Evaluation of Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01601470
• Collaborator: (none)
• Enrollment: 28
• Location: 1
• Arm: 1
• Duration (Months): 4
• Patients Per Site Per Month: 7

Study Details

Study Description

Brief Summary

This study was conducted to investigate the potential for a pharmacokinetic drug-drug interaction in support of the co-administration of LCZ696 and sildenafil.

Condition or Disease	Intervention/Treatment	Phase
Mild to Moderate Hypertension	Drug: LCZ696; Drug: Sildenafil	Phase 2

Detailed Description

This study was conducted to investigate the potential for a pharmacokinetic drug-drug interaction in patients with mild-to-moderate hypertension in support of the co-administration of LCZ696 and sildenafil.

Study Design

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Official Title: An Open Label, Three-period, Single Sequence Study to Evaluate the Pharmacokinetic Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension
• 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: Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696 , co-administered at the same time with a single dose of sildenafil.	Drug: LCZ696; LCZ696 400mg QD was administered alone for 4 days and in combination with sildenafil for 1 day; Drug: Sildenafil; Sildenafil 50 mg single dose was administered alone for 1 days and in combination with LCZ696 400mg QD for 1 day

Outcome Measures

Primary Outcome Measures

1. Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of LCZ696 Analytes [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.

2. Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan) [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmax is a mathematically-derived value from all measurements. Cmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.

3. Minimum Plasma Concentration Following Drug Administration at Steady State (Cmin,ss) of LCZ696 Analytes (AHU377, LBQ696 and Valsartan) [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmin is a mathematically-derived value from all measurements. Cmin is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.

4. Time to Reach the Maximum Concentration After Drug Administration (Tmax) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan) [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Tmax is a mathematically-derived value from all measurements. Tmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.

5. Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sildenafil and N-desmethyl-sildenafil Analytes [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.

6. Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Sildenafil and N-desmethyl-sildenafil Analytes [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.

7. Terminal Elimination Half-life (T1/2) of Sildenafil and N-desmethyl-sildenafil Analytes [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. T1/2 is a mathematically-derived value from all measurements. T1/2 is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.

8. Maximum Plasma Concentration Following Drug Administration (Cmax) of Sildenafil and N-desmethyl-sildenafil Analytes [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.

9. Time to Reach the Maximum Concentration After Drug Administration (Tmax) of Sildenafil and N-desmethyl-sildenafil Analytes [From pre-dose on day 1 until 12 hours post dose on day 8]

   The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed. 8pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.

Secondary Outcome Measures

1. Adverse Events, Serious Adverse Events and Deaths Were Monitored From Screening to End of Study [From the screening visit until 30 days past the final study assessment]

   Number of patients with adverse events, serious adverse events and death

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male subjects with mild to moderate hypertension, either treated or not currently on treatment, between age 18 and 65 years of age, and otherwise in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening.

• At screening: systolic blood pressure 120-140 mmHg on therapy, or 140-160 mmHg if untreated

• At screening: diastolic blood pressure, 70-95 mmHg on therapy, or 90-100 mmHg if untreated

• Baseline: BP ≥140/90;

Exclusion Criteria:

• Use of non-antihypertensive prescription drugs, herbal supplements, and/or over-the-counter (OTC) medication, dietary supplements (vitamins included) within two (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	Berlin		Germany	14050

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: NCT01601470
• Other Study ID Numbers: CLCZ696B2225; 2012-001632-64
• First Posted: May 18, 2012
• Last Update Posted: Oct 7, 2015
• Last Verified: Oct 1, 2015

• Keywords provided by Novartis Pharmaceuticals: LCZ696, sildenafil, pharmacokinetics, mild to moderate hypertension
• Additional relevant MeSH terms: Hypertension; Sildenafil Citrate; Sacubitril and valsartan sodium hydrate drug combination

Study Results

Participant Flow

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Period Title: Period 1 - Sildenafil
STARTED	28
PK Analysis Set	28
Safety Set	28
COMPLETED	28
NOT COMPLETED	0
Period Title: Period 1 - Sildenafil
STARTED	28
PK Analysis Set	27
Safety Set	27
COMPLETED	27
NOT COMPLETED	1
Period Title: Period 1 - Sildenafil
STARTED	27
PK Analysis Set	27
Safety Set	27
COMPLETED	27
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Overall Participants	28
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	51.8 (8.5)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	28 100%

Outcome Measures

1. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of LCZ696 Analytes
Description	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
AHU377	3700 (912)
LBQ657	147000 (31000)
valsartan	23600 (9500)

2. Primary Outcome

Title	Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
Description	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, and day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmax is a mathematically-derived value from all measurements. Cmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
AHU377	2310 (1020)
LBQ696	14000 (2420)
valsartan	3350 (1480)

3. Primary Outcome

Title	Minimum Plasma Concentration Following Drug Administration at Steady State (Cmin,ss) of LCZ696 Analytes (AHU377, LBQ696 and Valsartan)
Description	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Cmin is a mathematically-derived value from all measurements. Cmin is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
AHU377	0.0 (0.0)
LBQ657	2170 (733)
valsartan	197 (96.9)

4. Primary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
Description	The effect of co-administration of sildenafil on the pharmacokinetics of LCZ696 (analytes of LCZ696: AHU377, LBQ657 and valsartan) was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. Tmax is a mathematically-derived value from all measurements. Tmax is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
AHU377	1.00 (NA)
LBQ657	3.00
valsartan	2.00

5. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sildenafil and N-desmethyl-sildenafil Analytes
Description	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
Sildenafil	629 (303)
N-desmethyl-sildenafil	325 (143)

6. Primary Outcome

Title	Area Under the Plasma Concentration-time Curve From Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Sildenafil and N-desmethyl-sildenafil Analytes
Description	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. AUC is a mathematically-derived value from all measurements. AUC is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
Sildenafil	612 (297)
N-desmethyl-sildenafil	305 (133)

7. Primary Outcome

Title	Terminal Elimination Half-life (T1/2) of Sildenafil and N-desmethyl-sildenafil Analytes
Description	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. T1/2 is a mathematically-derived value from all measurements. T1/2 is a measure of the area under the curve that is obtained from plotting the plasma concentration by time point. All time-points were used to derive the single PK parameters.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
Sildenafil	3.84 (1.11)
N-desmethyl-sildenafil	6.20 (1.90)

8. Primary Outcome

Title	Maximum Plasma Concentration Following Drug Administration (Cmax) of Sildenafil and N-desmethyl-sildenafil Analytes
Description	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil was assessed. Blood samples were collected at pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
Sildenafil	189 (99.6)
N-desmethyl-sildenafil	84.6 (39.3)

9. Primary Outcome

Title	Time to Reach the Maximum Concentration After Drug Administration (Tmax) of Sildenafil and N-desmethyl-sildenafil Analytes
Description	The effect of co-administration of LCZ696 on the pharmacokinetics of Sildenafil and N-desmethyl-sildenafil will be assessed. 8pre-dose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose from day 1 to day 7, 24 hours post-dose from day 7, day 8 at 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12 hours post-dose. All time-points were used to mathematically derive the single PK parameter.
Time Frame	From pre-dose on day 1 until 12 hours post dose on day 8

Outcome Measure Data

Analysis Population Description

PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	27
Sildenafil	1.00 (NA)
N-desmethyl-sildenafil	1.00 (NA)

10. Secondary Outcome

Title	Adverse Events, Serious Adverse Events and Deaths Were Monitored From Screening to End of Study
Description	Number of patients with adverse events, serious adverse events and death
Time Frame	From the screening visit until 30 days past the final study assessment

Outcome Measure Data

Analysis Population Description

Safety Analysis Set: This set included participants who received at least one dose of study drug.

Arm/Group Title	Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by a wash out on Day 2. In Period 2 (study Days 3-7), participants received LCZ696 once daily. In Period 3, on study Day 8, participants received LCZ696, co-administered at the same time with a single dose of sildenafil.
Measure Participants	28
Adverse Events (Serious and non-serious)	17 60.7%
Serious Adverse Events	0 0%
Deaths	0 0%

Adverse Events

Arm/Group Title	Period 1: Sildenafil		Period 2: LCZ696		Period 3: LCZ696 + Sildenafil
Arm/Group Description	During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by wash out on Day 2.		In Period 2 (study Days 3-7), participants received LCZ696 once daily.		In Period 3, on study Day 8, participants received LCZ696 , co-administered at the same time with a single dose of sildenafil.
All Cause Mortality
	Period 1: Sildenafil		Period 2: LCZ696		Period 3: LCZ696 + Sildenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Period 1: Sildenafil		Period 2: LCZ696		Period 3: LCZ696 + Sildenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/27 (0%)		0/27 (0%)
Other (Not Including Serious) Adverse Events
	Period 1: Sildenafil		Period 2: LCZ696		Period 3: LCZ696 + Sildenafil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/28 (25%)		5/27 (18.5%)		6/27 (22.2%)
Eye disorders
EYE IRRITATION	2/28 (7.1%)		0/27 (0%)		0/27 (0%)
Gastrointestinal disorders
DIARRHOEA	0/28 (0%)		3/27 (11.1%)		1/27 (3.7%)
Nervous system disorders
DIZZINESS	0/28 (0%)		2/27 (7.4%)		3/27 (11.1%)
HEADACHE	3/28 (10.7%)		0/27 (0%)		2/27 (7.4%)
Renal and urinary disorders
POLLAKIURIA	0/28 (0%)		2/27 (7.4%)		0/27 (0%)
Respiratory, thoracic and mediastinal disorders
NASAL CONGESTION	2/28 (7.1%)		0/27 (0%)		0/27 (0%)

Limitations/Caveats

[Not Specified]

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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.