To assess the albuminuria lowering effects of dapagliflozin in subjects with and without diabetes or hypertension and persistent elevated albuminuria.
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Nephropathies
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change in albuminuria from baseline
Secondary outcome
Changes from baseline in:
• Systolic / diastolic blood pressure
• Body weight
• Hba1c
• eGFR
• Number of patients with >=30%, 40%, 50% reduction in UACR from baseline at
week 24
Background summary
During the last three decades, elevated albuminuria has been shown to be
relatively common in the general population (5-9%) and has been independently
associated with poor cardiovascular and renal prognosis.
Drugs proven to be renal and cardiovascular protective, such as ACE inhibitors
and angiotensin receptor blockers (ARBs), reduce albuminuria. Clinical practice
guidelines recommend ACE inhibitors and ARBs to optimize blood pressure control
and decrease albuminuria in patients with hypertension and diabetes. Although
ACE inhibitors and ARBs reduce albuminuria by approximately 30%, albuminuria is
not optimally controlled in all individuals and high albuminuria persists in a
significant proportion of individuals. In addition, among individuals with
elevated albuminuria but without diabetes or hypertension (isolated
albuminuria), there are no guidelines-recommended therapies available to reduce
albuminuria, despite the fact that individuals with isolated albuminuria are at
increased risk for progressive loss of renal or cardiovascular function. To
further optimize cardiovascular and renal prognosis, additional treatments that
reduce albuminuria are desirable for patients with isolated albuminuria and for
patients with diabetes or hypertension and persistent albuminuria despite
treatment with ACEi or ARB.
Sodium Glucose co Transporter 2 (SGLT2) inhibitors lower blood pressure, body
weight and albuminuria. Importantly, these agents also reduce cardiovascular
and renal outcome risks in large cardiovascular outcome studies in patients
with type 2 diabetes. In addition, the DAPA-CKD study recently reported that
dapagliflozin also reduced the risk of renal failure and heart failure, as well
as mortality in patients with chronic kidney disease with and without type 2
diabetes. Whether the effect of SGTL2i extends to a broad group of individuals
with and without type 2 diabetes or hypertension in earlier stages of renal
disease than recruited in the DAPA-CKD trial is unknown. This is clinically
important to note as early intervention in the course of CKD has been shown to
be more effective in delaying the time to dialysis compared to intervention in
advanced stages of the disease (Schievink et al. DOM 2016).
Study objective
To assess the albuminuria lowering effects of dapagliflozin in subjects with
and without diabetes or hypertension and persistent elevated albuminuria.
Study design
The TIMOTHY study consists of a screening period, double blind treatment period
and a follow-up period. Potential eligible participants will be recruited via
general practitioners or through a general population screening program for
increased albuminuria and risk factors for progressive chronic kidney disease
and cardiovascular disease.
Subjects with type 2 diabetes or hypertension have to be on a stable dose (no
changes in dose or type of drug) of ACEis or ARBs for at least 6 weeks prior to
the screening visit to be eligible to proceed to the randomization visit. These
subjects will maintain their stable doses of commercially available ACEis or
ARBs. ACEi or ARBs are not required for subjects without type 2 diabetes or
hypertension per clinical practice guidelines.
The randomization visit will occur 2 week after the subject*s screening visit.
Participants will be assigned in a 1:1 ratio to double blind treatment with
dapagliflozin 10 mg/d or matched placebo. At the randomization visit, three
consecutive first morning void urine samples will be collected and blood
samples taken for clinical chemistry measurements.
In patient follow-up visits take place after 2 weeks, 8 weeks, 16 weeks and 24
weeks. At each visit participants will be asked to collect 2 first morning void
urine samples for assessment of UACR. Vital signs (i.e. blood pressure and body
weight) and adverse events will be recorded at each visit and a blood sample
will be taken for clinical chemistry assessment. Blood and urine will be stored
for future biomarker studies.
Study medication will be discontinued at week 24 and patients will proceed in a
4 weeks wash-out period to assess off drug effects. Participants are asked to
collect three consecutive first morning void urine samples after 4 weeks and
visit the out-patient clinic where blood samples will be taken for clinical
chemistry measurements.
Intervention
Dapagliflozine 10mg/day for a duration of 24 weeks is the intervention
Study burden and risks
Side effects may occur as a result of the study medication. An allergic
reaction may occur as a result of the study medication. Subjects may experience
minor pain, local irritation, bleeding or bruising at the puncture site as a
result of venipuncture. There is a small chance of feeling light-headed and/or
fainting. In rare cases, the puncture site may also become infected or nerves
may be damaged. Patients are expected to follow the investigators' instructions
for 28 weeks as necessary for the study.
Hanzeplein 1
Groningen 9700 RB
NL
Hanzeplein 1
Groningen 9700 RB
NL
Listed location countries
Age
Inclusion criteria
• Age 45 to 80 years
• Persistent urinary albumin:creatinine ratio (UACR) >= 2.5 mg/mmol (~25 mg/g)
• Willing to sign informed consent
Exclusion criteria
• Diagnosis of type 1 diabetes mellitus
• eGFR < 25 ml/min/1.73m2
• UACR > 3500 mg/g
• Concurrent treatment with SGLT2 inhibitor
• Receiving immunosuppressive therapy within 6 months prior to enrollment
• History of diabetic ketoacidosis
• Active malignancy aside from treated squamous cell or basal cell carcinoma
of the skin.
• Initiation or changes in the dose of interventions in the
renin-angiotensin-aldosterone-system, diuretics, GLP-1 receptor agonists within
6 weeks of screening will not be allowed.
• 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 or difficulty in voiding at screening
• History of severe hypersensitivity or contraindications to dapagliflozin
• Subjects who, in the assessment of the investigator, may be at risk for
dehydration or volume depletion that may affect the interpretation of efficacy
or safety data
• Participation in any clinical intervention study within 3 months 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
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 | EUCTR2021-004073-31-NL |
| CCMO | NL78752.042.21 |