Study of the Efficacy and Safety of LCZ696 Alone and in Combination With Amlodipine in Patients With Hypertension

This study has been withdrawn prior to enrollment.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT01865188
First received: May 24, 2013
Last updated: August 4, 2014
Last verified: August 2014
  Purpose

To evaluate the blood pressure lowering effect and safety of LCZ696 when given alone and in combination with amlodipine in patients with essential hypertension.


Condition Intervention Phase
Hypertension
Drug: LCZ696
Drug: Amlodipine
Drug: LCZ696 and amlodipine combination
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Change from baseline in mean sitting systolic blood pressure (msSBP) of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    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 ] [ Designated as safety issue: No ]
    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 Outcome Measures:
  • Change from baseline in mean sitting Diastolic Blood Pressure (msDBP) of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    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 diastolic blood pressure measurements will be used as the mean sitting diastolic blood pressure for that visit.

  • Change from baseline in mean sitting Diastolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    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 diastolic blood pressure measurements will be used as the mean sitting diastolic blood pressure for that visit.

  • Change from baseline in pulse pressure [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    Pulse pressure will be calculated as the difference between msSBP and msDBP for both office BP and ABPM.

  • Change from baseline in mean 24-hour ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Change from baseline in mean 24-hour ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Change from baseline in mean daytime ( > 6am and ≤ 10 pm) ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Change from baseline in mean daytime ( > 6am and ≤ 10 pm) ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Change from baseline in mean nighttime (> 10 pm and ≤ 6 am) ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Change from baseline in mean nighttime (> 10 pm and ≤ 6 am) ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Change from baseline in trough to peak ratio of mean 24-hour ambulatory Systolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The trough to peak ratio of mean 24-hour ambulatory Systolic Blood Pressure will be calculated using the systolic blood pressure effects at trough (post-dosing hour 24) compared to the maximum systolic blood pressure effect found in the hours after dosing.

  • Change from baseline in trough to peak ratio of mean 24-hour ambulatory Diastolic Blood Pressure of LCZ696 monotherapy compared to placebo [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The trough to peak ratio of mean 24-hour ambulatory Diastolic Blood Pressure will be calculated using the diastolic blood pressure effects at trough (post-dosing hour 24) compared to the maximum diastolic blood pressure effect found in the hours after dosing.

  • Change from baseline in mean 24-hour ambulatory Systolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Change from baseline in mean 24-hour ambulatory Diastolic Blood Pressure of the combination of LCZ696 and amlodipine compared to LCZ696 and amlodipine alone [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • 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 [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • 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 [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • 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 [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • 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 [ Time Frame: baseline, 8 weeks ] [ Designated as safety issue: No ]
    The ABPM cuff will be placed on the non-dominant arm between approximately 7:00 am and 11:00 am and the device will measure blood pressure 3 times per hour for 24 hours.

  • Percentage of patients achieving msSBP <140 mmHg and msDBP <90 mmHg [ Time Frame: 8 weeks ] [ Designated as safety issue: No ]
    The percentage of patients achieving blood pressure control (msSBP <140 mmHg and msDBP <90 mmHg) after 8 weeks of treatment will be calculated.

  • Percentage of patients achieving msSBP <140 mmHg or a reduction ≥20 mmHg from baseline [ Time Frame: Baseline, 8 weeks ] [ Designated as safety issue: No ]
    The percentage of patients achieving a successful response in msSBP (msSBP <140 mmHg or a reduction ≥20 mmHg from baseline) after 8 weeks of treatment will be calculated.

  • Percentage of patients achieving msDBP <90 mmHg or a reduction ≥10 mmHg from baseline [ Time Frame: Baseline, 8 weeks ] [ Designated as safety issue: No ]
    The percentage of patients achieving a successful response in msSBP (msDBP <90 mmHg or a reduction ≥10 mmHg from baseline) after 8 weeks of treatment will be calculated.

  • Number of patients reporting adverse events [ Time Frame: 8 weeks ] [ Designated as safety issue: Yes ]
    As an assessment of safety of monotherapy and combination therapy of LCZ696, total adverse events, serious adverse events and deaths after 8 weeks of treatment will be reported .


Enrollment: 0
Study Start Date: April 2014
Estimated Study Completion Date: April 2015
Estimated Primary Completion Date: April 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: LCZ696 200 mg
Patients randomized to this treatment arm will receive LCZ696 200 mg once daily for 8 weeks.
Drug: LCZ696
Experimental monotherapy doses
Experimental: LCZ696 400 mg
Patients randomized to this treatment arm will receive LCZ696 400 mg once daily for 8 weeks.
Drug: LCZ696
Experimental monotherapy doses
Active Comparator: Amlodipine 5 mg
Patients randomized to this treatment arm will receive amlodipine 5 mg once daily for 8 weeks.
Drug: Amlodipine
Active comparator monotherapy doses
Active Comparator: Amlodipine 10 mg
Patients randomized to this treatment arm will receive amlodipine 10 mg once daily for 8 weeks.
Drug: Amlodipine
Active comparator monotherapy doses
Experimental: 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.
Drug: LCZ696 and amlodipine combination
Experimental combination doses
Experimental: 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.
Drug: LCZ696 and amlodipine combination
Experimental combination doses
Experimental: 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.
Drug: LCZ696 and amlodipine combination
Experimental combination doses
Experimental: 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.
Drug: LCZ696 and amlodipine combination
Experimental combination doses
Placebo Comparator: Placebo
Patients randomized to this treatment arm will receive placebo once daily for 8 weeks.
Drug: Placebo
Placebo comparator dose

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male or female outpatients
  2. Patients with mild-to-moderate hypertension, untreated or currently taking antihypertensive therapy
  3. 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.
  4. 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.
  5. Patients must have an absolute difference of ≤15 mmHg in msSBP between the randomization visit and the preceding visit.
  6. 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:

  1. Severe hypertension (msDBP ≥110 mmHg and/or msSBP ≥ 180 mmHg)
  2. History of angioedema, drug-related or otherwise
  3. 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
  4. Transient ischemic cerebral attack (TIA) during the 12 months prior to Visit 1 or any history of stroke
  5. History of myocardial infarction, coronary bypass surgery or any percutaneous coronary intervention (PCI) during the 12 months prior to Visit 1
  6. Pregnant or lactating women
  7. Women of child-bearing potential not using highly effective methods of contraception Other protocol defined inclusion/exclusion criteria may apply
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01865188

Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

No publications provided

Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT01865188     History of Changes
Other Study ID Numbers: CLCZ696A2320, 2013-001643-30
Study First Received: May 24, 2013
Last Updated: August 4, 2014
Health Authority: Argentina: Ministry of Health
Brazil: Ministry of Health
Colombia: INVIMA Instituto Nacional de Vigilancia de Medicamentos y Alimentos
Dominican Republic: Secretaría del Estado de Salud Pública y Asistencia Social (SESPAS)
Ecuador: Public Health Ministry
Guatemala: Ministry of Public Health and Social Assistance
Mexico: Ministry of Health
Panama: Ministry of Health
Peru: Ministry of Health
Philippines: Bureau of Food and Drugs
Russia: Pharmacological Committee, Ministry of Health
South Africa: Department of Health
Solvak Republic: Ethics Committee
Spain: Ministry of Health
Thailand: Food and Drug Administration
Vietnam: Ministry of Health
United States: Food and Drug Administration

Keywords provided by Novartis:
LCZ696,
amlodipine,
hypertension,
ABPM

Additional relevant MeSH terms:
Hypertension
Cardiovascular Diseases
Vascular Diseases
Amlodipine
Antihypertensive Agents
Calcium Channel Blockers
Cardiovascular Agents
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Therapeutic Uses
Vasodilator Agents

ClinicalTrials.gov processed this record on October 23, 2014