- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02962492
An Investigation Into the Effect of Dapagliflozin on Ketogenesis in Type 1 Diabetes
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The study investigations include evaluation of the acute effects of a single dose of dapagliflozin (10mg), exenatide (5µg), a combination of exenatide and dapagliflozin or placebo under insulinopenic condition and the long term effect under basal conditions before and after 12 weeks treatment with dapagliflozin, Exenatide extended release, a combination of Exenatide extended release and dapagliflozin or placebo on ketogenesis, glucagon and lipolysis.
In the acute effects study, qualified patients will come fasting to the research center. Review of study procedures and vitals will be performed. Insulin infusion (pump) will be stopped and basal blood, urine and adipose tissue biopsy samples will be obtained. Placebos, exenatide (5µg) or dapagliflozin (10mg) (with appropriate placebos) or combination of exenatide and dapagliflozin will be administered, according to a randomized fashion, and blood samples will be collected every 30 min for up to 8 hours after starting the treatment. Urine will be collected every hour up to 8 hours and a second adipose tissue biopsy will be collected at 6 hours after the start of the treatment. Additional blood samples will be collected at 1, 2, 4 and 6 and 8 hour marks for MNC isolation. Plasma and mononuclear cell (MNC) fractions will be prepared from the blood samples. The patient will then come back at the 24 hour mark for a fasting blood and urine collection. The long term study will then commence. Exenatide extended release or dapagliflozin (along with appropriate placebos) or a combination of both drugs will be started and continued for 12 weeks according to original randomization of day 0. In the long term study, dapagliflozin (or the appropriate placebo) will be started at 5mg dose and will be titrated to 10mg/day after 5 days. Fasting blood and 24hr urine samples will be collected at 1, 4 and 8 weeks. At 12 weeks, the 2nd acute effects testing study will be repeated as described above.
Measurements of beta-hydroxybutyrate, acetoacetic acid, glucose, FFA and glucagon, will be measured from all blood samples collected. HSL, GLP-1, glycerol, electrolytes, serum bicarbonate, cortisol and catecholamines will be measured at 0, 60, 120, 240, 360, 480 min and at 24hr following single dose studies at 0 and 12 weeks visits and at baseline on the 1, 4 and 8 weeks visits. Ketone bodies will be measured in all urine samples. All MNC and adipose tissue samples will be tested for HSL and SGLT2 expression.
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Contact
- Name: Husam Ghanim, PhD
- Phone Number: 716-881-8924
- Email: ghanim@buffalo.edu
Study Contact Backup
- Name: Paresh Dandona, MD
- Phone Number: 716-898-1940
- Email: pdandona@kaleidahealth.org
Study Locations
-
-
New York
-
Williamsville, New York, United States, 14221
- Diabetes and Endocrinology Research Center of WNY
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Type 1 Diabetes for at least 1 year on continuous subcutaneous insulin infusion (CSII; also known as insulin pump)
- HbA1c of 7-10% (inclusive)
- Ages 18-65 years (inclusive of ages 18 and 65)
- BMI 20-30 kg/m2
Exclusion Criteria:
- Inability to give informed consent
- Inability or refusal to comply with protocol
- Use of GLP-1 Receptor Agonists in the last 3 months or DPP-IV and SGLT-2 inhibitors therapy in the last 1 month.
- Risk for pancreatitis (e.g., history of gallstones, alcohol abuse, and hypertriglyceridemia)
- History of pancreatitis and or chronic pancreatitis
- Coronary event or procedure (myocardial infarction, unstable angina, coronary artery bypass, surgery or coronary angioplasty) or stroke in the previous 3 months.
- Congestive Heart Failure class III or IV or tachyarrhythmia.
Hepatic disease: Severe hepatic insufficiency and/or significant abnormal liver function defined as:
- Aspartate aminotransferase (AST) >3x upper limit of normal (ULN) and/or alanine aminotransferase (ALT) >3x ULN
- Total bilirubin >2.0 mg/dL (34.2 µmol/L)
- Positive serologic evidence of current infectious liver disease including Hepatitis B viral antibody IGM, Hepatitis B surface antigen and Hepatitis C virus antibody
- Liver function tests more than 3 times the upper limit of normal
- Renal impairment (e.g., serum creatinine levels ≥1.4 mg/dL for women, or eGFR <60 mL/min/1.73 m2) or history of unstable or rapidly progressing renal disease or end stage renal disease.
- History of unexplained microscopic or gross hematuria, or microscopic hematuria at visit 1, confirmed by a follow-up sample at next scheduled visit.
- HIV positive
- History of gastroparesis
- History of medullary thyroid carcinoma or MEN 2 syndrome
- History of recurring UTI
- Uncontrolled thyroid disease (documented normal TSH), Cushing's syndrome, congenital adrenal hyperplasia or hyperprolactinemia.
- Prior history of a malignant disease requiring chemotherapy or patients with a prior history of bladder cancer regardless of treatment
- Alcoholism or drug addiction.
- Hypertriglyceridemia (>400 mg/dl).
- Any other life-threatening, non-cardiac disease
- Uncontrolled hypertension (BP > 160/95 mm of Hg)
- Patients with hypotension or at risk for volume depletion due to co-existing conditions or concomitant medications, such as loop diuretics or recently donated >500ml of blood should have careful monitoring of their volume status
- Pregnant or breastfeeding patients or patient not willing to use two barrier method contraception during study period (unless sterilized or have an IUD)
- Use of hormonal medications, anti-obesity drugs or weight loss medications (prescription or OTC) and medications known to exacerbate glucose tolerance (such as isotretinoin, GnRH agonists, glucocorticoids, anabolic steroids, C-19 progestins) stopped for at least 8 weeks. Use of anti-androgens that act peripherally to reduce hirsutism such as 5-alpha reductase inhibitors (finesteride, spironolactone, flutamide) stopped for at least 4 weeks
- Presence of hypersensitivity to dapagliflozin or other SGLT2 inhibitors (e.g. anaphylaxis, angioedema, exfoliative skin conditions
- Known hypersensitivity or contraindications to use GLP1 receptor agonists (exenatide, liraglutide)
- Known hypersensitivity to heparin/ IV catheter equipment.
- Eating disorders (anorexia, bulimia) or gastrointestinal disorders
- Having a history of bariatric surgery
- Debilitating psychiatric disorder such as psychosis or neurological condition that might confound outcome variables
- Use of an investigational agent or therapeutic regimen within 30 days of study
- Participation in any other concurrent clinical trial
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Basic Science
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Dapagliflozin Arm:
dapagliflozin 10mg (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection)
|
Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks
Other Names:
|
Active Comparator: Exenatide extended release Arm:
subcutaneous injection of Exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin placebo
|
Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks
Other Names:
|
Placebo Comparator: Placebo Arm:
dapagliflozin placebo (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection)
|
Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks
Other Names:
|
Active Comparator: Exenatide extended release & dapagliflozin Arm:
Exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin 10mg
|
Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks
Other Names:
Eighty (80) patients with T1D will be enrolled and randomized into 4 groups(20 each) to receive placebo, or dapagliflozin, or exenatide (5µg acutely)/Exenatide extended release (long term), or exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin treatments acutely and for 12 weeks
Other Names:
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in Beta-hydroxybutyrate Levels in Blood
Time Frame: 12 weeks
|
Beta-hydroxybutyrate (BHB) was measured in blood during the acute stress conditions in all the groups after single dose intervention at baseline (0 Week) and at 12 weeks of treatment.
The magnitude of change at each of these visits was calculated from each visit baseline (0 hr) and the difference between the change at 12 weeks was compared to the change at 0 week and reported as: Change at week 12 - change at week 0.
|
12 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change in HbA1c Following Treatment
Time Frame: 12 weeks
|
Hemoglobin A1c (HbA1c) was measured in basal conditions in all the groups at week 0 and week 12 of treatment.
The change in HbA1c from baseline at 12 weeks is calculated as: HbA1c at week 12 - HbA1c at week 0.
|
12 weeks
|
Change in Urinary Beta-hydroxybutyrate (BHB) After 12 Weeks of Treatment
Time Frame: 12 weeks
|
Beta-hydroxybutyrate (BHB) was measured in urine during the acute stress conditions in all the groups after single dose intervention at baseline (0 Week) and at 12 weeks of treatment.
The magnitude of change at each of these visits was calculated from each visit baseline (0 hr) and the difference between the change at 12 weeks was compared to the change at 0 week and reported as: Change at week 12 - change at week 0.
|
12 weeks
|
Change in Plasma Glucagon
Time Frame: 12 weeks
|
change in basal plasma glucagon after 12 weeks of dapagliflozin and Bydureon or combination of both treatments compared to baseline
|
12 weeks
|
Change in Total Insulin Dose
Time Frame: 12 weeks
|
change in total (basal or long acting and short acting) insulin daily dose calculated as daily units/Kg body weight at 12 weeks from baseline (0 week).
Long acting or basal insulin dose (in units of insulin) plus short acting (meal) insulin doses administered through the day and reported by patients in patients logs or from insulin pumps are added and divided by body weight in Kg.
The reported total insulin dose/Kg represents the average of last 3-7 days before the visit.
|
12 weeks
|
Collaborators and Investigators
Sponsor
Collaborators
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Estimated)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Glucose Metabolism Disorders
- Metabolic Diseases
- Immune System Diseases
- Autoimmune Diseases
- Endocrine System Diseases
- Diabetes Mellitus
- Diabetes Mellitus, Type 1
- Hypoglycemic Agents
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Anti-Obesity Agents
- Incretins
- Sodium-Glucose Transporter 2 Inhibitors
- Dapagliflozin
- Exenatide
Other Study ID Numbers
- 1973
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Evaluate Ketogenic Stress
-
University of BelgradeCompleted
-
University of VirginiaTerminatedExercise | Ketogenic DietUnited States
-
University of AarhusCompleted
-
Texas Woman's UniversityCompound Solutions Inc.CompletedKetogenic DietingUnited States
-
TRC GEN+ managed by Trans Russian co CyKGK Science Inc.CompletedHealthy | Ketogenic DietingCanada
-
University of PadovaUniversity of Palermo; Universidade Federal de GoiasCompleted
-
Universidad MayorSociedad Chilena de PediatríaUnknownEvaluate the Effectiveness of Taxes on Unhealthy | Evaluate the Effectiveness Subsidies for Healthy FoodsChile
-
University of VirginiaTerminatedKidney Injury | Ketogenic DietUnited States
-
AstraZenecaIQVIA RDS (Shanghai) Co., Ltd.CompletedEvaluate PK ProfileChina
-
Beth Israel Deaconess Medical CenterCompletedFasting | Ketogenic Diet | Metabolic RegulationUnited States
Clinical Trials on Dapagliflozin
-
Dong-A ST Co., Ltd.CompletedType2 DiabetesKorea, Republic of
-
AstraZenecaRecruitingLiver CirrhosisSpain, Denmark, Germany, United States, China, Belgium, Netherlands, Switzerland, Austria, Australia
-
AstraZenecaBristol-Myers SquibbCompletedType 2 Diabetes MellitusUnited Kingdom
-
AstraZenecaCompletedType 1 Diabetes MellitusJapan
-
AstraZenecaCompletedType 1 Diabetes MellitusJapan
-
Daewoong Pharmaceutical Co. LTD.Not yet recruitingGlucose Metabolism Disorders | Diabetes Mellitus, Type 2 | Diabetes Mellitus | Endocrine System Diseases | Metabolic Disease
-
AstraZenecaCompletedChronic Kidney DiseaseUnited States
-
Hiddo Lambers HeerspinkAstraZenecaUnknownChronic Kidney Diseases | ProteinuriaCanada, Malaysia, Netherlands
-
Maastricht UniversityAstraZenecaCompletedPrediabetic State | Substrate OxidationNetherlands
-
AstraZenecaCompletedHealthy Subjects in Fasted and Fed StateBrazil