Randomized placebo-controlled dose-ranging and pharmacodynamics study of roxadustat (FG-4592) to treat anemia in nondialysis-dependent chronic kidney disease (NDD-CKD) patients.

BACKGROUND: Roxadustat (FG-4592) is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that stimulates erythropoiesis. This Phase 2a study tested efficacy (Hb response) and safety of roxadustat in anemic nondialysis-dependent chronic kidney disease (NDD-CKD) subjects. METHODS: NDD-CKD subjects with hemoglobin (Hb) ≤11.0 g/dL were sequentially enrolled into four dose cohorts and randomized to roxadustat or placebo two times weekly (BIW) or three times weekly (TIW) for 4 weeks, in an approximate roxadustat:placebo ratio of 3:1. Efficacy was assessed by (i) mean Hb change (ΔHb) from baseline (BL) and (ii) proportion of Hb responders (ΔHb ≥ 1.0 g/dL). Pharmacodynamic evaluation was performed in a subset of subjects. Safety was evaluated by adverse event frequency/severity. RESULTS: Of 116 subjects receiving treatment, 104 completed 4 weeks of dosing and 96 were evaluable for efficacy. BL characteristics for roxadustat and placebo groups were comparable. In roxadustat-treated subjects, Hb levels increased from BL in a dose-related manner in the 0.7, 1.0, 1.5 and 2.0 mg/kg groups. Maximum ΔHb within the first 6 weeks was significantly higher in the 1.5 and 2.0 mg/kg groups than in the placebo subjects. Hb responder rates were dose dependent and ranged from 30% in the 0.7 mg/kg BIW group to 100% in the 2.0 mg/kg BIW and TIW groups versus 13% in placebo. CONCLUSIONS: Roxadustat transiently and moderately increased endogenous erythropoietin and reduced hepcidin. Adverse events were similar in the roxadustat and placebo groups. Roxadustat produced dose-dependent increases in blood Hb among anemic NDD-CKD patients in a placebo-controlled trial. CLINICAL TRIALS REGISTRATION: Clintrials.gov #NCT00761657.

Randomized, Double-Blind, Placebo-Controlled, Withdrawal Study of Colestilan after Dose Titration in Chronic Kidney Disease Dialysis Patients with Hyperphosphatemia.

BACKGROUND/AIMS: Colestilan is a new non-calcium-based phosphate binder licensed in Europe for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis (CKD 5D). This study was conducted to evaluate efficacy in a North American patient population and also to examine secondary actions of colestilan on lipid profile and glycated hemoglobin (HbA1c). METHODS: This was a multicenter, randomized, double-blind, placebo-controlled withdrawal study, after an initial open-label titration period. Patients (n = 245) with stable phosphate control received 6-15 g/day colestilan during a 12-week, flexible titration period after which 169 were randomized to continue the same dose (n = 85) or switch to placebo (n = 84) for 4 weeks. The primary endpoint was the change in serum phosphorus level during the placebo-controlled withdrawal period. RESULTS: A significant difference of -1.01 mg/dl (-0.33 mmol/l) in mean change in serum phosphorus, favoring colestilan, was seen during the placebo-controlled withdrawal period (p < 0.001). Colestilan reduced serum phosphorus significantly from baseline to week 12 (-1.54 mg/dl (-0.50 mmol/l); p < 0.001). Serum calcium levels were not affected. Colestilan significantly reduced and maintained reductions in calcium × phosphorus ion product (Ca × P), parathyroid hormone, total cholesterol, low-density lipoprotein cholesterol, uric acid and also HbA1c in patients with elevated baseline HbA1c. Colestilan was generally well tolerated; most adverse events were gastrointestinal. CONCLUSION: In this first clinical trial with colestilan in a North American patient population, colestilan demonstrated significant efficacy in controlling serum phosphorus levels in CKD 5D patients with hyperphosphatemia, without increasing calcium levels.

A randomized comparison of ferumoxytol and iron sucrose for treating iron deficiency anemia in patients with CKD.

BACKGROUND AND OBJECTIVES: Few randomized controlled trials have compared intravenous iron products head to head in CKD patients with iron deficiency anemia. This study compared the efficacy and safety of two intravenous iron products (ferumoxytol [Feraheme injection] and iron sucrose [Venofer]) in patients with CKD and iron deficiency anemia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this phase II, randomized, open-label, active-controlled, multicenter clinical trial, patients were randomized 1:1 to either 1.02 g ferumoxytol (2 × 510-mg injections) or 1.0 g iron sucrose administered as either a slow injection or infusion (10 doses for dialysis patients and 5 doses for nondialysis patients). Inclusion criteria included hemoglobin<11.0 g/dl, transferrin saturation<30%, and eGFR<60 ml/min per 1.73 m(2) or a diagnosis of underlying CKD (e.g., nephropathy or nephritis). The primary end point was change in hemoglobin from baseline to week 5. RESULTS: In total, 162 patients were randomized. Demographics were balanced between the treatment groups. Adverse event profiles of the two regimens were fairly similar: overall adverse events, 48% ferumoxytol versus 65% iron sucrose; related adverse events, 10% ferumoxytol versus 16% iron sucrose; and adverse events leading to study discontinuation, 1% ferumoxytol versus 5% iron sucrose. Rates of serious adverse events and related serious adverse events were similar between the ferumoxytol and iron sucrose groups: serious adverse events, 9% versus 7%, respectively and related serious adverse events, 1% versus 1%, respectively. Overall, increases in hemoglobin were similar between treatment groups. Based on an ANOVA model adjusted for baseline hemoglobin level and dialysis status, the least squares mean change from baseline to week 5 was 0.8 ± 0.1 g/dl in the ferumoxytol-treated group and 0.7 ± 0.1 g/dl in the iron sucrose group. The difference in the mean change from baseline between the two treatment groups was 0.1 g/dl (95% confidence interval, -0.2 to 0.4). CONCLUSION: In this randomized, controlled trial, ferumoxytol and iron sucrose showed comparable efficacy and adverse events rates.

Converting to doxercalciferol capsules from intravenous paricalcitol or doxercalciferol.

OBJECTIVE: The purpose of the 2 studies presented in this article was to determine the clinically appropriate dose of doxercalciferol capsules that is required to maintain similar intact parathyroid hormone control when converting from intravenous (IV) paricalcitol or doxercalciferol. DESIGN: Both studies were multicenter, open-label, randomized designs comprising the following 3 periods: a screening period, a 5-week run-in period, and a 5-week treatment period. SETTING: Dialysis centers in the United States. PATIENTS: Patients with stage 5 chronic kidney disease receiving dialysis 3 times weekly for a minimum of 6 months and with recent intact parathyroid hormone measurements between 15.9 and 63.7 pmol/L (150 to 600 pg/mL) were included. INTERVENTION: After a 5-week fixed-dose IV paricalcitol or doxercalciferol run-in period, subjects were randomized to doxercalciferol capsules for the 5-week treatment period. Conversion factors for the paricalcitol study were 0.5, 1.0, and 1.5 times the current paricalcitol dose. Conversion factors for the doxercalciferol study were 1.0, 1.5, and 2.0 times the current doxercalciferol injection dose. RESULTS: The predicted conversion factor for paricalcitol injection to doxercalciferol capsules was 0.92, whereas the factor for doxercalciferol injection to doxercalciferol capsules was 1.49. No statistically significant changes in serum calcium and phosphorus levels were found in either study. The nature of adverse events was consistent with the administration of an active vitamin D therapy to patients with chronic kidney disease receiving dialysis. CONCLUSION: The studies demonstrate patients on dialysis can be safely and effectively converted from IV paricalcitol or doxercalciferol to oral doxercalciferol.

Improvement of hemodialysis catheter function with tenecteplase: a phase III, open-label study: TROPICS 4.

Hemodialysis (HD) catheters are prone to thrombotic occlusion. We evaluated tenecteplase, a thrombolytic, for the treatment of dysfunctional HD catheters. Patients with tunneled HD catheters and blood flow rate (BFR) <300 mL/min received open-label tenecteplase (2 mg/lumen) for a 1 h intracatheter dwell. Treatment success was defined as BFR ≥ 300 mL/min and a ≥ 25 mL/min increase from baseline BFR, 30 min before and at the end of HD. Patients without treatment success at the end of the initial visit received another 2 mg dose of tenecteplase for an up to 72 h extended dwell. Of 223 enrolled patients, 34% (95% confidence interval [CI], 28-40%) had treatment success after a 1 h dwell. Mean (standard deviation [SD]) BFR change from baseline was 82 (124) mL/min. Treatment success in those who received extended-dwell tenecteplase (n = 116) was 49% (95% CI, 40-58%), with mean (SD) BFR change from baseline of 117 (140) mL/min. Reported targeted adverse events included five catheter-related bloodstream infections and one thrombosis. No intracranial hemorrhage, major bleeding, embolic events, or catheter-related complications were reported. Tenecteplase administered as a 1 h or 1 h plus extended dwell was associated with improved HD catheter function in the TROPICS 4 trial.

Safety of ferumoxytol in patients with anemia and CKD.

BACKGROUND: Iron deficiency anemia is a common complication in patients with chronic kidney disease (CKD). Currently available intravenous (IV) iron replacement therapies have either inconvenient regimens of administration or adverse event profiles that limit their utility in the outpatient setting. Ferumoxytol is a novel, semisynthetic, carbohydrate-coated, superparamagnetic iron oxide nanoparticle that is administered IV as an injection. The main objective of this study was to assess the safety of ferumoxytol for the treatment of patients with CKD stages 1 to 5 and 5D. STUDY DESIGN: Phase 3, randomized, double-blind, placebo-controlled, crossover, multicenter study of a single 510-mg dose of ferumoxytol versus saline as placebo. SETTING & PARTICIPANTS: 750 patients with CKD stages 1 to 5 and 5D. INTERVENTION: An IV injection of either 17 mL of ferumoxytol or saline placebo over 17 seconds on day 0 and the alternate agent on day 7. OUTCOMES & MEASUREMENTS: Descriptive comparison of adverse events, laboratory tests, and vital signs. RESULTS: Of 750 randomly assigned patients with CKD, 60% were not on dialysis therapy. 713 patients received ferumoxytol, and 711 received placebo. There were 420 adverse events reported; 242 in 152 patients (21.3%) with ferumoxytol and 178 in 119 patients (16.7%) with placebo. The incidence of related adverse events was 5.2% with ferumoxytol and 4.5% with placebo. The most common related adverse events after each treatment included symptoms related to the injection/infusion site, dizziness, pruritus, headache, fatigue, and nausea. Serious adverse events occurred in 21 patients (2.9%) after ferumoxytol and 13 patients (1.8%) after placebo. Serious related adverse events were observed in 1 patient (0.1%) after each treatment. There was no meaningful decrease in blood pressure after administration of ferumoxytol or placebo. LIMITATIONS: Follow-up was 7 days after each study treatment. CONCLUSIONS: Ferumoxytol is well tolerated and has a safety profile similar to placebo in anemic patients with CKD stages 1 to 5 and 5D.

Assessment of the impact of weekly versus monthly erythropoiesis stimulating protein therapy on patients with CKD and their families.

This cross-sectional study measured patient and family member reported treatment and economic burden associated with monthly versus weekly erythropoiesis stimulating protein therapies for anemia in patients with CKD who were not yet on dialysis. The results indicated that compared to a weekly regimen, a monthly regimen saved patients 7 hours and family members 19 hours per month for routine anemia management. The monthly regimen substantially reduced the reported economic and treatment burdens of patient and their family members.

Darbepoetin alfa administration to achieve and maintain target hemoglobin levels for 1 year in patients with chronic kidney disease.

OBJECTIVE: To assess the efficacy and safety of every-other-week darbepoetin alfa therapy in treating anemia and maintaining hemoglobin levels for 1 year in patients with chronic kidney disease (CKD) who were not undergoing dialysis and who had not previously received erythropolesis-stimulating proteins (ESPs). PATIENTS AND METHODS: This multicenter 52-week study (evaluation period, weeks 20-32), a subanalysis of the Simplify the Treatment of Anemia with Aranesp study, enrolled patients with CKD who were not receiving dialysis (creatinine clearance < or =70 mL/min or estimated glomerular filtration rate [GFR] < or =60 mL/min). Patients evaluated in this analysis were not receiving ESPs, had hemoglobin concentrations less than 11 g/dL, and had transferrin saturation of 20% or higher during screening. Patients Initiated every-other-week darbepoetin alfa therapy at 0.75 microg/kg, with the dose subsequently titrated to maintain hemoglobin levels not to exceed 12 g/dL. The first study participant was enrolled on February 4, 2002, and the last participant completed the study on March 31, 2004. RESULTS: The analysis included 911 patients (mean [SD] age, 66.4 [14.2] years; 54.3% female; 55.3% white). The least squares mean evaluation hemoglobin concentration was 11.54 g/dL (95% confidence interval, 11.47-11.61 g/dL), and the change from baseline was 1.6 g/dL (95% confidence interval, 1.5-1.7 g/dL). The mean (SD) every-other-week darbepoetin alfa dose during evaluation was 44.5 (33.7) microg. Iron supplementation was administered to 573 patients (62.9%) during the study. Darbepoetin alfa was well tolerated throughout the study period. CONCLUSION: Darbepoetin alfa initiated every other week safely and effectively treated anemia and maintained hemoglobin for 1 year in patients with CKD who were not undergoing dialysis and who were not receiving prior ESP therapy.

Darbepoetin alfa administered every other week maintains hemoglobin levels over 52 weeks in patients with chronic kidney disease converting from once-weekly recombinant human erythropoietin: results from simplify the treatment of anemia with Aranesp (STAAR).

BACKGROUND/AIM: Darbepoetin alfa, an effective treatment for anemia of chronic kidney disease (CKD), can be administered at extended intervals. Simplify the Treatment of Anemia with Aranesp (STAAR), a multicenter, 52-week study, was conducted to assess the efficacy of darbepoetin alfa administered subcutaneously every other week (Q2W) in maintaining hemoglobin (Hb) in CKD patients not receiving dialysis. METHODS: This is a subgroup analysis of subjects converted from once-weekly (QW) recombinant human erythropoietin (rHuEPO; US Aranesp package insert) and who received up to 52 weeks of darbepoetin alfa therapy (evaluation period 20-32 weeks). Enrolled subjects had a creatinine clearance < or = 70 ml/min or an estimated glomerular filtration rate < or = 60 ml/min and transferrin saturation > or = 20%. Darbepoetin alfa doses were titrated to maintain Hb levels < or = 12 g/dl. The primary endpoint was mean Hb during evaluation. RESULTS: There were 524 subjects enrolled in the study who were previously receiving rHuEPO QW. Mean Hb +/- standard deviation was 11.2 +/- 1.27 g/dl at baseline, and the least squares mean +/- SE was 11.4 +/- 0.04 during evaluation. The mean +/- SD Q2W darbepoetin alfa dose was 49.7 +/- 21.9 microg at baseline and 48.9 +/- 35.5 microg at evaluation. Darbepoetin alfa was well tolerated. CONCLUSIONS: Study subjects with CKD receiving QW rHuEPO were effectively converted to Q2W darbepoetin alfa, which was well tolerated. Hb levels were maintained over 52 weeks without a significant change in darbepoetin alfa dose.

Assessment of time and practice resources required to provide weekly or monthly erythropoiesis-stimulating protein therapy to chronic kidney disease patients in the physician office setting.

BACKGROUND: There is an epidemic of chronic kidney disease (CKD) and a high prevalence of anemia (47%) observed in CKD patients. Little is known about the cost in physician office resources of routine erythropoiesis-stimulating protein (ESP) administration to treat patients with nondialysis CKD. OBJECTIVES: The objectives of this research were (1) to explore the patterns of care in physician offices where nondialysis CKD patients receive routine ESP injections, (2) to examine differences in the monthly resources and related costs incurred by physician offices in treating patients receiving either weekly (QW) or monthly (QM) ESP regimens, and (3) to identify opportunities to minimize the burden of CKD treatment on physician offices. METHODS: An observational, cross-sectional time and motion assessment was performed in 10 community-based outpatient nephrology practices (5 QW and 5 QM practices); each practice had 40 patients on routine ESP therapy for nondialysis CKD. Three observers trained in health care research documented injection-related tasks and time associated with 91 ESP injection procedures (47 QW and 44 QM) from patients. arrival to and departure from the physician office, office personnel follow-up on billing and documentation, and injection-related staff time. Monthly injection times for QM were calculated by summing the time required to perform the tasks associated with administering a single injection of ESP to subjects, as documented by observers. Total monthly per-patient medical practice costs for providing QM ESP injections were calculated, including labor costs (calculated by applying average wage rates of practice staff to time observed for the specific activities performed) and supply costs (based on average list prices found in medical supply catalogs). Monthly injection times and costs for the QW regimen were calculated by summing the same list of activities as for the QM regimen and multiplying by 4.3 (4.3 weeks per month). Nephrology practice personnel completed a questionnaire summarizing practice characteristics and estimated the time required for some of the injection-related activities. The time and cost associated with each task were analyzed using descriptive and comparative statistics (i.e., Fisher.s exact test and t test). RESULTS: On average, patients spent 21 minutes in the clinic for a routine injection visit (QW: 17 minutes, QM: 25 minutes; P=0.053), during which 11 minutes (52%) were spent interacting with clinic staff (QW: 8.9 minutes, QM: 13.4 minutes; P=0.005). In the time spent interacting with staff, 3 minutes (QW: 2.9 minutes, QM: 3.6 minutes; P=0.065) were for dose administration and 8 minutes (QW: 5.3 minutes, QM: 9.8 minutes; P=0.011) were for staff providing various services to the patients, including registering patients on arrival, examining patients (vital signs, weight, blood work), consulting with patients, and scheduling patients. next visits. Each month, clinic staff spent a total visit average of 38 minutes providing anemia-related treatment for each QW injection patient, compared with 13 minutes for each QM injection patient (P <0.001). After patients. departure, clinic staff spent additional time (not quantified) on billing, filing claims, and other administrative responsibilities most of which could not be observed during our 1-day observation. The average total monthly practice cost of providing ESP therapy to a QW patient (17.00 dollars [95% confidence interval (CI), 13.00-27.13]) was more than double that for a QM patient (6.78 dollars [95% CI, 5.34-9.12]); (P=0.004). Differences in visit-related labor costs (QW: 8.34 dollars, QM: 3.43 dollars; P=0.108) and injection supply costs (QW: 4.39 dollars, QM: 1.67 dollars; P <0.001) accounted for the largest portions of the total monthly cost differential between the treatment regimens. QM dosing would require, on average, 83 hours less staff time and 2,044 dollars less estimated cost treating 200 patients per month compared with weekly administration per clinic. CONCLUSIONS: Administering routine ESP injections to nondialysis CKD patients for anemia using a QM regimen results in substantial time and cost savings compared with a QW therapy regimen. Managing patients on less frequent ESP dosing schedules may alleviate medical practice burden by reducing the staff time and supplies related to providing injections in the office.