A Study to Evaluate the Effect of Long-term Treatment With BELVIQ (Lorcaserin HCl) on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, Double-blind, Placebo-controlled, Parallel-group Study to Evaluate the Effect of Long-term Treatment With BELVIQ (Lorcaserin HCl) on the Incidence of Major Adverse Cardiovascular Events and Conversion to Type 2 Diabetes Mellitus in Obese and Overweight Subjects With Cardiovascular Disease or Multiple Cardiovascular Risk Factors

Conditions
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Cardiovascular Disease, High Cardiovascular Risk, Obesity, Overweight, Type 2 Diabetes

Intervention / Treatment
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* Drug: Lorcaserin hydrochloride
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria BMI greater than or equal (>=) to 27 kilogram per meter square (kg/m^2) Subjects able and willing to comply with a reduced-calorie diet and an increased physical activity program Age >= to 40 years with established CV disease as defined by one of the following: History of documented MI or ischemic stroke History of peripheral artery disease History of revascularization (coronary, carotid, or peripheral artery) 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: Hypertension, or currently receiving therapy for documented hypertension Dyslipidemia, or currently taking prescription lipid-lowering therapy for documented dyslipidemia 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 High high sensitivity C-reactive protein (hsCRP) 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 Moderate or greater symptoms of congestive cardiac failure (New York Heart Association [NYHA] class III or IV) Known left ventricular (LV) ejection fraction < than 20% Moderate or greater symptoms of pulmonary hypertension (PH) Known severe valvular disease 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) Severe hepatic impairment Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, and herbal preparations Use of more than one other serotonergic drug 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 History or evidence of clinically significant disease (e.g., malignancy, cardiac, respiratory, gastrointestinal, renal or psychiatric disease) Use of lorcaserin HCl prior to Screening or hypersensitivity to lorcaserin HCl or any of the excipients Planned bariatric surgery Females must not be breastfeeding or pregnant

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lorcaserin hydrochloride (HCL)10 mg<br>APD356 10 mg twice daily | Drug: Lorcaserin hydrochloride<br>* APD356 10 mg twice daily<br>* Other names: BELVIQ;|
| Placebo Comparator: Placebo<br>Placebo twice daily | Drug: Placebo<br>* Placebo twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to Month 42 | 
| 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. | Baseline up to end of study (Month 56) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline up to end of study (Month 56) | 
| 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. | Baseline up to end of study (Month 56) | 
| Time From Randomization to Event of All-cause Mortality | The outcome data was assessed using Kaplan-Meier estimate and Greenwood Formula. | Baseline up to end of study (Month 56) | 
| 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. | Baseline up to end of study (Month 56) | 
| 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. | Baseline up to end of study (Month 56) | 
| 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 | 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. | Baseline up to end of study (Month 56) | 
| 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. | Baseline up to end of study (Month 56) | 
| 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. | Baseline up to end of study (Month 56) | 
| 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. | Baseline up to end of study (Month 56) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Cardiovascular Disease, Multiple Cardiovascular Risk Factors, Obesity, Overweight, MACE, Conversion to Diabetes