Clinical trial NCT04932512: A Study to Assess the Safety, Efficacy, and Pharmacokinetics of Multiple Doses of ION224
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Steatohepatitis, Nonalcoholic
Keywords: Non-Alcoholic Steatohepatitis
Non-alcoholic Fatty Liver Disease Activity Score
Alanine Aminotransferase
Aspartate Aminotransferase
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2021-06-21
Enrollment: 160
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
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
timeFrame: Up to Week 49
Secondary outcomes:
measure: Change From Baseline in Hepatic Fat Content Measurement as Evaluated by MRI-PDFF and Calculated by an Independent, Blinded-To-Treatment, Central Reader
timeFrame: Baseline up to Week 15, Week 29 and Week 49
measure: 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
timeFrame: Up to Week 49
measure: 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
timeFrame: Up to Week 49
measure: Percentage of Participants Achieving a Combination of NASH Resolution and a 1 Stage Improvement in Fibrosis at the EOT
timeFrame: Up to Week 49
measure: 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
timeFrame: Up to Week 49
measure: Absolute Change From Baseline in Liver-related Laboratory Test - ALT
timeFrame: Baseline up to Week 49
measure: Absolute Change From Baseline in Liver-related Laboratory Test - AST
timeFrame: Baseline up to Week 49
measure: Absolute Change From Baseline in Liver-related Laboratory Test - Total Bilirubin
timeFrame: Baseline up to Week 49
measure: Absolute Change From Baseline in Liver-related Laboratory Test - Gamma-glutamyl Transferase
timeFrame: Baseline up to Week 49
measure: Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Triglyceride (TG)
timeFrame: Baseline up to Week 49
measure: Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Total Cholesterol
timeFrame: Baseline up to Week 49
measure: Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - Low-density Lipoprotein-cholesterol (LDL-c)
timeFrame: Baseline up to Week 49
measure: Absolute Change From Baseline in Plasma Fasting Lipid Profile Test - High-density Lipoprotein-cholesterol (HDL-c)
timeFrame: Baseline up to Week 49
measure: Maximum Observed Plasma Concentration (Cmax) of ION224 and Metabolites
timeFrame: Baseline up to Week 49
measure: Time to Cmax (Tmax) of ION224 and Metabolites
timeFrame: Baseline up to Week 49
measure: Area Under the Plasma Concentration-time Curve (AUC) of ION224 and Metabolites
timeFrame: Baseline up to Week 49
measure: Plasma Half-life (t½) of ION224 and Metabolites
timeFrame: Baseline up to Week 49
Other outcomes:
Locations:
city: Chandler
country: United States
facility: Arizona Liver Health-Chandler
state: Arizona
city: Glendale
country: United States
facility: Arizona Liver Health
state: Arizona
city: Tucson
country: United States
facility: Arizona Liver Health
state: Arizona
city: North Little Rock
country: United States
facility: Arkansas Gastroenterology - North Little Rock
state: Arkansas
city: Chula Vista
country: United States
facility: GW Research, Inc.
state: California
city: Gardena
country: United States
facility: National Research Institute - Gardena
state: California
city: Huntington Park
country: United States
facility: National Research Institute
state: California
city: Los Angeles
country: United States
facility: National Research Institute
state: California
city: Panorama City
country: United States
facility: National Research Institute Panorama City
state: California
city: Santa Ana
country: United States
facility: National Research Institute - Santa Ana
state: California
city: Englewood
country: United States
facility: South Denver Gastroenterology, PC
state: Colorado
city: Boca Raton
country: United States
facility: Excel Medical Clinical Trials, LLC
state: Florida
city: Clearwater
country: United States
facility: Tampa Bay Medical Research, Inc.
state: Florida
city: Fort Myers
country: United States
facility: Southwest General Medical Center
state: Florida
city: Hialeah Gardens
country: United States
facility: Evolution Clinical Trials, INC
state: Florida
city: Maitland
country: United States
facility: ClinCloud, LLC.
state: Florida
city: Miami Lakes
country: United States
facility: Floridian Clinical Research, LLC.
state: Florida
city: Miami
country: United States
facility: Advanced Pharma CR, LLC
state: Florida
city: Miami
country: United States
facility: La Salud Research
state: Florida
city: Miami
country: United States
facility: Entrust Clinical Research
state: Florida
city: Ocoee
country: United States
facility: Sensible Healthcare, LLC
state: Florida
city: Sarasota
country: United States
facility: Covenant Metabolic Specialists, LLC
state: Florida
city: West Palm Beach
country: United States
facility: Metabolic Research Institute, Inc.
state: Florida
city: Marietta
country: United States
facility: Gastrointestinal Specialists of Georgia
state: Georgia
city: Houma
country: United States
facility: Tandem Clinical Research GI
state: Louisiana
city: Marrero
country: United States
facility: Tandem Clinical Research GI, LLC.
state: Louisiana
city: Metairie
country: United States
facility: Tandem Clinical Research GI
state: Louisiana
city: Monroe
country: United States
facility: Delta Research Partners
state: Louisiana
city: Shreveport
country: United States
facility: Louisiana Research Center, LLC
state: Louisiana
city: Jackson
country: United States
facility: Southern Therapy and Advanced Research
state: Mississippi
city: Reno
country: United States
facility: Advanced Research Institute
state: Nevada
city: East Syracuse
country: United States
facility: Clarity Clinical Research
state: New York
city: New York
country: United States
facility: Tandem Clinical Research GI, LLC.
state: New York
city: Fayetteville
country: United States
facility: Cumberland Research Associates, LLC
state: North Carolina
city: Columbus
country: United States
facility: Aventiv Research, Inc.
state: Ohio
city: Westlake
country: United States
facility: Clinical Research Institute of Ohio
state: Ohio
city: Chattanooga
country: United States
facility: WR-ClinSearch, LLC
state: Tennessee
city: Austin
country: United States
facility: Pinnacle Clinical Research
state: Texas
city: Brownsville
country: United States
facility: South Texas Research Institute
state: Texas
city: Dallas
country: United States
facility: Dallas Diabetes Research Center
state: Texas
city: Dallas
country: United States
facility: Velocity Clinical Research
state: Texas
city: Edinburg
country: United States
facility: South Texas Research Institute
state: Texas
city: Katy
country: United States
facility: R&H Clinical Research, Inc.
state: Texas
city: McAllen
country: United States
facility: DHR Health Institute for Research and Development
state: Texas
city: San Antonio
country: United States
facility: Quality Research, Inc.
state: Texas
city: San Antonio
country: United States
facility: Pinnacle Clinical Research
state: Texas
city: Ogden
country: United States
facility: Advanced Research Institute
state: Utah
city: Riverton
country: United States
facility: Granger Medical Clinic
state: Utah
city: Sandy
country: United States
facility: Advanced Research Institute
state: Utah
city: Manassas
country: United States
facility: Manassas Clinical Research Center
state: Virginia
city: San Juan
country: Puerto Rico
facility: FDI Clinical Research
Study officials:
References: