TITRATION: Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01922089
• Collaborator: (none)
• Enrollment: 498
• Locations: 105
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 4.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the safety and tolerability of initiating LCZ696 in heart failure patients with reduced ejection fraction (HF-rEF) using conservative (reaching target dose over 6 weeks) and condensed (reaching target dose over 3 weeks) up-titration regimens.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure With Reduced Ejection Fraction	Drug: LCZ696	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 498 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Randomized, Double-blind, Parallel Group Study to Assess the Safety and Tolerability of Initiating LCZ696 in Heart Failure Patients Comparing Two Titration Regimens
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 Condensed Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	Drug: LCZ696; LCZ696 50 mg/100 mg/200 mg bid
Experimental: LCZ696 Conservative Up-titration to LCZ696 200 mg bid over 6 weeks	Drug: LCZ696; LCZ696 50 mg/100 mg/200 mg bid

Outcome Measures

Primary Outcome Measures

1. Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) [12 weeks]

   Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)

Secondary Outcome Measures

1. Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low) [12 weeks]

   Treatment success was defined as the number of participants who achieved and maintained LCZ696 200 mg bid without any dose interruption or down-titration over 12 weeks and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)

2. Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low). [12 weeks]

   Tolerability was assessed as the number of participants who achieved LCZ696 200 mg bid and maintained this dose for at least 2 weeks before study completion, regardless of previous dose interruption or down-titration and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Age ≥ 18 years; CHF with New York Heart Association class II-IV; left ventricular ejection fraction ≤ 35%; on beta blockers

Exclusion Criteria:

• Potassium > 5.2 mmol/l; estimated glomerular filtration rate < 30 ml/min/1.73 m2; systolic blood pressure <100 mmHg or > 180 mmHg; history of intolerance to recommended target doses of angiotensin converting enzyme inhibitors or angiotensin receptor blockers

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Anchorage	Alaska	United States	99508
2	Novartis Investigative Site	Gilbert	Arizona	United States	85297
3	Novartis Investigative Site	Tucson	Arizona	United States	85710
4	Novartis Investigative Site	Anaheim	California	United States	92801
5	Novartis Investigative Site	Torrance	California	United States	90502
6	Novartis Investigative Site	Atlantis	Florida	United States	33462
7	Novartis Investigative Site	Chiefland	Florida	United States	32626
8	Novartis Investigative Site	Aurora	Illinois	United States	60504
9	Novartis Investigative Site	Peoria	Illinois	United States	61602
10	Novartis Investigative Site	Evansville	Indiana	United States	47714
11	Novartis Investigative Site	Slidell	Louisiana	United States	70458
12	Novartis Investigative Site	Minneapolis	Minnesota	United States	55417
13	Novartis Investigative Site	St. Louis	Missouri	United States	63110
14	Novartis Investigative Site	Buffalo	New York	United States	14215
15	Novartis Investigative Site	Laurelton	New York	United States	11422
16	Novartis Investigative Site	Marion	Ohio	United States	43302
17	Novartis Investigative Site	Oak Ridge	Tennessee	United States	37830
18	Novartis Investigative Site	Dallas	Texas	United States	75231
19	Novartis Investigative Site	Houston	Texas	United States	77030
20	Novartis Investigative Site	Houston	Texas	United States	77094
21	Novartis Investigative Site	Livingston	Texas	United States	77351
22	Novartis Investigative Site	Tacoma	Washington	United States	98405
23	Novartis Investigative Site	Gabrovo		Bulgaria	5300
24	Novartis Investigative Site	Plovdiv		Bulgaria	4000
25	Novartis Investigative Site	Plovdiv		Bulgaria	4004
26	Novartis Investigative Site	Smolian		Bulgaria	4700
27	Novartis Investigative Site	Sofia		Bulgaria	1202
28	Novartis Investigative Site	Sofia		Bulgaria	1407
29	Novartis Investigative Site	Jyvaskyla		Finland	40620
30	Novartis Investigative Site	Tampere		Finland	33520
31	Novartis Investigative Site	Bad Krozingen		Germany	79189
32	Novartis Investigative Site	Berlin-Buch		Germany	13125
33	Novartis Investigative Site	Berlin		Germany	10367
34	Novartis Investigative Site	Berlin		Germany	10787
35	Novartis Investigative Site	Berlin		Germany	10789
36	Novartis Investigative Site	Berlin		Germany	13055
37	Novartis Investigative Site	Berlin		Germany	13347
38	Novartis Investigative Site	Berlin		Germany	13353
39	Novartis Investigative Site	Berlin		Germany	13405
40	Novartis Investigative Site	Dietzenbach		Germany	63128
41	Novartis Investigative Site	Ebersbach		Germany	02730
42	Novartis Investigative Site	Frankfurt		Germany	60594
43	Novartis Investigative Site	Göttingen		Germany	D-37075
44	Novartis Investigative Site	Hassloch		Germany	67454
45	Novartis Investigative Site	Huy / OT Anderbeck		Germany	38836
46	Novartis Investigative Site	Ingelheim		Germany	55218
47	Novartis Investigative Site	Kelkheim		Germany	65779
48	Novartis Investigative Site	Kleve		Germany	47533
49	Novartis Investigative Site	Leipzig		Germany	04315
50	Novartis Investigative Site	Mainz		Germany	55116
51	Novartis Investigative Site	Mainz		Germany	55131
52	Novartis Investigative Site	Mühlheim		Germany	45468
53	Novartis Investigative Site	Siegen		Germany	57072
54	Novartis Investigative Site	Straubing		Germany	94315
55	Novartis Investigative Site	Wuerzburg		Germany	97078
56	Novartis Investigative Site	Budapest		Hungary	1042
57	Novartis Investigative Site	Budapest		Hungary	1145
58	Novartis Investigative Site	Budapest		Hungary	H-1096
59	Novartis Investigative Site	Debrecen		Hungary	4032
60	Novartis Investigative Site	Mosonmagyarovar		Hungary	9200
61	Novartis Investigative Site	Nyiregyháza		Hungary	4400
62	Novartis Investigative Site	Pecs		Hungary	7623
63	Novartis Investigative Site	Szekesfehervar		Hungary	8000
64	Novartis Investigative Site	Aosta	AO	Italy	11100
65	Novartis Investigative Site	Cortona	AR	Italy	52044
66	Novartis Investigative Site	Bergamo	BG	Italy	24128
67	Novartis Investigative Site	Bologna	BO	Italy	40138
68	Novartis Investigative Site	Cona	FE	Italy	44100
69	Novartis Investigative Site	Albano Laziale	RM	Italy	00041
70	Novartis Investigative Site	Roma	RM	Italy	00163
71	Novartis Investigative Site	Sassari	SS	Italy	07100
72	Novartis Investigative Site	Vittorio Veneto	TV	Italy	31029
73	Novartis Investigative Site	San Daniele Del Friuli	UD	Italy	33038
74	Novartis Investigative Site	San Juan		Puerto Rico	00936-6528
75	Novartis Investigative Site	Brezno	Slovak Republic	Slovakia	977 42
76	Novartis Investigative Site	Nitra	Slovak Republic	Slovakia	949 01
77	Novartis Investigative Site	Svidnik	Slovak Republic	Slovakia	08901
78	Novartis Investigative Site	Bratislava		Slovakia	821 07
79	Novartis Investigative Site	Bratislava		Slovakia	83301
80	Novartis Investigative Site	Kosice		Slovakia	040 01
81	Novartis Investigative Site	Lucenec		Slovakia	98439
82	Novartis Investigative Site	Nove Zamky		Slovakia	940 01
83	Novartis Investigative Site	Trebisov		Slovakia	075 01
84	Novartis Investigative Site	Almeria	Andalucia	Spain	04120
85	Novartis Investigative Site	Malaga	Andalucia	Spain	29010
86	Novartis Investigative Site	Sanlucar de Barrameda	Andalucia	Spain	11540
87	Novartis Investigative Site	Sevilla	Andalucia	Spain	41014
88	Novartis Investigative Site	Villamartin	Cadiz	Spain	11650
89	Novartis Investigative Site	Barcelona	Catalunya	Spain	08035
90	Novartis Investigative Site	A Coruna	Galicia	Spain	15006
91	Novartis Investigative Site	Madrid		Spain	28007
92	Novartis Investigative Site	Haydarpasa/Istanbul		Turkey	34668
93	Novartis Investigative Site	Istanbul		Turkey	34304
94	Novartis Investigative Site	Kocaeli		Turkey	41380
95	Novartis Investigative Site	Mersin		Turkey	33079
96	Novartis Investigative Site	Sivas		Turkey	58140
97	Novartis Investigative Site	Dorchester	Dorset	United Kingdom	DT1 2JY
98	Novartis Investigative Site	St Leonards on Sea	East Sussex	United Kingdom	TN37 7RD
99	Novartis Investigative Site	Oldham	Lancashire	United Kingdom	OL1 2JH
100	Novartis Investigative Site	Gateshead	Tyne and Wear	United Kingdom	NE9 6SX
101	Novartis Investigative Site	Bath		United Kingdom	BA1 3NG
102	Novartis Investigative Site	Bradford		United Kingdom	BD9 6RJ
103	Novartis Investigative Site	Coventry		United Kingdom	CV2 2DX
104	Novartis Investigative Site	Harrow		United Kingdom	HA1 3UJ
105	Novartis Investigative Site	Nuneaton		United Kingdom	CV10 7DJ

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01922089
• Other Study ID Numbers: CLCZ696B2228; 2013-001835-33
• First Posted: Aug 14, 2013
• Last Update Posted: Oct 15, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Novartis Pharmaceuticals: Heart failure, reduced ejection fraction, LCZ696, titration, safety, tolerability
• Additional relevant MeSH terms: Heart Failure; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	LCZ696 Condensed	LCZ696 Conservative
Arm/Group Description	Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	Up-titration to LCZ696 200 mg bid over 6 weeks
Period Title: Overall Study
STARTED	247	251
Safety Set	246	251
COMPLETED	208	221
NOT COMPLETED	39	30

Baseline Characteristics

Arm/Group Title	LCZ696 Condensed	LCZ696 Conservative	Total
Arm/Group Description	Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	Up-titration to LCZ696 200 mg bid over 6 weeks	Total of all reporting groups
Overall Participants	247	251	498
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	64.2 (11.86)	63.8 (10.94)	64.0 (11.39)
Sex: Female, Male (Count of Participants)
Female	56 22.7%	50 19.9%	106 21.3%
Male	191 77.3%	201 80.1%	392 78.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Experiencing Hypotension, Renal Dysfunction, Hyperkalemia and Angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Description	Participants experiencing hypotension, renal dysfunction, hyperkalemia and angioedema and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS) consisted of all randomized patients with the exception of mis-randomized patients who had not received the study drug, but had been inadvertently randomized into the study. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Arm/Group Title	LCZ696 Condensed	LCZ696 Conservative
Arm/Group Description	Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	Up-titration to LCZ696 200 mg bid over 6 weeks
Measure Participants	247	251
Hypotension High RAAS (n=120, 127)	5 2%	7 2.8%
Hypotension Low RAAS (n=127, 124)	19 7.7%	14 5.6%
Hypotension ALL	24 9.7%	21 8.4%
Renal Dysfunction High RAAS (n=120, 127)	5 2%	9 3.6%
Renal Dysfunction Low RAAS (n=127, 124)	13 5.3%	10 4%
Renal Dysfunction ALL	18 7.3%	19 7.6%
Hyperkalemia High RAAS (n=120, 127)	8 3.2%	5 2%
Hyperkalemia Low RAAS (n=127, 124)	11 4.5%	6 2.4%
Hyperkalemia ALL	19 7.7%	11 4.4%
Angioedema High RAAS (n=120, 127)	0 0%	1 0.4%
Angioedema Low RAAS (n=127, 124)	0 0%	1 0.4%
Angioedema ALL	0 0%	2 0.8%

2. Secondary Outcome

Title	Number of Participants Who Achieved Treatment Success Over the 12 Weeks and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low)
Description	Treatment success was defined as the number of participants who achieved and maintained LCZ696 200 mg bid without any dose interruption or down-titration over 12 weeks and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Evaluable patients in FAS with the exception of misrandomized patients who didn't received drug, but had been randomized into the study, excluding patients who discontinued the study prior to completion of 12 wks. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Arm/Group Title	LCZ696 Condensed	LCZ696 Conservative
Arm/Group Description	Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	Up-titration to LCZ696 200 mg bid over 6 weeks
Measure Participants	230	236
High RAAS (n=109,117)	90 36.4%	98 39%
Low RAAS (n=121,119)	89 36%	101 40.2%
ALL (n=230,236)	179 72.5%	199 79.3%

3. Secondary Outcome

Title	Number of Participants Who Tolerated Study Medication for at Least the Last Two Weeks of the Study and by Renin-Angiotensin-Aldosterone System (RAAS) Stratum (High vs. Low).
Description	Tolerability was assessed as the number of participants who achieved LCZ696 200 mg bid and maintained this dose for at least 2 weeks before study completion, regardless of previous dose interruption or down-titration and by Renin-Angiotensin-Aldosterone System (RAAS) stratum (high vs. low) High RAAS stratum Patients receiving > 160 mg of valsartan or > 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening Low RAAS stratum: Patients receiving ≤ 160 mg of valsartan or ≤ 10 mg total daily dose of enalapril, or equivalent doses of other ARBs/ACEIs, respectively, at screening. This stratum also included patients who were not on an ACEI or an ARB 4 weeks prior to screening (i.e., ACEI/ARB-naïve patients)
Time Frame	12 weeks

Outcome Measure Data

Analysis Population Description

Evaluable patients in FAS with the exception of misrandomized patients who didn't received drug, but had been randomized into the study, excluding patients who discontinued the study prior to completion of 12 wks. Following the intent-to-treat principle, patients were analyzed according to the treatment to which they were assigned at randomization.

Arm/Group Title	LCZ696 Condensed	LCZ696 Conservative
Arm/Group Description	Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks	Up-titration to LCZ696 200 mg bid over 6 weeks
Measure Participants	230	236
High RAAS (n=109,117)	94 38.1%	103 41%
Low RAAS (n=121,119)	97 39.3%	103 41%
ALL (n=230,236)	191 77.3%	206 82.1%

Adverse Events

Adverse Event Reporting Description	Hyperkalemia in primary outcome is when patient experiences any AE after randomization with preferred term Hyperkalaemia or Blood potassium increased and AE table has incidences of AEs on or after randomization by preferred terms which exceeds a threshold of 2%. therefore 3 less cases than Primary OM.
Arm/Group Title	LCZ696 Condensed		LCZ696 Conservative
Arm/Group Description	Up-titration to LCZ696 200 mg twice daily (bid) over 3 weeks		Up-titration to LCZ696 200 mg bid over 6 weeks
All Cause Mortality
	LCZ696 Condensed		LCZ696 Conservative
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ696 Condensed		LCZ696 Conservative
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/246 (8.5%)		14/251 (5.6%)
Cardiac disorders
Acute myocardial infarction	2/246 (0.8%)		1/251 (0.4%)
Atrial fibrillation	2/246 (0.8%)		1/251 (0.4%)
Cardiac failure	3/246 (1.2%)		2/251 (0.8%)
Cardiac failure acute	0/246 (0%)		1/251 (0.4%)
Cardiac failure chronic	1/246 (0.4%)		0/251 (0%)
Cardiac failure congestive	1/246 (0.4%)		1/251 (0.4%)
Cardiac ventricular thrombosis	0/246 (0%)		1/251 (0.4%)
Cardiogenic shock	3/246 (1.2%)		0/251 (0%)
Coronary artery disease	1/246 (0.4%)		0/251 (0%)
Coronary artery stenosis	1/246 (0.4%)		0/251 (0%)
Myocardial infarction	1/246 (0.4%)		0/251 (0%)
Tachycardia	1/246 (0.4%)		0/251 (0%)
Ventricular fibrillation	1/246 (0.4%)		0/251 (0%)
Ventricular tachycardia	2/246 (0.8%)		1/251 (0.4%)
Gastrointestinal disorders
Abdominal pain upper	0/246 (0%)		1/251 (0.4%)
Gastritis	1/246 (0.4%)		0/251 (0%)
Gastrointestinal haemorrhage	0/246 (0%)		1/251 (0.4%)
General disorders
Cardiac death	1/246 (0.4%)		0/251 (0%)
Non-cardiac chest pain	1/246 (0.4%)		0/251 (0%)
Pyrexia	0/246 (0%)		1/251 (0.4%)
Hepatobiliary disorders
Hepatic cyst	1/246 (0.4%)		0/251 (0%)
Infections and infestations
Gastrointestinal infection	0/246 (0%)		1/251 (0.4%)
Infected skin ulcer	0/246 (0%)		1/251 (0.4%)
Pneumonia	1/246 (0.4%)		0/251 (0%)
Staphylococcal sepsis	0/246 (0%)		1/251 (0.4%)
Injury, poisoning and procedural complications
Ankle fracture	1/246 (0.4%)		0/251 (0%)
Procedural complication	0/246 (0%)		1/251 (0.4%)
Investigations
International normalised ratio increased	1/246 (0.4%)		0/251 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder neoplasm	1/246 (0.4%)		0/251 (0%)
Nervous system disorders
Cerebrovascular accident	0/246 (0%)		1/251 (0.4%)
Dizziness	1/246 (0.4%)		0/251 (0%)
Syncope	0/246 (0%)		1/251 (0.4%)
Renal and urinary disorders
Renal failure	0/246 (0%)		1/251 (0.4%)
Renal failure acute	2/246 (0.8%)		0/251 (0%)
Renal failure chronic	1/246 (0.4%)		0/251 (0%)
Reproductive system and breast disorders
Postmenopausal haemorrhage	1/246 (0.4%)		0/251 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/246 (0%)		1/251 (0.4%)
Pulmonary oedema	0/246 (0%)		1/251 (0.4%)
Vascular disorders
Hypotension	0/246 (0%)		1/251 (0.4%)
Other (Not Including Serious) Adverse Events
	LCZ696 Condensed		LCZ696 Conservative
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	72/246 (29.3%)		52/251 (20.7%)
Cardiac disorders
Cardiac failure	6/246 (2.4%)		1/251 (0.4%)
Ear and labyrinth disorders
Vertigo	7/246 (2.8%)		3/251 (1.2%)
Infections and infestations
Nasopharyngitis	6/246 (2.4%)		3/251 (1.2%)
Metabolism and nutrition disorders
Hyperkalaemia	16/246 (6.5%)		11/251 (4.4%)
Hypokalaemia	6/246 (2.4%)		2/251 (0.8%)
Musculoskeletal and connective tissue disorders
Back pain	5/246 (2%)		2/251 (0.8%)
Nervous system disorders
Dizziness	8/246 (3.3%)		6/251 (2.4%)
Renal and urinary disorders
Renal failure	2/246 (0.8%)		7/251 (2.8%)
Renal impairment	10/246 (4.1%)		4/251 (1.6%)
Respiratory, thoracic and mediastinal disorders
Cough	2/246 (0.8%)		6/251 (2.4%)
Vascular disorders
Hypotension	24/246 (9.8%)		21/251 (8.4%)

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 (i.e., data from all sites) in the clinical trial or disclosure of trial results in their entirety.