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    Summary
    EudraCT Number:2021-000687-30
    Sponsor's Protocol Code Number:AROAPOC3-2001
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-06-18
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2021-000687-30
    A.3Full title of the trial
    A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of ARO-APOC3 in Adults with Severe Hypertriglyceridemia
    Kettős vak, placebo kontrollált IIb. fázisú vizsgálat az ARO-APOC3 készítmény hatásosságának és biztonságosságának értékelésére, súlyos hipertrigliceridémiában szenvedő felnőttek esetében
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to understand the safety and effectivness of ARO-APOC3 in Adults with Severe Hypertriglyceridemia
    Az ARO-APOC3 biztonságosságának és hatásosságának megismerésére vonatkozó vizsgálat súlyos hipertrigliceridémiás felnőtt betegek részvételével
    A.4.1Sponsor's protocol code numberAROAPOC3-2001
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT04720534
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorArrowhead Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportArrowhead Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationArrowhead Pharmaceuticals, Inc.
    B.5.2Functional name of contact pointArmine Balian
    B.5.3 Address:
    B.5.3.1Street Address177 East Colorado Boulevard, Suite 700
    B.5.3.2Town/ cityPasadena
    B.5.3.3Post code91105
    B.5.3.4CountryUnited States
    B.5.4Telephone number+16263043400
    B.5.5Fax number+16263043401
    B.5.6E-mailabalian@arrowheadpharma.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameARO-APOC3 Injection
    D.3.2Product code ARO-APOC3
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTo Be Determined
    D.3.9.1CAS number 2379776-40-4
    D.3.9.2Current sponsor codeADS-005
    D.3.9.3Other descriptive nameSynthetic double-stranded siRNA oligonucleotide directed against apolipoprotein C-III mRNA and covalently linked to a ligand containing three N-acetylgalactosamine residues
    D.3.9.4EV Substance CodeSUB208166
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Severe Hypertriglyceridemia
    E.1.1.1Medical condition in easily understood language
    abnormal triglyceride levels
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10020870
    E.1.2Term Hypertriglyceridemia
    E.1.2System Organ Class 100000004861
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of the study is to evaluate the safety and efficacy of ARO-APOC3 in adults with Severe Hypertriglyceridemia (SHTG) and to select a dosing regimen for later stage clinical studies in this patient population.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetics, Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF), Optional Genotype, and Future Research studies.
    E.3Principal 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, evidence of triglycerides (TG) ≥500 mg/dL (5.65 mmol/L) on more than 1 occasion;
    3. A mean fasting TG ≥500 mg/dL (5.65 mmol/L) collected at two separate and consecutive visits at least 7 days apart and no more than 14 days apart during the Screening period.
    4. Participants with a medical history of clinical atherosclerotic cardiovascular disease (ASCVD) or those with elevated 10-year ASVCD risk (e.g., ≥7.5% per American Heart Association / American College of Cardiology [ACC/AHA] risk calculator) must be on appropriate lipid-lowering therapy as per local standard of care (i.e., including moderate to high intensity statin, as indicated) prior to collection of qualifying TG levels;
    5. Able and willing to provide written informed consent prior to the performance of any study specific procedures;
    6. Willing to follow diet counseling and maintain a stable diet as per Investigator judgment based on local standard of care;
    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 not donate sperm during the study and for at least 24 weeks following the or 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; and
    9. Participants on 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

    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.
    E.4Principal 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. Active pancreatitis within 12 weeks prior to Day 1;
    3. Known genetically confirmed diagnosis of Familial Chylomicronemia Syndrome
    4. Any planned bariatric surgery or similar procedures to induce weight loss during the period starting at consent through the end of the study;
    5. History of major surgery within 12 weeks of Day 1 or planned major surgery during the study;
    6. Planned coronary intervention (such as stent placement or heart bypass) during the study;
    7. History of acute coronary syndrome event within 24 weeks of Day 1;
    8. New York Heart Association (NYHA) Class II, III, or IV heart failure or last known ejection fraction of <30%;
    9. Uncontrolled hypertension (blood pressure >160/100 mmHg at Screening); if untreated, participant may be re-screened once hypertension is treated and controlled;
    10. History of hemorrhagic stroke within 24 weeks of Day 1;
    11. History of bleeding diathesis or coagulopathy;
    12. Current diagnosis of nephrotic syndrome;
    13. 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. Glycosylated hemoglobin (HbA1c) >9.0% (or >75 mmol/mol International Federation of Clinical Chemistry [IFCC] units) at screening ;
    d. Persistently positive (≥ 2 consecutive tests for ≥1+) for protein on urine dipstick;
    e. Clinically significant abnormality in PT, aPTT, or INR;
    14. 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. Plasma apheresis within 4 weeks prior to Day 1 or planned during the study;
    15. Blood donation of 50 to 499 mL within 4 weeks of Screening (visit S2) laboratory collection or of >499 mL within 8 weeks of Screening (visit S2) laboratory collection;
    16. Known history of human immunodeficiency virus infection;
    17. 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);
    18. Clinical evidence of uncontrolled hypothyroidism or hyperthyroidism as per Investigator’s judgment;
    19. 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;
    20. 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;
    21. 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 21 units per week for men (1 unit = 150 mL of wine, 360 mL of beer, or 45 mL of 40% alcohol); or
    22. 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.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint of the study is:
    • Percent change from baseline at Week 24 in fasting TG.
    E.5.1.1Timepoint(s) of evaluation of this end point
    24 Weeks
    E.5.2Secondary end point(s)
    The following are the secondary endpoints to be evaluated in this study:
    • Percent change over time through Week 48 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 high-density lipoprotein-cholesterol (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 low density lipoprotein-cholesterol (LDL C) using ultracentrifugation;
    • Change from baseline in plasma concentrations of ARO-APOC3 over time through Week 12; and
    • The frequency and severity of AEs and SAEs over time through Week 48.

    The following are the exploratory endpoints defined in this study:
    • Change from baseline over time through Week 48 in TG and other fasting lipid parameters (total cholesterol, LDL/HDL ratio, very low-density lipoprotein cholesterol [VLDL-C], ApoB 48, lipoprotein [LP][a], ApoB-100, ApoC-II, ApoA-I and ApoA-V [all values drawn after at least a 10-hour fast]);
    • Change from baseline at Week 24 and overtime through Week 48 in fasting serum blood glucose, HbA1c, homeostatic model assessment for insulin resistance (HOMA-IR) and C peptide;
    • Change from baseline over time through Week 48 in high sensitivity C-reactive protein (hsCRP);
    • Cumulative number of on-study occurrences of acute pancreatitis events over time through Week 48;
    • Cumulative number of on-study hospitalizations for abdominal pain over time through Week 48;
    Note: All AEs and SAEs reported by the Investigator during the study that are consistent with an event of acute pancreatitis as per the 2013 Atlanta definition meeting 2 of the following 3 criteria: (1) abdominal pain consistent with acute pancreatitis (acute onset of a persistent, severe, epigastric pain often radiating to the back); (2) serum lipase activity (or amylase activity) ≥3× ULN; and (3) characteristic findings of acute pancreatitis on contrast-enhanced computed tomography (CECT) or magnetic resonance imaging (MRI) or transabdominal ultrasonography.
    • Proportion of participants requiring emergent apheresis over time through Week 48;
    • Change from baseline to Week 24 in liver fat content using MRI-proton density fat fraction (PDFF); only in participants with a liver fat fraction of ≥8% at Screening; and
    • Emergence of and levels of anti-drug antibodies to ARO-APOC3 in those receiving ARO-APOC3 over time through Week 48.
    E.5.2.1Timepoint(s) of evaluation of this end point
    12, 24 and 48 weeks
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA30
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If 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
    Germany
    Hungary
    Netherlands
    Poland
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months4
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 240
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 60
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state33
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 300
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    After Week 48, participants will be eligible and invited to consent and continue in an open-label extension study. All placebo participants who opt to continue will switch to active drug during the extension study. After discontinuation from the study the participants will be treated by their physician according to standard medical practice with the standard of care treatment.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-07-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-08-25
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-08-31
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