Dose Comparisons of Leucine-Metformin Combinations on Blood Glucose Levels In Type 2 Diabetic Patients

• Sponsor: NuSirt Biopharma (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02151461
• Collaborator: (none)
• Enrollment: 96
• Locations: 9
• Arms: 4
• Duration (Months): 18
• Patients Per Site: 10.7
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The goal of this study is to demonstrate that leucine in combination with a low does of metformin can serve as an adjunct to diet and exercise to improve blood glucose levels in type 2 diabetic subjects. This study will compare three doses of a leucine-metformin combination to the standard metformin dose in controlling blood glucose levels in type 2 diabetic patients.

Condition or Disease	Intervention/Treatment	Phase
Type 2 Diabetes Mellitus	Drug: Low Metformin; Drug: Metformin; Drug: Mid Metformin; Drug: High Metformin	Phase 2

Detailed Description

This is a randomized, 4-week, active-controlled, double-blind study to evaluate the effect of various fixed-dose combinations of leucine and metformin compared to standard metformin monotherapy on glycemic control. In this study, standard metformin therapy will be defined as 1000 g/day for Day 1 to Day 14 and then escalated to 1700 g/day for Day 15 to Day 28. Subjects meeting all inclusion criteria and no exclusion criteria will be randomized to one of four treatment arms.

The primary objective of the study is to evaluate the change in fasting plasma glucose from Baseline (Day 1) to Week 4 (Day 28) in subjects receiving various fixed-dose combinations of leucine and metformin compared to standard metformin monotherapy. Secondary objectives will also assess changes in baseline-corrected plasma glucose and insulin area under the concentration curves from baseline to day 28 and changes in insulin secretory rates as assessed during a 3-hour meal tolerance test. Finally the effects of gastrointestinal symptoms will be assessed by subject questionnaires.

The study will include a total of 3 periods: screening or washout of current diabetic monotherapy, a pre-treatment period to ensure subjects will be compliant, and a treatment period of 4 weeks, with the first dosing of medication on day 1 of the study. Each day blood glucose readings will be measured and recorded by patients. Three-hour standardized meal tests will be performed at Baseline (Day 1) and at Study Termination (Day 28). In addition, two, 7-day continuous glucose assessments will be conducted, as well as two seven point glucose profiles. Patients will also be asked about any gastrointestinal side effects they experience.

Study Design

• Study Type: Interventional
• Actual Enrollment: 96 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Active-Controlled Study to Evaluate the Effect of Various Fixed-Dose Leucine and Metformin Combinations (NS-0100) Versus Standard Metformin Monotherapy on Glycemic Control in Subjects With Type 2 Diabetes
• Study Start Date: Jul 1, 2014
• Actual Primary Completion Date: Aug 1, 2015
• Actual Study Completion Date: Jan 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low Metformin 3 capsules BID with each capsule containing 366.7 mg L-Leucine and 41.7 mg of metformin	Drug: Low Metformin; 1100 mg L Leucine in combination with 125 mg of Metformin BID; Other Names: Metformin Leucine L-Leucine
Experimental: Mid Metformin 3 capsules BID with each capsule containing 366.7 mg L-Leucine and 83.3 mg of metformin	Drug: Mid Metformin; 1100 mg of Leucine in combination with 250 mg Metformin BID; Other Names: Metformin Leucine L-Leucine
Experimental: High Metformin 3 capsules BID with each capsule containing 366.7 mg L-Leucine and 166.7 mg of metformin	Drug: High Metformin; 1100 mg of Leucine in combination with 500 mg Metformin BID; Other Names: Metformin Leucine L-Leucine
Experimental: Metformin Monotherapy 3 Capsules BID each containing 166.7 mg of metformin with dose escalation to 283.3 mg capsules BID (1,700 mg/Day) at Day 14.	Drug: Metformin; 500 mg metformin BID until day 14 with dose escalation at day 14 to 850 mg metformin BID

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Day 28 in Absolute Plasma Glucose Area Under the Curve (AUC) 0-3hr [0, 15min, 30min, 45min, 1hr, 1.5hrs, 2hrs, 2.5hrs and 3 hrs]

   The primary endpoint for NS 0100 01 was the absolute plasma glucose AUC (0-3 hr) change from Day 1 to Day 28.

Secondary Outcome Measures

1. Change From Baseline to Day 28 in Incremental Plasma Glucose Area Under the Curve (AUC) [Baseline, Day 28]

   The baseline incremental (baseline-subtracted) glucose AUC0-3h was evaluated for treatment differences at baseline.

2. Change in Fasting Plasma Glucose [Baseline, Day 28]

   Change in fasting plasma glucose for the fixed dose leucine and metformin combination treatments A, B and C was evaluated.

3. Change in Hemoglobin A1c (HbA1c) [Baseline, Day 28]

   Changes in HbA1c which is a marker of long-term glucose control was assessed.

4. Change in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) [Baseline, Day 28]

   Effect on insulin sensitivity across fixed-dose leucine and metformin combination treatments or the standard metformin reference treatment.

5. Change In 7-Point Glucose Profiles [Baseline, Day 7, Day 21, Day 28]

   The meal induced glucose change in pre-meal and post-meal glucose were measured 7 times during the day. Subjects self-monitored blood glucose (preprandial and postprandial) concentrations at least 7 times, including before and 1 to 2 hours after breakfast, lunch, dinner, and snacks). For each study day, the pre-meal values from the 7 point test for each subject were averaged to generate a single pre-meal glucose value. Similarly, for each study day the post-meal values from the 7-point test for each subject were averaged to generate a single post-meal glucose value. The average change from baseline (i.e., [(Mean Pre/Post-meal value at Day 28 - Mean Pre/Post-meal value at Baseline) + (Mean Pre/Post-meal value at Day 21- Mean Pre/Post-meal value at Baseline) + (Mean Pre/Post-meal value at Day 7- Mean Pre/Post-meal value at Baseline)]/ 3) over multiple time points listed in Time Frame. The mean pre-meal and post-meal values for baseline, day7, day 21 and day28 were used for comparison.

6. Plasma Insulin Absolute and Incremental Meal Tolerance Test Area Under the Curve (AUC) 0-2hr [Baseline,Day 28]

   Change in meal tolerance test insulin area under the curve (0-2 hr) from Day 1 to Day 28 for fixed-dose leucine and metformin combination treatments.

7. Change From Baseline to Day 28 in Fasting Plasma Insulin Concentration [Baseline, Day 28]

   Effect on fasting plasma insulin concentrations across fixed-dose leucine and metformin combination treatments or the standard metformin reference treatment was evaluated.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Over age 18 at study entry.

• Male, or female, if female, meets all of the following criteria:

• Not breastfeeding

• Post-menopausal or negative pregnancy test result (human chorionic gonadotropin, beta subunit [β- hCG]) at Screening (Visit 1) (not required for hysterectomized females)

• If of childbearing potential and sexually active, must practice and be willing to continue to practice appropriate birth control

• Is diagnosed with type 2 diabetes mellitus and either not adequately controlled by: diet and exercise alone or diet and exercise plus a single, first line treatment for type 2 diabetes.

• If treated with an oral anti-diabetes agent, be willing and able to withdraw from therapy for 4 weeks after the screening visit and prior to initiating study mediation at Baseline (Day 1/Visit 4).

• Be willing to avoid acetaminophen use for intervals up to 10 days as required for study procedures (see Section 4.6)

• Has a fasting plasma glucose ≥126 mg/dL to ≤220 mg/dL at Screening

• Has an HbA1c ≥7% to ≤8.5% at Screening

• Has a BMI ≤40 kg/m2

• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either normal or abnormal but consistent with type 2 diabetes mellitus.

• Is able to read, understand, and sign the informed consent forms (ICF) and if 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:

• Clinically significant renal dysfunction

• If using any of the following medications, has not been on a stable treatment regimen for a minimum of 4 weeks prior to screening:

Lipid-lowering agents Anti-hypertensive medications Thyroid replacement therapy Non-steroidal anti-inflammatory agents

• Unable to perform self-blood glucose monitoring employing a glucose meter.

• History of active cardio- or cerebro-vascular disease with an event within the previous 6 months

• Gastrointestinal disorders

• Endocrine disorders other than type 2 diabetes

• Chronic infection

• Hepatic disease

• Neurological or psychiatric diseases

• History of other psychiatric disorders

• Has been treated (within the last month), is currently treated, or is expected to require or undergo treatment with; any anti-diabetes medications (other than as allowed by the inclusion criteria), oral or parenteral steroids.

• Participation in a weight loss program within the past 3 months.

• Weight change by more than 10 pounds during the past month.

• History of alcohol or substance abuse in the past 3 months or a positive screen for alcohol or drugs of abuse at screening.

• Has received any investigational drug within 3 months of Screening.

• Has donated blood within 3 months before Screening or is planning to donate blood during the study.

• Has known allergies or hypersensitivity to metformin or leucine

• Is employed, contracted or has an immediate family member directly affiliated with NuSirt Biopharma.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Catalina Research Institute	Chino	California	United States	91710
2	Palm Beach Research	Palm Beach	Florida	United States	33409
3	Meridien Research	Tampa	Florida	United States	33606
4	River Birch Research Alliance	Blue Ridge	Georgia	United States	30513
5	Meridian Research	Savannah	Georgia	United States	31406
6	Streling Research Group	Cincinnati	Ohio	United States	45219
7	Medical Research South	Charleston	South Carolina	United States	29407
8	Meharry Medical College	Nashville	Tennessee	United States	37208
9	Vanderbilt University Medical Center, Diabetes, Endocrinology, and Metabolism	Nashville	Tennessee	United States	37232

Sponsors and Collaborators

• NuSirt Biopharma

Investigators

• Study Chair: Orville G Kolterman, MD, NuSirt Biopharma

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NuSirt Biopharma
• ClinicalTrials.gov Identifier: NCT02151461
• Other Study ID Numbers: NS-0100-01
• First Posted: May 30, 2014
• Last Update Posted: Feb 27, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by NuSirt Biopharma: Diabetes; Type 2 Diabetes
• Additional relevant MeSH terms: Diabetes Mellitus, Type 2; Metformin

Study Results

Participant Flow

Recruitment Details	Subjects meeting all inclusion criteria and no exclusion criteria were randomized to one of four treatment arms in the ratio of 1:1:1:1 (A:B:C:D). The randomization was stratified by fasting plasma glucose (≥126 mg/dL to <200 mg/dL, and ≥200 mg/dL to ≤220 mg/dL), as well as metformin experience. Yes/No history of abdominal side effects.

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Period Title: Overall Study
STARTED	24	25	24	23
COMPLETED	18	24	21	19
NOT COMPLETED	6	1	3	4

Baseline Characteristics

Arm/Group Title	FDC125	FDC250	FDC500	Control	Total
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg	Total of all reporting groups
Overall Participants	24	25	24	23	96
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.6 (9.87)	55.1 (8.3)	56.1 (10.08)	59.3 (9.64)	56.0 (9.56)
Age, Customized (Count of Participants)
<65 years	19 79.2%	21 84%	18 75%	17 73.9%	75 78.1%
≥65 years	5 20.8%	4 16%	6 25%	6 26.1%	21 21.9%
Sex: Female, Male (Count of Participants)
Female	15 62.5%	13 52%	13 54.2%	10 43.5%	51 53.1%
Male	9 37.5%	12 48%	11 45.8%	13 56.5%	45 46.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	14 58.3%	15 60%	12 50%	12 52.2%	53 55.2%
Not Hispanic or Latino	10 41.7%	10 40%	12 50%	11 47.8%	43 44.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 4%	0 0%	0 0%	1 1%
Asian	0 0%	1 4%	0 0%	1 4.3%	2 2.1%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	2 8.3%	3 12%	5 20.8%	6 26.1%	16 16.7%
White	22 91.7%	20 80%	19 79.2%	16 69.6%	77 80.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	87.049 (17.3747)	88.584 (19.4687)	84.493 (19.8622)	86.777 (16.5700)	86.745 (18.1696)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	31.142 (4.7113)	30.985 (5.5766)	29.927 (5.1504)	31.146 (4.5838)	30.798 (4.9778)
Fasting Plasma Glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	194.3 (50.86)	170.3 (44.28)	182.8 (40.97)	184.7 (50.87)	182.9 (46.93)
Haemoglobin A1c (HbA1c) (%) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [%]	7.95 (0.837)	8.01 (0.713)	7.82 (0.563)	8.24 (0.831)	8.00 (0.747)
Previous Metformin experience (Count of Participants)
No Previous Experience	4 16.7%	1 4%	5 20.8%	3 13%	13 13.5%
No Abdominal side effects from prior Metformin	18 75%	20 80%	17 70.8%	16 69.6%	71 74%
Had Abdominal side effects from prior Metformin	2 8.3%	4 16%	2 8.3%	4 17.4%	12 12.5%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Day 28 in Absolute Plasma Glucose Area Under the Curve (AUC) 0-3hr
Description	The primary endpoint for NS 0100 01 was the absolute plasma glucose AUC (0-3 hr) change from Day 1 to Day 28.
Time Frame	0, 15min, 30min, 45min, 1hr, 1.5hrs, 2hrs, 2.5hrs and 3 hrs

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of Plasma Glucose AUC change from day 1-day 28 Evaluable Population (n=73)

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	17	18	20	18
Mean (Standard Deviation) [mg*hrs/dL]	-18.005 (142.8374)	-45.029 (114.6701)	-64.010 (146.0917)	-141.848 (194.9300)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments	A mixed-effects model for analysis of covariance (ANCOVA) was used to analyze changes from Baseline in plasma glucose AUC(0-3hr) at Week 4 in the Day 28 Evaluable population. The model includes factors for treatment group and fasting plasma glucose stratum.
Statistical Test of Hypothesis	p-Value	0.0435
	Comments	Baseline plasma glucose AUC(0-3hr) is adjusted as a covariate.
	Method	ANCOVA
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.065
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.1216
	Comments
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	Change From Baseline to Day 28 in Incremental Plasma Glucose Area Under the Curve (AUC)
Description	The baseline incremental (baseline-subtracted) glucose AUC0-3h was evaluated for treatment differences at baseline.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of Incremental Plasma Glucose AUC change from day 1-day 28 Evaluable Population (n=73)

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	17	18	20	18
Mean (Standard Deviation) [mg*hrs/dL]	-2.338 (60.2834)	-17.614 (93.1243)	-23.061 (64.6290)	-29.604 (86.1126)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments	A mixed-effects model for analysis of covariance (ANCOVA) was used to analyze changes from Baseline in incremental plasma glucose AUC at Week 4 in the Day 28 Evaluable population. The model will include factors for treatment group and fasting plasma glucose stratum.
Statistical Test of Hypothesis	p-Value	0.8867
	Comments
	Method	ANCOVA
	Comments	The model includes factors for treatment group and fasting plasma glucose stratum.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.7641
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2518
	Comments
	Method	ANCOVA
	Comments

3. Secondary Outcome

Title	Change in Fasting Plasma Glucose
Description	Change in fasting plasma glucose for the fixed dose leucine and metformin combination treatments A, B and C was evaluated.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of Fasting Plasma Glucose change from day 1-day 28 Evaluable Population (n=73)

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	17	18	20	18
Mean (Standard Deviation) [mg/dL]	-6.8 (36.91)	-9.7 (26.50)	-13.4 (38.55)	-36.0 (47.36)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0179
	Comments
	Method	ANCOVA
	Comments	Total daily dose is twice the respective dose, Pairwise comparison using Treatment D as the reference group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0736
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0475
	Comments
	Method	ANCOVA
	Comments

4. Secondary Outcome

Title	Change in Hemoglobin A1c (HbA1c)
Description	Changes in HbA1c which is a marker of long-term glucose control was assessed.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of HbA1c change from day 1-day 28 Evaluable Population (n=73)

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	17	18	20	18
Mean (Standard Deviation) [percent]	0.11 (0.448)	-0.16 (0.485)	-0.01 (0.442)	-0.23 (0.607)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0089
	Comments
	Method	ANCOVA
	Comments	Total daily dose is twice the respective dose. Pairwise Comparison using Treatment D as the Reference Group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.376
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0578
	Comments
	Method	ANCOVA
	Comments

5. Secondary Outcome

Title	Change in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR)
Description	Effect on insulin sensitivity across fixed-dose leucine and metformin combination treatments or the standard metformin reference treatment.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of HOMA-IR. Some of the samples collected were not viable and could not be included in the analysis. So, the total samples collected were still the same but since they could not be included in the analysis the exact number analyzed is referenced.

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	17	18	17	16
Mean (Standard Deviation) [HOMA units]	-0.31 (1.010)	-0.14 (0.548)	0.11 (0.958)	-0.18 (1.017)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments	The HOMA Calculator,is an algorithm that takes account of variations in hepatic and peripheral glucose resistance, increases in insulin secretion curve for plasma glucose concentrations above 10 mmol/L (180 mg/dL), and contribution of circulating proinsulin (eg, C-peptide) to estimate steady state beta cell function (%HOMA-B) and insulin sensitivity (%HOMA-S), as percentages of a normal reference population. %HOMA-IR was analyzed on a logarithmic scale (natural logarithmic transformation).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2177
	Comments
	Method	ANCOVA
	Comments	Total daily dose is twice the respective dose. Pairwise Comparison using Treatment D as the Reference Group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.4144
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3117
	Comments
	Method	ANCOVA
	Comments

6. Secondary Outcome

Title	Change In 7-Point Glucose Profiles
Description	The meal induced glucose change in pre-meal and post-meal glucose were measured 7 times during the day. Subjects self-monitored blood glucose (preprandial and postprandial) concentrations at least 7 times, including before and 1 to 2 hours after breakfast, lunch, dinner, and snacks). For each study day, the pre-meal values from the 7 point test for each subject were averaged to generate a single pre-meal glucose value. Similarly, for each study day the post-meal values from the 7-point test for each subject were averaged to generate a single post-meal glucose value. The average change from baseline (i.e., [(Mean Pre/Post-meal value at Day 28 - Mean Pre/Post-meal value at Baseline) + (Mean Pre/Post-meal value at Day 21- Mean Pre/Post-meal value at Baseline) + (Mean Pre/Post-meal value at Day 7- Mean Pre/Post-meal value at Baseline)]/ 3) over multiple time points listed in Time Frame. The mean pre-meal and post-meal values for baseline, day7, day 21 and day28 were used for comparison.
Time Frame	Baseline, Day 7, Day 21, Day 28

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of 7 point glucose change from day 1-day 28 Evaluable Population (n=73). Some of the samples collected were not viable and could not be included in the analysis. The total samples collected were still the same but since they could not be included in the analysis the exact number analyzed is referenced.

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	16	17	18	15
28 day change in Pre-meal Glucose Level	-6.50 (32.343)	-8.96 (61.561)	-25.51 (42.198)	-53.78 (45.488)
28 day change in Post-meal Glucose Level	-15.98 (33.966)	10.56 (44.944)	-34.25 (77.268)	-50.33 (60.756)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments	Average Change in Pre-meal Glucose Level
Statistical Test of Hypothesis	p-Value	0.011
	Comments
	Method	ANCOVA
	Comments	Total daily dose is twice the respective dose Pairwise comparison using Treatment D as the reference group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments	Average Change in Pre-meal Glucose Level
Statistical Test of Hypothesis	p-Value	0.0152
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments	Average Change in Pre-meal Glucose Level
Statistical Test of Hypothesis	p-Value	0.0284
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments	Average Change in Post-meal Glucose Level
Statistical Test of Hypothesis	p-Value	0.1273
	Comments
	Method	ANCOVA
	Comments	Total daily dose is twice the respective dose Pairwise comparison using Treatment D as the reference group

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments	Average Change in Post-meal Glucose Level
Statistical Test of Hypothesis	p-Value	0.0085
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments	Average Change in Post-meal Glucose Level
Statistical Test of Hypothesis	p-Value	0.1289
	Comments
	Method	ANCOVA
	Comments

7. Secondary Outcome

Title	Plasma Insulin Absolute and Incremental Meal Tolerance Test Area Under the Curve (AUC) 0-2hr
Description	Change in meal tolerance test insulin area under the curve (0-2 hr) from Day 1 to Day 28 for fixed-dose leucine and metformin combination treatments.
Time Frame	Baseline,Day 28

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of Plasma Insulin AUC and Incremental AUC change from day 1-day 28 Evaluable Population (n=73). Some samples collected were not viable. The total samples collected were still the same but since they couldn't included in the analysis, exact number analyzed is referenced.

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	17	18	19	17
Plasma Insulin Absolute	-0.19 (74.531)	-5.64 (31.360)	-9.59 (34.987)	-18.06 (35.473)
Plasma Insulin Incremental	4.18 (67.120)	-4.25 (29.514)	-9.99 (27.956)	-15.91 (26.720)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments	Plasma Insulin Absolute AUC(0-2hr) (h*uIU/mL)
Statistical Test of Hypothesis	p-Value	0.3143
	Comments
	Method	ANCOVA
	Comments	Total daily dose is twice the respective dose. Pairwise comparison using Treatment D as the reference group.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments	Plasma Insulin Absolute AUC(0-2hr) (h*uIU/mL)
Statistical Test of Hypothesis	p-Value	0.5677
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments	Plasma Insulin Absolute AUC(0-2hr) (h*uIU/mL)
Statistical Test of Hypothesis	p-Value	0.8407
	Comments
	Method	ANCOVA
	Comments

8. Secondary Outcome

Title	Change From Baseline to Day 28 in Fasting Plasma Insulin Concentration
Description	Effect on fasting plasma insulin concentrations across fixed-dose leucine and metformin combination treatments or the standard metformin reference treatment was evaluated.
Time Frame	Baseline, Day 28

Outcome Measure Data

Analysis Population Description

Mixed Model Inferential Statistical Analysis of Plasma Insulin AUC and Incremental AUC change from day 1-day 28 Evaluable Population (n=73). Some collected were not viable. So, the total samples collected were still the same but since they could not be included in the analysis the exact number analyzed is referenced.

Arm/Group Title	FDC125	FDC250	FDC500	Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg	Leucine 1100mg +Metformin 250mg	Leucine 1100mg +Metformin 500mg	Day 1-14: 500mg, Day 15-28: 850mg
Measure Participants	17	18	19	17
Mean (Standard Deviation) [h*uIU/mL]	-2.06 (6.652)	-0.74 (4.069)	0.20 (7.278)	-1.03 (7.694)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	FDC125, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.9789
	Comments
	Method	ANCOVA
	Comments	Total daily dose is twice the respective dose Pairwise comparison using Treatment D as the reference group

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	FDC250, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.841
	Comments
	Method	ANCOVA
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	FDC500, Control
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.748
	Comments
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	30 days
Adverse Event Reporting Description	Treatment-Energent 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. Subjects experiencing multiple episodes of a given adverse event are counted once. This was a 28 day study and adverse event reporting went upto day 30.
Arm/Group Title	FDC125		FDC250		FDC500		Control
Arm/Group Description	Leucine 1100mg +Metformin 125mg		Leucine 1100mg +Metformin 250mg		Leucine 1100mg +Metformin 500mg		Day 1-14: 500mg, Day 15-28: 850mg
All Cause Mortality
	FDC125		FDC250		FDC500		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/24 (0%)		0/25 (0%)		0/24 (0%)		0/23 (0%)
Serious Adverse Events
	FDC125		FDC250		FDC500		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/24 (4.2%)		1/25 (4%)		0/24 (0%)		1/23 (4.3%)
Infections and infestations
Lacunar Infarction	0/24 (0%)	0	1/25 (4%)	1	0/24 (0%)	0	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Rhabdomyolysis	0/24 (0%)	0	0/25 (0%)	0	0/24 (0%)	0	1/23 (4.3%)	1
Psychiatric disorders
Suicidal Ideation	1/24 (4.2%)	1	0/25 (0%)	0	0/24 (0%)	0	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	FDC125		FDC250		FDC500		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/24 (12.5%)		3/25 (12%)		3/24 (12.5%)		5/23 (21.7%)
Endocrine disorders
Hyperglycemia	2/24 (8.3%)	2	0/25 (0%)	0	0/24 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Gastric Disorders	3/24 (12.5%)	3	3/25 (12%)	3	2/24 (8.3%)	2	5/23 (21.7%)	5
General disorders
Abdominal Distension	0/24 (0%)	0	0/25 (0%)	0	0/24 (0%)	0	2/23 (8.7%)	2
Infections and infestations
Infections	2/24 (8.3%)	2	1/25 (4%)	1	3/24 (12.5%)	3	2/23 (8.7%)	2
Metabolism and nutrition disorders
Food	2/24 (8.3%)	2	0/25 (0%)	0	0/24 (0%)	0	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Disorders	0/24 (0%)	0	1/25 (4%)	1	3/24 (12.5%)	3	2/23 (8.7%)	2
Arthralgia	0/24 (0%)	0	0/25 (0%)	0	2/24 (8.3%)	2	0/23 (0%)	0
Nervous system disorders
Nervous Disorders	0/24 (0%)	0	2/25 (8%)	2	0/24 (0%)	0	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory Disorders	2/24 (8.3%)	2	1/25 (4%)	1	0/24 (0%)	0	0/23 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.