Evaluate Ketogenic StressNCT02962492
An Investigation Into the Effect of Dapagliflozin on Ketogenesis in Type 1 Diabetes
A study testing Exenatide/Exenatide extended release and Dapagliflozin in people with Evaluate Ketogenic Stress, run by University at Buffalo at 1 site in United States.
Trial summary
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… Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Evaluate Ketogenic Stress
- What is being tested?
- Exenatide/Exenatide extended release and Dapagliflozin
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 70 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Nov 2016to 24 Oct 2021
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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.
Show all 35Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United States1 site
Diabetes and Endocrinology Research Center of WNY
Williamsville, New York, 14221
About this study
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.
Read the 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.
- Conditions
- Evaluate Ketogenic Stress
- Being tested
- Exenatide/Exenatide extended release, Dapagliflozin, Placebo
- Keywords
- Dapagliflozin, Ketogenesis, Type 1 Diabetes, DKA, ketones, exenatide/Bydureon
- Medical subject headings
- Diabetes Mellitus, Type 1, Ketosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Exenatide/Exenatide extended releaseDrug
Also called Bydureon
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
DapagliflozinDrug
Also called Farxiga
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
PlaceboDrug
Also called Placebo for both active drugs
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
| Study group | Role | What they receive |
|---|---|---|
| Dapagliflozin Arm: | Active comparator | dapagliflozin 10mg (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection) Receives: Drug: Dapagliflozin |
| Exenatide extended release Arm: | Active comparator | subcutaneous injection of Exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin placebo Receives: Drug: Exenatide/Exenatide extended release |
| Placebo Arm: | Placebo comparator | dapagliflozin placebo (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection) Receives: Drug: Placebo |
| Exenatide extended release & dapagliflozin Arm: | Active comparator | Exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin 10mg Receives: Drug: Exenatide/Exenatide extended release; Drug: Dapagliflozin |
What is being measured
The primary outcome is the main question the study is designed to answer.
Change in Beta-hydroxybutyrate Levels in Blood
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.
Measured: 12 weeks
Secondary outcomes (4)
Change in HbA1c Following Treatment
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.
Measured: 12 weeks
Change in Urinary Beta-hydroxybutyrate (BHB) After 12 Weeks of Treatment
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.
Measured: 12 weeks
Change in Plasma Glucagon
change in basal plasma glucagon after 12 weeks of dapagliflozin and Bydureon or combination of both treatments compared to baseline
Measured: 12 weeks
Change in Total Insulin Dose
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.
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Nov 2016 (estimated)
- Study start1 Nov 2016
- Primary completion1 Feb 2021
- Study completion24 Oct 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Evaluate Ketogenic StressStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Investigator
- Enrolment
- 70 participants (actual)
Sponsor and investigators
- Lead sponsor
- University at Buffalo
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Principal investigator, Paresh Dandona, University at Buffalo
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02962492
- Sponsor's protocol ID
- 1973
- Status last verified
- Feb 2024
- First submitted
- 9 Nov 2016
- Last updated
- 29 Feb 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Feb 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Investigation Into the Effect of Dapagliflozin on Ketogenesis in Type 1 Diabetes
- ClinicalTrials.gov ID
- NCT02962492
- Acronym / sponsor ID
- 1973
- Conditions
- Evaluate Ketogenic Stress
- Keywords
- Dapagliflozin, Ketogenesis, Type 1 Diabetes, DKA, ketones, exenatide/Bydureon
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 70 participants (actual)
- Lead sponsor
- University at BuffaloUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 1 Nov 2016 (actual)
- Primary completion
- 1 Feb 2021 (actual)
- Study completion
- 24 Oct 2021 (actual)
- First posted
- 11 Nov 2016 (estimated)
- Results
- Posted 29 Feb 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, care provider, investigator)
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Dapagliflozin Arm: | Active comparator | Drug: Dapagliflozindapagliflozin 10mg (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection) |
| Exenatide extended release Arm: | Active comparator | Drug: Exenatide/Exenatide extended releasesubcutaneous injection of Exenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin placebo |
| Placebo Arm: | Placebo comparator | Drug: Placebodapagliflozin placebo (oral tablet) and exenatide (5µg acutely)/Exenatide extended release (long term) placebo (subcutaneous injection) |
| Exenatide extended release & dapagliflozin Arm: | Active comparator | Drug: Exenatide/Exenatide extended release, Drug: DapagliflozinExenatide (5µg acutely)/Exenatide extended release (long term) and dapagliflozin 10mg |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- 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
Key exclusion criteria (35 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Exenatide/Exenatide extended releaseAlso: BydureonEighty (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 | Drug | Exenatide extended release & dapagliflozin Arm:, Exenatide extended release Arm: |
| DapagliflozinAlso: FarxigaEighty (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 | Drug | Dapagliflozin Arm:, Exenatide extended release & dapagliflozin Arm: |
| PlaceboAlso: Placebo for both active drugsEighty (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 | Drug | Placebo Arm: |
Primary outcome
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.
4 secondary outcomes
Change in HbA1c Following Treatment
Time frame: 12 weeks
Change in Urinary Beta-hydroxybutyrate (BHB) After 12 Weeks of Treatment
Time frame: 12 weeks
Change in Plasma Glucagon
Time frame: 12 weeks
Change in Total Insulin Dose
Time frame: 12 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Feb 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Exenatide/Exenatide extended release and Dapagliflozin in people with Evaluate Ketogenic Stress, run by University at Buffalo at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 35 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 29 Feb 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Beta-hydroxybutyrate Levels in Blood (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Feb 2024.