Hypertension
Conditions
Keywords
Hypertension, Type II Diabetes, Aliskiren, Valsartan,, Systolic blood pressure, Diastolic blood pressure,, Stage II, Combination
Brief summary
The purpose of the study was to evaluate the blood pressure (BP)-lowering efficacy of the combination of aliskiren and valsartan, as initial therapy, compared to valsartan monotherapy in Type II Diabetic patients with Stage II hypertension.
Detailed description
When protocol Amendment 2 was released, there were patients who had already been randomized into the study. These patients were included in the trial prior to making changes to the eligibility criteria. Thus, the study contains 2 distinct cohorts. Cohort 1 contains those patients who had already been randomized, and had been deemed eligible based on the original inclusion/exclusion criteria, prior to Amendment 2. No new patients were randomized to Cohort 1. Cohort 2 contains patients who were randomized, having been found eligible based on the revised inclusion/exclusion criteria, after Amendment 2. Differences in the inclusion and exclusion criteria are indicated below.
Interventions
DRUGAliskiren
Aliskiren 150 mg tablet
DRUGValsartan
Valsartan 160 mg capsules
Placebo for Aliskiren 150 mg tablets
DRUGPlacebo for Valsartan
Placebo for Valsartan 160 mg capsules
Sponsors
Novartis
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients who are eligible and able to participate in the study, and who give written informed consent before any assessment is performed. * Men or women 18 years and older. * Patients with Type 2 diabetes mellitus with an HbA1c ≤ 9 % at visit 1 and on a stable anti-diabetic regimen not including insulin or stable diet and exercise for at least 4 weeks prior to visit 1. Cohort 1: * Patients with Stage 2 systolic hypertension, defined as having a MSSBP ≥160 mmHg and \<200 mmHg at Visit 5 (randomization). * Patients who have been newly diagnosed with hypertension or who have not received antihypertensive medication for at least 4 weeks (28 days) prior to Visit 1 must have MSSBP ≥ 160 mmHg and \< 200 mmHg at Visit 1, otherwise, they will be considered screen failures. * Patients receiving antihypertensive medication must have a MSSBP of ≥150 mmHg and \<200 mmHg at Study Visit 1, otherwise they will be considered screen failures. Cohort 2: * Patients must also have had a mean 8-hour daytime ambulatory systolic blood pressure (ASBP) ≥140 mmHg AND mean 8-hour daytime ambulatory diastolic blood pressure (ADBP) ≥90 mmHg at Visit 5 (randomization). * Hypertensive patients with MSSBP ≥150 mmHg and but \<200 mmHg AND MSDBP ≥95 but \<120 mmHg at Visit 5 (randomization). * Patients who had been newly diagnosed with hypertension or who had not received antihypertensive medication for at least 4 weeks (28 days) prior to Visit 1 must have had MSSBP ≥150 mmHg but \<200 mmHg and MSDBP ≥95 but \<120 mmHg at Visit 1, otherwise, they were considered screen failures.
Exclusion criteria
* Office blood pressure measured by cuff (MSSBP ≥200 mmHg or MSDBP ≥120 mmHg). * History or evidence of secondary hypertension of any etiology. * Refractory hypertension, defined as having uncontrolled BP (≥140/90 mmHg) while receiving 3 antihypertensive medications at the maximum approved dose of each drug, one of which must be a diuretic. * Patients treated with more than 3 antihypertensive medications (each component of a combination drug counts individually). * Type 2 diabetes mellitus currently requiring insulin treatment. * modification of diet in renal disease (MDRD) estimated glomerular filtration rate (eGFR) \< 60 mL/min/1.73m2 * Serum sodium less than lower limit of normal, serum potassium \< 3.5 mEq/L or ≥ 5.3 mEq/L at Visit 1. * Known Keith-Wagener grade III or IV hypertensive retinopathy. Cohort 1: \- Patients with known diabetic retinopathy (eg, having a history of laser therapy for diabetic retinopathy) or diabetic neuropathy (eg, receiving medication for diabetic neuropathy). Cohort 2: \- Patients with known diabetic retinopathy or diabetic neuropathy and/or having a history of treatment for either. Other protocol-defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean 24-hour Ambulatory Systolic Blood Pressure (MASBP) at Week 8 | baseline, week 8 | The 24-hour ambulatory systolic blood pressure was evaluated at baseline (Week 0) and post-baseline visits. The mean hourly systolic blood pressure was calculated at post-dosing hours 1-24 for each patient. The MASBP for each patient was calculated by averaging the patient's available hourly means for post-dosing hours 1-24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (MADBP) at Week 8 | baseline, week 8 | The 24-hour ambulatory diastolic blood pressure was evaluated at baseline (Week 0) and post-baseline visits. The mean hourly diastolic blood pressure was calculated at post-dosing hours 1-24 for each patient. The MADBP for each patient was calculated by averaging the patient's available hourly means for post-dosing hours 1-24. |
| Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (MAPP) at Week 8 | baseline, week 8 | The 24-hour ambulatory pulse pressure was evaluated at baseline (Week 0) and post-baseline visits. |
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) | Baseline, week 8 | Sitting blood pressure was measured at trough (24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the arm in which the highest sitting diastolic blood pressure was found was the arm 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 were measured 3 times using the standard mercury sphygmomanometer. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting office blood pressure for that visit. |
| Change From Baseline in Mean Sitting Pulse Pressure (MSPP) at Week 8 | baseline, week 8 | At each visit, the pulse rate was measured for 30 seconds just prior to the first sitting blood pressure measurement. |
| Percentage of Patients Achieving Blood Pressure Control | 8 weeks | Blood pressure control was defined as MSSBP/MSDBP \<140/90 mmHg. Percentage of patients achieving of blood pressure control at the corresponding visit was reported |
| Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) | Baseline, week 8 | Sitting blood pressure was measured at trough (24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the arm in which the highest sitting diastolic blood pressure was found was the arm 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 were measured 3 times using the standard mercury sphygmomanometer. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting office blood pressure for that visit. |
| Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | Baseline, week 8 | — |
| Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | Baseline, week 8 | — |
| Change From Baseline in Plasma Aldosterone at Week 8 | Baseline, week 8 | — |
| Number of Patients With Adverse Events, Serious Adverse Events and Death | 8 weeks | Adverse events are 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 are 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 judgment of investigators represent significant hazards. |
| Percentage of Responders | Baseline, Week 8 | Responders were defined as patients with MSSBP \<130 mmHg or a reduction from baseline in MSSBP of \>20 mmHg.Percentage of responders achieving a response at the corresponding visit was reported. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Combination Therapy: Aliskiren + Valsartan To adequately blind the study, patients were required to take a total of 4 tablets/capsules a day (2 tablets and 2 capsules of study drug per day)for 8 weeks. 1 tablet of Aliskiren 150 mg + 1 tablet of placebo Aliskiren 150 mg + 1 capsule of Valsartan 160 mg + 1 capsule of placebo Valsartan 160 mg daily for 2 weeks. Forced titrated to: 2 tablets of Aliskiren 150 mg + 2 capsules of Valsartan 160 mg daily for 6 weeks | 574 |
| Monotherapy: Valsartan To adequately blind the study, patients were required to take a total of 4 tablets/capsules a day (2 tablets and 2 capsules of study drug per day) for 8 weeks. 1 capsule of Valsartan 160 mg + 1 capsule of placebo Valsartan 160 mg + 2 tablets of placebo Aliskiren 150 mg daily for 2 weeks. Forced titrated to: 2 capsules of Valsartan 160 mg + 2 tablets of placebo Aliskiren 150 mg daily for 6 weeks. | 565 |
| Total | 1,139 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Problem | 1 | 0 |
| Overall Study | Adverse Event | 14 | 9 |
| Overall Study | Death | 1 | 1 |
| Overall Study | Lost to Follow-up | 8 | 14 |
| Overall Study | Protocol deviation | 16 | 13 |
| Overall Study | Randomized in error | 0 | 1 |
| Overall Study | Unsatisfactory therapeutic effect | 17 | 23 |
| Overall Study | Withdrawal by Subject | 20 | 24 |
Baseline characteristics
| Characteristic | Combination Therapy: Aliskiren + Valsartan | Monotherapy: Valsartan | Total |
|---|---|---|---|
| Age Continuous | 55.0 years STANDARD_DEVIATION 9.3 | 55.2 years STANDARD_DEVIATION 9.6 | 55.1 years STANDARD_DEVIATION 9.44 |
| Sex: Female, Male Female | 233 Participants | 244 Participants | 477 Participants |
| Sex: Female, Male Male | 341 Participants | 321 Participants | 662 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 34 / 574 | 36 / 565 |
| serious Total, serious adverse events | 9 / 574 | 9 / 565 |
Outcome results
Primary
Change From Baseline in Mean 24-hour Ambulatory Systolic Blood Pressure (MASBP) at Week 8
The 24-hour ambulatory systolic blood pressure was evaluated at baseline (Week 0) and post-baseline visits. The mean hourly systolic blood pressure was calculated at post-dosing hours 1-24 for each patient. The MASBP for each patient was calculated by averaging the patient's available hourly means for post-dosing hours 1-24.
Time frame: baseline, week 8
Population: Full Analysis Set 2 (FAS 2) with ambulatory blood pressure monitoring (ABPM)- Consists of all patients in Cohort 2 to whom study treatments were assigned through randomization and who had both valid baseline and post-baseline ambulatory blood pressure monitoring (ABPM)assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Mean 24-hour Ambulatory Systolic Blood Pressure (MASBP) at Week 8 | -15.3 mmHg | Standard Deviation 14.62 |
| Monotherapy: Valsartan | Change From Baseline in Mean 24-hour Ambulatory Systolic Blood Pressure (MASBP) at Week 8 | -11.5 mmHg | Standard Deviation 14.75 |
Secondary
Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (MADBP) at Week 8
The 24-hour ambulatory diastolic blood pressure was evaluated at baseline (Week 0) and post-baseline visits. The mean hourly diastolic blood pressure was calculated at post-dosing hours 1-24 for each patient. The MADBP for each patient was calculated by averaging the patient's available hourly means for post-dosing hours 1-24.
Time frame: baseline, week 8
Population: Full Analysis Set 2 (FAS 2) with ambulatory blood pressure monitoring (ABPM)- Consists of all patients in Cohort 2 to whom study treatments were assigned through randomization and who had both valid baseline and post-baseline ambulatory blood pressure monitoring (ABPM)assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (MADBP) at Week 8 | -9.2 mmHg | Standard Deviation 8.8 |
| Monotherapy: Valsartan | Change From Baseline in Mean 24-hour Ambulatory Diastolic Blood Pressure (MADBP) at Week 8 | -6.7 mmHg | Standard Deviation 8.82 |
Secondary
Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (MAPP) at Week 8
The 24-hour ambulatory pulse pressure was evaluated at baseline (Week 0) and post-baseline visits.
Time frame: baseline, week 8
Population: Full Analysis Set 2 (FAS 2) with ambulatory blood pressure monitoring (ABPM)- Consists of all patients in Cohort 2 to whom study treatments were assigned through randomization and who had both valid baseline and post-baseline ambulatory blood pressure monitoring (ABPM)assessments.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (MAPP) at Week 8 | -6.1 mmHg | Standard Deviation 8.58 |
| Monotherapy: Valsartan | Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (MAPP) at Week 8 | -4.7 mmHg | Standard Deviation 8.26 |
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP)
Sitting blood pressure was measured at trough (24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the arm in which the highest sitting diastolic blood pressure was found was the arm 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 were measured 3 times using the standard mercury sphygmomanometer. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting office blood pressure for that visit.
Time frame: Baseline, week 8
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Patients with baseline and week 8 data were included in this analysis. Last-observation-carried-forward (LOCF) approach was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) | -11.0 mmHg | Standard Deviation 10.58 |
| Monotherapy: Valsartan | Change From Baseline in Mean Sitting Diastolic Blood Pressure (MSDBP) | -8.3 mmHg | Standard Deviation 10.6 |
Secondary
Change From Baseline in Mean Sitting Pulse Pressure (MSPP) at Week 8
At each visit, the pulse rate was measured for 30 seconds just prior to the first sitting blood pressure measurement.
Time frame: baseline, week 8
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Patients with baseline and week 8 data were included in this analysis. Last-observation-carried-forward (LOCF) approach was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Mean Sitting Pulse Pressure (MSPP) at Week 8 | -10.8 mmHg | Standard Deviation 13.46 |
| Monotherapy: Valsartan | Change From Baseline in Mean Sitting Pulse Pressure (MSPP) at Week 8 | -9.9 mmHg | Standard Deviation 13.83 |
Secondary
Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP)
Sitting blood pressure was measured at trough (24 hours ± 3 hours post dose) and recorded at all study visits. At the first study visit, the arm in which the highest sitting diastolic blood pressure was found was the arm 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 were measured 3 times using the standard mercury sphygmomanometer. The repeat sitting measurements were made at 1-2 minute intervals and the mean of these 3 sitting blood pressure measurements was used as the average sitting office blood pressure for that visit.
Time frame: Baseline, week 8
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Patients with baseline and week 8 data were included in this analysis. Last-observation-carried-forward (LOCF) approach was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) | -21.7 mmHg | Standard Deviation 18.7 |
| Monotherapy: Valsartan | Change From Baseline in Mean Sitting Systolic Blood Pressure (MSSBP) | -18.2 mmHg | Standard Deviation 18.06 |
Secondary
Change From Baseline in Plasma Aldosterone at Week 8
Time frame: Baseline, week 8
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Patients with baseline and week 8 assessments were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Plasma Aldosterone at Week 8 | -21.957 pmol/L | Standard Deviation 115.251 |
| Monotherapy: Valsartan | Change From Baseline in Plasma Aldosterone at Week 8 | -22.562 pmol/L | Standard Deviation 123.343 |
Secondary
Change From Baseline in Plasma Renin Activity (PRA) at Week 8
Time frame: Baseline, week 8
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Patients with baseline and week 8 assessments were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | 1.056 ng/mL/hr | Standard Deviation 4.966 |
| Monotherapy: Valsartan | Change From Baseline in Plasma Renin Activity (PRA) at Week 8 | 0.879 ng/mL/hr | Standard Deviation 4.646 |
Secondary
Change From Baseline in Plasma Renin Concentration (PRC) at Week 8
Time frame: Baseline, week 8
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Patients with baseline and week 8 assessments were included in this analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | 68.592 ng/L | Standard Deviation 209.544 |
| Monotherapy: Valsartan | Change From Baseline in Plasma Renin Concentration (PRC) at Week 8 | 124.721 ng/L | Standard Deviation 489.719 |
Secondary
Number of Patients With Adverse Events, Serious Adverse Events and Death
Adverse events are 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 are 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 judgment of investigators represent significant hazards.
Time frame: 8 weeks
Population: Safety Set - Consisted of all patients who received at least one dose of double-blind trial medication. Patients were analyzed according to the treatment that they received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Number of Patients With Adverse Events, Serious Adverse Events and Death | Adverse Events | 202 Patients |
| Combination Therapy: Aliskiren + Valsartan | Number of Patients With Adverse Events, Serious Adverse Events and Death | Serious Adverse events | 9 Patients |
| Combination Therapy: Aliskiren + Valsartan | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 1 Patients |
| Monotherapy: Valsartan | Number of Patients With Adverse Events, Serious Adverse Events and Death | Adverse Events | 182 Patients |
| Monotherapy: Valsartan | Number of Patients With Adverse Events, Serious Adverse Events and Death | Serious Adverse events | 9 Patients |
| Monotherapy: Valsartan | Number of Patients With Adverse Events, Serious Adverse Events and Death | Death | 1 Patients |
Secondary
Percentage of Patients Achieving Blood Pressure Control
Blood pressure control was defined as MSSBP/MSDBP \<140/90 mmHg. Percentage of patients achieving of blood pressure control at the corresponding visit was reported
Time frame: 8 weeks
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Number of patients with data at each visit were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Percentage of Patients Achieving Blood Pressure Control | 39.9 Percentage of patients |
| Monotherapy: Valsartan | Percentage of Patients Achieving Blood Pressure Control | 32.7 Percentage of patients |
Secondary
Percentage of Responders
Responders were defined as patients with MSSBP \<130 mmHg or a reduction from baseline in MSSBP of \>20 mmHg.Percentage of responders achieving a response at the corresponding visit was reported.
Time frame: Baseline, Week 8
Population: Combined FAS included all randomized patients in Cohort 1 (FAS 1) and all randomized patients in Cohort 2 who had a valid baseline assessment of 24-hour ambulatory systolic blood pressure measurement (FAS 2). Patients with baseline and week 8 assessments were included in this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Combination Therapy: Aliskiren + Valsartan | Percentage of Responders | 61.9 Percentage of patients |
| Monotherapy: Valsartan | Percentage of Responders | 53.8 Percentage of patients |