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Study of the Safety and Efficacy of LCZ696 on Arterial Stiffness in Elderly Patients With Hypertension

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ClinicalTrials.gov Identifier: NCT01692301
Recruitment Status : Completed
First Posted : September 25, 2012
Results First Posted : May 4, 2016
Last Update Posted : May 4, 2016
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )

Tracking Information
First Submitted Date  ICMJE September 20, 2012
First Posted Date  ICMJE September 25, 2012
Results First Submitted Date  ICMJE March 31, 2016
Results First Posted Date  ICMJE May 4, 2016
Last Update Posted Date May 4, 2016
Study Start Date  ICMJE December 2012
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 31, 2016)
Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 12 Weeks [ Time Frame: baseline, 12 weeks ]
Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.
Original Primary Outcome Measures  ICMJE
 (submitted: September 20, 2012)
Change from baseline in mean central aortic systolic blood pressure at 12 weeks [ Time Frame: baseline, 12 weeks ]
Change History Complete list of historical versions of study NCT01692301 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: March 31, 2016)
  • Change From Baseline in Mean Central Pulse (CPP) Pressure [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
  • Change From Baseline in Mean Pulse Wave Velocity (PWV) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
    Pulse wave velocity recordings were performed on patient while in a supine, face-up position. Tonometry was performed on the carotid simultaneously with the cuff inflation over the femoral artery. Two pulse wave velocity measures, meeting all quality control criteria were captured at baseline, week 12 and week 52.
  • Change From Baseline in Mean Central Aortic Systolic Pressure (CASP) at 52 Weeks [ Time Frame: baseline, 52 weeks ]
    Central aortic blood pressure was derived from peripheral pressure waveforms recorded noninvasively from the brachial artery using a cuff-based device. This technique uses the brachial pressure and a signal processing algorithm to transform brachial signals into central blood pressure (BP) waveforms. When the aortic pressure waveform was derived, key pulse wave analysis (PWA) parameters, such as CASP was calculated by the system software. At the first study visit, the arm with the highest systolic blood pressure (SBP) was used for all subsequent PWA. Brachial PWA measurements were performed on the same arm that the office blood pressures were taken. Two pulse waveform measurements, meeting all quality control criteria were captured at baseline and at week 12 visits.
  • Change From Baseline in Mean Sitting Systolic Blood Pressure (msSBP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
    At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, SBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
  • Change From Baseline in Mean Sitting Diastolic Blood Pressure (msDBP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
    At the first study visit, the patient had his/her blood pressure (BP) measured in both arms; the arm in which the highest sitting SBP was found was used for all subsequent readings throughout the study. At each study visit, after the patient had been sitting for 5 minutes, DBP were measured 3 times using a standard mercury sphygmomanometer and appropriate size cuff. The repeat sitting measurements were made at 1- to 2-minute intervals and the mean of those 3 measurements was used as the average sitting office BP for that visit.
  • Change From Baseline in Mean Sitting Pulse Pressure (msPP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
    Mean sitting pulse pressure for each patient and visit was calculated as the difference between the calculated values of mean sitting systolic blood pressure and mean sitting diastolic blood pressure.
  • Change From Baseline in Mean Arterial Pressure (MAP) [ Time Frame: baseline, 12 weeks, and 52 weeks ]
    Mean arterial pressure (MAP) was calculated from mean sitting systolic BP (msSBP) and mean sitting diastolic BP (msDBP) as (2 * msDBP + msSBP)/3.
  • Change From Baseline in Mean 24-hour Systolic Blood Pressure (maSBP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
    An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maSBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
  • Change From Baseline in Mean 24-hour Diastolic Blood Pressure (maDBP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
    An Ambulatory Blood Pressure Monitor (ABPM) measured a participant's blood pressure over a 24 hour period using an automated validated monitoring device at baseline, week 12 and at week 52 starting one day before each visit. The 24 hour maDBP was calculated by taking the mean of all ambulatory systolic blood pressure readings for the 24 hour period.
  • Change From Baseline in Mean 24-hour Ambulatory Pulse Pressure (maPP) [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
    Mean 24 hour ambulatory pulse pressure was calculated as the difference between the mean 24 hour systolic and diastolic ambulatory blood pressure in corresponding visits i.e. baseline, week 12 and week 52.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 20, 2012)
  • Change from baseline in mean central pulse pressure [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean aortic pulse wave velocity [ Time Frame: baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean central aortic systolic blood pressure at 52 weeks [ Time Frame: baseline, 52 weeks ]
  • Change from baseline in mean sitting systolic blood pressure [ Time Frame: baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean sitting diastolic blood pressure [ Time Frame: baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean sitting pulse pressure [ Time Frame: baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean arterial pressure [ Time Frame: baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean 24-hour systolic blood pressure [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean 24-hour diastolic blood pressure [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
  • Change from baseline in mean 24-hour ambulatory pulse pressure [ Time Frame: Baseline, 12 weeks, and 52 weeks ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of the Safety and Efficacy of LCZ696 on Arterial Stiffness in Elderly Patients With Hypertension
Official Title  ICMJE A Randomized, Double-blind 52-week Study to Evaluate the Safety and Efficacy of an LCZ696 Regimen Compared to an Olmesartan Regimen on Arterial Stiffness Through Assessment of Central Blood Pressure in Elderly Patients With Hypertension
Brief Summary The study examined the efficacy of LCZ696 in comparison to the ARB olmesartan on Central Aortic Systolic Blood Pressure (CASP) and other measures of central hemodynamics and arterial stiffness in elderly patients with an elevated systolic blood pressure (SBP) and widened pulse pressure (PP).
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Hypertension
Intervention  ICMJE
  • Drug: LCZ696
    200 mg tablet
    Other Name: sacubitril/valsartan
  • Drug: Olmesartan
    20 mg and 40 mg capsules
  • Drug: LCZ696 matching placebo
    LCZ696 Matching Placebo tablet
  • Drug: Olmesartan matching placebo
    Olmesartan matching placebo capsule
  • Drug: amlodipine
    amlodipine 2.5 mg or 5 mg tablets
  • Drug: hydrochlorothiazide
    hydrochlorothiazide 6.25mg, 12.5mg, or 25 mg tablets
Study Arms  ICMJE
  • Experimental: LCZ696 (sacubitril/valsartan)
    Randomized patients received LCZ696 once daily for four weeks, then they force-titrated to a higher dose at Week 4 and stayed on this dose of LCZ696 once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696, its matching placebo) and 1 capsule (olmesartan matching placebo) were given during the entire study.
    Interventions:
    • Drug: LCZ696
    • Drug: LCZ696 matching placebo
    • Drug: Olmesartan matching placebo
    • Drug: amlodipine
    • Drug: hydrochlorothiazide
  • Active Comparator: Olmesartan
    Randomized patients received olmesartan once daily for four weeks, then force-titrated to a higher dose at Week 4 and stayed on this dose of olmesartan once daily for the remainder of the treatment period. At week 12, patients with uncontrolled BP allowed to have amlodipine then hydrochlorothiazide (HCTZ) added at intervals of 4 weeks from Week 12 up to Week 24. To maintain the double dummy, double-blind design, 2 tablets (LCZ696 matching placebo) and 1 capsule (olmesartan) were given during the entire study.
    Interventions:
    • Drug: Olmesartan
    • Drug: LCZ696 matching placebo
    • Drug: amlodipine
    • Drug: hydrochlorothiazide
Publications * Williams B, Cockcroft JR, Kario K, Zappe DH, Cardenas P, Hester A, Brunel P, Zhang J. Rationale and study design of the Prospective comparison of Angiotensin Receptor neprilysin inhibitor with Angiotensin receptor blocker MEasuring arterial sTiffness in the eldERly (PARAMETER) study. BMJ Open. 2014 Feb 4;4(2):e004254. doi: 10.1136/bmjopen-2013-004254.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 7, 2015)
454
Original Estimated Enrollment  ICMJE
 (submitted: September 20, 2012)
432
Actual Study Completion Date  ICMJE April 2015
Actual Primary Completion Date April 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Key Inclusion Criteria:

  1. Male and female patients ≥ 60 years of age.
  2. Patients with essential hypertension, untreated or currently taking antihypertensive therapy.
  3. Untreated patients must have an office msSBP ≥150 mmHg and <180 mmHg at Visit 101 and Visit 201 if they are newly diagnosed or have not been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.
  4. Treated patients must have an office msSBP ≥140 mmHg and <180 mmHg at Visit 102 (or Visit 103) and msSBP ≥150 mmHg and <180 mmHg at Visit 201 if they have been treated with antihypertensive drugs for the 4 weeks prior to Visit 1.
  5. All patients must have pulse pressure >60 mmHg at Visit 201. Pulse pressure is defined as msSBP- msDBP.
  6. Patients must have a difference in msSBP within +/-15 mmHg between Visit 201 (randomization) and the visit immediately prior to Visit 201.

Key Exclusion Criteria:

  1. Malignant or severe hypertension (grade 3 of WHO classification; 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. History of atrial fibrillation or atrial flutter during the 3 months prior to Visit 1, or active atrial fibrillation or atrial flutter on the ECG at screening.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Colombia,   France,   Germany,   Greece,   Italy,   Japan,   Korea, Republic of,   Russian Federation,   Spain,   Taiwan,   United States
Removed Location Countries Brazil
 
Administrative Information
NCT Number  ICMJE NCT01692301
Other Study ID Numbers  ICMJE CLCZ696A2216
2012-002899-14 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Novartis ( Novartis Pharmaceuticals )
Study Sponsor  ICMJE Novartis Pharmaceuticals
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
PRS Account Novartis
Verification Date March 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP