Atherosclerosis
Conditions
Keywords
Cardiovascular Death, Myocardial Infarction, Stroke, Canakinumab, IL-1B, hsCRP
Brief summary
Main Study (CACZ885M2301): The purpose of the pivotal phase of this trial was to test the hypothesis that canakinumab treatment of patients with myocardial infarction (MI) at least one month prior to study entry and elevated hsCRP could prevent recurrent cardiovascular events. The purpose of the extension phase of the main study is to collect additional long-term safety data on continued exposure to canakinumab in patients who participated in the pivotal phase. Sub-study 1 (CACZ885M2301S1): The purpose of this sub-study was to evaluate the effect of quarterly subcutaneous canakinumab treatment for 24 months comparted with placebo on the carotid plaque burden measured by integrated vascular MRI in patients enrolled in the CACZ885M2301 study (CANTOS). Sub-study 2 (CACZ885M2301S2): The purpose of this CANTOS sub-study was to determine whether, in patients with type 2 diabetes participating in the CANTOS main study, canakinumab compared to placebo, on top of standard of care could increase insulin secretion and insulin sensitivity.
Detailed description
Sub-study 1 and 2 were terminated prior to data collection from subjects. However, there is an ongoing extension trial where patients are receiving open-drug label.
Interventions
DRUGCanakinumab
DRUGPlacebo
DRUGStandard of care
Standard of care post-MI background therapy includes, but is not limited to, lipid lowering, anti-hypertensive, beta blockers, and anti-platelet therapy as appropriate
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Main Study Inclusion Criteria: * Written informed consent * Male, or Female of non-child-bearing potential * Age ≥ 18 years. * Spontaneous MI at least 30 days before randomization. hsCRP ≥ 2 mg/L Substudy 1 Inclusion: * All Inclusion from Main Study * Acquisition of evaluable baseline MRI images of bilateral carotid arteries by the imaging core laboratory Substudy 2 Inclusion: * All inclusion from Main Study * T2D at baseline per Main protocol criteria and be on a stable anti-hyperglycemic medication for at least 4 weeks prior to the baseline OGTT test * Willing to have the OGTT assessment started before 10 am Main Study
Exclusion criteria
* Pregnant or nursing (lactating) women * Women of child-bearing potential * Any of the following concomitant diseases * Planned coronary revascularization (PCI or CABG) * Major non-cardiac surgical or endoscopic procedure within past 6 months * Multi-vessel CABG surgery within the past 3 years * Symptomatic patients with Class IV heart failure (HF) (New York Heart Association \[NYHA\]. * Uncontrolled hypertension * Uncontrolled diabetes * History or evidence of active tuberculosis (TB) infection Substudy 1 Exclusion * All Main exclusion * Patients with prior history of carotid angioplasty, stenting, or carotid atherectomy * Patients with contraindications to MRI examination (brain aneurysm clip, implanted neural stimulator, implanted cardiac pacemaker, pacemaker wires or defibrillator, prosthetic heart valves, cochlear implant, ocular foreign body or other implanted body, tattoos, implanted insulin pump, metal shrapnel or bullet) * Patients prone to claustrophobia or known anxiety disorders * BMI \> 40 kg/m2 Substudy 2 Exclusion * This sub-study does not have any additional
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | From randomization, to end of treatment plus 30 days, up to approximately 6 years | Time to occurrence of CEC (Cardiovascular clinical events adjudication committee) confirmed MACE, which was a composite endpoint consisting of CEC confirmed CV death, CEC confirmed non-fatal MI,or CEC confirmed non-fatal stroke. Patients with the CEC adjudicated reason for death of Unknown were counted as CV (cardiovascular) death. |
| Substudy 1 (Core Phase): Change From Baseline in Carotid Plaque Burden in the Bifurcation Region of the Index Carotid Artery | 24 months | — |
| Substudy 2 (Core Phase): Change From Baseline of the Insulin Secretion Rate (ISR) Relative to Glucose 0-30 Min Defined as Φ30 = AUCISR 0-30 / AUCGluc 0-30 Averaged Across the Year 3, 4, 5 Visits | From randomization up to approximately 6 years | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke | From randomization, to end of treatment plus 30 days, up to approximately 6 years | Occurrence of the composite endpoint consisting of all-cause mortality, non-fatal IM, or non-fatal stroke |
| Core Phase All-cause Mortality | From randomization, to end of treatment plus 30 days, up to approximately 6 years | Number of participant deaths |
| Summary of Adverse Events (Core Phase) | From randomization, to end of treatment plus 30 days, up to approximately 6 years | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the double-blind Core phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment. |
| Summary of Adverse Events (Extension Phase) | From start of Extension phase, to end of treatment plus 30 days, up to approximately 2 years | Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the Extension phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment. |
| Substudy 1 (Core Phase): Change From Baseline of the Total Vessel Wall Area at Month 3 in the Bifurcation Region of the Index Carotid Artery | 3 months | — |
| Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under Curve (AUC) 0-120 Min of Glucose Concentration, Insulin Concentration, Pro-insulin Concentration, and Insulin Concentration/Glucose Concentration Ratio | From randomization up to approximately 6 years | — |
| Substudy 1 (Core Phase): Change From Baseline in Corresponding Total Vessel Wall Area in the Left and Right Carotid Arteries | 24 months | — |
| Substudy 1 (Core Phase): The Existence of a Baseline Total Vessel Wall Area by Treatment Interaction as Well as the Consistency of the Treatment Effect Across Subgroups | 24 months | — |
| Substudy 2 (Core Phase): Change From Baseline in Insulin Sensitivity Index | From randomization up to approximately 6 years | — |
| Substudy 2 (Core Phase): Change From Baseline in Fasting Pro-Insulin Concentration/Insulin Concentration Ratio | From randomization up to approximately 6 years | — |
| Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under the Curve (AUC) 0-120 Min of C-peptide Concentration | From randomization up to approximately 6 years | — |
| Substudy 1 (Core Phase): Mean Total Vessel Wall Area Across the Left and Right Carotid Artery at Month 3 and Month 24 | 24 months | — |
| Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | From randomization, to end of treatment pus 30 days, up to approximately 6 years | Occurrence of the composite cardiovascular endpoint consisting of cardiovascular death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina requiring unplanned revascularization. MACE includes CV death, non-fatal MI and non-fatal stroke. CEC = Clinical Endpoints Committee |
| Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization | From randomization up to approximately 6 years | Time to CEC confirmed new onset of type 2 diabetes among those with pre-diabetes at randomization (i.e. excluding those that are normoglycemic at baseline) |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, China, Colombia, Croatia, Czechia, Estonia, Germany, Greece, Guatemala, Hungary, Iceland, India, Italy, Japan, Latvia, Lithuania, Mexico, Netherlands, Norway, Peru, Poland, Puerto Rico, Romania, Russia, Serbia, Slovakia, Slovenia, South Africa, South Korea, Sweden, Taiwan, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
10066 patients enrolled in the Core phase (4 randomized groups); 5 patients enrolled in the safety set were not included in efficacy set. 5777 patients continued in the Extension phase (539 entered only the washout period, 5238 entered the treatment period(s)). The Core phase completed as planned; terminated applies to the Extension phase.
Pre-assignment details
A total of 17482 patients were screened, and 10102 patients completed the screening phase. A total of 6430 patients did not complete the screening phase due to screen failure.
Participants by arm
| Arm | Count |
|---|---|
| Group I Core phase: Blinded Canakinumab 300 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy | 2,263 |
| Group II Core phase: Blinded Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy | 2,284 |
| Group III Core phase: Blinded Canakinumab 50 mg quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy | 2,170 |
| Group IV Core phase: Blinded matching placebo quarterly subcutaneous + standard of care (SoC) therapy Extension phase: Switched to open-label Canakinumab 150 mg quarterly subcutaneous + standard of care (SoC) therapy | 3,344 |
| Total | 10,061 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Core Phase | Lost to Follow-up | 3 | 3 | 4 | 5 |
| Core Phase | Subject decision (vital stat: alive) | 23 | 24 | 13 | 20 |
| Core Phase | Subject decision (vital stat: dead) | 1 | 3 | 4 | 4 |
| Core Phase | Subject decision (vital stat: unkn) | 0 | 0 | 3 | 3 |
| Core Phase | Subject decision (vital status: missing) | 1 | 2 | 2 | 1 |
| Extension Phase | Lost to Follow-up | 4 | 3 | 4 | 7 |
| Extension Phase | Study terminated by sponsor | 1,073 | 1,124 | 1,067 | 1,660 |
| Extension Phase | Technical Problems | 2 | 4 | 2 | 2 |
| Extension Phase | Withdrawal by Subject | 20 | 13 | 19 | 37 |
Baseline characteristics
| Characteristic | Group I | Group II | Group III | Group IV | Total |
|---|---|---|---|---|---|
| Age, Customized < 65 | 1424 Participants | 1428 Participants | 1350 Participants | 2089 Participants | 6291 Participants |
| Age, Customized >= 65 | 839 Participants | 856 Participants | 820 Participants | 1255 Participants | 3770 Participants |
| Race/Ethnicity, Customized Asian | 265 Participants | 278 Participants | 232 Participants | 388 Participants | 1163 Participants |
| Race/Ethnicity, Customized Black | 84 Participants | 67 Participants | 61 Participants | 106 Participants | 318 Participants |
| Race/Ethnicity, Customized Caucasian | 1804 Participants | 1808 Participants | 1772 Participants | 2652 Participants | 8036 Participants |
| Race/Ethnicity, Customized Native American | 47 Participants | 49 Participants | 41 Participants | 82 Participants | 219 Participants |
| Race/Ethnicity, Customized Other | 60 Participants | 79 Participants | 62 Participants | 112 Participants | 313 Participants |
| Race/Ethnicity, Customized Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race/Ethnicity, Customized Unknown | 3 Participants | 3 Participants | 1 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Female | 606 Participants | 575 Participants | 541 Participants | 865 Participants | 2587 Participants |
| Sex: Female, Male Male | 1657 Participants | 1709 Participants | 1629 Participants | 2479 Participants | 7474 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 239 / 2,263 | 240 / 2,285 | 228 / 2,170 | 378 / 3,348 | 211 / 5,777 |
| other Total, other adverse events | 1,271 / 2,263 | 1,324 / 2,285 | 1,199 / 2,170 | 1,905 / 3,348 | 1,497 / 5,777 |
| serious Total, serious adverse events | 759 / 2,263 | 743 / 2,285 | 686 / 2,170 | 1,099 / 3,348 | 1,216 / 5,777 |
Outcome results
Primary
Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components
Time to occurrence of CEC (Cardiovascular clinical events adjudication committee) confirmed MACE, which was a composite endpoint consisting of CEC confirmed CV death, CEC confirmed non-fatal MI,or CEC confirmed non-fatal stroke. Patients with the CEC adjudicated reason for death of Unknown were counted as CV (cardiovascular) death.
Time frame: From randomization, to end of treatment plus 30 days, up to approximately 6 years
Population: Full Analysis Set (FAS): All randomized patients except for those who were misrandomized or from sites with serious GCP violations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group I | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (non-fatal) | 51 Participants |
| Group I | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (non-fatal) | 171 Participants |
| Group I | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | CV death | 151 Participants |
| Group I | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (fatal and non-fatal) | 174 Participants |
| Group I | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (fatal and non-fatal) | 51 Participants |
| Group I | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MACE | 322 Participants |
| Group II | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (fatal and non-fatal) | 63 Participants |
| Group II | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (non-fatal) | 63 Participants |
| Group II | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | CV death | 144 Participants |
| Group II | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MACE | 320 Participants |
| Group II | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (fatal and non-fatal) | 159 Participants |
| Group II | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (non-fatal) | 158 Participants |
| Group III | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MACE | 313 Participants |
| Group III | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | CV death | 137 Participants |
| Group III | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (fatal and non-fatal) | 58 Participants |
| Group III | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (non-fatal) | 168 Participants |
| Group III | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (non-fatal) | 58 Participants |
| Group III | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (fatal and non-fatal) | 169 Participants |
| Group IV | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (non-fatal) | 91 Participants |
| Group IV | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MACE | 535 Participants |
| Group IV | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | CV death | 235 Participants |
| Group IV | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (fatal and non-fatal) | 292 Participants |
| Group IV | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | MI (non-fatal) | 291 Participants |
| Group IV | Analysis of Core Phase First CEC Confirmed Major Adverse Cardiovascular Events (MACE) and Its Components | Stroke (fatal and non-fatal) | 92 Participants |
Comparison: H11: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 300 mg dose group is greater than or equal to the hazard rate of the placebo groupp-value: 0.064895% CI: [0.75, 0.99]Log Rank
Comparison: H21: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 150 mg dose group is greater than or equal to the hazard rate of the placebo groupp-value: 0.024195% CI: [0.74, 0.98]Log Rank
Comparison: H31: The hazard rate of first adjudication committee confirmed MACE in the canakinumab 50 mg dose group is greater than or equal to the hazard rate of the placebo group.p-value: 0.189595% CI: [0.8, 1.07]Log Rank
p-value: 0.57295% CI: [0.77, 1.16]Regression, Cox
p-value: 0.29695% CI: [0.73, 1.1]Regression, Cox
p-value: 0.36995% CI: [0.73, 1.12]Regression, Cox
p-value: 0.06795% CI: [0.69, 1.01]Regression, Cox
p-value: 0.00695% CI: [0.63, 0.92]Regression, Cox
p-value: 0.54295% CI: [0.78, 1.14]Regression, Cox
95% CI: [0.68, 1]
95% CI: [0.62, 0.92]
95% CI: [0.78, 1.14]
p-value: 0.1995% CI: [0.56, 1.12]Regression, Cox
p-value: 0.91295% CI: [0.71, 1.35]Regression, Cox
p-value: 0.87195% CI: [0.74, 1.43]Regression, Cox
95% CI: [0.57, 1.13]
95% CI: [0.72, 1.37]
95% CI: [0.75, 1.45]
Primary
Substudy 1 (Core Phase): Change From Baseline in Carotid Plaque Burden in the Bifurcation Region of the Index Carotid Artery
Time frame: 24 months
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Primary
Substudy 2 (Core Phase): Change From Baseline of the Insulin Secretion Rate (ISR) Relative to Glucose 0-30 Min Defined as Φ30 = AUCISR 0-30 / AUCGluc 0-30 Averaged Across the Year 3, 4, 5 Visits
Time frame: From randomization up to approximately 6 years
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Core Phase All-cause Mortality
Number of participant deaths
Time frame: From randomization, to end of treatment plus 30 days, up to approximately 6 years
Population: FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I | Core Phase All-cause Mortality | 239 Participants |
| Group II | Core Phase All-cause Mortality | 238 Participants |
| Group III | Core Phase All-cause Mortality | 228 Participants |
| Group IV | Core Phase All-cause Mortality | 375 Participants |
p-value: 0.40695% CI: [0.79, 1.1]Regression, Cox
p-value: 0.32995% CI: [0.78, 1.09]Regression, Cox
p-value: 0.59795% CI: [0.81, 1.13]Regression, Cox
Secondary
Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke
Occurrence of the composite endpoint consisting of all-cause mortality, non-fatal IM, or non-fatal stroke
Time frame: From randomization, to end of treatment plus 30 days, up to approximately 6 years
Population: FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I | Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke | 403 Participants |
| Group II | Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke | 395 Participants |
| Group III | Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke | 394 Participants |
| Group IV | Core Phase All-cause Mortality, Non-fatal MI, or Non-fatal Stroke | 661 Participants |
p-value: 0.02895% CI: [0.77, 0.99]Regression, Cox
p-value: 0.01195% CI: [0.75, 0.96]Regression, Cox
p-value: 0.37795% CI: [0.83, 1.07]Regression, Cox
Secondary
Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization
Occurrence of the composite cardiovascular endpoint consisting of cardiovascular death, non-fatal MI, non-fatal stroke or hospitalization for unstable angina requiring unplanned revascularization. MACE includes CV death, non-fatal MI and non-fatal stroke. CEC = Clinical Endpoints Committee
Time frame: From randomization, to end of treatment pus 30 days, up to approximately 6 years
Population: FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group I | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | MACE or unstable angina | 348 Participants |
| Group I | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | Unstable angina | 34 Participants |
| Group II | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | Unstable angina | 38 Participants |
| Group II | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | MACE or unstable angina | 352 Participants |
| Group III | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | MACE or unstable angina | 344 Participants |
| Group III | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | Unstable angina | 38 Participants |
| Group IV | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | MACE or unstable angina | 601 Participants |
| Group IV | Patients With Core Phase CEC Confirmed CV Death, Non-fatal MI, Non-fatal Stroke, or Hospitalization for Unstable Angina Requiring Unplanned Revascularization | Unstable angina | 85 Participants |
p-value: 0.064895% CI: [0.72, 0.94]Log Rank
p-value: 0.024195% CI: [0.73, 0.95]Log Rank
p-value: 0.189595% CI: [0.79, 1.03]Log Rank
p-value: 0.00795% CI: [0.39, 0.86]Regression, Cox
p-value: 0.02295% CI: [0.44, 0.94]Regression, Cox
p-value: 0.08695% CI: [0.48, 1.05]Regression, Cox
Secondary
Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization
Time to CEC confirmed new onset of type 2 diabetes among those with pre-diabetes at randomization (i.e. excluding those that are normoglycemic at baseline)
Time frame: From randomization up to approximately 6 years
Population: FAS: All randomized patients except for those who were misrandomized or from sites with serious GCP violations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group I | Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization | 169 Participants |
| Group II | Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization | 171 Participants |
| Group III | Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization | 161 Participants |
| Group IV | Patients With Core Phase New Onset Type 2 Diabetes Among Patients With Pre-diabetes at Randomization | 246 Participants |
p-value: 0.845695% CI: [0.83, 1.23]Log Rank
p-value: 0.845695% CI: [0.87, 1.29]Log Rank
p-value: 0.654195% CI: [0.8, 1.2]Log Rank
Secondary
Substudy 1 (Core Phase): Change From Baseline in Corresponding Total Vessel Wall Area in the Left and Right Carotid Arteries
Time frame: 24 months
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Substudy 1 (Core Phase): Change From Baseline of the Total Vessel Wall Area at Month 3 in the Bifurcation Region of the Index Carotid Artery
Time frame: 3 months
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Substudy 1 (Core Phase): Mean Total Vessel Wall Area Across the Left and Right Carotid Artery at Month 3 and Month 24
Time frame: 24 months
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Substudy 1 (Core Phase): The Existence of a Baseline Total Vessel Wall Area by Treatment Interaction as Well as the Consistency of the Treatment Effect Across Subgroups
Time frame: 24 months
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Substudy 2 (Core Phase): Change From Baseline in Fasting Pro-Insulin Concentration/Insulin Concentration Ratio
Time frame: From randomization up to approximately 6 years
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Substudy 2 (Core Phase): Change From Baseline in Insulin Sensitivity Index
Time frame: From randomization up to approximately 6 years
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under Curve (AUC) 0-120 Min of Glucose Concentration, Insulin Concentration, Pro-insulin Concentration, and Insulin Concentration/Glucose Concentration Ratio
Time frame: From randomization up to approximately 6 years
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Substudy 2 (Core Phase): Change From Baseline in OGTT Stimulated Area Under the Curve (AUC) 0-120 Min of C-peptide Concentration
Time frame: From randomization up to approximately 6 years
Population: Data from subjects were not collected as the substudy was terminated prior to data collection.
Secondary
Summary of Adverse Events (Core Phase)
Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the double-blind Core phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment.
Time frame: From randomization, to end of treatment plus 30 days, up to approximately 6 years
Population: Safety set: All patients who received at least one dose of study treatment and had at least one post-baseline safety assessment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group I | Summary of Adverse Events (Core Phase) | Patients with at least one AE | 1987 Participants |
| Group I | Summary of Adverse Events (Core Phase) | AEs suspected to be related tostudy drug | 355 Participants |
| Group I | Summary of Adverse Events (Core Phase) | Patients with at least one SAE | 836 Participants |
| Group I | Summary of Adverse Events (Core Phase) | Discontinued due to SAEs | 135 Participants |
| Group I | Summary of Adverse Events (Core Phase) | Discontinued due to non-seriousAEs | 40 Participants |
| Group I | Summary of Adverse Events (Core Phase) | AEs leading to study treatmentinterruption | 268 Participants |
| Group II | Summary of Adverse Events (Core Phase) | AEs leading to study treatmentinterruption | 270 Participants |
| Group II | Summary of Adverse Events (Core Phase) | Discontinued due to SAEs | 130 Participants |
| Group II | Summary of Adverse Events (Core Phase) | Patients with at least one AE | 1970 Participants |
| Group II | Summary of Adverse Events (Core Phase) | Patients with at least one SAE | 812 Participants |
| Group II | Summary of Adverse Events (Core Phase) | AEs suspected to be related tostudy drug | 350 Participants |
| Group II | Summary of Adverse Events (Core Phase) | Discontinued due to non-seriousAEs | 34 Participants |
| Group III | Summary of Adverse Events (Core Phase) | AEs suspected to be related tostudy drug | 267 Participants |
| Group III | Summary of Adverse Events (Core Phase) | Patients with at least one SAE | 741 Participants |
| Group III | Summary of Adverse Events (Core Phase) | Discontinued due to SAEs | 117 Participants |
| Group III | Summary of Adverse Events (Core Phase) | AEs leading to study treatmentinterruption | 228 Participants |
| Group III | Summary of Adverse Events (Core Phase) | Discontinued due to non-seriousAEs | 26 Participants |
| Group III | Summary of Adverse Events (Core Phase) | Patients with at least one AE | 1872 Participants |
| Group IV | Summary of Adverse Events (Core Phase) | Discontinued due to non-seriousAEs | 47 Participants |
| Group IV | Summary of Adverse Events (Core Phase) | AEs leading to study treatmentinterruption | 399 Participants |
| Group IV | Summary of Adverse Events (Core Phase) | AEs suspected to be related tostudy drug | 474 Participants |
| Group IV | Summary of Adverse Events (Core Phase) | Discontinued due to SAEs | 198 Participants |
| Group IV | Summary of Adverse Events (Core Phase) | Patients with at least one AE | 2915 Participants |
| Group IV | Summary of Adverse Events (Core Phase) | Patients with at least one SAE | 1204 Participants |
Secondary
Summary of Adverse Events (Extension Phase)
Summary of Adverse Events (AEs) and Serious Adverse Events (SAEs) occurring during the Extension phase of the study. AEs/SAEs are any signs or symptoms that occur during the study treatment.
Time frame: From start of Extension phase, to end of treatment plus 30 days, up to approximately 2 years
Population: Extension Safety set: All patients who received at least one dose of study treatment during the Core Phase and who entered the Extension phase.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group I | Summary of Adverse Events (Extension Phase) | Discontinued due to non-seriousAEs | 8 Participants |
| Group I | Summary of Adverse Events (Extension Phase) | AEs suspected to be related tostudy drug | 40 Participants |
| Group I | Summary of Adverse Events (Extension Phase) | AEs leading to study treatmentinterruption | 59 Participants |
| Group I | Summary of Adverse Events (Extension Phase) | Patients with at least one SAE | 310 Participants |
| Group I | Summary of Adverse Events (Extension Phase) | Discontinued due to SAEs | 67 Participants |
| Group I | Summary of Adverse Events (Extension Phase) | Patients with at least one AE | 788 Participants |
| Group II | Summary of Adverse Events (Extension Phase) | Patients with at least one SAE | 326 Participants |
| Group II | Summary of Adverse Events (Extension Phase) | Patients with at least one AE | 845 Participants |
| Group II | Summary of Adverse Events (Extension Phase) | Discontinued due to non-seriousAEs | 6 Participants |
| Group II | Summary of Adverse Events (Extension Phase) | Discontinued due to SAEs | 71 Participants |
| Group II | Summary of Adverse Events (Extension Phase) | AEs leading to study treatmentinterruption | 72 Participants |
| Group II | Summary of Adverse Events (Extension Phase) | AEs suspected to be related tostudy drug | 34 Participants |
| Group III | Summary of Adverse Events (Extension Phase) | AEs leading to study treatmentinterruption | 62 Participants |
| Group III | Summary of Adverse Events (Extension Phase) | AEs suspected to be related tostudy drug | 43 Participants |
| Group III | Summary of Adverse Events (Extension Phase) | Discontinued due to SAEs | 71 Participants |
| Group III | Summary of Adverse Events (Extension Phase) | Patients with at least one SAE | 322 Participants |
| Group III | Summary of Adverse Events (Extension Phase) | Patients with at least one AE | 793 Participants |
| Group III | Summary of Adverse Events (Extension Phase) | Discontinued due to non-seriousAEs | 12 Participants |
| Group IV | Summary of Adverse Events (Extension Phase) | Patients with at least one SAE | 465 Participants |
| Group IV | Summary of Adverse Events (Extension Phase) | Patients with at least one AE | 1250 Participants |
| Group IV | Summary of Adverse Events (Extension Phase) | AEs suspected to be related tostudy drug | 65 Participants |
| Group IV | Summary of Adverse Events (Extension Phase) | AEs leading to study treatmentinterruption | 100 Participants |
| Group IV | Summary of Adverse Events (Extension Phase) | Discontinued due to SAEs | 98 Participants |
| Group IV | Summary of Adverse Events (Extension Phase) | Discontinued due to non-seriousAEs | 8 Participants |