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

• ClinicalTrials.gov Identifier: NCT03721874
• Recruitment Status: Recruiting
• First Posted: October 26, 2018
• Last Update Posted: November 6, 2020
• Sponsor: Maastricht University
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Patrick Schrauwen, Maastricht University

Tracking Information

• First Submitted Date: October 23, 2018
• First Posted Date: October 26, 2018
• Last Update Posted Date: November 6, 2020
• Actual Study Start Date: April 30, 2019
• Estimated Primary Completion Date: July 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 24, 2018)

Change in nightly substrate oxidation measured as respiration quotient (RQ) during the sleeping period [ Time Frame: From screening to day 14 ]

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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: October 24, 2018)

• Change in morning and late afternoon hepatic glycogen content [ Time Frame: 1 hour ]
  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
• Change in 24h substrate oxidation as determined by indirect calorimetry in a whole-body respiratory chamber and based on urinary nitrogen excretion [ Time Frame: 24 hours ]
  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
• Change in 24h plasma markers [ Time Frame: 24 hours ]
  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
• Change in muscle mitochondrial function [ Time Frame: 60 minutes ]
  Comparison of dapagliflozin versus placebo after 14 days of treatment on muscle mitochondrial function as determined by high resolution respirometry
• Change in intrahepatic lipid content and composition [ Time Frame: 45 minutes ]
  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 )
• Change in intramyocellular lipid content and composition - including acylcarnitine levels [ Time Frame: 45 minutes ]
  Comparison of dapagliflozin versus placebo after 14 days of treatment on intramyocellular lipid content and composition-including acylcarnitine levels as determined in muscle biopsies
• Change in muscle glycogen content [ Time Frame: 45 minutes ]
  Comparison of dapagliflozin versus placebo after 14 days of treatment on muscle glycogen content as determined biochemically in muscle biopsies
• Change in systolic and diastolic blood pressure [ Time Frame: 45 minutes ]
  Comparison of dapagliflozin versus placebo after 14 days of treatment on systolic and diastolic blood pressure

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Effects of 2 Weeks Treatment With Dapagliflozin in Subjects With an Impaired Glucose Homeostasis on Nocturnal Substrate Oxidation
• 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
• 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.
• Study Type: Interventional
• Study Phase: Phase 4

Study Design

Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description:

Double-Blind, Randomized, Phase IV, Mechanistic, Placebo-Controlled, Cross-Over, Single-Center Study

Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science

Condition

• Prediabetic State
• Substrate Oxidation

Intervention

• Drug: Dapagliflozin 10mg

  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.

• Drug: Placebo matching to Dapagliflozin 10 mg

  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.

Study Arms

• Active Comparator: Dapagliflozin 10 mg

  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.

  Intervention: Drug: Dapagliflozin 10mg
• Placebo Comparator: Placebo matching to dapagliflozin 10 mg

  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

  Intervention: Drug: Placebo matching to Dapagliflozin 10 mg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 24, 2018): 17
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: November 2021
• Estimated Primary Completion Date: July 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Provision of signed and dated informed consent prior to any study specific procedures.
2. 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
3. Body mass index (BMI) ≥ 27 and ≤ 38 kg/m2.
4. Sedentary lifestyle (not more than 3 hours of programmed exercise per week).
5. Stable dietary habits.

6. 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:

1. Clinical diagnosis of Type 1 or 2 Diabetes Mellitus.
2. 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.
3. Weight gain or loss > 5 kg in the last 3 months, ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents.
4. Regular smoking and other regular nicotine use.
5. Anaemia.
6. Uncontrolled hypertension.
7. 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.
8. Unstable or rapidly progressing renal disease or estimated Glomerular Filtration Rate (eGFR) <60 mL/min (Cockcroft-Gault formula).
9. Use of anti-coagulant treatment and other concomitant medication will be evaluated on a case to case basis with a general physician.
10. Use of medication such as oral glucocorticoids, anti-estrogens or other medications that are known to markedly influence insulin sensitivity.
11. Use of loop diuretics.
12. Intake of dietary supplements except multi-vitamins and minerals.
13. 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).
14. Known hypersensitivity to dapagliflozin or any of the excipients of the product.
15. For women only - currently pregnant (confirmed with positive pregnancy test) or breast-feeding.
16. Participation in another biomedical study within 1 month before the screening visit.
17. Any contraindication for MRI scanning.
18. 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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 40 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Anna Veelen, Msc; +31 43 388 4258; a.veelen@maastrichtuniversity.nl

Contact: Patrick Schrauwen, Prof. dr.; +31 43 388 1502; p.schrauwen@maastrichtuniversity.nl

• Listed Location Countries: Netherlands

Administrative Information

• NCT Number: NCT03721874
• Other Study ID Numbers: NL67170.068.18
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Responsible Party: Patrick Schrauwen, Maastricht University
• Study Sponsor: Maastricht University
• Collaborators: AstraZeneca

Investigators

• Principal Investigator: Patrick Schrauwen, Prof. dr.; principle investigator

• PRS Account: Maastricht University
• Verification Date: November 2020