Arterial Hypertension
Conditions
Brief summary
Assess and compare the efficacy and safety of Kanarb (Fimasartan), manufactured by Boryung Pharmaceutical Co., Ltd, Republic of Korea, tablets 60/120 mg and Cozaar® (Losartan), manufactured by MERCK SHARP & DOHME B.V., Netherlands, tablet 50/100 mg in adult patients with Grade I-II arterial hypertension in 12 weeks of therapy
Detailed description
1. To evaluate efficacy of 12-week Kanarb (Fimasartan), manufactured by Boryung Pharmaceutical Co., Ltd, Republic of Korea, tablets 60/120 mg and Cozaar® (Losartan), manufactured by MERCK SHARP & DOHME B.V., Netherlands, tablet 50/100 mg in adult patients with Grade I-II arterial hypertension. 2. To evaluate safety of 12-week Kanarb (Fimasartan), manufactured by Boryung Pharmaceutical Co., Ltd, Republic of Korea, tablets 60/120 mg and Cozaar® (Losartan), manufactured by MERCK SHARP & DOHME B.V., Netherlands, tablet 50/100 mg in adult patients with Grade I-II arterial hypertension. 3. Assess the pharmacokinetics parameters of Kanarb (Fimasartan), manufactured by Boryung Pharmaceutical Co., Ltd, Republic of Korea in adult patients with arterial hypertension I-II stage after a single dose. Starting dose of Kanarb (Fimasartan), manufactured by Boryung Pharmaceutical Co., Ltd, Republic of Korea is 60 mg, orally, once a day in the morning. The planned study duration for each subject is 18 weeks maximum: The screening period could takes up to 2 weeks (including the 1-week wash-out period ) - the screening period duration depends on the prior anti-hypertensive therapy: * naive subjects who never received therapy (which must be reflected in the source documents), may be randomized after completion of all screening procedures; * Subjects receiving anti-hypertensive therapy which may be discontinued without prior dose reduction must undergo a 7 days wash-out period, so the screening period will take at least 7 days; * Subjects, receiving anti-hypertensive therapy which requires dose reduction before discontinuation must undergo the 7 days wash-out period after the last dose administration, so the screening period will consist of dose reduction period and a wash-out period. Treatment period - 12 weeks. Follow-up period - 4 weeks. The subjects will visit the clinical site every 4 weeks to measure ABP. The dose will be doubled in case if SBP ≥140 mmHg or DBP ≥90 mmHg at Visit 3 (Day 28) or at Visit 4 (Day 56). If necessary, the dose of the study drug may be increased based on the assessment of patient's condition performed at the phone contact (Day14±3). Patient may be called for an unscheduled visit for treatment adjustment (decided individually, with possibility of dose titration as per investigator's judgment, indicated in source documents). When possibilities are, the patient should be administrated by the study medication at the same time in the morning. Governing conditions for defining the time of the drug administration is the subject comfort and the time of its visits the research center. If laboratory tests are scheduled, a patient should come to the research center fasting (food is prohibited for 8 hours before the visit). All of the clinical evaluations are conducted on the next morning after taking the medication. On the visit day a patient comes to the research center not taking the drug, and after all the planned procedures are conducted the patient is administrated by the drug.
Interventions
DRUGFimasartan
Starting dose of Kanarb (Fimasartan) is 60 mg, orally, once a day in the morning. The subjects will visit the clinical site every 4 weeks to measure Arterial blood pressure (ABP). The dose will be doubled in case if SBP ≥140 mmHg or DBP ≥90 mmHg at Visit 3 (Day 28) or at Visit 4 (Day 56). If necessary, the dose of the study drug may be increased based on the assessment of patient's condition performed at the phone contact (Day14±3). Patient may be called for an unscheduled visit for treatment adjustment (decided individually, with possibility of dose titration as per investigator's judgment, indicated in source documents). When possibilities are, the patient should be administrated by the study medication at the same time in the morning.
DRUGLosartan
Cozaar® (Losartan), manufactured by MERCK SHARP & DOHME B.V., Netherlands, tablets 50/100 mg
Sponsors
Covance
Boryung Pharmaceutical Co., Ltd
R-Pharm
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Subjects of both sex aged 18-75 inclusively. 2. Subjects who signed their written Informed Consent for participation in the study and willing to adhere to all Protocol procedures. 3. Subjects with documented diagnosis of grade I-II primary arterial hypertension within at least 3 months before screening. 4. Systolic blood pressure (SBP) (when seated) at Screening (Day -14) * For subjects administered with anti-hypertensive therapy: SBP ≤ 179 Hg * For subjects receiving no anti-hypertensive therapy (so called 'naïve' patients): 140≥SBP ≤179. 5. As per investigator's judgment, subjects with controlled arterial hypertension must benefit from the therapy switch to Kanarb (Fimasartan), manufactured by Boryung Pharmaceutical Co., Ltd, Republic of Korea, tablets 60/120 mg and Cozaar® (Losartan), manufactured by MERCK SHARP & DOHME B.V., Netherlands, . 6. For subjects administered with anti-hypertensive drugs: the anti-hypertensive drug may be safely cancelled during the wash-out period according to the investigator's judgment. 7. For women of child-bearing potential: negative urine pregnancy test at screening (Day -14). 8. Systolic blood pressure (SBP) (when seated) at Randomization (Day 0) ≥140 mmHg and ≤179 mmHg. 9\. For women of child-bearing potential: negative urine pregnancy test at Randomization (Day 0)
Exclusion criteria
1. Grade III Arterial Hypertension. 2. Arterial hypotension (SPB ≤100 mm Hg) at Screening (Day -14) and/or Randomization (Day 0). 3. Subjects needing treatment with more than one anti-hypertensive drug (more than one active substance, including complex drugs). 4. Secondary (symptomatic) arterial hypertension. 5. Known bilateral renal arterial stenosis or unilateral renal arterial stenosis. 6. Hyperpotassemia \>5,0 mmol/l (as per blood biochemistry results at Screening). 7. Primary hyperaldosteronism. 8. Known hypersensitivity to angiotensin-II receptors antagonists or any other study drug or comparator component. 9. Contraindications for use of angiotensin-II receptors antagonists. 10. Myocardial infarction and or unstable angina, and/or acute cerebrovascular accident/transient ischemic attack, and/or percutaneous coronary intervention, and/or coronary arterial bypass graft, acute coronary arteries involvement, and/or obliterative vascular atherosclerosis of low extremities, and/or grade III and IV retinopathy in anamnesis. 11. Clinically significant cardiac valves damage. 12. Cardiomyopathies 13. Chronic Heart failure (CHF) (except for CHF FC I NYHA). 14. Creatinine clearance less than 60 ml/min/1.73m2 calculated by Cockroft-Gault formula. 15. Known moderate to severe hepatic insufficiency and/or transaminase increase: AST and/or ALT ≥2\*ULN. 16. History of infections (HIV, hepatitis B or C, syphilis). 17. Uncontrolled Diabetes mellitus, Glycosylated hemoglobin level (HbA1c) \>7%. 18. Severe systemic diseases, such as gastro-intestinal tract diseases, autoimmune disorders, blood disorders and other conditions which may affect on the study drugs' absorption, distribution and and excretion. 19. Clinically significant abnormalities of laboratory parameters. 20. Drug or alcohol addiction, psychiatric disorders. 21. Medical history of oncological disease within 5 years before screening. 22. Subjects with biliary tracts obstruction. 23. Subjects with genetic disorders, such as galactose intolerance, congenital lactase insufficiency and glucose-galaclose malabsorption syndrome. 24. Any other acute disease or progression and/or decompensation at the moment of enrollment 25. Necessity to administer or administration of prohibited concomitant drugs from the List of Prohibited Drugs within 14 days before enrollment 26. Pregnancy or breast-feeding period; fertile women not using adequate contraception methods 27. Participation in another clinical trial within 3 months before Screening. 28. Other medical or psychiatric conditions or lab abnormalities that may increase potential risk associated with study participation and IP administration, or that may affect study results interpretation and as per investigator's judgment, make the subject ineligible. 29. Study site personnel or Sponsor's representatives immediately involved in the study. 30. Subjects, excluded from the study may not be included in it again.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Systolic Blood Pressure (SBP) After 12 Weeks of Treatment | Baseline and week 12 of treatment | The value of SBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of SBP at week 12 minus Value of SBP at baseline). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in DBP After 8 Weeks of Treatment | Baseline and week 8 of treatment | The value of DBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of DBP at week 8 minus Value of SBP at baseline). |
| Change in DBP After 12 Weeks of Treatment | Baseline and week 12 of treatment | The value of DBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of DBP at week 12 minus Value of SBP at baseline). |
| Change in Diastolic Blood Pressure (DBP) After 4 Weeks of Treatment | Baseline and week 4 of treatment | The value of DBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of DBP at week 4 minus Value of SBP at baseline). |
| Change in SBP After 8 Weeks of Treatment | Baseline and week 8 of treatment | The value of SBP( seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of SBP at week 8 minus Value of SBP at baseline). |
| Number of Subjects Who Responded on Therapy | Week 12 of treatment | The subject will be considered a responder if SBP (when seated) \<140 mmHg or SBP decrease is \>10% from baseline. |
| Change in SBP After 4 Weeks of Treatment | Baseline and week 4 of treatment | The value of SBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of SBP at week 4 minus Value of SBP at baseline). |
Countries
Russia
Participant flow
Recruitment details
Participants recruitment was conducted in 13 clinical sites of Moscow and Saint-Petersburg between May and October of 2014
Pre-assignment details
Duration of screening period was up to 14 days depended on prior antihypertensive treatment. 184 patients were screened, 179 randomized.
Participants by arm
| Arm | Count |
|---|---|
| Kanarb (Fimasartan) 60/120 mg Kanarb (Fimasartan) administered orally once a day in the morning for 12 weeks period | 89 |
| Cozaar® (Losartan) 50/100 mg Cozaar® (Losartan) administered orally once a day for 12 week period | 90 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
| Overall Study | Unmet inclusion/exclusion criteria | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Kanarb (Fimasartan) | Total | Cozaar® (Losartan) |
|---|---|---|---|
| Age, Continuous | 53.4 years | 53.6 years | 53.8 years |
| Alcohol history Drinking | 52 Participants | 109 Participants | 57 Participants |
| Alcohol history Drinking-in-the-past | 12 Participants | 21 Participants | 9 Participants |
| Alcohol history Never-drinking | 25 Participants | 48 Participants | 23 Participants |
| Alcohol history Unknown | 0 Participants | 1 Participants | 1 Participants |
| Arterial hypertension (AH) duration | 5.8 years | 6.0 years | 6.2 years |
| BMI | 29.4 kg/m^2 | 29.1 kg/m^2 | 28.9 kg/m^2 |
| Chronic heart failure (CHF) NYHA Class I | 10 Participants | 22 Participants | 12 Participants |
| Hypertension grade Grade I | 20 Participants | 47 Participants | 27 Participants |
| Hypertension grade Grade II | 69 Participants | 132 Participants | 63 Participants |
| Prior therapy for arterial hypertension | 55 Participants | 101 Participants | 46 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized European | 87 Participants | 177 Participants | 90 Participants |
| Sex: Female, Male Female | 30 Participants | 64 Participants | 34 Participants |
| Sex: Female, Male Male | 59 Participants | 115 Participants | 56 Participants |
| Smoking history Has never smoked | 63 Participants | 84 Participants | 21 Participants |
| Smoking history Smoker | 19 Participants | 81 Participants | 62 Participants |
| Smoking history Smoker-in-the-past | 7 Participants | 14 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 89 | 0 / 90 |
| other Total, other adverse events | 20 / 89 | 15 / 90 |
| serious Total, serious adverse events | 0 / 89 | 0 / 90 |
Outcome results
Primary
Change in Systolic Blood Pressure (SBP) After 12 Weeks of Treatment
The value of SBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of SBP at week 12 minus Value of SBP at baseline).
Time frame: Baseline and week 12 of treatment
Population: Full Analysis Set Population (FAS) - those subjects from Intent-to-treat population (ITT, all randomized patients), who had at least one assessment for efficacy analysis after the start of therapy. Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kanarb (Fimasartan) | Change in Systolic Blood Pressure (SBP) After 12 Weeks of Treatment | SBP at Baseline | 152.9 mm Hg | Standard Deviation 5.9 |
| Kanarb (Fimasartan) | Change in Systolic Blood Pressure (SBP) After 12 Weeks of Treatment | Change from Baseline at Week 12 | -25.2 mm Hg | Standard Deviation 8.6 |
| Cozaar® (Losartan) | Change in Systolic Blood Pressure (SBP) After 12 Weeks of Treatment | SBP at Baseline | 151.9 mm Hg | Standard Deviation 5.9 |
| Cozaar® (Losartan) | Change in Systolic Blood Pressure (SBP) After 12 Weeks of Treatment | Change from Baseline at Week 12 | -24.3 mm Hg | Standard Deviation 7.8 |
Comparison: The null hypothesis (H0) is that there is a decrease in SBP on the background treatment with Kanarb (fimasartan), that is at least 5.5 mmHg lower compared to Cozaar® (losartan).~Test of the hypotheses was performed using mixed linear models, where the site effect was considered a random effect, and the treatment group effect was considered a fixed effect. Baseline SBP on the study arm was included into the model as a covariate (a fixed effect) in all cases.p-value: =0.39Mixed Models Analysis
Secondary
Change in DBP After 12 Weeks of Treatment
The value of DBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of DBP at week 12 minus Value of SBP at baseline).
Time frame: Baseline and week 12 of treatment
Population: One patient (Kanarb (fimasartan) treatment group) was withdrawn from the study by the time of assessment at week 12
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kanarb (Fimasartan) | Change in DBP After 12 Weeks of Treatment | DBP at Baseline | 88.7 mm Hg | Standard Deviation 8.1 |
| Kanarb (Fimasartan) | Change in DBP After 12 Weeks of Treatment | Change from Baseline at Week 12 | -10.6 mm Hg | Standard Deviation 8.8 |
| Cozaar® (Losartan) | Change in DBP After 12 Weeks of Treatment | DBP at Baseline | 89.6 mm Hg | Standard Deviation 6.9 |
| Cozaar® (Losartan) | Change in DBP After 12 Weeks of Treatment | Change from Baseline at Week 12 | -11.3 mm Hg | Standard Deviation 7.8 |
p-value: =0.466Mixed Models Analysis
Secondary
Change in DBP After 8 Weeks of Treatment
The value of DBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of DBP at week 8 minus Value of SBP at baseline).
Time frame: Baseline and week 8 of treatment
Population: All randomized patients, who had at least one assessment for efficacy analysis after the start of therapy. One patient (Kanarb (fimasartan) treatment group) was withdrawn from the study by the time of assessment at week 8.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kanarb (Fimasartan) | Change in DBP After 8 Weeks of Treatment | DBP at Baseline | 88.7 mm Hg | Standard Deviation 8.1 |
| Kanarb (Fimasartan) | Change in DBP After 8 Weeks of Treatment | Change from Baseline at Week 8 | -10.3 mm Hg | Standard Deviation 9.5 |
| Cozaar® (Losartan) | Change in DBP After 8 Weeks of Treatment | Change from Baseline at Week 8 | -10.7 mm Hg | Standard Deviation 7.9 |
| Cozaar® (Losartan) | Change in DBP After 8 Weeks of Treatment | DBP at Baseline | 89.6 mm Hg | Standard Deviation 6.9 |
p-value: =0.579Mixed Models Analysis
Secondary
Change in Diastolic Blood Pressure (DBP) After 4 Weeks of Treatment
The value of DBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of DBP at week 4 minus Value of SBP at baseline).
Time frame: Baseline and week 4 of treatment
Population: All randomized patients, who had at least one assessment for efficacy analysis after the start of therapy. One patient (Kanarb (fimasartan) treatment group) was withdrawn from the study by the time of assessment at week 4.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kanarb (Fimasartan) | Change in Diastolic Blood Pressure (DBP) After 4 Weeks of Treatment | DBP at Baseline | 88.7 mm Hg | Standard Deviation 8.1 |
| Kanarb (Fimasartan) | Change in Diastolic Blood Pressure (DBP) After 4 Weeks of Treatment | Change from Baseline at Week 4 | -9.5 mm Hg | Standard Deviation 9.1 |
| Cozaar® (Losartan) | Change in Diastolic Blood Pressure (DBP) After 4 Weeks of Treatment | DBP at Baseline | 89.6 mm Hg | Standard Deviation 6.9 |
| Cozaar® (Losartan) | Change in Diastolic Blood Pressure (DBP) After 4 Weeks of Treatment | Change from Baseline at Week 4 | -7.4 mm Hg | Standard Deviation 7.5 |
p-value: =0.018Mixed Models Analysis
Secondary
Change in SBP After 4 Weeks of Treatment
The value of SBP (seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of SBP at week 4 minus Value of SBP at baseline).
Time frame: Baseline and week 4 of treatment
Population: One patient (Kanarb (fimasartan) treatment group) was withdrawn from the study by the time of assessment at week 4
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kanarb (Fimasartan) | Change in SBP After 4 Weeks of Treatment | SBP at Baseline | 152.9 mm Hg | Standard Deviation 5.9 |
| Kanarb (Fimasartan) | Change in SBP After 4 Weeks of Treatment | Change from Baseline at Week 4 | -19.7 mm Hg | Standard Deviation 10.3 |
| Cozaar® (Losartan) | Change in SBP After 4 Weeks of Treatment | SBP at Baseline | 151.9 mm Hg | Standard Deviation 5.9 |
| Cozaar® (Losartan) | Change in SBP After 4 Weeks of Treatment | Change from Baseline at Week 4 | -17.6 mm Hg | Standard Deviation 10.5 |
p-value: =0.118Mixed Models Analysis
Secondary
Change in SBP After 8 Weeks of Treatment
The value of SBP( seated) to be registered was mean of the 3 measurements performed with interval no less than 1 minute using the manual (mercury or mechanic) tonometer after 5 minutes rest. Change was calculated as (Value of SBP at week 8 minus Value of SBP at baseline).
Time frame: Baseline and week 8 of treatment
Population: One patient (Kanarb (fimasartan) treatment group) was withdrawn from the study by the time of assessment at week 8
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Kanarb (Fimasartan) | Change in SBP After 8 Weeks of Treatment | SBP at Baseline | 152.9 mm Hg | Standard Deviation 5.9 |
| Kanarb (Fimasartan) | Change in SBP After 8 Weeks of Treatment | Change from Baseline at Week 8 | -23.5 mm Hg | Standard Deviation 9 |
| Cozaar® (Losartan) | Change in SBP After 8 Weeks of Treatment | SBP at Baseline | 151.9 mm Hg | Standard Deviation 5.9 |
| Cozaar® (Losartan) | Change in SBP After 8 Weeks of Treatment | Change from Baseline at Week 8 | -23.9 mm Hg | Standard Deviation 8.6 |
p-value: =0.662Mixed Models Analysis
Secondary
Number of Subjects Who Responded on Therapy
The subject will be considered a responder if SBP (when seated) \<140 mmHg or SBP decrease is \>10% from baseline.
Time frame: Week 12 of treatment
Population: Full Analysis Set Population (FAS) - those subjects from Intent-to-treat population (ITT, all randomized patients), who had at least one assessment for efficacy analysis after the start of therapy. Last observation carried forward (LOCF) imputation method.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Kanarb (Fimasartan) | Number of Subjects Who Responded on Therapy | 85 Participants |
| Cozaar® (Losartan) | Number of Subjects Who Responded on Therapy | 90 Participants |
p-value: =0.143Mantel Haenszel