E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 diabetes mellitus (T2DM) |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | <Manually entered code. Term in E.1.1> |
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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 this study is to explore the safety and tolerability of three oral doses of a new anti-diabetic agent, SLV337, in subjects with type 2 diabetes mellitus (T2DM) treated with metformin monotherapy, during four weeks of administration. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are: - To investigate the pharmacokinetic (PK) profiles of these three oral doses of SLV337 in subjects with T2DM. - To explore the effect of SLV337 on metformin plasma levels in subjects on stable treatment dose administered in the morning. - To explore the exposure-response relationships and preliminary efficacies of these three oral doses of SLV337 in subjects with T2DM. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male or female of non-childbearing potential, aged 18 to 75 years inclusive. 2. Diagnosed with T2DM defined by the American Diabetes Association criteria: FPG ≥7.0 mmol/L (126 mg/dL), or two hours postprandial glucose ≥11.1 mmol/L (200 mg/dL). 3. Treated with life style modification and stable dose of metformin monotherapy, ≥850 mg daily dose, for at least three months; the dose of metformin, physical exercise and dietary recommendations will stay unchanged during the whole duration of the study. 4. With inadequate glycemic control, defined by hemoglobin A1c (HbA1c) ≥7%, but <10%. 5. With FPG <15 mmol/L (270 mg/dl). 6. If female, the subject should be of non-childbearing potential, defined as being post-menopausal for at least 24 months prior to dosing (with confirmed estradiol ≤20 pg/mL [73 pmol/L] and follicle-stimulating hormone ≥40 mIU/mL) at Screening if less than 60 years old, or surgically sterilized (with negative pregnancy test at Screening in the absence of hysterectomy). If male, unless the subject has undergone a vasectomy, he must abstain from sexual contact with women who may become pregnant, or use a combination of a condom and spermicide as a contraception measure from the first dosing up to three months after the last intake of study drug. 7. Subjects will have given their voluntary written informed consent to participate in the study in their own language and be willing to comply with the protocol. Consent will be documented by the subject’s name and dated signature prior to screening procedures. |
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E.4 | Principal exclusion criteria |
1. Type 1 diabetes mellitus, maturity onset diabetes of the young. 2. C-peptide <0.27 nmol/L (0.8 ng/mL). 3. Currently treated or treated during the last three months with insulin therapy. 4. Ongoing oral dual anti-diabetic therapy or treated during the last three months by oral anti-diabetic therapy other than metformin. 5. Treatment with a fibrate, ezetimibe or with any lipid lowering agents other than statins. 6. Treatment with warfarin and other coumarinic derivatives (i.e. acenocoumarol). 7. Body mass index >40.0 kg/m2. 8. Uncontrolled arterial hypertension defined by systolic blood pressure (SBP) ≥160 and/or diastolic blood pressure (DBP) ≥95 mmHg taken in a semi-recumbent position, after 5 minutes rest. 9. Renal failure or renal dysfunction defined by creatinine clearance <60 mL/min as calculated with the Modification of Diet in Renal Disease formula as follows:eGFR (mL/min/1.73m2)= 175 x [SerumCreatinine(μmol/L) x 0.0113]-1.154 x Age(years)-0.203 (x 0.742 if female). For African-Americans the value should be multiplied by 1.21. Note: values <60 mL/min are likely to deviate from the true value. 10. History of proliferative retinopathy or maculopathy requiring, or previously treated with, laser therapy. 11. Evidence of unstable cardiovascular diseases: 1) coronary bypass surgery, or angioplasty within three months of the screening visit; 2) myocardial infarction, unstable angina pectoris or other significant cardiac event (including history of cardiac arrhythmias or conduction delays on electrocardiogram [ECG]) or cerebral stroke within three months of the screening visit; 3) severe peripheral artery disease as evidenced by intermittent claudication within three months of the screening visit; 4) peripheral artery surgery within three months of the screening visit. 12. Heart failure New York Heart Association class I to IV. 13. History of pancreatitis or gall bladder disease, with the exception of subjects with gall bladder disease who have previously undergone a cholecystectomy. 14. History of gastric surgery, vagotomy, bowel resection or any surgical procedure that might interfere with gastrointestinal motility, pH or absorption. 15. History of gastric or duodenal ulcer within three months of the screening visit. 16. History of diagnosis of hepatitis B or hepatitis C. 17. History of solid organ transplant. 18. History of diagnosed hereditary or acquired myopathy. 19. History of mental instability, drug or alcohol abuse or subject who was treated for severe psychiatric illness, which, in the opinion of the Investigator, may interfere with optimal participation in the study. 20. History of cancer (except basal cell carcinoma or squamous cell skin cancer). 21. Evidence of other relevant diseases not related to T2DM as revealed by history, physical examination and laboratory assessments which are deemed to limit study evaluation or participation in the judgment of the Investigator. 22. Alanine aminotransferase (ALT) ≥ two times upper limit of normal. 23. Known to be positive to the human immunodeficiency virus (HIV)1 or HIV2 virus. 24. Known hypersensitivity to the excipients of SLV337 capsules (lactose monohydrate, sucrose, hydroxypropyl methylcellulose, sodium lauryl sulfate, sodium docusate, purified water, sodium starch glycolate and magnesium stearate). 25. Has taken one single dose of an investigational drug within 30 days or multiple doses of an investigational drug within 60 days prior to dosing. 26. Has an acute infection at the time of Screening and/or admission. 27. Has acute gastrointestinal symptoms at the time of Screening and/or admission (e.g. nausea, vomiting, diarrhoea, heartburn). 28. Unlikely to comply with the requirements of the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetics: For the calculation of the PK parameters the following rules will be applied: - Non-compartmental modeling will be applied. - Actual sampling times will be used. - At time points in the lag-time between time zero and the first concentration equal or above lower limit of quantification (LLOQ), concentrations below LLOQ will be set to zero. - Concentrations below LLOQ between two concentrations equal or above LLOQ will be set to half the LLOQ. - Trailing concentrations below LLOQ will not be used. - The AUC parameters will be calculated according to the lin-up log-down trapezoidal rule. The values of Cmax and tmax will be taken directly from the individual concentration versus time data.
Pharmacodynamics: The following PD endpoints will be calculated: - HMW/total adiponectin ratio. - HOMA-IR, calculated as fasting insulin [μU/L] × FPG [mmol/L] / 22.5 - ApoB/apoA1 ratio. - Mean of the seven blood glucose values (glucometer) on Days -1 and 28. - Mean of the three post-prandial measures of blood glucose values (glucometer); one hour post breakfast and two hours post lunch and two hours post dinner on Days -1 and 28
The relationship between SLV337 plasma parameters (AUC0-t, AUC0-τ and Cmax) and change from baseline PD measurements on Day 28 will be graphically presented for selected PD endpoints. This evaluation will be limited to those PD endpoints that exhibited a significant dose-response relationship.
An independent cardiovascular endpoints committee will be appointed to prospectively collect and review before adjudication, in a blinded fashion, cardiovascular events during the study. The safety sample will be used for the analysis of the safety and tolerability data. Safety variables will be summarized by descriptive statistics. |
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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 | No |
E.6.6 | Pharmacokinetic | Yes |
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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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.8.3 |
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 | 12 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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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End of Study is defined as Last Subject Last Visit + 30 days |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |