Digestive System Diseases, Fatty Liver, Nonalcoholic, NAFLD, Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis, Type 2 Diabetes Mellitus (T2DM)
Conditions
Brief summary
Randomized, double-blind, placebo-controlled, parallel-group study comparing multiple doses of HTD1801 to placebo.
Detailed description
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.
Interventions
DRUGHTD1801
HTD1801 tablets, 250mg
DRUGPlacebo
tablets manufactured to mimic HTD1801 tablets
Sponsors
HighTide Therapeutics (Hong Kong) Limited
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Clinical diagnosis of NASH as assessed by MRI * Clinically documented diagnosis of T2DM * Body mass index (BMI) \>25 kg/m2
Exclusion criteria
* Liver disease unrelated to NASH * Poorly controlled T2DM or Type 1 Diabetes Mellitus * History of alcohol or substance abuse or dependence * Inability to undergo MRI for any reason * History of significant cardiovascular disease
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF | Baseline through study Week 18 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Fasting Glucose | Baseline through study Week 18 | Change in fasting glucose from Baseline to Week 18 . |
| Changes in Hemoglobin A1c | Baseline through study week 18 | Changes in HbA1c from Baseline to Week 18. |
| Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF | Baseline through study week 18 | 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. |
| Relative Change in LFC as Measured by MRI-PDFF | Baseline through study week 18 | 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. |
| Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF | Baseline through study Week 18 | 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. |
| Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF | Baseline through study Week 18 | 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. |
| Change in HOMA-IR | Baseline through study week 18 | 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. |
| Change in LDL-c | Baseline visit through study week 18 | Change in low-density lipoprotein cholesterol (LDL-c) from Baseline to Week 18. |
| Change in Serum Triglycerides | Baseline through study week 18 | Change in serum triglycerides from Baseline to Week 18. |
| Change in HDL-c | Baseline through study week 18 | Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18. |
| Change in AST | Baseline through study week 18 | Absolute change in aspartate aminotransferase (AST) from Baseline to Week 18. |
| Change in ALT | Baseline through study week 18 | Absolute change in alanine aminotransferase (ALT) from Baseline to Week 18. |
| Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18 | Baseline through study week 18 | Proportion of subjects with elevated alanine aminotransferase (ALT) at Baseline who normalized ALT at Week 18. |
| Change in Pro-Peptide of Type III Collagen (Pro-C3) | Baseline through study week 18 | Change in Pro-C3 from Baseline to Week 18 for subjects with elevated Pro-C3 at Baseline. |
| Change in ELF Score | Baseline through study week 18 | 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. |
| Change in TIMP-1 | Baseline through study week 18 | Change in tissue inhibitor of metalloproteinases 1 (TIMP-1) from Baseline to Week 18. |
| Change in PIIINP | Baseline through study week 18 | Change in N-terminal pro-peptide of type III collagen (PIIINP) from Baseline to Week 18. |
| Change in HA | Baseline through study week 18 | Change in hyaluronic acid (HA) from Baseline to Week 18. |
| Change in Total Bile Acids | Baseline through study week 18 | Changes in total bile acids from Baseline to Week 18. |
| Change in FGF19 | Baseline through study week 18 | Change in fibroblast growth factor 19 (FGF19) from Baseline to Week 18 |
| Number of Participants Reporting an Adverse Events From Baseline Through Week 18 | 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. | 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. |
Countries
United States
Contacts
STUDY_DIRECTORAdrian Di Bisceglie, MD,FACP,FAASLD
HighTide Therapeutics USA, LLC
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 500mg HTD1801, Bid HTD1801: HTD1801 tablets, 250mg | 33 |
| 1000mg HTD1801, Bid HTD1801: HTD1801 tablets, 250mg | 34 |
| Placebo, Bid Placebo: tablets manufactured to mimic HTD1801 tablets | 33 |
| Total | 100 |
Baseline characteristics
| Characteristic | 500mg HTD1801, Bid | 1000mg HTD1801, Bid | Placebo, Bid | Total |
|---|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 10.2 | 53 years STANDARD_DEVIATION 12.2 | 58 years STANDARD_DEVIATION 10.7 | 56 years STANDARD_DEVIATION 11.2 |
| All Randomized Subjects Disposition | 33 Participants | 34 Participants | 33 Participants | 100 Participants |
| All Randomized Subjects Eligible Subjects | 32 Participants | 33 Participants | 33 Participants | 98 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 2 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 29 Participants | 31 Participants | 31 Participants | 91 Participants |
| Sex: Female, Male Female | 26 Participants | 24 Participants | 22 Participants | 72 Participants |
| Sex: Female, Male Male | 7 Participants | 10 Participants | 11 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 34 | 0 / 33 |
| other Total, other adverse events | 21 / 33 | 26 / 34 | 20 / 33 |
| serious Total, serious adverse events | 1 / 33 | 1 / 34 | 1 / 33 |
Outcome results
Primary
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
Population: Efficacy set which included all subjects who completed at least 80 days of study drug and had a Week 18 or Early Termination (ET) visit MRI-PDFF assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF | -2.918 Change in percentage of liver fat | Standard Deviation 4.0204 |
| 1000mg HTD1801, Bid | Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF | -4.829 Change in percentage of liver fat | Standard Deviation 4.3516 |
| Placebo, Bid | Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF | -1.962 Change in percentage of liver fat | Standard Deviation 4.8844 |
p-value: 0.199ANCOVA
p-value: 0.011ANCOVA
Secondary
Change in ALT
Absolute change in alanine aminotransferase (ALT) from Baseline to Week 18.
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the absolute change in alanine aminotransferase endpoint and had 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in ALT | -4 U/L | Standard Deviation 17.9 |
| 1000mg HTD1801, Bid | Change in ALT | -19 U/L | Standard Deviation 27.2 |
| Placebo, Bid | Change in ALT | -3 U/L | Standard Deviation 19.2 |
p-value: 0.674ANCOVA
p-value: 0.03ANCOVA
Secondary
Change in AST
Absolute change in aspartate aminotransferase (AST) from Baseline to Week 18.
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures included subjects with data was available for the change in AST endpoint and included 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in AST | 0 U/L | Standard Deviation 13.2 |
| 1000mg HTD1801, Bid | Change in AST | -13 U/L | Standard Deviation 26.3 |
| Placebo, Bid | Change in AST | -3 U/L | Standard Deviation 11.6 |
p-value: 0.488ANCOVA
p-value: 0.022ANCOVA
Secondary
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
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the change in ELF score endpoint and include 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in ELF Score | 0.05 score on a scale | Standard Deviation 0.723 |
| 1000mg HTD1801, Bid | Change in ELF Score | -0.10 score on a scale | Standard Deviation 0.592 |
| Placebo, Bid | Change in ELF Score | -0.05 score on a scale | Standard Deviation 0.461 |
p-value: 0.267ANCOVA
p-value: 0.911ANCOVA
Secondary
Change in Fasting Glucose
Change in fasting glucose from Baseline to Week 18 .
Time frame: Baseline through study Week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the change in glucose endpoint.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in Fasting Glucose | 120 mg/dL | Standard Deviation 28.6 |
| 1000mg HTD1801, Bid | Change in Fasting Glucose | 129 mg/dL | Standard Deviation 42.5 |
| Placebo, Bid | Change in Fasting Glucose | 131 mg/dL | Standard Deviation 40.9 |
p-value: 0.152ANCOVA
p-value: 0.109ANCOVA
Secondary
Change in FGF19
Change in fibroblast growth factor 19 (FGF19) from Baseline to Week 18
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the change in FGF-19 and include 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in FGF19 | -11 μmol/L | Standard Deviation 111.8 |
| 1000mg HTD1801, Bid | Change in FGF19 | -9 μmol/L | Standard Deviation 71.1 |
| Placebo, Bid | Change in FGF19 | -40 μmol/L | Standard Deviation 84.8 |
p-value: 0.124ANCOVA
p-value: 0.171ANCOVA
Secondary
Change in HA
Change in hyaluronic acid (HA) from Baseline to Week 18.
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the change in HA and included set had 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in HA | -0.64 µg/L | Standard Deviation 35.398 |
| 1000mg HTD1801, Bid | Change in HA | -5.25 µg/L | Standard Deviation 34.046 |
| Placebo, Bid | Change in HA | -3.83 µg/L | Standard Deviation 49.844 |
p-value: 0.515ANCOVA
p-value: 0.887ANCOVA
Secondary
Change in HDL-c
Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18.
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data was available for the change in HDL-c endpoint and included 4 more subjects than were in the Efficacy set..
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in HDL-c | 1 mg/dL | Standard Deviation 5.7 |
| 1000mg HTD1801, Bid | Change in HDL-c | 0 mg/dL | Standard Deviation 8.2 |
| Placebo, Bid | Change in HDL-c | 0 mg/dL | Standard Deviation 7.5 |
p-value: 0.955ANCOVA
p-value: 0.072ANCOVA
Secondary
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
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data was available for the changes in HOMA-IR endpoint and included 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in HOMA-IR | -3.38 score on a scale | Standard Deviation 6.779 |
| 1000mg HTD1801, Bid | Change in HOMA-IR | -4.21 score on a scale | Standard Deviation 7.074 |
| Placebo, Bid | Change in HOMA-IR | -6.66 score on a scale | Standard Deviation 17.752 |
p-value: 0.201ANCOVA
p-value: 0.534ANCOVA
Secondary
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
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data was available for the changes in LDL-c endpoint and included 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in LDL-c | 5 mg/dL | Standard Deviation 34.1 |
| 1000mg HTD1801, Bid | Change in LDL-c | -16 mg/dL | Standard Deviation 26.5 |
| Placebo, Bid | Change in LDL-c | 0 mg/dL | Standard Deviation 20.5 |
p-value: 0.955ANCOVA
p-value: 0.072ANCOVA
Secondary
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
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the change in PIIINP and included 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in PIIINP | 0.68 µg/L | Standard Deviation 2.905 |
| 1000mg HTD1801, Bid | Change in PIIINP | 0.03 µg/L | Standard Deviation 3.36 |
| Placebo, Bid | Change in PIIINP | -0.31 µg/L | Standard Deviation 2.016 |
p-value: 0.107ANCOVA
p-value: 0.489ANCOVA
Secondary
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
Population: The Modified Efficacy analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data was available for the change in Pro-C3 endpoint and included 4 more subjects than were in the Efficacy set...
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in Pro-Peptide of Type III Collagen (Pro-C3) | 0.5 ng/mL | Standard Deviation 5.17 |
| 1000mg HTD1801, Bid | Change in Pro-Peptide of Type III Collagen (Pro-C3) | -2.3 ng/mL | Standard Deviation 7.09 |
| Placebo, Bid | Change in Pro-Peptide of Type III Collagen (Pro-C3) | -0.8 ng/mL | Standard Deviation 2.94 |
p-value: 0.236ANCOVA
p-value: 0.944ANCOVA
Secondary
Change in Serum Triglycerides
Change in serum triglycerides from Baseline to Week 18.
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited subjects with data was available for the changes in serum triglycerides endpoint and included 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in Serum Triglycerides | -41 mg/dL | Standard Deviation 136.3 |
| 1000mg HTD1801, Bid | Change in Serum Triglycerides | -24 mg/dL | Standard Deviation 70.4 |
| Placebo, Bid | Change in Serum Triglycerides | 18 mg/dL | Standard Deviation 142.9 |
p-value: 0.041ANCOVA
p-value: 0.12ANCOVA
Secondary
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
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the change in TIMP-1 endpoint and include 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in TIMP-1 | 1.8 µg/L | Standard Deviation 53.26 |
| 1000mg HTD1801, Bid | Change in TIMP-1 | -8.9 µg/L | Standard Deviation 57.32 |
| Placebo, Bid | Change in TIMP-1 | -6.0 µg/L | Standard Deviation 31.55 |
p-value: 0.387ANCOVA
p-value: 0.855ANCOVA
Secondary
Change in Total Bile Acids
Changes in total bile acids from Baseline to Week 18.
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for the change in total bile acids and included for 4 more subjects than were in the Efficacy set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Change in Total Bile Acids | 1307 μmol/L | Standard Deviation 1432.6 |
| 1000mg HTD1801, Bid | Change in Total Bile Acids | 1625 μmol/L | Standard Deviation 2332.2 |
| Placebo, Bid | Change in Total Bile Acids | -581 μmol/L | Standard Deviation 1487.4 |
p-value: 0.003ANCOVA
p-value: 0.016ANCOVA
Secondary
Changes in Hemoglobin A1c
Changes in HbA1c from Baseline to Week 18.
Time frame: Baseline through study week 18
Population: The Modified Efficacy set was utilized for analyses of secondary endpoints, as well as select analyses of LFC. This analysis set included all randomized subjects who received at least one dose of study drug and who had at least one post-dose MRI-PDFF assessment. The summary measures are additionally limited to those subjects with data available for change in hemoglobin A1c endpoint..
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Changes in Hemoglobin A1c | -0.3 Percentage | Standard Deviation 0.68 |
| 1000mg HTD1801, Bid | Changes in Hemoglobin A1c | -0.6 Percentage | Standard Deviation 0.96 |
| Placebo, Bid | Changes in Hemoglobin A1c | 0.1 Percentage | Standard Deviation 0.82 |
p-value: 0.034ANCOVA
p-value: 0.004ANCOVA
Secondary
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.
Population: All subjects included in the safety set.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 500mg HTD1801, Bid | Number of Participants Reporting an Adverse Events From Baseline Through Week 18 | 21 Participants |
| 1000mg HTD1801, Bid | Number of Participants Reporting an Adverse Events From Baseline Through Week 18 | 26 Participants |
| Placebo, Bid | Number of Participants Reporting an Adverse Events From Baseline Through Week 18 | 20 Participants |
Secondary
Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF
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
Population: Efficacy set which included all subjects who completed at least 80 days of study drug and had a Week 18 or Early Termination (ET) visit MRI-PDFF assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 500mg HTD1801, Bid | Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF | 10 Participants |
| 1000mg HTD1801, Bid | Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF | 12 Participants |
| Placebo, Bid | Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF | 8 Participants |
p-value: 0.287Regression, Logistic
p-value: 0.09Regression, Logistic
Secondary
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
Population: Efficacy set which included all subjects who completed at least 80 days of study drug and had a Week 18 or Early Termination (ET) visit MRI-PDFF assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 500mg HTD1801, Bid | Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF | 1 Participants |
| 1000mg HTD1801, Bid | Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF | 0 Participants |
| Placebo, Bid | Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF | 0 Participants |
p-value: 0.294Cochran-Mantel-Haenszel
Secondary
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
Population: Efficacy set which included all subjects who completed at least 80 days of study drug and had a Week 18 or Early Termination (ET) visit MRI-PDFF assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 500mg HTD1801, Bid | Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF | 6 Participants |
| 1000mg HTD1801, Bid | Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF | 10 Participants |
| Placebo, Bid | Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF | 7 Participants |
p-value: 0.884Regression, Logistic
p-value: 0.236Regression, Logistic
Secondary
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
Population: Subjects with elevated alanine aminotransferase (ALT) at Baseline
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| 500mg HTD1801, Bid | Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18 | 3 Participants |
| 1000mg HTD1801, Bid | Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18 | 9 Participants |
| Placebo, Bid | Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18 | 5 Participants |
p-value: 0.588Regression, Logistic
p-value: 0.103Regression, Logistic
Secondary
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
Population: Efficacy set which included all subjects who completed at least 80 days of study drug and had a Week 18 or Early Termination (ET) visit MRI-PDFF assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| 500mg HTD1801, Bid | Relative Change in LFC as Measured by MRI-PDFF | -15.097 Percentage change | Standard Deviation 22.7749 |
| 1000mg HTD1801, Bid | Relative Change in LFC as Measured by MRI-PDFF | -24.140 Percentage change | Standard Deviation 21.702 |
| Placebo, Bid | Relative Change in LFC as Measured by MRI-PDFF | -8.322 Percentage change | Standard Deviation 24.4804 |
p-value: 0.196ANCOVA
p-value: 0.016ANCOVA