Cardiovascular Disease, High Cardiovascular Risk, Obesity, Overweight, Type 2 Diabetes
Conditions
Keywords
Diabetes, Cardiovascular Disease, Multiple Cardiovascular Risk Factors, Obesity, Overweight, MACE, Conversion to Diabetes
Brief summary
This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in overweight and obese subjects with cardiovascular (CV) disease and/or multiple CV risk factors.
Detailed description
Approximately 12,000 subjects will be randomized to two treatment groups in a ratio of 1:1, stratified by the presence of established CV disease (approximately 80%) or CV risk factors without established CV disease (approximately 20%). Subjects will receive lorcaserin HCl 10 mg BID or placebo BID. The study will consist of 2 phases: Prerandomization and Randomization. The Prerandomization Phase will last up to 30 days and consist of one visit during which subjects will be screened for eligibility. The Randomization Phase will consist of two periods: Treatment and Follow-up. The Treatment Period will last for approximately 5 years with approximately 18 visits and Follow-up period is 30 (+ or - 10 days) from the end of treatment visit.
Interventions
APD356 10 mg twice daily
DRUGPlacebo
Placebo twice daily
Sponsors
The TIMI Study Group
Eisai Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. BMI greater than or equal (\>=) to 27 kilogram per meter square (kg/m\^2) 2. Subjects able and willing to comply with a reduced-calorie diet and an increased physical activity program 3. Age \>= to 40 years with established CV disease as defined by one of the following: 1. History of documented MI or ischemic stroke 2. History of peripheral artery disease 3. History of revascularization (coronary, carotid, or peripheral artery) 4. Significant unrevascularized coronary arterial stenosis OR Age \>= to 55 years for women or \>= to 50 years for men who have type 2 diabetes mellitus (T2DM) without established CV disease plus at least one of the following CV risk factors: 1. Hypertension, or currently receiving therapy for documented hypertension 2. Dyslipidemia, or currently taking prescription lipid-lowering therapy for documented dyslipidemia 3. Estimated glomerular filtration rate \>= to 30 to less than equal (\<=) to 60 mililitre per minute per 1.73 meter square (mL/min/1.73 m\^) per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation 4. High high sensitivity C-reactive protein (hsCRP) 5. Urinary albumin-to-creatinine ratio (ACR) \>= 30 ug/mg Subjects with T2DM may have a pre-existing or new diagnosis of T2DM. A new diagnosis of T2DM (ie, discovered at Screening) should be based on the 2013 American Diabetes Association (ADA) guidelines. All T2DM subjects must have an HbA\[1c\] less (\<) than 10% at Screening. If subjects are being treated, or upon diagnosis need to be treated with antidiabetic agents, the T2DM treatment regimen must be stable for at least 3 months prior to randomization.
Exclusion criteria
1. Moderate or greater symptoms of congestive cardiac failure (New York Heart Association \[NYHA\] class III or IV) 2. Known left ventricular (LV) ejection fraction \< than 20% 3. Moderate or greater symptoms of pulmonary hypertension (PH) 4. Known severe valvular disease 5. Moderate renal impairment, severe renal impairment (estimated glomerular filtration rate \< 30 mL/min/1.73 m\^ per the CKD-EPI equation based on ideal body weight), or end stage renal disease (ESRD) 6. Severe hepatic impairment 7. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, and herbal preparations 8. Use of more than one other serotonergic drug 9. Use of drugs known to increase the risk for cardiac valvulopathy within 6 months prior to Screening including, but not limited to: pergolide, ergotamine, methysergide, cabergoline 10. History or evidence of clinically significant disease (e.g., malignancy, cardiac, respiratory, gastrointestinal, renal or psychiatric disease) 11. Use of lorcaserin HCl prior to Screening or hypersensitivity to lorcaserin HCl or any of the excipients 12. Planned bariatric surgery 13. Females must not be breastfeeding or pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to First Occurrence of Major Adverse Cardiovascular Events (MACE) at Interim Analysis | Baseline up to Month 42 | The MACE events involved myocardial infarction (MI), stroke, or cardiovascular (CV) death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Time From Randomization to First Occurrence of MACE+ | Baseline up to end of study (Month 56) | The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or heart failure (HF), or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Randomization to Event of All-cause Mortality | Baseline up to end of study (Month 56) | The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Time From Randomization to Conversion to Normal Glucose Homeostasis in Participants With Prediabetes at Baseline | Baseline up to end of study (Month 56) | Normal glucose homeostasis was defined as HbA1c less than or equal to (\<=) 5.6% and FPG \< 100 mg/dL without any antidiabetic treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Time From Randomization to Conversion to T2DM for Participants Without Any Type of Diabetes at Baseline | Baseline up to end of study (Month 56) | The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline | Baseline, and Month 6 | — |
| Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in All Participants | Baseline up to end of study (Month 56) | New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (albumin-to-creatinine ratio \[ACR\] \>=30mcg/mg and ACR\>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at Baseline developed macroalbuminuria, ACR increased \>=30% from Baseline during treatment), newly developed chronic kidney disease (CKD) (eGFR \>=90 milliliter per minute per 1.73 \[mL/min/1.73\]body surface area (BSA) and without kidney damage at Baseline changed to CKD Stage 1/higher as per National Kidney Foundation \[NKF\] Guidelines \[2002\]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines \[2002\] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times Baseline value and \>=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Time From Randomization to Conversion to Type 2 Diabetes Mellitus (T2DM) for Participants With Prediabetes at Baseline | Baseline up to end of study (Month 56) | Time from randomization to conversion to T2DM was defined as first occurrence of any component of the 2013 American Diabetes Association (ADA) Diagnostic Criteria (ADA, 2013) in participants with prediabetes at baseline. The diagnostic criteria were met if a participant had unequivocal hyperglycemia (random plasma glucose greater than or equal to (\>=) 200 milligram per deciliter (mg/dL) (11.1 millimole per liter \[mmol/L\]) with classic symptoms of hyperglycemia or hyperglycemic crisis) or any of the following criteria were observed and subsequently confirmed on repeat laboratory testing such as: glycosylated hemoglobin (HbA1c) \>=to 6.5%; fasting plasma glucose (FPG) \>=126 mg/dL (7.0 mmol/L); 2-hour plasma glucose \>=200 mg/dL (11.1 mmol/L) by an oral glucose tolerance test (OGTT). The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With T2DM at Baseline | Baseline up to end of study (Month 56) | New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR \>=30 mcg/mg and ACR \>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased \>=30% from baseline during treatment), CKD (eGFR \>=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines \[2002\]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines \[2002\] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and \>=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Time From Randomization to Event of Improvement in Renal Function in Participants With T2DM at Baseline | Baseline up to end of study (Month 56) | Improvement in renal function was defined as first occurrence of regression of albuminuria or regression of CKD. Regression of albuminuria was defined as when participants with macroalbuminuria at baseline developed microalbuminuria or nonalbuminuria (ACR \<30 mcg/mg in spot urine), or participants with microalbuminuria at baseline became nonalbuminuric, and ACR value decreased \>= 30% from previous assessment during treatment. Regression of CKD defined as when participants with CKD Stage 1 or higher at baseline improved to normal or lower stages by NKF guidelines (eGFR \>=90 with albuminuria at baseline improved to eGFR \>=90 without albuminuria, or eGFR 60 to 89 at baseline became eGFR \>=90 with or without albuminuria, or eGFR between 30 to 59 at baseline improved to \>60 mL/min/1.73 BSA) during treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes | Months 6 and 12 | — |
| Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy | Months 6 and 12 | — |
| Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure | Baseline, Month 12 | — |
| Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With Prediabetes at Baseline | Baseline up to end of study (Month 56) | New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR \>=30mcg/mg and ACR \>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased \>=30% from baseline during treatment), CKD (eGFR \>=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines \[2002\]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines \[2002\] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and \>=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
| Time From Randomization to First Occurrence of the Individual Components of MACE+ | Baseline up to end of study (Month 56) | The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or HF, or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. |
Countries
Australia, Canada, Chile, Mexico, New Zealand, Poland, The Bahamas, United States
Participant flow
Recruitment details
Participants took part in the study at investigative sites in the United States, Bahamas, Canada, Mexico, Chile, New Zealand, Poland, and Australia from 24 Jan 2014 to 14 May 2018.
Pre-assignment details
A total of 14,673 participants were screened and enrolled, of which 2673 participants were screen failures and 12,000 were randomized to receive lorcaserin hydrochloride (HCl) or placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants received lorcaserin HCL placebo-matching, tablets, orally, twice daily for up to 52 months. | 6,000 |
| Lorcaserin 10 mg Participants received lorcaserin HCL 10 mg, tablets, orally, twice daily for up to 52 months. | 6,000 |
| Total | 12,000 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative reason | 36 | 28 |
| Overall Study | Lost to Follow-up | 50 | 47 |
| Overall Study | Missing | 14 | 11 |
| Overall Study | Not treated | 6 | 4 |
| Overall Study | Withdrawal by Subject | 142 | 117 |
Baseline characteristics
| Characteristic | Total | Lorcaserin 10 mg | Placebo |
|---|---|---|---|
| Age, Continuous | 63.6 years STANDARD_DEVIATION 8.32 | 63.5 years STANDARD_DEVIATION 8.33 | 63.7 years STANDARD_DEVIATION 8.31 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1038 Participants | 502 Participants | 536 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10962 Participants | 5498 Participants | 5464 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 47 Participants | 26 Participants | 21 Participants |
| Race (NIH/OMB) Asian | 159 Participants | 85 Participants | 74 Participants |
| Race (NIH/OMB) Black or African American | 920 Participants | 454 Participants | 466 Participants |
| Race (NIH/OMB) More than one race | 181 Participants | 96 Participants | 85 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 53 Participants | 30 Participants | 23 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10640 Participants | 5309 Participants | 5331 Participants |
| Sex: Female, Male Female | 4298 Participants | 2112 Participants | 2186 Participants |
| Sex: Female, Male Male | 7702 Participants | 3888 Participants | 3814 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 202 / 5,992 | 219 / 5,995 |
| other Total, other adverse events | 4,788 / 5,992 | 4,946 / 5,995 |
| serious Total, serious adverse events | 2,021 / 5,992 | 1,974 / 5,995 |
Outcome results
Primary
Time From Randomization to First Occurrence of MACE+
The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or heart failure (HF), or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The total time analysis set used the ITT set, events were counted that occurred while participants were on and off treatment. Participants with no events were censored at their last study contact or at the visit following Sponsor Notification of Study Completion, whichever occurred first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to First Occurrence of MACE+ | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of MACE+ | NA days |
p-value: 0.546495% CI: [0.873, 1.074]Primary Analytic Method
Primary
Time From Randomization to First Occurrence of Major Adverse Cardiovascular Events (MACE) at Interim Analysis
The MACE events involved myocardial infarction (MI), stroke, or cardiovascular (CV) death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to Month 42
Population: The total time analysis set using the intent-to-treat (ITT) set, events were counted that occurred while participants were on and off treatment. Participants with no events were censored at their last study contact or at the visit following sponsor notification of study completion, whichever occurred first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to First Occurrence of Major Adverse Cardiovascular Events (MACE) at Interim Analysis | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of Major Adverse Cardiovascular Events (MACE) at Interim Analysis | NA days |
p-value: 0.000197.5% CI: [0.842, 1.198]Primary Analytic Method
Secondary
Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure
Time frame: Baseline, Month 12
Population: The ITT analysis set-participants in ECHO substudy included all randomized participants regardless of whether they took study drug or not. The ITT analysis set-participants in the ECHO substudy, where data was available at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure | Baseline | 26.4354 Millimeter of mercury (mmHg) | Standard Deviation 7.66312 |
| Placebo | Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure | Change at Month 12 | -0.6418 Millimeter of mercury (mmHg) | Standard Deviation 6.81716 |
| Lorcaserin 10 mg | Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure | Baseline | 26.2029 Millimeter of mercury (mmHg) | Standard Deviation 7.54123 |
| Lorcaserin 10 mg | Change From Baseline in Echocardiographically-Determined Pulmonary Arterial Systolic Pressure | Change at Month 12 | -0.8223 Millimeter of mercury (mmHg) | Standard Deviation 7.2377 |
p-value: 0.297695% CI: [-1.2908, -0.5163]Mixed-effects model
Secondary
Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline
Time frame: Baseline, and Month 6
Population: The T2DM analysis set included all participants in the ITT set who had T2DM at baseline. The T2DM analysis set where data was available at specified time points.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline | Baseline | 6.99 percentage of HbA1c | Standard Deviation 1.066 |
| Placebo | Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline | Change at Month 6 | 0.06 percentage of HbA1c | Standard Deviation 0.777 |
| Lorcaserin 10 mg | Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline | Change at Month 6 | -0.33 percentage of HbA1c | Standard Deviation 0.785 |
| Lorcaserin 10 mg | Change From Baseline in HbA1c at Month 6 in Participants With T2DM at Baseline | Baseline | 7.01 percentage of HbA1c | Standard Deviation 1.082 |
p-value: <0.000195% CI: [-0.43, -0.35]ANCOVA
Secondary
Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes
Time frame: Months 6 and 12
Population: The FDA-defined valvulopathy analysis set included all participants in the ITT set without FDA-defined valvulopathy at baseline. The FDA-defined valvulopathy analysis set where data was available at specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes | Month 6 | 1.4 percentage of participants |
| Placebo | Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes | Month 12 | 1.5 percentage of participants |
| Lorcaserin 10 mg | Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes | Month 6 | 2.1 percentage of participants |
| Lorcaserin 10 mg | Percentage of Participants Who Met FDA-Defined Valvulopathy in Echocardiographically Determined Heart Valve Changes | Month 12 | 1.8 percentage of participants |
p-value: 0.501595% CI: [0.69, 2.11]Regression, Logistic
Secondary
Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy
Time frame: Months 6 and 12
Population: The ITT analysis set in participants with FDA-defined valvulopathy at baseline was used. The ITT analysis set in participants with FDA-defined valvulopathy at baseline where data was available at specified time point.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy | Month 6 | 2.1 percentage of participants |
| Placebo | Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy | Month 12 | 1.7 percentage of participants |
| Lorcaserin 10 mg | Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy | Month 6 | 3.5 percentage of participants |
| Lorcaserin 10 mg | Percentage of Participants With FDA-Defined Valvulopathy at Baseline Who Demonstrated Worsened FDA-Defined Valvulopathy | Month 12 | 2.1 percentage of participants |
p-value: 0.724995% CI: [0.29, 5.98]Regression, Logistic
Secondary
Time From Randomization to Conversion to Normal Glucose Homeostasis in Participants With Prediabetes at Baseline
Normal glucose homeostasis was defined as HbA1c less than or equal to (\<=) 5.6% and FPG \< 100 mg/dL without any antidiabetic treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The prediabetes analysis set included all participants in the ITT set without a history of any type of diabetes and who were prediabetic at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Conversion to Normal Glucose Homeostasis in Participants With Prediabetes at Baseline | NA days |
| Lorcaserin 10 mg | Time From Randomization to Conversion to Normal Glucose Homeostasis in Participants With Prediabetes at Baseline | NA days |
p-value: 0.18195% CI: [0.947, 1.333]Primary Analytic Method
Secondary
Time From Randomization to Conversion to T2DM for Participants Without Any Type of Diabetes at Baseline
The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The nondiabetes analysis set included all participants in the ITT set without a history of any type of diabetes at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Conversion to T2DM for Participants Without Any Type of Diabetes at Baseline | NA days |
| Lorcaserin 10 mg | Time From Randomization to Conversion to T2DM for Participants Without Any Type of Diabetes at Baseline | NA days |
p-value: 0.011695% CI: [0.633, 0.944]Primary Analytic Method
Secondary
Time From Randomization to Conversion to Type 2 Diabetes Mellitus (T2DM) for Participants With Prediabetes at Baseline
Time from randomization to conversion to T2DM was defined as first occurrence of any component of the 2013 American Diabetes Association (ADA) Diagnostic Criteria (ADA, 2013) in participants with prediabetes at baseline. The diagnostic criteria were met if a participant had unequivocal hyperglycemia (random plasma glucose greater than or equal to (\>=) 200 milligram per deciliter (mg/dL) (11.1 millimole per liter \[mmol/L\]) with classic symptoms of hyperglycemia or hyperglycemic crisis) or any of the following criteria were observed and subsequently confirmed on repeat laboratory testing such as: glycosylated hemoglobin (HbA1c) \>=to 6.5%; fasting plasma glucose (FPG) \>=126 mg/dL (7.0 mmol/L); 2-hour plasma glucose \>=200 mg/dL (11.1 mmol/L) by an oral glucose tolerance test (OGTT). The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: Prediabetes and total time analysis set used ITT set: without a history of any type of diabetes and who were prediabetic at baseline; events were counted that occurred while participants were on, off treatment; participants with no events were censored at last study contact/at visit after notification of study completion, whichever occurred first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Conversion to Type 2 Diabetes Mellitus (T2DM) for Participants With Prediabetes at Baseline | NA days |
| Lorcaserin 10 mg | Time From Randomization to Conversion to Type 2 Diabetes Mellitus (T2DM) for Participants With Prediabetes at Baseline | NA days |
p-value: 0.03895% CI: [0.659, 0.988]Primary Analytic Method
Secondary
Time From Randomization to Event of All-cause Mortality
The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The total time analysis set used the ITT set, events were counted that occurred while participants were on and off treatment. Participants with no events were censored at their last study contact or at the visit following Sponsor Notification of Study Completion, whichever occurred first.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Event of All-cause Mortality | NA days |
| Lorcaserin 10 mg | Time From Randomization to Event of All-cause Mortality | NA days |
p-value: 0.421295% CI: [0.893, 1.31]Primary Analytic Method
Secondary
Time From Randomization to Event of Improvement in Renal Function in Participants With T2DM at Baseline
Improvement in renal function was defined as first occurrence of regression of albuminuria or regression of CKD. Regression of albuminuria was defined as when participants with macroalbuminuria at baseline developed microalbuminuria or nonalbuminuria (ACR \<30 mcg/mg in spot urine), or participants with microalbuminuria at baseline became nonalbuminuric, and ACR value decreased \>= 30% from previous assessment during treatment. Regression of CKD defined as when participants with CKD Stage 1 or higher at baseline improved to normal or lower stages by NKF guidelines (eGFR \>=90 with albuminuria at baseline improved to eGFR \>=90 without albuminuria, or eGFR 60 to 89 at baseline became eGFR \>=90 with or without albuminuria, or eGFR between 30 to 59 at baseline improved to \>60 mL/min/1.73 BSA) during treatment. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The T2DM analysis set included all participants in the ITT set who had T2DM at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Event of Improvement in Renal Function in Participants With T2DM at Baseline | NA days |
| Lorcaserin 10 mg | Time From Randomization to Event of Improvement in Renal Function in Participants With T2DM at Baseline | NA days |
p-value: 0.029795% CI: [1.017, 1.375]Primary Analytic Method
Secondary
Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in All Participants
New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (albumin-to-creatinine ratio \[ACR\] \>=30mcg/mg and ACR\>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at Baseline developed macroalbuminuria, ACR increased \>=30% from Baseline during treatment), newly developed chronic kidney disease (CKD) (eGFR \>=90 milliliter per minute per 1.73 \[mL/min/1.73\]body surface area (BSA) and without kidney damage at Baseline changed to CKD Stage 1/higher as per National Kidney Foundation \[NKF\] Guidelines \[2002\]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines \[2002\] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times Baseline value and \>=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The ITT set included all randomized participants regardless of whether they took study drug or not. This set was the same as the full analysis set.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in All Participants | NA days |
| Lorcaserin 10 mg | Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in All Participants | NA days |
p-value: 0.005495% CI: [0.787, 0.959]Primary Analytic Method
Secondary
Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With Prediabetes at Baseline
New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR \>=30mcg/mg and ACR \>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased \>=30% from baseline during treatment), CKD (eGFR \>=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines \[2002\]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines \[2002\] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and \>=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The prediabetes analysis set included all participants in the ITT set without a history of any type of diabetes and who were prediabetic at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With Prediabetes at Baseline | NA days |
| Lorcaserin 10 mg | Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With Prediabetes at Baseline | NA days |
p-value: 0.366195% CI: [0.727, 1.125]Primary Analytic Method
Secondary
Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With T2DM at Baseline
New onset/worsening of existing renal impairment was first occurrence of any events: microalbuminuria and macroalbuminuria (ACR \>=30 mcg/mg and ACR \>=300 mcg/mg in spot urine), worsening albuminuria (microalbuminuria at baseline developed macroalbuminuria, ACR increased \>=30% from baseline during treatment), CKD (eGFR \>=90 mL/min/1.73 BSA and without kidney damage at baseline changed to CKD Stage 1/higher as per NKF Guidelines \[2002\]) or worsening of CKD (CKD Stage 1/higher as per NKF Guidelines \[2002\] worsened to higher CKD stages during treatment), or doubling of serum creatinine (creatinine value at least 2 times baseline value and \>=1.5 mg/dL during treatment.), or any of the following: end-stage renal disease, renal transplant, renal death. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The T2DM analysis set included all participants in the ITT set who had T2DM at baseline.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With T2DM at Baseline | NA days |
| Lorcaserin 10 mg | Time From Randomization to Event of New Onset Renal Impairment or Worsening Existing Renal Impairment in Participants With T2DM at Baseline | NA days |
p-value: 0.008295% CI: [0.762, 0.96]Primary Analytic Method
Secondary
Time From Randomization to First Occurrence of the Individual Components of MACE+
The MACE+ events involved MI, stroke, or CV death or hospitalization for unstable angina or HF, or any coronary revascularization. The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula.
Time frame: Baseline up to end of study (Month 56)
Population: The total time analysis set used the ITT set, events counted occurred while participants were on and off treatment. Participants with no events were censored at last study contact or at the visit following Sponsor Notification of Study Completion, whichever first.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Placebo | Time From Randomization to First Occurrence of the Individual Components of MACE+ | Stroke | NA days |
| Placebo | Time From Randomization to First Occurrence of the Individual Components of MACE+ | CV death | NA days |
| Placebo | Time From Randomization to First Occurrence of the Individual Components of MACE+ | HF | NA days |
| Placebo | Time From Randomization to First Occurrence of the Individual Components of MACE+ | Hospitalization for unstable angina | NA days |
| Placebo | Time From Randomization to First Occurrence of the Individual Components of MACE+ | Coronary revascularization | NA days |
| Placebo | Time From Randomization to First Occurrence of the Individual Components of MACE+ | MI | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of the Individual Components of MACE+ | Coronary revascularization | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of the Individual Components of MACE+ | MI | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of the Individual Components of MACE+ | Stroke | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of the Individual Components of MACE+ | Hospitalization for unstable angina | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of the Individual Components of MACE+ | HF | NA days |
| Lorcaserin 10 mg | Time From Randomization to First Occurrence of the Individual Components of MACE+ | CV death | NA days |
p-value: 0.000197.5% CI: [0.824, 1.191]Primary Analytic Method
p-value: 0.000597.5% CI: [0.639, 1.145]Primary Analytic Method
p-value: 0.026297.5% CI: [0.778, 1.404]Primary Analytic Method
p-value: 0.324395% CI: [0.861, 1.571]Primary Analytic Method
p-value: 0.675895% CI: [0.757, 1.197]Primary Analytic Method
p-value: 0.781795% CI: [0.856, 1.125]Primary Analytic Method