Study of Nifedipine GITS and Candesartan Combination Compared to Monotherapy in Patients With Essential Hypertension

Study Overview
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Brief Summary
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The purpose of this study is to determine the blood pressure lowering responses of various dose combinations of nifedipine GITS and candesartan as compared to treatment with each component on their own (monotherapy) and placebo (a look-alike tablet without active ingredient). The drugs - nifedipine GITS and candesartan - which are being investigated are currently approved for use in patients with essential hypertension alone or together with other antihypertensive drugs (combination therapy), but the optimal dose of nifedipine GITS and candesartan used together in the treatment of essential hypertension has not been established yet. In this study patients will be treated with various doses of nifedipine GITS and/or candesartan or placebo. These different regimens will be administered once a day and will be assessed based on their blood pressure lowering effects (mean sitting diastolic blood pressure) in subjects with mild to moderate essential hypertension.

Official Title
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A Multicenter, Multifactorial, Randomized, Double-Blind, Placebo-Controlled Dose-Finding Study of Nifedipine GITS and Candesartan in Combination Compared to Monotherapy in Adult Patients With Essential Hypertension

Conditions
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Hypertension, Essential

Intervention / Treatment
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* Drug: Candesartan cilexetil (Atacand), 4 mg
* Drug: Candesartan cilexetil (Atacand), 8 mg
* Drug: Nifedipine GITS (Adalat, BAYA1040), 20 mg
* Drug: Nifedipine GITS (Adalat, BAYA1040), 30 mg
* Drug: Nifedipine GITS (Adalat, BAYA1040), 60 mg
* Drug: Placebo
* Drug: Candesartan cilexetil (Atacand), 16 mg
* Drug: Candesartan cilexetil (Atacand), 32 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female subjects 18 years or older. Female subjects must be either post-menopausal for one year, surgically sterile, or using an effective contraceptive method. Hormonal contraceptive use is disallowed. Subjects must have mild to moderate essential hypertension (Grade 1 and 2 WHO classifications) as measured by calibrated standard sphygmomanometer. (MSDBP of ≥90 mmHg and < 110 mmHg at Visit 1 (placebo run-in), and MSDBP of ≥95 mmHg and < 110 mmHg at visit 2 (randomization) Subjects must have an absolute difference in their MSDBP of less than 10 mmHg between Visit 1 (placebo run- in) and Visit 2 (randomization). Exclusion Criteria: Severe hypertension (Grade 3 WHO classification; MSDBP ≥110 mmHg and/or MSSBP ≥ 180 mmHg) Inability to washout of antihypertensive drugs (even if prescribed for another indication) safely for a period of 14 weeks. History of hypertensive retinopathy - known Keith-Wagener Grade III or IV History of hypertensive encephalopathy Cerebrovascular ischemic event (stroke, transient ischemic attack [TIA])within the previous 12 months History of intracerebral hemorrhage or subarachnoid hemorrhage Evidence of secondary hypertension such as coarchation of the aorta, pheochromocytoms, hypersaldosteronism, etc. Type I diabetes mellitus (DM) or poorly controlled DM Type II as evidenced by a glycosylated hemoglobin [HbA1C] of greater than 9% on visit 1. Allergies or known intolerance to one of the investigational drugs/drug class or to one of their ingredients Any history of heart failure, New York Heart Association (NYHA) classification III or IV Severe coronary heart disease as manifest by a history of myocardial infarction or unstable angina in the last 6 months prior to visit 1. Clinically significant cardiac valvular disease History of malignancy in the last 5 years, excluding basal or skin cancer Uncorrected hypokalemia or hyperkalemia: potassium outside 3.0-5.0 mmol/L Surgical or medical conditions that might alter the metabolism, excretion or distribution or absorption of any drug Gastrointestinal disease or surgery resulting in the potential for malabsorption Severe gastrointestinal tract narrowing; kock pouch (ileostomy after proctocolectomy) Cholestasis or biliary obstruction or history of pancreatic injury or clinical significant increase of lipase, amylase, or bilirubin. Liver disease or AST/ALT levels >3 x ULN Renal insufficiency, defined as eGFR of < 50 mL/min (computed using the Cockroft-Gault formula), or on hemodialysis Investigation trial participation with receipt of investigational study drug within the last month Previous assignment to treatment in this study Female subjects who are pregnant or lactating. Subjects who have night employment (night shift). Subjects with an aortic aneurysm that, in the opinion of the investigator, will be unsuitable to be enrolled in the study. Thought by the investigator for any reason to be unsuitable for participation in a clinical study Systemic use of known cytochrome P450-3A4 inhibitors (e.g cimetidine, anti-human immunodeficiency virus [HIV] protease inhibitors e.g. ritonavir, azole anti-mycotics eg. ketoconazole,) or inducers (e.g rifampicin, anti-epileptic drugs eg. phenytoin, carbamazepine and phenobarbitone) or some P450-3A4 substrates (e.g quinidine, digoxin, tacrolimus) Present severe rhythm or conduction disorder: Atrial fibrillation Second or third degree heart block without a pacemaker. Baseline QTc >450 msec History of non-compliance, alcoholism or drug abuse that in the opinion of the investigator will compromise successful completion of the study. If differences greater than 20 mmHg for SBP and 10 mmHg for DBP are present on 3 consecutive BP readings, the subject should be excluded from the study.

Ages Eligible for Study
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Minimum Age: 18 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nifedipine GITS 20 mg<br>Subjects received 20 mg of nifedipine GITS (single tablet) monotherapy once daily for 8 weeks along with 2 placebo tablets and 1 placebo capsule | Drug: Nifedipine GITS (Adalat, BAYA1040), 20 mg<br>* 20 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Nifedipine GITS 30 mg<br>Subjects received 30 mg of nifedipine GITS (single tablet) monotherapy once daily for 8 weeks along with 2 placebo tablets and 1 placebo capsule | Drug: Nifedipine GITS (Adalat, BAYA1040), 30 mg<br>* 30 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Nifedipine GITS 60 mg<br>Subjects received 60 mg of nifedipine GITS (single tablet) monotherapy once daily for 8 weeks along with 2 placebo tablets and 1 placebo capsule | Drug: Nifedipine GITS (Adalat, BAYA1040), 60 mg<br>* 60 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Candesartan cilexetil 4 mg<br>Subjects received 4 mg of candesartan cilexetil (single capsule) monotherapy once daily for 8 weeks along with 3 placebo tablets | Drug: Candesartan cilexetil (Atacand), 4 mg<br>* 4 mg of candesartan as capsule<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Candesartan cilexetil 8 mg<br>Subjects received 8 mg of candesartan cilexetil (single capsule) monotherapy once daily for 8 weeks along with 3 placebo tablets | Drug: Candesartan cilexetil (Atacand), 8 mg<br>* 8 mg candesartan as capsule<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Candesartan cilexetil 16 mg<br>Subjects received 16 mg of candesartan cilexetil (single capsule) monotherapy once daily for 8 weeks along with 3 placebo tablets | Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>Drug: Candesartan cilexetil (Atacand), 16 mg<br>* 16 mg of candesartan as capsule<br>|
| Experimental: Candesartan cilexetil 32 mg<br>Subjects received 32 mg of candesartan cilexetil (single capsule) monotherapy once daily for 8 weeks along with 3 placebo tablets | Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>Drug: Candesartan cilexetil (Atacand), 32 mg<br>* 32 mg of candesartan as capsule<br>|
| Experimental: Nifedipine/candesartan 20/4 mg<br>Subjects received the combination of 20 mg of nifedipine GITS/4 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Candesartan cilexetil (Atacand), 4 mg<br>* 4 mg of candesartan as capsule<br>Drug: Nifedipine GITS (Adalat, BAYA1040), 20 mg<br>* 20 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Nifedipine/candesartan 20/8 mg<br>Subjects received the combination of 20 mg of nifedipine GITS/8 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Candesartan cilexetil (Atacand), 8 mg<br>* 8 mg candesartan as capsule<br>Drug: Nifedipine GITS (Adalat, BAYA1040), 20 mg<br>* 20 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Nifedipine/candesartan 20/16 mg<br>Subjects received the combination of 20 mg of nifedipine GITS/16 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Nifedipine GITS (Adalat, BAYA1040), 20 mg<br>* 20 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>Drug: Candesartan cilexetil (Atacand), 16 mg<br>* 16 mg of candesartan as capsule<br>|
| Experimental: Nifedipine/candesartan 30/8 mg<br>Subjects received the combination of 30 mg of nifedipine GITS/8 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Candesartan cilexetil (Atacand), 8 mg<br>* 8 mg candesartan as capsule<br>Drug: Nifedipine GITS (Adalat, BAYA1040), 30 mg<br>* 30 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|
| Experimental: Nifedipine/candesartan 30/16 mg<br>Subjects received the combination of 30 mg of nifedipine GITS/16 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Nifedipine GITS (Adalat, BAYA1040), 30 mg<br>* 30 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>Drug: Candesartan cilexetil (Atacand), 16 mg<br>* 16 mg of candesartan as capsule<br>|
| Experimental: Nifedipine/candesartan 30/32 mg<br>Subjects received the combination of 30 mg of nifedipine GITS/32 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Nifedipine GITS (Adalat, BAYA1040), 30 mg<br>* 30 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>Drug: Candesartan cilexetil (Atacand), 32 mg<br>* 32 mg of candesartan as capsule<br>|
| Experimental: Nifedipine/candesartan 60/16 mg<br>Subjects received the combination of 60 mg of nifedipine GITS/16 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Nifedipine GITS (Adalat, BAYA1040), 60 mg<br>* 60 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>Drug: Candesartan cilexetil (Atacand), 16 mg<br>* 16 mg of candesartan as capsule<br>|
| Experimental: Nifedipine/candesartan 60/32 mg<br>Subjects received the combination of 60 mg of nifedipine GITS/32 mg of candesartan cilexetil once daily for 8 weeks along with 2 placebo tablets | Drug: Nifedipine GITS (Adalat, BAYA1040), 60 mg<br>* 60 mg nifedipine as tablet<br>Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>Drug: Candesartan cilexetil (Atacand), 32 mg<br>* 32 mg of candesartan as capsule<br>|
| Placebo Comparator: Placebo<br>Subjects received placebo (3 tablets and 1 capsule) once daily for 8 weeks | Drug: Placebo<br>* 3 different placebo tablets corresponding nifedipine doses and 1 placebo capsule corresponding to candesartan doses<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary efficacy variable is the change from baseline in mean seated diastolic blood pressure (MSDBP) at Week 8 |  | Baseline taken at Visit 1; primary outcome variable assesed at 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in mean seated systolic blood pressure (MSSBP) at Week 8 |  | 8 weeks | 
| Control rate at Week 8 |  | 8 weeks | 
| Response rate at Week 8 |  | 8 weeks | 
| Peripheral Edema |  | 8 weeks | 
| Time to achieve first BP control |  | 8 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nifedipine GITS, Candesartan, mild to moderate Hypertension, Combination therapy