Does Dapagliflozin Promote Favorable Health Benefits That Are Independent Of Weight Loss?

Phase 2

Terminated

Conditions: Weight Loss

Interventions: Drug: Dapagliflozin
Drug: Placebo
Behavioral: Ad libitum dietary intake
Behavioral: Weight maintenance
Behavioral: Dietary restriction

Registration Number: NCT02520518

Lead Sponsor: Christopher Bell

Brief Summary: Th mechanism of action of dapagliflozin is via sodium-glucose co-transporter 2 (SGLT2) inhibition. Sodium-glucose co-transporter 2 inhibition is associated with moderate weight (fat) loss, in addition to other health benefits, including decreased blood pressure, decreased inflammation, and decreased oxidative stress. It is unclear as to whether these health benefits are due to SGLT2 inhibition per se, or as a secondary effect of weight loss.

Detailed Description: This is a randomized, prospective, placebo-controlled, double-blind, repeated measures study. 92 overweight/obese adults (body mas index \> 27.5 kg/m\^2) will be recruited for participation and randomly assigned to one of four 12 week treatments: 1) daily oral administration of dapagliflozin with ad-libitum dietary intake; 2) daily oral administration of dapagliflozin with supplemented dietary intake to achieve weight maintenance; 3) daily oral administration of a placebo plus dietary restriction such that weight loss is matched to participants in treatment 1; or, 4) daily oral administration of a placebo with ad-libitum dietary intake.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 9

Inclusion Criteria

Provision of informed consent prior to any study specific procedures.
Aged 18-65 years.
No known Type 2 Diabetes
Body mass index greater than or equal to 27.5 kg/m^2
Sedentary (maximum of 2/week regularly scheduled activity sessions of < 20 minutes during the previous 2 years)
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)
Agree to abide by the study schedule and dietary restrictions and to return for the required assessments
Women of childbearing potential must have negative pregnancy test and be using acceptable contraception

Exclusion Criteria

Evidence of clinically significant cardiovascular, respiratory, renal, hepatic, pulmonary, gastrointestinal, haematological, 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
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, maybe allowed, but will be approved on a case-by-case basis.
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.
Habitual and/or recent use (within 2 years) of tobacco
Being considered unsuitable for participation in this trial for any reason, as judged by the investigator or medical monitor.
History of serious hypersensitivity reaction to dapagliflozin
Severe renal impairment, end-stage renal disease, or dialysis
Pregnant or breastfeeding patients
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
Total bilirubin >2.0 mg/dL (34.2 umol/L)
Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody Immunoglobulin M, Hepatitis B surface antigen and Hepatitis C virus antibody
Estimated Glomerular Filtration Rate <60 mL/min/1.73 m^2 (calculated by Cockcroft-Gault formula).
History of bladder cancer
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 enrollment; acute stroke or trans-ischemic attack within two months prior to enrollment; less than two months post coronary artery revascularization; 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
Blood pressure at enrolment: Systolic blood pressure ≥165 mmHg and/or diastolic blood pressure ≥100 mmHg
Blood pressure at randomization: Systolic blood pressure ≥165 mmHg and/or diastolic blood pressure ≥100 mmHg
Patients who, in the judgment of the medical monitor, may be at risk for dehydration

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Dapagliflozin: ad libitum dietary intake	Ad libitum dietary intake	Daily oral administration of dapagliflozin with ad libitum dietary intake. The dose of dapagliflozin will begin as one 5 mg tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two 5 mg tablets per day for the remainder of the study.
Dapagliflozin: weight maintenance	Dapagliflozin	Daily oral administration of dapagliflozin with supplemented dietary intake to achieve weight maintenance. The dose of dapagliflozin will begin as one 5 mg tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two 5 mg tablets per day for the remainder of the study.
Dapagliflozin: weight maintenance	Weight maintenance	Daily oral administration of dapagliflozin with supplemented dietary intake to achieve weight maintenance. The dose of dapagliflozin will begin as one 5 mg tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two 5 mg tablets per day for the remainder of the study.
Placebo: ad libitum dietary intake	Placebo	Daily oral administration of a placebo with ad-libitum dietary intake. Matching placebo for dapagliflozin 5 mg will begin as one tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two tablets for the remainder of the study.
Placebo: ad libitum dietary intake	Ad libitum dietary intake	Daily oral administration of a placebo with ad-libitum dietary intake. Matching placebo for dapagliflozin 5 mg will begin as one tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two tablets for the remainder of the study.
Placebo: dietary restriction	Placebo	Daily oral administration of a placebo plus dietary restriction such that weight loss is matched to participants in Arm 1. Matching placebo for dapagliflozin 5 mg will begin as one tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two tablets for the remainder of the study.
Placebo: dietary restriction	Dietary restriction	Daily oral administration of a placebo plus dietary restriction such that weight loss is matched to participants in Arm 1. Matching placebo for dapagliflozin 5 mg will begin as one tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two tablets for the remainder of the study.
Dapagliflozin: ad libitum dietary intake	Dapagliflozin	Daily oral administration of dapagliflozin with ad libitum dietary intake. The dose of dapagliflozin will begin as one 5 mg tablet per day for the first 14-days. In the absence of complications, side effects, or unfavorable reactions, the dose will then increase to two 5 mg tablets per day for the remainder of the study.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Marker of Inflammation (Tumor Necrosis Factor Alpha) at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Insulin Sensitivity at Week 12	Baseline,12 weeks	Via oral glucose tolerance test.
Change From Baseline in Blood Pressure at Week 12	Baseline, 12 weeks
Change From Baseline in Perception of Satiety at Week 12	Baseline, 12 weeks	Perceptions of satiety will be determined using a visual analog scale called a Hunger Rating Scales. The minimum value is 1 (not at all full) and the maximum value is 100 (extremely full). One value between 1 and 100 is reported by the participant dependent on their perception. No sub scores are used. The perceived values are reported as the group average at baseline and 12 weeks. There is not a better or worse outcome, but rather a measure of perceived satiety. If Dapagliflozin were effective at increasing fullness, respondents would exhibit 12-week scores for the question in comparison to their baseline scores.
Change From Baseline in Perception of Hunger at Week 12	Baseline, 12 weeks	Perceptions of Hunger will be determined using a visual analog scale called a Hunger Rating Scales. The minimum value is 1 (not at all hungry) and the maximum value is 100 (very hungry). One value between 1 and 100 is reported by the participant dependent on their perception. No sub scores are used. The perceived values are reported as the group average at baseline and 12 weeks. There is not a better or worse outcome, but rather a measure of perceived hunger. If Dapagliflozin were effective at decreasing hunger, respondents would exhibit 12-week scores for the question in comparison to their baseline scores.
Change From Baseline in Marker of Inflammation (High Sensitive C-reactive Protein) at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Marker of Inflammation (Interleukin 6) at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Hunger Hormone Ghrelin at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Hunger Hormone Peptide Tyrosine Tyrosine at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Maker of Oxidative Stress (Oxidized Low Density Lipoprotein) at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Maker of Oxidative Stress (Low Density Thiobarbituric Acid Reactive Substances) at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Satiety Hormone Leptin at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.
Change From Baseline in Satiety Hormone Insulin at Week 12	Baseline, 12 weeks	Will be analyzed using a commercially available biochemical assay.