Hypertension
Conditions
Keywords
Food effect, hypertension, aliskiren
Brief summary
The purpose of this study is to evaluate the effect of food on aliskiren's efficacy, pharmacokinetics and safety following an oral dose of 300 mg, given once daily under light meal versus fasted conditions.
Interventions
DRUGAliskiren
Aliskiren 300 mg once daily
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with essential hypertension, untreated or currently taking antihypertensive therapy (monotherapy or combination therapy). * Patients with an office BP ≥ 140/90 mmHg and \< 180/110mmHg at the randomization visit and the preceding visit * Patients must have an absolute difference of ≤ 10 mmHg in both their msSBP and their msDBP between the randomization visit and the preceding visit
Exclusion criteria
* Malignant hypertension or severe hypertension (grade 3 of WHO classification; msSBP ≥180 mmHg or msDBP ≥110 mmHg) * History or evidence of a secondary form of hypertension, such as renal parenchymal hypertension, renovascular hypertension, coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, drug-induced hypertension, unilateral or bilateral renal artery stenosis, pheochromocytoma, polycystic kidney disease (PKD). * Type 1 or Type 2 diabetes mellitus with a fasting glycosylated hemoglobin (HbA1c) \> 8% * Evidence of renal impairment as determined by one of the following: serum creatinine \>1.5 x ULN or eGFR \< 30 ml/min/1.73m2 at Visit 1, a history of dialysis, or a history of nephrotic syndrome Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Systolic Blood Pressure (maSBP) | Baseline, week 8 | 24 hour ambulatory blood pressure measurement (ABPM) were taken twice, at baseline and at the end of 8 weeks. An Ambulatory Blood Pressure Monitoring device (ABPM) was attached to the non-dominant arm. The mean change of 24 hours maSBP from baseline to week 8 was estimated using an Analysis of Covariance (ANCOVA) model by using treatment, region as factors, and baseline as covariate. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients Achieving Blood Pressure Control | 8 weeks | Patients achieving blood pressure control were patients who, at week 8, had a mean sitting systolic blood pressure (msSBP)/ mean sitting diastolic blood pressure (msDBP) \< 140/90 mmHg |
| Change From Baseline (Visit 3) to End of Study (8 Weeks) in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) | Baseline, Week 8 | Sitting blood pressure (BP) was measured at trough (approximately 24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the BP was checked in both arms and the arm with higher systolic BP (SBP) was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for five minutes, systolic and diastolic blood pressures (msSBP and msDBP) were measured four times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 2 minute intervals and the mean of all four sitting blood pressure measurements was used as the average sitting office blood pressure for that visit. The analysis of covariance (ANCOVA) model used treatment, region as factors, and baseline as covariate. |
| Percentage of Patients Achieving a Successful Response in Systolic Blood Pressure Reduction | Baseline, Week 8 | Successful response in systolic blood pressure reduction at end of 8-week treatment was defined as msSBP \<140 mmHg or a reduction in msSBP ≥ 20 mmHg from baseline. |
| Pharmacokinetic (PK) of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration in Fasted vs. Fed | Week 4 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) and week 8 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) | Blood samples were collected at Week 4 and Week 8 in a subset of patients (approximately 15% of each treatment group) for PK analysis. |
| Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Diastolic Blood Pressure (maDBP) | Baseline, week 8 | 24 hour ambulatory blood pressure measurement (ABPM) were taken twice, at baseline and at the end of 8 weeks. An Ambulatory Blood Pressure Monitoring device (ABPM) was attached to the non-dominant arm. The mean change of 24 hours maDBP from baseline to week 8 was estimated using an Analysis of Covariance (ANCOVA) model by using treatment, region as factors, and baseline as covariate. |
| Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration in Fasted vs. Fed | Week 4 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) and week 8 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) | Blood samples were collected at Week 4 and Week 8 in a subset of patients (approximately 15% of each treatment group) for PK analysis. |
| Change From Baseline to Week 8 in Plasma Renin Activity (PRA) | Baseline, Week 8 | Biomarkers related to hypertension-related pathophysiology were evaluated in this study, such as plasma renin activity (PRA) . Blood samples were taken at Visit 3 (baseline) and Visit 6 (week 8).The difference between baseline and week 8 was calculated. |
| Change From Baseline to Week 8 in Plasma Renin Concentration (PRC) | Baseline, Week 8 | Biomarkers related to hypertension-related pathophysiology were evaluated in this study, such as plasma renin concentration (PRC). Blood samples were taken at Visit 3 (baseline) and Visit 6 (week 8). The difference between baseline and week 8 was calculated. |
| Number of Patients With Adverse Events, Serious Adverse Events and Death | 8 weeks | — |
| Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) in Fasted vs. Fed | Week 4 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) and week 8 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) | Blood samples were collected at Week 4 and Week 8 in a subset of patients (approximately 15% of each treatment group) for PK analysis. |
Countries
Canada, Italy, Puerto Rico, Slovakia, Spain, Taiwan, United States
Participant flow
Pre-assignment details
A total of 691 patients enrolled in the study with 590 patients randomized. 1 patient was mis-randomized and did not receive study medication, therefore 589 patients actually received study medication.
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren: Fed Aliskiren 300 mg once daily, taken 30 minutes after start of light breakfast | 296 |
| Aliskiren: Fasting Aliskiren 300 mg once daily taken after after an overnight fast | 294 |
| Total | 590 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Abnormal test procedure result(s) | 1 | 1 |
| Overall Study | Administrative problems | 0 | 1 |
| Overall Study | Adverse Event | 8 | 6 |
| Overall Study | Lost to Follow-up | 4 | 3 |
| Overall Study | Protocol Deviation | 3 | 0 |
| Overall Study | Unsatisfactory therapeutic effect | 2 | 1 |
| Overall Study | Withdrawal by Subject | 4 | 4 |
Baseline characteristics
| Characteristic | Aliskiren: Fed | Aliskiren: Fasting | Total |
|---|---|---|---|
| Age, Continuous | 55.7 Years STANDARD_DEVIATION 10.44 | 56.1 Years STANDARD_DEVIATION 11.03 | 55.9 Years STANDARD_DEVIATION 10.73 |
| Sex: Female, Male Female | 152 Participants | 126 Participants | 278 Participants |
| Sex: Female, Male Male | 144 Participants | 168 Participants | 312 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 3 / 295 | 16 / 294 |
| serious Total, serious adverse events | 4 / 295 | 2 / 294 |
Outcome results
Primary
Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Systolic Blood Pressure (maSBP)
24 hour ambulatory blood pressure measurement (ABPM) were taken twice, at baseline and at the end of 8 weeks. An Ambulatory Blood Pressure Monitoring device (ABPM) was attached to the non-dominant arm. The mean change of 24 hours maSBP from baseline to week 8 was estimated using an Analysis of Covariance (ANCOVA) model by using treatment, region as factors, and baseline as covariate.
Time frame: Baseline, week 8
Population: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with ABPM measurements at both baseline and week 8 were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren: Fed | Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Systolic Blood Pressure (maSBP) | -7.03 mmHg | Standard Error 0.5 |
| Aliskiren: Fasting | Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Systolic Blood Pressure (maSBP) | -7.79 mmHg | Standard Error 0.5 |
Secondary
Change From Baseline to Week 8 in Plasma Renin Activity (PRA)
Biomarkers related to hypertension-related pathophysiology were evaluated in this study, such as plasma renin activity (PRA) . Blood samples were taken at Visit 3 (baseline) and Visit 6 (week 8).The difference between baseline and week 8 was calculated.
Time frame: Baseline, Week 8
Population: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with both baseline and week 8 measurement for PRA are included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren: Fed | Change From Baseline to Week 8 in Plasma Renin Activity (PRA) | -0.519 ng/mL/hr | Standard Deviation 1.4016 |
| Aliskiren: Fasting | Change From Baseline to Week 8 in Plasma Renin Activity (PRA) | -1.962 ng/mL/hr | Standard Deviation 6.7419 |
Secondary
Change From Baseline to Week 8 in Plasma Renin Concentration (PRC)
Biomarkers related to hypertension-related pathophysiology were evaluated in this study, such as plasma renin concentration (PRC). Blood samples were taken at Visit 3 (baseline) and Visit 6 (week 8). The difference between baseline and week 8 was calculated.
Time frame: Baseline, Week 8
Population: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with both baseline and week 8 measurement for PRC are included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren: Fed | Change From Baseline to Week 8 in Plasma Renin Concentration (PRC) | 37.881 ng/L | Standard Deviation 63.4412 |
| Aliskiren: Fasting | Change From Baseline to Week 8 in Plasma Renin Concentration (PRC) | 50.967 ng/L | Standard Deviation 81.8987 |
Secondary
Change From Baseline (Visit 3) to End of Study (8 Weeks) in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP)
Sitting blood pressure (BP) was measured at trough (approximately 24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the BP was checked in both arms and the arm with higher systolic BP (SBP) was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for five minutes, systolic and diastolic blood pressures (msSBP and msDBP) were measured four times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 2 minute intervals and the mean of all four sitting blood pressure measurements was used as the average sitting office blood pressure for that visit. The analysis of covariance (ANCOVA) model used treatment, region as factors, and baseline as covariate.
Time frame: Baseline, Week 8
Population: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with official mean sitting blood pressure measurements both at baseline and week 8 were icluded in this analysis.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren: Fed | Change From Baseline (Visit 3) to End of Study (8 Weeks) in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) | Mean sitting SBP (msSBP) | -13.65 mmHg | Standard Error 0.85 |
| Aliskiren: Fed | Change From Baseline (Visit 3) to End of Study (8 Weeks) in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) | Mean sitting DBP (msDBP) | -8.97 mmHg | Standard Error 0.5 |
| Aliskiren: Fasting | Change From Baseline (Visit 3) to End of Study (8 Weeks) in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) | Mean sitting SBP (msSBP) | -13.98 mmHg | Standard Error 0.85 |
| Aliskiren: Fasting | Change From Baseline (Visit 3) to End of Study (8 Weeks) in Mean Sitting Systolic Blood Pressure (msSBP) and Mean Sitting Diastolic Blood Pressure (msDBP) | Mean sitting DBP (msDBP) | -8.56 mmHg | Standard Error 0.5 |
Secondary
Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Diastolic Blood Pressure (maDBP)
24 hour ambulatory blood pressure measurement (ABPM) were taken twice, at baseline and at the end of 8 weeks. An Ambulatory Blood Pressure Monitoring device (ABPM) was attached to the non-dominant arm. The mean change of 24 hours maDBP from baseline to week 8 was estimated using an Analysis of Covariance (ANCOVA) model by using treatment, region as factors, and baseline as covariate.
Time frame: Baseline, week 8
Population: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with ABPM measurements at both baseline and week 8 were included in this analysis.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren: Fed | Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Diastolic Blood Pressure (maDBP) | -4.01 mmHg | Standard Error 0.31 |
| Aliskiren: Fasting | Change From Baseline (Visit 3) to End of Study (Week 8) in Mean 24 Hour Ambulatory Diastolic Blood Pressure (maDBP) | -4.39 mmHg | Standard Error 0.31 |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events and Death
Time frame: 8 weeks
Population: Safety Set (SAF): consisted of all patients who received at least one dose of randomized study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aliskiren: Fed | Number of Patients With Adverse Events, Serious Adverse Events and Death | Any Adverse event | 73 Patients |
| Aliskiren: Fed | Number of Patients With Adverse Events, Serious Adverse Events and Death | Serious Adverse events | 4 Patients |
| Aliskiren: Fed | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
| Aliskiren: Fasting | Number of Patients With Adverse Events, Serious Adverse Events and Death | Any Adverse event | 90 Patients |
| Aliskiren: Fasting | Number of Patients With Adverse Events, Serious Adverse Events and Death | Serious Adverse events | 2 Patients |
| Aliskiren: Fasting | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 0 Patients |
Secondary
Percentage of Patients Achieving a Successful Response in Systolic Blood Pressure Reduction
Successful response in systolic blood pressure reduction at end of 8-week treatment was defined as msSBP \<140 mmHg or a reduction in msSBP ≥ 20 mmHg from baseline.
Time frame: Baseline, Week 8
Population: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with mean sitting SBP measurement at baseline and over 8 weeks were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren: Fed | Percentage of Patients Achieving a Successful Response in Systolic Blood Pressure Reduction | 54.9 Percentage of patients |
| Aliskiren: Fasting | Percentage of Patients Achieving a Successful Response in Systolic Blood Pressure Reduction | 55.8 Percentage of patients |
Secondary
Percentage of Patients Achieving Blood Pressure Control
Patients achieving blood pressure control were patients who, at week 8, had a mean sitting systolic blood pressure (msSBP)/ mean sitting diastolic blood pressure (msDBP) \< 140/90 mmHg
Time frame: 8 weeks
Population: Full Analysis Set (FAS): consisted of all randomized patients. Mis-randomized patients were excluded from the FAS. Patients with mean sitting blood pressure measurement over 8 weeks were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren: Fed | Percentage of Patients Achieving Blood Pressure Control | 44.7 Percentage of patients |
| Aliskiren: Fasting | Percentage of Patients Achieving Blood Pressure Control | 41.5 Percentage of patients |
Secondary
Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) in Fasted vs. Fed
Blood samples were collected at Week 4 and Week 8 in a subset of patients (approximately 15% of each treatment group) for PK analysis.
Time frame: Week 4 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) and week 8 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose)
Population: Pharmacokinetics set included all patients who had evaluable aliskiren concentration data with no protocol deviations that presumably affect PK results were included in the pharmacokinetic evaluations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren: Fed | Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) in Fasted vs. Fed | Week 4 (Day 28) (N= 44, 50) | 872 ng*h/mL | Standard Deviation 603 |
| Aliskiren: Fed | Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) in Fasted vs. Fed | Week 8 (Day 56) (N= 40, 51) | 1100 ng*h/mL | Standard Deviation 1620 |
| Aliskiren: Fasting | Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) in Fasted vs. Fed | Week 4 (Day 28) (N= 44, 50) | 1580 ng*h/mL | Standard Deviation 1120 |
| Aliskiren: Fasting | Pharmacokinetic of Aliskiren: The Area Under the Plasma Concentration-time Curve From Time Zero to the End of the Dosing Interval Tau (AUCtau) in Fasted vs. Fed | Week 8 (Day 56) (N= 40, 51) | 1540 ng*h/mL | Standard Deviation 1120 |
Secondary
Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration in Fasted vs. Fed
Blood samples were collected at Week 4 and Week 8 in a subset of patients (approximately 15% of each treatment group) for PK analysis.
Time frame: Week 4 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) and week 8 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose)
Population: Pharmacokinetics set included all patients who had evaluable aliskiren concentration data with no protocol deviations that presumably affect PK results were included in the pharmacokinetic evaluations.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren: Fed | Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration in Fasted vs. Fed | Week 4 (Day 28) (N=46, 52) | 2.60 Hour | Standard Deviation 1.68 |
| Aliskiren: Fed | Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration in Fasted vs. Fed | Week 8 (Day 56) (N= 42, 53) | 3.33 Hour | Standard Deviation 3.71 |
| Aliskiren: Fasting | Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration in Fasted vs. Fed | Week 4 (Day 28) (N=46, 52) | 1.71 Hour | Standard Deviation 1.45 |
| Aliskiren: Fasting | Pharmacokinetic of Aliskiren: Time to Reach the Maximum Concentration (Tmax) After Drug Administration in Fasted vs. Fed | Week 8 (Day 56) (N= 42, 53) | 1.72 Hour | Standard Deviation 3.32 |
Secondary
Pharmacokinetic (PK) of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration in Fasted vs. Fed
Blood samples were collected at Week 4 and Week 8 in a subset of patients (approximately 15% of each treatment group) for PK analysis.
Time frame: Week 4 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose) and week 8 (0, 0.5, 1, 1.5, 2, 4, 6 and 24 hrs post-dose)
Population: Pharmacokinetics set included all patients who had evaluable aliskiren concentration data with no protocol deviations that presumably affect PK results were included in the pharmacokinetic evaluations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren: Fed | Pharmacokinetic (PK) of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration in Fasted vs. Fed | Week 4 (Day 28) (N= 46, 52) | 108 ng/mL | Standard Deviation 153 |
| Aliskiren: Fed | Pharmacokinetic (PK) of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration in Fasted vs. Fed | Week 8 (Day 56) (N= 42, 53) | 102 ng/mL | Standard Deviation 139 |
| Aliskiren: Fasting | Pharmacokinetic (PK) of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration in Fasted vs. Fed | Week 4 (Day 28) (N= 46, 52) | 273 ng/mL | Standard Deviation 276 |
| Aliskiren: Fasting | Pharmacokinetic (PK) of Aliskiren: The Observed Maximum Plasma Concentration (Cmax) Following Drug Administration in Fasted vs. Fed | Week 8 (Day 56) (N= 42, 53) | 252 ng/mL | Standard Deviation 220 |