Non-inferiority Analysis Research Articles

Comprehensive management of obstructive sleep apnea by telemedicine: Clinical improvement and cost-effectiveness of a Virtual Sleep Unit. A randomized controlled trial.

IntroductionObstructive sleep apnea (OSA) is a prevalent disease associated with significant morbidity and high healthcare costs. Information and communication technology could offer cost-effective management options.ObjectivesTo evaluate an out-of-hospital Virtual Sleep Unit (VSU) based on telemedicine to manage all patients with suspected OSA, including those with and without continuous positive airway pressure (CPAP) therapy.MethodsThis was an open randomized controlled trial. Patients with suspected OSA were randomized to hospital routine (HR) or VSU groups to compare the clinical improvement and cost-effectiveness in a non-inferiority analysis. Improvement was assessed by changes in the Quebec Sleep Questionnaire (QSQ), EuroQol (EQ-5D and EQ-VAS), and Epworth Sleepiness Scale (ESS). The follow-up was 3 months. Cost-effectiveness was assessed by a Bayesian analysis based on quality-adjusted life-years (QALYs).ResultsThe HR group (n: 92; 78% OSA, 57% CPAP) compared with the VSU group (n: 94; 83% OSA, 43% CPAP) showed: CPAP compliance was similar in both groups, the QSQ social interactions domain improved significantly more in the HR group whereas the EQ-VAS improved more in the VSU group. Total and OSA-related costs were lower in the VSU group than the HR. The Bayesian cost-effectiveness analysis showed that VSU was cost-effective for a wide range of willingness to pay for QALYs.ConclusionsThe VSU offered a cost-effective means of improving QALYs than HR. However, the assessment of its clinical improvement was influenced by the choice of the questionnaire; hence, additional measurements of clinical improvement are needed. Our findings indicate that VSU could help with the management of many patients, irrespective of CPAP use.

LB13. Trivalent Hepatitis B (HepB) Vaccine Yields Superior Seroprotection Rates in Adults: Results from the Phase 3 Double-Blind, Randomized Study Comparing Immunogenicity and Safety of a 3-Dose Regimen of Sci-B-Vac™ and Engerix B® (PROTECT)

BackgroundMany adults fail to achieve seroprotection after receiving 3 doses of monovalent HepB vaccines such as Engerix-B® and the response decreases with age and with common co-morbidities. Sci-B-Vac™ is a trivalent HepB vaccine produced in mammalian cells, adjuvanted with aluminum hydroxide, which in addition to small S antigen, contains preS1 and preS2 antigens expressing highly immunogenic T- and B-cell epitopes that may enhance seroprotection rates (SPR) in adults.MethodsIn a multicentre study, the immunogenicity of 10 µg dose of Sci-B-Vac™ was compared with a 20-µg dose of Engerix-B® given at days 0, 28, and 168 (NCT03393754). Randomization was stratified by study center and age (18–44, 45–64, ≥65 years). Immunogenicity, including SPR (% subjects with anti-HBs levels ≥10 mIU/mL), and safety outcomes were followed to Day 336. The co-primary objectives were (1) non-inferiority in adults ≥18 years and (2) superiority in adults ≥45 years of SPR, 4 weeks after the third dose.ResultsOf 1,607 randomized subjects, 42.3% were from United States, 41.6% EU, and 16.1% Canada. Males (38.5%) and females (61.5%) were enrolled to 18–44 (18.6%), 45–64 (44.6%), and ≥ 65 year (36.8%) age groups. Both co-primary endpoints were met. In the non-inferiority analysis, SPR in Sci-B-Vac™ recipients aged ≥18 years was 91.4% vs. 76.5% for Engerix-B®; SPR difference: 14.9%; 95% confidence interval (CI) [11.2%, 18.6%]. Superiority analysis showed that SPR in Sci-B-Vac™ recipients aged ≥45 years was 89.4% vs. 73.1% for Engerix-B®—SPR difference: 16.4%; 95% CI [12.2%, 20.7%] (figure). Significantly higher SPR for Sci-B-Vac™ vs. Engerix-B® was noted in subgroups (gender, BMI, diabetes, smoking and particularly age—SPR difference for 45–64 (14.7% [9.8–19.8%]) and ≥ 65 (18.9% [11.6–26.1%]) years. No major safety signals were observed; solicited and unsolicited adverse events were consistent with the known vaccine safety profiles.ConclusionSci-B-Vac™ met immunogenicity endpoints for non-inferiority in adults aged ≥ 8 years and was superior in adults aged ≥45 years, compared with the monovalent vaccine, Engerix-B®. Sci-B-Vac™ SPR was higher compared with Engerix-B® in key subgroups. No safety signals were observed and safety and tolerability were consistent with the known profile of Sci-B-Vac™. DisclosuresTimo Vesikari, MD, VBI (Grant/Research Support, I have received funding from VBI to carry out the reported clinical trial in Finland), Joanne M. Langley, MD, VBI Vaccines (Grant/Research Support), Johanna Spaans, BSc, MSc, VBI Vaccines (Employee), Nathalie Machluf, PhD, SciVac Ltd. (Employee), Dave Anderson, PhD, VBI Vaccines, Inc. (Employee, Shareholder), Vlad Popovic, MD, VBI Vaccines (Employee), Francisco Diaz-Mitoma, MD, VBI Vaccines, Inc. (Consultant, Shareholder, Independent Contractor). Other Authors: No reported disclosures.

Prospective cost analysis of early video capsule endoscopy versus standard of care in non-hematemesis gastrointestinal bleeding: a non-inferiority study

Background and aim: A non-inferiority cost analysis was performed to assess if the early capsule approach would incur higher costs than the standard of care approach in patients presenting with non-hematemesis gastrointestinal bleeding.Methods: A prospective non-inferiority cost analysis was performed on patients receiving either an early video capsule as the first diagnostic procedure or an endoscopic procedure as determined by gastroenterology staff that were not involved in the study. Primary outcome was total direct costs incurred in both groups.Results: Forty-five patients and 42 patients were enrolled into the early capsule and standard of care arms, respectively. There was no difference in total direct cost per inpatient case in both groups ($7,362 vs $7,148, p = 0.77 [CI = −2,285–2,315, equivalent margin = –$3,100]). Localization of a bleeding source after the first diagnostic procedure was identified more frequently in the early capsule group (69.2% vs 27.9%, p = 0.0003). If patients were discharged after their last non-diagnostic evaluation, then length of stay could be decreased by 50% in both groups (58.5 to 31.6 h, p = 0.02 in the early capsule group and 69.4 to 39.2 h in the standard of care group p = 0.001). Projections indicate the fastest a patient with non-diagnostic evaluations could be discharged is 0.88 days in the early capsule group vs 1.63 days in the standard of care group (p = 0.0005).Discussion: In patients with non-hematemesis bleeding, video capsule endoscopy may be a more efficient diagnostic approach than the standard of care approach, since it detects bleeding significantly more often without an increase in healthcare costs.

A single-dose indomethacin prophylaxis for reducing perinatal brain injury in extremely low birth weight infants: a non-inferiority analysis.

To evaluate whether rates of perinatal brain injury among extremely low birth weight infants are comparable between two treatments: single-dose indomethacin prophylaxis (SGL-IP) (0.2 mg/kg, given once) vs. standard-dose indomethacin prophylaxis (STD-IP) (0.1 mg/kg/day, 3 days). In this retrospective study, the primary outcome was perinatal brain injury (neuro-imaging evidence of intraventricular hemorrhage or periventricular leukomalacia) or death before discharge. A non-inferior efficacy of an SGL-IP regimen compared with a STD-IP regimen was determined by calculating the adjusted difference in the risk of the primary outcome using a multivariable logistic regression model. A 10-percentage point non-inferiority margin was favored. Prevalence rates of primary outcome were 41.7% in the SGL-IP group (n = 403) and 42.5% in the STD-IP group (n = 509) (adjusted risk difference: -1.2, 95% CI: -7.6 to +5.2, p = 0.71). Use of a single prophylactic indomethacin dose was as effective as a standard regimen in preventing perinatal brain injury.

PET-Guided Treatment of Early-Stage Favorable Hodgkin Lymphoma: Final Results of the International, Randomized Phase 3 Trial HD16 by the GHSG

Combined modality treatment (CMT) consisting of two cycles of ABVD and 20 Gy of involved-field radiation therapy (IFRT) is widely accepted standard of care for early-stage favorable Hodgkin lymphoma (HL). Recent clinical research suggests that metabolic response assessment after two cycles of chemotherapy using FDG-PET (PET-2) can predict the individual outcome and PET-2 negativity might allow reducing the overall treatment intensity. In this study, we assessed whether omitting consolidating radiation therapy in patients with negative PET-2 is feasible without loss of efficacy as determined by progression-free survival (PFS). Furthermore, we analyzed the prognostic impact of PET-2 among patients receiving CMT. Between November 2009 and December 2015, we recruited patients with newly diagnosed, early-stage favorable HL aged 18–75 years from Germany, Switzerland, Austria, and the Netherlands for this double-blind, randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard CMT with 2x ABVD and 20 Gy IFRT or PET-guided treatment, whereby IFRT was restricted to those patients with a positive PET after 2xABVD. A total of 1150 patients were enrolled; 628 patients with negative PET-2 were eligible for the per-protocol non-inferiority analysis and were treated with CMT (n=328) or ABVD alone (n=300). With a median follow-up of 47 months, the estimated 5-year PFS was 93.4% (90.4–96.5) with CMT and 86.1% (81.4–90.9) with chemotherapy only (difference 7.3%, 95% CI 1.6%–13.0%). The hazard ratio was 1.78 with a 95% CI ranging from 1.02 to 3.12, including the non-inferiority margin of 3.01. The PFS difference primarily resulted from a significant increase in disease recurrences with in-field recurrence rates of 2.1% vs. 8.7% (p=0.0003); there was no relevant difference regarding out-field recurrences (3.7% vs. 4.7%, p=0.55). Estimated 5-year overall survival in the per-protocol population was 98.1% (96.5–99.8) with CMT and 98.4% (96.5–100.0) with ABVD. Six hundred ninety-three patients assigned to receive CMT were eligible for the analysis of the PET objective and had a negative (n=353) or positive (n=340) PET-2. With a median follow-up of 46 months, estimated 5-year PFS was 93.2% (90.2–96.2) among PET-2-negative and 88.1% (83.8–92.3) among PET-2-positive patients (p=0.035). When using the more common liver cutoff (Deauville score 4) for the definition of PET-2 positivity, the difference became was more pronounced (5-year PFS 93.1% [90.7%–95.5%] vs. 80.1% [71.2%–88.9%], p=0.0004). In early-stage favorable HL, radiation therapy cannot be safely omitted from standard CMT without a clinically relevant loss of tumor control in patients with negative PET-2. PET positivity after 2xABVD represents a risk factor for PFS in HL patients treated with standard CMT, particularly when a Deauville score of 4 is considered as cutoff for positivity.

Quality Assurance of Non-Invasive Prenatal Screening (NIPS) for Fetal Aneuploidy Using Positive Predictive Values as Outcome Measures.

Non-invasive prenatal screening (NIPS) based on the analysis of cell-free DNA in maternal plasma has been shown to have high sensitivity and specificity. We gathered follow-up information for pregnancies in women with test-positive NIPS results from 2014–2017 with quarterly assessments of positive predictive values (PPVs). A non-inferiority analysis with a minimum requirement of 70%/80% of expected performance for trisomy 21 and 18 was used to ensure testing met expectations. PPVs were evaluated in the context of changes in the population receiving testing. For all quarters, PPVs for trisomies 21 and 18 exceeded the requirement of > 70% of the reference PPV. Overall observed PPVs for trisomy 21, 18, 13 and monosomy X were similar for women aged <35 (90.9%, 95% Confidence Interval (CI) 88.6–92.7%) compared to women with advanced maternal age (94.5%, 95% CI 93.1–95.6%). Despite significant declines in test-positive rates from 1.18% to 0.62% for trisomy 21, and from 0.75% to 0.48% for trisomies 18, 13 and monosomy X combined, PPVs remained stable through the four-year interval. We conclude that quarterly evaluation of PPV provides an overview of past testing and helps demonstrate long-term consistency in test performance, even in the setting of increasing use by women with lower a priori risks.

Evidence that Tenecteplase Is Noninferior to Alteplase for Acute Ischemic Stroke: Meta-Analysis of 5 Randomized Trials.

Background and Purpose- TNK (tenecteplase), a newer fibrinolytic agent, has practical delivery advantages over ALT (alteplase) that would make it a useful agent if noninferior in acute ischemic stroke treatment outcome. Accordingly, the most recent US American Heart Association/American Stroke Association acute ischemic stroke guideline recognized TNK as an alternative to ALT, but only based on informal consideration, rather than formal meta-analysis, of completed randomized control trials. Methods- Systematic literature search and formal meta-analysis were conducted per PRISMA guidelines (Preferred Reporting Items for Systemic Reviews and Meta-Analyses), adapted to noninferiority analysis. The primary outcome of freedom from disability (modified Rankin Scale score, 0-1) outcome at 3 m, and additional efficacy and safety outcomes, were analyzed. Results- Systematic search identified 5 trials enrolling 1585 patients (828 TNK, 757 ALT). Across all trials, mean age was 70.8, 58.5% male, baseline National Institutes of Health Stroke Scale mean 7.0, and time from last known well to treatment start mean 148 minutes. All ALT patients received standard 0.9 mg/kg dosing, while TNK dosing was 0.1 mg/kg in 6.8%, 0.25 mg/kg in 24.6%, and 0.4 mg/kg in 68.6%. For the primary end point, crude cumulative rates of disability-free (modified Rankin Scale score, 0-1) 3 m outcome were TNK 57.9% versus ALT 55.4%. Informal, random-effects meta-analysis, the risk difference was 4% (95% CI, -1% to 8%). The lower 95% CI bound fell well within the prespecified noninferiority margin. Similar results were seen for the additional efficacy end points: functional independence (modified Rankin Scale score, 0-2): crude TNK 71.9% versus ALT 70.5%, risk difference 2% (95% CI, -3% to 6%); and modified Rankin Scale shift analysis, common odds ratio 1.21 (95% CI, 0.93-1.57). For safety end points, lower event rates reduced power, but point estimates were also consistent with noninferiority Conclusions- Accumulated clinical trial data provides strong evidence that TNK is noninferior to ALT in the treatment of acute ischemic stroke. These findings provide formal support for the recent guideline recommendation to consider TNK an alternative to ALT.

Augmented reality-assisted pedicle screw insertion: a cadaveric proof-of-concept study.

Augmented reality (AR) is a novel technology that has the potential to increase the technical feasibility, accuracy, and safety of conventional manual and robotic computer-navigated pedicle insertion methods. Visual data are directly projected to the operator's retina and overlaid onto the surgical field, thereby removing the requirement to shift attention to a remote display. The objective of this study was to assess the comparative accuracy of AR-assisted pedicle screw insertion in comparison to conventional pedicle screw insertion methods. Five cadaveric male torsos were instrumented bilaterally from T6 to L5 for a total of 120 inserted pedicle screws. Postprocedural CT scans were obtained, and screw insertion accuracy was graded by 2 independent neuroradiologists using both the Gertzbein scale (GS) and a combination of that scale and the Heary classification, referred to in this paper as the Heary-Gertzbein scale (HGS). Non-inferiority analysis was performed, comparing the accuracy to freehand, manual computer-navigated, and robotics-assisted computer-navigated insertion accuracy rates reported in the literature. User experience analysis was conducted via a user experience questionnaire filled out by operators after the procedures. The overall screw placement accuracy achieved with the AR system was 96.7% based on the HGS and 94.6% based on the GS. Insertion accuracy was non-inferior to accuracy reported for manual computer-navigated pedicle insertion based on both the GS and the HGS scores. When compared to accuracy reported for robotics-assisted computer-navigated insertion, accuracy achieved with the AR system was found to be non-inferior when assessed with the GS, but superior when assessed with the HGS. Last, accuracy results achieved with the AR system were found to be superior to results obtained with freehand insertion based on both the HGS and the GS scores. Accuracy results were not found to be inferior in any comparison. User experience analysis yielded "excellent" usability classification. AR-assisted pedicle screw insertion is a technically feasible and accurate insertion method.

Immunogenicity noninferiority study of 2 doses and 3 doses of an Escherichia coli-produced HPV bivalent vaccine in girls vs. 3 doses in young women.

A new HPV-16/18 bivalent vaccine expressed by the Escherichia coli has been proven to be efficacious in adult women. A randomized, immunogenicity noninferiority study of this candidate vaccine was conducted in December 2015 in China. Girls aged 9–14 years were randomized to receive 2 doses at months 0 and 6 (n=301) or 3 doses at months 0, 1 and 6 (n=304). Girls aged 15–17 years (n=149) and women aged 18–26 years (n=225) received 3 doses. The objectives included noninferiority analysis of the IgG geometric mean concentration (GMC) ratio (95% CI, lower bound>0.5) to HPV-16 and HPV-18 at month 7 in girls compared with women. In the per-protocol set, the GMC ratio of IgG was noninferior for girls aged 9–17 years receiving 3 doses compared with women (1.76 (95% CI, 1.56, 1.99) for HPV-16 and 1.93 (95% CI, 1.69, 2.21) for HPV-18) and noninferior for girls aged 9–14 years receiving 2 doses compared with women (1.45 (95% CI, 1.25, 1.62) for HPV-16 and 1.17 (95% CI, 1.02, 1.33) for HPV-18). Noninferiority was also demonstrated for neutralizing antibodies. The immunogenicity of the HPV vaccine in girls receiving 3 or 2 doses was noninferior compared with that in young adult women.Electronic Supplementary MaterialSupplementary material is available for this article at 10.1007/s11427-019-9547-7 and is accessible for authorized users.

Whole-body MRI added to gadoxetic acid-enhanced liver MRI for detection of extrahepatic disease in patients considered eligible for hepatic resection and/or local ablation of colorectal cancer liver metastases.

Background Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) can detect extrahepatic disease before local treatment of colorectal liver metastases. Purpose To investigate if whole-body magnetic resonance imaging (MRI) added to gadoxetic acid liver MRI could replace FDG-PET/CT for detection of extrahepatic disease in patients with colorectal liver metastases eligible for hepatic local treatment. Material and Methods This health-research-ethics-committee-approved prospective consecutive diagnostic accuracy study with written informed consent analyzed 79 cases included between 29 June 2015 and 7 February 2017. Whole-body MRI covering the thorax, abdomen, and pelvis and FDG-PET/CT including contrast-enhanced CT was performed 0–3 days before local treatment of liver metastases. Whole-body MR images were read independently by two readers. FDG-PET/CT images were read independently by two pairs of readers. Histopathology and follow-up imaging were used as reference standard. Sensitivities and specificities were calculated and compared including noninferiority analysis. Results Seventy-five malignant lesions and 419 benign lesions were confirmed. Sensitivities of both PET/CT reader pairs 1 and 2 (56.7 and 67.9%) and MRI reader 2 (63.0%) were significantly higher than that of MRI reader 1 (42.7) (P&lt;0.04). Specificities of both PET/CT reader pairs 1 and 2 (92.5 and 92.4%) and MRI reader 1 (91.1%) were significantly higher than that of MRI reader 2 (86.3%) ( P &lt; 0.02). Sensitivity of MRI reader 2 was non-inferior compared to PET/CT reader pair 1. Specificities of both MRI readers were non-inferior to both PET/CT reader pairs. Conclusion For detection of extrahepatic disease in patients with colorectal liver metastases, whole-body MRI was non-inferior to FDG-PET/CT for some reader combinations. However, reader-independent non-inferiority could not be demonstrated.

Custom 3-Dimensional Printed Ultrasound-Compatible Vascular Access Models: Training Medical Students for Vascular Access

PurposeTo generate 3-dimensional (3D) printed ultrasound (US)-compatible vascular models (3DPVAM) and test them for noninferiority in training medical students in femoral artery access. Materials and MethodsA 3DPVAM of normal femoral artery (FA) anatomy was developed from an anonymized computerized tomography (CT) examination. Students were randomized to a 3DPVAM or a commercial model (CM) simulation experience (SE) for US-guided FA access. Students completed a pre-SE questionnaire ranking their self-confidence in accessing the artery on a 5-point Likert scale. A standardized SE was administered by interventional radiology faculty or trainees. Students completed a post-SE questionnaire ranking comfort with FA access on a Likert scale. Student questionnaire results from the 3DPVAM group were compared with those from the CM group by using chi-square, Wilcoxon signed-rank, and noninferiority analyses. ResultsTwenty-six and twenty-three students were randomized to 3DPVAM and commercial model training, respectively. A total of 76.9% of 3DPVAM trainees and 82.6% of CM trainees did not feel confident performing FA access prior to the SE. In both groups, training increased student confidence by 2 Likert points (3DPVAM: P < 0.001; CM P < 0.001). The confidence increase in 3DPVAM trainees was noninferior to that in CM trainees (P < 0.001). ConclusionsGeneration of a custom-made 3DPVAM is feasible, producing comparable subjective training outcomes to those of CM. Custom-made 3D-printed training models, including incorporation of more complex anatomical configurations, could be used to instruct medical students in procedural skills.

Randomized trial of adjuvant chemotherapy versus adjuvant radiation therapy for locally advanced bladder cancer after radical cystectomy.

4507 Background: Some chemotherapy-naïve patients with locally advanced bladder cancer (LABC) after radical cystectomy (RC) are sufficiently de-conditioned that they are not candidates for adjuvant chemotherapy or decline it, even though such treatment may be warranted. There is no clear alternative adjuvant therapy for these patients, who are usually observed. In this study, we compare post-op radiotherapy (PORT) vs. adjuvant chemotherapy in a randomized clinical trial. We hypothesized that PORT can achieve comparable disease-free survival (DFS). Methods: A randomized phase III trial was opened to compare PORT vs. sequential chemo+PORT after RC for LABC &amp; accrued from 2002–2008 at the NCI in Cairo. In 2007, a third arm comparing adjuvant chemo was added. Herein, we report the results of PORT vs. adjuvant chemo. Patients ≤70 y/o with ≥1 of the following factors (≥pT3b/T4a, grade 3, or positive nodes) with negative margins after RC + pelvic node dissection were eligible. Routine follow-up &amp; pelvic CT q6 months were performed. PORT included 3D conformal pelvic RT (45Gy/1.5Gy BID). Chemo included gemcitabine/cisplatin x 4. Post-hoc non-inferiority exploratory analysis was performed. Results: The PORT arm accrued 78; the chemo arm accrued 45. 51% had urothelial carcinoma; 49% had squamous cell carcinoma/other. The two arms were well-balanced except for gender (p = 0.06). Two-year outcomes &amp; overall adjusted hazard ratios (HR) for PORT vs. chemo alone were 54% vs. 47% (HR 0.65(95%CI 0.35-1.19, p = 0.16) for DFS; 92% vs. 69% (HR 0.28(95%CI 0.10-0.82), p = 0.02 for LRFS; 75% vs. 79% (HR 2.39(95%CI 0.94-6.09), p = 0.07) for DMFS; 61% vs. 60% (HR 0.94(95%CI 0.52-1.69), p = 0.83) for OS. Late grade ≥3 GI toxicity was observed in 6 PORT patients (8%) &amp; 1 chemo patient (2%). Based on our data, there is a greater than 90% probability that the true difference in 2 yr DFS is less than 10%, the pre-specified non-inferiority margin. Conclusions: This randomized study demonstrates superior local control with PORT vs. adjuvant chemo with no significant differences in DFS, DMFS or OS. Results suggest that PORT could be an option for patients with LABC after RC who are medically unfit for adjuvant chemo or who decline it. Clinical trial information: NCT01734798.

Nemesis: Non-inferiority meta-analysis of selective internal radiation therapy with yttrium-90 resin microspheres versus sorafenib in advanced hepatocellular carcinoma: A preliminary analysis.

e15604 Background: No survival benefit has been observed for selective internal radiation therapy (SIRT) with yttrium-90 resin microspheres versus (vs.) sorafenib in patients with advanced hepatocellular carcinoma (HCC). In NEMESIS, we assessed by an individual patient data meta-analysis whether SIRT, either as monotherapy or followed by sorafenib, is non-inferior to sorafenib and compared safety profiles. Here we present preliminary data. Methods: A systematic search of MEDLINE, EMBASE, and the Cochrane Library, up to 6 December 2018, found three randomized trials comparing SIRT as monotherapy, or followed by sorafenib, to sorafenib monotherapy among patients with advanced HCC. The main outcomes were overall survival (OS) and frequency of adverse events (AEs). Survival data were pooled (fixed effect analysis). The primary population for non-inferiority analysis was the per-protocol (PP) population. The non-inferiority margin for the hazard ratio (HR) upper boundary was set at 1.08 as specified in EASL guidelines. Results: The three included trials compared sorafenib to SIRT (SIRveNIB and SARAH) or to SIRT followed by sorafenib (SORAMIC) in 1243 patients. After randomization, 23.3% vs. 7.1% of patients (p &lt; 0.0001) did not receive the allocated intervention, and 542/608 (89.1%) vs. 418/635 (65.8%), (odds ratio [OR] 4.3, 95% CI: 3.2-5.8, p &lt; 0.0001) completed the study without major protocol deviations (PP population), in the SIRT and sorafenib arms, respectively. Baseline characteristics of the PP population did not differ between the two comparison groups. Median OS with SIRT followed or not by sorafenib was non-inferior to sorafenib (HR 0.90, 95% CI 0.78–1.02). Treatment-related AEs grades ≥3 were reported in 109/356 (30.6%) patients who received SIRT and 197/378 (52.1%) patients in the sorafenib arm (SIRveNIB and SARAH only, p = 0.0002). Conclusions: SIRT as initial therapy for advanced HCC is non-inferior to sorafenib in OS, and offers a better safety profile.

A German climbing study on depression: a bouldering psychotherapeutic group intervention in outpatients compared with state-of-the-art cognitive behavioural group therapy and physical activation \u2013 study protocol for a multicentre randomised controlled trial

BackgroundBesides classical approaches for treating depression, physical activity has been demonstrated to be an effective option. Bouldering psychotherapy (BPT) combines psychotherapeutic interventions with action-oriented elements from the field of climbing. The aim of this study is to investigate the effectiveness of BPT compared with a home-based exercise program (EP - active control group, superiority trial) and state-of-the-art cognitive behavioural therapy (CBT – non-inferiority trial).MethodsThe study is being conducted as a multicentre randomised controlled intervention trial at three locations in Germany. Participants are being randomised into three groups: BPT, CBT, or EP, each with a 10-week treatment phase. A power analysis indicated that about 240 people should initially be included. The primary outcome of the study is the Montgomery and Asberg Depression Rating Scale (MADRS) directly after the intervention. Additional measurement points are located three, six, and 12 months after the end of the intervention. The data are being collected via computer-assisted telephone interviews. Statistical analyses comprise regression analyses to test for the superiority of BPT over EP. To test for the non-inferiority of BPT and CBT, a non-inferiority margin of 1.9 points in the Patient Health Questionnaire (PHQ-9) and two non-inferiority margins for the MADRS (half of the two smallest Cohen’s d values from the current meta-analyses) was predefined. The mean difference between CBT and EP is being used as a supplementary equivalence margin.DiscussionThis is the first study to investigate the effect of a bouldering psychotherapy (BPT) on outpatients’ depressive symptoms compared with mere physical activity (superiority analysis) and state-of-the-art cognitive behavioural therapy (CBT, non-inferiority analysis).Methodological strengths of the study are the elaborated, multicentred, randomised, controlled design. Assessors are blinded with regard to group allocation which leads to high objectivity. The study is conducted in a naturalistic setting, which leads to high external validity. Methodological limitations might be the clinical heterogeneity of the sample, which may dilute the intervention effects.Trial registrationISRCTN12457760 (Registration date: 26 July 2017, retrospectively registered).

Relationship between body mass index and operative time in women receiving immediate postpartum tubal ligation

ObjectivesThe aim of the study was to (1) assess the relationship between body mass index (BMI) and operative time during immediate postpartum tubal ligation procedures and to (2) determine whether operative time is non-inferior in women with BMI ≥30 versus women with BMI <30 and in women with BMI ≥40 versus women with BMI <40. Study designWe conducted a retrospective cohort study of women who received immediate postpartum tubal ligations following vaginal delivery from 2013 to 2017 at a university hospital. We abstracted demographic information, patient and procedural characteristics, and clinical outcomes. We assessed the relationship between BMI and operative time via linear regression. We also conducted non-inferiority analysis to determine whether the mean operative time in women with BMI ≥30 was non-inferior to the mean operative time in women with BMI <30, within a non-inferiority margin of 10 min. We compared intraoperative and postoperative complications in the two groups. ResultsA total of 279 women were included for analysis, among whom N=79 (28%) had a BMI of 25–29.9 and N=171 (61%) had a BMI ≥30. Demographic characteristics were similar in both groups. We found that operative time increased by 35 s for each one-point increase in BMI (p<.01). Although mean operative time was 46.1 min (n=171; 95% CI 43.7, 48.6 min) for women with BMI ≥30 and 40.6 min (n=108; 95% CI 37.9 min, 43.4 min) for women with BMI <30, (p<.01), it was non-inferior within a 10-min margin. There was no difference in rates of intraoperative or postoperative complications, incision length, total anesthesia time, and median length of stay between women with BMI ≥30 and BMI <30. ConclusionThere is a small increase in postpartum tubal ligation operative time with increasing BMI. However, among women who received immediate postpartum tubal ligations at our institution, women with BMI ≥30 versus BMI <30 had operative times that were non-inferior within a 10-min margin. ImplicationsWhile increasing body mass index slightly increases the operative time for immediate postpartum tubal ligations, this increase in time does not appear to be clinically significant.

Digital vs face-to-face information provision in patient counselling for prenatal screening: A noninferiority randomized controlled trial.

ObjectiveTo evaluate face‐to‐face information provision in patient counselling for prenatal screening compared with two forms of digital information provision, namely, noninteractive instructional video or interactive video.MethodWe performed a prospective, noninferiority, cluster‐randomized controlled trial comparing face‐to‐face (usual care) with two forms of digital information provision (intervention) in counselling for prenatal screening. This study was performed in the Amsterdam UMC, the Netherlands, in 2017, and included women in the first trimester of pregnancy. Main outcomes were knowledge gained by the patient and counselling duration. We performed a noninferiority analysis.ResultsOne hundred forty‐one women were included, randomized, and analysed. The baseline characteristics were comparable. The intervention group was noninferior compared with the control group regarding the level of satisfaction. The knowledge grade difference was higher after using intervention, and the duration was significantly longer in the face‐to‐face group at 23 minutes versus 16 minutes. The addition of interaction with the video made no difference in any of the outcomes.ConclusionAdding an instructional video to patient counselling is of added value to improve patient's knowledge and shorten time consumption of the counsellor, therefore possibly saving costs. But this form of counselling maintains the same level of satisfaction.

Are we ready for a paradigm shift from high-dose conventional to moderate hypofractionated radiotherapy in intermediate-high risk prostate cancer? A systematic review of randomized controlled trials with trial sequential analysis.

to evaluate efficacy and late toxicity of moderate hypofractionated (HFRT) over high-dose (>76 Gy) conventional radiotherapy (CRT) in a non-inferiority perspective. Randomized controlled trials (RCTs) were included. HFRT regimens were deemed non-inferior to high-dose CRT if the computed CI for the overall RR did not exceed the non-inferiority margin of 7%. When the prespecified margin, corresponding to a critical RR of 0.930 for CCS, OS and BFS, was used all efficacy outcomes satisfied the criteria for the non-inferiority analysis indicating the non-inferiority of HFRT regimens over high-dose CRT in the medium term period. Differently, the evidence concerning the late toxicity was inconclusive. Noninferiority analysis indicates that moderate HFRT regimes are non-inferior over high-dose CRT in the medium-term. Inconclusive is the evidence for the late toxicity. Longer follow-up will provide a more clear answer concerning the non-inferiority of HFRT regimens in the long-term period.

Efficacy of cefquinome and a combination of cloxacillin and ampicillin for treatment of dairy cows with Streptococcus agalactiae subclinical mastitis.

A randomized clinical trial was conducted to assess efficacy of intramammary cloxacillin and ampicillin (CLOXIMM), intramammary cefquinome (CEFIMM), and intramuscular cefquinome (CEFIM) to treat Streptococcus agalactiae intramammary infections (Trial 1). Subsequently, two treatment groups were extended to assess whether CLOXIMM was not inferior to CEFIMM (Trial 2). Nine farms were included in the study. Milk samples were collected from all quarters of all lactating cows for microbiological identification of S. agalactiae. Positive cows were randomly allocated into four groups: CLOXIMM, CEFIMM, CEFIM, or negative control (CONTROL). Study outcomes were bacteriological cure at 14 (CURE14), 21 (CURE21), and 14 and 21 (CURE1421) days after treatment onset, and somatic cell count. Logistic regression was used to estimate the odds of cure between each treatment and CONTROL. Non-inferiority analysis was performed considering a one-sided 95% confidence interval (CI) and non-inferiority margins (Δ) of 0.10, 0.15, 0.20, and 0.25. Adjusted S. agalactiae bacteriological cure for CLOXIMM, CEFIMM, CEFIM, and CONTROL was 86, 98, 55, and 25% at day 14; 82, 93, 52, and 0% at day 21; and 82, 92, 40, and 0% at days 14 and 21, respectively. Treatment with CLOXIMM and CEFIMM resulted in greater bacteriological cure rates, as compared with CEFIM or CONTROL, which does not justify the use of CEFIM in S. agalactiae eradication programs. The CURE14 difference between CEFIMM and CLOXIMM was of 12.1 percentage points (95% CI: 0.056–0.184). CLOXIMM was considered not inferior to CEFIMM for Δ = 0.20 or 0.25 and inconclusive for Δ = 0.10 or 0.15. Thus, it should be pondered by veterinarians whether an expected 12.1 (5.6–18.4) percentage points increase in cure rate would justify the use of a fourth-generation cephalosporin, as opposed to a combination of traditional IMM drugs (cloxacillin and ampicillin) to treat S. agalactiae subclinical mastitis.

Assessing the non-inferiority of prosthesis constructs used in total and unicondylar knee replacements using data from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man: a benchmarking study

ObjectivesTo investigate the relative performance of knee replacement constructs compared with the best performing construct and illustrate the substantial variability in performance.DesignA non-inferiority study.SettingEngland and Wales.ParticipantsAll primary total and unicondylar...

Assessing the non-inferiority of prosthesis constructs used in hip replacement using data from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man: a benchmarking study

ObjectivesTo investigate the relative performance of hip prosthesis constructs as compared with the best performing prosthesis constructs and illustrate the substantial variability in performance of currently used prostheses.DesignA non-inferiority study.SettingThe...