Randomized, double-blind, placebo-controlled, parallel-group study comparing multiple doses of HTD1801 to placebo.
This 18-week randomized, double-blind, parallel-group, proof of concept (POC), dose-ranging study compared multiple doses of HTD1801 to placebo in a 1:1:1 ratio. Since accumulation of hepatic fat is considered the "first hit" in the pathogenesis of NASH (Adams and Angulo 2006), change in liver fat content (LFC) by magnetic resonance imaging estimated proton density fat fraction (MRI-PDFF) is an appropriate primary endpoint and is consistent with that used in other recent Phase 2 POC studies in NASH (Harrison et al., 2018, Madrigal Pharmaceuticals 2018). The Harrison et al., 2018, Madrigal Pharmaceuticals 2018 study showed clinically meaningful absolute and relative reductions in LFC assessed by MRI-PDFF over 12-week treatment periods thus, it was considered that an 18 week HTD1801 treatment period would therefore be adequate to assess the study's primary endpoint and to maximize collection of exposure and safety related data.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
101
Institute for Liver Health
Chandler, Arizona, United States
Institute for Liver Health
Tucson, Arizona, United States
Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF
The primary endpoint was the absolute change in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18.
Time frame: Baseline through study Week 18
Change in Fasting Glucose
Change in fasting glucose from Baseline to Week 18 .
Time frame: Baseline through study Week 18
Changes in Hemoglobin A1c
Changes in HbA1c from Baseline to Week 18.
Time frame: Baseline through study week 18
Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF
Proportion of subjects who achieved ≥ 30% relative reduction in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18.
Time frame: Baseline through study week 18
Relative Change in LFC as Measured by MRI-PDFF
Relative change in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18.
Time frame: Baseline through study week 18
Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF
Number of subjects who normalized liver fat content (LFC) to \<5% as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) at Week 18.
Time frame: Baseline through study Week 18
Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF
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Number of subjects who achieved ≥5% absolute reduction in liver fat content (LFC) as measured by magnetic resonance imaging derived proton density fat fraction (MRI-PDFF) from Baseline to Week 18.
Time frame: Baseline through study Week 18
Change in HOMA-IR
Change in homeostasis model assessment-estimated insulin resistance (HOMA-IR) from Baseline to Week 18. The higher the HOMA-IR score, the more insulin resistant a person is. Values of \<1 are considered optimal while values \>2.9 indicate significant insulin resistance.
Time frame: Baseline through study week 18
Change in LDL-c
Change in low-density lipoprotein cholesterol (LDL-c) from Baseline to Week 18.
Time frame: Baseline visit through study week 18
Change in Serum Triglycerides
Change in serum triglycerides from Baseline to Week 18.
Time frame: Baseline through study week 18
Change in HDL-c
Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18.
Time frame: Baseline through study week 18
Change in AST
Absolute change in aspartate aminotransferase (AST) from Baseline to Week 18.
Time frame: Baseline through study week 18
Change in ALT
Absolute change in alanine aminotransferase (ALT) from Baseline to Week 18.
Time frame: Baseline through study week 18
Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18
Proportion of subjects with elevated alanine aminotransferase (ALT) at Baseline who normalized ALT at Week 18.
Time frame: Baseline through study week 18
Change in Pro-Peptide of Type III Collagen (Pro-C3)
Change in Pro-C3 from Baseline to Week 18 for subjects with elevated Pro-C3 at Baseline.
Time frame: Baseline through study week 18
Change in ELF Score
Change in the enhanced liver fibrosis (ELF) score. The ELF score is calculated using a published algorithm combining the values of a set of extracellular matrix markers, including TIMP-1, PIIINP, and HA. The ELF score has been reported to show good correlations with fibrosis stages in chronic liver disease, with higher ELF scores associated with higher fibrosis stages. The ELF score is hence 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.
Time frame: Baseline through study week 18
Change in TIMP-1
Change in tissue inhibitor of metalloproteinases 1 (TIMP-1) from Baseline to Week 18.
Time frame: Baseline through study week 18
Change in PIIINP
Change in N-terminal pro-peptide of type III collagen (PIIINP) from Baseline to Week 18.
Time frame: Baseline through study week 18
Change in HA
Change in hyaluronic acid (HA) from Baseline to Week 18.
Time frame: Baseline through study week 18
Change in Total Bile Acids
Changes in total bile acids from Baseline to Week 18.
Time frame: Baseline through study week 18
Change in FGF19
Change in fibroblast growth factor 19 (FGF19) from Baseline to Week 18
Time frame: Baseline through study week 18
Number of Participants Reporting an Adverse Events From Baseline Through Week 18
AEs were mapped to MedDRA version 20.1 preferred term (PT) and system organ class (SOC). If the subject experienced multiple events that mapped to a single preferred term, the greatest severity grade according to CTCAE Version 4.0, and strongest investigator assessment of relation to study medication was assigned to the preferred term. If an event had a missing severity or relationship, it was classified as having the highest severity and/or strongest relationship to study medication. The occurrence of TEAEs was summarized by treatment group by SOC, PT, and severity. Separate summaries of treatment-emergent serious adverse events (SAEs), TEAEs related to study drug, severe or life threatening TEAEs, and TEAEs leading to the discontinuation of study treatment were generated. Additionally, the occurrence of liver-specific AEs was summarized by treatment group. All reported adverse events were listed for individual subjects showing verbatim term, PT and SOC.
Time frame: Adverse events were collected from the time the subject signed the informed consent form through the date of the last visit for a specific subject, that is, approximately 24 weeks in total for a completed subject.