NAFLD
Conditions
Brief summary
This is a randomized, single blind study to determine whether AXA1125 or AXA1957, novel compositions of amino acids, are safe and well tolerated. Subjects have non-alcoholic fatty liver disease (NAFLD) and the study will also examine liver biology using blood tests and magnetic resonance imaging (MRI).
Detailed description
This was a 16-week, single-blind, randomized, placebo-controlled food study of the safety and tolerability of AXA1125 and AXA1957 in subjects with NAFLD. Subjects signed an informed consent form and were screened for eligibility, per the inclusion and exclusion criteria below, up to 6 weeks before the start of the administration period. Subjects were randomized as soon as eligibility was confirmed. Eligible subjects were randomized in a 2:2:2:1 ratio to receive either AXA1125 24 g twice daily (BID), AXA1957 20.3 g BID, AXA1957 13.5 g BID, or placebo 24 g BID. Randomization occurred via an interactive web response system after eligibility was confirmed and approximately 3 to 5 days prior to the Day 1 visit. Assigned study food product (AXA1125, AXA1957, or placebo) were shipped to the study site upon randomization of each subject. Once randomization had occurred, subjects presented to the study site on Day 1 (Baseline/Visit 2) for their baseline assessments per the schedule of events. Study Day 1 was the beginning of the 16-week administration period. Subjects returned to the study site at Week 1 (Visit 3), Week 2 (Visit 4), Week 4 (Visit 5), Week 8 (Visit 6), Week 12 (Visit 7), and Week 16 (Visit 8) to receive their study food product and/or to return any unused study food product, provide blood samples for biomarker and other laboratory testing, undergo liver imaging, and complete other study safety assessments per the schedule of events. The Safety Follow-up Visit, which occurred approximately 2 weeks after the last visit in the administration period (ie, after the Week 16 visit or at the time of early termination), was the End of Study Visit (Visit 9). There were 9 study visits in total, including the Screening and Follow-up Visits.
Interventions
Sponsors
Axcella Health, Inc
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Willing to participate in the study and provide written informed consent. * Male and female adults aged \> 18 years. * Subjects must not have participated in any diet/lifestyle intervention or observational studies, or engaged in any body weight altering regimens that resulted in body weight fluctuations (i.e. body weight loss or gain by 5%) in the preceding 3 months prior to Screening. * A screening MRI consistent with liver inflammation and fibrosis. Key
Exclusion criteria
* Current or history of significant alcohol consumption. * History or presence of liver disease (other than NAFLD/NASH). * History or presence of cirrhosis and/or history or presence of hepatic decompensation. * Any diabetes other than Type 2. * Other poorly controlled medical condition (for example, uncontrolled hypertension with a systolic blood pressure \> 100 mmHg). * Known sensitivity and/or history of clinically significant food intolerance/allergies to proteins (including whey, soy, casein, amino acids, etc.). * Unable or unwilling to adhere to contraception requirements. * Any contraindications to a MRI scan. * Any other condition that, in the opinion of the Investigator, renders the subject at risk for compliance, compromises the well-being of the subject, or hinders study completion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Baseline to week 16 | Subjects received AXA1125 at 24 g twice daily ( BID), AXA1957 at 20.3 g BID or 13.5 g BID with Product related AEs and any SAEs up to 16 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Liver Fat as Assessed by MRI- Proton Density Fat Fraction (PDFF) | Baseline to week 16 | Relative Changes From Baseline in MRI-PDFF at Week 16 in Overall Subjects (Safety Analysis Population) |
| Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | Baseline to week 16 | Absolute Changes From Baseline in HOMA-IR at Week 16 in Overall Subjects (Safety Analysis Population) |
| Change in Glucose Homeostasis | Baseline to week 16 | Absolute Changes From Baseline in HbA1c at Week 16 in Subjects with Diabetes (Safety Analysis Population) |
| Relative Change in Alanine Aminotransferase (ALT) | Baseline to week 16 | Relative Changes From Baseline in ALT at Week 16 in Overall Subjects (Safety Analysis Population) |
| Change in Aspartate Aminotransferase (AST) | Baseline to Week 16 | Relative Changes From Baseline in AST at Week 16 in Overall Subjects (Safety Analysis Population) |
Countries
United States
Participant flow
Pre-assignment details
112 subjects signed consent and randomized. Ten subjects screen failed prior to day 1 dosing ( after signing consent) and the number of participants who started the study is 102 subjects.
Participants by arm
| Arm | Count |
|---|---|
| AXA1957 High Dose AXA1957 20.3g
AXA1957: Amino acids, food study | 32 |
| AXA1957 Low Dose AXA1957 13.5g
AXA1957: Amino acids, food study | 26 |
| AXA1125 AXA1125 24g
AXA1125: Amino acids, food study | 29 |
| Placebo Placebo 24g
Placebo: Amino acids, food study | 15 |
| Total | 102 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 | 1 |
| Overall Study | Lost to Follow-up | 1 | 1 | 1 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 0 | 0 |
| Overall Study | Subject noncompliance | 7 | 4 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | AXA1957 High Dose | AXA1957 Low Dose | AXA1125 | Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 50.1 years STANDARD_DEVIATION 12.79 | 49.6 years STANDARD_DEVIATION 10.74 | 49.2 years STANDARD_DEVIATION 12.79 | 53.2 years STANDARD_DEVIATION 9.62 | 50.2 years STANDARD_DEVIATION 11.77 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 31 Participants | 24 Participants | 26 Participants | 14 Participants | 95 Participants |
| Region of Enrollment United States | 32 participants | 26 participants | 29 participants | 15 participants | 102 participants |
| Sex: Female, Male Female | 19 Participants | 16 Participants | 17 Participants | 10 Participants | 62 Participants |
| Sex: Female, Male Male | 13 Participants | 10 Participants | 12 Participants | 5 Participants | 40 Participants |
| Type 2 diabetes mellitus status (T2DM) | 12 Participants | 10 Participants | 12 Participants | 6 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 26 | 0 / 29 | 0 / 15 |
| other Total, other adverse events | 10 / 32 | 8 / 26 | 13 / 29 | 2 / 15 |
| serious Total, serious adverse events | 1 / 32 | 0 / 26 | 1 / 29 | 0 / 15 |
Outcome results
Primary
Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs)
Subjects received AXA1125 at 24 g twice daily ( BID), AXA1957 at 20.3 g BID or 13.5 g BID with Product related AEs and any SAEs up to 16 weeks
Time frame: Baseline to week 16
Population: Subjects received AXA1125 at 24 g BID, AXA1957 at 20.3 g BID or 13.5 g BID, or placebo for up to 16 weeks.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AXA1957 High Dose | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any Product Related Product-Emergent AEs | 10 participants |
| AXA1957 High Dose | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any SAEs | 1 participants |
| AXA1957 Low Dose | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any SAEs | 0 participants |
| AXA1957 Low Dose | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any Product Related Product-Emergent AEs | 8 participants |
| AXA1125 | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any Product Related Product-Emergent AEs | 13 participants |
| AXA1125 | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any SAEs | 1 participants |
| Placebo | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any Product Related Product-Emergent AEs | 2 participants |
| Placebo | Number of Subjects With Incidence of Study Product Emergent Adverse Events (AEs) and Any Serious Adverse Events (SAEs) | Any SAEs | 0 participants |
Secondary
Change in Aspartate Aminotransferase (AST)
Relative Changes From Baseline in AST at Week 16 in Overall Subjects (Safety Analysis Population)
Time frame: Baseline to Week 16
Population: Relative Changes From Baseline in AST at Week 16 in Overall Subjects (Safety Analysis Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXA1957 High Dose | Change in Aspartate Aminotransferase (AST) | -13.40 percentage of AST from basline | Standard Deviation 30.898 |
| AXA1957 Low Dose | Change in Aspartate Aminotransferase (AST) | -17.02 percentage of AST from basline | Standard Deviation 30.898 |
| AXA1125 | Change in Aspartate Aminotransferase (AST) | -16.76 percentage of AST from basline | Standard Deviation 27.908 |
| Placebo | Change in Aspartate Aminotransferase (AST) | -7.49 percentage of AST from basline | Standard Deviation 40.499 |
Secondary
Change in Glucose Homeostasis
Absolute Changes From Baseline in HbA1c at Week 16 in Subjects with Diabetes (Safety Analysis Population)
Time frame: Baseline to week 16
Population: Absolute Changes From Baseline in HbA1c at Week 16 in Subjects with Diabetes (Safety Analysis Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXA1957 High Dose | Change in Glucose Homeostasis | 0.0138 change in HbA1c | Standard Deviation 0.01419 |
| AXA1957 Low Dose | Change in Glucose Homeostasis | .0001 change in HbA1c | Standard Deviation 0.00588 |
| AXA1125 | Change in Glucose Homeostasis | -0.0070 change in HbA1c | Standard Deviation 8.008 |
| Placebo | Change in Glucose Homeostasis | -0.0027 change in HbA1c | Standard Deviation 0.00874 |
Secondary
Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)
Absolute Changes From Baseline in HOMA-IR at Week 16 in Overall Subjects (Safety Analysis Population)
Time frame: Baseline to week 16
Population: Absolute Changes From Baseline in HOMA-IR at Week 16 in Overall Subjects (Safety Analysis Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXA1957 High Dose | Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | 8.421 percentage of change of HOM-IR | Standard Deviation 34.5866 |
| AXA1957 Low Dose | Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | 1.445 percentage of change of HOM-IR | Standard Deviation 3.6396 |
| AXA1125 | Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | -4.369 percentage of change of HOM-IR | Standard Deviation 16.868 |
| Placebo | Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) | 0.720 percentage of change of HOM-IR | Standard Deviation 4.7074 |
Secondary
Percent Change in Liver Fat as Assessed by MRI- Proton Density Fat Fraction (PDFF)
Relative Changes From Baseline in MRI-PDFF at Week 16 in Overall Subjects (Safety Analysis Population)
Time frame: Baseline to week 16
Population: Relative Changes From Baseline in MRI-PDFF at Week 16 in Overall Subjects (Safety Analysis Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXA1957 High Dose | Percent Change in Liver Fat as Assessed by MRI- Proton Density Fat Fraction (PDFF) | -8.12 percentage of change of MRI_PDFF | Standard Deviation 24.904 |
| AXA1957 Low Dose | Percent Change in Liver Fat as Assessed by MRI- Proton Density Fat Fraction (PDFF) | -20.29 percentage of change of MRI_PDFF | Standard Deviation 23.064 |
| AXA1125 | Percent Change in Liver Fat as Assessed by MRI- Proton Density Fat Fraction (PDFF) | -22.88 percentage of change of MRI_PDFF | Standard Deviation 23.04 |
| Placebo | Percent Change in Liver Fat as Assessed by MRI- Proton Density Fat Fraction (PDFF) | -5.74 percentage of change of MRI_PDFF | Standard Deviation 20.425 |
Secondary
Relative Change in Alanine Aminotransferase (ALT)
Relative Changes From Baseline in ALT at Week 16 in Overall Subjects (Safety Analysis Population)
Time frame: Baseline to week 16
Population: Relative Changes From Baseline in ALT at Week 16 in Overall Subjects (Safety Analysis Population)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| AXA1957 High Dose | Relative Change in Alanine Aminotransferase (ALT) | -20.65 percentage change of ALT | Standard Deviation 30.163 |
| AXA1957 Low Dose | Relative Change in Alanine Aminotransferase (ALT) | -19.19 percentage change of ALT | Standard Deviation 30.559 |
| AXA1125 | Relative Change in Alanine Aminotransferase (ALT) | -21.86 percentage change of ALT | Standard Deviation 25.991 |
| Placebo | Relative Change in Alanine Aminotransferase (ALT) | -7.20 percentage change of ALT | Standard Deviation 36.483 |