Hydrochlorothiazide as add-on to Olmesartan/Amlodipine in Hypertension

• Sponsor: Daiichi Sankyo, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00902538
• Collaborator: (none)
• Enrollment: 2,204
• Locations: 117
• Arms: 6
• Duration (Months): 18
• Patients Per Site: 18.8
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

Both Olmesartan (OLM)/Amlodipine (AML) combination and Hydrochlorothiazide (HCTZ) have proven to be efficacious and safe in lowering blood pressure, but may not always be sufficient. This study is to test efficacy and safety of the combination of OLM/AML and HCTZ in hypertensive patients whose blood pressure is not adequately controlled with OLM/AML alone. The following treatments will be included in the trial: OLM 40mg/AML 10mg; OLM 40mg/AML 10 mg/HCTZ 12.5 mg; OLM 40 mg/AML 10 mg/HCTZ 25 mg. The trial has four periods. The treatments that will be used are as follows:

Period 1 - OLM 40mg/AML 10mg; Period 2 - OLM 40mg/AML 10mg or OLM 40mg/AML 10 mg/HCTZ 12.5 mg or OLM 40 mg/AML 10 mg/HCTZ 25 mg; Period 3 - OLM 40mg/AML 10 mg/HCTZ 12.5 mg; Period 4 - Period 3 responders: OLM 40mg/AML 10 mg/HCTZ 12.5 mg; Period 4 - Period 3 non-responders: OLM 40mg/AML 10 mg/HCTZ 12.5 mg or OLM 40 mg/AML 10 mg/HCTZ 25 mg

Condition or Disease	Intervention/Treatment	Phase
Essential Hypertension	Drug: Olmesartan medoxomil 40 mg - Amlodipine 10 mg; Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 12.5mg; Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg; Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg; Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg; Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 2204 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Add-on Study of Hydrochlorothiazide in Patients With Moderate to Severe Hypertension Not Achieving Target Blood Pressure on Olmesartan/Amlodipine Alone
• Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Oct 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Olmesartan (OLM) 40mg-Amlodipine (AML) 10mg The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Drug: Olmesartan medoxomil 40 mg - Amlodipine 10 mg; Oral tablets containing Olmesartan medoxomil-Amlodipine 40-10 mg, given once daily
Experimental: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 12.5mg Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 12.5mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 1 Hydrochlorothiazide 12.5mg oral tablet + 1 Hydrochlorothiazide 12.5mg oral, placebo tablet. All tablets are given once a day.
Experimental: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.	Drug: Olmesartan 40mg-Amlodipine 10mg-Hydrochlorothiazide 25mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 2 Hydrochlorothiazide 12.5mg oral tablets. All tablets are given once a day.; Other Names: Olmesartan 40mg-Amlodipine 10mg tablet + 2 Hydrochlorothiazide 12.5mg tablets
Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg (Responders) Participants who meet their blood pressure goals in Period 3 and continued into the 8-week, double-blind Period 4 continued to receive this combination.	Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 1 Hydrochlorothiazide 12.5mg oral tablet + 1 Hydrochlorothiazide 12.5mg oral, placebo tablet. All tablets are given once a day.
Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg (Non-responders) Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4	Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 12.5mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 1 Hydrochlorothiazide 12.5mg oral tablet + 1 Hydrochlorothiazide 12.5mg oral, placebo tablet. All tablets are given once a day.
Experimental: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg (Non-responders) Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4	Drug: OLM 40mg-AML 10mg-Hydrochlorothiazide 25mg; Coated, oral tablets containing Olmesartan 40mg-Amlodipine 10mg + 2 Hydrochlorothiazide 12.5mg oral tablet. All tablets are given once a day.

Outcome Measures

Primary Outcome Measures

1. Change in Seated Diastolic Blood Pressure (SeDBP) of the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg vs. OM/AML 40/10 mg [baseline (8 weeks) to 16 weeks]

   Three cuff blood pressure measurements were taken at each visit.

Secondary Outcome Measures

1. Change in Seated Systolic Blood Pressure (SeSBP) of the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg vs. OM/AML 40/10 mg [baseline (8 weeks) to week 16]

   Three cuff blood pressure measurements were taken at each visit.

2. Number of Subjects Achieving Blood Pressure (BP) Goal at Week 16. [baseline (week 8) to week 16]

   Achieving blood pressure goal is defined as seated blood pressure <140/90 mm Hg; 130/80 mm Hg for participants with diabetes and/or other chronic renal and/or chronic cardiovascular disease. Three cuff blood pressure measurements were taken at each visit.

3. Change in 24-hour Diastolic Blood Pressure (DBP) Assessed by 24-hour Ambulatory Blood Pressure Measurement (ABPM). [Baseline (8 weeks) to 16 weeks]

   Three cuff blood pressure measurements were taken at each visit.

4. Change in 24-hour Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement. [Baseline (8 weeks) to 16 weeks]

   Three cuff blood pressure measurements were taken at each visit.

5. In Non-responders, the Change in Seated Diastolic Blood Pressure Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg. [week 24 to week 32]

   Change in seated diastolic blood pressure from the beginning to the end of Period 4. Three cuff blood pressure measurements were taken at each visit.

6. In Non-responders, the Change in Seated Systolic Blood Pressure Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg. [week 24 to week 32]

   Change in seated systolic blood pressure from the beginning to the end of Period 4. Three cuff blood pressure measurements were taken at each visit.

7. In Non-responders, the Number of Subject Meeting Their Blood Pressure Goals Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg. [week 24 to week 32]

   The number of non-responding participants who achieved their blood pressure goals at the end of Period 4. Achieving blood pressure goal is defined as seated blood pressure <140/90 mm Hg; 130/80 mm Hg for participants with diabetes and/or other chronic renal and/or chronic cardiovascular disease. Three cuff blood pressure measurements were taken at each visit.

8. In Non-responders, the Change in 24-hour Diastolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement. [Week 16 to week 32]

   In non-responders, the change in 24-hour diastolic blood pressure assessed by 24-hour ambulatory blood pressure measurement from the beginning to the end of Period 4.

9. In Non-responders, the Change in 24-hour Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement. [Week 16 to week 32]

   In non-responders, the change in 24-hour systolic blood pressure assessed by 24-hour ambulatory blood pressure measurement from the beginning to the end of Period 4.

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 aged 18 years or older.

• Mean trough seated systolic blood pressure (SeSBP) of ≥ 160/100 mmHg (SeSBP of ≥ 160 mmHg and seated diastolic blood pressure (SeDBP) ≥ 100 mmHg) at screening if not currently on antihypertensive medication (e.g. newly diagnosed subjects)

OR:

For subjects on monotherapy: mean trough SeSBP of ≥ 150/95 mmHg (SeSBP of ≥ 150 mmHg and SeDBP ≥ 95 mmHg) at screening

OR:

For subjects on any combination of antihypertensive medications that includes either hydrochlorothiazide or amlodipine or olmesartan for a duration of at least four weeks: mean trough SeSBP of ≥ 140/90 mmHg (SeSBP of ≥ 140 mmHg and SeDBP ≥ 90 mmHg) at screening

OR:

For subjects on any other combination of antihypertensive medications that includes neither hydrochlorothiazide, amlodipine nor olmesartan: mean trough SeSBP ≥ 160 mmHg, mean trough SeDBP ≥ 100mmHg, at the end of the taper-off period

• Subject freely signs the Informed Consent Form (ICF) after the nature of the study and the disclosure of his/her data has been explained.

• Female subjects of childbearing potential must be using adequate contraception (female of childbearing potential is defined as one who has not been postmenopausal for at least one year, or has not been surgically sterilised, or has not had a hysterectomy at least three months prior to the start of this study [Visit 1]). Females taking oral contraceptives should have been on therapy for at least three months. Adequate contraceptives include hormonal intra-uterine devices, hormonal contraceptives (oral, depot, patch or injectable), and double barrier methods such as condoms or diaphragms with spermicidal gel or foam. If a female becomes pregnant during the study, she has to be withdrawn immediately.

Exclusion Criteria:

• Female subjects of childbearing potential who are pregnant or lactating.

• Subjects with serious disorders which may limit the ability to evaluate the efficacy or safety of the investigational products, including cerebrovascular, cardiovascular, renal, respiratory, hepatic, gastrointestinal, endocrine or metabolic, haematological or oncological, neurological, and psychiatric diseases. The same applies for immunocompromised and/or neutropenic subjects.

• Subjects having a history of the following within the last six months: myocardial infarction (MI), unstable angina pectoris, percutaneous coronary intervention, heart failure, hypertensive encephalopathy, cerebrovascular accident (stroke), or transient ischaemic attack.

• Subjects with clinically significant abnormal laboratory values at Screening, including subjects with one or more of the following:

• Aspartate aminotransferase (AST) > 3 times upper limit of normal (ULN)

• Alanine aminotransferase (ALT) > 3 times ULN

• Gamma-glutamyltransferase (GGT) > 3 times ULN

• Potassium above ULN (unless high value is due to haemolytic blood sample)

• Subjects with secondary hypertension of any aetiology such as renal disease, phaeochromocytoma, or Cushing's syndrome.

• Subjects with contraindication to olmesartan, amlodipine, hydrochlorothiazide, or any of the excipients.

• Subjects with a mean SeSBP > 200 mmHg or mean SeDBP > 115 mmHg or bradycardia (heart rate < 50 beats/min at rest documented by mean radial pulse rate [PR] or electrocardiogram [ECG]) at Screening (Visit 1) or immediately before taking Period I study medication (Visit 2).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Graz		Austria
2		Salzburg		Austria
3		Wien		Austria
4		Antwerpen		Belgium
5		Lauwe		Belgium
6		Leuven		Belgium
7		Liege		Belgium
8		Massemen		Belgium
9		Oostham		Belgium
10		Haskovo		Bulgaria
11		Pleven		Bulgaria
12		Plovdiv		Bulgaria
13		Sofia		Bulgaria
14		Varna		Bulgaria
15		Bilovec		Czechia
16		Brno		Czechia
17		Havlickuv Brod		Czechia
18		Hodonin		Czechia
19		Kladno		Czechia
20		Kolin		Czechia
21		Ostrava-Vitkovice		Czechia
22		Ostrava		Czechia
23		Praha		Czechia
24		Copenhagen		Denmark
25		Frederiksberg		Denmark
26		Naestved		Denmark
27		Roskilde		Denmark
28		Albi		France
29		Angers		France
30		Brest		France
31		Cambrai		France
32		Creteil		France
33		Dijon		France
34		Dinard		France
35		Lyon		France
36		Nancy		France
37		Pessac		France
38		Roubaix		France
39		Strasbourg		France
40		Tierce		France
41		Vandoeuvre		France
42		Villefranche de Rouergue		France
43		Berlin		Germany
44		Dresden		Germany
45		Einbeck		Germany
46		Hamburg		Germany
47		Magdeburg		Germany
48		Muenchen		Germany
49		Strasskirchen		Germany
50		Villingen-Schwenningen		Germany
51		Wermsdorf		Germany
52		Almere		Netherlands
53		Beek en Donk		Netherlands
54		Doetinchem		Netherlands
55		Groningen		Netherlands
56		Losser		Netherlands
57		Maastricht		Netherlands
58		Bytom		Poland
59		Gdansk		Poland
60		Katowice		Poland
61		Krakow		Poland
62		Piotrkow Trybunalski		Poland
63		Pulawy		Poland
64		Siemianowice Slaskie		Poland
65		Tarnow		Poland
66		Torun		Poland
67		Warszawa		Poland
68		Wroclaw		Poland
69		Brasov		Romania
70		Bucharest		Romania
71		Cluj-Napoca		Romania
72		Iasi		Romania
73		Oradea		Romania
74		Pitesti		Romania
75		Targoviste		Romania
76		Targu Mures		Romania
77		Timisoara		Romania
78		Ekaterinburg		Russian Federation
79		Moscow		Russian Federation
80		Novosibirsk		Russian Federation
81		Orenburg		Russian Federation
82		Ryazan		Russian Federation
83		Saratov		Russian Federation
84		Smolensk		Russian Federation
85		St. Petersburg		Russian Federation
86		Tomsk		Russian Federation
87		Yaroslavl		Russian Federation
88		Banska Bysterica		Slovakia
89		Brastislava		Slovakia
90		Dolny Kubin		Slovakia
91		Kosice		Slovakia
92		Presov		Slovakia
93		Sahy		Slovakia
94		La Gineta	Albacete	Spain
95		La Roda	Albacete	Spain
96		Port De Sagunt	Valencia	Spain
97		Alicante		Spain
98		Barcelona		Spain
99		Elche		Spain
100		Granada		Spain
101		Madrid		Spain
102		Palma de Mallorca		Spain
103		Sevilla		Spain
104		Valencia		Spain
105		Vizcaya		Spain
106		Dnipropetrovsk		Ukraine
107		Donetsk		Ukraine
108		Ivano-Frankivsk		Ukraine
109		Kharkiv		Ukraine
110		Kiev		Ukraine
111		Lviv		Ukraine
112		Mykolayiv		Ukraine
113		Odesa		Ukraine
114		Simferopol		Ukraine
115		Uzhorod		Ukraine
116		Vinnytsya		Ukraine
117		Yalta		Ukraine

Sponsors and Collaborators

• Daiichi Sankyo, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daiichi Sankyo, Inc.
• ClinicalTrials.gov Identifier: NCT00902538
• Other Study ID Numbers: CS8635-A-E303
• First Posted: May 15, 2009
• Last Update Posted: Jan 11, 2019
• Last Verified: Feb 1, 2012

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Daiichi Sankyo, Inc.: Add on treatment; essential hypertension
• Additional relevant MeSH terms: Hypertension; Essential Hypertension; Amlodipine; Hydrochlorothiazide; Olmesartan; Olmesartan Medoxomil

Study Results

Participant Flow

Recruitment Details	First participant visit was 29 April 2009. The last participant follow up was 07 September 2010
Pre-assignment Detail	The number of subjects entering Period 2 was only 808 because 1278 did not meet the entry criteria.

Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25	OLM 40-AML 10-HCTZ 12.5 (Responders)	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5 (Non-responders)	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 25 (Non-responders)
Arm/Group Description	The participants in this arm received Olmesartan(OLM) 40 mg-Amlodipine(AML) 10 mg oral tablets, once a day, for the 8-week, single-blind, run-in Period 1. Then in Period 2, participants would be randomized to this same combination or have hydrochlorothiazide oral tablets (12.5 or 25 mg) added for an additional 8 weeks. All medication is given once a day.	Participants could start receiving OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5 oral tablets given once daily in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving OLM 40-AML 10-HCTZ 25 oral tablets, given once daily, in randomized, double-blind, 8- week Period 2.	Participants who meet their blood pressure goals (responded) in Period 3 and continued into 8-week, double-blind Period 4 continued to receive OLM 40-AML 10-HCTZ 12.5 oral tablets given once daily.	Participants finishing Period 3, but, who did not meet their blood pressure goals (non-responders) could receive OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5 oral tablets, given once daily, in double-blind, randomized, Period 4.	Participants finishing Period 3, but, who did not meet their blood pressure goals (non-responders) could receive OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 25 oral tablets, given once daily, in double-blind, randomized, Period 4
Period Title: 1-Single-blind, Run-in, Single-Treatment
STARTED	2204	0	0	0	0	0
COMPLETED	2086	0	0	0	0	0
NOT COMPLETED	118	0	0	0	0	0
Period Title: 1-Single-blind, Run-in, Single-Treatment
STARTED	269	269	270	0	0	0
COMPLETED	260	263	262	0	0	0
NOT COMPLETED	9	6	8	0	0	0
Period Title: 1-Single-blind, Run-in, Single-Treatment
STARTED	0	782	0	0	0	0
COMPLETED	0	767	0	0	0	0
NOT COMPLETED	0	15	0	0	0	0
Period Title: 1-Single-blind, Run-in, Single-Treatment
STARTED	0	0	0	467	97	197
COMPLETED	0	0	0	458	95	196
NOT COMPLETED	0	0	0	9	2	1

Baseline Characteristics

Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25	Total
Arm/Group Description	The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.	Total of all reporting groups
Overall Participants	269	269	270	808
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.9 (10.56)	56.5 (10.25)	54.9 (10.44)	55.8 (10.42)
Sex: Female, Male (Count of Participants)
Female	119 44.2%	104 38.7%	116 43%	339 42%
Male	150 55.8%	165 61.3%	154 57%	469 58%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	1 0.4%	1 0.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	269 100%	269 100%	269 99.6%	807 99.9%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	87.8 (18.14)	88.2 (16.03)	88.5 (16.28)	88.2 (16.83)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.9 (9.74)	170.5 (9.11)	170.4 (8.98)	170.3 (9.27)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	30.27 (4.90)	30.30 (4.65)	30.44 (4.87)	30.34 (4.80)
Obesity (Number) [Number]
Body Mass Index < 30 kg/m^2	138 51.3%	142 52.8%	133 49.3%	413 51.1%
Body Mass Index >= 30 kg/m^2	131 48.7%	125 46.5%	137 50.7%	393 48.6%

Outcome Measures

1. Primary Outcome

Title	Change in Seated Diastolic Blood Pressure (SeDBP) of the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg vs. OM/AML 40/10 mg
Description	Three cuff blood pressure measurements were taken at each visit.
Time Frame	baseline (8 weeks) to 16 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set 1 included 806 randomized subjects who received at least 1 dose of double-blind study medication in Period II and provided at least 1 SeDBP measurement in Period II: 269 subjects in the OM/AML 40/10 mg group, 268 subjects in the OM/AML/HCTZ 40/10/12.5 mg group, and 269 subjects in the OM/AML/HCTZ 40/10/25 mg group.

Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25
Arm/Group Description	The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
Measure Participants	269	268	269
Least Squares Mean (Standard Error) [mm Hg]	-6.1 (0.55)	-7.1 (0.55)	-8.9 (0.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1187
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-HCTZ 25
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Change in Seated Systolic Blood Pressure (SeSBP) of the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg vs. OM/AML 40/10 mg
Description	Three cuff blood pressure measurements were taken at each visit.
Time Frame	baseline (8 weeks) to week 16

Outcome Measure Data

Analysis Population Description

The Full Analysis Set 1 included 806 randomized subjects who received at least 1 dose of double-blind study medication in Period II and provided at least 1 SeDBP measurement in Period II: 269 subjects in the OM/AML 40/10 mg group, 268 subjects in the OM/AML/HCTZ 40/10/12.5 mg group, and 269 subjects in the OM/AML/HCTZ 40/10/25 mg group.

Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25
Arm/Group Description	The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
Measure Participants	269	268	269
Least Squares Mean (Standard Error) [mm Hg]	-6.9 (0.76)	-8.6 (0.77)	-10.5 (0.77)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0425
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-HCTZ 25
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Number of Subjects Achieving Blood Pressure (BP) Goal at Week 16.
Description	Achieving blood pressure goal is defined as seated blood pressure <140/90 mm Hg; 130/80 mm Hg for participants with diabetes and/or other chronic renal and/or chronic cardiovascular disease. Three cuff blood pressure measurements were taken at each visit.
Time Frame	baseline (week 8) to week 16

Outcome Measure Data

Analysis Population Description

The Full Analysis Set 1 included 806 randomized subjects who received at least 1 dose of double-blind study medication in Period II and provided at least 1 SeDBP measurement in Period II: 269 subjects in the OM/AML 40/10 mg group, 268 subjects in the OM/AML/HCTZ 40/10/12.5 mg group, and 269 subjects in the OM/AML/HCTZ 40/10/25 mg group.

Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25
Arm/Group Description	The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
Measure Participants	269	268	269
Number [Participants]	65 24.2%	79 29.4%	111 41.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1939
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-HCTZ 25
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments

4. Secondary Outcome

Title	Change in 24-hour Diastolic Blood Pressure (DBP) Assessed by 24-hour Ambulatory Blood Pressure Measurement (ABPM).
Description	Three cuff blood pressure measurements were taken at each visit.
Time Frame	Baseline (8 weeks) to 16 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set 1 included 806 randomized subjects who received at least 1 dose of double-blind study medication in Period II and provided at least 1 SeDBP measurement in Period II: 269 subjects in the OM/AML 40/10 mg group, 268 subjects in the OM/AML/HCTZ 40/10/12.5 mg group, and 269 subjects in the OM/AML/HCTZ 40/10/25 mg group.

Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25
Arm/Group Description	The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
Measure Participants	269	268	269
Least Squares Mean (Standard Error) [mm Hg]	-2.1 (0.52)	-4.0 (0.52)	-5.3 (0.52)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0009
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-HCTZ 25
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change in 24-hour Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.
Description	Three cuff blood pressure measurements were taken at each visit.
Time Frame	Baseline (8 weeks) to 16 weeks

Outcome Measure Data

Analysis Population Description

The Full Analysis Set 1 included 806 randomized subjects who received at least 1 dose of double-blind study medication in Period II and provided at least 1 SeDBP measurement in Period II: 269 subjects in the OM/AML 40/10 mg group, 268 subjects in the OM/AML/HCTZ 40/10/12.5 mg group, and 269 subjects in the OM/AML/HCTZ 40/10/25 mg group.

Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25
Arm/Group Description	The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.	Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
Measure Participants	269	268	269
Least Squares Mean (Standard Error) [mm Hg]	-1.9 (0.75)	-5.1 (0.75)	-6.6 (0.75)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0001
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-HCTZ 25
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	In Non-responders, the Change in Seated Diastolic Blood Pressure Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg.
Description	Change in seated diastolic blood pressure from the beginning to the end of Period 4. Three cuff blood pressure measurements were taken at each visit.
Time Frame	week 24 to week 32

Outcome Measure Data

Analysis Population Description

The analysis population includes those participants who had blood pressure values at both the beginning and end of Period 4.

Arm/Group Title	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5 (Non-responders)	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 25 (Non-responders)
Arm/Group Description	Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4	Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4
Measure Participants	96	196
Least Squares Mean (Standard Error) [mm Hg]	-6.7 (0.84)	-7.9 (0.69)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1611
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	In Non-responders, the Change in Seated Systolic Blood Pressure Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg.
Description	Change in seated systolic blood pressure from the beginning to the end of Period 4. Three cuff blood pressure measurements were taken at each visit.
Time Frame	week 24 to week 32

Outcome Measure Data

Analysis Population Description

The analysis population includes those participants who had blood pressure values at both the beginning and end of Period 4.

Arm/Group Title	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5 (Non-responders)	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 25 (Non-responders)
Arm/Group Description	Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4	Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4
Measure Participants	96	196
Least Squares Mean (Standard Error) [mm Hg]	-5.5 (1.10)	-7.8 (0.89)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0451
	Comments
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	In Non-responders, the Number of Subject Meeting Their Blood Pressure Goals Associated With the Triple Combinations OM/AML/HCTZ 40/10/12.5 and 40/10/25 mg.
Description	The number of non-responding participants who achieved their blood pressure goals at the end of Period 4. Achieving blood pressure goal is defined as seated blood pressure <140/90 mm Hg; 130/80 mm Hg for participants with diabetes and/or other chronic renal and/or chronic cardiovascular disease. Three cuff blood pressure measurements were taken at each visit.
Time Frame	week 24 to week 32

Outcome Measure Data

Analysis Population Description

The analysis population includes those participants who had blood pressure values at both the beginning and end of Period 4.

Arm/Group Title	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5 (Non-responders)	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 25 (Non-responders)
Arm/Group Description	Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4	Participants finishing Period 3, but, who did not meet their blood pressure goals could receive this combination in the double-blind, randomized, Period 4
Measure Participants	96	196
Number [Participants]	31 11.5%	89 33.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0412
	Comments
	Method	ANCOVA
	Comments

9. Secondary Outcome

Title	In Non-responders, the Change in 24-hour Diastolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.
Description	In non-responders, the change in 24-hour diastolic blood pressure assessed by 24-hour ambulatory blood pressure measurement from the beginning to the end of Period 4.
Time Frame	Week 16 to week 32

Outcome Measure Data

Analysis Population Description

The analysis population includes those participants who had blood pressure values at both the beginning and end of Period 4.

Arm/Group Title	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25
Arm/Group Description	Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
Measure Participants	96	196
Least Squares Mean (Standard Error) [mm Hg]	-2.2 (0.96)	-4.4 (0.81)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0253
	Comments
	Method	ANCOVA
	Comments

10. Secondary Outcome

Title	In Non-responders, the Change in 24-hour Systolic Blood Pressure Assessed by 24-hour Ambulatory Blood Pressure Measurement.
Description	In non-responders, the change in 24-hour systolic blood pressure assessed by 24-hour ambulatory blood pressure measurement from the beginning to the end of Period 4.
Time Frame	Week 16 to week 32

Outcome Measure Data

Analysis Population Description

The analysis population includes those participants who had blood pressure values at both the beginning and end of Period 4.

Arm/Group Title	OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5	OLM 40-AML 10-HCTZ 25
Arm/Group Description	Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.	Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
Measure Participants	96	196
Least Squares Mean (Standard Error) [mm Hg]	-0.4 (1.44)	-4.3 (1.21)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg, OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0063
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	Adverse events were collected from screening to 14 days after the last dose of study medication. Adverse events are reported for week 1 through week 16.
Arm/Group Title	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg		OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5		OLM 40-AML 10-HCTZ 25
Arm/Group Description	The participants in this arm received these 2 drugs for the 8-week, single-blind, run-in Period 1. Participants could then randomized to this same combination for an additional 8 weeks in the double-blind, Period 2.		Participants could start receiving this combination in randomized, double-blind, 8-week Period 2. This combination was continued into single-blind, 8-week Period 3 for all participants entering Period 3.		Participants could start receiving this combination in randomized, double-blind, 8- week Period 2.
All Cause Mortality
	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg		OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5		OLM 40-AML 10-HCTZ 25
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg		OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5		OLM 40-AML 10-HCTZ 25
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/2204 (0.8%)		15/269 (5.6%)		3/270 (1.1%)
Cardiac disorders
Atrial flbrillation	0/2204 (0%)	0	1/269 (0.4%)	1	1/270 (0.4%)	1
Atrial flutter	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Cardiac failure	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Cardio-respiratory arrest	0/2204 (0%)	0	0/269 (0%)	0	1/270 (0.4%)	1
Intracardiac thrombus	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Myocardial infarction	1/2204 (0%)	1	1/269 (0.4%)	1	0/270 (0%)	0
Gastrointestinal disorders
Erosive oesophagitis	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Pancreatitis chronic	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Infections and infestations
Lobar pneumonia	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Injury, poisoning and procedural complications
Foot fracture	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Wrist fracture	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Metabolism and nutrition disorders
Ankle fracture	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Hyperuricaemia	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Musculoskeletal and connective tissue disorders
Musculoskeletal chest pain	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Osteoarthritis	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Osteochondrosis	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Pseudarthrosis	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Pseudoathrosis	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Polycythaemia vera	0/2204 (0%)	0	0/269 (0%)	0	1/270 (0.4%)	1
Prostate cancer	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Tonsil cancer	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Uterine leiomyoma	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Nervous system disorders
Cerebral infarction	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Sciatica	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Spinal claudication	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Transient ischaemic attack	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Psychiatric disorders
Mental disorder	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Transient ischemic attack	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Renal and urinary disorders
Renal failure	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Status asthmaticus	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Vascular disorders
Hypertensive crisis	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Peripheral aterial occlusive disease	0/2204 (0%)	0	1/269 (0.4%)	1	0/270 (0%)	0
Thrombophelibitis	1/2204 (0%)	1	0/269 (0%)	0	0/270 (0%)	0
Other (Not Including Serious) Adverse Events
	Olmesartan(OLM) 40 Mg-Amlodipine(AML) 10 mg		OLM 40-AML 10-Hydrochlorothiazide (HCTZ) 12.5		OLM 40-AML 10-HCTZ 25
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	113/2204 (5.1%)		7/269 (2.6%)		7/270 (2.6%)
General disorders
Oedema peripheral	113/2204 (5.1%)	113	7/269 (2.6%)	7	7/270 (2.6%)	7

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

A site may not publish results until after a multi-center publication has been submitted for publication or until one year after the study has ended, whichever occurs first. Then, the site will have the opportunity to publish the results, provided that Daiichi Sankyo Europe has had the opportunity to review and comment on the site's proposed publication prior to its being submitted for publication with the advice of company patent council and in accord with needs for subject protection.