NAFLD, NASH
Conditions
Brief summary
Double-blind, randomized, placebo-controlled study to explore the efficacy and safety of elobixibat compared to placebo in adults with NAFLD (nonalcoholic fatty liver disease) or NASH (nonalcoholic steatohepatitis)
Detailed description
A total of 15 investigators at 15 sites received institutional review board (IRB)/ethics committee (EC) approval to participate in this study and enrolled at least 1 participant.
Interventions
DRUGElobixibat
Elobixibat is a small molecule and a potent inhibitor of the ileal bile acid transporter (iBAT).
DRUGPlacebo oral tablet
Placebo identical in appearance to active drug
Sponsors
Albireo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Double-Blind, Randomized, Placebo-Controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Have a current biopsy-confirmed NASH within 6 months of screening or a suspected diagnosis of NAFLD/NASH * Screening magnetic resonance imaging-proton density fat fraction (MRI-PDFF) with ≥10% liver steatosis * Fasting serum low density lipoprotein-cholesterol (LDL-C) \>130 mg/dL at Screening, \>110 mg/dL on lipid-lowering medications Key
Exclusion criteria
* Body mass index (BMI) \<25 kg/m2 * Fibrosis-4 index (Fib-4) \>2.6 * Any of the following laboratory abnormalities: 1. alanine aminotransferase (ALT) \>5 × upper limit of normal (ULN) or aspartate aminotransferase (AST) \>5 × ULN 2. International normalized ratio (INR) ≥1.3, unless on anticoagulant therapy 3. Total bilirubin \>ULN, except with an established diagnosis of Gilbert's syndrome 4. Platelet count less than the lower limit of normal (LLN) 5. Creatinine clearance as calculated by the modification of diet in renal disease (MDRD) estimated glomerular filtration rate (eGFR) equation \<60 mL/min * Uncontrolled Type 2 diabetes defined as hemoglobin A1c (HbA1c) \>9.5% * Clinical hyperthyroidism or hypothyroidism or screening hormone results pointing to thyroid dysfunction. * Uncontrolled hypertension * Participants with known intolerance to MRI or with conditions contraindicated for MRI procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Serum Low Density Lipoprotein-cholesterol (LDL-C) at Week 16 | Week 16 | The primary efficacy endpoint was the change from Baseline in serum LDL-C at Week 16. Baseline was defined as the last non-missing LDL-C value prior to the first dose of study drug. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) | From first dose of study drug (Day 1) up to end of follow-up per participant, approximately 13 months | An adverse event (AE) was any untoward medical occurrence in enrolled participant regardless of causal relationship with study drug. An SAE was defined as any AE that, at any dose, resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity, required or prolonged hospitalization, was a congenital anomaly/birth defect or an important medical event. TEAEs were defined as AEs that were new or worsened after the first dose of study drug. |
| Absolute Change From Baseline to Week 16 in Liver Fat Fraction | Baseline (Day 1) and Week 16 | The effect of elobixibat on liver steatosis was measured by magnetic resonance imaging (MRI) for liver fat fraction using proton density fat fraction \[PDFF\]). Baseline was defined as the last non-missing value prior to the first dose of study drug. |
| Absolute Change From Baseline to Week 16 in Total Liver Fat | Baseline (Day 1) and Week 16 | The effect of elobixibat on liver steatosis was measured by MRI for total liver fat using whole liver fat volume. Baseline was defined as the last non-missing value prior to the first dose of study drug. |
| Change From Baseline to Week 16 in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma-glutamyl Transferase (GGT) | Baseline (Day 1) and Week 16 | Serum samples were collected at specified timepoints to assess ALT, AST and GGT levels. Baseline was defined as the last non-missing value prior to the first dose of study drug. |
| Change From Baseline to Week 16 in High-density Lipoprotein (HDL) Cholesterol, Non-high-density Lipoprotein Cholesterol and Triglycerides | Baseline (Day 1) and Week 16 | Blood samples were collected at specified timepoints to assess HDL and non-HDL cholesterol levels and triglycerides. Baseline was defined as the last non-missing value prior to the first dose of study drug. |
| Change From Baseline to Week 16 in Low-density Lipoprotein (LDL) Cholesterol to High-density Lipoprotein Cholesterol Ratio | Baseline (Day 1) and Week 16 | Blood samples were collected at specified timepoints to assess LDL and HDL cholesterol levels and ratio was obtained. Baseline was defined as the last non-missing value prior to the first dose of study drug. |
| Change From Baseline to Week 16 in Total Bile Acids | Baseline (Day 1) and Week 16 | Blood samples were collected at specified timepoints to assess total bile acid levels. Baseline was defined as the last non-missing value prior to the first dose of study drug. |
Countries
United States
Participant flow
Recruitment details
This double-blind, randomized, placebo-controlled, phase 2 study was conducted at 15 sites in the United States to explore the efficacy and safety of elobixibat (oral dose of 5 milligrams \[mg\]) once daily for 16 weeks in participants with nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH).
Pre-assignment details
The study consisted of a 6-week screening period followed by a 16-week treatment period and a follow-up visit 2 weeks after the last dose of study drug.
Participants by arm
| Arm | Count |
|---|---|
| Elobixibat Elobixibat 5 mg once daily
Elobixibat: Elobixibat is a small molecule and a potent inhibitor of the ileal bile acid transporter (iBAT). | 23 |
| Placebo Placebo
Placebo oral tablet: Placebo identical in appearance to active drug | 24 |
| Total | 47 |
Baseline characteristics
| Characteristic | Elobixibat | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 51.8 years STANDARD_DEVIATION 10.77 | 50.9 years STANDARD_DEVIATION 12.07 | 50.0 years STANDARD_DEVIATION 13.36 |
| Disease under study Nonalcoholic Fatty Liver Disease (NAFLD) | 13 Participants | 26 Participants | 13 Participants |
| Disease under study Nonalcoholic Steatohepatitis (NASH) | 11 Participants | 22 Participants | 11 Participants |
| Duration of disease (Years) Nonalcoholic Fatty Liver Disease (NAFLD) | 1.879 years STANDARD_DEVIATION 2.667 | 1.707 years STANDARD_DEVIATION 2.739 | 1.534 years STANDARD_DEVIATION 2.908 |
| Duration of disease (Years) Nonalcoholic Steatohepatitis (NASH) | 1.610 years STANDARD_DEVIATION 2.918 | 1.251 years STANDARD_DEVIATION 2.22 | 0.892 years STANDARD_DEVIATION 1.246 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 16 Participants | 32 Participants | 16 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | 15 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Asian | 3 Participants | 3 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Black or African American | 2 Participants | 4 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Race Other | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 18 Participants | 39 Participants | 21 Participants |
| Region of Enrollment United States | 23 participants | 47 participants | 24 participants |
| Sex: Female, Male Female | 15 Participants | 31 Participants | 16 Participants |
| Sex: Female, Male Male | 8 Participants | 16 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 13 / 23 | 10 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 |
Outcome results
Primary
Change From Baseline in Serum Low Density Lipoprotein-cholesterol (LDL-C) at Week 16
The primary efficacy endpoint was the change from Baseline in serum LDL-C at Week 16. Baseline was defined as the last non-missing LDL-C value prior to the first dose of study drug.
Time frame: Week 16
Population: The intent-to-treat (ITT) population included all randomized participants who received at least 1 dose of study drug.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Elobixibat | Change From Baseline in Serum Low Density Lipoprotein-cholesterol (LDL-C) at Week 16 | -0.57 mmol/L | Standard Error 0.125 |
| Placebo | Change From Baseline in Serum Low Density Lipoprotein-cholesterol (LDL-C) at Week 16 | -0.17 mmol/L | Standard Error 0.134 |
Comparison: Change from baseline in serum LDL-C at Week 16 was analyzed using ANCOVA after the missing data imputation, with treatment group as a factor, baseline serum LDL-C, baseline LDL-C-by-treatment interaction values, and baseline lipid-lowering medications (Yes or No) as covariates. Missing data for serum LDL-C was imputed through multiple imputation method as described in the statistical analysis plan (SAP).p-value: 0.02995% CI: [-0.76, -0.04]ANCOVA