An 8-week Randomized, Double-blind, Placebo-controlled Factorial Study to Evaluate the Efficacy and Safety of LCZ696 Alone and in Combination With Amlodipine in Patients With Essential Hypertension
Trial Snapshot
- Phase
- Phase 3
- Status
- Withdrawn
- Sponsor
- Novartis Pharmaceuticals
- Primary Endpoint
- Change from baseline in mean sitting systolic blood pressure (msSBP) of LCZ696 monotherapy compared to placebo
Study Overview
Brief Summary
To evaluate the blood pressure lowering effect and safety of LCZ696 when given alone and in combination with amlodipine in patients with essential hypertension.
Study Design
- Study Type
- Interventional
- Allocation
- Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- Double (Participant, Investigator)
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Male or female outpatients
- •Patients with mild-to-moderate hypertension, untreated or currently taking antihypertensive therapy
- •Treated patients (using antihypertensive treatments within 4 weeks prior to Visit 1) must have an msSBP ≥150 mmHg and <180 mmHg at the randomization visit and msSBP ≥140 mmHg <180 mmHg at the preceding visit.
- •Untreated patients (newly diagnosed with essential hypertension or having a history of hypertension but have not been taking any antihypertensive drugs for at least 4 weeks prior to Visit 1) must have an msSBP ≥150 mmHg and <180 mmHg at both the randomization visit and the preceding visit.
- •Patients must have an absolute difference of ≤15 mmHg in msSBP between the randomization visit and the preceding visit.
- •Ability to communicate and comply with all study requirements and demonstrate good medication compliance (≥ 80% compliance rate) during the treatment run-in period.
Exclusion Criteria
- •Severe hypertension (msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg)
- •History of angioedema, drug-related or otherwise
- •History or evidence of a secondary form of hypertension, including but not limited to any of the following: renal parenchymal hypertension, renovascular hypertension (unilateral or bilateral renal artery stenosis), coarctation of the aorta, primary hyperaldosteronism, Cushing's disease, pheochromocytoma, polycystic kidney disease, and drug-induced hypertension
- •Transient ischemic cerebral attack (TIA) during the 12 months prior to Visit 1 or any history of stroke
- •History of myocardial infarction, coronary bypass surgery or any percutaneous coronary intervention (PCI) during the 12 months prior to Visit 1
- •Pregnant or lactating women
- •Women of child-bearing potential not using highly effective methods of contraception Other protocol defined inclusion/exclusion criteria may apply
Arms & Interventions
LCZ696 200 mg
Patients randomized to this treatment arm will receive LCZ696 200 mg once daily for 8 weeks.
Intervention: LCZ696 (Drug)
LCZ696 400 mg
Patients randomized to this treatment arm will receive LCZ696 400 mg once daily for 8 weeks.
Intervention: LCZ696 (Drug)
Amlodipine 5 mg
Patients randomized to this treatment arm will receive amlodipine 5 mg once daily for 8 weeks.
Intervention: Amlodipine (Drug)
Amlodipine 10 mg
Patients randomized to this treatment arm will receive amlodipine 10 mg once daily for 8 weeks.
Intervention: Amlodipine (Drug)
LCZ696 200 mg and amlodipine 5 mg
Patients randomized to this treatment arm will receive LCZ696 200 mg and amlodipine 5 mg once daily for 8 weeks.
Intervention: LCZ696 and amlodipine combination (Drug)
LCZ696 200 mg and amlodipine 10 mg
Patients randomized to this treatment arm will receive LCZ696 200 mg and amlodipine 5 mg once daily for 1 week followed by LCZ696 200 mg and amlodipine 10 mg once daily for 7 weeks.
Intervention: LCZ696 and amlodipine combination (Drug)
LCZ696 400 mg and amlodipine 5 mg
Patients randomized to this treatment arm will receive LCZ696 200 mg and amlodipine 5 mg once daily for 1 week followed by LCZ696 400 mg and amlodipine 5 mg once daily for 7 weeks.
Intervention: LCZ696 and amlodipine combination (Drug)
LCZ696 400 mg and amlodipine 10 mg
Patients randomized to this treatment arm will receive LCZ696 200 mg and amlodipine 5 mg once daily for 1 week followed by LCZ696 400 mg and amlodipine 10 mg once daily for 7 weeks.
Intervention: LCZ696 and amlodipine combination (Drug)
Placebo
Patients randomized to this treatment arm will receive placebo once daily for 8 weeks.
Intervention: Placebo (Drug)
Outcomes
Primary Outcomes
Change from baseline in mean sitting systolic blood pressure (msSBP) of LCZ696 monotherapy compared to placebo
Time Frame: baseline, 8 weeks
Sitting blood pressure will be measured at trough (immediately prior to dosing at clinic) and recorded at all study visits. At the first study visit, blood pressure will be measured in both arms and the arm with highest sitting SBP will be found and used for all subsequent readings throughout the study. The 4 repeat sitting measurements will be made at 2 minute intervals and the mean of these four sitting systolic blood pressure measurements will be used as the mean sitting systolic blood pressure for that visit.
Change from baseline in mean sitting systolic blood pressure (msSBP) of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone.
Time Frame: baseline, 8 weeks
Sitting blood pressure will be measured at trough (immediately prior to dosing at clinic) and recorded at all study visits. The 4 repeat sitting measurements will be made at 2 minute intervals and the mean of these four sitting systolic blood pressure measurements will be used as the mean sitting systolic blood pressure for that visit.
Secondary Outcomes
- Change from baseline in mean sitting Diastolic Blood Pressure (msDBP) of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in mean sitting Diastolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone(baseline, 8 weeks)
- Change from baseline in mean nighttime (> 10 pm and ≤ 6 am) ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in mean 24-hour ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in pulse pressure(baseline, 8 weeks)
- Change from baseline in mean 24-hour ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in mean daytime ( > 6am and ≤ 10 pm) ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in mean daytime ( > 6am and ≤ 10 pm) ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in mean nighttime (> 10 pm and ≤ 6 am) ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in mean 24-hour ambulatory Systolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone(baseline, 8 weeks)
- Change from baseline in mean daytime ( > 6am and ≤ 10 pm) ambulatory Systolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone(baseline, 8 weeks)
- Change from baseline in mean daytime ( > 6am and ≤ 10 pm) ambulatory Diastolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone(baseline, 8 weeks)
- Change from baseline in mean nighttime (> 10 pm and ≤ 6 am) ambulatory Systolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone(baseline, 8 weeks)
- Percentage of patients achieving msDBP <90 mmHg or a reduction ≥10 mmHg from baseline(Baseline, 8 weeks)
- Percentage of patients achieving msSBP <140 mmHg or a reduction ≥20 mmHg from baseline(Baseline, 8 weeks)
- Change from baseline in trough to peak ratio of mean 24-hour ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in trough to peak ratio of mean 24-hour ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo(baseline, 8 weeks)
- Change from baseline in mean 24-hour ambulatory Diastolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone(baseline, 8 weeks)
- Change from baseline in mean nighttime (> 10 pm and ≤ 6 am) ambulatory Diastolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone(baseline, 8 weeks)
- Percentage of patients achieving msSBP <140 mmHg and msDBP <90 mmHg(8 weeks)
- Number of patients reporting adverse events(8 weeks)