Efficacy and Safety of Fimasartan Alone or Combined With HCTZ in Mexican Patients With Essential Hypertension

Study Overview
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Brief Summary
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Fimasartan (FMS) is an AT1 receptor antagonist indicated for once a day administration, currently approved for the treatment of essential hypertension in Corea and Mexico. As the safety and efficacy of FMS was initially demonstrated in Korea only, it was necessary to address the potential for ethnic factors to have an effect on the drug´s efficacy and safety in the Mexican population. To address this need, a cohort of 272 Mexican subjects with grades 1-2 essential hypertension were sequentially treated on a treat to target basis (target: sitting Diastolic Blood Pressure (sDBP) <90 mmHg) with 60 mg FMS once a day (8 weeks), either 120 mg FMS or 60 mg FMS+12.5 mg HCTZ once a day (randomized 4 week treatment period) and 120 mg FMS once a day (during 12 weeks) for a total treatment period of 24 weeks.

Detailed Description
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This was a prospective, open, multicentre, 24 week study of subjects with grade 1-2 essential hypertension eligible, according to the participating investigator's clinical judgement, to initial monotherapy. Consenting, eligible subjects at 13 Mexican participating centers were initially assigned to monotherapy with 60 mg FMS once a day. At treatment week 8, those subjects with a sDBP ≥90 mmHg were randomized to either 120 mg FMS or to 60 mg FMS + 12.5 mg hydrochlorothiazide (HCTZ) once a day during 4 weeks. At treatment week 12, all non-responding subjects were finally assigned to 120 mg FMS + 12.5 mg HCTZ for the remaining 12 weeks of the planned 24 week treatment period. At treatment weeks 8 and 12, those subjects with a sDBP < 90 mmHg remained on their assigned treatment for the rest of the study. This cohort study was designed to collect information on treatment effect (blood pressure changes from baseline/reference time and treatment response rates), and safety (i.e., incidence and characterization of clinical, laboratory and ECG adverse events); accordingly, subjects were assessed at treatment weeks 4, 8, 12, 16, 20 and 24 in terms of vital signs, clinical laboratory safety parameters, concomitant medications and adverse events. 12-lead ECG recordings were obtained from all subjects both at screening and at treatment week 24 and a subset of 11 subjects underwent both baseline and treatment week 8 24-hour ABPM recordings.

Official Title
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A 24-week Trial of the Effectiveness and Safety of Fimasartan 60 mg Alone as Initial Treatment and Its Randomized Escalation to Fimasartan 120 mg or Fimasartan 60 mg/HCTZ 12.5 mg in Mexican Patients With Grade 1 and 2 Essential Hypertension

Conditions
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Hypertension, Essential

Intervention / Treatment
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* Drug: Fimasartan
* Drug: Fimasartan; Hydrochlorothiazide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to understand the study subject information and to voluntarily grant their informed consent. Men or women, 18 to 70 years old. With grade 1 or 2 essential arterial hypertension based on a sitting diastolic blood pressure (DBP) ≥90 mmHg and ≤109 mmHg (MEXICAN OFFICIAL NORM 030-SSA). Trustworthiness and willingness to attend all the study follow-up visits , according to the investigator's judgment. Patients already on antihypertensive therapy, not adequately controlled and that, according to the investigator's judgment, could be safely submitted to a two-week washout period. Exclusion Criteria: Severe hypertension (Grade 3), with SBP≥180 mmHg and/or DBP≥110 mmHg, according to OFFICIAL MEXICAN NORM NOM 030-SSA criteria. Secondary hypertension. Impossibility to safely undergo a two week washout period from previous treatment prior to assignment to the study treatment, if applicable and according to the principal investigator´s judgment. Systemic diseases such as renal dysfunction (creatinine ≥1.5 time above the upper limit of the reference range), gastrointestinal disorders, hematological disorders or liver dysfunction (AST y/o ALT ≥1.5 times the upper limit of the reference range), capable to affect the absorption, distribution, metabolism and excretion of the study drug. Non-controlled diabetes mellitus (HbA1c>9%) Morbid obesity (BMI≥40 kg/m2) Myocardial infarction or severe coronary artery disease or clinically significant congestive heart failure, within the six months prior to the screening visit. Auto-immune or connective tissue disease. Evidence in the medical record of serious infectious diseases such as hepatitis type B or C or a positive HIV test at screening. Clinically significant laboratory test abnormalities, according to the investigator's judgment. Concomitant treatment which might affect blood pressure values. Known allergies or contraindication to the use of angiotensin II receptor antagonists. Pregnancy, breastfeeding or in the case of women with childbearing potential, the rejection to use an effective contraceptive method, according to the investigator's judgment. History of alcohol or addictive substance abuse. Subjects participating in other clinical studies or who have participated in other study within the 6 months prior to screening. Any other reason which in the investigator's opinion might contraindicate the participation of a subject in the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Fimasartan 60 mg Tablets<br>FMS 60 mg tablets once a day during the initial 8 treatment weeks of the study | Drug: Fimasartan<br>* Fimasartan tablets<br>* Other names: Kanarb;|
| Active Comparator: Fimasartan 120 mg Tablets<br>FMS 120 mg tablets once a day during 4 weeks (treatment weeks 8 to 12) | Drug: Fimasartan<br>* Fimasartan tablets<br>* Other names: Kanarb;|
| Active Comparator: Fimasartan; Hydrochlorothiazide 60/12.5<br>FMS 60 mg + HCTZ 12.5 mg tablets (fixed dose combination) once a day during 4 weeks (treatment weeks 8 to 12) | Drug: Fimasartan; Hydrochlorothiazide<br>* Fimasartan plus hydrochlorothiazide fixed dose combination tablets<br>* Other names: Kanarb plus;|
| Experimental: Fimasartan; Hydrochlorothiazide 120/12.5<br>FMS 120 mg + HCTZ 12.5 mg tablets (fixed dose combination) once a day during 12 weeks (treatment weeks 12 to 24) | Drug: Fimasartan; Hydrochlorothiazide<br>* Fimasartan plus hydrochlorothiazide fixed dose combination tablets<br>* Other names: Kanarb plus;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure Change From Baseline | Treatment Week 8 mean sDBP and sitting Systolic Blood Pressure (SBP) changes from baseline (all study subjects treated with 60 mg FMS once a day) | Baseline to Treatment Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Blood Pressure Change from Week 8 | Treatment Week 12 mean sDBP and sSBP changes from week 8 on subjects randomized to either 120 mg FMS or 60 mg FMS + 12.5 mg HCTZ once a day | Treatment Week 8 to Treatment Week 12 | 
| Week 8 Treatment Response Rate | Proportion of subjects with sDBP < 90 mmHg at treatment week 8 (all subjects treated with 60 mg FMS once a day) | Baseline to Treatment Week 8 | 
| Week 12 Treatment Response Rate | Proportion of subjects with sDBP < 90 mmHg at treatment week 12 (subjects randomized to either 120 mg FMS or 60 mg FMS + 12.5 mg HCTZ once a day) | Treatment Weeks 8 to 12 | 
| Blood Pressure Change from Week 12 | Treatment Week 24 mean sDBP and sSBP changes from treatment week 12 (subjects assigned at treatment week 12 to 120 mg FMS + 12.5 mg HCTZ | Treatment Weeks 12 to 24 | 
| Week 24 Treatment Response Rate | Proportion of non-responding subjects assigned at treatment week 12 to 120 mg FMS + 12.5 mg HCTZ with sDBP < 90 mmHg at Treatment Week 24 | Treatment Weeks 12 to 24 | 
| Adverse Event Incidence | Incidence and characterization of clinical, laboratory and ECG adverse events observed in all subjects assigned to treatment in the study receiving at least one dose of the study medications | Baseline to Treatment Week 24 |