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

Sponsor:	GlaxoSmithKline
Information provided by:	GlaxoSmithKline
ClinicalTrials.gov Identifier:	NCT00742508

Purpose

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

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

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Study to Evaluate the Safety and Tolerability of SK&F-105517-D in Patients With Chronic Heart Failure - An Open-label Study to Evaluate the Safety and Tolerability, Pharmacokinetics and Pharmacodynamics of SK&F-105517-D in Patients With Chronic Heart Failure (Phase I/II Study)

Resource links provided by NLM:

MedlinePlus related topics: Heart Failure Potassium

Drug Information available for: Carvedilol Carvedilol phosphate

U.S. FDA Resources

Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:

Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) [ Time Frame: Treatment Period from Week 0 (Baseline) to Week 8 and 1-week Follow-up Period (Week 9) for CRV-IR; Treatment Period from Week 0 (Baseline) to Week 14 and 1-week Follow-up Period (Week 15) for SK&F-105517-D ] [ Designated as safety issue: No ]
Drug-related adverse events (AEs) were defined as AEs that were judged to have a relationship with the investigational product by the investigator (or subinvestigator) with the use of clinical judgment and the Clinical Investigator Brochure to determine the relationship. Refer to adverse event information for type and frequency of adverse events.
Mean Change From Baseline in Albumin and Total Protein at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Amylase at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value
Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value. (BB, brain-derived; MB=cardiac muscle-derived; MM=skeletal muscle-derived.
Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Hematocrit at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Red Blood Cell Count at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Mean Corpuscular Volume at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Dipstick test values: Negative (-), Traces (+-), +1, +2, +3. +4. Normal ranges (qualitative): protein, - or +-; glucose, - or +-; occult blood, -; ketones, -.
Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Heart Rate at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Mean Change From Baseline in Weight at Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Mean change from baseline was calculated as the Week 8 value minus the Baseline value.
Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
There are 3 categories for electrocardiogram (ECG) findings: normal; abnormal, not clinically significant; and abnormal, clinically significant. Each of the findings was classified by the investigator according to whether it was normal. Abnormal ECGs were further classified according to whether they were felt to be clinically significant in the medical and scientific judgment of the investigator.
Cardiothoracic Ratio at Baseline and Week 8 [ Time Frame: Baseline and Week 8 ] [ Designated as safety issue: No ]
Cardiothoracic ratio is a marker of the degree of heart enlargement and was measured by chest X-ray. It is shown as the ratio of the transverse diameter of the heart to the transverse diameter of the thorax, and is measured as a percentage.

Secondary Outcome Measures:

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

Enrollment:	41
Study Start Date:	August 2008
Study Completion Date:	August 2009
Primary Completion Date:	August 2009 (Final data collection date for primary outcome measure)

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

Eligibility

Ages Eligible for Study:	20 Years to 80 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion criteria:

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

Exclusion Criteria:

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00742508

Locations

Japan
GSK Investigational Site
Chiba, Japan, 296-8602
GSK Investigational Site
Ehime, Japan, 794-0006
GSK Investigational Site
Hiroshima, Japan, 737-0023
GSK Investigational Site
Hokkaido, Japan, 063-0005
GSK Investigational Site
Hokkaido, Japan, 060-0033
GSK Investigational Site
Kanagawa, Japan, 210-0852
GSK Investigational Site
Kanagawa, Japan, 238-8558
GSK Investigational Site
Mie, Japan, 511-0068
GSK Investigational Site
Nagano, Japan, 397-8555
GSK Investigational Site
Nagasaki, Japan, 859-3615
GSK Investigational Site
Oita, Japan, 879-5593
GSK Investigational Site
Osaka, Japan, 565-8565
GSK Investigational Site
Saga, Japan, 843-0393
GSK Investigational Site
Saitama, Japan, 364-8501
GSK Investigational Site
Shizuoka, Japan, 427-8502
GSK Investigational Site
Shizuoka, Japan, 410-2295
GSK Investigational Site
Shizuoka, Japan, 430-8502
GSK Investigational Site
Tokyo, Japan, 142-8666
GSK Investigational Site
Tokyo, Japan, 141-0001
GSK Investigational Site
Tokyo, Japan, 153-8515
GSK Investigational Site
Tokyo, Japan, 196-0003
GSK Investigational Site
Wakayama, Japan, 640-8158

Sponsors and Collaborators

GlaxoSmithKline

Investigators

Study Director:

GSK Clinical Trials

GlaxoSmithKline

More Information

No publications provided

Responsible Party:	Cheri Hudson; Clinical Disclosure Advisor, GSK Clinical Disclosure
ClinicalTrials.gov Identifier:	NCT00742508 History of Changes
Other Study ID Numbers:	CRV110734
Study First Received:	August 26, 2008
Results First Received:	May 17, 2010
Last Updated:	March 17, 2011
Health Authority:	Japan: Ministry of Health, Labor and Welfare

Keywords provided by GlaxoSmithKline:

carvedilol phosphate
ß-blocker
SK&F-105517-D
Chronic heart failure(CHF)

Additional relevant MeSH terms:

Heart Failure
Heart Diseases
Cardiovascular Diseases
Carvedilol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action

Pharmacologic Actions
Physiological Effects of Drugs
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists

ClinicalTrials.gov processed this record on February 09, 2012