E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cardiovascular Disease in overweight and obese subjects |
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E.1.1.1 | Medical condition in easily understood language |
Health of an overweight or obese subject's heart and/or vascular system (blood vessels) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10007648 |
E.1.2 | Term | Cardiovascular disease, unspecified |
E.1.2 | System Organ Class | 100000004849 |
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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 |
The primary objective of the study is to evaluate the effect of long-term treatment with Qsymia on the incidence of nonfatal myocardial infarction (MI), nonfatal stroke, or cardiovascular death in overweight and obese subjects with documented cardiovascular disease (CVD). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are the following:
• To evaluate the effect of long-term treatment with Qsymia on other cardiovascular morbidity and mortality endpoints in overweight and obese subjects with CVD; and
• To evaluate the effect of long-term treatment with Qsymia on body weight and various cardiovascular and metabolic markers in comparison to placebo in overweight and obese subjects with CVD. |
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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 |
Dual-energy X-ray Absorptiometry (DXA) Sub-study
A bone health sub-study will be conducted at selected sites in the USA in approximately 150 subjects (pre-dominantly women) per treatment arm to assess the long-term effect of Qsymia administration on bone health. DXA scans of the hip and lumbar spine will be performed at or around Month 0, Month 12, and every 12 months thereafter until the End of Study or Early Termination. |
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E.3 | Principal inclusion criteria |
1. Age ≥45 years;
2. BMI ≥27 kg/m2 (≥24 kg/m2 for Asians);
3. Waist circumference ≥102 cm (40 in) for men or ≥88 cm (35 in) for women (≥90 cm [35 in] and ≥80 cm [31 in] for Asian men and women, respectively);
4. Stable body weight during the previous 2 months (±3% self reported);
5. Be classified into one of the following three risk categories: Stratum A (High stroke risk), Stratum B (High CVD risk) or Stratum C (Intermediate CVD risk) - Please see protocol for details.
6. Women of childbearing potential must be using adequate contraception, defined as a double-barrier method, stable hormonal contraception plus single barrier, or previously documented tubal ligation. Women are considered to be of childbearing potential unless they are ≥50 years of age with spontaneous amenorrhea for at least 12 months or have had a hysterectomy and/or bilateral oophorectomy;
7. Ability to understand the study procedures and provide written informed consent; and
8. Willingness and ability to comply with scheduled study visits and study procedures. |
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E.4 | Principal exclusion criteria |
To be eligible for enrollment into this study, subjects must not meet any of the following criteria:
1. Concurrent use of glucagon-like peptide-1 (GLP-1) analogs and all forms of insulin;
2. Uncontrolled hypertension (SBP >180 mmHg or DBP >100 mmHg) at the time of randomization. Subjects with uncontrolled hypertension may be re-screened once blood pressure has been controlled and the antihypertensive regimen has been stabilized for at least 2 months prior to randomization;
3. Congestive Heart Failure (CHF) accompanied by hypotension; New York Heart Association (NYHA) CHF Class III or greater;
4. Condition or disease interfering with metabolism, such as untreated hypothyroidism, Cushing’s syndrome, or type 1 diabetes;
5. History or presence of significant eating disorder, such as binge eating, bulimia, or anorexia nervosa;
6. Pheochromocytoma or carcinoid syndrome;
7. Renal dialysis required or severe renal impairment, defined as creatinine clearance <30 mL/min;
8. History or presence of potentially life-threatening cardiac arrhythmia;
9. History of nephrolithiasis;
10. Severe hepatic impairment (i.e., Child-Pugh class C);
11. Prior or planned surgery for weight loss, including cosmetic liposuction;
12. Unwillingness or inability to participate in the diet or physical activity program;
13. Clinically significant thyroid dysfunction as evidenced by signs or symptoms of hypothyroidism or use of thyroid hormone treatment that has not been stable for at least 3 months prior to randomization;
14. Use of chronic systemic glucocorticoid therapy or any other steroid hormone therapy that has not been stable for at least 3 months prior to randomization;
15. Prior suicide attempt or any current active suicidal ideation (i.e., suicidal ideation with some intent to act, without specific plan or active suicidal ideation with specific plan and intent);
16. History of major depressive disorder within the last 2 years;
17. History of bipolar disorder, obsessive compulsive disorder, borderline personality disorder, psychotic depression, schizophrenia, schizoaffective disorder, or any other psychotic disorder;
18. Current abuse of or dependence on any drug (other than nicotine), including alcohol;
19. History of or current treatment for seizures;
20. History of any malignancy within the past 5 years other than basal or squamous cell carcinomas of the skin or cervical carcinomas following curative surgical resection;
21. Planned revascularization or angiography during the study;
22. History of angle-closure glaucoma or any past or present use of medications to treat increased intraocular pressure;
23. Women who are pregnant, breastfeeding, or intend to become pregnant during the study;
24. Any of the following abnormal laboratory values (tests may be repeated per discretion of the investigator):
a. Bicarbonate <20 mEq/L;
b. Potassium <3.5 mEq/L;
c. Triglycerides >500 mg/dL;
d. HbA1c >10.0%; or
e. Alanine transaminase (ALT) or aspartate transaminase (AST) >3 × upper limit of normal (ULN);
25. History of a positive screening test for hepatitis B surface antigen, hepatitis C virus, or human immunodeficiency virus;
26. Treatment with phentermine, topiramate, lorcaserin, or any other over-the-counter (OTC) or prescription weight loss drug within 3 months of screening;
27. Known allergy or hypersensitivity to phentermine or topiramate or history of anaphylaxis to any drug;
28. Use of any investigational medication or device for any indication or participation in a clinical study within 30 days prior to screening; or
29. Any medical or surgical condition which, in the opinion of the investigator, would impair the ability of the subject to complete the study, compromise the quality of study data, or pose an unacceptable risk to the safety of the subject.
Subjects with type 2 diabetes, hypertension, and/or dyslipidemia must be on stable therapy for at least 2 months prior to randomization. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the time to the first occurrence of a primary outcome event: nonfatal MI, nonfatal stroke, or cardiovascular death. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoint for evaluation of primary endpoint is the time of the the first occurrence of a primary outcome event: nonfatal MI, nonfatal stroke, or cardiovascular death. |
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E.5.2 | Secondary end point(s) |
• Time to the first occurrence of fatal or nonfatal stroke;
• Time to the first occurrence of cardiovascular death;
• Time to the first occurrence of all-cause mortality; and
• Time to the first occurrence of either cardiovascular death, MI, stroke, hospitalization for unstable angina, urgent revascularization, or hospitalization for HF. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoint for evaluation of the secondary endpoint is the time of the first occurrence of the events. |
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
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) | No |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 140 |
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 |
Chile |
China |
Colombia |
Czech Republic |
Germany |
Hungary |
Korea, Republic of |
Israel |
Mexico |
Philippines |
Poland |
Romania |
Singapore |
Slovakia |
South Africa |
Taiwan |
Ukraine |
United Kingdom |
United States |
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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
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |