Antihypertensive Efficacy and Safety of Candesartan/HCT 32/25 mg in Comparison With Individual Components and Placebo

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00434967
• Collaborator: (none)
• Enrollment: 2,207
• Locations: 27
• Arms: 4
• Duration (Months): 12
• Patients Per Site: 81.7
• Patients Per Site Per Month: 6.8

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Candesartan cilexetil; Drug: Hydrochlorothiazide; Drug: Candesartan/HCT 32/25 mg	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2207 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Double-blind, Randomised, 4-arm Parallel Group, Multicentre, 8-week, Phase III Study to Assess the Antihypertensive Efficacy and Safety of the Combination of Candesartan Cilexetil (CC) 32 mg and Hydrochlorothiazide (HCT) 25 mg Compared With CC 32 mg, HCT 25 mg and Placebo in Hypertensive Adults
• Study Start Date: Jan 1, 2007
• Actual Primary Completion Date: Jan 1, 2008
• Actual Study Completion Date: Jan 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: 4 Placebo
Active Comparator: 2 Candesartan cilexetil	Drug: Candesartan cilexetil; 32 mg oral tablet; Other Names: ATACAND
Active Comparator: 3 Hydrochlorothiazide (HCT)	Drug: Hydrochlorothiazide; 25 mg oral tablet; Other Names: HCTZ
Experimental: 1 Candesartan cilexetil + Hydrochlorothiazide Combination	Drug: Candesartan cilexetil; 32 mg oral tablet; Other Names: ATACAND ; Drug: Hydrochlorothiazide; 25 mg oral tablet; Other Names: HCTZ ; Drug: Candesartan/HCT 32/25 mg

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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 Outcome Measures

1. 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

2. 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]

3. 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]

4. 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]

5. 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]

6. 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]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts 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

• 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Dour		Belgium
2	Research Site	Gozée		Belgium
3	Research Site	Hasselt		Belgium
4	Research Site	Linkebeek		Belgium
5	Research Site	Marchovelette		Belgium
6	Research Site	Ronquières		Belgium
7	Research Site	Saint-Médard		Belgium
8	Research Site	Steenokkerzel		Belgium
9	Research Site	Daugavpils		Latvia
10	Research Site	Ogre		Latvia
11	Research Site	Riga		Latvia
12	Research Site	Gozo		Malta
13	Research Site	Gwardiamangia		Malta
14	Research Site	Arad		Romania
15	Research Site	Bucuresti		Romania
16	Research Site	Iasi		Romania
17	Research Site	Pitesti		Romania
18	Research Site	Ploiesti		Romania
19	Research Site	Targoviste		Romania
20	Research Site	Timisoara		Romania
21	Research Site	Moscow		Russian Federation
22	Research Site	St. Petersburg		Russian Federation
23	Research Site	Bratislava		Slovakia
24	Research Site	Levice		Slovakia
25	Research Site	Lucenec		Slovakia
26	Research Site	Presov		Slovakia
27	Research Site	Sahy		Slovakia

Sponsors and Collaborators

• AstraZeneca

Investigators

• Study Director: Michael Klibaner, MD, AstraZeneca
• Principal Investigator: Istvan Edes, MD, DEOEC Institute of Cardiology

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• AstraZeneca Clinical Trial Information - Outside US

Publications

None provided.

• ClinicalTrials.gov Identifier: NCT00434967
• Other Study ID Numbers: D2456C00002; EudraCT No. 2006-003963-30
• First Posted: Feb 14, 2007
• Last Update Posted: Dec 16, 2010
• Last Verified: Nov 1, 2010

• Keywords provided by , ,: Blood pressure reduction; combination therapy; candesartan cilexetil; hydrochlorothiazide
• Additional relevant MeSH terms: Hypertension; Hydrochlorothiazide; Candesartan; Candesartan cilexetil

Study Results

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 Detail	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.

Arm/Group Title	Placebo	Candesartan 32 mg	HCT 25 mg	Candesartan/HCT 32/25 mg
Arm/Group Description	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)	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)	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)	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)
Period Title: Overall Study
STARTED	97	465	470	492
COMPLETED	90	457	461	478
NOT COMPLETED	7	8	9	14

Baseline Characteristics

Arm/Group Title	Placebo	Candesartan 32 mg	HCT 25 mg	Candesartan/HCT 32/25 mg	Total
Arm/Group Description	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)	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)	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)	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)	Total of all reporting groups
Overall Participants	92	457	464	486	1499
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	52.7	51.7	50.9	52.7	52
Sex: Female, Male (Count of Participants)
Female	51 55.4%	255 55.8%	273 58.8%	285 58.6%	864 57.6%
Male	41 44.6%	202 44.2%	191 41.2%	201 41.4%	635 42.4%

Outcome Measures

1. Primary Outcome

Title	Change in Sitting Diastolic Blood Pressure (DBP) From Baseline to the End of the Study (From Baseline to 8 Weeks).
Description	Change (reduction) in sitting DBP at the end of the study, when compared to sitting DBP at baseline.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Candesartan 32 mg	HCT 25 mg	Candesartan/HCT 32/25 mg
Arm/Group Description	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)	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)	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)	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)
Measure Participants	89	431	441	464
Least Squares Mean (Standard Error) [mm Hg]	-3.3 (0.9)	-9.3 (0.4)	-7.7 (0.4)	-13.9 (0.4)

2. Primary Outcome

Title	Change in Sitting Systolic Blood Pressure (SBP) From Baseline to the End of the Study (Baseline to 8 Weeks)
Description	Change (reduction) in sitting SBP at the end of the study, when compared to sitting SBP at baseline.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Candesartan 32 mg	HCT 25 mg	Candesartan/HCT 32/25 mg
Arm/Group Description	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)	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)	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)	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)
Measure Participants	89	431	441	464
Least Squares Mean (Standard Error) [mm Hg]	-3.7 (1.5)	-13.1 (0.7)	-11.6 (0.7)	-21.4 (0.6)

3. Secondary Outcome

Title	The Number of Patients With Controlled Sitting DBP and Sitting SBP in Each Treatment Group at the End of the Study
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	Candesartan 32 mg	HCT 25 mg	Candesartan/HCT 32/25 mg
Arm/Group Description	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)	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)	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)	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)
Measure Participants	89	431	441	464
Number [participants]	8 8.7%	198 43.3%	168 36.2%	304 62.6%

4. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

8. Secondary Outcome

Title	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Arm/Group Title	Placebo		Candesartan 32 mg		HCT 25 mg		Candesartan/HCT 32/25 mg
Arm/Group Description	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)		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)		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)		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)
All Cause Mortality
	Placebo		Candesartan 32 mg		HCT 25 mg		Candesartan/HCT 32/25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Placebo		Candesartan 32 mg		HCT 25 mg		Candesartan/HCT 32/25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/ (NaN)		6/ (NaN)		2/ (NaN)		1/ (NaN)
Cardiac disorders
Acute Coronary Syndrome	0/97 (0%)		0/465 (0%)		1/470 (0.2%)		0/492 (0%)
Cardiac Failure	1/97 (1%)		0/465 (0%)		0/470 (0%)		0/492 (0%)
Hypotension	0/97 (0%)		0/465 (0%)		0/470 (0%)		1/492 (0.2%)
Infections and infestations
Pneumonia	0/97 (0%)		1/465 (0.2%)		0/470 (0%)		0/492 (0%)
Sudden Death	0/97 (0%)		1/465 (0.2%)		0/470 (0%)		0/492 (0%)
Injury, poisoning and procedural complications
Lower Limb Fracture	0/97 (0%)		1/465 (0.2%)		0/470 (0%)		0/492 (0%)
Investigations
Electrocardiogram Abnormal	1/97 (1%)		0/465 (0%)		0/470 (0%)		0/492 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	0/97 (0%)		1/465 (0.2%)		0/470 (0%)		0/492 (0%)
Nervous system disorders
Cerebrovascular Accident	0/97 (0%)		1/465 (0.2%)		0/470 (0%)		0/492 (0%)
Psychiatric disorders
Major Depression	0/97 (0%)		1/465 (0.2%)		1/470 (0.2%)		0/492 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		Candesartan 32 mg		HCT 25 mg		Candesartan/HCT 32/25 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/ (NaN)		38/ (NaN)		22/ (NaN)		23/ (NaN)
Cardiac disorders
Hypertension	0/97 (0%)		10/465 (2.2%)		0/470 (0%)		0/492 (0%)
Infections and infestations
Influenza	0/97 (0%)		10/465 (2.2%)		0/470 (0%)		0/492 (0%)
Nervous system disorders
Dizziness	0/97 (0%)		0/465 (0%)		0/470 (0%)		13/492 (2.6%)
Headache	0/97 (0%)		18/465 (3.9%)		22/470 (4.7%)		10/492 (2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

AstraZeneca shall have a period of 30 days from receipt of the proposed final manuscript for any publication or other disclosure to review it and may within such time require that submission for publication or disclosure of the manuscript be delayed in order for AstraZeneca to file patent applications.