NAFLD
Conditions
Brief summary
The goal of this study is to determine if NS-0200 can reduce the amount of liver fat in patients diagnosed with non-alcoholic fatty liver disease (NAFLD). This study will compare two doses of NS-0200 to placebo in NAFLD patients.
Detailed description
This is a randomized, 16-week, placebo-controlled, double-blind study to evaluate the effect of two fixed-dose combinations of leucine, metformin and sildenafil, NS-0200 compared to placebo, on the reduction of liver fat in patients diagnosed with non-alcoholic fatty liver disease (NAFLD). Subjects meeting all the inclusion criteria and no exclusion criteria will be randomized to one of three study arms. The primary objective of this study is to evaluate the change in hepatic fat content assessed by proton-density-fat-fraction (PDFF) employing magnetic resonance imaging (MRI) in subjects from : Screening/Visit 2 (Day-7/Week-1) to Study Termination/Visit 8 (Day 112/Week 16) receiving two fixed-dose combinations of leucine, metformin and sildenafil compared to placebo. Secondary objectives will also assess changes in serum alanine aminotransferase (ALT) activity, change in circulating cytokeratin 18, a surrogate marker of necro-inflammation, change in HbA1c, change in fasting glucose, insulin and insulin sensitivity, change in blood lipids such as cholesterol, LDL, HDL, triglycerides, and changes in in C-reactive protein. In addition this study will evaluate the safety and tolerability of NS-0200. Patients will have two screening visits, the first to determine their eligibility based on lab tests and the second based on the percentage of hepatic fat assessed by MRI imaging. Once qualified, patients will be randomly assigned to either one of the treatment groups or the placebo control group and monitored for a total of 16 weeks. Patients will return to the clinic each month for lab tests, and routine examinations. At the conclusion of the treatment period patients will again undergo an MRI scan to examine the percentage of hepatic fat.
Interventions
DRUGLeu-Met-Sil 0.5
NS-0200 low dose
DRUGLeu-Met-Sil 1.0
NS-200 high dose
DRUGPlacebo
Placebo
Sponsors
NuSirt Biopharma
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
1. Age 18-75 at study entry. 2. Is male, or female and, if female, meets all of the following criteria: 1. Not breastfeeding 2. Post-menopausal or negative serum pregnancy test result (human chorionic gonadotropin, beta subunit \[β-hCG\]) at Screening /Visit 1 (Day-14/Week-2) (not required for hysterectomized females) 3. If of childbearing potential (including peri-menopausal women who have had a menstrual period within one year) must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as double barrier methods \[male condom with spermicide, with or without cervical cap or diaphragm\], implants, injectables, oral contraceptives \[must have been using for at least the last 3 months\], some intrauterine contraceptive devices, tubal ligation, or in an established relationship with a vasectomized partner) during the entire duration of the study. 3. Has been diagnosed with NAFLD via CT (positive for excess liver fat), ultrasound (positive for excess liver fat), MRI (PDFF showing \> 15% liver fat) or via biopsy (showing \>33% fat) within the past six months. If diagnosis was between 3 and 6 months prior to Screening, an ultrasound (positive for excess liver fat) is required prior to the Screening /Visit 1 (Day-14/Week-2) MRI. 4. Has liver fat (as measured by PDFF via MRI) greater than 15% at Screening/Visit 2 (Day-7/Week-1) 5. Has had ALT levels \>30 U/L for men, \>19 U/L for women measured within 8 weeks of enrollment 6. Has an HbA1c equal to or less than 9% at Screening /Visit 1 (Day-14/Week-2) 7. Has a BMI between 25kg/m2 and 40 kg/m2 8. Otherwise stable health for preceding twelve weeks 9. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either normal or with abnormalities consistent with NAFLD. 10. Is able to read, understand, and sign the informed consent forms (ICF) and, when applicable, an authorization to use and disclose protected health information form (consistent with Health Insurance Portability and Accountability Act of 1996 \[HIPAA\] legislation), communicate with the investigator, and understand and comply with protocol requirements. \-
Exclusion criteria
1. Clinically significant renal dysfunction defined as a serum creatinine concentration \>1.4 mg/dL (females) or \>1.6 mg/dL (males) or a blood urea nitrogen concentration \>45 mg/dL at screening. 2. Use of any of the following medications: 1. Metformin 2. Combination drugs that include Metformin 3. Sildenafil 4. Tadalafil 5. Vardenafil 6. Pioglitazone 7. Rosiglitazone 8. Short acting insulins 9. An alpha blocker 10. Oral nitrates 11. Medications associated with increased hepatic steatosis 12. Insulins 13. OCT2/MATE inhibitors (e.g. cimetidine, quinidine, and pyrimethamine) * Methotrexate * Tamoxifen * Corticosteroids (Nasal steroids are allowed if the subject has been on a stable dose for the past 12 weeks and the dose employed does not exceed the maximal recommended dose.) * Estrogens * Amiodarone * Valproic acid * Coumadin * Isoniazide * Nucleoside analogues used for the treatment of HIV infections 14. Any dietary supplement other than multi-vitamins 3. Evidence of significant alcohol consumption (defined as \>7 drinks/week for females and \>14 drinks/week for males) within 6 months prior to randomization or presence or suspicion of other forms of chronic liver disease (e.g., cirrhosis, autoimmune hepatitis (\>1:160 ANA), Wilson's disease, Hemochromatosis (Ferritin \>1000 ug/L and percent iron saturation \>45%), hepatitis A, B or C) 4. Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being, as judged by the investigator, including but not limited to the following conditions: 1. Unable to undergo MRI or contraindications for MRI procedure 2. History of cardio- or cerebro-vascular disease event within the previous 6 months 3. Requires anti-coagulation therapy 4. Gastrointestinal disorders including, but not limited to, the following: pancreatitis, inflammatory bowel disease, or other diseases associated with malabsorption or persistent abdominal discomfort 5. Endocrine disorders other than type 2 diabetes and hypothyroidism on stable replacement therapy 6. Chronic infection (e.g., tuberculosis, human immunodeficiency virus infection, hepatitis A virus, hepatitis B virus, or hepatitis C virus) 7. Neurological or psychiatric diseases that preclude valid execution of informed consent or may interfere with the subject's compliance with study procedures (e.g., major depressive disorder within the last 2 years, a history of suicidal behavior in the last 3 months) 8. History of other psychiatric disorders including schizophrenia and bipolar disorder) 5. Participation in a weight loss program within the past 3 months. 6. Weight change ≥5% during the past month. 7. History of substance abuse (including alcohol abuse as defined above) in the past 3 months or a positive screen for drugs of abuse or alcohol at screening. 8. Has received any investigational drug within 3 months of Screening. 9. Has donated blood within 3 months before Screening or is planning to donate blood during the study. 10. Has had a serious infection, such as pneumonia in the previous 12 weeks 11. Has known allergies or hypersensitivity to metformin, sildenafil or leucine 12. Is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the clinical study site, or NuSirt Biopharma. 13. Is employed by NuSirt Biopharma (defined as an employee, temporary contract worker, or designee responsible for the conduct of the study). \-
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hepatic Fat | Baseline, Day 112 | To evaluate the change in hepatic fat content assessed by proton-density-fat-fraction (PDFF) employing magnetic resonance imaging (MRI). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Circulating Cytokeratin 18 Fragments (M30) | Baseline, Day 112 | Change in Circulating Cytokeratin 18 Fragments (M30) from Baseline to Week 16 will be examined through standard blood chemistry |
| Change in Heamoglobin A1c (HbA1c) | Baseline, Day 112 | HbA1c will be examined through standard blood chemistry |
| Change in Fasting Glucose | Baseline, Day 112 | Fasting glucose will be examined through standard fasting blood chemistry |
| Change in Insulin | Baseline, Day 112 | Insulin levels will be examined through standard blood chemistry |
| Change in Blood Lipids (Cholesterol) | Baseline, Day 112 | Lipid levels such as cholesterol will be examined by standard blood chemistry |
| Change in Serum AlanineAaminotransferase (ALT) Levels | Baseline, Day 112 | Serum AlanineAminotransferase (ALT) will be examined through standard blood chemistry |
| Change in Low Density Lipoproteins (LDL) | Baseline, Day 112 | Lipid levels such as LDL will be examined by standard blood chemistry |
| Change in Triglycerides | Baseline, Day 112 | Lipid levels such as triglycerides will be examined by standard blood chemistry |
| Change in C-reactive Protein | Baseline, Day 112 | CRP levels will be examined by standard blood chemistry |
| Change in Insulin Sensitivity (HOMA-IR) | Baseline, Day 112 | HOMA-IR levels will be examined by standard blood chemistry |
| Change in Blood Lipids (High Density Lipoprotein:HDL) | Baseline, Day 112 | Lipid levels such as HDL will be examined by standard blood chemistry |
Countries
United States
Participant flow
Recruitment details
Subjects meeting all inclusion criteria and no exclusion criteria were randomized to one of the three treatment arms in the ratio of 1:1:1. Adult males and females (age 18-75) with CT, MRI, biopsy, or ultrasound consistent with NAFLD within the past 6 months.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w)
Placebo: Placebo | 24 |
| Leu Met Sil 0.5mg 3 capsules BID consisting of 2 capsules containing 550 mg L-leucine each and 1 capsule containing 500 mg metformin and 0.5 mg of sildenafil.
Metformin: 500 mg Metformin BID
Leucine: 1100 mg Leucine BID
Sildenafil Citrate 0.5 mg: Sildenafil 0.5 mg BID | 34 |
| Leu Met Sil 1.0mg 3 capsules BID consisting of 2 capsules containing 550 mg L-leucine each and 1 capsule containing 500 mg metformin and 1.0 mg of sildenafil.
Sildenafil 1.0 mg: Sildenafil 1.0 mg
Metformin: 500 mg Metformin BID
Leucine: 1100 mg Leucine BID | 32 |
| Total | 90 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 6 | 1 |
| Overall Study | Lost to Follow-up | 2 | 3 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | travel or work schedule restriction | 0 | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 2 |
Baseline characteristics
| Characteristic | Total | Leu Met Sil 1.0mg | Leu Met Sil 0.5mg | Placebo |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 5 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 85 Participants | 27 Participants | 34 Participants | 24 Participants |
| Age, Continuous | 45.7 years STANDARD_DEVIATION 11.64 | 45.9 years STANDARD_DEVIATION 12.71 | 45.1 years STANDARD_DEVIATION 11.72 | 46.3 years STANDARD_DEVIATION 10.42 |
| Body mass Index (BMI) | 33.17 kg/m^2 STANDARD_DEVIATION 4.008 | 33.52 kg/m^2 STANDARD_DEVIATION 4.167 | 32.60 kg/m^2 STANDARD_DEVIATION 3.486 | 33.5 kg/m^2 STANDARD_DEVIATION 4.534 |
| Childbearing Potential Child-bearing potential with adequate birth contro | 12 Participants | 3 Participants | 6 Participants | 3 Participants |
| Childbearing Potential Postmenopausal | 8 Participants | 3 Participants | 4 Participants | 1 Participants |
| Childbearing Potential Surgically Sterile | 30 Participants | 11 Participants | 11 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 30 Participants | 12 Participants | 12 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 60 Participants | 20 Participants | 22 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Fasting Plasma Glucose | 109.3 mg/dL STANDARD_DEVIATION 20.86 | 115.4 mg/dL STANDARD_DEVIATION 27.61 | 104.3 mg/dL STANDARD_DEVIATION 14.28 | 108.2 mg/dL STANDARD_DEVIATION 16.53 |
| HbA1c | 5.71 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.609 | 5.86 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.738 | 5.65 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.528 | 5.59 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.495 |
| Height | 168.8 cm STANDARD_DEVIATION 10.34 | 167 cm STANDARD_DEVIATION 10.75 | 169.6 cm STANDARD_DEVIATION 10.58 | 170.1 cm STANDARD_DEVIATION 9.48 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 1 Participants | 1 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 | 3 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 81 Participants | 29 Participants | 31 Participants | 21 Participants |
| Sex: Female, Male Female | 50 Participants | 17 Participants | 21 Participants | 12 Participants |
| Sex: Female, Male Male | 40 Participants | 15 Participants | 13 Participants | 12 Participants |
| Weight | 94.96 kg STANDARD_DEVIATION 16.192 | 94.11 kg STANDARD_DEVIATION 17.225 | 94.44 kg STANDARD_DEVIATION 16.332 | 96.83 kg STANDARD_DEVIATION 15.061 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 34 | 0 / 32 |
| other Total, other adverse events | 18 / 24 | 25 / 34 | 26 / 32 |
| serious Total, serious adverse events | 0 / 24 | 1 / 34 | 1 / 32 |
Outcome results
Primary
Change in Hepatic Fat
To evaluate the change in hepatic fat content assessed by proton-density-fat-fraction (PDFF) employing magnetic resonance imaging (MRI).
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean percent change (SD) in hepatic fat content (%) from Baseline to Week 16 (Day 112) for each treatment group was assessed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Hepatic Fat | -10.046 percentage | Standard Deviation 17.5335 |
| Leu Met Sil 0.5mg | Change in Hepatic Fat | 3.083 percentage | Standard Deviation 25.523 |
| Leu Met Sil 1.0mg | Change in Hepatic Fat | -4.013 percentage | Standard Deviation 24.6302 |
Comparison: Analysis of variance (ANOVA) model: with treatment group as the factor. Placebo is used as the reference group.p-value: 0.0572ANCOVA
Comparison: Analysis of variance (ANOVA) model: with treatment group as the factor. Placebo is used as the reference group.p-value: 0.377ANCOVA
Secondary
Change in Blood Lipids (Cholesterol)
Lipid levels such as cholesterol will be examined by standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in total cholesterol from Baseline to Week 16 was assessed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Blood Lipids (Cholesterol) | -0.8 mg/dL | Standard Deviation 27.56 |
| Leu Met Sil 0.5mg | Change in Blood Lipids (Cholesterol) | -20.5 mg/dL | Standard Deviation 28.02 |
| Leu Met Sil 1.0mg | Change in Blood Lipids (Cholesterol) | -5.9 mg/dL | Standard Deviation 37.98 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.2265MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.8366MMRM
Secondary
Change in Blood Lipids (High Density Lipoprotein:HDL)
Lipid levels such as HDL will be examined by standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in LDL from Baseline to Week 16 was assessed. The difference in the actual participants analyzed and per protocol population is because HDL could not be calculated for some participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Blood Lipids (High Density Lipoprotein:HDL) | -1.0 mg/dL | Standard Deviation 23.81 |
| Leu Met Sil 0.5mg | Change in Blood Lipids (High Density Lipoprotein:HDL) | -13.3 mg/dL | Standard Deviation 27.16 |
| Leu Met Sil 1.0mg | Change in Blood Lipids (High Density Lipoprotein:HDL) | 1.2 mg/dL | Standard Deviation 42.27 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.347MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.6221MMRM
Secondary
Change in Circulating Cytokeratin 18 Fragments (M30)
Change in Circulating Cytokeratin 18 Fragments (M30) from Baseline to Week 16 will be examined through standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in circulating cytokeratin 18 fragments (M30, U/L) from Baseline to week 16 was assessed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Circulating Cytokeratin 18 Fragments (M30) | 70.685 U/L | Standard Deviation 306.348 |
| Leu Met Sil 0.5mg | Change in Circulating Cytokeratin 18 Fragments (M30) | 55.386 U/L | Standard Deviation 273.1235 |
| Leu Met Sil 1.0mg | Change in Circulating Cytokeratin 18 Fragments (M30) | 37.847 U/L | Standard Deviation 222.6792 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.7742Mixed effect Model Repeat Measurement
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.6666Mixed effect Model Repeat Measurement
Secondary
Change in C-reactive Protein
CRP levels will be examined by standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the geometric mean change (SE) in C-reactive protein from Baseline to Week 16 was assessed. The difference in the actual participants analyzed and per protocol population is due to missing or technically erroneous data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in C-reactive Protein | 1.02 mg/L | Standard Error 0.129 |
| Leu Met Sil 0.5mg | Change in C-reactive Protein | 1.27 mg/L | Standard Error 0.178 |
| Leu Met Sil 1.0mg | Change in C-reactive Protein | 1.08 mg/L | Standard Error 0.17 |
p-value: 0.1946MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.4697MMRM
Secondary
Change in Fasting Glucose
Fasting glucose will be examined through standard fasting blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in fasting glucose from Baseline to Week 16 was assessed. The difference in the actual participants analyzed and per protocol population is due to missing or technically erroneous data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Fasting Glucose | 0.8 mg/dL | Standard Deviation 10.66 |
| Leu Met Sil 0.5mg | Change in Fasting Glucose | -2.7 mg/dL | Standard Deviation 11.59 |
| Leu Met Sil 1.0mg | Change in Fasting Glucose | -6.3 mg/dL | Standard Deviation 9.13 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.4099MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.1455MMRM
Secondary
Change in Heamoglobin A1c (HbA1c)
HbA1c will be examined through standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in HbA1c from Baseline to Week 16 was assessed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Heamoglobin A1c (HbA1c) | 0.07 percentage | Standard Deviation 0.125 |
| Leu Met Sil 0.5mg | Change in Heamoglobin A1c (HbA1c) | -0.15 percentage | Standard Deviation 0.287 |
| Leu Met Sil 1.0mg | Change in Heamoglobin A1c (HbA1c) | -0.11 percentage | Standard Deviation 0.25 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.002MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.0164MMRM
Secondary
Change in Insulin
Insulin levels will be examined through standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in insulin from Baseline to Week 16 was assessed. The difference in the actual participants analyzed and per protocol population is due to missing or technically erroneous data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Insulin | -8.30 μIU/mL | Standard Deviation 24.38 |
| Leu Met Sil 0.5mg | Change in Insulin | -6.60 μIU/mL | Standard Deviation 12.3 |
| Leu Met Sil 1.0mg | Change in Insulin | -5.30 μIU/mL | Standard Deviation 15.84 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.2559MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.9776MMRM
Secondary
Change in Insulin Sensitivity (HOMA-IR)
HOMA-IR levels will be examined by standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the change in geometric mean (SE) in HOMA-IR from Baseline to Week 16 was assessed. The difference in the actual participants analyzed and per protocol population is due to missing or technically erroneous data.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Insulin Sensitivity (HOMA-IR) | 0.89 mU/L | Standard Error 0.076 |
| Leu Met Sil 0.5mg | Change in Insulin Sensitivity (HOMA-IR) | 0.80 mU/L | Standard Error 0.078 |
| Leu Met Sil 1.0mg | Change in Insulin Sensitivity (HOMA-IR) | 0.85 mU/L | Standard Error 0.096 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.3474MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.8832MMRM
Secondary
Change in Low Density Lipoproteins (LDL)
Lipid levels such as LDL will be examined by standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in LDL from Baseline to Week 16 was assessed. The difference in the actual participants analyzed and per protocol population is because LDL could not be calculated for some participants.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Low Density Lipoproteins (LDL) | -1.0 mg/dL | Standard Deviation 23.81 |
| Leu Met Sil 0.5mg | Change in Low Density Lipoproteins (LDL) | -13.3 mg/dL | Standard Deviation 27.16 |
| Leu Met Sil 1.0mg | Change in Low Density Lipoproteins (LDL) | 1.2 mg/dL | Standard Deviation 42.27 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.347MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.6221MMRM
Secondary
Change in Serum AlanineAaminotransferase (ALT) Levels
Serum AlanineAminotransferase (ALT) will be examined through standard blood chemistry
Time frame: Baseline, Day 112
Population: For the Per-Protocol Population (N=70), the mean change (SD) in serum ALT levels from Baseline to Week 16 was assessed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Serum AlanineAaminotransferase (ALT) Levels | -4.1 U/L | Standard Deviation 20.09 |
| Leu Met Sil 0.5mg | Change in Serum AlanineAaminotransferase (ALT) Levels | 1.8 U/L | Standard Deviation 22.67 |
| Leu Met Sil 1.0mg | Change in Serum AlanineAaminotransferase (ALT) Levels | -2.7 U/L | Standard Deviation 22.96 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.3811Mixed Effect Model Repeat Measurement
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.8479Mixed Effect Model Repeat Measurement
Secondary
Change in Triglycerides
Lipid levels such as triglycerides will be examined by standard blood chemistry
Time frame: Baseline, Day 112
Population: Geometric mean values are presented since the data were skewed. Corresponding arithmetic mean changes from baseline for Treatments A, B and C in the Per Protocol Population were +54.9, -48.9 and -28.0 mg/dL respectively. This accounts for the p-value of p=0.0129 for Treatment B.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change in Triglycerides | 1.0 mg/dL | Standard Error 0.06 |
| Leu Met Sil 0.5mg | Change in Triglycerides | 0.8 mg/dL | Standard Error 0.06 |
| Leu Met Sil 1.0mg | Change in Triglycerides | 0.9 mg/dL | Standard Error 0.06 |
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.0129MMRM
Comparison: MMRM model: with treatment group, visit, and treatment-by-visit interaction as fixed effects, the baseline value of the response variable as a covariate, and subject as a random effect. Placebo is used as the reference group.p-value: 0.4316MMRM