A Long-term (12 Months) Safety, Tolerability and Efficacy Study of LCZ696 in Patients With Essential Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01256411
• Collaborator: (none)
• Enrollment: 341
• Locations: 33
• Arm: 1
• Duration (Months): 17
• Patients Per Site: 10.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the long-term safety, tolerability and efficacy of LCZ696.

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: LCZ696; Drug: Amlodipine; Drug: Hydrochlorothiazide (HCTZ)	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 341 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Long-term Extension Study to Evaluate the Safety, Tolerability and Efficacy of 12 Months of LCZ696 Treatment in Patients With Essential Hypertension
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Apr 1, 2012
• Actual Study Completion Date: Apr 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: LCZ696

Drug: LCZ696; Participants received LCZ696 200 mg as the starting dose with optional down titration to 100 mg for tolerance and optional up titration to 400 mg for adequate blood pressure control.; Drug: Amlodipine; Optional add-on of amlodipine (5-10 mg) was allowed (as applicable per local country regulations) for adequate blood pressure control.; Drug: Hydrochlorothiazide (HCTZ); Optional add-on of hydrochlorothiazide (HCTZ) (12.5-25 mg) was allowed (as applicable per local country regulations) for adequate blood pressure control.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment) [Baseline to 12 months]

   Participants were monitored throughout the study for adverse events, serious adverse events and deaths.

Secondary Outcome Measures

1. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment) [Baseline, 12 months]

   Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.

2. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy) [Baseline, 12 months]

   Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.

3. Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment) [Baseline to 12 months]

   Blood pressure (BP) control is defined as BP <140/90 mmHg.

4. Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Mono or Combination Therapy) [Baseline to 12 months]

   Blood pressure (BP) control is defined as BP <140/90 mmHg.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients who have successfully completed protocol No. CLCZ696A2219 and who, as judged by the study investigator, are able to continue in the current study.

• Ability to communicate and comply with all study requirements and demonstrate good medication compliance during CLCZ696A2219.

Exclusion Criteria:

• Patients who did not complete CLCZ696A2219.

• Presence of significant protocol violation in CLCZ696A2219.

• Patients who are deemed to be unable to comply with the protocol by the investigator.

• Other protocol-defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Chongqing	Chongqing	China	400042
2	Novartis Investigative Site	Shijiazhuang	Hebei	China	050000
3	Novartis Investigative Site	Hangzhou	Zhejiang	China	310006
4	Novartis Investigative Site	Beijing		China	100044
5	Novartis Investigative Site	Beijing		China	100730
6	Novartis Investigative Site	Tianjin		China	300142
7	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	231-0023
8	Novartis Investigative Site	Shimotsuke-city	Tochigi	Japan	329-0498
9	Novartis Investigative Site	Bunkyo-ku	Tokyo	Japan	113-0031
10	Novartis Investigative Site	Chiyoda-ku	Tokyo	Japan	100-0005
11	Novartis Investigative Site	Kiyose-city	Tokyo	Japan	204-0021
12	Novartis Investigative Site	Kunitachi	Tokyo	Japan	186-0001
13	Novartis Investigative Site	Minato-ku	Tokyo	Japan	105-7390
14	Novartis Investigative Site	Minato-ku	Tokyo	Japan	108-0075
15	Novartis Investigative Site	Ota-ku	Tokyo	Japan	143-0023
16	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	141-0032
17	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	142-0053
18	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	142-0063
19	Novartis Investigative Site	Toshima-ku	Tokyo	Japan	171-0021
20	Novartis Investigative Site	Bucheon	Gyeonggi-do	Korea, Republic of	424-717
21	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	137-701
22	Novartis Investigative Site	Koyang	Kyunggi	Korea, Republic of	410-719
23	Novartis Investigative Site	Daegu		Korea, Republic of	705-703
24	Novartis Investigative Site	Seoul		Korea, Republic of	150-950
25	Novartis Investigative Site	Seoul		Korea, Republic of	152-703
26	Novartis Investigative Site	Changhua		Taiwan	500
27	Novartis Investigative Site	Taichung		Taiwan	40447
28	Novartis Investigative Site	Taipei		Taiwan	10002
29	Novartis Investigative Site	Taipei		Taiwan	10449
30	Novartis Investigative Site	Taipei		Taiwan	114
31	Novartis Investigative Site	Bangkok		Thailand	10400
32	Novartis Investigative Site	Bangkok		Thailand	10700
33	Novartis Investigative Site	Chiang Mai		Thailand	50200

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: NCT01256411
• Other Study ID Numbers: CLCZ696A2219E1
• First Posted: Dec 8, 2010
• Last Update Posted: Oct 21, 2015
• Last Verified: Sep 1, 2015

• Keywords provided by Novartis Pharmaceuticals: hypertension; blood pressure; LCZ696; dual-acting; neprilysin; nep inhibitor; vasopeptidase; angiotensin receptor; angiotensin receptor neprilysin inhibitor (ARNi)
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Amlodipine; Hydrochlorothiazide; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	Analyses on this open label extension study were performed according to treatment groups defined by the maximum and highest dose treatments received: 1) LCZ696 200 mg, 2) LCZ696 400 mg, 3) LCZ696 400 mg/Amlodipine, 4) LCZ696 400 mg/Amlodipine/HCTZ, 5) LCZ696 Mono (LCZ696 only), and 6) LCZ696 Combination LCZ696 with Amlodipine and/or HCTZ).

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ606 400 mg/Amlodipine	LCZ696 400 mg/Amlodipine/HCTZ	LCZ696 Monotherapy	LCZ696 Combination Therapy
Arm/Group Description	Participants received LCZ696 200 mg by mouth once daily (qd).	Participants received LCZ696 400 mg by mouth qd.	Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).	Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn.	Participants received LCZ696 only.	Participants received LCZ696 with amlodipine and/or HCTZ.
Period Title: Extension by Maximum Treatment
STARTED	139	89	109	4	0	0
Down Titrated to 100 mg	12	0	0	0	0	0
COMPLETED	132	79	105	4	0	0
NOT COMPLETED	7	10	4	0	0	0
Period Title: Extension by Maximum Treatment
STARTED	0	0	0	0	228	113
COMPLETED	0	0	0	0	211	109
NOT COMPLETED	0	0	0	0	17	4

Baseline Characteristics

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ606 400 mg/Amlodipine	LCZ696 400 mg/Amlodipine/HCTZ	Total
Arm/Group Description	Participants received LCZ696 200 mg by mouth once daily (qd).	Participants received LCZ696 400 mg by mouth qd.	Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).	Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn.	Total of all reporting groups
Overall Participants	139	89	109	4	341
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	52.2 (9.69)	50.3 (10.14)	52.5 (9.53)	46.3 (2.06)	51.8 (9.73)
Sex: Female, Male (Count of Participants)
Female	55 39.6%	18 20.2%	26 23.9%	0 0%	99 29%
Male	84 60.4%	71 79.8%	83 76.1%	4 100%	242 71%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment)
Description	Participants were monitored throughout the study for adverse events, serious adverse events and deaths.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

Actual extension treatment received: The participants are included in each treatment group for which they received treatment. For example, if a participant started on LCZ696 200 mg but was then down-titrated to LCZ696 100 mg, the participant was counted once in the LCZ696 100 mg group and once in the LCZ696 200 mg group.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ606 400 mg/Amlodipine	LCZ696 400 mg/Amlodipine/HCTZ	LCZ696 100 mg
Arm/Group Description	Participants received LCZ696 200 mg by mouth once daily (qd).	Participants received LCZ696 400 mg by mouth qd.	Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).	Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn.	Participants were down-titrated to 100 mg.
Measure Participants	340	201	112	4	12
Adverse events (serious and non-serious)	147 105.8%	78 87.6%	53 48.6%	0 0%	6 1.8%
Seroius adverse events	10 7.2%	2 2.2%	0 0%	0 0%	1 0.3%
Deaths	0 0%	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment)
Description	Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 400 mg/Amlodopine group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ606 400 mg/Amlodipine	LCZ696 400 mg/Amlodipine/HCTZ
Arm/Group Description	Participants received LCZ696 200 mg by mouth once daily (qd).	Participants received LCZ696 400 mg by mouth qd.	Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).	Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn.
Measure Participants	139	89	108	4
msDBP	-16.6 (7.63)	-14.2 (7.05)	-17.4 (7.71)	-16.8 (3.84)
msSBP	-24.1 (12.16)	-21.3 (11.46)	-28.1 (13.43)	-29.0 (9.23)

3. Secondary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy)
Description	Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.
Time Frame	Baseline, 12 months

Outcome Measure Data

Analysis Population Description

Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 combination group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.

Arm/Group Title	LCZ696 Monotherapy	LCZ696 Combination Therapy
Arm/Group Description	Participants received LCZ696 only.	Participants received LCZ696 with amlodipine and/or HCTZ.
Measure Participants	228	112
msDBP	-15.7 (7.49)	-17.3 (7.60)
msSBP	-23.0 (11.95)	-28.2 (13.27)

4. Secondary Outcome

Title	Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment)
Description	Blood pressure (BP) control is defined as BP <140/90 mmHg.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 400 mg/Amlodopine group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.

Arm/Group Title	LCZ696 200 mg	LCZ696 400 mg	LCZ606 400 mg/Amlodipine	LCZ696 400 mg/Amlodipine/HCTZ
Arm/Group Description	Participants received LCZ696 200 mg by mouth once daily (qd).	Participants received LCZ696 400 mg by mouth qd.	Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).	Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn.
Measure Participants	139	89	108	4
Number [Participants]	114 82%	62 69.7%	77 70.6%	3 75%

5. Secondary Outcome

Title	Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Mono or Combination Therapy)
Description	Blood pressure (BP) control is defined as BP <140/90 mmHg.
Time Frame	Baseline to 12 months

Outcome Measure Data

Analysis Population Description

Treated set: The treated set included all participants who received at least one dose of extension study medication. One participant in the LCZ696 combination group discontinued after 1 day in the extension study without having any BP measurements taken during the extension. Therefore, this participant was excluded from the analysis.

Arm/Group Title	LCZ696 Monotherapy	LCZ696 Combination Therapy
Arm/Group Description	Participants received LCZ696 only.	Participants received LCZ696 with amlodipine and/or HCTZ.
Measure Participants	228	112
Number [Participants]	176 126.6%	80 89.9%

Adverse Events

Arm/Group Title	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		LCZ696 400 mg/Aml		LCZ696 400 mg/Aml/HCTZ
Arm/Group Description	Participants were down-titrated to 100 mg.		Participants received LCZ696 200 mg by mouth once daily (qd).		Participants received LCZ696 400 mg by mouth qd.		Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn.		Participants received LCZ696 400 mg by mouth qd, amlodipine 5 mg up to 10 mg by mouth prn and HCTZ 6.25 mg and up to 25 mg by mouth prn.
All Cause Mortality
	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		LCZ696 400 mg/Aml		LCZ696 400 mg/Aml/HCTZ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		LCZ696 400 mg/Aml		LCZ696 400 mg/Aml/HCTZ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		10/340 (2.9%)		2/201 (1%)		0/112 (0%)		0/4 (0%)
Cardiac disorders
Acute myocardial infarction	0/12 (0%)		1/340 (0.3%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Hepatobiliary disorders
Bile duct stone	0/12 (0%)		0/340 (0%)		1/201 (0.5%)		0/112 (0%)		0/4 (0%)
Cholangitis acute	0/12 (0%)		0/340 (0%)		1/201 (0.5%)		0/112 (0%)		0/4 (0%)
Cholecystitis	0/12 (0%)		1/340 (0.3%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Infections and infestations
Appendicitis	0/12 (0%)		2/340 (0.6%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Bronchitis	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Gastroenteritis	0/12 (0%)		1/340 (0.3%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Pneumonia	0/12 (0%)		1/340 (0.3%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion	0/12 (0%)		0/340 (0%)		1/201 (0.5%)		0/112 (0%)		0/4 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cancer	0/12 (0%)		1/340 (0.3%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Nervous system disorders
Cerebral infarction	0/12 (0%)		1/340 (0.3%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Syncope	0/12 (0%)		2/340 (0.6%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Emphysema	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Nasal septum deviation	0/12 (0%)		1/340 (0.3%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Pneumothorax	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Pulmonary haemorrhage	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Other (Not Including Serious) Adverse Events
	LCZ696 100 mg		LCZ696 200 mg		LCZ696 400 mg		LCZ696 400 mg/Aml		LCZ696 400 mg/Aml/HCTZ
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/12 (50%)		77/340 (22.6%)		39/201 (19.4%)		32/112 (28.6%)		0/4 (0%)
Gastrointestinal disorders
Dysphagia	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Gastric ulcer	1/12 (8.3%)		0/340 (0%)		1/201 (0.5%)		1/112 (0.9%)		0/4 (0%)
Gastritis	1/12 (8.3%)		4/340 (1.2%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Gastritis erosive	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Gingivitis	1/12 (8.3%)		1/340 (0.3%)		1/201 (0.5%)		0/112 (0%)		0/4 (0%)
Oesophagitis	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Peptic ulcer	1/12 (8.3%)		0/340 (0%)		1/201 (0.5%)		0/112 (0%)		0/4 (0%)
Radicular cyst	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Infections and infestations
Nasopharyngitis	1/12 (8.3%)		37/340 (10.9%)		15/201 (7.5%)		15/112 (13.4%)		0/4 (0%)
Pharyngitis	0/12 (0%)		3/340 (0.9%)		2/201 (1%)		3/112 (2.7%)		0/4 (0%)
Upper respiratory tract infection	1/12 (8.3%)		20/340 (5.9%)		4/201 (2%)		1/112 (0.9%)		0/4 (0%)
Vestibular neuronitis	1/12 (8.3%)		0/340 (0%)		0/201 (0%)		0/112 (0%)		0/4 (0%)
Metabolism and nutrition disorders
Hyperuricaemia	1/12 (8.3%)		5/340 (1.5%)		3/201 (1.5%)		1/112 (0.9%)		0/4 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/12 (8.3%)		1/340 (0.3%)		1/201 (0.5%)		0/112 (0%)		0/4 (0%)
Nervous system disorders
Dizziness	2/12 (16.7%)		13/340 (3.8%)		6/201 (3%)		9/112 (8%)		0/4 (0%)
Headache	2/12 (16.7%)		6/340 (1.8%)		2/201 (1%)		2/112 (1.8%)		0/4 (0%)
Psychiatric disorders
Insomnia	0/12 (0%)		1/340 (0.3%)		5/201 (2.5%)		1/112 (0.9%)		0/4 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/12 (0%)		4/340 (1.2%)		2/201 (1%)		3/112 (2.7%)		0/4 (0%)
Rhinitis allergic	1/12 (8.3%)		5/340 (1.5%)		1/201 (0.5%)		1/112 (0.9%)		0/4 (0%)

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.