Trial Outcomes & Findings for A Study of HTD1801 in Adults With Nonalcoholic Steatohepatitis (NASH) and Type 2 Diabetes Mellitus (T2DM) (NCT NCT03656744)

NCT ID: NCT03656744

Last Updated: 2021-12-29

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 101 participants
• Primary outcome timeframe: Baseline through study Week 18
• Results posted on: 2021-12-29

Participant Flow

Participant milestones

Measure	500mg HTD1801, Bid HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid HTD1801: HTD1801 tablets, 250mg	Placebo, Bid Placebo: tablets manufactured to mimic HTD1801 tablets
Overall Study STARTED	34	34	33
Overall Study COMPLETED	29	27	32
Overall Study NOT COMPLETED	5	7	1

Reasons for withdrawal

Measure	500mg HTD1801, Bid HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid HTD1801: HTD1801 tablets, 250mg	Placebo, Bid Placebo: tablets manufactured to mimic HTD1801 tablets
Overall Study Adverse Event	1	4	1
Overall Study Protocol Violation	1	0	0
Overall Study Lost to Follow-up	2	2	0
Overall Study Withdrawal by Subject	0	1	0
Overall Study Randomized in error. Did not start investigational product. Considered an ET.	1	0	0

Baseline Characteristics

One subject was randomized in error and did not receive investigational study drug.

Baseline characteristics by cohort

Measure	500mg HTD1801, Bid n=33 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=34 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=33 Participants Placebo: tablets manufactured to mimic HTD1801 tablets	Total n=100 Participants Total of all reporting groups
Age, Continuous	58 years STANDARD_DEVIATION 10.2 • n=5 Participants • One subject was randomized in error and did not receive investigational study drug.	53 years STANDARD_DEVIATION 12.2 • n=7 Participants • One subject was randomized in error and did not receive investigational study drug.	58 years STANDARD_DEVIATION 10.7 • n=5 Participants • One subject was randomized in error and did not receive investigational study drug.	56 years STANDARD_DEVIATION 11.2 • n=4 Participants • One subject was randomized in error and did not receive investigational study drug.
Sex: Female, Male Female	26 Participants n=5 Participants • One subject randomized in error and did not receive investigational study medication.	24 Participants n=7 Participants • One subject randomized in error and did not receive investigational study medication.	22 Participants n=5 Participants • One subject randomized in error and did not receive investigational study medication.	72 Participants n=4 Participants • One subject randomized in error and did not receive investigational study medication.
Sex: Female, Male Male	7 Participants n=5 Participants • One subject randomized in error and did not receive investigational study medication.	10 Participants n=7 Participants • One subject randomized in error and did not receive investigational study medication.	11 Participants n=5 Participants • One subject randomized in error and did not receive investigational study medication.	28 Participants n=4 Participants • One subject randomized in error and did not receive investigational study medication.
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=7 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=4 Participants • One subject randomized in error and did not receive investigational study drug.
Race (NIH/OMB) Asian	1 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	1 Participants n=7 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	2 Participants n=4 Participants • One subject randomized in error and did not receive investigational study drug.
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=7 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=4 Participants • One subject randomized in error and did not receive investigational study drug.
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	2 Participants n=7 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	5 Participants n=4 Participants • One subject randomized in error and did not receive investigational study drug.
Race (NIH/OMB) White	29 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	31 Participants n=7 Participants • One subject randomized in error and did not receive investigational study drug.	31 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	91 Participants n=4 Participants • One subject randomized in error and did not receive investigational study drug.
Race (NIH/OMB) More than one race	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=7 Participants • One subject randomized in error and did not receive investigational study drug.	2 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	2 Participants n=4 Participants • One subject randomized in error and did not receive investigational study drug.
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=7 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=5 Participants • One subject randomized in error and did not receive investigational study drug.	0 Participants n=4 Participants • One subject randomized in error and did not receive investigational study drug.
All Randomized Subjects Disposition	33 Participants n=5 Participants	34 Participants n=7 Participants	33 Participants n=5 Participants	100 Participants n=4 Participants
All Randomized Subjects Eligible Subjects	32 Participants n=5 Participants	33 Participants n=7 Participants	33 Participants n=5 Participants	98 Participants n=4 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=30 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=27 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Absolute Change in Liver Fat Content (LFC) as Measured by MRI-PDFF	-2.918 Change in percentage of liver fat Standard Deviation 4.0204	-4.829 Change in percentage of liver fat Standard Deviation 4.3516	-1.962 Change in percentage of liver fat Standard Deviation 4.8844

SECONDARY outcome

Timeframe: 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.

Change in fasting glucose from Baseline to Week 18 .

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in Fasting Glucose	120 mg/dL Standard Deviation 28.6	129 mg/dL Standard Deviation 42.5	131 mg/dL Standard Deviation 40.9

SECONDARY outcome

Timeframe: 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..

Changes in HbA1c from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Changes in Hemoglobin A1c	-0.3 Percentage Standard Deviation 0.68	-0.6 Percentage Standard Deviation 0.96	0.1 Percentage Standard Deviation 0.82

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=30 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=27 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Proportion of Subjects Who Achieved ≥ 30% Relative Reduction in LFC as Measured by MRI-PDFF	6 Participants	10 Participants	7 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=30 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=27 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Relative Change in LFC as Measured by MRI-PDFF	-15.097 Percentage change Standard Deviation 22.7749	-24.140 Percentage change Standard Deviation 21.7020	-8.322 Percentage change Standard Deviation 24.4804

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=30 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=27 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Number of Subjects Who Normalized LFC to <5% as Measured by MRI-PDFF	1 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=30 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=27 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Number of Subjects Who Achieved ≥5% Absolute Reduction in Liver Fat Content (LFC) as Measured by MRI-PDFF	10 Participants	12 Participants	8 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in HOMA-IR	-3.38 score on a scale Standard Deviation 6.779	-4.21 score on a scale Standard Deviation 7.074	-6.66 score on a scale Standard Deviation 17.752

SECONDARY outcome

Timeframe: 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.

Change in low-density lipoprotein cholesterol (LDL-c) from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=27 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=25 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=29 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in LDL-c	5 mg/dL Standard Deviation 34.1	-16 mg/dL Standard Deviation 26.5	0 mg/dL Standard Deviation 20.5

SECONDARY outcome

Timeframe: 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.

Change in serum triglycerides from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in Serum Triglycerides	-41 mg/dL Standard Deviation 136.3	-24 mg/dL Standard Deviation 70.4	18 mg/dL Standard Deviation 142.9

SECONDARY outcome

Timeframe: 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..

Change in high-density lipoprotein cholesterol (HDL-c) from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in HDL-c	1 mg/dL Standard Deviation 5.7	0 mg/dL Standard Deviation 8.2	0 mg/dL Standard Deviation 7.5

SECONDARY outcome

Timeframe: 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.

Absolute change in aspartate aminotransferase (AST) from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in AST	0 U/L Standard Deviation 13.2	-13 U/L Standard Deviation 26.3	-3 U/L Standard Deviation 11.6

SECONDARY outcome

Timeframe: 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.

Absolute change in alanine aminotransferase (ALT) from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in ALT	-4 U/L Standard Deviation 17.9	-19 U/L Standard Deviation 27.2	-3 U/L Standard Deviation 19.2

SECONDARY outcome

Timeframe: Baseline through study week 18

Population: Subjects with elevated alanine aminotransferase (ALT) at Baseline

Proportion of subjects with elevated alanine aminotransferase (ALT) at Baseline who normalized ALT at Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=14 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=18 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=20 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Proportion of Subjects With Elevated ALT at Baseline Who Normalized ALT at Week 18	3 Participants	9 Participants	5 Participants

SECONDARY outcome

Timeframe: 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...

Change in Pro-C3 from Baseline to Week 18 for subjects with elevated Pro-C3 at Baseline.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in Pro-Peptide of Type III Collagen (Pro-C3)	0.5 ng/mL Standard Deviation 5.17	-2.3 ng/mL Standard Deviation 7.09	-0.8 ng/mL Standard Deviation 2.94

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=25 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in ELF Score	0.05 score on a scale Standard Deviation 0.723	-0.10 score on a scale Standard Deviation 0.592	-0.05 score on a scale Standard Deviation 0.461

SECONDARY outcome

Timeframe: 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.

Change in tissue inhibitor of metalloproteinases 1 (TIMP-1) from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=26 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in TIMP-1	1.8 µg/L Standard Deviation 53.26	-8.9 µg/L Standard Deviation 57.32	-6.0 µg/L Standard Deviation 31.55

SECONDARY outcome

Timeframe: 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.

Change in N-terminal pro-peptide of type III collagen (PIIINP) from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=25 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in PIIINP	0.68 µg/L Standard Deviation 2.905	0.03 µg/L Standard Deviation 3.360	-0.31 µg/L Standard Deviation 2.016

SECONDARY outcome

Timeframe: 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.

Change in hyaluronic acid (HA) from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=29 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=25 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=32 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in HA	-0.64 µg/L Standard Deviation 35.398	-5.25 µg/L Standard Deviation 34.046	-3.83 µg/L Standard Deviation 49.844

SECONDARY outcome

Timeframe: 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.

Changes in total bile acids from Baseline to Week 18.

Outcome measures

Measure	500mg HTD1801, Bid n=11 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=12 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=13 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in Total Bile Acids	1307 μmol/L Standard Deviation 1432.6	1625 μmol/L Standard Deviation 2332.2	-581 μmol/L Standard Deviation 1487.4

SECONDARY outcome

Timeframe: 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.

Change in fibroblast growth factor 19 (FGF19) from Baseline to Week 18

Outcome measures

Measure	500mg HTD1801, Bid n=11 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=12 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=13 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Change in FGF19	-11 μmol/L Standard Deviation 111.8	-9 μmol/L Standard Deviation 71.1	-40 μmol/L Standard Deviation 84.8

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	500mg HTD1801, Bid n=33 Participants HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=34 Participants HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=33 Participants Placebo: tablets manufactured to mimic HTD1801 tablets
Number of Participants Reporting an Adverse Events From Baseline Through Week 18	21 Participants	26 Participants	20 Participants

Adverse Events

500mg HTD1801, Bid

Serious events: 1 serious events

Other events: 21 other events

Deaths: 0 deaths

1000mg HTD1801, Bid

Serious events: 1 serious events

Other events: 26 other events

Deaths: 0 deaths

Placebo, Bid

Serious events: 1 serious events

Other events: 20 other events

Deaths: 0 deaths

Serious adverse events

Measure	500mg HTD1801, Bid n=33 participants at risk HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=34 participants at risk HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=33 participants at risk Placebo: tablets manufactured to mimic HTD1801 tablets
Respiratory, thoracic and mediastinal disorders Decreased oxygen saturation	0.00% 0/33 • 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 for a completed subject.	2.9% 1/34 • Number of events 1 • 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 for a completed subject.	0.00% 0/33 • 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 for a completed subject.
Cardiac disorders Myocardial infarction	3.0% 1/33 • Number of events 1 • 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 for a completed subject.	2.9% 1/34 • Number of events 1 • 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 for a completed subject.	0.00% 0/33 • 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 for a completed subject.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Bladder transitional cell carcinoma	0.00% 0/33 • 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 for a completed subject.	0.00% 0/34 • 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 for a completed subject.	3.0% 1/33 • Number of events 1 • 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 for a completed subject.

Other adverse events

Measure	500mg HTD1801, Bid n=33 participants at risk HTD1801: HTD1801 tablets, 250mg	1000mg HTD1801, Bid n=34 participants at risk HTD1801: HTD1801 tablets, 250mg	Placebo, Bid n=33 participants at risk Placebo: tablets manufactured to mimic HTD1801 tablets
Infections and infestations Infections and Infestations	12.1% 4/33 • Number of events 4 • 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 for a completed subject.	14.7% 5/34 • Number of events 5 • 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 for a completed subject.	33.3% 11/33 • Number of events 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 for a completed subject.
Gastrointestinal disorders Gastrointestinal Disorders	42.4% 14/33 • Number of events 27 • 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 for a completed subject.	55.9% 19/34 • Number of events 40 • 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 for a completed subject.	30.3% 10/33 • Number of events 19 • 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 for a completed subject.
Nervous system disorders Nervous system disorders	9.1% 3/33 • Number of events 3 • 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 for a completed subject.	14.7% 5/34 • Number of events 6 • 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 for a completed subject.	9.1% 3/33 • Number of events 4 • 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 for a completed subject.
General disorders General Disorders	6.1% 2/33 • Number of events 5 • 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 for a completed subject.	8.8% 3/34 • Number of events 4 • 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 for a completed subject.	0.00% 0/33 • 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 for a completed subject.
Respiratory, thoracic and mediastinal disorders Respiratory disorders	3.0% 1/33 • Number of events 2 • 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 for a completed subject.	2.9% 1/34 • Number of events 2 • 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 for a completed subject.	9.1% 3/33 • Number of events 6 • 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 for a completed subject.
Metabolism and nutrition disorders Metabolic disorders	0.00% 0/33 • 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 for a completed subject.	5.9% 2/34 • Number of events 4 • 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 for a completed subject.	6.1% 2/33 • Number of events 3 • 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 for a completed subject.
Skin and subcutaneous tissue disorders Skin disorders	3.0% 1/33 • Number of events 2 • 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 for a completed subject.	5.9% 2/34 • Number of events 3 • 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 for a completed subject.	3.0% 1/33 • Number of events 1 • 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 for a completed subject.
Injury, poisoning and procedural complications Injury	3.0% 1/33 • Number of events 1 • 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 for a completed subject.	0.00% 0/34 • 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 for a completed subject.	6.1% 2/33 • Number of events 2 • 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 for a completed subject.
Endocrine disorders Endocrine Disorders	0.00% 0/33 • 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 for a completed subject.	5.9% 2/34 • Number of events 2 • 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 for a completed subject.	0.00% 0/33 • 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 for a completed subject.

Additional Information

Chief Medical Officer

HighTide Therapeutics

Phone: 314-791-0593

Email: adibisceglie@hightidetx.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place