Conditions: Heart Failure, Reduced Ejection Fraction
Keywords: Heart failure with reduced left ventricular ejection fraction (LVEF) Cardiac dysfunction Heart muscle dysfunction Left ventricular (LV) dilation Left ventricular hypertrophy HF AHF CHF acute heart failure chronic heart failure congestive heart failure congestive cardiac failure Heart failure HReEF Physical Activity Actigraphy Home sleep test wake
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 140
Healthy volunteers: no

Brief summary:
The purpose of this study was to investigate the effects of initiation of sacubitril/valsartan vs enalapril treatment on objective measures of both waking activity and sleep in subjects with heart failure with reduced ejection fraction.

Detailed description:

Arms:
arm 1: Double blind treatment epoch: Patients randomized to this arm received 1 tablet of enalapril and 1 tablet of matching placebo sacubitril/valsartan twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 2.5 mg enalapril BID). Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 (i.e. 10 mg enalapril BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.

Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on enalapril Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1 of sacubitril/valsartan. Patients may have been sequentially up-titrated to achieve desired dose of Dose Level 3 of sacubitril/valsartan. Patients not tolerating dose escalation could have been titrated down to next lower dose level. arm 2: Double blind treatment epoch: Patients randomized to this arm received 1 tablet of sacubitril/valsartan and 1 tablet of matching placebo enalapril twice daily for 8 weeks. All Patients began the study on Dose Level 1 (i.e. 24/26 mg sacubitril/valsartan BID). Patients may have sequentially been up-titrated to achieve desired dose of Dose Level 3 (i.e. 97/103 mg sacubitril/valsartan BID). Patients not tolerating dose escalation could have been titrated down to next lower dose level.

Open-label treatment epoch: All patients entering this epoch (8 weeks) were given sacubitril/valsartan 49/51 mg BID (Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. Instead, these patients entered open-label epoch on Dose Level 1. Patients may sequentially have been up-titrated to achieve desired dose of Dose Level 3. Patients not tolerating dose escalation could have been titrated down to next lower dose level.

Interventions: intervention 1: sacubitril/valsartan (LCZ696) intervention 2: enalapril intervention 3: matching placebo sacubitril/valsartan (LCZ696) intervention 4: matching placebo enalapril
Intervention descriptions: intervention 1: sacubitril/valsartan tablet taken orally. intervention 2: Enalapril tablet taken orally. intervention 3: matching placebo sacubitril/valsartan tablet taken orally intervention 4: matching placebo enalapril tablet taken orally

Protocol document:
Prot_000.pdf: 
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

SAP_001.pdf: 
Clinical Development 
LCZ696/Sacubitril/Valsartan/Entresto® 
CLCZ696BUS14 / NCT02970669
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) 
Statistical Analysis Plan (SAP) 
Author(s): 
Document type: 
SAP Documentation 
Document status: 
Final 2.0 Amendment 1 
Release date: 
10-Apr-2018
Number of pages: 
33 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
SAP Amendment 1 
 
CLCZ696BUS14 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
06-Oct-
2017 
Prior 
to 
DB 
Lock 
Creation of 
final 
version 
NA – First version 
NA 
10-Apr-
2018 
Prior 
to 
DB 
Lock 
Creation of 
Amendment 
1 
1. Updated to align with protocol 
version 02 (amended protocol) dated 
13-Mar-2018: added statistical 
methodology to account for 
possibility that primary endpoint is 
not normally distributed 
2. Replaced ‘subject’ with ‘patient’ 
3. Clarified imputation rule for KCCQ 
domain/clinical/overall summary 
scores for patients who died 
7. Included mean activity during the 
daily active period in summary of 
baseline actigraphy variables 
1. Section 1 
Introduction; 
Section 2.5.2 
Statistical 
Hypothesis, 
Model, and 
Method of 
Analysis; 
Section 2.5.4 
Supportive 
Analyses; 
Section 3 
Sample Size 
Calculation 
2. Various 
sections 


Novartis 
For business use only 
Page 3 
SAP Amendment 1 
 
CLCZ696BUS14 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
9. Eliminated some patient disposition 
categories 
10. Modified baseline definition to 
account for randomized patients who 
were not treated 
11. Clarified definitions for randomized 
treatment phase and open-label 
extension phase 
12. Specified version of medication 
coding dictionary 
7. Section 2.3.3 
Demographics 
and Other 
Baseline 
Characteristics 
9. Section 2.3.1 
Patient 
Disposition 
10. Section 2.1.1 
General 
Definitions 
11. Section 2.1.1 
General 
Definitions 
12. Section 2.4.2 
Prior, 
Concomicant 
and Post 
Therapies 
 


Novartis 
For business use only 
Page 4 
SAP Amendment 1 
 
CLCZ696BUS14 
 
Table of contents 
Table of contents ................................................................................................................. 4 
List of abbreviations ............................................................................................................ 6 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................... 9 
2.1 
Data analysis general information ........................................................................... 9 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 11 
2.2.1 
Subgroup of interest .............................................................................. 11 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 12 
2.3.1 
Patient disposition ................................................................................. 12 
2.3.2 
Protocol deviations ................................................................................ 14 
2.3.3 
Demographics and other baseline characteristics ................................. 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 16 
2.4.1 
Study treatment / compliance ................................................................ 16 
2.4.2 
Prior, concomitant and post therapies ................................................... 17 
2.5 
Analysis of the primary objective .......................................................................... 17 
2.5.1 
Primary endpoint ................................................................................... 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 18 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 19 
2.5.4 
Supportive analyses ............................................................................... 19 
2.6 
Analysis of the key secondary objective ............................................................... 19 
2.7 
Analysis of secondary objectives ........................................................................... 19 
2.7.1 
Secondary endpoints ............................................................................. 19 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 20 
2.8 
Safety analyses ....................................................................................................... 20 
2.8.1 
Adverse events ...................................................................................... 20 
2.8.2 
Deaths .................................................................................................... 21 
2.8.3 
Laboratory data ..................................................................................... 21 
2.8.4 
Other safety data ................................................................................... 22 
2.9 
Pharmacokinetic endpoints .................................................................................... 25 
2.10 
PD and PK/PD analyses......................................................................................... 25 
 
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2.12 
Biomarkers ............................................................................................................. 26 
2.13 
Other exploratory analyses .................................................................................... 26 
2.14 
Interim analysis ...................................................................................................... 28 
3 
Sample size calculation ..................................................................................................... 29 
4 
Change to protocol specified analyses .............................................................................. 29 
5 
Appendix ........................................................................................................................... 29 
5.1 
Imputation rules ..................................................................................................... 29 
5.1.1 
Study treatment ..................................................................................... 29 
5.1.2 
AE date imputation ............................................................................... 29 
5.1.3 
Concomitant medication date imputation ............................................. 30 
5.2 
AEs coding/grading ............................................................................................... 31 
5.3 
Laboratory parameters derivations ........................................................................ 31 
5.3.1 
Laboratory grading ................................................................................ 31 
5.3.2 
Notable laboratory values ..................................................................... 31 
5.4 
Vital signs .............................................................................................................. 32 
5.4.1 
Notable vital sign values ....................................................................... 32 
5.5 
Statistical models ................................................................................................... 32 
5.5.1 
Primary analysis .................................................................................... 32 
5.5.2 
Key secondary analysis ......................................................................... 33 
5.6 
Rule of exclusion criteria of analysis sets.............................................................. 33 
6 
Reference ........................................................................................................................... 33 


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List of abbreviations 
AC 
Activity Count 
ACEi 
Angiotensin Converting Enzyme Inhibitor 
AE 
Adverse Event 
AHI 
Apnea Hypopnea Index 
ALT 
Alanine Aminotransferase 
ANCOVA 
Analysis of Covariance 
ARB 
Angiotensin Receptor Blocker 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
BID 
bis in diem/twice a day 
BMI 
Body Mass Index 
BPM 
Beats Per Minute 
BUN 
Blood Urea Nitrogen 
CABG 
Coronary Artery Bypass Graft 
CKD 
Chronic Kidney Disease 
CMH 
Cochran-Mantel-Haenszel 
CRO 
Contract Research Organization 
CRT-P 
Cardiac Resynchronization Therapy – No ICD 
CRT-D 
Cardiac Resynchronization Therapy – With ICD 
CSR 
Clinical Study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DCT 
Data Collection Tool 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
FAS 
Full Analysis Set 
H0 
Null Hypothesis 
HA 
Alternative Hypothesis 
HF 
Heart Failure 
 
 
ICD 
Implantable Cardioverter Defibrillator 
IRT 
Interactive Response Technology 
 
 
LOCF 
Last Observation Carried Forward 
MRI 
Magnetic Resonance Imaging 
MedDRA 
Medical Dictionary for Regulatory Activities 
NYHA 
New York Heart Association 
PCI 
Percutaneous Coronary Intervention 
PD 
Pharmacodynamic 
PK 
Pharmacokinetic 
PRO 
Patient-reported Outcomes 
PT 
Preferred Term 
RBC 
Red Blood Cell 


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RS 
Randomized Set 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SS 
Safety Set 
TEAE 
Treatment-emergent Adverse Event 
TFLs 
Tables, Figures, Listings 
TIA 
Transient Ischemic Attack 
 
 
USPI 
United States Package Insert 
WASO 
Wake After Sleep Onset 
WBC 
White Blood Cell 
WHO 
World Health Organization 
 


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1 
Introduction 
The statistical analysis plan (SAP) will outline in detail the analyses planned in the protocol. 
The analyses will be used to generate the Clinical Study Report (CSR). The SAP is based on 
protocol version 02 (amended protocol) dated 13-Mar-2018 and the data collection tool (DCT) 
version 3.0 dated 04-May-2017. 
1.1 
Study design 
This study is a multicenter, randomized, double-blind, double dummy, parallel group, active-
controlled 8-week study with open-label extension using medical device-grade patient worn 
sensors to measure waking and sleeping physical activity in the ambulatory outpatient setting. 
The 18-week study duration will consist of a 2-week baseline observation phase (with patients 
continuing their current heart failure [HF] drug therapy), followed by an 8-week blinded 
treatment phase during which approximately 136 patients will be randomized to either initiation 
of sacubitril/valsartan treatment or enalapril comparator in a 1:1 ratio with no stratification at 
approximately 25-30 centers in the United States, and finally an 8-week open-label extension 
phase during which all patients will be treated with sacubitril/valsartan.  
Each patient will undergo a 36-hour washout period (during which angiotensin converting 
enzyme inhibitor [ACEi], or study drug will be withheld) before the start of the randomized, 
blinded treatment phase, and again before beginning the open-label extension phase to ensure 
that the blinding of the core study is maintained and to reduce the risk of angioedema.  
Patients will be randomized to either sacubitril/valsartan 24/26 mg bis in diem/twice a day (BID) 
or enalapril 2.5 mg BID (Dose Level 1). At each subsequent study visit during the double-blind 
epoch, the study physician will sequentially up-titrate the study drug dose (based on clinical 
tolerance and the United States Package Insert [USPI]) to achieve the desired dose of 
sacubitril/valsartan 97/103 mg BID or enalapril 10 mg BID (Dose Level 3). Dose level 2 is 
defined as sacubitril/valsartan 49/51 mg BID or enalapril 5 mg BID. Patients not tolerating 
escalation from Dose Level 1 to Dose Level 2 (or Dose Level 2 to Dose Level 3) can be titrated 
down to the next lower Dose Level (including active medication and matching placebos), if, in 
the investigator’s judgement, the adjustment/elimination of concomitant medications is not 
possible or does not alleviate the side effects of concern. 
All patients entering the open-label epoch will be given sacubitril/valsartan 49/51 mg BID 
(Dose Level 2) unless they completed the double-blind treatment epoch on Dose Level 1. 
Instead, these patients will enter the open-label epoch on sacubitril/valsartan 24/26 mg BID 
(Dose Level 1). At each subsequent study visit during the open-label epoch, the study physician 
will sequentially up-titrate the study drug dose (based on clinical tolerance and the USPI) to 
achieve the targeted desired dose of sacubitril/valsartan 97/103 mg BID (Dose Level 3). Patients 
not tolerating escalation from Dose Level 1 to Dose Level 2 (or Dose Level 2 to Dose Level 3) 
can be titrated down to the next lower Dose Level, if, in the investigator’s judgement, the 
adjustment/elimination of concomitant medications is not possible or does not alleviate the side 
effects of concern. 
All eligible patients will be randomized via Interactive Response Technology (IRT) to one of 
the treatment arms. The investigator or his/her delegate will contact the IRT after confirming 
that the patient fulfills all the inclusion/exclusion criteria. The IRT will assign a randomization 


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number to the patient, which will be used to link the patient to a treatment arm and will specify 
a unique medication number for the first package of study drug to be dispensed to the patient. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from patients and investigator staff. A patient 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of patient numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 
Drug Supply Management using a validated system that automates the random assignment of 
medication numbers to packs containing the investigational drug(s). 
The primary analysis time point will be Week 8 (end of the double-blind period).  
There are no interim analyses planned. 
1.2 
Study objectives and endpoints 
The primary objective is to evaluate the effect of initiation of sacubitril/valsartan treatment 
versus enalapril on physical activity during the waking hours as an objective measure of 
physical function. 
The secondary objective is to evaluate the effect of initiation of sacubitril/valsartan treatment 
versus enalapril on patients’ sleep as an objective measure of physical function. 
2 
Statistical methods 
2.1 
Data analysis general information 
 a Novartis-designated Contract Research Organization 
(CRO) will be performing all analyses outlined in this SAP. SAS® version 9.3 (or higher) will 
be used for all analyses. 
Data from all centers that participate in this protocol will be combined, so that an adequate 
number of patients will be available for analysis. 
Unless otherwise specified, for continuous data, the mean, standard deviation, median, first and 
third quartiles, interquartile range, and minimum and maximum values will be presented. For 
categorical data, frequencies and percentages will be presented.  
All statistical tests will be conducted against a two-sided alternative hypothesis, employing a 
significance level of 0.05, unless otherwise specified. 


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All data will be provided in listings in addition to summaries described below. 
2.1.1 
General definitions  
Study treatment  
Patients will receive either sacubitril/valsartan or enalapril during the first 8 weeks of the study. 
Study treatment will refer to either of these two drugs. 
Baseline 
The last non-missing assessment prior to or on the start date of study treatment (randomization 
date for patients not treated) will be used as baseline, unless otherwise specified. 
Date of first administration of study treatment 
Randomized treatment phase: The date of first administration of study treatment in the 
randomized treatment phase is defined as the first date a dose of study treatment is administered 
and recorded on the Dosage Administration Record - At Visit (Visit 3) electronic case report 
form (eCRF). 
Open-label extension phase: The date of first administration of study treatment in the open-
label extension phase is defined as the first date a dose of sacubitril/valsartan is administered in 
the open-label extension phase and recorded on the Dosage Administration Record - Summary 
eCRF. 
Date of last administration of study treatment 
Randomized treatment phase: The date of last administration of study treatment in the 
randomized treatment phase is defined as the last date a dose of study treatment is administered 
in the randomized treatment phase and recorded on the Double-Blind Phase Disposition eCRF 
(for 
patients 
continuing 
into 
the 
open-label 
extension 
phase) 
or 
the 
Study 
Completion/Discontinuation eCRF (for patients not continuing into the open-label extension 
phase).  
Open-label extension phase: The date of last administration of study treatment in the open-label 
extension phase is defined as the last date a dose of sacubitril/valsartan is administered in the 
open-label extension phase and recorded on the Dosage Administration Record - Summary 
eCRF. 
Study day 
The study day describes the day of the assessment relative to the date of randomization. 
The study day will be calculated as the difference between the date of assessment and the date 
of randomization plus 1. If the date of assessment is prior to the date of randomization, the study 
day will be negative and will be calculated as the difference between the date of the assessment 
and the date of randomization. 
Randomized treatment phase 
Assessments performed at Weeks 2, 4, or 8 (e.g., vital signs) are assigned to the randomized 
treatment phase for summarization purposes. Unscheduled assessments are not assigned to a 
phase. 


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For summarization of adverse events [AEs], medications, protocol deviations, and notable vital 
signs and laboratory abnormalities by treatment phase, an assessment during the randomized 
treatment phase is defined as any assessment obtained in the following time interval:  
Date of randomization (or date of first administration of study treatment, as appropriate) through 
the date of the Week 8 visit, inclusive. 
Open-label extension phase 
Assessments performed at Weeks 10, 12, or 16 (e.g., vital signs) are assigned to the open-label 
extension phase for summarization purposes. Unscheduled assessments are not assigned to a 
study phase. 
For summarization of AEs, medications, protocol deviations, and notable vital signs and 
laboratory abnormalities by treatment phase, an assessment during the open-label extension 
phase is defined as any assessment obtained in the following time interval:  
After the date of the Week 8 visit.  
Last contact 
The date of last contact will be the last visit date for each patient and will be derived by 
examining all visit data collected in the eCRFs.  
Year, month and week 
For reporting purposes, the rules below will be followed to convert a year, month and week to 
days. 
1 year = 365.25 days 
1 month = 30.3475 days 
1 week = 7 days 
1 day = 24 hours 
2.2 
Analysis sets 
The following analysis data sets will be used in the analyses: 
Randomized Set (RS): The RS will consist of all randomized patients. 
Full Analysis Set (FAS): The FAS will consist of all randomized patients with the exception 
for those patients who have not been qualified for randomization and have not received study 
treatment, but have been inadvertently randomized into the study. Following the intent-to-treat 
principle, patients will be analyzed according to the treatment to which they were assigned at 
randomization. Efficacy variables will be analyzed based on the FAS as the primary set. 
Safety Set (SS): The SS will consist of all randomized patients who have received at least one 
dose of study treatment. Patients will be included in the analysis according to the treatment 
actually received. The SS will be used for the analyses of safety variables. 
2.2.1 
Subgroup of interest 
The following subgroups will be analyzed for the primary objective: 


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1. Age groups (<65, ≥65 years; and <75, ≥75 years) 
2. Baseline ejection fraction categories (<25%, 25% - <35%, ≥35%) 
3. Baseline quartiles of mean activity counts during the most active 30 minutes of the 
patient's day (counts) (mean of data collected each day during Week -1) (based on FAS) 
4. New York Heart Association (NYHA) classification [best value during the past month 
prior to screening visit] (II, III) 
5. Prior HF hospitalization (No, Yes) 
6. History of diabetes (No, Yes) 
7. Baseline body mass index (BMI) categories (<25, 25 - <30, ≥30 kg/m2) 
8. Baseline quartiles of mean activity during the daily active period (counts/minute) (mean 
of data collected each day during Week -1) 
9. Baseline sleep efficiency categories (<70%, 70-90%, >90%) 
10. Baseline apnea hypopnea index (AHI) 4% categories (<15, ≥15 events/hour) 
11. Baseline quartiles of the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall 
summary score 
See Section 2.5 for further details on the primary objective.  
2.3 
Patient disposition, demographics and other baseline 
characteristics 
2.3.1 
Patient disposition 
All patients will be used for the summary of patient disposition. The following categories will 
be summarized: 
• Number of patients who were screened 
• Screening phase disposition 
o Completed 
o Adverse event 
o Death 
o Pregnancy 
o Screen failure 
o Study terminated by sponsor 
o Technical problems 
o Lost to follow-up 
o Physician decision 
o Patient/guardian decision 


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• Number of patients who were randomized 
• Number and percentage of patients who were treated 
• Number and percentage of patients who achieved dose level 3 
• Number and percentage of patients who did not achieve dose level 3 
• Reason for not achieving dose level 3 
o Hyperkalemia 
o Symptomatic hypotension 
o Renal dysfunction 
o Angioedema 
o Other adverse event 
o Unrelated to study treatment tolerability 
• Number and percentage of patients who completed study treatment 
• Number and percentage of patients who prematurely discontinued study treatment 
during the double-blind phase 
o Treatment unblinded by site (No, Yes) 
• Number and percentage of patients who prematurely discontinued study treatment 
during the open-label phase 
• Reason for premature discontinuation of study treatment (during double-blind phase and 
open-label phase, separately) 
o Adverse event 
o Death 
o Pregnancy 
o Study terminated by sponsor 
o Technical problems 
o Lost to follow-up 
o Physician decision 
o Patient/guardian decision 
• Number and percentage of patients who continued into the open-label phase 
• Study duration in months [(date of last contact/death – date of randomization 
+1)/30.3475]  
Additionally, listings of inclusion/exclusion criteria, screening/double-blind/open-label phase 
disposition and study treatment disposition will be provided. 


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2.3.2 
Protocol deviations 
The number and percentage of patients with protocol deviations by category will be summarized 
by treatment phase (see Section 2.1.1 treatment phase definitions). Additionally, a listing of 
protocol deviations during the study will also be presented. The RS will be used. 
2.3.3 
Demographics and other baseline characteristics 
Descriptive summaries and/or listings will be provided for demographics, baseline 
characteristics and disease history. The number and percentage (categorical variables) and 
descriptive statistics (continuous data) for the information below will be summarized by 
treatment group for both the randomized treatment and open-label extension phases. 
The RS and FAS will be used. 
Demographics and baseline characteristics 
Demographic variables include: 
• Age (years), age group (<65, ≥65 years; and <75, ≥75 years) 
• Sex (Male, Female) 
o Child bearing status (Able to bear children, Post-menopausal, Sterile) 
• Race (Caucasian, Black, Asian, Native American, Pacific Islander, Other, Unknown) 
• Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Unknown) 
General baseline characteristic variables include: 
• Height (cm)  
• Weight (kg) 
• BMI (kg/m2) [= weight (kg)/height (m2) from Screening Visit 1] 
o BMI categories (<20, 20 - <25, 25 - 30, >30 kg/m2) 
• Estimated Glomerular Filtration Rate (eGFR) (ml/min/1.73 m2) 
o eGFR categories (<45, 45 - <60, ≥60 ml/min/1.73 m2) 
Key actigraphy 
 baseline characteristic variables include: 
• Mean activity counts during the most active 30 minutes of the patient's day (counts)  
• Mean activity counts during the most active 6 minutes of the patient's day (counts)  
• Mean activity during sleep (counts/minute) 
• Mean activity during the daily active period (counts/minute) 


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Disease history 
Disease history variables, as collected on the Heart Failure History eCRF at screening, include: 
• NYHA classification [best value during the past month prior to screening visit] (I, II, 
III, IV) 
• Primary HF etiology (Ischemic, Non-ischemic) 
o Non-ischemic etiology (Hypertensive [No, Yes], Diabetic [No, Yes], Alcoholic 
[No, Yes], Myocarditis [No, Yes], Peripartum [No, Yes], Drug induced [non-
chemotherapy] [No, Yes], Chemotherapy [No, Yes], Idiopathic Other [No, Yes], 
Valvular heart disease [No, Yes], Other [No, Yes]) 
• Myocardial infarction (No, Yes) 
• Coronary revascularization (No, Yes) 
o Coronary revascularization type (Percutaneous coronary intervention [PCI], 
Coronary Artery Bypass Graft [CABG]) 
• Prior heart failure hospitalization (No, Yes) 
o Number of heart failure hospitalizations in the last 12 months 
• Most recent ejection fraction (%) 
o Ejection fraction categories (<25%, 25% - <35%, ≥35%) 
o Method used (Magnetic Resonance Imaging [MRI], Echocardiography, Nuclear 
[SPECT/PET/MUGA], Ventriculogram, Other) 
• ACE inhibitor intolerant (No, Yes) 
• Known history of diabetes mellitus (No, Yes) 
o Controlled by: Insulin (No, Yes), Oral anti-diabetic agent (No, Yes), GLP-1 
agonist (No, Yes), Diet only (No, Yes) 
Cardiovascular history 
Cardiovascular history will be summarized. The following disease information will be collected: 
• Hypertension (No, Yes, Unknown) 
• Transient Ischemic Attack (TIA) (No, Yes, Unknown) 
• Stroke (No, Yes, Unknown) 
• Peripheral vascular disease (No, Yes, Unknown) 
• Chronic Kidney Disease (CKD) stage (CKD stage 1 [eGFR ≥90], CKD stage 2 [eGFR 
60 - 89], CKD stage 3 [eGFR 30 - 59], CKD stage 4 [eGFR 15 - 29], CKD stage 5 
[eGFR <15 or dialysis], No CKD) 


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• Arrhythmia (No, Yes, Unknown) 
o Arrhythmia type (Atrial fibrillation, Atrial flutter, Supraventricular tachycardia, 
Ventricular tachycardia) 
• Pacemaker/Implantable Cardioverter Defibrillator (ICD) (No, Yes, Unknown) 
o Device type (Pacemaker, Cardiac resynchronization therapy - no ICD [CRT-P], 
Cardiac resynchronization therapy - with ICD [CRT-D], ICD only [single/dual 
chamber], Unknown) 
• Moderate to severe valvular heart disease (No, Yes, Unknown) 
o Valvular heart disease type (Mitral regurgitation, Aortic regurgitation, Aortic 
stenosis, Tricuspid regurgitation, Other) 
• Prior valvular surgery (No, Yes, Unknown) 
o Valvular surgery type (Mitral, Aortic, Tricuspid, Pulmonic) 
Non-cardiovascular medical history 
Non-cardiovascular medical history will be summarized and listed. The summary will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment group for 
both the randomized treatment and open-label extension phases. Non-cardiovascular medical 
history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
terminology (v19.0 or later).  
Surgeries and Medical Procedures 
Surgeries and medical procedures will be listed. Surgeries and medical procedures will be coded 
using MedDRA terminology (v19.0 or later). 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
The SS will be used for all analyses associated with study treatment and medications, unless 
otherwise specified. 
2.4.1 
Study treatment / compliance 
The duration of treatment for the randomized treatment phase is defined as: 
Duration (days) = (date of last study treatment in randomized treatment phase – date of first 
study treatment) +1 
The first date of study treatment is recorded on the Dosage Administration Record - At Visit 
(Visit 3) eCRF. 
The duration of treatment for the open-label extension phase is defined as: 
Duration (days) = (date of last study treatment in open-label extension phase – date of first 
study treatment in open-label extension phase) +1 
Summary statistics will be displayed for the durations of treatment during the randomized 
treatment and open-label extension phases. 


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The durations will also be categorized into weekly time intervals (<7 days, 7 - <14 days, 14 - 
<21 days, …, etc.). The number and percentage of patients in each category will be presented 
by treatment phase. 
Total patient-days of exposure will also be summarized by treatment phase. 
In addition, the number and percentage of patients at each dose level dispensed by visit will be 
summarized by treatment group for both the randomized treatment and open-label extension 
phases. The number and percentage of the maximum dose levels dispensed will also be 
presented by treatment group for both the randomized treatment and open-label extension 
phases. Similarly, the up-titrated doses, down-titrated doses and unchanged doses will be 
summarized by visit and treatment group for both the randomized treatment and open-label 
extension phases. 
All information on dose administration will be listed. 
2.4.2 
Prior, concomitant and post therapies 
Prior and concomitant medications will be coded according to the World Health Organization 
(WHO) Drug Reference List (v15.3 or later). The WHO Drug version will be denoted in the 
corresponding tables and listings. Prior and concomitant medications are mutually exclusive, 
as defined below: 
• A prior medication is defined as any medication with an end date prior to the first dose 
of study treatment.  
• A concomitant medication is defined as any medication taken on or after the start of 
study treatment. A prior medication that is ‘ongoing’ at the time of the first study 
treatment or whose end date is after first study treatment will be considered a 
concomitant medication. 
The number and percentage of patients with prior medications will be summarized by 
Anatomical Therapeutic Chemical (ATC) class, preferred term and treatment group for both the 
randomized treatment and open-label extension phases. Concomitant medications will be 
summarized in a similar fashion. Separate summaries of prior ACEi and angiotensin receptor 
blocker (ARB) will also be produced. All medications will be listed. 
The number and percentage of patients in the following prior ACEi/ARB exposure categories 
(assessed at screening) will be summarized: 
• ACEi/ARB naïve (never exposed) 
• Previously on ACEi/ARB but not currently taking (previously exposed) 
• Currently taking 
2.5 
Analysis of the primary objective 
2.5.1 
Primary endpoint 
The primary endpoint is the change in mean activity counts collected during the most active 30 
minutes of the patient's day between baseline phase (mean of data collected each day during 


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Week -1) and the final randomized treatment phase measurement (mean of data collected each 
day during Week 8), as measured by wrist-worn accelerometer collected actigraphy (total 
counts per 30 minute period collected during the most active 30 minutes of each day). The 
analysis of the primary endpoint will be based on the FAS. 
The following algorithm will be used to exclude “invalid” actigraphy data from analysis of the 
primary endpoint. Note that AC = activity count. 
1. Isolate ‘ACTIVE’ intervals. 
2. For each ‘ACTIVE’ interval, use variables [duration] and [%Invalid AC] to create a new 
variable [duration valid AC]. This new variable reflects the duration of valid activity 
data within each active period. 
3. Find any [duration valid AC] that is <0.5 hours and remove it from the analysis. If an 
active period contains <30 minutes of valid data, then determining the most active 30 
minutes within the period is not possible. 
4. For each patient, sum the [duration valid AC] for each unique [Start Date] to create a 
new variable [all day duration valid AC]. This new variable reflects the total duration 
of valid activity data for each date. In most cases, each patient will have only one active 
period per date, but there are cases with two active periods within a single day (e.g., if 
patient had a nap in the middle of the day). 
5. Find any [all day duration valid AC] that is <8 hours and remove all data associated 
with that [Start Date] from the analysis. 
6. In the remaining data for analysis, each patient will have >=8 hours of valid activity data 
for each date.  It might be one long active period, or it might comprise two shorter active 
periods that add up to >=8 hours. 
7. For each patient, find the highest [mostActive30] for each date and use this in the 
analysis. In most cases, each date will have only one active period and therefore only 
one [mostActive30] datapoint. On dates that contain more than one active period, select 
the highest [mostActive30] regardless of the duration of the active period. 
As long as for a single date a patient has >=8 hours of valid activity data in total, the 30 minutes 
with the most activity will be used in the analysis. The 8-hour threshold was selected as this 
requires each patient to have at least 50% of valid activity data each day, assuming 8 hours of 
sleep per night. 
In order to calculate the mean [mostActive30] across 7 days of data during the given week, the 
patient must have at least 5 days of data. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
Let μj denote the population mean of change in mean activity count from baseline phase to 
Week 8 for treatment group j, j = 0, 1, where 0 corresponds to enalapril and 1 corresponds to 
sacubitril/valsartan. 
The following null hypothesis (H0) will be tested against the alternative hypothesis (HA): 
H0: μ1 – μ0 = 0 


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HA: μ1 – μ0 ≠ 0 
The primary endpoint will be analyzed by an analysis of covariance (ANCOVA) model with 
treatment and baseline activity as explanatory variables. The least squares means of the two 
treatment groups, least squares mean difference of the treatment groups, 95% confidence 
interval for the difference in the two treatment groups, and p-value based on the fitted linear 
model will be reported. If the p-value is <0.05 and the least squares mean difference of the 
treatment 
groups 
favors 
sacubitril/valsartan, 
statistical 
significance 
in 
favor 
of 
sacubitril/valsartan will be declared. 
Before performing the above analysis, tests of normality of the variable, change in mean activity 
counts collected during the most active 30 minutes of the patient’s day between baseline and 
Week 8, and the log of the variable (log (Week 8 value) – log (baseline value)) will be performed. 
In the event the variable is not normally distributed (based on Shapiro-Wilk test p-value <0.05) 
but the lognormal distribution fits better, the above analysis will be performed using the log 
transformed data. Anti-log of the least squares mean difference of the treatment groups will be 
used to report the ratio of the treatment difference in the original scale. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Missing data will be imputed using the last-observation-carried-forward (LOCF) method. If a 
patient has no post-baseline value, the missing value will not be imputed and the patient will be 
removed from the analysis. If a patient's data is missing or unevaluable for the week preceding 
randomization, the data from the previous week will be used as the baseline measurement. If a 
patient's data is missing or unevaluable for each of these weeks, the patient will be excluded 
from the analysis. 
2.5.4 
Supportive analyses 
A supportive nonparametric analysis will be performed to examine the consistency of results. 
For this supportive analysis, the primary endpoint will be analyzed using the Wilcoxon rank-
sum test. The probability of one treatment being better than the other treatment will be estimated 
(based on the Wilcoxon rank-sum test) and the associated 95% confidence interval will be 
reported (Chen and Kianifard 2000). 
In addition, subgroup analyses based on the FAS as described in Section 2.2.1 will be performed.  
2.6 
Analysis of the key secondary objective 
There is no key secondary objective. 
2.7 
Analysis of secondary objectives 
All analyses will be based on the FAS unless otherwise specified. 
2.7.1 
Secondary endpoints 
The secondary endpoints include the following: 
• Change in mean activity during sleep between baseline phase (mean of data collected 
during Week -1) and the final randomized treatment phase measurement (mean of data 


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collected during Week 8), as measured by actigraphy (activity counts per minute during 
daily sleep period, wrist-worn accelerometer). 
• Change in mean activity during sleep between baseline phase (mean of data collected 
during Week -1) and each randomized treatment and open-label extension phase 
measurement, as measured by actigraphy (Weeks 1, 9, and 16) (activity counts per 
minute during daily sleep period, wrist-worn accelerometer). 
• Change in mean activity counts during the most active 30 minutes of the patient’s day 
between baseline phase (mean of data collected each day during Week -1) and each 
randomized treatment and open-label extension phase measurement (Weeks 1, 9, and 
16), as measured by wrist worn accelerometer collected actigraphy. 
Endpoints will be based on the mean of data collected for at least 5 out of the 7 days during the 
given week.  
2.7.2 
Statistical hypothesis, model, and method of analysis 
During the randomized treatment phase, change from baseline for each secondary endpoint will 
be analyzed at each time point using the same ANCOVA model as for the primary endpoint. 
During the open-label extension phase, change from baseline (mean of Week -1) for each 
secondary endpoint will be analyzed at each time point using paired t-tests for the group 
randomized to sacubitril/valsartan. The analyses will be repeated using the Week 8 
measurement as baseline for the group randomized to enalapril.  
2.7.3 
Handling of missing values/censoring/discontinuations 
For the analysis of secondary endpoints during the randomized treatment phase, the same 
approach for the handling of missing data as for the primary endpoint will be used (see Section 
2.5.3). 
2.8 
Safety analyses 
All safety analyses will be based on the SS unless otherwise specified. There will be no 
inferential analyses of the safety data. 
2.8.1 
Adverse events  
2.8.1.1 
Coding of AEs 
AEs will be coded using MedDRA terminology (v19.0 or later). 
2.8.1.2 
General rules for AE reporting 
AE summaries will include all treatment-emergent AEs (TEAEs). TEAEs are defined as AEs 
starting on or after the first day of study treatment. All AEs will be listed. AEs starting prior to 
the first day of study treatment (non-TEAEs) will be flagged in the listings.  
All TEAEs will be summarized by treatment phase as defined in Section 2.1.1. 


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TEAEs will be summarized by presenting the number and percentage of patients having at least 
one TEAE, having at least one TEAE in each primary SOC, and for each PT using MedDRA 
terminology. A patient with multiple occurrences of a TEAE will be counted only once in the 
AE category. 
Separate summaries will be presented by SOC, PT and severity. A patient with multiple 
severities for an AE will be summarized under the worst severity recorded for the event.  
Any information collected will be listed as appropriate. 
2.8.1.3 
AE summaries 
The following summary tables will be provided: 
• AEs, regardless of study treatment relationship, by primary SOC, PT and worst severity 
• Most frequent (≥5%) AEs, regardless of study treatment relationship, by PT 
• AEs suspected to be related to study treatment by primary SOC and PT 
• Serious adverse events (SAE), regardless of study treatment relationship, by primary 
SOC and PT 
• SAEs suspected to be related to study treatment by primary SOC and PT 
• AEs leading to discontinuation, regardless of study treatment relationship, by primary 
SOC and PT 
• AEs requiring dose adjustment or study treatment interruption, regardless of study 
treatment relationship, by primary SOC and PT 
• AEs requiring additional therapy, regardless of study treatment relationship, by primary 
SOC and PT 
• Death resulting from AEs by primary SOC and PT 
2.8.1.4 
Adverse events of special interest / grouping of AEs 
Separate summaries will be provided for AEs related to angioedema, regardless of study 
treatment relationship. The summaries will be presented by primary SOC, PT and worst severity. 
2.8.2 
Deaths 
Patient deaths will be summarized by primary SOC, PT and treatment phase (see Section 2.1.1 
for treatment phase definitions). A patient listing of all deaths with primary and contributing 
reasons for death will be provided. All patients in the FAS will be included for the above 
analysis. Deaths will be coded using MedDRA terminology (v19.0 or later). 
2.8.3 
Laboratory data 
Laboratory values will be summarized using shift tables (from baseline to most extreme post 
baseline value) by each laboratory parameter at its worst severity by treatment phase (see 
Section 2.1.1 for treatment phase definitions). The number and percentage of patients with 


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laboratory values will be presented by low/normal/high (low and high) classifications to 
compare baseline to worst post baseline value.  
In addition, laboratory values and the change from baseline for each parameter by visit will be 
summarized by treatment group for both the randomized treatment and open-label extension 
phases. In the event there are multiple laboratory values within a visit, the worst value will be 
summarized. 
A separate summary table will be presented by treatment phase (see Section 2.2.1 for treatment 
phase definitions) with the number and percentage of patients having notable lab abnormalities 
based on percent change from baseline (see Section 5.3 for a list of notable laboratory 
abnormalities). 
Listings of all laboratory values will be provided. A separate listing for pregnancy tests will 
also be provided. Any notable laboratory abnormalities will be flagged. 
2.8.4 
Other safety data 
2.8.4.1 
Vital signs 
All vital signs (systolic and diastolic blood pressure [mmHg], pulse rate [beats per minute 
{bpm}], respiration rate [breaths per minute], weight [kg], height [cm], and BMI [kg/m2]) will 
be descriptively summarized at each visit by treatment group for both the randomized treatment 
and open-label extension phases. Change from baseline will also be presented. Note that height 
is only collected at Visit 1. 
A separate summary table will be presented with the number and percentage of patients having 
notable vital signs based on changes relative to baseline values (see Section 5.4 for a list of 
notable vital signs) by treatment phase (see Section 2.1.1 for treatment phase definitions). 
2.8.4.2 
Heart Failure (HF) Signs and Symptoms 
The number and percentage of patients in the following HF signs and symptoms categories will 
be summarized by visit and treatment group for both the randomized treatment and open-label 
extension phases: 
• Paroxysmal nocturnal dyspnea (Absent, Present) 
• Fatigue (Absent, Present) 
• Edema (Absent, Trace, Feet and Ankles, Lower Legs or Thighs, Sacrum) 
• Peripheral edema (Absent, Present) 
• Dyspnea at rest (Absent, Present) 
• Dyspnea at upon effort (Absent, Present) 
• Orthopnea (Absent, Present) 
• Rales (Absent, Basilar only, >1/3 of lung filled) 
• Jugular venous distention (Absent, Present) 


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• Presence of a third heart sound (Absent, Present) 
• NYHA classification (Class I, Class II, Class III, Class IV) 
2.8.4.3 
Angioedema 
The number and percentage of patients for categorical variables and summary statistics for 
continuous variables for the following angioedema assessment data will be presented by study 
phase and treatment group for both the randomized treatment and open-label extension phases. 
• Outcome (Not recovered/Not resolved, Recovered/Resolved, Recovering/Resolving, 
Recovered/Resolved with Sequelae, Fatal, Unknown) 
o Duration of angioedema in days [end date – start date + 1] 
• Timing of event (After first dose, after multiple doses, dose not given) [not asked for 
events that occurred during Screening study phase] 
o Study medication discontinued due to event (No, Yes, Unknown)  
o Event occurred within 1 day of dosing (Within 1 day of dose but less than or 
equal to 1 hour, Within 1 day of dose but greater than 1 hour, After 1 day of 
dosing, Unknown) 
• History of prior angioedema or angioedema like event (No, Yes, Unknown) 
• Medications taken at time of previous event 
o ACE inhibitor (No, Yes, Unknown)  
o ARB (No, Yes, Unknown) 
o Renin inhibitor (No, Yes, Unknown) 
o Other medications (No, Yes, Unknown) 
• Presence of hereditary angioedema (No, Yes, Unknown) 
• Any family members with history of angioedema-like events (No, Yes, Unknown) 
• Signs and symptoms for current event 
o Shortness of breath/dyspnea (No, Yes, Unknown) 
o Difficulty swallowing/dysphagia (No, Yes, Unknown) 
o Difficulty speaking/dysarthria (No, Yes, Unknown) 
o Pain on swallowing/odynophagia (No, Yes, Unknown) 
o Stridor (No, Yes, Unknown) 
o Abdominal pain (No, Yes, Unknown) 
o Other (No, Yes, Unknown) 
• Edema present (No, Yes) 
o Periorbital edema (No, Yes, Unknown) 


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o Head edema (No, Yes, Unknown) 
o Neck edema (No, Yes, Unknown) 
o Lip edema (No, Yes, Unknown) 
o Tongue edema (No, Yes, Unknown) 
o Throat edema (No, Yes, Unknown) 
o Submandibular edema (No, Yes, Unknown) 
o Genitalia edema (No, Yes, Unknown) 
o Extremities edema (No, Yes, Unknown) 
o Other (No, Yes, Unknown) 
• Previous edematous episodes (No, Yes, Unknown) 
o Number of previous edematous episodes 
• ACEi taken in the past (before screening) (No, Yes, Unknown) 
• ACEi taken (other than study medication) during trial participation after screening (No, 
Yes, Unknown) 
o Dose changed within 2 days of event (No, Yes, Unknown) 
• ARB taken in the past (before screening) (No, Yes, Unknown) 
• ARB taken (other than study medication) during trial participation after screening (No, 
Yes, Unknown) 
o Dose changed within 2 days of event (No, Yes, Unknown) 
• Patient suffering from influenza, common cold or upper respiratory tract infection at 
time of event (No, Yes, Unknown) 
• Medication allergies (No, Yes, Unknown) 
• Food allergies (No, Yes, Unknown) 
• Potential causes of angioedema-like event  
o Food (No, Yes, Unknown) 
o Insect bite (No, Yes, Unknown) 
o Animal exposure (No, Yes, Unknown) 
o Medication (No, Yes, Unknown) 
o Dental work (No, Yes, Unknown) 
o Pollen (No, Yes, Unknown) 
o Dust (No, Yes, Unknown) 
o Concomitant disease (No, Yes, Unknown) 


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o Idiopathic (No, Yes, Unknown) 
o Other (No, Yes, Unknown) 
• Medical intervention (No, Yes) 
o Administration of H-1 blocker (No, Yes) 
o Administration of H-2 blocker (No, Yes) 
o Administration of steroids (No, Yes) 
o Administration of epinephrine (No, Yes) 
o Admission to hospital (No, Yes) 
o Admission to ER (No, Yes) 
o Endotracheal intubation (No, Yes) 
o Tracheostomy (No, Yes) 
o Discontinuation of ACE inhibitor (other than study medication) (No, Yes) 
o Discontinuation of ARB (other than study medication) (No, Yes) 
o Other (No, Yes) 
All angioedema assessment data will be listed. Additionally, the adjudicated assessment of the 
event will be listed separately.  
2.9 
Pharmacokinetic endpoints   
Not applicable. 
2.10 
PD and PK/PD analyses 
Not applicable. 


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2.12 
Biomarkers 
Not applicable. 


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2.14 
Interim analysis 
No interim analysis is planned. 


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3 
Sample size calculation 
Primary endpoint: 
Assuming a significance level of 0.05, a total sample size of 136 patients would provide 90% 
power to detect a difference of 5000 in the change from baseline in mean activity counts 
collected during the most active 30 minutes between the sacubitril/valsartan treatment group 
and the enalapril group during Week 8, assuming a common standard deviation of 7400 (Maurer 
2009) and a 20% drop-out rate and a 10% rate of patients with non-evaluable data. The assumed 
effect size of 68% (5000/7400) will be maintained in the event the log transformation is needed 
for the primary analysis thus not affecting the sample size calculation and power of the study. 
Secondary endpoint: 
Assuming a significance level of 0.05, a sample size of 136 patients would provide 93% power 
to detect a 3.5 point difference in the change from baseline in mean activity value during the 
sleep (expressed as counts per minute) between the sacubitril/valsartan treatment group and the 
enalapril group during Week 8, assuming a common standard deviation of 4.9 and a 20% drop-
out rate and a 10% rate of patients with non-evaluable data (Peterson 2012). 
4 
Change to protocol specified analyses 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study treatment 
Full dates for study treatment collected on the eCRF are required; therefore, no imputations will 
be made. 
5.1.2 
AE date imputation 
The following algorithm should be used to estimate start dates for which only partial 
information is known:  


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• 
Missing day and month 
- 
If the year is the same as the year of first study treatment, then the day and 
month of the start date of treatment will be assigned to the missing fields. 
- 
If the year is prior to the year of first study treatment, then December 31 will be 
assigned to the missing fields. 
- 
If the year is after the year of first study treatment, then January 1 will be 
assigned to the missing fields. 
• 
Missing month only 
- 
Treat day as missing and replace both month and day according to the above 
procedure. 
• 
Missing day only  
- 
If the month and year are the same as the year and month of first study 
treatment, then the start date of treatment will be assigned to the missing day.  
- 
If the month and year are before the year and month of first study treatment, 
then the last day of the month will be assigned to the missing day. 
- 
If the month and year are after the year and month of first study treatment, then 
the first day of the month will be assigned to the missing day. 
If the imputed start date result is after the stop date (and the stop date is complete), the 
imputed start date will be reset to the stop date. 
The following algorithm should be used to estimate stop dates for which only partial 
information is known:  
• 
Missing year  
- 
Date left missing.  
• 
Missing month  
- 
Impute ‘December’. 
• 
Missing day  
- 
Impute ‘last date of that month’. 
5.1.3 
Concomitant medication date imputation 
The following algorithm should be used to estimate start dates for which only partial 
information is known:  
• 
Missing day and month 
- 
If the year is the same as the year of first study treatment, then the day and 
month of the start date of treatment will be assigned to the missing fields. 
- 
If the year is prior to the year of first study treatment, then December 31 will be 
assigned to the missing fields. 


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- 
If the year is after the year of first study treatment, then January 1 will be 
assigned to the missing fields. 
• 
Missing month only 
- 
Treat day as missing and replace both month and day according to the above 
procedure. 
• 
Missing day only  
- 
If the month and year are the same as the year and month of first study 
treatment, then the start date of treatment will be assigned to the missing day.  
- 
If the month and year are before the year and month of first study treatment, 
then the last day of the month will be assigned to the missing day. 
- 
If the month and year are after the year and month of first study treatment, then 
the first day of the month will be assigned to the missing day. 
If the imputed start date result is after the stop date (and the stop date is complete), the 
imputed start date will be reset to the stop date. 
The following algorithm should be used to estimate stop dates for which only partial 
information is known:  
• 
Missing year  
- 
Date left missing. Consider the medication to have been received at all periods 
after that period determined by the start date. 
• 
Missing month  
- 
Impute ‘December’. 
• 
Missing day  
- 
Impute ‘last date of that month’. 
5.2 
AEs coding/grading 
The UBC coding team will code the AE terms using MedDRA v19.0 or later. If any terms are 
not coded, the data management team will issue queries to sites to update the AE term 
appropriately.  
5.3 
Laboratory parameters derivations 
5.3.1 
Laboratory grading 
The collected laboratory values will be summarized by severity (low/normal/high) and not 
converted to Common Terminology Criteria for Adverse Events (CTCAE) grades. 
5.3.2 
Notable laboratory values 
Hematology 
Red blood cell (RBC) count  
>50% increase, >20% decrease 


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Hemoglobin  
 
 
>50% increase, >20% decrease 
Hematocrit 
 
 
 
>50% increase, >20% decrease 
White blood cell (WBC) count 
>50% increase, >50% decrease 
Platelet count  
 
 
>75% increase, >50% decrease 
Blood Chemistry 
Alanine aminotransferase (ALT) (SGPT) 
>150% increase 
Aspartate aminotransferase (AST) (SGOT) >150% increase 
Blood urea nitrogen (BUN)  
 
>50% increase 
Creatinine 
 
 
 
 
>50% increase 
Total bilirubin  
 
 
 
>100% increase 
Alkaline phosphatase  
 
 
>100% increase 
Potassium 
 
 
 
 
>20% increase, >20% decrease 
Chloride 
 
 
 
 
>10% increase, >10% decrease 
Calcium 
 
 
 
 
>10% increase, >10% decrease 
Uric acid 
 
 
 
 
>50% increase 
5.4 
Vital signs 
5.4.1 
Notable vital sign values 
Systolic blood pressure 
<90 mmHg and decrease of >20 mmHg from baseline 
 
 
 
 
>180 mmHg and increase of >20 mmHg from baseline 
Diastolic blood pressure 
<50 mmHg and decrease of >15 mmHg from baseline 
 
 
 
 
>105 mmHg and increase of >15 mmHg from baseline 
Pulse  
 
 
<50 bpm and decrease of > 15 bpm from baseline 
 
 
 
 
>120 bpm and increase of >15 bpm from baseline 
Weight 
 
 
>7% decrease, >7% increase 
5.5 
Statistical models 
5.5.1 
Primary analysis 
The null hypothesis for the primary analysis is the difference between the sacubitril/valsartan 
and enalapril groups in the mean change from baseline in mean activity count at Week 8 is equal 
to zero. An ANCOVA model will be used. The model will have the change from baseline as 
the dependent variable with treatment as a fixed effect factor and the baseline value as a 
covariate. The general form for the ANCOVA model is: 
𝑦𝑖𝑗= 𝜇+ 𝛼𝑖+ 𝛽(𝑥𝑖𝑗− 𝑥) + 𝜖𝑖𝑗 


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where i indexes treatment group and j indexes patient within treatment group. PROC MIXED 
in SAS will be used for the analysis (refer to the SAP TFL shells document for additional 
details).  
5.5.2 
Key secondary analysis 
The analysis of secondary endpoints will use the same approach as described for the analysis 
of the primary endpoint in Section 5.5.1.  
5.6 
Rule of exclusion criteria of analysis sets  
 
Table 1 
Protocol deviations that cause patients to be excluded 
Deviation 
ID 
Description of Deviation 
Exclusion in Analyses 
NA 
NA 
NA 
 
Table 2 
Patient Classification 
Analysis Set 
Protocol deviation ID that 
cause patients to be 
excluded 
Non-protocol deviation criteria that cause 
patients to be excluded 
RS 
NA 
Not randomized 
FAS 
NA 
Not in RS; Have not received study treatment 
but inadvertently randomized 
SS 
NA 
No double-blind study treatment received  
6 
Reference 
Chen M, Kianifard F (2000) A nonparametric procedure associated with a clinically meaningful 
efficacy measure. Biostatistics; 1(3):293-298. 
 
 
 
Maurer M, Cuddihy P, Weisenberg J, Delisle S, Strong BM, Gao Q, Kachnowski S, and Howell 
J. The Prevalence and Impact of Anergia (Lack of Energy) in Subjects With Heart Failure and 
its Associations With Actigraphy et al. Journal of Card Failure 2009; 15, 145 
Peterson B.T, Chiao P, Pickering E, Freeman J, Zammit G.K, Ding Y, and Badura L.L. 
Comparison of actigraphy and polysomnography to assess effects of zolpidem in a clinical 
research unit Sleep Medicine 13 (2012), pp.419-424