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Candesartan Cilexetil / Hydrochlorothiazide Combination Tablets Special Drug Use Surveillance: Long-term Use (12 Months)

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ClinicalTrials.gov Identifier: NCT02016183
Recruitment Status : Completed
First Posted : December 19, 2013
Results First Posted : November 9, 2018
Last Update Posted : November 9, 2018
Sponsor:
Information provided by (Responsible Party):
Takeda

Study Type Observational
Study Design Observational Model: Cohort;   Time Perspective: Prospective
Condition Hypertension
Intervention Drug: Candesartan cilexetil / hydrochlorothiazide
Enrollment 3222
Recruitment Details Participants took part in the study at 557 investigative sites in Japan, from 01-Apr-2009 to 30-Sep-2012.
Pre-assignment Details Participants with a diagnosis of hypertension were enrolled to receive candesartan cilexetil/hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months as per routine medical practice.
Arm/Group Title Candesartan Cilexetil/Hydrochlorothiazide
Hide Arm/Group Description Candesartan cilexetil/Hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months. This drug should not be used as a first-line drug for hypertension treatment. Participants received interventions as part of routine medical care.
Period Title: Overall Study
Started 3222
Completed 3157
Not Completed 65
Reason Not Completed
Case Report Forms Uncollected             13
Protocol Violation             52
Arm/Group Title Candesartan Cilexetil/Hydrochlorothiazide
Hide Arm/Group Description Candesartan cilexetil/Hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months. This drug should not be used as a first-line drug for hypertension treatment. Participants received interventions as part of routine medical care.
Overall Number of Baseline Participants 3157
Hide Baseline Analysis Population Description
The safety analysis set was defined as all participants who were enrolled and completed the study.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3157 participants
69.6  (12.27)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Female
1746
  55.3%
Male
1411
  44.7%
Region of Enrollment   [1] 
Measure Type: Number
Unit of measure:  Participants
Japan Number Analyzed 3157 participants
3157
[1]
Measure Description: All participants were enrolled in Japan.
Healthcare Category   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Outpatient
3065
  97.1%
Inpatient
18
   0.6%
Inpatient and outpatient
74
   2.3%
[1]
Measure Description: Participants were categorized as outpatient, inpatient, and outpatient and inpatient (participants who were both outpatient and inpatient during some point at the time and 3 months prior to enrollment).
BMI   [1] 
Mean (Standard Deviation)
Unit of measure:  Kg/m^2
Number Analyzed 3157 participants
24.61  (3.885)
[1]
Measure Description: Body Mass Index = weight (kg)/[height (m)^2]
Waist Circumference  
Mean (Standard Deviation)
Unit of measure:  Cm
Number Analyzed 3157 participants
87.21  (10.458)
Smoking Classification  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Never smoked
2332
  73.9%
Current/Ex smoker
409
  13.0%
Unknown
416
  13.2%
Allergy/Predisposition to Hypersensitivity  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Had no Allergy/Predisposition to Hypersensitivity
2811
  89.0%
Had Allergy/Predisposition to Hypersensitivity
345
  10.9%
Unknown
1
   0.0%
Medical Complications   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Had no Medical Complications
798
  25.3%
Had Medical Complications
2359
  74.7%
[1]
Measure Description: Complications defined as a disease or a health condition for each participant at the start of study. Complications were classified as congenital anomalies, endocrine disorders, hematologic disorders, psychiatric and nervous system disorders, cardiovascular disorders, respiratory disorders, gastrointestinal (GI) disorders, renal disease and other complications. Other complications included all complications except for those mentioned above.
Medical History   [1] 
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Had no Medical History
2603
  82.5%
Had Medical History
552
  17.5%
Unknown
2
   0.1%
[1]
Measure Description: Medical history defined as a disease or a health condition for each participant before start of the study. Medical history was classified as congenital anomalies, hematologic disorders, psychiatric and nervous system disorders, cardiovascular disorders, respiratory disorders, GI disorders, hepatic and biliary disorders, renal disease and other medical history. Other medical history included all medical history except for those mentioned above.
Duration of Disease  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 3157 participants
7.12  (7.289)
Use of Antihypertensive Drug Prior to the Start of the Study Drug  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Had Not Used Antihypertensive Drug
185
   5.9%
Had Used Antihypertensive Drug
2972
  94.1%
Violation of Inclusion or Exclusion Criteria  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 3157 participants
Had No Violation
3154
  99.9%
Had Any Violation
3
   0.1%
1.Primary Outcome
Title Number of Participants Who Experience at Least One Adverse Drug Reactions (ADRs)
Hide Description ADRs are defined as adverse events (AEs) which are in the investigator’s opinion of causal relationship to the study treatment. AEs are defined as any unfavorable and unintended signs, symptoms or diseases temporally associated with the use of a medicinal product reported from the first dose of study drug to the last dose of study drug.
Time Frame Up to 12 months
Hide Outcome Measure Data
Hide Analysis Population Description
The safety analysis set was defined as all participants who were enrolled and completed the study.
Arm/Group Title Candesartan Cilexetil/Hydrochlorothiazide
Hide Arm/Group Description:
Candesartan cilexetil/Hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months. This drug should not be used as a first-line drug for hypertension treatment. Participants received interventions as part of routine medical care.
Overall Number of Participants Analyzed 3157
Measure Type: Count of Participants
Unit of Measure: Participants
283
   9.0%
2.Secondary Outcome
Title Changes From Baseline in Systolic Blood Pressure (SBP) at Each Time Point
Hide Description Reported data are changes in SBP from baseline at Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and final assessment.
Time Frame Baseline, and Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and Final assessment (up to 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points. Here 'n' is number of participants analyzed at the given time point.
Arm/Group Title Candesartan Cilexetil/Hydrochlorothiazide
Hide Arm/Group Description:
Candesartan cilexetil/Hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months. This drug should not be used as a first-line drug for hypertension treatment. Participants received interventions as part of routine medical care.
Overall Number of Participants Analyzed 3072
Mean (Standard Deviation)
Unit of Measure: mmHg
Change in SBP at Month 1 Number Analyzed 2775 participants
-13.3  (18.02)
Change in SBP at Month 2 Number Analyzed 2516 participants
-14.8  (18.48)
Change in SBP at Month 3 Number Analyzed 2456 participants
-15.4  (19.06)
Change in SBP at Month 4 Number Analyzed 2324 participants
-15.7  (19.34)
Change in SBP at Month 5 Number Analyzed 2205 participants
-15.6  (19.17)
Change in SBP at Month 6 Number Analyzed 2240 participants
-16.1  (18.94)
Change in SBP at Month 7 Number Analyzed 2146 participants
-15.8  (19.27)
Change in SBP at Month 8 Number Analyzed 2071 participants
-15.8  (19.12)
Change in SBP at Month 9 Number Analyzed 2006 participants
-16.4  (18.86)
Change in SBP at Month 10 Number Analyzed 1996 participants
-16.6  (18.60)
Change in SBP at Month 11 Number Analyzed 1903 participants
-17.0  (18.88)
Change in SBP at Month 12 Number Analyzed 1818 participants
-18.1  (18.86)
Change in SBP at Final Number Analyzed 3072 participants
-17.5  (19.87)
3.Secondary Outcome
Title Changes From Baseline in Diastolic Blood Pressure (DBP) at Each Time Point
Hide Description Reported data are changes in DBP from baseline at Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and final assessment.
Time Frame Baseline, and Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and Final assessment (up to 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points. Here 'n' is number of participants analyzed at the given time point.
Arm/Group Title Candesartan Cilexetil/Hydrochlorothiazide
Hide Arm/Group Description:
Candesartan cilexetil/Hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months. This drug should not be used as a first-line drug for hypertension treatment. Participants received interventions as part of routine medical care.
Overall Number of Participants Analyzed 3072
Mean (Standard Deviation)
Unit of Measure: mmHg
Change in DBP at Month 1 Number Analyzed 2775 participants
-6.5  (11.40)
Change in DBP at Month 2 Number Analyzed 2516 participants
-7.3  (11.52)
Change in DBP at Month 3 Number Analyzed 2456 participants
-7.6  (11.93)
Change in DBP at Month 4 Number Analyzed 2324 participants
-7.8  (11.97)
Change in DBP at Month 5 Number Analyzed 2205 participants
-7.8  (12.01)
Change in DBP at Month 6 Number Analyzed 2240 participants
-8.0  (12.12)
Change in DBP at Month 7 Number Analyzed 2146 participants
-8.1  (12.42)
Change in DBP at Month 8 Number Analyzed 2071 participants
-8.2  (12.32)
Change in DBP at Month 9 Number Analyzed 2006 participants
-8.5  (12.26)
Change in DBP at Month 10 Number Analyzed 1996 participants
-8.7  (12.49)
Change in DBP at Month 11 Number Analyzed 1903 participants
-8.5  (12.37)
Change in DBP at Month 12 Number Analyzed 1818 participants
-9.1  (12.23)
Change in DBP at Final Number Analyzed 3072 participants
-8.5  (12.59)
4.Secondary Outcome
Title Changes From Baseline in Pulse Rate at Each Time Point
Hide Description Reported data are changes in Pulse Rate from baseline at Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and final assessment.
Time Frame Baseline, and Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and Final assessment (up to 12 months)
Hide Outcome Measure Data
Hide Analysis Population Description
The efficacy assessment population was defined as participants who completed the study and had efficacy data at baseline and post-baseline time points. Here 'n' is number of participants analyzed at the given time point.
Arm/Group Title Candesartan Cilexetil/Hydrochlorothiazide
Hide Arm/Group Description:
Candesartan cilexetil/Hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months. This drug should not be used as a first-line drug for hypertension treatment. Participants received interventions as part of routine medical care.
Overall Number of Participants Analyzed 2120
Mean (Standard Deviation)
Unit of Measure: Beats per minutes
Change in Pulse Rate at Month 1 Number Analyzed 1817 participants
-1.3  (9.16)
Change in Pulse Rate at Month 2 Number Analyzed 1667 participants
-1.1  (9.76)
Change in Pulse Rate at Month 3 Number Analyzed 1622 participants
-1.3  (9.40)
Change in Pulse Rate at Month 4 Number Analyzed 1527 participants
-1.5  (9.91)
Change in Pulse Rate at Month 5 Number Analyzed 1464 participants
-1.3  (9.99)
Change in Pulse Rate at Month 6 Number Analyzed 1492 participants
-1.5  (10.23)
Change in Pulse Rate at Month 7 Number Analyzed 1415 participants
-1.1  (10.45)
Change in Pulse Rate at Month 8 Number Analyzed 1370 participants
-1.5  (10.08)
Change in Pulse Rate at Month 9 Number Analyzed 1352 participants
-1.6  (10.37)
Change in Pulse Rate at Month 10 Number Analyzed 1340 participants
-1.7  (10.58)
Change in Pulse Rate at Month 11 Number Analyzed 1278 participants
-1.5  (10.56)
Change in Pulse Rate at Month 12 Number Analyzed 1275 participants
-1.8  (10.35)
Change in Pulse Rate at Final assessment Number Analyzed 2120 participants
-1.6  (10.86)
Time Frame Up to 12 months
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of AEs 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. Participants may be represented in more than 1 category.
 
Arm/Group Title Candesartan Cilexetil/Hydrochlorothiazide
Hide Arm/Group Description Candesartan cilexetil/Hydrochlorothiazide 4 mg/6.25 mg or 8 mg/6.25 mg combination tablets, orally, once daily for up to 12 months. This drug should not be used as a first-line drug for hypertension treatment. Participants received interventions as part of routine medical care.
All-Cause Mortality
Candesartan Cilexetil/Hydrochlorothiazide
Affected / at Risk (%)
Total   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Candesartan Cilexetil/Hydrochlorothiazide
Affected / at Risk (%)
Total   72/3157 (2.28%) 
Cardiac disorders   
Acute myocardial infarction  1  2/3157 (0.06%) 
Angina pectoris  1  1/3157 (0.03%) 
Atrial fibrillation  1  2/3157 (0.06%) 
Cardiac failure  1  4/3157 (0.13%) 
Cardiac failure acute  1  1/3157 (0.03%) 
Cardiac failure chronic  1  1/3157 (0.03%) 
Myocardial infarction  1  1/3157 (0.03%) 
Acute coronary syndrome  1  1/3157 (0.03%) 
Ear and labyrinth disorders   
Vertigo  1  1/3157 (0.03%) 
Gastrointestinal disorders   
Gastric ulcer  1  1/3157 (0.03%) 
Gastrointestinal haemorrhage  1  1/3157 (0.03%) 
Ileus  1  1/3157 (0.03%) 
Melaena  1  1/3157 (0.03%) 
General disorders   
Chest discomfort  1  2/3157 (0.06%) 
Death  1 [1]  2/3157 (0.06%) 
Oedema peripheral  1  1/3157 (0.03%) 
Sudden death  1 [1]  2/3157 (0.06%) 
Infections and infestations   
Bronchopneumonia  1  1/3157 (0.03%) 
Pharyngitis  1  1/3157 (0.03%) 
Pneumonia  1  5/3157 (0.16%) 
Pyelonephritis acute  1  1/3157 (0.03%) 
Urinary tract infection  1  1/3157 (0.03%) 
Pneumonia bacterial  1  1/3157 (0.03%) 
Atypical mycobacterial infection  1  1/3157 (0.03%) 
Injury, poisoning and procedural complications   
Compression fracture  1  1/3157 (0.03%) 
Fall  1  4/3157 (0.13%) 
Fracture  1  2/3157 (0.06%) 
Subdural haematoma  1  1/3157 (0.03%) 
Tendon rupture  1  1/3157 (0.03%) 
Heat illness  1  1/3157 (0.03%) 
Investigations   
Blood creatinine increased  1  2/3157 (0.06%) 
Blood urea increased  1  2/3157 (0.06%) 
Metabolism and nutrition disorders   
Diabetes mellitus  1  1/3157 (0.03%) 
Hyperkalaemia  1  1/3157 (0.03%) 
Hyponatraemia  1  1/3157 (0.03%) 
Hypophagia  1  1/3157 (0.03%) 
Musculoskeletal and connective tissue disorders   
Back pain  1  2/3157 (0.06%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)   
Acute monocytic leukaemia  1  1/3157 (0.03%) 
Bile duct cancer  1  1/3157 (0.03%) 
Breast cancer recurrent  1  1/3157 (0.03%) 
Colon cancer  1  1/3157 (0.03%) 
Gastric cancer  1  2/3157 (0.06%) 
Metastases to liver  1  1/3157 (0.03%) 
Pancreatic carcinoma  1  1/3157 (0.03%) 
Pancreatic carcinoma metastatic  1  1/3157 (0.03%) 
Lung cancer metastatic  1  1/3157 (0.03%) 
Lung neoplasm malignant  1  3/3157 (0.10%) 
Metastases to central nervous system  1  1/3157 (0.03%) 
Nervous system disorders   
Brain stem infarction  1  1/3157 (0.03%) 
Cerebral haemorrhage  1  3/3157 (0.10%) 
Cerebral infarction  1  5/3157 (0.16%) 
Convulsion  1  1/3157 (0.03%) 
Loss of consciousness  1  1/3157 (0.03%) 
Transient ischaemic attack  1  1/3157 (0.03%) 
Cerebral artery stenosis  1  1/3157 (0.03%) 
Psychiatric disorders   
Completed suicide  1  1/3157 (0.03%) 
Renal and urinary disorders   
Renal disorder  1  1/3157 (0.03%) 
Renal failure acute  1  1/3157 (0.03%) 
Renal failure chronic  1  1/3157 (0.03%) 
Urinary retention  1  1/3157 (0.03%) 
Diabetic nephropathy  1  1/3157 (0.03%) 
Renal impairment  1  1/3157 (0.03%) 
Respiratory, thoracic and mediastinal disorders   
Dyspnoea  1  1/3157 (0.03%) 
Interstitial lung disease  1  1/3157 (0.03%) 
Pneumonia aspiration  1  1/3157 (0.03%) 
Pulmonary fibrosis  1  1/3157 (0.03%) 
Respiratory failure  1  1/3157 (0.03%) 
Vascular disorders   
Hypertension  1  1/3157 (0.03%) 
Hypotension  1  1/3157 (0.03%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA/J ver. 16.0
[1]
The reasons of events are not determined because assessment findings were insufficient to specify the reason.
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 2%
Candesartan Cilexetil/Hydrochlorothiazide
Affected / at Risk (%)
Total   158/3157 (5.00%) 
Investigations   
Blood uric acid increased  1  77/3157 (2.44%) 
Metabolism and nutrition disorders   
Hyperuricaemia  1  81/3157 (2.57%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA/J ver. 16.0
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
Organization: Takeda
Phone: 1-877-825-3327
EMail: trialdisclosures@takeda.com
Layout table for additonal information
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT02016183     History of Changes
Other Study ID Numbers: 220-011
JapicCTI-132362 ( Registry Identifier: JapicCTI )
First Submitted: December 14, 2013
First Posted: December 19, 2013
Results First Submitted: September 1, 2017
Results First Posted: November 9, 2018
Last Update Posted: November 9, 2018