Non-inferiority Margin Research Articles

Efficacy and tolerability of a 4-month ofloxacin-containing regimen compared to a 6-month regimen in the treatment of patients with superficial lymph node tuberculosis: a randomized trial

BackgroundTuberculosis (TB) lymphadenitis is the most common form of extra-pulmonary TB, and the treatment duration is six months. This non-inferiority based randomized clinical trial in South India evaluated the efficacy and safety of a four-month ofloxacin containing regimen in tuberculosis lymphadenitis (TBL) patients.MethodsNew, adult, HIV-negative, microbiologically and or histopathologically confirmed superficial lymph node TB patients were randomized to either four-month oflaxacin containing test regimen [ofloxacin (O), isoniazid (H), rifampicin (R), pyrazinamide (Z) -2RHZO daily/ 2RHO thrice-weekly] or a six-month thrice-weekly control regimen (2HRZ, ethambutol/4RH). The treatment was directly observed. Clinical progress was monitored monthly during and up to 12 months post-treatment, and thereafter every three months up to 24 months. The primary outcome was determined by response at the end of treatment and TB recurrence during the 24 months post-treatment.ResultsOf the 302 patients randomized, 298 (98.7%) were eligible for modified intention-to-treat (ITT) analysis and 294 (97%) for per-protocol (PP) analysis. The TB recurrence-free favourable response in the PP analysis was 94.0% (95% CI: 90.1–97.8) and 94.5% (95% CI: 90.8–98.2) in the test and control regimen respectively, while in the ITT analysis, it was 92.7% and 93.2%. The TB recurrence-free favourable response in the test regimen was non-inferior to the control regimen 0.5% (95% CI: -4.8-5.9) in the PP analysis based on the 6% non-inferiority margin. Treatment was modified for drug toxicity in two patients in the test regimen, while one patient had a paradoxical reaction.ConclusionThe 4-month ofloxacin containing regimen was found to be non-inferior and as safe as the 6-month thrice-weekly control regimen.

Posterior Cervical Foraminotomy Compared with Anterior Cervical Discectomy with Fusion for Cervical Radiculopathy: Two-Year Results of the FACET Randomized Noninferiority Study.

Posterior cervical foraminotomy (posterior surgery) is a valid alternative to anterior discectomy with fusion (anterior surgery) as a surgical treatment of cervical radiculopathy, but the quality of evidence has been limited. The purpose of this study was to compare the clinical outcome of these treatments after 2 years of follow-up. We hypothesized that posterior surgery would be noninferior to anterior surgery. This multicenter, randomized, noninferiority trial assessed patients with single-level cervical radiculopathy in 9 Dutch hospitals with a follow-up duration of 2 years. The primary outcomes measured reduction of cervical radicular pain and were the success ratio based on the Odom criteria, and arm pain and decrease in arm pain, evaluated with the visual analog scale, with a 10% noninferiority margin, which represents the maximum acceptable difference between the new treatment (posterior surgery) and the standard treatment (anterior surgery), beyond which the new treatment would be considered clinically unacceptable. The secondary outcomes were neck pain, Neck Disability Index, Work Ability Index, quality of life, complications (including reoperations), and treatment satisfaction. Generalized linear mixed effects modeling was used for analyses. The study was registered at the Overview of Medical Research in the Netherlands (OMON), formerly the Netherlands Trial Register (NTR5536). From January 2016 to May 2020, 265 patients were randomized (132 to the posterior surgery group and 133 to the anterior surgery group). Among these, 25 did not have the allocated intervention; 11 of these 25 patients had symptom improvement, and the rest of the patients did not have the intervention due to various reasons. At the 2-year follow-up, of 243 patients, primary outcome data were available for 236 patients (97%). Predicted proportions of a successful outcome were 0.81 after posterior surgery and 0.74 after anterior surgery (difference in rate, -0.06 [1-sided 95% confidence interval (CI), -0.02]), indicating the noninferiority of posterior surgery. The between-group difference in arm pain was -2.7 (1-sided 95% CI, 7.4) and the between-group difference in the decrease in arm pain was 1.5 (1-sided 95% CI, 8.2), both confirming the noninferiority of posterior surgery. The secondary outcomes demonstrated small between-group differences. Serious surgery-related adverse events occurred in 9 patients (8%) who underwent posterior surgery, including 9 reoperations, and 11 patients (9%) who underwent anterior surgery, including 7 reoperations (difference in reoperation rate, -0.02 [2-sided 95% CI, -0.09 to 0.05]). This trial demonstrated that, after a 2-year follow-up, posterior surgery was noninferior to anterior surgery with regard to the success rate and arm pain reduction in patients with cervical radiculopathy. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Cognitive-behavioral treatment for insomnia and mindfulness-based stress reduction in nurses with insomnia: a non-inferiority internet delivered randomized controlled trial.

Insomnia is a highly prevalent sleep disorder frequently comorbid with mental health conditions in nurses. Despite the effectiveness of evidence-based cognitive behavioral therapy for insomnia (CBT-I), there is a critical need for alternative approaches. This study investigated whether internet-delivered mindfulness-based stress reduction (IMBSR) for insomnia could be an alternative to internet-delivered CBT-I (ICBT-I). The hypothesis was that the IMBSR would be noninferior to the ICBT-I in reducing the severity of insomnia among nurses with insomnia. Additionally, it was expected that ICBT-I would produce a greater reduction in the severity of insomnia and depression than IMBSR. Among 240 screened nurses, 134 with insomnia were randomly allocated (IMBSR, n =67; ICBT-I, n = 67). The assessment protocol comprised clinical interviews and self-reported outcome measures, including the Insomnia Severity Index (ISI), Patient Health Questionnaire-9 (PHQ-9), the 15-item Five Facet Mindfulness Questionnaire (FFMQ), and the Client Satisfaction Questionnaire (CSQ-I). The retention rate was 55% with 77.6% (n=104) of participants completing the study. At post-intervention, the noninferiority analysis of the ISI score showed that the upper limit of the 95% confidence interval was 4.88 (P=0.46), surpassing the pre-specified noninferiority margin of 4 points. Analysis of covariance revealed that the ICBT-I group had significantly lower ISI (Cohen's d = 1.37) and PHQ-9 (Cohen's d = 0.71) scores than did the IMBSR group. In contrast, the IMBSR group showed a statistically significant increase in the FFMQ-15 score (Cohen's d = 0.67). Within-group differences showed that both the IMBSR and ICBT-I were effective at reducing insomnia severity and depression severity and improving mindfulness. Overall, nurses demonstrated high levels of satisfaction and adherence to both interventions. The IMBSR significantly reduced insomnia severity and depression, but the findings of this study do not provide strong evidence that the IMBSR is at least as effective as the ICBT-I in reducing insomnia symptoms among nurses with insomnia. The ICBT-I was found to be significantly superior to the IMBSR in reducing insomnia severity, making it a recommended treatment option for nurses with insomnia.

Seizure Assessment and Forecasting With Efficient Rapid-EEG: A Retrospective Multicenter Comparative Effectiveness Study.

Approximately 30% of critically ill patients have seizures, and more than half of these seizures do not have an overt clinical correlate. EEG is needed to avoid missing seizures and prevent overtreatment with antiseizure medications. Conventional-EEG (cEEG) resources are logistically constrained and unable to meet their growing demand for seizure detection even in highly developed centers. Brief EEG screening with the validated 2HELPS2B algorithm was proposed as a method to triage cEEG resources, but it is hampered by cEEG requirements, primarily EEG technologists. Seizure risk-stratification using reduced time-to-application rapid response-EEG (rrEEG) systems (∼5 minutes) could be a solution. We assessed the noninferiority of the 2HELPS2B score on a 1-hour rrEEG compared to cEEG. A multicenter retrospective EEG diagnostic accuracy study was conducted from October 1, 2021, to July 31, 2022. Chart and EEG review performed with consecutive sampling at 4 tertiary care centers, included records of patients ≥18 years old, from January 1, 2018, to June 20, 2022. Monte Carlo simulation power analysis yielded n = 500 rrEEG; for secondary outcomes n = 500 cEEG and propensity-score covariate matching was planned. Primary outcome, noninferiority of rrEEG for seizure risk prediction, was assessed per area under the receiver operator characteristic curve (AUC). Noninferiority margin (0.05) was based on the 2HELPS2B validation study. A total of 240 rrEEG with follow-on cEEG were obtained. Median age was 64 (interquartile range 22); 42% were female. 2HELPS2B on a 1-hour rrEEG met noninferiority to cEEG (AUC 0.85, 95% CI 0.78-0.90, p = 0.001). Secondary endpoints of comparison with a matched contemporaneous cEEG showed no significant difference in AUC (0.89, 95% CI 0.83-0.94, p = 0.31); in false negative rate for the 2HELPS2B = 0 group (p = 1.0) rrEEG (0.021, 95% CI 0-0.062), cEEG (0.016, 95% CI 0-0.048); nor in survival analyses. 2HELPS2B on 1-hour rrEEG is noninferior to cEEG for seizure prediction. Patients with low-risk (2HELPS2B = 0) may be able to forgo prolonged cEEG, allowing for increased monitoring of at-risk patients. This study provides Class II evidence that rrEEG is noninferior to cEEG in calculating the 2HELPS2B score to predict seizure risk.

Stockholm3 in a Multiethnic Cohort for Prostate Cancer Detection (SEPTA): A Prospective Multicentered Trial.

Asian, Black, and Hispanic men are underrepresented in prostate cancer (PCa) clinical trials. Few novel prostate cancer biomarkers have been validated in diverse cohorts. We aimed to determine if Stockholm3 can improve prostate cancer detection in a diverse cohort. An observational prospective multicentered (17 sites) clinical trial (2019-2023), supplemented by prospectively recruited participants (2008-2020) in a urology clinic setting included men with suspicion of PCa and underwent prostate biopsy. Before biopsy, sample was collected for measurement of the Stockholm3 risk score. Parameters include prostate-specific antigen (PSA), free PSA, KLK2, GDF15, PSP94, germline risk (single-nucleotide polymorphisms), age, family history, and previous negative biopsy. The primary endpoint was detection of International Society of Urological Pathology (ISUP) Grade ≥2 cancer (clinically significant PCa, csPC). The two primary aims were to (1) demonstrate noninferior sensitivity (0.8 lower bound 95% CI noninferiority margin) in detecting csPC using Stockholm3 compared with PSA (relative sensitivity) and (2) demonstrate superior specificity by reducing biopsies with benign results or low-grade cancers (relative specificity). A total of 2,129 biopsied participants were included: Asian (16%, 350), Black or African American (Black; 24%, 505), Hispanic or Latino and White (Hispanic; 14%, 305), and non-Hispanic or non-Latino and White (White; 46%, 969). Overall, Stockholm3 showed noninferior sensitivity compared with PSA ≥4 ng/mL (relative sensitivity: 0.95 [95% CI, 0.92 to 0.99]) and nearly three times higher specificity (relative specificity: 2.91 [95% CI, 2.63 to 3.22]). Results were consistent across racial and ethnic subgroups: noninferior sensitivity (0.91-0.98) and superior specificity (2.51-4.70). Compared with PSA, Stockholm3 could reduce benign and ISUP 1 biopsies by 45% overall and between 42% and 52% across racial and ethnic subgroups. In a substantially diverse population, Stockholm3 significantly reduces unnecessary prostate biopsies while maintaining a similar sensitivity to PSA in detecting csPC.

Switch to fixed-dose ainuovirine, lamivudine, and tenofovir DF versus elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed people living with HIV-1: the 48-week results of the SPRINT trial, a multi-centre, randomised, double-blind, active-controlled, phase 3, non-inferiority trial

We compared the efficacy and safety profiles of ainuovirine (ANV), a new-generation non-nucleoside reverse transcriptase inhibitor (NNRTI), with boosted elvitegravir (EVG), both coformulated with two nucleoside reverse transcriptase inhibitors (NRTIs), in people living with HIV-1 (PLWH) who had achieved virological suppression on previous NNRTI-based antiretroviral (ARV) regimen. This study was a multi-centre, randomised, double-blind, active-controlled, non-inferiority trial recruiting PLWH from 10 clinical centres across China. Main inclusion criteria included age of 18-65 years (inclusive), and stably staying on an ARV regimen combining an NNRTI with a two-drug NRTI backbone for at least 12 months. Eligible participants must have maintained plasma HIV-1 ribonucleic acid (RNA) titre below 50 copies per mL confirmed on two successive tests at an interval of at least one month prior to randomisation. Participants were randomly assigned to receive ANV 150mg plus lamivudine (3TC) 300mg, and tenofovir disoproxil fumarate (TDF) 300mg (ANV/3TC/TDF), or cobicistat (Cobi) 150mg boosted EVG plus emtricitabine (FTC) 200mg, and tenofovir alafenamide (TAF) 10mg. The primary efficacy endpoint was the proportion of participants with HIV-1 RNA titre at 50 copies per mL or above at week 48 using the US Food and Drug Administration snapshot algorithm, with a non-inferiority margin of 4 percentage points at a two-side 95% confidence level. This trial is active, but not recruiting, and is registered with Chinese Clinical Trial Registry (ChiCTR), number ChiCTR2100051605. Between October 2021 and February 2022, 923 patients were screened for eligibility, among whom 762 participants were randomized and had received at least one dose of ANV/3TC/TDF (n=381) or EVG/Cobi/FTC/TAF (n=381). At week 48, 7 (1.8%) participants on ANV/3TC/TDF and 6 (1.6%) participants on EVG/Cobi/FTC/TAF had plasma HIV-1 RNA titre at 50 copies per mL or above, including missing virological data within the time window (the Cochran-Mantel-Haenszel method, estimated treatment difference [ETD], 0.3%, 95% CI-1.6 to 2.1), establishing the non-inferiority of ANV/3TC/TDF to EVG/Cobi/FTC/TAF. The proportions of participants experiencing at least one treatment-emergent adverse events (AEs) were comparable between the two arms (97.6% versus 97.6%). A small proportion of participants discontinued study drug due to AEs (0.3% versus 0.3%). Serious AEs occurred in 11 (2.9%) participants on ANV/3TC/TDF and 9 (2.4%) participants on EVG/Cobi/FTC/TAF, respectively, none of which was considered related to study drug at the jurisdiction of the investigator. At week 48, participants on ANV/3TC/TDF showed a significantly less weight gain from baseline compared to those on EVG/Cobi/FTC/TAF (least square mean, 1.16 versus 2.05kg, ETD-0.90kg, 95% CI,-1.43 to-0.37). The changes in serum lipids from baseline also favoured ANV/3TC/TDF over EVG/Cobi/FTC/TAF. In virologically suppressed PLWH on previous NNRTI-based ARV regimen, switch to ANV/3TC/TDF resulted in less weight gain, and improved lipid metabolism while maintaining virological suppression non-inferior to that to EVG/Cobi/FTC/TAF. Jiangsu Aidea Pharmaceutical & the National "Thirteenth Five-year Period" Major Innovative Drugs Research and Development Key Project of the People's Republic of China Ministry of Science and Technology.

Outpatient elective induction of labour at 39 weeks’ gestation (HOME INDUCTION): an open-label, randomised, controlled, phase III, non-inferiority trial

The increased demand for induction of labour (IOL) at 39 weeks' gestation in normal-risk nulliparous patients creates significant logistical challenges for busy maternity units. A potential innovation is commencing induction by means of outpatient cervical ripening, using either a vaginal prostaglandin preparation (Propess) or an osmotic cervical dilator (Dilapan-S). A Phase III, open label, single centre non-inferiority trial (EudraCT number 2019-004697-25) randomised healthy nulliparous women who chose elective IOL at 39 weeks to one of three methods of initial cervical ripening, specifically 12h of Dilapan-S(D12), 24h of Dilapan-S(D24), or 24h of Propess(P24) between November 2020 and July 2023. After initial administration of the IOL agent in the hospital, participants returned home for 12 or 24h, before readmission to complete delivery. The primary outcome was vaginal delivery achieved at any time, and this was compared in a non-inferiority analysis of Dilapan-S compared to Propess, within a 10% non-inferiority margin. Secondary outcomes included pairwise comparisons for each induction agent, and a range of logistical factors, such as time to delivery, the need for an additional cervical ripening agent, and length of hospital stay. Of the 327 women randomised at 38 weeks, 271 (83%) completed the induction intervention. The D24 and P24 groups showed similarly high rates of vaginal delivery, 75% and 76% respectively. D12 had a lower vaginal delivery rate of 64% and consequently the overall comparison of Dilapan-S to Propess did not demonstrate non-inferiority (difference=-6%, 95% CI=-17%, 5%) because the lower 95% CI exceeded the-10% threshold of non-inferiority. The majority of participants across all groups were delivered by any means within 72h of starting the induction process, inclusive of time spent at home (89% of the D24 group, 98% of the D12 group, 95% of the P24 group). There were no differences in rates of adverse events between groups. There were similarly high vaginal delivery rates for D24 and P24, with at least 75% of patients successfully delivering vaginally following outpatient cervical ripening, with no significant adverse maternal or neonatal outcomes. The Rotunda Foundation, Medicem Technology s.r.o.

Same-day discharge after laparoscopic hysterectomy for benign/premalignant disease: A multicentre randomised controlled trial.

To evaluate whether physical function and quality of life was influenced by discharge on the same-day after a total laparoscopic hysterectomy. Multicentre non-inferiority randomised controlled trial. Five teaching hospitals and two university hospitals in the Netherlands. Patients undergoing laparoscopic hysterectomy for benign or premalignant disease. Following informed consent, participants were allocated 1:1 either to same-day discharge (SDD) or next-day discharge (NDD). The primary outcome was physical function at 7 days after surgery measured by the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function short Form 10A. Secondary outcomes were physical function and quality of life at 1 and 3 days and 6 weeks after surgery measured with PROMIS short Form 10A and the EuroQol questionnaire (EQ-5D-5L). Two hundred and five patients were included of whom 105 were allocated to SDD and 100 to NDD. Physical function 7 days after surgery was 35.95 in the SDD group and 35.63 in the control group (mean difference 0.32; 95% CI [0.07-0.57]). As the upper limit of the 95% CI does not exceed the non-inferiority margin of 4 points, non-inferiority of SDD could be demonstrated. No difference in physical function nor quality of life on Days 1 and 3 and 6 weeks could be found. This research demonstrates same-day discharge after laparoscopic hysterectomy is non-inferior to next day discharge in physical function 7 days after surgery.

N-Butyl-2-Cyanoacrylate Adhesive Versus Absorbable Tacks in Laparoscopic Groin Hernia Repair: A Multicenter Randomized Clinical Trial.

We aimed to determine whether n-butyl-2-cyanoacrylate (NB2C) adhesive is a safe and effective mechanism for nonpenetrating mesh and peritoneal fixation during laparoscopic groin hernia repair. Chronic pain after laparoscopic groin hernia repair has been associated with penetrating fixation, but there had been no US Food and Drug Administration-approved devices for nonpenetrating fixation in this context. Patients undergoing laparoscopic transabdominal preperitoneal (TAP) or totally extraperitoneal (TEP) groin hernia repair with mesh at 1 of 5 academic medical centers were randomized to mesh (TAP/TEP) and peritoneal (TAP) fixation with NB2C adhesive or absorbable tacks. The primary outcome was improvement in pain (visual analog scale [VAS]) at 6 months. The noninferiority margin was 0.9 (α = 0.025; β = 80%). Recurrence, successful use of the device, quality of life, and rates of adverse events (AEs) were secondary outcomes. From 2019 to 2021, 284 patients were randomized to either NB2C adhesive or absorbable tacks (n = 142/142). Patient and hernia characteristics were comparable, and 65% were repaired using a TAP approach. The difference in VAS improvement at 6 months with NB2C adhesive was not inferior to absorbable tacks in intention-to-treat and per-protocol analyses, respectively (0.25 [95% CI, -0.33 to 0.82]; P = 0.013; 0.22 [95% CI, -0.36 to 0.80], noninferiority P = 0.011). There were no differences in secondary outcomes including recurrence, successful use of each device to fixate the mesh and peritoneum, quality of life, and additional VAS pain scores. Rates of adverse and serious AEs were also comparable. NB2C adhesive is safe and effective for mesh fixation and peritoneal closure during laparoscopic groin hernia repair.

Vitis Vinifera Seed Extract Versus Micronized Purified Flavonoid Fraction for Patients with Chronic Venous Disease: A Randomized Noninferiority Trial

Venoactive drugs (VADs) based on Vitis vinifera extract are widely used in Korea. However, studies on the clinical effects and head-to-head comparisons with other groups of VADs are limited. This trial aimed to evaluate whether Vitis vinifera seed extract was noninferior to the micronized purified flavonoid fraction (MPFF) in relieving venous symptoms and improving quality of life in patients with chronic venous disease. In this double-blind prospective randomized trial, patients from 13 hospitals, who were diagnosed with venous incompetence by duplex ultrasound and classified as clinical class 1, 2, or 3 in the Clinical, Etiological, Anatomical, and Pathophysiological classifications were enrolled. The primary outcome was the change in the Chronic Venous Disease Quality of Life Questionnaire (CIVIQ-20) score at 8weeks from baseline. Secondary outcomes included changes in the Aberdeen Varicose Vein Questionnaire, visual analog scale, and Venous Clinical Severity Score at 4 and 8weeks from baseline. Moreover, the change in leg circumferences was measured at 8weeks and compared to baseline. In total, 303 patients were enrolled and randomly assigned to receive either Vitis vinifera seed extract (n=154) or MPFF (n=149). The CIVIQ-20 scores at 8weeks were significantly reduced compared to those at baseline in both groups. No significant intergroup difference in the change of CIVIQ-20 at 8weeks from baseline was observed (-8.31±14.63 vs. -10.35±14.38, P=0.29, 95% confidence interval -1.65 to 5.72). The lower limit of the 95% confidence interval was within the predefined noninferiority margin of 6.9. Furthermore, the Aberdeen Varicose Vein Questionnaire, visual analog scale, and Venous Clinical Severity Score scores significantly decreased at 4 and 8weeks after randomization compared with baseline in both groups. No significant differences were observed in the reduction of each score between groups. The calf circumference measured at 8weeks was significantly reduced compared to that at baseline in patients receiving Vitis vinifera seed extract. Vitis vinifera seed extract was noninferior to MPFF in relieving venous symptoms and improving the quality of life in patients with chronic venous disease.

The Efficacy and Safety of DLBS3233, A Combined Bioactive Fraction of Cinnamomum burmanii and Lagerstroemia speciosa Plants on The Endocrine-Metabolic Profile of Women with Polycystic Ovary Syndrome: A Randomized Clinical Trial.

A bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa, DLBS3233, has recently been used for type-2-diabetes treatment due to its favorable effect on insulin sensitivity. The insulin resistance leading to metabolic syndrome is closely linked to hyperandrogenemia in polycystic ovary syndrome (PCOS). This study evaluated the metabolic and reproductive efficacy and safety of DLBS3233 in insulin-resistant PCOS women. This was a 2-arm, randomized, double-blind, controlled, noninferiority clinical study over a 6-month therapy with DLBS3233 100-mg daily in comparison to metformin-XR 750 mg twice daily, involving 124 PCOS women with insulin resistance. The primary efficacy endpoint was the improvement of Homeostasis Model Assessment-Insulin Resistance (HOMA-IR). Secondary endpoints were improvements in other metabolic and reproductive parameters. Safety endpoints were based on blood pressure, heart rate, electrocardiogram findings, liver and renal function, and adverse events. After 6 months, HOMA-IR improvement in DLBS3233-treated group (-1.03 ± 0.50) and metformin-XR (-1.19 ± 0.50) were comparable, with a between-group difference fell within the pre-set non-inferiority margin (0.16; 95% confidence interval (CI): -1.24, 1.56; P=0.3168). The HOMA-IR in both groups were significantly improved from baseline. On all secondary endpoints, both groups showed comparable effects. Markedly fewer adverse events occurred in the DLBS3233 treated group than in the Metformin-XR-treated group and most were mild clinically and had been resolved by the end of the study. Treatment with DLBS3233 100-mg daily in PCOS women demonstrated comparable efficacy to metformin- XR 750-mg twice daily in improving insulin resistance. However, the non-inferiority of DLBS3233 to metformin- XR remains inconclusive. DLBS3233 was more tolerable than metformin-XR (registration number: NCT01733459).

Pelvic floor muscle training vs radiofrequency for women with vaginal laxity: randomized clinical trial.

Vaginal laxity (VL) is a complaint of excessive vaginal looseness with a prevalence ranging from 24% to 38% across studies. The study sought to compare the effect of radiofrequency (RF) and pelvic floor muscle training (PFMT) on the treatment of women with VL. From February 2020 to December 2021, a prospective, parallel, noninferiority, randomized clinical trial was carried out in women ≥18years of age and complaining of VL in a tertiary hospital. Two groups (RF and PFMT) were evaluated at the beginning of the study and 30days and 6 months postintervention. A total of 42 participants per arm was sufficient to demonstrate a difference in sexual function on the Female Sexual Function Index at 90% power, 1-sided type 1 error of 0.025 with a noninferiority margin of 4 on the FSFI total score. Analysis was intention-to-treat and per-protocol based. The primary endpoint was the change of FSFI score after treatment, and the secondary outcomes were improvement in symptoms of VL and changes in questionnaire scores of sexual distress, vaginal symptoms, and urinary incontinence, in the quantification of pelvic organ prolapse, and pelvic floor muscle (PFM) contraction. Of 167 participants recruited, 87 were included (RF: n = 42; PFMT: n = 45). All questionnaires improved (P < .05) their total scores and subscales in both groups and during the follow-ups. After 30days of treatment, RF was noninferior to PFMT to improving FSFI total score (mean difference -0.08 [95% confidence interval, -2.58 to 2.42]) in the per-protocol analysis (mean difference -0.46 [95% confidence interval, -2.92 to 1.99]) and in the intention-to-treat analysis; however, this result was not maintained after 6 months of treatment. PFM contraction improved significantly in both groups (RF: P = .006, 30days; P = .049, 6 months; PFMT: P < .001, 30days and 6 months), with better results in the PFMT group. Sexual, vaginal, and urinary symptoms were improved after 30days and 6 months of treatment with RF and PFMT; however, better results were observed in the PFMT group after 6 months. The present randomized clinical trial used several validated questionnaires evaluating quality of life, sexual function and urinary symptoms, in addition to assessing PFM contraction and classifying the quantification of pelvic organ prolapse aiming at anatomical changes in two follow-up periods. The limitations were the lack of a sham-controlled group (third arm) and the difficulty of blinding researchers to assess treatments due to the COVID-19 pandemic. After 30days and 6 months of treatment, sexual, vaginal, and urinary symptoms improved with RF and PFMT; however, better results were observed in the PFMT group after 6 months. RF was noninferior to PFMT in improving FSFI total score after 30days; however, this result was not maintained after 6 months of treatment.

Clinical efficacy and safety of transvaginal natural orifice transluminal endoscopic surgery for benign adnexal disease: a prospective trial

BackgroundThere is a scarcity of prospective clinical research evidence regarding the utilization of transvaginal natural orifice translumenal endoscopic surgery (vNOTES) as a treatment option for ovarian cysts. The objective of this study was to assess the feasibility and safety of employing vNOTES for the management of ovarian cysts.MethodsOur study included women between the ages of 18 and 70 who intended to undergo surgical intervention for benign lesions. Stratified blocked randomization was employed to allocate participants into groups. The main objective was to assess whether the assigned group adhered to the recommended surgical technique for ovarian cystectomy or adnexectomy, without any deviation to alternative surgical methods.ResultsA total of 196 patients were included in the study, with all surgeries in each group being conducted according to the assigned procedures. Among them, the ovarian cystectomy layer included 58 cases in the vNOTES group and 58 cases in the conventional laparoscopy (CL) groups. The adnexectomy layer included 40 cases in the vNOTES group and 40 cases in the CL group. Utilizing a sensitivity analysis, the two-sided 95% lower confidence limit was determined to be 5.5% for the disparity in proportions between the vNOTES groups and CL groups. These lower limits fell below the predetermined non-inferiority margin of 10%.ConclusionsThe study findings demonstrate that vNOTES was not inferior to CL in terms of adnexectomy or ovarian cystectomy. vNOTES can be considered a more minimally invasive surgical approach, as it results in reduced postoperative pain, faster recovery, and absence of visible incisions. Overall, vNOTES proves to be a safe, feasible, and less invasive treatment option.Trial registrationThis study retrospectively registered with the China Clinical Trial Registry with the registration number ChiCTR2100052223(22-10-2021).

Transcutaneous neuromodulation versus oxybutynin for neurogenic detrusor overactivity in persons with spinal cord injury: A randomized, investigator blinded, parallel group, non-inferiority controlled trial

Study design This study is a randomized, investigator-blinded, controlled trial with a non-inferiority design. Objective To investigate the effectiveness of neuromodulation by transcutaneous electrical stimulation of the somatic afferent nerves of the foot in neurogenic detrusor overactivity (NDO) in persons with spinal cord injury (SCI) and compare its effectiveness with oral oxybutynin. Setting The study was conducted in a rehabilitation in-patient ward of a tertiary care hospital. Methods Twenty-nine persons with SCI with NDO, either sex, aged 18 years and above were randomized into two groups, one group receiving oral oxybutynin (5 mg thrice a day for two weeks) and the other transcutaneous electrical stimulation (5 Hz, 200 µs pulse, biphasic, amplitude up to 60 mA, 30 min/day for two weeks). Bladder capacity was evaluated by clinical bladder evaluation (i.e. bladder capacity measured by adding leak volume, voiding volume if any, and post-void residue using a catheter) and cystometric bladder capacity by one-channel cystometry. Maximum cystometric pressure was evaluated by one-channel water cystometry. Data were analyzed with Fisher's Exact, t-test, and Wilcoxon rank sum tests. Results Bladder capacity improved significantly in the oxybutynin and neuromodulation groups as measured by one-channel water cystometry (136 ml vs. 120.57 ml) and clinical evaluation (138.93 ml vs. 112 ml). The increase in the neuromodulation group achieved the pre-decided non-inferiority margin of 30 ml over the oxybutynin group when measured by one-channel water cystometry but not by clinical evaluation. Maximum cystometric pressure did not significantly improve in either group when compared with the baseline. Conclusion Transcutaneous neuromodulation and oxybutynin effectively increased bladder capacity in persons with SCI with NDO. Neuromodulation by once-a-day transcutaneous electrical stimulation was non-inferior to thrice-a-day oxybutynin when evaluated by one-channel water cystometry. Trial registration: Clinical Trials Registry India identifier: CTRI/2018/05/013735.

Treatment of Unfavorable Intrabony Defects with Autogenous Bone Graft in Combination with Leukocyte- and Platelet-Rich Fibrin or Collagen Membranes: A Non-Inferiority Study.

Background and Objectives: Unfavorable intrabony defects (IBDs) are associated with the progression of periodontal disease and tooth loss. Growing scientific evidence has demonstrated the effectiveness of platelet concentrations in periodontal treatment. The aim of our study was to demonstrate the non-inferiority of an autogenous bone graft (ABG) associated with leukocyte- and platelet-rich fibrin (L-PRF) compared to ABG + Collagen Membrane in the treatment of IBDs. Material and Methods: Sixty-four patients with at least one IBD were randomly assigned to two groups: ABG+L-PRF and CM+ABG. Clinical and radiographic evaluations were performed at baseline and 12-month follow-up. Clinical attachment level (CAL), gingival recession (GR), probing pocket depth (PPD), and radiograph defect bone level (DBL) were compared between the two treatments. To evaluate the effectiveness of ABG+L-PRF, a non-inferiority margin of =1 mm (-1 mm for GR) was chosen; a second non-inferiority margin of =0.5 mm (-0.5 mm for GR) was set for clinical relevance. Results: At 12-month follow up, both treatments showed clinical and radiographic improvements. The 90% confidence intervals of the CM+ABG-L-PRF+ABG mean difference for CAL gain (-0.0564 mm [-0.316 to 0.203]), DBL gain (-0.433 mm [-0.721 to -0.145]), and PPD reduction (0.232 mm [0.015 to 0.449]) were below the 0.5 mm non-inferiority margin; the GR increase (0.255 mm [0.0645 to 0.445]) stayed above the -0.5 mm. Conclusions: the L-PRF+ABG treatment of unfavorable IBDs is non-inferior with respect to the CM+ABG therapy for CAL gain, but with a lower GR, a slightly higher PPD, and DBL gain.

Effect of Residual Gastric Volume on Risk of Ventilator-Associated Pneumonia in Adults Receiving Mechanical Ventilation and Early Enteral Feeding

Abstract Background Early enteral nutrition is the standard of care in critically ill patients receiving invasive mechanical ventilation. However, numerous studies have shown that early enteral nutrition is frequently not used. The main reason for nonuse is gastrointestinal intolerance to enteral nutrition which has been ascribed to gastroparesis with increased gastric volume, gastroesophageal reflux, and regurgitation or vomiting carrying a risk of aspiration and ventilator-associated pneumonia. Aim of the Work To test the hypothesis that the risk of ventilator-associated pneumonia is not increased when residual gastric volume is not monitored compared with routine residual gastric volume monitoring in patients receiving invasive mechanical ventilation and early enteral nutrition. Furthermore residual gastric volume monitoring may be associated with decreased calorie delivery and therefore, with underfeeding and increased morbidity. Patients and Methods This is a Prospective cohort study that was conducted at Ain Shams University Hospitals&amp; Rashid General hospital for 6 months on critically ill patients admitted to ICU with mechanical ventilation. Sample sizes of 215 in each group totaling 430 in the study achieve 80% power to detect a non-inferiority margin difference between the group proportions of -0.0800. The reference group proportion is 0.158. The treatment group proportion is assumed to be 0.078 under the null hypothesis of inferiority. Results There was no significant difference between groups regard BMI (is calculated as weight in kilograms divided by height in meters squared), SAPS II or SOFA regard sex distribution the majority were male in both groups with no significant difference and also DM and HTN distributed with no significant difference between groups. Considering cause of admission and risk factors distribution between studied groups, in our study there is no significant difference or association between the two groups and the majority admission causes of both groups were respiratory and cancer. No significant difference between groups regard hospital stay or ICU days but MV days were significantly shorter in intervention group. In our study, Ventilator-Associated Pneumonia was significantly associated with control group as 47.4% had pneumonia while only 11.2% in intervention group had it. In the present study, cumulative calories deficit was significantly lower in intervention group, Intolerance and Prokinetic TTT were significantly associated with control group. Conclusion The current study supports the hypothesis that a protocol of enteral nutrition management without residual gastric volume monitoring is not inferior to a similar protocol including residual gastric volume monitoring in terms of protection against VAP. Residual gastric volume monitoring leads to unnecessary interruptions of enteral nutrition delivery with subsequent inadequate feeding and should be removed from the standard care of critically ill patients receiving invasive mechanical ventilation and early enteral nutrition.

O-226 Effects of preventive uterine artery occlusion during laparoscopic myomectomy on ovarian reserve markers: a randomized controlled trial

Abstract Study question Does definitive occlusion of uterine arteries have a short or long term impact on anti-Müllerian hormone (AMH) levels in reproductive age women undergoing laparoscopic myomectomy? Summary answer Preventive uterine artery occlusion during laparoscopic myomectomy does not impact AMH levels in reproductive age women. What is known already Uterine leiomyoma are the most common benign tumours in women of reproductive age. For symptomatic women willing to retain their uterus, especially for a future pregnancy, the current gold standard is the myomectomy for subserous/intramural leiomyoma. Temporary or definitive occlusion of uterine arteries can be performed to control bleeding during surgery but its impact on ovarian reserve markers is still unknown. A single randomized trial with a one-year follow-up demonstrated that temporary bilateral uterine artery occlusion during laparoscopic myomectomy slightly decreased AMH levels at day-2 after surgery but has no impact thereafter 3, 6 and 12 months postoperatively. Study design, size, duration We conducted a randomized controlled trial with a two-year follow-up evaluating the effect of definitive occlusion of uterine arteries on ovarian reserve via sequential measures of anti-Müllerian hormone (AMH) levels. Fifty-eight women with symptomatic leiomyoma type FIGO 3-6 scheduled for laparoscopic myomectomy at were included between July 2015 and October 2021. Participants/materials, setting, methods Patients were randomized into: the intervention group (laparoscopic myomectomy with preventive occlusion of uterine arteries) and the control group (laparoscopic myomectomy without occlusion of uterine arteries) ). AMH evaluated at T0 and followed at 1 month (T1), 3 months (T3), 6 months (T6), 12 months (T12) and 24 months (T24) after surgery. Intraoperative blood loss, leiomyoma recurrence and adenomyosis occurrence were also evaluated comparing pre- and post-operative findings. Finally, pregnancies and live births were monitored. Main results and the role of chance Women in both groups did not differ in their baseline characteristics in terms of age, body mass index, ethnicity, parity, wish to become pregnant, hormonal treatment, leiomyoma number and size, baseline haemoglobin levels, bleeding symptoms baseline AMH levels and antral follicular count (AFC). The mean operative time was similar in between both groups. Mean blood loss during surgery was on average 138 (±104)ml in the intervention group versus 436 (±498)ml in controls (p &amp;lt; 0.001). The difference in haemoglobin between before and after surgery was significantly higher in the control group 21.8 (±12.7)g/l compared with the intervention group 14.8 (±8.9)g/l (p = 0.02). Regarding clinical symptoms, most patients had decreased menstrual flow at the last follow-up visit (24 months) compared to baseline in both group improvement of dysmenorrhea followed the same trend with a reduction in pain levels in both groups. Risk of leiomyoma recurrence was found similar between both groups. Most importantly, AMH levels were similar between groups at all times (T1, T3, T6, T12 and T24) and non-inferiority of preventive occlusion was demonstrated with a non-inferiority margin of -3.5pmol/L (0.5 ng/ml). The pregnancy rate was not different between groups. Limitations, reasons for caution Our sample size was calculated to detect a clinically relevant difference of at least two-third of the standard deviation in AMH levels, but we cannot exclude a smaller impact on AMH with a different sample size. Wider implications of the findings Preventive uterine artery occlusion during laparoscopic myomectomy does not impact ovarian reserve markers and can be safely used to control perioperative bleeding. Trial registration number NCT02563392

A Randomized, Double-Blind, Phase III Study in India for Comparing Efficacy, Safety, and PK of ZRC-3277 (Pertuzumab Biosimilar) With Perjeta® in Patients With HER2-Positive Metastatic Breast Cancer

IntroductionTo evaluate the efficacy, safety, pharmacokinetics (PK), and immunogenicity of ZRC-3277 (pertuzumab biosimilar) with Perjeta® (pertuzumab) in previously untreated patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Patients and MethodsThis phase III, multicenter, double-blind study across 38 sites in India randomized (1:1) patients with HER2-positive MBC in either the ZRC-3277 or Perjeta® group. Both groups also received trastuzumab and docetaxel. Of 268 enrolled patients, mITT population had 243 patients (119 and 124 in the ZRC-3277 and Perjeta® groups, respectively). The primary objective was to compare the between-group objective response rate (ORR) after 6 cycles of treatment. ORR was determined by evaluating scans of computed tomography or magnetic resonance imaging following Response Evaluation Criteria in Solid Tumor (RECIST 1.1). Two-sided 95% confidence interval (95% CI) for the difference in ORR was determined to evaluate the noninferiority of ZRC-3277 to Perjeta®. The secondary outcomes included the assessment of PK, immunogenicity, and safety between the 2 groups. ResultsIn the mITT population, 104 (87.39%) and 114 (91.94%) participants achieved the ORR in the ZRC-3277 and Perjeta® groups, respectively. For predefined -15% noninferiority margin, obtained 2-sided 95% CIs (−12.19%, 3.11%) for the difference in ORR (−4.55%) between the 2 groups demonstrated the noninferiority of ZRC-3277 to Perjeta®. PK, immunogenicity, and safety were not significantly different between the 2 groups. ConclusionEfficacy, PK, immunogenicity, and safety profiles of ZRC-3277 was found to be similar to those of Perjeta®.

Comparison of brace to observation in stable, radiological developmental dysplasia of the hip: a protocol for a global multicentre non-inferiority randomised trial

IntroductionBrace treatment is common to address radiological dysplasia in infants with developmental dysplasia of the hip (DDH); however, it is unclear whether bracing provides significant benefit above careful observation by...

Stereotactic Ablative Radiotherapy for T1 to T2 Glottic Larynx Cancer: Mature Results From the Phase 2 GLoTtic Larynx-SABR Trial

PurposeTraditional radiotherapy for early-stage larynx cancer irradiates the whole larynx over 5.5-6 weeks. Phase I data suggest that stereotactic ablative radiotherapy (SAbR) is a viable strategy to reduce the irradiated volume and compress treatment time. This phase II study evaluated the efficacy of gLoTtic larynx SAbR (LT-SABR) in 5 or 16 fractions. MethodsEligibility required stage 0-II squamous cell carcinoma of the glottic larynx. The arytenoid cartilage could not be involved beyond the vocal process, and patients smoking more than one pack-per-day were excluded. The treatment volume consisted of the gross tumor volume, with a 3 mm margin (5 mm craniocaudal) to create the planning target volume (PTV). Patients without active smoking and PTV volume < 10 cc receive 4250 cGy in 5 fractions, twice per week; other patients received 58.08 Gy in 16 daily fractions. The primary endpoint was 2-year incidence of local failure. ResultsTwenty-five patients were accrued to this study, with 21 and 4 treated with 5 and 16 fractions, respectively. The stage distribution was in situ (n=1, 4%), T1a/b (n=16/5, 64%/20%), and T2 (n=3, 12%). The median age was 72 years, with a prior smoking history in 16 (64%) and active smoking in one (4%). At a median follow-up for surviving patients of 3.7 years (IQR 3.1-4.4 years), there have been two in-field recurrences (one in each dose cohort). The cumulative incidences of local failure were 4% (90% CI 0.8% - 20%) and 8% (90% CI 3%-24%) at 1 and 2 years, respectively. There have been no acute or late grade 3+ toxicities in disease-free patients. The median baseline, 6, 12 and 24 month Voice Handicap Index scores were 57 (IQR, 32-69), 28.5 (8-48), 4 (0-12), 7.5 (0-12), and 5 (0-24). ConclusionsHighly conformal stereotactic radiotherapy appears safe and efficacious for early-stage glottic larynx cancer, with encouraging patient-reported. These results need to be interpreted with caution given the small sample size and large non-inferiority margin. Additional follow-up and ultimately comparative studies are necessary to validate this paradigm.