Search

Purpose: Knee osteoarthritis (KOA) is one of the most prevalent degenerative joint diseases worldwide. The herbal decoction, Dokhwalgisaeng-tang (DHGST), has been commonly used in East Asia to treat osteoarthritis. However, there is insufficient evidence to draw clear conclusions concerning its effectiveness and safety for patients with KOA. We aim to determine the efficacy, safety, and economic feasibility of DHGST compared with Celecoxib, an oral COX-2 inhibitor, for patients with degenerative KOA. Trial Design and Methods: This multicenter, randomized, noninferiority trial, involving 160 participants who will be randomized using block randomization with 1:1 allocation, will compare DHGST and Celecoxib. The total trial period is 24 weeks after random allocation, comprising 12 weeks of treatment and 12 weeks of follow-up. Participants with KOA will be administered 200 mg of DHGST (treatment group) or Celecoxib capsules (control group) for 12 weeks. Efficacy and safety evaluations will be conducted at weeks 0, 4, 8, and 12, and 24. The primary outcome measurement is the Korean Western Ontario McMaster score at week 12. Changes in pain intensity using a 100 mm visual analog scale, changes in quality of life using a EuroQol 5-dimension 5-level self-report survey, and patient satisfaction will also be measured to evaluate effectiveness between the two groups. A trial-based economic feasibility evaluation will be conducted to analyze treatment cost-effectiveness from societal and healthcare system perspectives. Drug safety will be assessed through adverse reactions and laboratory test findings. Discussion: This trial protocol has the following limitations. Applying a double-dummy design is not possible, as the tablet and granule forms can easily be distinguished visually, and achieving participant blinding is challenging. The trial findings are intended to inform participants, physicians, and other stakeholders in determining whether DHGST could be used as an alternative therapeutic option for KOA. Trial Registration Number: KCT0008424 (Clinical Research Information Service of the Republic of Korea), registered on 12 May 2023. [ABSTRACT FROM AUTHOR]

Hypertension guidelines recommend diagnosis and treatment of obstructive sleep apnea (OSA) in patients with hypertension. The mandibular advancement device (MAD) is an oral appliance therapy for patients who decline or cannot tolerate continuous positive airway pressure (CPAP). We compared the relative effectiveness of MAD vs CPAP in reducing 24-hour ambulatory blood pressure (BP). In an investigator-initiated, randomized, noninferiority trial (prespecified margin 1.5 mm Hg), 321 participants aged ≥40 years with hypertension and increased cardiovascular risk were recruited at 3 public hospitals for polysomnography. Of these, 220 participants with moderate-to-severe OSA (apnea-hypopnea index ≥15 events per hour) were randomized to either MAD or CPAP (1:1). The primary outcome was the difference between the 24-hour mean arterial BP at baseline and 6 months. Compared with baseline, the 24-hour mean arterial BP decreased by 2.5 mm Hg (P = 0.003) at 6 months in the MAD group, whereas no change was observed in the CPAP group (P = 0.374). The between-group difference was −1.6 mm Hg (95% CI: −3.51 to 0.24, noninferiority P < 0.001). The MAD group demonstrated a larger between-group reduction in all secondary ambulatory BP parameters compared with the CPAP group, with the most pronounced effects observed in the asleep BP parameters. Both the MAD and CPAP improved daytime sleepiness, with the between-group difference similar (P = 0.384). There were no between-group differences in cardiovascular biomarkers. MAD is noninferior to CPAP for reducing 24-hour mean arterial BP in participants with hypertension and increased cardiovascular risk. (Cardiosleep Research Program on Obstructive Sleep Apnea, Blood Pressure Control and Maladaptive Myocardial Remodeling—Non-inferiority Trial [CRESCENT]; NCT04119999) [Display omitted] [ABSTRACT FROM AUTHOR]

The conduct and reporting of studies with a noninferiority hypothesis is challenging because of the complexity involved in their design and interpretation. However, studies with a noninferiority design have increased in popularity. A recently published trial reported on the noninferiority of lidocaine infusion to epidural analgesia in major abdominal surgeries. Apart from needing a critical appraisal, this draws attention to improve our understanding of noninferiority study framework and its unique features. Given the increasing focus on using various analgesic adjuncts and multiple approaches to fascial plane blocks to avoid more definitive and standard approaches, it is imperative that particular attention is paid to appropriate execution and reporting of noninferiority studies. [ABSTRACT FROM AUTHOR]

As one of the most commonly used data types, methods in testing or designing a trial for binary endpoints from two independent populations are still being developed until recently. However, the power and the minimum required sample size comparisons between different tests may not be valid if their type I errors are not controlled at the same level. In this article, we unify all related testing procedures into a decision framework, including both frequentist and Bayesian methods. Sufficient conditions of the type I error attained at the boundary of hypotheses are derived, which help reduce the magnitude of the exact calculations and lay out a foundation for developing computational algorithms to correctly specify the actual type I error. The efficient algorithms are thus proposed to calculate the cutoff value in a deterministic decision rule and the probability value in a randomized decision rule, such that the actual type I error is under but closest to, or equal to, the intended level, respectively. The algorithm may also be used to calculate the sample size to achieve the prespecified type I error and power. The usefulness of the proposed methodology is further demonstrated in the power calculation for designing superiority and noninferiority trials. [ABSTRACT FROM AUTHOR]

Background: Issues with specification of margins, adherence, and analytic population can potentially bias results toward the alternative in randomized noninferiority pragmatic trials. To investigate this potential for bias, we conducted a targeted search of the medical literature to examine how noninferiority pragmatic trials address these issues. Methods: An Ovid MEDLINE database search was performed identifying publications in New England Journal of Medicine, Journal of the American Medical Association, Lancet, or British Medical Journal published between 2015 and 2021 that included the words "pragmatic" or "comparative effectiveness" and "noninferiority" or "non-inferiority." Our search identified 14 potential trials, 12 meeting our inclusion criteria (11 individually randomized, 1 cluster-randomized). Results: Eleven trials had results that met the criteria established for noninferiority. Noninferiority margins were prespecified for all trials; all but two trials provided justification of the margin. Most trials did some monitoring of treatment adherence. All trials conducted intent-to-treat or modified intent-to-treat analyses along with per-protocol analyses and these analyses reached similar conclusions. Only two trials included all randomized participants in the primary analysis, one used multiple imputation for missing data. The percentage excluded from primary analyses ranged from ∼2% to 30%. Reasons for exclusion included randomization in error, nonadherence, not receiving assigned treatment, death, withdrawal, lost to follow-up, and incomplete data. Conclusion: Specification of margins, adherence, and analytic population require careful consideration to prevent bias toward the alternative in noninferiority pragmatic trials. Although separate guidance has been developed for noninferiority and pragmatic trials, it is not compatible with conducting a noninferiority pragmatic trial. Hence, these trials should probably not be done in their current format without developing new guidelines. [ABSTRACT FROM AUTHOR]

This article provides an overview of noninferiority clinical trials for clinical cardiologists. Noninferiority trials are designed to assess whether a new treatment is not worse than an established treatment by a certain degree. The article discusses the advantages and limitations of noninferiority trials, including scenarios where they might be preferred and challenges in their design and execution. Key statistical considerations, such as defining the noninferiority margin and the use of confidence intervals, are also addressed. Overall, noninferiority trials offer benefits when properly conducted and are likely to continue growing in cardiology. [Extracted from the article]

Background It is unclear whether the reporting quality of antiretroviral (ARV) noninferiority (NI) randomized controlled trials (RCTs) has improved since the CONSORT guideline release in 2006. The primary objective of this systematic review was assessing the methodological and reporting quality of ARV NI-RCTs. We also assessed reporting quality by funding source and publication year. Methods We searched Medline, Embase, and Cochrane Central from inception to 14 November 2022. We included NI-RCTs comparing ≥2 ARV regimens used for human immunodeficiency virus treatment or prophylaxis. We used the Cochrane Risk of Bias 2.0 tool to assess risk of bias. Screening and data extraction were performed blinded and in duplicate. Descriptive statistics were used to summarize data; statistical tests were 2 sided, with significance defined as P <.05. The systematic review was prospectively registered (PROSPERO CRD42022328586), and not funded. Results We included 160 articles reporting 171 trials. Of these articles, 101 (63.1%) did not justify the NI margin used, and 28 (17.5%) did not provide sufficient information for sample size calculation. Eighty-nine of 160 (55.6%) reported both intention-to-treat and per-protocol analyses, while 118 (73.8%) described missing data handling. Ten of 171 trials (5.9%) reported potentially misleading results. Pharmaceutical industry–funded trials were more likely to be double-blinded (28.1% vs 10.3%; P =.03) and to describe missing data handling (78.5% vs 59.0%; P =.02). The overall risk of bias was low in 96 of 160 studies (60.0%). Conclusions ARV NI-RCTs should improve NI margin justification, reporting of intention-to-treat and per-protocol analyses, and missing data handling to increase CONSORT adherence. [ABSTRACT FROM AUTHOR]

To evaluate if an internet-delivered parent training program is noninferior to its group-delivered counterpart in reducing child disruptive behavior problems (DBP). This noninferiority randomized clinical trial enrolled families seeking treatment in primary care in Stockholm, Sweden, for DBP in a child 3-11 years of age. Participants were randomized to internet-delivered (iComet) or group-delivered (gComet) parent training. The primary outcome was parent-rated DBP. Assessments were made at baseline and 3, 6, and 12 months. Secondary outcomes included child and parent behaviors and well-being and treatment satisfaction. The noninferiority analysis was determined by a one-sided 95% CI of the mean difference between gComet and iComet using multilevel modeling. This trial included 161 children (mean age 8.0); 102 (63%) were boys. In both intention-to-treat and per-protocol analyses, iComet was noninferior to gComet. There were small differences in between-group effect sizes (d = −0.02 to 0.13) on the primary outcome with the upper limit of the one-sided 95% CI below the noninferiority margin at 3-, 6-, and 12-month follow-up. Parents were more satisfied with gComet (d = 0.49, 95% CI [0.26, 0.71]). At 3-month follow-up, there were also significant differences in treatment effect on attention-deficit/hyperactivity disorder symptoms (d = 0.34, 95% CI [0.07, 0.61]) and parenting behavior (d = 0.41, 95% CI [0.17, 0.65]) favoring gComet. At 12-month follow-up, there were no differences in any outcomes. Internet-delivered parent training was noninferior to group-delivered parent training in reducing child DBP. The results were maintained at 12-month follow-up. This study supports internet-delivered parent training being used as an alternative to group-delivered parent training in clinical settings. Randomized Controlled Trial of Comet via the Internet or in Group Format; https://www.clinicaltrials.gov/ ; NCT03465384. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate whether the 24-weeks postoperative fracture union rate for the investigational TFNA intramedullary nail was non-inferior compared to the control product PFNA-II. Methods: The study was a prospective, randomized, single-blind, noninferiority dual-arm study drawing from 9 trauma centers across China, between November 2018 and September 2020, with follow-up measurements at 24 weeks after internal fixation. The full analysis data set (FAS [Intent-to-Treat]) was analyzed and is summarized here. The primary outcome was fracture union rate, a composite score combining clinical and radiographic assessment. Secondary endpoints comprised (a) clinical outcomes including (1) SF-12, (2) Harris Hip, and (3) EQ-5D Scores, (b) radiographic incidence of complications such as loosening or cut-out requiring revision, (c) revision rates, (d) reoperation rates, and (e) adverse events, including 24-weeks revision and reoperation rates. Results: Both TFNA and PFNA-II group fracture healing rates were 100% at 24 weeks; TFNA was therefore shown to be non-inferior to PFNA-II. With baseline data matched in all parameters except age in both the TFNA and PFNA-II groups, comparisons of union rates, SF-12, Harris Hip, and EQ-5D Scores yielded p values > 0.05 indicating no significant difference between the two groups, further supporting the noninferiority of TFNA. In both groups, revision and re-operation rates were 0, and the incidences of serious adverse events were 19.4% and 17.4%, respectively. Conclusion: In terms of fracture union rate at 24 weeks, the DePuy Synthes Trochanteric Fixation Nail Advanced (TFNA) was not inferior to the marketed Proximal Femoral Nail Antirotation (PFNA-II) device produced by the same manufacturer. Secondary and safety outcomes showed no significant differences between the two groups. Registration: Registration was completed at ClinicalTrials.gov NCT03635320. [ABSTRACT FROM AUTHOR]

Although use of drug-coated balloons (DCB) is a promising technique, little is known about the clinical efficacy of the Dissolve DCB in drug-eluting stent (DES) in-stent restenosis (ISR). This study sought to evaluate the efficacy and safety of the Dissolve DCB in patients with DES ISR. This was a prospective, multicenter, randomized, noninferiority trial comparing Dissolve DCB with SeQuent Please DCB in patients with DES ISR. Angiographic and clinical follow-up was planned at 9 months in all patients. The primary endpoint was 9-month in-segment late loss. A total of 260 patients with ISR from 10 Chinese sites were included (Dissolve DCB, n = 128; SeQuent Please DCB, n = 132). Nine-month in-segment late loss was 0.50 ± 0.06 mm with Dissolve DCB vs 0.47 ± 0.07 mm with SeQuent Please DCB; the 1-sided 97.5% upper confidence limit of the difference was 0.18 mm (P for noninferiority = 0.03). Rates of target lesion failure and binary restenosis were numerical higher in the Dissolve DCB cohort compared with the SeQuent Please DCB cohort at 9 months (17.5% vs 10.7%; P = 0.12; 23.4% vs 16.4%; P = 0.19, respectively). At 9 months, major adverse cardiac and cerebrovascular events occurred in 36 patients (28.3%) vs 30 patients (22.9%) in the Dissolve DCB and SeQuent Please DCB groups, respectively. In this head-to-head randomized trial, the Dissolve DCB was noninferior to the SeQuent Please DCB for 9-month in-segment late loss. However, Dissolve DCB with its numerical increase in target lesion failure and binary restenosis warrants assessment in larger clinical trials (A Safety and Efficacy Study of Dissolve™ in Treatment of Coronary In-Stent Restenosis; NCT03373695) [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract When designing a noninferiority (NI) study one of the most important steps is to set the noninferiority (NI) limit. The NI limit is an acceptable loss of efficacy for a new investigative treatment compared to an active control treatment – often standard care. The limit should be a value so small that the loss efficacy is clinically zero. An approach to the setting of a noninferiority limit such that an effect over placebo can be shown through an indirect comparison to placebo-controlled trials where the active control treatment was compared to placebo. In this context, the setting of the NI limit depends on three assumptions: assay sensitivity, bias minimisation, and the constancy assumption. The last assumption of constancy assumes the effect of the active control over placebo is constant. This paper aims to assess the constancy assumption in placebo-controlled trials. Methods: 236 Cochrane reviews of placebo-controlled trials published in 2015–2016 were collected and used to assess the relation between the placebo, active treatment, and the standardised treatment different (SMD) with the time (year of publication). Results : The analysis showed that both the size of the study and the treatment effect were associated with year of publication. The three main variables that affect the estimate of any future trial are the estimate from the meta-analysis of previous trials prior to the trial, the year difference in the meta-analysis, and the year of the trial conduction. The regression analysis showed that an increase of one unit in the point estimate of the historical meta-analysis would lead to an increase in the predicted estimate of future trial on the SMD scale by 0.88. This result suggests the final trial results are 12% smaller than that from the meta-analysis of trials until that point. Conclusion : The result of this study indicates that assuming constancy of the treatment difference between the active control and placebo can be questioned. It is therefore important to consider the effect of time in estimating the treatment response if indirect comparisons are being used as the basis of a NI limit.

We describe a new command, artcat, that calculates sample size or power for a randomized controlled trial or similar experiment with an ordered categorical outcome, where analysis is by the proportional-odds model. artcat implements the method of Whitehead (1993, Statistics in Medicine 12: 2257–2271). We also propose and implement a new method that 1) allows the user to specify a treatment effect that does not obey the proportional-odds assumption, 2) offers greater accuracy for large treatment effects, and 3) allows for noninferiority trials. We illustrate the command and explore the value of an ordered categorical outcome over a binary outcome in various settings. We show by simulation that the methods perform well and that the new method is more accurate than Whitehead's method. [ABSTRACT FROM AUTHOR]

We describe the command artbin, which offers various new facilities for the calculation of sample size for binary outcome variables that are not otherwise available in Stata. While artbin has been available since 2004, it has not been previously described in the Stata Journal. artbin has been recently updated to include new options for different statistical tests, methods and study designs, improved syntax, and better handling of noninferiority trials. In this article, we describe the updated version of artbin and detail the various formulas used within artbin in different settings. [ABSTRACT FROM AUTHOR]

Background: Subjective assumptions on the definition of surgical success are inherent to the design of clinical trials with a categorial outcome. The current study used reasonable alternative assumptions about surgical care to reassess data for the randomized controlled Cartiva trial (MOTION). Methods: Data from the published study were augmented by publicly accessible internal US Food and Drug Administration documents. As in the published report, 1-sided lower bound 95% CIs (LBCI95) for the difference of proportions were calculated for a series of alternative scenarios in which the assumptions underlying what constitutes surgical success were altered. Results: Using a noninferiority margin of −15%, the MOTION trial reported success based on a 1-sided LBCI95 of −10.9%. Each of the 3 independent alternative scenarios analyzed yielded results that altered the primary outcome of the trial: (1) eliminating failures based solely upon radiographs findings, thereby considering a painless pseudarthrosis as a success (1-sided LBCI95 of −15.9%), (2) considering only major surgical revision as a failure and discounting isolated hardware removal (1-sided LBCI95 of −15.1%), and (3) using a visual analog scale (VAS) pain threshold of <30 as the success criterion rather than a 30% reduction in VAS pain score (1-sided LBCI95 of −15.8%). Conclusion: In this reanalysis, applying any of 3 reasonable alternative assumptions about the definition of surgical success to the data resulted in failure to prove noninferiority of Cartiva over arthrodesis, a reversal of the reported trial result. These results highlight the effect of subjective assumptions in the design of clinical trials with a categorical outcome and illustrate how differing philosophies about what constitutes surgical success can be pivotal in determining the final result. Level of Evidence: Level II, prospective comparative study. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

When designing a noninferiority (NI) study one of the most important steps is to set the noninferiority (NI) limit. The NI limit is an acceptable loss of efficacy for a new investigative treatment compared to an active control treatment - often standard care. The limit should be a value so small that the loss efficacy is clinically zero. An approach to the setting of a noninferiority limit such that an effect over placebo can be shown through an indirect comparison to placebo-controlled trials where the active control treatment was compared to placebo. In this context, the setting of the NI limit depends on three assumptions: assay sensitivity, bias minimisation, and the constancy assumption. The last assumption of constancy assumes the effect of the active control over placebo is constant. This paper aims to assess the constancy assumption in placebo-controlled trials.Methods: 236 Cochrane reviews of placebo-controlled trials published in 2015-2016 were collected and used to assess the relation between the placebo, active treatment, and the standardised treatment different (SMD) with the time (year of publication).Results: The analysis showed that both the size of the study and the treatment effect were associated with year of publication. The three main variables that affect the estimate of any future trial are the estimate from the meta-analysis of previous trials prior to the trial, the year difference in the meta-analysis, and the year of the trial conduction. The regression analysis showed that an increase of one unit in the point estimate of the historical meta-analysis would lead to an increase in the predicted estimate of future trial on the SMD scale by 0.88. This result suggests the final trial results are 12% smaller than that from the meta-analysis of trials until that point.Conclusion: The result of this study indicates that assuming constancy of the treatment difference between the active control and placebo can be questioned. It is therefore important to consider the effect of time in estimating the treatment response if indirect comparisons are being used as the basis of a NI limit. [ABSTRACT FROM AUTHOR]

Aim: Quantitative analysis of brain single photon emission computed tomography (SPECT) perfusion imaging is dependent on normative datasets that are challenging to produce. This study investigated the combination of SPECT neuroimaging from a large clinical population rather than small numbers of controls. The authors hypothesized this “population template” would demonstrate noninferiority to a control dataset, providing a viable alternative for quantifying perfusion abnormalities in SPECT neuroimaging. Methods: A total of 2, 068 clinical SPECT scans were averaged to form the “population template”. Validation was three-fold. First, the template was imported into SPECT brain analysis software, MIMneuro®, and compared against its control dataset of 90 individuals through its region and cluster analysis tools. Second, a cohort of 100 cognitively impaired subjects was evaluated against both the population template and MIMneuro®’s normative dataset to compute region-based metrics. Concordance and intraclass correlation coefficients, mean square deviations, total deviation indices, and limits of agreement were derived from these data to measure agreement and test for noninferiority. Finally, the same patients were clinically read in CereMetrix® to confirm that expected perfusion patterns appeared after comparison to the template. Results: MIMneuro®’s default threshold for normality is ± 1.65 z-score and this served as our noninferiority margin. Direct comparison of the template to controls produced no regions that exceeded this threshold and all clusters identified were far from statistically significant. Agreement measures revealed consistency between the softwares and that CereMetrix® results were noninferior to MIMneuro®, albeit with proportional bias. Visual analysis also confirmed that expected perfusion patterns appeared when individual scans were compared to the population template within CereMetrix®. Conclusions: The authors demonstrated a population template was noninferior to a smaller control dataset despite inclusion of abnormal scans. This suggests that our patient-based population template can serve as an alternative for identifying and quantifying perfusion abnormalities in brain SPECT.

Noninferiority studies in surgery are, by their very nature, reductionist. They use multiple variables to generate a yes or no answer about the new device being tested. A binary outcome is appropriate for a regulatory agency such as the Food and Drug Administration, but the clinical situation is more nuanced. It is critical to understand the underlying philosophies and choices that go into trial design when a surgeon is recommending a new device. In the case of Cartiva, any of 3 reasonable alternative means of defining surgical success would have altered the final outcome of the MOTION trial. Additionally, using a more rigorous noninferiority margin rather than adding an additional cushion based upon the argument that motion alone had extra inherent value would have also led to failure of the trial to demonstrate noninferiority., Competing Interests: Disclosure The authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. ICMJE forms for all authors are available online. No disclosures related to this article., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Benign paroxysmal positional vertigo (BPPV) is the most common cause of peripheral vertigo among adults. Successful treatment often requires an appropriate canalith repositioning procedure (CRP), which has proven effective in the treatment of BPPV. However, some patients experience residual dizziness (RD) after CRP, affecting their daily activities and quality of life. Although oral betahistine is a common clinical treatment for RD, some patients may discontinue this medication due to adverse effects. Conversely, acupuncture has demonstrated efficacy in treating dizziness with minimal adverse effects. However, to date, no trials have directly compared the efficacy of acupuncture and betahistine in treating RD. Our goal was to assess the noninferiority of acupuncture in treating RD compared with the commonly used oral betahistine treatment., Methods and Analysis: A randomized, controlled, non-inferiority trial was conducted to compare the effectiveness of acupuncture and betahistine in patients with BPPV who experience RD after a successful CRP. Eighty-four participants were randomly assigned to two treatment groups, each receiving either acupuncture or betahistine. The assessors and statisticians were blinded to treatment allocation. The primary outcomes were the response rate and change in vertigo level, and secondary outcomes included Visual Analog Scores and the presence and change in depressive symptoms among patients. Scale measures were recorded at baseline, 2, 4, and 12 weeks after randomization. This trial aims to provide causal evidence supporting the non-inferiority of acupuncture therapy relative to oral betahistine, offering an alternative treatment avenue for patients intolerant to betahistine., Ethics and Dissemination: Ethics approval was obtained from the Affiliated Hospital of Shandong University of Traditional Chinese Medicine, with permission number 2023-095-KY. Written informed consent was obtained from the enrolled patients., (Copyright 2024, Mary Ann Liebert, Inc., publishers.)

Objective: To evaluate the costs and non‐inferiority of a strategy starting with the levonorgestrel intrauterine system (LNG‐IUS) compared with endometrial ablation (EA) in the treatment of heavy menstrual bleeding (HMB). Design: Cost‐effectiveness analysis from a societal perspective alongside a multicentre randomised non‐inferiority trial. Setting: General practices and gynaecology departments in the Netherlands. Population: In all, 270 women with HMB, aged ≥34 years old, without intracavitary pathology or wish for a future child. Methods: Randomisation to a strategy starting with the LNG‐IUS (n = 132) or EA (n = 138). The incremental cost‐effectiveness ratio was estimated. Main outcome measures: Direct medical costs and (in)direct non‐medical costs were calculated. The primary outcome was menstrual blood loss after 24 months, measured with the mean Pictorial Blood Assessment Chart (PBAC)‐score (non‐inferiority margin 25 points). A secondary outcome was successful blood loss reduction (PBAC‐score ≤75 points). Results: Total costs per patient were €2,285 in the LNG‐IUS strategy and €3,465 in the EA strategy (difference: €1,180). At 24 months, mean PBAC‐scores were 64.8 in the LNG‐IUS group (n = 115) and 14.2 in the EA group (n = 132); difference 50.5 points (95% CI 4.3–96.7). In the LNG‐IUS group, 87% of women had a PBAC‐score ≤75 points versus 94% in the EA group (relative risk [RR] 0.93, 95% CI 0.85–1.01). The ICER was €23 (95% CI €5–111) per PBAC‐point. Conclusions: A strategy starting with the LNG‐IUS was cheaper than starting with EA, but non‐inferiority could not be demonstrated. The LNG‐IUS is reversible and less invasive and can be a cost‐effective treatment option, depending on the success rate women are willing to accept. Treatment of heavy menstrual bleeding starting with LNG‐IUS is cheaper but slightly less effective than endometrial ablation. Treatment of heavy menstrual bleeding starting with LNG‐IUS is cheaper but slightly less effective than endometrial ablation. [ABSTRACT FROM AUTHOR]

In this trial, we sought to evaluate the efficacy and safety of the addition of the Maze performed by cryoablation (CryoMaze) to the mitral valve surgeries. The trial is a randomized, single-center trial to determine whether CryoMaze was noninferior to cut-and-sew maze procedure (CSM) in patients with persistent or long-standing persistent atrial fibrillation (AF), with a 15% margin to establish noninferiority. The primary endpoint was freedom from AF off antiarrhythmic drugs (AADs) at 12 months. Secondary endpoints included freedom from AF off AADs at 3 and 6 months, and a composite of serious adverse events. Two hundred patients were randomized to either CryoMaze (n = 100) or CSM (n = 100). Freedom from AF was achieved in 85 % (95% confidence interval, 0.76-0.91) in the CryoMaze group and 88% (95% confidence interval, 0.80-0.94) in the CSM group, showing that CryoMaze was noninferior to CSM at 12 months (P value for noninferiority = 0.0065). There was no significant difference in serious adverse effects (n = 12 in CryoMaze; n = 17 in CSM; P = 0.315). Perioperative bleeding and the length of surgery, ICU stay, postoperative hospital stay; and the need for temporary pacing decreased significantly in the CryoMaze group. CryoMaze was noninferior to CSM for efficacy and safety for patients with persistent or long-standing persistent AF undergoing mitral valve surgeries. CryoMaze significantly decreased bleeding, the length of surgery, ICU and hospital stay, as well the need for temporary pacing. (Chinese Clinical Trial Register number, ChiCTR-IOR-16008112.). [ABSTRACT FROM AUTHOR]

The care for individuals with cystic fibrosis (CF) with at least one F508del mutation will greatly change as a result of the unparalleled clinical benefits observed with the new triple-combination CFTR (CF transmembrane regulator)-modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). Incorporating ETI into the standard of care creates new motivation and opportunity to consider reductions in overall treatment burden and evaluate whether other chronic medications can now be safely discontinued without loss of clinical benefit. SIMPLIFY is a master protocol poised to test the impact of discontinuing versus continuing two commonly used chronic therapies in people with CF who are at least 12 years of age or older and stable on ETI therapy. The protocol is composed of two concurrent randomized controlled trials designed to evaluate the independent short-term effects of discontinuing hypertonic saline or dornase alfa, enabling individuals on both therapies to participate in one or both trials. The primary objective for each trial is to determine whether discontinuing treatment is noninferior to continuing treatment after establishment of ETI, as measured by the 6-week absolute change in the percent-predicted forced expiratory volume in 1 second. Developing this study required a balance between ideal study-design principles and feasibility. SIMPLIFY will be the largest multicenter, randomized, controlled medication-withdrawal study in CF. This study is uniquely positioned to provide timely evidence on whether the daily treatment burden can be reduced among individuals on CFTR-modulator therapy. Clinical trial registered with www.clinicaltrials.gov (NCT04378153). [ABSTRACT FROM AUTHOR]

Log-rank tests have been widely used to compare two survival curves in biomedical research. We describe a unified approach to power and sample size calculation for the unweighted and weighted log-rank tests in superiority, noninferiority and equivalence trials. It is suitable for both time-driven and event-driven trials. A numerical algorithm is suggested. It allows flexible specification of the patient accrual distribution, baseline hazards, and proportional or nonproportional hazards patterns, and enables efficient sample size calculation when there are a range of choices for the patient accrual pattern and trial duration. A confidence interval method is proposed for the trial duration of an event-driven trial. We point out potential issues with several popular sample size formulae. Under proportional hazards, the power of a survival trial is commonly believed to be determined by the number of observed events. The belief is roughly valid for noninferiority and equivalence trials with similar survival and censoring distributions between two groups, and for superiority trials with balanced group sizes. In unbalanced superiority trials, the power depends also on other factors such as data maturity. Surprisingly, the log-rank test usually yields slightly higher power than the Wald test from the Cox model under proportional hazards in simulations. We consider various nonproportional hazards patterns induced by delayed effects, cure fractions, and/or treatment switching. Explicit power formulae are derived for the combination test that takes the maximum of two or more weighted log-rank tests to handle uncertain nonproportional hazards patterns. Numerical examples are presented for illustration. [ABSTRACT FROM AUTHOR]

Background and purpose: Head down tilt 15° (HDT15°), applied before recanalization, increases collateral flow and improves outcome in experimental ischemic stroke. For its simplicity and low cost, HDT15° holds considerable potential to be developed as an emergency treatment of acute stroke in the prehospital setting, where hemorrhagic stroke is the major mimic of ischemic stroke. In this study, we assessed safety of HDT15° in the acute phase of experimental intracerebral hemorrhage. Methods: Intracerebral hemorrhage was produced by stereotaxic injection of collagenase in Wistar rats. A randomized noninferiority trial design was used to assign rats to HDT15° or flat position (n = 64). HDT15° was applied for 1 h during the time window of hematoma expansion. The primary outcome was hematoma volume at 24 h. Secondary outcomes were mass effect, mortality, and functional deficit in the main study and acute changes of intracranial pressure, hematoma growth, and cardiorespiratory parameters in separate sets of randomized animals (n = 32). Results: HDT15° achieved the specified criteria of noninferiority for hematoma volume at 24 h. Mass effect, mortality, and functional deficit at 24 h showed no difference in the two groups. HDT15° induced a mild increase in intracranial pressure with respect to the pretreatment values (+2.91 ± 1.76 mmHg). HDT15° had a neutral effect on MRI‐based analysis of hematoma growth and cardiorespiratory parameters. Conclusions: Application of HDT15° in the hyperacute phase of experimental intracerebral hemorrhage does not worsen early outcome. Further research is needed to implement HDT15° as an emergency collateral therapeutic for acute stroke. [ABSTRACT FROM AUTHOR]

In a series of articles, Gart and Nam construct the efficient score tests and confidence intervals with or without skewness correction for stratified comparisons of binomial proportions on the risk difference, relative risk, and odds ratio effect metrics. However, the stratified score methods and their properties are not well understood. We rederive the efficient score tests, which reveals their theoretical relationship with the contrast‐based score tests, and provides a basis for adapting the method by using other weighting schemes. The inverse variance weight is optimal for a common treatment effect in large samples. We explore the behavior of the score approach in the presence of extreme outcomes when either no or all subjects in some strata are responders, and provide guidance on the choice of weights in the analysis of rare events. The score method is recommended for studies with a small number of moderate or large sized strata. A general framework is proposed to calculate the asymptotic power and sample size for the score test in superiority, noninferiority and equivalence clinical trials, or case‐control studies. We also describe a nearly exact procedure that underestimates the exact power, but the degree of underestimation can be controlled to a negligible level. The proposed methods are illustrated by numerical examples. [ABSTRACT FROM AUTHOR]

Randomization is a common technique used in clinical trials to eliminate potential bias and confounders in a patient population. Equal allocation to treatment groups is the standard due to its optimal efficiency in many cases. However, in certain scenarios, unequal allocation can improve efficiency. In superiority trials with more than two groups, the optimal randomization is not always a balanced randomization. In noninferiority (NI) trials, additive margin with equal variance is the http://www.statlab.wisc.edu/shiny/SSNI/. [ABSTRACT FROM AUTHOR]

The aim of this study was to demonstrate the noninferiority of a novel teat disinfectant based on copper and zinc (ZkinCu; Copper Andino, Santiago de Chile, Chile) compared with a previously proven glycolic acid active disinfectant (OceanBlu; DeLaval, Kansas City, MO) as a positive control, with respect to the incidence of new intramammary infections under natural challenge conditions on a commercial robotic dairy farm. This study was conducted in 6 robotic pens of approximately 60 milking cows each. The pens were randomly assigned to 1 of the 2 studied disinfectants. Throughout the 8 wk study, the same pre- and post-milking teat disinfectant was used in each pen. The same milking procedures were used in each robot throughout the study. Pre-milking hygiene consisted of applying the disinfectant (OceanBlu or ZkinCu) with the robotic arm. The same product was applied on the teats after milking. At the beginning of the study, all quarters of all study cows were sampled. In successive samplings (wk 2, 4, 6, and 8), composite milk samples were collected on farm to determine SCC. Once composite SCC results were available (2 d) and based on an SCC of ≥100,000 cells/mL, quarter milk samples underwent bacteriological culture. Clinical mastitis was identified by study personnel. Intramammary infection in biweekly quarter milk samples was determined based on composite SCC levels (≥100,000 cells/mL) and the presence of bacteria. A new IMI was defined as a quarter in which the organism isolated was not present in the previous bacteriological sample, or the previous composite SCC sample was <100,000 cells/mL. Clinical mastitis samples were also considered to be new IMI. The trial was designed as a positive control field trial, in which the objective was to show noninferiority of ZkinCu versus the control (OceanBlu). The overall crude incidences of new IMI for 2 wk at risk were 4.9 and 7.3% for the ZkinCu and OceanBlu groups, respectively. The predominant organisms recovered from quarters with new IMI were Streptococcus uberis , Corynebacterium spp., and coagulase-negative staphylococci in both the ZkinCu and OceanBlu groups. The risk of infection in the OceanBlu group was higher (β = 0.644; 95% confidence interval = 0.05–1.22). The interaction of treatment by week was not significant. The new IMI rate estimates (95% confidence interval) for ZkinCu and OceanBlu were 1.7% (0.8–2.5) and 3.2% (1.7–4.7), respectively. One novel aspect of this study is that it was one of the first commercial noninferiority trials to evaluate a new pre- and post-milking teat disinfectant in a dairy herd with an automatic milking system. The experimental teat disinfectant ZkinCu, evaluated in this field trial with naturally occurring IMI, showed noninferiority relative to the positive control for the prevention of new IMI. This study was conducted in a herd with an automatic milking system, and the results are applicable to herds with similar characteristics. Additional studies are needed to ensure reproducibility under different management conditions. [ABSTRACT FROM AUTHOR]

Background: A frequent rehabilitation goal for children with gait disorders is to practice daily-life walking activities. Unfortunately, these are often difficult to practice in a conventional therapeutic setting. Virtual reality (VR) with head-mounted displays (HMDs) could be a promising approach in neurorehabilitation to train such activities in a safe environment. First, however, we must know whether obstacles in VR are indeed mastered as obstacles., Objective: This study aimed to provide information on whether VR is feasible and motivating to induce and practice movements needed to master real obstacles in children and adolescents with gait disorders. Furthermore, this project aims to evaluate which kinds of everyday walking activities are appropriate to be practiced in VR., Methods: In this cross-sectional study, participants stepped over a bar, crossed a gap, balanced over a beam, and circumvented stationary obstructions arranged in a course under real physical and virtual conditions wearing a VR HMD. We recorded the respective primary outcomes (step height, step length, step width, and minimal shoulder-obstacle distance) with motion capture. We then calculated the mean differences and 95% CI of the spatiotemporal parameters between the VR and physical setup and later compared them using noninferiority analysis with margins defined a priori by a clinical expert panel. Additionally, the participants responded to a standardized questionnaire while the therapists observed and evaluated their movement performance., Results: We recruited 20 participants (mean age 12.0, range 6.6-17.8 years) with various diagnoses affecting their walking ability. At 3.77 (95% CI 1.28 to 6.26) cm, the mean difference in step height of the leading foot in the overstepping task did not exceed the predefined margin of -2 cm, thus signifying noninferiority of the VR condition compared to mastering the physical obstacles. The same was true for step length (-1.75, 95% CI -4.91 to 1.41 cm; margin -10 cm), step width (1.05, 95% CI 0.20 to -1.90 cm; margin 3 cm), and the minimal shoulder-obstacle distance (0.25, 95% CI -0.85 to 0.35 cm; margin -2 cm) in the other tasks. Only the trailing foot in the overstepping task yielded inconclusive results., Conclusions: Children with gait disorders perform everyday walking tasks like overstepping, crossing, balancing, or circumventing similarly in physical and VR environments, suggesting that VR could be a feasible therapeutic tool to practice everyday walking tasks., (©Sophia Rhiel, Andrina Kläy, Urs Keller, Hubertus J A van Hedel, Corinne Ammann-Reiffer. Originally published in JMIR Serious Games (https://games.jmir.org), 18.03.2024.)

A noniterative sample size procedure is proposed for a general hypothesis test based on the t distribution by modifying and extending Guenther's approach for the one sample and two sample t tests. The generalized procedure is employed to determine the sample size for treatment comparisons using the analysis of covariance (ANCOVA) and the mixed effects model for repeated measures in randomized clinical trials. The sample size is calculated by adding a few simple correction terms to the sample size from the normal approximation to account for the nonnormality of the t statistic and lower order variance terms, which are functions of the covariates in the model. But it does not require specifying the covariate distribution. The noniterative procedure is suitable for superiority tests, noninferiority tests, and a special case of the tests for equivalence or bioequivalence and generally yields the exact or nearly exact sample size estimate after rounding to an integer. The method for calculating the exact power of the two sample t test with unequal variance in superiority trials is extended to equivalence trials. We also derive accurate power formulae for ANCOVA and mixed effects model for repeated measures, and the formula for ANCOVA is exact for normally distributed covariates. Numerical examples demonstrate the accuracy of the proposed methods particularly in small samples. [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 Knee osteoarthritis (OA) is the most common cause of knee pain in older adults. Despite the limited data supporting their use, non-steroidal anti-inflammatory drugs (NSAID) are among the most commonly prescribed medications for knee OA. The use of NSAIDs for knee pain warrants careful examination because of toxicity associated with this class of medications. Methods We describe the design of a placebo-controlled, noninferiority, randomized withdrawal trial to examine discontinuation of an NSAID in patients with painful knee OA. Participants will be veterans enrolled in the VA Healthcare System with knee OA pain despite NSAID use and/or relatively higher risk of NSAID toxicity. After a two-week run-in period where eligible subjects will replace their current NSAID with the study NSAID (meloxicam), those remaining eligible (target N = 544) will be randomized to receive four weeks of either placebo or continued meloxicam. The primary outcome is knee pain (Western Ontario and McMaster Universities Osteoarthritis Index pain subscale, range 0—20) at four weeks post-randomization. The primary hypothesis is that placebo will be noninferior to (that is, not much worse than) meloxicam within a noninferiority margin of 1. Secondary outcomes include lower extremity disability, global impression of change, adherence to study medication and use of co-therapies. Discussion This study is the first clinical trial to date examining the effects of withdrawing an NSAID for OA knee pain. If successful, this trial will provide evidence against the continued use of NSAIDs in patients with OA knee pain. Trial registration ClinicalTrials.gov : NCT01799213 . Registered February 22, 2013. [ABSTRACT FROM AUTHOR]

The increasing popularity of noninferiority trials reflects the ongoing efforts to replace existing treatments (reference treatments) with new treatments (experimental treatments) that retain a substantial fraction of the effect of the reference treatments. The adoption of any new treatment has to be vindicated by a demonstration of benefits that outweigh a possible clinically insignificant reduction in the reference treatment efficacy. Statistical methods have been developed to analyze data collected from noninferiority trials. However, these methods focus on cases with only one reference treatment. In this paper, we provide the statistical inferential procedures for situations with multiple reference treatments. The computation of the corresponding critical values for simultaneous testings of noninferiority of several new treatments to multiple reference treatments in the presence of a placebo is provided. Furthermore, for a prespecified level of test power, a technique to determine the optimal sample size before the onset of a noninferiority trial is derived. A clinical example is given to illustrate our proposed procedure. [ABSTRACT FROM AUTHOR]

Background Context: Recently, there has been increased public awareness of regulatory actions by the United States Food and Drug Administration (FDA) on spinal devices. There has also been increased scrutiny of the pivotal clinical trials of these devices.Purpose: To investigate the premarket approval (PMA) of class III spinal devices in the United States since the turn of the century. To explore clinically relevant issues that affect the interpretation of investigational device exemption trials.Study Design: Literature review.Methods: From 2000 to 2015, data on PMA applications for spinal devices were obtained from two sources. First, meetings of FDA's Orthopaedic and Rehabilitation Devices Panel were identified from the Federal Register. Second, the FDA database of approved PMA applications was queried. For each device, two authors reviewed all archival data. There was no external source of funding.Results: Twenty-one devices met the study criteria. There were 76.2% that received approval and 47.6% that went to panel. Arthroplasty devices were most common (52.4%), least likely to go to panel (3 of 11), and most likely to be approved after panel (3 of 3). Biologic devices were most likely to go to panel (3 of 3) and least likely to be approved after panel (1 of 3). Before and after 2009, there was no decrease in the number of spinal devices approved. All 21 devices were studied in a pivotal clinical trial. All trials except one were randomized controlled trials, and all trials except one were two-arm noninferiority designs.Conclusions: There has been no decrease in the number of new FDA-approved class III spinal devices since the turn of the century. The majority of devices have been for cervical arthroplasty. By contrast, biologic devices were most likely to go to panel and least likely to be approved after panel. The pivotal trials for nearly all devices were randomized, two-arm, noninferiority trials. [ABSTRACT FROM AUTHOR]

Clinical trials are essential for establishing the benefits and harms of various treatments. Among the various trial designs, superiority trials aim to establish the superiority of one treatment over another, while noninferiority trials demonstrate that a new treatment is not inferior to an established one while minimizing harms or patient burdens. In recent years, noninferiority trials have gained prominence. This mini-review explores noninferiority trials, focusing on challenges in their interpretation. Ultimately, we argue that the focus should be on the results from trials rather than their design, as clinicians and other stakeholders primarily seek evidence that helps patients and clinicians in trade-offs of the benefits and harms and burdens of treatment options. PATIENT SUMMARY: Our mini-review shows that looking at the overall treatment benefits and harms in noninferiority trials is better than focusing on the trial design. This approach would help patients and clinicians to better understand trial results and their implications., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)