E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe Hypertriglyceridemia (sHTG) |
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E.1.1.1 | Medical condition in easily understood language |
Severe Hypertriglyceridemia (sHTG) |
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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 | 100000004861 |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to determine the change in TG levels following 12 weeks of repeated IV doses of evinacumab in the subset of patients with a documented history of sHTG (TG ≥1000 mg/dL), a TG level of at least 500 mg/dL (5.6 mmol/L) at screening, a history of acute pancreatitis, and without loss of function (LOF) mutations in genes in the lipoprotein lipase (LPL) pathway; and to assess whether a reduction in TG of at least 40% from the baseline placebo period has been achieved. |
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E.2.2 | Secondary objectives of the trial |
To - Determine the % change from baseline in TG levels following 2 to 24 weeks of repeated IV doses of evinacumab overall and in subgroups with homozygous or compound heterozygous LOF mutations, heterozygous LOF mutations, and without LOF mutations in genes in the LPL pathway - Assess changes in patient reported abdominal and GI symptoms, dietary habits, and symptom/dietary impact measures - Aassess the degree of pancreatic injury/inflammation through 18F-FDG-PET imaging at baseline and change from baseline following 12 weeks of treatment with evinacumab as assessed by 18F-FDG standardized uptake values SUVmax and SUVmean - Assess the degree of pancreatic injury/inflammation through DW-MRI at baseline and the change from baseline following 12 and 24 weeks of treatment with evinacumab as assessed by ADC - Evaluate the total evinacumab and total ANGPTL3 concentrations, and ADA during the evinacumab treatment and follow-up periods - Evaluate the safety and tolerability of evinacumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females ≥18 to 75 years of age at screening 2. Previous documentation in the patient’s medical records of a fasting serum TG measurement ≥ 1000 mg/dL (11.3 mmol/L) on more than 1 occasion, and all fasting TG values >500 mg/dL (5.6 mmol/L) at screening 3. History of a hospitalization and diagnosis of acute pancreatitis in the past 10 years. 4. On a stable lipid-modifying diet with or without medications (eg, statins, niacin, omega-3 fatty acids). Lipid-modifying diet and doses of medications should be stable for at least 4 weeks (6 weeks for fibrates, 8 weeks for PCSK9 inhibitors) prior to screening 5. BMI index of 18-40 kg/m2 6. Provide signed informed consent 7. Willing and able to comply with clinic visits and study-related procedures |
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E.4 | Principal exclusion criteria |
1. A hospital or clinic discharge diagnosis of acute pancreatitis within 12 weeks of screening 2. Lipid apheresis or plasma exchange treatment within the last 4 weeks or plans to undergo apheresis or plasma exchange during the time frame of the study 3. History of class 3/4 heart failure at any time in the past, or hospitalization for heart failure, diagnosis of a myocardial infarction, stroke, TIA, unstable angina, CABG, PCI, carotid surgery/stenting within 3 months before the screening visit 4. History of bleeding disorders, esophageal varices, heparin induced thrombocytopenia, or contraindications to receiving heparin (eg, allergic reaction to heparin) 5. New clinically significant findings on 12-lead electrocardiogram (ECG) that would place the patient at risk or interfere with participation in the study 6. Women of childbearing potential (WOCBP)* who are unwilling to practice a highly effective birth control method prior to the initial dose, during the study, and for 24 weeks after the last dose of study drug. *Postmenopausal women must be amenorrheic for at least 12 months in order not to be considered of childbearing potential. Postmenopausal status will be confirmed by measurement of follicle-stimulating hormone (FSH). Pregnancy testing and contraception are not required for women with documented hysterectomy and/or oophorectomy. 7. Men who are sexually active with WOCBP and are unwilling to consistently use condoms during the study drug treatment period and for 24 weeks after the last administration of study drug, regardless of vasectomy status. Sperm donation is prohibited during the study and for up to 24 weeks after the last administration of study drug.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the percent lowering of TG levels from baseline following 12 weeks of repeated IV doses of evinacumab in the subset of patients with a documented history of sHTG (TG ≥1000 mg/dL [11.3 mmol/L]), a TG level of at least 500 mg/dL (5.6 mmol/L) at screening, a history of acute pancreatitis, and without LOF mutations in genes in the LPL pathway. (For patients randomized to evinacumab, baseline is defined as the period prior to the double-blind period; for patients randomized to placebo, baseline is defined as the period prior to the single-blind period). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Following 12 weeks of repeated IV doses of evinacumab |
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E.5.2 | Secondary end point(s) |
- Percent TG lowering from baseline following 2 to 24 weeks of repeated IV doses of evinacumab overall and in subgroups with homozygous or compound heterozygous LOF mutations, heterozygous LOF mutations, and without LOF mutations in genes in the LPL pathway - Changes in patient reported abdominal and GI symptoms, dietary habits, and symptom/dietary impact measures - Degree of pancreatic injury/inflammation through 18F-FDG-PET imaging at baseline (placebo run-in) and change from baseline following 12 weeks of treatment with evinacumab as assessed by 18F-FDG standardized uptake values SUVmax and SUVmean - Degree of pancreatic injury/inflammation through DW-MRI and T2-MRI at baseline (placebo run-in period) and the change from baseline following 12 and 24 weeks of treatment with evinacumab as assessed by ADC - The total evinacumab concentrations, total ANGPTL3 concentrations, and ADA during the evinacumab treatment and follow-up periods - Incidence and severity of treatment-emergent adverse event (TEAEs), SAEs, laboratory abnormalities, and other safety variables in patients treated with evinacumab |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
These will be assessed at various timepoints detailed in the protocol |
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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 | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
Double blind treatment period (Day 1 to 85) followed by single blind treatment period (Day 86 to 169 |
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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 | 2 |
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 | 1 |
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 |
Canada |
Italy |
Poland |
Ukraine |
United Kingdom |
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 | 8 |
E.8.9.1 | In the Member State concerned days | |
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 | 8 |