Hypertension
Conditions
Keywords
Drug combination, Nifedipine GITS, Candesartan Cilexetil, Hypertension, Combination therapy
Brief summary
This study examines the long term safety and efficacy of the Fixed Dose combination BAY98-7106 (nifedipine plus candesartan primarily at the highest dose in development) in patients with moderate to severe hypertension. Patients meeting the entry criteria, will receive the Fixed Dose combination for 28 weeks, including 8 weeks with stepwise dose increase up to the high target dose. The first 200 subjects completing 28 weeks will continue treatment for additional 24 weeks (52 weeks in total). Subjects who do not tolerate an increased dose will be treated at their highest tolerable dose.
Interventions
Nifedipine GITS/Candesartan Cilexetil FDC(BAY98-7106), tablet, 30/8 mg, orally once daily
Sponsors
Bayer
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Subjects must have moderate to severe essential hypertension (Grade 2 or Grade 3, WHO classifications). At Visit 1, subjects not treated with antihypertensive medications are to have MSSBP of \>/= 160 mmHg and \< 200 mmHg, as measured by a calibrated electronic BP measuring device. For other subjects who are treated with antihypertensive medication before, they should have MSSBP \>/= 160 mmHg and \<200 mmHg after wash out. * Women of childbearing potential and men must agree to use adequate contraception other than hormonal contraceptives when sexually active
Exclusion criteria
* Mean seated systolic blood pressure \>/= 200 mmHg and/or mean seated diastolic blood pressure \>/= 120 mm/Hg * Mean seated diastolic blood pressure \< 60 mm/Hg * Differences greater than 20 mmHg for systolic blood pressure and 10 mmHg for diastolic blood pressure are present on 3 consecutive blood pressure readings at visit 0 * Any history of hypertensive emergency * Evidence of secondary hypertension such as coarctation of the aorta, pheochromocytoma, hyperaldosteronism, etc. * Cerebrovascular ischemic event (stroke, transient ischemic attack \[TIA\])within the previous 12 months * History of intracerebral hemorrhage or subarachnoid hemorrhage * History of hypertensive retinopathy - known Keith-Wagener Grade III or IV * Any history of heart failure, New York Heart Association (NYHA) classification III or IV * Severe coronary heart disease as manifest by a history of myocardial infarction or unstable angina in the last 6 months prior to visit 0 * Type 1 diabetes mellitus (DM) or poorly controlled Type 2 DM as evidenced by HbA1C of greater than 9% on visit 0. * Hyperkalemia: potassium above the upper limit of normal in the laboratory range
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 28 | From the time of first study drug administration up to Week 28 | An adverse event (AE) is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | From the time of first study drug administration up to Week 28 | An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. TEAEs of special interest included the incidence of symptomatic hypotension and the incidence and severity of vasodilatory adverse events (such as oedema, headache, and flushing). Only subjects who had TEAEs of special interest as mild, moderate or severe were reported. |
| Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 52/End of Study (EOS) | From the time of first study drug administration up to Week 52/EOS | An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. |
| Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | From the time of study treatment up to Week 52/EOS | An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. TEAEs of special interest included the incidence of symptomatic hypotension and the incidence and severity of vasodilatory adverse events (such as oedema, headache, and flushing). Only subjects who had TEAEs of special interest as mild, moderate or severe were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Clinically Relevant Changes in Laboratory Parameters | Baseline (Week 0) up to Week 52/EOS | Laboratory evaluations of blood and urine samples were performed, including hematology (hematocrit, hemoglobin, red blood cells count, white blood cells count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets), blood chemistry (sodium, potassium, chloride, bicarbonate, uric acid, total protein, albumin, calcium, blood urea nitrogen, creatinine, aspartate transaminase, alanine transaminase, lactate dehydrogenase, gamma glutamyl transferase, alkaline phosphatase, creatine kinase, total bilirubin, direct bilirubin, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, fasting glucose), urinalysis (pH, blood, specific gravity, glucose, protein, cells/sediment). A laboratory test abnormality considered clinically relevant, for example, causing withdrawal by subject, requiring treatment or causing apparent clinical manifestations, or judged relevant by the investigator, were reported as AEs. |
| Blood Pressure Response Rate at Weeks 28 and 52 | Weeks 28 and 52 | Response rate was defined as the percentage of subjects who achieved a systolic blood pressure response (MSSBP of \<140 mmHg or a reduction of MSSBP of more than (\>) 20 mmHg from baseline value), or a diastolic blood pressure response (MSDBP of \<90 mmHg or a reduction of MSDBP of \>10 mmHg from baseline value). |
| Change From Baseline In Mean Seated Systolic Blood Pressure (MSSBP) At Weeks 28 And 52 | Baseline (Week 0), Weeks 28 and 52 | — |
| Change From Baseline in Mean Seated Diastolic Blood Pressure (MSDBP) at Weeks 28 and 52 | Baseline (Week 0), Weeks 28 and 52 | — |
| Blood Pressure Control Rate at Weeks 28 and 52 | Weeks 28 and 52 | Control rate was defined as the percentage of subjects that reached a predetermined blood pressure (BP) target of BP less than (\<) 140/90 mmHg. |
Countries
Belgium, Canada, Germany, Poland, United Kingdom, United States
Participant flow
Recruitment details
The study was conducted at 70 study centers between 14 February 2013 (first subject first visit) and 1 May 2014 (last subject last visit).
Pre-assignment details
Of 753 subjects screened, 245 subjects were not enrolled, due to screen failure for 215 subjects, consent withdrawal by 23 subjects, protocol violation by 5 subjects, 1 subject was lost to follow-up and recruitment stopped for 1 subject. Remaining 508 subjects were enrolled and received at least 1 treatment with study drug.
Participants by arm
| Arm | Count |
|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) Subjects received nifedipine gastrointestinal therapeutic system (GITS) / candesartan cilexetil fixed dose combination (FDC) (BAY98-7106) tablet orally, once daily in the morning of Visit 1 (Week 0) for 28 or 52 weeks. The starting dose (30/8 milligram \[mg\] or 30/16 mg) was determined based on local practice and clinical judgment by the investigator. Based on the experience of symptomatic and asymptomatic hypotension, peripheral edema or significant tolerability, the doses were up-titrated to the highest target dose (60/32 mg). | 508 |
| Total | 508 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 51 |
| Overall Study | Lack of Efficacy | 1 |
| Overall Study | Logistical difficulties | 1 |
| Overall Study | Lost to Follow-up | 5 |
| Overall Study | Other | 11 |
| Overall Study | Protocol Violation | 3 |
| Overall Study | Withdrawal by Subject | 26 |
Baseline characteristics
| Characteristic | Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) |
|---|---|
| Age, Continuous | 59 years STANDARD_DEVIATION 10.2 |
| Diastolic blood pressure | 95.6 mmHg STANDARD_DEVIATION 10.4 |
| Sex: Female, Male Female | 186 Participants |
| Sex: Female, Male Male | 322 Participants |
| Systolic blood pressure | 170.7 millimeter of mercury (mmHg) STANDARD_DEVIATION 8.9 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 279 / 508 |
| serious Total, serious adverse events | 15 / 508 |
Outcome results
Primary
Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 28
An adverse event (AE) is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication.
Time frame: From the time of first study drug administration up to Week 28
Population: Safety Analysis Set (SAF): All the subjects enrolled into the open-label treatment period and took at least one unit of the study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 28 | All TEAEs | 390 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 28 | Drug-related TEAEs | 230 Subjects |
Primary
Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 52/End of Study (EOS)
An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication.
Time frame: From the time of first study drug administration up to Week 52/EOS
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 52/End of Study (EOS) | All TEAEs | 404 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With All Treatment-emergent Adverse Events (TEAEs) and Drug-related TEAEs up to Week 52/End of Study (EOS) | Drug-related TEAEs | 238 Subjects |
Primary
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28
An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. TEAEs of special interest included the incidence of symptomatic hypotension and the incidence and severity of vasodilatory adverse events (such as oedema, headache, and flushing). Only subjects who had TEAEs of special interest as mild, moderate or severe were reported.
Time frame: From the time of first study drug administration up to Week 28
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | Oedema (mild) | 124 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | Oedema (moderate) | 54 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | Oedema (severe) | 7 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | Headache (moderate) | 15 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | Headache (mild) | 31 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | Flushing (mild) | 3 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 28 | Symptomatic hypotension (mild) | 4 Subjects |
Primary
Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS)
An AE is any untoward medical occurrence (that is, any unfavorable and unintended sign \[including abnormal laboratory findings\], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study. AEs were considered to be treatment-emergent if they had started or worsened after first application of study medication. TEAEs of special interest included the incidence of symptomatic hypotension and the incidence and severity of vasodilatory adverse events (such as oedema, headache, and flushing). Only subjects who had TEAEs of special interest as mild, moderate or severe were reported.
Time frame: From the time of study treatment up to Week 52/EOS
Population: SAF
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | Oedema (moderate) | 56 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | Oedema(severe) | 7 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | Headache (mild) | 31 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | Headache (moderate) | 17 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | Oedema (mild) | 131 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | Flushing (mild) | 3 Subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Treatment-emergent Adverse Events (TEAEs) of Special Interest up to Week 52/End of Study (EOS) | Symptomatic hypotension (mild) | 4 Subjects |
Secondary
Blood Pressure Control Rate at Weeks 28 and 52
Control rate was defined as the percentage of subjects that reached a predetermined blood pressure (BP) target of BP less than (\<) 140/90 mmHg.
Time frame: Weeks 28 and 52
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Blood Pressure Control Rate at Weeks 28 and 52 | Week 28 | 51.4 percentage of subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Blood Pressure Control Rate at Weeks 28 and 52 | Week 52 | 51.6 percentage of subjects |
Secondary
Blood Pressure Response Rate at Weeks 28 and 52
Response rate was defined as the percentage of subjects who achieved a systolic blood pressure response (MSSBP of \<140 mmHg or a reduction of MSSBP of more than (\>) 20 mmHg from baseline value), or a diastolic blood pressure response (MSDBP of \<90 mmHg or a reduction of MSDBP of \>10 mmHg from baseline value).
Time frame: Weeks 28 and 52
Population: mITT
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Blood Pressure Response Rate at Weeks 28 and 52 | Week 28 | 86.6 percentage of subjects |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Blood Pressure Response Rate at Weeks 28 and 52 | Week 52 | 86.2 percentage of subjects |
Secondary
Change From Baseline in Mean Seated Diastolic Blood Pressure (MSDBP) at Weeks 28 and 52
Time frame: Baseline (Week 0), Weeks 28 and 52
Population: mITT
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Change From Baseline in Mean Seated Diastolic Blood Pressure (MSDBP) at Weeks 28 and 52 | Baseline | 95.6 millimeter of mercury (mmHg) | Standard Deviation 10.4 |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Change From Baseline in Mean Seated Diastolic Blood Pressure (MSDBP) at Weeks 28 and 52 | Change at Week 28 | -12.7 millimeter of mercury (mmHg) | Standard Deviation 10.6 |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Change From Baseline in Mean Seated Diastolic Blood Pressure (MSDBP) at Weeks 28 and 52 | Change at Week 52 | -12.8 millimeter of mercury (mmHg) | Standard Deviation 10.7 |
Secondary
Change From Baseline In Mean Seated Systolic Blood Pressure (MSSBP) At Weeks 28 And 52
Time frame: Baseline (Week 0), Weeks 28 and 52
Population: Modified intention-to-treat analysis set (mITT): All the subjects enrolled into the open-label treatment period and took at least one unit of the study medication.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Change From Baseline In Mean Seated Systolic Blood Pressure (MSSBP) At Weeks 28 And 52 | Change at Week 28 | -30.4 millimeter of mercury (mmHg) | Standard Deviation 17.7 |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Change From Baseline In Mean Seated Systolic Blood Pressure (MSSBP) At Weeks 28 And 52 | Change at Week 52 | -30.1 millimeter of mercury (mmHg) | Standard Deviation 18.4 |
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Change From Baseline In Mean Seated Systolic Blood Pressure (MSSBP) At Weeks 28 And 52 | Baseline | 170.7 millimeter of mercury (mmHg) | Standard Deviation 8.9 |
Secondary
Number of Subjects With Clinically Relevant Changes in Laboratory Parameters
Laboratory evaluations of blood and urine samples were performed, including hematology (hematocrit, hemoglobin, red blood cells count, white blood cells count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets), blood chemistry (sodium, potassium, chloride, bicarbonate, uric acid, total protein, albumin, calcium, blood urea nitrogen, creatinine, aspartate transaminase, alanine transaminase, lactate dehydrogenase, gamma glutamyl transferase, alkaline phosphatase, creatine kinase, total bilirubin, direct bilirubin, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, triglycerides, fasting glucose), urinalysis (pH, blood, specific gravity, glucose, protein, cells/sediment). A laboratory test abnormality considered clinically relevant, for example, causing withdrawal by subject, requiring treatment or causing apparent clinical manifestations, or judged relevant by the investigator, were reported as AEs.
Time frame: Baseline (Week 0) up to Week 52/EOS
Population: SAF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nifedipine GITS/Candesartan Cilexetil FDC (BAY98-7106) | Number of Subjects With Clinically Relevant Changes in Laboratory Parameters | 0 Subjects |