Does Dapagliflozin Augment The Favorable Adaptation To Endurance Exercise Training?
Condition: Physical Activity
Intervention: Dapagliflozin; Placebo
Intervention description: Dapagliflozin tablets, 5 mg, one per day for the first 14 days, increase to two per day for 70 days.; Matching placebo for Dapagliflozin 5 mg, one per day for the first 14 days, increase to two per day for 70 days.
Intervention MeSH terms: Dapagliflozin
Phase: Phase 2
Study type: Interventional
Primary purpose: Basic Science
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Enrollment: 37.0
Sex: All
Minimum age: 18 Years
Maximum age: 50 Years
Healthy volunteers: Accepts Healthy Volunteers

Summary:

      Exercise is frequently prescribed as a favorable lifestyle intervention to prevent/reverse
      type 2 diabetes. It is also prescribed in addition to concurrent pharmacological treatment,
      such as metformin. Recent data (animal and human) suggest that metformin may attenuate the
      favorable benefits of exercise training. In light of the physiological mechanism of
      Dapagliflozin (sodium-glucose co-transporter 2 (SGLT2) inhibition), one might speculate that
      rather than inhibit, it will augment the favorable adaptations to exercise training.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Provision of informed consent prior to any study specific procedures.

          2. No known Type 2 Diabetes.

          3. Body mass index 25-45 kg/m^2

          4. Sedentary (maximum of 2/week regularly scheduled activity sessions of < 20 minutes
             during the previous 2 years).

          5. Completion of a screening visit consisting of medical history, physical examination,
             and 12-lead electrocardiogram and blood pressure assessment at rest and during
             incremental exercise to volitional exhaustion (Note: Subjects with abnormal screening
             values may be eligible if the results are not clinically significant, as judged by the
             investigator or medical monitor).

          6. Agree to abide by the study schedule and to return for the required assessments.

          7. Be willing and able to repeatedly perform exercise.

          8. Women of childbearing potential must have negative pregnancy test and be using
             acceptable contraception.

        Exclusion Criteria:

        Subjects should not enter the study if any of the following exclusion criteria are
        fulfilled:

          1. Evidence of clinically significant cardiovascular, respiratory, renal, hepatic,
             pulmonary, gastrointestinal, hematological, neurological, psychiatric, or other
             disease that may interfere with the objectives of the study or the safety of the
             subject, as judged by the investigator in agreement with the sponsor or medical
             monitor, have been hospitalized in the past 2 years as a result of these conditions,
             or are receiving pharmacological treatment for these conditions.

          2. Use of prescription drugs (see exceptions listed below) or herbal preparations in the
             4 weeks before study commencement.

             Permitted Prescription Drugs

               -  Birth Control

               -  Less than 7 days, short course antibiotics. Note: Rifampin is not permitted.

               -  Other medicines, for gastroesophageal reflux disease (GERD), depression, seasonal
                  allergies and over-the-counter analgesics, may be allowed, but will be approved
                  on a case-by-case basis.

          3. Is currently enrolled in another clinical study for another investigational drug or
             has taken any other investigational drug within 30 days before the screening visit.

          4. Habitual and/or recent use (within 2 years) of tobacco.

          5. Being considered unsuitable for participation in this trial for any reason, as judged
             by the investigator or medical monitor.

          6. History of serious hypersensitivity reaction to Dapagliflozin.

          7. Severe renal impairment, end-stage renal disease, or dialysis.

          8. Pregnant or breastfeeding patients.

          9. Severe hepatic insufficiency and/or significant abnormal liver function defined as
             aspartate aminotransferase (AST) >3x upper limit of normal and/or alanine
             aminotransferase (ALT) >3x upper limit of normal.

         10. Total bilirubin >2.0 mg/dL (34.2 umol/L).

         11. Positive serologic evidence of current infectious liver disease including Hepatitis B
             viral antibody Immunoglobulin M, Hepatitis B surface antigen and Hepatitis C virus
             antibody.

         12. Estimated Glomerular Filtration Rate <60 mL/min/1.73 m^2 (calculated by
             Cockcroft-Gault formula).

         13. History of bladder cancer.

         14. Recent cardiovascular events in a patient, including any of the following: acute
             coronary syndrome within 2 months prior to enrollment; hospitalization for unstable
             angina or acute myocardial infarction within 2 months prior to enrolment; acute stroke
             or trans-ischemic attack within two months prior to enrollment; less than two months
             post coronary artery re-vascularization; congestive heart failure defined as New York
             Heart Association class IV, unstable or acute congestive heart failure. Note: eligible
             patients with congestive heart failure,especially those who are on diuretic therapy,
             should have careful monitoring of their volume status throughout the study.

         15. Blood pressure at enrollment: Systolic blood pressure ≥165 mmHg and/or diastolic blood
             pressure ≥100 mmHg.

         16. Blood pressure at randomization: Systolic blood pressure ≥165 mmHg and/or diastolic
             blood pressure ≥100 mmHg

         17. Patients who, in the judgment of the medical monitor, may be at risk for dehydration.