Search

Background: Epilepsy and other seizure disorders account for a high disease burden in Germany. As a timely diagnosis and accurate treatment are crucial, improving the management of these disorders is important. Outside of Germany, outpatient long-term video EEGs (ALVEEGs) have demonstrated the potential to support the diagnosis and management of epilepsy and other seizure disorders. This study aims to evaluate the implementation of ALVEEGs as a new diagnostic pathway in eastern parts of Germany to diagnose epilepsy and other seizure disorders and to assess if ALVEEGs are equally effective as the current inpatient-monitoring gold standard, which is currently only available at a limited number of specialized centers in Germany. Methods: ALVEEG is a prospective, multicenter, randomized controlled equivalence trial, involving five epilepsy centers in the eastern states of Germany. Patients will be randomized into either intervention (IG) or control group (CG), using a permuted block randomization. The sample size targeted is 688 patients, continuously recruited over the trial. The IG will complete an ALVEEG in a home setting, including getting access to a smartphone app to document seizure activity. The CG will receive care as usual, i.e., inpatient long-term video-EEG monitoring. The primary outcome is the proportion of clinical questions being solved in the IG compared to the CG. Secondary outcomes include hospital stays, time until video EEG, time until diagnosis and result discussion, patients' health status, quality of life and health competence, and number and form of epilepsy-related events and epileptiform activity. Alongside the trial, a process implementation and health economic evaluation will be conducted. Discussion: The extensive evaluation of this study, including an implementation and health economic evaluation, will provide valuable information for health policy decision-makers to optimize future delivery of neurological care to patients affected by epilepsy and other seizure disorders and on the uptake of ALVEEG into standard care in Germany. Trial registration: German Clinical Trials Register (DRKS00032220), date registered: December 11, 2023. [ABSTRACT FROM AUTHOR]

Background: Hyperuricemia (HU) remains a priority research area in every medical science, including complementary and alternative medicine interventions and homeopathy; however, the research evidence is limited. In homeopathy, Thlaspi bursa pastoris (TBP) is considered to be a potential treatment option in HU. Methods: An open-label, randomized, equivalence trial was conducted comparing TBP with individualized homeopathic medicines (IHMs). Serum uric acid (SUA) was the primary outcome; Gout Assessment Questionnaire version 2.0 (GAQ-2) and Measure Yourself Medical Outcome Profile version 2.0 (MYMOP-2) were the secondary outcomes; all measured at baseline and after 6 and 12 weeks. Intention-to-treat analysis was carried out to detect noninferiority and group differences using unpaired t-tests and two-way repeated-measure analysis of variance (ANOVA). Results: There were no differences between the groups at baseline. Reduction in SUA after 6 and 12 weeks was similar between groups (P = 0.784). Group differences in the secondary outcomes were also nonsignificant (all P > 0.05). TBP revealed noninferiority against IHMs, both after 6 weeks and 12 weeks in SUA and MYMOP-2 profile scores, but not in GAQ2 scores. Sulfur and Calcarea carbonica were the most frequently prescribed medicines in the IHMs group. There were no harms or serious adverse events reported from either of the groups. Conclusion: TBP acted noninferior to IHM in HU and both appeared to be equally effective. Rigorous and larger trials are warranted. Trial Registration: This trial was registered in the Clinical Trials Registry – India (CTRI/2018/10/016174; UTN: U1111-1221-8000).

Background From previous studies, the frequency of administration of recombinant human erythropoietin injection (rHuEPO) has no association with its therapeutic effect in renal anemia in chronic kidney disease (CKD), and there is no significant difference in the efficacy between weekly single dosing and divided dosing. Most hemodialysis patients are clinically treated with moderate-dose rHuEPO, but there is a lack of research on the safety of single and divided administration of moderate-dose rHuEPO. Objective To compare the safety between weekly single and divided administration of moderate-dose rHuEPO for renal anemia in maintenance hemodialysis patients. Methods This study was designed as a randomized, parallel-group controlled, non-inferiority clinical trial. Eighty-eight patients with renal anemia who underwent maintenance hemodialysis at the Hemodialysis Room, Tongzhou Branch, Dongzhimen Hospital, Beijing University of Chinese Medicine from January 2019 to May 2021 were selected and randomly divided into an experimental group and a control group with 44 in each. For comparing the safety and efficacy of weekly single and divided administration of moderate-dose rHuEPO, 29 cases (experimental subgroup 1) and other 15 cases (experimental subgroup 2) in the experimental group received an rHuEPO dose of 6 000 U, and an rHuEPO dose of 4 000 U, once a week, respectively; 30 cases (control subgroup 1) in the control group received a single rHuEPO dose of 2 000 U, three times a week (6 000 U per week in total), and other 14 cases (control subgroup 2) received a single rHuEPO dose of 2 000 U, twice a week (4 000 U per week in total) . Results Safety analysis: two-factor repeated-measures ANOVA showed that the type of intervention scheme and duration had no interaction effects on systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pre-dialysis serum potassium between experimental subgroup 1 and control subgroup 1, and between experimental subgroup 2 and control subgroup 2 (P>0.05), and produced no main effects on systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pre-dialysis serum potassium in experimental subgroup 1 and control subgroup 1, and between experimental subgroup 2 and control subgroup 2 (P>0.05). The serum levels of AST, ALT and TBiL were similar between experimental subgroup 1 and control subgroup 1 at baseline and 12 weeks of treatment (P>0.05). Likewise, they were similar between experimental subgroup 2 and control subgroup 2 at baseline and 12 weeks of treatment (P>0.05). No thromboembolic, cardiovascular or cerebrovascular events and gastrointestinal reactions related to rHuEPO occurred in any of the subgroups during the 12-week treatment. Efficacy analysis: the hemoglobin level (reference range was 110-130 g/L) in experimental subgroup 1 〔65.5% (19/29) 〕was similar to that in control subgroup 1 〔73.3% (22/30) 〕at 12 weeks of treatment (χ2=0.425, P=0.514). The serum levels of hemoglobin were similar between experimental subgroup 2 and control subgroup 2 at 12 weeks of treatment (P>0.05). The levels of red blood cell count, hematocrit, percentage and absolute number of reticulocytes, ferritin and transferrin saturation did not vary between experimental subgroup 1 and control subgroup 1, and between experimental subgroup 2 and control subgroup 2 either at baseline or 12 weeks of treatment (P>0.05) . Conclusion Weekly single and divided administration of moderate-dose erythropoietin had no significant difference in medication safety in the treatment of renal anemia in maintenance hemodialysis patients.

Obstructive sleep apnea (OSA) is a high prevalent chronic disease that may lead to many complications, and cause great potential harm to health. Epidemiological studies have showed that OSA is closely related to the development of various cardiovascular diseases. There are about 66 million patients with moderate to severe OSA in China, but 80% of potential OSA patients have not been diagnosed and treated in time. OSA is mainly diagnosed and treated in a hospital-based sleep center currently, as the process is time-consuming and laborious, which may be lead to a delay in diagnosis and treatment of many patients. Supported by the development of Internet of Things, Internet technologies and other emerging technologies, remote medicine has been increasingly used in the diagnosis and management of chronic diseases owing to its advantages of easy access, interactivity, high efficiency, resource sharing, service continuity and without space-time constraints. Our center has initially built a management system for remote diagnosis and treatment of OSA, but its clinical efficacy and economic value need to be further verified. We designed a randomized controlled trial protocol to assess whether the clinical benefits of the low-cost remote healthcare model are similar to those of the traditional healthcare model by comparing them in terms of clinical efficacy and health economic benefits, hoping to provide a reference for the efficient use of medical resources and further promotion of remote diagnosis and treatment of chronic diseases.

Abstract Background Tic disorders (TD) is a neuropsychiatric disease with twitch as the main manifestation in childhood. Jiu-Wei-Xi-Feng granules has been marketed in China for treating children with TD. As Long Gu (Os Draconis) in the composition of this Chinese patent medicine is a rare and expensive medicinal material protected by the Chinese government, therefore, we consider replacing it with Mu Li (Concha Ostreae) that has the same effect and is cheaper. This study is designed to evaluate the clinical equivalence between Jiu-Wei-Xi-Feng granules (Os Draconis replaced by Concha Ostreae) (JWXFD) and Jiu-Wei-Xi-Feng granules (original formula) (JWXFO) in children with TD (consumption of renal yin and liver wind stirring up internally syndrome). Methods/design This is a multicenter, randomized, double-blind, equivalence trial comparing the efficacy and safety of JWXFD and JWXFO in treating Children with tic disorders (consumption of renal yin and liver wind stirring up internally syndrome). A total of 288 patients will be recruited and randomly assigned to two groups in a 1:1 ratio. The treatment course is 6 weeks, with a 2 weeks follow-up. The primary outcome is the mean change value from baseline to 6th week by the Yale Global Tic Severity Scale total tic score (YGTSS-TTS). Secondary outcomes include total effective rate of tic, Yale Global Tic Severity Scale (YGTSS) scores and its factor scores (the degree of motor tics, phonic tics and social function damage), Clinical Global Impression-Severity scale, and TCM syndrome efficacy. Discussion The design of this study refers to a large number of similar research design points, and asked for opinions of peer experts, and finally reached a consensus. This trial will provide high-quality evidence on the clinical equivalence between JWXFD and JWXFO and provide a basis for the marketing of JWXFD. Trial registration ChiCTR2000032312 Registered on 25 April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52630

Background: Using traditional patient-reported outcomes (PROs), such as paper-based questionnaires, is cumbersome in the era of web-based medical consultation and telemedicine. Electronic PROs may reduce the burden on patients if implemented widely. Considering promising reports of DryEyeRhythm, our in-house mHealth smartphone app for investigating dry eye disease (DED) and the electronic and paper-based Ocular Surface Disease Index (OSDI) should be evaluated and compared to determine their equivalency. Objective: The purpose of this study is to assess the equivalence between smartphone app–based and paper-based questionnaires for DED. Methods: This prospective, nonblinded, randomized crossover study enrolled 34 participants between April 2022 and June 2022 at a university hospital in Japan. The participants were allocated randomly into 2 groups in a 1:1 ratio. The paper-app group initially responded to the paper-based Japanese version of the OSDI (J-OSDI), followed by the app-based J-OSDI. The app-paper group responded to similar questionnaires but in reverse order. We performed an equivalence test based on minimal clinically important differences to assess the equivalence of the J-OSDI total scores between the 2 platforms (paper-based vs app-based). A 95% CI of the mean difference between the J-OSDI total scores within the ±7.0 range between the 2 platforms indicated equivalence. The internal consistency and agreement of the app-based J-OSDI were assessed with Cronbach α coefficients and intraclass correlation coefficient values. Results: A total of 33 participants were included in this study. The total scores for the app- and paper-based J-OSDI indicated satisfactory equivalence per our study definition (mean difference 1.8, 95% CI –1.4 to 5.0). Moreover, the app-based J-OSDI total score demonstrated good internal consistency and agreement (Cronbach α=.958; intraclass correlation=0.919; 95% CI 0.842 to 0.959) and was significantly correlated with its paper-based counterpart (Pearson correlation=0.932, P <.001). Conclusions: This study demonstrated the equivalence of PROs between the app- and paper-based J-OSDI. Implementing the app-based J-OSDI in various scenarios, including telehealth, may have implications for the early diagnosis of DED and longitudinal monitoring of PROs. [ABSTRACT FROM AUTHOR]

Background: Tic disorders (TD) is a neuropsychiatric disease with twitch as the main manifestation in childhood. Jiu-Wei-Xi-Feng granules has been marketed in China for treating children with TD. As Long Gu (Os Draconis) in the composition of this Chinese patent medicine is a rare and expensive medicinal material protected by the Chinese government, therefore, we consider replacing it with Mu Li (Concha Ostreae) that has the same effect and is cheaper. This study is designed to evaluate the clinical equivalence between Jiu-Wei-Xi-Feng granules (Os Draconis replaced by Concha Ostreae) (JWXFD) and Jiu-Wei-Xi-Feng granules (original formula) (JWXFO) in children with TD (consumption of renal yin and liver wind stirring up internally syndrome).Methods/design: This is a multicenter, randomized, double-blind, equivalence trial comparing the efficacy and safety of JWXFD and JWXFO in treating Children with tic disorders (consumption of renal yin and liver wind stirring up internally syndrome). A total of 288 patients will be recruited and randomly assigned to two groups in a 1:1 ratio. The treatment course is 6 weeks, with a 2 weeks follow-up. The primary outcome is the mean change value from baseline to 6th week by the Yale Global Tic Severity Scale total tic score (YGTSS-TTS). Secondary outcomes include total effective rate of tic, Yale Global Tic Severity Scale (YGTSS) scores and its factor scores (the degree of motor tics, phonic tics and social function damage), Clinical Global Impression-Severity scale, and TCM syndrome efficacy.Discussion: The design of this study refers to a large number of similar research design points, and asked for opinions of peer experts, and finally reached a consensus. This trial will provide high-quality evidence on the clinical equivalence between JWXFD and JWXFO and provide a basis for the marketing of JWXFD.Trial Registration: ChiCTR2000032312 Registered on 25 April 2020, http://www.chictr.org.cn/showproj.aspx?proj=52630. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to verify the equivalence and effectiveness of the tablet-administered Korean Repeatable Battery for the Assessment of Neuropsychological Status (K-RBANS) for the prevention and early detection of dementia. Methods: Data from 88 psychiatry and neurology patient samples were examined to evaluate the equivalence between tablet and paper administrations of the K-RBANS using a non-randomly equivalent group design. We calculated the prediction scores of the tablet-administered K-RBANS based on demographics and covariate-test scores for focal tests using norm samples and tested format effects. In addition, we compared the receiver operating characteristic curves to confirm the effectiveness of the K-RBANS for preventing and detecting dementia. Results: In the analysis of raw scores, line orientation showed a significant difference (t=-2.94, p<0.001), and subtests showed small to large effect sizes (0.04-0.86) between paper- and tablet-administered K-RBANS. To investigate the format effect, we compared the predicted scaled scores of the tablet sample to the scaled scores of the norm sample. Consequently, a small effect size (d≤0.20) was observed in most of the subtests, except word list and story recall, which showed a medium effect size (d=0.21), while picture naming and subtests of delayed memory showed significant differences in the one-sample t-test. In addition, the area under the curve of the total scale index (TSI) (0.827; 95% confidence interval, 0.738-0.916) was higher than that of the five indices, ranging from 0.688 to 0.820. The sensitivity and specificity of TSI were 80% and 76%, respectively. Conclusion: The overall results of this study suggest that the tablet-administered K-RBANS showed significant equivalence to the norm sample, although some subtests showed format effects, and it may be used as a valid tool for the brief screening of patients with neuropsychological disorders in Korea. [ABSTRACT FROM AUTHOR]

One of the key issues in biosimilar phase III clinical trials is the determination of biosimilarity margins. Although biological products generally have high product variability, it is not reflected in the methods most commonly used for determining biosimilarity margins. In order to take into account high product variability, in this paper, we propose (m + 1) -arm parallel design, which consists of one biosimilar product group and m reference product groups. Because there are m reference product groups, we can estimate the between-batch variation of reference products using a random effect model. A statistical testing procedure appropriate for assessing biosimilarity using (m + 1) -arm parallel design is developed based on asymptotic theory. From simulation studies, we conclude that at least three reference product batches are needed for practical use of the proposed method. [ABSTRACT FROM AUTHOR]

Background: Ultrasound-guided caudal epidural injection (CEI) is limited in that it cannot confirm drug distribution at the target site without fluoroscopy. We hypothesized that visualization of solution flow through the inter-laminar space of the lumbosacral spine using color Doppler ultrasound alone would allow for confirmation of drug distribution. Therefore, we aimed to prospectively evaluate the usefulness of this method by comparing the color Doppler image in the paramedian sagittal oblique view of the lumbosacral spine (LS-PSOV) with the distribution of the contrast medium observed during fluoroscopy. Methods: Sixty-five patients received a 10-mL CEI of solution containing contrast medium under ultrasound guidance. During injection, flow was observed in the LSPSOV using color Doppler ultrasonography, following which it was confirmed using fluoroscopy. The presence of contrast image at L5-S1 on fluoroscopy was defined as "successful CEI." We then calculated prediction accuracy for successful CEI using color Doppler ultrasonography in the LS-PSOV. We also investigated the correlation between the distribution levels measured via color Doppler and fluoroscopy. Results: Prediction accuracy with color Doppler ultrasonography was 96.9%. The sensitivity, specificity, positive predictive value, and negative predictive value were 96.7%, 100%, 100%, and 60.0%, respectively. In 52 of 65 patients (80%), the highest level at which contrast image was observed was the same for both color Doppler ultrasonography and fluoroscopy. Conclusions: Our findings demonstrate that color Doppler ultrasonography in the LS-PSOV is a new method for determining whether a drug solution reaches the lumbosacral region (i.e., the main target level) without the need for fluoroscopy. [ABSTRACT FROM AUTHOR]

Abstract Non-inferiority randomized clinical trials are indicated when it is intended to prove that an experimental group is not inferior to a control group by more than a margin of non-inferiority. However, this type of study differs from traditional randomized clinical trials (superiority studies) because they have particularities that impact on the formulation of hypothesis to be tested, experimental design (non-inferiority margin determination, adapted sample size calculation, sensitivity of the study and data final analysis) and also on the presentation of data when writing the manuscript. Therefore, this article aims to present and discuss the particularities of non-inferiority clinical studies, since these requirements are fundamental to guarantee the validity of the conclusions of this type of study.

SUMMARY: The main objective of a confirmatory multiregional clinical trial (MRCT) is to demonstrate the overall efficacy of test drugs in all participating regions as well as to evaluate the possibility of extrapolating the overall results to each region. With the emergence of the demands of biosimilar drugs development, some guidelines recommended using equivalence design to demonstrate the comparability of efficacy between biosimilar and reference drugs. Previous discussions about assessing regional consistency in MRCT are mainly focused on superiority or non‐inferiority designs, while the extensions to equivalence designs were limited. In this work, we proposed a flexible regional consistency criterion for the MRCT with equivalence design. Based on this criterion, sample size determination and sample allocation were also discussed. [ABSTRACT FROM AUTHOR]

In this paper, we propose a Bayesian design framework for a biosimilars clinical program that entails conducting concurrent trials in multiple therapeutic indications to establish equivalent efficacy for a proposed biologic compared to a reference biologic in each indication to support approval of the proposed biologic as a biosimilar. Our method facilitates information borrowing across indications through the use of a multivariate normal correlated parameter prior (CPP), which is constructed from easily interpretable hyperparameters that represent direct statements about the equivalence hypotheses to be tested. The CPP accommodates different endpoints and data types across indications (eg, binary and continuous) and can, therefore, be used in a wide context of models without having to modify the data (eg, rescaling) to provide reasonable information‐borrowing properties. We illustrate how one can evaluate the design using Bayesian versions of the type I error rate and power with the objective of determining the sample size required for each indication such that the design has high power to demonstrate equivalent efficacy in each indication, reasonably high power to demonstrate equivalent efficacy simultaneously in all indications (ie, globally), and reasonable type I error control from a Bayesian perspective. We illustrate the method with several examples, including designing biosimilars trials for follicular lymphoma and rheumatoid arthritis using binary and continuous endpoints, respectively. [ABSTRACT FROM AUTHOR]

Abstract Background Approximately 50% of the deaths of children under the age of 5 can be attributed to undernutrition, which also encompasses severe acute malnutrition (SAM). Diarrhoea is strongly associated with these deaths and is commonly diagnosed solely based on stool frequency and consistency obtained through maternal recall. This trial aims to determine whether this approach is equivalent to a ‘directly observed method’ in which a health care worker directly observed stool frequency using diapers in hospitalised children with complicated SAM. Methods This study was conducted at ‘Moyo’ Nutritional Rehabilitation Unit, Queen Elizabeth Central Hospital, Malawi. Participants were children aged 5–59 months admitted with SAM. We compared 2 days of stool frequency data obtained with next-day maternal-recall versus a ‘gold standard’ in which a health care worker observed stool frequency every 2 h using diapers. After study completion, guardians were asked their preferred method and their level of education. Results We found poor agreement between maternal recall and the ‘gold standard’ of directly observed diapers. The sensitivity to detect diarrhoea based on maternal recall was poor, with only 75 and 56% of diarrhoea cases identified on days 1 and 2, respectively. However, the specificity was higher with more than 80% of children correctly classified as not having diarrhoea. On day 1, the mean stool frequency difference between the two methods was −0.17 (SD; 1.68) with limits of agreement (of stool frequency) of −3.55 and 3.20 and, similarly on day 2, the mean difference was −0.2 (SD; 1.59) with limits of agreement of −3.38 and 2.98. These limits extend beyond the pre-specified ‘acceptable’ limits of agreement (±1.5 stool per day) and indicate that the 2 methods are non-equivalent. The higher the stool frequency, the more discrepant the two methods were. Most primary care givers strongly preferred using diapers. Conclusions This study shows lack of agreement between the assessment of stool frequency in SAM patients using maternal recall and direct observation of diapers. When designing studies, one should consider using diapers to determining diarrhoea incidence/prevalence in SAM patients especially when accuracy is essential. Trial registration number ISRCTN11571116 (registered 29/11/2013).

Non-inferiority randomized clinical trials are indicated when it is intended to prove that an experimental group is not inferior to a control group by more than a margin of non-inferiority. However, this type of study differs from traditional randomized clinical trials (superiority studies) because they have particularities that impact on the formulation of hypothesis to be tested, experimental design (noninferiority margin determination, adapted sample size calculation, sensitivity of the study and data final analysis) and also on the presentation of data when writing the manuscript. Therefore, this article aims to present and discuss the particularities of non-inferiority clinical studies, since these requirements are fundamental to guarantee the validity of the conclusions of this type of study. [ABSTRACT FROM AUTHOR]

Background: Noninferiority trials are increasingly being performed. However, little is known about their methodological quality. We sought to characterize noninferiority cardiovascular trials published in the highest-impact journals, features that may bias results toward noninferiority, features related to reporting of noninferiority trials, and the time trends.Methods: We identified cardiovascular noninferiority trials published in JAMA, Lancet, or New England Journal of Medicine from 1990 to 2016. Two independent reviewers extracted the data. Data elements included the noninferiority margin and the success of studies in achieving noninferiority. The proportion of trials showing major or minor features that may have affected the noninferiority inference was determined. Major factors included the lack of presenting the results in both intention-to-treat and per-protocol/as-treated cohorts, α>0.05, the new intervention not being compared with the best alternative, not justifying the noninferiority margin, and exclusion or loss of ≥10% of the cohort. Minor factors included suboptimal blinding, allocation concealment, and others.Results: From 2544 screened studies, we identified 111 noninferiority cardiovascular trials. Noninferiority margins varied widely: risk differences of 0.4% to 25%, hazard ratios of 1.05 to 2.85, odds ratios of 1.1 to 2.0, and relative risks of 1.1 to 1.8. Eighty-six trials claimed noninferiority, of which 20 showed superiority, whereas 23 (21.1%) did not show noninferiority, of which 8 also demonstrated inferiority. Only 7 (6.3%) trials were considered low risk for all the major and minor biasing factors. Among common major factors for bias, 41 (37%) did not confirm the findings in both intention-to-treat and per-protocol/as-treated cohorts and 4 (3.6%) reported discrepant results between intention-to-treat and per-protocol analyses. Forty-three (38.7%) did not justify the noninferiority margin. Overall, 27 (24.3%) underenrolled or had >10% exclusions. Sixty trials (54.0%) were open label. Allocation concealment was not maintained or unclear in 11 (9.9%). Publication of noninferiority trials increased over time (P<0.001). Fifty-two (46.8%) were published after 2010 and had a lower risk of methodological or reporting limitations for major (P=0.03) and minor factors (P=0.002).Conclusions: Noninferiority trials in highest-impact journals commonly conclude noninferiority of the tested intervention, but vary markedly in the selected noninferiority margin, and frequently have limitations that may impact the inference related to noninferiority. [ABSTRACT FROM AUTHOR]

With the increasing globalization of drug development, the multiregional clinical trial (MRCT) has gained extensive use. The data from MRCTs could be accepted by regulatory authorities across regions and countries as the primary sources of evidence to support global marketing drug approval simultaneously. The MRCT can speed up patient enrollment and drug approval, and it makes the effective therapies available to patients all over the world simultaneously. However, there are many challenges both operationally and scientifically in conducting a drug development globally. One of many important questions to answer for the design of a multiregional study is how to partition sample size into each individual region. In this paper, two systematic approaches are proposed for the sample size allocation in a multiregional equivalence trial. A numerical evaluation and a biosimilar trial are used to illustrate the characteristics of the proposed approaches. [ABSTRACT FROM AUTHOR]

The authors convey their thoughts on the ethics of non-inferiority trials related to a lack of equipoise based on the null hypothesis, the use of a margin, and biocreep. Topics mentioned include the possibility that any decrease in efficacy can be allowed through the use of a margin, hypothetical outcomes of non-inferiority trials in the control group and the test group, and the need for a margin to plan a trial but that the trial should ultimately be judged by its findings and conduct.

For decades, the superiority trial has been the most popular design to assess the efficacy of newly developed drugs in a randomized controlled clinical trial. In a superiority trial, the aim is to show that the new (experimental) treatment is better than the standard treatment or placebo. However, it becomes increasingly difficult to improve the efficacy upon that of existing drugs. For this reason, noninferiority designs have been suggested. In a noninferiority study, one aims to show that the experimental treatment does not lower the efficacy of the standard treatment toomuch, but this loss of efficacy should be compensated by other better properties. In this article, the design, aims, and properties of the superiority and the noninferiority trial are contrasted and illustrated on recently published studies to treat patientswith advanced hepatocellular carcinoma. The author discusses the reasons why noninferiority studies are becoming popular, but also why the results of noninferiority studiesmay be difficult to interpret and can be easily misused. Since only a few noninferiority studies in hepatocellular cancer have been organized, also examples fromother therapeutic areas were taken. Finally, it is indicated how to appreciate the qualities of published noninferiority studies. [ABSTRACT FROM AUTHOR]

Background: Approximately 50% of the deaths of children under the age of 5 can be attributed to undernutrition, which also encompasses severe acute malnutrition (SAM). Diarrhoea is strongly associated with these deaths and is commonly diagnosed solely based on stool frequency and consistency obtained through maternal recall. This trial aims to determine whether this approach is equivalent to a 'directly observed method' in which a health care worker directly observed stool frequency using diapers in hospitalised children with complicated SAM.Methods: This study was conducted at 'Moyo' Nutritional Rehabilitation Unit, Queen Elizabeth Central Hospital, Malawi. Participants were children aged 5-59 months admitted with SAM. We compared 2 days of stool frequency data obtained with next-day maternal-recall versus a 'gold standard' in which a health care worker observed stool frequency every 2 h using diapers. After study completion, guardians were asked their preferred method and their level of education.Results: We found poor agreement between maternal recall and the 'gold standard' of directly observed diapers. The sensitivity to detect diarrhoea based on maternal recall was poor, with only 75 and 56% of diarrhoea cases identified on days 1 and 2, respectively. However, the specificity was higher with more than 80% of children correctly classified as not having diarrhoea. On day 1, the mean stool frequency difference between the two methods was -0.17 (SD; 1.68) with limits of agreement (of stool frequency) of -3.55 and 3.20 and, similarly on day 2, the mean difference was -0.2 (SD; 1.59) with limits of agreement of -3.38 and 2.98. These limits extend beyond the pre-specified 'acceptable' limits of agreement (±1.5 stool per day) and indicate that the 2 methods are non-equivalent. The higher the stool frequency, the more discrepant the two methods were. Most primary care givers strongly preferred using diapers.Conclusions: This study shows lack of agreement between the assessment of stool frequency in SAM patients using maternal recall and direct observation of diapers. When designing studies, one should consider using diapers to determining diarrhoea incidence/prevalence in SAM patients especially when accuracy is essential.Trial Registration Number: ISRCTN11571116 (registered 29/11/2013). [ABSTRACT FROM AUTHOR]

Assessing equivalence or similarity has drawn much attention recently as many drug products have lost or will lose their patents in the next few years, especially certain best-selling biologics. To claim equivalence between the test treatment and the reference treatment when assay sensitivity is well established from historical data, one has to demonstrate both superiority of the test treatment over placebo and equivalence between the test treatment and the reference treatment. Thus, there is urgency for practitioners to derive a practical way to calculate sample size for a three-arm equivalence trial. The primary endpoints of a clinical trial may not always be continuous, but may be discrete. In this paper, the authors derive power function and discuss sample size requirement for a three-arm equivalence trial with Poisson and negative binomial clinical endpoints. In addition, the authors examine the effect of the dispersion parameter on the power and the sample size by varying its coefficient from small to large. In extensive numerical studies, the authors demonstrate that required sample size heavily depends on the dispersion parameter. Therefore, misusing a Poisson model for negative binomial data may easily lose power up to 20%, depending on the value of the dispersion parameter. [ABSTRACT FROM AUTHOR]

This study is to investigate the effectiveness and safety of bloodletting puncture (BP) for acute ischemic stroke (AIS) when used in combination with standard treatment, as well as the patients' feelings and attitudes toward the treatment. This is a mixed method research which includes a multi-center, superiority, randomized controlled clinical trial, and focus group interview. A total of 360 AIS participants will be enrolled. They will be randomized into one of the following two groups for 7 d: (a) BP with standard treatment group ( n = 180); (b) standard treatment group ( n = 180). The primary outcome will be National Institute of Health stroke scale (NIHSS) score at day 7 after treatment. Secondary outcomes will be changes of Glasgow Coma Scale score, NIHSS score, mRS and Traditional Chinese Medicine syndrome score from baseline to 7, 14, and 30 d after treatment, recurrence rate and all-cause mortality rate within 30 d, and the safety assessments. The focus group will be conducted with a purposive sample of 1-2 acupuncturists and 1-2 patients respectively at each center at 7 and 30 d after treatment. We designed a mixed method study to evaluate the effect of BP, an acupuncture therapy for patients with AIS. If the findings of this study confirm the effectiveness of BP to reduce the NIHSS score and other related outcomes and patients are willing to accept the therapy, we believe this study will help the implementation of this therapy in clinical practice, and provide new evidence for the treatment of AIS.