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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Low Metformin
* Drug: Metformin
* Drug: Mid Metformin
* Drug: High Metformin


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low Metformin<br>3 capsules BID with each capsule containing 366.7 mg L-Leucine and 41.7 mg of metformin | Drug: Low Metformin<br>* 1100 mg L Leucine in combination with 125 mg of Metformin BID<br>* Other names: L-Leucine;|
| Experimental: Mid Metformin<br>3 capsules BID with each capsule containing 366.7 mg L-Leucine and 83.3 mg of metformin | Drug: Mid Metformin<br>* 1100 mg of Leucine in combination with 250 mg Metformin BID<br>* Other names: L-Leucine;|
| Experimental: High Metformin<br>3 capsules BID with each capsule containing 366.7 mg L-Leucine and 166.7 mg of metformin | Drug: High Metformin<br>* 1100 mg of Leucine in combination with 500 mg Metformin BID<br>* Other names: L-Leucine;|
| Experimental: Metformin Monotherapy<br>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<br>* 500 mg metformin BID until day 14 with dose escalation at day 14 to 850 mg metformin BID<br>|

What is the study measuring?
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Primary Outcome Measures

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

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Day 28 in Incremental Plasma Glucose Area Under the Curve (AUC) | The baseline incremental (baseline-subtracted) glucose AUC0-3h was evaluated for treatment differences at baseline. | Baseline, Day 28 | 
| Change in Fasting Plasma Glucose | Change in fasting plasma glucose for the fixed dose leucine and metformin combination treatments A, B and C was evaluated. | Baseline, Day 28 | 
| Change in Hemoglobin A1c (HbA1c) | Changes in HbA1c which is a marker of long-term glucose control was assessed. | Baseline, Day 28 | 
| Change in Homeostasis Model Assessment-estimated Insulin Resistance (HOMA-IR) | Effect on insulin sensitivity across fixed-dose leucine and metformin combination treatments or the standard metformin reference treatment. | Baseline, Day 28 | 
| Change In 7-Point Glucose Profiles | 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. | Baseline, Day 7, Day 21, Day 28 | 
| Plasma Insulin Absolute and Incremental Meal Tolerance Test Area Under the Curve (AUC) 0-2hr | 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. | Baseline,Day 28 | 
| Change From Baseline to Day 28 in Fasting Plasma Insulin Concentration | Effect on fasting plasma insulin concentrations across fixed-dose leucine and metformin combination treatments or the standard metformin reference treatment was evaluated. | Baseline, Day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Type 2 Diabetes