E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hypertriglyceridemia and Type 2 Diabetes |
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E.1.1.1 | Medical condition in easily understood language |
High triglyceride levels in blood and type 2 diabetes |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020870 |
E.1.2 | Term | Hypertriglyceridemia |
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 | 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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Efficacy Objective: • To assess the efficacy of orally administered Epeleuton capsules versus placebo, in the treatment of adult patients with hypertriglyceridemia and type 2 diabetes.
Safety Objective: • To assess the safety of orally administered Epeleuton capsules versus placebo, in the treatment of adult patients with hypertriglyceridemia and type 2 diabetes.
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E.2.2 | Secondary objectives of the trial |
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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% (53-86mmol/mol) (both inclusive). 3.Patients with a fasting triglyceride level ≥200 mg/dL (2.26 mmol/L) and <750 mg/dL (8.46 mmol/L) at both screening visits. 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. Note: If a large difference in triglyceride level (>15%) is observed between Screening 1 and Screening 2, an additional measurement may be requested or patient may be deemed not eligible. 4.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. 5.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. Note: Stable statin therapy may consist of a statin with or without ezetimibe. 6.Patients with an LDL cholesterol level <130mg/dL (3.34 mmol/L) at both screening visits. 7.Patients who have a body mass index (BMI) ≥ 25kg/m2 and <50kg/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 subject medical record) and/or a sulfonylurea and/or a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sodium-glucose transport protein 2 inhibitor (SGLT2i) and/or a glucagon-like peptide 1 receptor agonist (GLP1-RA) and/or basal insulin for at least 90 days prior to the day of first screening visit. Note: Dose of GLP1-RA must be stable for 6 months prior to baseline with no weight change >2kg for 3 months prior to baseline. Note: Dose of basal insulin must be stable for 4 months prior to baseline. All types of basal insulin are permitted, including insulin glargine, insulin degludec, insulin detemir, NPH insulin and pre-mixed insulin. 9.Female patients and male patients with female partners of childbearing potential must use highly effective contraceptive methods or have a sterilised partner for the duration of the study. Highly effective contraceptive 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 hormonal contraception, 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 or statins. 2.Patients with uncontrolled hypertension defined as a systolic blood pressure ≥160 mmHg or a diastolic blood pressure ≥100mmHg. 3.Patients who have a body mass index (BMI) <25kg/m2 or ≥ 50kg/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 known familial lipoprotein lipase deficiency (Fredriksen type I), apolipoprotein C-II deficiency or familial dysbetaliproteinemia (Fredriksen type III). 8.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. 9.Patients with renal impairment defined as an estimated glomerular filtration rate <50mL/min/1.73m2 as per the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. 10.Patients with a history of malignancies within the past 5 years other than curatively treated non-melanoma skin cancer (basal cell or squamous cell carcinomas). 11.Patients who have been treated with any investigational product within 60 days prior to visit 1 (Screening 1), or 5 half-lives (whichever is longer). Patients cannot participate in any other investigational medication or medical device trial while participating in this study. 12.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. 13.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, SGLT2 inhibitors, basal insulin, GLP1-RAs (must be on a stable dose for at least 6 months) and short-term insulin treatment for acute illness for a total of below or equal to 14 days. 14.Patients who have been treated with fibrates, 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. 15.Patients who have a family or personal history of multiple endocrine neoplasia type 2 or medullary thyroid carcinomas. 16.Patients who have a history of acute or 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 3 months prior to screening. 20.Patients with 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 heart failure. 22.Patients who have a history of diabetic ketoacidosis. 23.Patients with known proliferative retinopathy or maculopathy requiring acute treatment. 24.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. 25.Patients who are pregnant, planning pregnancy, breastfeeding and/or are unwilling to use adequate contraception (as specified in Inclusion Criterion 9) during the trial. 26. Patients with active infectious diseases or chronic infectious disease (e.g. human immunodeficiency virus or tuberculosis). 27. Patients who have recently received a vaccination or for whom a vaccination is planned (apart from flu, SARS-COV2 and pneumococcal vaccines which are permitted at any time). 28.Patients who have previously been randomised into the study. 29.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) |
• Percent change in triglycerides from baseline to week 16. • Change in HbA1c from baseline to week 26.
Note: • Each of the independent primary endpoints will be analysed separately. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline, week 16 and week 26 |
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E.5.2 | Secondary end point(s) |
Secondary Endpoints • Percent change in triglycerides from baseline to weeks 4, 8, 12, 20 and 26. • Change in HbA1c from baseline to weeks 4, 8, 12, 16 and 20. • Proportion of patients achieving a HbA1c below 7.0% at weeks 4, 8, 12, 16, 20 and 26. • Percent change in very low-density lipoprotein cholesterol (VLDL-C) from baseline to weeks 4, 8, 12, 16, 20 and 26. • Percent change in non-high-density lipoprotein cholesterol (non-HDL-C) from baseline to weeks 4, 8, 12, 16, 20 and 26. • Percent change in total cholesterol from baseline to weeks 4, 8, 12, 16, 20 and 26. • Change in fasting plasma glucose from baseline to weeks 4, 8, 12, 16, 20 and 26. • Proportion of patients achieving a HbA1c below 6.5% at weeks 4, 8, 12, 16, 20 and 26. • Percent change in apolipoprotein B (ApoB) from baseline to weeks 16 and 26. • Percent change in remnant lipoprotein cholesterol (RLP-C) from baseline to weeks 8, 16 and 26. • Percent change in high-density lipoprotein cholesterol (HDL-C) from baseline to weeks 4, 8, 12, 16, 20 and 26. • Percent change in low-density lipoprotein cholesterol (LDL-C) (preparative ultracentrifugation) from baseline to weeks 16 and 26. • Change in body weight (kg) from baseline to weeks 4, 8, 12, 16, 20 and 26. • Change in high-sensitivity C-reactive protein (hsCRP) from baseline to weeks 8, 16 and 26. • Change in systolic blood pressure from baseline to weeks 4, 8, 12, 16, 20 and 26. • Change in diastolic blood pressure from baseline to weeks 4, 8, 12, 16, 20 and 26. • Change in urinary albumin-to-creatinine ratio (UACR) from baseline to week 26 in the subgroup of patients with microalbuminuria at baseline.
Exploratory Endpoints • Change in waist circumference from baseline to weeks 8, 16 and 26. • Percent change in apolipoprotein CIII (ApoCIII) from baseline to weeks 16 and 26. • Percent change in apolipoprotein A1 (ApoA1) from baseline to weeks 16 and 26. • Percent change in lipoprotein (a) (Lp(a)) from baseline to weeks 16 and 26. • Percent change in high-density lipoprotein particle concentration (HDL-P) from baseline to weeks 16 and 26. • Percent change in small low-density lipoprotein particle concentration (Small LDL-P) from baseline to weeks 16 and 26. • Percent change in large low-density lipoprotein particle concentration (Large LDL-P) from baseline to weeks 16 and 26. • Percent change in low-density lipoprotein size (LDL size) from baseline to weeks 16 and 26. • Percent change in very low-density lipoprotein size (VLDL size) from baseline to weeks 16 and 26. • Percent change in high-density lipoprotein size (HDL size) from baseline to weeks 16 and 26. • Change in fasting plasma insulin from baseline to weeks 16 and 26. • Change in Homeostatic model assessment insulin resistance (HOMA-IR) from baseline to weeks 16 and 26. • Change in Homeostatic model assessment β-cell function (HOMA-β) from baseline to weeks 16 and 26. • Change in interleukin 6 (IL-6) from baseline to week 26. • Change in interleukin 1β (IL-1β) from baseline to week 26. • Change in plasminogen activator inhibitor 1 (PAI-1) from baseline to week 26. • Change in vascular cell adhesion molecule 1 (VCAM-1) from baseline to week 26. • Change in intercellular adhesion molecule 1 (ICAM-1) from baseline to week 26. • Change in monocyte chemoattractant protein 1 (MCP-1) from baseline to week 26. • Change in red cell distribution width (RDW) from baseline to weeks 16 and 26. • Change in haemoglobin from baseline to weeks 16 and 26. • Change in reticulocyte count from baseline to weeks 16 and 26. • Change in erythrocyte (red blood cell) count from baseline to weeks 16 and 26. • Trough plasma concentrations of total and unesterified 15-hydroxy eicosapentaenoic acid (15(S)-HEPE) in treated population compared to placebo population at Baseline/Day 0, Week 4, Week 8, Week 16 and Week 26. • Trough plasma concentrations of EPA in treated population compared to placebo population at Baseline/Day 0, Week 4, Week 8, Week 16 and Week 26. • Determination of exploratory serum biomarkers in treated population compared to placebo population at Baseline and Week 26. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline, weeks 4, 8, 12, 16, 20, 26. |
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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 | Yes |
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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 6 |
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 |
Georgia |
Israel |
United States |
Germany |
Latvia |
United Kingdom |
Switzerland |
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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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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 | 1 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 27 |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial days | 27 |