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

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02016183
• Collaborator: (none)
• Enrollment: 3,222
• Location: 1
• Actual Duration (Months): 42
• Patients Per Site Per Month: 76.7

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of long-term use of candesartan cilexetil / hydrochlorothiazide combination tablets (ECARD) Combination Tablets LD&HD in hypertensive patients in the routine clinical setting

Condition or Disease	Intervention/Treatment	Phase
Hypertension	Drug: Candesartan cilexetil / hydrochlorothiazide

Detailed Description

This is a special drug use surveillance on long-term use of candesartan cilexetil / hydrochlorothiazide combination tablets (ECARD combination tablets) to evaluate in hypertensive patients in the routine clinical setting. Because the drug contains a diuretic (hydrochlorothiazide) , it is necessary to assess the safety, especially on serum uric acid. (the planned sample size is 3000).

The usual adult dosage is 1 tablet (4 mg/6.25 mg or 8 mg/6.25 mg as a candesartan cilexetil/hydrochlorothiazide) administered orally once daily. This drug should not be used as a first-line drug for hypertension treatment.

Study Design

• Study Type: Observational
• Actual Enrollment: 3222 participants
• Observational Model: Cohort
• Time Perspective: Prospective
• Official Title: ECARD Combination Tablets LD&HD Special Drug Use Surveillance: Long-term Use (12 Months)
• Actual Study Start Date: Apr 1, 2009
• Actual Primary Completion Date: Sep 30, 2012
• Actual Study Completion Date: Sep 30, 2012

Arms and Interventions

Arm	Intervention/Treatment
Candesartan cilexetil / hydrochlorothiazide 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.	Drug: Candesartan cilexetil / hydrochlorothiazide; Candesartan cilexetil / hydrochlorothiazide combination tablets; Other Names: ECARD® Combination Tablets LD&HD

Outcome Measures

Primary Outcome Measures

1. Number of Participants Who Experience at Least One Adverse Drug Reactions (ADRs) [Up to 12 months]

   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.

Secondary Outcome Measures

1. Changes From Baseline in Systolic Blood Pressure (SBP) at Each Time Point [Baseline, and Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and Final assessment (up to 12 months)]

   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.

2. Changes From Baseline in Diastolic Blood Pressure (DBP) at Each Time Point [Baseline, and Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and Final assessment (up to 12 months)]

   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.

3. Changes From Baseline in Pulse Rate at Each Time Point [Baseline, and Month 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, and Final assessment (up to 12 months)]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Hypertensive patients

Exclusion Criteria:

(1) Patients with a history of hypersensitivity to ingredients of ECARD LD&HD combination tablets, thiazides, or their analogues (e.g. sulphonamide derivatives such as chlortalidone) (2) Patients with anuria or patients under hemodialysis (3) Patients with acute renal failure (4) Patients with noticeably decreased Na and K levels in body fluids (5) Pregnant women or women planning to become pregnant

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Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Tokyo		Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Study Director, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT02016183
• Other Study ID Numbers: 220-011; JapicCTI-132362
• First Posted: Dec 19, 2013
• Last Update Posted: Nov 9, 2018
• Last Verified: Apr 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Takeda: Drug Therapy
• Additional relevant MeSH terms: Hypertension; Hydrochlorothiazide; Candesartan; Candesartan cilexetil

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 557 investigative sites in Japan, from 01-Apr-2009 to 30-Sep-2012.
Pre-assignment Detail	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
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

Baseline Characteristics

Arm/Group Title	Candesartan Cilexetil/Hydrochlorothiazide
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 Participants	3157
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	69.6 (12.27)
Sex: Female, Male (Count of Participants)
Female	1746 55.3%
Male	1411 44.7%
Region of Enrollment (Number) [Number]
Japan	3157 100%
Healthcare Category (Count of Participants)
Outpatient	3065 97.1%
Inpatient	18 0.6%
Inpatient and outpatient	74 2.3%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	24.61 (3.885)
Waist Circumference (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	87.21 (10.458)
Smoking Classification (Count of Participants)
Never smoked	2332 73.9%
Current/Ex smoker	409 13%
Unknown	416 13.2%
Allergy/Predisposition to Hypersensitivity (Count of Participants)
Had no Allergy/Predisposition to Hypersensitivity	2811 89%
Had Allergy/Predisposition to Hypersensitivity	345 10.9%
Unknown	1 0%
Medical Complications (Count of Participants)
Had no Medical Complications	798 25.3%
Had Medical Complications	2359 74.7%
Medical History (Count of Participants)
Had no Medical History	2603 82.5%
Had Medical History	552 17.5%
Unknown	2 0.1%
Duration of Disease (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	7.12 (7.289)
Use of Antihypertensive Drug Prior to the Start of the Study Drug (Count of Participants)
Had Not Used Antihypertensive Drug	185 5.9%
Had Used Antihypertensive Drug	2972 94.1%
Violation of Inclusion or Exclusion Criteria (Count of Participants)
Had No Violation	3154 99.9%
Had Any Violation	3 0.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Who Experience at Least One Adverse Drug Reactions (ADRs)
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

Outcome Measure Data

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
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.
Measure Participants	3157
Count of Participants [Participants]	283 9%

2. Secondary Outcome

Title	Changes From Baseline in Systolic Blood Pressure (SBP) at Each Time Point
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)

Outcome Measure Data

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
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.
Measure Participants	3072
Change in SBP at Month 1	-13.3 (18.02)
Change in SBP at Month 2	-14.8 (18.48)
Change in SBP at Month 3	-15.4 (19.06)
Change in SBP at Month 4	-15.7 (19.34)
Change in SBP at Month 5	-15.6 (19.17)
Change in SBP at Month 6	-16.1 (18.94)
Change in SBP at Month 7	-15.8 (19.27)
Change in SBP at Month 8	-15.8 (19.12)
Change in SBP at Month 9	-16.4 (18.86)
Change in SBP at Month 10	-16.6 (18.60)
Change in SBP at Month 11	-17.0 (18.88)
Change in SBP at Month 12	-18.1 (18.86)
Change in SBP at Final	-17.5 (19.87)

3. Secondary Outcome

Title	Changes From Baseline in Diastolic Blood Pressure (DBP) at Each Time Point
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)

Outcome Measure Data

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
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.
Measure Participants	3072
Change in DBP at Month 1	-6.5 (11.40)
Change in DBP at Month 2	-7.3 (11.52)
Change in DBP at Month 3	-7.6 (11.93)
Change in DBP at Month 4	-7.8 (11.97)
Change in DBP at Month 5	-7.8 (12.01)
Change in DBP at Month 6	-8.0 (12.12)
Change in DBP at Month 7	-8.1 (12.42)
Change in DBP at Month 8	-8.2 (12.32)
Change in DBP at Month 9	-8.5 (12.26)
Change in DBP at Month 10	-8.7 (12.49)
Change in DBP at Month 11	-8.5 (12.37)
Change in DBP at Month 12	-9.1 (12.23)
Change in DBP at Final	-8.5 (12.59)

4. Secondary Outcome

Title	Changes From Baseline in Pulse Rate at Each Time Point
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)

Outcome Measure Data

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
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.
Measure Participants	2120
Change in Pulse Rate at Month 1	-1.3 (9.16)
Change in Pulse Rate at Month 2	-1.1 (9.76)
Change in Pulse Rate at Month 3	-1.3 (9.40)
Change in Pulse Rate at Month 4	-1.5 (9.91)
Change in Pulse Rate at Month 5	-1.3 (9.99)
Change in Pulse Rate at Month 6	-1.5 (10.23)
Change in Pulse Rate at Month 7	-1.1 (10.45)
Change in Pulse Rate at Month 8	-1.5 (10.08)
Change in Pulse Rate at Month 9	-1.6 (10.37)
Change in Pulse Rate at Month 10	-1.7 (10.58)
Change in Pulse Rate at Month 11	-1.5 (10.56)
Change in Pulse Rate at Month 12	-1.8 (10.35)
Change in Pulse Rate at Final assessment	-1.6 (10.86)

Adverse Events

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
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 (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Candesartan Cilexetil/Hydrochlorothiazide
	Affected / at Risk (%)	# Events
Total	72/3157 (2.3%)
Cardiac disorders
Acute myocardial infarction	2/3157 (0.1%)
Angina pectoris	1/3157 (0%)
Atrial fibrillation	2/3157 (0.1%)
Cardiac failure	4/3157 (0.1%)
Cardiac failure acute	1/3157 (0%)
Cardiac failure chronic	1/3157 (0%)
Myocardial infarction	1/3157 (0%)
Acute coronary syndrome	1/3157 (0%)
Ear and labyrinth disorders
Vertigo	1/3157 (0%)
Gastrointestinal disorders
Gastric ulcer	1/3157 (0%)
Gastrointestinal haemorrhage	1/3157 (0%)
Ileus	1/3157 (0%)
Melaena	1/3157 (0%)
General disorders
Chest discomfort	2/3157 (0.1%)
Death	2/3157 (0.1%)
Oedema peripheral	1/3157 (0%)
Sudden death	2/3157 (0.1%)
Infections and infestations
Bronchopneumonia	1/3157 (0%)
Pharyngitis	1/3157 (0%)
Pneumonia	5/3157 (0.2%)
Pyelonephritis acute	1/3157 (0%)
Urinary tract infection	1/3157 (0%)
Pneumonia bacterial	1/3157 (0%)
Atypical mycobacterial infection	1/3157 (0%)
Injury, poisoning and procedural complications
Compression fracture	1/3157 (0%)
Fall	4/3157 (0.1%)
Fracture	2/3157 (0.1%)
Subdural haematoma	1/3157 (0%)
Tendon rupture	1/3157 (0%)
Heat illness	1/3157 (0%)
Investigations
Blood creatinine increased	2/3157 (0.1%)
Blood urea increased	2/3157 (0.1%)
Metabolism and nutrition disorders
Diabetes mellitus	1/3157 (0%)
Hyperkalaemia	1/3157 (0%)
Hyponatraemia	1/3157 (0%)
Hypophagia	1/3157 (0%)
Musculoskeletal and connective tissue disorders
Back pain	2/3157 (0.1%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute monocytic leukaemia	1/3157 (0%)
Bile duct cancer	1/3157 (0%)
Breast cancer recurrent	1/3157 (0%)
Colon cancer	1/3157 (0%)
Gastric cancer	2/3157 (0.1%)
Metastases to liver	1/3157 (0%)
Pancreatic carcinoma	1/3157 (0%)
Pancreatic carcinoma metastatic	1/3157 (0%)
Lung cancer metastatic	1/3157 (0%)
Lung neoplasm malignant	3/3157 (0.1%)
Metastases to central nervous system	1/3157 (0%)
Nervous system disorders
Brain stem infarction	1/3157 (0%)
Cerebral haemorrhage	3/3157 (0.1%)
Cerebral infarction	5/3157 (0.2%)
Convulsion	1/3157 (0%)
Loss of consciousness	1/3157 (0%)
Transient ischaemic attack	1/3157 (0%)
Cerebral artery stenosis	1/3157 (0%)
Psychiatric disorders
Completed suicide	1/3157 (0%)
Renal and urinary disorders
Renal disorder	1/3157 (0%)
Renal failure acute	1/3157 (0%)
Renal failure chronic	1/3157 (0%)
Urinary retention	1/3157 (0%)
Diabetic nephropathy	1/3157 (0%)
Renal impairment	1/3157 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/3157 (0%)
Interstitial lung disease	1/3157 (0%)
Pneumonia aspiration	1/3157 (0%)
Pulmonary fibrosis	1/3157 (0%)
Respiratory failure	1/3157 (0%)
Vascular disorders
Hypertension	1/3157 (0%)
Hypotension	1/3157 (0%)
Other (Not Including Serious) Adverse Events
	Candesartan Cilexetil/Hydrochlorothiazide
	Affected / at Risk (%)	# Events
Total	158/3157 (5%)
Investigations
Blood uric acid increased	77/3157 (2.4%)
Metabolism and nutrition disorders
Hyperuricaemia	81/3157 (2.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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.