Effects of 5 Weeks Treatment With Dapagliflozin in Type 2 Diabetes Patients on How the Hormone Insulin Acts on Sugar Uptake in Muscles. (DAPAMAAST)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03338855
Recruitment Status : Recruiting
First Posted : November 9, 2017
Last Update Posted : August 7, 2018
Information provided by (Responsible Party):

Brief Summary:
The purpose of this study is to investigate the effects of 5 weeks treatment with dapagliflozin in type 2 diabetes patients on how the hormone insulin acts on sugar uptake in muscles.

Condition or disease Intervention/treatment Phase
Diabetes Mellitus, Type 2 Skeletal Muscle Insulin Sensitivity Drug: Dapagliflozin Phase 4

Detailed Description:
To investigate if dapagliflozin improves skeletal muscle insulin sensitivity expressed as corrected glucose disposal rate (cGDR) in comparison with placebo after 5-week double blind treatment. Insulin sensitivity will be determined using a 2-step euglycemic hyperinsulinemic clamp (EHC) procedure.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: DAPAMAAST: A Double-blind, Randomized, Phase IV, Mechanistic, Placebo-controlled, Cross-over, Single-center Study to Evaluate the Effects of 5 Weeks Dapagliflozin Treatment on Insulin Sensitivity in Skeletal Muscle in Type 2 Diabetes Mellitus Patients.
Actual Study Start Date : March 5, 2018
Estimated Primary Completion Date : July 23, 2019
Estimated Study Completion Date : July 23, 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Allergy

Arm Intervention/treatment
Active Comparator: Dapagliflozin

Patients will receive dapagliflozin 10 mg in tablet for a maximum of 40 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 40 days.

Drug: Dapagliflozin

The study consist of 5 weeks treatment period 1, 6-8 weeks wash-out period and 5 weeks treatment period 2.

The patient may be administered dapagliflozin 10 mg during Period 1 or Period 2.

Placebo Comparator: Placebo matching to dapagliflozin

Patients will receive matching placebo in tablet for a maximum of 40 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 40 days

Drug: Dapagliflozin

The study consist of 5 weeks treatment period 1, 6-8 weeks wash-out period and 5 weeks treatment period 2.

The patient may be administered dapagliflozin 10 mg during Period 1 or Period 2.

Primary Outcome Measures :
  1. Change in skeletal muscle insulin sensitivity measured as corrected GDR using a 2-step euglycemic hyperinsulinemic clamp (EHC) procedure [ Time Frame: from Screening to week 5 ]
    Comparison of dapagliflozin versus placebo after 5 weeks treatment in skeletal muscle insulin sensitivity measured as corrected GDR using a 2-step EHC procedure.

Other Outcome Measures:
  1. Change of Endogenous Glucose Production (EGP) [ Time Frame: 5 hours 30 minutes ]
    Measured during EHC by infusion of 6,6-D2-glucose

  2. Change in metabolic flexibility, as determined by the respiratory exchange ration (RER) from fasted state to insulin stimulated state during EHC [ Time Frame: 5 hours 30 minutes ]
    Measured by indirect calorimetry in association with EHC

  3. Change in RER and energy expenditure as well as plasma metabolites such as betahydroxybutyrate and glucose before and after meals [ Time Frame: 36 hours ]
    Assessed in metabolic chambers and by taking blood samples

  4. Change in maximal capacity to form acetylcarnitine following exercise and muscle CRAT activity [ Time Frame: 30 minutes ]
    Assessed by 1H-MRS and from muscle biopsy

  5. Change in in vivo mitochondrial function [ Time Frame: 5 min during rest, 5 min during knee- extension exercise and 5 min after exercise ]
    Measured as 1H-MRS PCr recovery rate

  6. Change in ex vivo mitochondrial function in permeabilized muscle fibers [ Time Frame: 60 minutes ]
    Assessed in permeabilised muscle fibers from muscle biopsy using high resolution spirometry

  7. Change in body composition and skeletal muscle and liver fat content [ Time Frame: 1 hour 30 minutes ]
    Measured by DEXA and 1H-MRS

  8. Change of blood biomarkers [ Time Frame: 10 weeks ]
    Measured in blood

  9. Change expression of mRNA and/or proteins involved in metabolic regulation in muscle tissue. [ Time Frame: 10 weeks ]
    Assessed on material obtained from muscle fibers biopsy using high resolution spirometry

  10. Safety and tolerability of Dapagliflozin [ Time Frame: up to 23 weeks ]
    DAE/SAEs assessed, including laboratory values and clinical significant findings.

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Critieria:

  1. Patients are able to provide signed and dated written informed consent prior to any study specific procedures.
  2. Women are post-menopausal (defined as at least 1 year post cessation of menses) and aged ≥ 45 and ≤ 70 years. Males are aged ≥ 40 years and ≤ 70 years. Patients should have suitable veins for cannulation or repeated venipuncture.
  3. Patients are diagnosed with T2DM for at least the last 6 months.
  4. Patients are on no other anti-diabetic drug treatment, or on stable metformin treatment for at least the last 3 months: maximum 3000 mg metformin daily dose.
  5. HbA1c levels ≥6.0% (=42 mmol/mol) and ≤9.0% (75 mmol/mol).
  6. Have a body mass index (BMI) ≤ 35 kg/m2.

Exclusion Criteria:

  1. Involvement in the planning and conduct of the study (applies to both AstraZeneca staff and staff at third party vendor or at the investigational sites).
  2. Previous enrolment in the present study or participation in another clinical study with an investigational product during the last 3 months or as judged by the Investigator.
  3. History of or presence of any clinically significant disease or disorder including a recent (< 3 months) cardiovascular event which, in the opinion of the Investigator, may either put the patient at risk because of participation in the study or influence the results or the patient's ability to participate in the study.
  4. Clinical diagnosis of Type 1 diabetes, maturity onset diabetes of the young, secondary diabetes or diabetes insipidus.
  5. Unstable/rapidly progressing renal disease or estimated Glomerular Filtration Rate < 60 mL/min (Cockcroft-Gault formula).
  6. Clinically significant out of range values of serum levels of either alanine aminotransferase (ALT), aspartate aminotransferase (AST) or alkaline phosphatase (ALP) in the Investigator's opinion.
  7. Contraindications to dapagliflozin according to the local label.
  8. Use of antidiabetic drugs other than metformin within 3 months prior to screening.
  9. Weight gain or loss > 5 kg in the last 3 months, ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents.
  10. History of drug abuse or alcohol abuse in the past 12 months.
  11. Any clinically significant abnormalities in clinical chemistry, hematology or urinalysis or other condition the Investigator believes would interfere with the patient's ability to provide informed consent, comply with study instructions, or which might confound the interpretation of the study results or put the patient at undue risk.
  12. Plasma donation within one month of screening or any blood donation/blood loss > 500 mL within 3 months prior to screening or during the study.
  13. Anemia defined as Hemoglobin (Hb) < 115 g/L (7.1 mM) in women and < 120 g/L (7.5 mM) in men.
  14. Use of anti-coagulant treatment such as heparin, warfarin, platelet inhibitors, thrombin and factor X inhibitors.
  15. Use of medication such as oral glucocorticoids, anti-estrogens or other medications that are known to markedly influence insulin sensitivity.
  16. Use of loop diuretics.
  17. Regular smoking and other regular nicotine use.
  18. Any contra-indication to magnetic resonance imaging scanning. These contra-indications include patients with following devices:

    • Central nervous system aneurysm clip
    • Implanted neural stimulator
    • Implanted cardiac pacemaker of defibrillator
    • Cochlear implant
    • Metal containing corpora aliena in the eye or brain.
  19. Patients, 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03338855

Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479

Research Site Recruiting
Maastricht, Netherlands, 6229 HX
Sponsors and Collaborators

Responsible Party: AstraZeneca Identifier: NCT03338855     History of Changes
Other Study ID Numbers: D1690C00047
2016-003991-27 ( EudraCT Number )
First Posted: November 9, 2017    Key Record Dates
Last Update Posted: August 7, 2018
Last Verified: August 2018

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AstraZeneca:
T2DM, insulin resistance, skeletal muscle, mitochondrial function, Phase 4 trial, dapagliflozin

Additional relevant MeSH terms:
Insulin Resistance
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Immune System Diseases
Hypoglycemic Agents
Physiological Effects of Drugs