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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]

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]

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]

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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 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 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]

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]

Objectives The aim of this study was to investigate the hypothesis that a novel biodegradable polymer–coated, cobalt-chromium (CoCr), sirolimus-eluting stent (BP-SES) is noninferior in safety and efficacy outcomes compared with a durable polymer (DP)-SES. Background No randomized trials have the compared safety and efficacy of BP-SES versus DP-SES on similar CoCr platforms, thereby isolating the effect of the polymer type. Methods In this prospective, single-blind, randomized trial conducted at 32 Chinese sites, 2,737 patients eligible for coronary stenting were treated with BP- or DP-SES in a 2:1 ratio. The primary endpoint was 12-month target lesion failure (TLF), a composite of cardiac death, target vessel myocardial infarction, or clinically indicated target lesion revascularization. Secondary endpoints included TLF components, and definite/probable stent thrombosis. Results At 12 months, the difference in the primary endpoint of TLF between BP-SES (6.3%) and DP-SES (6.1%) groups was 0.25% (95% confidence interval: −1.67% to 2.17%, p for noninferiority = 0.0002), demonstrating noninferiority of BP-SES to DP-SES. Individual TLF components of cardiac death (0.7% vs. 0.6%, p = 0.62), target vessel myocardial infarction (3.6% vs. 4.3%, p = 0.39), and clinically indicated target lesion revascularization (2.6% vs. 2.2%, p = 0.50) were similar, as were low definite/probable stent thrombosis rates (0.4% vs. 0.6%, p = 0.55). Conclusions In this large-scale real-world trial, BP-SES was noninferior to DP-SES for 1-year TLF. (Evaluate Safety and Effectiveness of the Tivoli ® DES and the Firebird ® DES for Treatment of Coronary Revascularization; NCT01681381 ) [ABSTRACT FROM AUTHOR]

Abstract: Background: Group, rather than individual, family planning counseling has the potential to increase family planning knowledge and use through more efficient use of limited human resources. Study Design: A randomized, noninferiority study design was utilized to identify whether group family planning counseling is as effective as individual family planning counseling in Ghana. Female gynecology patients were enrolled from two teaching hospitals in Ghana in June and July 2008. Patients were randomized to receive either group or individual family planning counseling. The primary outcome in this study was change in modern contraceptive method knowledge. Changes in family planning use intention before and after the intervention and intended method type were also explored. Results: Comparisons between the two study arms suggest that randomization was successful. The difference in change in modern contraceptive methods known from baseline to follow-up between the two study arms (group–individual), adjusted for study site, was −0.21, (95% confidence interval: −0.53 to 0.12) suggesting no difference between the two arms. Conclusions: Group family planning counseling was as effective as individual family planning counseling in increasing modern contraceptive knowledge among female gynecology patients in Ghana. [Copyright &y& Elsevier]

Abstract: Objective: To examine the registration of noninferiority trials, with a focus on the reporting of study design and noninferiority margins. Study Design and Setting: Cross-sectional study of registry records of noninferiority trials published from 2005 to 2009 and records of noninferiority trials in the International Standard Randomized Controlled Trial Number (ISRCTN) or ClinicalTrials.gov trial registries. The main outcome was the proportion of records that reported the noninferiority design and margin. Results: We analyzed 87 registry records of published noninferiority trials and 149 registry records describing noninferiority trials. Thirty-five (40%) of 87 records from published trials described the trial as a noninferiority trial; only two (2%) reported the noninferiority margin. Reporting of the noninferiority design was more frequent in the ISRCTN registry (13 of 18 records, 72%) compared with ClinicalTrials.gov (22 of 69 records, 32%; P =0.002). Among the 149 records identified in the registries, 13 (9%) reported the noninferiority margin. Only one of the industry-sponsored trial compared with 11 of the publicly funded trials reported the margin (P =0.001). Conclusion: Most registry records of noninferiority trials do not mention the noninferiority design and do not include the noninferiority margin. The registration of noninferiority trials is unsatisfactory and must be improved. [Copyright &y& Elsevier]

Abstract: This methodological article provides a description of the design, methods, and rationale of the first prospective, noninferiority designed randomized clinical trial evaluating the clinical and cost implications of delivering an evidence-based cognitive-behavioral group intervention specifically treating posttraumatic stress disorder (PTSD) with a trauma-focused intervention via video teleconferencing (VTC). PTSD is a prevalent mental health problem found among returning Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) military populations. These returning military personnel often live in rural areas and therefore have limited access to care and specialized psychological treatments. In the field of mental health, telemental health (TMH) technology has introduced a potential solution to the persistent problem of access to care in remote areas. This study is enrolling approximately 126 returning veterans with current combat-related PTSD who are receiving services through the Veteran Administration (VA) mental health care clinics on 4 Hawaiian Islands. Cognitive Processing Therapy (CPT), an empirically supported manualized treatment for PTSD, is being delivered across 9 cohorts. Participants are assigned to either the experimental VTC condition or the in-person control condition. Assessments measuring clinical, process, and cost outcomes are being conducted at baseline, mid-treatment, post-treatment, and 3 and 6months post-treatment. The study employs a noninferiority design to determine if the group treatment delivered via VTC is as good as the traditional in-person modality. In addition, a cost analysis will be performed in order to compare the cost of the 2 modalities. Novel aspects of this trial and specific challenges are discussed. [Copyright &y& Elsevier]

Abstract: Objective: To present and compare three statistical approaches for analyzing a noninferiority trial when the noninferiority margin depends on the control event rate. Study design and setting: In noninferiority trials with a binary outcome, the noninferiority margin is often defined as a fixed δ, the largest clinically acceptable difference in event rates between treatment groups. An alternative and more flexible approach is to allow δ to vary according to the true event rate in the control group. The appropriate statistical method for evaluating noninferiority with a variable noninferiority margin is not apparent. Three statistical approaches are proposed and compared: an observed event rate (OER) approach based on equating the true control rate to the observed rate, a Bayesian approach, and a likelihood ratio test. Results and conclusions: Simulations studies indicate that the proportion of trials in which noninferiority was erroneously demonstrated was higher for the OER approach than with the Bayesian and likelihood ratio approaches. In some cases, the Type I error rate exceeded 10% for the OER approach. The OER approach is not recommended for the analysis of noninferiority trials with a variable margin of equivalence. The Bayesian and likelihood ratio methods yielded better operating characteristics. [Copyright &y& Elsevier]

• Included noninferiority trials of oncology interventions had key methodological shortcomings. • Approximately 15 % of included trials did not contain an alpha value and confidence intervals that matched. • Approximately 28 % did not justify the chosen noninferiority margin. • Only 13 % of trials provided enough information to calculate the amount of preserved effect size for the chosen margin. Noninferiority trials can show that new treatments with slightly less efficacy are safer, cheaper, or easier to administer. However, the conclusions of noninferiority trials depend on robust methodology. We conducted a 6 year cross-sectional investigation of the methodological quality of oncology noninferiority trials published in the top 10 oncology journals. Four key quality criteria were investigated. Nonefficacy benefits of the new treatment were stated in 88/110 (80.0 %) trials. Justification for the noninferiority margin was provided in 79/110 (71.8 %) trials. Authors most often used previous data as justification for the chosen margin (n = 42). In 15 noninferiority trials the percent preserved effect could be calculated and the median effect preserved was 56.8 %. The oncology noninferiority trials included in our study had key methodological shortcomings, counterbalanced by a clear delineation of expected nonefficacy benefits of the new treatment. [ABSTRACT FROM AUTHOR]