Prospective safety study of bardoxolone methyl in patients with type 2 diabetes mellitus, end-stage renal disease and peritoneal dialysis
David G Warnock, Sudarshan Hebbar, Joanne Bargman, John Burkart, Simon Davies, Frederic O Finkelstein, Rajnish Mehrotra, Claudio Ronco, Isaac Teitelbaum, Kingsley Urakpo, Glenn M Chertow
Patients on peritoneal dialysis experience inflammation associated with advanced chronic kidney disease and the therapy itself. An important consequence of the inflammation may be acceleration of the rate of decline in residual renal function. The decline in residual renal function has been associated with an increased mortal-ity for patients in this population. Bardoxolone methyl is a synthetic triterpenoid. To date, the effects of bardox-olone methyl on kidney function in humans have been studied in patients with type 2 diabetes mellitus.
A large-scale event-driven study of bardoxolone methyl in patients with type 2 diabetes mellitus with stage 4 chronic kidney disease is underway. The safety of bardoxolone methyl has not been evaluated in patients with more advanced (stage 5) chronic kidney disease or patients on dialysis. This report describes a proposed double blind, prospective evaluation of bardoxolone
methyl in patients with type 2 diabetes mellitus receiving peritoneal dialysis. In addition to assessing the safety of bardoxolone methyl in this population, the study will evaluate the effect of bardoxolone methyl on residual renal function over 6 months as compared to placebo.
Copyright © 2012 S. Karger AG, Basel
Chronic kidney disease (CKD) is characterized by inflammation and oxidative stress that wors-ens as patients progress to end-stage renal disease (ESRD) . Significantly higher levels of oxida-tive stress and impaired endothelial function, as compared to controls, are present in patients with ESRD being treated with peritoneal dialysis (PD) [2–4]. Hypertension, adiposity, insulin resistance,
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volume overload and infections are common in PD patients and all contribute to the inflamma-tory state. Glucose-based PD solutions exacerbate the inflammatory state by causing weight gain, hyperglycemia and dyslipidemia . In addition, sterilization of the glucose-based PD solutions generates glucose degradation products that, when exposed to the peritoneal membrane, enhance the production of advanced glycation end products that activate RAGE receptors and downstream inflammatory cascades [6–8]. Sustained inflam-mation promotes angiogenesis and fibrosis, which can be associated with ultrafiltration failure, lim-iting the long-term effectiveness of PD .
Inflammation in Peritoneal Dialysis Patients and the Link to Residual Renal Function
The chronic inflammatory state in PD patients is associated with a decline in residual renal function (RRF). Singhal et al. , found a gradual decline in RRF in patients on PD, with 40% of patients developing anuria an average of 20 months after starting treatment. Risk factors associated with a more rapid decline in RRF include a larger body mass, diabetes mellitus, history of heart failure, use of diuretics, episodes of volume depletion, hypotension and peritonitis .
The decline in RRF is associated with poor patient outcomes. Maiorca et al.  first described the association between RRF and sur-vival in patients on PD and hemodialysis. Since then, findings from multiple observational stud-ies have strengthened the documentation of the association. Reanalysis of the Canada-United States (CANUSA) Study identified RRF as the most important factor associated with survival in PD patients . The Adequacy of PD in Mexico (ADEMEX) study showed an 11% risk reduc-tion in patient mortality associated with each 10 liters/week/1.73 m2 increase in RRF . The Netherlands Cooperative Study on the Adequacy of Dialysis (NECOSAD) also found for each increase in RRF of 1 ml/min/1.73 m2, there was an associated 12% reduction in mortality rate . Recognition of the importance of RRF to
the success of PD treatment has led to KDOQI guidelines stressing the importance of monitor-ing and preserving RRF . Recommendations for preserving RRF include careful attention to glycemic control, use of drugs inhibiting the renin-angiotensin-aldosterone system, avoiding nephrotoxic agents, reduction in glucose deg-radation products in peritoneal dialysate, and avoiding volume depletion . Long-term pro-spective clinical trials will need to be performed to answer whether these approaches, alone or in combination, will attenuate the loss of RRF and enhance survival in patients on PD.
Bardoxolone Methyl: An Antioxidant and Inflammation Modulator
Bardoxolone methyl is a synthetic triterpenoid and an antioxidant and inflammation modula-tor. It is the most potent known inducer of the Keap1-Nrf2 pathway to enter clinical develop-ment . Activation of Keap1-Nrf2 induces transcription of a large number of genes that increase cellular antioxidant content, suppress NF-κB activity, and restores redox homeosta-sis in areas of inflammation. The structure and activity profile resemble that of cyclopentenone prostaglandins, endogenous activators of Nrf2, which play an important role in the resolution of inflammation . Activation of Nrf2 is sup-pressed in animal models of CKD; experiments conducted in mice with genetic deletion of Nrf2 demonstrate that Nrf2 plays an important role in maintaining the function and structure of the kidney [20–23].
Clinical Experience with Bardoxolone Methyl
Two recently published phase 2 trials have tested the effects of a crystalline formulation of bar-doxolone methyl in patients with type 2 diabetes mellitus and CKD. The first trial was an open-label study that enrolled 20 patients with type 2 diabetes mellitus and stage 3b/4 CKD . The study included a dose titrating regimen in which
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patients were administered 25 mg once daily for 4 weeks followed by 75 mg once daily for four addi-tional weeks. Statistically significant increases in estimated glomerular filtration rate (eGFR) over the 8 weeks were observed in approximately 90% of patients and were corroborated by highly cor-related reductions in blood urea nitrogen, phos-phorus, uric acid, and magnesium, without a change in the 24-hour creatinine excretion rate. Circulating endothelial cells, markers of endothe-lial dysfunction and vascular injury were signifi-cantly decreased at the end of 8 weeks.
The second trial (Bardoxolone Methyl Treatment: Renal Function in CKD/Type 2 Diabetes, BEAM) was a multicenter, double-blind, placebo-controlled trial that evaluated bar-doxolone methyl administered once daily for 52 weeks . In this study, 227 adults with CKD (eGFR between 20 and 45 ml/min/1.73 m2) and type 2 diabetes were randomized to receive either placebo or bardoxolone methyl at one of three titrated doses (25, 75 or 150 mg) of the crystalline formulation. The primary outcome was change in kidney function as assessed by eGFR following 24 weeks of treatment relative to placebo. Increases in eGFR, ranging from 8.3 ± 1.1 to 11.5 ± 1.1 ml/min/1.73 m2, were observed in each bardox-olone methyl group, whereas a change of 0.1 ± 1.1 ml/min/1.73 m2 was observed in the placebo group (p < 0.001 for each dose group relative to placebo). Improvement in eGFR from baseline plateaued with the 75 mg dose, and persisted through 52 weeks of treatment. The mean eGFR remained above baseline levels 4 weeks after dis-continuation of bardoxolone methyl, suggesting the potential for a persisting effect off drug.
Muscle spasms were the most frequent adverse events in the bardoxolone methyl groups and were generally mild, self-limiting, and not associated with markers of muscle injury. Hypomagnesemia and mild increases in alanine aminotransferase were more common in the bar-doxolone methyl groups. The hypomagnesemia was not present in the majority of patients before or at the time of muscle spasms in patients treated with bardoxolone methyl who complained of them. The transaminase elevations were usually
transient, peaking at 2–4 weeks and resolving while the patient continued with the study drug. There were no signs or symptoms of hepatic injury observed.
An amorphous spray dried dispersion for-mulation was developed to improve the bioavail-ability of the drug compared to the crystalline formulation. The amorphous formulation was tested in a multicenter, open-label, dose-ranging study in 131 patients with type 2 diabetes mel-litus and stage 3b/4 CKD . A linear dose-response trend was identified with a statistically significant increase in eGFR from baseline to days 29 (primary endpoint) and 85 (secondary endpoint) noted in all dose groups both individ-ually and combined. The doses were well toler-ated and no new safety signals were identified. The transaminase elevations followed a similar, consistent pattern noted in the previous clinical studies using the crystalline formulation. The results of this study, and subsequent pharma-cokinetic and pharmacodynamic dose-exposure modeling, were utilized to identify the dose (20 mg) that best balanced safety and efficacy. The 20-mg dose of the amorphous spray dried dis-persion formulation is currently being utilized in the ongoing phase 3 trial of patients with type 2 diabetes mellitus and stage 4 CKD with the composite primary endpoint of progression to end-stage renal disease or cardiovascular death .
Safety Study of Bardoxolone Methyl in Patients with Type 2 Diabetes Mellitus and End-Stage Renal Disease Treated with Peritoneal Dialysis
The previous and ongoing clinical trials with bar-doxolone methyl have excluded CKD patients with eGFR <15 ml/min/1.73 m2. The objective of this prospective double-blind placebo-controlled trial is to evaluate the safety profile of 20 mg amorphous formulation of bardoxolone methyl given daily for 6 months to patients with type 2 diabetes mellitus and ESRD on PD. In addition, the study will explore the effects of bardoxolone
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methyl on RRF in this population (PD Study:
clinicaltrials.gov NCT pending).
Study Design and Objectives
Forty-five patients with type 2 diabetes mellitus and ESRD on PD will be randomized to receive 20 mg of bardoxolone methyl or placebo once daily for 6 months on a 2:1 allocation stratified by study site. The study will consist of a 45-day screening period, 6 months of study drug admin-istration, and a 1-month post-treatment visit. RRF, defined as the mean of the urea and crea-tinine clearances on a 24-hour urine collection normalized to 1.73 m2 body surface area will be measured twice during the screening period to provide a baseline value, monthly after study ran-domization, and again at the post treatment visit.
The primary objective of the study is to assess the safety and pharmacokinetic profile of bar-doxolone methyl in patients with type 2 diabetes mellitus and ESRD on PD. The secondary objec-tive is to assess the effect of bardoxolone methyl on of RRF at 6 months compared to the baseline established during the screening visits.
Inclusion and Exclusion Criteria
To be eligible for the study, patients must have been on PD for more than 3 months and have a documented RRF ≥25 liters/week/1.73 m2 (2.5 ml/min/1.73 m2) in the 4 months prior to screen-ing. The patients must also have stable RRF ≥25 l/week/1.73 m2 documented during both screen-ing visits. Selected inclusion and exclusion crite-ria are listed in table 1.
When enrolled in the study, patients will be man-aged according to local standard of care. At each monthly visit, patients will report adverse events that will be categorized by intensity and relation-ship to study drug. Patients will receive monthly
laboratory measurements, and a single central laboratory will perform all analyses. Peritoneal equilibration testing will be performed at study randomization and again at 3 and 6 months. Pharmacokinetic profiling over the first 24 h after study drug administration will occur in the first 8 patients enrolled in the study, and plasma study drug levels will be collected monthly in all patients.
Early Study Termination
Patients who discontinue study drug because of an adverse event, and those who discontinue study drug because they received an organ trans-plant or changed modality to hemodialysis will then undergo a post-treatment visit. If a patient’s RRF improves sufficiently and a clinical deci-sion is made to discontinue PD, study drug will be continued for the remainder of the 6-month treatment period. The patient will continue monthly in-person visits and study assessments, as well as the post-treatment visit 30 days after discontinuation of study drug.
Sample Size and Intention-to-Treat Analysis
The sample size was calculated under assump-tions regarding the secondary efficacy outcome of a mean change from baseline RRF at 6 months. Allowing for a 25% drop out rate and a study design consisting of 7 repeated measures with a first-order autoregressive model covariance, where the standard deviation in measuring RRF is 8 liters/week/1.73 m2, the correlation between observations on the same subject is 0.9 and the alpha level is 0.05, group samples sizes of 11 in the placebo group and 22 in the bardoxolone methyl group achieve approximately 85% power to detect a difference in RRF of 8 liters/week/1.73 m2. Analyses of the efficacy data will be based on the intent to treat population, which will include all patients randomized into the study. Safety analy-ses will include patients receiving any dose or duration of study drug following enrollment.
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Table 1. Inclusion and exclusion criteria
The following criteria must be met for inclusion in the study:
1 Adult patients with type 2 diabetes mellitus and ESRD who have been treated with peritoneal dialysis for longer than 3 months, with RRFunction (mean of urea and creatinine clearance) ≥ 25 liters/week/1.73 m2 in the 4 months prior to screen visit A, and at both screen visits A and B.
2 Patients must have a mean systolic blood pressure, on three readings at both screen visits A and B, ≤160 mm Hg and ≥90 mm Hg. Patients must have a mean diastolic blood pressure, on three readings at both Screen visits A and B, ≤100 mm Hg and ≥40 mm Hg.
3 Willing to practice methods of birth control (both males who have partners of childbearing potential and females of childbearing potential) during screening, while taking study drug and for at least 30 days after the last dose of
study drug is ingested.
4 Patients must be willing and able to give written informed consent to participate in the study. They must provide consent for access to medical data according to appropriate local data protection legislation and allow authorization to access medical records that describe events captured in the endpoints. Patients must be willing and able to cooperate with all aspects of the protocol.
Patients with any of the following conditions must be excluded from the study:
1 Hepatitis B surface antigen-positive status; hepatitis C antibody-positive being treated with antiviral therapy, or cirrhosis of the liver.
2 Known history of amyloidosis or light chain nephropathy, autosomal dominant polycystic kidney disease.
3 Hemoglobin A1c level > 11.0% (97 mmol/mol) in the 4 months prior to screening.
4 A serum magnesium level less than 1.4 mEq/l on either screen A or screen B laboratory test results.
5 Total bilirubin, aspartate transaminase, or alanine transaminase level greater than the upper limit of normal or alkaline phosphatase level greater than two times the upper limit of normal on either the screen A or screen B laboratory test results.
6 Recently active cardiovascular disease defined as:
• Unstable angina pectoris within 12 weeks before study randomization.
• Myocardial infarction, coronary artery bypass graft surgery, or percutaneous transluminal coronary angioplasty/stent within 12 weeks before study randomization.
• Cerebrovascular accident, including transient ischemic attack within 12 weeks before study randomization.
• History of hospitalization for congestive heart failure or pulmonary edema within 12 weeks before study randomization.
• Known severe obstructive valvular heart disease or severe obstructive hypertrophic cardiomyopathy.
• Known 2o or 3o AV block not successfully treated with a pacemaker.
• Known history of resuscitated sudden cardiac death.
• Known history of an automatic implantable defibrillator.
• Rate-corrected QT interval (QTc) greater than 0.50 seconds on an ECG obtained during screening.
7 Currently active systemic lupus erythematosus.
8 Systemic immunosuppression for more than 15 days, cumulatively, within 12 weeks before study randomization or anticipated need for more than 15 cumulative days of therapy during the study.
9 History or planned organ transplant.
10 Clinically significant infection requiring intravenous administration of antibiotics or hospitalization within 12 weeks before study randomization. In a patient who has been on peritoneal dialysis for ≥6 months, two or more episodes of peritonitis in the 6 months before study randomization. In a patient who has been on peritoneal dialysis for <6 months, one episode of peritonitis before study randomization.
11 Diagnosis or treatment of a malignancy in the past 5 years, excluding nonmelanoma skin cancer and carcinoma in situ of the cervix.
12 Diagnostic or interventional procedure that required intravenous administration of an iodinated contrast agent or gadolinium within 12 weeks before study randomization.
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The previous and current studies of bardoxolone methyl therapy in patients with type 2 diabetes mellitus and CKD have not enrolled subjects with a baseline eGFR <15 ml/min/1.73 m2. Nrf2 expression is ubiquitous and multiple biochemi-cal and physiological changes can be seen with bardoxolone methyl therapy. While there is no reason to anticipate any untoward effects from these changes in patients with type 2 diabetes mellitus and stage 5 CKD on dialysis, it is impor-tant to prospectively evaluate the safety and pharmacokinetic profile of bardoxolone methyl therapy in a population downstream from those being studied in BEACON.
The data from this proposed study may pro-vide additional insight into the effects seen in
previous studies of bardoxolone methyl. For example, previous studies have shown that hypo-magnesemia occurs more frequently in patients taking bardoxolone methyl compared to placebo [24, 25]. Evaluating whether hypomagnesemia occurs with bardoxolone methyl in patients with ESRD will help narrow the potential causes since renal losses of magnesium are less likely in this population.
Finally, this proposed study will provide guid-ance for future studies in the ESRD population. If bardoxolone methyl is found have a similar safety profile in this population as earlier stages of CKD, and is shown to maintain or improve RRF, further consideration may be given to con-ducting additional clinically meaningful studies in a PD population.
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David G. Warnock, MD
Room 636 ZRB, UAB
1530 3rd Avenue South
Birmingham, AL 34294–0007 (USA)
Tel. +1 205 934 9509, E-Mail [email protected]
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