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出境医 / 临床实验 / The Effect of Nebivolol in Hypertensive Patients With Coronary Arterial Spasm

The Effect of Nebivolol in Hypertensive Patients With Coronary Arterial Spasm

Study Description
Brief Summary:
The correlation between endothelial dysfunction and the risk of coronary heart disease is well known through previous studies. The degradation of the function of nitric oxide acting on the endothelium of blood vessels is mainly explained by reduction of synthesis, loss due to oxidative stress, and decreased sensitivity to vascular dilatation action. In particular, patients with high blood pressure have been known to have impaired vascular endothelial function through animal experiments and several clinical studies, mainly due to increased biomechanical friction in the blood vessels and decreased biological availability of nitric oxide, which in turn causes incongruity in the production of nitric monoxide and changes in normal vascular dilatation. There have also been reports recently that early diagnosis and treatment may improve endothelial dysfunction and prevent the progression of coronary artery disease. However, the reality is that the drugs available in vasospastic angina patients with endothelial dysfunction are very limited. Until recently, beta-blockers were reported to inhibit vascular dilatation of adrenaline stimuli, a drug corresponding to relative contraindications in vasospastic angina patients, with one study reporting that propranolol cannot, but rather exacerbates, vasospastic angina. However, a series of reports on the vascular dilatation of the recently developed third-generation beta-blockers have reinvented the role of beta-blockers in vasospastic angina, especially nebivolol (selective, continuous beta-blockers) is known to act on β-1 adrenaline receptor blockings and endothelium to create vascular dilatation, and also to stimulate β-3 adrenaline receptors to cause nitric oxide generation and antioxidant effects in the endothelium of blood vessels. Therefore, this clinical trial seeks to find whether nebivolol will inhibit vascular contraction in hypertensive patients and will work in angiospastic angina patients.

Condition or disease Intervention/treatment Phase
Coronary Vasospasm Drug: Nebivolol Drug: Diltiazem Drug: Nebivolol+Diltiazem Phase 4

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 51 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Group 1: Nebivolol group Group 2: Diltiazem group Group 2: Nebivolol + Diltiazem group
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: The Effect of Nebivolol in Hypertensive Patients With Coronary Arterial Spasm
Actual Study Start Date : January 1, 2018
Actual Primary Completion Date : March 31, 2019
Actual Study Completion Date : March 31, 2019
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Nebivolol group
Oral Nebivolol 5mg / day (2 weeks) -> 10mg / day (10 weeks)
 Drug: Nebivolol
Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
Placebo Comparator: Diltiazem group
Oral Diltiazem 90mg / day (2 weeks) -> 180mg / day (10 weeks)
 Drug: Diltiazem
Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
Placebo Comparator: Nebivolol+Diltiazem group
Oral Nebivolol 2.5mg / day + Oral Diltiazem 45mg / day (2 weeks) -> Oral Nebivolol 5mg / day + Oral Diltiazem 90mg / day (10 weeks)
 Drug: Nebivolol+Diltiazem
Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
Outcome Measures
Primary Outcome Measures :
  1. Changes in coronary spasm [ Time Frame: Baseline to 12 weeks ]
    The descriptive statistics (mean subject number, standard deviation, median value, minimum value, and maximum value) of changes in the baseline and 12-week outcomes will be presented for each treatment group, and the comparison between the three groups for ANOVA or ANOVA Kruskal-Wallis test. Changes in each group will be analyzed using Paired t-test or Wilcoxon signed rank test. An ANCOVA analysis will be performed when there are more influencing factors.


Secondary Outcome Measures :
  1. Changes in Quality of Life [ Time Frame: Baseline to 12 weeks ]
    Changes in Quality of Life based on Seattle Angina Questionnaire

  2. Changes in mean sitting systolic blood pressure and mean sitting diastolic blood pressure [ Time Frame: Baseline to 6, 12 weeks ]
    Changes in mean sitting systolic blood pressure and mean sitting diastolic blood pressure

  3. Percentage of target blood pressure reached [ Time Frame: Baseline to 6, 12 weeks ]
    Percentage of target blood pressure reached from baseline to 6, 12 weeks


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   20 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • hypertension (stage I-2: Systolic blood pressure 140-179mmHg and diastolic blood pressure 90-109mmHg)
  • 20 to 80 years old
  • diagnosed with vasospastic angina through coronary angiography and provocation test
  • available to outpatient treatment
  • voluntarily signed a written consent to participate in the clinical trial

Exclusion Criteria:

  1. Previous history of hypersensitivity to beta blockers or calcium channel blockers
  2. History of dementia or accompanying psychiatric illness or history of drug abuse
  3. Those who participated in other clinical trials within 1 month before screening
  4. A person who is unable to perform compliance with the plan and procedures, or who has been judged by the tester to be in a medical condition inappropriate for participation
  5. Study subjects who are taking drugs that can affect the study drug efficacy evaluation (ACE inhibitors, angiotensin blockers, beta blockers other than clinical trial drugs, calcium antagonists other than clinical trial drugs, diuretics other than indapamide). These subjects are allowed to participate after a wash-out period of at least 2 weeks
  6. Malignant hypertension (with retinal hemorrhage or papilledema) or known moderate or severe retinopathy (retinal hemorrhage within the last 6 months, visual disturbance, retinal microaneurysm)
  7. A history of secondary hypertension and all suspected secondary hypertension: coarctation of the aorta, hyperaldosteronism, renal artery stenosis, Cushing's disease, chromatin-positive cell tumor, polycystic kidney disease, etc.
  8. Patients with orthostatic hypotension with symptoms
  9. Patients with severe heart disease (heart failure New York Heart Association class 3 and 4), recent 6-month ischemic heart disease (angina pectoris, myocardial infarction), percutaneous coronary intervention, or coronary artery bypass surgery)
  10. Patients with severe cerebrovascular disease (stroke, cerebral infarction, cerebral hemorrhage within the last 6 months)
  11. Patients with anuria or severe renal failure (creatinine clearance <30 mL / min)
  12. Severe liver failure or AST or ALT> 3 times the upper limit of normal, biliary obstruction, biliary cirrhosis, cholestasis
  13. Gastrointestinal diseases and surgery patients that may affect the absorption, distribution, metabolism, and excretion of drugs, current active gastritis and gastrointestinal / rectal bleeding that the tester considers clinically significant, active inflammatory bowel syndrome within the last 12 months
  14. Pregnant and lactating women, those who have a pregnancy plan during the trial and do not agree with the appropriate method of contraception
Contacts and Locations

Locations
Layout table for location information
Korea, Republic of
Korea University Anam Hospital
Seoul, Korea, Republic of, 02841
Sponsors and Collaborators
Korea University Anam Hospital
Korea University Guro Hospital
Korea Unversity Ansan Hospital
Severance Hospital
Tracking Information
First Submitted Date  ICMJE April 24, 2019
First Posted Date  ICMJE April 29, 2019
Last Update Posted Date March 10, 2020
Actual Study Start Date  ICMJE January 1, 2018
Actual Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 25, 2019) 		Changes in coronary spasm [ Time Frame: Baseline to 12 weeks ]
The descriptive statistics (mean subject number, standard deviation, median value, minimum value, and maximum value) of changes in the baseline and 12-week outcomes will be presented for each treatment group, and the comparison between the three groups for ANOVA or ANOVA Kruskal-Wallis test. Changes in each group will be analyzed using Paired t-test or Wilcoxon signed rank test. An ANCOVA analysis will be performed when there are more influencing factors.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 25, 2019)
  • Changes in Quality of Life [ Time Frame: Baseline to 12 weeks ]
    Changes in Quality of Life based on Seattle Angina Questionnaire
  • Changes in mean sitting systolic blood pressure and mean sitting diastolic blood pressure [ Time Frame: Baseline to 6, 12 weeks ]
    Changes in mean sitting systolic blood pressure and mean sitting diastolic blood pressure
  • Percentage of target blood pressure reached [ Time Frame: Baseline to 6, 12 weeks ]
    Percentage of target blood pressure reached from baseline to 6, 12 weeks
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE The Effect of Nebivolol in Hypertensive Patients With Coronary Arterial Spasm
Official Title  ICMJE The Effect of Nebivolol in Hypertensive Patients With Coronary Arterial Spasm
Brief Summary The correlation between endothelial dysfunction and the risk of coronary heart disease is well known through previous studies. The degradation of the function of nitric oxide acting on the endothelium of blood vessels is mainly explained by reduction of synthesis, loss due to oxidative stress, and decreased sensitivity to vascular dilatation action. In particular, patients with high blood pressure have been known to have impaired vascular endothelial function through animal experiments and several clinical studies, mainly due to increased biomechanical friction in the blood vessels and decreased biological availability of nitric oxide, which in turn causes incongruity in the production of nitric monoxide and changes in normal vascular dilatation. There have also been reports recently that early diagnosis and treatment may improve endothelial dysfunction and prevent the progression of coronary artery disease. However, the reality is that the drugs available in vasospastic angina patients with endothelial dysfunction are very limited. Until recently, beta-blockers were reported to inhibit vascular dilatation of adrenaline stimuli, a drug corresponding to relative contraindications in vasospastic angina patients, with one study reporting that propranolol cannot, but rather exacerbates, vasospastic angina. However, a series of reports on the vascular dilatation of the recently developed third-generation beta-blockers have reinvented the role of beta-blockers in vasospastic angina, especially nebivolol (selective, continuous beta-blockers) is known to act on β-1 adrenaline receptor blockings and endothelium to create vascular dilatation, and also to stimulate β-3 adrenaline receptors to cause nitric oxide generation and antioxidant effects in the endothelium of blood vessels. Therefore, this clinical trial seeks to find whether nebivolol will inhibit vascular contraction in hypertensive patients and will work in angiospastic angina patients.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Group 1: Nebivolol group Group 2: Diltiazem group Group 2: Nebivolol + Diltiazem group
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Coronary Vasospasm
Intervention  ICMJE
  • Drug: Nebivolol
    Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
  • Drug: Diltiazem
    Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
  • Drug: Nebivolol+Diltiazem
    Patients are randomly assigned to a ratio of 1: 1: 1, divided into 3 groups.
Study Arms  ICMJE
  • Active Comparator: Nebivolol group
    Oral Nebivolol 5mg / day (2 weeks) -> 10mg / day (10 weeks)
    Intervention: Drug: Nebivolol
  • Placebo Comparator: Diltiazem group
    Oral Diltiazem 90mg / day (2 weeks) -> 180mg / day (10 weeks)
    Intervention: Drug: Diltiazem
  • Placebo Comparator: Nebivolol+Diltiazem group
    Oral Nebivolol 2.5mg / day + Oral Diltiazem 45mg / day (2 weeks) -> Oral Nebivolol 5mg / day + Oral Diltiazem 90mg / day (10 weeks)
    Intervention: Drug: Nebivolol+Diltiazem
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 25, 2019) 		51
Original Actual Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE March 31, 2019
Actual Primary Completion Date March 31, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • hypertension (stage I-2: Systolic blood pressure 140-179mmHg and diastolic blood pressure 90-109mmHg)
  • 20 to 80 years old
  • diagnosed with vasospastic angina through coronary angiography and provocation test
  • available to outpatient treatment
  • voluntarily signed a written consent to participate in the clinical trial

Exclusion Criteria:

  1. Previous history of hypersensitivity to beta blockers or calcium channel blockers
  2. History of dementia or accompanying psychiatric illness or history of drug abuse
  3. Those who participated in other clinical trials within 1 month before screening
  4. A person who is unable to perform compliance with the plan and procedures, or who has been judged by the tester to be in a medical condition inappropriate for participation
  5. Study subjects who are taking drugs that can affect the study drug efficacy evaluation (ACE inhibitors, angiotensin blockers, beta blockers other than clinical trial drugs, calcium antagonists other than clinical trial drugs, diuretics other than indapamide). These subjects are allowed to participate after a wash-out period of at least 2 weeks
  6. Malignant hypertension (with retinal hemorrhage or papilledema) or known moderate or severe retinopathy (retinal hemorrhage within the last 6 months, visual disturbance, retinal microaneurysm)
  7. A history of secondary hypertension and all suspected secondary hypertension: coarctation of the aorta, hyperaldosteronism, renal artery stenosis, Cushing's disease, chromatin-positive cell tumor, polycystic kidney disease, etc.
  8. Patients with orthostatic hypotension with symptoms
  9. Patients with severe heart disease (heart failure New York Heart Association class 3 and 4), recent 6-month ischemic heart disease (angina pectoris, myocardial infarction), percutaneous coronary intervention, or coronary artery bypass surgery)
  10. Patients with severe cerebrovascular disease (stroke, cerebral infarction, cerebral hemorrhage within the last 6 months)
  11. Patients with anuria or severe renal failure (creatinine clearance <30 mL / min)
  12. Severe liver failure or AST or ALT> 3 times the upper limit of normal, biliary obstruction, biliary cirrhosis, cholestasis
  13. Gastrointestinal diseases and surgery patients that may affect the absorption, distribution, metabolism, and excretion of drugs, current active gastritis and gastrointestinal / rectal bleeding that the tester considers clinically significant, active inflammatory bowel syndrome within the last 12 months
  14. Pregnant and lactating women, those who have a pregnancy plan during the trial and do not agree with the appropriate method of contraception
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 20 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Korea, Republic of
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03930433
Other Study ID Numbers  ICMJE NevibololSpasm
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Soon Jun Hong, Korea University Anam Hospital
Study Sponsor  ICMJE Korea University Anam Hospital
Collaborators  ICMJE
  • Korea University Guro Hospital
  • Korea Unversity Ansan Hospital
  • Severance Hospital
Investigators  ICMJE Not Provided
PRS Account Korea University Anam Hospital
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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