Everolimus with cyclosporine withdrawal or low-exposure cyclosporine in kidney transplantation from Month 3: a multicentre, randomized trial.

BACKGROUND.: Randomized trials have shown that early adoption of everolimus-based immunosuppressive regimens without a calcineurin inhibitor (CNI) improves long-term kidney graft function, but the optimal strategy for CNI minimization remains uncertain. METHODS.: In a prospective, randomized, multicentre, 12-month trial, 499 de novo kidney transplant patients were randomized at Month 3 to (i) remain on standard CNI (cyclosporine) therapy with mycophenolic acid, (ii) convert to everolimus with mycophenolic acid or (iii) start everolimus with reduced CNI and no mycophenolic acid (clinical trials registry: ClinicalTrials.gov-NCT00514514). RESULTS.: The primary endpoint, change in estimated glomerular filtration rate (eGFR) (Nankivell) from randomization to Month 12, was significantly greater in the CNI-free arm versus standard CNI therapy: mean difference 5.6 mL/min/1.73 m 2 [95% confidence interval (CI) 2.8-8.3 mL/min/1.73 m 2 , P < 0.001]. The improvement in eGFR in the CNI-free arm was also higher than in the low-CNI group (mean difference 5.5 mL/min/1.73 m 2 , 95% CI 2.8-8.2 mL/min/1.73 m 2 , P < 0.001), while results were similar in the low-CNI and standard CNI arms. The post-randomization incidence of biopsy-proven acute rejection was 11.7%, 8.1% and 7.9% in the CNI-free, low-CNI and standard CNI groups, respectively (CNI-free versus standard CNI, P = 0.27; low-CNI versus standard CNI, P = 1.00). Adverse events led to study drug discontinuation in 28.7%, 15.5% and 15.2% of CNI-free, low-CNI and standard CNI patients, respectively. CONCLUSIONS.: Everolimus initiation with CNI withdrawal at Month 3 after kidney transplantation achieves a significant improvement in renal function at 12 months, with a similar rate of acute rejection.

Fast onset of action of glycopyrronium compared with tiotropium in patients with moderate to severe COPD - A randomised, multicentre, crossover trial.

BACKGROUND: Long-acting bronchodilators, including anticholinergics glycopyrronium and tiotropium, are central to symptomatic management of chronic obstructive pulmonary disease (COPD). In patients with moderate to severe COPD, glycopyrronium has demonstrated comparable efficacy to open-label and single-blinded tiotropium, but with faster onset of bronchodilation. The FAST study assessed the efficacy of glycopyrronium compared with tiotropium in serial spirometry and body plethysmography assessments to further characterize the earlier onset of action associated with glycopyrronium. METHODS: In this German multicentre, randomised, double-blinded, double-dummy, cross-over study, patients with moderate-to-severe COPD received single-dose of glycopyrronium 44 µg and tiotropium 18 µg via the Breezhaler® and Handihaler® devices, respectively. Primary objective was to demonstrate superiority of glycopyrronium over tiotropium in terms of improvement in forced expiratory volume in 1 s as assessed by the area under the curve from 0 to 2 h (FEV1 AUC 0-2h). Secondary endpoints were functional residual capacity (FRC), residual volume (RV), inspiratory capacity (IC), and specific airway resistance (sRaw), all measured by body plethysmography. RESULTS: Of the 152 patients randomised, 99.3% completed the study. After inhalation of the single dose, glycopyrronium demonstrated superiority over tiotropium in early bronchodilation as assessed by improvement in FEV1 AUC0-2h (least squares mean treatment difference = 37 mL; 95% CI: 16, 59 mL; p < 0.01) and FEV1 at 15 min post-dose (least square mean treatment difference = 36 mL; 95% CI: 14, 58 mL; p < 0.01). Both treatments showed similar improvements in FRCpleth, RV, and IC. Glycopyrronium showed statistically significant improvement in sRaw compared with tiotropium over the first 90 min after dosing, with the difference of 0.184 kPa × s at 90 min post-dose (95% CI: 0.315,0.054 kPa × s; p < 0.01). CONCLUSIONS: Glycopyrronium was superior to tiotropium in terms of early bronchodilation. Although both glycopyrronium and tiotropium showed similar improvements in static lung volume parameters, glycopyrronium reduced specific airway resistance faster than tiotropium, which could in part explain the earlier FEV1 response seen with glycopyrronium. TRIAL REGISTRATION: ClinicalTrials.govNCT01922271.

Octreotide LAR and Prednisone as Neoadjuvant Treatment in Patients with Primary or Locally Recurrent Unresectable Thymic Tumors: A Phase II Study.

Therapeutic options to cure advanced, recurrent, and unresectable thymomas are limited. The most important factor for long-term survival of thymoma patients is complete resection (R0) of the tumor. We therefore evaluated the response to and the induction of resectability of primarily or locally recurrent unresectable thymomas and thymic carcinomas by octreotide Long-Acting Release (LAR) plus prednisone therapy in patients with positive octreotide scans. In this open label, single-arm phase II study, 17 patients with thymomas considered unresectable or locally recurrent thymoma (n = 15) and thymic carcinoma (n = 2) at Masaoka stage III were enrolled. Octreotide LAR (30 mg once every 2 weeks) was administered in combination with prednisone (0.6 mg/kg per day) for a maximum of 24 weeks (study design according to Fleming´s one sample multiple testing procedure for phase II clinical trials). Tumor size was evaluated by volumetric CT measurements, and a decrease in tumor volume of at least 20% at week 12 compared to baseline was considered as a response. We found that octreotide LAR plus prednisone elicited response in 15 of 17 patients (88%). Median reduction of tumor volume after 12 weeks of treatment was 51% (range 20%-86%). Subsequently, complete surgical resection was achieved in five (29%) and four patients (23%) after 12 and 24 weeks, respectively. Octreotide LAR plus prednisone treatment was discontinued in two patients before week 12 due to unsatisfactory therapeutic effects or adverse events. The most frequent adverse events were gastrointestinal (71%), infectious (65%), and hematological (41%) complications. In conclusion, octreotide LAR plus prednisone is efficacious in patients with primary or recurrent unresectable thymoma with respect to tumor regression. Octreotide LAR plus prednisone was well tolerated and adverse events were in line with the known safety profile of both agents.

Early conversion from cyclosporine to everolimus following living-donor kidney transplantation: outcomes at 5 years posttransplant in the randomized ZEUS trial.

AIMS: To assess 5-year efficacy, renal, and safety outcomes following early conversion from cyclosporine to everolimus vs. a standard cyclosporine-based regimen in living-donor kidney transplant (LDKT) recipients. MATERIALS AND METHODS: The ZEUS study was a randomized, open-label, 1-year, multicenter study in which 300 de novo kidney transplant recipients continued to receive cyclosporine or converted to everolimus at 4.5 months post-transplant, with annual follow-up visits to 5 years post-transplant. RESULTS: Of the 80 LDKT patients who were randomized, 75 completed the 1-year core study and 60 attended the 5-year follow-up visit. At year 5, 15/31 (48.4%) everolimus patients and 20/29 (69.0%) cyclosporine patients remained on the study drug. Mean adjusted estimated glomerular filtration rate (GFR) at year 5 in LDKT recipients was 67.2 vs. 60.8 mL/min/1.73m2 for everolimus vs. cyclosporine (mean difference 6.4 mL/min/1.73m2; p = 0.031). For patients who remained on study drug, the mean difference was 13.2 mL/min/1.73m2 (p = 0.003), but no significant difference was seen in patients who switched from study drug (mean -2.6 mL/min/1.73m2, p = 0.701). Patient and graft survival rates were similar with everolimus and cyclosporine. Biopsy-proven acute rejection occurred in 22.0% vs. 7.5% of LDKT patients randomized to everolimus vs. cyclosporine (p = 0.116). Only 1 LDKT patient discontinued everolimus due to adverse events during years 1 - 5. CONCLUSIONS: Early initiation of everolimus with calcineurin-inhibitor (CNI) withdrawal after LDKT improved graft function to 5 years post-transplant compared to standard CNI-based therapy. The renal benefit was concentrated in patients who remained on everolimus. An increase in mild acute rejection was not associated with long-term graft loss.

The MANDELA study: A multicenter, randomized, open-label, parallel group trial to refine the use of everolimus after heart transplantation.

In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein.

Renal, efficacy and safety outcomes following late conversion of kidney transplant patients from calcineurin inhibitor therapy to everolimus: the randomized APOLLO study.

AIMS: The primary objective of this trial was to demonstrate, based on the estimated glomerular filtration rate (eGFR), superior renal function at month 12 after conversion of maintenance kidney transplant patients from calcineurin inhibitor (CNI) therapy to everolimus, compared to continuing a standard CNI regimen. MATERIALS AND METHODS: APOLLO was an open-label, 12-month, prospective, multicenter study in which 93 maintenance kidney transplant patients were randomized to convert from CNI to everolimus (n = 46) or remain on standard CNI-based immunosuppression (n = 47). The primary efficacy variable was eGFR (Nankivell formula) 12 months after randomization. The study was terminated prematurely due to slow recruitment and was thus underpowered. RESULTS: Mean time post-transplant was 83.5 months with everolimus and 70.1 months with CNI. Adjusted values for eGFR (Nankivell) at month 12 were 61.6 (95% CI 58.1, 65.1) mL/ min/1.73 m² with everolimus and 58.8 (95% CI 55.2, 62.3) mL/min/1.73 m² with CNI, a difference of 2.8 (95% CI -1.0, 6.7) mL/ min/1.73 m² (p = 0.145) i.e., the primary objective was not met. Using the modification of diet in renal disease (MDRD) formula, adjusted eGFR at month 12 was significantly higher with everolimus (p = 0.030). In the subpopulation who remained on the study drug (n = 52), the difference in the adjusted change from randomization was 6.6 (95% CI 1.5, 11.6) mL/min/1.73 m² (p = 0.013) in favor of everolimus. There was no biopsyproven acute rejection and no graft losses. Adverse events led to discontinuation of everolimus and CNI in 32.6% and 10.6% of patients, respectively. CONCLUSIONS: Conversion from CNI to everolimus to preserve renal function can be considered several years after kidney transplantation and does not compromise immunosuppressive efficacy.

Efficacy and safety of conversion from cyclosporine to everolimus in living-donor kidney transplant recipients: an analysis from the ZEUS study.

Conversion of living-donor kidney transplant patients from calcineurin inhibitor therapy to an mTOR inhibitor is poorly documented. In the prospective, multicentre ZEUS study, 300 kidney transplant recipients without prior rejection (Banff grade >1) and serum creatinine ≤265 µmol/l were randomized to continue cyclosporine or convert to everolimus at 4.5 months post-transplant. In a post hoc analysis of 80 living-donor recipients, adjusted estimated GFR (Nankivell) at month 12 (the primary endpoint) was 74.3 (95% CI [70.7, 77.9]) ml/min/1.73 m(2) with everolimus versus 63.8 (95% CI [60.0, 67.7]) ml/min/1.73 m(2) ) with cyclosporine, a difference of 10.5 ml/min/1.73 m(2) in favour of everolimus (P < 0.001). From randomization to month 12, adjusted estimated GFR increased by a mean of 9.8 (95% CI [6.2, 13.4]) ml/min/1.73 m(2) with everolimus versus -0.7 (95% CI [-4.6, 3.1]) ml/min/1.73 m(2) ) (P < 0.001) with cyclosporine. There were six biopsy-proven acute rejection episodes in everolimus-treated patients (five Banff grade I) and one episode in cyclosporine-treated patients (Banff grade 1). Overall safety profile was similar between groups. Discontinuation due to adverse events occurred in three everolimus patients (7.1%) and five cyclosporine patients (13.2%) between randomization and month 12. Initiation of everolimus with early elimination of calcineurin therapy is associated with a significant renal benefit at 12 months post-transplant that is observed in both living and deceased-donor recipients. (clinicaltrials.gov NCT00154310).

BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition.

BACKGROUND: Polyomavirus BK nephropathy (PyVAN) remains an important cause of early graft dysfunction and graft loss in kidney transplantation. METHODS: In this retrospective, single centre cohort study we studied the incidence and outcome of BK viral infection in 352 patients transplanted in 2008-2011. RESULTS: During follow-up viral replication was detected in 48 patients (13.6%); 22 patients (6.2%) had biopsy proven PyVAN.In multivariate logistic regression analyses risk factors for BK-viremia were lack of enrolment into randomized controlled trials (RCTs), biopsy proven acute rejections, cytomegaly virus (CMV) serostatus of both donor and recipient and previous transplantation.In patients without PyVAN reduction or switch of immunosuppression was associated with rapid viral clearance and stable graft function. In contrast, in most patients with PyVAN graft function deteriorated and 5 patients prematurely lost their allograft. Switch of immunosuppression to a low dose cyclosporine plus mTOR inhibitor based regimen in patients with PyVAN was safe, well tolerated and tended to be associated with a better short-term outcome in terms of graft function compared to reduction of existing immunosuppression alone. CONCLUSIONS: With the lack of licensed anti-polyoma viral drugs reduction or conversion of immunosuppression remains the mainstay of therapy in patients with PyVAN. The combination of low dose cyclosporine plus mTOR inhibition appears to be safe and warrants further investigation.

A randomized trial of intensified vs. standard dosing for enteric-coated mycophenolate sodium in de novo kidney transplant recipients: results at 1 year.

In a 6-month prospective, openlabel, multicenter study, 128 de novo kidney transplant patients receiving cyclosporine (CsA) and steroids were randomized to an intensified regimen of enteric-coated mycophenolate sodium (EC-MPS) or to a standard EC-MPS regimen to Week 6 posttransplant, after which the regimen was identical. In a follow-up study to Month 12 post-transplant (49 intensified regimen, 52 standard regimen), the reduced rate of BPAR observed at Month 6 (intensified regimen 3.2%, standard regimen 16.9%, p = 0.016) was maintained at Month 12 (4.8% vs. 18.5%, p = 0.026). Estimated GFR (Cockcroft-Gault) at Month 12 was comparable in the intensified group (mean (SD) 54.8 (22.9) ml/min) vs. the standard group (mean (SD) 57.5 (23.6) ml/min, p = 0.83). The incidence of adverse events and serious adverse events at Month 12 was similar in both treatment groups, although adverse events with a suspected relation to study drug were reported in 69.8% and 50.8% of patients in the intensified and standard regimen groups, respectively (p = 0.032). Infections and hematological parameters were similar between groups. In conclusion, an early regimen of intensified EC-MPS with CsA and steroids achieves a low rate of BPAR over the first year after kidney transplantation with similar renal function to a standard regimen, and without a clinically relevant impact on safety.

Positive effects of zoledronate on skeletal-related events in patients with renal cell cancer and bone metastases.

INTRODUCTION: Approximately 30% of patients with renal cell cancer (RCC) develop bone metastasis causing skeletal-related events (SRE): pathologic fracture, spinal cord compression, surgery to bone and radiotherapy. Zoledronic acid demonstrated significant clinical benefit in RCC patients in a retrospective analysis. Primary objective of this prospective study was the proportion of patients experiencing ≥ 1 SRE during 12 months of zoledronic acid treatment and to verify the retrospective data. MATERIALS AND METHODS: Fifty patients with histologically confirmed RCC and evidence of ≥ 1 cancer-related bone lesion and ≤ 3 prior bisphosphonate applications were enrolled in 19 German centers between 2004 and 2007. The patients received 4 mg zoledronic acid every 3 weeks for 12 months followed by a follow up period for overall survival of 12 months. Bone lesions were diagnosed by bone scan or MRI-quickscan. Greater and equal to 1 lesion had to be confirmed by x-ray, CT or MRI scan. Additional bone scans were performed after completion of study treatment and if clinically indicated. In case of suspicion or evidence of a SRE it had to be confirmed radiologically. RESULTS: In total, 49 of the 50 enrolled patients were treated. Only 11 of them (22.4%) experienced any SRE until month 12. Patients with > 6 lesions and higher baseline MSKCC (Memorial Sloan-Kettering Cancer Center) score had a higher risk for SREs. Zoledronic acid was generally well tolerated and its known safety profile was affirmed. CONCLUSIONS: This prospective study confirms the results of prior data about the efficacy of zoledronic acid in patients with metastatic (m)RCC, supporting its beneficial use in these patients.

The ZOTECT study: Effect of zoledronic acid on bone metabolism in patients with bone metastases from prostate or breast cancer.

PURPOSE: The ZOTECT study assesses the effect of zoledronic acid (ZOL) on bone-marker levels and potential correlations with disease outcomes in bisphosphonate-naive patients. METHODS: This prospective, single-arm, open-label study in bisphosphonate-naive (≥6 months) patients with bone metastases from prostate cancer (PC; n=301) or breast cancer (BC; n=99) enrolled at 98 German sites (May 2006 to July 2008) investigated the effect of ZOL (4 mg intravenously every 4 weeks×4 months, with a final follow-up at 12 months) on bone-marker levels. Secondary assessments: skeletal-related event (SRE) rate, pain, quality of life (QoL), and prostate-specific antigen levels. Endpoints were assessed using summary statistics by visit/tumor type and Kaplan-Meier analyses. RESULTS: ZOL treatment significantly decreased bone-marker levels (amino-terminal propeptide of type I collagen [P1NP], C-terminal cross-linking telopeptide of type I collagen [CTX]; P<0.0001), and this decrease was maintained through the final 1-year follow-up visit. Baseline P1NP and CTX levels correlated with extent of bone disease (P<0.0001, each) and on-treatment decreases in marker levels. Skeletal disease burden and bone-marker levels were similar between PC and BC patients, and ZOL did not significantly influence osteoprotegerin/receptor activator of nuclear factor-κB ligand levels. Only 13 SREs occurred in 11 patients, supporting the known ZOL-mediated reduction in SREs. On-treatment bone-marker level changes did not correlate with SRE rate, pain scores, or QoL. Generally, ZOL was well tolerated and adverse events were consistent with its known safety profile. CONCLUSIONS: This study confirms that ZOL therapy significantly reduces bone turnover (measured as P1NP and CTX levels) in patients with bone metastases from PC or BC.

Everolimus in patients with autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a slowly progressive hereditary disorder that usually leads to end-stage renal disease. Although the underlying gene mutations were identified several years ago, efficacious therapy to curtail cyst growth and prevent renal failure is not available. Experimental and observational studies suggest that the mammalian target of rapamycin (mTOR) pathway plays a critical role in cyst growth. METHODS: In this 2-year, double-blind trial, we randomly assigned 433 patients with ADPKD to receive either placebo or the mTOR inhibitor everolimus. The primary outcome was the change in total kidney volume, as measured on magnetic resonance imaging, at 12 and 24 months. RESULTS: Total kidney volume increased between baseline and 1 year by 102 ml in the everolimus group, versus 157 ml in the placebo group (P=0.02) and between baseline and 2 years by 230 ml and 301 ml, respectively (P=0.06). Cyst volume increased by 76 ml in the everolimus group and 98 ml in the placebo group after 1 year (P=0.27) and by 181 ml and 215 ml, respectively, after 2 years (P=0.28). Parenchymal volume increased by 26 ml in the everolimus group and 62 ml in the placebo group after 1 year (P=0.003) and by 56 ml and 93 ml, respectively, after 2 years (P=0.11). The mean decrement in the estimated glomerular filtration rate after 24 months was 8.9 ml per minute per 1.73 m2 of body-surface area in the everolimus group versus 7.7 ml per minute in the placebo group (P=0.15). Drug-specific adverse events were more common in the everolimus group; the rate of infection was similar in the two groups. CONCLUSIONS: Within the 2-year study period,as compared with placebo, everolimus slowed the increase in total kidney volume of patients with ADPKD but did not slow the progression of renal impairment [corrected]. (Funded by Novartis; EudraCT number, 2006-001485-16; ClinicalTrials.gov number, NCT00414440.)

Bone turnover markers as predictive tools for skeletal complications in men with metastatic prostate cancer treated with zoledronic acid.

BACKGROUND: Bone turnover markers are helpful to diagnose bone metastases. The aim of this study was to evaluate the usefulness of these markers in prostate cancer patients with bone metastases before and during the treatment with zoledronic acid as predictive and monitoring tools of skeletal-related events (SRE). METHODS: One hundred seventeen prostate cancer patients with bone metastases and treated with zoledronic acid (4 mg every 4 weeks) were examined. Fifty-six patients were with and 61 patients without SRE during a 60-week study. Total and bone-specific alkaline phosphatase, and amino-terminal procollagen propeptides of type-I-collagen (PINP), cross-linked N-terminal (NTx), cross-linked C-terminal telopeptides of type-I-collagen (ICTP), and C-terminal telopeptides of type-I-collagen as well as prostate-specific antigen (PSA) were measured before and 12, 24, 36, 48, and 60 weeks after starting treatment. RESULTS: Higher baseline concentrations were observed in the SRE group. The bone markers except for ICTP and tALP decreased to 20-80% of the baseline values at week 12 after the drug administration showing a generally higher decline in the non-SRE group except for NTx. At all time points during treatment higher and increasing concentrations of bone markers were observed in the SRE group compared with non-SRE group. Cox regression models with clinical data and bone markers showed the baseline NTx concentration as predictor of SREs. During the study, percentage changes of PINP and ICTP were most indicative for SREs. CONCLUSIONS: Bone markers are useful tools to predict and diagnose SRE in prostate cancer patients with bone metastases under receiving zoledronic acid therapy.