The Effect Of NS-0200 and NS-0300 Versus Placebo on Weight In Obesity

Study Overview
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Brief Summary
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This is a 24-week study to evaluate the effects of two fixed-dose combinations of leucine and sildenafil or two fixed-dose combinations of leucine, sildenafil and metformin compared to placebo. The primary objective of this study is to evaluate the percentage change in body weight in subjects from Baseline/Visit 2 (Day 1) to Study Termination/Visit 8 (Day 168/Week 24).

Detailed Description
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This is a randomized, 24-week, placebo-controlled, double-blind study to evaluate the effects of two fixed-dose combinations of leucine and sildenafil or two fixed-dose combinations of leucine, sildenafil and metformin compared to placebo. Subjects meeting all the inclusion criteria and no exclusion criteria will be randomized to one of five study arms. The primary objective of this study is to evaluate the percentage change in body weight in subjects from Baseline/Visit 2 (Day 1) to Study Termination/Visit 8 (Day 168/Week 24) receiving two fixed-dose combinations of leucine and sildenafil or two fixed-dose combinations of leucine, sildenafil and metformin compared to placebo. Secondary objectives will also assess changes in absolute body weight, percentage of patients with ≥5% body weight loss, change in waist circumference, change in HbA1c, change in fasting glucose, change in blood lipids such as cholesterol, LDL, HDL, triglycerides, change in blood pressure and changes in in C-reactive protein. In addition this study will evaluate the safety and tolerability of NS-0200 and NS-0300. Patients will have one screening visits which will determine their eligibility based on lab tests. Once qualified, patients will be randomly assigned to either one of the treatment groups or the placebo control group and monitored for a total of 24 weeks. Patients will return to the clinic each month for lab tests, and routine examinations.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study of Effects of Two Fixed-dose Leucine-sildenafil Combinations (NS-0300) or Two Fixed-dose Leucine-sildenafil-metformin Combinations (NS-0200) Versus Placebo on Body Weight in Obesity

Conditions
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Obesity

Intervention / Treatment
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* Drug: Leu Sil 1.0mg
* Drug: Leu Sil 4.0mg
* Drug: Leu Met Sil 1.0mg
* Drug: Leu Met Sil 4.0mg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 and ≤65 at study entry. Is male, or female and, if female, meets all of the following criteria: Not breastfeeding Post-menopausal or negative serum pregnancy test result (human chorionic gonadotropin, beta subunit [β-hCG]) at Screening/Visit 1 (Day-7/Week-1) (not required for hysterectomized females) If of childbearing potential (including peri-menopausal women who have had a menstrual period within one year) must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as double barrier methods [male condom with spermicide, with or without cervical cap or diaphragm], implants, injectables, oral contraceptives [must have been using for at least the last 3 months], some intrauterine contraceptive devices, tubal ligation, or in an established relationship with a vasectomized or same sex partner) during the entire duration of the study Stable body weight (±5%) and health over the last 3 months. Has a BMI between 30 kg/m2 and 45 kg/m2 Stable diet within the last three months Subjects on antidepressants, excluding those listed in the exclusion criteria, must have been on a stable dose regiment for at least 3 months prior to study enrollment and maintain stable dose during the study Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either normal, not clinically significant or with abnormalities consistent with obesity Is able to read, understand, and sign the informed consent forms (ICF) and, when applicable, an authorization to use and disclose protected health information form (consistent with Health Insurance Portability and Accountability Act of 1996 [HIPAA] legislation), communicate with the investigator, and understand and comply with protocol requirements. Exclusion Criteria: Diagnosis of diabetes or on a diabetes medication HbA1c ≥6.5% at Screening/Visit 1 (Day-7/Week-1) Severe renal impairment (eGFR < 45 mg/mL/1.73 m2) and/or patients with acute or chronic metabolic acidosis. Acidosis is defined as >25mmol/L computed without K. Normal is 8- 16, but acidosis is >25 Use of any of the following medications in the eight weeks prior to entering screening for study participation and during the study: Use of any anti-diabetes medication including metformin and any combination drug that contains metformin Sildenafil Tadalafil Vardenafil OCT2/MATE inhibitors (e.g. cimetidine, quinidine, and pyrimethamine) Riociguat (guanylate cyclase stimulant) Alpha blockers Nitrates (e.g. oral nitrates, sublingual nitroglycerine and nitroglycerine patches) Potent CYP3A4 inhibitors (e.g. clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir) All antihypertensive medications Medications associated with weight changes Drugs approved for the treatment of obesity Cypropheptadine or medroxyprogesterone Atypical anti-psychotic drugs Tricyclic antidepressants Lithium, MAO's, glucocorticoids SSRI's or SNRI's Antiepileptic drugs Systemic corticosteroids Stimulants e.g. amphetamines Any dietary supplement that is labeled for weight management or maintenance of healthy weight Diagnosis or evidence of eating disorders ≥ 5% weight change in the last 3 months Subjects who have had bariatric surgery An infection requiring antibiotic treatment within the last 30 days Any chronic inflammatory disease, e.g. inflammatory bowel disease rheumatoid arthritis, vasculitis, systemic lupus erythematosus Diseases interfering with metabolism (including metabolism of branched chain amino acids) and/or ingestive behavior (myxedema, Cushing's disease, diabetes, schizophrenia, major psychoses, maple syrup urine disease, unmanaged depression etc.) History of alcohol abuse (defined ≥ 21 drinks per week for males and > 14 drinks per week for females), within the past 3 months or failure on urinary drug screen History of substance abuse (including alcohol abuse as defined above) in the past 12 months or a positive screen for drugs (opioids without a prescription), including marijuana, of abuse or alcohol 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 (due to HbA1c reading at screening) Other medical conditions that may diminish life expectancy to <2 years, including known cancers Have been diagnosed with metastatic carcinomas in the last 5 years Has known allergies or hypersensitivity to metformin, sildenafil or leucine Have suffered myocardial infarction, stroke, arrhythmia in the last 6 months Resting hypotension (BP <90/50 mmHg) or severe hypertension (BP >170/110 mmHg) If both or one of the parameters for diastolic or systolic BP is meet Cardiac failure or coronary artery disease causing unstable angina History or evidence at screening of left ventricular outflow obstruction (e.g., aortic stenosis, idiopathic hypertrophic subaortic stenosis) and those with severely impaired autonomic control of blood pressure At risk for priapism due to anatomical deformation of the penis (e.g., angulation, cavernosal fibrosis, Peyronie's disease) or other conditions that predispose to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia) Clinical evidence of hepatic impairment and/or ALT/AST >5X ULN Is an immediate family member (spouse, parent, child, or sibling; biological or legally adopted) of personnel directly affiliated with the study at the clinical study site, or NuSirt Biopharma. Is employed by NuSirt Biopharma (defined as an employee, temporary contract worker, or designee responsible for the conduct of the study).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Each dose of placebo will consist of three tablets, identical in appearance to those used in the two active treatment arms, containing 93.5% Microcrystalline cellulose PH 102, 5.0% Crospovidone XL 10, 1.0% Silica gel (Syloid 244), 0.5% Magnesium stearate I MF3V for the leucine matched placebo and 99.5% Avicel PH200 , 0.5% magnesium stearate (w/w) and Opadry II White coating 3% weight gain for the sildenafil matched placebo. | Drug: Placebo<br>* Placebo<br>|
| Experimental: Leu Sil 1.0mg<br>3 capsules BID consisting of 2 capsules containing 550 mg L-leucine each and 1 capsule containing 1.0 mg of sildenafil | Drug: Leu Sil 1.0mg<br>* Leu 1100 mg + 1mg Sil BID<br>* Other names: NS-0300-1.0;Drug: Leu Sil 4.0mg<br>* Leu 1100 mg + 4mg Sil BID<br>* Other names: NS-0300-4.0;|
| Experimental: Leu Sil 4.0mg<br>3 capsules BID consisting of 2 capsules containing 550 mg L-leucine each and 1 capsule containing 4.0 mg of sildenafil | Drug: Leu Sil 1.0mg<br>* Leu 1100 mg + 1mg Sil BID<br>* Other names: NS-0300-1.0;Drug: Leu Met Sil 1.0mg<br>* Leu 1100 mg + Met 500mg + 1mg Sil BID<br>* Other names: NS-0200-1.0;|
| Experimental: Leu Met Sil 1.0mg<br>3 capsules BID consisting of 2 capsules containing 550 mg L-leucine and 250 mg metformin and 1 capsule containing 1.0 mg of sildenafil | Drug: Leu Sil 1.0mg<br>* Leu 1100 mg + 1mg Sil BID<br>* Other names: NS-0300-1.0;Drug: Leu Sil 4.0mg<br>* Leu 1100 mg + 4mg Sil BID<br>* Other names: NS-0300-4.0;Drug: Leu Met Sil 4.0mg<br>* Leu 1100 mg + Met 500mg + 4mg Sil BID<br>* Other names: NS-0200-4.0;|
| Experimental: Leu Met Sil 4.0mg<br>3 capsules BID consisting of 2 capsules containing 550 mg L-leucine and 250 mg metformin and 1 capsule containing 4.0 mg of sildenafil | Drug: Leu Sil 1.0mg<br>* Leu 1100 mg + 1mg Sil BID<br>* Other names: NS-0300-1.0;Drug: Leu Met Sil 1.0mg<br>* Leu 1100 mg + Met 500mg + 1mg Sil BID<br>* Other names: NS-0200-1.0;Drug: Leu Met Sil 4.0mg<br>* Leu 1100 mg + Met 500mg + 4mg Sil BID<br>* Other names: NS-0200-4.0;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Body Weight Change | The percentage body weight change from baseline to Day 168 was evaluated. | Baseline to Day 168 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Absolute Body Weight | The change in absolute body weight from baseline to day 168 was evaluated. | Baseline to Day 168 | 
| Change in Percentage of Patients With ≥5% Body Weight Loss | The number of patients with ≥5% body weight loss in each group was assessed from baseline to day 168. | Baseline to Day 168 | 
| Change in Waist Circumference | The change in waist circumference by using a tape measure across the mid-section was evaluated in subjects from baseline to day 168. | Baseline to Day 168 | 
| Change in Total Cholesterol | Changes in total cholesterol was examined by standard blood chemistry. | Baseline to Day 168 | 
| Change in HDL Cholesterol | Changes were measured in HDL cholesterol from Baseline to day 168 by standard blood chemistry. | Baseline, Day 168 | 
| Change in LDL Cholesterol | Changes in LDL Cholesterol was measured by standard blood chemistry from baseline to day 168. | Baseline, 168 days | 
| Change in Triglycerides | The change in triglycerides was evaluated by standard blood chemistry in subjects from Baseline to Day 168. | Baseline, Day 168 | 
| Change in Plasma Glucose | Change in plasma glucose was examined through standard fasting blood chemistry. | Baseline to Day 168 | 
| Change in Hemoglobin A1c (HbA1c) | Change in Hemoglobin A1c was assessed in the subjects from baseline to day 168. | Baseline, Day 168 | 
| Change in Diastolic Blood Pressure | Diastolic blood pressure was measured by standard blood pressure monitor. | Baseline to Day 168 | 
| Change in Systolic Blood Pressure | Change in Systolic blood pressure was assessed in patients from baseline to Day 168 | Baseline, Day 168 | 
| Change in Inflammatory Markers | hs-C-Reactive Protein (CRP) levels was examined by standard blood chemistry. | Baseline to Day 168 |