Assessment of LCZ696 and Valsartan in Asian Patients With Salt-sensitive Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01681576
• Collaborator: (none)
• Enrollment: 72
• Locations: 15
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This study will evaluate the effect of LCZ696 and valsartan on natriuresis, diuresis, and blood pressure in salt-sensitive Asian hypertensive patients.

Condition or Disease	Intervention/Treatment	Phase
Salt-sensitive Hypertension	Drug: Valsartan; Drug: LCZ696	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 72 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Official Title: A Randomized, Double-blind, Crossover Study to Assess the Effects of LCZ696 and Valsartan in Asian Patients With Salt-sensitive Hypertension
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Oct 1, 2013
• Actual Study Completion Date: Oct 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 followed by Valsartan Period 1: LCZ696 400mg QD for 4 weeks then washout followed by Period 2: Valsartan 320mg QD for 4 weeks	Drug: Valsartan; Valsartan 320mg tablet once daily; Drug: LCZ696; LCZ696 400mg tablet once daily
Experimental: Valsartan followed by LCZ696 Period 1: Valsartan 320mg QD for 4 weeks then washout followed by Period 2: LCZ696 400mg QD for 4 weeks	Drug: Valsartan; Valsartan 320mg tablet once daily; Drug: LCZ696; LCZ696 400mg tablet once daily

Outcome Measures

Primary Outcome Measures

1. Cumulative Sodium Excretion (Natriuresis) at Day 1 [0-6 and 0-24 hours on Day 1]

   Urine will be collected in fractions of 6 to 24 hours post-dose. From each fraction, a sample will be drawn for analysis of sodium Day 1

Secondary Outcome Measures

1. Cumulative Sodium Excretion (Natriuresis) at Day 28 [0-6 and 0-24 hours on Day 28]

   Urine will be collected in fractions of 6 to 24 hours post-dose. From each fraction, a sample will be drawn for analysis of sodium Day 28

2. Urine Volume (Diuresis) Over Time [Day -1, Day 1 & Day 28]

   Urine will be collected and volume measured in fractions of 0 to 6 hours and 0 to 24 hours Day-1, Day 1 and Day 28

3. Seated Office Blood Pressure (BP) (Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)) Over Time [Day-1, Day 14 and Day 28]

   Seated Office BP (systolic blood pressure (SBP) and diastolic blood pressure (DBP))measurements will be performed at trough(immediately prior to dosing at the clinic). Arterial BP readings will be made with an automated BP device.

4. Mean Sitting Pulse Pressure (PP) Over Time [Day-1, Day 14 and Day 28]

   Sitting mean pulse pressure rate was calculated between ambulatory SBP and DBP measurements

Eligibility Criteria

Criteria

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

Key Inclusion Criteria:

• Written informed consent must be obtained before any study assessment is performed.

• Males and females of non-childbearing potential and of legal age (at least 18 years or older as defined by local law).

• Asian patients with mild to moderate essential hypertension, untreated or currently taking antihypertensive therapy with up to two drugs.

Key Exclusion Criteria:

• Women of child-bearing potential.

• History of angioedema, drug-related or otherwise

• History of hypersensitivity to LCZ696, valsartan, 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.

• History or evidence of a secondary form of hypertension,

• Transient ischemic cerebral attack (TIA) during the 12 months prior to screening or any history of stroke.

• History of myocardial infarction, coronary bypass surgery or percutaneous coronary intervention (PCI) during 12 month prior to screening.

• Current or history of hypertensive retinopathy.

• Previous or current diagnosis of heart failure (NYHA Class II-IV).

• Clinically significant valvular heart disease at screening.

Other protocol defined inclusion/exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Anaheim	California	United States	92801
2	Novartis Investigative Site	Cypress	California	United States	90630
3	Novartis Investigative Site	Glendale	California	United States	91206
4	Novartis Investigative Site	Hong Kong	Shatin, NT	Hong Kong
5	Novartis Investigative Site	Bucheon	Gyeonggi-do	Korea, Republic of	424-717
6	Novartis Investigative Site	Koyang-si	Gyeonggi-do	Korea, Republic of	410-773
7	Novartis Investigative Site	Seoul	Korea	Korea, Republic of	110 744
8	Novartis Investigative Site	Seoul		Korea, Republic of	120-752
9	Novartis Investigative Site	Seoul		Korea, Republic of	152-703
10	Novartis Investigative Site	Singapore		Singapore	119228
11	Novartis Investigative Site	Singapore		Singapore	169609
12	Novartis Investigative Site	Taipei	Taiwan, ROC	Taiwan	112
13	Novartis Investigative Site	Taichung		Taiwan	40447
14	Novartis Investigative Site	Taipei		Taiwan	10002
15	Novartis Investigative Site	Taipei		Taiwan	114

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: NCT01681576
• Other Study ID Numbers: CLCZ696A2222
• First Posted: Sep 10, 2012
• Last Update Posted: Nov 10, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Novartis Pharmaceuticals: hypertension, salt sensitivity, valsartan, LCZ696
• Additional relevant MeSH terms: Hypertension; Hypersensitivity; Valsartan; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	Period 1: 4 weeks treatment with LCZ696 400mg QD or Valsartan 320mg, 1-2 weeks wash-out, followed by period 2, 4 weeks treatment with Valsartan 320mg QD or LCZ696 400mg QD

Arm/Group Title	LCZ696 Followed by Valsartan	Valsartan Followed by LCZ696
Arm/Group Description	Period 1: LCZ696 400mg QD for 4 weeks then washout followed by Period 2: Valsartan 320mg QD for 4 weeks	Period 1: Valsartan 320mg QD for 4 weeks then washout followed by Period 2: LCZ696 400mg QD for 4 weeks
Period Title: Period 1
STARTED	36	36
COMPLETED	34	36
NOT COMPLETED	2	0
Period Title: Period 1
STARTED	34	36
COMPLETED	30	35
NOT COMPLETED	4	1

Baseline Characteristics

Arm/Group Title	LCZ696 Followed by Valsartan	Valsartan 320mg	Total
Arm/Group Description	Period 1: LCZ696 400mg QD for 4 weeks then washout followed by Period 2: Valsartan 320mg QD for 4 weeks	Period 1: 4 weeks treatment with Valsartan 320mg QD, 1-2 weeks wash-out, followed by period 2, 4 weeks treatment with LCZ696 400mg QD	Total of all reporting groups
Overall Participants	36	36	72
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.7 (12.5)	58.9 (7.5)	57.3 (10.3)
Sex: Female, Male (Count of Participants)
Female	13 36.1%	13 36.1%	26 36.1%
Male	23 63.9%	23 63.9%	46 63.9%

Outcome Measures

1. Primary Outcome

Title	Cumulative Sodium Excretion (Natriuresis) at Day 1
Description	Urine will be collected in fractions of 6 to 24 hours post-dose. From each fraction, a sample will be drawn for analysis of sodium Day 1
Time Frame	0-6 and 0-24 hours on Day 1

Outcome Measure Data

Analysis Population Description

Pharmacodynamic PD analysis set: Patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.

Arm/Group Title	LCZ696 - ALL	Valsartan -ALL
Arm/Group Description	LCZ696 400mg QD	Valsartan 320mg QD
Measure Participants	70	67
0-6h (n=69,66)	61.26 (31.167)	37.13 (20.761)
0-24h (n=69,66)	188.87 (74.458)	138.92 (58.905)

2. Secondary Outcome

Title	Cumulative Sodium Excretion (Natriuresis) at Day 28
Description	Urine will be collected in fractions of 6 to 24 hours post-dose. From each fraction, a sample will be drawn for analysis of sodium Day 28
Time Frame	0-6 and 0-24 hours on Day 28

Outcome Measure Data

Analysis Population Description

Pharmacodynamic PD analysis set: Patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.

Arm/Group Title	LCZ696 - ALL	Valsartan - ALL
Arm/Group Description	LCZ696 400mg	Valsartan 320mg QD
Measure Participants	70	67
0-6h (n=69,66)	39.30 (18.841)	44.57 (23.479)
0-24h (n=69,66)	144.71 (51.094)	153.82 (62.449)

3. Secondary Outcome

Title	Urine Volume (Diuresis) Over Time
Description	Urine will be collected and volume measured in fractions of 0 to 6 hours and 0 to 24 hours Day-1, Day 1 and Day 28
Time Frame	Day -1, Day 1 & Day 28

Outcome Measure Data

Analysis Population Description

Pharmacodynamic PD analysis set: Patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.

Arm/Group Title	LCZ696 - ALL	Valsartan - ALL
Arm/Group Description	LCZ696 400mg	Valsartan 320mg QD
Measure Participants	70	67
Day -1 0-6h (n=70,67)	855.1 (450.28)	806.2 (462.20)
Day -1 0-24h (n=70,67)	2752.8 (722.53)	2756.2 (1010.86)
Day 1 0-6h (n=70,67)	1215.9 (475.57)	923.0 (443.65)
Day 1 0-24h (n=70,67)	3172.3 (957.70)	2813.8 (930.05)
Day 28 0-6h (n=69,66)	948.8 (415.14)	1042.7 (530.15)
Day 28 0-24h (n=69,66)	2820.0 (847.81)	3000.2 (1139.75)

4. Secondary Outcome

Title	Seated Office Blood Pressure (BP) (Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)) Over Time
Description	Seated Office BP (systolic blood pressure (SBP) and diastolic blood pressure (DBP))measurements will be performed at trough(immediately prior to dosing at the clinic). Arterial BP readings will be made with an automated BP device.
Time Frame	Day-1, Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Pharmacodynamic PD analysis set: Patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.

Arm/Group Title	LCZ696 - ALL	Valsartan - ALL
Arm/Group Description	LCZ696 400mg	Valsartan 320mg QD
Measure Participants	70	67
Day -1 Sitting SBP (n=70,67)	140.20 (13.691)	137.85 (12.703)
Day 28 Sitting SBP (n=69,66)	127.01 (12.723)	132.07 (15.195)
Day 14 Sitting DBP (n=69,66)	80.43 (7.808)	80.57 (9.246)
Day 28 Sitting DBP (n=69,66)	80.44 (7.840)	81.40 (9.276)
Day 14 Sitting SBP (n=69,66)	126.88 (12.451)	129.23 (12.784)
Day -1 Sitting DBP (n=70,67)	86.63 (8.955)	85.59 (9.299)

5. Secondary Outcome

Title	Mean Sitting Pulse Pressure (PP) Over Time
Description	Sitting mean pulse pressure rate was calculated between ambulatory SBP and DBP measurements
Time Frame	Day-1, Day 14 and Day 28

Outcome Measure Data

Analysis Population Description

Pharmacodynamic PD analysis set: Patients with any available PD data, who received any study drug and experienced no protocol deviations with relevant impact on PD data.

Arm/Group Title	LCZ696 - ALL	Valsartan - ALL
Arm/Group Description	LCZ696 400mg	Valsartan 320mg QD
Measure Participants	70	67
Day -1 Sitting mean PP (n=70,67)	63.91 (8.392)	64.92 (10.086)
Day 14 Sitting mean PP (n=69,66)	71.91 (10.370)	69.61 (8.888)
Day 28 Sitting mean PP (n=69,66)	65.21 (8.999)	63.63 (8.843)

Adverse Events

Adverse Event Reporting Description	Overall, 72 patients with salt-sensitive hypertension were randomized to one of the two crossover treatment arms. For the Safety Set: overall, 71 patients were exposed to at least one dose of LCZ696 400 mg and a total of 67 patients were exposed to at least one dose of valsartan 320 mg.
Arm/Group Title	LCZ696 400 mg QD		Valsartan 320 mg QD
Arm/Group Description	LCZ696 400 mg QD		Valsartan 320 mg QD
All Cause Mortality
	LCZ696 400 mg QD		Valsartan 320 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ696 400 mg QD		Valsartan 320 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/71 (0%)		0/67 (0%)
Other (Not Including Serious) Adverse Events
	LCZ696 400 mg QD		Valsartan 320 mg QD
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/71 (21.1%)		15/67 (22.4%)
Gastrointestinal disorders
DRY MOUTH	2/71 (2.8%)		0/67 (0%)
Infections and infestations
NASOPHARYNGITIS	2/71 (2.8%)		4/67 (6%)
Musculoskeletal and connective tissue disorders
BACK PAIN	0/71 (0%)		2/67 (3%)
FLANK PAIN	0/71 (0%)		2/67 (3%)
Nervous system disorders
DIZZINESS	5/71 (7%)		5/67 (7.5%)
HEADACHE	1/71 (1.4%)		4/67 (6%)
Renal and urinary disorders
HAEMATURIA	3/71 (4.2%)		2/67 (3%)
PYURIA	2/71 (2.8%)		0/67 (0%)
Respiratory, thoracic and mediastinal disorders
COUGH	4/71 (5.6%)		0/67 (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.