A multicenter, randomized, double-blind, parallel-group, comparative, active-controlled, phase III clinical trial to evaluate the efficacy and safety of Fixed-Dose Combination of Bisoprolol 5 mg and Cilnidipine 10 mg tablet versus Fixed-Dose Combination of Metoprolol Succinate ER 50 mg and Cilnidipine 10mg in subjects with Essential Hypertension associated with coronary artery disease (CAD)

Protocol Title : A multicenter, randomized, double-blind, parallel-group, comparative, active-controlled, phase III clinical trial to evaluate the efficacy and safety of Fixed-Dose Combination of Bisoprolol 5 mg and Cilnidipine 10 mg tablet versus Fixed-Dose Combination of Metoprolol Succinate ER 50 mg and Cilnidipine 10mg in subjects with Essential Hypertension associated with coronary artery disease (CAD).

Study Objectives:

Primary Objectives : To evaluate and compare the efficacy of Fixed-Dose Combination of Bisoprolol 5 mg and Cilnidipine 10 mg tablet versus Fixed-Dose Combination of Metoprolol Succinate ER 50 mg and Cilnidipine 10 mg tablets in subjects with essential hypertension associated with coronary artery disease (CAD).

Secondary Objective : To evaluate the safety of Fixed-Dose Combination of Bisoprolol 5 mg and Cilnidipine 10 mg tablet versus Fixed-Dose Combination of Metoprolol Succinate ER 50mg and Cilnidipine10 mg tablets in subjects with essential hypertension associated with coronary artery disease (CAD).

Investigational Product:

Test Arm: Treatment Arm 1: Fixed-Dose Combination (FDC) of Bisoprolol 5 mg and Cilnidipine 10 mg tablet (n=115)

Route of Administration: For oral use to take one tablet of test in morning (one hour before or two to three (2-3) hours after breakfast)

Reference Arm: Treatment Arm 2: Fixed-Dose Combination of Metoprolol Succinate ER 50 mg and Cilnidipine 10 mg (n=115)

Route of Administration: For oral use to take one tablet of reference in morning (one hour before or two to three (2-3) hours after breakfast)

S****tudy Duration:

Subject participation will be for 12 weeks. (84 Days)

Inclusion Criteria :

1. Male or female participants with age 18 years to 65 years (both inclusive) at the time of screening.

2. Adult subjects who are capable of understanding and giving written informed consent and willing to comply with the study protocol.

3. Subjects diagnosed with Essential Hypertension associated with stable coronary artery disease (CAD) with SBP ranging between 140-180 mmHg and/or DBP ranging between 90-110 mmHg (Stable CAD is defined as a patient who is apparently stable with no history of chest pain or any sign/symptom of chest discomfort and no alteration in the treatment taken for the past 3 months.)

4. Females of non-child bearing potential (surgically sterile or menopausal) OR females of child bearing potential using effective birth control measures and non-pregnant & non-lactating females.

Exclusion Criteria :

1. Subjects previously sensitive to any of the ingredients of the fixed-dose combination under study or beta-blockers or angiotensin receptor blockers,

2. Subjects with clinically significant renal disorders:

Estimated glomerular filtration rate: <60 mL/min per 1.73 m2)

Subjects with S. Creatinine values and S.BUN values ≥ 1.5 times the  upper limit of normal.

Subjects with abnormal lab values of Na+, K+, Mg++ and Uric acid. [Normal range: Na+ = 135-145 mEq/L, K+ = 3.5 – 5.0 mmol/L, Mg++ = 1.8-2.2 mg/dL and Uric acid 3.5 – 7.2 mg/dL]

3. Subjects with hepatocellular insufficiency and in subjects with hepatic failure or active liver disease [abnormal Liver Function Test with values more than 2.5 times the upper limit of normal]

4. Subjects with clinically Endocrine system disorders:

Subjects with abnormal Thyroid Function Test (TSH).

Subjects with Type 1 Diabetes Mellitus.

Subjects with Type 2 Diabetes Mellitus whose diabetes has not been stable and controlled for the previous three months and with HbA1c value greater than 8%.

5. Subjects with a known history of secondary or malignant hypertension.

6. Subjects with EF <40% as per Simpson’s method on 2D Echo.

7. Any known cardiac disease/disorder in which any of the study medication is contraindicated (e.g. severe bradycardia, heart block greater than a first degree or significant first-degree block, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome without pacemaker etc.)

8. Subjects with known significant respiratory/liver/kidney/neurological diseases/ uncontrolled diabetes,

9. Pregnant and lactating women or the women of child bearing age who are not practicing the effective means of contraception,

10. Subjects otherwise judged to be inappropriate for inclusion in the study by the investigator’s judgment.

11. Subjects who will receive some other drug during the study besides that in the protocol that could alter the pharmacokinetic/ pharmacodynamic profile of the study drug,

12. Subjects with known alcohol or drug abuse.

13. Subjects with known History of HIV, Hepatitis B and Hepatitis C.

Study Schedule:

Visit 1: Screening Visit (Day -3 to Day 0)

Visit 2: Baseline / Randomization Visit (Day 1)

Visit 3: Treatment Follow-up Visit 1 (Day 28 ± 1 Days)

Visit 4: Treatment Follow-up Visit 2 (Day 56 + 2 Days)

Visit 5: End of Study Visit (Day 84 ± 2 Days)

Visit 6: Unscheduled Visit / Early Discontinuation Visit

Primary efficacy endpoint will be:

Mean reduction in systolic and diastolic blood pressure measured in sitting position compared to baseline (12 weeks)

Secondary efficacy endpoints include:

Mean reduction in systolic and diastolic blood pressure measured in sitting position compared to baseline (After 4 and 8 weeks)

Percentage of the subjects achieved the target levels of clinical BP among hypertensive subjects (target level: SeSBP < 140 mm Hg) (After 4, 8 and 12 weeks).

Percentage of the subjects achieved the target levels of clinical BP among hypertensive subjects (target level: SeDBP < 90 mm Hg) (After 4, 8 and 12 weeks).

Proportion of responders after 12 weeks of dosing (Responder rate defined as the proportion of subjects with decrease in diastolic BP by at least 10 mmHg).

Reduction in mean heart rate compared to baseline (After 4, 8 and 12 weeks)