Trial Outcomes & Findings for Evaluation of Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension (NCT NCT01601470)
NCT ID: NCT01601470
Last Updated: 2015-10-07
Results Overview
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.
COMPLETED
PHASE2
28 participants
From pre-dose on day 1 until 12 hours post dose on day 8
2015-10-07
Participant Flow
Participant milestones
| Measure |
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 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 1 - Sildenafil
STARTED
|
28
|
|
Period 1 - Sildenafil
PK Analysis Set
|
28
|
|
Period 1 - Sildenafil
Safety Set
|
28
|
|
Period 1 - Sildenafil
COMPLETED
|
28
|
|
Period 1 - Sildenafil
NOT COMPLETED
|
0
|
|
Period 2 - LCZ696
STARTED
|
28
|
|
Period 2 - LCZ696
PK Analysis Set
|
27
|
|
Period 2 - LCZ696
Safety Set
|
27
|
|
Period 2 - LCZ696
COMPLETED
|
27
|
|
Period 2 - LCZ696
NOT COMPLETED
|
1
|
|
Period 3 - LCZ696+Sildenafil
STARTED
|
27
|
|
Period 3 - LCZ696+Sildenafil
PK Analysis Set
|
27
|
|
Period 3 - LCZ696+Sildenafil
Safety Set
|
27
|
|
Period 3 - LCZ696+Sildenafil
COMPLETED
|
27
|
|
Period 3 - LCZ696+Sildenafil
NOT COMPLETED
|
0
|
Reasons for withdrawal
| Measure |
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 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.
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|---|---|
|
Period 2 - LCZ696
Physician Decision
|
1
|
Baseline Characteristics
Evaluation of Drug-drug Interaction Between LCZ696 and Sildenafil in Subjects With Mild to Moderate Hypertension
Baseline characteristics by cohort
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=28 Participants
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.
|
|---|---|
|
Age, Continuous
|
51.8 Years
STANDARD_DEVIATION 8.5 • n=39 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=39 Participants
|
|
Sex: Female, Male
Male
|
28 Participants
n=39 Participants
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of LCZ696 Analytes
AHU377
|
3700 h*ng/mL
Standard Deviation 912
|
|
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of LCZ696 Analytes
LBQ657
|
147000 h*ng/mL
Standard Deviation 31000
|
|
Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval (AUCtau) of LCZ696 Analytes
valsartan
|
23600 h*ng/mL
Standard Deviation 9500
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
AHU377
|
2310 ng/mL
Standard Deviation 1020
|
|
Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
LBQ696
|
14000 ng/mL
Standard Deviation 2420
|
|
Maximum Plasma Concentration Following Drug Administration at Steady State (Cmax,ss) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
valsartan
|
3350 ng/mL
Standard Deviation 1480
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Minimum Plasma Concentration Following Drug Administration at Steady State (Cmin,ss) of LCZ696 Analytes (AHU377, LBQ696 and Valsartan)
AHU377
|
0.0 ng/mL
Standard Deviation 0.0
|
|
Minimum Plasma Concentration Following Drug Administration at Steady State (Cmin,ss) of LCZ696 Analytes (AHU377, LBQ696 and Valsartan)
LBQ657
|
2170 ng/mL
Standard Deviation 733
|
|
Minimum Plasma Concentration Following Drug Administration at Steady State (Cmin,ss) of LCZ696 Analytes (AHU377, LBQ696 and Valsartan)
valsartan
|
197 ng/mL
Standard Deviation 96.9
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Time to Reach the Maximum Concentration After Drug Administration (Tmax) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
AHU377
|
1.00 hours
Full Range NA • Interval 0.5 to 4.0
|
|
Time to Reach the Maximum Concentration After Drug Administration (Tmax) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
LBQ657
|
3.00 hours
Interval 1.5 to 6.0
|
|
Time to Reach the Maximum Concentration After Drug Administration (Tmax) of LCZ696 Analytes (AHU377, LBQ657 and Valsartan)
valsartan
|
2.00 hours
Interval 1.5 to 4.0
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sildenafil and N-desmethyl-sildenafil Analytes
Sildenafil
|
629 h*ng/mL
Standard Deviation 303
|
|
Area Under the Plasma Concentration-time Curve From Time Zero to Infinity (AUCinf) of Sildenafil and N-desmethyl-sildenafil Analytes
N-desmethyl-sildenafil
|
325 h*ng/mL
Standard Deviation 143
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
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
Sildenafil
|
612 h*ng/mL
Standard Deviation 297
|
|
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
N-desmethyl-sildenafil
|
305 h*ng/mL
Standard Deviation 133
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Terminal Elimination Half-life (T1/2) of Sildenafil and N-desmethyl-sildenafil Analytes
Sildenafil
|
3.84 hours
Standard Deviation 1.11
|
|
Terminal Elimination Half-life (T1/2) of Sildenafil and N-desmethyl-sildenafil Analytes
N-desmethyl-sildenafil
|
6.20 hours
Standard Deviation 1.90
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Maximum Plasma Concentration Following Drug Administration (Cmax) of Sildenafil and N-desmethyl-sildenafil Analytes
Sildenafil
|
189 ng/mL
Standard Deviation 99.6
|
|
Maximum Plasma Concentration Following Drug Administration (Cmax) of Sildenafil and N-desmethyl-sildenafil Analytes
N-desmethyl-sildenafil
|
84.6 ng/mL
Standard Deviation 39.3
|
PRIMARY outcome
Timeframe: From pre-dose on day 1 until 12 hours post dose on day 8Population: PK Analysis Set (Period 3): This set included participants with evaluable PK data and without any protocol deviations which could impact the PK data.
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.
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=27 Participants
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.
|
|---|---|
|
Time to Reach the Maximum Concentration After Drug Administration (Tmax) of Sildenafil and N-desmethyl-sildenafil Analytes
Sildenafil
|
1.00 hours
Full Range NA • Interval 0.5 to 3.0
|
|
Time to Reach the Maximum Concentration After Drug Administration (Tmax) of Sildenafil and N-desmethyl-sildenafil Analytes
N-desmethyl-sildenafil
|
1.00 hours
Full Range NA • Interval 0.5 to 3.0
|
SECONDARY outcome
Timeframe: From the screening visit until 30 days past the final study assessmentPopulation: Safety Analysis Set: This set included participants who received at least one dose of study drug.
Number of patients with adverse events, serious adverse events and death
Outcome measures
| Measure |
Period 1:Sildenafil;Period 2:LCZ696;Period 3:LCZ696+Sildenafil
n=28 Participants
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.
|
|---|---|
|
Adverse Events, Serious Adverse Events and Deaths Were Monitored From Screening to End of Study
Adverse Events (Serious and non-serious)
|
17 Participants
|
|
Adverse Events, Serious Adverse Events and Deaths Were Monitored From Screening to End of Study
Serious Adverse Events
|
0 Participants
|
|
Adverse Events, Serious Adverse Events and Deaths Were Monitored From Screening to End of Study
Deaths
|
0 Participants
|
Adverse Events
Period 1: Sildenafil
Period 2: LCZ696
Period 3: LCZ696 + Sildenafil
Serious adverse events
Adverse event data not reported
Other adverse events
| Measure |
Period 1: Sildenafil
n=28 participants at risk
During Treatment Period 1, on study Day 1, participants received a single dose of sildenafil followed by wash out on Day 2.
|
Period 2: LCZ696
n=27 participants at risk
In Period 2 (study Days 3-7), participants received LCZ696 once daily.
|
Period 3: LCZ696 + Sildenafil
n=27 participants at risk
In Period 3, on study Day 8, participants received LCZ696 , co-administered at the same time with a single dose of sildenafil.
|
|---|---|---|---|
|
Eye disorders
EYE IRRITATION
|
7.1%
2/28
|
0.00%
0/27
|
0.00%
0/27
|
|
Gastrointestinal disorders
DIARRHOEA
|
0.00%
0/28
|
11.1%
3/27
|
3.7%
1/27
|
|
Nervous system disorders
DIZZINESS
|
0.00%
0/28
|
7.4%
2/27
|
11.1%
3/27
|
|
Nervous system disorders
HEADACHE
|
10.7%
3/28
|
0.00%
0/27
|
7.4%
2/27
|
|
Renal and urinary disorders
POLLAKIURIA
|
0.00%
0/28
|
7.4%
2/27
|
0.00%
0/27
|
|
Respiratory, thoracic and mediastinal disorders
NASAL CONGESTION
|
7.1%
2/28
|
0.00%
0/27
|
0.00%
0/27
|
Additional Information
Study Director
Novartis Pharmaceuticals
Results disclosure agreements
- Principal investigator is a sponsor employee 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.
- Publication restrictions are in place
Restriction type: OTHER