Hypertension, Diabetes Mellitus
Conditions
Keywords
Hypertension, diabetes mellitus, aliskiren, hydrochlorothiazide, systolic blood pressure, diastolic blood pressure, amlodipine, stage 2
Brief summary
The purpose of the study is to evaluate the blood pressure lowering effect and safety of aliskiren in combination with Hydrochlorothiazide (HCTZ) given to diabetic patients with stage 2 systolic hypertension (mean sitting systolic blood pressure (msSBP) ≥ 160 mm Hg and \< 200 mm Hg).
Interventions
DRUGAmlodipine
Amlodipine 5 mg for 1 week followed by Amlodipine 10 mg for 7 weeks
Hydrochlorothiazide 12.5 mg for 1 week followed by Hydrochlorothiazide 25 mg for 7 weeks
DRUGAliskiren
Aliskiren 150 mg for 1 week followed by Aliskiren 300 mg for 7 weeks
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
1. Male or female outpatients ≥ 18 years old. 2. Patients with a diagnosis of stage 2 hypertension (defined as an office cuff msSBP ≥ 160 mmHg and \< 200 mmHg) at Visit 5 (randomization). 3. Patients with diabetes mellitus (Type 2) with an HbA1c at visit 1 ≤ 9.0 % and currently on stable anti-diabetic regimen or stable diet and exercise for at least 4 weeks prior to visit 1. 4. Patients who are eligible and able to participate in the study, and who are willing to give written informed consent before any assessment is performed.
Exclusion criteria
1. Office blood pressure measured by cuff (msSBP ≥ 200 mmHg or msDBP ≥ 110 mmHg) at Visits 1-5. 2. History or evidence of secondary hypertension of any etiology (e.g., uncorrected renal artery stenosis, pheochromocytoma). 3. History of hypertensive encephalopathy or heart failure (NYHA Class II-IV). 4. Cerebrovascular accident, transient ischemic cerebral attack (TIA), coronary bypass surgery, myocardial infarction or any percutaneous coronary intervention (PCI) within 1 year prior to Visit 1. 5. Serum sodium less than the lower limit of normal, serum potassium \< 3.5 mEq/L (corresponding to 3.5 mmol/L) or ≥ 5.3 mEq/L (corresponding to 5.3 mmol/L), or dehydration at Visit 1. 6. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (\> 5 mIU/mL). 7. Use of other investigational drugs within 30 days of enrollment. 8. History of hypersensitivity to any of the study drugs or to drugs belonging to the same therapeutic class (thiazide diuretics, renin inhibitors, calcium channel blockers, or dihydropyridine like calcium channel blockers) as the study drugs. 9. History of gouty arthritis. 10. Long QT syndrome or QTc \> 450 msec for males and \> 470 msec for females at screening. 11. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases. 12. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they are using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. * Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent. Reliable contraception should be maintained throughout the study and for 7 days after study drug discontinuation. * Women are considered post-menopausal and not of child bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or six months of spontaneous amenorrhea with serum FSH levels \> 40 mIU/mL (and estradiol\< 20 pg/mL) or have had surgical bilateral oophorectomy (with or without hysterectomy) at least six weeks ago. In the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment. 13. Known Keith-Wagener grade III or IV hypertensive retinopathy. 14. Current angina pectoris requiring pharmacological therapy (except sublingual nitroglycerin). 15. Second or third degree heart block without a pacemaker. 16. Atrial fibrillation or atrial flutter at Visit 1, or potentially life-threatening or any symptomatic arrhythmia during the 12 months prior to Visit 1. 17. Clinically significant valvular heart disease. 18. History of angioedema during use of an ACE inhibitor. 19. History or evidence of drug or alcohol abuse within the last 12 months. 20. Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study. 21. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs including, but not limited to, any of the following: * History of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection. * History of active inflammatory bowel disease during the 12 months prior to Visit 1. * Currently active gastritis, duodenal or gastric ulcers, or gastrointestinal bleeding during the 3 months prior to Visit 1. * Any history of pancreatic injury, pancreatitis, or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase during the 12 months prior to Visit 1. * Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3 x ULN at Visit 1, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt. * Evidence of renal impairment as determined by any one of the following: serum creatinine \> 1.5 x ULN at Visit 1, a history of dialysis, or a history of nephrotic syndrome. * Current treatment with cholestyramine or colestipol resins 22. History of noncompliance to medical regimes or unwillingness to comply with the study protocol. 23. Any condition that in the opinion of the investigator would confound the evaluation and interpretation of efficacy and/or safety data. 24. Persons directly involved in the execution of this protocol. 25. Known contraindications to the study drugs.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | Baseline and Week 8 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | Baseline and Week 8 | — |
| Percentage of Responders | Week 8 | Response defined by mean sitting Systolic Blood Pressure \< 130 mm Hg or a reduction of mean sitting Systolic Blood Pressure \>= 20 mm Hg from baseline |
| Percentage of Patients Achieving Blood Pressure Control | after 8 weeks of treatment | Blood pressure control is defined as patient achieving a target Blood Pressure of mean sitting Systolic BloodPressure / mean sitting Diastolic Blood Pressure \< 130/80 mmHg. |
| Biomarker Measurements | Baseline and Week 8 | Geometric mean of the post to baseline ratio in biomarkers of plasma renin activity (ng/ml/h), plasma renin concentration (ng/L), and cystatin C (mg/L) |
| Evaluate the Safety and Tolerability | after 8 weeks of treatment | Percentage of patients with Adverse Event and percentage of patients with edema |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Aliskiren/HCTZ Aliskiren / HCTZ 150/12.5 mg for 1 week followed by 300/25 mg for 7 weeks | 428 |
| Amlodipine Amlodipine 5 mg for 1 week followed by 10 mg for 7 weeks | 432 |
| Total | 860 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative Problems | 3 | 0 |
| Overall Study | Adverse Event | 14 | 25 |
| Overall Study | Lack of Efficacy | 13 | 9 |
| Overall Study | Lost to Follow-up | 3 | 6 |
| Overall Study | Protocol Violation | 7 | 3 |
| Overall Study | Withdrawal by Subject | 6 | 13 |
Baseline characteristics
| Characteristic | Aliskiren/HCTZ | Amlodipine | Total |
|---|---|---|---|
| Age, Continuous | 59.7 years STANDARD_DEVIATION 9.83 | 59.8 years STANDARD_DEVIATION 10.01 | 59.8 years STANDARD_DEVIATION 9.91 |
| Sex: Female, Male Female | 212 Participants | 209 Participants | 421 Participants |
| Sex: Female, Male Male | 216 Participants | 223 Participants | 439 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 28 / 428 | 86 / 431 |
| serious Total, serious adverse events | 3 / 428 | 4 / 431 |
Outcome results
Primary
Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP)
Time frame: Baseline and Week 8
Population: Full analysis set, intent-to-treat
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren/HCTZ | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | -28.82 mmHg | Standard Error 0.722 |
| Amlodipine | Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) | -26.22 mmHg | Standard Error 0.719 |
Secondary
Biomarker Measurements
Geometric mean of the post to baseline ratio in biomarkers of plasma renin activity (ng/ml/h), plasma renin concentration (ng/L), and cystatin C (mg/L)
Time frame: Baseline and Week 8
Population: Full analysis set, intent-to-treat
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Aliskiren/HCTZ | Biomarker Measurements | Cystatin C (mg/L) (N = 327 , 310) | 1.04 ratio | 95% Confidence Interval 0.15 |
| Aliskiren/HCTZ | Biomarker Measurements | Plasma Renin activity (ng/ml/h) (N= 317, 300) | 0.42 ratio | 95% Confidence Interval 2.41 |
| Aliskiren/HCTZ | Biomarker Measurements | Plasma Renin concentration (ng/L) (N=315, 299) | 9.53 ratio | 95% Confidence Interval 189.75 |
| Amlodipine | Biomarker Measurements | Cystatin C (mg/L) (N = 327 , 310) | 0.98 ratio | 95% Confidence Interval 0.09 |
| Amlodipine | Biomarker Measurements | Plasma Renin activity (ng/ml/h) (N= 317, 300) | 1.75 ratio | 95% Confidence Interval 2.1 |
| Amlodipine | Biomarker Measurements | Plasma Renin concentration (ng/L) (N=315, 299) | 1.49 ratio | 95% Confidence Interval 21.59 |
Secondary
Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP)
Time frame: Baseline and Week 8
Population: Full analysis set, intent-to-treat
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Aliskiren/HCTZ | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | -9.92 mmHg | Standard Error 0.414 |
| Amlodipine | Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) | -8.97 mmHg | Standard Error 0.412 |
Secondary
Evaluate the Safety and Tolerability
Percentage of patients with Adverse Event and percentage of patients with edema
Time frame: after 8 weeks of treatment
Population: safety
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Aliskiren/HCTZ | Evaluate the Safety and Tolerability | Any Adverse Event | 36.0 Percentage of participants |
| Aliskiren/HCTZ | Evaluate the Safety and Tolerability | edema | 2.6 Percentage of participants |
| Amlodipine | Evaluate the Safety and Tolerability | Any Adverse Event | 48.3 Percentage of participants |
| Amlodipine | Evaluate the Safety and Tolerability | edema | 17.6 Percentage of participants |
Secondary
Percentage of Patients Achieving Blood Pressure Control
Blood pressure control is defined as patient achieving a target Blood Pressure of mean sitting Systolic BloodPressure / mean sitting Diastolic Blood Pressure \< 130/80 mmHg.
Time frame: after 8 weeks of treatment
Population: Full analysis set, intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren/HCTZ | Percentage of Patients Achieving Blood Pressure Control | 23.2 Percentage of Participants |
| Amlodipine | Percentage of Patients Achieving Blood Pressure Control | 13.8 Percentage of Participants |
Secondary
Percentage of Responders
Response defined by mean sitting Systolic Blood Pressure \< 130 mm Hg or a reduction of mean sitting Systolic Blood Pressure \>= 20 mm Hg from baseline
Time frame: Week 8
Population: Full analysis set, intent-to-treat
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Aliskiren/HCTZ | Percentage of Responders | 74.2 Percentage of Participants |
| Amlodipine | Percentage of Responders | 68.5 Percentage of Participants |