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Safety and Tolerability of Azilsartan Medoxomil Plus Chlorthalidone Compared to Olmesartan Medoxomil Plus Hydrochlorothiazide in Participants With Essential Hypertension

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ClinicalTrials.gov Identifier: NCT00996281
Recruitment Status : Completed
First Posted : October 16, 2009
Results First Posted : November 12, 2012
Last Update Posted : November 12, 2012
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Essential Hypertension
Interventions Drug: Azilsartan medoxomil and chlorthalidone
Drug: Olmesartan medoxomil and hydrochlorothiazide
Enrollment 837
Recruitment Details Participants took part in the study at 79 investigative sites in the United States, Netherlands, Poland, the United Kingdom and Germany from 27 October 2009 to 17 November 2011.
Pre-assignment Details Participants with a diagnosis of essential hypertension were randomized to receive open-label treatment with either Azilsartan Medoxomil and Chlorthalidone or Olmesartan Medoxomil and Hydrochlorothiazide for up to 52 weeks.
Arm/Group Title Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide
Hide Arm/Group Description Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of azilsartan medoxomil 80 mg and chlorthalidone 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control. Participants in the United States: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg. Participants in Europe: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control.
Period Title: Overall Study
Started 418 419
Completed 287 330
Not Completed 131 89
Reason Not Completed
Adverse Event             75             37
Major Protocol Deviation             6             7
Lost to Follow-up             14             16
Withdrawal by Subject             31             20
Lack of Efficacy             0             2
Other             5             7
Arm/Group Title Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide Total
Hide Arm/Group Description Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of azilsartan medoxomil 80 mg and chlorthalidone 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control. Participants in the United States: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg. Participants in Europe: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control. Total of all reporting groups
Overall Number of Baseline Participants 418 419 837
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 418 participants 419 participants 837 participants
58.5  (10.79) 57.6  (10.80) 58.1  (10.80)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
<45 years 46 48 94
45 to 64 years 251 259 510
65 to 74 years 94 93 187
≥75 years 27 19 46
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
Female
192
  45.9%
173
  41.3%
365
  43.6%
Male
226
  54.1%
246
  58.7%
472
  56.4%
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
Hispanic or Latino 40 41 81
Non-Hispanic or Latino 209 205 414
Not collected 169 172 341
Missing 0 1 1
[1]
Measure Description: Ethnicity was only collected from U.S. sites.
Race/Ethnicity, Customized   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
American Indian or Alaska Native 4 5 9
Asian 4 7 11
Black or African American 72 74 146
Native Hawaiian or Other Pacific Islander 0 0 0
White 341 336 677
Multiracial 3 3 6
[1]
Measure Description: Participants could choose more than 1 category for race. Participants who choose more than 1 race category are included in each category indicated and are also included in the multiracial category.
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
Poland 52 54 106
United States 249 247 496
Netherlands 56 58 114
Germany 22 21 43
United Kingdom 39 39 78
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 418 participants 419 participants 837 participants
169.9  (10.2) 169.6  (10.1) 169.8  (10.1)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 418 participants 419 participants 837 participants
91.00  (21.025) 92.00  (21.727) 91.50  (21.373)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 418 participants 419 participants 837 participants
31.4  (6.21) 31.9  (6.63) 31.7  (6.42)
Smoking history  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
Never smoked 214 205 419
Current smoker 82 78 160
Ex-smoker 122 136 258
Diabetes Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
Yes 64 59 123
No 354 360 714
Estimated glomerular filtration rate  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
Moderate impairment: ≥30 and <60 ml/min/1.73 m^2 54 43 97
Mild impairment: ≥60 and <90 ml/min/1.73 m^2 275 265 540
Normal: ≥90 ml/min/1.73 m^2 87 110 197
Missing 2 1 3
Chronic Kidney Disease (CKD) status   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
Yes 59 51 110
No 359 368 727
[1]
Measure Description: Participants were considered to have CKD if their estimated glomerular filtration rate (GFR) was <60 mL/min/1.73 m^2 or urinary albumin:creatinine ratio (UACR) was >200 mg albumin/g creatinine at Screening.
Systolic blood pressure  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
≥140 - < 160 mmHg 1 1 2
≥160 - < 180 mmHg 382 385 767
≥180 mm Hg 35 33 68
Diastolic blood pressure  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 418 participants 419 participants 837 participants
< 90 mmHg 107 103 210
≥90 mmHg 311 316 627
1.Primary Outcome
Title Percentage of Participants With at Least 1 Adverse Event
Hide Description An adverse event is defined as any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product without regard to causality.
Time Frame From Week 0 (Day 1) to Week 52.
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set: All participants who received at least 1 dose of study medication.
Arm/Group Title Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide
Hide Arm/Group Description:
Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of azilsartan medoxomil 80 mg and chlorthalidone 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control.
Participants in the United States: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg. Participants in Europe: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control.
Overall Number of Participants Analyzed 418 419
Measure Type: Number
Unit of Measure: percentage of participants
78.5 76.4
2.Secondary Outcome
Title Percentage of Participants With Serum Creatinine Elevations Greater Than 50% From Baseline and Greater Than the Upper Limit of Normal (ULN)
Hide Description Serum creatinine was measured at every visit and evaluated as a laboratory parameter of special interest. The percentage of participants with creatinine increase ≥50% from Baseline and greater than ULN was summarized: - At any visit (includes transient and persistent elevations). - At the Final Visit (includes persistent elevations and participants whose first elevation may have been at the Final Visit). - At least 2 consecutive visits (includes only persistent elevations).
Time Frame Baseline and Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set.
Arm/Group Title Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide
Hide Arm/Group Description:
Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of azilsartan medoxomil 80 mg and chlorthalidone 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control.
Participants in the United States: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg. Participants in Europe: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control.
Overall Number of Participants Analyzed 418 419
Measure Type: Number
Unit of Measure: percentage of participants
At any postbaseline visit 14.2 5.8
at the Final Visit 5.9 1.0
≥2 consecutive elevations 5.1 1.2
Time Frame Treatment-emergent adverse events are adverse events that started after the first dose of double-blind study drug and no more than 14 days (or 30 days for a serious adverse event) after the last dose of study drug.
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide
Hide Arm/Group Description Azilsartan medoxomil 40 mg and chlorthalidone 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of azilsartan medoxomil 80 mg and chlorthalidone 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control. Participants in the United States: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 40 mg and hydrochlorothiazide 25 mg. Participants in Europe: Olmesartan medoxomil 20 mg and hydrochlorothiazide 12.5 mg combination tablet, orally, once daily for up to 52 weeks. For participants who did not achieve target blood pressure by Week 4, titration to a maximum dose of Olmesartan medoxomil 20 mg and hydrochlorothiazide 25 mg. Additional antihypertensive agents could be added as needed to achieve blood pressure control.
All-Cause Mortality
Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide
Affected / at Risk (%) Affected / at Risk (%)
Total   24/418 (5.74%)   26/419 (6.21%) 
Cardiac disorders     
Angina pectoris  1  0/418 (0.00%)  2/419 (0.48%) 
Atrial fibrillation  1  1/418 (0.24%)  1/419 (0.24%) 
Cardiac arrest  1  1/418 (0.24%)  0/419 (0.00%) 
Cardiogenic shock  1  1/418 (0.24%)  0/419 (0.00%) 
Coronary artery disease  1  0/418 (0.00%)  1/419 (0.24%) 
Mitral valve incompetence  1  1/418 (0.24%)  0/419 (0.00%) 
Myocardial infarction  1  0/418 (0.00%)  1/419 (0.24%) 
Congenital, familial and genetic disorders     
Hydrocele  1  1/418 (0.24%)  0/419 (0.00%) 
Ear and labyrinth disorders     
Vertigo  1  0/418 (0.00%)  1/419 (0.24%) 
Gastrointestinal disorders     
Colitis ulcerative  1  1/418 (0.24%)  0/419 (0.00%) 
Gastritis  1  0/418 (0.00%)  1/419 (0.24%) 
Hemorrhoid  1  0/418 (0.00%)  1/419 (0.24%) 
Pancreatitis acute  1  1/418 (0.24%)  0/419 (0.00%) 
Rectal hemorrhage  1  0/418 (0.00%)  1/419 (0.24%) 
General disorders     
Non-cardiac chest pain  1  1/418 (0.24%)  2/419 (0.48%) 
Drowning  1  1/418 (0.24%)  0/419 (0.00%) 
Hepatobiliary disorders     
Biliary colic  1  1/418 (0.24%)  0/419 (0.00%) 
Cholelitiasis  1  1/418 (0.24%)  0/419 (0.00%) 
Infections and infestations     
Pneumonia  1  0/418 (0.00%)  2/419 (0.48%) 
Septic shock  1  2/418 (0.48%)  0/419 (0.00%) 
Bronchitis  1  1/418 (0.24%)  0/419 (0.00%) 
Bronchopneumonia  1  1/418 (0.24%)  0/419 (0.00%) 
Cellulitis  1  0/418 (0.00%)  1/419 (0.24%) 
Diverticulitis  1  0/418 (0.00%)  1/419 (0.24%) 
Endocarditis  1  1/418 (0.24%)  0/419 (0.00%) 
Postoperative wound infection  1  1/418 (0.24%)  0/419 (0.00%) 
Rectal abscess  1  0/418 (0.00%)  1/419 (0.24%) 
Sepsis  1  1/418 (0.24%)  0/419 (0.00%) 
Urinary tract infection  1  1/418 (0.24%)  0/419 (0.00%) 
Injury, poisoning and procedural complications     
Road traffic accident  1  1/418 (0.24%)  2/419 (0.48%) 
Clavicle fracture  1  0/418 (0.00%)  1/419 (0.24%) 
Contusion  1  1/418 (0.24%)  0/419 (0.00%) 
Femur fracture  1  0/418 (0.00%)  1/419 (0.24%) 
Fibula fracture  1  0/418 (0.00%)  1/419 (0.24%) 
Gun shot wound  1  0/418 (0.00%)  1/419 (0.24%) 
Head injury  1  1/418 (0.24%)  0/419 (0.00%) 
Hip fracture  1  0/418 (0.00%)  1/419 (0.24%) 
Joint dislocation  1  1/418 (0.24%)  0/419 (0.00%) 
Rib fracture  1  0/418 (0.00%)  1/419 (0.24%) 
Skeletal injury  1  1/418 (0.24%)  0/419 (0.00%) 
Tibia fracture  1  0/418 (0.00%)  1/419 (0.24%) 
Wound secretion  1  1/418 (0.24%)  0/419 (0.00%) 
Investigations     
Blood creatinine increased  1  0/418 (0.00%)  2/419 (0.48%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  1/418 (0.24%)  1/419 (0.24%) 
Intervertebral disc protrusion  1  2/418 (0.48%)  0/419 (0.00%) 
Osteoarthritis  1  1/418 (0.24%)  1/419 (0.24%) 
Lumbar spinal stenosis  1  1/418 (0.24%)  0/419 (0.00%) 
Pseudarthrosis  1  1/418 (0.24%)  0/419 (0.00%) 
Vertebral foraminal stenosis  1  1/418 (0.24%)  0/419 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Bladder transitional cell carcinoma  1  0/418 (0.00%)  1/419 (0.24%) 
Breast cancer  1  1/418 (0.24%)  0/419 (0.00%) 
Breast cancer stage II  1  0/418 (0.00%)  1/419 (0.24%) 
Malignant melanoma  1  1/418 (0.24%)  0/419 (0.00%) 
Prostate cancer  1  1/418 (0.24%)  0/419 (0.00%) 
Renal cancer  1  1/418 (0.24%)  0/419 (0.00%) 
Nervous system disorders     
Syncope  1  2/418 (0.48%)  0/419 (0.00%) 
Loss of consciousness  1  1/418 (0.24%)  0/419 (0.00%) 
Presyncope  1  0/418 (0.00%)  1/419 (0.24%) 
Radicular syndrome  1  1/418 (0.24%)  0/419 (0.00%) 
Transient ischaemic attack  1  0/418 (0.00%)  1/419 (0.24%) 
Psychiatric disorders     
Major depression  1  1/418 (0.24%)  0/419 (0.00%) 
Renal and urinary disorders     
Renal failure acute  1  0/418 (0.00%)  1/419 (0.24%) 
Reproductive system and breast disorders     
Rectocele  1  1/418 (0.24%)  0/419 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Chronic obstructive pulmonary disease  1  1/418 (0.24%)  1/419 (0.24%) 
Pulmonary embolism  1  2/418 (0.48%)  0/419 (0.00%) 
Bronchitis chronic  1  0/418 (0.00%)  1/419 (0.24%) 
Interstitial lung disease  1  0/418 (0.00%)  1/419 (0.24%) 
Pulmonary mass  1  0/418 (0.00%)  1/419 (0.24%) 
Respiratory failure  1  0/418 (0.00%)  1/419 (0.24%) 
Vascular disorders     
Arteriosclerosis  1  0/418 (0.00%)  1/419 (0.24%) 
Orthostatic hypotension  1  1/418 (0.24%)  0/419 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (14.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Azilsartan Medoxomil and Chlorthalidone Olmesartan Medoxomil and Hydrochlorothiazide
Affected / at Risk (%) Affected / at Risk (%)
Total   217/418 (51.91%)   183/419 (43.68%) 
Gastrointestinal disorders     
Diarrhoea  1  20/418 (4.78%)  21/419 (5.01%) 
Nausea  1  20/418 (4.78%)  21/419 (5.01%) 
General disorders     
Fatigue  1  21/418 (5.02%)  17/419 (4.06%) 
Infections and infestations     
Nasopharyngitis  1  51/418 (12.20%)  48/419 (11.46%) 
Upper respiratory tract infection  1  20/418 (4.78%)  27/419 (6.44%) 
Investigations     
Blood creatinine increased  1  90/418 (21.53%)  35/419 (8.35%) 
Nervous system disorders     
Dizziness  1  68/418 (16.27%)  53/419 (12.65%) 
Headache  1  31/418 (7.42%)  46/419 (10.98%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (14.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Sr. VP, Clinical Science
Organization: Takeda Global Research and Development Center, Inc.
Phone: 800-778-2860
EMail: clinicaltrialregistry@tpna.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT00996281     History of Changes
Other Study ID Numbers: TAK-491CLD_308
2008-008260-28 ( Registry Identifier: EudraCT )
U1111-1111-7891 ( Other Identifier: WHO )
First Submitted: October 12, 2009
First Posted: October 16, 2009
Results First Submitted: October 15, 2012
Results First Posted: November 12, 2012
Last Update Posted: November 12, 2012