Trial Outcomes & Findings for The CLEVER Study - Coreg And Left Ventricular Mass Regression (NCT NCT00108082)

NCT ID: NCT00108082

Last Updated: 2016-12-16

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 287 participants
• Primary outcome timeframe: 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)
• Results posted on: 2016-12-16

Participant Flow

Following screening, 413 participants were enrolled into the study to begin an open-label run-in phase with lisinopril 10 mg once daily (OD) for 1 week and then lisinopril 20 mg OD for 1 week. Of these participants, 287 were randomized to 1 of the 3 treatment regimens.

Participant milestones

Measure	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 \[MR\].)	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.	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.
Overall Study STARTED	91	100	96
Overall Study COMPLETED	53	68	53
Overall Study NOT COMPLETED	38	32	43

Reasons for withdrawal

Measure	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 \[MR\].)	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.	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.
Overall Study Adverse Event	14	12	17
Overall Study Lost to Follow-up	6	3	7
Overall Study Consent Withdrawn	3	3	5
Overall Study Protocol Violation	1	2	0
Overall Study Lack of Efficacy	3	1	2
Overall Study Amendment 4: > Month 12	5	7	5
Overall Study Woman of Child-bearing Potential	2	0	2
Overall Study Incorrectly Randomized	0	0	2
Overall Study Non-compliance	1	0	2
Overall Study Stopped Study Medication	0	0	1
Overall Study Site Closed Study	0	2	0
Overall Study Protocol Amendment	0	1	0
Overall Study Study Medication Not Tapered	0	1	0
Overall Study Subject Left Site Location	1	0	0
Overall Study Investigator Not at Site	1	0	0
Overall Study Blood Pressure Not Controlled	1	0	0

Baseline Characteristics

The CLEVER Study - Coreg And Left Ventricular Mass Regression

Baseline characteristics by cohort

Measure	Carvedilol CR n=91 Participants 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 \[MR\].)	Atenolol n=100 Participants 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.	Lisinopril n=96 Participants 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.	Total n=287 Participants Total of all reporting groups
Age, Continuous	56.6 years STANDARD_DEVIATION 10.53 • n=5 Participants	57.4 years STANDARD_DEVIATION 10.95 • n=7 Participants	55.9 years STANDARD_DEVIATION 10.09 • n=5 Participants	56.7 years STANDARD_DEVIATION 10.52 • n=4 Participants
Gender Female	40 Participants n=5 Participants	41 Participants n=7 Participants	47 Participants n=5 Participants	128 Participants n=4 Participants
Gender Male	51 Participants n=5 Participants	59 Participants n=7 Participants	49 Participants n=5 Participants	159 Participants n=4 Participants
Race/Ethnicity, Customized African American/African Heritage	17 participants n=5 Participants	26 participants n=7 Participants	17 participants n=5 Participants	60 participants n=4 Participants
Race/Ethnicity, Customized American Indian/Alaska Native	0 participants n=5 Participants	1 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Race/Ethnicity, Customized Asian	2 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	3 participants n=4 Participants
Race/Ethnicity, Customized White/Caucasian	67 participants n=5 Participants	67 participants n=7 Participants	72 participants n=5 Participants	206 participants n=4 Participants
Race/Ethnicity, Customized Arabic/North African Heritage	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Race/Ethnicity, Customized Mixed Race	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	2 participants n=4 Participants
Race/Ethnicity, Customized Not Reported	3 participants n=5 Participants	5 participants n=7 Participants	4 participants n=5 Participants	12 participants n=4 Participants

PRIMARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid MRI at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=60 Participants 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 \[MR\].)	Atenolol n=76 Participants 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.	Lisinopril n=59 Participants 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.
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	-6.34 grams per meters squared (g/m^2) Standard Error 0.850	-6.67 grams per meters squared (g/m^2) Standard Error 0.756	-7.94 grams per meters squared (g/m^2) Standard Error 0.850

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid MRI at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=60 Participants 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 \[MR\].)	Atenolol n=76 Participants 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.	Lisinopril n=59 Participants 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.
Model-adjusted Mean Change From Baseline in Left Ventricular Mass Indexed by Height (LVMIH) as Measured by MRI at Month 12	-3.19 g/m raised to 2.7 (g/(m^2.7)) Standard Error 0.407	-3.37 g/m raised to 2.7 (g/(m^2.7)) Standard Error 0.361	-3.98 g/m raised to 2.7 (g/(m^2.7)) Standard Error 0.407

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid MRI at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=60 Participants 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 \[MR\].)	Atenolol n=76 Participants 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.	Lisinopril n=59 Participants 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.
Model-adjusted Mean Change From Baseline in Left Ventricular (LV) Mass as Measured by MRI at Month 12	-13.74 grams (g) Standard Error 1.732	-14.17 grams (g) Standard Error 1.540	-17.17 grams (g) Standard Error 1.734

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid echocardiogram at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=61 Participants 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 \[MR\].)	Atenolol n=71 Participants 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.	Lisinopril n=59 Participants 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.
Model-adjusted Mean Change From Baseline in Left Ventricular Mass Indexed (LVMI) by Body Surface Area as Measured by Echocardiography at Month 12	-20.35 grams per meters squared (g/m^2) Standard Error 4.027	-20.06 grams per meters squared (g/m^2) Standard Error 3.672	-18.48 grams per meters squared (g/m^2) Standard Error 3.998

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid echocardiogram at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=61 Participants 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 \[MR\].)	Atenolol n=71 Participants 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.	Lisinopril n=59 Participants 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.
Model-adjusted Mean Change From Baseline in Left Ventricular Mass Indexed by Height (LVMIH) as Measured by Echocardiography at Month 12	-11.78 g/m raised to 2.7 (g/(m^2.7)) Standard Error 2.292	-12.51 g/m raised to 2.7 (g/(m^2.7)) Standard Error 2.100	-11.61 g/m raised to 2.7 (g/(m^2.7)) Standard Error 2.280

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid echocardiogram at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=61 Participants 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 \[MR\].)	Atenolol n=71 Participants 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.	Lisinopril n=59 Participants 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.
Model-adjusted Mean Change From Baseline in LV Mass as Measured by Echocardiography at Month 12	-45.76 grams Standard Error 8.338	-40.56 grams Standard Error 7.645	-38.58 grams Standard Error 8.296

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid MRI at Baseline and Month 12 (LOCF on or after Month 9 to 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).

Outcome measures

Measure	Carvedilol CR n=48 Participants 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 \[MR\].)	Atenolol n=54 Participants 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.	Lisinopril n=41 Participants 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.
Mean Change From Baseline in LV Filling Parameters as Measured by MRI at Month 12 LV E-volume	0.364 milliliters (mL) Standard Error 2.2853	6.763 milliliters (mL) Standard Error 2.3870	-3.406 milliliters (mL) Standard Error 2.8779
Mean Change From Baseline in LV Filling Parameters as Measured by MRI at Month 12 LV A-volume	-0.513 milliliters (mL) Standard Error 1.3624	-0.565 milliliters (mL) Standard Error 1.5154	1.088 milliliters (mL) Standard Error 1.5630

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid MRI at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=60 Participants 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 \[MR\].)	Atenolol n=76 Participants 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.	Lisinopril n=59 Participants 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.
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 Volume	-1.44 milliliters (mL) Standard Error 1.578	-4.29 milliliters (mL) Standard Error 1.397	-3.04 milliliters (mL) Standard Error 1.581
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 Diastolic Volume	-2.86 milliliters (mL) Standard Error 2.848	-2.45 milliliters (mL) Standard Error 2.522	-7.45 milliliters (mL) Standard Error 2.858
Model-adjusted Mean Change From Baseline in LV End Systolic and Diastolic Volumes and Ejection Fraction as Measured by MRI at Month 12 LV Ejection Fraction	0.08 milliliters (mL) Standard Error 0.685	2.16 milliliters (mL) Standard Error 0.607	-0.01 milliliters (mL) Standard Error 0.685

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid echocardiogram at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=60 Participants 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 \[MR\].)	Atenolol n=76 Participants 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.	Lisinopril n=59 Participants 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.
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 Volume	-3.38 milliliters (mL) Standard Error 2.067	-4.74 milliliters (mL) Standard Error 1.892	-5.34 milliliters (mL) Standard Error 2.086
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 Diastolic Volume	-3.07 milliliters (mL) Standard Error 3.389	-3.64 milliliters (mL) Standard Error 3.108	-9.37 milliliters (mL) Standard Error 3.420
Model-adjusted Mean Change From Baseline in LV End Systolic and Diastolic Volumes and Ejection Fraction as Measured by Echocardiography at Month 12 LV Ejection Fraction	1.03 milliliters (mL) Standard Error 0.751	2.33 milliliters (mL) Standard Error 0.687	0.63 milliliters (mL) Standard Error 0.756

SECONDARY outcome

Timeframe: 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)

Population: All randomized participants who had a valid MRI at Baseline and Month 12 (LOCF on or after Month 9 to 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.

Outcome measures

Measure	Carvedilol CR n=60 Participants 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 \[MR\].)	Atenolol n=76 Participants 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.	Lisinopril n=59 Participants 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.
Model-adjusted Mean Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Month 12 Systolic blood pressure	-21.32 mmHg (millimeters of mercury) Standard Error 1.755	-21.12 mmHg (millimeters of mercury) Standard Error 1.535	-22.53 mmHg (millimeters of mercury) Standard Error 1.708
Model-adjusted Mean Change From Baseline in Systolic and Diastolic Blood Pressure (BP) at Month 12 Diastolic blood pressure	-12.77 mmHg (millimeters of mercury) Standard Error 1.103	-14.05 mmHg (millimeters of mercury) Standard Error 0.976	-11.13 mmHg (millimeters of mercury) Standard Error 1.117

SECONDARY outcome

Timeframe: Baseline and Month 12 (If Month 12 data were not available, the LOCF was used

Population: All randomized participants who had a valid measurements at Baseline and Month 12 (LOCF)

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].

Outcome measures

Measure	Carvedilol CR n=34 Participants 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 \[MR\].)	Atenolol n=42 Participants 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.	Lisinopril n=33 Participants 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.
Model-adjusted Ratio to Baseline as Percentage Change From Baseline in Log Transformed B-type Natriuretic Peptide (BNP) at Month 12	51.7 percentage of change Interval 13.2 to 103.2	48.3 percentage of change Interval 13.0 to 94.7	-39.1 percentage of change Interval -54.3 to -19.0

SECONDARY outcome

Timeframe: Baseline and Month 12 (If Month 12 data were not available, the LOCF was used)

Population: All randomized participants who had a valid measurements at Baseline and Month 12 (LOCF)

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.]

Outcome measures

Measure	Carvedilol CR n=48 Participants 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 \[MR\].)	Atenolol n=66 Participants 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.	Lisinopril n=53 Participants 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.
Model-adjusted Ratio to Baseline as Percentage Change From Baseline in Log Transformed C-Reactive Protein (CRP) at Month 12	-10.63 percentage of change Interval -27.41 to 10.02	-3.22 percentage of change Interval -18.82 to 15.38	2.70 percentage of change Interval -15.88 to 25.37

SECONDARY outcome

Timeframe: Baseline and Month 12 (If Month 12 data were not available, the LOCF was used)

Population: All randomized participants who had a valid measurements at Baseline and Month 12 (LOCF)

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.]

Outcome measures

Measure	Carvedilol CR n=83 Participants 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 \[MR\].)	Atenolol n=92 Participants 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.	Lisinopril n=90 Participants 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.
Percentage Change From Baseline in Log Transformed Lipid Parameters at Month 12 Total cholesterol	0.7 percentage of change Interval -3.3 to 4.9	-1.3 percentage of change Interval -4.7 to 2.3	-1.7 percentage of change Interval -5.5 to 2.3
Percentage Change From Baseline in Log Transformed Lipid Parameters at Month 12 Low-density lipid cholesterol	0.0 percentage of change Interval -6.5 to 7.0	-4.0 percentage of change Interval -9.6 to 1.8	-2.7 percentage of change Interval -9.0 to 4.1
Percentage Change From Baseline in Log Transformed Lipid Parameters at Month 12 High-density lipid cholesterol	-4.3 percentage of change Interval -7.7 to 0.7	-4.7 percentage of change Interval -7.7 to -1.6	-1.5 percentage of change Interval -4.9 to 2.1
Percentage Change From Baseline in Log Transformed Lipid Parameters at Month 12 Triglycerides	11.0 percentage of change Interval 2.0 to 20.9	7.1 percentage of change Interval -0.7 to 15.4	6.2 percentage of change Interval -2.4 to 15.5

SECONDARY outcome

Timeframe: Baseline and Month 12 (If Month 12 data were not available, the LOCF was used)

Population: All randomized participants who had a valid measurements at Baseline and Month 12 (LOCF)

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.]

Outcome measures

Measure	Carvedilol CR n=40 Participants 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 \[MR\].)	Atenolol n=51 Participants 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.	Lisinopril n=38 Participants 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.
Model-adjusted Ratio to Baseline as Percentage Change From Baseline in Log Transformed Albumin Creatinine Ratio (ACR) at Month 12	-27.1 percentage of change Interval -39.9 to -11.6	-20.1 percentage of change Interval -32.4 to -5.5	-21.5 percentage of change Interval -35.2 to -4.8

Adverse Events

Carvedilol CR

Serious events: 4 serious events

Other events: 54 other events

Deaths: 0 deaths

Atenolol

Serious events: 6 serious events

Other events: 61 other events

Deaths: 0 deaths

Lisinopril

Serious events: 12 serious events

Other events: 52 other events

Deaths: 0 deaths

Serious adverse events

Measure	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 \[MR\].)	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.	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.
Cardiac disorders Atrial fibrillation	1.1% 1/91	0.00% 0/100	2.1% 2/96
General disorders Non-cardiac chest pain	0.00% 0/91	2.0% 2/100	1.0% 1/96
Nervous system disorders Dizziness	0.00% 0/91	0.00% 0/100	2.1% 2/96
Nervous system disorders Transient ischemic attack	0.00% 0/91	0.00% 0/100	2.1% 2/96
Gastrointestinal disorders Abdominal pain	0.00% 0/91	0.00% 0/100	1.0% 1/96
Cardiac disorders Acute coronary syndrome	0.00% 0/91	0.00% 0/100	1.0% 1/96
General disorders Chest pain	0.00% 0/91	0.00% 0/100	1.0% 1/96
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon cancer	0.00% 0/91	0.00% 0/100	1.0% 1/96
Cardiac disorders Coronary artery disease	1.1% 1/91	0.00% 0/100	0.00% 0/96
Psychiatric disorders Depression	1.1% 1/91	0.00% 0/100	0.00% 0/96
Immune system disorders Drug hypersensitivity	0.00% 0/91	1.0% 1/100	0.00% 0/96
Metabolism and nutrition disorders Gout	0.00% 0/91	0.00% 0/100	1.0% 1/96
Nervous system disorders Headache	0.00% 0/91	0.00% 0/100	1.0% 1/96
Gastrointestinal disorders Inguinal hernia obstructive	0.00% 0/91	1.0% 1/100	0.00% 0/96
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.00% 0/91	1.0% 1/100	0.00% 0/96
Musculoskeletal and connective tissue disorders Muscular weakness	0.00% 0/91	0.00% 0/100	1.0% 1/96
Cardiac disorders Myocardial infarction	0.00% 0/91	0.00% 0/100	1.0% 1/96
Nervous system disorders Neuropathy peripheral	1.1% 1/91	0.00% 0/100	0.00% 0/96
Gastrointestinal disorders Pancreatitis	0.00% 0/91	1.0% 1/100	0.00% 0/96
Respiratory, thoracic and mediastinal disorders Pulmonary mass	0.00% 0/91	0.00% 0/100	1.0% 1/96
Nervous system disorders Syncope	0.00% 0/91	0.00% 0/100	1.0% 1/96
Eye disorders Vision blurred	0.00% 0/91	0.00% 0/100	1.0% 1/96

Other adverse events

Measure	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 \[MR\].)	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.	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.
Nervous system disorders Headache	14.3% 13/91	11.0% 11/100	10.4% 10/96
Respiratory, thoracic and mediastinal disorders Cough	8.8% 8/91	5.0% 5/100	16.7% 16/96
Nervous system disorders Dizziness	14.3% 13/91	8.0% 8/100	6.2% 6/96
General disorders Fatigue	6.6% 6/91	16.0% 16/100	5.2% 5/96
Infections and infestations Nasopharyngitis	6.6% 6/91	9.0% 9/100	8.3% 8/96
Gastrointestinal disorders Diarrhea	5.5% 5/91	7.0% 7/100	7.3% 7/96
General disorders Edema peripheral	6.6% 6/91	7.0% 7/100	5.2% 5/96
Infections and infestations Upper respiratory tract infection	5.5% 5/91	3.0% 3/100	7.3% 7/96
Musculoskeletal and connective tissue disorders Muscle spasms	6.6% 6/91	3.0% 3/100	4.2% 4/96
Infections and infestations Bronchitis	6.6% 6/91	4.0% 4/100	2.1% 2/96
Respiratory, thoracic and mediastinal disorders Dyspnea	3.3% 3/91	7.0% 7/100	0.00% 0/96

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

• Principal investigator is a sponsor employee GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.
• Publication restrictions are in place

Restriction type: OTHER