The new england journal of medicine

original article

Bardoxolone Methyl and Kidney Function in CKD with Type 2 Diabetes 28 Jul 2011

Chairperson: Dr. Sayta Ranjan Sutradhar Associate Professor and Head

Department of Medicine Mymensingh Medical College

Presenter: Dr. Md. Abdul Muqueet Assistant Professor and Head

Department of Nephrology Mymensingh Medical College

Pablo E. Pergola, M.D., Ph.D.,Philip Raskin, M.D., Robert D. Toto, M.D.,

Colin J. Meyer, M.D., J. Warren Huff, J.D., Eric B. Grossman, M.D.,

Melissa Krauth, M.B.A., Stacey Ruiz, Ph.D., Paul Audhya, M.D.,

Heidi Christ-Schmidt, M.S.E., Janet Wittes, Ph.D., and David G. Warnock, M.D.,

Introduction:

Diabetes mellitus is a major cause of chronic kidney disease (CKD) worldwide.

CKD in patients with diabetes is associated with chronic inflammation and oxidative stress.

Bardoxolone Methyl

Antioxidant inflammation modulator

Keap1–Nrf2 pathway

Up-regulation of cytoprotective genes

Inhibiting the proinflammatory nuclear factor κB pathway

Methods:

Patients-

CKD with T2DMeGFR-20 to 40

ml/min/1.73ACE and/ ARB 8 wk

Exclusion criteria:

* Type 1 diabetes * Nondiabetic renal

disease * HbA1c >10% * Hepatic dysfunction * Cardiovascular event

Study Design:

227 of 573 at 43 site USA Placebo or Bardoxolone 25,75,150

once oraly 52 wk 1:1:1:1 ratio Four period -3wk screening

-8 wk dose adjustment -52 wk maintanence -4 wk follow up

Patient stratified at randomization

eGFR <30 or ≥ 30 ml/min/1.73 ACR ≤300 or > 300 mg/g HbA1c < 7% or > 7%

Patient safety monitoredWritten informed consent

Procedures and Outcomes:

eGFR and routine lab test done on screening and every 4 wk

eGFR by 4 variable MDRD Creatinine calibrated IDMS

Primary outcome eGFR change at 24 Secondery outcome at 52 wk

compared to placebo

Exploratory outcomes:

Change eGFR at 52 wk Time, % patients with a reduced

eGFR of 25% or more Change eGFR 4 wk after the last

administration Bardoxolone Change ACR from baseline Change at 24, 52 wk compared to

placebo for basic lab tests

Statistical Analysis:

Here used a repeated-measures model to analyze the primary and secondary outcomes, with monthly measurement of the estimated GFR through 52 weeks as the response and with the baseline estimated GFR, ACR, and glycated hemoglobin

level as continuous covariates.

Statistical Analysis:

The model included all measurements up to the time of withdrawal from the study, regardless of the status of study-drug administration and categorical variables for treatment, week, and treatment-by-week inter -action. Within-patient correlation was modeled with a Toeplitz structure.

We used Kaplan–Meier methods to estimate the proportion of patients remaining event-free at time points of interest. The study groups were compared with the use of unstratified log-rank tests with unadjusted two-sided type I error rates.

Results:

Baseline variables are similar in 4 groups

Mean age-67 yrTotal 98% received ACE /or ARBMean eGFR 32.4±6.9 ml/min/1.73Normoalbuminuria-37%Microalbuminuria-29%Macroalbuminuria-34%Blood glucose levels well controlled

Primary and Secondary End Point

Bardoxolone group eGFR increases within 4 wk, peaked at 12 wk, stable through 52 wk

Primary End Point-24 wk

(P<0.001 for all comparisons)

25 mg 75 mg 150 mgeGFR change compared placebo

8.2±1.5 11.4±1.5 10.4±1.5

Primary and Secondary End Point

The difference in the change between the 25-mg group and the 75-mg group was significant (P=0.04), but the difference between the 75-mg group and the 150-mg group was not significant (P=0.54)

Secondary End Point: 52 wk

25mg 75mg 150mg

eGFR change compared to placebo

5.8±1.8(P<0.002)

10.5±1.8(P<0.001)

9.3±1.9(P<0.001)

Primary and Secondary End Point for placebo

There were no significant changes from baseline in the estimated GFR in the placebo group at 24 or 52 weeks

Exploratory Outcomes:

eGFR decreases at 52 wk completing therapy

Group Placebo 25 75 150

54% 20% 21% 27%

Exploratory Outcomes:

The proportion of patients with a reduction in the estimated GFR of 25% or more at 24 weeks was 13% (95% confidence interval [CI], 6 to 25) in the placebo group and 2% (95% CI, 1 to 6) in the combined bardoxolone methyl groups (P = 0.05)

Exploratory Outcomes:

Four weeks after the last administration of the study drug (at 56 wks) eGFR changes

Placebo 25 75 150

0.6±1.1 0.7±1.6 2.5±11.6 2.3±1.7

Exploratory Outcomes:

In a post hoc sensitivity analysis increases in the estimated GFR were sustained for 52 weeks in the 75-mg and 150-mg groups but not in the 25-mg group

Exploratory Outcomes:

At 24 wk significant decreases urea nitrogen, serum phosphorus, uric acid, and magnesium, as compared with placebo

Inverse correlation changes in the eGFR

Exploratory Outcomes:

In the 75-mg and 150-mg groups, there was a slight but significant increase in the ACR at 24and 52 weeks

Changes in the ACR and estimated GFR were positively correlated at 52 weeks.

At 56 weeks, the ACR generally returned to the

baseline level

Adverse Events:

Muscle spasm- 42% in the 25-mg group

61% in the 75-mg group 59% in the 150-mg group, 18% in the placebo group

(12 wk, calf, lactate dehydrogenage)

Adverse Events:

Alanine aminotransferase-

71%, within 2 to 4 wks, 11% three times

Not persistant, recur, bilirubin unchanged Weight reduction-

more pronounced in patients with an

increased body-mass index at baseline

independent of change eGFR

Adverse Events:

Discontinuations and withdrawal- Sixteen patients- muscle spasms six patients

nausea and vomiting in three patients

weight change in three patients

decreased appetite in two patients One death occurred

Discussion:

Bardoxolone methyl activates the Keap1–Nrf2 pathway- regulates inflammation and oxidative stress

Murine model Nrf2 delition AKI- Bardoxolone Nrf2, heme oxygenase 1,

decrease reactive oxygen

reduction in inflammation decrease urea nitrogen amelioration of both glomerular and tubular in -jury was observed

Discussion:

Sustained, significant improvement, short- long term, remained after stop--decrease inflamation and oxidative stress

Independently of changes in albumin excretion Absence of significant decline in Egfr placebo

BP,HbA1c well control,not macroalbuminuric Effects on multiple blood chemical values ACR significant increase, discontinution decrease

Discussion:

Nrf2 expression ubiquitous-transient, self-limited elevations in aminotransferase

Muscle spasm- calf, glucose uptake

Limitations:

many patients did not reach the target dose Measurement of the GFR to validate these

results would be important The confirmation of clinical benefit will require a

larger, long-term study involving the assessment of clinical outcomes

Conclusions:

Bardoxolone methyl was associated with improvement in the estimated GFR in patients with advanced CKD and type 2 diabetes at 24 weeks.

The improvement persisted at 52 weeks, suggesting that bardoxolone methyl may have promise for the treatment of CKD.