E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Type 2 diabetes and diabetic complications |
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E.1.1.1 | Medical condition in easily understood language |
Type 2 diabetes and diabetic complications |
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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 | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10067585 |
E.1.2 | Term | Type 2 diabetes mellitus |
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 | HLGT |
E.1.2 | Classification code | 10012653 |
E.1.2 | Term | Diabetic complications |
E.1.2 | System Organ Class | 10014698 - Endocrine disorders |
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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 |
Pharmacodynamic Objective:
To assess the molecular mechanism of orally administered Epeleuton capsules versus placebo, in the treatment of adult patients with type 2 diabetes and diabetic complications |
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E.2.2 | Secondary objectives of the trial |
Safety Objective:
To assess the safety of orally administered Epeleuton capsules versus placebo, in the treatment of adult patients with type 2 diabetes and diabetic complications.
Efficacy Objective:
To assess the efficacy of orally administered Epeleuton capsules versus placebo, in the treatment of adult patients with type 2 diabetes and diabetic complications. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients diagnosed with type 2 diabetes mellitus at least 90 days prior to the first screening visit. 2. Patients with a HbA1C (glycosylated haemoglobin) between 7.0-10.0% (53-85.8 mmol/mol) (both inclusive) 3. Patients with a fasting triglyceride level ≥120 mg/dL and <250mg/dL at the screening visit. Note: If the triglyceride level is outside the required range at the second screening visit, an additional measurement can be obtained 1 week later, to confirm eligibility. 4. Patients with a clinical diagnosis of diabetic peripheral neuropathy. 5. Patients who have been educated regarding diet and exercise at or before visit 1 (screening 1) and are willing to maintain and not alter a stable diet and activity routine throughout the study. 6. Patients who have been on a stable statin therapy at doses that are likely to achieve optimal LDL cholesterol and who are willing to continue this treatment throughout the study. 7. Patients who have a BMI ≥ 25kg/m2 and <45kg/m2. 8. Patients who have been on a stable daily dose of metformin (at least 1500mg or maximum tolerated dose for metformin monotherapy as documented in the patient medical record) and/or a sulfonylurea and/or a DPP-4 inhibitor and/or a SGLT2i and/or insulin for at least 90 days prior to the day of first screening visit. Note: Permitted insulin therapy does not include short-term insulin treatment for acute illness 9. Female patients and male patients with female partners of childbearing potential must use highly effective birth control methods or have a sterilised partner for the duration of the study. Highly effective birth control methods are defined as methods that can achieve a failure rate of less than 1% per year when used consistently and correctly. Such methods include intrauterine device or sexual abstinence. Note: A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. Note: Hormonal contraceptives must be on a stable dose for at least one month before baseline. Note: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. 10. Patients whose pre-study or screening clinical laboratory findings do not interfere with their participation in the study, in the opinion of the Investigator, and do not violate any inclusion or exclusion criteria 11. Male or female patients aged 18 years and older on the day of signing the informed consent form (ICF). 12. Patients who are able to communicate well with the Investigator, to understand and comply with the requirements of the study, and understand and sign the written informed consent prior to initiation of any study specific activities or procedures. |
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E.4 | Principal exclusion criteria |
1. Patients who have a history of intolerance or hypersensitivity to any substance in Epeleuton capsules, placebo capsules, statins, metformin, sulfonylureas, DPP-4 inhibitors or SGLT2i. 2. Patients with uncontrolled hypertension defined as a systolic blood pressure ≥160 mmHg or a diastolic blood pressure ≥100mmHg. 3. Patients who have a BMI <25kg/m2 or ≥ 45kg/m2. 4. Patients who have a weight change >2kg from the first screening visit to the baseline visit. 5. Patients who have type 1 diabetes mellitus. 6. Patients who have thyroid stimulating hormone (TSH) levels >1.5 times the upper limit of normal. 7. Patients with significant liver disease or liver function impairment defined as any of the following; cirrhosis, hepatitis, biliary obstruction with hyperbilirubinemia (total bilirubin >2 times the upper limit of normal) and aspartate aminotransferase (AST) or alanine aminotransferase levels (ALT) >3 times the upper limit of normal. 8. Patients with stage 4 or stage 5 chronic kidney disease (CKD) defined as an estimated glomerular filtration rate <30 mL/min/1.73m2 as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. 9. Patients with a history of malignancies within the past five years other than curatively treated non-melanoma skin cancer (basal cell or squamous cell carcinomas). 10. Patients who have been treated with any investigational product within 60 days prior to visit 1 (screening 1), or five half-lives (whichever is longer). Patients cannot participate in any other investigational medication or medical device trial while participating in this study. 11. Patients who have used dietary supplements or prescription products rich in omega-3 or omega-6 fatty acids in the four weeks prior to baseline. 12. Patients who have been treated with any medication for diabetes or obesity in the four weeks before the baseline visit, except for metformin, sulfonylureas, DPP-4 inhibitors, SGLT2i and short-term insulin treatment for acute illness for a total of below or equal to 14 days. 13. Patients who have been treated with fibrates, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, bile acid sequestrants, niacin, niacin analogues or dietary supplements for the purpose of lowering triglycerides or cholesterol in the six weeks prior to baseline. 14. Patients who have been treated with anti-psychotic medications in the six weeks prior to baseline. 15. Patients who have a family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinomas. 16. Patients who have chronic pancreatitis. 17. Patients who have a history of major surgical procedures involving the stomach potentially affecting absorption of investigational medicinal product (e.g. subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery) 18. Patients who have planned major surgical procedures, coronary intervention (such as stent placement or heart bypass), carotid or peripheral revascularisation. 19. Patients who have a history of myocardial infarction, stroke, coronary revascularisation or hospitalisation for unstable angina in the three months prior to screening. 20. Patients with unexplained creatine kinase concentrations > 10 times the upper limit of normal or creatine kinase elevation due to known muscle disease at visit 1 (screening 1) 21. Patients who are classified as being in New York Heart Association (NYHA) Class IV. 22. Patients who have a history of diabetic ketoacidosis. 23. Patients with significant systemic or major illnesses that, in the opinion of the Investigator, would preclude or interfere with treatment with Epeleuton, adequate follow up and/or compliance with the protocol. 24. Patients who are pregnant, planning pregnancy, breastfeeding and/or are unwilling to use adequate contraception (as specified in Inclusion Criterion 10) during the trial. 25. Patients with active infectious diseases or chronic infectious disease (e.g. human immunodeficiency virus or tuberculosis). 26. Patients who have recently received a vaccination or for whom a vaccination is planned (with the exception of influenza, SARS-COV2 and pneumococcal vaccines which are permitted at any time). 27. Patients who have previously been randomised in the study and received study medication. 28. Patients, in the opinion of the Investigator, not suitable to participate in the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Outcome Measures:
1. Change in the mononuclear methylation pattern from baseline to week 16. 2. Change in miRNAs from baseline to week 16. 3. Change in HbA1c from baseline to weeks 4, 8, 12 and 16. 4. Change in fasting plasma glucose from baseline to weeks 4, 8, 12 and 16. 5. Proportion of patients achieving a HbA1c below 6.5% at weeks 4, 8, 12 and 16. 6. Proportion of patients achieving a HbA1c below 7.0% at weeks 4, 8, 12 and 16. 7. Change in urinary albumin/creatinine ratio (UACR) from baseline to week 16. 8. Change in the signs and symptoms of diabetic peripheral neuropathy from baseline to week 16. 9. Change in high-sensitivity C-reactive protein (hsCRP) from baseline to week 16. 10. Change in exploratory serum and plasma biomarkers from baseline to week 16. 11. Change in exploratory urinary biomarkers from baseline to week 16. 12. Change in systolic blood pressure from baseline to weeks 4, 8, 12 and 16. 13. Change in diastolic blood pressure from baseline to weeks 4, 8, 12 and 16. 14. Change in whole body insulin sensitivity from baseline to week 16. 15. Change in insulin resistance in skeletal muscle from baseline to week 16.
Safety Variables:
1. Incidence of treatment-emergent level 2 and level 3 hypoglycaemic episodes o Level 2 – Glucose <54 mg/dL, with or without symptoms o Level 3 – A severe event characterised by altered mental and/or physical status requiring assistance for treatment of hypoglycaemia. 2. Adverse event (AE) and serious adverse event (SAE) frequency and severity 3. Safety laboratory parameters (haematology, clinical chemistry, coagulation) 4. Urinalysis 5. Electrocardiograms (ECGs) 6. Vital signs (heart rate, temperature, blood pressure) 7. Physical examination
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Days 0, 28, 56, 84, 112, 126
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
E.6.10 | Pharmacogenetic | No |
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.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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The end of trial is defined as 'last patient last visit (LPLV)'. LPLV is defined as the date the Investigator reviews the last patient's safety data and determines that no further evaluation is required for the patient to complete 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 | 0 |
E.8.9.1 | In the Member State concerned months | 8 |
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 | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |