Hypertension
Conditions
Keywords
Blood pressure reduction, combination therapy, candesartan cilexetil, hydrochlorothiazide
Brief summary
The aim is to compare the blood pressure lowering effect of the combination of candesartan cilexetil (candesartan) 32 mg and hydrochlorothiazide (HCT) 25 mg to that of candesartan 32 mg alone, HCT 25 mg alone and placebo in hypertensive adults.
Interventions
DRUGCandesartan cilexetil
32 mg oral tablet
DRUGHydrochlorothiazide
25 mg oral tablet
DRUGCandesartan/HCT 32/25 mg
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Patients will be eligible for enrolment into the study (Visit 1) if they fulfil all of the following criteria: * Provision of signed Informed Consent * Primary hypertension, untreated or treated with a maximum of 2 antihypertensive drugs (substances), which the patient and the physician are willing to withdraw at enrolment and replace with placebo. * Mean sitting DBP 90-114 mmHg (value calculated in the eCRF) at Visits 1 and 2 * Patients will be eligible for randomisation (Visit 4) if they fulfil the following criterion: * Mean sitting DBP of 90-114 mmHg (value calculated in the eCRF) at the end of the 4-week single-blind placebo run-in period. The run-in period should not be shorter than 4 weeks.
Exclusion criteria
* Pregnant or lactating women, or women of childbearing potential not practising an adequate method of contraception eg, intrauterine device, oral contraception or progesterone implant. Pregnancy must be excluded by a negative pregnancy test at Visit 1. * Secondary or malignant hypertension * Sitting SBP of 180 mmHg or more * Myocardial infarction, stroke, coronary bypass surgery or transient ischaemic attack within 6 months before enrolment * Angina pectoris requiring more treatment than short-acting nitrates * Chronic use of NSAIDs * Aortic or mitral valve stenosis * Cardiac failure requiring treatment * Cardiac arrhythmia requiring treatment * Gout * Renal artery stenosis or kidney transplantation * Intravascular volume depletion * Hypersensitivity to any component of the investigational products or to any sulphonamide derived drugs * Concomitant disease which may interfere with the assessment of the patient * Past or present alcohol or drug abuse, or any condition associated with poor compliance that in the opinion of the investigator might affect the patient's participation in the study * Chronic liver disease * Concomitant or previous treatment with any other investigational drug within 20 days of enrolment * Previous enrolment in the present study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Sitting Diastolic Blood Pressure (DBP) From Baseline to the End of the Study (From Baseline to 8 Weeks). | 8 weeks | Change (reduction) in sitting DBP at the end of the study, when compared to sitting DBP at baseline. |
| Change in Sitting Systolic Blood Pressure (SBP) From Baseline to the End of the Study (Baseline to 8 Weeks) | 8 weeks | Change (reduction) in sitting SBP at the end of the study, when compared to sitting SBP at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Describe Safety and Tolerability of the Study Treatments With Regard to Adverse Events Including Those That Lead to Treatment Discontinuation as Well as With Regard to Pulse Rate, Laboratory, Electrocardiographic and Physical Examination Findings. | Baseline to 8 weeks | — |
| To Compare Treatment With Candesartan/HCT 32/25 mg to Each of Its Components With Regard to Change From Baseline to Week 8 in Standing DBP and Standing SBP. | Baseline to 8 weeks | — |
| The Number of Patients With Controlled Sitting DBP and Sitting SBP in Each Treatment Group at the End of the Study | 8 weeks | Controlled sitting SBP and sitting DBP are defined as having sitting SBP \< 140 mmHg and sitting DBP \< 90 mmHg at the end of the study |
| To Compare Candesartan/HCT 32/25 mg to Its Components and to Placebo With Regard to Sitting DBP Responder Rate (Decrease in Sitting DBP ≥10 mmHg From Baseline to the End of the Study or a Sitting DBP <90 mmHg at the End of the Study). | Baseline to 8 weeks | — |
| To Compare Candesartan/HCT 32/25 mg to Its Components and to Placebo With Regard to Sitting DBP Control Rate at the End of the Study (Patients With Controlled Sitting DBP Are Defined as Having a Sitting DBP <90 mmHg at the End of the Study). | Baseline to 8 weeks | — |
| Compare Candesartan/HCT 32/25 mg to Its Components and to Placebo With Regard to Hypertension Control Rate at the End of the Study (Patients With Controlled Sitting SBP and Sitting DBP). | Baseline to 8 weeks | — |
Countries
Belgium, Latvia, Malta, Romania, Russia, Slovakia
Participant flow
Recruitment details
Following a screening evaluation, patients underwent a 4-week, single-blind treatment with placebo, after which eligible patients were randomly allocated in a 5:5:5:1 ratio to receive 8 weeks of double-blind treatment either with candesartan/Hydrochlorothiazide (HCT) 32/25 mg or candesartan 32 mg or HCT 25 mg or placebo, respectively.
Pre-assignment details
In total, 2207 patients were enrolled in the study at 128 centres in 10 countries, 1772 patients received run in medication and 1524 patients were subsequently randomised to double-blind treatment.
Participants by arm
| Arm | Count |
|---|---|
| Placebo given as 2 placebo tablets corresponding to candesartan/HCT 16/12.5 mg tablets, 1 placebo tablet corresponding to a candesartan 32 mg tablet and 2 placebo tablets corresponding to HCT 12.5 mg tablets for double dummy blinding purpose) | 92 |
| Candesartan 32 mg candesartan 32 mg (given as 1 candesartan 32 mg tablet plus 2 placebo tablets corresponding to candesartan/Hydrochlorothiazide (HCT) 16/12.5 mg tablets and 2 placebo tablets corresponding to HCT 12.5 mg tablets for double dummy blinding purposes) | 457 |
| HCT 25 mg HCT 25 mg (given as 2 HCT 12.5 mg tablets plus 2 placebo tablets corresponding to candesartan/HCT 16/12.5 mg tablets and 1 placebo tablet corresponding to a candesartan 32 mg tablet for double dummy blinding purpose) | 464 |
| Candesartan/HCT 32/25 mg candesartan/HCT 32/25 mg (given as 2 candesartan/HCT 16/12.5 mg tablets, plus 1 placebo tablet corresponding to candesartan 32 mg tablet and 2 placebo tablets corresponding to HCT 12.5 mg tablets for double dummy blinding purposes) | 486 |
| Total | 1,499 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 4 | 3 | 3 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 0 |
| Overall Study | Patient Disposition Challenges | 2 | 0 | 0 | 3 |
| Overall Study | Physician Decision | 1 | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 1 |
| Overall Study | Randomized in error | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 4 | 6 |
Baseline characteristics
| Characteristic | Placebo | Candesartan 32 mg | HCT 25 mg | Candesartan/HCT 32/25 mg | Total |
|---|---|---|---|---|---|
| Age Continuous | 52.7 years | 51.7 years | 50.9 years | 52.7 years | 52 years |
| Sex: Female, Male Female | 51 Participants | 255 Participants | 273 Participants | 285 Participants | 864 Participants |
| Sex: Female, Male Male | 41 Participants | 202 Participants | 191 Participants | 201 Participants | 635 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / — | 38 / — | 22 / — | 23 / — |
| serious Total, serious adverse events | 2 / — | 6 / — | 2 / — | 1 / — |
Outcome results
Primary
Change in Sitting Diastolic Blood Pressure (DBP) From Baseline to the End of the Study (From Baseline to 8 Weeks).
Change (reduction) in sitting DBP at the end of the study, when compared to sitting DBP at baseline.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Sitting Diastolic Blood Pressure (DBP) From Baseline to the End of the Study (From Baseline to 8 Weeks). | -3.3 mm Hg | Standard Error 0.9 |
| Candesartan 32 mg | Change in Sitting Diastolic Blood Pressure (DBP) From Baseline to the End of the Study (From Baseline to 8 Weeks). | -9.3 mm Hg | Standard Error 0.4 |
| HCT 25 mg | Change in Sitting Diastolic Blood Pressure (DBP) From Baseline to the End of the Study (From Baseline to 8 Weeks). | -7.7 mm Hg | Standard Error 0.4 |
| Candesartan/HCT 32/25 mg | Change in Sitting Diastolic Blood Pressure (DBP) From Baseline to the End of the Study (From Baseline to 8 Weeks). | -13.9 mm Hg | Standard Error 0.4 |
Primary
Change in Sitting Systolic Blood Pressure (SBP) From Baseline to the End of the Study (Baseline to 8 Weeks)
Change (reduction) in sitting SBP at the end of the study, when compared to sitting SBP at baseline.
Time frame: 8 weeks
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Sitting Systolic Blood Pressure (SBP) From Baseline to the End of the Study (Baseline to 8 Weeks) | -3.7 mm Hg | Standard Error 1.5 |
| Candesartan 32 mg | Change in Sitting Systolic Blood Pressure (SBP) From Baseline to the End of the Study (Baseline to 8 Weeks) | -13.1 mm Hg | Standard Error 0.7 |
| HCT 25 mg | Change in Sitting Systolic Blood Pressure (SBP) From Baseline to the End of the Study (Baseline to 8 Weeks) | -11.6 mm Hg | Standard Error 0.7 |
| Candesartan/HCT 32/25 mg | Change in Sitting Systolic Blood Pressure (SBP) From Baseline to the End of the Study (Baseline to 8 Weeks) | -21.4 mm Hg | Standard Error 0.6 |
Secondary
Compare Candesartan/HCT 32/25 mg to Its Components and to Placebo With Regard to Hypertension Control Rate at the End of the Study (Patients With Controlled Sitting SBP and Sitting DBP).
Time frame: Baseline to 8 weeks
Secondary
The Number of Patients With Controlled Sitting DBP and Sitting SBP in Each Treatment Group at the End of the Study
Controlled sitting SBP and sitting DBP are defined as having sitting SBP \< 140 mmHg and sitting DBP \< 90 mmHg at the end of the study
Time frame: 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | The Number of Patients With Controlled Sitting DBP and Sitting SBP in Each Treatment Group at the End of the Study | 8 participants |
| Candesartan 32 mg | The Number of Patients With Controlled Sitting DBP and Sitting SBP in Each Treatment Group at the End of the Study | 198 participants |
| HCT 25 mg | The Number of Patients With Controlled Sitting DBP and Sitting SBP in Each Treatment Group at the End of the Study | 168 participants |
| Candesartan/HCT 32/25 mg | The Number of Patients With Controlled Sitting DBP and Sitting SBP in Each Treatment Group at the End of the Study | 304 participants |
Secondary
To Compare Candesartan/HCT 32/25 mg to Its Components and to Placebo With Regard to Sitting DBP Control Rate at the End of the Study (Patients With Controlled Sitting DBP Are Defined as Having a Sitting DBP <90 mmHg at the End of the Study).
Time frame: Baseline to 8 weeks
Secondary
To Compare Candesartan/HCT 32/25 mg to Its Components and to Placebo With Regard to Sitting DBP Responder Rate (Decrease in Sitting DBP ≥10 mmHg From Baseline to the End of the Study or a Sitting DBP <90 mmHg at the End of the Study).
Time frame: Baseline to 8 weeks
Secondary
To Compare Treatment With Candesartan/HCT 32/25 mg to Each of Its Components With Regard to Change From Baseline to Week 8 in Standing DBP and Standing SBP.
Time frame: Baseline to 8 weeks
Secondary
To Describe Safety and Tolerability of the Study Treatments With Regard to Adverse Events Including Those That Lead to Treatment Discontinuation as Well as With Regard to Pulse Rate, Laboratory, Electrocardiographic and Physical Examination Findings.
Time frame: Baseline to 8 weeks