Heart Failure, Congestive
Conditions
Keywords
carvedilol phosphate, ß-blocker, SK&F-105517-D, Chronic heart failure(CHF)
Brief summary
The primary objective of this study is to evaluate the safety and tolerability of SK&F-105517-D in japanese patients with chronic heart failure.
Interventions
DRUGCarvedilol-IR 10 mg tablet
1 tablet twice a day
DRUGSK&F-105517-D 10 mg capsule
1 capsule once a day
DRUGCarvedilol-immediate release (IR) 2.5 mg tablet
1 or 2 tablet(s) twice a day
DRUGSK&F-105517-D 20 mg capsule
1 capsule once a day
DRUGSK&F-105517-D 40 mg capsule
1 or 2 capsule(s) once a day
Sponsors
GlaxoSmithKline
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Red Blood Cell Count at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Hematocrit at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) | Treatment Period from Week 0 (Baseline) to Week 8 and 1-week Follow-up Period (Week 9) for CRV-IR; Treatment Period from Week 0 (Baseline) to Week 14 and 1-week Follow-up Period (Week 15) for SK&F-105517-D | Drug-related adverse events (AEs) were defined as AEs that were judged to have a relationship with the investigational product by the investigator (or subinvestigator) with the use of clinical judgment and the Clinical Investigator Brochure to determine the relationship. Refer to adverse event information for type and frequency of adverse events. |
| Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Albumin and Total Protein at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value |
| Mean Change From Baseline in Amylase at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value |
| Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value |
| Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value |
| Mean Change From Baseline in Creatine Kinase BB Percentage, Creatine Kinase MB Percentage, and Creatine Kinase MM Percentage at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. (BB, brain-derived; MB=cardiac muscle-derived; MM=skeletal muscle-derived. |
| Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Mean Corpuscular Volume at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Baseline and Week 8 | Dipstick test values: Negative (-), Traces (+-), +1, +2, +3. +4. Normal ranges (qualitative): protein, - or +-; glucose, - or +-; occult blood, -; ketones, -. |
| Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Heart Rate at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Mean Change From Baseline in Weight at Week 8 | Baseline and Week 8 | Mean change from baseline was calculated as the Week 8 value minus the Baseline value. |
| Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Baseline and Week 8 | There are 3 categories for electrocardiogram (ECG) findings: normal; abnormal, not clinically significant; and abnormal, clinically significant. Each of the findings was classified by the investigator according to whether it was normal. Abnormal ECGs were further classified according to whether they were felt to be clinically significant in the medical and scientific judgment of the investigator. |
| Cardiothoracic Ratio at Baseline and Week 8 | Baseline and Week 8 | Cardiothoracic ratio is a marker of the degree of heart enlargement and was measured by chest X-ray. It is shown as the ratio of the transverse diameter of the heart to the transverse diameter of the thorax, and is measured as a percentage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 | Week 8 | Maximum Plasma Concentration (Cmax) and Trough Plasma Concentration (Cmin) of S-carvedilol, R-carvedilol, and M4 active Metabolite (SB-203231) were measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. The analysis was performed on log-transformed data. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol. |
| Area Under the Plasma Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 | Week 8 | Area under the plasma concentration versus time curve from time zero to 24 hours (AUC0-24) of S-carvedilol, R-carvedilol, and M4 active metabolite (SB-203231) was measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. The analysis was performed on log-transformed data. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol. |
| Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 | Week 8 | Time of maximal plasma concentration (tmax) of S-carvedilol, R-carvedilol, and M4 active metabolite (SB-203231) was measured. Participants in each treatment group were divided into 3 groups by pharmacokinetic sampling timing: Groups A, B, and C in the SK&F-105517-D group and Groups D, E, and F in the CRV-IR group. Carvedilol is a racemic mixture. Non-selective β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol. |
| Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Baseline and Week 8 | Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value. |
| Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Baseline and Week 8 | Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value. |
| Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Baseline and Week 8 | Pharmacodynamic (PD) assessment points were 24 hours (h) (from time of first reading to time of last reading), morning (6 am-12 pm), afternoon (12-6 pm), night (6 pm-6 am on following day), waking (8 am-9 pm), sleeping (0-5 am), PDmax (maximal value obtained with each participant during the 0-24 h interval), PDmin (minimal value obtained with each participant during the 0-24 h interval), and PDmax/PDmin. PDmax/PDmim was calculated as the ratio of the PDmax to PDmin, and it showed the degree of change during the 0-24 h interval. The mean was adjusted for Baseline value. |
| Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 | Baseline and Week 8 | The NYHA classification assesses the severity of symptoms of heart failure as judged by the investigator and is comprised of. 4 classes: I, no resulting limitations on physical activity (PA); II, slight limitations on PA; III, marked limitations on PA; IV, inability to carry out any PA without discomfort. The number of participants with any change from Baseline in the NYHA Functional Class at Week 8 was calculated. Improved=class at the visit is decreased compared to baseline class, Unchanged=class at the visit is stable, Worsened=class at the visit is increased compared to baseline class. |
| Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8 | Baseline and Week 8 | Brain natriuretic peptide is a surrogate marker of the severity of heart failure and was measured by a central laboratory. |
| Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 | Baseline and Week 8 | Left ventricular ejection fraction (LVEF) is a marker of left ventricular systolic function and was measured by echocardiogram. It is shown as the ratio of left ventricular stroke volume (LVSV) to left ventricular end-diastolic volume (LVEDV), and is measured as a percentage. |
Countries
Japan
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| 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. | 22 |
| 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. | 19 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 4-Week Exploratory Evaluation Period | Met Protocol-defined Stopping Criteria | 0 | 1 |
| 8-Week Primary Evaluation Period | Adverse Event | 2 | 4 |
| 8-Week Primary Evaluation Period | Met Protocol-defined Stopping Criteria | 8 | 5 |
| 8-Week Primary Evaluation Period | Protocol Violation | 1 | 0 |
| 8-Week Primary Evaluation Period | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | CRV-IR | SK&F-105517-D | Total |
|---|---|---|---|
| Age, Continuous | 62.7 years STANDARD_DEVIATION 8.17 | 66.7 years STANDARD_DEVIATION 12 | 64.6 years STANDARD_DEVIATION 10.2 |
| Race/Ethnicity, Customized Asian-Japanese Heritage | 22 participants | 19 participants | 41 participants |
| Sex: Female, Male Female | 2 Participants | 1 Participants | 3 Participants |
| Sex: Female, Male Male | 20 Participants | 18 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 11 / 22 | 15 / 19 |
| serious Total, serious adverse events | 1 / 22 | 3 / 19 |
Outcome results
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | Cardiothoracic Ratio at Baseline and Week 8 | Baseline, n=22, 19 | 53.70 percentage | Standard Deviation 4.536 |
| CRV-IR | Cardiothoracic Ratio at Baseline and Week 8 | Week 8, n=11, 8 | 50.91 percentage | Standard Deviation 4.309 |
| SK&F-105517-D | Cardiothoracic Ratio at Baseline and Week 8 | Baseline, n=22, 19 | 53.58 percentage | Standard Deviation 8.098 |
| SK&F-105517-D | Cardiothoracic Ratio at Baseline and Week 8 | Week 8, n=11, 8 | 52.35 percentage | Standard Deviation 7.545 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | Mean Change From Baseline in Albumin and Total Protein at Week 8 | Albumin | 0.7 grams per liter (g/L) | Standard Deviation 2.87 |
| CRV-IR | 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 |
| SK&F-105517-D | Mean Change From Baseline in Albumin and Total Protein at Week 8 | Albumin | -1.9 grams per liter (g/L) | Standard Deviation 2.9 |
| SK&F-105517-D | Mean Change From Baseline in Albumin and Total Protein at Week 8 | Total Protein | -1.6 grams per liter (g/L) | Standard Deviation 4.72 |
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
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| SK&F-105517-D | Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 | Creatine Kinase | -0.1 international units per liter (IU/L) | Standard Deviation 65.54 |
| SK&F-105517-D | Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 | Aspartate Aminotransferase | 1.4 international units per liter (IU/L) | Standard Deviation 7.19 |
| SK&F-105517-D | Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 | Alkaline Phosphatase | -5.0 international units per liter (IU/L) | Standard Deviation 21.13 |
| SK&F-105517-D | Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 | Gamma Glutamyl Transferase | 2.4 international units per liter (IU/L) | Standard Deviation 10.62 |
| SK&F-105517-D | Mean Change From Baseline in Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Creatine Kinase, and Gamma Glutamyl Transferase at Week 8 | Alanine Aminotransferase | 3.8 international units per liter (IU/L) | Standard Deviation 9.39 |
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
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRV-IR | Mean Change From Baseline in Amylase at Week 8 | -10.2 units per liter (U/L) | Standard Deviation 9.98 |
| SK&F-105517-D | Mean Change From Baseline in Amylase at Week 8 | -0.1 units per liter (U/L) | Standard Deviation 15.66 |
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
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 1.6 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 2.3 |
| CRV-IR | 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 |
| SK&F-105517-D | Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 | Sodium | 1.6 millimoles per liter (mmol/L) | Standard Deviation 1.41 |
| SK&F-105517-D | Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 | Calcium | -0.056138 millimoles per liter (mmol/L) | Standard Deviation 0.059268 |
| SK&F-105517-D | 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 0.474 |
| SK&F-105517-D | Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 | Chloride | 2.4 millimoles per liter (mmol/L) | Standard Deviation 2.2 |
| SK&F-105517-D | Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 | Urea/Blood Urea Nitrogen | -0.58013 millimoles per liter (mmol/L) | Standard Deviation 1.023316 |
| SK&F-105517-D | Mean Change From Baseline in Calcium, Chloride, Glucose, Potassium, Sodium, and Urea/Blood Urea Nitrogen at Week 8 | Glucose | -1.956728 millimoles per liter (mmol/L) | Standard Deviation 2.8733368 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 0.6 |
| CRV-IR | 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 |
| CRV-IR | 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 1.3 |
| SK&F-105517-D | 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 | 0.5 percentage of Total Creatine Kinase | Standard Deviation 0.93 |
| SK&F-105517-D | 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 | -0.1 percentage of Total Creatine Kinase | Standard Deviation 0.83 |
| SK&F-105517-D | 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 | 0.8 percentage of Total Creatine Kinase | Standard Deviation 1.75 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| SK&F-105517-D | Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 | Total Neutrophils | -4.31 percentage of each WBC type in WBC count | Standard Deviation 11.18 |
| SK&F-105517-D | 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 0.325 |
| SK&F-105517-D | Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 | Eosinophils | 0.76 percentage of each WBC type in WBC count | Standard Deviation 1.412 |
| SK&F-105517-D | Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 | Lymphocytes | 2.21 percentage of each WBC type in WBC count | Standard Deviation 9.174 |
| SK&F-105517-D | Mean Change From Baseline in Each Type of White Blood Cell (WBC) (Basophils, Eosinophils, Lymphocytes, Monocytes, and Total Neutrophils) at Week 8 | Monocytes | 1.28 percentage of each WBC type in WBC count | Standard Deviation 1.356 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRV-IR | Mean Change From Baseline in Heart Rate at Week 8 | -10.4 beats per minute | Standard Deviation 10.54 |
| SK&F-105517-D | Mean Change From Baseline in Heart Rate at Week 8 | -10.6 beats per minute | Standard Deviation 18.87 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRV-IR | Mean Change From Baseline in Hematocrit at Week 8 | -0.0085 proportion of 1 (SI) | Standard Deviation 0.02306 |
| SK&F-105517-D | Mean Change From Baseline in Hematocrit at Week 8 | -0.0095 proportion of 1 (SI) | Standard Deviation 0.02287 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 4.9 |
| SK&F-105517-D | Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8 | Hemoglobin | -3.9 grams per liter (g/L) | Standard Deviation 8.04 |
| SK&F-105517-D | Mean Change From Baseline in Hemoglobin and Mean Corpuscular Hemoglobin Concentration at Week 8 | Mean Corpuscular Hemoglobin Concentration | -1.9 grams per liter (g/L) | Standard Deviation 6.01 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRV-IR | Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8 | 0.12 picograms (pg) | Standard Deviation 0.515 |
| SK&F-105517-D | Mean Change From Baseline in Mean Corpuscular Hemoglobin at Week 8 | -0.21 picograms (pg) | Standard Deviation 0.372 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRV-IR | Mean Change From Baseline in Mean Corpuscular Volume at Week 8 | 0.1 femtoliters (fL) | Standard Deviation 1.38 |
| SK&F-105517-D | Mean Change From Baseline in Mean Corpuscular Volume at Week 8 | -0.1 femtoliters (fL) | Standard Deviation 1.96 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 0.985 |
| SK&F-105517-D | Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8 | Platelet Count | -11.1 gibi (2 to the power of 30)/liter (Gi/L) | Standard Deviation 14.54 |
| SK&F-105517-D | Mean Change From Baseline in Platelet Count and White Blood Cell Count at Week 8 | White Blood Cell Count | -0.498 gibi (2 to the power of 30)/liter (Gi/L) | Standard Deviation 1.9516 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRV-IR | 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 0.239 |
| SK&F-105517-D | Mean Change From Baseline in Red Blood Cell Count at Week 8 | -0.087 tebi (2 to the power of 40)/liter (Ti/L) | Standard Deviation 0.2295 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 |
| SK&F-105517-D | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8 | Systolic blood pressure | 10.0 millimeters of mercury (mmHg) | Standard Deviation 15.28 |
| SK&F-105517-D | Mean Change From Baseline in Systolic Blood Pressure and Diastolic Blood Pressure at Week 8 | Diastolic blood pressure | 2.8 millimeters of mercury (mmHg) | Standard Deviation 5.68 |
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
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| SK&F-105517-D | Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 | Total Bilirubin | -4.489 micromoles per liter (umol/L) | Standard Deviation 3.8712 |
| SK&F-105517-D | Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 | Creatinine | -4.5305 micromoles per liter (umol/L) | Standard Deviation 5.85307 |
| SK&F-105517-D | Mean Change From Baseline in Total Bilirubin, Creatinine, and Uric Acid at Week 8 | Uric Acid | 14.1265 micromoles per liter (umol/L) | Standard Deviation 80.67868 |
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.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CRV-IR | Mean Change From Baseline in Weight at Week 8 | 0.29 kilograms (kg) | Standard Deviation 1.49 |
| SK&F-105517-D | Mean Change From Baseline in Weight at Week 8 | -0.11 kilograms (kg) | Standard Deviation 2.303 |
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.
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
Population: Safety Population: all participants who received at least one dose of the investigational product
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| SK&F-105517-D | 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) | 3 participants |
| SK&F-105517-D | Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) | Severe | 1 participants |
| SK&F-105517-D | 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) | 1 participants |
| SK&F-105517-D | Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) | Moderate | 5 participants |
| SK&F-105517-D | 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) | 4 participants |
| SK&F-105517-D | Number of Participants With Adverse Events by Severity From Week 0 Through Week 8 (CRV-IR) or Week 14 (SK&F-105517-D) | Mild | 10 participants |
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CRV-IR | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Not clinically significant, BL, n=22, 19 | 12 participants |
| CRV-IR | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Normal, Week (W) 8, n=11, 8 | 2 participants |
| CRV-IR | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Normal, Baseline (BL), n=22, 19 | 2 participants |
| CRV-IR | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Not clinically significant, W8, n=11, 8 | 5 participants |
| CRV-IR | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Clinically significant, BL, n=22, 19 | 8 participants |
| CRV-IR | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Clinically significant, W8, n=11, 8 | 4 participants |
| SK&F-105517-D | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Clinically significant, BL, n=22, 19 | 9 participants |
| SK&F-105517-D | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Normal, Baseline (BL), n=22, 19 | 1 participants |
| SK&F-105517-D | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Not clinically significant, BL, n=22, 19 | 9 participants |
| SK&F-105517-D | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Clinically significant, W8, n=11, 8 | 6 participants |
| SK&F-105517-D | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Normal, Week (W) 8, n=11, 8 | 1 participants |
| SK&F-105517-D | Number of Participants With the Indicated Electrocardiogram Findings at Baseline and Week 8 | Abnormal-Not clinically significant, W8, n=11, 8 | 1 participants |
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, -.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, Negative, Baseline, n=22, 19 | 18 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Traces, Baseline, n=22, 19 | 1 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 1+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 2+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 3+, Baseline, n=22, 19 | 1 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 4+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Negative, Baseline, n=22, 19 | 22 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Traces, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 1+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 2+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 3+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 4+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Negative, Baseline, n=22, 19 | 20 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, Traces, Baseline, n=22, 19 | 1 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 1+, Baseline, n=22, 19 | 2 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 2+, Baseline, n=22, 19 | 1 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 3+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 4+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Negative, Baseline, n=22, 19 | 21 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Traces, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 1+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 2+, Baseline, n=22, 19 | 1 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 3+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 4+, Baseline, n=22, 19 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Negative, Week 8, n=11, 8 | 11 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Traces, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 1+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 2+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 3+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 4+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Negative, Week 8, n=11, 8 | 11 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Traces, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 1+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 2+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 3+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 4+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Negative, Week 8, n=11, 8 | 10 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Traces, Week 8, n=11, 8 | 1 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein 1+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 2+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 3+, Week 8, n=11, 8 | 0 participants |
| CRV-IR | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 4+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 3+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Negative, Baseline, n=22, 19 | 19 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Negative, Week 8, n=11, 8 | 8 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Traces, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, Negative, Week 8, n=11, 8 | 8 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 1+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, Traces, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 2+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Negative, Week 8, n=11, 8 | 8 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 3+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 1+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 4+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | 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 |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Negative, Baseline, n=22, 19 | 19 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 2+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Traces, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 2+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 1+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 3+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 2+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | 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 |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 3+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Glucose, 4+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 4+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Traces, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, Negative, Baseline, n=22, 19 | 16 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Negative, Week 8, n=11, 8 | 8 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, Traces, Baseline, n=22, 19 | 1 participants |
| SK&F-105517-D | 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 |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 1+, Baseline, n=22, 19 | 1 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, Traces, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 2+, Baseline, n=22, 19 | 1 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 4+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 3+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 1+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Occult Blood, 4+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | 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 |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Negative, Baseline, n=22, 19 | 18 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 2+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, Traces, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein 1+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 1+, Baseline, n=22, 19 | 1 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 3+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 2+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | 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 |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 3+, Baseline, n=22, 19 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Ketones, 4+, Week 8, n=11, 8 | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Urinalysis Dipstick Results at Baseline and Week 8 | Urine Protein, 4+, Baseline, n=22, 19 | 0 participants |
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Morning | -7.68 millimeters of mercury (mmHg) | Standard Error 4.449 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Sleeping | -12.68 millimeters of mercury (mmHg) | Standard Error 1.197 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Night | -9.01 millimeters of mercury (mmHg) | Standard Error 4.19 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | PDmax | -10.45 millimeters of mercury (mmHg) | Standard Error 6.702 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Afternoon | -5.32 millimeters of mercury (mmHg) | Standard Error 2.76 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | PDmin | -1.34 millimeters of mercury (mmHg) | Standard Error 3.852 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Waking | -5.11 millimeters of mercury (mmHg) | Standard Error 2.902 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | PDmax/PDmin | -0.24 millimeters of mercury (mmHg) | Standard Error 0.111 |
| CRV-IR | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | 24 h | -7.10 millimeters of mercury (mmHg) | Standard Error 3.387 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | PDmax/PDmin | -0.36 millimeters of mercury (mmHg) | Standard Error 0.094 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | 24 h | -4.89 millimeters of mercury (mmHg) | Standard Error 2.852 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Morning | -8.24 millimeters of mercury (mmHg) | Standard Error 3.766 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Afternoon | -10.25 millimeters of mercury (mmHg) | Standard Error 2.336 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Night | 0.73 millimeters of mercury (mmHg) | Standard Error 3.506 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Waking | -8.56 millimeters of mercury (mmHg) | Standard Error 2.458 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | Sleeping | 5.38 millimeters of mercury (mmHg) | Standard Error 1.011 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | PDmax | -17.91 millimeters of mercury (mmHg) | Standard Error 5.796 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Diastolic Blood Pressure at Week 8 | PDmin | -0.24 millimeters of mercury (mmHg) | Standard Error 3.291 |
95% CI: [-11.2, 15.63]
95% CI: [-17.95, 16.84]
95% CI: [-15.71, 5.86]
95% CI: [-7.11, 26.59]
95% CI: [-14.78, 7.88]
95% CI: [13.36, 22.76]
95% CI: [-32.17, 17.26]
95% CI: [-13.61, 15.8]
95% CI: [-0.54, 0.3]
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Morning | -9.59 beats per minute | Standard Error 2.225 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Sleeping | -11.16 beats per minute | Standard Error 3.536 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Night | -11.12 beats per minute | Standard Error 2.76 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | PDmax | -13.43 beats per minute | Standard Error 2.758 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Afternoon | -13.96 beats per minute | Standard Error 2.345 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | PDmin | -2.04 beats per minute | Standard Error 3.83 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Waking | -12.53 beats per minute | Standard Error 2.25 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | PDmax/PDmin | -0.93 beats per minute | Standard Error 0.095 |
| CRV-IR | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | 24 h | -11.38 beats per minute | Standard Error 2.385 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | PDmax/PDmin | -1.27 beats per minute | Standard Error 0.08 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | 24 h | -15.37 beats per minute | Standard Error 2.058 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Morning | -14.87 beats per minute | Standard Error 1.923 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Afternoon | -15.93 beats per minute | Standard Error 2.006 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Night | -15.26 beats per minute | Standard Error 2.387 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Waking | -15.53 beats per minute | Standard Error 1.933 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | Sleeping | -14.28 beats per minute | Standard Error 3.06 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | PDmax | -23.43 beats per minute | Standard Error 2.366 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Mean Heart Rate at Week 8 | PDmin | -3.47 beats per minute | Standard Error 3.276 |
95% CI: [-12.84, 4.86]
95% CI: [-13.5, 2.95]
95% CI: [-10.89, 6.94]
95% CI: [-14.32, 6.03]
95% CI: [-11.45, 5.47]
95% CI: [-16.12, 9.89]
95% CI: [-20.41, 0.41]
95% CI: [-16, 13.15]
95% CI: [-0.71, 0.03]
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.
Time frame: 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)
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Sleeping | -11.85 millimeters of mercury (mmHg) | Standard Error 3.223 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | 24 h | -10.84 millimeters of mercury (mmHg) | Standard Error 4.119 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Morning | -12.34 millimeters of mercury (mmHg) | Standard Error 4.412 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Afternoon | -10.14 millimeters of mercury (mmHg) | Standard Error 2.734 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Night | -9.04 millimeters of mercury (mmHg) | Standard Error 4.786 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Waking | -10.39 millimeters of mercury (mmHg) | Standard Error 2.857 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | PDmax | -9.74 millimeters of mercury (mmHg) | Standard Error 7.772 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | PDmin | -6.89 millimeters of mercury (mmHg) | Standard Error 5.416 |
| CRV-IR | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | PDmax/PDmin | 0.07 millimeters of mercury (mmHg) | Standard Error 0.103 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | PDmax/PDmin | -0.17 millimeters of mercury (mmHg) | Standard Error 0.088 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Waking | -9.99 millimeters of mercury (mmHg) | Standard Error 2.472 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | 24 h | -1.45 millimeters of mercury (mmHg) | Standard Error 3.567 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Sleeping | 13.20 millimeters of mercury (mmHg) | Standard Error 2.787 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Morning | -4.78 millimeters of mercury (mmHg) | Standard Error 3.819 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | PDmin | 1.42 millimeters of mercury (mmHg) | Standard Error 4.685 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Afternoon | -12.06 millimeters of mercury (mmHg) | Standard Error 2.361 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | PDmax | -10.19 millimeters of mercury (mmHg) | Standard Error 6.656 |
| SK&F-105517-D | Adjusted Mean Change From Baseline in Systolic Blood Pressure at Week 8 | Night | 5.17 millimeters of mercury (mmHg) | Standard Error 4.139 |
95% CI: [-5.75, 24.51]
95% CI: [-8.68, 23.79]
95% CI: [-12.04, 8.2]
95% CI: [-3.45, 31.87]
95% CI: [-10.12, 10.92]
95% CI: [13.16, 36.93]
95% CI: [-29.94, 29.03]
95% CI: [-11.67, 28.28]
95% CI: [-0.63, 0.15]
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 β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Time frame: Week 8
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)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| CRV-IR | 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) |
| CRV-IR | 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) |
| CRV-IR | 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) |
| SK&F-105517-D | 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 | 155.109 hours * nanograms per milliliter (ng/mL) |
| SK&F-105517-D | 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 | 284.313 hours * nanograms per milliliter (ng/mL) |
| SK&F-105517-D | 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 | 64.687 hours * nanograms per milliliter (ng/mL) |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 | Baseline, n=20, 19 | 34.0 percentage | Standard Deviation 8.43 |
| CRV-IR | Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 | Week 8, n=11, 8 | 42.0 percentage | Standard Deviation 13.36 |
| SK&F-105517-D | Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 | Baseline, n=20, 19 | 32.2 percentage | Standard Deviation 10.09 |
| SK&F-105517-D | Echocardiogram Results: Left Ventricular Ejection Fraction at Baseline and Week 8 | Week 8, n=11, 8 | 37.6 percentage | Standard Deviation 10.14 |
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 β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Time frame: Week 8
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)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| CRV-IR | 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) |
| CRV-IR | 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) |
| CRV-IR | 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) |
| CRV-IR | 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) |
| CRV-IR | 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) |
| CRV-IR | 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) |
| SK&F-105517-D | 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 | 6.3937 nanograms per milliliter (ng/mL) |
| SK&F-105517-D | 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 | 12.8171 nanograms per milliliter (ng/mL) |
| SK&F-105517-D | 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 | 4.2565 nanograms per milliliter (ng/mL) |
| SK&F-105517-D | 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 | 3.3796 nanograms per milliliter (ng/mL) |
| SK&F-105517-D | 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 | 1.2386 nanograms per milliliter (ng/mL) |
| SK&F-105517-D | 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 | 27.1306 nanograms per milliliter (ng/mL) |
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.
Time frame: 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.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 62.02 |
| SK&F-105517-D | Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8 | Baseline, n=20, 19 | 226.46 ng/L (nanogram per Liter) | Standard Deviation 339.64 |
| SK&F-105517-D | Mean Plasma Brain Natriuretic Peptide Concentration at Baseline and Week 8 | Week 8, n=11, 8 | 111.93 ng/L (nanogram per Liter) | Standard Deviation 84.298 |
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.
Time frame: 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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| CRV-IR | Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 | Improved | 0 participants |
| CRV-IR | Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 | Unchanged | 11 participants |
| CRV-IR | Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 | Worse | 0 participants |
| SK&F-105517-D | Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 | Improved | 1 participants |
| SK&F-105517-D | Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 | Unchanged | 7 participants |
| SK&F-105517-D | Number of Participants With the Indicated Change From Baseline New York Heart Association (NYHA) Functional Class at Week 8 | Worse | 0 participants |
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 β-blocking activity is shown by S-carvedilol, while α1-blocking activity is shown by both S-carvedilol and R-carvedilol.
Time frame: Week 8
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
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| CRV-IR | 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 |
| CRV-IR | 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 |
| CRV-IR | 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 |
| SK&F-105517-D | Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 | S-carvedilol | 5.958 hours |
| SK&F-105517-D | Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 | R-carvedilol | 5.958 hours |
| SK&F-105517-D | Time of Maximal Plasma Concentration (Tmax) of S-carvedilol, R-carvedilol, and M4 Active Metabolite (SB-203231) at Week 8 | SB-203231 | 5.958 hours |