A Study to Evaluate the Effect of Two Fixed-Dose Leucine, Sildenafil and Metformin Combinations on Blood Pressure in Individuals With Hypertension

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Two Fixed-Dose Leucine, Sildenafil and Metformin Combinations (NS-0200) Versus Placebo on Blood Pressure in Individuals With Hypertension

This 12-week, randomized, double-blind, placebo-controlled Phase 2 study will evaluate two fixed-dose oral combinations of L-leucine, sildenafil, and metformin (NS-0200) versus matching placebo in adults 18-75 years with hypertension. Approximately 150 subjects will be screened to randomize ~150 (≈50 per arm) with an expected completer population of ~120. The primary objective is to compare change in mean seated systolic blood pressure from baseline (Day 1) to Week 12 (Day 84) for each NS-0200 dose versus placebo. Secondary outcomes include change in seated diastolic blood pressure and change in body weight. Safety will be monitored through adverse events, labs, vital signs, ECGs, and pregnancy testing.

This is a 12-week, randomized, placebo-controlled, double-blind Phase 2 trial of two fixed-dose combinations (FDC) of L-leucine, sildenafil and metformin (NS-0200) versus placebo in adults 18-75 years with seated systolic blood pressure >130 mmHg who meet inclusion/exclusion criteria. Screening (Visit 1, Day -7) precedes Baseline/Randomization and first dose on Day 1 (Visit 2). Visits occur at Day 28 (Week 4) and Day 56 (Week 8); telephone contacts occur at Days 14, 42, and 70; Study Termination is Day 84 (Week 12). Study medication is self-administered orally BID (30 minutes before meals) as three tablets per dose. Subjects randomized 1:1:1 to placebo or one of two NS-0200 dose levels; stratified by baseline SBP (<145 vs ≥145 mmHg). Primary analysis compares change in mean seated SBP from Baseline (Day 1) to Day 84 for each active arm versus placebo using mixed-model ANCOVA; missing data handled with multiple imputation. Safety assessments include TEAEs/SAEs, clinical labs, ECGs, vitals, pregnancy testing, and monitoring for lactic acidosis, hypotension and vision changes

Inclusion criteria:

• Age ≥18 and ≤75 at study entry.
• 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 (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 Stable body weight (±5%) and health over the last 3 months.
• Systolic pressure > 130 mm Hg
• Not on antihypertensive therapy for the preceding 30 days or on a stable dose over the 30 days preceding study entry of 1 or 2 antihypertensive agents.
• HbA1c <9%.
• If on insulin, must be on a stable regimen for 3 months preceding study entry.
• If on GLP-1 agonist, must be on a stable regimen for 9 months with a stable total body weight for the preceding 3 months.
• Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) either normal or not clinically significant.
• 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:

• <18 or >75 years of age
• On >2 antihypertensive agent drug products
• Systolic pressure >160 mm Hg
• Diastolic pressure >110 mm Hg
• HbA1c >9% at screening
• Severe renal impairment (eGFR < 45 mg/mL/1.73 m2) and/or patients with acute or chronic metabolic acidosis (acidosis defined as >25mmol/L computed without K).
• 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)
• ≥ 5% weight change in the last 3 months
• Diseases interfering with metabolism (including metabolism of branched chain amino acids) and/or ingestive behavior (myxedema, Cushings 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) 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
• 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, Peyronies disease) or other conditions that predispose to priapism (e.g., sickle cell anemia, multiple myeloma, or leukemia)
• Clinical evidence of hepatic impairment and/or alanine aminotransferase (ALT) aspartate aminotransferase (AST) >5 times the upper limit of normal (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 Sciences, Inc. (NuSirt)
• Is employed by NuSirt (defined as an employee, temporary contract worker, or designee responsible for the conduct of the study)