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Phase 2b Study of GSK4532990 in Adults With NASH (HORIZON)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT05583344
Recruitment Status : Recruiting
First Posted : October 17, 2022
Last Update Posted : March 15, 2024
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline

Study Description
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Brief Summary:
The purpose of this study is to measure improvements in liver fibrosis and inflammation with GSK4532990 compared with placebo in participants with NASH and advanced fibrosis on biopsy (F3 or F4). The study duration will be up to 76 weeks including the screening period. The treatment duration will be up to 52 weeks.

Condition or disease Intervention/treatment Phase
Nonalcoholic Fatty Liver Disease Drug: GSK4532990 Drug: Placebo Phase 2

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 246 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 17 β-Hydroxysteroid Dehydrogenase Type 13 Minimization for the Treatment of NASH (HORIZON): A Double-Blind, Placebo-Controlled Phase 2b Study to Evaluate the Efficacy and Safety of GSK4532990 in Adults With Nonalcoholic Steatohepatitis
Actual Study Start Date : January 2, 2023
Estimated Primary Completion Date : September 8, 2025
Estimated Study Completion Date : December 15, 2025

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Arms and Interventions
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Arm Intervention/treatment
Experimental: High Dose GSK4532990 Drug: GSK4532990
GSK4532990 will be administered.
Experimental: Low Dose GSK4532990 Drug: GSK4532990
GSK4532990 will be administered.
Placebo Comparator: Placebo Drug: Placebo
Placebo will be administered.


Outcome Measures
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Primary Outcome Measures :
  1. Percentage of Participants Achieving ≥ 1 Stage Improvement in Histological Fibrosis with no Worsening of NASH - F3 Cohort [ Time Frame: At Week 52 ]
    Improvement in histological fibrosis is assessed with Clinical research network (CRN) Scoring. No worsening of NASH is defined as no increase in the NAFLD Activity Score (NAS) for steatosis, ballooning, or inflammation.

  2. Percentage of Participants Achieving NASH Resolution with no Worsening of Fibrosis - F3 Cohort [ Time Frame: At Week 52 ]
    NASH resolution is defined as a ballooning score of 0 and an inflammation score of 0-1. No worsening of fibrosis is defined as no increase in CRN fibrosis score.


Secondary Outcome Measures :
  1. Percentage of Participants Achieving ≥ 1 Stage Improvement in Histological Fibrosis with no Worsening of NASH - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: At Week 52 ]
    Improvement in histological fibrosis is assessed with Clinical research network (CRN) Scoring. No worsening of NASH is defined as no increase in the NAFLD Activity Score (NAS) for steatosis, ballooning, or inflammation.

  2. Percentage of Participants Achieving NASH Resolution with no Worsening of Fibrosis - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: At Week 52 ]
    NASH resolution is defined as a ballooning score of 0 and an inflammation score of 0-1. No worsening of fibrosis is defined as no increase in CRN fibrosis score.

  3. Change from baseline in Pro-peptide of type III collagen (Pro-C3) - F3 Cohort [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  4. Change from baseline in liver fat using Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) - F3 Cohort [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  5. Change from baseline in Liver stiffness measurement (LSM) by Vibration-controlled transient elastography (VCTE) - F3 Cohort [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  6. Change from baseline in Enhanced Liver Fibrosis (ELF) Score - F3 Cohort [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
    The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers, including tissue inhibitor of metalloproteinases-1 (TIMP-1), type III procollagen (PIIINP), and hyaluronic acid (HA). The ELF score is used as a prognostic marker for disease progression: ELF score < 9.8 : Low risk of progression, ELF score 9.8 to < 11.3 : Moderate risk of progression and ELF score > = 11.3 : High risk of progression.

  7. Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 24- F3 Cohort [ Time Frame: At Week 24 ]
  8. Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 52 - F3 Cohort [ Time Frame: At Week 52 ]
  9. Change from Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma-glutamyl transferase (GGT) (Units Per Liter) - F3 Cohort [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  10. Change from baseline in Pro-peptide of type III collagen (Pro-C3) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  11. Change from baseline in liver fat using Magnetic resonance imaging-proton density fat fraction (MRI-PDFF) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  12. Change from baseline in Liver stiffness measurement (LSM) by Vibration-controlled transient elastography (VCTE) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  13. Change from baseline in Enhanced Liver Fibrosis (ELF) Score - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
    The ELF score will be calculated using a published algorithm combining the values of a set of extracellular matrix markers, including tissue inhibitor of metalloproteinases-1 (TIMP-1), type III procollagen (PIIINP), and hyaluronic acid (HA). The ELF score is used as a prognostic marker for disease progression: ELF score < 9.8 : Low risk of progression, ELF score 9.8 to < 11.3 : Moderate risk of progression and ELF score > = 11.3 : High risk of progression.

  14. Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 24 - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: At Week 24 ]
  15. Percentage of Participants Achieving ≥30% relative reduction in liver fat from baseline using MRI-PDFF at Week 52 - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: At Week 52 ]
  16. Change from Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma-glutamyl transferase (GGT) (Units Per Liter) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and at Week 24 and 52 ]
  17. Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) - F3 Cohort [ Time Frame: Up to Week 66 ]
  18. Change from Baseline in Vital Signs - Blood Pressure (millimeters of Mercury) - F3 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  19. Change from Baseline in Vital Signs - Temperature (Celsius) - F3 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  20. Change from Baseline in Vital Signs - Heart Rate (Beats per minute) - F3 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  21. Change from Baseline in Vital Signs - Respiratory Rate (Breaths per minute) - F3 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  22. Change From Baseline in Clinical Chemistry Parameter: total bilirubin, direct Bilirubin and creatinine (Micromoles per Liter) - F3 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  23. Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) - F4 Cohort [ Time Frame: Up to Week 66 ]
  24. Change from Baseline in Vital Signs - Blood Pressure (millimeters of Mercury) - F4 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  25. Change from Baseline in Vital Signs - Temperature (Celsius) - F4 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  26. Change from Baseline in Vital Signs - Heart Rate (Beats per minute) - F4 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  27. Change from Baseline in Vital Signs - Respiratory Rate (Breaths per minute) - F4 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  28. Change From Baseline in Clinical Chemistry Parameter: total bilirubin, direct Bilirubin and creatinine (Micromoles per Liter) - F4 Cohort [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  29. Percentage of Participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Up to Week 66 ]
  30. Change from Baseline in Vital Signs - Blood Pressure (millimeters of Mercury) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  31. Change from Baseline in Vital Signs - Temperature (Celsius) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  32. Change from Baseline in Vital Signs - Heart Rate (Beats per minute) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  33. Change from Baseline in Vital Signs - Respiratory Rate (Breaths per minute) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  34. Change From Baseline in Clinical Chemistry Parameter: total bilirubin, direct Bilirubin and creatinine (Micromoles per Liter) - Pooled Cohort (F3 participants and F4 participants) [ Time Frame: Baseline (Day 1) and up to Week 52 ]
  35. Area under the concentration-time curve from time zero (pre-dose) to the last quantifiable concentration (AUC0-t) of GSK4532990 - F3 Cohort [ Time Frame: Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose ]
  36. Maximum observed concentration (Cmax) of GSK4532990- F3 Cohort [ Time Frame: Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose ]
  37. Percentage of Participants with Anti-drug Antibodies (ADA) to GSK4532990- F3 Cohort [ Time Frame: Up to Week 52 ]
  38. Area under the concentration-time curve from time zero (pre-dose) to the last quantifiable concentration (AUC0-t) of GSK4532990 - F4 Cohort [ Time Frame: Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose ]
  39. Maximum observed concentration (Cmax) of GSK4532990- F4 Cohort [ Time Frame: Pre-dose (Day 1), 0.25, 0.5, 1, 2, 4, 8, 12 and 24 hours post dose ]
  40. Percentage of Participants with Anti-drug Antibodies (ADA) to GSK4532990- F4 Cohort [ Time Frame: Up to Week 52 ]

Eligibility Criteria
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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Body Mass Index (BMI) ≥25 kilogram per meter square (kg/m^2) (all ethnic origins) except for Asian participants who qualify for the study with BMI ≥23 kg/m2 at Screening.
  • In the opinion of the investigator, there are features of metabolic syndrome and NAFLD is the most likely cause of liver disease. Metabolic syndrome may include type 2 diabetes mellitus (T2DM), obesity, dyslipidemia and hypertension.
  • A liver biopsy at baseline showing NAFLD Activity Score (NAS) >=4 with at least 1 point each in steatosis, inflammation and ballooning and either Fibrosis 3 or Fibrosis 4 using NASH CRN Scoring System.
  • Able and willing to comply with all study assessments, including a liver biopsy at Week 52.

Exclusion Criteria:

  • Current alcohol consumption ≥14 standard drinks (24 units, 196 g ethanol) per week for females or ≥21 standard drinks (37 units, 294g ethanol) per week for males.
  • Weight reduction surgery or procedures (including gastric banding and intragastric balloon insertion) within 2 years of Screening 1 and/or planned during the study.
  • History of cancer within previous 2 years from Screening 1, except basal or squamous cell carcinoma of the skin or in situ cervical carcinoma or any other type of cancer which has been treated medically or surgically with curative outcome.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05583344


Contacts
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Contact: US GSK Clinical Trials Call Center 877-379-3718 GSKClinicalSupportHD@gsk.com
Contact: EU GSK Clinical Trials Call Center +44 (0) 20 89904466 GSKClinicalSupportHD@gsk.com

Locations
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Sponsors and Collaborators
GlaxoSmithKline
Investigators
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Study Director: GSK Clinical Trials GlaxoSmithKline
More Information
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Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT05583344    
Other Study ID Numbers: 218672
2022-002538-14 ( EudraCT Number )
2023-507503-62-00 ( Other Identifier: EU CT number )
First Posted: October 17, 2022    Key Record Dates
Last Update Posted: March 15, 2024
Last Verified: March 2024
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD for this study will be made available via the Clinical Study Data Request site.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: IPD will be made available within 6 months of publishing the results of the primary endpoints, a key secondary endpoints and safety data of the study.
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by GlaxoSmithKline:
17β-Hydroxysteroid Dehydrogenase type 13 Minimization for the treatment of NASH (HORIZON)
GSK4532990
Non-alcoholic steatohepatitis (NASH)
Non-alcoholic fatty liver disease (NAFLD)
Additional relevant MeSH terms:
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Liver Diseases
Fatty Liver
Non-alcoholic Fatty Liver Disease
Digestive System Diseases