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

Chronic Heart Failure Clinical Trial

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00742508
• Other study ID #: CRV110734
• Status: Completed
• Phase: Phase 1
• First received: August 26, 2008
• Last updated: July 19, 2012
• Start date: August 2008
• Est. completion date: August 2009

Study information

• Verified date: May 2012
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and Welfare
• Study type: Interventional

Clinical Trial Summary

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 41
• Est. completion date: August 2009
• Est. primary completion date: August 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 20 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Heart Failure
• Heart Failure
• Heart Failure, Congestive

Intervention

Drug:
• SK&F-105517-D 10 mg capsule
1 capsule once a day
• Carvedilol-immediate release (IR) 2.5 mg tablet
1 or 2 tablet(s) twice a day
• SK&F-105517-D 20 mg capsule
1 capsule once a day
• SK&F-105517-D 40 mg capsule
1 or 2 capsule(s) once a day
• Carvedilol-IR 10 mg tablet
1 tablet twice a day

Locations

Country	Name	City	State
Japan	GSK Investigational Site	Chiba
Japan	GSK Investigational Site	Ehime
Japan	GSK Investigational Site	Hiroshima
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Hokkaido
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Mie
Japan	GSK Investigational Site	Nagano
Japan	GSK Investigational Site	Nagasaki
Japan	GSK Investigational Site	Oita
Japan	GSK Investigational Site	Saga
Japan	GSK Investigational Site	Saitama
Japan	GSK Investigational Site	Shizuoka
Japan	GSK Investigational Site	Shizuoka
Japan	GSK Investigational Site	Shizuoka
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Wakayama

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

Japan, 

References & Publications (1)

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D)	Drug-related adverse events (AEs) were defined as AEs that were judged to have a relationship with the investigational product by the investigator (or subinvestigator) with the use of clinical judgment and the Clinical Investigator Brochure to determine the relationship. Refer to adverse event information for type and frequency of adverse events.	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	No
Primary	Mean Change From Baseline in Albumin and Total Protein at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value	Baseline and Week 8	No
Primary	Mean Change From Baseline in Amylase at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value	Baseline and Week 8	No
Primary	Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value	Baseline and Week 8	No
Primary	Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value	Baseline and Week 8	No
Primary	Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at 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.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Hematocrit at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Red Blood Cell Count at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Mean Corpuscular Volume at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8	Dipstick test values: Negative (-), Traces (+-), +1, +2, +3. +4. Normal ranges (qualitative): protein, - or +-; glucose, - or +-; occult blood, -; ketones, -.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Heart Rate at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Mean Change From Baseline in Weight at Week 8	Mean change from baseline was calculated as the Week 8 value minus the Baseline value.	Baseline and Week 8	No
Primary	Number of Participants With the Indicated Electrocardiogram Findings at 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.	Baseline and Week 8	No
Primary	Cardiothoracic Ratio at 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.	Baseline and Week 8	No
Secondary	Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8	Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 active Metabolite (SB-203231) were measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. The analysis was performed on log-transformed data. Carvedilol is a racemic mixture. Non-selective ß-blocking activity is shown by S-carvedilol, while a1-blocking activity is shown by both S-carvedilol and R-carvedilol.	Week 8	No
Secondary	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	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 ß-blocking activity is shown by S-carvedilol, while a1-blocking activity is shown by both S-carvedilol and R-carvedilol.	Week 8	No
Secondary	Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8	Time of maximal plasma concentration (tmax) of S-carvedilol, R-carvedilol, and M4 active metabolite (SB-203231) was measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. Carvedilol is a racemic mixture. Non-selective ß-blocking activity is shown by S-carvedilol, while a1-blocking activity is shown by both S-carvedilol and R-carvedilol.	Week 8	No
Secondary	Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8	Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.	Baseline and Week 8	No
Secondary	Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8	Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.	Baseline and Week 8	No
Secondary	Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8	Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value.	Baseline and Week 8	No
Secondary	Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8	The NYHA classification assesses the severity of symptoms of heart failure as judged by the investigator and is comprised of. 4 classes: I, no resulting limitations on physical activity (PA); II, slight limitations on PA; III, marked limitations on PA; IV, inability to carry out any PA without discomfort. The number of participants with any change from Baseline in the NYHA Functional Class at Week 8 was calculated. Improved=class at the visit is decreased compared to baseline class, Unchanged=class at the visit is stable, Worsened=class at the visit is increased compared to baseline class.	Baseline and Week 8	No
Secondary	Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8	Brain natriuretic peptide is a surrogate marker of the severity of heart failure and was measured by a central laboratory.	Baseline and Week 8	No
Secondary	Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8	Left ventricular ejection fraction (LVEF) is a marker of left ventricular systolic function and was measured by echocardiogram. It is shown as the ratio of left ventricular stroke volume (LVSV) to left ventricular end-diastolic volume (LVEDV), and is measured as a percentage.	Baseline and Week 8	No