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TRANSITION: Comparison of Pre- and Post-discharge Initiation of LCZ696 Therapy in HFrEF Patients After an Acute Decompensation Event

Sponsor
Novartis Pharmaceuticals (Industry)
Overall Status
Completed
CT.gov ID
NCT02661217
Collaborator
(none)
1,002
Enrollment
153
Locations
2
Arms
28.2
Actual Duration (Months)
6.5
Patients Per Site
0.2
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

To explore two modalities of treatment initiation (Pre-discharge, and Post-discharge) with LCZ696 in HFrEF patients following stabilization after an ADHF episode.

Condition or Disease Intervention/Treatment Phase
Phase 4

Study Design

Study Type:
Interventional
Actual Enrollment :
1002 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Single (Outcomes Assessor)
Primary Purpose:
Supportive Care
Official Title:
A Multicenter, Randomized, Open Label, Parallel Group Study Comparing Pre-discharge and posT-discharge tReatment Initiation With LCZ696 in heArt Failure patieNtS With Reduced ejectIon-fracTion hospItalized for an Acute decOmpensation eveNt (ADHF)
Actual Study Start Date :
Feb 12, 2016
Actual Primary Completion Date :
Feb 20, 2018
Actual Study Completion Date :
Jun 20, 2018

Arms and Interventions

Arm Intervention/Treatment
Other: Pre-discharge treatment initiation

Patients received first dose at any point after Randomization but no later than 12 h before discharge.

Drug: LCZ696
LCZ696 film-coated tables were supplied to the investigators. Tablets were taken with a glass of water, and were administered with or without food. The target dose of LCZ696 was 200 mg twice daily. Starting dose of LCZ696 was either 50 or 100 mg, twice daily. The dose of LCZ696 should be doubled every 2-4 weeks to achieve the target dose of 200 mg twice daily, as tolerated by the patient.
Other: Post-discharge treatment initiation

Patients received first dose after discharge and up to 14 days thereafter.

Drug: LCZ696
LCZ696 film-coated tables were supplied to the investigators. Tablets were taken with a glass of water, and were administered with or without food. The target dose of LCZ696 was 200 mg twice daily. Starting dose of LCZ696 was either 50 or 100 mg, twice daily. The dose of LCZ696 should be doubled every 2-4 weeks to achieve the target dose of 200 mg twice daily, as tolerated by the patient.

Outcome Measures

Primary Outcome Measures

  1. Percentage of Patients Achieving the Target Dose of LCZ696 200 mg Bid at 10 Weeks Post Randomization [10 weeks after Randomization]

    Percentage of patients achieving and maintaining LCZ696 200 mg bid for at least 2 weeks leading to Week 10

Secondary Outcome Measures

  1. Percentage of Patients Achieving and Maintaining Either LCZ696 100 mg and/or 200 mg Bid [10 weeks after Randomization]

    Percentage of patients achieving and maintaining either LCZ696 100 mg and/or 200 mg bid for at least 2 weeks leading to Week 10

  2. Percentage of Patients Achieving and Maintaining Any Dose of LCZ696 [10 weeks after Randomization]

    Percentage of patients achieving any dose of LCZ696 for at least 2 weeks leading to 10 weeks of treatment

  3. Percentage of Patients Permanently Discontinued From Treatment [10 weeks after Randomization AND 26 weeks after randomization]

    Percentage of patients permanently discontinued from LCZ696 (1) up to week 10 due to AEs, and (2) up to week 26 due to any reasons

Eligibility Criteria

Criteria

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

  1. Patients hospitalized due to acute decompensated HF episode (ADHF) as primary diagnosis) and consistent Signs & Symptoms

  2. Diagnosis of HF New York Heart Association class II-to-IV and reduced ejection fraction: Left ventricular ejection fraction ≤ 40% at Screening

  3. Patients did not receive any IV vasodilators (except nitrates), and/or any IV inotropic therapy from the time of presentation for ADHF to Randomization

  4. Stabilized (while in the hospital) for at least 24 hours leading to Randomization.

  5. Meeting one of the following criteria:

  • Patients on any dose of ACEI or ARB at screening

  • ACEI/ARB naïve patients and patients not on ACEI or ARB for at least 4 weeks before screening.

Exclusion Criteria:

  1. History of hypersensitivity to the sacubitril, valsartan, or any ARBs, NEP inhibitors or to any of the LCZ696 excipients.

  2. Symptomatic hypotension and/or a SBP below 110 mm Hg or SBP above 180 mm Hg prior to randomization

  3. End stage renal disease at Screening; or estimated GFR below 30 mL/min/1.73 m2 (as measured by MDRD formula at Randomization.

  4. Serum potassium above 5.4 mmol/L at Randomization.

  5. Known history of hereditary or idiopathic angioedema or angioedema related to previous ACE inhibitor or ARB therapy

  6. Severe hepatic impairment, biliary cirrhosis and cholestasis

Contacts and Locations

Locations

Site City State Country Postal Code
1 Novartis Investigative Site Quilmes Buenos Aires Argentina B1878DKF
2 Novartis Investigative Site Villa Maria Cordoba Argentina X5900JKA
3 Novartis Investigative Site Buenos Aires Argentina C1405CNF
4 Novartis Investigative Site Buenos Aires Argentina C1426BOR
5 Novartis Investigative Site Cordoba Argentina X5000
6 Novartis Investigative Site Salta Argentina 4400
7 Novartis Investigative Site Tucuman Argentina T4000NIJ
8 Novartis Investigative Site Bruxelles Belgium 1200
9 Novartis Investigative Site Genk Belgium 3600
10 Novartis Investigative Site Huy Belgium 4500
11 Novartis Investigative Site Leuven Belgium 3000
12 Novartis Investigative Site Ronse Belgium 9600
13 Novartis Investigative Site Vancouver British Columbia Canada V5Z 1M9
14 Novartis Investigative Site Hamilton Ontario Canada L8L 2X2
15 Novartis Investigative Site Montreal Quebec Canada H3A 1A1
16 Novartis Investigative Site Montreal Quebec Canada H3T 1E2
17 Novartis Investigative Site Brno Czech Republic Czechia 656 91
18 Novartis Investigative Site Karlovy Vary Czech Republic Czechia 360 66
19 Novartis Investigative Site Liberec Czech Republic Czechia 460 63
20 Novartis Investigative Site Tabor Czech Republic Czechia 39003
21 Novartis Investigative Site Trebic Czech Republic Czechia 674 01
22 Novartis Investigative Site Beroun CZE Czechia 26601
23 Novartis Investigative Site Ostrava CZE Czechia 72880
24 Novartis Investigative Site Brno Bohunice Czechia 625 00
25 Novartis Investigative Site JIhlava Czechia 586 01
26 Novartis Investigative Site Kolin Czechia 280 20
27 Novartis Investigative Site Olomouc Czechia 775 20
28 Novartis Investigative Site Praha 10 Czechia 100 34
29 Novartis Investigative Site Praha Czechia 12808
30 Novartis Investigative Site Slany Czechia 274 01
31 Novartis Investigative Site Amiens France 80054
32 Novartis Investigative Site Besancon cedex France 25030
33 Novartis Investigative Site Paris cedex 10 France 75010
34 Novartis Investigative Site Paris France 75012
35 Novartis Investigative Site Toulouse Cedex France 31059
36 Novartis Investigative Site Tourcoing France 59200
37 Novartis Investigative Site Valenciennes France 59300
38 Novartis Investigative Site Mannheim Baden-Wuerttemberg Germany 68305
39 Novartis Investigative Site Regensburg Bavaria Germany 93053
40 Novartis Investigative Site Leverkusen Nordrhein-Westfalen Germany 51375
41 Novartis Investigative Site Berlin Germany 13353
42 Novartis Investigative Site Dortmund Germany 44379
43 Novartis Investigative Site Erfurt Germany 99089
44 Novartis Investigative Site Essen Germany 45356
45 Novartis Investigative Site Frankfurt Germany 65929
46 Novartis Investigative Site Gottingen Germany 37075
47 Novartis Investigative Site Hamburg Germany 20246
48 Novartis Investigative Site Jena Germany 07740
49 Novartis Investigative Site Koeln-Nippes Germany 50733
50 Novartis Investigative Site Langen Germany 63225
51 Novartis Investigative Site Lübeck Germany 23569
52 Novartis Investigative Site Magdeburg Germany 39120
53 Novartis Investigative Site Mainz Germany 55131
54 Novartis Investigative Site Moenchengladbach Germany 41063
55 Novartis Investigative Site Neuwied Germany 56564
56 Novartis Investigative Site Oldenburg Germany 26133
57 Novartis Investigative Site Ruesselsheim Germany 65428
58 Novartis Investigative Site Witten Germany 58455
59 Novartis Investigative Site Bergamo BG Italy 24127
60 Novartis Investigative Site Cremona CR Italy 26100
61 Novartis Investigative Site Roma RM Italy 00152
62 Novartis Investigative Site Milano Italy 20142
63 Novartis Investigative Site El Chouf LBN Lebanon 1503201002
64 Novartis Investigative Site Ashrafieh Lebanon 166830
65 Novartis Investigative Site Beirut Lebanon 1107 2020
66 Novartis Investigative Site Beirut Lebanon
67 Novartis Investigative Site Saida Lebanon 652
68 Novartis Investigative Site Alesund Norway NO-6026
69 Novartis Investigative Site Bergen Norway 5009
70 Novartis Investigative Site Gralum Norway 1714
71 Novartis Investigative Site Lillehammer Norway 2629
72 Novartis Investigative Site Lodz Lodzkie Poland 90 549
73 Novartis Investigative Site Bialystok Poland 15-276
74 Novartis Investigative Site Krakow Poland 31202
75 Novartis Investigative Site Poznan Poland 61-848
76 Novartis Investigative Site Pulawy Poland 24100
77 Novartis Investigative Site Warszawa Poland 04-749
78 Novartis Investigative Site Wroclaw Poland 50 420
79 Novartis Investigative Site Vila Real Portuigal Portugal 5000-508
80 Novartis Investigative Site Amadora Portugal 2720-276
81 Novartis Investigative Site Aveiro Portugal 3814-501
82 Novartis Investigative Site Coimbra Portugal 3000-075
83 Novartis Investigative Site Covilha Portugal 6200-251
84 Novartis Investigative Site Guimaraes Portugal 4835-044
85 Novartis Investigative Site Leiria Portugal 2410-187
86 Novartis Investigative Site Lisboa Portugal 1495 005
87 Novartis Investigative Site Lisboa Portugal 1500 650
88 Novartis Investigative Site Lisboa Portugal 1649-035
89 Novartis Investigative Site Porto Portugal 4099-001
90 Novartis Investigative Site Porto Portugal 4200-319
91 Novartis Investigative Site Gatchina Russian Federation 188300
92 Novartis Investigative Site Kazan Russian Federation 420012
93 Novartis Investigative Site Moscow Russian Federation 117292
94 Novartis Investigative Site Moscow Russian Federation 117556
95 Novartis Investigative Site Moscow Russian Federation 123182
96 Novartis Investigative Site Saint Petersburg Russian Federation 193312
97 Novartis Investigative Site Saint Petersburg Russian Federation 199106
98 Novartis Investigative Site Yaroslavl Russian Federation 150047
99 Novartis Investigative Site Dammam Saudi Arabia 31463
100 Novartis Investigative Site Jeddah Saudi Arabia 21499
101 Novartis Investigative Site Riyadh Saudi Arabia 11211
102 Novartis Investigative Site Dunajska Streda Slovak Republic Slovakia 92901
103 Novartis Investigative Site Kosice Slovak Republic Slovakia 4190
104 Novartis Investigative Site Liptovsky Mikulas Slovak Republic Slovakia 031 23
105 Novartis Investigative Site Bratislava Slovakia 826 06
106 Novartis Investigative Site Bratislava Slovakia 833 48
107 Novartis Investigative Site Dolny Kubin Slovakia 026 01
108 Novartis Investigative Site Martin Slovakia 036 59
109 Novartis Investigative Site Presov Slovakia 080 01
110 Novartis Investigative Site Rimavska Sobota Slovakia 97912
111 Novartis Investigative Site Trnava Slovakia 917 75
112 Novartis Investigative Site Malaga Andalucia Spain 29010
113 Novartis Investigative Site Sanlucar de Barrameda Andalucia Spain 11540
114 Novartis Investigative Site Sevilla Andalucia Spain 41009
115 Novartis Investigative Site Sevilla Andalucia Spain 41014
116 Novartis Investigative Site Barcelona Barcelona/ Cataluny/Espanya Spain 08035
117 Novartis Investigative Site Villamartin Cadiz Spain 11650
118 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46010
119 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46014
120 Novartis Investigative Site Valencia Comunidad Valenciana Spain 46026
121 Novartis Investigative Site A Coruna Galicia Spain 15006
122 Novartis Investigative Site La Coruna Galicia Spain 15006
123 Novartis Investigative Site Olot Girona Spain 17800
124 Novartis Investigative Site Mostoles Madrid Spain 28935
125 Novartis Investigative Site El Palmar Murcia Spain 30120
126 Novartis Investigative Site Las Palmas de Gran Canaria Spain 35010
127 Novartis Investigative Site Madrid Spain 28222
128 Novartis Investigative Site Goteborg Sweden 413 45
129 Novartis Investigative Site Joenkoeping Sweden 551 85
130 Novartis Investigative Site Basel Switzerland 4031
131 Novartis Investigative Site Geneve 14 Switzerland 1211
132 Novartis Investigative Site Eskisehir Meselik Turkey 26480
133 Novartis Investigative Site Ankara Turkey 06100
134 Novartis Investigative Site Istanbul Turkey 34304
135 Novartis Investigative Site Kocaeli Turkey 41380
136 Novartis Investigative Site Mersin Turkey 33343
137 Novartis Investigative Site Sivas Turkey 58140
138 Novartis Investigative Site Westcliff on Sea Essex United Kingdom SS0 0RY
139 Novartis Investigative Site Basingstoke Hampshire United Kingdom RG24 9NA
140 Novartis Investigative Site Ashford Kent United Kingdom TN24 0LZ
141 Novartis Investigative Site Bridgend Mid Glamorgan United Kingdom CF31 1RQ
142 Novartis Investigative Site Portadown Nothern Ireland United Kingdom BT63 5QQ
143 Novartis Investigative Site Sunderland Tyne And Wear United Kingdom SR4 7TP
144 Novartis Investigative Site Blackpool United Kingdom FY3 8NR
145 Novartis Investigative Site Leeds United Kingdom LS1 3EX
146 Novartis Investigative Site Leicester United Kingdom LE 3 9QP
147 Novartis Investigative Site Liverpool United Kingdom L9 7AL
148 Novartis Investigative Site London United Kingdom EC14 7BE
149 Novartis Investigative Site Middlesbrough United Kingdom TS4 3BW
150 Novartis Investigative Site Newcastle Upon Tyne United Kingdom NE1 4LP
151 Novartis Investigative Site Norwich United Kingdom NR4 7UY
152 Novartis Investigative Site Swindon United Kingdom SN3 6BB
153 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:
NCT02661217
Other Study ID Numbers:
  • CLCZ696B2401
  • 2015-003266-87
First Posted:
Jan 22, 2016
Last Update Posted:
Apr 26, 2021
Last Verified:
Mar 1, 2021
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Product Manufactured in and Exported from the U.S.:
Yes
Keywords provided by Novartis Pharmaceuticals
Acute decompensated heart failure
Reduced ejection fraction
Pre-discharge treatment
Post-discharge treatment
Angiotensin receptor neprilysine inhibitor
HFrEF
Additional relevant MeSH terms:
Heart Failure
Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details Patients were randomized to pre-discharge group or post-discharged group.
Pre-assignment Detail The study consisted of 3 Epochs: the Screening Epoch (from signing of informed consent form to randomization), the treatment epoch (10 weeks following randomization), and a 16 weeks Follow-up Epoch following treatment epoch.
Arm/Group Title LCZ696 Pre-discharge Treatment Initiation LCZ696 Post-discharge Treatment Initiation
Arm/Group Description Patients received first dose at any point after Randomization but no later than 12 h before discharge. Patients received first dose after discharge and up to 14 days thereafter.
Period Title: Overall Study
STARTED 500 502
Started 10 Weeks Treatment Epoch 497 501
Completed 10 Weeks Treatment Epoch 460 455
COMPLETED 425 419
NOT COMPLETED 75 83

Baseline Characteristics

Arm/Group Title LCZ696 Pre-discharge Treatment Initiation LCZ696 Post-discharge Treatment Initiation Total
Arm/Group Description Patients received first dose at any point after Randomization but no later than 12 h before discharge. Patients received first dose after discharge and up to 14 days thereafter. Total of all reporting groups
Overall Participants 500 502 1002
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
66.7
(12.27)
67.0
(11.67)
66.8
(11.97)
Sex: Female, Male (Count of Participants)
Female
126
25.2%
125
24.9%
251
25%
Male
374
74.8%
377
75.1%
751
75%
Race/Ethnicity, Customized (Count of Participants)
Caucasian
488
97.6%
486
96.8%
974
97.2%
Black
5
1%
8
1.6%
13
1.3%
Asian
7
1.4%
3
0.6%
10
1%
Native American
0
0%
1
0.2%
1
0.1%
Pacific Islander
0
0%
1
0.2%
1
0.1%
Other
0
0%
1
0.2%
1
0.1%
Unknown
0
0%
2
0.4%
2
0.2%

Outcome Measures

1. Primary Outcome
Title Percentage of Patients Achieving the Target Dose of LCZ696 200 mg Bid at 10 Weeks Post Randomization
Description Percentage of patients achieving and maintaining LCZ696 200 mg bid for at least 2 weeks leading to Week 10
Time Frame 10 weeks after Randomization

Outcome Measure Data

Analysis Population Description
Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.
Arm/Group Title LCZ696 Pre-discharge Treatment Initiation LCZ696 Post-discharge Treatment Initiation
Arm/Group Description Patients received first dose at any point after Randomization but no later than 12 h before discharge. Patients received first dose after discharge and up to 14 days thereafter.
Measure Participants 493 489
Count of Participants [Participants]
224
44.8%
248
49.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LCZ696 Pre-discharge Treatment Initiation, LCZ696 Post-discharge Treatment Initiation
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.099
Comments
Method Cochran-Mantel-Haenszel
Comments
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.896
Confidence Interval (2-Sided) 95%
0.786 to 1.021
Parameter Dispersion Type:
Value:
Estimation Comments
2. Secondary Outcome
Title Percentage of Patients Achieving and Maintaining Either LCZ696 100 mg and/or 200 mg Bid
Description Percentage of patients achieving and maintaining either LCZ696 100 mg and/or 200 mg bid for at least 2 weeks leading to Week 10
Time Frame 10 weeks after Randomization

Outcome Measure Data

Analysis Population Description
Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.
Arm/Group Title LCZ696 Pre-discharge Treatment Initiation LCZ696 Post-discharge Treatment Initiation
Arm/Group Description Patients received first dose at any point after Randomization but no later than 12 h before discharge. Patients received first dose after discharge and up to 14 days thereafter.
Measure Participants 493 489
Count of Participants [Participants]
306
61.2%
335
66.7%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LCZ696 Pre-discharge Treatment Initiation, LCZ696 Post-discharge Treatment Initiation
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.034
Comments
Method Cochran-Mantel-Haenszel
Comments
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.906
Confidence Interval (2-Sided) 95%
0.827 to 0.993
Parameter Dispersion Type:
Value:
Estimation Comments
3. Secondary Outcome
Title Percentage of Patients Achieving and Maintaining Any Dose of LCZ696
Description Percentage of patients achieving any dose of LCZ696 for at least 2 weeks leading to 10 weeks of treatment
Time Frame 10 weeks after Randomization

Outcome Measure Data

Analysis Population Description
Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.
Arm/Group Title LCZ696 Pre-discharge Treatment Initiation LCZ696 Post-discharge Treatment Initiation
Arm/Group Description Patients received first dose at any point after Randomization but no later than 12 h before discharge. Patients received first dose after discharge and up to 14 days thereafter.
Measure Participants 493 489
Count of Participants [Participants]
424
84.8%
438
87.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection LCZ696 Pre-discharge Treatment Initiation, LCZ696 Post-discharge Treatment Initiation
Comments
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.089
Comments
Method Cochran-Mantel-Haenszel
Comments
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.960
Confidence Interval (2-Sided) 95%
0.916 to 1.006
Parameter Dispersion Type:
Value:
Estimation Comments
4. Secondary Outcome
Title Percentage of Patients Permanently Discontinued From Treatment
Description Percentage of patients permanently discontinued from LCZ696 (1) up to week 10 due to AEs, and (2) up to week 26 due to any reasons
Time Frame 10 weeks after Randomization AND 26 weeks after randomization

Outcome Measure Data

Analysis Population Description
Safety Population (SAF). The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.
Arm/Group Title LCZ696 Pre-discharge Treatment Initiation LCZ696 Post-discharge Treatment Initiation
Arm/Group Description Patients received first dose at any point after Randomization but no later than 12 h before discharge. Patients received first dose after discharge and up to 14 days thereafter.
Measure Participants 493 489
up to week 10 due to AEs
36
7.2%
24
4.8%
up to week 26 due to any reasons
83
16.6%
78
15.5%
5. Post-Hoc Outcome
Title All Collected Deaths
Description Pre-treatment deaths were collected from randomization until first treatment with LCZ696. The period from randomization to first treatment was up to 14 days. On-treatment deaths were collected from first treatment with LCZ696 until 26 weeks post randomization.
Time Frame From randomization until 26 weeks after randomization

Outcome Measure Data

Analysis Population Description
Safety Population (SAF) and randomized patients who died prior to first dose of study drug. The SAF consisted of all randomized subjects who received at least one dose of study drug with the exception of those patients who were inadvertently randomized into the study. Subjects were analyzed according to treatment actually received.
Arm/Group Title LCZ696 Pre-discharge Treatment Initiation LCZ696 Post-discharge Treatment Initiation
Arm/Group Description Patients received first dose at any point after Randomization but no later than 12 h before discharge. Patients received first dose after discharge and up to 14 days thereafter.
Measure Participants 494 491
Pre-treatment deaths
1
0.2%
2
0.4%
On-treatment deaths
23
4.6%
13
2.6%
All deaths
24
4.8%
15
3%

Adverse Events

Time Frame From start of treatment until 26 weeks after randomization
Adverse Event Reporting Description Analysis is based on the Safety Population (SAF). It consists of all randomized patients who received at least one dose of study drug. Deaths not included in the SAF (i.e. did not receive study drug) are presented separately in the Participant Flow and . Patients are analyzed according to treatment actually received.
Arm/Group Title Pre-discharge Post-discharge All Patients
Arm/Group Description Pre-discharge Post-discharge All patients
All Cause Mortality
Pre-discharge Post-discharge All Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 23/493 (4.7%) 13/489 (2.7%) 36/982 (3.7%)
Serious Adverse Events
Pre-discharge Post-discharge All Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 159/493 (32.3%) 134/489 (27.4%) 293/982 (29.8%)
Blood and lymphatic system disorders
Anaemia 3/493 (0.6%) 2/489 (0.4%) 5/982 (0.5%)
Hypocoagulable state 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Leukocytosis 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Splenic haemorrhage 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Cardiac disorders
Acute coronary syndrome 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Acute myocardial infarction 1/493 (0.2%) 3/489 (0.6%) 4/982 (0.4%)
Angina pectoris 2/493 (0.4%) 1/489 (0.2%) 3/982 (0.3%)
Angina unstable 3/493 (0.6%) 0/489 (0%) 3/982 (0.3%)
Arrhythmia 2/493 (0.4%) 1/489 (0.2%) 3/982 (0.3%)
Arteriosclerosis coronary artery 2/493 (0.4%) 0/489 (0%) 2/982 (0.2%)
Atrial fibrillation 4/493 (0.8%) 5/489 (1%) 9/982 (0.9%)
Atrial flutter 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Atrial tachycardia 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Atrioventricular block complete 2/493 (0.4%) 2/489 (0.4%) 4/982 (0.4%)
Bradycardia 2/493 (0.4%) 1/489 (0.2%) 3/982 (0.3%)
Cardiac arrest 4/493 (0.8%) 1/489 (0.2%) 5/982 (0.5%)
Cardiac failure 46/493 (9.3%) 45/489 (9.2%) 91/982 (9.3%)
Cardiac failure acute 11/493 (2.2%) 9/489 (1.8%) 20/982 (2%)
Cardiac failure chronic 3/493 (0.6%) 2/489 (0.4%) 5/982 (0.5%)
Cardiac failure congestive 1/493 (0.2%) 4/489 (0.8%) 5/982 (0.5%)
Cardio-respiratory arrest 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Cardiogenic shock 1/493 (0.2%) 5/489 (1%) 6/982 (0.6%)
Cardiomyopathy 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Congestive cardiomyopathy 0/493 (0%) 2/489 (0.4%) 2/982 (0.2%)
Coronary artery disease 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Ischaemic cardiomyopathy 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Left ventricular failure 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Low cardiac output syndrome 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Mitral valve incompetence 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Myocardial fibrosis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Myocardial infarction 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Myocardial ischaemia 2/493 (0.4%) 0/489 (0%) 2/982 (0.2%)
Palpitations 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Sinus arrest 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Sinus node dysfunction 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Supraventricular tachycardia 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Ventricular arrhythmia 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Ventricular extrasystoles 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Ventricular fibrillation 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Ventricular tachycardia 3/493 (0.6%) 2/489 (0.4%) 5/982 (0.5%)
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Endocrine disorders
Hypothyroidism 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Gastrointestinal disorders
Abdominal pain upper 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Diarrhoea 0/493 (0%) 3/489 (0.6%) 3/982 (0.3%)
Diarrhoea haemorrhagic 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Gastritis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Gastrointestinal haemorrhage 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Gastrointestinal inflammation 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Intestinal haemorrhage 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Lip swelling 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Melaena 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Rectal haemorrhage 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Subileus 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
General disorders
Asthenia 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Impaired healing 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Multiple organ dysfunction syndrome 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Non-cardiac chest pain 2/493 (0.4%) 5/489 (1%) 7/982 (0.7%)
Oedema peripheral 1/493 (0.2%) 3/489 (0.6%) 4/982 (0.4%)
Pyrexia 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Sudden cardiac death 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Sudden death 2/493 (0.4%) 0/489 (0%) 2/982 (0.2%)
Hepatobiliary disorders
Acute hepatic failure 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Cholecystitis acute 2/493 (0.4%) 0/489 (0%) 2/982 (0.2%)
Hepatic function abnormal 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Hepatitis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Hyperbilirubinaemia 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Jaundice cholestatic 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Infections and infestations
Bacterial sepsis 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Biliary sepsis 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Bronchitis 1/493 (0.2%) 4/489 (0.8%) 5/982 (0.5%)
Catheter site abscess 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Cellulitis 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Device related infection 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Diarrhoea infectious 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Endocarditis 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Epididymitis 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Erysipelas 1/493 (0.2%) 3/489 (0.6%) 4/982 (0.4%)
Gangrene 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Gastroenteritis 1/493 (0.2%) 3/489 (0.6%) 4/982 (0.4%)
Influenza 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Localised infection 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Lower respiratory tract infection 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Lower respiratory tract infection viral 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Lung infection 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Pneumonia 7/493 (1.4%) 8/489 (1.6%) 15/982 (1.5%)
Postoperative wound infection 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Q fever 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Respiratory tract infection 0/493 (0%) 4/489 (0.8%) 4/982 (0.4%)
Sepsis 2/493 (0.4%) 1/489 (0.2%) 3/982 (0.3%)
Septic phlebitis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Septic shock 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Tuberculosis 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Urinary tract infection 4/493 (0.8%) 2/489 (0.4%) 6/982 (0.6%)
Urosepsis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Injury, poisoning and procedural complications
Concussion 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Craniocerebral injury 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Femoral neck fracture 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Hip fracture 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Humerus fracture 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Multiple injuries 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Patella fracture 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Post procedural haematoma 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Radius fracture 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Rib fracture 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Spinal fracture 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Subdural haematoma 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Transplant failure 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Investigations
Blood creatinine increased 2/493 (0.4%) 0/489 (0%) 2/982 (0.2%)
Cardiac output decreased 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Ejection fraction abnormal 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Ejection fraction decreased 0/493 (0%) 2/489 (0.4%) 2/982 (0.2%)
General physical condition abnormal 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Heart rate abnormal 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Hepatic enzyme abnormal 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Hepatic enzyme increased 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
International normalised ratio increased 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Weight increased 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Metabolism and nutrition disorders
Dehydration 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Diabetes mellitus inadequate control 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Fluid overload 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Gout 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Hyperglycaemia 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Hyperkalaemia 3/493 (0.6%) 6/489 (1.2%) 9/982 (0.9%)
Hypoglycaemia 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Hyponatraemia 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Musculoskeletal and connective tissue disorders
Bursitis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Fistula 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Intervertebral disc protrusion 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Musculoskeletal pain 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Myalgia 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Osteoarthritis 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Pain in extremity 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Brain neoplasm 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Breast cancer 2/493 (0.4%) 0/489 (0%) 2/982 (0.2%)
Lung neoplasm malignant 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Malignant neoplasm of ampulla of Vater 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Malignant peritoneal neoplasm 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Metastases to liver 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Metastases to lung 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Rectal adenocarcinoma 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Transitional cell carcinoma 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Nervous system disorders
Aphasia 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Autonomic nervous system imbalance 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Brain injury 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Cerebral arteriosclerosis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Cerebral ischaemia 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Cerebrovascular accident 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Cognitive disorder 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Dizziness 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Extrapyramidal disorder 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Headache 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Hypoxic-ischaemic encephalopathy 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Ischaemic stroke 0/493 (0%) 2/489 (0.4%) 2/982 (0.2%)
Loss of consciousness 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Presyncope 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Sciatica 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Syncope 3/493 (0.6%) 3/489 (0.6%) 6/982 (0.6%)
Transient ischaemic attack 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Product Issues
Device battery issue 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Device dislocation 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Psychiatric disorders
Insomnia 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Renal and urinary disorders
Acute kidney injury 12/493 (2.4%) 7/489 (1.4%) 19/982 (1.9%)
Chronic kidney disease 3/493 (0.6%) 2/489 (0.4%) 5/982 (0.5%)
Haematuria 0/493 (0%) 2/489 (0.4%) 2/982 (0.2%)
Renal failure 3/493 (0.6%) 4/489 (0.8%) 7/982 (0.7%)
Renal impairment 0/493 (0%) 4/489 (0.8%) 4/982 (0.4%)
Reproductive system and breast disorders
Benign prostatic hyperplasia 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Acute respiratory failure 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Asthma 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Chronic obstructive pulmonary disease 3/493 (0.6%) 4/489 (0.8%) 7/982 (0.7%)
Cough 1/493 (0.2%) 1/489 (0.2%) 2/982 (0.2%)
Dyspnoea 6/493 (1.2%) 5/489 (1%) 11/982 (1.1%)
Haemoptysis 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Mediastinal haematoma 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Orthopnoea 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Pleural effusion 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Pulmonary congestion 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Pulmonary embolism 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Pulmonary oedema 3/493 (0.6%) 7/489 (1.4%) 10/982 (1%)
Respiratory failure 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Skin and subcutaneous tissue disorders
Diabetic foot 1/493 (0.2%) 2/489 (0.4%) 3/982 (0.3%)
Skin ulcer 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Vascular disorders
Aortic aneurysm 0/493 (0%) 1/489 (0.2%) 1/982 (0.1%)
Hypertension 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Hypotension 6/493 (1.2%) 2/489 (0.4%) 8/982 (0.8%)
Peripheral arterial occlusive disease 1/493 (0.2%) 0/489 (0%) 1/982 (0.1%)
Peripheral vascular disorder 2/493 (0.4%) 0/489 (0%) 2/982 (0.2%)
Other (Not Including Serious) Adverse Events
Pre-discharge Post-discharge All Patients
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 200/493 (40.6%) 201/489 (41.1%) 401/982 (40.8%)
Gastrointestinal disorders
Diarrhoea 17/493 (3.4%) 29/489 (5.9%) 46/982 (4.7%)
General disorders
Oedema peripheral 20/493 (4.1%) 26/489 (5.3%) 46/982 (4.7%)
Infections and infestations
Urinary tract infection 29/493 (5.9%) 19/489 (3.9%) 48/982 (4.9%)
Metabolism and nutrition disorders
Hyperkalaemia 67/493 (13.6%) 59/489 (12.1%) 126/982 (12.8%)
Nervous system disorders
Dizziness 32/493 (6.5%) 30/489 (6.1%) 62/982 (6.3%)
Renal and urinary disorders
Renal impairment 36/493 (7.3%) 24/489 (4.9%) 60/982 (6.1%)
Vascular disorders
Hypotension 71/493 (14.4%) 67/489 (13.7%) 138/982 (14.1%)

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:
NCT02661217
Other Study ID Numbers:
  • CLCZ696B2401
  • 2015-003266-87
First Posted:
Jan 22, 2016
Last Update Posted:
Apr 26, 2021
Last Verified:
Mar 1, 2021