Diabetes Mellitus
Conditions
Keywords
Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic, Dyslipidemia, Drug Therapy, Atherosclerosis
Brief summary
The purpose of this study was to determine the efficacy of pioglitazone, once daily (QD), compared to glimepiride on atherosclerotic disease measured by intravascular ultrasound.
Detailed description
Diabetes is a chronic disease with multiple metabolic defects that result in hyperglycemia arising from inadequate insulin activity. Type 2 diabetes is usually the result of a progression from reduced sensitivity of hepatic and peripheral tissue cells to circulating insulin (ie, insulin resistance) to a progressive inability of the body to produce adequate insulin to overcome insulin resistance (ie, insulin deficiency due to beta-cell insufficiency) resulting in impaired glucose tolerance and ultimately overt diabetes. In the United States, an estimated 21 million people have diabetes, with type 2 diabetes occurring in approximately 90% to 95% of cases. The goal of treating type 2 diabetes is to control blood glucose and thereby prevent long-term complications. Adequate glycemic control is paramount in attempting to avert chronic complications, including blindness; renal dysfunction resulting in dialysis or renal transplantation; neuropathy; non-traumatic amputations; and macrovascular complications, including myocardial ischemia and myocardial infarction, stroke, and peripheral arterial disease. Intensive glucose management in the early stages of diabetes may help forestall such complications. Therapeutic agents have been developed to address each of the major functional metabolic defects associated with type 2 diabetes: decreased beta-cell function, elevated hepatic glucose output, and insulin resistance. Thiazolidinediones increase glucose utilization, decrease gluconeogenesis, and increase glucose disposal by binding to nuclear receptors known as peroxisome proliferator-activated receptors. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in muscle cells, adipose tissue, and hepatic cells (inhibiting hepatic gluconeogenesis), with no direct impact on insulin secretion. Thus, thiazolidinediones improve glycemic control and result in reduced levels of circulating insulin without predisposing patients to hypoglycemia. Peroxisome proliferator-activated receptors are found in tissues important for insulin action, such as adipose tissue, skeletal muscle, and the liver. The greatest concentration of peroxisome proliferator-activated receptors-gamma receptors is in adipose tissue. This study was designed to compare the effects of pioglitazone compared to glimepiride on progression of atherosclerotic disease, as measured by intravascular ultrasound.
Interventions
DRUGPioglitazone
Up to 45 mg pioglitazone (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.
DRUGGlimepiride
Up to 4 mg of glimepiride (optimized for glucose control), tablets, orally, once daily for up to 72 weeks.
Sponsors
Takeda
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Females of childbearing potential who were sexually active agreed to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study. * Had a diagnosis of type 2 diabetes mellitus * Have received appropriate counseling on lifestyle modification for type 2 diabetes, including diet and exercise. * naïve to or was not currently taking antidiabetic therapy, or were currently treated with monotherapy or combination therapy. * Had a glycosylated hemoglobin level greater than or equal to 6.0% and less than 9% at screening if taking antidiabetic medication or greater than or equal to 6.5% and less than 10% at screening if naive to or not taking antidiabetic medication. * Angiographic criteria: * Entire Coronary Circulation: must have angiographic evidence of coronary heart disease as defined by at least 1 lesion in a native coronary artery that has greater than or equal to 20% reduction in lumen diameter by angiographic visual estimation. * Left Main Coronary Artery: must not have greater than 50% reduction in lumen diameter by visual angiographic estimation. * Target Coronary Artery: * The target vessel, which includes the main artery and all of its side branches, had not undergone prior percutaneous coronary intervention or coronary artery bypass graft surgery. * The target vessel, which includes the main artery and all of its side branches, was not currently a candidate for intervention or a likely candidate for intervention over the next 72 weeks. * The target vessel was not a bypass graft. * The target vessel was not infarct related. * Had previous coronary artery bypass surgery at least six weeks prior to the qualifying intravascular ultrasound are eligible provided they are stable and meet all other entry criteria. * Had an intravascular ultrasound tape deemed to be of acceptable intravascular ultrasound image quality and demonstrated adherence to the intravascular ultrasound interrogation protocol, as determined by the intravascular ultrasound Core Laboratory™ assessment.
Exclusion criteria
* Had type I diabetes mellitus. * Had participated in another investigational study, or participated in an investigational study 30 days prior to the start of this study, or who were scheduled to participate in an investigational study during the time frame of this study. * Male subjects who had a serum creatinine level greater than or equal to 2.0 mg/dL (greater than or equal to 177 µmol/L) (greater than or equal to 1.5 mg/dL; \[greater than or equal to 133 µmol /L\] if taking metformin) and female subjects who have serum creatinine greater than or equal to 1.8 mg/dL \[greater than or equal to 159 µmol /L\] (greater than or equal to 1.4 mg/dL \[greater than or equal to 124 µmol /L\] if taking metformin). * Had unexplained microscopic hematuria greater than +1, confirmed by repeat testing. * Had a history of drug abuse or a history of alcohol abuse (defined as regular or daily consumption of more than 4 alcoholic drinks per day) within the past 2 years. * Had clinical cardiac failure as defined by New York Heart Association class III or IV, or known left ventricular dysfunction measured as left ventricular ejection fraction less than 40%, or by current use of diuretics or angiotensin converting enzyme inhibitors for treatment of heart failure. * Had an alanine transaminase level of greater than 2.5 times the upper limit of normal active liver disease, or jaundice. * Had a body mass index greater than 48 kg/m2 as calculated by weight (kg)/height (m2) or weight (pounds)/height (inches) 2 x 703. * Was required to take or intended to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may have interfered with evaluation of the study medication, including: * Chronically used oral glucocorticoids (eg, prednisone, cortisone, hydrocortisone, dexamethasone) * Niacin greater than100 mg a day, including niacin-containing products such as Advicor® * Chronically used steroid-joint injections * Thiazolidinediones * Sulfonylureas * Metformin/sulfonylurea combination * Other oral antidiabetic medications (eg, nateglinide \[Starlix®\], acarbose \[Precose®\]) with the exception of metformin * Had known or suspected malignancy or recurrence of malignancy within the past 5 years, with the exception of basal cell carcinoma and Stage 1 squamous cell carcinoma of the skin. * Had any disease where, in the opinion of the investigator (or designee), survival is expected to be less than 72 weeks. * Clinical status was unstable (ie, requiring vasopressors or intravenous inotropes, intra-aortic balloon pump, hypotension \[systolic blood pressure less than 90 mm Hg\]). * Prior to the screening visit, was scheduled for a staged cardiac intervention (percutaneous coronary intervention), peripheral vascular intervention, or coronary artery bypass graft surgery following the screening angiography. * In the opinion of the investigator (or designee) had clinically significant valvular heart disease likely to require surgical repair/replacement during the course of the study. * Had persistent, uncontrolled hypertension (ie, sitting systolic blood pressure greater than 160 mm Hg or sitting diastolic blood pressure greater than 100 mm Hg) at randomization. * Males who had hemoglobin less than 10.5 g/dL (less than 105 g/L) and female subjects who had hemoglobin less than 10.0 g/dL (less than 100 g/L). * Had a triglyceride level greater than 500 mg/dL (greater than 5.6 mmol/L).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Nominal Change From Baseline in Percent Atheroma Volume | Baseline and Final Visit (up to 72 weeks) | The nominal change from baseline in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Nominal Change From Baseline in Normalized Total Atheroma Volume | Baseline and Final Visit (up to 72 weeks) | The nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued. |
| Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events | Up to 72 weeks | Due to low event rates, number of subjects experiencing any of the composite endpoint A cardiovascular events is being reported instead of time to first occurrence. Endpoint A conditions listed in Limitations and Caveats section. |
| Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events | Up to 72 weeks | Due to low event rates, number of subjects experiencing any of the composite endpoint B cardiovascular events is being reported instead of time to first occurrence. Endpoint B conditions listed in Limitations and Caveats section. |
| Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events | Up to 72 weeks | Due to low event rates, number of subjects experiencing any of the composite endpoint C cardiovascular events is being reported instead of time to first occurrence. Endpoint C conditions listed in Limitations and Caveats section. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Up to 72 weeks | The incidence of cardiovascular events and composite endpoints occurring within 30 days of last dose as adjudicated by the Clinical Endpoint Committee. Abbreviations: PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; CHF: Congestive Heart Failure. |
Countries
Argentina, Canada, Chile, United States
Participant flow
Recruitment details
Subjects were enrolled at 97 sites in the United States, Canada, Argentina and Chile from 21 July 2003 to 18 October 2007.
Pre-assignment details
The participant flow results below do not include 4 subjects who were randomized but did not receive drug. Subjects participating in this study were enrolled in Pioglitazone or Glimepiride once daily (QD) treatment group.
Participants by arm
| Arm | Count |
|---|---|
| Pioglitazone QD Subjects received up to 45 mg Pioglitazone (dose optimized for glucose control) for up to 72 weeks. | 270 |
| Glimepiride QD Subjects received up to 4 mg Glimepiride (dose optimized for glucose control) for up to 72 weeks. | 273 |
| Total | 543 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 30 | 34 |
| Overall Study | Lack of Efficacy | 4 | 1 |
| Overall Study | Lost to Follow-up | 4 | 6 |
| Overall Study | Other | 7 | 9 |
| Overall Study | Physician Decision | 6 | 8 |
| Overall Study | Protocol Violation | 6 | 3 |
| Overall Study | Withdrawal by Subject | 40 | 34 |
Baseline characteristics
| Characteristic | Pioglitazone QD | Glimepiride QD | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 81 Participants | 80 Participants | 161 Participants |
| Age, Categorical Between 18 and 65 years | 189 Participants | 193 Participants | 382 Participants |
| Body Mass Index | 32.08 Kg/m squared FULL_RANGE 5.264 | 32.03 Kg/m squared FULL_RANGE 5.233 | 32.05 Kg/m squared FULL_RANGE 0 |
| Duration of Coronary Artery Disease | 40.4 Months FULL_RANGE 65.1 | 40.5 Months FULL_RANGE 67.2 | 40.4 Months FULL_RANGE 0 |
| Duration of Diabetes Mellitus | 98.0 Months FULL_RANGE 100.25 | 96.3 Months FULL_RANGE 89.51 | 97.1 Months FULL_RANGE 0 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 63 Participants | 71 Participants | 134 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 207 Participants | 202 Participants | 409 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Family History of Coronary Artery Disease Female Relative History | 60 Participants | 59 Participants | 119 Participants |
| Family History of Coronary Artery Disease Male Relative History | 91 Participants | 77 Participants | 168 Participants |
| Family History of Coronary Artery Disease No Family History | 119 Participants | 137 Participants | 256 Participants |
| Race/Ethnicity, Customized Asian | 12 participants | 16 participants | 28 participants |
| Race/Ethnicity, Customized Black or African American | 30 participants | 27 participants | 57 participants |
| Race/Ethnicity, Customized Native American | 3 participants | 10 participants | 13 participants |
| Race/Ethnicity, Customized White | 225 participants | 220 participants | 445 participants |
| Sex: Female, Male Female | 84 Participants | 93 Participants | 177 Participants |
| Sex: Female, Male Male | 186 Participants | 180 Participants | 366 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 226 / — | 225 / — |
| serious Total, serious adverse events | 76 / — | 77 / — |
Outcome results
Primary
Nominal Change From Baseline in Percent Atheroma Volume
The nominal change from baseline in percent atheroma volume for all slices of anatomically comparable segments of the target coronary artery. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.
Time frame: Baseline and Final Visit (up to 72 weeks)
Population: N at baseline included subjects who had both a baseline value and a final visit value. Baseline value is the last observation before first dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone QD | Nominal Change From Baseline in Percent Atheroma Volume | Baseline | 40.592 Percent volume | Standard Error 0.6925 |
| Pioglitazone QD | Nominal Change From Baseline in Percent Atheroma Volume | Nominal Change from Baseline | -0.161 Percent volume | Standard Error 0.2095 |
| Glimepiride QD | Nominal Change From Baseline in Percent Atheroma Volume | Baseline | 40.016 Percent volume | Standard Error 0.6663 |
| Glimepiride QD | Nominal Change From Baseline in Percent Atheroma Volume | Nominal Change from Baseline | 0.725 Percent volume | Standard Error 0.2017 |
Comparison: 2 Way analysis of covariance (ANCOVA), treatment and center effects with baseline value as covariate. Least Squares (LS) mean change and LS mean of the treatment difference reported.p-value: 0.00295% CI: [-1.448, -0.325]ANCOVA
Secondary
Nominal Change From Baseline in Normalized Total Atheroma Volume
The nominal change in normalized total atheroma volume as measured by the average of plaque areas for all slices of anatomically comparable segments of the target coronary artery multiplied by the mean number of matched slices in the population. Assessment completed at the Week 72 visit or Final Visit if treatment was prematurely discontinued.
Time frame: Baseline and Final Visit (up to 72 weeks)
Population: N at baseline included subjects who had both a baseline value and a final visit value. Baseline value is the last observation before first dose of study medication.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| Pioglitazone QD | Nominal Change From Baseline in Normalized Total Atheroma Volume | Baseline | 206.579 Percent volume | Standard Error 7.2778 |
| Pioglitazone QD | Nominal Change From Baseline in Normalized Total Atheroma Volume | Nominal Change from Baseline | -5.528 Percent volume | Standard Error 1.5989 |
| Glimepiride QD | Nominal Change From Baseline in Normalized Total Atheroma Volume | Baseline | 217.619 Percent volume | Standard Error 7.003 |
| Glimepiride QD | Nominal Change From Baseline in Normalized Total Atheroma Volume | Nominal Change from Baseline | -1.480 Percent volume | Standard Error 1.537 |
Comparison: 2 Way ANCOVA, treatment and center effects with baseline value as covariate. LS mean of the treatment difference reported.p-value: 0.06495% CI: [-8.3336, 0.2374]ANCOVA
Secondary
Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events
Due to low event rates, number of subjects experiencing any of the composite endpoint A cardiovascular events is being reported instead of time to first occurrence. Endpoint A conditions listed in Limitations and Caveats section.
Time frame: Up to 72 weeks
Population: Kaplan-Meier methodology was used to estimate time to event for each composite endpoint. P-value comparing survival function between groups was based on log-rank test. Time to first occurrence of cardiovascular events/hospitalizations had non-estimable medians due to very low event rates. Number of participants experiencing events are presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone QD | Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events | 5 Participants |
| Glimepiride QD | Number of Subjects Experiencing Any of the Composite Endpoint A Cardiovascular Events | 6 Participants |
p-value: 0.744Log Rank
Secondary
Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events
Due to low event rates, number of subjects experiencing any of the composite endpoint B cardiovascular events is being reported instead of time to first occurrence. Endpoint B conditions listed in Limitations and Caveats section.
Time frame: Up to 72 weeks
Population: Kaplan-Meier methodology was used to estimate time to event for each composite endpoint. P-value comparing survival function between groups was based on log-rank test. Time to first occurrence of cardiovascular events/hospitalizations had non-estimable medians due to very low event rates. Number of participants experiencing events are presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone QD | Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events | 40 Participants |
| Glimepiride QD | Number of Subjects Experiencing Any of the Composite Endpoint B Cardiovascular Events | 41 Participants |
p-value: 0.883Log Rank
Secondary
Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events
Due to low event rates, number of subjects experiencing any of the composite endpoint C cardiovascular events is being reported instead of time to first occurrence. Endpoint C conditions listed in Limitations and Caveats section.
Time frame: Up to 72 weeks
Population: Kaplan-Meier methodology was used to estimate time to event for each composite endpoint. P-value comparing survival function between groups was based on log-rank test. Time to first occurrence of cardiovascular events/hospitalizations had non-estimable medians due to very low event rates. Number of participants experiencing events are presented.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pioglitazone QD | Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events | 11 participants |
| Glimepiride QD | Number of Subjects Experiencing Any of the Composite Endpoint C Cardiovascular Events | 13 participants |
p-value: 0.663Log Rank
Other Pre-specified
Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee
The incidence of cardiovascular events and composite endpoints occurring within 30 days of last dose as adjudicated by the Clinical Endpoint Committee. Abbreviations: PCI: Percutaneous Coronary Intervention; CABG: Coronary Artery Bypass Graft; CHF: Congestive Heart Failure.
Time frame: Up to 72 weeks
Population: Safety Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Coronary Revascularization: PCI | 25 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Hospitalization for New CHF | 4 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Hospitalization for Unstable Angina | 4 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Hospitalization for Exacerbated CHF | 0 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Coronary Revascularization: CABG | 5 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Noncardiovascular Mortality | 0 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Coronary Revascularization: PCI/CABG counted once | 29 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Cardiovascular Mortality | 3 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Carotid Endarterectomy/Stenting | 1 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Composite Endpoint A | 5 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Nonfatal Stroke | 0 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Composite Endpoint B | 40 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | CHF Hospitalization: new/exacerbated counted once | 4 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Composite Endpoint C | 11 Number of Events |
| Pioglitazone QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Nonfatal Myocardial Infarction | 2 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Composite Endpoint C | 13 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Nonfatal Myocardial Infarction | 4 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Carotid Endarterectomy/Stenting | 0 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Nonfatal Stroke | 1 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Coronary Revascularization: PCI/CABG counted once | 30 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Coronary Revascularization: PCI | 28 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Coronary Revascularization: CABG | 2 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Hospitalization for Unstable Angina | 2 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | CHF Hospitalization: new/exacerbated counted once | 5 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Hospitalization for New CHF | 2 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Hospitalization for Exacerbated CHF | 3 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Noncardiovascular Mortality | 1 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Cardiovascular Mortality | 1 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Composite Endpoint A | 6 Number of Events |
| Glimepiride QD | Number of Cardiovascular Events as Adjudicated by the Clinical Endpoint Committee | Composite Endpoint B | 41 Number of Events |