Study of Plozasiran in Adults With Severe Hypertriglyceridemia at Risk of Acute Pancreatitis

Official title

Double-Blind, Placebo-Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Plozasiran in Adults With Severe Hypertriglyceridemia at High Risk of Acute Pancreatitis (SHASTA-5 Study)

Overview

This study will evaluate the efficacy and safety of plozasiran in approximately 288 adult participants with severe hypertriglyceridemia (SHTG) and history of at least two prior acute pancreatitis (AP) events not attributed to other etiologies, with at least one occurring within the last 12 months prior to screening. Eligible participants will be randomly assigned in a double-blind manner to either receive plozasiran 25 mg by subcutaneous (SC) injection every three months (Q3M) or matching placebo. Enrolled participants will be counseled to remain on the specified low-fat diet and background medications throughout the study. Following completion of the double-blind treatment period, or if the participant has a positively adjudicated AP event (whichever occurs first), participants will transition to the 12-month Open-Label Extension (OLE) treatment period receiving plozasiran 25 mg by SC injection Q3M.

Interventions

• Drug Plozasiran
  ARO-APOC3 injection
• Drug Placebo
  sterile normal saline (0.9% NaCl)

Primary outcome measures

• Time to First Occurrence of Positively Adjudicated AP Event (Event Occurring More Than 10 Days After First Dose of Study Drug) [Time frame: Randomization up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)]]

Secondary outcome measures (8)

• Percent Change from Baseline in Fasting Serum Triglyceride (TG) Levels [Time frame: Baseline up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)]
• Proportion of Participants Who Achieve Average Fasting TG Levels of < 880 mg/dL (10 mmol/L) [Time frame: From Month 3 up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)]
• Proportion of Participants Who Achieve Fasting TG Levels of < 500 mg/dL (5.65 mmol/L) [Time frame: From Month 3 up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)]
• Time to First Occurrence of Major Abdominal Pain Event (Event Occurring More Than 10 Days After the First Dose of Study Drug). [Time frame: Randomization up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)]
• 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 [Time frame: Baseline up to end of Double Blind Treatment Period Study compared to placebo (Approximate Maximum 50 Months)]
• Change from Baseline in Patient-Reported Health Status as Assessed by the EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) Score [Time frame: Baseline up to end of Double Blind Treatment Period compared to placebo (Approximate Maximum 50 Months)]
• Number of Participants with Treatment-Emergent Adverse Events (TEAEs) compared to placebo [Time frame: From first dose of study drug up to Study Completion (Approximate Maximum 62 Months)]
• Rate of Occurrence of Adjudicated Major Cardiovascular Events (MACE) [Time frame: From first dose of study drug up to Study Completion (Approximate Maximum 62 Months)]

Eligibility criteria

Inclusion criteria

• Males, or nonpregnant (who do not plan to become pregnant) nonlactating females
• Established diagnosis of SHTG and prior documented evidence of fasting TG levels of ≥ 880 mg/dL (≥ 10 mmol/L)
• Documented evidence of at least 1 prior AP event not attributed to other etiologies occurring within the last 60 months prior to Screening.
• Fasting low-density lipoprotein cholesterol (LDL-C) ≤ 130 mg/dL (≤ 3.37 mmol/L) at Screening
• Screening hemoglobin A1c (HbA1c) ≤ 9.5%
• Willing to follow diet counseling and maintain a stable low-fat diet
• Must be on standard of care lipid and TG-lowering medications per local guidelines (unless documented as intolerant, or a treatment failure as determined by the Investigator)

Exclusion criteria

• Use of any hepatocyte-targeted small interfering ribonucleic acid (siRNA) that targets lipids and/or triglycerides within 365 days before Day 1, except inclisiran.
• Use of any other hepatocyte targeted siRNA or antisense oligonucleotide molecule within 60 days or within 5 half-lives lives before day 1. Whichever is longer.
• AP ≤ 4 weeks prior to Randomization/Day 1
• Body mass index (BMI) > 45 kg/m\^2
• Any planned bariatric surgery or similar procedures to induce weight lost starting at consent through End of Study (EOS)
• Planned coronary intervention (e.g. stent placement or heart bypass) during the study
• History of arterial revascularization within 16 weeks of Screening
• History of acute coronary syndrome event within 24 weeks of Screening
• Recent atherosclerotic cardiovascular disease (ASCVD) event within 24 weeks of Screening
• Recent unstable or symptomatic cardiac arrhythmia (including any associated medication changes) within 90 days of Screening. Individuals with stable well-controlled atrial arrhythmia will be allowed to participate in the study
• History of pacemaker or automatic implantable cardioverter defibrillators implant within 30 days before Screening
• New York Heart Association Class III-IV heart failure or last known ejection fraction of < 30%
• Current diagnosis of nephrotic syndrome
• Chronic kidney disease, defined by an estimated glomerular filtration rate (eGFR) < 20 mL/min/1.73 m\^2
• Liver disease defined as cirrhosis or Child-Pugh Class B and C, or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >2.5× Upper Limit of Normal (ULN) at Screening

Note: Additional Inclusion/Exclusion Criteria may apply per protocol

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 19 centers

• Research Center — Beijing
• Research Site — Guiyang
• Research Site — Harbin
• Research Site — Luoyang
• Research Site — Luoyang
• Research Site — Zhuzhou
• Research Center — Baotou
• Research Site — Chifeng
• … and 11 more centers

United States · 16 centers

• Research Site — Los Angeles
• Clinical Research Site 4 — Santa Clarita
• Research Site — New Haven
• Clinical Research Site 6 — Springfield
• Research Site — Indianapolis
• Research Site — Kansas City
• Research Site — Ann Arbor
• Research Site — St Louis
• … and 8 more centers

Brazil · 11 centers

• Research Site — Fortaleza
• Research Site — Belo Horizonte
• Research Site — Belo Horizonte
• Research Site — Belo Horizonte
• Research Site — Curitiba
• Research Site — Porto Alegre
• Research Site — Porto Alegre
• Research Site — Pôrto Alegre
• … and 3 more centers

Bulgaria · 8 centers

• Research Site — Burgas
• Research Site — Pleven
• Research Center — Plovdiv
• Research Site — Plovdiv
• Research Site — Rousse
• Research Site — Sofia
• Research Site — Sofia
• Research Site — Stara Zagora

South Korea · 8 centers

Center list to be confirmed — check the primary protocol.

Colombia · 6 centers

• Research Site — Barranquilla
• Research Site — Bogotá
• Research Site — Bogotá
• Research Site — Cali
• Research Site — Cali
• Research Site — Puerto Colombia

Argentina · 5 centers

• Research Site — Ramos Mejía
• Research Site — Córdoba
• Research Site — Córdoba
• Research Site — Rosario
• Research Site — Ciudad Autonoma Buenos Aires

Jordan · 5 centers

• Research Site — Amman
• Research Center — Amman
• Research Site — Amman
• Research Center — Irbid
• Research Center — Irbid

Hungary · 4 centers

• Research Site — Budapest
• Research Site — Budapest
• Research Site — Pécs
• Research Site — Szeged

Serbia · 4 centers

Center list to be confirmed — check the primary protocol.

Austria · 3 centers

• Research Site — Graz
• Research Site — Linz
• Research Site — Vienna

Saudi Arabia · 3 centers

Center list to be confirmed — check the primary protocol.

United Arab Emirates · 3 centers

Center list to be confirmed — check the primary protocol.

Mexico · 2 centers

• Research Site — Guadalajara
• Research Site — Mexico City

Sweden · 2 centers

Center list to be confirmed — check the primary protocol.

Oman · 1 center

• Research Site — Muscat

Singapore · 1 center

Center list to be confirmed — check the primary protocol.

United Kingdom · 1 center

Center list to be confirmed — check the primary protocol.

Identifiers

NCT: NCT06880770 · AROAPOC3-3011

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗