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The Effect of a SGLT2 Inhibitor on Glucose Flux, Lipolysis and Exercise in Type 2 Diabetes (SINGLED)

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ClinicalTrials.gov Identifier: NCT04219124
Recruitment Status : Recruiting
First Posted : January 6, 2020
Last Update Posted : January 30, 2020
Sponsor:
Collaborators:
Royal Surrey County Hospital NHS Foundation Trust
AstraZeneca
Information provided by (Responsible Party):
University of Leicester

Brief Summary:
The study is a randomised double blind placebo control cross over trial with 4 weeks washout period. The expected duration of participant participation is 103 days. the study aims to investigate the effect of dapagliflozin, a SGLT2 inhibitor, on glucose flux, lipolysis and exercise in patients with type 2 diabetes.

Condition or disease Intervention/treatment Phase
Type 2 Diabetes Drug: IMP oral tablet Drug: Placebo oral tablet Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Intervention Model Description: The study is a randomised double blind placebo control cross over trial. with 4-weeks washout period.
Masking: Double (Participant, Investigator)
Masking Description: Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, and film coated tablet
Primary Purpose: Other
Official Title: The Effect of a SGLT2 Inhibitor on Glucose Flux, Lipolysis and Exercise in Type 2 Diabetes
Actual Study Start Date : September 20, 2018
Estimated Primary Completion Date : April 20, 2020
Estimated Study Completion Date : April 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Dapagliflozin
Investigational product: Dapagliflozin 10 mg Dosage form and strength: Green, plain, diamond shaped, film coated 10 mg tablet with frequency of 1 tablet per day for 4 weeks
Drug: IMP oral tablet
Dapagliflozin 10 MG
Other Name: Farexiga, gliflozin class, SGLT2 inhibitor

Placebo Comparator: Placebo
Investigational product: Matching placebo for Dapagliflozin 10 mg. Dosage form and strength: Green, plain, diamond shaped, and film coated tablet with frequency of 1 tablet per day for 4 weeks
Drug: Placebo oral tablet
Matching placebo tablets
Other Name: Matching placebo tablet for dapagliflozin 10 MG




Primary Outcome Measures :
  1. Plasma concentration of 3-hydroxybutyrate [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, concentration of 3-hydroxybutyrate in plasma at baseline and during the visit (hourly for 8hr) will be measured by an enzymatic assay using PENTRA clinical chemistry analyser. The mean concentration of 3-hydroxybutyrate between 420-480 mins and the AUC of 3-hydroxybutyrate concentration time curve between 0-240 mins and 0-480 mins where the IMP was given at 0 mins in visits 4 and 6 will be calculated.The response will be compared following 4 weeks treatment with dapagliflozin versus placebo.


Secondary Outcome Measures :
  1. Response to exercise testing: Plasma non-esterified fatty acid (NEFA) concentrations [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, plasma NEFA concentrations will be measured by an enzymatic assay using a clinical chemistry analyser (PENTRA). Plasma NEFA concentration measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and will be compared following 4-weeks dapagliflozin versus placebo treatment.

  2. Response to exercise testing: Plasma 3-hydroxybutyrate (BOHB) concentration [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, plasma BOHB concentrations will be measured by an enzymatic assay using a clinical chemistry analyser (PENTRA). Plasma BOHB concentration measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and will be compared following 4-weeks dapagliflozin versus placebo treatment.

  3. Response to exercise testing: Atrial natriuretic peptide, noradrenaline and adrenaline [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, plasma ANP, noradrenaline and adrenaline measured by ELISA assays. Atrial natriuretic peptide, noradrenaline and adrenaline concentrations will be measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) will be compared following 4-weeks dapagliflozin versus placebo treatment.

  4. Response to exercise testing: Glucose concentration, insulin and growth hormone [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, plasma glucose concentration measured by an enzymatic assay on PENTRA, a clinical chemistry analyser and insulin and GH concentrations measured by respective radioimmune assays (RIA). Plasma glucose, insulin and growth hormone concentrations will be measured at 0 minutes and at the end of each level of activity and AUC (0-60 minutes) and AUC (0-60 minutes)will be compared following 4-weeks dapagliflozin versus placebo treatment.

  5. Response to exercise testing:ECG abnormality [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, ECG taken at rest and during exercise will be compared following 4-weeks dapagliflozin versus placebo

  6. Response to exercise testing: BP, HR and Rate Pressure Product (RPP=HR*SBP) [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, blood pressure (BP) and heart rate taken at rest and during exercise. BP, HR and Rate Pressure Product (RPP=HR*SBP) will be measured at 0 minutes and at the end of each level of activity will be compared following 4-weeks dapagliflozin versus placebo

  7. Response to exercise testing: Carbohydrate and fat oxidation [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, volumes of inhaled and expired air measured by a Cardio2 Med Graphics breath analyser, (VO2 and VCO2) taken at rest and at the end of each level of activity will allow calculation of carbohydrate and fat oxidation using established mathematical formula. These will be compared following 4-weeks dapagliflozin versus placebo

  8. Response to exercise testing: whole blood capillary lactate concentration [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 3 and visit 5, whole blood capillary lactate concentration measured by single use test strips (lactate Pro) containing an enzyme coated electrode using a lactate analyser (Lactate Pro) in response to exercise at the end of each exercise activity level will be analysed following 4 weeks treatment with dapagliflozin versus Placebo.

  9. Endogenous glucose production and glucose metabolic clearance rate [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies approximately within 2 years ]
    At visit 4 and visit 6, plasma glucose enrichment will be measured at basal and in in the last 30 minutes of 2H2-glucose infusion (450-480 min). Enrichment of 2H2glucose in plasma glucose will be measured using gas chromatography mass spectroscopy. Glucose production rate and MCR will be calculated from glucose enrichment data using standard isotope dilution equations. Glucose uptake will be determined by subtracting the rate of glucose excretion from the rate of glucose disappearance. Glucose concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480 minutes)

  10. Glycerol production rate [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, plasma glycerol enrichment will be measured at basal and in in the last 30 minutes of 2H5-glycerol infusion (450-480 min). Glycerol production rate and MCR will be calculated from glycerol enrichment data using standard isotope dilution equations.

  11. Palmitate enrichment in plasma NEFA and TAG pools [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, following Folch extraction of the lipid moiety from plasma enrichment of 13C palmitate in NEFA and TAG pool will be measured by GCMS. The isotopic data for [13C] palmitate will be used to calculate the tracer concentration of [13C] palmitate in NEFA and TAG pool. • TAG concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480) and mean of last three points 420, 450 and 480 minutes. • The tracer concentration of [13C] palmitate in NEFA and TAG pool, will be measured as (AUC 0-240) minutes and AUC (0-480 minutes) and mean of last three points 420, 450 and 480 minutes.

  12. [13C] 3-hydroxybutyrate enrichment relative to [13C] palmitate enrichment [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, perchloric acid treated plasma from the studies will be used to extract BOHB and the enrichment of 13C BOHB will be measured by GCMS. The isotopic data for 3-hydroxybutyrate will be used to calculate the relative partitioning of systemic plasma NEFA into [13C] 3-hydroxybutyrate as the ratio of [13C] 3-hydroxybutyrate to [13C] palmitate (in NEFA and TAG pool) in the plasma, where [13C] is expressed in micromol/L. The ratio of [13C] 3-hydroxybutyrate to [13C] palmitate (in TAG pool) in the plasma will be calculated, where [13C] is expressed in micromol/l measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480 minutes) and mean of last three points 420, 450 and 480 minutes.

  13. Glucagon, insulin and cortisol concentrations [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, the concentration of Glucagon, insulin and cortisol will be measured by RIA. Ratio of glucagon to insulin concentration will be measured as AUC (0-240 minutes), AUC (0-360 minutes), AUC (0-480) and mean of last three points 420, 450 and 480 minutes. The data will be compared following 4-weeks dapagliflozin versus placebo treatment.

  14. Cardiac output via Transthoracic Echocardiogram [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, the cardiac output responses investigated using Echocardiogram will be compared following 4-weeks dapagliflozin versus placebo treatment.

  15. Pulse wave velocity [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, aortic pulse wave velocity (m/s) will be measured by Vicorder between a cuff placed on the leg and around the neck. The data will be compared following 4-weeks dapagliflozin versus placebo treatment.

  16. Plasma acylcarnitines measured by targeted metabolomics [ Time Frame: The main analysis will be conducted once all participants have completed the metabolic studies within 2 years ]
    At visit 4 and visit 6, targeted metabolomics will be used to measure 188 species from the metabolome including 40 species of acyl carnitines at 480 minutes. The data will be compared following 4-weeks dapagliflozin versus placebo treatment.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • • Able in the opinion of the investigator, and willing to give informed consent obtained before any study-related activities.

    • Diagnosis of type 2 diabetes greater than 12 months.
    • Single, dual or triple therapy glucose lowering agents comprising of sulphonylureas, biguanides and DDP-IV.
    • No previous exposure to SGLT2 inhibitors.
    • BMI of less than 40.
    • HbA1c of greater or equal to 6.5% and less than 9% within 1 month of screening.
    • Able to comply with the study and the study procedures.
    • Patients who are or who have previously been involved in research are eligible provided a participant has not received an investigational drug within one month of entry into the study.

Exclusion Criteria:

  • • Participants over 75.

    • Participants under 18.
    • Participants who cannot adequately understand verbal and / or written explanations given in English.
    • Clinical suspicion of Hypoglycaemic unawareness.
    • LADA -latent autoimmune diabetes in adults due to differing nature of the illness/Type 1.
    • Confirmed excessive and compulsive drinking of alcohol i.e. alcohol abuse as determined from GP medical notes by the Fast Alcohol Screening Test (FAST) or history of previous alcohol abuse.
    • Has a history of chronic pancreatitis.
    • Restricted food intake - Determined by history.
    • Diagnosis of osteoporosis confirmed by DEXA scan.
    • Participants on insulin, insulin analogs or GLP-1 in the preceding 6 months.
    • Proliferative retinopathy that has required acute treatment within last three months.
    • Moderate to severe renal impairment (creatinine clearance [CrCl] < 60 ml/min or estimated glomerular filtration rate [eGFR] < 60 ml/min/1.73 m2.
    • History of unstable or rapidly progressing renal disease.
    • Severe hepatic insufficiency / and or significant abnormal liver function defines as aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and / or alanine aminotransferase (ALT) > 3ULN.
    • Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody.
    • Congestive heart failure defined as New York Heart Association (NYHA) class III and IV, unstable or acute congestive heart failure.
    • Uncontrolled cardiac arrhythmias.
    • Uncontrolled hypertension. (BP greater than 160/90).
    • Mental incapacity.
    • Pregnancy or breast feeding women.
    • Those of child-bearing potential not taking adequate contraception precautions. Adequate protection is defined as barrier protection, oral contraceptive pill or intrauterine device.
    • Volume depleted patients, patients at risk of volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics should have careful monitoring of their volume status.
    • History of unstable angina.
    • Acute Coronary Syndrome (ACS) within 2 months prior to enrolmen.t
    • Hospitalisation for unstable angina or acute myocardial infarction within 2 months prior to enrolment.
    • Acute Stroke or TIA within two months prior to enrolment.
    • Less than two months post coronary artery revascularisation.
    • History of diabetic ketoacidosis (DKA) requiring medical intervention (e.g. emergency room visit and/or hospitalisation) within 1 month prior to the screening visit.
    • Known or suspected allergy to study products.
    • Known Lactose-intolerant.
    • Have severe and enduring mental health problems.
    • Are not primarily responsible for their own care

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 ClinicalTrials.gov identifier (NCT number): NCT04219124


Contacts
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Contact: Fariba Shojaee-Moradie, PhD +447962215473 f.shojaee-moradie@surrey.ac.uk
Contact: Roselle Herring, MD PhD +441483464049 roselle.herring@nhs.net

Locations
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United Kingdom
CEDAR, Royal Surrey County Hospital Recruiting
Guildford, Surrey, United Kingdom, GU2 7XX
Contact: Roselle Herring, MD PhD    +441483464049    roselle.herring@nhs.net   
Contact: Fariba Shojaee-Moradie, PhD    +447962215473    f.shojaee-moradie@surrey.ac.uk   
Sub-Investigator: Mary Stevenage, MD         
Sub-Investigator: David Russell-Jones, MD PhD         
Sub-Investigator: Fariba Shojaee-Moradie, PhD         
Sub-Investigator: Barbara Fielding, PhD         
Sub-Investigator: Margot Umpleby, PhD         
Sponsors and Collaborators
University of Leicester
Royal Surrey County Hospital NHS Foundation Trust
AstraZeneca
Investigators
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Principal Investigator: Roselle Herring, MD PhD CEDAR, Royal Surrey County Hospital
Study Chair: Mellanie Davis, MD PhD University of Leicester
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Responsible Party: University of Leicester
ClinicalTrials.gov Identifier: NCT04219124    
Other Study ID Numbers: 0585
First Posted: January 6, 2020    Key Record Dates
Last Update Posted: January 30, 2020
Last Verified: January 2020

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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
Additional relevant MeSH terms:
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Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
2-(3-(4-ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyltetrahydro-2H-pyran-3,4,5-triol
Sodium-Glucose Transporter 2 Inhibitors
Molecular Mechanisms of Pharmacological Action
Hypoglycemic Agents
Physiological Effects of Drugs