Trial Outcomes & Findings for A Phase I/II Clinical Study of SK&F-105517-D in Japanese Patients With Chronic Heart Failure (NCT NCT00742508)

Last Updated: 2017-08-02

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

41 participants

Primary outcome timeframe

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

Results posted on

2017-08-02

Participant Flow

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.

Participant milestones

Participant milestones
Measure	CRV-IR 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.	SK&F-105517-D 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.
8-Week Primary Evaluation Period STARTED	22	19
8-Week Primary Evaluation Period COMPLETED	11	8
8-Week Primary Evaluation Period NOT COMPLETED	11	11
4-Week Exploratory Evaluation Period STARTED	0	8
4-Week Exploratory Evaluation Period COMPLETED	0	7
4-Week Exploratory Evaluation Period NOT COMPLETED	0	1

Reasons for withdrawal

Reasons for withdrawal
Measure	CRV-IR 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.	SK&F-105517-D 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.
8-Week Primary Evaluation Period Adverse Event	2	4
8-Week Primary Evaluation Period Protocol Violation	1	0
8-Week Primary Evaluation Period Met Protocol-defined Stopping Criteria	8	5
8-Week Primary Evaluation Period Withdrawal by Subject	0	2
4-Week Exploratory Evaluation Period Met Protocol-defined Stopping Criteria	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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 n=41 Participants Total of all reporting groups
Age, Continuous	62.7 years STANDARD_DEVIATION 8.17 • n=5 Participants	66.7 years STANDARD_DEVIATION 12.00 • n=7 Participants	64.6 years STANDARD_DEVIATION 10.20 • n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	18 Participants n=7 Participants	38 Participants n=5 Participants
Race/Ethnicity, Customized Asian-Japanese Heritage	22 participants n=5 Participants	19 participants n=7 Participants	41 participants n=5 Participants

PRIMARY outcome

Timeframe: 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

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

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) Severe	0 participants	1 participants
Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) Moderate	2 participants	5 participants
Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) Mild	9 participants	10 participants
Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) Severe (drug-related)	0 participants	1 participants
Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) Moderate (drug-related)	2 participants	3 participants
Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) Mild (drug-related)	3 participants	4 participants

PRIMARY outcome

Timeframe: Baseline and Week 8

Population: 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.

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Albumin and Total Protein at Week 8 Albumin	0.7 grams per liter (g/L) Standard Deviation 2.87	-1.9 grams per liter (g/L) Standard Deviation 2.90
Mean Change From Baseline in Albumin and Total Protein at Week 8 Total Protein	0.4 grams per liter (g/L) Standard Deviation 4.27	-1.6 grams per liter (g/L) Standard Deviation 4.72

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 Alkaline Phosphatase	-10.9 international units per liter (IU/L) Standard Deviation 18.45	-5.0 international units per liter (IU/L) Standard Deviation 21.13
Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 Alanine Aminotransferase	-0.2 international units per liter (IU/L) Standard Deviation 6.48	3.8 international units per liter (IU/L) Standard Deviation 9.39
Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 Aspartate Aminotransferase	0.8 international units per liter (IU/L) Standard Deviation 3.87	1.4 international units per liter (IU/L) Standard Deviation 7.19
Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 Creatine Kinase	34.4 international units per liter (IU/L) Standard Deviation 55.58	-0.1 international units per liter (IU/L) Standard Deviation 65.54
Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 Gamma Glutamyl Transferase	-0.8 international units per liter (IU/L) Standard Deviation 3.68	2.4 international units per liter (IU/L) Standard Deviation 10.62

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Amylase at Week 8	-10.2 units per liter (U/L) Standard Deviation 9.98	-0.1 units per liter (U/L) Standard Deviation 15.66

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 Total Bilirubin	1.555 micromoles per liter (umol/L) Standard Deviation 2.3514	-4.489 micromoles per liter (umol/L) Standard Deviation 3.8712
Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 Creatinine	5.5451 micromoles per liter (umol/L) Standard Deviation 14.97638	-4.5305 micromoles per liter (umol/L) Standard Deviation 5.85307
Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 Uric Acid	30.8215 micromoles per liter (umol/L) Standard Deviation 48.16177	14.1265 micromoles per liter (umol/L) Standard Deviation 80.67868

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 Calcium	-0.027218 millimoles per liter (mmol/L) Standard Deviation 0.1364081	-0.056138 millimoles per liter (mmol/L) Standard Deviation 0.0592680
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 Chloride	0.2 millimoles per liter (mmol/L) Standard Deviation 1.60	2.4 millimoles per liter (mmol/L) Standard Deviation 2.20
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 Glucose	-0.136252 millimoles per liter (mmol/L) Standard Deviation 2.9159783	-1.956728 millimoles per liter (mmol/L) Standard Deviation 2.8733368
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 Potassium	-0.07 millimoles per liter (mmol/L) Standard Deviation 0.361	0.07 millimoles per liter (mmol/L) Standard Deviation 0.474
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 Sodium	0.5 millimoles per liter (mmol/L) Standard Deviation 2.30	1.6 millimoles per liter (mmol/L) Standard Deviation 1.41
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 Urea/Blood Urea Nitrogen	0.61339 millimoles per liter (mmol/L) Standard Deviation 2.523049	-0.58013 millimoles per liter (mmol/L) Standard Deviation 1.023316

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at Week 8 Creatine Kinase BB percentage	-0.2 percentage of Total Creatine Kinase Standard Deviation 0.60	0.5 percentage of Total Creatine Kinase Standard Deviation 0.93
Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at Week 8 Creatine Kinase MB percentage	-0.3 percentage of Total Creatine Kinase Standard Deviation 0.65	-0.1 percentage of Total Creatine Kinase Standard Deviation 0.83
Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at Week 8 Creatine Kinase MM percentage	1.1 percentage of Total Creatine Kinase Standard Deviation 1.30	0.8 percentage of Total Creatine Kinase Standard Deviation 1.75

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 Basophils	-0.06 percentage of each WBC type in WBC count Standard Deviation 0.403	-0.06 percentage of each WBC type in WBC count Standard Deviation 0.325
Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 Eosinophils	0.15 percentage of each WBC type in WBC count Standard Deviation 1.547	0.76 percentage of each WBC type in WBC count Standard Deviation 1.412
Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 Lymphocytes	0.05 percentage of each WBC type in WBC count Standard Deviation 6.052	2.21 percentage of each WBC type in WBC count Standard Deviation 9.174
Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 Monocytes	0.19 percentage of each WBC type in WBC count Standard Deviation 1.358	1.28 percentage of each WBC type in WBC count Standard Deviation 1.356
Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 Total Neutrophils	-0.41 percentage of each WBC type in WBC count Standard Deviation 7.875	-4.31 percentage of each WBC type in WBC count Standard Deviation 11.180

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8 Hemoglobin	-2.3 grams per liter (g/L) Standard Deviation 8.05	-3.9 grams per liter (g/L) Standard Deviation 8.04
Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8 Mean Corpuscular Hemoglobin Concentration	1.3 grams per liter (g/L) Standard Deviation 4.90	-1.9 grams per liter (g/L) Standard Deviation 6.01

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Hematocrit at Week 8	-0.0085 proportion of 1 (SI) Standard Deviation 0.02306	-0.0095 proportion of 1 (SI) Standard Deviation 0.02287

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8 Platelet Count	-6.9 gibi (2 to the power of 30)/liter (Gi/L) Standard Deviation 23.28	-11.1 gibi (2 to the power of 30)/liter (Gi/L) Standard Deviation 14.54
Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8 White Blood Cell Count	0.297 gibi (2 to the power of 30)/liter (Gi/L) Standard Deviation 0.9850	-0.498 gibi (2 to the power of 30)/liter (Gi/L) Standard Deviation 1.9516

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Red Blood Cell Count at Week 8	-0.091 tebi (2 to the power of 40)/liter (Ti/L) Standard Deviation 0.2390	-0.087 tebi (2 to the power of 40)/liter (Ti/L) Standard Deviation 0.2295

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8	0.12 picograms (pg) Standard Deviation 0.515	-0.21 picograms (pg) Standard Deviation 0.372

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Mean Corpuscular Volume at Week 8	0.1 femtoliters (fL) Standard Deviation 1.38	-0.1 femtoliters (fL) Standard Deviation 1.96

PRIMARY outcome

Timeframe: Baseline and Week 8

Dipstick test values: Negative (-), Traces (+-), +1, +2, +3. +4. Normal ranges (qualitative): protein, - or +-; glucose, - or +-; occult blood, -; ketones, -.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, Negative, Baseline, n=22, 19	20 participants	19 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, Traces, Baseline, n=22, 19	1 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 1+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 2+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 3+, Baseline, n=22, 19	1 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 4+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, Negative, Baseline, n=22, 19	22 participants	19 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, Traces, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 1+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 2+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 3+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 4+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, Negative, Baseline, n=22, 19	18 participants	16 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, Traces, Baseline, n=22, 19	1 participants	1 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 1+, Baseline, n=22, 19	2 participants	1 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 2+, Baseline, n=22, 19	1 participants	1 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 3+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 4+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, Negative, Baseline, n=22, 19	21 participants	18 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, Traces, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, 1+, Baseline, n=22, 19	0 participants	1 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, 2+, Baseline, n=22, 19	1 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, 3+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, 4+, Baseline, n=22, 19	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, Negative, Week 8, n=11, 8	11 participants	8 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, Traces, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 1+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 2+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 3+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Glucose, 4+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, Negative, Week 8, n=11, 8	11 participants	8 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, Traces, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 1+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 2+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 3+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Ketones, 4+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, Negative, Week 8, n=11, 8	11 participants	8 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, Traces, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 1+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 2+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 3+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Occult Blood, 4+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, Negative, Week 8, n=11, 8	10 participants	8 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, Traces, Week 8, n=11, 8	1 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein 1+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, 2+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, 3+, Week 8, n=11, 8	0 participants	0 participants
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 Urine Protein, 4+, Week 8, n=11, 8	0 participants	0 participants

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8 Systolic blood pressure	-5.7 millimeters of mercury (mmHg) Standard Deviation 20.68	10.0 millimeters of mercury (mmHg) Standard Deviation 15.28
Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8 Diastolic blood pressure	0.6 millimeters of mercury (mmHg) Standard Deviation 11.69	2.8 millimeters of mercury (mmHg) Standard Deviation 5.68

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Heart Rate at Week 8	-10.4 beats per minute Standard Deviation 10.54	-10.6 beats per minute Standard Deviation 18.87

PRIMARY outcome

Timeframe: Baseline and Week 8

Mean change from baseline was calculated as the Week 8 value minus the Baseline value.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Change From Baseline in Weight at Week 8	0.29 kilograms (kg) Standard Deviation 1.490	-0.11 kilograms (kg) Standard Deviation 2.303

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 Normal, Baseline (BL), n=22, 19	2 participants	1 participants
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 Abnormal-Not clinically significant, BL, n=22, 19	12 participants	9 participants
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 Abnormal-Clinically significant, BL, n=22, 19	8 participants	9 participants
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 Normal, Week (W) 8, n=11, 8	2 participants	1 participants
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 Abnormal-Not clinically significant, W8, n=11, 8	5 participants	1 participants
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 Abnormal-Clinically significant, W8, n=11, 8	4 participants	6 participants

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	CRV-IR n=22 Participants 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.	SK&F-105517-D n=19 Participants 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.
Cardiothoracic Ratio at Baseline and Week 8 Baseline, n=22, 19	53.70 percentage Standard Deviation 4.536	53.58 percentage Standard Deviation 8.098
Cardiothoracic Ratio at Baseline and Week 8 Week 8, n=11, 8	50.91 percentage Standard Deviation 4.309	52.35 percentage Standard Deviation 7.545

SECONDARY outcome

Timeframe: Week 8

Population: 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)

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.

Outcome measures

Outcome measures
Measure	CRV-IR n=3 Participants 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.	SK&F-105517-D n=4 Participants 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.
Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 S-carvedilol, Cmax	6.7952 nanograms per milliliter (ng/mL) Interval 5.8993 to 7.8272	12.8171 nanograms per milliliter (ng/mL) Interval 3.661 to 44.8731
Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 S-carvedilol, Cmin	1.2072 nanograms per milliliter (ng/mL) Interval 0.1282 to 11.3641	3.3796 nanograms per milliliter (ng/mL) Interval 1.8809 to 6.0727
Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 R-carvedilol, Cmax	19.1864 nanograms per milliliter (ng/mL) Interval 9.367 to 39.2994	27.1306 nanograms per milliliter (ng/mL) Interval 8.9369 to 82.3626
Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 R-carvedilol, Cmin	2.9445 nanograms per milliliter (ng/mL) Interval 1.7119 to 5.0647	4.2565 nanograms per milliliter (ng/mL) Interval 2.3297 to 7.7768
Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 SB-203231, Cmax	3.1665 nanograms per milliliter (ng/mL) Interval 2.5819 to 3.8833	6.3937 nanograms per milliliter (ng/mL) Interval 2.3918 to 17.0913
Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 SB-203231, Cmin	0.4843 nanograms per milliliter (ng/mL) Interval 0.2322 to 1.0101	1.2386 nanograms per milliliter (ng/mL) Interval 0.7761 to 1.9769

SECONDARY outcome

Timeframe: Week 8

Population: 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)

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.

Outcome measures

Outcome measures
Measure	CRV-IR n=3 Participants 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.	SK&F-105517-D n=4 Participants 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.
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 S-carvedilol	60.040 hours * nanograms per milliliter (ng/mL) Interval 12.856 to 280.396	155.109 hours * nanograms per milliliter (ng/mL) Interval 63.319 to 379.959
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 R-carvedilol	170.728 hours * nanograms per milliliter (ng/mL) Interval 131.607 to 221.478	284.313 hours * nanograms per milliliter (ng/mL) Interval 132.307 to 610.954
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 SB-203231	28.113 hours * nanograms per milliliter (ng/mL) Interval 14.853 to 53.209	64.687 hours * nanograms per milliliter (ng/mL) Interval 28.012 to 149.382

SECONDARY outcome

Timeframe: Week 8

Population: 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

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.

Outcome measures

Outcome measures
Measure	CRV-IR n=3 Participants 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.	SK&F-105517-D n=4 Participants 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.
Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 S-carvedilol	1.983 hours Interval 1.0 to 2.03	5.958 hours Interval 4.0 to 6.08
Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 R-carvedilol	1.983 hours Interval 1.0 to 2.03	5.958 hours Interval 4.0 to 6.08
Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 SB-203231	1.983 hours Interval 1.0 to 2.03	5.958 hours Interval 4.0 to 6.08

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: 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)

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.

Outcome measures

Outcome measures
Measure	CRV-IR n=18 Participants 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.	SK&F-105517-D n=19 Participants 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.
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 24 h	-10.84 millimeters of mercury (mmHg) Standard Error 4.119	-1.45 millimeters of mercury (mmHg) Standard Error 3.567
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 Morning	-12.34 millimeters of mercury (mmHg) Standard Error 4.412	-4.78 millimeters of mercury (mmHg) Standard Error 3.819
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 Afternoon	-10.14 millimeters of mercury (mmHg) Standard Error 2.734	-12.06 millimeters of mercury (mmHg) Standard Error 2.361
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 Night	-9.04 millimeters of mercury (mmHg) Standard Error 4.786	5.17 millimeters of mercury (mmHg) Standard Error 4.139
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 Waking	-10.39 millimeters of mercury (mmHg) Standard Error 2.857	-9.99 millimeters of mercury (mmHg) Standard Error 2.472
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 Sleeping	-11.85 millimeters of mercury (mmHg) Standard Error 3.223	13.20 millimeters of mercury (mmHg) Standard Error 2.787
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 PDmax	-9.74 millimeters of mercury (mmHg) Standard Error 7.772	-10.19 millimeters of mercury (mmHg) Standard Error 6.656
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 PDmin	-6.89 millimeters of mercury (mmHg) Standard Error 5.416	1.42 millimeters of mercury (mmHg) Standard Error 4.685
Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 PDmax/PDmin	0.07 millimeters of mercury (mmHg) Standard Error 0.103	-0.17 millimeters of mercury (mmHg) Standard Error 0.088

SECONDARY outcome

Timeframe: Baseline and Week 8

Outcome measures

Outcome measures
Measure	CRV-IR n=18 Participants 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.	SK&F-105517-D n=19 Participants 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.
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 24 h	-7.10 millimeters of mercury (mmHg) Standard Error 3.387	-4.89 millimeters of mercury (mmHg) Standard Error 2.852
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 Morning	-7.68 millimeters of mercury (mmHg) Standard Error 4.449	-8.24 millimeters of mercury (mmHg) Standard Error 3.766
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 Afternoon	-5.32 millimeters of mercury (mmHg) Standard Error 2.760	-10.25 millimeters of mercury (mmHg) Standard Error 2.336
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 Night	-9.01 millimeters of mercury (mmHg) Standard Error 4.190	0.73 millimeters of mercury (mmHg) Standard Error 3.506
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 Waking	-5.11 millimeters of mercury (mmHg) Standard Error 2.902	-8.56 millimeters of mercury (mmHg) Standard Error 2.458
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 Sleeping	-12.68 millimeters of mercury (mmHg) Standard Error 1.197	5.38 millimeters of mercury (mmHg) Standard Error 1.011
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 PDmax	-10.45 millimeters of mercury (mmHg) Standard Error 6.702	-17.91 millimeters of mercury (mmHg) Standard Error 5.796
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 PDmin	-1.34 millimeters of mercury (mmHg) Standard Error 3.852	-0.24 millimeters of mercury (mmHg) Standard Error 3.291
Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 PDmax/PDmin	-0.24 millimeters of mercury (mmHg) Standard Error 0.111	-0.36 millimeters of mercury (mmHg) Standard Error 0.094

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: 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)

Outcome measures

Outcome measures
Measure	CRV-IR n=18 Participants 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.	SK&F-105517-D n=19 Participants 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.
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 24 h	-11.38 beats per minute Standard Error 2.385	-15.37 beats per minute Standard Error 2.058
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 Morning	-9.59 beats per minute Standard Error 2.225	-14.87 beats per minute Standard Error 1.923
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 Afternoon	-13.96 beats per minute Standard Error 2.345	-15.93 beats per minute Standard Error 2.006
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 Night	-11.12 beats per minute Standard Error 2.760	-15.26 beats per minute Standard Error 2.387
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 Waking	-12.53 beats per minute Standard Error 2.250	-15.53 beats per minute Standard Error 1.933
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 Sleeping	-11.16 beats per minute Standard Error 3.536	-14.28 beats per minute Standard Error 3.060
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 PDmax	-13.43 beats per minute Standard Error 2.758	-23.43 beats per minute Standard Error 2.366
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 PDmin	-2.04 beats per minute Standard Error 3.830	-3.47 beats per minute Standard Error 3.276
Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 PDmax/PDmin	-0.93 beats per minute Standard Error 0.095	-1.27 beats per minute Standard Error 0.080

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: 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.

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.

Outcome measures

Outcome measures
Measure	CRV-IR n=20 Participants 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.	SK&F-105517-D n=19 Participants 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.
Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 Improved	0 participants	1 participants
Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 Unchanged	11 participants	7 participants
Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 Worse	0 participants	0 participants

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: 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.

Brain natriuretic peptide is a surrogate marker of the severity of heart failure and was measured by a central laboratory.

Outcome measures

Outcome measures
Measure	CRV-IR n=20 Participants 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.	SK&F-105517-D n=19 Participants 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.
Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8 Baseline, n=20, 19	108.93 ng/L (nanogram per Liter) Standard Deviation 112.192	226.46 ng/L (nanogram per Liter) Standard Deviation 339.640
Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8 Week 8, n=11, 8	64.88 ng/L (nanogram per Liter) Standard Deviation 62.020	111.93 ng/L (nanogram per Liter) Standard Deviation 84.298

SECONDARY outcome

Timeframe: Baseline and Week 8

Population: 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.

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.

Outcome measures

Outcome measures
Measure	CRV-IR n=20 Participants 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.	SK&F-105517-D n=19 Participants 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.
Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 Baseline, n=20, 19	34.0 percentage Standard Deviation 8.43	32.2 percentage Standard Deviation 10.09
Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 Week 8, n=11, 8	42.0 percentage Standard Deviation 13.36	37.6 percentage Standard Deviation 10.14

Adverse Events

CRV-IR

Serious events: 1 serious events

Other events: 11 other events

Deaths: 0 deaths

SK&F-105517-D

Serious events: 3 serious events

Other events: 15 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	CRV-IR n=22 participants at risk 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.	SK&F-105517-D n=19 participants at risk 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.
Cardiac disorders Bradycardia	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Cardiac disorders Cardiac failure	4.5% 1/22 • 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.	0.00% 0/19 • 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.
General disorders Oedema	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Infections and infestations Bronchitis	0.00% 0/22 • 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.	5.3% 1/19 • 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.

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

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

Restriction type: OTHER

Measure	CRV-IR n=22 participants at risk 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.	SK&F-105517-D n=19 participants at risk 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.
Gastrointestinal disorders Diarrhoea	9.1% 2/22 • 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.	10.5% 2/19 • 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.
Infections and infestations Nasopharyngitis	9.1% 2/22 • 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.	10.5% 2/19 • 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.
Skin and subcutaneous tissue disorders Dermatitis contact	4.5% 1/22 • 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.	10.5% 2/19 • 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.
Nervous system disorders Dizziness	4.5% 1/22 • 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.	10.5% 2/19 • 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.
Investigations Blood uric acid increased	4.5% 1/22 • 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.	5.3% 1/19 • 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.
Investigations Brain natriuretic peptide increased	4.5% 1/22 • 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.	5.3% 1/19 • 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.
Infections and infestations Bronchitis	0.00% 0/22 • 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.	10.5% 2/19 • 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.
Respiratory, thoracic and mediastinal disorders Dyspnoea	4.5% 1/22 • 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.	5.3% 1/19 • 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.
Gastrointestinal disorders Abdominal pain	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Cardiac disorders Atrial fibrillation	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Investigations Blood alkaline phosphatase increased	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Investigations Blood calcium decreased	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Investigations Blood creatine phosphokinase increased	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Cardiac disorders Cardiac failure congestive	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Gastrointestinal disorders Cheilitis	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Injury, poisoning and procedural complications Contusion	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Gastrointestinal disorders Dental caries	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Eye disorders Dry eye	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Nervous system disorders Dysgeusia	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Respiratory, thoracic and mediastinal disorders Epistaxis	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Investigations Gamma-glutamyltransferase increased	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Infections and infestations Gastroenteritis	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Gastrointestinal disorders Glossitis	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Nervous system disorders Headache	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Vascular disorders Hypotension	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Cardiac disorders Intracardiac thrombus	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Musculoskeletal and connective tissue disorders Musculoskeletal pain	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Cardiac disorders Nodal rhythm	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Investigations Platelet count decreased	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Respiratory, thoracic and mediastinal disorders Pleural effusion	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Nervous system disorders Presyncope	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Skin and subcutaneous tissue disorders Pruritus	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Skin and subcutaneous tissue disorders Rash	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Skin and subcutaneous tissue disorders Skin exfoliation	4.5% 1/22 • 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.	0.00% 0/19 • 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.
Gastrointestinal disorders Toothache	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract inflammation	0.00% 0/22 • 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.	5.3% 1/19 • 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.
Cardiac disorders Ventricular extrasystoles	0.00% 0/22 • 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.	5.3% 1/19 • 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.