A Phase I/II Clinical Study of SK&F-105517-D in Japanese Patients With Chronic Heart Failure

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Completed

CT.gov ID

NCT00742508

Collaborator

(none)

Enrollment

Locations

Arms

11.8

Actual Duration (Months)

1.8

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the safety and tolerability of SK&F-105517-D in japanese patients with chronic heart failure.

Condition or Disease	Intervention/Treatment	Phase
Heart Failure, Congestive	Drug: SK&F-105517-D 10 mg capsule Drug: Carvedilol-immediate release (IR) 2.5 mg tablet Drug: SK&F-105517-D 20 mg capsule Drug: SK&F-105517-D 40 mg capsule Drug: Carvedilol-IR 10 mg tablet	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

41 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Study to Evaluate the Safety and Tolerability of SK&F-105517-D in Patients With Chronic Heart Failure- An Open-label Study to Evaluate the Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of SK&F-105517-D in Patients With Chronic Heart Failure (Phase I/II Study)

Actual Study Start Date :

Aug 28, 2008

Actual Primary Completion Date :

Aug 21, 2009

Actual Study Completion Date :

Aug 21, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SK&F-105517-D group SK&F-105517-D 10-80 mg/day	Drug: SK&F-105517-D 10 mg capsule 1 capsule once a day Other Names: carvedilol phosphate Drug: SK&F-105517-D 20 mg capsule 1 capsule once a day Other Names: carvedilol phosphate Drug: SK&F-105517-D 40 mg capsule 1 or 2 capsule(s) once a day Other Names: carvedilol phosphate
Other: Carvedilol-IR group Carvedilol-IR 5-20 mg/day	Drug: Carvedilol-immediate release (IR) 2.5 mg tablet 1 or 2 tablet(s) twice a day Drug: Carvedilol-IR 10 mg tablet 1 tablet twice a day

Arm

Intervention/Treatment

Experimental: SK&F-105517-D group

SK&F-105517-D 10-80 mg/day

Drug: SK&F-105517-D 10 mg capsule

1 capsule once a day

Other Names:

carvedilol phosphate

Drug: SK&F-105517-D 20 mg capsule

1 capsule once a day

Other Names:

carvedilol phosphate

Drug: SK&F-105517-D 40 mg capsule

1 or 2 capsule(s) once a day

Other Names:

carvedilol phosphate

Other: Carvedilol-IR group

Carvedilol-IR 5-20 mg/day

Drug: Carvedilol-immediate release (IR) 2.5 mg tablet

1 or 2 tablet(s) twice a day

Drug: Carvedilol-IR 10 mg tablet

1 tablet twice a day

Outcome Measures

Primary Outcome Measures

Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) [Treatment Period from Week 0 (Baseline) to Week 8 and 1-week Follow-up Period (Week 9) for CRV-IR; Treatment Period from Week 0 (Baseline) to Week 14 and 1-week Follow-up Period (Week 15) for SK&F-105517-D]
Drug-related adverse events (AEs) were defined as AEs that were judged to have a relationship with the investigational product by the investigator (or subinvestigator) with the use of clinical judgment and the Clinical Investigator Brochure to determine the relationship. Refer to adverse event information for type and frequency of adverse events.
Mean Change From Baseline in Albumin and Total Protein at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Amylase at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value. (BB, brain-derived; MB=cardiac muscle-derived; MM=skeletal muscle-derived.
Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Hematocrit at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Red Blood Cell Count at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Mean Corpuscular Volume at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 [Baseline and Week 8]
Dipstick test values: Negative (-), Traces (+-), +1, +2, +3. +4. Normal ranges (qualitative): protein, - or +-; glucose, - or +-; occult blood, -; ketones, -.
Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Heart Rate at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Weight at Week 8 [Baseline and Week 8]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 [Baseline and Week 8]
There are 3 categories for electrocardiogram (ECG) findings: normal; abnormal, not clinically significant; and abnormal, clinically significant. Each of the findings was classified by the investigator according to whether it was normal. Abnormal ECGs were further classified according to whether they were felt to be clinically significant in the medical and scientific judgment of the investigator.
Cardiothoracic Ratio at Baseline and Week 8 [Baseline and Week 8]
Cardiothoracic ratio is a marker of the degree of heart enlargement and was measured by chest X-ray. It is shown as the ratio of the transverse diameter of the heart to the transverse diameter of the thorax, and is measured as a percentage.

Secondary Outcome Measures

Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 [Week 8]
Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 active Metabolite (SB-203231) were measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. The analysis was performed on log-transformed data. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 [Week 8]
Area under the plasma concentration versus time curve from time zero to 24 hours (AUC0-24) of S-carvedilol, R-carvedilol, and M4 active metabolite (SB-203231) was measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. The analysis was performed on log-transformed data. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 [Week 8]
Time of maximal plasma concentration (tmax) of S-carvedilol, R-carvedilol, and M4 active metabolite (SB-203231) was measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 [Baseline and Week 8]
Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 [Baseline and Week 8]
Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 [Baseline and Week 8]
Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.
Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 [Baseline and Week 8]
The NYHA classification assesses the severity of symptoms of heart failure as judged by the investigator and is comprised of. 4 classes: I, no resulting limitations on physical activity (PA); II, slight limitations on PA; III, marked limitations on PA; IV, inability to carry out any PA without discomfort. The number of participants with any change from Baseline in the NYHA Functional Class at Week 8 was calculated. Improved=class at the visit is decreased compared to baseline class, Unchanged=class at the visit is stable, Worsened=class at the visit is increased compared to baseline class.
Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8 [Baseline and Week 8]
Brain natriuretic peptide is a surrogate marker of the severity of heart failure and was measured by a central laboratory.
Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 [Baseline and Week 8]
Left ventricular ejection fraction (LVEF) is a marker of left ventricular systolic function and was measured by echocardiogram. It is shown as the ratio of left ventricular stroke volume (LVSV) to left ventricular end-diastolic volume (LVEDV), and is measured as a percentage.

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion criteria:

Patients with symptomatically stable chronic heart failure (CHF) based on ischemic heart disease or dilated cardiomyopathy
Patients who are maintained on basic heart failure therapy with angiotensin converting enzyme (ACE) inhibitors or angiotensin II receptor blocker (ARB) and their dosage/administration is not changed within 2 weeks
Patients diagnosed with New York Heart Association (NYHA) class I to III
Patients with a left ventricular ejection fraction (LVEF) between 25% and 45%

Exclusion Criteria:

Patients contraindicated for ß-blockers
Patients with occurrence of acute myocardial infarction within 2 weeks
Patients with unstable angina, coronary spastic angina, or angina at rest
Patients who have collected blood >400 mL within 4 months prior to screening or >200 mL within 1 months

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	GSK Investigational Site	Chiba	Japan	296-8602
2	GSK Investigational Site	Ehime	Japan	794-0006
3	GSK Investigational Site	Hiroshima	Japan	737-0023
4	GSK Investigational Site	Hokkaido	Japan	060-0033
5	GSK Investigational Site	Hokkaido	Japan	063-0005
6	GSK Investigational Site	Kanagawa	Japan	210-0852
7	GSK Investigational Site	Kanagawa	Japan	238-8558
8	GSK Investigational Site	Mie	Japan	511-0068
9	GSK Investigational Site	Nagano	Japan	397-8555
10	GSK Investigational Site	Nagasaki	Japan	859-3615
11	GSK Investigational Site	Oita	Japan	879-5593
12	GSK Investigational Site	Osaka	Japan	565-8565
13	GSK Investigational Site	Saga	Japan	843-0393
14	GSK Investigational Site	Saitama	Japan	364-8501
15	GSK Investigational Site	Shizuoka	Japan	410-2295
16	GSK Investigational Site	Shizuoka	Japan	411-8611
17	GSK Investigational Site	Shizuoka	Japan	427-8502
18	GSK Investigational Site	Shizuoka	Japan	430-8502
19	GSK Investigational Site	Tokyo	Japan	141-0001
20	GSK Investigational Site	Tokyo	Japan	142-8666
21	GSK Investigational Site	Tokyo	Japan	153-8515
22	GSK Investigational Site	Tokyo	Japan	196-0003
23	GSK Investigational Site	Wakayama	Japan	640-8158

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

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

Publications

Kitakaze M, Sarai N, Ando H, Sakamoto T, Nakajima H. Safety and tolerability of once-daily controlled-release carvedilol 10-80 mg in Japanese patients with chronic heart failure. Circ J. 2012;76(3):668-74. Epub 2012 Jan 12.

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT00742508

Other Study ID Numbers:

CRV110734

First Posted:

Aug 27, 2008

Last Update Posted:

Aug 2, 2017

Last Verified:

Jun 1, 2017

Individual Participant Data (IPD) Sharing Statement:

Yes

Plan to Share IPD:

Yes

Keywords provided by GlaxoSmithKline

carvedilol phosphate

ß-blocker

SK&F-105517-D

Chronic heart failure(CHF)

Additional relevant MeSH terms:

Heart Failure

Carvedilol

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail	Participants randomized to receive SK&F-105517-D underwent 2 weeks of observation, 8 weeks of Primary Evaluation, 4 weeks of Exploratory Evaluation, 2 weeks of dose-tapering, and 1 week of Follow-up period. Participants randomized to receive CRV-IR underwent 2 weeks of observation, 8 weeks of Primary Evaluation, and 1 week of Follow-up.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Period Title: 8-Week Primary Evaluation Period
STARTED	22	19
COMPLETED	11	8
NOT COMPLETED	11	11
Period Title: 8-Week Primary Evaluation Period
STARTED	0	8
COMPLETED	0	7
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	CRV-IR	SK&F-105517-D	Total
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.	Total of all reporting groups
Overall Participants	22	19	41
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.7 (8.17)	66.7 (12.00)	64.6 (10.20)
Sex: Female, Male (Count of Participants)
Female	2 9.1%	1 5.3%	3 7.3%
Male	20 90.9%	18 94.7%	38 92.7%
Race/Ethnicity, Customized (participants) [Number]
Asian-Japanese Heritage	22 100%	19 100%	41 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D)
Description	Drug-related adverse events (AEs) were defined as AEs that were judged to have a relationship with the investigational product by the investigator (or subinvestigator) with the use of clinical judgment and the Clinical Investigator Brochure to determine the relationship. Refer to adverse event information for type and frequency of adverse events.
Time Frame	Treatment Period from Week 0 (Baseline) to Week 8 and 1-week Follow-up Period (Week 9) for CRV-IR; Treatment Period from Week 0 (Baseline) to Week 14 and 1-week Follow-up Period (Week 15) for SK&F-105517-D

Outcome Measure Data

Analysis Population Description
Safety Population: all participants who received at least one dose of the investigational product

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Severe	0 0%	1 5.3%
Moderate	2 9.1%	5 26.3%
Mild	9 40.9%	10 52.6%
Severe (drug-related)	0 0%	1 5.3%
Moderate (drug-related)	2 9.1%	3 15.8%
Mild (drug-related)	3 13.6%	4 21.1%

2. Secondary Outcome

Title	Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8
Description	Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 active Metabolite (SB-203231) were measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. The analysis was performed on log-transformed data. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description
PK Parameter Population: total of 13 participants, including 3 who gave samples in group F at Week 8 in CRV-IR group; total of 15 participants, including 4 who gave samples at Week 8 in the SK&F-105517-D group)

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	3	4
S-carvedilol, Cmax	6.7952	12.8171
S-carvedilol, Cmin	1.2072	3.3796
R-carvedilol, Cmax	19.1864	27.1306
R-carvedilol, Cmin	2.9445	4.2565
SB-203231, Cmax	3.1665	6.3937
SB-203231, Cmin	0.4843	1.2386

3. Secondary Outcome

Title	Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8
Description	Area under the plasma concentration versus time curve from time zero to 24 hours (AUC0-24) of S-carvedilol, R-carvedilol, and M4 active metabolite (SB-203231) was measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. The analysis was performed on log-transformed data. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description
Pharmacokinetic (PK) Parameter Population: all participants who received the study drug at each dose level and provided sufficient PK concentration data and the data for estimation of PK parameters (total of 13 participants, 3 gave samples at Week 8 in CRV-IR group; total of 15 participants, 4 gave samples at Week 8 in the SK&F-105517-D group)

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	3	4
S-carvedilol	60.040	155.109
R-carvedilol	170.728	284.313
SB-203231	28.113	64.687

4. Secondary Outcome

Title	Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8
Description	Time of maximal plasma concentration (tmax) of S-carvedilol, R-carvedilol, and M4 active metabolite (SB-203231) was measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description
PK Parameter Population: total of 13 participants, including 3 in group F who gave samples at Week 8 in the CRV-IR group; total of 15 participants, including 4 in group C who gave samples at Week 8 in the SK&F-105517-D group

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	3	4
S-carvedilol	1.983	5.958
R-carvedilol	1.983	5.958
SB-203231	1.983	5.958

5. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8
Description	Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Pharmacodynamic (PD) Population: all participants measurable at the PD endpoints (18 participants at baseline and 3 participants at Week 8 in CRV-IR group, 19 participants at baseline and 4 participants at Week 8 in SK&F-105517-D group)

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	18	19
24 h	-10.84 (4.119)	-1.45 (3.567)
Morning	-12.34 (4.412)	-4.78 (3.819)
Afternoon	-10.14 (2.734)	-12.06 (2.361)
Night	-9.04 (4.786)	5.17 (4.139)
Waking	-10.39 (2.857)	-9.99 (2.472)
Sleeping	-11.85 (3.223)	13.20 (2.787)
PDmax	-9.74 (7.772)	-10.19 (6.656)
PDmin	-6.89 (5.416)	1.42 (4.685)
PDmax/PDmin	0.07 (0.103)	-0.17 (0.088)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	9.38
	Confidence Interval	(2-Sided) 95% -5.75 to 24.51
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.449
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the 24 h assessment.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	7.55
	Confidence Interval	(2-Sided) 95% -8.68 to 23.79
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.849
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Morning assessment.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.92
	Confidence Interval	(2-Sided) 95% -12.04 to 8.20
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.645
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Afternoon assessment.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	14.21
	Confidence Interval	(2-Sided) 95% -3.45 to 31.87
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.361
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Night assessment.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95% -10.12 to 10.92
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.790
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Waking assessment.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	25.04
	Confidence Interval	(2-Sided) 95% 13.16 to 36.93
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.281
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Sleeping assessment.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.45
	Confidence Interval	() 95% -29.94 to 29.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 10.62
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmax assessment.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	8.31
	Confidence Interval	(2-Sided) 95% -11.67 to 28.28
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.194
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmin assessment.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.24
	Confidence Interval	(2-Sided) 95% -0.63 to 0.15
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.142
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmax/PDmin assessment.

6. Primary Outcome

Title	Mean Change From Baseline in Albumin and Total Protein at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Albumin	0.7 (2.87)	-1.9 (2.90)
Total Protein	0.4 (4.27)	-1.6 (4.72)

7. Primary Outcome

Title	Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Alkaline Phosphatase	-10.9 (18.45)	-5.0 (21.13)
Alanine Aminotransferase	-0.2 (6.48)	3.8 (9.39)
Aspartate Aminotransferase	0.8 (3.87)	1.4 (7.19)
Creatine Kinase	34.4 (55.58)	-0.1 (65.54)
Gamma Glutamyl Transferase	-0.8 (3.68)	2.4 (10.62)

8. Primary Outcome

Title	Mean Change From Baseline in Amylase at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Mean (Standard Deviation) [units per liter (U/L)]	-10.2 (9.98)	-0.1 (15.66)

9. Primary Outcome

Title	Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Total Bilirubin	1.555 (2.3514)	-4.489 (3.8712)
Creatinine	5.5451 (14.97638)	-4.5305 (5.85307)
Uric Acid	30.8215 (48.16177)	14.1265 (80.67868)

10. Primary Outcome

Title	Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Calcium	-0.027218 (0.1364081)	-0.056138 (0.0592680)
Chloride	0.2 (1.60)	2.4 (2.20)
Glucose	-0.136252 (2.9159783)	-1.956728 (2.8733368)
Potassium	-0.07 (0.361)	0.07 (0.474)
Sodium	0.5 (2.30)	1.6 (1.41)
Urea/Blood Urea Nitrogen	0.61339 (2.523049)	-0.58013 (1.023316)

11. Primary Outcome

Title	Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value. (BB, brain-derived; MB=cardiac muscle-derived; MM=skeletal muscle-derived.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Creatine Kinase BB percentage	-0.2 (0.60)	0.5 (0.93)
Creatine Kinase MB percentage	-0.3 (0.65)	-0.1 (0.83)
Creatine Kinase MM percentage	1.1 (1.30)	0.8 (1.75)

12. Primary Outcome

Title	Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Basophils	-0.06 (0.403)	-0.06 (0.325)
Eosinophils	0.15 (1.547)	0.76 (1.412)
Lymphocytes	0.05 (6.052)	2.21 (9.174)
Monocytes	0.19 (1.358)	1.28 (1.356)
Total Neutrophils	-0.41 (7.875)	-4.31 (11.180)

13. Primary Outcome

Title	Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Hemoglobin	-2.3 (8.05)	-3.9 (8.04)
Mean Corpuscular Hemoglobin Concentration	1.3 (4.90)	-1.9 (6.01)

14. Primary Outcome

Title	Mean Change From Baseline in Hematocrit at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Mean (Standard Deviation) [proportion of 1 (SI)]	-0.0085 (0.02306)	-0.0095 (0.02287)

15. Primary Outcome

Title	Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Platelet Count	-6.9 (23.28)	-11.1 (14.54)
White Blood Cell Count	0.297 (0.9850)	-0.498 (1.9516)

16. Primary Outcome

Title	Mean Change From Baseline in Red Blood Cell Count at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Mean (Standard Deviation) [tebi (2 to the power of 40)/liter (Ti/L)]	-0.091 (0.2390)	-0.087 (0.2295)

17. Primary Outcome

Title	Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Mean (Standard Deviation) [picograms (pg)]	0.12 (0.515)	-0.21 (0.372)

18. Primary Outcome

Title	Mean Change From Baseline in Mean Corpuscular Volume at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Mean (Standard Deviation) [femtoliters (fL)]	0.1 (1.38)	-0.1 (1.96)

19. Primary Outcome

Title	Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8
Description	Dipstick test values: Negative (-), Traces (+-), +1, +2, +3. +4. Normal ranges (qualitative): protein, - or +-; glucose, - or +-; occult blood, -; ketones, -.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Urine Glucose, Negative, Baseline, n=22, 19	20 90.9%	19 100%
Urine Glucose, Traces, Baseline, n=22, 19	1 4.5%	0 0%
Urine Glucose, 1+, Baseline, n=22, 19	0 0%	0 0%
Urine Glucose, 2+, Baseline, n=22, 19	0 0%	0 0%
Urine Glucose, 3+, Baseline, n=22, 19	1 4.5%	0 0%
Urine Glucose, 4+, Baseline, n=22, 19	0 0%	0 0%
Urine Ketones, Negative, Baseline, n=22, 19	22 100%	19 100%
Urine Ketones, Traces, Baseline, n=22, 19	0 0%	0 0%
Urine Ketones, 1+, Baseline, n=22, 19	0 0%	0 0%
Urine Ketones, 2+, Baseline, n=22, 19	0 0%	0 0%
Urine Ketones, 3+, Baseline, n=22, 19	0 0%	0 0%
Urine Ketones, 4+, Baseline, n=22, 19	0 0%	0 0%
Urine Occult Blood, Negative, Baseline, n=22, 19	18 81.8%	16 84.2%
Urine Occult Blood, Traces, Baseline, n=22, 19	1 4.5%	1 5.3%
Urine Occult Blood, 1+, Baseline, n=22, 19	2 9.1%	1 5.3%
Urine Occult Blood, 2+, Baseline, n=22, 19	1 4.5%	1 5.3%
Urine Occult Blood, 3+, Baseline, n=22, 19	0 0%	0 0%
Urine Occult Blood, 4+, Baseline, n=22, 19	0 0%	0 0%
Urine Protein, Negative, Baseline, n=22, 19	21 95.5%	18 94.7%
Urine Protein, Traces, Baseline, n=22, 19	0 0%	0 0%
Urine Protein, 1+, Baseline, n=22, 19	0 0%	1 5.3%
Urine Protein, 2+, Baseline, n=22, 19	1 4.5%	0 0%
Urine Protein, 3+, Baseline, n=22, 19	0 0%	0 0%
Urine Protein, 4+, Baseline, n=22, 19	0 0%	0 0%
Urine Glucose, Negative, Week 8, n=11, 8	11 50%	8 42.1%
Urine Glucose, Traces, Week 8, n=11, 8	0 0%	0 0%
Urine Glucose, 1+, Week 8, n=11, 8	0 0%	0 0%
Urine Glucose, 2+, Week 8, n=11, 8	0 0%	0 0%
Urine Glucose, 3+, Week 8, n=11, 8	0 0%	0 0%
Urine Glucose, 4+, Week 8, n=11, 8	0 0%	0 0%
Urine Ketones, Negative, Week 8, n=11, 8	11 50%	8 42.1%
Urine Ketones, Traces, Week 8, n=11, 8	0 0%	0 0%
Urine Ketones, 1+, Week 8, n=11, 8	0 0%	0 0%
Urine Ketones, 2+, Week 8, n=11, 8	0 0%	0 0%
Urine Ketones, 3+, Week 8, n=11, 8	0 0%	0 0%
Urine Ketones, 4+, Week 8, n=11, 8	0 0%	0 0%
Urine Occult Blood, Negative, Week 8, n=11, 8	11 50%	8 42.1%
Urine Occult Blood, Traces, Week 8, n=11, 8	0 0%	0 0%
Urine Occult Blood, 1+, Week 8, n=11, 8	0 0%	0 0%
Urine Occult Blood, 2+, Week 8, n=11, 8	0 0%	0 0%
Urine Occult Blood, 3+, Week 8, n=11, 8	0 0%	0 0%
Urine Occult Blood, 4+, Week 8, n=11, 8	0 0%	0 0%
Urine Protein, Negative, Week 8, n=11, 8	10 45.5%	8 42.1%
Urine Protein, Traces, Week 8, n=11, 8	1 4.5%	0 0%
Urine Protein 1+, Week 8, n=11, 8	0 0%	0 0%
Urine Protein, 2+, Week 8, n=11, 8	0 0%	0 0%
Urine Protein, 3+, Week 8, n=11, 8	0 0%	0 0%
Urine Protein, 4+, Week 8, n=11, 8	0 0%	0 0%

20. Primary Outcome

Title	Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Systolic blood pressure	-5.7 (20.68)	10.0 (15.28)
Diastolic blood pressure	0.6 (11.69)	2.8 (5.68)

21. Primary Outcome

Title	Mean Change From Baseline in Heart Rate at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Mean (Standard Deviation) [beats per minute]	-10.4 (10.54)	-10.6 (18.87)

22. Primary Outcome

Title	Mean Change From Baseline in Weight at Week 8
Description	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Mean (Standard Deviation) [kilograms (kg)]	0.29 (1.490)	-0.11 (2.303)

23. Primary Outcome

Title	Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8
Description	There are 3 categories for electrocardiogram (ECG) findings: normal; abnormal, not clinically significant; and abnormal, clinically significant. Each of the findings was classified by the investigator according to whether it was normal. Abnormal ECGs were further classified according to whether they were felt to be clinically significant in the medical and scientific judgment of the investigator.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Normal, Baseline (BL), n=22, 19	2 9.1%	1 5.3%
Abnormal-Not clinically significant, BL, n=22, 19	12 54.5%	9 47.4%
Abnormal-Clinically significant, BL, n=22, 19	8 36.4%	9 47.4%
Normal, Week (W) 8, n=11, 8	2 9.1%	1 5.3%
Abnormal-Not clinically significant, W8, n=11, 8	5 22.7%	1 5.3%
Abnormal-Clinically significant, W8, n=11, 8	4 18.2%	6 31.6%

24. Primary Outcome

Title	Cardiothoracic Ratio at Baseline and Week 8
Description	Cardiothoracic ratio is a marker of the degree of heart enlargement and was measured by chest X-ray. It is shown as the ratio of the transverse diameter of the heart to the transverse diameter of the thorax, and is measured as a percentage.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Safety Population: 22 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	22	19
Baseline, n=22, 19	53.70 (4.536)	53.58 (8.098)
Week 8, n=11, 8	50.91 (4.309)	52.35 (7.545)

25. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8
Description	Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Pharmacodynamic (PD) Population: all participants measurable at the PD endpoints (18 participants at baseline and 3 participants at Week 8 in CRV-IR group, 19 participants at baseline and 4 participants at Week 8 in SK&F-105517-D group)

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	18	19
24 h	-7.10 (3.387)	-4.89 (2.852)
Morning	-7.68 (4.449)	-8.24 (3.766)
Afternoon	-5.32 (2.760)	-10.25 (2.336)
Night	-9.01 (4.190)	0.73 (3.506)
Waking	-5.11 (2.902)	-8.56 (2.458)
Sleeping	-12.68 (1.197)	5.38 (1.011)
PDmax	-10.45 (6.702)	-17.91 (5.796)
PDmin	-1.34 (3.852)	-0.24 (3.291)
PDmax/PDmin	-0.24 (0.111)	-0.36 (0.094)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	2.21
	Confidence Interval	(2-Sided) 95% -11.20 to 15.63
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.833
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the 24 h assessment.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.56
	Confidence Interval	(2-Sided) 95% -17.95 to 16.84
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.265
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Morning assessment.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.93
	Confidence Interval	(2-Sided) 95% -15.71 to 5.86
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.885
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Afternoon assessment.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	9.74
	Confidence Interval	(2-Sided) 95% -7.11 to 26.59
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.070
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Night assessment.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.45
	Confidence Interval	(2-Sided) 95% -14.78 to 7.88
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.080
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Waking assessment.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	18.06
	Confidence Interval	(2-Sided) 95% 13.36 to 22.76
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.694
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Sleeping assessment.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-7.46
	Confidence Interval	(2-Sided) 95% -32.17 to 17.26
	Parameter Dispersion	Type: Standard Error of the Mean Value: 8.902
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmax assessment.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	1.10
	Confidence Interval	(2-Sided) 95% -13.61 to 15.80
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.297
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmin assessment.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.12
	Confidence Interval	(2-Sided) 95% -0.54 to 0.30
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.152
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmax/PDmin assessment.

26. Secondary Outcome

Title	Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8
Description	Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
PD Population: all participants measurable at the PD endpoints (18 participants at baseline and 3 participants at Week 8 in CRV-IR group, 19 participants at baseline and 4 participants at Week 8 in SK&F-105517-D group)

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	18	19
24 h	-11.38 (2.385)	-15.37 (2.058)
Morning	-9.59 (2.225)	-14.87 (1.923)
Afternoon	-13.96 (2.345)	-15.93 (2.006)
Night	-11.12 (2.760)	-15.26 (2.387)
Waking	-12.53 (2.250)	-15.53 (1.933)
Sleeping	-11.16 (3.536)	-14.28 (3.060)
PDmax	-13.43 (2.758)	-23.43 (2.366)
PDmin	-2.04 (3.830)	-3.47 (3.276)
PDmax/PDmin	-0.93 (0.095)	-1.27 (0.080)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.99
	Confidence Interval	(2-Sided) 95% -12.84 to 4.86
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.187
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the 24 h assessment.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-5.27
	Confidence Interval	(2-Sided) 95% -13.50 to 2.95
	Parameter Dispersion	Type: Standard Error of the Mean Value: 2.962
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Morning assessment.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.98
	Confidence Interval	(2-Sided) 95% -10.89 to 6.94
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.209
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Afternoon assessment.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.14
	Confidence Interval	(2-Sided) 95% -14.32 to 6.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.665
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Night assessment.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-2.99
	Confidence Interval	(2-Sided) 95% -11.45 to 5.47
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.047
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Waking assessment.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-3.11
	Confidence Interval	(2-Sided) 95% -16.12 to 9.89
	Parameter Dispersion	Type: Standard Error of the Mean Value: 4.686
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the Sleeping assessment.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.00
	Confidence Interval	(2-Sided) 95% -20.41 to 0.41
	Parameter Dispersion	Type: Standard Error of the Mean Value: 3.749
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmax assessment.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-1.42
	Confidence Interval	(2-Sided) 95% -16.00 to 13.15
	Parameter Dispersion	Type: Standard Error of the Mean Value: 5.249
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmin assessment.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	CRV-IR, SK&F-105517-D
	Comments
	Type of Statistical Test	Superiority or Other
	Comments

Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments

Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.34
	Confidence Interval	(2-Sided) 95% -0.71 to 0.03
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.133
	Estimation Comments	The mean treatment difference is calculated as SK&F-105517-D minus CRV-IR for the PDmax/PDmin assessment.

27. Secondary Outcome

Title	Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8
Description	The NYHA classification assesses the severity of symptoms of heart failure as judged by the investigator and is comprised of. 4 classes: I, no resulting limitations on physical activity (PA); II, slight limitations on PA; III, marked limitations on PA; IV, inability to carry out any PA without discomfort. The number of participants with any change from Baseline in the NYHA Functional Class at Week 8 was calculated. Improved=class at the visit is decreased compared to baseline class, Unchanged=class at the visit is stable, Worsened=class at the visit is increased compared to baseline class.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Efficacy Population: all participants measurable at the efficacy endpoints (20 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group. Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	20	19
Improved	0 0%	1 5.3%
Unchanged	11 50%	7 36.8%
Worse	0 0%	0 0%

28. Secondary Outcome

Title	Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8
Description	Brain natriuretic peptide is a surrogate marker of the severity of heart failure and was measured by a central laboratory.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Efficacy Population: all participants measurable at the efficacy endpoints (20 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group). Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	20	19
Baseline, n=20, 19	108.93 (112.192)	226.46 (339.640)
Week 8, n=11, 8	64.88 (62.020)	111.93 (84.298)

29. Secondary Outcome

Title	Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8
Description	Left ventricular ejection fraction (LVEF) is a marker of left ventricular systolic function and was measured by echocardiogram. It is shown as the ratio of left ventricular stroke volume (LVSV) to left ventricular end-diastolic volume (LVEDV), and is measured as a percentage.
Time Frame	Baseline and Week 8

Outcome Measure Data

Analysis Population Description
Efficacy Population: all participants measurable at the efficacy endpoints (20 participants at baseline and 11 participants at Week 8 in the CRV-IR group; 19 participants at baseline and 8 participants at Week 8 in the SK&F-105517-D group). Some participants in each treatment arm withdrew prematurely.

Arm/Group Title	CRV-IR	SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
Measure Participants	20	19
Baseline, n=20, 19	34.0 (8.43)	32.2 (10.09)
Week 8, n=11, 8	42.0 (13.36)	37.6 (10.14)

Adverse Events

	CRV-IR		SK&F-105517-D
Time Frame	Treatment Period from Week 0 (Baseline) to Week 8 and 1-week Follow-up Period (Week 9) for CRV-IR; Treatment Period from Week 0 (Baseline) to Week 14 and 1-week Follow-up Period (Week 15) for SK&F-105517-D.
Adverse Event Reporting Description

Arm/Group Title	CRV-IR		SK&F-105517-D
Arm/Group Description	In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received an initial dose of an immediate-release (IR) formulation of carvedilol (CRV) as a 1.25 milligram (mg) tablet twice daily (BID) (2.5 mg/day) at Week 0, followed by an increased dose of CRV-IR 2.5 mg tablet BID (5 mg/day) at Week 1. The dose was then increased to 5 mg BID (10 mg/day) at Week 4, and finally to 10 mg BID (20 mg/day) at Week 6. The participants on CRV-IR were switched to the marketed CRV-IR in Week 1 of the Follow-up Period; the investigator or subinvestigator determined the dose of the marketed CRV-IR based on the last dose administered during the Primary Evaluation Period after confirming the safety and tolerability of the dose.		In the 8-week Primary Evaluation Period (including the 2-week Run-in Period [from Week 0 as Baseline]), participants received a CRV-IR 1.25 mg and 2.5 mg tablet BID at Weeks 0 and 1, respectively. They then received a 10 mg extended-release capsule of carvedilol (SK&F-105517-D) once daily (OD) at Week 2; the dose was then increased to 20 mg OD and finally to 40 mg OD at 2-week intervals. The dose was increased from 40 mg to 60 mg and finally to 80 mg at 2-week intervals in the 4-week Exploratory Evaluation Period after confirming that each dose was well tolerated without safety concern and that the participant met all of the dose-escalation criteria. During the 2-week Dose-tapering Period set up to prepare for switch to the marketed CRV-IR, the dose of SK&F-105517-D was reduced to 60 mg OD and then to 40 mg OD at weekly intervals; SK&F-105517-D was then switched to the marketed CRV-IR 10 mg tablet BID in the 1-week Follow-up Period.
All Cause Mortality
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	CRV-IR		SK&F-105517-D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/22 (4.5%)		3/19 (15.8%)
Cardiac disorders
Bradycardia	0/22 (0%)		1/19 (5.3%)
Cardiac failure	1/22 (4.5%)		0/19 (0%)
General disorders
Oedema	0/22 (0%)		1/19 (5.3%)
Infections and infestations
Bronchitis	0/22 (0%)		1/19 (5.3%)
Other (Not Including Serious) Adverse Events
	CRV-IR		SK&F-105517-D
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/22 (50%)		15/19 (78.9%)
Cardiac disorders
Atrial fibrillation	1/22 (4.5%)		0/19 (0%)
Cardiac failure congestive	0/22 (0%)		1/19 (5.3%)
Intracardiac thrombus	0/22 (0%)		1/19 (5.3%)
Nodal rhythm	0/22 (0%)		1/19 (5.3%)
Ventricular extrasystoles	0/22 (0%)		1/19 (5.3%)
Eye disorders
Dry eye	0/22 (0%)		1/19 (5.3%)
Gastrointestinal disorders
Diarrhoea	2/22 (9.1%)		2/19 (10.5%)
Abdominal pain	1/22 (4.5%)		0/19 (0%)
Cheilitis	1/22 (4.5%)		0/19 (0%)
Dental caries	0/22 (0%)		1/19 (5.3%)
Glossitis	1/22 (4.5%)		0/19 (0%)
Toothache	0/22 (0%)		1/19 (5.3%)
Infections and infestations
Nasopharyngitis	2/22 (9.1%)		2/19 (10.5%)
Bronchitis	0/22 (0%)		2/19 (10.5%)
Gastroenteritis	1/22 (4.5%)		0/19 (0%)
Injury, poisoning and procedural complications
Contusion	1/22 (4.5%)		0/19 (0%)
Investigations
Blood uric acid increased	1/22 (4.5%)		1/19 (5.3%)
Brain natriuretic peptide increased	1/22 (4.5%)		1/19 (5.3%)
Blood alkaline phosphatase increased	0/22 (0%)		1/19 (5.3%)
Blood calcium decreased	1/22 (4.5%)		0/19 (0%)
Blood creatine phosphokinase increased	0/22 (0%)		1/19 (5.3%)
Gamma-glutamyltransferase increased	1/22 (4.5%)		0/19 (0%)
Platelet count decreased	1/22 (4.5%)		0/19 (0%)
Musculoskeletal and connective tissue disorders
Musculoskeletal pain	1/22 (4.5%)		0/19 (0%)
Nervous system disorders
Dizziness	1/22 (4.5%)		2/19 (10.5%)
Dysgeusia	1/22 (4.5%)		0/19 (0%)
Headache	1/22 (4.5%)		0/19 (0%)
Presyncope	1/22 (4.5%)		0/19 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/22 (4.5%)		1/19 (5.3%)
Epistaxis	1/22 (4.5%)		0/19 (0%)
Pleural effusion	1/22 (4.5%)		0/19 (0%)
Upper respiratory tract inflammation	0/22 (0%)		1/19 (5.3%)
Skin and subcutaneous tissue disorders
Dermatitis contact	1/22 (4.5%)		2/19 (10.5%)
Pruritus	1/22 (4.5%)		0/19 (0%)
Rash	1/22 (4.5%)		0/19 (0%)
Skin exfoliation	1/22 (4.5%)		0/19 (0%)
Vascular disorders
Hypotension	0/22 (0%)		1/19 (5.3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.

Results Point of Contact

Name/Title	GSK Response Center
Organization	GlaxoSmithKline
Phone	866-435-7343
Email

Responsible Party:

GlaxoSmithKline

ClinicalTrials.gov Identifier:

NCT00742508

Other Study ID Numbers:

CRV110734

First Posted:

Aug 27, 2008

Last Update Posted:

Aug 2, 2017

Last Verified:

Jun 1, 2017