A study to assess the anti-albuminuric effects and variability in response to dapagliflozin in subjects with type 2 diabetes

Increased albuminuria is a strong risk marker for renal and cardiovascular
disease. The degree of albuminuria reduction in the first months of treatment
with pharmacological or dietary intervention correlates with the degree of
long-term (3 to 4 years) renal or cardiovascular protection. Despite the
various available treatments to decrease urinary albumin excretion, residual
albuminuria persists in many patients. Residual albuminuria predicts renal and
cardiovascular function loss. Novel treatment strategies are therefore required
to further decrease albuminuria. Dapagliflozin is a sodium-glucose transport
inhibitor and inhibits the re-absorption of glucose in the proximale tubule.
This leads to a decrease in fasting plasma glucose and HbA1c. In addition,
dapagliflozin administration causes a decrease in blood pressure and body
weight and increase in hematocrit suggestive of a diuretic effect. Previous
studies have suggested that dapagliflozin may also decrease albuminuria.
However, no study has prospectively investigated (and was designed) to assess
the albuminuria lowering effects of dapagliflozin.
Previous studies have shown a large variability in response to various
anti-albuminuric drugs including ACE-inhibitors, Angiotensin Receptor Blockers,
Direct renin inhibitors, NSAIDs, and endothelin antagonists. Very few studies
have prospectively investigated whether this response variability is a random
phenomenon due to biological or measurement variability or a *true* variability
in drug response. A secondary objective of this study is to address this
question.

Primary Objective:
To assess the change from baseline in 24-hr albuminuria with dapagliflozin for
six weeks relative to placebo treatment in patients with diabetes and
albuminuria > 100 mg/day on stable ACEi or ARB treatment.

Secondary Objective(s):
To assess:
• To assess the within-patient variability in HbA1c, 24-hr blood pressure, body
weight, and albuminuria response to dapagliflozin.
• To assess the between-patient variability in HbA1c, 24-hr blood pressure,
body weight, and albuminuria response to dapagliflozin.
• The variability in HbA1c, blood pressure, body weight, and albuminuria in
response to dapagliflozin during the first and second treatment period.

We conduct a double blind randomized cross-over study in subjects with type 2
diabetes with albuminuria > 100 mg/day. Since each subject is his/her own
control this design requires fewer patients as compared with a parallel study
design. A wash-out period after each treatment period has been included in the
design to avoid cross-over effects.

The study will consist of a screening visit, a run-in phase for those subjects
not on stable ACEi/ARB or glucose lowering medication, 3 consecutive 6-weeks
double blind treatment periods separated by 4-weeks wash-out periods. Subjects
will be assigned to one of the treatment The rationale to include two
treatment periods in each arm consisting of the same treatment is to verify the
consistency in response.

Each treatment period lasts 6 weeks followed by a 6 weeks wash-out period to
avoid cross-over effects. Patients receive dietary counseling provided by a
dietician throughout the study in order to standardize and stabilize dietary
sodium intake.

Dapagliflozin tablets and matching placebo*s are provided by
Bristol-Myers-Squibb. Patients take 10 mg dapagliflozin (once daily) or
matching placebo according to randomised treatment scheme. Study medication is
received at the study site by a designated person, handled and stored safely
and properly, and kept in a secured location. The study medication is stored
according to the instructions specified on the drug labels. Storage conditions
are adequately monitored. Subjects are asked to return all unused study drug
and packaging at the end of the study or at the time of study drug
discontinuation or in every visit to the outpatient clinic. Appropriate
documentation of the subject specific dispensing process is maintained. Unused
drugs are destroyed by the pharmacy department at the end of the study.

Patients will have their study visit in the morning in fasted condition.
Patients will be instructed to take the study medication once daily, in the
morning, except on study days; on those days, the study drug will be taken
after the patient visit.

The efficacy and safety of dapagliflzoine is established in multiple studies in
patients with type 2 diabetes. Hypoglycemia, urinary tract infections are the
most frequently reported side effects. Dapagliflozin does not cause a rise in
body weight unlike sulfonylurea derivatives and insulin. Patients are asked to
visit the outpatient clinical 11 times in 35 weeks. Blood will be drawn and
24-hr urine collection will be performed at 8 visits.

Advantages: we expect that dapagliflozin lowers albuminuria at a group level.