Randomized clinical trial to compare efficacy and safety of repeated courses of rituximab to single-course rituximab followed by maintenance mycophenolate-mofetil in children with steroid dependent nephrotic syndrome.

BACKGROUND: Approximately 30% of children with idiopathic nephrotic syndrome develop a complicated course with frequent relapses or steroid dependency. Rituximab, a B cell depleting monoclonal antibody, is a safe and effective alternative to steroids or other immunosuppressants for achieving and maintaining remission in this population at short term. Despite the good initial response relapses inevitably occur after regeneration of B lymphocytes, necessitating either repeat courses of rituximab or addition of another steroid-sparing immunosuppressant. METHODS: This is a prospective, single-center, open-label, two-parallel-arm randomized controlled phase III study among children with steroid dependent nephrotic syndrome who are maintained in remission with oral steroids. One hundred children will be randomized to either Rituximab and maintenance Mycophenolate mofetil (A) or repeated courses of prophylactic Rituximab only (B). In arm A, mycophenolate mofetil (1200 mg/m2 per day) will be started 3 months after Rituximab administration. In arm B, Rituximab infusions will be administered at 0, 8 and 16 months if B cell count normalize at the given time points. Prednisolone will be discontinued in both groups 2 weeks following first course of rituximab. Primary aim is to evaluate the difference in 24-month relapse-free survival. Main secondary endpoints are cumulative prednisolone dose, frequency of relapses and changes in anthropometry. Circulating B lymphocyte populations will be studied as biomarkers or predictors of rituximab responsiveness and adverse events will be analysed. DISCUSSION: The study will provide evidence as to the comparative safety and efficacy of two alternative steroid-sparing therapeutic options in children suffering from steroid dependent nephrotic syndrome. The two-year study design will address the long-term results obtained with the alternative treatment protocols. TRIAL REGISTRATION: This trial was prospectively registered to the Clinicaltrial.gov ( NCT03899103 dated 02/04/2019; https://clinicaltrials.gov/ ) and Clinical Trials Registry of India ( CTRI/2019/04/018517 dated 09/04/2019).

The impact of patient-held health records on continuity of care among asylum seekers in reception centres: a cluster-randomised stepped wedge trial in Germany.

INTRODUCTION: The aim of this study was to assess the effectiveness of a patient-held health record (PHR) for asylum seekers on the availability of health-related information. METHODS: An explorative, cluster-randomised stepped-wedge trial with reception centres as unit of randomisation was conducted. All reception centres (n=6) in two large administrative areas in South Germany with on-site health services were included. All physicians working at these centres were invited to participate in the study. The intervention was the implementation of a PHR. The primary outcome was the prevalence of written health-related information. Secondary outcomes were the physicians' dissatisfaction with the available written information and the prevalence of missing health-related information. All outcomes were measured at the level of patient-physician contacts by means of a standardised questionnaire, and analysed in logistic multi-level regression models. RESULTS: We obtained data on 2308 patient-physician contacts. The presence of the PHR increased the availability of health-related information (adjusted OR (aOR), 20.3, 95% CI: 12.74 to 32.33), and tended to reduce missing essential information (aOR 0.71, 95% CI: 0.39 to 1.26) and physicians' dissatisfaction with available information (aOR 0.5, 95% CI: 0.24 to 1.04). The availability of health-related information in the post-intervention period was higher (aOR 4.22, 95% CI: 2.64 to 6.73), missing information (aOR 0.89, 95% CI: 0.42 to 1.88) and dissatisfaction (aOR 0.43, 95% CI: 0.16 to 1.14) tended to be lower compared with the pre-intervention period. CONCLUSIONS: Healthcare planners should consider introducing PHRs in reception centres or comparable facilities. Future research should focus on the impact of PHRs on clinical outcomes and on intersectoral care. TRIAL REGISTRATION: ISRCTN13212716. Registered 24 November 2016. Retrospectively registered. http://www.isrctn.com/ISRCTN13212716.

[Health and primary care surveillance among asylum seekers in reception centres in Germany: concept, development, and implementation]. / Surveillance der Gesundheit und primärmedizinischen Versorgung von Asylsuchenden in Aufnahmeeinrichtungen: Konzept, Entwicklung und Implementierung.

BACKGROUND: Reliable data on health and primary care among asylum seekers in reception centres are not routinely available, but required to plan needs-based healthcare services. OBJECTIVES: To present the concept, development, and implementation of a routine surveillance system in reception centres for asylum seekers. METHODS: In the scope of the project PRICARE, medical records in reception centres were standardized and digitized, and continuous surveillance was enabled by means of suitable IT infrastructure. The core elements of the surveillance system were developed in three project phases using an iterative and participative design. FUNDING: Federal Ministry of Health (Grant no. 2516FSB415). RESULTS: Forming the basis for the surveillance, the electronic health record Refugee Care Manager® (RefCare®) was developed and gradually implemented in 13 reception centres in three federal states. For implementing the tool in daily care routines, IT infrastructure was implemented in all sites and a legally required data protection concept was established. An indicator set was developed and agreed upon for the surveillance, comprising a total of 64 indicators in four domains: morbidity, processes of care, quality of care, and syndromic alerts. CONCLUSIONS: For the first time in Germany, a harmonized infrastructure spanning federal states was implemented in healthcare settings ensuring medical documentation and surveillance of health and healthcare of asylum seekers in conformity with data protection requirements. The surveillance is feasible; the long-term benefits of routine surveillance and research within the network will be assessed in the future.

Using country of origin to inform targeted tuberculosis screening in asylum seekers: a modelling study of screening data in a German federal state, 2002-2015.

BACKGROUND: Screening programmes for tuberculosis (TB) among immigrants rarely consider the heterogeneity of risk related to migrants' country of origin. We assess the performance of a large screening programme in asylum seekers by analysing (i) the difference in yield and numbers needed to screen (NNS) by country and WHO-reported TB burden, (ii) the possible impact of screening thresholds on sensitivity, and (iii) the value of WHO-estimated TB burden to improve the prediction accuracy of screening yield. METHODS: We combined individual data of 119,037 asylum seekers screened for TB in Germany (2002-2015) with TB estimates of the World Health Organization (WHO) (1990-2014) for their 81 countries of origin. Adjusted rate ratios (aRR) and 95% credible intervals (CrI) of the observed yield of screening were calculated in Bayesian Poisson regression models by categories of WHO-estimated TB incidence. We assessed changes in sensitivity depending on screening thresholds, used WHO TB estimates as prior information to predict TB in asylum seekers, and modelled country-specific probabilities of numbers needed to screen (NNS) conditional on different screening thresholds. RESULTS: The overall yield was 82 per 100,000 and the annual yield ranged from 44.1 to 279.7 per 100,000. Country-specific yields ranged from 10 (95%- CrI: 1-47) to 683 (95%-CrI: 306-1336) per 100,000 in Iraqi and Somali asylum seekers, respectively. The observed yield was higher in asylum seekers from countries with a WHO-estimated TB incidence > 50 relative to those from countries ≤50 per 100,000 (aRR: 4.17, 95%-CrI: 2.86-6.59). Introducing a threshold in the range of a WHO-estimated TB incidence of 50 and 100 per 100,000 resulted in the lowest "loss" in sensitivity. WHO's TB prevalence estimates improved prediction accuracy for eight of the 11 countries, and allowed modelling country-specific probabilities of NNS. CONCLUSIONS: WHO's TB data can inform the estimation of screening yield and thus be used to improve screening efficiency in asylum seekers. This may help to develop more targeted screening strategies by reducing uncertainty in estimates of expected country-specific yield, and identify thresholds with lowest loss in sensitivity. Further modelling studies are needed which combine clinical, diagnostic and country-specific parameters.

Are we preparing future doctors to deal with emotionally challenging situations? Analysis of a medical curriculum.

OBJECTIVE: Skilful communication by doctors is necessary for healthcare delivery during emotionally challenging situations. This study analyses a medical curriculum for the frequency and intensity of teaching content on communication in emotionally challenging situations. METHODS: A questionnaire with 31 questions ("EmotCog31") was used to evaluate teaching sessions at 17 departments of a medical school for one semester. RESULTS: Teaching content on communication in emotionally challenging situations was observed in 62 of 724 (∼nine percent) teaching sessions. Fifty-six percent of these sessions were within psychosocial specialisations. Lecturers used mental diseases as teaching topics four times more than somatic diseases. Forty-two percent of the 62 sessions were large-group while fifty-eight percent were small-group, interactive sessions. Clinical examples were used in sixty-nine percent of these sessions. Eighty-one percent of the handouts provided and sixty-six percent of simulated patient scenarios used were rated as helpful. Two-thirds of teaching sessions were rated positively when they included practical context. CONCLUSION: There was a considerable lack of teaching on communication skills in an emotional context. Teaching was limited to psychosocial specialties, reducing the impact of available knowledge for other medical specialties. PRACTICE IMPLICATIONS: More interactive, practically oriented teaching methods are useful for teaching emotional communication skills.

Optimal sample size allocation and go/no-go decision rules for phase II/III programs where several phase III trials are performed.

The conduct of phase II and III programs is costly, time-consuming and, due to high failure rates in late development stages, risky. There is a strong connection between phase II and III trials as the go/no-go decision and the sample size chosen for phase III are based on the results observed in phase II. An integrated planning of phase II and III is therefore reasonable. The success of phase II/III programs crucially depends on the allocation of the resources to phase II and III in terms of sample size and the rule applied to decide whether to stop or to proceed with phase III. Recently, a utility-based approach was proposed, where optimal planning of phase II/III programs is achieved by taking fixed and variable costs of the drug development program and potential gains after a successful launch into account. However, this method is restricted to programs with a single phase III trial, while regulatory authorities usually require statistical significance in two or more phase III trials. We present a generalization of this procedure to programs where two or more phase III trials are performed. Optimal phase II sample sizes and go/no-go decision rules are provided for time-to-event outcomes and cases, where at least one, two, or three phase III trials need to be successful. Different drug development program strategies (e.g. one large vs. two phase III trials) are compared within these different cases. Application to practical examples typically met in oncology trials illustrates the proposed method.

Differences in pregnancy outcomes and obstetric care between asylum seeking and resident women: a cross-sectional study in a German federal state, 2010-2016.

BACKGROUND: Despite large numbers of asylum seekers, there is a lack of evidence on pregnancy outcomes and obstetric care of asylum seeking women in Germany. METHODS: Cross-sectional study (2010-2016) using administrative data of the main referral hospital for pregnant asylum seekers of the reception center of a large federal state in South Germany. INCLUSION CRITERIA: women aged 12-50 years, admitted in relation to pregnancy, childbirth or post-partum complications. OUTCOMES: differences between asylum seekers and residents in the prevalence of high-risk pregnancy conditions, abortive outcomes/stillbirths, peri- and postnatal maternal complications, neonatal complications, and caesarean sections. ANALYSIS: odds ratios (OR) and 95% confidence intervals (CI) obtained by single and multiple logistic regression analysis. Attributable fractions among the exposed (Afe) and among the total population (Afp) were calculated for selected outcomes. RESULTS: Of 19,864 women admitted in relation to pregnancy, childbirth or post-partum complications, 2.9% (n = 569) were asylum seekers. Adjusted odds for high-risk pregnancy conditions (OR = 0.76, 95%CI: 0.63-0.91, p < 0.0001), caesarean sections (OR = 0.84, 95%CI 0.66-1.07, p = 0.17) and perinatal complications (OR = 0.65, 95%CI: 0.55-0.78, p < 0.0001) were lower; those for abortive outcomes/stillbirths (OR = 1.58, 95%CI: 1.11-2.20, p = 0.01) and postnatal complications (OR = 1.80, 95%CI: 0.93-3.19, p = 0.06) higher among asylum seeking women relative to residents in models adjusted for age, length of admission, and high-risk pregnancy conditions. The Afe for abortive outcomes and stillbirths among asylum seekers was 40.3% (95% CI, 16.3-56.5) and the Afp was 1.8%. The Afe for postnatal complications was 53.1% (95% CI, 7.1-74.0) and the Afp was 3.1%. CONCLUSION: Asylum seeking women are at higher risk of abortive outcomes/stillbirths and show a tendency towards higher postnatal complications. This excess risk calls for adequate responses by health care providers and policy makers to improve outpatient postnatal care in reception centers and mitigate adverse birth outcomes among asylum seeking women. Although further research is needed, scaling-up midwivery care, improving outreach by maternity care teams, and routinely identifying and addressing mental illness by psychosocial services could be ways forward to improve outcomes in this population.

Efficacy of Rituximab vs Tacrolimus in Pediatric Corticosteroid-Dependent Nephrotic Syndrome: A Randomized Clinical Trial.

Importance: Calcineurin inhibitors are an established first-line corticosteroid-sparing therapy for patients with corticosteroid-dependent nephrotic syndrome (CDNS), whereas B-lymphocyte-depleting therapy is mostly used as a rescue for calcineurin inhibitor-resistant cases. The positive efficacy and safety profile of rituximab raises the question of whether it could be used as a first-line alternative to calcineurin inhibitor therapy. Objective: To compare the efficacy of rituximab and tacrolimus in maintaining relapse-free survival among children with CDNS. Design, Setting, and Participants: A parallel-arm, open-label, randomized clinical trial was performed from May 8, 2015, to September 20, 2016, with 1-year follow-up in a single-center, tertiary care unit. A total of 176 consecutive children aged 3 to 16 years with CDNS not previously treated with corticosteroid-sparing agents were screened for eligibility. Interventions: The children received either tacrolimus (along with tapering alternate-day prednisolone) for 12 months or a single course of rituximab (2 infusions of 375 mg/m2). Main Outcomes and Measures: Twelve-month relapse-free survival in the intention-to-treat population. Results: Of the 176 children screened for eligibility, 120 were randomized and all but 3 patients completed 1 year of follow-up. The groups were comparable, with mean (SD) age of 7.2 (2.8) years, 32 boys (53.3%) in each group, mean (SD) disease duration of 2.5 (1.5) years and 2.3 (1.7) in the tacrolimus and rituximab groups, respectively, disease duration less than 1 year among 15 children (25.0%) in each group, median (interquartile range) of 4 (3-5) relapses in each group, and mean (SD) cumulative prednisolone dose of 246 (48) mg/kg and 239 (52) mg/kg in the prestudy year in the tacrolimus and rituximab groups, respectively. Rituximab therapy was associated with a higher 12-month relapse-free survival rate than tacrolimus (54 [90.0%] vs 38 [63.3%] children; P < .001; odds ratio, 5.21; 95% CI, 1.93-14.07). Among the patients who experienced relapse, median time to first relapse was 40 weeks in the rituximab group and 29 weeks in the tacrolimus group. Only 2 patients in the rituximab group had more than 1 relapse during the study period compared with 10 patients in the tacrolimus group. The cumulative corticosteroid dose during the 12-month study period was lower with rituximab compared with tacrolimus (mean [SD], 25.8 [27.8] vs 86.3 [58.0] mg/kg). Although both treatments were well tolerated, mild to moderate infections were twice as common in the tacrolimus group (26 [43.3%] vs 13 [21.7%] events). Conclusions and Relevance: In children with CDNS, rituximab appears to be more effective than tacrolimus in maintaining disease remission and minimizing corticosteroid exposure and, given its good tolerability and lack of nephrotoxic effects, may be considered as first-line corticosteroid-sparing therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02438982; Clinical Trial Registry of India: CTRI/2014/01/004355.

Diurnal Variation of Intravenous Thrombolysis Rates for Acute Ischemic Stroke and Associated Quality Performance Parameters.

INTRODUCTION: Based on data from the Baden-Wuerttemberg stroke registry, we aimed to explore the diurnal variation of acute ischemic stroke (IS) care delivery. MATERIALS AND METHODS: 92,530 IS patients were included, of whom 37,471 (40%) presented within an onset-to-door time ≤4.5 h. Daytime was stratified in 3-h time intervals and working vs. non-working hours. Stroke onset and hospital admission time, rate of door-to-neurological examination time ≤30 min, onset-/door-to-imaging time IV thrombolysis (IVT) rates, and onset-/door-to-needle time were determined. Multivariable regression models were used stratified by stroke onset and hospital admission time to assess the relationship between IVT rates, quality performance parameters, and daytime. The time interval 0:00 h to 3:00 h and working hours, respectively, were taken as reference. RESULTS: The IVT rate of the whole study population was strongly associated with the sleep-wake cycle. In patients presenting within the 4.5-h time window and potentially eligible for IVT stratification by hospital admission time identified two time intervals with lower IVT rates. First, between 3:01 h and 6:00 h (IVT rate 18%) and likely attributed to in-hospital delays with the lowest diurnal rate of door-to-neurological examination time ≤30 min and the longest door-to-needle time Second, between 6:01 h and 15:00 h (IVT rate 23-25%) compared to the late afternoon and evening hours (IVT rate 27-29%) due to a longer onset-to-imaging time and door-to-imaging time. No evidence for a compromised stroke service during non-working hours was observed. CONCLUSION: The analysis provides evidence that acute IS care is subject to diurnal variation which may affect stroke outcome. An optimization of IS care aiming at constantly high IVT rates over the course of the day therefore appears desirable.

A DAG-based comparison of interventional effect underestimation between composite endpoint and multi-state analysis in cardiovascular trials.

BACKGROUND: Composite endpoints comprising hospital admissions and death are the primary outcome in many cardiovascular clinical trials. For statistical analysis, a Cox proportional hazards model for the time to first event is commonly applied. There is an ongoing debate on whether multiple episodes per individual should be incorporated into the primary analysis. While the advantages in terms of power are readily apparent, potential biases have been mostly overlooked so far. METHODS: Motivated by a randomized controlled clinical trial in heart failure patients, we use directed acyclic graphs (DAG) to investigate potential sources of bias in treatment effect estimates, depending on whether only the first or multiple episodes are considered. The biases first are explained in simplified examples and then more thoroughly investigated in simulation studies that mimic realistic patterns. RESULTS: Particularly the Cox model is prone to potentially severe selection bias and direct effect bias, resulting in underestimation when restricting the analysis to first events. We find that both kinds of bias can simultaneously be reduced by adequately incorporating recurrent events into the analysis model. Correspondingly, we point out appropriate proportional hazards-based multi-state models for decreasing bias and increasing power when analyzing multiple-episode composite endpoints in randomized clinical trials. CONCLUSIONS: Incorporating multiple episodes per individual into the primary analysis can reduce the bias of a treatment's total effect estimate. Our findings will help to move beyond the paradigm of considering first events only for approaches that use more information from the trial and augment interpretability, as has been called for in cardiovascular research.

Simulating recurrent event data with hazard functions defined on a total time scale.

BACKGROUND: In medical studies with recurrent event data a total time scale perspective is often needed to adequately reflect disease mechanisms. This means that the hazard process is defined on the time since some starting point, e.g. the beginning of some disease, in contrast to a gap time scale where the hazard process restarts after each event. While techniques such as the Andersen-Gill model have been developed for analyzing data from a total time perspective, techniques for the simulation of such data, e.g. for sample size planning, have not been investigated so far. METHODS: We have derived a simulation algorithm covering the Andersen-Gill model that can be used for sample size planning in clinical trials as well as the investigation of modeling techniques. Specifically, we allow for fixed and/or random covariates and an arbitrary hazard function defined on a total time scale. Furthermore we take into account that individuals may be temporarily insusceptible to a recurrent incidence of the event. The methods are based on conditional distributions of the inter-event times conditional on the total time of the preceeding event or study start. Closed form solutions are provided for common distributions. The derived methods have been implemented in a readily accessible R script. RESULTS: The proposed techniques are illustrated by planning the sample size for a clinical trial with complex recurrent event data. The required sample size is shown to be affected not only by censoring and intra-patient correlation, but also by the presence of risk-free intervals. This demonstrates the need for a simulation algorithm that particularly allows for complex study designs where no analytical sample size formulas might exist. CONCLUSIONS: The derived simulation algorithm is seen to be useful for the simulation of recurrent event data that follow an Andersen-Gill model. Next to the use of a total time scale, it allows for intra-patient correlation and risk-free intervals as are often observed in clinical trial data. Its application therefore allows the simulation of data that closely resemble real settings and thus can improve the use of simulation studies for designing and analysing studies.