Clincosm LogoSign in Get a demo

PARALLAX: A Randomized, Double-blind Controlled Study Comparing LCZ696 to Medical Therapy for Comorbidities in HFpEF Patients

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT03066804
Collaborator
(none)
2,572
Enrollment
381
Locations
2
Arms
26.2
Actual Duration (Months)
6.8
Patients Per Site
0.3
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to demonstrate the superiority of LCZ696 over individualized medical therapy for comorbidities in reducing N-terminal pro-brain natriuretic peptide (NT-proBNP) and improving exercise capacity and HF symptoms in patients with heart failure with preserved ejection fraction (HFpEF).

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

This study was a 24-week, randomized, double-blind, multi-center, parallel group, active controlled study to evaluate sacubitril/valsartan compared to individualized medical therapy on NT proBNP, exercise capacity, symptoms and QoL in patients with heart failure and preserved left ventricular ejection (HFpEF) fraction (LVEF > 40%). Patients were initially stratified into one of three strata according to prior treatment for comorbidities: Angiotensin converting enzyme inhibitor (ACEi), angiotensin receptor blocker (ARB) or no prior renin angiotensin system inhibitors (RASi). Patients in each stratum were randomized in a 1:1 ratio and received either sacubitril/valsartan or comparator (i.e.

enalapril for patients in ACEi strata, valsartan for patients in the ARB strata and placebo for patients in the No RASi strata). There was no designated proportion of patients planned in each stratum; the strata were populated based upon the patient's prior treatment regimen. The study consisted of a screening epoch of up to 2 weeks and a randomized treatment epoch of 24 weeks, which included a 1 to 4 week study drug up-titration epoch followed by a 20 to 23 week maintenance epoch. Uptitration to target doses was recommended to occur within the first four weeks of the study, and was performed by Investigator's discretion based on the patient's clinical status.

Study Design

Study Type:
Interventional
Actual Enrollment :
2572 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A 24-week, Randomized, Double-blind, Multi-center, Parallel LCZ696 on NT-proBNP, Exercise Capacity, Symptoms and Safety Compared to Individualized Medical Management of Comorbidities in Patients With Heart Failure and Preserved Ejection Fraction
Actual Study Start Date :
Aug 22, 2017
Actual Primary Completion Date :
Oct 28, 2019
Actual Study Completion Date :
Oct 28, 2019

Arms and Interventions

Arm Intervention/Treatment
Experimental: sacubitril/valsartan (LCZ696)

All patients who fulfill the inclusion/exclusion criteria will be stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients in the ACEi strata will receive LCZ696 or enalapril. Patients in the ARB strata will receive LCZ696 or valsartan. Patients in the no RASi strata will receive LCZ696 or matching placebo. Patients in the ACEi and ARB strata will take two pills twice daily for each dose: one tablet from the LCZ696 pack and one tablet from the comparator pack. Patients in the no RASi strata will take only one tablet twice daily (LCZ696 or matching placebo). In the LCZ696 arm, patients will receive active LCZ696 in titrated doses from level 1 up to level 3 (50 mg, 100 mg and 200 mg twice daily orally).

Drug: sacubitril/valsartan
Sacubitril/valsartan is available as 24 mg/26 mg, 49 mg/51 mg, 97 mg/103 mg, respectively in tablet form to be taken orally

Drug: Placebo to match enalapril
Placebo to match enalapril 2.5 mg, 5 mg, 10 mg tablet form to be taken orally

Drug: Placebo to match valsartan
Placebo to match valsartan 40 mg, 80 mg, 160 mg tablet form to be taken orally
Active Comparator: Comparator

Patients randomized to the comparator arm will receive either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Patients in the ACE stratum randomized to comparator, will receive enalapril in titrated doses from level 1 up to level 3 (2.5 mg, 5 mg and 10 mg twice daily). Patients in the ARB stratum randomized to comparator will receive valsartan in titrated doses from level 1 up to level 3 (40 mg , 80 mg and 160 mg twice daily). Patients in the no RASi stratum randomized to comparator will receive LCZ696 matching placebo.

Drug: Enalapril
Enalapril is available as 2.5 mg, 5 mg, and 10 mg tablet form to be taken orally

Drug: Valsartan
Valsartan is available as 40 mg, 80 mg, 160 mg tablet form to be taken orally

Drug: Placebo to match sacubitril/valsartan
Placebo to match LCZ696 50 mg, 100 mg, 200 mg tablet form to be taken orally

Outcome Measures

Primary Outcome Measures

  1. Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12 [Baseline, week 12]

    To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF

  2. Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24 [Baseline, week 24]

    Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002.

Secondary Outcome Measures

  1. Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24 [Baseline, Week 24]

    The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

  2. Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24 [Baseline, Week 24]

    Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

  3. Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24 [Baseline, Week 24]

    Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.

  4. Change From Baseline in NYHA Functional Class at Week 24 [Baseline, week 24]

    NYHA classification is a subjective physician's assessment of patient's functional capacity and symptomatic status and can change frequently over time. Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest The NYHA class change will be analyzed as a three category ordinal variable with levels: "improved", "unchanged", and "worsened", defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively.

  5. Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24 [Baseline, Week 24]

    The SF-36 PCS score reflects the measure of quality of life based on the 36 questions which evaluate the person's physical, emotional, and mental status, including general health. Specifically, the SF-36 PCS score focuses on assessing the person's physical status. The score ranges from 0 to 100 with a higher score indicating a better status of physical wellbeing (range = 0 "worst"-100 "best").

Eligibility Criteria

Criteria

Ages Eligible for Study:
45 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion Criteria:

  • Left ventricular ejection fraction (LVEF) >40% by echo within 6 months prior to study entry or during the screening epoch

  • Symptom(s) of heart failure (HF) requiring treatment with diuretics (including loop, or thiazide diuretics, or mineralocorticoid antagonist [MRAs]) for at least 30 days prior to study entry

  • NYHA class II-IV

  • Structural heart disease (left atrial enlargement or left ventricular hypertrophy) documented by echocardiogram.

  • NT-proBNP > 220 pg/mL for patients with no atrial fibrillation/atrial flutter (AF) or

600 pg/mL for patients with AF

  • KCCQ clinical summary score < 75

  • Patients on ACEi or ARB therapy must have a history of HTN

Exclusion Criteria:

  • Any prior measurement of LVEF ≤ 40%, under stable conditions

  • Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery within 3 months , or urgent percutaneous coronary intervention (PCI) within 3 months or an elective PCI within 30 days prior to study entry

  • Any clinical event within the 6 months prior to Visit 1 that could have reduced the LVEF (eg MI, coronary artery bypass graft [CABG]), unless an echo measurement was performed after the event confirming the LVEF to be >40%

  • Current (within 30 days from Visit 1) acute decompensated HF requiring therapy.

  • Current (within 30 days from Visit 1) use of renin inhibitor(s), dual RAS blockade or LCZ696

  • History of hypersensitivity to LCZ696 or its components

  • Patients with a known history of angioedema

  • Walk distance primarily limited by non-cardiac comorbid conditions at study entry

  • Alternative reason for shortness of breath such as: significant pulmonary disease or severe COPD, hemoglobin (Hgb) <10 g/dL males and < 9.5 g/dL females, or body mass index (BMI) > 40 kg/m^2.

  • Systolic blood pressure (SBP) ≥ 180 mmHg at study entry, or SBP >150 mmHg and <180 mmHg at study entry unless the patient is receiving 3 or more antihypertensive drugs, or SBP < 110 mmHg at study entry.

  • Patients with HbA1c > 7.5% not treated for diabetes

  • Patients with prior major organ transplant or intent to transplant (ie on transplant list)

  • eGFR < 30 ml/min/1.73 m^2 as measured by MDRD at screening

  • Serum potassium > 5.2 mmol /L (or equivalent plasma potassium value) at study entry

  • History or presence of any other disease with a life expectancy of < 3 years

  • Pregnant or nursing women or women of child-bearing potential unless they are using highly effective methods of contraception

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Andalusia Alabama United States 36420
2 Novartis Investigative Site Mobile Alabama United States 36608
3 Novartis Investigative Site Beverly Hills California United States 90211
4 Novartis Investigative Site Long Beach California United States 90813
5 Novartis Investigative Site Santa Ana California United States 92704
6 Novartis Investigative Site Sylmar California United States 91342
7 Novartis Investigative Site Aurora Colorado United States 80045
8 Novartis Investigative Site Stamford Connecticut United States 06905
9 Novartis Investigative Site Bradenton Florida United States 34209
10 Novartis Investigative Site Gainesville Florida United States 32608
11 Novartis Investigative Site Hollywood Florida United States 33312
12 Novartis Investigative Site Miami Florida United States 33133
13 Novartis Investigative Site Port Orange Florida United States 32127
14 Novartis Investigative Site Thomasville Georgia United States 31792
15 Novartis Investigative Site Arlington Heights Illinois United States 60004
16 Novartis Investigative Site Alexandria Louisiana United States 71301
17 Novartis Investigative Site Chalmette Louisiana United States 70043
18 Novartis Investigative Site Houma Louisiana United States 70360
19 Novartis Investigative Site Boston Massachusetts United States 02114
20 Novartis Investigative Site Lincoln Nebraska United States 68526
21 Novartis Investigative Site Omaha Nebraska United States 68114
22 Novartis Investigative Site Rochester New York United States 14621
23 Novartis Investigative Site Marion Ohio United States 43302
24 Novartis Investigative Site Corvallis Oregon United States 97330
25 Novartis Investigative Site Abington Pennsylvania United States 19001
26 Novartis Investigative Site Sioux Falls South Dakota United States 57104
27 Novartis Investigative Site Jackson Tennessee United States 38301
28 Novartis Investigative Site Dallas Texas United States 75234
29 Novartis Investigative Site Lufkin Texas United States 75904
30 Novartis Investigative Site Tomball Texas United States 77375
31 Novartis Investigative Site Falls Church Virginia United States 22042
32 Novartis Investigative Site Seattle Washington United States 98122
33 Novartis Investigative Site Caba Buenos Aires Argentina C1280AEB
34 Novartis Investigative Site Quilmes Buenos Aires Argentina B1878GEG
35 Novartis Investigative Site Posadas Misiones Argentina N3300AHX
36 Novartis Investigative Site Ciudad de Salta Provincia De Salta Argentina A4406BPF
37 Novartis Investigative Site Tucuman San Miguel De Tucuman Argentina T4000ICL
38 Novartis Investigative Site Rosario Santa Fe Argentina S2000DSV
39 Novartis Investigative Site San Miguel de Tucuman Tucuman Argentina T4000IFL
40 Novartis Investigative Site Buenos Aires Argentina C1430EGF
41 Novartis Investigative Site Cordoba Argentina X5000AAW
42 Novartis Investigative Site Cordoba Argentina X5000EVQ
43 Novartis Investigative Site Cordoba Argentina X5000
44 Novartis Investigative Site Cordoba Argentina X5004BAL
45 Novartis Investigative Site Cordoba Argentina X5006CBI
46 Novartis Investigative Site Formosa Argentina P3600
47 Novartis Investigative Site San Luis Argentina D5702JRS
48 Novartis Investigative Site Santa Fe Argentina 3080
49 Novartis Investigative Site Santa Fe Argentina S2200
50 Novartis Investigative Site Santa Fe Argentina S3000FWO
51 Novartis Investigative Site Braunau Austria A5280
52 Novartis Investigative Site Graz Austria A-8036
53 Novartis Investigative Site Hall in Tirol Austria 6060
54 Novartis Investigative Site Linz Austria 4010
55 Novartis Investigative Site Salzburg Austria 5020
56 Novartis Investigative Site Genk Belgium 3600
57 Novartis Investigative Site Gent Belgium 9000
58 Novartis Investigative Site Heusden-Zolder Belgium 3550
59 Novartis Investigative Site Huy Belgium 4500
60 Novartis Investigative Site Kortrijk Belgium 8500
61 Novartis Investigative Site Fortaleza CE Brazil 60430 370
62 Novartis Investigative Site Goiania GO Brazil 74223-130
63 Novartis Investigative Site Goiania GO Brazil 74605 050
64 Novartis Investigative Site Belo Horizonte MG Brazil 30140 062
65 Novartis Investigative Site Belo Horizonte MG Brazil 30150-221
66 Novartis Investigative Site Curitiba Parana Brazil 80230 130
67 Novartis Investigative Site Canoas Rio Grande Do Sul Brazil 92425 900
68 Novartis Investigative Site Porto Alegre RS Brazil 90880-480
69 Novartis Investigative Site Blumenau SC Brazil 89010 500
70 Novartis Investigative Site Campinas SP Brazil 13060 080
71 Novartis Investigative Site Ribeirao Preto SP Brazil 14048-900
72 Novartis Investigative Site Sao Jose do Rio Preto SP Brazil 15015-750
73 Novartis Investigative Site Sao Jose do Rio Preto SP Brazil 15090-000
74 Novartis Investigative Site Burgas Bulgaria 8018
75 Novartis Investigative Site Pazardzhik Bulgaria 4400
76 Novartis Investigative Site Pernik Bulgaria 2300
77 Novartis Investigative Site Pleven Bulgaria 5800
78 Novartis Investigative Site Plovdiv Bulgaria 4000
79 Novartis Investigative Site Plovdiv Bulgaria 4002
80 Novartis Investigative Site Shumen Bulgaria 9700
81 Novartis Investigative Site Sofia Bulgaria 1233
82 Novartis Investigative Site Sofia Bulgaria 1431
83 Novartis Investigative Site Sofia Bulgaria 1527
84 Novartis Investigative Site Sofia Bulgaria 1606
85 Novartis Investigative Site Veliko Tarnovo Bulgaria 5000
86 Novartis Investigative Site Moncton New Brunswick Canada E1G 1A7
87 Novartis Investigative Site Hamilton Ontario Canada L8L 2X2
88 Novartis Investigative Site Oakville Ontario Canada L6K 3W7
89 Novartis Investigative Site Montreal Quebec Canada H1T 1C8
90 Novartis Investigative Site St-Georges Beauce Quebec Canada G5Y 4T8
91 Novartis Investigative Site Medellin Antioquia Colombia 050036
92 Novartis Investigative Site Cali Valle Del Cauca Colombia 760001
93 Novartis Investigative Site Barranquilla Colombia 080020
94 Novartis Investigative Site Barranquilla Colombia
95 Novartis Investigative Site Monteria Colombia
96 Novartis Investigative Site San Gil Colombia 684031
97 Novartis Investigative Site Brandys nad Labem Czech Republic Czechia 250 01
98 Novartis Investigative Site Brno Czech Republic Czechia 60200
99 Novartis Investigative Site Cesky Krumlov Czech Republic Czechia 381 01
100 Novartis Investigative Site Jablonec nad Nisou Czech Republic Czechia 466 60
101 Novartis Investigative Site Kromeriz Czech Republic Czechia 767 55
102 Novartis Investigative Site Liberec Czech Republic Czechia 46063
103 Novartis Investigative Site Louny Czech Republic Czechia
104 Novartis Investigative Site Pardubice Czech Republic Czechia 532 03
105 Novartis Investigative Site Plzen Czech Republic Czechia 30100
106 Novartis Investigative Site Svitavy Czech Republic Czechia 568 25
107 Novartis Investigative Site Tabor Czech Republic Czechia 39003
108 Novartis Investigative Site Trebic Czech Republic Czechia 674 01
109 Novartis Investigative Site JIhlava CZE Czechia 58633
110 Novartis Investigative Site Policska CZE Czechia 57201
111 Novartis Investigative Site Kolin Czechia 280 20
112 Novartis Investigative Site Olomouc Lazce Czechia 77900
113 Novartis Investigative Site Prerov Czechia 751 52
114 Novartis Investigative Site Valasske Mezirici Czechia 75742
115 Novartis Investigative Site Copenhagen NV Denmark DK-2400
116 Novartis Investigative Site Hvidovre Denmark 2650
117 Novartis Investigative Site Randers Denmark 8930
118 Novartis Investigative Site Tallinn Estonia 10138
119 Novartis Investigative Site Tallinn Estonia 13419
120 Novartis Investigative Site Tartu Estonia 51014
121 Novartis Investigative Site Besancon cedex France 25030
122 Novartis Investigative Site Chambray les Tours France 37170
123 Novartis Investigative Site Corbeil Essonnes France 91100
124 Novartis Investigative Site Le Coudray France 28630
125 Novartis Investigative Site Le Kremlin Bicetre France 94275
126 Novartis Investigative Site Limoges cedex France 87042
127 Novartis Investigative Site Marseille France 13008
128 Novartis Investigative Site Rennes Cedex 9 France 35033
129 Novartis Investigative Site Tourcoing France 59200
130 Novartis Investigative Site Valenciennes France 59300
131 Novartis Investigative Site Regensburg Bavaria Germany 93053
132 Novartis Investigative Site Essen DEU Germany 45138
133 Novartis Investigative Site Detmold NRW Germany 32756
134 Novartis Investigative Site Dresden Sachsen Germany 01099
135 Novartis Investigative Site Bad Homburg Germany 61348
136 Novartis Investigative Site Bad Oeynhausen Germany 32545
137 Novartis Investigative Site Bamberg Germany 96049
138 Novartis Investigative Site Berlin Buch Germany 13125
139 Novartis Investigative Site Berlin Germany 10787
140 Novartis Investigative Site Berlin Germany 10789
141 Novartis Investigative Site Berlin Germany 12157
142 Novartis Investigative Site Berlin Germany 12683
143 Novartis Investigative Site Berlin Germany 13347
144 Novartis Investigative Site Berlin Germany 13353
145 Novartis Investigative Site Berlin Germany D 10559
146 Novartis Investigative Site Bielefeld Germany 33604
147 Novartis Investigative Site Bochum Wattenscheid Germany 44866
148 Novartis Investigative Site Brueel Germany 19412
149 Novartis Investigative Site Chemnitz Germany 09130
150 Novartis Investigative Site Coburg Germany 96450
151 Novartis Investigative Site Dortmund Germany 44137
152 Novartis Investigative Site Dortmund Germany 44379
153 Novartis Investigative Site Dresden Germany 01069
154 Novartis Investigative Site Dresden Germany 01277
155 Novartis Investigative Site Dresden Germany 01307
156 Novartis Investigative Site Elsterwerda Germany 04910
157 Novartis Investigative Site Erfurt Germany 99097
158 Novartis Investigative Site Essen Germany 45277
159 Novartis Investigative Site Frankfurt Germany 60594
160 Novartis Investigative Site Frankfurt Germany 65929
161 Novartis Investigative Site Fuerth Germany 90766
162 Novartis Investigative Site Fulda Germany 36037
163 Novartis Investigative Site Halle Saale Germany 06120
164 Novartis Investigative Site Hamburg Germany 21075
165 Novartis Investigative Site Hassloch Germany 67454
166 Novartis Investigative Site Jena Germany 07740
167 Novartis Investigative Site Kiel Germany 24105
168 Novartis Investigative Site Koeln-Nippes Germany 50733
169 Novartis Investigative Site Koln Germany D-51065
170 Novartis Investigative Site Leipzig Germany 04103
171 Novartis Investigative Site Lubeck Germany 23538
172 Novartis Investigative Site Ludwigshafen Germany 67067
173 Novartis Investigative Site Ludwigshafen Germany 67071
174 Novartis Investigative Site Lüneburg Germany 21339
175 Novartis Investigative Site Mainz Germany 55116
176 Novartis Investigative Site Mannheim Germany 68165
177 Novartis Investigative Site Muehldorf Germany 84453
178 Novartis Investigative Site Muenster Germany 48149
179 Novartis Investigative Site Munich Germany 80638
180 Novartis Investigative Site Neuruppin Germany 16816
181 Novartis Investigative Site Nienburg Germany 31582
182 Novartis Investigative Site Nuremberg Germany 90402
183 Novartis Investigative Site Papenburg Germany 26871
184 Novartis Investigative Site Potsdam Germany 14471
185 Novartis Investigative Site Riesa Germany 01589
186 Novartis Investigative Site Rodgau Germany 63110
187 Novartis Investigative Site Rostock Germany 18107
188 Novartis Investigative Site Rotenburg an der Fulda Germany 36199
189 Novartis Investigative Site Ruesselsheim Germany 65428
190 Novartis Investigative Site Schwaebisch Hall Germany 74523
191 Novartis Investigative Site Siegen Germany 57072
192 Novartis Investigative Site Stadtlohn Germany 48703
193 Novartis Investigative Site Ulm Germany 89077
194 Novartis Investigative Site Ulm Germany 89081
195 Novartis Investigative Site Wallerfing Germany 94574
196 Novartis Investigative Site Wedel Germany 22880
197 Novartis Investigative Site Wismar Germany 23966
198 Novartis Investigative Site Wuerzburg Germany 97080
199 Novartis Investigative Site Guatemala City Guatemala 01001
200 Novartis Investigative Site Guatemala City Guatemala 01010
201 Novartis Investigative Site Guatemala City Guatemala 01011
202 Novartis Investigative Site Guatemala City Guatemala 01015
203 Novartis Investigative Site Guatemala Guatemala 01010
204 Novartis Investigative Site Budapest HUN Hungary 1145
205 Novartis Investigative Site Budapest Hungary 1085
206 Novartis Investigative Site Budapest Hungary 1134
207 Novartis Investigative Site Mosanmagyarovar Hungary 9200
208 Novartis Investigative Site Szeged Hungary 6720
209 Novartis Investigative Site New Delhi Delhi India 110 060
210 Novartis Investigative Site New Delhi Delhi India 110007
211 Novartis Investigative Site Ahmedabad Gujarat India 380 060
212 Novartis Investigative Site Vadodara Gujarat India 390022
213 Novartis Investigative Site Manipal Karnataka India 576104
214 Novartis Investigative Site Nagpur Maharashtra India 440009
215 Novartis Investigative Site Nashik Maharashtra India 422005
216 Novartis Investigative Site Nashik Maharastra India 422007
217 Novartis Investigative Site Bikaner Rajasthan India 334003
218 Novartis Investigative Site Lucknow Uttar Pradesh India 226003
219 Novartis Investigative Site India India 560040
220 Novartis Investigative Site Ashkelon Israel 78278
221 Novartis Investigative Site Be'er Sheva Israel 84101
222 Novartis Investigative Site Hadera Israel
223 Novartis Investigative Site Haifa Israel 310 9601
224 Novartis Investigative Site Petach Tikva Israel 4941492
225 Novartis Investigative Site Rehovot Israel 76100
226 Novartis Investigative Site Cortona AR Italy 52044
227 Novartis Investigative Site Bergamo BG Italy 24127
228 Novartis Investigative Site Bologna BO Italy 40138
229 Novartis Investigative Site Legnano MI Italy 20025
230 Novartis Investigative Site Milano MI Italy 20132
231 Novartis Investigative Site Milano MI Italy 20162
232 Novartis Investigative Site Sesto San Giovanni MI Italy 20099
233 Novartis Investigative Site Palermo PA Italy 90127
234 Novartis Investigative Site Rovigo RO Italy 45100
235 Novartis Investigative Site Sassari SS Italy 07100
236 Novartis Investigative Site Cona Italy
237 Novartis Investigative Site San Vito al Tagliamento Italy
238 Novartis Investigative Site Liepaja LVA Latvia 3401
239 Novartis Investigative Site Daugavpils Latvia LV-5417
240 Novartis Investigative Site Ogre Latvia 5001
241 Novartis Investigative Site Riga Latvia 1012
242 Novartis Investigative Site Kaunas LTU Lithuania LT 50161
243 Novartis Investigative Site Kaunas Lithuania 47144
244 Novartis Investigative Site Vilnius Lithuania LT-08661
245 Novartis Investigative Site Guadalajara Jalisco Mexico 44200
246 Novartis Investigative Site Guadalajara Jalisco Mexico 44670
247 Novartis Investigative Site Queretaro Mexico 76000
248 Novartis Investigative Site San Luis Potosi Mexico 78200
249 Novartis Investigative Site Almelo Netherlands 7609 PP
250 Novartis Investigative Site Amsterdam Netherlands 1091AC
251 Novartis Investigative Site Deventer Netherlands 7416 SE
252 Novartis Investigative Site Doetinchem Netherlands 7009 BL
253 Novartis Investigative Site Gouda Netherlands 2803 HH
254 Novartis Investigative Site Groningen Netherlands 9713 GZ
255 Novartis Investigative Site Hardenberg Netherlands 7770 AA
256 Novartis Investigative Site Nijmegen Netherlands 6500 HB
257 Novartis Investigative Site Stadskanaal Netherlands 9501 HE
258 Novartis Investigative Site Tilburg Netherlands 5022 GC
259 Novartis Investigative Site Venlo Netherlands 5912 BL
260 Novartis Investigative Site Trujillo La Libertad Peru
261 Novartis Investigative Site Cercado De Lima Lima Peru 01
262 Novartis Investigative Site Jesus Maria Lima Peru 11
263 Novartis Investigative Site San Borja Lima Peru 41
264 Novartis Investigative Site San Isidro Lima Peru 27
265 Novartis Investigative Site San Miguel Lima Peru 32
266 Novartis Investigative Site Callao Peru CALLAO 2
267 Novartis Investigative Site Braga Portugal 4710243
268 Novartis Investigative Site Lisboa Portugal 1495 005
269 Novartis Investigative Site Lisboa Portugal 1500 650
270 Novartis Investigative Site Lisboa Portugal 1600190
271 Novartis Investigative Site Penafiel Portugal 4564-007
272 Novartis Investigative Site Porto Portugal 4099-001
273 Novartis Investigative Site Viana do Castelo Portugal 4901858
274 Novartis Investigative Site Vila Real Portugal 5000-508
275 Novartis Investigative Site Bucuresti District 4 Romania 4204179
276 Novartis Investigative Site Timisoara Timis Romania 300041
277 Novartis Investigative Site Timisoara Timis Romania 300362
278 Novartis Investigative Site Bacau Romania 600114
279 Novartis Investigative Site Baia Mare Romania 430123
280 Novartis Investigative Site Bucharest Romania 021659
281 Novartis Investigative Site Bucuresti Romania 022328
282 Novartis Investigative Site Bucuresti Romania 062272
283 Novartis Investigative Site Craiova Romania 200642
284 Novartis Investigative Site Craiova Romania 200931
285 Novartis Investigative Site Pitesti Romania 110084
286 Novartis Investigative Site Targu Mures Romania 540142
287 Novartis Investigative Site Targu Mures Romania 540143
288 Novartis Investigative Site Timisoara Romania 300736
289 Novartis Investigative Site Tirgoviste Romania 130095
290 Novartis Investigative Site Ekaterinburg Russian Federation 620028
291 Novartis Investigative Site Gatchina Russian Federation 188300
292 Novartis Investigative Site Ivanovo Russian Federation 153012
293 Novartis Investigative Site Moscow Russian Federation 101953
294 Novartis Investigative Site Moscow Russian Federation 117292
295 Novartis Investigative Site Moscow Russian Federation 117556
296 Novartis Investigative Site Moscow Russian Federation 121309
297 Novartis Investigative Site Moscow Russian Federation 129301
298 Novartis Investigative Site Nizhnii Novgorod Russian Federation 603126
299 Novartis Investigative Site Perm Russian Federation 614097
300 Novartis Investigative Site Rostov on Don Russian Federation 344022
301 Novartis Investigative Site Rostov on Don Russian Federation 344068
302 Novartis Investigative Site Saint Petersburg Russian Federation 199106
303 Novartis Investigative Site Saint-Petersburg Russian Federation 191144
304 Novartis Investigative Site Saratov Russian Federation 410012
305 Novartis Investigative Site St Petersburg Russian Federation 191015
306 Novartis Investigative Site St Petersburg Russian Federation 196601
307 Novartis Investigative Site St Petersburg Russian Federation 197376
308 Novartis Investigative Site Tyumen Russian Federation 625026
309 Novartis Investigative Site Yaroslavl Russian Federation 150047
310 Novartis Investigative Site Yekaterinburg Russian Federation 620109
311 Novartis Investigative Site Belgrade Serbia 11 000
312 Novartis Investigative Site Kragujevac Serbia 34000
313 Novartis Investigative Site Niska Banja Serbia 18205
314 Novartis Investigative Site Nis Serbia 18000
315 Novartis Investigative Site Sremska Kamenica Serbia 21204
316 Novartis Investigative Site Namestovo Slovak Republic Slovakia 02901
317 Novartis Investigative Site Presov Slovak Republic Slovakia 080 01
318 Novartis Investigative Site Bratislava SVK Slovakia 81108
319 Novartis Investigative Site Handlova SVK Slovakia 97251
320 Novartis Investigative Site Bardejov Slovakia 085 01
321 Novartis Investigative Site Bardejov Slovakia 08501
322 Novartis Investigative Site Bratislava Slovakia 821 07
323 Novartis Investigative Site Bratislava Slovakia 842 31
324 Novartis Investigative Site Dolny Kubin Slovakia 026 01
325 Novartis Investigative Site Kosice Slovakia 040 01
326 Novartis Investigative Site Lucenec Slovakia 98439
327 Novartis Investigative Site Moldava nad Bodvou Slovakia 045 01
328 Novartis Investigative Site Nitra Slovakia 949 01
329 Novartis Investigative Site Nove Zamky Slovakia 940 01
330 Novartis Investigative Site Nove Zamky Slovakia 94002
331 Novartis Investigative Site Povazska Bystrica Slovakia 01701
332 Novartis Investigative Site Presov Slovakia 08001
333 Novartis Investigative Site Snina Slovakia 09601
334 Novartis Investigative Site Svidnik Slovakia 089 01
335 Novartis Investigative Site Trnava Slovakia 91701
336 Novartis Investigative Site Cordoba Andalucia Spain 14004
337 Novartis Investigative Site Huelva Andalucia Spain 21005
338 Novartis Investigative Site Malaga Andalucia Spain 29010
339 Novartis Investigative Site Puerto Real Cadiz Spain 11510
340 Novartis Investigative Site Villamartin Cadiz Spain 11650
341 Novartis Investigative Site Lerida Cataluna Spain 25198
342 Novartis Investigative Site Torrevieja (Alicante) Comunidad Valenciana Spain 03186
343 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46010
344 Novartis Investigative Site A Coruna Galicia Spain 15006
345 Novartis Investigative Site San Sebastian de los Reyes Madrid Spain 28702
346 Novartis Investigative Site El Palmar Murcia Spain 30120
347 Novartis Investigative Site Manises Valencia Spain 46940
348 Novartis Investigative Site Alicante Spain 03700
349 Novartis Investigative Site Las Palmas De Gran Canarias Spain 35010
350 Novartis Investigative Site Madrid Spain 28040
351 Novartis Investigative Site Sevilla Spain 41014
352 Novartis Investigative Site Valencia Spain 46026
353 Novartis Investigative Site Khon Kaen THA Thailand 40002
354 Novartis Investigative Site Bangkok Thailand 10330
355 Novartis Investigative Site Bangkok Thailand 10400
356 Novartis Investigative Site Bangkok Thailand 10700
357 Novartis Investigative Site Muang Thailand 65000
358 Novartis Investigative Site Ubon Ratchathani Thailand 34000
359 Novartis Investigative Site Eskisehir Meselik Turkey 26480
360 Novartis Investigative Site Adana Turkey 01160
361 Novartis Investigative Site Ankara Turkey 06490
362 Novartis Investigative Site Antalya Turkey 07070
363 Novartis Investigative Site Aydin Turkey 09100
364 Novartis Investigative Site Bursa Turkey
365 Novartis Investigative Site Istanbul Turkey 34304
366 Novartis Investigative Site Istanbul Turkey 34662
367 Novartis Investigative Site Izmir Turkey 35040
368 Novartis Investigative Site Izmir Turkey 35340
369 Novartis Investigative Site Kocaeli Turkey 41380
370 Novartis Investigative Site Mersin Turkey 33343
371 Novartis Investigative Site Sivas Turkey 58140
372 Novartis Investigative Site Talas / Kayseri Turkey 38039
373 Novartis Investigative Site High Wycombe Buckinghamshire United Kingdom HP11 2TT
374 Novartis Investigative Site Stockton on Tees Cleveland United Kingdom TS19 8PE
375 Novartis Investigative Site Chesterfield Derbyshire United Kingdom S44 5BL
376 Novartis Investigative Site Craigavon Northern Ireland United Kingdom BT63 5QQ
377 Novartis Investigative Site Wansford Peterborough United Kingdom PE8 6PL
378 Novartis Investigative Site Addlestone Surrey United Kingdom KT15 2BH
379 Novartis Investigative Site Sunderland Tyne And Wear United Kingdom SR4 7TP
380 Novartis Investigative Site Leeds United Kingdom LS1 3EX
381 Novartis Investigative Site York United Kingdom YO31 8HE

Sponsors and Collaborators

  • Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT03066804
Other Study ID Numbers:
  • CLCZ696D2302
  • 2016-003410-28
First Posted:
Feb 28, 2017
Last Update Posted:
Oct 11, 2021
Last Verified:
Oct 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Novartis Pharmaceuticals
Cardiovascular Diseases
Heart Failure
Heart failure with Preserved Ejection Fraction
NT-proBNP
6 MWT
KCCQ
SF-36
NYHA Class
LCZ696
Enalapril
Valsartan
Angiotensin-Converting Enzyme Inhibitors (ACEi)
Angiotensin II Type 1 Receptor Blockers (ARB)
Renin Angiotensin System Inhibitors (RASi)
Additional relevant MeSH terms:
Heart Failure
Valsartan
Enalapril
Enalaprilat
Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details A total of 2572 participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan or Individualized Medical Therapy (IMT).
Pre-assignment Detail A total of 2572 participants were randomized in a 1:1 ratio to receive either sacubitril/valsartan or Individualized Medical Therapy (IMT).
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Period Title: Overall Study
STARTED 1286 1286
COMPLETED 1235 1236
NOT COMPLETED 51 50

Baseline Characteristics

Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator Total
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Total of all reporting groups
Overall Participants 1281 1285 2566
Age, Customized (Count of Participants)
<65 years
196
15.3%
221
17.2%
417
16.3%
>=65 years
1085
84.7%
1064
82.8%
2149
83.7%
Sex: Female, Male (Count of Participants)
Female
643
50.2%
658
51.2%
1301
50.7%
Male
638
49.8%
627
48.8%
1265
49.3%
Race/Ethnicity, Customized (Number) [Number]
Caucasian
1112
86.8%
1117
86.9%
2229
86.9%
Black
11
0.9%
16
1.2%
27
1.1%
Asian
56
4.4%
59
4.6%
115
4.5%
Native American
39
3%
33
2.6%
72
2.8%
Pacific Islander
0
0%
1
0.1%
1
0%
Unknown
4
0.3%
3
0.2%
7
0.3%
Other
59
4.6%
56
4.4%
115
4.5%

Outcome Measures

1. Primary Outcome
Title Change From Baseline in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Week 12
Description To demonstrate that LCZ696 is superior to individualized medical therapy for comorbidities in reducing NT-proBNP from baseline at Week 12 in patients with HFpEF
Time Frame Baseline, week 12

Outcome Measure Data

Analysis Population Description
Full Analysis Set: This outcome measure represents patients with non-missing change from baseline in log transformed NT-proBNP at Week 12. The model was fitting using change from baseline in log transformed NT-proBNP, and produced a difference in mean change from baseline in log transformed NT-proBNP, which was then transformed back to geometric mean ratio to baseline using an exponential transformation.
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Measure Participants 1203 1216
Geometric Mean (95% Confidence Interval) [Ratio]
0.8218
0.9828
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sacubitril/Valsartan (LCZ696), Individualized Medical Therapy (IMT) Comparator
Comments Week 12
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.0001
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Geometric Mean Ratio
Estimated Value 0.8362
Confidence Interval (2-Sided) 95%
0.7987 to 0.8754
Parameter Dispersion Type:
Value:
Estimation Comments
2. Primary Outcome
Title Change From Baseline in 6 Minute Walk Distance (6MWD) at Week 24
Description Change from baseline in 6-minute walk distance (6MWD) will be reported at Week 24. The 6 MWT will be performed in accordance with the guidelines of the American Thoracic Society 2002.
Time Frame Baseline, week 24

Outcome Measure Data

Analysis Population Description
Subset of Full Analysis Set: This outcome measure was analyzed on patients with a Baseline 6MWD from 100 meters to 450 meters.
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Measure Participants 1082 1075
Mean (95% Confidence Interval) [Meters]
9.6935
12.1920
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sacubitril/Valsartan (LCZ696), Individualized Medical Therapy (IMT) Comparator
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.4164
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -2.4985
Confidence Interval (2-Sided) 95%
-8.5267 to 3.52297
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Mean Change From Baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at Week 24
Description The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
Time Frame Baseline, Week 24

Outcome Measure Data

Analysis Population Description
Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Measure Participants 1207 1210
Mean (95% Confidence Interval) [Scores on a scale]
12.3399
11.8168
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sacubitril/Valsartan (LCZ696), Individualized Medical Therapy (IMT) Comparator
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.4791
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value 0.5231
Confidence Interval (2-Sided) 95%
-0.9258 to 1.9720
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Percentage of Patients With ≥ 5-points Deterioration in KCCQ Clinical Symptom Score(CSS) at Week 24
Description Percentage of patients with KCCQ CSS deterioration ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
Time Frame Baseline, Week 24

Outcome Measure Data

Analysis Population Description
Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Measure Participants 1207 1210
Number [Percentage of participants]
15.49
1.2%
16.69
1.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sacubitril/Valsartan (LCZ696), Individualized Medical Therapy (IMT) Comparator
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.5294
Comments
Method longitudinal binary logistic regression
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.8993
Confidence Interval (2-Sided) 95%
0.6461 to 1.2518
Parameter Dispersion Type:
Value:
Estimation Comments
5. Secondary Outcome
Title Percentage of Patients With ≥ 5-points Improvement in KCCQ Clinical Symptom Score(CSS) at Week 24
Description Percentage of patients with KCCQ CSS improvement ≥ 5-points will be reported at Week 24. The KCCQ is a self-administered questionnaire that requires 4 to 6 minutes to complete. It contains 23 items, covering physical function, clinical symptoms, social function, self-efficacy and knowledge, and Quality of Life (QoL). The CSS is a combined score based upon the clinical symptoms and physical function domains of the questionnaire. Scores are transformed to a range of 0 - 100, in which higher scores reflect better health status.
Time Frame Baseline, Week 24

Outcome Measure Data

Analysis Population Description
Full Analysis Set: This outcome measure represents patients with both baseline KCCQ Clinical Symptom Scores (CSS) and Week 24 KCCQ CSS observed and non-missing covariates.
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Measure Participants 1207 1210
Number [Percentage of participants]
67.94
5.3%
65.70
5.1%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sacubitril/Valsartan (LCZ696), Individualized Medical Therapy (IMT) Comparator
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.4938
Comments
Method longitudinal binary logistic regression
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.1060
Confidence Interval (2-Sided) 95%
0.8287 to 1.4760
Parameter Dispersion Type:
Value:
Estimation Comments
6. Secondary Outcome
Title Change From Baseline in NYHA Functional Class at Week 24
Description NYHA classification is a subjective physician's assessment of patient's functional capacity and symptomatic status and can change frequently over time. Class I - No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF Class II - Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in symptoms of HF Class III - Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes symptoms of HF Class IV - Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest The NYHA class change will be analyzed as a three category ordinal variable with levels: "improved", "unchanged", and "worsened", defined by at least one class improvement, no change, at least one class worsening, in NYHA class, respectively.
Time Frame Baseline, week 24

Outcome Measure Data

Analysis Population Description
Full Analysis Set: This outcome measure represents patients with both a baseline NYHA class and NYHA class at the visit observed.
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Measure Participants 1228 1229
Improved
23.62
1.8%
24.00
1.9%
Unchanged
72.23
5.6%
71.68
5.6%
Worsened
4.15
0.3%
4.31
0.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sacubitril/Valsartan (LCZ696), Individualized Medical Therapy (IMT) Comparator
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.8314
Comments
Method Proportional cumulative odds model
Comments
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.9798
Confidence Interval (2-Sided) 95%
0.8122 to 1.1820
Parameter Dispersion Type:
Value:
Estimation Comments
7. Secondary Outcome
Title Change From Baseline in The Short Form 36 Health Survey (SF-36) Physical Component Summary (PCS) Score at Week 24
Description The SF-36 PCS score reflects the measure of quality of life based on the 36 questions which evaluate the person's physical, emotional, and mental status, including general health. Specifically, the SF-36 PCS score focuses on assessing the person's physical status. The score ranges from 0 to 100 with a higher score indicating a better status of physical wellbeing (range = 0 "worst"-100 "best").
Time Frame Baseline, Week 24

Outcome Measure Data

Analysis Population Description
Full Analysis Set: This outcome measure represents patients with non-missing change from baseline in SF-36 PCS at Week 24.
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Comparator
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum).
Measure Participants 1185 1191
Mean (95% Confidence Interval) [Scores on a scale]
2.5405
2.6975
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Sacubitril/Valsartan (LCZ696), Individualized Medical Therapy (IMT) Comparator
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.6370
Comments
Method Mixed Models Analysis
Comments
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -0.1570
Confidence Interval () 95%
-0.8093 to 0.4953
Parameter Dispersion Type:
Value:
Estimation Comments

Adverse Events

Time Frame Adverse events were collected from first dose of study treatment until end of study treatment plus 30 days post treatment, up to maximum duration of approx. 2 years.
Adverse Event Reporting Description Any sign or symptom that occurs during the study treatment plus the 30 days post treatment. AEs were collected and analyzed based on the treatment arm (LCZ696 vs IMT) which the patient was randomized to, regardless of dose level. Hence no dose-specific analysis were performed. Eight patients were excluded from enrolled set [2572], as they did not receive any study treatment (6 patients in the LCZ696 arm and 2 patients in the IMT arm).
Arm/Group Title Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Total
Arm/Group Description All patients who fulfilled the inclusion/exclusion criteria were stratified before randomization based upon prior therapy for comorbidities to one of 3 strata: ACEi, ARB or no RASi. Patients randomized to the comparator arm received either enalapril (ACE stratum) valsartan (ARB stratum) or LCZ696 matching placebo (no RASi stratum). Total
All Cause Mortality
Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 23/1280 (1.8%) 17/1284 (1.3%) 40/2564 (1.6%)
Serious Adverse Events
Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 186/1280 (14.5%) 191/1284 (14.9%) 377/2564 (14.7%)
Blood and lymphatic system disorders
Anaemia 2/1280 (0.2%) 3/1284 (0.2%) 5/2564 (0.2%)
Febrile neutropenia 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Lymphadenopathy 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Cardiac disorders
Acute coronary syndrome 4/1280 (0.3%) 1/1284 (0.1%) 5/2564 (0.2%)
Acute myocardial infarction 2/1280 (0.2%) 4/1284 (0.3%) 6/2564 (0.2%)
Angina pectoris 8/1280 (0.6%) 8/1284 (0.6%) 16/2564 (0.6%)
Angina unstable 6/1280 (0.5%) 7/1284 (0.5%) 13/2564 (0.5%)
Aortic valve disease 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Aortic valve incompetence 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Atrial fibrillation 13/1280 (1%) 17/1284 (1.3%) 30/2564 (1.2%)
Atrial flutter 4/1280 (0.3%) 2/1284 (0.2%) 6/2564 (0.2%)
Atrial tachycardia 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Atrioventricular block complete 2/1280 (0.2%) 3/1284 (0.2%) 5/2564 (0.2%)
Atrioventricular block second degree 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Bradycardia 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Cardiac arrest 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Cardiac failure 21/1280 (1.6%) 31/1284 (2.4%) 52/2564 (2%)
Cardiac failure acute 3/1280 (0.2%) 9/1284 (0.7%) 12/2564 (0.5%)
Cardiac failure chronic 2/1280 (0.2%) 1/1284 (0.1%) 3/2564 (0.1%)
Cardiac failure congestive 2/1280 (0.2%) 7/1284 (0.5%) 9/2564 (0.4%)
Cardiac perforation 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cardiogenic shock 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Cor pulmonale acute 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Coronary artery disease 4/1280 (0.3%) 1/1284 (0.1%) 5/2564 (0.2%)
Dressler's syndrome 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Left ventricular failure 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Mitral valve incompetence 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Myocardial infarction 1/1280 (0.1%) 4/1284 (0.3%) 5/2564 (0.2%)
Myocardial ischaemia 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Pericardial effusion 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Sinus arrest 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Sinus node dysfunction 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Supraventricular tachycardia 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Congenital, familial and genetic disorders
Mitochondrial myopathy 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Ear and labyrinth disorders
Vertigo 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Vertigo positional 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Vestibular ataxia 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Eye disorders
Cataract 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Eye haemorrhage 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Iris neovascularisation 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Macular hole 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Retinal artery occlusion 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Visual acuity reduced 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Gastrointestinal disorders
Abdominal hernia 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Abdominal pain 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Diarrhoea 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Duodenal ulcer perforation 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Gastric haemorrhage 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Gastritis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Gastritis erosive 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Gastrointestinal haemorrhage 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Gastrointestinal ulcer haemorrhage 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Haemorrhagic erosive gastritis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Ileus 2/1280 (0.2%) 1/1284 (0.1%) 3/2564 (0.1%)
Incarcerated inguinal hernia 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Inguinal hernia 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Intestinal perforation 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Large intestine polyp 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Mallory-Weiss syndrome 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Rectal polyp 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Upper gastrointestinal haemorrhage 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
General disorders
Cardiac death 2/1280 (0.2%) 0/1284 (0%) 2/2564 (0.1%)
Chest pain 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Death 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Fatigue 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Gait disturbance 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Generalised oedema 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Malaise 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Multiple organ dysfunction syndrome 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Non-cardiac chest pain 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Oedema peripheral 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Pyrexia 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Sudden death 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Hepatobiliary disorders
Bile duct stenosis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Bile duct stone 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Cholangitis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Cholecystitis 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Cholelithiasis 2/1280 (0.2%) 1/1284 (0.1%) 3/2564 (0.1%)
Hepatic congestion 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Liver disorder 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Infections and infestations
Appendicitis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Bronchitis 3/1280 (0.2%) 2/1284 (0.2%) 5/2564 (0.2%)
Campylobacter gastroenteritis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cellulitis 3/1280 (0.2%) 0/1284 (0%) 3/2564 (0.1%)
Cholangitis infective 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cutaneous leishmaniasis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cystitis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Dengue fever 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Device related infection 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Diverticulitis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Endocarditis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Erysipelas 2/1280 (0.2%) 3/1284 (0.2%) 5/2564 (0.2%)
Gastroenteritis 2/1280 (0.2%) 1/1284 (0.1%) 3/2564 (0.1%)
Hepatitis C 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Infection 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Infectious pleural effusion 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Influenza 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Localised infection 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Lower respiratory tract infection 3/1280 (0.2%) 0/1284 (0%) 3/2564 (0.1%)
Nasopharyngitis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Pneumococcal sepsis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Pneumonia 13/1280 (1%) 13/1284 (1%) 26/2564 (1%)
Pneumonia bacterial 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Post procedural sepsis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Postoperative wound infection 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Pulmonary sepsis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Pyelonephritis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Respiratory tract infection 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Sepsis 2/1280 (0.2%) 1/1284 (0.1%) 3/2564 (0.1%)
Upper respiratory tract infection 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Urinary tract infection 4/1280 (0.3%) 1/1284 (0.1%) 5/2564 (0.2%)
Wound infection 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Injury, poisoning and procedural complications
Agitation postoperative 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Animal bite 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Contusion 2/1280 (0.2%) 0/1284 (0%) 2/2564 (0.1%)
Facial bones fracture 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Fall 0/1280 (0%) 4/1284 (0.3%) 4/2564 (0.2%)
Femoral neck fracture 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Fractured ischium 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Fractured sacrum 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Head injury 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Hip fracture 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Limb injury 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Meniscus injury 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Multiple injuries 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Post procedural complication 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Post procedural haemorrhage 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Pubis fracture 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Seroma 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Spinal fracture 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Subdural haematoma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Thoracic vertebral fracture 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Upper limb fracture 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Investigations
Blood urine present 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Haemoglobin decreased 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
International normalised ratio increased 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Liver function test abnormal 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Metabolism and nutrition disorders
Diabetes mellitus 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Diabetic metabolic decompensation 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Hyperkalaemia 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Hypoglycaemia 3/1280 (0.2%) 0/1284 (0%) 3/2564 (0.1%)
Hypokalaemia 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Hyponatraemia 2/1280 (0.2%) 1/1284 (0.1%) 3/2564 (0.1%)
Malnutrition 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Back pain 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Bone pain 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Intervertebral disc protrusion 3/1280 (0.2%) 0/1284 (0%) 3/2564 (0.1%)
Musculoskeletal chest pain 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Myalgia 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Osteoarthritis 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Osteochondrosis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Osteoporosis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Pathological fracture 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Rheumatoid arthritis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Spinal pain 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Spinal stenosis 0/1280 (0%) 4/1284 (0.3%) 4/2564 (0.2%)
Spondylolisthesis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Bladder neoplasm 2/1280 (0.2%) 0/1284 (0%) 2/2564 (0.1%)
Breast cancer 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Cervix carcinoma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Colon adenoma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Colon cancer 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Gastric cancer 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Gastrointestinal carcinoma 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Laryngeal cancer 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Lung cancer metastatic 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Lung neoplasm malignant 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Lymphoma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Malignant melanoma 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Metastases to liver 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Metastases to spine 2/1280 (0.2%) 0/1284 (0%) 2/2564 (0.1%)
Metastatic neoplasm 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Nasal cavity cancer 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Neuroendocrine tumour 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Oesophageal squamous cell carcinoma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Plasma cell myeloma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Prostate cancer 2/1280 (0.2%) 0/1284 (0%) 2/2564 (0.1%)
Prostate cancer metastatic 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Rectal adenocarcinoma 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Renal cell carcinoma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Renal neoplasm 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Spinal meningioma benign 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Squamous cell carcinoma 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Urinary tract neoplasm 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Nervous system disorders
Carotid artery aneurysm 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cerebral haemorrhage 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cerebral infarction 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cerebrovascular accident 2/1280 (0.2%) 0/1284 (0%) 2/2564 (0.1%)
Dementia 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Diabetic neuropathy 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Dizziness 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Encephalopathy 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Haemorrhagic transformation stroke 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Hepatic encephalopathy 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Hypoxic-ischaemic encephalopathy 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Ischaemic stroke 0/1280 (0%) 6/1284 (0.5%) 6/2564 (0.2%)
Parkinson's disease 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Sciatica 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Sensory disturbance 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Syncope 2/1280 (0.2%) 2/1284 (0.2%) 4/2564 (0.2%)
Transient ischaemic attack 4/1280 (0.3%) 0/1284 (0%) 4/2564 (0.2%)
Product Issues
Device breakage 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Psychiatric disorders
Alcohol abuse 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Depression 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Suicide attempt 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Renal and urinary disorders
Acute kidney injury 4/1280 (0.3%) 7/1284 (0.5%) 11/2564 (0.4%)
Diabetic nephropathy 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Haematuria 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Nephritic syndrome 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Nephrolithiasis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Renal failure 3/1280 (0.2%) 0/1284 (0%) 3/2564 (0.1%)
Renal impairment 2/1280 (0.2%) 0/1284 (0%) 2/2564 (0.1%)
Renal injury 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Urinary retention 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Acute respiratory failure 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Asthma 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Chronic obstructive pulmonary disease 3/1280 (0.2%) 4/1284 (0.3%) 7/2564 (0.3%)
Chronic respiratory failure 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Cough 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Dyspnoea 1/1280 (0.1%) 6/1284 (0.5%) 7/2564 (0.3%)
Epistaxis 0/1280 (0%) 3/1284 (0.2%) 3/2564 (0.1%)
Pneumonitis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Pulmonary embolism 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Pulmonary hypertension 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Pulmonary oedema 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Respiratory failure 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Skin and subcutaneous tissue disorders
Angioedema 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Diabetic foot 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Skin ulcer 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Vascular disorders
Accelerated hypertension 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Aortic dissection 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Aortic stenosis 1/1280 (0.1%) 1/1284 (0.1%) 2/2564 (0.1%)
Arterial rupture 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Deep vein thrombosis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Haematoma 1/1280 (0.1%) 2/1284 (0.2%) 3/2564 (0.1%)
Hypertension 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Hypertensive crisis 2/1280 (0.2%) 1/1284 (0.1%) 3/2564 (0.1%)
Hypertensive urgency 0/1280 (0%) 2/1284 (0.2%) 2/2564 (0.1%)
Hypotension 6/1280 (0.5%) 2/1284 (0.2%) 8/2564 (0.3%)
Iliac artery stenosis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Orthostatic hypotension 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Peripheral artery occlusion 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Peripheral vascular disorder 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Shock 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Thrombophlebitis 0/1280 (0%) 1/1284 (0.1%) 1/2564 (0%)
Thrombosis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Vasculitis 1/1280 (0.1%) 0/1284 (0%) 1/2564 (0%)
Other (Not Including Serious) Adverse Events
Sacubitril/Valsartan (LCZ696) Individualized Medical Therapy (IMT) Total
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 964/1280 (75.3%) 832/1284 (64.8%) 1796/2564 (70%)
Blood and lymphatic system disorders
Anaemia 17/1280 (1.3%) 28/1284 (2.2%) 45/2564 (1.8%)
Cardiac disorders
Atrial fibrillation 44/1280 (3.4%) 43/1284 (3.3%) 87/2564 (3.4%)
Cardiac failure 34/1280 (2.7%) 43/1284 (3.3%) 77/2564 (3%)
Gastrointestinal disorders
Diarrhoea 43/1280 (3.4%) 42/1284 (3.3%) 85/2564 (3.3%)
General disorders
Fatigue 38/1280 (3%) 21/1284 (1.6%) 59/2564 (2.3%)
Oedema peripheral 43/1280 (3.4%) 35/1284 (2.7%) 78/2564 (3%)
Infections and infestations
Bronchitis 29/1280 (2.3%) 35/1284 (2.7%) 64/2564 (2.5%)
Influenza 33/1280 (2.6%) 23/1284 (1.8%) 56/2564 (2.2%)
Nasopharyngitis 35/1280 (2.7%) 60/1284 (4.7%) 95/2564 (3.7%)
Urinary tract infection 49/1280 (3.8%) 35/1284 (2.7%) 84/2564 (3.3%)
Investigations
Blood creatinine increased 27/1280 (2.1%) 22/1284 (1.7%) 49/2564 (1.9%)
Blood potassium increased 26/1280 (2%) 10/1284 (0.8%) 36/2564 (1.4%)
Glomerular filtration rate decreased 137/1280 (10.7%) 150/1284 (11.7%) 287/2564 (11.2%)
Urine albumin/creatinine ratio increased 157/1280 (12.3%) 97/1284 (7.6%) 254/2564 (9.9%)
Urine protein/creatinine ratio increased 66/1280 (5.2%) 65/1284 (5.1%) 131/2564 (5.1%)
Metabolism and nutrition disorders
Hyperkalaemia 148/1280 (11.6%) 138/1284 (10.7%) 286/2564 (11.2%)
Musculoskeletal and connective tissue disorders
Arthralgia 35/1280 (2.7%) 21/1284 (1.6%) 56/2564 (2.2%)
Back pain 27/1280 (2.1%) 26/1284 (2%) 53/2564 (2.1%)
Nervous system disorders
Dizziness 70/1280 (5.5%) 63/1284 (4.9%) 133/2564 (5.2%)
Headache 18/1280 (1.4%) 30/1284 (2.3%) 48/2564 (1.9%)
Renal and urinary disorders
Haematuria 145/1280 (11.3%) 104/1284 (8.1%) 249/2564 (9.7%)
Microalbuminuria 26/1280 (2%) 19/1284 (1.5%) 45/2564 (1.8%)
Proteinuria 121/1280 (9.5%) 84/1284 (6.5%) 205/2564 (8%)
Renal failure 49/1280 (3.8%) 38/1284 (3%) 87/2564 (3.4%)
Renal impairment 148/1280 (11.6%) 110/1284 (8.6%) 258/2564 (10.1%)
Respiratory, thoracic and mediastinal disorders
Cough 41/1280 (3.2%) 25/1284 (1.9%) 66/2564 (2.6%)
Dyspnoea 47/1280 (3.7%) 46/1284 (3.6%) 93/2564 (3.6%)
Skin and subcutaneous tissue disorders
Pruritus 27/1280 (2.1%) 10/1284 (0.8%) 37/2564 (1.4%)
Vascular disorders
Hypertension 42/1280 (3.3%) 81/1284 (6.3%) 123/2564 (4.8%)
Hypotension 176/1280 (13.8%) 69/1284 (5.4%) 245/2564 (9.6%)

Limitations/Caveats

[Not Specified]

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.

Results Point of Contact

Name/Title Study Director
Organization Novartis Pharmaceuticals
Phone 862-778-8300
Email Novartis.email@novartis.com
Responsible Party:
Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:
NCT03066804
Other Study ID Numbers:
  • CLCZ696D2302
  • 2016-003410-28
First Posted:
Feb 28, 2017
Last Update Posted:
Oct 11, 2021
Last Verified:
Oct 1, 2021