Study of Plozasiran in Adults With Severe Hypertriglyceridemia (SHASTA-4)

Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Plozsiran in Adults With Severe Hypertriglyceridemia

This Phase 3 study will evaluate the safety and efficacy of plozasiran injection (ARO-APOC3) in adult participants with severe hypertriglyceridemia (SHTG). After providing informed consent eligible participants will be randomized to receive 4 doses (once every 3 months) of plozasiran or placebo, and be evaluated for efficacy and safety. After Month 12, eligible participants will be offered an opportunity to continue in an optional open-label extension under a separate protocol.

Study Overview

• Status: Active, not recruiting
• Conditions: Severe Hypertriglyceridemia
• Intervention / Treatment: Drug: Placebo; Drug: Plozasiran Injection

• Study Type: Interventional
• Enrollment (Actual): 311
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires
    • CABA, Buenos Aires, Argentina, 1128
      • Research Site 52
    • Ciudad Autónoma de Buenos Aires, Buenos Aires, Argentina, C1056ABJ
      • Research Site 51
  • Córdoba Province
    • Córdoba, Córdoba Province, Argentina, 5003
      • Research Site 54
  • Mendoza Province
    • Godoy Cruz, Mendoza Province, Argentina, 5501
      • Research Site 53
  • Santa Fe Province
    • Rosario, Santa Fe Province, Argentina, 2000
      • Research Site 55
• Brazil
  • Recife, Brazil, 52051-380
    • Research Site 63
  • Estado de Bahia
    • Salvador, Estado de Bahia, Brazil, 40170
      • Research Site 61
  • Federal District
    • Brasília, Federal District, Brazil, 70710
      • Research Site 56
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30150
      • Research Site 59
  • Sergipe
    • Aracaju, Sergipe, Brazil, 49055-530
      • Research Site 62
  • São Paulo
    • Campinas, São Paulo, Brazil, 13060
      • Research Site 57
    • Santo André, São Paulo, Brazil, 09080
      • Research Site 58
    • São José do Rio Preto, São Paulo, Brazil, 15090
      • Research Site 60
• Bulgaria
  • Byala, Bulgaria, 7100
    • Research Site 64
  • Dimitrovgrad, Bulgaria, 6400
    • Research Site 65
  • Haskovo, Bulgaria, 6300
    • Research Site 66
  • Kyustendil, Bulgaria, 2500
    • Research Site 67
  • Rousse, Bulgaria, 7013
    • Research Site 68
  • Sevlievo, Bulgaria, 5400
    • Research Site 69
  • Sofia, Bulgaria, 1202
    • Research Site 76
  • Sofia, Bulgaria, 1431
    • Research Site 70
  • Sofia, Bulgaria, 1431
    • Research Site 73
  • Sofia, Bulgaria, 1510
    • Research Site 71
  • Sofia, Bulgaria, 1616
    • Research Site 75
  • Sofia, Bulgaria, 1680
    • Research Site 72
  • Sofia, Bulgaria, 1750
    • Research Site 74
  • Stara Zagora, Bulgaria, 6003
    • Research Site 77
• Canada
  • British Columbia
    • North Vancouver, British Columbia, Canada, V7M 2H4
      • Research Site 78
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7K9
      • Research Site 79
    • Laval, Quebec, Canada, H7T 2P5
      • Research Site 80
    • Québec, Quebec, Canada, G1G 3Y8
      • Research Site 81
    • Terrebonne, Quebec, Canada, J6V2H2
      • Research Site 82
• Czechia
  • Brno, Czechia, 65691
    • Research Site 83
  • Náchod, Czechia, 547 01
    • Research Site 84
  • Olomouc, Czechia, 77900
    • Research Site 85
  • Prague, Czechia, 100 00
    • Research Site 86
  • Slaný, Czechia, 15006
    • Research Site 88
  • Teplice, Czechia, 41501
    • Research Site 89
  • Trutnov, Czechia, 541 01
    • Research Site 87
• France
  • Paris, France, 75013
    • Research Site 90
  • Bouches-du-Rhône
    • Marseille, Bouches-du-Rhône, France, 13005
      • Research Site 91
  • Gironde
    • Pessac, Gironde, France, 33604
      • Research Site 92
  • Pyrenees Atlantiques
    • Bayonne, Pyrenees Atlantiques, France, 64100
      • Research Site 93
  • Rhone
    • Lyon, Rhone, France, 69007
      • Research Site 94
• Germany
  • Baden-Wurttemberg
    • Deggingen, Baden-Wurttemberg, Germany, 73326
      • Research Site 95
  • Bavaria
    • Wallerfing, Bavaria, Germany, 94574
      • Research Site 96
  • Saxony-Anhalt
    • Magdeburg, Saxony-Anhalt, Germany
      • Research Site 97
  • State of Berlin
    • Berlin, State of Berlin, Germany, 13353
      • Research Site 98
• Hungary
  • Békéscsaba, Hungary, 5600
    • Research Site 99
  • Kaposvár, Hungary, 7400
    • Research Site 100
  • Miskolc, Hungary, 3530
    • Research Site 101
  • Pécs, Hungary, 7623
    • Research Site 102
  • Pécs, Hungary, 7635
    • Research Site 104
  • Zalaegerszeg, Hungary, 8900
    • Research Site 103
• Latvia
  • Daugavpils, Latvia, LV-5410
    • Research Site 107
  • Daugavpils, Latvia, LV-5417
    • Research Site 105
  • Daugavpils, Latvia, LV-5417
    • Research Site 106
  • Kuldīga, Latvia, LV-3301
    • Research Site 108
  • Riga, Latvia, LV-1002
    • Research Site 109
  • Riga, Latvia, LV-1038
    • Research Site 110
  • Riga, Latvia, LV-1050
    • Research Site 111
  • Tukums, Latvia, LV-3101
    • Research Site 112
• Lithuania
  • Kaunas, Lithuania, LT-48259
    • Research Site 115
  • Kaunas, Lithuania, LT-49387
    • Research Site 113
  • Kaunas, Lithuania, LT-50177
    • Research Site 114
  • Vilnius, Lithuania, LT-08406
    • Research Site 116
  • Vilnius, Lithuania, LT-08406
    • Research Site 117
  • Šiauliai, Lithuania, LT-76206
    • Research Site 118
• New Zealand
  • Christchurch, New Zealand, 8011
    • Research Site 119
  • New Plymouth, New Zealand, 4310
    • Research Site 120
  • Newtown, New Zealand, 6021
    • Research Site 121
• Poland
  • Bydgoszcz, Poland, 85-065
    • Research Site 122
  • Gdynia, Poland, 81-338
    • Research Site 123
  • Katowice, Poland, 40-156
    • Research Site 124
  • Lodz, Poland, 94-255
    • Research Site 129
  • Malbork, Poland, 82-200
    • Research Site 125
  • Szczecin, Poland, 71-500
    • Research Site 126
  • Torun, Poland, 87-100
    • Research Site 130
  • Wroclaw, Poland, 51-314
    • Research Site 127
  • Zamość, Poland, 22-400
    • Research Site 128
• Slovakia
  • Bratislava, Slovakia, 83101
    • Research Site 134
  • Nové Zámky, Slovakia, 94002
    • Research Site 131
  • Prešov, Slovakia, 08001
    • Research Site 132
  • Rožňava, Slovakia, 04801
    • Research Site 133
• South Africa
  • Gauteng
    • Centurion, Gauteng, South Africa, 0157
      • Research Site 135
    • Krugersdorp, Gauteng, South Africa, 1739
      • Research Site 136
    • Pretoria, Gauteng, South Africa, 0184
      • Research Site 137
  • KwaZulu-Natal
    • Durban, KwaZulu-Natal, South Africa, 4449
      • Research Site 138
  • Western Cape
    • Cape Town, Western Cape, South Africa, 7441
      • Research Site 144
    • Cape Town, Western Cape, South Africa, 7500
      • Research Site 139
    • Cape Town, Western Cape, South Africa, 7500
      • Research Site 140
    • Cape Town, Western Cape, South Africa, 7530
      • Research Site 143
    • Cape Town, Western Cape, South Africa, 7925
      • Research Site 145
    • Mossel Bay, Western Cape, South Africa, 6500
      • Research Site 146
    • Plettenberg Bay, Western Cape, South Africa, 6600
      • Research Site 142
    • Somerset West, Western Cape, South Africa, 7570
      • Research Site 141
• Spain
  • Madrid, Spain, 28041
    • Research Site 147
  • Seville, Spain, 41013
    • Research Site 148
  • La Coruña
    • A Coruña, La Coruña, Spain, 15006
      • Research Site 149
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • Research Site 1
    • Mobile, Alabama, United States, 36604
      • Research Site 2
  • California
    • Beverly Hills, California, United States, 90211
      • Research Site 3
    • Canoga Park, California, United States, 91303
      • Research Site 4
    • Huntington Beach, California, United States, 92648
      • Research Site 5
    • Lincoln, California, United States, 95648
      • Research Site 6
    • Long Beach, California, United States, 90822
      • Research Site 7
    • Oxnard, California, United States, 93030
      • Research Site 8
  • Florida
    • Clearwater, Florida, United States, 33756
      • Research Site 9
    • North Miami, Florida, United States, 33162
      • Research Site 10
    • Sarasota, Florida, United States, 34239
      • Research Site 11
  • Georgia
    • Lawrenceville, Georgia, United States, 30044
      • Research Site 12
    • Sugar Hill, Georgia, United States, 30518
      • Research Site 13
  • Indiana
    • Elkhart, Indiana, United States, 46514
      • Research Site 14
    • Indianapolis, Indiana, United States, 46290
      • Research Site 15
    • South Bend, Indiana, United States, 46617
      • Research Site 16
  • Kansas
    • Overland Park, Kansas, United States, 66211
      • Research Site 17
    • Topeka, Kansas, United States, 66606
      • Research Site 18
  • Louisiana
    • Metairie, Louisiana, United States, 70001
      • Research Site 19
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Research Site 20
  • Mississippi
    • Jackson, Mississippi, United States, 39202
      • Research Site 21
  • Nebraska
    • Fremont, Nebraska, United States, 68025
      • Research Site 22
    • Norfolk, Nebraska, United States, 68701
      • Research Site 23
  • New Jersey
    • Morristown, New Jersey, United States, 07960
      • Research Site 24
  • New York
    • New York, New York, United States, 10029
      • Research Site 26
    • Riverhead, New York, United States, 11901
      • Research Site 27
    • The Bronx, New York, United States, 10461
      • Research Site 25
  • North Carolina
    • Asheboro, North Carolina, United States, 27203
      • Research Site 28
    • Wilmington, North Carolina, United States, 28412
      • Research Site 29
  • Ohio
    • Beavercreek, Ohio, United States, 45431
      • Research Site 30
    • Columbus, Ohio, United States, 43214
      • Research Site 31
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73112
      • Research Site 32
  • Pennsylvania
    • Horsham, Pennsylvania, United States, 19044
      • Research Site 33
    • Newport, Pennsylvania, United States, 17074
      • Research Site 34
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site 35
    • Philadelphia, Pennsylvania, United States, 19104
      • Research Site 36
  • South Carolina
    • Fort Mill, South Carolina, United States, 29707
      • Research Site 37
    • Greenville, South Carolina, United States, 29607
      • Research Site 38
  • Tennessee
    • Chattanooga, Tennessee, United States, 37411
      • Research Site 39
  • Texas
    • Fort Worth, Texas, United States, 76132
      • Research Site 40
    • Houston, Texas, United States, 77040
      • Research Site 41
    • Houston, Texas, United States, 77090
      • Research Site 42
    • Houston, Texas, United States, 77090
      • Research Site 43
    • Sugar Land, Texas, United States, 77479
      • Research Site 44
    • Tomball, Texas, United States, 77375
      • Research Site 45
    • Victoria, Texas, United States, 77901
      • Research Site 46
  • Utah
    • Bountiful, Utah, United States, 84010
      • Research Site 47
    • St. George, Utah, United States, 84790
      • Research Site 48
  • Virginia
    • Manassas, Virginia, United States, 20110
      • Research Site 49
    • Roanoke, Virginia, United States, 24014
      • Research Site 50

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Established diagnosis of severe hypertriglyceridemia (SHTG) and prior documented evidence (medical history) of fasting TG levels of ≥500 mg/dL (≥5.65 mmol/L)
• Mean fasting TG level ≥500 mg/dL (≥5.65 mmol/L) collected at 2 separate and consecutive visits at least 7 days apart and no more than 17 days apart during the screening period
• Fasting low density lipoprotein-cholesterol (LDL-C) ≤130 mg/dL (≤3.37 mmol/L) at screening
• Screening HbA1C ≤9.0%
• Must be on standard of care lipid-lowering medications per local guidelines (unless documented as intolerant as determined by the Investigator, including an inability to safely administer or re-administer a specific drug because of fear, preference, genetic, clinical, or metabolic considerations, or due to a previous adverse reaction associated with, attributed to, or caused by specific drug)

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, which is permitted). Administration of investigational drug and inclisiran must be separated by at least 4 weeks
• 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 pharmacokinetics (PK), whichever is longer (except inclisiran, which is permitted)
• Known diagnosis of familial chylomicronemia syndrome (FCS) (type 1 Hyperlipoproteinemia) by documentation of confirmed homozygote or double heterozygote for loss-of-function mutations in type 1- causing genes
• Body mass index >45kg/m^2

Note: Additional Inclusion/Exclusion criteria may apply per protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; calculated volume to match active treatment by sc injection	Drug: Placebo; sterile normal saline (0.9% NaCl)
Experimental: Plozasiran Injection; 4 doses of plozasiran (ARO-APOC3) by subcutaneous (sc) injection	Drug: Plozasiran Injection; ARO-APOC3 Injection; Other Names: ARO-APOC3

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Percent change in fasting serum TG levels from baseline to Month 12 compared to placebo	Baseline, Month 12

Secondary Outcome Measures

Outcome Measure	Time Frame
Percent Change in Fasting Serum TG Levels from Baseline to Month 10 Compared to Placebo	Baseline, Month 10
Number of Subjects with Adverse Events (AEs) and Serious Adverse Events (SAEs) Over Time through Month 12 as Compared to Placebo	From first dose of study drug through Month 12
Incidence Rates of New-Onset Diabetes Mellitus (NODM) Throughout the Course of Treatment	From first dose of study drug through Month 12
Incidence Rates of Impaired Glucose Tolerance Throughout the Course of Treatment	From first dose of study drug through Month 12
Incidence Rates of Worsening of Existing Diabetes Throughout the Course of Treatment	From first dose of study drug through Month 12
Change from Baseline in Hemoglobin A1c (HbA1c) and Other Glycemic Control Parameters During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Change from Baseline in Fasting Blood Glucose During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Change from Baseline in C-Peptide During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Change from Baseline in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Change from Baseline in Treatment-Emergent Adverse Events (TEAEs) and Treatment-Related Adverse Events (TRAEs) Associated with Worsening Glycemic Control During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Initiation of New Medication for Hyperglycemia among Study Participants Not Known to Have Pre-existing Diabetes Mellitus During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Adjudicated Major Adverse Cardiovascular Events (MACE) Rates During the Treatment Period Compared to Placebo	From first dose of study drug through Month 12
Incidence of Anti-drug Antibodies (ADA) to Plozasiran in Subjects Receiving Plozasiran Over Time Through Month 12	From first dose of study drug through Month 12
Titers of Anti-drug Antibodies (ADA) to Plozasiran in Subjects Receiving Plozasiran Over Time Through Month 12	From first dose of study drug through Month 12
Percent change in non-HDL-C from baseline to Month 12 compared to placebo	Baseline, Month 12
Percent change in remnant cholesterol (VLDL-C) from baseline to Month 12 compared to placebo	Baseline, Month 12
Proportion of subjects who achieve fasting TG levels of <500 mg/dL (<5.65 mmol/L) at Month 12 compared to placebo	Baseline, Month 12
Proportion of Subjects Who Achieve Fasting TG Levels of < 150 mg/dL (<1.69 mmol/L) at Month 12 compared to placebo	Baseline, Month 12
Adjudicated AP Event Rate During the Treatment Period Compared to Placebo From Day 1 to Month 12	Month 12

Collaborators and Investigators

• Sponsor: Arrowhead Pharmaceuticals

Study record dates

Study Major Dates

• Study Start (Actual): July 23, 2024
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: March 29, 2024
• First Submitted That Met QC Criteria: March 29, 2024
• First Posted (Actual): April 4, 2024

Study Record Updates

• Last Update Posted (Estimated): October 24, 2025
• Last Update Submitted That Met QC Criteria: October 23, 2025
• Last Verified: October 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Nutritional and Metabolic Diseases; Hypertriglyceridemia; plozasiran
• Other Study ID Numbers: AROAPOC3-3004; 2023-509301-80 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No