An Open-label Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Dapagliflozin 70 mg Extended Release Capsules in Healthy Volunteers

Exclusion Criteria59

• Individuals with known clinically significant esophageal or GI disease, including but not limited to:
• a. Known strictures such as esophageal web, pyloric stenosis, or small intestinal stricture, or individuals with high risk of stricture, i.e., Crohn's disease.
• b. Diagnosis of a condition known to elevate or lower gastric pH, e.g., achlorhydria or hypochlorhydria.
• c. Prior varices or small or large bowel obstructions.
• d. Prior abdominal or upper GI surgery. (Prior uncomplicated laparoscopic procedures are permitted.)
• e. History of dysphagia or aspiration in the last 5 years.
• f. History of an esophageal motility disorder or undergoing treatment for a gastric motility disorder.
• g. Multiple episodes of abdominal pain, chronic constipation, or diarrhea in the prior 3 months.
• h. Moderate or severe dysmenorrhea or menorrhagia (with use of pain medication) in the prior 3 months.
• i. History of moderate to severe acid reflux disease or a score of equal and greater than 2 on the Acid Reflux Severity Scale (ARSS), indicating moderate to severe symptoms. The ARSS scale is as follows:
• None = 0 no symptoms.
• Mild = 1 awareness of symptom, but easily tolerated.
• Moderate = 2 discomfort sufficient to cause interference with normal activities.
• Severe = 3 incapacitating, with inability to perform normal activities.
• Individuals with PILL-5 questionnaire score of 5 or greater.
• Medical history or current diagnoses indicating the presence of any of the following conditions:
• a. Presence of an uncontrolled, unstable, clinically significant medical condition that could put the subject at risk because of participation in the study, interfere with the subject’s ability to participate in the study or influence the interpretation of safety or PK evaluations.
• b. History of a major cardiovascular event (myocardial infarction, cardiac surgery or revascularization, unstable angina, stroke, or transient ischemic attack) or a hospitalization for heart failure within 6 months of Screening.
• c. Any clinically significant illness, medical or surgical procedure, or trauma within 4 weeks of Screening.
• d. Known immunocompromised status, including individuals who have undergone organ transplantation, are on immunosuppression therapy for an immune mediated disease, or are positive for HIV.
• e. Positive test for active hepatitis B or C at Screening. Individuals with successfully treated hepatitis B infection which has been resolved for greater than 1 year or successfully treated hepatitis C infection will not be excluded.
• f. Donated more than 250 mL of blood within 4 weeks of Screening.
• g. Difficulties with venipuncture/cannulation, including difficulty accessing veins for blood sampling and/or history of coagulopathy or endocarditis.
• h. Active SARS-CoV-2 infection, as defined in the SARS-CoV-2 risk management plan.
• i. Chronic cystitis and/or recurrent urinary tract infections (3 or more in the last year).
• j. Individuals who are contraindicated to taking dapagliflozin (FORXIGA®, FARXIGA®), e.g., severe renal impairment, end-stage renal disease, or patients on dialysis.
• Use of the following medications/treatments in the 2 weeks before enrollment, including:
• a. Proton pump inhibitors (PPIs).
• b. H2 blockers.
• c. Non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA).
• d. Prokinetic agents.
• e. Medications that may interfere with the absorption, metabolism, or excretion of LYN-045.
• f. Concomitant medications, natural remedies, supplements or vitamins. Use of antacids is permissible, except within 2 hours of dosing with LYN-045.
• g. Use of blood products within 3 months of Screening.
• h. Loop diuretic medications, such as furosemide, ethacrynic acid, bumetanide, or torsemide.
• Individuals with clinically significant abnormal safety (e.g., physical examination, vital signs) or laboratory assessments at Screening, specifically:
• a. Presence of a clinically significant abnormal laboratory result on blood or urine safety tests.
• b. Anemia (hemoglobin below the lower limit of normal reference range).
• c. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) equal and greater than3.0 × the upper limit of normal (ULN) or total bilirubin equal and greater than1.5 × ULN.
• d. Moderate or severe renal insufficiency (glomerular filtration rate smaller than60 mL/min, as determined using the Cockcroft-Gault formula).
• e. Heart rate of smaller 50 beats per minute (bpm).
• f. Systolic blood pressure equal and greater than150 mmHg and/or diastolic blood pressure equal and greater100 mmHg.
• g. Glycated hemoglobin (HbA1c) equal and greater than7.0 % at Screening.
• h. Positive fecal occult blood test at Screening in subjects who are greater than45 years unless they have had a normal colonoscopy within the past 5 years.
• i. Creatine kinase >2 × ULN.
• j. Thrombocytopenia (platelet count under 150×109/L) or bleeding diathesis (international normalized ratio [INR] greater1.4).
• Individuals with a history of any drug or alcohol use disorder in the past 2 years. Positive results for drugs of abuse or positive ethanol breathalyzer screen finding will exclude individuals, unless the positive finding can be accounted for by documented prescription use. Exclusions include:
• a. History of alcohol consumption exceeding moderate use; in males exceeding 21 units per week and in females exceeding 14 units per week (1 unit = 360 ml beer, 25 mL of 40% spirit or a 125 mL glass of wine) over the past month. Subjects are not permitted to consume alcohol during the inpatient stay nor 12 hours before any clinic visit while an outpatient.
• b. Current smokers, users of e-cigarettes, vaping products, or nicotine replacement products and individuals who have smoked within the last 12 months. Positive results for cotinine are exclusionary.
• Individuals of reproductive potential who are (hetero) sexually active but unwilling to use acceptable means of contraception through the End of Study. For clarity, individuals who are at least 1 year post-menopausal are not of reproductive potential. Acceptable means of contraception include:
• a. Individuals who have been surgically sterilized.
• b. Females of reproductive potential: diaphragm, injectable, oral/patch contraceptives for a minimum of 6 weeks, contraceptive sponge, implant, or intrauterine device in use prior to enrollment, with use of condom for their male partners.
• c. Males: condom in combination with any of the above means of contraception for their female partners.
• d. All individuals: abstinence may be an acceptable means of contraception as long as the individual consents to initiate immediate use of double barrier protection for the duration of the study should (hetero) sexual intercourse occur.
• Individuals who are nursing or who have a positive or indeterminate pregnancy test at either Screening (serum test) or enrollment (urine test).
• Use of any experimental agent within 3 months or 5 half-lives of Screening, whichever is longer.
• Employee or immediate family member of employee of the site, Sponsor, or study-related vendors.
• History of a serious allergic or hypersensitivity reaction to dapagliflozin or LYN-045 excipients (refer to Investigator’s Brochure).
• Individuals with history of X-ray, computed tomography (CT) scan or angiogram of the abdomen within one year of Screening.