Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field

Characterization, treatment patterns, and patient-related outcomes of patients with Fragile X syndrome in Germany: final results of the observational EXPLAIN-FXS study

BACKGROUND: As data on the phenotype, characteristics and management of patients with Fragile X Syndrome (FXS) are limited, we aimed to collect such data in Germany in experienced centres involved in the treatment of such patients. METHODS: EXPLAIN-FXS is a prospective observational (non-interventional) study (registry) performed between April 2013 and January 2016 at 18 sites in Germany. Requirements for patient participation included confirmed diagnosis of FXS by genetic testing (>200 CGG repeats) and written informed consent. Patients were followed for up to 2 years. RESULTS: Seventy-five patients (84.0 % males, mean age 16.7 +/- 14.5 years, ranging from 2 - 82 years) were analysed. The mean 6-item score, determined according to Giangreco (J Pediatr 129:611-614, 1996), was 6.9 +/- 2.5 points. At least one neurological finding each was noted in 53 patients (69.7 %). Specifically, ataxia was noted in 5 patients (6.6 %), lack of fine motor skills in 40 patients, (52.6 %), muscle tonus disorder in 4 patients (5.3 %), and other neurological disorders in 39 patients (51.3 %). Spasticity was not noted in any patient. Seizures were reported in 6 patients (8.1 %), anxiety disorders in 22 patients (30.1 %), depression in 7 patients (9.6 %), ADHD/ADD in 36 patients (49.3 %), impairment of social behavior in 39 patients (53.4 %), and other comorbidities in 23 patients (31.5 %). The mean Aberrant Behaviour Checklist Community Edition (ABC-C) score on behavioral symptoms, obtained in 71 patients at first documentation, was 48.4 +/- 27.8 (median 45.0, range 5-115). The mean visual analogue scale (VAS) score, obtained in 59 patients at first documentation, was 84.9 +/- 14.6 points (median 90; range 50 - 100). CONCLUSIONS: This report describes the largest cohort of patients with FXS in Europe. The reported observations indicate a substantial burden of disease for patients and their caregivers. Based on these observations, an early expert psychiatric diagnosis is recommended for suspected FXS patients. Further recommendations include multimodal and multi-professional management that is tailored to the individual patient's needs

EXPLAIN Fragile-X: an explorative, longitudinal study on the characterization, treatment pathways, and patient-related outcomes of Fragile X Syndrome

BACKGROUND: Fragile X syndrome (FXS), caused by a mutation of the FMR1 gene on the X chromosome, is the most common inherited form of intellectual disability and autism spectrum disorders. Comprehensive data are lacking, however, on the characteristics and management patients with FXS in Germany. METHODS/DESIGN: EXPLAIN is a prospective, observational, longitudinal registry with a non-probability sampling approach. It collects data on patient characteristics, therapeutic interventions, psychosocial parameters (including those of family members and caregivers), quality of life of caregiver and patient, caregiver burden, and health economic parameters, such as hospitalisation time. It is designed to include data from 300 patients in ambulatory care from about 50 centres that employ psychiatrists, paediatricians, neurologists, and other relevant specialists, in Germany. The study was initiated in March, 2013. Patients will be followed for at least two years. DISCUSSION: The registry is expected to provide much-needed data on the characteristics and management of patients with FXS in Germany. It will also allow comparisons with other countries, and will enable gap analyses based on current guidelines for management of these patients. TRIAL REGISTRATION: The ClinicalTrials.gov identifier is NCT01711606

Characteristics, management and attainment of lipid target levels in diabetic and cardiac patients enrolled in Disease Management Program versus those in routine care: LUTZ registry

<p>Abstract</p> <p>Background</p> <p>Since 2002 the sick funds in Germany have widely implemented disease management programs (DMPs) for patients with type 2 diabetes mellitus (DM) and coronary heart disease (CHD). Little is known about the characteristics, treatment and target attainment lipid levels of these patients enrolled in DMPs compared to patients in routine care (non-DMP).</p> <p>Methods</p> <p>In an open, non-interventional registry (LUTZ) in Germany, 6551 physicians documented 15,211 patients with DM (10,110 in DMP, 5101 in routine care) and 14,222 (6259 in DMP, 7963 in routine care) over a follow-up period of 4 months. They received the NCEP ATP III guidelines as a reminder on lipid level targets.</p> <p>Results</p> <p>While demographic characteristics of DMP patients were similar to routine care patients, the former had higher rates of almost all cardiovascular comorbidities. Patients in DMPs received pharmacological treatment (in almost all drug classes) more often than non-DMP patients (e.g. antiplatelets: in DM 27.0% vs 23.8%; in CHD 63.0% vs. 53.6%). The same applied for educational measures (on life style changes and diet etc.). The rate of target level attainment for low density lipoprotein cholesterol (LDL-C) < 100 mg/dl was somewhat higher in DMP patients at inclusion compared to non-DMP patients (DM: 23.9% vs. 21.3%; CHD: 30.6% vs. 23.8%) and increased after 4 months (DM: 38.3% vs. 36.9%; CHD: 49.8% vs. 43.3%). Individual LDL-C target level attainment rates as assessed by the treating physicians were higher (at 4 months in DM: 59.6% vs. 56.5%; CHD: 49.8% vs 43.3%). Mean blood pressure (BP) and HbA_1cvalues were slightly lowered during follow-up, without substantial differences between DMP and non-DMP patients.</p> <p>Conclusion</p> <p>Patients with DM, and (to a greater extent) with CHD in DMPs compared to non-DMP patients in routine care have a higher burden of comorbidities, but also receive more intensive pharmacological treatment and educational measures. The present data support that the substantial additional efforts in DMPs aimed at improving outcomes resulted in quality gains for achieving target LDL-C levels, but not for BP or HbA_1c. Longer-term follow-up is needed to substantiate these results.</p

Interactions between rheumatologists and cardio-/pulmonologists in the assessment and use of outcome measures in pulmonary arterial hypertension related to systemic sclerosis

Objectives: Pulmonary arterial hypertension in patients with systemic sclerosis is a disease involving multiple organ systems. We investigated the differences in perceptions of how to measure PAH-SSc among cardiologists, pulmonologists and rheumatologists. We also examined how a Delphi exercise can improve agreement among these subspecialties. Methods: The outcome measures derived from the recent Delphi survey were used for a detailed analysis of the contribution of the various specialties contributing to it. We compared rheumatologists and cardiologist/pulmonologists with regards to preferences and ratings of various endpoints and the actual use of tools to measure these outcomes. We also examined the effects of the Delphi process among these groups. Results: We could show that the different expert groups each tended to contribute differently to the development of the core set of measures and that interactions in the Delphi process resulted in convergence of rankings. Despite agreement on the high importance of the domains in the Delphi, the use of tools within those domains was sometimes divergent and dependent on specialty. Conclusions: Based on these results, use of differing tools in the diagnosis and treatment of PAH-SSc can be anticipated. Further, the convergence of results provides evidence, for the first time, for the ability of various approaches in these disciplines to reach harmonious endpoints of care for PAHSSc patients. A collaborative, interdisciplinary approach is advantageous for PAH-SSc patients

oA novel nonparametric approach for estimating cut-offs in continuous risk indicators with application to diabetes epidemiology

<p>Abstract</p> <p>Background</p> <p>Epidemiological and clinical studies, often including anthropometric measures, have established obesity as a major risk factor for the development of type 2 diabetes. Appropriate cut-off values for anthropometric parameters are necessary for prediction or decision purposes. The cut-off corresponding to the Youden-Index is often applied in epidemiology and biomedical literature for dichotomizing a continuous risk indicator.</p> <p>Methods</p> <p>Using data from a representative large multistage longitudinal epidemiological study in a primary care setting in Germany, this paper explores a novel approach for estimating optimal cut-offs of anthropomorphic parameters for predicting type 2 diabetes based on a discontinuity of a regression function in a nonparametric regression framework.</p> <p>Results</p> <p>The resulting cut-off corresponded to values obtained by the Youden Index (maximum of the sum of sensitivity and specificity, minus one), often considered the optimal cut-off in epidemiological and biomedical research. The nonparametric regression based estimator was compared to results obtained by the established methods of the Receiver Operating Characteristic plot in various simulation scenarios and based on bias and root mean square error, yielded excellent finite sample properties.</p> <p>Conclusion</p> <p>It is thus recommended that this nonparametric regression approach be considered as valuable alternative when a continuous indicator has to be dichotomized at the Youden Index for prediction or decision purposes.</p

Pulmonary hypertension in patients with COPD. results from the comparative, prospective registry of newly initiated therapies for pulmonary hypertension (COMPERA)

Background: Pulmonary hypertension (PH) in COPD is a poorly investigated clinical condition. Research Question: Which factors determine the outcome of PH in COPD? Study Design and Methods: We analyzed the characteristics and outcome of patients enrolled in the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) with moderate or severe PH in COPD as defined during the 6th PH World Symposium who received medical therapy for PH and compared them with patients with idiopathic pulmonary arterial hypertension (IPAH). Results: The population included incident patients with moderate PH in COPD (n = 68), with severe PH in COPD (n = 307), and with IPAH (n = 489). Patients with PH in COPD were older, predominantly male, and treated mainly with phosphodiesterase-5 inhibitors. Despite similar hemodynamic impairment, patients with PH in COPD achieved a worse 6-min walking distance (6MWD) and showed a more advanced World Health Organization functional class (WHO FC). Transplant-free survival rates at 1, 3, and 5 years were higher in the IPAH group than in the PH in COPD group (IPAH: 94%, 75%, and 55% vs PH in COPD: 86%, 55%, and 38%; P = .004). Risk factors for poor outcomes in PH in COPD were male sex, low 6MWD, and high pulmonary vascular resistance (PVR). In patients with severe PH in COPD, improvements in 6MWD by ≥ 30 m or improvements in WHO FC after initiation of medical therapy were associated with better outcomes. Interpretation: Patients with PH in COPD were functionally more impaired and had a poorer outcome than patients with IPAH. Predictors of death in the PH in COPD group were sex, 6MWD, and PVR. Our data raise the hypothesis that some patients with severe PH in COPD may benefit from PH treatment. Randomized controlled studies are necessary to explore this hypothesis further. Trial Registry: ClinicalTrials.gov; No.: NCT01347216; URL: www.clinicaltrials.go

Prognostic value of improvement endpoints in pulmonary arterial hypertension trials. a COMPERA analysis

BACKGROUND: The prognostic value of improvement endpoints that have been used in clinical trials of treatments for pulmonary arterial hypertension (PAH) needs to be further investigated. METHODS: Using the COMPERA database, we evaluated the prognostic value of improvements in functional class (FC) and absolute or relative improvements in 6-min walking distance (6MWD) and N-terminal fragment of pro-brain natriuretic peptide (NT-proBNP). In addition, we investigated multicomponent endpoints based on prespecified improvements in FC, 6MWD and NT-proBNP that have been used in recent PAH trials. Finally, we assessed the predictive value of improvements determined by risk stratification tools. The effects of changes from baseline to first follow-up (3-12 months after initiation of PAH therapy) on consecutive survival were determined by Kaplan-Meier analysis with Log-Rank testing and Cox proportional hazard analyses. RESULTS: All analyses were based on 596 patients with newly diagnosed PAH for whom complete data were available at baseline and first follow-up. Improvements in FC were associated with improved survival, whereas absolute or relative improvements in 6MWD had no predictive value. For NT-proBNP, absolute declines conferred no prognostic information while relative declines by ≥35% were associated with better survival. Improvements in multicomponent endpoints were associated with improved survival and the same was found for risk stratification tools. CONCLUSION: While sole improvements in 6MWD and NT-proBNP had minor prognostic relevance, improvements in multicomponent endpoints and risk stratification tools based on FC, 6MWD, and NT-proBNP were associated with improved survival. These tools should be further explored as outcome measures in PAH trials

Selection effects may account for better outcomes of the German Disease Management Program for type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>The nationwide German disease management program (DMP) for type 2 diabetes was introduced in 2003. Meanwhile, results from evaluation studies were published, but possible baseline differences between DMP and usual-care patients have not been examined. The objective of our study was therefore to find out if patient characteristics as socio-demographic variables, cardiovascular risk profile or motivation for life style changes influence the chance of being enrolled in the German DMP for type 2 diabetes and may therefore account for outcome differences between DMP and usual-care patients.</p> <p>Methods</p> <p>Case control study comparing DMP patients with usual-care patients at baseline and follow up; mean follow-up period of 36 ± 14 months. We used chart review data from 51 GP surgeries. Participants were 586 DMP and 250 usual-care patients with type 2 diabetes randomly selected by chart registry. Data were analysed by multivariate logistic and linear regression analyses. Significance levels were p ≤ 0.05.</p> <p>Results</p> <p>There was a better chance for enrolment if patients a) had a lower risk status for diabetes complications, i.e. non-smoking (odds ratio of 1.97, 95% confidence interval of 1.11 to 3.48) and lower systolic blood pressure (1.79 for 120 mmHg vs. 160 mmHg, 1.15 to 2.81); b) had higher activity rates, i.e. were practicing blood glucose self-monitoring (1.67, 1.03 to 2.76) and had been prescribed a diabetes patient education before enrolment (2.32, 1.29 to 4.19) c) were treated with oral medication (2.17, 1.35 to 3.49) and d) had a higher GP-rated motivation for diabetes education (4.55 for high motivation vs. low motivation, 2.21 to 9.36).</p> <p>Conclusions</p> <p>At baseline, future DMP patients had a lower risk for diabetes complications, were treated more intensively and were more active and motivated in managing their disease than usual-care patients. This finding a) points to the problem that the German DMP may not reach the higher risk patients and b) selection bias may impair the assessment of differences in outcome quality between enrolled and usual-care patients. Suggestions for dealing with this bias in evaluation studies are being made.</p

PATHFINDER-CHD: prospective registry on adults with congenital heart disease, abnormal ventricular function, and/or heart failure as a foundation for establishing rehabilitative, prehabilitative, preventive, and health-promoting measures: rationale, aims, design and methods

Background Adults with congenital heart defects (ACHD) globally constitute a notably medically underserved patient population. Despite therapeutic advancements, these individuals often confront substantial physical and psychosocial residua or sequelae, requiring specialized, integrative cardiological care throughout their lifespan. Heart failure (HF) is a critical challenge in this population, markedly impacting morbidity and mortality. Aims The primary aim of this study is to establish a comprehensive, prospective registry to enhance understanding and management of HF in ACHD. Named PATHFINDER-CHD, this registry aims to establish foundational data for treatment strategies as well as the development of rehabilitative, prehabilitative, preventive, and health-promoting interventions, ultimately aiming to mitigate the elevated morbidity and mortality rates associated with congenital heart defects (CHD). Methods This multicenter survey will be conducted across various German university facilities with expertise in ACHD. Data collection will encompass real-world treatment scenarios and clinical trajectories in ACHD with manifest HF or at risk for its development, including those undergoing medical or interventional cardiac therapies, cardiac surgery, inclusive of pacemaker or ICD implantation, resynchronization therapy, assist devices, and those on solid organ transplantation. Design The study adopts an observational, exploratory design, prospectively gathering data from participating centers, with a focus on patient management and outcomes. The study is non-confirmatory, aiming to accumulate a broad spectrum of data to inform future hypotheses and studies. Processes Regular follow-ups will be conducted, systematically collecting data during routine clinical visits or hospital admissions, encompassing alterations in therapy or CHD-related complications, with visit schedules tailored to individual clinical needs. Assessments Baseline assessments and regular follow-ups will entail comprehensive assessments of medical history, ongoing treatments, and outcomes, with a focus on HF symptoms, cardiac function, and overall health status. Discussion of the design The design of the PATHFINDER-CHD Registry is tailored to capture a wide range of data, prioritizing real-world HF management in ACHD. Its prospective nature facilitates longitudinal data acquisition, pivotal for comprehending for disease progression and treatment impacts. Conclusion The PATHFINDER-CHD Registry is poised to offer valuable insights into HF management in ACHD, bridging current knowledge gaps, enhancing patient care, and shaping future research endeavors in this domain.Open Access funding enabled and organized by Projekt DEAL.Universitätsklinikum Erlangen (8546