Hypertension
Conditions
Keywords
Pediatric hypertension, primary hypertension, secondary hypertension
Brief summary
This double-blind 8 week study will evaluate dose response, efficacy (blood pressure lowering effect) and safety of aliskiren in children 6 - 17 years old with hypertension at low, mid and high weight-based doses. The low dose ranges from 6.25 mg to 25 mg of aliskiren, the mid dose ranges from 37.5 mg to 150 mg of aliskiren and the high dose ranges from 150 mg to 600 mg of aliskiren. This study is being conducted to support monotherapy registration of aliskiren for the treatment of hypertension in children 6-17 years of age.
Interventions
DRUGAliskiren (6.25/12.5/25 mg)
Aliskiren dispensing capsules containing minitablets (3.125 mg per minitablet). For the low dose arm, participants used one or more of the 6.25 mg capsule (containing 2 minitablets) once daily to reach the body-weight stratified dose of aliskiren.
DRUGAliskiren (37.5/75/150 mg)
Aliskiren dispensing capsules containing minitablets (3.125 mg per minitablet). For the medium dose arm, participants used one or more of the 37.5 mg capsule (containing 12 minitablets) once daily to reach the body- weight stratified dose of aliskiren.
DRUGAliskiren (150/300/600 mg)
Aliskiren dispensing capsules containing minitablets (3.125 mg per minitablet). For the high dose arm, participants used one or more of the 150 mg capsule (containing 48 minitablets) once daily to reach the body- weight stratified dose of aliskiren.
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Documented diagnosis of hypertension as defined in the NHLBI 4th Report, 2004 * msSBP (mean of 3 measurements) must be ≥ 95th percentile for age, gender and height, at Visit 2 (randomization) measurement as defined by the NHLBI 4th Report, 2004
Exclusion criteria
* Patient receiving immunosuppressant medication (e.g. cyclosporine, MMF, etc) other than oral/topical steroids, for any medical condition * Current diagnosis of heart failure (NYHA Class II-IV) or history of cardiomyopathy or obstructive valvular disease * msSBP ≥ 25% above the 95th percentile * Second or third degree heart block without a pacemaker * AST/SGOT or ALT/SGPT \>3 times the upper limit of the reference range * Total bilirubin \> 2 times the upper limit of the reference range * Creatinine clearance \< 30 mL/min/1.73m² (calculated using Modified Schwartz formula to estimate glomerular filtration rate \[GFR\]), based on the serum creatinine concentration obtained at the screening visit) * WBC count \< 3000/mm³ Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Endpoint (Phase 1) | Baseline to endpoint (Week 4 or Last observation carried forward (LOCF)) | Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit. |
| Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2) | Week 4 to endpoint (Week 8 or LOCF) | Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Endpoint (Phase 1) | Baseline to endpoint (Week 4 or LOCF) | Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit. |
| Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2) | Week 4 to endpoint (Week 8 or LOCF) | Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit. |
| Change From Baseline in Mean Arterial Pressure (MAP) at Endpoint (Phase 1) | Baseline to endpoint (Week 4 or LOCF) | MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of diastolic blood pressure (DBP) and one third of difference between systolic blood pressure (SBP) and DBP i.e. MAP = DBP+1/3\*(SBP-DBP). |
| Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2) | Week 4 to endpoint (Week 8 or LOCF) | MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of DBP and one third of difference between SBP and DBP i.e. MAP = DBP+1/3\*(SBP-DBP). |
| Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1) | Baseline up to Week 4 | Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. |
| Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1) | Baseline to endpoint (Week 4 or LOCF) | Ambulatory Blood Pressure Monitoring (ABPM) was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. The participants who were selected for this evaluation wore the ABPM device for 24 hours, returned to the clinic upon completion of the 24-hour monitoring period for removal of device and BP assessments. The ABPM device was pre-set to collect readings every 20 minutes. Mean hourly systolic and diastolic blood pressure were calculated for each participant at post dosing 1 - 24 hours. |
| Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1) | Baseline to Week 4 | ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Day time was defined as the average of the hourly means between 6 am and 10 pm while the night time mean was the average of the hourly means between 10 pm and 6 am. |
| Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1) | Baseline to endpoint (Week 4 or LOCF) | ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Dippers were defined as those participants in whom there was a decrease in mean night time (6pm - 6am) ABPM more than or equal to (≥ ) 10% as compared to average daytime (6am -6pm) ABPM. |
| Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1) | Baseline to endpoint (Week 4 or LOCF) | ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Non-dippers were defined as those participants in whom there was a decrease in mean night time ABPM less than 10% as compared to average daytime ABPM. |
| Percentage of Participants Achieving a Positive Treatment Response at Endpoint (Phase 1) | Baseline to endpoint (Week 4 or LOCF) | Treatment responders were defined as participants with msSBP less than 95th percentile (for age, gender and height) or a 7 mmHg decrease in msSBP from the baseline. |
| Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | From Week 4 to Week 8 | AEs were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards. |
Countries
Belgium, Germany, Guatemala, Hungary, Poland, Puerto Rico, Slovakia, Turkey (Türkiye), United States
Participant flow
Recruitment details
The study was conducted at 51 centers in 8 countries.
Pre-assignment details
A total of 334 participants were screened and placed in screening phase of single blind placebo washout period for up to a maximum of three weeks. Out of 334, 268 participants were randomized in Phase 1 including 1 mis-randomized participants who did not receive any medication. Therefore total of 267 was enrolled in this study
Participants by arm
| Arm | Count |
|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) Participants received body-weight stratified dose of aliskiren capsules (6.25/12.5/25 mg) once daily. Participants whose body weight greater than or equal to (≥) 20 kilogram (kg) to less than (\< ) 50 kg received 6.25 mg; ≥50 kg and \< 80 kg received 12.5 mg and ≥ 80 kg and less than or equal to (≤)150 kg received 25 mg of aliskiren. | 108 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) Participants received body-weight stratified dose of aliskiren capsules (37.5/75/150 mg) once daily. Participants whose body weight ≥ 20 kg to \< 50 kg received 37.5 mg; ≥50 kg and \< 80 kg received 75 mg and ≥ 80 kg and ≤ 150 kg received 150 mg of aliskiren. | 54 |
| Phase 1: Aliskiren High (150/300/600 mg) Participants received body-weight stratified dose of aliskiren capsules (150/300/600 mg) once daily. Participants whose body weight ≥ 20 kg to \< 50 kg received 150 mg; ≥50 kg and \< 80 kg received 300 mg and ≥ 80 kg and ≤ 150 kg received 600 mg of aliskiren. | 105 |
| Total | 267 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Dose Response Phase (Phase 1) | Adverse Event | 0 | 0 | 1 |
| Dose Response Phase (Phase 1) | Protocol Violation | 0 | 1 | 1 |
| Dose Response Phase (Phase 1) | Unsatisfactory therapeutic effect | 1 | 0 | 0 |
| Dose Response Phase (Phase 1) | Withdrawal by Participants | 0 | 2 | 1 |
| Placebo-controlled Withdrawal (Phase 2) | Adverse Event | 0 | 0 | 2 |
| Placebo-controlled Withdrawal (Phase 2) | Lost to Follow-up | 1 | 0 | 0 |
| Placebo-controlled Withdrawal (Phase 2) | Withdrawal by Subject | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Phase 1: Aliskiren Mid (37.5/75/150 mg) | Phase 1: Aliskiren High (150/300/600 mg) | Total |
|---|---|---|---|---|
| Age, Continuous | 11.9 years STANDARD_DEVIATION 3.27 | 11.6 years STANDARD_DEVIATION 3.29 | 11.8 years STANDARD_DEVIATION 3.5 | 11.8 years STANDARD_DEVIATION 3.36 |
| Age, Customized Adolescents 12 - 17 years | 59 participants | 26 participants | 54 participants | 139 participants |
| Age, Customized Children 6 - 11 years | 49 participants | 28 participants | 51 participants | 128 participants |
| Sex: Female, Male Female | 35 Participants | 17 Participants | 39 Participants | 91 Participants |
| Sex: Female, Male Male | 73 Participants | 37 Participants | 66 Participants | 176 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 11 / 108 | 6 / 54 | 14 / 105 | 8 / 50 | 7 / 30 | 9 / 50 | 7 / 57 | 3 / 21 | 5 / 52 |
| serious Total, serious adverse events | 0 / 108 | 0 / 54 | 1 / 105 | 0 / 50 | 0 / 30 | 2 / 50 | 0 / 57 | 0 / 21 | 0 / 52 |
Outcome results
Primary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Endpoint (Phase 1)
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit.
Time frame: Baseline to endpoint (Week 4 or Last observation carried forward (LOCF))
Population: The primary analysis was performed on the Full Analysis Set (FAS), defined as all participants who received at least one dose of study treatment and had at least one post-baseline assessment for primary efficacy. Here, Number of participants analyzed signifies participants evaluable for msSBP at Week 4 or LOCF for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Endpoint (Phase 1) | -5.54 millimeter(s) of mercury (mmHg) | Standard Error 0.78 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Endpoint (Phase 1) | -5.42 millimeter(s) of mercury (mmHg) | Standard Error 1.331 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) at Endpoint (Phase 1) | -9.03 millimeter(s) of mercury (mmHg) | Standard Error 1.008 |
Primary
Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2)
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sSBP measurements were used as the average sitting office blood pressure for that visit.
Time frame: Week 4 to endpoint (Week 8 or LOCF)
Population: The primary analysis was performed on the FAS population.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2) | -0.53 mmHg | Standard Error 0.947 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2) | -0.64 mmHg | Standard Error 1.256 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2) | -2.59 mmHg | Standard Error 1.119 |
| Phase 2: Placebo Mid | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2) | -2.9 mmHg | Standard Error 1.481 |
| Phase 2: Aliskiren High (150/300/600 mg) | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2) | -1.97 mmHg | Standard Error 1.071 |
| Phase 2: Placebo High | Change in Mean Sitting Systolic Blood Pressure (msSBP) From Week 4 to Endpoint (Phase 2) | 1.11 mmHg | Standard Error 1.185 |
Secondary
Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1)
ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Dippers were defined as those participants in whom there was a decrease in mean night time (6pm - 6am) ABPM more than or equal to (≥ ) 10% as compared to average daytime (6am -6pm) ABPM.
Time frame: Baseline to endpoint (Week 4 or LOCF)
Population: Analysis was performed in subset of FAS participants from selected centers who consented to undergo ABPM at baseline and at Week 4 or LOCF. Here, Number of participants analyzed signifies participants evaluable for this outcome measure at Week 4 or LOCF for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1) | MADBP | -0.6 mmHg | Standard Deviation 5.78 |
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1) | MASBP | -1.2 mmHg | Standard Deviation 6.18 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1) | MADBP | -3.6 mmHg | Standard Deviation 4.19 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1) | MASBP | -4.6 mmHg | Standard Deviation 5.47 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1) | MASBP | -6 mmHg | Standard Deviation 6.19 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Dipper Participants at Endpoint (Phase 1) | MADBP | -5.3 mmHg | Standard Deviation 5.55 |
Secondary
Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1)
ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Non-dippers were defined as those participants in whom there was a decrease in mean night time ABPM less than 10% as compared to average daytime ABPM.
Time frame: Baseline to endpoint (Week 4 or LOCF)
Population: Analysis was performed in subset of FAS participants from selected centers who consented to undergo ABPM at baseline and at Week 4 or LOCF. Here, Number of participants analyzed signifies participants evaluable for this outcome measure at Week 4 or LOCF for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1) | MADBP | -2.3 mmHg | Standard Deviation 4.05 |
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1) | MASBP | -2.6 mmHg | Standard Deviation 7.21 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1) | MADBP | -6.7 mmHg | Standard Deviation 4.45 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1) | MASBP | -9.3 mmHg | Standard Deviation 5.54 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1) | MASBP | -5.2 mmHg | Standard Deviation 9.39 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Blood Pressure (MABP) in Non--Dipper Participants at Endpoint (Phase 1) | MADBP | -5.2 mmHg | Standard Deviation 7.3 |
Secondary
Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1)
Ambulatory Blood Pressure Monitoring (ABPM) was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. The participants who were selected for this evaluation wore the ABPM device for 24 hours, returned to the clinic upon completion of the 24-hour monitoring period for removal of device and BP assessments. The ABPM device was pre-set to collect readings every 20 minutes. Mean hourly systolic and diastolic blood pressure were calculated for each participant at post dosing 1 - 24 hours.
Time frame: Baseline to endpoint (Week 4 or LOCF)
Population: Analysis was performed in subset of FAS participants from selected centers who consented to undergo ABPM at baseline and at Week 4 or LOCF. Here 'Number of participants analyzed' signifies those participants evaluable for this measure at specified time points for each arm, respectively.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1) | MASBP (n=58, 29, 65) | -1.6 mmHg | Standard Deviation 6.48 |
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1) | MADBP (n=58, 29, 65) | -1.1 mmHg | Standard Deviation 5.33 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1) | MADBP (n=58, 29, 65) | -4.4 mmHg | Standard Deviation 4.41 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1) | MASBP (n=58, 29, 65) | -5.9 mmHg | Standard Deviation 5.8 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1) | MASBP (n=58, 29, 65) | -5.8 mmHg | Standard Deviation 7.15 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Systolic and Diastolic Blood Pressure (MASBP and MADBP) at Endpoint (Phase 1) | MADBP (n=58, 29, 65) | -4.9 mmHg | Standard Deviation 6.05 |
Secondary
Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1)
ABPM was performed over a 24-hour period using an automatic ABPM device to record the blood pressure as per study defined criteria. Day time was defined as the average of the hourly means between 6 am and 10 pm while the night time mean was the average of the hourly means between 10 pm and 6 am.
Time frame: Baseline to Week 4
Population: Analysis was performed in subset of FAS participants from selected centers who consented to undergo ABPM at baseline and at Week 4. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1) | Day time (n= 58, 29, 65) | -2.72 mmHg | Standard Error 1.031 |
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1) | Night time (n= 57, 29, 65) | -2.55 mmHg | Standard Error 1.035 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1) | Day time (n= 58, 29, 65) | -6.76 mmHg | Standard Error 1.381 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1) | Night time (n= 57, 29, 65) | -4.67 mmHg | Standard Error 1.381 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1) | Day time (n= 58, 29, 65) | -6.56 mmHg | Standard Error 0.95 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Ambulatory Systolic Blood Pressure (MASBP) During Day and Night at Week 4 (Phase 1) | Night time (n= 57, 29, 65) | -4.9 mmHg | Standard Error 0.95 |
Secondary
Change From Baseline in Mean Arterial Pressure (MAP) at Endpoint (Phase 1)
MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of diastolic blood pressure (DBP) and one third of difference between systolic blood pressure (SBP) and DBP i.e. MAP = DBP+1/3\*(SBP-DBP).
Time frame: Baseline to endpoint (Week 4 or LOCF)
Population: The analysis was performed on the FAS population. Here, Number of participants analyzed signifies participants evaluable for MAP at Week 4 (or LOCF) for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Arterial Pressure (MAP) at Endpoint (Phase 1) | -3.65 mmHg | Standard Error 0.613 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Arterial Pressure (MAP) at Endpoint (Phase 1) | -4.51 mmHg | Standard Error 1.064 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Arterial Pressure (MAP) at Endpoint (Phase 1) | -7.23 mmHg | Standard Error 0.711 |
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Endpoint (Phase 1)
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit.
Time frame: Baseline to endpoint (Week 4 or LOCF)
Population: The analysis was performed on the FAS population. Here, Number of participants analyzed signifies participants evaluable for msDBP at Week 4 or LOCF for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Endpoint (Phase 1) | -2.71 mmHg | Standard Error 0.67 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Endpoint (Phase 1) | -4.05 mmHg | Standard Error 1.116 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) at Endpoint (Phase 1) | -6.33 mmHg | Standard Error 0.793 |
Secondary
Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2)
MAP was defined as the average arterial pressure during a single cardiac cycle. The MAP was measured as sum of DBP and one third of difference between SBP and DBP i.e. MAP = DBP+1/3\*(SBP-DBP).
Time frame: Week 4 to endpoint (Week 8 or LOCF)
Population: The analysis was performed on the FAS population. The 'n' signifies those participants evaluable for this measure at specified time points for each group, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2) | 0.67 mmHg | Standard Error 0.864 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2) | -0.93 mmHg | Standard Error 0.964 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2) | -0.27 mmHg | Standard Error 1.239 |
| Phase 2: Placebo Mid | Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2) | 0.05 mmHg | Standard Error 1.14 |
| Phase 2: Aliskiren High (150/300/600 mg) | Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2) | -0.41 mmHg | Standard Error 0.885 |
| Phase 2: Placebo High | Change in Mean Arterial Pressure (MAP) From Week 4 to Endpoint (Phase 2) | 1.37 mmHg | Standard Error 0.918 |
Secondary
Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2)
Sitting blood pressure was measured using a calibrated standard sphygmomanometer after the participants remained in sitting position for 5 minutes at clinic during the visit. The repeat sitting measurements were made at 1-2 minute intervals and the mean of three sDBP measurements were used as the average sitting office blood pressure for that visit.
Time frame: Week 4 to endpoint (Week 8 or LOCF)
Population: The analysis was performed on the FAS population. Here, Number of participants analyzed signifies participants evaluable for msDBP at Week 8 or LOCF for each arm, respectively.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2) | 1.27 mmHg | Standard Error 1.025 |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2) | -1.08 mmHg | Standard Error 1.012 |
| Phase 1: Aliskiren High (150/300/600 mg) | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2) | 0.89 mmHg | Standard Error 1.502 |
| Phase 2: Placebo Mid | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2) | 1.52 mmHg | Standard Error 1.248 |
| Phase 2: Aliskiren High (150/300/600 mg) | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2) | 0.37 mmHg | Standard Error 1.052 |
| Phase 2: Placebo High | Change in Mean Sitting Diastolic Blood Pressure (msDBP) From Week 4 to Endpoint (Phase 2) | 1.51 mmHg | Standard Error 1.009 |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1)
Adverse events (AEs) were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events (SAEs) were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.
Time frame: Baseline up to Week 4
Population: The analysis was performed on the Safety Sets (SAF), SAF is all participants who received at least one dose of study treatment during phase 1 (baseline to week 4)
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1) | AEs | 30 participants |
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1) | SAEs | 0 participants |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1) | AEs | 14 participants |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1) | SAEs | 0 participants |
| Phase 1: Aliskiren High (150/300/600 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1) | AEs | 37 participants |
| Phase 1: Aliskiren High (150/300/600 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Baseline to Week 4 (Phase 1) | SAEs | 1 participants |
Secondary
Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2)
AEs were defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. SAEs were defined as any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgement of investigators represent significant hazards.
Time frame: From Week 4 to Week 8
Population: The analysis was performed on the SAF which included all participants who received at least one dose of study treatment during phase 2 (week 4 to week 8).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | SAEs | 0 participants |
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | AEs | 18 participants |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | SAEs | 0 participants |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | AEs | 22 participants |
| Phase 1: Aliskiren High (150/300/600 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | AEs | 10 participants |
| Phase 1: Aliskiren High (150/300/600 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | SAEs | 0 participants |
| Phase 2: Placebo Mid | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | SAEs | 0 participants |
| Phase 2: Placebo Mid | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | AEs | 5 participants |
| Phase 2: Aliskiren High (150/300/600 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | SAEs | 2 participants |
| Phase 2: Aliskiren High (150/300/600 mg) | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | AEs | 21 participants |
| Phase 2: Placebo High | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | SAEs | 0 participants |
| Phase 2: Placebo High | Number of Participants With Adverse Events and Serious Adverse Events From Week 4 to Week 8 (Phase 2) | AEs | 17 participants |
Secondary
Percentage of Participants Achieving a Positive Treatment Response at Endpoint (Phase 1)
Treatment responders were defined as participants with msSBP less than 95th percentile (for age, gender and height) or a 7 mmHg decrease in msSBP from the baseline.
Time frame: Baseline to endpoint (Week 4 or LOCF)
Population: The analysis was performed on the FAS population. Here, Number of participants analyzed signifies participants evaluable for this outcome measure at Week 4 or LOCF for each arm, respectively.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1: Aliskiren Low (6.25/12.5/25 mg) | Percentage of Participants Achieving a Positive Treatment Response at Endpoint (Phase 1) | 50.9 Percentage of participants |
| Phase 1: Aliskiren Mid (37.5/75/150 mg) | Percentage of Participants Achieving a Positive Treatment Response at Endpoint (Phase 1) | 58.5 Percentage of participants |
| Phase 1: Aliskiren High (150/300/600 mg) | Percentage of Participants Achieving a Positive Treatment Response at Endpoint (Phase 1) | 69.2 Percentage of participants |