Efficacy and safety of sevelamer carbonate in hyperphosphatemic pediatric patients with chronic kidney disease.

BACKGROUND: Treatment for hyperphosphatemia in chronic kidney disease (CKD) involves dietary control of phosphorus intake, dialysis, and treatment with oral phosphate binders, none of which were approved by the Federal Food and Drug Administration in pediatric patients at the time of this study. METHODS: This was a phase 2, multicenter study (NCT01574326) with a 2-week, randomized, placebo-controlled, fixed-dose period (FDP) followed by a 6-month, single-arm, open-label, dose-titration period (DTP), with the aim to evaluate the safety and efficacy of sevelamer carbonate (SC) in hyperphosphatemic pediatric patients with CKD. Following a 2-4 week screening phase, pediatric patients with a serum phosphorus level higher than age-appropriate levels were randomized to receive either SC or placebo as powder/tablets in 0.4-1.6 g doses, based on body surface area. The primary efficacy outcome was the change in serum phosphorus from baseline to end of the FDP in the SC versus placebo arms (analysis of covariance). The secondary outcome was mean change in serum phosphorus from baseline to end of DTP by treatment group and overall. Treatment-emergent/serious adverse events (AEs) were recorded. RESULTS: Of 101 enrolled patients (29 centers), 66 completed the study. The majority of patients were adolescents (74%; mean age 14.1 years) and on dialysis (77%). Renal transplant was the main reason for discontinuation. SC significantly reduced serum phosphorus from baseline levels (7.16 mg/dL) during the FDP compared to placebo (least square mean difference - 0.90 mg/dL, p = 0.001) and during the DTP (- 1.18 mg/dL, p < 0.0001). The safety and tolerability of SC and placebo were similar during the FDP, with patients in both groups reporting mild/moderate gastrointestinal AEs during the DTP. CONCLUSIONS: Sevelamer carbonate significantly lowered serum phosphorus levels in hyperphosphatemic children with CKD, with no serious safety concerns identified.

A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study of Fresolimumab in Patients With Steroid-Resistant Primary Focal Segmental Glomerulosclerosis.

INTRODUCTION: Steroid-resistant focal segmental glomerulosclerosis (SR-FSGS) is a common glomerulopathy associated with nephrotic range proteinuria. Treatment goals are reduction in proteinuria, which can delay end-stage renal disease. METHODS: Patients with SR-FSGS were enrolled in a randomized, double-blind placebo-controlled trial of fresolimumab, a monoclonal anti-transforming growth factor-ß antibody, at 1 mg/kg or 4 mg/kg for 112 days, followed double-blind for 252 days (NCT01665391). The primary efficacy endpoint was the percentage of patients achieving partial (50% reduction) or complete (< 300 mg/g Cr) remission of proteinuria. RESULTS: Of 36 enrolled patients, 10, 14, and 12 patients received placebo, fresolimumab 1 mg/kg, and fresolimumab 4 mg/kg, respectively. The baseline estimated glomerular filtration rate (eGFR) and urinary protein/creatinine ratio were 63 ml/min/1.73 m2 and 6190 mg/g, respectively. The study was closed before reaching its target of 88 randomized patients. None of the prespecified efficacy endpoints for proteinuria reduction were achieved; however, at day 112, the mean percent change in urinary protein/creatinine ratio (a secondary efficacy endpoint) was -18.5% (P = 0.008), +10.5% (P = 0.52), and +9.0% (P = 0.91) in patients treated with fresolimumab 1 mg/kg, fresolimumab 4 mg/kg, and placebo, respectively. There was a nonsignificant trend toward greater estimated glomerular filtration rate decline in the placebo group compared to either of the fresolimumab-treated arms up to day 252. DISCUSSION: The study was underpowered and did not meet the primary or secondary endpoints. However, fresolimumab was well tolerated and is appropriate for continued evaluation in larger studies with adequate power.

Seprafilm® adhesion barrier: (1) a review of preclinical, animal, and human investigational studies.

The aim of this study was to provide a single site resource for investigators, clinicians, and others seeking preclinical, animal, and human investigational studies concerning the postsurgical, anti-adhesion barrier Seprafilm™ (Genzyme Corporation, Cambridge, MA). All published preclinical, animal, human extra-abdominal research as of July 2011 have been summarized and included in this document. Searches of Medline and EMBASE Drugs and Pharmaceuticals databases were conducted for original preclinical, animal, and human extra-abdominal studies involving Seprafilm. Preclinical, animal, and extra-abdominal human investigational studies are the study selection for this manuscript. Intraabdominal use is discussed in the accompanying manuscript. Data extraction includes systematic manuscript review. Summary of preclinical, animal, and extra-abdominal human investigational use of Seprafilm by surgical discipline were gathered for data synthesis. The clinical use of Seprafilm, which was approved by the FDA for intra-abdominal procedures, is supported by preclinical and animal studies relating to general surgical and obstetrical/gynecological applications. Findings from preclinical, animal, and human investigational studies at other sites throughout the body raises the potential for additional human clinical trials to assess efficacy and safety following surgical procedures at non-abdominal locations.

Seprafilm(®) adhesion barrier: (2) a review of the clinical literature on intraabdominal use.

This study seeks to provide a review of the clinical data published as of July 2011 concerning the postsurgical adhesion barrier, Seprafilm (chemically modified hyaluronic acid and carboxymethylcelulose; Genzyme Corporation, Cambridge, MA). Included articles detail the application of Seprafilm for intraabdominal uses that have been approved (on-label) and those considered investigational (off-label) by the FDA. Medline and EMBASE Drugs and Pharmaceuticals databases were searched for all original clinical Seprafilm research published as of July 2011. All human Seprafilm intraabdominal clinical reports and studies, excluding those related to prosthetic mesh were included. Data extraction involved the systematic review of each article. The data synthesis is the summary of Seprafilm human intraabdominal clinical reports and studies describing safety and/or efficacy. The safety and efficacy of Seprafilm in reducing postoperative adhesions has been clearly demonstrated in abdominal and pelvic laparotomy. While reports have described the safe and successful use of Seprafilm following laparoscopy, pediatric laparotomy, and in patients with malignancy and/or infection, the safety and efficacy of Seprafilm use in these procedures has not been definitively established in randomized controlled trials.