A study to understand the safety and effectiveness of ARO-APOC3 in Adults with Mixed Dyslipidemia

Phase 1

Conditions: Mixed Dyslipidemia
MedDRA version: 26.0Level: LLTClassification code 10027763Term: Mixed hyperlipidemiaSystem Organ Class: 100000004850
Therapeutic area: Diseases [C] - Nutritional and Metabolic Diseases [C18]

Registration Number: EUCTR2021-000688-57-PL

Lead Sponsor: Arrowhead Pharmaceuticals, Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 320

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.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 256
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 64

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 wit

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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