Despite multifactorial treatment approaches residual risk for the development and progression of DKD remains high and novel therapies to halt renal burden in T2DM are urgently needed. SGLT-2 inhibitors are a relatively recent additions to the…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Nephropathies
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To investigate the effect of 4-week treatment with SGLT-2 inhibitor
ertugliflozin 15mg QD on renal (separated as cortical and medullar) oxygenation
measured by BOLD-MRI (R2*)
Secondary outcome
The most important secondary efficacy parameters include the effect of
ertugliflozin on:
• Renal oxygen consumption as determined by positron emission tomography (PET)
¹¹C-acetate (compartment model parameter k2).
• Renal hemodynamic (GFR en ERPF); measured by the gold standard iohexol and
PAH-clearance method
• Calculated filtration fraction (FF) and local filtration fraction as measured
by dynamic contrast enhanced MRI (DCE-MRI)
• Renal efficiency measured as sodium reabsorption (TNa) divided by oxygen
consumption
• Cortical blood flow measured by contrast-enhanced ultrasound (CEUS)
• Renal arterial blood flow measured by arterial spin labelling (ASL) and
DCE-MRI
• 24-hour sodium and glucose excretion after 2 days (acute response) and 4
weeks (chronic response)
• Renal tubular function
o Iohexol-corrected fractional sodium excretion
o Urine osmolality
o Urinary pH
• Renal damage markers, measured as:
o Urinary albumin excretion in 24-hour urine samples
• Change in inflammatory profile assessed by flow cytometry and fluorescence
activated cell sorting (FACS)
• Changes in erythropoietin (EPO) levels
• Changes in plasma substrates including glucose, free fatty acids, ketone
bodies, and triglycerides
• Insulin sensitivity (OGIS, Matsuda Index) and beta-cell function (as derived
from HOMA-B) during an oral glucose tolerance test (OGTT).
• Peripheral insulin extraction and total arterial insulin extraction
(extraction x arterial flow)
• Fasting energy expenditure by resting energy expenditure (REE)
Background summary
Diabetic Kidney Disease (DKD) is a major global health problem affecting ~35%
of the patients with type 2 diabetes (T2DM) and it is the leading cause of
chronic kidney disease (CKD) (Tonneijck et al., 2017; Wanner et al., 2016).
Despite the advancements in treatment of DKD by controlling renal risk factors
(e.g. hyperglycemia, hypertension, smoking) and widespread use of
renin-angiotensin-aldosteron-system (RAAS) inhibitors, DKD still causes
significant morbidity and mortality. This includes both the development of
end-stage kidney disease (ESKD) as well as cardiovascular disease, which is
strongly associated with DKD. Finding new, safe, and effective medication to
halt DKD has proven to be challenging, which is partly due to the fact that
the mechanisms underlying DKD are complex and not fully understood.
Former research indicates that chronic hypoxia can be the common pathway of
chronic kidney disease. In patients with Diabetes the kidneys are highly
susceptible to a disturbance in oxygenation due to several factors. Oxygen
delivery can be compromised due to hyperglycemia associated microvascular
damage. A decrease in tissue oxygenation induces deterioration of affected
nephrons, which leads to hyperfiltration of the remnant nephrons and therefore
oxygen demand. Additionally, workload is increased by upregulation of SGLT-2
and accompanied sodium reabsorption. This vicious cycle of gradual aggravation
of oxygen delivery and demand mismatch can results in progressive
tubulointerstitial fibrosis and loss of kidney function. Earlier studies, which
is foremost comprised of animal research, has shown an increase in
sodiumreabsorption accopanied by a state of renal cell hypoxia.
Study objective
Despite multifactorial treatment approaches residual risk for the development
and progression of DKD remains high and novel therapies to halt renal burden in
T2DM are urgently needed. SGLT-2 inhibitors are a relatively recent additions
to the treatment armamentarium of T2DM, and are associated with renoprotective
effects. Current study aims to elucidate whether targeting sodium-glucose
cotransporter 2 improves renal tissue oxygenation and oxygen consumption. There
are four main theories as to why it is proposed SGLT-2 inhibitors exert this
positive effect:
-Oxygen demand might be decreased by:
(1) A decrease in GFR
(2) A a shift of fuel metabolites towards ketones, which produce ATP very
oxygen-efficient in a state of relative starvation such as Diabetes.
-Oxygen supply might be increased by:
(3) a change in systemic and intrarenal hemodynamics and perfusion.
(4) an increase in EPO
Current research is designed to primarly study renal tissue oxygenation through
BOLD-MRI and oxygen consumption by PET-CT in patients with diabetes mellitus
and SGLT-2 intervention. The data will be compared with healthy participants
matched for age and renal function. Secundary objectives are a change in fuel
metabolites (such as ketone bodies), renal hemodynamics, cardiovascular
function, EPO-levels, markers of damage and inflammation, and
insulineresistance.
Study design
A phase 4, monocenter, prospective, randomized, placebo-controlled,
double-blind, cross-over mechanistic intervention trial to assess effect of
4-week Ertugliflozin (SGLT-2 inhibitor) therapy on renal oxygenation as
determined by BOLD-MRI
Intervention
Cross-over conditions:
(1) 4 weeks of ertugliflozin 15mg
(2) 4 weeks of matchted placebo
Study burden and risks
Over the last 10 years, we have gained ample experience with similarly
demanding mechanistic drug intervention studies in T2DM patients on renal
hemodynamics (SAFEGUARD 2012.391, RENALIS 2013.459, ELIXIRS 2014.275, RED
2015.421). Based on the positive feedback from our participants, the low
drop-out rate (max 5%) and the large proportion of participants that returns to
participate in yet another (similarly demanding) study, we are confident that
the burden on participants is perceived as not being too high. Indeed, we have
built in different ways to alleviate the burden for participants, including
clear, repeated communication, frequent contacting, intensified (diabetes)
care, 24-hour availability of research staff, study and travel reimbursement,
enabling participants to receive the newest study medication (that for most of
them would not be reimbursed in daily practice) and offering follow-up care in
our out-patient clinic.
We are aware of the fact that in the current study participants will undergo
multiple tests that demand a considerable time investment from their end. For
the participants in the studygroup the total duration of the visits is
estimated at 40hours. For the participants in the control group the total
duration of the visits is estimated at 12hours. These renal / cardiovascular
test-days may be perceived as demanding that amongst others involves
the placement of an arterial line. This procedure will be done by an
experiences anesthesiologist to minimize the burden and risk of bleeding.
Furthermore, during the cardiac autonomous nervous system function tests
participants may experience transient dizziness or lightheadedness. As
mentioned above, all possible measures will be taken to minimize the discomfort
for the participants during the tests (e.g. comfortable beds are available
which allow a semi-recumbent position).
The studymedication is considered to be safe and has been approved (FDA, EMA)
for bloodglucose lowering treatment in type 2 Diabetes.Most common side effects
are genital- or urinary tract infection, pruritus, pollakisuria, and nycturia.
The used test agents (i.e. Iohexol, PAH, 11C-acetate, Dotarem, and Sonovue
microbubbles) are all considered to be safe in absence of allergy for any of
the products. In case of an anafylactic reaction, appropriate actions will be
undertaken.
Possible benefits for the participants include the positive effects of
SGLT2-inhibitors on blood glucose levels. blood pressure, and weight.
Boelelaan 1117
Amsterdam 1081HV
NL
Boelelaan 1117
Amsterdam 1081HV
NL
Listed location countries
Age
Inclusion criteria
Group 1:Participants with diabetes
* 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 at least 1-year post cessation of menses 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 kg/m²
* In order to increase homogeneity.
Group 2:age-matched and eGFR matched non-diabetic controls
* 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 at least 1-year post cessation of menses and
follicle stimulating hormone (FSH) >31 U/L)*.
* Normal glucose tolerance screening as confirmed by OGTT
* Maximum tolerated antihypertensive dose of an ARB for at least 6 weeks prior
to randomization.
* eGFR 60-90 ml/min/1.73m²
* BMI >=25 kg/m²
* In order to increase homogeneity.
Exclusion criteria
Group 1: participants with diabetes
* 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 macro-albuminuria (defined as UACR
>30mg/mmol)
* Cardiovascular disease event in the last 6 months prior to enrollment, as
assessed by the investigator: myocardial infarction, cardiac surgery or
revascularization (CABG/PTCA), unstable angina, heart failure, transient
ischemic attack (TIA) or significant cerebrovascular disease, unstable or
previously undiagnosed arrhythmnia.
* Current/chronic use of the following medication: 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 and active nephritis
* History of ketoacidosis
* History of allergy/hypersensitivity to any of the testagents
* Contra-indication for MRI
* Any other condition that prevents participation as judged by the investigator
Group 2: age-matched and eGFR matched non-diabetic controls
* 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<60 ml/min/1.73m² or macro-albuminuria (defined as UACR
>30mg/mmol)
* Cardiovascular disease event in the last 6 months prior to enrollment, as
assessed by the investigator: myocardial infarction, cardiac surgery or
revascularization (CABG/PTCA), unstable angina, heart failure, transient
ischemic attack (TIA) or significant cerebrovascular disease, unstable or
previously undiagnosed arrhythmnia.
* Current/chronic use of the following medication: oral glucocorticoids,
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
* History of allergy/hypersensitivity to any of the testagents.
* Contra-indication for MRI
* Any other condition that prevents participation as judged by the investigator
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-000730-19-NL |
| ClinicalTrials.gov | NCT04027530 |
| CCMO | NL69150.029.19 |