A Study of LCZ696 in Subjects With Mild and Moderate Hepatic Impairment Compared With Normal Healthy Volunteers

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01621633
• Collaborator: (none)
• Enrollment: 32
• Location: 1
• Arms: 3
• Duration (Months): 4
• Patients Per Site Per Month: 8

Study Details

Study Description

Brief Summary

This is a study to characterize the pharmacokinetics as well as safety and tolerability of a single oral dose of LCZ696 200 mg in subjects with mild and moderate hepatic impairment compared to matched healthy subjects

Condition or Disease	Intervention/Treatment	Phase
Hepatic Impairment	Drug: LCZ696	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: A Single-dose, Open-label Parallel-group Study to Assess the Pharmacokinetics of LCZ696 in Subjects With Hepatic Impairment Compared to Matched Healthy Subjects
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Jan 1, 2013
• Actual Study Completion Date: Jan 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Group 1: mild hepatic impairment LCZ696 200 mg, given as a single oral dose	Drug: LCZ696
Experimental: Group 2: moderate hepatic impairment LCZ696 200 mg, given as a single oral dose	Drug: LCZ696
Experimental: Group 3: healthy volunteers LCZ696 200 mg, given as a single oral dose. Each healthy volunteer will match in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in groups 1 and 2	Drug: LCZ696

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) [From pre-dose on Day 1 until 96h post-dose (Day 5)]

   Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing

2. Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan) [From pre-dose on Day 1 until 96h post-dose (Day 5)]

   Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing

3. Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan) [From pre-dose on Day 1 until 96h post-dose (Day 5)]

   Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing

Secondary Outcome Measures

1. Number of Participants With Adverse Events, Serious Adverse Events and Death [From the screening visit until Day 5]

   Adverse events, serious adverse events and death were monitored from screening to end of study

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• All subjects:

• Male and female subjects aged 18-75 years.

• Body weight at least 55 kg with a body mass index between 18-35 kg/m2.

• Hepatic impairment subjects:

• Mild or moderate hepatic impairment.

Exclusion Criteria:

• All subjects:

• Clinical manifestations of postural symptomatic hypotension at screening or baseline.

• History of hypersensitivity to LCZ696 or to drugs of similar classes.

• Hepatic impairment subjects:

• Hepatic impairment due to non-liver disease.

• Treatment with any vasodilator, autonomic alpha blocker or beta2 agonist within 2 weeks of dosing.

• Encephalopathyy Stage III or IV.

• Primary biliary liver cirrhosis or biliary obstruction.

• History of gastro-intestinal bleeding within 3 months prior to screening.

• Healthy subjects:

• Any surgical or medical condition which might significantly alter the distribution, or excretion of drugs, or which may jeopardize the subject in case of participation in the study.

• Use of prescription drugs, herbal supplements, and/or over-the-counter medication, dietary supplements (vitamins included) within 2 weeks prior to initial dosing.

Other protocol-defined inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Grunstadt		Germany	D-67269

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: NCT01621633
• Other Study ID Numbers: CLCZ696B2203; 2012-000983-27
• First Posted: Jun 18, 2012
• Last Update Posted: Aug 10, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by Novartis Pharmaceuticals: hepatic impairment
• Additional relevant MeSH terms: Liver Diseases; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Recruitment Details	Participants received the study treatment according to the population subset that was defined based on the severity of hepatic impairment and healthy volunteers: Group 1, subjects with mild hepatic impairment; Group 2, subjects with moderate hepatic impairment; Groups 3 and 4, healthy volunteers matching to Groups 1 and 2, respectively.

Arm/Group Title	Participants With Mild Hepatic Impairment (HI)	Participants With Moderate Hepatic Impairment (HI)	Healthy Volunteers (Mild HI Matched)	Healthy Volunteers (Moderate HI Matched)
Arm/Group Description	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2
Period Title: Overall Study
STARTED	8	8	8	8
COMPLETED	8	8	8	8
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Participants With Mild Hepatic Impairment (HI)	Participants With Moderate Hepatic Impairment (HI)	Healthy Volunteers (Mild HI Matched)	Healthy Volunteers (Moderate HI Matched)	Total
Arm/Group Description	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2	Total of all reporting groups
Overall Participants	8	8	8	8	32
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	59.1 (7.92)	57.9 (11.67)	58.9 (8.68)	60.3 (11.21)	59.0 (9.54)
Sex: Female, Male (Count of Participants)
Female	3 37.5%	1 12.5%	3 37.5%	1 12.5%	8 25%
Male	5 62.5%	7 87.5%	5 62.5%	7 87.5%	24 75%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration-time Profile From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of LCZ696 Analytes (AHU377, LBQ657, and Valsartan)
Description	Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Time Frame	From pre-dose on Day 1 until 96h post-dose (Day 5)

Outcome Measure Data

Analysis Population Description

PK analysis set: The PK analysis set included all subjects with at least one available, valid (i.e. not flagged for exclusion) PK concentration measurement, who received any study drug, and experienced no protocol deviations with relevant impact on PK data.

Arm/Group Title	Participants With Mild Hepatic Impairment (HI)	Participants With Moderate Hepatic Impairment (HI)	Healthy Volunteers (Mild HI Matched)	Healthy Volunteers (Moderate HI Matched)
Arm/Group Description	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2
Measure Participants	8	8	8	8
AHU377	2540 (1010)	6200 (2970)	1580 (390)	1740 (520)
LBQ657	118000 (37000)	173000 (99900)	77900 (14700)	83100 (14700)
Valsartan	28500 (16900)	63800 (48700)	21600 (5980)	25300 (11800)

2. Primary Outcome

Title	Area Under the Plasma Concentration-time Profile From Time Zero Extrapolated to Infinite Time [AUCinf)] of LCZ696 Analytes (AHU377, LBQ657, and Valsartan)
Description	Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Time Frame	From pre-dose on Day 1 until 96h post-dose (Day 5)

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Participants With Mild Hepatic Impairment (HI)	Participants With Moderate Hepatic Impairment (HI)	Healthy Volunteers (Mild HI Matched)	Healthy Volunteers (Moderate HI Matched)
Arm/Group Description	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2
Measure Participants	8	8	8	8
AHU377	2540 (1010)	6200 (2980)	1590 (390)	1740 (519)
LBQ657	121000 (41000)	187000 (124000)	78500 (14700)	84100 (14800)
Valsartan	28800 (16900)	65600 (50100)	21900 (5950)	26500 (12400)

3. Primary Outcome

Title	Maximum Plasma Concentration (Cmax) for LCZ696 Analytes (AHU377, LBQ657, and Valsartan)
Description	Blood samples were taken on Day 1 (treatment day) within 60 minutes prior to dosing, then, 0.5,1,1.5,2,3,4,6,8,12 hours after the dosing and on Days 2, 3, 4 and 5 post dosing
Time Frame	From pre-dose on Day 1 until 96h post-dose (Day 5)

Outcome Measure Data

Analysis Population Description

PK analysis set

Arm/Group Title	Participants With Mild Hepatic Impairment (HI)	Participants With Moderate Hepatic Impairment (HI)	Healthy Volunteers (Mild HI Matched)	Healthy Volunteers (Moderate HI Matched)
Arm/Group Description	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2
Measure Participants	8	8	8	8
AHU377	2530 (1400)	4430 (1760)	1510 (585)	1410 (445)
LBQ657	7730 (1470)	6690 (917)	7450 (1320)	6770 (1710)
Valsartan	4000 (2310)	4180 (2340)	3880 (1490)	3730 (1540)

4. Secondary Outcome

Title	Number of Participants With Adverse Events, Serious Adverse Events and Death
Description	Adverse events, serious adverse events and death were monitored from screening to end of study
Time Frame	From the screening visit until Day 5

Outcome Measure Data

Analysis Population Description

Safety set: The safety set includes all participants who received study treatment.

Arm/Group Title	Participants With Mild Hepatic Impairment (HI)	Participants With Moderate Hepatic Impairment (HI)	Healthy Volunteers (Mild HI Matched)	Healthy Volunteers (Moderate HI Matched)
Arm/Group Description	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1	LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2
Measure Participants	8	8	8	8
Adverse events (serious and non-serious)	0 0%	2 25%	0 0%	0 0%
Serious adverse events	0 0%	0 0%	0 0%	0 0%
Deaths	0 0%	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Moderate Hepatic Impaired Patients		Healthy Volunteers (Mild HI Matched)		Healthy Volunteers (Moderate HI Matched)		Participants With Mild Hepatic Impairment (HI)
Arm/Group Description	Moderate hepatic impaired patients		LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 1		LCZ696 200 mg, given as a single oral dose. Each healthy volunteer matched in race, age (±5 years), gender, weight (±15%) to an individual subject with hepatic impairment in group 2		LCZ696 200 mg, given as a single oral dose
All Cause Mortality
	Moderate Hepatic Impaired Patients		Healthy Volunteers (Mild HI Matched)		Healthy Volunteers (Moderate HI Matched)		Participants With Mild Hepatic Impairment (HI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Moderate Hepatic Impaired Patients		Healthy Volunteers (Mild HI Matched)		Healthy Volunteers (Moderate HI Matched)		Participants With Mild Hepatic Impairment (HI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Moderate Hepatic Impaired Patients		Healthy Volunteers (Mild HI Matched)		Healthy Volunteers (Moderate HI Matched)		Participants With Mild Hepatic Impairment (HI)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/8 (25%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Gastrointestinal disorders
DIARRHOEA	1/8 (12.5%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Investigations
BLOOD POTASSIUM DECREASED	1/8 (12.5%)		0/8 (0%)		0/8 (0%)		0/8 (0%)
Renal and urinary disorders
RENAL IMPAIRMENT	1/8 (12.5%)		0/8 (0%)		0/8 (0%)		0/8 (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.