Randomized investigation of increased dialyzer membrane hydrophilicity on hemocompatibility and performance.

BACKGROUND: Hemodialyzers should efficiently eliminate small and middle molecular uremic toxins and possess exceptional hemocompatibility to improve well-being of patients with end-stage kidney disease. However, performance and hemocompatibility get compromised during treatment due to adsorption of plasma proteins to the dialyzer membrane. Increased membrane hydrophilicity reduces protein adsorption to the membrane and was implemented in the novel FX CorAL dialyzer. The present randomized controlled trial compares performance and hemocompatibility profiles of the FX CorAL dialyzer to other commonly used dialyzers applied in hemodiafiltration treatments. METHODS: This prospective, open, controlled, multicentric, interventional, crossover study randomized stable patients on post-dilution online hemodiafiltration (HDF) to FX CorAL 600, FX CorDiax 600 (both Fresenius Medical Care) and xevonta Hi 15 (B. Braun) each for 4 weeks. Primary outcome was ß2-microglobulin removal rate (ß2-m RR). Non-inferiority and superiority of FX CorAL versus comparators were tested. Secondary endpoints were RR and/or clearance of small and middle molecules, and intra- and interdialytic profiles of hemocompatibility markers, with regards to complement activation, cell activation/inflammation, platelet activation and oxidative stress. Further endpoints were patient reported outcomes (PROs) and clinical safety. RESULTS: 82 patients were included and 76 analyzed as intention-to-treat (ITT) population. FX CorAL showed the highest ß2-m RR (76.28%), followed by FX CorDiax (75.69%) and xevonta (74.48%). Non-inferiority to both comparators and superiority to xevonta were statistically significant. Secondary endpoints related to middle molecules corroborated these results; performance for small molecules was comparable between dialyzers. Regarding intradialytic hemocompatibility, FX CorAL showed lower complement, white blood cell, and platelet activation. There were no differences in interdialytic hemocompatibility, PROs, or clinical safety. CONCLUSIONS: The novel FX CorAL with increased membrane hydrophilicity showed strong performance and a favorable hemocompatibility profile as compared to other commonly used dialyzers in clinical practice. Further long-term investigations should examine whether the benefits of FX CorAL will translate into improved cardiovascular and mortality endpoints. TRIAL REGISTRATION: eMPORA III registration on 19/01/2021 at ClinicalTrials.gov (NCT04714281).

Hemodiafiltration: Technical and Medical Insights.

Despite the significant medical and technical improvements in the field of dialytic renal replacement modalities, morbidity and mortality are excessively high among patients with end-stage kidney disease, and most interventional studies yielded disappointing results. Hemodiafiltration, a dialysis method that was implemented in clinics many years ago and that combines the two main principles of hemodialysis and hemofiltration-diffusion and convection-has had a positive impact on mortality rates, especially when delivered in a high-volume mode as a surrogate for a high convective dose. The achievement of high substitution volumes during dialysis treatments does not only depend on patient characteristics but also on the dialyzer (membrane) and the adequately equipped hemodiafiltration machine. The present review article summarizes the technical aspects of online hemodiafiltration and discusses present and ongoing clinical studies with regards to hard clinical and patient-reported outcomes.

Lifestyle aspects in a contemporary middle-European cohort of patients undergoing androgen deprivation therapy for advanced prostate cancer: data from the non-interventional LEAN study.

Androgen deprivation therapy (ADT) in men with prostate cancer (PCa) is associated with significant side effects. With the transition of PCa from a foudroyant course to a chronic disease, managing these side effects has become increasingly important. There is growing evidence that nutritional changes and physical activity are beneficial in these patients. Here we examine the impact of written patient information on the physical activity and dietary habits of PCa patients receiving ADT and behaviour changes between baseline and 1 year, in the open-label, non-interventional LEAN study. In total, 959 patients with advanced hormone-sensitive PCa requiring ADT with the Leuprorelin Sandoz® implant were included from January 2014 to July 2015 and followed for ≥ 12 months. At the start of the study, urologists received a questionnaire concerning the written information provided to patients regarding their disease, patient advocacy groups, diet and physical activity. Patients received a questionnaire on their dietary habits and physical activity at the start and end of the study. Urologists from 147 study centres and 540 patients responded to the questionnaires. While 69 % of these patients received disease-specific information, only 30 % and 17 % received information regarding nutrition and physical activity, respectively. The majority of urologists estimate that their patients rarely or never follow guidance on nutrition or physical activity, yet > 90 % of patients indicate they would make use of this information, if provided. Few patients showed behavioural changes between baseline and 1 year without evident differences between patients that received information and those that did not.

Impact of Hydrophilic Modification of Synthetic Dialysis Membranes on Hemocompatibility and Performance.

The dialyzer is the core element in the hemodialysis treatment of patients with end-stage kidney disease (ESKD). During hemodialysis treatment, the dialyzer replaces the function of the kidney by removing small and middle-molecular weight uremic toxins, while retaining essential proteins. Meanwhile, a dialyzer should have the best possible hemocompatibility profile as the perpetuated contact of blood with artificial surfaces triggers complement activation, coagulation and immune cell activation, and even low-level activation repeated chronically over years may lead to undesired effects. During hemodialysis, the adsorption of plasma proteins to the dialyzer membrane leads to a formation of a secondary membrane, which can compromise both the uremic toxin removal and hemocompatibility of the dialyzer. Hydrophilic modifications of novel dialysis membranes have been shown to reduce protein adsorption, leading to better hemocompatibility profile and performance stability during dialysis treatments. This review article focuses on the importance of performance and hemocompatibility of dialysis membranes for the treatment of dialysis patients and summarizes recent studies on the impact of protein adsorption and hydrophilic modifications of membranes on these two core elements of a dialyzer.

Randomized comparison of three high-flux dialyzers during high-volume online hemodiafiltration-the comPERFORM study.

Background: Dialyzers should be designed to efficiently eliminate uraemic toxins during dialysis treatment, given that the accumulation of small and middle molecular weight uraemic solutes is associated with increased mortality risk of patients with end-stage renal disease. In the present study we investigated the novel FX CorAL dialyzer with a modified membrane surface for performance during online hemodiafiltration (HDF) in a clinical setting. Methods: comPERFORM was a prospective, open, controlled, multicentric, interventional, crossover study with randomized treatment sequences. It randomized stable patients receiving regular post-dilution online HDF to FX CorAL 600 (Fresenius Medical Care Deutschland), xevonta Hi 15 (B. Braun) and ELISIO 150H (Nipro) each for 1 week. The primary outcome was ß2-m removal rate (ß2-m RR) during online HDF. Secondary endpoints were RR and/or clearance of ß2-m and other molecules. Albumin removal over time was an exploratory endpoint. Non-inferiority and superiority of FX CorAL 600 versus comparators were tested. Results: Fifty-two patients were included and analysed. FX CorAL 600 showed the highest ß2-m RR (75.47%), followed by xevonta Hi 15 (74.01%) and ELISIO 150H (72.70%). Superiority to its comparators was statistically significant (P = 0.0216 and P < 0.0001, respectively). Secondary endpoints related to middle molecules affirmed these results. FX CorAL 600 demonstrated the lowest albumin removal up to 60 minutes and its sieving properties changed less over time than with comparators. Conclusions: FX CorAL 600 efficiently removed middle and small molecules and was superior to the two comparators in ß2-m RR. Albumin sieving kinetics point to reduced formation of a secondary membrane.

Effectiveness and Distribution of Testosterone Levels within First Year of Androgen Deprivation Therapy in a Real-World Setting: Results from the Non-Interventional German Cohort LEAN Study.

BACKGROUND: Observational studies generate information on real-world therapy and complement data from prospective randomized trials. LEAN is an open-label, non-interventional, multi-centre, German cohort study on leuprorelin in routine clinical practice. OBJECTIVES: To extend knowledge on the use, effectiveness, and tolerability of HEXAL/Sandoz leuprorelin (in this article, the term Leuprone® HEXAL® covers Leuprorelin Sandoz® as well) solid implant in patients with prostate cancer (PCa) in a real-world setting. METHODS: 959 PCa patients scheduled for androgen deprivation therapy (ADT) received leuprorelin acetate implant. Metabolism, serum prostate-specific antigen (PSA), and testosterone data, if available, were collected at baseline and follow-up visits for ≥12 months. RESULTS: Of 694 patients in the modified full analysis set, 26.4% received GnRH analogues ≤6 months before enrolment. Fifty-one percent of patients were treated for locally advanced or metastatic PCa. In 19.6% of patients, ADT was used in neoadjuvant or adjuvant settings and in 28.5% with rising PSA after definite therapy. Testosterone levels <0.5 ng/mL were achieved in >90% of patients. Safety profile was in line with the summary of product characteristics. Therapy was well tolerated, with patient-triggered therapy discontinuation in 3.6%. CONCLUSIONS: This interim analysis confirmed previous efficacy findings for leuprorelin implant in a real-world setting. This contemporary cohort showed a shift in the use of ADT to non-metastatic PCa stages.

Survey to estimate the prevalence of type 2 diabetes mellitus in hospital patients in Germany by systematic HbA1c measurement upon admission.

OBJECTIVES: The objective of this survey was to estimate the prevalence of type 2 diabetes mellitus (T2DM) in hospitalised patients ≥55 years based on routine HbA1c measurement upon admission, using the diagnosis algorithm according to the German National Diabetes Care Guideline. DESIGN: Non-interventional survey. SETTING: Four German maximum care hospitals. POPULATION: Consecutive patients ≥55 years of age admitted to hospital. MAIN OUTCOME MEASURES: Participating hospitals measured HbA1c upon admission and applied the algorithm for diagnosing T2DM per the clinical recommendations of the American Diabetes Association (ADA) and the German National Diabetes Care Guideline as part of the clinical routine and allocated patients to three diagnostic categories: T2DM, increased risk for T2DM, no T2DM. RESULTS: Between Oct 2014 and May 2015, the survey documented data from 6092 patients; the analyses included 5820 patients fulfilling validity criteria (95.5%). Of these, 1906 (32.7%) had a known history of T2DM. Among the 3914 remaining patients, 2181 had no T2DM (55.8%), 1180 an increased risk for T2DM (30.1%) and 553 unrecognised T2DM (14.1%; 95% CI: 13.1%-15.3%). The overall prevalence of known and unrecognised T2DM was 42.3% (95% CI: 41.0%-43.5%). Patients with previously unrecognised T2DM were admitted to hospital predominantly for cardiac disorders (21.9%), nervous system disorders such as cerebral infarction (15.0%) and infections/infestations (13.4%). CONCLUSIONS: This survey revealed an overall prevalence of known and unrecognised T2DM of more than 40%. Among patients with unrecognised T2DM on admission, the prevalence of T2DM was 14%. These data indicate that systematic documentation of T2DM in in-patients is clinically useful. Hospitals should consider using the diagnostic algorithm and to streamline pathways of care to secure adequate care considering patients' diabetic risk profiles, and to manage related additional costs.

Tolerability and effectiveness of an antitrauma cream with comfrey herb extract in pediatric use with application on intact and on broken skin.

OBJECTIVE: The safety of comfrey herbal cream application to broken skin is still a matter of regulatory debate. It was therefore examined in children with intact and with broken skin treated for blunt traumas and sports injuries, with the aim of collecting data for pharmacovigilance and clinical safety assessments. METHODS: A total of 712 children (386 children with intact skin and 326 children with abrasions and superficial wounds) were openly treated for up to 2 weeks with 1-5 applications daily of comfrey herb cream after presenting for blunt traumas and sports accidents. The incidence rate of adverse events was calculated, next to a global assessment of treatment effects. RESULTS: No adverse events occurred in the group of children with intact skin, and one intolerability reaction (burning and reddening) was observed after application to broken skin. The overall incidence rate of intolerability reactions per patient was calculated as 0.14% (95% CI 0.00-0.78%) and that of systemic adverse effects as 0.00% (95% CI 0.00-0.42%). Accordingly, the probability of the occurrence of local reactions and systemic adverse events is well below, which is one in 100 treated patients. The global assessment of effects corresponded to previously published experience. CONCLUSION: These studies confirm an excellent benefit-to-risk ratio for the application of comfrey herb cream in the treatment of blunt traumas and sports injuries in children with intact and with broken skin.

Comparative Study with a Lip Balm Containing 0.5% Propolis Special Extract GH 2002 versus 5% Aciclovir Cream in Patients with Herpes Labialis in the Papular/Erythematous Stage: A Single-blind, Randomized, Two-arm Study.

BACKGROUND AND OBJECTIVES: This controlled single-blind trial compared the efficacy of a lip balm with propolis special extract GH 2002 at a concentration of 0.5% in the treatment of episodes of herpes labialis with that of 5% aciclovir cream. METHODS: Patients in the erythematous/papular stage were randomized: 189 patients were treated with propolis cream, 190 patients were treated with aciclovir cream (intention-to-treat population). Application was 5 times daily. The primary parameter was the difference in median time to complete encrustation or epithelialization of lesions. Secondary parameters were the development of typical herpes symptoms (eg, pain, burning and itching, tension, and swelling), the global assessment of efficacy, and the safety of application. RESULTS: The predefined clinical situation was reached after a median of 4 days with propolis and after 5 days with aciclovir (P < 0.0001). Significant differences in favor of the study preparation were found with all secondary parameters and symptoms. No allergic reactions, local irritations, or other adverse events were observed. CONCLUSIONS: A formulation of 0.5% propolis GH 2002 extract lip balm was found to be superior in the treatment of episodes of herpes labialis over 5% aciclovir cream in patients in the papular/erythematous phase upon inclusion. EudraCT Registration No. 2006-001971-38.

Early onset of efficacy in patients with functional and motility-related gastrointestinal disorders : A noninterventional study with Iberogast®.

STW 5 (Iberogast®; Steigerwald Arzneimittelwerk GmbH, Darmstadt, Germany) contains nine plant extracts and possesses well-documented overall efficacy in functional gastrointestinal disorders (FGID). Little is known about the onset of symptom relief. Twenty-nine centers in Germany recruited 272 patients with established FGID. These patients were treated with STW 5 for approximately 3 weeks in this noninterventional study. Patients assessed the severity of their gastrointestinal complaints before and at defined times after the intake of STW 5 (10 cm visual analogue scale; VAS). Fifteen minutes after the first dose, the severity of gastrointestinal complaints had decreased by 1.4 cm (mean; initial mean: 5.2 of 10 cm). After 1 h, more than 90% of the maximum effect of 3.2 cm on the 10 cm VAS had been reached. Most patients with symptoms experienced a marked improvement within 5, 15 or 30 min of taking STW 5. Absolute improvements were larger in patients with more pronounced baseline complaints. Subgroups with upper (80% of the study population) and lower FGID (20%) did not present major differences. Neither did subgroups by age and duration of complaints. Treatment with STW 5 resulted in rapid improvement of symptoms.

Prevention and treatment of chemotherapy-induced neutropenia with the biosimilar filgrastim: a non-interventional observational study of clinical practice patterns.

BACKGROUND: Biosimilars are similar but non-identical versions of existing biological drugs. The HEXAFIL study was an observational study that assessed the clinical usage, safety and efficacy of the biosimilar filgrastim in routine clinical practice in Germany. PATIENTS AND METHODS: A total of 1,337 cancer patients received the biosimilar filgrastim for primary prophylaxis (PP), secondary prophylaxis (SP) or interventional treatment (TX) plus chemotherapy. Data including neutropenic complications and adverse events (AEs) were documented for up to 3 consecutive cycles. RESULTS: In cycle 1, 44.9% of the patients received the biosimilar filgrastim as PP, 31.0% as SP, and 23.6% as TX. Approximately 90% of the patients required no modifications to their chemotherapy regimen, with lower rates among the PP/SP versus the TX patients. Neutropenic complications occurred in 7.9%, 6.9%, and 3.9% of the patients (cycles 1, 2, and 3, respectively). Only 1.8% of the patients experienced febrile neutropenia during cycle 1. Earlier and longer filgrastim treatment reduced grade 3/4 leukopenia and neutropenic complications. The observed safety/tolerability profile was as expected; the most common AE (4.3%) was musculoskeletal back/bone pain. CONCLUSION: In this observational real-life study of clinical practice, the biosimilar filgrastim was effective and well tolerated, with results consistent with those reported in phase II and phase III trials. © 2015 S. Karger GmbH, Freiburg.

[Drugs in chronic venous insufficiency--the challenge of demonstrating clinical efficacy]. / Der Nachweis der klinischen Wirksamkeit von Odemprotektiva und seine Tücken.

Approximately 90% of German adults show alterations of their lower limb veins; about every fifth suffers from symptoms of chronic venous insufficiency (CVI). With compression therapy showing low compliance, CVI oedemas and accompanying subjective symptoms are frequently treated with anti-oedematous drugs of herbal origin. A guideline outlines the requirements for clinical studies with CVI drugs. Water displacement plethysmometry (volumetry) is the gold standard for determining the reduction ofoedemas. Besides reducing oedemas, drugs should also demonstrate effects on accompanying symptoms influencing quality of life. Despite assistance provided by the guideline, clinical studies in CVI are complex and subject to multiple error sources in planning and execution. The corroboration of successful studies in further confirmatory studies is good practice and demanded by regulatory authorities. This practice reduces the risk of drugs being accepted as effective just based on the play of chance. As an example, placebo controlled studies with an extract from red vine leaves show that a careful definition of patients as well as meticulous study planning and execution can reproducibly verify significant and clinically relevant treatment effects. When evaluating clinical studies it is recommended to refer to the CONSORT statement. Publications missing certain minimum information make interpretation difficult and may result in a biased judgment of the effects of therapy.

STW 5 (Iberogast®)--a safe and effective standard in the treatment of functional gastrointestinal disorders.

Functional dyspepsia (FD) and irritable bowel syndrome (IBS) are frequent disorders affecting quality of life. They often require long-term treatment. Abdominal symptoms of both disorders can overlap, making differential diagnosis and treatment challenging. The extracts of the herbal combination preparation STW 5 (Iberogast(®)) exert pharmacological effects in different gastrointestinal regions and can address symptoms of both FD and IBS. This review summarizes safety and efficacy data of 12 clinical trials using STW 5 in FD and IBS since 1990. Double-blind and randomized studies versus placebo or active control found statistically significant effects of STW 5 on patients' symptoms with a comparable efficacy to a standard prokinetic. Non-interventional and retrospective studies confirmed these effects. Various studies evaluated the tolerability profile of STW 5: the incidence of adverse drug reactions was 0.04%. The worldwide spontaneous reporting system confirmed this profile. STW 5 has a favorable tolerability which is relevant for long-term treatment.

Acute bronchitis therapy with ivy leaves extracts in a two-arm study. A double-blind, randomised study vs. an other ivy leaves extract.

Ivy leaves extracts are authorised in medicinal products for the treatment of acute bronchitis. Different studies and the long experience on the market show safety and efficacy of this drug. A double-blind, randomised study was conducted to assess the efficacy and tolerability of ivy leaves soft extract with an other ivy leaves extract. 590 patients with acute bronchitis participated in this study. They were treated with test or comparator for 7 days (±1). The Bronchitis Severity Score (BSS) decreased gradually and to a similar extent from Day 1 to Day 7 in both treatment groups. Starting from values of 6.2-6.3±1.2, the BSS decreased by approximately 4.7-4.9 points until Day 7, so that patients left the study with a mean BSS of 1.4-1.6. The BSS subscales cough, sputum, rhales/rhonchi, chest pain during coughing, and dyspnoea improved to a similar extent in both treatment groups. Overall, 2.7% of patients (per group and overall) experienced an adverse event, all of which were non-serious. Fewer patients younger than ten years had adverse events than would have been expected from their share of the study population (p=0.015; Fisher's exact test). As a conclusion, the test product with ivy leaves soft extract proved to be non-inferior to the comparator ivy leaves extract in improving symptoms of acute bronchitis.

Water displacement leg volumetry in clinical studies--a discussion of error sources.

BACKGROUND: Water displacement leg volumetry is a highly reproducible method, allowing the confirmation of efficacy of vasoactive substances. Nevertheless errors of its execution and the selection of unsuitable patients are likely to negatively affect the outcome of clinical studies in chronic venous insufficiency (CVI). DISCUSSION: Placebo controlled double-blind drug studies in CVI were searched (Cochrane Review 2005, MedLine Search until December 2007) and assessed with regard to efficacy (volume reduction of the leg), patient characteristics, and potential methodological error sources. Almost every second study reported only small drug effects (

Alpha-dihydroergocryptine in the long-term therapy of Parkinson's disease.

The trial was designed as an open-label, post-authorisation safety study, aimed to complete the available information on adverse events and drug reactions to alpha-dihydroergocryptine (CAS 14271-05-7, alpha-DHEC). The study included 294 patients with idiopathic Parkinson's disease who received levodopa (CAS 59-92-7, L-DOPA) and started taking alpha-DHEC (Cripar). Adverse events were analysed descriptively, Parkinson's disease symptoms were documented using a questionnaire applied by the physicians. Patients were evaluated at study start and three and six months later, respectively. In 31 patients, 32 adverse events were observed, gastrointestinal and nervous system disorders being the most frequent. Dyskinesias, psychoses/hallucinations, sleep disturbances, and cardiovascular disorders were uncommon (< or = 1%). in total, 21 adverse events were classified as adverse drug reactions. In nearly 80 % of the cases, Parkinson symptoms had improved or completely vanished. Symptoms were unchanged in 16.7 % of patients and had worsened in 3.1%. The results confirm that the use of alpha-DHEC in combination therapy with levodopa in patients with Parkinson's disease is a well-tolerated and efficacious treatment option.