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

Steatohepatitis, Nonalcoholic Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04932512
• Other study ID #: ION224-CS2
• Status: Completed
• Phase: Phase 2
• Start date: June 17, 2021
• Est. completion date: February 28, 2024

Study information

• Verified date: March 2024
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical 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 proton density fat fraction (MRI-PDFF), additional changes in NASH histologic features, liver biochemistry tests, and plasma lipid profile.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 160
• Est. completion date: February 28, 2024
• Est. primary completion date: January 10, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• 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

Exclusion Criteria:

• 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)

• 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

Related Conditions & MeSH terms

• Fatty Liver
• Non-alcoholic Fatty Liver Disease
• Steatohepatitis, Nonalcoholic

Intervention

Drug:
• ION224
ION224 will be administered by SC injection.

Other:
• Placebo
ION224-matching placebo solution will be administered by SC injection.

Locations

Country	Name	City	State
Puerto Rico	FDI Clinical Research	San Juan
United States	Pinnacle Clinical Research	Austin	Texas
United States	Excel Medical Clinical Trials, LLC	Boca Raton	Florida
United States	South Texas Research Institute	Brownsville	Texas
United States	Arizona Liver Health-Chandler	Chandler	Arizona
United States	WR-ClinSearch, LLC	Chattanooga	Tennessee
United States	GW Research, Inc.	Chula Vista	California
United States	Tampa Bay Medical Research, Inc.	Clearwater	Florida
United States	Aventiv Research, Inc.	Columbus	Ohio
United States	Dallas Diabetes Research Center	Dallas	Texas
United States	Velocity Clinical Research	Dallas	Texas
United States	Clarity Clinical Research	East Syracuse	New York
United States	South Texas Research Institute	Edinburg	Texas
United States	South Denver Gastroenterology, PC	Englewood	Colorado
United States	Cumberland Research Associates, LLC	Fayetteville	North Carolina
United States	Southwest General Medical Center	Fort Myers	Florida
United States	National Research Institute - Gardena	Gardena	California
United States	Arizona Liver Health	Glendale	Arizona
United States	Evolution Clinical Trials, INC	Hialeah Gardens	Florida
United States	Tandem Clinical Research GI	Houma	Louisiana
United States	National Research Institute	Huntington Park	California
United States	Southern Therapy and Advanced Research	Jackson	Mississippi
United States	R&H Clinical Research, Inc.	Katy	Texas
United States	National Research Institute	Los Angeles	California
United States	ClinCloud, LLC.	Maitland	Florida
United States	Manassas Clinical Research Center	Manassas	Virginia
United States	Gastrointestinal Specialists of Georgia	Marietta	Georgia
United States	Tandem Clinical Research GI, LLC.	Marrero	Louisiana
United States	DHR Health Institute for Research and Development	McAllen	Texas
United States	Tandem Clinical Research GI	Metairie	Louisiana
United States	Advanced Pharma CR, LLC	Miami	Florida
United States	Entrust Clinical Research	Miami	Florida
United States	La Salud Research	Miami	Florida
United States	Floridian Clinical Research, LLC.	Miami Lakes	Florida
United States	Delta Research Partners	Monroe	Louisiana
United States	Tandem Clinical Research GI, LLC.	New York	New York
United States	Arkansas Gastroenterology - North Little Rock	North Little Rock	Arkansas
United States	Sensible Healthcare, LLC	Ocoee	Florida
United States	Advanced Research Institute	Ogden	Utah
United States	National Research Institute Panorama City	Panorama City	California
United States	Advanced Research Institute	Reno	Nevada
United States	Granger Medical Clinic	Riverton	Utah
United States	Pinnacle Clinical Research	San Antonio	Texas
United States	Quality Research, Inc.	San Antonio	Texas
United States	Advanced Research Institute	Sandy	Utah
United States	National Research Institute - Santa Ana	Santa Ana	California
United States	Covenant Metabolic Specialists, LLC	Sarasota	Florida
United States	Louisiana Research Center, LLC	Shreveport	Louisiana
United States	Arizona Liver Health	Tucson	Arizona
United States	Metabolic Research Institute, Inc.	West Palm Beach	Florida
United States	Clinical Research Institute of Ohio	Westlake	Ohio

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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).	Up to Week 49
Secondary	Change From Baseline in Hepatic Fat Content Measurement as Evaluated by MRI-PDFF and Calculated by an Independent, Blinded-To-Treatment, Central Reader		Baseline up to Week 15, Week 29 and Week 49
Secondary	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		Up to Week 49
Secondary	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		Up to Week 49
Secondary	Percentage of Participants Achieving a Combination of NASH Resolution and a 1 Stage Improvement in Fibrosis at the EOT		Up to Week 49
Secondary	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		Up to Week 49
Secondary	Absolute Change From Baseline in Liver-related Laboratory Test - ALT		Baseline up to Week 49
Secondary	Absolute Change From Baseline in Liver-related Laboratory Test - AST		Baseline up to Week 49
Secondary	Absolute Change From Baseline in Liver-related Laboratory Test - Total Bilirubin		Baseline up to Week 49
Secondary	Absolute Change From Baseline in Liver-related Laboratory Test - Gamma-glutamyl Transferase		Baseline up to Week 49
Secondary	Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Triglyceride (TG)		Baseline up to Week 49
Secondary	Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Total Cholesterol		Baseline up to Week 49
Secondary	Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Low-density Lipoprotein-cholesterol (LDL-c)		Baseline up to Week 49
Secondary	Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - High-density Lipoprotein-cholesterol (HDL-c)		Baseline up to Week 49
Secondary	Maximum Observed Plasma Concentration (Cmax) of ION224 and Metabolites		Baseline up to Week 49
Secondary	Time to Cmax (Tmax) of ION224 and Metabolites		Baseline up to Week 49
Secondary	Area Under the Plasma Concentration-time Curve (AUC) of ION224 and Metabolites		Baseline up to Week 49
Secondary	Plasma Half-life (t½) of ION224 and Metabolites		Baseline up to Week 49