Bruce Spinowitz

Design and Baseline Characteristics for the Aminoguanidine Clinical Trial in Overt Type 2 Diabetic Nephropathy (ACTION II)

Advanced glycosylation endproduct (AGE) formation has been implicated in the development and progression of nephropathy in type 2 diabetes mellitus. In diabetic animals, aminoguanidine inhibits AGE-mediated cross-linking of proteins in vascular and renal tissue and slows the progression of renal disease. ACTION II is a randomized, double-blind, placebo-controlled trial comparing two dose levels of aminoguanidine with placebo on the progression of nephropathy in 599 type 2 diabetic patients with renal disease from 84 centers in the United States and Canada. The primary endpoint is time to doubling of serum creatinine concentration. Secondary endpoints include the effect of aminoguanidine on time to all-cause mortality, end-stage renal disease (ESRD), cardiovascular morbidity and mortality, rate of change in indices of renal function (iothalamate, Cockcroft and Gault [C&G] calculated creatinine and measured creatinine clearances), proteinuria, retinopathy, circulating and urinary AGE levels, and estimation of the relationship between plasma aminoguanidine concentrations and primary and secondary efficacy endpoints and adverse events. Progression of macrovascular disease was monitored and fundus photography performed. Type 2 diabetic patients aged 30 to 70 years were eligible for the trial if their blood pressure was < or =180 mm Hg systolic and < or =120 mm Hg diastolic, serum creatinine concentration > or =1.0 mg/dL (in women) or > or =1.2 mg/dL (in men), C&G clearance > or =40 mL/min, and proteinuria > or =500 mg/d with diabetic retinopathy or diabetic nephropathy on renal biopsy. Recruitment began in July 1995 and terminated in December 1996. The trial randomized a total of 599 subjects. At baseline, the mean (standard deviation [SD]) age was 58 (7.7) years, diabetes duration 16.5 (7.5) years, body mass index 32 kg/m2 (10-90% range 2642), arterial blood pressure 105 (12) mm Hg, C-peptide concentration 2.55 (1.71) ng/mL, serum glucose concentration 201 (89) mg/dL, hemoglobin A1c 8.7% (1.6), serum creatinine concentration 1.6 (0.5) mg/dL, iothalamate clearance 52 (25) mL/min/1.73 m2, proteinuria 4.1 (4.2) g/d, triglycerides 259 (214) mg/dL, and LDL cholesterol 144 (40) mg/dL. Patients are 72% male, 68% white, 16% black, and 16% Asian American and Native American. At baseline, 76% were receiving concomitant angiotensin-converting enzyme (ACE) inhibitors and 43% lipid-lowering agents. Follow-up in ACTION II was scheduled to continue through December 1998, so that follow-up was to be 2 years after the date of randomization of the final enrolled patient. The trial in fact ended in March 1998. This trial will contribute to our understanding of the natural history of type 2 diabetes mellitus-associated nephropathy and determine whether aminoguanidine will slow the progression of established diabetic renal disease.

Fluoxetine in Depressed Patients on Dialysis

Objective: To test the safety and efficacy of fluoxetine in patients with renal failure on dialysis. Method: Fourteen patients with major depression and end stage renal disease on hemodialysis were randomized into two groups for an eight-week study. Subjects as well as investigators were blinded as to which subject received fluoxetine and which placebo. Patients were carefully monitored concerning adverse events, serum fluoxetine and norfluoxetine levels, and psychological measurements of degree of depression. Results: No patients discontinued treatment because of adverse events, all of which were minor. All psychological tests showed improvement in depression at the four-week and eight-weeks point, although statistical significance could only be demonstrated at the fourth week of this study. All patients in the active group had serum plasma concentrations of fluoxetine and norfluoxetine less than 250 ng/ml at eight weeks, similar to levels in patients with normal renal function in a previous open label study. Conclusions: This study confirms the relative safety of fluoxetine in depressed patients in renal failure on hemodialysis. It also suggests that fluoxetine may be efficacious in depressed patients on dialysis.

Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference

Before the introduction of erythropoiesis-stimulating agents (ESAs) in 1989, repeated transfusions given to patients with end-stage renal disease caused iron overload, and the need for supplemental iron was rare. However, with the widespread introduction of ESAs, it was recognized that supplemental iron was necessary to optimize hemoglobin response and allow reduction of the ESA dose for economic reasons and recent concerns about ESA safety. Iron supplementation was also found to be more efficacious via intravenous compared to oral administration, and the use of intravenous iron has escalated in recent years. The safety of various iron compounds has been of theoretical concern due to their potential to induce iron overload, oxidative stress, hypersensitivity reactions, and a permissive environment for infectious processes. Therefore, an expert group was convened to assess the benefits and risks of parenteral iron, and to provide strategies for its optimal use while mitigating the risk for acute reactions and other adverse effects.

Peginesatide for Anemia in Patients with Chronic Kidney Disease Not Receiving Dialysis

BACKGROUND Peginesatide is a peptide-based erythropoiesis-stimulating agent (ESA) that may have therapeutic potential for anemia in patients with advanced chronic kidney disease. We evaluated the safety and efficacy of peginesatide, as compared with another ESA, darbepoetin, in 983 such patients who were not undergoing dialysis. METHODS In two randomized, controlled, open-label studies (PEARL 1 and 2), patients received peginesatide once a month, at a starting dose of 0.025 mg or 0.04 mg per kilogram of body weight, or darbepoetin once every 2 weeks, at a starting dose of 0.75 μg per kilogram. Doses of both drugs were adjusted to achieve and maintain hemoglobin levels between 11.0 and 12.0 g per deciliter for 52 weeks or more. The primary efficacy end point was the mean change from the baseline hemoglobin level to the mean level during the evaluation period; noninferiority was established if the lower limit of the two-sided 97.5% confidence interval was -1.0 g per deciliter or higher. Cardiovascular safety was evaluated on the basis of an adjudicated composite end point. RESULTS In both studies and at both starting doses, peginesatide was noninferior to darbepoetin in increasing and maintaining hemoglobin levels. The mean differences in the hemoglobin level with peginesatide as compared with darbepoetin in PEARL 1 were 0.03 g per deciliter (97.5% confidence interval [CI], -0.19 to 0.26) for the lower starting dose of peginesatide and 0.26 g per deciliter (97.5% CI, 0.04 to 0.48) for the higher starting dose, and in PEARL 2 they were 0.14 g per deciliter (97.5% CI, -0.09 to 0.36) and 0.31 g per deciliter (97.5% CI, 0.08 to 0.54), respectively. The hazard ratio for the cardiovascular safety end point was 1.32 (95% CI, 0.97 to 1.81) for peginesatide relative to darbepoetin, with higher incidences of death, unstable angina, and arrhythmia with peginesatide. CONCLUSIONS The efficacy of peginesatide (administered monthly) was similar to that of darbepoetin (administered every 2 weeks) in increasing and maintaining hemoglobin levels. However, cardiovascular events and mortality were increased with peginesatide in patients with chronic kidney disease who were not undergoing dialysis. (Funded by Affymax and Takeda Pharmaceutical; ClinicalTrials.gov numbers, NCT00598273 [PEARL 1], NCT00598442 [PEARL 2], NCT00597753 [EMERALD 1], and NCT00597584 [EMERALD 2].).

Long-term effects of the iron-based phosphate binder, sucroferric oxyhydroxide, in dialysis patients

Background Hyperphosphatemia necessitates the use of phosphate binders in most dialysis patients. Long-term efficacy and tolerability of the iron-based phosphate binder, sucroferric oxyhydroxide (previously known as PA21), was compared with that of sevelamer carbonate (sevelamer) in an open-label Phase III extension study. Methods In the initial Phase III study, hemo- or peritoneal dialysis patients with hyperphosphatemia were randomized 2:1 to receive sucroferric oxyhydroxide 1.0−3.0 g/day (2−6 tablets/day; n = 710) or sevelamer 2.4−14.4 g/day (3−18 tablets/day; n = 349) for 24 weeks. Eligible patients could enter the 28-week extension study, continuing the same treatment and dose they were receiving at the end of the initial study. Results Overall, 644 patients were available for efficacy analysis (n = 384 sucroferric oxyhydroxide; n = 260 sevelamer). Serum phosphorus concentrations were maintained during the extension study. Mean ± standard deviation (SD) change in serum phosphorus concentrations from extension study baseline to Week 52 end point was 0.02 ± 0.52 mmol/L with sucroferric oxyhydroxide and 0.09 ± 0.58 mmol/L with sevelamer. Mean serum phosphorus concentrations remained within Kidney Disease Outcomes Quality Initiative target range (1.13–1.78 mmol/L) for both treatment groups. Mean (SD) daily tablet number over the 28-week extension study was lower for sucroferric oxyhydroxide (4.0 ± 1.5) versus sevelamer (10.1 ± 6.6). Patient adherence was 86.2% with sucroferric oxyhydroxide versus 76.9% with sevelamer. Mean serum ferritin concentrations increased over the extension study in both treatment groups, but transferrin saturation (TSAT), iron and hemoglobin concentrations were generally stable. Gastrointestinal-related adverse events were similar and occurred early with both treatments, but decreased over time. Conclusions The serum phosphorus-lowering effect of sucroferric oxyhydroxide was maintained over 1 year and associated with a lower pill burden, compared with sevelamer. Sucroferric oxyhydroxide was generally well tolerated long-term and there was no evidence of iron accumulation.

C.E.R.A. maintains stable control of hemoglobin in patients with chronic kidney disease on dialysis when administered once every two weeks.

Background/Aims: This Phase III study examined the efficacy and safety of C.E.R.A., a continuous erythropoietin receptor activator, given once every 2 weeks (Q2W) via subcutaneous or intravenous injection using pre-filled syringes, for maintaining hemoglobin (Hb) levels in patients with chronic kidney disease (CKD) on dialysis who converted directly from epoetin therapy. Methods: Patients (n = 336) were randomized 1:1 to continue epoetin at their current dose, route and administration interval (once to three times weekly (QW–TIW)), or receive C.E.R.A. Q2W by the same route as previous epoetin treatment for 36 weeks. Dosage was adjusted to maintain patients’ Hb within ±1.0 g/dl of baseline value and within 10.0–13.5 g/dl. Primary endpoint was mean change in Hb between baseline and the evaluation period (weeks 29–36). Results: Mean change in Hb for C.E.R.A. and epoetin was 0.088 and –0.030 g/dl, respectively (endpoint Hb 11.93 and 11.86 g/dl, respectively). Analysis showed that C.E.R.A. was as effective as epoetin in maintaining Hb (p < 0.0001), and was well tolerated. The administration route had no impact on primary endpoint. Conclusion: Q2W C.E.R.A. administered using pre-filled syringes effectively maintains stable control of Hb in patients on dialysis who convert directly from epoetin QW–TIW.

Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease

Current treatment of anemia in chronic kidney disease (CKD) with erythropoiesis-stimulating agents can lead to substantial hemoglobin oscillations above target range and high levels of circulating erythropoietin. Vadadustat (AKB-6548), a novel, titratable, oral hypoxia-inducible factor prolyl hydroxylase inhibitor induces endogenous erythropoietin synthesis and enhances iron mobilization. In this 20-week, double-blind, randomized, placebo-controlled, phase 2b study, we evaluated the efficacy and safety of once-daily vadadustat in patients with stages 3a to 5 non-dialysis-dependent CKD. The primary endpoint was the percentage of patients who, during the last 2 weeks of treatment, achieved or maintained either a mean hemoglobin level of 11.0 g/dl or more or a mean increase in hemoglobin of 1.2 g/dl or more over the predose average. Significantly, the primary endpoint was met in 54.9% of patients on vadadustat and 10.3% of patients on placebo. Significant increases in both reticulocytes and total iron-binding capacity and significant decreases in both serum hepcidin and ferritin levels were observed in patients on vadadustat compared with placebo. The overall incidence of adverse events was comparable between the 2 groups. Serious adverse events occurred in 23.9% and 15.3% of the vadadustat- and placebo-treated patients, respectively. Three deaths occurred in the vadadustat arm. Thus, this phase 2b study demonstrated that vadadustat raised and maintained hemoglobin levels in a predictable and controlled manner while enhancing iron mobilization in patients with nondialysis-dependent CKD.

Safety of Iron Sucrose in Hemodialysis Patients Intolerant to Other Parenteral Iron Products

Background/Aims: This report summarizes the data gathered in four prospective studies of intravenous iron sucrose therapy administered to iron-deficient hemodialysis patients with a history of intolerance to other parenteral iron preparations. Methods: A total of 130 iron dextran- and/or sodium ferric gluconate-sensitive patients received intravenous iron sucrose therapy to correct iron deficiency, and/or maintain body iron stores. A history of intolerance to iron dextran alone was reported in 109 patients, to ferric sodium gluconate alone in 6 patients, and to both iron dextran and ferric sodium gluconate in 15 patients. Therapy with iron sucrose consisted of 100- or 200-mg doses administered undiluted intravenously over 2–5 min, or diluted in normal saline and infused over 15–30 min. Test doses of iron sucrose were not administered. The median cumulative dose was 1,000 mg, with a range of 100–5,000 mg. Results: There were no serious adverse events related to iron sucrose therapy in the 130 patients intolerant to other iron preparations. There were 14 nonserious drug-related adverse events in 8 patients attributed to iron sucrose, none of which resulted in discontinuation of therapy. These events were classified as either of severe (diarrhea), moderate (hypotension, nausea, vomiting), or mild severity (constipation, dry mouth, skin irritation). Conclusion: Iron sucrose therapy is safe and well tolerated in hemodialysis patients intolerant to iron dextran and/or sodium ferric gluconate.

Effect of Angiotensin-Converting Enzyme Inhibitors on Response to Erythropoietin Therapy in Chronic Dialysis Patients

Background: Erythropoietin (EPO) therapy is a common and effective treatment for the correction of anemia in patients with end-stage renal disease. Simultaneous treatment with angiotensin-converting enzyme (ACE) inhibitors for the control of hypertension and/or heart failure is often necessary. Recent reports in the literature have raised concern about a potential interaction between these drugs, with a resultant decreased EPO efficacy. Methods: To investigate whether this interaction occurs in chronic dialysis patients, we retrospectively reviewed the records of 175 patients receiving chronic dialysis. All study patients were treated with EPO for at least 3 months, and had normal iron indices. Patients were treated with ACE inhibitors for at least 3 months, at a constant daily dose for at least 1 month (group 1, n = 32), or did not receive ACE inhibitors (group 2, n = 143). Patients with infections or overt iron deficiency were excluded. Total weekly EPO doses and hematocrit (Hct)/hemoglobin (Hgb) values in the two groups were compared. Variables known to affect response to EPO were compared, including ferritin, transferrin saturation, dialysis dose and serum aluminum. Results: Total weekly EPO dose was 17,358 ± 6,871 units in group 1 and 17,612 ± 7,744 units in group 2 (p = 0.854). The achieved Hct was 32.1 ± 4.4% (group 1) and 30.5 ± 4.0% (group 2) (p = 0.079). Similarly, Hgb, ferritin, transferrin saturation, Kt/V, and serum aluminum were not different. The dose or duration of ACE inhibitor therapy did not affect Hgb or Hct. Thus, ACE inhibitor therapy does not appear to affect response to EPO in chronic dialysis patients.

A Randomized Study of Extended Dosing Regimens for Initiation of Epoetin Alfa Treatment for Anemia of Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Although epoetin alfa is commonly initiated weekly (QW) in anemic chronic kidney disease (CKD) patients, recent evidence indicates that it can be initiated every 2 wk (Q2W) and used in maintenance therapy every 4 wk (Q4W). This study examined the feasibility of initiating epoetin alfa Q4W in anemic CKD patients not receiving dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This open-label study randomized subjects (1:2:2:2) to treatment with epoetin alfa 10,000 IU QW, 20,000 IU Q2W, 20,000 IU Q4W, or 40,000 IU Q4W for 16 wk. Subjects were > or =18 yr, had hemoglobin <11 g/dl, a glomerular filtration rate of 15 to 90 ml/min per 1.73 m(2), and had not received erythropoietic therapy within 8 wk. The primary analysis was a noninferiority comparison of the 40,000 IU Q4W to the 20,000 IU Q2W group in the per-protocol population with respect to hemoglobin change from baseline to the end of study. RESULTS Of 262 subjects randomized, 229 comprised the per-protocol population. Mean hemoglobin change from baseline for the 40,000 IU Q4W group (1.24 g/dl) was not inferior to the 20,000 IU Q2W group (1.11 g/dl) with the lower limit of 95% CI, -0.21 g/dl. In the QW, 20,000 IU Q2W, 20,000 IU Q4W, and 40,000 IU Q4W groups, 90%, 87%, 75%, and 86% of subjects, respectively, achieved a hemoglobin increase > or =1 g/dl. Serious adverse events were similar across all groups. CONCLUSIONS Epoetin alfa can be initiated Q4W in anemic CKD subjects.