Safety and Tolerability During Open-label Treatment With LCZ696 in Patients With CHF and Reduced Ejection Fraction

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02226120
• Collaborator: (none)
• Enrollment: 1,980
• Locations: 397
• Arm: 1
• Actual Duration (Months): 38.4
• Patients Per Site: 5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study was to collect safety and tolerability data on LCZ696 in eligible PARADIGM-HF patients who received open-label investigational drug. The parent PARADIGM-HF (NCT01035255) trial was terminated early due to compelling efficacy of LCZ696 in patients with heart failure with reduced ejection fraction (HFrEF) after the final pre-specified interim analysis in March 2014.

Condition or Disease	Intervention/Treatment	Phase
Chronic Heart Failure With Reduced Ejection Fraction	Drug: LCZ696	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1980 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Study to Evaluate Safety and Tolerability in Patients With Chronic Heart Failure and Reduced Ejection Fraction From PARADIGM-HF Receiving Open Label LCZ696
• Actual Study Start Date: Oct 16, 2014
• Actual Primary Completion Date: Dec 28, 2017
• Actual Study Completion Date: Dec 28, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid	Drug: LCZ696; Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696 [From first dose of study treatment to 30 days after last dose of study treatment, up to 30 months.]

   The primary assessments for safety were the reporting of angioedema, AEs suspected to be related to LCZ696, AEs leading to study drug discontinuation and serious adverse events (SAE) including death. The assessment of safety were based primarily on the frequency of adverse events of special interest, sitting systolic and diastolic blood pressure, heart rate, and serious adverse events suspected by the investigators to be related to LCZ696 for the Safety set. Only descriptive analysis done.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Written informed consent for the extension must be obtained before any assessment is performed.

2. Patients who have completed PARADIGM-HF (protocol CLCZ696B2314) and are able to be safely enrolled into the open-label trial as judged by the investigator.

Exclusion Criteria:

1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer

2. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEIs, ARBs, or NEP inhibitors as well as known or suspected contraindications to LCZ696

3. Known history of angioedema

4. Requirement of simultaneous treatment with both ACEIs and ARBs

5. Current acute decompensated HF (exacerbation of chronic HF manifested by signs and symptoms that may require intravenous therapy)

6. Symptomatic hypotension and/or a SBP < 100 mmHg at Visit 1 (screening)

7. Estimated GFR < 30 mL/min/1.73m^2 as measured by the simplified MDRD formula at Visit 1 (screening)

8. Presence of bilateral renal artery stenosis

9. Serum potassium > 5.2 mmol/L at Visit 1 (screening)

10. Evidence of hepatic disease as determined by any one of the following: AST or ALT values exceeding 3 x ULN at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of portacaval shunt

11. Pregnant or nursing (lactating) women

12. Women of child-bearing potential

13. Any condition, not identified in the protocol, that in the opinion of the investigator is likely to prevent the patient from safely tolerating LCZ696 or complying with the requirements of the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Huntsville	Alabama	United States	35801
2	Novartis Investigative Site	Muscle Shoals	Alabama	United States	35662
3	Novartis Investigative Site	Little Rock	Arkansas	United States	72204
4	Novartis Investigative Site	Oceanside	California	United States	92056
5	Novartis Investigative Site	Palm Springs	California	United States	92262
6	Novartis Investigative Site	San Diego	California	United States	92161
7	Novartis Investigative Site	Santa Rosa	California	United States	95405
8	Novartis Investigative Site	Boynton Beach	Florida	United States	33472-2952
9	Novartis Investigative Site	Des Moines	Iowa	United States	50314
10	Novartis Investigative Site	Covington	Louisiana	United States	70433
11	Novartis Investigative Site	Columbia	Maryland	United States	21044
12	Novartis Investigative Site	Saginaw	Michigan	United States	48601
13	Novartis Investigative Site	Minneapolis	Minnesota	United States	55417
14	Novartis Investigative Site	Fremont	Nebraska	United States	68025
15	Novartis Investigative Site	New York	New York	United States	10032
16	Novartis Investigative Site	Rosedale	New York	United States	11422
17	Novartis Investigative Site	Raleigh	North Carolina	United States	27610
18	Novartis Investigative Site	Marion	Ohio	United States	43302
19	Novartis Investigative Site	Rapid City	South Dakota	United States	57701
20	Novartis Investigative Site	Dallas	Texas	United States	75235
21	Novartis Investigative Site	Dallas	Texas	United States	75251
22	Novartis Investigative Site	Livingston	Texas	United States	77351
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24	Novartis Investigative Site	Waukesha	Wisconsin	United States	53188
25	Novartis Investigative Site	Caba	Buenos Aires	Argentina	C1221ADC
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27	Novartis Investigative Site	Mar del Plata	Buenos Aires	Argentina	B7600FZN
28	Novartis Investigative Site	Quilmes	Buenos Aires	Argentina	B1878DVB
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32	Novartis Investigative Site	Rosario	Santa Fe	Argentina	2000
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34	Novartis Investigative Site	Rosario	Santa Fe	Argentina	S2000QID
35	Novartis Investigative Site	Cordoba		Argentina	5000
36	Novartis Investigative Site	Cordoba		Argentina	X5000AAX
37	Novartis Investigative Site	Cordoba		Argentina	X5016KET
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120	Novartis Investigative Site	Dessau-Roßlau		Germany	06846
121	Novartis Investigative Site	Dresden		Germany	01307
122	Novartis Investigative Site	Dresden		Germany	01309
123	Novartis Investigative Site	Elsterwerda		Germany	04910
124	Novartis Investigative Site	Frankfurt		Germany	60488
125	Novartis Investigative Site	Frankfurt		Germany	65929
126	Novartis Investigative Site	Hamburg		Germany	22291
127	Novartis Investigative Site	Hamburg		Germany	22765
128	Novartis Investigative Site	Huy / OT Anderbeck		Germany	38836
129	Novartis Investigative Site	Ingelheim		Germany	55218
130	Novartis Investigative Site	Kelkheim		Germany	65779
131	Novartis Investigative Site	Koethen		Germany	06366
132	Novartis Investigative Site	Künzelsau		Germany	74653
133	Novartis Investigative Site	Leipzig		Germany	04109
134	Novartis Investigative Site	Leipzig		Germany	04129
135	Novartis Investigative Site	Leipzig		Germany	04315
136	Novartis Investigative Site	Loehne		Germany	32584
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143	Novartis Investigative Site	Guatemala	Ciudad	Guatemala	01010
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146	Novartis Investigative Site	Hong Kong SAR		Hong Kong
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148	Novartis Investigative Site	Budapest		Hungary	1096
149	Novartis Investigative Site	Budapest		Hungary	1122
150	Novartis Investigative Site	Budapest		Hungary	1125
151	Novartis Investigative Site	Budapest		Hungary	1134
152	Novartis Investigative Site	Budapest		Hungary	1145
153	Novartis Investigative Site	Debrecen		Hungary	4032
154	Novartis Investigative Site	Nyiregyháza		Hungary	4400
155	Novartis Investigative Site	Szekesfehervar		Hungary	H-8000
156	Novartis Investigative Site	Szekszard		Hungary	7100
157	Novartis Investigative Site	Zalaegerszeg		Hungary	8900
158	Novartis Investigative Site	Guntur	Andhra Pradesh	India	522001
159	Novartis Investigative Site	Dehli	Delhi	India	110080
160	Novartis Investigative Site	Ahmedabad	Gujarat	India	380 051
161	Novartis Investigative Site	Ahmedabad	Gujarat	India	380054
162	Novartis Investigative Site	Anand	Gujarat	India	388325
163	Novartis Investigative Site	Surat	Gujarat	India	395 002
164	Novartis Investigative Site	Surat	Gujrat	India	395002
165	Novartis Investigative Site	Vadodara	Gujrat	India	390015
166	Novartis Investigative Site	Mumbai	Maharashtra	India	400012
167	Novartis Investigative Site	Nagpur	Maharashtra	India	400012
168	Novartis Investigative Site	Nagpur	Maharashtra	India	440010
169	Novartis Investigative Site	Nashik	Maharashtra	India	422 005
170	Novartis Investigative Site	Nashik	Maharashtra	India	422002
171	Novartis Investigative Site	Nashik	Maharashtra	India	422005
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173	Novartis Investigative Site	Pune	Maharashtra	India	411011
174	Novartis Investigative Site	Ludhiana	Punjab	India	141002
175	Novartis Investigative Site	Bikaner	Rajasthan	India	334003
176	Novartis Investigative Site	Hyderabad	Telangana	India	500 063
177	Novartis Investigative Site	Indore		India	452014
178	Novartis Investigative Site	Ashkelon		Israel	78278
179	Novartis Investigative Site	Hadera		Israel	38100
180	Novartis Investigative Site	Haifa		Israel	3436212
181	Novartis Investigative Site	Haifa		Israel	3525408
182	Novartis Investigative Site	Jerusalem		Israel	91120
183	Novartis Investigative Site	Petach Tikva		Israel	49100
184	Novartis Investigative Site	Rehovot		Israel	76100
185	Novartis Investigative Site	Safed		Israel	13100
186	Novartis Investigative Site	Aosta	AO	Italy	11100
187	Novartis Investigative Site	Cortona	AR	Italy	52044
188	Novartis Investigative Site	Bergamo	BG	Italy	24127
189	Novartis Investigative Site	Treviglio	BG	Italy	24047
190	Novartis Investigative Site	Cosenza	CS	Italy	87100
191	Novartis Investigative Site	Cona	FE	Italy	44100
192	Novartis Investigative Site	Genova	GE	Italy	16132
193	Novartis Investigative Site	Pozzilli	IS	Italy	86077
194	Novartis Investigative Site	Lido di Camaiore	LU	Italy	55041
195	Novartis Investigative Site	Milazzo	ME	Italy	98057
196	Novartis Investigative Site	Pisa	PI	Italy	56126
197	Novartis Investigative Site	Pescia	Point	Italy	51017
198	Novartis Investigative Site	Pavia	PV	Italy	27100
199	Novartis Investigative Site	Ariccia	RM	Italy	00041
200	Novartis Investigative Site	Roma	RM	Italy	00163
201	Novartis Investigative Site	Salerno	SA	Italy	84131
202	Novartis Investigative Site	Sassari	SS	Italy	07100
203	Novartis Investigative Site	Wonju	Gangwon-Do	Korea, Republic of	26426
204	Novartis Investigative Site	Suwon	Gyeonggi-do	Korea, Republic of	16499
205	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	05505
206	Novartis Investigative Site	Seoul	Seocho-gu	Korea, Republic of	06591
207	Novartis Investigative Site	Daegu		Korea, Republic of	705 718
208	Novartis Investigative Site	Daegu		Korea, Republic of	705703
209	Novartis Investigative Site	Seoul		Korea, Republic of	05355
210	Novartis Investigative Site	Seoul		Korea, Republic of	156-707
211	Novartis Investigative Site	Daugavpils		Latvia	LV-5417
212	Novartis Investigative Site	Ventspils		Latvia	LV-3601
213	Novartis Investigative Site	Kaunas		Lithuania	LT-49387
214	Novartis Investigative Site	Kedainiai		Lithuania	LT-57164
215	Novartis Investigative Site	Vilnius		Lithuania	LT-08661
216	Novartis Investigative Site	Kuala Lumpur		Malaysia	50400
217	Novartis Investigative Site	Kuala Lumpur		Malaysia	59100
218	Novartis Investigative Site	San Juan del Rio	Queretaro	Mexico	76800
219	Novartis Investigative Site	Aguascalientes		Mexico	20230
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221	Novartis Investigative Site	San Luis Potosí		Mexico	78200
222	Novartis Investigative Site	Breda	CK	Netherlands	4818
223	Novartis Investigative Site	Amersfoort		Netherlands	3813 TZ
224	Novartis Investigative Site	Arnhem		Netherlands	6815 AD
225	Novartis Investigative Site	Blaricum		Netherlands	1261 AN
226	Novartis Investigative Site	Delft		Netherlands	2625 AD
227	Novartis Investigative Site	Den Bosch		Netherlands	5223 GZ
228	Novartis Investigative Site	Ede		Netherlands	6716 RP
229	Novartis Investigative Site	Gorinchem		Netherlands	4204 AA
230	Novartis Investigative Site	Hardenberg		Netherlands	7770 AA
231	Novartis Investigative Site	Harderwijk		Netherlands	3840 AC
232	Novartis Investigative Site	Heerenveen		Netherlands	8441 PW
233	Novartis Investigative Site	Hengelo		Netherlands	7555 DL
234	Novartis Investigative Site	Sneek		Netherlands	8601 ZK
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239	Novartis Investigative Site	Bellavista	Lima	Peru	CALLAO 02
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241	Novartis Investigative Site	La Molina	Lima	Peru	12
242	Novartis Investigative Site	San Borja	Lima	Peru	41
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245	Novartis Investigative Site	Arequipa		Peru	AREQ01
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268	Novartis Investigative Site	Deva		Romania	330084
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270	Novartis Investigative Site	Timisoara		Romania	300736
271	Novartis Investigative Site	Ekaterinburg		Russian Federation	620137
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273	Novartis Investigative Site	Kazan		Russian Federation	420012
274	Novartis Investigative Site	Kemerovo		Russian Federation	650002
275	Novartis Investigative Site	Kirov		Russian Federation	610027
276	Novartis Investigative Site	Krasnodar		Russian Federation	350012
277	Novartis Investigative Site	Moscow		Russian Federation	101990
278	Novartis Investigative Site	Moscow		Russian Federation	115280
279	Novartis Investigative Site	Moscow		Russian Federation	115516
280	Novartis Investigative Site	Moscow		Russian Federation	117198
281	Novartis Investigative Site	Moscow		Russian Federation	119881
282	Novartis Investigative Site	Moscow		Russian Federation	121309
283	Novartis Investigative Site	Moscow		Russian Federation	121552
284	Novartis Investigative Site	Moscow		Russian Federation	127473
285	Novartis Investigative Site	N. Novgorod		Russian Federation	603003
286	Novartis Investigative Site	N.Novgorod		Russian Federation	603005
287	Novartis Investigative Site	Nizhnii Novgorod		Russian Federation	603126
288	Novartis Investigative Site	Novosibirsk-117		Russian Federation	630117
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290	Novartis Investigative Site	Orenburg		Russian Federation	460040
291	Novartis Investigative Site	Perm		Russian Federation	614097
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307	Novartis Investigative Site	Singapore		Singapore	308433
308	Novartis Investigative Site	Brezno	Slovak Republic	Slovakia	977 42
309	Novartis Investigative Site	Kosice	Slovak Republic	Slovakia	040 22
310	Novartis Investigative Site	Levice	Slovak Republic	Slovakia	93401
311	Novartis Investigative Site	Presov	Slovak Republic	Slovakia	08001
312	Novartis Investigative Site	Svidnik	Slovak Republic	Slovakia	08901
313	Novartis Investigative Site	Bratislava		Slovakia	821 07
314	Novartis Investigative Site	Bratislava		Slovakia	842 31
315	Novartis Investigative Site	Bratislava		Slovakia	851 07
316	Novartis Investigative Site	Kosice		Slovakia	040 01
317	Novartis Investigative Site	Lucenec		Slovakia	984 01
318	Novartis Investigative Site	Martin		Slovakia	036 01
319	Novartis Investigative Site	Bloemfontein	Free State	South Africa	9301
320	Novartis Investigative Site	Soweto	Gauteng	South Africa	2013
321	Novartis Investigative Site	Durban	Kwa-Zulu Natal	South Africa	4052
322	Novartis Investigative Site	Cape Town	Western Cape	South Africa	7405
323	Novartis Investigative Site	Alberton		South Africa	1449
324	Novartis Investigative Site	Bloemfontein		South Africa	9301
325	Novartis Investigative Site	Cape Town		South Africa	7405
326	Novartis Investigative Site	Cape Town		South Africa	7505
327	Novartis Investigative Site	Durban		South Africa	4110
328	Novartis Investigative Site	Johannesburg		South Africa	2193
329	Novartis Investigative Site	Kempton Park		South Africa	1620
330	Novartis Investigative Site	Pretoria		South Africa	0121
331	Novartis Investigative Site	Pretoria		South Africa	0184
332	Novartis Investigative Site	Worcester		South Africa	6850
333	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
334	Novartis Investigative Site	Marbella	Andalucia	Spain	29600
335	Novartis Investigative Site	Sevilla	Andalucia	Spain	41014
336	Novartis Investigative Site	Sant Joan Despi	Cataluna	Spain	08970
337	Novartis Investigative Site	Barcelona	Catalunya	Spain	08003
338	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
339	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46010
340	Novartis Investigative Site	Valencia	Comunidad Valenciana	Spain	46015
341	Novartis Investigative Site	A Coruna	Galicia	Spain	15006
342	Novartis Investigative Site	La Coruna	Galicia	Spain	15006
343	Novartis Investigative Site	Santiago de Compostela	Galicia	Spain	15706
344	Novartis Investigative Site	Vigo	Galicia	Spain	36211
345	Novartis Investigative Site	Alcala de Henares	Madrid	Spain	28805
346	Novartis Investigative Site	Mostoles	Madrid	Spain	28935
347	Novartis Investigative Site	Madrid		Spain	28007
348	Novartis Investigative Site	Madrid		Spain	28222
349	Novartis Investigative Site	Stockholm	SE	Sweden	141 86
350	Novartis Investigative Site	Goteborg		Sweden	416 85
351	Novartis Investigative Site	Göteborg		Sweden	416 85
352	Novartis Investigative Site	Karlshamn		Sweden	37480
353	Novartis Investigative Site	Motala		Sweden	59185
354	Novartis Investigative Site	Changhua		Taiwan	50006
355	Novartis Investigative Site	Kaohsiung		Taiwan	82445
356	Novartis Investigative Site	Taichung		Taiwan	40447
357	Novartis Investigative Site	Taipei		Taiwan	10002
358	Novartis Investigative Site	Taipei		Taiwan	11217
359	Novartis Investigative Site	Taipei		Taiwan	114
360	Novartis Investigative Site	Yilan		Taiwan	26058
361	Novartis Investigative Site	Taladkwan	Nonthaburi	Thailand	11000
362	Novartis Investigative Site	Khon Kaen	THA	Thailand	40002
363	Novartis Investigative Site	Muang		Thailand	12120
364	Novartis Investigative Site	Istanbul		Turkey	34093
365	Novartis Investigative Site	Istanbul		Turkey	34304
366	Novartis Investigative Site	Izmir		Turkey	35040
367	Novartis Investigative Site	Izmir		Turkey	35340
368	Novartis Investigative Site	Kocaeli		Turkey	41380
369	Novartis Investigative Site	Sivas		Turkey	58140
370	Novartis Investigative Site	Durham	County Durham	United Kingdom	DH1 5TW
371	Novartis Investigative Site	Dorchester	Dorset	United Kingdom	DT1 2JY
372	Novartis Investigative Site	Basingstoke	Hampshire	United Kingdom	RG24 9NA
373	Novartis Investigative Site	Portsmouth	Hampshire	United Kingdom	PO6 3LY
374	Novartis Investigative Site	Inverness	Invernesshire	United Kingdom	IV2 3RE
375	Novartis Investigative Site	Oldham	Lancashire	United Kingdom	OL1 2JH
376	Novartis Investigative Site	Leicester	Leicestershire	United Kingdom	LE2 7LX
377	Novartis Investigative Site	Craigavon	Northern Ireland	United Kingdom	BT63 5QQ
378	Novartis Investigative Site	Dundee	Perthshire	United Kingdom	DD1 9SY
379	Novartis Investigative Site	Taunton	Somerset	United Kingdom	TA1 5DA
380	Novartis Investigative Site	Yeovil	Somerset	United Kingdom	BA21 4AT
381	Novartis Investigative Site	Sheffield	South Yorkshire	United Kingdom	S10 2JF
382	Novartis Investigative Site	Redhill	Surrey	United Kingdom	RH1 5RH
383	Novartis Investigative Site	South Shields	Tyne And Wear	United Kingdom	NE34 0PL
384	Novartis Investigative Site	Sunderland	Tyne And Wear	United Kingdom	SR4 7TP
385	Novartis Investigative Site	Dudley	West Midlands	United Kingdom	DY1 2HQ
386	Novartis Investigative Site	Cheshire		United Kingdom	CW1 4QJ
387	Novartis Investigative Site	Coventry		United Kingdom	CV2 2DX
388	Novartis Investigative Site	Exeter		United Kingdom	EX2 5AX
389	Novartis Investigative Site	Kent		United Kingdom	DA2 8DA
390	Novartis Investigative Site	Manchester		United Kingdom	M13 9WL
391	Novartis Investigative Site	Milton Keynes		United Kingdom	MK6 5LD
392	Novartis Investigative Site	Newport		United Kingdom	NP20 2UB
393	Novartis Investigative Site	Newport		United Kingdom	P030 5TG
394	Novartis Investigative Site	Norwich		United Kingdom	NR4 7UY
395	Novartis Investigative Site	Poole		United Kingdom	BH15 2JB
396	Novartis Investigative Site	Rotherham		United Kingdom	S60 2OD
397	Novartis Investigative Site	Worcester		United Kingdom	WR5 1DD

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Mar 2, 2018
• Study Protocol - Apr 28, 2015

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT02226120
• Other Study ID Numbers: CLCZ696B2317; 2014-001971-30
• First Posted: Aug 27, 2014
• Last Update Posted: Feb 20, 2019
• Last Verified: Feb 1, 2019

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: LCZ696; chronic heart failure; ARNI; Congestive heart failure (CHF); heart failure (HF); acute heart failure syndrome; congestive cardiac failure (CCF)
• Additional relevant MeSH terms: Heart Failure; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	This study was conducted at 417 sites in 41 countries worldwide.
Pre-assignment Detail	The total number in the participant flow and baseline characteristics sections reflects the number of participants treated (1980).

Arm/Group Title	LCZ696
Arm/Group Description	Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid
Period Title: Overall Study
STARTED	1980
COMPLETED	1660
NOT COMPLETED	320

Baseline Characteristics

Arm/Group Title	LCZ696
Arm/Group Description	Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid
Overall Participants	1980
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	67.2 (10.56)
Sex: Female, Male (Count of Participants)
Female	453 22.9%
Male	1527 77.1%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	39 2%
Asian	305 15.4%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	80 4%
White	1450 73.2%
More than one race	0 0%
Unknown or Not Reported	106 5.4%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Treatment Emergent Adverse Events (AEs), Serious Adverse Events (SAEs) and Deaths as a Measure of Safety and Tolerability of LCZ696
Description	The primary assessments for safety were the reporting of angioedema, AEs suspected to be related to LCZ696, AEs leading to study drug discontinuation and serious adverse events (SAE) including death. The assessment of safety were based primarily on the frequency of adverse events of special interest, sitting systolic and diastolic blood pressure, heart rate, and serious adverse events suspected by the investigators to be related to LCZ696 for the Safety set. Only descriptive analysis done.
Time Frame	From first dose of study treatment to 30 days after last dose of study treatment, up to 30 months.

Outcome Measure Data

Analysis Population Description

Safety Set (SAF), which consisted of all enrolled participants who received at least one dose of open-label study medication, was considered. Only descriptive analysis done.

Arm/Group Title	LCZ696
Arm/Group Description	Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid
Measure Participants	1980
AEs by Primary System Organ Class (SOC)	1289 65.1%
SAEs by Primary System Organ Class (SOC)	555 28%
Deaths by Primary System Organ Class (SOC)	186 9.4%

Adverse Events

Time Frame	From first dose of study treatment to 30 days after last dose of study treatment, approximately 30 months
Arm/Group Title	LCZ696
Arm/Group Description	Angiotensin receptor antagonist neprilysin inhibitor (ARNI) with target dose of 200 mg bid
All Cause Mortality
	LCZ696
	Affected / at Risk (%)	# Events
Total	186/1980 (9.4%)
Serious Adverse Events
	LCZ696
	Affected / at Risk (%)	# Events
Total	555/1980 (28%)
Blood and lymphatic system disorders
Anaemia	1/1980 (0.1%)
Normocytic anaemia	1/1980 (0.1%)
Cardiac disorders
Acute coronary syndrome	3/1980 (0.2%)
Acute left ventricular failure	1/1980 (0.1%)
Acute myocardial infarction	9/1980 (0.5%)
Adams-Stokes syndrome	1/1980 (0.1%)
Angina pectoris	14/1980 (0.7%)
Angina unstable	10/1980 (0.5%)
Arrhythmia	4/1980 (0.2%)
Atrial fibrillation	14/1980 (0.7%)
Atrioventricular block complete	5/1980 (0.3%)
Bradycardia	3/1980 (0.2%)
Cardiac arrest	13/1980 (0.7%)
Cardiac failure	144/1980 (7.3%)
Cardiac failure acute	21/1980 (1.1%)
Cardiac failure chronic	32/1980 (1.6%)
Cardiac failure congestive	20/1980 (1%)
Cardio-respiratory arrest	7/1980 (0.4%)
Cardiogenic shock	8/1980 (0.4%)
Cardiorenal syndrome	1/1980 (0.1%)
Cardiovascular disorder	1/1980 (0.1%)
Congestive cardiomyopathy	4/1980 (0.2%)
Cor pulmonale	1/1980 (0.1%)
Coronary artery disease	2/1980 (0.1%)
Left ventricular dysfunction	2/1980 (0.1%)
Left ventricular failure	4/1980 (0.2%)
Myocardial infarction	16/1980 (0.8%)
Myocardial ischaemia	2/1980 (0.1%)
Nodal rhythm	1/1980 (0.1%)
Palpitations	1/1980 (0.1%)
Sinus node dysfunction	2/1980 (0.1%)
Supraventricular tachycardia	1/1980 (0.1%)
Systolic dysfunction	1/1980 (0.1%)
Ventricular arrhythmia	5/1980 (0.3%)
Ventricular fibrillation	5/1980 (0.3%)
Ventricular tachycardia	31/1980 (1.6%)
Congenital, familial and genetic disorders
Phimosis	1/1980 (0.1%)
Ear and labyrinth disorders
Vertigo	2/1980 (0.1%)
Endocrine disorders
Adrenal insufficiency	1/1980 (0.1%)
Hypothyroidism	1/1980 (0.1%)
Eye disorders
Cataract	1/1980 (0.1%)
Open angle glaucoma	1/1980 (0.1%)
Refraction disorder	1/1980 (0.1%)
Gastrointestinal disorders
Abdominal pain	9/1980 (0.5%)
Abdominal pain upper	3/1980 (0.2%)
Ascites	2/1980 (0.1%)
Constipation	1/1980 (0.1%)
Diarrhoea	3/1980 (0.2%)
Diverticulum intestinal	1/1980 (0.1%)
Duodenal ulcer	1/1980 (0.1%)
Duodenitis	1/1980 (0.1%)
Dyspepsia	1/1980 (0.1%)
Enteritis	1/1980 (0.1%)
Enterocolitis	1/1980 (0.1%)
Gastric haemorrhage	1/1980 (0.1%)
Gastric ulcer	1/1980 (0.1%)
Gastritis	2/1980 (0.1%)
Gastrointestinal angiodysplasia	1/1980 (0.1%)
Gastrointestinal haemorrhage	2/1980 (0.1%)
Ileus paralytic	1/1980 (0.1%)
Incarcerated inguinal hernia	1/1980 (0.1%)
Inguinal hernia	2/1980 (0.1%)
Intestinal pseudo-obstruction	1/1980 (0.1%)
Large intestinal obstruction	1/1980 (0.1%)
Large intestine polyp	1/1980 (0.1%)
Melaena	1/1980 (0.1%)
Mesenteric vein thrombosis	1/1980 (0.1%)
Mouth ulceration	1/1980 (0.1%)
Pancreatic mass	1/1980 (0.1%)
Rectal haemorrhage	1/1980 (0.1%)
Umbilical hernia	1/1980 (0.1%)
Vomiting	1/1980 (0.1%)
General disorders
Asthenia	3/1980 (0.2%)
Cardiac death	4/1980 (0.2%)
Chest discomfort	1/1980 (0.1%)
Chest pain	1/1980 (0.1%)
Death	3/1980 (0.2%)
General physical health deterioration	1/1980 (0.1%)
Malaise	1/1980 (0.1%)
Multiple organ dysfunction syndrome	7/1980 (0.4%)
Non-cardiac chest pain	4/1980 (0.2%)
Oedema peripheral	3/1980 (0.2%)
Sudden cardiac death	15/1980 (0.8%)
Sudden death	13/1980 (0.7%)
Hepatobiliary disorders
Bile duct obstruction	1/1980 (0.1%)
Cholangitis	3/1980 (0.2%)
Cholecystitis	3/1980 (0.2%)
Cholecystitis acute	1/1980 (0.1%)
Cholecystitis chronic	1/1980 (0.1%)
Cholelithiasis	1/1980 (0.1%)
Hepatic cirrhosis	2/1980 (0.1%)
Hepatic congestion	1/1980 (0.1%)
Hepatic failure	1/1980 (0.1%)
Infections and infestations
Abdominal sepsis	1/1980 (0.1%)
Appendicitis	3/1980 (0.2%)
Arthritis bacterial	1/1980 (0.1%)
Bacteraemia	1/1980 (0.1%)
Bronchitis	1/1980 (0.1%)
Bursitis infective	1/1980 (0.1%)
Campylobacter gastroenteritis	1/1980 (0.1%)
Cellulitis	2/1980 (0.1%)
Cholecystitis infective	1/1980 (0.1%)
Cystitis	1/1980 (0.1%)
Diabetic foot infection	1/1980 (0.1%)
Diarrhoea infectious	1/1980 (0.1%)
Diverticulitis	3/1980 (0.2%)
Ecthyma	1/1980 (0.1%)
Erysipelas	2/1980 (0.1%)
Gangrene	3/1980 (0.2%)
Gastroenteritis	5/1980 (0.3%)
Hepatitis E	1/1980 (0.1%)
Hepatitis viral	1/1980 (0.1%)
Implant site infection	1/1980 (0.1%)
Infection	1/1980 (0.1%)
Infectious pleural effusion	1/1980 (0.1%)
Influenza	1/1980 (0.1%)
Intervertebral discitis	1/1980 (0.1%)
Localised infection	1/1980 (0.1%)
Lower respiratory tract infection	4/1980 (0.2%)
Lung infection	1/1980 (0.1%)
Orchitis	2/1980 (0.1%)
Otitis media chronic	1/1980 (0.1%)
Ovarian abscess	1/1980 (0.1%)
Peritonitis	4/1980 (0.2%)
Pneumococcal sepsis	1/1980 (0.1%)
Pneumonia	47/1980 (2.4%)
Postoperative wound infection	1/1980 (0.1%)
Pyelonephritis acute	2/1980 (0.1%)
Respiratory tract infection	3/1980 (0.2%)
Sepsis	12/1980 (0.6%)
Sepsis syndrome	1/1980 (0.1%)
Septic shock	10/1980 (0.5%)
Stoma site infection	1/1980 (0.1%)
Streptococcal bacteraemia	1/1980 (0.1%)
Tooth infection	1/1980 (0.1%)
Tracheobronchitis	1/1980 (0.1%)
Upper respiratory tract infection	2/1980 (0.1%)
Urinary tract infection	10/1980 (0.5%)
Urosepsis	3/1980 (0.2%)
Viral diarrhoea	1/1980 (0.1%)
Viral infection	2/1980 (0.1%)
Wound sepsis	1/1980 (0.1%)
Injury, poisoning and procedural complications
Chest injury	1/1980 (0.1%)
Craniocerebral injury	1/1980 (0.1%)
Electric shock	1/1980 (0.1%)
Fall	2/1980 (0.1%)
Femur fracture	5/1980 (0.3%)
Fibula fracture	1/1980 (0.1%)
Foot fracture	1/1980 (0.1%)
Fractured skull depressed	1/1980 (0.1%)
Head injury	1/1980 (0.1%)
Hip fracture	3/1980 (0.2%)
Humerus fracture	1/1980 (0.1%)
Incisional hernia, obstructive	1/1980 (0.1%)
Laceration	1/1980 (0.1%)
Limb injury	1/1980 (0.1%)
Lower limb fracture	1/1980 (0.1%)
Multiple injuries	1/1980 (0.1%)
Pelvic fracture	1/1980 (0.1%)
Procedural haemorrhage	1/1980 (0.1%)
Respiratory fume inhalation disorder	1/1980 (0.1%)
Rib fracture	3/1980 (0.2%)
Road traffic accident	2/1980 (0.1%)
Subarachnoid haemorrhage	3/1980 (0.2%)
Subdural haematoma	1/1980 (0.1%)
Subdural haemorrhage	1/1980 (0.1%)
Tendon rupture	1/1980 (0.1%)
Thoracic vertebral fracture	1/1980 (0.1%)
Tibia fracture	1/1980 (0.1%)
Toxicity to various agents	2/1980 (0.1%)
Vascular graft occlusion	1/1980 (0.1%)
Vascular pseudoaneurysm	1/1980 (0.1%)
Investigations
Arteriogram coronary	1/1980 (0.1%)
Blood bilirubin increased	1/1980 (0.1%)
Blood creatinine increased	1/1980 (0.1%)
Blood potassium decreased	1/1980 (0.1%)
Blood potassium increased	2/1980 (0.1%)
Ejection fraction abnormal	1/1980 (0.1%)
Functional residual capacity decreased	1/1980 (0.1%)
Hepatic enzyme increased	2/1980 (0.1%)
International normalised ratio increased	1/1980 (0.1%)
Liver function test increased	1/1980 (0.1%)
Weight decreased	2/1980 (0.1%)
Metabolism and nutrition disorders
Dehydration	4/1980 (0.2%)
Diabetes mellitus	4/1980 (0.2%)
Diabetes mellitus inadequate control	2/1980 (0.1%)
Diabetic complication	1/1980 (0.1%)
Fluid overload	1/1980 (0.1%)
Hyperkalaemia	2/1980 (0.1%)
Hypoglycaemia	1/1980 (0.1%)
Hyponatraemia	2/1980 (0.1%)
Metabolic acidosis	1/1980 (0.1%)
Type 2 diabetes mellitus	1/1980 (0.1%)
Musculoskeletal and connective tissue disorders
Arthritis	1/1980 (0.1%)
Back pain	1/1980 (0.1%)
Joint effusion	1/1980 (0.1%)
Osteoarthritis	3/1980 (0.2%)
Rheumatic disorder	1/1980 (0.1%)
Spinal osteoarthritis	1/1980 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	2/1980 (0.1%)
B-cell lymphoma	1/1980 (0.1%)
Basal cell carcinoma	1/1980 (0.1%)
Bladder cancer recurrent	1/1980 (0.1%)
Bladder neoplasm	1/1980 (0.1%)
Bone cancer	1/1980 (0.1%)
Bone cancer metastatic	1/1980 (0.1%)
Breast cancer	3/1980 (0.2%)
Cholangiocarcinoma	1/1980 (0.1%)
Colon adenoma	1/1980 (0.1%)
Colon cancer	1/1980 (0.1%)
Laryngeal cancer	2/1980 (0.1%)
Lung adenocarcinoma	1/1980 (0.1%)
Lung neoplasm	1/1980 (0.1%)
Lung neoplasm malignant	4/1980 (0.2%)
Oesophageal squamous cell carcinoma	1/1980 (0.1%)
Plasma cell myeloma	1/1980 (0.1%)
Rectal cancer	1/1980 (0.1%)
Renal cancer	1/1980 (0.1%)
Squamous cell carcinoma	2/1980 (0.1%)
Nervous system disorders
Aphasia	1/1980 (0.1%)
Brain injury	1/1980 (0.1%)
Brain oedema	1/1980 (0.1%)
Cerebellar infarction	1/1980 (0.1%)
Cerebral haemorrhage	2/1980 (0.1%)
Cerebral infarction	6/1980 (0.3%)
Cerebral ischaemia	1/1980 (0.1%)
Cerebrovascular accident	13/1980 (0.7%)
Cervicogenic vertigo	1/1980 (0.1%)
Coma	1/1980 (0.1%)
Dementia	1/1980 (0.1%)
Dizziness	4/1980 (0.2%)
Dysarthria	1/1980 (0.1%)
Epilepsy	1/1980 (0.1%)
Facial paralysis	1/1980 (0.1%)
Haemorrhagic stroke	1/1980 (0.1%)
Hemianaesthesia	1/1980 (0.1%)
Hemiparesis	1/1980 (0.1%)
Hypoxic-ischaemic encephalopathy	1/1980 (0.1%)
Ischaemic cerebral infarction	2/1980 (0.1%)
Ischaemic stroke	7/1980 (0.4%)
Loss of consciousness	2/1980 (0.1%)
Post stroke seizure	1/1980 (0.1%)
Presyncope	2/1980 (0.1%)
Radiculopathy	1/1980 (0.1%)
Seizure	1/1980 (0.1%)
Syncope	7/1980 (0.4%)
Transient ischaemic attack	4/1980 (0.2%)
Product Issues
Device battery issue	3/1980 (0.2%)
Device malfunction	1/1980 (0.1%)
Lead dislodgement	1/1980 (0.1%)
Psychiatric disorders
Delirium	1/1980 (0.1%)
Depression	2/1980 (0.1%)
Disorientation	1/1980 (0.1%)
Mental disorder	1/1980 (0.1%)
Renal and urinary disorders
Acute kidney injury	18/1980 (0.9%)
Chronic kidney disease	1/1980 (0.1%)
Haematuria	1/1980 (0.1%)
Leukocyturia	1/1980 (0.1%)
Nephrolithiasis	1/1980 (0.1%)
Renal failure	12/1980 (0.6%)
Renal impairment	8/1980 (0.4%)
Urethral stenosis	1/1980 (0.1%)
Urinary retention	2/1980 (0.1%)
Reproductive system and breast disorders
Acquired hydrocele	1/1980 (0.1%)
Acquired phimosis	1/1980 (0.1%)
Genital ulceration	1/1980 (0.1%)
Vaginal haemorrhage	1/1980 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema	5/1980 (0.3%)
Acute respiratory failure	3/1980 (0.2%)
Asphyxia	1/1980 (0.1%)
Bronchial oedema	1/1980 (0.1%)
Bronchitis chronic	1/1980 (0.1%)
Bronchospasm	1/1980 (0.1%)
Chronic obstructive pulmonary disease	10/1980 (0.5%)
Dyspnoea	10/1980 (0.5%)
Dyspnoea exertional	1/1980 (0.1%)
Epistaxis	1/1980 (0.1%)
Haemoptysis	1/1980 (0.1%)
Hiccups	1/1980 (0.1%)
Hydrothorax	2/1980 (0.1%)
Pleural effusion	3/1980 (0.2%)
Pleurisy	1/1980 (0.1%)
Pulmonary embolism	8/1980 (0.4%)
Pulmonary fibrosis	1/1980 (0.1%)
Pulmonary hypertension	1/1980 (0.1%)
Pulmonary oedema	8/1980 (0.4%)
Respiratory acidosis	1/1980 (0.1%)
Respiratory failure	2/1980 (0.1%)
Skin and subcutaneous tissue disorders
Decubitus ulcer	1/1980 (0.1%)
Diabetic foot	2/1980 (0.1%)
Social circumstances
Treatment noncompliance	1/1980 (0.1%)
Vascular disorders
Aortic aneurysm	2/1980 (0.1%)
Aortic embolus	1/1980 (0.1%)
Circulatory collapse	1/1980 (0.1%)
Deep vein thrombosis	2/1980 (0.1%)
Diabetic vascular disorder	1/1980 (0.1%)
Haematoma	1/1980 (0.1%)
Hypertension	2/1980 (0.1%)
Hypotension	18/1980 (0.9%)
Leriche syndrome	1/1980 (0.1%)
Orthostatic hypotension	1/1980 (0.1%)
Peripheral arterial occlusive disease	2/1980 (0.1%)
Peripheral artery occlusion	1/1980 (0.1%)
Peripheral artery stenosis	1/1980 (0.1%)
Peripheral artery thrombosis	1/1980 (0.1%)
Shock	1/1980 (0.1%)
Other (Not Including Serious) Adverse Events
	LCZ696
	Affected / at Risk (%)	# Events
Total	352/1980 (17.8%)
Metabolism and nutrition disorders
Hyperkalaemia	118/1980 (6%)
Vascular disorders
Hypotension	252/1980 (12.7%)

Limitations/Caveats

Two patients had missing treatment epoch disposition pages but were included in Safety Analysis Set (SAF)

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.