Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT05196347 |
| Other study ID # |
ESR-21-21200 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
Phase 3
|
| First received |
|
| Last updated |
|
| Start date |
March 1, 2022 |
| Est. completion date |
September 30, 2023 |
Study information
| Verified date |
January 2022 |
| Source |
Kaohsiung Medical University |
| Contact |
Chi-Chih Hung, MD |
| Phone |
886-975356110 |
| Email |
chichi[@]kmu.edu.tw |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This is an investigator-led, randomized, open-label, blinded-endpoint, multicenter study that
will include a total of approximately 225 subjects from 3 sites. Subjects with an estimated
glomerular filtration rate (eGFR) of 10 to 30 mL/min/1.73m2 will be included. The goal of
this study is to assess the efficacy and safety of dapagliflozin (Forxiga®, AstraZeneca) in
reducing renal function progression and complications of chronic kidney disease (CKD) in
patients with CKD stage 4 and 5 under the integrated CKD care. Subjects will be allocated to
integrated CKD care program + dapagliflozin or integrated CKD care program alone. The primary
end point is eGFR decline 12-52 weeks after randomization between 2 arms.
Description:
Preamble Estimated glomerular filtration rate (eGFR) eGFR 30 mL/min/1.73m2 is a clinical cut
point, below which advanced chronic kidney disease (CKD) (stage 4 and 5) is associated with a
significantly increased risk of mortality and a 50-fold increased requirement of renal
replacement therapy (RRT). Physicians are suggested to refer patients to nephrologists when
eGFR <30 mL/min/1.73m2 for multidisciplinary care. The pre-ESRD care program of CKD stage
3b-5 patients in Taiwan for modifiable risk factors of CKD progression and for preparation of
RRT has shown to improve clinical outcomes.
"Advanced" CKD was usually viewed as "predialysis" CKD and sometimes used interchangeably,
probably because of limited time of treatment and limited medications in advanced CKD. The
time of treatment in CKD stage 4 in our cohort (median survival of RRT or mortality) was
still up to 4.7 (interquartile range 2.1-8.7) years under the practice of late dialysis
initiation (median eGFR 5 mL/min/1.73m2). However, renin-angiotensin system blockade was the
only effective medication in patients with advanced CKD, implied by albuminuria reduction and
proved for reduction of renal outcome only in some randomized controlled trials (RCTs).
Furthermore, there is no effective medication for patients with normoalbuminuria,
tubulointerstitial nephropathy, hyperkalemia or blood pressure <130/80 mmHg. Thus, the unmet
need in advanced CKD patients is the lack of effective medication.
Recently, two large renal outcome RCTs of sodium-glucose co-transporter 2 inhibitors
(SGLT2is), which has been developed as an oral anti-hyperglycemic agent for type 2 diabetes
mellitus (T2DM), show a reduction of renal composite outcome and probably of mortality in CKD
stage 2 and 3 (CREDENCE and DAPA-CKD trials). Subgroup analyses show similar reduction of
renal composite outcome in patients with or without diabetes, albuminuria, or high blood
pressure. Consistent with previous large cardiovascular (CV) outcome trials, patients with
eGFR 25-30 mL/min/1.73m2 also suggest promising benefits.
Beside, in view of the high atherosclerotic CV risk in advanced CKD, SGLT2is show a reduction
of major adverse cardiovascular event in large CV outcome RCTs in T2DM, especially in
patients with high CV risk. Also considering the high incidence of cardiorenal syndrome and
fluid overload in advanced CKD, SGLT2is show a reduction of congestive heart failure (CHF)
event in large CHF RCTs, regardless of T2DM and regardless of preserved or reduced ejection
fraction. Analysis in patients with eGFR <30 mL/min/1.73m2 suggest similar protection for
atherosclerotic and CHF events.
Study in advanced CKD is difficult. In theory, SGLT2i could decrease hyperfiltration in the
residual glomeruli in advanced CKD. Our preliminary data showed some improvements in certain
types of advanced CKD after SGLT2i treatment. However, a "Point of no return" theory suggests
medication may not alter the natural history of progressive deterioration in renal function
in advanced CKD. Subjects with advanced CKD may be at higher risk of adverse effects of the
medication being tested. Overall, our integrated CKD care program based on the The Kidney
Disease: Improving Global Outcomes (KDIGO) 2017 conference on the prognosis of CKD stage 4
and 5, which emphasizes on the monitoring of diet, blood pressure, fluid status and cardiac
function, could be the foundation of treatment in advanced CKD.
Thus, the goal of this study is to assess the efficacy and safety of dapagliflozin (Forxiga®,
AstraZeneca) in reducing renal function progression and complications of CKD in patients with
CKD stage 4 and 5 under the integrated CKD care and to find out the target subgroups for
future RCT.
Study design This is an investigator-led, randomized, open-label, blinded-endpoint,
multicenter study that will include a total of approximately 225 subjects from 3 sites. The
study design is shown in Figure 1. Subjects with an eGFR of 10 to 30 mL/min/1.73m2 within the
6 months prior to screening will be eligible for screening. Subjects must have at least 3
eGFR measurements in previous 1 year and at least 9 months between first and last eGFR
measurements to calculate eGFR decline. Subjects must be in the pre-end stage renal disease
(ESRD) care and education program of Ministry of Health and Welfare of Taiwan for 3 months
with stable renin-angiotensin system blockade, anti-hypertensive, diuretics and
anti-hyperglycemic therapy. In the 4-week screening phase, review of medical history, renal
echography, cardiac echography and bioimpedance analysis will be done to assure the safety of
study drug treatment. Education for self-monitoring of blood pressure and blood sugar (in
diabetes) will also be done.
Qualified subjects will enter the study phase at the randomization visit and will be
randomized 2:1 to either integrated CKD care program + dapagliflozin or integrated CKD care
program. In both arms, the integrated CKD care prograM includes CKD stage 4 and 5 education,
diet counseling, bioimpedance and cardiovascular measurements, which is more intensive than
the pre-ESRD program, will be done as scheduled in table 1 to control overhydration at 0-1
liter by body composition monitor (BCM; Fresenius). In dapagliflozin arm, subjects will be
received dapagliflozin 5 mg for 4 weeks. Uptitration to 10 mg will be done between 5 to 12th
weeks, if eGFR dip <20%. Education for drug safety of dapagliflozin will be done.
Subjects will return to the clinic every 4 weeks in the first 24 weeks (intensive monitor)
and return to the clinic every 8 weeks thereafter (regular monitor). Laboratory assessments,
measurements, concomitant medication review, adverse event collection and determination of
clinical endpoints will be done as scheduled in table 1. All subjects will be managed to
reach their glycemic, blood pressure and lipid goals according to guidelines. Subjects who
discontinue study medication prematurely should continue to attend all subsequent study
visits and be followed to the trial end, which will be 52 weeks.
Statistical methods Analysis sets: All patients randomized in the treatment period will be
included in the intention-to-treat analysis for primary, secondary, and exploratory outcome
irrespective of their protocol adherence and continued participation in the study.
Per-protocol analysis will be on those that are 80% compliant. Because biomarkers may be done
in a subset of patients, not all patients randomized will be included in the analysis for
biomarker.
Sample size determination: The study aims to observe the differences of eGFR slope between 2
arms by 1 ml/min/1.73m2/yr to have 80% power accounting for the effect of treatment using a
two-sided alpha of 5%. A total of approximately 128 subjects will be in the study group based
on the assumptions: (1) eGFR slope in control group: -4 ± 4 ml/min/1.73m2/yr, (2) Premature
treatment discontinuation rate: 5% per year, (3) Overall lost-to-follow-up 1%, and (4)
Duration of enrollment period: 52 weeks.
Primary efficacy analysis: A linear mixed effect model will be fitted to eGFR as a dependent
variable for eGFR decline. The comparison of eGFR decline will be assessed by difference of
eGFR decline between 2 arms from 12 to 52 weeks.
Secondary efficacy analyses: Mixed models of repeated measures will be performed for
albuminuria/proteinuria and hemoglobin/iron profile.
Exploratory objectives: The risk for cardiorenal events will be assessed by a stratified
competing risk regression model and strata defined by baseline eGFR, diabetes and use of
renin-angiotensin system blockade. Estimates of hazard ratio and the corresponding 95%
confidence interval will be derived from the model.
Safety analyses: Subjects in the safety analysis set will be included in the denominators for
the summaries of adverse event, exposure, and concomitant medication data.
Multiplicity adjustment: A closed testing procedure will be implemented to control the
overall type I error at 5% for a pre-specified hierarchical ordering of the primary and
secondary endpoints.
