Comparison of Efficacy and Safety of Combination Therapy and Monotherapy of Candesartan and Amlodipine for Dose-Finding in Patients With Essential Hypertension

A Multi-center, Randomized, Double-blind, Phase II Clinical Trial to Evaluate the Efficacy and Safety of Combination Therapy vs. Monotherapy of Candesartan and Amlodipine for Dose-Finding in Patients With Essential Hypertension

The purpose of this study is to explore the optimal dose of fixed-dose combination of candesartan cilexetil and amlodipine besylate by examining the safety and efficacy of the combination therapy compared to each of the monotherapy in patients with essential hypertension.

Study Overview

• Status: Completed
• Conditions: Essential Hypertension
• Intervention / Treatment: Drug: Candesartan Cilexetil 8mg; Drug: Candesartan Cilexetil 16mg; Drug: Amlodipine 5mg; Drug: Amlodipine 10mg

• Study Type: Interventional
• Enrollment (Actual): 392
• Phase: Phase 2

Contacts and Locations

Study Locations

• Korea, Republic of
  • Bucheon
    • Wonmi-gu, Bucheon, Korea, Republic of
      • Catholic University of Korea Bucheon St. Mary's Hospital
  • Busan
    • Busanjin-gu, Busan, Korea, Republic of
      • Inje University Busan Paik Hospital
    • Seo-gu, Busan, Korea, Republic of
      • Pusan National University Hospital
  • Daegu
    • Joong-gu, Daegu, Korea, Republic of
      • Keimyung University Dongsan Medical Center
    • Joong-gu, Daegu, Korea, Republic of
      • Kyungpook National University Hospital
    • Nam- gu, Daegu, Korea, Republic of
      • Daegu Catholic University Medical Center
  • Goyang-si, Gyeoggi-do
    • Ilsandong-gu, Goyang-si, Gyeoggi-do, Korea, Republic of
      • DongGuk University ilsan Hospital
  • Gwangju
    • Dong-Gu, Gwangju, Korea, Republic of
      • Chonnam National University Hospital
  • Gyeoggi-do
    • Uijeongbu-si, Gyeoggi-do, Korea, Republic of
      • Catholic University of Korea Uijeongbu St. Mary's hospital
  • Incheon
    • Namdong-gu, Incheon, Korea, Republic of
      • Gachon University Gil Hospital
  • Jeollanam-do
    • Suncheon-si, Jeollanam-do, Korea, Republic of
      • St. Carollo General Hospital
  • Kangwon-Do
    • Wonju, Kangwon-Do, Korea, Republic of
      • Wonju Severance Christian Hospital
  • Seoul
    • Dongdaemun-gu, Seoul, Korea, Republic of
      • Catholic University of Korea St. Paul's Hospital
    • Dongdaemun-gu, Seoul, Korea, Republic of
      • Kyunghee University Medical Center
    • Gangdong-Gu, Seoul, Korea, Republic of
      • Kyung Hee University Hospital at Gangdong
    • Gangdong-gu, Seoul, Korea, Republic of
      • Hallym University Kangdong Sacred Heart Hospital
    • Gangdong-gu, Seoul, Korea, Republic of
      • VHS( Veterans Medical Service) Medical Center
    • Gwangjin-gu, Seoul, Korea, Republic of
      • Konkuk University Medical Center
    • Jongro-gu, Seoul, Korea, Republic of
      • Seoul National University Hospital
    • Seocho-Gu, Seoul, Korea, Republic of
      • Catholic University of Korea Seoul St. Mary's Hospital
    • Seongbuk-Gu, Seoul, Korea, Republic of
      • Korea University Anam Hospital
    • Yeongdeungpo-gu, Seoul, Korea, Republic of
      • Catholic University of Korea Yeouido St. Mary's Hospital
  • Ulsan
    • Dong-gu, Ulsan, Korea, Republic of
      • Ulsan University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Male or female patients greater than or equal to 19 years of age
2. Subject who was diagnosed with essential hypertension or after administer the antihypertensive drug (Subject who may temporarily suspend antihypertensive treatment based on doctor's decision)
3. Subject who have voluntarily agreed to participate in the trial and signed the written informed consent form

Exclusion Criteria:

1. Subject with severe hypertension (in a selected arm with msSBP ≥ 200 mmHg or msDBP ≥ 115 mmHg) during the Screening and Randomized Trial.
2. Subject with difference of the blood pressure of over 20 mmHg for SBP or 10 mmHg for diastolic blood pressure (DSP) between three consecutive measurements in a selected arm during the screening visit
3. Secondary hypertension (such as, coarctation of the aorta, primary hyperaldosteronism, renal artery stenosis, Cushing's disease, pheochromocytoma, polycystic kidney disease, etc.)
4. Symptomatic orthostatic hypotension
5. Severe heart failure( New York Heart Association(NYHA) Class III/IV)
6. Subject with acute coronary syndrome(myocardial infarction or unstable angina), peripheral vascular disease within the past 6 months
7. History of switching to another Antiarrhythmic drugs(not including electrolyte correction), or received Cardioversion or ICU treatment within the past 6 months
8. Type 1 diabetes mellitus or Uncontrolled Type 2 diabetes mellitus (HbA1c > 9.0%)
9. Subject with Haemodynamic disturbance, heart valve disease with structural defects
10. Severe cerebrovascular disease (stroke, cerebral infarction, or cerebral hemorrhage, etc. within the past 6 months)
11. Severe eye disease (retinal hemorrhage, visual impairment, retinal microaneurysm, etc. within the past 6 months)
12. Autoimmune diseases (rheumatoid arthritis, systemic lupus erythematosus, etc.)
13. Chronic inflammatory disease requiring continuous anti-inflammatory treatment
14. Clinically significant Renal or liver impairment, or laboratory abnormalities such as Ccr: below 30ml/min or Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) > 3 x Upper Limit Normal (ULN)
15. Hypokalaemia(Serum potassium < 3.5 mmol/L) or hyperkalaemia(Serum potassium > 5.5 mmol/L)
16. Subject with gastrointestinal disease(such as Crohn's disease, gastric ulcer, acute or chronic pancreatitis) or history of gastrointestinal surgery(not including appendectomy or hernia surgery) that might significantly alter the absorption of the drug
17. history of allergy or hypersensitivity to Angiotensin II Receptor Blockers(Candesartan) or Calcium Channel Blocker(amlodipine)
18. Subject with heredity defects such as galactose intolerance, Lapp lactose deficiency, or glucose-galactose malabsorption
19. Subject requiring concomitant use of other antihypertensive or contraindicated drugs( Tizanidine, dolasetron, Itraconazole, potassium, potassium-sparing diuretics, etc.) during the clinical trial
20. history of malignant tumors within the past 5 years
21. history of alcohol or drug abuse
22. Pregnant women and lactating mothers

23. Women who is planning to be pregnant during or 2 months after the study, or women or men who are not using medically acceptable methods of contraception *

    * progestin oral or implant contraceptive, intra-uterine device, condom, partner with surgical sterilization, etc.

24. Use of other investigational products within the past 1 month
25. Subject who are judged by the investigator unsuitable to participate in the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

8

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Candesartan Cilexetil (CC) 8mg; Candesartan Cilexetil 8mg, once a day for 8 weeks	Drug: Candesartan Cilexetil 8mg; Candesartan Cilexetil 8mg Daily oral administration for 8 weeks; Other Names: Atacand 8mg
Experimental: CC 16mg; Candesartan Cilexetil 16mg, once a day for 8 weeks	Drug: Candesartan Cilexetil 16mg; Candesartan Cilexetil 16mg Daily oral administration for 8 weeks; Other Names: Atacand 16mg
Experimental: Amlodipine(AML) 5mg; Amlodipine 5mg, once a day for 8 weeks	Drug: Amlodipine 5mg; Amlodipine 5mg Daily oral administration for 8 weeks; Other Names: Norvasc 5mg
Experimental: AML 10mg; Amlodipine 10mg, once a day for 8 weeks	Drug: Amlodipine 10mg; Amlodipine 10mg Daily oral administration for 8 weeks; Other Names: Norvasc 10mg
Experimental: CC 8mg / AML 5mg; Candesartan 8mg and Amlodipine 5mg, once a day for 8 weeks	Drug: Candesartan Cilexetil 8mg; Candesartan Cilexetil 8mg Daily oral administration for 8 weeks; Other Names: Atacand 8mg; Drug: Amlodipine 5mg; Amlodipine 5mg Daily oral administration for 8 weeks; Other Names: Norvasc 5mg
Experimental: CC 8mg / AML 10mg; Candesartan 8mg and Amlodipine 10mg, once a day for 8 weeks	Drug: Candesartan Cilexetil 8mg; Candesartan Cilexetil 8mg Daily oral administration for 8 weeks; Other Names: Atacand 8mg; Drug: Amlodipine 10mg; Amlodipine 10mg Daily oral administration for 8 weeks; Other Names: Norvasc 10mg
Experimental: CC 16mg / AML 5mg; Candesartan 16mg and Amlodipine 5mg, once a day for 8 weeks	Drug: Candesartan Cilexetil 16mg; Candesartan Cilexetil 16mg Daily oral administration for 8 weeks; Other Names: Atacand 16mg; Drug: Amlodipine 5mg; Amlodipine 5mg Daily oral administration for 8 weeks; Other Names: Norvasc 5mg
Experimental: CC 16mg / AML 10mg; Candesartan 16mg and Amlodipine 10mg, once a day for 8 weeks	Drug: Candesartan Cilexetil 16mg; Candesartan Cilexetil 16mg Daily oral administration for 8 weeks; Other Names: Atacand 16mg; Drug: Amlodipine 10mg; Amlodipine 10mg Daily oral administration for 8 weeks; Other Names: Norvasc 10mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Change mean sitting Diastolic Blood Pressure (msDBP) at week 8 compared to baseline	Week 8

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change mean sitting Diastolic Blood Pressure (msDBP) at week 4 compared to baseline		Week 4
Change mean sitting Systolic Blood Pressure (msSBP) at week 4 and 8 compared to baseline		Week 4 and 8
Proportion of patients achieving treatment goal at week 4 and 8: < 140/90 mmHg	Joint National Committee VII Guideline Treatment goal: < 140/90 mmHg (< 130/80 mmHg, diabetic or chronic renal failure patient)	Week 4 and 8
Blood Pressure Response rate at week 4 and 8: msSBP reduction ≥ 20 mmHg and msDBP reduction ≥ 10 mmHg		Week 4 and 8

Collaborators and Investigators

• Sponsor: Shin Poong Pharmaceutical Co. Ltd.
• Investigators: Study Director: Chong-Jin Kim, Kyunghee University Hospital at Gangdong

Publications and helpful links

General Publications

• Sohn IS, Kim CJ, Ahn T, Youn HJ, Jeon HK, Ihm SH, Cho EJ, Chung WB, Chae SC, Kim WS, Nam CW, Park SM, Choi JY, Kim YK, Hong TJ, Lee HY, Cho JH, Shin ES, Yoon JH, Yang TH, Jeong MH, Lee JH, Park JI. Efficacy and Tolerability of Combination Therapy Versus Monotherapy with Candesartan and/or Amlodipine for Dose Finding in Essential Hypertension: A Phase II Multicenter, Randomized, Double-blind Clinical Trial. Clin Ther. 2017 Aug;39(8):1628-1638. doi: 10.1016/j.clinthera.2017.06.014. Epub 2017 Jul 19.

Study record dates

Study Major Dates

• Study Start: September 1, 2014
• Primary Completion (Actual): December 1, 2015
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: October 24, 2016
• First Submitted That Met QC Criteria: October 24, 2016
• First Posted (Estimate): October 26, 2016

Study Record Updates

• Last Update Posted (Estimate): November 22, 2016
• Last Update Submitted That Met QC Criteria: November 21, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: Vascular Diseases; Cardiovascular Diseases; Hypertension; Amlodipine; Antihypertensive Agents; Candesartan; Vasodilator Agents; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Calcium Channel Blockers
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension; Essential Hypertension; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Vasodilator Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Amlodipine; Candesartan; Candesartan cilexetil
• Other Study ID Numbers: SP-AC-002