 2 
U N S C H E D
Ti m e of Visit 
Wee k   - 2 
Wee k   - 1
D a y 1 
Wee k  1 
Wee k  2 
Wee k  4 
Wee k  6 
Wee k  8
Wee k  
9
Wee k  
1 0
Wee k  
1 2
Wee k  
1 4
Wee k  
1 6 
U N S C H E D
Visit t y pe 
Office 
Tele -visit
Office
(ra n d o mizati o n)
Tele -visit 
Office   
Office
Tele -
visit 
Office
Tele -
visit 
Office   
Office
Tele -
visit 
Office   
Office
Titr ati o n
X   
X
X
X   
X
L a b or at or y E v al u ati o ns 
( per pr ot oc ol)3
X
X
X
X
X
X
X
Uri ne pre g n a nc y (site) 4
X
Ser u m pre g n a nc y
X
X
X
X
X
O pe n l a bel titr ati o n f or 
c o ntr ol ar m
X 
(c o ntr ol 
o nl y)
R a n d o miz ati o n
X
Se ns or use tr ai ni n g 6
S
Acti W atc h E xc h a n ge & 
D at a U pl o a d
X
X
X
X
X

N o v arti s
C o nfi d e nti al
P a g e 4 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
P h ase
Scree ni n g/ B aseli ne
R a n d o mize d Tre at me nt
O pe n L a bel E xte nsi o n
U nsc he d ule d ◊
Visit N u m ber
1
2
3
4  
5  
6  
7  
8  
9 
1 0  
1 1  
1 2  
1 3 / E O S
D a ys
- D a y 1 4
- D a y 7 t o - D a y 
1
D a y 1   
D a y 7 
D a y 1 4   
D a y 2 8   
D a y 4 2   
D a y 5 6
D a y 
6 3 
D a y 7 0   
D a y 8 4   
D a y 9 8 
D a y 1 1 2 
U N S C H E D
Ti m e of Visit 
Wee k   - 2 
Wee k   - 1
D a y 1 
Wee k  1 
Wee k  2 
Wee k  4 
Wee k  6 
Wee k  8
Wee k  
9
Wee k  
1 0
Wee k  
1 2
Wee k  
1 4
Wee k  
1 6 
U N S C H E D
Visit t y pe 
Office 
Tele -visit
Office
(ra n d o mizati o n)
Tele -visit 
Office   
Office
Tele -
visit 
Office
Tele -
visit 
Office   
Office
Tele -
visit 
Office   
Office
A d verse E ve nts/ Seri o us 
A d verse E ve nts 8
X
X 8
X
X 8
X   
X   
X 8
X   
X 8
X   
X   
X 8
X
X
C o nc o mit a nt 
Me dic ati o ns
X
X
X
X   
X   
X   
X   
X   
X   
X   
X   
X   
X
X
D os a ge A d mi nistr ati o n 
Rec or d
X
X   
X
X
X   
X
X
X
Dr u g Acc o u nt a bilit y
S 
S
S
S 
S
S
S
I R T C all
X
X
X 
X
X
X 
X
X
X
St u d y C o m pleti o n/
E arl y Ter mi n ati o n
X
A n gi oe de m a
Assess me nts
X
X
X   
X
X
X   
X
X
X
**I C m u st b e o bt ai n e d pri or t o all st u d y s p e cifi c s cr e e ni n g pr o c e d ur e s d uri n g or a s cl o s e t o t h e st art of t h e s cr e e ni n g p h a s e a s p o s si bl e
◊= U n s c h e d ul e d vi sit a s s e s s m e nt s m ar k e d wit h ( X) ar e o pti o n al pr o c e d ur e s t h at m a y b e p erf or m e d at t h e i n v e sti g at or s di s cr eti o n , or if t h e p ati e nt wit h dr a w s e arl y fr o m tr e at m e nt or st u d y.
X = a s s e s s m e nt t o b e r e c or d e d o n cli ni c al d at a b a s e
S = a s s e s s m e nt t o b e d o c u m e nt e d i n s o ur c e d at a
1. 
H ei g ht s h o ul d b e m e a s ur e d i n c e nti m et er s if p o s si bl e
2. 
W e i g ht s h o ul d b e c a pt ur e d i n e v er y offi c e vi sit t o t h e n e ar e st 0. 1 k g, wit h o ut s h o e s a n d i n i n d o or cl ot hi n g
3. 
L a b or at or y e v al u ati o n s i n cl u d e C h e mi str y, H e m at ol o g y, a n d Uri n al y si s
4. 
Uri n e pr e g n a n c y t e st m u st b e p erf or m e d o n sit e at vi sit 1
6. 
A cti w at c h t o b e pr o v i d e d at b a s eli n e vi sit.
 
8. 
At vi sit 2, 4, 7, 9, a n d 1 2 if a s u bj e ct r e p ort s a n a n gi o e d e m a -li k e e v e nt, t h e s u bj e ct s h o ul d b e r e q u e st e d t o c o m e i n f or a n u n s c h e d ul e d vi sit f or s af et y a s s e s s m e nt. 

N o v arti s
C o nfi d e nti al
P a g e 4 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 4 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
6. 1 
I nf or m ati o n t o b e c oll e ct e d o n s cr e e ni n g f ail ur e s 
All s u bjects w h o ha ve si g ne d i nf or me d c o nse nt b ut n ot e ntere d i nt o t he ne xt e p oc h will ha ve 
t he st u d y co m pleti o n pa ge f or t he scree ni n g e p oc h, de m o gra p hics, i ncl usi o n/e xcl usi o n, a n d 
seri o us a d verse e ve nt ( S A E) data c ollecte d. A d verse e ve nts t hat are n ot S A Es will be f oll o we d 
b y  t he i n vesti gat or a n d c ollecte d o nl y i n t he s o urce data.
6. 2 
P ati e nt d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s
S u bject de m o gra p hic a n d baseli ne c haracteristic data t o be c ollecte d o n all s u bjects i ncl u de: 
ye ar of birt h, a ge, se x, race, et h nicit y, rele va nt me dical hist or y /c urre nt me dical c o n diti o n 
prese nt bef ore si g ni n g i nf or me d c o nse nt w here p ossi ble, dia g n oses a n d n ot s ym pt o ms will be 
rec or de d. H F me dicati o ns a n d ot her C V me dicati o ns will be rec or de d i n e C R Fs
s uc h t hat t he y 
ca n be se parate d fr o m ot her me dicati o ns. Li ke wise, detaile d H F hist or y an d ot her rele va nt C V 
me dical hist or y  will be rec or de d o n e C R Fs se paratel y fr o m ot her me dical hist or y. 
I n vesti gat ors will ha ve t he discreti o n t o rec or d a b n or mal test fi n di n gs o n t he Me dical Hist or y 
eC R F w he ne ver i n t heir j u d g me nt, t he test a b n or malit y occ urre d pri or t o t he i nf or me d c o nse nt 
si g nat ure.
6. 3 
Tr e at m e nt e x p o s ur e a n d c o m pli a n c e
C o m plia nce will be assesse d b y  t he i n vesti gat or a n d/ or st u d y pers o n nel at eac h visit usi n g pill 
c o u nts a n d i nf or mati o n pr o vi de d b y  t he care gi ver. T his i nf or mati o n s h o ul d be ca pt ure d i n t he 
s o urce d oc u me nt at eac h visit. 
S u bject c o m plia nce s h o ul d be at least 8 0 % d uri n g t he titrati o n a n d mai nte na nce treat me nt p hase . 
T he i n vesti gat or a n d/ or st u d y pers o n nel will c o u nsel t he s u bject if c o m plia nce is bel o w 8 0 %. 
St u d y  dr u g acc o u nta bilit y will als o be deter mi ne d b y t he site m o nit or w hile perf or mi n g r o uti ne 
site visits a n d at t he c o m pleti o n of t he st u d y.
D urati o n of t he st u d y titrati o n a n d mai nte na nce st u d y dr u g e x p os ure will be calc ulate d base d 
u p o n t he start a n d st o p dates rec or de d i n t he e C R F.
6. 4 
Effi c a c y
6. 4. 1 
Effi c a c y  a s s e s s m e nt
T he efficac y  e n d p oi nts are:
Pri m ar y: 
T he c ha n ge i n mea n acti vit y co u nts c ollecte d d uri n g t he m ost acti ve 3 0 mi n utes of t he s u bject’s 
da y  bet wee n baseli ne p hase ( mea n of data c ollecte d eac h d a y  duri n g wee k - 1) a n d t he fi nal 
ra n d o mize d treat me nt p hase ( mea n of data c ollecte d eac h da y d uri n g wee k 8 ), as meas ure d b y  
wrist -w or n acceler o meter c ollecte d acti gra p h y (t otal c o u nts per 3 0 mi n peri o d c ollecte d d uri n g 
t he m ost acti ve 3 0 mi n utes of eac h da y).
Sec o n d ar y:  

N o v arti s
C o nfi d e nti al
P a g e 4 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T he c ha n ge i n mea n acti vit y duri n g slee p bet wee n baseli ne p hase ( mea n of data c ollected d uri n g 
wee k - 1) a n d t he fi nal ra n d o mize d treat me nt p hase ( mea n of data c ollecte d d uri n g wee k 8 ), as 
meas ure d b y  acti gra p h y (acti vit y co u nts per mi n ute d uri n g dail y slee p peri o d, wrist -w or n 
acceler o meter) .
Ot her sec o n d ar y e n d p oi nts:
T he c ha n ge i n mea n acti vit y duri n g slee p bet wee n baseli ne ( mea n of ni g hts c ollecte d d uri n g 
wee k - 1) a n d eac h ra n d o mize d treat me nt a n d o pe n la bel p hase, as meas ure d b y  acti gra p h y 
(wee k 1, 9 a n d 1 6 ) (acti vit y co u nts per mi n ute 
d uri n g dail y slee p peri o d, wrist -w or n 
acceler o meter) .
T he c ha n ge i n mea n acti vit y co u nts c ollecte d d uri n g t he m ost acti ve 3 0 mi n utes of t he s u bject’s 
da y  bet wee n baseli ne p hase ( mea n of data c ollecte d eac h da y  duri n g wee k -1 )a n d eac h 
ra n d o mize d treat me nt a n d o pe n la bel p hase (wee k 1, 9 a n d 1 6 ),  as meas ure d
b y  wrist w or n 
acceler o meter c ollecte d acti gra p h y.
6. 4. 2 
A p pr o pri at e n e s s of effi c a c y  a s s e s s m e nt s
Acti gra p h y is a n a p pr o priate a n d effecti ve met h o d f or t he o bjecti ve meas ure me nt of p h y sical 
acti vit y in a s u bject’s e ver yd a y  life ( b ot h wa ki n g a n d slee pi n g). T he sens or e m pl o ye d i n t his 
st u d y, t he P hili ps Acti watc h S pectr u m, is a n F D A cleare d class II me dical de vice i n dicate d f or 
t his p ur p ose. Assess me nt of b ot h p h y sical acti vit y a n d slee p metrics usi n g t his met h o d wit h t his 
a n d si milar de vices (acceler o meters) has bee n pre vi o usl y  re p orte d b y ot her i n vesti gat ors. T his 
met h o d has bee n use d effecti vel y i n t he H F p o p ulati o n t o assess: t he effect of s ym pt o m 
treat me nt o n d a y ti me acti vit y le vels (Re dfiel d 2 0 1 5 ), t he i m pact of a ner gia o n slee p a n d d a y ti me 
acti vit y (Ma urer 2 0 0 9 ), t he effect of slee p o n Q o L (Re de ker 2 0 0 5 ), a n d p h y sical acti vit y 
patter ns ass ociate d wit h l o n g ter m s ur vi val ( Meli n 2 0 1 6 ).
W hile p ol y s o m n o gra p hy ( P S G) is t he sta n dar d assess me nt t o ol f or slee p dis or dere d breat hi n g, 
 
T he P orta ble M o nit ori n g 
Tas k F orce of t he A merica n Aca de m y of Slee p Me dici n e ( A A S M) rec o m me n ds t he use of 
p orta ble m o nit ors as a n alter nati ve t o P S G f or t he assess me nt of slee p dis or dere d breat hi n g i n 
patie nts wit h hi g h pretest pr o ba bilit y  of m o derate t o se vere slee p a p nea (C oll o p 2 0 0 7 ).

N o v arti s
C o nfi d e nti al
P a g e 5 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
6. 5 
S af et y
Safet y  assess me nts will c o nsist of m o nit ori n g a n d rec or di n g of all a d verse e ve nts a n d seri o us 
a d verse e ve nts, e val uati o n of he mat ol o g y , bl o o d c he mistr y an d uri ne val ues, re g ular 
meas ure me nt of vital si g ns a n d t he perf or ma nce of p h y sical e xa mi nati o ns.
6. 5. 1 
P h y si c al e x a mi n ati o n
A c o m plete p h y sical e xa m will be perf or me d at visit n u m ber 1, 8, a n d 1 3 . It will i ncl u de t he 
e xa mi nati o n of ge neral a p peara nce, s ki n, nec k, e yes, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, 
bac k, l ym p h n o des, e xtre mities, a n d vasc ular a n d ne ur ol o gical e xa mi nati o ns. If i n dicate d base d 
o n me dical hist or y, a n d/ or s y m pt o ms, rectal , e xter nal ge nitalia, breast a n d pel vic e xa ms will be 
perf or me d. 
Li mite d car di o vasc ular p h y sical e xa mi nati o n will be perf or me d at visit 3 a n d 1 1, a n d will 
i ncl u de t he e xa mi nati o n of vital si g ns (s yst olic a n d diast olic bl o o d press ure, p ulse a n d 
res pirati o n rate), heart a n d l u n g s o u n ds, j u g ular ve n o us diste nsi o n, a n d e xtre mities.
Si g ns a n d s ym pt o ms of heart fail ure will be re vie we d b y  the i n vesti gat or at all office visits 
d uri n g t he st u d y. T he si g ns a n d s ym pt o ms e val uati o n ma y  incl u de, b ut are n ot li mite d t o, 
par o x ys mal n oct ur nal d y s p nea, fati g ue, e de ma, d y s p nea at rest, d y s p nea u p o n eff ort, ort h o p nea, 
rales, j u g ular ve n o us diste nti o n, prese nce of a t hir d heart s o u n d. N Y H A classificati o n will be 
assesse d a n d sc ore d at eac h visit.
I nf or mati o n f or all p h ysical e xa mi nati o ns m ust be i ncl u de d i n t he s o urce d oc u me ntati o n at t he 
st u d y site. Si g nifica nt fi n di n gs t hat were prese nt pri or t o t he s u bject pr o vi di n g writte n i nf or me d 
c o nse nt f or t he st u d y must be i ncl u de d i n t he Rele va nt Me dical 
Hist or y / C urre nt Me dical 
C o n di ti o ns e C R F. Si g nifica nt fi n di n gs ma de after t he s u bject pr o vi des writte n i nf or me d c o nse nt 
f or t he st u d y whic h meet t he defi niti o n of a n a d verse e ve nt m ust be rec or de d o n t he A d verse 
E ve nt e C R F.

N o v arti s
C o nfi d e nti al
P a g e 5 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
6. 5. 2  
Vit al si g n s
Vital si g ns will be assesse d at e ver y office visit.  This will i ncl u de bl o o d press ure a n d p ulse 
meas ure me nts. B P will be meas ure d usi n g a sta n dar d s p h y g m o ma n o meter wit h a n a p pr o priate 
size d c uff a n d t he n o n -d o mi na nt ar m i n t he sitti n g p ositi o n after 5 mi n utes of rest.  E ver y eff ort 
s h o ul d be ma de t o use t he sa me ar m f or t he s u bject f or all vital si g ns assess me nts a n d w here 
p ossi ble, t he sa me pers o n d oi n g t he assess me nt.
6. 5. 3 
H ei g ht a n d w ei g ht
Hei g ht i n ce nti meters if p ossi ble, b o d y  wei g ht t o t he nearest 0. 1 k g wit h o ut s h oes will be 
meas ure d at visit 1. B o d y wei g ht (t o t he nearest 0. 1 kil o gra m ( k g) i n i n d o or cl ot hi n g, b ut 
wit h o ut s h oes) will be meas ure d at e ver y  office visit.
6. 5. 4 
A n gi o e d e m a
A n gi oe de ma is a t y pe of a br u pt s welli n g t hat occ urs u n der t he s ki n a n d/ or m uc o us me m bra nes 
a n d is ofte n l ocalize d t o t he he a d, nec k, t hr oat, a n d/ or t o n g ue, b ut ma y  occ ur else w here, 
i ncl u di n g t he ge nitalia a n d i ntesti nes. Se vere cases ma y  be ass ociate d wit h air wa y co m pr o mise. 
Alt h o u g h, t he mec ha nis m is n ot f ull y un derst o o d, bra d y ki ni n has bee n i m plicate d as t he p utati ve 
me diat o r. T heref ore, me dicati o ns t hat raise t he le vels of e n d o ge n o us bra d y ki ni n b y  in hi biti n g 
t he e nz ymes res p o nsi ble f or its brea k d o w n, s uc h as A C E, a mi n o pe pti dase P, a n d N E P, ma y 
res ult i n t his p ote ntiall y da n ger o us si de effect. All s us pecte d cases of a n gi oe de m a, re gar dless 
of s us pecte d ca usalit y, m ust be re p orte d. T he A dj u dicati o n Q uesti o n naire f or A n gi oe de ma -li ke 
E ve nt a n d A d verse E ve nt e C R Fs m ust be c o m plete d a n d t he N o vartis Me dical M o nit or m ust 
be n otifie d. 
If t he a n gi oe de ma e ve nt meets S A E criteria, t he in vesti gat or m ust e ns ure t hat a n S A E f or m is 
c o m plete d a n d s u b mitte d t o N o vartis Dr u g Safet y a n d E pi de mi ol o g y . I n a d diti o n, all 
a n gi oe de ma e ve nts will be a dj u dicate d as descri be d i n Secti o n 8. 5 .
6. 5. 5 
L a b or at or y e v al u ati o n s
A ce ntral la b orat or y will be use d f or all la b orat or y e val uati o ns wit h t he e x ce pti o n of t he uri ne 
pre g na nc y  test ( h C G) perf or me d at visit 1 (scree ni n g) at t he site, re q uire d t o deter mi ne 
eli gi bilit y a n d a nal ys is of all c ollecte d s peci me ns fr o m scree ni n g t hr o u g h t he fi nal visit. Details 
o n t he c ollecti o ns, s hi p me nt of sa m ples a n d re p orti n g of res ults b y  the ce ntral la b orat or y will 
be pr o vi de d t o i n vesti gat ors i n t he la b orat or y  ma n ual.      
Cli nicall y  n ota ble la b orat or y fi n di n gs are defi ne d i n A p pe n di x 1 .
W he n la b orat or y  val ues e xcee d t he b o u n daries of a n ota ble la b orat or y  ab n or malit y , a d diti o nal 
la b orat or y eval uati o ns s h o ul d be perf or me d, as j u d ge d a p pr o priate b y  the i n vesti gat or. If t he 
la b orat or y ab n or malit y  in d uces cli nical si g ns or s ym pt o ms, or re q uires t hera pe utic i nter ve nti o n, 
t he n t he dia g n osis or me dical c o n diti o n m ust be e ntere d o n t he A Es scree n of t he s u bject's e C R F. 
If t he la b orat or y ab n or malit y  is t he pri mar y  reas o n f or a n u nf ores ee n h os pitalizati o n or 
ot her wise f ulfills t he seri o us ness cate g or y of a n A E, t he n t he pr oce d ure f or ra pi d n otificati o n 
of S A Es m ust be f oll o we d. Li ke wise, if t he la b orat or y ab n or malit y  lea ds t o disc o nti n uati o n 
fr o m t he st u d y dr u g (te m p oraril y or per ma ne ntl y) , t he s u bject m ust be f oll o we d u ntil t he 
a b n or malit y res ol ves or u ntil it is j u d ge d t o be per ma ne nt. T his i n vesti gati o n ma y  incl u de 

N o v arti s
C o nfi d e nti al
P a g e 5 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
c o nti n ue d m o nit ori n g b y  re peat la b orat or y testi n g or b y  perf or mi n g a d diti o nal la b orat or y tests 
as dee me d necessar y b y t he i n vesti gat or or t he N o vartis me dical m o nit or.
6. 5. 5. 1 
H e m at ol o g y
He m o gl o bi n, he mat ocrit, re d bl o o d cell c o u nt, w hite bl o o d cell c o u nt wit h differe ntial, a n d 
platelet c o u nt will be meas ure d at all visits: 1, 3, 5, 8, 1 0, a n d 1 3 (ce ntral la b).
6. 5. 5. 2 
Cli ni c al c h e mi str y
Bl o o d urea nitr o ge n ( B U N), gl uc ose, creati ni ne, t otal bilir u bi n, A S T ( S G O T), A L T ( S G P T), 
al kali ne p h os p hatase, s o di u m, p otassi u m, c hl ori de, calci u m, he m o gl o bi n A 1 C, t otal pr otei n, 
al b u mi n, uric aci d, a n d li pi d pr ofile will be meas ure d at all visits 1, 3, 5 , 8, 1 0, a n d 13  (ce ntral 
la b).
6. 5. 5. 3 
Uri n al y si s
Di pstic k -test deter mi nati o n of s pecific gra vit y, p H, bl o o d, t otal pr otei n, bilir u bi n, ket o nes, a n d 
le u k oc ytes will be meas ure d at Visits 1, 3, 5, 8, 1 0, a n d 1 3 (ce ntral la b). If di pstic k is p ositi ve, 
a q ualitati v e micr osc o pic 
deter mi nati o n, i ncl u di n g w hite 
bl o o d cells hi g h p o wer fiel d 
( W B Cs/ H P F) a n d re d bl o o d cells hi g h p o wer fiel d ( R B Cs/ H P F) will be perf or me d.
6. 5. 6 
Pr e g n a n c y  a n d a s s e s s m e nt s of f ertilit y
All fe male s u bjects of c hil d beari n g p ote ntial will ha ve a uri ne p re g na nc y test ( h C G) perf or me d 
at Visit 1 (site)  I n a d diti o n, t hese s u bjects will ha ve a ser u m pre g na nc y test perf or me d at visits 
3, 6, 8, 1 1 a n d 1 3 (ce ntral la b). If a n y of t hese tests are p ositi ve, t he s u bject m ust be disc o nti n ue d 
fr o m t he st u d y.
6. 5. 7 
A p pr o pr i at e n e s s of s af et y m e a s ur e m e nt s 
T he maj orit y of safety assess me nts selecte d f or t his st u d y are sta n dar d f or t his i n dicati o n/s u bject 
p o p ulati o n. T he y  incl u de t he m o nit ori n g a n d rec or di n g of all a d verse e ve nts a n d seri o us a d verse 
e ve nts, e val uati o n of he mat ol o g y , bl o o d c he mistr y an d uri ne, re g ular meas ure me nts of vital 
si g ns a n d t he perf or ma nce of p hys ical e xa mi nati o ns.
6. 6 
Ot h er a s s e s s m e nt s

N o v arti s
C o nfi d e nti al
P a g e 5 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
6. 6. 4 
S e n s or M e a s ur e m e nt s
T here are t w o weara ble se ns or s ys te ms t hat will be use d f or meas ure me nt: 
Acti w atc h

Wrist w or n acti vit y  a n d li g ht m o nit or usi n g t he P hili ps Acti watc h ( water pr o of) ( P hili ps 
Res pir o nics, B ost o n M A):  T his de vice is a 5 1 0 k re gistere d class 2 me dical de vice 
i n dicate d t o: “c ollect a n d sc ore data f or slee p para meters a n d assess acti vit y i n a ny 
i nsta nce w here q ua ntifia ble a nalys is of p h ysical m oti o n is desire d”.

T his de vice will be w or n o n t he n o n -d o mi na nt wrist of t he s u bject, da y  a n d ni g ht f or 
t he e ntire st u dy d urati o n fr o m t he ti me of e nr oll me nt (start of t he 2 wee k baseli ne 
p hase) t o t he e n d of t he o pe n-la bel e xte nsi o n p hase (treat me nt wee k 1 6). T his de vice 
uses a n acceler o meter t o m o nit or t he occ urre nce a n d de gree of se ns or m oti o n w hic h is 
ca pt ure d i n ‘c o u nts’ ( 0. 0 0 0 1 7 5 G- f orce per acti vit y c o u nt). Data fr o m t he 
acceler o meter will be sa m ple d at a fre q ue nc y  of 3 2 Hz a n d st ore d i n 3 0 sec o n d data 
e p oc hs. Data fr o m t he se ns or will be u pl oa de d fr o m t he Acti wat c h t o P hili ps data 
c ollecti o n s yste m d uri n g assess me nt peri o ds, w hic h will be sc ore d b y P hili ps a n d will 
be bli n de d t o treat me nt. F or t he p ur p ose of e n d p oi nt deter mi nati o n, o nset of slee p will 
be defi ne d b y 1 0 c o nsec uti ve m oti o nless ( < 4 0 c o u nts/ mi n) 1 -mi n ute i nter vals a n d 
wa ki n g will be deter mi ne d b y  1 0 c o nsec uti ve i nter vals of acti vit y ( < 4 0 c o u nts/ mi n). 
Slee p o nset a n d a wa ke ni n g ti mes will be c o nfir me d b y  a P hili ps tec h nicia n, o ver-rea d 
a n d verifie d t o ali g n wit h t y pical slee p wa ke ti mes a n d a m bie nt li g h t se ns or data .

N o v arti s
C o nfi d e nti al
P a g e 5 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

Acti watc h data ca pt ure d d uri n g t he baseli ne p hase is cr ucial. If a s u bject is n ot 
c o m plia nt ( n ot weari n g t he Acti watc h m ore t ha n 3 da y s or less t ha n half of t he 2 wee k 
baseli ne p hase), t he y  will be as ke d t o re peat t he 2 wee k baseli ne p hase. After 
ra n d o mizati o n, s u bjects w h o ref use t o wear t he de vice will be disc o nti n ue d; s u bjects 
w h o ha ve a n u ni nte nti o nal la pse of c o m plia nce will be as ke d t o i m me diatel y res u me 
weari n g t he de vice.

D uri n g visit 1, s u bjects will be trai ne d o n t he P hili ps Acti wat c h. T he Acti watc h will 
be e xc ha n ge d a n d data u pl oa de d b y t he site at visit 3, 6, 8, 1 1 a n d 1 3. 
A c ti w at c h d at a:

T otal acti vit y  c o u nts fr o m m ost acti ve 3 0 mi n utes of da y

T otal acti vit y  c o u nts fr o m m ost acti ve c o nti g u o us 3 0 mi n utes of da y

T otal acti vit y  c o unts fr o m m ost acti ve 6 mi n utes of da y

T otal acti vit y  c o u nts fr o m m ost acti ve c o nti g u o us 6 mi n utes of da y

Mea n acti vit y c o u nts per mi n ute d uri n g slee p i nter val 

Mea n acti vit y per da y: T his is t he a vera ge acti vit y val ue d uri n g all acti vit y peri o ds 
a b o ve 2 0 0 cts/ mi n i n a 2 4 -hr da y . It is a c o m pre he nsi ve assess me nt of acti vit y.

Slee p Efficie nc y : ( Sc ore d T otal Slee p Ti me di vi de d b y ( Slee p I nter val D urati o n mi n us 
T otal I n vali d Ti me ( Slee p/ Wa ke)) of t he gi ve n Rest I nter val) m ulti plie d b y  1 0 0.

Wa ke After Slee p O nse t ( W A S O): T he t otal n u m ber of e p oc hs bet wee n t he Start Ti me 
a n d t he E n d Ti me of t he gi ve n Slee p I nter val sc ore d as W A K E b y Acti ware s oft ware 
( or ma n ually set as W A K E d uri n g o ver rea d) m ulti plie d b y t he E p oc h Le n gt h i n 
mi n utes (s o t he Wa ke After Slee p O nset is i n mi n utes). 

N o v arti s
C o nfi d e nti al
P a g e 5 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
6. 6. 5 
R e s o ur c e utili z ati o n 
N ot A p plica ble.
7 
S af et y  m o nit ori n g
7. 1 
A d v er s e e v e nt s
A n a d verse e ve nt ( A E) is a n y u nt o war d me dical occ urre nce (e. g., a n y unfa v ora ble a n d 
u ni nte n de d si g n [i ncl u di n g a b n or mal la b orat or y fi n di n gs], s ym pt o m or disease) i n a s u bject or 
cli nical i n vesti gati o n s u bject after pr ovi di n g writte n i nf or me d c o nse nt f or partici pati o n i n t he 
st u d y until t he e n d of st u d y visit. T heref ore, a n A E m a y  or m a y  not be te m p orall y or ca usall y 
ass ociate d wit h t he use of a me dici nal (i n vesti gati o nal) pr o d uct.
I n a d diti o n, all re p orts of i nte nti o nal mis use a n d a b use of t he pr o d u ct are als o c o nsi dere d a n 
a d verse e ve nt irres pecti ve if a cli nical e ve nt has occ urre d.
T he occ urre nce of a d verse e ve nts m ust be s o u g ht b y n o n -directi ve q uesti o ni n g of t he patie nt at 
eac h visit d uri n g t he st u d y. A d verse e ve nts als o ma y be detecte d w he n t he y are v ol u nteere d b y 
t he s u bject d uri n g or bet wee n visits or t hr o u g h p h y sical e xa mi nati o n fi n di n gs, la b orat or y test 
fi n di n gs, or ot her assess me nts.
A b n or mal la b orat or y val ues or test res ults c o nstit ute a d verse e ve nts o nl y  if the y  fulfill at least 
o ne of t he f oll o wi n g criteria:

t he y i n d uce cli nical si g ns or s ym pt o ms, 

t he y are c o nsi dere d cli nicall y si g nifica nt, 

t he y re q uire t hera p y. 
Cli nicall y  si gnifica nt a b n or mal la b orat or y val ues or test res ults m ust be i de ntifie d t hr o u g h a 
re vie w of val ues o utsi de of n or mal ra n ges/cli nicall y nota ble ra n ges, si g nifica nt c ha n ges fr o m 
baseli ne or t he pre vi o us visit, or val ues w hic h are c o nsi dere d t o be n o n -t ypical i n s u bjects wit h 
u n derl y i n g disease. I n vesti gat ors ha ve t he res p o nsi bilit y for ma na gi n g t he safety of i n di vi d ual
s u bject a n d i de ntif yi n g a d verse e ve nts. Alert ra n ges f or la b orat or y a n d ot her test a b n or malities 
are i ncl u de d i n A p pe n di x 1 .
A d verse e ve nts m ust be rec or de d i n t he A d verse E ve nts C R F u n der t he si g ns, s ym pt o ms or 
dia g n osis ass ociate d wit h t he m, acc o m pa nie d b y  t he f oll o wi n g i nf or mati o n:

N o v arti s
C o nfi d e nti al
P a g e 5 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
t he [se verit y gra de] (select as a p pr o pri ate)
If severity gr a de is selecte d, a d d t he f oll o wi n g

mil d: us uall y  tra nsie nt i n nat ure a n d ge nerall y n ot i nterferi n g wit h n or mal acti vities

m o derate: s ufficie ntl y  disc o mf orti n g t o i nterfere wit h n or mal acti vities

se vere: pre ve nts n or mal acti vities
All a d verse e ve nts m ust be treate d a p pr o priatel y. Treat me nt m a y  incl u de o ne or m ore of t he 
f oll o wi n g: 

n o acti o n ta ke n (e. g. f urt her o bs er vati o n o nl y) 

[i n vesti gati o nal] treat me nt d osa ge i ncrease d/re d uce d

[i n vesti gati o nal] treat me nt i nterr u pte d/ wit h dra w n

c o nc o mita nt me dicati o n or n o n- dr u g t hera p y gi ve n 

n o n- dr u g t hera p y gi ve n 

patie nt h os pitalize d/ patie nt’s h os pitalizati o n pr ol o n ge d (see Secti o n 7. 2 f or defi niti o n 
of S A E)

its o utc o me ( n ot rec o vere d/ n ot res ol ve d; rec o vere d/res ol ve d; rec o veri n g/res ol vi n g, 
rec o vere d/res ol ve d wit h se q uelae; fatal; or u n k n o w n)
O nce a n a d verse e ve nt is detecte d , it m ust be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d t o 
be per ma ne nt, a n d assess me nt m ust be ma de at eac h visit ( or m ore fre q ue ntl y , if necessar y) of 
a n y c ha n ges i n se verit y, t he s us pecte d relati o ns hi p t o t he st u d y dr u g, t he i nter ve nti o ns re q uire d 
t o treat it, a n d t he o utc o me.
I nf or mati o n a b o ut c o m m o n si de effects alrea d y k n o w n a b o ut t he i n vesti gati o nal dr u g ca n be 
f o u n d i n t he I nvesti gat or Br oc h ure (IB). T his i nf or mati o n will be i ncl u de d i n t he s u bject 
i nf or me d c o nse nt a n d s h o ul d be disc usse d w it h t he s u bject d uri n g t he st u d y as nee de d. A n y n e w 
i nf or mati o n re gar di n g t he safety pr ofile of t he me dici nal pr o d uct t hat is i de ntifie d bet wee n I B 
u p dates will be c o m m u nicate d as a p pr o priate, f or e xa m ple, via a n I n vesti gat or N otificati o n or 
a n A g gre gate S afet y Fi n di n g. Ne w i nf or mati o n mi g ht re q uire a n u p date t o t he i nf or me d c o nse nt 
a n d has t he n t o be disc usse d wit h t he s u bject.
T he i n vesti gat or m ust als o i nstr uct eac h s u bject t o re p ort a n y ne w a d verse e ve nt ( be yo n d t he 
pr ot oc ol o bser vati o n peri o d) t hat t he s u bject, or t he s u bject’s pers o nal p h y sicia n, belie ves mi g ht 
reas o na bly be relate d t o st u d y treat me nt. T his i nf or mati o n m ust be rec or de d i n t he i n vesti gat or’s 
s o urce d oc u me nts; h o we ver, if t he A E meets t he criteria of a n S A E, it m ust be re p orte d t o 
N o vart is.

N o v arti s
C o nfi d e nti al
P a g e 5 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
7. 2 
S eri o u s a d v er s e e v e nt s
7. 2. 1 
D efi niti o n of S A E
A n S A E is defi ne d as a n y ad verse e ve nt [a p peara nce of ( or w orse ni n g of a n y pre-e xisti n g)] 
u n desira ble si g n(s), s ym pt o m(s) or me dical c o n diti o ns(s)) w hic h meets a n y o ne of t he f oll o wi n g 
criteria:

is fatal or life-t hreate ni n g 

res ults i n persiste nt or si g nifica nt disa bilit y/i nca pacit y

c o nstit utes a c o n ge nital a n o mal y / birt h defect

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, u nless 
h os pitalizati o n is f or:

r o uti ne treat me nt or m o nit ori n g of t he st u die d i n dicati o n, n ot ass ociate d wit h a n y 
deteri orati o n i n c o n diti o n (s pecif y  w hat t his i ncl u des)

electi ve or pre-pla n ne d treat me nt f or a pre -e xisti n g c o n diti o n t hat is u nrelate d t o t he 
i n dicati o n u n der st u d y a n d has n ot w orse ne d si nce si g ni n g t he i nf or me d c o nse nt

treat me nt o n a n e mer ge nc y o ut patie nt basis f or a n e ve nt n ot f ulfilli n g a n y of t he 
defi niti o ns of a S A E gi ve n a b o ve a n d n ot res ulti n g i n h os pital a d missi o n 

s ocial reas o ns a n d res pite care i n t he a bse nce of a n y deteri orati o n i n t he patie nt’s 
ge neral c o n diti o n

is me dicall y si g nifica nt, e. g. defi ne d as a n e ve nt t hat je o par dizes t he patie nt or ma y re q uire 
me dical or s ur gical i nter ve nti o n.
All mali g na nt ne o plas ms will be assesse d as seri o us u n der “ me dicall y si g nifica nt” if ot her 
seri o us ness criteria are n ot met.
Life -t hreate ni n g i n t he c o nte xt of a S A E refers t o a reacti o n i n w hic h t he patie nt was at ris k of 
deat h at t he ti me of t he reacti o n; it d oes n ot refer t o a reacti o n t hat h y p ot heticall y  mi ght ha ve 
ca use d deat h if it were m ore se ver e ( please refer t o A n ne x IV, I C H - E 2 D G ui deli ne).
Me dical a n d scie ntific j u d g me nt s h o ul d be e xercise d i n deci di n g w het her ot her sit uati o ns s h o ul d 
be c o nsi dere d seri o us reacti o ns, s uc h as i m p orta nt me dical e ve nts t hat mi g ht n ot be i m me diatel y 
life t hreate ni ng or res ult i n deat h or h os pitalizati o n b ut mi g ht je o par dize t he patie nt or mi g ht 
re q uire i nter ve nti o n t o pre ve nt o ne of t he ot her o utc o mes liste d a b o ve. E xa m ples of s uc h e ve nts 
are i nte nsi ve treat me nt i n a n e mer ge nc y ro o m or at h o me f or aller gic br o nc h os p as m, bl o o d 
d y scrasias or c o n v ulsi o ns t hat d o n ot res ult i n h os pitalizati o n or de vel o p me nt of de pe n de nc y or 
a b use ( please refer t o A n ne x IV, I C H - E 2 D G ui deli ne).
A n y  s us pecte d tra ns missi o n via a me dici nal pr o d uct of a n i nfecti o us a ge nt is als o c o nsi dere d a 
seri o us a d verse reacti o n.
7. 2. 2 
S A E r e p orti n g
T o e ns ure patie nt safety,  ever y  SA E, re gar dless of ca usalit y, occ urri n g after t he patie nt has 
pr o vi de d i nf or me d c o nse nt a n d u ntil 3 0 da y s [ after t he last st u d y visit/ f oll o wi n g t he last 
a d mi nistrati o n of st u d y treat ment if t here are p ost -treat me nt f oll o w- u p visits wit h n o re q uire d 
pr oce d ures] m ust be re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. A n y 

N o v arti s
C o nfi d e nti al
P a g e 5 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
S A Es e x perie nce d after t he 3 0 da y  peri o d [after t he last st u d y visit/ f oll o wi n g t he last 
a d mi nistrati o n of st u d y treat me nt if t here are p ost -treat me nt f oll o w- u p visits wit h n o re q uire d 
pr oce d ures] s h o ul d o nl y  be re p orte d t o N o vartis if t he i n vesti gat or s us pects a ca usal relati o ns hi p 
t o st u d y treat me nt. 
All f oll o w -u p i nf or mati o n f or t he S A E i ncl u di n g i n f or mati o n o n c o m plicati o ns, pr o gressi o n of 
t he i nitial S A E a n d rec urre nt e pis o des m ust be re p orte d as f oll o w- u p t o t he ori gi nal e pis o de 
wit hi n 2 4 h o urs of t he i n vesti gat or recei vi n g t he f oll o w -u p i nf or mati o n. A n S A E occ urri n g at a 
differe nt ti me i nter val o r ot her wise c o nsi dere d c o m pletel y unrelate d t o a pre vi o usl y  re p orte d 
o ne m ust be re p orte d se paratel y as a ne w e ve nt.
I nf or mati o n a b o ut all S A Es is c ollecte d a n d rec or de d o n t he Seri o us A d verse E ve nt Re p ort 
F or m; all a p plica ble secti o ns of t he f or m m ust be c o m plete d i n or der t o pr o vi de a cli nicall y 
t h or o u g h re p ort. T he i n vesti gat or m ust assess t he relati o ns hi p of eac h S A E c o m plete t he S A E 
Re p ort F or m i n E n glis h, a n d s u b mit t he c o m plete d f or m wit hi n 2 4 h o urs t o N o vartis. Detaile d 
i nstr ucti o ns re gar di n g t he s ub missi o n pr ocess a n d re q uire me nts f or si g nat ure are t o be f o u n d i n 
t he i n vesti gat or f ol der pr o vi de d t o eac h site. 
F oll o w - u p i nf or mati o n is s u b mitte d as i nstr ucte d i n t he i n vesti gat or f ol der. Eac h re-occ urre nce, 
c o m plicati o n, or pr o gressi o n of t he ori gi nal e ve nt m ust be re p orte d as a f oll o w -u p t o t hat e ve nt 
re gar dless of w he n it occ urs. T he f oll o w-u p i nf or mati o n s h o ul d descri be w het her t he e ve nt has 
res ol ve d or c o nti n ues, if a n d h o w it was treate d, w het her t he bli n d was br o ke n or n ot, a n d 
w het her t he s u bjec t c o nti n ue d or wit h dre w fr o m st u d y partici pati o n.
If t he S A E is n ot pre vi o usl y d oc u me nte d i n t he I n vesti gat or’s Br oc h ure or Pac ka ge I nsert ( ne w 
occ urre nce) a n d is t h o u g ht t o be relate d t o t he st u d y treat me nt a Dr u g Safet y a n d E pi de mi ol o g y 
De part me nt ass oci ate ma y ur ge ntly re q uire f urt her i nf or mati o n fr o m t he i n vesti gat or f or healt h 
a ut h orit y re p orti n g. N o vartis ma y  nee d t o iss ue a n I nvesti gat or N otificati o n (IN) t o i nf or m all 
i n vesti gat ors i n v ol ve d i n a n y st u d y wit h t he sa me st u d y treat me nt t hat t his S A E ha s bee n 
re p orte d. 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 c ollecte d a n d 
re p orte d t o t he c o m pete nt a ut h orities a n d rele va nt et hics c o m mittees i n acc or da nce wit h E U 
G ui da nce 2 0 1 1/ C 1 7 2/ 0 1 or as per nati o nal re g ulat or y  re q uire me nts i n partici pati n g c o u ntries.
7. 3 
R e p orti n g of st u d y  tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e
Me dicati o n err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a d mi nistrati o n or 
m o nit ori n g of a me dici ne w hile u n der t he c o ntr ol of a healt hcare pr ofessi o nal, patie nt or 
c o ns u mer ( E M A defi niti o n).
Mis use refers t o sit uati o ns w here t he me dici nal pr o d uct is i nte nti o nall y an d i na p pr o priately use d 
n ot i n acc or da nce wit h t he pr ot oc ol.
A b use c orres p o n ds t o t he persiste nt or s p ora dic, i nte nti o nal e xcessi ve use of a me d ici nal pr o d uct, 
w hic h is acc o m pa nie d b y har mf ul p h ys ical or psyc h ol o gical effects.
St u d y  treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol will be c ollecte d i n 
t he D A R ( d ose a d mi nistrati o n rec or d) e C R F irres pecti ve of w het her or n ot associate d wit h a n 
A E/ S A E a n d re p orte d t o Safet y onl y  if ass ociate d wit h a n S A E. Mis use or a b use will be 
c ollecte d a n d re p orte d i n t he safety data base irres pecti ve of it bei n g ass ociate d wit h a n A E/ S A E.

N o v arti s
C o nfi d e nti al
P a g e 5 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T a bl e 7- 1 
G ui d a n c e f or c a pt uri n g t h e st u d y  tr e at m e nt err or s i n cl u di n g mi s u s e
Tr e at m e nt err or 
t y p e
D o c u m e nt i n D o s e 
A d mi ni str ati o n ( D A R) 
e C R F ( Y e s/ N o)
D o c u m e nt i n A E 
e C R F
C o m pl et e S A E f or m
U ni nt e nti o n al st u d y 
tr e at m e nt err or
Y e s
O nl y if a s s o ci at e d wit h 
a n A E
O nl y if a s s o ci at e d wit h a n 
S A E
Mi s u s e/ A b u s e 
Y e s
Y e s 
Y e s, e v e n if n ot a s s o ci at e d 
wit h a S A E
7. 4 
Pr e g n a n c y  r e p orti n g
T o e ns ure s u bject safet y, eac h pre g na nc y occ urri n g after si g ni n g t he i nf or me d c o nse nt m ust be 
re p orte d t o N o vartis wit hi n 2 4 h o urs of lear ni n g of its occ urre nce. T he pre g na nc y  sh o ul d be 
f oll o we d u p t o deter mi ne o utc o me, i ncl u di n g s p o nta ne o us or v ol u ntar y  t er mi nati o n, details of 
t he birt h, a n d t he prese nce or a bse nce of a n y b irt h defects, c o n ge nital a b n or malities, or mater nal 
a n d/ or ne w b or n c o m plicati o ns.
Pre g na nc y  must be rec or de d o n t he P har mac o vi gila nce Pre g na nc y  For m a n d re p orte d b y  the 
i n vesti gat or t o t he l ocal N o vartis Dr u g Safet y a n d E pi de mi ol o g y  De part me nt. Pre g na nc y 
f oll o w- u p s h o ul d be rec or de d o n t he sa me f or m a n d s h o ul d i ncl u de a n assess me nt of the 
p ossi ble relati o ns hi p t o t he st u d y  treat me nt. 
A n y  SA E e x perie nce d d uri n g t he pre g na nc y  an d u nrelate d t o t he pre g na nc y  must be re p orte d 
o n a S A E f or m.
8 
D at a r e vi e w a n d d at a b a s e m a n a g e m e nt
8. 1 
Sit e m o nit ori n g
Bef ore st u d y initiati o n, at a site i nitiati o n visi t or at a n i n vesti gat or’s meeti n g, a N o vartis 
re prese ntati ve will re vie w t he pr ot oc ol a n d (e) C R Fs wit h t he i n vesti gat ors a n d t heir staff. 
D uri n g t he st u d y, N o vartis e m pl o y s se veral met h o ds of e ns uri n g pr ot oc ol a n d G C P c o m plia nce 
a n d t he q ualit y /i nte grit y of t he sites’ data. T he fiel d m o nit or will visit t he site t o c hec k t he 
c o m plete ness of patie nt rec or ds, t he acc urac y of e ntries o n t he (e) C R Fs, t he a d here nce t o t he 
pr ot oc ol a n d t o G o o d Cli nical Practice, t he pr o gress of e nr oll me nt, a n d t o e ns ure t hat st u dy
treat me nt is bei n g st ore d, dis pe nse d, a n d acc o u nte d f or acc or di n g t o s pecificati o ns. Ke y  st u dy 
pers o n nel m ust be a vaila ble t o assist t he fiel d m o nit or d uri n g t hese visits. C o nti n u o us re m ote 
m o nit ori n g of eac h site’s data ma y be perf or me d b y  a ce ntralize d N o vartis C R A or ga nizati o n. 
A d diti o nall y , a ce ntral a nal ytics or ga nizati o n ma y  anal yz e data & i de ntif y ris ks & tre n ds f or 
site o perati o nal para meters, a n d pr o vi de re p orts t o N o vartis Cli nical Tea ms t o assist wit h trial 
o versi g ht.
T he i n vesti gat or m ust mai nt ai n s o urce d oc u me nts f or eac h patie nt i n t he st u d y, c o nsisti n g of 
case a n d visit n otes ( h os pital or cli nic me dical rec or ds) c o ntai ni n g de m o gra p hic a n d me dical 

N o v arti s
C o nfi d e nti al
P a g e 6 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
i nf or mati o n, la b orat or y data, electr ocar di o gra ms, a n d t he res ults of a n y ot her tests or 
assess me n ts. All i nf or mati o n o n C R Fs m ust be tracea ble t o t hese s o urce d oc u me nts i n t he 
s u bject’s file. T he i n vesti gat or m ust als o kee p t he ori gi nal i nf or me d c o nse nt f or m si g ne d b y t he 
s u bject (a si g ne d c o py is gi ve n t o t he patie nt).
T he i n vesti gat or m ust gi ve t he m o nit or access t o all rele va nt s o urce d oc u me nts t o c o nfir m t heir 
c o nsiste nc y wit h t he (e) C R F e ntries. N o vartis m o nit ori n g sta n dar ds re q uire f ull verificati o n f or 
t he prese nce of i nf or me d c o nse nt, a d here nce t o t he i ncl usi o n/e xcl usi o n criteria, d oc u me ntati o n
of S A Es, a n d of data t hat will be use d f or all pri mar y  varia bles. A d diti o nal c hec ks of t he 
c o nsiste nc y of t he s o urce data wit h t he (e) C R Fs are perf or me d acc or di n g t o t he st u d y-s pecific 
m o nit ori n g pla n. N o i nf or mati o n i n s o urce d oc u me nts a b o ut t he i de ntit y of t he s u bjects will be 
discl ose d.
8. 2 
D at a c oll e cti o n
Desi g nate d i n vesti gat or staff will e nter t he data re q uire d b y  the pr ot oc ol i nt o t he Electr o nic 
Case Re p ort F or ms usi n g f ully vali date d s oft ware t hat c o nf or ms t o U S C F R 2 1 Part 1 1 
re q uire me nts. Desi g nate d i n vesti gat or site staff will n ot be gi ve n access t o the E D C s yste m u ntil 
t he y ha ve bee n trai ne d. A ut o matic vali dati o n pr o gra ms c hec k f or data discre pa ncies a n d, b y  
ge nerati n g a p pr o priate err or messa ges, all o w t he data t o be c o nfir me d or c orrecte d bef ore 
tra nsfer of t he data t o t he C R O w or ki n g o n be half of N o vartis. T he I n vesti gat or m ust certif y 
t hat t he data e ntere d i nt o t he Electr o nic Case Re p ort F or ms are c o m plete a n d acc urate. After 
data base l oc k, t he i n vesti gat or will recei ve c o pies of t he patie nt data f or arc hi vi n g at t he 
i n vesti gati o nal site. 
8. 3 
D at a b a s e m a n a g e m e nt a n d q u alit y  c o ntr ol
C R O w or ki n g o n be half of N o vartis re vie w t he data e ntere d i nt o t he C R Fs b y  in vesti gati o nal 
staff f or c o m plete ness a n d acc urac y an d i nstr uct t he site pers o n nel t o ma ke a n y re q uire d 
c orrecti o ns or a d diti o ns. Q ueries are se nt t o t he i n vesti gati o nal site usi n g a n electr o nic data 
q uer y . Desi g nate d i n vesti gat or site staff is re q uire d t o res p o n d t o t he q uer y a n d c o nfir m or 
c orrect t he data. 
C o nc o mita nt me dicati o ns e ntere d i nt o t he data base will be c o de d usi n g t he W H O 
Dr u g 
Refere nce Li st, w hic h e m pl o ys t he A nat o mical T hera pe utic C he mical classificati o n s yste m. 
C o nc o mita nt pr oce d ures, n o n- dr u g t hera pies a n d a d verse e ve nts will be c o de d usi n g t he 
Me dical dicti o nar y  f or re g ulat or y acti vities ( Me d D R A) ter mi n ol o g y.
La b orat or y  sa m ples will be pr ocesse d ce ntrall y a n d t he res ults will be se nt electr o nicall y t o 
N o vartis ( or a desi g nate d C R O ).
Diar y  data will be e ntere d i nt o a n electr o nic diar y b y t he s u bject w h o will fill i n t heir P R O data 
i n a site base d ta blet. T he s yste m will be s u p plie d b y  a ve n d or(s), w h o will als o ma na ge t he 
data base. T he data base will be se nt electr o nicall y t o N o vartis pers o n nel ( or desi g nate d C R O).
Ra n d o mizati o n c o des a n d data a b o ut all st u d y dr u g(s) dis pe nse d t o t he patie nt a n d all d osa ge 
c ha n ges will be trac ke d usi n g an I nteracti ve Res p o nse Tec h n ol o g y  (I RT). T he s yste m will be 

N o v arti s
C o nfi d e nti al
P a g e 6 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
s u p plie d b y  a ve n d or, w h o will als o ma na ge 
t he data base. T he data base will be se nt 
electr o nicall y t o N o vartis ( or a desi g nate d C R O).
Eac h occ urre nce of a c o de brea k via I R T will be re p orte d t o t he cli nical tea m a n d m o nit or.  T he 
c o de brea k f u ncti o nalit y will re mai n a vaila ble u ntil st u d y sh ut d o w n or u p o n re q uest of N o vartis. 
T he occ urre nce of rele va nt pr ot oc ol de viati o ns will be deter mi ne d. After t hese acti o ns ha ve 
bee n c o m plete d a n d t he data base has bee n declare d t o be c o m plete a n d acc urate, it will be 
l oc ke d a n d t he treat me nt c o des will be u n bli n de d a n d ma de a vaila ble f or data a nal ys is. A n y 
c ha n ges t o t he data base after t hat ti me ca n o nl y be ma de after writte n a gree me nt b y  No vartis 
ma na ge me nt.
8. 4 
D a t a M o nit ori n g C o m mitt e e
N ot re q uire d.
8. 5 
A n gi o e d e m a A d j u di c ati o n C o m mitt e e
It is i m p orta nt t hat t he i n vesti gat or pa y s s pecial atte nti o n t o a n y s welli n g or e de ma t hat ma y 
rese m ble a n gi oe de ma or a n gi oe de ma-li ke e ve nts t hat m a y  be re p orte d b y  su bjects. T here wil l 
be a se parate e C R F f or a n gi oe de ma e ve nts. If s uc h a n e ve nt occ urs, t he i n vesti gat or will 
c o m plete a n A dj u dicati o n Q uesti o n naire f or A n gi oe de ma -li ke E ve nt f or m ( pr o vi de d b y  
N o vartis) t o s u m marize t he e ve nt, its treat me nt, a n d its ulti mate o utc o me a n d c o m mu nicate t his 
re p ort t o N o vartis as s o o n as p ossi ble. F oll o w-u p re p orts m ust be c o m m u nicate d t o N o vartis as 
s o o n as ne w i nf or mati o n re gar di n g t he e ve nt bec o mes a vaila ble. All h os pital rec or ds relate d t o 
t he e ve nt m ust be c o m m u nicate d t o N o vartis. 
Occasi o na ll y, t he i n vesti gat or ma y be c o ntacte d b y N o vartis re gar di n g A Es t hat were re p orte d 
o n be half of s u bjects t hat ma y  rese m ble a n a n gi oe de ma-li ke e ve nt. T he i n vesti gat or or his/ her
dele gate d staff m ust c o m plete t he re q uire d re p ort f or ms a n d s u p pl y the re q uired me dical rec or ds 
f or s uc h e ve nts, re gar dless of w het her t he i n vesti gat or vie ws t he e ve nt i n q uesti o n as 
a n gi oe de ma or n ot.
All a n gi oe de ma re p orts will be f or war de d t o a n A n gi oe de ma A dj u dicati o n C o m mittee ( A A C) 
b y  No vartis f or assess me nt. T he a dj u dicati o n c o m mittee will 
a dj u dicate all s us pecte d 
a n gi oe de ma e ve nts i n a u nif or m a n d c o nsiste nt ma n ner, a n d will assi g n se verit y for eac h 
c o nfir me d case.  
T he A n gi oe de ma A dj u dicati o n C o m mittee ( A A C) c o nsists of a gr o u p of e x perts i n cli nical 
a n gi oe de ma w h o ha ve bee n selecte d acc or di n g t o t heir e d ucati o nal, cli nical, a n d researc h 
e x perie nce a n d are i n de pe n de nt fr o m N o vartis. T he p ur p ose of t he A A C is t o re vie w a n d t o 
a dj u dicate all s us pecte d a n gi oe de ma e ve nts i n a u nif or m a n d c o nsiste nt ma n ner a n d t o assi g n 
se verity f or eac h c o nfir me d case f or t he pr oject wi de sac u bitril/ valsarta n pr o gra m. T he A A C 
will re mai n bli n de d t o treat me nt all ocati o n d uri n g t he a dj u dicati o n pr ocess w he ne ver p ossi ble 
a n d necessar y .
T he a dj u dicati o n c o m mittee will re mai n bli n de d t o treat me nt all o cati o n d uri n g t he a dj u dicati o n 
pr ocess w he ne ver p ossi ble a n d necessar y .

N o v arti s
C o nfi d e nti al
P a g e 6 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
S u b missi o n of a n a n gi oe de ma re p ort is n ot a s u bstit uti o n f or t he s u b missi o n of a S A E re p ort. If 
a n a n gi oe de ma-li ke e ve nt satisfies t he defi niti o n of a S A E, t he i n vesti gat or m ust s u b mit a S A E 
re p ort i n a d diti o n t o t he A dj u dicati o n Q uesti o n naire f or a n A n gi oe de ma-li ke E ve nt.
9 
D at a a n al y si s 
T he a nal ys is will be c o n d ucte d o n all s u bject data at t he ti me t he trial e n ds. A n y  data a nal ys is 
carrie d o ut i n de pe n de ntl y b y  the i n vesti gat or s h o ul d b e s u b mitte d t o N o vartis bef ore p u blicati o n 
or prese ntati o n.
A desi g nate d C o ntract Researc h Or ga nizati o n will perf or m t he statistical a nal y sis.
It is pla n ne d t hat t he data fr o m all ce nters t hat partici pate i n t his pr ot oc ol will be c o m bi ne d, s o 
t hat a n a de q uate n u m ber of s u bjects will be a vaila ble f or a nal y sis.
U nless ot her wise s pecifie d, all statistical tests will be c o n d ucte d a gai nst a t w o -si de d alter nati ve 
h y p ot hesis, e m pl o y i n g a si g nifica nce le vel of 0. 0 5.
Efficac y , safety, a n d ot her data will be s u m marize d. F or c o nti n u o us varia bles, s u m mar y 
statistics ( mea n, sta n dar d de viati o n, me dia n, 2 5t h a n d 7 5t h perce ntiles, i nter q uartile ra n ge, 
mi ni m u m, a n d ma xi m u m) at eac h ti me p oi nt a n d f or c ha n ge fr o m baseli ne t o eac h ti me p oi nt 
will be re p orte d b y treat me nt gr o u p. Discrete varia bles will be s u m marize d b y  fre q ue ncies a n d 
perce nta ges.
9. 1 
A n al y si s s et s 
T he f oll o wi n g s u bject sets will be use d f or t he statistical re p orti n g a n d a nal yses:
T he Ra n d o mize d Set will c o nsist of all ra n d o mize d s u bjects.
T he F ull A nal ys is Set ( F A S) will c o nsist of all s u bjects wit h t he e xce pti o n f or t h ose s u bjects 
w h o ha ve n ot bee n q ualifie d f or ra n d o mizati o n a n d ha ve n ot recei ve d st u d y dr u g, b ut ha ve bee n 
i na d verte ntly ra n d o mize d i nt o t he st u d y. F oll o wi n g t he i nte nt-t o-treat pri nci ple, s ubjects will 
be a nal yz e d acc or di n g t o t he treat me nt t o w hic h t he y were assi g ne d at ra n d o mizati o n.  Efficacy 
varia bles will be a nal yz e d base d o n t he F A S as t he pri mar y  set.
T he Safet y  Set ( S A F) will c o nsist of all ra n d o mize d s u bjects w h o recei ve d at least o ne d ose of 
st u d y dr u g. S u bjects will be i ncl u de d i n t he a nal ys is acc or di n g t o t he treat me nt act uall y recei ve d. 
T he Safet y Set will be use d f or t he a nal ys es of safet y varia bles.
9. 2 
S u bj e ct d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s
Baseli ne val ue is defi ne d as t he last n o n- missi n g assess me nt pri or t o t he first d ose of 
ra n d o mize d st u d y me dicati o n, u nless s pecifie d ot her wise i n t he pr ot oc ol.
S u m mar y  statistics will be pr o vi de d b y  treat me nt gr o u p f or de m o gra p hics a n d baseli ne 
c haracteristics. Cate g orical varia bles will be s u m marize d usi n g fre q ue nc y  a n d perce nta ge.
T he Ra n d o mize d Set a n d F A S will be t he s u bject sets f or t he a b o ve a nal ys es.

N o v arti s
C o nfi d e nti al
P a g e 6 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
9. 3 
Tr e at m e nt s 
T he o verall d urati o n o n t he d o u ble -bli n d st u d y dr u g a n d d uri n g t he o pe n la bel treat me nt wit h 
st u d y dr u g will be s u m marize d b y  treat me nt gr o u p usi n g mea n, sta n dar d de viati o n, me dia n, 
2 5t h a n d 7 5t h perce ntiles, i nter q uartile ra n ge, mi ni m u m, a n d ma xi m u m. A d diti o nall y , t he 
n u m ber a n d perce nta ge of s u bjects will be s u m marize d b y  treat me nt gr o u p f or d urati o n cate g or y.
C o n c o mita nt me dicati o ns 
a n d si g nifica nt n o n -dr u g t hera pies, pri or t o a n d after t he 
ra n d o mizati o n date will be s u m marize d (fre q ue nc y a n d perce nt) by t hera pe utic class, preferre d 
ter m, a n d treat me nt gr o u p.
T he Safet y Set will be use d f or t he a b o ve a nal ys es.
9. 4 
A n al y si s of t h e pri m ar y  vari a bl e( s)
9. 4. 1 
Pri m ar y  V ari a bl e( s)
T he pri mar y e n d p oi nt is t he c ha n ge i n mea n acti vit y c o u nts c ollecte d d uri n g t he m ost acti ve 3 0 
mi n utes of t he s u bject’s da y  bet wee n baseli ne p hase ( mea n of data c ollecte d eac h d a y  duri n g 
wee k - 1) a n d t he fi nal ra n d o mize d treat me nt p hase meas ure me nt ( mea n of data c ollecte d eac h 
da y  duri n g wee k 8 ), as meas ure d b y  wrist-w or n acceler o meter c ollecte d acti gra p h y (t otal c o u nts 
per 3 0 mi n peri o d c ollecte d d uri n g t he m ost acti ve 3 0 mi n utes of eac h da y ).
9. 4. 2 
St ati sti c al m o d el, h y p ot h e si s, a n d m et h o d of a n al y si s
Let µ j de n ote t he p o p ulati o n mea n of c ha n ge i n mea n acti vit y c o u nt fr o m baseli ne p hase t o 
Wee k 8 f or treat me nt gr o u p j, j = 0, 1, w here 0 c orres p o n ds t o e nala pril a n d 1 c orres p o n ds t o 
sac u bitril/ valsarta n.
T he f oll o wi n g n ull h y p ot hesis ( H 0) will be teste d a gai nst t he alter nati ve hy p ot hesis ( H A ):
H 0: µ1 – µ 0 = 0 
H A : µ1 – µ 0 ≠ 0
T he pri mar y  efficac y varia ble will be a nal yz e d b y  a n a nal ys is of c o varia nce ( A N C O V A) m o del 
wit h treat me nt a n d baseli ne acti vit y as e x pla nat or y varia bles. T he least s q uares mea ns of t he 
t w o treat me nt gr o u ps, least s q uares mea n differe nce of t he treat me nt gr o u ps, 9 5 % c o nfi de nce 
i nter val f or t he differe nce i n t he t w o treat me nt gr o u ps, a n d p- val ue base d o n t he fitte d li near 
m o del will be re p orte d. If t he p- val ue is < 0. 0 5 a n d t he least s q uares mea n differe nce of t he 
treat me nt 
gr o u ps 
fa v ors 
sac u bitril/ valsarta n, 
statistical 
si g nifica nce 
i n 
fa v or 
of 
sac u bitril/ valsarta n will be declare d.
  
Bef ore perf or mi n g t he a b o ve a nal ys is, tests of n or malit y of t he varia ble, c ha n ge i n mea n 
acti vit y c o u nts c ollecte d d uri n g t he m ost acti ve 3 0 mi n utes of t he s u bject’s da y bet wee n 
baseli ne a n d Wee k 8, a n d t he l o g of t he varia ble (l o g ( Wee k 8 val ue) – l o g ( baseli ne val ue)) 
will be perf or me d. I n t he e ve nt t he varia ble is n ot n or mall y distri b ute d ( base d o n S ha pir o-
Wil k test p -val ue < 0. 0 5) b ut t he l o g n or mal distri b uti o n fits better, t he a b o ve a nalys is will be 
perf or me d usi n g t he l o g tra nsf or me d data. A nti-l o g of t he least s q uares mea n differe nce of t he 

N o v arti s
C o nfi d e nti al
P a g e 6 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
treat me nt gr o u ps will be use d t o re p ort t he rati o of t he treat me nt differe nce i n t he ori gi nal 
scale.
T he pri mar y  a nalys is of t he pri mar y efficac y varia ble will be base d o n t he F ull A nalys is Set.
9. 4. 3 
H a n dli n g of mi s si n g v al u e s/ c e n s ori n g/ di s c o nti n u ati o n s
Missi n g data will be i m p ute d usi n g t he last-o bser vati o n -carrie d-f or war d ( L O C F) met h o d. If a 
s u bject has n o p ost -baseli ne val ue, t he missi n g val ue will n ot be i m p ute d a n d t he s u bject will 
be re m o ve d fr o m t he a nal ysis. If a s u bject’s data is missi n g or u ne val ua ble f or t he wee k 
prece di n g ra n d o mizati o n, t he data fr o m t he pre vi o us wee k will be use d as t he baseli ne 
meas ure me nt. If a s u bject’s data is missi n g or u ne val ua ble f or eac h of t hese wee ks, t he s u bject 
will be e xcl u de d fr o m t he a nal ys is. 
9. 4. 4 
S e n siti vit y a n al y s e s
A s u p p orti ve n o n para metric a nal ys is will be perf or me d t o e xa mi ne t he c o nsiste nc y of 
res ults. F or t his s u p p orti ve a nal ys is, t he pri mar y  efficac y varia ble will be a nal yz e d usi n g t he 
Wilc o x o n ra n k- s u m test. T he pr o ba bilit y of o ne treat me nt bei n g better t ha n t he ot her treat me nt 
will be esti mate d ( base d o n t he Wilc o x o n ra n k-s u m test) a n d t he ass ociate d 9 5 % c o nfi de nce 
i nter val will be re p orte d (C he n a n d Kia nifar d 2 0 0 0 ).
9. 5 
A n al y si s of s e c o n d ar y  vari a bl e s
9. 5. 1 
Effi c a c y  vari a bl e s
T he sec o n dar y efficac y varia bles are t he f oll o wi n g assess me nts defi ne d base d o n acti gra p h y 
data :

C ha n ge i n mea n acti vit y  (c o u nts per mi n ute) d uri n g slee p bet wee n baseli ne p hase a n d 
wee k 8 ( Ra n d o mize d treat me nt p hase )

C ha n ge i n mea n acti vit y  d uri n g slee p bet wee n baseli ne p hase a n d wee k 1 ( Ra n d o mize d 
treat me nt p hase )

C ha n ge i n mea n acti vit y  d uri n g slee p bet wee n baseli ne p hase a n d w ee k 9 a n d 1 6 ( O pe n 
la bel e xte nsi o n p hase )

C ha n ge i n mea n acti vit y  c o u nts d uri n g t he m ost acti ve 3 0 mi n utes of t he s u bject’s da y 
bet wee n baseli ne p hase a n d wee k 1 ( Ra n d o mize d treat me nt p hase )

C ha n ge i n mea n acti vit y  c o u nts d uri n g t he m ost acti ve 3 0 mi n utes of t he s u bject’s da y 
bet wee n baseli ne p hase a n d wee k 9 a n d 1 6 ( O pe n la bel e xte nsi o n p hase )
D uri n g t he ra n d o mize d treat me nt p hase , mea n c ha n ge fr o m baseli ne f or eac h c o nti n u o us 
varia ble will be a nal yz e d at eac h ti me p oi nt usi n g t he sa me A N C O V A m o del as f or t he pri mar y 
efficac y varia ble, a n d missi n g data will be i m p ute d usi n g t he L O C F met h o d.
D uri n g t he o pe n la bel e xte nsi o n p hase , c ha n ge fr o m baseli ne ( mea n of wee k - 1) f or eac h 
c o nti n u o us varia ble will be a nal yz e d at eac h ti me p oi nt usi n g paire d t-tests f or t he gr o u p 
ra n d o mize d t o sac u bitril/ valsarta n. T he a nal ys es will be re peate d usi n g t he wee k 8 meas ure me nt 
as baseli ne f or t he gr o u p ra n d o mize d t o E nala pril.

N o v arti s
C o nfi d e nti al
P a g e 6 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
9. 5. 2 
S af et y  vari a bl e s
T he safet y a n d t olera bilit y assess me nts are liste d bel o w:

A Es a n d S A Es

Sitti n g s y st olic, diast olic B P, a n d p ulse press ure

Heart rate

La b orat or y  val ues
T he assess me nt of safety will be base d pri maril y  on t he fre q ue nc y of a d verse e ve nts, S A Es, a n d 
la b orat or y a b n or malities. Ot her safet y data will be s u m marize d as a p pr o priate.
T he i nci de nce of treat me nt -e mer ge nt a d verse e ve nts ( ne w or w orse ne d) will be s u m marize d b y 
pri mar y  sys te m or ga n class, preferre d ter m, se verit y, a n d relati o ns hi p t o st u d y dr u g. I n a d diti o n, 
t he i nci de nce of deat h, S A Es, a n d A Es lea di n g t o disc o nti n uati o n will be s u m marize d se parately 
b y  pri mar y sys te m or ga n class a n d preferre d ter m.
La b orat or y  data will be s u mmarize d b y  prese nti n g s hift ta bles usi n g e xte n de d refere nce ra n ges 
( baseli ne t o m ost e xtre me p ost -baseli ne val ue), b y prese nti n g s u m mar y statistics of ra w data 
a n d c ha n ge fr o m baseli ne val ues ( mea n, me dia n, sta n dar d de viati o n, 2 5t h a n d 7 5 t h perce ntiles, 
i nter q uartile ra n ge, mi ni m u m a n d ma xi m u m) a n d b y  the fla g gi n g of n ota ble val ues i n data 
listi n gs.
Data fr o m ot her tests will be liste d, n ota ble val ues will be fla g ge d, a n d a n y ot her i nf or mati o n 
c ollecte d will be liste d as a p pr o priate.
Safet y  a nalys es will be perf or me d base d o n t he Safet y  Set. T here will be n o i nfere ntial a nalys es 
of t he safet y data.
9. 5. 3   
R e s o ur c e utili z ati o n
N ot A p plica ble.
9. 5. 4  
P h ar m a c o ki n eti c s
N ot A p plica ble.
9. 5. 5 
D N A
N ot A p plica ble.
9. 5. 6 
Bi o m ar k er s
N ot A p plica ble.
9. 5. 7 
P K/ P D
N ot A p plica ble.

N o v arti s
C o nfi d e nti al
P a g e 6 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 6 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
9. 7 
I nt eri m a n al ys e s
N ot a p plica ble.
9. 8 
S a m pl e si z e c al c ul ati o n
Pri mar y  e n d p oi nt: 
Ass u mi n g a si g nifica nce le vel of 0. 0 5, a t otal sa m ple size of 1 3 6 s u bjects w o ul d pr o vi de 9 0 % 
p o wer t o detect a differe nce of 5 0 0 0 i n t he c ha n ge fr o m baseli ne i n mea n acti vit y co u nts 
c ollecte d d uri n g t he m ost acti ve 3 0 mi n utes bet wee n t he sac u bitril/ valsarta n treat me nt gr o u p 
a n d t he e nala pril gr o u p d uri n g Wee k 8 , ass u min g a c o m m o n sta n dar d de viati o n of 7 4 0 0 (Ma urer 
2 0 0 9 ) a n d a 2 0 % dr o p -o ut rate a n d a 1 0 % rate of s u bjects wit h n o n- e val ua ble data.   T he ass u me d 
effect size of 6 8 % ( 5 0 0 0/ 7 4 0 0) will be mai ntai ne d i n t he e ve nt t he l o g tra nsf or mati o n is nee de d 
f or t he pri mar y a nalys is t h us n ot affecti n g t he sa m ple size calc ulati o n a n d p o wer of t he st u dy .
S ec o n dar y e n d p oi nt:  
Ass u mi n g a si g nifica nce le vel of 0. 0 5, a sa m ple size of 1 3 6 s u bjects w o ul d pr o vi de 9 3 % p o wer 
t o detect a 3. 5 p oi nt differe nce i n t he c ha n ge fr o m baseli ne i n mea n acti vit y val ue d uri n g t he 
slee p (e x presse d as c o u nts per mi n ute) bet wee n t he sac u bitril/ valsarta n treat me nt gr o u p a n d t he 
e nala pril gr o u p d uri n g Wee k 8 , ass u mi n g a c o m m o n sta n dar d de viati o n of 4. 9 a n d a 2 0 % dr o p -
o ut rate a n d a 1 0 % rate of s u bjects wit h n o n- e val ua ble data (Peters o n 2 0 1 2 ). 

N o v arti s
C o nfi d e nti al
P a g e 6 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 0 
Et hi c al c o n si d er ati o n s
1 0. 1 
R e g ul at or y  a n d et hi c al c o m pli a n c e
T his cli nical st u d y was desi g ne d a n d s hall be i m ple me nte d, e xec ute d a n d re p orte d i n acc or da nce 
wit h t he I CH Har m o nize d Tri partite G ui deli nes f or G o o d Cli nical Practice, wit h a p plica ble 
l ocal re g ulati o ns (i ncl u di n g E ur o pea n Directi ve 2 0 0 1/ 2 0/ E C, U S C F R 2 1, a n d Ja pa nese 
Mi nistr y  of Healt h, La b or, a n d Welfare), 
a n d wit h t he et hical pri nci ples lai d d o w n i n t he 
Declarati o n of Helsi n ki.
1 0. 2 
I nf or m e d c o n s e nt pr o c e d ur e s
Eli gi ble s u bjects m a y  onl y  be i ncl u de d i n t he st u d y after pr o vi di n g writte n ( wit nesse d, w here 
re q uire d b y  l aw or re g ulati o n), I RB/I E C -a p pr o ve d i nf or me d c o nse nt, or, if i ncapa ble of d oi n g 
s o, after s uc h c o nse nt has bee n pr o vi de d b y  a le gall y acce pta ble re prese ntati ve(s) of t he s u bject. 
I n cases w here t he patie nt’s re prese ntati ve gi ves c o nse nt, t he s u bject m ust be i nf or me d a b o ut 
t he st u d y to t he e xte nt p ossi ble gi ve n his/ her u n dersta n di n g. If t he patie nt is ca pa ble of d oi n g 
s o, he/s he m ust i n dicate asse nt b y  pers o nall y si g ni n g a n d dati n g t he writte n i nf or me d c o nse nt 
d oc u me nt or a se parate asse nt f or m. I nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y 
st u d y-s pecific pr oce dures (e. g. all of t he pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of 
o btai ni n g i nf or me d c o nse nt m ust be d oc u me nte d i n t he patie nt s o urce d oc u me nts. 
N o vartis will pr o vi de t o i n vesti gat ors i n a se parate d oc u me nt a pr o p ose d i nf or me d c o nse nt f or m 
t hat c o m plies wit h t he I C H G C P g ui deli ne a n d re g ulat or y re q uire me nts a n d is c o nsi dere d 
a p pr o priate f or t his st u d y. A n y c ha n ges t o t he pr o p ose d c o nse nt f or m s u g geste d b y  the 
i n vesti gat or m ust be a gree d t o b y N o vartis bef ore s u b missi o n t o t he I R B/I EC, a n d a c o p y of t he 
a p pr o ve d versi o n m ust be pr o vi de d t o t he N o vartis m o nit or after I R B/ I E C a p pr o val.
W o me n of c hil d beari n g p ote ntial m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y  in v ol ve 
u n k n o w n ris ks t o t he fet us if pre g na nc y were t o occ ur d uri n g t he st u d y an d a gree t hat i n or der 
t o partici pate i n t he st u d y t he y m ust a d here t o t he c o ntrace pti o n re q uire me nt f or t he d urati o n of 
t he st u d y. If t here is a n y q uesti o n t hat t he patie nt will n ot relia bl y co m pl y, t he y must n ot be 
e ntere d i n t he st u d y.
1 0. 3 
R e s p o n si biliti e s o f t h e i n v e sti g at or a n d I R B/I E C
Bef ore i nitiati n g a trial, t he i n vesti gat or/i nstit uti o n m ust o btai n a p pr o val/fa v ora ble o pi ni o n fr o m 
t he I nstit uti o nal Re vie w B oar d/I n de pe n de nt Et hics C o m mittee (IR B/I E C) f or t he trial pr ot oc ol, 
writte n i nf or me d c o nse nt f or m, c o nse nt f or m u p dates, s u bject recr uit me nt pr oce d ures (e. g., 
a d vertise me nts) a n d a n y ot her writte n i nf or mati o n t o be pr o vi de d t o s u bjects. Pri or t o st u d y 
start, t he i n vesti gat or is re q uire d t o si g n a pr ot oc ol si g nat ure pa ge c o nfir mi n g his/ her a gree me nt 
t o co n d uct t he st u d y in acc or da nce wit h t hese d oc u me nts a n d all of t he i nstr ucti o ns a n d 
pr oce d ures f o u n d i n t his pr ot oc ol a n d t o gi ve access t o all rele va nt data a n d rec or ds t o N o vartis 
m o nit ors, a u dit ors, N o vartis Q ualit y  Ass ura nce re prese ntati ves, desi g nate d a ge nts of N o vartis, 
I RBs/I E Cs, a n d re g ulat or y aut h orities as re q uire d. If a n i ns pecti o n of t he cli nical site is 
re q ueste d b y  a re g ulat or y a ut h orit y, t he i n vesti gat or m ust i nf or m N o vartis i m me diatel y that t his 
re q uest has bee n ma de.

N o v arti s
C o nfi d e nti al
P a g e 6 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 0. 4 
P u bli c ati o n of st u d y  prot o c ol a n d r e s ult s
T he ke y  desi g n ele me nts of t his pr ot oc ol will be p oste d i n a p u blicl y  accessi ble data base s uc h 
as cli nicaltrials. g o v. I n a d diti o n, u p o n st u d y  c o m pleti o n a n d fi nalizati o n of t he st u d y re p ort t he 
res ults of t his trial will be eit her s u b mitte d f or p u blicati o n a n d/ or p oste d i n a p u blicl y  accessi ble 
data base of cli nical trial res ults.
1 0. 5 
Q u alit y C o ntr ol a n d Q u alit y  As s ur a n c e
N o vartis mai ntai ns a r o b ust Q ualit y  Ma na ge me nt ( Q M) s yste m t hat i ncl u des all acti vities 
i n v ol ve d i n q ualit y  ass ura nce a n d q ualit y c o ntr ol, i ncl u di n g t he assi g n me nt of r oles a n d 
res p o nsi bilities, t he re p orti n g of res ults, a n d t he d oc u me ntati o n of acti o ns a n d escalati o n of 
iss ues i de ntifie d d uri n g t he re vie w of q uality metrics, i nci de nts, a u dits a n d i ns pecti o ns.
A u dits of i n ves ti gat or sites, ve n d ors, a n d N o vartis s y ste ms are perf or me d b y No vartis P har ma 
A u diti n g a n d C o m plia nce Q ualit y  Ass ura nce, a gr o u p i n de pe n de nt fr o m t h ose i n v ol ve d i n 
c o n d ucti n g, m o nit ori n g or perf or mi n g q ualit y  co ntr ol of t he cli nical trial. T he cli nical a u dit 
pr ocess uses a k n o wle d ge/ris k base d a p pr oac h.
A u dits are c o n d ucte d t o assess G C P c o m plia nce wit h gl o bal a n d l ocal re g ulat or y re q uire me nts, 
pr ot oc ols a n d i nter nal S O Ps, a n d are perf or me d acc or di n g t o writte n N o vartis pr ocesses.
1 1 
Pr ot o c ol a d h er e n c e
T his pr ot oc ol defi nes t he st u d y  o bjecti ves, t he st u d y pr oce d ures a n d t he data t o be c ollecte d o n 
st u d y partici pa nts. A d diti o nal assess me nts re q uire d t o e ns ure safet y of s u bjects s h o ul d be 
a d mi nistere d as dee me d necessar y  on a case b y  case basis. U n der n o circ u msta nces is a n 
i n vesti gat or all o we d t o c ollect a d diti o nal data or c o n d uct a n y a d diti o nal pr oce d ures f or a n y 
researc h relate d p ur p ose i n v ol vi n g a ny i n vesti gati o nal dr u gs u n der t he pr ot oc ol.
I n vesti gat ors ascertai n t he y will a p pl y d ue dili ge nce t o a v oi d pr ot oc o l de viati o ns. If a n 
i n vesti gat or feels a pr ot oc ol de viati o n w o ul d i m pr o ve t he c o n d uct of t he st u d y this m ust be 
c o nsi dere d a pr ot oc ol a me n d me nt, a n d u nless s uc h a n a me n d me nt is a gree d u p o n b y  No vartis 
a n d a p pr o ve d b y  the I R B/I E C a n d healt h a ut h orities, w he re re q uire d, it ca n n ot be i m ple me nte d. 
1 1. 1 
Pr ot o c ol a m e n d m e nt s
A n y  c ha n ge or a d diti o n t o t he pr ot oc ol ca n o nly be ma de i n a writte n pr ot oc ol a me n d me nt t hat 
m ust be a p pr o ve d b y  No vartis, healt h a ut h orities w here re q uire d, a n d t he I RB/I E C pri or t o 
i m ple me ntati on. O nl y  ame n d me nts t hat are i nte n de d t o eli mi nate a n a p pare nt i m me diate hazar d 
t o s u bjects ma y  b e im ple me nte d i m me diatel y pro vi de d t he healt h a ut h orities are s u bse q ue ntly 
n otifie d b y  pr ot oc ol a me n d me nt a n d t he re vie wi n g I R B/I E C is n otifie d. N ot wit hsta n di n g t he 
nee d f or a p pr o val of f or mal pr ot oc ol a me n d me nts, t he i n vesti gat or is e x pecte d t o ta ke a n y 
i m me diate acti o n re q uire d f or t he safety o f a ny s u bject i ncl u de d i n t his st u d y, e ve n if t his acti o n 
re prese nts a de viati o n fr o m t he pr ot oc ol. I n s uc h cases, t he re p orti n g re q uire me nts i de ntifie d i n 
Secti o n 7 Safet y  M o nit ori n g m ust be f oll o we d.

N o v arti s
C o nfi d e nti al
P a g e 7 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 2 
R ef er e n c e s
Refere nces are a vaila ble u p o n re q uest
Ber ma n, Earl J., et al. " Ri g ht ve ntric ular h y pertr o p h y  detecte d by ec h ocar di o gra p h y i n 
patie nts wit h ne wl y  dia g n ose d o bstr ucti ve slee p a p nea." C hest 1 0 0. 2 ( 1 9 9 1): 3 4 7- 3 5 0.
B ocali ni, Da nil o Sales, Le o nar d o d os Sa nt os, a n d A n dre y  J or ge Serra. " P h ysical e xercise 
i m pr o ves t he f u ncti o nal ca pacity a n d q ualit y of life i n patie nts wit h heart fail ure." Cli nics 6 3. 4 
( 2 0 0 8): 4 3 7- 4 4 2.
Cas perse n, Carl J., et al. " T he pre vale nce of selecte d p h ysical acti vities a n d t heir relati o n wit h 
c or o nar y heart disease ris k fact ors i n el derly me n: t he Z ut p he n St u d y, 1 9 8 5." A meric a n 
j o ur n al of E pi de mi ol o gy 1 3 3. 1 1 ( 1 9 9 1): 1 0 7 8 -1 0 9 2. 
Cas perse n, Carl J., Ke n net h E. P o well, a n d Gre g or y  M. C hriste ns o n. " P h ysical acti vit y, 
e xercise, a n d p h ys ical fit ness: defi niti o ns a n d disti ncti o ns f or healt h-relate d researc h." P u blic 
healt h re p orts 1 0 0. 2 ( 1 9 8 5): 1 2 6.
C he n M, Kia nifar d F ( 2 0 0 0) A n o n para metric pr oce d ure ass ociate d wit h a cli nicall y  
mea ni n gf ul efficac y  meas ure. Bi ostatistics; 1: 2 9 3- 2 9 8.
C oll o p N A; A n ders o n W M; B oe hlec ke B; Cla ma n D; G ol d ber g R; G ottlie b DJ; H u d gel D; 
Sateia M; Sc h wa b R. Cli nical g ui deli nes f o r t he use of u natte n de d p orta ble m o nit ors i n t he 
dia g n osis of o bstr ucti ve slee p a p nea i n a d ult patie nts. J Cli n Slee p Me d 2 0 0 7 ; 3( 7): 7 3 7 - 7 4 7. 
C o nraa ds V M, S pr uit M A, Bra u nsc h wei g F, C o wie M R, Ta vazzi L , B or g grefe M, Hill M. R. S, 
Jac o bs S, Gerritse B, Dir k J, a n d Vel d h uise n V.  P h ysical Acti vit y Meas ure d Wit h Im pla nte d 
De vices Pre dicts Patie nt O utc o me i n C hr o nic Heart Fail ure.   et al. Circ He art F ai 2 0 1 4 ; 2 7 9 
1 0. 1 1 6 1/ CI R C H E A R T F AI L U R E. 1 1 3. 0 0 0 8 8 3
Ga mi A S, H o d ge D O, Her ges R M, Ols o n EJ, N y k o d y m J, Kara T, a n d S o mers V K. 
O bstr ucti ve slee p a p nea, o besit y, a n d t he ris k of i nci de nt atrial fi brillati o n. J A m C oll Car di ol. 
4 9 ( 2 0 0 7) p p. 5 6 5 – 5 7 1.
 
G u y att, G or d o n H., et al. " T he 6 -mi n ute wal k: a ne w meas ure of e xercise ca pacit y  i n patie nts 
wit h c hr o nic heart fail ure." Ca na dia n Me dical Ass ociati o n J o ur nal 1 3 2. 8 ( 1 9 8 5): 9 1 9.
Ha nl y , Patric k, a n d Na hee d Z u beri-K h o k har. " Da y ti me slee pi ness i n patie nts wit h c o n gesti ve 
heart fail ure a n d C he y n e - St o kes res pirati o n." C H E S T J o ur nal 1 0 7. 4 ( 1 9 9 5): 9 5 2- 9 5 8
Hasti n gs P. C, Vazir A, O’ Drisc oll D. M, M orrell M.J., a n d Si m o n ds A. K. S y m pt o m b ur de n of 
slee p-dis or dere d breat hi n g i n mil d -t o-m o derate c o n gesti ve heart fail ure patie nts E ur o pe a n 
Res pir J.   2 7 ( 2 0 0 6), p p. 7 4 8- 7 5 5
H o well J, Str o n g M. B, Weise n ber g J, Ka ka de A, Ga o Q, C u d di h y  P, Delisle S, Kac h n o ws ki S, 
a n d Ma urer M. S. Y o u ha ve f ull te xt access t o t his c o nte nt Ma xi m u m Dail y  6 Mi n utes of 
Acti vit y : A n I n de x of F u ncti o nal Ca pacity Deri ve d fr o m Acti gra p h y a n d Its A p plicati o n t o 
Ol der A d ults wit h Heart Fail ure. J A m Geriat S oc 5 8 ( 2 0 1 0), p p. 9 3 1- 9 3 6
J h u n d, Par dee p S., et al. " Efficac y a n d safety of L C Z 6 9 6 (sac u bitril -valsarta n) acc or di n g t o 
a ge: i nsi g hts fr o m P A R A DI G M -H F." E ur o pea n heart j o ur nal ( 2 0 1 5): e h v 3 3 0.

N o v arti s
C o nfi d e nti al
P a g e 7 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
Kasai T, Fl oras J. S, a n d Bra dle y  T. D. Slee p A p nea a n d Car di o vasc ular Disease A 
Bi directi o nal Relati o ns hi p Circ ul ati o n . 1 2 6  ( 2 0 1 2), p p. 1 4 9 5- 1 5 1 0 
K n uts o n K. L , Rat h o uz P.J, Ya n L. L, Li u K, a n d La u der dale D. S. I ntra-I n di vi d ual Dail y a n d 
Yearl y Varia bilit y i n Acti gra p hicall y Rec or de d Slee p Meas ures: t he C A R DI A St u d y K n uts o n 
et al Slee p 3 0 ( 2 0 0 7), p p. 7 9 3 - 7 9 6
K us hi da C . A, C ha n g A, Ga d kar y C, G uille mi na ult C, Carrill o O, a n d De me nt W. C. 
C o m paris o n of acti gra p hic, p ol y s o m n o gra p hic, a n d s u bjecti ve assess me nt of slee p para meters 
i n slee p-dis or dere d patie nts Slee p Me dici ne 2 ( 2 0 0 1 ), p p. 3 8 9- 3 9 6
La nfra nc hi, Pa ola A., et al. " Pr o g n ostic val ue of n oct ur nal C he yne- St o kes res pirati o n i n 
c hr o nic heart fail ure." Circ ulati o n 9 9. 1 1 ( 1 9 9 9): 1 4 3 5- 1 4 4 0.
Ma urer M, C u d di h y P, Weise n ber g J, Delisle S, Str o n g B M, Ga o Q, Kac h n o ws ki S, a n d 
H o well J. T he Pre vale nce a n d I m pact of A ner gia ( Lac k of E ner g y ) i n S u bjects Wit h Heart 
Fail ure a n d its Ass ociati o ns Wit h Acti gra p h y et al. J o ur n al of C ar d F ail ure 2 0 0 9; 1 5, 1 4 5
Meli n M, Ha ger ma n I, G o n o n A, G ustafss o n T, a n d R ull ma n E. Varia bilit y i n P h ysical 
Acti vit y  Assesse d wit h Acceler o meter Is a n I n de pe n de nt Pre dict or of M ortalit y i n C H F 
Patie nts et al P L O S O N E 2 0 1 6; htt p:// d x. d oi. or g/ 1 0. 1 3 7 1/j o ur nal. p o ne. 0 1 5 3 0 3 6
Ne m ot o, O., M. F ur ue, H. Na ka ga wa, M. S hira m ot o, R. Ha na da, S. Mats u ki, S. I m a y a ma et 
al. " T he first trial of CI M 3 3 1, a h u ma nize d a nti h u ma n i nter le u ki n-3 1 rece pt or A a nti b o d y , i n 
healt h y  v ol u nteers a n d patie nts wit h at o pic der matitis t o e val uate safety, t olera bilit y  a n d 
p har mac o ki netics of a si n gle d ose i n a ra n d o mize d, d o u ble -bli n d, place b o -c o ntr olle d 
st u d y." Britis h J o ur n al of Der m at ol o gy 1 7 4, n o . 2 ( 2 0 1 6): 2 9 6- 3 0 4. 
Pe nzel T a n d Garcia C. Car di o vasc ular Disease a n d Slee p Me dici ne 2 0 1 5; C h p 4 7, 4 1 5
Peters o n B. T, C hia o P, Pic keri n g E, Free ma n J, Za m mit G. K, Di n g Y, a n d Ba d ura L. L. 
C o m paris o n of acti gra p h y a n d p ol ys o m n o gra p h y  t o assess effects of z ol pi de m i n a cli nical 
researc h u nit Slee p Me dici ne 1 3 ( 2 0 1 2 ), p p. 4 1 9-4 2 4
Re de ker N. S a n d Hil kert R.  Slee p a n d q ualit y  of life i n sta ble heart fail ure. J C ar d F ail 2 0 0 5 ; 
1 1, 2 0 0 5
Re dfiel d, Mar garet M., Ke vi n J. A nstr o m , Ja mes A. Le vi ne, Ga be A. K oe p p, Barr y A. 
B orla u g, H or n g H. C he n, Marti n M. Le Wi nter et al. "Is os or bi de m o n o nitrate i n heart fail ure 
wit h preser ve d ejecti o n fracti o n." Ne w E n gl a n d J o ur n al of Me dici ne 3 7 3, n o. 2 4 ( 2 0 1 5): 
2 3 1 4- 2 3 2 4. 
Sallis J. F a n d Saele ns B. E. Assess me nt of P h y sical Acti vit y b y Self-Re p ort: Stat us, 
Li mitati o ns, a n d F ut ure Directi o ns Res Q E xerc S p ort 7 1 ( 2 0 0 0 ), p p. S 1- 1 4
Si n D. D, Fitz geral d F, Par ker J. D, Ne wt o n G, Fl oras J. S, a n d Bra dle y s T. D. Ris k Fact ors f or 
Ce ntral a n d O bstr ucti ve Slee p A p nea i n 4 5 0 Me n A n d W o me n wit h C o n gesti ve Heart Fail ure 
A m J Res pir Crit C are Me d 1 6 0 ( 1 9 9 9 ), p p. 1 1 0 1- 1 1 0 6
Steele, B o n nie G., et al. " Q ua ntitati n g p hys ical acti vit y i n C O P D usi n g a tria xial 
acceler o meter." C H E S T J o ur n al 1 1 7. 5 ( 2 0 0 0): 1 3 5 9 - 1 3 6 7.
Tr u dea u, Jere mia h, Ric har d Va n I n we ge n, T h o mas Eat o n, Gaja na n B hat, Fl ore nce Paillar d, 
Di k N g, Keit h Ta n, a n d Nat ha niel P. Katz. " Assess me nt of Pai n a n d Acti vit y  Usi n g a n 

N o v arti s
C o nfi d e nti al
P a g e 7 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
Electr o nic Pai n Diar y  a n d Acti gra p h y De vice i n a Ra n d o mize d, Place b o-C o ntr olle d Cr oss o ver 
Tria l of Celec o xi b i n Oste oart hritis of t he K nee." P ai n Pr actice 1 5, n o. 3 ( 2 0 1 5): 2 4 7 - 2 5 5. 
Vas u nilas h or n, Sari n na p ha: Use of t he S h ort P h ys ical Perf or ma nce Batter y Sc ore t o Pre dict 
L oss of A bilit y t o Wal k 4 0 0 Meters: A nal ys is Fr o m t he In C HI A N TI St u d y J Ger o ntol A Bi ol 
Sci Me d Sci ( 2 0 0 9) 6 4 A ( 2): 2 2 3- 2 2 9 first p u blis he d o nli ne J a n u ary 1, 
2 0 0 9 d oi: 1 0. 1 0 9 3/ ger o n a/ gl n 0 2 2
Wa n g M, H u n g H L, a n d Tsai P. S. T he Slee p L o g a n d Acti gra p h y:  C o n gr ue nc y of 
Meas ure me nt Res ults f or Heart Fail ure Patie nts J o ur nal of N ursi n g Researc h et al J o ur n al of 
N ursi n g Rese arc h 2 0 1 1 ; 1 9, 1 7 3
Wiele n ga, R o bert P., et al. " T he r ole of e xercise trai ni n g i n c hr o nic heart fail ure." He art 7 8. 5 
( 1 9 9 7): 4 3 1- 4 3 6. 
Y u mi n o D, Wa n g H, Fl oras J S, Ne wt o n G E, Ma k S, R utta na u m pa wa n P, Par ker J D,  a n d 
Bra dle y  T D. Pre vale nce a n d p h ysi ol o gical pre dict ors of slee p a p nea i n patie nts wit h heart 
fail ure a n d sys t olic d ysf u ncti o n. J Car d Fail. 1 5( 2 0 0 9), p p. 2 7 9 – 2 8 5.
Y u mi n o D, Wa n g H, Fl oras J S, Ne wt o n G E, Ma k S, R utta na u m pa wa n P, Par ker J D, a n d 
Bra dle y  T D. Relati o ns hi p bet wee n slee p a p n oea a n d m ortalit y i n patie nts wit h isc hae mic heart 
fail ure. Heart. 9 5 ( 2 0 0 9) p p. 8 1 9– 8 2 4. 

N o v arti s
C o nfi d e nti al
P a g e 7 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 3 
A p p e n di x 1: Cli ni c all y  n ot a bl e l a b or at or y val u e s a n d vit al 
si g n s
Cli nicall y  nota ble la b orat or y ab n or malities f or selecte d tests base d o n a perce nt c ha n ge fr o m 
baseli ne:
He m at ol o g y
R B C c o u nt 
> 5 0 % i ncrease, > 2 0 % decrease
He m o gl o bi n 
> 5 0 % i ncrease, > 2 0 % decrease
He mat ocrit 
> 5 0 % i ncrease, > 2 0 % decrease
W B C c o u nt 
> 5 0 % i ncrease, > 5 0 % decrease
Platelet c o u nt 
> 7 5 % i ncrease, > 5 0 % decrease
Bl o o d C he mistr y
A L T ( S G P T) 
> 1 5 0 % i ncrease
A S T ( S G O T) 
> 1 5 0 % i ncrease
B U N
> 5 0 % i ncrease
Creati ni ne
> 5 0 % i ncrease
T ota l bilir u bi n 
> 1 0 0 % i ncrease
Al kali ne p h os p hatase
> 1 0 0 % i ncrease
P otassi u m
> 2 0 % i ncrease, > 2 0 % decrease
C hl ori de
> 1 0 % i ncrease, > 1 0 % decrease
Calci u m
> 1 0 % i ncrease, > 1 0 % decrease
Uric aci d
> 5 0 % i ncrease 

N o v arti s
C o nfi d e nti al
P a g e 7 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 4 
A p p e n di x 2: Li v er e v e nt a n d L a b or at or y tri g g er D efi niti o n s 
a n d F oll o w- u p R e q uir e m e nt s
T a bl e 1 4 - 1 
Li v er E v e nt a n d L a b or at or y  Tri g g er D efi niti o n s
D efi niti o n/ t hr e s h ol d
LI V E R L A B O R A T O R Y T RI G G E R S
 
3 x U L N < A L T / A S T 5 x  U L N
 
1. 5 x U L N < T B L 2 x U L N
LI V E R E V E N T S
 
A L T or A S T > 5 × U L N
 
A L P > 2 × U L N (i n t h e a b s e n c e of k n o w n b o n e p at h ol o g y)
 
T B L > 2 × U L N (i n t h e a b s e n c e of k n o w n Gil b ert s y n dr o m e)
 
A L T or A S T > 3 × U L N a n d I N R > 1. 5 
 
P ot e nti al H y’ s L a w c a s e s ( d efi n e d a s A L T or A S T > 3 × U L N a n d 
T B L > 2 × U L N [ m ai nl y c o nj u g at e d fr a cti o n] wit h o ut n ot a bl e 
i n cr e a s e i n A L P t o > 2 × U L N)
 
A n y cli ni c al e v e nt of j a u n di c e ( or e q ui v al e nt t er m)
 
A L T or A S T > 3 × U L N a c c o m p a ni e d b y ( g e n er al) m al ai s e, 
f ati g u e, a b d o mi n al p ai n, n a u s e a, or v o miti n g, or r a s h wit h 
e o si n o p hili a
 
A n y a d v er s e e v e nt p ot e nti all y i n di c ati v e of a li v er t o xi cit y*
* T h e s e e v e nt s c o v er t h e f oll o wi n g: h e p ati c f ail ur e, fi br o si s a n d cirr h o si s, a n d ot h er li v er d a m a g e -r el at e d 
c o n diti o n s; t h e n o n -i nf e cti o u s h e p atiti s; t h e b e ni g n, m ali g n a nt a n d u n s p e cifi e d li v er n e o pl a s m s
T B L: t ot al bilir u bi n; U L N: u p p er li mit of n or m al 

N o v arti s
C o nfi d e nti al
P a g e 7 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
T a bl e 1 4 - 2 
F oll o w U p R e q uir e m e nt s f or Li v er E v e nt s a n d L a b or at or y  Tri g g er s
Crit eri a
A cti o n s r e q uir e d
F oll o w -u p m o nit ori n g
P ot e nti al H y’ s L a w 
c a s e a
 
Di s c o nti n u e t h e st u d y tr e at m e nt 
i m m e di at el y
 
H o s pit ali z e, if cli ni c all y a p pr o pri at e
 
E st a bli s h c a u s alit y
A L T, A S T, T B L, Al b, P T/I N R, A L P a n d 
γ G T u ntil r e s ol uti o n c (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n)
A L T or A S T
> 8 × U L N
 
Di s c o nti n u e t h e st u d y tr e at m e nt 
i m m e di at el y
 
H o s pit ali z e if cli ni c all y a p pr o pri at e
 
E st a bli s h c a u s alit y
A L T, A S T, T B L, Al b, P T/I N R, A L P a n d 
γ G T u ntil r e s ol uti o n c (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n)
> 3 × U L N a n d I N R > 
1. 5
 
Di s c o nti n u e t h e st u d y tr e at m e nt 
i m m e di at el y
 
H o s pit ali z e, if cli ni c all y a p pr o pri at e
 
E st a bli s h c a u s alit y
A L T, A S T, T B L, Al b, P T/I N R, A L P a n d 
γ G T u ntil r e s ol uti o n c (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n)
> 5 t o ≤ 8 × U L N
 
R e p e at L F T wit hi n 4 8 h o ur s
 
If el e v ati o n p er si st s, c o nti n u e f oll o w-u p 
m o nit ori n g
 
If el e v ati o n p er si st s f or m or e t h a n 2 w e e k s, 
di s c o nti n u e t h e st u d y dr u g
 
E st a bli s h c a u s alit y
A L T, A S T, T B L, Al b, P T/I N R, A L P a n d 
γ G T u ntil r e s ol uti o n c (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n)
> 3 × U L N 
a c c o m p a ni e d b y 
s y m pt o m s b
 
Di s c o nti n u e t h e st u d y tr e at m e nt 
i m m e di at el y
 
H o s pit ali z e if cli ni c all y a p pr o pri at e
 
E st a bli s h c a u s alit y
A L T, A S T, T B L, Al b, P T/I N R, A L P a n d 
γ G T u ntil r e s ol uti o n c (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n)
> 3 t o ≤ 5 × U L N 
( p ati e nt i s 
a s y m pt o m ati c)
 
R e p e at L F T wit hi n t h e n e xt w e e k
 
If el e v ati o n i s c o nfir m e d, i niti at e cl o s e 
o b s er v ati o n of t h e p ati e nt
I n v e sti g at or di s cr eti o n
M o nit or L F T wit hi n 1 t o 4 w e e k s 
A L P (i s ol at e d)
> 2 × U L N (i n t h e 
a b s e n c e of k n o w n 
b o n e p at h ol o g y)
 
R e p e at L F T wit hi n 4 8 h o ur s
 
If el e v ati o n p er si st s, e st a bli s h c a u s alit y
I n v e sti g at or di s cr eti o n
M o nit or L F T wit hi n 1 t o 4 w e e k s or at 
n e xt vi sit
T B L (i s ol at e d)

N o v arti s
C o nfi d e nti al
P a g e 7 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
Crit eri a
A cti o n s r e q uir e d
F oll o w -u p m o nit ori n g
> 2 × U L N (i n t h e 
a b s e n c e of k n o w n 
Gil b ert s y n dr o m e)
 
R e p e at L F T wit hi n 4 8 h o ur s
 
If el e v ati o n p er si st s, di s c o nti n u e t h e st u d y 
dr u g i m m e di at el y
 
H o s pit ali z e if cli ni c all y a p pr o pri at e
 
E st a bli s h c a u s alit y
A L T, A S T, T B L, Al b, P T/I N R, A L P a n d 
γ G T u ntil r e s ol uti o n c (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n)
T e st f or h e m ol y si s ( e. g., r eti c ul o c yt e s, 
h a pt o gl o bi n, u n c o nj u g at e d [i n dir e ct] 
bilir u bi n)
> 1. 5 t o ≤ 2 × U L N 
( p ati e nt i s 
a s y m pt o m ati c)
 
R e p e at L F T wit hi n t h e n e xt w e e k
 
If el e v ati o n i s c o nfir m e d, i niti at e cl o s e 
o b s er v ati o n of t h e p ati e nt 
I n v e sti g at or di s cr eti o n
M o nit or L F T wit hi n 1 t o 4 w e e k s or at 
n e xt vi sit
J a u n di c e
 
Di s c o nti n u e t h e st u d y tr e at m e nt 
i m m e di at el y
 
H o s pit ali z e t h e p ati e nt
 
E st a bli s h c a u s alit y
A L T, A S T, T B L, Al b, P T/I N R, A L P a n d 
γ G T u ntil r e s ol uti o n c (fr e q u e n c y at 
i n v e sti g at or di s cr eti o n)
A n y A E p ot e nti all y 
i n di c ati v e of a li v er 
t o xi cit y*
 
C o n si d er st u d y tr e at m e nt i nt err u pti o n or 
di s c o nti n u ati o n 
 
H o s pit ali z ati o n if cli ni c all y a p pr o pri at e
 
E st a bli s h c a u s alit y
I n v e sti g at or di s cr eti o n
a El e v at e d A L T/ A S T > 3 × U L N a n d T B L > 2 × U L N b ut wit h o ut n ot a bl e i n cr e a s e i n A L P t o > 2 × U L N
b ( G e n er al) m al ai s e, f ati g u e, a b d o mi n al p ai n, n a u s e a, or v o miti n g, or r a s h wit h e o si n o p hili a 
cR e s ol uti o n i s d efi n e d a s a n o ut c o m e of o n e of t h e f oll o wi n g: ( 1) r et ur n t o b a s eli n e v al u e s, ( 2) st a bl e v al u e s at 
t hr e e s u b s e q u e nt m o nit ori n g vi sit s at l e a st 2 w e e k s a p art, ( 3) r e m ai n at el e v at e d l e v el aft er a m a xi m u m of 6 
m o nt h s, ( 4) li v er tr a n s pl a nt ati o n, a n d ( 5) d e at h.

N o v arti s
C o nfi d e nti al
P a g e 7 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 5 
A p p e n di x 3: S p e cifi c R e n al A l ert Crit eri a a n d Acti o n s
T a bl e 1 5 - 1 
S p e cifi c R e n al A l ert Crit eri a a n d Acti o n s
S er u m E v e nt
S er u m cr e ati ni n e i n cr e a s e
2 5 – 4 9 % c o m p ar e d t o b a s eli n e
C o nfir m 2 5 % i n cr e a s e aft er 2 4 -4 8 h 
F oll o w u p wit hi n 2 -5 d a y s
A c ut e Ki d n e y I nj ur y: S er u m cr e ati ni n e i n cr e a s e 5 0 % 
c o m p ar e d t o b a s eli n e
F oll o w u p wit hi n 2 4 -4 8 h if p o s si bl e
C o n si d er st u d y tr e at m e nt i nt err u pti o n 
C o n si d er p ati e nt h o s pit ali z ati o n / s p e ci ali z e d tr e at m e nt
Uri n e E v e nt
N e w di p sti c k pr ot ei n uri a ≥1 +
Al b u mi n - or Pr ot ei n -cr e ati ni n e r ati o i n cr e a s e ≥2 -f ol d
Al b u mi n - cr e ati ni n e r ati o ( A C R) ≥3 0 m g/ g or ≥3 
m g/ m m ol;
Pr ot ei n - cr e ati ni n e r ati o ( P C R )≥1 5 0 m g/ g or > 1 5 
m g/ m m ol
C o nfir m v al u e aft er 2 4 -4 8 h
P erf or m uri n e mi cr o s c o p y
C o n si d er st u d y tr e at m e nt i nt err u pti o n / or di s c o nti n u ati o n 
N e w di p sti c k gl y c o s uri a ≥1 + n ot d u e t o di a b et e s 
Bl o o d gl u c o s e (f a sti n g)
P erf or m s er u m cr e ati ni n e, A C R 
N e w di p sti c k h e m at uri a ≥1 + n ot d u e t o tr a u m a 
Uri n e s e di m e nt mi cr o s c o p y
P erf or m s er u m cr e ati ni n e, A C R 
F or all r e n al e v e nt s:
D o c u m e nt c o ntri b uti n g f a ct or s i n t h e C R F : c o-m e di c ati o n, ot h er c o -m or bi d c o n diti o n s, a n d a d diti o n al di a g n o sti c 
pr o c e d ur e s p erf or m e d 
M o nit or p ati e nt r e g ul arl y (fr e q u e n c y at i n v e sti g at or’ s di s cr eti o n) u ntil eit h er: 
E v e nt r e s ol uti o n: s Cr wit hi n 1 0 % of b a s eli n e or pr ot ei n -cr e ati ni n e r ati o wit hi n 5 0 % of b a s eli n e, or
E v e nt st a bili z ati o n: s Cr l e v el wit h ± 1 0 % v ari a bilit y o v er l a st 6 m o nt h s or pr ot ei n-cr e ati ni n e r ati o st a bili z ati o n at a 
n e w l e v el wit h ± 5 0 % v ari a bilit y o v er l a st 6 m o nt h s.

N o v arti s
C o nfi d e nti al
P a g e 7 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 6 
A p p e n di x 4: G ui d eli n e f or t h e m a n a g e m e nt of r e n al 
d y sf u n cti o n
Ge neral pri nci ples:
Gl o mer ular filtrati o n rate i n H F s u bjects de pe n ds o n i ntri nsic re nal f u ncti o n a n d o n a bala nce 
bet wee n affere nt a n d effere nt gl o mer ular arterial t o nicit y . T his t o nicit y is partl y re g ulate d b y a 
sti m ulati o n of a n gi ote nsi n II a n d c o ul d be affecte d b y eit her st u d y me dicati o n. M oreo ver, re nal 
d y sf u ncti o n ma y  de vel o p or ma y  deteri orate i n s o me s u bjects after st u d y dr u g a d mi nistrati o n. 
T hese rec o m me n dati o ns ha ve bee n de vel o pe d t o g ui de t he i n vesti gat ors i n ma na gi n g s u bjects 
wit h re nal d ys f u ncti o n after ra n d o mizati o n.
T w o t y pes of res p o nse t o ser u m creati ni ne i ncrease are descri be d:
S ur veill a nce sit u ati o n 
If, at a n y ti me after ra n d o mizati o n, e G F R decreases b y  ≥ 2 5 % fr o m baseli ne ( or if ser u m 
creati ni ne c o nce ntrati o n i ncrease t o 2. 5 m g/ d L [ 2 2 1 µ m ol/ L ]), t he i n vesti gat or will c hec k f or 
p ote ntiall y  re versi ble ca uses of re nal d ysf u ncti o n s uc h as:

N o n -ster oi dal a nti-i nfla m mat or y dr u g i nta ke, a nti bi otics, or ot her treat me nts k n o w n t o 
affect creati ni ne mia

V ol u me decrease, i ncl u di n g t hat res ulti n g fr o m e xcessi ve d osi n g of di uretics

Uri nar y  i nfecti o n

Uri nar y  tract o bstr ucti o n

St u d y  me dicati o n
Acti o n sit u ati o n 
If a s u bjects e G F R decreases b y  ≥ 4 0 % fr o m baseli ne ( or if ser u m creati ni ne c o nce ntrati o n rises 
a b o ve 3 m g / d L ( 2 6 5 µ m ol/ L ), t he i n vesti gat or will c hec k f or p ote ntiall y re versi ble ca uses of 
re nal dys f u ncti o n (see a b o ve).
If t he i n vesti gat or j u d ges t hat st u d y me dicati o n has t o be st o p pe d, he/s he will ha ve t o c o ntact 
t he N o vartis me dical m o nit or or his/ her desi g nee. T hereafter, ser u m creati ni ne assess me nts will 
ha ve t o be re peate d at least eac h wee k u ntil le vels ret ur n t o acce pta ble val ues. If st u d y 
me dicati o n was st o p pe d, e ver y eff ort will be d o ne t o restart it a gai n, acc or di n g t o cli nical 
c o n diti o ns.

N o v arti s
C o nfi d e nti al
P a g e 7 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
1 7 
A p p e n di x 5: G ui d eli n e s f or t h e m a n a g e m e nt of bl o o d 
pr e s s ur e
G ui deli nes
1.
I n vesti gat or s h o ul d m o nit or bl o o d press ure cl osel y 
2.
If sy m pt o matic h y p ote nsi o n occ urs:
a.
C orrect a n y treata ble ca use, e. g. h y p o v ole mia
b.
If hy p ote nsi o n persists, a n y a nti h y perte nsi ve dr u g a n d n o n -disease -m o dif y i n g dr u gs, 
s uc h as di uretics, C C Bs, nitrates, a n d α-bl oc kers, s h o ul d be d o w n -titrate d or st o p pe d 
first bef ore d o w n-titrati o n of t he st u d y dr u g is c o nsi dere d
3.
If hy p ote nsi o n persists, t he st u d y dr u g s h o ul d be d o w n -titrate d or e ve n te m p oraril y 
wit h dra w n. T he d ose re -c halle n ge a n d me dicati o n a dj ust me nt g ui deli nes descri be d i n
Secti o n 5. 5. 4 s h o ul d be a d here d t o as m uc h as p ossi ble.

N o v arti s
C o nfi d e nti al
P a g e 8 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 2
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 3
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 4
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 5
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 6
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 7
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 8
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 8 9
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 9 0
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4

N o v arti s
C o nfi d e nti al
P a g e 9 1
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n )
C L C Z 6 9 6 B U S 1 4
2 1
A p p e n di x 9: Pr o hi bit e d M e di c ati o n s : Pr e s cri pti o n a n d n o n -
pr e s cri pti o n m e di c ati o n s t a k e n f or i n s o m ni a or t o i n d u c e sl e e p
C A T A G O R Y
E X A M P L E S
B e n z o di a z e pi n e s wit h s e d ati n g pr o p erti e s f or i n s o m ni a; or 
alt er n ati v e i n di c ati o n s t a k e n at b e dti m e
E x a m pl e s i n cl u d e: 
Al pr a z ol a m ( X a n a x)
Cl o n a z e p a m ( Cl o z aril)
Di a z e p a m ( V ali u m)
E st a z ol a m ( Pr o s o m)
Fl ur a z e p a m ( D al m a n e)
L or a z e p a m ( Ati v a n)
Q u a z e p a m ( D or al)
O x a z e p a m ( S er a x)
T e m a z a p e m ( R e st oril)
Tri a z ol a m ( H al ci o n)
N o n -b e n z o di a z e pi n e s f or i n s o m ni a
E x a m pl e s i n cl u d e: 
E s z o pi cl o n e ( L u n e st a)
R a m elt e o n ( R o z er e m)
S u v or e x a nt ( B el s o mr a)
T a si m elt e o n ( H etli o z)
Z al e pl o n ( S o n at a) 
Z ol pi d e m ( A m bi e n, A m bi e n C R, E dl u ar, I nt er m e z z o, 
Z ol pi mi st) 
A nti d e pr e s s a nt s wit h s e d ati n g pr o p erti e s f or i n s o m ni a; or 
alt er n ati v e i n di c ati o n s t a k e n at b e dti m e
E x a m pl e s i n cl u d e: 
A mitri pt yli n e ( El a vil), 
D o x e pi n ( Sil e n or, Si n e q u a n)
Mirt a z a pi n e ( R e m er o n)
Tr a z o d o n e ( Ol e ptr o, D e s yr el)
Ot h er pr e s cri pti o n s wit h s e d ati n g pr o p erti e s f or i n s o m ni a; or 
a lt er n ati v e i n di c ati o n s t a k e n at b e dti m e
E x a m pl e s i n cl u d e: 
B a cl of e n ( Li or e s al, G a bl of e n)
C y cl o b e n z a pri n e ( Fl e x eril)
G a b a p e nti n ( N e ur o nti n)
H y dr o x y zi n e ( At ar a x)
Ol a n z a pi n e ( Z y pr e x a) 
P h e n o b ar bit al ( P h e n o b ar b)
Q u eti a pi n e ( S er o q u el)
Ti a g a bi n e ( G a bitril)
N o n -pr e s cri pti o n Dr u g s f or sl e e p/i n s o m ni a or d e si g n at e d f or 
“ ni g htti m e” or “ P M” u s e c o nt ai ni n g a n y of t h e f oll o wi n g a cti v e 
i n gr e di e nt s: Di p h e n h y dr a mi n e, D o x yl a mi n e, 
C hl or p h e nir a mi n e
E x a m pl e s i n cl u d e: 
A d vil P. M.
Al e v e P. M.
B e n a dr yl
C hl or p h e n
N yt ol
N y q uil
S o mi n e x
T yl e n ol P. M
U ni s o m
Z z z Q uil
N o n -pr e s cri pti o n H er b s/ S u p pl e m e nt s f or sl e e p/i n s o m ni a or 
d e si g n at e d f or “ ni g htti m e” or “ P M” 
E x a m pl e s i n cl u d e: 
5- H T P 
K a v a K a v a
M el at o ni n
V al eri a n R o ot