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Long-Term Safety of Azilsartan Medoxomil and Chlorthalidone Compared to Olmesartan Medoxomil and Hydrochlorothiazide in Participants With Hypertension and Kidney Disease

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ClinicalTrials.gov Identifier: NCT01309828
Recruitment Status : Completed
First Posted : March 7, 2011
Results First Posted : December 13, 2013
Last Update Posted : December 13, 2013
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 Safety
Interventions Drug: Azilsartan medoxomil and chlorthalidone
Drug: Olmesartan medoxomil and hydrochlorothiazide
Enrollment 153
Recruitment Details Participants took part in the study at 46 investigative sites in the United States, Germany, Latvia, Lithuania, Poland, Slovakia, and the Ukraine from 02 March 2011 to 11 October 2012.
Pre-assignment Details Participants with high blood pressure and moderate renal impairment were enrolled in 1 of 2 once-daily (QD) treatment groups.
Arm/Group Title Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Hide Arm/Group Description United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks. United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks.
Period Title: Overall Study
Started 77 76
Completed 61 60
Not Completed 16 16
Reason Not Completed
Adverse Event             10             11
Voluntary Withdrawal             5             4
Major Protocol Deviation             0             1
Other             1             0
Arm/Group Title Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide Total
Hide Arm/Group Description United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks. United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Total of all reporting groups
Overall Number of Baseline Participants 77 76 153
Hide Baseline Analysis Population Description
[Not Specified]
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 77 participants 76 participants 153 participants
67.9  (8.24) 68.9  (9.10) 68.4  (8.66)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
<45 years 0 1 1
≥45 to <65 years 21 18 39
≥65 to <75 years 38 39 77
≥75 years 18 18 36
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
Female
45
  58.4%
31
  40.8%
76
  49.7%
Male
32
  41.6%
45
  59.2%
77
  50.3%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
White 57 62 119
Black or African American 18 12 30
Asian 2 2 4
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
Germany 10 9 19
Latvia 4 5 9
Lithuania 5 2 7
Poland 7 6 13
Slovakia 6 6 12
Ukraine 6 11 17
United States 39 37 76
Weight  
Mean (Standard Deviation)
Unit of measure:  Kg
Number Analyzed 77 participants 76 participants 153 participants
83.54  (17.894) 90.14  (21.587) 86.82  (20.025)
Height  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 77 participants 76 participants 153 participants
165.7  (9.65) 168.7  (9.48) 167.2  (9.65)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 77 participants 76 participants 153 participants
30.44  (6.226) 31.57  (6.524) 31.00  (6.380)
Smoking Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
Never Smoked 46 40 86
Current Smoker 11 11 22
Ex-smoker 20 25 45
Diabetes Status  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
Yes 33 32 65
No 44 44 88
Estimated glomerular filtration rate (eGFR)  
Mean (Standard Deviation)
Unit of measure:  mL/min/1.73 m^2
Number Analyzed 77 participants 76 participants 153 participants
48.25  (10.205) 47.73  (8.761) 47.99  (9.487)
Baseline estimated glomerular filtration rate (eGFR) category  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
≥45 and <60 mL/min/1.73 m^2 40 39 79
≥30 and <45 mL/min/1.73 m^2 31 33 64
≥60 mL/min/1.73 m^2 6 4 10
Systolic blood pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 77 participants 76 participants 153 participants
151.1  (10.30) 149.0  (7.80) 150.1  (9.18)
Diastolic blood pressure  
Mean (Standard Deviation)
Unit of measure:  Mm Hg
Number Analyzed 77 participants 76 participants 153 participants
84.8  (10.31) 84.7  (9.68) 84.7  (9.97)
Systolic blood pressure categories  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
<140 mm Hg 11 10 21
≥140 to <160 mm Hg 60 64 124
≥160 to <180 mm Hg 5 2 7
≥180 mm Hg 1 0 1
Diastolic blood pressure categories  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 76 participants 153 participants
<90 mm Hg 52 50 102
≥90 mm Hg 25 26 51
1.Primary Outcome
Title Number of Participants With at Least 1 Adverse Event (AE)
Hide Description An AE is any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have a causal relationship with this treatment. A serious AE is defined as any untoward medical occurrence that resulted in death, was life threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, led to a congenital anomaly/birth defect or was an important medical event that may have required intervention to prevent any of items above.
Time Frame From the first dose of open-label study drug until 14 days (or 30 days for a serious adverse event) after the last dose of open- label study drug (up to 56 weeks).
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set - All participants who received at least 1 dose of open-label study drug.
Arm/Group Title Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Hide Arm/Group Description:
United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks.
United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks.
Overall Number of Participants Analyzed 77 76
Measure Type: Number
Unit of Measure: participants
Adverse Events 68 58
Adverse Events Leading to Discontinuation 17 15
Serious Adverse Events 8 9
Serious Adverse Events Leading to Discontinuation 5 4
Death 0 1
2.Secondary Outcome
Title Percentage of Participants at Final Visit Who Achieve Target Systolic Blood Pressure <130 mm Hg
Hide Description Systolic blood pressure is the arithmetic mean of the 3 serial sitting systolic blood pressure measurements. Percentage of participants who achieve a sitting clinic systolic blood pressure response defined as less than 130 mm Hg at Week 52.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set participants (all randomized participants who received at least 1 dose of open-label study drug) with both Baseline and a post-baseline value; last observation carried forward was used.
Arm/Group Title Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Hide Arm/Group Description:
United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks.
United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks.
Overall Number of Participants Analyzed 75 74
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
69.3
(57.6 to 79.5)
78.4
(67.3 to 87.1)
3.Secondary Outcome
Title Percentage of Participants at Final Visit Who Achieved Target Diastolic Blood Pressure <80 mm Hg
Hide Description Diastolic blood pressure is the arithmetic mean of the 3 serial sitting diastolic blood pressure measurements. Percentage of participants at Week 52 who achieved a sitting clinic diastolic blood pressure response, defined as less than 80 mm Hg.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set participants (all randomized participants who received at least 1 dose of open-label study drug) with both Baseline and a post-baseline value; last observation carried forward was used.
Arm/Group Title Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Hide Arm/Group Description:
United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks.
United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks.
Overall Number of Participants Analyzed 75 74
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
80.0
(69.2 to 88.4)
87.8
(78.2 to 94.3)
4.Secondary Outcome
Title Percentage of Participants at Final Visit Who Achieved Both a Clinic Systolic and Diastolic Blood Pressure Response
Hide Description Systolic/diastolic blood pressure is the arithmetic mean of the 3 serial sitting systolic/diastolic blood pressure measurements. Percentage of participants who achieved both a sitting clinic systolic and diastolic blood pressure response, defined as systolic blood pressure less than 130 mm Hg and diastolic blood pressure less than 80 mm Hg at Week 52.
Time Frame Week 52
Hide Outcome Measure Data
Hide Analysis Population Description
Full analysis set participants (all randomized participants who received at least 1 dose of open-label study drug) with both Baseline and a post-baseline value; last observation carried forward was used.
Arm/Group Title Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Hide Arm/Group Description:
United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks.
United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks.
Overall Number of Participants Analyzed 75 74
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
58.7
(46.7 to 69.9)
73.0
(61.4 to 82.6)
Time Frame From the first dose of open-label study drug until 14 days (or 30 days for a serious adverse event) after the last dose of open-label study drug (up to 56 weeks).
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 + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Hide Arm/Group Description United States and Europe: Azilsartan medoxomil 20 mg plus chlorthalidone 12.5 mg fixed dose combination tablets (TAK-491CLD), titrated up to azilsartan medoxomil 40 mg plus chlorthalidone 25 mg orally, once daily for up to 52 weeks. United States: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets (OLM/HCTZ), titrated up to olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks. Europe: Olmesartan medoxomil 20 mg plus hydrochlorothiazide 12.5 mg fixed dose combination tablets, titrated up to olmesartan medoxomil 20 mg plus hydrochlorothiazide 25 mg orally, once daily for up to 52 weeks.
All-Cause Mortality
Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Affected / at Risk (%) Affected / at Risk (%)
Total   8/77 (10.39%)   9/76 (11.84%) 
Cardiac disorders     
Angina unstable  1  2/77 (2.60%)  1/76 (1.32%) 
Coronary artery disease  1  2/77 (2.60%)  1/76 (1.32%) 
Angina pectoris  1  0/77 (0.00%)  2/76 (2.63%) 
Atrial tachycardia  1  0/77 (0.00%)  1/76 (1.32%) 
Bradycardia  1  0/77 (0.00%)  1/76 (1.32%) 
Gastrointestinal disorders     
Vomiting  1  0/77 (0.00%)  1/76 (1.32%) 
General disorders     
Device malfunction  1  1/77 (1.30%)  0/76 (0.00%) 
Infections and infestations     
Gastroenteritis salmonella  1  1/77 (1.30%)  0/76 (0.00%) 
Injury, poisoning and procedural complications     
Concussion  1  0/77 (0.00%)  1/76 (1.32%) 
Hip fracture  1  0/77 (0.00%)  1/76 (1.32%) 
Metabolism and nutrition disorders     
Diabetes mellitus  1  0/77 (0.00%)  1/76 (1.32%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Pituitary tumour recurrent  1  0/77 (0.00%)  1/76 (1.32%) 
Nervous system disorders     
Cervicobrachial syndrome  1  1/77 (1.30%)  0/76 (0.00%) 
Hypoglycaemic coma  1  1/77 (1.30%)  0/76 (0.00%) 
Renal and urinary disorders     
Renal failure acute  1  1/77 (1.30%)  0/76 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Pulmonary artery thrombosis  1  0/77 (0.00%)  1/76 (1.32%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Azilsartan Medoxomil + Chlorthalidone Olmesartan Medoxomil + Hydrochlorothiazide
Affected / at Risk (%) Affected / at Risk (%)
Total   52/77 (67.53%)   41/76 (53.95%) 
Gastrointestinal disorders     
Diarrhoea  1  1/77 (1.30%)  4/76 (5.26%) 
General disorders     
Asthenia  1  3/77 (3.90%)  4/76 (5.26%) 
Infections and infestations     
Bronchitis  1  4/77 (5.19%)  3/76 (3.95%) 
Pharygitis  1  0/77 (0.00%)  4/76 (5.26%) 
Investigations     
Blood creatinine increased  1  34/77 (44.16%)  29/76 (38.16%) 
Metabolism and nutrition disorders     
Hyperuricaemia  1  3/77 (3.90%)  4/76 (5.26%) 
Hypokalaemia  1  4/77 (5.19%)  3/76 (3.95%) 
Nervous system disorders     
Dizziness  1  6/77 (7.79%)  5/76 (6.58%) 
Headache  1  8/77 (10.39%)  2/76 (2.63%) 
Vascular disorders     
Hypotension  1  4/77 (5.19%)  3/76 (3.95%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 15.0
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: Medical Director, Clinical Science
Organization: Takeda
Phone: 800-778-2860
EMail: clinicaltrialregistry@tpna.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01309828     History of Changes
Other Study ID Numbers: TAK-491CLD_309
2010-023098-21 ( EudraCT Number )
U1111-1119-5131 ( Registry Identifier: WHO )
NL35552.072.11 ( Registry Identifier: CCMO )
First Submitted: March 4, 2011
First Posted: March 7, 2011
Results First Submitted: September 28, 2013
Results First Posted: December 13, 2013
Last Update Posted: December 13, 2013