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出境医 / 临床实验 / Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study. (ROCKIES)
Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study. (ROCKIES)
Study Description
Brief 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. 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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Type 2 Diabetes Mellitus Diabetic Kidney Disease Diabetic Nephropathy Renal Hypoxia Renoprotection SGLT2 Inhibitor Ertugliflozin | Drug: Ertugliflozin 15 mg | Phase 4 |
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).
Study Design
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 40 participants |
| Allocation: | Randomized |
| Intervention Model: | Crossover Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Primary Purpose: | Prevention |
| 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. |
| Actual Study Start Date : | December 10, 2020 |
| Estimated Primary Completion Date : | December 2021 |
| Estimated Study Completion Date : | January 2022 |
Arms and Interventions
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Ertugliflozin 15mg once daily
Once daily treatment with oral ertugliflozin (steglatro) 15mg for 4 consecutive weeks.
|
Drug: Ertugliflozin 15 mg
Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks
Other Name: Steglatro
|
|
Placebo Comparator: Placebo
Once daily treatment with a placebo pill for 4 consecutive weeks.
|
Drug: Ertugliflozin 15 mg
Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks
Other Name: Steglatro
|
Outcome Measures
Primary Outcome Measures :
- Renal oxygenation measured by BOLD-MRI (R2*) [ Time Frame: After 4 week treatment with ertugliflozin 15mg QD versus placebo ]Renal (separated as cortical and medullar) oxygenation measured by BOLD-MRI (R2*)
Secondary Outcome Measures :
- Renal oxygen consumption by PET/CT-scan using 11C-Acetate [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Renal oxygen consumption will be measured by PET/CT-scan using 11C-Acetate and compartment model parameter k2
- Renal hemodynamics [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]GFR and ERPF
- Renal efficiency [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Measured as sodium reabsorption divided by oxygen consumption
- Cortical blood flow [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]measured by contrast-enhanced ultrasound
- Renal arterial blood flow [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]measured by arterial spin labelling
- Acute 24-hour sodium and glucose excretion [ Time Frame: After 2 days of treatment with active drug intervention versus placebo ]
24-hour sodium and glucose excretion after 2 days
- Urine osmolality
- Urinary pH
- Chronic 24-hour sodium and glucose excretion [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]24-hour sodium and glucose excretion after 4 weeks
- Renal tubular function: Urinary pH [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Urinary pH
- Renal tubular function: Urine Osmolality [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Urine osmolality
- Renal tubular function: sodium transport [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Iohexol corrected sodium excretion
- Renal damage markers [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]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.
- Changes in plasma energy substrate: glucose [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Changes in plasma energy substrate: glucose
- Changes in plasma energy substrate: free fatty acids [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Changes in plasma energy substrate: free fatty acids
- Changes in plasma energy substrate: ketone bodies [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Changes in plasma energy substrate: ketone bodies
- Changes in plasma energy substrate:triglycerides [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Changes in plasma energy substrate:triglycerides
- Energy expenditure [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]By resting energy expenditure
- Changes in erythropoietin (EPO) levels [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Changes in erythropoietin (EPO) levels
- Insulin sensitivity [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]OGIS and Matsuda Index during an oral glucose tolerance test (OGTT)
- Beta-cell function [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Beta-cell function will be derived from HOMA-B modelling during an oral glucose tolerance test (OGTT).
- Peripheral insulin extraction [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Arterial-venous difference before and following an OGTT
- Total insulin extraction [ Time Frame: After 4 week treatment with active drug intervention versus placebo ]Arterial-venous difference before and following an OGTT
Eligibility Criteria
| Ages Eligible for Study: | 18 Years to 80 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Criteria
Group 1: T2DM patients
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)*.
- 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
Exclusion criteria
- 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.
- 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
Exclusion criteria
- 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.
Contacts and Locations
Contacts
| Contact: Anne Hesp, Msc. | +31-20-4444260 | a.c.hesp@amsterdamumc.nl | |
| Contact: Daniel van Raalte, Dr. | +31-20-4440534 | d.vanraalte@amsterdamumc.nl |
Locations
| Netherlands | |
| VU University Medical Center | Recruiting |
| Amsterdam, Netherlands, 1081 HV | |
| Contact: Anne Hesp, Msc. +31-20-444 4260 a.c.hesp@amsterdamumc.nl | |
| Contact: Daniel van Raalte, Dr. +31-20-4440534 d.vanraalte@amsterdamumc.nl | |
Sponsors and Collaborators
VU University Medical Center
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | July 9, 2019 | ||||||||
| First Posted Date ICMJE | July 22, 2019 | ||||||||
| Last Update Posted Date | April 2, 2021 | ||||||||
| Actual Study Start Date ICMJE | December 10, 2020 | ||||||||
| Estimated Primary Completion Date | December 2021 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures ICMJE |
Renal oxygenation measured by BOLD-MRI (R2*) [ Time Frame: After 4 week treatment with ertugliflozin 15mg QD versus placebo ] Renal (separated as cortical and medullar) oxygenation measured by BOLD-MRI (R2*)
|
||||||||
| Original Primary Outcome Measures ICMJE | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures ICMJE |
|
||||||||
| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Original Other Pre-specified Outcome Measures | Not Provided | ||||||||
| Descriptive Information | |||||||||
| Brief Title ICMJE | Renal Oxygenation, Oxygen Consumption and Hemodynamic Kinetics in Type 2 DIabetes: an Ertugliflozin Study. | ||||||||
| Official Title ICMJE | 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. | ||||||||
| Brief 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. 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. | ||||||||
| 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). |
||||||||
| Study Type ICMJE | Interventional | ||||||||
| Study Phase ICMJE | Phase 4 | ||||||||
| Study Design ICMJE | Allocation: Randomized Intervention Model: Crossover Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) Primary Purpose: Prevention |
||||||||
| Condition ICMJE |
|
||||||||
| Intervention ICMJE | Drug: Ertugliflozin 15 mg
Once daily treatment with oral ertugliflozin 15mg for 4 consecutive weeks
Other Name: Steglatro
|
||||||||
| Study Arms ICMJE |
|
||||||||
| Publications * | Not Provided | ||||||||
|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
|||||||||
| Recruitment Information | |||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||
| Estimated Enrollment ICMJE |
40 | ||||||||
| Original Estimated Enrollment ICMJE | Same as current | ||||||||
| Estimated Study Completion Date ICMJE | January 2022 | ||||||||
| Estimated Primary Completion Date | December 2021 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria ICMJE |
Group 1: T2DM patients Inclusion criteria
Exclusion criteria
Group 2: Age-matched and eGFR-matched non-diabetic controls Inclusion criteria
Exclusion criteria
|
||||||||
| Sex/Gender ICMJE |
|
||||||||
| Ages ICMJE | 18 Years to 80 Years (Adult, Older Adult) | ||||||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||||||
| Contacts ICMJE |
|
||||||||
| Listed Location Countries ICMJE | Netherlands | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number ICMJE | NCT04027530 | ||||||||
| Other Study ID Numbers ICMJE | DC2019 ROCKIES 1 | ||||||||
| Has Data Monitoring Committee | No | ||||||||
| U.S. FDA-regulated Product |
|
||||||||
| IPD Sharing Statement ICMJE | Not Provided | ||||||||
| Responsible Party | D van Raalte, VU University Medical Center | ||||||||
| Study Sponsor ICMJE | VU University Medical Center | ||||||||
| Collaborators ICMJE | Not Provided | ||||||||
| Investigators ICMJE | Not Provided | ||||||||
| PRS Account | VU University Medical Center | ||||||||
| Verification Date | March 2021 | ||||||||
|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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