BACKGROUND: The conduct of rare disease clinical trials is still hampered by methodological problems. The number of patients suffering from a rare condition is variable, but may be very small and unfortunately statistical problems for small and finite populations have received less consideration. This paper describes the outline of the iSTORE project, its ambitions, and its methodological approaches. METHODS: In very small populations, methodological challenges exacerbate. iSTORE's ambition is to develop a comprehensive perspective on natural history course modelling through multiple endpoint methodologies, subgroup similarity identification, and improving level of evidence. RESULTS: The methodological approaches cover methods for sound scientific modeling of natural history course data, showing similarity between subgroups, defining, and analyzing multiple endpoints and quantifying the level of evidence in multiple endpoint trials that are often hampered by bias. CONCLUSION: Through its expected results, iSTORE will contribute to the rare diseases research field by providing an approach to better inform about and thus being able to plan a clinical trial. The methodological derivations can be synchronized and transferability will be outlined.
Rare Diseases , Research Design , Humans
When data is derived under a single or multiple lower limits of quantification (LLOQ), estimation of distribution parameters as well as precision of these estimates appear to be challenging, as the way to account for unquantifiable observations due to LLOQs needs particular attention. The aim of this investigation is to characterize the precision of censored sample maximum likelihood estimates of the mean for normal, exponential and Poisson distribution affected by one or two LLOQs using confidence intervals (CI). In a simulation study, asymptotic and bias-corrected accelerated bootstrap CIs for the location parameter mean are compared with respect to coverage proportion and interval width. To enable this examination, we derived analytical expressions of the maximum likelihood location parameter estimate for the assumption of exponentially and Poisson distributed data, where the censored sample method and simple imputation method are used to account for LLOQs. Additionally, we vary the proportion of observations below the LLOQs. When based on the censored sample estimate, the bootstrap CI led to higher coverage proportions and narrower interval width than the asymptotic CI. The results differed by underlying distribution. Under the assumption of normality, the CI's coverage proportion and width suffered most from high proportions of unquantifiable observations. For exponentially and Poisson distributed data, both CI approaches delivered similar results. To derive the CIs, the point estimates from the censored sample method are preferable, because the point estimate of the simple imputation method leads to higher bias for all investigated distributions. This biased simple imputation estimate impairs the coverage proportion of the respective CI. The bootstrap CI surpassed the asymptotic CIs with respect to coverage proportion for the investigated choice of distributional assumptions. The variety of distributions for which the methods are suitable gives the applicant a widely usable tool to handle LLOQ affected data with appropriate approaches.
Models, Statistical , Likelihood Functions , Confidence Intervals , Computer Simulation , Bias
BACKGROUND: When assessing the efficacy of a treatment in any clinical trial, it is recommended by the International Conference on Harmonisation to select a single meaningful endpoint. However, a single endpoint is often not sufficient to reflect the full clinical benefit of a treatment in multifaceted diseases, which is often the case in rare diseases. Therefore, the use of a combination of several clinically meaningful outcomes is preferred. Many methodologies that allow for combining outcomes in a so-called composite endpoint are however limited in a number of ways, not in the least in the number and type of outcomes that can be combined and in the poor small-sample properties. Moreover, patient reported outcomes, such as quality of life, often cannot be integrated in a composite analysis, in spite of their intrinsic value. RESULTS: Recently, a class of non-parametric generalized pairwise comparisons tests have been proposed, which members do allow for any number and type of outcomes, including patient reported outcomes. The class enjoys good small-sample properties. Moreover, this very flexible class of methods allows for prioritizing the outcomes by clinical severity, allows for matched designs and for adding a threshold of clinical relevance. Our aim is to introduce the generalized pairwise comparison ideas and concepts for rare disease clinical trial analysis, and demonstrate their benefit in a post-hoc analysis of a small-sample trial in epidermolysis bullosa. More precisely, we will include a patient relevant outcome (Quality of life), in a composite endpoint. This publication is part of the European Joint Programme on Rare Diseases (EJP RD) series on innovative methodologies for rare diseases clinical trials, which is based on the webinars presented within the educational activity of EJP RD. This publication covers the webinar topic on composite endpoints in rare diseases and includes participants' response to a questionnaire on this topic. CONCLUSIONS: Generalized pairwise comparisons is a promising statistical methodology for evaluating any type of composite endpoints in rare disease trials and may allow a better evaluation of therapy efficacy including patients reported outcomes in addition to outcomes related to the diseases signs and symptoms.
Quality of Life , Rare Diseases , Humans , Clinical Relevance , Patient Reported Outcome Measures , Clinical Trials as Topic
Aim: To evaluate general shortcomings and faculty-specific pitfalls as well as to improve antibiotic prescription quality (ABQ) in non-ICU wards, we performed a prospective cluster trial. Methods: An infectious-disease (ID) consulting service performed a prospective investigation consisting of three 12-week phases with point prevalence evaluation conducted once per week (=36 evaluations in total) at seven non-ICU wards, followed by assessment of sustainability (weeks 37-48). Baseline evaluation (phase 1) defined multifaceted interventions by identifying the main shortcomings. Then, to distinguish intervention from time effects, the interventions were performed in four wards, and the 3 remaining wards served as controls; after assessing effects (phase 2), the same interventions were performed in the remaining wards to test the generalizability of the interventions (phase 3). The prolonged responses after all interventions were then analyzed in phase 4. ABQ was evaluated by at least two ID specialists who assessed the indication for therapy, the adherence to the hospital guidelines for empirical therapy, and the overall antibiotic prescription quality. Results: In phase 1, 406 of 659 (62%) patients cases were adequately treated with antibiotics; the main reason for inappropriate prescription was the lack of an indication (107/253; 42%). The antibiotic prescription quality (ABQ) significantly increased, reaching 86% in all wards after the focused interventions (502/584; nDf=3, ddf=1,697, F=6.9, p=0.0001). In phase 2 the effect was only seen in wards that already participated in interventions (248/347; 71%). No improvement was seen in wards that received interventions only after phase 2 (189/295; 64%). A given indication significantly increased from about 80% to more than 90% (p<.0001). No carryover effects were observed. Discussion: ABQ can be improved significantly by intervention bundles with apparent sustainable effects.
BACKGROUND: A tele-emergency medical service with a remote emergency physician for severe prehospital emergencies may overcome the increasing number of emergency calls and shortage of emergency medical service providers. We analysed whether routine use of a tele-emergency medical service is non-inferior to a conventional physician-based one in the occurrence of intervention-related adverse events. METHODS: This open-label, randomised, controlled, parallel-group, non-inferiority trial included all routine severe emergency patients aged ≥ 18 years within the ground-based ambulance service of Aachen, Germany. Patients were randomised in a 1:1 allocation ratio to receive either tele-emergency medical service (n = 1764) or conventional physician-based emergency medical service (n = 1767). The primary outcome was the occurrence of intervention-related adverse events with suspected causality to the group assignment. The trial was registered with ClinicalTrials.gov (NCT02617875) on 30 November 2015 and is reported in accordance with the CONSORT statement for non-inferiority trials. RESULTS: Among 3531 randomised patients, 3220 were included in the primary analysis (mean age, 61.3 years; 53.8% female); 1676 were randomised to the conventional physician-based emergency medical service (control) group and 1544 to the tele-emergency medical service group. A physician was not deemed necessary in 108 of 1676 cases (6.4%) and 893 of 1544 cases (57.8%) in the control and tele-emergency medical service groups, respectively. The primary endpoint occurred only once in the tele-emergency medical service group. The Newcombe hybrid score method confirmed the non-inferiority of the tele-emergency medical service, as the non-inferiority margin of - 0.015 was not covered by the 97.5% confidence interval of - 0.0046 to 0.0025. CONCLUSIONS: Among severe emergency cases, tele-emergency medical service was non-inferior to conventional physician-based emergency medical service in terms of the occurrence of adverse events.
Emergency Medical Services , Physicians , Telemedicine , Humans , Female , Middle Aged , Male , Emergencies , Germany
OBJECTIVE: The Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem-level relations to ataxia severity and patient-focused outcomes) across a large number of ataxias, and provide first natural history data for several of them. METHODS: Subitem-level correlation and distribution-based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2-8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes. RESULTS: Although SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions ("static periods"), and fluctuating decreases/increases. All subitems except nose-finger showed moderate-to-strong correlations to activities of daily living, indicating that metric properties-not content validity-limit SARA responsiveness. SARA captured mild-to-moderate progression in many genotypes (eg, SYNE1-ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG-ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix-Saguenay, COQ8A-ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7-fold sample size). Use of a novel rank-optimized SARA without subitems finger-chase and nose-finger reduces sample sizes by 20 to 25%. INTERPRETATION: This study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023;94:470-485.
Cerebellar Ataxia , Spinocerebellar Ataxias , Humans , Activities of Daily Living , Ataxia , Spinocerebellar Ataxias/diagnosis , Spinocerebellar Ataxias/genetics , Upper Extremity
STUDY DESIGN: A randomized, controlled, prospective multicenter clinical trial with a parallel group design was initiated in eight surgical centers to compare a large-pore polypropylene mesh (Ultrapro®) to a small-pore polypropylene mesh (Premilene®) within a standardized retromuscular meshplasty for incisional hernia repair. METHODS: Between 2004 and 2006, patients with a fascial defect with a minimum diameter of 4 cm after vertical midline laparotomy were recruited for the trial. Patients underwent retromuscular meshplasty with either a large-pore or a small-pore mesh to identify the superiority of the large-pore mesh. Follow-up visits were scheduled at 5 and 21 days and 4, 12, and 24 months after surgery. A clinical examination, a modified short form 36 (SF-36®), a daily activity questionnaire, and an ultrasound investigation of the abdominal wall were completed at every follow-up visit. The primary outcome criterion was foreign body sensation at the 12-month visit, and the secondary endpoint criteria were the occurrence of hematoma, seroma, and chronic pain within 24 months postoperatively. RESULTS: In 8 centers, 181 patients were included in the study. Neither foreign body sensation within the first year after surgery (27.5% Ultrapro®, 32.2% Premilene®) nor the time until the first occurrence of foreign body sensation within the first year was significantly different between the groups. Regarding the secondary endpoints, no significant differences could be observed. At the 2-year follow-up, recurrences occurred in 5 Ultrapro® patients (5.5%) and 4 Premilene® patients (4.4%). CONCLUSION: Despite considerable differences in theoretical and experimental works, we have not been able to identify differences in surgical or patient-reported outcomes between the use of large- and small-pore meshes for retromuscular incisional hernia repair. TRIAL REGISTRATION: Clinical Trials NCT04961346 (16.06.2021) retrospectively registered.
Foreign Bodies , Hernia, Ventral , Incisional Hernia , Humans , Incisional Hernia/surgery , Polypropylenes , Prospective Studies , Hernia, Ventral/surgery , Surgical Mesh , Foreign Bodies/surgery , Herniorrhaphy/adverse effects
The objective of this prospective randomized controlled single-center clinical trial was to prove the efficacy of adjunctive photobiomodulation in improving selected outcomes following the use of laterally closed tunnel technique for the management of isolated gingival recession. Nineteen participants (with isolated gingival recession) each treated by laterally closed tunnel technique were randomized to either add on treatment with control (sham laser application) or test group (photobiomodulation with 660 nm diode, 3.5 J/cm2 per point of application). The primary outcome variable was change in recession depth and secondary variables included recession width, width of keratinized gingiva, periodontal biotype, and VAS score for pain assessment and EHS index for early wound healing assessment. Analysis was performed using a linear mixed effects model. There were no significant differences in the gingival recession depth (p = 0.8324) and recession width (p-0.969) at 3-month follow-up. The VAS scores were significantly lower for the test (laterally closed tunnel technique + photobiomodulation) group as compared to control (laterally closed tunnel technique + sham laser) over time (p = < 0.0001) as well as per site (p = 0.0006) The Early Wound Healing Index scores were significantly higher in the test (laterally closed tunnel technique + photobiomodulation) group as compared to control (laterally closed tunnel technique + sham laser) group (p < 0.0001). The adjunctive use of photobiomodulation did not show a better outcome concerning recession depth but appears to provide faster healing of the surgical wounds and better patient comfort. The result needs further evaluation in particular with respect to long-term effect and due to limitation in sample size. Clinical Trial Registry of India: CTRI/2019/11/022012.
Gingival Recession , Low-Level Light Therapy , Connective Tissue , Follow-Up Studies , Gingiva , Gingival Recession/radiotherapy , Gingival Recession/surgery , Humans , Prospective Studies , Surgical Flaps , Tooth Root/surgery , Treatment Outcome
Background: Cardiovascular calcifications are prevented by matrix Gla protein (MGP), a vitamin K-dependent protein. Haemodialysis patients exhibit marked vitamin K deficiency. The randomized, prospective, open-label, multicentre VitaVasK trial analysed whether vitamin K1 supplementation reduces progression of coronary artery calcifications (CACs) and thoracic aortic calcifications (TACs). Methods: Patients with pre-existing CACs were randomized to continue on standard care or to additionally receive 5 mg of vitamin K1 orally thrice weekly. Hierarchically ordered primary endpoints were progression of TAC and CAC in computed tomography scans at 18 months. Linear mixed effects models with repeated measures at baseline and 12 and 18 months assessed treatment effects after adjusting for study site. Results: Of 60 randomized patients, 20 dropped out for reasons unrelated to vitamin K1, resulting in 23 control and 17 vitamin K1 patients. The trial was stopped early due to slow recruitment. At 18 months, the average TAC progression was 56% lower in the vitamin K1 compared with the control group (p = .039). CAC significantly progressed within the control group, but not within the vitamin K1 group. Average progression at 18 months was 68% lower in the vitamin K1 compared to the control group (P = .072). Vitamin K1 reduced plasma levels of pro-calcific uncarboxylated MGP by 69% at 18 months. No treatment-related adverse events were noted. Conclusion: Vitamin K1 intervention is a potent, safe and cost-effective approach to correct vitamin K deficiency and to potentially reduce cardiovascular calcification in this high-risk population.
BACKGROUND: Randomization is the foundation of any clinical trial involving treatment comparison. It helps mitigate selection bias, promotes similarity of treatment groups with respect to important known and unknown confounders, and contributes to the validity of statistical tests. Various restricted randomization procedures with different probabilistic structures and different statistical properties are available. The goal of this paper is to present a systematic roadmap for the choice and application of a restricted randomization procedure in a clinical trial. METHODS: We survey available restricted randomization procedures for sequential allocation of subjects in a randomized, comparative, parallel group clinical trial with equal (1:1) allocation. We explore statistical properties of these procedures, including balance/randomness tradeoff, type I error rate and power. We perform head-to-head comparisons of different procedures through simulation under various experimental scenarios, including cases when common model assumptions are violated. We also provide some real-life clinical trial examples to illustrate the thinking process for selecting a randomization procedure for implementation in practice. RESULTS: Restricted randomization procedures targeting 1:1 allocation vary in the degree of balance/randomness they induce, and more importantly, they vary in terms of validity and efficiency of statistical inference when common model assumptions are violated (e.g. when outcomes are affected by a linear time trend; measurement error distribution is misspecified; or selection bias is introduced in the experiment). Some procedures are more robust than others. Covariate-adjusted analysis may be essential to ensure validity of the results. Special considerations are required when selecting a randomization procedure for a clinical trial with very small sample size. CONCLUSIONS: The choice of randomization design, data analytic technique (parametric or nonparametric), and analysis strategy (randomization-based or population model-based) are all very important considerations. Randomization-based tests are robust and valid alternatives to likelihood-based tests and should be considered more frequently by clinical investigators.
Random Allocation , Computer Simulation , Humans , Likelihood Functions , Sample Size , Selection Bias
BACKGROUND AND AIMS: Wilson's disease (WD) is an autosomal-recessive disorder caused by ATP7B gene mutations leading to pathological accumulation of copper in the liver and brain. Adoption of initial treatments for WD was based on empirical observations. These therapies are effective, but there are still unmet needs for which treatment modalities are being developed. An increase of therapeutical trials is anticipated. APPROACH AND RESULTS: The first Wilson Disease Aarhus Symposium (May 2019) included a workshop on randomized clinical trial design. The authors of the article were organizers or presented during this workshop, and this article presents their consensus on the design of clinical trials for WD, addressing trial population, treatment comparators, inclusion and exclusion criteria, and treatment endpoints. To achieve adequate recruitment of patients with this rare disorder, the study groups should include all clinical phenotypes and treatment-experienced as well as treatment-naïve patients. CONCLUSIONS: The primary study endpoint should be clinical or a composite endpoint until appropriate surrogate endpoints are validated. Standardization of clinical trials will permit pooling of data and allow for better treatment comparisons, as well as reduce the future numbers of patients needed per trial.
Hepatolenticular Degeneration/therapy , Randomized Controlled Trials as Topic/methods , Adolescent , Biomarkers , Child , Disease Progression , Education , Hepatolenticular Degeneration/genetics , Hepatolenticular Degeneration/pathology , Humans , Treatment Outcome , Young Adult
BACKGROUND: The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia. METHODS: EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov, NCT02069509. FINDINGS: Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included. INTERPRETATION: Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia. FUNDING: European Commission, Voyager Therapeutics, and EuroAtaxia.
Activities of Daily Living , Disease Progression , Friedreich Ataxia/complications , Friedreich Ataxia/physiopathology , Adult , Cohort Studies , Europe , Female , Friedreich Ataxia/pathology , Humans , Male , Middle Aged , Mobility Limitation , Registries , Time Factors , Young Adult
OBJECTIVE: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS: Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing-based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ≥2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. RESULTS: Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ≈1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C-like progression (SARA points 2.5-5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. CONCLUSIONS: RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.
Multiple System Atrophy/diagnosis , Multiple System Atrophy/genetics , Replication Protein C/genetics , Adult , Aged , Ataxia , Bilateral Vestibulopathy , Cohort Studies , DNA Repeat Expansion , Disease Progression , Europe , Exome , Female , Genetic Testing , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Multiple System Atrophy/diagnostic imaging , Phenotype , Predictive Value of Tests , Turkey , Vestibular Diseases
BACKGROUND: Inhibitors of the renin-angiotensin system (RAS) are cornerstones of supportive therapy in patients with IgA nephropathy (IgAN). We analyzed the effects of single versus dual RAS blockaQueryde during our randomized STOP-IgAN trial. METHODS: STOP-IgAN participants with available successive information on their RAS treatment regimen and renal outcomes during the randomized 3-year trial phase were stratified post hoc into two groups, i.e. patients under continuous single or dual RAS blocker therapy over the entire 3 years of the trial phase. Primary and secondary STOP-IgAN trial endpoints, i.e. frequencies of full clinical remission, eGFR-loss ≥ 15 and ≥ 30 ml/min/1.73 m2 and ESRD onset, were analyzed by logistic regression and linear mixed effects models. RESULTS: Among the 112 patients included in the present analysis, 82 (73%) were maintained on single and 30 (27%) on dual RAS inhibitor therapy throughout the trial. Neither RAS blocker strategy significantly affected full clinical remission, eGFR-loss rates, onset of ESRD. Proteinuria moderately increased in patients under dual RAS blockade by 0.1 g/g creatinine during the 3-year trial phase. This was particularly evident in patients without additional immunosuppression during the randomized trial phase, where proteinuria increased by 0.2 g/g creatinine in the dual RAS blockade group. In contrast, proteinuria decreased in patients under single RAS blocker therapy by 0.3 g/g creatinine. The course of eGFR remained stable and did not differ between the RAS treatment strategies. CONCLUSION: In the STOP-IgAN cohort, neither RAS blocker regimen altered renal outcomes. Patients on dual RAS blockade even exhibited higher proteinuria over the 3-year trial phase.
Glomerulonephritis, IGA , Glomerular Filtration Rate , Glomerulonephritis, IGA/diagnosis , Glomerulonephritis, IGA/drug therapy , Humans , Immunosuppression Therapy , Proteinuria/drug therapy , Renin-Angiotensin System
[This corrects the article DOI: 10.18632/oncotarget.27303.].
The randomized, controlled STOP-IgAN trial in patients with IgA nephropathy (IgAN) and substantial proteinuria showed no benefit of immunosuppression added on top of supportive care on renal function over three years. As a follow-up we evaluated renal outcomes in patients over a follow-up of up to ten years in terms of serum creatinine, proteinuria, end-stage kidney disease (ESKD), and death. The adapted primary endpoint was the time to first occurrence of a composite of death, ESKD, or a decline of over 40% in the estimated glomerular filtration rate (eGFR) compared to baseline at randomization into STOP-IgAN. Data were analyzed by Cox-regression models. Follow-up data were available for 149 participants, representing 92% of the patients originally randomized. Median follow-up was 7.4 years (inter quartile range 5.7 to 8.3 years). The primary endpoint was reached in 36 of 72 patients randomized to supportive care and 35 of 77 patients randomized to additional immunosuppression (hazard ratio 1.20; 95% confidence interval 0.75 to 1.92). ESKD occurred in 17 of the patients with supportive care and in 20 of the patients with additional immunosuppression. Additionally, the rates of eGFR loss over 40% and annual eGFR loss did not differ between groups. Two patients died with supportive care and three with additional immunosuppression. Thus, within the limitations of a retrospective study, over a follow-up of up to ten years, and using an adapted primary endpoint, we failed to detect differences in key clinical outcomes in IgAN patients randomized to receive added immunosuppression on top of supportive care versus supportive care alone.
Glomerulonephritis, IGA , Follow-Up Studies , Glomerular Filtration Rate , Glomerulonephritis, IGA/diagnosis , Glomerulonephritis, IGA/therapy , Humans , Immunosuppression Therapy , Immunosuppressive Agents/adverse effects , Proteinuria/therapy , Retrospective Studies
Objective: To validate the capability of the dual wavelength laser (Er,Cr:YSGG and diode 940 nm) and the XP-Endoshaper and finisher in removing the smear layer from curved canals. Methods: Forty curved root canals were prepared using the R25 file of the Reciproc® system. The teeth were randomly divided into five groups: G1: negative control irrigated with distilled water, G2: positive control irrigated with EDTA 17% and a final rinse of NaOCl 3%, G3: XP-Endoshaper and finisher with EDTA 17%, G4: dual wavelength Er,Cr:YSGG (1.25 W, 50 Hz, 50 µs) and diode 940 nm (2 W, 50% DC), and G5: dual wavelength Er,Cr:YSGG (2 W, 20 Hz, 50 µs) and diode 940 nm (2 W, 50% DC). Laser scanning microscope images (1000 × ) were scored with the Hülsmann scoring system. Results: Superior smear layer removal was observed in G5 in comparison with G4, especially in the apical third of the canal. Furthermore, the XP-Endoshaper and finisher exhibited positive results in all parts of the canal. Conclusions: The higher power output of the Er,Cr:YSGG in the dual wavelength laser may be a suitable approach to remove the smear layer from the apical third of curved canals. Moreover, the XP-Endoshaper and finisher with EDTA could expose the dentinal tubules, however, the negative side effects of applying EDTA 17% for longer periods must be taken into consideration. This work is clinically significant as it addresses the main aim of endodontic treatment and provides a suitable method to remove the debris, smear layer, and bacterial remnants from the clinically challenging curved root canals.
Dental Pulp Cavity/radiation effects , Lasers, Semiconductor , Lasers, Solid-State , Root Canal Preparation/instrumentation , Smear Layer , Dental Pulp Cavity/ultrastructure , Dentin/radiation effects , Dentin/ultrastructure , Humans , In Vitro Techniques , Microscopy, Electron, Scanning , Random Allocation , Root Canal Irrigants/pharmacology , Surface Properties
BACKGROUND: Among various design aspects, the choice of randomization procedure have to be agreed on, when planning a clinical trial stratified by center. The aim of the paper is to present a methodological approach to evaluate whether a randomization procedure mitigates the impact of bias on the test decision in clinical trial stratified by center. METHODS: We use the weighted t test to analyze the data from a clinical trial stratified by center with a two-arm parallel group design, an intended 1:1 allocation ratio, aiming to prove a superiority hypothesis with a continuous normal endpoint without interim analysis and no adaptation in the randomization process. The derivation is based on the weighted t test under misclassification, i.e. ignoring bias. An additive bias model combing selection bias and time-trend bias is linked to different stratified randomization procedures. RESULTS: Various aspects to formulate stratified versions of randomization procedures are discussed. A formula for sample size calculation of the weighted t test is derived and used to specify the tolerated imbalance allowed by some randomization procedures. The distribution of the weighted t test under misclassification is deduced, taking the sequence of patient allocation to treatment, i.e. the randomization sequence into account. An additive bias model combining selection bias and time-trend bias at strata level linked to the applied randomization sequence is proposed. With these before mentioned components, the potential impact of bias on the type one error probability depending on the selected randomization sequence and thus the randomization procedure is formally derived and exemplarily calculated within a numerical evaluation study. CONCLUSION: The proposed biasing policy and test distribution are necessary to conduct an evaluation of the comparative performance of (stratified) randomization procedure in multi-center clinical trials with a two-arm parallel group design. It enables the choice of the best practice procedure. The evaluation stimulates the discussion about the level of evidence resulting in those kind of clinical trials.
Research Design , Bias , Humans , Probability , Random Allocation
INTRODUCTION: Mammography is the gold standard for early breast cancer detection, but shows important limitations. Blood-based approaches on basis of cell-free DNA (cfDNA) provide minimally invasive screening tools to characterize epigenetic alterations of tumor suppressor genes and could serve as a liquid biopsy, complementing mammography. METHODS: Potential biomarkers were identified from The Cancer Genome Atlas (TCGA), using HumanMethylation450-BeadChip data. Promoter methylation status was evaluated quantitatively by pyrosequencing in a serum test cohort (n = 103), a serum validation cohort (n = 368) and a plasma cohort (n = 125). RESULTS: SPAG6, NKX2-6 and PER1 were identified as novel biomarker candidates. ITIH5 was included on basis of our previous work. In the serum test cohort, a panel of SPAG6 and ITIH5 showed 63% sensitivity for DCIS and 51% sensitivity for early invasive tumor (pT1, pN0) detection at 80% specificity. The serum validation cohort revealed 50% sensitivity for DCIS detection on basis of NKX2-6 and ITIH5. Furthermore, an inverse correlation between methylation frequency and cfDNA concentration was uncovered. Therefore, markers were tested in a plasma cohort, achieving a 64% sensitivity for breast cancer detection using SPAG6, PER1 and ITIH5. CONCLUSIONS: Although liquid biopsy remains challenging, a combination of SPAG6, NKX2-6, ITIH5 and PER1 (SNiPER) provides a promising tool for blood-based breast cancer detection.
