Safety and Tolerability and Efficacy of LCZ696 in Japanese Hypertensive Patients With Renal Dysfunction

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01593787
• Collaborator: (none)
• Enrollment: 32
• Locations: 13
• Arms: 3
• Duration (Months): 10
• Patients Per Site: 2.5
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This study assessed the safety, tolerability, and efficacy of LCZ696 in hypertensive patients with renal dysfunction.

Condition or Disease	Intervention/Treatment	Phase
Hypertension With Renal Dysfunction	Drug: LCZ696	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Open Label Study for Evaluation of the Safety, Tolerability and Efficacy of 8-week Treatment With LCZ696 in Japanese Hypertensive Patients With Renal Dysfunction
• Study Start Date: May 1, 2012
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LCZ696 100 mg All participants were started on LCZ696 100 mg once daily on day 1.	Drug: LCZ696; 100 mg, 200 mg, 400 mg tablets.
Experimental: LCZ696 200 mg All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	Drug: LCZ696; 100 mg, 200 mg, 400 mg tablets.
Experimental: LCZ696 400 mg All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	Drug: LCZ696; 100 mg, 200 mg, 400 mg tablets.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Reported Adverse Events (Total Adverse Events, Serious Adverse Events and Death) [8 weeks]

   Percentage of patients with total adverse events, serious adverse events and death were reported.

Secondary Outcome Measures

1. Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 8 [baseline, 8 weeks]

   Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurements.

2. Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 8 [baseline, 8 weeks]

3. Percentage of Participants Achieving a Successful BP Control at Week 8 [8 weeks]

   A successful BP control was defined as msSBP <130 mmHg and msDBP <80 mmHg

4. Percentage of Participants Achieving SBP Control at Week 8 [8 weeks]

   SBP control was defined as msSBP <130 mmHg.

5. Percentage of Participants Achieving DBP Control at Week 8 [8 weeks]

   DBP control was defined as msDBP <80 mmHg.

6. Percentage of Participants Achieving a Successful Response Rate in msSBP at Week 8 [8 weeks]

   Successful response rate was defined as msSBP <130 mmHg or a reduction of ≥20 mmHg from baseline

7. Percentage of Participants Achieving a Successful Response Rate in msDBP at Week 8 [8 weeks]

   Successful response rate was defined as msDBP <80 mmHg or a reduction of ≥10 mmHg from baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Renal findings: Hypertensive patients with renal dysfunction and stable renal condition at least 4 weeks before screening visit.

• Satisfy office msSBP ≥140 mmHg and <180 mmHg at baseline.

Exclusion Criteria:

• Patients show msDBP ≥110 mmHg and/or msSBP ≥180 mmHg.

• History of angioedema, drug-related or otherwise, as reported by the patient.

• Any other following renal disorder:

• Patients show eGFR < 15mL/min/1.73m^2

• Patients on dialysis

• Patients who previously entered a LCZ696 study and had been randomized or enrolled into the active drug treatment epoch.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Sapporo-city	Hokkaido	Japan	063-0842
2	Novartis Investigative Site	Sapporo	Hokkaido	Japan	003-0026
3	Novartis Investigative Site	Sapporo	Hokkaido	Japan	003-0825
4	Novartis Investigative Site	Aira-city	Kagoshima	Japan	899-5431
5	Novartis Investigative Site	Kawasaki-city	Kanagawa	Japan	210-0852
6	Novartis Investigative Site	Yokohama-city	Kanagawa	Japan	231-0023
7	Novartis Investigative Site	Sendai-city	Miyagi	Japan	980-8574
8	Novartis Investigative Site	Kurashiki	Okayama	Japan	701-0192
9	Novartis Investigative Site	Fujimino	Saitama	Japan	356-0053
10	Novartis Investigative Site	Hachioji-city	Tokyo	Japan	192-0918
11	Novartis Investigative Site	Minato-ku	Tokyo	Japan	108-0075
12	Novartis Investigative Site	Shinagawa-ku	Tokyo	Japan	141-0032
13	Novartis Investigative Site	Osaka		Japan	536-0008

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

• Ito S, Satoh M, Tamaki Y, Gotou H, Charney A, Okino N, Akahori M, Zhang J. Safety and efficacy of LCZ696, a first-in-class angiotensin receptor neprilysin inhibitor, in Japanese patients with hypertension and renal dysfunction. Hypertens Res. 2015 Apr;38(4):269-75. doi: 10.1038/hr.2015.1. Epub 2015 Feb 19.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT01593787
• Other Study ID Numbers: CLCZ696A1304
• First Posted: May 8, 2012
• Last Update Posted: Aug 13, 2015
• Last Verified: Aug 1, 2015

• Keywords provided by Novartis Pharmaceuticals: Hypertension; Renal dysfunction; LCZ696
• Additional relevant MeSH terms: Renal Insufficiency; Hypertension; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.
Period Title: Overall Study
STARTED	6	8	18
COMPLETED	5	8	18
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	Total of all reporting groups
Overall Participants	6	8	18	32
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	69.0 (5.10)	71.3 (8.80)	62.3 (9.04)	65.8 (9.12)
Sex: Female, Male (Count of Participants)
Female	2 33.3%	4 50%	2 11.1%	8 25%
Male	4 66.7%	4 50%	16 88.9%	24 75%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Reported Adverse Events (Total Adverse Events, Serious Adverse Events and Death)
Description	Percentage of patients with total adverse events, serious adverse events and death were reported.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Safety Set: This set included all participants who received at least one dose of LCZ696. AE analysis was determined by actual treatment, i.e. the LCZ696 dose on the day in which the corresponding summary was targeting. Other safety analysis was determined by the maximum treatment.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	32	26	18	32
Adverse events (serious and non-serious)	31.3 521.7%	0 0%	27.8 154.4%	43.8 136.9%
Serious Adverse Events	0 0%	0 0%	0 0%	0 0%
Deaths	0 0%	0 0%	0 0%	0 0%

2. Secondary Outcome

Title	Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Week 8
Description	Sitting BP measurements were performed at screening through the end of study at every visit. Four separate sitting BP were obtained with a full two-minute interval between measurements.
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set (FAS): This set included all participants who entered the treatment epoch. Patients who were not qualified to enter the treatment epoch were excluded from the FAS provided those participants did not receive LCZ696.

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	6	8	18	32
Mean (Standard Deviation) [mmHg]	-19.71 (12.314)	-27.19 (10.557)	-17.79 (10.701)	-20.50 (11.329)

3. Secondary Outcome

Title	Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Week 8
Time Frame	baseline, 8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	6	8	18	32
Mean (Standard Deviation) [mmHg]	-7.17 (4.690)	-9.94 (7.557)	-7.99 (6.385)	-8.32 (6.308)

4. Secondary Outcome

Title	Percentage of Participants Achieving a Successful BP Control at Week 8
Description	A successful BP control was defined as msSBP <130 mmHg and msDBP <80 mmHg
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	6	8	18	32
Number [Percentage of Participants]	66.7 1111.7%	37.5 468.8%	5.6 31.1%	25.0 78.1%

5. Secondary Outcome

Title	Percentage of Participants Achieving SBP Control at Week 8
Description	SBP control was defined as msSBP <130 mmHg.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	6	8	18	32
Number [Percentage of participants]	66.7 1111.7%	50.0 625%	44.4 246.7%	50.0 156.3%

6. Secondary Outcome

Title	Percentage of Participants Achieving DBP Control at Week 8
Description	DBP control was defined as msDBP <80 mmHg.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	6	8	18	32
Number [Percentage of participants]	83.3 1388.3%	62.5 781.3%	27.8 154.4%	46.9 146.6%

7. Secondary Outcome

Title	Percentage of Participants Achieving a Successful Response Rate in msSBP at Week 8
Description	Successful response rate was defined as msSBP <130 mmHg or a reduction of ≥20 mmHg from baseline
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	6	8	18	32
Number [Percentage of participants]	66.7 1111.7%	75.0 937.5%	50.0 277.8%	59.4 185.6%

8. Secondary Outcome

Title	Percentage of Participants Achieving a Successful Response Rate in msDBP at Week 8
Description	Successful response rate was defined as msDBP <80 mmHg or a reduction of ≥10 mmHg from baseline.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

FAS

Arm/Group Title	LCZ696 100 mg	LCZ696 200 mg	LCZ696 400 mg	Total LCZ696
Arm/Group Description	All participants were started on LCZ696 100 mg once daily on day 1.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 2 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 200 mg.	All participants were started on LCZ696 100 mg once daily on day 1. For participants who received LCZ696 200 mg and did not achieve msDBP <80 mmHg and msSBP <130 mmHg at or after week 4 and had no signs of safety concerns at specified visits during the treatment epoch, the LCZ696 dose was increased to LCZ696 400 mg.	All participants who received LCZ696
Measure Participants	6	8	18	32
Number [Percentage of participants]	83.3 1388.3%	87.5 1093.8%	61.1 339.4%	71.9 224.7%

Adverse Events

Arm/Group Title	LCZ 100 mg		LCZ 400 mg		Total LCZ696		LCZ 200 mg
Arm/Group Description	LCZ 100 mg		LCZ 400 mg		All participants who received LCZ696		LCZ 200 mg
All Cause Mortality
	LCZ 100 mg		LCZ 400 mg		Total LCZ696		LCZ 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	LCZ 100 mg		LCZ 400 mg		Total LCZ696		LCZ 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/18 (0%)		0/32 (0%)		0/26 (0%)
Other (Not Including Serious) Adverse Events
	LCZ 100 mg		LCZ 400 mg		Total LCZ696		LCZ 200 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/32 (15.6%)		5/18 (27.8%)		9/32 (28.1%)		0/26 (0%)
Cardiac disorders
SUPRAVENTRICULAR EXTRASYSTOLES	0/32 (0%)		1/18 (5.6%)		1/32 (3.1%)		0/26 (0%)
Gastrointestinal disorders
DYSPEPSIA	0/32 (0%)		1/18 (5.6%)		1/32 (3.1%)		0/26 (0%)
TOOTHACHE	0/32 (0%)		1/18 (5.6%)		1/32 (3.1%)		0/26 (0%)
Infections and infestations
NASOPHARYNGITIS	5/32 (15.6%)		1/18 (5.6%)		6/32 (18.8%)		0/26 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	0/32 (0%)		1/18 (5.6%)		1/32 (3.1%)		0/26 (0%)
Skin and subcutaneous tissue disorders
PRURITUS	0/32 (0%)		1/18 (5.6%)		1/32 (3.1%)		0/26 (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.