Evaluation of the Metabolic Effects of LCZ696 and Amlodipine in Obese Hypertensive Subjects

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01631864
• Collaborator: (none)
• Enrollment: 98
• Locations: 3
• Arms: 2
• Duration (Months): 9
• Patients Per Site: 32.7
• Patients Per Site Per Month: 3.6

Study Details

Study Description

Brief Summary

This study investigated the effects of LCZ696 on insulin sensitivity, lipolysis, and oxidative metabolism in obese hypertensive subjects.

Condition or Disease	Intervention/Treatment	Phase
Hypertension; Concurrent Obesity	Drug: LCZ696; Drug: amlodipine; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Official Title: A Randomized, Double-blind, Parallel Group Study to Evaluate Metabolic Effects of LCZ696 and Amlodipine in Obese Hypertensive Subjects
• Study Start Date: Oct 1, 2012
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks	Drug: LCZ696; LCZ696 was provided as 400 mg tablets.; Drug: Placebo; Matching placebo to LCZ696 and amlodipine.
Active Comparator: amlodipine amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks	Drug: amlodipine; amlodipine was provided as 5 mg tablets.; Drug: Placebo; Matching placebo to LCZ696 and amlodipine.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. Local Adipose Tissue Lipolysis, Glycerol Concentrations [57 days]

   Lipolysis was assessed through subcutaneous adipose tissue microdialysis. The actual measure type is adjusted geometric mean.

2. Oxidative Metabolism [57 days]

   Oxidative metabolism was assessed by indirect calorimetry.

3. Number of Participants With Adverse Events, Serious Adverse Events and Deaths [8 weeks]

   Adverse event monitoring was conducted throughout the study.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Hannover		Germany	30625
2	Novartis Investigative Site	Neuss		Germany	41460
3	Novartis Investigative Site	Maastricht		Netherlands	5800

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: NCT01631864
• Other Study ID Numbers: CLCZ696B2207; 2012-002606-40
• First Posted: Jun 29, 2012
• Last Update Posted: Aug 10, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Novartis Pharmaceuticals: Hypertension, obesity, insulin sensitivity, lipolysis, LCZ696
• Additional relevant MeSH terms: Hypertension; Amlodipine; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	LCZ696	Amlodipine
Arm/Group Description	LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks	amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks
Period Title: Overall Study
STARTED	50	48
COMPLETED	48	44
NOT COMPLETED	2	4

Baseline Characteristics

Arm/Group Title	LCZ696	Amlodipine	Total
Arm/Group Description	LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks	amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks	Total of all reporting groups
Overall Participants	50	48	98
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.9 (9.6)	50.5 (9.4)	51.2 (9.5)
Sex: Female, Male (Count of Participants)
Female	9 18%	13 27.1%	22 22.4%
Male	41 82%	35 72.9%	76 77.6%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Insulin Sensitivity Index
Description	The insulin sensitivity index was assessed by hyperinsulinemic euglycemic clamp (HEGC). A positive change from baseline indicates improvement.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

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/Group Title	LCZ696	Amlodipine
Arm/Group Description	LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks	amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks
Measure Participants	48	41
Mean (95% Confidence Interval) [ug/kg*min/(mmol/L*pmol/L)]	0.192	0.065

2. Secondary Outcome

Title	Local Adipose Tissue Lipolysis, Glycerol Concentrations
Description	Lipolysis was assessed through subcutaneous adipose tissue microdialysis. The actual measure type is adjusted geometric mean.
Time Frame	57 days

Outcome Measure Data

Analysis Population Description

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/Group Title	LCZ696	Amlodipine
Arm/Group Description	LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks	amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks
Measure Participants	47	42
Geometric Mean (95% Confidence Interval) [micro mol/L]	82.46	65.91

3. Secondary Outcome

Title	Oxidative Metabolism
Description	Oxidative metabolism was assessed by indirect calorimetry.
Time Frame	57 days

Outcome Measure Data

Analysis Population Description

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/Group Title	LCZ696	Amlodipine
Arm/Group Description	LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks	amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks
Measure Participants	46	40
Least Squares Mean (95% Confidence Interval) [carbon dioxide to oxygen ratio]	0.787	0.775

4. Secondary Outcome

Title	Number of Participants With Adverse Events, Serious Adverse Events and Deaths
Description	Adverse event monitoring was conducted throughout the study.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Safety Analysis Set (SAS): The SAS included all randomized participants who received at least one dose of study drug.

Arm/Group Title	LCZ696	Amlodipine
Arm/Group Description	LCZ696 400 mg plus placebo to amlodipine once daily for 8 weeks	amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks
Measure Participants	50	48
Adverse events (serious and non-serious)	30 60%	37 77.1%
Serious adverse events	1 2%	1 2.1%
Deaths	0 0%	0 0%

Adverse Events

Arm/Group Title	LCZ696		Amlodipine
Arm/Group Description	LCZ696 400 mg plus placebo to Amlodipine once daily for 8 weeks		Amlodipine 10 mg plus placebo to LCZ696 once daily for 8 weeks
All Cause Mortality
	LCZ696		Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ696		Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/50 (2%)		1/48 (2.1%)
Nervous system disorders
RUPTURED CEREBRAL ANEURYSM	1/50 (2%)		0/48 (0%)
Renal and urinary disorders
NEPHROLITHIASIS	0/50 (0%)		1/48 (2.1%)
Other (Not Including Serious) Adverse Events
	LCZ696		Amlodipine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/50 (46%)		26/48 (54.2%)
Gastrointestinal disorders
DIARRHOEA	3/50 (6%)		1/48 (2.1%)
General disorders
OEDEMA PERIPHERAL	1/50 (2%)		16/48 (33.3%)
Infections and infestations
NASOPHARYNGITIS	9/50 (18%)		8/48 (16.7%)
Nervous system disorders
DIZZINESS	3/50 (6%)		1/48 (2.1%)
HEADACHE	4/50 (8%)		6/48 (12.5%)
Skin and subcutaneous tissue disorders
PRURITUS	5/50 (10%)		0/48 (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.