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 (CAMELLIA-TIMI)

Study Description

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Brief Summary:

This is a multicenter, randomized, double-blind, placebo-controlled, parallel-group study in overweight and obese subjects with CV disease and/or multiple CV risk factors.

Condition or disease	Intervention/treatment	Phase
Cardiovascular Disease; High Cardiovascular Risk; Obesity; Overweight; Type 2 Diabetes	Drug: APD356-Lorcaserin hydrochloride; Drug: Placebo	Phase 4

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	12000 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Double (Participant, Investigator)
Primary Purpose:	Treatment
Official Title:	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
Actual Study Start Date :	January 2014
Estimated Primary Completion Date :	September 2018
Estimated Study Completion Date :	November 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: APD356 10 mg; APD356 10 mg twice daily	Drug: APD356-Lorcaserin hydrochloride; APD356 10 mg twice daily
Placebo Comparator: Placebo; Placebo twice daily	Drug: Placebo; Placebo twice daily

Outcome Measures

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Primary Outcome Measures :

1. Time from randomization to first occurrence of Major Adverse Cardiovascular Events (MACE) [ Time Frame: Up to 5 years ]
   MACE events include: myocardial infarction, stroke and cardiovascular (CV) death
2. Time from randomization to conversion to type 2 diabetes mellitus (T2DM) for subjects without any type of diabetes at Baseline [ Time Frame: Baseline, and specified timepoints up to 5 years ]
3. Time from randomization to first occurrence of MACE+ [ Time Frame: Up to 5 years ]
   MACE+ events include: myocardial infarction, stroke, CV death, and hospitalization due to unstable angina, heart failure, or any coronary revascularization

Secondary Outcome Measures :

1. Time from randomization to event of each component of MACE+ [ Time Frame: Up to 5 years ]
2. Time from randomization to event of all-cause mortality [ Time Frame: Up to 5 years ]
3. Time from randomization to event of new onset renal impairment or worsening existing renal impairment in subjects with T2DM at Baseline [ Time Frame: Up to 5 years ]
   New onset renal impairment or worsening existing renal impairment include the first occurrence of microalbuminuria, macroalbuminuria, worsening of albuminuria, newly developed CKD, or worsening of CKD, doubling of serum creatinine, or any of the following: ESRD, renal transplant, and renal death.
4. Time from randomization to event of improvement in renal function [ Time Frame: Up to 5 years ]
5. Change from Baseline in HbA[1c] at 6 months in subjects with T2DM at Baseline [ Time Frame: Baseline and 6 months ]
6. The proportion of subjects who meet FDA-defined valvulopathy in echocardiographically determined heart valve changes [ Time Frame: Baseline and 1 year ]
   Comparison between lorcaserin HCl and placebo will be made at 1 year.
7. The percent change from Baseline in echocardiographically-determined pulmonary arterial systolic pressure [ Time Frame: Baseline and 1 year ]
   Comparison between lorcaserin HCl and placebo will be made at 1 year.
8. Time to conversion to normal glucose homeostasis [ Time Frame: Baseline and 1 year ]

Eligibility Criteria

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Ages Eligible for Study:	40 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria

1. BMI greater than or equal to 27 kg/m^2
2. Subjects able and willing to comply with a reduced-calorie diet and an increased physical activity program

3. Age greater than or equal 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 greater than or equal to 55 years for women or greater than or equal to 50 years for men who have 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. Calculated creatinine clearance greater than or equal to 30 to less than or equal to 60 mL/min per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
4. High hsCRP
5. Urinary albumin-to-creatinine ratio (ACR) greater than or equal to 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 less than 20%
3. Moderate or greater symptoms of pulmonary hypertension (PH)
4. Known severe valvular disease Moderate renal impairment, severe renal impairment, or end stage renal disease (ESRD) (calculated creatinine clearance less than 30 mL/min per the CKD-EPI equation based on ideal body weight)
5. Severe hepatic impairment
6. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, and herbal preparations
7. Use of more than one other serotonergic drug
8. Use of drugs known to increase the risk for cardiac valvulopathy prior to Screening including, but not limited to: cyproheptadine, amoxapine, TCAs, mirtazapine, pergolide, ergotamine, methysergide, cabergoline
9. History or evidence of clinically significant disease (e.g., malignancy, cardiac, respiratory, gastrointestinal, renal or psychiatric disease)
10. Use of lorcaserin HCl prior to Screening or hypersensitivity to lorcaserin HCl or any of the excipients
11. Planned bariatric surgery
12. Females must not be breastfeeding or pregnant

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

  Show 484 Study Locations

Sponsors and Collaborators

Eisai Inc.

Thrombolysis In Myocardial Infarction (TIMI) Academic Research Organization

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Eisai Inc.
ClinicalTrials.gov Identifier:	NCT02019264 History of Changes
Other Study ID Numbers:	APD356-G000-401; 2013-000324-34 ( EudraCT Number )
First Posted:	December 24, 2013
Last Update Posted:	November 6, 2017
Last Verified:	November 2017

Studies a U.S. FDA-regulated Drug Product:		Yes

Keywords provided by Eisai Inc.:

Diabetes; Cardiovascular Disease; Multiple Cardiovascular Risk Factors; Obesity	Overweight; MACE; Conversion to Diabetes

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Overweight; Glucose Metabolism Disorders	Metabolic Diseases; Endocrine System Diseases; Body Weight; Signs and Symptoms