Trial Outcomes & Findings for The Effect Of NS-0200 Versus Placebo On Hepatic Fat Content In Patients With Non Alcoholic Fatty Liver Disease (NCT NCT02546609)

Last Updated: 2018-05-02

Results Overview

To evaluate the change in hepatic fat content assessed by proton-density-fat-fraction (PDFF) employing magnetic resonance imaging (MRI).

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

91 participants

Primary outcome timeframe

Baseline, Day 112

Results posted on

2018-05-02

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Placebo 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	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	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
Overall Study STARTED	24	35	32
Overall Study COMPLETED	22	24	25
Overall Study NOT COMPLETED	2	11	7

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	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	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
Overall Study Withdrawal by Subject	0	1	2
Overall Study Adverse Event	0	6	1
Overall Study Protocol Violation	0	1	1
Overall Study Lost to Follow-up	2	3	1
Overall Study travel or work schedule restriction	0	0	2

Baseline Characteristics

Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=24 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=34 Participants 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	Leu Met Sil 1.0mg n=32 Participants 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	Total n=90 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=24 Participants	0 Participants n=34 Participants	0 Participants n=32 Participants	0 Participants n=90 Participants
Age, Categorical Between 18 and 65 years	24 Participants n=24 Participants	34 Participants n=34 Participants	27 Participants n=32 Participants	85 Participants n=90 Participants
Age, Categorical >=65 years	0 Participants n=24 Participants	0 Participants n=34 Participants	5 Participants n=32 Participants	5 Participants n=90 Participants
Age, Continuous	46.3 years STANDARD_DEVIATION 10.42 • n=24 Participants	45.1 years STANDARD_DEVIATION 11.72 • n=34 Participants	45.9 years STANDARD_DEVIATION 12.71 • n=32 Participants	45.7 years STANDARD_DEVIATION 11.64 • n=90 Participants
Sex: Female, Male Female	12 Participants n=24 Participants	21 Participants n=34 Participants	17 Participants n=32 Participants	50 Participants n=90 Participants
Sex: Female, Male Male	12 Participants n=24 Participants	13 Participants n=34 Participants	15 Participants n=32 Participants	40 Participants n=90 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	6 Participants n=24 Participants	12 Participants n=34 Participants	12 Participants n=32 Participants	30 Participants n=90 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=24 Participants	22 Participants n=34 Participants	20 Participants n=32 Participants	60 Participants n=90 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=24 Participants	0 Participants n=34 Participants	0 Participants n=32 Participants	0 Participants n=90 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=24 Participants	0 Participants n=34 Participants	1 Participants n=32 Participants	1 Participants n=90 Participants
Race (NIH/OMB) Asian	0 Participants n=24 Participants	0 Participants n=34 Participants	0 Participants n=32 Participants	0 Participants n=90 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=24 Participants	0 Participants n=34 Participants	0 Participants n=32 Participants	0 Participants n=90 Participants
Race (NIH/OMB) Black or African American	2 Participants n=24 Participants	1 Participants n=34 Participants	0 Participants n=32 Participants	3 Participants n=90 Participants
Race (NIH/OMB) White	21 Participants n=24 Participants	31 Participants n=34 Participants	29 Participants n=32 Participants	81 Participants n=90 Participants
Race (NIH/OMB) More than one race	1 Participants n=24 Participants	1 Participants n=34 Participants	0 Participants n=32 Participants	2 Participants n=90 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=24 Participants	1 Participants n=34 Participants	2 Participants n=32 Participants	3 Participants n=90 Participants
Weight	96.83 kg STANDARD_DEVIATION 15.061 • n=24 Participants	94.44 kg STANDARD_DEVIATION 16.332 • n=34 Participants	94.11 kg STANDARD_DEVIATION 17.225 • n=32 Participants	94.96 kg STANDARD_DEVIATION 16.192 • n=90 Participants
Height	170.1 cm STANDARD_DEVIATION 9.48 • n=24 Participants	169.6 cm STANDARD_DEVIATION 10.58 • n=34 Participants	167 cm STANDARD_DEVIATION 10.75 • n=32 Participants	168.8 cm STANDARD_DEVIATION 10.34 • n=90 Participants
Body mass Index (BMI)	33.5 kg/m^2 STANDARD_DEVIATION 4.534 • n=24 Participants	32.60 kg/m^2 STANDARD_DEVIATION 3.486 • n=34 Participants	33.52 kg/m^2 STANDARD_DEVIATION 4.167 • n=32 Participants	33.17 kg/m^2 STANDARD_DEVIATION 4.008 • n=90 Participants
Fasting Plasma Glucose	108.2 mg/dL STANDARD_DEVIATION 16.53 • n=24 Participants	104.3 mg/dL STANDARD_DEVIATION 14.28 • n=34 Participants	115.4 mg/dL STANDARD_DEVIATION 27.61 • n=32 Participants	109.3 mg/dL STANDARD_DEVIATION 20.86 • n=90 Participants
HbA1c	5.59 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.495 • n=24 Participants	5.65 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.528 • n=34 Participants	5.86 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.738 • n=32 Participants	5.71 percentage of glycosylated hemoglobin STANDARD_DEVIATION 0.609 • n=90 Participants
Childbearing Potential Child-bearing potential with adequate birth contro	3 Participants n=12 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	6 Participants n=21 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	3 Participants n=17 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	12 Participants n=50 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.
Childbearing Potential Postmenopausal	1 Participants n=12 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	4 Participants n=21 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	3 Participants n=17 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	8 Participants n=50 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.
Childbearing Potential Surgically Sterile	8 Participants n=12 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	11 Participants n=21 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	11 Participants n=17 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.	30 Participants n=50 Participants • Childbearing potential is only applicable to the female participants hence the difference in overall population and number analyzed for this category.

PRIMARY outcome

Timeframe: 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.

To evaluate the change in hepatic fat content assessed by proton-density-fat-fraction (PDFF) employing magnetic resonance imaging (MRI).

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=24 Participants 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	Leu Met Sil 1.0mg n=24 Participants 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
Change in Hepatic Fat	-10.046 percentage Standard Deviation 17.5335	3.083 percentage Standard Deviation 25.5230	-4.013 percentage Standard Deviation 24.6302

SECONDARY outcome

Timeframe: 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

Serum AlanineAminotransferase (ALT) will be examined through standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=24 Participants 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	Leu Met Sil 1.0mg n=24 Participants 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
Change in Serum AlanineAaminotransferase (ALT) Levels	-4.1 U/L Standard Deviation 20.09	1.8 U/L Standard Deviation 22.67	-2.7 U/L Standard Deviation 22.96

SECONDARY outcome

Timeframe: 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

Change in Circulating Cytokeratin 18 Fragments (M30) from Baseline to Week 16 will be examined through standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=24 Participants 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	Leu Met Sil 1.0mg n=24 Participants 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
Change in Circulating Cytokeratin 18 Fragments (M30)	70.685 U/L Standard Deviation 306.3480	55.386 U/L Standard Deviation 273.1235	37.847 U/L Standard Deviation 222.6792

SECONDARY outcome

Timeframe: Baseline, Day 112

Population: For the Per-Protocol Population (N=70), the mean change (SD) in HbA1c from Baseline to Week 16 was assessed.

HbA1c will be examined through standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=24 Participants 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	Leu Met Sil 1.0mg n=24 Participants 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
Change in Heamoglobin A1c (HbA1c)	0.07 percentage Standard Deviation 0.125	-0.15 percentage Standard Deviation 0.287	-0.11 percentage Standard Deviation 0.250

SECONDARY outcome

Timeframe: 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.

Fasting glucose will be examined through standard fasting blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=23 Participants 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	Leu Met Sil 1.0mg n=23 Participants 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
Change in Fasting Glucose	0.8 mg/dL Standard Deviation 10.66	-2.7 mg/dL Standard Deviation 11.59	-6.3 mg/dL Standard Deviation 9.13

SECONDARY outcome

Timeframe: 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.

Insulin levels will be examined through standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=23 Participants 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	Leu Met Sil 1.0mg n=23 Participants 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
Change in Insulin	-8.30 μIU/mL Standard Deviation 24.38	-6.60 μIU/mL Standard Deviation 12.30	-5.30 μIU/mL Standard Deviation 15.84

SECONDARY outcome

Timeframe: 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.

Lipid levels such as cholesterol will be examined by standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=24 Participants 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	Leu Met Sil 1.0mg n=24 Participants 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
Change in Blood Lipids (Cholesterol)	-0.8 mg/dL Standard Deviation 27.56	-20.5 mg/dL Standard Deviation 28.02	-5.9 mg/dL Standard Deviation 37.98

SECONDARY outcome

Timeframe: 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.

Lipid levels such as HDL will be examined by standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=22 Participants 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	Leu Met Sil 1.0mg n=21 Participants 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
Change in Blood Lipids (High Density Lipoprotein:HDL)	-1.0 mg/dL Standard Deviation 23.81	-13.3 mg/dL Standard Deviation 27.16	1.2 mg/dL Standard Deviation 42.27

SECONDARY outcome

Timeframe: Baseline, Day 112

Lipid levels such as LDL will be examined by standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=22 Participants 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	Leu Met Sil 1.0mg n=21 Participants 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
Change in Low Density Lipoproteins (LDL)	-1.0 mg/dL Standard Deviation 23.81	-13.3 mg/dL Standard Deviation 27.16	1.2 mg/dL Standard Deviation 42.27

SECONDARY outcome

Timeframe: 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.

Lipid levels such as triglycerides will be examined by standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=24 Participants 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	Leu Met Sil 1.0mg n=24 Participants 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
Change in Triglycerides	1.0 mg/dL Standard Error 0.06	0.8 mg/dL Standard Error 0.06	0.9 mg/dL Standard Error 0.06

SECONDARY outcome

Timeframe: 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.

CRP levels will be examined by standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=21 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=24 Participants 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	Leu Met Sil 1.0mg n=24 Participants 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
Change in C-reactive Protein	1.02 mg/L Standard Error 0.129	1.27 mg/L Standard Error 0.178	1.08 mg/L Standard Error 0.170

SECONDARY outcome

Timeframe: 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.

HOMA-IR levels will be examined by standard blood chemistry

Outcome measures

Outcome measures
Measure	Placebo n=20 Participants 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=22 Participants 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	Leu Met Sil 1.0mg n=22 Participants 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
Change in Insulin Sensitivity (HOMA-IR)	0.89 mU/L Standard Error 0.076	0.80 mU/L Standard Error 0.078	0.85 mU/L Standard Error 0.096

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 18 other events

Deaths: 0 deaths

Leu Met Sil 0.5mg

Serious events: 1 serious events

Other events: 25 other events

Deaths: 0 deaths

Leu Met Sil 1.0mg

Serious events: 1 serious events

Other events: 26 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Placebo n=24 participants at risk 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=34 participants at risk 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	Leu Met Sil 1.0mg n=32 participants at risk 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
Gastrointestinal disorders Appendicitis	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/34 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Gastritis erosive	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	2.9% 1/34 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/32 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Ileus	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	2.9% 1/34 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/32 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Vomiting	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	2.9% 1/34 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/32 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.

Other adverse events

Additional Information

Barbara Cannon

Nusirt Biopharma Inc.

Phone: 615-656-7898

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Placebo n=24 participants at risk 3 capsules BID containing 99% Avicel PH302 and 1% magnesium stearate (w/w) Placebo: Placebo	Leu Met Sil 0.5mg n=34 participants at risk 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	Leu Met Sil 1.0mg n=32 participants at risk 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
Eye disorders Vision Blurred	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	5.9% 2/34 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/32 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Abdominal pain	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	8.8% 3/34 • Number of events 3 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	5.9% 2/34 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Musculoskeletal and connective tissue disorders Back pain	4.2% 1/24 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/34 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	9.4% 3/32 • Number of events 3 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Hepatobiliary disorders Blood triglycerides increase	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/34 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	6.2% 2/32 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Constipation	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	5.9% 2/34 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Respiratory, thoracic and mediastinal disorders Cough	8.3% 2/24 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/34 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Skin and subcutaneous tissue disorders Dermatitis Contact	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	5.9% 2/34 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/32 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Diarrhoea	8.3% 2/24 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	44.1% 15/34 • Number of events 15 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	37.5% 12/32 • Number of events 12 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Nervous system disorders Dizziness	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	2.9% 1/34 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	12.5% 4/32 • Number of events 4 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Dyspepsia	16.7% 4/24 • Number of events 4 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	8.8% 3/34 • Number of events 3 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	6.2% 2/32 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Social circumstances Fatigue	4.2% 1/24 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	5.9% 2/34 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Flatulence	4.2% 1/24 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	8.8% 3/34 • Number of events 3 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	12.5% 4/32 • Number of events 4 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	0.00% 0/34 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	6.2% 2/32 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
General disorders Headache	8.3% 2/24 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	14.7% 5/34 • Number of events 5 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
General disorders Nausea	12.5% 3/24 • Number of events 3 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	17.6% 6/34 • Number of events 6 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	15.6% 5/32 • Number of events 5 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Endocrine disorders Type 2 Diabetes mellitus	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	2.9% 1/34 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	6.2% 2/32 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Respiratory, thoracic and mediastinal disorders Upper respiratory tract infection	4.2% 1/24 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	5.9% 2/34 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Eye disorders Vision blurred	0.00% 0/24 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	5.9% 2/34 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	3.1% 1/32 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.
Gastrointestinal disorders Vomiting	4.2% 1/24 • Number of events 1 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	14.7% 5/34 • Number of events 5 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.	6.2% 2/32 • Number of events 2 • 112 days Treatment-Emergent Adverse Event (TEAE) is defined as an adverse event occurring on or after the first dose of randomized study medication, or existing prior to the time of and worsening after the time of the first dose of randomized study medication.