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One-Year Safety and Tolerability Study of Azilsartan Medoxomil in Participants With Essential Hypertension

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ClinicalTrials.gov Identifier: NCT00695955
Recruitment Status : Completed
First Posted : June 12, 2008
Results First Posted : April 19, 2011
Last Update Posted : April 19, 2011
Sponsor:
Information provided by:
Takeda

Study Type Interventional
Study Design Allocation: Non-Randomized;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Hypertension
Interventions Drug: Azilsartan medoxomil with or without add-on chlorthalidone
Drug: Azilsartan medoxomil with or without add-on hydrochlorothiazide
Enrollment 669
Recruitment Details Participants enrolled at 39 investigative sites in Chile, Mexico and the United States from 22 June 2007 to 30 April 2010.
Pre-assignment Details Participants with essential hypertension were enrolled in a once-daily (QD) treatment group.
Arm/Group Title Azilsartan Medoxomil
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Cohort 1: Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved.

Cohort 2: Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved.

Period Title: Cohort 1
Started 362
Completed 260
Not Completed 102
Reason Not Completed
Adverse Event             26
Protocol Violation             2
Lost to Follow-up             30
Withdrawal by Subject             25
Lack of Efficacy             3
Other             16
Period Title: Cohort 2
Started 307
Completed 203
Not Completed 104
Reason Not Completed
Adverse Event             24
Protocol Violation             5
Lost to Follow-up             38
Withdrawal by Subject             28
Lack of Efficacy             4
Other             5
Arm/Group Title Azilsartan Medoxomil
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Cohort 1: Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved.

Cohort 2: Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved.

Overall Number of Baseline Participants 669
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[Not Specified]
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 669 participants
<45 years (Cohort 1) 81
Between 45 and 64 years (Cohort 1) 233
≥65 years (Cohort 1) 48
<45 years (Cohort 2) 90
Between 45 and 64 years (Cohort 2) 193
≥65 years (Cohort 2) 24
Sex/Gender, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 669 participants
Female (Cohort 1) 173
Male (Cohort 1) 189
Female (Cohort 2) 144
Male (Cohort 2) 163
1.Primary Outcome
Title Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 1.
Hide Description Treatment-emergent adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug.
Time Frame 56 weeks.
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Full Analysis Set.
Arm/Group Title Cohort 1
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Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved.
Overall Number of Participants Analyzed 362
Measure Type: Number
Unit of Measure: participants
Number of Participants 267
Percentage of Participants 73.8
2.Primary Outcome
Title Number of Participants Reporting One or More Treatment-emergent Adverse Events From Day 1 Through End of the Study - Cohort 2.
Hide Description Treatment-emergent adverse events are defined as any unfavorable and unintended sign, symptom or disease temporally associated with the use of a medicinal product reported from first dose of study drug through 14 days after the last dose of study drug, or if a serious adverse event, within 30 days after the last dose of study drug.
Time Frame 56 weeks.
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Full Analysis Set.
Arm/Group Title Cohort 2
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Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved.
Overall Number of Participants Analyzed 307
Measure Type: Number
Unit of Measure: participants
Number of Participants 241
Percentage of Participants 78.5
3.Secondary Outcome
Title Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 1.
Hide Description The change between sitting clinic systolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time Frame 52 weeks
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Hide Analysis Population Description
Full Analysis Set.
Arm/Group Title Cohort 1
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Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved.
Overall Number of Participants Analyzed 362
Mean (Standard Deviation)
Unit of Measure: mmHg
Week 4 -10.1  (15.21)
Week 8 -13.1  (16.72)
Week 12 -21.5  (15.80)
Week 16 -25.4  (15.09)
Week 26 -26.3  (15.97)
Week 36 -27.3  (16.63)
Week 46 -28.1  (17.21)
Week 56 -25.2  (18.05)
Final Visit -22.1  (18.64)
4.Secondary Outcome
Title Change From Baseline in Sitting Clinic Systolic Blood Pressure - Cohort 2
Hide Description The change between sitting clinic systolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time Frame 52 weeks
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set.
Arm/Group Title Cohort 2
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Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved.
Overall Number of Participants Analyzed 307
Mean (Standard Deviation)
Unit of Measure: mmHg
Week 4 -14.4  (13.57)
Week 8 -17.5  (15.07)
Week 12 -23.8  (15.97)
Week 16 -26.2  (15.65)
Week 26 -24.8  (15.25)
Week 36 -22.5  (14.89)
Week 46 -23.8  (15.35)
Week 56 -24.2  (15.96)
Final Visit -22.7  (17.14)
5.Secondary Outcome
Title Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 1.
Hide Description The change between sitting clinic diastolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time Frame 52 weeks.
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Hide Analysis Population Description
Full Analysis Set.
Arm/Group Title Cohort 1
Hide Arm/Group Description:
Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved.
Overall Number of Participants Analyzed 362
Mean (Standard Deviation)
Unit of Measure: mmHg
Week 4 -8.9  (8.73)
Week 8 -11.0  (9.97)
Week 12 -15.9  (9.12)
Week 16 -18.7  (9.06)
Week 26 -18.6  (9.15)
Week 36 -19.9  (9.13)
Week 46 -19.8  (9.67)
Week 56 -18.4  (9.52)
Final Visit -16.5  (10.23)
6.Secondary Outcome
Title Change From Baseline in Sitting Clinic Diastolic Blood Pressure - Cohort 2.
Hide Description The change between sitting clinic diastolic blood pressure measured at each week assessed relative to the baseline measurement. Mean calculated by using the average (arithmetic mean) of 3 measurements performed at each visit.
Time Frame 52 weeks.
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
Full Analysis Set.
Arm/Group Title Cohort 2
Hide Arm/Group Description:
Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved.
Overall Number of Participants Analyzed 307
Mean (Standard Deviation)
Unit of Measure: mmHg
Week 4 -10.6  (9.23)
Week 8 -12.3  (9.05)
Week 12 -16.8  (9.48)
Week 16 -18.2  (10.28)
Week 26 -17.7  (10.95)
Week 36 -16.2  (9.08)
Week 46 -17.2  (9.57)
Week 56 -17.9  (10.85)
Final Visit -16.2  (11.05)
Time Frame Treatment-emergent adverse events (TEAEs) defined as any AEs, regardless of relationship to study drug, that occur after the first dose of study drug and within 14 days after last dose, or if an SAE, within 30 days 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 Cohort 1 Cohort 2
Hide Arm/Group Description Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with chlorthalidone 25 mg, once-daily, if target blood pressure not achieved. Azilsartan medoxomil 40 mg, tablets, orally, once daily for four weeks; increased to azilsartan medoxomil 80 mg, tablets, orally, once daily for remainder of 56-week treatment period, if tolerated. Additional antihypertensive medications added, beginning with hydrochlorothiazide 12.5 to 25 mg, once-daily, if target blood pressure not achieved.
All-Cause Mortality
Cohort 1 Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Cohort 1 Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   30/362 (8.29%)   22/307 (7.17%) 
Blood and lymphatic system disorders     
Anaemia  1  0/362 (0.00%)  1/307 (0.33%) 
Cardiac disorders     
Coronary artery disease  1  2/362 (0.55%)  0/307 (0.00%) 
Acute myocardial infarction  1  1/362 (0.28%)  0/307 (0.00%) 
Angina pectoris  1  0/362 (0.00%)  1/307 (0.33%) 
Atrial flutter  1  0/362 (0.00%)  1/307 (0.33%) 
Atrioventricular block  1  0/362 (0.00%)  1/307 (0.33%) 
Myocardial infarction  1  0/362 (0.00%)  1/307 (0.33%) 
Tachycardia  1  0/362 (0.00%)  1/307 (0.33%) 
Eye disorders     
Maculopathy  1  1/362 (0.28%)  0/307 (0.00%) 
Gastrointestinal disorders     
Small intestinal obstruction  1  1/362 (0.28%)  1/307 (0.33%) 
Abdominal pain upper  1  1/362 (0.28%)  0/307 (0.00%) 
Appendiceal mucocoele  1  1/362 (0.28%)  0/307 (0.00%) 
Appendicitis perforated  1  1/362 (0.28%)  0/307 (0.00%) 
Diarrhoea  1  1/362 (0.28%)  0/307 (0.00%) 
Dyspepsia  1  1/362 (0.28%)  0/307 (0.00%) 
Gastritis  1  0/362 (0.00%)  1/307 (0.33%) 
Gastrooesophageal reflux disease  1  0/362 (0.00%)  1/307 (0.33%) 
Oesophagitis  1  1/362 (0.28%)  0/307 (0.00%) 
Retroperitoneal haemorrhage  1  0/362 (0.00%)  1/307 (0.33%) 
Vomiting  1  1/362 (0.28%)  0/307 (0.00%) 
General disorders     
Chest pain  1  1/362 (0.28%)  2/307 (0.65%) 
Hepatobiliary disorders     
Cholecystitis  1  1/362 (0.28%)  0/307 (0.00%) 
Infections and infestations     
Acquired immunodeficiency syndrome  1  1/362 (0.28%)  0/307 (0.00%) 
Cellulitis  1  0/362 (0.00%)  1/307 (0.33%) 
Diverticulitis  1  1/362 (0.28%)  0/307 (0.00%) 
Gastroenteritis viral  1  0/362 (0.00%)  1/307 (0.33%) 
Septic shock  1  1/362 (0.28%)  0/307 (0.00%) 
Staphylococcal infection  1  1/362 (0.28%)  0/307 (0.00%) 
Subcutaneous abscess  1  0/362 (0.00%)  1/307 (0.33%) 
Urinary tract infection  1  1/362 (0.28%)  0/307 (0.00%) 
Viral infection  1  1/362 (0.28%)  0/307 (0.00%) 
Injury, poisoning and procedural complications     
Road traffic accident  1  1/362 (0.28%)  1/307 (0.33%) 
Alcohol poisoning  1  0/362 (0.00%)  1/307 (0.33%) 
Splenic haematoma  1  0/362 (0.00%)  1/307 (0.33%) 
Thermal burn  1  1/362 (0.28%)  0/307 (0.00%) 
Tibia fracture  1  1/362 (0.28%)  0/307 (0.00%) 
Investigations     
Blood creatinine increased  1  1/362 (0.28%)  0/307 (0.00%) 
Metabolism and nutrition disorders     
Dehydration  1  1/362 (0.28%)  0/307 (0.00%) 
Diabetic ketoacidosis  1  1/362 (0.28%)  0/307 (0.00%) 
Hypokalaemia  1  1/362 (0.28%)  0/307 (0.00%) 
Hypovolaemia  1  0/362 (0.00%)  1/307 (0.33%) 
Musculoskeletal and connective tissue disorders     
Compartment syndrome  1  1/362 (0.28%)  0/307 (0.00%) 
Pain in extremity  1  0/362 (0.00%)  1/307 (0.33%) 
Spinal osteoarthritis  1  1/362 (0.28%)  0/307 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Breast cancer  1  1/362 (0.28%)  0/307 (0.00%) 
Prostate cancer  1  1/362 (0.28%)  0/307 (0.00%) 
Thyroid cancer  1  1/362 (0.28%)  0/307 (0.00%) 
Nervous system disorders     
Syncope vasovagal  1  2/362 (0.55%)  0/307 (0.00%) 
Cerebrovascular accident  1  1/362 (0.28%)  0/307 (0.00%) 
Syncope  1  1/362 (0.28%)  0/307 (0.00%) 
Transient ischaemic attack  1  0/362 (0.00%)  1/307 (0.33%) 
Psychiatric disorders     
Completed suicide  1  1/362 (0.28%)  0/307 (0.00%) 
Depression  1  0/362 (0.00%)  1/307 (0.33%) 
Post-traumatic stress disorder  1  0/362 (0.00%)  1/307 (0.33%) 
Psychotic disorder  1  0/362 (0.00%)  1/307 (0.33%) 
Renal and urinary disorders     
Renal impairment  1  1/362 (0.28%)  0/307 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Asthma  1  1/362 (0.28%)  1/307 (0.33%) 
Pulmonary embolism  1  0/362 (0.00%)  2/307 (0.65%) 
Skin and subcutaneous tissue disorders     
Stevens-Johnson syndrome  1  0/362 (0.00%)  1/307 (0.33%) 
Vascular disorders     
Hypotension  1  1/362 (0.28%)  1/307 (0.33%) 
Deep vein thrombosis  1  0/362 (0.00%)  1/307 (0.33%) 
Malignant hypertension  1  0/362 (0.00%)  1/307 (0.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (11.1)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Cohort 1 Cohort 2
Affected / at Risk (%) Affected / at Risk (%)
Total   134/362 (37.02%)   106/307 (34.53%) 
General disorders     
Fatigue  1  32/362 (8.84%)  16/307 (5.21%) 
Infections and infestations     
Upper respiratory tract infection  1  25/362 (6.91%)  20/307 (6.51%) 
Urinary tract infection  1  26/362 (7.18%)  11/307 (3.58%) 
Nervous system disorders     
Dizziness  1  52/362 (14.36%)  44/307 (14.33%) 
Headache  1  38/362 (10.50%)  28/307 (9.12%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (11.1)
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.
No publication related to study results will be published prior to publication of a multi-center report submitted for publication within 18 months after conclusion or termination of a study at all study sites. Results publications will be submitted to sponsor for review 60 days in advance of publication. Sponsor can require removal of confidential information unrelated to study results. Sponsor can embargo a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Name/Title: Sr. VP, Clinical Science
Organization: Takeda Global Research and Development Center, Inc.
Phone: 800-778-2860
Responsible Party: Sr. VP, Clinical Science, Takeda Global Research & Development Center, Inc.
ClinicalTrials.gov Identifier: NCT00695955     History of Changes
Other Study ID Numbers: 01-05-TL-491-006
U1111-1113-8874 ( Registry Identifier: WHO )
First Submitted: June 10, 2008
First Posted: June 12, 2008
Results First Submitted: March 24, 2011
Results First Posted: April 19, 2011
Last Update Posted: April 19, 2011