E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Diabetes Mellitus, Type 2 |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 17.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10045242 |
E.1.2 | Term | Type II diabetes mellitus |
E.1.2 | System Organ Class | 100000004861 |
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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 |
To confirm that treatment with semaglutide does not result in an unacceptable increase in cardiovascular risk as compared to placebo in adults with type 2 diabetes. This is done by demonstrating that the upper limit of the two-sided 95% confidence interval (CI) of the hazard ratio for semaglutide versus placebo is less than 1.8 when comparing time to first occurrence of a major adverse cardiovascular event (MACE). |
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E.2.2 | Secondary objectives of the trial |
To assess the long-term safety and efficacy of semaglutide 0.5 mg and 1.0 mg once weekly compared to placebo, both added on to standard of care, in adults with type 2 diabetes at high risk for cardiovascular events. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Men and women with type 2 diabetes mellitus.
- Age ≥50 years at screening and clinical evidence of cardiovascular disease or age ≥60 years at screening and subclinical evidence of cardiovascular disease.
- Anti-diabetic drug naïve, or treated with one or two OAD(s), or treated with human NPH insulin or long-acting insulin analogue or pre-mixed insulin, both types of insulin either alone or in combination with one or two OAD(s).
- HbA1c ≥7.0% at screening. |
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E.4 | Principal exclusion criteria |
- Type 1 diabetes mellitus.
- Use of GLP-1 receptor agonist (exenatide, liraglutide, or other) or pramlintide within 90 days prior to screening.
- Use of any DPP-IV inhibitor within 30 days prior to screening.
- Treatment with insulin other than basal and pre-mixed insulin within 90 days prior to screening - except for short-term use in connection with intercurrent illness.
- Acute decompensation of glycaemic control requiring immediate intensification of treatment to prevent acute complications of diabetes (eg diabetes ketoacidosis) within 90 days prior to screening.
- History of chronic pancreatitis or idiopathic acute pancreatitis.
- Acute coronary or cerebro-vascular event within 90 days prior to randomisation.
- Currently planned coronary, carotid or peripheral artery revascularisation.
- Chronic heart failure NYHA class IV.
- Personal or family history of multiple endocrine neoplasia type 2 (MEN2) or familial medullary thyroid carcinoma.
- Personal history of non-familial medullary thyroid carcinoma.
- Screening calcitonin ≥50 ng/L. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time from randomisation to first occurrence of a MACE, defined as cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from randomisation to first occurrence of a major adverse cardiovascular event (MACE). |
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E.5.2 | Secondary end point(s) |
1 - Time from randomisation to first occurrence of an expanded composite cardiovascular outcome.
2 - Time from randomisation to each individual component of the expanded composite cardiovascular outcome.
3 - Time from randomisation to first occurrence of all-cause death, non-fatal MI, or non-fatal stroke.
4 - Change from baseline to last assessment during the treatment period in other treatment outcomes, including HbA1c, fasting plasma glucose, body weight, lipid profile, urinary albumin to creatinine ratio, vital signs, hypoglycaemic events, adverse events, antisemaglutide antibodies and patient reported outcome (PRO). |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Time from randomisation up to end of Follow-up (up to max. 148 weeks)
2. Time from randomisation up to end of Follow-up (up to max. 148 weeks)
3. Time from randomisation up to end of Follow-up (up to max. 148 weeks)
4. From randomisation to end of treatment (up to max. 143 weeks)
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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 | Yes |
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 | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
Evaluation of cardiovascular outcome |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Two different doses of test IMP |
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E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 35 |
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 |
Algeria |
Argentina |
Australia |
Brazil |
Canada |
European Union |
India |
Israel |
Malaysia |
Mexico |
Russian Federation |
Taiwan |
Thailand |
Turkey |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 11 |
E.8.9.2 | In all countries concerned by the trial days | 0 |