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

Study Overview
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Brief Summary
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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.

Official Title
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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)

Conditions
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Heart Failure, Congestive

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 20 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol. | 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) 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 β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol. | Week 8 | 
| 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 β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol. | Week 8 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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carvedilol phosphate, ß-blocker, SK&F-105517-D, Chronic heart failure(CHF)