SYNTHETIC DOUBLE-STRANDED SIRNA OLIGONUCLEOTIDE DIRECTED AGAINST APOLIPOPROTEIN C-III MRNA AND COVALENTLY LINKED TO A LIGAND CONTAINING THREE N-ACETYLGALACTOSAMINE RESIDUES for Severe hypertriglyceridemia

Inclusion criteria

• {"criterion_text":"- Males, or nonpregnant (who do not plan to become pregnant) nonlactating females, who are ≥18 years of age at screening"}
• {"criterion_text":"- Established diagnosis of SHTG and prior documented evidence (medical history) of fasting TG levels of ≥880 mg/dL (≥10 mmol/L)"}
• {"criterion_text":"- Fasting TG level ≥500 mg/dL (≥5.65 mmol/L) collected during the screening period"}
• {"criterion_text":"- Documented evidence of at least 1 prior AP event (according to the clinical diagnosis per medical records) not attributed to other etiologies (eg, gallstones, alcohol), occurring within the last 5 years (60 months) prior to screening"}
• {"criterion_text":"- Fasting LDL-C ≤130 mg/dL (≤3.37 mmol/L) at screening"}
• {"criterion_text":"- Screening HbA1c ≤9.5%"}
• {"criterion_text":"- Willing to follow diet counseling and maintain a stable low-fat diet"}
• {"criterion_text":"- Participants must be on standard of care lipid- and TG-lowering medications per local guidelines (unless documented as intolerant as determined by the Investigator)"}

Exclusion criteria

• {"criterion_text":"- Use of any hepatocyte-targeted siRNA that targets lipids and/or triglycerides within 365 days before Day 1 (except inclisiran, which is permitted). Administration of investigational drug and inclisiran must be separated by at least 4 weeks."}
• {"criterion_text":"- Use of any other hepatocyte-targeted siRNA or antisense oligonucleotide molecule within 60 days or within 5-half-lives before Day 1 based on plasma PK, whichever is longer."}
• {"criterion_text":"- Acute pancreatitis ≤ 4 weeks prior to Randomization/Day 1."}
• {"criterion_text":"- Body mass index >45 kg/m2"}
• {"criterion_text":"- Use of any hepatocyte-targeted siRNA that targets lipids and/or triglycerides within 365 days before Day 1 (except inclisiran, which is permitted). Administration of investigational drug and inclisiran must be separated by at least 4 weeks."}

Primary endpoints

• {"endpoint_text":"- Time to first occurrence of positively adjudicated AP event (event occurring more than 10 days after the first dose of study drug) compared with placebo during the double-blind treatment period","definition_or_measurement_approach":"Time-to-first-event analysis of positively adjudicated acute pancreatitis (AP) events occurring more than 10 days after first dose; events adjudicated and compared versus placebo during the double-blind treatment period."}

Secondary endpoints

• {"endpoint_text":"- Percent change in fasting serum TG levels from baseline to Month 12 (V9) compared with placebo","definition_or_measurement_approach":"Percent change from baseline to Month 12 (visit V9) in fasting serum triglycerides compared against placebo."}
• {"endpoint_text":"- Proportion of participants who achieve average fasting TG levels of <880 mg/dL (10 mmol/L) from Month 3 to the end of the double-blind treatment period","definition_or_measurement_approach":"Proportion achieving mean fasting TG <880 mg/dL (10 mmol/L) averaged from Month 3 through end of double-blind period."}
• {"endpoint_text":"- Proportion of participants who achieve average fasting TG levels of <500 mg/dL (5.65 mmol/L) from Month 3 to the end of the double-blind treatment period","definition_or_measurement_approach":"Proportion achieving mean fasting TG <500 mg/dL (5.65 mmol/L) averaged from Month 3 through end of double-blind period."}
• {"endpoint_text":"- Time to first occurrence of major abdominal pain event* (event occurring more than 10 days after the first dose of study drug) compared with placebo * Major abdominal pain event defined as any of the following: 1) positively adjudicated AP, or 2) positively adjudicated presentation to emergency room and/or hospitalization with abdominal pain for which no other etiology has been identified, or 3) need to initiate apheresis to decrease TG levels","definition_or_measurement_approach":"Time-to-first-event analysis for major abdominal pain events (defined as positively adjudicated AP; or adjudicated ER visit/hospitalization for abdominal pain with no other identified etiology; or initiation of apheresis to lower TG), events occurring >10 days after first dose, compared to placebo."}
• {"endpoint_text":"- Change from baseline in patient-reported productivity and activity impairment as assessed by the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem (WPAI SHP) score","definition_or_measurement_approach":"Change from baseline in WPAI-SHP score (patient-reported productivity and activity impairment)."}
• {"endpoint_text":"- Change from baseline in patient-reported health status as assessed by the EuroQol 5-dimension instrument (EQ 5D 5L) score","definition_or_measurement_approach":"Change from baseline in EQ-5D-5L patient-reported health status score."}
• {"endpoint_text":"- The frequency and severity of treatment-emergent adverse events (TEAEs) from baseline to end of study (EOS) of each treatment period","definition_or_measurement_approach":"Frequency and severity summary of TEAEs from baseline to end of study for each treatment period."}
• {"endpoint_text":"- Adjudicated MACE event rates","definition_or_measurement_approach":"Adjudicated major adverse cardiovascular event (MACE) rates."}

Methods

• Doctor-to-Patient Letter (K2_Recruitment Material / Doctor-to-Patient Letter) — channel: letter from physician to patient; country-specific versions present (e.g., AUT, SWE, BG).
• Physician Referral Letter / Physician Referral Brochure (K2_Physician Referral Letter / K2_Physician Referral Brochure) — channel: physician outreach/referral; country-specific materials (e.g., HUN).
• Patient Brochure / Patient-facing materials (K2_Recruitment Material_Patient Brochure / K1_Patient Brochure) — channel: patient information brochures for potential participants; country-specific versions available.
• Recruitment arrangements and informed consent procedure forms (K1_Informed consent and patient recruitment procedure) — channel: recruitment process documentation and procedures provided to sites; English and country-specific versions.
• Patient ID Card / Patient Study Guide / Emergency Room Visit Request Card — materials provided to enrolled participants to support recruitment/enrolment and retention.

Austria

Earliest CTIS Part Ii Submission Date

05-09-2025

Latest Decision Or Authorization Date

29-09-2025

Processing Time Days

24

Number Of Sites

3

Number Of Participants

9

Sweden

Earliest CTIS Part Ii Submission Date

17-06-2025

Latest Decision Or Authorization Date

23-09-2025

Processing Time Days

98

Number Of Sites

2

Number Of Participants

6

Bulgaria

Earliest CTIS Part Ii Submission Date

17-06-2025

Latest Decision Or Authorization Date

29-09-2025

Processing Time Days

104

Number Of Sites

12

Number Of Participants

24

Hungary

Earliest CTIS Part Ii Submission Date

18-07-2025

Latest Decision Or Authorization Date

26-09-2025

Processing Time Days

70

Number Of Sites

4

Number Of Participants

16

Primary sponsor

Full Name

Arrowhead Pharmaceuticals Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

IQVIA Limited

Responsibilities

Multiple sponsor duties including operational and safety support (codes: 1,10,11,12,13,15,2,5,6,8); contact eu_clinical_trials_information@iqvia.com

Name

Sharp Clinical Services LLC

Responsibilities

Sponsor duties code: 14; contact Dan.gourley@sharpclinical.com

Name

Cisys Inc.

Responsibilities

Electronic Adjudication System (EAS) vendor for adjudication services; duties code 15; contact dbeach@cisys.com

Name

Medidata Solutions Inc.

Responsibilities

Data/technology vendor duties code 7; contact Lyndsay.Zizza@3ds.com

Third parties

• {"country":"United Kingdom","full_name":"IQVIA Limited","duties_or_roles":"Sponsor duties codes: 1,10,11,12,13,15 (Safety reporting to Ethics Committees only, eTMF),2,5,6,8","organisation_type":"Pharmaceutical company"}
• {"country":"Netherlands","full_name":"Manufacturing Packaging Farmaca (MPF) B.V.","duties_or_roles":"Sponsor duties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Sharp Clinical Services LLC","duties_or_roles":"Sponsor duties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Cisys Inc.","duties_or_roles":"Sponsor duties codes: 15 (Electronic Adjudication System (EAS) Vendor for adjudication services)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Medidata Solutions Inc.","duties_or_roles":"Sponsor duties codes: 7","organisation_type":"Non-Pharmaceutical company"}
• {"country":"Belgium","full_name":"MEDPACE LABORATORIES","duties_or_roles":"Sponsor duties codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Almac Clinical Technologies LLC","duties_or_roles":"Sponsor duties codes: 3","organisation_type":"Pharmaceutical company"}