E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
high LDL cholesterol and triglyceride levels |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10027763 |
E.1.2 | Term | Mixed hyperlipidemia |
E.1.2 | System Organ Class | 100000004850 |
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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 the study is to evaluate the safety and efficacy of ARO-APOC3 in adults with mixed dyslipidemia (MD) and to select a dose and dosing regimen for later stage clinical studies in this patient population. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Pharmacokinetics, Optional Genotype, and Future Research studies. |
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E.3 | Principal inclusion criteria |
To be eligible for enrollment, participants must meet all the following inclusion criteria: 1. Males or nonpregnant (who do not plan to become pregnant), nonlactating females ≥18 years of age; 2. Based on medical history, prior evidence of TG ≥150 mg/dL or 1.69 mmol/L and ≤499 mg/dL or 5.64 mmol/L; 3. A mean fasting TG level of ≥150 mg/dL (≥1.69 mmol/L) and ≤499 mg/dL (5.64 mmol/L) collected at two separate and consecutive visits and at least 7 days apart and no more than 17 days apart during the Screening period; 4. Fasting levels at Screening of non-HDL-C ≥100 mg/dL (2.59 mmol/L),OR LDL-C ≥70 mg/dL (1.8 mmol/L) after at least 2 weeks of stable diet and 4 weeks on stable optimal statin therapy (unless documented as statin intolerant as defined in Section 8.4); 5. Able and willing to provide written informed consent prior to the performance of any study-specific procedures; 6. Willing to follow diet counseling as per Investigator judgment based on local standard of care; and 7. Participants of childbearing potential must agree to use highly effective contraception during the study and for at least 24 weeks following the last dose of IP. Males must agree to not donate sperm during the study and for at least 24 weeks following the last dose of IP. Females must agree to not donate eggs during the study and for at least 24 weeks following the last dose of IP. 8. Women of childbearing potential on hormonal contraceptives must be stable on the medication for ≥2 menstrual cycles prior to Day 1; 9. Participants taking any of the following medications must be on a stable regimen for the specified duration prior to collection of Screening visit (S2) laboratory tests and for the duration of study participation:
Medication: Time on stable regimen prior to collection of Screening visit (S2) laboratory tests • Lipid lowering therapies (including statins): ≥ 4 weeks • Beta-blockers, thiazide diuretics: ≥ 4 weeks • Fibrates: ≥ 6 weeks • PCSK9 inhibitors: ≥ 8 weeks • Retinoids: ≥ 8 weeks • Atypical antipsychotics: ≥ 12 weeks • Diabetes mellitus medications: ≥ 12 weeks • Oral estrogens, tamoxifen, raloxifene: ≥ 16 weeks • Immunosuppressants: ≥ 24 weeks • Thyroid hormone replacement therapy: ≥ 12 weeks • Anticoagulation therapy: ≥ 12 weeks • Testosterone replacement therapy: ≥ 16 weeks
NOTE: All laboratory tests used as inclusion criteria will be assessed by a central laboratory and may be repeated once and the repeat value may be used for inclusion purposes. Local laboratory testing may be permitted in limited circumstances and only with prior Sponsor approval. |
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E.4 | Principal exclusion criteria |
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: 1. Current use or use within last 365 days from Day 1 of any hepatocyte targeted siRNA or antisense oligonucleotide molecule; 2. Active pancreatitis within 12 weeks prior to Day 1; 3. Any planned bariatric surgery or similar procedures to induce weight loss during the period starting at consent through the end of the study; 4. History of major surgery within 12 weeks of Day 1 or planned major surgery during the study 5. Planned coronary intervention (such as stent placement or heart bypass) during the study; 6. History of acute coronary syndrome event within 24 weeks of Day 1 7. New York Heart Association (NYHA) Class II, III, or IV heart failure or last known ejection fraction of <30%; 8. Uncontrolled hypertension (sitting blood pressure >160/100 mmHg at Screening); participant may be re-screened once hypertension is controlled; 9. History of hemorrhagic stroke within 24 weeks of Day 1; 10. History of bleeding diathesis or coagulopathy; 11. Current diagnosis of nephrotic syndrome; 12. Any of the following laboratory values at Screening: a. Hepatic: ALT or AST >2× ULN at Screening, b. Estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (using the Modification of Diet in Renal Disease [MDRD] equation) at Screening, c. HbA1c >9.0% (or >75 mmol/mol IFCC units) at Screening ; d. Spot urine protein/spot urine creatinine ratio >3 grams per day; e. Clinically significant abnormality in PT, aPTT, or INR; 13. Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or planned use during the study (stable doses of testosterone replacement therapy ≥16 weeks prior to Screening [Visit S2] is permitted for a documented history of hypogonadism [low testosterone] as verified in subject health records); 14. Blood donation of 50 to 499 mL within 4 weeks of Screening (Visit S2) or of >499 mL within 8 weeks of Screening (Visit S2) laboratory collection; 15. Known history of human immunodeficiency virus infection. 16. Seropositive (hepatitis B surface antigen [HBsAg] +) for hepatitis B virus (HBV) or hepatitis C virus (HCV) (HCV seropositivity requires positive test for antibodies confirmed with positive test for HCV RNA); 17. Clinical evidence of uncontrolled hypothyroidism or hyperthyroidism,as per Investigator's judgment; 18. History of malignancy within the last 2 years prior to the date of consent requiring systemic treatment except for adequately treated basal cell carcinoma, squamous cell skin cancer, superficial bladder tumors, or in situ cervical cancer. Currently receiving systemic cancer treatment(s) or, in the Investigator's opinion, at risk of relapse for recent cancer; 19. Use of an investigational agent or device within 30 days or within 5 half-lives, based on plasma pharmacokinetics (PK) (whichever is longer) prior to Day 1 or current participation in an interventional investigational study. Participants previously exposed to ARO-APOC3 or ARO-ANG3 will require a washout period of at least 1 year from last dose; 20. Unwilling to limit alcohol consumption to within moderate limits for the duration of the study, as follows: not more than 14 units per week (1 unit = 80 mL of wine, 200 mL of beer, or 25 mL of 40% alcohol); 21. Any concomitant medical or psychiatric condition or social situation or any other situation that, in the Investigator's judgment, would make it difficult to comply with protocol requirements or put the participant at additional safety risk.
All laboratory tests used as exclusion criteria may be repeated once and the repeat value may be used for exclusion purposes. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of the study is: • Percent change from baseline at Week 24 in fasting TG. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The following are the secondary endpoints to be evaluated in this study: • Percent change from baseline at each scheduled assessment in fasting TG; • Percent change from baseline at Week 24 and over time through Week 48 in apolipoprotein (Apo)C-III; • Percent change from baseline at Week 24 and over time through Week 48 in fasting non-HDL-C; • Percent change from baseline at Week 24 and over time through Week 48 in fasting HDL C; • Percent change from baseline at Week 24 and over time through Week 48 in fasting total ApoB; • Percent change from baseline at Week 24 and over time through Week 48 in fasting LDL-C using ultracentrifugation; • Subject incidence of TEAEs |
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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 | Yes |
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 | Yes |
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.8.2.4 | Number of treatment arms in the trial | 5 |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Australia |
Canada |
New Zealand |
United States |
Hungary |
Poland |
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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 | 1 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 20 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 11 |