Trial Outcomes & Findings for A Long-term (12 Months) Safety, Tolerability and Efficacy Study of LCZ696 in Patients With Essential Hypertension (NCT NCT01256411)
NCT ID: NCT01256411
Last Updated: 2015-10-21
Results Overview
Participants were monitored throughout the study for adverse events, serious adverse events and deaths.
Recruitment status
COMPLETED
Study phase
PHASE2
Target enrollment
341 participants
Primary outcome timeframe
Baseline to 12 months
Results posted on
2015-10-21
Participant Flow
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).
Participant milestones
| Measure |
LCZ696 200 mg
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
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.
|
LCZ696 Monotherapy
Participants received LCZ696 only.
|
LCZ696 Combination Therapy
Participants received LCZ696 with amlodipine and/or HCTZ.
|
|---|---|---|---|---|---|---|
|
Extension by Maximum Treatment
STARTED
|
139
|
89
|
109
|
4
|
0
|
0
|
|
Extension by Maximum Treatment
Down Titrated to 100 mg
|
12
|
0
|
0
|
0
|
0
|
0
|
|
Extension by Maximum Treatment
COMPLETED
|
132
|
79
|
105
|
4
|
0
|
0
|
|
Extension by Maximum Treatment
NOT COMPLETED
|
7
|
10
|
4
|
0
|
0
|
0
|
|
Extension by Mono or Combination Therapy
STARTED
|
0
|
0
|
0
|
0
|
228
|
113
|
|
Extension by Mono or Combination Therapy
COMPLETED
|
0
|
0
|
0
|
0
|
211
|
109
|
|
Extension by Mono or Combination Therapy
NOT COMPLETED
|
0
|
0
|
0
|
0
|
17
|
4
|
Reasons for withdrawal
| Measure |
LCZ696 200 mg
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
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.
|
LCZ696 Monotherapy
Participants received LCZ696 only.
|
LCZ696 Combination Therapy
Participants received LCZ696 with amlodipine and/or HCTZ.
|
|---|---|---|---|---|---|---|
|
Extension by Maximum Treatment
Protocol deviation
|
0
|
0
|
1
|
0
|
0
|
0
|
|
Extension by Maximum Treatment
Lost to Follow-up
|
1
|
2
|
0
|
0
|
0
|
0
|
|
Extension by Maximum Treatment
Withdrawal by Subject
|
1
|
6
|
1
|
0
|
0
|
0
|
|
Extension by Maximum Treatment
Lack of Efficacy
|
1
|
0
|
1
|
0
|
0
|
0
|
|
Extension by Maximum Treatment
Adverse Event
|
4
|
2
|
1
|
0
|
0
|
0
|
|
Extension by Mono or Combination Therapy
Adverse Event
|
0
|
0
|
0
|
0
|
6
|
1
|
|
Extension by Mono or Combination Therapy
Protocol deviation
|
0
|
0
|
0
|
0
|
0
|
1
|
|
Extension by Mono or Combination Therapy
Lost to Follow-up
|
0
|
0
|
0
|
0
|
3
|
0
|
|
Extension by Mono or Combination Therapy
Withdrawal by Subject
|
0
|
0
|
0
|
0
|
7
|
1
|
|
Extension by Mono or Combination Therapy
Lack of Efficacy
|
0
|
0
|
0
|
0
|
1
|
1
|
Baseline Characteristics
A Long-term (12 Months) Safety, Tolerability and Efficacy Study of LCZ696 in Patients With Essential Hypertension
Baseline characteristics by cohort
| Measure |
LCZ696 200 mg
n=139 Participants
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=89 Participants
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
n=109 Participants
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
n=4 Participants
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
n=341 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Continuous
|
52.2 Years
STANDARD_DEVIATION 9.69 • n=5 Participants
|
50.3 Years
STANDARD_DEVIATION 10.14 • n=7 Participants
|
52.5 Years
STANDARD_DEVIATION 9.53 • n=5 Participants
|
46.3 Years
STANDARD_DEVIATION 2.06 • n=4 Participants
|
51.8 Years
STANDARD_DEVIATION 9.73 • n=21 Participants
|
|
Sex: Female, Male
Female
|
55 Participants
n=5 Participants
|
18 Participants
n=7 Participants
|
26 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
99 Participants
n=21 Participants
|
|
Sex: Female, Male
Male
|
84 Participants
n=5 Participants
|
71 Participants
n=7 Participants
|
83 Participants
n=5 Participants
|
4 Participants
n=4 Participants
|
242 Participants
n=21 Participants
|
PRIMARY outcome
Timeframe: Baseline to 12 monthsPopulation: 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.
Participants were monitored throughout the study for adverse events, serious adverse events and deaths.
Outcome measures
| Measure |
LCZ696 200 mg
n=340 Participants
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=201 Participants
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
n=112 Participants
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
n=4 Participants
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.
|
LCZ696 100 mg
n=12 Participants
Participants were down-titrated to 100 mg.
|
|---|---|---|---|---|---|
|
Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment)
Adverse events (serious and non-serious)
|
147 Participants
|
78 Participants
|
53 Participants
|
0 Participants
|
6 Participants
|
|
Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment)
Seroius adverse events
|
10 Participants
|
2 Participants
|
0 Participants
|
0 Participants
|
1 Participants
|
|
Number of Participants With Adverse Events, Serious Adverse Events, and Deaths (Analysis by Actual Treatment)
Deaths
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
0 Participants
|
SECONDARY outcome
Timeframe: Baseline, 12 monthsPopulation: 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.
Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.
Outcome measures
| Measure |
LCZ696 200 mg
n=139 Participants
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=89 Participants
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
n=108 Participants
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
n=4 Participants
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.
|
LCZ696 100 mg
Participants were down-titrated to 100 mg.
|
|---|---|---|---|---|---|
|
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment)
msDBP
|
-16.6 mmHg
Standard Deviation 7.63
|
-14.2 mmHg
Standard Deviation 7.05
|
-17.4 mmHg
Standard Deviation 7.71
|
-16.8 mmHg
Standard Deviation 3.84
|
—
|
|
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Maximum Treatment)
msSBP
|
-24.1 mmHg
Standard Deviation 12.16
|
-21.3 mmHg
Standard Deviation 11.46
|
-28.1 mmHg
Standard Deviation 13.43
|
-29.0 mmHg
Standard Deviation 9.23
|
—
|
SECONDARY outcome
Timeframe: Baseline, 12 monthsPopulation: 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.
Sitting BP measurements were performed at every study visit. A negative change from baseline indicates improvement.
Outcome measures
| Measure |
LCZ696 200 mg
n=228 Participants
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=112 Participants
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
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.
|
LCZ696 100 mg
Participants were down-titrated to 100 mg.
|
|---|---|---|---|---|---|
|
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy)
msSBP
|
-23.0 mmHg
Standard Deviation 11.95
|
-28.2 mmHg
Standard Deviation 13.27
|
—
|
—
|
—
|
|
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) (Analysis by Mono or Combination Therapy)
msDBP
|
-15.7 mmHg
Standard Deviation 7.49
|
-17.3 mmHg
Standard Deviation 7.60
|
—
|
—
|
—
|
SECONDARY outcome
Timeframe: Baseline to 12 monthsPopulation: 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.
Blood pressure (BP) control is defined as BP \<140/90 mmHg.
Outcome measures
| Measure |
LCZ696 200 mg
n=139 Participants
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=89 Participants
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
n=108 Participants
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
n=4 Participants
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.
|
LCZ696 100 mg
Participants were down-titrated to 100 mg.
|
|---|---|---|---|---|---|
|
Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Maximum Treatment)
|
114 Participants
|
62 Participants
|
77 Participants
|
3 Participants
|
—
|
SECONDARY outcome
Timeframe: Baseline to 12 monthsPopulation: 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.
Blood pressure (BP) control is defined as BP \<140/90 mmHg.
Outcome measures
| Measure |
LCZ696 200 mg
n=228 Participants
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=112 Participants
Participants received LCZ696 400 mg by mouth qd.
|
LCZ606 400 mg/Amlodipine
Participants received LCZ696 400 mg by mouth qd and amlodipine 5mg up to 10 mg by mouth as needed (prn).
|
LCZ696 400 mg/Amlodipine/HCTZ
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.
|
LCZ696 100 mg
Participants were down-titrated to 100 mg.
|
|---|---|---|---|---|---|
|
Number of Participants With Blood Pressure Control Rate of <140/90 mmHg (Analysis by Mono or Combination Therapy)
|
176 Participants
|
80 Participants
|
—
|
—
|
—
|
Adverse Events
LCZ696 100 mg
Serious events: 1 serious events
Other events: 6 other events
Deaths: 0 deaths
LCZ696 200 mg
Serious events: 10 serious events
Other events: 77 other events
Deaths: 0 deaths
LCZ696 400 mg
Serious events: 2 serious events
Other events: 39 other events
Deaths: 0 deaths
LCZ696 400 mg/Aml
Serious events: 0 serious events
Other events: 32 other events
Deaths: 0 deaths
LCZ696 400 mg/Aml/HCTZ
Serious events: 0 serious events
Other events: 0 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
LCZ696 100 mg
n=12 participants at risk
Participants were down-titrated to 100 mg.
|
LCZ696 200 mg
n=340 participants at risk
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=201 participants at risk
Participants received LCZ696 400 mg by mouth qd.
|
LCZ696 400 mg/Aml
n=112 participants at risk
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.
|
LCZ696 400 mg/Aml/HCTZ
n=4 participants at risk
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.
|
|---|---|---|---|---|---|
|
Hepatobiliary disorders
Cholecystitis
|
0.00%
0/12
|
0.29%
1/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Cardiac disorders
Acute myocardial infarction
|
0.00%
0/12
|
0.29%
1/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Hepatobiliary disorders
Bile duct stone
|
0.00%
0/12
|
0.00%
0/340
|
0.50%
1/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Hepatobiliary disorders
Cholangitis acute
|
0.00%
0/12
|
0.00%
0/340
|
0.50%
1/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Infections and infestations
Appendicitis
|
0.00%
0/12
|
0.59%
2/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Infections and infestations
Bronchitis
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Infections and infestations
Gastroenteritis
|
0.00%
0/12
|
0.29%
1/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Infections and infestations
Pneumonia
|
0.00%
0/12
|
0.29%
1/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
|
0.00%
0/12
|
0.00%
0/340
|
0.50%
1/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Renal cancer
|
0.00%
0/12
|
0.29%
1/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Nervous system disorders
Cerebral infarction
|
0.00%
0/12
|
0.29%
1/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Nervous system disorders
Syncope
|
0.00%
0/12
|
0.59%
2/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Respiratory, thoracic and mediastinal disorders
Emphysema
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Respiratory, thoracic and mediastinal disorders
Nasal septum deviation
|
0.00%
0/12
|
0.29%
1/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Respiratory, thoracic and mediastinal disorders
Pneumothorax
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Respiratory, thoracic and mediastinal disorders
Pulmonary haemorrhage
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
Other adverse events
| Measure |
LCZ696 100 mg
n=12 participants at risk
Participants were down-titrated to 100 mg.
|
LCZ696 200 mg
n=340 participants at risk
Participants received LCZ696 200 mg by mouth once daily (qd).
|
LCZ696 400 mg
n=201 participants at risk
Participants received LCZ696 400 mg by mouth qd.
|
LCZ696 400 mg/Aml
n=112 participants at risk
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.
|
LCZ696 400 mg/Aml/HCTZ
n=4 participants at risk
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.
|
|---|---|---|---|---|---|
|
Gastrointestinal disorders
Dysphagia
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Gastrointestinal disorders
Gastric ulcer
|
8.3%
1/12
|
0.00%
0/340
|
0.50%
1/201
|
0.89%
1/112
|
0.00%
0/4
|
|
Gastrointestinal disorders
Gastritis
|
8.3%
1/12
|
1.2%
4/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Gastrointestinal disorders
Gastritis erosive
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Gastrointestinal disorders
Gingivitis
|
8.3%
1/12
|
0.29%
1/340
|
0.50%
1/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Gastrointestinal disorders
Oesophagitis
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Gastrointestinal disorders
Peptic ulcer
|
8.3%
1/12
|
0.00%
0/340
|
0.50%
1/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Gastrointestinal disorders
Radicular cyst
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Infections and infestations
Nasopharyngitis
|
8.3%
1/12
|
10.9%
37/340
|
7.5%
15/201
|
13.4%
15/112
|
0.00%
0/4
|
|
Infections and infestations
Pharyngitis
|
0.00%
0/12
|
0.88%
3/340
|
1.00%
2/201
|
2.7%
3/112
|
0.00%
0/4
|
|
Infections and infestations
Upper respiratory tract infection
|
8.3%
1/12
|
5.9%
20/340
|
2.0%
4/201
|
0.89%
1/112
|
0.00%
0/4
|
|
Infections and infestations
Vestibular neuronitis
|
8.3%
1/12
|
0.00%
0/340
|
0.00%
0/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Metabolism and nutrition disorders
Hyperuricaemia
|
8.3%
1/12
|
1.5%
5/340
|
1.5%
3/201
|
0.89%
1/112
|
0.00%
0/4
|
|
Musculoskeletal and connective tissue disorders
Arthralgia
|
8.3%
1/12
|
0.29%
1/340
|
0.50%
1/201
|
0.00%
0/112
|
0.00%
0/4
|
|
Nervous system disorders
Dizziness
|
16.7%
2/12
|
3.8%
13/340
|
3.0%
6/201
|
8.0%
9/112
|
0.00%
0/4
|
|
Nervous system disorders
Headache
|
16.7%
2/12
|
1.8%
6/340
|
1.00%
2/201
|
1.8%
2/112
|
0.00%
0/4
|
|
Psychiatric disorders
Insomnia
|
0.00%
0/12
|
0.29%
1/340
|
2.5%
5/201
|
0.89%
1/112
|
0.00%
0/4
|
|
Respiratory, thoracic and mediastinal disorders
Cough
|
0.00%
0/12
|
1.2%
4/340
|
1.00%
2/201
|
2.7%
3/112
|
0.00%
0/4
|
|
Respiratory, thoracic and mediastinal disorders
Rhinitis allergic
|
8.3%
1/12
|
1.5%
5/340
|
0.50%
1/201
|
0.89%
1/112
|
0.00%
0/4
|
Additional Information
Study Director
Novartis Pharmaceuticals
Phone: 862-778-8300
Results disclosure agreements
- Principal investigator is a sponsor employee 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.
- Publication restrictions are in place
Restriction type: OTHER