| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Type II Diabetes Mellitus | |
| MedDRA Classification |
| 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 the long term efficacy (durability) of add-on therapy with LAF237 in patients with type 2 diabetes inadequately controlled with prior metformin monotherapy by testing the hypothesis that the risk of failure of glycemic control over time (defined as HbA1c > 8.0%, see Section 10.4) is lower with LAF237 compared to that with glimepiride. | |
| E.2.2 | Secondary objectives of the trial | To demonstrate the efficacy of add-on therapy with LAF237 in patients with type 2 diabetes inadequately controlled with prior metformin monotherapy by testing the hypothesis that the HbA1c reduction with LAF237 is superior to that with glimepiride at end of study.
2.To demonstrate the safety of LAF237 in patients with type 2 diabetes inadequately controlled with prior metformin monotherapy by showing that add-on therapy with LAF237 has a favorable adverse event profile, including the frequency and severity of hypoglycemia, compared to glimepiride after up to 5 years of treatment.
3.To demonstrate the long term efficacy of add-on therapy with LAF237 in patients with type 2 diabetes inadequately controlled with prior metformin monotherapy by testing the hypothesis that the coefficient of failure for HbA1c of LAF237 from Week 24 until end of study is lower than that of glimepiride.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria | 1.Male, non-fertile female (i.e. post menopausal, post hysterectomy, or sterilized by tubal ligation) or female of childbearing potential using a medically approved birth control method (e.g. hormonal contraceptives, IUD, double-barrier contraception). A female of childbearing potential using a medically approved birth control method must be willing to use the same method of contraception during the full course of the study.
2.Patients with type 2 diabetes who have received metformin for at least three months and have been on a stable dose of at least 1500 mg daily for a minimum of 4 weeks prior to Visit 1.
3.Agreement to maintain the same dose of metformin throughout the study.
4.Age in the range of 18-73 years inclusive.
5.Body mass index (BMI) in the range of 22-45 kg/m2 inclusive at Visit 1.
6.HbA1c of > 6.5% and ≤ 8.5% at Visit 1.
7.Intent to maintain prior diet and exercise habits during the full course of the study.
8.Written informed consent to participate in the study.
9.Ability to comply with all study requirements.
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| E.4 | Principal exclusion criteria | 1.Pregnant or lactating female.
2.Diagnosis of or a history of:
•type 1 diabetes, diabetes that is a result of pancreatic injury, or secondary forms of diabetes, e.g. Cushing’s syndrome and acromegaly.
•acute metabolic diabetic complications such as ketoacidosis or hyperosmolar state (coma) within the past 6 months.
3.Evidence of significant diabetic complications, e.g. symptomatic autonomic neuropathy or gastroparesis.
4.Acute infections which may affect blood glucose control within 4 weeks prior to Visit 1.
5.A history of:
•Torsades de pointes, sustained and clinically relevant ventricular tachycardia or ventricular fibrillation.
•percutaneous coronary intervention within the past 3 months.
•any of the following within the past 6 months: myocardial infarction (MI) (if the Visit 1 electrocardiogram (ECG) reveals patterns consistent with an MI and the date of the event cannot be determined, then the patient can enter the study at the discretion of the investigator and the sponsor); coronary artery bypass surgery; unstable angina; or stroke.
6.Congestive heart failure (CHF) requiring pharmacologic treatment.
7.Any of the following ECG abnormalities:
•second degree atrioventricular (AV) block (Mobitz 1 and 2)
•third degree AV block
•prolonged QTc (> 500 ms)
8.Malignancy including leukemia and lymphoma (not including basal cell skin cancer) within the last 5 years.
9.Liver disease such as cirrhosis or chronic active hepatitis.
10.Renal disease or significant renal dysfunction.
11.Treatment with growth hormone or similar drugs.
12.Concurrent medical condition that may interfere with the interpretation of efficacy and safety data during the study.
13.Donation of one unit (500 mL) or more of blood, significant blood loss equaling to at least one unit of blood within the past 2 weeks or a blood transfusion within the past 8 weeks.
14.Contraindications and warnings according to the country specific label for metformin or glimepiride not listed in the other exclusion criteria.
15.Known sensitivity to glimepiride or other sulfur containing drugs.
16.Treatment with any oral anti-diabetic other than metformin within 3 months prior to Visit 1.
17.Chronic insulin treatment (> 4 weeks of treatment in the absence of an intercurrent illness) within the past 6 months.
18.Chronic oral or parenteral corticosteroid treatment (> 7 consecutive days of treatment) within 8 weeks prior to Visit 1.
19.Treatment with class Ia, Ib and Ic or III anti-arrhythmics.
20.Thyroid hormone replacement is allowed if the dosage has been stable for at least 3 months and the thyroid stimulating hormone (TSH) is within normal limits at Visit 1.
21.Investigational drug treatment within 4 weeks prior to Visit 1 unless local health authority guidelines mandate a longer period.
22.Treatment with any drug with a known and frequent toxicity to a major organ system within the past 3 months (i.e. cytostatic drugs).
23.Any of the following laboratory abnormalities:
•ALT, AST greater than three times the upper limit of the normal range at Visit 1.
•Direct bilirubin greater than 1.3 times the upper limit of the normal range at Visit 1.
•Serum creatinine levels ≥ 132 mol/L (1.5 mg/dL) males, ≥ 123 mol/L (1.4 mg/dL) females at Visit 1.
•Clinically significant TSH outside of normal range at Visit 1.
•Clinically significant laboratory abnormalities, confirmed by repeat measurement, other than hyperglycemia, hyperinsulinemia and glycosuria at Visit 1.
•Fasting triglycerides 7.9 mmol/L (> 700 mg/dL) at Visit 1.
•Positive glutamic acid decarboxylase (GAD) antibodies at Visit 1 (GAD antibodies will be tested in patients < 30 years of age).
24.History of active substance abuse (including alcohol) within the past 2 years.
25.Potentially unreliable patients and those judged by the investigator to be unsuitable for the study.
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| E.5 End points |
| E.5.1 | Primary end point(s) | | The primary efficacy variable, time to failure, is defined as the time from randomization until HbA1c rises above the threshold of 8%. The time to failure is defined as the first scheduled visit of the trial (prior to the addition of rescue medication) at which HbA1c is measured above 8%, confirmed by a subsequent repeat measurement within 4 weeks (≤ 28 days). Non-confirmed measurements will not be treated as failures, and will continue as per protocol. | |
| 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 | Information not present in EudraCT |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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 | Information not present in EudraCT |
| E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
| E.7.1.3 | Other | Information not present in EudraCT |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| 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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | |
| E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
| 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 | | it will be one the first patient included in the trials done the last trial visit. | |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
