| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Familial Chylomicronemia Syndrome |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Genetic Phenomena [G05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 24.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10085051 |
| E.1.2 | Term | Familial chylomicronemia syndrome |
| E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
|
| 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 evaluate the efficacy and safety of ARO-APOC3 in adults with FCS |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or nonpregnant (who do not plan to become pregnant), nonlactating females ≥18 years of age
2. Able and willing to provide written informed consent prior to the performance of any study specific procedures
3. Fasting TG ≥10 mmol/L (≥880 mg/dL) at screening, that is refractory to standard lipid lowering therapy (sample drawn after at least the minimum time on stable lipid lowering regimen described in the protocol). Two repeat tests are allowed to qualify.
4. A diagnosis of FCS based on a documented history of fasting TG levels in excess of 1000 mg/dL on repeated testing (for at least 3 prior occasions), and at least one of the following:
a. A supportive genetic test (from a source-verifiable medical record or based on screening genotype). Supportive genetic testing includes but is not limited to homozygous, compound heterozygous, or double heterozygote for loss of function or otherwise inactivating mutations in genes affecting lipoprotein lipase activity including LPL, APOC2, APOA5, GPIHBP1, GPD1, or LMF1; or evidence of low LPL activity (<20% of normal) based on source verifiable documentation; or
b. Documented history of recurrent episodes of acute pancreatitis, not caused by alcohol or cholelithiasis; or
c. Documented history of recurrent hospitalizations for severe abdominal pain without other explainable cause; or
d. Documented history of childhood pancreatitis; or
e. Family history of hypertriglyceridemia-induced pancreatitis
5. Willing to follow dietary counseling as per PI judgment based on local standard of care, consistent with an intake of ≤ 20 g of fat per day during the study
6. If on medications for management of type 2 diabetes, or other medications specified in the protocol, the dosing regimen must be stable before collection of qualifying lipid parameter at screening.
7. Participants with a medical history of clinical atherosclerotic cardiovascular disease (ASCVD) or those with elevated 10-year ASCVD risk (eg, ≥7.5% per American Heart Association / American College of Cardiology risk calculator) must be on appropriate lipid-lowering therapy as per local standard of care (ie, including moderate to high intensity statin, as indicated) prior to collection of qualifying TG levels.
8. Participants of childbearing potential must agree to use a highly effective form of contraception in addition to a male condom, during the study and for at least 24 weeks after the last dose of IP. Women of childbearing potential on a hormonal contraceptive must be stable on the medication for ≥2 menstrual cycles prior to Day 1. Men must not donate sperm during the study and for at least 24 weeks after the last dose of IP.
|
|
| E.4 | Principal exclusion criteria |
1. Current use or use within the last 365 days from Day 1 of any hepatocyte-targeted siRNA or antisense oligonucleotide molecule
2. Diabetes mellitus with any of the following:
a. Newly diagnosed within 12 weeks of screening
b. HbA1c ≥9.0% (or >75 mmol/mol International Federation of Clinical Chemistry [IFCC] units) at screening
3. Active pancreatitis within 12 weeks before Day 1
4. History of acute coronary syndrome events (myocardial infarction or unstable angina) or procedures (coronary revascularization, angioplasty, or stenting) within 24 weeks of Day 1
5. History of major surgeries within 12 weeks of Day 1 (including cardiac and vascular surgeries, eg, coronary artery bypass graft)
6. Any of the following laboratory values at screening:
a. ALT or AST ≥3×ULN at screening
b. Total bilirubin ≥1.5 ULN (if the participant has a prior diagnosis and documentation of Gilbert’s syndrome, then total bilirubin must be ≤3 mg/dL at screening)
c. Estimated glomerular filtration rate <30 mL/min/1.73 m2 at screening, using the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) creatinine equation (Levey 2009)
d. Spot urine protein/spot urine creatinine ratio greater than 3 grams per day
e. Clinically significant abnormality in prothrombin time, partial thromboplastin time, or INR
7. Uncontrolled hypertension (blood pressure >160/100 mmHg at screening); if untreated, participant may be rescreened once hypertension is treated and controlled
8. Use of any of the following:
a. Systemic use of corticosteroids or anabolic steroids within 4 weeks prior to Day 1 or planned use during the study
b. GLP-1 receptor agonists
c. Plasma apheresis within 4 weeks prior to Day 1 or planned during the study
d. Blood donation of 50 to 499 mL within 4 weeks of collection of qualifying lipid parameter collection or of >499 mL within 8 weeks of qualifying lipid parameter collection
9. On treatment with HIV antiretroviral therapy
10. 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)
11. New York Heart Association (NYHA) Class II, III, or IV heart failure or last known ejection fraction of <30%
12. Clinical evidence of primary hypothyroidism (screening TSH > ULN and free T4<LLN), primary subclinical hypothyroidism (screening TSH > ULN and free T4 WNL), or secondary hypothyroidism (screening TSH < LLN and free T4< LLN)
13. History of stroke, transient ischemic attack, or peripheral artery disease within 24 weeks of first dose
14. History of bleeding diathesis or coagulopathy
15. Current diagnosis of nephrotic syndrome
16. Unwilling to limit alcohol consumption to within moderate limits for the duration of the study, as follows: not more than 14 units per week for women and men (1 unit approximately corresponds to 80 mL of wine, 200 mL of beer, or 25 mL of 40% alcohol)
17. 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 PI’s opinion, at risk of relapse for recent cancer.
18. Use of an investigational agent or device within 30 days or within 5 half-lives, based on plasma 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.
19. Any concomitant medical or psychiatric condition or social situation or any other situation that, in the PI’s judgment, would make it difficult to comply with protocol requirements or put the participant at additional safety risk.
20. Clinical evidence of Cushing's syndrome |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from baseline at Month 10 in fasting TG |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary endpoints:
1. Percent change from baseline at Month 10 and 12 (averaged) in fasting TG
2. Percent change from baseline at Month 10 in fasting APOC3
3. Percent change from baseline at Month 12 in fasting APOC3
Secondary endpoints:
4. Percent change from baseline at Month 10 in non-high density lipoprotein cholesterol (non-HDL-C), and HDL-C
5. Percent change from baseline at Month 12 in fasting TG, non-HDL-C, and HDL-C
6. Proportion of participants achieving TG of <500 mg/dL at Month 10
7. Proportion of participants achieving TG of <500 mg/dL at Month 12
8. Change and percent change from baseline at each scheduled assessment in fasting TG up to Month 12
9. Participant incidence of TEAEs
10. Incidence of positively adjudicated events of acute pancreatitis |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary endpoints:
1. month 10 and 12 (averaged)
2. month 10
3. month 12
Secondary end points:
4 and 6 month 10
5 and 7 month 12
8. each scheduled assessment up to month 12
9 and 10- throughout both periods |
|
| 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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 |
| Randomized double-blind period followed by an open-label extension period |
|
| 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 | 4 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Argentina |
| New Zealand |
| Oman |
| Singapore |
| Australia |
| Canada |
| Japan |
| Mexico |
| Serbia |
| United States |
| Austria |
| Belgium |
| France |
| Ireland |
| Poland |
| Spain |
| Türkiye |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
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