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Steatohepatitis, NonalcoholicPhase 2NCT04932512

A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224

A Phase 2 study testing ION224 in people with Steatohepatitis, Nonalcoholic, run by Ionis Pharmaceuticals, Inc. at 51 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to assess the effect of multiple ION224 doses when administered by subcutaneous (SC) injection for 49 weeks (end of the treatment [EOT]) on non-alcoholic steatohepatitis (NASH) histologic improvement and to assess the effect on liver steatosis by magnetic resonance imaging-determined… Read more about this study

Who is it for?
Ages 18 to 75 years
Conditions the study is for
Steatohepatitis, Nonalcoholic
What is being tested?
ION224
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
160 participants
Where
51 sitesin 2 countries
Study dates
17 Jun 2021to 28 Feb 2024
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 75 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Males or females greater than or equal to (≥) 18 and less than or equal to (≤) 75 years old at the time of informed consent
  • Body mass index ≥ 25 kg/m^2 and ≥ 22 kg/m^2 for participants of Asian race, as assessed during screening
  • Liver fat ≥ 10% as assessed by MRI-PDFF before randomization
  • Presence of NASH confirmed by centrally read liver biopsy
  • Weight loss < 5% after historical biopsy. Otherwise, weight loss < 5% in the previous 3 months prior to randomization
  • ALT and AST ≤ 200 units per liter (U/L) and confirmed to be stable
  • Total Bilirubin ≤ 1.3 milligrams per deciliter (mg/dL) and confirmed to be stable

Who cannot join

  • Prior or planned (during the Study Period) bariatric surgery or previous bariatric surgery within 2 years prior to screening
  • History of solid organ transplant
  • Screening laboratory values that would render a participant unsuitable for inclusion, including but not limited to:
  • Clinically significant albuminuria or proteinuria
  • Positive test for blood on urinalysis
  • Estimated glomerular filtration rate (eGFR) < 60 milliliters (mL)/minute (min)/1.73 square meter (m^2)
Show all 27Show fewer
  • Hemoglobin A1c (HbA1c) > 9.5%
  • Platelet count < 170 × 10^9/liter (L)
  • Diagnosis of Gilbert's syndrome
  • Known history of or evidence of liver disease other than NASH
  • Clinical evidence of liver decompensation
  • Active SARS-CoV-2 infection (COVID-19) or confirmed SARS-CoV-2 infection-related complication within 8 weeks of Screening
  • Uncontrolled arterial hypertension
  • History of bleeding diathesis or coagulopathy
  • Participants with known intolerance to magnetic resonance imaging (MRI) or with conditions contraindicated for MRI Procedures
  • History of, or current hard drug or alcohol abuse within 2 years prior to Screening
  • Use of drugs historically associated with NAFLD for more than 2 weeks in the year prior to Screening
  • Use of obeticholic acid, ursodeoxycholic acid, icosapent ethyl, niacin, PCSK9 inhibitors, and bile acid sequestrants
  • Participants taking the following medicines UNLESS on a stable dose:
  • Anti-diabetic medications
  • statins, fenofibrate, and ezetimibe
  • Estrogen containing contraceptives
  • Glucagon-like peptide (GLP)-1 agonists
  • Pioglitazone
  • Vitamin E at doses ≤ 800 international unit (IU)/day
  • Herbal medicines, other prescription medicines, vitamins or supplements known to affect lipid metabolism
  • Other protocol-defined inclusion/exclusion criteria could apply

Trial locations and contacts

51 sites in 2 countries.

51 sites in 2 countries

United States50 sites

  • Pinnacle Clinical Research

    Austin, Texas, 78757

  • Excel Medical Clinical Trials, LLC

    Boca Raton, Florida, 33434

  • South Texas Research Institute

    Brownsville, Texas, 78520

  • Arizona Liver Health-Chandler

    Chandler, Arizona, 85224

  • WR-ClinSearch, LLC

    Chattanooga, Tennessee, 37421

  • GW Research, Inc.

    Chula Vista, California, 91910

  • Tampa Bay Medical Research, Inc.

    Clearwater, Florida, 33761

  • Aventiv Research, Inc.

    Columbus, Ohio, 43213

  • Dallas Diabetes Research Center

    Dallas, Texas, 75230

  • Velocity Clinical Research

    Dallas, Texas, 75230

  • Clarity Clinical Research

    East Syracuse, New York, 13057

  • South Texas Research Institute

    Edinburg, Texas, 78539

  • South Denver Gastroenterology, PC

    Englewood, Colorado, 80113

  • Cumberland Research Associates, LLC

    Fayetteville, North Carolina, 28304

  • Southwest General Medical Center

    Fort Myers, Florida, 33907

  • National Research Institute - Gardena

    Gardena, California, 90247

  • Arizona Liver Health

    Glendale, Arizona, 85306

  • Evolution Clinical Trials, INC

    Hialeah Gardens, Florida, 33016

  • Tandem Clinical Research GI

    Houma, Louisiana, 70363

  • National Research Institute

    Huntington Park, California, 90255

  • Southern Therapy and Advanced Research

    Jackson, Mississippi, 39216

  • R&H Clinical Research, Inc.

    Katy, Texas, 77494

  • National Research Institute

    Los Angeles, California, 90057

  • ClinCloud, LLC.

    Maitland, Florida, 32751

  • Manassas Clinical Research Center

    Manassas, Virginia, 20110

  • Gastrointestinal Specialists of Georgia

    Marietta, Georgia, 30060

  • Tandem Clinical Research GI, LLC.

    Marrero, Louisiana, 70072

  • DHR Health Institute for Research and Development

    McAllen, Texas, 78504

  • Tandem Clinical Research GI

    Metairie, Louisiana, 70006

  • Advanced Pharma CR, LLC

    Miami, Florida, 33147

  • La Salud Research

    Miami, Florida, 33155

  • Entrust Clinical Research

    Miami, Florida, 33176

  • Floridian Clinical Research, LLC.

    Miami Lakes, Florida, 33016

  • Delta Research Partners

    Monroe, Louisiana, 71201

  • Tandem Clinical Research GI, LLC.

    New York, New York, 10033

  • Arkansas Gastroenterology - North Little Rock

    North Little Rock, Arkansas, 72117

  • Sensible Healthcare, LLC

    Ocoee, Florida, 34761

  • Advanced Research Institute

    Ogden, Utah, 84405

  • National Research Institute Panorama City

    Panorama City, California, 91402

  • Advanced Research Institute

    Reno, Nevada, 89511

  • Granger Medical Clinic

    Riverton, Utah, 84096

  • Quality Research, Inc.

    San Antonio, Texas, 78209

  • Pinnacle Clinical Research

    San Antonio, Texas, 78229

  • Advanced Research Institute

    Sandy City, Utah, 84092

  • National Research Institute - Santa Ana

    Santa Ana, California, 92704

  • Covenant Metabolic Specialists, LLC

    Sarasota, Florida, 34240

  • Louisiana Research Center, LLC

    Shreveport, Louisiana, 71105

  • Arizona Liver Health

    Tucson, Arizona, 85712

  • Metabolic Research Institute, Inc.

    West Palm Beach, Florida, 33401

  • Clinical Research Institute of Ohio

    Westlake, Ohio, 44145

Other trials in United States

Puerto Rico1 site

  • FDI Clinical Research

    San Juan, 00927

Other trials in Puerto Rico

About this study

Official title: An Adaptive Two-Part Phase 2, Multi-Center, Randomized, Double Blind, Placebo-Controlled Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224 Administered Once Monthly in Adult Subjects With Confirmed Non-Alcoholic Steatohepatitis

The purpose of this study is to assess the effect of multiple ION224 doses when administered by subcutaneous (SC) injection for 49 weeks (end of the treatment [EOT]) on non-alcoholic steatohepatitis (NASH) histologic improvement and to assess the effect on liver steatosis by magnetic resonance imaging-determined proton density fat fraction (MRI-PDFF), additional changes in NASH histologic features, liver biochemistry tests, and plasma lipid profile.

Read the detailed description

This is a Phase 2, double-blind, randomized, placebo-controlled study of ION224 in up to 150 participants. The study consists of 3 periods: 1) Screening Period: Week -8 to Week -1 (up to 8 weeks); 2) Treatment Period up to Week 49; and 3) Post-Treatment Period: Week 50 to Week 62 (12 weeks).

Initially, 48 patients will be enrolled in three different dose cohorts to receive ION224 or placebo every four weeks and based on safety and effects on liver steatosis (assessed at Week 15), two dose cohorts will be selected to be expanded. After dose selection, an additional 102 patients will be enrolled in the 2 selected dose cohorts and will receive ION224 or placebo for up to 49 weeks. Participants in the 3rd cohort (not selected) will continue to complete up to 49 weeks of treatment without any cohort expansion.

Being tested
ION224, Placebo
Keywords
Non-Alcoholic Steatohepatitis, Non-alcoholic Fatty Liver Disease Activity Score, Alanine Aminotransferase, Aspartate Aminotransferase
Medical subject headings
Non-alcoholic Fatty Liver Disease

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • ION224Drug

    ION224 will be administered by SC injection.

  • PlaceboOther

    ION224-matching placebo solution will be administered by SC injection.

Study groups in NCT04932512
Study groupRoleWhat they receive
ION224ExperimentalMultiple doses of ION224 will be administered by SC injection once every 4 weeks for up to 49 weeks.
Receives: Drug: ION224
PlaceboPlacebo comparatorMultiple doses of matching placebo will be administered by SC injection once every 4 weeks for up to 49 weeks.
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Participants With at Least 2-point Reduction in Non-alcoholic Fatty Liver Disease Activity Score (NAS) With at least 1-point Improvement in Hepatocellular Ballooning or Lobular Inflammation, and Without Worsening in Fibrosis Stage at EOT

    The NAS is a histology grading score composed on the assessment of steatosis (scale 0-3), hepatocellular ballooning (scale 0-2), and lobular inflammation (scale 0-3), with higher scores indicating more severe hepatitis. Worsening of fibrosis is defined as an increase in fibrosis of at least one stage on the Kleiner fibrosis classification: fibrosis stages range from 0-4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis).

    Measured: Up to Week 49

Secondary outcomes (17)

  1. Change From Baseline in Hepatic Fat Content Measurement as Evaluated by MRI-PDFF and Calculated by an Independent, Blinded-To-Treatment, Central Reader

    Measured: Baseline up to Week 15, Week 29 and Week 49

  2. Percentage of Participants Achieving Non-alcoholic Steatohepatitis (NASH) Resolution, as Defined by Scores of 0 for Ballooning and 0 or 1 for Inflammation by the NAS, and Without Worsening of Fibrosis, Assessed Through Liver Biopsy at the EOT

    Measured: Up to Week 49

  3. Percentage of Participants Achieving Reduction of at Least 1 Stage in the Fibrosis Score, and Without Worsening of Steatohepatitis by the NAS, Assessed Through Liver Biopsy at the EOT

    Measured: Up to Week 49

  4. Percentage of Participants Achieving a Combination of NASH Resolution and a 1 Stage Improvement in Fibrosis at the EOT

    Measured: Up to Week 49

  5. Percentage of Participants With Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) Less than or Equal to (≤) 1.5 Upper Limit of Normal (ULN) at the EOT

    Measured: Up to Week 49

  6. Absolute Change From Baseline in Liver-related Laboratory Test - ALT

    Measured: Baseline up to Week 49

  7. Absolute Change From Baseline in Liver-related Laboratory Test - AST

    Measured: Baseline up to Week 49

  8. Absolute Change From Baseline in Liver-related Laboratory Test - Total Bilirubin

    Measured: Baseline up to Week 49

  9. Absolute Change From Baseline in Liver-related Laboratory Test - Gamma-glutamyl Transferase

    Measured: Baseline up to Week 49

  10. Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Triglyceride (TG)

    Measured: Baseline up to Week 49

  11. Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Total Cholesterol

    Measured: Baseline up to Week 49

  12. Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Low-density Lipoprotein-cholesterol (LDL-c)

    Measured: Baseline up to Week 49

  13. Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - High-density Lipoprotein-cholesterol (HDL-c)

    Measured: Baseline up to Week 49

  14. Maximum Observed Plasma Concentration (Cmax) of ION224 and Metabolites

    Measured: Baseline up to Week 49

  15. Time to Cmax (Tmax) of ION224 and Metabolites

    Measured: Baseline up to Week 49

  16. Area Under the Plasma Concentration-time Curve (AUC) of ION224 and Metabolites

    Measured: Baseline up to Week 49

  17. Plasma Half-life (t½) of ION224 and Metabolites

    Measured: Baseline up to Week 49

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted21 Jun 2021
  2. Study start17 Jun 2021
  3. Primary completion10 Jan 2024
  4. Study completion28 Feb 2024

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
160 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04932512
Sponsor's protocol ID
ION224-CS2
Status last verified
Nov 2024
First submitted
10 Jun 2021
Last updated
27 Nov 2024
Results posted
No
Data monitoring committee
No
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Loomba R, Morgan E, Yousefi K, Li D, Geary R, Bhanot S, Alkhouri N; ION224-CS2 Investigators. Antisense oligonucleotide DGAT-2 inhibitor, ION224, for metabolic dysfunction-associated steatohepatitis (ION224-CS2): results of a 51-week, multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2025 Aug 23;406(10505):821-831. doi: 10.1016/S0140-6736(25)00979-1.

    PubMed 40849139

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing ION224 in people with Steatohepatitis, Nonalcoholic, run by Ionis Pharmaceuticals, Inc. at 51 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 7 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 27 Nov 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 51 sites in United States, Puerto Rico. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Participants With at Least 2-point Reduction in Non-alcoholic Fatty Liver Disease Activity Score (NAS) With at least 1-point Improvement in Hepatocellular Ballooning or Lobular Inflammation, and Without Worsening in Fibrosis Stage at EOT (time frame: Up to Week 49). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04932512, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Nov 2024.

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