Effects of 2 Weeks Treatment With Dapagliflozin in Subjects With an Impaired Glucose Homeostasis on Nocturnal Substrate Oxidation

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate the effect of 2 weeks dapagliflozin treatment in individuals with a disrupted glucose homeostasis on the switch between carbohydrate and lipid oxidation during the night

Detailed Description
-----------------
To investigate if dapagliflozin improves nocturnal substrate oxidation expressed as respiration quotient (RQ) during the sleeping period in comparison with placebo after 2-weeks double blind treatment in subjects with a disrupted glucose homeostasis.

Official Title
-----------------
MaasFlex: Double-Blind, Randomized, Phase IV, Mechanistic, Placebo-Controlled, Cross-Over, Single-Center Study to Evaluate the Effects of 2 Weeks Dapagliflozin Treatment on Nocturnal Substrate Oxidation, Glucose Metabolism and Muscle Mitochondrial Function in Individuals With Impaired Glucose Homeostasis

Conditions
-----------------
Prediabetic State, Substrate Oxidation

Intervention / Treatment
-----------------
* Drug: Dapagliflozin 10mg
* Drug: Placebo matching to Dapagliflozin 10 mg


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Provision of signed and dated informed consent prior to any study specific procedures. Males aged ≥ 40 and ≤ 75 years and post-menopausal women (defined as at least 1 year post cessation of menses) aged ≥ 50 and ≤ 75 years Body mass index (BMI) ≥ 27 and ≤ 38 kg/m2. Sedentary lifestyle (not more than 3 hours of programmed exercise per week). Stable dietary habits. Impaired glucose homeostasis based on one or a combination of the following criteria: Impaired Glucose Tolerance (IGT): plasma glucose values ≥ 7.8 mmol/l and ≤ 11.1 mmol/l 120 minutes after consumption of the glucose drink during the 2h, 3-point OGTT. Impaired Fasting Glucose (IFG): fasting plasma glucose ≥ 6.1 mmol/l and ≤ 6.9 mmol/l. Insulin Resistance: glucose clearance rate ≤ 360 ml/kg/min, as calculated by Oral Glucose Insulin Sensitivity 120 (OGIS120) model based on the 2h, 3-point OGTT. HbA1c ≥ 5.7% and ≤ 6.4%. Exclusion Criteria: Clinical diagnosis of Type 1 or 2 Diabetes Mellitus. Active cardiovascular disease: participants who experienced a heart attack in the last year, or participants who are currently under regular control of a physician for a heart condition. Weight gain or loss > 5 kg in the last 3 months, ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents. Regular smoking and other regular nicotine use. Anaemia. Uncontrolled hypertension. Clinically significant out of range values of serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) in the Investigator's opinion. Unstable or rapidly progressing renal disease or estimated Glomerular Filtration Rate (eGFR) <60 mL/min (Cockcroft-Gault formula). Use of anti-coagulant treatment and other concomitant medication will be evaluated on a case to case basis with a general physician. Use of medication such as oral glucocorticoids, anti-estrogens or other medications that are known to markedly influence insulin sensitivity. Use of loop diuretics. Intake of dietary supplements except multi-vitamins and minerals. Alcohol consumption of > 14 drinks per week for women and > 21 drinks per week for men (1 drink = 35 cl beer, 14 cl wine or 4 cl hard liquor). Known hypersensitivity to dapagliflozin or any of the excipients of the product. For women only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding. Participation in another biomedical study within 1 month before the screening visit. Any contraindication for MRI scanning. Participants who do not want to be informed about unexpected medical findings, or do not wish that their physician be informed about coincidental findings, cannot participate in the study.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Double-Blind, Randomized, Phase IV, Mechanistic, Placebo-Controlled, Cross-Over, Single-Center Study
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Dapagliflozin 10 mg<br>Patients will receive dapagliflozin 10 mg in tablet for a maximum of 14 days based on randomization sequence in Period 1. Patients that received 10 mg dapagliflozin in the first treatment period will receive matching placebo in the second treatment period for a maximum of 14 days. | Drug: Dapagliflozin 10mg<br>* The study consist of 2 weeks treatment period 1, 6-8 weeks wash-out period and 2 weeks treatment period 2. The subject may be administered dapagliflozin 10 mg during Period 1 or Period 2.<br>|
| Placebo Comparator: Placebo matching to dapagliflozin 10 mg<br>Patients will receive matching placebo in tablet for a maximum of 14 days based on randomization sequence. Patients who received placebo in the first treatment will receive 10 mg dapagliflozin in the second treatment period, for a maximum of 14 days | Drug: Placebo matching to Dapagliflozin 10 mg<br>* The study consist of 2 weeks treatment period 1, 6-8 weeks wash-out period and 2 weeks treatment period 2. The subject may be administered placebo during Period 1 or Period 2.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in nightly substrate oxidation measured as respiration quotient (RQ) during the sleeping period | Comparison of dapagliflozin versus placebo after 14 days of treatment on nightly substrate oxidation as measured by respiratory quotient (VCO2/VO2) during the sleeping period. | From screening to day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in morning and late afternoon hepatic glycogen content | Comparison of dapagliflozin versus placebo after 14 days of treatment on hepatic glycogen content determined by non-invasive 13C-MRS (magnetic resonance spectroscopy) in the morning and evening | 1 hour | 
| Change in 24h substrate oxidation as determined by indirect calorimetry in a whole-body respiratory chamber and based on urinary nitrogen excretion | Comparison of dapagliflozin versus placebo after 14 days of treatment on 24h substrate oxidation as determined by indirect calorimetry in a whole-body respiratory chamber and based on urinary nitrogen excretion | 24 hours | 
| Change in 24h plasma markers | Comparison of dapagliflozin versus placebo after 14 days of treatment on 24h plasma markers including plasma glucose, NEFA, total amino acid levels incl BCAA levels, insulin and glucagon | 24 hours | 
| Change in muscle mitochondrial function | Comparison of dapagliflozin versus placebo after 14 days of treatment on muscle mitochondrial function as determined by high resolution respirometry | 60 minutes | 
| Change in intrahepatic lipid content and composition | Comparison of dapagliflozin versus placebo after 14 days of treatment on intrahepatic lipid content and composition as determined by non-invasive 1H-MRS (magnetic resonance spectroscopy ) | 45 minutes | 
| Change in intramyocellular lipid content and composition - including acylcarnitine levels | Comparison of dapagliflozin versus placebo after 14 days of treatment on intramyocellular lipid content and composition-including acylcarnitine levels as determined in muscle biopsies | 45 minutes | 
| Change in muscle glycogen content | Comparison of dapagliflozin versus placebo after 14 days of treatment on muscle glycogen content as determined biochemically in muscle biopsies | 45 minutes | 
| Change in systolic and diastolic blood pressure | Comparison of dapagliflozin versus placebo after 14 days of treatment on systolic and diastolic blood pressure | 45 minutes | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Dapagliflozin, Disrupted glucose homeostasis, Nocturnal substrate oxidation, Glucose metabolism