Primary:To investigate change in 24-hr sodium excretion during dapagliflozintreatment between Baseline (average of Days *3 to *1) and averageof Days 2 to 4 within each study group in patients withtype 2 diabetes mellitus (T2DM) with preserved or…
ID
Source
Brief title
Condition
- Glucose metabolism disorders (incl diabetes mellitus)
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Average change in 24-hr sodium excretion from average baseline to average
values at Day 2 to 4 within each study group.
Secondary outcome
see paragraph 'criteria of evaluation of efficacy' in the synopsis of Protocol
V5.0
The secondary endpoints to be evaluated during or following
dapagliflozin treatment within each study group are:
• Average change in 24-hr sodium excretion from average
Baseline values to average end of treatment values (Day 12 to
14); and from average end of treatment values (Day 12 to 14) to
average values during follow-up (Day 15 to 17).
• Average change in 24-hr glucose excretion from average
Baseline values to average values at Day 2 to 4; from average
Baseline values to average end of treatment values (Day 12 to
14); and from average end of treatment values (Day 12 to 14) to
average values during follow-up (Day 15 to 17).
• Change in mean 24-hr systolic blood pressure from Baseline to
Day 4; from Baseline to end of treatment (Day 13); and from end
of treatment (Day 13) to end of follow-up (Day 18).
• Change in plasma volume, from Baseline to Day 4; from Baseline to end of
treatment (Day 14); and from end of treatment (Day 14) to end
of follow-up (Day 18).
• Change in extracellular volume, from Baseline to Day 4;
from Baseline to end of treatment (Day 14); and from end of treatment (Day 14)
to end of follow-up (Day 18).
• Dapagliflozin pharmacokinetics on Day 4 and Day 14.
• Average change in mean 24-hr UACR from average Baseline to
Day 4; from average Baseline values to average end of treatment
values (Day 12 to 14).
Background summary
T2DM is associated with an elevated risk of cardiovascular morbidity and
mortality as
well as renal failure. The cardiovascular benefit of SGLT2 inhibition was
demonstrated
in the EMPA-REG study by showing a lower rate of the primary composite
cardiovascular outcome and of death in the active empagliflozin treatment arm
(Zinman
et al, 2015 [3]). There is also a growing body of evidence indicating that SGLT2
inhibition is nephroprotective. Post-hoc analysis from the dapagliflozin phase
II and
phase III programme have shown in T2DM patients with moderate renal impairment
on
top of renin-angiotensin-aldosterone system (RAAS) blockade reduction around
40% in
albuminuria and stabilization of eGFR decline for up to 1 year (Sjöström et al,
2015 [4])
and 2 years (Fioretto et al, 2015 [5]). After an initial drop in eGFR, kidney
function was
stable over time while a progressive decrease in eGFR was seen in the placebo
group. In
another trial with the SGLT2 inhibitor empagliflozin, a 38%, 44% and 55% risk
reduction was found in new onset of macroalbuminuria, doubling of serum
creatinine and
initiation of dialysis treatment respectively. Moreover, the overall risk
reduction in
cardiovascular death was 22% in patients with chronic kidney disease (CKD) 3
(eGFR 30 to 59 mL/min) (Wanner et al, 2016 [6]).
The nephroprotective effect is thought to be achieved by mechanisms independent
of
blood glucose reduction (Rajasekeran et al, 2016 [7]), such as by reduced
intra-glomerular pressure through an enhanced tubuloglomerular feedback
mechanism
(De Nicola, et al 2014 [8] and Thomas, 2014 [9]), reduced glucose and sodium
transport
over the proximal tubule cells (Pollock, et al 1991 [10] and Komala, et al 2013
[11]),increased natriuresis (Heerspink et al, 2013 [12]) and reduced systemic
blood pressure
(Baker et al, 2015 [13]).
Since the sodium/volume related effects are believed to be independent of HbA1c
reduction this trial will include both patients with and without T2DM.
See protocol V5.0
Study objective
Primary:
To investigate change in 24-hr sodium excretion during dapagliflozin
treatment between Baseline (average of Days *3 to *1) and average
of Days 2 to 4 within each study group in patients with
type 2 diabetes mellitus (T2DM) with preserved or impaired renal
function and in non-diabetics with impaired renal function.
Secondary:
The secondary objectives to be evaluated within each study group
during or following dapagliflozin treatment are:
• To evaluate the change in 24-hr sodium excretion during
dapagliflozin treatment from Baseline to end of treatment, and
during follow-up.
• To evaluate the change in 24-hr glucose excretion.
• To evaluate the change in mean 24-hr systolic blood pressure.
• To evaluate the change in plasma volume.
• To evaluate the change in extracellular volume.
• To evaluate pharmacokinetics of dapagliflozin.
• To evaluate the change in 24-hr urine albumin: creatinine ratio (UACR)
Exploratory:
The exploratory objectives to be evaluated within each study group,
during or following dapagliflozin treatment are:
• To assess change in day (0600 - 2200):night (2200 - 0600) ratio
of systolic blood pressure.
•To evaluate change in the following:
- Hormones of the renin-angiotensin-aldosterone system
(RAAS) (plasma/urine renin, urine aldosterone, plasma
Angiotensin II [AngII], urine angiotensinogen
[uAngiotensinogen]).
- N-terminal pro b-type natriuretic peptide (NT-proBNP) and
B-type natriuretic peptide (BNP).
- Urinary adenosine.
- Plasma Co-peptin.
• To evaluate change in 24-hr urinary volume, uric acid, creatinine,
cortisol, isoprostanes, and electrolytes.
• To evaluate changes in serum/plasma biomarkers of metabolism,
renal and cardiovascular function, electrolytes, uric acid, and
haematocrit.
• To evaluate changes in body weight.
• To evaluate changes in calculated intracellular red blood cell
concentrations of electrolytes.
• To evaluate change in intracellular volume.
• To evaluate change in total body water.
• To assess the changes in extracellular volume and intracellular volume over a
4-hr time course after 2 weeks of dapagliflozin treatment in relation to
pharmacokinetics measurements.
• To collect samples for analysis of urinary exosomes obtained from samples
from 24-hr urine collections for changes in specific solute transporters
present in the exosomes as well as to test for changes in their phosphorylation
state.
• To collect data on body composition analysis for later exploratory analysis.
• To collect serum/plasma samples for later exploratory analysis of
metabolic, cardiovascular, and renal biomarkers.
• To collect 24-hr urine samples for later exploratory analysis of
metabolic, cardiovascular, and renal biomarkers.
• To collect samples for analysis of urinary exosomes obtained
from samples from 24-hr urine collections for changes in specific
solute transporters present in the exosomes as well as to test for
changes in their phosphorylation state.
Safety:
• To evaluate the safety and tolerability of dapagliflozin in each of
the target patient populations
Study design
This is an open label, mechanistic, three-arm study to evaluate the
natriuretic effect of 2 weeks dapagliflozin treatment in T2DM
patients with either preserved or impaired renal function and in
non-diabetic patients with impaired renal function. The study
population will comprise 3 groups of patients as described in study
population below. The maximum duration of the study will be
62 days including the allowed window periods for the study (±1 day
for Day -6 and for Visit 7 at Day 13). The study will allow for an up to
6-week Screening and Run-in Period. The Run-in Period should
always last 6 days (Day -6 to Day -1) for patients not on insulin
(Group 2 and 3). ; however, for patients on insulin (Group 1) the
Run-in Period may be longer (Day -20 to Day *1). Patients on
insulin may require a longer Run-in Period in order to be able to
adjust their insulin requirements according to the caloric content of
the food boxes, if needed. However, it is not mandatory for the
patient on insulin to use the entire extended Run-in Period. Based on
the Investigator*s judgement, the Run-in Period may be shortened
once each patient (on insulin) has had sufficient time to adapt to the
food boxes, and it is determined that the patient*s insulin requirement
has stabilised sufficiently to continue in the study.The study will
then include a 2-week Treatment Period (Day 1 to Day 14) and a 5-
day Follow-up Period: Day 15 to Day 19. Patients will consume food
from standardised food boxes (with sodium content 150 mmol)
starting on Day *6 (patients not on insulin) or Day *20 at the earliest
(patients on insulin) of the study until Day 18 (inclusive). Eligibility
will be confirmed on Day *1 based on 24-hr urinary assessments
performed on Days *3 and *2 (stable urinary sodium excretion on 2
successive 24-hr urinary sodium excretion measurements ie, <20%
difference between Days *3 and *2). Eligible patients will receive
dapagliflozin 10 mg tablets once daily for 14±1 days starting on Day
1. This will be followed by a Follow-up Period of 5 days.
Intervention
Patients will receive dapagliflozin 10 mg tablets per day for a total period of
13-15 days. This dose is the recommended dose for monotherapy and for add-on
combination therapy with other glucose-lowering medicinal products including
insulin to improve glycaemic control in T2DM.
Study burden and risks
Disadvantages of participation in the study may be the possible side effects of
dapagliflozin (as described above), the procedures of blood plasma volume
measurement involve drawing of blood using catheters inserted in the forearm of
the patient. You may experience minor discomfort from these procedures and
occasionally some bruising or irritation of the veins used for blood sampling.
Also, allergic reactions due to the injections are known to occur in some
people. These effects normally clear up completely in a few days.
Forskargatan 18
Södertälje SE-15185
SE
Forskargatan 18
Södertälje SE-15185
SE
Listed location countries
Age
Inclusion criteria
Based on Protocol amendment 5.0, 1. In the diabetic arms - a diagnosis of T2DM
with glycosylated haemoglobin (HbA1c) >=6.5% (>=48 mmol/mol)
and <10% (<86 mmol/mol); and eGFR (CKD-EPI) between >=25 and <=50 mL/min/1.73m2
or between >90 and <=130 mL/min/1.73m2 for patients aged 59 or younger, between
>85 and <=130 mL/min/1.73m2 for patients aged 60 to 69, and between >75 and <=130
mL/min/1.73m2 for patients aged 70 or older at the Screening Visit (Visit 1).,
2. In the non-diabetic arms, HbA1c <6.5% (<48 mmol/mol) and an eGFR (CKD-EPI)
between >=25 and <=50 mL/min/1.73m2 at the Screening Visit (Visit 1)., 3. Patient
specific optimal antihypertensive dose of an angiotensin receptor blocker (ARB)
(as per Investigator*s judgement) for at least 6 weeks prior to Visit 4 (Day
1)., 4. In the diabetic arm (Group 2) an appropriate stable dose of metformin,
or sulphonylurea, or metformin+sulphonylurea as anti-diabetic therapy for the
last 12 weeks prior to (Visit 4, Day 1)., 5. In the diabetic arm with impaired
renal function (Group 1) a stable insulin dosing (intermediate, long*acting,
premixed insulin, basal bolus insulin) for the last 12 weeks prior to Visit 4
(Day 1) as judged by the Investigator. Metformin or sulphonylurea, or
metformin+sulphonylurea together with insulin would be accepted, but is not
mandatory. If used, stable dose of metformin or sulphonylurea, or
metformin+sulphonylurea as anti-diabetic therapy for the last 12 weeks prior to
Visit 4 (Day 1) is required., 6. Stable urinary sodium excretion on 2
successive 24-hr urinary sodium excretion measurements (<20% difference between
Days *3 and *2)., For an extensive description of the inclusion criteria, see
Protocol paragraph 4.1
Exclusion criteria
Study-related:
1. Previous enrolment in the present study or participation in another clinical
study with an investigational product during the last 6 months prior to
Screening Visit (Visit 1, Day *28 until day -8).
2. Involvement in the planning and conduct of the study (applies to both
AstraZeneca staff and staff at third party vendor or at the investigational
sites).
3. Hypersensitivity to dapagliflozin, indocyanine green, sodium iodide, or
iodine, or patients who have poorly tolerated indocyanine green in the past.
4. Pacemaker or other implanted electronic devices.
5. Pregnancy.
6. Breastfeeding., General health-related:
7. Known clinically significant disease or disorder; or clinically relevant
abnormal findings in physical examination, clinical chemistry, haematology, and
urinalysis; or unstable or rapidly progressing renal disease; or any other
condition or minor medical complaint, which, in the opinion of the
Investigator, may either put the patient at risk because of participation in
the study, or influence the results, or the patient*s ability to participate in
the study and comply with study procedures, restrictions and requirements.
8. Diagnosis of T1DM.
9. Hyperthyroidism or autonomic thyroid adenomas.
10. Abnormal vital signs, after 10 minutes supine rest, defined as any of the
following (Visit 1):
- Systolic blood pressure above 180 mmHg.
- Diastolic blood pressure above 110 mmHg.
- Pulse <50 bpm or >100 bpm
11. Any of the following cardiovascular/vascular diseases within 3 months prior
to signing the consent at Visit 1, as assessed by the Investigator: myocardial
infarction, cardiac surgery or revascularization (coronary artery bypass graft
[CABG]/ percutaneous transluminal coronary angioplasty [PTCA]), unstable
angina, unstable heart failure, heart failure New York Heart Association Class
IV, transient ischemic attack or significant cerebrovascular disease, unstable
or previously undiagnosed arrhythmia.
12. Patients with severe hepatic impairment (Child-Pugh C).
13. Ongoing weight-loss diet (hypocaloric diet) or use of weight loss agents,
unless the diet or treatment has been stopped at least 3 months before
Screening Visit, ensuring patients having a stable body weight with no verified
body weight variability of >3 kg during the 3 months before Screening Visit.,
Renal failure-related:
14. Symptoms/complaints suggestive of established neurogenic bladder and/or
incomplete bladder emptying.
15. History of bladder cancer.
16. Diagnosis of polycystic kidney disease.
17. History of or current lupus nephritis.
18. Urinary albumin excretion >1000 mg/g per day at the Screening Visit based
on spot urine sample (quantitative assessment)., for further details, see
Protocol v5.0 paragraph 4.2.1
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 | EUCTR2016-002961-79-NL |
| CCMO | NL59193.028.17 |