| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Obese and overweight patients with cardiovascular (CV) disease and/or multiple CV risk factors |
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| E.1.1.1 | Medical condition in easily understood language |
| Obese and overweight patients with cardiovascular disease and/or at higher risk of developing this diesease |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10029883 |
| E.1.2 | Term | Obesity |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10033307 |
| E.1.2 | Term | Overweight |
| E.1.2 | System Organ Class | 10027433 - Metabolism and nutrition disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
-To demonstrate that, in obese and overweight subjects with cardiovascular (CV) disease and/or multiple CV risk factors, lorcaserin HCl 10 mg administered twice daily (BID) does not increase the incidence of major adverse cardiovascular events (MACE = myocardial infarction [MI], or stroke, or CV death) compared to placebo, with a noninferiority margin for the hazard ratio of 1.4
-To demonstrate that, in obese and overweight subjects with CV disease and/or multiple CV risk factors, lorcaserin HCl 10 mg BID reduces the incidence of MACE+ (MACE or hospitalization for unstable angina or heart failure (HF), or any coronary revascularization) compared to placebo |
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| E.2.2 | Secondary objectives of the trial |
Key secondary objective: To confirm that, in subjects with prediabetes at Baseline based on the 2013 ADA guideline, lorcaserin HCl 10 mg BID reduces the incidence of conversion to type 2 diabetes mellitus (T2DM) compared to placebo.
For other Secondary Objectives: MACE and MACE+, Prediabetes, Renal, Safety and exploratory related please refer to the protocol amendment 2 pages 3 and 4. |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
For correction of the previous Sub-studies included, the correct Sub-Study is:
Echo Sub Study
Echocardiograms will be obtained on a subset of approximately 3600 subjects at selected sites as designated on the Schedule of
Procedures/Assessments (Table 4Table 4). Acquisition of new ECHO data in all subjects will cease when at least 1000 subjects have completed the Month 36 echocardiographic assessment.
In this study, echocardiographic images will be acquired in a subset of subjects to establish the cardiac safety of lorcaserin HCl. Standardized training will be provided for all echocardiographers, and will implement centralized procedures for collecting, analyzing, and reporting echocardiographic data. All echocardiograms will be over-read by 2 blinded central readers (primary and secondary). Baseline echocardiograms will be performed in between Visits 1 and 2, after the results of screening assessments have been obtained but prior to randomization, and subject eligibility is confirmed. |
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| E.3 | Principal inclusion criteria |
1. Body mass index (BMI) ≥27kg/m2
2. Subjects able and willing to comply with a reduced-calorie diet and an increased physical activity program
3. Age ≥40 years with established CV disease as defined by one of the following:
a. History of documented MI or ischemic stroke >1 month before randomization
b. History of peripheral artery disease as manifested by symptomatic claudication with an ankle-brachial pressure index of <0.85
c. History of revascularization (coronary, carotid, or peripheral artery)
d. Significant unrevascularized coronary arterial stenosis defined as ≥50% in two or more coronary arteries
OR
Age ≥55 years for women or ≥50 years for men who have T2DM without established CV disease plus at least one of the following CV risk factors:
a. Hypertension, defined as systolic blood pressure (SBP) >140 or diastolic blood pressure (DBP) >90, or currently receiving therapy for documented hypertension
b. Dyslipidemia, defined as low density lipoprotein-cholesterol (LDL-C) >130 mg/dL, or high density lipoprotein-cholesterol (HDL-C) <40 mg/dL, or currently taking prescription lipid-lowering therapy for documented dyslipidemia
c. c. Estimated glomerular filtration rate (eGFR) ≥30 to ≤60 mL/min/1.73 m2 per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
d. High sensitivity C-reactive protein (hsCRP) > 3 mg/L detected by the central laboratory in the absence of known acute or chronic inflammatory conditions (eg, infection, rheumatologic disease)
e. Urinary albumin-to-creatinine ratio (ACR) ≥30 μg/mg in spot urine
Subjects with T2DM may have a pre-existing or new diagnosis of T2DM. Subjects with pre-existing T2DM should have prior documentation consistent with the diagnosis and/or be on active pharmacotherapy for T2DM. A new diagnosis of T2DM (ie, discovered at Screening) should be based on the 2013 American Diabetes Association (ADA) guidelines. The diagnostic criteria are met if a subject has unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis) OR any of the following criteria are observed and confirmed:
o HbA1c ≥6.5%
o fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)
o 2-hour plasma glucose ≥200 mg/dL (11.1mmol/L) by an oral glucose tolerance test (OGTT)
All T2DM subjects must have an HbA1c <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. A single rescreen is allowed following stabilization. Stable control refers to minimal dose changes to existing medications for glycemic control and no medications being initiated for glycemic control in the 3 months before randomization. Minimal changes are defined as a change in insulin dose < 10% of daily dose, without any change in dose frequency, no add-on or discontinuation of other antidiabetic agents, and the subject has not been hospitalized due to hypo- or hyperglycemic events.
4. Provide written informed consent
5. Willing and able to comply with all aspects of the protocol |
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| E.4 | Principal exclusion criteria |
1.Current moderate or greater symptoms of congestive cardiac failure (New York Heart Association [NYHA] class III or IV)
2. Known left ventricular (LV) ejection fraction <20%
3. Current moderate or greater symptoms of pulmonary hypertension (PH) (World Health Organization [WHO] functional Class III and IV)
4. Known severe valvular disease defined by clinical diagnosis and/or most recent echocardiography. History of severe valvular disease is allowed if it has been corrected by valve replacement or repair
5. Severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m2 per the CKD-EPI equation based on ideal body weight), or end-stage renal disease (ESRD)
6. Severe hepatic impairment (Child-Pugh score 10 to 15)
7. Use of other products intended for weight loss including prescription drugs, over-the-counter (OTC) drugs, and herbal preparations within 1 month prior to Screening
8. Use of more than 1 serotonergic drug, within 1 month before Screening, or during the screening window, but not limited to:
a. selective serotonin reuptake inhibitors (SSRIs)
b. serotonin norepinephrine reuptake inhibitors (SNRIs)
c. tricyclic antidepressants (TCAs)
d. bupropion
e. triptans
f. St. John’s Wort and tryptophan
g. Monoamine oxidase inhibitors [MAOIs]
h.linezolid
i.dextromethorphan
j.lithium
k.tramadol
l.antipsychotics or other dopamine antagonists
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 or cabergoline
10. History or evidence of clinically significant disease (e.g., malignancy, cardiac, respiratory, gastrointestinal, renal, or psychiatric disease) that in the opinion of the investigator(s) could affect the subject’s safety, interfere with the study assessments, or result in a life expectancy of less than 1 year
11. Use of lorcaserin HCl within 6 months prior to Screening or hypersensitivity to lorcaserin HCl or any of the excipients
12. History of alcohol dependence or abuse within 2 years prior to Visit 1 (Screening)
13. Recreational drug use within the 2 years prior to Visit 1 (Screening)
14. Currently enrolled in another clinical trial or used any investigational drug or device within 30 days preceding informed consent (the exclusion criterion will not apply if the subjects are no longer in follow- up and have discontinued use of an investigational drug or device for at least 30 days. It will not apply if subjects are enrolled in registries or observational studies)
15. Planned bariatric surgery or bariatric surgery performed within 1 year before screening
16. Subjects considered by the investigator to have insufficient motivation to remain in a long-term clinical trial or who are considered likely to drop out for nonmedical reasons, e.g., social issues
17. Females must not be breastfeeding or pregnant at Visit 1 (Screening) or Visit 2 (Baseline) (as documented by a negative beta-human chorionic gonadotropin [β-hCG]). A separate Baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
18. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy or bilateral oophorectomy, all with surgery at least 1 month before dosing). Females of childbearing potential are defined as those who:
•Had unprotected sexual intercourse within 30 days before study entry
•Do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 28 days after study drug discontinuation.
•Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexual activity during the study period and for 28 days after study drug discontinuation.
•Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study and for 28 days after study drug discontinuation |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
-Time from randomization to first occurrence of MACE (first occurrence of any of the following events: MI, stroke, or CV death)
-Time from randomization to first occurrence of MACE+ (first occurrence of any of the following events: MACE or hospitalization for unstable angina or HF, or any coronary revascularization) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-Potential MACE/MACE+ events will be recorded throughout the study
|
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoint:
Time from randomization to conversion to T2DM, defined as first occurrence of any component of the 2013 ADA diagnostic criteria in subjects with prediabetes at Baseline. The diagnostic criteria are met if a subject has unequivocal hyperglycemia (random plasma glucose ≥200 mg/dL (11.1 mmol/L) with classic symptoms of hyperglycemia or hyperglycemic crisis) OR any of the following criteria are observed and subsequently confirmed on repeat laboratory testing
o HbA1c ≥6.5%
o FPG≥126 mg/dL (7.0 mmol/L)
o 2-hour plasma glucose ≥200mg/dL (11.1 mmol/L) by an OGTT
Investigators should make every effort to obtain central lab confirmatory testing no later than 6 weeks after meeting any of the above criteria. Abnormalities of any 1 of the above 3 criteria on repeat testing constitutes diagnostic confirmation of diabetes. Subjects who have been started on anti-diabetic medications following abnormalities in preliminary testing do not require confirmatory testing.
Other secondary endpoints:
Other secondary endpoints are detailed on pages 12, 13 and 14 of the protocol amendment 2. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Potential MACE/MACE+ events recorded throughout the study
-HbA1c, random plasma glucose and fasting plasma glucose will be measured in blood samples collected at Screening, Baseline, and specified timepoints throughout the study
-Glycemic and end-organ benefits in subjects with T2DM at Baseline: HbA1c, random plasma glucose and fasting plasma glucose (FPG) will be measured in blood samples collected at Screening, Baseline, and specified timepoints throughout the study
-Cardiac valve function and pulmonary arterial pressure: Baseline and 1 year
- Exploratory Endpoints: cv risk factors, eGFR,ACR and LFTs baseline, 1 year and yearly thereafter; OAD use at baseline and 6 months;FDAdefined valvulopathy and estimated pulmonary artery systolic pressure baseline, 2 years and yearly thereafter |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 35 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 145 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Bahamas |
| Canada |
| Chile |
| Mexico |
| New Zealand |
| Poland |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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