The outcomes of immunosuppressive therapy, when added to supportive care, in patients with IgA nephropathy are uncertain.
We conducted a multicenter, open-label, randomized, controlled trial with a ...two-group, parallel, group-sequential design. During a 6-month run-in phase, supportive care (in particular, blockade of the renin-angiotensin system) was adjusted on the basis of proteinuria. Patients who had persistent proteinuria with urinary protein excretion of at least 0.75 g per day were randomly assigned to receive supportive care alone (supportive-care group) or supportive care plus immunosuppressive therapy (immunosuppression group) for 3 years. The primary end points in hierarchical order were full clinical remission at the end of the trial (protein-to-creatinine ratio <0.2 with both protein and creatinine measured in grams and a decrease in the estimated glomerular filtration rate eGFR of <5 ml per minute per 1.73 m(2) of body-surface area from baseline) and a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) at the end of the trial. The primary end points were analyzed with the use of logistic-regression models.
The run-in phase was completed by 309 of 337 patients. The proteinuria level decreased to less than 0.75 g of urinary protein excretion per day in 94 patients. Of the remaining 162 patients who consented to undergo randomization, 80 were assigned to the supportive-care group, and 82 to the immunosuppression group. After 3 years, 4 patients (5%) in the supportive-care group, as compared with 14 (17%) in the immunosuppression group, had a full clinical remission (P=0.01). A total of 22 patients (28%) in the supportive-care group and 21 (26%) in the immunosuppression group had a decrease in the eGFR of at least 15 ml per minute per 1.73 m(2) (P=0.75). There was no significant difference in the annual decline in eGFR between the two groups. More patients in the immunosuppression group than in the supportive-care group had severe infections, impaired glucose tolerance, and weight gain of more than 5 kg in the first year of treatment. One patient in the immunosuppression group died of sepsis.
The addition of immunosuppressive therapy to intensive supportive care in patients with high-risk IgA nephropathy did not significantly improve the outcome, and during the 3-year study phase, more adverse effects were observed among the patients who received immunosuppressive therapy, with no change in the rate of decrease in the eGFR. (Funded by the German Federal Ministry of Education and Research; STOP-IgAN ClinicalTrials.gov number, NCT00554502.).
Randomization in clinical trials is the key design technique to ensure the comparability of treatment groups. Although there exist a large number of software products which assist the researcher to ...implement randomization, no tool which would cover a wide range of procedures and allow the comparative evaluation of the procedures under practical restrictions has been proposed in the literature so far. The R package randomizeR addresses this need. The paper includes a detailed description of the randomizeR package that serves as a tutorial for the generation of randomization sequences and the assessment of randomization procedures.
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.
We investigated whether an abbreviated protocol (AP), consisting of only one pre- and one postcontrast acquisition and their derived images (first postcontrast subtracted FAST and maximum-intensity ...projection MIP images), was suitable for breast magnetic resonance imaging (MRI) screening.
We conducted a prospective observational reader study in 443 women at mildly to moderately increased risk who underwent 606 screening MRIs. Eligible women had normal or benign digital mammograms and, for those with heterogeneously dense or extremely dense breasts (n = 427), normal or benign ultrasounds. Expert radiologists reviewed the MIP image first to search for significant enhancement and then reviewed the complete AP (consisting of MIP and FAST images and optionally their nonsubtracted source images) to characterize enhancement and establish a diagnosis. Only thereafter was the regular full diagnostic protocol (FDP) analyzed.
MRI acquisition time for FDP was 17 minutes, versus 3 minutes for the AP. Average time to read the single MIP and complete AP was 2.8 and 28 seconds, respectively. Eleven breast cancers (four ductal carcinomas in situ and seven invasive cancers; all T1N0 intermediate or high grade) were diagnosed, for an additional cancer yield of 18.2 per 1,000. MIP readings were positive in 10 (90.9%) of 11 cancers and allowed establishment of the absence of breast cancer, with a negative predictive value (NPV) of 99.8% (418 of 419). Interpretation of the complete AP, as with the FDP, allowed diagnosis of all cancers (11 100% of 11). Specificity and positive predictive value (PPV) of AP versus FDP were equivalent (94.3% v 93.9% and 24.4% v 23.4%, respectively).
An MRI acquisition time of 3 minutes and an expert radiologist MIP image reading time of 3 seconds are sufficient to establish the absence of breast cancer, with an NPV of 99.8%. With a reading time < 30 seconds for the complete AP, diagnostic accuracy was equivalent to that of the FDP and resulted in an additional cancer yield of 18.2 per 1,000.
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.
Multiple lower limits of quantification (MLOQs) result if various laboratories are involved in the analysis of concentration data and some observations are too low to be quantified. For normally ...distributed data under MLOQs there exists only the multiple regression method of Helsel to estimate the mean and variance. We propose a simple imputation method and two new maximum likelihood estimation methods: the multiple truncated sample method and the multiple censored sample method. A simulation study is conducted to compare the performances of the newly introduced methods to Helsel's via the criteria root mean squared error (RMSE) and bias of the parameter estimates. Two and four lower limits of quantification (LLOQs), various amounts of unquantifiable observations and two sample sizes are studied. Furthermore, the robustness is investigated under model misspecification. The methods perform with decreasing accuracy for increasing rates of unquantified observations. Increasing sample sizes lead to smaller bias. There is almost no change in the performance between two and four LLOQs. The magnitude of the variance impairs the performance of all methods. For a smaller variance, the multiple censored sample method leads to superior estimates regarding the RMSE and bias, whereas Helsel's method is superior regarding the bias for a larger variance. Under model misspecification, Helsel's method was inferior to the other methods. Estimating the mean, the multiple censored sample method performed better, whereas the multiple truncated sample method performs best in estimating the variance. Summarizing, for a large sample size and normally distributed data we recommend to use Helsel's method. Otherwise, the multiple censored sample method should be used to obtain estimates of the mean and variance of data including MLOQs.
Orphan drug development faces numerous challenges, including low disease prevalence, patient population heterogeneity, and strong presence of paediatric patient populations. Consequently, clinical ...trials for orphan drugs are often smaller than those of non-orphan drugs, and they require the development of efficient trial designs relevant to small populations to gain the most information from the available data. The International Rare Diseases Research Consortium (IRDiRC) is aimed at promoting international collaboration and advance rare diseases research worldwide, and has as one of its goals to contribute to 1000 new therapies for rare diseases. IRDiRC set up a Small Population Clinical Trials (SPCT) Task Force in order to address the shortcomings of our understanding in carrying out clinical trials in rare diseases.
The IRDiRC SPCT Task Force met in March 2016 to discuss challenges faced in the design of small studies for rare diseases and present their recommendations, structured around six topics: different study methods/designs and their relation to different characteristics of medical conditions, adequate safety data, multi-arm trial designs, decision analytic approaches and rational approaches to adjusting levels of evidence, extrapolation, and patients' engagement in study design.
Recommendations have been issued based on discussions of the Small Population Clinical Trials Task Force that aim to contribute towards successful therapy development and clinical use. While randomised clinical trials are still considered the gold standard, it is recommended to systematically take into consideration alternative trial design options when studying treatments for a rare disease. Combining different sources of safety data is important to give a fuller picture of a therapy's safety profile. Multi-arm trials should be considered an opportunity for rare diseases therapy development, and funders are encouraged to support such trial design via international networks. Patient engagement is critical in trial design and therapy development, a process which sponsors are encouraged to incorporate when conducting trials and clinical studies. Input from multiple regulatory agencies is recommended early and throughout clinical development. Regulators are often supportive of new clinical trial designs, provided they are well thought through and justified, and they also welcome discussions and questions on this topic. Parallel advice for multiregional development programs should also be considered.
Objectives
Collagen barrier membranes are used in guided bone regeneration/guided tissue regeneration because of their excellent bio‐ and cytocompatibility. However, they are considered to have ...limitations in clinical outcome because of rapid and unpredictable degradation profiles. The aim of this study was to investigate the degradation behavior of two porcine‐based, non‐cross‐linked collagen membranes in vitro and in vivo.
Materials and Methods
Remaix™ (RX; Matricel GmbH, Herzogenrath, Germany) and Bio‐Gide® (BG; Geistlich Pharma AG, Wolhusen, Switzerland) membranes were characterized by testing mechanical strength, denaturation temperature, enzymatic degradation and hydroxyproline content in vitro (n = 5 up to 16). Thereafter, both membranes were implanted subcutaneously in rats (n = 20) for up to 20 weeks to investigate tissue compatibility with respect to membrane thickness.
Results
BG contained a significant higher hydroxyproline content compared with RX, but RX showed a higher stress at break (dry: 11.4 (SD 2.9) vs. 5.5 (SD 1.5) N/mm²), higher suture retention (wet: 5.6 (SD 1.3) vs. 2.7 (SD 0.7) N), increased denaturation temperature (55.1 (SD 1) vs. 49.4 (SD 0.6)°C) and an almost twofold reduction in degradation rate (15.6% (SEM 1.3)/h vs. 24.8% (SEM 2.9)/h) in vitro. In the rat model, both membranes showed excellent tissue compatibility without signs of inflammatory reactions. Shortly after implantation, RX and BG showed moderate infiltration of mononuclear cells that appeared not to be influenced by the surface texture of the membranes. In the histomorphometric analysis, both membranes showed significant different thickness over the 20 weeks period (P = 0.0002). Although the thickness remained almost stable during the first 9 weeks after implantation, after 20 weeks, the thickness of RX decreased only slightly, whereas BG showed a thickness loss of around 50% and stronger degradation than RX. Therefore, the higher stability of RX against biodegradation found in vitro was confirmed in the animal study.
Conclusion
This study shows differences in the biodegradation characteristics of two non‐cross‐linked collagen membranes in vitro and in vivo. Whether the higher stability of RX is of clinical relevance should be analyzed in future clinical investigations.
The impact of selection bias on the results of clinical trials has been analyzed extensively for trials of two treatments, yet its impact in multi-arm trials is still unknown. In this paper, we ...investigate selection bias in multi-arm trials by its impact on the type I error probability. We propose two models for selection bias, so-called biasing policies, that both extend the classic guessing strategy by Blackwell and Hodges. We derive the distribution of the F-test statistic under the misspecified outcome model and provide a formula for the type I error probability under selection bias. We apply the presented approach to quantify the influence of selection bias in multi-arm trials with increasing number of treatment groups using a permuted block design for different assumptions and different biasing strategies. Our results confirm previous findings that smaller block sizes lead to a higher proportion of sequences with inflated type I error probability. Astonishingly, our results also show that the proportion of sequences with inflated type I error probability remains constant when the number of treatment groups is increased. Realizing that the impact of selection bias cannot be completely eliminated, we propose a bias adjusted statistical model and show that the power of the statistical test is only slightly deflated for larger block sizes.
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