Combination of Olmesartan and Hydrochlorothiazide in Essential Hypertension

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00430950
• Collaborator: Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company (Industry)
• Enrollment: 1,011
• Locations: 41
• Arms: 2
• Duration (Months): 20
• Patients Per Site: 24.7
• Patients Per Site Per Month: 1.2

Study Details

Study Description

Brief Summary

The study will evaluate the blood pressure lowering effects of two different dosages of the combination of olmesartan and hydrochlorothiazide in patients with moderate or severe high blood pressure.

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: olmesartan medoxomil (OM)+ hydrochlorothiazide (HCTZ) tablets; Drug: olmesartan medoxomil (OM)/ hydrochlorothiazide (HCTZ) 20mg/25mg	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1011 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Efficacy and Safety of Olmesartan Medoxomil/Hydrochlorothiazide Combination 20/25 mg Versus 40/25 mg in Moderately to Severely Hypertensive Patients Not Adequately Controlled by Olmesartan Medoxomil 40 mg Monotherapy
• Study Start Date: Feb 1, 2007
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 olmesartan medoximil (OM)/ hydrochlorothiazide (HCTZ) 40/25 mg + OM/HCTZ 20/25 mg matching placebo	Drug: olmesartan medoxomil (OM)+ hydrochlorothiazide (HCTZ) tablets; olmesartan medoxomil (OM)+ hydrochlorothiazide (HCTZ)tablets 40mg/25mg + 20mg/25mg matching placebo tablets once daily for 8 weeks
Experimental: 2 olmesartan medoximil (OM)/ hydrochlorothiazide (HCTZ)20/25 mg + OM/HCTZ 40/25 matching placebo	Drug: olmesartan medoxomil (OM)/ hydrochlorothiazide (HCTZ) 20mg/25mg; olmesartan medoxomil (OM)/hydrochlorothiazide (HCTZ)20mg/25mg tablet + 40mg/25mg matching placebo tablet once a day for 8 weeks

Outcome Measures

Primary Outcome Measures

1. Change in Mean Trough Sitting Diastolic Blood Pressure [8 weeks]

   Change in mean trough sitting diastolic Blood Pressure between OM/HCTZ 20/25 mg vs. 40/25 mg, in those patients inadequately controlled on OM 40 mg monotherapy, after eight weeks of double blind treatment, as compared to baseline. Change = Week 16 - Week 8 (baseline).

Secondary Outcome Measures

1. Change in Mean Trough Sitting Diastolic Blood Pressure From Week 8(Baseline) to Week 12 [4 weeks]

   Change = Week 12 - Week 8 (baseline).

2. Change in Sitting Systolic Blood Pressure 4 Weeks and 8 Weeks After Baseline. [8 weeks]

   4 weeks Change = Week 12 - Week 8 (baseline). 8 weeks Change = Week 16 - Week 8 (baseline).

3. Change in Daytime, Nighttime and 24-hour Blood Pressure Evaluated by Ambulatory Blood Pressure Monitoring 8 Weeks After Baseline. [8 weeks]

   Change = Week 16 - Week 8 (baseline).

4. Number of Participants Achieving Blood Pressure Goal. [8 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male or female Europeans aged 18 years or older with moderate to severe HTN, defined as follows (conventional BP measurements)

Exclusion Criteria:

• Female patients of childbearing potential pregnant, lactating or planning to become pregnant during the trial period.

• Patients with serious disorders which may limit the ability to evaluate the efficacy or safety of the study medication, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, haematological or oncological, neurological and psychiatric diseases.

• Patients having a history of the following within the last six months:

• myocardial infarction,

• unstable angina pectoris,

• percutaneous coronary intervention,

• severe heart failure,

• hypertensive encephalopathy, cerebrovascular accident (stroke) or

• transient ischaemic attack.

• Patients with clinically significant abnormal laboratory values at screening.

• Patients with secondary HTN.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Brugge		Belgium
2		Brussels		Belgium
3		Drongen		Belgium
4		Godinne		Belgium
5		Mouscron		Belgium
6		Wetteren		Belgium
7		Berlin		Germany
8		Dortmund		Germany
9		Essen		Germany
10		Frankfurt		Germany
11		Goch		Germany
12		Hamburg		Germany
13		Kallstadt		Germany
14		Karlsruhe		Germany
15		Kassel		Germany
16		Magdeburg		Germany
17		Marburg		Germany
18		Muenchen		Germany
19		Wiesbaden		Germany
20		Wuppertal		Germany
21		Alphen aan den Rijn		Netherlands
22		Amsterdam Zuidoost		Netherlands
23		Andijk		Netherlands
24		De Bilt		Netherlands
25		Den Bosch		Netherlands
26		Den Haag		Netherlands
27		Ewijk		Netherlands
28		Heerlen		Netherlands
29		Hengelo		Netherlands
30		Landgraaf		Netherlands
31		Nijmegen		Netherlands
32		Oud-Beijerland		Netherlands
33		Ridderkerk		Netherlands
34		Wildervank		Netherlands
35		Zwijndrecht		Netherlands
36		Bratislava		Slovakia
37		Levice		Slovakia
38		Lucenec		Slovakia
39		Nitra		Slovakia
40		Nove Zamky		Slovakia
41		Vrable		Slovakia

Sponsors and Collaborators

• Daiichi Sankyo, Inc.
• Daiichi Sankyo Europe, GmbH, a Daiichi Sankyo Company

Investigators

• Study Chair: Professor Lars Christian Rump, M.D., University of Ruhr-Bochum

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT00430950
• Other Study ID Numbers: CS866CM-B-E302
• First Posted: Feb 2, 2007
• Last Update Posted: Jan 10, 2019
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Daiichi Sankyo, Inc.: Moderate-to-Severe Hypertension; Essential Hypertension; Combination Therapy; Fixed-Combination Dose
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Hydrochlorothiazide; Olmesartan; Olmesartan Medoxomil

Study Results

Participant Flow

Recruitment Details	92 principal investigators screened patients at clinical sites in Europe (8 in Belgium, 17 in Germany, 12 in the Netherlands, 17 in Poland, 19 in Russia, 10 in Slovakia, and 9 in the Ukraine).Sites were either hospitals or general practitioners. First patient in: 05 December 2006 Last patient out: 07 May 2008
Pre-assignment Detail	Trial is 2 week taper-off phase and 2 treatment periods. Period I - 8-week open-label OM 40mg. Only non-responders eligible to randomise into Period II. Period II - 8-week double-blind patients assigned into one of two arms. Results provided for Period II only.

Arm/Group Title	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo	OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
Arm/Group Description	Olmesartan Medoxomil/Hydrochlorothiazide 40/25 mg with 20/25 mg matching placebo	Olmesartan Medoxomil/Hydrochlorothiazide 20/25mg + 40/25mg matching placebo
Period Title: Overall Study
STARTED	502	508
COMPLETED	489	495
NOT COMPLETED	13	13

Baseline Characteristics

Arm/Group Title	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo	OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo	Total
Arm/Group Description	Olmesartan Medoxomil/Hydrochlorothiazide 40/25 mg with 20/25 mg matching placebo	Olmesartan Medoxomil/Hydrochlorothiazide 20/25mg + 40/25mg matching placebo	Total of all reporting groups
Overall Participants	502	508	1010
Age, Customized (Number) [Number]
<=18 years	0 0%	0 0%	0.0 0%
Between 18 and 65 years	404 80.5%	422 83.1%	826.0 81.8%
>=65 years	93 18.5%	75 14.8%	168.0 16.6%
>= 75 years	5 (1.0) 1%	11 (2.2) 2.2%	16.0 1.6%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.7 (9.67)	54.4 (9.77)	54.6 (9.72)
Sex: Female, Male (Count of Participants)
Female	194 38.6%	201 39.6%	395 39.1%
Male	308 61.4%	307 60.4%	615 60.9%
Race/Ethnicity, Customized (participants) [Number]
European	502 100%	508 100%	1010 100%

Outcome Measures

1. Primary Outcome

Title	Change in Mean Trough Sitting Diastolic Blood Pressure
Description	Change in mean trough sitting diastolic Blood Pressure between OM/HCTZ 20/25 mg vs. 40/25 mg, in those patients inadequately controlled on OM 40 mg monotherapy, after eight weeks of double blind treatment, as compared to baseline. Change = Week 16 - Week 8 (baseline).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

The main analysis will be performed on the full analysis set last observation carried forward (LOCF). Pooling will be applied for small centres.

Arm/Group Title	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo	OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
Arm/Group Description	Olmesartan Medoxomil/Hydrochlorothiazide 40/25 mg with 20/25 mg matching placebo	Olmesartan Medoxomil/Hydrochlorothiazide 20/25mg + 40/25mg matching placebo
Measure Participants	502	508
Mean (Standard Deviation) [mm Hg]	-11.16 (8.851)	-10.45 (7.928)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments	The ANCOVA model included treatment as main effect and baseline mean trough sitting dBP as covariate. Significance level alpha = 5%. Power = 80%. The following statistical superiority hypothesis was tested: Superiority of OM/HCTZ combination therapy 40/25 mg over OM/HCTZ 20/25 mg
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2648
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.5
	Confidence Interval	() 95%; -1.51 to 0.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Change in Mean Trough Sitting Diastolic Blood Pressure From Week 8(Baseline) to Week 12
Description	Change = Week 12 - Week 8 (baseline).
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo	OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
Arm/Group Description	Olmesartan Medoxomil/Hydrochlorothiazide 40/25 mg with 20/25 mg matching placebo	Olmesartan Medoxomil/Hydrochlorothiazide 20/25mg + 40/25mg matching placebo
Measure Participants	502	508
Mean (Standard Deviation) [mm Hg]	-9.32 (7.820)	-8.83 (7.584)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4246
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.4
	Confidence Interval	() 95%; -1.26 to 0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Change in Sitting Systolic Blood Pressure 4 Weeks and 8 Weeks After Baseline.
Description	4 weeks Change = Week 12 - Week 8 (baseline). 8 weeks Change = Week 16 - Week 8 (baseline).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo	OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
Arm/Group Description	Olmesartan Medoxomil/Hydrochlorothiazide 40/25 mg with 20/25 mg matching placebo	Olmesartan Medoxomil/Hydrochlorothiazide 20/25mg + 40/25mg matching placebo
Measure Participants	502	508
Change from baseline (Week 8) to Week 16 in sBP	-17.41 (13.930)	-17.09 (13.126)
Change from baseline (Week 8) to Week 12 in sBP	-14.07 (12.654)	-13.80 (12.519)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7019
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -1.84 to 1.24
	Parameter Dispersion	Type: Value:
	Estimation Comments	refers to 8 week change; from week 8 to week 16

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7328
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.3
	Confidence Interval	() 95%; -1.71 to 1.21
	Parameter Dispersion	Type: Value:
	Estimation Comments	refers to 4 week change; from week 8 to week 12

4. Secondary Outcome

Title	Change in Daytime, Nighttime and 24-hour Blood Pressure Evaluated by Ambulatory Blood Pressure Monitoring 8 Weeks After Baseline.
Description	Change = Week 16 - Week 8 (baseline).
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

Exploratory analysis: ANCOVA was used to compare the differences in change from baseline (Visit 4, Week 8) to Week 16 (Visit 6) in daytime, nighttime and 24-hr ABPM dBP and sBP.

Arm/Group Title	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo	OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
Arm/Group Description	Olmesartan Medoxomil/Hydrochlorothiazide 40/25 mg with 20/25 mg matching placebo	Olmesartan Medoxomil/Hydrochlorothiazide 20/25mg + 40/25mg matching placebo
Measure Participants	442	442
Change from Week 8 to Wk 16 in mean 24-hr ABPM dBP	-9.2 (8.69)	-7.6 (8.03)
Change from Week 8 to wk16 in daytime ABPM dBP	-9.3 (9.18)	-7.7 (8.48)
Change from Week 8 to wk16 in nighttime ABPM dBP	-8.6 (9.52)	-7.0 (9.49)
Change from Week 8 to wk16 in mean 24-hr ABPM sBP	-14.7 (13.75)	-12.0 (11.81)
Change from Week 8 to wk16 in daytime ABPM sBP	-15.0 (14.36)	-12.3 (12.45)
Change from Week 8 to wk16 in nighttime ABPM sBP	-13.4 (14.59)	-10.7 (13.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0016
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.6
	Confidence Interval	() 95%; -2.58 to -0.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	24 hour Ambulatory Blood Pressure Monitoring (ABPM) diastolic blood pressure (dBP)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.6
	Confidence Interval	() 95%; -2.61 to -0.53
	Parameter Dispersion	Type: Value:
	Estimation Comments	daytime Ambulatory Blood Pressure Monitoring (ABPM) diastolic blood pressure (dBP)

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0073
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.5
	Confidence Interval	() 95%; -2.58 to -0.40
	Parameter Dispersion	Type: Value:
	Estimation Comments	night-time Ambulatory Blood Pressure Monitoring (ABPM) diastolic blood pressure (dBP)

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.3
	Confidence Interval	() 95%; -3.71 to -0.82
	Parameter Dispersion	Type: Value:
	Estimation Comments	24 hour Ambulatory Blood Pressure Monitoring (ABPM) systolic blood pressure (sBP)

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0031
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.3
	Confidence Interval	() 95%; -3.76 to -0.76
	Parameter Dispersion	Type: Value:
	Estimation Comments	daytime Ambulatory Blood Pressure Monitoring (ABPM) systolic blood pressure (sBP)

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0104
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.0
	Confidence Interval	() 95%; -3.61 to -0.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	night-time Ambulatory Blood Pressure Monitoring (ABPM) systolic blood pressure (sBP)

5. Secondary Outcome

Title	Number of Participants Achieving Blood Pressure Goal.
Time Frame	8 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo	OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
Arm/Group Description	Olmesartan Medoxomil/Hydrochlorothiazide 40/25 mg with 20/25 mg matching placebo	Olmesartan Medoxomil/Hydrochlorothiazide 20/25mg + 40/25mg matching placebo
Measure Participants	502	508
Number [participants]	260 51.8%	255 50.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OM/HCTZ 40/25 mg + 20/25 mg Matching Placebo, OM/HCTZ 20/25 mg + 40/25 mg Matching Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.09
	Confidence Interval	() 95%; 0.85 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Results of Study shall not be published without prior express written consent and approval of Sponsor. If Contractor wishes to use data generated at Sites by Investigator, such data includes but not limited to data used in collection of metrics, copy of any intended publication, details of use must be sent in writing to Quintiles and Sponsor for review. Sponsor has right to change proposed publication and/or prohibit publication and Contractor must comply with requirements of Sponsor