The Effect Of NS-0200 and NS-0300 Versus Placebo on Weight In Obesity
Condition: Obesity
MeSH terms: Obesity
Intervention: Leu Sil 1.0mg; Leu Sil 4.0mg; Leu Met Sil 1.0mg; Leu Met Sil 4.0mg; Placebo
Intervention description: Leu 1100 mg + 1mg Sil BID; Leu 1100 mg + 4mg Sil BID; Leu 1100 mg + Met 500mg + 1mg Sil BID; Leu 1100 mg + Met 500mg + 4mg Sil BID; Placebo
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Masking description: This is a double blind, placebo controlled trial
Enrollment: 267.0
Sex: All
Minimum age: 18 Years
Maximum age: 65 Years
Healthy volunteers: No

Summary:

      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).
    

Eligibility criteria:

        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).