Concurrent Obesity, Hypertension
Conditions
Keywords
Hypertension, obesity, insulin sensitivity, lipolysis, LCZ696
Brief summary
This study investigated the effects of LCZ696 on insulin sensitivity, lipolysis, and oxidative metabolism in obese hypertensive subjects.
Interventions
DRUGLCZ696
LCZ696 was provided as 400 mg tablets.
DRUGamlodipine
amlodipine was provided as 5 mg tablets.
DRUGPlacebo
Matching placebo to LCZ696 and amlodipine.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent must be obtained before any study assessment is performed. * Males and females of non-childbearing potential ≥ 18 years of age. * Subjects with mild to moderate essential hypertension, * Untreated subjects must have a mean seated SBP (msSBP) ≥ 130 mmHg and \< 180 mmHg at screening. * Pre-treated subjects must have a msSBP ≤ 160 mmHg at screening and \< 180 mmHg at the end of the washout period. * Waist circumference ≥ 102 cm (men) and ≥ 88 cm (women);
Exclusion criteria
* Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer; or longer if required by local regulations. * History of angioedema, drug-related or otherwise * History of hypersensitivity to LCZ696, amlodipine, or drugs of similar chemical classes. * Severe hypertension (grade 3 of WHO classification; msDBP ≥100 mmHg and/or msSBP ≥ 180 mmHg) at screening or at the end of the washout period. * Type 1 or Type 2 diabetes mellitus. * Dyslipidemia requiring pharmacological therapy with a fibrate or nicotinic acid. * Concomitant use of anti-hypertensives, anti-diabetics, or drugs with effects on glucose or lipid metabolism for the duration of the study. Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Insulin Sensitivity Index | baseline, 8 weeks | The insulin sensitivity index was assessed by hyperinsulinemic euglycemic clamp (HEGC). A positive change from baseline indicates improvement. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Oxidative Metabolism | 57 days | Oxidative metabolism was assessed by indirect calorimetry. |
| Number of Participants With Adverse Events, Serious Adverse Events and Deaths | 8 weeks | Adverse event monitoring was conducted throughout the study. |
| Local Adipose Tissue Lipolysis, Glycerol Concentrations | 57 days | Lipolysis was assessed through subcutaneous adipose tissue microdialysis. The actual measure type is adjusted geometric mean. |
Countries
Germany, Netherlands
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| LCZ696 LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks | 50 |
| Amlodipine amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks | 48 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 3 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | LCZ696 | Amlodipine | Total |
|---|---|---|---|
| Age, Continuous | 51.9 Years STANDARD_DEVIATION 9.6 | 50.5 Years STANDARD_DEVIATION 9.4 | 51.2 Years STANDARD_DEVIATION 9.5 |
| Sex: Female, Male Female | 9 Participants | 13 Participants | 22 Participants |
| Sex: Female, Male Male | 41 Participants | 35 Participants | 76 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 23 / 50 | 26 / 48 |
| serious Total, serious adverse events | 1 / 50 | 1 / 48 |
Outcome results
Primary
Change From Baseline in Insulin Sensitivity Index
The insulin sensitivity index was assessed by hyperinsulinemic euglycemic clamp (HEGC). A positive change from baseline indicates improvement.
Time frame: baseline, 8 weeks
Population: Pharmacodynamic Analysis Set (PDS): Only participants from the PDS, who had both baseline and day 56 values, were included in the analysis. The PDS included all randomized participants who received at least one dose of study drug and had no protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| LCZ696 | Change From Baseline in Insulin Sensitivity Index | 0.192 ug/kg*min/(mmol/L*pmol/L) |
| Amlodipine | Change From Baseline in Insulin Sensitivity Index | 0.065 ug/kg*min/(mmol/L*pmol/L) |
Secondary
Local Adipose Tissue Lipolysis, Glycerol Concentrations
Lipolysis was assessed through subcutaneous adipose tissue microdialysis. The actual measure type is adjusted geometric mean.
Time frame: 57 days
Population: Pharmacodynamic Analysis Set (PDS): Only participants from the PDS, who had both baseline and day 56 values, were included in the analysis. The PDS included all randomized participants who received at least one dose of study drug and had no protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| LCZ696 | Local Adipose Tissue Lipolysis, Glycerol Concentrations | 82.46 micro mol/L |
| Amlodipine | Local Adipose Tissue Lipolysis, Glycerol Concentrations | 65.91 micro mol/L |
Secondary
Number of Participants With Adverse Events, Serious Adverse Events and Deaths
Adverse event monitoring was conducted throughout the study.
Time frame: 8 weeks
Population: Safety Analysis Set (SAS): The SAS included all randomized participants who received at least one dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| LCZ696 | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Adverse events (serious and non-serious) | 30 Participants |
| LCZ696 | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Serious adverse events | 1 Participants |
| LCZ696 | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Deaths | 0 Participants |
| Amlodipine | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Adverse events (serious and non-serious) | 37 Participants |
| Amlodipine | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Serious adverse events | 1 Participants |
| Amlodipine | Number of Participants With Adverse Events, Serious Adverse Events and Deaths | Deaths | 0 Participants |
Secondary
Oxidative Metabolism
Oxidative metabolism was assessed by indirect calorimetry.
Time frame: 57 days
Population: Pharmacodynamic Analysis Set (PDS): Only participants from the PDS, who had both baseline and day 56 values, were included in the analysis. The PDS included all randomized participants who received at least one dose of study drug and had no protocol deviations with relevant impact on PD data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| LCZ696 | Oxidative Metabolism | 0.787 carbon dioxide to oxygen ratio |
| Amlodipine | Oxidative Metabolism | 0.775 carbon dioxide to oxygen ratio |