Type 2 Diabetes MellitusPhase 4ROCKIESNCT04027530
Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study.
A Phase 4 study testing Ertugliflozin 15 mg in people with Type 2 Diabetes Mellitus and Diabetic Kidney Disease, run by Amsterdam UMC, location VUmc at 1 site in Netherlands.
Trial summary
Current study will render insight in to the role of renal hypoxia in the diabetic kidney and is able to associate its finding with measurements of renal perfusion and glomerular filtration rate. Read more about this study
- Who is it for?
- Ages 18 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Type 2 Diabetes Mellitus, Diabetic Kidney Disease, Diabetic Nephropathy
- What is being tested?
- Ertugliflozin 15 mg
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 40 participants
- Where
- 1 siteNetherlands
- Study dates
- 10 Dec 2020to 9 Jan 2023
- Phase
- Phase 4
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 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Who may be able to join
- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Caucasian*; female or male aged ≥18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*.
- Type 2 diabetes mellitus since at least 3 years with HbA1c ≥ 6.5% (≥57mmol/mol) and <10% (<94mmol/mol)
- An appropriate stable dose of metformin and/or sulfonylurea as glucose-lowering therapy for the last 12 weeks
- Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization.
- eGFR 60-90 ml/min/1.73m²
- BMI 25-35 kg/m² * In order to increase homogeneity
Who cannot join
- Involvement in the planning and/or conduction of another study
- Participation in another clinical study with an investigational product during the last 3 months
- Diagnosis of type 1 diabetes mellitus
- CKD defined as eGFR<60 ml/min/1.73m² or albuminuria (defined as an UACR > 2.5 mg/mol).
- Cardiovascular disease event in the last 6 months prior to enrollment as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia.
- Current/chronic use of the following medication: insulin, thiazolidinediones, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2 inhibitors, oral glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors.
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- Current urinary tract infection or active nephritis
- History of ketoacidosis
- History of allergy/hypersensitivity to any of the test agents.
- Group 2: Age-matched and eGFR-matched non-diabetic controls Inclusion criteria
- Provision of signed and dated, written informed consent prior to any study specific procedures.
- Caucasian*; female or male aged ≥18 years and <80 years. Females must be post-menopausal (defined as no menses >1 year and follicle stimulating hormone (FSH) >31 U/L)*.
- Normal glucose tolerance at screening as confirmed by OGTT
- Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior to randomization in case of hypertension.
- BMI 25-35 kg/m2
- eGFR 60-90ml/min * In order to increase homogeneity
- Involvement in the planning and/or conduction of another study
- Participation in another clinical study with an investigational product during the last 3 months
- CKD defined as eGFR<60ml/min or macro-albuminuria or proteinuria
- Cardiovascular disease event in the last 6 months prior to enrollment, as assessed by the investigator, including: myocardial infarction, cardiac surgery or revascularization (CABG/PTCA), unstable angina, heart failure, transient ischemic attack (TIA) or significant cerebrovascular disease, unstable or previously undiagnosed arrhythmia.
- Use of medication that may interfere with study endpoints non-steroidal anti-inflammatory drugs (NSAIDs), immune suppressants, chemotherapeutics, antipsychotics, tricyclic antidepressants (TCAs), diuretics, and monoamine oxidase inhibitors.
- Current urinary tract infection and active nephritis
- Any other condition that prevents participation as judged by investigator.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 4, Randomized, Placebo-controlled, Cross-over Trial to Assess the Effect of 4-week Ertugliflozin (SGLT-2 Inhibitor) Therapy on Renal Oxygenation by BOLD-MRI and Renal Oxygen Consumption by PET Using ¹¹C-acetate in T2DM Without Kidney Disease and Healthy Controls.
Current study will render insight in to the role of renal hypoxia in the diabetic kidney and is able to associate its finding with measurements of renal perfusion and glomerular filtration rate. Moreover, this research will focus on the effects of sodium-glucose cotransporter 2 inhibition on renal tissue oxygenation and oxygen consumption as well as a change in intrarenal hemodynamics and perfusion, and a shift of fuel metabolites. Elucidation the mechanisms underlying the effects of SGLT2 inhibition will advance our knowledge and contribute to their optimal clinical utilization in the treatment of chronic kidney disease in diabetes and possibly beyond.
Read the detailed description
Sodium-glucose cotransporter-2 inhibitors (SGLT2-i) are a relatively new class of drugs in the treatment of diabetes and improve glycemic control by blocking SGLT-2 in the proximal tubule, the main transporter of coupled sodium-glucose reabsorption Three large cardiovascular outcome trials (EMPA-REG, CANVAS, DECLARE- TIMI 58) showed SGLT-2 inhibition to have a renoprotective effect, including on renal outcomes. Moreover, the recently publicized CREDENCE trial concluded early after the planned interim analyses showed a striking renoprotective effect of SGLT-2 inhibition in patients with T2DM and CKD. The mechanisms underlying their beneficial effects remain to be elucidated, as the small SGLT-2 induced reduction in glucose level (0.5% HbA1c), bodyweight (about 3%), systolic blood pressure (about 4 mmHg), or uric acid (about 6%) are insufficient to fully account for the effect.
The pathological mechanisms underlying DKD involve complex interactions between metabolic and haemodynamic factors which are not fully understood. However, accumulating evidence of foremost animal studies indicates that a chronic state of renal tissue hypoxia is the final common pathway in the development and progression of diabetic kidney disease. Therefore several hypothesis have been proposed on the alleviation of chronic tissue hypoxia following SGLT-2 inhibition: (1) A decrease in workload by a decrease in GFR. (2) A shift in renal fuel energetics by increasing ketone body oxidation, which renders high ATP/oxygen consumption ratio's compared to glucose or free fatty acids. (3) An improvement of cardiac function and systemic hemodynamics to lead to an increase in renal perfusion, and (4) an increase in erythropoietin (EPO) levels to stimulate oxygen delivery.
Current study will examine the above hypothesis by researching renal oxygenation by BOLD-MRI, oxygen consumption by PET-CT, and hemodynamic kinetics by the Iohexol clearance method/contrast-enhance ultrasound/arterial spin labeling. Blood sampling will allow for the measurement of EPO and ketone bodies, as well as a resting energy expenditure will elucidate a shift in use of energy substrate metabolism. The research will be performed in T2DM without overt kidney disease (n=20) before and after a 4 week treatment with SGLT-2 inhibition (ertugliflozin), and will be compared the obtained results from healthy controls (n=20).
- Conditions
- Type 2 Diabetes Mellitus, Diabetic Kidney Disease, Diabetic Nephropathy, Renal Hypoxia, Renoprotection, SGLT2 Inhibitor
- Being tested
- Ertugliflozin 15 mg
- Medical subject headings
- Diabetes Mellitus, Type 2, Diabetic Nephropathies
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Ertugliflozin 15 mgDrug
Also called Steglatro
Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks
| Study group | Role | What they receive |
|---|---|---|
| Ertugliflozin 15mg once daily | Experimental | Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks. Receives: Drug: Ertugliflozin 15 mg |
| Placebo | Placebo comparator | Once daily treatment with a placebo pill for 4 consecutive weeks. Receives: Drug: Ertugliflozin 15 mg |
What is being measured
The primary outcome is the main question the study is designed to answer.
Renal oxygenation measured by BOLD-MRI (R2*)
Renal (separated as cortical and medullar) oxygenation measured by BOLD-MRI (R2*)
Measured: After 4 week treatment with ertugliflozin 15mg QD versus placebo
Secondary outcomes (21)
Renal oxygen consumption by PET/CT-scan using 11C-Acetate
Renal oxygen consumption will be measured by PET/CT-scan using 11C-Acetate and compartment model parameter k2
Measured: After 4 week treatment with active drug intervention versus placebo
Renal hemodynamics
GFR and ERPF
Measured: After 4 week treatment with active drug intervention versus placebo
Renal efficiency
Measured as sodium reabsorption divided by oxygen consumption
Measured: After 4 week treatment with active drug intervention versus placebo
Cortical blood flow
measured by contrast-enhanced ultrasound
Measured: After 4 week treatment with active drug intervention versus placebo
Renal arterial blood flow
measured by arterial spin labelling
Measured: After 4 week treatment with active drug intervention versus placebo
Acute 24-hour sodium and glucose excretion
24-hour sodium and glucose excretion after 2 days
- Urine osmolality
- Urinary pH
Measured: After 2 days of treatment with active drug intervention versus placebo
Chronic 24-hour sodium and glucose excretion
24-hour sodium and glucose excretion after 4 weeks
Measured: After 4 week treatment with active drug intervention versus placebo
Renal tubular function: Urinary pH
Urinary pH
Measured: After 4 week treatment with active drug intervention versus placebo
Renal tubular function: Urine Osmolality
Urine osmolality
Measured: After 4 week treatment with active drug intervention versus placebo
Renal tubular function: sodium transport
Iohexol corrected sodium excretion
Measured: After 4 week treatment with active drug intervention versus placebo
Renal damage markers
Renal damage markers will include: urinary albumin excretion in 24-hour urine samples and other markers depending on relevant (emerging) metabolic and humoral biomarkers of renal damage, conditional to available budget.
Measured: After 4 week treatment with active drug intervention versus placebo
Changes in plasma energy substrate: glucose
Changes in plasma energy substrate: glucose
Measured: After 4 week treatment with active drug intervention versus placebo
Changes in plasma energy substrate: free fatty acids
Changes in plasma energy substrate: free fatty acids
Measured: After 4 week treatment with active drug intervention versus placebo
Changes in plasma energy substrate: ketone bodies
Changes in plasma energy substrate: ketone bodies
Measured: After 4 week treatment with active drug intervention versus placebo
Changes in plasma energy substrate:triglycerides
Changes in plasma energy substrate:triglycerides
Measured: After 4 week treatment with active drug intervention versus placebo
Energy expenditure
By resting energy expenditure
Measured: After 4 week treatment with active drug intervention versus placebo
Changes in erythropoietin (EPO) levels
Changes in erythropoietin (EPO) levels
Measured: After 4 week treatment with active drug intervention versus placebo
Insulin sensitivity
OGIS and Matsuda Index during an oral glucose tolerance test (OGTT)
Measured: After 4 week treatment with active drug intervention versus placebo
Beta-cell function
Beta-cell function will be derived from HOMA-B modelling during an oral glucose tolerance test (OGTT).
Measured: After 4 week treatment with active drug intervention versus placebo
Peripheral insulin extraction
Arterial-venous difference before and following an OGTT
Measured: After 4 week treatment with active drug intervention versus placebo
Total insulin extraction
Arterial-venous difference before and following an OGTT
Measured: After 4 week treatment with active drug intervention versus placebo
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Jul 2019
- Study start10 Dec 2020
- Primary completion9 Jan 2023
- Study completion9 Jan 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Type 2 Diabetes MellitusStudies 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 4
- Primary purpose
- Prevention
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 40 participants (actual)
Sponsor and investigators
- Lead sponsor
- Amsterdam UMC, location VUmc
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, D van Raalte, Amsterdam UMC, location VUmc
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04027530
- Sponsor's protocol ID
- DC2019 ROCKIES 1
- Acronym
- ROCKIES
- Status last verified
- Apr 2023
- First submitted
- 9 Jul 2019
- Last updated
- 1 May 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No