The CLEVER Study - Coreg And Left Ventricular Mass Regression

A Randomized, Double-Blind, Multi-Center Study Comparing the Effects of Carvedilol Modified Release Formulation (COREG MR) and Atenolol in Combination With and Compared to an Angiotensin Converting Enzyme Inhibitor (Lisinopril) on Left Ventricular Mass Regression in Hypertensive Patients With Left Ventricular Hypertrophy (LVH).

This study is designed to compare the effects of COREG MR (carvedilol modified release formulation) to atenolol on indices of left ventricular dimensions when added to standardized angiotensin converting enzyme (ACE) inhibition, and to the effect of ACE inhibition alone. Subjects with LVH (left ventricular hypertrophy) and hypertension will be studied. The primary endpoint will be the change in left ventricular mass index (LVMI) characterized by magnetic resonance imaging (MRI) following 12 months of treatment. Secondary endpoints include the change in LV (left ventricular) mass, LV wall thickness, diastolic left ventricular filling parameters, and left ventricular ejection fraction by echocardiographic methods at Treatment Month 12. Composite outcomes and individual event data will also be evaluated by treatment group.

Study Overview

• Status: Completed
• Conditions: Hypertrophy, Left Ventricular
• Intervention / Treatment: Drug: carvedilol MR; Drug: lisinopril; Drug: atenolol

Detailed Description

A Randomized, Double-Blind, Multi-Center Study Comparing the Effects of Carvedilol Modified Release Formulation (COREG MR) and Atenolol in Combination with and Compared to an Angiotensin Converting Enzyme Inhibitor (Lisinopril) on Left Ventricular Mass Regression in Hypertensive Patients with Left Ventricular Hypertrophy (LVH).

• Study Type: Interventional
• Enrollment (Actual): 287
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35235
      • GSK Investigational Site
    • Birmingham, Alabama, United States, 35249
      • GSK Investigational Site
    • Mobile, Alabama, United States, 36608
      • GSK Investigational Site
  • Arizona
    • Chandler, Arizona, United States, 77030
      • GSK Investigational Site
    • Mesa, Arizona, United States, 85206
      • GSK Investigational Site
    • Peoria, Arizona, United States, 85381 - 4828
      • GSK Investigational Site
    • Scottsdale, Arizona, United States, 85251
      • GSK Investigational Site
    • Scottsdale, Arizona, United States, 85260
      • GSK Investigational Site
    • Sun City, Arizona, United States, 85351
      • GSK Investigational Site
  • California
    • Fresno, California, United States, 93720
      • GSK Investigational Site
    • Los Angeles, California, United States, 90095
      • GSK Investigational Site
    • Los Angeles, California, United States, 90048
      • GSK Investigational Site
    • Los Angeles, California, United States, 90033
      • GSK Investigational Site
    • Palo Alto, California, United States, 94301
      • GSK Investigational Site
    • Poway, California, United States, 92064
      • GSK Investigational Site
    • Sacremento, California, United States, 95819
      • GSK Investigational Site
    • San Diego, California, United States, 92120
      • GSK Investigational Site
    • San Leandro, California, United States, 94578
      • GSK Investigational Site
    • Santa Ana, California, United States, 92705
      • GSK Investigational Site
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • GSK Investigational Site
    • Colorado Springs, Colorado, United States, 80919
      • GSK Investigational Site
    • Denver, Colorado, United States, 80204
      • GSK Investigational Site
    • Denver, Colorado, United States, 80218
      • GSK Investigational Site
  • Delaware
    • Newark, Delaware, United States, 19718
      • GSK Investigational Site
  • District of Columbia
    • Washington, District of Columbia, United States, 20037
      • GSK Investigational Site
    • Washington, District of Columbia, United States, 20422
      • GSK Investigational Site
  • Florida
    • Altamonte Springs, Florida, United States, 32714
      • GSK Investigational Site
    • Atlantis, Florida, United States, 33462
      • GSK Investigational Site
    • Jacksonville, Florida, United States, 32209
      • GSK Investigational Site
    • Kissimmee, Florida, United States, 34741
      • GSK Investigational Site
    • Longwood, Florida, United States, 32779
      • GSK Investigational Site
    • Miami, Florida, United States, 33156
      • GSK Investigational Site
    • Ormond Beach, Florida, United States, 32714
      • GSK Investigational Site
    • Pembroke Pines, Florida, United States, 33029
      • GSK Investigational Site
  • Illinois
    • Evanston, Illinois, United States, 60201
      • GSK Investigational Site
    • Vernon Hills, Illinois, United States, 60061
      • GSK Investigational Site
  • Indiana
    • Fort Wayne, Indiana, United States, 46804
      • GSK Investigational Site
    • Indianapolis, Indiana, United States, 46202
      • GSK Investigational Site
  • Maine
    • Scarborough, Maine, United States, 04074
      • GSK Investigational Site
  • Maryland
    • Baltimore, Maryland, United States, 21224
      • GSK Investigational Site
    • Columbia, Maryland, United States, 21044
      • GSK Investigational Site
    • Pikesville, Maryland, United States, 21215
      • GSK Investigational Site
  • Michigan
    • Grand Rapids, Michigan, United States, 49525
      • GSK Investigational Site
  • Minnesota
    • Edina, Minnesota, United States, 55435
      • GSK Investigational Site
    • Minneapolis, Minnesota, United States, 55417
      • GSK Investigational Site
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • GSK Investigational Site
  • New York
    • Buffalo, New York, United States, 14215
      • GSK Investigational Site
    • New York, New York, United States, 10021
      • GSK Investigational Site
    • New York, New York, United States, 10011
      • GSK Investigational Site
    • New York, New York, United States, 10128
      • GSK Investigational Site
    • Williamsville, New York, United States, 14221
      • GSK Investigational Site
  • North Carolina
    • Fayetteville, North Carolina, United States, 28304
      • GSK Investigational Site
    • Greensboro, North Carolina, United States, 27401
      • GSK Investigational Site
    • Winston-Salem, North Carolina, United States, 27157
      • GSK Investigational Site
  • Ohio
    • Cincinnati, Ohio, United States, 45224
      • GSK Investigational Site
    • Cincinnati, Ohio, United States, 45267
      • GSK Investigational Site
    • Cleveland, Ohio, United States, 44122
      • GSK Investigational Site
  • Oregon
    • Hillsboro, Oregon, United States, 97123-4117
      • GSK Investigational Site
    • Portland, Oregon, United States, 97210
      • GSK Investigational Site
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • GSK Investigational Site
    • Camp Hill, Pennsylvania, United States, 17011
      • GSK Investigational Site
    • Doylestown, Pennsylvania, United States, 18901
      • GSK Investigational Site
    • Philadelphia, Pennsylvania, United States, 19140
      • GSK Investigational Site
    • Pittsburgh, Pennsylvania, United States, 15212
      • GSK Investigational Site
    • West Grove, Pennsylvania, United States, 19390
      • GSK Investigational Site
  • Rhode Island
    • Warwick, Rhode Island, United States, 02886
      • GSK Investigational Site
  • South Carolina
    • Columbia, South Carolina, United States, 29204
      • GSK Investigational Site
    • Greenville, South Carolina, United States, 29615
      • GSK Investigational Site
    • Greer, South Carolina, United States, 29651
      • GSK Investigational Site
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • GSK Investigational Site
    • Knoxville, Tennessee, United States, 37920
      • GSK Investigational Site
    • Nashville, Tennessee, United States, 37205
      • GSK Investigational Site
  • Texas
    • Houston, Texas, United States, 77030
      • GSK Investigational Site
  • Virginia
    • Danville, Virginia, United States, 24541
      • GSK Investigational Site
    • Roanoke, Virginia, United States, 24014
      • GSK Investigational Site
    • Springfield, Virginia, United States, 22151
      • GSK Investigational Site
  • Washington
    • Tacoma, Washington, United States, 98405
      • GSK Investigational Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53215
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 78 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• Stage 1 or Stage 2 hypertension.
• Left ventricular hypertrophy.

Exclusion criteria:

• In atrial fibrillation.
• Takes beta-blocker for MI (myocardial infarction) or arrhythmia.
• Has uncontrolled diabetes, uncontrollable or symptomatic arrhythmias, unstable angina, second or third degree heart block, history of MI, COPD (chronic obstructive pulmonary disease), liver or kidney disease.
• Uses beta-2-agonists.
• Unable to undergo MRI (magnetic resonance imaging).
• Females of childbearing potential.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Carvedilol CR; Carvedilol controlled release (CR) 20 to 80 mg once daily (OD) plus lisinopril 20 mg OD. Participants were titrated from the starting dosage to higher dosages until their blood pressure was controlled. Participants continued to receive lisinopril 20 mg OD throughout the study. (In the protocol, carvedilol CR was referred to as carvedilol modified-release [MR].)	Drug: carvedilol MR; Study drug; Other Names: Carvedilol controlled release or modified release; Drug: lisinopril; Comparator; Other Names: atenolol; carvedilol MR
Experimental: Atenolol; Atenolol 50 to 100 mg OD plus lisinopril 20 mg OD. Participants were titrated from the starting dosage to higher dosages until their blood pressure was controlled. Participants continued to receive lisinopril 20 mg OD throughout the study.	Drug: lisinopril; Comparator; Other Names: atenolol; carvedilol MR; Drug: atenolol; Comparator
Experimental: Lisinopril; Lisinopril 10 to 40 mg OD plus lisinopril 20 mg OD. Participants were titrated from the starting dosage to higher dosages until their blood pressure was controlled. Participants continued to receive lisinopril 20 mg OD throughout the study.	Drug: lisinopril; Comparator; Other Names: atenolol; carvedilol MR

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Model-adjusted Mean Change From Baseline in Left Ventricular Mass Indexed (LVMI) by Body Surface Area as Measured by Magnetic Resonance Imaging (MRI) at Month 12	LVMI was measured by MRI at Baseline and after 12 months of treatment/Month 12. A reduction in left ventricular mass, calculated as LVMI, of 5 g/m^2 was assumed to be clinically meaningful. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.	Baseline and Month 12 (If Month 12 data were not available, the Last Observation Carried Forward [LOCF] analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Model-adjusted Mean Change From Baseline in Left Ventricular Mass Indexed by Height (LVMIH) as Measured by MRI at Month 12	LVMIH was measured by MRI at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value. LV mass depends on body size. One method of determining whether an individual has LV hypertrophy relates LV mass to height raised to a power of 2.7.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Model-adjusted Mean Change From Baseline in Left Ventricular (LV) Mass as Measured by MRI at Month 12	LV Mass was measured by MRI at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Model-adjusted Mean Change From Baseline in Left Ventricular Mass Indexed (LVMI) by Body Surface Area as Measured by Echocardiography at Month 12	LVMI was measured by echogradiography at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Model-adjusted Mean Change From Baseline in Left Ventricular Mass Indexed by Height (LVMIH) as Measured by Echocardiography at Month 12	LVMIH was measured by echogradiography at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was available)
Model-adjusted Mean Change From Baseline in LV Mass as Measured by Echocardiography at Month 12	LV Mass was measured by echocardiography at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Mean Change From Baseline in LV Filling Parameters as Measured by MRI at Month 12	LV filling parameters, LV E-Volume and LV A-Volume, were measured by MRI at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value. These filling parameters represent the volumes of blood filling the ventricle during the passive filling phase (E-volume) and the active filling phase caused by atrial contraction (A-volume).	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Model-adjusted Mean Change From Baseline in LV End Systolic and Diastolic Volumes and Ejection Fraction as Measured by MRI at Month 12	LV End Systolic and Diastolic Volumes and Ejection Fraction were measured by MRI at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value. The ejection fraction is the fraction of the blood volume available at the end of diastole that is pumped out of the ventricules during systole.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Model-adjusted Mean Change From Baseline in LV End Systolic and Diastolic Volumes and Ejection Fraction as Measured by Echocardiography at Month 12	LV End Systolic and Diastolic Volumes and Ejection Fraction were measured by echocardiography at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Model-adjusted Mean Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Month 12	Systolic and Diastolic BP were measured at Baseline and after 12 months of treatment/Month 12. Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.	Baseline and Month 12 (If Month 12 data were not available, the LOCF analysis, which includes data collected on or after Month 9 of treatment to Month 12 of treatment, was used)
Model-adjusted Ratio to Baseline as Percentage Change From Baseline in Log Transformed B-type Natriuretic Peptide (BNP) at Month 12	BNP concentration (picagram per milliter) was measured at Baseline and after 12 months of treatment/Month 12. Percentage change from Baseline was based on log transformed data and was calculated as 100 x (exponent (mean change on log scale) -1) [Change is the Month 12 value (or value after 12 months of treatment) minus the Baseline value].	Baseline and Month 12 (If Month 12 data were not available, the LOCF was used
Model-adjusted Ratio to Baseline as Percentage Change From Baseline in Log Transformed C-Reactive Protein (CRP) at Month 12	CRP concentration (milligrams per deciliter) was measured at Baseline and after 12 months of treatment/Month 12. Percentage change from Baseline was based on log transformed data and calculated as 100 x (exponent (mean change on log scale) - 1). [Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.]	Baseline and Month 12 (If Month 12 data were not available, the LOCF was used)
Percentage Change From Baseline in Log Transformed Lipid Parameters at Month 12	Plasma lipid concentrations (milligrams per deciliter) were measured at Baseline and after 12 months of treatment/Month 12. Percentage change from Baseline was based on log transformed data and calculated as 100 x (exponent(mean change on log scale) - 1). [Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.]	Baseline and Month 12 (If Month 12 data were not available, the LOCF was used)
Model-adjusted Ratio to Baseline as Percentage Change From Baseline in Log Transformed Albumin Creatinine Ratio (ACR) at Month 12	Urinary ACR (micrograms per milligram) was determined at Baseline and after 12 months of treatment/Month 12. Percentage change from Baseline was based on log transformed data and was calculated as 100 x (exponent (exponent (mean change on log scale) - 1. [Change in Baseline was calculated as Month 12 value (or value after 12 months of treatment) minus the Baseline value.]	Baseline and Month 12 (If Month 12 data were not available, the LOCF was used)

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Bakris GL, Tarka EA, Waterhouse B, Goulding MR, Madan A, Anderson KM, St John Sutton M, Miller AB, Reichek N. Cardiovascular risk factors in hypertension: rationale and design of studies to investigate the effects of controlled-release carvedilol on regression of left ventricular hypertrophy and lipid profile. Am J Cardiol. 2006 Oct 2;98(7A):46L-52L. doi: 10.1016/j.amjcard.2006.08.002. Epub 2006 Aug 28. Erratum In: Am J Cardiol. 2007 Aug 1;100(3):562. Am J Cardiol. 2007 Mar 15;99(6):878. St John Sutton, Martin [added]; Miller, Alan B [added]; Reichek, Nathaniel [added].
• Miller AB, Reichek N, St John Sutton M, Iyengar M, Henderson LS, Tarka EA, Bakris GL. Importance of blood pressure control in left ventricular mass regression. J Am Soc Hypertens. 2010 Nov-Dec;4(6):302-10. doi: 10.1016/j.jash.2010.09.003. Epub 2010 Oct 27.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: January 1, 2005
• Primary Completion (Actual): August 1, 2008
• Study Completion (Actual): August 1, 2008

Study Registration Dates

• First Submitted: April 13, 2005
• First Submitted That Met QC Criteria: April 13, 2005
• First Posted (Estimate): April 14, 2005

Study Record Updates

• Last Update Posted (Estimate): December 16, 2016
• Last Update Submitted That Met QC Criteria: November 4, 2016
• Last Verified: November 1, 2016

More Information

Terms related to this study

• Keywords: cardiac MRI; echocardiogram; left ventricular hypertrophy (LVH); left ventricular mass regression; left ventricular mass index (LVMI)hypertension
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Cardiomegaly; Hypertrophy; Hypertrophy, Left Ventricular; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Protease Inhibitors; Protective Agents; Cardiotonic Agents; Membrane Transport Modulators; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Antioxidants; Angiotensin-Converting Enzyme Inhibitors; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Carvedilol; Lisinopril; Atenolol
• Other Study ID Numbers: COR100216

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Dataset Specification
   Information identifier: COR100216
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Informed Consent Form
   Information identifier: COR100216
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Individual Participant Data Set
   Information identifier: COR100216
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Clinical Study Report
   Information identifier: COR100216
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Annotated Case Report Form
   Information identifier: COR100216
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Statistical Analysis Plan
   Information identifier: COR100216
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Study Protocol
   Information identifier: COR100216
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register