An open-label, sequential, dose-finding study of peginesatide for the maintenance treatment of anemia in chronic hemodialysis patients

ABSTRACT: BACKGROUND: Peginesatide is a peptide-based erythropoiesis-stimulating agent that was designed and engineered to stimulate specifically the erythropoietin receptor dimer that governs erythropoiesis. The primary objective of this phase 2 dose-finding study was to determine the once-monthly peginesatide dosing strategy that would maintain hemoglobin within [PLUS-MINUS SIGN]1.0 g/dL of baseline values after conversion from epoetin alfa; the safety of peginesatide was evaluated concurrently. METHODS: Chronic hemodialysis patients on stable regimens of epoetin alfa were sequentially assigned to cohorts that differed on (1) how the peginesatide starting dose was determined (using a single epoetin alfa--to-peginesatide dose conversion ratio or a tiered, weight-based or absolute-dose conversion table) and on (2) whether or not a 1-week erythropoiesis-stimulating agent-free interval was used. Peginesatide doses were titrated to maintain hemoglobin levels within [PLUS-MINUS SIGN]1.0 g/dL from baseline. RESULTS: A total of 164 patients were enrolled and received intravenous peginesatide every 4 weeks for up to 6 doses; the duration of the study including follow-up was [LESS-THAN OR EQUAL TO]29 weeks. Overall, the proportion of patients with hemoglobin levels within [PLUS-MINUS SIGN]1.0 g/dL of baseline increased over the course of the study from 39% (Weeks 2--13) to 54% (Weeks 18--25). Cohorts that used tiered dose conversion tables trended towards having more stable peginesatide doses than did those cohorts that used a single dose conversion ratio. Moreover, cohorts that used an erythropoiesis-stimulating agent-free interval did not have the substantial initial increase in hemoglobin levels that was seen in those cohorts that did not use such an interval. In this study, the safety profile of peginesatide was consistent with those of marketed erythropoiesis-stimulating agents. CONCLUSIONS: The results of this study were used to guide the dosing regimens used subsequently in phase 3 studies. Once-monthly peginesatide is feasible in hemodialysis patients.Trial registrationClinicalTrials.gov registration: NCT00228449.     

Changes in frailty-related characteristics of the hip fracture population and their implications for healthcare services: evidence from Quebec, Canada

Summary

This study provides evidence that a number of frailty-related characteristics (older age, de novo admission to long-term care (LTC), comorbidities [Charlson Index, osteoporosis, osteoporosis risk factors, sarcopenia risk factors, and dementia]) have increased in the hip fracture population from 2001–2008. This will have significant impact on community resources, as the number of people discharged to the community is also increasing.

Introduction

The aim of this study is to estimate secular changes in the prevalence of selected frailty-related characteristics among the hip fracture population in the Canadian province of Quebec (2001–2008) and the potential impact of these changes on healthcare services.

Methods

The Quebec hospitalization database was used to identify nontraumatic hip fractures for the purposes of calculating age- and sex-specific rates. Also estimated were time trends for selected frailty-related characteristics and discharge destinations.

Results

A significant decline in fracture rates was evident for all age groups except for those <65; sex differences were also observed. Almost all frailty-related characteristics increased over time, ranging from 2 to 14 % per year, which translates to an estimated increase from 16 to 112 %, over the study period. For those whose prior living arrangement was LTC, rates of hip fractures declined significantly (women OR?=?0.93, 0.91–0.95; men OR?=?0.97, 0.94–0.99). In-hospital mortality and discharge to inpatient rehabilitation decreased, while discharges back to community and to LTC increased.

Conclusions

Although hip fracture rates decreased for older hip fracture patients, the absolute number and prevalence of specific frailty-related characteristics increased. Policy makers should review care models to ensure that adequate resources are provided to the community to offset the expected increase in demand arising from ongoing changes in patients’ characteristics.     

Bayesian design for two-arm randomized Phase II clinical trials with endpoints from the exponential family using multiple constraints

Frequentist design for two-arm randomized Phase II clinical trials with outcomes from the exponential dispersion family was proposed previously, where the total sample sizes are minimized under multiple constraints on the standard errors of the estimated group means and their difference. This design was generalized from an approach specific for dichotomous outcomes. The two previous approaches measure the central tendency of each group and treatment effect based on mean and difference in means. Other measures such as median or hazard ratio are more appropriate under certain situations. In addition, the frequentist approaches assume that unknown parameters are fixed values. This does not reflect the reality that uncertainty always exists for unknowns. Compared to the frequentist methods, the Bayesian approach offers a flexible way to measure central tendency and treatment effect, and incorporate uncertainty in parameters of interest into considerations. In this article, we generalize a Bayesian design for Phase II clinical trials with endpoints in the exponential family from the two previously developed frequentist approaches. The proposed design minimizes the total sample sizes under pre-specified constraints on the expected length of posterior credible intervals for measures of treatment effect and central tendency in each group. The design is applicable for trials with fixed or optimal randomization allocation ratio and can be applied under adaptive procedure. Examples of method implementations are provided for different types of endpoints from the exponential family in both fixed and adaptive settings.     

Improvements in Back and Leg Pain After Minimally Invasive Lumbar Decompression

HSS Journal ® - Few studies have quantified clinical improvement following minimally invasive lumbar decompression based on predominant back pain or leg pain. To quantify improvement in...     

Etiology-Based Classification of Adjacent Segment Disease Following Lumbar Spine Fusion

Background

Adjacent segment disease (ASDz) is a potential complication following lumbar spinal fusion. A common nomenclature based on etiology and ASDz type does not exist and is needed to assist with clinical prognostication, decision making, and management.

Questions/Purposes

The objective of this study was to develop an etiology-based classification system for ASDz following lumbar fusion.

Methods

We conducted a retrospective chart review of 65 consecutive patients who had undergone both a lumbar fusion performed by a single surgeon and a subsequent procedure for ASDz. We established an etiology-based classification system for lumbar ASDz with the following six categories: “degenerative” (degenerative disc disease or spondylosis), “neurologic” (disc herniation, stenosis), “instability” (spondylolisthesis, rotatory subluxation), “deformity” (scoliosis, kyphosis), “complex” (fracture, infection), or “combined.” Based on this scheme, we determined the rate of ASDz in each etiologic category.

Results

Of the 65 patients, 27 (41.5%) underwent surgery for neurogenic claudication or radiculopathy for adjacent-level stenosis or disc herniation and were classified as “neurologic.” Ten patients (15.4%) had progressive degenerative disc pathology at the adjacent level and were classified as “degenerative.” Ten patients (15.4%) had spondylolisthesis or instability and were classified as “instability,” and three patients (4.6%) required revision surgery for adjacent-level kyphosis or scoliosis and were classified as “deformity.” Fifteen patients (23.1%) had multiple diagnoses that included a combination of categories and were classified as “combined.”

Conclusion

This is the first study to propose an etiology-based classification scheme of ASDz following lumbar spine fusion. This simple classification system may allow for the grouping and standardization of patients with similar pathologies and thus for more specific pre-operative diagnoses, personalized treatments, and improved outcome analyses.

     

Decreased inhibin gene expression in preovulatory follicles requires primary gonadotropin surges

We have examined the role of the primary gonadotropin surges in regulating inhibin alpha- and beta A-subunit mRNA levels in rat ovarian follicles. Inhibin subunit mRNA levels decline dramatically on the evening of proestrus in follicles of the ovulatory pool. Because this decline is temporally associated with primary gonadotropin surges, we investigated the contribution of LH and FSH to this process. The primary gonadotropin surges were blocked by injection of a GnRH antagonist (WY45760) at 1200 h on proestrus. This resulted in sustained elevation of inhibin mRNA levels through 0700 h of the subsequent day, a time when inhibin mRNA levels would normally be very low. Replacement of either exogenous LH or FSH in ovulatory doses to an antagonist-treated animal at 1530 h on proestrus resulted in a decrease in inhibin mRNA levels by 4-5 h postreplacement. We conclude that LH and FSH act via a common mechanism to repress inhibin mRNA levels in stimulated preovulatory follicles.