Treatment Outcomes Among Patients With a Positive Candida Culture Close to Randomization Receiving Rezafungin or Caspofungin in the ReSTORE Study.

BACKGROUND: Rezafungin, a novel, once-weekly echinocandin for the treatment of candidemia and/or invasive candidiasis (IC) was noninferior to caspofungin for day 30 all-cause mortality (ACM) and day 14 global cure in the phase 3 ReSTORE trial (NCT03667690). We conducted preplanned subgroup analyses for patients with a positive culture close to randomization in ReSTORE. METHODS: ReSTORE was a multicenter, double-blind, double-dummy, randomized trial in patients aged ≥18 years with candidemia and/or IC treated with once-weekly intravenous rezafungin (400 mg/200 mg) or once-daily intravenous caspofungin (70 mg/50 mg). This analysis comprised patients with a positive blood culture drawn between 12 hours before and 72 hours after randomization or a positive culture from another normally sterile site sampled between 48 hours before and 72 hours after randomization. Efficacy endpoints included day 30 ACM, day 14 global cure rate, and day 5 and 14 mycological response. Adverse events were evaluated. RESULTS: This analysis included 38 patients randomized to rezafungin and 46 to caspofungin. In the rezafungin and caspofungin groups, respectively, day 30 ACM was 26.3% and 21.7% (between-group difference [95% confidence interval], 4.6% [-13.7%, 23.5%]), day 14 global response was 55.3% and 50.0% (between-group difference, 5.3% [-16.1%, 26.0%]), and day 5 mycological eradication was 71.1% and 50.0% (between-group difference, 21.1% [-0.2%, 40.2%]). Safety was comparable between treatments. CONCLUSIONS: These findings support the efficacy and safety of rezafungin compared with caspofungin for the treatment of candidemia and/or IC in patients with a positive culture close to randomization, with potential early treatment benefits for rezafungin.

Rezafungin versus caspofungin for patients with candidaemia or invasive candidiasis in the intensive care unit: pooled analyses of the ReSTORE and STRIVE randomised trials.

BACKGROUND: Rezafungin is an echinocandin approved in the US and EU to treat candidaemia and/or invasive candidiasis. This post-hoc, pooled analysis of the Phase 2 STRIVE and Phase 3 ReSTORE trials assessed rezafungin versus caspofungin in patients with candidaemia and/or invasive candidiasis (IC) in the intensive care unit (ICU) at randomisation. METHODS: STRIVE and ReSTORE were randomised double-blind trials in adults with systemic signs and mycological confirmation of candidaemia and/or IC in blood or a normally sterile site ≤ 96 h before randomisation. Data were pooled for patients in the ICU at randomisation who received intravenous rezafungin (400 mg loading dose then 200 mg once weekly) or caspofungin (70 mg loading dose then 50 mg once daily) for ≤ 4 weeks. Outcomes were Day 30 all-cause mortality (primary outcome), Day 5 and 14 mycological eradication, time to negative blood culture, mortality attributable to candidaemia/invasive candidiasis, safety, and pharmacokinetics. RESULTS: Of 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, ~ 30% of patients in each group had impaired renal function and/or an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥ 20. One patient (in the caspofungin group) was neutropenic at baseline. Day 30 all-cause mortality was 34.8% for rezafungin versus 25.4% for caspofungin. Day 5 and 14 mycological eradication was 78.3% and 71.7% for rezafungin versus 59.7% and 65.7% for caspofungin, respectively. Median time to negative blood culture was 18 (interquartile range, 12.6-43.0) versus 38 (interquartile range, 15.9-211.3) h for rezafungin versus caspofungin (stratified log-rank P = 0.001; nominal, not adjusted for multiplicity). Candidaemia/IC-attributable deaths occurred in two rezafungin patients versus one caspofungin patient. Safety profiles were similar between groups. Overall, 17.4% (rezafungin) versus 29.9% (caspofungin) of patients discontinued due to treatment-emergent adverse events. Rezafungin exposure following the initial 400-mg dose was comparable between patients in the ICU at randomisation (n = 50) and non-ICU patients (n = 117). CONCLUSIONS: Rezafungin was well tolerated and efficacious in critically ill, mainly non-neutropenic patients with candidaemia and/or IC. This analysis provides additional insights into the efficacy and safety of rezafungin in the ICU population.

Outcomes in patients with chronic kidney disease not on dialysis receiving extended dosing regimens of darbepoetin alfa: long-term results of the EXTEND observational cohort study.

BACKGROUND: Extended dosing of the erythropoiesis-stimulating agent (ESA) darbepoetin alfa (DA) once biweekly or monthly reduces anaemia treatment burden. This observational study assessed outcomes and dosing patterns in patients with chronic kidney disease not on dialysis (CKD-NoD) commencing extended dosing of DA. METHODS: Adult CKD-NoD patients starting extended dosing of DA in Europe or Australia in June 2006 or later were followed up until December 2012. Outcomes included haemoglobin (Hb) concentration, ESA dosing, mortality rates and receipt of dialysis and renal transplantation. Subgroup analyses were conducted for selected outcomes. RESULTS: Of 6035 enrolled subjects, 5723 (94.8%) met analysis criteria; 1795 (29.7%) received dialysis and 238 (3.9%) underwent renal transplantation. Mean (standard deviation) Hb concentration at commencement of extended dosing was 11.0 (1.5) g/dL. Mean [95% confidence interval (CI)] Hb 12 months after commencement of extended dosing (primary outcome) was 11.6 g/dL (11.5, 11.6) overall and was similar across countries, with no differences between subjects previously treated with an ESA versus ESA-naïve subjects, subjects with versus without prior renal transplant or diabetics versus non-diabetics. Weekly ESA dose gradually decreased following commencement of extended DA dosing and was similar across subgroups. The decrease in weekly DA dose was accompanied by an increase in the proportion of patients receiving iron therapy. Hb concentrations declined following changes in ESA labels and treatment guidelines. The mortality rate (95% CI) was 7.06 (6.68, 7.46) deaths per 100 years of follow-up. Subjects alive at study end had stable Hb concentrations in the preceding year, while those who died had lower and declining Hb concentrations in their last year. CONCLUSIONS: Long-term, extended dosing of DA maintained Hb concentrations in patients already treated with an ESA and corrected and maintained Hb in ESA-naïve patients.

Data sharing and the evolving role of statisticians.

BACKGROUND: Greater transparency and, in particular, sharing of clinical study reports and patient level data for further research is an increasingly important topic for the pharmaceutical and biotechnology industry and other organisations who sponsor and conduct clinical research as well as academic researchers and patient advocacy groups. Statisticians are ambassadors for data sharing and are central to its success. They play an integral role in data sharing discussions within their companies and also externally helping to shape policy and processes while providing input into practical solutions to aid data sharing. Data sharing is generating changes in the required profile for statisticians in the pharmaceutical and biotechnology industry, as well as academic institutions and patient advocacy groups. DISCUSSION: Successful statisticians need to possess many qualities required in today's pharmaceutical environment such as collaboration, diplomacy, written and oral skills and an ability to be responsive; they are also knowledgeable when debating strategy and analytical techniques. However, increasing data transparency will require statisticians to evolve and learn new skills and behaviours during their career which may not have been an accepted part of the traditional role. Statisticians will move from being the gate-keepers of data to be data facilitators. To adapt successfully to this new environment, the role of the statistician is likely to be broader, including defining new responsibilities that lie beyond the boundaries of the traditional role. Statisticians should understand how data transparency can benefit them and the potential strategic advantage it can bring and be fully aware of the pharmaceutical and biotechnology industry commitments to data transparency and the policies within their company or research institute in addition to focusing on reviewing requests and provisioning data. Data transparency will evolve the role of statisticians within the pharmaceutical and biotechnology industry, academia and research bodies to a level which may not have been an accepted part of their traditional role or career. In the future, skills will be required to manage challenges arising from data sharing; statisticians will need strong scientific and statistical guiding principles for reanalysis and supplementary analyses based on researchers' requests, have enhanced consultancy skills, in particular the ability to defend good statistical practice in the face of criticism and the ability to critique methods of analysis. Statisticians will also require expertise in data privacy regulations, data redaction and anonymisation and be able to assess the probability of re-identification, an ability to understand analyses conducted by researchers and recognise why such analyses may propose different results compared to the original analyses. Bringing these skills to the implementation of data sharing and interpretation of the results will help to maximise the value of shared data while guarding against misleading conclusions.

Safety and usage of darbepoetin alfa in children with chronic kidney disease: prospective registry study.

BACKGROUND: Limited prospective data are available on the long-term safety of darbepoetin alfa (DA) for treating anemia in children with chronic kidney disease (CKD). METHODS: In this prospective, phase IV, observational registry study, children ≤16 years of age with CKD anemia and receiving DA were observed for ≤2 years. Adverse events (AEs), DA dosing, hemoglobin (Hb) concentrations, and transfusions were recorded. RESULTS: A total of 319 patients were included in the analysis (mean age, 9.1 years), 158 (49.5%) of whom were on dialysis at study entry. Of 434 serious AEs reported in 162 children, the most common were peritonitis (10.0%), gastroenteritis (6.0%), and hypertension (4.1%). Six patients (1.9%) died (unrelated to DA). Four patients (1.3%) experienced six serious adverse drug reactions. The geometric mean DA dose range was 1.4-2.0 µg/kg/month. Mean baseline Hb concentration was 11.1 g/dl; mean values for children receiving and not receiving dialysis at baseline ranged between 10.9 and 11.5 g/dl and 11.2-11.7 g/dl, respectively. Overall, 48 patients (15.0%) received ≥1 transfusion. CONCLUSIONS: No new safety signals for DA were identified in children receiving DA for CKD anemia for ≤2 years. Based on Hb concentrations and transfusion requirements, DA was effective at managing anemia in these patients.

Darbepoetin alfa once monthly corrects anaemia in patients with chronic kidney disease not on dialysis.

AIM: While darbepoetin alfa (DA) can be administered once monthly (QM) to maintain haemoglobin (Hb) concentrations in anaemic patients with chronic kidney disease not on dialysis (CKD-ND), the QM use of DA for anaemia correction has not been previously investigated. METHODS: In this randomized, double-blind, non-inferiority, active-controlled study, adult subjects with CKD-ND, Hb levels <10 g/dL, and not treated with an erythropoiesis-stimulating agent were randomized 1:1 to receive DA every 2 weeks (Q2W) or QM for 33 weeks with initial doses of 0.75 µg/kg Q2W or 1.5 µg/kg QM. Subjects were treated to target Hb levels of 10-12 g/dL and ≥1 g/dL increase from baseline. The primary end-point was Hb change between baseline and the evaluation period (weeks 29-33), with a non-inferiority margin of -0.5 g/dL. RESULTS: Three hundred and fifty-five subjects received ≥1 dose of DA. Mean (95% confidence interval [CI]) change in Hb between baseline and the evaluation period was 2.16 (1.98-2.33) g/dL for the Q2W group and 1.97 (1.80-2.14) g/dL for the QM group, the mean (95% CI) difference in Hb change being -0.19 (-0.43 to 0.05) g/dL. Most subjects (97.9% Q2W; 98.1% QM) achieved a Hb level ≥10.0 g/dL and ≥1.0 g/dL increase in Hb from baseline. Mean DA (SD) weekly equivalent doses over the evaluation period were 0.20 (0.23) and 0.27 (0.31) µg/kg per week for the Q2W and QM groups, respectively. Safety profiles were similar between groups. CONCLUSION: In subjects with CKD-ND, QM dosing was non-inferior to Q2W dosing for anaemia correction and had a similar safety profile.

Pooled analysis of pralatrexate single-agent studies in patients with relapsed/refractory peripheral T-cell lymphoma.

ABSTRACT: Patients with relapsed or refractory (R/R) mature natural killer cell and T-cell lymphoma have limited treatment options. To evaluate pralatrexate's performance and factors influencing its safety and efficacy in R/R peripheral T-cell lymphoma (PTCL), we performed a pooled analysis of data from 4 similarly designed, regulatory-mandated prospective clinical trials. Of 221 patients (median age, 59 years; 67.0% male) in the study population, 48.9% had PTCL not otherwise specified (PTCL-NOS), 21.3% angioimmunoblastic T-cell lymphoma, and 11.8% ALK-negative anaplastic large cell lymphoma (ALCL). Patients received pralatrexate for a median of 2.56 months (range, 0.03-24.18) and had a 40.7% objective response rate with a median duration of response of 9.1 months, progression-free survival 4.6 months, and overall survival 16.3 months. The most common treatment-related all-grade adverse events were stomatitis, thrombocytopenia, white blood cell count decrease, pyrexia, and vomiting. Subgroup exploratory analyses suggest improved efficacy with 1 prior line of chemotherapy vs 2 or ≥4 prior lines; PTCL-NOS or ALCL vs transformed mycosis fungoides; chemotherapy and transplant before pralatrexate vs chemotherapy alone or chemotherapy with other nontransplant treatments. In conclusion, these pooled analysis results further support using pralatrexate in patients with R/R PTCL. Prospective studies are needed to confirm the findings of subgroups analyses.

Preservation of anemia control and weekly ESA dosage after conversion from PEG-Epoetin beta to darbepoetin alfa in adult hemodialysis patients: the TRANSFORM study.

INTRODUCTION: There is scant real-world information on switching treatment for anemia associated with chronic kidney disease (CKD) from methoxy polyethylene glycol-epoetin beta (PEG-Epo) to darbepoetin alfa (DA). TRANSFORM was a multi-center, observational study designed to describe the time course of hemoglobin (Hb) concentration (primary outcome measure) and other parameters of clinical management of anemia in European hemodialysis patients in clinical practice before and after a switch from PEG-Epo to DA. METHODS: Eligible subjects were adult patients with CKD dialyzed at European dialysis centers for ≥26 weeks and treated with PEG-Epo for ≥14 weeks immediately prior to being switched to DA and no earlier than January 2011. Erythropoiesis-stimulating agent doses and Hb values were recorded for the 14-week pre-switch and 26-week post-switch periods. RESULTS: Of the 1,027 eligible patients enrolled at 42 hemodialysis centers in 7 European countries, 785 were included in analyses. Mean (95% confidence interval [CI]) Hb was generally stable: 11.19 (11.11, 11.26), 11.48 (11.40, 11.57), and 11.29 (11.20, 11.37) g/dL at month -1 pre-switch and months 3 and 6 post-switch, respectively. The geometric mean (95% CI) PEG-Epo dose at month -1 was 27.4 (26.0, 28.8) µg/week; DA dose was 29.4 (27.9, 30.9), 23.3 (21.9, 24.9), and 25.6 (24.1, 27.1) µg/week at months 1, 4, and 6, respectively. The geometric mean (95% CI) dose ratio at switching was 1.06 (1.01, 1.11). When stratifying by dose-ratio categories <0.8, 0.8-1.2, and >1.2 at switching, mean DA dose and Hb converged within narrow ranges by month 6 post-switch: 23.9-27.0 µg/week and 11.1-11.5 g/dL, respectively. Hb excursions <10 g/dL were less frequent post-switch versus pre-switch. CONCLUSION: Mean Hb values remained within a narrow range following switching from PEG-Epo to DA in this population of hemodialysis patients. Time trends of mean Hb and DA dose indicate that physicians titrated DA doses post-switch, to attain Hb concentrations comparable to those attained pre-switch with PEG-Epo.

Dose conversion ratio in hemodialysis patients switched from darbepoetin alfa to PEG-epoetin beta: AFFIRM study.

INTRODUCTION: There is limited information published on switching erythropoiesis-stimulating agent (ESA) treatment for anemia associated with chronic kidney disease (CKD) from darbepoetin alfa (DA) to methoxy polyethylene glycol-epoetin beta (PEG-Epo) outside the protocol of interventional clinical studies. AFFIRM (Aranesp Efficiency Relative to Mircera) was a retrospective, multi-site, observational study designed to estimate the population mean maintenance dose conversion ratio [DCR; dose ratio achieving comparable hemoglobin level (Hb) between two evaluation periods] in European hemodialysis patients whose treatment was switched from DA to PEG-Epo. METHODS: Eligible patients had received hemodialysis for ≥ 12 months and DA for ≥ 7 months. Data were collected from 7 months before until 7 months after switching treatment. DCR was calculated for patients with Hb and ESA data available in both evaluation periods (EP; Months 1 and 2 were defined as the pre-switch EP, and Months 6 and 7 as the post-switch EP). Red blood cell transfusions pre- and post-switch were quantified. RESULTS: Of 302 patients enrolled, 206 had data available for DCR analysis. The geometric mean DCR was 1.17 (95% CI 1.05, 1.29). Regression analysis indicated a non-linear relationship between pre- and post-switch ESA doses; DCR decreased with increasing pre-switch DA dose. The geometric mean weekly ESA doses were 24.1 µg DA in the pre-switch EP and 28.6 µg PEG-Epo in the post-switch EP. Mean Hb was 11.5 g/dL in the pre-switch EP and 11.4 g/dL in the post-switch EP. There were 16 transfusions and 34 units transfused in the pre-switch period, versus 48 transfusions and 95 units transfused post-switch. Excluding patients receiving a transfusion within 90 days of or during either EP, the DCR was 1.21 (95% CI 1.09, 1.35). CONCLUSION: In these hemodialysis patients switched from DA to PEG-Epo the DCR was 1.17 and 1.21 after accounting for the effect of transfusions. The number of transfusions and units transfused increased approximately threefold from the pre-switch to the post-switch period.

Serum phosphorus reduction in dialysis patients treated with cinacalcet for secondary hyperparathyroidism results mainly from parathyroid hormone reduction.

BACKGROUND: The calcimimetic cinacalcet lowers parathyroid hormone (PTH), calcium (Ca) and phosphorus (P) in dialysis patients with secondary hyperparathyroidism (SHPT). We explored serum P changes in dialysis patients treated with cinacalcet, while controlling for vitamin D sterol and phosphate binder (PB) changes, based on data from the pan-European observational study ECHO. METHODS: Patients were categorized by serum P change (decreased/unchanged/increased) at 12 months after starting cinacalcet and subcategorized by vitamin D sterol and PB dose changes (decreased/unchanged/increased). The impact of PTH, Ca and P, and vitamin D sterol, PB and cinacalcet doses (absolute values and/or change) was evaluated. Predictors of P change were explored using univariate and multivariate general linear models (GLM) and logistic regression analysis. RESULTS: At Month 12, 661 (41%) of 1607 patients had decreased, 61 (4%) unchanged and 400 (25%) increased serum P, while 485 patients had missing data. In 45% of the patients with serum P reduction, vitamin D was either increased or unchanged and P binders decreased or unchanged. PTH was a key predictor of serum P reduction, with an estimated 3% decrease in P per 10% reduction in PTH. Changes in vitamin D sterol and PB doses were not generally significant factors in GLM and regression analyses. CONCLUSIONS: The serum P reduction observed in a significant proportion of dialysis patients after adding cinacalcet to an existing therapeutic regimen for SHPT appears to result mainly from PTH reduction, rather than from changes in vitamin D sterol or PB doses. Financial support for the ECHO study was provided by Amgen.