Primary: * To assess the change baseline in 24-hr proteinuria with dapagliflozin for six weeks relative to placebo treatment in patients with non-diabetic kidney disease and proteinuria > 500 mg/day on stable ACEi or ARB treatment. Secondary: *…
ID
Source
Brief title
Condition
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Main study parameters/endpoints: Change in 24-hr proteinuria
Secondary outcome
Secondary study parameters/endpoints (if applicable)
* Glomerular Filtration Rate measured with iohexol
* Systolic/diastolic blood pressure
* Neurohormones/biomarkers
o Hormones of the RAAS (renin, aldosterone in plasma and urine)
o Natriuretic Peptides
o Urinary adenosine
o Co-peptin
o Immunoglobulin G
Other study parameters (if applicable)
* Number of hypoglycaemic episodes
* Serious Adverse Events
* Drug related adverse events (causality to investigational product assessed by
research physician).
Background summary
Despite optimal treatment with renin-angiotensin-aldosterone-system (RAAS)
inhibitors, many patients with non-diabetic kidney disease show progressive
kidney function loss, which is associated with high residual albuminuria. Novel
treatment strategies are therefore required to further decrease albuminuria and
to slow kidney function decline.
Dapagliflozin is a sodium-glucose transport (SGLT2) inhibitor and inhibits the
reabsorption of glucose and sodium in the proximal tubule. The increased
natriuresis following dapagliflozin administration normalizes tubuloglomerular
feedback resulting in a reduction in intra-glomerular hypertension, which is in
turn manifested by acute reductions in glomerular filtration rate and
albuminuria. Since many etiologies of non-diabetic nephropathy are
characterized by intraglomerular hypertension, we hypothesize that
dapagliflozin acutely decreases GFR and albuminuria in patients without
diabetes at risk of progressive kidney function loss via a glucose independent
hemodynamic mechanism.
Study objective
Primary:
* To assess the change baseline in 24-hr proteinuria with dapagliflozin for six
weeks relative to placebo treatment in patients with non-diabetic kidney
disease and proteinuria > 500 mg/day on stable ACEi or ARB treatment.
Secondary:
* To assess the effect of dapagliflozin 10 mg/d compared to placebo on
Glomerular Filtration Rate (GFR) using iohexol clearance.
* To assess the effect of dapagliflozin 10 mg/d compared to placebo on
systolic/diastolic blood pressure
* To assess the effect of dapagliflozin 10 mg/d compared to placebo on body
weight
* To assess the effect of dapagliflozin 10 mg/d on selected
neurohormones/biomarkers:
o Hormones of the RAAS (plasma and urine)
o Natriuretic peptides
o Urinary adenosine
o Co-peptin
o Immunoglobulin G (plasma and urine)
* To characterize the safety of dapagliflozin vs. placebo by determining the
number of hypoglycemic episodes between groups, and serious adverse events.
Study design
Randomized placebo controlled double blind cross-over trial
Eligible participants will be randomly assigned to one of the two treatment
orders: placebo-dapagliflozin or dapagliflozin-placebo. Each treatment period
lasts 6 weeks followed by a 6 week wash-out period to avoid cross-over effects.
Intervention
Dapagliflozin 10 mg/day, once a day in the morning OR matched placebo once a
day in the morning.
Study burden and risks
Patients visit the outpatient clinic on a more regular base than standard
patient care - i.e. at study inclusion and at start and end of each treatment
period (8 hospital visits in a total study duration of 25 or up to 29 weeks) -
for clinical assessment. A fasting blood sample is collected with venipuncture.
Non-radioactive iohexol GFR measurements are performed at start and end of each
treatment period as well as at the end of the wash-out period. 24hr urine will
be collected one the day prior to the hospital visit. No other invasive
measurements will be executed. Patients receive restitution of all travel
costs. Patients receive no priority in treatment of other diseases in the
clinic during this study. There are no direct benefits for the patients to be
included and participation is on a voluntary basis.
There are no direct benefits for the patients to be included. Participation in
the study is on a free-will base. Patients will receive restitution of all
costs of transportation. Patients will not receive priority for treatment of
other diseases in the clinic during this study. Participation in the proposed
study is accompanied with only minor risks. The blood samples will be drawn by
means of venipuncture that will be performed during the visit to the outpatient
clinic. All further performed measurements are non-invasive and therefore only
minor risks are associated with participation.
At each of the visits, approximately 20 ml will be taken for routine blood
tests (approximately 20 ml/ 9 visits = 180 ml). At each of the 5 visits to
assess kidney function, approximately 24 ml will be taken (total 96 ml), plus
another 20 ml at each kidney function visit for measurement of hormones and
other factors associated with kidney disease (approximately 20 ml for each of
the 4 kidney visits = 80 ml). At the end of the treatment period, 9 blood
samples of 1ml will be taken for dapagliflozin PK analysis. A total of
approximately 374 ml of blood will be collected over a 6 month (24 week) period
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
- Age *18 and *75 years
- Urinary protein excretion > 500 mg/g and * 3500 mg/g in a 24-hr urine collection
- eGFR * 25 mL/min/1.73m2
- On a stable dose of an ACEi or ARB for at least 4 weeks prior to randomization
- Willing to sign informed consent
- Women of Child-Bearing Potential (WOCBP) must be using an acceptable method of contraception to avoid pregnancy throughout the study and for up to 4 weeks after the last dose of study drug in such a manner that the risk of pregnancy is minimized.
- WOCBP must have a negative serum or urine pregnancy test result (minimum sensitivity 25 IU/L or equivalent units of HCG) within 0 to 72 hours before the first dose of study drug.
- Women must not be breast-feeding
Exclusion criteria
- Diagnosis of type 1 or type 2 diabetes mellitus
- Urinary protein excretion > 3500 mg/day
- Peripheral Vascular Disease
- Autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease, lupus nephritis, or ANCA-associated vasculitis
- Indication for immunosuppressants as per the treating physician*s judgment.
- Receiving cytotoxic therapy, immunosuppressive therapy, or other immunotherapy for primary or secondary renal disease within 6 months prior to enrolment.
- Active malignancy aside from treated squamous cell or basal cell carcinoma of the skin.
- Any medication, surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of medications including, but not limited to any of the following:
o History of active inflammatory bowel disease within the last six months;
o Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection;
o Gastro-intestinal ulcers and/or gastrointestinal or rectal bleeding within last six months;
o Pancreatic injury or pancreatitis within the last six months;
o Evidence of hepatic disease as determined by any one of the following: ALT or AST values exceeding 3x ULN at the screening visit, a history of hepatic encephalopathy, a history of esophageal varices, or a history of portocaval shunt;
o Evidence of urinary obstruction of difficulty in voiding at screening
- History of severe hypersensitivity or contraindications to dapagliflozin
- History of hypersensitivity or contraindications to iodinated contrast media
- Subject who may be at risk for dehydration or volume depletion that may affect the interpretation of efficacy or safety data
- Participation in any clinical investigation within 3 months prior to initial dosing.
- Donation or loss of 400 ml or more of blood within 8 weeks prior to initial dosing.
- History of drug or alcohol abuse within the 12 months prior to dosing, or evidence of such abuse as indicated by the laboratory assays conducted during the screening.
- History of noncompliance to medical regimens or unwillingness to comply with the study protocol.
- Any surgical or medical condition, which in the opinion of the investigator, may place the patient at higher risk from his/her participation in the study, or is likely to prevent the patient from complying with the requirements of the study or completing the study.
- Pregnancy or breastfeeding
- WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and up to 4 weeks after the last dose of study drug.
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 | EUCTR2017-001090-16-NL |
| ClinicalTrials.gov | NCT03190694 |
| CCMO | NL61865.042.17 |