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

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

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).

Study Overview

• Status: Completed
• Conditions: Obesity
• Intervention / Treatment: Drug: Placebo; Drug: Leu Sil 1.0mg; Drug: Leu Sil 4.0mg; Drug: Leu Met Sil 1.0mg; Drug: Leu Met Sil 4.0mg

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 267
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Mobile, Alabama, United States, 36608
      • AMR
  • California
    • Montclair, California, United States, 91763
      • Catalina Research Institute
    • Sacramento, California, United States, 95821
      • Northern California Research
  • Idaho
    • Meridian, Idaho, United States, 83642
      • ACR
  • Illinois
    • Chicago, Illinois, United States, 60602
      • Synexus
  • Louisiana
    • Baton Rouge, Louisiana, United States, 70808
      • Pennington Biomedical Research Center
    • Metairie, Louisiana, United States, 70006
      • Clinical Trials Management
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Synexus
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • AMR
  • Ohio
    • Cleveland, Ohio, United States, 44122
      • Rapid Medical Research
  • South Carolina
    • Charleston, South Carolina, United States, 29407
      • Medical Research South
  • Tennessee
    • Clarksville, Tennessee, United States, 37040
      • Premier
  • Texas
    • Dallas, Texas, United States, 75234
      • Synexus
    • San Antonio, Texas, United States, 78229
      • Synexus
  • Utah
    • Jordan, Utah, United States, 84088
      • ACR

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age ≥18 and ≤65 at study entry.

2. Is male, or female and, if female, meets all of the following criteria:

   1. Not breastfeeding
   2. Post-menopausal or negative serum pregnancy test result (human chorionic gonadotropin, beta subunit [β-hCG]) at Screening/Visit 1 (Day-7/Week-1) (not required for hysterectomized females)
   3. If of childbearing potential (including peri-menopausal women who have had a menstrual period within one year) must practice and be willing to continue to practice appropriate birth control (defined as a method which results in a low failure rate, i.e., less than 1% per year, when used consistently and correctly, such as double barrier methods [male condom with spermicide, with or without cervical cap or diaphragm], implants, injectables, oral contraceptives [must have been using for at least the last 3 months], some intrauterine contraceptive devices, tubal ligation, or in an established relationship with a vasectomized or same sex partner) during the entire duration of the study
3. Stable body weight (±5%) and health over the last 3 months.
4. Has a BMI between 30 kg/m2 and 45 kg/m2
5. Stable diet within the last three months
6. 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
7. Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either normal, not clinically significant or with abnormalities consistent with obesity
8. Is able to read, understand, and sign the informed consent forms (ICF) and, when applicable, an authorization to use and disclose protected health information form (consistent with Health Insurance Portability and Accountability Act of 1996 [HIPAA] legislation), communicate with the investigator, and understand and comply with protocol requirements.

Exclusion Criteria:

1. Diagnosis of diabetes or on a diabetes medication
2. HbA1c ≥6.5% at Screening/Visit 1 (Day-7/Week-1)

3. 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

4. Use of any of the following medications in the eight weeks prior to entering screening for study participation and during the study:

   1. Use of any anti-diabetes medication including metformin and any combination drug that contains metformin
   2. Sildenafil
   3. Tadalafil
   4. Vardenafil
   5. OCT2/MATE inhibitors (e.g. cimetidine, quinidine, and pyrimethamine)
   6. Riociguat (guanylate cyclase stimulant)
   7. Alpha blockers
   8. Nitrates (e.g. oral nitrates, sublingual nitroglycerine and nitroglycerine patches)
   9. Potent CYP3A4 inhibitors (e.g. clarithromycin, telithromycin, nefazodone, itraconazole, ketoconazole, atazanavir, darunavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, tipranavir)
   10. All antihypertensive medications

   11. 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
   12. Any dietary supplement that is labeled for weight management or maintenance of healthy weight
5. Diagnosis or evidence of eating disorders
6. ≥ 5% weight change in the last 3 months
7. Subjects who have had bariatric surgery
8. An infection requiring antibiotic treatment within the last 30 days
9. Any chronic inflammatory disease, e.g. inflammatory bowel disease rheumatoid arthritis, vasculitis, systemic lupus erythematosus
10. 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.)
11. 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
12. 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.
13. Has received any investigational drug within 3 months of Screening.
14. Has donated blood within 3 months before Screening or is planning to donate blood during the study (due to HbA1c reading at screening)
15. Other medical conditions that may diminish life expectancy to <2 years, including known cancers
16. Have been diagnosed with metastatic carcinomas in the last 5 years
17. Has known allergies or hypersensitivity to metformin, sildenafil or leucine
18. Have suffered myocardial infarction, stroke, arrhythmia in the last 6 months
19. 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
20. Cardiac failure or coronary artery disease causing unstable angina
21. 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
22. 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)
23. Clinical evidence of hepatic impairment and/or ALT/AST >5X ULN
24. 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.
25. Is employed by NuSirt Biopharma (defined as an employee, temporary contract worker, or designee responsible for the conduct of the study).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; 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; Placebo
Experimental: Leu Sil 1.0mg; 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; Leu 1100 mg + 1mg Sil BID; Other Names: NS-0300-1.0; Drug: Leu Sil 4.0mg; Leu 1100 mg + 4mg Sil BID; Other Names: NS-0300-4.0
Experimental: Leu Sil 4.0mg; 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; Leu 1100 mg + 1mg Sil BID; Other Names: NS-0300-1.0; Drug: Leu Met Sil 1.0mg; Leu 1100 mg + Met 500mg + 1mg Sil BID; Other Names: NS-0200-1.0
Experimental: Leu Met Sil 1.0mg; 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; Leu 1100 mg + 1mg Sil BID; Other Names: NS-0300-1.0; Drug: Leu Sil 4.0mg; Leu 1100 mg + 4mg Sil BID; Other Names: NS-0300-4.0; Drug: Leu Met Sil 4.0mg; Leu 1100 mg + Met 500mg + 4mg Sil BID; Other Names: NS-0200-4.0
Experimental: Leu Met Sil 4.0mg; 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; Leu 1100 mg + 1mg Sil BID; Other Names: NS-0300-1.0; Drug: Leu Met Sil 1.0mg; Leu 1100 mg + Met 500mg + 1mg Sil BID; Other Names: NS-0200-1.0; Drug: Leu Met Sil 4.0mg; Leu 1100 mg + Met 500mg + 4mg Sil BID; Other Names: NS-0200-4.0

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: NuSirt Biopharma
• Investigators: Study Chair: Michael B Zemel, PhD, NuSirt Biopharma

Study record dates

Study Major Dates

• Study Start (Actual): January 8, 2018
• Primary Completion (Actual): August 6, 2018
• Study Completion (Actual): August 17, 2018

Study Registration Dates

• First Submitted: November 30, 2017
• First Submitted That Met QC Criteria: December 5, 2017
• First Posted (Actual): December 6, 2017

Study Record Updates

• Last Update Posted (Actual): August 21, 2019
• Last Update Submitted That Met QC Criteria: August 19, 2019
• Last Verified: November 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Overnutrition; Nutrition Disorders; Overweight; Body Weight; Obesity
• Other Study ID Numbers: NS-WM-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No