Hypertension
Conditions
Keywords
aliskiren, pediatric, hypertension, pharmacokinetics (PK), pharmacodynamics (PD), plasma renin activity, mini-tablet formulation
Brief summary
This first open-label study in a pediatric population was designed to evaluate aliskiren safety and pharmacokinetics after single and multiple dosing in 6-17 year old children with hypertension.
Interventions
DRUGAliskiren 3.125 mini-tablets
Oral mini-tablets (3.125 mg) of aliskiren once each morning
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Male or female, 6-17 years of age * Documented history of hypertension as defined in National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents (2004) * Must be ≥ 21.0 kg and ≤ 100.0 kg at randomization * Able to safely wash out previous antihypertensive therapy for 1-2 weeks
Exclusion criteria
* Body weight of \< 21 kg (45 lbs) or \> 100 kg (220 lbs) * Inability to discontinue prior antihypertensive medication as required during the washout period * Any clinically significant abnormalities or clinically noteworthy abnormal laboratory values * Renal artery stenosis * Current diagnosis of heart failure (NYHA Class II-IV) * msSBP ≥ 25% above the 95th percentile for age, gender, and height at Visit 2 * Second or third degree heart block with or without a pacemaker * Atrial fibrillation or atrial flutter at Visit 1, or potentially life threatening or any symptomatic arrhythmia during the 12 months prior to Visit 1 * Evidence of current symptomatic valvular disease Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1 and Day 8 | Blood samples (1 mL) for pharmacokinetic (PK) evaluation were drawn pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 hours following administration of aliskiren on Day 1 and Day 8. The pre-dose PK evaluations were collected in a fasted state (7-12 hours without food or beverage except water). PK parameters were calculated from plasma concentration-time data and actual recorded sampling times for each patient, using non-compartmental methods with the software program WinNonlin Pro v5.2. |
| Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1 and Day 8 | Blood samples (1 mL) for pharmacokinetic (PK) evaluation were drawn pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 hours following administration of aliskiren on Day 1 and Day 8. The pre-dose PK evaluations were collected in a fasted state (7-12 hours without food or beverage except water). PK parameters were calculated from plasma concentration-time data and actual recorded sampling times for each patient, using non-compartmental methods with the software program WinNonlin Pro v5.2. |
| Apparent Plasma Clearance (CL/F) at Day 8 in 6-11 and 12-17 Year Old Patients | Day 8 | Blood samples (1 mL) for pharmacokinetic (PK) evaluation were drawn pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 hours following administration of aliskiren on Day 1 and Day 8. The pre-dose PK evaluations were collected in a fasted state (7-12 hours without food or beverage except water). PK parameters were calculated from plasma concentration-time data and actual recorded sampling times for each patient, using non-compartmental methods with the software program WinNonlin Pro v5.2. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Baseline to 2 and 10 hours post-dose on Day 1; pre-dose, 2, 10, and 24 hours post-dose on Day 8-9 | Blood samples (2 mL) for pharmacodynamics evaluation of plasma renin activity were drawn pre-dose and at 2 and 10 hours following the dose of study medication on Day 1 and at pre-dose and at 2, 10, and 24 hours post-dose on Day 8-9. |
| Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | Baseline to end of treatment (Day 9) | Blood pressure (BP) measurements were made with a mercury sphygmomanometer or an automated blood pressure measuring device. Sitting BP was measured 3 times at 2-3 minute intervals after the patient had been sitting for 5 minutes. Means of the 3 measurements were calculated. A negative change in BP indicates lowered BP. |
Countries
Belgium, Brazil, Hungary, Poland, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren 2 mg/kg Patients received aliskiren 2 mg/kg of their body weight orally once daily at approximately 8 AM. | 19 |
| Aliskiren 6 mg/kg Patients received aliskiren 6 mg/kg of their body weight orally once daily at approximately 8 AM. | 20 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Aliskiren 2 mg/kg | Aliskiren 6 mg/kg | Total |
|---|---|---|---|
| Age Continuous | 12.2 years STANDARD_DEVIATION 3.12 | 11.8 years STANDARD_DEVIATION 3.78 | 12.0 years STANDARD_DEVIATION 3.44 |
| Age, Customized 12-17 years old | 9 participants | 10 participants | 19 participants |
| Age, Customized 6-11 years old | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 10 Participants | 8 Participants | 18 Participants |
| Sex: Female, Male Male | 9 Participants | 12 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 10 / 19 | 7 / 20 |
| serious Total, serious adverse events | 0 / 19 | 1 / 20 |
Outcome results
Primary
Apparent Plasma Clearance (CL/F) at Day 8 in 6-11 and 12-17 Year Old Patients
Blood samples (1 mL) for pharmacokinetic (PK) evaluation were drawn pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 hours following administration of aliskiren on Day 1 and Day 8. The pre-dose PK evaluations were collected in a fasted state (7-12 hours without food or beverage except water). PK parameters were calculated from plasma concentration-time data and actual recorded sampling times for each patient, using non-compartmental methods with the software program WinNonlin Pro v5.2.
Time frame: Day 8
Population: Pharmacokinetic population: All patients who had evaluable aliskiren concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 2 mg/kg | Apparent Plasma Clearance (CL/F) at Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 6-11 years old, n=9, 10 | 9694.0 mL/h/kg | Standard Deviation 8704.71 |
| Aliskiren 2 mg/kg | Apparent Plasma Clearance (CL/F) at Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 12-17 years old, n=9, 10 | 5388.1 mL/h/kg | Standard Deviation 5580.55 |
| Aliskiren 6 mg/kg | Apparent Plasma Clearance (CL/F) at Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 6-11 years old, n=9, 10 | 3905.4 mL/h/kg | Standard Deviation 2628.52 |
| Aliskiren 6 mg/kg | Apparent Plasma Clearance (CL/F) at Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 12-17 years old, n=9, 10 | 3539.0 mL/h/kg | Standard Deviation 1587.49 |
Primary
Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients
Blood samples (1 mL) for pharmacokinetic (PK) evaluation were drawn pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 hours following administration of aliskiren on Day 1 and Day 8. The pre-dose PK evaluations were collected in a fasted state (7-12 hours without food or beverage except water). PK parameters were calculated from plasma concentration-time data and actual recorded sampling times for each patient, using non-compartmental methods with the software program WinNonlin Pro v5.2.
Time frame: Day 1 and Day 8
Population: Pharmacokinetic population: All patients who had evaluable aliskiren concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 2 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 6-11 years old, n=10, 10 | 278.3 h*ng/mL | Standard Deviation 237.29 |
| Aliskiren 2 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 6-11 years old, n=9, 10 | 403.6 h*ng/mL | Standard Deviation 326.76 |
| Aliskiren 2 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 12-17 years old, n=9, 10 | 390.9 h*ng/mL | Standard Deviation 264.5 |
| Aliskiren 2 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 12-17 years old, n=9, 10 | 847.2 h*ng/mL | Standard Deviation 803.44 |
| Aliskiren 6 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 12-17 years old, n=9, 10 | 2087.0 h*ng/mL | Standard Deviation 999.1 |
| Aliskiren 6 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 6-11 years old, n=10, 10 | 1231.0 h*ng/mL | Standard Deviation 728.46 |
| Aliskiren 6 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 12-17 years old, n=9, 10 | 1808.7 h*ng/mL | Standard Deviation 806.78 |
| Aliskiren 6 mg/kg | Area Under the Plasma Concentration-time Curve (AUC0-τ) in One Dosing Interval (24 h) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 6-11 years old, n=9, 10 | 1959.9 h*ng/mL | Standard Deviation 821.43 |
Primary
Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients
Blood samples (1 mL) for pharmacokinetic (PK) evaluation were drawn pre-dose and at 0.5, 1, 1.5, 2, 3, 4, 6, 10, and 24 hours following administration of aliskiren on Day 1 and Day 8. The pre-dose PK evaluations were collected in a fasted state (7-12 hours without food or beverage except water). PK parameters were calculated from plasma concentration-time data and actual recorded sampling times for each patient, using non-compartmental methods with the software program WinNonlin Pro v5.2.
Time frame: Day 1 and Day 8
Population: Pharmacokinetic population: All patients who had evaluable aliskiren concentration data.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 2 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 6-11 years old, n=10, 10 | 76.8 ng/ml | Standard Deviation 78.21 |
| Aliskiren 2 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 6-11 years old, n=9, 10 | 82.2 ng/ml | Standard Deviation 97.85 |
| Aliskiren 2 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 12-17 years old, n=9, 10 | 136.5 ng/ml | Standard Deviation 132.57 |
| Aliskiren 2 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 12-17 years old, n=9, 10 | 278.7 ng/ml | Standard Deviation 357.54 |
| Aliskiren 6 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 12-17 years old, n=9, 10 | 485.7 ng/ml | Standard Deviation 300.58 |
| Aliskiren 6 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 6-11 years old, n=10, 10 | 393.3 ng/ml | Standard Deviation 377.37 |
| Aliskiren 6 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 1: 12-17 years old, n=9, 10 | 424.3 ng/ml | Standard Deviation 188.79 |
| Aliskiren 6 mg/kg | Maximum Plasma Concentration (Cmax) at Day 1 and Day 8 in 6-11 and 12-17 Year Old Patients | Day 8: 6-11 years old, n=9, 10 | 397.1 ng/ml | Standard Deviation 187.06 |
Secondary
Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients
Blood pressure (BP) measurements were made with a mercury sphygmomanometer or an automated blood pressure measuring device. Sitting BP was measured 3 times at 2-3 minute intervals after the patient had been sitting for 5 minutes. Means of the 3 measurements were calculated. A negative change in BP indicates lowered BP.
Time frame: Baseline to end of treatment (Day 9)
Population: Full Analysis Set (FAS): All randomized patients, excluding mis-randomized patients.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 2 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msSBP: 6-11 years old, n=10, 10 | -4.5 mmHg | Standard Deviation 14.63 |
| Aliskiren 2 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msSBP: 12-17 years old,n=9, 10 | -7.6 mmHg | Standard Deviation 9.07 |
| Aliskiren 2 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msDBP: 6-11 years old, n=10, 10 | -1.7 mmHg | Standard Deviation 4.69 |
| Aliskiren 2 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msDBP: 12-17 years old, n=9, 10 | -5.3 mmHg | Standard Deviation 8.78 |
| Aliskiren 6 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msDBP: 12-17 years old, n=9, 10 | -5.8 mmHg | Standard Deviation 8 |
| Aliskiren 6 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msSBP: 6-11 years old, n=10, 10 | -7.7 mmHg | Standard Deviation 11.76 |
| Aliskiren 6 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msDBP: 6-11 years old, n=10, 10 | 0.0 mmHg | Standard Deviation 8.87 |
| Aliskiren 6 mg/kg | Change in Mean Sitting Systolic and Diastolic Blood Pressure (msSBP and msDBP) From Baseline to the End of Treatment (Day 9) in 6-11 and 12-17 Year Old Patients | msSBP: 12-17 years old,n=9, 10 | -7.7 mmHg | Standard Deviation 9.38 |
Secondary
Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9
Blood samples (2 mL) for pharmacodynamics evaluation of plasma renin activity were drawn pre-dose and at 2 and 10 hours following the dose of study medication on Day 1 and at pre-dose and at 2, 10, and 24 hours post-dose on Day 8-9.
Time frame: Baseline to 2 and 10 hours post-dose on Day 1; pre-dose, 2, 10, and 24 hours post-dose on Day 8-9
Population: Full Analysis Set (FAS): All randomized patients, excluding mis-randomized patients. Data was not available for all patients at all time points. For each time point, n = the number of subjects for whom data was available for each treatment group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren 2 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 1: 2 h post-dose, n=15, 15 | -1.8 ng/mL/h | Standard Deviation 1.62 |
| Aliskiren 2 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 1: 10 h post-dose, n=14, 13 | -1.8 ng/mL/h | Standard Deviation 1.73 |
| Aliskiren 2 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8: pre-dose, n=14, 15 | -1.3 ng/mL/h | Standard Deviation 1.77 |
| Aliskiren 2 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8: 2 h post-dose, n=11, 14 | -1.4 ng/mL/h | Standard Deviation 1.6 |
| Aliskiren 2 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8: 10 h post dose, n=13, 15 | -1.7 ng/mL/h | Standard Deviation 1.81 |
| Aliskiren 2 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8-9: 24 h post dose, n=13, 15 | -1.5 ng/mL/h | Standard Deviation 1.82 |
| Aliskiren 6 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8: 10 h post dose, n=13, 15 | -3.8 ng/mL/h | Standard Deviation 6.41 |
| Aliskiren 6 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 1: 2 h post-dose, n=15, 15 | -4.0 ng/mL/h | Standard Deviation 6.68 |
| Aliskiren 6 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8: 2 h post-dose, n=11, 14 | -3.6 ng/mL/h | Standard Deviation 6.79 |
| Aliskiren 6 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 1: 10 h post-dose, n=14, 13 | -3.8 ng/mL/h | Standard Deviation 6.79 |
| Aliskiren 6 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8-9: 24 h post dose, n=13, 15 | -3.6 ng/mL/h | Standard Deviation 6.46 |
| Aliskiren 6 mg/kg | Change in Plasma Renin Activity From Baseline on Day 1, Day 8, and Day 9 | Day 8: pre-dose, n=14, 15 | -3.5 ng/mL/h | Standard Deviation 5.91 |